Dissertations / Theses on the topic 'Bladder. Diseases'

Urinary tract sensory symptoms provide an additional symptomatic burden for women with fibromyalgia. The urogenital symptoms of both fibromyalgia and interstitial cystitis have been described as non-infective sensory disorders, suggesting the existence of substantial clinical overlap between the two conditions. Research suggests that although interstitial cystitis has been treated as a specific bladder condition, it may be part of the disorder of central processing of sensory information as seen in fibromyalgia. The interstitial cystitis symptom index and problem index (ICSI/ICPI) have been used to measure lower urinary tract symptoms and to examine the impact of these symptoms in patients with interstitial cystitis. This current two phase study was designed to test the ICSI/ICPI for use within a population of women diagnosed with fibromyalgia known to be experiencing sensory bladder symptoms. Phase I involved focus group interviews and discussions with women who reported fibromyalgia and bladder irritability (N=lO). This phase was designed to identify whether the key indicators and the way in which women experienced bladder irritability were indexed by the ICSI/ICPI instrument. The second phase of the study tested the ICSI/ICPI within the fibromyalgia population for reliability and validity. Phase II data was derived via a self-administered questionnaire issued to women (N=90) who had been diagnosed with fibromyalgia by a rheumatologist and who were experiencing lower urinary tract sensory symptoms. Data analysis revealed two separate components in urinary symptom/problem combinations within the fibromyalgia population. These components were distinct from those described in the ICSI/ICPI. Subsequently, two separate subscales were developed to form the Fibromyalgia Bladder Index (FBI). The development and testing of the FBI within the fibromyalgia population has provided an accurate measure for assessing the symptoms and symptom impact of urinary symptoms for women with this condition. The FBI has been developed as an adjunct to clinical assessment and as an outcome measure for intervention therapies for patients with fibromyalgia and bladder irritability. Outcomes of this study form the basis to the following recommendations: further refinement of the FBI; utilisation of the index in fibromyalgia assessments; development of fibromyalgia educational, support and self help programs; pelvic fitness awareness and intervention studies.

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.

Urinary incontinence has already been identified worldwide for years as a health problem affecting essentially women, which can interfere with their overall quality of life. However in Rwanda, this problem has yet not been addressed adequately either because of lack of expertise, or because of cultural traditions associated with taboos among women. Social conditions of women facing this problem hinder them from seeking possibly adequate medical assistance. It is important that this problem be addressed because it may lead to disability, social seclusion, psychological stress and economic burdens. This study was a pioneer one, intended to diagnose the extent of the problem through determining the prevalence of urinary incontinence as well as its impact on the quality of life among women. The study will hopefully be followed by the promotion of physiotherapy to tackle the problem and therefore reduce the number of people suffering from urinary incontinence.

Titre : Nano-plaquettes à mobilité dirigée et adhésion amplifiée pour l’administration locale: vers un nouveau traitement des maladies vésicalesAbstract : L’administration locale des médicaments, définie comme une voie d’administration où la substance active est directement administrée sur ou proche de la cible ou tissus souhaités, permet d’apporter des grandes quantités des médicaments avec moins d’effets secondaires, et permet une simplification du système nanoparticulaire du fait de la non-extravasation des médicaments. Dans ce contexte, le projet de recherche de cette thèse s’est focalisé sur la voie intra-vésicale comme voie d’administration locale car il existe un besoin clinique de la part des patients, n’étant pas encore résolu. Malgré les hypothétiques avantages fournis par l’administration locale des médicaments, la voie intra-vésicale présente certaines limitations qui diminuent l’efficacité des traitements et l’observance des patients. La plupart des médicaments pour le traitement des maladies vésicales, notamment pour le cancer de la vessie et les cystites interstitielles, sont sous forme de solutions ou suspensions administrées de manière intra-vésicale via un cathéter qui passe à travers l’urètre. Dès leur arrivée à la vessie, les substances actives sont fortement diluées par les urines et éliminées rapidement lors de la miction. Cela conduit à une diminution des concentrations des substances actives au plus proche de l’épithélium, nécessitant plusieurs instillations intra-vésicales, réalisées par des praticiens hospitaliers, pour atteindre des concentrations thérapeutiques. Il y a donc un réel besoin de développer des nouvelles formulations permettant de contrecarrer les phénomènes décrits au préalable.L’objectif de cette thèse de doctorat est de créer un nouveau système nanoparticulaire de morphologie non-sphérique qui serait susceptible d’avoir un mouvement diffèrent et dirigé ainsi qu’une adhésion amplifiée. En conséquence, nous attendons de ces systèmes qu’ils apportent des concentrations en substances actives plus importantes que les systèmes nanoparticulaires sphériques et formulations galéniques traditionnelles.Aux cours de nos travaux expérimentaux, nous avons réussi à développer un système nanoparticulaire de morphologie hexagonale et aplatie. Ces nanoparticules, appellées nano-plaquettes, sont conçues à partir de l’auto-assemblage des molécules d’α-CD et des chaines alkyles greffées sur les squelettes de polysaccharides tels que l’acide hyaluronique, la chondroïtine sulfate ou l’héparine. Ces systèmes présentent l’originalité de ne pas avoir de substance active encapsulé parce que les molécules de polymère elles mêmes agissent à la fois en tant que substance active et de véhicule. Ces nano-plaquettes ont montré un mouvement en milieu isotrope et statique très diffèrent des nano-sphères utilisées comme contrôle. En effet, la majorité d’entre elles diffuse de manière plus importante et dirigée, avec des trajectoires rectilignes. Grâce à leur mouvement et aux propriétés inhérentes liées à leur forme, ces systèmes se sont montrés particulièrement intéressants vis-à-vis des interactions avec des cellules. Ils adhèrent mieux et plus longtemps à la muqueuse vésicale, elles sont mieux internalisées par des cellules et sont éliminées plus lentement une fois adhérées à la surface de l’urothélium.Un modelé in vivo de Syndrome de la Vessie Douloureuse / Cystite Interstitielle développé chez le rat nous a permis de montrer l’efficacité thérapeutique des nano-plaquettes, notamment celle constituées d’acide hyaluronique. En effet, elles présentent une meilleure bioaccumulation dans la vessie et une meilleure activité anti-inflammatoire et de régénération de la muqueuse urothéliale.Ces systèmes nanoparticulaires, conçues lors de nos travaux de thèse, constituent une approche innovante, rationnelle et efficace pouvant ouvrir de nouvelles voies de recherche pour le traitement des maladies vésicales
Title: Directed-mobility and enhanced-adhesion nano-platelets for local drug delivery: towards a new treatment of bladder diseases.Abstract: Local drug delivery, defined as the administration route where the drug is delivered directly or very close to its target or tissue, allows to bring large amounts of drugs with reduced side effects, in comparison with systemic administration. In this context, our research project has been focused on the intravesical drug delivery as local administration route, because there is a real need to develop new pharmaceutical formulations to thwart several limitations. Despite the advantages provided by the local drug delivery, intravesical drug delivery exhibited some issues which are decreasing the therapeutic efficacy and the patient compliance to the treatment. Most of therapies for the treatment of bladder diseases are simple drug solutions or suspensions administered intravesically by using a catheter through the urethra in order to reach easily the bladder and, consequently, the urothelium. Since the drug is administered into the bladder, drug dilution is occurring because the continuous production of urine. Furthermore, active substances are being eliminated during washout when bladder urine voiding is happening. These two processes lead to the decrease of local drug concentration close to the urothelium. Patients need repeated catheterization, performed by health care practitioners, to reach therapeutic dose of the drug. Therefor, there is a need of new drug formulations to avoid these main limitations.The main goal of this PhD thesis was to create and design a new nanoparticulate system with non-spherical shape susceptible to move in a different manner compared to spherical nanoparticles. These systems may exhibit an amplified mucoadhesion allowing to bring more important amounts of drug than classical and nanoparticle administration.During this thesis, we developed a new nanoparticulate system presenting non-spherical, hexagonal and flattened shape. The driven force for the design of these nanoparticles was the self-assembling of α-cyclodextrin molecules with alkyl chains grafted on the polymer skeleton. Polymers used belong to a polysaccharide family called glycosaminoglycans including hyaluronic acid, chondroitin sulfate or heparin. This original and innovative nanoparticulate system does not encapsulate an active drug. Our polysaccharide will act, at the same time, as the active drug and the carrier. These nanoparticles, called now nano-platelets have shown different movement behavior than the spherical ones. Indeed, they diffuse more rapidly in a straight-line way. Thanks to their oriented and directed motion and to their intrinsic properties, due to the shape, these systems have shown a better mucoadhesion on the bladder tissue, a better uptake in different cell lines and they were far less rapidly eliminated from the urothelium mucosa.An in vivo model of Bladder Painful Syndrome / Interstitial Cystitis in rats demonstrated the therapeutic efficacy of nano-platelets, especially for hyaluronic acid nanoparticles. Indeed, they demonstrated a better bioaccumulation into the bladder and a better therapeutic efficacy as anti-inflammatory and urothelium regenerating agents.These nanoparticulate systems, designed during this work, represent a new innovative, rational and effectiveness approach allowing to open new research pathways for the treatment of bladder diseases

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Diuron is a substituted urea herbicide, carcinogenic to the rat urinary bladder at high dietary levels (2500 ppm). Different scanning electron microscopy (SEM) processing methods resulted in differing observations of early urothelial changes induced by exposure to this herbicide. This study evaluated the influence of SEM processing methods on the detection of urothelial alterations induced by diuron. Male Wistar rats were divided into 3 groups: control (basal diet), 7.1% Sodium Saccharin (NaS) (positive control) and 2500 ppm diuron, and fed for 7 days or 15 weeks. Urinary bladders were fixed with Bouin’s or glutaraldehyde fixative and processed by critical point drying (CPD) or by hexamethyldisilazane (HMDS) for comparison of the cytotoxic and proliferative changes induced by diuron in the urothelium. Histological and cell proliferation evaluations were also performed. After seven days, no differences in the incidence of histological urothelial lesions or labeling indices were detected among the groups; however, the incidence of urothelial lesions after 15 weeks was significantly increased in the animals fed diuron or NaS. After seven days or 15 weeks, the severity of urothelial alterations was significantly higher in animals fed with diuron. Both fixative and drying methods allowed for the identification of prenecrotic swollen superficial cells in the urothelium after seven days exposure to 2500 ppm diuron. Our results confirmed that the presence of prenecrotic swollen cells in the urothelium is an early key event due to diuron cytotoxicity and is not an artifact related to the processing methods used

Orientador: Maria Luiza Cotrim Sartor de Oliveira
Coorientador: Mirielen Garcia Nascimento e Pontes
Banca: Maria Lucia Zaidan Dagli
Banca: Daniela Carvalho dos Santos
Resumo: Não disponivel
Abstract: Diuron is a substituted urea herbicide, carcinogenic to the rat urinary bladder at high dietary levels (2500 ppm). Different scanning electron microscopy (SEM) processing methods resulted in differing observations of early urothelial changes induced by exposure to this herbicide. This study evaluated the influence of SEM processing methods on the detection of urothelial alterations induced by diuron. Male Wistar rats were divided into 3 groups: control (basal diet), 7.1% Sodium Saccharin (NaS) (positive control) and 2500 ppm diuron, and fed for 7 days or 15 weeks. Urinary bladders were fixed with Bouin's or glutaraldehyde fixative and processed by critical point drying (CPD) or by hexamethyldisilazane (HMDS) for comparison of the cytotoxic and proliferative changes induced by diuron in the urothelium. Histological and cell proliferation evaluations were also performed. After seven days, no differences in the incidence of histological urothelial lesions or labeling indices were detected among the groups; however, the incidence of urothelial lesions after 15 weeks was significantly increased in the animals fed diuron or NaS. After seven days or 15 weeks, the severity of urothelial alterations was significantly higher in animals fed with diuron. Both fixative and drying methods allowed for the identification of prenecrotic swollen superficial cells in the urothelium after seven days exposure to 2500 ppm diuron. Our results confirmed that the presence of prenecrotic swollen cells in the urothelium is an early key event due to diuron cytotoxicity and is not an artifact related to the processing methods used
Mestre

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Objetivos: O declínio da função vesical com a idade pode levar a comprometimento da qualidade de vida além de sérios problemas de saúde aos idosos. Assim, avaliaremos as alterações da função vesical com o envelhecimento em mulheres através do estudo urodinâmico e tentaremos desenvolver fórmulas que possam estimar os valores esperados dos parâmetros urodinâmicos avaliados de acordo com a idade. Materiais e métodos: Foi realizada uma análise retrospectiva dos estudos urodinâmicos realizados no Serviço de Urologia do Departamento de Cirurgia do Hospital das Clínicas da UFPE, cadastrados no prontuário eletrônico www.infomed.net.br entre maio de 2011 e novembro de 2015, a fim de obter e calcular os parâmetros necessários para avaliar a função vesical em diferentes faixas etárias (18-30, 31-40, 41-50, 51-60, 61-70, 71-80 e maior que 80 anos). Além disso, excluímos pacientes com qualquer fator conhecido que tenha o potencial de afetar a função vesical que não a idade. Resultados: De um total de 3103 exames analisados, foram selecionadas 719 pacientes do sexo feminino para serem incluídas no estudo. A média de idade das pacientes foi de 49,3 anos e em todos os parâmetros avaliados (fluxo máximo, volume urinado, complacência vesical, capacidade cistométrica máxima, pressão detrusora no fluxo máximo, resíduo pós-miccional, índice de contratilidade vesical e índice de eficiência vesical) obtivemos correlação estatisticamente significante entre o declínio da função vesical e a idade. Ainda, conseguimos expressar por equações matemáticas a relação de causa-efeito por regressão linear. Conclusão: O presente estudo observou que há uma diminuição da função vesical tanto de armazenamento (diminuição da capacidade cistométrica máxima e complacência vesical) quanto de esvaziamento (diminuição do fluxo máximo, da pressão detrusora no fluxo máximo, do volume urinado, do índice de contratilidade vesical e do índice de eficiência vesical, assim como o aumento do resíduo pós-miccional) com o envelhecimento. Paralelamente, estamos propondo fórmulas que podem estimar os valores esperados dos parâmetros urodinâmicos avaliados de acordo com a idade, na população estudada.
Purposes: The bladder function declines with age and can lead to impaired quality of life and serious health problems in the elderly. The aim of the study is to evaluate changes in bladder function with aging in women by urodynamic study and try to develop equations that can estimate the expected values of the urodynamic parameters evaluated according to the age. Methods: A retrospective analysis of urodynamic studies in the Urology Service of the Department of Surgery - Hospital das Clínicas, Federal University of Pernambuco, recorded in the electronic medical database www.infomed.net.br among May 2011 and November 2015 was performed in order to obtain and calculate the parameters necessary to evaluate bladder function in different age groups (18-30, 31-40, 41-50, 51-60, 61-70, 71-80 and above 80 years). Patients with any factor that had the potential to affect bladder function were excluded. Results: 3103 urodynamics studies were analyzed and 719 female patients were selected. The average age of patients was 49.3 years and in all evaluated parameters (maximum flow, volume of urination, bladder compliance, maximum cystometric capacity, detrusor pressure at maximum flow, post-void residual urine volume, bladder contractility index and bladder voiding efficiency) statistically significant correlation between the decline of bladder function and age were obtained. Also we presented mathematical equations with cause-effect relationship by linear regression. Conclusion: The present study showed that there is a decrease in the bladder storage function (reduction in maximum cystometric capacity and bladder compliance) and in the bladder emptying function (reduction of the maximum flow, detrusor pressure at maximum flow, volume of the urination, contractility index urinary bladder and bladder voiding efficiency , as well increased post-void residual urine volume) with aging. Analyzing data let us to propose equations that can estimate the expected values of the urodynamic parameters evaluated according to the age in the studied population.

Introdução: Apesar de recentes inovações e aprimoramentos no tratamento do Câncer de Bexiga (CaB) não músculo invasivo, o índice de progressão e recorrência continuam altos possivelmente devido a tumores residuais ou não evidenciados na ressecção transuretral de bexiga (RTU), o que profundamente afeta o prognóstico desta doença e evidencia a importância da qualidade desse procedimento padrão não só para o diagnóstico, mas também para o estadiamento e tratamento do tumor de bexiga. A presença de muscular própria no espécime é essencial para conduzir o tratamento, embora esta esteja presente apenas em cerca de 36-51% dos casos. Na sua ausência muitas vezes torna-se necessário um novo procedimento, vindo com isso a morbidade e os gastos de uma nova cirurgia. Dessa forma várias técnicas têm sido propostas com o intuito de melhorar a acurácia da RTUb, o que pode reduzir as ressecções incompletas e o subestadiamento. Objetivo: Avaliar a importância da biópsia de congelação do leito da lesão ressecada no que diz respeito ao estadiamento inicial e controle local da doença. Materiais e Métodos: Estudo prospectivo e randomizado dos pacientes com tumor de bexiga sem tratamento prévio que foram submetidos à RTUb no período de 09/2011 a 08/2013 em uma única instituição (Instituto do Câncer do Estado de São Paulo - ICESP). Esses pacientes foram submetidos à RTUb convencional, conforme o Guideline Europeu (EAU, 2011). No grupo 1, foi realizada biópsia de congelação do leito da lesão após a RTU, onde o cirurgião julgou esta ser possivelmente invasiva, aguardando análise do patologista quanto a presença de muscular própria, se caso esta não estivesse representada, era feita nova biópsia até sua representatividade. O grupo 2 são os controles não sendo submetidos à biópsia de congelação. Foram incluídos apenas os pacientes que tiveram critério e foram submetidos à re-RTUb. Um total de 150 pacientes foram randomizados, tornando-se elegíveis 131, sendo 64 no grupo 1 e 67 no grupo 2. Resultados: Comparando-se os grupos, não houve diferença em relação ao sexo, idade, quantidade e tamanho do tumor. No estudo anatomo-patológico da RTUb houve representatividade muscular em 100% x 58,5%, entre os grupos 1 e 2, respectivamente, com p < 0,001. Na Re-RTUb o índice de tumor residual foi 10,4% x 35,2%, entre os grupos 1 e 2, respectivamente, com p = 0,005. No grupo 1, 15 pacientes foram diagnosticados como pT2 com 100% do diagnóstico na primeira RTUb; no grupo 2, 6 pacientes tiveram diagnóstico de pT2 com apenas 33,3% na primeira RTUb, p=0,003. O tempo cirúrgico médio foi de 50 min no grupo 1 e 42min no grupo 2 (p= 0,037). Não houve diferença em relação à complicações (transfusão e perfuração vesical). Conclusão: A biópsia de congelação melhorou o correto estadiamento e controle local do câncer de bexiga, além de aumentar a acurácia do diagnóstico de doença pT2, podendo permitir o planejamento precoce do tratamento definitivo sem aumentar as complicações
Background and Purpose: Despite recent improvements of bladder cancer treatment, recurrence and progression rates are still high, possibly related to residual or overlooked tumors at the first transurethral resection (TUR), which strongly emphasizes the importance of the quality of this method. In order to improve the effectiveness of the procedure, we sought to evaluate the impact of frozen section during TUR, aiming on increasing muscular layer sample in the specimen, which may minimize incomplete resections and understaging. Patients and Methods: We prospectively included 150 consecutive patients assigned to TUR which were randomized to undergo either frozen section biopsy of the tumor bed during the TUR procedure until muscle was obtained or standard resection procedure (no frozen section). Nineteen patients were excluded after randomization, leaving 131 for analysis. All patients underwent a second TUR performed 4-6 weeks later. Frozen sections and final pathology reports were centralized and all performed by pathologists, the doubtful cases were reviewed by one uropathologist. Exclusion criteria: incomplete resection at first TUR, no criteria for second TUR according to EUA Guideline Update 2011 and previous bladder cancer treatment. (Group w/ biopsy, n = 64; Group control, n=67). Results: Both groups were comparable regarding age, gender, size and number of lesions. The majority of patients had high grade tumor in both groups. In the group where frozen section was obtained, muscle-invasive disease was higher (23% x 3%, p < 0,001). All patients in this group had muscle layer represented in the final pathology at the first TUR, while only 60% of patients in the control group (p < 0.001), including 40,5% of patients with pTa, 81,5% with pT1 e 100% with pT2 and Cis. Ninety percent of patients in the biopsy group had no residual tumor compared to 65% of the control group at second TUR (p=0,002). While all 15 patients in the frozen section group with T2 disease were diagnosed at first TUR, only 2 of 6 patients (33%) in the control group were diagnosed initially. The surgery duration was longer in the study group with mean of 50 min x 42 min (p=0,037) and there were no significant differences regarding complications (perforation and transfusion rates). Conclusion: Our results support the prove of principal that standard TUR with frozen section biopsy of bladder tumor bed increase the disease control and improve the diagnosis of T2 tumors, which may lead to reduced the number of patients in need a second TUR and avoid pT2 disease diagnosis delay, with no more complications

Posterior urethral valves cause bladder outflow obstruction and damage to the developing fetal kidney. Posterior urethral valves affect 1 in 8000 new-born males. A third of these children develop end stage renal failure by adolescence, despite valve ablation in the early post-natal period, implying that majority of the damage to the kidneys occurs in utero. How does this damage occur, and should we intervene in utero? The answers to these questions require further research, and are the basis to this thesis. This thesis focused on the effect bladder outflow obstruction has on morphology and apoptosis in the fetal kidney in a fetal lamb model. It also looked at the effect of bladder outflow obstruction on fetal stress hormone levels. Bladder outflow obstruction was created surgically in fetal lambs at day 70 of gestation, and fetal kidneys were analysed at day 2, 5, 10, 20 and 30 after creation of obstruction. Controls undergoing sham surgery were used for comparison. Four aspects were investigated: - effects of bladder outflow obstruction on renal histology effects of bladder outflow obstruction on expression of pro-apoptosis gene Bax and anti-apoptosis gene Bcl-X - effects of bladder outflow obstruction on renal regional apoptosis effects of bladder outflow obstruction on serum fetal ACTH and cortisol levels. Bladder outflow obstruction resulted in sequential morphological change in the fetal kidney over time. By 2 days post-obstruction, cystic change was noted. In addition, patchy attenuation of the nephrogenic blastema was evident by 5 days post-obstruction, with more confluent blastemal attenuation as well as generalized renal architectural disorganization by 10 days post-obstruction. By 20 and 30 days post-obstruction, cystic renal dysplasia had developed. Bladder outflow obstruction resulted in an increase in the ratio of renal expression of pro-apoptosis gene Bax to anti-apoptosis gene Bcl-X. Regional apoptosis counts showed increased tubular apoptosis compared to controls at 2 days post-obstruction, and increased blastemal apoptosis compared to controls at 5 days post-obstruction. By 10 days post-obstruction, blastemal apoptosis counts were reduced compared to controls. There were no significant differences in fetal serum ACTH and cortisol levels between fetal lambs with bladder outflow obstruction and controls. In conclusion, the results of this thesis outline the spectrum of morphological change in the fetal kidney over 30 days of bladder outflow obstruction. They show that detectable changes in morphology occur within two days of bladder outflow obstruction. Likewise, detectable changes in gene expression occur within 2 days of bladder outflow obstruction. The increased ratio of expression of Bax to Bcl-X suggests a swing towards increased apoptosis in response to bladder outflow obstruction. Further research is required to ascertain if these changes are reversible. However, the early onset of these changes as shown in this thesis suggests that any fetal intervention to protect the fetal kidney from the effects of bladder outflow obstruction may need to be instituted very early in gestation

Thesis (Ph. D.)--University of Missouri-Columbia, 2006.
The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. Includes bibliographical references.

Trabalho prospectivo estudando a matriz extracelular da parede vesical em pacientes com extrofia vesical comparados ao grupo controle, pela microscopia óptica comum e luz polarizada com morfometria, quantificando-se as fibras colágenas e reticulínicas. Estudou-se 17 pacientes de ambos os sexos, biopsiando-se toda a parede vesical e empregando colorações HE, PS e Reticulina. Diferenças estatisticamente significantes foram notadas na análise quantitativa de fibras colágenas e reticulínicas o número de fibras colágenas foi significativamente maior e o número de fibras reticulínicas foi menor no grupo de pacientes com extrofia vesical quando comparado ao grupo controle.
A prospective study was done to evaluate the detrusor muscle\'s extracellular matrix in classical bladder exstrophy in comparison to a control group, by use of light microscopy and polarization method with morphometry, to quantify collagen and reticular fibers. Seventeen patients from both sexes were analysed and samples were obtained from the bladder and stained with Haematoxylin-eosin, Picrosirius red and the silver impregnation method. There were significant differences when comparing the quantity of collagen and reticular fibers. The collagen fibers were more abundant in the exstrophy bladders compared to controls, while the reticular fibers were present in smaller amounts.

Orientador: Edson Antunes
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A hipertensão renovascular é uma forma secundária da hipertensão arterial, que corresponde de 1-5% dos casos de hipertensão. A associação entre hipertensão arterial e disfunções miccionais foi observada no modelo experimental de ratos espontaneamente hipertensos (SHR). Até o momento nenhum estudo avaliou as disfunções miccionais em animais hipertensos renovasculares. Dessa forma, neste estudo, caracterizamos a disfunção miccional em ratos hipertensos renovasculares através do modelo de dois rins, um clip (2K-1C). Em ratos Wistar (200-220 g) colocou-se um clip em torno da artéria renal. Depois de oito semanas, os ratos foram utilizados. Realizou-se estudo cistométrico em ratos anestesiados, assim como curvas concentração-resposta para agentes contráteis e relaxantes em detrusor isolado (DSM). Foram também realizados estudos histomorfométricos e da expressão de RNAm dos receptores muscarínicos M3 e M2 em DSM isolado. Os resultados histomorfométricos mostraram aumentos significantes na espessura da parede da bexiga, no volume intravesical, na densidade de musculatura lisa e na densidade de fibras neurais no grupo 2K-1C em comparação ao SHAM. O agonista muscarínico, carbacol, produziu contrações concentração-dependentes do DSM, as quais foram significantemente maiores no grupo 2K-1C. O inibidor da Rho-quinase, Y27-632 (10 µM), reduziu significantemente a contração induzida pelo carbacol nos ratos SHAM e 2K-1C; porém, no grupo 2K-1C, o DSM continuou hiperativo na presença do Y27-632. A estimulação elétrica (1 - 32 Hz) produziu contração freqüência-dependente do DSM as quais foram maiores no grupo 2K-1C. O agonista purinérgico P2X, ?,?-metileno-ATP (1 - 100 µM), o KCl (1 - 300 µM) e o Ca2+ extracelular (0,01-100 µM) produziram contrações concentração-dependente; porém, não observamos diferenças entre o grupo SHAM e 2K-1C. O agonista não seletivo ?-adrenérgico, isoproterenol, o agonista seletivo ?2-adrenérgico, metaproterenol, e o agonista seletivo ?3-adrenérgico, BRL37-344, produziram relaxamentos menores do DSM nos ratos 2K-1C, e também redução nos níveis intracelulares de AMPc nos detrusores. O efeito relaxante ao nitroprussiato de sódio e BAY41-2272 mantiveram-se iguais nos animais SHAM e 2K-1C. A expressão do RNAm do receptor muscarínico M3 (mas não do M2) no DSM foi significantemente maior nos ratos 2K-1C em comparação ao grupo controle. Os tratamentos crônicos com losartan e captopril normalizaram a pressão arterial sistólica dos animais 2K-1C, normalizaram a função miccional, e reduziram a hipercontratilidade do detrusor induzida pela estimulação elétrica e pelo carbacol, assim como restabeleceram o relaxamento induzido pelo isoproterenol ao nível do grupo SHAM. Concluimos que os ratos hipertensos renovasculares apresentam hiperatividade do detrusor, a qual envolve remodelamento tecidual e aumento da contração via receptor muscarínico M3 associado à redução no relaxamento ?-adrenérgico com redução da sinalização intracelular e produção de AMPc. Os tratamentos com losartan e captopril restauram a função miccional dos animais 2K-1C
Abstract: Renovascular hypertension is a secondary form of arterial hypertension, accounting for 1-5% of cases in unselected population. Association between arterial hypertension and urinary bladder dysfunction has been reported in spontaneously hypertensive rats, but no study evaluated the bladder dysfunction in renovascular hypertensive animals. Therefore, in this study, we explored the bladder dysfunction in renovascular hypertensive rats, using the two-kidney one-clip (2K-1C) model. A silver clip was placed around the renal artery of male Wistar Kyoto rats (200-220 g). After eight weeks, rats were used. Cystometric study in anesthetized rats, along with concentration-response curves to both contractile and relaxant agents in isolated detrusor smooth muscle (DSM) were performed. Histomorphometry and mRNA expression of muscarinic M3 and M2 receptors in DSM were also determined. The histomorphometric data showed significant increases in bladder wall thickness, intravesical volume and density of smooth muscle, as well as density of neural fibers in the 2K-1C group compared with SHAM. The muscarinic agonist carbachol produced concentration-dependent DSM contractions, which were markedly greater in 2K-1C rats. The Rho-kinase inhibitor Y27-632 (10 µM) significantly reduced the carbachol-induced contractions in sham and 2K-1C rats, but DSM in 2K-1C rats remained overactive in the presence of Y27632. Electrical-field stimulation (EFS; 1-32 Hz) produced frequency-dependent DSM contractions that were also greater in 2K-1C group. The P2X receptor agonist ?,?-methylene ATP (1-100 µM), KCl (1-300 mM) and extracellular Ca2+ (0.01-100 M) produced concentration-dependent DSM contractions, but no changes among sham and 2K-1C rats were seen. In 2K-1C rats, the non-selective ?-adrenoceptor agonist isoproterenol, the ?2-adrenoceptor agonist metaproterenol and the ?3-adrenoceptor agonist BRL 37-344 produced lower DSM relaxations, as well as decreased cAMP levels. The relaxant responses to sodium nitroprusside and BAY 41-2272 remained unchanged in 2K-1C rats. Expression of mRNA of muscarinic M3 (but not of M2) receptors in DSM was significantly increased in 2K-1C rats. The chronic treatment with losartan and captopril normalized the blood systolic pressure of 2K-1C animals, improved their urinary function by reducing DSM hypercontractility to EFS and carbacol stimulation, and restored the relaxation induced by the ?-adrenergic agonist isoproterenol to the level of SHAM group. In conclusion, renovascular hypertensive rats exhibit overactive DSM that involves tissue remodeling and enhanced muscarinic M3-mediated contractions associated with reduced ?-adrenoceptor-mediated signal transduction. The treatments with losartan and captopril improved urinary function of 2K-1C animals
Mestrado
Mestre em Farmacologia

Orientador: Matheus Bertanha
Resumo: Introdução: Diversas doenças congênitas ou adquiridas promovem alterações anatômicas ou funcionais, dificultando ou impossibilitando a função de reservatório da bexiga, ou até mesmo necessitando sua remoção cirúrgica. Quando as terapias conservadoras não são eficazes, algumas técnicas cirúrgicas podem ser empregadas para o aumento ou reconstrução da bexiga e por fim, o desvio urinário pode ser a única alternativa terapêutica. No entanto, todas as técnicas cirúrgicas atuais podem levar a complicações. A substituição de tecidos da bexiga por equivalentes criados em laboratório poderia melhorar o resultado da cirurgia reconstrutiva. Objetivos: Propor um modelo de remendo de bexiga urinária produzido com uso de veias descelularizadas e semeadas com células-tronco mesenquimais em modelo animal em coelhos. Material e Métodos: Foram constituídos dois grupos de 5 coelhos fêmeas não prenhas. Os dois grupos de animais foram submetidos a anestesia inalatória e foi realizada uma cirurgia para retirada de um fragmento de 1 cm2 de bexiga para implantação do produto de teste. Grupo 1: Controle – foi implantado um segmento de 1cm2 de veia cava de coelho descelularizada com pontos contínuos de Vicryl 7.0; Grupo 2: Experimento – foi implantado um segmento de veia cava descelularizada semeada com células tronco autólogas, também fixado por pontos cirúrgicos de Vicryl 7.0 com pontos contínuos. Para o grupo 2, foram coletadas células-tronco mesenquimais autólogas derivadas de tecido adiposo que f... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Background: Several congenital or acquired diseases promote anatomical or functional changes, making it difficult or impossible for the bladder reservoir function, or even requiring its surgical removal. When conservative therapies are ineffective, some surgical techniques may be used to increase or reconstruct the bladder, and ultimately, urinary diversion may be the only therapeutic alternative. However, all current surgical techniques can lead to complications. Replacement of bladder tissues with laboratory-created equivalents could improve the outcome of reconstructive surgery. Recent research involving stem cells and cell engineering points to a promising future based on regenerative and tissue replacement therapy. Objectives: To propose a model of urinary bladder patch produced with the use of decellularized veins and seeded with mesenchymal stem cells in an animal model in rabbits. To evaluate the biointegration of the graft implanted in the urinary bladder of rabbits after 21 days by histomorphological study of the explant. Methods: Two groups of 5 non-pregnant female rabbits were formed. Both groups of animals underwent inhalation anesthesia and surgery was performed to remove a 1 cm2 bladder fragment for implantation of the test product. Group 1: Control - a 1cm2 segment of decellularized rabbit vena cava with continuous Vicryl 7.0 stitches was implanted; Group 2: Experiment - a decellularized vena cava segment seeded with autologous stem cells was implanted, also f... (Complete abstract click electronic access below)
Mestre

Tissue mechanics determines tissue homeostasis, disease development and progression. Bladder strongly relies on its mechanical properties to perform its physiological function, but these are poorly unveiled under normal and pathological conditions. In addition, the bladder is a multilayer organ and it is thus needed to understand tissue mechanics at the microscale, spatially resolving the different bladder layers and their contribution to altered tissue mechanics. This thesis aimed to characterize the micromechanical fingerprints of the healthy bladder wall, and to identify modifications associated with the onset and progression of pathological conditions of actinic cystitis and bladder cancer. To do so I used two indentation-based instruments (an Atomic Force Microscope and a nanoindenter) and compared the micromechanical maps with a comprehensive histological analysis. I found that the healthy bladder is a mechanically inhomogeneous tissue, with a gradient of increasing stiffness (in terms of Young’s modulus, YM) from the urothelium to the lamina propria, which gradually decreased when reaching the muscle layer. Stiffening in fibrotic tissues correlated with increased deposition of dense extracellular matrix in the lamina propria. An increase in tissue compliance was observed before the onset and invasion of the tumor. In addition, aiming to establish an experimental approach that would facilitate its application to the clinical environment, I here used Brillouin imaging to investigate healthy and fibrotic bladder, and confront the mechanical information from this non-contact technique to the gold-standard in nanomechanics (indentation-based mechanical tests). While Brillouin imaging reported the same mechanical trend observed by indentation-based mechanical tests when investigating intrinsic mechanical heterogeneities of the bladder wall, a decrease of Brillouin shift in fibrotic bladder was observed contrary to the increased YM measured by indentation-based mechanical tests, thus highlighting different physical phenomena detected by the different techniques and the need to further investigate correlations between both techniques. By providing high resolution micromechanical investigation of each tissue layer of the bladder, I here depicted the intrinsic mechanical heterogeneity of the layers of the healthy bladder as compared with the mechanical properties alterations associated with either actinic cystitis or bladder tumor; and provided an accurate comparison of the gold-standard technique in biomechanics to Brillouin imaging.
Tissue mechanics determines tissue homeostasis, disease development and progression. Bladder strongly relies on its mechanical properties to perform its physiological function, but these are poorly unveiled under normal and pathological conditions. In addition, the bladder is a multilayer organ and it is thus needed to understand tissue mechanics at the microscale, spatially resolving the different bladder layers and their contribution to altered tissue mechanics. This thesis aimed to characterize the micromechanical fingerprints of the healthy bladder wall, and to identify modifications associated with the onset and progression of pathological conditions of actinic cystitis and bladder cancer. To do so I used two indentation-based instruments (an Atomic Force Microscope and a nanoindenter) and compared the micromechanical maps with a comprehensive histological analysis. I found that the healthy bladder is a mechanically inhomogeneous tissue, with a gradient of increasing stiffness (in terms of Young’s modulus, YM) from the urothelium to the lamina propria, which gradually decreased when reaching the muscle layer. Stiffening in fibrotic tissues correlated with increased deposition of dense extracellular matrix in the lamina propria. An increase in tissue compliance was observed before the onset and invasion of the tumor. In addition, aiming to establish an experimental approach that would facilitate its application to the clinical environment, I here used Brillouin imaging to investigate healthy and fibrotic bladder, and confront the mechanical information from this non-contact technique to the gold-standard in nanomechanics (indentation-based mechanical tests). While Brillouin imaging reported the same mechanical trend observed by indentation-based mechanical tests when investigating intrinsic mechanical heterogeneities of the bladder wall, a decrease of Brillouin shift in fibrotic bladder was observed contrary to the increased YM measured by indentation-based mechanical tests, thus highlighting different physical phenomena detected by the different techniques and the need to further investigate correlations between both techniques. By providing high resolution micromechanical investigation of each tissue layer of the bladder, I here depicted the intrinsic mechanical heterogeneity of the layers of the healthy bladder as compared with the mechanical properties alterations associated with either actinic cystitis or bladder tumor; and provided an accurate comparison of the gold-standard technique in biomechanics to Brillouin imaging.

The major aim of this thesis was to perform the first ever proteomics study on bladder cancer exosomes. Initially, exosomes were isolated from urine specimens but hypervariable yields and poor sample quality made proteomics analysis challenging. As an alternative approach, exosomes were isolated from HT1376 bladder cancer cells. Exosomes were purified by ultracentrifugation on a sucrose cushion, and preparations verified as high quality by immunoblotting, flow cytometry and electron microscopy. For global proteomics analysis, the sample was solubilised using SDS and DTT and subjected to LC-MALDI-TOF/TOF MS. We identified 353 proteins with high confidence and 63 of these have not previously been identified in other proteomics studies on human exosomes. Overrepresentation analysis demonstrated that the proteome was consistent with that of other exosomes with significant overlap with exosomes of carcinoma origin. Comparisons with the Gene Ontology database also highlighted strong associations with carcinoma of the bladder and other sites. A GeneGo generated protein interaction network highlighted c-Myc as a major node of protein interaction within this dataset. Several MS-identified proteins were confirmed as genuinely exosomally expressed using a combination of immunoblotting, flotation on continuous sucrose gradients, and flow cytometry. Expression was also verified in exosomes from a variety of sources, including urine. The data will aid our understanding of exosome biogenesis and function and may inform the development of urine exosome-based clinical tools in bladder cancer.

Foi realizado o estudo prospectivo de uma amostra da população portadora de Síndrome de Down que procurou o Departamento de Genética do Hospital Infantil Darcy Vargas,no período de 1959 a 1996. Dos 2816 portadores de Síndrome de Down que compareceram a este Serviço, neste período , a amostra estudada consistiu de 518 pacientes que mantiveram períodos de retomo ambulatorial conforme previsto pelo Protocolo de segmento clínico adotado. O objetivo do estudo foi caracterizar a incidência de colecistopatia litiásica em pacientes portadores de Síndrome de Down . Para desenvolver este estudo, após o diagnóstico citogenético e clínico da Síndrome de Down, procurou-se correlacionar faixa etária dos genitores, uso de anticoncepcionais e principalmente promover a utilização de exames subsidiários específicos que permitiram melhores condições diagnósticas e definição de mecanismos fisiopatológicos eventuais relacionados à colilitiase. Verificou-se a presença de cálculos de vesícula biliar em 27 pacientes ( 3,28%) comparando-se à incidência descrita na população como um todo (0,07%). Estes dados caracterizam a prevalência de cálculos de vesícula biliar em portadores de Síndrome de Down ( a distribuição das probabilidades da frequência de cálculo de vesícula biliar em Sindrome de Down está dentro do intervalo de 95%, entre 3,6% e 7,7%). As correlações realizadas vieram a excluir,na amostra estudada, algumas etiologias comumente descritas para colelitíase e provavelmente vincula o fenômeno da colelitíase a mecanismos fisioembriopatológicos ligados à hipotonia e estase do conteúdo da vesícula biliar( e/ou redução na velocidade do seu esvaziamento). Em consequência torna-se importante propor uma investigação rotineira para esta patologia, com ênfase nos mecanismos fisiopatológicos, prováveis responsáveis pela incidência aumentada na população com Síndrome de Down.
The purpose of this study has been the prospective analysis of the Down syndrome population received by the Genetic Department of \"Hospital Infantil Darcy Vargas\", in the period from 1959 to 1996. The Department has received 2816 Down Syndrome patients\' in this period, and this study has selected 518 patients, clinical and cytogenetically diagnosed, which were studied following the specific clinical protocol, in periodical evaluations. The incidence of cholelithiasis was verified and it has been analysed the possible relationships among this disease and parentaI age, contraceptive use and clinical features leading to the discussion of eventual aetiologic mechanisms causing gallstones. It was verified 27 patients affected by Down Syndrome and presenting cholelithiasis in the survey of 518 patients ( 3.28 %) compared to the frequency of 7/10000 in the non Down population ( 0.07% ). The statistical analysis has shown that the distribution of the frequency probabilities have been between 3.6% and 7.7%, These studies have verified that the aetiology of the gallstones in the Down syndrome patients could be related to the hypotonic characteristic of the patients, leading to cholestasis, It is very important the suggestion of routine evaluation for this pathology, related to the eventual aetiologic features.

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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Os cães podem ser acometidos por diversos tipos de doenças vesicais incluindo cistites, neoplasias e urolitíases, dentre outras. A variedade da etiopatogenia e das formas de apresentação clínica das cistites constitui um fator complicante para o diagnóstico. O presente estudo teve por objetivo evidenciar a importância da inclusão de alguns exames complementares com vistas ao diagnóstico correto das afecções vesicais. Foi realizado um estudo prospectivo para o diagnóstico da condição vesical de 46 animais, machos e fêmeas, selecionados ao acaso dentre os encaminhados para check-up de rotina e os pacientes com algum tipo de sinal ou achado sugestivo de doença vesical. A avaliação consistiu de exame clínico completo e exame específico do trato urinário incluindo urinálise, exame microbiológico da urina por meio de cultura em lâmina e cultura tradicional, e avaliação vesical por meio do exame ultrassonográfico. Os dados foram submetidos à analise estatística descritiva e ao Teste Exato de Fisher para associações. Os resultados evidenciaram que os sinais clínicos e os achados de sedimentoscopia da urina não são específicos, dada a semelhança das manifestações das diversas doenças vesicais. A urocultura e a ultrassonografia vesical foram exames complementares decisivos que possibilitaram o diagnóstico dos casos de cistite bacteriana (n=32) bem como das doenças vesicais coexistentes (n=3) e das doenças vesicais não infecciosas (n=2). Concluiu-se que o exame clínico de rotina, mesmo que a urinálise seja incluída, não é apropriado para diagnosticar doenças vesicais e que a urocultura e o exame ultrassonográfico contribuem de modo decisivo para o diagnóstico correto dos cães com ou sem sinais clínicos de cistite
Dogs can be affected by several types of bladder diseases including cystitis, neoplasia, and urolithiasis, among others. The variety of etiopathology and clinical presentation forms of cystitis is a complicating factor for the diagnosis. The aim of this study was to show the importance of some additional exams inclusion in order to achieve the correct diagnosis for bladder diseases. A prospective study was conducted for bladder condition diagnosis in 46 animals, males and females, taken for random among dogs referred for routine checkup and the patients with some type of signs or finding suggestive of bladder disease. The evaluation included complete clinical exam and specific examination of the urinary tract including urinalysis, urine microbiologic examination by commercially manufactured screening urine culture kit and traditional culture, and ultrasound bladder evaluation. The data were analyzed by descriptive statistic and Fisher’s Exact Text. The results showed that clinical signs and urine sediment findings are nonspecific, given the similarity of the bladder diseases manifestations. The urine culture and bladder ultrasound were decisive additional exams that enable the diagnosis of bacterial cystitis (n=32), as well as of the coexisting bladders diseases (n=3) and non infectious bladder diseases (n=2). It was concluded that the routine clinical examination, even when the urinalysis is included, isn`t appropriated for bladder diseases diagnosis, moreover the urine culture and the ultrasonographyc exam contribute in a decisive way for the correct diagnosis of dogs showing or not clinical signs of cystitis

Orientador: Marileda Bonafim Carvalho
Banca: Angela Akamatsu
Banca: Andrigo Barboza de Nardi
Resumo: Os cães podem ser acometidos por diversos tipos de doenças vesicais incluindo cistites, neoplasias e urolitíases, dentre outras. A variedade da etiopatogenia e das formas de apresentação clínica das cistites constitui um fator complicante para o diagnóstico. O presente estudo teve por objetivo evidenciar a importância da inclusão de alguns exames complementares com vistas ao diagnóstico correto das afecções vesicais. Foi realizado um estudo prospectivo para o diagnóstico da condição vesical de 46 animais, machos e fêmeas, selecionados ao acaso dentre os encaminhados para check-up de rotina e os pacientes com algum tipo de sinal ou achado sugestivo de doença vesical. A avaliação consistiu de exame clínico completo e exame específico do trato urinário incluindo urinálise, exame microbiológico da urina por meio de cultura em lâmina e cultura tradicional, e avaliação vesical por meio do exame ultrassonográfico. Os dados foram submetidos à analise estatística descritiva e ao Teste Exato de Fisher para associações. Os resultados evidenciaram que os sinais clínicos e os achados de sedimentoscopia da urina não são específicos, dada a semelhança das manifestações das diversas doenças vesicais. A urocultura e a ultrassonografia vesical foram exames complementares decisivos que possibilitaram o diagnóstico dos casos de cistite bacteriana (n=32) bem como das doenças vesicais coexistentes (n=3) e das doenças vesicais não infecciosas (n=2). Concluiu-se que o exame clínico de rotina, mesmo que a urinálise seja incluída, não é apropriado para diagnosticar doenças vesicais e que a urocultura e o exame ultrassonográfico contribuem de modo decisivo para o diagnóstico correto dos cães com ou sem sinais clínicos de cistite
Abstract: Dogs can be affected by several types of bladder diseases including cystitis, neoplasia, and urolithiasis, among others. The variety of etiopathology and clinical presentation forms of cystitis is a complicating factor for the diagnosis. The aim of this study was to show the importance of some additional exams inclusion in order to achieve the correct diagnosis for bladder diseases. A prospective study was conducted for bladder condition diagnosis in 46 animals, males and females, taken for random among dogs referred for routine checkup and the patients with some type of signs or finding suggestive of bladder disease. The evaluation included complete clinical exam and specific examination of the urinary tract including urinalysis, urine microbiologic examination by commercially manufactured screening urine culture kit and traditional culture, and ultrasound bladder evaluation. The data were analyzed by descriptive statistic and Fisher's Exact Text. The results showed that clinical signs and urine sediment findings are nonspecific, given the similarity of the bladder diseases manifestations. The urine culture and bladder ultrasound were decisive additional exams that enable the diagnosis of bacterial cystitis (n=32), as well as of the coexisting bladders diseases (n=3) and non infectious bladder diseases (n=2). It was concluded that the routine clinical examination, even when the urinalysis is included, isn't appropriated for bladder diseases diagnosis, moreover the urine culture and the ultrasonographyc exam contribute in a decisive way for the correct diagnosis of dogs showing or not clinical signs of cystitis
Mestre

The burdensomeness of bowel and bladder dysfunction, investigated among 67 people with Parkinson’s disease (PD), exploring current clinical and self-management interventions related to incontinence. Higher rates of bowel and bladder dysfunction are common among people with PD, yet knowledge of how these symptoms are differentiated and managed in the community is scarce. Using mixed method design incorporating quantitative surveys and qualitative semi-structured interviews, the study focused on dysfunctional bowel and bladder symptoms and management. The surveys and interview data, from which participant-generated burden scores were derived, supported statistical comparisons to reveal the severity and importance of participants’ perceptions of efforts to manage their diagnosis and treatment. Bowel and bladder dysfunctions were found to be directly linked to their neuro-pathophysiology rather than ageing related factors; and these symptoms caused higher levels of anxiety and distress than did other PD non-motor symptoms. Further, their own preconceptions of what constitutes a 'legitimate' health concern, affected participants' capacity to source information and assistance. Little symptom relief was obtained from medications and treatments commonly used for bowel and bladder difficulties and exacerbated the unpredictability of their bowel and bladder problems, which then prompted participants to self-impose social restrictions and report poor quality-of-life.

INTRODUÇÃO: A bexiga neurogênica é considerada um fator de risco importante para insuficiência renal crônica. A preservação da função renal é um dos principais objetivos do tratamento nefrourológico dos portadores desta doença. OBJETIVOS: Descrever as características demográficas de 58 pacientes com bexiga neurogênica congênita, as características anatômicas e funcionais do trato urinário superior e inferior desta população ao início do seguimento e ao final da coleta dos dados e identificar fatores de risco associados à piora de função glomerular e tubular nesta população, utilizando como marcadores a quantificação do ritmo de filtração glomerular e o desenvolvimento de microalbuminúria e acidose metabólica. MÉTODOS: Estudo retrospectivo de uma coorte de 58 pacientes portadores de bexiga neurogênica congênita com seguimento mínimo de seis meses, matriculados no ambulatório de Disfunções Miccionais da Infância da Unidade de Nefrologia Pediátrica do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. O período de coleta de dados foi encerrado em janeiro de 2006. Os resultados obtidos no estudo foram descritos por médias e desvios padrões, medianas, valores mínimos e máximos, ou por frequências e percentuais. A comparação entre a avaliação inicial e a final para variáveis quantitativas contínuas foi feita usando-se o teste t de Student para amostras pareadas. A associação entre variáveis dicotômicas foi feita considerando-se o teste exato de Fisher. Para avaliação da evolução dos pacientes e comparação de subgrupos definidos por variáveis dicotômicas, foram construídas curvas de Kaplan-Meier e aplicado o teste de Long-rank. Valores de p<0,05 indicaram significância estatística. RESULTADOS: Das 58 crianças avaliadas, 33 eram do sexo feminino (56,9%). A idade média com que as crianças chegaram ao serviço foi de 4,2±3,5 anos, a média de tempo de seguimento foi de 3,8±3,1 anos. A etiologia predominante de bexiga neurogênica foi mielomeningocele, em 42 dos 58 pacientes (72,4%). O encaminhamento à Unidade ocorreu por infecção urinária em 48 (82,8%) casos, por enurese em 5 (8,6%) e por retenção urinária em 5 (8,6%). Dentre os 49/58 (84,5%) pacientes com ITU de repetição ao início do seguimento, 41/49 (83,7%) pacientes apresentaram melhora no período de seguimento. A hipertensão arterial foi diagnosticada em 11 (19,3%) das crianças na avaliação inicial e em 18 (31%) na avaliação final. A média do RFG inicial foi de 146,7±70,1 mL/1,73m2/min e a média final de 193,6±93,6 mL/1,73m2/min, com p=0,0004. A microalbuminúria estava presente em 20 (54,1%) dos exames na avaliação inicial e em 26 (61,9%) na avaliação final. A acidose metabólica estava presente em 11 (19%) dos exames na avaliação inicial e em 19 (32,8%) na avaliação final. As crianças que chegaram à Unidade de Nefrologia mais precocemente (< 3 anos) foram aquelas que mais apresentaram acidose metabólica no decorrer do acompanhamento (p=0,01). Os pacientes que não tinham acidose metabólica ao final do estudo apresentaram valores menores de Z-escore peso final (p= 0,048), Zescore altura/estatura inicial (p= 0,047) e Z-escore altura/estatura final (p=0,022) com relação aos pacientes do grupo que evoluiu com acidose. CONCLUSÃO: Pacientes com bexiga neurogênica congênita evoluem com acometimento renal glomerular e tubular precoce, cujo manejo demanda acompanhamento por profissional especializado.
INTRODUCTION: Neurogenic bladder is considered an important risk factor for chronic renal failure. In these patients, preservation of renal function is one of the most important goals of nephro-urological treatment. PURPOSE: To describe demographic data of 58 children with congenital neurogenic bladder, the anatomic and functional characteristics of their upper and lower urinary tracts at the beginning of the follow-up and at the end of the data collection period and to identify risk factors associated with worsening of the glomerular and tubular functions using as markers the quantitation of glomerular filtration rate and the development of microalbuminuria and metabolic acidosis. METHODS: Retrospective study of a cohort of 58 children with congenital neurogenic bladder treated at the Voiding Dysfunction Clinic, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, with a minimum follow-up period of 6 months. The period of data collection ended in January 2006. The obtained results were described as means, standard deviations, medians, minimum and maximum values, or as frequencies and percentages. The comparison between the initial and final evaluations for continuous quantitative variables was done using the Student´s t test for paired samples. The association between dichotomous variables was performed considering the Fisher´s exact test. For evaluation of patients` outcomes and comparison of subgroups defined by dichotomous variables, Kaplan-Meier curves were performed and Long-rank test was applied. P values < 0.05 indicated statistical significance. RESULTS: 58 children were evaluated with 33 females (56,9%). The mean age at presentation to the service was 4.2 ± 3.5 years, the mean follow-up period was 3.8 ± 3.1 years. Myelomeningocele was the leading aetiology, corresponding to 42/58 patients (72.4%). Referral to the service occurred in 48 (82.8%) patients due to urinary tract infection, in 5 (8.6%) due to enuresis and in 5 (8.6%) due to urinary retention. Recurrent urinary tract infections were found in 49/58 patients (84.5%) at the beginning and 41/49 (83.7%) had improvement during the follow-up period. Systemic Hypertension was diagnosed in 11 (19.3%) children at the first visit and in 18 (31%) in the final evaluation. The initial mean glomerular filtration rate was 146.7 ±70.1 mL/1.73m²/min and the final mean was 193.6±mL/1.73m²/min, p = 0.0004. Microalbuminuria was found in 20 (54.1%) samples in the initial evaluation and in 26 (61.9%) in the final evaluation. Metabolic acidosis was present in 11 (19%) samples in the initial evaluation and in 19 (32.8%) in the final assessment. The children who most developed metabolic acidosis during the follow-up period were those who presented earlier to the service (< 3 years of age), p= 0.01. The group of patients that did not present metabolic acidosis at the end of the study had lower values of final weight z-score (p=0.048), initial height/stature z-score (p=0.047) and final height/stature z-score (p=0.022) than the patients of the group that developed acidosis. CONCLUSIONS: Children with congenital neurogenic bladder develop early compromise of renal glomerular and tubular functions and require adequate management by specialized professionals.

Orientador: Elizabeth Maria Aparecida Barasnevicius Quagliato
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Objetivos: Avaliar em mulheres com doença de Parkinson e disfunções urinárias as correlações dos sintomas urinários com os sintomas motores e disfunções mentais. Verificar a prevalência de hiper-reflexia detrusora (HD), bem como analisar em longo prazo a gravidade do desempenho motor, estadiamento de Hoenh-Yahr, habilidades funcionais, funções neuropsicológicas e a magnitude da progressão desses aspectos clínicos e do declínio cognitivo em pacientes com HD. Sujeitos e Métodos: Estudamos uma coorte ambulatorial de sessenta e três (63) pacientes com DP cujos aspectos neurológicos foram avaliados com a utilização das escalas Unified Parkinson's Disease Rating Scale (UPDRS) e a escala de Hoehn-Yahr. As habilidades funcionais foram avaliadas pela escala Schwab & England e a função urológica foi quantificada pela International Prostatic Symptom Scale (IPSS) e qualificada pelo estudo urodinâmico. Foram então categorizados dois grupos: pacientes com e sem HD. Após sete anos os mesmos parâmetros foram reavaliados e a escala Montreal Cognitive Assessment (MoCA)-versão brasileira foi utilizada para o rastreamento neuropsicológico. Resultados: Na avaliação inicial foi constatada correlação positiva entre os sintomas urinários e a gravidade da doença, porém não havia correlação entre a sintomatologia urinária e os sintomas mentais. Sintomas motores, estágio de gravidade da doença e habilidades funcionais eram mais graves em pacientes com HD. Na reavaliação, os grupos não apresentavam diferença quanto à magnitude da progressão dos sintomas motores, do estadiamento da doença e das inabilidades funcionais. Foi observado no grupo com HD maior declínio cognitivo e uma nítida progressão dos escores mentais com risco aumentado para demência. Conclusão: Hiper-reflexia detrusora é um achado urodinâmico frequente em mulheres com DP e embora esteja associada à pior desempenho motor, estágios de maior gravidade da doença e inabilidades funcionais, não é um fator de maior progressão desses aspectos clínicos. Por outro lado as pacientes com HD tiveram, em longa duração, significante progressão da sintomatologia neuropsicológica.O perfil do declínio cognitivo e o risco para demência necessitam ser confirmados em estudos posteriores
Abstract: Objectives: This long-term study in women with Parkinson's disease (PD) and lower urinary tract dysfunctions aimed to verify the correlation of urinary symptoms with the severity of the disease and mental functions. Verify the prevalence of detrusor hiper-reflexia (DH) and analyze the severity of motor symptoms, Hoehn and Yahr stage, functional abilities and neuropsychological functions, as well as analyze the progression of these clinical aspects and cognitive decline in patients with DH. Subjects and Methods: We studied a cohort of sixty-three (63) PD patients whose neurological aspects were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn-Yahr scale. Functional abilities were evaluated by Schwab and England scale and the urological function was quantified by International Prostatic Symptom Scale (IPSS) and qualified by urodynamic study. Two groups were then categorized: patients with and without HD. After seven years the same parameters were re-evaluated and the cognitive functions were assessed with the Montreal Cognitive Assessment (MoCA). Results: At baseline a correlation between urinary symptoms and motor dysfunction was verified but no correlation between urinary symptoms and mental symptoms was observed. The severity of motor symptoms, stage of the disease and functional disabilities were significant in patients with DH. In the follow up, the groups were similar in regards to progression of motor symptoms, Hoehn and Yahr stage and functional disabilities. On the other hand, decline in cognitive function and clear progression of mental scores and risk for dementia was observed in the group with DH. Conclusion: Urinary symptoms are correlated with the severity of the Parkinson's disease. Detrusor hyper-reflexia is a frequent urodynamic finding in women with DP and although it is associated with worse motor performance, stage of the disease and functional disabilities, it is not a factor of greater progression of these clinical aspects of the disease. On the other hand, patients with DH had a significant progression of the neuropsychological symptoms and risk of dementia. The profile of cognitive decline and dementia risk need to be confirmed in subsequent prospective studies
Doutorado
Neurologia
Doutor em Ciências Médicas

Penetration of sink as well as source leaves of wheat plants by the Russian wheat aphid, Diuraphis noxia (Mordvilko) was investigated using light, fluorescence and transmission electron techniques, to determine the feeding strategies adopted by the aphid in penetrating and successfully feeding from the phloem, and to assess the structural effects of the probing and feeding behaviour of D. noxia on the feeding sites. Examination of aphid-infested sink, as well as source leaf tissue, showed that D.noxia probed in cells of the vascular bundle more frequently than mesophyll cells. Within the vascular bundle, thin-walled sieve tubes were visited (probed) more than the other cells. In sink leaf material, 68 of 82 (83%) stylets and stylet tracks encountered during the examination of 1000 serial sections (from 5 different plants) terminated in thin-walled sieve tubes and only 14 (17%) in thick-walled sieve tubes. Thin-walled sieve tubes were visited more significantly than thick-walled sieve tubes. However, examination of the aphid.,.infested sink leaf on a per centimetre basis, from the tip of the leaf, revealed that thick-walled sieve tubes in the area closest to the tip (0-2cm from the tip) were as attractive to the aphid as were thin-walled sieve tubes, with no significant difference in the number of times thick- and thin-walled sieve tubes were probed in this area. Some 2-4cm from the tip however, thinwalled sieve tubes were significantly more probed and therefore more attractive than thick-walled sieve tubes. Examination of 2000 serial sections using aphid-infested source leaf tissue, showed that the thin-walled sieve tubes were significantly more probed than thickwalled sieve tubes, along the whole leaf, expressed as a total of all leaves, as well as on a per centimetre basis along the length of the leaf, with 212 (95%) of 222 terminations within the thin-walled sieve tubes and only 10 (5%) in thick-walledsieve tubes. The aphid probed the small vascular bundles (loading bundles) many more times than intermediate or large transport vascular bundles, in sink as well as source leaf. Of a total of 82 stylets and stylet tracks encountered in sink leaf tissue, 31 terminated in small vascular bundles ang the remaining 28 and 16 were located within large and intermediate vascular bundles respectively. In source leaf tissue 121 of 222 stylets and stylet tracks encountered were associated with small vascular bundles and only 58 tracks and 43 tracks with intermediate and large vascular bundles, respectively. The effect of sustained RWA feeding on the transport capacity was examined after the application of 5,6 carboxyfluoresceine diacetate (5,6-CFDA) in control (sink and source leaf tissue) and aphid-infested (source) wheat leaves, using fluorescence microscopy. After 3h acropetal longitudinal transport of 5,6-CF had occurred in sink leaves in longitudinal veins, as well as a lateral transfer via cross veins and subsequent unloading into mesophyll cells close to the tip of the leaf was observed. In control leaf tissue, the fluorescence front was detected up to about 5cm from the point of application and was only associated with the phloem and not unloaded. In contrast, aphid-infested leaf tissue showed very little 5,6-CF transport, being limited to 2cm or less from the point of application. Structural damage to the phloem in general and to the sieve tubes in particular within of control and infested wheat leaves was investigated using transmission electron microscopy (TEM). In addition, leaf strips were mounted in aniline blue to visualise callose deposition using the fluorescence microscopy. At the TEM level. infested leaf tissue showed various abnormalities, which included destruction of cell contents, membrane damage and subsequent loss of cell contents. TEM studies suggest severe osmotic shock resulted from the aphid's probing. Examination of leaf tissue using fluorescence microscopy showed that there was very little characteristic aniline blue-stained callose visible in control leaf tissue, other than the thin diffuse patches along the sieve plates and punctate spots associated with pore plasmodesmatal areas and plasmodesmatal aggregates. In contrast, the aphid-infested leaf tissue was heavily callosed, with callose deposited not only within the phloem tissue but also in neighbouring vascular parE:}nchyma cells as well. The data collectively suggest that D. noxia feeds preferentially within thin-walled sieve tubes, within the small longitudinal vascular bundles in sink , as well source leaf tissue. Based upon the data presented here the thin-walled sieve tubes in the wheat leaf appear to be more attractive to the aphid and that they are probably more functional in terms of transport system and unlo?lding in sink leaves. Aniline blue stained leaf material that had previously hosted large aphid colonies showed evidence of extensive callose deposits 24 to 36h after the aphids were removed, suggesting that the aphids caused severe mechanical damage to the vascular tissue and mesohyll cells as well. Damage (transient or more permanent) and the subsequent deposition of wound callose, disrupted phloem transport and hence the export of photoassimilate from the leaves.

Захворювання жовчного міхура (ЖМ) за частотою випадків поступаються хіба що атеросклерозу. Раннє виявлення та адекватне лікування холестерозу ЖМ має велике клінічне значення внаслідок можливості позитивно вплинути на перебіг захворювання. Мета: вивчення впливу розувастатину, мосаприду та урсодезоксихолієвої кислоти (УДХК) на перебіг хронічного холециститу та холестерозу жовчного міхура у хворих на ІХС, кардіосклероз та ожиріння.

Diseases of the urinary system are regularly encountered in daily veterinary practice. The development of increasingly efficient diagnostic tools is crucial to meet the high-quality requirements of contemporary professional standards. This project had many purposes, aiming to describe pioneering methods, protocols and diagnosis related to imaging of ureters and urinary bladder, chosen as they represent daily diagnostic challenges in daily routine practice. This project consisted of three papers: the first paper is a prospective pilot project concerning quantitative CEUS exam applied to distinguish neoplastic and non-neoplastic lesions of the urinary bladder in small animals; the second paper is a multicentric retrospective observational project describing the CT appearance of a novel CVC congenital malformation; the third paper is a retrospective study conducted on canine healthy patients, aimed at assessing the visibility of the ureters on high field MR on T1 and T2 sequences avoiding the use of paramagnetic contrast agents. The results of this project allowed to obtain objectifiable parameters for the distinction of neoplastic and non-neoplastic lesions of urinary bladder using quantitative CEUS; we also described the CT appearance of the transcaval ureter, a malfomaration of the CVC never described in veterinary medicine; finally, we described the feasibility of evaluation of normal ureters through high-field MR on T2-weighted sequences, in healthy canine patients. In conclusion, this project allowed to describe new diseases that could affect urinary tract function and contributes to the development of new methods and protocols with the potential to reduce the invasiveness of certain diagnostic procedures related to the urinary tract.

Bladder cancer is the second most common urological cancer after prostate cancer and is one of the leading causes of cancer mortality in most western countries. For organ-confined, muscle-invasive disease, the standard of care, in terms of definitive cure, remains radical surgery (cystectomy) with lymphadenectomy. However, survival rates remain poor following supposedly curative treatment. Radical radiotherapy and more recently, multimodality treatment incorporating chemo-radiotherapy, are alternatives which allow bladder preservation in those choosing not to undergo or are unsuitable for radical surgery. However, survival rates following radiotherapy are generally lower relative to radical cystectomy and multimodality treatments can only be offered to select cases in few institutions. Biomarkers which can accurately predict tumour response to radiotherapy or chemotherapy can aid the selection of patients who are likely to respond well to treatment options incorporating radiotherapy and/or chemotherapy, as alternatives to radical cystectomy, in the management of bladder cancer. Such a strategy would allow personalised cancer care with patients likely to benefit from treatments that they are likely to respond well to and concomitantly avoid complications arising from other treatments less likely to benefit them. This thesis investigated the novel tumour suppressor gene, AIMP3 which is involved in the DNA damage response (DDR) pathway following exposure to genotoxic insults such as irradiation and chemotherapy. The expression and cellular localisation of AIMP3 protein was characterised in a panel of bladder cancer cell lines. Expression of AIMP3 was altered by gene knockdown with siRNA transfection and survival outcomes assessed following irradiation and chemotherapy. The predictive value of AIMP3 expression in determining survival outcome of patients with muscle-invasive bladder cancer who had undergone radical radiotherapy, with or without carbogen supplementation, in the BCON trial, was assessed. Prognostic significance was evaluated by interrogating a control cohort of patients who had undergone radical cystectomy and had not had exposure to radiotherapy or either neoadjuvant or adjuvant chemotherapy. Reportedly important DDR proteins, including Mre11, p53 and ERCC1, were also interrogated in the BCON, Radical Cystectomy, Neodjuvant and LaMB trial TMA datasets. Clonogenic survival outcomes following AIMP3 knockdown were also investigated in cisplatin-sensitive (RT112) and cisplatin-resistant (RT112CP) cell lines following cisplatin exposure. Survival outcome, stratified for AIMP3 as well as ERCC1, Mre11 and p53 status, were interrogated in the Neoadjuvant set, which incorporated a cohort of patients who had undergone cisplatin-based neoadjuvant chemotherapy prior to radical treatment. This was validated in a second cohort of patients who had undergone cisplatin-based chemotherapy as part of the LaMB trial.

INTRODUÇÃO E OBJETIVOS: Distúrbios miccionais são freqüentes em pacientes com doença de Parkinson, mas sua associação com parâmetros como idade do paciente, gênero, gravidade do comprometimento neurológico e duração da doença não é bem conhecida. Neste estudo, avaliamos prevalência e características dos sintomas miccionais em pacientes com doença de Parkinson e examinamos sua associação com parâmetros clínicos com potencial impacto sobre a disfunção miccional. MÉTODOS: Avaliamos prospectivamente 110 pacientes, incluindo 84 homens (76,4%) e 26 mulheres (23,6%), com idade média de 61,8 ± 9,6 anos. Os critérios de inclusão foram doença de Parkinson idiopática e idade acima de 40 anos. Pacientes com outras doenças neurológicas, história de cirurgia e radioterapia pélvica foram excluídos. A duração média da doença foi 12,3 ± 7,2 anos. O comprometimento neurológico foi avaliado pelas escalas Hoehn-Yahr (HY) e Escala Unificada de Avaliação da Doença de Parkinson (UPDRS). Os sintomas miccionais foram avaliados pelo questionário da Sociedade Internacional de Continência para Homens, incluindo uma questão de qualidade de vida relacionada a sintomas miccionais. Consideramos sintomáticos os pacientes que queriam tratamento para sua disfunção miccional. Estes foram avaliados com análise de urina, creatinina sérica, PSA, ultra-sonografia do aparelho urinário e urodinâmica. Avaliamos a associação da disfunção miccional com idade, gênero, tempo de duração da doença, grau de comprometimento neurológico, impacto na qualidade de vida e achados urodinâmicos. RESULTADOS: A avaliação neurológica demonstrou média de 3,0 ± 0,8 na escala de HY e 70,0 ± 31,1 na escala de UPDRS. A média do escore miccional foi de 11,9 ± 9,3 e os sintomas mais comuns foram noctúria em 89 (80,9%) pacientes, urgência em 40 (36,3%) e aumento da freqüência miccional em 39 (35,4%) pacientes. A duração média dos sintomas miccionais foi de 3,8 ± 3,4 anos. A prevalência da disfunção miccional aumentou significativamente com o aumento no grau de comprometimento neurológico, mas não com a idade nem com a duração da doença. A qualidade de vida relacionada aos sintomas miccionais foi afetada pela severidade da disfunção miccional e os sintomas de freqüência e noctúria são os de pior impacto na qualidade de vida. Sessenta e três pacientes (57,2%) eram sintomáticos e 54 (43 homens e 11 mulheres) completaram a avaliação. Os pacientes sintomáticos apresentaram disfunção neurológica mais severa (HY médio 3,2 ± 0,8 vs 2,8 ± 0,9 para os assintomáticos; p=0,035). A idade, a duração da doença e dos sintomas miccionais não diferiram entre sintomáticos e assintomáticos. O volume médio da próstata foi 30,3 ± 10,7 cc. Os achados urodinâmicos foram obstrução infravesical em 38 (70,3%) pacientes, hiperatividade detrusora em 27 (50,0%), e hipocontratilidade detrusora em seis (11,1%) pacientes. O grau de comprometimento neurológico não se associou com nenhum padrão urodinâmico. Na comparação entre homens e mulheres sintomáticos a única diferença observada foi a maior gravidade dos sintomas de esvaziamento nos homens. CONCLUSÕES: A maior parte dos pacientes com doença de Parkinson apresenta disfunção miccional significativa e a gravidade da doença neurológica é o principal fator preditivo para a ocorrência de disfunção miccional. Obstrução infravesical e hiperatividade detrusora são os achados urodinâmicos mais comuns, mas não estão associados com o grau de comprometimento neurológico. Homens e mulheres são similarmente afetados pelos sintomas miccionais e não demonstraram distinção quanto aos achados urodinâmicos.
INTRODUCTION AND OBJECTIVES: Voiding dysfunction often occurs in patients with Parkinsons disease, but its association with patients age, gender, degree of neurological impairment, and disease duration is not fully known. In this study, we assessed the prevalence and characteristics of lower urinary tract symptoms (LUTS) in patients with Parkinson\'s disease and examined their association with those clinical parameters that could have an impact on voiding dysfunction. METHODS: We prospectively evaluated 110 patients, of which 84 were men (76.4%) and 26 were women (23.6%), with a mean age of 61.8 ± 9.6 years. The inclusion criteria were: idiopathic Parkinsons disease and age > 40 years. Patients with other neurological diseases and history of pelvic surgery and radiotherapy were excluded. Mean duration of the disease was 12.3 ± 7.2 years. The neurological impairment was assessed by the Hoehn-Yahr scale (HY) and the Unified Parkinson Disease Rating Scale (UPDRS). Lower urinary tract symptoms were assessed by the International Continence Society male questionnaire, which included a question about quality of life related to LUTS. Those patients who wanted to be treated for their voiding dysfunction were considered as symptomatic. They underwent urine analysis, serum creatinine measurement, PSA, urinary tract imaging and urodynamic study. We examined the association between voiding dysfunction and age, gender, disease duration, degree of neurological impairment, impact on quality of life, and urodynamic findings. RESULTS: The neurological assessment showed a mean HY score of 3.0 ± 0.8 and a mean UPDRS score of 70.0 ± 31.1. Mean LUTS score was 11.9 ± 9.3, and the most prevalent symptoms were nocturia in 89 (80.9%) patients, urgency in 40 (36.3%), and frequency in 39 (35.4%). Mean duration of LUTS was 3.8 ± 3.4 years. The prevalence of voiding dysfunction increased significantly with the degree of neurological impairment, but not with patients age or disease duration. Quality of life was affected by the severity of the voiding dysfunction, and the symptoms with the worst impact on quality of life were frequency and nocturia. Sixty-three patients (57.2%) were symptomatic and 54 (43 men and 11 women) concluded the evaluation. Symptomatic patients had more severe neurological dysfunction (mean HY 3.2 ± 0.8 vs 2.8 ± 0.9 for asymptomatic patients; p=0.035). Symptomatic and asymptomatic patients did not differ as to age, disease duration and LUTS. Mean prostate volume was 30.3 ± 10.7 cc. The urodynamic findings were bladder outlet obstruction in 38 (70.3%) patients, detrusor overactivity in 27 (50.0%), and detrusor underactivity in 6 (11.1%). The degree of neurological impairment was not associated with any urodynamic pattern. The only difference observed between symptomatic men and women was that the voiding symptoms were more severe in men. CONCLUSIONS: Most patients with Parkinsons disease have significant voiding dysfunction, and the severity of the neurological disease is the main predictive factor for the occurrence of voiding dysfunction. Bladder outlet obstruction and detrusor overactivity are the most common urodynamic findings, although not associated with the degree of neurological impairment. Men and women are equally affected by LUTS and show similar urodynamic findings.

This thesis addresses the three principal questions concerning the development of CT urography for investigating haematuria and each question is the subject of a separate chapter. The questions are: What is the reasoning behind using CT urography? What is the optimum diagnostic strategy using CT urography? What are the problems with using CT urography and how may solutions be provided? Haematuria can signify serious disease such as urinary tract stones, renal cell cancer, upper tract urothelial cancer (UTUC) and bladder cancer (BCa). CT urography is defined as contrast enhanced CT examination of kidneys, ureters and bladder. The technique used here includes unenhanced, nephrographic and excretory-phases for optimized diagnosis of stones, renal masses and urothelial cancer respectively. The reasoning behind using excretory-phase CT urography for investigating haematuria is based on results showing its high diagnostic accuracy for UTUC and BCa. Patients with haematuria are classified as low risk or high risk for UTUC and BCa, by a risk score, determined by the presence/absence of risk factors: age > 50 years, visible or nonvisible haematuria, history of smoking and occupational exposure. The optimum diagnostic strategy for patients at high risk for urothelial cancer, uses CT urography as a replacement test for ultrasonography and intravenous urography and as a triage test for flexible and rigid cystoscopy, resulting in earlier diagnosis and potentially improving prognosis. For patients at low risk, ultrasonography, unenhanced and nephrographic-phase CT urography are proposed as initial imaging tests. Problems with using CT urography include false positive results for UTUC, which are eliminated by retrograde ureteropyelography-guided biopsy, an innovative technique, for histopathological confirmation of diagnosis. Recommendations for the NHS and possible future developments are discussed. CT urography, including excretory-phase imaging, is recommended as the initial diagnostic imaging test before cystoscopy for patients with haematuria at high risk for urothelial cancer.

Base teórica: Disfunções do trato urinário inferior são sintomas não motores comuns na Doença de Parkinson (DP) e incluem a Síndrome da Bexiga Hiperativa Neurogênica (SBHN), caracterizada pela urgência miccional, com ou sem urgeincontinência, acompanhada de aumento da frequência urinária e noctúria. A estimulação do nervo tibial posterior (ENTP) é uma das modalidades de tratamento disponíveis para o tratamento da SBHN. Objetivo: Determinar e comparar os efeitos do tratamento com ENTP em pacientes com DP e sintomas de SBHN e a manutenção dos resultados em 1 e 3 meses após o término do tratamento. Métodos: Ensaio-clínico, duplo-cego, randomizado, controlado e comparado com placebo. A pesquisa foi realizada com mulheres com DP e sintomas de SBHN no Hospital de Clínicas de Porto Alegre. Para o tratamento com ENTP domiciliar por 12 semanas as pacientes foram divididas em dois grupos: grupo ENTP e grupo ENTP sham/placebo. A avaliação da resposta pré e pós-tratamento foi realizada através de formulário específico, questionários de avaliação da incontinência urinária e qualidade de vida (OAB-V8 e KHQ) e de um diário miccional (DM) de 24 horas. Após, o fim do tratamento foi feito seguimento dos resultados para avaliação da melhora subjetiva em 30 e 90 dias. Resultados: O grupo ENTP apresentou uma diminuição da noctúria, número de episódios de urgência micciional e urge-incontinência, número de uso de proteções para incontinência, pontuação OAB-V8 e em sete domínios do KHQ (p <0,001). Embora, o grupo controle também tenha apresentado melhora dos sintomas, o grupo ENTP apresentou uma melhora superior no final do tratamento nas medidas do DM, OAB-V8 e na maioria dos domínios do KHQ. A ETNTP foi considerada um tratamento efetivo para SBHN em 93,3%, enquanto 33,3% dos tratados com placebo também melhoraram (p = 0,002). No seguimento de 30 e 90 dias, 53,3% e 33,31%, respectivamente, do grupo ENTP relataram que mantinham- se melhores dos sintomas da SBHN. Conclusão: a ENTP foi um tratamento efetivo para as pacientes com DP e SBHN. Nossa hipótese de superioridade clínica do grupo ENTP foi confirmada e a melhora subjetiva foi considerada positiva, mesmo que parcialmente em 30 e 90 dias após fim do tratamento.
Blackround: Lower urinary tract dysfunctions are common non-motor symptoms in Parkinson's disease (PD) and include Neurogenic Overactive Bladder Syndrome (NOBS), characterized by urinary urgency, with or without urge incontinence, accompanied by increased urinary frequency and nocturia . Posterior Tibial Nerve Stimulation (PTNS) is one of the treatment modalities available for the treatment of NOBS. Objective: To determine and compare the effects of PTNS treatment in patients with PD and NOBS symptoms and to maintain long-term results (1 and 3 months). Methods: Controlled, randomized, double-blind and compared with placebo clinical trial. The research was carried out with women with PD and symptoms of NOBS at the Hospital de Clínicas de Porto Alegre. For treatment with PTNS at 12 weeks, patients were divided into two groups: PTNS group and PTNS sham/placebo group. The evaluation of the pre- and post-treatment response was through a specific form, questionnaires to evaluate incontinence and quality of life (OVA-V8 and KHQ), and a voiding diary. After the end of the treatment, the results were followed up to evaluate the subjective improvement in 30 and 90 days. Results: The PTNS group presented a decreased nighttime urinary frequency, number of urgency and urinary incontinence episodes, number of incontinence protection, OAB-V8 and 7 domains of KHQ (p<0.001). Although the control group also showed improvement of the symptoms, the ENTP group presented a superior improvement at the end of the treatment in DM, OAB-V8 and most KHQ domains. PTNS was considered an effective treatment for OAB in 93.3%, while 33.3% of those treated with placebo was considered a responder (p=0.002). After 30 and 90 days, 53.3% and 33.31%, respectively, of the ENTP group reported that they maintained better SBHN symptoms. Conclusion: PTNS was an effective treatment for patients with PD and NOBS. Our hypothesis of clinical superiority of the ENTP group was confirmed and the subjective improvement was considered positive, even if partially at 30 and 90 days after the end of the treatment.!

Background: Recently, several studies have demonstrated that phosphodiesterase type 5 inhibitors (PDE5-Is), drugs widely used as first-line oral treatment of erectile dysfunction (ED), are clinically effective in the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) and/or ED, although their mechanism of action is still unclear and under investigation. It has been suggested that PDE5-Is beneficial effects on storage symptoms are partially independent from nitric oxide signalling and they cause bladder detrusor relaxation through the involvement of intracellular cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), KATP, BKCa and SKCa channels. Hydrogen sulfide (H2S) is a newly discovered gas-transmitter with myorelaxant properties. It is endogenously generated by cystathionine β- synthase (CBS) and cystathionine γ-lyase (CSE) from L-cysteine. Purpose I: To investigate whether H2S signalling pathway contributes to human bladder function and accounts for sildenafil relaxing effect on human detrusor muscle. Material and methods I: Full thickness bladder samples (detrusor plus urothelium) were obtained by prostatectomy from male patients aged between 61 and 73 years and affected with severe LUTS secondary to BPH. CBS and CSE expression was evaluated by Western blot. H2S production was measured in basal condition and after stimulation with L-cysteine, the endogenous substrate (10 mM), and in response to sildenafil (10 µM; 15, 30, 45 min; or 1, 3, 10, and 30 µM; 30 min), 8-bromo-cGMP (8-Br-cGMP, 100 µM; 30 min) or dibutyryl-cAMP (d-cAMP, 100 µM; 30 min) by using a colorimetric assay. On a stable contraction of bladder strips induced by carbachol, a curve concentration effect of sodium hydrosulfide (NaHS), a stable H2S donor in solution (0.1 µM to 1 mM), or L-cysteine (0.1 µM to 1 mM), or sildenafil (0.1 µM to 10 µM) was performed. To investigate H2S signalling in sildenafil effect, DL-propargylglicine (PPG, 10 mM) and/or aminooxyacetic acid (AOAA, 1 mM) were used as CSE and CBS inhibitors, respectively. Data were expressed as mean ± SEM. Statistical analysis was determined by using ANOVA followed by Bonferroni as a post hoc test. Differences were considered significant when p value was less than 0.05. Results I: Both CBS and CSE were expressed in the human bladder and efficiently converted L-cysteine into H2S. Both NaHS and L-cysteine caused a concentration-dependent relaxation of human bladder strips. Furthermore, sildenafil-induced a relaxation of bladder dome strips and a concentration dependent increase in H2S production. Both effects were significantly reduced by pretreatment of tissue with CBS and CSE inhibitors. Both 8-Br-cGMP and d-cAMP caused a significant increase in H2S production, similar to that induced by sildenafil. Conclusions I: Sildenafil induced relaxation of human bladder involves H2S signalling pathway. The increase in H2S levels triggered by cGMP and cAMP may account for the PDE5-Is beneficial effect in LUTS. Furthermore, it can be hypothesized that the stimulation of L-cysteine/H2S pathway is a common characteristic among all commercially available PDE5-Is. It is also well established that cGMP or cAMP activates protein kinase G (PKG) or protein kinase A (PKA) respectively, which in turn phosphorylates downstream proteins thereby triggering signal transduction. On the basis of the above results, it can be hypothesized that the increase in H2S production triggered by 8-Br-cGMP or d-cAMP involves CBS and/or CSE phosphorylation mediated by PKG or PKA, leading to an increased catalytic activity. Purpose II: To investigate whether cGMP-dependent PKG and/or cAMP-dependent PKA promotes CBS phosphorylation, leading to an increase in H2S production in human urothelium. Material and Methods II: Bladder samples were obtained as previously described in Material and Methods I. Urothelium was carefully dissected and separated from detrusor muscle. Human urothelial T24 cell line wild type (WT), silenced for CBS (CBSΔT24) or site-directed mutated for CBS (HA-CBS S32A, HA-CBS S227A and HA-CBS S525A; the amino acids Ser32, Ser227 and Ser525, the putative phosphorylation sites predicted by GPS 2.1 software, were mutated in Ala) were cultured in DMEM supplemented with FBS 10%. CBS and CSE expression was evaluated in human urothelium and T24 cells, while PKG and PKA expression was evaluated in human urothelium, T24 cell line, detrusor muscle and full thickness bladder by Western blot. H2S production in human urothelium and T24 cells was measured in basal condition and after stimulation with L-cysteine (10 mM), 8-Br-cGMP (100 µM; 30 min for urothelium; 5, 15, 30 min for T24 cells) or d-cAMP (100 µM; 30 min for urothelium; 5, 15, 30 min for T24 cells), in presence or in absence of PKG or PKA inhibitor, such as KT5823 or KT5720, respectively. CBS phosphorylation was evaluated either in a cell free phosphorylation assay and in T24 cells treated with or without 8-Br-cGMP and d-cAMP, in presence or absence of PKG or PKA inhibitor, using antibody against phospho-Ser/Thr (anti-pS/T). CBS phosphorylation and H2S production were also measured in HA-CBS S32A, HA-CBS S227A and HA-CBS S525A mutated T24 cells following the treatment with 8-Br-cGMP (100 µM; 15 min). A specific rabbit polyclonal antibody against phosphorylated CBS at site Ser227 (pCBSSer227) was designed and validated. Data were expressed as mean ± SEM. Statistical analysis was determined by using t Student test or ANOVA followed by Bonferroni as a post hoc test. Differences were considered significant when p value was less than 0.05. Results II: Both CBS and CSE were expressed in human urothelium and T24 cell line, and they efficiently converted L-cysteine into H2S. Treatment of both urothelium and T24 cells with 8-Br-cGMP, significantly increased H2S production in a time dependent manner, reaching the maximum effect at 30 and 15 min, respectively. This effect was markedly reverted by inhibition of PKG with the selective inhibitor KT5823. d-cAMP treatment did not cause any change in H2S production in both urothelium and T24 cells. The increase of H2S in urothelium observed with 8-Br-cGMP treatment was associated to a significant raise in CBS phosphorylation (pCBS) at the same time dosing. Interestingly, d-cAMP did not modify pCBS levels in both urothelium and T24 cells. The lacking of effect on pCBS following d-cAMP treatment was depending on a very weak PKA expression in both urothelium and T24 cell line compared to PKG expression. To identify the PKG phosphorylation site(s), CBS WT or HA-CBS mutants proteins (HA-CBS S32A, HA-CBS S227A, HA-CBS S525A) were subjected to a cell free kinase assay. A significant reduction of phosphorylation of HA-CBS S227A and HA-CBS S525A proteins was observed when compared to CBS WT. The same results were obtained when the kinase assay was performed on T24 cells WT and T24 mutants HA-CBS S32A, HA-CBS S227A, HA-CBS S525A. Levels of pCBS in HA-CBS S227A and HA-CBS S525A after 8-Br-cGMP treatment were significantly reduced when compared to CBS WT. Furthermore, mutation of CBS Ser227 significantly reduced H2S production in basal condition and following incubation with 8-Br-cGMP compared to CBS WT, while H2S levels were not modified by mutation of CBS Ser525. This result suggested that phosphorylation at Ser227 accounts for H2S production and CBS activity. Finally,the phosphopeptide-specific CBS antibody (anti-pCBSSer227) generated efficiently recognized pCBSSer227 protein in human urothelium and in T24 cells following the treatment with 8-Br-cGMP. Conclusions II: It is known that urothelium influences the contractile state of detrusor smooth muscle and contributes to bladder homeostasis by releasing several agents that modulate muscle contractility. In bladder urothelium PKG/cGMP signalling triggers H2S production through a selective activation of CBS by phosphorylation at Ser227. We suggest that CBS-derived H2S contributes to bladder homeostasis by controlling detrusor muscle contractility. Furthermore, the modulation of intracellular cGMP levels in bladder by using PDE5-Is promotes H2S induction via PKG, contributing to explain the efficacy of PDE5-Is in LUTS therapy. Background: H2S is a physiological signalling molecule with cytoprotective effects in several cardiovascular disease, such as myocardial ischemia (MI) and heart failure. Reactive oxygen species (ROS) represent a major cause of myocardial injury and cellular damage during ischemia/reperfusion. Increasing the activity of cellular antioxidant enzymes, cardiomyocytes can protect myocardium tissue against ischemia/reperfusion injury. H2S is produced in mammalian tissue by three different enzymes: cystathionine γ-lyase (CSE), cystationine β-synthase (CBS) and 3-mercaptopopyruvate sulfurtransferase (3-MST) It has been demonstrated that acute injection of H2S, either prior to ischemia or at reperfusion, markedly ameliorates in vivo myocardial ischemia/reperfusion (MI/R) injury and induces cardioprotection by enhancing eNOS activity, thus increasing myocardial NO bioavailability. Furthermore, H2S exerts antioxidant properties in myocardium through nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signalling. Angiotensin converting enzyme inhibitors (ACEIs) are recommended for the management of myocardial ischemia. Even though ACEIs have been shown to reduce cardiovascular morbidity and mortality in patients affected with myocardial infarction, their cardioprotection is not dependent entirely on inhibition of angiotensin II production. Zofenopril is a sulphydryl-ACEI characterized by high lipophilicity, long-lasting tissue penetration, selective cardiac ACE inhibition and antioxidant and cardioprotective activities. Recently, it has been reported that zofenopril promotes H2S signalling through the upregulation of CSE or by acting as an H2S donor. Thus, it can be hypothesized that the antioxidant and cardioprotective effects of zofenopril may be mediated through H2S and NO dependent signalling. Purpose: To investigate i) the effect of a single administration of zofenopril on myocardial and circulating H2S and NO bioavailability; ii) the effect of zofenopril treatment on the extent of cardiac injury in a murine model of MI/R; 3) the effect of zofenopril therapy on oxidative stress and associated Nrf2 signalling. Material and Methods: Male C57BL/6J mice were treated per oral gavage with vehicle (carboxymethylcellulose 0.02% m/v) or zofenopril calcium {[(1(S), 4(S)]-1(3-mercapto-2 methyl-1-oxopropyl) 4-phenyl-thio-L-proline-S-benzoylester], 10 mg/kg} for 1-8-24 hours. Free H2S levels were measured in heart tissue and plasma by gas chromatography coupled with sulfur chemiluminescence. Nitrite levels in plasma and heart tissue were quantified by using HPLC methods. Gene expression of H2S producing enzymes CBS, CSE and 3-MST was evaluated by RT-qPCR. Myocardial CBS, CSE, 3-MST, eNOS, p-eNOS1177, p-eNOS495, GPX-1, Trx-1, Trx-2, Nrf2, Keap1 protein expression was evaluated by Western blot. Mice were subjected to 45 min of MI by occluding the left coronary artery. Troponin-I levels were measured at 4 hours of reperfusion by using a specific mouse ELISA kit. Infarct size per area at risk (INF/AAR) was determined after 24 hours of reperfusion. Tissue and circulating biomarkers of oxidative stress were determined by measuring malondialdehyde (MDA) and advanced oxidation protein products (AOPP) levels. Data were expressed as mean ± SEM. Statistical analysis was determined by using Student's unpaired, two-tailed t-test or ANOVA followed by Dunnett as a post hoc test. Results: A single zofenopril administration resulted in a significant increase in H2S bioavailability in both heart tissue and plasma at 8 hours of treatment when compared to vehicle. 8 hours were considered the best time dosing to perform the further experiments. A significant increase in tissue and circulating nitrite levels was observed after zofenopril therapy. Myocardial gene expression related to CBS and CSE was not modified by zofenopril treatment, while 3-MST mRNA levels were significantly increased by drug administration. 3-MST as well as CBS and CSE protein levels were similar in both vehicle and zofenopril treated groups. Acute administration of zofenopril promoted eNOS activation through phosphorylation at Ser1177. Furthermore, zofenopril administration 8 hours before MI/R was cardioprotective reducing significantly INF/AAR and circulating troponin-I levels compared to vehicle. Interestingly, zofenopril therapy induced a significant up-regulation of transcription factor Nrf2 without affecting Keap1 levels. Zofenopril therapy induced a significant up-regulation of antioxidant protein, such as GPX-1 and Trx-1 while it did not alter Trx-2 protein expression. Zofenopril treatment markedly reduced the biomarkers of oxidative stress in myocardial tissue (MDA) and plasma (AOPP). Conclusions: Our findings demonstrate that a single administration of zofenopril significantly increases the H2S bioavailability and enhances NO levels in both heart tissue and plasma. The induction in H2S availability occurs mainly in an non enzymatic manner, while the augmented levels of NO are due to the eNOS phosphorylation at the site Ser1177 enhanced by H2S. Furthermore, this study supports the concept that zofenopril-mediated increases in H2S scavenge ROS directly and/or indirectly by activation of Nrf2 increasing antioxidant enzymes expression. In conclusion, our studies demonstrate that zofenopril may prevent cardiac injury during ischemic conditions primarily through the enhancement of cardiovascular antioxidant defense induced by H2S activated Nrf2 signalling.

Thesis (MSc.Med.(Urology))--University of the Witwatersrand, Faculty of Health Sciences, 2014.
Bladder cancer is the second commonest urological malignancy and haematuria is the commonest symptom. Cystoscopy and urine cytology are integral for the investigation of haematuria, while the role of molecular markers such as the NMP22 BladderChek test is still being defined. The BladderChek is a qualitative point of care test developed for the detection of the elevated urinary levels of NMP22 associated with bladder cancer. No studies have been performed in South Africa using the BladderChek nor considered using this test to increase the efficiency of the workup of patients with gross haematuria. The primary aim was to establish the percentage of office cystoscopies done as part of a gross haematuria workup at Charlotte Maxeke Johannesburg Academic Hospital that are unnecessary and may be avoided if the BladderChek is positive under defined conditions. A cross-sectional study of the BladderChek test using prospective consecutive sampling, with special care to limit false positives and negatives, of 64 patients with a history of gross haematuria was conducted. The sensitivity, specificity, positive predictive value and negative predictive value for the BladderChek and the urine cytology were 78.9%, 84.4%, 68.2%, 90.5% and 36.8%, 93.0%, 70.0%, 76.9% respectively. The performance of the BladderChek was not affected by the history of gross haematuria, the stage nor grade of malignancy. Urine cytology detected only one malignancy missed by the BladderChek. Approximately 12.6% of office cystoscopies may be avoided and 78.9% of bladder tumours detected if the BladderChek is selectively applied as in this study. This may “fast-track” patients for transurethral resection of bladder tumour. The BladderChek may be a cost-effective alternative to urine cytology.

Bibliography: leaves 231-266.
271 leaves : col. ill. ; 30 cm.
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.
Indicates that injections under the ureteric orifice can cure VUR and that the tissue response to the plastics becomes quiescent. Research into embolisation from solid implants from intravenous tubing and the possibility of antibody formation to implanted plastics is also included. A model for fetal VUR has been developed to clarify focus of the uncertainity about reflux disease.
Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 1999

Yes
Context: Urinary biomarkers are promising as simple alternatives to cystoscopy for the diagnosis of de novo and recurrent bladder cancer. Objective: To identify a highly sensitive and specific biomarker candidate set with potential clinical utility in bladder cancer. Materials and methods: Urinary biomarkers concentrations were determined by ELISA. The performance of individual markers and marker combinations was assessed using ROC analysis. Results: A 5-biomarker panel (IL8, MMP9, VEGFA, PTGS2 and EN2) was defined from the candidate set. Discussion and conclusion: This panel showed a better overall performance than the best individual marker. Further validation studies are needed to evaluate its clinical utility in bladder cancer.
This work has been supported in part by the European Commission Program DIPROMON - HEALTH-F5-2012-306157-2: Development of an integrated protein- and cell-based device for non-invasive diagnostics in the urogenital tract.

Objectives: To establish a mouse orthotopic bladder cancer model with consistent tumor-take rate. This orthotopic model was subsequently used to evaluate small animal imaging techniques and investigate new therapeutic agents for bladder cancer treatment.
Materials and Methods: Different orthotopic implantation techniques have been tested. MBT-2 cells and syngeneic C3H/He mice were used in all experiments. Chemical bladder pre-treatment with different agents (saline, hydrochloric acid, trypsin and poly-L-lysine) and different concentration of instilled tumor cells (1 x 10⁶ or 2 x 10⁶) were investigated. In the second part of the experiment, trans-abdominal micro-ultrasound imaging (MUI) technique was investigated and validated. Bladder tumor growths were monitored with longitudinal measurement. Mice were killed at every MUI session. Bladder tumor volumes were measured and correlated with gross stereomicroscopy. Using the optimized orthotopic bladder cancer model, targeted contrast enhanced micro-ultrasound imaging has been investigated. VEGFR2 targeted contrast agent was prepared and injected intravenously before imaging sessions. The intra-tumoral perfusion, VEGFR2 expression and blood volume in real time were quantified. Contrast enhanced MUI was performed on Days 14 and 21. The feasibility of targeted contrast enhanced micro-ultrasound imaging was confirmed. After the establishment of orthotopic model and in vivo molecular imaging techniques, this robust platform was used for investigating new treatment agent in localized bladder cancer. Tumor-bearing mice were randomized into control and sunitinibtreated (40 mg/kg) groups. Tumor volume, intra-tumoral perfusion, and in vivo VEGFR2 expression were measured using a targeted contrast-enhanced micro-ultrasound imaging system. The effects of sunitinib malate on angiogenesis and cellular proliferation were measured by CD31 and Ki-67 immunohistochemistry. The clinical outcomes including total bladder weight, tumor stage, and survival were evaluated.
Results: A consistent tumor take-rate of over 90% was achieved by using poly-L-lysine pretreatment with 2 x 10⁶ MBT-2 cells in all of the experiments. MUI identified all tumors that were present on final histology. Measurements of tumor size by MUI and gross microscopy had a high correlation coefficient (r = 0.97). Measurements of intra-tumoral perfusion and in vivo VEGFR2 expression were also proved to be feasible. After the technical refinement and modification, complete measurements could be performed in all mice (n = 10) at 2 consecutive imaging sessions. No adverse effects occurred due to anesthesia or the ultrasound contrast agent. This is the first report of applying targeted contrast enhanced MUI in orthotopic bladder cancer model. Finally, sunitinib was found to have significant tumor growth inhibition in both in vitro and in vivo experiments. In the orthotopic model, tumors in sunitinib-treated mice had reduced tumor volume and stage, lower proliferation index and micro-vessel density. Sunitinib prolonged survival in tumor-bearing mice as compared to control group.
Conclusions: The development of reliable orthotopic animal models assists in the discovery of novel therapeutic agents. The establishment in the methods of implantation with improved tumor-take rate and the advances in imaging technology form the important foundation of basic research in bladder cancer. Trans-abdominal MUI is proven to be a valuable tool for translational studies involving orthotopic mouse bladder cancer models. Furthermore, the first report of the application of targeted contrast enhanced MUI in deep-seated tumor in bladder has been published. It enables investigators to monitor tumor angiogenesis and vascular changes after treatment. It will be useful for direct, noninvasive, in vivo evaluation of anti-angiogenesis therapeutic agents. The preclinical study has demonstrated the activities of a new class of targeted therapy against localized bladder cancer in an orthotopic mouse model. Sunitinib inhibits tumor growth and thus decreases the tumor burden and prolongs survival compared with placebo. These results provide a rationale for future clinical trials using VEGFR-targeted treatments of localized bladder cancer in the neo-adjuvant and adjuvant settings.
Chan, Shu Yin Eddie.
Thesis (M.D) Chinese University of Hong Kong, 2014.
Includes bibliographical references (leaves 189-212).

abstract: Early detection and treatment of disease is paramount for improving human health and wellness. Micro-scale devices promote new opportunities for the rapid, cost-effective, and accurate identification of altered biological states indicative of disease early-onset; these devices function at a scale more sensitive to numerous biological processes. The application of Micro-Electro-Mechanical Systems (MEMS) in biomedical settings has recently emerged and flourished over course of the last two decades, requiring a deep understanding of material biocompatibility, biosensing sensitively/selectively, biological constraints for artificial tissue/organ replacement, and the regulations in place to ensure device safety. Capitalizing on the inherent physical differences between cancerous and healthy cells, our ultra-thin silicone membrane enables earlier identification of bladder cancer—with a 70% recurrence rate. Building on this breakthrough, we have devised an array to multiplex this sample-analysis in real-time as well as expanding beyond bladder cancer. The introduction of new materials—with novel properties—to augment current and create innovative medical implants requires the careful analysis of material impact on cellular toxicity, mutagenicity, reactivity, and stability. Finally, the achievement of replacing defective biological systems with implanted artificial equivalents that must function within the same biological constraints, have consistent reliability, and ultimately show the promise of improving human health as demonstrated by our hydrogel check valve. The ongoing proliferation, expanding prevalence, and persistent improvement in MEMS devices through greater sensitivity, specificity, and integration with biological processes will undoubtedly bolster medical science with novel MEMS-based diagnostics and therapeutics.
Dissertation/Thesis
Doctoral Dissertation Electrical Engineering 2018

碩士
南台科技大學
生物科技系
99
Abstract In our previous studies, comparative proteomics demonstrated that lactate dehydrogenase B subunit (LDH-B) is down-regulated in high grade urinary bladder urothelial carcinoma (UBUC) compared to non-high grade ones. However, this finding has not been validated by clinical cohort investigation. Therefore, in present study 269 primary localized UBUC specimens were examined for LDH-B expression to clarify the relevance of LDH-B expression level to UBUC progression. Immunohistochenmistry (IHC) was implemented to investigate LDH-B protein expression in 269 primary localized UBUC specimens and to evaluate the association with tumor progression and prognosis. Our data demonstrated that dwindled LDH-B expression level was strongly associated with increment of primary tumor status (p<0.0001), higher histological grade (p=0.0024), the presence of vascular (p=0.0118) as well as perineurial (p=0.0094) invasion, suggesting that LDH-B might be related to tumor progression. At the univariate level, low LDH-B expression is one of many parameters which significantly predicted both disease-specific survival (DSS) (p=0.0001) and metastasis-free survival (MeFS) (p=0.0024). In Cox multivariate regression model, higher pT status was the strongest independent prognosticator for both DSS (p=0.0006) and MeFS (p=0.0067) while Low LDH-B expression remained prognostically significant for DSS (p=0.0401). The above results confirmed the prognostic roles of LDH-B in UBUC

Trabalho de Projeto do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina
Contexto:A Síndrome da Bexiga Dolorosa/Cistite Intersticial é parte integrante das designadas Síndromes de Dor Pélvica Crónica. Inicialmente descrita apenas como Cistite Intersticial, com base em achados cistoscópicos específicos (lesões de Hunner), tem hoje uma abrangência mais vasta englobando muitos outros casos sintomáticos, mas sem achados diagnósticos característicos. Apesar de não se tratar de uma doença ameaçadora da vida, é bem reconhecido o seu impacto negativo na qualidade de vida. A incerteza da sua etiologia e fisiopatologia causa grandes entraves no diagnóstico e tratamento desta patologia. Objectivos:Este artigo revê e actualiza alguns conceitos base acerca desta patologia, desde a sua própria definição à apresentação clínica e congrega as hipóteses etiopatogénicas mais aceites correntemente, procurando articulá-las com a orientação diagnóstica e tratamento mais adequados. Métodos:A evidência científica citada foi adquirida através da plataforma PubMed, referenciando-se 49 artigos no total. Foram também consultadas revistas, guidelines e livros de texto.Síntese:Com base na leitura e análise da pesquisa efectuada, conclui-se que ainda muitos aspectos acerca desta patologia permanecem por esclarecer. A sua definição como conceito mais amplo veio beneficiar a estratificação dos doentes, factor importante na sua orientação e tratamento. Várias são as opções terapêuticas já apresentadas, algumas com bons resultados em casos específicos.Conclusão:A evidência científica actual mostra-se insuficiente para explicar todos os factores envolvidos nesta patologia. O reconhecimento da sua apresentação clínica poderá sugerir o diagnóstico em doentes com queixas do tracto urinário de outra forma inexplicadas.
Context:Bladder pain syndrome / Interstitial cystitis is an integral part of the so-called Chronic Pelvic Pain Syndromes. Initially described only as Interstitial Cystitis, based on specific cystoscopic findings (Hunner's lesions), it now has a broader scope encompassing many other symptomatic cases but without characteristic diagnostic findings. Although it is not a life threatening disease, its negative impact on quality of life is well recognized. The uncertainty of its etiology and pathophysiology causes great obstacles in the diagnosis and treatment of this pathology.Objectives:This article reviews and updates some basic concepts about this pathology, from its own definition to clinical presentation, and brings together the currently accepted etiopathogenic hypotheses, seeking to articulate them with the most appropriate diagnostic and treatment orientation.Methods:The cited scientific evidence was acquired through the PubMed platform, referencing 49 articles in total. Magazines, guidelines and textbooks were also consulted.Synthesis:Based on the reading and analysis of the research carried out, it is concluded that still many aspects about this pathology remain unclear. Its definition as a broader concept has benefited patient stratification, an important factor in its orientation and treatment. There are several therapeutic options already presented, some with good results in specific cases.Conclusion:Current scientific evidence is insufficient to explain all the factors involved in this pathology. Recognition of its clinical presentation may suggest the diagnosis in patients with otherwise unexplained urinary tract complaints.

Noble metal nanostructures display collective oscillation of the surface conduction electrons upon light irradiation as a form of localized surface plasmon resonance (LSPR) properties. Size, shape and the refractive index of surrounding environment are the key features that controls the LSPR properties. Surface passivating ligands have the ability to modify the charge density of nanostructures to allow resonant wavelength to match that of the incident light, a phenomenon called “plasmoelectric effect,”. According to the drude model Red and blue shifts of LSPR peak of nanostructures are observed in the event of reducing and increasing charge density, respectively. However, herein we report unusual LSPR properties of gold triangular nanoprisms (Au TNPs) upon functionalization with para-substituted thiophenols (X-Ph-SH, X = -NH₂, -OCH₃, -CH₃, -H, -Cl, -CF₃, and -NO₂). Accordingly, we hypothesized that an appropriate energy level alignment between the Au Fermi energy and the HOMO or LUMO of ligands allows delocalization of surface plasmon excitation at the hybrid inorganic-organic interface, and thus provides a thermodynamically driven plasmoelectric effect. We further validated our hypothesis by calculating the HOMO and LUMO levels and also work function changes of Au TNPs upon functionalization with para substituted thiol. We further utilized our unique finding to design ultrasensitive plasmonic substrate for biosensing of cancer microRNA in bladder cancer and owe to unpresidential sensitivity of the developed Au TNPs based LSPR sensor, for the first time we have been utilized to analysis the tumor suppressor microRNA for more accurate diagnosis of BC. Additionally, we have been advancing our sensing platform to mitigate the false positive and negative responses of the sensing platform using surface enhanced fluorescence technique. This noninvasive, highly sensitive, highly specific, also does not have false positives technique provide strong key to detect cancer at very early stage, hence increase the cancer survival rate. Moreover, the electromagnetic field enhancement of Surface-Enhanced Raman Scattering (SERS) and other related surface-enhanced spectroscopic processes resulted from the LSPR property. This dissertation describes the design and development of entirely new SERS nanosensors using flexible SERS substrate based on unique LSPR property of Au TNPs and developed sensors shows excellent SERS activity (enhancement factor = ~6.0 x 106) and limit of detection (as low as 56 parts-per-quadrillions) with high selectivity by chemometric analyses among three commonly used explosives (TNT, RDX, and PETN). Further we achieved the programable self-assembly of Au TNPs using molecular tailoring to form a 3D supper lattice array based on the substrate effect. Here we achieved the highest reported sensitivity for potent drug analysis, including opioids and synthetic cannabinoids from human plasma obtained from the emergency room. This exquisite sensitivity is mainly due to the two reasons, including molecular resonance of the adsorbate molecules and the plasmonic coupling among the nanoparticles. Altogether we are highly optimistic that our research will not only increase the patient survival rate through early detection of cancer but also help to battle the “war against drugs” that together is expected to enhance the quality of human life.