Muscle invasive bladder cancer (MIBC) has a poor prognosis. Currently, therapy consists of radical radiotherapy or cystectomy with or without chemotherapy. The average age of patients with MIBC is high and older patients are less able to tolerate surgery or chemoradiation due to their impaired physical fitness and generally poor renal function. There is an urgent need to find new treatment regimes that are both tolerable and effective. The aims of this project were to investigate the radiosensitising effects of the histone deacetylase (HDAC) inhibitor panobinostat in bladder cancer cell lines, with the ultimate goal of proposing a novel radiosensitising therapy for MIBC, and to study the effects of panobinostat on the major DNA double strand break (DSB) repair pathways, homologous recombination (HR) and non-homologous end joining (NHEJ), to determine the predominant pathway targeted and to look further upstream at effects on the MRE11/RAD50/NBS1 (MRN) complex. The HDAC inhibitor panobinostat was found to be toxic in the low nanomolar range and significant radiosensitising effects were demonstrated at doses lower than IC50 in all the bladder cell lines studied. The radiosensitising effect of panobinostat was not influenced by TP53 status, which is generally regarded as an important determinant of bladder cancer response to radiotherapy. In the “synthetic lethality” bladder cancer cell model, panobinostat predominantly targets the HR pathway, reportedly the only proficient DNA repair pathway in MIBC. HR proteins RAD51 and CtIP were downregulated upon panobinostat treatment in a dose-dependent manner. Upstream, MRE11 and NBS1 proteins were also targeted by panobinostat, with levels slightly decreased in RT112 and T24 cells and in CAL29 cells post-ionising radiation. In summary, the HDAC inhibitor panobinostat was shown to be an efficient radiosensitiser in bladder cancer cells at low toxic doses and to predominantly target the HR pathway. These findings are promising and may contribute towards establishing a novel combination therapy of panobinostat with IR for MIBC patients.

O câncer de bexiga é uma neoplasia urogenital que acomete homens e mulheres, sendo que somente no Brasil 8.600 novos casos ao ano são diagnosticados. Cistoscopia transuretral é a conduta padrão no diagnóstico e acompanhamento do câncer de bexiga. Entretanto, tal procedimento é extremamente invasivo e doloroso além de ter elevado custo e não garantir todos os resultados. Assim, busca-se por marcadores moleculares que possam auxiliar no diagnóstico e progressão do câncer de bexiga, bem como diminuir a necessidade de exames invasivos no acompanhamento de pacientes tratados. Nesse sentido, a urina tem papel de destaque como fonte de biomarcadores devido principalmente ao seu caráter não invasivo. <br /> Nesse trabalho foram utilizadas duas abordagens \'ômicas\': proteômica e metabolômica, para a busca de biomarcadores em urina para o diagnóstico e prognóstico do câncer de bexiga, respectivamente. Com a abordagem proteômica buscou-se apenas por biomarcadores para o diagnóstico da doença e, utilizando as técnicas de eletroforese 2-DE, OFFGEL e MS, juntamente com análise estatística multivariada, foi possível identificar 32 proteínas que apresentam-se como potenciais marcadores para o câncer de bexiga. A abordagem metabolômica foi empregada para a busca de biomarcadores para reincidência e progressão da doença. As técnicas analíticas utilizadas nessa abordagem, LC-MS e CE-MS, mostraram-se complementares e, dos resultados obtidos com ambas e avaliados com análise estatística multivariada foi possível indicar 19 metabólitos para reincidência e 23 metabólitos para progressão do câncer de bexiga. <br /> Assim, neste trabalho explorou-se como as ciências \'ômicas\', a qual abrange técnicas analíticas de high-throughput, estatística multivariada e ferramentas de bioinformática auxiliando na descoberta de potenciais biomarcadores não invasivos para o diagnóstico e prognóstico do câncer de bexiga. Portanto, o presente estudo foi de grande importância e relevância à medida que ilustrou como tais técnicas podem potencialmente auxiliar no diagnóstico e prognóstico de doenças e contribuir para tratamentos personalizados no futuro, indicando a potencialidade de estudos dessa natureza. / Bladder cancer is an urogenital cancer affecting men and women, and just in Brazil 8,600 new cases are diagnosed annually. Transurethral cystoscopy is a standard conduct in the diagnosis and monitoring of bladder cancer. However, this procedure is extremely invasive, painful, expensive and does not guarantee the best results. Thus, the searching for molecular markers may assist in the diagnosis and monitoring of bladder cancer, as well as decreasing the need for invasive tests in the monitoring of patients treatment. In this way, urine shows an important role as a source of biomarkers, mainly due to its non-invasive nature. <br /> In this work we used two \'omics\' approaches: proteomics and metabolomics, to search for biomarkers in urine for the diagnosis and progression of bladder cancer, respectively. The proteomics approach was explored for biomarkers for diagnosing disease. Using 2-DE, OFFGEL electrophoresis, and MS techniques, as well multivariate statistical analysis, they were identified 32 proteins that may be pointed as potential markers for bladder cancer. The metabolomics approach was used to search for biomarkers for progression and recurrence of the disease. The analytical techniques used for this approach, LC-MS and CE-MS, were complementary to each other and the results evaluated with multivariate statistical analysis indicated that 19 metabolites for recurrence and 23 metabolites for progression of bladder cancer could possibly be used for validation studies. <br /> Thus, we demonstrated how the \'omics\' sciences, which include high- throughput analytical techniques, multivariate statistical analysis, and bioinformatics tools, aid in the discovery of potential biomarkers for noninvasive diagnosis, evaluate recurrence and monitor progression of bladder cancer. Therefore, this study was of high relevance to demonstrate the potential of such techniques to contribute to studies of personalized medicine.

Este estudo teve por objetivos analisar a experiência do cateterismo vesical intermitente por crianças e adolescentes portadores de bexiga neurogênica e suas mães, bem como analisar os fatores limitantes e facilitadores para o autocateterismo vesical intermitente nessas crianças e adolescentes na realidade das suas vidas cotidianas. No referencial teórico, buscamos a compreensão dessa construção da realidade, do cuidar/cuidado humano como uma questão de cidadania e valorização da vida nesse cotidiano, e a educação em saúde como uma prática de enfermagem para a valorização do cuidar cuidado. A pesquisa é de natureza qualitativa, aplicando as representações sociais como categoria de análise. Para a coleta dos dados, utilizamos os prontuários das crianças, formulário com questões semi-estruturadas, entrevista e diário de campo. A análise dos dados baseou-se em aspectos da hermenêutica dialética. A interposição das categorias empíricas com o referencial teórico fez emergir dimensões que mostraram esses atores sociais pertencentes a um contexto micro e macro social que determinam o seu modo de agir na e para a vida. A realidade no dia-a-dia das crianças, adolescentes e respectivas mães revelou-se em seis categorias empíricas: “CVI – corpo e sexualidade em evidência" e “CVI – conformação e relutância" são as categorias empíricas que traduzem as falas das crianças e adolescentes; “A responsabilização materna", “A agenda da vida", “O enfrentamento" e “A acomodação/compartilha" são as categorias empíricas que surgiram das falas das mães. Nessas seis categorias, revelam-se importantes elementos limitantes e facilitadores à experiência de cuidar da vida e, conseqüentemente, à experiência do autocateterismo pelas crianças e adolescentes. Cabe aos profissionais de saúde e em especial ao enfermeiro uma atitude solidária, num esquema de co-responsabilidade por meio da educação em saúde, que deverá ser desenvolvida como um processo emancipatório que, além do enfoque biológico, dê importância considerável aos aspectos ligados à vida cotidiana e amplie a consciência de cidadania desses atores sociais para viverem de modo mais pleno nos seus limiares próprios. / This study is aimed at analyzing the experience of intermittent vesical catheterism of children and adolescents with neurogenic bladders and their mothers, as well as analyzing limiting and facilitating factors for intermittent vesical autocatheterism in these children and adolescents in their daily lives. As for theoretical referentials, we sought to understand this construction of reality in human care as a matter of citizenship and valorization of life in this daily life; moreover, the health education as nursing practice on these values were the theoretical reference used in this study. This research is of a qualitative nature applying social representations as an analysis category. For data collection, we used children's reference books, forms with semi-structured questions, interviews and field diaries. The data analysis was based on aspects of dialectic hermeneutics. The interposition of empirical categories with the theoretical basis led to the appearance of dimensions which showed these social actors belonging to a micro- and macro-social context which determines their way of acting in and for life. The children's, adolescents' and their mothers' daily reality was revealed through six empirical categories: “CVI – body and sexuality in evidence" and “CVI – conformation and reluctance" are empirical categories which translate children's and adolescents' speech; “Maternal responsibility", “Life agenda", “Confrontation" and “Acceptance / sharing" are empirical categories which arose from the mothers' speech. In these six categories, important limiting and facilitating elements for the experience of taking care of life are revealed and, consequently, for autocatheterism by children and adolescents. It is the responsibility of the health professional, and especially of the nurse, to express a supportive attitude in a scheme of co-responsibility by means of health education, which should be developed as an emancipatory process which, besides the biological focus, values the aspects related to daily life and increases the citizenry conscience of these social actors so that they can live more fully according to their own thresholds.

Este estudo teve por objetivos analisar a experiência do cateterismo vesical intermitente por crianças e adolescentes portadores de bexiga neurogênica e suas mães, bem como analisar os fatores limitantes e facilitadores para o autocateterismo vesical intermitente nessas crianças e adolescentes na realidade das suas vidas cotidianas. No referencial teórico, buscamos a compreensão dessa construção da realidade, do cuidar/cuidado humano como uma questão de cidadania e valorização da vida nesse cotidiano, e a educação em saúde como uma prática de enfermagem para a valorização do cuidar cuidado. A pesquisa é de natureza qualitativa, aplicando as representações sociais como categoria de análise. Para a coleta dos dados, utilizamos os prontuários das crianças, formulário com questões semi-estruturadas, entrevista e diário de campo. A análise dos dados baseou-se em aspectos da hermenêutica dialética. A interposição das categorias empíricas com o referencial teórico fez emergir dimensões que mostraram esses atores sociais pertencentes a um contexto micro e macro social que determinam o seu modo de agir na e para a vida. A realidade no dia-a-dia das crianças, adolescentes e respectivas mães revelou-se em seis categorias empíricas: “CVI – corpo e sexualidade em evidência" e “CVI – conformação e relutância" são as categorias empíricas que traduzem as falas das crianças e adolescentes; “A responsabilização materna", “A agenda da vida", “O enfrentamento" e “A acomodação/compartilha" são as categorias empíricas que surgiram das falas das mães. Nessas seis categorias, revelam-se importantes elementos limitantes e facilitadores à experiência de cuidar da vida e, conseqüentemente, à experiência do autocateterismo pelas crianças e adolescentes. Cabe aos profissionais de saúde e em especial ao enfermeiro uma atitude solidária, num esquema de co-responsabilidade por meio da educação em saúde, que deverá ser desenvolvida como um processo emancipatório que, além do enfoque biológico, dê importância considerável aos aspectos ligados à vida cotidiana e amplie a consciência de cidadania desses atores sociais para viverem de modo mais pleno nos seus limiares próprios. / This study is aimed at analyzing the experience of intermittent vesical catheterism of children and adolescents with neurogenic bladders and their mothers, as well as analyzing limiting and facilitating factors for intermittent vesical autocatheterism in these children and adolescents in their daily lives. As for theoretical referentials, we sought to understand this construction of reality in human care as a matter of citizenship and valorization of life in this daily life; moreover, the health education as nursing practice on these values were the theoretical reference used in this study. This research is of a qualitative nature applying social representations as an analysis category. For data collection, we used children\'s reference books, forms with semi-structured questions, interviews and field diaries. The data analysis was based on aspects of dialectic hermeneutics. The interposition of empirical categories with the theoretical basis led to the appearance of dimensions which showed these social actors belonging to a micro- and macro-social context which determines their way of acting in and for life. The children\'s, adolescents\' and their mothers\' daily reality was revealed through six empirical categories: “CVI – body and sexuality in evidence\" and “CVI – conformation and reluctance" are empirical categories which translate children\'s and adolescents\' speech; “Maternal responsibility", “Life agenda", “Confrontation" and “Acceptance / sharing" are empirical categories which arose from the mothers\' speech. In these six categories, important limiting and facilitating elements for the experience of taking care of life are revealed and, consequently, for autocatheterism by children and adolescents. It is the responsibility of the health professional, and especially of the nurse, to express a supportive attitude in a scheme of co-responsibility by means of health education, which should be developed as an emancipatory process which, besides the biological focus, values the aspects related to daily life and increases the citizenry conscience of these social actors so that they can live more fully according to their own thresholds.

The aim of this thesis is to investigate the prevalence and management of bladder pain syndrome (BPS) amongst women with chronic pelvic pain (CPP) through a series of systematic reviews, a structured survey and primary study. It has been acknowledged that the diagnosis and management of BPS is a contentious subject. The mean prevalence of BPS in women with CPP is 61%. I initially carried out a patient and clinician survey to understand how BPS was being managed in the UK. I found wide variation in diagnostic methods and treatments of BPS used by clinicians and experienced by patients with no obvious consensus. Since we know the predominant complaint in these patients is pain (bladder or pelvic) I used patients with pelvic pain as my cohort. Cystoscopy is no longer used as a diagnostic test for BPS. It is possible to diagnose BPS through a consensus expert panel using symptom-based criteria. This method of deriving a reference standard is demonstrated in the primary study, since no gold standard diagnostic test exists for BPS. A case-control feasibility study was undertaken to investigate the accuracy of a group of urinary symptoms to diagnose BPS. While, neither index test of bladder filling pain or bladder wall tenderness can sensitively diagnose BPS alone, the symptoms of bladder filling pain, urinary frequency, pain on urination and pain on full bladder are a good predictor of the condition. A systematic review assessing the reporting outcomes identified five measures that should be included in studies; pain, urinary symptoms, general 8 wellbeing, quality of life and bladder capacity. Of the 19 treatments used for BPS, the level and strength of evidence ratings overestimated quality compared to the GRADE ratings. BPS can be diagnosed symptomatically but there is variable reporting of outcome measures and poor evidence for treatment effectiveness.

Les tumeurs de vessie suivent deux voies de progression tumorale. La voie des tumeurs papillaires qui progressent rarement vers des tumeurs invasives mais qui récidivent très fréquemment et la voie des carcinomes in situ (CIS) qui progressent pour envahir le chorion puis le muscle. Les tumeurs infiltrant le muscle sont de mauvais pronostic et les traitements par chimiothérapie restent d’efficacité limitée. Il est alors important d’en comprendre les bases moléculaires. Les microRNAs sont d’importants régulateurs de l’expression post-transcriptionnelle des gènes. Des perturbations de leur expression et/ou de leur activité contribuent au développement tumoral en dérégulant l’expression de gènes clés dans les cancers. Nos travaux ont porté sur l’étude de l’expression et des fonctions des microRNAs dans la carcinogenèse urothéliale. Dans la première partie, nous avons choisi d’étudier, par une approche de gènes candidats, miR-155, un oncomiR dont l’expression dérégulée a été rapportée dans plusieurs cancers mais pas encore dans le cancer de la vessie. J’ai identifié une surexpression significative de ce miARN dans un sous-groupe de cancers invasifs de vessie. Ensuite, j’ai montré par des analyses fonctionnelles, le rôle de miR-155 dans l’invasion et la migration tumorale mais pas dans la prolifération cellulaire. Dans la deuxième partie, nous avons utilisé une approche plus globale. J’ai d'abord effectué une revue extensive de la littérature pour rechercher les miR dont l'expression avait été montrée comme dérégulée dans les cancers de vessie et/ou les miR impliqués fonctionnellement dans ce cancer. J’ai ensuite réalisé une analyse multiparamétrique en intégrant les données d'expression de ces miR, les données anatomopathologiques et moléculaires (stade et grade, statut mutationel de TP53 et FGFR3, phénotype épigénétique MRES et signature CIS) et les données du transcriptome (puces Affymetrix U133 Plus 2.0), des altérations génomiques (puces Illumina 370.000 sondes) et de méthylation (puces Illumina 27.000 sondes). Ce travail m’a permis, d'identifier des miR associés à l'une des deux voies de progression identifiées dans les cancers de vessie et de proposer des cibles candidates de ces miR. La recherche des altérations épigénétiques pouvant affecter l’expression de ces miR a permis d’identifier une association significative entre l’expression d’un miARN (miR-17-5p) et la méthylation d’un promoteur. En revanche les altérations génétiques n’ont été associées à aucune expression de miR. Ce travail propose une liste de très bons candidats miARNs pour lesquels des études fonctionnelles pourront être envisagées au-delà de mon travail de thèse. / Bladder tumors are characterized by two progression pathways. The first pathway leads to the developpement of papillary tumors, which are at high risk of recurrence but that rarely progress to invasive tumors. Another pathway involves carcinoma in situ (CIS), which often progresses by first invading the lamina propria and then the muscle. Tumors infiltrating the muscle have a poor prognosis and chemotherapy regimens are of limited benefits. It is yet important to understand the molecular basis underlying these events. The microRNAs are important regulators of post-transcriptional gene expression. Alteration in their expression and /or activity is believed to contribute to tumor development by deregulating the expression of cancer-related genes. Our work has been focused on studying the expression and function of microRNAs in urothelial carcinogenesis. In the first part, we employed a candidate gene approach to study miR-155, a oncomiR whose dysregulated expression has been reported in many cancers, but not in bladder cancer. I identified a significant overexpression of this miRNA in a subgroup of invasive bladder cancers. Next, I demonstrated a role for miR-155 in tumor invasion and migration, without any apparent effect on cell proliferation. In the second part, we used a more comprehensive approach in which I first conducted an extensive review of the literature to search for miR whose expression was already found to be deregulated and/or miR functionally involved in bladder cancer. I then performed a multiparametric analysis by integrating expression data of miR, pathological and molecular data (stage and grade, mutational status of FGFR3 and TP53, MRES epigenetic phenotype and CIS signature) data of the transcriptome (Affymetrix U133 Plus 2.0), genomic alterations (370,000 chips Illumina probes) and methylation (Illumina chips 27,000 probes). This work allowed us to identify miRs associated with one or the other pathway linked to progression of bladder cancer and also, it revealed candidate targets for these miRs. The search for epigenetic alterations capable to affect the expression of those miRs showed significant association between expression of a particular miRNA (miR-17-5p) and the methylation of its promoter. Genetic alterations however, have failed to associate with expression of miR. Finally, this work suggests a list of good candidates miRNAs for which future functional studies should help to get insight into the role of these miRNAs

Leung Yee Fong, Vivian. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (leaves 159-169). / Acknowledgments --- p.i / Legend for figures --- p.ii / Legend for tables --- p.v / List of abbreviations --- p.vii / Abstract --- p.viii / Chapter Ch 1 --- Introduction --- p.1 / Chapter 1.1 --- Embryology --- p.1 / Chapter 1.1.1 --- Embryology of amniotic cavity --- p.1 / Chapter 1.1.2 --- Embryology of kidney and bladder --- p.3 / Chapter Ch 2 --- Background: What is already known about amniotic fluid volume? --- p.7 / Chapter 2.1 --- Normal physiology --- p.7 / Chapter 2.1.1 --- The origin of amniotic fluid: Where does it come from? --- p.8 / Chapter 2.1.2 --- Where does the amniotic fluid go? How reabsorbed? --- p.14 / Chapter 2.1.3 --- How is amniotic fluid volume controlled? --- p.18 / Chapter 2.2 --- Abnormal physiology --- p.26 / Chapter 2.2.1 --- Too much liquor: polyhydramnios --- p.26 / Chapter 2.2.2 --- Too little liquor: oligohydramnios --- p.28 / Chapter 2.2.3 --- Diseases and gender differences that may be related to parity and amniotic fluid volume --- p.30 / Chapter 2.3 --- Techniques of measuring amniotic fluid volume --- p.32 / Chapter 2.3.1 --- History --- p.32 / Chapter 2.3.2 --- Current most popular technique: amniotic fluid index --- p.38 / Chapter 2.4 --- Summary of what is known and not yet known about amniotic fluid volume --- p.48 / Chapter Ch 3 --- Aims of this study --- p.49 / Chapter Ch4 --- Method --- p.50 / Chapter 4.1 --- Equipment --- p.50 / Chapter 4.2 --- Subject selection criteria --- p.50 / Chapter 4.2.1 --- Criteria --- p.50 / Chapter 4.2.2 --- Total number of subjects studied --- p.51 / Chapter 4.2.3 --- Total number of subjects selected fulfilling all criteria --- p.51 / Chapter 4.2.4 --- Subject preparation --- p.52 / Chapter 4.3 --- Technique --- p.53 / Chapter 4.3.1 --- "Standard measurement of BPD， AC, FL and EFW" --- p.53 / Chapter 4.3.2 --- Standard measurement of Doppler --- p.54 / Chapter 4.3.3 --- Amniotic fluid index --- p.55 / Chapter 4.3.4 --- Bladder volume --- p.59 / Chapter 4.3.5 --- Fetal renal pelvis --- p.61 / Chapter 4.3.6 --- Intra-observer error techniques and calculation --- p.63 / Chapter 4.4 --- Techniques used in analysis --- p.65 / Chapter Ch5 --- Results --- p.67 / Chapter 5.1 --- Fetal parameters --- p.68 / Chapter 5.1.1 --- Fetal biparietal diameter (BPD) --- p.68 / Chapter 5.1.2 --- Fetal abdominal circumference (AC) --- p.69 / Chapter 5.1.3 --- Fetal femur length (FL) --- p.70 / Chapter 5.1.4 --- Pulsatility index values of umbilical artery --- p.71 / Chapter 5.1.5 --- Birth weight (BW) --- p.74 / Chapter 5.1.6 --- Estimated fetal weight --- p.76 / Chapter 5.2 --- Amniotic fluid index --- p.79 / Chapter 5.2.1 --- Amniotic fluid index-overall --- p.79 / Chapter 5.2.2 --- Amniotic fluid index-male and female --- p.81 / Chapter 5.2.3 --- The ten segments of amniotic fluid index distribution --- p.83 / Chapter 5.2.4 --- Amniotic fluid index relationship to estimated fetal weight --- p.86 / Chapter 5.2.5 --- Amniotic fluid index with gravidity and parity --- p.89 / Chapter 5.2.6 --- Amniotic fluid index with estimated fetal weight of different parity (best fit line) for both male and female --- p.93 / Chapter 5.3 --- Fetal urinary bladder volume (BV) --- p.96 / Chapter 5.3.1 --- Bladder volume-overall --- p.96 / Chapter 5.3.2 --- Bladder volume-male and female --- p.97 / Chapter 5.3.3 --- Bladder volume with estimated fetal weight- overall --- p.100 / Chapter 5.3.4 --- Bladder volume with estimated fetal weight in both male and female --- p.101 / Chapter 5.3.5 --- Bladder volume with gravidity and parity --- p.103 / Chapter 5.3.6 --- Bladder volume with amniotic fluid index --- p.105 / Chapter 5.4 --- Anteroposterior diameter of the fetal renal pelvis --- p.106 / Chapter 5.5 --- Hydronephrosis index values --- p.107 / Chapter Ch 6 --- Discussion --- p.108 / Chapter 6.1 --- Review of the study --- p.108 / Chapter 6.2 --- Discussion on subject --- p.111 / Chapter 6.2.1 --- Gestational age chosen --- p.111 / Chapter 6.2.2 --- Subject preparation --- p.112 / Chapter 6.3 --- Discussion of method --- p.114 / Chapter 6.3.1 --- Equipment --- p.114 / Chapter 6.3.2 --- Technique --- p.117 / Chapter 6.4 --- Discussion on results --- p.128 / Chapter 6.4.1 --- Normality of population --- p.128 / Chapter 6.4.2 --- Low birth weight/ IUGR in Chinese and Caucasian --- p.129 / Chapter 6.4.3 --- Cut-off points to detect oligohydramnios and polyhydramnios --- p.132 / Chapter 6.4.4 --- Amniotic fluid index-relationship with fetal weight --- p.143 / Chapter 6.4.5 --- Amniotic fluid index-relationship to parity --- p.145 / Chapter 6.4.6 --- "Relationship between gender, estimated fetal weight and amniotic fluid index" --- p.147 / Chapter 6.4.7 --- Parity and cut-off points for oligohydramnios and polyhydramnios --- p.150 / Chapter 6.4.8 --- Relationship of amniotic fluid volume to urinary function --- p.152 / Chapter Ch 7 --- Conclusions --- p.157 / References --- p.159

Este estudo teve por objetivos analisar a experiência do cateterismo vesical intermitente por crianças e adolescentes portadores de bexiga neurogênica e suas mães, bem como analisar os fatores limitantes e facilitadores para o autocateterismo vesical intermitente nessas crianças e adolescentes na realidade das suas vidas cotidianas. No referencial teórico, buscamos a compreensão dessa construção da realidade, do cuidar/cuidado humano como uma questão de cidadania e valorização da vida nesse cotidiano, e a educação em saúde como uma prática de enfermagem para a valorização do cuidar cuidado. A pesquisa é de natureza qualitativa, aplicando as representações sociais como categoria de análise. Para a coleta dos dados, utilizamos os prontuários das crianças, formulário com questões semi-estruturadas, entrevista e diário de campo. A análise dos dados baseou-se em aspectos da hermenêutica dialética. A interposição das categorias empíricas com o referencial teórico fez emergir dimensões que mostraram esses atores sociais pertencentes a um contexto micro e macro social que determinam o seu modo de agir na e para a vida. A realidade no dia-a-dia das crianças, adolescentes e respectivas mães revelou-se em seis categorias empíricas: “CVI – corpo e sexualidade em evidência” e “CVI – conformação e relutância” são as categorias empíricas que traduzem as falas das crianças e adolescentes; “A responsabilização materna”, “A agenda da vida”, “O enfrentamento” e “A acomodação/compartilha” são as categorias empíricas que surgiram das falas das mães. Nessas seis categorias, revelam-se importantes elementos limitantes e facilitadores à experiência de cuidar da vida e, conseqüentemente, à experiência do autocateterismo pelas crianças e adolescentes. Cabe aos profissionais de saúde e em especial ao enfermeiro uma atitude solidária, num esquema de co-responsabilidade por meio da educação em saúde, que deverá ser desenvolvida como um processo emancipatório que, além do enfoque biológico, dê importância considerável aos aspectos ligados à vida cotidiana e amplie a consciência de cidadania desses atores sociais para viverem de modo mais pleno nos seus limiares próprios. / This study is aimed at analyzing the experience of intermittent vesical catheterism of children and adolescents with neurogenic bladders and their mothers, as well as analyzing limiting and facilitating factors for intermittent vesical autocatheterism in these children and adolescents in their daily lives. As for theoretical referentials, we sought to understand this construction of reality in human care as a matter of citizenship and valorization of life in this daily life; moreover, the health education as nursing practice on these values were the theoretical reference used in this study. This research is of a qualitative nature applying social representations as an analysis category. For data collection, we used children's reference books, forms with semi-structured questions, interviews and field diaries. The data analysis was based on aspects of dialectic hermeneutics. The interposition of empirical categories with the theoretical basis led to the appearance of dimensions which showed these social actors belonging to a micro- and macro-social context which determines their way of acting in and for life. The children's, adolescents' and their mothers' daily reality was revealed through six empirical categories: “CVI – body and sexuality in evidence" and “CVI – conformation and reluctance” are empirical categories which translate children's and adolescents' speech; “Maternal responsibility”, “Life agenda”, “Confrontation” and “Acceptance / sharing” are empirical categories which arose from the mothers' speech. In these six categories, important limiting and facilitating elements for the experience of taking care of life are revealed and, consequently, for autocatheterism by children and adolescents. It is the responsibility of the health professional, and especially of the nurse, to express a supportive attitude in a scheme of co-responsibility by means of health education, which should be developed as an emancipatory process which, besides the biological focus, values the aspects related to daily life and increases the citizenry conscience of these social actors so that they can live more fully according to their own thresholds.

O câncer de bexiga é uma neoplasia urogenital que acomete homens e mulheres, sendo que somente no Brasil 8.600 novos casos ao ano são diagnosticados. Cistoscopia transuretral é a conduta padrão no diagnóstico e acompanhamento do câncer de bexiga. Entretanto, tal procedimento é extremamente invasivo e doloroso além de ter elevado custo e não garantir todos os resultados. Assim, busca-se por marcadores moleculares que possam auxiliar no diagnóstico e progressão do câncer de bexiga, bem como diminuir a necessidade de exames invasivos no acompanhamento de pacientes tratados. Nesse sentido, a urina tem papel de destaque como fonte de biomarcadores devido principalmente ao seu caráter não invasivo. <br /> Nesse trabalho foram utilizadas duas abordagens \'ômicas\': proteômica e metabolômica, para a busca de biomarcadores em urina para o diagnóstico e prognóstico do câncer de bexiga, respectivamente. Com a abordagem proteômica buscou-se apenas por biomarcadores para o diagnóstico da doença e, utilizando as técnicas de eletroforese 2-DE, OFFGEL e MS, juntamente com análise estatística multivariada, foi possível identificar 32 proteínas que apresentam-se como potenciais marcadores para o câncer de bexiga. A abordagem metabolômica foi empregada para a busca de biomarcadores para reincidência e progressão da doença. As técnicas analíticas utilizadas nessa abordagem, LC-MS e CE-MS, mostraram-se complementares e, dos resultados obtidos com ambas e avaliados com análise estatística multivariada foi possível indicar 19 metabólitos para reincidência e 23 metabólitos para progressão do câncer de bexiga. <br /> Assim, neste trabalho explorou-se como as ciências \'ômicas\', a qual abrange técnicas analíticas de high-throughput, estatística multivariada e ferramentas de bioinformática auxiliando na descoberta de potenciais biomarcadores não invasivos para o diagnóstico e prognóstico do câncer de bexiga. Portanto, o presente estudo foi de grande importância e relevância à medida que ilustrou como tais técnicas podem potencialmente auxiliar no diagnóstico e prognóstico de doenças e contribuir para tratamentos personalizados no futuro, indicando a potencialidade de estudos dessa natureza. / Bladder cancer is an urogenital cancer affecting men and women, and just in Brazil 8,600 new cases are diagnosed annually. Transurethral cystoscopy is a standard conduct in the diagnosis and monitoring of bladder cancer. However, this procedure is extremely invasive, painful, expensive and does not guarantee the best results. Thus, the searching for molecular markers may assist in the diagnosis and monitoring of bladder cancer, as well as decreasing the need for invasive tests in the monitoring of patients treatment. In this way, urine shows an important role as a source of biomarkers, mainly due to its non-invasive nature. <br /> In this work we used two \'omics\' approaches: proteomics and metabolomics, to search for biomarkers in urine for the diagnosis and progression of bladder cancer, respectively. The proteomics approach was explored for biomarkers for diagnosing disease. Using 2-DE, OFFGEL electrophoresis, and MS techniques, as well multivariate statistical analysis, they were identified 32 proteins that may be pointed as potential markers for bladder cancer. The metabolomics approach was used to search for biomarkers for progression and recurrence of the disease. The analytical techniques used for this approach, LC-MS and CE-MS, were complementary to each other and the results evaluated with multivariate statistical analysis indicated that 19 metabolites for recurrence and 23 metabolites for progression of bladder cancer could possibly be used for validation studies. <br /> Thus, we demonstrated how the \'omics\' sciences, which include high- throughput analytical techniques, multivariate statistical analysis, and bioinformatics tools, aid in the discovery of potential biomarkers for noninvasive diagnosis, evaluate recurrence and monitor progression of bladder cancer. Therefore, this study was of high relevance to demonstrate the potential of such techniques to contribute to studies of personalized medicine.

Interstitial cystitis (IC)/painful bladder syndrome (PBS) is a functional visceral disorder characterized by increased bladder activity and chronic pelvic pain in the absence of a pathobiological condition. Enhanced sensory transduction of peripheral bladder afferents is hypothesized to contribute to the pain and mechanical hypersensitivity of IC/PBS patients. The aim of this thesis is to test the hypothesis that purinergic receptors, including ionotropic P2X and metabotropic P2Y, are important for sensory transmission in bladder afferent neurons and may be involved in bladder hypersensitivity after bladder tissue insults. Electrophysiological, single cell RT-PCR and immunohistochemistry techniques were performed in bladder afferent neurons from naïve and bladder inflamed mice to test the hypothesis. In Chapter 2, I characterized the distribution and function of P2X receptors in thoracolumbar (TL) and lumbosacral (LS) dorsal root ganglia (DRG) neurons innervating the urinary bladder, and found that LS and TL bladder neurons have differential purinergic signaling and distinct membrane electrical properties. In Chapter 3, I examined the sensitization of bladder afferent neurons and the plasticity of P2X receptor function in a mouse model of chemical induced bladder inflammation. P2X-mediated signals in LS and TL bladder neurons after bladder inflammation were enhanced compared with those in saline-treated controls, suggesting the importance of P2X in bladder hypersensitivity associated with cystitis. In Chapter 4, the modulation of P2Y on P2X function and the co-localization of P2Y and P2X were examined in bladder sensory neurons. It has been found that P2Y2 receptor enhances bladder sensory neuron excitability and facilitates the response of homomeric P2X2 receptor to the purinergic agonist (ATP). The present study provides evidence that LS and TL mouse bladder sensory neurons exhibit distinct P2X signaling, and the function of P2X receptors could be facilitated during bladder inflammation and modulated by activation of P2Y2 receptor, indicating an involvement of P2X and P2Y2 receptors as mechano- and chemosensors in bladder sensory transmission under normal conditions and in bladder hypersensitivity associated with inflammation.