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BACKGROUND:Neurogenic detrusor overactivity (NDO) leads to impaired health-related quality of life (HRQoL), productivity, and greater healthcare resource burden. The humanistic and economic burden may be more apparent in NDO patients with urinary incontinence (UI). The objective of this study was to compare the HRQoL, productivity, and health resource use (HRU) between continent and incontinent NDO patients.METHODS:A retrospective database analysis was conducted using the Adelphi Overactive Bladder (OAB)/UI Disease Specific Programme, a multi-national, cross-sectional survey reported from both patients' and physicians' perspectives. The population for this analysis included NDO patients with or without UI. General and disease-specific HRQoL were assessed using the EuroQoL-5D (EQ-5D), Incontinence Quality of Life questionnaire (I-QOL), and the Overactive Bladder Questionnaire (OAB-q). Productivity and daily activity impairment were measured using the Work Productivity and Activity Impairment (WPAI) questionnaire. HRU indicators included OAB-related surgery, OAB-related hospitalizations, incontinence pad usage, switching anticholinergics used for OAB due to inadequate response or adverse effects, and OAB-related physician visits. Bivariate analyses, multivariate ordinary least squares (OLS) regression analyses and published minimal clinically important differences (MCID) were used to assess relationships between incontinent status and the aforementioned outcome measures.RESULTS:A total of 324 NDO patients with or without urinary incontinence were included, averaging 54years of age (SD 16), of whom 43.8 percent were male. Bivariate analyses detected no significant relationship between incontinent status and HRU variables. Regression analyses revealed that incontinent patients had clinically and statistically lower disease-specific HRQoL and greater impairment in daily activities as compared to continent patients. On average, incontinent patients scored 10 points lower on the I-QOL total score, 9 points lower on the OAB-q HRQoL score, 15 points higher on OAB-q symptom severity, and experienced 8.2 percent higher activity impairment due to their bladder condition (all p <0.001).CONCLUSIONS:Incontinent NDO patients experience significantly lower HRQoL and activity impairment as compared to continent NDO patients.

OBJETIVOSLos objetivos eran estudiar la fiabilidad y reproductibilidad de la morfometría del detrusor mediante la valoración del diámetro del miocito y la cuantificación de la ratio colágeno/músculo, estudiar las diferencias entre pacientes con obstrucción infravesical y los varones control y analizar las diferencias, tanto morfológicas como funcionales, de los pacientes obstruidos en función del antecedente de retención urinaria aguda.PACIENTES Y MÉTODOSSe realizó un estudio prospectivo sobre 62 pacientes que se dividieron en tres grupos, pacientes con clínica y diagnóstico urodinámico de obstrucción infravesical (grupo Obstrucción), pacientes con clínica y diagnóstico urodinámico de obstrucción infravesical y antecedentes de episodio de retención urinaria aguda (grupo RAO) y pacientes sin obstrucción infravesical (grupo Control). El estudio fue aprobado por el Comité de Ensayos e Investigación Clínica de la Fundación Puigvert y todos los pacientes firmaron el consentimiento informado para participar en él. Como valoración funcional se realizó un cuestionario de síntomas (IPSS y Calidad de vida) y un estudio urodinámico. El estudio morfométrico se realizó a partir de muestras de detrusor obtenidas durante la resección transuretral (RTU) de próstata (pacientes del grupo Obstrucción y RAO) y RTU de tumor vesical inicial (grupo Control). Tras digitalización de la imagen de microscopía óptica, se valoró el diámetro del miocito y la relación o ratio entre colágeno y músculo (interfascicular y pericelular). Finalmente se realizó un estudio evolutivo funcional temprano a los 6 meses de la cirugía desobstructiva.RESULTADOSSe valoraron un total de 62 pacientes, con una edad media de 63 años. Los pacientes con obstrucción infravesical y antecedentes de RAO tenían una menor puntuación en la escala de síntomas y un mayor residuo postmiccional en la flujometría. En la valoración morfométrica, los pacientes con obstrucción infravesical (grupo Obstrucción y RAO) tenían un mayor diámetro del miocito (hipertrofia), así como una mayor ratio colágeno/músculo (fibrosis). Entre el grupo Obstrucción y RAO no se observaron diferencias en el diámetro del miocito y si un mayor infiltrado de colágeno pericelular en el grupo RAO. Tras la cirugía desobstructiva no se observaron diferencias evolutivas entre los pacientes del grupo Obstrucción y RAO. Existía una relación entre el diámetro del miocito y la recuperación funcional, pero no con la ratio colágeno/músculo. CONCLUSIONESLa morfometría del detrusor mediante medición del diámetro del miocito y cuantificación de la ratio colágeno/músculo es una técnica fiable y reproducible. En la obstrucción infravesical existe una hipertrofia del miocito y una fibrosis del detrusor. Existen diferencias morfométricas en los pacientes con obstrucción infravesical en función del antecedente de retención urinaria aguda y no existen diferencias funcionales previas a la cirugía desobtructiva ni en la evolución postoperatoria temprana. / OBJECTIVESThe objectives were to study reability and efficacy of bladder morphometry by means of measurement of the diameter of detrusor cell and connective tissue-to-smooth muscle ratio, to study differences between bladder outlet obstruction (BOO) and group control and to study morphometric and urodynamic differences in patients with bladder outlet obstruction relation to episode of acute urinary retention (AUR).PATIENTS AND METHODSSixty-two patients were included. There was three groups; control group, BOO group (lower urinary tracts symptoms and urodynamic bladder outlet obstruction) and AUR group (lower urinary tracts symptoms, urodynamic bladder outlet obstruction and episode of acute urinary retention). Study was accepted by committee of clinical studies of Fundación Puigvert. All patients were informed and they sign written consent. Functional study was made by symptoms (IPSS and quality life) and urodymanic study. Detrusor specimens were obtained from the lateral-posterior wall bladder after finish TURP (BOO and AUR groups) and bladder tumor resection (control group). Each section was viewed under a microscope and digitized using a personal computer. The diameter of detrusor muscle cell and connective tissue-to-smooth muscle ratio (between and within muscles fascicles) was measured. Six months after surgery urodynamic studies was repeat to evaluate patient evolution.RESULTSSixty-two patients were included (mean age, 63 years). Score IPSS was lower in AUR group than in BOO group and postvoid residual volume was higher in AUR group in flowmetry. The diameter of the detrusor muscle cell and connective tissue-to-smooth muscle ratio determined by morphometry (between muscle fascicles) was higher in BOO and AUR group than control group. In patients with BOO (BOO and AUR group) no differences exist relation to an episode of acute urinary retention. However, in AUR group the connective tissue-to-smooth muscle ratio within fascicles was higher than BOO group. There were no differences in postoperative TURP between BOO and AUR groups. There was relation between diameter of the detrusor muscle cell and functional recovery after TURP. There was no relation between connective tissue-to-smooth muscle ratio and functional recovery after TURP.CONCLUSIONSMeasurement of the diameter of detrusor cells and connective tissue-to-smooth muscle ratio is useful to study bladder morphometry. There was increase in the diameter of detrusor muscle cell (hypertrophy) and connective tissue-to-smooth muscle ratio (fibrosis) in BOO. There was morphometric differences in patients with bladder outlet obstruction relation to episode of acute urinary retention. There was no functional and postoperative differences in patients with bladder outlet obstruction relation to episode of acute urinary retention.

Orientador: Edson Antunes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-13T02:36:06Z (GMT). No. of bitstreams: 1 Monica_FabiolaZakiaTaufic_D.pdf: 2654981 bytes, checksum: c328869077bc46f3d7418b53ed54d2aa (MD5) Previous issue date: 2009 / Resumo: A bexiga urinária recebe inervação autonômica simpática e parassimpática, que atuam conjuntamente para a manutenção do ciclo normal da micção; ou seja, para a fase de enchimento e de esvaziamento. O mediador primário para a contração muscular do músculo liso detrusor é a acetilcolina (Ach), sendo suas ações mediadas, principalmente, pelos receptores muscarínicos dos subtipos M2 e M3, cuja densidade é maior no corpo em comparação à base da bexiga. O músculo detrusor também é inervado por fibras NANC nitrérgicas, mas a função do NO neste tecido ainda não está bem definida. Com o objetivo de investigar se a inibição crônica do NO acarreta alterações funcionais, morfológicas e moleculares do músculo liso detrusor isolado da bexiga urinária de rato utilizamos ratos adultos machos WISTAR (200-350 g), tratados cronicamente L-NAME, na dose de 20 mg/rato/dia durante 7, 15 e 30 dias. Avaliamos os seguintes parâmetros: 1) Atividade da sintase de óxido nítrico (NOS) em bexiga urinária; 2) a dosagem de nitrito/nitrato (NOx) plasmáticos; 3) a resposta contrátil aos agentes carbacol (agonista muscarínico), cloreto de potássio (KCl), cloreto de cálcio (CaCl2) e à estimulação elétrica (1-32 Hz, 80 V, 10 segundos) assim como a resposta relaxante a agonistas beta (?)-adrenérgicos; a dosagem de fosfatos de inositol; 5) a determinação dos parâmetros de KD e Bmax, 6) análise histológica quantitativa das camadas do músculo liso detrusor e trígono. Fragmentos do músculo detrusor foram adaptados em câmaras para órgãos isolados, contendo solução de Krebs-Henseleit e, após o período de equilíbrio, realizamos curvas concentração efeito cumulativas ao carbacol (0,001-10 µM), isoproterenol, metaproterenol e BRL- 37-344 (0,0001-100 µM), ao CaCl2 (0,01-100 mM) e KCl (20-200 mM). Nossos dados mostraram que a inibição crônica de NO aumentou a potência (pEC50) ao carbacol nos períodos de 15 e 30 dias de tratamento com L-NAME, sendo esse aumento cinco vezes maior aos trinta dias de tratamento (6.82±0.06) comparando-se com o respectivo grupo controle (6.09±0.02). Não observamos alterações da resposta máxima (Emax). Este aumento da sensibilidade ao agonista muscarínico pode ser explicado, em parte, pelo aumento do acúmulo de fosfato de inositol, que foi seis vezes maior nos ratos tratados com LNAME por 30 dias em comparação ao respectivo grupo controle. Entretanto, nos ensaios de saturação, o número de receptores (Bmax) não se mostrou alterado, porém, observamos que o tratamento com L-NAME aumentou em, aproximadamente, duas vezes o valor da constante de afinidade (KD) aos receptores muscarínicos em relação ao grupo controle. Observamos que a resposta relaxante ao agonista ?3 (BRL 37-344) mostrou-se diminuída nos ratos tratados com L-NAME, sem alterações na reposta ao isoproterenol e metaproterenol. A análise histológica quantitativa da bexiga urinária revelou que a camada muscular do trígono dos ratos tratados com L-NAME estava 28 % mais espessa em relação à do grupo controle, sem alterações na camada do detrusor. Não foram vistas alterações nas contrações mediadas pelo CaCl2 e nem ao KCl em ambos os grupos. A estimulação elétrica (1-32 Hz, 80 V, duração estímulo 10 s) produziu contrações dependentes da frequência em ambos os grupos, sendo que na freqüência de 32 Hz obtivemos a resposta máxima. Entretanto, nos ratos tratados com L-NAME não foram observadas alterações nas amplitudes das contrações em relação ao respectivo grupo controle. A adição do antagonista purinérgico, suramin (100 µM), reduziu as amplitudes das contrações; porém, a resposta do grupo L-NAME não se alterou em relação ao grupo controle. Nossos dados mostram que a inibição crônica de NO levou à redução da resposta relaxante mediada por agonista ?3-adrenérgico e aumento da sensibilidade aos agonistas muscarínicos. As alterações observadas na resposta muscarínica é devido ao aumento do segundo mensageiro. Além disso, aventamos a hipótese que a hipersensibilidade do detrusor a agonistas muscarínicos pelo bloqueio crônico de NO passa ser secundária à hipertrofia do músculo liso trígono (mas não do trígono) e à deficiência do NO em nível de uretra, levando assim a um detrusor hiperativo / Abstract: The urinary bladder is innervated by parassimpathetic and sympathetic fibers, which both contribute to the maintenance of the normal micturition cycle: the voiding and filling phase. Acethylcholine (ACh) is the main neurotransmitter responsible for the detrusor smooth muscle contraction, acting mainly at the muscarinic M2 and M3 subtypes. The detrusor smooth muscle is also innervated by the non adrenergic non cholinergic (NANC) nitrergic fibers, although the exactly mechanism of nitric oxide (NO) in this region is not well established. The aim of the present study was to investigated the functional, morphological and biochemical alterations in isolated detrusor smooth muscle after chronic NO inhibition. Male Wistar rats received N - nitro-L-arginine methyl ester (L-NAME) for 7 to 30 days. The following assays were carried out: 1) NO synthase activity; 2) plasma nitrite and nitrate (NOx) measurement; 3) functional assays to muscarinic, b-adrenoceptor agonists, potassium chloride (KCl) calcium chrolide (CaCl2) and electrical field stimulation; 4) Measurements of [3H]-inositol phosphate; 5) [3H]QNB binding assay to determine the dissociation constant (KD) and the maximum specific binding (Bmax) and 6) bladder morphology. Detrusor smooth muscle strips were mounted in organ baths, containing Krebs-Henseliet at 37oC and aerated with 95% O2 and 5% CO2. Each tissue was connected to an isometric transducer. After the stabilization period concentration responses curves to carbacol (0.001-10 µM), isoproterenol, metaproterenol and BRL 37-344 (0.0001-100 µM), KCl (20-200 mM) and CaCl2 (0.01-100 mM) were carried out. Our data showed that chronic NO inhibition has increased the potency values for carbachol after 15 and 30 days of treatment, being this increase 5-fold higher at 30 days (6.82 ± 0.06) when compared to the control group (6.09 ± 0.09). This alterations in the sensitivity for carbachol could be explained, in part, by the 6-fold increase in [3H]-inositol phosphate in bladder from LNAME in comparison with the control group. Although no alterations on the Bmax values were seen, a 2-fold increase in the KD values was observed. At 30 days, detrusor smooth muscle relaxing responses to b3-adrenoceptor agonist BRL 34-377 was significantly reduced by L-NAME, whereas the relaxing responses to isoproterenol and metaproterenol were not modified. The constitutive NO synthase activity was reduced by 86% in bladder at 7-days L-NAME treatment, which was maintained up to 30 days. No morphological alterations in detrusor smooth muscle were found; however in the trigone smooth muscle, L-NAME treatment caused an increase, approximately 28%, in the thickness of the muscular layer. The amplitude of contraction induced by CaCl2 and KCl was not different in L-NAME treated group when compared to the control one. The contraction induced by electrical field stimulation (1-32 Hz, 80 V, 10 sec) was not different between the treated and non treated group; the addition of suramin, a non selective purinergic antagonist, significantly reduced the amplitude of contraction on both groups; however, no difference on the amplitude response between these groups was observed. Long-term NO-deficiency increases rat DSM contractile responses mediated by muscarinic agonist that are accompanied by significant enhancement in KD values for muscarinic receptors and [3H]-inositol phosphate accumulation in bladder. This supersensitivity for muscarinic agonists along with reductions of b3-adrenoceptormediated relaxations indicates that overactive DSM results from chronic NO deficiency. It is plausible to suggest that chronic NO deficiency at the level of trigone (and/or urethra) triggers a persistent contraction leading in turn to a DSM overactive / Doutorado / Doutor em Farmacologia

Orientador: Fernandes Denardi / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-20T19:06:19Z (GMT). No. of bitstreams: 1 Souto_SophiaConsuelo_D.pdf: 3071045 bytes, checksum: afe55b12d7449fe8664becdbca0eec4a (MD5) Previous issue date: 2012 / Resumo: Introdução: Conforme a Sociedade Internacional de Continência (ICS), o diagnóstico clínico da bexiga hiperativa (BH) é baseado nos sintomas de urgência miccional, com ou sem incontinência de urgência, acompanhado de aumento da frequência miccional e noctúria, na ausência de fatores patológicos ou metabólicos, que explicariam estes sintomas. O tratamento através do relaxamento da musculatura vesical visa diminuir a frequência miccional diurna e noturna, aumentar o volume urinado e diminuir os episódios de urgência e incontinência de urgência. Objetivo: Comparar a eficácia do tratamento farmacológico com a estimulação do nervo tibial posterior e a associação de ambos nos sintomas de bexiga hiperativa. Pacientes e Métodos: Foram randomizado 75 mulheres com sintomas clínicos de bexiga hiperativa, divididas em 3 grupos de 25 pacientes, grupo I (G I) - eletroestimulação do nervo tibial posterior (EENTP), grupo II (G II) - oxibutinina e grupo III (G III) - eletroestimulação + oxibutinina (Multimodal). Todas pacientes responderam os questionários "International Consultation on Incontinence Short-Form" (ICIQ-Short-Form) e "International Consultation on Incontinence-OAB" (ICIQ-OAB) para avaliar a presença de incontinência urinária e os sintomas de bexiga hiperativa com escala analógica de zero a dez para quantificar o impacto causado por cada sintoma na qualidade de vida, e preencheram um diário miccional de três dias. Foram reavaliadas após o tratamento. Resultados: Foram analisados os dados de 58 pacientes, com idade média de 58 anos (p=0.76) A média de frequência urinária, noctúria e incontinência urinária não apresentou diferença estatisticamente significativa entre os grupos. Durante avaliação com questionário ICIQ-SF, o escore médio inicial não apresentou diferença estatisticamente significativa entre os grupos (p=0.88). Após o tratamento todos os grupos tiveram diminuição dos escores (p=0.31). Na avaliação após 3 meses do término do tratamento, as pacientes do G II apresentaram aumento do escore (p=0.0006). Na avaliação com questionário ICQ-OAB, o escore médio inicial não apresentou diferença entre os grupos (p=0.15). Após o tratamento, o G III apresentou melhora dos sintomas superior ao G I (p=0.01). Após 3 meses do término do tratamento, o G II teve aumento significativo do escore (p<0.0001). A média do incomodo dos sintomas na avaliação inicial não apresentou diferença entre os grupos (p=0.92). Após o tratamento todas tiveram diminuição do incomodo (p=0.06). Após 3 meses do tratamento as pacientes do G III apresentavam menor incomodo dos sintomas, em seguida as pacientes do G I e depois as do G II com incomodo maior (p<0,0001). Conclusão: O tratamento multimodal mostrou-se mais eficaz para melhora dos sintomas clínicos de bexiga hiperativa e diminuição do incomodo causado por eles, que o tratamento fisioterapêutico e a oxibutinina isoladamente / Abstract: Introduction: According to the International Continence Society (ICS), the clinical diagnosis of overactive bladder (OAB) is based on symptoms of urinary urgency, with or without urge incontinence, accompanied by increased urinary frequency and nocturia in the absence of pathological or metabolic factors, that would explain these symptoms. The aim of the treatment is to decrease the daytime and nighttime urinary frequency, increase voided volume and decrease episodes of urgency and urge incontinence by relaxing the bladder muscle. Objective: The objective of this study was to compare the efficacy of pharmacological treatment and the stimulation of the posterior tibial nerve, and the association of both, in the symptoms of overactive bladder. Patients and Methods: A total of 75 women with clinical symptoms of overactive bladder were randomized, divided into three groups; 25 in Group I - electrical stimulation of the posterior tibial nerve (PTNS), 25 in group II - oxybutynin and 25 in group III - electro + oxybutynin (Multimodal). During the evaluation all patients answered the questionnaires "International Consultation on Incontinence-Short Form" (ICIQ-Short-Form) to assess the presence of incontinence, and "International Consultation on Incontinence-OAB" (ICIQ-OAB) to assess symptoms of overactive bladder with analogue scale from zero to ten to quantify the impact of each symptom on quality of life, and completed a three-day voiding diary. The same tools were used for further evaluation after the treatment. Results: It was analyzed data from 58 patients, the average age of patients was 58 years (p=0,76). The mean urinary frequency, nocturia and urinary incontinence no evidenced statistically significant difference between groups. During evaluation with questionnaire ICIQ-SF, the average initial score no evidenced difference between groups (p=0,88). After treatment, all groups had a decrease in scores (p=0,31). In the evaluation after three months of the end of treatment, patients in GII had an increase in score (p=0,0006). In the evaluation with ICQ-OAB questionnaire, the average initial score no evidenced difference between groups (p=0,15). The evaluation after treatment G III evidenced improvement in symptoms than the G I (p=0,01). When assessed after 3 months after the end of treatment, the G II had significant increase in score (p<0,0001). The average symptom bother of patients at baseline evidenced no difference between groups (p=0,92). After treatment all of them evidenced a lower symptom bother score (p=0,06). And when reassessed after 3 months of treatment the G III patients had the lowest average symptom bother score, then the GI patients and then those of G II with higher symptom bother score (p<0,0001). Conclusions: The multimodal treatment was more effective in the management of symptom bother of patients than physical therapy or medication alone / Doutorado / Fisiopatologia Cirúrgica / Doutor em Ciências

Please read the abstract in the section 00front of this document / Dissertation (MSc (Anatomy))--University of Pretoria, 2001. / Anatomy / unrestricted

L’exagération de l’activité contractile spontanée (ACS) et les tumeurs de vessie (TV) sont des modifications morphologiques vésicales observées à moyen et long terme chez les patients ayant une hyperactivité détrusorienne neurogène. Cependant la carcinogénèse vésicale chez les patients neurologiques n’a jamais été étudiée à ce jour et la signification de l’ACS est non élucidée. Nos buts étaient d’étudier la carcinogénèse des vessies neurologiques (en particulier le rôle de l’inflammation chronique) et d’étudier les mécanismes de l’ACS.Nous rapportons que l’expression immunohistochimique de Foxp3 est caractéristique des patients neurologiques ayant une TV agressive de différenciation épidermoïde. Ainsi Foxp3 pourrait être une cible pour le développement d’immunothérapies anti-tumorales. Par une étude en bains d’organes sur des fragments de vessies fraîches issus de patients ayant une hyperactivité détrusorienne neurogène réfractaire, nous observons que l’ACS vésicale in vitro est corrélée à l'âge et la présence de muqueuse vésicale. La modulation pharmacologique de la communication intercellulaire médiée par les connexines 40, 43 et 45 n’inhibe pas l’ACS. La traduction clinique de ces résultats préliminaires est encore difficile. Cependant la compréhension de la signification de l’ACS pourrait identifier de nouvelles voies thérapeutiques pour l’hyperactivité détrusorienne neurogène. Nos résultats ne peuvent pas être argumentés par la littérature encore pauvre à ce sujet. Ce programme de recherche innovant sur les modifications morphologiques à moyen et long terme des vessies neurologiques est poursuivi grâce à une collaboration nationale et à la transversalité des domaines d’expertises des chercheurs impliqués. / Increased spontaneous contractile activity (SCA) and bladder cancer are medium and long-term morphological changes of the bladder observed in patients with neurogenic detrusor overactivity. However, urothelial carcinogenesis in neurological patients has never been studied and the signification of ACS remains unknown. Our objectives were to study the bladder carcinogenesis in neurological patients (in particular the role of chronic inflammation), and the mechanisms of SCA in neurogenic bladders. We report that Foxp3 expression appears to be a characteristic of neurological patients presenting with aggressive bladder cancer and squamous cell differentiation. Thus, targeting Foxp3 may represent an interesting strategy to improve anti-tumor immunotherapy for bladder cancer. By conducting organ bath studies on bladder strips from patients with refractory neurogenic detrusor overactivity, we observe that the in vitro SCA may be modulated by age and the presence of mucosa. The pharmacological modulation of intercellular communication, targeting connexins 40, 43 and 45, cannot inhibit the SCA of neurogenic bladder strips. These results are still difficult to translate into clinical practice. However, understanding the origin of bladder SCA could help identify new therapeutic strategies for detrusor overactivity. Our results are still preliminary and cannot be supported by the literature due to paucity of data. This research program on medium and long-term morphological changes of human neurogenic bladders is pursued through a national collaboration and cross-disciplinary areas of expertise of the researchers involved.

Adipöse Patienten und Typ-2-Diabetiker zeigen ein erhöhtes Risiko für Harnwegsinfekte. Die Ursache der höheren Prävalenz ist noch nicht nachhaltig geklärt. Bekannt ist, dass Typ-2-Diabetiker erhöhte Konzentrationen freier Fettsäuren im Blut aufweisen. Der veränderte Fettstoffwechsel könnte neben bakteriellen Ursachen ein möglicher Grund für abakterielle Entzündungsreaktionen der Harnblase sein. Zur Prüfung dieser Hypothese wurden zeit- und konzentrationsabhängig kultivierte humane Detrusormyozyten im Vergleich zur Lipopolysaccharid (LPS) induzierten Entzündungsreaktion mit Palmitat stimuliert. Es wurde geprüft, ob eine autokrine und/oder endokrine Regulation des IL-6-Signalwegs vorliegt. Im Fokus standen insbesondere die IL-6- und MCP-1-Expression und deren möglichen regulatorischen Proteine gp80, gp130, NF-κB, STAT3, SOCS3 und MEK1. Die Stimulationsversuche mit LPS und Palmitat zeigen einen differenten zeit- und konzentrationsabhängigen Effekt auf die IL-6- und MCP-1-Expression in den humanen Detrusormyozyten. LPS und Palmitat induzieren eine zeitabhängige autokrine Regulation der IL-6-Signalkaskade über phosphoryliertes STAT3 und Feedback-mechanismen via SOCS3. Sowohl LPS als auch Palmitat bewirken über 48h eine mögliche endokrine Regulation des IL-6-Signalwegs. Zusammenfassend zeigt die Palmitatstimulation zeit- und konzentrationsabhängig einen stärkeren Effekt auf die IL-6-Signalwirkung als die Stimulation mit LPS. / Background: Urinary tract infections (UTI) are more frequent in type-2 diabetes mellitus patients than in subjects with normal glucose metabolism. The mechanisms underlying this higher prevalence of UTI are unknown. However, cytokine levels are altered in diabetic patients and may thus contribute to the development of UTI. Increased levels of free fatty acids (FFA), as observed in obese patients, can induce IL-6 production in various cell types. Therefore we studied the effects of the free fatty acid palmitate and bacterial lipopolysaccharide (LPS) on interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) expression and secretion in cultured human bladder smooth muscle cells (hBSMC). Methodology/Principal Findings: Biopsies were taken from patients undergoing cystectomy due to bladder cancer. Palmitate or LPS stimulated hBSMC were analysed for the production and secretion of the IL-6, gp80, gp80soluble, gp130, MCP-1, pSTAT3, SOCS3, NF-kB and SHP2 by quantitative PCR, ELISA, Western blotting, and confocal immunofluorescence. In signal transduction inhibition experiments we evaluated the involvement of NF-kB and MEK1 in IL-6 and MCP-1 regulation. Palmitate upregulates IL-6 mRNA expression and secretion via NF-kB dependent pathways in a concentration- and timedependent manner. MCP-1 was moderately upregulated by palmitate but was strongly upregulated by LPS involving NF-kB and MEK1 dependent pathways. Soluble IL-6 receptor (gp80soluble) was downregulated by palmitate and LPS, while membrane-bound gp80 was moderately upregulated. LPS increased SOCS3 and SHP2, whereas palmitate only induced SOCS3. Secondary finding: most of the IL-6 is secreted. Conclusions/Significance: Bacterial infection (LPS) or metabolic alterations (palmitate) have distinct effects on IL-6 expression in hBSMC, (i) short term LPS induced autocrine JAK/STAT signaling and (ii) long-term endocrine regulation of IL-6 by palmitate. Induction of IL-6 in human bladder smooth muscle cells by fatty acids may represent a pathogenetic factor underlying the higher frequency and persistence of urinary tract infections in patients with metabolic diseases.

Introdução: A investigação dos sintomas do trato urinário inferior se inicia, geralmente, pela história, exame físico e testes clínicos simples. Entretanto, esta investigação, muitas vezes, se mostra insuficiente para o diagnóstico correto da incontinência urinária. Nestes casos, a avaliação, ou estudo, urodinâmica (o) é realizada para confirmação do diagnóstico. No entanto, o melhor método para avaliação urodinâmica ainda não foi bem estabelecido. Apesar de a cistometria convencional ser considerada padrão ouro, e ser o método mais aceito para investigação de hiperatividade detrusora, o método de enchimento (retrógrado) da urodinâmica convencional permanece controverso. Por ser um enchimento não fisiológico, vários estudos têm demonstrado altos índices de falsos negativos em relação ao diagnóstico de hiperatividade detrusora. Objetivo: Estimar a prevalência de hiperatividade detrusora durante avaliação urodinâmica ambulatorial de pacientes encaminhadas ao ambulatório de uroginecologia do Hospital de Clínicas de Porto Alegre com sintoma de urgência e avaliação urodinâmica convencional normal. Métodos: Estudo transversal, no qual foram incluídas mulheres com idade superior a 19 anos, apresentando queixa de urgência, urge-incontinência ou incontinência mista, atendidas no ambulatório de uroginecologia do Hospital de Clínicas de Porto Alegre e que já realizaram avaliação urodinâmica convencional, cuja cistometria não tenha detectado hiperatividade detrusora. O cálculo do tamanho da amostra foi realizado no programa WinPEPI (Programs for Epidemiologists for Windows) versão 11.43 , baseado nos achados de um estudo piloto com 6 pacientes. Para um nível de confiança de 95%, uma prevalência de hiperatividade em avaliação urodinâmica ambulatorial estimada em 83% e uma margem de erro de 17%, obtevese um total mínimo de 19 pacientes. O nível de significância adotado foi de 5% (p≤0,05) e as análises foram realizadas no programa SPSS versão 21.0. Resultados: Vinte pacientes com sintomas de urgência e cistometria convencional normal foram submetidas à avaliação urodinâmica ambulatorial. A média de idade foi de 56 anos. Os sintomas mistos de urgência e incontinência por esforço foram mais prevalentes do que sintomas puros de urgência (18/20). A prevalência de hiperatividade detrusora em avaliação urodinâmica ambulatorial de pacientes com sintoma de urgência e com avaliação urodinâmica convencional normal foi de 70% (14/20). O intervalo de 95% de confiança para a verdadeira prevalência na população é de 48% a 87% Conclusão: A avaliação urodinâmica ambulatorial parece ter um papel importante na avaliação adicional de casos mais complexos de pacientes com disfunções do trato urinário, quando há falha diagnóstica e terapêutica – em especial na avaliação de hiperatividade detrusora. Foi encontrado um falso negativo de 70% na avaliação urodinâmica convencional. No entanto, tendo em vista o maior custo do equipamento e das sondas em relação ao convencional, mais estudos são necessários para a incorporação deste exame na prática clínica brasileira. / Introduction: The investigation of lower urinary tract symptoms usually starts with the history, physical exam and simple clinical tests. However, quite often this investigation is not sufficient for the correct diagnosis of urinary incontinence. In these cases, the urodynamic test is accomplished to confirm it. The best method to evaluate the urodynamic has not been established. In spite of the conventional cystometry being considered as the gold standard and being the most accepted investigative method for detrusor overactivity, the conventional retrograde filling urodynamic method of remains controversial. Since it is a non-physiologic filling, several studies have shown high rates of false negatives concerning the diagnosis of detrusor overactivity. Objective: To estimate the prevalence of detrusor overactivity during ambulatory urodynamic tests in symptomatic patients whose results of conventional urodynamic evaluation were normal. Methodology: The research subjects were women referred to the urogynecology service of Hospital de Clínicas, Porto Alegre, Brazil for further investigation due to urinary incontinence symptoms (overactive bladder syndrome, urge incontinence or mixed incontinence), whose conventional urodynamics results did not show any detrusor overactivity. The sample size was calculated using the WinPEPI program (Programs for Epidemiologists for Windows) 11.43 version and was based on the findings of a pilot study with 6 patients. Using a 95% confidence interval and an estimated urodynamic detrusor overactivity prevalence of 83% with a standard error of 17%, a sample size of 19 patients was obtained. A level of significance of 5% (p≤0.05) was considered. SPSS 21.0 version program was used to accomplish the statistical analysis. Results: A total of 20 women were included in this study. The mean age was 56.1 years, the mean body mass index was 29.7 and the mean time of the symptoms was 5 years. We found mixed urinary incontinence in 18 (90%) and urge incontinence in 2 (10%) patients. All conventional cystometry tests were normal; however, in 14 (70%) patients the ambulatory urodynamics was able to diagnose detrusor overactivity. Conclusion: The ambulatory urodynamics evaluation seems to have a major role in the additional evaluation of more complex cases of urinary tract dysfunctions, when there is a diagnostic and therapeutic flaw – especially in the evaluation of detrusor overactivity. We found 70 % of false negative in the conventional cystometry. However, having in mind the higher cost of the equipment and catheters in relation to the conventional one, more studies are necessary for the incorporation of this test in the Brazilian clinical practice.

Introdução: A investigação dos sintomas do trato urinário inferior se inicia, geralmente, pela história, exame físico e testes clínicos simples. Entretanto, esta investigação, muitas vezes, se mostra insuficiente para o diagnóstico correto da incontinência urinária. Nestes casos, a avaliação, ou estudo, urodinâmica (o) é realizada para confirmação do diagnóstico. No entanto, o melhor método para avaliação urodinâmica ainda não foi bem estabelecido. Apesar de a cistometria convencional ser considerada padrão ouro, e ser o método mais aceito para investigação de hiperatividade detrusora, o método de enchimento (retrógrado) da urodinâmica convencional permanece controverso. Por ser um enchimento não fisiológico, vários estudos têm demonstrado altos índices de falsos negativos em relação ao diagnóstico de hiperatividade detrusora. Objetivo: Estimar a prevalência de hiperatividade detrusora durante avaliação urodinâmica ambulatorial de pacientes encaminhadas ao ambulatório de uroginecologia do Hospital de Clínicas de Porto Alegre com sintoma de urgência e avaliação urodinâmica convencional normal. Métodos: Estudo transversal, no qual foram incluídas mulheres com idade superior a 19 anos, apresentando queixa de urgência, urge-incontinência ou incontinência mista, atendidas no ambulatório de uroginecologia do Hospital de Clínicas de Porto Alegre e que já realizaram avaliação urodinâmica convencional, cuja cistometria não tenha detectado hiperatividade detrusora. O cálculo do tamanho da amostra foi realizado no programa WinPEPI (Programs for Epidemiologists for Windows) versão 11.43 , baseado nos achados de um estudo piloto com 6 pacientes. Para um nível de confiança de 95%, uma prevalência de hiperatividade em avaliação urodinâmica ambulatorial estimada em 83% e uma margem de erro de 17%, obtevese um total mínimo de 19 pacientes. O nível de significância adotado foi de 5% (p≤0,05) e as análises foram realizadas no programa SPSS versão 21.0. Resultados: Vinte pacientes com sintomas de urgência e cistometria convencional normal foram submetidas à avaliação urodinâmica ambulatorial. A média de idade foi de 56 anos. Os sintomas mistos de urgência e incontinência por esforço foram mais prevalentes do que sintomas puros de urgência (18/20). A prevalência de hiperatividade detrusora em avaliação urodinâmica ambulatorial de pacientes com sintoma de urgência e com avaliação urodinâmica convencional normal foi de 70% (14/20). O intervalo de 95% de confiança para a verdadeira prevalência na população é de 48% a 87% Conclusão: A avaliação urodinâmica ambulatorial parece ter um papel importante na avaliação adicional de casos mais complexos de pacientes com disfunções do trato urinário, quando há falha diagnóstica e terapêutica – em especial na avaliação de hiperatividade detrusora. Foi encontrado um falso negativo de 70% na avaliação urodinâmica convencional. No entanto, tendo em vista o maior custo do equipamento e das sondas em relação ao convencional, mais estudos são necessários para a incorporação deste exame na prática clínica brasileira. / Introduction: The investigation of lower urinary tract symptoms usually starts with the history, physical exam and simple clinical tests. However, quite often this investigation is not sufficient for the correct diagnosis of urinary incontinence. In these cases, the urodynamic test is accomplished to confirm it. The best method to evaluate the urodynamic has not been established. In spite of the conventional cystometry being considered as the gold standard and being the most accepted investigative method for detrusor overactivity, the conventional retrograde filling urodynamic method of remains controversial. Since it is a non-physiologic filling, several studies have shown high rates of false negatives concerning the diagnosis of detrusor overactivity. Objective: To estimate the prevalence of detrusor overactivity during ambulatory urodynamic tests in symptomatic patients whose results of conventional urodynamic evaluation were normal. Methodology: The research subjects were women referred to the urogynecology service of Hospital de Clínicas, Porto Alegre, Brazil for further investigation due to urinary incontinence symptoms (overactive bladder syndrome, urge incontinence or mixed incontinence), whose conventional urodynamics results did not show any detrusor overactivity. The sample size was calculated using the WinPEPI program (Programs for Epidemiologists for Windows) 11.43 version and was based on the findings of a pilot study with 6 patients. Using a 95% confidence interval and an estimated urodynamic detrusor overactivity prevalence of 83% with a standard error of 17%, a sample size of 19 patients was obtained. A level of significance of 5% (p≤0.05) was considered. SPSS 21.0 version program was used to accomplish the statistical analysis. Results: A total of 20 women were included in this study. The mean age was 56.1 years, the mean body mass index was 29.7 and the mean time of the symptoms was 5 years. We found mixed urinary incontinence in 18 (90%) and urge incontinence in 2 (10%) patients. All conventional cystometry tests were normal; however, in 14 (70%) patients the ambulatory urodynamics was able to diagnose detrusor overactivity. Conclusion: The ambulatory urodynamics evaluation seems to have a major role in the additional evaluation of more complex cases of urinary tract dysfunctions, when there is a diagnostic and therapeutic flaw – especially in the evaluation of detrusor overactivity. We found 70 % of false negative in the conventional cystometry. However, having in mind the higher cost of the equipment and catheters in relation to the conventional one, more studies are necessary for the incorporation of this test in the Brazilian clinical practice.