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OBJECTIVES: To compare isolates from deep wound and superficial swab cultures to evaluate the detectability of pathogens by each culture in Fournier's gangrene; and evaluate the association between microorganisms isolated from deep wounds and those isolated from blood or urine. METHODS: Patients with Fournier's gangrene who underwent debridement between October 2006 and January 2023 were retrospectively reviewed. In addition to comparing the isolates from deep wound cultures at initial debridement with those from superficial swab, blood, and urine cultures, the relationship between the traits of the organisms from deep wounds and patient disease severity and prognosis was examined. RESULTS: Among 25 patients, deep wound and superficial swab cultures were obtained from 25 to 18 patients, respectively. The frequency of anaerobic isolates was significantly lower in the superficial cultures than in the deep wound cultures (31/76 versus 13/56, p = 0.034). Bacteria not isolated from deep wounds were isolated from superficial cultures in 55.6 % of the patients; the concordance rate between deep and superficial cultures was 27.8 % (5/18). The positive rates of blood and urine cultures were 20.8 % and 35.7 %, respectively; all isolates from the urine and blood cultures reflected the results of the deep wound culture. No significant association was observed between the severity or mortality and the type of causative bacteria. CONCLUSIONS: Superficial swab cultures cannot be substituted for deep wound cultures in Fournier's gangrene. Although the positivity rates for blood and urine cultures were not high, they were helpful in determining antibiotic de-escalation.
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Background: Renal artery pseudoaneurysm (RAP) is one of the most stressful and life-threatening complications of partial nephrectomy, the standard treatment for small renal cell carcinoma. The use of a monopolar soft coagulation system for hemostasis during robot-assisted partial nephrectomy (RAPN) is expected to prevent post-surgical RAP development. In this study, we aimed to investigate how the use of a soft coagulation system in RAPN reduces postoperative pseudoaneurysms and changes renal function over time. Methods: The incidence of pseudoaneurysms and postoperative renal function were compared in 208 partial nephrectomies performed between May 2016 and March 2023 at a single institution, with propensity score matching to balance patient backgrounds. Outcomes were analyzed using multivariate logistic or linear regression analyses. Results: In total, 80 matched pairs were analyzed. One (1.2%) and eighteen (22.5%) pseudoaneurysms were found in the soft coagulation users and non-users, respectively (P<0.001). Compared to the non-user group, postoperative estimated glomerular filtration rates (eGFRs) in the user group were 89% vs. 96% (P<0.001), 87% vs. 93% (P=0.009), and 88% vs. 92% (P=0.15) at 1, 3, and 12 months, respectively. Subsequent multivariate analyses showed a lower incidence of pseudoaneurysms in the user group with an odds ratio of 0.05 [95% confidence interval (CI): 0.01 to 0.44; P=0.007], and no significant difference in the rate of change in renal function at 12 months postoperatively (-1.1%, 95% CI: -5.5% to 3.3%; P=0.61). Conclusions: The use of a soft coagulation system reduces pseudoaneurysm occurrence after partial nephrectomy. Although renal function decreased in the short-term for the use group, no long-term differences were observed.
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INTRODUCTION: Antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using the national surveillance data, comprising 793 bacterial strains from eight clinically relevant species. MATERIALS AND METHODS: Data were collected for the fourth national surveillance project from July 2020 to December 2021 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was supervised with the cooperation of 43 medical institutions throughout Japan. RESULTS: Fluoroquinolone required a minimum inhibitory concentration (MIC) of 2-64 mg/L to inhibit the 330 tested Escherichia coli strains. The proportion of levofloxacin-resistant E. coli strains increased from 28.6% in 2008 to 29.6% in 2011, 38.5% in 2015, and 44.5% in 2021. The proportion of levofloxacin-resistant strains of Pseudomonas aeruginosa also increased from previous survey results, showing a continuing downward trend. Conversely, the proportion of levofloxacin-resistant strains of Enterococcus faecalis decreased relative to previous reports. Neither multidrug-resistant P. aeruginosa nor carbapenem-resistant Enterobacteriaceae were detected. For methicillin-resistant Staphylococcus aureus (MRSA), the proportion of vancomycin-susceptible strains (MIC of 2 µg/mL) decreased from 14.7% to 7.7%. DISCUSSION: Bacterial strains that produced extended-spectrum ß-lactamase included E. coli (82/330 strains, 24.8%), Klebsiella pneumoniae (11/68 strains, 16.2%), and Proteus mirabilis (4/26 strains, 15.4%). As compared to previous surveillance reports, these strains showed an increase in proportion over the years.
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Antibacterianos , Levofloxacino , Testes de Sensibilidade Microbiana , Infecções Urinárias , Humanos , Infecções Urinárias/microbiologia , Infecções Urinárias/epidemiologia , Infecções Urinárias/tratamento farmacológico , Japão/epidemiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Levofloxacino/farmacologia , Levofloxacino/uso terapêutico , Farmacorresistência Bacteriana , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/isolamento & purificação , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Feminino , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/isolamento & purificação , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Monitoramento Epidemiológico , População do Leste AsiáticoRESUMO
OBJECTIVES: We investigated the correlation between surgical outcomes and postoperative urinary continence recovery in robot-assisted radical prostatectomy (RARP). METHODS: Patients who underwent RARP in our institution (n = 195) were included in this study. Preserved urethral length (PUL) was assessed during the procedure. Other outcomes of the surgical procedure were collected from operative records. Kaplan-Meier analysis with log-rank test was used to compare urinary continence recovery rate with the PUL, sparing of the neurovascular bundle (NVB), and other surgical procedures. Univariate and multivariate analyses were performed using Cox proportional hazards model, and p-values of <0.05 were considered significant. RESULTS: Patients with a PUL ≥26 mm had 10.0%, 24.7%, 36.6%, and 89.0% continence recovery rates at 30, 60, 90, and 365 days after surgery, respectively, while patients with a PUL <26 mm had 0%, 17.8%, 26.1%, and 80.9% recovery rates, respectively. Kaplan-Meier curves showed significantly better postoperative urinary continence recovery at 30 days after RARP in patients with a PUL ≥26 mm than those with a PUL <26 mm (p = 0.0028) and in patients with NVB preservation than those with no NVB preservation (p = 0.014). Urinary continence recovery within 30, 60, and 90 days after surgery was 90.6% for patients with a PUL of ≥26 mm and NVB preservation, while only 82.3% for patients with a PUL of <26 mm or no NVB preservation. CONCLUSION: Our results suggest that a PUL ≥26 mm and NVB preservation after RARP correlate with a significantly higher postoperative rate of recovery of urinary continence.
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Prostatectomia , Neoplasias da Próstata , Recuperação de Função Fisiológica , Procedimentos Cirúrgicos Robóticos , Uretra , Incontinência Urinária , Humanos , Masculino , Prostatectomia/efeitos adversos , Prostatectomia/métodos , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Procedimentos Cirúrgicos Robóticos/métodos , Idoso , Uretra/cirurgia , Uretra/inervação , Neoplasias da Próstata/cirurgia , Incontinência Urinária/prevenção & controle , Incontinência Urinária/etiologia , Estudos Retrospectivos , Tratamentos com Preservação do Órgão/métodos , Tratamentos com Preservação do Órgão/efeitos adversos , Próstata/cirurgia , Próstata/inervação , Estimativa de Kaplan-Meier , Resultado do Tratamento , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/etiologiaRESUMO
OBJECTIVES: To compare the incidence of surgical site infections (SSI) between robot-assisted and open radical cystectomies and investigate the risk factors for SSI after radical cystectomies. METHODS: Consecutive patients who underwent radical cystectomy between July 2008 and December 2022 were retrospectively reviewed. The prevalence and characteristics of SSI after open and robot-assisted radical cystectomies were compared, and the risk factors for SSI were investigated using propensity score matching. RESULTS: This study enrolled 231 patients (open: 145, robot-assisted: 86). In the robot-assisted group, urinary diversion was performed using an intracorporeal approach. SSI occurred in 34 (open: 28, robot-assisted: 6) patients, and the incidence was significantly lower in the robot-assisted group (19.3% vs. 7.0%, p = 0.007). After propensity score matching cohort (open: 34, robot-assisted: 34), increased bleeding volume, blood transfusion, and delayed postoperative oral feeding were significantly associated with SSI. Only increased bleeding volume remained a significant risk factor in the multivariate regression analysis (odds ratio, 1.13 [per 100 mL increase]; 95% confidence interval: 1.02-1.25; p = 0.001). The cutoff bleeding volume for predicting SSI was 1630 mL with an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.773, 0.73, and 0.75, respectively. CONCLUSIONS: The incidence of SSI after robot-assisted radical cystectomy was significantly lower than that after the open procedure. However, decreased bleeding volume, which was significantly associated with robot-assisted procedures, was an independent and more significant factor for reducing SSI after radical cystectomy than the differences of the surgical procedure even after propensity score matching.
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Procedimentos Cirúrgicos Robóticos , Robótica , Neoplasias da Bexiga Urinária , Derivação Urinária , Humanos , Cistectomia/efeitos adversos , Cistectomia/métodos , Infecção da Ferida Cirúrgica/epidemiologia , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Pontuação de Propensão , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/cirurgia , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Procedimentos Cirúrgicos Robóticos/métodos , Derivação Urinária/métodos , Resultado do Tratamento , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controleRESUMO
We present a constrained mixture-micturition-growth (CMMG) model for the bladder. It simulates bladder mechanics, voiding function (micturition) and tissue adaptations in response to altered biomechanical conditions. The CMMG model is calibrated with both in vivo and in vitro data from healthy male rat urinary bladders (cystometry, bioimaging of wall structure, mechanical testing) and applied to simulate the growth and remodeling (G&R) response to partial bladder outlet obstruction (BOO). The bladder wall is represented as a multi-layered, anisotropic, nonlinear constrained mixture. A short time scale micturition component of the CMMG model accounts for the active and passive mechanics of voiding. Over a second, longer time scale, G&R algorithms for the evolution of both cellular and extracellular constituents act to maintain/restore bladder (homeostatic) functionality. The CMMG model is applied to a spherical membrane model of the BOO bladder utilizing temporal data from an experimental male rodent model to parameterize and then verify the model. Consistent with the experimental studies of BOO, the model predicts: an initial loss of voiding capacity followed by hypertrophy of SMC to restore voiding function; bladder enlargement; collagen remodeling to maintain its role as a protective sheath; and increased voiding duration with lower average flow rate. This CMMG model enables a mechanistic approach for investigating the bladder's structure-function relationship and its adaption in pathological conditions. While the approach is illustrated with a conceptual spherical bladder model, it provides the basis for application of the CMMG model to anatomical geometries. Such a mechanistic approach has promise as an in silico tool for the rational development of new surgical and pharmacological treatments for bladder diseases such as BOO.
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Obstrução do Colo da Bexiga Urinária , Animais , Modelos Animais de Doenças , Guanina/análogos & derivados , Masculino , Ratos , Bexiga Urinária , Obstrução do Colo da Bexiga Urinária/patologia , Micção/fisiologia , UrodinâmicaRESUMO
The aim of this report is to introduce an on-going, multicenter, randomized controlled trial to evaluate whether tailored antimicrobial prophylaxis guided by rectal culture screening prevents acute bacterial prostatitis following transrectal prostate biopsy (TRPB). Patients will be randomized into an intervention or non-intervention group; tazobactam-piperacillin or levofloxacin will be prophylactically administered according to the results of rectal culture prior to TRPB in the intervention group whereas levofloxacin will be routinely given in the non-intervention group. The primary endpoint is the occurrence rate of acute bacterial prostatitis after TRPB. Recruitment begins in April, 2021 and the target total sample size is 5,100 participants.
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Antibacterianos/uso terapêutico , Infecções Bacterianas/microbiologia , Estudos Multicêntricos como Assunto , Doenças Prostáticas/microbiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/tratamento farmacológico , Humanos , Masculino , Doenças Prostáticas/tratamento farmacológico , Doenças Prostáticas/patologiaRESUMO
AIMS: Spinal cord injury (SCI) above the sacral level causes bladder dysfunction and remodeling with fibrosis. This study examined the antifibrotic effects using nintedanib, an inhibitor of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors, on detrusor overactivity (DO) and bladder fibrosis, as well as the modulation mechanisms of C-fiber afferent pathways. METHODS: Thirty female C57BL/6 mice were divided into group A (spinal intact), group B (SCI with vehicle), and group C (SCI with nintedanib). At 2 weeks after SCI, vehicle or 50 mg/kg nintedanib was administered subcutaneously for 2 weeks. Then, cystometry was conducted, followed by RT-PCR measurements of fibrosis-related molecules, muscarinic, ß-adrenergic, TRP and purinergic receptors in the bladder or L6-S1 dorsal root ganglia (DRG). Trichrome stain and Western blot analysis of transforming growth factor-beta and fibronectin were performed in the bladder. TRPV1 expression in L6 DRG was measured by immunohistochemistry. RESULTS: In cystometry, intercontraction intervals, nonvoiding contractions, voided volume, and voiding efficiency were significantly improved in group C versus group B. RT-PCR, Western blotting, and trichrome staining revealed the fibrotic changes in the bladder of group B, which was improved in group C. Increased messenger RNA levels of TRPV1, TRPA1, P2X2 , and P2X3 in DRG of group B were significantly decreased in group C. TRPV1 immunoreactivity in DRG was increased in group B, but decreased in group C. CONCLUSIONS: Nintedanib improves storage and voiding dysfunctions and bladder fibrosis in SCI mice. Also, nintedanib-induced improvement of DO is associated with reduced expression of C-fiber afferent markers, suggesting the modulation of bladder C-fiber afferent activity.
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Traumatismos da Medula Espinal , Bexiga Urinária , Animais , Feminino , Fatores de Crescimento de Fibroblastos , Camundongos , Camundongos Endogâmicos C57BL , Receptores do Fator de Crescimento Derivado de Plaquetas , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/tratamento farmacológico , Fator A de Crescimento do Endotélio VascularRESUMO
AIMS: We investigated the quality of life (QOL) of a homogenous group of ambulant patients with neurogenic lower urinary tract dysfunction without significant comorbidities to elucidate the impact of clean intermittent catheterization (CIC) on QOL. METHODS: The subjects were 71 female patients who underwent radical hysterectomy (RH) without recurrent disease. QOL was cross-sectionally measured with the Short-Form 36-Item Health Survey (SF-36) and King's Health Questionnaire (KHQ). We divided urinary management into spontaneous voiding (SV) and CIC as well as postoperative elapsed time into the entire period, less than 24 months (<24 months) and 24 months or more (≥24 months). RESULTS: Patients with CIC showed significantly poorer QOL than patients with SV in some subscale/domain scores on SF-36 and KHQ for the entire period as well as <24 months after RH. In contrast, significant differences were not revealed between scores on both measures of patients with CIC and SV ≥24 months after RH. Moreover, in patients with CIC ≥24 months, some subscale/domain scores on both measures were significantly better than in those with <24 months. Norm-based scoring of SF-36 revealed that all subscales of patients with CIC <24 months were below the average score of healthy Japanese people, while only four subscales of those ≥24 months remained below the average. CONCLUSIONS: QOL in patients with CIC was worse than in patients with SV in the short term, but similar in the long term, which suggests that QOL probably might improve with time in patients with CIC.
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Histerectomia/efeitos adversos , Qualidade de Vida , Bexiga Urinaria Neurogênica/etiologia , Cateterismo Urinário , Adulto , Estudos Transversais , Humanos , Pessoa de Meia-Idade , Inquéritos e Questionários , Bexiga Urinaria Neurogênica/terapia , Cateterismo Urinário/métodosRESUMO
AIMS: The urethral dysfunction produced by a rat model of peripheral neurogenic detrusor underactivity (DU) using pelvic nerve crush (PNC) injury was characterized and then tested with the administration of tadalafil, a phosphodiesterase type 5 (PDE 5) inhibitor. METHODS: Ten days after producing PNC rats, awake cystometrograms (CMGs) and isovolumetric cystometrograms with urethral perfusion pressure (IC-UPP) measurements were performed. Also, in control rats, IC-UPP was recorded before and after intravenous atropine administration to determine if the reduction of bladder contraction pressure affects urethral relaxation during voiding. Then, CMG and IC-UPP measurements in PNC rats were recorded after intravenous administration of tadalafil. Lastly, real-time polymerase chain reaction was used to measure transcript levels of neuronal nitric oxide synthases (nNOS), endothelial nitric oxide synthases, and PDE 5 in urethral specimens from PNC and control rats. RESULTS: PNC rats demonstrated the characteristics of DU in CMG. Also, PNC rats exhibited significant decreases in isovolumetric bladder contraction amplitudes and urethral relaxation. Atropine attenuated the amplitude of isovolumetric bladder contractions; however, atropine did not affect urethral relaxation in control rats. Tadalafil decreased postvoid residual and increased voiding efficiency without changing bladder contraction amplitude in PNC rats. Also, tadalafil improved the amplitude of urethral relaxation during bladder contraction in PNC rats. Urethral nNOS transcript levels were upregulated in PNC rats compared to control rats. CONCLUSIONS: PNC rats revealed both DU and impaired urethral relaxation. PDE 5 inhibition in PNC rats enhanced urethral relaxation during voiding, resulting in improved voiding efficiency. Thus, urethral dysfunction could be a potential target for the treatment of inefficient voiding associated with neurogenic DU.
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Traumatismos dos Nervos Periféricos/fisiopatologia , Inibidores da Fosfodiesterase 5/farmacologia , Tadalafila/farmacologia , Uretra/efeitos dos fármacos , Bexiga Urinaria Neurogênica/fisiopatologia , Bexiga Inativa/fisiopatologia , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Animais , Lesões por Esmagamento/fisiopatologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Feminino , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Pelve , Ratos , Ratos Sprague-Dawley , Uretra/inervação , Uretra/metabolismo , Uretra/fisiopatologia , Bexiga Urinária/inervação , Bexiga Urinária/fisiopatologia , Micção/fisiologiaRESUMO
BACKGROUND: We retrospectively evaluated the clinical outcomes of patients with histologic variants of muscle invasive bladder cancer (MIBC) treated with trimodal bladder-preserving therapy (TMT). METHODS: Among 148 patients with clinical T2-3N0M0 MIBC treated with TMT at Tsukuba University Hospital from 1990 to 2015, 11 patients (7.4%) had pathological components of variant urothelial carcinoma (UC). The complete response (CR), overall survival (OS), cause-specific survival (CSS) and progression-free survival (PFS) rates were analyzed in these 11 patients. RESULTS: Among the 11 patients with variant UC, 7 (64%) had UC with squamous and/or glandular differentiation and 4 (36%) had sarcomatoid (n = 1), plasmacytoid (n = 1), signet ring cell (n = 1), or clear cell variant (n = 1). Median follow-up was 49.0 months. Nine (82%) out of 11 patients achieved CR and 2 (22%) out of the 9 developed recurrence. Among seven patients who had UC with squamous and/or glandular differentiation, two developed recurrence and one died of disease. In contrast, 2 (50%) out of four patients with other variants, which were sarcomatoid variant or signet ring cell, developed recurrence and died of disease. Overall, the 5-year OS, CSS, and PFS rates of variant UC were 75%, 75%, and 58%, respectively. CONCLUSIONS: TMT might provide acceptable clinical outcomes for well-selected MIBC patients with histologic variants, especially for those with squamous and/or glandular differentiation. However, we need to pay special attention to other variants such as sarcomatoid variant or signet ring cell. TMT might be an alternative treatment option for patients with histologic variants, although further experiments will be needed to confirm this.
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Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/terapia , Idoso , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/terapia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tratamentos com Preservação do Órgão , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidadeRESUMO
The present study evaluated real-time changes in urethral pressure during the storage phase using a rat model with stress urinary incontinence (SUI) induced by simulated multiple birth traumas and investigated the relationship between urethral continence function and dynamic parameters associated with the changes in urethral pressure. Sprague-Dawley rats were divided into the following two groups: the sham group, which underwent three catheterizations of the vagina without distension at 2-wk intervals, and the vaginal distension (VD) group, which underwent three VDs at 2-wk intervals. After transection of the T8-T9 spinal cord, simultaneous bladder and urethral pressure recordings were performed during intravesical pressure elevation. Urodynamic parameters such as leak point pressure (LPP), urethral baseline pressure (UBP), maximum urethral pressure (MUP), the MUP-UBP differential (dUP) during intravesical pressure elevation, the bladder pressure when urethral contraction begins (Puc), and the bladder pressure at bladder neck opening (Pno) were then measured and compared. Compared with the sham group, LPP, UBP, dUP, MUP, Puc, and Pno were significantly decreased in the VD group. Pressure differences between LPP and Pno and between LPP and UBP (LPP-UBP) were also significantly different in the two groups. However, difference values of LPP and MUP or Pno and UBP were not altered after VD. Our new methods of simultaneous recordings of dynamic changes in bladder and urethral pressures are useful to fully evaluate the functional alterations in urethral continence function in the SUI model induced by multiple VDs. Moreover, LPP-UBP values, which correspond to the difference between Valsalva LPP and maximum urethral closure pressure in clinical urodynamics, would be useful to evaluate the impaired urethral continence function after simulated birth traumas in animal models.
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Parto , Reflexo , Uretra/fisiopatologia , Incontinência Urinária por Estresse/fisiopatologia , Animais , Feminino , Contração Muscular , Gravidez , Pressão , Ratos , Ratos Sprague-Dawley , Bexiga Urinária/fisiopatologia , Urodinâmica , Vagina/fisiopatologiaRESUMO
OBJECTIVES: To evaluate, using a rat model of non-bacterial prostatic inflammation, the prostaglandin production and expression profiles of E-series prostaglandin (EP) receptor subtypes, which are reportedly implicated in the development of overactive bladder, in the bladder mucosa, and to investigate the effect of EP receptor type 4 (EP4) blockade on bladder overactivity after prostatic inflammation. METHODS: Male Sprague-Dawley rats were used. Prostatic inflammation was induced by formalin injection (5%; 50 µL per lobe) into the bilateral ventral lobes of the prostate. At 10 days after induction of prostatic inflammation or vehicle injection, bladder tissues from the deeply anaesthetized rats were harvested and separated into mucosal and detrusor layers. Then, prostaglandin E2 (PGE2) concentrations and protein levels of PGE2 receptors (EP1-4) in the bladder mucosa and detrusor were measured by ELISA and Western blotting, respectively. In separate groups of control and formalin-treated rats, awake cystometry was performed to evaluate the changes in bladder activity after prostatic inflammation. In addition, the effect of intravesical administration of a selective EP4 antagonist (ONO-AE3-208; 30 µm) on bladder activity was evaluated in control rats and rats with prostatic inflammation. RESULTS: PGE2 concentration and protein levels of EP4, but not other EP receptor subtypes, in the bladder mucosa and detrusor layers were significantly increased in formalin-injected rats vs vehicle-injected control rats. In cystometry, rats with prostatic inflammation exhibited a significant decrease in intercontraction intervals (ICIs) compared with control rats. Intravesical application of ONO-AE3-208 (30 µm), but not vehicle application, significantly increased ICIs in rats with prostatic inflammation, whereas ONO-AE3-208 at this concentration did not significantly affect any cystometric values in control rats. CONCLUSIONS: Because intravesical administration of an EP4 antagonist effectively improved bladder overactivity after prostatic inflammation, EP4 activation, along with increased PGE2 production in the bladder mucosa, seems to be an important contributing factor to bladder overactivity induced by prostatic inflammation. Thus, blockade of EP4 in the bladder could be a therapeutic approach to male lower urinary tract symptoms attributable to benign prostatic hyperplasia with prostatic inflammation.
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Inflamação , Prostaglandinas E/metabolismo , Prostatite/metabolismo , Receptores de Prostaglandina E , Bexiga Urinária Hiperativa , Animais , Modelos Animais de Doenças , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Mucosa/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E/antagonistas & inibidores , Receptores de Prostaglandina E/metabolismo , Bexiga Urinária/metabolismo , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/metabolismo , Bexiga Urinária Hiperativa/fisiopatologiaRESUMO
BACKGROUND: Benign prostatic hyperplasia (BPH) is one of the major causes of lower urinary tract symptoms (LUTS), including storage LUTS such as urinary frequency and urgency. Recently, a growing number of clinical studies indicate that prostatic inflammation could be an important pathophysiological mechanism inducing storage LUTS in patients with BPH. Here we aimed to investigate whether nonbacterial prostatic inflammation in a rat model induced by intraprostatic formalin injection can lead to long-lasting bladder overactivity and changes in bladder afferent neuron excitability. METHODS: Male Sprague-Dawley rats were divided into four groups (n = 12 each): normal control group, 1-week prostatic inflammation group, 4-week inflammation group, and 8-week inflammation group. Prostatic inflammation was induced by formalin (10%; 50 µL per lobe) injection into bilateral ventral lobes of the prostate. Voiding behavior was evaluated in metabolic cages for each group. Ventral lobes of the prostate and the bladder were then removed for hematoxylin and eosin (HE) staining to evaluate inflammation levels. Continuous cystometrograms (CMG) were recorded to measure intercontraction intervals (ICI) and voided volume per micturition. Whole-cell patch clamp recordings were performed on dissociated bladder afferent neurons labeled by fluorogold injected into the bladder wall, to examine the electrophysiological properties. RESULTS: Results of metabolic cage measurements showed that formalin-treated rats exhibited significantly (P < 0.05) increases in micturition episodes/12 hours and decrease in voided volume per micturition at every time point post injection. Continuous CMG illustrated the significant ( P < 0.05) higher number of nonvoiding contractions per void and shorter ICI in formalin-treated rats compared with control rats. HE staining showed significant prostatic inflammation, which declined gradually, in prostate tissues of formalin-induced rats. In patch clamp recordings, capsaicin-sensitive bladder afferent neurons from rats with prostatic inflammation had significantly ( P < 0.05) lower thresholds for spike activation and a "multiple" firing pattern compared with control rats at every time point post injection. CONCLUSIONS: Formalin-induced prostatic inflammation can lead to long-lasting bladder overactivity in association with bladder afferent neuron hyperexcitability. This long-lasting model could be a useful tool for the study of inflammation-related aspects of male LUTS pathophysiology.
Assuntos
Prostatite/fisiopatologia , Bexiga Urinária Hiperativa/etiologia , Animais , Modelos Animais de Doenças , Formaldeído , Masculino , Neurônios Aferentes/patologia , Técnicas de Patch-Clamp , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/etiologia , Hiperplasia Prostática/patologia , Hiperplasia Prostática/fisiopatologia , Prostatite/induzido quimicamente , Prostatite/patologia , Ratos , Ratos Sprague-Dawley , Bexiga Urinária Hiperativa/patologia , Bexiga Urinária Hiperativa/fisiopatologia , MicçãoRESUMO
KEY POINTS: There is clinical evidence showing that prostatic inflammation contributes to overactive bladder symptoms in male patients; however, little is known about the underlying mechanisms In this study, we investigated the mechanism that prostatic inflammation causes detrusor overactivity by using a rat model of chemically induced prostatic inflammation. We observed a significant number of dorsal root ganglion neurons with dichotomized afferents innervating both prostate and bladder. We also found that prostatic inflammation induces bladder overactivity and urothelial NGF overexpression in the bladder, both dependent on activation of the pelvic nerve, as well as changes in ion channel expression and hyperexcitability of bladder afferent neurons. These results indicate that the prostate-to-bladder cross-sensitization through primary afferent pathways in the pelvic nerve, which contain dichotomized afferents, could be an important mechanism contributing to bladder overactivity and afferent hyperexcitability induced by prostatic inflammation. ABSTRACT: Prostatic inflammation is reportedly an important factor inducing lower urinary tract symptoms (LUTS) including urinary frequency, urgency and incontinence in patients with benign prostatic hyperplasia (BPH). However, the underlying mechanisms inducing bladder dysfunction after prostatic inflammation are not well clarified. We therefore investigated the effects of prostatic inflammation on bladder activity and afferent function using a rat model of non-bacterial prostatic inflammation. We demonstrated that bladder overactivity, evident as decreased voided volume and shorter intercontraction intervals in cystometry, was observed in rats with prostatic inflammation versus controls. Tissue inflammation, evident as increased myeloperoxidase activity, and IL-1α, IL-1ß, and IL-6 levels inside the prostate, but not in the bladder, following intraprostatic formalin injection induced an increase in NGF expression in the bladder urothelium, which depended on activation of the pelvic nerve. A significant proportion (18-19%) of dorsal root ganglion neurons were double labelled by dye tracers injected into either bladder or prostate. In rats with prostatic inflammation, TRPV1, TRPA1 and P2X2 increased, and Kv1.4, a potassium channel α-subunit that can form A-type potassium (KA ) channels, decreased at mRNA levels in bladder afferent and double-labelled neurons vs. non-labelled neurons, and slow KA current density decreased in association with hyperexcitability of these neurons. Collectively, non-bacterial inflammation localized in the prostate induces bladder overactivity and enhances bladder afferent function. Thus, prostate-to-bladder afferent cross-sensitization through primary afferents in the pelvic nerve, which contain dichotomized afferents, could underlie storage LUTS in symptomatic BPH with prostatic inflammation.
Assuntos
Vias Aferentes , Próstata/patologia , Prostatite/induzido quimicamente , Prostatite/patologia , Bexiga Urinária Hiperativa/patologia , Bexiga Urinária/patologia , Animais , Biomarcadores , Citocinas/metabolismo , Regulação da Expressão Gênica , Inflamação/sangue , Inflamação/metabolismo , Masculino , Neurônios Aferentes , Ratos , Ratos Sprague-DawleyRESUMO
AIMS: To produce an animal model of peripheral neurogenic detrusor underactivity (DU) and to evaluate the effect of TRPV4 receptor activation in this DU model. METHODS: In female Sprague-Dawley rats, bilateral pelvic nerve crush (PNC) was performed by using sharp forceps. After 10 days, awake cystometrograms (CMG) were recorded in sham and PNC rats. A TRPV4 agonist (GSK 1016790A) with or without a TRPV4 antagonist (RN1734) were administered intravesically and CMG parameters were compared before and after drug administration in each group. The TRPV4 transcript level in the bladder mucosa and histological changes were also evaluated. RESULTS: In CMG, PNC rats showed significant increases in intercontraction intervals (ICI), number of non-voiding contractions (NVCs), baseline pressure, threshold pressure, bladder capacity, voided volumes, and post-void residual (PVR) compared to sham rats. Contraction amplitude and voiding efficiency were significantly decreased in PNC rats. In PNC rats, intravesical application of GSK1016790A (1.5 µM) significantly decreased ICI, bladder capacity, voided volume, and PVR without increasing NVCs, and these effects were blocked by RN1734 (5.0 µM). In contrast, 1.5 µM GSK1016790A had no significant effects on CMG parameters in normal rats. TRPV4 expression within the bladder mucosa of PNC rats was increased in association with urothelial thickening. CONCLUSIONS: Rats with bilateral PNC showed characteristics of DU, and this model seems appropriate for further evaluation of peripheral neurogenic mechanisms of DU. Also, TRPV4 receptors, the activation of which reduced bladder capacity and PVR, could be a target for DU treatment.
Assuntos
Plexo Hipogástrico/lesões , Compressão Nervosa , Canais de Cátion TRPV/efeitos dos fármacos , Bexiga Inativa/tratamento farmacológico , Animais , Modelos Animais de Doenças , Feminino , Leucina/análogos & derivados , Contração Muscular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Sulfonamidas/uso terapêutico , Canais de Cátion TRPV/antagonistas & inibidores , Bexiga Inativa/etiologiaRESUMO
Nerve growth factor (NGF) is reportedly involved in the changes in C-fiber bladder afferent pathways that induce detrusor overactivity (DO) following spinal cord injury (SCI). This study examined the roles of NGF in TRP channel expression in bladder afferent neurons in mice with SCI using laser-capture microdissection (LCM) methods. Spinal intact (SI) and SCI mice were divided into 3 groups: (1) SI with vehicle treatment; (2) SCI with vehicle treatment; and (3) SCI with anti-NGF antibody. Two weeks after SCI, an osmotic pump was placed subcutaneously into the back of the mice and vehicle or anti-NGF antibody was administered at a rate of 10 µg/kg per hour for two weeks. Four weeks after SCI, the L6 dorsal root ganglia (DRG) were removed. Expression of the TRPV1, TRPC1, TRPC3, and TRPC6 genes was analyzed using real-time polymerase chain reaction (PCR) following LCM of the bladder afferent neurons, which were labeled by Fast Blue injected into the bladder wall 1 week prior to tissue removal. The mRNA expression of TRPV1 was found to be higher in vehicle-treated SCI mice than in SI mice. The expression level of TRPC3 and TRPC6 in vehicle-treated SCI mice was lower than in SI mice. However, in SCI mice treated with anti-NGF antibody, the mRNA expression of TRPV1 was lower, and the mRNA levels of TRPC3 and TRPC6 were higher than in vehicle-SCI mice. These results suggest that the NGF-dependent changes in specific TRP channel genes, such as TRPV1, TRPC3, and TRPC6, could be involved in SCI-induced afferent hyperexcitability and DO.
Assuntos
Microdissecção e Captura a Laser/métodos , Fator de Crescimento Neural/metabolismo , Neurônios Aferentes/metabolismo , Traumatismos da Medula Espinal/metabolismo , Canais de Potencial de Receptor Transitório/biossíntese , Bexiga Urinária/metabolismo , Animais , Feminino , Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/antagonistas & inibidores , Canais de Potencial de Receptor Transitório/genética , Bexiga Urinária/inervaçãoRESUMO
NEW FINDINGS: What is the central question of this study? Nerve growth factor (NGF) is reportedly a mediator inducing urinary bladder dysfunction. Is NGF directly involved in hyperexcitability of capsaicin-sensitive C-fibre bladder afferent pathways after spinal cord injury (SCI)? What is the main finding and its importance? Neutralization of NGF by anti-NGF antibody treatment reversed the SCI-induced increase in the number of action potentials and the reduction in spike thresholds and A-type K+ current density in mouse capsaicin-sensitive bladder afferent neurones. Thus, NGF plays an important and direct role in hyperexcitability of capsaicin-sensitive C-fibre bladder afferent neurones attributable to the reduction in A-type K+ channel activity in SCI. ABSTRACT: Nerve growth factor (NGF) has been implicated as an important mediator in the induction of C-fibre bladder afferent hyperexcitability, which contributes to the emergence of neurogenic lower urinary tract dysfunction after spinal cord injury (SCI). In this study, we determined whether NGF immunoneutralization using an anti-NGF antibody (NGF-Ab) normalizes the SCI-induced changes in electrophysiological properties of capsaicin-sensitive C-fibre bladder afferent neurones in female C57BL/6 mice. The spinal cord was transected at the Th8/Th9 level. Two weeks later, continuous administration of NGF-Ab (10 µg kg-1 h-1 , s.c. for 2 weeks) was started. Bladder afferent neurones were labelled with Fast-Blue (FB), a fluorescent retrograde tracer, injected into the bladder wall 3 weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurones were prepared. Whole-cell patch-clamp recordings were then performed in FB-labelled neurones. After recording action potentials or voltage-gated K+ currents, the sensitivity of each neurone to capsaicin was evaluated. In capsaicin-sensitive FB-labelled neurones, SCI significantly reduced the spike threshold and increased the number of action potentials during membrane depolarization for 800 ms. These SCI-induced changes were reversed by NGF-Ab. Densities of slow-decaying A-type K+ (KA ) and sustained delayed rectifier-type K+ currents were significantly reduced by SCI. The NGF-Ab treatment reversed the SCI-induced reduction in the KA current density. These results indicate that NGF plays an important role in hyperexcitability of mouse capsaicin-sensitive C-fibre bladder afferent neurones attributable to a reduction in KA channel activity. Thus, NGF-targeting therapies could be effective for treatment of afferent hyperexcitability and neurogenic lower urinary tract dysfunction after SCI.
Assuntos
Potenciais de Ação/fisiologia , Capsaicina/farmacologia , Fator de Crescimento Neural/metabolismo , Neurônios Aferentes/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Bexiga Urinária/fisiopatologia , Vias Aferentes/metabolismo , Vias Aferentes/fisiopatologia , Animais , Feminino , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neurônios/fisiologia , Neurônios Aferentes/metabolismo , Potássio/metabolismo , Traumatismos da Medula Espinal/metabolismo , Bexiga Urinária/metabolismo , Doenças Urológicas/metabolismo , Doenças Urológicas/fisiopatologiaRESUMO
In the past 40 years, intravesical immunotherapy with Mycobacterium bovis bacillus Calmette-Guérin has been carried out as the most effective treatment for preventing local recurrences and tumor progression of non-muscle-invasive bladder cancer. Bacillus Calmette-Guérin is a family of vaccines derived in 1921 by the in vitro attenuation of Mycobacterium bovis. Subsequently, bacillus Calmette-Guérin seed lots were spread around the world, and both phenotypic and genotypic differences among the strains have been compiled. In recent genomic comparisons, the evolution of the different bacillus Calmette-Guérin substrains has begun to emerge. However, some of these genetic alterations in bacillus Calmette-Guérin strains have yet to be shown to affect the therapeutic effects and/or adverse effects. There are thus ongoing research efforts to assess the effects of these genetic alterations on the properties of bacillus Calmette-Guérin strains, with the ultimate goal of identifying an ideal bacillus Calmette-Guérin strain for treatment of non-muscle-invasive bladder cancer and providing clues for the improvement of bacillus Calmette-Guérin strains. The present review provides a history of bacillus Calmette-Guérin immunotherapy, and discusses the genetic differences among bacillus Calmette-Guérin strains, the different clinical outcomes afforded by bacillus Calmette-Guérin strains and possible future developments.
Assuntos
Vacina BCG/uso terapêutico , Carcinoma de Células de Transição/terapia , Mycobacterium bovis/genética , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Vacina BCG/história , Citocinas/imunologia , História do Século XX , Humanos , Imunoterapia/métodos , Mycobacterium bovis/imunologia , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologiaRESUMO
To clarify the role of serotonin (5-HT) in the prevention of stress urinary incontinence (SUI) during sneezing, we investigated the effect of intraperitoneal application of p-chlorophenylalanine (PCPA; a serotonin synthesis inhibitor) and intravenous application of CP-809101 (a 5-HT2C agonist) or LP44 (a 5-HT7 agonist) using female rats, in which the neurally evoked continence reflex during sneezing was examined. Amplitudes of urethral pressure response during sneezing (A-URS), urethral baseline pressure (UBP) at the middle urethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats with or without drug administration. PCPA decreased A-URS by 35.1 cmH2O and UBP by 13.3 cmH2O compared with normal rats. In PCPA-administrated rats, CP-809101 increased A-URS by 24.1 cmH2O and UBP by 15.1 cmH2O, and LP44 also increased A-URS by 20.6 cmH2O and UBP by 11.4 cmH2O compared with rats treated with PCPA alone. SUI was observed with S-LPP of 40.1 cmH2O in PCPA-administrated rats, in which CP-809101 and LP44 increased S-LPP by 28.0 and 15.2 cmH2O, respectively, compared with rats treated with PCPA alone. The effects of CP-809101 and LP44 were antagonized by SB-242084 (a selective 5-HT2C antagonist) and SB-269970 (a selective 5-HT7 antagonist), respectively. These results indicate that activation of 5-HT receptors enhances the active urethral closure reflex during sneezing, at least in part via 5-HT2C and 5-HT7 receptors.