Pathophysiology of Overactive Bladder and Pharmacologic Treatments Including ß3-Adrenoceptor Agonists -Basic Research Perspectives.

Overactive bladder (OAB) is a symptom-based syndrome defined by urinary urgency, frequency, and nocturia with or without urge incontinence. The causative pathology is diverse; including bladder outlet obstruction (BOO), bladder ischemia, aging, metabolic syndrome, psychological stress, affective disorder, urinary microbiome, localized and systemic inflammatory responses, etc. Several hypotheses have been suggested as mechanisms of OAB generation; among them, neurogenic, myogenic, and urothelial mechanisms are well-known hypotheses. Also, a series of local signals called autonomous myogenic contraction, micromotion, or afferent noises, which can occur during bladder filling, may be induced by the leak of acetylcholine (ACh) or urothelial release of adenosine triphosphate (ATP). They can be transmitted to the central nervous system through afferent fibers to trigger coordinated urgency-related detrusor contractions. Antimuscarinics, commonly known to induce smooth muscle relaxation by competitive blockage of muscarinic receptors in the parasympathetic postganglionic nerve, have a minimal effect on detrusor contraction within therapeutic doses. In fact, they have a predominant role in preventing signals in the afferent nerve transmission process. ß3-adrenergic receptor (AR) agonists inhibit afferent signals by predominant inhibition of mechanosensitive Aδ-fibers in the normal bladder. However, in pathologic conditions such as spinal cord injury, it seems to inhibit capsaicin-sensitive C-fibers. Particularly, mirabegron, a ß3-agonist, prevents ACh release in the BOO-induced detrusor overactivity model by parasympathetic prejunctional mechanisms. A recent study also revealed that vibegron may have 2 mechanisms of action: inhibition of ACh from cholinergic efferent nerves in the detrusor and afferent inhibition via urothelial ß3-AR.

Improvement of lower urinary tract dysfunction by a monoacylglycerol lipase inhibitor in mice with spinal cord injury.

AIMS: Activation of the endocannabinoid system by monoacylglycerol lipase (MAGL) blockade may affect the lower urinary tract function. We investigated the effect of an MAGL inhibitor, MJN110, on neurogenic lower urinary tract dysfunction (LUTD) in the mouse model of spinal cord injury (SCI). METHODS: Female C57BL/6 mice that underwent spinal cord transection at T8-10 level were divided into three groups consisting of (1) vehicle-treated SCI mice, (2) 5 mg/kg, or (3) 10 mg/kg of MJN110-treated SCI mice. MJN110 and vehicle were administered intraperitoneally for 7 days from 4 weeks after spinal cord transection. We then conducted awake cystometrograms and compared urodynamic parameters between three groups. The expression of cannabinoid (CB) receptors, TRP receptors, and inflammatory cytokines in L6-S1 dorsal root ganglia (DRG) or the bladder mucosa were evaluated and compared among three groups. Changes in the level of serum 2-arachidonoylglycerol (2-AG) and bladder MAGL were also evaluated. RESULTS: In the cystometrogram, detrusor overactivity (DO) parameters, such as the number of nonvoiding contraction (NVC), a ratio of time to the 1st NVC to intercontraction interval (ICI), and NVC integrals were improved by MJN110 treatment, and some effects were dose dependent. Although MJN110 did not improve voiding efficiency, it decreased bladder capacity, ICI, and residual urine volume compared to vehicle injection. MJN110 treatment groups had lower CB2, TRPV1, TRPA1, and inflammatory cytokines mRNA levels in DRG and bladder mucosa. Serum 2-AG was increased, and bladder MAGL was decreased after MAGL inhibitor treatment. CONCLUSIONS: MAGL inhibition improved LUTD including attenuation of DO after SCI. Thus, MAGL can be a therapeutic target for neurogenic LUTD after SCI.

Sex differences in lower urinary tract function in mice with or without spinal cord injury.

OBJECTIVES: We examined sex differences of lower urinary tract function and molecular mechanisms in mice with and without spinal cord injury (SCI). METHODS: SCI was induced by Th8-9 spinal cord transection in male and female mice. We evaluated cystometrograms (CMG) and electromyography (EMG) of external urethral sphincter (EUS) at 6 weeks after SCI in spinal intact (SI) and SCI mice. The mRNA levels of Piezo2 and TRPV1 were measured in L6-S1 dorsal root ganglia (DRG). Protein levels of nerve growth factor (NGF) in the bladder mucosa was evaluated using an enzyme-linked immunosorbent assay. RESULTS: Sex differences were found in the EUS behavior during voiding as voiding events in female mice with or without SCI occurred during EUS relaxation periods without EUS bursting activity whereas male mice with or without SCI urinated during EUS bursting activity in EMG recordings. In both sexes, SCI decreased voiding efficiency along with increased tonic EUS activities evident as reduced EUS relaxation time in females and longer active periods of EUS bursting activity in males. mRNA levels of Piezo2 and TRPV1 of DRG in male and female SCI mice were significantly upregulated compared with SI mice. NGF in the bladder mucosa showed a significant increase in male and female SCI mice compared with SI mice. However, there were no significant differences in Piezo2 or TRPV1 levels in DRG or NGF protein levels in the bladder mucosa between male and female SCI mice. CONCLUSIONS: We demonstrated that female and male mice voided during EUS relaxation and EUS bursting activity, respectively. Also, upregulation of TRPV1 and Piezo2 in L6-S1 DRG and NGF in the bladder could be involved in SCI-induced lower urinary tract dysfunction in both sexes of mice.

Intravesical Contrast-Enhanced MRI: A Potential Tool for Bladder Cancer Surveillance and Staging.

This review article gives an overview of the current state of the art of bladder cancer imaging and then discusses in depth the scientific and technical merit of a novel imaging approach, tracing its evolution from murine cancer models to cancer patients. While the poor resolution of soft tissue obtained by widely available imaging options such as abdominal sonography and radiation-based CT leaves them only suitable for measuring the gross tumor volume and bladder wall thickening, dynamic contrast-enhanced magnetic resolution imaging (DCE MRI) is demonstrably superior in resolving muscle invasion. However, major barriers still exist in its adoption. Instead of injection for DCE-MRI, intravesical contrast-enhanced MRI (ICE-MRI) instills Gadolinium chelate (Gadobutrol) together with trace amounts of superparamagnetic agents for measurement of tumor volume, depth, and aggressiveness. ICE-MRI leverages leaky tight junctions to accelerate passive paracellular diffusion of Gadobutrol (604.71 Daltons) by treading the paracellular ingress pathway of fluorescein sodium and of mitomycin (<400 Daltons) into bladder tumor. The soaring cost of diagnosis and care of bladder cancer could be mitigated by reducing the use of expensive operating room resources with a potential non-surgical imaging option for cancer surveillance, thereby reducing over-diagnosis and over-treatment and increasing organ preservation.

Treating Lower Urinary Tract Symptoms in Older Adults: Intravesical Options.

This article provides an overview of the diagnosis and the treatment of lower urinary tract symptoms in older adults complicated by the neurodegenerative changes in the micturition reflex and further confounded by age-related decline in hepatic and renal clearance raising the propensity of adverse drug reactions. The first-line drug treatment for lower urinary tract symptoms, orally administered antimuscarinics, fails to reach the equilibrium dissociation constant of muscarinic receptors even at their maximum plasma concentration and tends to evoke a half-maximal response at a muscarinic receptor occupancy of just 0.206% in the bladder with a minimal difference from exocrine glands, which raises the adverse drug reaction risk. On the contrary, intravesical antimuscarinics are instilled at concentrations 1000-fold higher than the oral maximum plasma concentration and the equilibrium dissociation constant erects a downhill concentration gradient that drives passive diffusion and achieves a mucosal concentration around ten-fold lower than the instilled concentration for a long-lasting occupation of muscarinic receptors in mucosa and sensory nerves. A high local concentration of antimuscarinics in the bladder triggers alternative mechanisms of action and is supposed to engage retrograde transport to nerve cell bodies for neuroplastic changes that underlie a long-lasting therapeutic effect, while an intrinsically lower systemic uptake of the intravesical route lowers the muscarinic receptor occupancy of exocrine glands to lower the adverse drug reaction relative to the oral route. Thus, the traditional pharmacokinetics and pharmacodynamics of oral treatment are upended by intravesical antimuscarinics to generate a dramatic improvement (~ 76%) noted in a meta-analysis of studies enrolling children with neurogenic lower urinary tract symptoms on the primary endpoint of maximum cystometric bladder capacity as well as the secondary endpoints of filling compliance and uninhibited detrusor contractions. The therapeutic success of intravesical multidose oxybutynin solution or oxybutynin entrapped in the polymer for sustained release in the pediatric population bodes well for patients with lower urinary tract symptoms at the other extreme of the age spectrum. Though generally used to predict oral drug absorption, Lipinski's rule of five can also explain the ten-fold lower systemic uptake from the bladder of positively charged trospium over oxybutynin, a tertiary amine. Chemodenervation by an intradetrusor injection of onabotulinumtoxinA is merited for patients with idiopathic overactive bladder discontinuing oral treatment because of a lack of efficacy. However, age-related peripheral neurodegeneration potentiates the adverse drug reaction risk of urinary retention that motivates the quest of liquid instillation, delivering larger fraction of onabotulinumtoxinA to the mucosa as opposed to muscle by an intradetrusor injection can also probe the neurogenic and myogenic predominance of idiopathic overactive bladder. Overall, the treatment paradigm of lower urinary tract symptoms in older adults should be tailored to individual's overall health status and the risk tolerance for adverse drug reactions.

Outcomes of Artificial Urinary Sphincter Implantation in Patients with Detrusor Underactivity and Postprostatectomy Incontinence.

PURPOSE: There is insufficient evidence for postoperative outcomes of artificial urinary sphincter (AUS) implantation for postprostatectomy incontinence (PPI) with detrusor underactivity (DU). Thus, we assessed the impact of preoperative DU on the outcomes of AUS implantation for PPI. MATERIALS AND METHODS: Medical records of men who underwent AUS implantation for PPI were reviewed. Patients who had bladder outlet obstruction surgery before radical prostatectomy or AUS-related complications that required revision of AUS within three months were excluded. Patients were divided into two groups based on the preoperative urodynamic study including pressure flow study, a DU group, and a non-DU group. DU was defined as a bladder contractility index less than 100. The primary outcome was postoperative postvoid residual urine volume (PVR). The secondary outcomes included maximum flow rate (Qmax), postoperative satisfaction, and international prostate symptom score (IPSS). RESULTS: A total of 78 patients with PPI were assessed. The DU group consisted of 55 patients (70.5%) and the non-DU group comprised 23 patients (29.5%). Qmax was lower in the DU group than in the non-DU group and PVR was higher in the DU group as per a urodynamic study before AUS implantation. There was no significant difference in postoperative PVR between the two groups, although the Qmax after AUS implantation was significantly lower in the DU group. While the DU group showed significant improvements in Qmax, PVR, IPSS total score, IPSS storage subscore, and IPSS quality of life (QoL) score after AUS implantation, the non-DU group showed postoperative improvement in IPSS QoL score. CONCLUSION: There was no clinically significant impact of preoperative DU on the outcome of AUS implantation for PPI; thus, surgery can be safely performed in patients with PPI and DU.

Changes in transient receptor potential vanilloid 1 and transient receptor potential vanilloid 4 in patients with lower urinary tract dysfunction.

PURPOSE: We investigated the association between transient receptor potential vanilloid (TRPV) expression in human urothelium tissue and lower urinary tract dysfunction (LUTD). MATERIALS AND METHODS: We prospectively enrolled men who planned to undergo surgical treatment for benign prostatic obstruction to analyze TRPV1 and TRPV4 expression in the urothelium using enzyme-linked immunosorbent assay and immunofluorescence staining. Patients were divided into two groups based on urodynamics: the detrusor underactivity (DU) group and the non-DU group. Levels of TRPV1 and TRPV4 were compared between the two groups. We also divided patients into two groups according to degree of subjective urinary urgency symptoms using a 5-point urinary sensation scale and compared the differences in TRPV1 and TRPV4 levels between the two groups. The correlations between urodynamic parameters with TRPV1 or TRPV 4 in all patients were also analyzed. RESULTS: The levels of TRPV1 and TRPV 4 were not significantly different between the DU group (n=10) and the non-DU group (n=11). When we divided the patients according to degree of subjective urgency, the level of TRPV1 was not significantly different between the urgency group (n=10) and the non-urgency group (n =11), but the level of TRPV4 was significantly increased in the urgency group (p=0.029). There was no significant correlation between the level of TRPV1 or TRPV4 and urodynamic parameters in any patients. CONCLUSIONS: TRPV4 could be a useful diagnostic biomarker for patients with LUTD.

Translation and validation of the Korean version of acute cystitis symptom score.

PURPOSE: Acute Cystitis Symptom Score (ACSS) is a simple self-reporting questionnaire initially developed in Uzbek language to help diagnose acute uncomplicated cystitis (AUC). The purpose of this study was to translate the ACSS to Korean and validate the Korean version of ACSS using Korean-speaking women. MATERIALS AND METHODS: The original version of ACSS in Uzbek was translated into the target (Korean) version according to internationally accepted guidelines for the translation and cultural adaptation. Cognitive interviews were then conducted for five women with symptoms of AUC and five women without AUC who were native speakers of the Korean language to investigate the clarity, understandability, and acceptability of the translation. The final Korean version of the ACSS was tested in 50 women (31 AUC patients and 19 controls) for clinical validation. RESULTS: Reliability test for 9 questions (6 questions about typical symptoms of AUC, and 3 questions on quality of life) showed high values (Cronbach's alpha=0.853). The sum score of typical symptoms showed the highest balance for diagnostic sensitivity and specificity (area under the ROC curve=0.935). Sensitivity and specificity to predict AUC were 90.3% and 89.5% at cut-off score 6 of the typical domain. CONCLUSIONS: The Korean version of the ACSS showed high levels of reliability and validity, similar to other validated versions in different languages. It will play an important role in practice and/or clinical research for diagnosis and treatment efficacy monitoring of Korean-speaking women suffering from AUC.

Correlation Between Nitric Oxide and Urodynamics in Men With Bladder Outlet Obstruction.

PURPOSE: To investigate the correlation between nitric oxide (NO) and urodynamics in men with bladder outlet obstruction (BOO) by analyzing nitric oxide synthase (NOS) in the urothelium. METHODS: We prospectively enrolled 25 men who planned to undergo surgical treatment for benign prostatic obstruction and identified as BOO in the preoperative urodynamics. Bladder tissue was taken during surgical prostate resection. Expressions of endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS) in the urothelium were analyzed, and their correlation with urodynamic parameters was also assessed in all patients. We also compared the expressions of eNOS, iNOS, and nNOS between BOO with detrusor underactivity (DU) group and BOO without DU group. RESULTS: In all patients, the level of eNOS positively correlated with maximal flow rate and with maximum cystometric capacity (MCC). The level of iNOS positively correlated with MCC. nNOS levels were positively correlated with detrusor pressure at maximal flow and with bladder contractility index in all patients. The level of eNOS, iNOS, and nNOS did not significantly differ between BOO without DU group and BOO with DU group. CONCLUSION: This study suggests that NO was correlated with bladder dysfunction in men with BOO. Particularly, nNOS may reflect the change in detrusor function.

Management of Urinary Incontinence With Underactive Bladder: A Review.

Urinary incontinence is caused by storage function failure, while underactive bladder (UAB) is caused by a decline in detrusor contractility and voiding dysfunction. As the treatment mechanisms for incontinence and UAB are contrary to each other, it is difficult to treat both incontinence and UAB, and the patient's quality of life can be further degraded. Conventional midurethral sling (MUS), such as transobturator tape or retropubic MUS, introduces a risk of postoperative voiding dysfunction in stress urinary incontinence with UAB. However, there have been several reports about the efficacy and safety of conventional MUS. Adjustable sling procedures, such as transobturator adjustable tape or the Remeex system, have better outcomes than conventional MUS because they control tension both during and after surgery. When voiding dysfunction occurs after incontinence treatment with UAB, voiding symptoms can be improved by various therapeutic modalities. Clean intermittent catheterization is recommended for patients with significant increased postvoid residual volumes or urinary retention. Although pharmacotherapy such as with alpha-blockers or parasympathomimetics can be considered for UAB, there is insufficient evidence of their effect on incontinence with UAB. Future therapies, such as stem cell therapy or gene therapy, may be used to treat incontinence with UAB. The possibility of management urgency urinary incontinence that related to detrusor hyperactivity with impaired contractility using sacral neuromodulation has been suggested. Further research is needed to establish evidence for the efficacy and safety of treatments for incontinence with UAB and improve patient quality of life.

Changes in uroplakin expression in the urothelium of patients with ulcerative interstitial cystitis/bladder pain syndrome.

Purpose: We evaluated changes in the expression of uroplakin (UP) in the urothelium of patients with ulcerative interstitial cystitis/bladder pain syndrome (IC/BPS). Materials and Methods: Bladder samples were collected from 19 patients with ulcerative IC/BPS who were treated with augmentation ileocystoplasty and from 5 control patients. Frequency-volume charts, the pain visual analogue scale (VAS), and the O'Leary-Sant interstitial cystitis symptom index (ICSI) and problem index (ICPI) were used to evaluate the patients' symptoms preoperatively. The expression levels of UP-Ib and UP-III in the urothelium were compared between the IC/BPS patients and control patients. Results: Sixteen women and three men with IC/BPS were evaluated. Their values for preoperative mean voiding frequency, number of nocturia episodes, and functional bladder capacity as recorded in frequency-volume charts were 21.1±12.8, 5.9±4.2, and 151.1±62.7 mL, respectively. The mean pain VAS, ICSI, and ICPI scores were 8.4±1.3, 17.7±2.2, and 14.7±1.8, respectively. Immunofluorescence staining showed that UP-Ib and UP-III were localized in the urothelium. Upon Western blot analysis, the expression of UP-III was significantly increased in the IC/BPS group compared with the control group. However, expression of UP-Ib did not differ significantly between the IC/BPS and control groups. Conclusions: UP-III was significantly upregulated in patients with ulcerative IC/BPS. UP-III is a potential biomarker for the diagnosis of ulcerative IC/BPS.

Evaluating the Efficacy and Safety of Silodosin on Nocturia in Patients With Benign Prostatic Hyperplasia: A Multicenter, Prospective, Open-label, Single-arm, Phase IV Trial.

OBJECTIVE: To evaluate the efficacy and safety of silodosin on nocturia in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: This was a 12-week, single-arm, open-label, prospective, multicenter study. The study included men aged 50 years or older with nocturia (≥2 events/night) based on a voiding diary, an International Prostate Symptom Score (IPSS) ≥8, and a quality of life score ≥3. Enrolled patients received 8 mg of silodosin once daily for 12 weeks. We evaluated changes in the mean number of nocturia episodes (using a voiding diary) from baseline to the final assessment. Safety assessments included the rate of adverse events and adverse drug reactions. RESULTS: There were 118 patients included in the safety evaluation analysis, and 112 patients in the full analysis set group. The number of nocturia episodes decreased significantly after 12 weeks of treatment with silodosin (-1.12 ± 1.05, P < .0001). The secondary efficacy variables, including IPSS, overactive bladder symptom score and International Consultation on Incontinence Questionnaire-Nocturia score, also improved with treatment (P < .0001). There were abnormal drug reactions in 11.8% of patients. The most common adverse drug reaction was an ejaculatory disorder (7.6%). There were no significant adverse drug reactions reported. CONCLUSION: Silodosin was found to be safe and effective in the treatment of nocturia in patients with BPH.

A useful method for assessing differences of compensatory hypertrophy in the contralateral kidney before and after radical nephrectomy in patients with renal cell carcinoma: ellipsoid formula on computed tomography.

OBJECTIVE: To investigate the usefulness of the ellipsoid formula for assessing compensatory hypertrophy of the contralateral kidney on pre-operative and post-operative CT in renal cell carcinoma (RCC) patients. METHODS: We retrospectively identified 389 patients who had radical nephrectomy for RCC between 2011  and 2015. Contrast-enhanced CT was performed within 3 months pre-operative and at 1 year post-operative. The kidney volumes were calculated from CT using the ellipsoid formula. We subdivided patients into three groups based on tumour size (I: ≤4 cm, II: 4-7 cm, III: >7 cm). Volumetric renal parameters were compared and multivariate analyses were performed to determine predictors associated with pre-operative  and post-operative compensatory hypertrophy. RESULTS: Kidney volume calculation using the ellipsoid  method took a median of 51 s. Group III had a significantly larger median pre-operative contralateral renal volume than Groups I and II (I:  140.4, II: 141.6, III: 166.7 ml, p < 0.05). However, the median ratio of post-operative contralateral renal volume change was significantly higher in Groups I and II than Group III (I: 0.36, II: 0.23, III: 0.12, p < 0.001). On multivariate analysis, tumour size revealed the strongest positive association with pre-operative contralateral kidney volume (partial regression coefficient: ß = 30.8, >7 cm) and ratio of post-operative contralateral kidney volume change (ß  = 0.214, I vs III; ß = 0.168, II vs III). CONCLUSION: Kidney volume calculation for assessing pre- and post-operative compensatory hypertrophy of the contralateral kidney in RCC patients can be easily and rapidly performed from CT images using the ellipsoid formula. Advances in knowledge: The ellipsoid formula allows reliable method for assessing pre-operative and post-operative compensatory hypertrophy of the contralateral kidney in RCC.

Expression of cannabinoid 1 and, 2 receptors and the effects of cannabinoid 1 and, 2 receptor agonists on detrusor overactivity associated with bladder outlet obstruction in rats.

BACKGROUND: This study investigated changes in the expression of cannabinoid (CB) receptors and the effects of CB1 and CB2 agonists on detrusor overactivity (DO) associated with bladder outlet obstruction (BOO) in rats. METHODS: Male Sprague Dawley rats were randomly assigned to four groups (n = 10) in each group. The control group comprised sham-operated rats. A animals in the BOO, CB1 agonist and CB2 agonist groups all underwent BOO surgery. Three weeks postoperatively, cystometrography (CMG) was performed on all rats. After confirming the presence of DO in the CB1 and CB2 agonist groups, a CB1 agonist (WIN 55,212-2) and a CB2 agonist (CB65) were instilled intravesically, and CMG was repeated. CMG parameters, including the contraction interval (CI) and contraction pressure (CP) were then analyzed. The bladders of rats in all four groups were excised following CMG. Immunofluorescence staining and Western blotting were performed to localize CB1 and CB2 and measure their expression levels in the urothelium and detrusor muscle. RESULTS: The CI was significantly longer and the CP was significantly lower in the CB1 agonist group than in the BOO group. CI and CP in the CB2 agonist group showed the same results. CB1 receptor immunofluorescence staining signals and immunoreactive bands in Western blotting were increased in the BOO group compared with results in the control group. Similarly, results for the CB2 receptor were also increased in the BOO group, although this difference was not significant. The CMG parameters in the BOO group were significantly improved by the inhibitory effects of CB1 and CB2 agonists on BOO-associated DO. The expression of CB1 was significantly increased in the urothelium and detrusor muscle in BOO-associated DO, but no significant change in CB2 expression was observed. CONCLUSIONS: CB1 and CB2 receptors, especially CB1, play a role in the pathophysiology of BOO-associated DO, and could serve as therapeutic targets.

Changes in Adenosine Triphosphate and Nitric Oxide in the Urothelium of Patients with Benign Prostatic Hyperplasia and Detrusor Underactivity.

PURPOSE: We investigated changes in the levels of adenosine triphosphate and nitric oxide in the urothelium of men with detrusor underactivity and benign prostatic hyperplasia. MATERIALS AND METHODS: We prospectively enrolled in study 30 men who planned to undergo surgical treatment for benign prostatic hyperplasia. The 15 patients with a bladder contractility index less than 100 were assigned to the detrusor underactivity group while the 15 with a bladder contractility index more than 100 were assigned to the no detrusor underactivity group. Bladder mucosal specimens were collected at surgical prostate resection, and adenosine triphosphate and endothelial nitric oxide synthase were analyzed in these specimens. The levels of adenosine triphosphate and endothelial nitric oxide synthase were compared between the 2 groups. The correlation of urodynamic parameters with adenosine triphosphate and endothelial nitric oxide synthase was assessed in all patients. RESULTS: Mean ± SEM endothelial nitric oxide synthase did not significantly differ between the detrusor underactivity and no underactivity groups (3.393 ± 0.969 vs 1.941 ± 0.377 IU/ml, p = 0.247). However, the mean level of adenosine triphosphate in the detrusor underactivity group was significantly lower than in the no detrusor underactivity group (1.289 ± 0.320 vs 9.262 ± 3.285 pmol, p = 0.011). In addition, in all patients adenosine triphosphate positively correlated with the bladder contractility index (r = 0.478, p = 0.018) and with detrusor pressure on maximal flow (r = 0.411, p = 0.046). CONCLUSIONS: Adenosine triphosphate was significantly decreased in the urothelium in men with detrusor underactivity and benign prostatic hyperplasia, reflecting the change in detrusor function.

Expressions of vaginal endothelial nitric oxide synthase and phosphodiesterase 5 in female sexual dysfunction: a pilot study.

INTRODUCTION AND HYPOTHESIS: The objective was to investigate the expression of endothelial nitric oxide synthase (eNOS) and phosphodiesterase (PDE) 5 in vaginal tissue of premenopausal women experiencing stress urinary incontinence (SUI) with and without sexual dysfunction. METHODS: Women presenting for treatment of SUI were screened using the Female Sexual Function Index (FSFI) and 10 were selected who met the criteria for female sexual dysfunction (FSD) and 10 asymptomatic controls. Vaginal tissue specimens were obtained from those premenopausal women aged ≥40 years who had had sexual activity ≥2 times every month for the last 6 months and who were scheduled to undergo surgery for SUI. FSD criteria was FSFI scores <18 and arousal domain scores <3. The control group had FSFI scores ≥26 and individual domain scores ≥4. The expressions of eNOS and PDE 5 were compared in the two groups using immunofluorescence staining and western blotting. RESULTS: The mean total FSFI scores were 30.4 ± 2.6 and 15.3 ± 2.3 in the control and FSD groups respectively. In immunofluorescence staining, eNOS and PDE5 were localized in the vaginal epithelium. In western blotting, the expressions of eNOS and PDE5 were significantly lower in the FSD group than in the control group (p = 0.003 and p = 0.038 respectively). CONCLUSIONS: eNOS and PDE5 in the vagina may play important roles in the pathophysiology of FSD.

Predictors of urgency improvement after Holmium laser enucleation of the prostate in men with benign prostatic hyperplasia.

PURPOSE: To investigate the change in urinary urgency and predictors of urgency improvement after holmium laser enucleation of the prostate (HoLEP) in men with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: We retrospectively analyzed the medical records of patients who were treated with HoLEP for BPH and had preoperative urgency measuring ≥3 on a 5-point urinary sensation scale. Those with prostate cancer diagnosed prior to or after HoLEP, a history of other prostatic and/or urethral surgery, moderate to severe postoperative complications, and neurogenic causes were excluded. Patients who had improved urgency with antimuscarinic medication after HoLEP were excluded. We divided the patients into 2 groups based on urgency symptoms 3 months after HoLEP: improved and unimproved urgency. Improved urgency was defined as a reduction of 2 or more points on the 5-point urinary sensation scale. Preoperative clinical and urodynamic factors as well as perioperative factors were compared between groups. RESULTS: In total, 139 patients were included in this study. Voiding parameters in all patients improved significantly after HoLEP. Seventy-one patients (51.1%) had improved urgency, while 68 (48.9%) did not show any improvement. A history of acute urinary retention (AUR) and postvoid residual were associated with postoperative urgency improvement in univariate analysis. In multivariate analysis, a history of AUR was an independent factor affecting urgency improvement. CONCLUSIONS: A preoperative history of AUR could influence the change in urgency after HoLEP surgery in patients with BPH.

Hyaluronic acid-carboxymethylcellulose reduced postoperative bowel adhesions following laparoscopic urologic pelvic surgery: a prospective, randomized, controlled, single-blind study.

BACKGROUND: To assess the anti-adhesive effect of treatment with hyaluronic acid-carboxymethylcellulose following laparoscopic radical prostatectomy. METHODS: This was a randomized, controlled, single-blind, parallel-group study using hyaluronic acid-carboxymethylcellulose in patients who underwent laparoscopic radical prostatectomy. Sixty patients were enrolled in the study. All patients were randomly assigned to either the hyaluronic acid-carboxymethylcellulose treatment group (n = 30) or the control group (n = 30). Viscera slide ultrasounds and plain X-rays were obtained at enrollment (V0), postoperative week 12 (V1), and 24 (V2). The primary end point was the difference in the excursion distance in the viscera slide ultrasound between V0 and V2. RESULTS: A total of 50 patients completed this study. The average excursion distance at V2 in the experimental group (n = 25) was significantly longer than in the control group (n = 25, 2.7 ± 1.2 vs. 1.3 ± 1.0 cm, respectively; p < 0.001). The differences in the V0 and V2 excursion distances were significantly higher in the control group than in the experimental group (1.48 ± 1.5 vs. 2.9 ± 1.2 cm, respectively; p < 0.001). None of patients showed adverse events associated with the use of hyaluronic acid-carboxymethylcellulose. CONCLUSION: This randomized study demonstrated that hyaluronic acid-carboxymethylcellulose treatment resulted in a reduction in bowel adhesion to the abdominal wall after laparoscopic pelvic surgery and had good clinical safety. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02773251 Date: May 12, 2016.

Evaluation of female overactive bladder using urodynamics: relationship with female voiding dysfunction

ABSTRACTPurpose:To investigate the role of urodynamic study (UDS) in female patients with overactive bladder (OAB) analyzing the relationship between OAB symptoms and female voiding dysfunction (FVD).Materials and Methods:We analyzed the clinical and urodynamic data of 163 women with OAB symptoms. OAB symptoms were categorized as dry and wet. FVD was described as detrusor underactivity (DUA), which was defined as a maximum flow rate (Qmax) of ≤15mL/s associated with a detrusor pressure at Qmax (PdetQmax) of ≤20cmH2O, along with bladder outlet obstruction (BOO), which was defined as a Qmax of ≤15mL/s with a PdetQmax of >20cmH2O. Clinical and urodynamic results were compared between patients with dry and wet symptoms and between those with and without FVD.Results:78 (47.9%) had dry, and 85 (52.1%) had wet symptoms. The entire group had a relatively low Qmax (15.1±6.6mL/s) and relatively high number of BOO (42.9%, 70/163) and DUA (8.6%, 14/163). A significantly higher number of patients with wet symptoms had detrusor overactivity compared to those with dry, as detected by the UDS (p<0.05). No significant differences were found in BOO and DUA number between dry and wet groups. Further, the international prostate symptom score did not different significantly between patients with and without FVD.Conclusion:A significant number of women with OAB had voiding dysfunction. However, the OAB symptoms themselves were not useful for predicting the presence of FVD. Therefore, UDS may be necessary for accurate diagnosis in women with OAB symptoms.

Expression of transient receptor potential vanilloid 4 and effects of ruthenium red on detrusor overactivity associated with bladder outlet obstruction in rats.

PURPOSE: To investigate transient receptor potential vanilloid 4 (TRPV4) expression and the effects of ruthenium red (RR)-TRPV antagonist-on detrusor overactivity (DO) associated with bladder outlet obstruction (BOO). METHODS: Rats were randomly assigned to 3 groups. The control group (n = 10) included sham-operated rats. The BOO-group without RR (n = 15) and BOO-group with RR (n = 15) underwent partial BOO surgery. Three weeks postoperatively, cystometrography was performed in all rats. After confirming DO, RR was instilled intravesically in the BOO-group with RR. Urodynamic parameters were investigated, including contraction interval (CI) and contraction pressure (CP). TRPV4 expression was evaluated through immunofluorescence staining and western blotting. RESULTS: The BOO-group without RR had significantly shorter CI and significantly higher CP compared to the control. In the BOO-group with RR, CI was significantly longer compared to the BOO-group without RR. However, change in CP between BOO-group without and with RR was not significantly different. Immunofluorescence staining showed that TRPV4 was localized in the urothelium and detrusor muscles. TRPV4 immunofluorescence signals were increased in the urothelium and detrusor muscle in BOO-group without RR, compared with the control. In western blot analysis, immunoreactive bands indicating expression of TRPV4 were detected in the urothelium and detrusor muscle, and those were significantly increased in the BOO-group without RR compared with the control in the urothelium and detrusor muscle. CONCLUSIONS: TRPV4 plays an important role in the pathophysiology of DO, and RR has a beneficial effect on DO associated with BOO.