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Angiotensin II signaling plays a crucial role in many different diseases. Although it has been known for several decades that local angiotensin II signaling molecules are present in the bladder, the understanding of their functions there is still limited, especially compared with other organ systems such as cardiovascular and respiratory systems. This article reviews current literature regarding local angiotensin II signaling in the urinary bladder. By reviewing several decades of literature, the field has provided strong evidence to support the presence of local angiotensin II signaling in the bladder, including the expression of angiotensin type 1 receptor and angiotensin type 2 receptor in both human and animal tissues. In addition, evidence suggests a functional role of angiotensin type 1 receptor in mediating bladder contractions. In bladder disease models, angiotensin II signaling can be upregulated, and angiotensin type 1 receptor activity is associated with increases in inflammation, fibrosis, and oxidative stress. We also address the gaps in knowledge that remain in understanding local angiotensin II signaling in the bladder, including limitations on clinical translatability. Although there is a strong foundation regarding the local presence and role of angiotensin II signaling in the bladder, further research is needed to support translational applications.

Purpose: Diabetic bladder dysfunction (DBD) is the most common diabetic complication. Logically, regulation of blood glucose should reverse dysfunction, but the Epidemiology of Diabetes Interventions and Complications study found strict control ineffective. However, it is possible that strict control may prevent DBD if initiated before symptoms appear. We examine the effect of early glucose control on development of DBD in the female diabetic Akita mouse (Type 1) and test the potential of inhibiting/deleting NLRP3 as adjunct therapy to glucose control., Materials and Methods: Female Akita mice were bred NLRP3 +/+ or NLRP3 -/- . At 6 weeks of age, diabetics received either no glucose control or insulin pellets (s.c., Linshin) designed to poorly or strictly control blood glucose. At Week 15, blood glucose (glucometer), the extravasation potential of bladder (an indirect measurement of inflammation) and bladder function (urodynamics) were assessed., Results: Blood glucose of diabetics was reduced in poorly controlled and strongly reduced in strictly controlled groups. Levels were not affected by deletion of NLRP3. Evans blue dye extravasation correlated with glucose control and was eliminated in the NLRP3 -/-  groups. Urodynamics found markers of overactivity in diabetics which was improved in the poorly controlled group and eliminated in the strictly controlled group. In the NLRP3 -/-  mice, no bladder dysfunction developed, regardless of glucose control., Conclusions: Early-initiated strict glycemic control and NLRP3 elimination can effectively prevent DBD, suggesting hyperglycemia acts through NLRP3-induced inflammation to trigger DBD., (© 2024 Wiley Periodicals LLC.)

Objective: To observe the efficacy of pelvic floor muscle training combined with electroacupuncture (EA) for bladder dysfunction after incomplete spinal cord injury (SCI)., Methods: Ninety patients with bladder dysfunction after incomplete SCI were randomly divided into an EA group (30 cases), a pelvic floor muscle training group (30 cases, 1 case dropped out), and a combined group (30 cases, 1 case dropped out). All groups received routine rehabilitation. The EA group received EA at Zhongji (CV 3), Guanyuan (CV 4), Mingmen (GV 4), Yaoyangguan (GV 3), bilateral Shenshu (BL 23), Ciliao (BL 32), and Pangguangshu (BL 28), with continuous waves at frequency of 100 Hz, and the needles were retained for 30 min, once daily, 6 times a week for 6 weeks. The pelvic floor muscle training group underwent pelvic floor muscle training two times a day, for 6 weeks. The combined group received both EA and pelvic floor muscle training. The daily average number of urinations, daily average number of urinary leakages, urodynamic indexes (residual urine volume, maximum bladder capacity, bladder compliance, and maximum urine flow rate), and generic quality of life inventory-74 (GQOLI-74) were compared before and after treatment in each group., Results: Compared before treatment, the daily average number of urinations and urinary leakages were decreased ( P <0.05), residual urine volume, maximum bladder capacity, and bladder compliance were reduced ( P <0.05), and maximum urine flow rate and GQOLI-74 scores were increased ( P <0.05) after treatment in all groups. After treatment, the combined group showed greater differences in the daily average number of urinations, daily average number of urinary leakages, residual urine volume, maximum bladder capacity, bladder compliance, maximum urine flow rate, and GQOLI-74 score compared to the EA group and the pelvic floor muscle training group ( P <0.05). There was no statistically significant differences in the changes in these indexes between the EA group and the pelvic floor muscle training group ( P >0.05)., Conclusion: Pelvic floor muscle training combined with EA can effectively alleviate urination problems in patients with bladder dysfunction after incomplete SCI, improve bladder function, and enhance patients' quality of life.

Objectives: Diabetes is highly prevalent worldwide, with an estimated 536 million living with diabetes in 2021, and that number projected to increase to 783 million by 2045. Diabetic bladder dysfunction is thought to affect up to 60%-90% of individuals with diabetes and can significantly impact quality of life. Despite the prevalence of diabetic bladder dysfunction, the exact pathophysiological mechanism, and resulting clinical presentation, remains debated. Our objective was to compare urodynamic parameters between diabetic and nondiabetic women, assessing the impact of various markers of diabetes severity on bladder function., Methods: A retrospective chart review was conducted on female patients aged 18 and above who underwent urodynamic studies at a single tertiary care university hospital system from 2014 to 2020. Patients were categorized based on diabetes status, and diabetes severity including duration of disease, hemoglobin A1c levels, insulin dependence, and markers of end-organ dysfunction. Urodynamic variables, including compliance, bladder voided efficiency, bladder contractility index, postvoid residual, maximum flow rate, capacity, voided volume, and detrusor overactivity, were assessed by two independent reviewers. Statistical analyses were performed to assess the impact of diabetes and diabetic severity on urodynamic parameters., Results: A total of 652 female patients were included in the study, of which, 152 (23.3%) had diabetes, with an average duration of diagnosis of 82.3 months. Diabetic women were older and had higher body mass index compared to nondiabetic women. Diabetic retinopathy and neuropathy were present in 18% and 54.6% of diabetic patients, respectively. Significant differences in urodynamic parameters were observed between diabetic and nondiabetic women, with diabetic women showing higher rates of detrusor overactivity (p = 0.01), particularly associated with increasing BMI (p = 0.03). However, classic markers of diabetes severity including duration, as well as markers of end-organ damage, showed mixed associations with urodynamic changes., Conclusions: Despite the prevalence of diabetic bladder dysfunction and its impact on patient quality of life, the exact mechanisms and clinical presentation remain elusive. Our study highlights the significant differences in urodynamic parameters between diabetic and nondiabetic women, emphasizing the need for further research into the relationship between diabetes and diabetic bladder dysfunction., (© 2024 The Author(s). Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Aims: The nitric oxide (NO•)/soluble guanylate cyclase/cyclic-GMP (cGMP) signaling pathway is ubiquitous and regulates several functions in physiological systems as diverse as the vascular, nervous, and renal systems. However, its roles in determining normal and abnormal lower urinary tract functions are unclear. The aim was to identify potential therapeutic targets associated with this pathway to manage lower urinary tract functional disorders., Methods: This review summarizes a workshop held under the auspices of ICI-RS with a view to address these questions., Results: Four areas were addressed: NO• signaling to regulate neurotransmitter release to detrusor smooth muscle; its potential dual roles in alleviating and exacerbating inflammatory pathways; its ability to act as an antifibrotic mediator; and the control by nitrergic nerves of lower urinary tract vascular dynamics and the contractile performance of muscular regions of the bladder wall. Central to much of the discussion was the role of the NO• receptor, soluble guanylate cyclase (sGC) in regulating the generation of the enzyme product, the second messenger cGMP. The redox state of sGC is crucial in determining its enzymic activity and the role of a class of novel agents, sGC activators, to optimize activity and to potentially alleviate the consequences of lower urinary tract disorders was highlighted. In addition, the consequences of a functional relationship between nitrergic and sympathetic nerves to regulate vascular dynamics was discussed., Conclusions: Several potential NO•-dependent drug targets in the lower urinary tract were identified that provide the basis for future research and translation to clinical trials., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Background: It is increasingly significant that adults with diabetes experience lower urinary tract symptoms, however, there has been limited research in younger individuals with type 1 diabetes., Objective: To investigate bladder function using non-invasive urodynamics as a potential indicator of autonomic neuropathy in adolescents with type 1 diabetes. This involved examining the association between urinary flow disturbances, reported symptoms, and results from other autonomic tests., Study Design: Cross-sectional study enrolling 49 adolescents with type 1 diabetes and 18 control subjects. All participants underwent uroflowmetry and ultrasound scanning, completed the Composite Autonomic Symptom Score (COMPASS)-31 questionnaire, and were instructed to record their morning urine volume and voiding frequencies and report them back. Cardiovascular reflex tests (CARTs) and the quantitative sudomotor axon reflex test (QSART) were performed., Results: The main results are shown in the Summary figure., Discussion: In this study, urological abnormalities were not significantly more frequent in adolescents with diabetes, however, urological issues were observed. This is supported by previous findings of Szabo et al. who found that adolescents with type 1 diabetes had reduced flow acceleration and time to maximum flow compared to control subjects. In our study, we observed cases with reduced acceleration and prolonged uroflow curves, possibly indicating detrusor underactivity. People with diabetes had a higher risk of nocturia than healthy controls, which our results supported. Some adolescents reported urination twice per night. Based on these findings, it is considered beneficial to ask about urological symptoms annually to determine if more examinations (frequency-volume charts and uroflowmetry) are necessary and/or if any opportunities for treatment optimization exist. However, uroflowmetry has limitations, as bladder filling and emptying is a complex process involving multiple pathways and neurological centers, making it difficult to standardize and evaluate. Another limitation of this study was that our control group was smaller and consisted of fewer males than females, which could affect the results due to differences in anatomy and physiology in the lower urinary tract system., Conclusion: In conclusion, adolescents with type 1 diabetes, as well as healthy adolescents, frequently experience urological symptoms. Although urological abnormalities were not significantly more frequent in adolescents with diabetes in this study, the focus on nocturia and risk for bladder dysfunction seems relevant, even in adolescents without any other tests indicating autonomic dysfunction., Competing Interests: Conflict of interest No potential conflicts are relevant to this article., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Opinions differ on what drugs have both a rationale and a development potential for the treatment of bladder storage dysfunction., Areas Covered: In the present review, the focus is given to small molecule blockers of TRP channels (TRPV1, TRPV4, TRPA1, and TRPM8), P2 × 3receptor antagonists, drugs against oxidative stress, antifibrosis agents, cyclic nucleotide - dependent pathways, and MaxiK±channel - gene therapy., Expert Opinion: TRPV1 channel blockers produce hypothermia which seems to be a problem even with the most efficacious second-generation TRPV1 antagonists. This has so far precluded their application to urine storage disorders. Other TRP channel blockers with promising rationale have yet to be tested on the human lower urinary tract. The P2 × 3receptor antagonist, eliapixant, was tested in a randomized controlled clinical trial, was well tolerated but did not meet clinical efficacy endpoints. Antifibrosis agent still await application to the human lower urinary tract. New drug principles for oxidative stress, purine nucleoside phosphorylase inhibition, and NOX inhibition are still at an experimental stage, and so are soluble guanylate cyclase stimulators. Gene therapy with MaxiK±channels is still an interesting approach but no new trials seem to be in pipeline.

Introduction: Bladder storage dysfunction is associated with low quality of life in men and remains a challenging field in pharmacotherapy because of low persistence followed by patient-perceived lack of efficacy and adverse effects. The persistent desire for the development of novel pharmacotherapy is evident, leading to numerous research efforts based on its pathophysiology., Areas Covered: This review describes the pathophysiology, current pharmacotherapeutic strategies, and emerging novel drugs for male bladder storage dysfunction. The section on emerging pharmacotherapy provides an overview of current research, focusing on high-potential target molecules, particularly those being evaluated in ongoing clinical trials., Expert Opinion: As pharmacotherapies targeting alpha-adrenergic, beta-adrenergic, and muscarinic receptors - the current primary targets for treating male bladder storage dysfunction - have demonstrated insufficient efficacy and side effects, researchers are exploring various alternative molecular targets. Numerous targets have been identified as central to regulating bladder afferent nerve activity, and their pharmacological effects and potential have been evaluated in animal-based experiments. However, there is a limited number of clinical trials for these new pharmacotherapies, and they have not demonstrated clear superiority over current treatments. Further research is needed to develop new effective pharmacotherapies for bladder storage dysfunction in men.

Stress causes symptom exacerbation in functional disorders of the urinary bladder. However, the potential mediators and underlying mechanisms of stress effects on micturition reflex function are unknown. We have characterized PACAP (Adcyap1) and PAC1 receptor (Adcyap1r1) signaling in stress-induced urinary bladder dysfunction in mice. We determined PACAP and PAC1 transcripts and protein expressions in the urinary bladder and lumbosacral dorsal root ganglia (DRG) and spinal cord in repeated variate stress (RVS) or control mouse (handling only) groups. RVS in mice significantly (p ≤ 0.01) increased serum corticosterone and urinary bladder NGF content and decreased weight gain. PACAP and PAC1 mRNA and protein were differentially regulated in lower urinary tract tissues with changes observed in lumbosacral DRG and spinal cord but not in urinary bladder. RVS exposure in mice significantly (p ≤ 0.01) increased (2.5-fold) voiding frequency as determined using conscious cystometry. Intrabladder administration of the PAC1 receptor antagonist, PACAP(6-38) (300 nM), significantly (p ≤ 0.01) increased infused volume (1.5-2.7-fold) to elicit a micturition event and increased the intercontraction interval (i.e., decreased voiding frequency) in mice exposed to RVS and in control mice, but changes were smaller in magnitude in control mice. We also evaluated the effect of PAC1 blockade at the level of the urinary bladder on pelvic sensitivity in RVS or control mouse groups using von Frey filament testing. Intrabladder administration of PACAP(6-38) (300 nM) significantly (p ≤ 0.01) reduced pelvic sensitivity following RVS. PACAP/receptor signaling in the CNS and PNS contributes to increased voiding frequency and pelvic sensitivity following RVS and may represent a potential target for therapeutic intervention., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

This study evaluated the time-course changes in bladder and external urinary sphincter (EUS) activity and the expression of mechanosensitive channels in lumbosacral dorsal root ganglia (DRG) after spinal cord injury (SCI). Female C57BL/6N mice in the SCI group underwent transection of the Th8/9 spinal cord. Spinal intact mice and SCI mice at 2, 4, and 6 wk post-SCI were evaluated by single-filling cystometry and EUS-electromyography (EMG). In another set of mice, the bladder and L6-S1 DRG were harvested for protein and mRNA analyses. In SCI mice, nonvoiding contractions were confirmed at 2 wk post-SCI and did not increase over time to 6 wk. In 2-wk SCI mice, EUS-EMG measurements revealed detrusor sphincter dyssynergia, but periodic EMG reductions during bladder contraction were hardly observed. At 4 wk, SCI mice showed increases of EMG activity reduction time with increased voiding efficiency. At 6 wk, SCI mice exhibited a further increase in EMG reduction time. RT-PCR of L6-S1 DRG showed increased mRNA levels of transient receptor potential vanilloid 1 and acid-sensing ion channels (ASIC1-ASIC3) in SCI mice with a decrease of ASIC2 and ASIC3 at 6 wk compared with 4 wk, whereas Piezo2 showed a slow increase at 6 wk. Protein assay showed SCI-induced overexpression of bladder brain-derived neurotrophic factor with a time-dependent decrease post-SCI. These results indicate that detrusor overactivity is established in the early phase, whereas detrusor sphincter dyssynergia is completed later at 4 wk with an improvement at 6 wk post-SCI, and that mechanosensitive channels may be involved in the time-dependent changes. NEW & NOTEWORTHY This is the first paper to evaluate the time-course changes of bladder dysfunction associated with mechanosensitive channels in a mouse model.

Introduction: Detrusor contractility (DC) can have a considerable impact on the management oflower urinary tract symptoms (LUTS). However, it is currently impossible to predict, based on clinical data alone, which woman has an impaired DC. Our aim was to determine if DC, assessed by projected isovolumetric pressure-1 (PIP1) and VBN contractility parameter k, was associated with age, main complaint, and urodynamic diagnosis in a population of older women., Methods: Pressure-flow studies of non-neurologic post menopausal women over 65 referred for investigation of LUTS were retrospectively analyzed. Associations between DC indices PIP1 and k, and age, main complaint and urodynamic diagnosis were assessed in univariate analysis., Results: One hundred and ninety women were included (mean age 74.5 years). There was no significant association between detrusor contractility indices and age considered as a continuous or a categorical variable. Urge urinary incontinence was significantly associated with greater detrusor contractility regardless of age. Regarding urodynamic diagnoses, DC was greater when bladder outlet obstruction and detrusor overactivity were diagnoses vs. detrusor underactivity alone or associated with detrusor overactivity, regardless of age., Conclusion: PIP1 and k indices allow an easy evaluation of detrusor contractility. In that population of older, post menopausal women, no significant change in the value of the indices is observed with aging whatever the complaint or the urodynamic diagnosis. None of these indices has predominance., Level of Evidence: 4., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Objective: The present study aimed to investigate the protective effect of nebivolol in the bladder isolated from rats exposed to ischemia-reperfusion (IR) injury., Methods: Sprague-Dawley rats were divided into control, IR, and nebivolol+IR groups. In the nebivolol+IR group, nebivolol was administered (0.4 mg/kg, subcutaneous) in rats prior to IR insult. At the end of the experimental protocol, the urinary bladder was rapidly isolated and bladder strips were mounted in an organ bath. After the equilibration period, potassium chloride (KCl, 20-100 mM) or carbachol (0.01-10 μM) was cumulatively added to the organ bath to generate cumulative concentration-response curves (CCRCs). Oxidative stress and interleukin 6 (IL-6) levels were also evaluated in the bladder tissue., Results: The CCRCs of KCl and carbachol were significantly reduced in the IR group compared to those of the control, and this inhibition was reversed by the pretreatment of rats with nebivolol (P < .05). The IR group's total antioxidant status was significantly lower with a concomitant increase in IL-6 levels than that of the control and nebivolol+IR groups (P < .05)., Conclusions: The present study indicates that pretreatment of rats with nebivolol (0.4 mg/kg) could improve bladder contractile dysfunction caused by IR injury through suppression of increased oxidative stress and IL-6 levels., (© 2020 John Wiley & Sons Australia, Ltd.)

Objective: To investigate the incidence of diabetic cystopathy in relation to age, gender, type of diabetes, duration of diabetic disease and clinical evidence of peripheral neuropathy and to analyze the physiopathology of the various forms of diabetic cystopathy due to sensory impairment, motor-sensory impairment, motor impairment and hyperreflexia., Materials and Methods: In a retrospective multicenter cohort study the medical records of a cohort of 126 diabetic patients with (128 patients) or without (48 patients) urological symptoms were analyzed. Patients were observed at the Città di Alessandria Clinic of Policlinico di Monza and/or at the outpatient clinic of Alessandria Hospital from June 2018 to June 2020. The study excluded patients with central and/or peripheral neuropathy, spina bifida (mylomeningocele or meningocele) or spina bifida occulta; with persistent urinary infections; in anticholinergic treatment for enteric dysfunctions; in medical treatment for cervical-prostatic-urethral obstruction; with vaginal and/or rectal prolapse of II, III, IV degree; with previous spinal or pelvic surgery including radical prostatectomy, Wertheim hysterectomy or colorectal surgery. All the patients were studied with computed tomography (CT) scan of the urinary tract, voiding cystourethrography (VCUG), uroflowmetry, cystomanometry with intrinsic pressure assessment and compliance evaluation, electromyography (EMG) of the anal sphincter, pressure flow analysis, urethral pressure profile and, when advised, pharmacological tests., Results: Out of 126 diabetic patients, 48 did not show any signs or symptoms of urine voiding dysfunction; 30 were men and 18 women with an average age of 62.6 years; 20 had type I diabetes and were in treatment with insulin and 28 type II diabetes treated with oral hypoglycemic medication. The remaining 78 patients (48 men and 30 women), with an average age of 64.8 years, presented urological symptoms; 31 had type I diabetes and 47 had II type diabetes., Conclusions: Diagnosis of the various forms of diabetic cystopathy and early treatment decreases complications and consequently accesses to outpatient facilities and hospital admissions, resulting in an improved quality of life.

Purpose: To evaluate the expression of urinary biomarkers of inflammation and tissue remodeling in patients with BPH undergoing surgery and evaluate the association of biomarkers with postoperative urodynamic outcomes MATERIALS AND METHODS: We analyzed urine samples from 71 patients treated with TURP from 2011 to 2017. Urinary levels of epidermal growth factor (EGF), matrix-metalloproteinase-1 (MMP-1), interleukin-6 (IL-6), nerve growth factor (NGF) and monocyte-chemoattractant protein-1 (MCP-1) (by commercial ELISA kit) were measured, adjusted by urinary creatinine (Cr) and analyzed according to patients clinical and urodynamic characteristics (baseline and 12-month postoperative urodynamic) RESULTS: MMP-1/Cr levels were significantly higher among subjects with higher detrusor pressure on preoprative urodynamic. MCP-1/Cr levels were significantly higher amongs subjects with preoperative DO. Preoperative levels of NGF/Cr (0.13 vs 0.08, p = 0.005) and MMP-1/Cr (0.11 vs 0.04, p = 0.021) were predictors of persistent DO 12 months after surgery. The following factors were shown to be useful for predicting the persistence of DO in the postoperative period: NGF/Cr, with an AUC of 0.77 (95% CI 0.62-0.92) (p = 0.006), and MMP-1/Cr, with an AUC of 0.72 (95% CI 0.56-0.88) (p = 0.022)., Conclusions: MMP-1/Cr was associated with higher detrusor pressure and MCP-1/CR with DO. NGF/Cr and MMP-1/Cr were shown to be predictors of persistent postoperative DO.

In this review, we will discuss and illustrate the pathophysiology, presentation, and multidetector computed tomography findings associated with emergent bladder conditions, limiting our discussion to traumatic, infectious, and obstructive etiologies. After reviewing computed tomography cystographic technique, the commonly utilized classification systems for bladder trauma will be presented with illustrative examples of associated typical and more infrequent secondary injuries and complications. Next, the pathogenesis and imaging appearance of both mechanical and neurogenic acute urinary retention will be addressed, including less common though potentially pathognomonic obstructive etiologies including urethral calculi and ectopic ureteroceles. Finally, we will review and illustrate the imaging features of both inflammatory and infectious cystitis, including hemorrhagic and emphysematous variants, as well as the potentially encountered secondary complications., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Spinal cord injury (SCI) above the lumbosacral level results in lower urinary tract dysfunction, including (1) detrusor hyperreflexia, wherein bladder compliance is low, and (2) a lack of external urethral sphincter (EUS) control, leading to detrusor-sphincter dyssynergia (DSD) with poor voiding efficiency. Experimental studies in animals have shown a dense innervation of serotonergic (5-HT) fibers and multiple 5-HT receptors in the spinal reflex circuits that control voiding function. Here, we investigated the efficacy of NLX-112 (a.k.a. befiradol or F13640), in regulating lower urinary tract function after T8 contusive SCI in rats. NLX-112 is a very potent, highly-selective, and fully efficacious 5-HT 1A receptor agonist, which has been developed for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease patients. We performed urodynamics tests and external urethral sphincter electromyogram recordings to assess lower urinary tract function while NLX-112 was infused through the femoral vein in rats with chronic complete SCI or contusive SCI. The dose response studies indicated that NLX-112 was able to improve voiding behavior by regulating both detrusor and EUS activity. These included improvements in voiding efficiency, reduction of detrusor hyperactivity, and phasic activity of EUS during the micturition period. In addition, the application of a selective 5-HT 1A receptor antagonist, WAY100635, reversed the improved detrusor and EUS activity elicited by NLX-112. In summary, the current data suggest that pharmacological activation of 5-HT 1A receptors by NLX-112 may constitute a novel therapeutic strategy to treat neurogenic bladder after SCI., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: To investigate the effect of anagliptin (Ana), a dipeptidyl peptidase-4 (DPP-4) inhibitor, on acute ischemia-induced bladder dysfunction in rats., Methods: Eight-week-old female Wistar-ST rats were randomly assigned into four groups: (a) sham; (b) ligation (Lig); (c) Lig + Ana; and (d) Lig + Liraglutide (a glucagon-like peptide-1 [GLP-1] receptor agonist; Lira). Rats in the Lig, Lig + Ana, and Lig + Lira groups underwent ligature of the bilateral internal iliac arteries. Ana was orally administered mixed with the CE-2 diet. Lira was subcutaneously administered once a day. Blood glucose levels, plasma dipeptidyl peptidase 4 (DPP-4) activity, GLP-1 levels, and bladder function were measured in all groups. Bladder blood flow was measured in the sham, Lig, and Lig + Ana groups, 4 weeks postsurgery., Results: No differences in blood glucose levels among the groups were observed. DPP-4 activity decreased in the Lig + Ana group (P < .01). GLP-1 levels in the Lig + Ana and Lig + Lira groups were higher than those in the sham and Lig groups (P < .01). Intercontraction intervals (ICIs) were longer in the Lig and Lig + Lira groups than in the sham group (P < .05), but similar to those observed in the Lig + Ana and sham groups. The Lig group exhibited reduced bladder blood flow relative to the sham group (P < .01); however, this measure improved in the Lig + Ana group (P < .01)., Conclusions: Ana administration improved ICIs and bladder blood flow after acute bladder ischemia through a GLP-1 receptor-independent signaling pathway, without altering the blood glucose levels. Therefore, Ana dosing might be useful to prevent ischemia-induced bladder dysfunctions., (© 2020 Wiley Periodicals LLC.)

The cytotoxic drugs cyclophosphamide (CPO) and ifosfamide (IFO) cause toxic urological effects due to the production of urinary metabolites that cause bladder inflammation. This study aimed to identify changes in the bladder afferent system following treatment with these drugs that might explain reported urological adverse effects. Intravesical pressure and afferent nerve activity were recorded during bladder distension and drug administration in isolated bladders from mice, 24 h after intraperitoneal treatment with cyclophosphamide (100 mg/kg), ifosphamide (200 mg/kg) or saline (control). In isolated bladders, total afferent nerve activity at maximum bladder distension was increased from 182 ± 13 imp/s in control animals, to 230 ± 14 imp/s in CPO-treated (p < 0.05) and 226 ± 17 imp/s in IFO-treated (p < 0.001) mice. Single fibre analysis revealed the increase resulted from an enhanced activity in low threshold, wide dynamic range fibres (23.3 ± 1.9 imp/s/fibre in controls to 31.5 ± 2.5 (p < 0.01) in CPO and 29.9 ± 2.0 imp/s/fibre (p < 0.05) in IFO treated). CPO treatment was accompanied by an increase in urinary frequency in vivo, but was not associated with increases in urothelial release of ATP or acetylcholine, bladder compliance or spontaneous muscle activity. Also, CPO-treatment did not affect afferent nerve responses or pressure responses to purinergic, muscarinic or nicotinic agonists. This is the first report of CPO and IFO-induced changes in specific populations of bladder afferents, namely an increase in low threshold, wide dynamic range fibres. These effects appear to be direct and not secondary to increases in smooth muscle activity or the release of urothelial mediators.

Introduction: Bladder Bowel Dysfunction (BBD) has been described in patients with Down's Syndrome (DS). Our aim was to report the incidence, demographics, presentation, complications and management of the bladder in DS patients with BBD., Methods: A systematic review was performed using PRISMA guidelines and search terms "{[(trisomy 21) OR down's syndrome]} AND [("non-neurogenic") OR voiding dysfunction]" in the search engines MEDLINE and SCOPUS. We also include a case series from two paediatric urology centres., Results: A total of 38 patients with BBD and DS were included. Mean age was 12 years (newborn to 21 years), the male:female ratio was 2:1. Functional constipation (90%), recurrent urinary tract infections (38%) and enuresis were common at presentation (56%), while over 56% patients required surgical intervention. Medical treatment and behavioral modification were less successful while intermittent catheterisation did not work., Conclusion: This study reviews the largest cohort of patients with BBD in DS. It is common with serious consequences requiring operative intervention. Usual interventions are unreliable due to poor compliance. Early identification and management protect the renal tract. Regular screening for urogenital anomalies in DS is currently not performed. We recommend a thorough history of bladder function in DS patients to identify these cases early.

Introduction: Widely accepted consensus terminology and calculations of detrusor contractility in females do not exist but may be useful. We report the output of a proposal session at the International Consultation on Incontinence Research Society meeting 2019, addressing the title topic., Methods: Three formal presentations and a lively discussion addressed several questions including: which is the optimal cutoff value of female bladder voiding efficiency during uroflow to suspect obstruction or detrusor underactivity? Is there a definition of pure underactive and pure obstructed voiding in females? Is there a place to distinguish those relatively obstructed from those relatively underactive females especially in those cases of equivocal obstruction? Current measures of contractility were reviewed for their usefulness in women., Results: No recommendation for a specific index or calculation can be made based on current knowledge. "Contractility" may be context-dependent regarding clinical care, clinical prognostication, and physiologic research., Conclusions: This group proposes that context-sensitive definitions of "Contractility" deserve attention by international leadership. Cooperative clinical and physiologic expertise will be needed to achieve this goal. Following initial recommendations based on expert opinion, the development of final definitions and measures of contractility should be iterative, based upon validation studies to be considered as part of the definitional process., (© 2019 Wiley Periodicals, Inc.)

The goal of this study in anesthetized cats was to identify silent hypogastric nerve (HGN) afferent fibers that do not respond to bladder distention but become responsive after chemical irritation of the bladder. The HGN was split into multiple filaments small enough for recording action potentials from single or multiple afferent fibers. The bladder was distended by infusion of either saline or 0.5% acetic acid (AA) through a urethral catheter while recording intravesical pressure. A total of 90 HGN filaments from 17 cats responded to bladder distention with saline or AA. Three types of HGN afferents were identified. The first type was non-nociceptive mechano-sensitive that responded to bladder distention at normal physiological pressures (10-40 cmH 2 O). The second type was nociceptive mechano-sensitive that only responded to high-pressure (50-80 cmH 2 O) bladder distention with saline but responded to low-pressure bladder distention after sensitization with AA. The third type was chemo-sensitive nociceptive that was silent even during high-pressure bladder distention but after sensitization with AA did respond to low-pressure bladder distention. These results indicate that HGN afferents as well as pelvic nerve afferents may play a role in bladder nociception. The HGN afferent fibers that are silent during bladder distention at normal physiological pressures but become responsive after chemical irritation are important for understanding the possible pathophysiological mechanism underlying bladder allodynia in painful bladder syndrome., Competing Interests: Declaration of Competing Interest No conflicts of interests are declared by the authors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The effects of human amniotic fluid stem cell (hAFSC) transplantation on bladder function and molecular changes in spinal cord-injured (SCI) rats were investigated. Four groups were studied: sham and SCI plus phosphate-buffered saline (SCI + PBS), human embryonic kidney 293 (HEK293) cells, and hAFSCs transplantation. In SCI + PBS rat bladders, cystometry showed increased peak voiding pressure, voiding volume, bladder capacity, residual volume, and number of non-voiding contractions, and the total elastin/collagen amount was increased but collagen concentration was decreased at days 7 and 28. Immunoreactivity and mRNA levels of IGF-1, TGF-β1, and β3-adrenoceptor were increased at days 7 and/or 28. M2 immunoreactivity and M3 mRNA levels of muscarinic receptor were increased at day 7. M2 immunoreactivity was increased, but M2/M3 mRNA and M3 immunoreactivity levels were decreased at day 28. Brain derived-neurotrophic factor mRNA was increased, but immunoreactivity was decreased at day 7. HEK293 cell transplantation caused no difference compared to SCI + PBS group. hAFSCs co-localized with neural cell markers and expressed BDNF, TGF-β1, GFAP, and IL-6. The present results showed that SCI bladders released IGF-1 and TGF-β1 to stimulate elastin and collagen for bladder wall remodelling, and hAFSC transplantation improved these changes, which involved the mechanisms of BDNF, muscarinic receptors, and β3-adrenoceptor expression.

Aims: We examined the time course of urodynamic changes and the effect of the short or long-term inhibition of brain-derived neurotrophic factor (BDNF) from the early phase after spinal cord injury (SCI) in mice., Methods: The spinal cord of female C57BL/6N mice was completely transected. We examined filling cystometry and bladder BDNF levels at 10, 20, and 30 days after SCI, with an additional day-5 measurement of BDNF. In a separate group of mice, anti-BDNF antibody (Ab) (10 µg/kg/h) was subcutaneously administered using osmotic pumps from day 3 after SCI, and single-filling cystometry was performed at 10 and 30 days (7 and 27 days of treatment, respectively) after SCI., Results: Compared to spinal intact mice, bladder mucosal BDNF was increased at each time point after SCI with the maximal level at day 5 after SCI. Voiding efficiency was lower at each time point after SCI than that of spinal intact mice. The number of non-voiding contractions (NVC) during bladder filling was gradually increased with time. In both 10- and 30-day SCI groups treated with anti-BDNF Ab, voiding efficiency was improved, and the duration of notch-like intravesical pressure reductions during voiding bladder contractions was prolonged. The number of NVC was significantly decreased only in 30-day SCI mice with 27-day anti-BDNF treatment., Conclusions: Overexpression of BDNF is associated with the deterioration of voiding efficiency after SCI. The early-started, long-term inhibition of BDNF improved voiding dysfunction and was also effective to reduce the later-phase development of detrusor overactivity after SCI., (© 2020 Wiley Periodicals LLC.)

As far as we know this is the first report on bulking agent injection into intravesical ectopic ejaculatory orifices reported in the English literature. During a follow-up period of 23 months, the child was free of episodes of epididymo-orchitis. Deflux injection in this rare anomaly of intravesical refluxing ducts had prevented irreversible damage to the testes from recurrent EO. Thus, it may be a better option than vasectomy when antibiotic treatment fails., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Various berries demonstrate antioxidant activity, and this effect is expected to prevent chronic diseases. We examined whether a diet containing blueberry powder could prevent the development of bladder dysfunction secondary to bladder outlet obstruction (BOO). Eighteen 8-week-old male Sprague-Dawley rats were randomly divided into three groups: Sham (sham operated + normal diet), N-BOO (BOO operated + normal diet) and B-BOO (BOO operated + blueberry diet). Four weeks after BOO surgery, the N-BOO group developed bladder dysfunction with detrusor overactivity. The B-BOO group showed significantly improved micturition volume and micturition interval. The urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) were measured as oxidative stress markers. In the N-BOO group, 8-OHdG increased 1.6-fold and MDA increased 1.3-fold at 4 weeks after surgery, whereas the increase in 8-OHdG was significantly reduced by 1.1-fold, despite a similar increase in MDA, in the B-BOO group. Bladder remodeling was confirmed due to bladder hypertrophy, fibrosis and increased connexin43 expression in the N-BOO group, but these histological changes were reduced in the B-BOO group. The intake of blueberries prevented the development of bladder dysfunction secondary to BOO. This effect seems to be related to antioxidation and the inhibition of bladder remodeling., Competing Interests: The authors declare no conflicts of interest.

The signaling pathways and effectors that drive the response of the bladder to nonmalignant insults or injury are incompletely defined. Interrogation of biological systems has been revolutionized by the ability to generate high-content data sets that capture information on a variety of biomolecules in cells and tissues, from DNA to RNA to proteins. In oncology, such an approach has led to the identification of cancer subtypes, improved prognostic capability, and has provided a basis for precision treatment of patients. In contrast, systematic molecular characterization of benign bladder disorders has lagged behind, such that our ability to uncover novel therapeutic interventions or increase our mechanistic understanding of such conditions is limited. Here, we discuss existing literature on the application of omics approaches, including transcriptomics and proteomics, to urinary tract conditions characterized by pathological tissue remodeling. We discuss molecular pathways implicated in remodeling, challenges in the field, and aspirations for omics-based research in the future.

Bladder oversensitivity arises from several different conditions involving the bladder, bladder outlet, systemic or central nervous system diseases. Increase of the bladder sensation results from activation of the sensory receptors in the urothelial cells or suburothelial tissues. Medical treatment targeting the overactive bladder (OAB) or interstitial cystitis (IC) might relieve oversensitive bladder symptoms (frequency, urgency and pain) in a portion of patients, but a certain percentage of patients still need active management. Botulinum toxin A (BoNT-A) has been demonstrated to have anti-inflammatory and antinociceptive effects in bladder sensory disorders and has been shown effective in the reduction of bladder oversensitivity and the increase of functional bladder capacity. For patients with OAB, urgency and urinary incontinence improved, while in patients with IC, bladder pain could be relieved in association with reduction of bladder oversensitivity after BoNT-A intravesical injection. Histological evidence has confirmed the therapeutic mechanism and clinical efficacy of intravesical BoNT-A injection on patients with OAB or IC. Bladder oversensitivity can also be relieved with the instillation of liposome encapsulated BoNT-A or low energy show waves (LESWs), which enable the BoNT-A molecule to penetrate into the urothelium and suburothelial space without affecting the detrusor contractility. Liposome encapsulated BoNT-A or combined LESWs and BoNT-A instillation might be future treatment alternatives for bladder oversensitivity in sensory bladder disorders.

Botulinum toxin A (BTX-A) is a powerful neurotoxin with long-lasting activity that blocks muscle contractions. In addition to effects on neuromuscular junctions, BTX-A also plays a role in sensory feedback loops, suggesting the potentiality for pain relief. Although the only approved indications for BTX-A in the bladder are neurogenic detrusor overactivity and refractory overactive bladder, BTX-A injections to treat bladder pain refractory to conventional therapies are also recommended. The mechanism of BTX-A activity in bladder pain is complex, with several hypotheses proposed in recent studies. Here we comprehensively reviewed properties of BTX-A in peripheral afferent and efferent nerves, the inhibition of nociceptive neurotransmitter release, the reduction of stretch-related visceral pain, and its anti-inflammatory effects on the bladder urothelium. Studies have also revealed possible effects of BTX-A in the human brain. However, further basic and clinical studies are warranted to provide solid evidence-based support in using BTX-A to treat bladder pain.

Aims: To determine the effects of early sacral neuromodulation (SNM) and pudendal neuromodulation (PNM) on lower urinary tract (LUT) function, minipigs with complete spinal cord injury (cSCI) were analyzed. SNM and PNM have been proposed as therapeutic approaches to improve bladder function, for example after cSCI. However, further evidence on efficacy is required before these methods can become clinical practice., Methods: Eleven adults, female Göttingen minipigs with cSCI at vertebral level T11-T12 were included: SNM (n = 4), PNM (n = 4), and SCI control (SCIC: n = 3). Tissue from six healthy minipigs was used for structural comparisons. Stimulation was started 1 week after cSCI. Awake urodynamics was performed on a weekly basis. After 16 weeks follow-up, samples from the urinary bladder were taken for analyses., Results: SNM improved bladder function with better capacities and lower detrusor pressures at voiding and avoided the emergence of detrusor sphincter dyssynergia (DSD). PNM and untreated SCI minipigs had less favorable outcomes with either DSD or constant urinary retention. Structural results revealed SCI-typical fibrotic alterations in all cSCI minipigs. However, SNM showed a better-balanced distribution of smooth muscle to connective tissue with a trend towards the reduced progression of bladder wall scarring., Conclusion: Early SNM led to an avoidance of the emergence of DSD showing a more physiological bladder function during a 4 month follow-up period after cSCI. This study might pave the way for the clinical continuation of early SNM for the treatment of neurogenic LUT dysfunction after SCI., (© 2019 The Authors. Neurourology and Urodynamics published by Wiley Periodicals, Inc.)

Study Design: Cross-sectional study OBJECTIVES: To determine clinical factors associated with telomere length in persons with chronic spinal cord injury (SCI)., Setting: Veterans Affairs Medical Center, Boston, MA., Methods: Two hundred seventy-eight participants with chronic SCI provided blood samples for measurement of C-reactive protein (CRP), interleukin-6 (IL-6), and telomere length, completed respiratory health questionnaires, underwent dual X-ray absorptiometry (DXA) to assess body fat, and completed spirometry. High-throughput real-time PCR assays were used to assess telomere length in leukocyte genomic DNA. Linear regression models were used to assess cross-sectional associations with telomere length., Results: Telomere length was inversely related to age (p < 0.0001). In age-adjusted models, gender, race, injury duration, %-total and %-trunk fat, body mass index (BMI), %-predicted forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV 1 ), chronic cough or phlegm, CRP, IL-6, wheeze, smoking, diabetes, heart disease, chronic obstructive pulmonary disease (COPD), skin ulcer, urinary tract infection (UTI), or chest illness history were not significantly associated with telomere length. There was a suggestive age-adjusted association between persons with the most severe SCI (cervical motor complete and AIS C) and shorter telomere length (p = 0.055), an effect equivalent to ~8.4 years of premature aging. There were similar age-adjusted associations with telomere length between persons using a wheelchair (p = 0.059) and persons with chronic urinary catheter use (p = 0.082) compared to persons without these characteristics., Conclusions: Our results suggest that clinical characteristics such as decreased mobility and bladder dysfunction that are common in individuals with more severe SCI are associated with shorter telomere length.

Aims: In recent years, the human brain-bladder control network has been visualized in different functional magnetic resonance imaging (fMRI) studies. The role of the brainstem and suprapontine regions has been elucidated. Especially the pontine region and the periaqueductal gray, as the central structures of the micturition circuit, were demonstrated. Detrusor sphincter dyssynergia (DSD) is a common problem in patients with neurological diseases. Residual urine and consecutive urinary tract infections with the risk of kidney damage remain a problem. In the present study, we used fMRI of the brain to compare the activation sites of patients with DSD with those of our previously published healthy controls with special emphasis on the brainstem region., Methods: fMRI was performed in 11 patients with DSD who had an urge to void due to a filled bladder. In a nonvoiding model, they were instructed to contract or to relax the pelvic floor muscles repetitively., Results: In patients with DSD, we could reproduce the activation sites found in healthy subjects, showing the regions in the brainstem as well as the other micturition-related areas. The activation of the pontine region was more rostral/dorsal compared with the healthy volunteers., Conclusion: Interestingly, we detected the well-known activation in the pontine region in the patients in the dorsal/rostral part compared with the more ventral activation in the healthy volunteers, suggesting that the L-region of the pontine micturition center is more prominent in cases of DSD., (© 2019 The Authors. Neurourology and Urodynamics published by Wiley Periodicals, Inc.)

Aim: To assess the long-term urologic outcomes in follow-up of patients of sacrococcygeal teratoma (SCT) using urodynamic study (UDS) in addition to clinical and radiologic evaluation., Methods: A prospective study of clinical, radiological and urodynamic evaluation in patients with SCT who underwent resection between January 2002-June 2015 and were followed up till January 2016 was conducted., Results: Total 57 patients, 42 (73.7%) females and 15 (26.3%) males with 35 (62.4%) following treatment for benign and 22 (38.5%) for malignant disease were included. Twenty-eight of 57 (49.12%) had urological problems. Clinical complaints in 21 (36.8%) patients included stress urinary incontinence-14 (66.7%), enuresis-9 (42.9%), and poor stream or dribbling of urine-6 (28.6%). Eight of 51 patients (15.7%) had abnormal ultrasound findings, which included contracted, trabeculated thick walled bladder (3), bilateral hydronephrosis (3) and significant post void residue (PVR) (6). Seven of 57 underwent micturating cystourethrogram (MCU), 5 had an abnormal report[significant PVR (4), small trabeculated bladder (3), reflux (2) and large capacity bladder (1)]. Urodynamic study was done in 27 patients, 18/27 (66.7%) had abnormalities. Six patients without any clinical or ultrasonographic abnormalities had abnormal UDS. Total 28 (49.12%) had urological comorbidities. Three patients had overactive bladder, five dysfunctional voiding, one underactive bladder and one had giggle incontinence. Children were managed by behaviour therapy and pharmacotherapy., Conclusion: Urodynamic evaluation could detect abnormalities in patients who had no urinary complaints or abnormality on ultrasound. The abnormalities have a potential for progressive upper tract damage. Urodynamics should be an integral part of urological surveillance in patients operated for SCT., Type of Study: Prognostic study., Level of Evidence: Level II (Prospective cohort study)., (Copyright © 2018. Published by Elsevier Inc.)

Introduction : In the lower urinary tract (LUT) several members of the TRP superfamily are involved in nociception and mechanosensory transduction. Animal studies have suggested a therapeutic potential of some of these channels, including TRPV1, TRPV4, TRPM8, TRPA1, and TRPM4, for treatment of bladder over- and underactivity and bladder pain disorders, but translation of this information to clinical application has been slow. Areas covered : An update on and discussion of current information on the potential clinical use of TRP channel agonists/antagonists in the treatment of different types of bladder dysfunction. The electronic databases PubMed and Scopus were used to identify relevant clinical and animal studies. Expert opinion : The therapeutic effect of TRPV1 channel desensitizing agonists (capsaicin, resiniferatoxin, given intravesically) has been convincingly demonstrated in some forms of bladder overactivity. However, so far, the potential of any of the small-molecule TRP channel blockers developed for non-bladder indications and tested in early human trials for safety has not been explored clinically in LUT dysfunction. The adverse effects of hyperthermia and reduction of noxious heat sensation of the first generation TRPV1 blockers have delayed development. Despite lack of translational information, TRP channels remain interesting targets for future LUT drugs.

Objective: This study evaluated the effect of human umbilical cord blood mononuclear cells (HUCB-MNCs) on bladder dysfunction in streptozotocin (STZ; 35 mg/kg, i.v.)-induced diabetic rats., Methods: Adult male Sprague-Dawley rats (n = 30) were equally divided into three groups: control group, STZ-diabetic group, and HUCB-MNC-treated group (1 × 10 6 cells). HUCB-MNCs were isolated by density gradient centrifugation from eight healthy donors and injected into the corpus cavenosum in STZ-diabetic rats 4 weeks after the induction of diabetes. Studies were performed 4 weeks after HUCB-MNC or vehicle injection. In vitro organ bath studies were performed on bladder strips, whereas protein expression of hypoxia-inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF), and α-smooth muscle actin (SMA) in the bladder and the ratio of smooth muscle cells (SMCs) to collagen were determined using western blotting and Masson trichrome staining., Results: Neurogenic contractions of detrusor smooth muscle strips were 55% smaller in the diabetic group than control group (P < 0.05); these contractions were normalized by HUCB-MNC treatment. In addition, HUCB-MNC treatment restored the impaired maximal carbachol-induced contractile response in detrusor strips in the diabetic group (29%; P < 0.05). HUCB-MNC treatment improved the KCl-induced contractile response in the diabetic bladder (68%; P < 0.05), but had no effect on ATP-induced contractile responses. Increased expression of HIF-1α and VEGF protein and decreased expression of α-SMA protein and the SMC/collagen ratio in diabetic rats were reversed by HUCB-MNC., Conclusion: Administration of HUCB-MNCs facilitates bladder function recovery, which is likely related to downregulation of HIF-1α expression and attenuation of fibrosis in STZ-diabetic rats., (© 2019 John Wiley & Sons Australia, Ltd.)

The internal surface of the urinary bladder is covered by the urothelium, a stratified epithelium that forms an impermeable barrier to urinary solutes. Increased urothelial permeability is thought to contribute to symptom generation in several forms of cystitis by sensitizing bladder afferents. In this report we investigate the physiological mechanisms that mediate bladder afferent hyperexcitability in a rat model of cystitis induced by overexpression in the urothelium of claudin-2 (Cldn2), a tight junction-associated protein upregulated in bladder biopsies from patients with interstitial cystitis/bladder pain syndrome. Patch-clamp studies showed that overexpression of Cldn2 in the urothelium sensitizes a population of isolectin GS-IB4-negative [IB4(-)] bladder sensory neurons with tetrodotoxin-sensitive (TTX-S) action potentials. Gene expression analysis revealed a significant increase in mRNA levels of the delayed-rectifier voltage-gated K + channel (K v )2.2 and the accessory subunit K v 9.1 in this population of bladder sensory neurons. Consistent with this finding, K v 2/K v 9.1 channel activity was greater in IB4(-) bladder sensory neurons from rats overexpressing Cldn2 in the urothelium than in control counterparts. Likewise, current density of TTX-S voltage-gated Na + (Na v ) channels was greater in sensitized neurons than in control counterparts. Significantly, guangxitoxin-1E (GxTX-1E), a selective blocker of K v 2 channels, blunted the repetitive firing of sensitized IB4(-) sensory neurons. In summary, our studies indicate that an increase in the activity of TTX-S Na v and K v 2/K v 9.1 channels mediates repetitive firing of sensitized bladder sensory neurons in rats with increased urothelial permeability. NEW & NOTEWORTHY Hyperexcitability of sensitized bladder sensory neurons in a rat model of interstitial cystitis/bladder pain syndrome (IC/BPS) results from increased activity of tetrodotoxin-sensitive voltage-gated Na + and delayed-rectifier voltage-gated K + (K v )2/K v 9.1 channels. Of major significance, our studies indicate that K v 2/K v 9.1 channels play a major role in symptom generation in this model of IC/BPS by maintaining the sustained firing of the sensitized bladder sensory neurons.

Purpose: This study investigates whether functionality and/or expression changes of transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) channels, oxidative stress, and hydrogen sulfide (H 2 S) are involved in the bladder dysfunction from an insulin-resistant obese Zucker rat (OZR)., Materials and Methods: Detrusor smooth muscle (DSM) samples from the OZR and their respective controls, a lean Zucker rat (LZR), were processed for immunohistochemistry for studying the expression of TRPA1 and TRPV1 and the H 2 S synthase cystathionine beta-synthase (CBS) and cysthathionine- γ -lyase (CSE). Isometric force recordings to assess the effects of TRPA1 agonists and antagonists on DSM contractility and measurement of oxidative stress and H 2 S production were also performed., Results: Neuronal TRPA1 expression was increased in the OZR bladder. Electrical field stimulation- (EFS-) elicited contraction was reduced in the OZR bladder. In both LZR and OZR, TRPA1 activation failed to modify DSM basal tension but enhanced EFS contraction; this response is inhibited by the TRPA1 blockade. In the OZR bladder, reactive oxygen species, malondialdehyde, and protein carbonyl contents were increased and antioxidant enzyme activities (superoxide dismutase, catalase, GR, and GPx) were diminished. CSE expression and CSE-generated H 2 S production were also reduced in the OZR. Both TRPV1 and CBS expressions were not changed in the OZR., Conclusions: These results suggest that an increased expression and functionality of TRPA1, an augmented oxidative stress, and a downregulation of the CSE/H 2 S pathway are involved in the impairment of nerve-evoked DSM contraction from the OZR., Competing Interests: The authors declare that they have no competing interests.

Objectives: Incomplete spinal cord injury (SCI) accounts for two-thirds of all SCIs in clinical practice. Preclinical research on the effect of sacral neuromodulation (SNM) on bladder function, however, has been focused only on animal models of complete SCI. We aimed to evaluate the effect of early SNM on bladder responses in a rat model of incomplete SCI., Materials and Methods: Altogether, 21 female Sprague-Dawley rats were equally assigned to control (CTR), SCI + sham stimulation (SHAM), and SCI + SNM (SNM) groups. In the SHAM and SNM groups, incomplete SCI was created by producing a moderate contusion with an NYU-MASCIS impactor at the T9-T10 level of the spine, with needle electrodes implanted bilaterally into the S2 or S3 sacral foramen. Only SNM group underwent electrical stimulation for 28 days, beginning on day 7 after SCI. Cystometry was performed 35 days after SCI., Results: Although the interval between voiding contractions was significantly longer in the SHAM group than the CTR group (25.5 ± 1.4 vs. 12.5 ± 1.7 min; p < 0.05), there were no significant differences between the SNM group (16.5 ± 1.5 min) and the CTR group. Maximum voiding contraction pressure did not differ among the groups. The SNM group had a significantly lower frequency (3.5 ± 0.5 vs. 14.6 ± 2.0; p < 0.05) and maximum pressure (11.4 ± 6.2 vs. 21.3 ± 1.8 cmH 2 O; p < 0.05) of nonvoiding contractions than the SHAM group., Conclusions: Our results provide experimental evidence that early SNM treatment may prevent or diminish bladder dysfunctions (e.g., detrusor overactivity, abnormal micturition reflex) in a clinical condition of incomplete SCI., (© 2018 International Neuromodulation Society.)

Neural injury, inflammation, or diseases commonly and adversely affect micturition reflex function that is organized by neural circuits in the CNS and PNS. One neuropeptide receptor system, pituitary adenylate cyclase-activating polypeptide (PACAP; Adcyap1), and its cognate receptor, PAC1 (Adcyap1r1), have tissue-specific distributions in the lower urinary tract. PACAP and associated receptors are expressed in the LUT and exhibit changes in expression, distribution, and function in preclinical animal models of bladder pain syndrome (BPS)/interstitial cystitis (IC), a chronic, visceral pain syndrome characterized by pain, and LUT dysfunction. Blockade of the PACAP/PAC1 receptor system reduces voiding frequency and somatic (e.g., hindpaw, pelvic) sensitivity in preclinical animal models and a transgenic mouse model that mirrors some clinical symptoms of BPS/IC. The PACAP/receptor system in micturition pathways may represent a potential target for therapeutic intervention to reduce LUT dysfunction following urinary bladder inflammation.

Cytotoxic chemotherapy is the foundation for the treatment of the wide variety of childhood malignancies; however, these therapies are known to have a variety of deleterious side effects. One common chemotherapy used in children, doxorubicin (DOX), is well known to cause cardiotoxicity and cardiomyopathy. Recent studies have revealed that DOX impairs skeletal and smooth muscle function and contributes to fatigue and abnormal intestinal motility in patients. In this study, we tested the hypothesis that systemic DOX administration also affects detrusor smooth muscle (DSM) function in the urinary bladder, especially when administered at a young age. The effects on the DSM and bladder function were assessed in BALB/cJ mice that received six weekly intravenous injections of DOX (3 mg·kg -1 ·wk -1 ) or saline for the control group. Systemic DOX administration resulted in DSM hypertrophy, increased voiding frequency, and a significant attenuation of DSM contractility, followed by a slower relaxation compared with the control group. Gene expression analyses revealed that unlike DOX-induced cardiotoxicity, the bladders from DOX-administered animals showed no changes in oxidative stress markers; instead, downregulation of large-conductance Ca 2+ -activated K + channels and altered expression of myosin light-chain kinase coincided with reduced myosin light-chain phosphorylation. These results indicate that in vivo DOX exposure caused DSM dysfunction by dysregulation of molecules involved in the detrusor contractile-relaxation mechanisms. Collectively, our findings suggest that survivors of childhood cancer treated with DOX may be at increased risk of bladder dysfunction and benefit from followup surveillance of bladder function.

Objective: The objective of bladder augmentation (BA) is to create a low-pressure reservoir with adequate capacity. Despite its benefits, the use of intestinal patches in bladder enlargement provides a high risk of developing complications and BA with demucosalised bowel represents a potential alternative. Therefore, this study evaluated urological parameters and long-term clinical follow-up of patients submitted to nonsecretory BA in a single center with 25 years of experience., Materials and Methods: Patients treated with BA underwent urological evaluation, which included history, physical examination and urodynamic study. The main urodynamic parameters (bladder capacity and bladder compliance) were assessed in the pre and postoperative moments, and compared by the Wilcoxon Signed Rank test. The main long-term complications were described., Results: 269 patients (mean age 14±13 years, 47% male) underwent BA with the use of demucolised intestinal segments. Among the patients in the sample, 187 (69.52%) had neurogenic bladder, 68 (25.28%) had bladder exstrophy, nine had tuberculosis (3.34%), four had a posterior urethral valve (1.49%) and one with hypospadia (0.37%). After the surgical procedure, a significant increment in both urodynamic parameters was found, with a 222% increase in bladder capacity and 604% in bladder compliance (p < 0.001 in both analyzes). Mean follow-up time ranged from 2 to 358 months, with a median of 72 months (IQR 74-247). Among all patients, 5 presented spontaneous perforation., Conclusion: The study showed statistically signifi cant increase in both compliance and bladder capacity after non-secretory BA, with a low rate of severe complications., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Impact Statement: The search for an ideal "off-the-shelf" biomaterial for augmentation cystoplasty remains elusive and current scaffold configurations are hampered by mechanical and biocompatibility restrictions. In addition, preclinical evaluations of potential scaffold designs for bladder repair are limited by the lack of tractable large animal models of obstructive bladder disease that can mimic clinical pathology. The results of this study describe a novel, minimally invasive, porcine model of partial bladder outlet obstruction that simulates clinically relevant phenotypes. Utilizing this model, we demonstrate that acellular, bi-layer silk fibroin grafts can support the formation of vascularized, innervated bladder tissues with functional properties.

Bowel and bladder dysfunction (BBD) refers to a heterogeneous group of voiding disorders, accounting for an estimated 40% of pediatric urology visits. Symptoms of BBD include enuresis, urgency, and urinary retention, often accompanied by constipation. The aim of this pilot study was to explore whether a pupillary response can be characterized for BBD, by examining the pupillary light reflex (PLR) before and after voiding among patients with BBD. A total of 28 patients aged from 7 to 21 years were recruited from the Wetting, Infections, and Stooling Help clinic at Children's National Medical Center. An infrared pupilometer was used to assess the PLR. Both baseline static and dynamic pupillometry assessments were obtained before and after voiding. Measurements were also taken after 5 min in the supine position, followed by 5 min standing to induce an orthostatic stressor. Visual inspection of the graphed data revealed a characteristic shape in 11 of 28 patients with voiding symptoms. In these 11 patients, the redilation arm of the PLR shows a 'notch,' or a brief reconstriction of the pupil before resting pupil size is reestablished (figure). This feature of the PLR has not been seen in previous and parallel studies using pupillometry to evaluate other populations. The results of this study suggest that a subset of patients with BBD may have a significant perturbation of autonomic regulation, identifiable through analysis of the PLR. To our knowledge, this 'notch' during redilation has not been previously described or seen in other patient populations and may represent a distinctive and readily identifiable physiologic marker of disease. These results are broadly aligned with results of other studies that have examined ANS activity in patients with BBD, although further study is needed to confirm the results of this pilot study and to assess relative contributions of sympathetic and parasympathetic function in producing pupillary abnormalities. This study has several limitations, including the small sample size, the absence of data on severity and duration of symptoms, and the absence of a control group of patients without any voiding symptoms. A simple tool for diagnosing BBD and for monitoring response to treatment could significantly improve the quality of treatment for one of the most common pediatric urologic complaints. Given the heterogeneity of symptoms under the BBD umbrella, pupillometric data could guide selection of treatment options, as well as assess adequacy of response to pharmacologic therapy., (Copyright © 2019. Published by Elsevier Ltd.)

Due to the rising abuse of ketamine usage in recent years, ketamine‑induced urinary tract syndrome has received increasing attention. The present study aimed to investigate the molecular mechanism underlying ketamine‑associated cystitis in a mouse model. Female C57BL/6 mice were randomly divided into two groups: One group was treated with ketamine (100 mg/kg/day of ketamine for 20 weeks), whereas, the control group was treated with saline solution. In each group, micturition frequency and urine volume were examined to assess urinary voiding functions. Mouse bladders were extracted and samples were examined for pathological and morphological alterations using hematoxylin and eosin staining, Masson's trichrome staining and scanning electron microscopy. A cDNA microarray was conducted to investigate the differentially expressed genes following treatment with ketamine. The results suggested that bladder hyperactivity increased in the mice treated with ketamine. Furthermore, treatment with ketamine resulted in a smooth apical epithelial surface, subepithelial vascular congestion and lymphoplasmacytic aggregation. Microarray analysis identified a number of genes involved in extracellular matrix accumulation, which is associated with connective tissue fibrosis progression, and in calcium signaling regulation, that was associated with urinary bladder smooth muscle contraction. Collectively, the present results suggested that these differentially expressed genes may serve critical roles in ketamine‑induced alterations of micturition patterns and urothelial pathogenesis. Furthermore, the present findings may provide a theoretical basis for the development of effective therapies to treat ketamine‑induced urinary tract syndrome.

Purpose: Hinman syndrome is a rare disease with urodynamic findings and a clinical course resembling neuropathic bladder, without a neuropathic etiology. Diffusion tensor imaging is a special technique of magnetic resonance imaging that has recently been used to evaluate the peripheral nerves but has been demonstrated to be applicable for evaluation of the lumbosacral plexus. We examined the lumbosacral plexus using diffusion tensor imaging, which has not previously been reported in patients with Hinman syndrome., Materials and Methods: The study included 12 patients who fulfilled criteria for Hinman syndrome, with severe bladder dysfunction on urodynamics, renal scarring on scintigraphy and no pathological findings on magnetic resonance imaging. The 12 subjects serving as controls required pelvic or spinal magnetic resonance imaging for reasons other than spinal abnormalities. Evaluation was performed with a 3.0 Tesla magnetic resonance imaging system and 16-channel body coil. Tractography was done to examine the lumbosacral plexus. Fractional anisotropy and mean diffusivity were computed and compared between groups for the right and left plexuses., Results: Mean fractional anisotropy was 0.24 and 0.35 for the right plexus in patients and controls, respectively, and 0.24 and 0.36 for the left plexus. Mean diffusivity was 1.39 for the right and left plexuses in patients, and 1.28 for the right and left plexuses in controls (p <0.001 for all)., Conclusions: Our study focusing on the lumbosacral plexus as a possible origin of neuropathy revealed abnormal findings in patients with Hinman syndrome resembling nerve injury series. This is the first known study to provide data showing that Hinman syndrome may have a neuropathic etiology.

Introduction and Hypothesis: The aim of this study was to evaluate the functional outcomes and urodynamic findings after laparoscopic sacrocolpopexy (LSC) in patients with stages II-IV pelvic organ prolapse (POP)., Methods: In this single-center prospective study, we evaluated 63 women (mean age 62.5 ± 7.5 years) women with symptomatic and advanced POP (stage II-IV) who underwent LSC without concomitant anti-incontinence surgery. The preoperative evaluation incuded history, clinical examination, and urodynamic testing. Women were followed up at 1, 3, 6, and 12 months after surgery and then annually using history, examination, and uroflowmetry. At 6 months, we performed urodynamic testing. To evaluate urinary symptoms, we used the Urogenital Distress Inventory (UDI)-6 questionnaire before and 6 months after surgery., Results: Median follow- up was 22 months (range 8-48). After surgery, maximum flow (Q max ) significantly improved compared with baseline (14.17 ± 2.3 vs 27 ± 8.4 ml/s; p = 0.02), and the percentage of patients with elevated postvoid residual (PVR) significantly decreased (33.3% vs 11.1%; p = 0.001). Detrusor overactivity and bladder outlet obstruction disappeared in 73.6% and 85.7% of patients, respectively, while detrusor underactivity persisted in 66.6% of women. Twenty women (31.7%) reported stress urinary incontinence (SUI) before surgery (14 clinically evident and 6 as occult form), which persisted in only 7/20 (11%) patients following LSC, with no de novo cases. The most common preoperative symptoms were voiding symptoms, present in 42/63 (66.6%) patients, which resolved in 36 (85.7%). The overactive bladder syndrome disappeared in 60% of women, with no de novo cases. Results were reflected by a significant decrease in UDI-6 score from a median of 16 (0-45) at baseline to 5.5 (0-17) at the final follow-up (p = 0.001). The domain on storage symptoms (median 3 vs 1) and voiding symptoms (median 3 vs 1) of UDI-6 showed an improvement after surgery (p = 0.001)., Conclusions: The urodynamic finding showed that LSC in women with advanced POP provides good functional outcomes.

Purpose: To assess the efficacy of combined transcutaneous interferential (IF) electrical stimulation and pelvic floor muscle training through biofeedback on non-neuropathic urinary incontinence in children., Methods: This prospective study comprised of 46 anatomically and neurologically normal children (9 boys, 37 girls; mean age of 8.4 ± 2.2 years old) with non-neuropathic urinary incontinence. All children were evaluated by kidney and bladder ultrasounds, uroflowmetry with electromyography (EMG), a complete voiding diary and a dysfunctional voiding scoring questionnaire at the baseline. Children were randomly allocated into two treatment groups including group A (n = 23) who underwent biofeedback therapy in addition to IF electrical stimulation and group B (n = 23) who received only biofeedback therapy. Re-evaluation was performed 6 months and one year after completion of the treatment sessions., Results: Improvement of non-neuropathic urinary incontinence was significantly higher in group A in comparison to group B at two follow ups (P < 0.05). Daytime incontinence was improved in 19/23(82%) and 13/23(56.5%) of children in groups A and B respectively after the treatment (P < 0.01). There was no significant difference in uroflowmetry measures between two groups after the treatment., Conclusions: Combination of biofeedback therapy and transcutaneous IF electrical stimulation is a potential effective modality in treating non-neuropathic urinary incontinence in children., Level of Evidence: Type of study: Treatment study. Level I: Randomized controlled trials with adequate statistical power to detect differences (narrow confidence intervals) and follow up >80%., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Autonomic nerves are attractive targets for medical therapies using electroceutical devices because of the potential for selective control and few side effects. These devices use novel materials, electrode configurations, stimulation patterns, and closed-loop control to treat heart failure, hypertension, gastrointestinal and bladder diseases, obesity/diabetes, and inflammatory disorders. Critical to progress is a mechanistic understanding of multi-level controls of target organs, disease adaptation, and impact of neuromodulation to restore organ function.

Background: This study aimed to elucidate the effects and mechanisms of Radix Linderae (RL) extracts on a mouse model of diabetic bladder dysfunction (DBD), especially on later decompensated phase., Methods: Male C57BL/6J mice were intraperitoneally injected with streptozotocin (STZ) after 4 weeks of high-fat diet (HFD) feeding. DBD mouse models (later decompensated phase) were developed by 12-weeks persistent hyperglycemia and then treated with RL extracts for 4 weeks. During administration, the fasting blood glucose (FBG) test was performed once a week. Four weeks later, oral glucose tolerance test (OGTT), voided stain on paper (VSOP), and urodynamic alteration were explored. We also performed haematoxylin and eosin (H&E) and Masson's trichrome staining to observe the histology of the bladder. Then, the contractile responses to α, β-methylene ATP, capsaicin (CAP), KCl and carbachol were measured. Moreover, qPCR assay was performed to analyse the bladder gene expression levels of M 3 receptors and TRPV1., Results: The diabetic mice exhibited higher FBG, OGTT and urine production, and no substantial alteration was observed after RL treatment. Urodynamic test showed the maximum bladder capacity (MBC), residual volume (RV) and bladder compliance (BC), as well as the decrement of voided efficiency (VE) and micturition volume (MV), remarkably increased in the DBD mice. Furthermore, RL treatment significant improved urodynamic urination, with lower MBC, RV, and, BC, as well as higher VE and MV, as compared with the model groups. The wall thickness of the bladder and the ratio of smooth muscle/collagen remarkably increased, and RL could effectively attenuate the pathological change. The response of bladder strips to the stimulus was also reduced in the DBD mice, and RL treatment markedly increased the contraction. Furthermore, the gene expression levels of M 3 receptors and TRPV1 were down-regulated in the bladders of the diabetic mice, whereas RL treatment retrieved those gene expression levels., Conclusions: RL extracts can improve the bladder voiding functions of the DBD model mice in later decompensated phase, and underlying mechanisms was associated with mediating the gene expression of M 3 receptors and TRPV1 in the bladder instead of improving blood sugar levels.