PTHrP attenuates spontaneous contractions in detrusor smooth muscle of the rat bladder by activating spontaneous transient outward potassium currents.

Parathyroid hormone-related protein (PTHrP) released from detrusor smooth muscle (DSM) cells upon bladder distension attenuates spontaneous phasic contractions (SPCs) in DSM and associated afferent firing to facilitate urine storage. Here, we investigate the mechanisms underlying PTHrP-induced inhibition of SPCs, focusing on large-conductance Ca2+-activated K+ channels (BK channels) that play a central role in stabilizing DSM excitability. Perforated patch-clamp techniques were applied to DSM cells of the rat bladder dispersed using collagenase. Isometric tension changes were recorded from DSM strips, while intracellular Ca2+ dynamics were visualized using Cal520 AM -loaded DSM bundles. DSM cells developed spontaneous transient outward potassium currents (STOCs) arising from the opening of BK channels. PTHrP (10 nM) increased the frequency of STOCs without affecting their amplitude at a holding potential of - 30 mV but not - 40 mV. PTHrP enlarged depolarization-induced, BK-mediated outward currents at membrane potentials positive to + 20 mV in a manner sensitive to iberiotoxin (100 nM), the BK channel blocker. The PTHrP-induced increases in BK currents were also prevented by inhibitors of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) (CPA 10 µM), L-type voltage-dependent Ca2+ channel (LVDCC) (nifedipine 3 µM) or adenylyl cyclase (SQ22536 100 µM). PTHrP had no effect on depolarization-induced LVDCC currents. PTHrP suppressed and slowed SPCs in an iberiotoxin (100 nM)-sensitive manner. PTHrP also reduced the number of Ca2+ spikes during each burst of spontaneous Ca2+ transients. In conclusion, PTHrP accelerates STOCs discharge presumably by facilitating SR Ca2+ release which prematurely terminates Ca2+ transient bursts resulting in the attenuation of SPCs.

Faster bladder filling in rats reduces detrusor overactivity but worsens (i.e., decreases) bladder compliance.

The impact of bladder filling rate on cystometric outcomes remains unclear. Clinically, faster bladder filling is believed to increase the likelihood of observing detrusor overactivity (DO) in those with bladder dysfunction, although evidence of this is lacking. We executed this study to clarify how changes in bladder filling rate impacted cystometric parameters. Urethane anesthetized female CD rats (n = 19) underwent bladder filling at five different fill rates, a baseline rate scaled to have a filling phase of approximately seven minutes (in line with our previous work), and scaled rates of 1/3x, 2x, 4x, and 8x that speed. Contrary to expectations, filling at faster rates decreased the likelihood of observing detrusor overactivity, with 4x and 8x filling rates demonstrating less detrusor overactivity than the baseline (1x) rate (P = 0.0091 for 4x and P = 0.019 for 8x). However, faster filling rates did decrease bladder compliance. Filling at 4x and 8x demonstrated decreased bladder compliance compared to 1x (P = 0.032 for 4x and P < 0.0001 for 8x). Finally, increasing the filling rate led to increases in bladder capacity at 4x (P = 0.034) and 8x (P = 0.0066) relative to 1x. These results suggest that contrary to expectations, faster filling may not be more effective at eliciting detrusor overactivity (i.e., not a better diagnostic approach). As reductions in detrusor overactivity and increases in bladder capacity are critical parameters for evaluating preclinical therapeutics, faster filling may impair the ability to demonstrate further improvements.

Nerve transfer for restoration of lower motor neuron-lesioned bladder, urethral and anal sphincter function. Part 4: Effectiveness of the motor reinnervation.

In pilot work, we showed that somatic nerve transfers can restore motor function in long-term decentralized dogs. We continue to explore the effectiveness of motor reinnervation in 30 female dogs. After anesthesia, 12 underwent bilateral transection of coccygeal and sacral (S) spinal roots, dorsal roots of lumbar (L)7, and hypogastric nerves. Twelve months postdecentralization, eight underwent transfer of obturator nerve branches to pelvic nerve vesical branches, and sciatic nerve branches to pudendal nerves, followed by 10 mo recovery (ObNT-ScNT Reinn). The remaining four were euthanized 18 mo postdecentralization (Decentralized). Results were compared with 18 Controls. Squat-and-void postures were tracked during awake cystometry. None showed squat-and-void postures during the decentralization phase. Seven of eight ObNT-ScNT Reinn began showing such postures by 6 mo postreinnervation; one showed a return of defecation postures. Retrograde dyes were injected into the bladder and urethra 3 wk before euthanasia, at which point, roots and transferred nerves were electrically stimulated to evaluate motor function. Upon L2-L6 root stimulation, five of eight ObNT-ScNT Reinn showed elevated detrusor pressure and four showed elevated urethral pressure, compared with L7-S3 root stimulation. After stimulation of sciatic-to-pudendal transferred nerves, three of eight ObNT-ScNT Reinn showed elevated urethral pressure; all showed elevated anal sphincter pressure. Retrogradely labeled neurons were observed in L2-L6 ventral horns (in laminae VI, VIII, and IX) of ObNT-ScNT Reinn versus Controls in which labeled neurons were observed in L7-S3 ventral horns (in lamina VII). This data supports the use of nerve transfer techniques for the restoration of bladder function.NEW & NOTEWORTHY This data supports the use of nerve transfer techniques for the restoration of bladder function.

Fosaprepitant improves cyclophosphamide-induced bladder damage by alleviating inflammatory response in mice.

Inhibition of inflammatory process is a key therapeutic target for the treatment of interstitial cystitis (IC). Recent reports indicate that neurokinin 1 receptor (NK1R) antagonists have beneficial roles in inflammatory-based diseases. Herein, we investigate the protective effects of fosaprepitant (FOS), a NK1R antagonist, in cyclophosphamide (CP)-induced cystitis. The cystitis model was established multiple CP (80 mg/kg; i.p.) injection one day apart, and mice were treated with FOS (20 and 60 mg/kg/day; i.p.) for seven consecutive days. Detrusor contractility, vesical vascular permeability, myeloperoxidase (MPO) activity and protein expression levels of the TLR4 pathway were evaluated in mice bladder. Carbachol and electric field stimulation-evoked contractions of detrusor strips were significantly increased in CP-treated mice, which was significantly attenuated by FOS (60 mg/kg/day) treatment (p<0.001, p<0.05). Notably, vesical vascular permeability was markedly impaired in CP-induced cystitis, that was restored by FOS (60 mg/kg/day) treatment (p<0.01). MPO activity was significantly increased in cystitis group whereas FOS (20 and 60 mg/kg/day) treatment remarkably suppressed MPO activity in bladder tissue (p<0.001). Although TLR4 expression increased with cystitis, MyD88 and p-NFκBSer536/total NFκB did not change, FOS (20 and 60 mg/kg/day) treatment caused a dramatic decrease in TLR4 expression (p<0.001), indicating the anti-inflammatory effect of FOS. In conclusion, FOS improved detrusor overactivity and inflammatory response by inhibiting MPO activity and TLR4 expression, resulting in functional and histological recovery in CP-induced cystitis.

Neurogenic-derived 6-nitrodopamine is the most potent endogenous modulator of the mouse urinary bladder relaxation.

6-Nitrodopamine (6-ND) modulates vas deferens, seminal vesicles, and corpus cavernosum contractility; however, its role on the lower urinary tract organs has not been evaluated. Investigations of isolated urinary bladders from wild-type (WT) mice revealed 6-ND release was comparable to that of dopamine and adrenaline, whereas noradrenaline was hardly detected, as assessed by liquid chromatography coupled to tandem mass spectrometry. In vitro, 6-ND induced concentration-dependent relaxations in carbachol pre-contracted bladders with high potency (pEC50: 8.04 ± 0.86), independently of eNOS/sGC activity. Co-incubation of 6-ND (1-10 µM) antagonizes the contractile effects of acetylcholine (p < 0.05). Experiments using nitric oxide synthase (NOS) knockout mice demonstrated that 6-ND release from isolated urinary bladder was significantly reduced by neuronal NOS (nNOS-/-) deletion and abolished by triple NOSs deletion (n/i/eNOS-/-), while no significant changes were observed in endothelial (eNOS-/-) or inducible (iNOS-/-) knockout mice. Incubation with tetrodotoxin resulted in a significant decrease in 6-ND release in bladders obtained from WT, but not in nNOS-/- mice. The bladders from nNOS-/- and n/i/eNOS-/- mice exhibited significantly higher contractile responses to electric field stimulation (EFS), compared to eNOS-/-, iNOS-/-, or WT bladders. The hyperreactivity observed in triple NOS knockouts was reversed by the incubation with bladder mucosal layer obtained from a donor WT mice, but not with the muscular layer. These findings clearly demonstrate 6-ND is the most potent endogenous relaxing agent of urinary bladder, and inhibition of its release is associated with bladder hyperreactivity.

Detrusor relaxing agents for neurogenic detrusor overactivity: a systematic review, meta-analysis and network meta-analysis.

OBJECTIVE: To evaluate the evidence regarding the therapeutic benefits and safety of oral detrusor relaxing agents (DRAs) in treating neurogenic detrusor overactivity (NDO). METHODS: A comprehensive search was performed on 1 September 2022. Two authors independently reviewed the articles to extract data using a pre-designed form. The meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A common-effect or random-effects model was used based on the heterogeneity among studies. Bayesian network meta-analysis (NMA) was further performed to make indirect comparisons of antimuscarinics and mirabegron. RESULTS: A total of 23 randomised controlled trials (RCTs) comprising 1697 patients were included in our analysis. Compared to placebo, the clinical benefits of oral DRAs, along with more adverse events (AEs), were demonstrated in the treatment of NDO. In the subgroup analysis, antimuscarinics significantly improved both urodynamic and bladder diary outcomes (including urinary incontinence episodes, urinary frequency, and residual volume), with a higher rate of AEs, such as xerostomia. Mirabegron improved some of the parameters and had fewer bothersome side-effects in patients with NDO. The NMA showed that none of the antimuscarinics or mirabegron was superior or inferior to the other. CONCLUSIONS: Detrusor relaxing agents are associated with improved outcomes in patients with NDO and our analysis has added new evidence regarding antimuscarinics. Evidence concerning mirabegron as first-line therapy for NDO is still limited. Well-designed RCTs are still required in this specific population.

Efficiency of HoLEP in patients with detrusor underactivity and renal dysfunction secondary to BPO.

PURPOSE: The purpose of this study was to assess the bladder and renal functional outcomes of holmium laser enucleation of the prostate (HoLEP) in patients with benign prostatic obstruction (BPO) complicated by detrusor underactivity (DU) and secondary renal dysfunction. METHODS: Thirty-one patients were included in this prospective study. Eligible patients had urinary retention, a bladder outlet obstruction index (BOOI) greater than 40, a bladder contractility index (BCI) less than 100, abnormal renal function at the initial diagnosis (serum creatinine > 132 µmol/L) and a renal pelvis anteroposterior diameter (PRAPD) > 1.5 cm bilaterally. All patients underwent HoLEP in a routine manner and were evaluated preoperatively and at 1, 3 and 6 months after surgery. The baseline characteristics of the patients, perioperative data, postoperative outcomes and complications were assessed. RESULTS: Significant improvement was observed in the international prostate symptom score (IPSS), quality of life (QoL) score, maximal urinary flow rate (Qmax), post-void residual volume (PVR), Scr and RPAPD at the 6-month follow-up. Bladder wall thickness (BWT) exhibited a decreasing trend but did not significantly differ from the preoperative values. No grade 3 or higher adverse events occurred, and grade 3 and lower complications were treated conservatively. Three patients required reinsertion of indwelling catheters, and they were able to void spontaneously after two weeks of catheterisation training and medication treatment. CONCLUSION: HoLEP is an effective treatment for men with BPO accompanied by DU and consequent renal function impairment. Patients are able to regain spontaneous voiding. Both bladder and renal functions were preserved and improved.

Clinical features and sequelae of detrusor underactivity: a study of possible cause and effect.

PURPOSE: To describe the clinical presentation and urodynamic findings in detrusor underactivity (DU) patients and investigate the association between DU and straining related complications such as pelvic organ prolapse (POP), inguinal hernia, and hemorrhoids. METHODS: We retrospectively reviewed all consecutive patients who underwent urodynamic studies (UDS) from 2012 to 2023, divided into two groups: those with evidence of DU (n = 573), and control subjects with normal voiding parameters (n = 522). Exclusion criteria were patients who lacked sufficient data, those with obstructive voiding parameters, and those who had received intravesical botulinum toxin injections within the previous nine months. Demographic information, clinical presentation, straining related complications, and UDS findings were compared between the two groups using univariate statistical analysis. RESULTS: The male DU group had a statistically significant higher prevalence of spinal disease and previous cerebrovascular accidents, while the female DU group had a statistically significant higher prevalence of spinal disease, multiple sclerosis, diabetes, previous colorectal surgery, previous transabdominal gynecological surgery, POP surgery, and recurrent UTIs. Female DU patients had a higher prevalence of pronounced vaginal bulging symptoms, recurrent POP, inguinal hernia, and hemorrhoids. The predominant LUTS were voiding symptoms (81.2% in males and 77.9% in females), followed closely by storage symptoms (66.2% in males and 74.7% in females). The median Qmax, PdetQmax, and PVR were 6 ml/sec, 18 cmH2O, 190 ml for male DU patients, and 8 ml/sec, 11 cmH2O, and 200 ml for female DU patients, respectively. CONCLUSION: Risk factors for DU that were identified include age, neurological diseases (spinal disease, CVA in men, MS in women), diabetes and transabdominal surgery (colorectal, gynecological) that can cause pelvic denervation in women. DU patients commonly present with both voiding and storage symptoms. There is approximately twice the risk of having POP surgery and inguinal hernia, an eight-fold risk of hemorrhoids, and a three-fold risk of recurrent UTIs for females. This is thought to be secondary to increased intra-abdominal pressure during urinary straining.

Efficacy and safety of the implantable, magnetic resonance imaging-compatible StimRouter neuromodulation system in the treatment of refractory lower urinary tract symptoms in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Lower urinary tract symptoms (LUTS) significantly affect quality of life (QoL) of multiple sclerosis (MS) patients, and pharmacotherapy has limited efficacy. We investigated efficacy and safety of the implantable StimRouter neuromodulation system for treating refractory LUTS in MS. METHODS: This prospective, single-center, clinical trial was conducted at the Multiple Sclerosis Center of Lugano, Switzerland, involving MS patients treated with self-administered percutaneous tibial nerve stimulation delivered by StimRouter over 24 weeks. Changes in video-urodynamic parameters as well as LUTS severity were measured by Overactive Bladder Questionnaire (OAB-q), QoL using the Multiple Sclerosis Quality of Life (MSQoL-54), and treatment satisfaction using a 1-10 visual analogue scale. Adverse events were also recorded. RESULTS: Of 23 MS patients recruited, six had neurogenic detrusor overactivity (NDO), five had detrusor sphincter dyssynergia (DSD), and 12 had both NDO and DSD. Of patients with NDO, median bladder volume at first uninhibited contraction significantly increased from baseline to week 24 (median = 136 mL, interquartile range [IQR] = 101-244 mL vs. 343 mL, IQR = 237-391 mL; ß = 138.2, p = 0.001). No significant changes of urodynamic parameters were found in patients with DSD. OAB-q symptom scores progressively decreased, and OAB-q quality of life scores increased (ß = -0.50, p < 0.001 and ß = 0.47, p < 0.001, respectively), whereas MSQoL-54 scores did not significantly change (ß = 0.24, p = 0.084) in the overall population. Treatment satisfaction was overall high (median = 8, IQR = 6-9). No serious adverse events were recorded. CONCLUSIONS: StimRouter represents a minimally invasive, magnetic resonance imaging-compatible, self-administered neuromodulation device leading to objective and subjective improvements of OAB symptoms and related QoL in MS patients with refractory LUTS.

Determination of voiding pressure in infants with normal lower urinary tracts: Exploring the possible effect of sacral development.

OBJECTIVE: To investigate the association between sacral underdevelopment, as defined by subnormal sacral ratio (SR) measurements, with increased maximum detrusor voiding pressure (P det. Max) in infants. METHODS: In this 2007-2015 retrospective cohort study, the medical records of all infants who underwent a pyeloplasty due to congenital ureteropelvic junction obstruction were added. Their P det. Max was evaluated through the suprapubic catheter utilized for urinary drainage intraoperatively, without imposing any additional risk of urethral catheterization on the infant. SR was calculated via the plain kidney, ureter, and bladder (KUB) radiography film obtained during the voiding cystourethrogram (VCUG) evaluation before the surgery. Participants were categorized into SR < 0.74 or SR ≥ 0.74. P det. Max was subsequently compared between these two groups. RESULTS: A total of 45 patients were included in our analysis. Twenty-eight (62.2%) patients had a (SR < 0.74), while 17 (37.8%) had a (SR ≥ 0.74). P det. Max was shown to be significantly higher in the SR < 0.74 compared to the SR ≥ 0.74 group (167.5 ± 60.8 vs. 55.7 ± 17.9 cmH2O, p < 0.001). After adjusting for age and sex, SR remained a significant contributor to P det. Max (p < 0.001). Physiologic detrusor sphincter dyscoordination (PDSD) rate was significantly higher in the SR < 0.74 versus SR ≥ 0.74 group (100.0% vs. 70.6%, respectively; p = 0.005). CONCLUSION: Lumbosacral underdevelopment, as indicated by subnormal sacral ratios, is associated with sphincter-detrusor dyscoordination, which causes PDSD and can ultimately result in higher P det. Max in infants.

Detrusor underactivity after radical prostatectomy: A prospective observational study.

OBJECTIVE: To evaluate the impact of radical prostatectomy (RP) on bladder function with special interest in detrusor underactivity (DU) and to appraise clinical significance of DU in postprostatectomy patients. MATERIAL AND METHODS: This was a prospective, observational study conducted on male patients subjected to laparoscopic RP (LPR). Urodynamic studies were performed at the day before surgery (visit 1), 3-6 months postoperatively (visit 2) and more than 12 months after surgery (visit 3). Incidence of DU that occurred after LPR (de novo DU), incidence of persisting de novo DU after 12 months, clinical relevance of DU after LPR and predictive factors of de novo DU were assessed. RESULTS: 99 of 100 patients underwent preoperative urodynamic study (visit 1) and those were included in further analysis. 84 and 76 patients were available for follow-up at second and third visit respectively. De novo DU occurred after LPR in 25 (29.7%) patients at visit 2 (p < 0.001). Sixteen from 24 patients (66,7%) who developed de novo DU after RP (visit 2) continued to have DU 1 year after surgery (visit 3) (p = 0.04). On the multivariate analysis, urinary incontinence requiring more than 1 pad per day (odds ratio [OR] 5.11; confidence interval [CI] 1.69-17.19; p = 0.005) and preoperative IPSS storage sub-score (OR 1.25; CI 1.03-1.63; p = 0.030) were significantly associated with de novo DU. Postprostatectomy patients with DU had significantly lower Urinary Assessment of the Expanded Prostate Cancer Index Composite (EPIC) total score (819 vs. 911, p = 0.02), EPIC Function domain score (300 vs. 357, p = 0.002) and EPIC Urinary incontinence domain (137 vs. 224, p = 0.002) when compared to their counterparts without DU. CONCLUSIONS: RP substantially influences bladder function, causing de novo DU, which persists in substantial number of patients 1 year postoperatively. Furthermore, significant correlation between DU and postprostatectomy urinary incontinence may play a role when anti-incontinence surgery is considered.

Is It Possible to Regenerate the Underactive Detrusor? Part 1 Molecular and Stem Cell Therapies Targeting the Urinary Bladder and Neural Axis ICI-RS 2024.

INTRODUCTION: Detrusor muscle weakness is commonly noted on urodynamics in patients with refractory voiding difficulty. No approved therapies have been proven to augment the strength of a detrusor voiding contraction. METHODS: This subject was discussed by a think-tank at the International Consultation on Incontinence- Research Society (ICI-RS) meeting held in Bristol, June 2024. The discussions of the think-tank are being published in two parts. This first part discusses molecular and stem cell therapies targeting the urinary bladder and the neural axis. RESULTS: Senescence of the urothelium and extracellular ATP acting through P2X3 receptors might be important in detrusor underactivity. Several molecules such as parasympathomimetics, acotiamide, ASP8302, neurokinin-2 agonists have been explored but none has shown unequivocal clinical benefit. Different stem cell therapy approaches have been used, chiefly in neurogenic dysfunction, with some studies showing benefit. Molecular targets for the neural axis have included TRPV-4, Bombesin, and serotoninergic receptors and TAC-302 which induces neurite growth. CONCLUSIONS: Several options are currently being pursued in the search for an elusive molecular or stem cell option for enhancing the power of the detrusor muscle. These encompass a wide range of approaches that target each aspect of the contraction mechanism including the urothelium of bladder and urethra, myocyte, and neural pathways. While none of these have shown unequivocal clinical utility, some appear promising. Lessons from other fields of medicine might prove instructive. CLINICAL TRIAL REGISTRATION: Not necessary. Not a clinical trial.

Is detrusor overactivity with detrusor underactivity limited to the elderly?

OBJECTIVE: Detrusor overactivity with detrusor underactivity (DO-DU) is classically described in frail institutionalized elderly patients, but we have also observed this diagnosis in younger populations. This research aims to identify the differences between two age groups of DO-DU patients. MATERIALS AND METHODS: This study included DO-DU patients from a single center from 2012 to 2023. Patients were divided into two groups: the "Younger" group (aged less than 70 years) and the "Older" group (aged 70 years or older). We separately compared demographics, the number of risk factors considered to affect bladder function, clinical presentations, and urodynamic findings between these two groups in each gender. RESULTS: There were 210 patients included in the analysis, with 50.48% in the younger group and 49.52% in the older group. The median ages of males and females in the younger group were 57 and 62 years, whereas the median ages of males and females in the older group were 76.5 and 76 years. Multiple sclerosis exhibited statistically significant prevalence in the younger patients (7.7% vs. 0%, p = 0.03 in males and 19.9% vs. 4.6% in females). While diabetes mellitus (DM) was more prevalent in the older males (20.0% vs. 4.6%, p = 0.01), transabdominal hysterectomy was more common in the younger females (46.3% vs. 25%, p = 0.04). 69.8% of the younger group and 71.2% of the older group have at least one risk factor that impact their bladder function. There was no statistically significant difference between the two groups across various risk factor categories. The older males reported a higher incidence of urgency (78.3% vs. 58.5%, p = 0.02) and urge incontinence (61.7% vs. 32.3%, p < 0.01), while the younger females reported a higher incidence of straining during voiding on history (46.3% vs. 20.5%, p = 0.01). The younger males exhibited a greater volume of strong desire to void (385 vs. 300 mL, p = 0.01), maximal cystometric capacity (410 vs. 300 mL, p < 0.01), and a lower highest detrusor overactivity (DO) pressure (37 vs. 50.5 cmH2O, p = 0.02). The younger group had a higher postvoid residual (170 vs. 85 mL in males, p < 0.01 and 180 vs. 120 mL in females, p = 0.02). The voiding efficiency was lower in younger females (40% vs. 60%, p = 0.02). In both ages, the ICS detrusor contraction index and projected isovolumetric pressure 1 were similar. However, without considering risk factors, the older males had the highest DO pressure (57 vs. 29 cmH2O, p < 0.01), and the younger males had a higher voiding pressure (PdetQmax) than the older males (28 vs. 20 cmH2O, p = 0.02). CONCLUSION: DO-DU is not exclusive to elderly patients. It can also be diagnosed in individuals with risk factors regardless of age; therefore, clinicians need a high degree of suspicion, especially in patients who have risk factor(s) for DO and DU. A notable clinical differentiation is that older males diagnosed with DO-DU have a higher incidence of urgency and urge urinary incontinence, while younger females have a higher incidence of straining.

Is it Possible to Regenerate the Underactive Detrusor? Part 2 Electrical Stimulation Therapies, Treatment of Bladder Outlet Obstruction, Constipation, and Pelvic Floor Disorders ICI-RS 2024.

INTRODUCTION: Detrusor muscle weakness is commonly noted on urodynamics in patients with refractory voiding difficulty. No clinical therapy has been proven to augment the strength of a detrusor contraction. METHODS: This subject was discussed at a think-tank at the International Consultation on Incontinence-Research Society (ICI-RS) held in Bristol, June 2024. The discussions of the think-tank are being published in two parts. This second part discusses the role of electrical stimulation therapies, treatment of bladder outlet obstruction, constipation, and pelvic floor disorders, in the enhancement of strength of a detrusor contraction. RESULTS: Electrical stimulation therapies, specifically sacral neuromodulation, have long been used in the salvage of patients with refractory nonobstructive voiding dysfunction. Clinical improvements can be noted in men following bladder outlet resistance reduction surgery especially, though not limited to those with demonstrable obstruction. Some patients may also show improvement with pelvic floor relaxation therapies and constipation care. However, there is a lack of high-quality urodynamic data to demonstrate an improvement in the strength of a detrusor contraction with these therapies. The think-tank recommends standards for future clinical studies examining treatments aimed at improving an underactive detrusor. CONCLUSIONS: Studies need to examine whether clinical improvement following treatment of patients with an underactive detrusor is associated with improvement in strength of the detrusor contraction. New therapeutic options should apply specified standards for assessing and reporting the impact on detrusor contraction.

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.

A new nomogram for the evaluation of detrusor underactivity and bladder outlet obstruction in nonneurogenic female patients with lower urinary tract symptoms who undergo urodynamic studies.

INTRODUCTION: Micturition physiology differs in men and women. However, the results in standard urodynamic studies in women with lower urinary tract symptoms (LUTS) were extrapolated from studies in men. Nowadays, the only validated nomogram for females is Solomon-Greenwell's. However, it only evaluated bladder outlet obstruction (BOO) without considering detrusor underactivity (DU). This study aims to create a nomogram that includes an evaluation of DU and BOO in nonneurogenic women and validate it against videourodynamic studies along with other nomograms. MATERIALS AND METHODS: For the first analysis (creation cohort), we included 183 women with LUTS who underwent videourodynamic study between 2022 and 2023. Exclusion criteria were females with neurologic diseases, renal transplantation, and trouble performing the flow-pressure study. Baseline characteristics of the patients, urodynamic parameters, and classifications on different nomograms and indexes were evaluated. A logistic regression found Qmax and PdetQmax as predictors for DU and BOO. The Barco-Castillo nomogram was created by clustering analysis and adjusted by the results of the logistic regression. A second (test) cohort was evaluated from 2023 to 2024, including 142 patients for the validation of the nomogram. A p < 0.05 was considered significant. RESULTS: All urodynamic parameters were compared between both cohorts, with no significant differences. The median age of the creation cohort was 50 years old (interquartile range [IQR] 39-63). All patients had LUTS and a previous standard urodynamic study without a clear diagnosis. The cluster analysis had a p < 0.05 for two groups of BOO (yes/no) and two of DU (yes/no). We created the graph based on the logistic regression results and adjusted it according to the data. The median age of the test cohort was 44 years old (IQR 33.75-59) and had the same indication for the videourodynamic study. The receiver operating characteristic (ROC) curve for BOO showed an accuracy of 85.4% for Barco-Castillo nomogram, 68.5% for Blaivas-Groutz, 58.1% for Solomon-Greenwell, 57.1% for BOOI, and 50% for LinPURR. For DU, accuracy was 80.5% for PIP-1, 80.2% for Barco-Castillo, 76.6% for BCI, and 70.1% for LinPURR. CONCLUSIONS: When evaluating women's urodynamic studies, it is important to focus on female physiology and discourage the use of parameters previously standardized in men. We encourage using the new Barco-Castillo nomogram to determine BOO and DU in women as the currently easiest and more accurate tool.

How to define failure of intradetrusor injections of botulinum toxin A for neurogenic detrusor overactivity.

INTRODUCTION: Neurogenic detrusor overactivity (NDO) has a major impact on patients' quality of life and can lead to upper urinary tract complications. Intradetrusor botulinum toxin type A injections are administered as second-line treatment to these patients following the failure of anticholinergic agents. The aim of the DETOX 2 study is to propose a consensus definition of the failure of intradetrusor botulinum toxin injections for NDO in patients presenting spinal cord injury, spina bifida, or multiple sclerosis (MS) with self-catheterization. METHOD: This study followed the method adopted by the French National Authority for Health for recommendations by consensus. Based on a review of the literature and a preliminary survey, a steering committee compiled a questionnaire and selected a rating group comprising 16 experts from the Neuro-Urology Committee of the French Urology Association (cnuAFU) and Genulf. The experts were asked to complete the online questionnaire. At the end of the first round, all participants came together to discuss any disagreements and a second-round online questionnaire was completed to reach a consensus. RESULTS: Thirteen of the 16 experts approached completed both rounds of questionnaires. A strong consensus was reached for two proposals (median score = 9/10) which were therefore included in the definition from the first round: at least one repeat injection of the same botulinum toxin at the same dose must be given to rule out failure on technical grounds and a duration of efficacy <3 months must be considered a failure. At the end of round 2, a relative consensus was reached regarding the clinical criterion defining failure (median score = 7/10) and the urodynamic criterion of failure (median score = 8/10). An additional proposal was selected during this second round on the need for a voiding diary (median score = 8/10). CONCLUSION: The first consensus definition of failure of an intradetrusor injection of TB-A for NDO has been achieved with this study: persistence of detrusor overactivity with maximum detrusor pressures >40 cm H2O and/or a compliance issue and/or persistence of urinary incontinence and/or urgency and/or a number of daily self-catheterizations >8/day and/or efficacy <3 months. This study will help to standardize research on the failure of the intradetrusor botulinum toxin for NDO in clinical practice and clinical research.

The Orexin OX2 Receptor-Dependent Pathway Is Implicated in the Development of Overactive Bladder and Depression in Rats Exposed to Corticosterone.

AIM: In the present study, we wanted to check whether TCS OX2 29 (TCS), a potent selective antagonist of OX2 receptors, would have positive effects in an animal model of detrusor overactivity co-existed with the depression-like state in Wistar male rats. METHODS: The forced swim test with the measurement of spontaneous locomotor activity, conscious cystometry, determination of c-Fos expression in central micturition areas, and a set of biochemical analyses (with the use of urine, hippocampus, bladder urothelium, and detrusor muscle of tested animals) were carried out. RESULTS: The outcomes showed that a 7-day administration of TCS (3 mg/kg/day, subcutaneously) normalizes the cystometric parameters corresponding to overactivity of the detrusor and reverses the pro-depressive response. Furthermore, the antagonism of OX2 receptors restored the abnormal levels of overactive bladder markers (i.e., ATP, CGRP, OCT3, TRPV1, ROCK1, and VAChT), diminished neuronal overactivity in central micturition areas (i.e., pontine micturition center, ventrolateral periaqueductal gray, and medial preoptic area) as well as restored the altered hippocampal levels of CRF, cytokines (IL-1ß, IL-6, IL-10, and TNF-α), and growth factors (BDNF and NGF) that reflected biochemical disturbances detected in depressed people. CONCLUSIONS: It seems that our findings open new perspectives regarding the implication of the orexin system in the functioning of the urinary bladder and in the pathophysiology of depression.

Establishing initial resting abdominal pressure in children undergoing urodynamics.

INTRODUCTION: The International Continence Society recommends zeroing of transducers to the atmospheric pressure for invasive urodynamics. The range of abdominal pressure relative to atmospheric pressure is well-known in adults but has not been described in children. This prospective observational study was carried out to establish baseline abdominal in children. MATERIALS AND METHODS: Prospective, multicenter, observational study of 100 children aged 0-18 years undergoing invasive urodynamics using water-filled systems. Initial resting abdominal pressure, intravesical pressure and detrusor pressure were recorded in supine, sitting, and standing position (as age- and diagnosis-appropriate). This data was analyzed using SPSS 20.0.0 with regard to age, gender, height, weight, body mass index, and underlying diagnosis (classified as neurogenic or non-neurogenic). Nonparametric tests were used (2-sided p < 0.05, significant). RESULTS: Initial resting abdominal pressure (inter-quartile range) in children was between 5 and 15 cmH2 O in the supine, 13-20 cmH2 O in the sitting, and 15-21 cmH2 O in the standing position. These pressures were not consistently influenced by age, gender, height, weight or underlying diagnosis. The initial resting detrusor pressure was noted to be 0-4 cmH2 O without any difference based on posture. Limitations include use of two-tube technique, relatively small number of subjects across each age group, wide range of underlying diagnoses and need for manual smoothing of some traces. CONCLUSION: This study defines initial resting abdominal pressure at urodynamics in children and notes that, as with adults, it is possible to define widely applicable ranges regardless of individual characteristics. These pressures appear lower than those noted historically in adults.

Novel clinical diagnostic criteria based on noninvasive examination findings to predict the presence of urodynamic detrusor underactivity in men.

AIMS: To investigate the usefulness of novel clinical diagnostic criteria based on noninvasive examination findings to diagnose urodynamic detrusor underactivity (DU) in men. METHODS: We developed clinical diagnostic criteria to predict the presence of urodynamic DU in men as follows: (a) bladder voiding efficiency <70% on uroflowmetry, (b) existence of "sawtooth and interrupted waveforms" on uroflowmetry, and (c) ultrasonography-documented intravesical prostatic protrusion <10 mm. We analyzed the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of these clinical criteria for diagnosing urodynamic DU in men aged 50 years or above with lower urinary tract symptoms who underwent urodynamic studies. RESULTS: Of the 314 men analyzed (mean age, 72.4 years; mean detrusor contraction index [DCI], 98.8; and mean bladder outlet obstruction index [BOOI], 43.9), 89 men met this clinical DU diagnostic criteria. Of these, 79 men (88.8%) had urodynamic DU (DCI < 100 and BOOI < 40), nine (10.1%) had DU + BOO (DCI < 100 and BOOI ≥ 40), and one (1.1%) had normal voiding functions. None of the men with urodynamic BOO (DCI ≥ 100 and BOOI ≥ 40) met the clinical DU diagnostic criteria. The sensitivity, specificity, PPV, and NPV of these clinical diagnostic criteria for urodynamic DU were 69.3%, 95.0%, 88.8%, and 84.4%, respectively. CONCLUSION: The proposed clinical DU diagnostic criteria showed a high PPV (88.8%) for diagnosing urodynamic DU. None of the patients with BOO met the clinical diagnostic criteria for DU. These clinical DU diagnostic criteria may be useful in identifying men with urodynamic DU in clinical practice.