Androgen deprivation therapy in advanced prostate cancer: insights from a real-world patient survey on health-related quality of life and information and communication sources.

PURPOSE: Androgen deprivation therapy (ADT) is a cornerstone treatment for advanced and metastatic prostate cancer. Real-world and patient-reported insights into ADT's impact on health-related quality of life (HRQoL) and communication experiences in healthcare settings remain underexplored. This patient organisation-initiated online survey aimed to assess these aspects. METHODS: Between December 2022 and August 2023, the patient organisation Think Blue Vlaanderen and the AZ Sint-Jan Hospital (Bruges, Belgium) invited ADT-treated patients to participate in a prospective, online, cross-sectional, patient-reported outcome survey. Demographic, clinical, HRQoL (FACT and EPIC-26), communication sources and information modality data were collected. Descriptive statistics and comparative analyses were applied. RESULTS: A total of 276/312 (88.5%) participating patients were on ADT at time of survey administration and completion, with the majority receiving a 3-monthly regimen. Sexual HRQoL was low and narrowly distributed (median (IQR): 16.7 (16.7-16.7)), with 84% of patients having erectile dysfunction (ED). Patients finding their ED problematic were more likely to seek pharmaceutical treatment. Hormonal HRQoL was widely distributed (median (IQR): 65 (45-85)), which improved with prolonged ADT duration. Physically active patients reported less lack of energy, but increased hot flashes. Within consistent FACT-G summary scores (median (IQR): 64.50 (54.75-77.00)), improved emotional wellbeing with prolonged ADT was noted. Multidisciplinary communication and multimodal information provision improved patient satisfaction. CONCLUSION: Patient organisation-initiated surveys offer real-world and patient-reported insights. Patient-tailored HRQoL assessments and longitudinal follow-up, physical activity, and multidisciplinary and multimodal communication approaches are warranted to improve patient-centred care in patients receiving ADT.

Phase II open-label study investigating apalutamide in patients with biochemical progression after radical prostatectomy.

Apalutamide, a competent inhibitor of the androgen receptor, has shown promising clinical efficacy results for patients with advanced prostate cancer. Here, we describe the rationale and design for the SAVE trial, a multi-center, Phase II study, wherein 202 men with biochemical progression after radical prostatectomy are randomly assigned 1:1 to apalutamide plus salvage radiotherapy (SRT) or androgen-deprivation therapy with an luteinizing hormone-releasing hormone agonist or antagonist plus SRT. The primary objective is to compare sexual function between the two treatment arms based on the expanded prostate cancer index-26 sexual domain score at nine months after start of hormonal treatment. The key secondary objectives are to assess quality of life, to evaluate the safety profile and the short-term efficacy of apalutamide in combination with SRT. ClinicalTrials.gov identifier: NCT03899077.

Use of fosfomycin as targeted antibiotic prophylaxis before prostate biopsy: A prospective randomized study.

OBJECTIVES: To investigate whether switching ciprofloxacin to fosfomycin in the case of fluoroquinolone-resistant rectal bacteria influences the incidence of infectious complications after transrectal prostate biopsy. METHODS: From December 2015 until December 2017, patients undergoing prostate biopsy were randomly assigned to a control group or an intervention group in a prospective, open-label fashion at three different centers. The presence of fluoroquinolone-resistant organisms was detected by rectal swabs. Patients in the control group received ciprofloxacin. Patients in the intervention group received fosfomycin instead of ciprofloxacin in the case of fluoroquinolone-resistant bacteria on rectal swab culture. The primary end-point was the difference in occurrence of major (febrile) and minor (afebrile) infections between both groups. RESULTS: A total of 102 patients were randomized to the control group, and 102 patients to the intervention group. In the control group, nine complications occurred, of which five were major febrile complications. In the intervention group, six complications occurred, of which four were major febrile complications. The total number of complications (major and minor) did not differ between both groups (P = 0.59). A subgroup analysis of patients with fluoroquinolone-resistant bacteria on rectal swab showed five complications in the control group and one complication in the intervention group (P = 0.09). CONCLUSIONS: This represents the first prospective randomized study using rectal cultures for targeted antibiotic prophylaxis. Study findings show promising results for use of fosfomycin in patients with fluoroquinolone resistance.

Additive effects of the Rho kinase inhibitor Y-27632 and vardenafil on relaxation of the corpus cavernosum tissue of patients with erectile dysfunction and clinical phosphodiesterase type 5 inhibitor failure.

OBJECTIVES: To evaluate the expression of the Rho/Rho-associated protein kinase (ROCK) pathway in the corpus cavernosum of patients with severe erectile dysfunction (ED) compared with healthy human corpus cavernosum, and to test the functional effects of two Rho kinase inhibitors (RKIs) on erectile tissue of patients with severe ED, which did not respond to phosphodiesterase type 5 inhibitors (PDE5Is). PATIENTS AND METHODS: Human corpus cavernosum samples were obtained after consent from men undergoing penile prosthesis implantation (n = 7 for organ bath experiments, n = 17 for quantitative PCR [qPCR]). Potent control subjects (n = 5) underwent penile needle biopsy. qPCR was performed for the expression of RhoA and ROCK subtypes 1 and 2. Immunohistochemistry staining against ROCK and α smooth muscle actin (αSMA) was performed on the corpus cavernosum of patients with ED. Tissue strips were precontracted with phenylephrine and incubated with 1 µm of the PDE5I vardenafil or with DMSO (control). Subsequently, increasing concentrations of the RKIs azaindole or Y-27632 were added, and relaxation of tissue was quantified. RESULTS: The expression of ROCK1 was unchanged (P > 0.05), while ROCK2 (P < 0.05) was significantly upregulated in patients with ED compared with controls. ROCK1 and ROCK2 protein colocalized with αSMA, confirming the presence of this kinase in cavernous smooth muscle cells and/or myofibroblasts. After incubation with DMSO, 10 µm azaindole and 10 µm Y-27632 relaxed precontracted tissues with 49.5 ± 7.42% (P = 0.1470 when compared with vehicle) and 85.9 ± 10.3% (P = 0.0016 when compared with vehicle), respectively. Additive effects on relaxation of human corpus cavernosum were seen after preincubation with 1 µm vardenafil. CONCLUSION: The RKI Y-27632 causes a significant relaxation of corpus cavernosum in tissue strips of patients with severe ED. The additive effect of vardenafil and Y-27632 shows that a combined inhibition of Rho-kinase and phosphodiesterase type 5 could be a promising orally administered treatment for severe ED.

Bladder dysfunction in a transgenic mouse model of multiple system atrophy.

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder presenting with motor impairment and autonomic dysfunction. Urological function is altered in the majority of MSA patients, and urological symptoms often precede the motor syndrome. To date, bladder function and structure have never been investigated in MSA models. We aimed to test bladder function in a transgenic MSA mouse featuring oligodendroglial α-synucleinopathy and define its applicability as a preclinical model to study urological failure in MSA. Experiments were performed in proteolipid protein (PLP)-human α-synuclein (hαSyn) transgenic and control wild-type mice. Diuresis, urodynamics, and detrusor strip contractility were assessed to characterize the urological phenotype. Bladder morphology and neuropathology of the lumbosacral intermediolateral column and the pontine micturition center (PMC) were analyzed in young and aged mice. Urodynamic analysis revealed a less efficient and unstable bladder in MSA mice with increased voiding contraction amplitude, higher frequency of nonvoiding contractions, and increased postvoid residual volume. MSA mice bladder walls showed early detrusor hypertrophy and age-related urothelium hypertrophy. Transgenic hαSyn expression was detected in Schwann cells ensheathing the local nerve fibers in the lamina propria and muscularis of MSA bladders. Early loss of parasympathetic outflow neurons and delayed degeneration of the PMC accompanied the urological deficits in MSA mice. PLP-hαSyn mice recapitulate major urological symptoms of human MSA that may be linked to αSyn-related central and peripheral neuropathology and can be further used as a preclinical model to decipher pathomechanisms of MSA.

Safety and efficacy of software-assisted MRI-TRUS fusion-guided transperineal prostate biopsy in an outpatient setting using local anaesthesia.

PURPOSE: To evaluate diagnostic accuracy, safety, and efficiency of an MRI-TRUS fusion-guided transperineal prostate biopsy method in an outpatient setting under local anaesthesia. METHODS: Patients undergoing transperineal prostate biopsy were included from March 2021 to May 2022. Biopsies were performed under local anaesthesia in an outpatient setting, using specialised fusion software. Primary outcome was (clinically significant) cancer detection rate. Secondary outcomes were procedure time, patient discomfort during the procedure and complication rate. RESULTS: We included 203 male patients (69 years +-SD 8.2) with PI-RADS score > 2. In total 223 suspicious lesions were targeted. Overall cancer detection rate and clinically significant cancer detection rate were 73.5% and 60.1%, respectively. (Clinically significant) cancer detection rates in PI-RADS 3, 4 and 5 lesions were 46.4% (23.2%), 78.5% (66.1%) and 93.5% (89.1%), respectively. Mean duration of the procedure including fusion, targeted and systematic biopsies was 22.5 min. Patients rated injection of local anaesthesia on a numeric pain rating scale on average 3.7/10 (SD 2.09) and biopsy core sampling 1.6/10 (SD 1.65). No patient presented with acute urinary retention on follow-up consultation. Two (1%) patients presented with infectious complications. Four (2%) patients experienced a vasovagal reaction. CONCLUSION: Transperineal targeted biopsy with MRI-TRUS fusion software has high overall and clinically significant cancer detection rates. The method is well tolerated under local anaesthesia and in an outpatient setting.

Discrimination, Reliability, Sensitivity, and Specificity of Robotic Surgical Proficiency Assessment With Global Evaluative Assessment of Robotic Skills and Binary Scoring Metrics: Results From a Randomized Controlled Trial.

Objective: To compare binary metrics and Global Evaluative Assessment of Robotic Skills (GEARS) evaluations of training outcome assessments for reliability, sensitivity, and specificity. Background: GEARS-Likert-scale skills assessment are a widely accepted tool for robotic surgical training outcome evaluations. Proficiency-based progression (PBP) training is another methodology but uses binary performance metrics for evaluations. Methods: In a prospective, randomized, and blinded study, we compared conventional with PBP training for a robotic suturing, knot-tying anastomosis task. Thirty-six surgical residents from 16 Belgium residency programs were randomized. In the skills laboratory, the PBP group trained until they demonstrated a quantitatively defined proficiency benchmark. The conventional group were yoked to the same training time but without the proficiency requirement. The final trial was video recorded and assessed with binary metrics and GEARS by robotic surgeons blinded to individual, group, and residency program. Sensitivity and specificity of the two assessment methods were evaluated with area under the curve (AUC) and receiver operating characteristics (ROC) curves. Results: The PBP group made 42% fewer objectively assessed performance errors than the conventional group (P < 0.001) and scored 15% better on the GEARS assessment (P = 0.033). The mean interrater reliability for binary metrics and GEARS was 0.87 and 0.38, respectively. Binary total error metrics AUC was 97% and for GEARS 85%. With a sensitivity threshold of 0.8, false positives rates were 3% and 25% for, respectively, the binary and GEARS assessments. Conclusions: Binary metrics for scoring a robotic VUA task demonstrated better psychometric properties than the GEARS assessment.

Irrigation fluid absorption syndrome during HoLEP: A case study.

The classical transurethral resection syndrome as described with monopolar prostate resection has become rare since the switch to bipolar resection and even more so since the introduction of HoLEP. We report a case of a 74-year-old male patient who presented with an irrigation fluid absorption syndrome during a HoLEP for benign prostate hypertrophy. Biochemically this presented as metabolic acidosis and hyperchloremia instead of hyponatremia. He was treated with diuretics and had a swift recovery.

Functional characterization of a chronic cyclophosphamide-induced overactive bladder model in mice.

AIMS: To describe a new mouse model of overactive bladder (OAB) at the histological level, pain, voiding behavior, and urodynamics, while assessing the physiological state of mice. METHODS: This paper compares the pathophysiological features of mice that received intraperitoneal injections of cyclophosphamide (CYP) (40 and 80 mg/kg - body weight) every 2 days for 7 days. Specifically, the heart rate, the body temperature, and the general activity were assessed by telemetry. The abdominal sensitivity was determined with Von Frey filaments. Voiding behavior and detrusor activity were respectively quantified by urine spotting experiments and cystometry. Hematoxylin & Eosin staining was performed to detect inflammation in tissue and NGF concentration in urine was quantified. RESULTS: Affected mice exhibit clearly an OAB characterized by an increase in the number of voiding events and an urodynamically-demonstrated detrusor overactivity associated with referred hyperalgesia. The injected mice displayed inflamed bladder, urothelial hyperplasia, and increased NGF concentration in urine in dose dependant manner. However, the physiological features of mice with CYP-induced cystitis are not changed. CONCLUSIONS: We can show that this model of chronic OAB with pain in mice fits more closely to the clinical signs of patients with OAB than the available animal models (acute and chronic) and will therefore be useful to highlight potential drug targets in genetically modified mice in the future.

The Effect of Surgical Experience on Perioperative and Oncological Outcomes After Robot-assisted Radical Cystectomy with Intracorporeal Urinary Diversion: Evidence from a Referral Centre with Extensive Experience in Robotic Surgery.

BACKGROUND: Evidence on the learning curve for robot-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) is limited. OBJECTIVE: To assess the effect of surgical experience (SE) on perioperative and intermediate-term oncological outcomes in a large contemporary cohort of RARC patients after accounting for the impact of intersurgeon variability. DESIGN, SETTING, AND PARTICIPANTS: The study cohort included 164 patients treated with RARC and ICUD by two surgeons between 2004 and 2017 at a single European referral centre. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: For each patient, SE was defined as the total number of RARCs performed by each surgeon before the patient's operation. The relationship between SE and operative time (OT), lymph node yield (LNY), positive surgical margins (PSMs), Clavien-Dindo grade ≥2 30-d postoperative complication (CD≥2), and oncological outcomes (18-mo recurrence rate) was evaluated in multivariable linear and logistic regression models, clustering at a single-surgeon level. RESULTS AND LIMITATIONS: After adjusting for case mix, SE was associated with shorter OT (p= 0.003), lower probability of postoperative CD≥2 rates (p= 0.01), and lower 18-mo recurrence rates (p= 0.002). Conversely, SE did not predict lower PSM rates (p= 0.3) and higher LNY (p= 0.4). The relationship between SE and OT was nonlinear, with a plateau observed after 50 cases. Conversely, the relationship between SE and CD≥2 and 18-mo recurrence was linear without reaching a plateau after 88 procedures. CONCLUSIONS: SE affects perioperative and oncological outcomes after RARC with ICUD in a linear fashion, and its beneficial effect does not reach a plateau. Conversely, after 50 cases, no further improvement was observed for OT. PATIENT SUMMARY: Robot-assisted radical cystectomy with intracorporeal urinary diversion is a complex surgical procedure with a relatively long learning curve.

Time to Move On: The Impending Need for a New Disease-specific Comorbidity Index for Bladder Cancer Patients Undergoing Robot-assisted Radical Cystectomy.

The Charlson comorbidity index is an outdated comorbidity assessment tool which is not disease specific and is not applicable to contemporary BCa patients.

Undergraduate Education for Urology in Europe. Where Do We Stand?

Regardless of career intentions, junior doctors will meet patients with urological problems. There are no studies on the status of undergraduate education for urology in Europe. We designed an 18-item online survey using the platform www.surveymonkey.com to assess the current status of undergraduate education in urology. A total of 347 medical students, trainees, and urologists responded to the survey. Medical students' exposure to urology during their undergraduate career was heterogeneous. Although the quality of urology education was valued from moderate to high, urology as a speciality did not influence their future training decision making. Decision making in relation to residency training correlated with the number of hours spent on practical training, duration of urology rotation, and year of medical school in which urological exposure was introduced. The current European exposure to urology at undergraduate level is heterogeneous, with various factors influencing future decisions regarding training and specialisation. A uniform undergraduate curriculum would eliminate such heterogeneous exposure and facilitate a workforce fit for the future urological needs. PATIENT SUMMARY: Junior doctors will meet patients with urological problems in the wards, emergency departments, and primary care. Institutions should work together for a urological curriculum that fits the future clinical requirements.

TRPV4 Mediates Acute Bladder Responses to Bacterial Lipopolysaccharides.

Urinary tract infections (UTI) affect a large proportion of the population, causing among other symptoms, more frequent and urgent micturition. Previous studies reported that the gram-negative bacterial wall component lipopolysaccharides (LPS) trigger acute epithelial and bladder voiding responses, but the underlying mechanisms remain unknown. The cation channel TRPV4 is implicated in the regulation of the bladder voiding. Since TRPV4 is activated by LPS in airway epithelial cells, we sought to determine whether this channel plays a role in LPS-induced responses in urothelial cells (UCs). We found that human-derived UCs display a fast increase in intracellular Ca2+ concentration upon acute application of Escherichia coli LPS. Such responses were detected also in freshly isolated mouse UCs, and found to be dependent on TRPV4, but not to require the canonical TLR4 signaling pathway of LPS detection. Confocal microscopy experiments revealed that TRPV4 is dispensable for LPS-induced nuclear translocation of NF-κB in mouse UCs. On the other hand, quantitative RT PCR determinations showed an enhanced LPS-induced production of proinflammatory cytokines in TRPV4-deficient UCs. Cystometry experiments in anesthetized wild type mice revealed that acute intravesical instillation of LPS rapidly increases voiding frequency. This effect was not observed in TRPV4-deficient animals, but was largely preserved in Tlr4 KO and Trpa1 KO mice. Our results suggest that activation of TRPV4 by LPS in UCs regulates the proinflammatory response and contributes to LPS-induced increase in voiding frequency. These findings further support the concept that TRP channels are sensors of LPS, mediating fast innate immunity mechanisms against gram-negative bacteria.

Perceived Role of Social Media in Urologic Knowledge Acquisition Among Young Urologists: A European Survey.

BACKGROUND: Social media (SoMe) are increasingly being integrated into personal and professional life, with urology being a leading medical specialty in SoMe adoption. OBJECTIVE: We aimed to assess the perceived role of SoMe in urologic knowledge acquisition among young urologists across Europe. DESIGN, SETTING, AND PARTICIPANTS: Members of the European Society of Residents in Urology designed a 20-item online survey via surveymonkey.com. The survey was designed in accordance with Checklist for Reporting Results of Internet E-Surveys (CHERRIES) guidelines and was distributed via e-mail and social media in 23 European countries to urology residents and young urologists. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statistical Package for the Social Sciences (SPSS) software was used for descriptive statistics and statistical analysis. For comparative analysis the Mann-Whitney U test was used. RESULTS AND LIMITATIONS: A total of 316 young urologists with a mean age of 31.2±3.9 yr responded to the survey. Of the respondents, 99% use SoMe in a personal and/or professional way. YouTube and LinkedIn are the most frequently used platforms for professional use. SoMe were ranked in third place as an information source for urologic news/updates, lying behind journals and websites but ahead of congresses and books. Video content from YouTube or other sources was ranked as a preferred tool to see/understand surgical techniques ahead of websites and reference books. 61% follow urologic associations, 47% follow urologic events, 44% follow urologic journals, and 39% follow urologic experts on SoMe. The perceived influence of SoMe on urology knowledge was rated as moderate to high by 63% and as low to none by 37% of young urologists. Of the respondents, 44% apply guidelines on the appropriate use of SoMe in urology. CONCLUSIONS: SoMe play a significant role in knowledge acquisition by young urologists in Europe. Physicians, organizations, and institutions should strive to spread and provide valuable educational content through SoMe. PATIENT SUMMARY: Social media can be valuable for education in urology because it is useful to keep abreast of new developments in this field of medicine.

[Fatigue syndrome: Stress, Burnout and depression in Urology.] / "Síndrome de agotamiento": Estrés, Burnout y depresión en Urología.

OBJECTIVE: To determine the factors related to stress, Burnout and depression in urology, as well as consequences in residents and urologists, in addition to the possible applicable strategies to diminish and treat them. ACQUISITION OF THE EVIDENCE: Depression, stress and Burnout syndrome has become a problem in urology specialty. These topics have gained interest in international congresses and urological associations. Efforts are being made to find related factors as well as possible strategies and applicable support programs. SYNTHESIS OF EVIDENCE: Burnout frequency is higher among health professionals than general population, 40-76% in students and residents, its incidence has skyrocketed in recent years, in addition Urology is one of the specialties with highest incidence and severity. Its increase has been related to work overload, documentation, administrative/bureaucratic workload, hostile work environment; its consequences include poor work performance, medical errors, depression, substance abuse, disruption in family and couple relationships and suicidal ideation. Strategies for prevention including resilience training, lifestyle balance, teamwork, and support programs. CONCLUSION: Stress, burnout and depression are problems in urology, early detection, promoting individual techniques in resilience, lifestyle and teamwork are fundamental now and for the future of the specialty. Developing and implementing support programs should be seriously considered by health systems and urological associations.

Ultrasonography Is Not Inferior to Fluoroscopy to Guide Extracorporeal Shock Waves during Treatment of Renal and Upper Ureteric Calculi: A Randomized Prospective Study.

OBJECTIVE: To investigate whether the visualization modality (ultrasound or fluoroscopy) used during shockwave lithotripsy (SWL) affects the clinical outcome in those instances where both imaging modalities are optional. METHODS: Between November 2014 and July 2016, 114 patients with radiopaque upper urinary tract calculi were randomly assigned to an ultrasound- or fluoroscopy-guided SWL group in a prospective, open-label, single-center study. A standardized SWL protocol was used. The stone-free rate and the positive outcome rate (stone-free or asymptomatic residual fragments ≤ 4 mm) were compared. RESULTS: The stone-free rate was 52% in the ultrasound-guided group compared to 42% in the fluoroscopy-guided group (p = 0.06) and the positive outcome rate was 79% in the ultrasound-guided group compared to 70% in the fluoroscopy-guided group (p = 0.28). These results were not significantly different but proved to be noninferior based on a Wilson confidence interval of independent proportions (noninferiority limit 10%). The mean number of SWL sessions was not significantly different (p = 0.4). CONCLUSION: Our study demonstrated that the clinical results of ultrasound-guided SWL were not inferior to the results of fluoroscopy-guided SWL, while no ionizing radiation is needed.

Essential role of transient receptor potential M8 (TRPM8) in a model of acute cold-induced urinary urgency.

BACKGROUND: Acute exposure of part of the skin to cold stimuli can evoke urinary urgency, a phenomenon termed acute cold-induced urgency (ACIU). Despite its high prevalence, particularly in patients with overactive bladder, little is known about the mechanisms that induce ACIU. OBJECTIVE: To develop an animal model of ACIU and test the involvement of cold-activated ion channels transient receptor potential (TRP) M8 and TRPA1. DESIGN, SETTING, AND PARTICIPANTS: Intravesical pressure and micturition were monitored in female mice (wild-type C57BL/6J, Trpa1(-/-), Trpm8(+/+), and Trpm8(-/-)) and Sprague Dawley rats. INTERVENTIONS: An intravesical catheter was implanted. Localized cooling of the skin was achieved using a stream of air or topical acetone. The TRPM8 antagonist (N-(3-aminopropyl)-2-{[(3-methylphenyl) methyl]oxy}-N-(2-thienylmethyl)benzamide (AMTB) or vehicle was injected intraperitoneally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of bladder contractions and voids in response to sensory stimuli were compared using the Mann-Whitney or Kruskal-Wallis test. RESULTS AND LIMITATIONS: Brief, innocuously cold stimuli applied to different parts of the skin evoked rapid bladder contractions and voids in anesthetized mice and rats. These responses were strongly attenuated in Trpm8(-/-) mice and in rats treated with AMTB. As rodent bladder physiology differs from that of humans, it is difficult to directly extrapolate our findings to human patients. CONCLUSIONS: Our findings indicate that ACIU is an evolutionarily conserved reflex rather than subconscious conditioning, and provide a useful in vivo model for further investigation of the underlying mechanisms. Pharmacological inhibition of TRPM8 may be useful for treating ACIU symptoms in patients. PATIENT SUMMARY: Brief cold stimuli applied to the skin can evoke a sudden desire to urinate, which can be highly bothersome in patients with overactive bladder. We developed an animal model to study this phenomenon, and found that it depends on a specific molecular cold sensor, transient receptor potential M8 (TRPM8). Pharmacological inhibition of TRPM8 may alleviate acute cold-induced urinary urgency in humans.

Crucial role of TRPC1 and TRPC4 in cystitis-induced neuronal sprouting and bladder overactivity.

PURPOSE: During cystitis, increased innervation of the bladder by sensory nerves may contribute to bladder overactivity and pain. The mechanisms whereby cystitis leads to hyperinnervation of the bladder are, however, poorly understood. Since TRP channels have been implicated in the guidance of growth cones and survival of neurons, we investigated their involvement in the increases in bladder innervation and bladder activity in rodent models of cystitis. MATERIALS AND METHODS: To induce bladder hyperactivity, we chronically injected cyclophosphamide in rats and mice. All experiments were performed a week later. We used quantitative transcriptional analysis and immunohistochemistry to determine TRP channel expression on retrolabelled bladder sensory neurons. To assess bladder function and referred hyperalgesia, urodynamic analysis, detrusor strip contractility and Von Frey filament experiments were done in wild type and knock-out mice. RESULTS: Repeated cyclophosphamide injections induce a specific increase in the expression of TRPC1 and TRPC4 in bladder-innervating sensory neurons and the sprouting of sensory fibers in the bladder mucosa. Interestingly, cyclophosphamide-treated Trpc1/c4(-/-) mice no longer exhibited increased bladder innervations, and, concomitantly, the development of bladder overactivity was diminished in these mice. We did not observe a difference neither in bladder contraction features of double knock-out animals nor in cyclophosphamide-induced referred pain behavior. CONCLUSIONS: Collectively, our data suggest that TRPC1 and TRPC4 are involved in the sprouting of sensory neurons following bladder cystitis, which leads to overactive bladder disease.

Chronic administration of anticholinergics in rats induces a shift from muscarinic to purinergic transmission in the bladder wall.

BACKGROUND: First-line pharmacotherapy for overactive bladder consists of anticholinergics. However, patient compliance is exceptionally low, which may be due to progressive loss of effectiveness. OBJECTIVE: To decipher the involved molecular mechanisms and to evaluate the effects of chronic systemic administration of anticholinergics on bladder function and on muscarinic and purinergic receptors expression in rats. DESIGN, SETTING, AND PARTICIPANTS: Female Wistar rats were implanted with an osmotic pump that chronically administered vehicle (Vehc), 0.36 mg/kg per day oxybutynin (Oxyc), or 0.19 mg/kg per day fesoterodine (Fesoc) for 28 d. INTERVENTIONS: For cystometry experiments, a small catheter was implanted in the bladder. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Urologic phenotype was evaluated by the analysis of the micturition pattern and urodynamics. Expression of muscarinic and purinergic receptors was assessed by Western blot analysis of detrusor membrane protein. Functional responses to carbachol and adenosine triphosphate (ATP) were evaluated using muscle-strip contractility experiments. RESULTS AND LIMITATIONS: The number of voided spots was transiently decreased in Oxyc rats. In Oxyc rats, the effect of an acute high dose of oxybutynin (1mg/kg intraperitoneally [IP]) on the intermicturition interval was abolished. Expression experiments revealed a decrease of muscarinic acetylcholine receptors M2 (mAChR2) and M3 (mAChR3), whereas the purinergic receptor P2X, ligand-gated ion channel, 1 (P2X1) was enhanced in Oxyc and Fesoc rats compared to Vehc rats. In concordance with the modification of the expression pattern in Oxyc rats, the force generated by carbachol and ATP in muscle-strip contractility experiments was, respectively, lower and higher. Urodynamics revealed that the effects of systemic administration of the purinergic blocker pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (50mg/kg IP) were enhanced in Oxyc rats. As rat bladder physiology is different from that of humans, it is difficult to directly extrapolate our findings to human patients. CONCLUSIONS: Chronic administration of anticholinergics in rats induces receptor loss of efficiency and a shift from muscarinic to purinergic transmission.