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Objectives: To test the hypothesis that an implantable sensing system containing accelerometers can detect small-scale autonomous movements, also termed micromotions, which might be relevant to bladder physiology., Methods: We developed a 6-mm submucosal implant containing a pressure sensor (MS5637) and a triaxial accelerometer (BMA280). Sensor prototypes were tested by implantation in the bladders of Gottingen minipigs. Repeated awake voiding cystometry was carried out with air-charged catheters in a standard urodynamic set-up as comparators. We identified four phases of voiding similar to cystometry in other animal models based on submucosal pressure. Acceleration signals were separated by frequency characteristics to isolate linear acceleration from the baseline acceleration. The total linear acceleration was calculated by the root mean square of the three measurement axes. Acceleration activity during voiding was investigated to adjacent 1-s windows and was compared with the registered pressure., Results: We observed a total of 19 consecutive voids in five measurement sessions. A good correlation (r > 0.75) was observed between submucosal and catheter pressure in 14 of 19 premicturition traces. The peak-to-peak interval between maximum total linear acceleration was correlated with the interval between submucosal voiding pressure peaks (r = 0.760, P < 0.001). The total linear acceleration was higher during voiding compared with pre- and postmicturition periods (start of voiding/phase 1)., Conclusions: To the best of our knowledge, this is the first report of bladder wall acceleration, a novel metric that reflects bladder wall movement. Submucosal sensors containing accelerometers can measure bladder pressure and acceleration., (© 2020 The Japanese Urological Association.)

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 Ca 2+ 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., (Copyright © 2020 Alpizar, Uvin, Naert, Franken, Pinto, Sanchez, Gevaert, Everaerts, Voets, De Ridder and Talavera.)

Traditional urodynamics have poor correlation with urological symptoms. Ambulatory urodynamics may improve this correlation but the need for a transurethral catheter and the time-consuming nature of this examination limits its use. Therefore, the objective of this study was to develop a wireless real-time bladder pressure measurement device for repeated and prolonged-term measurement of bladder behavior in awake pigs. The Bladder Pill is an intravesical device with a pressure microsensor and a 3-dimensional inductive coupling coil for energy supply. A corresponding external coil provides wireless power transmission and real-time communication of bladder pressure data. To test the correlation between the pressure data measured by the device and by standard methods, we compared static water column pressures with this device and water-filled urodynamic catheter systems. In vivo assessment of awake voiding by the pill was done by introducing the bladder pill into the bladder of Göttingen minipigs. An air-charged urodynamic catheter was introduced transurethrally as control for pressure measurements. The optimal physical configuration of the pill was investigated to maximize the containment in the bladder. We used two versions of external signal receivers (one waistband and one rectangular frame) to test the optimal external signal capture. Next to that, we performed short-term and medium-term comparative pressure studies. The in vitro static pressure measurement demonstrated a mean difference of less than 1 cm H2O between the methods. The optimal design of the pill for maximal retainment in the bladder proved to be a pigtail configuration. The bending of the device during bladder contractions caused offset of 2.7 +/- 1.4 cm H2O (mean +/- SD) on the pressure measurements. The rectangular frame performed signal capture during 5 consecutive voids with a good correlation of the pressure measurements. The device can be inserted through the urethra and is retrieved using string or endoscopic extraction. In conclusion, wireless long-term measurement of bladder pressure is demonstrated and yields comparable results to current available catheter methods of measurement in a pig model., Competing Interests: The authors have declared that no competing interests exist.

Background: Improvement of bladder emptying by modulating afferent nerve activity is an attractive therapeutic strategy for detrusor underactivity. Transient receptor potential vanilloid 4 (TRPV4) is a sensory ion channel in urothelial cells that contribute to the detection of bladder filling., Objective: To investigate the potential benefit of intravesical TRPV4 agonists in a pelvic nerve injury rat model for detrusor underactivity., Design, Setting, and Participants: Female wild-type and Trpv4 knockout rats underwent sham surgery or bilateral pelvic nerve injury (bPNI). Four weeks later, rats underwent cystometry with infusion of the TRPV4 agonist GSK1016790A. Bladders were harvested for in vitro pharmacological studies, quantitative reverse polymerase chain reaction and immunohistochemistry., Outcome Measurements and Statistical Analysis: Data are expressed as median ± interquartile range. Statistical comparisons were made using the Mann-Witney U test and Wilcoxon signed rank test as appropriate., Results and Limitations: Rats with bPNI showed a phenotype characteristic of detrusor underactivity with lower-amplitude voiding contractions, decreased voiding frequency, and increased postvoid residual. Intravesical application of GSK1016790A increased voiding frequency and reduced postvoid residual in wild-type, but not Trpv4 -/- , rats. In isolated bladder strips, GSK1016790A did not induce relevant contractions, indicating that the observed improvements in bladder function are the result of increased afferent signalling through TRPV4 activation, rather than a local effect on the detrusor. The altered urinary phenotype of Trpv4 -/- mice was not apparent in the Trpv4 -/- rat model, suggesting species-related functional variations. Our results are limited to the preclinical setting in rodents., Conclusions: Intravesical activation of TRPV4 improves bladder dysfunction after bPNI by increasing afferent signalling., Patient Summary: We demonstrate that the sensory protein transient receptor potential vanilloid 4 (TRPV4) can be targeted to improve bladder function in animals that have iatrogenic injury to the nerves innervating the bladder. Further research is required to determine whether these results can be translated to patients with an underactive bladder., (Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: To create an animal model for neurogenic underactive bladder disease (UAB) and identify markers to describe secondary myogenic changes in the bladder wall., Materials and Methods: Male rats underwent either bilateral pelvic nerve injury or sham surgery. Four weeks after surgery functional evaluation was performed and tissue was harvested. Functional evaluation consisted of analysis of voiding pattern, 24-h urine collection in a metabolic cage, in vivo cystometry and in-vitro contractile function assessment. PCR and immunohistochemical localization of different smooth muscle cell and extracellular matrix markers was performed on bladder strips., Results: After pelvic nerve injury, dry bladder weight increased and voiding contractions were absent, resulting in overflow incontinence. In-vitro contractile response to carbachol was decreased. This was paired with an upregulation of synthetic smooth muscle cell (SMC) markers mRNA expression such as retinol binding protein 1 (RBP1), myosin 10 (MYH10) and osteopontin (OPN), and a downregulation of contractile SMC marker smoothelin (SMTL). The SMTL/OPN mRNA ratio was 50 times higher in sham bladders compared to PNI bladders., Conclusions: The loss of in-vivo and in-vitro contractile function following pelvic nerve transection is characterized by a switch from a contractile to synthetic SMC phenotype, which is best characterized by the ratio SMTL/OPN mRNA expression. Modulating this phenotypical switch is a potential target for the development of UAB therapy. We suggest for the first time a set of markers that may be useful to evaluate therapeutic strategies on improvements in bladder wall structure., (© 2018 Wiley Periodicals, Inc.)

Interstitial cells (ICs) are thought to play a functional role in urinary bladder. Animal models are commonly used to elucidate bladder physiology and pathophysiology. However, inter-species comparative studies on ICs are rare. We therefore analyzed ICs and their distribution in the upper lamina propria (ULP), the deeper lamina propria (DLP) and the detrusor muscular layer (DET) of human, guinea pig (GP) and pig. Paraffin slices were examined by immunohistochemistry and 3D confocal immunofluorescence of the mesenchymal intermediate filament vimentin (VIM), alpha-smooth muscle actin (αSMA), platelet-derived growth factor receptor alpha (PDGFRα) and transient receptor potential cation channel A1 (TRPA1). Image stacks were processed for analysis using Huygens software; quantitative analysis was performed with Fiji macros. ICs were identified by immunoreactivity for VIM (excluding blood vessels). In all species ≥ 75% of ULP ICs were VIM + /PDGFRα + and ≥ 90% were VIM + /TRPA1 + . In human and pig ≥ 74% of ULP ICs were VIM + /αSMA + , while in GP the percentage differed significantly with only 37% VIM + /αSMA + ICs. Additionally, over 90% of αSMA + ICs were also TRPA1 + and PDGFRα + in human, GP and pig. In all three species, TRPA1 + and PDGFRα + ICs point to an active role for these cells in bladder physiology, regarding afferent signaling processes and signal modification. We hypothesize that decline in αSMA-positivity in GP reflects adaptation of bladder histology to smaller bladder size. In our experiments, pig bladder proved to be highly comparable to human urinary bladder and seems to provide safer interpretation of experimental findings than GP.

With most research on interstitial cells (IC) in the bladder being conducted on animal models, it remains unclear whether all structural and functional data on IC from animal models can be translated to the human context. This prompted us to compare the structural and immunohistochemical properties of IC in bladders from mouse, rat and human. Tissue samples were obtained from the bladder dome and subsequently processed for immunohistochemistry and electron microscopy. The ultrastructural properties of IC were compared by means of electron microscopy and IC were additionally characterized with single/double immunohistochemistry/immunofluorescence. Our results reveal a similar organization of the IC network in the upper lamina propria (ULP), the deep lamina propria (DLP) and the detrusor muscle in human, rat and mouse bladders. Furthermore, despite several similarities in IC phenotypes, we also found several obvious inter-species differences in IC, especially in the ULP. Most remarkably in this respect, ULP IC in human bladder predominantly displayed a myoid phenotype with abundant presence of contractile micro-filaments, while those in rat and mouse bladders showed a fibroblast phenotype. In conclusion, the organization of ULP IC, DLP IC and detrusor IC is comparable in human, rat and mouse bladders, although several obvious inter-species differences in IC phenotypes were found. The present data show that translating research data on IC in laboratory animals to the human setting should be carried out with caution.

Context: The incidence and awareness of postprostatectomy incontinence (PPI) has increased during the past few years, probably because of an increase in prostate cancer surgery. Many theories have been postulated to explain the pathophysiology of PPI., Objective: The current review scrutinizes various pathophysiologic mechanisms underlying the occurrence of PPI., Evidence Acquisition: A search was conducted on PubMed and EMBASE for publications on PPI. The primary search returned 2518 publications. Animal and basic research studies, letters, publications on prostatectomy for benign reasons, pathology of prostatic carcinoma, radiotherapy and hormone therapy of prostatic carcinoma, and review articles were all used as criteria for exclusion from the study. A total of 128 publications were selected for final analysis., Evidence Synthesis: Neuromuscular anatomic elements and pelvic support are known to influence PPI as evidenced by multiple publications. A number of non-anatomic and surgical elements have been postulated as contributing factors to PPI. Biological factors and preoperative parameters include: functional bladder changes, age, body mass index (BMI), pre-existing lower urinary tract symptoms (LUTS), prostate size, and oncologic factors. Multiple studies reported the impact of specific anatomic/surgical factors, including fibrosis, shorter membranous urethral length (MUL), anastomotic stricture, damage to the neurovascular bundle, and extensive dissection, all of which have a negative impact on the continence status of patients following radical prostatectomy (RP). Investigation of the impact of techniques to spare the bladder neck and additional procedures to reconstruct the posterior or anterior support structures (eg, the Rocco stitch) on continence status is ongoing., Conclusions: Anatomic support and pelvic innervation appear to be important factors in the etiology of PPI. Biological/preoperative factors including greater age at time of surgery, pre-existing LUTS, high BMI, shorter MUL, and functional bladder changes have a negative impact on continence after RP. Extensive dissection during surgery, damage to the neurovascular bundle, and postoperative fibrosis also have a substantial negative impact on the continence status of men undergoing RP. Sparing of the bladder neck and anterior fixation of the bladder-urethra anastomosis are associated with better continence rates. There is still debate about whether posterior pelvic reconstruction leads to better postoperative continence rates., Patient Summary: Radical prostatectomy is an oncologic procedure and thus requires removal of the entire prostate gland and seminal vesicles, ideally with negative surgical margins. This sometimes results in urinary incontinence. The factors contributing to urinary incontinence are explained in this article., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The ability to store urine in the bladder and to void at an appropriate time depends on several complex mechanisms in the lower urinary tract (LUT) and its neural control. Normal LUT function requires coordination of the urinary bladder, urethra, pelvic floor, efferent and afferent neurons and specific spinal cord and brain areas. These structures can be visualised using different imaging modalities, such as ultrasound, X-ray and magnetic resonance imaging. The supraspinal neural control of the LUT can be studied using functional brain imaging. During the last two decades, the many technological improvements of these imaging techniques have increased our knowledge of voiding dysfunction. Here, we review the different imaging modalities of the LUT and its neural control and discuss their importance for diagnosing and understanding voiding dysfunction., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Steroid hormones such as progesterone are known to influence bladder function. Progesterone effects are mediated by the progesterone receptor (PR) but no detailed studies of PR in bladder exist. We have investigated the presence, topography and subtypes of PR in mouse, rat and human bladder. Fresh tissue samples were obtained from cystectomies in female humans, rats and mice (n = 7 per group). Tissue samples were processed for immunohistochemistry (IHC), immunofluorescence (IF) and western blot (WB) and, for each species, a panel of specific PR antibody clones was used. Interpretation of IHC/IF was carried out by light/fluorescent microscopy and of WB via standard WB software. IHC/IF in female human bladder showed PR on the interstitial cells in the lamina propria and between detrusor smooth muscle cells, whereas in female rat and mouse bladder, PR was only found on the urothelium. WB in human bladder showed a 78-kD and a 60-kDa band, respectively, corresponding to a modified PR isoform A and PR isoform C. WB in rat and mice bladder showed a 60 kDa band and a 37 kDa band, respectively corresponding with PR isoform C and an unknown isoform. This is the first detailed investigation of the precise location and presence of several isoforms of PR in bladder, together with a comparison of these data between human, rat and mouse. Our study has revealed complex PR families in bladders from the various species studied and demonstrates obvious inter-species differences in PR topography and isoforms.

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., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The upper (suburothelial) lamina propria (ULP) is a distinct region in the human bladder with dense populations of interstitial cells (IC), fine vascular networks and variable development of muscularis mucosae (MM). It is more and more obvious that the ULP plays an important role in bladder physiology and bladder disease, and in the present study we have quantified changes in the cellular key players of the ULP in bladders from patients with carcinoma in situ (CIS), multiple sclerosis (MS) and bladder pain syndrome (BPS). Tissue samples for the different patient groups were obtained from radical cystectomy-specimens. Standardized immunohistochemistry with a panel of specific cell markers was used to characterise the ULP cellular structures, followed by digitalised morphometry and quantitative staining analysis. Alterations in the ULP area were most pronounced in MS bladders, but also present in BPS and CIS bladders. We observed an increased thickness and increased variability in thickness of the ULP IC area in MS and BPS bladders; a significantly increased development of MM in MS bladders; a changed organization of vascular plexuses in the lamina propria in most pathologic bladders and a changed phenotype of ULP IC: a significantly decreased expression of progesterone receptor in MS bladders and a trend towards decreased expression of alpha-smooth muscle actin in BPS bladders. We show here for the first time the presence of disease-specific changes in organisation and/or phenotype of the different key players of the ULP area in human bladder. The present findings further support the hypothesis that the ULP area is involved and altered in different bladder diseases.

Aim: To report the effects of radical hysterectomy and nerve-sparing techniques on lower urinary tract function in women., Methods: A literature search was performed in Pubmed and Medline using the keywords bladder after radical hysterectomy, nerve sparing radical hysterectomy, and urinary dysfunction following radical hysterectomy. Significant results and citations were reviewed manually by the authors., Results: The sympathetic and parasympathetic systems innervating the lower urinary tract may be disrupted due to resection of uterosacral and rectovaginal ligaments, the dorsal and lateral paracervix, the caudal part of the vesico-uterine ligaments, and the vagina. This supports the neurogenic etiology of early and late bladder dysfunction after radical surgery. Bladder disorders are also related to the extent of radical surgery. The neuropathopysiology of lower urinary tract symptoms after radical hysterectomy is not fully understood. Recent data have highlighted the role of urethral sphincter pressure in the etiology of postoperative incontinence. Various surgical approaches have been developed to preserve autonomic pelvic innervation., Conclusions: Nerve-sparing techniques appear to improve bladder function without compromising overall survival. Studies comparing the effects of nerve-sparing radical hysterectomy with standard surgery yielded encouraging results in respect of postoperative lower urinary tract function. Clinical trials with a long period of follow-up are required for better comprehension of the complex pathophysiology of bladder dysfunction after radical hysterectomy., (© 2014 Wiley Periodicals, Inc.)

Purpose: There is increasing evidence for an important role of the lamina propria in bladder physiology and interstitial cells seem to have a key role in this area. Interstitial cells in the upper lamina propria have been studied most frequently. We characterized interstitial cells in the deeper lamina propria and hypothesized that the 2 interstitial cell populations have different phenotypes based on their ultrastructural and immunohistochemical properties., Materials and Methods: Tissue samples were obtained from macroscopically and microscopically normal areas of radical cystectomy specimens. A panel of immunohistochemical markers was used to characterize lamina propria interstitial cells. Single/double immunohistochemistry/immunofluorescence was performed. At a second phase electron microscopy was used to compare upper and deeper lamina propria interstitial cells., Results: Overall the phenotype of upper lamina propria interstitial cells was vimentin, α-smooth muscle actin, caveolin-1 and 2, PDGFRα, and nonphosphorylated and phosphorylated connexin 43 positive, and CD34 and c-kit negative. The overall phenotype of deeper lamina propria interstitial cells was vimentin, CD34 and nonphosphorylated connexin 43 positive, and α-smooth actin, caveolin-1 and 2, PDGFRα, phosphorylated connexin 43 and c-kit negative. Based on ultrastructural findings upper lamina propria interstitial cells were fibroblasts with myoid features and sparse myofibroblasts while deeper lamina propria interstitial cells were interstitial cell of Cajal-like cells., Conclusions: To our knowledge this is the first study of 2 main interstitial cell populations in the upper and deeper lamina propria of the human bladder with distinct ultrastructural and immunohistochemical phenotypes. Future research is needed to elucidate whether these morphological findings reflect different roles for upper and deeper lamina propria interstitial cells in bladder physiology., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To report our long-term experience of sacral neuromodulation (SNM) for various lower urinary tract dysfunctions but with a focus on efficacy, safety, re-interventions and degree of success., Patients and Methods: This is a single tertiary referral centre study that included 217 patients (86% female) who received an implantable pulse generator (IPG) (Interstim™, Medtronic, Minneapolis, USA) between 1996 and 2010. Success was considered if the initial ≥50% improvement in any of primary voiding diary variables persisted compared with baseline, but was further stratified., Results: The mean duration of follow-up was 46.88 months. Success and cure rates were ≈70% and 20% for urgency incontinence, 68% and 33% for urgency frequency syndrome and 73% and 58% for idiopathic retention. In those patients with an unsuccessful therapy outcome, the mean time to failure was 24.6 months after implantation. There were 88 (41%) patients who had at least one device or treatment related surgical re-intervention. The re-intervention rate was 1.7 per patient with most of them (47%) occurring ≤2 years of follow-up., Conclusions: SNM appears effective in the long-term with a success rate after definitive IPG implant of ≈70% and complete cure rates ranging between 20% and 58% depending on indication. Patients with idiopathic retention appear to do best. The re-intervention rate is high with most occurring ≤2 years of implantation. It is likely that with the newer techniques used, efficacy and re-intervention rates will improve., (© 2013 The Authors. BJU International © 2013 BJU International.)

Objective: To validate the Bladder Control Self-Assessment Questionnaire (B-SAQ), a short screener to assess lower urinary tract symptoms (LUTS) and overactive bladder (OAB) in men., Patients and Methods: This was a prospective, single-centre study including 211 patients in a urology outpatient setting. All patients completed the B-SAQ and Kings Health Questionnaire (KHQ) before consultation, and the consulting urologist made an independent assessment of LUTS and the need for treatment. The psychometric properties of the B-SAQ were analysed., Results: A total of 98% of respondents completed all items correctly in <5 min. The mean B-SAQ scores were 12 and 3.3, respectively for cases (n = 101) and controls (n = 108) (P < 0.001). Good correlation was evident between the B-SAQ and the KHQ. The agreement percentages between the individual B-SAQ items and the KHQ symptom severity scale were 86, 85, 84 and 79% for frequency, urgency, nocturia and urinary incontinence, respectively. Using a B-SAQ symptom score threshold of ≥4 alone had sensitivity, specificity and positive predictive values for detecting LUTS of 75, 86 and 84%, respectively, with an area under the curve of 0.88; however, in combination with a bother score threshold of ≥1 these values changed to 92, 46 and 86%, respectively., Conclusions: The B-SAQ is an easy and quick valid case-finding tool for LUTS/OAB in men, but appears to be less specific in men than in women. The B-SAQ has the potential to raise awareness of LUTS. Further validation in a community setting is required., (© 2013 The Authors. BJU International © 2013 BJU International.)

Aims: The KIT receptor is considered as a reliable marker for a subpopulation of interstitial cells (IC), and by persistent neonatal inhibition of KIT we have investigated the role of this receptor in the development of IC-networks in bladder and we have observed the functional consequences of this inhibition., Methods: Newborn rat pups were treated daily with the KIT inhibitor imatinib mesylate (IM). After 7 days animals were sacrificed and bladder samples were dissected for morphological and functional studies. Morphological research consisted of immunohistochemistry with IC specific antigens (KIT and vimentin) and electron microscopy. The functional studies were based on isolated bladder strips in organ baths, in which spontaneous bladder contractility and the response to a non-subtype selective muscarinic agonist was evaluated., Results: Suburothelial and intramuscular IC were found and characterized in neonatal rat bladder. IM-treatment induced a significant decrease in numbers of IC based on specific immunohistochemical markers, and electron microscopy revealed evidence of IC cell injury. These morphological alterations were observed on intramuscular IC only and not on IC in the suburothelium. Isolated muscle strips from IM-treated animals had a lower contractile frequency and an altered response to muscarinic agonists., Conclusions: The present study shows the presence of regional subpopulations of IC in neonatal rat bladder, provides evidence for a dependence on KIT of the development of intramuscular IC and supports the hypothesis that a poor development of networks of intramuscular IC might have repercussions on spontaneous and muscarinic-induced bladder contractility., (© 2013 Wiley Periodicals, Inc.)

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., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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.

The lower urinary tract (LUT) functions as a dynamic reservoir that is able to store urine and to efficiently expel it at a convenient time. While storing urine, however, the bladder is exposed for prolonged periods to waste products. By acting as a tight barrier, the epithelial lining of the LUT, the urothelium, avoids re-absorption of harmful substances. Moreover, noxious chemicals stimulate the bladder's nociceptive innervation and initiate voiding contractions that expel the bladder's contents. Interestingly, the bladder's sensitivity to noxious chemicals has been used successfully in clinical practice, by intravesically infusing the TRPV1 agonist capsaicin to treat neurogenic bladder overactivity. This underscores the advantage of viewing the bladder as a chemosensory organ and prompts for further clinical research. However, ethical issues severely limit the possibilities to perform, in human subjects, the invasive measurements that are necessary to unravel the molecular bases of LUT clinical pharmacology. A way to overcome this limitation is the use of several animal models. Here we describe the implementation of cystometry in mice and rats, a technique that allows measuring the intravesical pressure in conditions of controlled bladder perfusion. After laparotomy, a catheter is implanted in the bladder dome and tunneled subcutaneously to the interscapular region. Then the bladder can be filled at a controlled rate, while the urethra is left free for micturition. During the repetitive cycles of filling and voiding, intravesical pressure can be measured via the implanted catheter. As such, the pressure changes can be quantified and analyzed. Moreover, simultaneous measurement of the voided volume allows distinguishing voiding contractions from non-voiding contractions. Importantly, due to the differences in micturition control between rodents and humans, cystometric measurements in these animals have only limited translational value. Nevertheless, they are quite instrumental in the study of bladder pathophysiology and pharmacology in experimental pre-clinical settings. Recent research using this technique has revealed the key role of novel molecular players in the mechano- and chemo-sensory properties of the bladder.

The upper lamina propria (ULP) area of interstitial cells (IC) in bladder has been studied for more than a decade in several species including human beings. Nevertheless there is still lack of uniformity in terminology of this cell layer. The aim of the present study was to add new data to the morphological and immunohistochemical phenotype of these cells and to find out whether this phenotype is changed in bladders from patients with neurogenic detrusor overactivity (NDO) and bladder pain syndrome (BPS). Bladder tissue was obtained from a control group and from patients with NDO and BPS. Samples were processed for morphology, electron microscopy and immunohistochemistry. A morphological and immunohistochemical phenotype for the ULP IC was assessed and changes in this phenotype were looked for in samples from patients with NDO and BPS. The ULP IC were characterized ultrastructurally by the presence of actin filaments with densifications, many caveolae and abundant rough endoplasmic reticulum (RER); on immunohistochemistry ULP IC were immunoreactive for α-sma, vimentin, CD10 and podoplanin and categorized as interstitial Cajal-like cells (ICLC). In NDO and BPS bladders we found a phenotypical shift towards a fibroblastic phenotype which was even more pronounced in the NDO group. In both groups there was also an increased presence in ULP lymphocytes. The ULP area in the human bladder contains a population of ICLC with distinct ultrastructural morphology and immunohistochemical phenotype. Their unique α-sma(+) /desmin(-) /CD34(-) phenotype allows studying this population in various bladder disorders. In bladders form patients with BPS and NDO, we observed these ULP ICLC to shift towards a fibroblast phenotype., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

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., (Copyright © 2011 Wiley Periodicals, Inc.)

Reduced functional bladder capacity and concomitant increased micturition frequency (pollakisuria) are common lower urinary tract symptoms associated with conditions such as cystitis, prostatic hyperplasia, neurological disease, and overactive bladder syndrome. These symptoms can profoundly affect the quality of life of afflicted individuals, but available pharmacological treatments are often unsatisfactory. Recent work has demonstrated that the cation channel TRPV4 is highly expressed in urothelial cells and plays a role in sensing the normal filling state of the bladder. In this article, we show that the development of cystitis-induced bladder dysfunction is strongly impaired in Trpv4(-/-) mice. Moreover, we describe HC-067047, a previously uncharacterized, potent, and selective TRPV4 antagonist that increases functional bladder capacity and reduces micturition frequency in WT mice and rats with cystitis. HC-067047 did not affect bladder function in Trpv4(-/-) mice, demonstrating that its in vivo effects are on target. These results indicate that TRPV4 antagonists may provide a promising means of treating bladder dysfunction.

It is becoming increasingly clear that a variety of metabolic, cardiovascular, and endocrine factors contribute to male pelvic health. In particular, a growing body of evidence suggests a relationship between lower urinary tract symptoms, benign prostatic hyperplasia, overactive bladder, erectile dysfunction, and the metabolic syndrome. This article explores these relationships, focusing on the role of the autonomic nervous system and hyperinsulinemia, together with their implications for urological practice., (© 2010 Wiley-Liss, Inc.)

Aim: Besides the establishment of neural reflex pathways, developmental changes in local bladder properties probably also contribute to the onset of mature voiding reflexes. Here we explored the behavior of stretch-induced contractile activity (SIC) and its muscarinic regulation in neonatal and adult rat bladders., Methods: SIC was studied in bladder strips from D0, D7, D28 rat pups and adult rats (15 weeks). The responses to a non-selective [Carbachol (CA), 10(-8.5)-10(-6) M] and an M(2)-selective muscarinic agonist [arecaidine but-2-ynyl ester tosylate (ABET), 10(-9.5)-10(-7) M] were studied. The expression of M(2) and M(3) mRNA was investigated using quantitative PCR in whole bladders. The response of SIC to KCl (50 mM) and to the non-adrenergic non-cholinergic (NANC) drugs Substance P (1 microM) and alpha,beta-Methyleneadenosine 5'-triphosphate lithium salt (MATP) (1 microM) were also studied., Results: We found evidence for an enhanced response to the muscarinic agonists CA and ABET in neonatal bladders. This might be due to the onset of a direct contractile role for M(2), given the moderate M(2)-properties of ABET and the absence of ABET-effects on adult bladder strips. Further data showed an increased expression of both M(2) and M(3) at the mRNA level and a changed response of SIC to NANC drugs in neonatal bladder., Conclusions: This study reveals a changed response of SIC to muscarinic and NANC drugs in neonatal rat bladder together with changes at the muscarinic mRNA level, which might all contribute to a better insight in the role of SIC in the onset of mature voiding., ((c) 2010 Wiley-Liss, Inc.)

The bladder urothelium is currently believed to be a sensory structure, contributing to mechano- and chemosensation in the bladder. Transient receptor potential (TRP) cation channels act as polymodal sensors and may underlie some of the receptive properties of urothelial cells. However, the exact TRP channel expression profile of urothelial cells is unclear. In this study, we have performed a systematic analysis of the molecular and functional expression of various TRP channels in mouse urothelium. Urothelial cells from control and trpv4-/- mice were isolated, cultured (12-48 h), and used for quantitative real-time PCR, immunocytochemistry, calcium imaging, and whole cell patch-clamp experiments. At the mRNA level, TRPV4, TRPV2, and TRPM7 were the most abundantly expressed TRP genes. Immunohistochemistry showed a clear expression of TRPV4 in the plasma membrane, whereas TRPV2 was more prominent in the cytoplasm. TRPM7 was detected in the plasma membrane as well as cytoplasmic vesicles. Calcium imaging and patch-clamp experiments using TRP channel agonists and antagonists provided evidence for the functional expression of TRPV4, TRPV2, and TRPM7 but not of TRPA1, TRPV1, and TRPM8. In conclusion, we have demonstrated functional expression of TRPV4, TRPV2, and TRPM7 in mouse urothelial cells. These channels may contribute to the (mechano)sensory function of the urothelial layer and represent potential targets for the treatment of bladder dysfunction.

Transient receptor potential channel-vanilloid subfamily member 1 (TRPV1) is an important target in the treatment of bladder overactivity. This receptor is suggested to function as a mechanosensor in the normal bladder and to mediate the development of bladder overactivity during cystitis. Our aim was to determine the cellular distribution of TRPV1 in mouse and rat bladder tissue. We used three different commercial TRPV1 antibodies to perform immunohistochemistry on bladder tissue from rats and wild-type and TRPV1(-/-) mice, using trigeminal ganglia as a control tissue for TRPV1 expression. Although two of the antibodies seemed to react specifically in trigeminal ganglion tissue, all the antibodies produced a similar staining pattern in the urothelium of wild-type and TRPV1(-/-) mice. These data show that TRPV1 antibodies can cause an aspecific immunostaining in bladder tissue, urging for additional research to confirm the exact distribution of TRPV1 in bladder. In conclusion, we think that the use of negative controls on knockout mice, whenever available, is mandatory when conducting immunohistochemical localization studies.

Aims: To evaluate the long term outcome, to review the complication ratio and to analyze predicting factors of catheterizable continent vesicostomy in an adult population. To deduct a proper patient counseling policy., Methods: We identified all patients that underwent a continent vesicostomy between 1998 and 2008. We did not consider patients that underwent orthotopic bladder reconstruction. Patient satisfaction, urinary leakage, catheterization problems were assessed by chart review or interview. Type of primary surgery, revisions (number and type), renal function and complications were assessed by chart review., Results: Thirty-four patients underwent continent vesicostomy using an ileal segment (Monti or Spiral-Monti/Casale technique) or the appendix (Mitrofanoff). One patient underwent a detrusor wall flap. Twenty-one out of 35 patients underwent concomitant bladder augmentation and 2/35 patients bladder neck closure. Mean age at the time of the procedure was 44 years (range 21-80 years). Mean follow up is 60 months (range 6-117 months). Six out of 35 patients undergo surgical excision of the conduit because of untreatable problems. One patient has a permanent indwelling catheter. Two patients voided normal after sacral nerve stimulation. Ten out of 35 patients undergo stoma related revisions. Sixteen out of 35 patients undergo no stoma related revisions. Finally 26/35 patients were continent and had an easy catheterizable stoma., Conclusions: Continent urinary diversion in an adult population is associated with a high complication and revision rate. Although conversion rate to an ileal conduit is appreciable, the majority of patients (26/35) finally achieve full continence and unobstructed access to the bladder., ((c) 2009 Wiley-Liss, Inc.)

The mammalian TRP family consists of 28 channels that can be subdivided into 6 different classes: TRPV (vanilloid), TRPC (canonical), TRPM (Melastatin), TRPP (Polycystin), TRPML (Mucolipin), and TRPA (Ankyrin). TRP channels are activated by a diversity of physical (voltage, heat, cold, mechanical stress) or chemical (pH, osmolality) stimuli and by binding of specific ligands, enabling them to act as multifunctional sensors at the cellular level. Currently, a lot of scientific research is devoted to these channels and their role in sensing mechanisms throughout the body. In urology, there's a growing conviction that disturbances in afferent (sensory) mechanisms are highly important in the pathogenesis of functional problems. Therefore, the TRP family forms an interesting new target to focus on. In this review we attempt to summarize the existing knowledge about TRP channels in the urogenital tract. So far, TRPV1, TRPV2, TRPV4, TRPM8, and TRPA1 have been described in different parts of the urogenital tract. Although only TRPV1 (the vanilloid receptor) has been extensively studied so far, more evidence is slowly accumulating about the role of other TRP channels in the (patho)physiology of the urogenital tract., ((c) 2007 Wiley-Liss, Inc)

Here we provide evidence for a critical role of the transient receptor potential cation channel, subfamily V, member 4 (TRPV4) in normal bladder function. Immunofluorescence demonstrated TRPV4 expression in mouse and rat urothelium and vascular endothelium, but not in other cell types of the bladder. Intracellular Ca2+ measurements on urothelial cells isolated from mice revealed a TRPV4-dependent response to the selective TRPV4 agonist 4alpha-phorbol 12,13-didecanoate and to hypotonic cell swelling. Behavioral studies demonstrated that TRPV4-/- mice manifest an incontinent phenotype but show normal exploratory activity and anxiety-related behavior. Cystometric experiments revealed that TRPV4-/- mice exhibit a lower frequency of voiding contractions as well as a higher frequency of nonvoiding contractions. Additionally, the amplitude of the spontaneous contractions in explanted bladder strips from TRPV4-/- mice was significantly reduced. Finally, a decreased intravesical stretch-evoked ATP release was found in isolated whole bladders from TRPV4-/- mice. These data demonstrate a previously unrecognized role for TRPV4 in voiding behavior, raising the possibility that TRPV4 plays a critical role in urothelium-mediated transduction of intravesical mechanical pressure.

Aim: Vanilloids like capsaicin and resiniferatoxin (RTX) have been used for more than a decade in the treatment of neurogenic detrusor overactivity. Recently, the vanilloid molecule piperine (PIP) has been shown to have similar pharmacological properties as these drugs. In this study, we looked at PIP-effects on autonomous bladder contractile activity, with particular interest for its selectivity for the transient receptor potential channel 1 (TRPV1) receptor. Additionally, we studied the role of TRPV1 in volume-induced contractile changes using selective and non-selective TRPV1 antagonists., Methods: The acute and prolonged effects of PIP were studied on rat bladders. Each bladder was excised and placed in a heated organ bath, where intravesical pressures were measured. In acute experiments, PIP was added directly to the bathing solution. For prolonged effects, animals were pre-treated intravesically with vehicle (ethanol 5%) or PIP (10(-4) M) and sacrificed 72 hr later. The effects of selective (capsazepine (CZP)) and non-selective (ruthenium red (RR)) TRPV1 antagonists on volume-evoked contractile parameters were also studied., Results: Acute administration of PIP 10(-4) M significantly increased amplitude of bladder contractions (P < 0.05). These effects were significantly antagonized (P < 0.05) by the TRPV1-selective antagonist CZP (10(-5) M) and the non-selective TRP-antagonist RR (10(-5) M). Intravesical pre-treatment with PIP induced shorter contractions with more periods of non-activity (P < 0.05) compared to controls. Inhibition of TRPV1 with CZP and RR significantly reduced the volume-evoked rise in contractile amplitude in isolated bladders (P < 0.05)., Conclusion: We found evidence for acute and prolonged effects of PIP on bladder contractility, which seem to be mediated through TRPV1. Furthermore, we found evidence for involvement of TRPV1 in afferent signaling of mechanical stimuli.

Aims: Resiniferatoxin (RTX), a vanilloid compound and agonist of the transient receptor potential channel 1 (TRPV1), is known for its beneficial effects on neurogenic detrusor overactivity. The mainstream rationale for its use is the desensitization of TRPV1 on sensory bladder afferents. However, recent findings showed that TRPV1 is present in other cell types in the bladder. To eliminate the effects of RTX on spinal and central neural circuits, we investigated autonomous contractility in normal and neurogenic rat bladders after treatment with RTX., Methods: Female Wistar rats were made paraplegic at vertebral level T8-T9. Animals were intravesically pre-treated with vehicle (ethanol 5%) or RTX (100 nM) and sacrificed after 72 hr. Each bladder was excised and placed in a heated organ bath, where intravesical pressures were measured. Effects on contractile parameters of intravesical volume load, the non-selective muscarinic receptor agonist carbachol (CA) and electrical stimulation (ES) of nerves were studied in both groups., Results: In RTX-treated normal bladders we found shorter contractions with higher amplitude than in control bladders (P < 0.05). In RTX-treated neurogenic bladders the amplitude and duration of autonomous contractions were increased compared with controls (P < 0.05). Furthermore RTX induced an increased response to CA and to ES (P < 0.05)., Conclusions: RTX significantly affected the properties of autonomous bladder contractile activity. This provides evidence for local effects of RTX on bladder contractile activity, which are not mediated by afferent neural pathways and which may contribute to the beneficial effects on detrusor overactivity. TRPV1 and TRPV1(+) cells seem to play an important role in (autonomous) bladder contractility.

Aim: To identify differences in the pattern of pressure generated by isolated bladders from normal and paraplegic rats., Materials and Methods: Nine female Wister rats were made paraplegic by spinal cord transsection at the vertebral level T8-T9 and sacrificed between D21 and D28. A further group (n = 9) was used as a control group. Each bladder was excised and placed in an organ bath where intravesical pressures were measured. Pressure changes were divided in two well-defined groups: macro-transients and spikes. The effects of intravesical volume load and muscarinic (M) agonists were studied., Results: We demonstrated a higher frequency, a longer duration, and a higher variance of duration in macro-transients in the neurogenic group. Intravesical volume load influenced the amplitude and frequency of macro-transients in both groups similarly. The effects of the muscarinic (M(2))-selective agonist arecaïdine were different in neurogenic bladder; the effects of the non-selective muscarinic (M)-agonist carbachol were similar in both groups., Conclusion: We showed that the pattern of autonomous activity was significantly different between normal and neurogenic rat bladders. We also found evidence for alterations in the muscarinic response of isolated neurogenic rat bladders. This model offers an exciting new research tool to evaluate the detrusor activity in neurogenic and normal conditions.

Purpose: We determined the presence and distribution of vanilloid receptor-1 in the human bladder and confirmed or rejected previous findings of other groups that used indirect methods or vanilloid receptor-1 antibodies made by immunizing experimental animals. Also, we tested the reproducibility of results using commercially available antibodies against the N-terminus and C-terminus of the vanilloid receptor., Materials and Methods: A total of 11 normal bladder tissue samples were obtained from cystectomy specimens and fresh frozen processed. Specimens were studied by immunohistochemistry and confocal laser microscopy using 3 vanilloid receptor-1 antibodies. Immunohistochemical co-localization studies for neurofilament, neuronal nitric oxide synthase and nerve growth factor were performed., Results: Our results confirm the presence of vanilloid receptor-1 on nonmyelinated and myelinated nerve fibers. There was vanilloid receptor-1 immunoreactivity on smooth muscle cells but different sensitivities for the antibodies. There was immunoreactivity on interstitial cells located in the suburothelium and intermuscular septa of the muscularis. There was co-localization of neuronal nitric oxide synthase with interstitial cells but not with neurofilament. No co-localization was found for nerve growth factor and vanilloid receptor-1., Conclusions: Vanilloid receptor-1 is located on small unmyelinated and myelinated nerve fibers. In addition, vanilloid receptor-1 is also present on interstitial cells in the suburothelium. There is smooth muscle cell immunoreactivity but a difference in antibodies raised against the C-terminus and N-terminus. These data suggest that the current hypothesis about the mechanism of action of vanilloids is through blocking the afferent reflex arc must be revised and the function of interstitial cells deserves further attention.

Objective: To review current management of neurogenic lower urinary tract dysfunction (NLUTD) in MS patients and give recommendations on the joint role of the neurologist and urologist in NLUTD management. Methods: An algorithm for evaluation and referral of MS patients to urologists was created. It is an outcome of discussions about current knowledge, existing guidelines, and key issues during two Belgian consensus meetings attended by neurologists, urologists and other stakeholders involved in MS management. At these meetings, updated information on management of NLUTD in MS was exchanged and the neurologists' opinion on how to integrate this in the other aspects of care in MS patients was explored. Results: Short evaluation of NLUTD in MS patients by neurologists and appropriate referral to urologists could accelerate proper diagnosis and treatment. Neurologists can play a central role in the interdisciplinary communication on interactions between disease manifestations of MS and their treatments. Conclusion: The coordinating role of neurologists in NLUTD management may considerably improve QoL in MS patients. More research is needed to evaluate outcomes of urological assessments and treatment. [ABSTRACT FROM AUTHOR]

ABSTRACT 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. © 2013 Movement Disorder Society [ABSTRACT FROM AUTHOR]