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Purpose: The aim of this study was to evaluate the prevalence of bowel/bladder dysfunction in multiple sclerosis (MS) and its associations with cognitive impairment.Methods: We prospectively enrolled 150 MS patients. Patients were administered the Symbol Digit Modality Test (SDMT), the Neurogenic Bowel Dysfunction Score (NBDS), and the Actionable Bladder Symptom Screening Tool (ABSST). The associations between bowel/bladder dysfunction and cognitive function were assessed through hierarchical regression models using the SDMT and clinicodemographic features as independent variables and NBDS and ABSST scores as dependent variables.Results: The prevalence of bowel/bladder deficits was 44.7%, with 26 patients (17.3%) suffering from bowel deficits and 60 patients (40%) from bladder deficits. The total NBDS and ABSST scores were correlated with the SDMT (β=-0.10, P

AimsTo determine whether the amount of ATP, prostaglandin E2 (PGE2), and acetylcholine (ACh) in voided urine are influenced enough by that released within the lower urinary tract (LUT) for them to be useful biomarkers of bladder function.MethodsParticipants without LUT symptoms collected total urine voids at 15, 30, 60, and 120 min (20 males/23 females) and 240 min (18 males/26 females) following the previous void. Aliquots of urine were immediately frozen at −20°C and later used to measure ATP (luciferin‐luciferase), PGE2 (enzyme‐linked immunosorbent assay), ACh (mass spectrometry), creatinine (colorimetric), and lactose dehydrogenase (colorimetric).ResultsThe amount of ATP in voided urine correlated strongly with the rate of urine production, suggesting that the majority, if not all, the ATP in voided urine has an LUT, and likely bladder, origin. In contrast, there appeared to be no significant net LUTs release of creatinine or ACh into the urine. PGE2 was intermediate with an LUT component that increased with urine production rate and contributed about 25% of the total at 1 ml/min in women but a smaller fraction in men.ConclusionWhereas the majority of the ATP measured within the voided urine originates in the LUT, ACh reflects that extracted from the plasma in the kidneys and PGE2 is a mixture of both sources. ATP has the most potential as a biomarker of benign bladder disorders. Expressing urinary ATP concentration relative to creatinine concentration is questioned in light of these results.

Summary Congenital lower urinary tract disorders are a family of diseases affecting both urinary storage and voiding as well as upstream kidney function. Current treatments include surgical reconstruction but many children still fail to achieve urethral continence or progress to chronic kidney disease. New therapies can only be achieved through undertaking research studies to enhance our understanding of congenital lower urinary tract disorders. Animal models form a critical component of this research, a corner of the triangle composed of human in-vitro studies and clinical research. We describe the current animal models for two rare congenital bladder disorders, posterior urethral valves (PUV) and bladder exstrophy (BE). We highlight important areas for researchers to consider when deciding which animal model to use to address particular research questions and outline the strengths and weaknesses of current models available for PUV and BE. Finally, we present ideas for refining animal models for PUV and BE in the future to stimulate future researchers and help them formulate their thinking when working in this field.

Drug administration for treatment of bladder disorder has always been impeded by the urothelium integrity and short residence time of therapeutic forms. In this study, polysaccharides chitosan and carboxymethylcellulose are used to confer the mucoadhesive property to graphene oxide as a potential drug-delivery system for therapeutic drugs in the bladder. The synthesized chitosan-functionalized graphene oxide (CS-sGO) and carboxymethylcellulose-functionalized graphene oxide (CMC-sGO) had good dispersion stability at a wide range of pH values as well as physiological media, signifying the suitability for application in diverse constituents and pH conditions of diseased bladder. The nanoparticles exhibited good mucoadhesion to porcine bladder tissues, with prospective retention as high as 20 urine voiding. Ministry of Education (MOE) Nanyang Technological University The reported research work was completed with support from Interdisciplinary Graduate School, Nanyang Technological University (NTU), Singapore, under NTU Research Scholarship. The authors acknowledge the NTU-Northwestern Institute for Nanomedicine (NNIN) and MOE Tier 1 (RG 46/18) for the financial support.

The current trends in understanding the pathogenesis of infectious and inflammatory urogenital disorders are highlighted in the review. The etiological and pathogenetic significance of increased intestinal permeability for pathogens in the development of various diseases has been convincedly proved. There is no doubt about the pathogenetic role of increased permeability of the bladder mucosa, which can result in interstitial cystitis (IC). The association of intestinal diseases with IC has been established. In rats, the induction of intestinal inflammation may cause increased permeability of the bladder mucosa. In the postoperative period, bacteria are translocated from the gastrointestinal tract to the urinary tract, which is associated with stress. Particular attention is paid to the therapy based on new knowledge about the pathogenesis of infectious and inflammatory diseases of the urogenital tract. Possibilities of decreasing intestinal and bladder permeability using rebamipide are described. Various therapeutic mechanisms of action made it possible to use this drug in endoscopy, ophthalmology, chemotherapy and rheumatology. The antioxidant and anti-inflammatory properties of rebamipide has been shown in-vitro. Intravesical instillation of rebamipide accelerates the recovery of damaged urothelium and its barrier function, and also influences on bladder hyperactivity. Thus, the first results of using rebamipide in urology are encouraging; however, further researches are required.

Background One of the consequences of breast cancer treatments may be the onset of new, or aggravation of preexisting bladder and bowel disorders. However, the presence and impact of these disorders in women with breast cancer are poorly documented. The aim of this systematic review was to assess the prevalence, incidence and impact of bladder and bowel disorders in women undergoing breast cancer treatment. Methods A systematic search of six databases was conducted. Pooled prevalence rates and impact of bladder and bowel disorders were calculated using random-effects models. Results A total of 32 studies met the inclusion criteria, and 17 studies were included in the meta-analyses. The pooled estimate of women who experienced bladder disorders following sensitivity analysis, which removed one study reporting a result that deviated from the pooled estimate, was 38% (95% confidence interval [CI]: 32%-44%; I2 = 98%; n = 4584). The impact of bladder and bowel disorders on women's daily lives was relatively low (bladder [scale: 0-4]: mean: 0.8; 95% CI: 0.4-1.1; I2 = 99%; n = 4908; bowel [scale: 0-100]: mean 14.2; 95% CI: 9.4-19; I2 = 95%; n = 1024). Conclusion This is the first study to comprehensively document the magnitude of bladder and bowel disorders in the breast cancer population. This meta-analysis found that women with breast cancer had a higher prevalence of urinary incontinence (38%) compared to women without breast cancer (21%). Given the extent and impact of our findings, screening and management of bladder and bowel disorders may be indicated in women with breast cancer to improve their health-related quality of life.

AIMS: Neuromodulation (nerve stimulation) can produce analgesia. One form, bilateral pudendal nerve stimulation (bPNS), suppresses responses to urinary bladder distension (UBD) in hypersensitive rats. Drugs can modify this effect (e.g., benzodiazepines, but not opioids, suppress bPNS effects). Prior to a clinical trial of bPNS effects on bladder pain, we felt it was prudent to survey the effects of medications commonly used in patients with bladder disorders. METHODS: Bladder hypersensitivity was produced by neonatal bladder inflammation in rat pups coupled with a second inflammatory insult as an adult. Antimuscarinic (oxybutynin), β(3)-adrenoceptor agonist (mirabegron, CL316243), α(1)-adrenoceptor antagonist (tamsulosin), antidepressant (amitriptyline), muscle relaxing (baclofen), and sedative (propofol) agents were administered and effects of bPNS on responses to UBD assessed. bPNS consisted of bilateral biphasic electrical stimulation of the mixed motor/sensory component of the pudendal nerves. Visceromotor responses (VMRs; abdominal muscle contractile responses) were used as nociceptive endpoints. RESULTS: Many of these drugs directly inhibited the VMRs to UBD, but only mirabegron, at the doses employed, significantly reduced inhibitory effects of bPNS. In the presence of the other drugs, bPNS continued to produce statistically significant inhibition of VMRs to UBD. CONCLUSIONS: This study suggests that concurrent therapy with drugs used to treat bladder disorders could affect assessment of the effects of bPNS on bladder hypersensitivity. This study gives guidance to clinical trials using bPNS for the treatment of painful bladder syndromes and suggests potential clinical use of some of these medications in the treatment of these same disorders.

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

Objective: This multicenter study aimed to evaluate risk factors, prevalence and severity of pelvic floor disorders (PFDs) as well as their consequences on women's emotional well-being, using a questionnaire validated specifically for pregnancy and postpartum. Methods: Prospective study conducted in eight teaching hospitals in Italy and Italian-speaking Switzerland. Pregnant and postpartum women completed the Italian Pelvic Floor Questionnaire for Pregnancy and Postpartum anonymously. Prevalence of, severity of, and risk factors for PFDs were evaluated for all the four domains considered: bladder, bowel, prolapse, and sexual function. Results: A total of 2007 women were included: 983 of the patients were bothered by at least one kind of PFD: bladder, bowel, and sexual dysfunction were more frequently reported. There were no significant differences in PFD prevalence between pregnancy and postpartum, except for bladder disorders, which were more prevalent in pregnancy. Familiarity for PFDs, pelvic floor contraction inability, cigarette smoking, body mass index more than 25 (calculated as weight in kilograms divided by the square of height in meters), and age more than 35 years were confirmed risk factors for the development of PFDs during pregnancy and postpartum. Conclusion: Almost half of the women included in the study suffered from PFD-related symptoms with important consequences on quality of life. Validated questionnaires are fundamental in early diagnosis and treatment of PFDs.

ObjectiveMany women with overactive bladder (OAB) do not seek medical care despite urinary symptoms. As the diagnosis and treatment of OAB are often late, there is a need to identify undiagnosed OAB patients and start effective treatment. Furthermore, an objective and appropriate screening biomarker for OAB is needed. This study aimed to investigate the relationship between serum neutrophil-to-lymphocyte ratio (NLR) and OAB in South Korean women.DesignCross-sectional, retrospective study.SettingJeju National University Hospital.ParticipantsThis study included a total of 4394 women (mean age=48.6 years) who underwent self-referred health screenings.InterventionsBlood tests were conducted and the NLR was calculated by dividing the number of neutrophils by the number of lymphocytes.Outcome measuresThe severity of OAB was evaluated using the OAB Symptom Score (OABSS).ResultsApproximately 9.8% of participants (n=432) were diagnosed with OAB. The association pattern between the NLR and urinary tract symptoms was variable; however, NLR was associated with OAB, by the OABSS and OAB severity (pConclusionsElevated NLR is associated with OAB; hence, NLR may be a cost-effective and readily available biomarker of OAB in women.

IntroductionNon-muscle invasive bladder cancer (NMIBC) accounts for about 75% of newly diagnosed bladder cancers. The treatment for NMIBC involves surgical removal of the tumour followed by 6 weekly instillations of immunotherapy or chemotherapy directly into the bladder (ie, intravesical therapy). NMIBC has a high rate of recurrence (31%–78%) and progression (15%). Moreover, bladder cancer and its treatment may affect patient functioning and quality of life. Exercise is a safe and effective intervention for many patient with cancer groups, however, no studies have examined exercise during intravesical therapy for NMIBC. The primary objective of the Bladder cancer and exeRcise trAining during intraVesical thErapy (BRAVE) trial is to examine the safety and feasibility of an exercise intervention in patients with bladder cancer undergoing intravesical therapy. The secondary objectives are to investigate the preliminary efficacy of exercise on health-related fitness and patient-reported outcomes; examine the social cognitive predictors of exercise adherence; and explore the potential effects of exercise on tumour recurrence and progression.Methods and analysisBRAVE is a phase II randomised controlled trial that aims to include 66 patients with NMIBC scheduled to receive intravesical therapy. Participants will be randomly assigned to the exercise intervention or usual care. The intervention consists of three supervised, high-intensity interval training sessions per week for 12 weeks. Feasibility will be evaluated by eligibility, recruitment, adherence and attrition rates. Preliminary efficacy will focus on changes in cardiorespiratory fitness and patient-reported outcomes from baseline (prior to intravesical therapy) to pre-cystoscopy (3 months). Cancer outcomes will be tracked at 3 months, and 1-year follow-up by cystoscopy. Analysis of covariance will compare between-group differences at post-intervention (pre-cystoscopy) for all health-related fitness and patient-reported outcomes.Ethics and disseminationThe study was approved by the Health Research Ethics Board of Alberta-Cancer Committee (#20–0184). Dissemination will include publication and presentations at scientific conferences and public channels.Trial registration numberNCT04593862; Pre-results.

The urothelium displays mechano- and chemosensory functions via numerous receptors and channels. The calcium-sensing receptor (CaSR) detects extracellular calcium and modulates several physiological functions. Nonetheless, information about the expression and the role of CaSR in lower urinary tract has been absent. We aimed to determine the existence of urothelial CaSR in urinary bladder and its effect on micturition function. We utilized Western blot to confirm the expression of CaSR in bladder and used immunofluorescence to verify the location of the CaSR in the bladder urothelium via colocalization with uroplakin III A. The activation of urothelial CaSR via the CaSR agonist, AC-265347 (AC), decreased urinary bladder smooth muscle (detrusor) activity, whereas its inhibition via the CaSR antagonist, NPS-2143 hydrochloride (NPS), increased detrusor activity in in vitro myography experiments. Cystometry, bladder nerve activities recording, and bladder surface microcirculation detection were conducted to evaluate the effects of the urothelial CaSR via intravesical administrations. Intravesical AC inhibited micturition reflex, bladder afferent and efferent nerve activities, and reversed cystitis-induced bladder hyperactivity. The urothelial CaSR demonstrated a chemosensory function, and modulated micturition reflex via regulating detrusor activity. This study provided further evidence of how the urothelial CaSR mediated micturition and implicated the urothelial CaSR as a potential pharmacotherapeutic target in the intervention of bladder disorders.

ObjectivesTo compare the risk of bladder cancer and bladder cancer mortality among patients with chronic bladder catheterisation (indwelling or intermittent) to patients from the general population.DesignRetrospective cohort study.SettingPopulation-based study in Ontario, Canada between 2003 and 2018.ParticipantsAdult patients 18–90 years of age with chronic bladder catheterisation were hard matched to patients from the general population without a history of bladder catheterisation.InterventionsThe presence of a chronic catheter was defined as a minimum of two physician encounters for bladder catheterisation, suprapubic tube insertion or home care for catheter care separated by at least 28 days. Urinary tract infection (UTI) rates were collected.Main outcome measuresBladder cancer and bladder cancer-specific mortality after a 1-year lag period were compared between groups.ResultsWe identified 36 903 patients with chronic catheterisation matched to 110 709 patients without a history of catheterisation. Patients were followed for a median of 8.8 years (IQR: 5.2–11.9 years). The median age was 62 years (IQR: 50–71) and 52% were female. More patients in the catheter group developed bladder cancer (393 (1.1%) vs 304 (0.3%),pConclusionsThis is the first study to quantify the increase in bladder cancer incidence and mortality in a large, diverse cohort of patients with chronic indwelling or intermittent bladder catheterisation. The risk was highest among patients with a chronic catheter beyond 2.9 years.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a multifactorial, chronic bladder disorder with limited therapeutic options currently available. The present review provides an extensive overview of therapeutic approaches used in in vitro, ex vivo, and in vivo experimental models of IC/BPS. Publications were identified by electronic search of three online databases. Data were extracted for study design, type of treatment, main findings, and outcome, as well as for methodological quality and the reporting of measures to avoid bias. A total of 100 full-text articles were included. The majority of identified articles evaluated therapeutic agents currently recommended to treat IC/BPS by the American Urological Association guidelines (21%) and therapeutic agents currently approved to treat other diseases (11%). More recently published articles assessed therapeutic approaches using stem cells (11%) and plant-derived agents (10%), while novel potential drug targets identified were proteinase-activated (6%) and purinergic (4%) receptors, transient receptor potential channels (3%), microRNAs (2%), and activation of the cannabinoid system (7%). Our results show that the reported methodological quality of animal studies could be substantially improved, and measures to avoid bias should be more consistently reported in order to increase the value of preclinical research in IC/BPS for potential translation to a clinical setting.

Key points\ud \ud \ud Functional disorders (i.e., interstitial cystitis/painful bladder syndrome and irritable bowel syndrome) are associated with hyperexcitability of afferent nerves innervating the urinary tract and the bowel respectively.\ud Various non‐5‐HT3 receptor mRNA transcripts are expressed in mouse urothelium and exert functional responses to 5‐HT. \ud Whilst 5‐HT3 receptors were not detected in mouse urothelium, 5‐HT3 receptors expressed on bladder sensory neurons plays a role in bladder afferent excitability under both normal conditions and in a mouse model of chronic visceral hypersensitivity (CVH). \ud These data suggest that the role 5‐HT3 receptors play in bladder afferent signaling warrants further study as a potential therapeutic target for functional bladder disorders. \ud \ud \ud \ud Abstract\ud \ud Serotonin (5‐HT) is an excitatory mediator, which in the gastrointestinal (GI) tract, plays a physiological role in gut‐brain signaling and which is dysregulated in functional GI disorders such as irritable bowel syndrome (IBS). Patients suffering from IBS frequently suffer from urological symptoms characteristic of interstitial cystitis/painful bladder syndrome, which manifests due to cross‐sensitization of shared innervation pathways between the bladder and colon. However, a direct modulatory role of 5‐HT in bladder afferent signaling and its role in colon‐bladder neuronal crosstalk remain elusive. The aim of this study was to investigate the action of 5‐HT on bladder afferent signaling in normal mice and mice with chronic visceral hypersensitivity (CVH) following trinitrobenzenesulfonic acid (TNBS) induced colitis. Bladder afferent activity was recorded directly using ex vivo afferent nerve recordings. Expression of 14 5‐HT receptor subtypes, the serotonin transporter (SERT) and 5‐HT producing enzymes were determined in the urothelium using RT‐PCR. Retrograde labelling of bladder projecting dorsal root ganglion (DRG) neurons was used to investigate expression of 5‐HT3 receptors using single cell RT‐PCR, while sensory neuronal and urothelial responses to 5‐HT were determined by live cell calcium imaging. 5‐HT elicited bladder afferent firing predominantly via 5‐HT3 receptors expressed on afferent terminals. CVH animals showed a downregulation of SERT mRNA expression in urothelium, suggesting increased 5‐HT bioavailability. Granisetron, a 5‐HT3 antagonist, reversed bladder afferent hypersensitivity in CVH mice. These data suggest 5‐HT exerts a direct effect on bladder afferents to enhance signaling.5‐HT3 antagonists could therefore be a potential therapeutic target to treat functional bladder and bowel disorders.

CHRM3 codes for the M3 muscarinic acetylcholine receptor that is located on the surface of smooth muscle cells of the detrusor, the muscle that effects urinary voiding. Previously, we reported brothers in a family affected by a congenital prune belly‐like syndrome with mydriasis due to homozygous CHRM3 frameshift variants. In this study, we describe two sisters with bladders that failed to empty completely and pupils that failed to constrict fully in response to light, who are homozygous for the missense CHRM3 variant c.352G > A; p.(Gly118Arg). Samples were not available for genotyping from their brother, who had a history of multiple urinary tract infections and underwent surgical bladder draining in the first year of life. He died at the age of 6 years. This is the first independent report of biallelic variants in CHRM3 in a family with a rare serious bladder disorder associated with mydriasis and provides important evidence of this association.

Underactive bladder (UAB) is a common urological problem in elderly patients presenting with urinary retention and lower urinary tract symptoms. UAB causes chronic urinary retention or a large post-void residual urine which is usually difficult to manage. Treatment of UAB is a challenge to urologists. The underlying pathophysiology has not been completely elucidated. Molecular diagnosis for the clinical characteristics of UAB is important for us to understand the pathogenesis and develop new therapeutic modalities. The urodynamic finding of UAB might be detrusor acontractility of low contractility and is often termed detrusor underactivity. UAB is frequently encountered in elderly patients with chronic medical or neurological diseases. The pathophysiology of UAB may involve neurogenic, myogenic, and bladder outlet pathologies. Recent studies also reveal that increased suburothelial inflammation and altered sensory protein expressions in bladder mucosa were prominent in patients with UAB. Impaired urothelial signaling and sensory transduction pathways might be associated with impaired bladder sensation as well as impaired detrusor contractility. In addition, the bladder outlet obstruction, inflammation, or bladder ischemia-induced oxidative stress might also decrease the energy of the detrusor and result in UAB. Neurogenic inhibition, myogenic factor, and psychogenic inhibition might also be the causes for UAB. This article reviews recent researches on the pathophysiology and molecular characteristics of UAB. Neurogenic, myogenic, urotheliogenic, bladder outlet, and psychogenic factors might all contribute to UAB. Comprehensive clinical investigations and basic researches may provide a better understanding and effective treatment for this common but difficult bladder disorder.

Interstitial cystitis is a chronic bladder disorder causing pelvic pain and urinary frequency or urgency, with an estimated prevalence of 2.7%–6.5% among adult women.[1][1] Pentosan polysulfate may buffer the bladder epithelium against irritants and is the only oral medication approved by Health

Objective To investigate the relationship between the bladder microbiota and overactive bladder (OAB) symptom severity. Design Cross-sectional study of female OAB patients who contributed catheterised urine samples, completed validated symptom questionnaires, and provided demographic data. Setting Nanfang Hospital, Southern Medical University. Population Adult women with overactive bladder symptom. Methods 70 OAB patients were recruited, finished symptoms questionnaires, demographic data, and contributed catheterised urine samples that were analysed by 16S rRNA gene sequencing. Main outcome measures Associations between the total/sub scores of Overactive Bladder Symptom Score (OABSS) and bladder microbiota (diversity, overall community structure, and specific organisms). Results We found that bacterial diversity (Simpson index, P = 0.024) and richness (Chao1, P = 0.023) of mild patients (OABSS ≤5, N = 17) were lower than those of moderate/severe patients (OABSS > 5, N = 53). And bacterial communities of two groups were significantly different. Further, there were positive correlations between scores of OABSS and both richness (Chao1, P = 0.002) and diversity (Shannon index, P = 0.044) of urinary microbiome. Some bacterial genera (e.g., Porphyromona and Prevotella) were significantly related to sub-symptoms of OAB. Conclusion This cross-sectional analysis revealed that increased diversity and richness of the bladder microbiota was associated with worse OAB severity, and specific urinary dysbiosis may constitute an etiological factor in exacerbating functional bladder disorders. Keywords overactive bladder; LUTS; urinary microbiome; urinary microbiota; bladder microbiota Funding National Natural Science Foundation of China (Grant No. 81870522) Tweetable abstract Bladder microbiota is associated with female OAB severity.

IntroductionPatients with muscle invasive bladder cancer (MIBC) who are unfit and unsuitable for standard radical treatment with cystectomy or daily radiotherapy present a large unmet clinical need. Untreated, they suffer high cancer specific mortality and risk significant disease-related local symptoms. Hypofractionated radiotherapy (delivering higher doses in fewer fractions/visits) is a potential treatment solution but could be compromised by the mobile nature of the bladder, resulting in target misses in a significant proportion of fractions. Adaptive ‘plan of the day’ image-guided radiotherapy delivery may improve the precision and accuracy of treatment. We aim to demonstrate within a randomised multicentre phase II trial feasibility of plan of the day hypofractionated bladder radiotherapy delivery with acceptable rates of toxicity.Methods and analysisPatients with T2-T4aN0M0 MIBC receiving 36 Gy in 6-weekly fractions are randomised (1:1) between treatment delivered using a single-standard plan or adaptive radiotherapy using a library of three plans (small, medium and large). A cone beam CT taken prior to each treatment is used to visualise the anatomy and select the most appropriate plan depending on the bladder shape and size. A comprehensive radiotherapy quality assurance programme has been instituted to ensure standardisation of radiotherapy planning and delivery. The primary endpoint is to exclude >30% acute grade >3 non-genitourinary toxicity at 3 months for adaptive radiotherapy in patients who received >1 fraction (p0=0.7, p1=0.9, α=0.05, β=0.2). Secondary endpoints include local disease control, symptom control, late toxicity, overall survival, patient-reported outcomes and proportion of fractions benefiting from adaptive planning. Target recruitment is 62 patients.Ethics and disseminationThe trial is approved by the London-Surrey Borders Research Ethics Committee (13/LO/1350). The results will be disseminated via peer-reviewed scientific journals, conference presentations and submission to regulatory authorities.Trial registration numberNCT01810757.

Summary Introduction Posterior urethral valves (PUV) is the most common cause of congenital bladder outflow obstruction with persistent lower urinary tract and renal morbidities. There is a spectrum of functional bladder disorders ranging from hypertonia to bladder underactivity, but the aetiology of these clinical conditions remains unclear. Aims and objectives We tested the hypothesis that replacement of detrusor muscle with non-muscle cells and excessive deposition of connective tissue is an important factor in bladder dysfunction with PUV. We used isolated detrusor samples from children with PUV and undergoing primary or secondary procedures in comparison to age-matched data from children with functionally normal bladders. In vitro contractile properties, as well as passive stiffness, were measured and matched to histological assessment of muscle and connective tissue. We examined if a major pathway for fibrosis was altered in PUV tissue samples. Methods Isometric contractions were measured in vitro in response to either stimulation of motor nerves to detrusor or exposure to cholinergic and purinergic receptor agonists. Passive mechanical stiffness was measured by rapid stretching of the tissue and recording changes to muscle tension. Histology measured the relative amounts of detrusor muscle and connective tissue. Multiplex quantitative immunofluorescence labelling using five epitope markers was designed to determine cellular pathways, in particular the Wnt-signalling pathway, responsible for any changes to excessive deposition of connective tissue. Results and Discussion PUV tissue showed equally reduced contractile function to efferent nerve stimulation or exposure to contractile agonists. Passive muscle stiffness was increased in PUV tissue samples. The smooth muscle:connective tissue ratio was also diminished and mirrored the reduction of contractile function and the increase of passive stiffness. Immunofluorescence labelling showed in PUV samples increased expression of the matrix metalloproteinase, MMP-7; as well as cyclin-D1 expression suggesting cellular remodelling. However, elements of a fibrosis pathway associated with Wnt-signalling were either reduced (β-catenin) or unchanged (c-Myc). The accumulation of extracellular matrix, containing collagen, will contribute to the reduced contractile performance of the bladder wall. It will also increase tissue stiffness that in vivo would lead to reduced filling compliance. Conclusions Replacement of smooth muscle with fibrosis is a major contributory factor in contractile dysfunction in the hypertonic PUV bladder. This suggests that a potential strategy to restore normal contractile and filling properties is development of the effective use of antifibrotic agents. Download : Download high-res image (132KB) Download : Download full-size image Summary Figure .

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

Motility disorders of biliary system include gall bladder dyskinesia and sphincter of Oddi dysfunction (SOD). Impaired contractility with or without inflammation of gall bladder is presumed to result in symptoms associated with gall bladder dyskinesia. However, gall bladder contractility is not always impaired in these patients and therefore, the term functional gall bladder disorder may be preferred to gall bladder dyskinesia. The diagnosis of gall bladder dyskinesia relies on clinical history suggestive of biliary pain, exclusion of gall stones and objective evidence of impaired gall bladder contractility measured by cholecystoscintigraphy. The mainstay of management in patients with functional gall bladder disorder is cholecystectomy. In SOD, the pathophysiology is more complex and incompletely understood. Interruption of cholecysto-sphincteric reflex and visceral hyperalgesia after cholecystectomy have been proposed as plausible mechanisms of pain in patients with SOD. The classical phenotyping of SOD into three phenotypes (type I, II and III) has been challenged by recent evidence which disapproves the existence of type III SOD. The diagnosis of SOD relies on clinical suspicion, exclusion of functional and organic mimickers, and SO manometry. The mainstay of management is endoscopic sphincterotomy in appropriately selected patients with suspected SOD. Both SO manometry and endoscopic sphincterotomy are considered as high risk procedures for pancreatitis. Therefore, careful selection of patients is paramount. Endotherapy does not benefit patients with type III SOD regardless of the results of SO manometry.

Cystoscopic onabotulinumtoxinA (onaBoNTA) intradetrusor injection is an efficient and durable modality for treating sensory bladder disorders. However, the inconvenience of using the cystoscopic technique and anesthesia, and the adverse effects of direct needle injection (e.g., haematuria, pain, and infections) have motivated researchers and clinicians to develop diverse injection-free procedures to improve accessibility and prevent adverse effects. However, determining suitable approaches to transfer onaBoNTA, a large molecular and hydrophilic protein, through the impermeable urothelium to reach therapeutic efficacy remains an unmet medical need. Researchers have provided potential solutions in three categories: To disrupt the barrier of the urothelium (e.g., protamine sulfate), to increase the permeability of the urothelium (e.g., electromotive drug delivery and low-energy shock wave), and to create a carrier for transportation (e.g., liposomes, thermosensitive hydrogel, and hyaluronan-phosphatidylethanolamine). Thus far, most of these novel administration techniques have not been well established in their long-term efficacy; therefore, additional clinical trials are warranted to validate the therapeutic efficacy and durability of these techniques. Finally, researchers may make progress with new combinations or biomaterials to change clinical practices in the future.

ZusammenfassungDie neurogene Detrusorhyperaktivität und die nicht-neurogene. sog. idiopathische überaktive Blase (engl. Overactive Bladder OAB) sind gekennzeichnet durch einen imperativen Harndrang mit oder ohne Harninkontinenz, eine deutlich erhöhte Miktionsfrequenz, und sie sind häufig begleitet von einer Nykturie. Als second-line Therapie nach Versagen einer anticholinergen Behandlung dieser Erkrankungen hat sich die OnabotulinumtoxinA Detrusorinjektion fest etabliert. Der Eingriff ist sowohl im stationären als auch im ambulanten Setting und unter Allgemein- oder Lokalanästhesie durchführbar. Nebenwirkungen betreffen hauptsächlich das Auftreten von Harnwegsinfekten sowie – insbesondere bei neurogen bedingten Funktionsstörungen – den Harnverhalt. Wenn der Neurologe Hinweise auf eine Detrusorhyperaktivität hat und bisherige medikamentöse Therapieversuche nicht zu dem gewünschten Erfolg führen, empfiehlt sich somit eine Vorstellung beim Urologen zur Frage der OnabotulinumtoxinA-Detrusorinjektion.Dieser Artikel beschränkt sich auf die zugelassenen Indikationen der OnabotulinumtoxinA Detrusorinjektionen und fasst ihre aktuelle Datenlage zusammen.

Background Current treatment options for bladder disorders of neurogenic etiology often leave unsatisfactory results. Therefore, new and effective treatments must be investigated. High-frequency spinal cord stimulation (HF-SCS) at 10 kHz has proven to be effective in the treatment of refractory chronic back and leg pain. Objective To evaluate the efficacy of HF-SCS at 10 kHz in alleviating lower urinary tract dysfunction and bladder incontinence in 5 patients with underlying neurological disease or spinal cord injury, through retrospective study. Methods Urodynamic parameters such as voiding frequency, residual volume, episodes of incontinence, and the patients' subjective impression impairment of life were assessed and compared pre- and postoperatively. Reduction in pain intensity was assessed as change on the Numeric Rating Scale (NRS). Results All 5 patients had significantly positive outcomes. Episodes of leakage per day improved by 83% on average. Quality of life questionnaires and subjective bother scale revealed an improvement of 36% and 57%, respectively. Individual symptoms among the patient group such as residual volume also responded to the treatment as well. Mean pain NRS of 8.6 cm was reduced to 3.9 cm (55%) at 6 mo follow-up. Conclusion HF-SCS at 10 kHz significantly alleviated symptoms of neurogenic bladder incontinence in patients suffering from neurological disease or spinal cord injury. However, larger and prospective, randomized studies are necessary to make a clear statement regarding the efficacy of this therapy in lower urinary tract dysfunction and bladder incontinence.

Aim. Based on the analysis of the scientific literature sources, the authors aimed to summarize and present the existing information about the role of parathyroid hormone-related protein (PTHrP) in pathogenesis of disorders of bladder contractile function. Materials and methods . Analysis of literature in databases Google Scholar, Scopus, Web of Scence, PabMed for the whole time period of studying the stated problem. Results . In the recent years, one can observe a growing interest to dysfunction of bladder with insuffi contractile activity of detrusor. The low level activity of bladder can be often observed, while its diagnostics and treatment remain problematic. The existing ideas about the role of parathyroid hormone-related protein (PTHrP) in regulation of bladder’s functional condition are based on the results of few and mostly experimental research studies. It is proved that PTHrP secretion is induced in bladder as a result of bladder stretching, and prevents spontaneous contraction of detrusor’s smooth muscles, which has PTH/PTHrPreceptors, and also reduces contraction amplitude of bladder. It was stated that increased PTHrP secretion in response to the stretching smooth muscles is a part of autocrine effect, relaxing the bladder during its fi The existing scientifi data show that PTHrP is a unique endogenous detrusor relaxant, which functions by means of PTH/PTHrP-receptors located in bladder. It is assumed that PTHrP can also have a paracrine effect on vessels that regulate the blood fl bladder fi or can change neural activity. Thus, PTHrP is a powerful endogenous relaxant of bladder contraction, while autocrine or paracrine mechanisms of this effect are physiologically relevant processes happening in bladder. It is assumed that disturbed binding PTHrP with its receptor can be part ofpathogenesis of bladder disorders. In our opinion, the infl of chronic high PTHrP level in blood fl on the detrusor muscle structures can be also considered as one of the reasons that cause functional insuffi of bladder. This assumption is based on comparison of the PTHrP-effects on the bladder functional condition, presented in the experiment, as well as in the few clinical studies. Direct infl targeting the interaction of PTHrP with its specifi PTH/PTHrP-receptor is considered as a potential therapeutic approach to treat pathological conditions related to disorder of bladder contractile function. Conclusion . The literature survey covers general ideas about functional insufficiency of bladder, as well as information about the role of PTHrP in its development. The studied problem is rather relevant and frequent in the population, and besides being seen as a urological pathology, it is associated with a considerable reduction of the quality of life for patients. More detailed clinical studies will let us specify the diagnostics criteria of this syndrome and develop the schemes for pathogenetic therapy .

Background and aims: Urinary incontinence is common among multiple sclerosis (MS) patients, which affects their quality of life negatively. This study examined the effectiveness of a behavioral training program on severity of urinary incontinence among Iranian women with MS. Methods: This is a quasi experimental study. The sample was selected using purposeful sampling from all those who presented for routine follow-up care and treatment in an MS clinic in Tehran from March 2015 to September 2015. The training consisted of 2 sessions (each were 45 minutes) video, small group discussion and group lecture in which all aspects of the urinary incontinence were taught. Before the study initiation, patients were asked to complete the Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQUI-SF) and a demographic questionnaire. Three month after the first educational intervention, MS patients were reassessed using the ICIQUI-SF. Data analyzed in SPSS 21. Results: The mean total scores of ICIQ-SF were 12.4 ± 3.3 and 7.1 ± 3.2 before and after training, respectively. According to the results of paired t test, this difference before and after study was statistically significant (P

Traumatic brain injury (TBI) typically causes permanent brain tissue damage, which leads to permanent severe voiding dysfunction. Urinary retention is often refractory to standard therapies, and most patients require self-catheterization, which results in frequent urinary tract infections and reduces quality of life. Deep brain stimulation (DBS) might be a feasible alternative approach for treating bladder disorders in patients with TBI. In this study, we developed a DBS system with a closed-loop control strategy and determined the feasibility of this DBS system for improving bladder voiding function in a TBI animal model. A prototype of the DBS system was designed, fabricated and integrated with a closed-loop control algorithm based on the real-time external urethral sphincter-electromyogram feedback. A series of animal experiments was conducted to determine whether the feedback algorithm accurately detects the bladder status during cystometric measurements. Subsequent animal experiments were conducted to implement this DBS system and determine the performance of the closed-loop strategy for improving bladder functions in the TBI animal model. We successfully implemented a closed-loop algorithm for DBS control, and the accuracy of the bladder voiding phase detection was > 90%. Our system significantly improved the voiding efficiency in TBI rats from 22 to 74%. Although the prototype of the DBS feedback system was fabricated with surface-mounted device components and mounted on a 3D printed circuit board, the design principles and animal experience gathered from this research can serve as a basis for developing a new implantable bladder controller in the future.

In this review, we will describe the techniques which we have developed to properly diagnose the constipation component of pediatric bowel and bladder disorders (BBD) in children and the treatment techniques that most rapidly and effectively resolve these issues. Constipation is commonly understood to be a major component of dysfunctional elimination syndrome in children. All methodologies described for the treatment of overactive bladder dysfunction in the pediatric population include the treatment of constipation as a critical component. Diagnostic techniques that remain inconclusive are best used to diagnose constipation and the treatment modalities most ideally suited to address bowel dysfunction in these patients.

Overactive bladder is often characterized by biomechanical changes in the bladder wall, but there is no established method to measure these changes in vivo. The goal of this study was to develop a novel method to determine detrusor wall biomechanical parameters during urodynamics through the incorporation of transabdominal ultrasound imaging. Individuals with overactive bladder (OAB) underwent ultrasound imaging during filling. The fill rate was 10% of the cystometric capacity per minute as determined by an initial fill. Transabdominal ultrasound images were captured in the midsagittal and transverse planes at 1 min intervals. Using image data and Pves, detrusor wall tension, stress, and compliance were calculated. From each cross−sectional image, luminal and wall areas along with inner perimeters were measured. In the sagittal and transverse planes, wall tension was calculated as Pves*luminal area, wall stress as tension/wall area, and strain as the change in perimeter normalized to the perimeter at 10% capacity. Elastic modulus was calculated as stress/strain in the medial-lateral and cranial-caudal directions. Patient-reported fullness sensation was continuously recorded. Data from five individuals with OAB showed that detrusor wall tension, volume, and strain had the highest correlations to continuous bladder sensation of all quantities measured. This study demonstrates how detrusor wall tension, stress, strain, and elastic modulus can be quantified by adding ultrasound imaging to standard urodynamics. This technique may be useful in diagnosing and better understanding the biomechanics involved in OAB and other bladder disorders.

Interstitial cystitis (IC) is a progressive bladder disorder that presents with symptoms of bladder urgency, frequency and pain. The aetiology of the disease remains uncertain, but it is postulated that there is an initial infective insult which damages the glycosaminoglycan (GAG) layer of the bladder urothelium. This defect allows an influx of ions, particularly potassium, which initiates an inflammatory reaction in the bladder wall, which incites the symptoms described above. Treatment initially involves behavioural and oral medication, with second line being intravesical instillation therapy. Treatment strategies focus on restoring lower urinary tract epithelial function, inhibiting neural activation, controlling allergies and relieving symptoms. In this review, current intravesical therapy will be discussed, as well as what lies on the horizon for intravesical therapy in IC.

The role of cannabinoid type 1 (CB1) receptors in tibial and pudendal neuromodulation of bladder overactivity induced by intravesical infusion of 0.5% acetic acid (AA) was determined in α-chloralose anesthetized cats. AA irritation significantly ( P < 0.01) reduced bladder capacity to 36.6 ± 4.8% of saline control capacity. Tibial nerve stimulation (TNS) at two or four times threshold (2T or 4T) intensity for inducing toe movement inhibited bladder overactivity and significantly ( P < 0.01) increased bladder capacity to 69.2 ± 9.7 and 79.5 ± 7.2% of saline control, respectively. AM 251 (a CB1 receptor antagonist) administered intravenously at 0.03 or 0.1 mg/kg significantly ( P < 0.05) reduced the inhibition induced by 2T or 4T TNS, respectively, without changing the prestimulation bladder capacity. However, intrathecal administration of AM 251 (0.03 mg) to L7 spinal segment had no effect on TNS inhibition. Pudendal nerve stimulation (PNS) also inhibited bladder overactivity induced by AA irritation, but AM 251 at 0.01–1 mg/kg iv had no effect on PNS inhibition or the prestimulation bladder capacity. These results indicate that CB1 receptors play an important role in tibial but not pudendal neuromodulation of bladder overactivity and the site of action is not within the lumbar L7 spinal cord. Identification of neurotransmitters involved in TNS or PNS inhibition of bladder overactivity is important for understanding the mechanisms of action underlying clinical application of neuromodulation therapies for bladder disorders.

Urinary tract infections and other related pathophysiological conditions are a plethora of ailments affecting mankind. Ailments that are as common as the urinary tract infection, uropathy, incontinence, calculi and many other disorders. With the advancement of research into newer and more potent drugs with better efficacy and lesser side effects, treatment is becoming more specific and efficacious. This review examines the recent development in the treatment of these disorders and impressive progress in the pharmacotherapy, it also gives an overview of current and future prospects of drugs for bladder disorders.

Several studies suggest that HTLV-1 infection may be associated with a wider spectrum of neurologic manifestations that do not meet diagnostic criteria for HAM/TSP. These conditions may later progress to HAM/TSP or constitute an intermediate clinical form, between asymptomatic HTLV-1 carriers and those with full myelopathy. Our aim was to determine the prevalence of HTLV-1-associated disease in subjects without HAM/TSP, and the relationship between these findings with HTLV-1 proviral load (PVL). Methods: 175 HTLV-1-infected subjects were submitted to a careful neurological evaluation, during their regular follow up at the HTLV outpatient clinic of the Institute of Infectious Diseases “Emilio Ribas”, São Paulo city, Brazil. Clinical evaluation and blinded standardized neurological screening were performed for all the subjects by the same neurologist (MH). Results: After the neurological evaluation, 133 patients were classified as asymptomatic and 42 fulfilled the criteria for intermediate syndrome (IS). The mean age of the enrolled subjects was 46.3 years and 130 (74.3%) were females. Clinical classification shows that neurological symptoms (p, Author summary At least 5–10 million people live with the Human T-Cell Lymphotropic Virus type 1 (HTLV-1) worldwide, and around 0.25–5% of them may develop HTLV-1-associated myelopathy/Tropical spastic paraparesis (HAM/TSP), which is associated with chronic inflammation. In this study, involving 175 HTLV-1-infected subjects originally classified as asymptomatic, we found that 42 of them in reality presented some early clinical conditions, including alterations related not only to the neurological system, but also to the eyes and the skin. We called such conditions intermediate syndrome. Thus, it seems reasonable to suggest that all HTLV-1-infected subjects should be monitored for symptoms that may arise earlier in the course of their infection.

The urinary bladder is a hollow muscular organ that stores urine and enables urination to be intermittent and voluntary. Its histologic structure consists of smooth muscle, urothelium, vessel, and nerve. Common bladder disorders include congenital anomalies, infectious diseases, trauma, tumors, and situations subsequently affecting the bladder structure. Although several surgical procedures such as gastro- and enterocystoplasty have improved the treatment of bladder diseases, cell-based therapy provides a promising alternative to repair diseased bladders. This review focuses on the state of art and advancements in tissue regeneration in treating bladder diseases. We address mechanisms, rationales, strategies, and methodologies using various cells to direct cell differentiation, paracrine effects, and resident cell recruitment. In addition, we highlight research into three-dimensional porous biodegradable scaffolds, synthetic and natural collagen-based biomaterials, preclinical animal models, and clinical trials. At the end, we discuss the challenges and the future directions of bladder regeneration.

The urothelium, the epithelial layer of bladder mucosa, has the classic barrier function of preventing harmful urinary constituents from leaking into the underlying submucosal structures and smooth muscle. In recent years, this epithelial layer has been recognised as a new sensory structure that responds to bladder distension as well as pathological stimuli. This has changed our view on bladder sensory mechanisms and generated intense interest in its role in pathophysiology underlying many bladder disorders.

In order to understand the role of the brain in the control of the urinary bladder and its sphincter, it is important to make a distinction between (1) Areas and pathways which are intrinsic part of the micturition and continence reflex, and (2) Areas and pathways which modulate these micturition and continence areas. Most of the clinical therapies aimed at alleviating functional bladder disorders are not specifically targeted on the central reflex areas, like the pontine micturition center (PMC), but influence cortical and subcortical brain areas which modulate the micturition reflex components. This chapter gives an overview of the central areas involved in the control of micturition and continence and highlights their role in the pathophysiology of functional bladder problems.

Case History Herniation of the urinary bladder into the inguinal canal is rare and constitutes 1–3% of all inguinal hernias. Bladder herniation is usually asymptomatic and is determined incidentally; however, it may rarely present with urinary obstruction symptoms. Here, we described an incidental bladder hernia in a 76-year-old man who is evaluated in radiology department for fever and left-sided flank pain for three days duration. He had no previous history of trauma, medication abuse, surgery or familial bladder disorders. His additional co morbidities included hypertension and diabetes mellitus. There were no remarkable findings on abdominal examination except left side loin tenderness. On evaluation Computed tomography (CT) revealed that a left inguinal hernia with fluid density lesion continuous with left lateral bladder wall. No bowel was contained in the hernia (Figure 1, 2). The inguinal hernia was confirmed as bladder hernia by CT cystogram (Figure 3). Inguinal hernia usually contains the peritoneum that surrounds the abdominal organs. Bowel loops, omentum, or extraperitoneal fat can be detected within the hernia sac in the inguinal canal. However, as in this case, the bladder can also be present within the hernia sac. Early diagnosis with radiological imaging is important to prevent complications during surgery.

Multiple sclerosis journal 135245851989471 (2019). doi:10.1177/1352458519894714, Published by Sage, London