Bryophyllum pinnatum inhibits detrusor contractility in porcine bladder strips--a pharmacological study towards a new treatment option of overactive bladder

A broad spectrum of synthetic agents is available for the treatment of overactive bladder. Anti-cholinergic drugs show a poor compliance due to side effects. There is an increasing use of plant extracts in medicine. We have therefore investigated the inhibitory effects of leaf press juice from Bryophyllum pinnatum (Lam.) Oken (Kalanchoe pinnata L.) on bladder strips and compared the effects to that of oxybutynin.

Cadherin-11 up-regulation in overactive bladder suburothelial myofibroblasts

PURPOSE: We investigated whether the adherens junction proteins cadherin-11 and beta-catenin can be immunohistochemically visualized in the human bladder using commercially available antibodies and, if so, whether there are differences between patients with overactive bladder and refractory detrusor overactivity, and controls without lower urinary tract symptoms. MATERIALS AND METHODS: In a prospective, nonrandomized single center study 32 patients with overactive bladder and refractory detrusor overactivity, and 8 controls without lower urinary tract symptoms underwent cystoscopic bladder biopsy. Quantitative immunohistochemistry was performed. The primary outcome was cadherin-11 and beta-catenin expression in the human bladder using commercially available antibodies. The secondary outcome was differences in cadherin-11 and beta-catenin in patients with overactive bladder and refractory detrusor overactivity, and controls. RESULTS: Double labeling experiments showed co-localization of cadherin-11 and connexin 43 in the suburothelium. There was also strong co-localization of cadherin-11 and beta-catenin in the suburothelium and detrusor. Significant 2-fold up-regulation of cadherin-11 was found in the suburothelium of patients with overactive bladder compared with that in controls (p = 0.018), whereas beta-catenin was similar in the groups (p = 0.6). In the detrusor cadherin-11 and beta-catenin expression was comparable in patients with overactive bladder and controls (each p = 0.5). No difference was observed in cadherin-11 and beta-catenin in patients with overactive bladder with idiopathic vs neurogenic detrusor overactivity in the suburothelium and the detrusor (p >0.3 and >0.2, respectively). CONCLUSIONS: Using commercially available antibodies cadherin-11 and beta-catenin expression in human bladder suburothelial myofibroblasts and detrusor smooth muscle cells was noted. Cadherin-11 up-regulation in suburothelial myofibroblasts in patients with overactive bladder may be significant in overactive bladder pathogenesis.

Suburothelial myofibroblasts in the human overactive bladder and the effect of botulinum neurotoxin type A treatment

BACKGROUND: An increasing body of evidence suggests a possible role of suburothelial myofibroblasts (MFs) in bladder mechanosensation and in the pathophysiology of detrusor overactivity (DO). OBJECTIVE: To determine whether markers of MFs, including gap junction protein connexin43 (Cx43) and c-kit have altered immunohistochemical expression in the suburothelium of patients with neurogenic DO (NDO) or idiopathic DO (IDO) and whether this is affected by successful treatment of DO with botulinum neurotoxin type A (BoNTA). DESIGN, SETTING, AND PARTICIPANTS: Patients with NDO (n=10) or IDO (n=11) were treated in a single-centre, open-label study of intradetrusor BoNTA injections. Control tissue was obtained from 10 patients undergoing pelvic-floor repair procedures who had no overactive bladder (OAB) symptoms. This study is registered with ClinicalTrials.gov, number NCT00662064. INTERVENTIONS: Bladder biopsies performed with flexible cystoscopes were obtained from control subjects and from NDO and IDO patients before BoNTA treatment and at 4 wk and 16 wk after treatment. They were studied with quantitative immunofluorescence using antibodies to connexin 43 (Cx43), vimentin, and c-kit. MEASUREMENTS: Differences in Cx43, vimentin, and c-kit immunoreactivity between control subjects and NDO or IDO patients (primary outcomes). Changes in NDO or IDO, Cx43 immunoreactivity, and c-kit immunoreactivity after BoNTA treatment (secondary outcomes). RESULTS AND LIMITATIONS: Cx43 immunoreactivity was increased in both IDO and NDO patients compared to controls, but remained unchanged after BoNTA treatment. C-kit immunoreactivity was similar in NDO/IDO patients and controls and remained unchanged after BoNTA treatment. CONCLUSIONS: Increased gap junction formation in the suburothelium has been demonstrated in biopsies from humans with DO. It is hypothesised that this change could have a significant role in the pathogenesis of the detrusor abnormality. Successful treatment of NDO or IDO does not appear to be associated with changes in the expression of Cx43 or c-kit on suburothelial MFs.

Transcutaneous electrical nerve stimulation: an effective treatment for refractory non-neurogenic overactive bladder syndrome?

PURPOSE: To assess the effect of transcutaneous electrical nerve stimulation (TENS) for treating refractory overactive bladder syndrome (OAB). PATIENTS AND METHODS: A consecutive series of 42 patients treated with TENS for refractory OAB was prospectively investigated at an academic tertiary referral centre. Effects were evaluated using bladder diary for at least 48 h and satisfaction assessment at baseline, after 12 weeks of TENS treatment, and at the last known follow-up. Adverse events related to TENS were also assessed. RESULTS: Mean age of the 42 patients (25 women, 17 men) was 48 years (range, 18-76). TENS was successful following 12 weeks of treatment in 21 (50 %) patients, and the positive effect was sustained during a mean follow-up of 21 months (range, 6-83 months) in 18 patients. Following 12 weeks of TENS treatment, mean number of voids per 24 h decreased significantly from 15 to 11 (p < 0.001) and mean voided volume increased significantly from 160 to 230 mL (p < 0.001). In addition, TENS completely restored continence in 7 (39 %) of the 18 incontinent patients. Before TENS, all 42 patients were dissatisfied or very dissatisfied; following 12 weeks of TENS treatment, 21 (50 %) patients felt satisfied or very satisfied (p < 0.001). No adverse events related to TENS were noted. CONCLUSIONS: TENS seems to be an effective and safe treatment for refractory OAB warranting randomized, placebo-controlled trials.

Electrical stimulation with non-implanted electrodes for overactive bladder in adults

External sources The National Institute for Health Research (NIHR), UK. This project was supported byNIHR via Cochrane Infrastructure, Cochrane Programme Grant or Cochrane Incentive funding to the Incontinence Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service (NHS) or the Department of Health. NHS Grampian Endowment Research Grants, UK. This project was also supported by NHS Grampian Endowment Research Grants.

Mucosal modulation of contractility in bladder strips from normal and overactive rat models and the effect of botulinum toxin A on overactive bladder strips

AIMS: To investigate the local, regulatory role of the mucosa on bladder strip contractility from normal and overactive bladders and to examine the effect of botulinum toxin A (BoNT-A).

METHODS: Bladder strips from spontaneously hyperactive rat (SHR) or normal rats (Sprague Dawley, SD) were dissected for myography as intact or mucosa-free preparations. Spontaneous, neurogenic and agonist-evoked contractions were investigated. SHR strips were incubated in BoNT-A (3 h) to assess effects on contractility.

RESULTS: Spontaneous contraction amplitude, force-integral or frequency were not significantly different in SHR mucosa-free strips compared with intacts. In contrast, spontaneous contraction amplitude and force-integral were smaller in SD mucosa-free strips than in intacts; frequency was not affected by the mucosa. Frequency of spontaneous contractions in SHR strips was significantly greater than in SD strips. Neurogenic contractions in mucosa-free SHR and SD strips at higher frequencies were smaller than in intact strips. The mucosa did not affect carbachol-evoked contractions in intact versus mucosa-free strips from SHR or SD bladders. BoNT-A reduced spontaneous contractions in SHR intact strips; this trend was also observed in mucosa-free strips but was not significant. Neurogenic and carbachol-evoked contractions were reduced by BoNT-A in mucosa-free but not intact strips. Depolarisation-induced contractions were smaller in BoNT-A-treated mucosa-free strips.

CONCLUSIONS: The mucosal layer positively modulates spontaneous contractions in strips from normal SD but not overactive SHR bladder strips. The novel finding of BoNT-A reduction of contractions in SHR mucosa-free strips indicates actions on the detrusor, independent of its classical action on neuronal SNARE complexes.

The role of inflammatory mediators in the overactive and bladder pain syndromes

The Overactive Bladder (OAB) and Bladder Pain Syndrome (BPS) are debilitating disorders for which the pathophysiological mechanisms are poorly understood. Injury or dysfunction of the protective urothelial barrier layer, specifically the proteoglycan composition and number, has been proposed as the primary pathological characteristic of BPS. For OAB, the myogenic theory with dysfunction of the muscarinic receptors is the most reiterated hypothesis. For both over activity of the inflammatory response has been posited to play a major role in these diseases. We hypothesise that BPS and OAB are peripheral sensory disorders, with an increase in inflammatory mediators, such as cytokines and chemokines, which are capable of activating, either directly or indirectly, sensory nerve activity causing the disease. The aim of the PhD is to identify potential new therapeutic targets for the treatment of BPS and OAB. We used medium throughput quantitative gene expression analysis of 96 inflammation associated mediators to measure gene expression levels in BPS and OAB bladder biopsies and compared them to control samples. Then we created a novel animal model of disease by specific proteoglycan deglycosylation of the bladder mucosal barrier, using the bacterial enzymes Chondroitinase ABC and Heparanase III. These enzymes specifically remove the glycosaminoglycan side chains from the urothelial proteoglycan molecules. We tested role of the identified mediators in this animal model. In addition, in order to determine on which patients peripheral treatment strategies may work, we assessed the effect of local anaesthetics on patients with bladder pain. Gene expression analysis did not reveal a difference in inflammatory genes in the OAB versus control biopsies. However, several genes were upregulated in BPS versus control samples, from which two genes, FGF7 and CLL21 were correlated with patient clinical phenotypes for ICS/PI symptom and problem indices respectively. In order to determine which patients are likely to respond to treatment, we sought to characterise the bladder pain in BPS patients. Using urodynamics and local anaesthetics, we differentiated patients with peripherally mediated pain and patients with central sensitisation of their pain. Finally to determine the role of these mediators in bladder pain, we created an animal model of disease, which specifically replicates the human pathology: namely disruption in the barrier proteoglycan molecules. CCL21 led to an increase in painrelated behaviour, while FGF7 attenuated this behaviour, as measured by cystometry, spinal c-fos expression and mechanical withdrawal threshold examination. In conclusion, we have identified CCL21 and FGF7 as potential targets for the treatment of BPS. Manipulation of these ligands or their receptors may prove to be valuable previously unexploited targets for the treatment of BPS.

Interstitial Cells in the Urinary Bladder-Localization and Function

Aims: This review summarizes the currently available literature on the localization and proposed functions of a novel group of cells in the urinary bladder known as interstitial cells or interstitial cells of Cajal (ICC).

Methods: On-line searches of "Pubmed" for bladder, c-Kit, ICC, interstitial cell and myofibroblast were performed to identify relevant studies for the review.

Results: The literature contains substantial data that several sub-populations of ICC are present in the wall of the mammalian urinary bladder. These are located in the lamina propria and within the detrusor with distinctive cell shapes and morphological arrangements. Bladder ICC are identified with transmission electron microscopy or by immunohistochemical labeling using antibodies to the Kit receptor which is an established ICC marker. Lamina propria-ICC form a loose network connected via Cx43 gap junctions and are associated with mucosal nerves. Detrusor ICC track the smooth muscle bundles and make frequent contacts with intramural nerves. Both groups of ICC exhibit spontaneous electrical and Ca²⁺-signalling and also respond to application of neurotransmitter substances including ATP and carbachol. There is emerging evidence that the expression of ICC is upregulated in pathophysiological conditions including the overactive bladder.

Conclusions: There is now a convincing body of evidence that specialized ICC are present in the urinary bladder making important associations with other cells that make up the bladder wall and possessing physiological properties consistent with a role of bladder activity modulation. Neurourol. Urodynam. 29: 82–87, 2010. © 2009 Wiley-Liss, Inc.

Non-invasive antidromic neurostimulation:A simple effective method for improving bladder storage

Patients with intractably diminished bladder storage function are encountered frequently by neurourologists, occasionally requiring reconstructive surgery for appropriate resolution. Although sacral neuromodulation is a recognized effective therapeutic modality, present techniques are technically demanding, invasive, and expensive. This study investigated the effect of non-invasive third sacral nerve (S3) stimulation on bladder activity during filling cystometry. One hundred forty-six patients underwent standard urodynamic filling cystometry that was then immediately repeated. Patients in the study group (n = 74) received antidromic transcutaneous sacral neurostimulation during the second fill and the control group (n = 72) underwent a second fill without neurostimulation. A statistically significant increase in bladder storage capacity without a corresponding rise in detrusor pressure was observed in the neurostimulated patients. This improvement in functional capacity is an encouraging finding that further supports the use of this non-invasive treatment modality in clinical practice. Neurourol. Urodynam. 20:73-84. 2001. (C) 2001 Wiley-Liss, Inc.

Estudo do tempo de trânsito colônico em crianças e adolescentes com constipação intestinal crônica e disfunção do trato urinário inferior

A constipação intestinal e a disfunção do trato urinário inferior são condições associadas e bastante prevalentes na infância e adolescência. Existem múltiplas teorias para explicar essa associação, como: o efeito mecânico do reto cheio sobre a parede e o colo vesical; estimulo de reflexos sacrais a partir do reto distendido, e mais recentemente, a associação entre a bexiga e o reto no sistema nervoso central. Muitas destas crianças e adolescentes apresentam constipação refratária. Esse fato chama a atenção para a possibilidade de existência de uma desordem neuromuscular comum envolvendo o cólon e o trato urinário inferior. O objetivo desse estudo foi avaliar o trânsito colônico de crianças e adolescentes com constipação crônica refratária e sintomas do trato urinário inferior. Foi realizado um estudo observacional com análise transversal, no qual foram incluídos 16 indivíduos com constipação refratária e sintomas do trato urinário inferior, com idades entre sete e 14 anos (média de idade de 9,67 anos). Os participantes foram avaliados utilizando anamnese padrão; exame físico; diário miccional e das evacuações; escala de Bristol; Disfunctional Voiding Scoring System com versão validada para o português; ultrassonografia renal, de vias urinárias e medida de diâmetro retal; urodinâmica, estudo de trânsito colônico com marcadores radiopacos e manometria anorretal. O estudo de trânsito foi normal em três (18,75%) crianças, dez (62,5%) apresentaram constipação de trânsito lento e três (18,75%) obstrução de via de saída. A avaliação urodinâmica estava alterada em 14 das 16 crianças estudadas: dez (76,9%) apresentaram hiperatividade detrusora associada à disfunção miccional, três (23,1%) hiperatividade vesical isolada e um (6,25%) disfunção miccional sem hiperatividade vesical. Ao compararmos constipação de trânsito lento e disfunção do trato urinário inferior, dez (100%) sujeitos com constipação de trânsito lento e três (50%) sem constipação de trânsito lento apresentavam hiperatividade vesical (p=0,036). Sete (70%) sujeitos com constipação de trânsito lento e quatro (66,7%) sem constipação de trânsito lento apresentavam disfunção miccional (p=0,65). Ao compararmos constipação de trânsito lento e a presença de incontinência urinária, esta estava presente em nove (90%) participantes com constipação de trânsito lento e em um (16,7%) sem constipação de trânsito lento (p = 0,008). Quanto à urgência urinária, estava presente em 10 (100%) e três (50%) respectivamente (p = 0,036). O escore do Disfunctional Voiding Scoring System variou de 6 a 21. O subgrupo com constipação de trânsito lento mostrou um escore de Disfunctional Voiding Scoring System significativamente maior que o subgrupo sem constipação de trânsito lento. O presente estudo demonstrou alta prevalência de constipação de trânsito lento em crianças e adolescentes com constipação refratária e sintomas do trato urinário inferior. Este estudo foi pioneiro em demonstrar a associação entre hiperatividade vesical e constipação de trânsito lento e coloca em voga a possibilidade de uma desordem neuromuscular comum, responsável pela dismotilidade vesical e colônica. Futuros estudos envolvendo a motilidade intestinal e vesical são necessários para melhor compreensão do tema e desenvolvimento de novas modalidades terapêuticas.

The impact of first pregnancy and delivery on pelvic floor dysfunction

Background: The first childbirth has the greatest impact on a woman’s pelvic floor when major changes occur. The aim of this study was to comprehensively describe pelvic floor dysfunction (PFD) in young nulliparous women, and its correlation with postnatal pathology. Methods: A prospective study was performed at Cork University Maternity Hospital, Ireland. Initially 1484 nulliparous women completed the validated Australian Pelvic Floor Questionnaire at 15 weeks’ gestation and repeatedly at one year postnatally (N=872). In the second phase, at least one year postnatally, 202 participants without subsequent pregnancies attended the clinical follow up which included: pelvic organ prolapse quantification, a 3D-Transperineal ultrasound scan and collagen level assessment. Results: A high pre-pregnancy prevalence of various types of PFD was detected, which in the majority of cases persisted postnatally and included multiple types of PFD. The first birth had a negative impact on severity of pre-pregnancy symptoms in <15% of cases. Apart from prolapse, vaginal delivery, including instrumental delivery did not increase the risk of PFD symptoms, where as Caesarean section was protective for all types of PFD. The first birth had a bigger impact on pre-existing symptoms of overactive bladder compared to stress urinary incontinence. Pelvic organ prolapse is extremely prevalent in young primiparous women, however usually it is low grade and asymptomatic. Congenital factors and high collagen type III levels play an important role in the aetiology of pelvic organs prolapse. Levator ani trauma is present in one in three women after the first pregnancy and delivery. Conclusion: The main damage to the pelvic floor most likely occurs due to an undiagnosed congenital intrinsic weakness of the pelvic floor structures. PFD is highly associated with first childbirth, however it seems that pregnancy and delivery are contributing factors only which unmask the congenital intrinsic weakness of the pelvic floor support.

Cadaveric fascia lata pubovaginal slings:early results on safety, efficacy and patient satisfaction

Objective To prospectively evaluate and quantify the efficacy of cadaveric fascia lata (CFL) as an allograft material in pubovaginal sling placement to treat stress urinary incontinence (SUI).

Patients and methods Thirty-one women with SUI (25 type II and six type III; mean age 63 years, range 40-75) had a CFL pubovaginal sling placed transvaginally. The operative time, blood loss, surgical complications and mean hospital stay were all documented. Before and at 4 months and 1 year after surgery each patient completed a 3-day voiding diary and validated voiding questionnaires (functional inquiry into voiding habits, Urogenital Distress Inventory and Incontinence Impact Questionnaire, including visual analogue scales).

Results The mean (range) operative time was 71 (50-120) min, blood loss 78.7 (20-250) mL and hospital stay 1.2 (1-2) days; there were no surgical complications. Over the mean follow-up of 13.5 months, complete resolution of SUI was reported by 29 (93%) patients. Overactive bladder symptoms were present in 23 (74%) patients before surgery, 21 (68%) at 4 months and two (6%) at 1 year; 80% of patients with low (<15 cmH (2) O) voiding pressures before surgery required self-catheterization afterward, as did 36% at 4 months, but only one (3%) at 1 year. Twenty-four (77%) patients needed to adopt specific postures to facilitate voiding. After surgery there was a significant reduction in daytime frequency, leakage episodes and pad use (P <0.05). The severity of leak and storage symptoms was also significantly less (P <0.002), whilst the severity of obstructive symptoms remained unchanged. Mean subjective levels of improvement were 69% at 4 months and 85% at 1 year, with corresponding objective satisfaction levels of 61% and 69%, respectively. At 1 year, approximate to 80% of the patients said they would undergo the procedure again and/or recommend it to a friend.

Conclusion Placing a pubovaginal sling of CFL allograft is a highly effective, safe surgical approach for resolving SUI, with a short operative time and rapid recovery. Storage symptoms are significantly improved, and subjective improvement and satisfaction rates are high.