Chitin-based hydrogel loaded with bFGF and SDF-1 for inducing endogenous mesenchymal stem cells homing to improve stress urinary incontinence.

Nonoperative treatments for Stress Urinary Incontinence (SUI) represent an ideal treatment method. Mesenchymal stem cell (MSCs) treatment is a new modality, but there is a lack of research in the field of gynecological pelvic floor and no good method to induce internal MSC homing to improve SUI. Herein, we develop an injectable and self-healing hydrogel derived from ß-chitin which consists of an amino group of quaternized ß-chitin (QC) and an aldehyde group of oxidized dextran (OD) between the dynamic Schiff base linkage.it can carry bFGF and SDF-1a and be injected into the vaginal forearm of mice in a non-invasive manner. It provides sling-like physical support to the anterior vaginal wall in the early stages. In the later stage, it slowly releasing factors and promoting the homing of MSCs in vivo, which can improve the local microenvironment, increase collagen deposition, repair the tissue around urethra and finally improve SUI (Scheme 1). This is the first bold attempt in the field of pelvic floor using hydrogel mechanical support combined with MSCs homing and the first application of chitin hydrogel in gynecology. We think the regenerative medicine approach based on bFGF/SDF-1/chitin hydrogel may be an effective non-surgical approach to combat clinical SUI.

Menopause hormone therapy and urinary symptoms: a systematic review.

IMPORTANCE: Urogenital changes associated with menopause are now classified as genitourinary syndrome of menopause (GSM), which includes symptoms of urgency, frequency, dysuria, and recurrent urinary tract infections for which the recommended treatment is estrogen. However, the association between menopause and urinary symptoms and the efficacy of hormone therapy for these symptoms is uncertain. OBJECTIVE: Our objective was to define the relationship between menopause and urinary symptoms including dysuria, urgency, frequency, recurrent urinary tract infections (UTIs), and urge and stress incontinence by conducting a systematic review of the effects of hormone therapy (HT) for urinary symptoms in perimenopausal and postmenopausal women. EVIDENCE REVIEW: Eligible studies included randomized control trials with perimenopausal and postmenopausal women with a primary or secondary outcome of the following urinary symptoms: dysuria, frequent UTI, urgency, frequency, and incontinence, included at least one treatment arm of estrogen therapy, and were in English. Animal trials, cancer studies and pharmacokinetic studies, secondary analyses, and conference abstracts were excluded. PubMed, Scopus, and the Cochrane Central Register of Controlled Trials were searched until April 2022. Two authors reviewed each article with discrepancies resolved through whole group consensus. Data extracted included the following: publication date, country, setting, subject number, follow-up, duration, age, race/ethnicity, study design, inclusion criteria, and main findings. FINDINGS: There is insufficient evidence to confirm that menopause is associated with urinary symptoms. The effect of HT on urinary symptoms depends on type. Systemic HT may cause urinary incontinence or worsen existing urinary symptoms. Vaginal estrogen improves dysuria, frequency, urge and stress incontinence, and recurrent UTI in menopausal women. CONCLUSIONS AND RELEVANCE: Vaginal estrogen improves urinary symptoms and decreases the risk of recurrent UTI in postmenopausal women.

Short and Medium-Term Results of the Autologous Adult Mucosa Stem Cell Therapy Compared with Mini-Sling Surgery in the Treatment of Women's Stress Urinary Incontinence; A Randomized Clinical Trial.

OBJECTIVE: This study aimed to compare the results of stem cell therapy with mini-sling for women's stress urinary incontinence. METHODS: This study was a parallel groups noninferiority randomized clinical trial. Patients with pure stress urinary incontinence who did not improve after three months of conservative and medical therapy were included. Patients were divided into two groups mini-sling insertion or peri-urethral injection of the autologous mucosa stem cell with simple equal randomization. Standard Incontinence Impact Questionnaire (IIQ) for patients' satisfaction as well as objective Marshal Test as primary outcomes were compared. RESULTS: From October 2016 to March 2018, 30 patients (mean age of 52 years) were randomly divided equally into two groups. Finally, a negative Marshal test was observed in 73% of the stem cell group vs. 80% in the mini-sling group (p = 0.6). The mean decrease in the IIQ results was 12 points in the stem cell group vs. 25 points in the mini-sling group (p = 0.05). Favorable results at 6 m and 26 m follow-up were 40% vs. 80% (p = 0.06) and 53% vs. 60% (p = 0.7) in stem cell and mini-sling group, respectively. Patients in the mini-sling group experienced a higher rate of dyspareunia. Intervention time and hospital stay were 6.46 ± 1.24 minutes vs. 19.40 ± 4.30 minutes (p = 0.001) and 4.33 ± 1.23 vs. 9.20 ± 3.16 hours (p = 0.001) in stem cell and mini-sling groups, respectively. CONCLUSION: Results of the periurethral injection of the autologous adult mucosa-derived stem cells are not inferior to the less invasive mini-sling procedure; while, the stem cell group showed shorter intervention time and hospital stay as well as fewer complications. This noninferiority pilot randomized trial compared the results of stem cell therapy with mini-sling surgery and showed that in the medium-term followup, the results are comparable.

Application of estrogen for the treatment of stress urinary incontinence in mice.

BACKGROUND: Stress urinary incontinence (SUI) is a pervasive health tissue among women, which seriously affects the quality of life. The etiology of SUI is complex and diverse in women, with past studies having demonstrated that estrogen deficiency plays an important role in pelvic floor muscle atrophy and urethral degeneration. We comprehensively investigated the effects of estrogen in the treatment of SUI in female mice at cellular and animal levels. METHODS: L929 fibroblasts mechanical injury model was established by four-point bending device, and SUI mouse model was established by vaginal dilation method commonly used to simulate labor injury. After estrogen treatment, the expressions of Collagen I, Collagen III, Elastin, TIMP-1, TIMP-2, MMP-2, and MMP-9 were detected, the leak point pressure (LPP) and abdominal leak point pressure (ALPP) of mice in each group were detected, and both the effect of estrogen on extracellular matrix remodeling of mouse urethra and anterior vaginal wall was observed from the histological level. RESULTS: The results revealed that an appropriate amount of estrogen can promote the expression of Collagen I, Collagen III, Elastin, TIMP-1, and TIMP-2, decrease the expression of MMP-2 and MMP-9, and maintain the dynamic balance of MMPs/TIMPs at both cellular and animal levels. Meanwhile, we determined that estrogen can increase the LPP and ALPP values of SUI mice. The collagen fibers' content in the mice treated with estrogen was significantly greater than in the control group mice. CONCLUSIONS: The estrogen may alleviate the symptoms of SUI by reconstituting ECM, thus laying a solid foundation for further exploration of estrogen therapy.

Efficacy and safety of onabotulinumtoxin A injection in male patients with detrusor overactivity after stress urinary incontinence surgery.

INTRODUCTION AND OBJECTIVE: The use of onabotulinumtoxin A (BoNT-A) injection in male patients with detrusor overactivity (DO) after stress urinary incontinence (SUI) surgery has been scarcely described. Our aim was to assess results of this treatment in this specific population. MATERIALS AND METHODS: Retrospective analysis of men with previous SUI surgery who had been treated with a first injection of 100 U BoNT-A because of DO since 2010 in our department. Treatment response was assessed with the Treatment Benefit Scale: 1) greatly improved; 2) improved; 3) not changed; 4) worsened after treatment (Treatment Benefit Scale 1 or 2: treatment response). Complications were classified according to the Clavien-Dindo classification. Treatment continuation was considered present if, at the last visit, patients had received a BoNT-A injection within the preceding 12 months. Pre- and post-treatment urodynamic variables were compared. RESULTS: Eighteen patients were included, median age 71.1 (59.1-83.5) years. Twelve (66.7%) patients reported response to treatment. Two (11.1%) complications were detected: urinary retention requiring clean intermittent catheterization (Clavien-Dindo 2). No complications related to previous SUI surgery were detected. Fifteen (83.3%) patients had a follow-up >12 months (median follow-up 57 [15-89] months) and all of them had discontinued treatment at the end of follow-up. Urodynamic studies showed significant improvement in terms of DO and bladder compliance. CONCLUSION: Although most men with DO after SUI surgery respond to intradetrusor BoNT-A injection, all of them discontinue treatment due to personal reasons. It is a safe procedure, with urinary retention requiring clean intermittent catheterization being the most frequent complication.

Combination therapy with botulinum toxin and bulking agent-An efficient, sustainable, and safe method to treat elderly women with mixed urinary incontinence.

AIMS: To evaluate the efficacy, sustainability and safety of combined botulinum toxin and polyacrylamide hydrogel (PAHG) therapy to treat urgency and stress components of therapy-refractory mixed urinary incontinence (MUI) in an elderly study population. METHODS: Fifty-five women with therapy-refractory MUI were treated with botulinum toxin and PAHG in one surgical procedure. Urgency urinary incontinence (UUI) and stress urinary incontinence (SUI) outcomes were separately assessed after 4 and 12 months by objective UUI episodes/24 h and cough test, subjective impact of UUI and SUI on quality of life, and subjective International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF). MUI outcome was calculated by combining UUI and SUI outcomes. Complications were monitored throughout the study. RESULTS: At 4 months, objective cure rates were 73%, 53%, and 42%, and subjective cure rates were 71%, 52%, and 50% for SUI, UUI, and MUI. At 12 months, objective cure rates were 73%, 56%, 50% and subjective cure rates were 78%, 42%, and 40% for SUI, UUI, and MUI. The ICIQ-UI SF score decreased by 9.0 and 8.7 points after 4 and 12 months. All complications were transient and included 22% clean intermittent catheterization immediately after surgery, 33% postvoid residual volumes >100 ml at 14 days, and 13% symptomatic urinary tract infection within the first postoperative month. CONCLUSIONS: The combination of botulinum toxin and PAHG is effective, sustainable and safe to treat therapy-refractory MUI, even in an elderly and frail study population. Patients benefit from the short surgical procedure without the need for general anaesthesia or discontinuation of anticoagulation.

False-negative finding in urodynamic study for the chief complaint. Does it interfere with the clinical outcomes for the treatment of SUI or OAB syndromes?

ABSTRACT Purpose: False-negative urodynamic findings may mislead or prevent planned treatments due to unmatched findings with the clinical presentation. We hypothesized that the absence of urodynamic demonstration of SUI or OAB on urodynamics would interfere with clinical outcomes. Materials and Methods: Materials and Methods: We prospectively studied 124 women with (94) or without (30) demonstrable SUI after sling operations. Similarly, 64 women with OAB syndrome with (38) or without (26) demonstrable DO were also compared after treatment with anticholinergic agents. Patients were assessed with the UDI-6 and IIQ-7 questionnaires 3 and 6 months after treatment. Results: Only 76% of SUI patients demonstrated urine leakage during urodynamics. The UDI-6 score was higher in the demonstrable-SUI and demonstrable-DO groups, while the IIQ-7 score was comparable within the incontinence or urgency/frequency groups. Demonstrable and non-demonstrable SUI-operated patients showed similar outcomes. Patients with urgency syndromes with or without demonstrable DO had a similar rate of improvement with anticholinergic therapy. Conclusions: Women with clinical complaints of SUI objectively demonstrated on urodynamics presented the same subjective clinical outcome as those with SUI lacking objective demonstration when measured by the UDI-6 and IIQ-7 questionnaires. Similarly, patients with OAB syndrome with or without demonstrable DO had similar clinical improvement when treated with anticholinergics and measured using the same questionnaires.

The Effect of Symptomatic Stress Urinary Incontinence on Catheterization Rates After Intradetrusor OnabotulinumtoxinA Injections.

OBJECTIVES: To determine whether catheterization rates after intradetrusor onabotulinumtoxinA injection for nonneurogenic overactive bladder and urgency incontinence differ between women with urgency urinary incontinence only and women with urgency-predominant mixed urinary incontinence. METHODS: This was a retrospective cohort study of patients that underwent intradetrusor onabotulinumtoxinA injection of 100 U for nonneurogenic urgency urinary incontinence. The primary outcome was the difference in catheterization rates between women with urgency urinary incontinence alone compared with women with urgency-predominant mixed urinary incontinence. Descriptive statistics and multivariate logistic regression analysis were performed. RESULTS: Of the 177 women included in the final analysis, 105 had urgency urinary incontinence and 72 had urgency-predominant mixed urinary incontinence. The overall catheterization rate after onabotulinumtoxinA injection was 11.3%, with significantly fewer women with mixed urinary incontinence requiring catheterization when compared with women with urgency urinary incontinence alone (4.2% vs 16.2%; P = 0.03), despite an older population (P = 0.02). Patient-reported improvement (P = 0.37) and decision to continue onabotulinumtoxinA treatments (P = 0.89) were similar between groups. Multivariate logistic regression analysis revealed that women with mixed urinary incontinence had significantly lower odds of requiring catheterization after onabotulinumtoxinA injections than women with urgency urinary incontinence alone (odds ratio, 0.16; 95% confidence interval, 0.04-0.67; P = 0.01). CONCLUSIONS: Findings suggest that the presence of symptomatic stress urinary incontinence is associated with lower rates of catheterization after intradetrusor onabotulinumtoxinA, but does not compromise efficacy of treatment for urgency-predominant mixed urinary incontinence.

Bone marrow stem cells secretome accelerates simulated birth trauma-induced stress urinary incontinence recovery in rats.

Stress urinary incontinence (SUI) is defined as involuntary urine leakage during physical activities that increase the intra-abdominal pressure on the bladder. We studied bone marrow stem cell (BMSC) secretome-induced activation of anterior vaginal wall (AVW) fibroblasts and its ability to accelerate SUI recovery following vaginal distention (VD) in a rat model of birth trauma using BMSC-conditioned medium (BMSC-CM) and concentrated conditioned medium (CCM). BMSC-CM enhanced the proliferation, migration, and collagen synthesizing abilities of fibroblasts. Differentially expressed genes in BMSC-CM-induced fibroblasts were mainly enriched for cell adhesion, extracellular fibril organization and angiogenesis. Treatment with the JAK2 inhibitor AG490 reversed BMSC-CM-induced activation of the JAK2/STAT4 pathway. Periurethral injection with BMSC-CCM markedly enhanced the abdominal leak point pressure (LPP) in rats after VD. Histological analysis revealed increased numbers of fibroblasts, improved collagen fibers arrangement and elevated collagens content in the AVW of rats receiving BMSC-CCM. These findings suggest the BMSC secretome activates AVW fibroblasts and contributes to the functional and anatomic recovery of simulated birth trauma-induced SUI in rats.

Use of Duloxetine for Postprostatectomy Stress Urinary Incontinence: A Systematic Review.

CONTEXT: The recommended treatment of postprostatectomy stress urinary incontinence (PPSUI) after failure of pelvic floor muscle training is primarily surgical intervention with a male sling or artificial urinary sphincter. The use of pharmacological therapy in this setting is unlicensed and controversial. OBJECTIVE: To systematically review the available evidence regarding the efficacy and safety of duloxetine for the treatment of stress urinary incontinence following prostate surgery (radical or endoscopic). EVIDENCE ACQUISITION: The EMBASE, MEDLINE/PubMed, and Cochrane Central Register of Controlled Trials were searched from inception up until April 17, 2020. All studies evaluating the role of duloxetine in men with PPSUI were included. Two reviewers independently screened all articles, searched the reference lists of retrieved articles, and performed data extraction. The quality of evidence and risk of bias were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE); Cochrane; and Risk of Bias in Nonrandomised Studies of Interventions (ROBINS-I) tools. EVIDENCE SYNTHESIS: The search yielded 234 studies. After excluding duplicates, 140 titles and abstracts were screened, and eight reports (348 patients) were eligible for inclusion in the final review. Duloxetine was assessed in two scenarios: (1) early use to reduce the time to attain continence and (2) treatment of persistent PPSUI. Most men had mild-to-moderate incontinence at baseline. Overall, duloxetine resulted in a mean dry rate of 58% (25-89%), mean improvement in pad number of 61% (12-100%), and mean improvement in 1-h pad weight of 68% (53-90%) at short-term follow-up (mean 1-9 mo; low to moderate certainty of evidence). However, mean adverse event rates were relatively high, and treatment was discontinued in 38% (low certainty of evidence). CONCLUSIONS: Duloxetine has demonstrated good short-term cure and/or improvement in treating men with persistent PPSUI, as well as in reducing the time to attain continence. However, a proportion of men discontinue treatment due to adverse events. The overall certainty evidence is moderate to low, with heterogeneity between studies and methodological limitations. However, we have highlighted the need for further randomised trials with longer follow-up, utilising consistent outcome reporting measures. Despite these limitations, the findings from this review will aid patient counselling regarding this less invasive treatment option, thereby allowing personalisation of care centred around the values and preferences of individual patients. PATIENT SUMMARY: Duloxetine has good success rates in the short term, in terms of improving incontinence symptoms in men who have undergone prostate surgery. However, some men experience side effects bad enough to require cessation of treatment. Further studies are needed to determine whether duloxetine maintains its effectiveness in the long term.

Injection of Urethral Bulking Agents.

Urethral injection is a safe and minimally invasive method of treating female stress urinary incontinence with multiple bulking agents currently commercially available. Although there are numerous studies that demonstrate efficacy, long-term success is not yet proven. This article aims to describe the mechanism of action and properties of various agents, patient selection factors, available techniques for injection, outcomes of urethral injections, and complications associated with the procedure.

Does assessing urethral function allow the selection of the optimal therapy for recurrent SUI? Report from the ICI-RS 2017.

AIMS: The management of recurrent stress urinary incontinence following failed previous continence surgery remains challenging. Whilst the role of urodynamic investigations has been questioned in the management of primary stress incontinence there is a widely held view that women with recurrent symptoms require further investigation although there is no agreement regarding which tests are required. We sought to understand what testing is recommended prior to managing this difficult cohort of patients. METHOD: This research proposal was presented at the International Consultation on Incontinence Research Society (ICI-RS) in order to clarify our current knowledge regarding the assessment of urethral function and to set research priorities for the future. RESULTS: Whilst the majority of clinicians would advocate urodynamic evaluation of women with recurrent stress incontinence following previous surgery there is no consensus of opinion as to which tests should be performed, on whom or where. The available evidence to date suggests that urethral function tests do have a role with regard to prognosis following surgery and also in planning the most appropriate surgical intervention. CONCLUSION: The ICI-RS developed a list of research questions which may be able to assist in improving the investigation and management of women with recurrent SUI. Questions included whether patients felt the information gained via urethral function tests had an important role in their counseling regarding outcome of repeat SUI surgery.

MORPHOLOGICAL ASSESSMENT OF NO-SYNTHASE DISTRIBUTION IN OVERACTIVE BLADDER AND STRESS URINE INCONTINENCE IN ANIMAL MODELS ADMINISTERED WITH EXPERIMENTAL PHARMACOCORRECTION REGIMENS.

The objective of the study was immunohistochemical evaluation of distribution of various NO synthase fractions in the structural elements of the bladder wall under stress urinary incontinence and its overactivity prior and post Mirabegron, Spasmex, Quercetin therapies and their combinations with Testosterone and Estradiol. Using the immunohistochemical method, we studied the expression of the main fractions of NO synthase in experimental models of hyperactive bladder (OAB) and stress urinary incontinence (SUI). We found that OAB and SUI were characterized by emergence of expression of the inducible fraction (iNOS) predominantly in the interstitial cells of the muscular layer of the bladder and reduced expression of endothelial (eNOS) and neuronal (nNOs) NO synthase fractions. In contrast to Spasmex, Mirabegron and Quercetin in combination with Testosterone and Estradiol contributed to stabilization of eNOS and nNOs expression already at early observation phases, and reduced the level of iNOS expression with its further disappearance in the later observation period.

[Effects of 7-difluoromethy-5, 4'-dimethoxygenistein on stress urinary incontinence model in rats and its mechanisms].

OBJECTIVE: To investigate the effects of 7-difluoromethy-5, 4'-dimethoxygenistein (DFMG) on stress urinary incontinence (SUI) model in Sprague Dawley (SD) rats and its possible mechanisms.
 Methods: SD rat model of SUI was established through simulating pregnancy, birth trauma and ovarian castration. The rats were divided into a normal control group, a SUI group, and a DFMG group at 10 or 20 mg/kg. They were treated with 10 mg/kg normal saline (NS), 10 mg/kg NS, 10 mg/kg DFMG and 20 mg/kg DFMG, respectively, via gastric gavage every other day. Maximal bladder capacity (MBC), leak point pressure (LPP), abdominal leak point pressure (ALPP), hematoxylin-eosin (HE) staining, and Masson staining were performed to detect the index for the model. MiR-26b and its down-stream gene phosphatase and tensin homolog deleted on chromosome 10 (PENT) mRNA in urethral sphincter muscles cells (USMCs) were analyzed by RT-PCR. The protein levels of PENT, phosphatidylinositol 3-kinase (PI3K), protein kinaseB (AKT), B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), cytochrome C(Cyt-c) and caspase-3 were examined by Western blot. The apoptotic rate of USMCs was determined by flow cytometry (FCM), and the proliferative rate of USMCs was examined by MTT assay.
 Results: The SD rat model of SUI was successfully established. HE staining and Masson staining showed that the pathological features of urethral sphincter were improved in the DFMG-treated groups compared with the SUI group. The urine dynamics indexes of model rats, such as MBC, LPP and ALPP, were improved (all P﹤0.05). The results of RT-PCR showed that the miR-26b mRNA was up-regulated (P﹤0.05) and PENT mRNA was down-regulated (P﹤0.05) in the DFMG-treated groups compared with the SUI group. Simultaneously, compared with the SUI group, the protein levels of PENT, Bax, Cyt-c and caspase-3 were down-regulated (all P﹤0.05) and the protein levels of PI3K, AKT and Bcl-2 protein were up-regulated (all P﹤0.05), accompanied by the decreased apoptotic rate of USMCs (P﹤0.05) and the increased proliferative rate of USMCs (P﹤0.05) in the DFMG-treated groups.
 Conclusion: The DFMG can significantly improve the symptoms of urinary dynamics, which might be related to the up-regulation of miR-26b expression and the regulation of PI3/AKT-Bcl-2/ Bax signaling pathways.

Results of an innovative bulking agent in patients with stress urinary incontinence who are not optimal candidates for mid-urethral sling surgery.

AIMS: To assess the efficacy and safety of peri-urethral bulking injections (PBI) with an innovative bulking material (PDMS-U) in women with stress-urinary incontinence (SUI) who are not optimal candidates for mid-urethral sling surgery. METHODS: A prospective study was performed in women with SUI who, for several reasons, have a relative contraindication for a mid-urethral sling procedure. These reasons include: (i) recurrent SUI after a prior SUI surgical procedure; (ii) a history of oncologic gynaecological surgery; (iii) a history of neurologic disease resulting in voiding problems; (iv) a maximal flow rate of less than 15 mL per second or; (v) women with a contraindication for surgery with general or regional anaesthesia. All women were treated with PBI consisting of PDMS-U, a bulking agent that polymerizes in situ. The primary outcome was subjective improvement, defined as "a little better" to "very much better" on the PGI-I. Secondary outcomes included objective cure, disease specific quality of life and adverse events. RESULTS: Subjective improvement was reported by 18 (90%) of the 20 included patients. The subjective cure rate was 56% and the objective cure rate was 65%. There was a statistically significant improvement of all domain scores of the UDI-6, IIQ-7, and PISQ-12 at 6 months follow up. Abnormal post voiding residual volume (>150 mL) was the most common adverse event (40%), but persisted in only one patient, based on the patient's preference for a catheter. CONCLUSIONS: PBI with PDMS-U is a viable treatment option in women with a relative contra-indication for mid-urethral sling surgery.

Controlled release of insulin-like growth factor 1 enhances urethral sphincter function and histological structure in the treatment of female stress urinary incontinence in a rat model.

OBJECTIVES: To determine the effects of controlled release of insulin-like growth factor 1 (IGF-1) from alginate-poly-L-ornithine-gelatine (A-PLO-G) microbeads on external urethral sphincter (EUS) tissue regeneration in a rat model of stress urinary incontinence (SUI), as SUI diminishes the quality of life of millions, particularly women who have delivered vaginally, which can injure the urethral sphincter. Despite several well-established treatments for SUI, growth factor therapy might provide an alternative to promote urethral sphincter repair. MATERIALS AND METHODS: In all, 44 female Sprague-Dawley rats were randomised into four groups: vaginal distension (VD) followed by periurethral injection of IGF-1-A-PLO-G microbeads (VD + IGF-1 microbeads; 1 × 104 microbeads/1 mL normal saline); VD + empty microbeads; VD + saline; or sham-VD + saline (sham). RESULTS: Urethral function (leak-point pressure, LPP) was significantly lesser 1 week after VD + saline [mean (sem) 23.9 (1.3) cmH2 O] or VD + empty microbeads [mean (sem) 21.7 (0.8) cmH2 O) compared to the sham group [mean (sem) 44.4 (3.4) cmH2 O; P < 0.05), indicating that the microbeads themselves do not create a bulking or obstructive effect in the urethra. The LPP was significantly higher 1 week after VD + IGF-1 microbeads [mean (sem) 28.4 (1.2) cmH2 O] compared to VD + empty microbeads (P < 0.05), and was not significantly different from the LPP in sham rats, demonstrating an initiation of a reparative effect even at 1 week after VD. Histological analysis showed well-organised skeletal muscle fibres and vascular development in the EUS at 1 week after VD + IGF-1 microbeads, compared to substantial muscle fibre attenuation and disorganisation, and less vascular formation at 1 week after VD + saline or VD + empty microbeads. CONCLUSION: Periurethral administration of IGF-1-A-PLO-G microbeads facilitates recovery from SUI by promoting skeletal myogenesis and revascularisation. This therapy is promising, but detailed and longer term studies in animal models and humans are needed.

Sulforaphane Treatment of Stress Urinary Incontinence Via the Nrf2-ARE Pathway in a Rat Model.

BACKGROUND/AIMS: To explore the effect of sulforaphane (SFN) treatment in rats through the induction of Stress Urinary Incontinence (SUI) via the Nrf2-ARE pathway. METHODS: A total of 18 female rats (Sprague-Dawley) were assigned to three groups: a control group, an SUI group, and an SUI+SFN group (six rats per group). Rats in the treatment groups were induced via postpartum vaginal balloon dilation and bilateral ovariectomy. Rats in the SUI+SFN group were treated via intraperitoneal injection once per day for a total of one month. Urethral sphincter muscle histological was observed by HE and Masson staining. Peak voiding pressure and interval of micturition were measured by cystometry. Oxidative stress markers and protein expression in the Nrf2-ARE pathway were examined by immunohistochemical staining and western blotting. RESULTS: Prolonged micturition interval and higher peak voiding pressure were observed in the SUI+SFN group. Disturbance of muscle morphology was ameliorated, muscle content was elevated, and collagen content was restrained in response to SFN treatment. The SOD, GSH-Px, and CAT activities were elevated in the SUI+SFN group compared to those in the control group. The level of cell apoptosis was decreased in SUI rats after SFN treatment; however, apoptosis was mainly located in the urethral mucosa instead of the muscle layer. SFN reduced the Bax/Bcl-2 expression ratio. Nrf2 and Nrf2 target antioxidant proteins were elevated in the SFN group. CONCLUSIONS: SFN was effective for SUI treatment via decreasing oxidative stress and activating the Nrf2-ARE pathway.

Traditional suburethral sling operations for urinary incontinence in women.

BACKGROUND: Stress urinary incontinence constitutes a significant health and economic burden to society. Traditional suburethral slings are one of the surgical operations used to treat women with symptoms of stress urinary incontinence. OBJECTIVES: To determine the effects of traditional suburethral slings on stress or mixed incontinence in comparison with other management options. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register (searched 3 June 2010) and the reference lists of relevant articles. SELECTION CRITERIA: Randomised or quasi-randomised trials that included traditional suburethral slings for the treatment of stress or mixed urinary incontinence. DATA COLLECTION AND ANALYSIS: At least three reviewers independently extracted data from included trials onto a standard form and assessed trial methodological quality. The data abstracted were relevant to predetermined outcome measures. Where appropriate, we calculated a summary statistic: a relative risk for dichotomous data and a weighted mean difference for continuous data. MAIN RESULTS: We included 26 trials involving 2284 women. The quality of evidence was moderate for most trials and there was generally short follow-up ranging from 6 to 24 months.One medium-sized trial compared traditional suburethral sling operations with oxybutynin in the treatment of women with mixed urinary incontinence. Surgery appeared to be more effective than drugs in treating participant-reported incontinence (n = 75, risk ratio (RR) 0.18, 95% confidence interval (CI) 0.08 to 0.43).One trial found that traditional slings were more effective than transurethral injectable treatment (RR for clinician-assessed incontinence within a year 0.21, 95% CI 0.09 to 0.21)Seven trials compared slings with open abdominal retropubic colposuspension. Participant-reported incontinence was lower with the slings after one year (RR 0.75, 95% CI 0.62 to 0.90), but not when assessed by clinicians. Colposuspension, however, was associated with fewer peri-operative complications, shorter duration of use of indwelling catheter and less long-term voiding dysfunction. One study showed there was a 20% lower risk of bladder perforation with the sling procedure but a 50% increase in urinary tract infection with the sling procedure compared with colposuspension. Fewer women developed prolapse after slings (compared with after colposuspension) in two small trials but this did not reach statistical significance.Twelve trials addressed the comparison between traditional sling operations and minimally invasive sling operations. These seemed to be equally effective in the short term (RR for incontinence within first year 0.97, 95% CI 0.78 to 1.20) but minimally invasive slings had a shorter operating time, fewer peri-operative complications (other than bladder perforation) and some evidence of less post-operative voiding dysfunction and detrusor symptoms.Six trials compared one type of traditional sling with another. Materials included porcine dermis, lyophilised dura mater, fascia lata, vaginal wall, autologous dermis and rectus fascia. Participant-reported improvement rates within the first year favoured the traditional autologous material rectus fascia over other biological materials (RR 0.45, 95% CI 0.21 to 0.98). There were more complications with the use of non-absorbable Gore-Tex in one trial.Data for comparison of bladder neck needle suspension with suburethral slings were inconclusive because they came from a single trial with a small specialised population.No trials compared traditional suburethral slings with anterior repair, laparoscopic retropubic colposuspension or artificial sphincters. Most trials did not distinguish between women having surgery for primary or recurrent incontinence when reporting participant characteristics.For most of the comparisons, clinically important differences could not be ruled out. AUTHORS' CONCLUSIONS: Traditional slings seem to be as effective as minimally invasive slings, but had higher rates of adverse effects. This should be interpreted with some caution however, as the quality of evidence for the studies was variable, follow-up short and populations small, particularly for identifying complication rates. Tradional sling procedures appeared to confer a similar cure rate in comparison to open retropubic colposuspension, but the long-term adverse event profile is still unclear. A brief economic commentary (BEC) identified two studies suggesting that traditional slings may be more cost-effective compared with collagen injection but not cost-effective when compared with minimally invasive sling operations. Reliable evidence to clarify whether or not traditional suburethral slings may be better or worse than other surgical or conservative management options is lacking.

Tumor necrosis factor-alpha inhibits differentiation of myogenic cells in human urethral rhabdosphincter.

OBJECTIVES: To examine the inhibitory effects of tumor necrosis factor-α on myogenic differentiation of human urethral rhabdosphincter cells. METHODS: A rhabdosphincter sample was obtained from a patient who underwent total cystectomy. To expand the lifespan of the primary cultured cells, rhabdosphincter myogenic cells were immortalized with mutated cyclin-dependent kinase 4, cyclin D1 and telomerase. The differential potential of the cells was investigated. The transfected human rhabdosphincter cells were induced for myogenic differentiation with recombinant human tumor necrosis factor-α and/or the tumor necrosis factor-α antagonist etanercept at different concentrations, and activation of signaling pathways was monitored. RESULTS: Human rhabdosphincter cells were selectively cultured for at least 40 passages. Molecular analysis confirmed the expression of myosin heavy chain, which is a specific marker of differentiated muscle cells, significantly increased after differentiation induction. Although tumor necrosis factor-α treatment reduced the myosin heavy chain expression in a concentration-dependent manner, etanercept inhibited this suppression. Tumor necrosis factor-α suppressed phosphorylation of protein kinase B and p38, whereas etanercept pretreatment promoted phosphorylation and myosin heavy chain expression in a concentration-dependent manner. CONCLUSIONS: Tumor necrosis factor-α inhibits differentiation of urethral rhabdosphincter cells in part through the p38 mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. Inhibition of tumor necrosis factor-α might be a useful strategy to treat stress urinary incontinence.