Female Urethroplasty with a Buccal Mucosa Graft using a Supraurethral Approach.

INTRODUCTION AND HYPOTHESIS: In the setting of recurrent female urethral stricture, urethroplasty offer the best chance of cure. However, which approach (dorsal or ventral) and which tissue (buccal mucosa, vaginal graft, vaginal flap) remain areas of controversy. In this article and accompanying video, we describe female urethroplasty with a supraurethral approach using a buccal mucosa graft. METHODS: A stricture of 3 cm in length was observed in the mid urethra. A supraurethral semi-lunar incision was made and dissection was performed up to the stricture. A dorsal urethrotomy was performed and a 3 × 2 cm oral mucosal graft was harvested from the left cheek. The mucosal graft was anastomosed to both urethral edges with running sutures. The graft was fixed to the supraurethral tissue with quilting sutures. A urethral catheter and a suprapubic catheter were left in place for 3 weeks. RESULTS: Following removal of the catheters, the patient was able to void satisfactorily with no incontinence. No complications were observed in the urethral area or at the graft harvest site. CONCLUSIONS: Buccal mucosa graft urethroplasty with a supraurethral approach is a reliable method in the treatment of female urethral stricture.

A diagnostic conundrum: Is it a periurethral diverticulum/cyst or a bulking agent (Bulkamid)?

INTRODUCTION: Urethral bulking agents are commonly used to manage female stress urinary incontinence (SUI) as they have been suggested to be safe, efficacious, and a minimally invasive surgical option. Bulkamid is a newer bulking agent that has been introduced and promoted in the market for use. It is non-particulate in nature with high tissue biocompatibility, and consequently, it is difficult to differentiate between Bulkamid and a periurethral cyst on magnetic resonance imaging (MRI). This, therefore, presents a diagnostic dilemma. METHODS AND MATERIALS: Here we describe two cases with previous injections of Bulkamid referred to our Centre for management of a presumed periurethral diverticulum based on MRI findings. Both patients were reviewed and examined in outpatient clinics with MRI findings discussed at MDT, further imaging was required. RESULTS: We found that a limited noncontrast computed tomography (CT) pelvis, followed by a voiding cystometrogram (VCMG), and then a repeat limited noncontrast CT pelvis effectively differentiated between Bulkamid and these presumed periurethral diverticulae. The theory behind this was that during micturition, the contrast would pass through to the urethral diverticulum and appear as high-density (bright) material within the periurethral region (the pre-VCMG was required to prove that any high-density material was due to the contrast and not pre-existing high-contrast material). CONCLUSION: A CT scan done in conjunction with a VCMG is likely to be more effective in differentiating between Bulkamid and a true periurethral diverticulum than an MRI scan. Appropriate diagnostic evaluation of periurethral lesions can lead to time-saving and cost-effective patient management as this will bypass the need for unnecessary investigations and possible unwarranted surgical intervention.

The patient burden of nocturnal polyuria in the United States: Results from the epidemiology of nocturnal polyuria (EpiNP) study.

OBJECTIVES: To explore the impact of nocturnal polyuria (NP) on health-related quality of life (HRQoL), work productivity, mental health, fatigue, bother, and daytime sleepiness. MATERIALS AND METHODS: This large-scale, US population-representative epidemiologic study was conducted in two parts: a web-based survey and 3-day bladder diary. Consenting participants completed the baseline Epidemiology of NP (EpiNP) survey online (Lower Urinary Tract Symptoms [LUTS] Tool, comorbidities, burden, and multiple HRQoL measures). Participants who reported ≥2 voids/night, and a random sample of 100 respondents each reporting 0 or 1 void/night, were sent urine measurement containers and asked to complete the 3-day bladder diary. NP was defined as Nocturnal Polyuria Index >0.33 (NPI33) or nocturnal urine production >90 ml/h (NUP90). Five subgroups were created: Idiopathic NP (NP with no underlying cause), NP associated with symptoms of overactive bladder (NPOAB) or bladder outlet obstruction (NPBOO; men only), NP associated with other comorbidities (NPCOM; e.g., diabetes, hypertension, heart disease, sleep apnea), and no NP (did not meet NP criteria). RESULTS: A total of 4893 men and 5297 women completed the EpiNP survey; mean age was 54.4 (SD = 14.7). Significantly greater patient burden (p < 0.0001) was evidenced in the nocturia group (≥2 voids/night) versus no nocturia group (0-1 void/night) on daily impact of nocturia, LUTS Bother, prostate symptoms (men only), work productivity, physical and mental health component scores, depression, fatigue, and daytime sleepiness. NP subgroup analyses showed men in the NPBOO group and women in the NPOAB group reported the greatest impact on LUTS bother, fatigue, physical health, work productivity impairment, daytime sleepiness, and depression (women only). CONCLUSION: This was the first large-scale, epidemiologic study to explore the impact of different forms of NP on patients' HRQoL. Findings demonstrate that NP associated with other urologic or comorbid conditions appears to have greater patient burden than idiopathic NP, in particular for women.

Sleep Disorders, Comorbidities, Actions, Lower Urinary Tract Dysfunction, and Medications ("Sleep C.A.L.M.") in the evaluation and management of nocturia: A simple approach to a complex diagnosis.

INTRODUCTION: Nocturia arises from a fundamental mismatch between nocturnal urine production, storage capacity, and sleep architecture, which may be driven by abnormalities of the genitourinary tract, but also by sleep disorders, medical diseases, patient actions/lifestyle factors, or medications. This article introduces a novel system for organizing the complex differential diagnosis for nocturia, as proposed by an international collective of practicing urologists, physician specialists, and sleep experts: "Sleep CALM"-Sleep Disorders, Comorbidities, Actions, Lower Urinary Tract Dysfunction, and Medications. METHODS: Narrative review of current evidence regarding the relevance of each "Sleep CALM" factor to nocturia pathogenesis, evaluation, and management. RESULTS: Nocturia and sleep disorders are highly intertwined and often bidirectional, such that nocturnal awakenings for reasons other than a sensation of bladder fullness should not be used as grounds for exclusion from nocturia treatment, but rather leveraged to broaden therapeutic options for nocturia. Nocturia is an important potential harbinger of several serious medical conditions beyond the genitourinary tract. Urologists should have a low threshold for primary care and medical specialty referral for medical optimization, which carries the potential to significantly improve nocturnal voiding frequency in addition to overall health status. Adverse patient actions/lifestyle factors, lower urinary tract dysfunction, and medication use commonly coexist with disordered sleep and comorbid medical conditions, and may be the primary mediators of nocturia severity and treatment response, or further exacerbate nocturia severity and complicate treatment. CONCLUSION: "Sleep CALM" provides a memorable and clinically relevant means by which to structure the initial patient history, physical exam, and clinical testing in accordance with current best-practice guidelines for nocturia. Although not intended as an all-encompassing diagnostic tool, the "Sleep CALM" schema may also be useful in guiding individualized ancillary testing, identifying the need for specialty referral and multidisciplinary care, and uncovering first-line treatment targets.

Nocturnal polyuria in women: results from the EpiNP study.

INTRODUCTION AND HYPOTHESIS: Data from a large US population-based, cross-sectional, epidemiological study (the EpiNP Study) were used to assess the symptoms and bother experienced by women with nocturnal polyuria (NP). METHODS: Consenting participants recruited from an online panel completed the baseline EpiNP survey online (Lower Urinary Tract Symptoms Tool and urological comorbidities). All reporting ≥2 voids/night and a random sample of 100 respondents, each reporting 0 or 1 void/night were asked to complete a 3-day web-based bladder diary recording time, volume, and urgency rating of each void. NP was calculated by the proportion of urine production that occurred during nocturnal hours using a Nocturnal Polyuria Index (NPI33) threshold of >0.33 or nocturnal urine production of >90 ml/h (NUP90). The frequency of participants reporting LUTS and bother was determined by age and NP: idiopathic NP, NP associated with overactive bladder (NPOAB), NP associated with comorbidities (NPCom), and no NP (did not meet NP criteria). RESULTS: A total of 5,290 women completed the baseline survey. Mean age (range) was 54.9 (30-95) years; 1,841 (34.8%) reported ≥2 nocturnal voids. The prevalence of LUTS increased across the lifespan; however, bother associated with each LUTS decreased with increasing age. The percentage of women rating bother by nocturia episodes ≥2 "> somewhat" ranged from 40.3% to 68.3%, with bother ratings highest in the NPOAB and No NP groups. CONCLUSIONS: NP is prevalent in women with considerable bother and is often associated with other urinary symptoms. Multifactorial causes and potential treatments of NP should be considered, particularly at a later age.

Robotic ureteral reconstruction for benign ureteral strictures: a systematic review of surgical techniques, complications and outcomes : Robotic Ureteral Reconstruction for Ureteral Strictures.

INTRODUCTION: Robotic ureteral reconstruction (RUR) has been widely used to treat ureteral diseases. To summarize the surgical techniques, complications, and outcomes following RUR, as well as to compare data on RUR with open and laparoscopic ureteral reconstruction. METHODS: Our systematic review was registered on the PROSPERO (CRD42022309364) database. The PubMed, Cochrane and Embase databases were searched for publications in English on 06-Feb-2022. Randomised-controlled trials (RCTs) or non-randomised cohort studies with sample size ≥ 10 cases were included. RESULTS: A total of 23 studies were included involving 996 patients and 1004 ureters from 13 non-comparative, and 10 retrospective comparative studies. No RCT study of RUR was reported. The success rate was reported ≥ 90% in 15 studies. Four studies reported 85-90% success rate. Meta-analyses for comparative studies showed that RUR had significantly lower estimated blood loss (EBL) (P = 0.006) and shorter length of stay (LOS) (P < 0.001) than the open approach. RUR had shorter operative time than laparoscopic surgery (P < 0.001). CONCLUSIONS: RUR is associated with lower EBL and shorter LOS than the open approach, and shorter operative time than the laparoscopic approach for the treatment of benign ureteral strictures. However, further studies and more evidence are needed to determine whether RUR is more superior.

Differences in the Prevalence of Nocturnal Polyuria in the U.S. by Definition: Results from the Epidemiology of Nocturnal Polyuria Study.

PURPOSE: Prevalence data on nocturnal polyuria (NP), nocturia caused by overproduction of urine during sleep, is primarily limited to men and varies by NP definition. This U.S.-representative epidemiological study of men and women ≥30 years old assessed the prevalence of NP. MATERIALS AND METHODS: Consenting participants completed the baseline EpiNP (Epidemiology of Nocturnal Polyuria) survey (eg Lower Urinary Tract Symptoms Tool, comorbidities). All reporting ≥2 voids/night and a target of 100 random respondents reporting 0 or 1 void/night were asked to complete 3-day bladder diaries. NP was defined as nocturnal polyuria index (NPI) >0.33 (NPI33) and nocturnal urine production >90 ml/hour (NUP90). Extrapolated prevalence was stratified by sex and subgroups: idiopathic (without underlying causes), associated with overactive bladder (NPOAB), bladder outlet obstruction (NPBOO; men) and comorbidities. Voided volumes and timing, including first uninterrupted sleep period, were assessed by subgroup. RESULTS: A total of 10,190 individuals completed the baseline survey; mean age (range) was 54.4 (30-95). A total of 3,938 individuals were invited to complete the diary; 1,763 (49.3%) completed 3-day bladder diaries. Urine production (maximum nighttime volume, total volume, nocturnal urine production, nocturia index) was higher in both men and women with idiopathic NP and comorbidities. The median number of nighttime voids was greatest for NPBOO in men and NPOAB in women. Bother associated with nighttime voiding differed by NP subgroup but was highest in NPBOO for men (NPI33: 69.6%; NUP90: 71.1%) and NPOAB for women (NPI33: 67.5%; NUP90: 66.0%). CONCLUSIONS: This population-based NP prevalence study including men and women characterizes NP subgroups and provides insights into nocturia treatment by emphasizing factors influencing urine production versus factors influencing bladder capacity.

Muscarinic-3-receptor positive allosteric modulator ASP8302 in patients with underactive bladder. A randomized controlled trial.

AIM: The aim of this study is to evaluate safety and efficacy of ASP8302, a novel positive allosteric modulator for the muscarinic M3 receptor (M3-PAM), in patients with underactive bladder (UAB). METHODS: A randomized, double-blind, placebo-controlled multicenter study was performed in adult male/female subjects with UAB, defined as incomplete bladder emptying (postvoid residual volume [PVR] > 100 ml) without significant bladder outlet obstruction and/or overactive bladder. Subjects were randomized (1:1) to receive 4-week oral once-daily administration of 100 mg ASP8302 or matching placebo. Primary endpoint was a change from baseline in PVR measured by catheterization after standardized bladder filling (PVRC2 ). Other endpoints included PVR and bladder voiding efficiency (BVE) measured in various ways, uroflowmetry, bladder diary, and questionnaires. Pressure-flow studies were performed in a subgroup. RESULTS: One hundred and thirty-five patients were randomized (ASP8302 group: 65 patients, placebo group: 70 patients). The median change in PVRC2 was -40.0 ml (ASP8302) versus -35.0 ml (placebo) and the difference between groups was -5.0 ml (p = 0.960). In males, functional and symptomatic outcomes improved, for example, maximum urine flow rate (Qmax ) and detrusor pressure at Qmax (Pdet.Qmax ) increased (mean difference in change ASP8302 vs. placebo: 3.8 ml/s, p = 0.031 and 12.7 cm H2 O, p = 0.034, respectively). Urinary incontinence episodes/24 h decreased in males with preexisting incontinence (mean difference: -0.35; p = 0.028). The incidence of adverse events was similar between study groups (ASP8302: 33.3%, placebo: 31.4%). In the included subjects, both baseline urine flow and bladder voiding pressure was low. Compared with PVR, simultaneous BVE measurements were more consistent between various methods (spontaneous vs. standardized bladder filling, catheterization vs. ultrasound [US]). CONCLUSIONS: ASP8302 was safe and well tolerated in patients with UAB identified by nonurodynamic clinical criteria, but it did not show efficacy in the primary endpoint. However, in males it showed improvement of symptoms and functional parameters. BVE (using US) is a more optimal outcome measure than PVR in UAB.

Tissue engineering: recent advances and review of clinical outcome for urethral strictures.

PURPOSE OF REVIEW: Urethrotomy remains the first-line therapy in the treatment of a urethral stricture despite data showing no real chance of a cure after repeated urethrotomies. An anastomotic or an augmentation urethroplasty using oral mucosa can be offered to patients following failed urethrotomy. The potential for a tissue engineered solution as an alternative to native tissue has been explored in recent years and is reviewed in this article. RECENT FINDINGS: More than 80 preclinical studies have investigated a tissue-engineered approach for urethral reconstruction mostly using decellularized natural scaffolds derived from natural extracellular matrix with or without cell seeding. The animal models used in preclinical testing are not representative of disease processes seen with strictures in man. The available clinical studies are based on small noncontrolled series. SUMMARY: There is a potential role for tissue engineering to provide a material for substitution urethroplasty and work has demonstrated this. Further work will require a rigorous basic science programme and adequate evaluation of the material prior to its introduction into clinical practice. The research with tissue engineering applied to the urethra has not yet been resulted in a widely available material for clinical use that approaches the efficacy seen with the use of autologous grafts.

Complications related to use of mesh implants in surgical treatment of stress urinary incontinence and pelvic organ prolapse: infection or inflammation?

The surgical mesh material used in the surgical treatment of stress urinary incontinence (SUI) and pelvic organ prolapse (POP) in women is associated with significant complications in some women. This has recently become a public health issue with involvement of national parliaments and regulatory bodies. The occurrence of mesh complications is thought to be a result of multifactorial processes involving problems related to the material design, the surgical techniques used and disease, and patient-related factors. However, the infectious complications and mesh-tissue interactions are least studied. The aim of this article is to review any previous clinical and basic scientific evidence about the contribution of infectious and inflammatory processes to the occurrence of mesh-related complications in SUI and POP. A literature search for the relevant publications without any time limits was performed on the Medline database. There is evidence to show that vaginal meshes are associated with an unfavourable host response at the site of implantation. The underlying mechanisms leading to this type of host response is not completely clear. Mesh contamination with vaginal flora during surgical implantation can be a factor modifying the host response if there is a subclinical infection that can trigger a sustained inflammation. More basic science research is required to identify the biological mechanisms causing a sustained inflammation at the mesh-tissue interface that can then lead to contraction, mesh erosion, and pain.

The use of implanted materials for treating women with pelvic organ prolapse and stress urinary incontinence.

PURPOSE OF REVIEW: To review the current clinical management of stress urinary incontinence and pelvic organ prolapse following the adverse complications seen in the use of polypropylene mesh to treat both. RECENT FINDINGS: Materials developed for use in abdominal hernia repair have not proven risk-free when used to support pelvic organs particularly when inserted via the vagina. Following unacceptably high levels of severe complications when high-density polypropylene mesh is inserted via the vagina to treat pelvic organ prolapse, reported over the last decade, there is now an agreed consensus between surgeons about surgical approaches and materials, which should be recommended for use in stress urinary incontinence and pelvic organ prolapse. SUMMARY: There is a need for new biomaterials and tissue engineered/regenerative medicine approaches to treat stress urinary incontinence and pelvic organ prolapse. New materials need to be evaluated critically in both preclinical and clinical studies before being adopted into routine clinical use.

Current state of urethral tissue engineering.

PURPOSE OF REVIEW: Urethrotomy remains the first-line therapy in the treatment of a urethral stricture despite data showing no real chance of a cure after repeated urethroplasties. An anastomotic or an augmentation urethroplasty with oral mucosa should be offered to patients with a failed urethrotomy. The availability of grafts can be a concern for both patients and surgeons. The potential for a tissue-engineered solution has been explored in recent years and is explored in this article. RECENT FINDINGS: More than 80 preclinical studies have investigated a tissue-engineered approach for urethral reconstruction mostly using decellularized natural scaffolds with or without cell seeding. The animal models used in preclinical testing are not representative of disease processes seen with strictures in man. The available clinical studies were of small sample size and lacked control groups. The choice of biomaterial were mostly acellular matrices derived from natural extracellular matrix. The reported success rates in the pilot clinical studies were highly variable. SUMMARY: The research with tissue engineering of the urethra has not yet been translated into a clinically available material. This is an area where much more research is needed and we would conclude that it is an area of unmet clinical need where users of tissue-engineered urethra in the future need to carry out a rigorous basic science programme and need to be cautious in drawing conclusions based on initial experience and report on long-term clinical results.

Management of neurogenic bladder in patients with Parkinson's disease: A systematic review.

AIMS: To assess the different treatment methods in management of neurogenic bladder (NGB) in patients with Parkinson's disease (PD). METHODS: A systematic search was performed in Cochrane library, EMBASE, Proquest, Clinicaltrial.gov, WHO, Google Scholar, MEDLINE via PubMed, Ovid, ongoing trials registers, and conference proceedings in November 11, 2017. All randomized controlled trials (RCTs) or quasi-RCTs comparing any treatment method for management of NGB in patients with PD were included. The titles and abstracts of all identified studies were evaluated independently by two investigators. Once all of the potential related articles were retrieved, each author separately evaluated the full text of each article and the quality of the methodology of the selected studies using the Cochrane appraisal risk of bias checklist and then the data about the patient's outcomes was extracted. We registered the title in Joanna Briggs Institute (JBI) that is available in http://joannabriggs.org/research/registered_titles.aspx. RESULTS: We included 41 RCTs or quasi-RCTs or three observational study with a total of 1063 patients that evaluated pharmacological, neurosurgical, botulinum toxin, electrical neuromodulation, and behavioral therapy effects on NGB. Among the included studies only solifenacin succinate double-blind, randomized, placebo-controlled study was assessed as low risk of bias, and treatment led to an improvement in urinary incontinence. CONCLUSIONS: Although several interventions are available for treatment NGB in patients with PD, at present there is little or no evidence that treatment improves patient outcomes in this population. Additional large, well designed, randomized studies with improved methodology and reporting focused on patient-centered outcomes are needed.

An estradiol releasing, proangiogenic hydrogel as a candidate material for use in soft tissue interposition.

INTRODUCTION AND OBJECTIVES: Soft tissue interposition (STI) using local and/or regional flaps is often necessary in urogenital reconstruction to stimulate wound healing and prevent recurrence. Harvesting STI flaps can cause donor site morbidity and may not be available in some patients. In this study, we designed estradiol (E2) releasing hydrogel that could be used as an alternative to a STI flap and to investigate its ability to stimulate tissue production and angiogenesis. MATERIALS AND METHODS: A hydrogel was constructed by crosslinking a solution of estradiol, methacrylated gelatin (15%, w/v), and methacrylated hyaluronic acid (1%, w/v). The release of estradiol was measured using a UV-spectrophotometer (λmax = 220 nm). Angiogenesis was evaluated by an ex ovo chicken embryo chorioallantoic membrane (CAM) assay. RESULTS: Estradiol was gradually released from the hydrogel over 21 days. The hydrogels could be easily manipulated with surgical forceps without any deformation. The hydrogels significantly increased collagen production of human dermal fibroblasts (HDFs). Scanning electron microscopic examination demonstrated that HDFs produced significantly more extracellular matrix (ECM) on estradiol releasing hydrogels compared with the controls. Estradiol releasing hydrogels doubled the number of blood vessels growing toward the hydrogel compared with the controls (vasculogenic index, 59.6 [±6.4] and 25.6 [±4.0], respectively; [P < 0.05]). CONCLUSION: We present a proangiogenic, degradable hydrogel that can be used as an off-the-shelf available substitute to traditional STI flaps. This is achieved by using estradiol as a potent stimulator of new tissue production and new blood vessel formation.

Use of a simple in vitro fatigue test to assess materials used in the surgical treatment of stress urinary incontinence and pelvic organ prolapse.

AIMS: Stress urinary incontinence and pelvic organ prolapse are very common conditions with a proportion of patients requiring implantation of synthetic materials for a durable repair. However increasing numbers of post-surgical complications have been reported related to the use of polypropylene meshes. One hypothesis for the adverse response is poor mechanical matching of the relatively stiff polypropylene mesh particularly as materials in the pelvic floor will need to cope with decades of distension as occurs with increase of intraabdominal pressure on coughing, laughing, or sneezing. METHODS: In this study we have undertaken a very simple fatigue testing regime to compare the mechanical abilities of six materials. Four commercial meshes in clinical use and two novel electrospun materials not yet evaluated in the clinic were assessed using a uniaxial tensile test. This was performed on six samples of each dry material and on another six samples of each material after just 3 days of fatigue conditions using a dynamic bioreactor. RESULTS: The four commercial materials showed permanent mechanical deformation after just 3 days of stretching these materials by 25% elongation on a regular dynamic cycle, whereas the two new materials presented more elastic properties without deformation. CONCLUSIONS: We suggest that a test as simple as this 3-day fatigue testing is sufficient to distinguish between materials which have already been found to cause complications clinically and newer materials yet to be tested clinically which will hopefully prove more mechanically appropriate for implantation in the pelvic floor.

Contemporary outcomes of hypospadias retrieval surgery in adults.

OBJECTIVE: To describe the surgical approach and outcomes in the treatment of adult patients with complications of childhood hypospadias surgery, as such patients present a significant reconstructive challenge due to the combination of anatomical and cosmetic deformity, which often results in major functional and psychosexual sequelae. PATIENTS AND METHODS: We analysed prospectively collected data on 79 adults with complications of childhood hypospadias surgery, who were operated on between 2004 and 2016. Of the 79 patients, 48 underwent a two-stage urethroplasty using a buccal mucosa graft, and 31 underwent a one-stage distal urethroplasty. RESULTS: Patients were followed up using flexible cystoscopy (every 6-9 months). The mean (range) follow-up was 48 (12-96) months. Of the 48 patients who underwent a two-stage repair, eight (16%) needed a revision of the first-stage graft. In total, nine of the 48 patients (16%) developed fistula requiring closure after the second stage; all but one was closed successfully on the first attempt, whilst one required two attempts before closure. Only two of the 48 patients that underwent a two-stage procedure required a re-do urethroplasty within 3 years. Of the 31 patients who underwent a one-stage repair, six (19%) needed fistula closure, all of which were successful. No patient required a further urethroplasty during follow-up. CONCLUSIONS: Despite the significant surgical challenges found in this patient group, excellent long-term functional outcomes can be achieved. As expected there is a need for additional intervention, either for revision of the first stage or to close fistulae and less commonly for further reconstruction for stricture recurrence.

α1L-adrenoceptors mediate contraction of human erectile tissue.

α1-adrenoceptor antagonists can impact upon sexual function and have potential in the treatment of erectile dysfunction. Human erectile tissue contains predominantly α1A-adrenoceptors, and here we examined whether contractions of this tissue are mediated by the functional phenotype, the α1L-adrenoceptor. Functional experiments using subtype selective agonists and antagonists, along with radioligand ([3H]tamsulosin) binding assays, were used to determine the α1-adrenoceptor population. A61603, a α1A-adrenoceptor agonist, was a full agonist with a potency 21-fold greater than that of noradrenaline. The α1A- and α1D-adrenoceptor antagonist tamsulosin antagonized noradrenaline responses with high affinity (pKD = 9.7 ± 0.3), whilst BMY7378 (100 nM) (α1D-adrenoceptor antagonist) failed to antagonize responses. In contrast, relatively low affinity estimates were obtained for both prazosin (pKD = 8.2 ± 0.1) and RS17053 (pKD = 6.9 ± 0.2), antagonists which discriminate between the α1A- and α1L-adrenoceptors. [3H]Tamsulosin bound with high affinity to the receptors of human erectile tissue (pKD = 10.3 ± 0.1) with a receptor density of 28.1 ± 1.4 fmol mg-1 protein. Prazosin displacement of [3H]tamsulosin binding revealed a single homogenous population of binding sites with a relatively low affinity for prazosin (pKi = 8.9). Taken together these data confirm that the receptor mediating contraction in human erectile tissue has the pharmacological properties of the α1L-adrenoceptor.

Demonstration of improved tissue integration and angiogenesis with an elastic, estradiol releasing polyurethane material designed for use in pelvic floor repair.

AIMS: Pelvic organ prolapse and stress urinary incontinence affect 40-50% of postmenopausal women worldwide. Polypropylene meshes have been extensively used for the surgical intervention of these disorders; however, these meshes can lead to severe complications in some patients. The need for synthetic materials more suited for use in pelvic floor repair is widely accepted. This study aims to develop an electrospun 17-ß-estradiol releasing polyurethane (PU) scaffold that not only provides the appropriate mechanical support but can also stimulate new extracellular matrix (ECM) production and angiogenesis. METHODS: PU scaffolds with and without 17-ß-estradiol (25 and 50 mg/g) were prepared by blend electrospinning. Mechanical properties of scaffolds were assessed by uniaxial cyclic and non-cyclic testing. The viability and ECM production of human adipose derived mesenchymal stem cells (hADMSCs) cultured on 17-ß-estradiol releasing PU scaffolds was evaluated. Angiogenic potential of estradiol releasing scaffolds was demonstrated by using an ex ovo chick chorioallantoic membrane (CAM) assay. RESULTS: The inclusion of estradiol in PU scaffolds did not change the ultrastructure but it significantly increased the ultimate tensile strength of scaffolds. hADMSCs on estradiol-releasing PU scaffolds showed more ECM production. The CAM assay revealed a significantly higher angiogenic potential of estradiol-releasing PU scaffolds with an additive effect seen when hADMSCs cultured on estradiol scaffolds. Histological examination of CAM tissue sections showed extensive cellular infiltration and a good tissue integration for all constructed scaffolds. CONCLUSIONS: This study shows the angiogenic potential of estradiol-releasing PU scaffolds with appropriate strength and elasticity desirable to support the pelvic floor.

Comparative assessment of the efficacy of onabotulinumtoxinA and oral therapies (anticholinergics and mirabegron) for overactive bladder: a systematic review and network meta-analysis.

OBJECTIVES: To compare the efficacy of onabotulinumtoxinA, mirabegron, and anticholinergics in adults with idiopathic overactive bladder (OAB) using network meta-analysis (NMA). PATIENTS AND METHODS: Information sources were searched for blinded randomised controlled trials (RCTs), of ≥2 weeks duration, comparing any dose of onabotulinumtoxinA, eligible oral/transdermal anticholinergics, or mirabegron, with each other or placebo, in adults with OAB. Bayesian random-effects models were used to synthesise the results at week 12: NMA for responder analyses and network meta-regression (NMR) for change from baseline analyses. The NMR was used to adjust for differences in baseline severity between studies. Sensitivity analysis, excluding studies considered to be at a high risk of methodological bias, was conducted. RESULTS: In all, 56 RCTs were included in the networks. For each outcome, results are reported for all licensed treatment doses. For each NMR, results are based on patients with an average number of episodes of the outcome at baseline. After 12 weeks, all treatments were more efficacious than placebo. Patients who received onabotulinumtoxinA (100 U) had, on average, the greatest reductions in urinary incontinence episodes (UIE), urgency episodes, and micturition frequency, and the highest odds of achieving decreases of 100% and ≥50% from baseline in UIE/day. When comparing onabotulinumtoxinA with other pharmacotherapies, mean differences favoured onabotulinumtoxinA 100 U over all comparators for UIE and urgency episodes (credible intervals excluded zero) and all but two of the comparators for micturition frequency. OnabotulinumtoxinA 100 U was also associated with higher odds of achieving a 100% and ≥50% decrease in UIE/day than most other licensed treatments in the network. The exclusion of studies with a high risk of bias had little impact on the conclusions. CONCLUSION: The results indicate that, after 12 weeks, onabotulinumtoxinA 100 U provides greater relief of OAB symptoms compared with most other licensed doses of other pharmacotherapies in the network.