Impact of Sleep Disturbance, Physical Function, Depression and Anxiety on Male Lower Urinary Tract Symptoms: Results from the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN).

PURPOSE: The impact of nonurological factors on male lower urinary tract symptoms (LUTS) remains unclear. We investigated cross-sectional and longitudinal associations among anxiety, depression, physical function, sleep quality and urinary symptom subdomains. MATERIALS AND METHODS: Data from 518 men in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) study were analyzed to identify associations between Patient-Reported Outcomes Measurement Information System® (PROMIS®) depression, anxiety, sleep disturbance and physical function measures and LUTS subdomains, as derived from the American Urological Association Symptom Index and LUTS Tool. Multivariable linear regression was used to assess the relationships between PROMIS measures and LUTS subdomains at baseline and at 3- and 12-month followup. RESULTS: Baseline depression and anxiety were associated with urinary incontinence (p <0.001), voiding symptoms (p <0.001) and quality of life (p=0.002), whereas baseline sleep disturbance was associated with voiding and storage symptoms and quality of life (p <0.001 for all). Urinary symptom severity improved in all subdomains at 3 and 12 months. Similar associations between PROMIS measures and LUTS subdomains were observed at all time points, but baseline depression, anxiety, sleep disturbance and physical function measures were not associated with longitudinal trajectories of LUTS. CONCLUSIONS: Urinary symptom subdomains are independently associated with modifiable clinical variables including sleep quality and depression at all time points, but these variables do not predict the degree of improvement in LUTS following urological evaluation and treatment over the medium term. Bidirectional assessment and randomized experiments may improve our understanding of these relationships.

Best practices for cystometric evaluation of lower urinary tract function in muriform rodents.

AIMS: Rodent cystometry has provided valuable insights into the impact of the disease, injury, and aging on the cellular and molecular pathways, neurologic processes, and biomechanics of lower urinary tract function. The purpose of this white paper is to highlight the benefits and shortcomings of different experimental methods and strategies and to provide guidance on the proper interpretation of results. METHODS: Literature search, selection of articles, and conclusions based on discussions among a panel of workers in the field. RESULTS: A range of cystometric tests and techniques used to explore biological phenomena relevant to the lower urinary tract are described, the advantages and disadvantages of various experimental conditions are discussed, and guidance on the practical aspects of experimental execution and proper interpretation of results are provided. CONCLUSIONS: Cystometric evaluation of rodents comprises an extensive collection of functional tests that can be performed under a variety of experimental conditions. Decisions regarding which approaches to choose should be determined by the specific questions to be addressed and implementation of the test should follow standardized procedures.

Timing of sacral neurostimulation is important for increasing bladder capacity in the anesthetized rat.

We assessed the effects of limited application of sacral neurostimulation (SNS) during bladder filling on bladder capacity using our previously published SNS model in rats. Female Sprague-Dawley rats (n = 24) were urethane anesthetized (1.2 g/kg sc) and implanted with jugular venous and transvesical bladder catheters. L6/S1 nerve trunks were isolated bilaterally, and two electrodes were placed on each exposed nerve. True bladder capacity (TBC) was determined using stable single-fill cystometrograms. In the first series of experiments, SNS was applied at the onset of bladder filling for 25%, 50%, 75%, and 100% of the previous control filling cycle duration (n = 10). In the second series of experiments, SNS was applied during the first, second, third, and fourth 25% and the first and second 50% of the control fill. In the first series, a significant increase in TBC was observed only when SNS was applied for 75% or 100% of the control fill duration (30% and 35%, respectively, P < 0.05). In the second series, significant increases in TBC only occurred during the fourth 25% period and second 50% period (32% and 43%, respectively, P < 0.001). Results from the second series also revealed an increase in subsequent single-fill bladder capacities (TBC) only when SNS was applied during the second 50% of the prior fill cycle. These data indicate that the application of SNS during the final 50% of the bladder fill cycle is necessary and sufficient for increasing bladder capacity.

Patient Characteristics Associated with More Bother from Lower Urinary Tract Symptoms.

PURPOSE: Some patients continue to have bothersome lower urinary tract symptoms despite treatment. We examined characteristics associated with bother from lower urinary tract symptoms in a prospective cohort. MATERIALS AND METHODS: In this 1-year prospective, observational cohort study we obtained data on patients with lower urinary tract symptoms who were seeking care at a total of 6 tertiary care centers in the United States. Participants answered the AUA-SI (American Urological Association Symptom Index) global urinary bother question at study entry and 12 months later. Multilevel logistic and linear regression was used to identify factors associated with worsening bother and bother at 12 months, respectively. RESULTS: Of the 756 participants 121 (16%) had worsened lower urinary tract symptom bother during the study period. When adjusted for other variables, worsened lower urinary tract symptom bother was more likely among men who were nonwhite (OR 1.79, 95% CI 0.94-3.40) or who had diabetes (OR 1.68, 95% CI 0.86-3.27) and among women with diabetes (OR 1.77, 95% CI 0.85-3.67), prior treatment of lower urinary tract symptoms (OR 2.58, 95% CI 1.22-5.46) or a higher depression level (OR 1.29, 95% CI 1.10-1.52). Baseline factors associated with more severe bother at 12 months in men included more severe bother at baseline, nonwhite race, worse urinary frequency and incontinence, and higher levels of stress (p <0.05). Among women more severe bother at baseline, urinary urgency and frequency, and worse physical function were associated with more severe bother at 12 months. CONCLUSIONS: Urinary symptom severity at baseline, race, depression and psychological stress were associated with the bother of lower urinary tract symptoms in a prospective cohort of men and women treated at tertiary care facilities. These findings may inform the clinical care of patients with bothersome lower urinary tract symptoms and direct providers to better prognosticate for patients with challenging lower urinary tract symptoms cases.

Chronic high-fat diet decreased detrusor mitochondrial respiration and increased nerve-mediated contractions.

AIMS: To assess the impact of chronic high-fat diet (HFD) on behavioral voiding patterns, detrusor contractility, and smooth muscle mitochondrial function in male mice. MATERIALS AND METHODS: Male C57BL/6J mice (6 weeks) were fed a control or HFD for 20 weeks. Bladder function was assessed by void spot assays. Bladders were collected and detrusor contractility to carbachol (10-9 -10-5 M), and electrical field stimulation (EFS, 0.5-32 Hz) in the presence and absence of atropine was measured. Homogenized detrusor samples were placed in oxygraphs to assess the rate of oxygen consumption of the mitochondria within the detrusor in the presence of different substrates. Mitochondrial hydrogen peroxide (H2 O2 ) emission was measured fluorometrically. Detrusor citrate synthase activity was measured via enzyme activity kit and Western blots assessed the electron transport chain (ETC) protein content. RESULTS: HFD significantly increased body weight, adiposity, and blood glucose levels. HFD mice demonstrated increased voiding frequency and increased EFS-induced detrusor contractility. There were no changes in detrusor relaxation or cholinergic-medicated contraction. Mitochondrial respiration was decreased with HFD and H2 O 2 emission was increased. The relative amount of mitochondria in the detrusor was similar between groups. However, ETC complexes V and III were increased following HFD. CONCLUSIONS: Chronic HFD increased adiposity, lead to more frequent voiding, and enhanced EFS-mediated detrusor contractions. Mitochondrial respiration was decreased and H2 O 2 emission increased following HFD. Further research is required to determine if alterations in mitochondrial function could play a role in the development of HFD-induced bladder dysfunction.

Symptom Based Clustering of Women in the LURN Observational Cohort Study.

PURPOSE: Women with lower urinary tract symptoms are often diagnosed based on a predefined symptom complex or a predominant symptom. There are many limitations to this paradigm as often patients present with multiple urinary symptoms which do not perfectly fit the preestablished diagnoses. We used cluster analysis to identify novel, symptom based subtypes of women with lower urinary tract symptoms. MATERIALS AND METHODS: We analyzed baseline urinary symptom questionnaire data obtained from 545 care seeking female participants enrolled in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) Observational Cohort Study. Symptoms were measured with the LUTS (lower urinary tract symptoms) Tool and the AUA SI (American Urological Association Symptom Index), and analyzed using a probability based consensus clustering algorithm. RESULTS: Four clusters were identified. The 138 women in cluster F1 did not report incontinence but experienced post-void dribbling, frequency and voiding symptoms. The 80 women in cluster F2 reported urgency incontinence as well as urgency and frequency but minimal voiding symptoms or stress incontinence. Cluster F3 included 244 women who reported all types of incontinence, urgency, frequency and mild voiding symptoms. The 83 women in cluster F4 reported all lower urinary tract symptoms at uniformly high levels. All but 2 of 44 LUTS Tool and 8 AUA SI questions significantly differed between at least 2 clusters (p <0.05). All clusters contained at least 1 member from each conventional group, including continence, and stress, urgency, mixed and other incontinence. CONCLUSIONS: Women seeking care for lower urinary tract symptoms cluster into 4 distinct symptom groups which differ from conventional clinical diagnostic groups. Further validation is needed to determine whether management improves using this new classification.

Bowel function, sexual function, and symptoms of pelvic organ prolapse in women with and without urinary incontinence.

AIMS: Bowel symptoms, pelvic organ prolapse, and sexual dysfunction are common, but their frequency among women with lower urinary tract symptoms (LUTS) has not been well described. Our aims were to describe pelvic floor symptoms among women with and without urinary incontinence (UI) and among subtypes of UI. METHODS: Women with LUTS seeking care at six U.S. tertiary care centers enrolled in prospective cohort study were studied. At baseline, participants completed the Pelvic Floor Distress Inventory (PFDI-20), Pelvic Organ Prolapse/Incontinence Sexual Questionnaire (PISQ-IR), and PROMIS GI Diarrhea, Constipation, and Fecal Incontinence Scales. RESULTS: Mean age among the 510 women was 56.4 ± 14.4 years. Women who reported UI (n = 420) had more diarrhea and constipation symptoms (mean scores 49.5 vs 46.2 [P = 0.01] and 51.9 vs 48.4 [P < 0.01], respectively) at baseline. Among sexually active women, mean PISQ-IR subscale scores were lower among those with UI (condition specific: 89.8 vs 96.7, P < 0.01; condition impact: 79.8 vs 92.5, P < 0.01). Women with mixed urinary incontinence (MUI) (n = 240) reported more prolapse symptoms, fecal incontinence, and worse sexual function compared to those with stress urinary incontinence (SUI) and urgency urinary incontinence (UUI). CONCLUSIONS: Women presenting with LUTS with UI reported significantly worse constipation, diarrhea, fecal incontinence, and sexual function compared to women without UI. In women with UI, sexual function and pelvic organ prolapse (POP) symptoms were worse in those with MUI compared to SUI and UUI.

Autonomic response during bladder hydrodistention reflects the severity of symptoms in patients with bladder pain syndrome/interstitial cystitis.

AIMS: To evaluate the correlation between symptom severity of bladder pain syndrome/interstitial cystitis (BPS/IC) and autonomic nervous system activity, we examined autonomic responses during bladder hydrodistention. METHODS: Medical records were collected from a prospective database for patients who underwent bladder hydrodistention with a fixed protocol from March 2012 to December 2013. A total of 40 patients (16 males, 24 females) were included for the analysis. Hydrodistention was performed under general anesthesia (31 patients), spinal anesthesia (six patients), and both types of anesthesia (three patients) at different times. Twenty-five patients who underwent holmium laser enucleation of the prostate served as controls. Pulse rate (PR), systolic (SBP), and diastolic blood pressure (BP) were measured pre-hydrodistention, during hydrodistention, and after drainage. RESULTS: The spinal anesthesia and control groups exhibited little change in BP and PR during hydrodistention, while a significant increase was demonstrated in the general anesthesia group (e.g., ΔSBP 4.89 ± 4.80, 10.40 ± 19.03, and 56.26 ± 30.38 mm Hg, respectively, P < 0.001). Under general anesthesia, autonomic response during hydrodistention was more prominent in patients with preoperative visual analogue scale (VAS) pain score ≥7, Hunner's lesion, and glomerulation grade 4. Preoperative maximal cystometric capacity negatively correlated with changes in SBP during hydrodistention (R2 = 0.294, P = 0.009), while VAS score and interstitial cystitis problem index demonstrated a positive correlation with the changes (R2 = 0.208, P = 0.012; R2 = 0.173, P = 0.015). CONCLUSIONS: Under general anesthesia, exaggerated autonomic responses to bladder hydrodistention were demonstrated in BPS/IC patients, which reflected the severity of symptoms. These results support the hypothesis of altered activity of autonomic system in BPS/IC. Neurourol. Urodynam. 36:677-682, 2017. © 2016 Wiley Periodicals, Inc.

A standard for terminology in chronic pelvic pain syndromes: A report from the chronic pelvic pain working group of the international continence society.

AIMS: Terms used in the field of chronic pelvic pain (CPP) are poorly defined and often confusing. An International Continence Society (ICS) Standard for Terminology in chronic pelvic pain syndromes (CPPS) has been developed with the aim of improving diagnosis and treatment of patients affected by chronic pelvic pain syndromes. The standard aims to facilitate research, enhance therapy development and support healthcare delivery, for healthcare providers, and patients. This document looks at the whole person and all the domains (organ systems) in a systematic way. METHODS: A dedicated working group (WG) was instituted by the ICS Standardisation Steering Committee according to published procedures. The WG extracted information from existing relevant guidelines, consensus documents, and scientific publications. Medline and other databases were searched in relation to each chronic pelvic pain domain from 1980 to 2014. Existing ICS Standards for terminology were utilized where appropriate to ensure transparency, accessibility, flexibility, and evolution. Consensus was based on majority agreement. RESULTS: The multidisciplinary CPPS Standard reports updated consensus terminology in nine domains; lower urinary tract, female genital, male genital, gastrointestinal, musculoskeletal, neurological aspects, psychological aspects, sexual aspects, and comorbidities. Each is described in terms of symptoms, signs and further evaluation. CONCLUSION: The document presents preferred terms and definitions for symptoms, signs, and evaluation (diagnostic work-up) of female and male patients with chronic pelvic pain syndromes, serving as a platform for ongoing development in this field. Neurourol. Urodynam. 36:984-1008, 2017. © 2016 Wiley Periodicals, Inc.

What is the role of combination drug therapy in the treatment of overactive bladder? ICI-RS 2014.

AIMS AND METHODS: The role of combination therapy using oral antimuscarinic medications for the treatment of overactive bladder was proposed at the 2014 International Consultation on Incontinence-Research Society in Bristol, UK to identify key factors to consider when making clinical decisions and to guide future research design. RESULTS: Combination therapy is justified if monotherapy is associated with suboptimal efficacy or bothersome side effects. Combination therapy has the potential to improve efficacy with fewer side effects than monotherapy. Two Phase 2 studies comparing combination therapy that included an antimuscarinic demonstrated improvement in mean voided volume, the primary outcome chosen, with some combinations showing improved micturition frequency and quality of life. The two studies found no evidence of an increased safety risk with combination therapy compared to monotherapy. Future studies should use clinically meaningful or patient reported outcomes such as incontinence episodes when comparing efficacy. If surrogate measures are used, a clear justification should be provided. Cost analyses should be planned for clinical research trials evaluating combination drug therapy. CONCLUSIONS: Combination therapy is reasonable when monotherapy has suboptimal efficacy or bothersome side effects. Future research studies evaluating combination therapy for urgency urinary incontinence should ideally(1) be performed as part of a randomized clinical trial,(2) evaluate non-responders to monotherapy,(3) evaluate combination therapy using medications with different mechanisms of action,(4) include clinically meaningful and patient reported outcomes when evaluating efficacy, and(5) include cost-effectiveness analyses to justify any increased cost by showing improvement in efficacy or reduction in side effects.

Genetic contributions to urgency urinary incontinence in women.

PURPOSE: We identify genetic variants associated with urgency urinary incontinence in postmenopausal women. MATERIALS AND METHODS: A 2-stage genome-wide association analysis was conducted to identify variants associated with urgency urinary incontinence. The WHI GARNET substudy with 4,894 genotyped post-reproductive white women was randomly split into independent discovery and replication cohorts. Genome-wide imputation was performed using IMPUTE2 with the 1000 Genomes ALL Phase I integrated variant set as a reference. Controls reported no urgency urinary incontinence at enrollment or followup. Cases reported monthly or greater urgency urinary incontinence and leaked sufficiently to wet/soak underpants/clothes. Logistic regression models were used to predict urgency urinary incontinence case vs control status based on genotype, assuming additive inheritance. Age, obesity, diabetes and depression were included in the models as covariates. RESULTS: Following quality control, 975,508 single nucleotide polymorphisms in 2,241 cases (discovery 1,102; replication 1,133) and 776 controls (discovery 405, replication 371) remained. Genotype imputation resulted in 9,077,347 single nucleotide polymorphisms and insertions/deletions with minor allele frequency greater than 0.01 available for analysis. Meta-analysis of the discovery and replication samples identified 6 loci on chromosomes 5, 10, 11, 12 and 18 associated with urgency urinary incontinence at p <10(-6). Of the loci 3 were within genes, the zinc finger protein 521 (ZFP521) gene on chromosome 18q11, the ADAMTS16 gene on chromosome 5p15 and the CIT gene on chromosome 12q24. The other 3 loci were intergenic. CONCLUSIONS: Although environmental factors also likely contribute, this first exploratory genome-wide association study for urgency urinary incontinence suggests that genetic variants in the ZFP521, CIT and ADAMTS16 genes might account for some of the observed heritability of the condition.

The effects of bilateral bipolar sacral neurostimulation on urinary bladder activity during filling before and after irritation in a rat model.

AIMS: To design an optimal rat model for studying sacral neurostimulation (SNS), and examine the effect of SNS on myogenic non-voiding contractions (NVC) during filling before and after intraluminal irritation. METHODS: Bilateral paired bipolar SNS was performed in 10 female urethane anesthetized Sprague-Dawley rats at the L6-S1 trunks at 10 Hz, 0.1 msec pulse duration and 0.15-0.80 mA (below motor threshold). Transvesical cystometry was performed before and during SNS under conditions of control (saline, N = 10) and irritation [0.25% acetic acid (AA), N = 5]. RESULTS: Functional bladder capacity (FBC) and NVC count were significantly increased during SNS under both control and irritation conditions (P < 0.01 for all). In six instances (four in control, two in irritation), micturition reflexes were completely inhibited by SNS resulting in overflow incontinence. Filling compliance, NVC period and NVC maximum amplitude were not affected by SNS (P > 0.05 for all). Non-parametric two-way analysis of variance for repeated measures revealed increased FBC and NVC count during SNS under both control and irritation conditions (P = 0.004 for both, N = 5 rats). Linear regression analysis of NVC count versus FBC revealed a slope significantly different than zero, independent of control or irritation conditions (slope 33.10 ± 2.43, R(2) = 0.81, P < 0.001). CONCLUSIONS: This model achieved reliable, reversible and robust increases in bladder capacity up to overflow incontinence at stimulations below somatic motor threshold. SNS dramatically increased FBC and reversed AA-induced changes without affecting the character of normal NVC associated with bladder filling. Increased number of NVC is simply a consequence of increased fill time.

The effects of Ins2(Akita) diabetes and chronic angiotensin II infusion on cystometric properties in mice.

AIMS: Diabetes is associated with both dysfunction of the lower urinary tract (LUT) and overactivity of the renin-angiotensin system (RAS). Although it is well known that the RAS affects normal LUT function, very little is known about RAS effects on the diabetic LUT. Accordingly, we investigated the effects of chronic angiotensin II (AngII) treatment on the LUT in a model of type 1 diabetes. METHODS: Ins2(Akita) diabetic mice (20 weeks old) and their age-matched background controls underwent conscious cystometric evaluation after 4 weeks of chronic AngII treatment (700 ng/kg/min by osmotic pump) or vehicle (saline). RESULTS: Diabetic mice had compensated LUT function with bladder hypertrophy. Specifically, micturition volume, residual volume, and bladder capacity were all increased, while voiding efficiency and pressure generation were unchanged as bladder mass, contraction duration, and phasic urethral function were increased. AngII significantly increased voiding efficiency and peak voiding pressure and decreased phasic frequency irrespective of diabetic state and, in diabetic but not normoglycemic control mice, significantly decreased residual volume and increased contraction duration and nonphasic contraction duration. CONCLUSIONS: The Ins2(Akita) diabetic mice had compensated LUT function at 20 weeks of age. Even under these conditions, AngII had beneficial effects on LUT function, resulting in increased voiding efficiency. Future studies should therefore be conducted to determine whether AngII can rescue the decompensated LUT function occurring in end-stage diabetic uropathy.

Urodynamic evaluation of female cats with idiopathic cystitis.

OBJECTIVE: To compare values of urodynamic measurements of cats with idiopathic cystitis (IC) with previously published data for healthy female cats. ANIMALS: 11 female cats with IC. PROCEDURES: 2 sequential cystometrograms and 2 urethral pressure profiles were obtained for each cat. All tracings were evaluated for evidence of overactive urinary bladder (OAB). Maximum urethral pressure (MUP), maximum urethral closure pressure (MUCP), and functional profile length were recorded. RESULTS: Only 3 cats had obvious micturition events. None of the 11 cats had evidence of OAB. Although not significant, threshold pressure was lower in cats with IC than in healthy cats (mean ± SD, 89.0 ± 12.0 cm H(2)O vs 75.7 ± 16.3 cm H(2)O, respectively); however, the total volume infused was significantly lower in cats with IC (4.8 ± 2.1 mL/kg vs 8.3 ± 3.2 mL/kg). The MUCP was significantly higher in cats with IC than in healthy cats (158.0 ± 47.7 cm H(2)O vs 88.9 ± 23.9 cm H(2)O, respectively). The MUP was also significantly higher in all portions of the urethra in cats with IC. CONCLUSIONS AND CLINICAL RELEVANCE: No evidence of OAB was identified in any cat evaluated; therefore, medications used to target this abnormality did not appear justified. The high MUCP in cats with IC suggested that α(1)-adrenoceptor antagonists or skeletal muscle relaxants may be useful in this disease, and if these data were applicable to male cats, then α(1)-adrenoceptor antagonism may help prevent recurrent obstructive IC. Further studies are indicated to determine the effects, if any, these drugs might have in cats with IC.

Evaluation of Host Immune Cellular and Extracellular Matrix Responses to Prolapse Mesh With and Without Tension in a Rat Model.

OBJECTIVES: We sought to determine whether vaginal host immune cellular and extracellular matrix responses are altered in a rat sacrocolpopexy model when lightweight polypropylene mesh is attached on tension versus without tension. METHODS: We performed hysterectomy and ovariectomy in 32 Sprague-Dawley rats. Animals were assigned to 4 groups (n = 8/group): (1) controls with sham operation only (control), (2) mesh sutured only on the vagina (vaginal mesh), (3) sacrocolpopexy without tension, and (4) sacrocolpopexy with tension. Ninety days later, we excised vagina-mesh complexes. A histomorphologic scoring system of hematoxylin/eosin and Masson trichrome stained slides was used to assess host inflammatory responses. The cellular inflammatory response was further quantified using (1) identification of M1 and M2 macrophage subsets and (2) quantification of proinflammatory and anti-inflammatory cytokines. The extracellular matrix response was evaluated by measuring (1) matrix metalloproteinase-2 and matrix metalloproteinase-9 levels and (2) type I/III collagen. RESULTS: Histomorphological tissue responses were greater in all groups with mesh compared with sham controls. Both sacrocolpopexy groups had similar scores, but each group scored significantly higher than the vaginal mesh group. Among the 4 groups, there were no statistically significant differences in M1 or M2 macrophage subsets, proinflammatory or anti-inflammatory cytokines, or extracellular matrix remodeling responses. CONCLUSIONS: Attachment of prolapse mesh resulted in an increased histologic inflammatory response independent of tension. Other markers of cellular inflammation and extracellular matrix remodeling showed no differences among experimental groups. Tension on lightweight polypropylene mesh did not significantly alter the host response in this rat sacrocolpopexy model.

Polycarbonate Urethane Mesh: A New Material for Pelvic Reconstruction.

OBJECTIVE: Polycarbonate urethane (PCU) is a new biomaterial, and its mechanical properties can be tailored to match that of vaginal tissue. We aimed to determine whether vaginal host immune and extracellular matrix responses differ after PCU versus lightweight polypropylene (PP) mesh implantation. METHODS: Hysterectomy and ovariectomy were performed on 24 Sprague-Dawley rats. Animals were divided into 3 groups: (1) PCU vaginal mesh, (2) PP vaginal mesh, and (3) sham controls. Vagina-mesh complexes or vaginas (controls) were excised 90 days after surgery. We quantified responses by comparing: (1) histomorphologic scoring of hematoxylin and eosin- and Masson trichrome-stained slides, (2) macrophage subsets (immunolabeling), (3) pro-inflammatory and anti-inflammatory cytokines (Luminex panel), (4) matrix metalloproteinase (MMP)-2 and -9 using an enzyme-linked immunosorbent assay, and (5) type I/III collagen using picrosirius red staining. RESULTS: There was no difference in histomorphologic score between PCU and PP (P = 0.211). Although the histomorphologic response was low surrounding all mesh fibers, groups with PCU and PP mesh had a higher histomorphologic score than the control group (P < 0.005 and P < 0.002, respectively). There were no differences between groups in terms of macrophage subsets, pro-inflammatory cytokines, anti-inflammatory cytokines, MMP-2 and MMP-9, or collagen ratio. CONCLUSIONS: Polycarbonate urethane, an elastomer with material properties similar to those of vaginal tissue, elicits minimal host inflammatory responses in a rat model. Because its implantation does not elicit more inflammation than currently used lightweight PP, using PCU for prolapse mesh warrants further investigation with larger animal models.

Differential vulnerabilities of urethral afferents in diabetes and discovery of a novel urethra-to-urethra reflex.

Urethral reflexes are important regulators of micturition, and impairment of urethral afferent neuronal function may disrupt coordinated bladder and urethral activity, thereby contributing to voiding dysfunction in lower urinary tract disorders. Chemical stimulation by intraurethral irritant solution perfusion was used to determine whether urethral afferent neuronal function is altered in diabetes mellitus (DM). Sprague-Dawley rats were studied 10 wk after streptozotocin injection to induce DM or vehicle alone. Escalating doses of capsaicin (0.1-30 microM) or acetic acid (0.01-1%; AA) were perfused intraurethrally while recording isovolumetric bladder activity, urethral perfusion pressure, and electromyography of the external urethral sphincter (EUS-EMG). Some rats were additionally treated with alpha-bungarotoxin, hexamethonium, or bilateral transection of the sensory branches of the pudendal nerves (PudSNx). Intraurethral capsaicin inhibited bladder contractions in six out of seven control rats but not in any of six DM rats. Low-frequency oscillations (LFOs) of intraurethral pressure were observed in five out of six control rats with capsaicin-induced bladder inhibition. In contrast, intraurethral AA inhibited bladder contractions and enhanced tonic EUS-EMG activity in six out of six control and five out of six DM rats. LFOs occurred in four out of six control and three of five DM rats with AA-induced bladder inhibition. Chemically induced bladder inhibition and LFOs were not prevented by alpha-bungarotoxin but were eliminated by PudSNx and hexamethonium. Finally, LFOs were followed by phasic EUS activity. These findings show that DM affects urethral afferent neurons differentially, compromising those expressing TRPV1 receptors. Urethral smooth muscle LFOs are neurogenically mediated and induce EUS activity, revealing the existence of a hitherto undescribed reflex pathway: a smooth-to-striated muscle urethra-to-urethra reflex.

Cross-talk and sensitization of bladder afferent nerves.

The coordination of pelvic physiologic function requires complex integrative sensory pathways that may converge both peripherally and/or centrally. Following a focal, acute irritative or infectious pelvic insult, these same afferent pathways may produce generalized pelvic sensitization or cross-sensitization as we show bi-directionally for the bladder and bowel in an animal model. Single unit bladder afferent recordings following intracolonic irritation reveal direct sensitization to both chemical and mechanical stimuli that's dependent upon both intact bladder sensory (C-fiber) innervation and neuropeptide content. Concurrent mastocytosis (preponderantly neurogenic) likely plays a role in long-term pelvic organ sensitization via the release of nociceptive and afferent-modulating molecules. Prolonged pelvic sensitization as mediated by these convergent and antidromic reflexive pathway may likewise lead to chronic pelvic pain and thus the overlap of chronic pelvic pain disorders.

Impact of diabetes and obesity on the prostate and urethra: implications to improved bladder dysfunction understanding and treatment.

PURPOSE: Alterations in bladder function are well documented in response to diabetes and obesity. Nonetheless, clinical manifestations of bladder dysfunction are diverse and the efficacy of available therapy is suboptimal. Since the bladder is only 1 component of the lower urinary tract, we explored existing evidence for the potential contribution(s) of other major lower urinary tract structures to diabetes and obesity related bladder dysfunction, namely the prostate and the urethra. MATERIALS AND METHODS: We performed a MEDLINE database search of the relevant literature. RESULTS: A relatively large literature exists on bladder dysfunction and the urethra. However, when additional search terms were added, such as prostate, diabetes and obesity, there was a dramatic decrease in the number of retrieved citations. These observations are consistent with the vanishingly small available literature on the impact of diabetes on prostatic biology and urethral function, and their potential impact on bladder physiology/dysfunction. The available literature documents significant alterations in prostatic biology and urethral function in the setting of diabetes and/or obesity. CONCLUSIONS: The observed diversity in diabetes and obesity related bladder dysfunction, and the variable efficacy of currently available treatments may be related at least in part to the differential impact of these disease states on the complex integration of bladder function with other structural components of the lower urinary tract, namely the urethra and the prostate. More comprehensive investigations of this system should lead to improved understanding of the mechanistic basis for the observed pathophysiology and identify novel treatment regimens.

The Distribution of Post-Void Residual Volumes in People Seeking Care in the Symptoms of Lower Urinary Tract Dysfunction Network Observational Cohort Study With Comparison to Asymptomatic Populations.

OBJECTIVE: To describe the distribution of post-void residual (PVR) volumes across patients with and without lower urinary tract symptoms (LUTS) and examine relationships between self-reported voiding symptoms, storage symptoms, and PVR. METHODS: PVR and demographic data were obtained from the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) observational cohort study. Self-reported symptoms were collected using the American Urological Association Symptom Index and the LUTS Tool. PVR values were obtained from 2 other cohorts: living kidney donors with unknown LUTS from the Renal and Lung Living Donors Evaluation Study (RELIVE), and continent women in the Establishing the Prevalence of Incontinence (EPI) study, a population-based study of racial differences in urinary incontinence prevalence. RESULTS: Across the 3 studies, median PVRs were similar: 26 mL in LURN (n = 880, range 0-932 mL), 20 mL in EPI (n = 166, range 0-400 mL), and 14 mL in RELIVE (n = 191, range 0-352 mL). In LURN, males had 3.6 times higher odds of having PVR > 200 mL (95% CI = 1.72-7.48). In RELIVE, median PVR was significantly higher for males (20 mL vs 0 mL, P= .004). Among women, only the intermittency severity rating was associated with a probability of an elevated PVR. Among men, incomplete emptying and burning severity rating were associated with a higher odds of elevated PVR, but urgency severity ratings were associated with lower odds of elevated PVR. CONCLUSION: Care-seeking patients have PVRs similar to those in people with unknown history of LUTS (RELIVE) and without self-reported LUTS (EPI). Although PVR was correlated with voiding symptoms, the mean differences only explain ∼2% of the variance.