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Abstract A dataset to describe exposed bedrock and surficial geology of Antarctica has been constructed by the GeoMAP Action Group of the Scientific Committee on Antarctic Research (SCAR) and GNS Science. Our group captured existing geological map data into a geographic information system (GIS), refined its spatial reliability, harmonised classification, and improved representation of glacial sequences and geomorphology, thereby creating a comprehensive and coherent representation of Antarctic geology. A total of 99,080 polygons were unified for depicting geology at 1:250,000 scale, but locally there are some areas with higher spatial resolution. Geological unit definition is based on a mixed chronostratigraphic- and lithostratigraphic-based classification. Description of rock and moraine polygons employs the international Geoscience Markup Language (GeoSciML) data protocols to provide attribute-rich and queryable information, including bibliographic links to 589 source maps and scientific literature. GeoMAP is the first detailed geological map dataset covering all of Antarctica. It depicts ‘known geology’ of rock exposures rather than ‘interpreted’ sub-ice features and is suitable for continent-wide perspectives and cross-discipline interrogation.

Background: Immunoglobulin supplies are limited; their access for patients diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) may have been difficult during the COVID-19 pandemic. Methods: A retrospective cross-sectional study was conducted with CIDP patients (n=16, 68.8% female, mean age 60.4±11.3) recruited from three Montreal tertiary care institutions. Inclusion criteria were patients over 18 years old who were receiving immunoglobulin treatment as of March 1st, 2020. Patients were asked to complete a questionnaire inquiring about changes in their immunoglobulin treatment during the pandemic and about their quality of life. Their charts were reviewed by an independent investigator. We used weighted chi-squared statistical tests and Cramer’s V correlation ratios to measure associations with treatment change. Results: Eighteen months after the pandemic started, 50% of patients were receiving the same treatment, 25% were receiving immunoglobulin treatment at a different frequency, 6.3% were receiving a different dose, 12.5% were receiving a different dose and frequency, and 6.3% were receiving a different treatment. Reasons associated with treatment change were worsening of neurological condition (18.8%; Cramer’s V=0.480; p-value=0.055), improvement of neurological condition (25%; Cramer’s V=0.577; p-value=0.021) and reduced availability of treatment (6.3%; Cramer’s V=0.258; p-value=0.302). There were no significant correlations between lower quality of life (p-value=0.323) or lower Rasch-built Overall Disability Scale score (p-value=0.574) and treatment change. Conclusion: Difficulty accessing immunoglobulin treatment was infrequent and not significantly associated with treatment change for CIDP patients during the COVID-19 pandemic. A larger multicentre study across multiple sites might identify other treatment access problems resulting from the pandemic.

Abstract To understand the contribution of mononuclear phagocytes (MNP), which include monocyte-derived intestinal macrophages, to the pathogenesis of inflammatory bowel disease (IBD), it is necessary to identify functionally-different MNP populations. We aimed to characterise intestinal macrophage populations in patients with IBD. We developed 12-parameter flow cytometry protocols to identify and human intestinal MNPs. We used these protocols to purify and characterize colonic macrophages from colonic tissue from patients with Crohn’s disease (CD), ulcerative colitis (UC), or non-inflamed controls, in a cross-sectional study. We identify macrophage populations (CD45+CD64+ HLA-DR+) and describe two distinct subsets, differentiated by their expression of the mannose receptor, CD206. CD206+ macrophages expressed markers consistent with a mature phenotype: high levels of CD68 and CD163, higher transcription of IL-10 and lower expression of TREM1. CD206− macrophages appear to be less mature, with features more similar to their monocytic precursors. We identified and purified macrophage populations from human colon. These appear to be derived from a monocytic precursor with high CCR2 and low CD206 expression. As these cells mature, they acquire expression of IL-10, CD206, CD63, and CD168. Targeting the newly recruited monocyte-derived cells may represent a fruitful avenue to ameliorate chronic inflammation in IBD.

Background: Frailty, an age-related decline in physiological reserve, is an increasingly important concept in the management of chronic diseases. The implications of frailty in people with rheumatoid arthritis are not well understood. We undertook a systematic review to assess prevalence of frailty in people with rheumatoid arthritis, and the relationship between frailty and disease activity or clinical outcomes. Methods: We searched four electronic databases (January 2001 to April 2021) for observational studies assessing the prevalence of frailty (any frailty measure) in adults (≥18 years) with rheumatoid arthritis, or analysing the relationship between frailty and disease activity or clinical outcomes (e.g. quality of life, hospitalisation or mortality) in people with rheumatoid arthritis. Study quality was assessed using an adapted Newcastle-Ottawa Scale. Screening, quality assessment and data extraction were performed independently by two reviewers. We used narrative synthesis. Results: We identified 17 analyses, from 14 different populations. 15/17 were cross-sectional. Studies used 11 different measures of frailty. Frailty prevalence ranged from 10% (frailty phenotype) to 36% (comprehensive rheumatologic assessment of frailty) in general adult populations with rheumatoid arthritis. In younger populations (60 or >65) prevalence ranged from 31.2% (Kihon checklist) to 55% (Geriatric 8 tool). Frailty was cross-sectionally associated with higher disease activity (10/10 studies), lower physical function (7/7 studies) and longer disease duration (2/5 studies), and with hospitalization and osteoporotic fractures (1/1 study, 3.7 years follow-up). Conclusion: Frailty is common in rheumatoid arthritis, including those aged

Objective. To compare patterns of associations of changes in mental and physical health dimensions of health-related quality of life (HRQoL) over time with relapse occurrence and changes in Expanded Disability Status Scale (EDSS) scores in patients with relapsing multiple sclerosis (RMS). Methods. This 24-month, phase IV, observational study enrolled 334 patients with RMS who received interferon β-1a 44 μg or 22 μg subcutaneously three times weekly. At each 6-month visit, patients completed the Multiple Sclerosis Quality of Life-54 (MSQOL-54) and site investigators assessed EDSS and recorded relapse occurrence. A generalized linear model procedure was used for multivariable analyses (per protocol) that explored unique associations of EDSS score change and relapse occurrence with MSQOL-54 physical health composite score (PCS) and mental health composite score (MCS). Results. HRQoL improved over 2 years among those who completed the study. Occurrence of ≥1 relapse was significantly associated with lower MSQOL-54 PCS and MCS. Changes in EDSS score were significantly associated with MSQOL-54 PCS, but not MCS. Conclusions. HRQoL assessments, particularly those that examine mental health, may provide information on the general health status of patients with RMS that would not be recognized using traditional clinician-assessed measures of disease severity and activity. This trial is registered with ClinicalTrials.gov; identifier: NCT01141751.

We estimate the extent of ecological impacts of the invasive Asian paper wasp across different landscapes in New Zealand. We used: (i) a baseline distribution layer (modelled via MaxEnt); (ii) Asian paper wasp nest density (from >460 field plots, related to their preferences for specific land cover categories); and (iii) and their foraging intensity (rates of foraging success, and the time available to forage on a seasonal basis). Using geographic information systems this information is combined and modelled across different landscapes in New Zealand in a step-wise selection process. The highest densities of Asian paper wasps were in herbaceous saline vegetation, followed closely by built-up areas, and then scrub and shrubland. Nest densities of 34 per ha, and occupancy rates of 0.27 were recorded for herbaceous saline vegetation habitats. However, the extent of impacts of the Asian paper wasp remains relatively restricted because of narrow climate tolerances and spatial restriction of preferred habitats. A step-wise process based on geographic information systems and species distribution models, in combination with factors such as distribution, density, and predation, create a useful tool that allows the extent of impacts of invasive species to be assessed across large spatial scales. These models will be useful for conservation managers as they provide easy visual interpretation of results, and can help prioritise where direct conservation action or control of the invader are required.

ObjectivesTo compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics.MethodsTreatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded.ResultsOverall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as "lack of efficacy" (3.3% vs. 1.7%), "scheduled stop" (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages.ConclusionsTreatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from "real-world" database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry.

OBJECTIVES: We conducted a prospective study, MSBASIS, to assess factors leading to first treatment discontinuation in patients with a clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS). METHODS: The MSBASIS Study, conducted by MSBase Study Group members, enrols patients seen from CIS onset, reporting baseline demographics, cerebral magnetic resonance imaging (MRI) features and Expanded Disability Status Scale (EDSS) scores. Follow-up visits report relapses, EDSS scores, and the start and end dates of MS-specific therapies. We performed a multivariable survival analysis to determine factors within this dataset that predict first treatment discontinuation. RESULTS: A total of 2314 CIS patients from 44 centres were followed for a median of 2.7 years, during which time 1247 commenced immunomodulatory drug (IMD) treatment. Ninety percent initiated IMD after a diagnosis of MS was confirmed, and 10% while still in CIS status. Over 40% of these patients stopped their first IMD during the observation period. Females were more likely to cease medication than males (HR 1.36, p = 0.003). Patients treated in Australia were twice as likely to cease their first IMD than patients treated in Spain (HR 1.98, p = 0.001). Increasing EDSS was associated with higher rate of IMD cessation (HR 1.21 per EDSS unit, p

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.

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., Competing Interests: N.Y.S. has a research grant with Medtronic Inc. The other authors report no conflict of interest., (Copyright © 2020 American Urogynecologic Society. All rights reserved.)

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., Competing Interests: N.Y.S. has a research grant with Medtronic Inc. The other authors report no conflict of interest., (Copyright © 2020 American Urogynecologic Society. All rights reserved.)

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., (© 2020 Wiley Periodicals LLC.)

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.

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.

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 (H 2 O 2 ) 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 H 2 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 H 2 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., (© 2019 Wiley Periodicals, Inc.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

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., (© 2018 Wiley Periodicals, Inc.)

Females and males differ significantly in gross anatomy and physiology of the lower urinary tract, and these differences are commonly discussed in the medical and scientific literature. However, less attention is dedicated to investigating the varied development, function, and biology between females and males on a cellular level. Recognizing that cell biology is not uniform, especially in the lower urinary tract of females and males, is crucial for providing context and relevance for diverse fields of biomedical investigation. This review serves to characterize the current understanding of biological sex differences between female and male lower urinary tracts, while identifying areas for future research. First, the differences in overall cell populations are discussed in the detrusor smooth muscle, urothelium, and trigone. Second, the urethra is discussed, including anatomic discussions of the female and male urethra followed by discussions of cellular differences in the urothelial and muscular layers. The pelvic floor is then reviewed, followed by an examination of the sex differences in hormonal regulation, the urinary tract microbiome, and the reticuloendothelial system. Understanding the complex and dynamic development, anatomy, and physiology of the lower urinary tract should be contextualized by the sex differences described in this review.

Objectives: The 2016 American Urogynecologic Society Prolapse Consensus Conference brought together thought leaders in the field of pelvic organ prolapse (POP). The goal was to identify critical areas of need for future research. This article summarizes the findings., Methods: Prior to the conference, 5 major focus areas were identified. Focus areas were explored over the 2-day conference. Clinicians, clinical and basic science researchers, and representatives from government agencies, industry, patient advocacy groups, and the public convened to identify the major gaps in knowledge in each of these focus areas., Results: The 5 major topics were as follows: (1) mechanistic research on pelvic supportive structures and how these are altered with pregnancy, delivery, and aging; (2) novel prostheses or implants that address pathophysiology and provide mechanical support; (3) large-scale community-based research; (4) clinical trials to optimize outcomes after POP surgery; and (5) evidence-based quality measures for POP outcomes. Key recommendations were made for each topic., Conclusions: Critical gaps in our knowledge were identified. These limit scientific discovery across all 5 topic areas. Further scientific progress would be advanced by (1) developing a standardized group of POP outcomes and quality measures for large trials and community-based research, (2) creating specimen biorepositories that are integrated with robust clinical data, and (3) developing collaborative teams with expertise from a variety of disciplines, convened to tackle our most challenging and complex scientific questions.

Aims: The present study aims to investigate the role of Akt in the regulation of urinary bladder organ hypertrophy caused by partial bladder outlet obstruction (pBOO)., Main Methods: Male rats were surgically induced for pBOO. Real-time PCR and western blot were used to examine the levels of mRNA and protein. A phosphoinositide 3-kinase (PI3K) inhibitor LY294002 was used to inhibit the activity of endogenous Akt., Key Findings: The urinary bladder developed hypertrophy at 2 weeks of pBOO. The protein but not mRNA levels of type I collagen and α-smooth muscle actin (αSMA) were increased in pBOO bladder when compared to sham control. The phosphorylation (activation) levels of Akt1 (p-Ser 473 ), mammalian target of rapamycin (mTOR), p70S6 kinase (p70S6K), and 4E-BP1 were also increased in pBOO bladder. LY294002 treatment reduced the phosphorylation levels of Akt1 and 4E-BP1, and the protein levels of type I collagen and αSMA in pBOO bladder. The mRNA and protein levels of proliferating cell nuclear antigen (PCNA) were increased in pBOO bladder, and PCNA up-regulation occurred in urothelial not muscular layer. LY294002 treatment had no effect on the mRNA and protein levels of PCNA in pBOO bladder. LY294002 treatment partially reduced the bladder weight caused by pBOO., Significance: pBOO-induced urinary bladder hypertrophy is attributable to fibrosis, smooth muscle cellular hypertrophy, and urothelium cell hyper-proliferation. Akt1-mediated protein synthesis in pBOO bladder contributes to type I collagen and αSMA but not PCNA up-regulation. Target of Akt1 is necessary but not sufficient in treatment of urinary bladder hypertrophy following pBOO., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: This is the 34th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January 2016, 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 9.50 [7.33, 14.6] (median [25%, 75%]) min, facilitating a near real-time national exposure and information database and surveillance system., Methods: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure., Results: In 2016, 2,710,042 closed encounters were logged by NPDS: 2,159,032 human exposures, 54,019 animal exposures, 490,215 information cases, 6687 human confirmed non-exposures, and 89 animal confirmed non-exposures. US PCs also made 2,718,022 follow-up calls in 2016. Total encounters showed a 2.94% decline from 2015, while health care facility (HCF) human exposure cases increased by 3.63% from 2015. All information calls decreased by 12.5% but HCF information calls increased 0.454%, and while medication identification requests (Drug ID) decreased 29.6%, human exposure cases were essentially flat, decreasing by 0.431%. Human exposures with less serious outcomes have decreased 2.59% per year since 2008 while those with more serious outcomes (moderate, major or death) have increased by 4.39% per year since 2000. The top five substance classes most frequently involved in all human exposures were analgesics (11.2%), household cleaning substances (7.54%), cosmetics/personal care products (7.20%), sedatives/hypnotics/antipsychotics (5.84%), and antidepressants (4.74%). As a class, sedative/hypnotics/antipsychotics exposures increased most rapidly, by 10.7% per year (2088 cases/year), over the last 15 years for cases showing more serious outcomes. The top five most common exposures in children age 5 years or less were cosmetics/personal care products (13.3%), household cleaning substances (11.1%), analgesics (9.21%), foreign bodies/toys/miscellaneous (6.48%), and topical preparations (5.07%). Drug identification requests comprised 28.1% of all information calls. NPDS documented 1977 human exposures resulting in death; 1492 (75.5%) of these were judged as related (RCF of 1 - undoubtedly responsible, 2 - probably responsible, or 3 - contributory)., Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures, despite a decrease in cases involving less serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national public health resource for collecting and monitoring US exposure cases and information calls. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g. foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the real-time surveillance of national and global public health.

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., (© 2016 Wiley Periodicals, Inc.)

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 (R 2  = 0.294, P = 0.009), while VAS score and interstitial cystitis problem index demonstrated a positive correlation with the changes (R 2  = 0.208, P = 0.012; R 2  = 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., (© 2016 Wiley Periodicals, Inc.)

Urologic and kidney problems are common in women across their life span and affect their daily life, including physical activity, sexual relations, social life, and future health. Urological health in women is still understudied and the underlying mechanisms of female urological dysfunctions are not fully understood. The Society for Women's Health Research (SWHR ® ) recognized the need to have a roundtable discussion where researchers and clinicians would define the current state of knowledge, gaps, and recommendations for future research directions to transform women's urological health. This report summarizes the discussions, which focused on epidemiology, clinical presentation, basic science, prevention strategies, and efficacy of current therapies. Experts around the table agreed on a set of research, education, and policy recommendations that have the potential to dramatically increase awareness and improve women's urological health at all stages of life., Competing Interests: Author Disclosure Statement No competing financial interests exist.

Objectives: The aim of this study was to characterize the response of the rat bladder neuromuscular system to intramural injection of onabotulinum toxin type A (BoNT/A) over 9 weeks using in vivo cystometry (CMG) and in vitro contractility (IVC)., Methods: Chronic bladder catheters were implanted in female Sprague-Dawley rats, and either (1) BoNT/A (10 units in 20 μL saline) or (2) saline (20 μL) was injected in 5 × 4 μL doses throughout the bladder wall. At 1, 3, 6, and 9 weeks after injection, conscious restrained CMG was performed. At each time point, 25% of each group (8 BoNT/A and 4 controls) was euthanized and bladders harvested for IVC. We measured IVC in response to electric field stimulation, carbachol, and potassium chloride., Results: In total, 47 animals were included; 31 underwent BoNT/A injection, and 16 received sham (saline). Bladder capacities did not differ significantly between groups for each time point. One week after injection BoNT/A animals exhibited significantly longer bladder contraction durations and lower voiding efficiencies compared with controls. By 3 weeks these values returned to control levels. For BoNT/A animals, contractile response to carbachol stimulation was enhanced at 3 weeks. Otherwise, there were no differences in IVC responses., Conclusions: One week after BoNT/A injection, prolonged bladder contractions are noted in rats. This may reflect supraspinal compensation for denervation by increasing the duration of efferent drive during voiding. After 3 weeks postinjection, we observed no differences in either CMG or IVC responses suggesting either compensatory efferent sprouting, increased gap junction formation, or loss of BoNT/A effect., Competing Interests: and Source Funding: The authors have nothing to declare..

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., (© 2016 Wiley Periodicals, Inc.)

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., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

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., (© 2014 Wiley Periodicals, Inc.)

Background: In urine, factors such as timing of voids, and duration at room temperature (RT) may affect the quality of recovered protein and metabolite data. Additives may aid with detection, but can add more complexity in sample collection or analysis. We aimed to identify the optimal urine processing protocol for clinically-obtained urine samples that allows for the highest protein and metabolite yields with minimal degradation., Methods: Healthy women provided multiple urine samples during the same day. Women collected their first morning (1 st AM) void and another "random void". Random voids were aliquotted with: 1) no additive; 2) boric acid (BA); 3) protease inhibitor (PI); or 4) both BA + PI. Of these aliquots, some were immediately stored at 4°C, and some were left at RT for 4 hours. Proteins and individual metabolites were quantified, normalized to creatinine concentrations, and compared across processing conditions. Sample pools corresponding to each processing condition were analyzed using mass spectrometry to assess protein degradation., Results: Ten Caucasian women between 35-65 years of age provided paired 1 st morning and random voided urine samples. Normalized protein concentrations were slightly higher in 1 st AM compared to random "spot" voids. The addition of BA did not significantly change proteins, while PI significantly improved normalized protein concentrations, regardless of whether samples were immediately cooled or left at RT for 4 hours. In pooled samples, there were minimal differences in protein degradation under the various conditions we tested. In metabolite analyses, there were significant differences in individual amino acids based on the timing of the void., Conclusions: For comparative translational research using urine, information about void timing should be collected and standardized. For urine samples processed in the same day, BA does not appear to be necessary while the addition of PI enhances protein yields, regardless of 4°C or RT storage temperature.

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., (© 2013 Wiley Periodicals, Inc.)

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.

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.

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.

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.

Calcium-activated potassium channels are attractive targets for the development of therapeutics for overactive bladder. In the current study, we addressed the role of calcium-activated potassium channels of small (SK; K(Ca)2) and intermediate (IK; K(Ca)3) conductance in bladder function pharmacologically. We identified and characterized a novel positive modulator of SK/IK channels, 4,5-dichloro-1,3-diethyl-1,3-dihydro-benzoimidazol-2-one (NS4591). In whole-cell patch-clamp experiments, NS4591 doubled IK-mediated currents at a concentration of 45 +/- 6 nM(n = 16), whereas 530 +/- 100 nM (n = 7) was required for doubling of SK3-mediated currents. In acutely dissociated bladder primary afferent neurons, the presence of SK channels was verified using apamin and 1-ethyl-2-benzimidazolinone. In these neurons, NS4591 (10 microM) inhibited the number of action potentials generated by suprathreshold depolarizing pulses. NS4591 also reduced carbachol-induced twitches in rat bladder detrusor rings in an apamin-sensitive manner. In vivo, NS4591 (30 mg/kg) inhibited bladder overactivity in rats and cats induced by capsaicin and acetic acid, respectively. In conclusion, the present study supports the involvement of calcium-activated potassium channels in bladder function and identifies NS4591 as a potent modulator of IK and SK channels that is effective in animal models of bladder overactivity.

The primary afferent neurotransmitter triggering the spinal micturition reflex after complete spinal cord injury (SCI) in the rat is unknown. Substance P detected immunohistochemically in the sacral parasympathetic nucleus was significantly higher in 12 SCI rats than in 12 spinally intact rats (P = 0.008), suggesting substance P as a plausible candidate for the primary afferent neurotransmitter. The effects of the tachykinin NK1 receptor antagonist L-733060 on the spinal micturition reflex were then determined by performing conscious cystometry in an additional 14 intact rats and 14 SCI rats with L-733060 (0.1-100 microg) administered intrathecally at L6-S1. L-733060 was without effect in intact rats, but blocked the spinal micturition reflex in 10 of 14 SCI rats and increased the intermicturition interval in 2 of 4 others at doses ranging from 10 to 100 microg. Both phasic and nonphasic voiding contractions, differentiated according to the presence of phasic external urethral sphincter (EUS) activity, were present in most SCI rats. Both types of contractions were blocked by high doses of L-733060. Interestingly, there was a relative decline in phasic voiding contractions at high doses as well as a decline in contraction amplitude in nonphasic voiding contractions. In other respects, cystometric variables were largely unaffected in either spinally intact or SCI rats. L-733060 did not affect tonic EUS activity at any dose except when the spinal micturition reflex was blocked and tonic activity was consequently lost. These experiments show that tachykinin action at spinal NK1 receptors plays a major role in the spinal micturition reflex in SCI rats.

Urethra-to-bladder and urethra-to-urethra reflexes appear to be important for coordination of proper voiding. Diabetes mellitus (DM) is known to result in afferent neuropathy. Neuropathic alterations in electrophysiological properties of urethral afferent neurons may therefore contribute to voiding dysfunction seen in diabetes mellitus. Accordingly, we studied urethral afferent neuronal somata in streptozotocin-induced DM or age-matched vehicle controls by whole-cell patch clamp at 5- or 10-week time points. One week prior to study, Fast Blue was injected into the proximal urethra to label urethral afferent neurons. A previously undescribed diminution of afferent neuronal voltage-dependent potassium currents was a prominent feature of urethral afferent neuropathy in DM, acting to increase neuronal excitability. Thus, unlike bladder afferent neurons, urethral afferent neurons may be hyperexcitable well into DM progression.

Purpose: The effects of short-term and long-term diabetes mellitus on urethral function were investigated to determine the contribution of urethral dysfunction to diabetes mellitus voiding dysfunction., Materials and Methods: Isovolumetric bladder pressure, urethral perfusion pressure and external urethral sphincter electromyography were measured in urethane anesthetized, female Sprague-Dawley rats (Charles River Laboratories, Wilmington, Massachusetts) 5 or 10 weeks after streptozotocin induced diabetes mellitus. Urethral responses to serial administration of the skeletal muscle blocker alpha-bungarotoxin, the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine and the alpha-adrenergic agonist L-phenylephrine were determined in diabetes mellitus and age matched controls., Results: Peak bladder pressures and contraction amplitudes were significantly decreased in diabetes mellitus rats. Detrusor-sphincter dyssynergia occurred in approximately 30% of diabetes mellitus rats but never in controls. Alpha-Bungarotoxin caused a greater decrease in baseline urethral perfusion pressure in diabetes mellitus rats than in controls (approximately 40% vs approximately 15%). Bladder contraction associated urethral smooth muscle relaxation amplitudes were significantly less in diabetes mellitus rats than in controls. N(omega)-nitro-L-arginine significantly suppressed urethral relaxation in controls but not in diabetes mellitus rats. L-phenylephrine significantly increased baseline urethral perfusion pressure in diabetes mellitus rats but not in controls. The unassociated conditions of insensitivity to N-nitro-L-arginine and hypersensitivity to L-phenylephrine were more common in 10-week diabetes mellitus rats than in control rats., Conclusions: Diabetes mellitus induced urethropathy is characterized by external urethral sphincter dysfunction, decreased urethral smooth muscle relaxation and nitric oxide responsiveness, and increased urethral smooth muscle responsiveness to alpha(1)-adrenergic agonists. These changes increase outlet resistance and, thereby, decrease voiding efficiency. This exacerbates voiding dysfunction, creating a vicious cycle of progressive lower urinary tract damage and dysfunction. Early intervention targeting outlet resistance may be indicated.

We recently demonstrated that treatment with the 5-HT(1A/7) receptor agonist [(R)-(+)-8-hydroxy-2-di-n-propylamino]tetralin (8-OH-DPAT) increases bladder capacity in chloralose-anesthetized female cats with chronic spinal cord injury. In the current study, we investigated the effects of 8-OH-DPAT on bladder capacity and external urethral sphincter (EUS) activity in urethane-anesthetized female rats (initial body mass 175-200 g) with chronic spinal cord injury (transsection at T10). Cystometric study took place 8-12 wk posttranssection. Intravesical pressure was monitored in urethane-anesthetized rats with a transvesical catheter, and EUS activity was assessed electromyographically. Spinal cord injury disrupts phasic activity of the EUS, resulting in decreased voiding efficiency and increased residual volume. 8-OH-DPAT induced a dose-dependent decrease in bladder capacity (the opposite of its effect in chronic spinal cord-injured cats) with an increase in micturition volume and decrease in residual volume resulting from improvement in voiding efficiency. The unexpected improvement in voiding efficiency can be explained by the 8-OH-DPAT-induced emergence of phasic EUS relaxation. Phasic EUS relaxation was also altered by 8-OH-DPAT in spinally intact rats, whereas the 5-HT(1A) receptor antagonist N-tert-butyl-3-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-phenylpropanamide (WAY-100635), on its own, was without effect. It remains to be determined when phasic relaxation is restored after spinal cord injury, and indeed whether it is ever truly lost or is only temporarily separated from excitatory input.

Dichotomizing afferents are individual dorsal root ganglion (DRG) neurons that innervate two distinct structures thereby providing a form of afferent convergence that may be involved in pelvic organ cross-sensitization. To determine the distribution of dichotomizing afferents supplying the distal colon and bladder of the Sprague-Dawley rat and the C57Bl/6 mouse, we performed concurrent retrograde labeling of urinary bladder and distal colon afferents using cholera toxin subunit B (CTB) fluorescent conjugates. Animals were perfused 4-5 days after sub-serosal organ injections, and the T10-S2 DRG were removed, sectioned, and analyzed using confocal microscopy. In the rat, CTB-positive afferents retrogradely labeled from the bladder were nearly three times more numerous than those labeled from the distal colon, while in the mouse, each organ was equally represented. In both species, the majority of colon and bladder afferents projected from lumbosacral (LS) ganglia and secondarily from thoracolumbar (TL) ganglia. In the rat, 17% of the total CTB-positive neurons were retrogradely labeled from both organs with 11% localized in TL, 6% in LS, and 0.8% in thoracic (TH) ganglia. In the mouse, 21% of the total CTB-positive neurons were dually-labeled with 12% localized in LS, 4% in TH, and 4% in TL ganglia. These findings support the existence of dichotomizing pelvic afferents, which provide a pre-existing neuronal substrate for possible immediate and maintained pelvic organ cross-sensitization and ultimately may play a role in the overlap of pelvic pain disorders.

Aims: Chronic pelvic pain disorders often overlap. We have shown that acute colonic irritation can produce acute irritative micturition patterns and acutely sensitize bladder afferent responses to mechanical and chemical stimuli. We hypothesize that with time, colonic irritation can lead to neurogenic changes in the bladder and the development of chronic bladder sensitization., Methods: Micturition patterns were measured in rats 60-90 days after the induction of trinitrobenzenesulfonic acid (TNBS) colitis in the resolution phase of this model. Total and activated mast cells (MCs) were quantified in the bladder, while mRNA levels of stem cell factor (SCF; a.k.a. MC growth factor) and nerve growth factor (NGF; a MC and nociceptive C-fiber stimulator) were quantified in the bladder and L6-S1 dorsal root ganglia (DRG)., Results: Following intra-rectal TNBS, voiding volume was reduced (P < 0.005), while voiding frequency was increased (P < 0.05), both by approximately 50%. Furthermore, both the percentage and density of activated bladder MCs were significantly elevated (P < 0.05), although total MC counts were not statistically increased. At the molecular level, urinary bladder SCF expression increased twofold (P < 0.005), as did NGF (P < 0.01), while L6-S1 DRG levels were not significantly elevated., Conclusions: Chronic cystitis in the rat as evidenced by changes in micturition patterns and the recruitment of activated MCs can occur during the resolution phase of TNBS colitis. These changes, of which MCs may play an important role, appear to be maintained over time and may occur via stimulation of convergent pelvic afferent input resulting in the upregulation of neurotrophic factors in the target organ., ((c) 2007 Wiley-Liss, Inc.)

Chronic pelvic pain (CPP) disorders frequently overlap. We have demonstrated that acute and chronic colonic irritation can lead to neurogenic cystitis. We hypothesize that acute colonic irritation can sensitize urinary bladder afferents to mechanical and chemical stimuli. Single-unit afferent activity was recorded from fine filaments of the pelvic nerve in urethane-anesthetized Sprague-Dawley female rats before and 1 h after intracolonic administration of trinitrobenzenesulfonic acid (TNBS). Only spontaneously active afferents with receptive fields in the bladder and conduction velocities <2.5 m/s (unmyelinated C-fibers) were studied. Mechanical sensitivity was tested by bladder distension (BD) during saline infusion, whereas chemical sensitivity was tested with intravesical capsaicin, bradykinin, or substance P. Colonic irritation increased the resting firing rate of bladder afferents twofold (1.0 +/- 0.2 vs. 0.49 +/- 0.2 impulses/s, P < 0.05). Moreover, at low-pressure BDs (10-20 mmHg), a greater percentage of afferents exhibited increased activity following TNBS (73 vs. 27%, P < 0.05). Although the magnitude of the afferent response to BD was unchanged at low pressures, the response was greatly enhanced at pressures 30 mmHg and above (2.36 +/- 0.56 vs. 8.55 +/- 0.73 impulses/s, P < 0.05). Responses to capsaicin, bradykinin, and substance P were also significantly enhanced following TNBS, and all responses were blocked by bladder denervation. In rats, colonic irritation sensitizes urinary bladder afferents to noxious mechanical and chemical stimuli. Interruption of the neural input to the bladder minimized this effect, suggesting a local afferent pathway from the colon. Thus, the overlap of CPP disorders may be a consequence of pelvic afferent cross-sensitization.

Background & Aims: Irritable bowel syndrome, interstitial cystitis, and other chronic pelvic pain (CPP) disorders often occur concomitantly. Neural cross-talk may play a role in the overlap of CPP disorders via the convergence of pelvic afferents. We investigated the hypothesis that afferent irritation of one pelvic organ may adversely influence and sensitize another via neural interactions., Methods: We measured pelvic organ smooth muscle and striated muscle reflexes during micturition and colorectal distention (CRD) in urethane-anesthetized rats. The effects of acute cystitis on distal colonic sensory thresholds to CRD and the effects of acute colonic irritation on micturition parameters were assessed., Results: External urethral sphincter (EUS) electromyography (EMG) was typical for the rat, with phasic firing during micturition. External anal sphincter EMG also showed phasic firing during micturition in synchrony with EUS activity but, in addition, showed both tonic bursts and phasic firing independent of EUS activity. Before bladder irritation, graded CRDs to 40 cm H2O produced no notable changes in abdominal wall EMG activity. Following acute bladder irritation, dramatic increases in abdominal wall EMG activity in response to CRD were observed at much lower distention pressures, indicating colonic afferent sensitization. Analogously, following acute colonic irritation, bladder contraction frequency increased 66%, suggesting sensitization of lower urinary tract afferents., Conclusions: We report compelling evidence of bidirectional cross-sensitization of the colon and lower urinary tract in a novel experimental model. This cross-sensitization may account for the substantial overlap of CPP disorders; however, further studies are needed to fully characterize these pathways.

In higher primates, the mechanisms that govern the ontogeny of gonadotropin-releasing hormone pulse generator activity and that, therefore, dictate the timing of the onset of puberty remain intriguingly elusive. Groups of three infant agonadal male monkeys were treated with sex steroids [17beta-estradiol (E(2)), testosterone (T), or dihydrotestosterone (DHT)] for the first year of life to advance bone age (BA). E(2) and T resulted in a significant advancement of BA, and a pubertal BA of 130 wk was attained at a mean chronological age of 64 and 67 wk, respectively. In contrast, DHT failed to advance BA during treatment but stimulated linear growth. All animals exhibited a pubertal resurgence in LH secretion, but the timing of this developmental event did not differ between treatment and control groups (the mean for all animals was 117.7 +/- 8.9 wk). Two of the three T-treated animals, however, displayed a pubertal LH resurgence at a remarkably young age (70 and 76 wk of age) that coincided with T withdrawal. During the period of steroid treatment, all three groups were significantly heavier than the controls. The rate of body weight gain was most rapid in the DHT-treated group. Steroid treatments also resulted in accelerated linear growth. Body weight gain and linear growth continued at the same rate as controls after withdrawal of treatment. These data indicate that attainment of a pubertal BA may be a necessary but not a sufficient factor to trigger the onset of puberty. The results not only are consistent with the view that androgen-induced skeletal maturation in males is mediated by estrogen receptor activity but also indicate that androgen receptor activity contributes to the pubertal growth spurt in males.

Lower urinary tract dysfunction encompasses a number of different pathologies, and affects the lives of millions of patients worldwide. Although several pharmaceutical companies have been involved in urological drug discovery over the last several years, therapeutic options remain limited. The mainstay of treatment for overactive bladder and urinary incontinence for several years has been antimuscarinic agents. While additional antimuscarinic compounds are currently undergoing clinical development, next generation compounds aimed at novel targets and mechanisms of action are in clinical and preclinical development. This review highlights new compounds and approaches under clinical investigation by various pharmaceutical companies. These novel therapeutic strategies offer the promise of expanded treatment options for patients suffering from these disorders.

Purpose: We investigated the effects of diabetes mellitus (DM) on urethral relaxation mechanisms during reflex bladder contractions in rats., Materials and Methods: Five weeks after streptozotocin injection (65 mg/kg intraperitoneally) the effects of DM on urethral relaxation mechanisms were evaluated by simultaneous recordings of intravesical pressure under isovolumetric conditions and urethral perfusion pressure (UPP) using urethane anesthesia., Results: In diabetic rats the UPP nadir during urethral relaxation and intravesical pressure thresholds for inducing urethral relaxation were significantly higher (199% and 92%, respectively) than in normal rats, while baseline UPPs were not significantly different. The mean rate and amplitude of high frequency oscillations of urethral striated muscle in diabetic rats were also significantly lower (17% and 64%, respectively) compared with normal rats. Following alpha-bungarotoxin treatment to eliminate striated muscle sphincter contractions intravenous administration of L-arginine (200 mg/kg) [corrected] , the substrate of nitric oxide (NO) synthase, decreased the UPP nadir (36% and 22%, in diabetic and normal rats) as well as intravesical pressure thresholds (49% and 22%, respectively). The effect was greater (61% to 126%) in diabetic rats than in normal rats. In each group of rats the effect of L-arginine was inhibited by Nomega-nitro-L-arginine (100 mg/kg intravenously) [corrected], a NO synthase inhibitor., Conclusions: During reflex bladder contractions streptozotocin induced diabetic rats exhibited smooth and striated muscle dysfunctions of the urethral outlet. L-arginine therapy, which could augment urethral smooth muscle relaxation by increasing NO production, may be useful for partially restoring the urethral relaxation mechanism in DM.