Voluntary exercise improves voiding function and bladder hyperalgesia in an animal model of stress-induced visceral hypersensitivity: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome research network study.

OBJECTIVE: The underlying mechanism of interstitial cystitis/bladder pain syndrome (IC/BPS) is not well understood and evaluation of current therapeutic interventions has not identified any generally effective treatments. Physical activity has shown beneficial effects on individuals suffering from chronic pain. Anxiety-prone rats exposed to water avoidance stress (WAS) develop urinary frequency and lower bladder sensory thresholds with high face and construct validity for the study of IC/BPS. The aim of this study was to evaluate the role of chronic voluntary exercise on urinary frequency, voiding function, and hyperalgesia in animals exposed to WAS. MATERIALS AND METHODS: Twenty-six female Wistar-Kyoto rats were exposed to WAS and thereafter randomized to either voluntary exercise for 3 weeks or sedentary groups. Voiding parameters were assessed at baseline, post-WAS, and weekly for 3 weeks. Before euthanasia, the animals underwent cystometrogram (CMG), external urinary sphincter electromyography, and assessment of visceromotor response (VMR) to isotonic bladder distension (IBD). RESULTS: WAS exposure resulted in adverse changes in voiding parameters. Compared with sedentary animals, animals in the voluntary exercise group had improved voiding parameters during metabolic cage and CMG testing, as well as improved bladder sensory thresholds as determined by VMR during IBD. CONCLUSION: Voluntary exercise in an animal model of chronic stress leads to improvement in voiding function and visceral bladder hyperalgesia.

The effects of microenergy acoustic pulses on an animal model of obesity-associated stress urinary incontinence. Part 1: Functional and histologic studies.

AIM: Obesity is a strong independent risk factor for urinary incontinence. Effective therapeutic approaches for obesity-associated stress urinary incontinence (OA-SUI) are lacking as the mechanisms remain unclear. The aim of our study is to explore the impacts of microenergy acoustic pulse (MAP) therapy on urethral and pelvic floor muscle structure and function in female lean and fatty rats. METHODS: A total 24 Zucker fatty (ZF) and 24 Zucker lean (ZL) female 24-week-old rats were grouped into four groups: ZL control, ZLMAP, ZF control, and ZFMAP. For MAP treatment, 500 pulses were delivered at an energy level of 0.033 mJ/mm 2 and a frequency of 3 Hz and were applied twice a week for 4 weeks. After a 1-week washout, all rats underwent conscious cystometry and leak-point pressure (LPP) measurements followed by ex vivo organ-bath assay and histological study. RESULTS: ZF rats had lower LPP as compared to ZL rats, and MAP treatment significantly improved LPP in ZF rats (P < .05). Impaired muscle contractile activity (MCA) in organ-bath study was noted in ZF rats. MAP treatment significantly increased MCA in ZF rats (P < .05) and also increased the thickness of the striated muscle layer and the number of neuromuscular junctions (NMJs). In situ, MAP activated muscle satellite cells significantly (P < .05). CONCLUSIONS: Obesity impairs the function of both the urethral sphincter and the pelvic floor and leads to atrophy and distortion of the striated muscle in obese female rats. These issues contribute to OA-SUI. MAP improves continence by stimulating muscle regeneration and nerve innervation as well as by activating satellite cells.

Transgenic animal model for studying the mechanism of obesity-associated stress urinary incontinence.

OBJECTIVE: To study and compare the function and structure of the urethral sphincter in female Zucker lean (ZL) and Zucker fatty (ZF) rats and to assess the viability of ZF fats as a model for female obesity-associated stress urinary incontinence (SUI). MATERIALS AND METHODS: Two study arms were created: a ZL arm including 16-week-old female ZL rats (ZUC-Leprfa 186; n = 12) and a ZF arm including 16-week-old female ZF rats (ZUC-Leprfa 185; n = 12). I.p. insulin tolerance testing was carried out before functional study. Metabolic cages, conscious cystometry and leak point pressure (LPP) assessments were conducted. Urethral tissues were harvested for immunofluorescence staining to check intramyocellular lipid (IMCL) and sphincter muscle (smooth muscle and striated muscle) composition. RESULTS: The ZF rats had insulin resistance, a greater voiding frequency and lower LPP compared with ZL rats (P < 0.05), with more IMCL deposition localized in the urethral striated muscle fibres of the ZF rats (P < 0.05). The thickness of the striated muscle layer and the ratio of striated muscle to smooth muscle were lower in ZF than in ZL rats. CONCLUSION: Obesity impairs urethral sphincter function via IMCL deposition and leads to atrophy and distortion of urethral striated muscle. The ZF rats could be a consistent and reliable animal model in which to study obesity-associated SUI.

The role of environmental stress on lower urinary tract symptoms.

PURPOSE OF REVIEW: Lower urinary tract symptoms (LUTS) have been associated with comorbid conditions such as anxiety and depression. In addition, stress appears to influence the development or exacerbation of LUTS. This article seeks to review literature regarding the role of environmental stress on LUTS, focusing on findings presented in the last year. RECENT FINDINGS: Numerous authors have published on the impact early childhood experiences, acute and chronic stress, and psychiatric illness play in the development of LUTS. The exact nature of the association between bladder symptoms and psychosocial measures remains unknown and is likely due to a complex interplay between heritability, psychosocial factors, and environmental stress. The proposed pathophysiological pathways involved in emotional states such as anxiety and depression, stress, and bladder function include activation of the hypothalamic-pituitary axis, dysregulation of the serotonergic pathways, and central sensitization. Recent work has additionally suggested that urinary syndromes involving abnormal or augmented sensory input, such as overactive bladder and interstitial cystitis/bladder pain syndrome, may be a spectrum of the same disorder. SUMMARY: There are numerous developments in our understanding of the role of environmental stress on the development and exacerbation of LUTS with new developments both clinically and in translational basic science work. Clinicians must acknowledge the high prevalence of affective disorders in patients with LUTS and realize their potential therapeutic influence. Simply addressing mechanisms at the level of the bladder alone may fail in a subpopulation of patients with LUTS who may have significant psychosocial drivers of their symptoms.

Low-energy Shock Wave Therapy Ameliorates Erectile Dysfunction in a Pelvic Neurovascular Injuries Rat Model.

INTRODUCTION: Erectile dysfunction (ED) caused by pelvic injuries is a common complication of civil and battlefield trauma with multiple neurovascular factors involved, and no effective therapeutic approach is available. AIMS: To test the effect and mechanisms of low-energy shock wave (LESW) therapy in a rat ED model induced by pelvic neurovascular injuries. METHODS: Thirty-two male Sprague-Dawley rats injected with 5-ethynyl-2'-deoxyuridine (EdU) at newborn were divided into 4 groups: sham surgery (Sham), pelvic neurovascular injury by bilateral cavernous nerve injury and internal pudendal bundle injury (PVNI), PVNI treated with LESW at low energy (Low), and PVNI treated with LESW at high energy (High). After LESW treatment, rats underwent erectile function measurement and the tissues were harvested for histologic and molecular study. To examine the effect of LESW on Schwann cells, in vitro studies were conducted. MAIN OUTCOME MEASUREMENTS: The intracavernous pressure (ICP) measurement, histological examination, and Western blot (WB) were conducted. Cell cycle, Schwann cell activation-related markers were examined in in vitro experiments. RESULTS: LESW treatment improves erectile function in a rat model of pelvic neurovascular injury by leading to angiogenesis, tissue restoration, and nerve generation with more endogenous EdU(+) progenitor cells recruited to the damaged area and activation of Schwann cells. LESW facilitates more complete re-innervation of penile tissue with regeneration of neuronal nitric oxide synthase (nNOS)-positive nerves from the MPG to the penis. In vitro experiments demonstrated that LESW has a direct effect on Schwann cell proliferation. Schwann cell activation-related markers including p-Erk1/2 and p75 were upregulated after LESW treatment. CONCLUSION: LESW-induced endogenous progenitor cell recruitment and Schwann cell activation coincides with angiogenesis, tissue, and nerve generation in a rat model of pelvic neurovascular injuries.

De novo erectile dysfunction after anterior urethroplasty: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the likelihood of developing de novo erectile dysfunction (ED) after anterior urethroplasty and to determine if this likelihood is influenced by age, stricture length, number of previous procedures or timing of evaluation. MATERIALS AND METHODS: PubMed, Embase, Cochrane, and Google Scholar databases were searched for the terms 'urethroplasty', 'urethral obstruction', 'urethral stricture', 'sexual function', 'erection', 'erectile function', 'erectile dysfunction', 'impotence' and 'sexual dysfunction'. Two reviewers evaluated articles for inclusion based on predetermined criteria. RESULTS: In a meta-analysis of 36 studies with a total of 2323 patients, de novo ED was rare, with an incidence of 1%. In studies that assessed postoperative erectile function at more than one time point, ED was transient and resolved at between 6 and 12 months in 86% of cases. CONCLUSIONS: Men should be counselled regarding the possibility of transient or permanent de novo ED after anterior urethroplasty procedures. Increasing mean age was associated with an increased likelihood of de novo ED, but this was not statistically significant.

Exercise modulates neuronal activation in the micturition circuit of chronically stressed rats: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study.

BACKGROUND: Rats exposed to water avoidance stress (WAS) show increased urinary frequency, increased somatosensory nociceptive reflex responses, as well as altered brain responses to bladder distension, analogous to similar observations made in patients with urologic chronic pelvic pain syndrome (UCPPS). Exercise has been proposed as a potential treatment option for patients with chronic urinary frequency and urgency. We examined the effects of exercise on urinary voiding parameters and functional brain activation during bladder distension in rats exposed to WAS. METHODS: Adult, female Wistar Kyoto rats were exposed to 10 days of WAS and thereafter randomized to either voluntary exercise for 3 weeks or sedentary groups. Voiding parameters were assessed at baseline, post-WAS, and weekly for 3 weeks. Thereafter, cerebral blood flow (CBF) mapping was performed during isotonic bladder distension (20 cm H2O) after intravenous bolus injection of [14C]-iodoantipyrine. Regional CBF was quantified in autoradiographs of brain slices and analyzed in 3-D reconstructed brains by statistical parametric mapping. Functional connectivity was examined between regions of the micturition circuit through interregional correlation analysis. RESULTS: WAS exposure in sedentary animals (WAS/no-EX) increased voiding frequency and decreased urinary volumes per void. Exercise exposure in WAS animals (WAS/EX) resulted in a progressive decline in voiding frequency back to the baseline, as well as increased urinary volumes per void. Within the micturition circuit, WAS/EX compared to WAS/no-EX demonstrated a significantly lower rCBF response to passive bladder distension in Barrington's nucleus that is part of the spinobulbospinal voiding reflex, as well as in the periaqueductal gray (PAG) which modulates this reflex. Greater rCBF was noted in WAS/EX animals broadly across corticolimbic structures, including the cingulate, medial prefrontal cortex (prelimbic, infralimbic areas), insula, amygdala, and hypothalamus, which provide a 'top-down' decision point where micturition could be inhibited or triggered. WAS/EX showed a significantly greater positive brain functional connectivities compared to WAS/no-EX animals within regions of the extended reflex loop (PAG, Barrington's nucleus, intermediodorsal thalamic nucleus, pons), as well as within regions of the corticolimbic decision-making loop of the micturition circuit, with a strikingly negative correlation between these pathways. Urinary frequency was positively correlated with rCBF in the pons, and negatively correlated with rCBF in the cingulate cortex. CONCLUSION: Our results suggest that chronic voluntary exercise may decrease urinary frequency at two points of control in the micturition circuit. During the urine storage phase, it may diminish the influence of the reflex micturition circuit itself, and/or it may increase corticolimbic control of voiding. Exercise may be an effective adjunct therapeutic intervention for modifying the urinary symptoms in patients with UCPPS.

Does perception of catheterization limit its use in pediatric UTI?

INTRODUCTION: Urinary tract infections (UTIs) affect 3-8% of febrile children annually, but correctly diagnosing UTI in young children can present a challenge. Diagnosis requires a non-contaminated urine sample, which requires catheterization or suprapubic aspiration in infants and young children that have not completed toilet training. To improve adherence to these guidelines, it is critical to understand the barriers to urine testing and catheterization. OBJECTIVE: The purpose of this study was to investigate parental perception of pediatric UTI evaluation to better understand factors that impede urine testing prior to treatment of suspected UTI. STUDY DESIGN: We conducted an electronic, cross-sectional survey via social media targeting parents of children with a history of UTI. Participants were queried regarding demographics, urine specimen collection method, factors influencing urine collection method, and perception of the experience. Multivariable logistic regression was used to assess factors associated with catheterization distress and urine testing. RESULTS: Of 2726 survey respondents, > 80% were female and White; 74% of the children with a history of UTI were female. Fifty-six percent of parents perceived extreme distress with catheterization. Among parents whose child was catheterized, extreme distress was less likely perceived if the parent was White (OR 0.6, 95% CI 0.4-0.9) or if the child was circumcised (OR 0.7, 95% CI 0.4-0.98). Among those whose child was not catheterized, extreme distress was more likely if parents had a college education (OR 3.2, 95% CI 2.2-4.5) and the child was more than 1 year old (OR 1.7, 95% CI 1.2-2.5). Catheterization was less likely to be withheld if parents had a college education (OR 0.1, 95% CI 0.1-0.2), and if the child was circumcised (OR 0.5, 95% CI 0.3-0.8) or had only one UTI (OR 0.6, 95% CI 0.4-0.8) (Table). DISCUSSION: Parental education level, child age, and circumcision status play an important role in the subjective distress associated with catheterization. This highlights the substantial impact of parental factors on adherence to guidelines for children suspected of UTI. For example, college-educated parents were more likely to be offered catheterization. However, these parents are also more likely to associate the catheterization experience with extreme distress, possibly limiting their likelihood of consent to this procedure. More studies are required to better understand the impact of these factors on catheterization. But, it is clear that parental input has a substantial impact on the evaluation of their child's suspected UTI.

Neuromodulation in neurogenic bladder.

While neuromodulation is a well-established treatment option for patients with non-neurogenic overactive bladder and urinary retention, its applicability to the neurogenic bladder population has only recently been examined more in depth. In this article we will discuss the outcomes, contraindications, and special considerations of sacral and percutaneous tibial nerve stimulation (PTNS) in patients with neurogenic lower urinary tract dysfunction.

Role of Schwann cells in the regeneration of penile and peripheral nerves.

Schwann cells (SCs) are the principal glia of the peripheral nervous system. The end point of SC development is the formation of myelinating and nonmyelinating cells which ensheath large and small diameter axons, respectively. They play an important role in axon regeneration after injury, including cavernous nerve injury that leads to erectile dysfunction (ED). Despite improvement in radical prostatectomy surgical techniques, many patients still suffer from ED postoperatively as surgical trauma causes traction injuries and local inflammatory changes in the neuronal microenvironment of the autonomic fibers innervating the penis resulting in pathophysiological alterations in the end organ. The aim of this review is to summarize contemporary evidence regarding: (1) the origin and development of SCs in the peripheral and penile nerve system; (2) Wallerian degeneration and SC plastic change following peripheral and penile nerve injury; (3) how SCs promote peripheral and penile nerve regeneration by secreting neurotrophic factors; (4) and strategies targeting SCs to accelerate peripheral nerve regeneration. We searched PubMed for articles related to these topics in both animal models and human research and found numerous studies suggesting that SCs could be a novel target for treatment of nerve injury-induced ED.

The incidence of erectile dysfunction after pelvic fracture urethral injury: A systematic review and meta-analysis.

BACKGROUND: Pelvic fracture urethral injury (PFUI) is associated with a high risk of erectile dysfunction (ED). The effect of the type of posterior urethral disruption repair on erectile function has not been clearly established. We systematically reviewed and conducted a meta-analysis of the proportion of patients with ED at (i) baseline after pelvic fracture with PFUI, (ii) after immediate primary realignment, and (iii) after delayed urethroplasty. METHODS: Using search terms for primary realignment or urethroplasty and urethral disruption, we systematically reviewed PubMed and EMBASE. A meta-analysis of the proportion of patients with ED was conducted assuming a random-effects model. RESULTS: Of 734 articles found, 24 met the inclusion criteria. The estimate of the proportion (95% confidence interval) of patients with ED after (i) PFUI was 34 (25-45)%, after (ii) immediate primary realignment was 16 (8-26)%, and after (iii) delayed urethroplasty was an additional 3 (2-5)% more than the 34% after pelvic fracture in this cohort. CONCLUSIONS: After pelvic fracture, 34% of patients had ED. After primary endoscopic alignment, patients had a lower reported rate of ED (16%). Delayed urethroplasty conferred an additional 3% risk above the 34% associated with PFUI alone, with 37% of patients having de novo ED. The difference in de novo ED after primary endoscopic alignment vs. delayed urethroplasty is probably due to reporting differences in ED and/or patients with less severe injury undergoing primary realignment.

Novel therapeutic approach for neurogenic erectile dysfunction: effect of neurotrophic tyrosine kinase receptor type 1 monoclonal antibody.

BACKGROUND: Erectile dysfunction (ED) is a major health issue in aged populations, and neurogenic ED is particularly difficult to treat. Novel therapeutic approaches are needed for treatment of neurogenic ED of peripheral origin. OBJECTIVE: To investigate the therapeutic effects of a neurotrophic tyrosine kinase receptor type 1 monoclonal antibody (TrkA-mAb) on erectile function and sexual behavior in a rat model of cavernous nerve injury (CNI). DESIGN, SETTING, AND PARTICIPANTS: In one experiment, 84 male rats were randomly assigned to seven groups. The groups underwent either CNI or sham surgery, subsequent injection into the major pelvic ganglion (IMPG) of phosphate-buffered saline (PBS), an immunoglobulin G (IgG) control, or TrkA-mAb, and then intracavernosal (IC) injection of either PBS or varying TrkA-mAb concentrations immediately after surgery and then 1 wk later. Erectile function was assessed and histologic/molecular analyses were performed at 6 wk after surgery. In a second experiment, 36 male rats were randomly divided into three groups. The groups underwent CNI or sham surgery and then IC injection of PBS, IgG, or TrkA-mAb immediately after surgery and for 5 wk thereafter. At 6 wk after surgery, the performance of the rats in sexual behavior tests was videotaped. INTERVENTION: CNI or sham surgery; IMPG of PBS, IgG, or TrkA-mAb; IC injection of PBS or TrkA-mAb. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The intracavernous pressure response to cavernous nerve electrostimulation was measured and midpenile cross-sections were histologically examined. Western blotting (WB) of cavernous tissue protein was performed. Rats were assessed for chasing, mounting, intromission, and ejaculation behaviors during sexual behavior tests. The data were analyzed using one-way analysis of variance followed by the Tukey-Kramer t test. RESULTS AND LIMITATIONS: Recovery of erectile function of varying degrees was observed in the TrkA-mAb groups. TrkA-mAb treatment significantly suppressed tyrosine hydroxylase-positive nerve fibers in the corpus cavernosum and enhanced neuronal nitric oxide synthase-positive fibers in the dorsal nerve. The ratio of smooth muscle to collagen in the corpus cavernosum was significantly improved in TrkA-mAb treatment groups compared to PBS vehicle and IgG control groups. WB confirmed these biological changes. There was a nonsignificant increase in the average number of intromissions and ejaculations in the TrkA-mAb group. The study limitations include small sample size, variability in sexual behavior, lack of data on the neuromuscular mechanism involved, and lack of information of the role of neurotrophins or cytokines in regeneration. CONCLUSIONS: TrkA-mAb successfully inhibits sympathetic nerve regeneration, leads to parasympathetic nerve regeneration, and has therapeutic effects on ED and sexual behavior disorder in a rat model of CNI. PATIENT SUMMARY: This report provides strong evidence that a neurotrophic tyrosine kinase receptor type 1 monoclonal antibody (TrkA-mAb) inhibits sympathetic nerve regeneration, leads to parasympathetic nerve regeneration, and has therapeutic effects on erectile dysfunction and sexual behavior disorder in a rat model of cavernous nerve injury. The results raise the possibility that human patients with neurogenic erectile dysfunction may respond to TrkA-mAb in a manner that parallels the response seen in our rodent study.