Male Akita mice develop signs of bladder underactivity independent of NLRP3 as a result of a decrease in neurotransmitter release from efferent neurons.

Diabetic bladder dysfunction (DBD) is a prevalent diabetic complication that is recalcitrant to glucose control. Using the Akita mouse model (type 1) bred to be NLR family pyrin domain containing 3 (NLRP3)+/+ or NLRP3-/-, we have previously found that females (mild hyperglycemia) progress from an overactive to underactive bladder phenotype and that this progression was dependent on NLRP3-induced inflammation. Here, we examined DBD in the male Akita mouse (severe hyperglycemia) and found by urodynamics only a compensated underactive-like phenotype (increased void volume and decreased frequency but unchanged efficiency). Surprisingly, this phenotype was still present in the NLRP3-/- strain and so was not dependent on NLRP3 inflammasome-induced inflammation. To examine the cause of the compensated underactive-like phenotype, we assessed overall nerve bundle density and afferent nerve bundles (Aδ-fibers). Both were decreased in density during diabetes, but denervation was absent in the diabetic NLRP3-/- strain so it was deemed unlikely to cause the underactive-like symptoms. Changes in bladder smooth muscle contractility to cell depolarization and receptor activation were also not responsible as KCl (depolarizing agent), carbachol (muscarinic agonist), and α,ß-methylene-ATP (purinergic agonist) elicited equivalent contractions in denuded bladder strips in all groups. However, electrical field stimulation revealed a diabetes-induced decrease in contractility that was not blocked in the NLRP3-/- strain, suggesting that the bladder compensated underactive-like phenotype in the male Akita mouse is likely through a decrease in efferent neurotransmitter release.NEW & NOTEWORTHY In this study, we show that diabetic bladder dysfunction (the most common diabetic complication) manifests through different mechanisms that may be related to severity of hyperglycemia and/or sex. Male Akita mice, which have severe hyperglycemia, develop bladder underactivity as a result of a decrease in efferent neurotransmitter release that is independent of inflammation. This contrasts with females, who have milder hyperglycemia, where diabetic bladder dysfunction progresses from overactivity to underactivity in an inflammation-dependent manner.

Infection rates following urologic prosthetic revision without replacement of any device components compared to partial or complete device exchange: a single-center retrospective cohort study.

Urologic implant revision carries a higher infection risk than virgin implantation. Historically, exchanging device components at the time of revision was performed to reduce infection risk. We hypothesize that revision without replacement of any parts of the device may not be associated with increased infection risk. A single-center, retrospective cohort study was performed on patients undergoing urologic implant revision from 2000 to 2021. Revisions involving exchange of any/all device components (+CE) were compared to revisions without exchange of any components (-CE). The primary outcome was infection or erosion within 12 weeks of revision. Infection rates were compared using Fischer exact test. Infection-free survival (IFS) was compared with Kaplan-Meier (KM) log-rank test and Cox proportional hazards (CPH) model. 551 revisions were included, including 497 revisions with CE and 54 without CE. Among those with at least 12 weeks follow-up, no difference was seen in infection rates within 12 weeks of revision [-CE 3/39 (7.7%) vs. +CE 10/383 (2.6%)], p = 0.109). In addition, IFS was comparable between groups (log-rank test p = 0.22, HR for -CE 1.65 (0.65-4.21). Revision surgery for IPP or AUS without CE may not present an elevated risk of infection in the properly selected patient.

Diabetic bladder dysfunction progresses from an overactive to an underactive phenotype in a type-1 diabetic mouse model (Akita female mouse) and is dependent on NLRP3.

AIMS: Diabetic bladder dysfunction (DBD) is a prevalent diabetic complication thought to progress from overactive (OAB) to underactive (UAB) bladder. Previously we found OAB at 15 weeks in the Akita mouse, a genetic model of Type 1 diabetes. The first aim of this study assesses bladder function at 30 weeks to assess progression. In addition, inflammation triggered by the NLRP3 inflammasome is implicated in DBD. In a second aim we assessed a role for NLRP3 by crossing Akita mice with NLRP3-/- mice. MAIN METHODS: Akita mice were bred with NLRP3-/- mice. The effect of diabetes was assessed by comparing nondiabetic to diabetic mice (all NLRP3+/+). The effect of diabetes in the absence of the NLRP3 inflammasome was assessed by comparing nondiabetic/NLRP3-/- to diabetic/NLRP3-/- mice. Mice were assessed at 30 weeks for blood glucose (glucometer), inflammation (Evans blue), bladder morphology (histology) and bladder function (urodynamics). KEY FINDINGS: At 30 weeks blood glucose of nondiabetics and diabetics was not affected by the presence of absence of NLRP3. Diabetic/NLRP3+/+ mice showed bladder inflammation and detrusor hypertrophy which was blocked in the diabetic/NLRP3-/- mice, clearly showing a role for NLRP3. When bladder function was examined, diabetic/NLRP3+/+ showed an increase in voiding volume and a decrease in frequency, two signs of underactive bladder. However, in the NLRP3-/- mice, diabetes was unable to effectuate these changes, demonstrating that NLRP3-induced inflammation is responsible for UAB symptoms in these mice. SIGNIFICANCE: Akita diabetic mice progress from OAB to UAB. NLRP3 is a possible target to treat DBD.

Specialized pro-resolution mediators in the bladder: Receptor expression and recovery of bladder function from cystitis.

Inflammation is a central process in most benign bladder disorders, and its control is a delicate balance between initiating factors and resolving factors. While recent discoveries have shown a central role for the NLRP3 inflammasome in initiation, the resolving pathways remain unexplored. Resolution is controlled by specialized pro-resolution mediators (SPMs) functioning through seven receptors (six in rodents). Here we demonstrate expression of all seven in humans (six in mice) through immunocytochemistry. Expression was universal in urothelia with most also expressed in smooth muscle. We next explored the therapeutic potential of three SPMs; Resolvin E1 (RvE1), Maresin 1 (MaR1), and Protectin D1 (PD1). SPMs promote epithelial wound/barrier repair and RvE1 triggered dose-dependent wound closure in urothelia in vitro (scratch assay) (EC90 = 12.5 nM). MaR1 and PD1 were equally effective at this concentration. In vivo analyses employed a cyclophosphamide (CP) model of bladder inflammation (Day 0-CP [150 mg/kg], Day 1 to 3 SPM [25 µg/kg/day], Day 4 - analysis). All three SPMs reduced bladder inflammation (Evans blue) and bladder weights to control levels. Effects of RvE1 were also examined by urodynamics. CP decreased void volume, increased frequency and decreased bladder capacity while RvE1 restored values to control levels. Finally, SPMs reduce fibrosis and RvE1 reduced urothelial expression of TGF-ß and collagen I to control values. Together these results expand the known SPMs active in the bladder tissue and provide promising therapeutic targets for controlling inflammation in a wide variety of inflammation-associated benign bladder diseases.

Small Diameter Penile Implants: A Survey on Current Utilization and Review of Literature.

BACKGROUND: Inflatable penile prostheses (IPPs) with smaller diameter cylinders have been in use for over 30 years, yet the literature is sparse on their utilization patterns amongst prosthetic surgeons. AIM: To understand current usage of small diameter penile implants (SDPI) among prosthetic surgeons. METHODS: IRB approval was obtained to conduct a survey of prosthetic surgeons. A 23-question online survey was distributed via email to physician members of the Sexual Medicine Society of North America (SMSNA) and Society of Urologic Prosthesis Surgeons (SUPS). The survey included questions regarding surgeon experience and volume, frequency of SDPI utilization, indications for SDPI, surgical strategy in the setting of SDPI (approach, use of concordant modeling/grafting), reservoir and pump management, and perceived infection risk and patient satisfaction. MAIN OUTCOME MEASURE: SDPI were utilized by the vast majority of respondents in certain clinical situations such as corporal fibrosis or anatomically small corpora, and surgeons have had a favorable experience with these as a final destination implant or as a place-holder until reimplantation with a normal diameter device. RESULTS: Fifty individuals responded to the survey, 48 of whom routinely utilized SDPI. The most common indication for SDPI placement was corporal fibrosis from prior infection, followed by anatomically small corpora and priapism. The most common maximal dilation diameter was 10 mm (47%), an additional 23% of respondents utilized SDPI with 11 mm dilation. 75.4% of respondents sometimes or always intended to upsize to standard diameter cylinders in the future. 68.8% of surgeons routinely counseled patients on the possibility of reduced grith and rigidity with SDPI. Patient satisfaction was perceived to be comparable to standard diameter cylinders in 56.3% of respondents, while the remaining 43.6% believed it to be lower than traditional cylinders. Utilization of SDPI can be an important tool for prosthetic surgeons faced with difficult cases due to corporal fibrosis or small corpora. This survey provides new insight into patterns of SDPI utilization by surgeons. A limitation of the study is that patient satisfaction is indirectly addressed through surgeons' perception and experience, further research will be necessary to include patient questionnaires regarding device satisfaction. CONCLUSION: SDPI are necessary in certain scenarios that preclude the use of normal diameter cylinders. These implants may offer satisfactory erections, but can also be upsized to standard diameter cylinders in the future. Campbell SP, Kim CJ, Allkanjari A et al. Small Diameter Penile Implants: A Survey on Current Utilization and Review of Literature. Sex Med 2022;10:100458.

Update on the Medical and Surgical Management of Urethral Condyloma.

INTRODUCTION: Condyloma acuminata (CA) of the urethra presents a management challenge due to high recurrence rates, difficulty in accessing urethral lesions, risk of stricture formation, and potential for sexual dysfunction. While standard treatment modalities are acceptable for some external genital condyloma, they are not always feasible or appropriate for urethral lesions. OBJECTIVES: We sought to review the literature on epidemiology, presentation, diagnosis and treatment of urothelial CA with a focus on surgical treatment options. METHODS: We performed a comprehensive literature search of PubMed to identify all studies pertaining to urethral CA through November 2020. RESULTS: Urethral CA is a relatively rare, but challenging disease to manage with a considerable amount of treatment side effects and downstream morbidity associated. In our comprehensive review we have found a wide selection of treatment modalities ranging from minimally invasive strategies to surgical reconstructive techniques. Proper follow-up to monitor for disease recurrence at the 3-4 month mark is appropriate and will determine subsequent treatment strategies as needed. Future studies and treatment directions include novel drug delivery models to optimize minimally invasive topical drug efficacy. CONCLUSION: Treatment of urethral CA should be approached in a step-wise fashion. Medical therapy would be an appropriate option for asymptomatic or minimally symptomatic patients with small lesions who desire to avoid any interventions. If patient is symptomatic, has extensive disease burden or has failed medical therapy intervention should be considered with options including PDT, laser ablation or surgical excision with or without urethral reconstruction. Appropriate selection depends on patient characteristics and preferences along with prior treatment history. Kim CJ, Campbell SP, Allkanjari A, et al. Update on the Medical and Surgical Management of Urethral Condyloma. Sex Med Rev 2022;238-252.

Specialized proresolution mediators in the bladder: annexin-A1 normalizes inflammation and bladder dysfunction during bladder outlet obstruction.

Bladder outlet obstruction (BOO) is ultimately experienced by ≈90% of men, most commonly secondary to benign prostatic hyperplasia. Inflammation is a critical driver of BOO pathology in the bladder and can be divided into two critical steps: initiation and resolution. Although great strides have been made toward understanding the initiation of inflammation in the bladder [through the NLR family pyrin domain containing 3 (NLRP3) inflammasome], no studies have examined resolution. Resolution is controlled by five classes of compounds known as specialized proresolving mediators (SPMs), all of which bind to one or more of the seven different receptors. Using immunocytochemistry, we showed the presence of six of the known SPM receptors in the bladder of control and BOO rats; the seventh SPM receptor has no rodent homolog. Expression was predominantly localized to urothelia, often with some expression in smooth muscle, but little to none in interstitial cells. We next examined the therapeutic potential of the annexin-A1 resolution system, also present in control and BOO bladders. Using the peptide mimetic Ac2-26, we blocked inflammation-initiating pathways (NLRP3 activation), diminished BOO-induced inflammation (Evans blue dye extravasation), and normalized bladder dysfunction (urodynamics). Excitingly, Ac2-26 also promoted faster and more complete functional recovery after surgical deobstruction. Together, the results demonstrate that the bladder expresses a wide variety of potential proresolving pathways and that modulation of just one of these pathways can alleviate many detrimental aspects of BOO and speed recovery after deobstruction. This work establishes a precedent for future studies evaluating SPM effectiveness in resolving the many conditions associated with bladder inflammation.NEW & NOTEWORTHY To our knowledge, this is the first study of proinflammation-resolving pathways in the bladder, which is the basis of a new pharmacological genus-dubbed "resolution pharmacology" aimed at reducing inflammation without creating an immunocompromised state. Inflammation plays a causative or exacerbating role in numerous bladder maladies. We documented proresolution receptors in the rat bladder and the effectiveness of a specialized proresolving mediator, annexin-A1, in alleviating detrimental aspects of bladder outlet obstruction and speeding recovery after deobstruction.