LRRK2 secretion in exosomes is regulated by 14-3-3.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset Parkinson's disease (PD). Emerging evidence suggests a role for LRRK2 in the endocytic pathway. Here, we show that LRRK2 is released in extracellular microvesicles (i.e. exosomes) from cells that natively express LRRK2. LRRK2 localizes to collecting duct epithelial cells in the kidney that actively secrete exosomes into urine. Purified urinary exosomes contain LRRK2 protein that is both dimerized and phosphorylated. We provide a quantitative proteomic profile of 1673 proteins in urinary exosomes and find that known LRRK2 interactors including 14-3-3 are some of the most abundant exosome proteins. Disruption of the 14-3-3 LRRK2 interaction with a 14-3-3 inhibitor or through acute LRRK2 kinase inhibition potently blocks LRRK2 release in exosomes, but familial mutations in LRRK2 had no effect on secretion. LRRK2 levels were overall comparable but highly variable in urinary exosomes derived from PD cases and age-matched controls, although very high LRRK2 levels were detected in some PD affected cases. We further characterized LRRK2 exosome release in neurons and macrophages in culture, and found that LRRK2-positive exosomes circulate in cerebral spinal fluid (CSF). Together, these results define a pathway for LRRK2 extracellular release, clarify one function of the LRRK2 14-3-3 interaction and provide a foundation for utilization of LRRK2 as a biomarker in clinical trials.

Intralesional Injection of Interferon-α2b Improves Penile Curvature in Men with Peyronie's Disease Independent of Plaque Location.

PURPOSE: Collagenase clostridium histolyticum is the only FDA (Food and Drug Administration) approved treatment for Peyronie's disease. However, to our knowledge collagenase clostridium histolyticum has not been studied in men with ventral plaques. Given this limitation and the paucity of literature on ventral plaque outcomes, we compared the results of Peyronie's disease treatment in men with different plaque locations treated with intralesional interferon-α2b. MATERIALS AND METHODS: We retrospectively analyzed the records of men treated with intralesional interferon-α2b for Peyronie's disease at 1 institution from 2001 to 2014. The men received 2 million U interferon-α2b injected every 2 weeks for 6 to 24 treatments. All men underwent penile duplex Doppler ultrasound before and after interferon-α2b treatment. Patient characteristics, penile duplex Doppler ultrasound and objective measurements were reviewed. Patients were stratified into ventral and dorsal/lateral plaque cohorts with a positive response defined as a 20% or greater reduction in curvature. RESULTS: A total of 131 patients with a mean±SD age of 53.8±9.5 years underwent a median of 12 intralesional interferon-α2b injections (range 6 to 24). Mean pretreatment dorsal curvature was 42.5±18.6 degrees in group 1 of 111 men and mean ventral curvature was 44.5±21.5 degrees in group 2 of 21 men (p=0.66). Overall 91% of patients responded to therapy. No significant difference was noted between the 2 groups in response rate (54% vs 52%, p=0.92) or absolute change in curvature (mean 8.7±12.6 vs 9.3±17.7 degrees, p=0.84). CONCLUSIONS: Treatment with intralesional interferon-α2b provided a greater than 20% reduction in curvature in the majority of men with Peyronie's disease. This improvement was independent of plaque location.

Outcomes of Prophylactic Mid-Urethral Sling at the Time of Robotic Sacrocolpopexy.

OBJECTIVE: To compare outcomes of patients who underwent robotic sacrocolpopexy (RSC) with and without concomitant mid-urethral sling (MUS) placement for prophylaxis or treatment of preoperative stress urinary incontinence (SUI) METHODS: We performed a retrospective review of all patients without prior incontinence procedures who underwent RSC with or without MUS placement by 3 surgeons (JA, LA, KE) at a single institution from 2012 to 2017 for treatment of pelvic organ prolapse. Patients had a MUS placed for either documented SUI or prophylaxis of SUI. We compared patient characteristics, operative details, postoperative outcomes, and complications between the groups. RESULTS: A total of 134 patients were identified. 58 (43%) had a MUS placed for documented SUI, 43 (32%) had prophylactic MUS, and 33 (25%) did not have a MUS placed. There were no differences in baseline characteristics between the 3 groups. Patients who did not have a MUS placed had less estimated blood loss (76.4 vs 63.8 vs 36.9 mL, P = .018) but no difference in operative time (P = .408), length of stay (P = .427), or postoperative urinary retention (P = .988). A total of 4 (7%) patients who had a MUS placed for SUI had persistent SUI postoperatively. There were 2 (5%) patients who had a MUS placed prophylactically and 4 (12%) patients who did not have a MUS that developed de novo SUI. CONCLUSION: In this series, we demonstrate the safety and efficacy of prophylactic MUS placement at the time of RSC. Randomized studies evaluating concomitant prophylactic sling at time of robotic sacrocolpopexy could further guide preoperative patient counseling and decision-making.

Technology Based Treatment for UreteroPelvic Junction Obstruction.

Surgical management of ureteropelvic junction obstruction (UPJO) has historically been performed with open pyeloplasty. With the advent of endourology, laparoscopy, and robotics, minimally-invasive techniques have been described and accepted as alternatives to open surgery. Each of these approaches has its own advantages and disadvantages, equipment needs, degree of invasiveness, and experience of the treating urologist. Advocates and critics have their own say as to their preferred technique. In this article, we review the chronological evolution of these techniques and discuss their current role in the management of UPJO.

Flow characteristics of urethral catheters of the same caliber vary between manufacturers.

BACKGROUND: Clean intermittent catheterization (CIC) is frequently prescribed for bladder dysfunction, either per urethra or via a continent catheterizable channel. Small catheters may be required for infants or continent channels. Success with CIC is highly dependent upon patient and family compliance. The urinary flow rate through the catheter is an important factor, which can decrease CIC time and improve quality of life. There is little objective information regarding flow rate through urinary catheters to guide catheter recommendation or prescription. Clinically, we noted that there was a difference in flow among catheter brands, and we questioned if catheters of the same-labeled diameter exhibit the same flow characteristics, which could have implications for catheter selection. METHODS: Twenty-one commercially available male pediatric urinary catheters from nine brands were tested (11 straight tip, 10 coude tip). Nine of the 21 tested catheters had a hydrophilic coating. All tested catheters shared a 10F outer diameter. For each, microscopic imaging and a precision caliper were used to measure the inner diameter and tip inlet area. A hydraulic system modified from ASTM standard testing specifications was used to simulate bladder catheterization. Measurement of each catheter was repeated five times using three different static hydraulic pressures (20, 40 and 50 cmH2O). Catheter flow rate and structural measurements were identified and the fastest and slowest of the catheters are presented in the table. The variable flow rates between brands were due to the differences in catheter structural characteristics such as the inner diameter (ID) and the tip inlet area to inner lumen area ratio (AR). The maximum variation of flow rate of all tested 10F catheters was 48%, ID varied up to 22%, from 1.71 to 2.11 mm or 5.13-6.33F. AR varied up to 166%. The table delineates the fastest and slowest rates at three measured pressures. The outer diameter labeled 10F on packaging was true to size. CONCLUSIONS: Based on packaging information, providers, and patients are unable to predict urinary flow through a catheter and thus use information regarding flow rate to guide catheter selection. This information cannot be calculated based on ideal flow calculations and could be listed on packaging to assist physicians and families in selecting the optimal urinary catheter for CIC.

Avanafil for the treatment of erectile dysfunction.

INTRODUCTION: Erectile dysfunction (ED) affects millions of men worldwide, and the incidence of ED will continue to increase as the aging population grows. The first generation of phosphodiesterase-5 (PDE5) inhibitors, the mainstay of oral ED therapy, has revolutionized the treatment of this condition, but not without some drawbacks. Avanafil, the only United States and European Union-approved second-generation PDE5 inhibitor, is a safe and efficacious alternative to its predecessors. AREAS COVERED: We reviewed the current and most up-to-date literature regarding Avanafil, as well as the pivotal trials that measured efficacy and tolerability. As Avanafil is still a relatively new drug, there is still a relative paucity of literature which inherently limited the search parameters. We searched the PUBMED database for articles detailing the clinical trials, chemistry, pharmacokinetics and dynamics, safety, and efficacy of the drug. Expert commentary: Avanafil's unique pharmacologic profile both narrows and minimizes side effects while reducing the time of onset of action to half of its closest competitor, providing men who suffer with ED a return to a more spontaneous sex life.