Clinical outcomes of the Burnett "snake" maneuver shunt modification for ischemic priapism.

BACKGROUND: Major ischemic priapism (IP) is defined as a persistent penile erection for >4 hours. IP may cause serious complications, especially if prompt resolution is not achieved. Therefore, selecting the most effective and usable shunt technique is crucial in IP cases that are refractory to medical therapy. AIM: To compare the effectiveness and complication risks of distal corporoglanular shunt procedures with and without the Burnett "snake" maneuver. METHODS: We conducted a retrospective study of patients who presented with IP and underwent surgical treatment at our institution between 2005 and 2021. The patients were categorized into 2 groups: group 1 (n = 26) underwent distal shunt + Burnett snake maneuver, and group 2 (n = 56) underwent distal shunt-only. Clinical history, parameters of IP, details of medical and surgical treatments, and follow-up information were evaluated. OUTCOMES: Outcomes included differences in IP resolution and recurrence, functional erections, and complications between corporoglanular shunt procedures with and without the Burnett snake maneuver. RESULTS: In group 1, 24 of 26 patients (92.3%) experienced priapism resolution with a single surgical intervention, while this outcome was observed in 30 of 56 patients (53.6%) in group 2 (P < .001). Notably, priapism recurrence was significantly lower in group 1, occurring in 1 of 24 patients (4.2%), as opposed to 8 of 30 patients (26.6%) in group 2 (P < .001). Of the patients with documented sexual function status at follow-up, functional erections (capable of penetration with or without phosphodiesterase 5 inhibitors) were noted in 6 of 14 patients (42.8%) in group 1 and 13 of 26 patients (50%) in group 2 (P = .66). CLINICAL IMPLICATIONS: This study provides valuable insights regarding technical aspects of distal shunt procedures with and without the Burnett snake maneuver for treating major IP episodes. These results can help surgeons with clinical decision making for patients who present with IP. STRENGTH AND LIMITATIONS: Limitations include the single-site retrospective design with potential selection bias, inaccuracies in medical record data, challenges in controlling confounding variables, and the lack of validated questionnaire scores for erectile function evaluation. CONCLUSION: Our study demonstrates that modifying distal shunt procedures using the Burnett snake maneuver significantly improves priapism resolution and effectively prevents further priapism episodes without introducing additional complications or erectile function loss, thereby distinguishing it from distal shunt-only procedures.

Early-onset and uncontrolled diabetes mellitus factors correlate with complications of Peyronie's disease.

BACKGROUND: Peyronie's disease (PD) is a connective tissue disorder that affects the penis and is characterized by abnormal collagen structure in the penile tunica albuginea, resulting in plaque formation and penile deformity. PD's overall prevalence is estimated at 3.2% to 8.9%, with rates as high as 20.3% among men with type 2 diabetes mellitus (DM). However, the characteristics of DM associated with PD complications remain unclear. AIM: To explore clinical associations between DM characteristics and PD complications. METHODS: We conducted a retrospective analysis of patients with DM and PD who presented at our institution between 2007 and 2022. We examined patients' clinical histories, DM- and PD-related clinical parameters, and complications. Penile deformities were assessed through physical examination, photographs, and penile Doppler ultrasound. Patients were categorized into subgroups based on age of DM onset: early (<45 years), average (45-65 years), and late (>65 years). OUTCOMES: Outcomes included effects of DM characteristics on PD development, progression, and severity. RESULTS: In total, 197 patients were included in the evaluation. Early-onset diabetes and elevated hemoglobin A1c (HbA1c) levels exhibited significant correlations with the early development of PD (ρ = 0.66, P < .001, and ρ = -0.24, P < .001, respectively). Furthermore, having DM at an early age was associated with the occurrence of penile plaque (ρ = -0.18, P = .03), and there were no significant differences in plaque dimensions (ρ = -0.29, P = .053). A rise in HbA1c levels after the initial PD diagnosis displayed positive correlations with the formation of penile plaque (ρ = 0.22, P < .006). CLINICAL IMPLICATIONS: These findings emphasize the need for comprehensive assessments and personalized treatment strategies for individuals with DM and PD. Enhanced management approaches can improve outcomes for those facing both challenges. STRENGTHS AND LIMITATIONS: Limitations include the single-site retrospective design with potential selection bias, inaccuracies in medical record data, and challenges in controlling confounding variables. CONCLUSIONS: This study highlights that early-onset diabetes and poor diabetes control, as indicated by a subsequent rise in HbA1c levels following PD diagnosis, are significantly correlated with the onset and severity of PD. Revealing the mechanisms behind these findings will help us develop better management strategies for individuals with DM and PD.

Low-Intensity Electrostimulation Enhances Neuroregeneration and Improves Erectile Function in a Rat Model of Cavernous Nerve Injury.

BACKGROUND: Neurogenic erectile dysfunction (ED) following radical prostatectomy (RP) is a frequent complication often leading to erectile tissue remodeling and permanent ED. Low-intensity electrostimulation (LIES) has been shown to enhance peripheral nerve regeneration, however, its application on cavernous nerves (CN) has never been investigated. AIMS: To investigate whether LIES enhances CN regeneration, improves erectile function (EF) recovery, and prevents corpora cavernosal remodeling after CN injury, which is a principal factor for ED following RP. METHODS: Adult male Sprague-Dawley rats were divided into Sham, Bilateral Cavernous Nerve Injury (BCNI), and BCNI + LIES (1V, 0.1ms, 12Hz, 1h/day). After 7days, EF was assessed (ICP measurement). Penes and CN were collected for molecular analyses of TGF-ß1, Il-6, CRP, eNOS, ERK and AKT protein levels in corpus cavernosum (CC), and immunohistological analysis of DHE, total collagen and α-SMA in CC and S-100, Tub-III, DAPI, TUNEL, and nNOS in CN. OUTCOMES: Effects of LIES on EF, erectile tissue remodeling and CN structure. RESULTS: EF was decreased (P < .05) 7 days after BCNI and increased (P < .05) by LIES. Intracavernosal reactive oxygen species (DHE) was increased (P < .05) after BCNI and normalized by LIES. Protein expressions of TGF-ß1, IL-6, and CRP were increased in the penis (P < .05) after BCNI and normalized by LIES. The α-SMA and/or total collagen ratio was decreased (P < .05) after BCNI in the penis and normalized by LIES. Protein expression ratio of p-ERK/ERK and p-AKT/AKT did not change after BCNI but increased (P < .05) in LIES group. Myelination and number of nNOS positive cells in the CN were decreased (P < .05) after BCNI and normalized by LIES. The number of apoptotic nerve cells within the dorsal penile nerve was increased (P < .05) after BCNI and decreased (P < .05) by LIES compared to the BCNI group. There were no differences in eNOS expression in the penis between study groups. CLINICAL TRANSLATION: LIES may offer a potential new tool for penile rehabilitation and ED management following RP, potentially enhancing EF recovery and minimizing the side effects of this surgery. STRENGTHS & LIMITATIONS: This study provides evidence of the protective effect of LIES on EF and tissue remodeling following CN injury; nevertheless, this study has been conducted on animals and the translation to humans remains to be demonstrated. Further research to identify the underlying mechanisms of action is required. CONCLUSION: This study demonstrates that LIES of the CN after CN injury protects CN structure, enhances EF recovery, and prevents corpora cavernosal remodeling. Sturny M, Karakus S, Fraga-Silva R, et al. Low-Intensity Electrostimulation Enhances Neuroregeneration and Improves Erectile Function in a Rat Model of Cavernous Nerve Injury. J Sex Med 2022;19:686-696.

Detection of ataxia with hybrid convolutional neural network using static plantar pressure distribution model in patients with multiple sclerosis.

OBJECTIVE: In this study, it is aimed to detect ataxia for Persons with Multiple Sclerosis (PwMS) through a deep learning-based approach using an image dataset containing static plantar pressure distribution. Here, an alternative and objective method will be proposed to assist physicians who diagnose PwMS in the early stages. METHODS: A total of 406 static bipedal pressure distribution image data for 43 ataxic PwMS and 62 healthy individuals were used in the study. After preprocessing, these images were given as input to pre-trained deep learning models such as VGG16, VGG19, ResNet, DenseNet, MobileNet, and NasNetMobile. The data of each model is utilized to generate its feature vectors. Finally, feature vectors obtained from static pressure distribution images were classified by SVM (Support Vector Machine), K-NN (K-Nearest Neighbors), and ANN (Artificial Neural Network). In addition, a cross-validation method was used to examine the validity of the classifier. RESULTS: The performance of the proposed models was evaluated with accuracy, sensitivity, specificity, and F1-measure criteria. The VGG19-SVM hybrid model showed the best performance with 95.12% acc, 94.91% sen, 95.31% spe, and 94.44% F1. CONCLUSIONS: In this study, a specific and sensitive automatic test evaluation system was proposed for Ataxic syndromes using digital images to observe the motor skills of the subjects. Comparative results show that the proposed method can be applied in practice for ataxia that is clinically difficult to detect or not yet symptomatic. It can be defined using only static plantar pressure distribution in the early stage and it can be recommended as an assistant system to physicians in clinical practice.

Mirabegron improves erectile function in men with overactive bladder and erectile dysfunction: a 12-week pilot study.

Phosphodiesterase type 5 inhibitors (PDE5i) is the only approved oral treatment for erectile dysfunction (ED) in the US, and alternative management remains necessary when this treatment fails or is contraindicated. Targeting other pathways than the NO-cGMP pathway and/or combining this approach with PDE5i may introduce new treatments for men who are unresponsive to PDE5i. This study aims to evaluate whether Mirabegron improves erectile function in men with concurrent overactive bladder and mild to moderate ED. Twenty subjects, 40-70 years old, registering International Index of Erectile Function (IIEF) score 11-25 and International Prostate Symptom Score 8-20, were treated with Mirabegron therapy for 12 weeks. Study participants were re-administered IIEF and OAB-q questionnaires on weeks 2, 4, 8, and 12 and assessed for adverse events. The primary and secondary endpoints were an increase in the IIEF-5 score of 4 units and a decrease in the Overactive Bladder questionnaire (OAB-q) symptom severity score of 10 units between study time points. Thirteen men completed the 12-week study. Mirabegron treatment improved the IIEF-5 scores in five patients (38.4%) by 4 points or more, whereas IIEF-5 scores were not affected by Mirabegron treatment in eight patients (61.5%). There were no clinically relevant decreases in the IIEF-5 score. Significant improvements were observed in intercourse satisfaction at week eight compared to baseline (p = 0.01). Orgasmic function and sexual desire were not affected by Mirabegron treatment. As expected, Mirabegron treatment reduced OAB symptoms based on OAB-q short form (p = 0.006) and OAB-q total health-related quality of life (HRQL) scores compared to baseline (p = 0.03). Residual bladder volumes were not affected by treatment. No serious side effects were reported during the study period. This study suggests that Mirabegron may improve both EF and OAB-related symptoms in some individuals without causing serious adverse events.

Chronic pain associated with penile prostheses may persist despite revision or explantation.

INTRODUCTION: Inflatable penile prosthesis (IPP) implantation is the gold standard treatment for medically refractory erectile dysfunction. New chronic pain after IPP implantation is rarely discussed and the optimal treatment is unclear. We evaluated whether IPP re-operation for a primary indication of chronic pain improves patients' symptoms. Our secondary aim was to explore factors associated with resolution or persistence of pain after IPP reoperation. METHODS: We conducted a retrospective analysis of 315 patients who had an IPP revision or explantation at two high-volume prosthetic centers between May 2007 and May 2017. We excluded patients who had device malfunction, pain for <2 months, pain associated with infection or erosion, and patients without long-term followup data. Persistent pain was diagnosed based on patient self-report. RESULTS: A total of 31 patients met our criteria for having undergone a surgical revision (n=18) or explantation (n=13) for pain relief. Eighteen (58%) patients had persistent pain despite surgical intervention. Only patients who had pain secondary to a device malposition improved after re-operation (n=13). A prior diagnosis of a chronic pain syndrome was associated with persistent pain despite intervention. Pain improvement was not associated with age, comorbid conditions, duration of implant, or the number of surgical revisions performed. CONCLUSIONS: Surgical intervention for chronic penile prosthesis pain is unlikely to relieve symptoms, particularly for patients with chronic pain disorders. Patients should be counselled that IPP reoperative procedures as a treatment for pain should be avoided unless the device is identified to be malpositioned, and consideration of alternative therapeutic options may be more beneficial.

TSPO ligand FGIN-1-27 controls priapism in sickle cell mice via endogenous testosterone production.

Priapism, a prolonged penile erection in the absence of sexual arousal, is common among patients with sickle cell disease (SCD). Hypogonadism is also common in patients with SCD. While the administration of exogenous testosterone reverses hypogonadism, it is contraceptive. We hypothesized that the stimulation of endogenous testosterone production decreases priapism by normalizing molecular signaling involved in penile erection without decreasing intratesticular testosterone production, which would affect fertility. Treatment of SCD mice with FGIN-1-27, a ligand for translocator protein (TSPO) that mobilizes cholesterol to the inner mitochondrial membrane, resulted in eugonadal levels of serum testosterone without decreasing intratesticular testosterone production. Normalized testosterone levels, in turn, decreased priapism. At the molecular level, TSPO restored phosphodiesterase 5 activity and decreased NADPH oxidase-mediated oxidative stress in the penis, which are major molecular signaling molecules involved in penile erection and are dysregulated in SCD. These results indicate that pharmacologic activation of TSPO could be a novel, targetable pathway for treating hypogonadal men, particularly patients with SCD, without adverse effects on fertility.

The medical and surgical treatment of erectile dysfunction: a review and update.

INTRODUCTION: Erectile dysfunction (ED) is a common condition affecting more than 3 million men in the United States every year. Given the prevalence of severe co-morbidities associated with ED, the clinician must take a thorough history and conduct a diagnostic exam accordingly. The clinician should consider that every man who presents with ED is unique with regards to his symptoms, degree of stress, associated health conditions, sexual relationship quality, and sociocultural context. The clinician determines an appropriate treatment plan that is aligned with the patient's and his partner's priorities and values, adopting a shared decision-making process. The clinician must possess sufficient knowledge of all available treatment modalities and be able to offer to all treatment options that are not contraindicated, regardless of invasiveness or irreversibility, as potential first-line treatments. MATERIALS AND METHODS: Current medical and surgical treatment options in ED, including novel and innovative therapeutic options, were reviewed. RESULTS: There are a variety of treatment options for the management of ED, both medical and surgical. The most commonly considered medical treatment option is phosphodiesterase type 5 inhibitors (PDE5i), which has been proven successful in up to 65% of men with ED. Other treatment options, such as vacuum erection device or intracavernosal injection therapy using vasodilator medications, should be considered in men who have contraindications or are non-responders to PDE5i. Surgical treatment of ED using penile implants has undergone multiple improvements over the years with low device failure and infection risks providing an effective and satisfying treatment alternative. Other therapies, such as penile vascular surgery, extracorporeal shock wave therapy, and intracavernosal stem cell therapies, are novel and should be considered investigational due to lack of evidence supporting their long term safety and efficacy. CONCLUSIONS: The management of ED requires considerations of all aspects of the patient's health and involvement of the patient and his partner in the decision-making process. Patients should be informed of all available treatment options and be able to choose the option that is most aligned with their condition, goals, and risk tolerance. There are medical and surgical therapeutic options available in the management of ED, all supported with the best level of evidence. Novel therapeutic options are promising; however, randomized controlled trials with long term follow up periods and larger sample sizes are needed to support their safety and efficacy.

Real-time, functional intra-operative localization of rat cavernous nerve network using near-infrared cyanine voltage-sensitive dye imaging.

Despite current progress achieved in the surgical technique of radical prostatectomy, post-operative complications such as erectile dysfunction and urinary incontinence persist at high incidence rates. In this paper, we present a methodology for functional intra-operative localization of the cavernous nerve (CN) network for nerve-sparing radical prostatectomy using near-infrared cyanine voltage-sensitive dye (VSD) imaging, which visualizes membrane potential variations in the CN and its branches (CNB) in real time. As a proof-of-concept experiment, we demonstrate a functioning complex nerve network in response to electrical stimulation of the CN, which was clearly differentiated from surrounding tissues in an in vivo rat prostate model. Stimulation of an erection was confirmed by correlative intracavernosal pressure (ICP) monitoring. Within 10 minutes, we performed trans-fascial staining of the CN by direct VSD administration. Our findings suggest the applicability of VSD imaging for real-time, functional imaging guidance during nerve-sparing radical prostatectomy.

NO-Releasing Nanoparticles Ameliorate Detrusor Overactivity in Transgenic Sickle Cell Mice via Restored NO/ROCK Signaling.

Sickle cell disease (SCD) is associated with overactive bladder (OAB). Detrusor overactivity, a component of OAB, is present in an SCD mouse, but the molecular mechanisms for this condition are not well-defined. We hypothesize that nitric oxide (NO)/ ras homolog gene family (Rho) A/Rho-associated kinase (ROCK) dysregulation is a mechanism for detrusor overactivity and that NO-releasing nanoparticles (NO-nps), a novel NO delivery system, may serve to treat this condition. Male adult SCD transgenic, combined endothelial NO synthases (eNOSs) and neuronal NOS (nNOS) gene-deficient (dNOS-/-), and wild-type (WT) mice were used. Empty nanoparticle or NO-np was injected into the bladder, followed by cystometric studies. The expression levels of phosphorylated eNOS (Ser-1177), protein kinase B (Akt) (Ser-473), nNOS (Ser-1412), and myosin phosphatase target subunit 1 (MYPT1) (Thr-696) were assessed in the bladder. SCD and dNOS-/- mice had a greater (P < 0.05) number of voiding and nonvoiding contractions compared with WT mice, and they were normalized by NO-np treatment. eNOS (Ser-1177) and AKT (Ser-473) phosphorylation were decreased (P < 0.05) in the bladder of SCD compared with WT mice and reversed by NO-np. Phosphorylated MYPT1, a marker of the RhoA/ROCK pathway, was increased (P < 0.05) in the bladder of SCD mice compared with WT and reversed by NO-np. nNOS phosphorylation on positive (Ser-1412) regulatory site was decreased (P < 0.05) in the bladder of SCD mice compared with WT and was not affected by NO-np. NO-nps did not affect any of the measured parameters in WT mice. In conclusion, dysregulation of NO and RhoA/ROCK pathways is associated with detrusor overactivity in SCD mice; NO-np reverses these molecular derangements in the bladder and decreases detrusor overactivity. SIGNIFICANCE STATEMENT: Voiding abnormalities commonly affect patients with sickle cell disease (SCD) but are problematic to treat. Clarification of the science for this condition in an animal model of SCD may lead to improved interventions for it. Our findings suggest that novel topical delivery of a vasorelaxant agent nitric oxide into the bladder of these mice corrects overactive bladder by improving deranged bladder physiology regulatory signaling.

Dysregulated NO/PDE5 signaling in the sickle cell mouse lower urinary tract: Reversal by oral nitrate therapy.

AIMS: Nitric oxide (NO) has a critical, but not well understood, influence in the physiology of the lower urinary tract. We evaluated the effect of NO/phosphodiesterase (PDE)5 signaling in voiding dysfunction in the sickle cell disease (SCD) mouse, characterized by low NO bioavailability. MAIN METHODS: Adult SCD (Sickle) and wild-type (WT) male mice were treated daily with sodium nitrate (10 mM) or vehicle. After 18 days, blood was obtained for nitrite measurement, urethra was collected for organ bath study, and bladder and urethra were collected for Western blot analysis of PDE5 phosphorylation (Ser-92) (activated form). Non-anesthetized mice underwent evaluation of urine volume by void spot assay. eNOS phosphorylation (Ser-1177) and nNOS phosphorylation (Ser-1412) (positive regulatory sites) were evaluated in the bladder and urethra of untreated mice. KEY FINDINGS: Sickle mice exhibited decreased eNOS, nNOS, and PDE5 phosphorylation in the bladder and urethra, decreased plasma nitrite levels, increased relaxation of phenylephrine-contracted urethral tissue to an NO donor sodium nitroprusside, and increased total urine volume, compared with WT mice. Nitrate treatment normalized plasma nitrite levels, relaxation of urethra to sodium nitroprusside, PDE5 phosphorylation in the urethra and bladder, and urine volume in Sickle mice. SIGNIFICANCE: Derangement in PDE5 activity associated with basally low NO bioavailability in the bladder and urethra contributes to the molecular basis for voiding abnormalities in Sickle mice. Inorganic nitrate supplementation normalized voiding in Sickle mice through mechanisms likely involving upregulation of PDE5 activity. These findings suggest that interventions targeting dysregulatory NO/PDE5 signaling may ameliorate overactive bladder in SCD.

Urinary dysfunction in transgenic sickle cell mice: model of idiopathic overactive bladder syndrome.

Voiding abnormalities are common among the sickle cell disease (SCD) population, among which overactive bladder (OAB) syndrome is observed at rates as high as 39%. Although detrusor overactivity is the most common cause of OAB, its molecular pathophysiology is not well elucidated. The nitric oxide (NO) signaling pathway has been implicated in the regulation of lower genitourinary tract function. In the present study, we evaluated the role of the NO signaling pathway in voiding function of transgenic SCD mice compared with combined endothelial and neuronal NO synthase gene-deficient mice, both serving as models of NO deficiency. Mice underwent void spot assay and cystometry, and bladder and urethral specimens were studied using in vitro tissue myography. Both mouse models exhibited increased void volumes; increased nonvoiding and voiding contraction frequencies; decreased bladder compliance; increased detrusor smooth muscle contraction responses to electrical field stimulation, KCl, and carbachol; and increased urethral smooth muscle relaxation responses to sodium nitroprusside compared with WT mice. In conclusion, our comprehensive behavioral and functional study of the SCD mouse lower genitourinary tract, in correlation with that of the NO-deficient mouse, reveals NO effector actions in voiding function and suggests that NO signaling derangements are associated with an OAB phenotype. These findings may allow further study of molecular targets for the characterization and evaluation of OAB.

Phosphodiesterase type 5 in men with vasculogenic and post-radical prostatectomy erectile dysfunction: is there a molecular difference?

OBJECTIVES: To clarify the molecular basis of penile erection at the human level and distinguish the mechanisms underlying vasculogenic and post-radical prostatectomy (RP) erectile dysfunction (ED) subtypes. PATIENTS AND METHODS: Erectile tissue was obtained from men without history of ED who underwent penile surgery for Peyronie's disease (control group, n = 5) and from men with ED who underwent penile prosthesis implantation (n = 17). ED was categorized into vasculogenic (n = 8) and post-RP (n = 9) subtypes. Penile erectile tissue samples were collected for molecular analyses of protein expressions of neuronal and endothelial isoforms of nitric oxide synthase (nNOS and eNOS, respectively), phospho-nNOS (Ser-1412), phospho-eNOS (Ser-1177), phospho-protein kinase B (Ser-473), phosphodiesterase type 5 (PDE5), α-smooth muscle actin, phospho-myosin phosphatase target subunit 1, RhoA/Rho-associated protein kinase (ROCK)-α, ROCK-ß, 4-hydroxy-2-nonenal, and nNOS and eNOS uncoupling by Western blot. RESULTS: Vasculogenic ED was characterized by decreased eNOS protein expression and eNOS and nNOS phosphorylation on their activatory sites (Ser-1177 and Ser-1412, respectively), uncoupled eNOS, upregulated PDE5 protein expression, increased ROCK activity, and increased oxidative stress in erectile tissue. Post-RP ED was characterized by decreased nNOS protein expression, increased nNOS phosphorylation on its activatory site (Ser-1412), uncoupled nNOS, downregulated PDE5 protein expression, and increased oxidative stress in erectile tissue. CONCLUSION: The mechanisms of vasculogenic and post-RP ED in the human penis involve derangements in constitutive nitric oxide synthase function, PDE5 protein expression and ROCK activity, and increased oxidative stress, which conceivably provide a molecular basis for chronically reduced nitric oxide bioavailability and increased smooth muscle contraction contributing to erectile impairment. Selective differences in PDE5 protein expression suggest distinct molecular mechanisms are in play for these ED subtypes.

S-nitrosylation of NOS pathway mediators in the penis contributes to cavernous nerve injury-induced erectile dysfunction.

cGMP-independent nitric oxide (NO) signaling occurs via S-nitrosylation. We evaluated whether aberrant S-nitrosylation operates in the penis under conditions of cavernous nerve injury and targets proteins involved in regulating erectile function. Adult male Sprague-Dawley rats underwent bilateral cavernous nerve crush injury (BCNI) or sham surgery. Rats were given a denitrosylation agent N-acetylcysteine (NAC, 300 mg/kg/day) or vehicle in drinking water starting 2 days before BCNI and continuing for 2 weeks following surgery. After assessment of erectile function (intracavernous pressure), penes were collected for measurements of S-nitrosylation by Saville-Griess and TMT-switch assays and PKG-I function by immunoblotting of phospho (P)-VASP-Ser-239. Erectile function was decreased (P < 0.05) after BCNI, and it was preserved (P < 0.05) by NAC treatment. Total S-nitrosothiols and total S-nitrosylated proteins were increased (P < 0.05) after BCNI, and these were partially prevented by NAC treatment. S-nitrosylation of sGC was increased (P < 0.05) after BCNI, and it was prevented (P < 0.05) by NAC treatment. S-nitrosylation of eNOS was increased (P < 0.05) after BCNI, and showed a trend towards decrease by NAC treatment. Protein expression of P-VASP-Ser-239 was decreased (P < 0.05) after BCNI, and showed a trend towards increase by NAC treatment. In conclusion, erectile dysfunction following BCNI is mediated in part by S-nitrosylation of eNOS and its downstream signaling mediator GC, while denitrosylation protects erectile function by preserving the NO/cGMP signaling pathway.

cAMP-dependent post-translational modification of neuronal nitric oxide synthase neuroprotects penile erection in rats.

OBJECTIVES: To evaluate neuronal nitric oxide (NO) synthase (nNOS) phosphorylation, nNOS uncoupling, and oxidative stress in the penis and major pelvic ganglia (MPG), before and after the administration of the cAMP-dependent protein kinase A (PKA) agonist colforsin in a rat model of bilateral cavernous nerve injury (BCNI),which mimics nerve injury after prostatectomy. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were divided into BCNI and sham-operated groups. Each group included two subgroups: vehicle and colforsin (0.1 mg/kg/day i.p.). After 3 days, erectile function (intracavernosal pressure) was measured and penis and MPG were collected for molecular analyses of phospho (P)-nNOS (Ser-1412 and Ser-847), total nNOS, nNOS uncoupling, binding of protein inhibitor of nNOS (PIN) to nNOS, gp91phox subunit of NADPH oxidase, active caspase 3, PKA catalytic subunit α (PKA-Cα; by Western blot) and oxidative stress (hydrogen peroxide [H2 O2 ] and superoxide by Western blot and microdialysis method). RESULTS: Erectile function was decreased 3 days after BCNI and normalized by colforsin. nNOS phosphorylation on both positive (Ser-1412) and negative (Ser-847) regulatory sites, and nNOS uncoupling, were increased after BCNI in the penis and MPG, and normalized by colforsin. H2 O2 and total reactive oxygen species production were increased in the penis after BCNI and normalized by colforsin. Protein expression of gp91phox was increased in the MPG after BCNI and was normalized by colforsin treatment. Binding of PIN to nNOS was increased in the penis after BCNI and was normalized by colforsin treatment. Protein expression of active Caspase 3 was increased in the MPG after BCNI and was normalized by colforsin treatment. Protein expression of PKA-Cα was decreased in the penis after BCNI and normalized by colforsin. CONCLUSION: Collectively, BCNI impairs nNOS function in the penis and MPG by mechanisms involving its phosphorylation and uncoupling in association with increased oxidative stress, resulting in erectile dysfunction. PKA activation by colforsin reverses these molecular changes and preserves penile erection in the face of BCNI.

Roles of Signal Transducer Pathways in Investigation of Biopsies from Patients with Bladder Tumors

Background:The process of development of bladder cancer features alteration of normal biological conditions caused by changes in molecular pathways. Removing control over regulation of these pathways could lead to changes in signal transduction and abnormal regulation of genes. During tumor formation and progression, genes regulate critical cellular processes, involved in cell cycling, growth and death. Here we evaluated the expression and prognostic importance of FGFR1, HRAS, CCND1, CCND3, STAT3 and FAS genes. Methods: Tumor tissues of 44 patients diagnosed with bladder cancer were investigated for changes in expression levels of FGFR1, HRAS, CCND1, CCND3, FAS and STAT3 genes by the RT-PCR method. Signal transduction pathways and expression of individual genes related to these pathways were analyzed using the "One Sample Test". Results: There were statistically significant changes in the expression levels of HRAS, CCND1, CCND3 and STAT3, but not FGFR1 and FAS genes. Examination of associations with age, gender, smoking, chemotherapy, tumor grade and tumor growth pattern using the "Independent Samples Test", showed importance relations between the CCND1 gene and cigarette smoking and sex. Conclusion: Over-expression of HRAS, CCND1, CCND3 and STAT3 genes may play roles in bladder cancer development and progression, while cigarette smoking is significantly associated with CCND1 gene expression and consequently concluded to be contributing to the development of bladder cancer.

Beneficial Effect of the Nitric Oxide Donor Compound 3-(1,3-Dioxoisoindolin-2-yl)Benzyl Nitrate on Dysregulated Phosphodiesterase 5, NADPH Oxidase, and Nitrosative Stress in the Sickle Cell Mouse Penis: Implication for Priapism Treatment.

Patients with sickle cell disease (SCD) display priapism, and dysregulated nitric oxide (NO) pathway may contribute to this condition. However, current therapies offered for the prevention of priapism in SCD are few. The 3-(1,3-dioxoisoindolin-2-yl)benzyl nitrate (compound 4C) was synthesized through molecular hybridization of hydroxyurea and thalidomide, which displays an NO-donor property. This study aimed to evaluate the effects of compound 4C on functional and molecular alterations of erectile function in murine models that display low NO bioavailability, SCD transgenic mice, and endothelial NO synthase and neuronal NO synthase double gene-deficient (dNOS-/) mice, focusing on the dysregulated NO-cGMP- phosphodiesterase type 5 (PDE5) pathway and oxidative stress in erectile tissue. Wild-type, SCD, and dNOS-/- mice were treated with compound 4C (100 µmol/kg/d, 3 weeks). Intracavernosal pressure in anesthetized mice was evaluated. Corpus cavernosum tissue was dissected free and mounted in organ baths. SCD and dNOS-/- mice displayed a priapism phenotype, which was reversed by compound 4C treatment. Increased corpus cavernosum relaxant responses to acetylcholine and electrical-field stimulation were reduced by 4C in SCD mice. Likewise, increased sodium nitroprusside-induced relaxant responses were reduced by 4C in cavernosal tissue from SCD and dNOS-/- mice. Compound 4C reversed PDE5 protein expression and reduced protein expressions of reactive oxygen species markers, NADPH oxidase subunit gp91phox, and 3-nitrotyrosine in penises from SCD and dNOS-/- mice. In conclusion, 3-week therapy with the NO donor 4C reversed the priapism in murine models that display lower NO bioavailability. NO donor compounds may constitute an additional strategy to prevent priapism in SCD.

Prospective evaluation of complications in laparoscopic urology at a mid-volume institution using standardized criteria: Experience of 1023 cases including learning curve in 9 years.

AIM: To evaluate the laparoscopic operations performed in our department according to the modified Clavien classification system of complications. MATERIALS AND METHODS: Between September, 2005 and February, 2014, a total of 1023 laparoscopic cases were performed. This period was divided into three terms (Terms 1, 2 and 3 consisting of 38, 32 and 32 months, respectively). According to the European Scoring System (ESS), easy (E), slightly difficult (SD), fairly difficult (FD), difficult (D), very difficult (VD) and extremely difficult (ED) cases were 35, 88, 170, 390, 203 and 137, respectively. The perioperative complications were evaluated based on the 3 time periods, with a specific emphasis on determining the learning curve according to the modified Clavien classification system of complications. RESULTS: A total of 236 (23.1%) complications were observed according to the modified Clavien classification. The minor (Clavien I-II) and major (Clavien III, IV and V) complication rates were 20.5% (n = 210) and 2.4% (n = 26), respectively. Clavien I was the most frequently encountered type of complication (n = 120, %11.7). No significant difference was observed among all 3 time periods regarding total complication rates. The D cases had the highest complication rate compared to E, SD, FD, VD and ED cases among all three terms. The total number of complications increased significantly with increasing grade of technical difficulty according to the ESS. CONCLUSION: Complications encountered in our laparoscopic surgery experience were predominantly minor, and the rate of complications was not significantly increased during the learning curve. The present data can provide guidance and manage expectations for surgeons introducing laparoscopy into their practice.

Urinary IP-10, MCP-1, NGAL, Cystatin-C, and KIM-1 Levels in Prenatally Diagnosed Unilateral Hydronephrosis: The Search for an Ideal Biomarker.

OBJECTIVE: To investigate the urinary interferon gamma-induced protein 10 (IP-10), monocyte chemotactic protein 1 (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), cystatin-C, and kidney injury molecule-1 (KIM-1) levels in the management of children with prenatally diagnosed unilateral hydronephrosis. MATERIALS AND METHODS: Twenty-seven children with antenatally diagnosed hydronephrosis were enrolled into the study. The controls consisted of 9 healthy children (6 boys, 3 girls; mean age: 41.77 ± 5.30 months). Thirteen children (9 boys, 4 girls; mean age: 48.46 ± 21.11 months) underwent pyeloplasty on follow-up; the remaining 14 (13 boys, 1 girl; mean age: 36.57 ± 14.02 months) were followed up after being diagnosed as having nonobstructive dilatation (NOD). The urinary marker levels were measured in the pyeloplasty, the NOD, and the control groups. RESULTS: The preoperative concentrations of IP-10, MCP-1, NGAL, and KIM-1 were significantly higher in the pyeloplasty group than in the control group (P = .024, P = .002, P = .032, P = .001, respectively). The urinary IP-10 and MCP-1 levels were also significantly higher in the pyeloplasty group than in the NOD group (P = .038, P = .037, respectively). There was no significant difference between the pyeloplasty group and the NOD group regarding urinary NGAL and KIM-1. In the pyeloplasty group, urinary marker levels except cystatin-C were significantly decreased in the postoperative period. CONCLUSION: A decrease in levels of IP-10, MCP-1, NGAL, and KIM-1 after pyeloplasty may be used as a predictor of surgical outcome. Additionally, IP-10 and MCP-1 were superior to NGAL and KIM-1 in predicting who required surgery.

Retroperitoneoscopic ablative renal surgery in children:the feasibility of using three trocars.

PURPOSE: We report the results of pediatric retroperitoneoscopic renal ablative surgeries, which were performed with only three trocars. MATERIALS AND METHODS: We retrospectively reviewed the charts of children who underwent laparoscopic urological procedures on the upper urinary tract at our institution between 2006 and 2012. These procedures consisted of nephrectomies, nephroureterectomies and heminephroureterectomies. The operations were performed retroperitoneoscopically with three trocars. The specimens were removed intact through the primary trocar site. RESULTS: A total of 30 retroperitoneoscopic ablative surgeries were performed in 13 girls and 17 boys. The mean patient age was 7.8 ± 4.3 years (range, 1-14 years). The interventions consisted of nephrectomy in 10 cases (33.3%), nephroureterectomy in 17 cases (56.6%) and heminephroureterectomy in 3 (10%) cases. The open conversion rate was 3.3% (1/30). The difference between the initial 10 cases and the latter 20 cases, in terms of mean operative time, was statistically significant (144.5 vs. 115.78 minutes, respectively, P = .031). Apart from 3 nephroureterectomies, all of the procedures (86.6%) were completed successfully using three trocars only, without the need for a separate extraction incision. The patients were hospitalized for a mean duration of 2.2 days (range, 2-4 days). None of the patients required blood transfusion. We did not encounter any major perioperative or postoperative complication. CONCLUSION: Retroperitoneoscopic renal ablative surgery is a safe and effective treatment alternative for a variety of upper urinary tract disorders in children.