Staged urethroplasty with groin full-thickness skin graft for managing complex anterior urethral strictures: surgical outcomes and predictive factors.

PURPOSE: To describe outcomes of staged-urethroplasty in complex anterior urethral strictures using full-thickness-skin-graft (FTSG) harvested from the hairless groin area, and to identify factors influencing successful outcomes. METHODS: Through retrospective chart review, we identified a total of 67 men who underwent the first-stage operation (grafting) using groin-FTSG for staged-urethroplasty to treat complex anterior urethral strictures unsuitable for one-stage urethroplasty. Among these, 59 underwent the second-stage operation (tubularization) at a median duration of 5.1-months after grafting. Patients were assessed for outcomes as scheduled after tubularization outcomes were analyzed only for 48 patients for whom ≥ 1-year follow-up data after tubularization were available. Their mean follow-up duration was 27.1 months. Success was defined as achieving physiologic voiding without requiring further procedures. RESULTS: Median stricture-length was 5.5 cm in all 67 patients. After grafting, neourethral-opening-narrowing occurred in 18. Partial graft-loss occurred in 8, of whom only 3 underwent re-grafting. The percentage of patients who achieved successful outcomes was 81.3%. Improvements in maximum-urine-flow-rate and post-void-residual-urine-volume were maintained until the last follow-up visit. A urethrocutaneous-fistula occurred in one patient, while meatal-stenosis occurred in two. On multivariate-regression-analysis, the presence of neourethral-opening-narrowing was the only predictor of non-success after tubularization. Furthermore, the presence of hypertension, longer stricture-length, and a history of prior direct-vision-internal-urethrotomy were predictors of the occurrence of neourethral-opening-narrowing. CONCLUSION: Staged-urethroplasty using groin-FTSG is well worth considering as a useful therapeutic option for complex anterior urethral strictures, with an acceptable success rate and low morbidity. The absence of neourethral-opening-narrowing after the first-stage operation leads to success.

Chronic treatment with a combination of hepatocyte growth factor and JNK inhibitor ameliorates cavernosal veno-occlusive dysfunction: a rat model of cavernous nerve injury.

BACKGROUND: Structural alterations of the penis, including cavernosal apoptosis and fibrosis, induce venous leakage into the corpus cavernosum or cavernosal veno-occlusive dysfunction, a key pathophysiology associated with erectile dysfunction after radical prostatectomy. We hypothesized that the effect of JNK inhibitors on reducing apoptosis and hepatocyte growth factor (HGF) on inducing tissue regeneration could be another treatment mechanism of erectile dysfunction after radical prostatectomy. AIM: To investigate whether JNK inhibition combined with intracavernosal administration of HGF can completely preserve cavernosal veno-occlusive function (CVOF) in a rat model of erectile dysfunction induced via bilateral cavernosal nerve crush injury (CNCI). METHODS: A total of 42 male Sprague-Dawley rats were randomly assigned to sham control (group S), CNCI (group I), and CNCI treated with a combination of JNK inhibitor and HGF (group J + H) for 5 weeks after surgery. OUTCOMES: Rats in each group were evaluated via dynamic infusion cavernosometry (DIC), caspase-3 activity assay, Masson trichrome staining, immunohistochemical staining of α-smooth muscle actin, and immunoblotting at 5 weeks after surgery. RESULTS: Regarding CVOF, group I showed decreased papaverine response, increased maintenance, and drop rates of DIC when compared with group S. Group J + H showed significant improvement in the 3 DIC parameters vs group I. No differences in the 3 DIC parameters were found between group J + H and group S. Regarding the structural integrity of the corpus cavernosum, group I showed increased caspase-3 activity, decreased smooth muscle (SM):collagen ratio, decreased SM content, decreased protein expression of PECAM-1, and decreased phosphorylation of c-Jun and c-Met. Group J + H showed significant attenuation in histologic and molecular derangement as compared with group I. There were no differences in caspase-3 activity, SM content, SM:collagen ratio, PECAM-1 protein expression, c-Jun phosphorylation, and c-Met phosphorylation between groups J + H and S. CLINICAL IMPLICATIONS: Our results suggest that antiapoptotic and regenerative therapy for the corpus cavernosum is a potential mechanism of penile rehabilitation after radical prostatectomy. STRENGTHS AND LIMITATIONS: This study provides evidence that combination treatment of JNK inhibitor and HGF preserves erectile function by restoring corporal SM and endothelium. However, additional human studies are needed to confirm the clinical effect. CONCLUSION: Chronic treatment with JNK inhibitor and HGF may preserve CVOF to levels comparable to sham control by preserving the structural integrity of the corpus cavernosum and so represents a potential therapeutic option for preventing the development of cavernosal veno-occlusive dysfunction.

Restoration of erectile function by a combination of antiapoptosis by JNK inhibitor and preservation of smooth muscle or endothelium by hepatocyte growth factor in a rat model of cavernous nerve injury.

BACKGROUND: Because of structural alterations in the corpus cavernosum after radical prostatectomy (RP), post-RP erectile dysfunction remains a very difficult condition to treat. We aimed to determine if the combined administration of a Jun-amino terminal kinase (JNK) inhibitor and hepatocyte growth factor (HGF) in the immediate post-injury period would restore erectile function by antiapoptotic and pro-regenerative effects through the rectification of molecular pathways related to the structural integrity of the penis in a rat model of bilateral cavernosal nerve crush injury (CNCI). METHODS: A total of 70 rats were divided into five groups: Sham surgery (S), CNCI (I), and once-daily intraperitoneal administration of 10.0 mg/kg JNK inhibitor + twice-weekly intracavernosal administration of low-dose (2.1 µg), medium-dose (4.2 µg), or high-dose (8.4 µg) HGF (I + J + LH or I + J + MH or I + J + HH, respectively) in the immediate post-injury period. Erectile responses to electrostimulation (1.0, 3.0, and 5.0 V), histological staining, caspase-3 activity, and Western blotting were evaluated 9 days after surgery. RESULTS: Group I showed lower intracavernosal pressure (ICP)/mean arterial pressure (MAP) after stimulation at each voltage, lower area under the curve (AUC)/MAP after stimulation at each voltage, less smooth muscle (SM) content, a lower SM/collagen ratio, higher caspase-3 activity, increased cJun phosphorylation, decreased protein expression of PECAM-1, decreased cMet phosphorylation, and decreased endothelial nitric oxide synthase (eNOS) phosphorylation compared to Group S. The SM content, SM/collagen ratio, protein expression of ICP/MAP, or AUC/MAP after stimulation at each voltage in Group I + J + LH were partially restored, despite the normalization of cJun phosphorylation and caspase-3 activity. The ICP/MAP, AUC/MAP, caspase-3 activity, SM content, protein expression of PECAM-1, cJun phosphorylation, cMet phosphorylation, and eNOS phosphorylation in both Groups I + J + MH and I + J + HH were restored to the levels observed in Group S, while the SM/collagen ratio was significantly improved but not completely normalized. CONCLUSIONS: Our data indicated that the combined administration of a JNK inhibitor and medium or high-dose HGF to nerve-injured rats in the immediate post-injury period after CNCI may restore erectile function to a level comparable to the normal level by suppressing cavernosal apoptosis and preserving the integrity of SM or endothelium via rectification of the cJun and cMet/eNOS pathways.

Combination Therapy with a JNK Inhibitor and Hepatocyte Growth Factor for Restoration of Erectile Function in a Rat Model of Cavernosal Nerve Injury: Comparison with a JNK Inhibitor Alone or Hepatocyte Growth Factor Alone.

We determined if combined administration of JNK-inhibitors and HGF (hepatocyte-growth-factor) would restore erectile-function through both antiapoptotic and regenerative effects in a rat model of cavernous-nerve-crush-injury (CNCI), and compared the results with administration of JNK-inhibitor alone or HGF alone. We randomized 70 rats into 5 groups: sham-surgery-group (S), CNCI (I) group, a group treated with once-daily intraperitoneal-administration of 10.0-mg/kg of JNK-inhibitors (J), a twice-weekly intracavernosal-administration of 4.2-µg HGF group (H), and a combined-treatment with 10.0-mg/kg JNK-inhibitors and 4.2-µg HGF group (J+H). We investigated erectile-responses to electrostimulation, histological-staining, caspase-3-activity-assay, and immunoblotting at two-weeks postoperatively. The three treatment groups showed improvements in erectile-responses (ICP/MAP and AUC/MAP ratios) compared to Group-I. The erectile-responses in Group-J+H were greater than those in Group-J or Group-H. The erectile-responses in Group-J+H were generally normalized. Caspase-3-activity and cJun-phosphorylation in Group-J and Group-J+H improved compared to Group-I, whereas caspase-3-activity in Group-H partially improved. Protein-expression of PECAM-1, eNOS-phosphorylation, and smooth-muscle content in Group-J+H were normalized, although those in Group-J or Group-H were partially restored. Combination therapy with JNK-inhibitors and HGF can generally normalize erectile-function through anti-apoptosis and preservation of endothelium or SM in rat CNCI model. The combined treatment appears to be superior to the respective agent alone in terms of therapeutic effects.

Mirabegron as a treatment for overactive bladder symptoms in men (MIRACLE study): Efficacy and safety results from a multicenter, randomized, double-blind, placebo-controlled, parallel comparison phase IV study.

AIMS: To evaluate the efficacy and safety of mirabegron in males with overactive bladder (OAB) symptoms. METHODS: In total, 464 males with OAB symptoms were enrolled from 14 institutes and were sorted into either the mirabegron 50 mg (n = 310) or placebo (n = 154) groups. The change in (i) the mean number of 24-h micturition episodes; (ii) OAB Symptom Scale (OABSS); and (iii) International Prostate Symptom Score (IPSS) from baseline to 12 weeks of treatment were compared between the two groups. Safety assessments included treatment-emergent adverse events, blood pressure, pulse rate, postvoid residual volume, and maximum urinary flow rate. After 12 weeks, the study was extended for 14 additional weeks by administering mirabegron 50 mg to both groups. RESULTS: The reduction in the mean number of 24-h micturition episodes from baseline to 12 weeks of treatment was similar between the two groups. However, significantly greater changes from baseline to 12 weeks were observed in total OABSS, OABSS urgency incontinence score (Q4), IPSS storage subscore (Q2 + Q4 + Q7), and IPSS urgency score (Q4) in the mirabegron group (P = 0.01 for all). According to the extended study, the changes of all efficacy variables from baseline to 26 weeks were similar between both groups. The safety assessment results were also similar between the two groups at 12 and 26 weeks. CONCLUSION: A daily 50 mg dose of mirabegron for 12 weeks reduced OAB symptoms in men, and no significant adverse events compared to the placebo group were noted.

Effects of Initiation Time of Glycemic Control on Skin Collagen Recovery in Streptozotocin-Induced Diabetic Rats.

BACKGROUND: Diabetes damages the collagen in the skin. No study has investigated the relationship between the treatment initiation time and the degree of collagen recovery. This study aimed to evaluate the effects of the initiation time of glycemic control on collagen recovery and to determine the basic molecules mediating the process. METHODS: Streptozotocin-induced diabetic rats were divided into five groups: normal controls (C), those with untreated diabetes (DM), and those with diabetes treated with daily insulin injections from 7 weeks (7W), 10 weeks (10W), and 13 weeks (13W) after diabetes induction. The levels of collagen and several molecules were compared among skin tissues collected at 14 weeks. RESULTS: The amounts of total collagen, collagen 1, and collagen 3 were significantly lower in DM than in C. Among the treated groups, recovery reaching normal levels was only observed in 7W and 10W. The earlier the treatment began, the greater was the collagen recovery. Similar to that of collagen, the expression of transforming growth factor-ß1 (TGF-ß1), vascular endothelial growth factor (VEGF), and insulin-like growth factor 1 receptor (IGF-1R) significantly decreased in DM compared with that in C. Higher recovery of TGF-ß1 and VEGF was detected in groups with earlier treatment, whereas the IGF-1R level was identically elevated in all treated groups. The results suggest that these molecules affect collagen recovery at different time points during glycemic control. CONCLUSION: The initiation time of glycemic control is expected to have a considerable effect on collagen recovery in the diabetic skin through modulation of TGF-ß1, VEGF, and IGF-1R.

Efficacy and Safety of a Fixed-Dose Combination Therapy of Tamsulosin and Tadalafil for Patients With Lower Urinary Tract Symptoms and Erectile Dysfunction: Results of a Randomized, Double-Blinded, Active-Controlled Trial.

BACKGROUND: Phosphodiesterase type 5 inhibitors and α-adrenergic blocking agents (α-blockers) are widely used for the treatment of erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). AIMS: To assess the efficacy and safety of fixed-dose combinations (FDCs) of tamsulosin and tadalafil compared with tadalafil monotherapy in patients with comorbid BPH-associated LUTS and ED. METHODS: A randomized, double-blinded, active-controlled trial was conducted of 510 men with BPH-associated LUTS and ED. Patients were treated with FDCs of tamsulosin 0.4 mg plus tadalafil 5 mg (FDC 0.4/5 mg), tamsulosin 0.2 mg plus tadalafil 5 mg (FDC 0.2/5 mg), or tadalafil 5 mg for a 12-week treatment period. For a subsequent 12-week extension period, the patients were administered FDC 0.4/5 mg. OUTCOMES: The primary outcomes were changes from baseline in total International Prostate Symptom Score (IPSS) and International Index of Erectile Function erectile function domain (IIEF-EF) score at week 12 to prove superiority and non-inferiority of FDCs compared with tadalafil 5 mg. The safety assessments were adverse reactions, laboratory test results, and vital signs at week 24. RESULTS: The mean changes in total IPSS and IIEF-EF scores were -9.46 and 9.17 for FDC 0.4/5 mg and -8.14 and 9.49 for tadalafil 5 mg, respectively, which indicated superiority in LUTS improvement (P = .0320) and non-inferiority in ED treatment with FDC 0.4/5 mg compared with tadalafil 5 mg. However, the results from FDC 0.2/5 mg failed to demonstrate superiority in LUTS improvement. No clinically significant adverse events regarding the investigational products were observed during the 24-week period. CLINICAL IMPLICATIONS: The FDC 0.4/5 mg is the first combined formulation of an α-blocker and a phosphodiesterase type 5 inhibitor that offers benefits in patient compliance and as add-on therapy in patients with comorbid BPH-associated LUTS and ED. STRENGTHS AND LIMITATIONS: The study clearly demonstrated the advantage of FDC 0.4/5 mg. The main advantage of FDC 0.4/5 mg was the enhanced efficacy on BPH-associated LUTS comorbidity with ED, the lower incidence of side effects, and the simplification and convenience of therapy, which led to better overall patient compliance. However, the lack of a tamsulosin monotherapy control group was a limitation of this study. CONCLUSION: The FDC 0.4/5 mg therapy was safe, well tolerated, and efficacious, indicating that combination therapy could provide clinical benefits for patients with BPH-associated LUTS complaints and ameliorate the comorbidity of ED. Kim SW, Park NC, Lee SW, et al. Efficacy and Safety of a Fixed-Dose Combination Therapy of Tamsulosin and Tadalafil for Patients With Lower Urinary Tract Symptoms and Erectile Dysfunction: Results of a Randomized, Double-Blinded, Active-Controlled Trial. J Sex Med 2017;14:1018-1027.

A multicenter real-life study of the efficacy of an alpha-blocker with or without anticholinergic agent (imidafenacin) treatment in patients with lower urinary tract symptoms/benign prostatic hyperplasia and storage symptoms.

AIMS: To evaluate the efficacy and safety of combination therapy comprising a short-acting anticholinergic, imidafenacin and an alpha-blocker compared with monotherapy with an alpha-blocker only in men with lower urinary tract symptoms (LUTS) and storage symptoms. METHODS: The 12-week, prospective, double-blind, randomised trial enrolled men with LUTS and storage symptom. The inclusion criteria were a total International Prostate Symptom Score (IPSS) ≥12, an IPSS question 4 score ≥2, ≥8 micturitions in 24 hours, and a prostate volume >20 mL. The primary outcome was a change in the micturition number from baseline. Bladder diary variables, Patient Perception of Intensity of Urgency Scale (PPIUS) scores, IPSS and safety were assessed. RESULTS: Of 260 patients screened, 221 completed the study. Patients were randomly assigned to receive an alpha-blocker only (n=111, group 1) or combination therapy comprising an alpha-blocker and an anticholinergic (n=110, group 2) for 12 weeks. Group 1 and 2 showed significant improvement in their 24-hour micturition numbers (-1.87 and -2.08, respectively), nocturia episodes (-0.48 and -0.53, respectively), total IPSS (-9.9 and -8.8, respectively), and PPIUS scores (-0.19 and -0.24, respectively). Micturition number per 24 hours, daytime frequency, urgency, the PPIUS score, the IPSS question 4 score and IPSS QoL score improved significantly in the combination therapy group, but changes in total IPSS, nocturia episodes, and safety outcomes did not differ significantly between the groups. CONCLUSIONS AND CLINICAL IMPLICATIONS: Compared with treatment with an alpha-blocker alone, combination therapy comprising an anticholinergic and an alpha-blocker showed superior efficacy and its safety was similar in patients with LUTS and storage symptoms.

Restoration of erectile function by suppression of corporal apoptosis, fibrosis and corporal veno-occlusive dysfunction with rho-kinase inhibitors in a rat model of cavernous nerve injury.

PURPOSE: We determined whether Rho-kinase inhibition would improve corporal veno-occlusive dysfunction by suppressing apoptosis and fibrosis via normalization of the Rho-kinase driven pathways related to the 2 structural alterations in a rat model of cavernous nerve crush injury. MATERIALS AND METHODS: A total of 30 male 10-week-old male Sprague Dawley® rats were equally divided into 3 groups, including sham surgery, cavernous nerve crush injury and cavernous nerve crush injury treated with fasudil. The treated group received fasudil (30 mg/kg) daily for 4 weeks starting day 1 postoperatively. Electrostimulation and dynamic infusion cavernosometry were performed 4 weeks postoperatively. Penile tissue was processed for imm unohistochemistry, double immunofluorescent and Masson trichrome staining, TUNEL, caspase-3 activity assay and Western blot. RESULTS: The cavernous nerve crush injury group showed significantly lower intracavernous pressure/mean arterial pressure, and higher maintenance and drop rates than the sham surgery group. Rho-kinase inhibition in the injury plus fasudil group restored erectile responses and dynamic infusion cavernosometry parameters. Increased apoptosis, decreased immunohistochemical staining of α-SMA and increased caspase-3 activity were noted in the injury group. In that group densitometry revealed increased ROCK1 expression, increased MYPT1 phosphorylation, decreased Akt phosphorylation, decreased Bad phosphorylation and a decreased Bcl2-to-Bax ratio. A significantly decreased smooth muscle-to-collagen ratio and increased fibroblast pCofilin were also observed in the injury group, as was increased phosphorylation of cofilin, a downstream effector of LIMK2. Rho-kinase inhibition in the injury plus fasudil group alleviated the histological and molecular dysregulation. CONCLUSIONS: Our data suggest that early inhibition of Rho-kinase after cavernous nerve crush injury may prevent corporal apoptosis and fibrosis by suppressing the Akt/Bad/Bax/caspase-3 and LIMK2/cofilin pathways, preventing corporal veno-occlusive dysfunction and erectile dysfunction.

Effect of chronic administration of PDE5 combined with glycemic control on erectile function in streptozotocin-induced diabetic rats.

INTRODUCTION: Chronic treatment with phosphodiesterase type 5 inhibitors (PDE5) is effective in an animal model of diabetes-induced erectile dysfunction (DMED). In addition, recent research indicates that glycemic control can restore DMED. AIMS: We evaluated the effect of chronic administration of PDE5 combined with glycemic control on DMED. METHODS: Sprague-Dawley rats (8 weeks old) were divided into five groups (n = 10 each): normal control (C), diabetes (DM), DM treated with insulin (DM-I), DM treated with PDE5 (DM-P), and DM treated with insulin and PDE5 (DM-I + P). Rats in the diabetic groups received an injection of streptozotocin (45 mg/kg). After 10 weeks of induced diabetes, the DM-I group was treated with a daily injection of neutral protamine Hagedorn, and the DM-P group was treated with a daily dosage of 20 mg/kg PDE5 (DA-8159) for 4 weeks. The DM-I + P group was treated with both treatments simultaneously. After 14 weeks of induced diabetes, an evaluation of erectile function and histological and biochemical markers of corporal tissue was performed. MAIN OUTCOME MEASURES: Erectile function and histological and biochemical markers in corporal tissue. RESULTS: Rats in the DM group showed markedly lower erectile parameters than those in the C group, whereas rats in the DM-I and DM-P groups showed intermediate erectile function between the DM and C groups. Rats in the DM-I + P group showed restored erectile function, comparable with group C. A comparison of apoptotic index, expression of the endothelial marker, and phosphorylation of endothelial nitric oxide synthase and Akt displayed a similar pattern with the results from cavernosometry (DM < DM-I = DM-P < DM-I + P = C, P < 0.05). The distribution of phosphorylated myosin phosphatase target subunit 1 was in the reverse order. CONCLUSIONS: Chronic administration of PDE5 or glycemic control with insulin resulted in restoration of overt DMED. The combination of both treatments was superior to monotherapy with insulin or PDE5.

Involvement of Rho-Kinase/LIM Kinase/Cofilin Signaling Pathway in Corporal Fibrosis after Cavernous Nerve Injury in Male Rats.

INTRODUCTION: The molecular mechanism of corporal fibrosis leading to erectile dysfunction (ED) following cavernous nerve (CN) injury is poorly understood. AIM: To determine whether the LIMK2/cofilin pathway, the downstream effectors of ROCK1, was involved in ED and corporal fibrosis following bilateral CN injury in male rats. METHODS: Forty-eight 10-week-old male Sprague-Dawley rats were equally divided into three groups: sham surgery (S); bilateral CN crush injury (I); and bilateral CN resection (R). Within each groups, two subgroups were analyzed at 1 and 4 weeks postoperatively. MAIN OUTCOME MEASURES: Electrostimulation was performed to assess erectile function by the ratio of maximal intracavernous pressure to mean arterial pressure (ICP/MAP) and areas under the ICP curve to MAP (AUC/MAP). Penile tissue was processed for Masson's trichrome staining, Western blot (ROCK1, total LIMK2, phospho-LIMK2, total cofilin, phospho-cofilin), immunohistochemistry (alpha-SM actin [α-SMA]), and double immunofluorescent staining (ROCK1, phospho-LIMK2, vimentin). RESULTS: At each time point, both I and R groups showed a significantly lower percent of ICP/MAP and AUC, and decreased SM cell/collagen ratio and expression of α-SMA than S group. Densitometry revealed a significantly higher expression of ROCK1 in I and R groups compared with S group at all time points. The LIMK2 phosphorylation in I and R groups significantly increased at 1 week, but not at 4 weeks. The cofilin phosphorylation in R group significantly increased to that in S group starting at 1 week, while that in I group was increased significantly at 4 weeks. The double immunofluorescent staining noted that coexpression of vimentin with ROCK1 or phospho-LIMK2 in I and R groups was significantly increased mainly in the subtunical area at 1 week but not at 4 weeks. CONCLUSIONS: The ROCK1/LIMK2/cofilin pathway may be involved in ED related to corporal fibrosis, and it appears to be functional particularly in the early period after CN injury.

Change in storage symptoms following laser prostatectomy: comparison between photoselective vaporization of the prostate (PVP) and holmium laser enucleation of the prostate (HoLEP).

PURPOSE: To compare serial changes of postoperative storage symptoms between PVP and HoLEP, and to identify the predictors influencing postoperative improvement of storage symptoms. METHODS: A total of 486 men (PVP group: 213 cases; HoLEP group: 273 cases), in whom 12-month follow-up data were available, were included in this retrospective study. Surgical outcomes were evaluated at 1-, 3-, 6-, and 12 months postoperatively using the IPSS, uroflowmetry with post-void residual urine volume (PVR) and serum PSA levels. Improvement of storage symptoms was defined as a reduction by ≥50 % of the subtotal storage symptom score postoperatively compared to baseline. RESULTS: In both PVP and HoLEP groups, total IPSS, quality-of-life index, frequency score, nocturia score, maximum flow rate and PVR were significantly decreased compared to baseline starting from 1 month after surgery. Whereas urgency score was numerically increased compared to baseline at 1 month after PVP, it was reduced compared to baseline at 1 month after HoLEP. While the subtotal storage symptom score was significantly decreased compared to baseline starting from 3 months after PVP, it was significantly reduced starting from 1 month after HoLEP. On logistic regression analysis, a higher baseline subtotal storage symptom score was the only independent predictor of improvement in storage symptoms after PVP or HoLEP. CONCLUSIONS: Our data suggest that improvement in storage symptoms after HoLEP begins earlier than that after PVP. Also, this study indicates that patients with more severe baseline storage symptoms have a higher likelihood of improvement after PVP or HoLEP compared to those with less severe symptoms.

Should men with mild erectile dysfunction be closely evaluated for cardiovascular diseases in the Korean population?

This study compared demographic characteristics and prevalence of cardiovascular comorbidities between men with mild erectile dysfunction (ED) and men with more severe ED. Men with 6-month history of ED and in monogamous heterosexual relationships were included. Non-responders to type 5 phosphodiesterase inhibitors or patients receiving regular treatment with nitrate, anticoagulants, androgens, and anti-androgens were excluded. ED was defined according to the International Index of Erectile Function questionnaire score: no ED (≥26), mild ED (22-25), and others (<22). The review identified 70 patients with mild ED (6.0%, group A) and 1098 patients with more severe ED (94.0%, group B) were included. Of the patients in group B, 365 had mild-to-moderate ED (30.5%), 505 had moderate ED (43.2%), and 233 had severe ED (20.0%). Mean ages and body mass indices showed no differences between groups A and B. Group A had shorter mean duration of ED (p = 0.025). Although patients in group A had milder ED with shorter duration than group B patients, cardiovascular risk factors such as diabetes, hypertension and lipid disorder were still common for group A. The most common comorbidity was diabetes, which was twice as likely for patients in group B. Except for diabetes the prevalence of all diseases was comparable between the two groups. In conclusion, patients with mild ED should be closely evaluated for cardiovascular comorbidities.

Analysis of DAZ gene expression in a partial AZFc deletion of the human Y chromosome.

The azoospermia factor c (AZFc) region of the Y chromosome consists of repetitive amplicons and is therefore highly susceptible to structural rearrangements, such as deletions and duplications. The b2/b3 deletion is a partial AZFc deletion that is conventionally determined by the selective absence of sY1191 in sequence-tagged site polymerase chain reaction (PCR) and is generally believed to retain two of the four deleted in azoospermia (DAZ) genes on the Y chromosome. In the present study we determined the copy number and expression of DAZ genes in sY1191-negative individuals. Using a DAZ dosage PCR assay and Southern blot analysis we evaluated the expression of four DAZ genes in five of six sY1191-negative individuals. Furthermore, cloning and immunoblot analyses revealed that three or more DAZ genes are expressed in sY1191-negative testes with germ cells. The results indicate that the selective absence of sY1191 not only means b2/b3 deletion with two DAZ genes, but also includes another AZFc configuration with four DAZ genes. These results exemplify the prevalence of variations in the AZFc region of the human Y chromosome.

Dutasteride, who is it more effective for? Second to fourth digit ratio and the relationship with prostate volume reduction by dutasteride treatment.

UNLABELLED: Study Type--Prognosis (cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? The second to fourth digit ratio (hereafter the digit ratio) of the right hand is related to the activity of the androgen receptor. Five α-reductase inhibitor (5ARI) reduces the prostate volume of patients with BPH. In terms of prostate volume reduction, large-scale placebo-controlled studies show that patients with BPH do not always respond well to 5ARI treatment. Patients with a higher digit ratio respond well to dutasteride treatment compared to those with a lower digit ratio. These results suggest that the digit ratio might be a predictor of the response to dutasteride treatment. OBJECTIVE: • To investigate the relationship between second to fourth digit ratio (hereafter the digit ratio) and prostate volume reduction by dutasteride treatment. PATIENTS AND METHODS: • A total of 142 men aged ≥ 40 years with a clinical diagnosis of benign prostatic hyperplasia and an enlarged prostate (prostate volume ≥ 30 mL) were prospectively enrolled. • Before prostate-specific antigen (PSA) level determination and transrectal ultrasonography (TRUS), the lengths of the second and fourth digits of the right hand were measured by an investigator using a digital vernier calliper. • Using TRUS, pre- and post-treatment prostate volume (PV1 and PV2) were measured by an uroradiologist who was unaware of finger lengths. We investigated the change in prostate volume and PSA level at least 6 months after the initiation of dutasteride therapy. RESULTS: • When the patients were divided into two groups according to digit ratio (A: digit ratio <0.95, n = 71; B: digit ratio ≥ 0.95, n = 71), there was a greater reduction in prostate volume in group B compared to group A (PV2-PV1: -9.4 mL vs -13.2 mL, P = 0.042; [PV2-PV1]/PV1: -17.5% vs -24.5%, P = 0.027; [PV2-PV1]/duration: -1.1 mL/month vs -1.6 mL/month, P = 0.041; [PV2-PV1]/PV1/duration: -2.0%/month vs -3.0%/month, P= 0.016). • Significant negative correlations were found between the digit ratio and reduction rate ([PV2-PV1]/duration: r = -0.165, P = 0.049; [PV2-PV1]/PV1/duration: r = -0.191, P = 0.023). CONCLUSIONS: • Patients with higher digit ratios respond well to dutasteride treatment. • The results obtained in the present study suggest that the digit ratio is a predictor of the response to dutasteride treatment.

Investigation of the effects of the level of glycemic control on erectile function and pathophysiological mechanisms in diabetic rats.

INTRODUCTION: Poor glycemic control is associated with erectile dysfunction (ED); however, differences in ED according to the level of glycemic control have been poorly investigated. AIM: The aim of this paper is to investigate the change in erectile function according to the level of glycemic control and to clarify the pathophysiological mechanism of diabetes-associated ED. METHODS: Streptozotocin was injected into 55 male Sprague-Dawley rats classified into four groups: control (group 1), diabetes with multiple insulin injections (group 2), diabetes with a single injection (group 3), and untreated diabetes (group 4). Daily insulin injections in groups 2 and 3 were administered for 4 weeks after 10 weeks of diabetic induction. MAIN OUTCOME MEASURES: The main outcome measures are the anova or Kruskal-Wallis tests to evaluate glycosylated hemoglobin (HbA1c), testosterone levels, the ratios of intracavernosal pressure to mean arterial pressure (ICP/MAP), area under the ICP curve to MAP (AUC/MAP), and changes in cavernous tissue and protein expression related to Rho kinase and nitric oxide pathways. RESULTS: HbA1c levels were different between pairs of groups. Group 4 showed the lowest erectile parameters and group 2 showed near normal level. No differences in erectile parameters were found between groups 1 and 2 or between groups 3 and 4, except the ratio of AUC to MAP for group 1 was significantly higher than that of group 2 (20 Hz stimulation). Decrease in erectile function of group 2 was related to decreased expression of nitrergic nitric oxide synthase or decreased testosterone level compared with group 1. Groups 2 and 3 showed significant differences in erectile parameters, which were associated with difference in apoptotic index. Groups 3 and 4 showed no differences in erectile parameters, although these groups had significant differences in apoptotic index, smooth muscle component, and protein expression ratios of phosphorylated to total myosin phosphatase target subunit 1, endothelial nitric oxide synthase, and Akt. CONCLUSIONS: Improvement in glycemic control assists recovery from diabetes-associated ED; however, only tight glycemic control can provide recovery from ED to a near normal status.

Restoring erectile function by combined treatment with JNK inhibitor and HDAC inhibitor in a rat model of cavernous nerve injury.

BACKGROUND: The main pathophysiologic conditions of erectile dysfunction (ED) after radical prostatectomy are considered to be corporal fibrosis and apoptosis induced by cavernosal nerve (CN) injury. OBJECTIVES: In a rat model of CN crush injury (CNCI), we investigated whether combination treatment with JNK inhibitor (JNKi), SP600125, and HDAC inhibitor (HDACi), suberoylanilide-hydroxamic-7 acid (SAHA), for 2 weeks after CNCI would restore erectile function by suppressing fibrosis and apoptosis through normalization of JNK and HDAC pathways. MATERIALS AND METHODS: Seventy 12-week-old rats were randomly divided into five groups: Sham surgery, CNCI alone, CNCI treated with daily intraperitoneal injection of 10 mg/kg JNKi, CNCI treated with daily oral administration of 25.0 mg/kg HDACi, and CNCI daily treated with a combination. Two weeks after CNCI, we investigated the erectile response to electrostimulation and conducted histological staining, caspase-3 activity assay, and western blot analysis. RESULTS: CNCI alone resulted in significantly reduced intracavernosal pressure/mean arterial pressure (MAP) and area under the curve/MAP, decreased smooth muscle (SM)/collagen ratio and SM content, higher caspase-3 activity, and increased protein levels of total HDAC3, transforming growth factor (TGF)-ß, fibronectin, and c-Jun phosphorylation, compared with the Sham surgery. The CNCI groups exposed to JNKi, HDACi or both showed improvements in erectile-responses and SM/collagen ratio, compared to the CNCI alone. The combined treatment showed additional improvement in erectile responses at 1.0V stimulation and in SM/collagen ratio compared to the single agent treatment. SM content, caspase-3 activity, and c-Jun phosphorylation improved in the two CNCI groups exposed to JNKi. The two CNCI groups exposed to HDACi showed normalization of protein levels of HDAC3, fibronectin, and TGF-ß. DISCUSSION AND CONCLUSIONS: The combined administration of JNKi and HDACi during the acute phase after CNCI in rats can preserve ED by suppressing cavernosal fibrosis and apoptosis by normalizing the HDAC/TGF-ß and JNK pathways.

The surgical difficulty of microsurgical subinguinal varicocelectomy is similar regardless of age.

PURPOSE: The reason for the low popularity of microsurgical subinguinal varicocelectomy in children has not been thoroughly explored. We investigated whether the lower popularity of microsurgical subinguinal varicocelectomy in children could be due to surgical difficulty. Therefore, we prospectively conducted a comparison of microsurgical subinguinal varicocelectomy in adults and children. MATERIALS AND METHODS: This study enrolled 93 male patients (62 children and 31 adults). During microsurgical subinguinal varicocelectomy with testicular delivery the number of internal spermatic, external spermatic, gubernacular and lymphatic vessels was systematically counted. In addition, the difficulty of separating the main internal spermatic artery from the internal spermatic veins was qualitatively graded. These variables were compared between adults and children, and the same comparison was conducted with regard to pubertal status. A multiple linear regression model was used to determine the factors affecting operative time, a surrogate marker for surgical difficulty. RESULTS: Comparison revealed a significantly longer operative time and a greater number of vessels involved in all venous systems in adults. With the exception of the gubernacular vein, which began to enlarge during puberty, an increased number of all venous systems was found after puberty. Regarding the difficulty of separation, no difference was noted based on age. Operative time was significantly affected by the number of ligated external spermatic and internal spermatic veins as well as the difficulty of the separation. CONCLUSIONS: These results indicated that the surgical difficulty of microsurgical subinguinal varicocelectomy was similar between adults and children. The lack of gubernacular vein enlargement in prepubertal boys may suggest the sparing of testicular delivery in this population.

Chronic treatment with an oral rho-kinase inhibitor restores erectile function by suppressing corporal apoptosis in diabetic rats.

INTRODUCTION: It has been suggested that the up-regulation of the contractile RhoA/Rho-kinase (ROCK) signaling pathway is one of the important mechanisms for diabetes-associated erectile dysfunction (ED). However, the exact role of RhoA/ROCK signaling in the pathogenesis of diabetes-related ED has not been fully delineated. AIM: To determine whether the RhoA/ROCK pathway is involved in the regulation of corporal apoptosis and whether administration of insulin or fasudil, a specific ROCK inhibitor, could ameliorate ED in streptozotocin-induced diabetic rats. MAIN OUTCOME MEASURES: At 16 weeks after diabetes induction, erectile function was assessed by cavernous nerve stimulation. Penile tissue was assessed for apoptosis with terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick end labeling assay. Expression of myosin phosphatase target subunit 1 (MYPT1), protein kinase B (Akt), and phospho-endothelial nitric oxide synthase (eNOS) were evaluated by Western blot. Immunohistochemical study was carried out for smooth muscle alpha-actin, B-cell leukemia/lymphoma 2 (Bcl-2), and Bcl-2-associated X Protein (Bax). Activity of caspase-3 and phosphatase and tensin homolog deleted on chromosome ten (PTEN) was also determined. METHODS: Male Sprague-Dawley rats (8 weeks old) were randomly divided into four groups: age-matched controls, diabetic controls, and diabetic rats treated with insulin (10 U/day, subcutaneous injection) or fasudil (30 mg/kg/day, oral) for the last 4 weeks of the 16 weeks after diabetes induction. RESULTS: Diabetic rats showed impairment of erectile function, increased MYPT1 phosphorylation, and corporal apoptosis. Expression of phospho-Akt, phospho-eNOS, and Bcl-2 were decreased, whereas activity of PTEN and caspase-3 and expression of Bax were increased. Treatment with fasudil normalized these molecular and histologic alterations, and restored erectile function. Insulin treatment showed similar effects to those of fasudil, however, the effects were smaller than fasudil. CONCLUSIONS: This study indicates that up-regulation of the penile RhoA/ROCK pathway in diabetic rats enhances corporal apoptosis via the PTEN/Akt pathway resulting in ED, which could be prevented by chronic treatment with fasudil.

Change of erectile function and responsiveness to phosphodiesterase type 5 inhibitors at different stages of streptozotocin-induced diabetes in rats.

INTRODUCTION: It has been suggested that risk of erectile dysfunction (ED) increases with duration of diabetes and phosphodiesterase type 5 inhibitors (PDE5I) are not as effective in treatment of diabetes-associated ED. However, few studies have investigated time-dependent change in erectile function during the course of diabetes. AIM: To investigate time-dependent change in erectile function and responsiveness to PDE5I in streptozotocin-induced diabetic rats and to understand the pathophysiology of diabetic ED. MAIN OUTCOME MEASURES: At 6, 8, 10, 12, and 14 weeks after diabetic induction, erectile function was assessed by cavernous nerve stimulation before and after administration of DA-8159, a novel PDE5I. Penile tissue was assessed for apoptosis with immunohistochemistry. Protein expression of Rho-kinase 2 (ROCK2), myosin phosphatase targeting subunit 1 (MYPT1), and endothelial nitric oxide synthase (eNOS) was evaluated by Western blot. METHODS: Streptozotocin was injected into 50 8-week-old male Sprague-Dawley rats, which were then classified into five diabetic groups according to the observation period. RESULTS: Diabetic rats maintained normal erectile responses until 6 weeks of diabetes. Following 8 weeks, the rats showed lower erectile responses at higher frequencies of nerve stimulation, which were normalized to control by administration of DA-8159. In contrast, erectile responses were significantly decreased in 10-week diabetic rats, and administration of DA-8159 resulted in partial recovery of normal responses. At more than 12 weeks, rats demonstrated severe deterioration of erectile function, which did not fully respond to PDE5I. Corporal apoptosis was significantly increased after 10 weeks. Upregulation of ROCK2 was found at 6 weeks, and was followed by an increase of MYPT1 phosphorylation. Phosphorylation of eNOS showed marked suppression at 6 weeks and remained lower during the experimental period. CONCLUSIONS: Impairment of erectile function was followed by decreased responsiveness to PDE5I during the course of diabetes. The RhoA/ROCK pathway played an important role in diabetes-associated ED.