Effects of transforming growth factor on the developing embryonic ureter: An in-vitro megaureter model in mice.

INTRODUCTION: It is generally agreed that the cause of a megaureter is narrowing at the vesicoureteral junction, with a functional obstruction arising from an aperistaltic, juxtavesical segment that is unable to transport urine at an acceptable rate. Histological examinations of megaureter specimens have reported several histological analyses, and the pathogenic role of transforming growth factor is still a matter of speculation. OBJECTIVE: To evaluate whether transforming growth factor-beta (TGF-ß) and its receptors (TGFRs) are expressed during ureterovesical junction (UVJ) and lower ureter development in mice, and whether exogenous TGF-ß might postpone the maturation of smooth muscle cells, in the pathogenesis of megaureter using an embryonic organ-culture model. METHODS: Expression of TGF-ß and TGFRs on the lower ureter and UVJ were determined at different embryonic days (E) (E16, 18, 20 and postnatal day 1). The functional studies were performed by harvesting ureters from wild-type mice at embryonic day 16 (E16), which were grown in serum-free organ-culture; some cultures were supplemented with TGF-ß (2 and 20 ng/ml) and/or with soluble TGFR, which blocks bioactivity. Organs were harvested after 6 days and the expression of CD31 and Ki67 were assessed using immunohistochemistry. The muscle content of the UVJ and ureter were analyzed by flowcytometry. RESULTS: The TGF-ß and TGFR positive cells were immune detected in embryonic ureters. The TGF-ß expression was highest on E18 and decreased postnatally. Exogenous TGF-ß decreased ureterovesical (UV) muscle differentiation and proliferation. The longitudinal muscle fibers were significantly less in TGF-ß explants. The TGF-ß also decreased the proportions of cells expressing α smooth muscle actin (α-SMA). Soluble TGFR blocked the effects of exogenous TGF-ß. CONCLUSIONS: In organ culture, exogenous TGF-ß postpones the UV smooth muscle proliferation and affects the muscular structure. Whether the effects of TGF-ß are direct or indirect, these form an in-vitro megaureter model. The finding that TGF-ß is highest in embryonic ureters in vivo and decreased postnatally suggests that a pathological persistence might potentially explain the pathogenesis of primary megaureters.

Can the effect of adhesion barriers and/or intravesical balloon inflation improve bladder autoaugmentation outcomes in a rabbit model?

INTRODUCTION: Bladder augmentation is used for the treatment of bladder dysfunction in order to minimize intravesical pressure and increase bladder capacity. However, less-invasive procedures, such as autoaugmentation, have been proposed due to several complications that have occurred using bowel and gastric segments. The technique of autoaugmentation involves wide excision of the detrusor by leaving the bladder mucosa intact and has shown increased bladder capacity and compliance. An additional step to keep the achieved surface area of this non-contractible bladder segment and, thus, bladder capacity, was reported by using an intravesical balloon to prevent shrinkage of the surgically achieved diverticulum during autoaugmentation. On the other hand, adhesion barriers (AB) with absorbable hydrogel, which can spare tissue and organ plans, are used to prevent postsurgical adhesions. The efficacy of sprayable AB has been demonstrated in animal models and it is now mostly used in laparoscopic surgeries. OBJECTIVE: The present study aimed to compare the efficacy of AB and/or intravesical balloon insertion, which might potentially improve the urodynamic and histopathological outcomes of autoaugmentation in a rabbit model. METHODS: A total of 25 New Zealand rabbits were included in the study. Following the surgical reduction to form a low-capacity bladder model (35-40% of the initial volume), standard detrusorotomy was performed in all groups except the sham group. Group 2 had only autoaugmentation as the control group. The bladders in Group 3 were supported with an intravesical balloon. An Adhesion Barrier System (CUI Tissue Expander) was used for all bladders in Group 4, without balloon inflation. In Group 5, both intravesical balloon inflation and adhesion barrier application were performed following autoaugmentation. Urodynamic evaluations were performed at day 0 before reduction, day 0 after reduction, and the 90th postoperative day. Capacity and compliance measurements were noted. Bladders were histopathologically evaluated. Expression of CD31 (microvessel density) and fibrosis were noted. RESULTS: Autoaugmentation does not result in a reliable increase in bladder capacity and compliance when compared to a sham group. Urodynamic measurements were similar in balloon-inflated groups (Group 3 and Group 5), showing a statistically significant improvement. Sprayable AB system alone revealed a slight, but not statistically significant, increase (Table). No significant differences between all five groups were detected regarding microvessel density (CD31 expression) and fibrosis. DISCUSSION: In the present study, the intravesical balloon application (IVBA) efficiency was investigated alone and in combination with AB. The main basis of this study were the previous findings, which demonstrated prevention or decrease in the contraction of diverticula by IVBA. The role of AB alone or within a combination was also evaluated. Adhesion barriers are mostly used in laparoscopic gynecologic and colorectal operations. They decrease the postoperative adhesions by forming a physical barrier. In the present study, it was thought that AB might reduce postoperative adhesions and enhance the outcome of autoaugmentation. One of the most important outcomes was the inconsistency of fibrosis density with final bladder capacity and compliance values; this finding did not support the role of fibrosis prevention with IVBA. The present study had some limitations: the partial cystectomy method, which was used to form a low-compliance bladder, is a different clinical condition to neurogenic bladder, and a rectal catheter was not used during urodynamic evaluation. General anesthesia and muscle relaxant were performed during urodynamy and abdominal contractions were not seen. CONCLUSION: Bladder autoaugmentation in a rabbit model, followed by intravesical balloon inflation offers improvement in bladder capacity and compliance. The use of sprayable adhesion barrier hydrogel technology may facilitate tissue healing and result in it being easier to maintain the success achieved by surgery when only supported with an intravesical balloon.

Efficacy and tolerability of udenafil in Turkish men with erectile dysfunction of psychogenic and organic aetiology: a randomized, double-blind, placebo-controlled study.

Udenafil is a potent phosphodiesterase type-5 inhibitor (PDE5) previously shown in studies conducted in populations of Eastern-Asian ethnicity, to significantly improve sexual function, in addition to a favourable safety profile. The purpose of this study was to evaluate the efficacy and safety of udenafil for the treatment of erectile dysfunction (ED), for the first time in a non-Eastern-Asian population. In this multicentre, randomized, double-blind, parallel, placebo-controlled study conducted in five centres in Turkey, 118 eligible subjects were randomized to receive udenafil 100 mg taken as on-demand or matching placebo for an 8-week treatment period. The primary efficacy variable was the change from baseline of the International Index of Erectile Function Questionnaire-Erectile Function Domain (IIEF-EFD) score, secondary efficacy variables were changes from baseline in IIEF Questionnaire Domains' 2-5 scores (Intercourse Satisfaction, Orgasmic Function, Sexual Desire, Overall Sexual Satisfaction) and IIEF Questionnaire Grand Total score, changes from baseline in penetration success rates (SEP2) and intercourse completion rates (SEP3) and evaluation of responses to the global assessment question (GAQ). Patients treated with udenafil demonstrated significantly higher increase in the IIEF-EFD scores compared with placebo-treated subjects [4.0 (95% CI: 1.3-6.6; p = 0.003)]. Similarly, greater improvements were observed in the scores for SEP2 [0.65 (95% CI: 0.02-1.3, p = 0.043)], SEP3 [0.9 (95% CI: 0.3-1.5, p = 0.003)] and two other IIEF Questionnaire Domains (Domain 4: Sexual Desire, Domain 5: Overall Sexual Satisfaction). The proportion of positive responses to the GAQ was greater in the udenafil compared to the placebo group (72.2% vs. 49.1%, p = 0.014). The most frequent treatment-emergent adverse events were headache, flushing and rhinorrhea, all of mild or moderate severity. This is the first study to demonstrate in a non-Eastern-Asian population that udenafil 100 mg taken as on-demand can effectively improve erectile function and is well tolerated.