Inhibition of growth and contraction in human prostate stromal cells by silencing of NUAK1 and -2, and by the presumed NUAK inhibitors HTH01-015 and WZ4003.

Background: NUAKs promote myosin light chain phosphorlyation, actin organization, proliferation and suppression of cell death in non-muscle cells, which are critical for smooth muscle contraction and growth. In benign prostatic hyperplasia (BPH), contraction and growth in the prostate drive urethral obstruction and voiding symptoms. However, a role of NUAKs in smooth muscle contraction or prostate functions are unknown. Here, we examined effects of NUAK silencing and the presumed NUAK inhibitors, HTH01-015 and WZ4003 on contraction and growth-related functions in prostate stromal cells (WPMY-1) and in human prostate tissues. Methods: Effects of NUAK1 and -2 silencing, HTH01-015 and WZ4003 on matrix plug contraction, proliferation (EdU assay, Ki-67 mRNA), apoptosis and cell death (flowcytometry), viability (CCK-8) and actin organization (phalloidin staining) were examined in cultured WPMY-1 cells. Effects of HTH01-015 and WZ4003 on smooth muscle contraction were assessed in organ bath experirments with human prostate tissues. Results: Effects of silencing were most pronounced on proliferation and cell death, resulting in decreases of proliferation rate by 60% and 70% by silencing of NUAK1 and NUAK2 (compared to scramble siRNA-transfected controls), decreases in Ki-67 by 75% and 77%, while numbers of dead cells after silencing of NUAK1 and NUAK2 amounted to 2.8 and 4.9 fold of scramble-transfected controls. Silencing of each isoform was paralleled by reduced viability, breakdown in actin polymerization, and partial decreases in contractility (maximally 45% by NUAK1 silencing, 58% by NUAK2 silencing). Effects of silencing were mimicked by HTH01-015 and WZ4003, with numbers of dead cells amounting up to 16.1 fold or 7.8 fold with HTH01-015 or WZ4003, compared to solvent-treated controls. Using concentrations of 500 nM, neurogenic contractions of prostate tissues were inhibited partly by HTH01-015 and U46619-induced contractions were inhibited partly by HTH01-015 and WZ4003, while α1-adrenergic and endothelin-1-induced contractions remained unaffected. Using 10 µM, inhibition of endothelin-1-induced contractions by both inhibitors and inhibition of α1-adrenergic contractions by HTH01-015 added to effects seen by 500 nM. Conclusion: NUAK1 and -2 suppress cell death and promote proliferation in prostate stromal cells. A role in stromal hyperplasia appears possible in BPH. Effects of NUAK silencing are mimicked by HTH01-015 and WZ4003.

Inhibition of α1-Adrenergic, Non-Adrenergic and Neurogenic Human Prostate Smooth Muscle Contraction and of Stromal Cell Growth by the Isoflavones Genistein and Daidzein.

Isoflavone-rich legumes, including soy, are used for food production, as dietary supplements and in traditional medicine. Soy consumption correlates negatively with benign prostatic hyperplasia (BPH) and voiding symptoms. However, isoflavone effects on the prostate are hardly known. Here, we examined the effects on human prostate smooth muscle contractions and stromal cell growth, which are driving factors of voiding symptoms in BPH. Smooth muscle contractions were induced in prostate tissues from radical prostatectomy. Growth-related functions were studied in cultured stromal cells (WPMY-1). Neurogenic, α1-adrenergic and non-adrenergic contractions were strongly inhibited with 50 µM and by around 50% with 10 µM genistein. Daidzein inhibited neurogenic contractions using 10 and 100 µM. Agonist-induced contractions were inhibited by 100 µM but not 10 µM daidzein. A combination of 6 µM genistein with 5 µM daidzein still inhibited neurogenic and agonist-induced contractions. Proliferation of WPMY-1 cells was inhibited by genistein (>50%) and daidzein (<50%). Genistein induced apoptosis and cell death (by seven-fold relative to controls), while daidzein induced cell death (6.4-fold) without apoptosis. Viability was reduced by genistein (maximum: 87%) and daidzein (62%). In conclusion, soy isoflavones exert sustained effects on prostate smooth muscle contractions and stromal cell growth, which may explain the inverse relationships between soy-rich nutrition, BPH and voiding symptoms.

Antagonism of α1-adrenoceptors by ß3-adrenergic agonists: Structure-function relations of different agonists in prostate smooth muscle contraction.

Effects of ß3-adrenergic agonists on prostate smooth muscle contraction are poorly characterized, although mirabegron is used for treatment of lower urinary tract symptoms. Off-target effects of several ß3-adrenergic agonists include antagonism of α1-adrenoceptors. Proposed, but unconfirmed explanations include phenylethanolamine backbones, found in some ß3-adrenergic agonists and imparting interaction with catecholamine binding pockets of adrenoceptors. Here, we examined effects of ß3-adrenergic agonists on contractions of human prostate tissues, including ZD7114 (without phenylethanolamine moiety), ZD2079 (phenylethanolamine backbone), BRL37344 and CL316243 (chloride-substituted phenylethanolamine deriatives). Prostate tissues were obtained from radical prostatectomy. Contractions by α1-adrenergic agonists and electric field stimulation (EFS) were studied in an organ bath. ZD7114 (10 µM) right-shifted concentration responses curves for α1-adrenergic agonists, resulting in increased EC50 values for phenylephrine, methoxamine and noradrenaline up to one magnitude, without affecting Emax values. ZD7114 (10 µM) inhibited EFS-induced contractions, resulting in reduced Emax values. All effects of ZD7114 were resistant to the ß3-adrenergic antagonist L-748337, including increases in EC50 values for α1-adrenergic agonists, up to more than two magnitudes. Using 10 µM, neither ZD2079, BRL37344 or CL316243 affected α1-adrenergic or EFS-induced contractions. At escalated concentrations, BRL37344 (200 µM) right-shifted concentration response curves for phenylephrine, increased EC50 values for phenylephrine, and inhibited EFS-induced contractions, while CL316243 (300 µM) did not affect phenylephrine- or EFS-induced contractions. In conclusion, phenylethanolamine backbones are not decisive to impart α1-adrenoceptor antagonism to ß3-agonists. Effects of ß3-adrenergic agonists on prostate smooth muscle contraction are limited to off-target effects, including α1-adrenoceptor antagonism by ZD7114 and BRL37344.

Clinical Evaluation of Single-Use, Fiber-Optic, and Digital Ureterorenoscopes in the Treatment of Kidney Stones.

INTRODUCTION: Indication of ureteroscopy for the treatment of urolithiasis has expanded immensely over the last decade. Fiber-optic and digital reusable instruments present the standard in clinical practice, but various newly available single-use devices might offer an exciting alternative. To date, the evidence is limited to clinical evaluation and efficacy of single-use ureteroscopes (URS) compared to standard instruments. Therefore, we evaluate a single-use instrument's clinical characteristics and efficacy in direct comparison with a fiber-optic and digital device. METHODS: A prospective study was conducted for patients undergoing endoscopic therapy for urolithiasis at a tertiary care center. We evaluated the different instruments' clinical performance in categories of visibility, the stability of visibility, irrigation flow, and surgeon's satisfaction. Statistical analyses were performed by SPSS using the Chi-Quadrat and Kruskal-Wallis test. A p value of p ≤ 0.05 was defined as statistically significant. RESULTS: A total number of 77 patients were included and distributed as follows: 35 (46.7%) single-use, 19 (25.3%) digital, and 23 (28%) fiber-optic URS. Patients' characteristics were homogenous over the three cohorts in sex, stone amount, and localization. The stone-free rate was equal in all three cohorts (p = 0.31). We identify stability of visibility, irrigation flow, and satisfaction were equal in all cohorts (p = 0.73; p = 0.20; p = 0.20). We report a significant difference in visibility, with 100% rated excellent in the digital URS group (p = 0.028). DISCUSSION/CONCLUSIONS: Single-use URS achieve comparable clinical outcomes with equal stone-free rates in direct comparison with fiber-optic and digital reusable instruments. Accordingly, single-use devices present an adequate alternative for endoscopic therapy of urolithiasis.

Inhibition of Full Smooth Muscle Contraction in Isolated Human Detrusor Tissues by Mirabegron Is Limited to Off-Target Inhibition of Neurogenic Contractions.

Mirabegron is used for treatment of storage symptoms in overactive bladder (OAB) caused by spontaneous bladder smooth muscle contractions. However, owing to limitations in available studies using human tissues, central questions are still unresolved, including mechanisms underlying improvements by mirabegron and its anticontractile effects in the detrusor. Here, we assessed concentration-dependent mirabegron effects on contractions of human detrusor tissues in frequency-response curves and concentration-response curves for different cholinergic and noncholinergic agonists. Detrusor tissues were sampled from patients undergoing radical cystectomy. Contractions were induced by electric field stimulation (EFS) and by cumulative concentrations of cholinergic agonists, endothelin-1, and the thromboxane A2 analog U46619. EFS-induced contractions were inhibited using 10 µM mirabegron, but not using 1 µM. Inhibition by 10 µM mirabegron was resistant to the ß 3-adrenergic antagonist L-748,337. Concentration-dependent contractions by carbachol were not inhibited by 1 µM or 10 µM mirabegron. Concentration-response curves for methacholine were slightly right-shifted by 10 µM, but not 1 µM mirabegron. Concentration-dependent contractions by endothelin-1 or U46619 were not changed by mirabegron. In contrast, the muscarinic antagonist tolterodine right-shifted concentration-response curves for carbachol and methacholine and inhibited EFS-induced contractions. In conclusion, inhibition of neurogenic contractions in isolated detrusor tissues by mirabegron requires concentrations highly exceeding known plasma levels during standard dosing and the known binding constant (Ki values) for ß 3-adrenoceptors. Full contractions by cholinergic agonists, endothelin-1, and U46619 are not affected by therapeutic concentrations of mirabegron. Improvements of storage symptoms are most likely not imparted by inhibition of ß 3-adrenoceptors in the bladder wall itself. SIGNIFICANCE STATEMENT: Mirabegron is used for overactive bladder (OAB) treatment, but the underlying mechanisms are unclear, and preclinical and clinical findings are controversial due to limitations in available studies. Our findings suggest that inhibition of detrusor contractions by mirabegron is limited to neurogenic contractions, which requires unphysiologic concentrations and does not involve ß 3-adrenoceptors. Mechanisms accounting for improvements of OAB by mirabegron are located outside the urinary bladder.

Inhibition of human prostate smooth muscle contraction by the inhibitors of protein kinase C, GF109203X, and Go6983.

INTRODUCTION: Prostate smooth muscle contraction is promoted by receptor-induced activation of intracellular signaling pathways. The presumed involvement in etiology and medical treatment of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) imparts a high clinical relevance to prostate smooth muscle contraction, which is contrasted by incomplete understanding at the molecular level. Involvement of protein kinase C (PKC) has been commonly assumed, but available studies were limited to nonhuman prostate smooth muscle or cell cultures. Here, we examined the effects of the PKC inhibitors Go6983 and GF109203x on contractions of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS), α1 -adrenergic agonists (noradrenaline, phenylephrine, methoxamine), thromboxane A2 analog U46619, endothelin-1, or calcium chloride in an organ bath. RESULTS: GF109203X (500 nM) and Go6983 (300 nM) reduced EFS-, noradrenaline-, phenylephrine-, methoxamine-, and U46619-induced contractions of human prostate tissues, with maximum inhibitions approaching up to 55%. Using concentrations of 3 µM, GF109203X and Go6983 inhibited EFS- and noradrenaline-induced contractions, with similar effect sizes as 500 and 300 nM, respectively. Endothelin-1-induced contractions were not inhibited by GF109203X, and to neglectable extent by Go6983. After depolarization in calcium-free solution, calcium chloride-induced concentration-dependent contractions, which were inhibited by GF109203X and Go6983. CONCLUSIONS: GF109203X and Go6983 inhibit neurogenic, α1 -adrenergic, and thromboxane A2 -induced smooth muscle contractions in the human prostate, suggesting a role of PKC for human prostate smooth muscle contraction. The inhibition may by be imparted by inhibition of calcium sensitivity.

Concentration-dependent alpha1-Adrenoceptor Antagonism and Inhibition of Neurogenic Smooth Muscle Contraction by Mirabegron in the Human Prostate.

Introduction: Mirabegron is available for treatment of storage symptoms in overactive bladder, which may be improved by ß3-adrenoceptor-induced bladder smooth muscle relaxation. In addition to storage symptoms, lower urinary tract symptoms in men include obstructive symptoms attributed to benign prostatic hyperplasia, caused by increased prostate smooth muscle tone and prostate enlargement. In contrast to the bladder and storage symptoms, effects of mirabegron on prostate smooth muscle contraction and obstructive symptoms are poorly understood. Evidence from non-human smooth muscle suggested antagonism of α1-adrenoceptors as an important off-target effect of mirabegron. As α1-adrenergic contraction is crucial in pathophysiology and medical treatment of obstructive symptoms, we here examined effects of mirabegron on contractions of human prostate tissues and on proliferation of prostate stromal cells. Methods: Contractions were induced in an organ bath. Effects of mirabegron on proliferation, viability, and cAMP levels in cultured stromal cells were examined by EdU assays, CCK-8 assays and enzyme-linked immunosorbent assay. Results: Mirabegron in concentrations of 5 and 10 µM, but not 1 µM inhibited electric field stimulation-induced contractions of human prostate tissues. Mirabegron in concentrations of 5 and 10 µM shifted concentration response curves for noradrenaline-, methoxamine- and phenylephrine-induced contractions to the right, including recovery of contractions at high concentrations of α1-adrenergic agonists, increased EC50 values, but unchanged Emax values. Rightshifts of noradrenaline concentration response curves and inhibition of EFS-induced contractions were resistant to L-748,337, l-NAME, and BPIPP. 1 µM mirabegron was without effect on α1-adrenergic contractions. Endothelin-1- and U46619-induced contractions were not affected or only inhibited to neglectable extent. Effects of mirabegron (0.5-10 µM) on proliferation and viability of stromal cells were neglectable or small, reaching maximum decreases of 8% in proliferation assays and 17% in viability assays. Mirabegron did not induce detectable increases of cAMP levels in cultured stromal cells. Conclusion: Mirabegron inhibits neurogenic and α1-adrenergic human prostate smooth muscle contractions. This inhibition may be based on antagonism of α1-adrenoceptors by mirabegron, and does not include activation of ß3-adrenoceptors and requires concentrations ranging 50-100fold higher than plasma concentrations reported from normal dosing. Non-adrenergic contractions and proliferation of prostate stromal cells are not inhibited by mirabegron.

Evaluation of intrarenal pressure stability at different lithotripter suction settings in a porcine kidney model.

PURPOSE: Using the Swiss LithoClast® Trilogy, urinary stones can be fragmented and removed simultaneously by suction at different selectable suction settings. The aim was to evaluate pressure stability at different settings and test stone fragmentation and suction at the optimal settings. METHODS: In an ex vivo porcine kidney model, we recorded intrarenal pressure levels with different suction levels. Storz® Nephroscopes MIP-M and MIP-L and Swiss LithoClast® Trilogy probes were used. RESULTS: Pressure stabilized at 19 cm H2O with the MIP-M at 1 m gravity irrigation with no instrument introduced. After inserting the 1.5 mm probe, the pressure dropped to 5 cm H2O. With a suction setting of 10%, the pressure stabilized at 3 cm H2O and remained stable for the maximum time of 120 s. After increasing the suction to 20, 30, 40, and 50%, we recorded the pressure drop time to 0 after 22, 14, 11, and 8 s. Using the MIP-L, pressure stabilized at 44 cm H2O and decreased to 8 cm H2O after inserting the 3.4 mm probe. With 10% suction, a pressure stabilization was measured at 2 cm H2O and remained stable for 120 s. At suction levels of 20 and 30%, the pressure drop time to 0 was 6 and 5 s. With a 10% suction, removing stones was efficient, and the kidney's filling volume was maintained. CONCLUSIONS: When using the LithoClast® Trilogy, a suction setting of 10% seems to be optimal for the treatment of urinary calculi when applying suction continuously.

Purinergic smooth muscle contractions in the human prostate: estimation of relevance and characterization of different agonists.

Non-adrenergic prostate smooth muscle contractions may account for the limited effectiveness of α1-adrenoceptor antagonists, which are the first-line option for medical treatment of voiding symptoms suggestive of benign prostatic hyperplasia. In non-human prostates, purinergic agonists induce contractions reaching similar magnitudes as α1-adrenergic contractions. However, evidence for the human prostate is highly limited, and pointed to much weaker purinergic contractions. Here, we examined contractions of different purinergic agonists in human prostate tissues. Tissues were obtained from radical prostatectomy. Contractions were studied in an organ bath, and expression of purinergic receptors was studied by RT-PCR. Electric field stimulation (EFS)-induced contractions amounted to 104% of KCl-induced contractions (95% CI: 84-124%). From all tested agonists, only ATP induced concentration-dependent contractions, reaching an average maximum of 18% (12-24%) of KCl. Maximum tensions following application of other agonists averaged to 7.1% of KCl for α,ß-methylene-ATP (1.8-12.4%), 3.9% for ß,γ-methylene-ATP (2.0-5.4%), 3.1% for 2-methylthio-ATP (- 0.1-6.3%), and 5.1% for ATPγS (1.0-9.2%). Responses were not affected by the P2X antagonist NF023 or the P2Y antagonist PPADS. mRNA expression of P2X1-4 correlated with expression of a marker for catecholaminergic nerves, although neither ATP, NF023, nor PPADS changed EFS-induced contractions. Correlation between expression of receptors and the smooth muscle marker calponin was not observed. Our findings point to a low relevance of purinergic contractions in the human prostate, compared to other contractile stimuli in the human prostate and compared to purinergic contractions in non-human prostates. Purinergic contractions in the human prostate are not sensitive to NF023 or PPADS.

Adherence to guidelines in the management of urolithiasis: are there differences among distinct patient care settings?

INTRODUCTION: Urolithiasis is a common diagnosis in urology. New technologies offer a variety of diagnostic and therapy and consequently display a financial burden on healthcare systems. Hence, clinical practice guidelines (CPG) are essential to implement evidence-based medicine and assure a standard of care considering limited resources. To date, there is no evidence of the use and adherence to CPG on urolithiasis. MATERIAL AND METHODS: Therefore, we performed a cross-sectional study to analyze the use of CPG on urolithiasis. Data collection was carried out by a questionnaire given to 400 German urologists. The survey included use and adherence to guidelines, evaluation of the clinical situation, therapy spectrum, and workplace. In total, 150 (37%) questionnaires were received and included in our survey. Statistics were performed by SPSS using Chi-quadrat test/Fisher's exact test. RESULTS: In our study, urologists were office based, hospital affiliated, non-academic, or academic centers in 53%, 32%, 16% and 5%, respectively. In 74% and 70%, urologists adhere to CPG in diagnostic and therapy. Interestingly, workplace and therapy spectrum determines the use of different CPG (p = 0.01; p = 0.022). Academic urologists were more likely to use international CPG of EAU (40%), while outpatient urologists significantly orientated on national CPG (46%). 86% of urologists with high volume of urolithiasis practice interventions in contrast to 53% in low volume (p = 0.001). More than 80% of urologists use short versions and app version of CPG. CONCLUSION: We firstly describe compliance and the use of CPG on urolithiasis. EAU and DGU present the most commonly used CPG. Short version and app version of CPG find frequent clinical utilization.

Impact of previous transurethral prostate surgery on health-related quality of life after radical prostatectomy: Does the interval between surgeries matter?

PURPOSE: To assess the impact of previous transurethral surgery for benign prostate enlargement (BPE) and time interval between procedures on functional outcomes and health-related quality of life (HRQOL) after radical prostatectomy (RP). METHODS: A propensity score-matched patient cohort [n = 685, (513 without previous BPE surgery, 172 with BPE surgery)] was created and HRQOL was pre- and postoperatively assessed using validated questionnaires (EORTC QLQ-C30). Urinary continence was measured via ICIQ-SF questionnaire and pad usage. Multivariable analysis included binary logistic and Cox regression models (p < 0.05). RESULTS: Median follow-up was 18 months. There was no significant difference in recurrence-free survival in multivariate analysis (HR 0.66, 95%CI 0.40-1.07, p = 0.093). We observe higher mean ICIQ-SF scores (5.7 vs. 8.2, p < 0.001) and daily pad usage (1.3 vs. 2.5, p < 0.001), and decreased continence recovery (OR 0.46, 95%CI 0.30-0.71, p < 0.001) for patients with BPE surgery. Postoperative general HRQOL scores were significantly lower for patients with previous BPE surgery (70.6 vs. 63.4, p = 0.003). In multivariate analysis, continence recovery (OR 5.19, 95%CI 3.10-8.68, p < 0.001) but not previous BPE surgery (0.94, 0.57-1.54, p = 0.806) could be identified as independent predictors of good general HRQOL. There was no significant correlation between time interval between both surgeries and continence (p = 0.408), and HRQOL (p = 0.386) outcomes. CONCLUSIONS: We observe favourable continence outcomes for patients without previous BPE surgery. Our results indicate that RP can be safely performed after transurethral BPE surgery, regardless of the time interval between both interventions.

Comparison of stone elimination capacity and drilling speed of endoscopic clearance lithotripsy devices.

PURPOSE: To investigate the fragmentation capacity, clearance time, and drilling speed of combined ultrasonic with impact dual-energy and single energy ultrasonic lithotripter devices. METHODS: Stone fragmentation and clearance tests were performed under direct view in an underwater layered hemisphere by four different operators using artificial stones (n = 10/operator). Time for complete clearance was measured. Drilling tests were performed using an underwater setup, consisting of a mounting rack for fixing the lithotripter handpiece with the probe in vertical position and in contact with the stone phantom placed on one side of a balance for defined and constant contact application pressure equivalent to 450 g load. Time until complete perforation or in case of no perforation, the penetration depth after 60 s into the stone sample was recorded. Four devices, one single energy device (SED), one dual-energy dual probe (DEDP), two dual-energy single probe (DESP-1, DESP-2), with different parameters were tested. RESULTS: Stone fragmentation and clearance speed were significantly faster for dual-energy device DESP-1 compared to all other devices (p < 0.001). Using DESP-1, the clearance time needed was 26.0 ± 5.0 s followed by DESP-2, SED and DEDP requiring 38.4 ± 5.8 s, 40.1 ± 6.3 s and 46.3 ± 11.6 s, respectively. Regarding the drilling speed, DESP-1 was faster compared to all other devices used (p < 0.05). While the drilling speed of DESP-1 was 0.69 ± 0.19 mm/s, compared to 0.49 ± 0.18 mm/s of DESP-2, 0.47 ± 0.09 mm/s of DEDP, and 0.19 ± 0.03 mm/s of SED. CONCLUSIONS: The dual-energy/single-probe device combining ultrasonic vibrations with electromechanical impact was significantly faster in fragmentation and clearing stone phantoms as well as in drilling speed compared to all other devices.

The transient receptor potential A1 ion channel (TRPA1) modifies in vivo autonomous ureter peristalsis in rats.

AIMS: The current study aimed to explore the expression of transient receptor potential A1 ion channels (TRPA1) in the rat ureter and to assess if TRPA1-active compounds modulate ureter function. METHODS: The expression of TRPA1 in rat ureter tissue was studied by immunofluorescence. The TRPA1 distribution was compared to calcitonin gene-related peptide (CGRP), α-actin (SMA1), anoctamin-1 (ANO1), and c-kit. For in vivo analyses, a catheter was implanted in the right ureter of 50 rats. Ureter peristalsis and pressures were continuously recorded by a data acquisition set-up during intraluminal infusion of saline (baseline), saline plus protamine sulfate (PS; to disrupt the urothelium), saline plus PS with hydrogen sulfide (NaHS) or cinnamaldehyde (CA). Comparisons were made between rats treated systemically with vehicle or a TRPA1-antagonist (HC030031). RESULTS: TRPA1-immunoreactive nerves co-expressed CGRP and were mainly located in the suburothelial region of the ureter. Immunoreactivity for TRPA1 was also encountered in c-kit-positive but ANO1-negative cells of the ureter suburothelium and wall. In vivo, HC030031-treated rats had elevated baseline peristaltic frequency (p < 0.05) and higher intraluminal pressures (p < 0.01). PS increased the frequency of ureter peristalsis versus baseline in vehicle-treated rats (p < 0.001) but not in HC030031-treated rats. CA (p < 0.001) and NaHS (p < 0.001) decreased ureter peristalsis. This was counteracted by HC030031 (p < 0.05 and p < 0.01). CONCLUSIONS: In rats, TRPA1 is expressed on cellular structures considered of importance for peristaltic and mechanoafferent functions of the ureter. Functional data indicate that TRPA1-mediated signals regulate ureter peristalsis. This effect was pronounced after mucosal disruption and suggests a role for TRPA1 in ureter pathologies involving urothelial damage.

Influence of the laser pulse shape in the treatment of stones in the upper urinary tract.

PURPOSE: Urinary stones can be successfully treated using a Holmium: Yttrium-Aluminum-Garnet (Ho: YAG) laser. Regarding success rates, laser pulse energy, frequency, and pulse width are well-known contributing factors. Whether the pulse shape might be a further factor influencing the laser efficiency is unclear. This study aimed to evaluate different modes of laser pulse shapes in a real-world setting. MATERIALS AND METHODS: The Dornier Medilas® H Solvo (Weßling, Germany) was used in the treatment of ureter and kidney stones. Patients were randomized into standard pulse shape (SPS) and new pulse shape groups (NPS1; ureter) and (NPS2; kidney pelvis), depending on the stone localization. The primary endpoint was laser efficiency defined as mm³ stone destruction per overall operating time. Secondary endpoints encompassed number of stone recoveries and stone-free rate. RESULTS: Altogether 145 patients (24 SPS vs. 32 NPS1; 51 SPS vs. 38 NPS2) were included. No differences in sex, age, body mass index, stone localization and stone composition were found, except for preoperative stone size (133±95 [SPS] vs. 197±139 [NPS1] mm³; p=0.023) and (348±298 [SPS] vs. 525±429 [NPS2] mm³; p=0.042). Regarding the primary endpoint, a significant increase in laser efficiency could be detected for the NPS1 and NPS2 groups compared to the SPS groups (39.9±44.9 vs. 28.8±30.2 and 51.7±61.3 vs. 22.4±24.2 mm³/min [mean±standard deviation]). No statistically significant differences were found for secondary endpoints and perioperative complication rates. CONCLUSIONS: Efficiency of the Ho: YAG laser can be positively influenced by different pulse shapes. This adds the variable of individualized intraoperative decision making.

Open ureteroplasty with buccal mucosa graft for long proximal strictures: A good option for a rare problem.

Purpose: To report a single surgeon experience with one year follow-up after open ureteroplasty with buccal mucosa graft (OUBMG) in the rare situation of long segment proximal ureteral strictures. Materials and Methods: Four patients with long segment proximal ureteral stricture underwent OU-BMG between February and July 2017. Functional outcome was assessed by pre- and postoperative serum creatinine, ultrasound and renal scintigraphy as well as patient reported outcomes. Results: Four patients with an average stricture length of 4 cm underwent OU-BMG between February and July 2017. No major postoperative complications occurred. Retrograde uretero-pyelography 6 weeks postoperatively revealed a watertight anastomosis followed by immediate emptying of the renal pelvis and ureter in all four patients. Ureteroscopy at this time showed a wide lumen with well-vascularized pink mucosa. After a mean follow-up time of 12.5 (12-14) months, postoperative serum creatinine was unimpaired. Renal scintigraphy revealed no signs of renal obstruction. With regard to intraoral surgery, no difficulties with mouth opening or intraoral dryness or numbness were reported. Conclusions: For patients with long segment ureteral strictures OU-BMG is a safe technique with excellent surgical and functional outcomes. Hence, the application of this technique should be encouraged and regarded as one of the standard options in case of this rare problem.

Inhibition of Female and Male Human Detrusor Smooth Muscle Contraction by the Rac Inhibitors EHT1864 and NSC23766.

INTRODUCTION: Lower urinary tract symptoms (LUTS) due to overactive bladder (OAB) are caused by spontaneous detrusor contractions. Medical treatment with muscarinic receptor antagonists or ß3-adrenoceptor agonists aims to inhibit detrusor contractions, but overall results are unsatisfactory. Consequently, improved understanding of bladder smooth muscle contraction and identification of novel compounds for its inhibition are needed to develop alternative options. A role of the GTPase Rac1 for smooth muscle contraction has been reported from the prostate, but is unknown in the human detrusor. Here, we examined effects of the Rac inhibitors NSC23766, which may also antagonize muscarinic receptors, and EHT1864 on contraction of human detrusor tissues. METHODS: Female and male human detrusor tissues were obtained from radical cystectomy. Effects of NSC23766 (100 µM) and EHT1864 (100 µM) on detrusor contractions were studied in an organ bath. RESULTS: Electric field stimulation induced frequency-dependent contractions of detrusor tissues, which were inhibited by NSC23766 and EHT1864. Carbachol induced concentration-dependent contractions. Concentration response curves for carbachol were shifted to the right by NSC23766, reflected by increased EC50 values, but unchanged Emax values. EHT1864 reduced carbachol-induced contractions, resulting in reduced Emax values for carbachol. The thromboxane analog U46619 induced concentration-dependent contractions, which remained unchanged by NSC23766, but were reduced by EHT1864. CONCLUSIONS: NSC23766 and EHT1864 inhibit female and male human detrusor contractions. NSC23766, but not EHT1864 competitively antagonizes muscarinic receptors. In addition to neurogenic and cholinergic contractions, EHT1864 inhibits thromboxane A2-induced detrusor contractions. The latter may be promising, as the origin of spontaneous detrusor contractions in OAB is noncholinergic. In vivo, both compounds may improve OAB-related LUTS.

Comparative investigation of reusable and single-use flexible endoscopes for urological interventions.

In order to evaluate the technical adaptability of a type of disposable endoscope compared to reusable flexible endoscopes, in vitro and in vivo studies were conducted. A disposable digital ureteroscope ("chip on tip") and two reusable endoscopes were investigated with respect to spatial resolution, geometric distortion in air and water the maximum. Additionally, the clinical performance of the disposable device was tested during clinical procedures (n = 20). The disposable endoscope showed an optical resolution of 6.72 lines/mm at 10 mm distance, similar to the other devices. In comparison, the disposable endoscope showed a barrel-shaped image distortion in air of -24.2%, which is in the middle range, but was best under water (-8.6%). The bendability of 297° (275 µm fiber) and 316° (empty channel, 1.5 F basket) and the maximum irrigation (1 m: 58.1 ml/min, 2 m: 91.9 ml/min) were convincing. Clinically the maneuverability was very good in (13/20), good or satisfactory in (7/20). Visibility was evaluated as very good in (11/20), just in (1/20) either satisfactory or sufficient. The consistency of visibility was not affected in (19/20). In all cases there were no adverse events. The technical examination and clinical application of the disposable endoscope are of equal quality compared to reusable devices. Disposable endoscopes can be an alternative to reusable devices, but economic aspects such as reduction of repair costs, sterilization effort and additional waste must be taken into account.

Health-related quality of life after open and robot-assisted radical prostatectomy in low- and intermediate-risk prostate cancer patients: a propensity score-matched analysis.

PURPOSE: Introduction of robot-assisted radical prostatectomy (RARP) has revolutionized the therapeutic landscape of organ-confined prostate cancer (PCa). However, comparative analyses focused on health-related quality of life (HRQOL) after RARP and open retropubic prostatectomy (ORP) are sparse. METHODS: In the current retrospective analysis, inclusion criteria encompassed PSA ≤ 10 ng/ml, ≤ pT2c, ISUP ≤ 3, age ≤ 65 years, and preoperative continence. A propensity score-matched patient cohort [n = 418 (ORP: 209, RARP: 209)] was created and HRQOL was prospectively assessed based on validated questionnaires (EORTC QLQ-C30) preoperatively, 3 months, 12 months, and 24 months postoperatively. Primary endpoint was good general HRQOL based on previously published cut-off values. Erectile function was measured via IIEF-5, urinary continence via ICIQ-SF questionnaire. Multivariable analysis included binary logistic regression models (p < 0.05). RESULTS: Open retropubic prostatectomy and RARP cohorts were well balanced. General HRQOL was significantly higher for ORP compared to RARP after 3 months (70.1 vs. 61.6, p = 0.001), but not at the remaining follow-up time points. There were no significant differences for the remaining QLQ-C30 functioning and symptom scores. In multivariable analysis stratified for IIEF-5 and ICIQ-SF scores and surgeon experience, RARP could be confirmed as a marginally independent predictor for lower ratios of good general HRQOL after 3 months (OR 0.464, 95% CI 0.215-0.999; p = 0.050) without any differences at the remaining time points. CONCLUSIONS: The current study addresses various HRQOL outcomes over a postoperative period of up to 2 years in a homogenous propensity score-matched contemporary cohort. Marginally better general HRQOL outcomes could be detected for ORP compared to RARP 3 months postoperatively.