Cytokine Effects on Gap Junction Communication and Connexin Expression in Human Bladder Smooth Muscle Cells and Suburothelial Myofibroblasts

BACKGROUND: The last decade identified cytokines as one group of major local cell signaling molecules related to bladder dysfunction like interstitial cystitis (IC) and overactive bladder syndrome (OAB). Gap junctional intercellular communication (GJIC) is essential for the coordination of normal bladder function and has been found to be altered in bladder dysfunction. Connexin (Cx) 43 and Cx45 are the most important gap junction proteins in bladder smooth muscle cells (hBSMC) and suburothelial myofibroblasts (hsMF). Modulation of connexin expression by cytokines has been demonstrated in various tissues. Therefore, we investigate the effect of interleukin (IL) 4, IL6, IL10, tumor necrosis factor-alpha (TNFα) and transforming growth factor-beta1 (TGFβ1) on GJIC, and Cx43 and Cx45 expression in cultured human bladder smooth muscle cells (hBSMC) and human suburothelial myofibroblasts (hsMF). METHODOLOGY/PRINCIPAL FINDINGS: HBSMC and hsMF cultures were set up from bladder tissue of patients undergoing cystectomy. In cytokine stimulated cultured hBSMC and hsMF GJIC was analyzed via Fluorescence Recovery after Photo-bleaching (FRAP). Cx43 and Cx45 expression was assessed by quantitative PCR and confocal immunofluorescence. Membrane protein fraction of Cx43 and Cx45 was quantified by Dot Blot. Upregulation of cell-cell-communication was found after IL6 stimulation in both cell types. In hBSMC IL4 and TGFβ1 decreased both, GJIC and Cx43 protein expression, while TNFα did not alter communication in FRAP-experiments but increased Cx43 expression. GJ plaques size correlated with coupling efficacy measured, while Cx45 expression did not correlate with modulation of GJIC. CONCLUSIONS/SIGNIFICANCE: Our finding of specific cytokine effects on GJIC support the notion that cytokines play a pivotal role for pathophysiology of OAB and IC. Interestingly, the effects were independent from the classical definition of pro- and antiinflammatory cytokines. We conclude, that connexin regulation involves genomic and/or post-translational events, and that GJIC in hBSMC and hsMF depend of Cx43 rather than on Cx45

New Aspects in the Differential Diagnosis and Therapy of Bladder Pain Syndrome/Interstitial Cystitis

Diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC) is presently based on mainly clinical symptoms. BPS/IC can be considered as a worst-case scenario of bladder overactivity of unknown origin, including bladder pain. Usually, patients are partially or completely resistant to anticholinergic therapy, and therapeutical options are especially restricted in case of BPS/IC. Therefore, early detection of patients prone to develop BPS/IC symptoms is essential for successful therapy. We propose extended diagnostics including molecular markers. Differential diagnosis should be based on three diagnostical “columns”: (i) clinical diagnostics, (ii) histopathology, and (iii) molecular diagnostics. Analysis of molecular alterations of receptor expression in detrusor smooth muscle cells and urothelial integrity is necessary to develop patient-tailored therapeutical concepts. Although more research is needed to elucidate the pathomechanisms involved, extended BPS/IC diagnostics could already be integrated into routine patient care, allowing evidence-based pharmacotherapy of patients with idiopathic bladder overactivity and BPS/IC

Different Nerve-Sparing Techniques during Radical Prostatectomy and Their Impact on Functional Outcomes

The purpose of this narrative review is to describe the different nerve-sparing techniques applied during radical prostatectomy and document their functional impact on postoperative outcomes. We performed a PubMed search of the literature using the keywords “nerve-sparing”, “techniques”, “prostatectomy” and “outcomes”. Other potentially eligible studies were retrieved using the reference list of the included studies. Nerve-sparing techniques can be distinguished based on the fascial planes of dissection (intrafascial, interfascial or extrafascial), the direction of dissection (retrograde or antegrade), the timing of the neurovascular bundle dissection off the prostate (early vs. late release), the use of cautery, the application of traction and the number of the neurovascular bundles which are preserved. Despite this rough categorisation, many techniques have been developed which cannot be integrated in one of the categories described above. Moreover, emerging technologies have entered the nerve-sparing field, making its future even more promising. Bilateral nerve-sparing of maximal extent, athermal dissection of the neurovascular bundles with avoidance of traction and utilization of the correct planes remain the basic principles for achieving optimum functional outcomes. Given that potency and continence outcomes after radical prostatectomy are multifactorial endpoints in addition to the difficulty in their postoperative assessment and the well-documented discrepancy existing in their definition, safe conclusions about the superiority of one technique over the other cannot be easily drawn. Further studies, comparing the different nerve-sparing techniques, are necessary

The relationship of quality of life and distress in prostate cancer patients compared to the general population

Background: The aim of this study is two-fold. The first part compares quality of life (QoL) data of prostate cancer patients with those of a representative and age-specific sample of the general population and analyzes the influence of cancer related as well as socio-demographic parameters on QoL. Secondly, differences in QoL depending on the experienced psychological distress will be shown both in prostate cancer patients and in the general population

Palmitate Induced IL-6 and MCP-1 Expression in Human Bladder Smooth Muscle Cells Provides a Link between Diabetes and Urinary Tract Infections

Therefore we studied the effects of the free fatty acid palmitate and bacterial lipopolysaccharide (LPS) on interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) expression and secretion in cultured human bladder smooth muscle cells (hBSMC).Biopsies were taken from patients undergoing cystectomy due to bladder cancer. Palmitate or LPS stimulated hBSMC were analysed for the production and secretion of the IL-6, gp80, gp80soluble, gp130, MCP-1, pSTAT3, SOCS3, NF-κB and SHP2 by quantitative PCR, ELISA, Western blotting, and confocal immunofluorescence. In signal transduction inhibition experiments we evaluated the involvement of NF-κB and MEK1 in IL-6 and MCP-1 regulation. Palmitate upregulates IL-6 mRNA expression and secretion via NF-κB dependent pathways in a concentration- and time-dependent manner. MCP-1 was moderately upregulated by palmitate but was strongly upregulated by LPS involving NF-κB and MEK1 dependent pathways. Soluble IL-6 receptor (gp80soluble) was downregulated by palmitate and LPS, while membrane-bound gp80 was moderately upregulated. LPS increased SOCS3 and SHP2, whereas palmitate only induced SOCS3. Secondary finding: most of the IL-6 is secreted.Bacterial infection (LPS) or metabolic alterations (palmitate) have distinct effects on IL-6 expression in hBSMC, (i) short term LPS induced autocrine JAK/STAT signaling and (ii) long-term endocrine regulation of IL-6 by palmitate. Induction of IL-6 in human bladder smooth muscle cells by fatty acids may represent a pathogenetic factor underlying the higher frequency and persistence of urinary tract infections in patients with metabolic diseases

Comments on the Extraperitoneal Approach for Standard Laparoscopic Radical Prostatectomy: What Is Gained and What Is Lost

Laparoscopic extraperitoneal radical prostatectomy (LERP) is considered the standard care treatment option for the management of localized and locally advanced prostatic cancer (PCa) in many institutes worldwide. In this work, the main advantages and disadvantages of LERP approach are reviewed with regard to its outcomes, the complication management, the learning curve, and the extend of pelvic lymph node dissection (PLND). It is concluded that LERP demonstrates comparable cancer control, urinary continence, and potency outcomes with the open and the robot-assisted radical prostatectomy, while offering advantages in complication management in comparison to the transperitoneal approach. Learning curve of LERP is considered long and stiff and significantly affects perioperative outcomes and morbidity, cancer control, and functional results. Thus, close mentoring especially in the beginning of the learning curve is advised. Finally, LERP still has a role in the limited or modified PLND offered in intermediate risk PCa patients

Acceptance, Prevalence and Indications for Robot-Assisted Laparoscopy - Results of a Survey Among Urologists in Germany, Austria and Switzerland

Background: Robotic-assisted laparoscopy (RAL) is being widely accepted in the field of urology as a replacement for conventional laparoscopy (CL). Nevertheless, the process of its integration in clinical routines has been rather spontaneous. Objective: To determine the prevalence of robotic systems (RS) in urological clinics in Germany, Austria and Switzerland, the acceptance of RAL among urologists as a replacement for CL and its current use for 25 different urological indications. Materials and Methods: To elucidate the practice patterns of RAL, a survey at hospitals in Germany, Austria and Switzerland was conducted. All surgically active urology departments in Germany (303), Austria (37) and Switzerland (84) received a questionnaire with questions related to the one-year period prior to the survey. Results: The response rate was 63%. Among the participants, 43% were universities, 45% were tertiary care centres, and 8% were secondary care hospitals. A total of 60 RS (Germany 35, Austria 8, Switzerland 17) were available, and the majority (68%) were operated under public ownership. The perception of RAL and the anticipated superiority of RAL significantly differed between robotic and non-robotic surgeons. For only two urologic indications were more than 50% of the procedures performed using RAL: pyeloplasty (58%) and transperitoneal radical prostatectomy (75%). On average, 35% of robotic surgeons and only 14% of non-robotic surgeons anticipated RAL superiority in some of the 25 indications. Conclusions: This survey provides a detailed insight into RAL implementation in Germany, Austria and Switzerland. RAL is currently limited to a few urological indications with a small number of high-volume robotic centres. These results might suggest that a saturation of clinics using RS has been achieved but that the existing robotic capacities are being utilized ineffectively. The possible reasons for this finding are discussed, and certain strategies to solve these problems are offered

Critical appraisal of literature comparing minimally invasive extraperitoneal and transperitoneal radical prostatectomy:A systematic review and meta-analysis

Objectives: To systematically review studies comparing extraperitoneal (E-RP) and transperitoneal minimally invasive radical prostatectomy (T-RP). Methods: The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in September 2015. Several databases were searched including Medline and Scopus. Only studies comparing E-RP and T-RP (either laparoscopic or robot-assisted approach) were evaluated. The follow-up of the included patients had to be â¥6 months. Results: In all, 1256 records were identified after the initial database search. Of these 20 studies (2580 patients) met the inclusion criteria. The hospital stay was significantly lower in the E-RP cohort, with a mean difference of â0.30 days (95% confidence interval [CI] â0.35, â0.24) for the laparoscopic group and 1.09 days (95% CI â1.47, â0.70) for the robotic group (P < 0.001). Early continence rates favoured the E-RP group, although this was statistically significant only in the laparoscopic group (odds ratio [OR] 2.52, 95% CI 1.72, 3.70; P < 0.001). There was no statistically significant difference between the E-RP and T-RP cohorts for 12-month continence rates for both the laparoscopic (OR 1.55, 95% CI 0.89, 2.69; P = 0.12) and robotic groups (OR 3.03, 95% CI 0.54, 16.85; P = 0.21). The overall complication and ileus rates were significantly lower in the E-RP cohort for both the laparoscopic and robotic groups. The symptomatic lymphocele rate favoured the T-RP cohort, although this was statistically significant only in the laparoscopic group (OR 8.69, 95% CI 1.60, 47.17; P = 0.01). Conclusion: This review suggests that the extraperitoneal approach is associated with a shorter hospital stay, lower overall complication rate, and earlier return to continence when compared to the transperitoneal approach. The transperitoneal approach has a lower lymphocele rate. Keywords: Extraperitoneal, Laparoscopy, Minimally invasive, Robotic, Transperitoneal, Prostatectom

Bilateral Peritoneal Flaps Reduce Incidence and Complications of Lymphoceles after Robotic Radical Prostatectomy with Pelvic Lymph Node Dissection-Results of the Prospective Randomized Multicenter Trial ProLy

Purpose: The purpose of this study was to investigate the effect of a surgically constructed bilateral peritoneal flap (PIF) as an adjunct to robot-assisted radical prostatectomy (RARP) and pelvic lymph node dissection (PLND) on the incidence of lymphoceles. Materials and Methods: A total of 530 men with localized prostate cancer underwent a RARP with bilateral extended standardized PLND in a prospective randomized controlled trial. In group A, a PIF was created by suturing the margins of the bladder peritoneum to the ipsilateral endopelvic fascia at 2 points on each side. In group B, no PIF was created. The patients were followed 30 and 90 days after the surgery to assess the incidence, extent and treatment of lymphoceles. Results: Lymphoceles occurred in 22% of group A patients and 33% of group B patients (p=0.008). Symptomatic lymphoceles were observed in 3.3% of group A patients and 8.1% of group B patients (p=0.027). Lymphoceles requiring intervention occurred significantly less frequently in group A patients (1.3%) than in group B patients (6.8%, p=0.002). The median lymphocele size was 4.3 cm in group A and 5.0 cm in group B (p=0.055). No statistically significant differences were observed in minor or major complications unrelated to lymphocele, blood loss, or surgical time between groups A and B. Conclusions: Bilateral PIFs in conjunction with RARP and PLND significantly reduce the total incidence of lymphoceles, the frequency of symptomatic lymphoceles and the rate of associated secondary interventions