Safety and efficacy of percutaneous nephrolithotomy in the Galdakao - Modified Supine Valdivia position: A prospective analysis.

OBJECTIVE: Aim of the present study was to evaluate the safety and efficacy of Percutaneous Nephrolithotomy (PCNL) in the Galdakao- Modified Supine Valdivia (GMSV) position in order to predict operative time, stone-free rate and onset of complications taking into account comorbidity, stone-related parameters and anatomic upper urinary tract abnormalities. MATERIAL AND METHODS: A prospective evaluation of patients who underwent to PCNL in GMSV position for renal stones > 2 cm, from January 2009 to February 2015 was performed. According to the technique, upper urinary tract abnormalities, stone chemical and morphological characteristics, and patients' history were matched with operative outcome, in terms of stone-free, intervention time and incidence of perioperative complications. RESULTS: Seventy-two cases were collected; mean operative time was 105 minutes (DS 41): staghorn stones and the presence of comorbidity resulted statistically significant variables. The complication-rate resulted in line with data showed in literature: hyperpyrexia and hemorrhage were the more frequently complications found. The overall stone-free was reached in 48 patients (67%), and it was influenced by patients' anatomic abnormalities. CONCLUSIONS: In the treatment of renal stones, PCNL may be a safe and effective choice; nevertheless, patients' anatomic abnormalities or staghorn-stones may influence the outcomes. Thus, a prospective study with a larger population is needed to verify our outcomes.

Non-muscle invasive high grade urothelial carcinoma of the bladder. Which factors can influence understaging at the time of radical cystectomy?

OBJECTIVE: To evaluate the main factors which influence understaging in patients with T1G3 non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: 109 patients with T1/G3 underwent transurethral resection of bladder tumor (TURBT) and then radical cystectomy (RC) with pelvic lymph nodes dissection. A number of variables were considered when evaluating the detection of understaging. We considered the patients age and gender, as well as the size, number, location and morphology of their tumor. We also considered coexistence of bladder carcinoma in situ (CIS), microscopic vascular invasion and deep lamina propria invasion. The level of experience of the surgeon was also analyzed. RESULTS: in RC samples muscle invasion, that is understaging, was detected in 74 (67.9%) patients, while 35 (32.1%) patients were appropriately staged. In these cohort of patients with high grade tumors, understaging was associated with deep lamina propria and microscopic vascular invasion, multiple tumors, tumor size > 6 cm, tumor location (trigone and dome), presence of residual tumor; age, gender, tumor morphology, CIS associated, and experience of urological surgeon were not associated with clinical understaging. CONCLUSIONS: in our study, evaluating patients with high grade NMIBC at first TURBT, we identified some risk factors that need to be considered and that are able to increase the risk of understaging: deep lamina propria and microscopic vascular invasion, multiple tumors, tumor size > 6 cm, tumor location (trigone and dome), presence of residual tumor. When these risk factors are present, performing an early cystectomy, and not a re-TURBT, could lower the risk of worse pathological finding due to rapid disease progression of the high grade tumors, and can prolong survival.

Spontaneous recurrent hematuria and hematospermia: Unique manifestations of von Willebrand disease type I. Case report.

In this report we describe the case of a patient with unrecognized von Willebrand disease (vWD), in whom the only presenting symptoms were spontaneous and recurrent hematuria with bladder tamponade, associated with recurrent hematospermia. The diagnosis was made only after several admissions to the hospital. We suggest to include coagulopathies such as vWD as part of the evaluation in patients with unexplained genito-urinary bleeding.

Loss of nuclear BAP1 protein expression is a marker of poor prognosis in patients with clear cell renal cell carcinoma.

INTRODUCTION: BRCA1-associated protein 1 (BAP1) is a gene situated on chromosome 3p in a region that is deleted in more than 90% of renal cell carcinomas (RCCs). In the present study, we studied BAP1 immunohistochemical expression in a large series of conventional clear cell RCCs (ccRCCs) treated with radical nephrectomy; we assessed the prognostic value of their expression in terms of patients׳ survival at long-term follow-up. MATERIALS AND METHODS: A total of 154 consecutive patients with ccRCC were selected from a prospective database and considered for the study purpose; all patients were treated with radical nephrectomy and lymphadenectomy at our Institute of Urology between 1983 and 1985. The features considered in this study were tumor size, grade and stage, vascular and capsular invasion, incidence of metastasis, and patient-specific survival; all these parameters were correlated with immunohistochemical cytoplasmic and nuclear expression of BAP1 in tumoral tissue. RESULTS: Median follow-up was 196.18 months and median survival was 125.34 months. Nuclear BAP1 expression showed a high frequency of loss in tumoral cells; nuclear BAP1-negative tumors had higher tumor size, higher Fuhrman grade, and higher stage, a greater amount of vascular and capsular invasion and a higher incidence of metastases. In multivariate analysis, pathological stage and nuclear BAP1 expression resulted independent prognostic factors. CONCLUSION: We have demonstrated that nuclear BAP1 expression is a marker of prognosis in ccRCC, having an influence on cancer-specific survival. The clinical importance for BAP1 will be realized with the identification and application of targeted therapies and with individualized approaches in the adjuvant setting or in the metastatic setting or in both the settings.

Small renal masses in the era of personalized medicine: Tumor heterogeneity, growth kinetics, and risk of metastasis.

Small renal masses (SRMs) represent a heterogeneous group showing a variety of clinical and biological behaviors. The best treatment for SRMs has been the focus of much debate over the past decades. Present strategies include surgery (partial or radical nephrectomy), local treatments (radiofrequency and cryoablation), or active surveillance. The choice among these therapeutic options is based on patient clinical features such as age or comorbidities rather than on tumor characteristics. Several studies have recently focused on the molecular behavior of SRMs. They showed that SRMs present histotype and nuclear grading heterogeneity, together with not unvarying growth kinetics and risk of recurrence or metastasis, suggesting that personalized approaches should be designed to optimize the management of these patients. At present, several studies are in course to identify predictive biomarkers to guide the decision-making process in this subpopulation. In this review, we summarized the data on growth kinetics, tumor heterogeneity, and risk of metastasis in patients with SRMs, with focus on the current role of biopsies and imaging in the management of these patients.

A conservative approach to perineal Fournier's gangrene.

Fournier's gangrene (FG) is a disease involving necrosis of perineum and external genitalia; in 95% of cases it is possible to diagnose the Fournier's gangrene just by physical examination. The clinical presentation of FG varies from an initial localized infection to large areas with necrotizing infection. The disease typically affect elderly men (6°-7° decade) with important systemic comorbidities; women are less frequently affected. Despite improvements in diagnosis and management, the mortality rate nowadays is between 20% and 43%. The severity and mortality of the disease is dependent upon the general condition of the patient at presentation and upon the rate of spread of the infection. Treatment involves a multidisciplinary approach: intensive systematic management, broad-spectrum antibiotic therapy, early surgical debridement (wide abscission of necrotic tissues and surgical drainage of peritoneum, scrotum, penis, and inguinal areas), hyperbaric oxygen therapy; surgery can eventually be repeated if necessary; reconstructive surgery has an important role in the final treatment of the disease. The technical difficulties frequently encountered and the inability to make a complete removal of the necrotizing tissues at the time of surgery in some cases has led to the application of combined techniques, in view of the enhancement effect of specific advanced medications, targeted antibiotic therapy and hyperbaric medicine. We have considered 6 patients affected by Fournier's gangrene treated at our institution; all the patients received treatment with the help of plastic surgeons of the same institution. After debridement, all the patients were treated with advanced specific dressings consisting of plates and strips made of calcium alginate, hydrogels and polyurethane and twodimensional cavity foams. Reconstructive surgery was necessary in one case. Hyperbaric oxygen therapy (HBO) has been performed in all cases. The multidisciplinary approach, the combined use of HBO therapy and the adoption of advanced specific dressings, have made possible the complete healing of the lesions in a shorter period, avoiding further surgery in 5 out of 6 patients.

Is it possible to predict the need of inguinal lymphadenectomy in patients with squamous cell carcinoma of the penis? A clinical and a pathological study.

OBJECTIVE: to investigate the role of CD- 44 immunohistochemical expression within tumoural and non-tumoural tissue, aiming to understand if it can help us to predict the need of performing inguinal lymph nodes dissection to complete surgery of the penis. MATERIALS AND METHODS: CD44 immunohistochemical expression was investigated in tissue specimens from 39 patients with squamous cell carcinoma of the penis who underwent partial or total penectomy between 1987 and 2008. Patient age, tumour size, and grade; CD44 intensity score, cytological expression, topographic and distribution pattern were evaluated by immunohistochemistry on archived material and correlated with disease-specific survival. RESULTS: mean patients age was 67.7 years; mean followup was 130.44 months. Bilateral inguinal lymphadenectomy was performed in 14 patients; there were 8 N+ patients (23.5%). pTis-pT1 vs. > pT1 and the EAU classification of risk group resulted to be predictive of lymph nodal metastases at univariate analysis (respectively p = 0.006 and p = 0.045), but not the grading. The intensity score, cytological expression, topographic and distribution pattern of CD44 staining did not correlate with stage, grade and lymph nodes metastases. All disease related deaths occurred only in patients showing an high CD44 intratumoral expression, but this correlation is not statistically significant. Multivariate analysis showed that only lymph node metastasis was an independent prognostic factor predictive of lymph nodes metastases. CONCLUSIONS: CD44 expression in patients with squamous cell carcinoma of the penis is not able to predict the need of performing inguinal lymphadenectomy; staging and the EAU classification of risk group resulted to be predictive of lymph nodal metastases.

Enterovesical fistula caused by a toothpick.

We present a case of enterovesical fistula caused by an accidental ingestion of a foreign body. A 23-year-old man presented to our hospital with pneumaturia, fecaluria, and abdominal pain but no recent possible causes of enterovesical fistula at anamnesis. Cystoscopy, cystography, and also colonoscopy were not able to detect the fistulous tract. Computer tomography (CT) revealed a fistula between bladder and bowels caused by a toothpick accidentally swallowed 2 years earlier. We tried to remove the foreign body endoscopically by cystoscopy and colonoscopy but with no success. The failure of endoscopic procedures required a surgical treatment. The patient underwent laparoscopic segmental resection of the sigmoid colon to remove the fistulous tract and the foreign body. The cystography revealed no external leakage of contrast from the bladder with complete resolution of the problem.

Reassessing the role of subclinical varicocele in infertile men with impaired semen quality: a prospective study.

OBJECTIVE: To evaluate the seminal, hormonal, and spontaneous pregnancy outcome after percutaneous embolization of the internal spermatic vein in infertile men with left-sided subclinical varicocele and one or more abnormal semen parameters. METHODS: A total of 218 patients underwent percutaneous embolization, and 119 patients were included as the observation group. All patients were followed up prospectively for 39.4 ± 6.5 months. Semen parameters and hormonal levels were evaluated before any procedure and 6 months after. RESULTS: Significant improvement in the mean sperm concentration, total motility, and lower follicle-stimulating hormone levels was noted in those who underwent varicocele embolization as compared with those not treated. After 39.4 ± 6.5 months, pregnancy rates were 46.3% for the treated group and 11.8% for the control group (P = .011). CONCLUSION: In infertile men, small varicoceles, even subclinical ones, should be identified and treated.

[Ureterovaginal fistulae]. / Fistole ureterovaginali.

Ureterovaginal fistulae are pathological communications between the ureter and the vagina; it commonly occur as a rare but serious sequela of unrecognized distal ureteral injuries during pelvic operations. Patients may present symptoms as leakage of urine from the vagina, flank pain and fever; in some cases it could be possible also the loss of renal function. The purpose of this study is to review the articles from 1991 to 2014 to evaluate the most correct diagnostic procedures and endourological and surgical techniques used in the management of ureterovaginal fistula. Nowadays computered tomography and retrograde pielography are the most commonly diagnostic modalities used to identify fistulous tract and to describe its anatomical position. The major of ureterovaginal fistulae can be successfully managed by conservative methods. Modern endourological treatment will result in resolution of a ureterovaginal fistula if retrograde or anterograde passage of a suitable internal stent is feasible. When stenting failed or in complicated cases, ureteral reimplantation is necessary. Ureteroneocystostomy, psoas hitch and Boari flap are three different possible surgical techniques used to realized an ureteral reimplantation. Both open and mini invasive (laparoscopy and robot assisted) surgical approach have proved successful.

Prognostic significance of host immune status in patients with late relapsing renal cell carcinoma treated with targeted therapy.

We aimed to assess the prognostic role of pretreatment neutrophilia, lymphocytopenia, and neutrophil to lymphocyte ratio (NLR) in patients treated with vascular endothelial growth factor-tyrosine kinase inhibitors (VEGFR-TKIs) for late relapsing (>5 years) metastatic renal cell carcinoma (mRCC). Data were collected from 13 Italian centers involved in the treatment of metastatic RCC. Late relapse was defined as >5 years after initial radical nephrectomy. One hundred fifty-one patients were included in this analysis. Among them, MSKCC risk score was favorable in 68 %, intermediate in 29 %, and poor in 3 %. Fifty-six patients (37 %) had NLR ≥3 at the start of VEGFR-TKI therapy (group A), while 95 had lower NLR (63 %, group B). The median overall survival (OS) was 28.8 months in group A and 68.7 months (95 % confidence interval (CI) 45.3-NA) in group B (p < 0.001). The median progression-free survival (PFS) was 15.8 months in group A and 25.1 months in group B (p = 0.03). At multivariate analysis, MSKCC risk group and NLR were independent prognostic factors for both OS and PFS. Pretreatment NLR is an independent prognostic factor for patients with late relapsing mRCC treated with first-line VEGFR-TKIs. A better characterization of baseline immunological impairment may optimize the management of this RCC subpopulation.

Survival in patients with clear cell renal cell carcinoma is predicted by HIF-1α expression.

AIM: To investigate hypoxia inducible factor-1α's (HIF-1α) immunohistochemical expression in clear cell renal cell carcinoma (ccRCC) treated with radical nephrectomy. PATIENTS AND METHODS: One hundred and forty-eight patients were considered from those who underwent radical nephrectomy between 1983 and 1993. Archived materials were retrieved from the Institute of Pathological Anatomy for immunostaining. The features considered on the histological specimens were tumor stage, grade, as well as cellular and vascular HIF-1α expression. All considered parameters were correlated with time to recurrence (TTR) and overall survival (OS). RESULTS: TTR was significantly longer in patients with low cellular HIF-1α expression; patients' survival was higher in those with low HIF-1α expression. Regarding vascular HIF-1α expression, the differences were not statistically significant when considering TTR and OS. On univariate analysis, age, clinical stage and HIF-1α cellular expression showed a significant association with OS. CONCLUSION: Cellular HIF-1α is an important indicator of prognosis in patients with ccRCC; high HIF-1α expression predicts poor survival.

Recent aspects of sunitinib therapy in patients with metastatic clear-cell renal cell carcinoma: a systematic review of the literature.

Sunitinib is an orally available inhibitor of multiple tyrosine-kinase receptors approved for the treatment of advanced clear-cell renal cell carcinoma (ccRCC), a disease which has habitually had a very poor patient survival rate. Although it has become the most widely used drug for this disease, it remains not completely clear the best treatment strategy with these agent. The aim of this review is to highlight the most recent and interesting aspects of the research on treatment of advanced ccRCC with sunitinib and eventually determine alternative treatment schedule to reduce the incidence of side effects; we also wanted to review recent biomarkers able to predict response to therapy and also to point out the mechanism of acquired resistance to this drug.

Tumor VEGF expression correlates with tumor stage and identifies prognostically different groups in patients with clear cell renal cell carcinoma.

OBJECTIVES: Vascular endothelial growth factor (VEGF) is a potent inducer of tumor angiogenesis and represents the key element in the pathogenesis of clear cell renal cell carcinoma (ccRCC). The aim of this study was to investigate the use of tumor VEGF expression as a parameter to identify tumor stage and prognostically different patient groups. METHODS AND MATERIALS: We retrospectively collected clinical data of 137 patients treated with partial or radical nephrectomy at our institutions for organ-confined, locally advanced, and metastatic ccRCCs between 1984 and 2013. Tumor cell VEGF immunohistochemical expression was compared with pathological and clinical features including age, sex, tumor stage, and Fuhrman grade. Comparison of VEGF expression levels between tumor stages was performed via Kruskal-Wallis nonparametric test. Survival analysis was conducted via Kaplan-Meier product-limit method, and Mantel-Haenszel log-rank test was employed to compare survival among groups. RESULTS: Median age at diagnosis was 61 years (range: 33-85 y). Tumor stage was pT1N0M0 in 67 patients (49%), pT2N0M0 in 5 (4%), and pT3N0M0 in 25 (18%), while 40 patients (29%) had metastatic tumors at diagnosis. Fuhrman nuclear grade was G1 in 22 patients (16%), G2 in 60 (44%), G3 in 33 (24%), G4 in 13 patients (9%), and unknown in 9 patients. Tumor VEGF was differentially expressed among different stages (P<0.001) and in low (G1-2) and high (G3-4) Fuhrman grade tumors (P<0.001). No significant differences were found when stratifying by sex (P = 0.06) or age (P = 0.29). Median overall survival (OS) from partial or radical nephrectomy was 161 months (range: 1-366). We observed a significantly longer OS in patients with low (<25%) vs. high (>25%) VEGF expression levels (median OS 206 vs. 65 mo, P<0.001). CONCLUSIONS: Our data show that tumor cell VEGF expression is significantly associated with tumor stage and Fuhrman grade and is able to predict patient outcome, suggesting a potential use of this parameter in identifying prognostically different patients with ccRCC.

Sunitinib, pazopanib or sorafenib for the treatment of patients with late relapsing metastatic renal cell carcinoma.

PURPOSE: Late recurrence of renal cell carcinoma is not a rare event. In this retrospective study we investigate the clinicopathological features and the outcome of patients treated with sorafenib, sunitinib and pazopanib for late relapsing renal cell carcinoma. MATERIALS AND METHODS: Data were collected from 21 Italian centers involved in the treatment of metastatic renal cell carcinoma. Late relapse was defined as more than 5 years after initial radical nephrectomy. RESULTS: A total of 2,490 patients were screened and 269 (11%) were included in the study. First line therapy was sunitinib in 190 patients (71%), sorafenib in 58 (21%) and pazopanib in 21 (8%). Median progression-free survival was 20.0 months for sunitinib (95% CI 17.0-25.1), and 14.1 months for sorafenib (95% CI 11.0-29.0) and pazopanib (95% CI 11.2-not reported). On multivariate analysis MSKCC score and metastases to lymph nodes, liver and brain were associated with worst overall survival, while pancreatic metastases were associated with longer survival. Furthermore, age, MSKCC score and brain metastases were associated with worst progression-free survival. CONCLUSIONS: Patients with late relapsing renal cell carcinoma seem to present a characteristic pattern of metastatic spread without showing significant differences in terms of progression-free survival among sorafenib, sunitinib and pazopanib.

α1-Blockers for the treatment of recurrent urinary tract infections in women with dysfunctional voiding: a prospective randomized study.

OBJECTIVES: To evaluate the therapeutic effects of tamsulosin on recurrent urinary tract infections in women with dysfunctional voiding. METHODS: A total of 155 women with recurrent urinary tract infections and dysfunctional voiding were included and randomly assigned to the following groups: uroflowmetry biofeedback (group 1), α1-adrenoceptor antagonists (group 2), uroflowmetry biofeedback combined with α1-adrenoceptor antagonists (group 3) and no treatment (group 4). Patients were evaluated by the American Urological Association Symptom Index at 3, 6 and 12 months. Urodynamics was carried out in patients of groups 1, 2, and 3 at 3, 6 and 12 months, whereas urodynamics was only carried out at 12 months in group 4. All patients were followed up for 1 year with monthly urine cultures. RESULTS: The incidence of storage and emptying symptoms decreased significantly at 3, 6 and 12 months. Mean flow rate, flow time and voiding volume increased significantly (with a better outcome in patients of group 3), whereas post-void residual urine decreased. Mean opening detrusor pressure and detrusor pressure at maximum flow decreased significantly (with a better outcome in patients of group 3). Mean urethral closure pressure and maximum urethral closure pressure decreased significantly with a more significant decrease for patients in group 3. The prevalence of urinary tract infection decreased significantly in all groups after treatment, and this decrease remained stable during the follow up. CONCLUSIONS: In women with dysfunctional voiding and recurrent urinary tract infection, tamsulosin associated with uroflowmetry biofeedback might be an effective and safe treatment option for improving urinary symptoms and quality of life.

Conditional survival of patients treated with first-line chemotherapy for metastatic urothelial cancer.

BACKGROUND: Measures of prognosis for cancer patients are typically evaluated at the time of diagnosis. However, this study assessed the changes in 2-year CS rates after first-line chemotherapy for metastatic UC. PATIENTS AND METHODS: Conditional overall survival and CPFS probability were estimated using the Kaplan-Meier method. Adjusted survival functions were stratified according to age groups (< 70 years vs. ≥ 70 years), sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS; ECOG PS ≤ 2 vs. ECOG PS > 2), pretreatment Hb levels (< 12 mg/dL vs. ≥ 12 mg/dL) and pretreatment NLR (< 3 vs. ≥ 3). Pairs of CS curves were compared using the Mantel-Haenszel log-rank test. RESULTS: Two hundred ninety-eight patients were included in this analysis, 233 were male, and their median age was 69 years. First-line median overall survival and progression-free survival were 10.7 months (95% confidence interval [CI], 9.6-12.6) and 6.0 months (95% CI, 5.5-7.1), respectively. CPFS and COS showed an increasing trend in the population considered (b = 0.35; P < .001 and b = 0.79; P < .001, respectively). A significant increase in terms of COS and CPFS trends was identified in patients with age < 70 years (P = .02 and P = .005, respectively) and pretreatment NLR ≤ 3 (P = .05 and P < .001, respectively). Patients with Hb levels < 12 g/dL showed a significantly poorer 2-year COS. CONCLUSION: The conditional probability of survival at 2 years from the start of first-line chemotherapy for advanced UC changes over time according to clinical characteristics.

Plication corporoplasty for congenital penile curvature: our results with long-term follow-up.

OBJECTIVE: To evaluate the outcome of the long-term follow-up in patients who underwent corporoplasty-straightening treatment for congenital penile curvature (CPC). METHODS: Between 1989 and 2012, a total of 60 patients underwent corporoplasty-straightening surgery using penile plication for CPC. We followed up on all the correction of the curvature; (a) any penile shortening; (b) sexual function; (c) complications. RESULTS: The mean follow-up period was of 98 months. Complete correction of the curvature was obtained in 54 patients (90 %). Shortening of the penis (1.5 to not more than 3 cm) occurred in 16 patients (26.6 %). All patients had good erectile function (IIEF-5 > 21). The most frequent complication was the sensitivity reduction of the glans in five patients (8.3 %), which was resolved with in about a year after surgery (mean 11 months) and the shortening of the penis in 16 patients (26.6 %), which, however, did not result in problems during sexual intercourse. CONCLUSIONS: Corporoplasty using penile straightening plication is a safe procedure whose results are maintained even after many years after surgery. It is a procedure that can be applied to any type of curvature. Any reduction in the length of the penis, as a result of the surgery procedure, does not lead to difficulties in sexual intercourse.

Testicular microlithiasis and dyspermia: is there any correlation?

BACKGROUND: Testicular microlithiasis (MT) is an uncommon sonographic finding (prevalence in the literature: 0.7 to 6%). Several studies have highlighted its possible correlation with an increased risk of testicular cancer, but few studies have investigated its possible link with dyspermia. OBJECTIVES: The aim of our study was to investigate in our series the number of patients with microlithiasis, diagnosed by ultrasound, and compare the quality of their sperm with that of patients in a control group with normal testicular ultrasound exam. MATERIALS AND METHODS: We performed 277 consecutive testicular ultrasound examinations from January 2012 to July 2012. Among all these, we selected 86 patients that showed no pathological elements at echography and 11 patients affected by MT, to one or both testicles. Each patient was also submitted to a short-term semen analysis using the WHO2010 parameters for sperm evaluation. RESULTS: Among 11 patients with MT, 7 (63.63%) were dyspermic and 4 (36.36%) were normospermic. Among the 86 patients with normal testicular ultrasound 51 (59.3%) were dyspermic, 4 (4.65%) were azoospermic, while the remaining 31 (36.05%) were normospermic. Comparing the results of the two groups we obtained an odds ratio of 0.99 (95% CI: 0.27 to 3.64, p: 0.98). CONCLUSIONS: This study, although preliminary, with a low number of participants, shows that sperm quality is not affected by the presence of testicular microlithiasis, because the results of spermiograms are almost comparable between the two groups.

Nebivolol induces, via ß3 adrenergic receptor, lipolysis, uncoupling protein 1, and reduction of lipid droplet size in human adipocytes.

OBJECTIVES: Most ß-blockers may induce weight gain, dysglycemia, and dyslipidemia. Nebivolol is a third-generation ß1-blocker with vasodilating properties mediated by ß3 adrenergic receptors (ß3AR). We investigated whether nebivolol is able to induce ß3AR-mediated lipolysis, uncoupling protein 1 (UCP1), and size-reduction in human adipocytes. METHODS: Human visceral (n = 28) and subcutaneous adipose tissue (n = 26) samples were used to obtain differentiated subcutaneous and visceral preadipocytes. Adipocytes were used to verify the effects of nebivolol onlipolysis, uncoupling protein 1 (UCP1) and other genes of the thermogenic program. RESULTS: Lipolysis was induced by isoproterenol and specific ß3AR agonist, as expected,and also by nebivolol at 100 nmol/l and by its L-enantiomer at 10 nmol/l (P < 0.01). Nebivolol-mediated lipolysis was blocked by SR59230A, a specific ß3AR antagonist, suggesting that nebivolol acts through ß3AR in human adipocytes. Interestingly, in human adipocytes, nebivolol activated UCP1, PPARγ coactivator-1α (PGC-1α) and cytochrome c (CYCS) gene expression in a p38 MAPK-dependent manner. Using propranolol (ß1 and ß2 antagonist) together with nebivolol we showed that the induction of these genes was still present suggesting again ß3AR activation. Moreover, nebivolol significantly reduced the diameter of lipid droplets in cultured adipocytes. CONCLUSION: In summary, nebivolol, through ß3AR, is able to induce lipolysis and promote thermogenic and mitochondrial genes. The induction of lipolysis and the thermogenic program could explain the reduction of lipid droplets size. In conclusion, the lower dysmetabolic effects of nebivolol in humans may depend on its ß3 agonist activity and the consequent induction of thermogenic program in human adipocytes.