Enhanced uropathogenic Escherichia coli-induced infection in uroepithelial cells by sugar through TLR-4 and JAK/STAT1 signaling pathways.

BACKGROUND: Patients with diabetes mellitus (DM) have higher incidence and more severe urinary tract infections (UTIs) for longer duration than those of the patients without DM. It causes more complicated etiologies during uropathogenic Escherichia coli (UPEC) infection. However, studies regarding the molecular mechanism are scarce. METHODS: The present study (1) aimed to verify if sugar influences the process of UPEC-induced cystitis and invasion into the uroepithelial cells and (2) illustrated the mechanism of effects for sugar enhanced the UPEC infection into uroepithelial cells is related to TLR-4-mediated and JAK/STAT1-dependent pathway. RESULTS: The results of the present study indicated that sugar can enhance UPEC infection in uroepithelial cells by up-regulating the transduced circuit between TLR-4-mediated UPEC interaction and JAK/STAT-1 signal pathways. The results of the inhibitor-co-incubating experiments demonstrated that the mechanism involved in the synergistic amplification of TLR-4-mediated UPEC interaction and JAK/STAT1 signaling pathways is responsible for the increased UPEC infection in uroepithelial cells. CONCLUSION: The results also proved that STAT-1 plays a critical role in the regulation of UPEC invasion and infection in the uroepithelial cells, especially those pretreated with glucose. The present study suggests a possible therapeutic approach to preferentially suppress UPEC infection during UTIs in the patients with diabetes.

Testosterone regulates the intracellular bacterial community formation of uropathogenic Escherichia coli in prostate cells via STAT3.

BACKGROUND: UPEC can internalize clonally in prostate to form biofilm-like intracellular bacterial communities (IBCs) for recurrent or chronic infection. We previously indicated that the exposure of prostate cells to testosterone could suppress UPEC invasion and their persistent survival within cells by effectively inhibiting the JAK/STAT1 signaling pathway. However, the regulatory mechanism by which testosterone affects UPEC-induced prostatitis via STAT3, another latent transcription factor signaling pathway is still unclear. The present study aimed to clarify the role of STAT3 in the process of UPEC-induced inflammation and colonization in prostate epithelial cells. METHODS: The effects of testosterone-mediated inhibition were compared between the prostatitis by different UPEC strains (CFT073 and J96) through the specific GFP-UPEC-infected prostate cell model. Fluorescence microscopy was used for UPEC IBCs detection and quantifying, and Flow cytometry, RT-PCR and western blotting were used for analyzing related gene and protein expressions. Pretreatment of JAK and STAT3 inhibitors were also applied to verify the regulation of transduction pathway in testosterone-mediated anti-UPEC infection. RESULTS: This study revealed that testosterone effectively suppresses UPEC infection and IBC formation in prostate cells through the JAK/STAT3 pathway. The results show that CFT073 and J96 UPEC infection rates and colony numbers were dose-dependently reduced in RWPE-1 cells pretreated with 5 and 20 µg/mL testosterone at 0 and 24 h post-infection. Further, testosterone reduced the amounts of UPEC infecting and surviving within the prostate cells, as well as suppressed the size of IBCs formed. We demonstrated that pretreating testosterone effectively inhibited UPEC infection along with dose-dependent suppression of STAT3 and the phosphorylated-STAT3 expression in prostate cells, especially in 24 h J96 UPEC infected groups. The STAT inhibitor, SOCS3 also up-regulated at the same time. In addition, we pretreated the JAK1 or STAT3 inhibitor with testosterone to block the signaling transduction before CFT073 and J96 UPEC infection, and found the significant restoring in both the sizes of IBCs and bacterial numbers in RWPE-1 cells. Therefore, our results suggest that the suppression of STAT3 by testosterone treatment attenuate UPEC growing within IBCs and interfere with their infection to prostate cells. CONCLUSIONS: Overall, our study demonstrates that testosterone suppresses the initial infection of prostate epithelial cells by UPEC and reduces the survival of UPEC within IBCs after infection. These results indicate a critical role for STAT3 in facilitating UPEC infection and persistence, and its participation in driving testosterone-suppressive responses in prostate epithelial cells. In conclusion, this study suggests that testosterone may be beneficial in treating clinically recurrent UPEC infections and, thus, the persistent recurrence of prostatic inflammation.

Correction: Testosterone suppresses uropathogenic Escherichia coli invasion and colonization within prostate cells and inhibits inflammatory responses through JAK/STAT-1 signaling pathway.

[This corrects the article DOI: 10.1371/journal.pone.0180244.].

CCN3 promotes epithelial-mesenchymal transition in prostate cancer via FAK/Akt/HIF-1α-induced twist expression.

Epithelial-mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm for explaining metastatic behavior during cancer progression. NOV/CCN3 is a matrix-associated protein involved in many cellular functions. Previous studies have shown that CCN3 expression is upregulated in prostate cancer (PCa) cells and in PCa patients. In this study, we have provided evidence of tumor promoting effects of CCN3, which includes induction of epithelial-to-mesenchymal transition (EMT) and tumor metastasis. We used an orthotopic in vivo model to demonstrate the prometastatic effects of CCN3. Overexpression or knockdown of CCN3 changed the EMT phenotype in PCa cells. Moreover, treatment with recombinant CCN3 promoted EMT in PCa cells. We also found that CCN3 may promote EMT by activating the FAK/Akt/HIF-1α pathway and this activation is responsible for Twist expression. IHC staining confirmed a positive correlation between the expression of CCN3, Twist, and tumor stage in PCa tissue. Our findings provide insight into the involvement of CCN3 in the EMT regulation of prostate cancer. CCN3 is a promising molecular target that may contribute to a novel therapeutic strategy against metastatic PCa.

Testosterone suppresses uropathogenic Escherichia coli invasion and colonization within prostate cells and inhibits inflammatory responses through JAK/STAT-1 signaling pathway.

Prostatitis is a common condition in adult men of all ages. Uropathogenic Escherichia coli (UPEC) are most frequent pathogen involved in bacterial prostatitis by refluxing the infected urine into prostatic ducts and resulting in an ascending urethral infection. However, the study about the mechanisms of UPEC to invade, replicate and persist in normal prostate epithelial cell is only few. Given the fact that UPEC is pathogen most frequently involved in prostatitis and that testosterone has been demonstrated to attenuate prostate inflammation caused by other etiologies. In this study we investigated whether the testosterone reduces the prostatitis and related mechanism by regulating IFN-γ/STAT1 signaling pathway. In the current study aimed to clarify whether testosterone influences the process of UPEC-induced prostate inflammation and invasion into the prostate epithelial cells. In addition, we set up a normal prostate cell model for UPEC infection to evaluate the ability to invade the urothelial cells as well as the colonization of intercellular bacterial communities in vitro. By using the model, we examine the effects of testosterone to suppress effectively the invasion and survival of UPEC in the prostate cells, and inhibit LPS-induced inflammatory responses through the JAK/STAT1 pathway have also been indicated. Our results demonstrated testosterone not only suppressed the invasion and colonization of UPEC, but also inhibited the expression of pro-inflammatory IL-1ß, IL-6 and IL-8 cytokines expression induced by UPEC in a dose-dependent manner. We found the effective dose of testosterone to suppress UPEC infect prostate cells may be appropriate under 40µg/ml. Our data also revealed 20µg/ml testosterone treated PZ-HPV-7 cells significantly suppressed the LPS-induced JAK/STAT1 pathway and inflammatory responses, and reached to maximal effects at 40µg/ml treatment. These results indicate that testosterone plays an anti-inflammatory role in LPS-induced prostate cell inflammation by down-regulating JAK/STAT1 signaling pathway. Interestingly, the JAK inhibitor and testosterone for 24hr pretreatment rather markedly induced the colonization of UPEC in the PZ-HPV-7 cells. Based on the above data, the suppression of UPEC colonization in the prostate cells by testosterone seems to be unrelated with JAK/STAT signaling pathway, whereas the JAK may involve into the UPEC infection. Summing up these data, our findings have demonstrated the suppressive effects of testosterone on the invasion and survival of UPEC and induced inflammation in prostate epithelial cells. These findings indicate the action mechanism of testosterone as an anti-inflammatory mediator in the prostate cells is regulated through JAK/STAT1 signaling pathway, may be beneficial in treating prostate inflammation. Altogether, this study has provided the possibility that using testosterone in the prevention and clinical treatment of prostatitis is a new direction.

l-Theanine inhibits proinflammatory PKC/ERK/ICAM-1/IL-33 signaling, apoptosis, and autophagy formation in substance P-induced hyperactive bladder in rats.

AIMS: Upregulation of substance P (SP) and neurokinin-1 receptor (NK1R) activation induces pro-inflammatory bladder hyperactivity through the PKC/ERK/NF-κB/ICAM-1/IL-33 signaling pathways to increase the leukocyte infiltration and adhesion leading to reactive oxygen species (ROS) production, autophagy, and apoptosis. l-Theanine is a unique non-protein-forming amino acid present in tea (Camellia sinensis [L.] O. Kuntze) with its antioxidant, anti-inflammatory, and relaxation effects to improve cognition, mood, gastric ulcer injury, and cerebral ischemia/reperfusion injury, and posttraumatic stress disorder. We explored the protective effect of l-theanine on SP-induced bladder hyperactivity. METHODS: In urethane-anesthetized female Wistar rats, we explored the transcystometrogram, pelvic nerve activity, proinflammatory PKC/ERK/NF-κB/ICAM-1/IL-33 signaling, apoptosis-related Caspase 3/poly-(ADP-ribose)-polymerase (PARP), and autophagy-mediated LC3 II expression by Western blot, electrophoretic-mobility shift assay and immunohistochemistry, bladder ROS amount by a ultrasensitive chemiluminescence method, and possible ROS sources from the different leukocytes by specific stains in SP-evoked hyperactive bladder. RESULTS: l-Theanine dose-dependently depressed H2 O2 and HOCl activity in vitro. In urethane-anesthetized female Wistar rats, intra-arterial SP through NK1R activation increased voiding frequency (shortened intercontraction intervals) associated with the increase in bladder nerve activity, proinflammatory PKC/ERK/NF-κB/ICAM-1/IL-33 signaling, Caspase 3/PARP-mediated apoptosis, LC3 II-mediated autophagy, ROS amount, neutrophils adhesion, CD68 (monocyte/macrophage) infiltration, and mast cells degranulation in the hyperactive bladder. Intragastrical l-theanine (15 mg/kg) twice daily for 2 weeks efficiently ameliorated all the enhanced parameters in the SP-treated hyperactive bladder. CONCLUSIONS: In conclusion, l-theanine through antioxidant and anti-inflammatory actions ameliorates SP-induced bladder hyperactivity via the inhibition of proinflammatory PKC/ERK/NF-κB/ICAM-1/IL-33 signaling, oxidative stress, bladder nerve hyperactivity, apoptosis, and autophagy. Neurourol. Urodynam. 36:297-307, 2017. © 2016 Wiley Periodicals, Inc.

Testosterone Threshold for Increased Cardiovascular Risk in Middle-Aged and Elderly Men: A Locally Weighted Regression Analysis.

INTRODUCTION: Although testosterone deficiency has a well-known association with increased risk of cardiovascular disease (CVD), the threshold remains to be determined. AIM: To investigate whether there is a discriminatory testosterone level below which the CVD risk increases. METHODS: The study included 876 men 45 to 74 years old who underwent a general health checkup. The Framingham Risk Score was used to estimate the 10-year CVD risk; a high-sensitivity C-reactive protein (hsCRP) level of at least 1 mg/L was considered an indicator of increased CVD risk. Aging symptoms and sexual function were evaluated with the Aging Males' Symptom Scale. MAIN OUTCOME MEASURES: Locally weighted regression was performed to determine the testosterone threshold for Framingham CVD risk and increased hsCRP. RESULTS: The mean age was 56.6 ± 7.0 years. The mean total testosterone level was 394.3 ± 115.7 ng/dL. The mean 10-year Framingham CVD risk was 16.6 ± 10.7%, and 169 (19.3%) had increased hsCRP. The locally weighted regression showed that total testosterone levels of 440 and 480 ng/dL were associated with increased Framingham CVD risk and an increased probability of increased hsCRP, respectively. Men with sexual dysfunction (poor sexual performance, decreased morning erection, and loss of libido) had significantly greater CVD risk. Their risk appeared to increase at a relatively higher testosterone level, and it reached a plateau at a testosterone level of 300 to 350 ng/dL. In contrast, the risk in those with no or less sexual dysfunction remained low at a higher testosterone level, and a threshold level of 425 to 475 ng/dL was associated with increased CVD risk. A similar pattern and threshold were identified in the analyses of the relation between testosterone and hsCRP. CONCLUSION: These data showed that a testosterone threshold of 440 ng/dL was associated with increased Framingham 10-year CVD risk in middle-aged and elderly men. Poor sexual performance, decreased morning erection, and loss of libido had an impact on the testosterone threshold for CVD risk. The threshold level was higher in men with sexual dysfunction. Further study is required to evaluate the validity of these testosterone thresholds for CVD risk.

Sulforaphane Improves Ischemia-Induced Detrusor Overactivity by Downregulating the Enhancement of Associated Endoplasmic Reticulum Stress, Autophagy, and Apoptosis in Rat Bladder.

Atherosclerosis-associated pelvic ischemia has been reported to be a risk factor for bladder dysfunction and subsequent lower urinary tract symptoms (LUTS) in the elderly population. However, the molecular mechanisms of this association remain unclear. We hypothesized that stress-induced cellular responses might play a role in the pathogenesis of ischemia-induced bladder dysfunction. In the present study, the animal model of bladder ischemia was induced by bilateral partial arterial occlusion (BPAO) in rats. We found that BPAO significantly induced the presence of detrusor overactivity (DO) and upregulated the expression of several molecular reactions, including biomarkers in endoplasmic reticulum stress (78 kDa glucose-regulated protein, GRP78 and C/EBP-homologous protein, CHOP), autophagy (Beclin-1, p62 and LC3 II) and apoptosis (caspase 3). BPAO also disturbed the Kelch-like ECH-associated protein 1-nuclear factor erythroid-2-related factor 2 (Keap1-Nrf2) pathways. These responses might collectively alter muscarinic and purinergic signaling and contribute to the presence of DO in the ischemic bladder. Therapeutically, treatment with neither a muscarinic nor purinergic receptor antagonist restored bladder function. Interestingly, sulforaphane effectively attenuated ischemia-enhanced endoplasmic reticulum stress, autophagy and apoptosis in the bladder, subsequently ameliorated ischemia-induced bladder dysfunction and might emerge as a novel strategy to protect the bladder against ischemia-induced oxidative damage.

Associations between lower urinary tract dysfunction and glycemic control in women with type 2 diabetes: A cross-sectional study.

AIMS: Patients with diabetes are predisposed to develop a variety of complications, including lower urinary tract (LUT) dysfunction. We aimed to examine the associations between glycemic control and LUT dysfunction in women with type 2 diabetes (T2D). METHODS: We included 400 women with T2D (age range, 48-75 years) in this cross-sectional analysis. The participants were divided into tertiles according to glycosylated hemoglobin (HbA1c) measurements. The mean HbA1c levels for tertiles 1, 2, and 3 were 6.2% (N=132), 7.1% (N=132), and 8.4% (N=136), respectively. We evaluated LUT dysfunction with the American Urological Association Symptom Index (AUA-SI) questionnaire, uroflowmetry (UFM), and post-void residual (PVR). RESULTS: No significant differences were found among HbA1c tertiles regarding storage, voiding and total AUA-SI scores, and prevalence of LUT symptoms. However, women in tertile 3 had higher prevalences of severe LUT symptoms (AUA-SI≥20) and clinically significant PVR (≥100mL) compared to women in the other tertiles. Multivariate analysis revealed that diabetic neuropathy, but not HbA1c, significantly predicted LUT symptoms in women with T2D after adjustment for age, body mass index (BMI) and hypertension. However, HbA1c was associated with an increased risk of developing clinically significant PVR. CONCLUSIONS: Our findings do not support significant associations between glycemic control and LUT symptoms in women with T2D. However, women with poor glycemic control are more likely to develop urinary retention than women with proper glycemic control. Clinicians should, therefore, be aware of and educate patients about the association between urinary retention and glycemic control.

Differences in toxicity and outcome associated with circadian variations between patients undergoing daytime and evening radiotherapy for prostate adenocarcinoma.

This retrospective study tested the hypothesis that disease control and treatment-related toxicity in patients undergoing high-dose radiotherapy (HDRT) for prostate cancer varies in a circadian manner. Patients with localized prostate adenocarcinoma receiving HDRT (median 78 Gy) to the prostate and involved seminal vesicle(s) without elective pelvic irradiation were divided into a daytime treatment (before 5 PM) group (n = 267) and evening treatment (after 5 PM) group (n = 142). Biochemical failure (Phoenix definition), acute and late gastrointestinal (GI) and genitourinary toxicities (Common Terminology Criteria for Adverse Events version 4), biochemical failure-free survival (BFFS) and freedom from late toxicity were assessed. Analyses were performed by binary logistic regression and Cox proportional hazard regression. The median follow-up was 68 months, and 75% of patients were ≥70 years old. Evening HDRT was significantly associated with worse freedom from ≥grade 2 late GI complications (hazard ratio = 2.96; p < 0.001). The detrimental effect of evening HDRT was significant in patients older than 70 years old (p < 0.001) but not in younger patients (p = 0.63). In a subgroup of propensity score-matched cohort with T2b-T3 disease (n = 154), the 5-year BFFS was worse in the evening group than the daytime group (72% vs. 85%, hazard ratio = 1.95, p = 0.05). Our study indicates that evening HDRT may lead to more GI complications, especially in older patients, and worse BFFS in patients with T2b-T3 disease.

Erectile dysfunction, loss of libido and low sexual frequency increase the risk of cardiovascular disease in men with low testosterone.

INTRODUCTION: Testosterone deficiency increases the cardiovascular disease (CVD) risk. AIM: To evaluate the effect of erectile dysfunction (ED), sexual frequency and hypogonadal symptoms on CVD risk. METHODS: A total of 395 hypogonadal men aged 45-74 years were surveyed using the Androgen Deficiency in the Aging Male and the International Index of Erectile Function. MAIN OUTCOME MEASURES: The 10-year CVD risk was measured with the Framingham Risk Score. Logistic regression was performed to obtain the odds ratios of sexual function and hypogonadal symptoms for a 10-year CVD risk ≥20% (high risk). RESULTS: The mean age was 56.1 ± 6.7 years. The mean 10-year CVD risk of the whole cohort was 18.1% ± 11.4%, while 131 subjects (33.2%) were classified as high risk. Logistic regression revealed that ED severity was associated with CVD risk [OR = 2.37 (CI 1.24-4.51) for mild-to-moderate ED, OR = 4.39 (1.78-8.43) for moderate ED and OR = 12.81 (4.65-26.11) for severe ED]. Compared to sexual frequency <1 per month, sexual frequency ≥4 decreased the risk of high CVD risk [OR = 0.35 (0.23-0.780)]. Loss of libido [OR = 2.95 (1.91-4.12)] and less strong erection [OR = 3.87 (CI 2.11-4.95)] increased the risk of high CVD risk. All remained significant after adjustment for age and testosterone. CONCLUSIONS: ED, decreased sexual frequency and loss of libido predict a high 10-year CVD risk in hypogonadal men.

Malignant Ureteral Obstruction: Functional Duration of Metallic versus Polymeric Ureteral Stents.

BACKGROUND: Ureteral obstruction caused by extrinsic compression is often associated with intra-abdominal cancers. Internal drainage with ureteral stents is typically the first-line therapy to relieve such obstructions. Novel designs of ureteral stents made of different materials have been invented to achieve better drainage. In this study, we described the functional outcomes of a Resonance metallic ureteral stent (Cook Medical, Bloomington, Indiana, USA) in patients with malignant ureteral obstruction and compare the functional duration of Resonance stents with regular polymeric stents in the same cohort. METHODS: Cancer patients who received polymeric stents and subsequent Resonance stents for ureteral obstruction between July 2009 and November 2012 were included in a chart review. Stent failure was detected by clinical symptoms, imaging studies, and renal function tests. The functional durations of each stent were calculated, and possible factors affecting stent patency were investigated. RESULTS: A total of 50 stents were successfully inserted into 50 ureteral units in 42 patients with malignant ureteral obstruction. There were 7 antegrade stents and 43 retrograde stents. There were no major complications. Stent-related symptoms were similar in both kinds of stents. After polymeric stents were replaced with Resonance metallic stents, hydronephrosis subsided or remained stable in 90% (45/50) of the ureteral units. Serum creatinine decreased or remained stable in 90% (38/42) of these patients. The Resonance stent exhibited a mean increase in functional duration of 4 months compared with the polymeric stents (p<0.0001), and 50% (25/50) of the Resonance stents exhibited a significant increase in functional duration (more than 3 months). Pre-operative serum creatinine < 2 was associated with a substantial increase in stent duration. CONCLUSIONS: Resonance stents are effective and safe in relieving malignant ureteral obstructions after polymeric stents failure. Resonance stents can provide a longer functional duration than polymeric stents and should be offered as an option for internal drainage.

The prevalence and the risk factors of testosterone deficiency in newly diagnosed and previously known type 2 diabetic men.

INTRODUCTION: While the epidemiology of testosterone deficiency has been well described in men with previously known type 2 diabetes mellitus (T2DM), it was less reported in those with untreated, newly diagnosed T2DM. AIM: The aim of this study was to investigate the prevalence and the risk factors of testosterone deficiency of men with newly diagnosed T2DM. METHODS: The cross-sectional study included 105 men (mean age: 61.2 ± 6.8 years) with previously known T2DM and another 81 (57.8 ± 8.8 years) with newly diagnosed T2DM. All received health checkup and sex hormone measurement at our institute in 2009. MAIN OUTCOME MEASURES: We calculated the prevalence and explored the risk factors of low total (<300 ng/dL) and free (<6 ng/dL) testosterone in men with newly diagnosed and previously known T2DM. RESULTS: Men with previously known T2DM were older and had higher diastolic pressure and greater fasting glucose. There was no significant difference in total (358.0 [155.0] ng/dL vs. 363.0 [154.0] ng/dL, P=0.68) and free (7.2 [2.5] ng/dL vs. 7.4 [2.4]ng/dL, P=0.84) testosterone and sex-hormone binding globulin (SHBG) (27.3 [22.3]nmol/L vs. 28.7 [14.9]nmol/L, P=0.46). The prevalence of low total and free testosterone was 28.4% and 21.0%, respectively, in men with newly diagnosed T2DM, and was 26.7% and 19.0% in those with previously known T2DM. In men with previously known T2DM, better glycemic control (HbA1c <7%) was associated with a higher level of total testosterone and a lower risk of low total testosterone. Men with newly diagnosed and previously known T2DM shared similar risk factors of low total testosterone, including high HbA1c (≥ 7%), low SHBG (<20 nmol/L), obesity, hyperuricemia, hypertriglycemia, and metabolic syndrome. Elevated prostate-specific antigen was a protective factor of low total testosterone. However, none of these factors was associated with low free testosterone. CONCLUSIONS: The prevalence and the risk factors of testosterone deficiency are similar between newly diagnosed and previously known type 2 diabetic men.

Laparoendoscopic single-site (LESS) retroperitoneal partial adrenalectomy using a custom-made single-access platform and standard laparoscopic instruments: technical considerations and surgical outcomes.

BACKGROUND: We previously reported our initial experience with laparoendoscopic single-site (LESS) retroperitoneal partial adrenalectomy using a custom-made single-port device and conventional straight laparoscopic instruments. METHODS: Between December 2010 and February 2012, LESS retroperitoneal partial adrenalectomies were performed in 11 patients. Six patients had aldosterone-producing adenomas (APAs) and five patients had nonfunctioning tumors. A single-port access was created with an Alexis wound retractor (Applied Medical, Rancho Santa Margarita, CA, USA) through an incision of 2-3 cm beneath the tip of the 12th rib. All procedures were performed with straight laparoscopic instruments. RESULTS: All LESS procedures were successfully completed without conversion to traditional laparoscopic conversion. The tumors ranged from 1 cm to 4.7 cm (mean, 2.3 cm). The operative time was 71-257 minutes (mean, 121 minutes). Most patients (n = 8) had minimal blood loss; the other three patients had a blood loss of 150 mL, 100 mL, and 100 mL. The mean hospital stay was 3 days (range, 1-6 days). There were no perioperative or postoperative complications. Pathological examinations revealed negative surgical margins in all specimens. All patients with Conn's syndrome had an improvement in blood pressure and normalization of plasma renin activity and serum aldosterone levels; all patients were free of potassium supplementation. CONCLUSION: Our results clearly demonstrate that LESS retroperitoneal partial adrenalectomy can be performed safely and effectively using a custom-made single-access platform and standard laparoscopic instruments.

Osteoblast-derived WNT-induced secreted protein 1 increases VCAM-1 expression and enhances prostate cancer metastasis by down-regulating miR-126.

Bone metastases of prostate cancer (PCa) may cause intractable pain. Wnt-1-induced secreted protein 1 (WISP-1) belongs to the CCN family (CTGF/CYR61/NOV) that plays a key role in bone formation. We found that osteoblast-conditioned medium (OBCM) stimulates migration and vascular adhesion molecule-1 (VCAM)-1 expression in human PCa (PC3 and DU145) cells. Osteoblast transfection with WISP-1 shRNA reduced OBCM-mediated PCa migration and VCAM-1 expression. Stimulation of PCa with OBCM or WISP-1 elevated focal adhesion kinase (FAK) and p38 phosphorylation. Either FAK and p38 inhibitors or siRNA abolished osteoblast-derived WISP-1-induced migration and VCAM-1 expression. Osteoblast-derived WISP-1 inhibited miR-126 expression. Moreover, miR-216 mimic reversed the WISP-1-enhanced migration and VCAM-1 expression. This study suggests that osteoblast-derived WISP-1 promotes migration and VCAM-1 expression in human PCa cells by down-regulating miR-126 expression via αvß1 integrin, FAK, and p38 signaling pathways. Thus, WISP-1 may be a new molecular therapeutic target in PCa bone metastasis.

Surgical management in enterovesical fistula in Crohn disease at a single medical center.

Crohn disease is a chronic, transmural, inflammatory disease of the gastrointestinal tract with unknown etiology. It can affect any part of the gastrointestinal tract and may cause fistula, stricture, or abscess formation with disease progression. The preoperative diagnosis and definite management of this rare complication are challenges for physicians, urologists, and surgeons.

Hyposensitivity of C-fiber afferents at the distal extremities as an indicator of early stages diabetic bladder dysfunction in type 2 diabetic women.

PURPOSE: To investigate the relationship between distal symmetric peripheral neuropathy and early stages of autonomic bladder dysfunction in type 2 diabetic women. MATERIALS AND METHODS: A total of 137 diabetic women with minimal coexisting confounders of voiding dysfunction followed at a diabetes clinic were subject to the following evaluations: current perception threshold (CPT) tests on myelinated and unmyelinated nerves at the big toe for peroneal nerve and middle finger for median nerve, uroflowmetry, post-void residual urine volume, and overactive bladder (OAB) symptom score questionnaire. Patients presenting with voiding difficulty also underwent urodynamic studies and intravesical CPT tests. RESULTS: Based on the OAB symptom score and urodynamic studies, 19% of diabetic women had the OAB syndrome while 24.8% had unrecognized urodynamic bladder dysfunction (UBD). The OAB group had a significantly greater mean 5 Hz CPT test value at the big toe by comparison to those without OAB. When compared to diabetic women without UBD, those with UBD showed greater mean 5 Hz CPT test values at the middle finger and big toe. The diabetic women categorized as C-fiber hyposensitivity at the middle finger or big toe by using CPT test also had higher odds ratios of UBD. Among diabetic women with UBD, the 5 Hz CPT test values at the big toe and middle finger were significantly associated with intravesical 5 Hz CPT test values. CONCLUSIONS: Using electrophysiological evidence, our study revealed that hyposensitivity of unmyelinated C fiber afferents at the distal extremities is an indicator of early stages diabetic bladder dysfunction in type 2 diabetic women. The C fiber dysfunction at the distal extremities seems concurrent with vesical C-fiber neuropathy and may be a sentinel for developing early diabetic bladder dysfunction among female patients.

Laparoscopic radical prostatectomy monotherapy, a more aggressive yet less invasive option, is oncologically effective in selected men with high-risk prostate cancer having only one D'Amico risk factor: experience from an Asian tertiary referral center.

PURPOSE: To present oncologic results of laparoscopic radical prostatectomy (LRP) monotherapy for men with high-risk, localized prostate cancer, and to find factors associated with a good prognosis via surgery alone. PATIENTS AND METHODS: Between 2002 and 2009, 241 men underwent LRP at an Asian tertiary referral center. Among them, we retrospectively identified 85 (35.3%) men who met the D'Amico's high-risk criteria: Prostate-specific antigen level >20 ng/mL, Gleason score of 8 to 10, or clinical stage ≥T2c. Perioperative parameters were analyzed against biochemical recurrence (BCR)-free survival. RESULTS: At a median follow-up of 54 months, BCR developed in 28 (34.1%), with an actuarial BCR-free survival rate of 63.3% at 5 years. Pathologically, 37.6% of the men had organ-confined (OC) disease. Positive surgical margins (PSM) were identified in 49.4% of the patients. A favorable pathologic outcome, defined as OC(+)PSM(-), was observed in 24 patients and associated with a 5-year BCR-free survival rate of 87.0%, compared with 100%, 54.0%, and 46.4% in men with OC(+)PSM(+), OC(-)PSM(-) and OC(-)PSM(+) disease (log-rank, P=0.008). The overall positive lymph node rate was 14.1%. Men (65.9%) with only one D'Amico risk factor had a 5-year BCR-free survival rate of 76.9%, compared with 34.6% in men (34.1%) with ≥2 risk factors (log-rank, P<0.001). CONCLUSIONS: Radical prostatectomy monotherapy performed laparoscopically or robotically appears to be an option for high-risk prostate cancer, especially in men with a single D'Amico risk factor. Men with ≥2 risk factors are more prone for BCR to develop after surgery and may need second-line therapy.