5-alpha-reductase inhibitors and the risk of diabetes mellitus: A nationwide population-based study.

BACKGROUND: This nationwide population-based study investigated the risk of type 2 diabetes mellitus (DM) after 5-alpha-reductase inhibitor (5ARI) therapy for benign prostate hyperplasia (BPH) using the National Health Insurance Research Database (NHIRD) in Taiwan. METHODS: In total, 1,298 adult patients newly diagnosed with BPH and who used more than 28 cumulative defined daily doses (cDDD) of 5ARI were recruited as the therapy group cohort, along with 1,2887 subjects who did not use more than 28 cDDD of 5ARI as a control group from 2002 to 2009. Each patient was monitored for 5 years (from 2003 to 2008) to identify those who subsequently developed type 2 DM. A Cox proportional hazards model was used to compare the risk of type 2 DM between the study and comparison cohorts after adjusting for possible confounding risk factors. RESULTS: Patients who received 5ARI therapy had a lower cumulative rate of type 2 DM than those who did not receive 5ARI during the five-year follow-up period (3.5% vs. 5.3%, P = 0.003). In sub-group analysis, among the BPH patients aged <65 years, the five-year type 2 DM events hazard ratio (HR) of 5ARI users was lower than that of nonusers (HR: 0.47, 95% confidence interval (CI): 0.24-0.91; P = 0.026). CONCLUSIONS: Therapy with 5ARI may decrease the five-year risk of type 2 DM in the BPH patients younger than 65 years. Further mechanistic research is warranted to validate the results.

CCL2 increases αvß3 integrin expression and subsequently promotes prostate cancer migration.

BACKGROUND: Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), belongs to the CC chemokine family which is associated with the disease status and outcomes of cancers. Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to the bone. However, the effect of CCL2 on human prostate cancer cells is largely unknown. The aim of this study was to examine the role of CCL2 in integrin expression and migratory activity in prostate cancers. METHODS: Prostate cancer migration was examined using Transwell, wound healing, and invasion assay. The PKCδ and c-Src phosphorylations were examined by using western blotting. The qPCR was used to examine the mRNA expression of integrins. A transient transfection protocol was used to examine AP-1 activity. RESULTS: Stimulation of prostate cancer cell lines (PC3, DU145, and LNCaP) induced migration and expression of integrin αvß3. Treatment of cells with αvß3 antibody or siRNA abolished CCL2-increased cell migration. CCL2-increased migration and integrin expression were diminished by CCR2 but not by CCR4 inhibitors, suggesting that the CCR2 receptor is involved in CCL2-promoted prostate cancer migration. CCL2 activated a signal transduction pathway that includes PKCδ, c-Src, and AP-1. Reagents that inhibit specific components of this pathway each diminished the ability of CCL2 to effect cell migration and integrin expression. CONCLUSIONS: Interaction between CCL2 and CCR2 enhances migration of prostate cancer cells through an increase in αvß3 integrin production. GENERAL SIGNIFICANCE: CCL2 is a critical factor of prostate cancer metastasis.

Potential therapeutic roles of tanshinone IIA in human bladder cancer cells.

Tanshinone IIA (Tan-IIA), one of the major lipophilic components isolated from the root of Salviae Miltiorrhizae, has been found to exhibit anticancer activity in various cancer cells. We have demonstrated that Tan-IIA induces apoptosis in several human cancer cells through caspase- and mitochondria-dependent pathways. Here we explored the anticancer effect of Tan-IIA in human bladder cancer cell lines. Our results showed that Tan-IIA caused bladder cancer cell death in a time- and dose-dependent manner. Tan-IIA induced apoptosis through the mitochondria-dependent pathway in these bladder cancer cells. Tan-IIA also suppressed the migration of bladder cancer cells as revealed by the wound healing and transwell assays. Finally, combination therapy of Tan-IIA with a lower dose of cisplatin successfully killed bladder cancer cells, suggesting that Tan-IIA can serve as a potential anti-cancer agent in bladder cancer.

Machine learning-based comparison of factors influencing estimated glomerular filtration rate in Chinese women with or without non-alcoholic fatty liver.

BACKGROUND: The prevalence of non-alcoholic fatty liver (NAFLD) has increased recently. Subjects with NAFLD are known to have higher chance for renal function impairment. Many past studies used traditional multiple linear regression (MLR) to identify risk factors for decreased estimated glomerular filtration rate (eGFR). However, medical research is increasingly relying on emerging machine learning (Mach-L) methods. The present study enrolled healthy women to identify factors affecting eGFR in subjects with and without NAFLD (NAFLD+, NAFLD-) and to rank their importance. AIM: To uses three different Mach-L methods to identify key impact factors for eGFR in healthy women with and without NAFLD. METHODS: A total of 65535 healthy female study participants were enrolled from the Taiwan MJ cohort, accounting for 32 independent variables including demographic, biochemistry and lifestyle parameters (independent variables), while eGFR was used as the dependent variable. Aside from MLR, three Mach-L methods were applied, including stochastic gradient boosting, eXtreme gradient boosting and elastic net. Errors of estimation were used to define method accuracy, where smaller degree of error indicated better model performance. RESULTS: Income, albumin, eGFR, High density lipoprotein-Cholesterol, phosphorus, forced expiratory volume in one second (FEV1), and sleep time were all lower in the NAFLD+ group, while other factors were all significantly higher except for smoking area. Mach-L had lower estimation errors, thus outperforming MLR. In Model 1, age, uric acid (UA), FEV1, plasma calcium level (Ca), plasma albumin level (Alb) and T-bilirubin were the most important factors in the NAFLD+ group, as opposed to age, UA, FEV1, Alb, lactic dehydrogenase (LDH) and Ca for the NAFLD- group. Given the importance percentage was much higher than the 2nd important factor, we built Model 2 by removing age. CONCLUSION: The eGFR were lower in the NAFLD+ group compared to the NAFLD- group, with age being was the most important impact factor in both groups of healthy Chinese women, followed by LDH, UA, FEV1 and Alb. However, for the NAFLD- group, TSH and SBP were the 5th and 6th most important factors, as opposed to Ca and BF in the NAFLD+ group.

D-pinitol inhibits prostate cancer metastasis through inhibition of αVß3 integrin by modulating FAK, c-Src and NF-κB pathways.

Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to the bone. D-pinitol, a 3-methoxy analogue of d-chiro-inositol, was identified as an active principle in soy foods and legumes, and it has been proven to induce tumor apoptosis and metastasis of cancer cells. In this study, we investigated the anti-metastasis effects of D-pinitol in human prostate cancer cells. We found that D-pinitol reduced the migration and the invasion of prostate cancer cells (PC3 and DU145) at noncytotoxic concentrations. Integrins are the major adhesive molecules in mammalian cells and have been associated with the metastasis of cancer cells. Treatment of prostate cancer cells with D-pinitol reduced mRNA and cell surface expression of αvß3 integrin. In addition, D-pinitol exerted its inhibitory effects by reducing focal adhesion kinase (FAK) phosphorylation, c-Src kinase activity and NF-kB activation. Thus, D-pinitol may be a novel anti-metastasis agent for the treatment of prostate cancer metastasis.

Ethnic differences in the age-related distribution of serum prostate-specific antigen values: A study in a Taiwanese male population.

This study investigates age-specific prostate-specific antigen (PSA) distributions in Taiwanese men and recommends reference ranges for this population after comparison with other studies. From January 1999 to December 2016, a total of 213,986 Taiwanese men aged above 19 years old without history of prostate cancer, urinary tract infection, or prostate infection were recruited from the Taiwan MJ cohort, an ongoing prospective cohort of health examinations conducted by the MJ Health Screening Center in Taiwan. Participants were divided into seven age groups. Simple descriptive statistical analyses were carried out and quartiles and 95th percentiles were calculated for each group as reference ranges for serum PSA in screening for prostate cancer in Taiwanese men. Serum PSA concentration correlated with age (r = 0.274, p<0.001). The median serum PSA concentration (5th to 95th percentile) ranged from 0.7 ng/ml (0.3 to 1.8) for men 20-29 years old (n = 6,382) to 1.6 ng/ml (0.4 to 8.4) for men over 79 years old (n = 504). The age-specific PSA reference ranges are as follows: 20-29 years, 1.80 ng/ml; 30-39 years, 1.80 ng/ml; 40-49 years, 2.0 ng/ml; 50-59 years, 3.20 ng/ml; 60-69 years, 5.60 ng/ml; 70-79 years, 7.40 ng/ml; over 80 years, 8.40 ng/ml. Almost no change occurred in the median serum PSA value in men 50 years old or younger, while a gradual increase was observed in men over 50. Taiwanese men aged 60 years above showed higher 95th percentile serum PSA values compared to Caucasian men and men in other Asian countries but were closer to those of Asian American and African American men. Results indicate significantly different PSA levels correlating to different ethnicities, suggesting that Oesterling's age-specific PSA reference ranges might not be appropriate for Taiwanese men. Our results should be further studied to validate the age-specific PSA reference ranges for Taiwanese men presented in this study.

Limited Wegener's granulomatosis of the epididymis and testis.

A case is presented of Wegener's granulomatosis limited to the testis and epididymis, simultaneously, in a 69-year-old man. Orchiectomy was carried out through an inguinal incision under the presumptive diagnosis of a right testicular tumor. A hard, irregular mass occupied the upper testicle and a portion of the epididymal head was visualized. Histopathologic examination of the specimen showed granulomatous inflammation of the testis and epididymis with prominent angiocentric granulomata in the walls of arteries, veins and foci of fibrinoid necrosis, surrounded by palisading inflammatory cells with a few giant cells. The diagnosis of limited Wegener's granulomatosis was considered, although antineutrophil cytoplasmic antibody (c-ANCA) test was negative 2 weeks after orchiectomy. The patient showed an excellent response after local complete excision. He remains free of disease 18 months after orchiectomy.

Insulin resistance & secretion in subjects with normal fasting plasma glucose.

BACKGROUND & OBJECTIVES: Lowering the diagnostic threshold of normal fasting plasma glucose (FPG) from 6.1 to 5.56 mmol/l has been proposed by American Diabetes Association. As early detection of subjects with risk of diabetes is important, it is crucial to understand the relationship between different levels of FPG, insulin resistance (IR) and insulin secretion. We measured IR and insulin secretion in subjects with different levels of FPG to investigate the relationship between FPG and IR and insulin secretion, and to see whether lowering the cut-off improves the sensitivity of impaired fasting glucose to predict diabetes. METHODS: Apparently healthy subjects (294) were enrolled and divided into 3 groups according to their FPG levels; group 1 (<5.56 mmol/l, n=129), group 2 (5.56-6.09 mmol/l, n=99) and group 3 (6.1-6.9 mmol/l, n=66). Steady state plasma glucose (SSPG) derived from insulin suppression test was used to quantify insulin resistance and 30 min insulinogenic index during an oral glucose tolerance test to measure acute insulin secretion. RESULTS: The blood pressure was higher in group 3 than group 2 and fasting plasma insulin and triglyceride were higher in group 3 than that in group 1. The insulinogenic index was higher in the group 1 than group 3 and the SSPG was significantly higher in group 3 compared to group 1. INTERPRETATION & CONCLUSION: Our study showed a trend of progressive deterioration of both insulin action and secretion with increasing FPG level. These are supportive evidences for lowering the FPG to 5.56 mmol/l as suggested by the ADA.

Maximum Urine Flow Rate of Less than 15ml/Sec Increasing Risk of Urine Retention and Prostate Surgery among Patients with Alpha-1 Blockers: A 10-Year Follow Up Study.

BACKGROUND: The aim of this study was to determine the subsequent risk of acute urine retention and prostate surgery in patients receiving alpha-1 blockers treatment and having a maximum urinary flow rate of less than 15ml/sec. METHODS: We identified patients who were diagnosed with benign prostate hyperplasia (BPH) and had a maximum uroflow rate of less than 15ml/sec between 1 January, 2002 to 31 December, 2011 from Taiwan's National Health Insurance Research Database into study group (n = 303). The control cohort included four BPH/LUTS patients without 5ARI used for each study group, randomly selected from the same dataset (n = 1,212). Each patient was monitored to identify those who subsequently developed prostate surgery and acute urine retention. RESULTS: Prostate surgery and acute urine retention are detected in 5.9% of control group and 8.3% of study group during 10-year follow up. Compared with the control group, there was increase in the risk of prostate surgery and acute urine retention in the study group (HR = 1.83, 95% CI: 1.16 to 2.91) after adjusting for age, comorbidities, geographic region and socioeconomic status. CONCLUSIONS: Maximum urine flow rate of less than 15ml/sec is a risk factor of urinary retention and subsequent prostate surgery in BPH patients receiving alpha-1 blocker therapy. This result can provide a reference for clinicians.

CHADS2 scores as a predictor of ischemic stroke after radical prostatectomy.

Patients with prostate cancer have an increased risk of stroke, but their absolute rate of stroke depends on age and comorbid conditions. The Charlson Comorbidity Index Score (CCIS) is a widely accepted measure for risk adjustment in administrative claims data sets. This study assesses the predictive value of CHADS2 scores and CCIS for stroke among patients with prostate cancer. The study was conducted based on data taken from Taiwan's National Health Insurance Research Database (NHIRD). We identified a total of 5414 participants with nonatrial fibrillation (AF) prostate cancer diagnoses who underwent radical prostatectomy between 1997 and 2011. CHADS2 scores and CCIS were used to stratify the 5-year ischemic stroke risk. All participants were followed from the date of enrollment until ischemic stroke, death, or the end of the 5-year follow-up period. The 5-year risk of ischemic stroke in the present study was 1.7%. Ischemic stroke has a better correlation with CHADS2 (CHADS2 score = 0 to 1: 0.02%, CHADS2 score = 2 to 3: 13.9%, CHADS2 score ≥ 4: 44.4%; AUC = 0.978) than CCIS (CCIS = 0 to 1: 1.6%, CCIS = 2 to 3: 1.7%, CCIS ≥ 4: 3.8%; AUC = 0.520). Our results show that patients with prostate cancer who underwent radical prostatectomy show significantly higher risk of ischemic stroke in high CHADS2 score patients, and the CHADS2 score could be applied for ischemic stroke prediction. Cardiovascular risks evaluation and management are suggested for prostate cancer patients with higher CHADS2 score.

Use of 5-alpha-reductase inhibitors did not increase the risk of cardiovascular diseases in patients with benign prostate hyperplasia: a five-year follow-up study.

BACKGROUND: This nationwide population-based study investigated the risk of cardiovascular diseases after 5-alpha-reductase inhibitor therapy for benign prostate hyperplasia (BPH) using the National Health Insurance Research Database (NHIRD) in Taiwan. METHODS: In total, 1,486 adult patients newly diagnosed with BPH and who used 5-alpha-reductase inhibitors were recruited as the study cohort, along with 9,995 subjects who did not use 5-alpha-reductase inhibitors as a comparison cohort from 2003 to 2008. Each patient was monitored for 5 years, and those who subsequently had cardiovascular diseases were identified. A Cox proportional hazards model was used to compare the risk of cardiovascular diseases between the study and comparison cohorts after adjusting for possible confounding risk factors. RESULTS: The patients who received 5-alpha-reductase inhibitor therapy had a lower cumulative rate of cardiovascular diseases than those who did not receive 5-alpha-reductase inhibitor therapy during the 5-year follow-up period (8.4% vs. 11.2%, P=0.003). In subgroup analysis, the 5-year cardiovascular event hazard ratio (HR) was lower among the patients older than 65 years with 91 to 365 cumulative defined daily dose (cDDD) 5-alpha-reductase inhibitor use (HR=0.63, 95% confidence interval (CI) 0.42 to 0.92; P=0.018), however there was no difference among the patients with 28 to 90 and more than 365 cDDD 5-alpha-reductase inhibitor use (HR=1.14, 95% CI 0.77 to 1.68; P=0.518 and HR=0.83, 95% CI 0.57 to 1.20; P=0.310, respectively). CONCLUSIONS: 5-alpha-reductase inhibitor therapy did not increase the risk of cardiovascular events in the BPH patients in 5 years of follow-up. Further mechanistic research is needed.

Apoptosis and kinematics of ejaculated spermatozoa in patients with varicocele.

Increased DNA fragmentation is found in sperm from infertile men. Varicocele is an important cause of male infertility, even though it is present in 15% of men who father children. Semen analysis does not always identify infertility in these patients. Sperm motility is strongly correlated with male fertility potential. The goal of this study was to determine the correlation between apoptosis and kinematics in the ejaculated spermatozoa of patients affected by varicocele. Fresh semen samples were obtained from 30 patients with varicocele and 15 fertile controls. These samples were compared using computer-assisted semen analysis and were assayed to determine the degree of sperm apoptosis. The apoptotic index (AI) was calculated by dividing the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine-5'-triphosphate nick end labeling (TUNEL) stained spermatozoa by the total number of Hoechst 33258-stained sperm cells for 300 sperm. Five microscopic fields were analyzed to obtain 5 AIs for each individual. Results demonstrated no significant difference in semen quality and sperm motion characteristics; however, a significantly higher AI (23.05% +/- 4.07%: mean difference +/- SE, 95% CI, 15.06%-31.03%, P <.0001) was identified in the varicocele group than in the fertile controls. We concluded that sperm apoptosis does not seem to correlate with semen quality and sperm kinematics and that apoptosis is increased in ejaculated spermatozoa in patients with varicocele compared to normal fertile men.

Apoptosis-related phenotype of ejaculated spermatozoa in patients with varicocele.

OBJECTIVE: To determine the integrity of the sperm plasma membrane, mitochondria, and DNA, which are essential for accurate transmission of genetic material to offspring, and to quantify possible apoptosis and investigate any relationship between these parameters in ejaculated sperm from men with or without varicoceles. DESIGN: Retrospective study. SETTING: University teaching hospital. PATIENT(S): Twenty-five patients with varicocele and 10 normal, fertile controls. INTERVENTION(S): Apoptosis-related phenotype activations including the plasma membrane translocation of phosphatidylserine, mitochondrial dysfunction, and nuclear DNA damage, were assessed by using the annexin-V/propidium iodide double staining assay, 3,3'-dihexloxacarbocyanine iodide staining assay, and single-cell gel electrophoresis assay (comet assay). MAIN OUTCOME MEASURE(S): Apoptosis-related phenotype. RESULT(S): Patients with varicocele had statistically significantly more annexin V live sperm cells and nuclear DNA fragmentation than did the control men. In contrast, their numbers of 3,3'-dihexloxacarbocyanine iodide live cells were statistically significantly less than those in control men. CONCLUSION(S): The increased externalization of phosphatidylserine, mitochondrial dysfunction, and nuclear DNA damage occurred in the sperm of men with varicoceles, suggesting that certain apoptotic mechanisms may relate to the condition of varicocele, originating in the mitochondria of spermatocytes and then functioning within the nucleus of the cell.

Testicular microlithiasis in Taiwanese men.

Testicular microlithiasis (TM) is an unusual ultrasonographic manifestation in testicular parenchyma. Limited information is available about TM in Taiwanese men. We performed a retrospective analysis to investigate the characteristics of TM and its association with testicular cancer and infertility in Taiwan. Male patients who had received scrotal ultrasonography because of scrotal symptoms or infertility between January 2000 and December 2003 were recruited. The incidence of TM was 7.6%. Both testicular microlithiasis and testicular cancer occurred chiefly in the third decade. Patients with TM exhibit a higher chance of testicular cancer (6% vs. 0.9%). No local field effect between TM and testicular cancer was observed. Testicular microlithiasis severity is not positively correlated with sperm quality and sterility. Forty-eight patients (32%) were available at follow-up. No patient developed a testicular tumor or elevated tumor markers (AFP, beta-hCG) during follow-up. We suggest monthly self-examination, annual scrotal ultrasonography and tumor markers screening between the age of 20 and 30 years of patients with TM.

Comparison of prevalence between self-reported erectile dysfunction and erectile dysfunction as defined by five-item International Index of Erectile Function in Taiwanese men older than 40 years.

OBJECTIVES: To conduct a cohort study in men older than 40 years in Taiwan to evaluate the prevalence of erectile dysfunction (ED) by self-report and the use of the abridged, five-item version of the International Index of Erectile Function (IIEF-5). METHODS: From July to August 2003, 990 Taiwanese men older than 40 years of age completed a telephone survey designed to assess ED prevalence and sexual functioning. ED was identified through respondent self-report and investigator assessment using the IIEF-5 instrument. Data were analyzed using the analysis of variance test, t test, and chi-square test, with Yates' correction or Fisher's method. RESULTS: The prevalence of self-reported ED was 13.1%, with 26.2% of this subgroup subsequently deemed to not have ED by IIEF-5 assessment. Among the subgroup of men self-reported to not have ED, 18.8% were found to have ED by IIEF-5 assessment. In total, 26.0% of respondents had ED by IIEF-5 assessment. The ED prevalence increased with age and a history of chronic illness. The frequency of sexual contact and sexual satisfaction were also reduced in the respondents with ED. CONCLUSIONS: The prevalence of self-reported ED in Taiwanese men older than 40 years of age was 13.1% compared with 26.0% using the IIEF-5 assessment. Estimates of ED prevalence in the general population should not rely on self-reporting alone because it is likely to underestimate the true prevalence of ED.

Botryoid-type pleomorphic rhabdomyosarcoma of the renal pelvis in an adult. A rare case report and review of the literature.

Rhabdomyosarcoma of the renal pelvis is an extremely rare lesion for which only two reports are available. Here, we report another case of botryoid-type pleomorphic rhabdomyosarcoma in the renal pelvis. The tumor produced mild hydroureteronephrosis and right nephrectomy was performed after the needle aspiration cytology revealed abnormal epithelial clusters. The surgical specimen disclosed a polypoid mass attached to the wall of the lower pole of the renal pelvis. Light microscopy examination revealed a large polypoid tumor protruding from the inner surface of the renal pelvis with intact surface urothelium. Immunohistochemical stains for actin, myoglobin, and vimentin were positive. Although rhabdomyosarcoma has formerly been reported to occur at the renal pelvis, to our knowledge, this is the first case of renal pelvis botryoid-type pleomorphic rhabdomyosarcoma diagnosed by light microscopy and immunohistochemical stains.

Efficacy and safety of on-demand oral tadalafil in the treatment of men with erectile dysfunction in Taiwan: a randomized, double-blind, parallel, placebo-controlled clinical study.

INTRODUCTION: Tadalafil is a phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction (ED). Past clinical trials have assessed its efficacy and safety in western populations. Tadalafil has not been investigated in a large clinical trial with a South-east Asian population. AIM: To assess the efficacy and safety of on-demand tadalafil for the treatment of ED in a 12-week, double-blind, placebo-controlled study in Taiwan. METHODS: Men with mild to severe ED of various etiologies were randomized to receive placebo, tadalafil 10 mg, or tadalafil 20 mg, taken as needed (maximum once daily). Efficacy assessments included the International Index of Erectile Function, the Sexual Encounter Profile (SEP) diary, and a Global Assessment Question (GAQ). RESULTS: Tadalafil significantly improved erectile function compared with placebo (P < 0.005, all measures). At endpoint, the patients receiving tadalafil reported a greater mean per-patient percentage of successful intercourse attempts (SEP question 3: 70.0%, 10 mg; 78.0%, 20 mg) than placebo-treated patients (42.8%) and a greater proportion of improved erections (GAQ: 92.3% and 84.6% vs. 54.5%). Most treatment-emergent adverse events were mild or moderate. The most common adverse events were back pain, dyspepsia, and myalgia. CONCLUSIONS: Tadalafil was an effective, well-tolerated therapy for men in Taiwan with ED of broad-spectrum severity and etiology.