Association between chronic prostatitis and the subsequent benign prostatic hyperplasia: a population-based national cohort study.

PURPOSE: To explore the association between chronic prostatitis (CP) and the subsequent development of benign prostatic hyperplasia (BPH). METHODS: Data analyzed were medical claims of Taiwan's National Health Insurance program. From 2010 to 2017, 3571 patients ≧20 years with CP diagnosed by certified urologists were enrolled. Patients with past BPH diagnosis and diagnosis of prostate cancer, inguinal hernia, interstitial cystitis, and urethritis in the past and within one year after the first CP diagnosis were excluded. Age-matched controls were randomly selected from all non-CP individuals of the same exclusion criteria in the study period with a CP/non-CP ratio of 1:4. The follow-up was made from the first CP diagnosis to death or the end of 2018. The endpoint was the newly diagnosed BPH. Cox proportional hazard regression model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of BPH in association with CP. RESULTS: Over a maximum of 8 years of follow-up, 287 (8.03%) and 258 (0.43%) BPH events were noted for the CP and non-CP group, respectively, representing a covariate adjusted HR (aHR) of 4.30 (95% CI, 3.61-5.13). Younger patients tended to suffer from higher aHRs, especially those aged 20-39 years (aHR: 11.45, 95% CI, 5.12-25.64). CONCLUSION: The Taiwan national health database indicated that CP patients had a significantly higher risk of developing BPH later than non-CP patients. Interestingly, the younger the CP is diagnosed (under 40), the greater the risk.

The MAEL expression in mitochondria of human spermatozoa and the association with asthenozoospermia.

PURPOSE: The maelstrom spermatogenic transposon silencer (MAEL) function in postmeiotic germ cells remains unclear, and its protein localization in human testis and spermatozoa awaits determination. This study aims to clarify the MAEL expression in human spermatogenesis and to explore its role in sperm function. MATERIALS AND METHODS: Twenty-seven asthenozoospermic men, 40 normozoospermic controls, and three obstructive azoospermic men were enrolled. The transcripts of MAEL in the seminiferous epithelium and MAEL downstream targets were identified by bioinformatics analysis. MAEL protein expression in human testis and ejaculated sperms were examined by immunohistochemical and immunogold staining, respectively. The roles of MAEL in mitochondria function were investigated by siRNA knockdown in human H358 cells. The association between MAEL protein levels and clinical sperm features was evaluated. RESULTS: Abundant MAEL was expressed in spermatid and spermatozoa of the human testis. Remarkably, MAEL was located in the mitochondria of ejaculated sperm, and bioinformatics analysis identified GPX4 and UBL4B as MAEL's downstream targets. Knockdown of MAEL sabotaged mitochondria function and reduced adenosine triphosphate (ATP) production in H358 cells. MAEL, GPX4, and UBL4B expression levels were significantly decreased in asthenozoospermic sperms than in controls. The MAEL protein levels were positively correlated with GPX4 and UBL4B in human sperm. Total motile sperm count (TMSC) was positively correlated with protein levels of MAEL, GPX4, and UBL4B in ejaculated sperms. CONCLUSIONS: We highlight prominent MAEL expression in the intratesticular spermatid and the mitochondria of ejaculated spermatozoa. MAEL directly binds to GPX4 and UBL4B, and loss of MAEL induces mitochondrial dysfunction. MAEL-mitochondrial function-motility relationship might advance our understanding of the causes of asthenozoospermia.

The sufficient multidisciplinary specialists under a government-led health care system associated with the downward mortality trend of Fournier's gangrene in Taiwan.

OBJECTIVES: To explore the trends in Fournier's gangrene (FG) incidence and mortality rate in Taiwan and to investigate the contributing factors to such changes. METHODS: Between 2002 and 2016, hospitalized FG patients who underwent subsequent surgical intervention were included in this retrospective study. Incidence, outcomes, age-adjusted Charlson Comorbidity Index (ACCI), hospitalization cost, surgical timing, and the number of multidisciplinary specialists involved in the first-line management of FG in each year were collected. Simple linear regression and Pearson correlation coefficient (r) were used for the subsequent analysis. RESULTS: The national cohort enrolled 2183 FG patients from 2002 to 2016 in Taiwan. The age-standardized incidence rate of FG was between 0.4 and 0.8 per 100 000 population, and overall mortality was 7.8% in these 15 years. We illustrated the downward trendline of FG mortality with a 0.62 coefficient of determination. The mortality of FG patients who underwent surgery within 24 h and after 24 h were found to be 8.3 ± 3.9% and 14.6 ± 25.2%, respectively (p = 0.02). The numbers of urologists, anesthesiologists, emergency doctors, and physicians per 100 000 population had a strong negative linear correlation with FG mortality (r = 0.8, p < 0.001). ACCI score had a moderate linear relationship with FG mortality (r = 0.57, p = 0.027). The hospitalization cost showed a weak linear correlation with FG mortality (r = -0.03, p = 0.92). CONCLUSIONS: We demonstrated the downward trend of the FG mortality rate in Taiwan from 2002 to 2016. Besides underlying comorbidities and surgical timing, sufficient multidisciplinary specialists are essential for the survival benefit of FG patients in Taiwan experience.

Airway hyperresponsiveness induced by intermittent hypoxia in rats.

This study investigated whether intermittent hypoxia (IH) induces airway hyperresponsiveness (AHR) and associated with lung inflammation. Male Brown Norway rats were exposed to 14-day IH or room air (RA) for 6 h/day. One day after the last exposure, total lung resistance to various doses of methacholine was measured as an index of bronchoconstrictive responses. Compared with RA controls, methacholine significantly induced an augmented bronchoconstriction in IH-exposed rats. Moreover, IH exposure evoked lung inflammation which was reflected by increased inflammatory cell infiltration, concentrations of interleukin-6 and prostaglandin E2 in bronchoalveolar lavage fluid, and lung lipid peroxidation. IH-induced AHR and lung inflammation were completely abolished by daily intraperitoneal injection of N-acetylcysteine (an antioxidant) or ibuprofen (a cyclooxygenase inhibitor), but not by apocynin (an inhibitor of NADPH oxidase) or vehicle. In conclusion, AHR and lung inflammation occur after 14-day IH exposure, with endogenous reactive oxygen species and cyclooxygenase metabolites being responsible for these responses.

Preoperative Urine Analysis is An Effective Tool to Predict Fever After Miniaturized Percutaneous Nephrolithotomy on Large Renal Stones.

PURPOSE: To investigate the preoperative and intraoperative potential risk factors associated with miniaturized percutaneous nephrolithotomy (mPCNL) fever in the treatment of patients with large renal stones. MATERIALS AND METHODS: All patients with renal stones larger than 2.5 cm, who had undergone mPCNL, were included in the period between April 2018 and September 2019. Logistic regression analyses were performed to identify clinical variables associated with post-operative fever (>38°C). RESULTS: A total of 53 patients were enrolled for whom the median maximal stone length was 3.08 cm. 24 (45%) patients had a fever after mPCNL. Significantly more patients with urine WBC ≥ 27(/HPF) had a fever after surgery (p = 0.004). No significant between-group differences in urine cultures were found for the fever and non-fever groups (p = 0.094). Stepwise and multivariable logistic regression analyses all revealed that urine WBC ≥ 27(/HPF) is the only risk factor for developing post-mPCNL fever. Based on the highest body temperature, all of the patients were assigned into no fever, mild fever (37.5 ≤ Temp < 38.0), and fever groups, and an ordinal logistic regression analysis still supported the premise that the result of urine analysis is strongly associated with post-mPCNL fever. CONCLUSION: Large renal stones are challenging to treat and associated with severe complications. Approximately 45% of large renal stone patients treated via mPCNL developed a fever. Urine WBC can easily and directly predict the risk of fever.

The fertility preservation decision-making and testicular sperm retrieval outcome in older adolescents with nonmosaic Klinefelter syndrome and azoospermia.

BACKGROUND: This study aims to analyze the fertility preservation decision-making and the sperm retrieval rate (SRR) in older adolescents (age 15-19 years) with nonmosaic Klinefelter syndrome (KS) and azoospermia in a male reproductive clinic, and to determine the accumulated SRR in older adolescents by literature review. METHODS: Older adolescents with nonmosaic KS and azoospermia referred for hypogonadism and fertility concerns were enrolled. Reproductive counseling and fertility preservation options were offered to patients/parents. The acceptability and the reasons affecting the reproductive decision-making were analyzed. Patients/parents who agreed on fertility preservation received microdissection testicular sperm extraction (mTESE) and cryopreservation. A comprehensive literature review regarding the SRRs in older adolescents with KS was conducted. RESULTS: A total of eight older adolescents were enrolled. After fertility preservation counseling, three patients/parents (37.5%) agreed to receive mTESE, and spermatozoa were successfully retrieved in two. "Lack of interest" and "inconsistent sperm retrieval result" were the main reasons for refusal. A total of 89 older adolescents from nine articles, and ours were collected for SRR analysis. Most of the reports had a limited number of cases, and none of them described the acceptance rate of sperm retrieval in adolescents. Forty-three out of 89 older adolescents (48.3%) had successful sperm retrieval, and there was no significant difference in the SRR between the mTESE and conventional TESE. CONCLUSION: Successful testicular sperm retrieval in older adolescents with KS is not superior to those reported in adults. Adolescents and their parents should undergo a detailed reproductive consultation process and shared decision-making discussion before considering testicular sperm retrieval.

The Crosstalk of Long Non-Coding RNA and MicroRNA in Castration-Resistant and Neuroendocrine Prostate Cancer: Their Interaction and Clinical Importance.

Prostate cancer is featured by its heterogeneous nature, which indicates a different prognosis. Castration-resistant prostate cancer (CRPC) is a hallmark of the treatment-refractory stage, and the median survival of patients is only within two years. Neuroendocrine prostate cancer (NEPC) is an aggressive variant that arises from de novo presentation of small cell carcinoma or treatment-related transformation with a median survival of 1-2 years from the time of diagnosis. The epigenetic regulators, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been proven involved in multiple pathologic mechanisms of CRPC and NEPC. LncRNAs can act as competing endogenous RNAs to sponge miRNAs that would inhibit the expression of their targets. After that, miRNAs interact with the 3' untranslated region (UTR) of target mRNAs to repress the step of translation. These interactions may modulate gene expression and influence cancer development and progression. Otherwise, epigenetic regulators and genetic mutation also promote neuroendocrine differentiation and cancer stem-like cell formation. This step may induce neuroendocrine prostate cancer development. This review aims to provide an integrated, synthesized overview under current evidence to elucidate the crosstalk of lncRNAs with miRNAs and their influence on castration resistance or neuroendocrine differentiation of prostate cancer. Notably, we also discuss the mechanisms of lncRNA-miRNA interaction in androgen receptor-independent prostate cancer, such as growth factors, oncogenic signaling pathways, cell cycle dysregulation, and cytokines or other transmembrane proteins. Conclusively, we underscore the potential of these communications as potential therapeutic targets in the future.

Incorporating Simplified Fournier's Gangrene Severity Index with early surgical intervention can maximize survival in high-risk Fournier's gangrene patients.

OBJECTIVES: To determine the optimal surgical timing in high-risk patients with Fournier's gangrene by the Simplified Fournier's Gangrene Severity Index. METHODS: From 1989 to 2018, 118 male patients diagnosed with Fournier's gangrene with complete medical records were retrospectively reviewed. Patients' demographics, laboratory parameters at initial diagnosis, Fournier's Gangrene Severity Index and Simplified Fournier's Gangrene Severity Index, and the time interval from emergency room arrival to surgical intervention were collected. The Fournier's gangrene patients were categorized into low-risk (Simplified Fournier's Gangrene Severity Index ≤2) and high-risk groups (Simplified Fournier's Gangrene Severity Index >2). Differences between the variables within the two groups were analyzed. The optimal surgical timing was analyzed with the receiver operating characteristic curve in high-risk Fournier's gangrene patients. RESULTS: The overall mortality of 118 Fournier's gangrene patients was 14.4%. After risk stratification with the Simplified Fournier's Gangrene Severity Index scoring system, the mortality of low-risk and high-risk Fournier's gangrene patients was 1.3% and 41.0%, respectively. In the high-risk group, the time interval from emergency room arrival to surgical intervention was the only variable with a significant difference between survivors and non-survivors (P = 0.039). The optimal surgical timing was determined at 14.35 h, which allowed the highest sensitivity (0.688) and specificity (0.762) to affect mortality. The mortality was significantly lower in high-risk Fournier's gangrene patients with early surgical intervention compared with late intervention (23.8% vs 68.8%, P = 0.007). CONCLUSIONS: The Simplified Fournier's Gangrene Severity Index is a quick and reliable screening tool for first-line physicians to identify high-risk patients with Fournier's gangrene (Simplified Fournier's Gangrene Severity Index >2) who have poor survival outcomes. We recommended early surgical intervention within 14.35 h to maximize the survival of high-risk Fournier's gangrene patients.

MAEL promoter hypermethylation is associated with de-repression of LINE-1 in human hypospermatogenesis.

STUDY QUESTION: Does the hypermethylation of the maelstrom spermatogenic transposon silencer (MAEL) promoter and subsequent de-repression of transposable elements represent one of the causes of spermatogenic failure in infertile men? SUMMARY ANSWER: Experimental hypermethylation of a specific region (-131 to +177) of the MAEL promoter leads to decreased expression of MAEL with increased expression of the transposable element LINE-1 (L1) and in infertile men methylation of the MAEL promoter is associated with the severity of spermatogenic failure. WHAT IS KNOWN ALREADY: MAEL induces transposon repression in the male germline and is required for mammalian meiotic progression and post-meiotic spermiogenesis. Patients with non-obstructive azoospermia (NOA), defined as no sperm in the ejaculate due to spermatogenic failure, and histopathologically proven hypospermatogenesis (HS) is not uncommon and its etiology is largely unknown. STUDY DESIGN, SIZE, DURATION: Luciferase reporter assay and a targeted DNA methylation model were used to explore the effects of hypermethylation of MAEL promoter on gene expression. Germ cell-enriched testicular cells from infertile patients were used to determine the methylation levels of MAEL and expressions of MAEL and L1. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty-six patients with histopathologically proven NOA and HS and 12 patients with obstructive azoospermia and normal spermatogenesis (NS) were enrolled in this study. Demographic and clinical information were obtained. The severity of HS was determined by a spermatogenic scoring system. The methylation levels of 26 CpGs in the MAEL promoter was measured, and quantitative real-time RT-PCR was used to determine the expressional levels of MAEL and L1. MAIN RESULTS AND THE ROLE OF CHANCE: Targeted DNA methylation of MAEL promoter suppressed MAEL expression and de-repressed L1 activity in vitro. Patients with HS had significantly higher mean methylation levels of 26 consecutive CpGs in the MAEL promoter, compared to patients with NS. The MAEL methylation levels were negatively correlated with MAEL transcript levels and higher methylation level of MAEL was associated with severe spermatogenic defect. L1 transcript level was significantly higher in patients with HS. No differences in age, frequency of testicular insults and genetic anomalies was noted between patients with high or low MAEL methylation levels. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Because of the difficulty in the use of human germ cells for study, the in vitro targeted DNA methylation model was performed by using human NCI-H358 cells to explore the effects of MAEL methylation on transposable elements activity. Because the germ cell-enriched testicular cells isolated from a testicular sample were relatively few, the purity of cell populations was not determined. WIDER IMPLICATIONS OF THE FINDINGS: Measurement of the methylation level of MAEL gene may be feasible to predict the severity of spermatogenic failure or the outcome of testicular sperm retrieval. STUDY FUNDING/COMPETING INTERESTS: This work was supported through grants from the Ministry of Science and Technology of Taiwan (100-2314-B-006-017) and National Cheng Kung University Hospital, Tainan, Taiwan (NCKUH 20120266). The authors declare no conflicts of interest.

Causes and Clinical Features of Infertile Men With Nonobstructive Azoospermia and Histopathologic Diagnosis of Hypospermatogenesis.

OBJECTIVE: To analyze the causes and the clinical features of infertile men with nonobstructive azoospermia and hypospermatogenesis (HS). MATERIALS AND METHODS: This retrospective cohort study included 100 patients with nonobstructive azoospermia and HS and 8 patients with obstructive azoospermia and normal spermatogenesis. The severity of HS was subdivided into 3 groups (mild, moderate, and severe) based on spermatogenic score. Data of history, physical findings, serum hormone profiles, genetic studies, and sperm retrieval rate were collected. Whole genome DNA methylation analysis and microarray mRNA expression analysis were used to identify the candidate genes of methylation dysregulation in HS. RESULTS: Thirty-two (32%) patients had at least 1 prior/current testicular insults and 13 (13%) patients had genetic anomalies. Fifty-five (55%) patients were categorized as idiopathic HS. Patients with mild HS had a higher frequency of testicular insults, and patients with severe HS had a significantly higher frequency of genetic anomalies. Sperm retrieval rate was 100%, 100%, and 88.4% for patients with mild, moderate, and severe HS, respectively. Four sterility-related genes, including BOLL, DDX4, HORMAD1, and MAEL, were found to have increased methylation at CpGs of the promoter regions and decreased mRNA expressions in HS testis. CONCLUSION: The causes of HS are complex and multifactorial. The main causes of HS were prior or current testicular insults and chromosomal or genetic anomalies. More than half of the patients were categorized as idiopathic HS. With high throughput analysis, methylation dysregulations of BOLL, DDX4, HORMAD1, and MAEL are believed to be associated with HS.

Validation and simplification of Fournier's gangrene severity index.

OBJECTIVES: To validate the predictive value of Fournier's Gangrene Severity Index in patients with Fournier gangrene and to facilitate patient mortality risk-stratification by simplifying the Fournier's Gangrene Severity Index. METHODS: From January 1989 to December 2011, 85 male patients with clinically-documented Fournier's gangrene undergoing intensive treatment and with complete medical records were recruited. The demographic information and nine parameters of Fournier's Gangrene Severity Index were compared between survivors and non-survivors. The parameters that showed a significant difference between the two groups were selected to generate a simplified scoring index. RESULTS: Of the 85 patients recruited, 16 patients died of the disease with mortality rate of 18.8%. The Fournier's Gangrene Severity Index score at initial diagnosis was significantly higher in non-survivors than in survivors. Of the nine parameters of Fournier's Gangrene Severity Index, the scores of serum creatinine level, hematocrit level and serum potassium level were significantly different between the two groups. However, the mean body temperatures, heart rate, respiration rate, white blood cell count, serum sodium and bicarbonate levels were non-significantly different. Of the 12 patients with chronic kidney disease or end-stage renal disease, 10 died of severe sepsis. A simplified scoring index including parameters of creatinine, hematocrit and potassium was generated, which provided sensitivity and specificity of 87% and 77% in predicting patient mortality, respectively. The predictive values of this simplified Fournier's Gangrene Severity Index were shown to be non-inferior to Fournier's Gangrene Severity Index in our patients. CONCLUSIONS: The simplified Fournier's Gangrene Severity Index is easy to use at initial diagnosis, and offers a way to compare outcomes in different clinical populations.

Clinical characteristics and reproductive outcomes in infertile men with testicular early and late maturation arrest.

OBJECTIVE: To compare the clinical characteristics and reproductive outcomes of nonobstructive azoospermic men with uniform early and late maturation arrest. METHODS: Patients with biopsy-documented uniform maturation arrest undergoing testicular sperm retrieval and complete medical records were enrolled in the present study. Their medical history, physical examination findings, testicular volume, serum hormone parameters, genetic anomalies, sperm retrieval, and reproductive outcomes were retrospectively analyzed. RESULTS: In a cohort of 223 nonobstructive azoospermic men, 34 men with uniform maturation arrest (21 early maturation arrest and 13 late maturation arrest) were identified. No significant differences were seen in the age distribution, testicular volume, or hormone parameters between patients with early and late maturation arrest. Only 13 patients (38.2%) had a normal serum follicle-stimulating hormone level and normal testicular volume. Patients with early maturation arrest had a greater frequency of overall genetic anomalies, and patients with late maturation arrest had a greater frequency of previous testicular insults. The sperm retrieval and impregnation rate were nonsignificantly greater in patients with late maturation arrest. CONCLUSION: Maturation arrest has a variety of causes and presents with diverse phenotypes. Not all patients with uniform maturation arrest have a normal follicle-stimulating hormone level or testicular volume. Patients with early maturation arrest have a greater incidence of genetic anomalies and are more likely to have worse reproductive outcomes than are patients with late maturation arrest.