Transcriptomic analysis of bladder tissue in a rat model of ketamine-induced bladder fibrosis.

INTRODUCTION: Ketamine-induced cystitis (KIC) is a disease caused by ketamine that can cause lower urinary tract symptoms (LUTS). Its end-stage is bladder contracture, which is related to bladder fibrosis and poses a serious burden to patient lives. METHODS: We established a KIC model in female Sprague Dawley rats and verified bladder fibrosis in the model by Masson trichrome staining and western blot analysis. The bladders of the rats from the ketamine and control groups were used to perform transcriptome analysis. In particular, association analysis with metabolomics was also used to determine the potential mechanisms of ketamine-induced bladder fibrosis. RESULTS: A total of 685 differentially expressed messenger RNAs, 71 differentially expressed long noncoding RNAs, 23 differentially expressed microRNAs, and 68 differentially expressed circular RNAs were identified. We found that ribosome, Wnt signaling, vascular endothelial growth factor signaling, cytoskeleton organization, and cytoskeletal protein binding may be potential pathways in ketamine-induced bladder fibrosis as identified by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. In addition, the mitogen-activated protein kinase pathway appeared to be closely related to the development of ketamine-induced bladder fibrosis according to association analysis. CONCLUSIONS: In this study, using transcriptomic and correlation analyses of metabolomics, we identified pathways that may be potential targets for the prevention and treatment of ketamine-induced bladder fibrosis.

The role of Wnt signaling in male reproductive physiology and pathology.

Accumulating evidence has shown that Wnt signaling is deeply involved in male reproductive physiology, and malfunction of the signal path can cause pathological changes in genital organs and sperm cells. These abnormalities are diverse in manifestation and have been constantly found in the knockout models of Wnt studies. Nevertheless, most of the research solely focused on a certain factor in the Wnt pathway, and there are few reports on the overall relation between Wnt signals and male reproductive physiology. In our review, Wnt findings relating to the reproductive system were sought and summarized in terms of Wnt ligands, Wnt receptors, Wnt intracellular signals and Wnt regulators. By sorting out and integrating relevant functions, as well as underlining the controversies among different reports, our review aims to offer an overview of Wnt signaling in male reproductive physiology and pathology for further mechanistic studies.

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Recturethral fistula (RUF) is a kind of serious complication that mainly happened during the treatment of prostate cancer. It has become one of the most difficult diseases to treat in urology because of its special anatomical location, complicated condition, and the varied prognosis. At present, the main treatment methods for RUF are conservative treatment such as application of antibiotics and indwelling catheters, etc. and surgical treatment such as transperineal approach, transsphincter approach, transanal approach, transabdominal approach, etc. However, there is no explicit treatment protocol for RUF. What's more, the etiology of RUF has changed greatly in recent years. Summarizing the advantages and disadvantages of different RUF's treatment methods and their prognosis will be helpful for the decision of clinical treatment.

MTSS1 hypermethylation is associated with prostate cancer progression.

This study was conducted to evaluate the influence of DNA methylation of metastasis suppressor 1 (MTSS1) on prostate cancer (PCa) progression. Forty-nine paired PCa tissue samples and normal tissue samples from The Cancer Genome Atlas were analyzed. Methylome analysis, CpG island arrays and Hierarchical clustering were used to analyze methylation profiles of PCa tissues. MTSS1 methylation level was detected by methylation-specific PCR. Relative messenger RNA and the expression level of MTSS1 protein were identified by quantitative real-time PCR (qRT-PCR) and western blot analysis. The migration, invasion, proliferation, and cell cycle were detected separately by wound-healing assay, transwell chamber assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and flow cytometry. The roles of MTSS1 in PCa progression were demonstrated in vivo by tumor formation assays in nude mice. MTSS1 expression was decreased in PCa tissues in comparison with paired adjacent normal prostate tissues. Compared to the methylation of MTSS1 in normal prostate tissues based on the MethHC website, the MTSS1 in PCa tissues was hypermethylated. The expression of MTSS1 detected by qRT-PCR and western blot analysis was found to be downregulated in PCa cells and tissues. The reduced expression of MTSS1 by small interfering RNA-MTSS1 was recovered by 5-aza-2'-deoxycytidine treatment. Besides, MTSS1 demethylation inhibited migration, invasion, and proliferation of PCa cells, and induced cell cycle to be arrested at G0/G1 phase. Furthermore, it was shown by tumor xenograft assay that MTSS1 inhibited the growth of tumor in vivo. Hypermethylated MTSS1 promoted PCa cells migration, invasion, and proliferation, and suppressed cell cycle arrest at the G0/G1 phase.

Is milder psychological stress responsible for more severe erectile dysfunction?

China is a sexually conservative country compared with Western countries. To evaluate the psychological characteristics of Chinese erectile dysfunction (ED) patients, we conducted a cross-sectional study of 153 ED outpatients. Patients were interviewed with the Structured Interview on Erectile Dysfunction (SIEDY) for pathogenic quantification. ED was measured by International Index of Erectile Function (IIEF). Depression and anxiety were evaluated with 9-item Patient Health Questionnaire (PHQ-9) and 7-item Generalised Anxiety Disorder Scale (GAD-7) respectively. Most patients (74.5%) were <40 years old. IIEF-5 were significantly correlated with SIEDY scale 3 (r = .16, p = .040) and GAD-7 (p = .15, p = .033). The SIEDY scale 1 increased with age, but the IIEF-5, SIEDY scale 3, PHQ-9 and GAD-7 decreased with age. A negative correlation was observed between ED and psychological stress, which conflicts with many Western-country studies. Younger patients were characterised by milder ED but more psychological stress, while older patients were characterised by worse ED but less psychological stress. Which may be responsible for the conflicting result. Meanwhile, the much younger age distribution among Chinese ED outpatients may indicate that quite a few older ED patients (≥40 years) in China do not seek outpatient service which should merit more attention.

Dysuria due to benign prostatic hyperplasia of the median lobe with ketamine-associated uropathy in a young male.

BACKGROUND: Benign prostatic hyperplasia (BPH) rarely occurs in children or young males. In this case report, a 29-year-old male patient diagnosed with BPH coexisting with ketamine-associated uropathy was reported to investigate the possible relationship between BPH and ketamine-associated uropathy as well as therapeutic strategies. CASE PRESENTATION: A 29-year-old male patient with a 3-year history of ketamine inhalation, complaining of dysuria with frequency and urgency, was admitted. Hydronephrosis, hydroureters, uneven bladder wall thickening and a tumour located in the outlet of the bladder were detected with computed tomography (CT). The patient agreed to cystoscopy under general anaesthesia. A spherical tumour with a diameter of approximately 2 cm was found to originate from the median lobe of the prostate and follicular lesions were diffusely distributed on the right bladder wall. The tumour and follicular lesions in the bladder were resected successfully, and pathology demonstrated BPH and chronic inflammation of the mucous membranes separately. The patient quit ketamine completely during the one-year follow-up. Dysuria was relieved completely and no tumour or follicular neoplasm recurrence was found. CONTRIBUTION: Inflammation in the urothelium, as a direct or indirect consequence of ketamine, may contribute to the development of BPH. Both surgical interventions to remove obstruction and ketamine cessation are necessary approaches.

[Anti-cicatricial and anti-restenosis effect of verapamil on anterior urethral stricture: A randomized controlled clinical trial].

OBJECTIVE: To evaluate the anti-cicatricial and anti-restenosis effect of verapamil on anterior urethral stricture.
 Methods: A total of 32 patients received anterior urethral stricture were enrolled in this study. They were divided into 4 blocks according to the duration of previous urethral operations and dilations. Every block was further randomly divided into an experimental group and a control group. Experimental groups received 2 mL injection of verapamil around the anastomosis site of urethra before and after the surgery (2, 4, 6, 8, and 10 weeks after the surgery), while the control groups only received the anastomosis surgery. After surgery, maximal urinary flow rate (Qmax) was examined for all patients once the catheter was removed. In addition, they were also conducted palpation of urethral scar range. The sum of long transverse diameters of urethral scar was measured, and the narrowest urethral inner diameter was examined. The Qmax was rechecked and the urethral scar range was assessed by penis color Doppler elastography after 12 weeks of surgery. The above 4 indexes were used to evaluate the inhibitory effect of verapamil on urethral scar.
 Results: The length of palpated urethral scar in the Block 1 to 4 of the experimental groups was (22.75±1.03), (21.25±0.25), (20.75±1.03), and (20.0±0.58) mm, respectively; and those in the control groups (26.00±0.82), (24.5±1.04), (25.75±1.65), and (28.25±1.75) mm, respectively. The Qmax rates in the Block 1 to 4 of the experimental groups were (11.85±0.77), (11.33±0.81), (10.23±0.26), and (10.35±0.17) mL/s, respectively; and those in the control groups were (10.85±0.39), (10.50±0.76), (10.53±1.00), (12.60±0.39) mL/s, respectively. The Qmax rates in the Block 1 to 4 of the experimental groups were (11.73±0.87), (10.65±0.25), (10.23±0.19), and (10.35±0.29) mL/s, respectively; and those in the control groups were (8.05±0.28), (7.73±0.68), (7.53±0.92), and (9.60±0.32) mL/s, respectively. The narrowest diameters of urethral in the Block 1 to 4 of the experimental groups were (9.00±0.58), (7.50±2.89), (7.00±0.10), and (7.00±0.41) mm, respectively; and those in the control groups were (5.50±0.29), (5.00±0.41), (4.75±0.48), and (6.75±0.48) mm, respectively. The ultrasound strain ratio in the Block 1 to 4 of the experimental groups were 6.10±0.22, 6.10±0.17, 5.10±0.16, and 6.90±0.19, respectively; and those in the control groups were 8.00±0.25, 10.60±0.29, 11.30±0.16, and 8.90±0.33, respectively. Compared with the control groups, the experimental groups displayed smaller urethral scar range, less severe scarring, improved Qmax rates and wider inner diameters (all P<0.05).
 Conclusion: Urethral regional injection of verapamil intraoperatively or postoperatively can prevent overgrowth of urethral scar tissues after the transperineal anastomosis surgery, and reduce the tendency of postoperative restenosis of anterior urethral stricture.

[Causes and management for male urethral stricture].

OBJECTIVE: To explore the etiology of male urethral stricture, analyze the therapeutic strategies of urethral stricture, and summarize the complicated cases.
 Methods: The data of 183 patients with urethral stricture were retrospectively analyzed, including etiology, obstruction site, stricture length, therapeutic strategy, and related complications.
 Results: The mean age was 49.7 years, the average course was 64.7 months, and the constituent ratio of 51 to 65 years old patients was 38.8% (71/183). The traumatic injury of patients accounted for 52.4% (96/183), in which the pelvic fracture accounted for 35.5% (65/183) and the straddle injury accounted for 16.9% (31/183). There were 54 cases of iatrogenic injury (29.5%). The posterior urethral stricture accounted for 45.9% (84/183), followed by the anterior urethral stricture (44.8%, 82/183) and the stenosis (6.6%, 12/183). A total of 99 patients (54.1%) received the end to end anastomosis, and 40 (21.9%) were treated with intracavitary surgery, such as endoscopic holmium laser, cold knife incision, endoscopic electroknife scar removal, balloon dilation, and urethral dilation. In the patients over 65-years old, the urethral stricture rate was 14.8% and the complication rate (70.4%) for transurethral resection of the prostate (TURP) was significantly higher than that of all samples (P<0.01).
 Conclusion: Both the etiology of male urethral stricture and the treatment strategy have changed and the incidence of traumatic and iatrogenic urethral stricture has increased in recent 3 years. The main treatment of urethral stricture has been transformed from endoscopic surgery into urethroplasty.

A Variant in the Precursor of MicroRNA-146a is Responsible for Development of Erectile Dysfunction in Patients with Chronic Prostatitis via Targeting NOS1.

BACKGROUND The morbidity of erectile dysfunction (ED) has been found to be substantially increased in patients with chronic prostatitis (CP). Accumulating evidence shows that single-nucleotide polymorphism (SNP) located in pre-miRNA or mature microRNA may affect the processing of microRNA (miRNA) and alter the expression of the miRNA, as well as its target gene. In this study we investigated the association between rs2910164 G/C polymorphism and risk of ED in patients with CP, as well as the underlying molecular mechanism. MATERIAL AND METHODS Computational analysis was used to search for the target of miR-146a, and the luciferase reporter assay system was used to validate NOS1 to be the target gene of miR-146a. We also treated PC-3 cells with miR-146a mimics/inhibitors to verify the negative regulatory relationship between miR-146a and NOS1, and real-time PCR and Western blot analysis were used to estimate the expression of the NOS1 mRNA and miR-146a. RESULTS The binding site of miR-146a was found to be located within the 3'-UTR of the NOS1 by searching an online miRNA database (www.mirdb.org), and luciferase reporter assay was done to confirm that NOS1 is a direct target gene of miR-146a. We also found that mRNA and protein expression level of NOS1 in PC-3 cells treated with miR-146a mimics and NOS1 siRNA was substantially down-regulated compared with scramble control, while cells treated with miR-146a inhibitors showed increased expression of NOS1. In addition, 705 people were recruited for our research - 342 CP patients with ED and 363 CP patients without ED - and we found that the presence of minor allele of rs2910164 polymorphism is significantly associated with reduced risk of ED in patients with CP. CONCLUSIONS The findings indicate a decreased risk of ED in patients with CP who are carriers of miR-146a rs2910164 C allele, and this association might be due to its ability to compromise the expression of miR-146a, and thereby increase the expression of its target gene, NOS1.

[Effect of calcium channel blockers on primary cultured human urethra scar fibroblasts].

OBJECTIVE: To investigate effects of verapamil on primary cultured human urethral scar fibroblasts (USFs) and to provide basis for protecting the formation of urethra scar.
 Methods: The cell proliferation was evaluated with the cell counting kit (CCK)-8 method after USFs were incubated various verapamil concentrations (50, 100, 150, 200, or 250 µmol/L) or solvent for 12, 24, or 48 h. The protein level of matrix metalloproteinase (MMP) was evaluated with ELISA after cells were incubated with verapamil (100 µmol/L) or solvent (control cells) for 24 h.
 Results: The proliferation of USFs was obviously suppressed after verapamil treatment, which was in a dose-dependent and time-dependent manner. Meanwhile, the protein levels of MMP-2 and MMP-9 in the verapamil treatment group increased obviously compared with those of the control groups (P<0.05).
 Conclusion: Calcium channel blockers may prevent the excessive formation of urethra scar by inhibiting the proliferation of urethral scar fibroblasts and enhancing the activity of MMP.

Laparoscopic ureteroureterostomy with the intraoperative retrograde ureteroscopy-assisted technique for inverted-Y ureteral duplication with a blind-ending branch.

Inverted-Y ureteral duplications are an extremely rare variant of congenital ureteral malformation with few cases reported in the literature. We describe here a case of inverted-Y ureteral duplication with a blind-ending branch, which was managed by laparoscopic ureteroureterostomy with the intraoperative retrograde ureteroscopy-assisted technique. This is the first report that reveals that inverted-Y ureteral duplication was managed by ureteroureterostomy in a laparoscopic approach.

[A preliminary study on mechanisms for urinary system disorders before and after ketamine withdrawal in rats].

OBJECTIVE: To explore the mechanisms for urinary system disorders before and after ketamine withdrawal in rats and to evaluate the recovery degree of the urinary system damage after ketamine withdrawal. METHODS: Fifteen male healthy Sprague-Dawley rats were randomly divided into 3 groups: A control group, an experimental group, and a withdrawal group. The rats in the control group were given normal saline. The rats in the experimental group were given ketamine 30 mg/(kg.day) for 30 days. The rats in the withdrawal group were treated as the experimental group except for drug withdrawal for 2 weeks. In the experimental period, we randomly selected 1 rat of kidney, ureter, and bladder from each group to perform HE staining. The bladder tissues in each group were used to detect mRNA expression by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: 1) The behavior of ketamine-injected rats was obviously changed, but the weight of ketamine-induced rats was not changed. 2) As compared with the control group, the experimental and withdrawal groups showed infiltration of mononuclear inflammatory cells in the kidney tissues, the thinner epithelium of bladder and infiltration of submucosal mononuclear inflammatory cells under the optical microscope. 3) As compared with the control group, the expression of H1R mRNA was increased in the experimental group (P<0.05). As compared with the experimental group, H1R mRNA expression was significantly decreased in the withdrawal group (P<0.05). CONCLUSION: Ketamine abuse could induce behavior changes in rats. The infiltration of mononuclear inflammatory cells in kidney and bladder, the thinner bladder epithelial layer, and the increased H1R gene mRNA expression in bladder might be an important pathogenesis of KAUD. Ketamine withdrawal may effectively reverse the pathogenic process of KAUD.

[Analysis of influential factors for prostate biopsy and establishment of logistic regression model for prostate cancer].

OBJECTIVE: To establish logistic regression model for prostate cancer and provide basis for prostate biopsy.
 METHODS: A total of 117 cases of prostate biopsy were retrospectively analyzed in chronological sequence. All cases were assigned into a model group (n=78) and a validation group (n=39). Logistic regression model was established and its value was estimated by receiver operating characteristic (ROC) curve. 
 RESULTS: Digital rectal examination(DRE), transrectal ultrasound(TRUS), MRI, prostate-specific antigen density (PSAD), and free PSA/total PSA (fPSA/tPSA) were the influential factors for prostate biopsy (P<0.01). The established logistic regression model for prostate cancer by regression coefficient was: logit P=-2.362+2.561×DRE+1.747×TRUS+2.901×MRI+1.126×PSAD-2.569×fPSA/tPSA and area under curve was 0.907. When the cutoff aimed at 0.12, the sensitivity and specificity were 81.80% and 89.30%, respectively.
 CONCLUSION: Logistic regression model for prostate cancer can provide sufficient basis for prostate biopsy. Prostate biopsy should be performed when P value is more than 0.12.

Comparison of the simplified International Index of Erectile Function (IIEF-5) in patients of erectile dysfunction with different pathophysiologies.

BACKGROUND: The simplified International Index of Erectile Function (IIEF-5) is a convenient, reliable and validated diagnostic tool for erectile dysfunction (ED). However, few studies focused on IIEF-5 in ED patients with different pathophysiological causes. ,We aim to compare the IIEF-5 score among ED patients with specific pathophysiologies in this study. METHODS: The IIEF-5 score of 3,327 ED patients (median age 39 years) was analyzed. The primary causes of ED were determined by comprehensive diagnostic procedures in the urology/andrology clinics in five training hospitals. Patients with uncertain pathophysiologic cause were excluded. RESULTS: 176 patients were excluded, 3151 patients with ED history between 0.5 year and 20 years, were enrolled. The causes of ED was classified as psychogenic (59.2%), vasoculogenic (21.3%), neurogenic (4.1%), anatomical/structural (2.8%), hormonal (7.1%) or drug-induced (5.5%). A significant difference was detected in the median IIEF-5 score between psychogenic ED and organic ED (15 (IQR 13, 17) versus 12 (IQR 9.5, 14.5), P < 0.001). There was no significant difference of IIEF-5 scores among the organic groups (P = 0.073), or between arteriogenic and venogenic groups (13 (IQR 10.5, 15.5) versus 13 (IQR 11-15), P = 0.912 (adjusted α = 0.017)). However, the median IIEF-5 score of those with a mixed vascular cause was the lowest among vasculogenic patients (11 (IQR 8.5-13.5), scores for the three groups: P = 0.003.). CONCLUSIONS: The IIEF-5 scores of men with psychological ED are higher than those with organic causes, but there is no difference among patients with different organic pathophysiologies. Our data indicate that IIEF-5 is not a definitive diagnostic tool to discriminate the pathophysiological causes of ED.

[Ketamine induces apoptosis of human uroepithelial SV-HUC-1 cells].

OBJECTIVE: To determine the effect of ketamine on the apoptosis of human uroepithelial cells (SVHUC-1) and the pathogenesis of ketamine-associated cystitis. METHODS: SV-HUC-1 cells were cultured under various concentrations of ketamine and differenttime. Flow cytometry was used to analyze the rate of cell apoptosis. The protein levels of Bax, Bcl-2, pro-caspase-3, and cleaved caspase-3 were detected by Western blot. RESULTS: Compared with the control group, the apoptotic rate of ketamine cultured SV-HUC-1 cells increased. The expression of Bax increased, Bcl-2 expression decreased, and Bax/Bcl-2 in the ketamine cultured SV-HUC-1 cells was significantly higher. The protein level of pro-caspase-3 was significantly lower, and that of cleaved caspase-3 was significantly higher than that in the control group (P<0.05), positively correlated with the dose of ketamine and time of culture (P<0.05). CONCLUSION: Ketamine can induce the apoptosis of SV-HUC-1 cells in a dose and time dependent manner.

[Therapeutic effect of regular urethral dilatation on patients with postoperative urethral stricture].

OBJECTIVE: To determine the therapeutic effect of regular urethral dilatation on patients with postoperative urethral stricture. METHODS: A total of 142 patients underwent urethral stricture. The unimproved patients after the surgery were divided into a reoperation group and a regular urethral dilatation group. All the patients were followed up for 1-3 months, and the curative effect was compared. RESULTS: Of the 142 patients, 42 had no improvement and 27 of them had reoperation, and symptoms in 21 were improved. Another 15 patients received regular urethral dilatation, and 5 improved. There was significant difference between the 2 groups (P<0.01). CONCLUSION: Regular urethral dilatation has some effect on postoperative patients, but no obvious effect on patients with dissatisfied operation for urethral stricture or restenosis.

A novel trauma induced urethral stricture in rat model.

Urethral stricture (US) is a longstanding disease, while there has not existed a suitable animal model to mimic the condition. We aimed to establish a trauma-induced US animal model to simulate this clinical scenario. A total of 30 rats were equally distributed into two groups, sham and US group. All rats were anesthetized with isoflurane and undergone cystostomy. In the US group, a 2 mm incision was made in the urethra and sutured to induce US. The sham group only make a skin incision on the ventral side of the anterior urethra. 4 weeks later, ultrasound and cystourethrography were performed to evaluate the degree of urethral stricture, pathological examinations were carried out to evaluate the degree of fibrosis. Urodynamic evaluation and mechanical tissue testing were performed to evaluate the bladder function and urethral tissue stiffness. The results showed that the urethral mucosa was disrupted and urethral lumen was stenosed in the US group. Additionally, the US group showed elevated bladder pressure, prolonged micturition intervals and increased tissue stiffness. In conclusion, the rat urethral stricture model induced by trauma provides a closer representation of the real clinical scenario. This model will significantly contribute to advancing research on the mechanisms underlying traumatic urethral stricture.

Effects of internet-based exercise intervention on depression and anxiety: A systematic review and meta-analysis.

BACKGROUND: While exercise is acknowledged for its positive effects on depression and anxiety symptoms, the benefits of internet-based exercise on mental health have not been extensively examined. This study seeks to systematically review and quantify the outcomes of high-quality randomized controlled trials (RCTs) that investigate the impact of internet-based exercise on depression and anxiety symptoms. METHODS: Following the PRISMA 2020 guidelines, we conducted a comprehensive meta-analysis of RCTs. Databases, including Web of Science Core Collection, PubMed, PsycINFO, Medline, BIOSIS Previews, SPORTDiscus, and Education Source, were scoured through in September 2023. After quality assessment and data extraction, the analysis was performed using R. Using random effects models, effect sizes were determined and subsequently represented as standardized mean differences (SMD). RESULTS: Our analysis incorporated data from 11 RCTs, involving a cohort of 1009 participants. We observed a modest yet significant reduction in depression and anxiety symptoms, with an SMD of -0.44 [95% confidence interval (CI) (-0.63, -0.26), I^2 = 79.3%, P < .01]. Interestingly, the effects were more pronounced in individuals diagnosed with depression, as indicated by an SMD of -0.96 [95% CI (-1.55, -0.37), I^2 = 82%, P < .01]. Furthermore, participants utilizing smartphone applications as part of their intervention reported a meaningful reduction in their symptoms, evidenced by an SMD of -0.52 [95% CI (-0.90, -0.14), I^2 = 87%, P < .01]. Additionally, short-term interventions, specifically those lasting <12 weeks, indicated a notable alleviation in depression symptoms, with an SMD of -0.76 [95% CI (-1.38, -0.14), I^2 = 86%, P < .01]. CONCLUSION: Internet-based exercise interventions yield significant amelioration in depression and anxiety symptoms, with heightened efficacy observed among individuals with depression. Notably, short-term interventions, specifically those under 12 weeks, demonstrate enhanced benefits for depression relief.