Mirabegron for overactive bladder in frail patients 80 years or over (HOKUTO study).

BACKGROUND: We assessed the efficacy and safety of mirabegron, a ß3-adrenoceptor agonist, in older adults (≥ 80 years old) with overactive bladder (OAB). METHODS: OAB patients aged ≥ 80 years were enrolled in this prospective, single-arm observational study. OAB was diagnosed based on the OAB symptom score (OABSS); i.e., a total score of ≥ 3 points and an urgency score of ≥ 2 points. Patients who received 50 mg mirabegron once daily were evaluated at the baseline and at 4, 8, and 12 weeks. The changes from the baseline in the OABSS, International Prostate Symptom Score (IPSS), OAB questionnaire (OAB-q) score, and Vulnerable Elders Survey (VES-13) score were determined. Adverse events, laboratory tests, 12-lead electrocardiography, the QT interval according to Fridericia's formula (QTcF), uroflowmetry, the post-void residual urine volume (PVR), and the Mini-Mental State Examination (MMSE) score were used to assess safety. RESULTS: Forty-three patients (median age: 84 years, range: 80-96 years) were examined. They had high rates of comorbidities and polypharmacy. Mirabegron significantly improved in total score of the OABSS, including urgency and urge incontinence. The total IPSS, IPSS quality-of-life (QOL) index, and OAB-q scores also significantly improved. Mirabegron improved in the VES-13 score. There were no significant changes in laboratory test values, uroflowmetry findings, PVR, the QTcF, or MMSE score. Two patients (4.7%) withdrew from the study after experiencing adverse events. CONCLUSIONS: Mirabegron was well tolerated and significantly improved in OAB symptoms, and QOL in older patients. Trial registration The present clinical study was approved by University of Yamanashi Institutional Review Board prior to study initiation (ID1447) and was retrospectively registered with the UMIN Clinical Trials Registry (UMIN-CTR), Japan (UMIN000045996) on Nov 6, 2021.

Potential Targets for Overactive Bladder in Older Men Based on Urinary Analysis of Metabolomics.

OBJECTIVE: We investigated the association between overactive bladder (OAB) and urinary metabolites in men. METHODS: This prospective observational study included 42 men aged 65-80 years. The 3-day frequency volume chart (FVC), International Prostate Symptom Score (IPSS), and quality of life score were adapted to assess the micturition behavior. Participants with IPSS urgency score ≥2 were included in the OAB group, and those with IPSS urgency score <2 were included in the control group. We performed a comprehensive metabolomic analysis using urine samples. Metabolites were compared between the groups using an unpaired t test and Fisher's exact test in a nonadjusted analysis. Multivariable logistic regression analysis was performed to investigate the association between OAB and the metabolites. RESULTS: Overall, 23 men were included in the OAB group and 19 in the control group. There were no differences in the background factors except age between the groups. FVC analysis demonstrated that nocturnal urine volume, 24-h micturition frequency, and nocturnal micturition frequency were significantly higher, and the maximum voided volume was significantly lower in the OAB group than in the controls. Metabolomic analysis revealed 14 metabolites that were differentially expressed between the groups. Multivariate analysis indicated that an increase in the levels of 5-iso prostaglandin F2α-VI (5-iPF2a-VI) and 5-methoxyindoleacetic acid was associated with OAB. CONCLUSION: Abnormal urinary metabolites, including metabolites in the tryptophan (5-methoxyindoleacetic acid, 3-indoleacetonitrile, and 3-hydroxyanthranilic acid) and arachidonic acid (5-iPF2a-VI) pathways, play a role in the pathogenesis of OAB in older men.

Urinary metabolites identified using metabolomic analysis as potential biomarkers of nocturia in elderly men.

PURPOSE: To investigate the association between nocturia and urinary metabolites in elderly men using metabolomic analysis. METHODS: We recruited 66 men aged 65-80 years. The 3-day frequency volume chart (FCV), International Prostate Symptom Score (IPSS), and quality of life score were used to assess micturition behavior. Participants with the total IPSS > 0 and ≥ 1.5 micturition on an average for three nights were included in the nocturia group. Participants with the total IPSS < 8 and < 1.5 micturition at night were included in the control group. We conducted a comprehensive metabolomic analysis of urine samples. Metabolites were compared between the groups using an unpaired t test. A multivariable logistic regression analysis was used to determine the relationship between nocturia and these metabolites. RESULTS: The nocturia and control groups consisted of 45 and 21 men, respectively. There were no differences in the background factors between the groups except for receiving anticholinergic drug and having life style-related diseases. The FVC revealed that nocturnal urine volume, 24 h micturition frequency, and nocturnal micturition frequency were significantly higher in the nocturia group than in the control group. The metabolomic analysis revealed 16 metabolites, which were differentially expressed between the groups. The multivariate analysis showed that increased serotonin level and decreased 3-hydroxypropionic acid and 3-indoleacetonitrile levels were associated with nocturia. CONCLUSIONS: These findings suggest that abnormal urinary metabolites including serotonin, 3-hydroxypropionic acid, and 3-indoleacetonitrile are involved in the pathogenesis of nocturia in elderly men.

Liquid chromatography-mass spectrometry identification of serum biomarkers for nocturia in aged men.

PURPOSE: We aimed to investigate the association between nocturia and serum metabolites identified using metabolomics analysis. METHODS: This study enrolled 66 men aged 65-80 years, recruited from the outpatient department of a university hospital. The participants were stratified as follows: Nocturia group [45 men with any total international prostate symptom score (IPSS) and an average of 3 nights ≥ 1.5 micturitions/night] and Control group (21 men with total IPSS < 8 and an average of 3 nights < 1.5 micturitions/night). The 24-h frequency-volume chart, IPSS, and Quality-of-Life questionnaire were used to evaluate micturition behavior. Serum metabolite profiles were obtained using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics analysis and compared between the two groups using the unpaired t test. The relationship between serum metabolites and nocturia was determined using multivariable logistic regression analysis. RESULTS: There were no differences in background factors between the Nocturia and Control groups. In the IPSS, mean total scores in the Nocturia and Control groups were 12.4 and 4.0, respectively. On frequency-volume chart analysis, nocturnal urine volume and micturition frequency during daytime and nighttime were significantly higher in the Nocturia group. LC-MS highlighted 13 serum metabolites as potential biomarkers of nocturia. On multivariate analysis, increased levels of palmitoylethanolamide, 4-hydroxydocosahexaenoic acid, 9-hydroxyoctadecadienoic acid, 20-hydroxydocosahexaenoic acid, 13-hydroxyoctadecadienoic acid, arachidonoylethanolamide, eicosapentaenoic acid, 12-hydroxy-eicosatetraenoic acid, and arachidonic acid were associated with nocturia. CONCLUSIONS: In aged men, the pathogenesis of nocturia involves abnormal metabolism in several signaling pathways involving omega-3 and omega-6 polyunsaturated fatty acids, as well as endocannabinoids.

Connexin43 Is Required for the Effective Activation of Spleen Cells and Immunoglobulin Production.

Gap junctions (Gjs), formed by specific protein termed connexins (Cxs), regulate many important cellular processes in cellular immunity. However, little is known about their effects on humoral immunity. Here we tested whether and how Gj protein connexin43 (Cx43) affected antibody production in spleen cells. Detection of IgG in mouse tissues and serum revealed that wild-type (Cx43+/+) mouse had a significantly higher level of IgG than Cx43 heterozygous (Cx43+/-) mouse. Consistently, spleen cells from Cx43+/+ mouse produced more IgG under both basal and lipopolysaccharide (LPS)-stimulated conditions. Further analysis showed that LPS induced a more dramatic activation of ERK and cell proliferation in Cx43+/+ spleen cells, which was associated with a higher pro-oxidative state, as indicated by the increased NADPH oxidase 2 (NOX2), TXNIP, p38 activation and protein carbonylation. In support of a role of the oxidative state in the control of lymphocyte activation, exposure of spleen cells to exogenous superoxide induced Cx43 expression, p38 activation and IgG production. On the contrary, inhibition of NOX attenuated the effects of LPS. Collectively, our study characterized Cx43 as a novel molecule involved in the control of spleen cell activation and IgG production. Targeting Cx43 could be developed to treat certain antibody-related immune diseases.

Induction of inactive TGF-ß1 monomer formation by hydrogen sulfide contributes to its suppressive effects on Ang II- and TGF-ß1-induced EMT in renal tubular epithelial cells.

Hydrogen sulfide (H2S), an endogenous gas mediator with multifaced biological functions, has been shown to be effective in the prevention and treatment of renal sclerosis in several models of chronic renal diseases. The mechanisms involved are still unclear. Given that Ang II- and TGF-ß-induced renal tubular epithelial-mesenchymal transition (EMT) is a pivotal cellular event leading to renal sclerosis, we examined whether and how H2S intervened the processes of EMT. Ang II stimulated EMT in renal tubular epithelial cells, as indicated by the increased level of α-smooth muscle actin and a decreased level of E-cadherin. This effect of Ang II was blocked by a TGF-ß receptor kinase inhibitor, indicative of a mediating role of TGF-ß. Consistently, Ang II stimulated TGF-ß activation and addition of the exogenous TGF-ß1 also induced EMT. In the presence of H2S donor NaHS, the EMT-promoting actions of Ang II and TGF-ß1 were abolished, which was associated with a reduced TGF-ß activity. Further analysis using a human recombinant active TGF-ß1 revealed that H2S cleaved the disulfide bond in the dimeric active TGF-ß1 and promoted the formation of inactive TGF-ß1 monomer. Collectively, these results indicate that H2S counteracted Ang II- and TGF-ß1-induced EMT through mechanisms involving direct inactivation of TGF-ß1. Our study thus provides novel mechanistic insight into the anti-fibrotic actions of H2S and suggest that H2S could be used to treat renal sclerotic diseases.

Metabolomics Approach to Male Lower Urinary Tract Symptoms: Identification of Possible Biomarkers and Potential Targets for New Treatments.

PURPOSE: We identified metabolites using a metabolomics approach and investigated the association between these metabolites and lower urinary tract symptoms. MATERIALS AND METHODS: We used a 24-hour bladder diary and I-PSS (International Prostate Symptom Score) to assess micturition behavior and lower urinary tract symptoms in 58 male patients without apparent neurological disease. Lower urinary tract symptoms were defined as a total I-PSS score of 8 or greater. Patients with a score of 7 or less were placed in the control group. A comprehensive study of plasma metabolites was also performed by capillary electrophoresis time-of-flight mass spectrometry. Metabolites were compared between the lower urinary tract symptoms and control groups using the Mann-Whitney U test. Biomarkers of male lower urinary tract symptoms from the metabolites were analyzed using multivariable logistic regression analysis to determine the OR. RESULTS: Of the 58 men 32 were in the lower urinary tract symptoms group and the remaining 26 were in the control group. The 24-hour bladder diary showed that nocturnal urine volume, 24-hour micturition frequency, nocturnal micturition frequency and the nocturia index were significantly higher in the lower urinary tract symptoms group. Metabolomics analysis identified 60 metabolites from patient plasma. Multivariate analysis revealed that increased glutamate and decreased arginine, asparagine and inosine monophosphate were significantly associated with lower urinary tract symptoms in males. Decreases in citrulline and glutamine could also be associated with male lower urinary tract symptoms. CONCLUSIONS: Male lower urinary tract symptoms may develop due to abnormal metabolic processes in some pathways. Potential new treatments for lower urinary tract symptoms can be developed by identifying changes in the amino acid profiles.

Tadalafil attenuates hypotonicity-induced Ca2+ influx via TRPV2 and TRPV4 in primary rat bladder urothelial cell cultures.

AIMS: To investigate the localization of phosphodiesterase 5 (PDE5) and the molecular mechanism underlying the effect of the PDE5 inhibitor tadalafil in signal transduction in the bladder urothelium. METHODS: PDE5 expression in rat bladder tissues and cultured primary rat bladder urothelial cells was evaluated using immunochemistry and western blot assays. Ca2+ influx in cells exposed to isotonic solution, hypotonic solution, a selective transient receptor potential vanilloid 2 (TRPV2) channel agonist (cannabidiol), a selective TRPV4 channel agonist (GSK1016790A), a TRP cation channel melastatin 7 (TRPM7) channel agonist (PIP2), or a purinergic receptor agonist (ATP) in the presence or absence of 10 µM tadalafil was evaluated using calcium imaging techniques. We also evaluated stretch-induced changes in ATP concentration in the mouse bladder in the presence or absence of 100 µM tadalafil. RESULTS: Immunochemistry and western blot analyses demonstrated that PDE5 is abundantly expressed in the bladder urothelium and in primary rat urothelial cells. Ca2+ influx induced by hypotonic stimulation, GSK1016790A, or cannabidiol was significantly inhibited by tadalafil, whereas ATP-induced Ca2+ influx was unaffected by tadalafil. PIP2 did not induce Ca2+ influx. ATP release in tadalafil-pretreated bladders significantly decreased compared to control bladders. CONCLUSIONS: Tadalafil attenuates Ca2+ influx via TRPV4 and TRPV2, and inhibits ATP release in the bladder urothelium. These findings indicate that tadalafil functions as an inhibitor of urothelial signal transduction.

Development of novel and non-invasive diagnostic markers for lower urinary tract symptoms using urothelial cells in voided urine.

OBJECTIVES: We evaluated the association between lower urinary tract symptoms (LUTS) and the expression of connexin (Cx) and transient receptor potential (TRP) channel on urothelial cells non-invasively collected from voided urine in humans. METHODS: A total of 55 patients (36 males and 19 females, median age: 71 years old), who were followed up at University of Yamanashi Hospital, were enrolled in the present study. Urothelial cells were collected from voided urine of patients, and the mRNA expression of each subtype of Cxs and TRP channels was measured using quantitive real-time reverse transcription polymerase chain reaction. We then analyzed the correlation between the expression of Cxs and TRP channels and symptom scores in International Prostate Symptom Scoreand Overactive Bladder Symptom Score, in addition to Interstitial Cystitis Symptom Index (ICSI) from only interstitial cystitis (IC) patients. RESULTS: Non-adjusted statistical procedure using Spearman's rank-correlation showed that there were significant correlations between the following expressions and symptom scores; (positive correlations) Cx26 versus urgency score, Cx40 versus nocturia, TRPM2 versus intermittency, TRPV1 versus urge incontinence, (negative correlation) Cx40 versus intermittency, TRPM7 versus pollakisuria. However, a multiple comparison adjustment using Bonferroni correction showed that only Cx40 had a trend of correlation with nocturia in ICSI. CONCLUSIONS: The expressions of Cxs and TRP channels on urothelial cells in voided urine could be related to LUTS. Further analysis of urothelial cells in voided urine has the potential to reveal the mechanism of the LUTS and develop new markers with non-invasive methods.

The Circadian expression of Piezo1, TRPV4, Connexin26, and VNUT, associated with the expression levels of the clock genes in mouse primary cultured urothelial cells.

AIMS: To investigate circadian gene expressions in the mouse bladder urothelium to establish an experimental model and study the functions of the circadian rhythm. METHODS: The gene expression rhythms of the clock genes, mechano-sensors such as Piezo1 and TRPV4, ATP release mediated molecules (ARMM) such as Cx26 and VNUT were investigated in mouse primary cultured urothelial cells (UCs) of wild-type (WT) and Clock mutant (ClockΔ19/Δ19 ) mice using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and western blotting analysis. The long-term oscillation of the clock genes in UC was investigated by measuring bioluminescence from UC isolated from Period2luciferase knock-in mice (Per2::luc) and Per2::luc with ClockΔ19/Δ19 using a luminometer. The mRNA expression rhythms after treatment with Clock short interfering RNA (siRNA) were also measured to compare differences between Clock point mutations and Clock deficiency. RESULTS: The UCs from WT mice showed the time-dependent gene expressions for clock genes, mechano-sensors, and ARMM. The abundances of the products of these genes also correlated with the mRNA expression rhythms in UCs. The bioluminescence of Per2::Luc in UCs showed a circadian rhythm. By contrast, all the gene expressions rhythms observed in WT mice were abrogated in the ClockΔ19/Δ19 mice. Transfection with Clock siRNA in UCs had the same effect as the Clock mutation. CONCLUSIONS: We demonstrated that the time-dependent gene expressions, including clock genes, mechano-sensors, and ARMM, were reproducible in UCs. These findings demonstrated that UCs have the potential to progress research into the circadian functions of the lower urinary tract regulated by clock genes.

The time-dependent variation of ATP release in mouse primary-cultured urothelial cells is regulated by the clock gene.

AIMS: The sensation of bladder fullness (SBF) is triggered by the release of ATP. Therefore, the aim of this study was to investigate whether time-dependent changes in the levels of stretch-released ATP in mouse primary-cultured urothelial cells (MPCUCs) is regulated by circadian rhythm via clock genes. METHODS: MPCUCs were derived from wild-type and Clock mutant mice (ClockΔ19/Δ19 ), presenting a nocturia phenotype. They were cultured in elastic silicone chambers. Stretch-released ATP was quantified every 4 h by ATP photon count. An experiment was also performed to determine whether ATP release correlated with the rhythm of the expression of Piezo1, TRPV4, VNUT, and Connexin26 (Cx26) in MPCUCs regulated by clock genes with circadian rhythms. MPCUCs were treated with carbenoxolone, an inhibitor of gap junction protein; were derived from VNUT-KO mice; or treated with Piezo1-siRNA, TRPV4-siRNA, and Cx26-siRNA. RESULTS: Stretch-released ATP showed time-dependent changes in wild-type mice and correlated with the rhythm of the expression of Piezo1, TRPV4, VNUT, and Cx26. However, these rhythms were disrupted in ClockΔ19/Δ19 mice. Carbenoxolone eliminated the rhythmicity of ATP release in wild-type mice. However, time-dependent ATP release changes were maintained when a single gene was deficient such as VNUT-KO, Piezo1-, TRPV4-, and Cx26-siRNA. CONCLUSIONS: ATP release in the bladder urothelium induces SBF and may have a circadian rhythm regulated by the clock genes. In the bladder urothelium, clock gene abnormalities may disrupt circadian ATP release by inducing Piezo1, TRPV4, VNUT, and Cx26. All these genes can trigger nocturia.

Lack of Change in the Adaptation Ability of the Bladder for the Urine Production Rate in Aged Men with Nocturia.

INTRODUCTION: To investigate the association between bladder capacity and the urine production rate in aged men with or without nocturia using a frequency volume chart (FVC). MATERIALS AND METHODS: One-hundred and thirty-eight men aged 65-80 years were enrolled. After the International Prostate Symptom Score (IPSS) and 3 consecutive days FVC were evaluated, men were divided into 2 groups: Nocturia group, with any total IPSS, and ≥1.5 micturition on average at night; and Control group, with total IPSS < 8 and < 1.5 micturition on average at night. Each parameter was compared between the 2 groups using unpaired t tests. Linear and multiple regression analyses were performed between the urine production rate and volume/voids. RESULTS: Men numbering 45 and 21 were assigned to the Nocturia and Control groups respectively. There were no differences in background factors between the 2 groups. Volume/voids positively correlated with the urine production rate in both groups for day and night. A multivariate regression model also showed the same results. In the Control group, the degree of slope at night was higher than that during the day. However, in the Nocturia group, there were no differences in the degree of slope between day and night. CONCLUSIONS: This novel finding has led to a possibility for resolving nocturia.

The Clock mutant mouse is a novel experimental model for nocturia and nocturnal polyuria.

AIMS: The pathophysiologies of nocturia (NOC) and nocturnal polyuria (NP) are multifactorial and their etiologies remain unclear in a large number of patients. Clock genes exist in most cells and organs, and the products of Clock regulate circadian rhythms as representative clock genes. Clock genes regulate lower urinary tract function, and a newly suggested concept is that abnormalities in clock genes cause lower urinary tract symptoms. In the present study, we investigated the voiding behavior of Clock mutant (ClockΔ19/Δ19 ) mice in order to determine the effects of clock genes on NOC/NP. METHODS: Male C57BL/6 mice aged 8-12 weeks (WT) and male C57BL/6 ClockΔ19/Δ19 mice aged 8 weeks were used. They were bred under 12 hr light/dark conditions for 2 weeks and voiding behavior was investigated by measuring water intake volume, urine volume, urine volume/void, and voiding frequency in metabolic cages in the dark and light periods. RESULTS: No significant differences were observed in behavior patterns between ClockΔ19/Δ19 and WT mice. ClockΔ19/Δ19 mice showed greater voiding frequencies and urine volumes during the sleep phase than WT mice. The diurnal change in urine volume/void between the dark and light periods in WT mice was absent in ClockΔ19/Δ19 mice. Additionally, functional bladder capacity was significantly lower in ClockΔ19/Δ19 mice than in WT mice. CONCLUSIONS: We demonstrated that ClockΔ19/Δ19 mice showed the phenotype of NOC/NP. The ClockΔ19/Δ19 mouse may be used as an animal model of NOC and NP. Neurourol. Urodynam. 36:1034-1038, 2017. © 2016 Wiley Periodicals, Inc.

Detrusor pressures in urodynamic studies during voiding in women.

INTRODUCTION AND HYPOTHESIS: To investigate detrusor pressure during voiding in women using urodynamic studies (UDS). METHODS: The study group comprised 57 women with non-neurogenic lower urinary tract symptoms. All patients underwent UDS between January 2010 and December 2014. UDS included filling cystometry, pressure flow study (PFS), uroflowmetry for the maximum flow rate (Qmax) and mean flow rate, and postvoid residuals. Existence of voluntary detrusor contraction was defined as a continuous and smooth increase in detrusor pressure (Pdet) after the instruction to micturate in the PFS. The bladder contractility index (BCI) was calculated as Pdet at Qmax + 5 × Qmax. Statistical analyses were performed using the Mann-Whitney U test and p < 0.05 was considered statistically significant. RESULTS: The PFS showed that 23 patients had detrusor contraction (Pdet+ group) and 34 patients had no detrusor contraction (Pdet- group) during voiding. There were no significant differences in urodynamic parameters between the Pdet+ and Pdet- groups except in Pdet at Qmax and BCI. In the Pdet- group, 21 patients showed an increase in abdominal pressure during voiding (Pabd+ group), while the other 13 patients did not (Pabd- group). There were no differences in any of the urodynamic parameters between the Pabd+ and Pabd- groups. CONCLUSIONS: Based on UDS, an increase in detrusor or abdominal pressure may not be necessary in micturition in women. The present study suggests that relaxation of pelvic floor muscles including normal urethral function are important for micturition in women.

Melatonin Improves Erectile Function in Rats With Chronic Lower Body Ischemia.

INTRODUCTION: Arterial occlusive disease is the leading cause of erectile dysfunction (ED). Using an established rat model we wanted to characterize the changes caused by atherosclerosis-induced chronic ischemia on penile structures and erectile function. AIM: To investigate the effect of melatonin on these parameters. METHODS: Adult male Sprague-Dawley rats were divided into control, arterial injury (AI) and AI with melatonin treatment groups. AI and AI-melatonin groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI surgery for 8 weeks. AI-melatonin group rats received melatonin (20 mg/kg/day) orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, erectile function was tested. Corpus cavernosum (CC) tissues were processed for pharmacological and immunohistochemical studies, histological examination, and Western blotting. MAIN OUTCOME MEASURES: Apomorphine test was performed to evaluate erectile function. Organ bath study was performed to measure the CC-contraction induced by KCl and phenylephrine, and relaxation induced by electrical field stimulation (EFS) and sodium nitroprusside (SNP). RESULTS: The number of erectile responses was significantly lower in the AI group (2.5 ± 0.5/hour) than in the control (5.0 ± 0.7/hour) and in the melatonin-treated groups (5.0 ± 0.3/hour). The responses to phenylephrine were lower in the AI-groups than in the controls, but there were no differences between control and AI-melatonin groups. SNP-induced relaxation in the AI-melatonin group was higher than in the AI, but lower than in control group. The EFS-elicited relaxation responses in the AI group were significantly lower than in the control and AI-melatonin groups. Compared to controls, CC tissues from the AI group showed significantly higher collagen content, and lower protein expression of eNOS and nNOS, and increased expression of iNOS. These changes were reduced or prevented by melatonin treatment. CONCLUSION: Treatment with melatonin reduced/prevented functional and morphological changes induced by chronic ischemia on penile structure and function.

INTRAVESICAL MIGRATION OF A HEM-O-LOK CLIP AFTER ROBOT-ASSISTED RADICAL PROSTATECTOMY: A CASE REPORT.

The Hem-o-lok clips (HOLC) is frequently used for hemostasis of the lateral pedicles in robot-assisted prostatectomy (RARP) and laparoscopic radical prostatectomy (LRP). We report a rare post-operative complication, the migration of a HOLC into the bladder leading to calculus formation after RARP. A 54 year-old man underwent RARP with nerve- sparing procedure with HOLCs in the left neurovascular bundle. Three months later, he was referred to our hospital for pollakisuria and spontaneous hematuria. Abdominal ultrasonographic examination and computed tomography (CT) demonstrated a bladder stone that was 7 mm in diameter. On cystourethroscopy, he was noted to have a yellow-colored stone at 9 o'clock position of vesicourethral anastomosis. A cystolithotripsy for a bladder stone was performed until the surface of it was broken. A HOLC with a calculus was revealed and retrieved by stone forceps through the urethra. Since then, Intravesical migration of a HOLC has not been observed.

Protective effect of tadalafil on the functional and structural changes of the rat ventral prostate caused by chronic pelvic ischemia.

BACKGROUND: The etiology of Benign Prostatic Hyperplasia (BPH), a common among aged men, is not fully understood, however, in addition to androgens and aging, chronic ischemia has been proposed to contribute. Using an established rat model, we investigated whether chronic ischemia alters the structural and functional properties of the ventral rat prostate, and whether phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) may have a protective action. METHODS: Adult male Sprague-Dawley rats were divided into control, arterial endothelial injury (AI), and AI with tadalafil treatment (AI-tadalafil) groups. AI and AI-tadalafil groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI. AI-tadalafil rats were treated with tadalafil (2 mg/kg/day) orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, animals were sacrificed, and pharmacological and morphological studies on prostate tissues were performed. RESULTS: Iliac arteries from AI rats displayed neo-intimal formation and luminal occlusion, an effect that was not prevented by tadalafil treatment. In the AI group, there was an obvious epithelial atrophy and a statistically significant increase in collagen fibers compared with the controls. Immunohistochemically, there was an up-regulation of smooth muscle α-actin (SMA). Contractile responses of prostate strips to KCl, electrical field stimulation (EFS), and phenylephrine (PE) were significantly higher after AI than in controls. Chronic treatment with tadalafil prevented the increase in contractile responses in ischemic tissue, and decreased the collagen deposition compared with the AI group. CONCLUSIONS: In this rat model, chronic pelvic ischemia caused distinct functional and morphological changes in the prostate. Prostatic tissue from ischemic animals showed an increased contractile response to electrical and pharmacological stimulation, an increase in SMA, and an increased deposition of collagen. All these changes could be prevented by treatment with the PDE5 inhibitor, tadalafil, suggesting an involvement of cyclic guanosine monophosphate (cGMP).

Urinary bladder mucosal responses to ischemia.

PURPOSE: The objectives of this study were to examine the expression of various cellular proteins within the urothelium (UT) and lamina propria (LP) following chronic bladder ischemia in the rat urinary bladder. MATERIALS AND METHODS: Urinary bladders were removed from adult Sprague-Dawley rats 8 weeks after creation of bladder ischemia and from sham controls. Immunocytochemistry was used to examine distribution of LP-vimentin-immunoreactive (IR) cells and connexins (Cx26; Cx43), and western immunoblotting or ELISA for proteins involved in UT barrier and sensory functions. RESULTS: Ischemia was associated with a significant increase in LP-vimentin-IR cells and increased expression of the gap junction proteins Cx26 and Cx43 within the bladder UT as compared to sham control. Ischemia also resulted in an increased (p < 0.05) expression level of the junctional marker (ZO-1) and non-significantly increased expressions of the trophic factor nerve growth factor as well as norepinephrine. CONCLUSIONS: Our findings reveal that chronic ischemia alters a number of proteins within the UT and underlying LP. These proteins are involved in barrier function, remodeling, repair as well as intercellular communication. The increased expression of LP-vimentin-IR cells suggests that changes in cell-cell interactions could play a role in ischemia-induced changes in bladder activity.