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Purpose: We performed a multicenter, prospective, observational study to assess outcomes, including changes in continence status and quality of life, after artificial urinary sphincter implantation., Materials and Methods: Prospectively enrolled in this study were 135 patients who underwent primary AMS 800™ implantation between 2011 and 2014 at 1 of 5 institutions. Perioperative complications were categorized according to the Clavien-Dindo classification. We estimated the revision-free rate, that is the incidence of patients who did not undergo artificial urinary sphincter revision surgery. Cox regression analysis was performed to identify patient risk factors for revision surgery. The number of pads needed per day, ICIQ-SF (International Consultation on Incontinence Questionnaire-Short Form) and KHQ (King's Health Questionnaire) were used to estimate continence status and quality of life preoperatively, and 1, 3 and 12 months postoperatively., Results: The artificial urinary sphincter was implanted without major complications. The revision-free rate 1, 2 and 3 years after implantation was 94%, 88% and 81%, respectively. Diabetes mellitus and poor preoperative American Society of Anesthesiologists® physical status were significant risk factors for revision surgery. Continence status and quality of life were markedly improved after surgery. However, ICIQ-SF and some KHQ items showed slight but significant deterioration at 12 months compared with scores 1 month after surgery., Conclusions: Artificial urinary sphincter implantation is a safe and durable procedure that substantially improves patient continence status and quality of life soon after surgery. Our results indicate that patients start to experience slight but noticeable deterioration in continence status and quality of life relatively early (within 1 year) after surgery. This finding might be helpful with appropriately counseling patients who undergo artificial urinary sphincter implantation., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Cancer cachexia is a progressive wasting syndrome characterized by anorexia and weight loss, specifically muscle wasting and fat depletion. There is no therapeutic agent for treatment of this syndrome. We investigated the anti-cachexia effects of Z-505 hydrochloride (Z-505), a new oral growth hormone secretagogue receptor 1a (GHSR1a) agonist, using a mouse model of cancer cachexia. We performed a calcium flux assay in Chinese hamster ovary (CHO-K1) cells stably expressing human GHSR1a to quantify the agonistic activity of Z-505. In Colon 26 tumor-bearing mice, Z-505 (300mg/kg, p.o., twice daily) was administered for 7 days to assess its anti-cachexia effects. Body weight and food intake were monitored during the period, and the skeletal muscle and epididymal fat weights were measured. Serum levels of insulin, insulin-like growth factor 1 (IGF-1), interleukin-6 (IL-6), and corticosterone were measured to confirm the mechanism of the anti-cachexia action of Z-505. Z-505 showed strong agonistic activity similar to that of human ghrelin, with a half maximal effective concentration (EC 50 ) value of 0.45nM. Z-505 treatment significantly increased food intake and inhibited the progression of weight loss. Z-505 also significantly attenuated muscle wasting and fat loss, and increased circulating levels of anabolic factors such as insulin and IGF-1, but not catabolic factors such as IL-6 and corticosterone. These findings suggest that Z-505 might be effective in the treatment of cachexia via the increased anabolic hormone levels stimulated by the activation of the ghrelin receptor, GHSR1a., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The "Japanese Clinical Guideline for Female Lower Urinary Tract Symptoms," published in Japan in November 2013, contains two algorithms (a primary and a specialized treatment algorithm) that are novel worldwide as they cover female lower urinary tract symptoms other than urinary incontinence. For primary treatment, necessary types of evaluation include querying the patient regarding symptoms and medical history, examining physical findings, and performing urinalysis. The types of evaluations that should be performed for select cases include evaluation with symptom/quality of life (QOL) questionnaires, urination records, residual urine measurement, urine cytology, urine culture, serum creatinine measurement, and ultrasonography. If the main symptoms are voiding/post-voiding, specialized treatment should be considered because multiple conditions may be involved. When storage difficulties are the main symptoms, the patient should be assessed using the primary algorithm. When conditions such as overactive bladder or stress incontinence are diagnosed and treatment is administered, but sufficient improvement is not achieved, the specialized algorithm should be considered. In case of specialized treatment, physiological re-evaluation, urinary tract/pelvic imaging evaluation, and urodynamic testing are conducted for conditions such as refractory overactive bladder and stress incontinence. There are two causes of voiding/post-voiding symptoms: lower urinary tract obstruction and detrusor underactivity. Lower urinary tract obstruction caused by pelvic organ prolapse may be improved by surgery., (© 2015 Wiley Publishing Asia Pty Ltd.)

Background: To explore the real-life practice of clinical management of interstitial cystitis (IC) in Japan., Methods: A questionnaire on the number of IC patients, cystoscopic findings, diagnostic methods, and the treatment modalities was sent via e-mail to 114 medical institutions belonging to the Society of Interstitial Cystitis of Japan (SICJ)., Results: Completed questionnaires were returned from 62 institutions (20 university hospitals, 26 general hospitals and 16 clinics), with a response rate of 54%. The median of patient number per institution was 20 and the national number of IC patients was counted as 4,531 in Japan. The number of new patients in 2013 was 7 (median) per institution and calculated as 1,214 in total. The case volume per institution distributed broadly and skewed to a lower volume. The patients were categorized according to cystoscopic findings as either Hunner type IC with Hunner lesions (n=2,066, 45%), non-Hunner type IC with glomerulations on hydrodistension (n=1,720, 38%) or hypersensitive bladder without endoscopic abnormalities (n=304, 7%), excluding unknown (n=441, 10%). The proportion of Hunner type IC was highly variable among the institutions, ranging from 0% to 100% with a median of 29%. As for evaluation, symptom and quality of life (QOL) assessment by questionnaires, frequency volume chart, urinalysis, urine cytology, urine culture, post-void residual measurement, uroflowmetry, ultrasound and cystoscopy were widely adapted. Administration of oral medicines and intravesical instillation therapy were undertaken at 98% and 63% of institutions, respectively. Hydrodistension was commonly performed, totaling in 812 procedures at 53 institutions, while only five cystectomies were reported from four institutions., Conclusions: The survey estimated about 4,500 IC patients and 2,000 Hunner type IC patients in Japan. It also revealed a wide range of case volume, acceptable adherence to clinical guidelines, and high variability in the proportion of Hunner type IC. The variable proportions of Hunner type IC despite a high performing rate of endoscopy suggest inconsistency in diagnostic criteria for the Hunner lesion.

Macrophages are a major component of the innate immune system, and the cytokines they secrete are involved in antitumor responses. Z-100 is obtained from hot-water extract of human-type Mycobacterium tuberculosis strain Aoyama B and activates the innate immune response. However, while Z-100 is known to modulate macrophage activity, the mechanism behind this modulation is not fully understood. We evaluated the effects of Z-100 on the murine macrophage cell line RAW264.7. Tumor necrosis factor-alpha (TNF-α) production from RAW264.7 cells was strongly induced by Z-100 and interferon-gamma (IFN-γ) stimulation but only weakly induced by Z-100 alone. Quantitative gene expression analysis showed that nucleotide-binding oligomerization domain containing 2 (Nod2) expression was up-regulated by IFN-γ treatment in RAW264.7 cells while Z-100-induced TNF-α production was attenuated by Nod2 gene silencing. Further, componential analysis demonstrated that muramic acid and amino acids distinctive of muramyl dipeptide (MDP) were contained within Z-100 and Z-100Fr I, the low-molecular-weight fraction containing components <3 kDa in size. In addition, Z-100Fr I enhanced TNF-α production in RAW264.7 cells and promoted NOD2-dependent nuclear factor-kappa B (NF-κB) activation in murine NOD2-expressing SEAP reporter HEK293 (HEK-Blue-mNOD2) cells. Taken together, these results suggest that Z-100 contains MDP-like molecules and augments NF-κB signaling via the direct activation of Nod2 in macrophages, which might be one mechanism driving the innate immune responses induced by Z-100 in cancer immunotherapy., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: The aim of the present study was to assess the effects of onabotulinumtoxinA injection for refractory non-neurogenic overactive bladder (OAB) for 12 months., Methods: For patients with persistent urgency urinary incontinence (UUI) more than once a week despite taking anti-cholinergic agents or incapability to continue the agents because of adverse effects, 100 units of onabotulinumtoxinA was injected at 30 sites in the sub-epithelial bladder wall. Efficacy was assessed every month up to 12 months after injection, using a three-day frequency-volume chart (FVC) and postvoid residual urine (PVR), three questionnaires, and a simple score of Global Response Assessment (GRA). Failure was defined as when GRA was negative and additional treatment was administered., Results: Nine men and eight women aged 67 ± 12 years were included. On FVC, frequencies of urgency, UUI and daytime urination significantly decreased up to the 11th month. PVR significantly increased at the first and second months but no patient required catheterization. The total scores of Overactive Bladder Symptom Score and International Consultation on Incontinence Questionnaire Short Form were significantly decreased for 10 and eight months, respectively. The score of GRA was significantly improved for eight months. The median time to failure was 11.0 months., Conclusion: This study suggests that onabotulinumtoxinA submucosal injection is promising for refractory non-neurogenic OAB. It is anticipated that the treatment is effective for eight to nine months and approximately 40% of the patients do not require anticholinergics at the 12th month postoperatively., (© 2012 Wiley Publishing Asia Pty Ltd.)

Zinc, one of essential trace elements, functions as a structural component in more than 300 different enzymes in the human body, playing crucial roles in performing a number of functions, including protein and DNA synthesis. Also hereditary or dietary zinc deficiency leading to pathological changes such as growth retardation, skin symptoms and taste disorders in human has been well investigated. Polaprezinc (Promac(®), Zeria Pharmaceutical Co., Ltd.), a chelate compound consisting of zinc and L-carnosine, is a zinc-related medicine approved for the first time in Japan, which has been clinically used to treat gastric ulcers. Its mechanism of action is believed to oxygen radical scavenging, anti-oxidation, and acceleration of wound healing. Further, as zinc deficiency is known to be a primary cause of taste disorders, a clinical phase III study is in progress to determine taste disorders as a new indication of polaprezinc. The pharmacological action of polaprezinc, however, on taste disorders remains unclear. So we examined the effect of polaprezinc on taste disorders induced by feeding rats a zinc-deficient diet and clarified its mechanism of action in restoring the reduced zinc content in the lingual epithelium and improving delayed cell proliferation of taste bud cells due to zinc deficiency. In this review, we primarily make reference to our own data on the pharmacological action of polaprezinc on taste disorders and introduce recent research on the effects of polaprezinc in treating other diseases.

The novel gastroprokinetic agent acotiamide improves gastric motility by inhibiting acetylcholinesterase activity in stomach; however, the mechanism of distribution of acotiamide from blood to stomach has not been clarified. Here, the tissue distribution of acotiamide was investigated in rats. The tissue-to-plasma concentration ratio (K(p,app,in vivo)) for stomach decreased from 4.1 to 2.4 mL/g of tissue at steady state with increasing plasma concentrations, whereas the K(p,app,in vivo) for skeletal muscle was much lower and constant, regardless of the concentration of acotiamide in plasma. In vitro binding to stomach tissue protein exhibited a linear profile, with a predicted K(p,app,in vitro) of 2.2 from free fractions under linear conditions. Therefore, protein binding to stomach tissue might only play a limited role in the stomach distribution of acotiamide. The influx permeability (f (u,b) × PS(inf,app)) in the stomach exhibited dose-dependent saturation at the lowest range of examined blood unbound concentrations of acotiamide, whereas that in skeletal muscle exhibited only minimal dose dependence. In addition, the unbound concentration ratio of stomach to plasma (2.8) at steady state was markedly higher than unity. Taken together, these results suggest that carrier-mediated concentrative uptake processes play an important role in the distribution of acotiamide to the stomach but not skeletal muscle., (Copyright © 2011 Wiley-Liss, Inc.)

Aims: As activation and overexpression of the cholecystokinin-2 (CCK-2)/gastrin receptor can lead to carcinogenesis, it has been explored as a therapeutic target in pancreatic cancer. We demonstrated that Z-360, a CCK-2/gastrin receptor antagonist, combined with gemcitabine prolonged survival and reduced gemcitabine-induced vascular endothelial growth factor (VEGF) expression in a pancreatic carcinoma orthotopic xenograft mouse. In this study, we investigated the role of the CCK-2/gastrin signaling pathway on gemcitabine-induced VEGF expression in PANC-1 human pancreatic carcinoma cells., Main Methods: In PANC-1 cells treated with Z-360, anti-gastrin IgG or kinase inhibitors, the gene expression levels were analyzed by quantitative real-time RT-PCR, and the protein levels of Akt and phosphorylated Akt (p-Akt) in cellular extracts were measured by ELISA., Key Findings: Gemcitabine-induced expression of VEGF and hypoxia-inducible factor-1 alpha (HIF-1 alpha) were suppressed by the treatment with an anti-gastrin antibody. In addition, VEGF and HIF-1 alpha gene expression was inhibited by treatment with an inhibitor of phosphatidylinositol 3-kinase (PI3K), which is involved in the downstream signaling pathway of the CCK-2/gastrin receptor, and was also suppressed by treatment with Z-360. Moreover, although Akt phosphorylation was increased by treatment with gemcitabine, this elevation was partially, but significantly, inhibited by an exposure of Z-360., Significance: Gemcitabine might induce gene expression of VEGF via the PI3K/Akt signaling pathway in the downstream of the CCK-2/gastrin receptor. The suppression of the CCK-2/gastrin signaling pathway by treatment with Z-360 could be a useful approach for potentiating prolonged survival of pancreatic cancer patients receiving gemcitabine therapy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

In clinical trials, acotiamide hydrochloride (acotiamide: Z-338) has been reported to be useful in the treatment of functional dyspepsia. Here, we investigated the effects of acotiamide on gastric contraction and emptying activities in rats in comparison with itopride hydrochloride (itopride) and mosapride citrate (mosapride). We also examined in vitro the compound's inhibitory effect on acetylcholinesterase (AChE) activity derived from rat stomach. In in vivo studies, acotiamide (30 and 100mg/kg s.c.) and itopride (100mg/kg s.c.) markedly enhanced normal gastric antral motility in rats. In gastric motility dysfunction models, acotiamide (100mg/kg s.c.) and itopride (100mg/kg s.c.) improved both gastric antral hypomotility and the delayed gastric emptying induced by clonidine, an α(2)-adrenoceptor agonist. In contrast, mosapride (10mg/kg s.c.) had no effect on these models. Like the AChE inhibitors itopride (30 mg/kg s.c.) and neostigmine (10 μg/kg s.c.), acotiamide (10mg/kg s.c.) also clearly enhanced gastric body contractions induced by electrical stimulation of the vagus, which were abolished by atropine and hexamethonium, whereas mosapride (3 and 10mg/kg s.c.) did not. In in vitro studies, acotiamide concentration-dependently inhibited rat stomach-derived AChE activity (IC(50)=2.3 μmol/l). In addition, stomach tissue concentrations of acotiamide after administration at 10mg/kg s.c. were sufficient to produce inhibition of AChE activity in rat stomach. These results suggest that acotiamide stimulates gastric motility and improves gastric motility dysfunction in rats by inhibiting AChE activity, and may suggest a role for acotiamide in improving gastric motility dysfunction in patients with functional dyspepsia., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: • To assess the effect of α1-D/A adrenoceptor antagonist naftopidil on patients with neurogenic lower urinary tract dysfunction (NLUTD) and voiding difficulty. • To explore the effectiveness of naftopidil in these patients by using urodynamic variables, including pressure flow study (PFS), and to find good and simple parameters (International Prostate Symptom Score (IPSS), Post-void residual urine (PVR), and uroflowmetry (UFM) parameters) as substitution of PFS for predicting the effect of naftopidil., Patients and Methods: • The main inclusion and exclusion criteria were, IPSS ≥8, voiding symptoms with IPSS ≥5, IPSS-quality of life (QOL) ≥2, PVR ≥50 mL, and without prostatic enlargement ≥ 20 mL. • After initial assessment, patients were stepwisely administered for 12 weeks with the following: placebo for 2 weeks, naftopidil 25 mg/day for 2 weeks, naftopidil 50 mg/day for 2 weeks, and naftopidil 75 mg/day for 6 weeks. At the end of both placebo and 6 weeks' naftopidil 75 mg/day, their IPSS, UFM, PVR, and PFS were assessed. • A total of 82 Japanese patients (men 40, women 42) with lower urinary tract symptoms complicated by NLUTD, with a mean age of 63.9 years, were included from private or institutional clinics. • The lesions were spinal cord 42, and peripheral nervous system 40. The spinal cord lesions were all lumbar spine (injury or lumbar canal stenosis)., Results: • In all patients, pressure at maximum urinary flow rate (P(det) Q(max) ) in PFS significantly decreased (P < 0.05), and maximum urinary flow rate in UFM significantly increased (P < 0.01). Analysis of data for men and for women also showed a significant decrease in PVR, %PVR, and total IPSS score. • The degree of improvement of voided volume, PVR (%), and IPSS in patients with PVR <300 mL was significantly greater than those in patients with PVR ≥300 mL. • The degree of improvement of P(det) Q(max) in PFS, and IPSS in patients with bladder contractility was significantly greater than that in patients without bladder contractility., Conclusions: • α1-D/A adrenoceptor antagonist naftopidil has a significant effect on both symptoms and urodynamic variables of patients of both genders with NLUTD in Japan. • PVR <300 mL and bladder contractility are predictive factors for the efficacy of naftopidil on patients with NLUTD., (© 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.)

Objectives: The aim of this study was to identify the urodynamic features of women with stress urinary incontinence (SUI) or with high-stage (stage 3 or greater) cystocele (HSC) as compared with symptom-free women., Methods: Fifty-six neurologically intact women with SUI and 47 women with HSC but without SUI were prospectively evaluated. All patients underwent full urodynamics, in addition to basic clinical evaluations. The urodynamic parameters of SUI and HSC were compared to the ones obtained from 78 urologically symptom-free normal women over the same period., Results: Patients with HSC, after correction of cystocele using a temporary vaginal pessary, had consistently lower maximum urinary flow rate with a lower detrusor pressure during micturition than the controls or those with SUI. On the other hand, patients with SUI had an equivalent to higher maximum urinary flow rate, normal detrusor contraction strength with a lower detrusor pressure during micturition than the controls. Both maximum Watts factor and bladder contractility index were significantly lower in the whole HSC cohort in comparison to the controls and patients with SUI. The urodynamic characteristics observed among the three groups were all maintained even after adjusting for age., Conclusions: Women with SUI demonstrate voiding with low-pressure, normal contraction strength with an equivalent to high urinary flow rate. Women with HSC demonstrate voiding with low pressures with weak contraction strengths and low urinary flow rates, suggesting a higher prevalence of detrusor underactivity. Chronically decreased or increased urethral resistance might alter voiding dynamics and performance., (© 2011 The Japanese Urological Association.)

Acotiamide hydrochloride (acotiamide; N-[2-[bis(1-methylethyl) amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole-4-carboxamide monohydrochloride trihydrate, Z-338) has been reported to improve meal-related symptoms of functional dyspepsia in clinical studies. Here, we examined the gastroprokinetic effects of acotiamide and its antiacetylcholinesterase activity as a possible mechanism of action in conscious dogs. Acotiamide increased postprandial gastric motor activity in conscious dogs with chronically implanted force transducers and, like itopride, mosapride, and cisapride, exhibited gastroprokinetic activity in these dogs. Furthermore, acotiamide improved clonidine-induced hypomotility and delayed gastric emptying. Acotiamide-enhanced postprandial gastroduodenal motility was suppressed completely by pretreatment with atropine, a muscarinic receptor antagonist. In in vitro studies, acotiamide enhanced acetylcholine- but not carbachol-induced contractile responses of guinea pig gastric antrum strips. Moreover, like itopride and neostigmine, acotiamide inhibited recombinant human and canine stomach-derived acetylcholinesterase (AChE) activity in vitro. The mode of the AChE inhibitory action of acotiamide was selective and reversible. Unlike itopride or mosapride, acotiamide showed no affinity for dopamine D(2) or serotonin 5-HT(4) receptors. With regard to cardiovascular side effects, unlike cisapride, acotiamide did not affect myocardial monophasic action potential duration, QT interval, or corrected QT interval in anesthetized dogs. These results suggest that acotiamide stimulates gastric motility in vivo by inhibiting AChE activity without affecting QT interval. Acotiamide thus represents a beneficial new drug for the treatment of functional dyspepsia involving gastric motility dysfunction, with differences from other prokinetic agents.

Aim: Transobturator tape (TOT) kits approved as medical instruments are still not available in Japan. This study aimed to: (1) assess the outcomes of TOT using Monarc (American Medical Systems; AMS Inc, Minnetonka, MN, USA) in women with stress urinary incontinence (SUI); (2) evaluate possible different surgical outcomes in women with urethral hypermobility (UH) and/or intrinsic urethral deficiency (ISD); and (3) evaluate the possibility of improvement of preoperative urgency and urge urinary incontinence after TOT in mixed urinary incontinence (MUI)., Methods: Data from 140 women with SUI in a prospective multicenter study were examined at 3-6 months follow-up., Results: 82.1% of the patients were cured and 10.7% showed improvement. The surgical outcome was significantly better in UH than in UH combined with ISD or ISD. In 44 MUI patients, 79.6% were cured and 15.9% showed improvement. Urgency improved in about 75% of patients after TOT., Conclusion: TOT is effective for both SUI and MUI, with urgency improving., (© 2010 The Authors. Journal of Obstetrics and Gynaecology Research © 2010 Japan Society of Obstetrics and Gynecology.)

Aims: To clarify the mechanism underlying the effect of polaprezinc on hypogeusia, we investigated the uptake of polaprezinc by the tongue in rats., Main Methods: Rats were fed a zinc-sufficient (Zn(+)) or zinc-deficient (Zn(-)) diet. After 4weeks on the Zn(-) diet, polaprezinc (1, 3, or 10mg/kg) or [(65)Zn] polaprezinc (10mg/kg) was administered orally once a day. The zinc concentration or the (65)Zn radioactivity of the tongue was measured by inductively-coupled plasma mass spectrometry or gamma counting, respectively. In addition, the distribution of (65)Zn in the tongue was analyzed by microautoradiography and the proliferative activity of taste bud cells was measured from the uptake of 5-bromo-2'-deoxyuridine., Key Findings: The zinc concentration of the lingual epithelium, but not the whole tongue, was markedly decreased in Zn(-) rats compared with Zn(+) rats. After administration of polaprezinc to Zn(-) rats at doses of 1, 3, and 10mg/kg, the zinc concentration in the lingual epithelium increased significantly from 85+/-4 to 105+/-7 (p<0.05), 120+/-3 (p<0.001), and 124+/-3 (p<0.001) microg/g, respectively. After administration of [(65)Zn] polaprezinc, the (65)Zn radioactivity of the tongue and serum were higher in Zn(-) rats than in Zn(+) rats. (65)Zn was mainly detected in the epithelium on microautoradiograms of the tongue in Zn(-) rats. In addition, polaprezinc (3 and 10mg/kg) improved the reduced proliferation of taste bud cells due to zinc deficiency., Significance: Polaprezinc is distributed to the lingual epithelium and restores its zinc concentration in Zn(-) rats resulting in improvement of cellular functions, especially proliferation.

Objective: To determine the burden of male stress urinary incontinence (SUI) in Japan and to identify candidates for artificial urinary sphincter (AUS) implantation., Methods: In 2008, a survey form was sent to all 1202 training hospitals certified by the Japanese Urological Association. The survey included questions about the number of patients with moderate to severe SUI who could be candidates for AUS implantation, the etiology, and incidence of SUI in 2007., Results: Overall, 682 (56.7%) responded to the survey. The total number of patients was 1276. The most common reported etiology for SUI was post-radical prostatectomy (59.1%), followed by neurogenic bladder (23.0%), surgery for benign prostatic hyperplasia (10.3%), neobladder reconstruction (2.8%), urethral injury (2.4%), and others (2.4%). There were 203 new cases in 2007. Adjusted by the response rate, the prevalence and annual incidence were estimated to be 2235 and 358 cases, respectively., Conclusions: This survey confirms that a significant number of men suffer from moderate to severe SUI, with the majority of cases being post-prostatectomy incontinence. The Japanese urological community needs to provide appropriate treatment for these patients.

Objectives: To evaluate changes in prostate volume (PV) and its association with selected urological measures and risk of surgical intervention in Japanese men with benign prostatic hyperplasia (BPH)., Methods: The medical records of all consecutive urologist-diagnosed BPH patients of >or=40 years old who attended any of four urology clinics in Japan during January 2004-June 2006 were reviewed. Both cross-sectional and longitudinal data were captured to analyze baseline correlations among urological measures, to evaluate the longitudinal changes in PV and selected urological measures, and to examine the predictors of surgical intervention., Results: The follow-up period was 2.8 years. Mean PV and mean prostate-specific antigen (PSA) of 1331 eligible patients were 34.0 mL and 4.0 ng/mL, respectively. Both measures increased directly with age. Baseline PV correlated with residual urine volume (r = 0.18, P < 0.05) and PSA (r = 0.41, P < 0.001). Among 319 patients who had more than one PV measurement, PV increased in 51% of patients, remained the same in 28% and decreased in 21%. Use of alpha-blockers at baseline and during follow up was not associated with PV change. Patients who had a PV >or=30 mL, a severe International Prostate Symptom Score and a PSA level >or=1.5 ng/mL at baseline, were more likely to have surgical intervention during the follow-up period., Conclusions: Predictors generated in this study may help to identify a subset of BPH patients at high risk of surgical intervention.

Interstitial cystitis (IC) is a disease of the urinary bladder with lower urinary tract symptoms such as urinary frequency, bladder hypersensitivity and/or bladder pain and resultant serious impairment of quality of life. In Japan, assuming that IC is very rare, research activity and medical care of IC have been sparse until 2001, when the Society of Interstitial Cystitis of Japan (SICJ) and a patient support group were founded.(1,2) Subsequently the International Consultation on Interstitial Cystitis Japan (ICICJ) was held in Kyoto in 2003.(3) On the other hand, the etiology of IC has not been well clarified, which complicates its diagnosis and treatment at clinical settings. We have thus developed the Japanese Clinical Guideline,(4) which is targeted at healthcare professionals including specialists in urology and women's health care who may engage in the diagnosis and treatment of IC. This article is the English translation of a shortened version of the Guideline for convenience of readers worldwide.

Objectives: Although the artificial urinary sphincter (AUS) is one of the most effective surgical treatments for severe urinary incontinence, little is known about its use in Japan. A nationwide survey was done to determine contemporary trends in AUS use and its long-term durability., Methods: Data on AUS units sold in Japan were provided directly by Takai Hospital Supply Co., Ltd., Tokyo, Japan, and a survey form was sent to all 44 institutes where AUS implantation had been carried out. The survey included various demographic and preoperative variables, surgical variables, and postoperative outcomes., Results: Between 1994 and 2007, a total of 100 AUS devices had been provided in Japan. Of the 44 institutes, 24 responded to the survey, and a total of 64 patients were enrolled in the study. Post-urological surgery incontinence accounted for 81.3% of the indications. During the mean follow-up of 50 months, mechanical failure occurred in four (6.2%), and the device was removed in 13 (20.3%) due to infection (14.0%), erosion (4.7%), or urination difficulty (1.5%). Of the 58 patients evaluated, 91.4% reported social continence. Five- and 10-year failure-free rates were 74.8% and 70.1%, respectively. On multivariate analysis, operative time was an independent predictor of treatment failure (P = 0.0334)., Conclusions: Considering recent trends in prostate surgery, the AUS may be significantly underused in Japan. Although excellent long-term durability has been achieved, a learning effect appears to be evident. The Japanese urological community needs to provide appropriate patients with this treatment option.

Area postrema (AP) is considered to be an important neural center for emesis in carnivores. However, it is also known that AP mediates motor responses induced by apomorphine in rats which do not have an emetic reflex. To shed more light on the possible role of AP in the control of gastric motility in physiological or pathophysiological conditions, we observed the effects of electrical or chemical (apomorphine) stimulation of AP neurons on intragastric pressure (IGP) or intragastric volume (IGV) in rat. We found that electrical stimulation (ES) reduces IGP, and this is sensitive to hexamethonium or L-NAME, and apomorphine also reduces IGP and increases IGV. In slice preparations, apomorphine (10 micromol/l) increased the frequency of spontaneous single unit discharges of AP neurons recorded extracellularly. We also succeeded retrograde labeling of AP neurons by DiI applied into the gastric corpus, for the first time. These observations indicate that rat stomach receives efferent neural input from AP and the excitation of AP neurons relaxes the stomach in rat, suggesting some functional roles of AP neurons in the regulation of gastric motility.

Purpose: Gastrin is known to enhance the growth of pancreatic carcinoma via the cholecystokinin (CCK)-2/gastrin receptor. We investigated the anti-tumor effect of Z-360 (calcium bis [(R)-(-)-3-[3-{5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}ureido]benzoate]), a novel orally active CCK-2 receptor antagonist alone or combined with the chemotherapeutic agent, gemcitabine in human pancreatic adenocarcinoma cell lines., Results: Z-360 potently inhibited specific binding of [3H]CCK-8 to the human CCK-2 receptor, with a Ki value of 0.47 nmol/l, and showed antagonistic activity for this receptor. The anti-tumor effect of Z-360 alone or combined with gemcitabine was assessed using subcutaneous xenografts of MiaPaCa2 and PANC-1 and an orthotopic xenograft model (PANC-1). Oral administration of Z-360 significantly inhibited the growth of MiaPaCa2 (41.7% inhibition at 100 mg/kg, P<0.01). Combined administration of Z-360 and gemcitabine significantly inhibited subcutaneous PANC-1 tumor growth compared with either agent alone (27.1% inhibition compared to effect with gemcitabine, P<0.05), and significantly prolonged survival compared with the vehicle control (median survival of 49 days in vehicle compared to 57 days in the combination group, P<0.05). In vitro studies showed that Z-360 significantly inhibited gastrin-induced proliferation of human CCK-2 receptor-expressing cells, and also significantly reduced gastrin-induced PKB/Akt phosphorylation to the level of untreated controls., Conclusion: In the present study, we have shown that Z-360 combined with gemcitabine can inhibit pancreatic tumor growth and prolong survival in a pancreatic carcinoma xenograft model, on a possible mode of action being the inhibition of gastrin-induced PKB/Akt phosphorylation through blockade of the CCK-2 receptor. Our results suggest that Z-360 may be a useful adjunct to gemcitabine for the treatment of pancreatic carcinoma and a therapeutic option for patients with advanced pancreatic cancer.

Objectives: We investigated the characteristics of recent male and female patients diagnosed with interstitial cystitis (IC), then investigated which therapy was chosen by the attending urologist., Methods: Materials were 282 IC patients diagnosed and treated during the past 3 years (sampling from Japanese IC database). Gender, age, medical history and predominant symptoms were investigated. In addition, we investigated the interval before a diagnosis was established. In laboratory findings, we investigated voided volume, urinalysis findings and cystoscopic findings. Regarding therapy, we investigated which therapy was chosen as the first line., Results: The gender ratio was about 1.0:5.6 (male : female). Regarding age distribution, patients in their 60s were the most frequent (65 cases, 31.3%). The interval before diagnosis of IC was 36.5 months on average (1-360 months). Regarding medical history, intrapelvic surgery was the most common and repeated urinary tract infection was next. The most frequent symptom was urinary frequency (295 cases, 98.3%). Urinary urgency was noted in 186 cases (62%) and supra-pubic pain was noted in 125 cases (41.6%). The once voided volume was 104.3 mL on average (50-200 mL). The most common cystoscopic finding was glomerulation (158 cases). Ulcer was present in only 19 cases. The most widely carried out therapy was hydrodistension (208 cases, 67.9%). Oral suplatast tosilate (197 cases, 65.6%), antihistamine (77 cases, 25.6%) and intravesical dimethylsulfoxide (69 cases, 23%) followed., Conclusions: Regarding characteristics, the age distribution was older than other countries. The most frequent symptom was urinary frequency. Oral suplatast tosilate was one of the popular therapies in Japan.

Purpose: We investigated whether continuous bladder irrigation after Transurethral Resection of the Prostate (TURP) would prevent catheter obstruction by the clot., Materials and Methods: We analyzed data from 761 patients registered in "a multi-institutional study of TURP clinical pathway" sponsored by the Ministry of Health, Labor and Welfare between 2001 and 2003. The difference of clinical backgrounds of the cases, resected weight, operating time, risk of being feverish, risk of catheter obstruction and chance of postoperative Transurethral Fulguration (TUF) between each institution were investigated. The risk factor of catheter obstruction is characterized and the significance of continuous bladder irrigation is discussed., Results: The incidence of catheter obstruction in the four institutions, in which 90% or more of patients underwent continuous bladder irrigation, was significantly lower than that in the three institutions, in which continuous bladder irrigation was performed in selected patients whose hematuria was severe (4.4% VS 12.9%, p<0.001). There was no difference in the frequency of either pyrexia or postoperative TUF. Logistic regression analysis showed that significant factors for catheter obstruction are continuous bladder irrigation, resected tissue weight and preoperative urinary infection., Conclusions: Routine continuous bladder irrigation achieved a lower incidence of catheter obstruction. However, we recommend that urologists should decide whether to perform routine continuous irrigation, considering the frequency of catheter obstruction, safety, labor and cost.

Although Knudson's two-hit hypothesis with functional loss of a tumor suppressor gene has been widely accepted, accumulating evidence suggests that several genes are regulated by the quantity of their product in a dose-dependent manner (gene dosage effect). The study was designed to identify the influence of gene dosage effect of 8p22 on patient prognosis. With a median age of 71 years, 40 patients with prostate cancer (11 organ-confined, 13 capsular penetrating, and 16 nodal and/or distant metastatic) were followed for a median of 68.5 months. A fluorescence in situ hybridization (FISH) technique was applied using a region-specific cosmid probe combined with centromeric probe. Allelic losses of 8p22, 8p21.3, 8p21.1 approximately 2, and 8p12 were found in 23, 22, 14, and 9 patients, respectively. A Cox proportional hazard model revealed that decreased fraction (i.e., the fraction of nuclei with a lesser number of cosmid signals than of centromeric probe signals) of 8p22 proved to be the sole independent prognostic factor predicting cancer-specific death, as well as disease progression--but allelic loss of 8p22 was not predictive. Cytogenetic estimation of 8p22 by FISH can yield quantitative evaluation of relevant gene dosage, which may become a useful biomolecular marker predicting poor patient prognosis.

Objectives: We investigated perioperative management for transurethral resection of the prostate (TURP) in Japan., Methods: The questionnaire survey was conducted in 1,213 educational institutions for urology., Results: The questionnaires were returned from 722 (60%) institutions. Admission to hospital was most frequently scheduled on preoperative day 1; termination of continuous drip infusion, starting meal intake and walking on postoperative day 1; intravenous antibiotics for three days; removal of Foley catheter on postoperative day 4; oral antibiotics for 7 days; and discharge from hospital on postoperative day 7., Conclusion: Although hospitalization was 14 days or less at most institutions, several procedures, especially the administration of prophylactic antibiotics, were fairly varied. Discussions from various perspectives might be needed to standardize the perioperative management of TURP in Japan.

Aim: To report the prospective multicentered study of the tension-free vaginal tape (TVT) procedure for stress urinary incontinence., Methods: One hundred and fifty-one women with stress urinary incontinence were operated on by the TVT procedure and were followed up at 3, 12, and 24 months after surgery. Patients' age and body mass index (BMI) averaged 57 years and 23.9, respectively. Forty-nine women were classified as type I, 46 women type II and 56 women type III (McGuire's classification). Local anesthesia was used in the operations on 137 women (91%) and epidural or general anesthesia was used in 14 (9%). Surgical outcomes were analyzed with Kaplan-Meier survival curves., Results: The subjective and objective cumulative cure rates 24 months later were 92% and 77%, respectively (P > 0.05). The TVT operation for women with type III (62%) resulted in a significantly lower cure rate compared to those with type I or with type II (83%) (P < 0.001). Post-operatively a urethral catheter was indwelt one day in 77 women (51%), two days in 14 (9%) and 3-7 days in 60 (40%). Surgical complications were encountered in 43 women (28%). The most frequent was bladder perforation in 24 women followed by postoperative difficulty in urination and de novo urgency., Conclusions: The TVT surgery was promising for the treatment of stress incontinence because of minimal surgical invasiveness and satisfactory surgical results. Women with type III incontinence resulted in fewer satisfactory outcomes than those with type I or II incontinence.

Objectives: To elucidate the predictive factors regarding the treatment outcomes after transurethral resection of the prostate for symptomatic benign prostatic enlargement with detrusor underactivity., Methods: A retrospective study was conducted in 190 patients with detrusor underactivity of 1397 men who had undergone transurethral resection of the prostate. All patients had completed the International Prostate Symptom Score and quality-of-life (QOL) questionnaires and had undergone a full urodynamic analysis before surgery. The outcomes were assessed at 3 and 12 months postoperatively using the International Prostate Symptom Score, QOL score, and peak urinary flow rate. The association between the baseline variables and improvement in the outcome variables was analyzed statistically., Results: Preoperative urodynamic abnormalities included bladder outlet obstruction in 58.9% and detrusor overactivity (DO) in 32.1%. Multivariate analysis suggested that the initial level of storage symptoms, as well as the QOL score, were predictive of an improvement in the QOL. Postoperative improvement in symptoms and QOL was consistently influenced by the presence of DO before surgery. The baseline degree of bladder outlet obstruction, as well as patient age, consistently influenced the improvement in the peak urinary flow rate., Conclusions: In selected patients with benign prostatic enlargement associated with detrusor underactivity, greater baseline storage symptom scores and the presence of DO were negative predictive factors for QOL improvement. Baseline DO was also predictive of poorer improvement in the subjective symptoms after transurethral resection of the prostate. A greater degree of baseline bladder outlet obstruction positively predicted for postoperative peak urinary flow rate improvement, and patient age predicted negatively for it.

The effect of polaprezinc, a chelate compound consisting of zinc ion and L-carnosine, on abnormalities of taste sensation induced by feeding a zinc-deficient diet to rats was examined by using the two-bottle preference test (quinine hydrochloride as a bitter taste and sodium chloride as a salty taste). Rats were fed either a zinc-deficient or a zinc-sufficient diet. The zinc-deficient diet increased the preference for both taste solutions, while polaprezinc (at doses of 3 and 10 mg/kg) restored the altered taste preferences. We also evaluated the proliferation of taste bud cells using 5-bromo-2'-deoxyuridine (BrdU). The BrdU incorporation into taste bud cells was significantly reduced in rats fed a zinc-deficient diet compared with rats fed a zinc-sufficient diet (from 50.8% to 45.0%, p<0.05) and this reduction was reversed by polaprezinc at doses of 1, 3, and 10 mg/kg, increasing to 50.2%, 53.5%, and 52.5%, respectively. These findings indicate that zinc deficiency induces the delayed of proliferation of taste bud cells, while polaprezinc improves cell proliferation. In conclusion, polaprezinc had a therapeutic effect in a rat model of abnormal taste sensation. Its mechanism of action was suggested to involve improvement of the decrease in taste bud cell proliferation caused by zinc deficiency.

The aim of the study was to evaluate quality of life (QOL) prospectively in women who undergo tension-free vaginal tape (TVT) operation for stress urinary incontinence. Sixty-six women who completed QOL questionnaires and a 2-year follow-up examination were included. Improvement of health-related QOL was assessed by the Incontinence Impact Questionnaire-7 (IIQ-7), the Urogenital Distress Inventory-6 (UDI-6), and two questions regarding patient satisfaction and de novo urge incontinence. Prior to surgery, patients complained most of stress symptoms followed by physical activities and emotional health. Postoperatively IIQ-7 and UDI-6 as a whole and all seven domains improved significantly (p<0.001). Scores of IIQ-7, UDI-6, and seven domains did not differ between the adult and the elderly groups. Of the patients 88% were much satisfied or satisfied with surgical outcomes. Incidence of de novo urge incontinence was 12%. It is concluded that the TVT procedure significantly improved health-related quality of life.

Purpose: To investigate the length of hospitalization and medical charges when a common clinical path for TURP (transurethral resection of prostate) was implemented in multiple hospitals., Patients and Methods: This study included 310 patients in 2001 and 298 in 2002, who were diagnosed with benign prostatic hyperplasia and who underwent TURP in seven hospitals in Japan. While the patients were treated according to the managing methods of each hospital in 2001, the patients were managed using a common clinical path in 2002, on which we conferred and established in 2001. We investigated the change of various outcome indicators before and after implementation of the common clinical path., Results: The background of patients and surgical outcome in 2002 were equal to those in 2001, except in incidence of preoperative urinary tract infection, general anesthesia and blood transfusion, and number of surgeons. Implementation of a common clinical path shortened the pre- and postoperative hospital stay, duration of bed rest, administration of antibiotics and Foley catheter indwelling, and reduced the standard deviation of these indicators. The total medical charge decreased from 515,439 to 491,935 yen. However, outcomes were considerably different among the seven hospitals. Multivariate analyses identified the hospitals, cognitive impairment, preoperative indwelling catheter and preoperative variance as the factors affecting preoperative hospital stay, and the hospitals, co-existing disease, blood transfusion, postoperative urinary tract infection and postoperative variance as factors affecting postoperative stay. Based on these analyses, we determined four exclusion criteria against using a common clinical path: 1) patients requiring examination or surgery other than TURP simultaneously, 2) patients whose ADL disturbance, cognitive impairment, past history and/or coexisting disease are expected to affect postoperative convalescence, 3) patients with a preoperative indwelling catheter just before operation, and 4) patients with preoperative urinary tract infection. By excluding 122 (39.4%) and 129 (43.3%) patients fulfilling the above criteria in 2001 and 2002, respectively, there were reduction in the length of pre- and postoperative hospital stay, and the total admission fee. Furthermore, there were decrease in their standard deviations., Conclusions: A common clinical path was valid for reducing variance of the critical indicators affecting the clinical course of TURP and shortening the pre- and postoperative stay in the multiple hospitals. It is mandatory to establish the standard perioperative management for TURP from the viewpoint of urologists, under the circumstances of the impending introduction of the Diagnosis Procedure Combination (DPC).

Purpose: We conducted a questionnaire survey to elucidate the rating of the patients who underwent transurethral resection of the prostate (TURP) and were managed by a common clinical path during hospitalization., Patients and Methods: At the day of discharge from seven hospitals in Japan, the questionnaires were handed to 298 patients who underwent TURP in 2002. In the path, it was determined that the patients should be admitted one day before surgery and discharged on the seventh postoperative day., Results: The questionnaires were returned by 240 (80.5%) patients. Of the 212 patients answering a question regarding the desirable preoperative hospital stay, 58 (27.4%), 85 (40.1%) and 46 (21.7%) considered 1, 2 and 3 days as a desirable preoperative stay, respectively. Of the 206 answering a question about the desirable postoperative hospital stay, 54 (26.2%), 28 (13.6%) and 60 (29.1%) considered 7, 8 and 9-10 days as a desirable postoperative hospital stay, respectively. Of the 240 patients, 229 (95.4%) received the path for the patients, 234 (97.5%) understood the treatment methods well and 229 (95.4%) understood the schedule during hospitalization well. Two hundred thirty-six (98.3%) and 218 (90.8%) patients answered that as scheduled, they started to have meals and started to walk, respectively. Continuous drip infusion was terminated in 219 (91.3%) as scheduled, and indwelling catheters were removed in 215 (89.6%) as scheduled., Conclusions: This questionnaire survey elucidated that approximately 70% of the patients who underwent TURP wanted to stay 1 or 2 days before surgery and 7 to 10 days after surgery. We consider it very important that patients understand well the treatment methods, complications, schedules during hospitalization and criteria for discharge when they are managed using the clinical path, so they will accept better a length of hospital stay that is shorter than that which they had desired.

Purpose: The characteristics of bile canalicular transport processes for xenobiotic taurine conjugates have not yet been clarified. To elucidate the biliary excretion characteristics of xenobiotic taurine conjugates, we investigated the transport of a novel thromboxane A2 receptor antagonist, Z-335, and its taurine conjugate (Z-335-Tau) across the bile canalicular membrane., Methods: We examined the uptake of Z-335 and Z-335-Tau by isolated bile canalicular membrane vesicles (CMVs) from Sprague Dawley and Eisai-hyperbilirubinemic rats (EHBRs) which EHBRs have a hereditary defect of canalicular multidrug resistance-associated protein 2 (Mrp2) function. Also, the in vitro and in vivo kinetics of Z-335-Tau uptake and excretion were compared., Results: Z-335 uptake by CMVs from normal rats exhibited marked ATP-dependence, whereas ATP-dependent uptake of Z-335 into CMVs from EHBRs was not observed. In contrast, Z-335-Tau uptake into CMVs from both normal rats and EHBRs was ATP dependent. The initial uptake velocity was concentration-dependent, with an in vitro Michaelis constant for initial uptake of 189 microM, which was similar to the in vivo value., Conclusions: The biliary excretion of Z-335 involves Mrp2, whereas that of Z-335-Tau involves active transport systems that remain intact in EHBRs and show marked ATP dependence, which ATP-dependent transport is involved in the biliary excretion of Z-335-Tau in vivo.

Objective: We have the impression that the degree of obstruction was stronger in the patients with a middle lobe of hyperplastic nodule than in those without such a lobe in patients with benign prostatic hyperplasia. In the present study, we compared the data from a pressure-flow study (PFS) and a presence of a middle lobe., Materials and Methods: A transurethral resection for benign prostatic hyperplasia was performed in 2,439 patients, 798 underwent PFS. The PFS findings and the presence of a middle lobe were compared with the following parameters, namely, the bladder detrusor function, the degree of obstruction, the post-voided residual volume, the maximum flow rate, the prostate volume and the resected volume., Results: In the pressure-flow study, the rate of the normal bladder detrusor function was higher in the patients with a middle lobe than in those without such a lobe (71.9 versus 53.3%). The degree of obstruction was also stronger in the patients with a middle lobe than in those without in the patients with a normal bladder detrusor function (89.0 versus 79.4%). Then in the patients with a middle lobe, the quantity of the post-voided residual volume was greater, however, the maximum flow rate was lower., Conclusion: Most patients with a middle lobe demonstrate an improved voiding ability after underwent a transurethral resection.