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to evaluate the effects of phosphodiesterase-5 inhibitors (PDE5-i) on Leydig cell secretory function (LCSF).in all, 75 men with oligoasthenospermia were treated daily for 12 weeks with either vardenafil (23 men, group A), sildenafil (25 men, group B) or l-carnitine (26 men, group C); a further group of 22 men with oligoasthenospermia (group D) received no treatment. Serum levels of insulin-like-3 peptide (INSL3) were evaluated before and after the end of the treatment in each of groups A, B and C, respectively. Serum INSL3 levels were measured in each participant of group D before and after the 12-week experimental period.within group A and B, the peripheral serum mean INSL3 concentration, sperm concentration, percentage of motile spermatozoa, and percentage of morphologically normal spermatozoa were significantly greater after PDE5-i treatment than before.we suggest that PDE5-i enhances LCSF, as the mean INSL3 concentration was significantly greater after PDE5-i administration than before, within groups A and B. This enhancement in LCSF might contribute to the increase in sperm concentration and sperm motility after administration of PDE5-i.

INTRODUCTION: We evaluated the effects of intra-vesical injection of botulinum toxin type A in the detrusor muscle in patients with neurogenic overactive bladder (OAB), patients with non-neurogenic overactive bladder and patients with interstitial cystitis. MATERIALS AND METHODS: Between January 2003 and December 2006 we treated 30 patients with 100 I. U. to 300 I. U. of botulinum toxin A in the -detrusor muscle. Patients were clinically and urodynamically followed up for 4, 12 and 36 weeks thereafter. RESULTS: Neurogenic overactive bladder: of the 19 injected doses, 18 (94.7 %) in 7 patients were judged as effective, and 1 (5.2 %) of 200 U of BTX-A was judged as ineffective. Mean bladder volume increased from 137 to 396 ml. Non-neurogenic overactive bladder: of 7 injections, 6 (85.7 %) were judged effective in 5 patients. Mean bladder volume increased from 149 to 322 ml. Interstitial -cystitis: in all 4 patients the treatments were deemed ineffective. CONCLUSIONS: Injecting 300 units of BTX-A into 30 sites in the muscle located in the body of the bladder region is effective for neurogenic bladder patients with intermittent catheterization who have urge and reflective types of incontinence. Injec-tions of 100 and 200 units of BTX-A to treat non-neurogenic overactive bladder with urinary incontinence provided together without retention. The optimal dose of BTX-A requires further investigation. Injection with 200 units of BTX-A was not useful against interstitial cystitis. None of the patients developed any adverse effects after injecting the bladder wall with BTX-A.

Behçet’s disease is a multiple disorder in which urogenital involvement mainly consists of genital aphthous ulcers, epididymitis, urethritis and recurrent cystitis. We report 2 cases of neurogenic bladder due to Behçet’s disease. Both cases showed detrusor hyperreflexia and detrusor-sphincter dyssynergia. One case has been managed by twice-daily intravesical oxybutynin treatment (5 mg/10 ml) and clean intermittent catheterization (CIC) 7 times/day, and the other case has been managed by CIC 6 times/day.

OBJECTIVE To investigate the effect of edaravone, a radical scavenger, on ischaemia-reperfusion (I-R) injury in the testes. MATERIALS AND METHODS Eight-week-old male Sprague-Dawley rats were allocated to one of four groups: a no-drug group subjected to induction of 30-min of ischaemia and 60-min reperfusion; two drug groups administered edaravone at 1 or 10 mg/kg intraperitoneal and then subjected to 30-min ischaemia and 60-min reperfusion; and a sham-operated control group administered edaravone at 10 mg/kg intraperitoneal. To induce testicular I-R, the right testis was exposed outside of the body and the testicular artery was clamped with a small clip for 30 min. Blood flow and nitric oxide (NO) release were monitored in real time simultaneously with a laser Doppler flowmeter and an NO-selective electrode, respectively. After death the tissue levels of NO2-NO3 (a marker of NO production), malondialdehyde (a marker of lipid peroxidation), 8-hydroxydeoxyguanosine (a marker of oxidative DNA damage), myeloperoxidase (a marker of neutrophil infiltration), and heat-shock protein 70 (HSP 70) and its mRNA were measured. The testicular tissue was also analysed histologically. RESULTS Clamping the testicular artery resulted in a decrease of blood flow to 0–5% of the basal level measured before clamping. NO release was increased during clamping and gradually recovered to the basal level on removing the clip. Interestingly, the peak of NO release in rats of the no-drug group occurred at the start of reperfusion, while that in the high-dose drug group occurred several minutes later. The levels of NO2-NO3, malondialdehyde, 8-hydroxydeoxyguanosine, myeloperoxidase and HSP 70 and its mRNA, and histological variables, were significantly greater in the no-drug I-R group than in the control, and these variables were ameliorated by treatment with edaravone. CONCLUSION These results indicate that edaravone reduces the oxidative stress and prevents the testicular damage induced by I-R.

We evaluated the development of embryos generated from the fertilisation of oocytes with spermatozoa isolated from animals with primary testicular damage (PTD). Embryos derived in vivo or in vitro from oocytes fertilised with spermatozoa produced by PTD rats that had undergone surgical treatment for the PTD (group A1), or PTD rats (group A2), or control rats (group B) were cultured and transferred to recipients. At the end of the experimental period, the fertilisation potential of each rat was assessed in vitro (IVF trials). Sperm 8-oxodG/dG ratio (a marker of DNA oxidative status) was significantly larger in group A2 than in groups A1 and B. Blastocysts of the group A2 transferred to recipients demonstrated a significantly larger loss before implantation than transferred blastocysts of groups A1 or B. In addition, the proportion of implanted blastocysts that could not complete the intrauterine development was significantly larger in group A2 than in groups A1 and B. This study reveals a post-fertilisation detrimental effect in animals with PTD on the capacity of oocytes (fertilised either in vitro or in vivo) to develop in vitro and implant after transferring them to recipients probably attributable to sperm DNA oxidative damage. Andrologia

This reports tha development of bioactive glass ceramic particles and evaluates their use inclinical applications. 1. The subjects of the evaluation were 13 impacted teeth, 17 intramaxillary cysts (not including radicular cysts), and 7 atrophic mandibular alveolar ridges. 2. The results were classified into effective, slightly effective, ineffective, and harmful, a very high proportion, 33 or 89.3%,were judged effective or slightly effective. 3. None were evaluated to be harmful, showing the safety of the present material. Among the ineffective cases there were open wounds due to infection, leakage of the supplied material, and fistulation. In cases where inflammation had not disappeared at the supply there were cases where the particles had to be completely removed due to infection, It was determined the that this was not due to the material, but possidly due to the surgical procedures, as there were no further complications in the tretment. 4. From the results reported here, the bioactive glass ceramic material here was found to be useful in the articial bone needed after atrophic mandibular alveolar ridge surgery.

We report an unusual case of an inflammatory pseudotumor of the bladder. A biopsy specimen prior to surgical treatment suggested leiomyosarcoma, and computerized tomography and magnetic resonance imaging strongly suggested bladder tumor with sigmoid colon invasion. Accordingly, radical surgical treatment consisting of total cystectomy, anterior resection of the sigmoid colon, and ileal conduit was performed. After operation, however, histological examination revealed an inflammatory pseudotumor of bladder and sigmoid colon. These findings were confirmed by immunohistochemical staining for smooth muscle specific actin, desmin, S-100, and vimentin. Histological examination revealed a diverticulum of the sigmoid colon in the middle of the pseudotumor, and this diverticulum may have ruptured to cause the inflammatory pseudotumor of bladder and sigmoid colon.

The main pathophysiology of torsion-detorsion is associated with ischemia-reperfusion injury in the testis caused by the twisted spermatic cord and its release. It is most likely mediated by oxygen free radicals. We investigated the effects of ischemic preconditioning and post-conditioning on rat testicular ischemia-reperfusion injury.Eight-week-old male Sprague-Dawley rats (SLC, Shizuoka, Japan) were randomly divided into 4 age matched groups, including 1-control sham operation, 2-60-minute ischemia/120-minute reperfusion, 3-3 cycles of 5-minute ischemia/5-minute reperfusion and then 60-minute ischemia/120-minute reperfusion (ischemic preconditioning) and 4-60-minute ischemia, 5 cycles of 10-second reperfusion/10-second ischemia and then 120-minute reperfusion (ischemic post-conditioning). After sacrifice the levels of malondialdehyde, 8-hydroxydeoxyguanosine, myeloperoxidase, superoxide dismutase, catalase, heat shock protein 70 protein and mRNA, and DNA fragmentation were measured in the rat testes. Testicular tissue was also histologically analyzed.The levels of malondialdehyde, 8-hydroxydeoxyguanosine, myeloperoxidase, heat shock protein 70 mRNA, superoxide dismutase, catalase, DNA fragmentation and apoptosis cells were significantly higher in the ischemia-reperfusion group than in controls. Ischemic preconditioning decreased histological parameters, including vacuolation and necrosis, and decreased malondialdehyde, 8-hydroxydeoxyguanosine, myeloperoxidase, heat shock protein 70 mRNA but not protein, superoxide dismutase, catalase, DNA fragmentation and apoptosis compared to the ischemia-reperfusion group. Ischemic post-conditioning ameliorated 8-hydroxydeoxyguanosine, superoxide dismutase, heat shock protein 70 mRNA, DNA fragmentation and apoptosis compared to the ischemia-reperfusion group.Our data indicate that ischemic preconditioning and post-conditioning ameliorated the testicular damage induced by ischemia-reperfusion injury.

The aim of this review study is to elucidate the effects that phosphodiesterase 5 (PDE5) inhibitors exert on spermatozoa motility, capacitation process and on their ability to fertilize the oocyte. Second messenger systems such as the cAMP/adenylate cyclase (AC) system and the cGMP/guanylate cyclase (GC) system appear to regulate sperm functions. Increased levels of intracytosolic cAMP result in an enhancement of sperm motility and viability. The stimulation of GC by low doses of nitric oxide (NO) leads to an improvement or maintenance of sperm motility, whereas higher concentrations have an adverse effect on sperm parameters. Several in vivo and in vitro studies have been carried out in order to examine whether PDE5 inhibitors affect positively or negatively sperm parameters and sperm fertilizing capacity. The results of these studies are controversial. Some of these studies demonstrate no significant effects of PDE5 inhibitors on the motility, viability, and morphology of spermatozoa collected from men that have been treated with PDE5 inhibitors. On the other hand, several studies demonstrate a positive effect of PDE5 inhibitors on sperm motility both in vivo and in vitro. In vitro studies of sildenafil citrate demonstrate a stimulatory effect on sperm motility with an increase in intracellular cAMP suggesting an inhibitory action of sildenafil citrate on a PDE isoform other than the PDE5. On the other hand, tadalafil's actions appear to be associated with the inhibitory effect of this compound on PDE11. In vivo studies in men treated with vardenafil in a daily basis demonstrated a significantly larger total number of spermatozoa per ejaculate, quantitative sperm motility, and qualitative sperm motility; it has been suggested that vardenafil administration enhances the secretory function of the prostate and subsequently increases the qualitative and quantitative motility of spermatozoa. The effect that PDE5 inhibitors exert on sperm parameters may lead to the improvement of the outcome of assisted reproductive technology (ART) programs. In the future PDE5 inhibitors might serve as adjunct therapeutical agents for the alleviation of male infertility.

Patients with ovarian clear cell adenocarcinoma (OCCA) show a poor response to conventional platinum-based chemotherapy. Recently, it was reported that combination chemotherapy with cisplatin plus irinotecan hydrochloride (P-CPT) achieves high response rates for primary advanced and recurrent or resistant OCCA. We retrospectively reviewed the outcome of 20 OCCA patients treated with P-CPT by the Gynecology Service at The Jikei University Hospital after initial surgery. These patients received a total of 101 cycles of P-CPT, with a median of 5 cycles each. Two complete responses (CRs) were obtained in the three patients with measurable disease, and response duration was 7 and 15 months, respectively. One patient had stable disease (SD), and the time to progression was 5 months. The estimated 3- and 5-year survival rates were 69% and 69%, respectively. Our current data and previous reports suggest that P-CPT is a candidate first-line chemotherapy regimen for OCCA.

In the present study, we evaluated the effect of neutrophil elastase inhibitor, sivelestat sodium hydrate on ischemia-reperfusion injury in the rat bladder. Rat abdominal aorta was clamping with a small clip to induce ischemia-reperfusion injury in the bladder. Eight-week-old male Sprague Dawley rats were divided into four groups; sham-operated control rats, 30 min ischemia-60 min reperfusion (IR) rats, and IR rats treated with 15 or 60 mg/kg of sivelestat sodium hydrate. Sixty minutes prior to induction of ischemia, sivelestat sodium hydrate was administrated intraperitoneally. Real-time monitoring of blood flow and nitric oxide (NO) release were measured simultaneously with a laser Doppler flowmeter and an NO-selective electrode, respectively. The NO2-NO3 and malonaldehyde (MDA) concentrations were measured in the experimental urinary bladders. Clamping of the abdominal aorta, blood flow was rapidly decreased and NO release was gradually increased. After removing the clip, blood flow was rapidly increased and NO release was gradually returned to the basal level. These movements of blood flow and NO release were inhibited by treatment with sivelestat sodium hydrate in a dose-dependent manner. Both NO2-NO3 and MDA concentrations in the bladder were increased by induction of IR, and NO2-NO3 and MDA concentrations were decreased by treatment with high dose of sivelestat sodium hydrate significantly. Our data indicated that sivelestat sodium hydrate could inhibit increasing NO2-NO3 and MDA concentrations by IR, and it has potentiality protective effects on IR injury in the rat urinary bladder.

Pregnancies achieved by assisted reproduction technologies and particularly by ooplasmic injections of either in vivo or in vitro generated immature male germ cells are susceptible to genetic risks inherent to the male population treated with assisted reproduction and additional risks inherent to these innovative procedures. The documented, as well as the theoretical risks, are discussed in this review. These risks represent mainly the consequences of genetic abnormalities underlying male infertility and may become stimulators for the development of novel approaches and applications in the treatment of infertility. Recent data suggest that techniques employed for in vitro spermatogenesis, male somatic cell haploidization, stem cell differentiation in vitro and assisted reproductive technology may also affect the epigenetic characteristics of the male gamete, the female gamete, or may have an impact on early embryogenesis. They may be also associated with an increased risk for genomic imprinting abnormalities. Production of haploid male gametes in vitro may not allow the male gamete to undergo all the genetic and epigenetic alterations that the male gamete normally undergoes during in vivo spermatogenesis. Andrologia

We previously reported that indoleamine-2,3-dioxygenase (IDO) is associated with paclitaxel resistance and that IDO serves as a marker of poor prognosis in ovarian serous adenocarcinomas (SA). In this study, to explore the role of IDO in the development of various histological types of ovarian cancer, we further examined IDO expression not only in SA but also in other types of ovarian cancers. Expression of IDO protein was analyzed by immunohistochemistry for a total of 122 ovarian cancers including 40 SA, 67 clear cell adenocarcinomas (CCA), and 15 endometrioid adenocarcinomas (EA) with informed consent. Among these cases, there were 11 CCA accompanied with endometriosis and 60 cases with lymph node metastasis. We classified the samples into four categories by IDO staining pattern. IDO staining was positive in 57.5% of SA, 49.2% of CCA, and 73.3% of EA, respectively. The Kaplan-Meier survival curve showed a clear relationship between staining score and overall survival for patients with advanced (stages III and IV) SA (n=33) who underwent optimal surgery and paclitaxel-carboplatin (TC) chemotherapy as a first-line regimen. There was no association between IDO staining score and overall survival in the CCA cases. Eight of 11 cases (72.7%) of CCA accompanied by endometriosis presented identical staining patterns of IDO between CCA and endometriosis. In 43 of 60 cases (71.6%) with lymph node metastasis, the staining patterns of IDO showed a correspondence between the primary lesion and metastatic site. These results suggested that the increased synthesis of IDO protein was positively associated with impaired survival only in the serous type of ovarian cancer.

Objective We have previously reported that intravesical oxybutynin chloride with hydroxypropylcellulose (modified intravesical oxybutynin) is an effective therapeutic agent for patients with detrusor overactivity. In this study, we report on the efficacy, safety and side effects of modified intravesical oxybutynin administration in children with neurogenic bladder. Patients Modified intravesical oxybutynin (1.25 mg/5 mL, twice a day) was administered to four children (three males and one female) with neurogenic bladder (detrusor overactivity and/or low compliance bladder), who were previously unresponsive to or experienced intolerable side effects from oral medications. A cystometrogram was obtained before, 1 week after, and 1 year after the first intravesical instillation of modified oxybutynin. We also carefully observed anticholinergic side effects, occurrence of urinary tract infection and degree of incontinence during this treatment. Results After 1 week, both cystometric bladder capacity and compliance were improved in all patients, and detrusor overactivity was undetectable in three of four patients. At 1 year, there was further improvement in bladder compliance in three patients, and detrusor overactivity was not observed in two patients. Significant improvement in the degree of incontinence was achieved. No systemic anticholinergic side effects were observed in any of the patients. One patient with vesicoureteral reflux discontinued the therapy after 2 months due to upper urinary tract infections. Conclusion Modified intravesical oxybutynin is an effective and relatively safe therapeutic option for children with neurogenic bladders.

We investigated the effect of preconditioning on ischemia-reperfusion injury in the rat bladder. Rat abdominal aorta was clamped with a small clip to induce ischemia-reperfusion injury in the bladder. Twelve-week-old male SD rats were divided into three groups; sham-operated control (Cont), 30 min ischemia-60 min reperfusion (IR) and three times of 5 min ischemia and then 30 min ischemia-60 min reperfusion (PC) groups. The bladder functions were estimated by cystometric and functional studies. Contractile response curves to increasing concentrations of carbachol were constructed in the absence and presence of various concentrations of subtype selective muscarinic antagonists, i.e. atropine (non-selective), pirenzepine (M1 selective), methoctramine (M2 selective), and 4-DAMP (M1/M3 selective). We also measured tissue levels of malonaldehyde (MDA) and examined possible histological changes in these rats' bladders. Preconditioning partially prevented the reduction of bladder dysfunction induced by ischemia-reperfusion. Estimation of the pA2 values for atropine, pirenzepine, methoctramine, and 4-DAMP indicates that the carbachol-induced contractile response in bladder dome is mediated through the M3 receptor subtype in all groups. The MDA concentration in the IR group was significantly larger than that of the control group, and preconditioning significantly reduced MDA production in the bladder. In histological studies, the ischemia-reperfusion with or without preconditioning caused infiltration of leukocytes and rupture of microcirculation in the regions of submucosa and smooth muscle without a corresponding sloughing of mucosal cells. Our data indicate that preconditioning has a beneficial effect on ischemia-reperfusion injury in the rat bladder.

In this study, we investigated the preventive effect of n-hexacosanol on diabetes-induced bladder dysfunction in the rat. Diabetes was induced in 8-week-old male Sprague–Dawley rats by administering an injection of streptozotocin (50 mg/kg, i.p.). The rats were randomly divided into 4 groups (age-matched control rats, diabetic rats without treatment with n-hexacosanol, and diabetic rats treated with n-hexacosanol (2 and 8 mg/kg, i.p. every day)) and maintained for 4 weeks. The serum glucose and serum insulin levels were determined, and the functions of bladder were estimated by voiding behavior, cystometric, and functional studies to carbachol and KCl. Furthermore, we examined possible diabetic induced histological changes in these rats. Treatment with n-hexacosanol did not alter diabetic status including body mass, bladder mass, and serum glucose and serum insulin levels, but significantly improved the maximum contraction pressure of the detrusor and residual urine volume in cystometric studies and Emax values to carbachol in functional studies in a dose-dependent manner. Diabetes induced bladder smooth muscle hypertrophy, which tended to be ameliorated by treatment with n-hexacosanol in a dose-dependent manner. Treatment with n-hexacosanol did not alter the diabetic status, but significantly improved diabetic cystopathy in a dose-dependent manner.

Objectives We investigated the ability of 3-(15 hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen 1-one (N-hexacosanol), a neurotrophic substance, to reverse diabetes-induced cystopathy in the rat. Materials and methods Eight-week-old male Sprague-Dawley rats were divided randomly into four age-matched groups. In three of these groups, diabetes was induced by streptozotocin (STZ; 50mg/kg intraperitoneal [IP]). Four weeks after the induction of diabetes, the three groups received another 4 weeks of treatment by vehicle or N-hexacosanol (2 or 8mg/kg IP every day). The serum glucose and serum insulin levels were determined, and the bladder functions were estimated by voiding behavior studies, cystometric studies, and functional studies using carbachol and KCl. The participation levels of M 2 and M 3 receptors were investigated by real-time polymerase chain reaction and immunohistochemical staining. Typical hematoxylin-eosin staining was also performed. Results Treatment with N-hexacosanol did not alter the rats' diabetic status, but did significantly improve the diabetes-induced dysfunction of the detrusor in a dose-dependent manner. Furthermore, N-hexacosanol significantly reversed the upregulation of muscarinic M 2 and M 3 receptor messenger RNAs (mRNAs) in STZ-diabetic rats. Muscarinic M 2 and M 3 receptors were localized in detrusor and urothelium, and there was no difference between any of the groups in the distribution of muscarinic M 2 and M 3 receptors. Conclusions These results indicate that N-hexacosanol has a beneficial effect on hyperreactivity in the diabetic detrusor by ameliorating overexpression of muscarinic M 2 and M 3 receptor mRNAs.

Two cases of intractable overactive bladder which were treated by intradetrusor botulinum-A toxin (BTX-A) are presented. Case 1: A 53-year-old woman suffered from adhesive arachinoiditis. She had severe detrusor hyperreflexia and urge urinary incontinence despite a high dose of anticholinergic medication. Under cystoscopic control, a total of 300 units of BTX-A were injected into the detrusor muscle at 30 sites (10 units per ml per site), sparing the trigone area using a 27G flexible injection needle. This procedure was done under both caudal anesthesia with 10 ml 1% lidocaine and bladder mucosa anesthesia by instilling 40 ml 2% lidocaine. At a 12-week followup she was completely continent. Case 2: A 63-year-old man with intractable detrusor overactivity of idiopathic origin was treated using the above technique. Urge urinary incontinence decreased 4 weeks after the BTX-A injections. However, postvoid residual urine volume was increased, and intermittent self-catheterization was needed. Intradetrusor BTX-A dramatically increases the bladder capacity and decreases the frequency of urge urinary incontinence. However, this treatment caused urinary retention in Case 2. We believe that the dosage amount of BTX-A should be changed case by case.

Few nonpuerperal uterine inversions have been reported, with only 101 cases during the period from 1940 to date. Moreover, uterine inversion resulting from endometrial cancer is an extremely rare condition, with only 7 reported cases. In this article, we present a case of a patient with uterine inversion caused by endometrial cancer that could be diagnosed and treated with surgery. We also discuss the mechanism of onset and present a review of the literature.

In order to investigate the diabetes-associated neuropathy and prevent effects of cyclohexenonic long-chain fatty alcohol, a neurotrophic substance, in trachea, we studied its effect on streptozotocin-diabetic hyper-reactivity in the rat trachea. Diabetes was induced in 8-week-old male Sprague-Dawley rats by administering an intraperitoneal injection of streptozotocin (50 mg/kg). The rats were divided randomly into four groups and were maintained for four weeks: age-matched control rats, diabetic rats without treatment with cyclohexenonic long-chain fatty alcohol, and diabetic rats treated with cyclohexenonic long-chain fatty alcohol (2 and 8 mg/kg, i.p. every day). The serum glucose and insulin levels were determined, and the contractile responses of the trachea induced by carbachol and KCl were investigated. Treatment with cyclohexenonic long-chain fatty alcohol did not alter the rats' diabetic status, i.e., body weight, thickness of the trachea, serum glucose levels, and serum insulin levels, but significantly improved the diabetic-induced hyper-reactivity of the rat trachea in a dose-dependent manner. There was no significant difference in either the carbachol- or KCl-induced contractile forces between groups with or without mucosa in the functional studies. In histological examinations, thinning of cricoid cartilage, thickness of basal membrane, and degeneration, fragmentation of elastic fibers in the submucosal layer, and hypertrophy of smooth muscle bundle in the membranous wall of trachea were observed in the diabetic rat trachea, which were improved by treatment with cyclohexenonic long-chain fatty alcohol. Our data indicate that this drug can prevent hyper-reactivity in the diabetic trachea.

We attempted to clarify the preventive effects of cyclohexenonic long-chain fatty alcohol on detrusor overactivity induced by mild bladder neck obstruction. Bladder neck obstruction was created by partial ligation of the urethra. Female Sprague-Dawley rats were divided into three groups: those with bladder neck obstruction treated without long-chain fatty alcohol, those with bladder neck obstruction with long-chain fatty alcohol (8 mg/kg, i.p., every day) and the sham-operated control group (A, B, and C groups, respectively). Six weeks after the induction of bladder neck obstruction, voiding behavior was observed in the metabolic cage, and a cystometrogram was performed in the experimental animals. Furthermore, Hematoxylin and Eosin, Azan-Mallory, and Bodian stainings were performed in these bladders. Bladder weight, voiding behaviors and a cystometry indicated that rats in the A group showed detrusor overactivity, which was improved by treatment with long-chain fatty alcohol. The proportion of connective tissue and the density of bundles of neurofibers in the bladder of the A group was significantly less than that in the other bladders. Mild bladder neck obstruction induces detrusor overactivity, which is improved by treatment with long-chain fatty alcohol.

We investigated the expression of heat shock protein (HSP) 70 and its mRNAs during ischemia–reperfusion in the rat prostate. Eight-week-old rats were divided into six groups: a control group, a 30-min ischemia group, and 30-min ischemia+30-min, 60-min, 1-day, and 1-week reperfusion groups (groups A, B, C, D, E, and F, respectively). In vivo real-time blood flow and HSP 70-1 and 70-2 mRNAs and proteins in the prostate were measured using laser Doppler flow meter, real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) methods, respectively. Clamping of the aorta decreased blood flow to 10% of the basal level. The expressions of HSP 70-1/2 mRNAs increased in groups B, C, and D, and decreased in groups E and F. The expression of HSP 70 proteins was increased after a short interval of increase in their mRNAs. Our data indicated that the expressions of HSP 70 proteins and their mRNAs are dramatically changed during ischemia–reperfusion in the rat prostate.

An interactive four-dimensional (4D) visualizing system for the heart was developed by the authors. The system realizes high-resolution three-dimensional (3D) imaging with temporal resolution in a beating heart by using eight or more data sets reconstructed from multi-detector row computed tomography (MDCT) with a retrospective electrocardiograph-gated reconstruction algorithm. The motion of heart walls, papillary muscles, septa, and valves can now be observed in 4D multiplanar reformations (MPRs), as with sonography, while coronary arteries, coronary sinuses, and cardiac veins can be analyzed during the optimal phase in 4D volume-rendering images, as with angiography. All parameters such as window width, window level, field of view, panning, tilt, thresholds, opacity, color, and segmentation function are completely interactive in 4D imaging. Two longitudinal views and one latitudinal view of a heart can be simultaneously visualized in the three relative 4D MPR views. These newly developed capabilities in viewing both 3D volume and temporal resolution data, functional data, and even multiphase data with registration add considerable diagnostic potential. The advent of this real-time 4D visualizing system has enhanced the capabilities of MDCT.

Aims. To evaluated the effects of NG-nitro-L-arginine methylester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on apoptosis induced by ischemia-reperfusion injury in the rat through a muscle bath and TUNEL staining. Methods. The rat abdominal aorta was clamped to induce ischemia-reperfusion (I-R) injury in the rat bladder dome with or without L-NAME (30 mg/kg, i.p. 30 minutes before the ischemia) according to our previous reports [Saito et al., 1998 Life Sci. 62:PL149–56; Saito and Miyagawa, 1999 J. Urol. 162:1490–5]. Some rats were exposed to 30 minutes of ischemia only, whereas others also received 30 minutes, 3 days, or 7 days of reperfusion after the ischemia. Muscle bath studies with carbachol and 100 mM KCl were performed to confirm the bladder function. TUNEL and hematoxylin and eosin staining were performed in the experimental rat bladders to detect apoptosis. Results. The contractile responses of the rat bladder dome after 30 minutes of ischemia differed slightly, not significantly, from those of controls. Reperfusion (30 minutes) produced significant reductions in the contractile responses to carbachol and KCl in the rat bladders. The treatment with L-NAME significantly reduced the extent of reperfusion injury, as judged by pharmacologic experiments. At 3 and 7 days after the induction of ischemia-reperfusion, the contractile responses were improved compared with the 30-minute reperfusion group. For each duration group, treatment with L-NAME significantly increased the contractile responses compared with the I-R group without L-NAME. Ischemia-reperfusion induced apoptosis, and the peak in TUNEL-positive cells was observed 3 days after the insult. Preteatment with L-NAME reduced the induction of apoptosis. Conclusion. Our data indicated treatment with L-NAME can reduce apoptosis induced by ischemia-reperfusion in the bladder. Neurourol. Urodynam. 21:566–571, 2002. © 2002 Wiley-Liss, Inc.

Intravesical oxybutynin chloride has been reported to be effective for overactive bladder, although sometimes the efficacy does not last long enough. To improve this deficiency, we report the effects of intravesical oxybutynin chloride with hydroxypropylcellulose (modified intravesical oxybutynin). Modified intravesical oxybutynin (5 mg/10 mL, twice a day) was administered to six overactive bladder patients for more than 1 year (two men and four women; average age, 56.5 years) who did not respond to oral anticholinergic agents and electric stimulation. Cystometography (CMG) was performed before, 2 hours, and 1 week after the start of modified intravesical oxybutynin. In addition, plasma levels of oxybutynin and its active metabolite, N-desethyl-oxybutynin (DEOB), were measured by high-performance liquid chromatography before, 1, 2, and 4 hours after the initial treatment of modified intravesical oxybutynin. CMG studies revealed that two of the six patients did not demonstrate uninhibited contractions 1 week after the treatment and that cystocapacity of before, 2 hours, and 1 week after the initial modified intravesical oxybutynin was 141.8 ± 15.3, 210.0 ± 35.5, and 305.0 ± 21.3 mL, respectively. Plasma levels of oxybutynin and DEOB before, 1, 2, and 4 hours after the first instillation of modified intravesical oxybutynin were oxybutynin; not detected, 8.8 ± 2.5, 6.8 ± 1.1, 3.0 ± 1.0 ng/ml, and DEOB; not detected, 4.2 ± 1.3, 6.4 ± 1.7, 5.1 ± 1.4 ng/ml, respectively. No side effects were observed in any of the patients. Modified intravesical oxybutynin is an effective and safe therapy option for overactive bladder patients who do not respond to other treatments such as oral anticholinergic agents and electric stimulation. Neurourol. Urodynam. 19:683–688, 2000. © 2000 Wiley-Liss Inc.

We attempted to investigate the role of nitric oxide (NO) in ischemia-reperfusion injury in the rat bladder.Rat abdominal aorta were clamped with a small clip to induce ischemia-reperfusion injury in the rat bladder dome. To investigate the role of NO in ischemia-reperfusion injury, N(G)-nitro-L-arginine methylester (L-NAME, 30 mg./kg.) was injected intraperitoneally to measure carbachol-induced contractions of 60 minutes ischemia-30 minutes reperfusion in the rat bladder dome. In vivo real-time blood flow and NO release were measured in the rat bladder with a laser Doppler flowmeter and an NO-selective electrode, respectively. Moreover, participation of NO synthase subtypes was investigated by immunohistochemical staining of bladder sections with anti-endothelial I and anti-inducible NO synthase subtype antibodies.Treatment with L-NAME (30 mg./kg., i.p.) partially prevented the reduction of bladder strips in contraction induced by the ischemia-reperfusion. Clamping of the aorta decreased blood flow to 10% of the basal level measured before the clamping. Administration of L-NAME reduced the blood flow to the bladder by 65% compared to the control level during ischemia-reperfusion. Real-time monitoring of NO in the bladder revealed that ischemia increased NO release, which, in turn, reached a plateau 30-40 minutes after the induction of ischemia. Immediately after the reperfusion, NO release returned to the basal level. In the control rat bladder, the endothelial subtype (eNOS) was observed in the mucosa. After the ischemia-reperfusion, iNOS was detected in the infiltrated neutrophils in the muscular and submucosal regions.Our data indicate that NO from leukocytes may participate in cell/tissue injury during ischemia-reperfusion of the rat bladder and that the damage may be preventable by treatment with L-NAME.

Background: The present investigation was undertaken to examine the effect of insulin treatment on diabetes-induced alterations in endothelin (ET) receptors in rat ureters. Methods: The biochemical properties of ET receptors were examined in rat ureters from the following groups: 8 weeks diabetic (D8); 8 weeks age-matched control (C8); 16 weeks diabetic (D16); 16 weeks diabetic-insulin treated (insulin started 8 weeks after the onset of diabetes) (DI16); and 16 weeks age-matched control (C16). Diabetes was induced by the i.v. injection of 65 mg/kg streptozotocin (STZ). Results: The densities of ET receptors (Bmax values), as determined by saturation experiments with [125I]-ET-1, in the ureteral plasma membranes of D8, C8, D16, DI16 and C16 were 91.7 ± 10.1, 42.1 ± 7.2, 71.1 ± 2.4, 51.5 ± 6.3 and 45.1 ± 3.3 fmol/mg of protein, respectively. [125I]-ET-1 binding to the ET receptors in rat ureteral membrane particulates was inhibited by ET-1 (non-selective), ET-3 (ETB/C selective), BQ 610 (ETA selective) and IRL 1620 (ETB selective) with the following rank order of Ki values: ET-1 < BQ 610 < ET-3 < < IRL 1620. The pharmacological profile of the ET receptors was similar in all groups examined and was consistent with the predominance of the ETA receptor subtype in the ureteral membrane particulates. The subtype specificity of ET receptors in the ureteral tissues is confirmed with inhibition data obtained from similar binding studies in cloned human ETA and ETB receptors. Conclusion: The data indicate that diabetes results in an up-regulation of ET receptors in the rat ureter, which is normalized by insulin treatment.

We report 2 cases of micturitional disturbances due to labial adhesion. Two women, aged 78 and 77 years old, visited our hospital with chief complaints of difficult voiding and urinary retention. On examination, their labias were found to be extensively fused. In both cases, the labial adhesions were separated by surgical repair under spinal anesthesia. Gentamicin and steroid ointments were used to prevent readhesion of the labia postoperatively.

The subtype specificity, localization and distribution of urethral alpha1-adrenoceptors were studied in the male rabbit urethra.The properties of the urethral alpha1-adrenoceptors were investigated using radioligand receptor binding and light microscopic autoradiography with [125I]iodo-2-[b-(4-hydroxyphenyl)-ethylaminomethyl]tetralone (HEAT), and immunohistochemistry with monoclonal anti-alpha smooth muscle actin and anti-alpha sarcomeric actin antibodies.Saturation experiments with [125I]HEAT demonstrated the presence of significant amounts of a single high affinity binding site for alpha1 adrenoceptors in the male rabbit urethra. The pharmacological profile of the alpha1 adrenoceptors in rabbit urethra, determined by inhibition experiments with subtype selective alpha1 adrenoceptor antagonists, was characterized by the following rank order of potency of inhibition constants (Ki values): prazosinor = WB 4101spiperone5-methylurapidilBMY 7378. The pKi values for the rabbit urethra were correlated with the pKi values for rat spleen, submaxillary glands, and vas deferens and for those reported for cloned alpha1d receptors with correlation coefficients of 0.68, 0.929, 0.909, and 0.523, respectively.The pharmacological characterization demonstrates the predominance of alpha1A or alpha1A + alpha1B adrenoceptor subtype(s) in male rabbit urethral smooth muscle. Furthermore, the autoradiographic and immunohistochemical studies show a heterogeneous distribution of alpha1 adrenoceptors along the longitudinal axis of the urethra, within the smooth muscle fibers, with the receptors being localized more densely in the proximal than in the distal urethra.

Because there are increasing evidences that nitric oxide (NO) plays important roles in ischemia-reperfusion injury in several systems, we investigated the role of NO in ischemia-reperfusion injury of the rat urinary bladder. Rat abdominal aorta was clamped with a small clip to induce ischemia-reperfusion injury in the rat bladder dome. In functional studies, contractile responses to carbachol were cumulatively measured after the urinary bladder was treated with various duration (0, 30, 60, and 90 min) of ischemia. The injury of rat bladder functioning was dependent on ischemic periods. Significant decreases in the Emax (maximum contractile response) values were observed in the bladder subjected to 60 or 90 min ischemia. Furthermore, the subsequent 30 min reperfusion caused additional damages of the contractile response in bladder muscles. To investigate the role of NO in the ischemia (30 min)-reperfusion (30 min) injury, NG-nitro-L-arginine methylester (L-NAME) was injected intraperitoneally 30 min before the ischemia. Treatment of L-NAME (30 and 100 mg/kg) partly but significantly prevented the reduction contractile responses to carbachol of the rat bladder dome. In histological studies, the ischemia-reperfusion caused infiltration of leukocytes and rupture of microcirculation in the regions of submucosa and smooth muscle without a corresponding sloughing of mucosal cells. The histological damages were also prevented by treatment with L-NAME. Therefore, these data suggested that ischemia-reperfusion of the urinary bladder may result in dysfunction of the contractile response to autonomic nervous system and that nitric oxide may act as a cell/tissue damaging agent in ischemia-reperfusion injury.

We investigated the binding characteristics of endothelin (ET) receptors in the ureters of rats with experimentally induced diabetes and diuresis. Receptor binding experiments demonstrated an upregulation in the expression of [125I]ET-1 binding sites in the diabetic rat ureter but not in the diuretic rat ureter. ET-1, ET-3, IRL 1620, and BQ 610 inhibited [125I]ET-binding to the rat ureter consistent with the predominance of ETA receptors in these tissues. The subtype specificity of ET receptors in ureteral tissues was confirmed with inhibition data obtained from cloned human ETA and ETB receptors.

Objective To investigate the effect of intrathecal galanin on the micturition reflex in rats. Methods Continuous cystometrograms (0.04 mL/min infusion rate) were performed in female Sprague-Dawley rats (225-248 g) under urethane anesthesia. After stable micturition cycles were established, galanin was administered intrathecally to evaluate changes in bladder activity. Then, to examine the involvement of opioid systems in the galanin effects, galanin was administered intrathecally when the first bladder contraction was observed after intrathecal administration of naloxone, an opioid receptor antagonist. Results Intrathecal administration of galanin (1-10 μg) increased intercontraction intervals in a dose-dependent fashion. Intrathecal administration of galanin (1-10 μg) also increased pressure threshold in a dose-dependent fashion. These inhibitory effects of galanin (10 μg) were partially antagonized by intrathecal administration of naloxone (10 μg). Conclusion These results indicate that in urethane-anesthetized rats, galanin delays the onset of micturition through activation of the opioid mechanism, suggesting the inhibitory role of galanin system in the control of the micturition reflex.

We studied the properties of endothelin receptors in the prostate of 8-week streptozotocin-diabetic and control rats. The density of endothelin receptors, as determined by saturation experiments with [ 125 I]endothelin-1, were 95.8 ± 5.4 and 171.3 ± 16.7 fmol/mg of protein in control and diabetic rat prostates, respectively. The pharmacological profile of the endothelin receptors was similar in both groups and was consistent with the predominance of the endothelin ET A receptor subtype in the prostate. Thus, the induction of diabetes upregulates the expression of endothelin receptors in the rat prostate, but does not alter the pharmacological profile of the receptors in these tissues.

Objective TP is the standard regimen for advanced or recurrent cervical cancer. However, JCOG0505 presented statistically significant non-inferiority of TC to TP in terms of overall survival (OS), for stage IVB or recurrent cervical cancer in ASCO ‘12 annual meeting. By subset analyses of JCOG0505, we investigated whether the treatment effect of TP or TC is different among some specific subgroups including the one by prior platinum status. Methods Patients (Pts) with stage IVB or recurrent cervical cancer; not amenable to curative therapy; 0-1 prior platinum; no prior taxanes; were randomized with minimization method to either TP (T 135 mg/m2 24h d1 + P 50 mg/m2 2h d2) or TC (T 175 mg/m2 3h d1 + C AUC5 1h d1), both for maximum 6 cycles every 21 days. We estimated the hazard ratios and 95% confidence intervals in OS among subgroups (including prior platinum status) for the eligible patients, comparing TC and TP. Each hazard ratio (HR) was estimated by an unstratified Cox regression. Results Total 253 pts were enrolled. Median follow-up of all randomized patients is 17.4 months (mo). As was reported before, it was demonstrated that TC was not inferior to TP for OS (17.5 mo in TC and 18.3 mo in TP, HR 0.99 (non-inferiorityp = 0.032 with a non-inferiority margin 1.29)). Both arms were comparable with respect to toxicity except for grade 4 neutropenia (45% in TC vs. 75% in TP). In a subset analysis (n = 244), TP was superior to TC for OS in non-prior platinum group (n = 117) (13.0 mo in TC and 23.2 mo in TP, HR 1.57 (95% CI:1.06-2.32)). Contrary, TC tended to show better survival than TP for OS in prior platinum group (n = 127) (19.0 mo in TC and 16.3 mo in TP, HR 0.69 (95% CI:0.47-1.02)). Furthermore, TP tended to be superior to TC for OS in stage IVB (n = 51) (14.8 mo in TC and 25.4 mo in TP, HR 1.50 (95% CI:0.84-2.67)). Conclusion Non-inferiority of TC to TP was demonstrated in the whole population of JCOG0505. By the subset analyses, however, TP may be still the first choice for patients without prior cisplatin-based treatment such as those with primary stage IVB cervical cancer. Disclosure All authors have declared no conflicts of interest.

Objective To investigate the effect of hydroxyfasudil, a nonselective Rho-kinase inhibitor, on hypertension-related bladder dysfunction in spontaneously hypertensive rats (SHRs), as there is an increasing evidence that the Rho-associated protein kinase (ROCK) system plays an important role in bladder contraction. Methods Twelve-week-old male SHRs were treated with hydroxyfasudil (1 mg/kg i.p.) once a day for 6 weeks. Wistar rats and SHRs without treatment with hydroxyfasudil were used as controls. Six weeks after the hydroxyfasudil treatment, voiding functions were evaluated by metabolic cages and cystometric studies under urethane anesthesia (1.0 g/kg i.p.). Bladder blood flow (BBF) was estimated by the hydrogen clearance method. The bladder tissue levels of nerve growth factor (NGF) and ROCK activity were evaluated by the ELISA method. Results The SHR showed significant increases in micturition frequency and decreases in single-voided volume in metabolic cages, and significantly increases in micturition frequency and intercontractile interval in cystometric studies. Furthermore, the SHR showed significant increases in the BBF and bladder NGF concentration compared with the Wistar rats. These alterations in the SHR were significantly ameliorated after treatment with hydroxyfasudil, with small changes in blood pressure. However, the maximum detrusor pressures during voiding and the ROCK activities in the experimental bladders were similar in all rats examined. Conclusion Our data indicate that this dose of hydroxyfasudil was effective on the BBF, whereas it had no significant effect on micturition pressure. These findings suggest that hydroxyfasudil could ameliorate hypertension-related bladder dysfunction in the SHR via improvement of the BBF (248 words).

An 85-year-old Japanese man presented with abdominal discomfort and general fatigue. History included (stage A1) prostate cancer, G1T1a transitional cell carcinoma of the bladder for 4 years and ulcerative colitis, which had been treated with 4.5 gm. sulfasalazine daily for 14 years. Laboratory examination showed renal failure (serum blood urea nitrogen was 26 mg./dl. and creatinine was 1.71 mg./dl.). Ultrasonography, computerized tomography and x-ray revealed bilateral hydronephrosis, right multiple renal stones, a ureteropelvic junction stone and a left ureterovesical junction stone (see figure). The left ureteral stone was spontaneously discharged 5 days after the initial consult. The patient underwent 4 sessions of shock wave lithotripsy and percutaneous nephrolithotomy to remove stones in the right renal pelvis and ureteropelvic junction, after ureteral stenting. After stenting, renal function returned to normal (blood urea nitrogen 10 mg./dl. and serum creatinine 0.89 mg./dl.). Stone analysis revealed acetylsulfapyridine, which is a metabolite of sulfasalazine. After the final diagnosis, sulfasalazine was replaced with mesalamine (5-aminosalicylic acid) to treat the ulcerative colitis, and at 6-month followup no recurrence of stone disease was observed.

A novel anthracycline antibiotic, cinerubin R, was isolated from the fermentation broth of Streptomyces eurythermus strain H1715MY2. The structure of cinerubin R was elucidated to be 4"-aculosyl-4'-rhodinosyl-7-rhodosaminyl-epsilon-py rromycinone. Cinerubin R was active against Gram-positive bacteria and inhibited the growth of divergent multi-drug-resistant cells to the same extent as their parental cells.

Purpose: We describe a simple technique to replace an obstructed ureteral stent in patients with an ileal conduit and ureteral stenosis.Materials and Methods: Our study included 4 patients with an ileal conduit and ureteral stenosis. A total of 10 obstructed ureteral stents were replaced with a new stent using this simple technique under radiographic guidance.Results: All obstructed ureteral stents were successfully replaced with a new stent without endoscopy, percutaneous nephrostomy or any special devices.Conclusions: Our technique is simple, easy and highly successful for changing an obstructed ureteral stent.