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Because ultrahigh-molecular-weight polyethylene (UHMWPE) is susceptible to frictional wear when used in sliding members of artificial joints, it is common practice to use cross-linked UHMWPE instead. However, cross-linked UHMWPE has low impact resistance; implant breakage has been reported in some cases. Hence, sliding members of artificial joints pose a major trade-off between wear resistance and impact resistance, which has not been resolved by any UHMWPE. On the other hand, multiwall carbon nanotubes (MWCNTs) are used in industrial products for reinforcement of polymeric materials but not used as biomaterials because of their unclear safety. In the present study, we attempted to solve this trade-off issue by complexing UHMWPE with MWCNTs. In addition, we assessed the safety of these composites for use in sliding members of artificial joints. The results showed the equivalence of MWCNT/UHMWPE composites to cross-linked UHMWPE in terms of wear resistance and to non-cross-linked UHMWPE in terms of impact resistance. In addition, all MWCNT/UHMWPE composites examined complied with the requirements of biosafety testing in accordance with the ISO10993-series specifications for implantable medical devices. Furthermore, because MWCNTs can occur alone in wear dust, MWCNTs in an amount of about 1.5 times that contained in the dust produced from 50 years of wear (in the worst case) were injected into rat knees, which were monitored for 26 weeks. Although mild inflammatory reactions occurred in the joints, the reactions soon became quiescent. In addition, the MWCNTs did not migrate to other organs. Furthermore, MWCNTs did not exhibit carcinogenicity when injected into the knees of mice genetically modified to spontaneously develop cancer. The MWCNT/UHMWPE composite is a new biomaterial expected to be safe for clinical applications in both total hip arthroplasty and total knee arthroplasty as the first sliding member of artificial joints to have both high wear resistance and high impact resistance.

Background: Frailty is a prognostic factor in patients with atrial fibrillation (AF). However, there is no report on the associations between frailty and clinical adverse events in patients with AF taking direct oral anticoagulants (DOAC). The factors related to the occurrence of clinical adverse events are still under discussion. Therefore, we examined the associations between frailty and clinical adverse events in patients with AF taking DOAC in daily clinical practice., Methods: We retrospectively evaluated 240 consecutive patients with AF who had been newly prescribed DOAC in our hospital from April 2016 through May 2017. Data collected included Clinical Frailty Scale (CFS) scores, laboratory results and basic demographic information., Results: During the mean follow-up period of 13.4 months, 20 patients died (7.6 per 100 person-years), stroke or systemic embolism occurred in seven patients (2.6 per 100 person-years) and major bleeding occurred in 11 patients (4.2 per 100 person-years). We defined these adverse events as composite end points, and we estimated adjusted HRs and 95% CIs for risk factors using the Cox proportional hazard regression model. Frailty (defined as a CFS score of 5 or more; HR: 3.71; 95% CI: 1.59 to 8.65), female sex (HR: 3.49; 95% CI: 1.73 to 7.07), serum albumin level (HR: 0.47; 95% CI: 0.28 to 0.79) and malignancy (HR: 4.02; 95% CI: 1.83 to 8.84) were independent predictors of the composite end points., Conclusions: Frailty, female sex, hypoalbuminaemia and malignancy were associated with clinical adverse events in patients with AF who were prescribed DOAC., Competing Interests: Competing interests: None declared.

(Purpose) This study is to evaluate the efficacy and safety of sequential therapy with two novel drugs, abiraterone and enzalutamide after docetaxel (DOC) therapy for castration-resistant prostate cancer (CRPC). (Material and methods) Twenty-one patients were identified received sequential therapy with abiraterone and enzalutamide after DOC therapy at our institution. We investigated PSA response (decrease of 50% or more) to prior administered drug as primary endpoint, and overall survival rate and occurrence of adverse events as secondary endpoint. (Results) There were 12 patients in the group preliminarily administered enzalutamide (Group E) and 9 patients in the group preliminarily administered abiraterone (Group A). The novel drugs were administered immediately following DOC therapy in nearly all cases. Of the 9 patients in Group A, only one patient (11%) and of the 12 patients in Group E, only one patient (9%) achieved PSA decrease of 50% or more, thus resulting in a poor response rate. There was not significantly difference in both groups. The overall survival rates of Group A and E were not significantly difference. There were three adverse events which required change drug. Those were two cases (appetite loss and general fatigue) on enzalutamide and one case (edema) on abiraterone. (Conclusion) This study suggested that sequential therapy with abiraterone and enzalutamide after DOC therapy had poor clinical benefit regardless of the order of administration of both drugs.

Supramolecular materials cross-linked between polymer chains by noncovalent bonds have the potential to provide dynamic functions that are not produced by covalently cross-linked polymeric materials. We focused on the formation of supramolecular polymeric materials through host-guest interactions: a powerful method for the creation of nonconventional materials. We employed two different kinds of host-guest inclusion complexes of β-cyclodextrin (βCD) with adamantane (Ad) and ferrocene (Fc) to bind polymers together to form a supramolecular hydrogel (βCD-Ad-Fc gel). The βCD-Ad-Fc gel showed self-healing ability when damaged and responded to redox stimuli by expansion or contraction. Moreover, the βCD-Ad-Fc gel showed a redox-responsive shape-morphing effect. We thus succeeded in deriving three functions from the introduction of two kinds of functional units into a supramolecular material., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: To evaluate long-term continuous administration of docetaxel (DOC), over survival rate, PSA level and adverse effects were analyzed, retrospectively. We also compared the results of long-term treatment group and short-term treatment group., Material and Methods: This study reported that 14 cases of long-term continuous administration of DOC consisting of 11 or more cycles among 51 patients of castration-resistant prostate cancer (CRPC) treated with DOC from October 2008 to September 2013 at our institution, retrospectively. Nineteen patients who had treated with DOC 10 or less cycles were defined as short-term dose group, and both groups were compared. DOC was administered every 3 to 4 weeks at 60 to 70 mg/m2, and was treated with prednisolone at 10 mg/day as a general., Results: The median number of treatment cycles was 15. Thirteen cases showed a decrease in PSA levels and 10 cases showed a decrease in PSA levels of 50% or more, the 1-year survival rate of long-term dose and short-term dose group were 100% and 16%. Adverse effects of grade 3 or lower consisted of leukocytopenia in 85% and thrombocytopenia in 28%, however, grade 4 or higher were not observed in long-term dose group. In multivariable analysis of parameters, long-term treatment was related to PSA levels at start of treatment and ALP levels., Conclusion: Forty-two percent of patients who have CRPC at our institution undergo long-term DOC based chemotherapy treatment It may be suggested that long-term DOC based chemotherapy for some cases contribute to extend survival time with no serious adverse events.

Purpose: We assessed the outcome after radical prostatectomy and pelvic lymphadenectomy for lymph node positive prostate cancer retrospectively. Furthermore, we compared the efficacy of immediate androgen deprivation adjuvant therapy in node positive patients who have undergone radical prostatectomy., Material and Methods: We investigated 62 patients who have undergone radical prostatectomy and pelvic lymphadenectomy and have been found to have lymph node positive prostate cancer at our facility between January 1992 and January 2008. We researched the clinical stages, the pathological stages and Gleason scores for pathological pN1 + prostate cancer, retrospectively. The serum PSA levels were followed up every 6 months, and we considered that biochemical progression was PSA >0.4 ng/ml. We classified the groups treated with or without immediate androgen deprivation adjuvant therapy, the biochemical progression free survival and cause specific survival were analyzed by the Kaplan-Meier method, and the statistical significance was determined by the log rank test., Results: The rate of lymph node positive patients who have undergone radical prostatectomy was 7.1%. The rate of 8 or greater in Gleason score of all the lymph node positive patients was 68.3%. The 5-year prostate cancer specific survival and 5-year biochemical progression free survival rates were 90.3 and 67.4% of all the patients. The biochemical progression free survival rate of the group of patients who have received immediate androgen deprivation therapy after radical prostatectomy was significantly higher than that of the group of patients who have not received immediately androgen deprivation therapy., Conclusion: It may be suggested that early androgen deprivation adjuvant therapy benefits patients with nodal metastases who have undergone radical prostatectomy and lymphadenectomy, compared with those who received deferred treatment, although in a retrospective nonrandomized study.

Purpose: There were many case reports about bladder tamponade resulting from clots of blood. However, there were few reports about the clinical study that result from collecting cases of bladder tamponade. Thus, we performed a retrospective study about bladder tamponade resulting from clots of blood that we had managed., Material and Methods: We investigated 20 patients who had bladder tamponade and were consulted at our facility between October 2002 and September 2005. We researched causes of the bleeding, characteristics of the patients, the laboratory data of coagulation system and treatments of our experience in managing patients. There were 17 males and 3 females. The average age of the patients was 74.0 years old., Results: 8 cases took anticoagulant drugs, 6 cases had medical history of cerebral infarction or cardiac infarction, 4 cases took anticholinergic drugs and 9 cases had benign prostate hypertrophy or urethral stricture. Bleeding was due to bladder tumor in 9, prostate cancer in 1, radiation cystitis in 3, chronic cystitis in 1, malignant lymphoma in 1, idiopathic causes in 3 and unknown causes in 2 cases. Except 1 case, in all cases, evacuation of the clots was the first procedure followed by saline irrigation. This initial line of treatment was able to control the hemorrhage in 40% of the patients. For the remaining cases, transurethral coagulation and resection of bladder tumor were used as the second line treatment, and furthermore, radical cystectomy was performed in 1 case. Surgical treatments were required in 12 cases. Blood transfusion was required in 4 cases., Conclusion: According to progress aging society, the amounts of taken anticoagulant drugs and the patients who had lower urinary tract dysfunction may increase. It may be suggested that the cases of bladder tamponade resulting from clots of blood without bladder tumor or radiation cystitis tend to increase.

Aim: Recent studies have shown that various factors contribute to the increased excitability into the bladder afferent nerves in spinal cord injury (SCI) rats. It has been reported that prostaglandins (PG) act as local modulators of reflex micturition in pathological conditions. In the present study, we measured the amount of PGE2 release from the bladder of chronic SCI rats., Methods: Spinal cord was transected at the level of T8-9 in adult female Sprague-Dawley rats. After 10 weeks, specimens of the urinary bladder were obtained from SCI rats and sham-injured control rats, and bladder strips were dissected from the bladder. Using an muscle-bath technique and a microdialysis procedure, the dialysate, containing substance released from bladder strips, was collected. Then the amount of PGE2 in the dialysate was measured by radioimmunoassay., Results: Excretion of urinary PGE2 was significantly higher in SCI rats than in control rats. PGE2 release from bladder strips was significantly higher in SCI rats than in control rats. Removal of urothelium caused significant decreases in PGE2 release in both control and SCI rats. Stretches of the bladder strips caused significant resting tension-dependent increases in PGE2 release from the strips with urothelium., Conclusions: The present data suggest that bladder urothelium partly contributes to the increase in PGE2 release from the bladder, and that bladder distension may cause increases in PGE2 release in SCI rats.

A new type of electrolyzed hydrogen-saturated (EHS) water was produced using a water-electrolyzing device equipped with a special cation exchanger. Use of the EHS water for drinking in a feeding test with rats elicited an antioxidative effect. After intraperitoneal injection of 2,2-azobis-amidinopropane dihydrochloride, urinary secretion of 8-hydroxydeoxyguanosine and hepatic formation of peroxidized lipid were significantly lessened in rats which had received the EHS water for one week. These results suggest the possibility that this drinking water shows an effect in reduction of oxidative stress in the body.

Background: Muscarinic M3 (M3) receptor has been recognized as a major muscarinic receptor for smooth muscle contractions of the urinary bladder. Under the hypothesis that overexpression of M3 receptor in the urinary bladder would enhance urinary bladder contractions, we have transferred the M3 receptor gene into rat bladders using electroporation (EP) and evaluated the functional expression of the transferred gene., Methods: Plasmids expressing luciferase, a green fluorescence protein and M3 receptor were injected into the rat bladder and square-wave electric pulses were immediately applied. Two days after gene transfer, we analyzed gene expression. Immunohistochemical staining was performed and the contractile responses from isolated bladder strips, which were induced KCl, carbachol and electrical field stimulation (EFS), were evaluated., Results: The optimal conditions of electroporation were 8 pulses, 45 voltages, 50 milliseconds/pulses and 1 Hz. Under these conditions, luciferase gene expression was enhanced approximately 300-fold, compared to an injection of DNA only. Regarding immunohistochemistry with an anti-M3 receptor, an increase in immunoactivity was observed in the M3 receptor gene transferred rat bladder, compared to the bladder of the control rat. In rats with the transferred M3 receptor gene, carbachol- and EFS-induced maximum contractile responses of bladder smooth muscle strips significantly increased., Conclusions: These findings suggest that an in vivo EP procedure is an useful method for gene transfer into the bladder and that an overexpression of M3 receptor in the rat bladder enhances bladder contractility. This technique may become a new treatment modality for detrusor underactivity.

Numerous studies have detailed age-related changes in the structure and function of the bladder that may contribute to the high prevalence of overactive bladder (OAB) in the elderly population, but the relation of these changes to OAB symptoms remains unclear. Physiologic and neurochemical studies have been conducted in human detrusor strips obtained from people of different ages, focusing on potential changes in cholinergic and purinergic neurotransmission, as well as the release and actions of acetylcholine (ACh) from nonneuronal bladder cells. Results from physiologic and microdialysis experiments indicate that purinergic transmission increases with age, whereas cholinergic transmission decreases. These effects are most likely because of decreased release of ACh and increased release of adenosine triphosphate (ATP) from postganglionic parasympathetic axons innervating the bladder. Immunohistochemical experiments showed that choline acetyltransferase in the human detrusor is contained not only in parasympathetic axons, but also in cells of the urothelium. The release of nonneuronal ACh increases with age and detrusor stretch. The age-related increase in purinergic transmission in the detrusor and other data indicating that responses to ATP are increased in detrusor overactivity suggest that purinergic receptor antagonists may provide a useful complement to muscarinic receptor antagonists in the treatment of older patients with OAB. Nonneuronal ACh release may play a key role in the storage phase of the micturition reflex, and this may explain, at least in part, the effectiveness of antimuscarinic agents for the treatment of OAB.

Introduction: To investigate the mechanism of voiding dysfunction in non-insulin-dependent diabetes mellitus, we attempted to measure the acetylcholine (ACh) release using an in vivo microdialysis technique and measuring the detrusor pressure after electrical field stimulation (EFS) of the pelvic nerve., Materials and Methods: Eight- and 32-week-old female Goto-Kakizaki (GK) rats (non-insulin-dependent diabetes mellitus model) and age-matched female Wistar rats (controls) were used in this study. The pelvic nerve was exposed on a bipolar platinum electrode to EFS, and a cannula was inserted into the bladder to measure the detrusor pressure. The microdialysis probe was inserted into the bladder wall and was connected to a microinfusion syringe pump. Dialysate was constantly perfused, collected in a microtube, and then injected into the ACh assay system. Histological examinations were performed by staining with hematoxylin and eosin and S-100 immunohistochemical staining in bladder preparations of both GK and control rats., Results: In 8-week-old rats, both detrusor pressures and amounts of ACh release of GK rats were not significantly different from those of control rats. In 32-week-old rats, both detrusor pressures and ACh releases were only significantly increased at 5 and 10 Hz of EFS. In the histological study, the number of nerve fibers or bundles of 32-week-old GK rats was significantly decreased as compared with control rats., Conclusion: The present data suggest that the decrease in EFS-induced ACh release in GK rats, which may be caused by the decreased number of nerve fibers, may contribute to the decrease in bladder contractions., (Copyright 2004 S. Karger AG, Basel)

Darifenacin [(S)-2--2,2-diphenylacetamide] is a novel antimuscarinic drug currently undergoing phase III trials for the treatment of overactive bladder. We investigated the functional antagonist potency of darifenacin, and the antimuscarinic drugs propiverine, oxybutynin and atropine, on human detrusor smooth muscle. Urinary bladder specimens were obtained from 20 patients who underwent total cystectomy for malignant bladder tumor. Using an organ-bath technique, the effects of the compounds on carbachol-, KCl-, CaCl(2)- or electrical field stimulation (EFS)-induced contractions of the tissues were evaluated. The order of antagonist potency (pA(2 )values) at the muscarinic M(3) receptors was: darifenacin (9.34) > atropine (9.26) > oxybutynin (7.74) > propiverine (7.68). Darifenacin and atropine, at concentrations up to 10(-6) mol/l, did not inhibit the KCl- and CaCl(2)-induced contractions (concentrations 80 and 5 mmol/l, respectively), while propiverine and oxybutynin (10(-5) mol/l) significantly inhibited these contractions. Pretreatment with darifenacin (10(-9)-10(-6) mol/l), propiverine (10(-8)- 10(-5) mol/l), oxybutynin (10(-8)-10(-5) mol/l) and atropine (10(-9)-10(-6) mol/l) significantly inhibited maximum EFS-induced contractions. Darifenacin inhibited contractions of human detrusor smooth muscle only through its antimuscarinic action, while propiverine and oxybutynin had both antimuscarinic and Ca(2+) channel antagonist actions. These findings indicate that darifenacin is a potent antagonist at the M(3) receptor and support its use as a treatment for overactive bladder., (Copyright 2003 S. Karger AG, Basel)

KRP-197, 4-(2-methylimidazol-l-yl)-2,2-diphenylbutyramide, is a newly synthesized antimuscarinic drug, developed for the treatment for overactive bladder. For evaluation of pharmacological characteristics of KRP-197, we investigated whether it influenced both prejunctional and postjunctional muscarinic receptors on the isolated human detrusor smooth muscles as compared with the effects of atropine, oxybutynin, and propiverine. Using the muscle bath technique, we investigated the effects of various antimuscarinic drugs on the contractions induced by carbachol, KCl, CaCl(2), and electrical field stimulation. Furthermore, using high-performance liquid chromatography with a microdialysis technique, we measured the acetylcholine release from the muscle strips during electrical field stimulation. The effects of various antimuscarinic drugs on acetylcholine releases were also evaluated. Pretreatment with various antimuscarinic drugs caused parallel shifts to the right in carbachol-induced concentration-response curves. The rank order of pA(2) values was KRP-197 > or = atropine > oxybutynin > propiverine. Atropine and KRP-197 did not cause significant inhibition of KCl- and CaCl(2)-induced contractions. All drugs caused concentration-dependent inhibitions in electrical field stimulation-induced contractions. Pretreatment with atropine and propiverine did not cause significant changes in electrical field stimulation-induced acetylcholine release. However, KRP-197, and oxybutynin caused significant decreases in acetylcholine release. The present study demonstrates that KRP-197 has an inhibitory effect on postjunctional muscarinic receptors as well as on prejunctional muscarinic receptors to modulate acetylcholine release in human detrusor smooth muscles. The findings suggest the usefulness of KRP-197 as a therapeutic drug for an overactive bladder with symptoms of frequency, urgency, and urge incontinence., (Copyright 2003 S. Karger AG, Basel)

We measured the serum TPA level in 260 patients with benign urogenital diseases, 189 patients with urogenital cancer and 72 healthy blood donors by using a radio-immunoassay kit in order to evaluate its usefulness as an indicator for the presence of cancer. TPA value (mean +/- 2SD) in healthy blood donors was in the range of 36.8-110.8 units per liter, so that values higher than 110 U/L were considered to be abnormal. Significantly higher serum TPA levels were observed in patients with non-treated cancers, compared to healthy blood donors. But elevated serum TPA levels were also observed in the patients with benign diseases, especially in cases of benign prostatic hyperplasia with urinary tract infection. Consequently, it is considered that the serum TPA test is very useful for detecting urogenital diseases, but not for screening urogenital cancer. In cases of urogenital cancer, serum TPA levels elevated significantly by recurrence or recrudescence of the disease. Therefore, a good correlation was established between serum TPA and the efficiency of a given therapy in patients with prostatic cancer and bladder cancer.