SERCA2aの持続的過剰発現は、生理的条件下では膀胱機能に影響を及ぼすが、膀胱出口部閉塞亜急性期の病的条件下では膀胱機能に影響しない

A functional impairment of the bladder and heart in a decompensated state caused by a pressure overload is accompanied by a decrease in the sarcoplasmic reticulum Ca2+-ATPase (SERCA2). The beneficial effects of SERCA2 overexpression in preserving cardiac functions have been previously reported. The aim of the present study was to investigate the effects of overexpressed SERCA2 on bladder functions under physiological and pathological conditions using partial bladder outlet obstruction (BOO) in SERCA2a transgenic Wistar rats (TG). Bladder cystometry and western blot analysis were performed using the wild-type Wistar rats (WT), TG, and BOO models (WTBOO and TGBOO). Persistent overexpression of SERCA2 induces reduced bladder compliance without hypertrophy in TG. BOO induces reduced bladder compliance and hypertrophy in WT and TG in the sub-acute phase, but persistent overexpression of SERCA2a in TG does not aggravate the bladder compliance and hypertrophy. In conclusion, SERCA2a overexpression affects bladder functions under physiological conditions, but not in BOO-induced sub-acute pathological conditions.博士（医学）・甲第623号・平成26年5月28

飲水指導は夜間頻尿患者の頻尿症状を有効に改善する

OBJECTIVES: To evaluate how guidance on water-intake impacts the degree of nocturia. METHODS: A total of 67 male patients were enrolled in the present study. Patients were asked to adjust their water and food intakes so that their 24-h urine production/bodyweight would be equal or lower than 30 mL/kg. One month after the treatment, the therapeutic gain from and adverse effects of fluid restriction were examined by comparing the pretreatment and post-treatment value of various parameters. RESULTS: Overall, 65 eligible patients were evaluated. In 44 patients (67%), the frequency of nocturia was improved to one or more times. The change in frequency of nocturia showed a positive correlation with the change in nocturnal urine volume. The change in nocturnal urine volume showed a positive correlation with the changes in 24-h urine production/bodyweight, 24-h drinking volume and daytime drinking volume. The changes in 24-h urine production/bodyweight and daytime drinking volume were independent factors influencing therapeutic effect. None of the participants reported any adverse event. CONCLUSIONS: In patients with a 24-h urine production/bodyweight equal or higher than 30 mL/kg, guidance on water intake might be considered effective and safe as a lifestyle therapy. Water restriction should be carried out not only in the evening, but also during daytime.博士（医学）・乙第1348号・平成26年12月3日© 2014 The Japanese Urological Associatio

Salvage brachytherapy for seminal vesicle recurrence after initial brachytherapy for prostate cancer: a case report

BACKGROUND: To report the efficacy and safety of salvage brachytherapy for seminal vesicle recurrence after initial brachytherapy in a patient with prostate cancer. As far as we know, this is a first report of salvage brachytherapy for seminal vesicle recurrence in Japan. CASE PRESENTATION: A 70-year-old Japanese man with low-risk prostate cancer received low-dose-rate brachytherapy. Forty-two months after the seed implantation, he showed biochemical recurrence based on the nadir + 2 ng/mL definition. The prostate specific antigen (PSA) level was 5.11 ng/mL at 58 months after seed implantation. A saturation biopsy of the prostate showed no recurrence. Systemic screening also showed no distant metastases. However, T2-weighted magnetic resonance imaging (MRI) demonstrated a low intensity area at the base of the right seminal vesicle, which was strongly suggestive of recurrence. Sixty months after the initial therapy, a seminal vesicle biopsy confirmed recurrence with a Gleason score of 4 + 3 before salvage brachytherapy was performed. The prescribed dose was 145 Gy, the same as the dose of the initial therapy. One month later, the PSA level had rapidly declined to 0.898 ng/mL without androgen deprivation therapy. Ten months after the salvage brachytherapy, the PSA level reached 0.078 ng/mL. No adverse events were seen during the follow-up period. CONCLUSIONS: We experienced a patient who was successfully treated with salvage brachytherapy for seminal vesicle recurrence. Salvage brachytherapy is one of the promising therapeutic options for recurrence after initial brachytherapy

前立腺癌マウスモデルにおけるジクロフェナク局所投与によるCOX-2発現の阻害はTRAILの増幅を介して放射線感受性を増強させる

BACKGROUND: COX-2 inhibitors have an antitumor potential and have been verified by many researchers. Treatment of cancer cells with external stressors such as irradiation can stimulate the over-expression of COX-2 and possibly confer radiation resistance. In this study, we tested if topical diclofenac, which inhibits both COX-1 and COX-2, administration rendered prostate tumor cells sensitize to the effects of radiation. METHODS: LNCaP-COX-2 and LNCaP-Neo cells were treated with 0 to 1000 μM diclofenac. Next, a clonogenic assay was performed in which cells were subjected to irradiation (0 to 4 Gy) with or without diclofenac. COX-2 expression and other relevant molecules were measured by real-time PCR and immunohistochemistry after irradiation and diclofenac treatment. In addition, we assessed the tumor volumes of xenograft LNCaP-COX-2 cells treated with topical diclofenac with or without radiation therapy (RT). RESULTS: LNCaP-COX-2 and LNCaP-Neo cell lines experienced cytotoxic effects of diclofenac in a dose related manner. Clonogenic assays demonstrated that LNCaP-COX-2 cells were significantly more resistant to RT than LNCaP-Neo cells. Furthermore, the addition of diclofenac sensitized LNCaP-COX-2 not but LNCaP-Neo cells to the cytocidal effects of radiation. In LNCaP-COX-2 cells, diclofenac enhanced radiation-induced apoptosis compared with RT alone. This phenomenon might be attributed to enhancement of RT-induced TRAIL expression as demonstrated by real-time PCR analysis. Lastly, tumor volumes of LNCaP-COX-2 cells xenograft treated with diclofenac or RT alone was >4-fold higher than in mice treated with combined diclofenac and radiation (p<0.05). CONCLUSIONS: These in vitro and in vivo findings suggest that conventional COX inhibitor, diclofenac enhances the effect of RT on prostate cancer cells that express COX-2. Thus, diclofenac may have potential as radiosensitizer for treatment of prostate cancer.博士（医学）・甲第606号・平成25年11月27日© 2013 Inoue et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

ラット膀胱での水吸収におけるアクアポリン-2の役割

AIM: We investigated the role of the bladder wall in permeating water, focusing on aquaporins. METHODS: Female Sprague-Dawley rats weighing 300 g were used to investigate the role of the bladder wall in saline permeation. Changes in intravesical fluid volume and sodium concentration were measured in the desmopressin acetate hydrate-loaded and control groups 3 h after administration. Bladders were resected to measure aquaporin-1, 2, and 3 gene expression using qRT-PCR. Additionally, the change of aquaporin-2 expression was measured using Western blotting and immunohistochemistry in intravesical aquaporin-2 siRNA-treated and control groups. RESULTS: Although the intravesical fluid volume and sodium concentration significantly decreased from 0 to 3 h (1.00 ± 0.00 vs 0.83 ± 0.08 mL, 157.80 ± 1.30 vs 146.8 ± 1.92 mEq/mL, P < 0.01, respectively in the control group), administration of desmopressin did not affect the extent of volume change. Aquaporin-2 expression was significantly higher in the 3-h distended bladders than in the empty bladder. Aquaporin-2 siRNA treatment suppressed aquaporin-2 expression and the change of intravesical fluid volume from 0 to 3 h (1.00 ± 0.00 and 0.99 ± 0.02 mL), which was related to the suppression of sodium concentration change in comparison with control siRNA treatment (149.6 ± 2.4 vs 143.6 ± 3.67 mEq/mL, P < 0.05). CONCLUSIONS: The rat urinary bladder absorbs water and salts under the full-filled condition. Aquaporin-2 plays an important role in the transport of water, accompanied by sodium concentration change. We demonstrated a part of the bladder absorption mechanism, which may lead to development of a new method for regulating bladder storage function.博士（医学）・甲第697号・平成31年3月15日© 2018 Wiley Periodicals, Inc.This is the pre-peer reviewed version of the following article: [https://onlinelibrary.wiley.com/doi/full/10.1002/nau.23715], which has been published in final form at [http://dx.doi.org/10.1002/nau.23715]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions

日本人男性における携帯式尿流量計(P-Flowdiary®)を用いた排尿量/尿流量に関する年齢階層別ノモグラムの作成

Background: To develop a nomogram of urinary volume and flow based on the data of Japanese men without lower urinary tract symptoms and multiple flows per participant whose characteristics were clear. Methods: Overall, 101 Japanese male volunteers without lower urinary tract symptoms aged between 20 and 59 years were enrolled. A portable uroflowmeter (P-Flowdiary®) was used to record urinary information (flow rate and volume) for 2 successive days. The model (quadratic, linear, or logarithmic regression) most fit for the relationship between maximum flow rate and voided volume was determined. The maximum flow rate at > 150 mL was compared among the 20-29-, 30-39-, 40-49-, and 50-59-year age groups. Nomograms appropriate for the age groups were created. Results: The mean age, International Prostate Symptom Score, and Overactive Bladder Symptom Score were 38.5 years, 0.42, and 0.24, respectively. The quadratic regression model was the most fit because its mean coefficient determination was 0.93 ± 0.06. The mean maximum flow rate was significantly lower in the 50-59-year age group (21.8 ± 5.05 mL/s, P < 0.01) than in the younger groups (24.14 ± 4.94, 24.05 ± 6.99, and 24.64 ± 5.72 mL/s). The 2 nomograms are Y = 28.99 {1 - exp(- 0.01 × X)} and Y = 25.67 {1 - exp(- 0.01 × X)} for the 20-49- and 50-59-year age groups, respectively. Conclusions: The nomogram can predict maximum flow rate based on voided volume in Japanese men aged 20-59 years without lower urinary tract symptoms.博士（医学）・甲第858号・令和4年12月22日© 2022. The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data

高齢者における睡眠の質と夜間頻尿関連 : 在宅脳波データを用いた地域密着研究

PURPOSE: We objectively investigated the relationship between sleep quality/efficiency and factors associated with micturition using at-home electroencephalogram assessment. MATERIALS AND METHODS: Participants were recruited from among those enrolled in the Fujiwara-kyo Study, a community based longitudinal evaluation that began in Nara Prefecture, Japan, in 2007. Included participants were men at least 65 years old who woke up in the middle of the night/early morning at least 3 times per week with the urge to void. We evaluated lower urinary tract symptoms using the I-PSS and subjective sleep quality using the Pittsburgh Sleep Quality Index. Uroflowmetry and 3-day frequency volume charting measurements were also obtained. Electroencephalogram recordings were obtained during sleep to evaluate objective sleep quality. RESULTS: Final analysis included data from 47 participants. I-PSS-quality of life score and slow wave sleep time were independent predictors of good subjective sleep quality as determined by Pittsburgh Sleep Quality Index scores. Nocturnal urinary volume was an independent predictor of greater sleep efficiency. Maximum flow rate was an independent predictor of longer slow wave sleep time. CONCLUSIONS: In elderly men with nocturia, sleep quality is associated with lower urinary tract function. Higher subjective sleep quality is associated with longer slow wave sleep time and less severe lower urinary tract symptoms. Higher objective sleep quality is further associated with a higher urinary flow rate and lower nocturnal urinary volume.博士（医学）・甲第669号・平成29年3月15日Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved

臥床早期の下肢水分移行はHUSを減少させる

OBJECTIVE: To investigate whether or not the leg fluid displacement observed when moving from the standing to recumbent position at bedtime reduces the hours of undisturbed sleep (HUS). METHODS: Men aged 50 years or older who were hospitalized for urological diseases were investigated. Body water evaluation was performed three times with a bioelectric impedance method: (i) 17:00, (ii) 30 min after (short-term), and (iii) waking up (long-term). A frequency volume chart was used to evaluate the status of nocturnal urine production, and the factors affecting HUS were investigated. RESULTS: A total of 50 patients (mean age: 68 years) were enrolled. Short-term changes in extracellular fluid (ECF in the legs showed a significant positive correlation with urine production per unit of time at the first nocturnal voiding (UFN/HUS) (r = 0.45, P = 0.01). In the comparison between patients who had <3 HUS vs. those who had ≥3 HUS, the <3 HUS group showed significantly greater short-term changes in leg fluid volume, night-time water intake (17:00-06:00), and UFN/HUS. Multivariate analysis to assess the risk factors for <3 HUS indicated UFN/HUS as a risk factor in the overall model, and short-term changes in leg ECF and night-time water intake as risk factors in the model that only considered factors before sleep. CONCLUSIONS: Nocturnal leg fluid displacement may increase urine production leading up to first voiding after going to bed, and consequently, induce early awakening after falling asleep.博士（医学）・甲第703号・平成31年3月15日© 2017 John Wiley & Sons Australia, LtdThis is the pre-peer reviewed version of the following article: [https://onlinelibrary.wiley.com/doi/10.1111/luts.12176], which has been published in final form at [http://dx.doi.org/10.1111/luts.12176]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions

Calculated Tumor Volume Is an Independent Predictor of Biochemical Recurrence in Patients Who Underwent Retropubic Radical Prostatectomy

Purpose. The purpose of this study is to investigate whether the clinicopathological biopsy findings can predict the oncological outcome in patients who undergo radical prostatectomy. Materials and Methods. Between January 1997 and March 2006, 255 patients with clinically localized adenocarcinoma of the prostate (clinical T1-3N0M0) who had undergone retropubic radical prostatectomy were enrolled in this study. None of the patients received neoadjuvant or adjuvant therapy. Clinicopathological parameters were assessed to determine a predictive parameter of biochemical recurrence. Results. Of the total 255 patients, 77 showed biochemical recurrence during the follow-up period. The estimated 5-year overall survival, 5-year cause-specific survival, and 5-year biochemical recurrence-free survival rates were 97.7%, 99.5%, and 67.3%, respectively. Multivariate analysis using the Cox proportional hazards model showed that calculated cancer volume was an independent predictor among the preoperative clinicopathological parameters (P < 0.05). SVI and PSM were independent predictors among the postoperative parameters (SVI; P < 0.001, PSM; P = 0.049). Among the significant preoperative and postoperative parameters, calculated cancer volume remained an independent predictive parameter in multivariate analysis (P < 0.01). Conclusions. Tumor volume, as calculated by preoperative parameters, is an independent predictor of biochemical recurrence in patients who had undergone radical prostatectomy

高齢男性における塩分摂取量と下肢浮腫、夜間頻尿との関連について

Aims: There is accumulating evidence that excessive salt intake contributes to nocturnal polyuria. We aimed to investigate the relationship between salt intake, leg edema, and nocturnal urine volume (NUV) to assess the etiology of nocturnal polyuria. Methods: A total of 56 men aged ≥60 years who were hospitalized for benign prostatic hyperplasia or with suspected prostatic cancer were enrolled. Urine frequency-volume charts of the patients were maintained, and they underwent bioelectrical impedance analysis twice daily (at 5:00 pm and 6:00 am) and examination of blood (brain natriuretic peptide levels) and urine (sodium and creatinine levels and osmotic pressure) samples once daily (at 6:00 am). Free-water clearance, solute clearance, and sodium clearance at night were measured, and daily salt intake was estimated. Results: The data of 52 patients were analyzed. Daily salt intake positively correlated with leg edema at 5:00 pm, differences in leg extracellular fluid levels between 5:00 pm and 6:00 am, and NUV, but not with diurnal urine volume. Partial correlation coefficients showed that salt intake was a factor of the correlation between NUV and change in extracellular volume in the legs between 5:00 pm and 6:00 am. A multivariate logistic model showed that sleep duration and sodium clearance were independent predictive factors for nocturnal polyuria. Conclusions: Sodium intake correlates with diurnal leg edema and NUV in elderly men. These results provide evidence supporting sodium restriction as an effective treatment for nocturnal polyuria.博士（医学）・乙第1507号・令和3年3月15日© 2020 Wiley Periodicals LLC.This is the peer reviewed version of the following article: https://onlinelibrary.wiley.com/doi/10.1002/nau.24401, which has been published in final form at https://doi.org/10.1002/nau.24401. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions