論文 - 黒部　匡広

超音波検査,MRI検査による無精子症の病態分類の試み

太田 智行, 黒部 匡広, 高山 達也, 古城 公佑, 岩本 晃明, 山崎 一恭, 岡田 真也

超音波医学 ( (公社)日本超音波医学会 )  50 ( Suppl. ) S636 - S636   2023年04月 [ 査読有り ]

掲載種別: 研究論文（その他学術会議資料等）

Analysis of the correlation between gene copy deletion in the AZFc region and male infertility in Japanese men.

Yusuke Nakagawa, Atsushi Tada, Kosuke Kojo, Haruki Tsuchiya, Masahiro Kurobe, Masahiro Uchida, Kazumitsu Yamasaki, Teruaki Iwamoto, Youichi Sato

Reproductive biology   23 ( 1 ) 100728 - 100728   2023年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

Deletion of the azoospermia factor c (AZFc), located on the long arm of the Y chromosome, is a cause of male infertility. The structure of the Y chromosome is diversified by the copy number of various genes, such as deleted in azoospermia (DAZ), basic protein Y2, chromodomain Y1, testis-specific transcript Y-linked 4, and Golgi autoantigen golgin subfamily a2 like Y, located in the AZF region. In this study, we investigated the deletion of each gene copy and analyzed its relationship with Japanese male infertility. Deletions of single nucleotide variants of each gene copy in 721 proven fertile men as controls, 139 patients with non-obstructive azoospermia (NOA), and 56 patients with oligozoospermia (OS) were analyzed via polymerase chain reaction-restriction fragment length polymorphism analysis. Their association with infertility was analyzed using logistic regression analysis adjusted for the Y-chromosome haplogroup, D1a2a. Deletions of DAZ/II in the r1 region and DAZ/V in the r1 and r2 regions showed significant associations with NOA (odds ratio [OR] = 4.15, 95 % confidence interval [CI] = 1.18-14.6, P = 0.026; OR = 4.19, 95 % CI = 1.19-14.7, P = 0.025, respectively). They did not show any association with OS. Partial deletion of the AZFc region affects spermatogenesis in Japanese male.

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A constrained mixture-micturition-growth (CMMG) model of the urinary bladder: Application to partial bladder outlet obstruction (BOO).

Fangzhou Cheng, Paul N Watton, Giulia Pederzani, Masahiro Kurobe, Ei-Ichiro Takaoka, Chris Chapple, Lori Birder, Naoki Yoshimura, Anne M Robertson

Journal of the mechanical behavior of biomedical materials   134   105337 - 105337   2022年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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We present a constrained mixture-micturition-growth (CMMG) model for the bladder. It simulates bladder mechanics, voiding function (micturition) and tissue adaptations in response to altered biomechanical conditions. The CMMG model is calibrated with both in vivo and in vitro data from healthy male rat urinary bladders (cystometry, bioimaging of wall structure, mechanical testing) and applied to simulate the growth and remodeling (G&R) response to partial bladder outlet obstruction (BOO). The bladder wall is represented as a multi-layered, anisotropic, nonlinear constrained mixture. A short time scale micturition component of the CMMG model accounts for the active and passive mechanics of voiding. Over a second, longer time scale, G&R algorithms for the evolution of both cellular and extracellular constituents act to maintain/restore bladder (homeostatic) functionality. The CMMG model is applied to a spherical membrane model of the BOO bladder utilizing temporal data from an experimental male rodent model to parameterize and then verify the model. Consistent with the experimental studies of BOO, the model predicts: an initial loss of voiding capacity followed by hypertrophy of SMC to restore voiding function; bladder enlargement; collagen remodeling to maintain its role as a protective sheath; and increased voiding duration with lower average flow rate. This CMMG model enables a mechanistic approach for investigating the bladder's structure-function relationship and its adaption in pathological conditions. While the approach is illustrated with a conceptual spherical bladder model, it provides the basis for application of the CMMG model to anatomical geometries. Such a mechanistic approach has promise as an in silico tool for the rational development of new surgical and pharmacological treatments for bladder diseases such as BOO.

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勃起障害に対するProstaglandin E1陰茎海綿体自己注射の多施設共同臨床試験

大平 伸, 清水 真次朗, 福元 和彦, 永井 敦, 小谷 俊一, 川西 泰夫, 天野 俊康, 内田 洋介, 岩佐 厚, 木村 将貴, 小林 皇, 小堀 善友, 松下 一仁, 市川 孝治, 今井 伸, 梅本 幸裕, 黒部 匡広

日本性機能学会雑誌 ( (一社)日本性機能学会 )  36 ( 3 ) 131 - 141   2021年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

目的:勃起障害(ED)に対するProstaglandin E1陰茎海綿体注射(PGE1-ICI)は、海外において確立された治療法である。本研究では、日本性機能学会主導のもと日本における勃起障害に対するPGE1自己注射の有効性および安全性を多施設共同臨床試験により検討した。対象・方法:2014年1月20日から2018年9月30日までにPGE1自己注射を開始した113症例を対象とし、ED診断時、治療開始後12週、24週、24週以降(平均:45.8週)における、SHIMおよびEHSを含む治療日誌の変化、治療継続率、有害事象の発生率について検討した。結果:ED診断時の年齢は61.1歳(平均、以下同表記)、PGE1-ICIテストresponse doseは19.3μg、response scoreは2.6点であり、ED病型は、器質性が94.7%、心因性が5.3%であった。PGE1自己注射により、長期的なSHIM、EHS、勃起の維持、射精までの到達、研究対象症例およびパートナーの満足度に関する統計学的に有意な改善を認めた。また、治療継続率は、治療開始後12週83.2%、24週68.8%、36週64.8%、48週63.2%、60週61.0%であり、治療経過において、薬剤投与量、効果発現時間、勃起持続時間の変化および重篤な有害事象は認めなかった。結論:EDに対するPGE1自己注射は長期間にわたり安全性および有用性の高い治療法である。(著者抄録)

Functional and histologic imaging of urinary bladder wall after exposure to psychological stress and protamine sulfate.

Tetsuichi Saito, T Kevin Hitchens, Lesley M Foley, Nishant Singh, Shinsuke Mizoguchi, Masahiro Kurobe, Daisuke Gotoh, Teruyuki Ogawa, Tomonori Minagawa, Osamu Ishizuka, Christopher Chermansky, Jonathan Kaufman, Naoki Yoshimura, Pradeep Tyagi

Scientific reports   11 ( 1 ) 19440 - 19440   2021年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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To quantify the urinary bladder wall T1 relaxation time (T1) before and after the instillation contrast mixture in rats previously subjected to water avoidance stress (WAS) and/or acute exposure to protamine sulfate (PS). Female Wistar rats were randomized to receive either sham (control) or 1 h of WAS for ten consecutive days before the evaluation of nocturnal urination pattern in metabolic cages. T1 mapping of urinary bladder wall at 9.4 T was performed pre- and post- instillation of 4 mM Gadobutrol in a mixture with 5 mM Ferumoxytol. Subsequently, either T1 mapping was repeated after brief intravesical PS exposure or the animals were sacrificed for histology and analyzing the mucosal levels of mRNA. Compared to the control group, WAS exposure decreased the single void urine volume and shortened the post-contrast T1 relaxation time of mucosa- used to compute relatively higher ingress of instilled Gadobutrol. Compromised permeability in WAS group was corroborated by the urothelial denudation, edema and ZO-1 downregulation. PS exposure doubled the baseline ingress of Gadobutrol in both groups. These findings confirm that psychological stress compromises the paracellular permeability of bladder mucosa and its non-invasive assay with MRI was validated by PS exposure.

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Editorial Comment from Dr Kurobe to Telomerase reverse transcriptase promoter mutation in tumorigenesis of bladder cancer: Evolutionary trajectory by algorithmic inference from cross-sectional data.

Masahiro Kurobe

International journal of urology : official journal of the Japanese Urological Association   28 ( 7 ) 777 - 777   2021年07月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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【泌尿器科当直医マニュアル】入院編 処方・処置に伴う合併症・トラブル 腫瘍崩壊症候群

黒部 匡広, 河合 弘二, 宮崎 淳

臨床泌尿器科 ( (株)医学書院 )  75 ( 4 ) 228 - 231   2021年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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＜文献概要＞絶対に見逃してはいけないポイント ▼化学療法開始後に腎不全,不整脈,痙攣などが出現したら,腫瘍崩壊症候群を疑う.▼腫瘍崩壊症候群の死亡率は約40%と高く,適切なリスク評価と予防処置で発症を防ぐことが肝要である.▼固形腫瘍のなかでも精巣腫瘍は腫瘍崩壊症候群の発症リスクが高く,注意が必要である.

Clinical features of multiply recurrent retroperitoneal liposarcoma: A single-center experience.

Noriyuki Masaki, Mizuki Onozawa, Takamitsu Inoue, Masahiro Kurobe, Koji Kawai, Jun Miyazaki

Asian journal of surgery   44 ( 1 ) 380 - 385   2021年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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BACKGROUND: To elucidate the clinicopathological features of multiply recurrent retroperitoneal liposarcoma referred to a tertiary center. METHODS: We retrospectively analyzed the clinical data of 40 patients with pathologically proven primary retroperitoneal liposarcoma treated between January 2015 and June 2019. RESULTS: The initial pathology was well-differentiated liposarcoma (WDLS) in 23 patients, dedifferentiated liposarcoma (DDLS) in 15 patients, and myxoid liposarcoma in two patients. Before and after referral to our hospital, the patients underwent 142 surgeries (median number of surgeries: 3) for initial and recurrent tumors. Of these, 35 (87.5%) patients underwent surgeries for recurrent tumors. In 11 (47.8%) of the 23 patients with initial WDLS, pathological progression (PP) to DDLS was observed in recurrent tumors at the median interval of 7.8 years. In eight patients (72.7%), the PP occurred at the first recurrence. In contrast, all 15 patients with DDLS recurred as DDLS. Distant metastases developed in eight patients (34.8%) with WDLS and five patients (29.4%) with DDLS/myxoid subtype. All eight WDLS patients who developed metastasis were alive with disease at the median interval of 3.6 years, whereas four of the five patients with primary diagnosis of DDLS/myxoid subtype died at the median interval of 5.6 months from the development of metastasis. The 5-year overall survival of the patients with initial WDLS and those with DDLS/myxoid subtype were 100% and 67.4% (p = 0.0006), respectively. CONCLUSIONS: The prognosis of the initial-WDLS patients was favorable despite multiple recurrences. In WDLS patients, if distant metastases develop, it is possible to remain alive with disease for years.

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The early, long-term inhibition of brain-derived neurotrophic factor improves voiding, and storage dysfunctions in mice with spinal cord injury.

Naoki Wada, Naoki Yoshimura, Masahiro Kurobe, Tetsuichi Saito, Pradeep Tyagi, Hidehiro Kakizaki

Neurourology and urodynamics   39 ( 5 ) 1345 - 1354   2020年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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AIMS: We examined the time course of urodynamic changes and the effect of the short or long-term inhibition of brain-derived neurotrophic factor (BDNF) from the early phase after spinal cord injury (SCI) in mice. METHODS: The spinal cord of female C57BL/6N mice was completely transected. We examined filling cystometry and bladder BDNF levels at 10, 20, and 30 days after SCI, with an additional day-5 measurement of BDNF. In a separate group of mice, anti-BDNF antibody (Ab) (10 µg/kg/h) was subcutaneously administered using osmotic pumps from day 3 after SCI, and single-filling cystometry was performed at 10 and 30 days (7 and 27 days of treatment, respectively) after SCI. RESULTS: Compared to spinal intact mice, bladder mucosal BDNF was increased at each time point after SCI with the maximal level at day 5 after SCI. Voiding efficiency was lower at each time point after SCI than that of spinal intact mice. The number of non-voiding contractions (NVC) during bladder filling was gradually increased with time. In both 10- and 30-day SCI groups treated with anti-BDNF Ab, voiding efficiency was improved, and the duration of notch-like intravesical pressure reductions during voiding bladder contractions was prolonged. The number of NVC was significantly decreased only in 30-day SCI mice with 27-day anti-BDNF treatment. CONCLUSIONS: Overexpression of BDNF is associated with the deterioration of voiding efficiency after SCI. The early-started, long-term inhibition of BDNF improved voiding dysfunction and was also effective to reduce the later-phase development of detrusor overactivity after SCI.

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Effects of a selective androgen receptor modulator (SARM), GSK2849466A, on stress urinary incontinence and bladder activity in rats with ovariectomy-induced oestrogen deficiency.

Katsumi Kadekawa, Naoki Kawamorita, Takahiro Shimizu, Masahiro Kurobe, Philip S Turnbull, Sundeep Chandra, Takahito Kambara, Joanna C Barton, Alan J Russell, Naoki Yoshimura

BJU international   125 ( 6 ) 911 - 919   2020年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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OBJECTIVES: To report the effect of a selective androgen receptor modulators (SARMs) on the urethral continence mechanisms in a rat model of stress urinary incontinence (SUI) induced by bilateral ovariectomy (OVX). MATERIALS AND METHODS: Female Sprague-Dawley rats with bilateral OVX were used. Rats were divided into five groups; sham operated, vehicle-treated OVX, low-dose SARM-treated OVX (GSK2849466A: 0.005 mg/kg/day, per os [p.o.]), high-dose SARM-treated OVX (GSK2849466A: 0.03 mg/kg/day, p.o.) and dihydrotestosterone (DHT)-treated OVX (1 mg/kg/day, subcutaneous) groups. After 4 weeks of SARM treatments or 3 weeks of DHT treatment (6 weeks after OVX), rats were subjected to evaluation of the sneeze-induced continence reflex using microtransducer-tipped catheter methods, sneeze-induced leak-point pressure, and continuous cystometry measurements, followed by histological analyses of urethral tissues. RESULTS: (i) OVX significantly impaired urethral continence function after 6 weeks to induce SUI during sneezing. (ii) Low-dose SARM treatment restored urethral baseline pressure (UBP) without affecting the amplitude of urethral response during sneezing (A-URS), partially reversing OVX-induced SUI during sneezing. (iii) High-dose SARM treatment reversed decreases in both UBP and A-URS, more effectively preventing SUI during sneezing. (iv) DHT treatment only restored A-URS without affecting UBP, partially preventing OVX-induced SUI during sneezing. (v) The high-dose SARM treatment induced hypertrophy of the striated and smooth muscle around the urethra. (vi) SARM treatment did not affect bladder function in sham or OVX rats. CONCLUSION: Treatment with SARMs could be a more effective modality for the treatment of SUI than DHT, without affecting bladder function, by enhancing smooth- and striated muscle-mediated urethral function under stress conditions such as sneezing.

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Urethral dysfunction and alterations of nitric oxide mechanisms in streptozotocin-induced diabetic rats with or without low-dose insulin treatment.

Nailong Cao, Eduardo C Alexandre, Daisuke Gotoh, Masahiro Kurobe, Shinsuke Mizoguchi, Baojun Gu, Naoki Yoshimura

Life sciences   249   117537 - 117537   2020年05月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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AIMS: To establish an animal model of diabetes mellitus (DM) with moderately elevated blood glucose levels, and to examine the nitric oxide (NO) mechanism controlling urethral function in streptozotocin (STZ)-induced DM rats. MAIN METHODS: Female Sprague-Dawley rats were used. DM was induced by intraperitoneal injection of STZ (65 mg/kg) and some of them received subcutaneous implantation of a low-dose insulin pellet. Voiding behavior was evaluated in metabolic cages. Isovolumetric cystometry and urethral perfusion pressure (UPP) were then evaluated under urethane anesthesia, during which L-arginine (100 mg/kg) and N-nitro-L-arginine methyl ester hydrochloride (L-NAME) (50 mg/kg) were administered intravenously. In vitro urethral activity was also tested by organ bath muscle strip studies. KEY FINDINGS: UPP changes and high-frequency oscillation (HFO) were significantly (P < 0.05) smaller in 8-weeks DM rats vs. normal control (NC) rats or insulin-treated DM rats, which showed reductions in urine overproduction and voided volume per micturition vs. untreated DM rats. UPP nadir was decreased by L-arginine in NC and insulin-treated DM groups, and decreased by L-NAME in all groups. Five of 6 untreated DM rats showed a detrusor-sphincter dyssynergia pattern after L-NAME. In in vitro studies, the relative ratio of L-NAME-induced reductions of urethral relaxation against pre-drug urethral relaxation was significantly smaller in DM vs. NC rats (P < 0.05). SIGNIFICANCE: Low-dose insulin-treated DM rats would be a useful model for studying natural progression of DM-induced lower urinary tract dysfunction. The impaired NO-mediated urethral relaxation mechanisms play an important role in DM-induced urethral dysfunction, which could contribute to DM-induced inefficient voiding.

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Urethral dysfunction in a rat model of chemically induced prostatic inflammation: potential involvement of the MRP5 pump.

Eduardo C Alexandre, Nailong Cao, Shinsuke Mizoguchi, Tetsuichi Saito, Masahiro Kurobe, Daisuke Gotoh, Meri Okorie, Taro Igarashi, Edson Antunes, Naoki Yoshimura

American journal of physiology. Renal physiology   318 ( 3 ) F754-F762   2020年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Prostate inflammation (PI) is a clinical condition associated with infection and/or inflammation of the prostate. It is a common disease frequently associated to lower urinary tract (LUT) symptoms. The urethra is an understudied structure in the LUT and plays a fundamental role in the urinary cycle. Here, we proposed to evaluate the effect of PI on the urethra tissue. Male Sprague-Dawley rats were used, and PI was induced by formalin injection into the ventral lobes of the prostate. The pelvic urethra at the prostatic level was harvested for histological analysis, contraction (electrical field stimulation and phenylephrine), and relaxation (sodium nitroprusside/MK-571) experiments. Various gene targets [cytochrome c oxidase subunit 2, transforming growth factor-β1, interleukin-1β, hypoxia-inducible factor-1α, α1A-adrenoceptor, inositol 1,4,5-trisphosphate receptor type 1, voltage-gated Ca2+ channel subunit-α1D, neuronal nitric oxide synthase, soluble guanylyl cyclase, phosphodiesterase 5A, protein kinase CGMP-dependent 1, and multidrug resistance-associated protein 5 (MRP5; ATP-binding cassette subfamily C member 5)] were quantified, and cGMP levels were measured. No histological changes were detected, and functional assays revealed decreased contraction and increased relaxation of urethras from the PI group. The addition of MK-571 to functional assays increased urethral relaxation. Genes associated with inflammation were upregulated in urethras from the PI group, such as cytochrome oxidase c subunit 2, transforming growth factor-β1, interleukin-1β, and hypoxia-inducible factor-1α. We also found increased expression of L-type Ca2+ channels and the neuronal nitric oxide synthase enzyme and decreased expression of the MRP5 pump. Finally, cGMP production was enhanced in urethral tissue of PI animals. The results indicate that PI is associated with proinflammatory gene expression in the urethra without histologically evident inflammation and that PI produces a dysfunctional urethra and MRP5 pump downregulation, which results in cGMP accumulation inside the cell. These findings would help to better understand LUT dysfunctions associated with PI and the role of MRP pumps in the control of LUT function.

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Urethral dysfunction and therapeutic effects of a PDE 5 inhibitor (tadalafil) in a rat model of detrusor underactivity induced by pelvic nerve crush injury.

Ei-Ichiro Takaoka, Masahiro Kurobe, Takahisa Suzuki, Nobutaka Shimizu, Joonbeom Kwon, Hiroki Okada, Naoki Yoshimura, Christopher J Chermansky

Neurourology and urodynamics   39 ( 3 ) 916 - 925   2020年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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AIMS: The urethral dysfunction produced by a rat model of peripheral neurogenic detrusor underactivity (DU) using pelvic nerve crush (PNC) injury was characterized and then tested with the administration of tadalafil, a phosphodiesterase type 5 (PDE 5) inhibitor. METHODS: Ten days after producing PNC rats, awake cystometrograms (CMGs) and isovolumetric cystometrograms with urethral perfusion pressure (IC-UPP) measurements were performed. Also, in control rats, IC-UPP was recorded before and after intravenous atropine administration to determine if the reduction of bladder contraction pressure affects urethral relaxation during voiding. Then, CMG and IC-UPP measurements in PNC rats were recorded after intravenous administration of tadalafil. Lastly, real-time polymerase chain reaction was used to measure transcript levels of neuronal nitric oxide synthases (nNOS), endothelial nitric oxide synthases, and PDE 5 in urethral specimens from PNC and control rats. RESULTS: PNC rats demonstrated the characteristics of DU in CMG. Also, PNC rats exhibited significant decreases in isovolumetric bladder contraction amplitudes and urethral relaxation. Atropine attenuated the amplitude of isovolumetric bladder contractions; however, atropine did not affect urethral relaxation in control rats. Tadalafil decreased postvoid residual and increased voiding efficiency without changing bladder contraction amplitude in PNC rats. Also, tadalafil improved the amplitude of urethral relaxation during bladder contraction in PNC rats. Urethral nNOS transcript levels were upregulated in PNC rats compared to control rats. CONCLUSIONS: PNC rats revealed both DU and impaired urethral relaxation. PDE 5 inhibition in PNC rats enhanced urethral relaxation during voiding, resulting in improved voiding efficiency. Thus, urethral dysfunction could be a potential target for the treatment of inefficient voiding associated with neurogenic DU.

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Role of p38 MAP kinase signaling pathways in storage and voiding dysfunction in mice with spinal cord injury.

Nobutaka Shimizu, Naoki Wada, Takahiro Shimizu, Takahisa Suzuki, Masahiro Kurobe, Anthony J Kanai, William C de Groat, Mamoru Hashimoto, Akihide Hirayama, Hirotsugu Uemura, Naoki Yoshimura

Neurourology and urodynamics   39 ( 1 ) 108 - 115   2020年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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AIM: To investigate the role of p38 MAP kinase in lower urinary tract dysfunction in mice with spinal cord injury (SCI). METHODS: Cystometry and external urethral sphincter-electromyography were performed under an awake condition in 4-week SCI female mice. Two weeks after SCI, a catheter connected to an osmotic pump filled with a p38 mitogen-activated protein kinase (MAPK) inhibitor or artificial cerebrospinal fluid (CSF) was implanted into the intrathecal space of L6-S1 spinal cord for continuous intrathecal instillation at infusion rate of 0.51 μL/h for 2 weeks before the urodynamic study. L6 dorsal root ganglia were then removed from CSF and p38 MAPK inhibitor-treated SCI mice as well as from CSF-treated normal (spinal intact) mice to evaluate the levels of transient receptor potential cation channel subfamily V member 1 (TRPV1), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) transcripts by real-time polymerase chain reaction. RESULTS: In p38 MAPK inhibitor-treated SCI mice, nonvoiding contractions during bladder filling, bladder capacity, and post-void residual volume were significantly reduced while micturition pressure and voiding efficiency were significantly increased in comparison to these measurements in CSF-treated SCI mice. The expression of TRPV1, TNF-α, and iNOS messenger RNA was increased in SCI mice compared with expression in spinal intact mice and significantly decreased after p38 MAPK inhibitor treatment. CONCLUSIONS: The p38 MAPK signaling pathway in bladder sensory neurons or in the spinal cord plays an important role in storage and voiding problems such as detrusor overactivity and inefficient voiding after SCI.

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