Updated on 2022/01/07

写真a

 
OTSUKA Fumio
 
Organization
Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
Other name(s)
FUMIO OTSUKA
External link

Degree

  • M. D., Ph. D. ( Okayama University )

Research Interests

  • Internal Medicine

  • General Prcatice

  • Endocrinology

  • Internal Medicine

  • General Practice

Research Areas

  • Life Science / Metabolism and endocrinology

Education

  • Okayama University   医学研究科   内分泌代謝学

    - 1998

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    Country: Japan

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  • Okayama University    

    - 1998

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  • Okayama University    

    - 1992

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  • Okayama University   医学部  

    - 1992

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    Country: Japan

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Research History

  • Okayama University   総合内科学   Professor

    2012

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  • Okayama University Hospital   内分泌センター   Associate Professor

    2009 - 2012

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  • 岡山大学医歯薬学総合研究科   助教

    2007 - 2009

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  • 岡山大学医歯薬学総合研究科   助手

    2005 - 2007

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  • Okayama University   Okayama University Hospital   Medical Staff

    2003 - 2005

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  • 米国カルフォルニア大学サンディエゴ校 研究員

    1999 - 2002

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  • Okayama University   Okayama University Hospital

    1998 - 1999

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  • Medical Staff,University Hospital of Medicine and Dentistry,Okayama University

    1998 - 1999

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  • Medical Staff

    1992 - 1994

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  • 呉共済病院 職員(医療系)

    1992 - 1994

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Professional Memberships

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Committee Memberships

  •   日本内分泌学会 中国支部副支部長  

    2020   

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    Committee type:Academic society

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  •   日本下垂体研究会 評議員  

    2019   

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    Committee type:Academic society

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  •   日本医療安全調査機構調査支援医(中国四国ブロック)  

    2018   

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    Committee type:Academic society

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  •   日本ステロイドホルモン学会 理事  

    2016   

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    Committee type:Academic society

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  •   日本内分泌学会 保険委員会委員  

    2015   

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    Committee type:Academic society

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  •   日本間脳下垂体腫瘍学会 理事  

    2015   

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    Committee type:Academic society

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  •   日本病院総合診療医学会 評議員・理事  

    2014   

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    Committee type:Academic society

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  •   日本神経内分泌学会 評議員・理事  

    2014   

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    Committee type:Academic society

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  •   日本生殖内分泌学会 評議員・理事  

    2013   

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    Committee type:Academic society

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  •   日本内科学会 評議員  

    2013   

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    Committee type:Academic society

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  •   日本内分泌学会 若手臨床内分泌医育成委員会委員  

    2011   

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    Committee type:Academic society

    日本内分泌学会

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  •   日本内分泌学会 中国支部内分泌疾患コンサルタント委員会委員長  

    2010   

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    Committee type:Academic society

    日本内分泌学会

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  •   成人成長ホルモン分泌不全症地区委員  

    2010   

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    Committee type:Academic society

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  •   日本医療安全調査機構 診療行為に関連した死亡の調査 分析モデル事業 解剖立ち会い臨床医 (2010-)  

    2010   

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  •   岡山県難病対策協議会 特定疾患認定審査部会  

    2009   

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    Committee type:Municipal

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  •   日本内科学会 中国支部評議員  

    2008   

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    Committee type:Academic society

    日本内科学会

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  •   日本内分泌学会 中国支部幹事  

    2008   

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    Committee type:Academic society

    日本内分泌学会

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  •   日本内分泌学会 評議員  

    2007   

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    Committee type:Academic society

    日本内分泌学会

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  • 日本内分泌学会   教育責任者  

    2006   

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    Committee type:Academic society

    日本内分泌学会

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  •   日本内分泌学会 代議員  

    2005   

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    Committee type:Academic society

    日本内分泌学会

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Papers

  • Comment on: Short versus prolonged courses of antimicrobial therapy for patients with uncomplicated Pseudomonas aeruginosa bloodstream infection: a retrospective study. International journal

    Hideharu Hagiya, Fumio Otsuka

    The Journal of antimicrobial chemotherapy   2021.12

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    DOI: 10.1093/jac/dkab464

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  • Adult Hypogonadism Due to Testicular Adrenal Rest Tumors.

    Koichiro Yamamoto, Kosuke Oka, Kou Hasegawa, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   60 ( 23 )   3839 - 3840   2021.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:JAPAN SOC INTERNAL MEDICINE  

    DOI: 10.2169/internalmedicine.6501-20

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  • Roles of NR5A1 and NR5A2 in the regulation of steroidogenesis by Clock gene and bone morphogenetic proteins by human granulosa cells.

    Atsuhito Suyama, Nahoko Iwata, Yoshiaki Soejima, Yasuhiro Nakano, Koichiro Yamamoto, Takahiro Nada, Fumio Otsuka

    Endocrine journal   68 ( 11 )   1283 - 1291   2021.11

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:JAPAN ENDOCRINE SOC  

    The functional role of the transcription factors NR5A1 and NR5A2 and their interaction with Clock gene and bone morphogenetic proteins (BMPs) were investigated in human granulosa KGN cells. Treatment with BMP-15 and GDF-9 suppressed forskolin (FSK)-induced steroidogenesis as shown by the mRNA expression levels of StAR and P450scc but not the mRNA expression level of P450arom. Of interest, treatment with BMP-15 and GDF-9 also suppressed FSK-induced NR5A2 mRNA expression. Treatment with BMP-15 suppressed NR5A2 mRNA and protein expression but increased Clock mRNA and protein expression levels by granulosa cells. The mRNA expression levels of NR5A1, but not those of NR5A2, were positively correlated with the levels of Clock mRNA, while the mRNA levels of Id-1, the target gene of BMP signaling, were positively correlated with those of NR5A1 but not with those of NR5A2. It was also demonstrated that the mRNA expression levels of NR5A1 were positively correlated with those of P450arom and 3βHSD, whereas the mRNA expression level of NR5A2 was correlated with those of StAR and P450scc. Furthermore, inhibition of Clock gene expression by siRNA attenuated the expression of NR5A1, and the mRNA levels of Clock gene were significantly correlated with those of NR5A1. Collectively, the results suggested a novel mechanism by which Clock gene expression induced by BMP-15 is functionally linked to the expression of NR5A1, whereas NR5A2 expression is suppressed by BMP-15 in granulosa cells. The interaction between Clock NR5A1/NR5A2 and BMP-15 is likely to be involved in the fine-tuning of steroidogenesis by ovarian granulosa cells.

    DOI: 10.1507/endocrj.EJ21-0223

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  • Burnout of Healthcare Workers Amid the COVID-19 Pandemic: A Follow-Up Study. International journal

    Yoshito Nishimura, Tomoko Miyoshi, Asuka Sato, Kou Hasegawa, Hideharu Hagiya, Yoshinori Kosaki, Fumio Otsuka

    International journal of environmental research and public health   18 ( 21 )   2021.11

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:MDPI  

    The coronavirus disease 2019 (COVID-19) pandemic has posed a significant challenge to the modern healthcare system and led to increased burnout among healthcare workers (HCWs). We previously reported that HCWs who engaged in COVID-19 patient care had a significantly higher prevalence of burnout (50.0%) than those who did not in November 2020 (period 1). We performed follow-up surveys in HCWs in a Japanese national university hospital, including basic demographics, whether a participant engaged in care of COVID-19 patients in the past 2 weeks, and the Maslach Burnout Inventory in February 2021 (period 2) and May 2021 (period 3). Periods 1 and 3 were amid the surges of COVID-19 cases, and period 2 was a post-surge period with a comparatively small number of COVID-19 patients requiring hospitalization. Response rates to the surveys were 33/130 (25.4%) in period 1, 36/130 (27.7%) in period 2, and 56/162 (34.6%) in period 3, respectively. While no consistent tendency in the prevalence of burnout based on variables was observed throughout the periods, the prevalence of burnout tends to be higher in periods 1 and 3 in those who engaged in COVID-19 patient care in the last 2 weeks (50.0%, 30.8%, 43.1% in period 1, 2, and 3, respectively). Given the prolonged pandemic causing stigmatization and hatred against HCWs leading to increased prevalence of burnout, high-level interventions and supports are warranted.

    DOI: 10.3390/ijerph182111581

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  • Clinical utility of urinary levels of catecholamines and their fraction ratios related to heart rate and thyroid function.

    Naruhiko Sunada, Yoshihisa Hanayama, Koichiro Yamamoto, Yasuhiro Nakano, Takahiro Nada, Hiroyuki Honda, Kou Hasegawa, Hideharu Hagiya, Fumio Otsuka

    Endocrine journal   2021.11

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    Urinary catecholamines (CAs) have been examined for the screening of pheochromocytomas. The decision to perform screening is based on symptoms suggesting secondary hypertension or hyperactivities of the sympathetic nervous system. To elucidate the usefulness of urinary fractions and ratios of CAs, 79 patients in whom 24-h excretions of urinary CAs including adrenaline (AD), noradrenaline (NA) and dopamine (DA) had been examined from 2015 until 2020 were retrospectively analyzed. There were no significant differences in urinary CA levels between two age groups, gender groups and two BMI groups. Patients with histories of preexisting hypertension and diabetes showed significantly higher levels of urinary NA excretion, and the urinary ratio of NA/DA was also increased in the patients with a history of hypertension. Heart rate (HR) was significantly correlated with the urinary ratio of NA/DA. Serum free thyroxine (FT4) concentration and ratio of FT4/thyrotropin (TSH) were correlated with the level of urinary AD. The levels of TSH and FT4/TSH showed negative and positive correlations, respectively, with the urinary NA/DA ratio. Thus, increases of HR are related to the enhanced conversion of DA to NA and increased thyroid hormones are involved in the increase in urinary AD and the conversion of DA to NA. History of lifestyle-related diseases and changes of HR and thyroid functions need to be considered for the evaluation of urinary CAs and their ratios.

    DOI: 10.1507/endocrj.EJ21-0488

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  • Subcutaneous edema as rare complication of abdominal paracentesis. International journal

    Yuki Otsuka, Hirokazu Nagaoka, Yasuhiro Nakano, Hiroyuki Sakae, Kou Hasegawa, Fumio Otsuka

    Clinical case reports   9 ( 11 )   e05116   2021.11

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY  

    Although ascites leakage to the skin is the most frequent complication after abdominal paracentesis, leakage to the subcutaneous space has not been reported. Here, we report a subcutaneous effusion after paracentesis suggesting ascites leakage. We should be aware of this rare complication due to the potential risk of dissemination.

    DOI: 10.1002/ccr3.5116

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  • Impact of the world hand hygiene and global handwashing days on public awareness between 2016 and 2020: Google trends analysis. International journal

    Yoshito Nishimura, Hideharu Hagiya, Koichi Keitoku, Toshihiro Koyama, Fumio Otsuka

    American journal of infection control   2021.10

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    BACKGROUND: Scientific evidence suggest that hand hygiene as one of the most effective measures to control infection. To promote good hand hygiene practices, the World Health Organization introduced May 5 as World Hand Hygiene Day (WHHD), and international stakeholders established Global Handwashing Day (GHD) on October 15. However, its contributions to raising public awareness of hand hygiene is unclear. METHODS: This study evaluates the impact of the WHHD and GHD on the public awareness of hand hygiene in Japan, the United Kingdom, the United States, and worldwide from 2016 to 2020, using the relative search volume of "Hand hygiene" in Google Trends as a surrogate. To identify a statistically significant timepoint of a trend change, we performed Joinpoint regression analysis. RESULTS: Upticks of the relative search volumes as well as joinpoints were noted worldwide around the WHHD and GHD from 2016 to 2019, but no joinpoints were identified around the WHHD and GHD in 2020. No such changes were observed in Japan, the United Kingdom, and the United States during these periods. CONCLUSIONS: While the WHHD was originally established to raise awareness of hand hygiene in healthcare facilities, our result suggests that the WHHD and GHD may not have effectively disseminated the importance of hand hygiene to the general public at a country level. Additional policy measures to advocate hand hygiene to the public are necessary to communicate its benefits.

    DOI: 10.1016/j.ajic.2021.08.033

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  • Temporal artery thickening in giant cell arteritis. International journal

    Hiromi Ihoriya, Yasuhiro Nakano, Fumio Otsuka

    BMJ case reports   14 ( 10 )   2021.10

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    DOI: 10.1136/bcr-2021-247123

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  • Radiologic features of Erdheim-Chester disease. International journal

    Koichiro Yamamoto, Yasuhiro Nakano, Kou Hasegawa, Fumio Otsuka

    Rheumatology (Oxford, England)   2021.10

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    DOI: 10.1093/rheumatology/keab799

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  • Idiopathic combined adrenocorticotropin and growth hormone deficiency mimicking chronic fatigue syndrome. International journal

    Kazuki Tokumasu, Kanako Ochi, Fumio Otsuka

    BMJ case reports   14 ( 10 )   2021.10

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    A 42-year-old man who had suffered from severe fatigue for 5 years was diagnosed as having chronic fatigue syndrome (CFS) and fibromyalgia. Endocrinological workup using combined anterior pituitary function tests showed that the patient had adrenocorticotropin hormone (ACTH) deficiency, with a normal pituitary MRI. Treatment with a physiologic dose of oral hydrocortisone replacement physically ameliorated his general fatigue. A secondary workup using a growth hormone-releasing peptide-2 test revealed that he also had growth hormone (GH) deficiency, and GH replacement therapy was started. His muscle pain and depression were improved by the therapy. Here, we present a rare case of combined deficiency of ACTH and GH in a middle-aged man with severe general fatigue. This case report aims to raise awareness of combined deficiency of ACTH and GH as a differential diagnosis of CFS and its mimics.

    DOI: 10.1136/bcr-2021-244861

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  • Detection of in-frame mutation by IS30-family insertion sequence in the phospholipid phosphatidylglycerol synthase gene (pgsA2) of high-level daptomycin-resistant Corynebacterium striatum. International journal

    Kazuyoshi Gotoh, I Putu Bayu Mayura, Yusaku Enomoto, Koji Iio, Osamu Matsushita, Fumio Otsuka, Hideharu Hagiya

    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology   2021.10

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    The emergence of high-level daptomycin (DAP)-resistant (HLDR) Corynebacterium striatum has been reported as a result of loss-of-function point mutations or premature stop codon mutations in a responsible gene, pgsA2. We herein describe the novel detection of an HLDR C. striatum clinical isolate, in which IS30-insertion was corroborated to cause destruction of pgsA2 gene. We isolated an HLDR C. striatum from a critically ill patient with underlying mycosis fungoides who had been treated with DAP for 10 days. With a sequence investigation, IS30-insertion was discovered to split pgsA2 in the HLDR C. striatum strain, which may cause disrupted phospholipid phosphatidylglycerol (PG) production. Future studies should survey the prevalence of IS-mediated gene inactivation among HLDR C. striatum clinical isolates.

    DOI: 10.1007/s10096-021-04369-1

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  • Impact of the day of the week on the discontinuation of broad-spectrum antibiotic prescriptions; a multi-centered observational study. International journal

    Hiroyuki Honda, Hideharu Hagiya, Tsukasa Higashionna, Yuto Haruki, Mai Haruki, Shiho Kajita, Kengo Mukuda, Yuji Yokoyama, Yasuhiro Nakano, Hiroko Ogawa, Yasuyo Morimoto, Yoshihisa Hanayama, Setsuko Kanda, Hitomi Kataoka, Hitomi Muguruma, Fumio Otsuka

    Scientific reports   11 ( 1 )   20784 - 20784   2021.10

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    To encourage and guide antimicrobial stewardship team (AST) activity and promote appropriate antibiotic use, we studied the impact of day of the week on the initiation and discontinuation of antibiotic administration. This was a multicenter observational study conducted at 8 Japanese hospitals from April 1 to September 30, 2019, targeting patients who underwent treatment with broad-spectrum antibiotics, such as anti-methicillin-resistant Staphylococcus aureus agents and anti-pseudomonal agents. We compared the weekly numbers of initiations and discontinuations of antibiotic prescription on each day of the week or on the days after a holiday. There was no statistical difference in the number of antibiotic initiations on both weekdays and the day after a holiday. However, antibiotic discontinuation was significantly higher from Tuesday onward than Monday and from the second day than the first day after a holiday. Similar trends were observed regardless of the categories of antibiotics, hospital and admission ward, and AST activity. This study suggests that broad-spectrum antibiotics tend to be continued during weekends and holidays and are most likely to be discontinued on Tuesday or the second day after a holiday. This was probably due to behavioral factors beyond medical indications, requiring further antimicrobial stewardship efforts in the future.

    DOI: 10.1038/s41598-021-00206-9

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  • Biphasic Roles of Clock Genes and Bone Morphogenetic Proteins in Gonadotropin Expression by Mouse Gonadotrope Cells. International journal

    Yoshiaki Soejima, Nahoko Iwata, Yasuhiro Nakano, Koichiro Yamamoto, Atsuhito Suyama, Takahiro Nada, Fumio Otsuka

    International journal of molecular sciences   22 ( 20 )   2021.10

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    Roles of Clock genes and the bone morphogenetic protein (BMP) system in the regulation of gonadotropin secretion by gonadotropin-releasing hormone (GnRH) were investigated using mouse gonadotropin LβT2 cells. It was found that luteinizing hormone (LH)β mRNA expression level in LβT2 cells changed gradually over time, with LHβ expression being suppressed in the early phase up to 12 h and then elevated in the late phase 24 h after GnRH stimulation. In addition, the mRNA expression levels of Clock genes, including Bmal1, Clock, Per2, and Cry1, also showed temporal changes mimicking the pattern of LHβ expression in the presence and absence of GnRH. Notably, the expression levels of Bmal1 and Clock showed strong positive correlations with LHβ mRNA expression levels. Moreover, a functional link of the ERK signaling of mitogen-activated protein kinases (MAPKs) in the suppression of LHβ mRNA expression, as well as Bmal1 and Clock mRNA expression by GnRH at the early phase, was revealed. Inhibition of Bmal1 and Clock expression using siRNA was involved in the reduction in LHβ mRNA levels in the late phase 24 h after GnRH stimulation. Furthermore, in the presence of BMP-6 and -7, late-phase Bmal1 and LHβ mRNA expression after GnRH stimulation was significantly attenuated. Collectively, the results indicated that LH expression in gonadotrope cells exhibits Bmal1/Clock-dependent fluctuations under the influence of GnRH and that the fluctuations are regulated by ERK and BMPs in the early and late stages, respectively, in a phase-dependent manner after GnRH stimulation.

    DOI: 10.3390/ijms222011186

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  • Calcified spleen associated with Pneumocystis jirovecii infection. International journal

    Koichiro Yamamoto, Hiroyuki Honda, Hideharu Hagiya, Fumio Otsuka

    QJM : monthly journal of the Association of Physicians   2021.10

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    DOI: 10.1093/qjmed/hcab260

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  • Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric Castleman disease. International journal

    Yoshito Nishimura, David C Fajgenbaum, Sheila K Pierson, Noriko Iwaki, Asami Nishikori, Mitsuhiro Kawano, Naoya Nakamura, Koji Izutsu, Kengo Takeuchi, Midori Filiz Nishimura, Yoshinobu Maeda, Fumio Otsuka, Kazuyuki Yoshizaki, Eric Oksenhendler, Frits van Rhee, Yasuharu Sato

    American journal of hematology   96 ( 10 )   1241 - 1252   2021.10

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    Thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome is a heterogeneous entity manifesting with a constellation of symptoms described above that can occur in the context of idiopathic multicentric Castleman disease (iMCD) as well as infectious diseases, malignancies, and rheumatologic disorders. So, iMCD-TAFRO is an aggressive subtype of iMCD with TAFRO syndrome and often hyper-vascularized lymph nodes. Since we proposed diagnostic criteria of iMCD-TAFRO in 2016, we have accumulated new insights on the disorder and additional cases have been reported worldwide. In this systematic review and cohort analysis, we established and validated a definition for iMCD-TAFRO. First, we searched PubMed and Japan Medical Abstracts Society databases using the keyword "TAFRO" to extract cases. Patients with possible systemic autoimmune diseases and hematologic malignancies were excluded. Our search identified 54 cases from 50 articles. We classified cases into three categories: (1) iMCD-TAFRO (TAFRO syndrome with lymph node histopathology consistent with iMCD), (2) possible iMCD-TAFRO (TAFRO syndrome with no lymph node biopsy performed and no other co-morbidities), and (3) TAFRO without iMCD or other co-morbidities (TAFRO syndrome with lymph node histopathology not consistent with iMCD or other comorbidities). Based on the findings, we propose an international definition requiring four clinical criteria (thrombocytopenia, anasarca, fever/hyperinflammatory status, organomegaly), renal dysfunction or characteristic bone marrow findings, and lymph node features consistent with iMCD. The definition was validated with an external cohort (the ACCELERATE Natural History Registry). The present international definition will facilitate a more precise and comprehensive approach to the diagnosis of iMCD-TAFRO.

    DOI: 10.1002/ajh.26292

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  • Intravascular lymphoma presenting as spinal cord infarction. International journal

    Yukichika Yamamoto, Yoshito Nishimura, Misa Okumura, Yuki Otsuka, Kosuke Oka, Kazuhiro Ikeuchi, Hisakazu Nishimori, Kohei Taniguchi, Fumio Otsuka

    Postgraduate medical journal   97 ( 1152 )   672 - 673   2021.10

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    DOI: 10.1136/postgradmedj-2020-138602

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  • Clinical Characteristics of Japanese Patients Who Visited a COVID-19 Aftercare Clinic for Post-Acute Sequelae of COVID-19/Long COVID. International journal

    Yuki Otsuka, Kazuki Tokumasu, Yasuhiro Nakano, Hiroyuki Honda, Yasue Sakurada, Naruhiko Sunada, Daisuke Omura, Kou Hasegawa, Hideharu Hagiya, Mikako Obika, Keigo Ueda, Hitomi Kataoka, Fumio Otsuka

    Cureus   13 ( 10 )   e18568   2021.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:CUREUS INC  

    Introduction The long-term clinical course, prognosis, and optimal management of symptoms and conditions after the acute phase of coronavirus disease 2019 (COVID-19) remain to be elucidated. The purpose of this study was to clarify the characteristics of patients referred to a COVID-19 aftercare (CAC) clinic established at a tertiary academic hospital in Japan. Methods This study was a descriptive case series study. All patients who visited the CAC clinic between February 15 and September 17 in 2021 were included. Patients' background, chief complaints, and clinical courses after the onset of COVID-19 were described. Results A total of 87 Japanese patients (median age, 40.0 years; interquartile range [IQR], 26.5-53.0 years; 52.9% women) were referred to the CAC clinic. The median interval between the onset of COVID-19 and the visit to the clinic was 79.0 (IQR, 52.5-112.0) days. Referral sources were hospitals (36 patients), clinics (47 patients), a local healthcare center (3 patients), and other (1 patient). The most common chief complaint was general fatigue (50.4%) followed by dysosmia (28.7%), dysgeusia (26.4%), hair loss (18.4%), headache (17.2%), dyspnea (16.1%), and dyssomnia (13.1%). Respiratory symptoms were common in the early stages of the disease but were less common as the chief complaints when visiting the clinic. On the other hand, neurological, psychiatric, and extremity symptoms were predominant one month after the onset of COVID-19. Conclusions Regardless of the severity in the acute phase, patients visiting our CAC clinic suffered from a variety of symptoms. General physicians skilled in using a comprehensive approach would be optimal to see patients with such complex symptoms.

    DOI: 10.7759/cureus.18568

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  • Celiac artery dissection in polycystic kidney disease. International journal

    Koichiro Yamamoto, Kou Hasegawa, Kosuke Oka, Fumio Otsuka

    Clinical case reports   9 ( 10 )   e04922   2021.10

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    Autosomal-dominant polycystic kidney disease (ADPKD) is rarely complicated by celiac artery dissection. Dissection of the aorta and its major branches should be carefully differentiated in ADPKD patients with acute-onset abdominal pain.

    DOI: 10.1002/ccr3.4922

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  • In vitro effectiveness of biapenem against IMP-producing Enterobacteriaceae. International journal

    Kazuyoshi Gotoh, Makoto Miyoshi, I Putu Bayu Mayura, Koji Iio, Osamu Matsushita, Fumio Otsuka, Hideharu Hagiya

    Journal of medical microbiology   70 ( 10 )   2021.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:MICROBIOLOGY SOC  

    The options available for treating infections with carbapenemase-producing Enterobacteriaceae (CPE) are limited; with the increasing threat of these infections, new treatments are urgently needed. Biapenem (BIPM) is a carbapenem, and limited data confirming its in vitro killing effect against CPE are available. In this study, we examined the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of BIPM for 14 IMP-1-producing Enterobacteriaceae strains isolated from the Okayama region in Japan. The MICs against almost all the isolates were lower than 0.5 µg ml-1, indicating susceptibility to BIPM, while approximately half of the isolates were confirmed to be bacteriostatic to BIPM. However, initial killing to a 99.9 % reduction was observed in seven out of eight strains in a time-kill assay. Despite the small data set, we concluded that the in vitro efficacy of BIPM suggests that the drug could be a new therapeutic option against infection with IMP-producing CPE.

    DOI: 10.1099/jmm.0.001430

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  • Impact of the World Antimicrobial Awareness Week on public interest between 2015 and 2020: A Google Trends analysis. International journal

    Koichi Keitoku, Yoshito Nishimura, Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases   111   12 - 20   2021.10

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    OBJECTIVES: To evaluate the impact of the World Antimicrobial Awareness Week (WAAW) on public awareness of antimicrobial resistance using Google Trends analysis. METHODS: The impact of WAAW on public awareness of 'antimicrobial resistance' (AMR), 'antibacterial', and 'antibiotics' in Japan, the UK, the United States, and worldwide from 2015 to 2020 was analyzed, using the relative search volume (RSV) of Google Trends as a surrogate. A joinpoint regression analysis was performed to identify a statistically significant time point of a change in trend. RESULTS: No joinpoints around WAAW were identified in Japan, the United Kingdom, or the United States from 2015 to 2020 with RSVs of 'AMR', whereas increasing RSVs were noted worldwide in 2017 and 2020. Further, there were decreasing RSVs of 'antibiotics' in the first half of 2020, which could be due to the COVID-19 pandemic. The study results suggest that WAAW did little to improve public awareness of AMR in the selected countries despite its contribution worldwide. CONCLUSIONS: This study implies that we need to develop a more effective method to improve public awareness to fight against AMR.

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  • Triad signs shown by bone scintigraphy in FGF23-related osteomalacia. International journal

    Koichiro Yamamoto, Hiroyuki Honda, Itsuro Ota, Fumio Otsuka

    QJM : monthly journal of the Association of Physicians   2021.9

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  • Sternoclavicular Joint Hypertrophy Involved in Polymyalgia Rheumatica.

    Koichiro Yamamoto, Kosuke Oka, Kou Hasegawa, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   60 ( 18 )   3057 - 3057   2021.9

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  • Ivermectin for Coronavirus Disease 2019: Yet to Be Well Evaluated Before Clinical Use. International journal

    Hideharu Hagiya, Fumio Otsuka

    Clinical therapeutics   43 ( 9 )   1622 - 1623   2021.9

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    DOI: 10.1016/j.clinthera.2021.07.007

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  • Gender-Dependent Characteristics of Serum 1,25-Dihydroxyvitamin D/25-Hydroxyvitamin D Ratio for the Assessment of Bone Metabolism. International journal

    Manami Fujita-Yamashita, Koichiro Yamamoto, Hiroyuki Honda, Yoshihisa Hanayama, Kazuki Tokumasu, Yasuhiro Nakano, Kou Hasegawa, Hideharu Hagiya, Mikako Obika, Hiroko Ogawa, Fumio Otsuka

    Cureus   13 ( 9 )   e18070   2021.9

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    Objectives Vitamin D deficiency, which is common worldwide, increases the risks of falls and fractures and can lead to increased morbidity and mortality. However, the clinical utility and relevance of vitamin D activation remain unknown. The aim of the present study was to clarify the clinical usefulness of serum 1,25-dihydroxyvitamin D (1,25D)/25-hydroxyvitamin D (25D) ratio for assessment of the extent of bone metabolism. Methods We retrospectively screened data for 87 patients whose serum 1,25D and 25D levels were measured. Eight patients who were taking vitamin D preparations were excluded, and data for 79 patients (33 males and 46 females) were analyzed. Since menopausal status can be associated with serum vitamin D level, we divided the patients by gender and divided the female patients into two groups at the age of 50 years. Results The median serum 1,25D/25D ratio was significantly lower in males than in females, with the most considerable difference in all males [4.1 (interquartile range: 2.3-5.8) × 10-3] versus elderly females (aged ≧50 years) [7.9 (3.3-10.1) × 10-3). Main disorders were endocrine (30.6%), inflammatory (18.5%), and bone-related (16.7%) disorders. The ratios of serum 1,25D/25D had significant negative correlations with femoral dual-energy X-ray absorptiometry % young adult mean (DEXA %YAM) (R=-0.35) and lumbar DEXA %YAM (R=-0.32). Significant correlations were found between the 1,25D/25D ratio and serum levels of inorganic phosphate (iP), parathyroid hormone, and alkaline phosphatase (ALP). The 1,25D/25D ratio had gender-specific characteristics: the ratio was significantly correlated with age in males (R=-0.49), while it was significantly correlated with BMI in females (R=0.34). Conclusions The results of this study suggested that vitamin D activity is negatively correlated with bone mineral density, being reduced in aged males but enhanced in obese females.

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  • Candidemia in COVID-19 treated with corticosteroids and tocilizumab. International journal

    Koichiro Yamamoto, Kaoru Nakamura, Hideharu Hagiya, Fumio Otsuka

    Clinical case reports   9 ( 9 )   e04858   2021.9

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    COVID-19 patients treated with anti-inflammatory drugs are rarely complicated by candidemia. Since immunosuppressive therapy can blunt inflammatory reactions, clinicians should actively survey latent candidemia during severe COVID-19 treatment.

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  • Total vascular resistance, augmentation index, and augmentation pressure increase in patients with peripheral artery disease. International journal

    Rika Takemoto, Haruhito A Uchida, Hironobu Toda, Ken Okada, Fumio Otsuka, Hiroshi Ito, Jun Wada

    Medicine   100 ( 32 )   e26931   2021.8

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    ABSTRACT: Peripheral arterial disease (PAD) is one of major vascular diseases which frequently coexists with coronary arterial disease and cerebrovascular disease. The patients with PAD have a poor prognosis when it progresses. A new blood pressure testing device enables to simultaneously measure brachial blood pressure (BP), central BP, and several vascular parameters, with easy and non-invasive, in a short time. Here, we aimed to evaluate these arterial stiffness parameters in patients with PAD.In this study, 243 consecutive patients who were suspected of having PAD and referred to our hospital from September 2016 to June 2019, were registered. Several parameters, such as brachial BP, central BP, aortic pulse wave velocity (aPWV), total vascular resistance (TVR), augmentation index (AI) and augmentation pressure (AP), were determined by Mobil-O-Graph. Ankle-brachial pressure index (ABI) was used to define PAD (ABI ≤ 0.9 as PAD). The relationship between PAD and central BP, aPWV, TVR, AI, or AP were investigated.One hundred sixty-two patients (67%) were categorized as the PAD group and 81 patients (33%) as the non-PAD group. In the PAD group, the systolic brachial BP and central systolic BP were significantly higher than those in the non-PAD group (138 ± 24 mmHg vs 131 ± 19 mmHg, P < .05, 125 ± 22 mmHg vs 119 ± 18 mmHg, P < .05, respectively). TVR, AI, and AP were significantly higher in the PAD group (1785 ± 379 dyn s/cm5 vs 1661 ± 317 dyn s/cm5, P < .05, 26.2 ± 13.0% vs 22.2 ± 13.3%, P < .05, 13.5 ± 9.4 mmHg vs 10.7 ± 7.2 mmHg, P < .05, respectively). No significant differences in diastolic BP, central diastolic BP, and aPWV were found between the groups. Multivariate logistic regression analysis revealed that PAD was significantly associated with TVR, AI, and AP (P < .05, respectively).TVR/AP/AI were significantly higher in the PAD group than in the non-PAD group.

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  • Effectiveness of supplemental oral calcium drink in preventing citrate-related adverse effects in peripheral blood progenitor cell collection. International journal

    Keiko Fujii, Nobuharu Fujii, Takumi Kondo, Toshiharu Mitsuhashi, Makoto Nakamura, Keisuke Seike, Yasuhisa Sando, Maiko Kimura, Masayuki Matsuda, Shuntaro Ikegawa, Hiroyuki Sugiura, Fumio Otsuka, Yoshinobu Maeda

    Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis   60 ( 4 )   103147 - 103147   2021.8

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    Peripheral blood progenitor cells (PBPCs) are a predominant graft source in allogeneic hematopoietic cell transplantation. Citrate-induced hypocalcemia remains the most frequent side effect of PBPC apheresis. Although the method for preventing severe adverse events is established, more efficient prophylaxis is required so that volunteer donors can donate PBPCs without pain and anxiety. We studied 80 healthy donors who underwent PBPC harvest between February 2014 and June 2020. Of these, 23 donors who underwent apheresis between February 2014 and December 2015 received only the standard prophylaxis of intravenous calcium gluconate. Oral calcium drinks were provided to 57 donors who underwent apheresis from January 2016 to June 2020 to supplement intravenous calcium gluconate prophylaxis. The ionized calcium (ICa) levels at multiple time intervals and the hypocalcemic symptoms were evaluated. Oral supplementation with a calcium drink maintained significantly higher ICa levels. Analysis using the inverse probability weighted regression adjustment method suggested that calcium drinks reduced the frequency of citrate-related reactions by 39.2 %. Administering a prophylactic oral calcium drink before apheresis with intravenous administration of calcium gluconate is promising to further reduce citrate-induced hypocalcemia in volunteer donors.

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  • High-Dose Corticosteroids for a Pregnant Woman Critically Ill With Coronavirus Disease 2019. International journal

    Koichiro Yamamoto, Hideharu Hagiya, Jota Maki, Shuji Okahara, Kou Hasegawa, Fumio Otsuka

    Cureus   13 ( 8 )   e17398   2021.8

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    Pregnancy was reported to be a risk factor for coronavirus disease 2019 (COVID-19), with an increased risk for premature birth. Corticosteroids and remdesivir are used for patients with COVID-19; however, there is no established treatment for these patients. In particular, the effective management of pregnant, critically ill patients with COVID-19 remains unknown. We describe a 34-year-old, critically ill woman at 30 weeks of gestation with COVID-19, who was successfully treated with remdesivir and combined high-dose betamethasone (12 mg/day for two days) and methylprednisolone (125 mg/day for three days) followed by steroid tapering. During treatment, fetal biophysical profile scores on obstetric ultrasound were normal; her pregnancy course progressed well. Since high-dose corticosteroids improve fetal lung maturation and as well as cytokine storm due to COVID-19, this case provides an insight into the management of pregnant COVID-19 patients.

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  • No Association Observed Between the Number of Infectious Disease Experts and Prevalence of Antimicrobial-Resistant Pathogens in Japan. International journal

    Hideharu Hagiya, Fumio Otsuka

    Cureus   13 ( 8 )   e16918   2021.8

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    INTRODUCTION: The global spread of emerging infections has increased the demand for infectious disease (ID) experts. There is no established method to evaluate the sufficiency of professionals on a regional basis. We aimed to determine the correlation of the number of ID doctors and certified nurses in infection control (CNIC) with the prevalence of representative antimicrobial-resistant (AMR) pathogens across the 47 prefectures in Japan using publicly available databases. METHODS: We determined the number of ID doctors and CNIC registered in each prefecture based on the Japanese Association for Infectious Diseases and the Japanese Nursing Association websites and calculated their numbers per 100,000 population. Data on representative AMR pathogens were extracted from the Japan Nosocomial Infections Surveillance database. Spearman's correlation coefficient was used to measure statistical associations. RESULTS: There was no epidemiologically applicable correlation between the deployment of ID doctors and CNIC and the isolation rates of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, cefotaxime- or levofloxacin-resistant Escherichia coli and Klebsiella pneumoinae, and meropenem-resistant Pseudomonas aeruginosa. Solely, the isolation rate of levofloxacin-resistant K. pneumoinae and the number of CNIC were statistically correlated (correlation coefficient = -0.33; p = 0.02), while the isolation rate of cefotaxime-resistant E. coli was paradoxically correlated with the number of ID doctors (correlation coefficient = 0.33; p = 0.02). Conclusions: Our macroscopic analysis using the open database was not a reliable method to evaluate the sufficiency of ID experts across the prefectures in Japan. A scheme to assess the appropriate distribution of ID experts should be developed.

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  • An Elderly Male with Primary Sjögren's Syndrome Presenting Pleuritis as the Initial Manifestation.

    Yukichika Yamamoto, Yuki Otsuka, Takayuki Katsuyama, Yoshito Nishimura, Kosuke Oka, Kou Hasegawa, Hideharu Hagiya, Fumio Otsuka

    Acta medica Okayama   75 ( 4 )   539 - 542   2021.8

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    Primary Sjögren's syndrome (SS) is an autoimmune disease that usually affects the exocrine glands in mid-dle-aged women. Fifteen percent of SS patients experience severe systemic extraglandular complications, and pleuritis is one of the rare complications of SS. We report the case of an elderly Japanese man who initially pre-sented with a prolonged fever and chest pain and was finally diagnosed with primary SS-associated pleuritis. Of the nine reported cases of primary SS that initially presented with pleuritis, up to six cases were elderly males. This case highlights the complication of pleuritis among elderly males with primary SS.

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  • High-dose steroids for the treatment of severe COVID-19: comment. International journal

    Shuichi Tanaka, Koichiro Yamamoto, Hideharu Hagiya, Kou Hasegawa, Fumio Otsuka

    Internal and emergency medicine   16 ( 5 )   1415 - 1416   2021.8

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  • Pseudo-Cushing's state in a patient with non-functioning pituitary adenoma. International journal

    Koichiro Yamamoto, Yoshihisa Hanayama, Fumio Otsuka

    BMJ case reports   14 ( 7 )   2021.7

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  • Trends in the Nontuberculous Mycobacterial Disease Mortality Rate in Japan: A Nationwide Observational Study, 1997-2016. International journal

    Ko Harada, Hideharu Hagiya, Tomoko Funahashi, Toshihiro Koyama, Mitsunobu R Kano, Fumio Otsuka

    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America   73 ( 2 )   e321-e326 - E326   2021.7

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    BACKGROUND: The incidence of nontuberculous mycobacterial (NTM) infections has been increasing worldwide, becoming a significant healthcare burden especially among elderly people. This study aimed to evaluate the trends in NTM-associated mortality in Japan. METHODS: This study used vital statistics data and data on all NTM-associated deaths (N = 18 814) among individuals aged ≥40 years in Japan from 1997 to 2016. We calculated the crude and age-adjusted mortality rates by age and sex and used joinpoint regression to analyze trends and estimate the average annual percentage change (AAPC). We compared crude NTM- and tuberculosis-associated mortality rates by sex. RESULTS: The overall crude annual mortality rate increased from 0.63/100 000/year in 1997 to 1.93/100 000/year in 2016 and was the highest among individuals aged 80-84 years. The AAPC of the crude mortality rates among men of all ages and women aged 40-59 years were stable but increased among women aged 60-79 years (3.5%; 95% confidence interval [CI], 2.8-4.3) and ≥80 years (4.3%; 95% CI, 3.7-4.9). Among men, the age-adjusted mortality rates did not show a significant trend, while among women, the rates increased over the study period (AAPC, 4.6%; 95% CI, 2.7-6.6). In women, the crude NTM-associated mortality rate exceeded the tuberculosis mortality rate in 2014, 2015, and 2016. CONCLUSIONS: NTM mortality increased in Japan between 1997 and 2016, especially among the elderly female population. Given the increasing NTM-associated mortality and the susceptible aging population, public health authorities in Japan should pay greater attention to NTM infections.

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  • Acute Pancreatitis Related to COVID-19 Infection.

    Koichiro Yamamoto, Kosuke Oka, Hiroyuki Sakae, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   60 ( 13 )   2159 - 2160   2021.7

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  • Large-vessel vasculitis induced by granulocyte colony-stimulating factor administration after chemotherapy. International journal

    Koichiro Yamamoto, Nayu Tamura, Kosuke Oka, Kou Hasegawa, Hideharu Hagiya, Madoka Hokama, Joji Ishida, Fumio Otsuka

    Modern rheumatology case reports   5 ( 2 )   322 - 326   2021.7

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    Granulocyte colony-stimulating factor (G-CSF) is a relatively new drug that is used for recovery of chemotherapy-associated neutropenia. It is known to cause bone pain, headache and fatigue as side-effects; however, large-vessel vasculitis is extremely rare and its relation with G-CSF remains unknown. We describe a 49-year-old woman in whom arteritis developed after chemotherapy and subsequent G-CSF administration. She had experienced pinealoma 3 months ago and received surgery and chemotherapy, leading to neutropenia. After administration of lenograstim at 100 μg/day for 1 week, high fever and neck pain appeared. White blood cell count and serum levels of C-reactive protein and interleukin-6 were increased to 37,930/μL, 23.71 mg/dL, and 241 pg/mL, respectively. Contrast-enhanced computed tomography revealed thickened walls of large vessels including the bilateral common carotid artery (CCA), right brachiocephalic artery, and ascending aorta. Ultrasonography showed wall thickening of the CCA (maximum of intima media thickness: right, 2.9 mm; left, 3.2 mm). As differential diagnoses, infection, chemotherapy, autoimmune diseases, and cancer were considered other than G-CSF. Blood culture tests, lumbar puncture, β-D-glucan tests, and tests for viral antibodies indicated no active infection, and autoantibodies were negative. Empirical antibiotic therapy was ineffective. The score of Naranjo's algorithm to lenograstim was 6, indicating "probable" causality. Considering the clinical course and test results, we made a diagnosis of G-CSF-associated arteritis and commenced glucocorticoid therapy, which drastically improved the symptoms and inflammation. Clinicians should be aware of this uncommon but significant complication of GCS-F administration, for which glucocorticoid treatment can be a useful therapeutic option.

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  • Successful deceased donor kidney transplantation to a recipient with a history of COVID-19 treatment. International journal

    Kasumi Yoshinaga, Motoo Araki, Koichiro Wada, Kou Hasegawa, Takanori Sekito, Shuji Miyake, Shogo Watari, Yuki Maruyama, Takuya Sadahira, Shingo Nishimura, Katsuyuki Tanabe, Hidemi Takeuchi, Yuri Nakashima, Masaru Kinomura, Herik Acosta, Yosuke Mitsui, Risa Kubota, Hirochika Nakajima, Kohei Edamura, Yasuyuki Kobayashi, Masami Watanabe, Toyohiko Watanabe, Fumio Otsuka, Jun Wada, Yasutomo Nasu

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   27 ( 7 )   1097 - 1101   2021.7

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    CASE PRESENTATION: A 49-year-old Asian male, who had undergone hemodialysis for >16 years, complained of a fever, dysgeusia and dysosmia, and was diagnosed with COVID-19 pneumonia based on severe acute respiratory syndrome coronavirus 2 polymerase chain reaction (SARS-CoV-2 PCR) and computed tomography (CT). Treatment was started with oral favipiravir and ciclesonide inhalation. On the 10th day of treatment, the patient had a persistent high fever and a chest CT showed exacerbation of pneumonia, so dexamethasone was intravenously started. He was discharged after confirming two consecutive negative SARS-CoV-2 PCR tests. Three months after COVID-19 treatment, a SARS-CoV-2 PCR test was negative and he underwent a deceased donor kidney transplantation. Basiliximab induction with triple drug immunosuppression consisting of extended-release tacrolimus, mycophenolate mofetil and prednisolone, which is our regular immunosuppression protocol, was used. He was discharged on postoperative day 18 without the need for postoperative hemodialysis or any complications. The serum creatinine level was 1.72 mg/dL 95 days postoperatively and he had a favorable clinical course that was similar to deceased donor kidney recipients without a history of SARS-CoV-2 infection. CONCLUSION: We report the first case of a kidney transplantation after COVID-19 treatment in Japan and the fourth case globally. We would like to provide information about our successful case due to the anticipated increase in similar candidates in the near future.

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  • Deployment of Infectious Disease Experts and Prevalence of Antimicrobial Resistance in Okayama: A Call for Training of Specialists. International journal

    Hideharu Hagiya, Koji Fujita, Shinya Kamiyama, Kazuki Ocho, Haruto Yamada, Fumio Otsuka

    Cureus   13 ( 7 )   e16643   2021.7

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    Objective During the ongoing global pandemic of novel coronavirus disease 2019 (COVID-19), an emerging infectious disease, the implementation and execution of infection prevention and control (IPC) is of paramount importance. In this study, we aimed to assess the current deployment of infection control medical personnel in Okayama prefecture, who are supposed to play an essential role to prevent the outbreak of infectious diseases, and the current prevalence of antimicrobial-resistant (AMR) bacteria isolated in Okayama. Materials and methods This was a descriptive study using publicly available data. The numbers of infectious disease (ID)-doctors and the certified nurses in infection control (CNIC) per 100,000 population in 47 prefectures in Japan were calculated. We then compared the detected proportions of AMR pathogens among the prefectures in 2019 to be employed as a comparative parameter, which was obtained from Japan Nosocomial Infections Surveillance (JANIS) data. Results The number of ID-doctors was the 11th highest in Japan; however, they were unevenly distributed in southern Okayama, particularly at three tertiary hospitals. While the deployment of CNIC was geographically less uneven in the prefecture, their number was lower than the domestic average. According to the JANIS data, isolation rates of AMR pathogens were high in Okayama compared to other prefectures in Japan: vancomycin-resistant Enterococcus faecium (the third-worst); cefotaxime-resistant Escherichia coli and Klebsiella pneumoniae (the third-worst and the second-worst, respectively); and meropenem-resistant Pseudomonas aeruginosa (the worst). Conclusions Our assessment provides underlying data and reinforces the need for educating multi-professional experts in the field of infectious diseases to prevent future public health threats in Okayama.

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  • Barium appendicitis. International journal

    Daisuke Omura, Naoko Yunoki, Yuki Otsuka, Yasuhiro Nakano, Hideharu Hagiya, Fumio Otsuka

    Clinical case reports   9 ( 7 )   e04583   2021.7

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    We have presented a case of barium appendicitis, which is a rare complication of barium enema studies. Barium sulfate is used widely for gastrointestinal radiographic studies and is associated with few complications. Clinicians need to be fully aware of this complication.

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  • A patient with human coronavirus NL63 falsely diagnosed with COVID-19; Lesson learned for the importance of definitive diagnosis. International journal

    Yuki Otsuka, Hideharu Hagiya, Yasuhiro Nakano, Daisuke Omura, Kou Hasegawa, Haruto Yamada, Koji Iio, Tomoyuki Honda, Fumio Otsuka

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   27 ( 7 )   1126 - 1128   2021.7

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    The gold standard for the diagnosis of coronavirus disease 2019 (COVID-19) is a nucleic acid detection test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may occasionally reveal false-positive or false-negative results. Herein, we describe a case of a patient infected with human coronavirus NL63 (HCoV-NL63) who was falsely diagnosed with COVID-19 using the Ampdirect™ 2019-nCoV detection kit (Shimadzu Corporation, Japan) and SARS-CoV-2 Detection Kit (TOYOBO co., ltd.), and was admitted to a COVID-19 hospital ward. We suspected a cross-reaction between HCoV-NL63 and SARS-CoV-2; however, the reported genome sequences of HCoV-NL63 and N1/N2 primers for SARS-CoV-2 do not correspond. Thus, the PCR result was supposed to be a false positive possibly due to contamination or human error. Although the issue of a false-negative result has been the focus of much attention to prevent the spread of the disease, a false positive is fraught with problems as well. Physicians should recognize that unnecessary isolation violates human rights and a careful diagnosis is indispensable when the results of laboratory testing for COVID-19 are unclear. Generally, in cases such as a duplicate PCR test was partially positive, either N1 or N2 alone was positive, PCR testing for two or more target regions resulted in a positive only for single region, a high cycle threshold >35 was obtained, a false positive should be suspected. Especially, when these conditions coincide, we should recognize the high likelihood of a false positive.

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  • Acute pancreatitis without abdominal pain induced by administration of nivolumab and ipilimumab. International journal

    Koichiro Yamamoto, Kosuke Oka, Reina Son, Hiroyuki Honda, Hiroyuki Sakae, Kou Hasegawa, Shigeru Horiguchi, Hironari Kato, Osamu Yamasaki, Fumio Otsuka

    Modern rheumatology case reports   5 ( 2 )   425 - 430   2021.7

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    Immune checkpoint inhibitors (ICIs) such as nivolumab and ipilimumab are emerging agents for the treatment of cancers including melanoma. ICIs are known to cause immune-related adverse events (irAEs), including the development of enterocolitis, dermatitis, and nephritis. However, ICI-induced pancreatitis has seldom been reported, and its pathophysiology and clinical importance remain largely unknown. We describe a 76-year-old man with melanoma who developed acute pancreatitis without abdominal pain after immunotherapy with nivolumab and ipilimumab. The patient was referred due to 2-week-long general fatigue, anorexia, and dermatitis after his second immunotherapy. Laboratory examinations in serum showed high inflammation and renal dysfunction. Plain computed tomography (CT) on admission showed no new lesions including colitis or pancreatitis. On the 4th day of hospitalisation, serum pancreatic enzymes were extremely elevated. Amylase was increased to 683 U/L (normal range: 44-132) and lipase was increased to 1520 U/L (13-55), but he had no abdominal tenderness. Contrast-enhanced CT showed enlarged pancreatic parenchyma and magnetic resonance cholangiopancreatography showed peripancreatic fat stranding, suggesting pancreatitis. Blood culture tests and empirical antibiotic therapy with ceftriaxone indicated no active infectious diseases. We diagnosed ICI-induced pancreatitis and treated him with 0.5 mg/kg/day of prednisolone, which improved his general fatigue, anorexia, dermatitis, and pancreatitis. The potential significance of asymptomatic elevations of pancreatic enzymes has been unclear; however, this case suggested that ICI-induced pancreatitis without abdominal tenderness could be clinically significant. Clinicians should pay attention to the development of latent pancreatitis in patients receiving ICIs, even those without abdominal pain.

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  • Preclinical diagnosis and identification of the chimeric CYP11B1/CYP11B2 gene in two pediatric cases of a Japanese family with glucocorticoid-remediable aldosteronism. International journal

    Yasuhiro Nakano, Nahoko Iwata, Kanako Ogura-Ochi, Kosei Hasegawa, Akira Hirasawa, Fumio Otsuka

    Hypertension research : official journal of the Japanese Society of Hypertension   44 ( 7 )   891 - 893   2021.7

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  • Involvement of BMP-15 in glucocorticoid actions on ovarian steroidogenesis by rat granulosa cells. International journal

    Chiaki Kashino, Toru Hasegawa, Yasuhiro Nakano, Nahoko Iwata, Koichiro Yamamoto, Yasuhiko Kamada, Hisashi Masuyama, Fumio Otsuka

    Biochemical and biophysical research communications   559   56 - 61   2021.6

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    To elucidate the impact of glucocorticoids on ovarian steroidogenesis and its molecular mechanism by focusing on bone morphogenetic proteins (BMPs), we examined the effect of dexamethasone (Dex) on estradiol and progesterone synthesis by using primary culture of rat granulosa cells. It was revealed that Dex treatment dose-dependently decreased estradiol production but increased progesterone production induced by follicle-stimulating hormone (FSH) by granulosa cells. In accordance with the effects of Dex on estradiol synthesis, Dex suppressed P450arom mRNA expression and cAMP synthesis induced by FSH. Dex treatment in turn enhanced basal as well as FSH-induced levels of mRNAs encoding the enzymes for progesterone synthesis including P450scc and 3βHSD but not StAR and 20αHSD. Of note, Dex treatment significantly upregulated transcription of the BMP target gene Id-1 and Smad1/5/9 phosphorylation in the presence of BMP-15 among the key ovarian BMP ligands. It was also found that Dex treatment increased the expression level of BMP type-I receptor ALK-6 among the type-I and -II receptors for BMP-15. Inhibitory Smad6/7 expression was not affected by Dex treatment. On the other hand, BMP-15 treatment upregulated glucocorticoid receptor (GR) expression in granulosa cells. Collectively, it was revealed that glucocorticoids elicit differential effects on ovarian steroidogenesis, in which GR and BMP-15 actions are mutually enhanced in granulosa cells.

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  • Hypothalamic Mass Detected in Langerhans Cell Histiocytosis.

    Ryosuke Takase, Yasuhiro Nakano, Shin Morizane, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   60 ( 11 )   1795 - 1795   2021.6

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  • Isolated adrenocorticotropin deficiency induced by pembrolizumab for hypopharyngeal cancer: A case report. International journal

    Koichiro Yamamoto, Kazuki Tokumasu, Kosuke Oka, Kou Hasegawa, Fumio Otsuka

    Clinical case reports   9 ( 6 )   e04305   2021.6

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    We report a case of isolated adrenocorticotropin deficiency caused by pembrolizumab. This condition can be fatal, but its rarity causes under-recognition. Oncologists should pay attention to adrenal insufficiency due to pembrolizumab.

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  • Interrelationships Between Serum Levels of Procalcitonin and Inflammatory Markers in Patients Who Visited a General Medicine Department.

    Jo Araki, Kosuke Oka, Koichiro Yamamoto, Yoshihisa Hanayama, Kazuki Tokumasu, Hideharu Hagiya, Hiroko Ogawa, Koichi Itoshima, Fumio Otsuka

    Acta medica Okayama   75 ( 3 )   299 - 306   2021.6

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    Various laboratory markers of inflammation are utilized in general practice, but their clinical diagnostic significance is often ambiguous. In the present study, we determined the clinical significance of the examination of serum levels of procalcitonin (PCT) by comparing the PCT levels with the levels of other inflammatory markers, based on a retrospective review of 332 PCT-positive patients, including cases of bacterial infection (20.5%), non-specific inflammation (20.8%), neoplasm (9.9%), connective tissue diseases (8.4%), and non-bacterial infection (7.2%), were analyzed. The serum PCT level was highest in the bacterial infection group (1.94 ng/ml) followed by the non-specific inflammatory group (0.58 ng/ml) and neoplastic diseases group (0.34 ng/ml). The serum PCT level was positively correlated with serum levels of C-reactive protein (rho=0.62), soluble interleukin-2 receptor (sIL-2R; rho=0.69), and ferritin, the plasma level of D-dimer, and white blood cell count, and negatively correlated with the serum albumin level (rho=-0.52), hemoglobin concentration, and platelet count. The serum PCT level showed a stronger positive correlation with the serum sIL-2R level than the other biomarkers. The results suggest that an increased PCT level may indicate not only an infectious state but also a non-bacterial inflammatory condition in the diagnostic process in general practice.

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  • Orbital mass and hairy kidney as characteristics of Erdheim-Chester disease. International journal

    Koichiro Yamamoto, Kosuke Oka, Kou Hasegawa, Fumio Otsuka

    Clinical case reports   9 ( 6 )   e04333   2021.6

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    Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, involving multiple organs. We report a case of ECD with typical features of an orbital mass and "hairy kidneys," whose recognition can lead to early diagnosis and treatment.

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  • Leucine-rich alpha-2 glycoprotein as a marker of mucosal healing in inflammatory bowel disease. International journal

    Eriko Yasutomi, Toshihiro Inokuchi, Sakiko Hiraoka, Kensuke Takei, Shoko Igawa, Shumpei Yamamoto, Masayasu Ohmori, Shohei Oka, Yasushi Yamasaki, Hideaki Kinugasa, Masahiro Takahara, Keita Harada, Masaki Furukawa, Kouichi Itoshima, Ken Okada, Fumio Otsuka, Takehiro Tanaka, Toshiharu Mitsuhashi, Jun Kato, Hiroyuki Okada

    Scientific reports   11 ( 1 )   11086 - 11086   2021.5

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    Leucine-rich alpha-2 glycoprotein (LRG) may be a novel serum biomarker for patients with inflammatory bowel disease. The association of LRG with the endoscopic activity and predictability of mucosal healing (MH) was determined and compared with those of C-reactive protein (CRP) and fecal markers (fecal immunochemical test [FIT] and fecal calprotectin [Fcal]) in 166 ulcerative colitis (UC) and 56 Crohn's disease (CD) patients. In UC, LRG was correlated with the endoscopic activity and could predict MH, but the performance was not superior to that of fecal markers (areas under the curve [AUCs] for predicting MH: LRG: 0.61, CRP: 0.59, FIT: 0.75, and Fcal: 0.72). In CD, the performance of LRG was equivalent to that of CRP and Fcal (AUCs for predicting MH: LRG: 0.82, CRP: 0.82, FIT: 0.70, and Fcal: 0.88). LRG was able to discriminate patients with MH from those with endoscopic activity among UC and CD patients with normal CRP levels. LRG was associated with endoscopic activity and could predict MH in both UC and CD patients. It may be particularly useful in CD.

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  • Droopy eyelid due to IgG4-related dacryoadenitis. International journal

    Ryosuke Takase, Hideharu Hagiya, Kazuki Tokumasu, Yoshito Nishimura, Atsunobu Sakurai, Kou Hasegawa, Yoshihisa Hanayama, Fumio Otsuka

    Postgraduate medical journal   97 ( 1147 )   333 - 334   2021.5

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  • Clinical Utility of the Ratio of Urinary Free Cortisol to Aldosterone as an Index for Inflammatory and Metabolic Dysregulation. International journal

    Yuki Otsuka, Yasuhiro Nakano, Kazuki Tokumasu, Hiroyuki Honda, Mikako Obika, Kou Hasegawa, Yoshihisa Hanayama, Koichi Itoshima, Fumio Otsuka

    Annals of clinical and laboratory science   51 ( 3 )   352 - 358   2021.5

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    OBJECTIVE: Urinary free cortisol (UFC) is a reliable marker to avoid cortisol fluctuation and the effects of binding proteins. However, UFC levels are affected by fluid intake and urine volume, and the normal levels range widely. METHODS: To discover the utility of the ratio of urinary cortisol to aldosterone excretions, 246 patients in whom daily excretions of UFC and aldosterone (UAC) were measured were retrospectively analyzed. RESULTS: The UFC/UAC ratio showed significant positive and negative correlations with the levels of serum cortisol (R=0.287) and aldosterone (R=-0.762), respectively. The UFC/UAC ratio increased with aging in female patients, while it was not altered by the level of BMI in either gender. Markers for metabolic and inflammatory status, including hemoglobin A1c (R=0.327), albumin (R=-0.331), C-reactive protein (R=0.317), ferritin (R=0.473), and D-dimer (R=0.569), showed correlations with the ratio of UFC/UAC that were more significant than the correlations with the serum level of cortisol or UFC alone. Of note, the UFC/UAC ratio was shown to be an indicator for the risk of diabetes (AUC: 0.765), hypoalbuminemia (0.839), hyper-CRPemia (0.748), and thrombophilia (0.824), in which the cut-off levels of the UFC/UAC ratio were around 12. CONCLUSION: The UFC/UAC ratio is a variable for detecting metabolic and inflammatory complications related to adrenocortical dysfunction.

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  • Pseudoacromegaly with acromegalic features in radiography. International journal

    Koichiro Yamamoto, Kosuke Oka, Hiroyuki Honda, Kou Hasegawa, Fumio Otsuka

    Clinical case reports   9 ( 5 )   e04095   2021.5

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    Pseudoacromegaly is a condition characterized by acromegalic physical features without growth hormone excess, for which radiographic observation has seldom been reported. This is a rare case of pseudoacromegaly.

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  • HIV-associated cerebral lymphoma in an elderly patient.

    Yuki Otsuka, Hideharu Hagiya, Yasuhiro Nakano, Ryu Kimura, Kentaro Fujii, Fumio Otsuka

    Geriatrics & gerontology international   21 ( 5 )   435 - 436   2021.5

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  • Orexin A Enhances Pro-Opiomelanocortin Transcription Regulated by BMP-4 in Mouse Corticotrope AtT20 Cells. International journal

    Satoshi Fujisawa, Motoshi Komatsubara, Naoko Tsukamoto-Yamauchi, Nahoko Iwata, Takahiro Nada, Jun Wada, Fumio Otsuka

    International journal of molecular sciences   22 ( 9 )   2021.4

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    Orexin is expressed mainly in the hypothalamus and is known to activate the hypothalamic-pituitary-adrenal (HPA) axis that is involved in various stress responses and its resilience. However, the effects of orexin on the endocrine function of pituitary corticotrope cells remain unclear. In this study, we investigated the roles of orexin A in pro-opiomelanocortin (POMC) transcription using mouse corticotrope AtT20 cells, focusing on the bone morphogenetic protein (BMP) system expressed in the pituitary. Regarding the receptors for orexin, type 2 (OXR2) rather than type 1 (OX1R) receptor mRNA was predominantly expressed in AtT20 cells. It was found that orexin A treatment enhanced POMC expression, induced by corticotropin-releasing hormone (CRH) stimulation through upregulation of CRH receptor type-1 (CRHR1). Orexin A had no direct effect on the POMC transcription suppressed by BMP-4 treatment, whereas it suppressed Smad1/5/9 phosphorylation and Id-1 mRNA expression induced by BMP-4. It was further revealed that orexin A had no significant effect on the expression levels of type I and II BMP receptors but upregulated inhibitory Smad6/7 mRNA and protein levels in AtT20 cells. The results demonstrated that orexin A upregulated CRHR signaling and downregulated BMP-Smad signaling, leading to an enhancement of POMC transcription by corticotrope cells.

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  • Dysphagia Induced by Acromegalic Arthropathy.

    Manami Fujita, Yasuhiro Nakano, Hiroyuki Sakae, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   60 ( 7 )   1127 - 1128   2021.4

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  • An adrenal incidentaloma caused by synchronous and isolated metastasis. International journal

    Koichiro Yamamoto, Kosuke Oka, Hiroyuki Honda, Kou Hasegawa, Yoshihisa Hanayama, Tomofumi Watanabe, Yusuke Tominaga, Atsushi Takamoto, Takayuki Hara, Fumio Otsuka

    Clinical case reports   9 ( 4 )   2494 - 2495   2021.4

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    We report a patient with adrenal incidentaloma due to synchronous and isolated metastasis from lung cancer, which is a relatively rare condition. Close checkups for incidentaloma in oncologic patients are mandatory, leading to successful operation.

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  • 性腺機能低下を伴いコロナ禍で高度肥満を呈した成人21-水酸化酵素欠損症の1例

    山本 紘一郎, 岡 浩介, 長谷川 功, 越智 可奈子, 中野 靖浩, 徳増 一樹, 本多 寛之, 小比賀 美香子, 大塚 文男

    日本内分泌学会雑誌   96 ( 4 )   1041 - 1041   2021.4

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  • 高度肥満・性腺機能低下を来した21-水酸化酵素欠損症成人男性の1例

    山本 紘一郎, 岡 浩介, 藤田 茉奈美, 孫 麗那, 長谷川 功, 越智 可奈子, 中野 靖浩, 徳増 一樹, 本多 寛之, 小比賀 美香子, 大塚 文男

    日本内分泌学会雑誌   97 ( 1 )   351 - 351   2021.4

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  • 総合診療における血清プロカルシトニン値と炎症・代謝マーカーの関連性

    荒木 晴, 岡 浩介, 山本 紘一郎, 花山 宜久, 徳増 一樹, 萩谷 英大, 小比賀 美香子, 小川 弘子, 糸島 浩一, 大塚 文男

    日本内分泌学会雑誌   97 ( 1 )   338 - 338   2021.4

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  • ビタミンD活性化指標(1,25D/25D比)の臨床的有用性の検討

    藤田 茉奈美, 山本 紘一郎, 本多 寛之, 花山 宜久, 徳増 一樹, 中野 靖浩, 長谷川 功, 小比賀 美香子, 大塚 文男

    日本内分泌学会雑誌   97 ( 1 )   337 - 337   2021.4

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  • グルココルチコイドによる卵胞ステロイド合成調節とBMP分子の関与

    樫野 千明, 長谷川 徹, 中野 靖浩, 山本 紘一郎, 長尾 聡子, 岩田 菜穂子, 鎌田 泰彦, 増山 寿, 大塚 文男

    日本内分泌学会雑誌   96 ( 4 )   1076 - 1076   2021.4

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  • グルココルチコイドによる卵胞顆粒膜細胞のステロイド合成調節とBMP-15の関与

    樫野 千明, 長谷川 徹, 中野 靖浩, 岩田 菜穂子, 山本 紘一郎, 鎌田 泰彦, 増山 寿, 大塚 文男

    日本内分泌学会雑誌   97 ( 1 )   359 - 359   2021.4

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  • 副腎皮質ステロイド合成における時計遺伝子およびBMP/activinの関与

    副島 佳晃, 岩田 菜穂子, 中野 靖浩, 山本 紘一郎, 須山 敦仁, 灘 隆宏, 小川 弘子, 大塚 文男

    日本内分泌学会雑誌   97 ( 1 )   281 - 281   2021.4

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  • 著明なALP高値を契機に発見された若年発症の副甲状腺癌の1例

    長谷川 功, 大塚 勇輝, 原田 洸, 中野 靖浩, 安田 美帆, 萩谷 英大, 三好 智子, 小川 弘子, 小野 早和子, 枝園 忠彦, 平沢 晃, 柳井 広之, 大塚 文男

    日本内分泌学会雑誌   97 ( 1 )   277 - 277   2021.4

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  • 副腎皮質ステロイド合成における時計遺伝子およびBMP/activinの関与

    副島 佳晃, 岩田 菜穂子, 中野 靖浩, 山本 紘一郎, 須山 敦仁, 灘 隆宏, 小川 弘子, 大塚 文男

    日本内分泌学会雑誌   97 ( 1 )   228 - 228   2021.4

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  • Endogenous Bacterial Endophthalmitis Caused by Iliopsoas Abscess.

    Weiying Sun, Yusuke Shiode, Kazuki Tokumasu, Shuhei Kimura, Mio Hosokawa, Shinichiro Doi, Kosuke Takahashi, Ryo Matoba, Fumio Otsuka, Yuki Morizane

    Acta medica Okayama   75 ( 2 )   249 - 253   2021.4

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    A 79-year-old woman presented to our hospital with a 10-day history of gradually worsening binocular vision and severe backache. Further investigations revealed poor bilateral best-corrected visual acuities (BCVA), bilateral vitreous opacities, gray-white lesions scattered throughout the retina, and a left iliopsoas abscess on CT that later grew out methicillin-sensitive S. aureus. The abscess was drained and intravenous antibiotics were initiated, but the left eye additionally required intravitreal vancomycin. BCVA for both eyes normalized within 1 year. Intramuscular abscess should be considered as a possible primary lesion in cases of endogenous bacterial endophthalmitis.

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  • Trends in the incidence and mortality of legionellosis in Japan: a nationwide observational study, 1999-2017. International journal

    Shinnosuke Fukushima, Hideharu Hagiya, Yuki Otsuka, Toshihiro Koyama, Fumio Otsuka

    Scientific reports   11 ( 1 )   7246 - 7246   2021.3

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    This study examined temporal trend, seasonality, and geographical variations of legionellosis incidence and mortality in Japan. This nationwide observational study used the Japanese Vital Statistics and Infectious Diseases Weekly Report (1999-2017) data to calculate legionellosis crude and age-adjusted incidence and mortality rates per 100,000 population by age and sex. Incidence was compared among the 4 seasons and regional incidence among 47 prefectures. Of 13,613 (11,194 men) people with legionellosis in Japan, 725 (569 men) were fatal. Increasing incidence trend occurred from 0.0004 (1999) to 1.37 (2017) per 100,000 population. People aged ≥ 70 years accounted for 43.1% overall; men's age-adjusted incidence rate was consistently approximately five times higher than for women. Significantly higher incidence occurred in summer than in winter (p = 0.013). Geographically, highest incidence (≥ 2.0 per 100,000 population) occurred in Hokuriku District, with increasing trends in Hokkaido and middle-part of Japan. Estimated fatality rates decreased consistently at 5.9% (95% confidence interval: - 8.1, - 3.5) annually, from 1999 to 2017, with no trend change point. Increasing legionellosis incidence occurred in Japan during 1999-2017, with declining estimated fatality rates. In this aging society and warming world, disease clinical burden may further deteriorate in future due to increasing incidence trends.

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  • Angina Simultaneously Diagnosed with the Recurrence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International journal

    Koki Li, Yuki Otsuka, Yasuhiro Nakano, Daisuke Omura, Kou Hasegawa, Mikako Obika, Keigo Ueda, Hitomi Kataoka, Fumio Otsuka

    Diagnostics (Basel, Switzerland)   11 ( 3 )   2021.3

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    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) mainly affects young adults and can have a potential impact on social functioning. As this syndrome is associated with endothelial dysfunction, the heart can be damaged via ischemia due to endothelial damage. This might potentially lead to heart failure, which accounts for approximately 20% of deaths among patients with ME/CFS. While cardiac ischemia is thought be a pathophysiologically important manifestation of this syndrome, this is not yet reported. Herein, we present a case of a young female with newly diagnosed vasospastic or microvascular angina and concurrent exacerbation of ME/CFS severity. Her anginal symptoms, including exertional chest pain and transient chest discomfort, mimicked those of ME/CFS but were relieved after the administration of a calcium channel blocker. We emphasize the possibility of concurrent angina and exacerbation of ME/CFS and the importance of detecting cardiac ischemia to avoid unfavorable outcomes.

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  • Burnout of Healthcare Workers amid the COVID-19 Pandemic: A Japanese Cross-Sectional Survey. International journal

    Yoshito Nishimura, Tomoko Miyoshi, Hideharu Hagiya, Yoshinori Kosaki, Fumio Otsuka

    International journal of environmental research and public health   18 ( 5 )   2021.3

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    The coronavirus disease 2019 (COVID-19) global pandemic has drastically changed how we live and work. Amid the prolonged pandemic, burnout of the frontline healthcare professionals has become a significant concern. We conducted a cross-sectional survey study to provide data about the relationship between the COVID-19 pandemic and the prevalence of burnout in healthcare professionals in Japan. Healthcare workers in a single Japanese national university hospital participated in the survey, including basic demographics, whether a participant engaged in care of COVID-19 patients in the past 2 weeks and the Maslach Burnout Inventory. Of those, 25.4% fully answered the survey; 33.3% were doctors and 63.6% were nurses, and 36.3% engaged in care of COVID-19 patients in the past 2 weeks. Compared to those belonging to General Medicine, those in Emergency Intensive Care Unit were at higher risk of burnout (odds ratio (OR), 6.7; 95% CI, 1.1-42.1; p = 0.031). Of those who engaged in care of COVID-19 patients, 50% reported burnout while 6.1% did not (OR 8.5, 95% CI; 1.3-54.1; p = 0.014). The burnout of healthcare workers is a significant concern amid the pandemic, which needs to be addressed for sustainable healthcare delivery.

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  • Ulcer-like Projection Accompanied by Giant Cell Arteritis.

    Yuki Otsuka, Kosuke Oka, Yoshihisa Hanayama, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   60 ( 5 )   819 - 820   2021.3

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  • 総合内科診療に潜む内分泌代謝疾患

    大塚 文男, 小比賀 美香子, 長谷川 功, 中野 靖浩, 徳増 一樹

    日本内科学会雑誌   110 ( 3 )   486 - 491   2021.3

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  • Gingival lesion leading to a diagnosis of angiosarcoma.

    Yasuhiro Nakano, Yosuke Sazumi, Yuki Mizuta, Hiroyuki Sakae, Fumio Otsuka

    Journal of general and family medicine   22 ( 2 )   90 - 91   2021.3

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    A man who presented with a gingival tumor was finally diagnosed with angiosarcoma. It is important for primary care physicians to perform checkups of the oral cavity since oral lesions can lead to a diagnosis of serious systemic diseases.

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  • Simultaneous hot and cold thyroid nodules: Which is malignant? International journal

    Yuki Otsuka, Yasuhiro Nakano, Daisuke Omura, Takayuki Iwamoto, Ruiko Hayashi, Fumio Otsuka

    Clinical case reports   9 ( 3 )   1810 - 1811   2021.3

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    Physicians should be aware of the risk of malignancy in patients with toxic multinodular goiter. Radionuclide scan cannot be used to predict the malignant potential of thyroid nodules. A comprehensive evaluation of imaging studies is needed.

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  • Left-sided appendicitis due to situs inversus totalis. International journal

    Yuki Otsuka, Ruiko Hayashi, Shinichi Urano, Akihide Yashima, Yasuo Nanba, Fumio Otsuka

    Clinical case reports   9 ( 3 )   1791 - 1792   2021.3

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    Situs inversus may mimic the pain localization of acute abdomen. In patients with acute abdomen, especially elderly patients who are medically healthy, physicians should cautiously diagnose the etiology of acute abdomen in combination with imaging studies.

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  • Involvement of clock gene expression, bone morphogenetic protein and activin in adrenocortical steroidogenesis by human H295R cells.

    Yoshiaki Soejima, Nahoko Iwata, Yasuhiro Nakano, Koichiro Yamamoto, Atsuhito Suyama, Takahiro Nada, Hiroko Ogawa, Fumio Otsuka

    Endocrine journal   68 ( 2 )   243 - 250   2021.2

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    Functional interactions between the levels of clock gene expression and adrenal steroidogenesis were studied in human adrenocortical H295R cells. Fluctuations of Bmal1, Clock, Per2 and Cry1 mRNA levels were found in H295R cells treated with forskolin (FSK) in a serum-free condition. The changes of clock gene expression levels were diverged, with Clock mRNA level being significantly higher than Cry1 and Per2 mRNA levels after 12-h stimulation with FSK. After FSK induction, mRNA levels of StAR and CYP11B2 were highest at 12 hours and CYP17 mRNA level reached a peak at 6 hours, but HSD3B1 mRNA level was transiently decreased at 3 hours. The expression levels of Clock mRNA showed a significant positive correlation with StAR among the interrelationships between mRNA levels of key steroidogenic factors and clock genes. Knockdown of Clock gene by siRNA led to a significant reduction of FSK-induced expression of StAR and CYP17 after 12-h treatment with FSK. BMP-6 and activin, which modulate adrenal steroidogenesis, had inhibitory effects on Clock mRNA expression, whereas treatment with follistatin, a binding protein of activin, increased Clock mRNA levels in the presence of FSK, suggesting an endogenous function of activin in regulation of Clock mRNA expression. Collectively, the results indicated that changes of Clock mRNA expression, being upregulated by FSK and suppressed by BMP-6 and activin, were tightly linked to StAR expression by human adrenocortical cells.

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  • Impact of the COVID-19 Pandemic on the Psychological Distress of Medical Students in Japan: Cross-sectional Survey Study. International journal

    Yoshito Nishimura, Kanako Ochi, Kazuki Tokumasu, Mikako Obika, Hideharu Hagiya, Hitomi Kataoka, Fumio Otsuka

    Journal of medical Internet research   23 ( 2 )   e25232   2021.2

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    BACKGROUND: The COVID-19 pandemic has negatively affected medical education. However, little data are available about medical students' distress during the pandemic. OBJECTIVE: This study aimed to provide details on how medical students have been affected by the pandemic. METHODS: A cross-sectional study was conducted. A total of 717 medical students participated in the web-based survey. The survey included questions about how the participants' mental status had changed from before to after the Japanese nationwide state of emergency (SOE). RESULTS: Out of 717 medical students, 473 (66.0%) participated in the study. In total, 29.8% (141/473) of the students reported concerns about the shift toward online education, mostly because they thought online education would be ineffective compared with in-person learning. The participants' subjective mental health status significantly worsened after the SOE was lifted (P<.001). Those who had concerns about a shift toward online education had higher odds of having generalized anxiety and being depressed (odds ratio [OR] 1.97, 95% CI 1.19-3.28) as did those who said they would request food aid (OR 1.99, 95% CI 1.16-3.44) and mental health care resources (OR 3.56, 95% CI 2.07-6.15). CONCLUSIONS: Given our findings, the sudden shift to online education might have overwhelmed medical students. Thus, we recommend that educators inform learners that online learning is not inferior to in-person learning, which could attenuate potential depression and anxiety.

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  • Positron emission tomography for the diagnosis of prosthetic heart valve endocarditis. International journal

    Yuki Otsuka, Hideharu Hagiya, Kosuke Oka, Fumio Otsuka

    BMJ case reports   14 ( 2 )   2021.2

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  • Septic pulmonary emboli caused by Tsukamurella inchonensis: A case report. International journal

    Kazuyoshi Gotoh, I Putu Bayu Mayura, Hideharu Hagiya, Kyoichi Obata, Tatsuo Ogawa, Koji Iio, Takumi Fujimori, Fumio Otsuka, Osamu Matsushita

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   27 ( 2 )   369 - 372   2021.2

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    The genus Tsukamurella is a fastidious, environmental organism that potentially causes various infections in humans. Due to the morphological and biochemical similarities to others pathogens, such as Gordona, Rhodococcus, Corynebacterium, Nocardia, and Mycobacterium, a molecular-based approach is indispensable to correctly identify them. Herein, we describe a case of Tsukamurella inchonensis bacteremia complicated with septic pulmonary emboli (SPE), which is the first in the literature. A 44-year-old Japanese woman diagnosed with tongue cancer had undergone partial tongue resection. While receiving chemotherapy and radiotherapy, she developed high fever. Chest computed tomography suggested multiple emboli at the bilateral, peripheral lungs, indicating SPE. Blood culture detected Gram-positive rods, to which matrix-assisted laser desorption/ionization-time of flight mass spectrometry failed to identify. Then, we attempted to characterize it by 16S rRNA sequence, which suggested the organism to be Tsukamurella species but resulted in low resonance of the species-level identification. Additionally, we employed a confidence gene targeting groEL, leading to 100% matching (753/753 bps) with T. inchonensis NCTC 10741 (GenBank accession no. LR131273.1), which has been incorrectly registered as wrong species name Tsukamurella paurometabola in the database. Under the diagnosis of T. inchonensis-associated SPE, we successfully treated the patient with imipenem/cilastatin administration for 4 weeks. Sequencing analysis of groEL was of great use in identifying the organism in this case. More clinical cases based on molecular diagnosis of the fastidious pathogens need to be accumulated to further understand the characteristics and appropriate treatment regimen.

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  • Clinical Characteristics of Low Androgen Status in Males with Type 2 Diabetes Mellitus.

    Jun Hamahara, Hiroyuki Honda, Koichiro Yamamoto, Kazuki Tokumasu, Yoshihisa Hanayama, Hideharu Hagiya, Mikako Obika, Keigo Ueda, Masayuki Kishida, Fumio Otsuka

    Acta medica Okayama   75 ( 1 )   1 - 8   2021.2

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    To determine the clinical characteristics of low androgen status in adult males with diabetes, we retrospectively analyzed the medical records of patients with type 2 diabetes mellitus in whom serum free testosterone (FT) levels were examined for 1 year. Among the 46 patients (56 ± 1.5 years old), decreases in serum FT levels to < 8.5 pg/ml (indicating the occurrence of late-onset hypogonadism [LOH]) were detected in 18 (39%). The per-centages of patients with low FT levels were high in the ≥ 50 years age group (83%), the HbA1c < 7% group (67%), and the 25 ≤ BMI < 30 kg/m2 group (56%). The serum FT levels tended to decrease age-dependently. The level of HbA1c was significantly correlated with the Heinemann Aging Male Symptoms (AMS) score (R = 0.47). The low-FT group had decreased levels of hemoglobin. Of note, the serum FSH level (R = -0.32) was negatively correlated with the serum FT level, whereas the serum TSH level (R = 0.36) was positively correlated with the serum FT level. Collectively, these results revealed that many diabetic males may have low FT levels and that the AMS score is related to the HbA1c level. A slightly anemic condition, thyroid dysfunction, and obesity (class 1) might be involved in LOH in middle-aged diabetic males.

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  • De-escalation concept and MIC literacy among medical students and clinical residents. International journal

    Hideharu Hagiya, Kazuki Tokumasu, Mikako Obika, Fumio Otsuka

    Postgraduate medical journal   2021.1

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  • Without a silhouette. International journal

    Yosuke Sazumi, Kazuki Tokumasu, Hideharu Hagiya, Fumio Otsuka

    Clinical case reports   9 ( 1 )   574 - 575   2021.1

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    Primary effusion lymphoma (PEL) is a kind of malignant lymphoma that develops without a tumor mass. A fluid smear is of no use for the diagnosis of miscellaneous condition. Repeated cell-block smear with immunostaining is useful for the diagnosis of PEL.

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  • 男性2型糖尿病患者におけるアンドロゲン低下と臨床的特徴

    浜原 潤, 本多 寛之, 山本 紘一郎, 中野 靖浩, 徳増 一樹, 花山 宜久, 萩谷 英大, 小比賀 美香子, 植田 圭吾, 岸田 雅之, 大塚 文男

    日本内分泌学会雑誌   96 ( 3 )   789 - 789   2021.1

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  • Clinical Manifestations of Patients with Influenza Differ by Age : A Prospective, Multi-centered Study in the Setouchi Marine Area.

    Ryosuke Takase, Hideharu Hagiya, Hiroyuki Honda, Yasuhiro Nakano, Hiroko Ogawa, Mikako Obika, Keigo Ueda, Hitomi Kataoka, Yoshihisa Hanayama, Fumio Otsuka

    Acta medica Okayama   75 ( 5 )   567 - 574   2021

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    Influenza potentially has a high mortality rate when it affects the elderly. We aimed to examine the differences in clinical manifestations in patients with influenza according to their age. This multicenter prospective study was performed in six medical institutions in Okayama and Kagawa prefectures (Japan). Between December 1, 2019 and March 31, 2020, we collected data on adult patients diagnosed with influenza type A, who were strat-ified into younger (20-49 years), middle-aged (50-64 years), and older groups (≥ 65 years). We compared the presence or absence of fever, respiratory symptoms, and extrapulmonary symptoms according to age group. In total, 203 patients (113, younger; 51, middle-aged; and 39, older) were eligible for the analysis. The maxi-mum body temperature and temperature at first physician visit in the older group were significantly lower than those in the younger group. The incidence of respiratory symptoms was not different among the three groups. Chills, muscle pain, and arthralgia as systemic symptoms were noted significantly more frequently in the younger (80.9%) and middle-aged (75.5%) groups than in the older group (51.3%) (p = 0.002). Fever and sys-temic symptoms were less likely to appear in older patients, possibly resulting in the delaying of hospital visits among older adults.

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  • Antimicrobial prescription practices for outpatients with acute respiratory tract infections: A retrospective, multicenter, medical record-based study. International journal

    Tomoharu Ishida, Hideharu Hagiya, Hiroyuki Honda, Yasuhiro Nakano, Hiroko Ogawa, Mikako Obika, Keigo Ueda, Hitomi Kataoka, Yoshihisa Hanayama, Fumio Otsuka

    PloS one   16 ( 11 )   e0259633   2021

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    Antimicrobial stewardship for outpatients with acute respiratory tract infections (ARTIs) should be urgently promoted in this era of antimicrobial resistance. Previous large-sample studies were based on administrative data and had limited reliability. We aimed to identify current antimicrobial prescription practices for ARTIs by directly basing on medical records. This multicenter retrospective study was performed from January to December in 2018, at five medical institutes in Japan. We targeted outpatients aged ≥18 years whose medical records revealed International Classification of Diseases (ICD-10) codes suggesting ARTIs. We divided the eligible cases into three age groups (18-64 years, 65-74 years, and ≥75 years). We defined broad-spectrum antimicrobials as third-generation cephalosporins, macrolides, fluoroquinolones, and faropenem. Primary and secondary outcomes were defined as the proportion of antimicrobial prescriptions for the common cold and other respiratory tract infections, respectively. Totally, data of 3,940 patients were collected. Of 2,914 patients with the common cold, 369 (12.7%) were prescribed antimicrobials. Overall, compared to patients aged ≥75 years (8.5%), those aged 18-64 years (16.6%) and those aged 65-74 years (12.1%) were frequently prescribed antimicrobials for the common cold (odds ratio [95% confidential interval]; 2.15 [1.64-2.82] and 1.49 [1.06-2.09], respectively). However, when limited to cases with a valid diagnosis of the common cold by incorporating clinical data, no statistical difference was observed among the age groups. Broad-spectrum antimicrobials accounted for 90.2% of the antimicrobials used for the common cold. Of 1,026 patients with other respiratory infections, 1,018 (99.2%) were bronchitis, of which antimicrobials were prescribed in 49.9% of the cases. Broad-spectrum antimicrobials were the main agents prescribed, accounting for nearly 90% of prescriptions in all age groups. Our data suggested a favorable practice of antimicrobial prescription for outpatients with ARTIs in terms of prescribing proportions, or quantitative aspect. However, the prescriptions were biased towards broad-spectrum antimicrobials, highlighting the need for further antimicrobial stewardship in the outpatient setting from a qualitative perspective.

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  • Recurrence of Hypoglycemic Coma in a Patient with Anorexia Nervosa.

    Koichiro Yamamoto, Daisuke Omura, Mai Yamane, Reina Son, Kou Hasegawa, Hiroyuki Honda, Mikako Obika, Nozomu Minao, Satoru Edahiro, Norihito Yamada, Fumio Otsuka

    Acta medica Okayama   75 ( 5 )   631 - 636   2021

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    Anorexia nervosa (AN) is occasionally complicated with hypoglycemic coma, which may cause sudden death by unknown mechanisms. We present the case of a 36-year-old woman with recurrent comas and a nineteen-year history of AN. She was found in a coma with remarkable hypoglycemia (28 mg/dL). Her BMI was 11.1 kg/m2. Endocrine workup revealed extremely low serum levels of glucagon, IGF-I and insulin. Asymptomatic hypoglycemia occurred with liver injury in the refeeding process. An aberrant glucose metabolism due to liver damage might have been involved in her susceptibility to hypoglycemia. This case suggests a possible mechanism of hypoglycemic coma in AN.

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  • Involvement of serum dehydroepiandrosterone sulfate in erythropoietic activity. International journal

    Ko Harada, Yoshihisa Hanayama, Mikako Obika, Koichi Itoshima, Ken Okada, Fumio Otsuka

    The aging male : the official journal of the International Society for the Study of the Aging Male   23 ( 5 )   756 - 763   2020.12

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    PURPOSE: The aim of the present study was to determine how age-related decreases in serum dehydroepiandrosterone sulfate (DHEAS) levels affect various physiological processes. METHODS: We retrospectively reviewed the medical records of patients in whom serum DHEAS levels were measured in our department and assessed the relationships between serum DHEAS levels and various patient characteristics. RESULTS: Among the 149 patients included in our analysis (mean age: 52.7 ± 17.6 years, range: 15-84 years), 54 (36.2%) were men. Serum DHEAS levels inversely correlated with age in men (R = -0.810, p < .01) and to a lesser extent in women (R = -0.391, p < .01). Of note, there were significant positive associations between DHEAS levels and hemoglobin (R = 0.317, p ≤ .01) and hematocrit (R = 0.324, p ≤ .01) levels, which were observed in men, but not in women. CONCLUSIONS: Our study suggests that reduced DHEAS secretion inhibits erythropoietic activity in aging men, perhaps owing to the erythropoietic androgenic actions of DHEAS. Importantly, it suggests that the age-associated decline in DHEAS secretion might decrease erythropoietic activity in aging men. It is also possible that the adrenal cortex, the source of DHEAS, is dysfunctional in anemic men.

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  • Intra-arterial gas, a clue for diagnosis of peri-aortic inflammation due to infection. International journal

    Daisuke Omura, Masatoshi Ogata, Yoshio Sakane, Ryuichi Matsuo, Harushige Nakatsukasa, Hideharu Hagiya, Fumio Otsuka

    Clinical case reports   8 ( 12 )   3619 - 3620   2020.12

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    We have presented a case of Salmonella-induced infective aortic aneurysm in which the presence of peri-aortic gas was a clue for diagnosis. The disease is clinically infrequent but potentially has a high mortality rate. Clinicians should consider this fatal disease from any trivial findings.

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  • A rare complication: Infection in acromegalic renal cysts. International journal

    Yuki Mori, Yuki Otsuka, Yasuhiro Nakano, Hiroyuki Sakae, Kou Hasegawa, Fumio Otsuka

    Clinical case reports   8 ( 12 )   3551 - 3552   2020.12

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    Renal cysts are detected in one third of acromegaly patients, especially in uncontrolled cases. Clinicians should pay attention to unexpected infection of enlarged renal cysts in acromegaly patients.

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  • Clinical Application of the Ratio of Serum Bone Isoform to Total Alkaline Phosphatase in General Practice.

    Yuya Yokota, Yoshito Nishimura, Akemi Ando, Yoshihisa Hanayama, Kou Hasegawa, Hideharu Hagiya, Hiroko Ogawa, Mikako Obika, Keigo Ueda, Fumio Otsuka

    Acta medica Okayama   74 ( 6 )   467 - 474   2020.12

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    Alkaline phosphatase (ALP) is an enzyme that is expressed in a variety of tissues. Among the isoforms of ALP, bone-specific alkaline phosphatase (BAP) is used as a marker for evaluating bone metabolism. We investigated the clinical usefulness of the ratio of serum BAP to total ALP for the diagnosis of various disorders in general practice. We retrospectively analyzed the cases of 107 Japanese patients whose serum BAP levels were exam-ined, focusing on clinical characteristics. We observed that the BAP/ALP ratios of the patients with fever and those with inflammatory diseases were significantly lower than the ratios of other patient groups. The BAP/ALP ratios of the patients with osteoporosis and those with metabolic bone diseases were higher than those of the patients with other conditions. The BAP/ALP ratio was found to be negatively correlated with age, a cor-relation that has not been found in other ethnicities. The serum BAP/ALP ratio was inversely correlated with serum CRP levels but was positively correlated with serum albumin levels and hemoglobin concentrations. Collectively, our results suggest that the BAP/ALP ratio could be a useful predictor for important geriatric con-ditions seen in general practice.

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  • Clinical relevance of insulin-like growth factor-1 to cardiovascular risk markers. International journal

    Ko Harada, Yoshihisa Hanayama, Mikako Obika, Koichi Itoshima, Ken Okada, Fumio Otsuka

    The aging male : the official journal of the International Society for the Study of the Aging Male   23 ( 5 )   1030 - 1038   2020.12

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    OBJECTIVE: Insulin-like growth factor-1 (IGF-1) is an anabolic hormone, the levels of which decline with age. The present study aimed to determine the impact of age-related declines in serum IGF-1 levels on various physiological processes. DESIGN: We retrospectively reviewed the medical records of patients whose serum IGF-1 levels were estimated in our department, and assessed the relationships between serum IGF-1 levels and various physiological parameters. RESULTS: A total of 427 patients with a mean (± standard deviation) age of 52.8 (± 17.1) years were included in the analysis. The levels of serum IGF-1 showed significant positive correlation with those of hemoglobin and hematocrit, and negative correlation with the presence of inflammatory and fibrin-related markers including C-reactive protein (CRP) and procalcitonin (PCT), and D-dimer and fibrin degradation products (FDP). These tendencies persisted after exclusion of patients with pituitary disease. CONCLUSIONS: In this study population of diverse diseases and backgrounds, a decline in serum IGF-1 levels with age was associated with an increase in inflammatory and fibrin-related markers. This may explain the correlation between low serum IGF-1 levels and an increased risk of cardiovascular events. Our findings suggest that serum IGF-1 is a clinically relevant marker of cardiovascular risk, particularly in males.

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  • Comparison of the Clinico-Microbiological Characteristics of Culture-Positive and Culture-Negative Septic Pulmonary Embolism: A 10-Year Retrospective Study. International journal

    Yoshito Nishimura, Hideharu Hagiya, Mikako Obika, Fumio Otsuka

    Pathogens (Basel, Switzerland)   9 ( 12 )   9 - 12   2020.11

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    Septic pulmonary embolism (SPE) is a rare yet serious infectious disorder with nonspecific clinical findings due to microorganism-containing emboli disseminating from extrapulmonary infectious foci. It is unknown whether a positive blood culture correlates with a worse clinical outcome. We compared the clinical and microbiologic characteristics of patients with SPE divided into the culture-positive group and the culture-negative one. This study was a retrospective observational study of the patients diagnosed with SPE and treated in an academic hospital from April 2010 to May 2020. We identified six culture-positive and four culture-negative patients with SPE during the study period. The culture-positive group had significantly longer periods of hospitalization (median: 75 days, range: 45-125 days) than the culture-negative group (median: 14.5 days, range: 3-43 days) (p < 0.05), as well as significantly elevated serum C-reactive protein and procalcitonin. Patients with culture-negative SPE more commonly had odontogenic infections as the primary infectious foci. Our study highlights the importance of giving extra attention to SPE patients who have a positive blood culture, as they may have worse clinical outcomes. Physicians need to collaborate with dentists when faced with patients with culture-negative SPE, since they may have primary odontogenic infections.

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  • Efficacy of HLA virtual cross-matched platelet transfusions for platelet transfusion refractoriness in hematopoietic stem cell transplantation (vol 60, pg 473, 2020)

    Keisuke Seike, Nobuharu Fujii, Naomi Asano, Shigenori Ohkuma, Yasushi Hirata, Keiko Fujii, Yasuhisa Sando, Makoto Nakamura, Kazunori Naito, Yusuke Meguri, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken-ichi Matsuoka, Kazuo Tsubaki, Fumio Otsuka, Yoshinobu Maeda

    TRANSFUSION   60 ( 11 )   2765 - 2765   2020.11

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  • Adult-onset Still's disease accompanying noninfective endocarditis.

    Kosuke Oka, Yokota Yuya, Miho Yasuda, Fumio Otsuka

    Journal of general and family medicine   21 ( 6 )   268 - 269   2020.11

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    Adult-onset Still's disease can develop valve lesions. Since AOSD may complicate valvular lesion, differentiation of endocarditis in patients with AOSD is required.

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  • Ectopic hyperparathyroidism due to an auto-transplanted parathyroid gland. International journal

    Ko Harada, Fumio Otsuka

    Clinical case reports   8 ( 11 )   2312 - 2313   2020.11

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    Hyperparathyroidism due to the autografted parathyroid gland should be suspected in patients who undergone parathyroid auto-transplantation.

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  • Massive pheochromocytoma. International journal

    Terumitsu Anai, Kosuke Oka, Yuya Yokota, Yoshito Nishimura, Hideharu Hagiya, Fumio Otsuka

    Clinical case reports   8 ( 11 )   2308 - 2309   2020.11

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    Complications of pheochromocytoma, such as hypertensive emergency, can be critical. Clinicians should recognize that pheochromocytoma is not uncommon in patients with large adrenal tumors, and screening should be undertaken prior to any intervention.

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  • Similar safety and efficacy in previously treated adults with growth hormone deficiency randomized to once-weekly somapacitan or daily growth hormone. International journal

    Fumio Otsuka, Yutaka Takahashi, Shigeyuki Tahara, Yoshihisa Ogawa, Michael Højby Rasmussen, Koji Takano

    Clinical endocrinology   93 ( 5 )   620 - 628   2020.11

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    OBJECTIVE: Somapacitan is a long-acting, reversible albumin-binding growth hormone (GH) derivative in development. This study aimed to evaluate the safety and efficacy of once-weekly somapacitan versus daily GH over 52 weeks in Japanese patients with adult growth hormone deficiency (AGHD). DESIGN: Phase 3, multicentre, randomized, parallel-group, open-label, active-controlled trial (NCT03075644). PATIENTS: Previously GH-treated Japanese patients with AGHD were randomized 3:1 to somapacitan (n = 46) or daily GH (n = 16) for 20 weeks' dose titration and 32 weeks' fixed-dose treatment. MEASUREMENTS: Primary endpoint was the incidence of adverse events (AEs). Secondary endpoints included change from baseline to week 52 in visceral, subcutaneous and total adipose tissue (VAT, SAT and TAT). RESULTS: Mean (SD) prescribed doses after titration were 1.780 (1.058) mg/week for somapacitan and 0.197 (0.083) mg/day for daily GH. Rate of AEs per 100 patient-years was similar between arms (somapacitan, 312.7; daily GH, 309.8). Four AEs in the somapacitan arm were serious; none were considered treatment-related. Mean insulin-like growth factor-I standard deviation score (IGF-I SDS) was maintained from baseline in both arms. No significant differences were observed between arms for change from baseline to week 52 in VAT, SAT or TAT (estimated difference, somapacitan - daily GH [95% CI]: -1.74 [-18.13; 14.66], -11.53 [-35.54; 12.48] and - 12.85 [-47.31; 21.62] cm2 , respectively). CONCLUSIONS: Treatment in both groups was well tolerated, with no unexpected safety findings. Impact on adipose tissue was similar to somapacitan and daily GH in patients with AGHD. A short visual summary of our work is available at https://bit.ly/3946YNF.

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  • Localized Lymph Node Light Chain Amyloidosis.

    Akira Yamamoto, Nobuharu Fujii, Mikako Obika, Taro Yamashita, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   59 ( 19 )   2415 - 2418   2020.10

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    The prognosis of systemic amyloid light chain (AL) amyloidosis is generally poor, hence requiring chemotherapy or hematopoietic stem cell transplantation, while the prognosis of localized AL amyloidosis without an abnormal monoclonal immunoglobulin light chain is good. Localized AL amyloidosis has been previously reported to be observed in pulmonary, urinary tract, gastrointestinal, oropharyngeal, and laryngeal sites. However, only a few cases of localized lymph node AL amyloidosis have so far been reported. We herein present a case of localized lymph node AL amyloidosis that could possibly be misdiagnosed as systematic AL amyloidosis.

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  • Antibiotic literacy among Japanese medical students. International journal

    Hideharu Hagiya, Hideo Ino, Kazuki Tokumasu, Hiroko Ogawa, Tomoko Miyoshi, Kanako Ochi, Fumio Otsuka

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   26 ( 10 )   1107 - 1109   2020.10

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    Antimicrobial resistance (AMR) is an urgent global issue. After the AMR action plan was introduced in 2016, a study on antibiotic literacy (i.e., awareness, knowledge, and attitude relating to antimicrobial use) among clinicians and lay people was conducted in Japan. However, no studies have hitherto targeted medical students who are expected to have a high level of antibiotic literacy. The present study was conducted between September 2019 and February 2020, enrolling undergraduate students at Okayama University Medical School. We collected data using a paper-based questionnaire form with 11 questions about antibiotic literacy. The response rate was 93.8% (661/705 students). Overall, 92.6% of the students knew that antibiotics inhibit the growth of bacteria. Student reporting that antibiotics could treat the common cold accounted for 77.0% (Year 1), 50.9% (Year 2), 48.2% (Year 3), 49.1% (Year 4), 23.8% (Year 5), and 26.2% (Year 6). Only 43 (6.5%) had heard about the AMR action plan. The study data suggested that medical students' level of literacy on antimicrobial use should be further enhanced to address AMR and promote antimicrobial stewardship.

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  • ALP高値から上縦隔に発見されたMEN1疑い副甲状腺機能亢進症の1例

    大塚 勇輝, 西村 義人, 原田 洸, 岡 浩介, 長谷川 功, 小川 弘子, 三好 智子, 花山 宜久, 枝園 忠彦, 平沢 晃, 大塚 文男

    日本内分泌学会雑誌   96 ( 2 )   549 - 549   2020.10

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  • CYP11B1/B2キメラ遺伝子を確認した家族性アルドステロン症小児例

    中野 靖浩, 岩田 菜穂子, 長谷川 高誠, 越智 可奈子, 山本 紘一郎, 高瀬 了輔, 長谷川 功, 堀口 繁, 山本 英喜, 平沢 晃, 大塚 文男

    日本内分泌学会雑誌   96 ( 2 )   535 - 535   2020.10

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  • 男性2型糖尿病患者におけるLOH症候群の潜在と臨床的特徴

    浜原 潤, 本多 寛之, 山本 絋一郎, 中野 靖浩, 徳増 一樹, 花山 宜久, 萩谷 英大, 小比賀 美香子, 植田 圭吾, 岸田 雅之, 大塚 文男

    日本内分泌学会雑誌   96 ( 2 )   544 - 544   2020.10

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  • Clinical Relevance of Serum Prolactin Levels to Inflammatory Reaction in Male Patients.

    Koichiro Yamamoto, Yoshihisa Hanayama, Kou Hasegawa, Kazuki Tokumasu, Tomoko Miyoshi, Hideharu Hagiya, Hiroko Ogawa, Mikako Obika, Koichi Itoshima, Fumio Otsuka

    Acta medica Okayama   74 ( 5 )   381 - 389   2020.10

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    To clarify the relevance of prolactin (PRL) to clinical parameters in patients who visited our general medicine department, medical records of 353 patients in whom serum PRL levels were measured during the period from 2016 to 2018 were retrospectively reviewed. Data for 140 patients (M/F: 42/98) were analyzed after excluding patients lacking detailed records and patients taking dopaminergic agents. Median serum PRL levels were significantly lower in males than females: 6.5 ng/ml (IQR: 4.2-10.3) versus 8.1 ng/ml (5.9-12.9), respectively. Pain and general fatigue were the major symptoms at the first visit, and past histories of hypertension and dyslipidemia were frequent. Male patients with relatively high PRL levels (≥ 10 ng/ml) had significantly lower levels of serum albumin and significantly higher levels of serum LDH than those with low PRL (< 10 ng/ml). There were significant correlations of male PRL level with the erythrocyte sedimentation rate (R=0.62), serum LDH level (R=0.39) and serum albumin level (R=-0.52), while the level of serum CRP (R=0.33) showed an insignificant but weak positive correlation with PRL level. Collectively, these results show that PRL levels had gender-specific relevance to various clinical factors, with PRL levels in males being significantly related to inflammatory status.

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  • Generation of four induced pluripotent stem cell lines (FHUi003-A, FHUi003-B, FHUi004-A and FHUi004-B) from two affected individuals of a familial neurohypophyseal diabetes insipidus family. International journal

    Satoru Yoshida, Hanayuki Okura, Hidetaka Suga, Mika Soen, Yohei Kawaguchi, Junki Kurimoto, Takashi Miyata, Hiroshi Takagi, Hiroshi Arima, Tatsuya Fujikawa, Fumio Otsuka, Akifumi Matsuyama

    Stem cell research   48   101960 - 101960   2020.10

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    Four disease-specific induced pluripotent stem cell (iPSC) lines were respectively derived from peripheral blood mononuclear cells of two affected individuals in a family affected by familial neurohypophyseal diabetes insipidus carrying the c.314G>C mutation. The expression of pluripotency markers (NANOG, OCT4, and SOX2), maintenance of a normal karyotype, absence of episomal vectors used for iPSC generation, and presence of the original pathogenic mutation were confirmed for each iPSC line. The ability to differentiate into three germ layers was confirmed by a teratoma formation assay. These iPSC lines can help in disease recapitulation in vitro using organoids and elucidation of disease mechanisms.

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  • Aldosterone enhances progesterone biosynthesis regulated by bone morphogenetic protein in rat granulosa cells. International journal

    Yasuhiro Nakano, Toru Hasegawa, Chiaki Kashino, Nahoko Iwata, Koichiro Yamamoto, Atsuhito Suyama, Yoshiaki Soejima, Takahiro Nada, Fumio Otsuka

    The Journal of steroid biochemistry and molecular biology   203   105738 - 105738   2020.10

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    Aldosterone (Aldo) is involved in various cardiovascular diseases such as hypertension and heart failure. Aldo levels are known to be increased in patients with polycystic ovary syndrome, and expression of the mineralocorticoid receptor (MR) has also been detected in the ovary. However, the effect of Aldo on reproductive function has yet to be elucidated. Here, we examined the effects of Aldo on follicular steroidogenesis using primary culture of rat granulosa cells by focusing on the ovarian bone morphogenetic protein (BMP) system acting as a luteinizing inhibitor. We found that Aldo treatment increased FSH-induced progesterone production in a concentration-responsive manner. Consistent with the effects on steroidogenesis, Aldo increased mRNA levels of progesterogenic factor and enzymes including StAR and P450scc, whereas Aldo failed to change FSH-induced estradiol and cAMP synthesis or P450arom expression by granulosa cells. Progesterone production and StAR expression induced by FSH and Aldo were reversed by co-treatment with spironolactone, suggesting the involvement of geonomic MR action. Aldo treatment attenuated Smad1/5/9 phosphorylation and Id1 transcription induced by BMP-6. Furthermore, Aldo enhanced the expression of inhibitory Smad6 in the presence of BMP-6. In addition, BMP-6 downregulated MR expression, while Aldo modulated the mRNA levels of endogenous BMP-6 and BMP type-II receptors, indicating the existence of a feedback loop between the BMP system and MR in granulosa cells. Collectively, the results indicated that Aldo predominantly enhances FSH-induced progesterone production by inhibiting BMP-Smad signaling, suggesting a novel role of Aldo in ovarian steroidogenesis and a functional link between MR and BMP pathways in granulosa cells.

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  • Disseminated Mycobacterium genavense infection mimicking TAFRO syndrome. International journal

    Kosuke Oka, Mai Yamane, Yuya Yokota, Miho Yasuda, Kou Hasegawa, Takumi Fujimori, Koji Iio, Hideharu Hagiya, Fumio Otsuka

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   26 ( 10 )   1095 - 1099   2020.10

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    TAFRO syndrome is a rare variant of idiopathic multicentric Castleman's disease, for which disseminated non-tuberculous mycobacteria (NTM) infection must be excluded. However, due to the slow and fastidious growth of the organisms, identification of the pathogen is often challenging. We herein describe a case of disseminated Mycobacterium genavence infection, in which manifestations of the patient were confusingly similar to those of TAFRO syndrome. A 69-year-old Japanese man presented with prolonged fever accompanying pain in his back and ribs on the right side. Systemic investigations revealed thrombocytopenia, marked elevation of alkaline phosphatase, anasarca (pleural effusion and ascites), megakaryocytosis in the bone marrow, and hepatomegaly. Magnetic resonance imaging (MRI) showed diffuse, T1-and T2-low-intensity spotted lesions on his vertebral bodies, but biopsy showed inconclusive results. The patient met the diagnostic criteria of TAFRO syndrome and was started on prednisolone, which improved his general condition shortly thereafter. Blood culture after 42 days of incubation revealed the presence of Mycobacterium; however, we considered it a contamination at that time because no organisms grew on conventional agars, and the patient was discharged. Ten weeks after the isolation of Mycobacterium, he developed persistent fever and was readmitted. This time, vertebral bone mallow biopsy demonstrated a large amount of mycobacterium, which was later successfully identified as M. genavense by sequencing analysis. Under a final diagnosis of disseminated M. genavense infection, we treated the patient with clarithromycin, rifampicin, and ethambutol. This case highlighted that disseminated NTM infection may follow a similar clinical course as that of TAFRO syndrome.

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  • A nationwide trend analysis in the incidence and mortality of Creutzfeldt-Jakob disease in Japan between 2005 and 2014. International journal

    Yoshito Nishimura, Ko Harada, Toshihiro Koyama, Hideharu Hagiya, Fumio Otsuka

    Scientific reports   10 ( 1 )   15509 - 15509   2020.9

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    In the era of hyper-ageing, Creutzfeldt-Jakob disease (CJD) can become more prevalent as an important cause of dementia. This study aimed to evaluate the trends in crude and age-adjusted CJD-associated mortality and incidence rates in Japan using national vital statistics data on CJD-associated deaths among individuals aged over 50 years, as well as the government-funded nationwide CJD surveillance data (pertaining to the years 2005-2014) in Japan. The data were analysed using the Joinpoint Regression Program to estimate the long-term trends and average annual percentage changes (AAPCs). Overall, the AAPCs of age-adjusted CJD-associated mortality rates rose significantly over the study period (3.2%; 95% confidence interval [CI] 1.4-5.1%). The AAPC of the age-adjusted incidence rates also increased (overall 6.4%; 95% CI 4.7-8.1%). The CJD-associated increases in the mortality and incidence rates were especially prominent among adults over the age of 70 years. Given this trend in aging of population, the disease burden of CJD will continue to increase in severity. Our findings thus recommend that policymakers be aware of the importance of CJD and focus on preparing to address the increasing prevalence of dementia.

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  • Hashimoto's hyroiditis and primary thyroid lymphoma

    Y Otsuka, M Yasuda, K Tokumasu, K Hasegawa, F Otsuka

    QJM   0 ( 0 )   691 - 692   2020.9

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  • Bilateral massive empyema with bronchopleural fistula. International journal

    Ko Harada, Hideharu Hagiya, Fumio Otsuka

    Postgraduate medical journal   96 ( 1139 )   573 - 573   2020.9

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  • Hepatic encephalopathy due to extrahepatic portosystemic shunt. International journal

    Yosuke Sazumi, Yoshito Nishimura, Yuki Otsuka, Yuki Mizuta, Yasuhiro Nakano, Hiroyuki Sakae, Fumio Otsuka

    Clinical case reports   8 ( 9 )   1852 - 1853   2020.9

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    Clinicians should recognize extrahepatic portosystemic shunt as a cause of refractory or intermittent hepatic encephalopathy. Treatment strategies should be individualized according to patients' anatomic and hemodynamic status.

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  • Calcinosis Cutis. International journal

    Ko Harada, Ei Miyasaka, Fumio Otsuka

    The American journal of medicine   133 ( 9 )   e528-e529 - E529   2020.9

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  • A rare case of oncocytic adrenocortical carcinoma clinically presented as an incidentaloma.

    Ko Harada, Miho Yasuda, Yasuhiro Nakano, Kazuhiro Yoshida, Yuzo Umeda, Takahito Yagi, Yuto Yamazaki, Hironobu Sasano, Fumio Otsuka

    Endocrine journal   67 ( 8 )   883 - 888   2020.8

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    Adrenocortical carcinoma (ACC) is a rare aggressive tumor originating from adrenocortical parenchymal cells and its incidence is approximately 1 per million population per year. An oncocytic ACC is a recently identified entity among the several known histopathological variants of ACC, which is characterized by oncocytic cells, and only a few cases in the available literature have reported this tumor. In contrast to conventional ACCs, oncocytic ACCs usually manifest as solitary lesions presenting in adults without any sex predilection. We report a case of a 70-year-old Japanese man who presented with an incidentally discovered retroperitoneal mass without any evidence of excessive corticosteroid secretion. Laboratory and imaging studies, as well as transgastric endoscopic ultrasound-guided fine needle aspiration failed to establish a definitive diagnosis. Thus, the patient underwent surgical resection of the left-sided peritoneal tumor. Weiss score was positive in 6/9 points and the tumor met two major criteria of the Lin-Weiss-Bisceglia (LWB) system leading to a diagnosis of an oncocytic variant of ACC. Based on our findings in this patient, we conclude that a combination of the Weiss and LWB criteria is required to determine the malignant potential of oncocytic adrenal tumors because ACCs and oncocytomas could be frequently indistinguishable. Careful histopathological examination is pivotal in confirming the oncocytic component in the lesion and hence definitive diagnosis of ACCs.

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  • Multiple Deep-seated Dentofacial Abscesses Caused by Multidrug-resistant Viridans Group Streptococci.

    Shinnosuke Fukushima, Hideharu Hagiya, Yuki Mizuta, Yasuhiro Nakano, Masahiro Takahara, Kayo Okamoto, Yuko Hayashi, Kiyoshi Yamada, Kou Hasegawa, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   59 ( 16 )   2067 - 2070   2020.8

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    Odontogenic infections, generally caused by dental caries and periodontal disease, can result in fatal illness. We herein report a 71-year-old Japanese woman with type 2 diabetes and hemodialysis who suffered from multiple dentofacial abscesses mainly caused by multidrug-resistant Streptococcus oralis. She complained of pain and swelling of her face, with an extraoral fistula from the left cheek. Following 3 surgical debridement procedures and partial mandibulectomy, in addition to 12 weeks of antimicrobial therapy, the multiple dentofacial abscesses were ameliorated. A combination of surgical and antimicrobial treatments following an early diagnosis is essential for reducing further complications.

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  • Coronary Spastic Angina Induced by Adrenal Insufficiency.

    Yuki Otsuka, Ko Harada, Miho Yasuda, Yasuhiro Nakano, Kou Hasegawa, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   59 ( 15 )   1873 - 1877   2020.8

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    Adrenal insufficiency patients are treated with glucocorticoid replacement therapy. However, mimicking the in vivo circadian rhythm of cortisol levels is challenging, and suboptimal replacement increases the risk of mortality from cardiovascular disease. We herein report a case of coronary spastic angina (CSA) with simultaneous low early-morning serum cortisol levels in a patient undergoing corticosteroid replacement therapy for primary adrenal insufficiency. Steroid therapy is reportedly effective for refractory angina, but underlying adrenal deficiency has never been revealed. Our case intimates the probable risk of CSA as a complication of relative adrenal insufficiency and highlights the effectiveness of dexamethasone in these patients.

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  • Mycobacterium chelonae bloodstream infection induced by osteomyelitis of toe: A case report. International journal

    Yayoi Ueda, Kazuki Tokumasu, Hideharu Hagiya, Koji Iio, Takumi Fujimori, Ayaka Kakehi, Mami Okura, Hiroshi Minabe, Fumio Otsuka

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   26 ( 8 )   843 - 846   2020.8

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    Mycobacterium chelonae is a rapidly growing mycobacterium that has the potential to cause refractory infections in humans. Mycobacteremia resulting from the organism is extremely rare, and its clinical features are yet to be uncovered. We herein present a case of M. chelonae bloodstream infection involving an immunocompromised older patient. A 79-year-old woman, on a long-term treatment with prednisolone plus tacrolimus for rheumatoid arthritis, visited our outpatient department complaining of deteriorating pain and swelling at her right 1st toe. Laboratory parameters showed elevated C-reactive protein and leukocytosis, and magnetic resonance imaging indicated osteomyelitis at the proximal phalanx of her right 1st toe. Considering the refractory course, the infected toe was immediately amputated. M. chelonae was isolated from bacterial cultures of the resected tissue and blood (BD BACTEC™ FX blood culture system, Becton Dickinson, Sparks, MD, USA), leading to a diagnosis of disseminated M. chelonae infection. We treated the patient with an antibiotic combination of clarithromycin, minocycline, and imipenem (2 weeks), which was converted to oral therapy of clarithromycin, doxycycline, and levofloxacin. This case highlighted the potential pathogenesis of M. chelonae to cause mycobacteremia in an immunocompromised patient.

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  • グルココルチコイドによる卵胞ステロイド合成への影響とBMPの関与

    樫野 千明, 長谷川 徹, 中野 靖浩, 長尾 聡子, 岩田 菜穂子, 鎌田 泰彦, 増山 寿, 大塚 文男

    日本内分泌学会雑誌   96 ( 1 )   376 - 376   2020.8

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  • 相対的副腎不全により冠攣縮性狭心症が惹起された1例

    大塚 勇輝, 安田 美帆, 中野 靖浩, 長谷川 功, 萩谷 英大, 三好 智子, 小比賀 美香子, 片岡 仁美, 大塚 文男

    日本内分泌学会雑誌   96 ( 1 )   372 - 372   2020.8

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  • アルドステロンによる卵胞プロゲステロン分泌の増強とBMP-6の関与

    中野 靖浩, 長谷川 徹, 樫野 千明, 長尾 聡子, 灘 隆宏, 岩田 菜穂子, 大塚 文男

    日本内分泌学会雑誌   96 ( 1 )   304 - 304   2020.8

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  • Invasive non-typeable Haemophilus influenzae infection due to endometritis associated with adenomyosis. International journal

    Yoshito Nishimura, Hideharu Hagiya, Kaoru Kawano, Yuya Yokota, Kosuke Oka, Koji Iio, Kou Hasegawa, Mikako Obika, Tomoko Haruma, Sawako Ono, Hisashi Masuyama, Fumio Otsuka

    BMC infectious diseases   20 ( 1 )   521 - 521   2020.7

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    BACKGROUND: The widespread administration of the Haemophilus influenzae type b vaccine has led to the predominance of non-typable H. influenzae (NTHi). However, the occurrence of invasive NTHi infection based on gynecologic diseases is still rare. CASE PRESENTATION: A 51-year-old Japanese woman with a history of adenomyoma presented with fever. Blood cultures and a vaginal discharge culture were positive with NTHi. With the high uptake in the uterus with 67Ga scintigraphy, she was diagnosed with invasive NTHi infection. In addition to antibiotic administrations, a total hysterectomy was performed. The pathological analysis found microabscess formations in adenomyosis. CONCLUSIONS: Although NTHi bacteremia consequent to a microabscess in adenomyosis is rare, this case emphasizes the need to consider the uterus as a potential source of infection in patients with underlying gynecological diseases, including an invasive NTHi infection with no known primary focus.

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  • Clinical and biochemical characteristics of patients having general symptoms with increased serum IgG4. International journal

    Kou Hasegawa, Yoshihisa Hanayama, Mikako Obika, Tomoko Miyoshi, Hiroko Ogawa, Eisei Kondo, Hitomi Kataoka, Yasuharu Sato, Fumio Otsuka

    Modern rheumatology   30 ( 4 )   721 - 728   2020.7

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    Objective: To differentiate patients with IgG4-related diseases (RD) from patients with other hyper IgG4 conditions who visit general medicine department.Methods: Fifty-six patients with high serum IgG4 levels (>135 mg/dL) were classified into three groups based on the final diagnosis: definite and possible IgG4-RD and others. Clinical and laboratory characteristics of the three groups of patients were retrospectively analyzed.Results: Major manifestations were renal dysfunction and general malaise, while thirst was the most frequent symptom in the definite group, in which submandibular glands and lymph nodes were likely to be affected. Biopsy of minor salivary glands was the least diagnostic for IgG4-RD despite the high frequency of biopsy. In the definite group, serum levels of IgG4 and IgG, IgG4/IgG ratio and basophil number were increased, while serum levels of CRP, IgA and complements were decreased. A negative correlation between serum levels of IgG4 and IgM was found in the definite group.Conclusion: The results indicated that in patients with renal dysfunction, malaise, thirst or weight loss, measurements of the levels of basophils, immunoglobulins and complements are helpful for diagnosing IgG4-RD. Considering distribution of affected tissues and localization of diagnostic biopsies, physical examination and laboratory workup are required for early diagnosis.

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  • 大学病院における研修医メンター制度 メンターの視点、メンティーの視点

    佐藤 明香, 小河 七子, 植田 真司, 矢野 修也, 小川 弘子, 三好 智子, 難波 志穂子, 大塚 文男

    医学教育   51 ( Suppl. )   226 - 226   2020.7

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  • Vision loss, tractional retinal detachment, and profound anemia due to rectal carcinoma. International journal

    Akira Yamamoto, Yoshito Nishimura, Mikako Obika, Yuki Morizane, Fumio Otsuka

    Clinical case reports   8 ( 7 )   1304 - 1305   2020.7

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    Profound anemia can cause severe proliferative retinopathy and tractional retinal detachment; therefore, it is important to closely investigate the cause of anemia. Endoscopy and computed tomography are valuable tools for this purpose.

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  • Macromolecules detected in highly increased serum luteinizing hormone

    K Ogura-Ochi, K Itoshima, Y Kamada, F Otsuka

    J. Endocrinol. Invest.   856 - 866   2020.6

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  • X-linked Hypophosphatemia (XLH) Mimicking Rheumatic Disease. Reviewed

    Ryosuke Takase, Yasuhiro Nakano, Kosei Hasegawa, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   59 ( 9 )   1233 - 1234   2020.5

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  • Clinical Significance of Total Vascular Resistance, Augmention Index and Augmentation Pressure in Patients With Peripheral Artery Disease

    Rika Takemoto, Haruhito A. Uchida, Nozomu Otaka, Shugo Okamoto, Mariko Nishiwaki, Yasuhiro Onishi, Natsumi Matsuoka, Yoshiko Hada, Hironobu Toda, Fumio Otsuka, Hiroshi Ito, Jun Wada

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY   40   2020.5

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  • An Endoscopic Biopsy Specimen Contains Adequate Lymphocytes for Flow Cytometric Analysis of Light Chain Expression in the Gastrointestinal Mucosa. International journal

    Masaya Iwamuro, Katsunori Matsueda, Takahide Takahashi, Sizuma Omote, Takehiro Tanaka, Daisuke Ennishi, Fumio Otsuka, Tadashi Yoshino, Hiroyuki Okada

    Annals of clinical and laboratory science   50 ( 3 )   348 - 353   2020.5

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    OBJECTIVE: Flow cytometry has not been widely used in routine clinical practice for the diagnosis of gastrointestinal lymphoma; this is mainly because of the absence of an appropriate protocol. Here, we established a protocol for flow cytometric analysis of a single biopsy specimen from the gastrointestinal mucosa and investigated its sensitivity and specificity. DESIGN: In this prospective study, we enrolled patients with previously diagnosed gastrointestinal lymphoma and patients with gastrointestinal lesions that were suspected to be lymphoma. RESULTS: Overall, 15 patients with gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (N=8), duodenal follicular lymphoma (grade 1; N=5), and benign lymphoid hyperplasia (ileum, N=1, and rectum, N=1) were included in this study. Of these, lymphocytes were isolated from 14 patients (93.3%). There were 200,000-1,500,000 viable cells per patient. Biopsy specimens from 10 out of the 12 patients with lymphoma were positive for light chain restriction; the two patients with benign lymphoid hyperplasia showed negative results. CONCLUSIONS: An adequate number of lymphocytes for flow cytometry could be isolated from a single specimen of endoscopic mucosal biopsy from 93.3% of the patients. Overall, the sensitivity of flow cytometric analysis of light chain expression for the diagnosis of B-cell lymphoma was 83.3%, and the specificity was 100%. Although further investigation is required as the sample size of the present study was small, our study suggests a potential option for diagnosing B-cell lymphoma in the gastrointestinal mucosa.

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  • Rigid Ears and Hyperpigmentation in Addison's Disease. International journal

    Ko Harada, Fumio Otsuka

    The American journal of medicine   133 ( 5 )   e192   2020.5

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  • Cardiac mucosa-associated lymphoid tissue lymphoma involved in IgG4-related disease. International journal

    Ko Harada, Fumio Otsuka

    European heart journal   41 ( 15 )   1519 - 1519   2020.4

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  • Malignant Lymphoma Developed in the Hypothalamus.

    Ryosuke Takase, Yasuhiro Nakano, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   59 ( 7 )   1009 - 1010   2020.4

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  • Gastrointestinal: Massive right pleural effusion caused by a pancreaticopleural fistula

    K Tokumasu, K Harada, F Otsuka

    J. Gastroenterol. Hepatol.   525   2020.4

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  • Observer agreement for the diagnosis of intestinal acute graft-vs.-host disease based on the presence of villous atrophy in the terminal ileum. International journal

    Yuusaku Sugihara, Sakiko Hiraoka, Eriko Yasutomi, Shohei Oka, Yasushi Yamasaki, Toshihiro Inokuchi, Hideaki Kinugasa, Masahiro Takahara, Yuki Morito, Sakuma Takahashi, Keita Harada, Takehiro Tanaka, Fumio Otsuka, Hiroyuki Okada

    Experimental and therapeutic medicine   19 ( 4 )   3076 - 3080   2020.4

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    Intestinal graft-vs.-host disease (GVHD) is a serious complication of allo-hematopoietic stem cell transplantation (allo-HSCT). Villous atrophy in the terminal ileum is considered a useful diagnostic indicator for GVHD. However, the inter- and intra-observer agreement regarding the ileocolonoscopic findings indicative of acute intestinal GVHD, i.e., villous atrophy in the terminal ileum, are currently insufficient in multiple institutions. Thus, the present study aimed to investigate the incidence of villous atrophy in the terminal ileum to diagnose acute intestinal GVHD and determine the inter- and intra-observer agreement regarding this result for experienced endoscopists from multiple institutions. Consecutive patients who underwent allo-HSCT were referred to our institution between May 2008 and September 2015. A total of 54 patients underwent total ileocolonoscopy after allo-HSCT due to suspected intestinal acute GVHD. Subsequently, three observers from different institutions evaluated the cases for the presence of villous atrophy in the terminal ileum. In this study, the pathology results were a gold standard to evaluate the predictive value of ileocolonoscopy detection. Definitive pathological and non-pathological GVHD was diagnosed in 22 and 32 cases, respectively. The results of examining whether villous atrophy could predict GVHD were as follows. For three observers (A, B and C), the sensitivity of villous atrophy in the terminal ileum was 86.4, 77.3 and 79.2%, respectively, whereas the specificity was 62.5, 62.5 and 86.7%, respectively. The positive predictive value (PPV) and negative predictive value (NPV) of villous atrophy for GVHD were as follows: The PPV of appearance was 61.3, 58.6 and 82.6%, respectively, whereas the NPV was 87.0, 80.0 and 83.9%, respectively. Kappa coefficients for the inter-observer reliability were 0.85, 0.63 and 0.63 for observers A and B, A and C, and B and C, respectively. The intra-observer kappa coefficient was 0.88 for observer A, 0.73 for observer B and 0.75 for observer C. A substantial observer agreement was achieved for the analysis of villous atrophy in the terminal ileum and the agreement for the predictive histological diagnosis was also excellent. Based on the results of the present study, identification of villous atrophy in the terminal ileum was a clinically effective diagnostic parameter, even if different endoscopists were involved in the diagnosis at multiple institutions. The present study was registered as a trial with the University Hospital Medical Information Network (UMIN; registration no. UMIN000025390).

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  • Albright’s Hereditary Osteodystrophy

    Ko Harada , Fumio Otsuka

    QJM   2020.3

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  • Osmotic Demyelination Syndrome Triggered by Pituitary Apoplexy.

    Yuya Yokota, Kosuke Oka, Miho Yasuda, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   59 ( 6 )   869 - 870   2020.3

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  • Efficacy of HLA virtual cross-matched platelet transfusions for platelet transfusion refractoriness in hematopoietic stem cell transplantation. International journal

    Keisuke Seike, Nobuharu Fujii, Naomi Asano, Shigenori Ohkuma, Yasushi Hirata, Keiko Fujii, Yasuhisa Sando, Makoto Nakamura, Kazunori Naito, Kyosuke Saeki, Yusuke Meguri, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken-Ichi Matsuoka, Kazuo Tsubaki, Fumio Otsuka, Yoshinobu Maeda

    Transfusion   60 ( 3 )   473 - 478   2020.3

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    BACKGROUND: Cross-matched platelet (cross-matched PLT) transfusion is effective for immune-mediated platelet transfusion refractoriness (PTR), but is more costly and time-consuming for physical cross-match than using standard PLT units. Recent studies have reported the utility of human leucocyte antigens (HLA) virtual cross-matched PLT (HLA-matched PLT) that is defined as HLA-A/B matched or no antibody against donor-specific antigen. Here, we evaluated the effect of HLA-matched PLTs for PTR in post hematopoietic stem cell transplant (HSCT) recipients. STUDY DESIGN AND METHODS: Our study included a total of 241 PLTs in 16 patients who underwent HSCT at Okayama University Hospital between 2010 and 2017, receiving either HLA-matched or cross-matched PLTs. We calculated the 24-hour corrected count increments (CCI-24) to evaluate the effect of PLTs. A CCI-24 ≥ 4500 was considered to be a successful transfusion. RESULTS: We analyzed 139 cross-matched PLTs and 102 HLA-matched PLTs. In the immune-mediated PTR, the rate of successful transfusion was 60.5% for cross-matched PLT and 63.4% for HLA-matched PLT (p = 0.825). On the other hand, the median CCI-24 for cross-matched PLT transfusions and HLA-matched PLT transfusions were 1856 and 5824 (p < 0.001), with a success rate of 28.1 and 54.1% in cases with non-immune-mediated PTR, respectively (p = 0.001). CONCLUSION: The effectiveness of HLA-matched PLT is not inferior to cross-matched PLT. This result indicates that physical cross-match can be omitted in post HSCT PTR.

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  • Calciphylaxis of the fingers.

    Ko Harada, Jo Araki, Kazuki Tokumasu, Hideharu Hagiya, Fumio Otsuka

    Journal of general and family medicine   21 ( 2 )   25 - 26   2020.3

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    A 69-year-old Japanese man with a 10-year history of hemodialysis for end-stage renal disease presented with painful necrosis of the fingers of his right hand. A plain radiograph of the right hand revealed severely calcified arteries, particularly in the ring finger, suggesting the diagnosis of calciphylaxis of the fingers.

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  • Comparison of the clinical characteristics of TAFRO syndrome and idiopathic multicentric Castleman disease in general internal medicine: a 6-year retrospective study. International journal

    Yoshito Nishimura, Yoshihisa Hanayama, Nobuharu Fujii, Eisei Kondo, Fumio Otsuka

    Internal medicine journal   50 ( 2 )   184 - 191   2020.2

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    BACKGROUND: Although thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly (TAFRO) syndrome was first described as a variant of idiopathic multicentric Castleman disease (CD), patients with TAFRO syndrome demonstrate more aggressive clinical features. Because these patients may present with fever of unknown origin, general physicians need to recognise its characteristic laboratory data and clinical features during hospitalisation. AIMS: to describe the features, symptoms and characteristics of TAFRO syndrome and to compare them to those of idiopathic CD. METHODS: This was a retrospective study of patients with histopathologically confirmed TAFRO syndrome and idiopathic multicentric CD who were diagnosed and managed between April 2012 and June 2018 in a Japanese university hospital's General Medicine Department. RESULTS: We found that the hospitalisations were significantly longer among patients with TAFRO syndrome compared to those with idiopathic CD (median: 87 days; range: 34-236 days vs median: 30 days; range: 13-59 days; P < 0.01). Patients with TAFRO syndrome were more likely to present with fever, abdominal pain and elevated inflammatory markers and be misdiagnosed with an infectious disease during the first hospital visit. Approximately 40% of patients with TAFRO syndrome had no radiographically enlarged lymph nodes. CONCLUSIONS: TAFRO syndrome may present as an infectious disease with an aggressive clinical course. Our study highlights the importance of giving significance to chief complaints and laboratory data. Physicians need to recognise the clinical and laboratory features of this disease to avoid missing this potentially fatal disorder.

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  • グルココルチコイドとBMPによる卵胞ステロイド合成調節への影響

    樫野 千明, 長谷川 徹, 中野 靖浩, 長尾 聡子, 岩田 菜穂子, 鎌田 泰彦, 増山 寿, 大塚 文男

    日本内分泌学会雑誌   95 ( 4 )   1556 - 1556   2020.2

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  • 卵胞プロゲステロン産生におけるアルドステロンとBMP-6の影響

    中野 靖浩, 長谷川 徹, 樫野 千明, 長尾 聡子, 灘 隆宏, 岩田 菜穂子, 西山 悠紀, 細谷 武史, 大塚 文男

    日本内分泌学会雑誌   95 ( 4 )   1514 - 1514   2020.2

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  • Clinical Relevance of Blood Glucose and Gastroesophageal Reflux Symptoms to Depressive Status in Patients with Type 2 Diabetes Mellitus.

    Hiroyuki Honda, Yoshihisa Hanayama, Mikako Obika, Kou Hasegawa, Jun Hamahara, Masayuki Kishida, Hideharu Hagiya, Hiroko Ogawa, Hitomi Kataoka, Fumio Otsuka

    Acta medica Okayama   74 ( 1 )   33 - 40   2020.2

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    A relationship between diabetes and depression is apparent. To clarify the clinical relevance of diabetic patients' gastroesophageal symptoms to their psychological status, we retrospectively analyzed the data from a Selfrating Depression Scale (SDS) and a Frequency Scale for Symptoms of Gastroesophageal reflux disease (FSSG) among 143 type 2 diabetic patients who visited a general medicine department. Among the 45 Japanese patients enrolled, the group with relatively high SDS scores (≥ 36) showed higher (FSSG) dysmotility symptom scores versus the low-SDS (< 36) group, although the 2 groups' characteristics and laboratory data were not significantly different. Positive correlations of postprandial plasma glucose (PPG) levels with FSSG scores (R=0.321, p<0.05), particularly with reflux scores (R=0.455, p<0.01) were revealed. PPG and HbA1c levels were not correlated with SDS scores. The patients' SDS scores were significantly correlated with their FSSG scores (R=0.41, p<0.01), suggesting that depressive status is linked to GERD-related manifestations. Considering that the patients' PPG levels were correlated with GERD-related symptoms, diabetic patients' blood glucose levels are associated with depressive status. Collectively, key symptoms related to GERD and glucose level values would be helpful.

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  • Panda and lambda sign' in sarcoidosis

    K Harada, M Yasuda, F Otsuka

    QJM   113 ( 1 )   61 - 62   2020.1

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  • Purple Urine Bag Syndrome.

    Ko Harada, Chihiro Hiraiwa, Ei Miyasaka and Fumio Otsuka

    J. Hosp. Gen. Med.   2020.1

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  • Dysgeusia in a Psychiatric Patient: A Case of Chronic Lithium Intoxication.

    Harada K, Tokumasu K, Hagiya H, Obika M and Otsuka F:

    J. Hosp. Gen. Med.   116 - 120   2020.1

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  • Technique for single-step lymphocyte isolation from an endoscopic biopsy specimen for the diagnosis of gastrointestinal lymphoma. International journal

    Masaya Iwamuro, Takahide Takahashi, Natsuki Watanabe, Sizuma Omote, Katsunori Matsueda, Takehiro Tanaka, Daisuke Ennishi, Fumio Otsuka, Tadashi Yoshino, Hiroyuki Okada

    MethodsX   7   101095 - 101095   2020

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    In this paper, we introduce a simplified, one-step procedure for lymphocyte isolation from an endoscopically biopsied fragment. For lymphocyte isolation, an endoscopically harvested specimen and 5 mL of normal saline solution were placed in a wire mesh strainer set in a porcelain bowl. To obtain the lymphocyte suspension, the solid specimen was crushed using the rubber portion of a plunger of a 10 mL injection syringe. Flow cytometry was performed using the lymphocyte suspension. For validating our methods, the one-step lymphocyte isolation technique was used to perform flow cytometry on samples from 23 patients with (n = 12) or without (n = 11) gastrointestinal lymphoma. Flow cytometry of light chain expression was performed in all patient samples (feasibility: 100%). Sensitivity was 83.3% (10/12) and specificity was 100% (11/11). In conclusion, lymphocytes isolated from a single endoscopic biopsy specimen using our simplified and quick procedure are suitable for flow cytometry. Considering that flow cytometry has an important advantage of providing the results on the examination day itself, the results of this study suggest that flow cytometric analysis using our single-step lymphocyte isolation technique can be potentially used to diagnose lymphoma in the gastrointestinal mucosa. •We introduce a simplified, one-step procedure for lymphocyte isolation from an endoscopically biopsied fragment.•Our technique is feasible for flow cytometric analysis in patients with gastrointestinal lymphoma as well as those with gastrointestinal lesions that are suspected to be lymphoma.

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  • Correlations between Depressive Condition and Gastroesophageal Reflux Symptoms in Patients Visiting a Department of General Medicine.

    Yu Suganami, Kosuke Oka, Yoshihisa Hanayama, Hiroyuki Honda, Jun Hamahara, Mikako Obika, Kazuya Kariyama, Masayuki Kishida, Fumio Otsuka

    Acta medica Okayama   73 ( 6 )   479 - 486   2019.12

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    To clarify the potential relevance of patients' chief complaints at a general medicine department to their self-rating depression scale (SDS) and frequency scale for symptoms of gastroesophageal reflux disease (GERD) (FSSG) scores, we analyzed data of 478 patients who visited our general medicine department. The chief complaints (553 symptoms of 447 patients) were categorized into major symptom-based groups: respiratory (31%), circulatory (3%), gastrointestinal (GI) tract (26%), neurology (8%), orthopedic and skin (10%), and systemic (22%) symptoms. The SDS score tended to be higher in females and younger patients. The FSSG score did not differ by gender but was higher in younger patients. The patients receiving social welfare had higher SDS and FSSG scores. A close inter-relationship between the FSSG (including both degrees of reflux and dysmotility) and SDS was observed in all patients. Although the averages of the SDS and FSSG scores were not significantly different among the symptom-based categories, we observed significantly positive correlations between the FSSG and SDS in each category, suggesting that depressive status may be closely related to GERD-related symptoms regardless of the patients' chief complaints. An initial checkup of patients' psychological condition and/or GERD-like symptoms could help screen for latent disorders in outpatients with uncertain complaints.

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  • "Small Heart Syndrome" with Orthostatic Hypotension.

    Ko Harada, Miho Yasuda, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   58 ( 22 )   3337 - 3338   2019.11

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  • 冠攣縮性狭心症との関連が疑われた副腎皮質機能低下症の1例

    大塚 勇輝, 安田 美帆, 中野 靖浩, 山本 晃, 長谷川 功, 萩谷 英大, 小比賀 美香子, 片岡 仁美, 大塚 文男

    日本病院総合診療医学会雑誌   15 ( 6 )   590 - 590   2019.11

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  • Risk Factors for Low Bone Mineral Density Determined in Patients in a General Practice Setting.

    Akemi Ando, Toshiharu Mitsuhashi, Mitsugi Honda, Yoshihisa Hanayama, Kou Hasegawa, Mikako Obika, Hitomi Kataoka, Fumio Otsuka

    Acta medica Okayama   73 ( 5 )   403 - 411   2019.10

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    Osteoporosis increases the risk of bone fractures. It is diagnosed based on an individual's bone mineral density (BMD) or a fracture without trauma. BMD is usually measured by the dual energy X-ray absorptiometry (DXA) method. Here we investigated factors for the earliest possible prediction of decreased BMD by examining the relationships between patients' BMD values and changes in the patients' physical and laboratory values. We retrospectively reviewed the medical records of 149 patients who visited our department in 2014-2015 for a variety of reasons and underwent an area BMD examination by DXA. We analyzed the relationships between decreasing BMD and the patients' gender, age, body mass index (BMI), medical background, hemoglobin, electrolytes, and thyroid function. Thirty-nine of the patients were diagnosed with osteoporosis based on their T-scores. An adjusted analysis showed that female gender, aging, and increased serum calcium level were significantly related to decreasing femoral BMD, whereas high BMI was associated with an increase in femoral BMD. Collectively the results indicate that for the early detection of low BMD, it is important for general-practice physicians to consider conducting a BMD checkup when treating female and elderly patients with a low BMI and/or elevated serum calcium level.

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  • 原発性副甲状腺機能亢進症を合併した神経線維腫症1型の1例 Reviewed

    小松原 基志, 稲垣 兼一, 森本 栄作, 藤澤 諭, 西山 悠紀, 原 孝行, 細谷 武史, 当真 貴志雄, 越智 可奈子, 大塚 文男, 和田 淳

    日本内分泌学会雑誌   95 ( 2 )   735 - 735   2019.10

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  • 妊娠尿崩症をきたした経蝶形骨型髄膜瘤の一例 Reviewed

    森本 栄作, 稲垣 兼一, 三好 智子, 西山 悠紀, 藤澤 諭, 小松原 基志, 原 孝行, 細谷 武史, 当真 貴志雄, 越智 可奈子, 大塚 文男, 和田 淳

    日本内分泌学会雑誌   95 ( 2 )   724 - 724   2019.10

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  • 総合診療における血清プロラクチン値の性差と炎症性病態への関与

    山本 紘一郎, 花山 宜久, 安田 美帆, 長谷川 功, 原田 洸, 徳増 一樹, 萩谷 英大, 三好 智子, 小川 弘子, 小比賀 美香子, 大塚 文男

    日本内分泌学会雑誌   95 ( 2 )   769 - 769   2019.10

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  • Composite pheochromocytomaの1例 Reviewed

    原 孝行, 稲垣 兼一, 森本 栄作, 西山 悠紀, 藤澤 諭, 小松原 基志, 越智 可奈子, 細谷 武史, 当真 貴志雄, 三好 智子, 小林 泰之, 大塚 文男, 竹越 一博, 和田 淳

    日本内分泌学会雑誌   95 ( 2 )   747 - 747   2019.10

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  • AVシャントによる著明な拡張血管を伴った褐色細胞腫の1例 Reviewed

    山岡 主知, 稲垣 兼一, 森本 栄作, 藤澤 諭, 西山 悠紀, 小松原 基志, 原 孝行, 細谷 武史, 当真 貴志雄, 越智 可奈子, 大塚 文男, 和田 淳

    日本内分泌学会雑誌   95 ( 2 )   806 - 806   2019.10

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  • 家族性孤発性副甲状腺機能亢進症が疑われる2症例 Reviewed

    西山 悠紀, 稲垣 兼一, 藤澤 諭, 森本 栄作, 小松原 基志, 原 孝行, 細谷 武史, 当真 貴志雄, 越智 可奈子, 大塚 文男, 和田 淳

    日本内分泌学会雑誌   95 ( 2 )   791 - 791   2019.10

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  • 遺伝性出血性末梢血管拡張症に合併したパラガングリオーマの一例 Reviewed

    藤澤 諭, 稲垣 兼一, 当真 貴志雄, 森本 栄作, 西山 悠紀, 小松原 基志, 原 孝行, 細谷 武史, 越智 可奈子, 三好 智子, 大塚 文男, 竹越 一博, 和田 淳

    日本内分泌学会雑誌   95 ( 2 )   748 - 748   2019.10

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  • Feasibility of flow cytometric analysis of restricted light chain in endoscopic biopsy specimens from patients with gastrointestinal tract B cell lymphoma: a pilot study. International journal

    Katsunori Matsueda, Masaya Iwamuro, Takahide Takahashi, Sizuma Omote, Kenji Nishida, Takehiro Tanaka, Daisuke Ennishi, Fumio Otsuka, Tadashi Yoshino, Hiroyuki Okada

    BMC research notes   12 ( 1 )   571 - 571   2019.9

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    OBJECTIVE: Gastrointestinal tract lymphomas are currently detected more frequently due to advances in endoscopic technology. The aim of this study was to assess the feasibility of flow cytometric analysis of restricted light chain in endoscopic biopsy specimens for the diagnosis of gastrointestinal tract B-cell lymphoma. We prepared viable cell suspensions from unfixed specimens obtained from 10 consecutive patients who had a previous histological diagnosis of gastrointestinal tract B-cell lymphoma. We performed immunophenotypic studies with multi-color flow cytometry and assessed clonality through examination of immunoglobulin light chain expression exclusively in a population identified by anti-CD45 or CD20 antibodies. RESULTS: We could perform light chain expression analysis with 2 endoscopic biopsy specimens from all 10 patients with gastrointestinal tract B-cell lymphoma. We conclude that flow cytometric analysis of endoscopic biopsy specimens is feasible and thus likely useful for the diagnosis of gastrointestinal tract B-cell lymphoma in clinical settings. Trial registration UMIN Clinical Trials Registry, UMIN000027730. Registered 12 June 2017.

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  • A case of pseudo-pheochromocytoma possibly induced by a preceding respiratory infection.

    Hagiya H, Nakagami F, Yoshida S, Nagawasa M, Takami Y, Akasaka H, Yamamoto K, Otsuka F, Rakugi H

    J. Hosp. Gen. Med.   1 ( 3 )   16 - 20   2019.9

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  • Myxedema coma accompanied by sick sinus syndrome and hypoventilation: A case report.

    Ko Harada, Shuntaro Murakami, Kazuki Tokumasu, Yu Togawa, Fumio Otsuka

    Journal of general and family medicine   20 ( 5 )   206 - 208   2019.9

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    Myxedema coma is an emergency presentation of hypothyroidism, and cardiopulmonary manifestations of the disease are related to a high mortality rate. We herein report a case of myxedema coma accompanied by sick sinus syndrome requiring temporary cardiac pacing and hypercapnic respiratory failure in an 87-year-old woman. This case is unique because both of the cardiac and pulmonary manifestations were reversible and successfully treated with thyroid hormone replacement. Our case indicates that early detection of the condition and administration of levothyroxine are essential to improve the life-threatening condition and avoid invasive treatment such as permanent pacemaker implantation or intubation.

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  • A novel case of myxoid variant of adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1.

    Ko Harada, Miho Yasuda, Kou Hasegawa, Yuto Yamazaki, Hironobu Sasano, Fumio Otsuka

    Endocrine journal   66 ( 8 )   739 - 744   2019.8

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    Adrenocortical carcinoma (ACC) is a rare malignancy arising from adrenocortical parenchymal cells. Myxoid ACC is one of the newly identified, rare, but important histological variants of ACC, characterized by the presence of abundant extracellular Alcian Blue-positive myxoid material. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer predisposition syndrome, and the incidence of ACC in MEN1 patients has been reported to be between 1.4% and 6%. Here, we report the case of a 68-year-old Japanese woman harboring the past history of MEN1 associated with insulinoma, pituitary tumor, and hyperparathyroidism. She presented to our hospital with hypertension and hypokalemia. Imaging studies revealed a right adrenal tumor, and histological examination revealed myxoid ACC. Despite surgical resection of the tumor and mitotane therapy, the patient died 6 months after the surgery. To the best of our knowledge, this is the first reported case of the myxoid variant of ACC in a patient with MEN1. The patient's clinical course was characterized by the development of both multiple endocrine and non-endocrine neoplasm, hyperaldosteronism, and aggressive biological behavior. This case confirmed that myxoid morphology was also associated with aggressive behavior in ACC, but further studies are required to clarify the association between MEN1 and myxoid ACC.

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  • FDG uptake in toxic multinodular goiter.

    Ocho K, Hasegawa K, Otsuka F

    J. Hosp. Gen. Med.   1 ( 2 )   14 - 15   2019.7

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  • Factors related to burnout in resident physicians in Japan. International journal

    Yoshito Nishimura, Tomoko Miyoshi, Mikako Obika, Hiroko Ogawa, Hitomi Kataoka, Fumio Otsuka

    International journal of medical education   10   129 - 135   2019.7

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    Objectives: We explore the prevalence and characteristics of burnout among Japanese resident physicians and identifies factors associated with burnout. Methods: A cross-sectional study was conducted three times between April 2017 and March 2018 at a Japanese teaching hospital. Resident physicians were invited to answer an online survey that included existing valid instruments related to burnout, depression, and empathy. Demographic, background, occupational, and socioeconomic data were also collected. Participants were prompted to report the average daily work hours and the specialty they wish to pursue. Results: Overall, 39/76 (51%), 27/76 (36%), and 21/76 (28%) resident physicians responded to surveys in April 2017, October 2017, and March 2018, respectively. The percentages of participants with burnout for surveys in April 2017, October 2017, and March 2018 were 7/39 (18%), 6/27 (22%), and 7/21 (33.3%). Emotional exhaustion (EE) was the only burnout component strongly correlated with the severity of depression (r = .615, p < .001; r = .706, p < .001; r = .601, p < .01). EE and depersonalization (DP) had no significant correlation with average daily working hours (β = .156, p = .343 for EE; β = .061, p = .711 for DP). Conclusions: The results suggest that capping working hours alone may not be effective in reducing burnout in Japanese resident physicians. Medical educators might need to consider not only working hours but also individual job quality and satisfaction to address burnout. Future studies may need to incorporate qualitative methods to explore the characteristics of burnout.

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  • Surface related tunneling leakage in beta-Ga2O3 (001) vertical Schottky barrier diodes

    Ravikiran Lingaparthi, Kohei Sasaki, Quang Tu Thieu, Akio Takatsuka, Fumio Otsuka, Shigenobu Yamakoshi, Akito Kuramata

    APPLIED PHYSICS EXPRESS   12 ( 7 )   2019.7

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    beta-Ga2O3 (001) Schottky barrier diodes (SBDs) fabricated on a halide vapor phase epitaxy-grown epilayer showed anomalous reverse leakage characteristics, which could not be explained through thermionic field emission theory. A systematic investigation through the measurements and simulations of capacitance-voltage and current density-voltage characteristics suggested the presence of a thin surface layer on the epilayer with high density of oxygen vacancy states. This thin surface layer allowed the tunneling of electrons and caused anomalous reverse leakage properties (Thin surface barrier model). Annealing of the epilayer in an oxidative environment passivated the surface oxygen vacancy states and reduced the reverse leakage current enormously. (C) 2019 The Japan Society of Applied Physics

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  • 岡山大学病院研修医メンター制度の実態調査

    佐藤 明香, 植田 真司, 宇賀 麻由, 矢野 修也, 小川 弘子, 三好 智子, 難波 志穂子, 大塚 文男

    医学教育   50 ( Suppl. )   187 - 187   2019.7

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  • Swollen Hands and "Fist Sign" in Acromegaly. International journal

    Ko Harada, Kou Hasegawa, Fumio Otsuka

    The American journal of medicine   132 ( 7 )   e618-e619 - E619   2019.7

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    DOI: 10.1016/j.amjmed.2019.02.022

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  • A Huge Liver Cyst Manifesting Dyspnea and Edema.

    Satoko Nagao, Masaya Iwamuro, Hidenori Shiraha, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   58 ( 12 )   1811 - 1812   2019.6

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    DOI: 10.2169/internalmedicine.1957-18

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  • Histidine-rich glycoprotein augments natural killer cell function by modulating PD-1 expression via CLEC-1B. International journal

    Yoshito Nishimura, Hidenori Wake, Kiyoshi Teshigawara, Dengli Wang, Masakiyo Sakaguchi, Fumio Otsuka, Masahiro Nishibori

    Pharmacology research & perspectives   7 ( 3 )   e00481 - e00481   2019.6

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    Augmentation of natural killer (NK) cell cytotoxicity is one of the greatest challenges for cancer immunotherapy. Although histidine-rich glycoprotein (HRG), a 75-kDa glycoprotein with various immunomodulatory activities, reportedly elicits antitumor immunity, its effect on NK cell cytotoxicity is unclear. We assessed NK cell cytotoxicity against K562 cells. We also measured concentrations of cytokines and granzyme B in the cell supernatant. The proportion of CD56bright NK cells and NK cell surface PD-1 expression was assessed with flow cytometry. The neutralizing effects of anti-C-type lectin-like receptor (CLEC) 1B against HRG were also measured. NK cell morphological changes were analyzed via confocal microscopy. HRG significantly increased NK cell cytotoxicity against K562 cell lines. HRG also increased the release of granzyme B and the proportion of CD56bright NK cells. Further, HRG was able to decrease NK cell surface PD-1 expression. The effects of HRG on NK cells were reversed with anti-CLEC-1B antibodies. Additionally, we confirmed NK cell nuclear morphology and F-actin distribution, which are involved in the regulation of cytotoxic granule secretion. Because both PD-1 and CLEC-1B are associated with prognosis during malignancy, HRG incorporates these molecules to exert the antitumor immunity role. These facts indicate the potential of HRG to be a new target for cancer immunotherapy.

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  • Anterior Cutaneous Nerve Entrapment Syndrome Possibly Triggered by Oral Contraceptives.

    Daisuke Omura, Mikako Obika, Masaya Iwamuro, Satoko Nagao, Takahiro Nada, Takashi Matsuzaki, Yoshitaka Kondo, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   58 ( 10 )   1507 - 1509   2019.5

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    We herein report a teenage girl who had been taking oral contraceptive pills for three months and complained of left lower abdominal pain that had continued for two months. A physical examination indicated anterior cutaneous nerve entrapment syndrome (ACNES), although no abnormality was found in various biochemical and imaging examinations. The pain was only transiently ameliorated by trigger-point injection, and neurectomy surgery was eventually effective. Sex steroids can be involved in the progress of local tissue edema causing ACNES. ACNES should be considered in cases of abdominal pain in patients taking oral contraceptives.

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  • Retention cysts due to latent pancreatic cancer.

    Oka K, Horiguchi S, Obika M, Otsuka F

    J. Hosp. Gen. Med.   ( 1 )   6 - 6   2019.5

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  • Cardiac Computed Tomography of Aortic Infective Endocarditis.

    Harada K, Otsuka F

    QJM   112 ( 5 )   377 - 378   2019.5

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  • Total Vascular Resistance and Augmentation Pressure in Patients with Peripheral Artery Disease

    Rika Takemoto, Haruhito A. Uchida, Nozomu Otaka, Yoshiko Hada, Yasuhiro Onishi, Natsumi Matsuoka, Shugo Okamoto, Mariko Nishiwaki, Hironobu Toda, Fumio Otsuka, Hiroshi Ito, Jun Wada

    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY   39   2019.5

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  • 総合内科診療における主訴と生化学データの関連 浸透圧マーカーに着目して

    大村 大輔, 佐藤 明香, 岡 浩介, 小川 弘子, 花山 宜久, 小比賀 美香子, 大塚 文男

    日本病院総合診療医学会雑誌   15 ( 3 )   175 - 175   2019.5

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  • 膵酵素とアミノ酸製剤補充により改善した吸収不良症候群の1例

    山本 紘一郎, 中野 靖浩, 大村 大輔, 徳増 一樹, 長谷川 功, 堀口 繁, 花山 宜久, 小比賀 美香子, 小川 弘子, 大塚 文男

    日本病院総合診療医学会雑誌   15 ( 3 )   311 - 311   2019.5

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  • Mesenteric follicular lymphoma. International journal

    Yoshito Nishimura, Akira Yamamoto, Masahiro Takahara, Fumio Otsuka

    Clinical case reports   7 ( 5 )   1108 - 1109   2019.5

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    When you see a patient with solid mesenteric tumors, malignant lymphoma should be considered as an important differential diagnosis. It is essential to include abdominal CT and 18F-FDG PET/CT examinations in these patients for early diagnosis of malignant lymphoma, giving extra weight on patients' complaints.

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  • Septic pulmonary emboli caused by infected central venous port. International journal

    Ko Harada, Fumio Otsuka

    Postgraduate medical journal   95 ( 1123 )   282 - 282   2019.5

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    DOI: 10.1136/postgradmedj-2019-136461

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  • Diffuse Vascular FDG Uptake in Late Onset Takayasu Arteritis. International journal

    Ko Harada, Kou Hasegawa, Fumio Otsuka

    The American journal of medicine   132 ( 5 )   e560-e561 - E561   2019.5

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    DOI: 10.1016/j.amjmed.2019.01.018

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  • Symptomatic Adrenal Myelolipoma.

    Daisuke Omura, Yasuhiro Nakano, Ryosuke Takase, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   58 ( 8 )   1181 - 1181   2019.4

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  • Renal intravascular lymphoma diagnosed by FDG-PET.

    J. Hosp. Gen. Med.   2019.4

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  • Axillary lymph node tuberculosis in the elderly.

    Ocho K, Tanimoto S, Shioji Y, Fujita K, Otsuka F

    J. Hosp. Gen. Med.   15   106 - 107   2019.4

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  • FDG PET/CT findings in infected abdominal aortic aneurysm.

    Harada K, Fukushima F, Tokumasu K, Hagiya H, Otsuka F

    J. Hosp. Gen. Med.   1 ( 4 )   59 - 60   2019.4

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  • Fever of unknown origin without increase of serum C-reactive protein in a patient with acute lymphoblastic leukemia/ lymphoblastic lymphoma.

    Oka K, Fujimura T, Horiguchi S, Yano T, Kondo E, Otsuka F

    J. Hosp. Gen. Med   1 ( 3 )   45 - 49   2019.4

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  • Peripartum cardiomyopathy with marked pulmonary edema: A case report.

    Harada K, Otsuka F

    J. Hosp. Gen. Med.   1 ( 3 )   26 - 30   2019.4

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  • Delayed postoperative hyponatremia after endoscopic transsphenoidal surgery for pituitary adenoma. International journal

    Yusuke Tomita, Kazuhiko Kurozumi, Kenichi Inagaki, Masahiro Kameda, Joji Ishida, Takao Yasuhara, Tomotsugu Ichikawa, Tomoko Sonoda, Fumio Otsuka, Isao Date

    Acta neurochirurgica   161 ( 4 )   707 - 715   2019.4

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    BACKGROUND: Hyponatremia generally occurs after transsphenoidal surgery (TSS) in a delayed fashion. Most patients with delayed postoperative hyponatremia (DPH) are asymptomatic or only express non-specific symptoms; consequently, DPH is associated with prolonged hospitalization. No consensus has been reached on which patients are at greatest risk of developing DPH. We reviewed patients with DPH and evaluated predictive factors for DPH. METHODS: We retrospectively analyzed 107 consecutive patients who underwent endoscopic TSS for pituitary adenoma (January 2010-December 2016). Patients with DPH (hyponatremia group) and without DPH (normonatremia group) were compared according to their nadir sodium levels on postoperative days 3 to 10. We documented the patients' demographics, clinical features, and postoperative physiological characteristics. RESULTS: Twenty-five (23.4%) patients developed DPH after endoscopic TSS. The patients' mean age was 54 ± 17 years, and 63.6% of the patients were female. The overall prevalence of DPH was 23.4%. The non-parametric χ2 test and the Mann-Whitney U test revealed statistically significant differences in age, use of antihypertensive drugs, nonfunctioning pituitary adenoma, and higher yet normal preoperative thyroid-stimulating hormone level between the hyponatremia and normonatremia groups (P < 0.05). Logistic regression analysis revealed that only older age was a useful independent predictive factor for DPH (odds ratio, 1.05; 95% confidence interval, 1.01-1.08; P = 0.01). The serum sodium levels on postoperative day 2 were significantly lower in the hyponatremia than normonatremia group (P < 0.01) and were negatively correlated with age (r = - 0.25, P < 0.05). The cut-off age for predicting DPH was 55 years. The hospital stay was significantly longer in the hyponatremia than normonatremia group (P < 0.01). CONCLUSIONS: Age of more than 55 years was an independent predictive factor for DPH even after adjusting for potential confounders. Older age was negatively correlated with the serum sodium level on postoperative day 2. Preventing early decreases in the sodium level could reduce the risk of DPH. TRIAL REGISTRATION: 1707-027.

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  • 非機能性下垂体腺腫の術後に急速に肝障害を来した1例 Reviewed

    越智 可奈子, 稲垣 兼一, 森本 栄作, 藤澤 諭, 小松原 基志, 原 孝行, 細谷 武史, 当真 貴志雄, 黒住 和彦, 和田 淳, 大塚 文男

    日本内分泌学会雑誌   95 ( 1 )   491 - 491   2019.4

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  • Orexinによる下垂体前葉ホルモン分泌への影響とBMP-4の関与 Reviewed

    藤澤 諭, 小松原 基志, 森本 栄作, 西山 悠紀, 原 孝行, 細谷 武史, 当真 貴志雄, 越智 可奈子, 稲垣 兼一, 和田 淳, 大塚 文男

    日本内分泌学会雑誌   95 ( 1 )   490 - 490   2019.4

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  • インクレチンによるカテコラミン合成への影響 BMPとステロイドに着目して Reviewed

    小松原 基志, 西山 悠紀, 灘 隆宏, 岩田 菜穂子, 藤澤 諭, 原 孝行, 細谷 武史, 当真 貴志雄, 稲垣 兼一, 和田 淳, 大塚 文男

    日本内分泌学会雑誌   95 ( 1 )   423 - 423   2019.4

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  • カテコラミン産生に対するスクレロスチンの影響 PC12細胞を用いた検討 Reviewed

    森本 栄作, 稲垣 兼一, 小松原 基志, 藤澤 諭, 西山 悠紀, 原 孝行, 細谷 武史, 当真 貴志雄, 越智 可奈子, 大塚 文男, 和田 淳

    日本内分泌学会雑誌   95 ( 1 )   423 - 423   2019.4

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  • 卵巣顆粒膜細胞のステロイド合成におけるClock遺伝子とBMP-7の関与

    長尾 聡子, 岩田 菜穂子, 中野 靖浩, 灘 隆宏, 樫野 千明, 長谷川 徹, 大塚 文男

    日本内分泌学会雑誌   95 ( 1 )   504 - 504   2019.4

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  • グルココルチコイドによる卵胞ステロイド合成に与える影響とその機序の検討

    樫野 千明, 長谷川 徹, 中野 靖浩, 長尾 聡子, 岩田 菜穂子, 西山 悠紀, 細谷 武史, 鎌田 泰彦, 増山 寿, 大塚 文男

    日本内分泌学会雑誌   95 ( 1 )   500 - 500   2019.4

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  • アルドステロンによる卵胞ステロイド産生への影響とBMPの関与

    中野 靖浩, 長谷川 徹, 樫野 千明, 長尾 聡子, 灘 隆宏, 岩田 菜穂子, 西山 悠紀, 細谷 武史, 大塚 文男

    日本内分泌学会雑誌   95 ( 1 )   427 - 427   2019.4

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  • Effects on postgraduate-year-I residents of simulation-based learning compared to traditional lecture-style education led by postgraduate-year-II residents: a pilot study. International journal

    Akira Yamamoto, Mikako Obika, Yasuhiro Mandai, Taku Murakami, Tomoko Miyoshi, Hideo Ino, Hitomi Kataoka, Fumio Otsuka

    BMC medical education   19 ( 1 )   87 - 87   2019.3

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    BACKGROUND: Simulation-based learning plays an important role in contemporary medical education, although there are problems providing tutors. Peer-assisted learning has begun being formally adopted in medical education. Although it is considered useful for simulation-based learning, its effectiveness remains unclear. This study was designed to compare the effect of simulation-based learning with that of traditional lectures conducted by postgraduate-year (PGY)-II residents on PGY-I residents. METHODS: This study was conducted at Okayama University Hospital over three years, for one week each year, before residents entered clinical practice. The study enrolled 76 PGY-I residents, who were randomized into two groups: simulation and lecture groups. PGY-II residents volunteered to conduct simulations and lectures. Knowledge evaluation was performed using pre- and post-tests, and self-evaluation of competence and behaviour-change and program evaluations were conducted using questionnaires. RESULTS: In both groups, knowledge test scores were found to improve significantly, and the score difference between pre- and post-tests in both the groups was not significant. Self-evaluation of competence and behaviour-change was found to be higher in the simulation group than the lecture group. The trainees in the simulation group valued the program and the PGY-II residents as teaching staff more than those in the lecture group. CONCLUSIONS: The combination of simulation-based learning and peer-assisted learning led by PGY-II residents is potentially more effective in improving the postgraduate education of PGY-I residents than the combination of lecture and peer-assisted learning.

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  • Ludwig's Angina and Mandibular Osteomyelitis after Dental Extraction.

    Yuki Otsuka, Ko Harada, Yoshito Nishimura, Fumio Otsuka

    JMA journal   2 ( 1 )   87 - 88   2019.3

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  • Crowned Dens Syndrome Associated with Hyperuricemia.

    Yuusaku Sugihara, Hiroko Ogawa, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   58 ( 5 )   765 - 765   2019.3

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  • Orexin A modulates prolactin production by regulating BMP-4 activity in rat pituitary lactotorope cells. International journal

    Satoshi Fujisawa, Motoshi Komatsubara, Kanako Ogura-Ochi, Naoko Tsukamoto-Yamauchi, Kishio Toma, Kenichi Inagaki, Jun Wada, Fumio Otsuka

    Peptides   113   35 - 40   2019.3

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    The impact of orexins on anterior pituitary function has yet to be clarified. We studied the effects of orexin A and its interaction with the bone morphogenetic protein (BMP) system on the regulatory role of prolactin synthesis using rat lactotrope GH3 cells expressing BMP-4. Orexin type 1 receptor (OX1R), but not type 2 receptor (OX2R), was predominantly expressed in GH3 cells. Orexin A suppressed forskolin-induced, but not basal, prolactin mRNA expression without reducing cAMP levels. Of note, orexin A suppressed BMP-4-induced prolactin mRNA and cAMP synthesis. Impairment of the effects of orexin by chemical inhibitors suggested involvement of the P38 pathway in the OX1R activity that suppresses BMP-4-induced PRL expression. Given that inhibition of BMP-receptor signaling reduced prolactin mRNA levels, endogenous BMP action is likely to be linked to the activation of prolactin synthesis by GH3 cells. Orexin A was revealed to suppress Smad1/5/9 phosphorylation and Id-1 transcription induced by BMP-4, which was restored in the presence of orexin-receptor antagonists, suggesting that the inhibitory effect of orexin A occurred via OX1R. Orexin A also reduced ALK-3 expression but increased inhibitory Smad6/7 expression, while BMP-4 treatment downregulated OX1R expression. These results indicated that orexin A plays an inhibitory role in prolactin production through suppression of endogenous BMP activity in GH3 cells, suggesting that a new functional role of the interaction between orexin and BMP-4 is modulation of prolactin levels in lactotrope cells.

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  • Runx3 regulates folliculogenesis and steroidogenesis in granulosa cells of immature mice. Reviewed International journal

    Fumiya Ojima, Yuka Saito, Yukiko Tsuchiya, Maho Ogoshi, Hiroshi Fukamachi, Kenichi Inagaki, Fumio Otsuka, Sakae Takeuchi, Sumio Takahashi

    Cell and tissue research   375 ( 3 )   743 - 754   2019.3

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    We previously demonstrated that female Runx3 knockout (Runx3-/-) mice were anovulatory and their uteri were atrophic and that Runx3 mRNA was expressed in granulosa cells. To clarify how Runx3 regulates folliculogenesis and ovulation, we examine the effects of Runx3 knockout on the gene expression of growth factors associated with folliculogenesis and enzymes associated with steroidogenesis. In Runx3-/- mouse ovaries, the numbers of primary and antral follicles were lower than those in wild-type (wt) mice at 3 weeks of age, indicating that the loss of Runx3 affects folliculogenesis. The expression of genes encoding activin and inhibin subunits (Inha, Inhba and Inhbb) was also decreased in ovaries from the Runx3-/- mice compared with that in wt mice. Moreover, the expression of the genes Cyp11a1 and Cyp19a1 encoding steroidogenic enzymes was also decreased. In cultured granulosa cells from 3-week-old mouse ovaries, Cyp19a1 mRNA levels were lower in Runx3-/- mice than those in wt mice. Follicle-stimulating hormone (FSH) treatment increased Cyp19a1 mRNA levels in both wt and Runx3-/- granulosa cells in culture but the mRNA level in Runx3-/- granulosa cells was lower than that in wt ones, indicating that granulosa cells could not fully function in the absence of Runx3. At 3 weeks of age, gonadotropin α subunit, FSHβ subunit and luteinizing hormone (LH) β subunit mRNA levels were decreased in Runx3-/- mice. These findings suggest that Runx3 plays a key role in female reproduction by regulating folliculogenesis and steroidogenesis in granulosa cells.

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  • Interaction of ovarian steroidogenesis and clock gene expression modulated by bone morphogenetic protein-7 in human granulosa cells.

    Satoko Nagao, Nahoko Iwata, Yoshiaki Soejima, Takaaki Takiguchi, Tamami Aokage, Yuka Kozato, Yasuhiro Nakano, Takahiro Nada, Toru Hasegawa, Fumio Otsuka

    Endocrine journal   66 ( 2 )   157 - 164   2019.2

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    A functional link between clock gene expression and ovarian steroidogenesis was studied using human granulosa KGN cells. Similarities between changes in the mRNA and protein expression levels of Bmal1 and Clock and those of Per2 and Cry1 were found in KGN cells after treatment with forskolin. Among the interrelationships between the expression levels of clock and steroidogenic factors, Clock mRNA had a strongly positive correlation with P450arom and a negative correlation with 3βHSD. Knockdown of Clock gene by siRNA resulted in a significant reduction of estradiol production by inhibiting P450arom expression, while it induced a significant increase of progesterone production by upregulating 3βHSD in KGN cells treated with forskolin. Moreover, BMP-7 had an enhancing effect on the expression of Clock mRNA and protein in KGN cells. Thus, the expression levels of Clock, being upregulated by forskolin and BMP-7, were functionally linked to estradiol production and progesterone suppression by human granulosa cells.

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  • Diagnostic FDG PET/CT findings in Polymyalgia Rheumatica.

    Otsuka Y, Harada K, Otsuka F

    QJM: An International Journal of Medicine   112 ( 2 )   139 - 140   2019.2

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  • Auricle Pain Due to Tophi.

    Yasuhiro Nakano, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   58 ( 3 )   453 - 453   2019.2

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  • Comparison of Two Electrosurgical Modes for Endoscopic Submucosal Dissection of Superficial Colorectal Neoplasms: A Prospective Randomized Study.

    Yuusaku Sugihara, Keita Harada, Shohei Oka, Eriko Yasutomi, Yasushi Yamasaki, Toshihiro Inokuchi, Hideaki Kinugasa, Masahiro Takahara, Sakiko Hiraoka, Fumio Otsuka, Hiroyuki Okada

    Acta medica Okayama   73 ( 1 )   81 - 84   2019.2

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    Endoscopic submucosal dissection (ESD) is reportedly one of the standard treatment strategies for large superficial colorectal neoplasms in Japan because of its high en bloc resection rate. A few technical issues regarding ESD should be considered, one of which is the selection of the Endo-cut I mode versus the Swift-coagulation mode as the electrosurgical unit mode setting during submucosal dissection. We seek to determine which of these two modes is more suitable for submucosal dissections of colorectal tumors with regard to procedure time and safety.

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  • A Remarkable Uptake of FDG in Huge Mediastinal Hashimoto's Goiter.

    Kosuke Oka, Takeshi Hosoya, Naruto Taira, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   58 ( 2 )   313 - 314   2019.1

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  • A Case of Juvenile Hypertension Suggestive of Adrenomedullary Hyperplasia.

    Yoshito Nishimura, Miho Yasuda, Kou Hasegawa, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   58 ( 2 )   311 - 311   2019.1

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  • Hyperthyroidism with Selective Immunoglobulin A Deficiency.

    Ko Harada, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   58 ( 1 )   145 - 146   2019.1

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  • Actinomycosis-induced Trismus with Orbital Involvement.

    Daisuke Omura, Kammei Rai, Nobuchika Kusano, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   58 ( 1 )   153 - 154   2019.1

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  • Pleomorphic parotid adenoma with Graves’hyperthyroidism.

    Ogura-Ochi K, Otsuka F

    J. Hosp. Gen. Med.   15   26 - 27   2019.1

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  • A marked goiter involved in Marine-Lenhart syndrome.

    Kosuke Oka, Miho Yasuda, Tadahiko Shien, Fumio Otsuka

    Journal of general and family medicine   20 ( 1 )   37 - 38   2019.1

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    Marine-Lenhart syndrome is rare disease defined as coexistence of Graves' disease and autonomously functioning thyroid nodule. We will introduce a case of Marine-Lenhart with a huge goiter.

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  • Cognitive decline due to ectopic primary hyperparathyroidism. International journal

    Yoshito Nishimura, Akira Yamamoto, Masahiro Takahara, Fumio Otsuka

    Clinical case reports   6 ( 12 )   2513 - 2514   2018.12

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    When you see a patient with cognitive dysfunction, hypercalcemia due to hyperparathyroidism is an important differential diagnosis. It is important to consider including chest computed tomography and 131I-MIBI SPECT examinations in patients with possible hyperparathyroidism and normal thyroid ultrasound.

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  • Orexinのプロラクチン産生への影響とBMP-4の関与 Reviewed

    藤澤 諭, 小松原 基志, 山内 尚子, 西山 悠紀, 原 孝行, 細谷 武史, 当真 貴志雄, 稲垣 兼一, 和田 淳, 大塚 文男

    日本内分泌学会雑誌   94 ( 4 )   1328 - 1328   2018.12

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  • 出血により高PRL血症を呈した胸髄海綿状血管腫の1例 Reviewed

    森本 栄作, 稲垣 兼一, 原 孝行, 藤澤 諭, 越智 可奈子, 三好 智子, 大塚 文男, 和田 淳

    日本内分泌学会雑誌   94 ( 3 )   1036 - 1036   2018.12

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  • Changes in Serum Biochemical Markers in Relation to Chief Complaints and Aging in General Medicine.

    Daisuke Omura, Asuka Sato, Kosuke Oka, Yoshihisa Hanayama, Hiroko Ogawa, Mikako Obika, Fumio Otsuka

    Acta medica Okayama   72 ( 6 )   553 - 562   2018.12

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    To clarify potential relationships between chief complaints of patients and laboratory data with a focus on aging-related changes, we retrospectively analyzed the data of 843 patients who visited a general medicine department for the first time. Their chief complaints were classified into 8 major symptoms: visceral pain, somatic pain, fever, cough, dizziness, fatigue, appetite loss, and edema. We compared the laboratory data obtained from the patients with complaints with the data of symptom-free (control) patients. The serum sodium and potassium levels in the fever group were decreased compared to those in the control group. In the fever group, the serum sodium level was inversely correlated with age. The ratio of serum urea nitrogen to creatinine (UN/Cr) was increased in the appetite-loss group. There were significant age-dependent increases in the UN/Cr ratio in the appetite-loss and edema groups. Of note, serum levels of free thyroxin were lower in the dizziness group compared to the control group. In addition, the free thyroxin level was inversely correlated with age in the dizziness group but not in the asymptomatic control group. Collectively, the results indicated that osmolality-related laboratory data are strongly associated with individual primary symptoms at the first visit regardless of the final diagnosis. The consideration of age-dependent changes of these markers is helpful for diagnosing latent disorders based on various primary symptoms.

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  • アルドステロンとBMPによる卵胞プロゲステロン産生への影響とその機序

    中野 靖浩, 長谷川 徹, 長尾 聡子, 灘 隆宏, 岩田 菜穂子, 西山 悠紀, 細谷 武史, 大塚 文男

    日本内分泌学会雑誌   94 ( 4 )   1439 - 1439   2018.12

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  • メトホルミンとBMPによる卵胞ステロイド合成系への影響とその機序

    岩田 菜穂子, 長谷川 徹, 藤田 志帆, 長尾 聡子, 中野 靖浩, 灘 隆宏, 西山 悠紀, 細谷 武史, 大塚 文男

    日本内分泌学会雑誌   94 ( 4 )   1438 - 1438   2018.12

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  • 卵胞ステロイド合成における時計遺伝子とBMPの関与 ヒト顆粒膜細胞を用いた検討

    長尾 聡子, 岩田 菜穂子, 副島 佳晃, 滝口 隆章, 青景 珠実, 上里 祐賀, 中野 靖浩, 灘 隆宏, 長谷川 徹, 大塚 文男

    日本内分泌学会雑誌   94 ( 4 )   1434 - 1434   2018.12

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  • 顆粒膜細胞における時計遺伝子とBMPによる卵胞ステロイド合成調節

    長尾 聡子, 岩田 菜穂子, 副島 佳晃, 滝口 隆章, 青影 珠実, 上里 祐賀, 中野 靖浩, 灘 隆宏, 長谷川 徹, 大塚 文男

    日本内分泌学会雑誌   94 ( 4 )   1394 - 1394   2018.12

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  • A Case of Diffuse Esophageal Spasm Treated with Peroral Endoscopic Myotomy.

    Yuusaku Sugihara, Keita Harada, Ryo Kato, Kenji Yamauchi, Hiroyuki Sakae, Seiji Kawano, Sakiko Hiraoka, Yoshiro Kawahara, Fumio Otsuka, Hiroyuki Okada

    Acta medica Okayama   72 ( 6 )   595 - 600   2018.12

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    The indications for peroral endoscopic myotomy (POEM) have been expanded to include diffuse esophageal spasm (DES). A 67-year-old Japanese man presented with a 4-year history of dysphagia. Endoscopy and upper gastrography revealed abnormal peristaltic movements involving interruption of normal peristalsis, and a diverticulum located at the 2 o'clock esophageal position. High-resolution manometry indicated DES. POEM with a long (15 cm) myotomy was performed for the abnormal contractions, which subsequently disappeared along with dysphagia improvement. Our results suggest that esophageal motility disorders accompanying a diverticulum may be eliminated by POEM without treating the diverticulum itself. We speculate that POEM ameliorates esophageal diverticulum by reducing internal esophageal pressure.

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  • Clival Osteomyelitis with Cavernous Sinus Thrombosis Due to Fusobacterium nucleatum and Campylobacter rectus Induced by Tooth Extraction.

    Kosuke Oka, Yasuhiro Nakano, Yosuke Sazumi, Tomo Michitani, Shigeru Horiguchi, Kazuki Ocho, Masaya Iwamuro, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   57 ( 22 )   3325 - 3328   2018.11

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    A 70-year-old woman who had suffered from aseptic meningitis complained of chronic headache after dental treatment including tooth extraction. She developed a fever and respiratory failure. Based on chest computed tomography and head magnetic resonance imaging (MRI), she was diagnosed with osteomyelitis in the clivus accompanying moderate pituitary involvement, cavernous sinus thrombosis and septic pulmonary embolism. Both of the causal bacteria, Fusobacterium nucleatum and Campylobacter rectus, were isolated from her blood. Dual infection leading to clival osteomyelitis and cavernous sinus thrombosis has not been reported. It is important to perform enhanced MRI and blood culture for patients with chronic headache related to dental treatment.

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  • Clinical relevance of low androgen to gastroesophageal reflux symptoms.

    Ko Harada, Yoshihisa Hanayama, Miho Yasuda, Kou Hasegawa, Mikako Obika, Hitomi Kataoka, Koichi Itoshima, Ken Okada, Fumio Otsuka

    Endocrine journal   65 ( 10 )   1039 - 1047   2018.10

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    The aim of this study was to determine the relationships between free testosterone (FT) level and parameters including laboratory data and data from questionnaires and to determine symptoms leading to the detection of late onset hypogonadism (LOH). We retrospectively reviewed medical records of patients in whom serum FT was measured in our hospital. Aging Male Symptoms (AMS) score, self-rating depression scale (SDS) and frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) score were used for questionnaires. A total of 205 patients were included in the analysis (55.2 ± 15.6 years of age, mean ± SD). Among them, 119 patients (58.0%) had an FT level of less than 8.5 pg/mL, which fulfills the diagnostic criterion of LOH syndrome according to the clinical practice manual for LOH in Japan. It was revealed that FSSG score was inversely correlated to serum FT levels (r = -0.3395, p < 0.001), although SDS and AMS scales did not show significant correlations to FT levels. Our study revealed a high prevalence of LOH syndrome among patients in whom the majority complained of general symptoms. Although GERD symptoms are generally not considered to be typical symptoms of LOH, our study indicates that those symptoms might be clues for the detection of LOH.

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  • Photophobia in a Patient with Hashimoto's Thyroiditis.

    Yoshito Nishimura, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   57 ( 19 )   2919 - 2920   2018.10

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  • Clinical Characteristics of Febrile Outpatients : Possible Involvement of Thyroid Dysfunction in Febrile Tachycardia.

    Kosuke Oka, Yoshihisa Hanayama, Asuka Sato, Daisuke Omura, Miho Yasuda, Ko Hasegawa, Mikako Obika, Fumio Otsuka

    Acta medica Okayama   72 ( 5 )   447 - 456   2018.10

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    We retrospectively analyzed the cases of 148 febrile patients whose body temperature (BT) was ≥ 37.5°C at our hospital. We categorized them into seven groups; those with bacterial and viral infection, nonspecific inflammation, neoplasm, connective tissue disease (CTD), drug-induced disease, and unidentified causes. Our analysis revealed that the patient's BT at the 1st visit (BT-1st visit) and highest BT during the febrile period (BT-max) differed significantly among all categories except neoplasm. The greatest difference between BT-1st visit and BT-max was highest in the CTD group (1.5°C). Positive correlations of heart rate and C-reactive protein (CRP) level with BT-max and a negative correlation between serum sodium level with BT-max were uncovered. The serum thyroid-stimulating hormone (TSH) level and the ratio of TSH/free thyroxine were negatively correlated with BT-max, especially in the viral infection group, suggesting the existence of occult thyrotoxicosis in accord with a febrile condition, possibly leading to febrile tachycardia. A febrile gap between BT-1st visit and BT-max (except in the neoplasm group) was shown, in which BT-max was correlated with thyroid function. Clinicians should recognize the fluctuation of BT when diagnosing febrile patients, and tachycardia in such febrile patients may be, at least in part, associated with subclinical thyroid dysfunction.

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  • The Esophagus on Sight: Ultrasonography in Achalasia.

    Yoshito Nishimura, Yuusaku Sugihara, Fumio Otsuka

    JMA journal   1 ( 1 )   71 - 72   2018.9

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  • Effect of the interaction of metformin and bone morphogenetic proteins on ovarian steroidogenesis by human granulosa cells. International journal

    Nahoko Iwata, Toru Hasegawa, Shiho Fujita, Satoko Nagao, Yasuhiro Nakano, Takahiro Nada, Yuki Nishiyama, Takeshi Hosoya, Fumio Otsuka

    Biochemical and biophysical research communications   503 ( 3 )   1422 - 1427   2018.9

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    In the present study, we studied the effects of metformin and its interactions with the actions of bone morphogenetic proteins (BMPs) on ovarian steroidogenesis. It was revealed that metformin treatment enhanced progesterone production by human granulosa KGN cells and rat primary granulosa cells induced by forskolin and FSH, respectively. In human granulosa cells, it was found that metformin treatment suppressed phosphorylation of Smad1/5/9 activated by BMP-15 compared with that induced by other BMP ligands. Moreover, metformin treatment increased the expression of inhibitory Smad6, but not of that Smad7, in human granulosa cells, while metformin had no significant impact on the expression levels of BMP type-I and -II receptors. Thus, the mechanism by which metformin suppresses BMP-15-induced Smad1/5/9 phosphorylation is likely, at least in part, to be upregulation of inhibitory Smad6 expression in granulosa cells. The results suggest the existence of functional interaction between metformin and BMP signaling, in which metformin enhances progesterone production by downregulating endogenous BMP-15 activity in granulosa cells.

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  • Enterovaginal and colovesical fistulas as late complications of pelvic radiotherapy.

    Masaya Iwamuro, Kou Hasegawa, Yoshihisa Hanayama, Hitomi Kataoka, Takehiro Tanaka, Yoshitaka Kondo, Fumio Otsuka

    Journal of general and family medicine   19 ( 5 )   166 - 169   2018.9

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    A 72-year-old Japanese woman presented with a fever, diarrhea, intermittent spotting, and constant fluid discharge from the vagina. Imaging studies revealed an enterovaginal fistula. She underwent radical hysterectomy and radiotherapy 35 years previously. She also had a surgical history of nephrostomy, nephrectomy, ileoascending anastomosis, and colostomy. As bleeding from the enterovaginal fistula was uncontrollable, ileocecal resection was performed. However, a colovesical fistula with urinary tract infection occurred 3 months later. The present case indicates that fistula formation occurs and causes various symptoms in patients who underwent postpelvic radiotherapy, particularly in those with prior surgeries in the irradiated field.

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  • 超音波検査にて経時的変化の観察が可能であった巨細胞性動脈炎の2症例

    武本 梨佳, 内田 治仁, 戸田 洋伸, 竹内 英実, 大高 望, 大塚 寛昭, 大塚 文男, 伊藤 浩, 和田 淳

    脈管学   58 ( Suppl. )   S211 - S211   2018.9

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  • Thyroid follicular carcinoma in a teenager: A case report.

    Kosuke Oka, Tadahiko Shien, Fumio Otsuka

    Journal of general and family medicine   19 ( 5 )   170 - 172   2018.9

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    A 19-year-old girl complained of an enlarged cervical mass. Based on clinical and cytological assessments, it was diagnosed as thyroid follicular carcinoma and left thyroidectomy was performed. Although thyroid neoplasms are rare in young people, differentiation is needed when the rapid growth of a goiter is detected.

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  • オレキシンによるBMPシグナルの抑制と卵胞プロゲステロン産生への影響

    藤田 志保, 長谷川 徹, 西山 悠紀, 藤澤 諭, 細谷 武史, 中野 靖浩, 岩田 菜穂子, 鎌田 泰彦, 増山 寿, 大塚 文男

    日本生殖医学会雑誌   63 ( 3 )   309 - 309   2018.8

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  • Manifestation of Central Diabetes Insipidus in a Patient with Thyroid Storm.

    Akiko Nakamichi, Kazuki Ocho, Kosuke Oka, Miho Yasuda, Kou Hasegawa, Masaya Iwamuro, Mikako Obika, Kammei Rai, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   57 ( 13 )   1939 - 1942   2018.7

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    We herein report a case of central diabetes insipidus complicated with thyroid storm. A middle-aged woman who was receiving treatment for Graves' disease suddenly complained of polydipsia, polyuria and general fatigue. Laboratory tests showed hyperthyroidism, hypernatremia, hypoosmolar urine and a decreased plasma vasopressin level. The occurrence of central diabetes insipidus with hyperthyroidism was revealed on the basis of pituitary magnetic resonance imaging, a water deprivation test and a desmopressin test. The clinical co-existence of diabetes insipidus and hyperthyroidism is very rare; however, the complication should be considered when hypernatremia and/or dehydration progress in patients with Graves's disease as a common autoimmune-related etiology.

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  • Interaction between orexin A and bone morphogenetic protein system on progesterone biosynthesis by rat granulosa cells. International journal

    Shiho Fujita, Toru Hasegawa, Yuki Nishiyama, Satoshi Fujisawa, Yasuhiro Nakano, Takahiro Nada, Nahoko Iwata, Yasuhiko Kamada, Hisashi Masuyama, Fumio Otsuka

    The Journal of steroid biochemistry and molecular biology   181   73 - 79   2018.7

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    The involvement of orexins in reproductive function has been gradually uncovered. However, the functional role of orexins in ovarian steroidogenesis remains unclear. In the present study, we investigated the effects of orexin A on ovarian steroidogenesis by using rat primary granulosa cells that express both OX1 and OX2 receptors for orexins. Treatment with orexin A enhanced progesterone, but not estradiol, biosynthesis induced by FSH, whereas it did not affect basal levels of progesterone or estradiol. In accordance with the effects on steroidogenesis, orexin A increased the mRNA levels of progesterogenic enzymes, including StAR, P450scc and 3βHSD, but not P450arom, and cellular cAMP synthesis induced by FSH. Under the condition of blockage of endogenous BMP actions by noggin or BMP-signaling inhibitors, orexin A failed to increase levels of progesterone synthesis induced by FSH treatment, suggesting that endogenous BMP activity in granulosa cells might be involved in the enhancement of progesterone synthesis by orexin A. Treatment with orexin A impaired Smad1/5/9 activation as well as Id-1 mRNA expression stimulated by BMP-6 and BMP-7, the latter of which was reversed by treatment with an OX1 antagonist. It was also found that orexin A suppressed the mRNA expression of both type-I and -II receptors for BMPs and increased that of inhibitory Smad6 and Smad7 in granulosa cells. On the other hand, treatments with BMP-6 and -7 suppressed the expression of OX1 and OX2. Collectively, the results indicated that orexin A enhances FSH-induced progesterone production, at least in part, by downregulating BMP signaling in granulosa cells. Thus, a new role of orexin A in facilitating progesterone synthesis and functional interaction between the orexin and BMP systems in granulosa cells were revealed.

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  • Modulation of bone morphogenetic protein activity by melatonin in ovarian steroidogenesis.

    Fumio Otsuka

    Reproductive medicine and biology   17 ( 3 )   228 - 233   2018.7

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    Background: Melatonin regulates circadian and seasonal rhythms and the activities of hormones and cytokines that are expressed in various tissues, including the ovary, in which melatonin receptors are expressed. In the ovary, follicular growth occurs as a result of complex interactions between pituitary gonadotropins and autocrine and paracrine factors, including bone morphogenetic proteins (BMPs) that are expressed in the ovary. Methods: The effects of melatonin and BMPs on steroidogenesis were examined by using the primary cultures of rat granulosa cells. Main findings Results: It was shown that melatonin has antagonistic effects on BMP-6 actions in the granulosa cells, suggesting that melatonin is likely to contribute to balancing the biological activity of endogenous BMPs that maintain progesterone production and luteinization in the growing follicles. Similar interactions between melatonin and BMP-smad signaling also were shown in the mechanism of controlling ovarian steroidogenesis by other ligands. Conclusion: A new role of melatonin in the regulation of endocrine homeostasis in relation to BMP activity is introduced in this review.

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  • Isolated Follicle-stimulating Hormone Deficiency Coincidentally Diagnosed by Hematospermia.

    Satoshi Fujisawa, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   57 ( 12 )   1799 - 1799   2018.6

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  • Unilateral Exophthalmos due to Lymphomatous Involvement.

    Miho Yasuda, Masaya Iwamuro, Kosuke Kimura, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   57 ( 9 )   1335 - 1335   2018.5

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  • A case of chemical meningitis due to transsphenoidal surgery for craniopharyngioma

    Hasegawa K, Yasuda M, Miyoshi T, Ogawa H, Obika M, Kurozumi K, Otsuka F, et al.

    ACTH related peptides   29   16 - 18   2018.4

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  • Incretins modulate progesterone biosynthesis by regulating bone morphogenetic protein activity in rat granulosa cells. International journal

    Yuki Nishiyama, Toru Hasegawa, Shiho Fujita, Nahoko Iwata, Satoko Nagao, Takeshi Hosoya, Kenichi Inagaki, Jun Wada, Fumio Otsuka

    The Journal of steroid biochemistry and molecular biology   178   82 - 88   2018.4

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    The effects of incretins on ovarian steroidogenesis have not been clarified. In this study, we investigated the effects of incretins, including GIP and GLP-1, on ovarian steroidogenesis using rat primary granulosa cells. Treatment with incretins significantly suppressed progesterone synthesis in the presence of FSH, and the effect of GIP was more potent than that of GLP-1. In contrast, incretins had no significant effect on estrogen synthesis by rat granulosa cells. In accordance with the effects of incretins on steroidogenesis, GIP and GLP-1 suppressed the expression of progesterogenic factors and enzymes, including StAR, P450scc, 3βHSD, but not P450arom, and cellular cAMP synthesis induced by FSH. In addition, incretins moderately increased FSHR mRNA expression in granulosa cells. Of note, treatment with GIP, but not treatment with GLP-1, augmented Smad1/5/8 phosphorylation and transcription of the BMP target gene Id-1 induced by BMP-6 stimulation, suggesting that GIP upregulates BMP receptor signaling that can inhibit FSH-induced progesterone synthesis in rat granulosa cells. On the other hand, BMP-6 treatment suppressed the expression of GIP receptor but not that of GLP-1 receptor. Expression of the BMP type-I receptor ALK-3 was upregulated by treatment with GIP and GLP-1 and that of ALK-6 was also increased by GIP, while inhibitory Smad6 expression was impaired by GIP and GLP-1 in rat granulosa cells. Collectively, the results indicate that incretins, particularly GIP, impair FSH-induced progesterone production, at least in part, by upregulating BMP signaling in rat granulosa cells. The modulatory effects of incretins on endogenous BMP activity may be applicable to treatment of dysregulated steroidogenesis such as polycystic ovary syndrome.

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  • RS3PE syndrome mimicking venous thrombosis

    Nakano Y, Oka K, Horiguchi S and Otsuka F

    J. Hosp. Gen. Med   14 ( 3 )   223 - 224   2018.4

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  • Colonoscopy examination requires a longer time in patients with acromegaly than in other individuals.

    Masaya Iwamuro, Miho Yasuda, Kou Hasegawa, Satoshi Fujisawa, Kanako Ogura-Ochi, Yuusaku Sugihara, Keita Harada, Sakiko Hiraoka, Hiroyuki Okada, Fumio Otsuka

    Endocrine journal   65 ( 2 )   151 - 157   2018.2

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    This study aimed to determine the prevalence of colorectal neoplasms and to investigate the rate of and time required for cecal intubation in patients with acromegaly. A database search performed at our institution identified 29 patients with acromegaly who underwent colonoscopy. Data regarding the endoscopic, biological, and pathological examinations performed were retrospectively reviewed from the clinical records. Subsequently, the rate of and time required for cecal intubation were investigated in 23 patients with acromegaly and compared with the corresponding data of the control group. Control subjects were selected from a 2:1 matched historical control cohort, according to baseline characteristics. The mean age of the acromegaly group (17 female and 12 male) was 60.4 ± 12.6 years. Twelve patients had adenoma (41.4%), eight patients had hyperplastic polyps (27.6%), three patients had sessile serrated adenoma/polyps (10.3%), and three patients had colon cancer (10.3%). Successful cecal intubation was achieved in all patients in both groups. The difference in the time required for successful intubation between the acromegaly group (15.7 ± 9.8 minutes) and the control group (8.7 ± 6.0 minutes) was statistically significant. Linear regression analysis revealed that increased patient age was significantly related to longer colonoscope insertion times. In conclusion, although cecal intubation during colonoscopy was successful in all participants, it required a longer time in patients with acromegaly. Our results underscore the importance of and certain technical difficulties involved in colonoscopy procedures in patients with acromegaly, especially in older patients.

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  • Far East Scarlet-like Fever Masquerading as Adult-onset Kawasaki Disease.

    Kazuki Ocho, Masaya Iwamuro, Kou Hasegawa, Hideharu Hagiya, Kammei Rai, Tetsuya Yumoto, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   57 ( 3 )   437 - 440   2018.2

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    A previously healthy 31-year-old man was referred to us with refractory septic shock accompanied by bilateral conjunctival congestion and erythema of his right lower limb. Nine days after admission, he had bilateral desquamation of the fingertips, and his presentation satisfied the criteria for Kawasaki disease. A serological examination was positive for Yersinia pseudotuberculosis, and he was diagnosed with Far East scarlet-like fever (FESLF). Interestingly, his 11-month-old baby boy had similar symptoms around the same time, indicating the intrafamilial transmission of the pathogen. We should consider FESLF when we encounter a familial occurrence of systemic manifestations of Kawasaki disease.

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  • Severe Gastritis after Administration of Nivolumab and Ipilimumab

    Yoshito Nishimura, Miho Yasuda, Kazuki Ocho, Masaya Iwamuro, Osamu Yamasaki, Takehiro Tanaka, Fumio Otsuka

    CASE REPORTS IN ONCOLOGY   11 ( 2 )   549 - 556   2018

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    Immune checkpoint inhibitors such as ipilimumab, a cytotoxic T-lymphocyte-associated anti-gen-4 inhibitor, have been widely used for advanced malignancies. As these inhibitors improve antitumor immunity via T-cell modulation, immune-mediated adverse events associated with T-cell activation, such as colitis, might occur. Herein, we describe a 75-year-old Japanese woman with metastatic malignant melanoma who developed hemorrhagic gastritis after ipilimumab treatment. There was no macroscopic or clinical improvement of gastritis after proton pump inhibitor treatment. However, her condition improved after approximately 3 weeks of corticosteroid therapy and Helicobacter pylori eradication. This case suggests a potential association between severe gastritis and immune checkpoint inhibitor treatment. Although several reports have mentioned ipilimumab-associated colitis, gastritis is considered to be rare. In the present case, H. pylori-associated gastritis might have been exacerbated by the T-cell modulation effect of ipilimumab. To date, no report has clarified the mechanism by which ipilimumab modifies H. pylori infection. The present treatment course provides a helpful perspective for similar cases. (C) 2018 The Author(s) Published by S. Karger AG, Basel

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  • Interaction of Melatonin and BMP-6 in Ovarian Steroidogenesis. International journal

    Fumio Otsuka

    Vitamins and hormones   107   137 - 153   2018

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    The bone morphogenetic protein (BMP) system in the ovary plays a physiological role as a luteinization inhibitor in growing follicles. BMP-6 secreted from oocytes and granulosa cells can exert an inhibitory effect on follicle-stimulating hormone (FSH) actions by suppressing adenylate cyclase activity downstream of the FSH receptor. The inhibition of FSH-induced progesterone production by BMP-6 is impaired by melatonin treatment in granulosa cells. Intracellular Smad signaling induced by BMP-6 is suppressed by melatonin, suggesting that melatonin has a regulatory role in BMP receptor signaling in granulosa cells. Since the expression of BMP-6 in granulosa cells is increased in patients with polycystic ovary syndrome, melatonin may play an important role in the maintenance of progesterone production by suppressing BMP-6 signaling, leading to the preservation of ovarian function.

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  • Psoas abscess secondary to paravertebral inflammation. International journal

    Yoshito Nishimura, Fumio Otsuka

    IDCases   13   e00435   2018

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  • Diffuse Intestinal Ganglioneuromatosis Showing Multiple Large Bowel Ulcers in a Patient with Neurofibromatosis Type 1. Reviewed

    Masaya Iwamuro, Rika Omote, Takehiro Tanaka, Naruhiko Sunada, Takahiro Nada, Yoshitaka Kondo, Soichiro Nose, Mitsuhiko Kawaguchi, Fumio Otsuka, Hiroyuki Okada

    Internal medicine (Tokyo, Japan)   56 ( 24 )   3287 - 3291   2017.12

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    A 67-year-old Japanese man with neurofibromatosis type 1 underwent right hemicolectomy owing to abscess formation around the cecum. A pathological analysis revealed diffuse intestinal ganglioneuromatosis in the cecum and colon. Colonoscopy performed eight months after hemicolectomy revealed multiple ulcers throughout the colon and rectum. The colorectal ulcers failed to respond to conservative treatment and ultimately required surgical resection. Diffuse ganglioneuromatosis was observed again in the resected specimen. This report illustrates a rare manifestation of diffuse intestinal ganglioneuromatosis in a patient with neurofibromatosis type 1.

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  • Rapid laboratory tests for malaria detection in Japan.

    Naoko Kashihara, Masaya Iwamuro, Nobuchika Kusano, Fumio Otsuka

    Journal of general and family medicine   18 ( 6 )   470 - 471   2017.12

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    Although malaria is not a common disease in Japan, malaria can be a mortal illness. The malaria rapid diagnostic immune-chromatographic test (ICT) enables a more rapid and easier diagnosis of malaria.

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  • Pulmonary intravascular lymphoma detected by FDG-PET.

    Takahiro Nada, Masaya Iwamuro, Kousuke Kimura, Fumio Otsuka

    Journal of general and family medicine   18 ( 6 )   477 - 478   2017.12

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    A 69-year-old woman visited our hospital with a 2-month history of general fatigue, high fever, and dyspnea. Physical examination showed no abnormalities in superficial lymph nodes or respiratory sound. A chest computed tomography scan showed diffuse mild ground-glass attenuation in bilateral lung fields, whereas FDG-PET revealed intense uptake of FDG throughout the lung.

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  • Neck schwannoma mimicking a thyroid tumor.

    Kosuke Oka, Masaya Iwamuro, Fumio Otsuka

    Journal of general and family medicine   18 ( 6 )   473 - 474   2017.12

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    Although we often see patients with neck tumors, neck schwannomas are quite rare. We should keep schwannnoma in mind when we identified tumors on the side of the neck.

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  • Hypersensitivity Pneumonitis Caused by a Home Ultrasonic Humidifier Contaminated with Candida guilliermondii.

    Akemi Ando, Hideharu Hagiya, Takahiro Nada, Kosuke Kimura, Koichi Waseda, Kammei Rai, Yoshihisa Hanayama, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   56 ( 22 )   3109 - 3112   2017.11

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    We herein report the first documented case of acute hypersensitivity pneumonitis in which Candida guilliermondii was the possible causative organism. A young Japanese woman presented to our hospital with relapsing respiratory symptoms accompanied by high fever. A detailed interview revealed that the onset of the symptoms occurred shortly after using a humidifier in her home. Her symptoms showed spontaneous improvement soon after admission, and an examination of her bronchoalveolar lavage fluid revealed the specific infiltration of inflammatory cells, which predominantly consisted of lymphocytes. Precipitin testing showed a positive reaction to C. guilliermondii, which was isolated from the home humidifier. Repeated history taking is essential for diagnosing occult respiratory disorders.

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  • Regulation of gonadotropins by urocortin 2 in gonadotropic tumor LβT2 cells. International journal

    Kazunori Kageyama, Shingo Murasawa, Kanako Niioka, Fumio Otsuka, Hiroko Yagi, Makoto Daimon

    Neuroscience letters   660   63 - 67   2017.11

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    A close interaction has been shown between the hypothalamo-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis. Urocortin 2 (Ucn2) has a very high affinity for the corticotropin-releasing factor (CRF) type 2 (CRF2) receptor. Pituitary Ucn2 regulates expression and secretion of gonadotropins in response to stress. The CRF2 receptor in the pituitary contributes to the modulation of gonadotropins. To explore the possible function of Ucn2 and the CRF2 receptor in pituitary gonadotropic tumor cells, we examined the direct regulation of gonadotropins by Ucn2 in a representative pituitary gonadotropic tumor, mouse LβT2 cells. LβT2 cells were found to express CRF1 receptor and CRF2 receptor mRNA. Ucn2 decreased CRF1 receptor mRNA levels, while it increased CRF2 receptor mRNA levels. Ucn2 directly decreased the mRNA levels of both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in LβT2 cells. Ucn2 also decreased gonadotropin-releasing hormone receptor (GnRHR) mRNA levels. A selective CRF2 receptor antagonist suppressed the Ucn2-induced decreases in LH, FSH, and GnRHR mRNA levels. Ucn2 acts on gonadotrophs expressing the CRF2 receptor, and inhibits the production of gonadotropins in the pituitary gonadotropic tumor cells. (177 words).

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  • Reply to "The Difficulty in Administering Appropriate Antimicrobial Therapy for Stenotrophomonas maltophilia Bacteremia".

    Hirotaka Ebara, Hideharu Hagiya, Yuto Haruki, Eisei Kondo, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   56 ( 20 )   2817 - 2817   2017.10

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  • Multiple abscesses caused by repetitive intramuscular injections.

    Ko Harada, Naoko Kashihara, Masaya Iwamuro, Fumio Otsuka

    Journal of general and family medicine   18 ( 5 )   301 - 302   2017.10

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  • Perimandibular abscess associated with bisphosphonate-related osteonecrosis of the jaw. Reviewed

    Kazuki Ocho, Masaya Iwamuro, Hideharu Hagiya, Soichiro Ibaragi, Fumio Otsuka

    Journal of general and family medicine   18 ( 5 )   305 - 306   2017.10

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  • The Clinical and Hormonal Characteristics of Primary Adrenal Lymphomas: The Necessity of Early Detection of Adrenal Insufficiency. Reviewed

    Ko Harada, Kosuke Kimura, Masaya Iwamuro, Tomohiro Terasaka, Yoshihisa Hanayama, Eisei Kondo, Eiko Hayashi, Tadashi Yoshino, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   56 ( 17 )   2261 - 2269   2017.9

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    Objective To analyze the clinical and endocrine characteristics of patients with primary adrenal lymphoma.
    Patients We retrospectively reviewed the cases of five patients with primary adrenal lymphoma who were treated in our hospital between April 2004 and March 2015. We investigated the characteristics of the clinical and pathological findings, treatment, prognosis and complications of adrenal insufficiency.
    Results Adrenal insufficiency, which was confirmed by the laboratory data at the initial presentation, was observed in two cases. One case was complicated by relative adrenal insufficiency during a course of chemotherapy. The plasma adrenaline and urinary adrenaline levels were decreased in four cases and three cases, respectively. Diffusion MRI was radiologically diagnostic. In all of the cases, the patients were pathologically diagnosed with diffuse large-B cell lymphoma and were treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like chemotherapy. Two patients received central nervous system prophylaxis with high-dose methotrexate. Four of the patients survived and one patient died during the follow-up period.
    Conclusion The early detection of adrenal insufficiency and the administration of an appropriate dose of hydrocortisone are necessary during the course of chemotherapy as well as at the initial manifestation. The exclusion of adrenal dysfunction prior to invasive diagnostic procedures, such as CT-guided needle biopsy, is also critical.

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  • A regulatory role of androgen in ovarian steroidogenesis by rat granulosa cells. International journal

    Toru Hasegawa, Yasuhiko Kamada, Takeshi Hosoya, Shiho Fujita, Yuki Nishiyama, Nahoko Iwata, Yuji Hiramatsu, Fumio Otsuka

    The Journal of steroid biochemistry and molecular biology   172   160 - 165   2017.9

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    Excess androgen and insulin-like growth factor (IGF)-I in the ovarian follicle has been suggested to be involved in the pathophysiology of polycystic ovary syndrome (PCOS). Here we investigated the impact of androgen and IGF-I on the regulatory mechanism of ovarian steroidogenesis using rat primary granulosa cells. It was revealed that androgen treatment with dihydrotestosterone (DHT) amplified progesterone synthesis in the presence of FSH and IGF-I, whereas it had no significant effect on estrogen synthesis by rat granulosa cells. In accordance with the effects of androgen on steroidogenesis, DHT enhanced the expression of progesterogenic factors and enzymes, including StAR, P450scc and 3βHSD, and cellular cAMP synthesis induced by FSH and IGF-I. Of note, treatment with DHT and IGF-I suppressed Smad1/5/8 phosphorylation and transcription of the BMP target gene Id-1, suggesting that androgen and IGF-I counteract BMP signaling that inhibits FSH-induced progesterone synthesis in rat granulosa cells. DHT was revealed to suppress the expression of BMP-6 receptors, consisting of ALK-2, ALK-6 and ActRII, while it increased the expression of inhibitory Smads in rat granulosa cells. In addition, IGF-I treatment upregulated androgen receptor (AR) expression and DHT treatment suppressed IGF-I receptor expression on rat granulosa cells. Collectively, the results indicate that androgen and IGF-I mutually interact and accelerate progesterone production, at least in part, by regulating endogenous BMP signaling in rat granulosa cells. Cooperative effects of androgen and IGF-I counteract endogenous BMP-6 activity in rat granulosa cells, which is likely to be functionally linked to the steroidogenic property shown in the PCOS ovary.

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  • Regulatory role of melatonin and BMP-4 in prolactin production by rat pituitary lactotrope GH3 cells. Reviewed International journal

    Kanako Ogura-Ochi, Satoshi Fujisawa, Nahoko Iwata, Motoshi Komatsubara, Yuki Nishiyama, Naoko Tsukamoto-Yamauchi, Kenichi Inagaki, Jun Wada, Fumio Otsuka

    Peptides   94   19 - 24   2017.8

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    The effects of melatonin on prolactin production and its regulatory mechanism remain uncertain. We investigated the regulatory role of melatonin in prolactin production using rat pituitary lactotrope GH3 cells by focusing on the bone morphogenetic protein (BMP) system. Melatonin receptor activation, induced by melatonin and its receptor agonist ramelteon, significantly suppressed basal and forskolin-induced prolactin secretion and prolactin mRNA expression in GH3 cells. The melatonin MT2 receptor was predominantly expressed in GH3 cells, and the inhibitory effects of melatonin on prolactin production were reversed by treatment with the receptor antagonist luzindole, suggesting functional involvement of MT2 action in the suppression of prolactin release. Melatonin receptor activation also suppressed BMP-4-induced prolactin expression by inhibiting phosphorylation of Smad and transcription of the BMP-target gene Id-1, while BMP-4 treatment upregulated MT2 expression. Melatonin receptor activation suppressed basal, BMP-4-induced and forskolin-induced cAMP synthesis; however, BtcAMP-induced prolactin mRNA expression was not affected by melatonin or ramelteon, suggesting that MT2 activation leads to inhibition of prolactin production through the suppression of Smad signaling and cAMP synthesis. Experiments using intracellular signal inhibitors revealed that the ERK pathway is, at least in part, involved in prolactin induction by GH3 cells. Thus, a new regulatory role of melatonin involving BMP-4 in prolactin secretion was uncovered in lactotrope GH3 cells.

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  • 顕性クッシングを呈しメチラポンで加療中のAIMAHの2例

    藤澤 諭、稲垣兼一、西山悠紀、小松原基志、原 孝行、細谷武史、当真貴志雄、越智可奈子、和田 淳、大塚文男

    日本内分泌学会雑誌   93   44 - 45   2017.6

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  • Predictors of vasovagal reactions during preoperative autologous blood donation: a single-institution analysis.

    Hisakazu Nishimori, Nobuharu Fujii, Keiko Fujii, Tohru Ikeda, Naomi Asano, Hiroaki Ogo, Miwa Yamakawa, Naoe Takagi, Fumio Otsuka, Kazuma Ikeda

    International journal of hematology   105 ( 6 )   812 - 818   2017.6

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    Studies examining risk factors associated with vasovagal reactions (VVRs) during autologous blood donations, especially in younger subjects, have been limited. The aim of the present study was to define risk factors for VVRs during preoperative autologous blood donation in patients, including those younger than 18 years old. We retrospectively analyzed 4192 autologous, preoperative blood donations between 2007 and 2015 at Okayama University Hospital. Eighty-seven (2.08%) of the patients experienced VVRs. VVRs occurred approximately three times as often in patients 0-17 years old (16/320, 5.0%) than in patients 18 years and older (71/3872, 1.8%). In particular, VVRs occurred more frequently in those 10-13 years old, and decreased with older age (P = 0.006). In a univariate analysis, younger age, lower body mass index, lower systolic blood pressure, lower body weight, lower total blood volume, female gender, first-time collection, and higher heart rate were associated with a higher incidence of VVRs. In a multivariate analysis, lower systolic blood pressure (P < 0.001), higher heart rate (P = 0.007), and first-time collection (P = 0.015), remained independent predictors of VVRs. These results emphasize the need for careful attention during blood collection.

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  • Successful treatment with glucocorticoid for secondary Fanconi syndrome caused by sarcoidosis. Reviewed International journal

    Daisuke Omura, Hideharu Hagiya, Yoshihisa Hanayama, Kou Hasegawa, Hiroshi Morinaga, Atsue Kikuta, Hitomi Kataoka, Fumio Otsuka

    Modern rheumatology   27 ( 3 )   545 - 547   2017.5

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    A 77-year-old female with renal dysfunction, hypercalcemia, and hypercalciuria was presented. Systemic investigations including renal biopsy showed that the patient had Fanconi syndrome secondary to renal sarcoidosis. Treatment with 25 mg per day of prednisolone was initiated and her condition improved. Complication of Fanconi syndrome in patients with sarcoidosis is extremely rare. Although the pathological mechanism is still unknown, corticosteroid therapy was effective for ameliorating proteinuria, glycosuria, hypercalciuria, and aminoaciduria.

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  • 両側上腕血圧測定不能を契機に発見された巨細胞性動脈炎の1例 Reviewed

    武本 梨佳, 内田 治仁, 戸田 洋伸, 江尻 健太郎, 竹内 英実, 垣尾 勇樹, 奥山 由加, 岡田 健, 大塚 文男, 伊藤 浩, 和田 淳

    日本高血圧学会臨床高血圧フォーラムプログラム・抄録集   6回   177 - 177   2017.5

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  • A unique acromegalic osteoarthropathy: manubriosternal joint arthritis. International journal

    Satoshi Fujisawa, Fumio Otsuka

    Clinical case reports   5 ( 5 )   725 - 726   2017.5

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    Osteoarthritis of the manubriosternal joint can be found in patients with inflammatory arthritis. Acromegalic arthropathy is often found in the shoulders, wrists, knees, hips, and spine; however, attention should also be given to sternalgia as a complication of acromegalic involvement of the manubriosternal joint.

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  • Endoscopic Manifestations and Clinical Characteristics of Cytomegalovirus Infection in the Upper Gastrointestinal Tract.

    Masaya Iwamuro, Eisei Kondo, Takehiro Tanaka, Hideharu Hagiya, Seiji Kawano, Yoshiro Kawahara, Fumio Otsuka, Hiroyuki Okada

    Acta medica Okayama   71 ( 2 )   97 - 104   2017.4

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    We retrospectively analyzed the cases of 14 patients (9 women, 5 men, mean age: 51.6 years) with cytomegalovirus (CMV) involvement in the esophagus, stomach, and/or duodenum diagnosed at a single center, to determine their endoscopic features and clinical backgrounds. Thirteen patients (92.9%) had hematologic disease; the other had rheumatoid arthritis. Of the former, 12 patients underwent allogeneic hematopoietic stem cell transplantation, and 9 of these patients had graft-versus-host disease (GVHD) before undergoing esophagogastroduodenoscopy (EGD). All 14 patients had been taking one or more immunosuppressive agents including cyclosporine (n=10), corticosteroids (n=9), mycophenolic acid (n=6), tacrolimus (n=3), and methotrexate (n=1). Tests for CMV antigenemia were positive in 11 patients (78.6%). EGD examinations revealed esophageal (n=3), gastric (n=9), and duodenal involvement (n=6). Macroscopically, esophageal lesions by CMV infection presented as redness (n=1), erosions (n=1), and ulcers (n=1). Gastric lesions manifested as redness (n=7), erosions (n=3), exfoliated mucosa (n=2), and verrucous erosions (n=1). Mucosal appearances in the duodenum varied: redness (n=2), ulcers (n=2), multiple erosions (n=2), single erosion (n=1), edema (n=1). CMV was detected even in the intact duodenal mucosa (n=1). In conclusion, physicians must recall the relevance of CMV infection when any mucosal alterations exist in the upper gastrointestinal tract of immunosuppressed patients.

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  • Idiopathic adult ileo-colonic intussusception.

    Masaya Iwamuro, Takahiro Nada, Kosuke Kimura, Yoshihisa Hanayama, Fumio Otsuka

    Journal of general and family medicine   18 ( 2 )   94 - 95   2017.4

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  • Lanthanum Deposition in the Stomach: Usefulness of Scanning Electron Microscopy for Its Detection.

    Masaya Iwamuro, Haruo Urata, Takehiro Tanaka, Akemi Ando, Takahiro Nada, Kosuke Kimura, Kenji Yamauchi, Chiaki Kusumoto, Fumio Otsuka, Hiroyuki Okada

    Acta medica Okayama   71 ( 1 )   73 - 78   2017.2

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    After having been treated with lanthanum carbonate administration for 4 years for hyperphosphatemia, a 75-year-old Japanese woman undergoing hemodialysis was diagnosed with lanthanum phosphate deposition in the stomach. The deposition, seen as white microgranules, was observed using esophagogastroduodenoscopy with magnifying observation. To the best of our knowledge, these are the minutest endoscopy images of lanthanum phosphate deposition in the gastric mucosa. Scanning electron microscopy (SEM) observation enabled easier identification of the deposited material, which was visible as bright areas. The present case suggests the usefulness of SEM observation in the detection of lanthanum phosphate deposition in the gastrointestinal tract.

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  • Combined Effects of Androgen and Growth Hormone on Osteoblast Marker Expression in Mouse C2C12 and MC3T3-E1 Cells Induced by Bone Morphogenetic Protein. Reviewed International journal

    Kosuke Kimura, Tomohiro Terasaka, Nahoko Iwata, Takayuki Katsuyama, Motoshi Komatsubara, Ryota Nagao, Kenichi Inagaki, Fumio Otsuka

    Journal of clinical medicine   6 ( 1 )   2017.1

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    Osteoblasts undergo differentiation in response to various factors, including growth factors and steroids. Bone mass is diminished in androgen- and/or growth hormone (GH)-deficient patients. However the functional relationship between androgen and GH, and their combined effects on bone metabolism, remains unclear. Here we investigated the mutual effects of androgen and GH on osteoblastic marker expression using mouse myoblastic C2C12 and osteoblast-like MC3T3-E1 cells. Combined treatment with dihydrotestosterone (DHT) and GH enhanced BMP-2-induced expression of Runx2, ALP, and osteocalcin mRNA, compared with the individual treatments in C2C12 cells. Co-treatment with DHT and GH activated Smad1/5/8 phosphorylation, Id-1 transcription, and ALP activity induced by BMP-2 in C2C12 cells but not in MC3T3-E1 cells. The insulin-like growth factor (IGF-I) mRNA level was amplified by GH and BMP-2 treatment and was restored by co-treatment with DHT in C2C12 cells. The mRNA level of the IGF-I receptor was not significantly altered by GH or DHT, while it was increased by IGF-I. In addition, IGF-I treatment increased collagen-1 mRNA expression, whereas blockage of endogenous IGF-I activity using an anti-IGF-I antibody failed to suppress the effect of GH and DHT on BMP-2-induced Runx2 expression in C2C12 cells, suggesting that endogenous IGF-I was not substantially involved in the underlying GH actions. On the other hand, androgen receptor and GH receptor mRNA expression was suppressed by BMP-2 in both cell lines, implying the existence of a feedback action. Collectively the results showed that the combined effects of androgen and GH facilitated BMP-2-induced osteoblast differentiation at an early stage by upregulating BMP receptor signaling.

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  • Melatonin regulates catecholamine biosynthesis by modulating bone morphogenetic protein and glucocorticoid actions. Reviewed International journal

    Motoshi Komatsubara, Takayuki Hara, Takeshi Hosoya, Kishio Toma, Naoko Tsukamoto-Yamauchi, Nahoko Iwata, Kenichi Inagaki, Jun Wada, Fumio Otsuka

    The Journal of steroid biochemistry and molecular biology   165 ( Pt B )   182 - 189   2017.1

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    Melatonin is functionally involved in the control of circadian rhythm and hormonal secretion. In the present study, we investigated the roles of melatonin in the interaction of catecholamine synthesis with adrenocortical steroids by focusing on bone morphogenetic protein (BMP)-4 expressed in the adrenal medulla using rat pheochromocytoma PC12 cells. Melatonin treatment significantly reduced the mRNA expression of catecholamine synthases, including the rate-limiting enzyme tyrosine hydroxylase (Th), 3,4-dihydroxyphenylalanine decarboxylase and dopamine-beta-hydroxylase expressed in PC12 cells. In accordance with changes in the expression levels of enzymes, dopamine production and CAMP synthesis determined in the culture medium and cell lysate were also suppressed by melatonin. The MT1 receptor, but not the MT2 receptor, was expressed in PC12 cells, and luzindole treatment reversed the inhibitory effect of melatonin on Th expression, suggesting that MT1 is a functional receptor for the control of catecholamine synthesis. Interestingly, melatonin enhanced the inhibitory effect of BMP-4 on Th mRNA expression in PC12 cells. Melatonin treatment accelerated BMP-4-induced phosphorylation of SMAD1/5/8 and transcription of the BMP target gene Id1. Of note, melatonin significantly upregulated Alk2 and Bmpr2 mRNA levels but suppressed inhibitory Smac16/7 expression, leading to the enhancement of SMAD1/5/8 signaling in PC12 cells, while BMP-4 did not affect Mt1 expression. Regarding the interaction with adrenocortical steroids, melatonin preferentially enhanced glucocorticoid-induced Th mRNA through upregulation of the glucocorticoid receptor and downregulation of Bmp4 expression, whereas melatonin repressed Th mRNA expression induced by aldosterone or androgen without affecting expression levels of the receptors for mineralocorticoid and androgen. Collectively, the results indicate that melatonin plays a modulatory role in catecholamine synthesis by cooperating with BMP-4 and glucocorticoid in the adrenal medulla. (C) 2016 Elsevier Ltd. All rights reserved.

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  • Clinical Characteristics of Stenotrophomonas maltophilia Bacteremia: A Regional Report and a Review of a Japanese Case Series.

    Hirotaka Ebara, Hideharu Hagiya, Yuto Haruki, Eisei Kondo, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   56 ( 2 )   137 - 142   2017

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    Objective Stenotrophomonas maltophilia is an emerging nosocomial pathogen that causes fatal infections in critically ill or immunocompromised patients. S. maltophilia bacteremia (SMB) is a rare condition, and its clinical characteristics in Japanese settings are not well known. Methods The medical charts of patients with SMB were retrospectively reviewed at two medical facilities (Okayama University Hospital and Tsuyama Chuo Hospital) for seven years. The data were analyzed along with those previously reported from other Japanese facilities. Result A total of 181 patients (110 men and 71 women) were evaluated. The major underlying diseases included hematologic malignancy (36.5%), solid organ malignancy (25.4%), and neutropenia (31.5%). The recent use of carbapenem was seen in 56.9% of the cases in total, and more than one-third of the patients in our hospitals were treated with carbapenem at the onset of SMB. Of 28 (63.6%) of 44 cases treated for S. maltophilia, those who did not survive were more likely to have been treated with broad-spectrum antibiotics. A multivariate analysis revealed that a higher updated Charlson Comorbidity Index [odds ratio (95% confidence interval), 1.75 (1.11-2.75); p=0.015] and intubation [odds ratio (95% confidence interval), 12.6 (1.62-97.9); p=0.016] were associated with mortality in our cases. Pathogens were often resistant to ceftazidime but susceptible to minocycline, trimethoprim/sulfamethoxazole, and fluoroquinolones. The overall mortality rates within 30 and 90 days were 37.5% and 62.5%, respectively. Conclusion The clinical characteristics of SMB in Japanese cases were similar to those reported from other countries. Clinicians should be aware that breakthrough infection by S. maltophilia may occur during administration of carbapenem.

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  • Paroxysmal Hypertension Induced by an Insulinoma. Reviewed

    Ko Harada, Yoshihisa Hanayama, Kou Hasegawa, Masaya Iwamuro, Hideharu Hagiya, Ryuichi Yoshida, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   56 ( 4 )   413 - 417   2017

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    Insulinoma is a rare, usually benign, pancreatic neuroendocrine tumor. The clinical features of an insulinoma are fasting hypoglycemia with neuroglycopenic symptoms including confusion and unusual behavior, while hypertension is usually not associated with the disease. We herein report a patient with insulinoma who manifested paroxysmal hypertension and neuroglycopenic symptoms. The possible etiology of hypertension induced by an insulinoma is catecholamine release in response to hypoglycemia, which may cause acute hypertension through activation of the sympatho-adrenal system. This case implies that sustained hyperinsulinemia due to insulinoma can be functionally linked to the induction of paroxysmal hypertension.

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  • 脳梗塞を発症した、頸動脈・腎動脈狭窄症を呈した若年男性の1例 Reviewed

    武本 梨佳, 内田 治仁, 戸田 洋伸, 竹内 麻梨, 中村 知子, 戸田 由香, 渡辺 修久, 江尻 健太郎, 麻植 浩樹, 岡田 健, 大塚 文男, 伊藤 浩

    超音波検査技術   41 ( 5 )   584 - 584   2016.10

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  • A Rare Case of Diffuse Large B-cell Lymphoma in a Patient with IgG4-Related Autoimmune Pancreatitis. Reviewed

    Yoshito Nishimura, Masaya Iwamuro, Kazuki Ocho, Kou Hasegawa, Kosuke Kimura, Yoshihisa Hanayama, Eisei Kondo, Takehiro Tanaka, Fumio Otsuka

    Acta medica Okayama   70 ( 4 )   279 - 83   2016.8

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    A 61-year-old Japanese man with IgG4-related autoimmune pancreatitis was referred to our hospital because of perspiration during food intake. Abdominal computed tomography (CT) with contrast media revealed multiple mesenteric lymphadenopathies. An open surgical abdominal biopsy and subsequent histopathological analysis revealed abnormally large lymphoid cells that were negative for CD3, CD5, and c-myc and positive for CD20 and bcl-2, leading to a diagnosis of diffuse large B-cell lymphoma. Here, we discuss the risk of malignancies, particularly malignant lymphoma in patients with IgG4-related disease. The importance of pathological analysis to reach the appropriate diagnosis in such cases should be emphasized.

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  • Increased Serum KL-6 Levels Induced by Pulmonary Mycobacterium Avium Complex Infection in a Patient with RA-associated Lung Disease. Reviewed

    Koichi Waseda, Kazuki Ocho, Kou Hasegawa, Kosuke Kimura, Masaya Iwamuro, Yoshihisa Hanayama, Eisei Kondo, Nobuaki Miyahara, Fumio Otsuka

    Acta medica Okayama   70 ( 3 )   217 - 221   2016.6

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    KL-6 is a glycoprotein found predominantly on type II pneumocytes and alveolar macrophages, and often shows increased serum levels in patients with interstitial pneumonia. We report a case of mycobacterium avium complex (MAC) infection whose disease activity was correlated with KL-6 levels in serum. During treatment of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) with prednisolone, chest image findings improved in association with decreased KL-6 levels. Following tapering of prednisolone, chest image findings deteriorated again as levels of KL-6 increased, suggesting recurrence of RA-ILD. Bronchoscopic examination revealed active MAC infection. Treatment of MAC infection not only improved chest image findings but also decreased KL-6 levels in serum, suggesting that KL-6 was increased by active MAC infection by itself, not by recurrence of RA-ILD. To the best of our knowledge, this is the first documentation of KL-6 elevation in serum in association with active MAC infection.

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  • [A Case of an Adrenocorticotropic Hormone-Producing Pituitary Adenoma Removed via Electromagnetic-Guided Neuroendoscopy]. Reviewed

    Yusuke Tomita, Kazuhiko Kurozumi, Tomohiro Terasaka, Kenichi Inagaki, Fumio Otsuka, Isao Date

    No shinkei geka. Neurological surgery   44 ( 6 )   473 - 9   2016.6

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    The use of navigation systems is safe and reliable for neurological surgery. We performed endoscopic transsphenoidal surgery to totally resect an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma associated with oculomotor nerve palsy. A 70-year-old woman developed right ptosis 4 months before admission. She developed anisocoria 2 months later and was referred to the department of neurology from clinic. Brain magnetic resonance imaging(MRI)showed an intrasellar tumor that partially invaded the right cavernous sinus, and she was then referred to our department. She exhibited a round face ("moon face") and central obesity. Laboratory test results showed a high urinary cortisol level and high serum ACTH level, and neither the serum cortisol nor ACTH level was suppressed by a low-dose dexamethasone test. We performed transsphenoidal surgery using high-dimensional endoscopy under electromagnetic navigation. The tumor invading the cavernous sinus was visualized via endoscopy and confirmed on navigation using a flexible needle probe. Postoperative MRI showed total removal of the tumor, and the serum ACTH level recovered to the normal range. The patient's right oculomotor palsy resolved within 1 week postoperatively. In summary, electromagnetic navigation was useful for total resection of a pituitary tumor invading the cavernous sinus, contributing to normalization of the ACTH level and improvement in neurological symptoms.

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  • 右総頸動脈に収縮期に逆行性血流を呈した腕頭動脈閉塞の1例 Reviewed

    武本 梨佳, 戸田 洋伸, 戸田 由香, 勢井 麻梨, 中村 知子, 渡辺 修久, 江尻 健太郎, 麻植 浩樹, 杉生 憲志, 岡田 健, 大塚 文男, 伊藤 浩

    超音波検査技術   41 ( Suppl. )   S230 - S230   2016.6

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  • Antiobesity Action of ACAM by Modulating the Dynamics of Cell Adhesion and Actin Polymerization in Adipocytes. Reviewed International journal

    Kazutoshi Murakami, Jun Eguchi, Kazuyuki Hida, Atsuko Nakatsuka, Akihiro Katayama, Miwa Sakurai, Haruki Choshi, Masumi Furutani, Daisuke Ogawa, Kohji Takei, Fumio Otsuka, Jun Wada

    Diabetes   65 ( 5 )   1255 - 67   2016.5

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    Coxsackie virus and adenovirus receptor-like membrane protein (CLMP) was identified as the tight junction-associated transmembrane protein of epithelial cells with homophilic binding activities. CLMP is also recognized as adipocyte adhesion molecule (ACAM), and it is upregulated in mature adipocytes in rodents and humans with obesity. Here, we present that aP2 promoter-driven ACAM transgenic mice are protected from obesity and diabetes with the prominent reduction of adipose tissue mass and smaller size of adipocytes. ACAM is abundantly expressed on plasma membrane of mature adipocytes and associated with formation of phalloidin-positive polymerized form of cortical actin (F-actin). By electron microscopy, the structure of zonula adherens with an intercellular space of approximate to 10-20 nm was observed with strict parallelism of the adjoining cell membranes over distances of 1-20 m, where ACAM and -actin are abundantly expressed. The formation of zonula adherens may increase the mechanical strength, inhibit the adipocyte hypertrophy, and improve the insulin sensitivity.

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  • レボドパと酸化マグネシウムの同時内服で黒色痰・黒色尿を呈した1例 Reviewed

    岩室 雅也、灘 隆宏、大塚文男

    内科   117 ( 2 )   2016.2

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  • BMP-6 modulates somatostatin effects on luteinizing hormone production by gonadrotrope cells. Reviewed International journal

    Kishio Toma, Fumio Otsuka, Kohei Oguni, Tomohiro Terasaka, Motoshi Komatsubara, Naoko Tsukamoto-Yamauchi, Kenichi Inagaki, Hirofumi Makino

    Peptides   76   96 - 101   2016.2

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    The effects of somatostatin analogs and roles of BMP-6 in the regulation of luteinizing hormone (LH) secretion were investigated using mouse gonadotrope LβT2 cells. LH mRNA expression and LH secretion induced by GnRH were suppressed by treatments with somatostatin analogs, including octreotide and pasireotide, in LβT2 cells. Of note, the inhibitory effects of somatostatin analogs on LH secretion were enhanced by the action of BMP-6. BMP-6 increased the expression levels of somatostatin receptor (SSTR)5, suggesting that BMP-6 upregulates SSTR activity that leads to reduction of GnRH-induced LH secretion. In addition, GnRH-induced phosphorylation of MAPKs including ERK, but not P38 or SAPK, was suppressed by pasireotide in the presence of BMP-6. Given that each inhibitor of ERK, JNK or P38 signaling suppressed GnRH-induced LH transcription, MAPKs are individually involved in the induction of LH production by LβT2 cells. Somatostatin analogs also impaired BMP-6-induced Smad1/5/8 phosphorylation by suppressing BMPRs and augmenting Smad6/7 expression. Collectively, the results indicate that somatostatin analogs have dual effects on the modulation of GnRH-induced MAPK signaling and BMP activity. The pituitary BMP system may play a regulatory role in GnRH-induced LH secretion by tuning the responsiveness to somatostatin analogs in gonadotrope cells.

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  • Eagle症候群の1例 Reviewed

    岩室 雅也、小牧稔幸、大塚文男

    内科   117 ( 2 )   2016.1

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  • Emergence of Daptomycin-Resistant Staphylococcus aureus during Treatment. Reviewed

    Hideharu Hagiya, Yuto Haruki, Taeko Uchida, Tomoko Wada, Sumiko Shiota, Tomoharu Ishida, Hiroko Ogawa, Tomoko Murase, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   55 ( 1 )   73 - 8   2016

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    A 68-year-old man with persistent bacteremia accompanying a large iliopsoas abscess, vertebral osteomyelitis, discitis and central venous port infection caused by methicillin-resistant Staphylococcus aureus (MRSA) was admitted to our hospital. During the course of treatment, the emergence of a daptomycin (DAP)-resistant MRSA strain was confirmed; the minimum inhibitory concentration was 1 to 2 μg/mL for vancomycin and more than 1 μg/mL for DAP. Although the bacterial cell wall was not significantly thickened, an increased positive surface charge and single-nucleotide polymorphism within mprF have been confirmed in DAP-resistant strains. Still rare, but clinicians need to be cautious of the emergence of DAP-resistant MRSA during treatment.

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  • White Feces Caused by the Administration of a Somatostatin Analogue. Reviewed

    Iwamuro M, Terasaka T, Otsuka F, Okada H

    Internal medicine (Tokyo, Japan)   55 ( 13 )   1817 - 1817   2016

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  • Invasive Intrasellar Plasmacytoma Mimicking Pituitary Adenoma. Reviewed

    Terasaka T, Inagaki K, Otsuka F

    Internal medicine (Tokyo, Japan)   55 ( 11 )   1501 - 1502   2016

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  • Reactivation of Human Herpes Virus-6 in the Renal Tissue of a Patient with Drug-induced Hypersensitivity Syndrome/Drug Rash with Eosinophilia and Systemic Symptoms (DIHS/DRESS). Reviewed

    Hideharu Hagiya, Masaya Iwamuro, Takehiro Tanaka, Kou Hasegawa, Yoshihisa Hanayama, Maya Kimura, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   55 ( 13 )   1769 - 74   2016

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    A 74-year-old man who had been administered trimethoprim-sulfamethoxazole for three weeks suffered from drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms (DIHS/DRESS). In the early stage of the clinical course, he developed renal dysfunction. A renal biopsy showed granulomatous tubulointerstitial nephritis accompanying the proliferation of human herpes virus ( HHV)-6 in tubular epithelial cells. With corticosteroid therapy, the systemic rash and renal function gradually improved. The present patient is the second case of DIHS/DRESS demonstrating a possible reactivation of HHV-6 in the renal tissue. The clinical role of viral reactivation in DIHS/DRESS must be further elucidated.

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  • An Uncommon Manifestation of Fitz-Hugh-Curtis Syndrome with Right-side Chest Pain. Reviewed

    Ko Harada, Masaya Iwamuro, Yoshihisa Hanayama, Fumio Otsuka

    Acta medica Okayama   70 ( 2 )   145 - 9   2016

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    Fitz-Hugh-Curtis syndrome is characterized by an inflammation of the perihepatic capsules associated with pelvic inflammatory disease. The typical symptom is severe right upper quadrant abdominal pain. We report a patient with Fitz-Hugh-Curtis syndrome who presented with an atypical chief complaint of right-side chest pain unaccompanied by symptoms specific to pelvic inflammatory disease. This case indicates that Fitz-Hugh-Curtis syndrome should be considered in the differential diagnosis of right-side chest pain in young women, because early diagnosis and treatment of the disease are essential to prevent chronic complications.

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  • Detection of Minute Duodenal Follicular Lymphoma Lesions Using Magnifying Endoscopy. Reviewed

    Masaya Iwamuro, Eisei Kondo, Fumio Otsuka, Katsuyoshi Takata, Tadashi Yoshino, Yoshiro Kawahara, Hiroyuki Okada

    Acta medica Okayama   70 ( 2 )   139 - 44   2016

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    Esophagogastroduodenoscopy revealed small duodenal lesions in a 56-year-old Japanese man and a 92-year-old Japanese woman with stage IV follicular lymphoma. Magnifying endoscopy examination revealed tiny white deposits in the second duodenal portion of the former patient and slightly enlarged duodenal villi in the latter. In both cases, biopsy revealed infiltration of follicular lymphoma cells and incipient formation of neoplastic follicles. Here, we discuss the usefulness of magnifying endoscopy and narrow-band imaging for the detection of small duodenal lesions in follicular lymphoma cases.

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  • Endoscopic detection of the gastric lesions of peripheral T-cell lymphoma. Reviewed International journal

    Masaya Iwamuro, Kosuke Kimura, Eisei Kondo, Takahiro Nada, Eri Nakamura, Katsuyoshi Takata, Takehiro Tanaka, Fumio Otsuka, Tadashi Yoshino, Hiroyuki Okada

    Ecancermedicalscience   10   625 - 625   2016

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    An 82-year-old Japanese man presented with a gastric involvement of peripheral T-cell lymphoma, not otherwise specified. Although gastrointestinal lesions were not detected on computed tomography, oesophagogastroduodenoscopy revealed a slight elevation of the gastric mucosa, with changes in mucosal colour and the presence of abnormal microvessels. This led to the prompt detection of gastric involvement in lymphoma. This case highlights the usefulness of detailed observation of the gastric mucosa for the endoscopic detection of gastric involvement of peripheral T-cell lymphoma.

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  • Hypoparathyroidism Solely Manifesting Otological Symptoms. Reviewed

    Tokiko Urabe, Hideharu Hagiya, Eri Nakamura, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   55 ( 2 )   211 - 2   2016

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  • Pheochromocytoma Manifesting Persistent Right Shoulder Pain and Hypochondralgia Reviewed

    Hideharu Hagiya, Eri Nakamura, Tomohiro Terasaka, Kou Hasegawa, Kikuko Asano, Takahiro Nada, Kosuke Kimura, Koichi Waseda, Yoshihisa Hanayama, Fumio Otsuka

    JOURNAL OF GENERAL AND FAMILY MEDICINE   16 ( 4 )   292 - 296   2015.12

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    We report a 42-year-old female who initially complained of sub-acute onset of right upper quadrant abdominal pain with right shoulder pain. A CT scan incidentally revealed an adrenal tumor, and a final diagnosis of pheochromocytoma was made on the basis of endocrinological examinations. Symptomatically, the pheochromocytoma in our patient mimicked a hepato-biliary disease by presenting abdominal pain accompanying right shoulder pain that was assumed to be referred pain via the right phrenic nerve. Physicians may need to consider the possibility of pheochromocytoma in patients with abdominal symptoms.

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  • Refractory chyluria due to filariasis. Reviewed International journal

    Hideharu Hagiya, Fumio Otsuka

    Infection   43 ( 6 )   785 - 6   2015.12

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  • Regulatory effects of fibroblast growth factor-8 and tumor necrosis factor-α on osteoblast marker expression induced by bone morphogenetic protein-2. Reviewed International journal

    Takayuki Katsuyama, Fumio Otsuka, Tomohiro Terasaka, Kenichi Inagaki, Mariko Takano-Narazaki, Yoshinori Matsumoto, Ken-Ei Sada, Hirofumi Makino

    Peptides   73   88 - 94   2015.11

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    BMP induces osteoblast differentiation, whereas a key proinflammatory cytokine, TNF-α, causes inflammatory bone damage shown in rheumatoid arthritis. FGF molecules are known to be involved in bone homeostasis. However, the effects of FGF-8 on osteoblast differentiation and the interaction between FGF-8, BMPs and TNF-α have yet to be clarified. Here we investigated the effects of FGF-8 in relation to TNF-α actions on BMP-2-induced osteoblast marker expression using myoblast cell line C2C12, osteoblast precursor cell line MC3T3-E1 and rat calvarial osteoblasts. It was revealed that FGF-8 inhibited BMP-2-induced expression of osteoblast differentiation markers, including Runx2, osteocalcin, alkaline phosphatase, type-1 collagen and osterix, in a concentration-dependent manner. The inhibitory effects of FGF-8 on BMP-induced osteoblast differentiation and Smad1/5/8 activation were enhanced in the presence of TNF-α action. FGF-8 also inhibited BMP-2-induced expression of Wnt5a, which activates a non-canonical Wnt signaling pathway. FGF-8 had no significant influence on the expression levels of TNF receptors, while FGF-8 suppressed the expression of inhibitory Smad6 and Smad7, suggesting a possible feedback activity through FGF to BMP receptor (BMPR) signaling. Of note, inhibition of ERK activity and FGF receptor (FGFR)-dependent protein kinase, but not JNK or NFκB pathway, suppressed the FGF-8 actions on BMP-induced osteoblast differentiation. FGF-8 was revealed to suppress BMP-induced osteoblast differentiation through the ERK pathway and the effects were enhanced by TNF-α. Given the finding that FGF-8 expression was increased in synovial tissues of rheumatoid arthritis, the functional interaction between FGFR and BMPR signaling may be involved in the development process of inflammatory bone damage.

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  • Superior ophthalmic vein thrombosis associated with severe facial trauma: a case report. Reviewed International journal

    Momoko Mishima, Tetsuya Yumoto, Hiroaki Hashimoto, Takao Yasuhara, Atsuyoshi Iida, Kohei Tsukahara, Keiji Sato, Toyomu Ugawa, Fumio Otsuka, Yoshihito Ujike

    Journal of medical case reports   9   244 - 244   2015.10

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    INTRODUCTION: Superior ophthalmic vein thrombosis is a rare entity, but is associated with significant morbidities. We describe a case in which superior ophthalmic vein thrombosis occurred shortly after severe facial trauma. CASE PRESENTATION: A 77-year-old Japanese man was transferred to our tertiary hospital after a motor vehicle accident. Le Fort III facial bone fractures and a minor cerebral contusion were detected. Follow-up computed tomography scans detected dilatation of his left superior ophthalmic vein on day 3 and thrombosis on day 12; however, no causative carotid cavernous fistula was observed. As he did not present with any symptoms other than slight conjunctival congestion, a conservative management strategy was adopted along with anticoagulant therapy against deep venous thrombosis. The superior ophthalmic vein thrombosis resolved spontaneously and the conjunctival congestion also improved. CONCLUSIONS: Superior ophthalmic vein thrombosis should be taken into consideration and managed properly after severe facial injuries, and further investigation of its cause is necessary to prevent morbidities.

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  • 脳梗塞を発症した、頸動脈狭窄症及び腎動脈狭窄症を呈した若年男性の1例 Reviewed

    武本 梨佳, 内田 治仁, 戸田 洋伸, 勢井 麻梨, 中村 知子, 戸田 由香, 江尻 健太郎, 麻植 浩樹, 岡田 健, 大塚 文男, 伊藤 浩

    脈管学   55 ( Suppl. )   S246 - S246   2015.10

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  • Mutual effects of melatonin and activin on induction of aldosterone production by human adrenocortical cells. Reviewed International journal

    Takayuki Hara, Fumio Otsuka, Naoko Tsukamoto-Yamauchi, Kenichi Inagaki, Takeshi Hosoya, Eri Nakamura, Tomohiro Terasaka, Motoshi Komatsubara, Hirofumi Makino

    The Journal of steroid biochemistry and molecular biology   152   8 - 15   2015.8

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    Melatonin has been reported to suppress adrenocorticotropin (ACTH) secretion in the anterior pituitary and cortisol production in the adrenal by different mechanisms. However, the effect of melatonin on aldosterone production has remained unknown. In this study, we investigated the role of melatonin in the regulation of aldosterone production using human adrenocortical H295R cells by focusing on the activin system expressed in the adrenal. Melatonin receptor MT1 mRNA and protein were expressed in H295R cells and the expression levels of MT1 were increased by activin treatment. Activin increased ACTH-induced, but not angiotensin II (Ang II)-induced, aldosterone production. Melatonin alone did not affect basal synthesis of either aldosterone or cortisol. However, melatonin effectively enhanced aldosterone production induced by co-treatment with ACTH and activin, although melatonin had no effect on aldosterone production induced by Ang II in combination with activin. These changes in steroidogenesis became apparent when the steroid production was evaluated by the ratio of aldosterone/cortisol. Melatonin also enhanced dibutyryl-AMP-induced aldosterone/cortisol levels in the presence of activin, suggesting a functional link to the cAMP-PKA pathway for induction of aldosterone production by melatonin and activin. In accordance with the data for steroids, ACTH-induced, but not Ang II-induced, cAMP synthesis was also amplified by co-treatment with melatonin and activin. Furthermore, the ratio of ACTH-induced mRNA level of CYP11B2 compared with that of CYP17 was amplified in the condition of treatment with both melatonin and activin. In addition, melatonin increased expression of the activin type-I receptor ALK-4 but suppressed expression of inhibitory Smads6/7, leading to the enhancement of Smad2 phosphorylation. Collectively, the results showed that melatonin facilitated aldosterone production induced by ACTH and activin via the cAMP-PKA pathway. The results also suggested that mutual enhancement of melatonin and activin receptor signaling is involved in the induction of aldosterone output by adrenocortical cells.

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  • A Rare Cause of Esophageal Ulcers. Reviewed International journal

    Masaya Iwamuro, Takao Tsuzuki, Fumio Otsuka

    Gastroenterology   149 ( 1 )   31 - 2   2015.7

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  • Atypical Onset of Eosinophilic Granulomatosis with Polyangitis in a Patient with Long-term Well-controlled Bronchial Asthma Reviewed

    Satoshi Akao, Hideharu Hagiya, Kou Hasegawa, Takahiro Nada, Eri Nakamura, Kosuke Kimura, Koichi Waseda, Yoshihisa Hanayama, Kentaro Deguchi, Fumio Otsuka

    JOURNAL OF GENERAL AND FAMILY MEDICINE   16 ( 2 )   99 - 102   2015.6

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    Eosinophillic glanuromatosis with polyangitis (EGPA) usually occurs in patients with a recent history (usually less than 10 years) of uncontrolled bronchial asthma. Here we describe a case of EGPA that occurred in a 68-year-old female who had well-controlled bronchial asthma for 17 years. A leukotriene receptor antagonist that had been prescribed one week before onset might have triggered the disease. Our case shows that there is a wide spectrum of clinical characteristics of EGPA, making diagnosis difficult in a primary care setting.

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  • Gastric pseudopolyposis formed after recovery from gastric gangrene. Reviewed International journal

    Masaya Iwamuro, Yoshihisa Hanayama, Fumio Otsuka, Hiroyuki Okada

    Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver   47 ( 6 )   e9 - E9   2015.6

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  • Complication of chronic eosinophilic pneumonia in an elderly patient with Sjögren syndrome. Reviewed

    Koichi Waseda, Hideharu Hagiya, Yoshihisa Hanayama, Tomohiro Terasaka, Kosuke Kimura, Takao Tsuzuki, Kou Hasegawa, Takahiro Nada, Eri Nakamura, Kazutoshi Murakami, Eisei Kondo, Fumio Otsuka

    Acta medica Okayama   69 ( 2 )   123 - 7   2015.4

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    An 81-year-old Japanese male with primary Sjogren syndrome (pSS) developed a low-grade fever and productive cough which were refractory to antibiotic therapy. Based on the high level of eosinophils observed in his bronchial alveolar lavage, he was diagnosed with chronic eosinophilic pneumonia (CEP) and successfully treated by oral prednisolone. Interstitial lung diseases associated with pSS (pSS-ILDs) usually present as nonspecific interstitial pneumonia or usual interstitial pneumonia; therefore, the present case is extremely unique in that the patient's condition was complicated with CEP. A diagnosis of advanced gallbladder cancer was made in the patient's clinical course, suggesting the advisability of a whole-body workup in cases of pSS, especially in elderly patients.

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  • Interaction of pituitary hormones and expression of clock genes modulated by bone morphogenetic protein-4 and melatonin. Reviewed International journal

    Naoko Tsukamoto-Yamauchi, Tomohiro Terasaka, Yasumasa Iwasaki, Fumio Otsuka

    Biochemical and biophysical research communications   459 ( 1 )   172 - 7   2015.3

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    Functional interaction of clock genes and pituitary hormones was investigated by focusing on bone morphogenetic protein (BMP)-4 and melatonin actions in anterior pituitary cells. A significant correlation between the mRNA expression of proopiomelanocortin (POMC) and Per2 was revealed in serial cultures of corticotrope AtT20 cells. Knockdown of Per2 expression by siRNA in AtT20 cells resulted in a significant reduction of POMC mRNA level with or without corticotropin-releasing hormone (CRH) stimulation. Treatments with BMP-4 and melatonin, both of which suppress POMC expression, reduced Per2 mRNA as well as protein levels in AtT20 cells. On the other hand, in lactosomatotrope GH3 cells, an expressional correlation was found between prolactin (PRL) and Clock mRNA levels, which was attenuated in the presence of forskolin treatment. The siRNA-mediated knockdown of Clock expression, but not that of Bmal1, significantly reduced PRL mRNA levels in GH3 cells. Interestingly, Clock mRNA and protein levels did not fluctuate with melatonin, BMP-4 or forskolin treatment, although Bmal1 expression was significantly increased by forskolin treatment. Collectively, a significant correlation between the expression of POMC and Per2 and that between PRL and Clock were uncovered in corticotrope and lactosomatotrope cells, respectively. Per2 expression was inhibited by POMC modulators including melatonin and BMP-4, while Clock expression was steadily maintained. Thus, the effects of melatonin and BMP-4 on clock gene expression may imply differential stability of circadian rhythms of adrenocorticotropin (ACTH) and PRL secreted from the anterior pituitary.

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  • Regulatory role of BMP-9 in steroidogenesis by rat ovarian granulosa cells. Reviewed International journal

    Takeshi Hosoya, Fumio Otsuka, Eri Nakamura, Tomohiro Terasaka, Kenichi Inagaki, Naoko Tsukamoto-Yamauchi, Takayuki Hara, Kishio Toma, Motoshi Komatsubara, Hirofumi Makino

    The Journal of steroid biochemistry and molecular biology   147   85 - 91   2015.3

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    BMPs expressed in the ovary differentially regulate steroidogenesis by granulosa cells. BMP-9, a circulating BMP, is associated with cell proliferation, apoptosis and differentiation in various tissues. However, the effects of BMP-9 on ovarian function have yet to be elucidated. Here we investigated BMP-9 actions on steroidogenesis using rat primary granulosa cells. BMP-9 potently suppressed FSH-induced progesterone production, whereas it did not affect FSH-induced estradiol production by granulosa cells. The effects of BMP-9 on FSH-induced steroidogenesis were not influenced by the presence of oocytes. FSH-induced cAMP synthesis and FSH-induced mRNA expression of steroidogenic factors, including StAR, P450scc, 3βHSD2 and FSHR, were suppressed by treatment with BMP-9. BMP-9 mRNA expression was detected in granulosa cells but not in oocytes. BMP-9 readily activated Smad1/5/8 phosphorylation and Id-1 transcription in granulosa cells. Analysis using ALK inhibitors indicated that BMP-9 actions were mediated via type-I receptors other than ALK-2, -3 and -6. Furthermore, experiments using extracellular domains (ECDs) for BMP type-I and -II receptor constructs revealed that the effects of BMP-9 were reversed by ECDs for ALK-1 and BMPRII. Thus, the functional receptors for BMP-9 in granulosa cells were most likely to be the complex of ALK-1 and BMPRII. Collectively, the results of the present study showed that BMP-9 can affect luteinization and that there are two possible sources of BMP-9, serum and granulosa cells in the ovary.

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  • Lemierre syndrome involving external jugular vein. Reviewed International journal

    Hideharu Hagiya, Yuto Haruki, Fumio Otsuka

    Acute medicine & surgery   2 ( 1 )   64 - 68   2015.1

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    Case: A 74-year-old woman with a week-long history of cold symptoms was diagnosed with Lemierre syndrome that involved her left external jugular vein. Outcome: The patient was successfully treated with 4 weeks of antibiotics and anticoagulant treatment. Typical cases of Lemierre syndrome involve only the internal jugular vein. The external jugular vein is anatomically distant from the pharyngolaryngeal space and usually does not receive blood or lymphatic flow from there. Thus, Lemierre syndrome ordinarily does not involve the external jugular vein and clinical characteristics of external jugular vein-involving Lemierre syndrome have not been uncovered, mainly due to its rarity. Based on our review, it would not much differ from those of typical cases. Conclusion: Considering the potential severity and mortality, more attention should be paid to this potentially fatal disease that may demonstrate atypical manifestation, as shown in this case. Accumulation of cases would be needed for further understanding.

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  • Disseminated streptococcal endophthalmitis in two diabetic patients. Reviewed

    Hideharu Hagiya, Kotaro Aoki, Kazuhiro Tateda, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   54 ( 10 )   1317 - 8   2015

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  • A paraganglioma in a hypertensive patient with unilateral renal hypoplasia. Reviewed

    Tomohiro Terasaka, Hideharu Hagiya, Kosuke Kimura, Takahiro Nada, Eri Nakamura, Yoshihisa Hanayama, Hitoshi Sugiyama, Yasuyuki Kobayashi, Hiroyuki Yanai, Fumio Otsuka

    Acta medica Okayama   69 ( 2 )   119 - 22   2015

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    We report the case of a 46-year-old hypertensive Japanese female with renal insufficiency related to unilateral renal hypoplasia. The patient was found to have developed paraganglioma in the retroperitoneal space over a 5-year period. Catecholamine-producing tumors are not usually recognized as conditions associated with renal hypoplasia. Our long-term observation of the patient eventually led us to the diagnosis of paraganglioma. In hypertensive patients with chronic kidney disease, not only the renin-angiotensin-aldosterone system but also catecholamine activity may be involved, particularly in the patients whose cases are complicated with unilateral renal hypoplasia.

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  • An Insulinoma Discovered in a Patient with Diffusely Calcified Chronic Pancreatitis. Reviewed

    Tomohiro Terasaka, Keiko Tsukamoto, Kenichi Inagaki, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   54 ( 21 )   2785 - 6   2015

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  • Myopathy and eosinophilic pneumonia coincidentally induced by treatment with daptomycin. Reviewed

    Hideharu Hagiya, Kou Hasegawa, Kikuko Asano, Tomohiro Terasaka, Kosuke Kimura, Takahiro Nada, Eri Nakamura, Koichi Waseda, Yoshihisa Hanayama, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   54 ( 5 )   525 - 9   2015

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    A 34-year-old man with 22q11.2 deletion syndrome (DiGeorge syndrome) concurrently suffered from myopathy and eosinophilic pneumonia shortly after receiving daptomycin (DAP) for right-sided infective endocarditis. The simultaneous occurrence of these phenomena in relation to DAP therapy has not been previously well described. An allergic reaction was suspected as a possible etiology of these DAP-related complications. This case highlights the need for close observation in order to detect both musculoskeletal and respiratory disorders from the start of DAP therapy. Physicians should pay more attention to this new drug, which is expected to be frequently used in various clinical settings.

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  • Hyperintense Lesion in the Pons in Intravascular Lymphoma. Reviewed

    Masaya Iwamuro, Kosuke Kimura, Eisei Kondo, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   54 ( 18 )   2421 - 2   2015

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  • Infective Internal Iliac Artery Aneurysm Caused by Campylobacter fetus. Reviewed

    Hideharu Hagiya, Hiroko Ogawa, Yusuke Takahashi, Kou Hasegawa, Yoshihisa Hanayama, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   54 ( 16 )   2021 - 4   2015

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    A 67-year-old man with a persistent high fever was diagnosed to have an infective aneurysm in his left internal iliac artery. A blood culture detected a gram-negative spiral rod that was first identified as Campylobacter fetus subsp. venerealis based on a matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) analysis. However, the strain was finally confirmed to be Campylobacter fetus subsp. fetus based on a genetic analysis. The infection was successfully treated with emergency resection of the aneurysm, followed by 4 weeks of antibiotic therapy. Involvement of the peripheral artery is uncommon in cases of C. fetus-infective aneurysm. To figure out the epidemiology and pathogenicity of C. fetus infection, the accurate identification of the responsible organisms is essential.

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  • A Nephrostomy-associated Urinary Tract Infection Caused by Elizabethkingia meningoseptica. Reviewed

    Hideharu Hagiya, Hiroko Ogawa, Yusuke Takahashi, Kou Hasegawa, Masaya Iwamuro, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   54 ( 24 )   3233 - 6   2015

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    We report a case of nephrostomy-associated urinary tract infection caused by Elizabethkingia meningoseptica that occurred in a patient with retroperitoneal fibrosis. Though conventional identification methods failed to detect the causative organism, it was identified on the basis of the complete sequencing of 16S rRNA. Four weeks of levofloxacin and minocycline administration successfully eradicated the infection. E. meningoseptica rarely causes urinary tract infections, and we believe that this is the first such case in which the isolate was genetically confirmed. The accurate identification of the organism is necessary for the provision of appropriate treatment and to obtain a better understanding of its epidemiology and pathogenicity.

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  • Klebsiella oxytoca-producing IMP-1 Detected as the First Strain of Carbapenem-resistant Enterobacteriaceae in Our Hospital. Reviewed

    Hideharu Hagiya, Hiroko Ogawa, Yusuke Takahashi, Akira Yamamoto, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   54 ( 22 )   2939 - 41   2015

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    We herein report a case of Klebsiella oxytoca-producing IMP-1 that was detected as a first isolate of carbapenem-resistant Enterobacteriaceae (CRE) at our facility. Since K. oxytoca is an uncommon strain for CRE, we speculated that the resistant organism had already spread out inside the hospital. Metallo-β-lactamases promotes antibiotic resistance in Enterobacteriaceae, which potentially yields problematic issues in clinical settings. Active surveillance of antibiotic resistant strains is important and should be repeatedly highlighted. Furthermore, appropriate methods should be established to detect highly resistant strains.

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  • Clinical ineffectiveness of latamoxef for Stenotrophomonas maltophilia infection. Reviewed International journal

    Hideharu Hagiya, Ken Tasaka, Toshiaki Sendo, Fumio Otsuka

    Infection and drug resistance   8   353 - 7   2015

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    OBJECTIVES: Stenotrophomonas maltophilia shows wide-spectrum resistance to antimicrobials and causes various infections in immunocompromised or critically ill patients with high mortality. In this era of antibiotics resistance, a revival of old antibiotics is now featured. We examined the clinical usefulness of latamoxef (LMOX) for the treatment of S. maltophilia infection. PATIENTS AND METHODS: The observational study was retrospectively performed at Okayama University Hospital (Okayama, Japan) from January 2011 to December 2013. LMOX was administered to 12 patients with S. maltophilia infection, with eleven of those patients being admitted to the intensive care unit. RESULTS: Underlying conditions of the patients included postoperation, hematological transplantation, hepatic transplantation, and burn. Major infectious foci were surgical site infection (six cases), respiratory infection (four cases), blood stream infection (three cases), and burn site infection (one case). The doses of LMOX administered ranged from 1 g/d to 3 g/d for ten adult patients and from 40 mg/kg/d to 80 mg/kg/d for two pediatric patients. Microbiologic failure was seen in five (41.7%) of 12 cases, and 30-day and hospital mortality rates were 25% and 50%, respectively. Minimum inhibitory concentrations of LMOX were higher in the deceased group (4-64 µg/mL) than in the surviving group (1-4 µg/mL). CONCLUSION: LMOX treatment is not recommended for the treatment of S. maltophilia infection. Further investigation would be needed before its clinical use.

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  • Actinomyces turicensis Bacteremia Secondary to Pyometra. Reviewed

    Hideharu Hagiya, Hiroko Ogawa, Yusuke Takahashi, Kosuke Kimura, Kan Hasegawa, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   54 ( 21 )   2775 - 7   2015

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    We herein present a rare case of Actinomyces turicensis bacteremia that was caused by pyometra. The patient was successfully treated with transvaginal drainage and antibiotic therapy. A literature review in MEDLINE showed that there have been only 8 previously reported cases of A. turicensis bacteremia. This infection frequently occurs in patients with visceral abscesses, and blood culture examinations usually reveal a polymicrobial pattern. However, the prognosis of such patients has been reported to generally be benign. Due to difficulties in performing bacterial identification and the wide-spectrum clinical pictures associated with this bacteremia, no comprehensive understanding of the clinical features of each Actinomyces species has yet been established.

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  • Neurosyphilis Is a Long-forgotten Disease but Still a Possible Etiology for Dementia. Reviewed

    Hideharu Hagiya, Kentaro Deguchi, Kiyohiro Kawada, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   54 ( 21 )   2769 - 73   2015

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    We herein report a heterosexual Japanese man in his forties who had been suffering from advanced dementia and personality change for 4 years. Positive results of a serological test for syphilis, Treponema pallidum hemagglutination assay, and fluorescent treponemal antibody-absorption test of both serum and cerebral spinal fluid led to the diagnosis of neurosyphilis. Jarisch-Herxheimer reaction was seen shortly after the first dose of penicillin was administered to the patient. His cognitive function did not recover after treatment. The incidence of syphilis has been reported to be increasing. Neurosyphilis should not be overlooked as an etiology for progressive dementia even in this post-antibiotic era.

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  • Cytomegalovirus as an Insidious Pathogen Causing Duodenitis. Reviewed

    Hideharu Hagiya, Masaya Iwamuro, Takehiro Tanaka, Yoshihisa Hanayama, Fumio Otsuka

    Acta medica Okayama   69 ( 5 )   319 - 23   2015

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    A 60-year-old woman with rheumatoid arthritis treated with methotrexate for a decade complained of slight epigastric discomfort. A positive cytomegalovirus (CMV) antigenemia test indicated the probability of CMV-related gastrointestinal infection, for which esophagogastroduodenoscopy was performed. Endoscopic findings showed a non-specific duodenal mucosal lesion;however, pathological investigation revealed evidence of CMV duodenitis. There is scarce information on the clinical and pathological features of CMV-related duodenitis, likely due to its low prevalence. CMV infection in the upper gastrointestinal tract should be considered as a differential diagnosis in high-risk individuals, particularly those with symptoms relating to the digestive system. Biopsy examinations are preferable for the definitive diagnosis of CMV gastrointestinal infection, even without specific endoscopic features.

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  • Relationships between Causes of Fever of Unknown Origin and Inflammatory Markers: A Multicenter Collaborative Retrospective Study. Reviewed

    Toshio Naito, Keito Torikai, Masafumi Mizooka, Fujiko Mitsumoto, Kenji Kanazawa, Shiro Ohno, Hiroyuki Morita, Akira Ukimura, Nobuhiko Mishima, Fumio Otsuka, Yoshio Ohyama, Noriko Nara, Kazunari Murakami, Kouichi Mashiba, Kenichiro Akazawa, Koji Yamamoto, Mika Tanei, Masashi Yamanouchi, Shoichi Senda, Susumu Tazuma, Jun Hayashi

    Internal medicine (Tokyo, Japan)   54 ( 16 )   1989 - 94   2015

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    OBJECTIVE: Although inflammatory markers, such as the white blood cell (WBC) count, erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP) and procalcitonin, are widely used to differentiate causes of fever of unknown origin (FUO), little is known about the usefulness of this approach. We evaluated relationships between the causes of classical FUO and the levels of inflammatory markers. METHODS: A nationwide retrospective study including 17 hospitals affiliated with the Japanese Society of Hospital General Medicine was conducted. PATIENTS: This study included 121 patients ≥18 years old diagnosed with "classical FUO" (axillary temperature ≥38.0°C at least twice over a ≥3-week period without elucidation of the cause on three outpatient visits or during three days of hospitalization) between January and December 2011. RESULTS: The causative disease was infectious diseases in 28 patients (23.1%), non-infectious inflammatory disease (NIID) in 37 patients (30.6%), malignancy in 13 patients (10.7%), other in 15 patients (12.4%) and unknown in 28 patients (23.1%). The rate of malignancy was significantly higher for a WBC count of <4,000/μL than for a WBC count of 4,000-8,000/μL (p=0.015). Among the patients with a higher WBC count, the rate of FUO due to NIID tended to be higher and the number of unknown cases tended to be lower. All FUO patients with malignancy showed an ESR of >40 mm/h. A normal ESR appeared to constitute powerful evidence for excluding a diagnosis of malignancy. In contrast, the concentrations of both serum CRP and procalcitonin appeared to be unrelated to the causative disease. CONCLUSION: The present study identified inflammatory markers that should be considered in the differential diagnosis of classical FUO, providing useful information for future diagnosis.

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  • Tetanus in a 19-year-old Japanese Woman. Reviewed

    Hideharu Hagiya, Takahiro Hirayama, Toyomu Ugawa, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   54 ( 14 )   1825 - 1825   2015

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  • Relapsing Polychondritis Followed Up with FDG-PET. Reviewed

    Hideharu Hagiya, Koichi Waseda, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   54 ( 13 )   1675 - 6   2015

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  • Eagle's Syndrome Manifesting as Chronic Swallowing Pain. Reviewed

    Hideharu Hagiya, Koichi Waseda, Hiroko Ogawa, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   54 ( 10 )   1321 - 1321   2015

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  • CT visualising infective vegetation. International journal

    Hideharu Hagiya, Kou Hasegawa, Kikuko Asano, Fumio Otsuka

    BMJ case reports   2014   2014.12

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  • Gingival overgrowth caused by vitamin C deficiency associated with metabolic syndrome and severe periodontal infection: a case report. Reviewed International journal

    Kazuhiro Omori, Yoshihisa Hanayama, Koji Naruishi, Kentaro Akiyama, Hiroshi Maeda, Fumio Otsuka, Shogo Takashiba

    Clinical case reports   2 ( 6 )   286 - 95   2014.12

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    It has been suggested that vitamin C deficiency/scurvy is associated with gingival inflammatory changes; however, the disorder is very infrequently encountered in the modern era. Here, we report a case of extensive gingival overgrowth caused by vitamin C deficiency associated with metabolic syndrome and severe periodontal infection.

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  • Aortic vascular graft infection caused by Cardiobacterium valvarum: a case report. Reviewed International journal

    Hideharu Hagiya, Susumu Kokeguchi, Hiroko Ogawa, Tomohiro Terasaka, Kosuke Kimura, Koichi Waseda, Yoshihisa Hanayama, Kaori Oda, Hisatoshi Mori, Toru Miyoshi, Fumio Otsuka

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   20 ( 12 )   804 - 9   2014.12

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    A 53-year-old man with a past medical history of total arch replacement surgery and severe aortic regurgitation presented with a 1-month history of persistent general malaise, anorexia, body weight loss and night sweats. His recent history included gingival hyperplasia for 6 years, gingivitis after tooth extraction 3 years before, prolonged inflammatory status for 4 months, fundal hemorrhage and leg tenderness for 2 months. A pathogen was detected from blood culture, but conventional microbiological examination failed to identify the pathogen. The organism was eventually identified as Cardiobacterium valvarum by 16S rRNA analysis, and the patient was diagnosed with infective endocarditis and prosthetic vascular graft infection. The patient received intravenous antibiotic therapy using a combination of ceftriaxone and levofloxacin for 5 weeks and was discharged with a good clinical course.
    C. valvarum is a rare human pathogen in clinical settings. Only 10 cases have been reported to date worldwide, and therefore, the clinical characteristics of C. valvarum infection are not fully known. This is a first well-described case of C. valvarum infection in Japan, and further, a first report of aortic prosthetic vascular graft infection worldwide. Identification of C. valvarum is usually difficult due to its phenotypic characteristics, and molecular approaches would be required for both clinicians and microbiologists to facilitate more reliable diagnosis and uncover its clinical picture more clearly. (C) 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

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  • Pantoea dispersa bacteremia caused by central line-associated bloodstream infection

    Hideharu Hagiya, Fumio Otsuka

    BRAZILIAN JOURNAL OF INFECTIOUS DISEASES   18 ( 6 )   696 - 697   2014.11

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  • Mycotic abdominal aortic aneurysm caused by Campylobacter fetus: a case report and literature review. International journal

    Hideharu Hagiya, Mitsuaki Matsumoto, Hiroshi Furukawa, Tomoko Murase, Fumio Otsuka

    Annals of vascular surgery   28 ( 8 )   1933.e7-1933.e14   2014.11

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    Campylobacter spp. usually cause gastrointestinal infections, but among them, Campylobacter fetus is a well-known organism causing mycotic abdominal aortic aneurysm (MAAA), which requires proper surgical intervention and antibiotic therapy. We report a 65-year-old man who was successfully treated by an in situ operation using a rifampicin (RFP)-bonded J-Graft for C. fetus-induced MAAA. We performed a review of the English literature on MAAA caused by C. fetus and summarized the results of the cases (28 cases). All but 2 of the patients (92.9%) were men. Blood culture and arterial wall culture were positive in 63% and 73.1% of the cases, respectively. Aneurysm rupture was seen in half of the patients, and approximately half of those patients died. Among the 18 patients who underwent in situ graft replacement, only 1 patient (5.6%) died after surgery. Antibiotic therapy was performed for more than 1 month in most cases, and overall mortality rate was 25.9% (7 of 27 cases, 3 deaths before the operation and 4 deaths after surgery). Although extra-anatomic bypass has been conventionally performed after complete resection of an MAAA, the utility of in situ surgery has generally been recognized. Our review suggests that the in situ operation can be a choice also in cases of C. fetus-associated MAAA. Furthermore, our case suggested the clinical utility of a newly manufactured prosthetic graft, J-Graft, for such surgical treatment.

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  • Clinical utility of string test as a screening method for hypermucoviscosity-phenotype Klebsiella pneumoniae. Reviewed International journal

    Hideharu Hagiya, Naoto Watanabe, Miyako Maki, Tomoko Murase, Fumio Otsuka

    Acute medicine & surgery   1 ( 4 )   245 - 246   2014.10

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  • Emergence of third-generation cephalosporin-resistant Enterobacteriacae in a Japanese critical care setting. Reviewed International journal

    Hideharu Hagiya, Tomoko Murase, Masato Suzuki, Fumio Otsuka, Keigo Shibayama

    Acute medicine & surgery   1 ( 4 )   256 - 258   2014.10

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    Aim: Extended-spectrum beta-lactamases and AmpC beta-lactamases give resistance to Enterobacteriaceae against cephalosporins, which are important drugs in various clinical settings. Within 5 days, a total of eight strains of Citrobacter freundii and two strains of Escherichia coli, all of which were resistant to third-generation cephalosporins, were isolated from six different patients in a critical care center. We carried out epidemiological and genetic studies to confirm the situation to be an outbreak by a single strain or a beta-lactamase-producing gene. Methods: A review of patients' clinical data, pulsed-field gel electrophoresis epidemiological study against the strains, and polymerase chain reaction analysis for the detection of extended-spectrum beta-lactamase genes (TEM, SHV, CTX-M-1, CTX-M-2, and CTX-M-9) and multiplex polymerase chain reaction analysis for plasmid-mediated AmpC-beta-lactamase genes were carried out. Results: Pulsed-field gel electrophoresis showed none of the subjects were genetically identical organisms. However, all strains possessed either extended-spectrum beta-lactamases (TEM, CTX-M-2, and CTX-M-9) or AmpC-beta-lactamases. One patient carried both extended-spectrum beta-lactamase- and AmpC- beta-lactamase-producing organisms. Conclusion: This study revealed that various types of easily transmittable drug resistance genes exist in the critical care setting concurrently. This case was not an outbreak of such strains, but the present situation might indicate a more serious condition than a mere outbreak of a single resistant strain. Enterobacteriaceae that possess extended-spectrum beta-lactamases or AmpC-beta-lactamases are increasingly common in many medical institutions in Japan, and constitutive monitoring of drug-resistant organisms and proper contact precautions are essential to prevent possible outbreaks.

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  • Melatonin counteracts BMP-6 regulation of steroidogenesis by rat granulosa cells. Reviewed International journal

    Eri Nakamura, Fumio Otsuka, Tomohiro Terasaka, Kenichi Inagaki, Takeshi Hosoya, Naoko Tsukamoto-Yamauchi, Kishio Toma, Hirofumi Makino

    The Journal of steroid biochemistry and molecular biology   143   233 - 9   2014.9

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    The ovarian bone morphogenetic protein (BMP) system is a physiological inhibitor of luteinization in growing ovarian follicles. BMP-6, which is expressed in oocytes and granulosa cells of healthy follicles, specifically inhibits FSH actions by suppressing adenylate cyclase activity. In the present study, we studied the role of melatonin in ovarian steroidogenesis using rat primary granulosa cells of immature female rat ovaries by focusing on the interaction with BMP-6 activity. Treatment with melatonin had no direct effect on FSH-induced progesterone or estradiol production by granulosa cells, and the results were not affected by the presence of co-cultured oocytes. In addition, synthesis of cAMP by granulosa cells was not significantly altered by melatonin treatment. To elucidate the interaction between activities of melatonin and BMPs, the effect of melatonin treatment on suppression of progesterone synthesis by BMP-6 was investigated. Interestingly, the inhibitory effect of BMP-6 on FSH-induced progesterone production was impaired by co-treatment with melatonin. Granulosa cells express higher levels of MT1 than MT2, and BMP-6 had no significant effect on MT1 expression in granulosa cells. However, BMP-6-induced Smad1/5/8 phosphorylation and Id-1 transcription were suppressed by melatonin, suggesting that melatonin has an inhibitory effect on BMP receptor signaling in granulosa cells. Although the expression levels of ALK-2, -6, ActRII and BMPRII were not affected by melatonin, inhibitory Smad6, but not Smad7, expression was upregulated by melatonin. Thus, melatonin plays a role in the regulation of BMP-6 signal intensity for controlling progesterone production in the ovary. These findings suggest that the effect of melatonin on maintenance of ovarian function is, at least in part, due to the regulation of endogenous BMP activity in granulosa cells.

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  • Vasohibin-1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction. Reviewed International journal

    Hiroyuki Watatani, Yohei Maeshima, Norikazu Hinamoto, Hiroko Yamasaki, Haruyo Ujike, Katsuyuki Tanabe, Hitoshi Sugiyama, Fumio Otsuka, Yasufumi Sato, Hirofumi Makino

    Physiological reports   2 ( 6 )   2014.6

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    Tubulointerstitial injuries are known to predict the deterioration of renal function in chronic kidney disease (CKD). We recently reported the protective role of Vasohibin-1(VASH-1), a negative feedback regulator of angiogenesis, in diabetic nephropathy, but its impact on tubulointerstitial injuries remains to be elucidated. In the present study, we evaluated the role of endogenous VASH-1 in regulating the tubulointerstitial alterations induced by unilateral ureteral obstruction (UUO), and assessed its role on fibrogenesis and the activation of Smad3 signaling in renal fibroblasts. UUO was induced in female Vasohibin-1 heterozygous knockout mice (VASH-1(+/-)) or wild-type (WT) (VASH-1(+/+)) littermates. Mice were sacrificed on Day 7 after left ureter ligation, and the kidney tissue was obtained. Interstitial fibrosis, the accumulation of type I and type III collagen and monocytes/macrophages infiltration in the obstructed kidneys (OBK) were significantly exacerbated in VASH-1(+/-) mice compared with WT mice (Day 7). The increases in the renal levels of TGF-β1, pSmad3, NF-κB pp65, CCL2 mRNA, and the number of interstitial fibroblast-specific protein-1 (FSP-1)(+) fibroblasts in the OBK were significantly aggravated in VASH-1(+/-) mice. In addition, treatment with VASH-1 siRNA enhanced the TGF-β1-induced phosphorylation of Smad3, the transcriptional activation of the Smad3 pathway and the production of type I/type III collagen in fibroblasts, in vitro. Taken together, our findings demonstrate a protective role for endogenous VASH-1 on tubulointerstitial alterations via its regulation of inflammation and fibrosis and also show the direct anti-fibrotic effects of VASH-1 on renal fibroblasts through its modulation of TGF-β1 signaling.

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  • Retroperitoneal bronchogenic cyst: a rare incidentaloma discovered in a juvenile hypertensive patient. Reviewed International journal

    Tomohiro Terasaka, Fumio Otsuka, Kanako Ogura-Ochi, Tomoko Miyoshi, Kenichi Inagaki, Yasuyuki Kobayashi, Yasutomo Nasu, Hirofumi Makino

    Hypertension research : official journal of the Japanese Society of Hypertension   37 ( 6 )   595 - 7   2014.6

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  • Runx3 Regulates Ovulation and Steroidogenesis in Granulosa Cells in Mice

    Fumiya Ojima, Yuka Saito, Yukiko Tsuchiya, Kenichi Inagaki, Eri Nakamura, Fumio Otsuka, Maho Ogoshi, Sakae Takeuchi, Sumio Takahashi

    ENDOCRINE REVIEWS   35 ( 3 )   2014.6

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  • Chromobacterium violaceum nosocomial pneumonia in two Japanese patients at an intensive care unit. International journal

    Hideharu Hagiya, Tomoko Murase, Masato Suzuki, Keigo Shibayama, Yumi Kokumai, Naoto Watanabe, Miyako Maki, Fumio Otsuka

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   20 ( 2 )   139 - 42   2014.2

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    Chromobacterium violaceum is sensitive to temperature and the infection is usually confined to tropical or subtropical regions. Since Japan has a warm climate, C. violaceum has been scarcely isolated from clinical specimens. With global warming, however, the geographical distribution of C. violaceum infection is likely to change. We report two cases of C. violaceum nosocomial pneumonia that occurred at an intensive care center in Japan. C. violaceum was first detected from a patient in the same center as a pathogenic organism of pneumonia. Later, the organism was isolated from sputum and a ventilator circuit tube of another patient in the center. The two patients were admitted to the center in nearby beds for several days. All of the pathogens were confirmed to be C. violaceum by the nucleic acid sequence of the 16S rRNA gene and were proven to be genetically identical organisms by pulsed field gel electrophoresis. Both patients were managed with well-humidified and heated oxygen using a venturi mask and ventilator to promote excretion of sputum. It was thought that the medical respiratory care devices that provide a humid and warm environment, an optimal condition for proliferation of C. violaceum, can contribute to C. violaceum infection in a hospital environment.

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  • Long-term observation of osteomalacia caused by adefovir-induced Fanconi's syndrome. Reviewed

    Tomohiro Terasaka, Eijiro Ueta, Hirotaka Ebara, Koichi Waseda, Yoshihisa Hanayama, Akinobu Takaki, Tomoko Kawabata, Hitoshi Sugiyama, Ko Hidani, Fumio Otsuka

    Acta medica Okayama   68 ( 1 )   53 - 6   2014.2

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    A 64-year-old man suffering polyarthralgia and bone pain was referred to our hospital. Renal dysfunction, hypophosphatemia and increased levels of bone alkaline phosphatase were found. The patient's serum creatinine level had gradually increased after the initiation of adefovir dipivoxil administration for hepatitis B. In agreement with multifocal uptakes of bone scintigraphy, iliac bone biopsy revealed an abnormal increase in osteoid tissues. Reducing the dose of adefovir and initiating the administration of eldecalcitol were effective for reducing proteinuria and glucosuria, and for ameliorating bone pain with an increase in serum phosphate level. This case first showed a clinical course of hypophosphatemic osteomalacia caused by secondary Fanconi's syndrome for 8 years after adefovir administration. Early diagnosis is important for the reversibility of bone damage and for a better renal prognosis.

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  • Postpartum Breast Abscess Caused by Community-Acquired Methicillin-Resistant Staphylococcus aureus in Japan

    Hideharu Hagiya, Sumiko Shiota, Wakana Sugiyama, Fumio Otsuka

    BREASTFEEDING MEDICINE   9 ( 1 )   45 - 46   2014.1

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  • Acute generalized exanthematous pustulosis caused by daptomycin in a critically ill burn victim.

    Hideharu Hagiya, Maya Kimura, Toru Miyamoto, Yuto Haruki, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   53 ( 5 )   511 - 4   2014

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    Acute generalized exanthematous pustulosis (AGEP) is a self-limiting type of drug eruption that frequently occurs as a reaction to antibiotics, particularly penicillins or macrolides. Daptomycin (DAP) is a newly developed antibiotic that specifically targets methicillin-resistant Staphylococcus aureus infection. We herein present the case of a 77-year-old severe burn victim who was diagnosed with DAP-induced AGEP while receiving treatment in an intensive care unit. Although rare, physicians should be aware that the administration of DAP can cause AGEP, which may complicate the clinical course of patients with a high fever and inflammation.

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  • Fosfomycin for the treatment of prostate infection. Reviewed

    Hideharu Hagiya, Megumi Ninagawa, Kou Hasegawa, Tomohiro Terasaka, Kosuke Kimura, Koichi Waseda, Yoshihisa Hanayama, Toshiaki Sendo, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   53 ( 22 )   2643 - 6   2014

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    A 69-year-old man with diabetes mellitus was diagnosed with a prostate abscess. Although the pathogen was fluoroquinolone-resistant Escherichia coli and the oral administration of trimethoprim-sulfamethoxazole was initiated, the infection recurred after three months. The antibiotic therapy was subsequently changed to intravenous fosfomycin, and the patient's condition promptly improved. Four weeks of fosfomycin therapy was successfully continued without any adverse events. In the era of antibiotic resistance, revival of forgotten drugs is an important issue for clinicians. Fosfomycin can be applied as an alternative option for prostate infections, considering the remaining susceptibility of multidrug-resistant pathogens to fosfomycin and the good pharmacokinetics of this drug in prostatic tissue.

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  • Filarial chyluria as a rare cause of urinary retention. Reviewed

    Hideharu Hagiya, Tomohiro Terasaka, Kosuke Kimura, Asuka Satou, Kikuko Asano, Koichi Waseda, Yoshihisa Hanayama, Takahide Takahashi, Michinori Aoe, Koji Iio, Toshiyuki Watanabe, Eisei Kondo, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   53 ( 17 )   2001 - 5   2014

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    We herein describe a case of Wuchereria bancrofti infection in a previously healthy 37-year-old Nepalese man. The patient presented with a history of milky urine with subsequent acute urinary retention lasting for a few days. The presence of microfilariae was confirmed on both peripheral blood and urine smears obtained at midnight. He was conservatively treated with diethylcarbamazine combined with doxycycline. Filariasis was previously endemic in southern parts of Japan, although it has been eradicated. Clinicians should remember filariasis as a potential etiology of urinary retention, especially in cases that may be associated with imported infectious disease.

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  • Recurrent Stenotrophomonas maltophilia bacteremia after iliac crest bone graft harvest. Reviewed

    Hideharu Hagiya, Hiroko Ogawa, Tomoharu Ishida, Tomohiro Terasaka, Kosuke Kimura, Koichi Waseda, Yoshihisa Hanayama, Masahiro Horita, Yasunori Shimamura, Eisei Kondo, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   53 ( 15 )   1693 - 8   2014

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    We describe a rare case of recurrent Stenotrophomonas maltophilia bacteremia in a previously healthy 45-year-old man. The infection was caused by osteomyelitis at the site of an iliac crest bone graft harvest. A genetic analysis using enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) revealed that the blood isolates and pathogens obtained from the surgical wound were identical. Initial treatment with levofloxacin and cefozopran was ineffective, but the patient's infection was successfully treated by long-term administration of latamoxef and trimethoprim-sulfamethoxazole. The present case suggests that attention should be given to the possibility of S. maltophilia infection in any situations.

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  • Successful treatment of persistent MRSA bacteremia using high-dose daptomycin combined with rifampicin. Reviewed

    Hideharu Hagiya, Tomohiro Terasaka, Kosuke Kimura, Asuka Satou, Kikuko Asano, Koichi Waseda, Yoshihisa Hanayama, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   53 ( 18 )   2159 - 63   2014

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    We herein report a case of persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia that was successfully treated with combination therapy consisting of high-dose daptomycin (DAP, 10 mg/kg) and rifampicin. The patient's condition was complicated with multiple infectious foci, including an iliopsoas abscess and epidural abscess, as well as discitis and spondylitis at the cervical, thoracic and lumbar levels. Monotherapy treatments with vancomycin, linezolid and usual-dose DAP were all ineffective. It has been shown that usual-dose DAP administration may result in the emergence of a resistant strain and treatment failure. We would like to emphasize the importance of high-dose DAP therapy for MRSA bacteremia, a condition with a potentially high mortality rate.

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  • Actinomyces meyeri meningitis: the need for anaerobic cerebrospinal fluid cultures. Reviewed

    Hideharu Hagiya, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   53 ( 1 )   67 - 71   2014

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    We herein present a rare case of Actinomyces meyeri-induced meningitis that occurred in a patient of advanced age with poor oral hygiene. Although Gram staining of the cerebrospinal fluid (CSF) revealed Grampositive rods and a blood culture was positive for the organism, a bacterial culture of the CSF was negative. Anaerobic cultures of CSF specimens are not routinely performed; however, anaerobes are sometimes involved in central nervous system infection. We therefore believe that anaerobic cultures should be considered in high-risk cases, such as those involving necrotizing bowel lesions or poor oral hygiene. A negative result on a CSF culture can result in misdiagnosis and inappropriate treatment.

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  • Ceftriaxone-induced biliary sludge in a patient with uncontrolled diabetes.

    Hideharu Hagiya, Kou Hasegawa, Kikuko Asano, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   53 ( 21 )   2549 - 50   2014

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  • Calcium oxalate crystals in the lungs.

    Hideharu Hagiya, Soichiro Fushimi, Junya Itakura, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   53 ( 17 )   2025 - 6   2014

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  • Epiglottic aphthous ulcers.

    Hideharu Hagiya, Hiroyuki Hanakawa, Takayuki Katsuyama, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   53 ( 15 )   1731 - 1731   2014

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  • A case of vascular graft infection caused by Staphylococcus lugdunensis after femoropopliteal bypass operation.

    Hideharu Hagiya, Mitsuaki Matsumoto, Takahiko Yamasawa, Yuto Haruki, Fumio Otsuka

    Acta medica Okayama   68 ( 3 )   171 - 5   2014

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    A 79-year-old man who had undergone a right femoropopliteal (FP) bypass operation 6 weeks previously was diagnosed with vascular graft infection caused by Staphylococcus lugdunensis. Another FP bypass operation was performed, with long-term administration of antibiotics, and the patient eventually recovered well without any recurrences for over 2 years. Although S. lugdunens is classified as coagulase-negative Staphylococcus, its pathogenicity has been reported to be equal to that of S. aureus. Based on the literature review, the organism characteristically colonizes the inguinal area of human skin;thus, operations such as FP bypass grafting may place patients at a relatively high risk for infection by S. lugdunensis, a potentially high-pathogenicity organism.

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  • Triangle sign on neck MRI.

    Kosuke Kimura, Hideharu Hagiya, Yoshihisa Hanayama, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   53 ( 9 )   1035 - 6   2014

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  • Effects of antibiotics administration on the incidence of wound infection in percutaneous dilatational tracheostomy. Reviewed

    Hideharu Hagiya, Hiromichi Naito, Shingo Hagioka, Shuji Okahara, Naoki Morimoto, Nobuchika Kusano, Fumio Otsuka

    Acta medica Okayama   68 ( 2 )   57 - 62   2014

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    The effect of antibiotics during the perioperative period of percutaneous dilatational tracheostomy (PDT) is still controversial. A total of 297 patients who underwent the PDT procedure were divided into 2 groups:those administered antibiotics perioperatively and those not administered antibiotics. Wound infections were noted in 7 cases (incidence rate, 2.36%) and no death was recorded. Of the 69 patients without antibiotics, 5 developed wound infections (incidence rate, 7.25%), while only 2 of the 228 patients with antibiotics developed wound infections (incidence rate, 0.88%) (p=0.002;risk ratio, 8.82;95% confidence interval, 1.67-46.6). Of the 7 cases of wound infection, 5 cases occurred during the early period after PDT (within 7 days). Collectively, the present results suggest that prophylactic administration of antibiotics may prevent the incidence of PDT-induced wound infection, especially in the early phase after the PDT procedures. The need for antibiotics in PDT should be reconsidered.

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  • Comprehensive analysis of systemically disseminated ST8/non-USA300 type community-acquired methicillin-resistant Staphylococcus aureus infection.

    Hideharu Hagiya, Junzo Hisatsune, Taro Kojima, Sumiko Shiota, Hiromichi Naito, Shingo Hagioka, Naoki Morimoto, Fumio Otsuka, Motoyuki Sugai

    Internal medicine (Tokyo, Japan)   53 ( 8 )   907 - 12   2014

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    Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is genetically heterogeneous and various genotypes are spreading worldwide. We herein report a case of systematically disseminated Japan-intrinsic CA-MRSA infection that was successfully treated. A genetically identical single strain was isolated from a total of 11 different parts of the patient's body, and the pathogen was found to be multilocus sequence type 8, staphylococcal cassette chromosome mec IV, coagulase type III and negative for both Panton-Valentine leukocidin and arginine catabolic mobile element. The epidemiology and pathogenicity of the Japan-intrinsic CA-MRSA strain remain unknown, and further investigation of this life-threatening organism is warranted.

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  • Rhombencephalitis caused by Listeria monocytogenes.

    Hideharu Hagiya, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   53 ( 6 )   639 - 40   2014

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  • Diagnostic workup for fever of unknown origin: a multicenter collaborative retrospective study. Reviewed International journal

    Toshio Naito, Masafumi Mizooka, Fujiko Mitsumoto, Kenji Kanazawa, Keito Torikai, Shiro Ohno, Hiroyuki Morita, Akira Ukimura, Nobuhiko Mishima, Fumio Otsuka, Yoshio Ohyama, Noriko Nara, Kazunari Murakami, Kouichi Mashiba, Kenichiro Akazawa, Koji Yamamoto, Shoichi Senda, Masashi Yamanouchi, Susumu Tazuma, Jun Hayashi

    BMJ open   3 ( 12 )   e003971 - e003971   2013.12

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    OBJECTIVE: Fever of unknown origin (FUO) can be caused by many diseases, and varies depending on region and time period. Research on FUO in Japan has been limited to single medical institution or region, and no nationwide study has been conducted. We identified diseases that should be considered and useful diagnostic testing in patients with FUO. DESIGN: A nationwide retrospective study. SETTING: 17 hospitals affiliated with the Japanese Society of Hospital General Medicine. PARTICIPANTS: This study included patients ≥18 years diagnosed with 'classical fever of unknown origin' (axillary temperature ≥38°C at least twice over a ≥3-week period without elucidation of a cause at three outpatient visits or during 3 days of hospitalisation) between January and December 2011. RESULTS: A total of 121 patients with FUO were enrolled. The median age was 59 years (range 19-94 years). Causative diseases were infectious disease in 28 patients (23.1%), non-infectious inflammatory disease in 37 (30.6%), malignancy in 13 (10.7%), other in 15 (12.4%) and unknown in 28 (23.1%). The median interval from fever onset to evaluation at each hospital was 28 days. The longest time required for diagnosis involved a case of familial Mediterranean fever. Tests performed included blood cultures in 86.8%, serum procalcitonin in 43.8% and positron emission tomography in 29.8% of patients. CONCLUSIONS: With the widespread use of CT, FUO due to deep-seated abscess or solid tumour is decreasing markedly. Owing to the influence of the ageing population, polymyalgia rheumatica was the most frequent cause (9 patients). Four patients had FUO associated with HIV/AIDS, an important cause of FUO in Japan. In a relatively small number of cases, cause remained unclear. This may have been due to bias inherent in a retrospective study. This study identified diseases that should be considered in the differential diagnosis of FUO.

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  • Mutual interaction of kisspeptin, estrogen and bone morphogenetic protein-4 activity in GnRH regulation by GT1-7 cells. Reviewed International journal

    Tomohiro Terasaka, Fumio Otsuka, Naoko Tsukamoto, Eri Nakamura, Kenichi Inagaki, Kishio Toma, Kanako Ogura-Ochi, Christine Glidewell-Kenney, Mark A Lawson, Hirofumi Makino

    Molecular and cellular endocrinology   381 ( 1-2 )   8 - 15   2013.12

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    Reproduction is integrated by interaction of neural and hormonal signals converging on hypothalamic neurons for controlling gonadotropin-releasing hormone (GnRH). Kisspeptin, the peptide product of the kiss1 gene and the endogenous agonist for the GRP54 receptor, plays a key role in the regulation of GnRH secretion. In the present study, we investigated the interaction between kisspeptin, estrogen and BMPs in the regulation of GnRH production by using mouse hypothalamic GT1-7 cells. Treatment with kisspeptin increased GnRH mRNA expression and GnRH protein production in a concentration-dependent manner. The expression levels of kiss1 and GPR54 were not changed by kisspeptin stimulation. Kisspeptin induction of GnRH was suppressed by co-treatment with BMPs, with BMP-4 action being the most potent for suppressing the kisspeptin effect. The expression of kisspeptin receptor, GPR54, was suppressed by BMPs, and this effect was reversed in the presence of kisspeptin. It was also revealed that BMP-induced Smad1/5/8 phosphorylation and Id-1 expression were suppressed and inhibitory Smad6/7 was induced by kisspeptin. In addition, estrogen induced GPR54 expression, while kisspeptin increased the expression levels of ERα and ERβ, suggesting that the actions of estrogen and kisspeptin are mutually enhanced in GT1-7 cells. Moreover, kisspeptin stimulated MAPKs and AKT signaling, and ERK signaling was functionally involved in the kisspeptin-induced GnRH expression. BMP-4 was found to suppress kisspeptin-induced GnRH expression by reducing ERK signaling activity. Collectively, the results indicate that the axis of kisspeptin-induced GnRH production is bi-directionally controlled, being augmented by an interaction between ERα/β and GPR54 signaling and suppressed by BMP-4 action in GT1-7 neuron cells.

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  • 2型糖尿病初期治療における経口糖尿病降下薬の処方選択基準に関するアルゴリズムの作成と有用性の検討 Reviewed

    塩見明日香、三好智子、村上和敏、水島孝明、黒田真生、尾上 洋、相良英憲、座間味義人、大塚文男、名倉弘哲

    ライフ・サイエンスProgress in Medicine   33 ( 10 )   2261 - 2268   2013.10

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  • Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells. Reviewed International journal

    Naoko Tsukamoto, Fumio Otsuka, Kanako Ogura-Ochi, Kenichi Inagaki, Eri Nakamura, Kishio Toma, Tomohiro Terasaka, Yasumasa Iwasaki, Hirofumi Makino

    Molecular and cellular endocrinology   375 ( 1-2 )   1 - 9   2013.8

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    The role of melatonin, a regulator of circadian rhythm, in adrenocorticotropin (ACTH) production by corticotrope cells has not been elucidated. In this study, we investigated the effect of melatonin on ACTH production in relation to the biological activity of bone morphogenetic protein (BMP)-4 using mouse corticotrope AtT20 cells that express melatonin type-1 (MT1R) but not type-2 (MT2R) receptors. We previously reported that BMP-4 inhibits corticotropin-releasing hormone (CRH)-induced ACTH production and proopiomelanocortin (POMC) transcription by inhibiting MAPK signaling. Both melatonin and an MT1R/MT2R agonist, ramelteon, suppressed CRH-induced ACTH production, POMC transcription and cAMP synthesis. The inhibitory effects of ramelteon on basal and CRH-induced POMC mRNA and ACTH levels were more potent than those of melatonin. Treatment with melatonin or ramelteon in combination with BMP-4 additively suppressed CRH-induced ACTH production. Of note, the level of MT1R expression was upregulated by BMP-4 stimulation. The suppressive effects of melatonin and ramelteon on POMC transcription and cAMP synthesis induced by CRH were not affected by an MT2R antagonist, luzindole. On the other hand, BMP-4-induced Smad1/5/8 phosphorylation and the expression of a BMP target gene, Id-1, were augmented in the presence of melatonin and ramelteon. Considering that the expression levels of BMP receptors, ALK-3/BMPRII, were increased by ramelteon, MT1R action may play an enhancing role in BMP-receptor signaling. Among the MT1R signaling pathways including AKT, ERK and JNK pathways, inhibition of AKT signaling functionally reversed the MT1R effects on both CRH-induced POMC transcription and BMP-4-induced Id-1 transcription. Collectively, MT1R signaling and BMP-4 actions were mutually augmented, leading to fine-tuning of ACTH production by corticotrope cells.

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  • Systemic varicella-zoster virus infection in two critically ill patients in an intensive care unit. Reviewed International journal

    Hideharu Hagiya, Maya Kimura, Toru Miyamoto, Fumio Otsuka

    Virology journal   10   225 - 225   2013.7

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    Varicella-zoster virus (VZV) usually causes localized zoster in adults. However, in immunocompromised patients, it can cause systemic infection accompanied by complications such as pneumonia, encephalitis, and hepatitis. Although most of critically ill patients in intensive care unit (ICU) are immunologically compromised, they are usually not considered to be at risk for systemic VZV infection.We report two cases of systemic VZV infection occurring in critically ill patients in an ICU. One patient was a 69-year-old man with Streptococcus pneumoniae-induced purpurafulminans, and the other was a 75-year-old woman with severe acute pancreatitis. During the clinical course in the ICU, characteristic vesicles with umbilical fossa appeared diffusely and bilaterally on their face, trunk, and extremities. VZV-specific IgG levels were confirmed to be elevated compared to that of the pre-onset, and a diagnosis of recurrent VZV infection was made in both patients. The patients were treated at the same ICU but did not coincide with each other; therefore a cross-infection was unlikely. They were treated with intravenous acyclovir, but the latter patient eventually died of respiratory failure.VZV infection can cause a number of serious complications, and can lead to death in some patients. Early detection and proper treatment are needed to prevent the infection from spreading out and save the patients. It might be necessary to consider antiviral prophylaxis against VZV infection for a part of critically ill patients in ICU, although the effectiveness of this approach is yet to be established.

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  • Erdheim-Chester病が強く疑われた下垂体機能低下症の一例 Reviewed

    三好智子、大塚文男、稲垣兼一、田中康司、越智可奈子、藤井一恭、藤井伸治、当真貴志雄、中村絵里、塚本尚子、武田昌也、三村由香里、小倉俊郎、景山甚郷、槇野博史

    日本内分泌学会雑誌   89 ( suppl )   21 - 23   2013.6

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  • GRK-6 mediates FSH action synergistically enhanced by estrogen and the oocyte in rat granulosa cells. Reviewed International journal

    Tomoko Miyoshi, Fumio Otsuka, Shunichi Shimasaki

    Biochemical and biophysical research communications   434 ( 2 )   401 - 6   2013.5

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    Estrogen is known to play a pivotal role in granulosa cell responses to follicle-stimulating hormone (FSH) that is critical for the establishment of dominant follicles and subsequent ovulation in mammals. Thus, elucidating the cellular and molecular mechanisms that regulate FSH activity is important to understand female fertility. We previously discovered that the oocyte is required for estrogen to exert its positive effects on FSH activity in rat granulosa cells. This finding supports the new concept that estrogen action in granulosa cells is mediated by the oocyte. In the current study, we explored the underlying mechanism. In the presence of oocytes, estrogens enhanced FSH-induced increases in aromatase, steroidogenic acute regulatory protein and FSH receptor mRNA expression as well as cAMP production. However, as forskolin did not mimic FSH activity this indicated that coexistence of estrogen/oocytes increases FSH activity at a site upstream of adenylate cyclase in granulosa cells. We therefore sought a possible involvement of the autoregulatory molecules for FSH receptor, G protein-coupled receptor kinases (GRKs) and beta-arrestins in enhancing FSH activity in response to the estrogen/oocyte co-treatment in granulosa cells. Among the seven known GRK and two beta-arrestin molecules, we found that estrogens with oocytes suppressed FSH-induced GRK-6 mRNA expression. Consistent with this finding, transfecting granulosa cells with small interfering RNA of GRK-6 significantly increased FSH induction of aromatase mRNA, suggesting that endogenous GRK-6 plays an inhibitory role in FSH-induced aromatase mRNA expression. Consequently, these findings strongly suggest that GRK-6 is involved in the mechanism by which estrogen and oocytes synergistically augment FSH activity in granulosa cells. (c) 2013 Elsevier Inc. All rights reserved.

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  • Estrogen facilitates osteoblast differentiation by upregulating bone morphogenetic protein-4 signaling. Reviewed International journal

    Yoshinori Matsumoto, Fumio Otsuka, Mariko Takano-Narazaki, Takayuki Katsuyama, Eri Nakamura, Naoko Tsukamoto, Kenichi Inagaki, Ken-Ei Sada, Hirofumi Makino

    Steroids   78 ( 5 )   513 - 20   2013.5

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    Imbalanced functions of osteoclasts and osteoblasts are involved in various types of bone damage including postmenopausal osteoporosis. In the present study, we investigated the cellular mechanism by which estrogen interacts in the process of osteoblastic differentiation regulated by BMP-4 using mouse MC3T3-E1 cells that express estrogen receptors (ER) and BMP-4. Estradiol enhanced BMP-4-induced Runx2, osterix, ALP and osteocalcin expression in MC3T3-E1 cells. BMP-4-induced mineralization shown by Alizarin red staining was also facilitated by estrogen treatment. It was revealed that estrogen upregulated BMP-4-induced Smad1/5/8 phosphorylation, BRE-Luc activity and Id-1 mRNA expression. The expression of BMPRII was increased by estrogen in MC3T3-E1 cells, and inhibition of BMPRII or ALK-2/3 signaling impaired the effect of estrogen on BMP-4 signaling. Of note, the enhanced expression of osterix, ALP and osteocalcin mRNAs induced by BMP-4 and estrogen was reversed in the presence of an ER antagonist. Given that membrane-impermeable estrogen also upregulated BMP-4-induced expression of osteoblastic markers and Id-1 mRNA, non-genomic ER activity is involved in the mechanism by which estrogen enhances BMP-4-induced osteoblast differentiation in MC3T3-E1 cells. On the other hand, the expression of ERα and endogenous BMP-4 was suppressed by BMP-4 treatment regardless of the presence of estrogen, implying the presence of a negative feedback loop for osteoblast differentiation. Thus, estrogen is functionally involved in the process of osteoblast differentiation regulated by BMP-4 through upregulating BMP sensitivity of MC3T3-E1 cells.

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  • 中枢性尿崩症で発症したリンパ球性汎下垂体炎の1例 Reviewed

    竹本玲加、大塚文男、森下美智子、森本尚孝、寺田洋明、斉藤信幸、正岡哲也、宮谷克也、田中健大

    三豊総合病院雑誌   34   59 - 63   2013.4

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  • 左眼瞼下垂を契機に診断された若年胃癌のトルコ鞍部転移の一例 Reviewed

    稲垣兼一、当真貴志雄、中村絵里、越智可奈子、塚本尚子、三好智子、三村由香里、小倉俊郎、大塚文男、槇野博史

    ACTH Related Peptides   24   56 - 58   2013.3

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  • Involvement of bone morphogenetic protein activity in somatostatin actions on ovarian steroidogenesis. Reviewed International journal

    Eri Nakamura, Fumio Otsuka, Kenichi Inagaki, Naoko Tsukamoto, Kanako Ogura-Ochi, Tomoko Miyoshi, Kishio Toma, Masaya Takeda, Hirofumi Makino

    The Journal of steroid biochemistry and molecular biology   134   67 - 74   2013.3

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    Somatostatin is expressed in the hypothalamus, pancreas and gastrointestinal tracts and it inhibits the secretion of various hormones in vivo. In the rodent ovary, somatostatin receptor (SSTR) subtypes 2 and 5 are expressed in granulosa cells and oocytes. Somatostatin analogs have been clinically used for treatment of endocrine tumors. For this purpose, relatively high-dose or long-term treatments of somatostatin analogs are necessary; however, the direct and continuous impact of somatostatin analogs on gonadal functions has yet to be elucidated. In the present study, we investigated the effects of somatostatin analogs (octreotide and pasireotide) on ovarian steroidogenesis by rat primary granulosa cell culture. The expression levels of SSTR2 and SSTR5 in granulosa cells were upregulated by FSH treatment. Treatment with somatostatin analogs decreased FSH-induced estradiol production with reduction in aromatase mRNA expression, while the treatment also suppressed FSH-induced progesterone production with reduction of mRNAs levels of StAR, P450scc and 3 beta HSD2 in granulosa cells. This trend was also observed in a granulosa/oocyte co-culture condition. The effect of pasireotide was more potent than that of octreotide. FSH-induced synthesis of steroids and cAMP was also suppressed by somatostatin analog treatment. Notably, pretreatment with a BMP-binding protein, noggin reversed the suppressive effects of somatostatin analogs on progesterone and cAMP production, suggesting that the endogenous BMP system is functionally involved in the SSTR effects in granulosa cells. Treatment with BMP-2, -4, -6 and -7 decreased the mRNA expression of inhibitory Smads6 and 7, leading to enhancement of BMP actions detected by Id-1 transcription in granulosa cells. Collectively, the results revealed that SSTR activation modulates ovarian steroidogenesis by upregulating endogenous BMP activity in growing follicles. (c) 2012 Elsevier Ltd. All rights reserved.

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  • Is wet swab superior to dry swab as an intranasal screening test? Reviewed International journal

    Hideharu Hagiya, Mitsunobu Mio, Tomoko Murase, Keiko Egawa, Yumi Kokumai, Taeko Uchida, Naoki Morimoto, Fumio Otsuka, Sumiko Shiota

    Journal of intensive care   1 ( 1 )   10 - 10   2013

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    Methicillin-resistant Staphylococcus aureus is still a great concern, and recognition of the carrier is essential for appropriate infection control in intensive care units. The utility of wet swab compared to dry swab as an intranasal screening test has not been well assessed yet. A comparative study of the wet and dry swab in its ability to detect the organism was performed against critically ill patients, and it was found that there were no statistically significant differences between the two different methods. The wet swab did not show increased sensitivity compared to dry one.

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  • Group A streptococcal meningitis in a patient with palmoplantar pustulosis. Reviewed

    Hideharu Hagiya, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   52 ( 23 )   2675 - 8   2013

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    A 64-year-old man with a 10-year history of palmoplantar pustulosis, a recent history of cranial surgery and a persistent upper airway infection presented with a high fever and deep coma. The patient was diagnosed with Group A Streptococcal meningitis and promptly treated with antibiotics. Although his general condition recovered well, sensorineural hearing loss and facial palsy remained. Group A Streptococcal meningitis is a rare condition, and its typical clinical picture and epidemiological features remain poorly understood. Physicians need to be more aware of this infection, which is extremely rare but frequently causes various complications and yields a high mortality.

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  • Disseminated gonococcal infection in an elderly Japanese man. Reviewed

    Hideharu Hagiya, Nobuhiko Onishi, Hirotaka Ebara, Yoshihisa Hanayama, Susumu Kokeguchi, Motoko Nose, Nobuchika Kusano, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   52 ( 23 )   2669 - 73   2013

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    We herein present the case of a 69-year-old Japanese man who had unprotected sexual contact with a local commercial sex worker in an East Asian country and was diagnosed as having disseminated gonococcal infection (DGI). The organism was confirmed to be Neisseria gonorrhoeae based on 16S rRNA sequencing and positive results for the cppB gene. This case indicates that a diagnosis of DGI should also be considered in elderly individuals. DGI potentially causes many complications, and the pathogen has recently been reported to be resistant to various antibiotics. Physicians must therefore pay more attention to the possible occurrence of DGI in various clinical settings.

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  • Ineffectiveness of daptomycin in the treatment of septic pulmonary emboli and persistent bacteremia caused by methicillin-resistant Staphylococcus aureus. Reviewed

    Hideharu Hagiya, Shingo Hagioka, Fumio Otsuka

    Internal medicine (Tokyo, Japan)   52 ( 22 )   2577 - 82   2013

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    A 73-year-old man with long-term food deprivation and total parenteral nutrition was diagnosed with septic pulmonary emboli (SPE) and a persistent bacteremia caused by central line-associated blood stream methicillin-resistant Staphylococcus aureus (MRSA) infection. Although daptomycin (DAP) failed to treat the persistent bacteremia, linezolid successfully controlled it. DAP is inactivated by lung surfactant, and therefore, it should not be administered for lower respiratory infections. However, SPE caused by MRSA has been reported to be treatable with DAP since it is an infection of the lung parenchyma. We herein report the lack of effect of daptomycin in SPE treatment.

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  • A comprehensive analysis of 174 febrile patients admitted to Okayama University Hospital. Reviewed

    Hiromasa Ryuko, Fumio Otsuka

    Acta medica Okayama   67 ( 4 )   227 - 37   2013

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    Primary care physicians often encounter patients with fever of unknown origin and without apparent causes. Recent advances in laboratory medicine have facilitated diagnostic procedures;however, it is still difficult to determine the critical febrile factor at an early stage. We reviewed the medical records of 174 patients who were admitted due to a chief complaint of fever (>37.5℃) to our hospital during the period from 2004 to 2010. The patients were categorized into patients with infection, inflammation, neoplasm and drug-induced fever. Based on the analysis done by category, it was revealed that the patient's age, body temperature and duration of fever were closely related to the final diagnosis. Serum CRP levels were significantly low in the nonbacterial infection group, while serum levels of sIL-2R were high in neoplasm and drug-induced cases. CRP level on admission was weakly but significantly correlated with body temperature, while duration of fever was inversely related to body temperature. The effectiveness of PET-CT and tissue biopsy for diagnosis was considerably high, particularly in the categories of neoplasm and nonspecific inflammation, respectively, though the effectiveness of bacterial culture was low. Thus, a careful review of physical and laboratory information including body temperature, CRP level, duration of fever, gender difference and history of medication is indispensable for diagnosis. Stepwise categorization and disease classification by comprehensive and systemic checkup are very helpful for determining the causes of fever.

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  • Multifunctional bone morphogenetic protein system in endocrinology.

    Fumio Otsuka

    Acta medica Okayama   67 ( 2 )   75 - 86   2013

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    New biological activities of bone morphogenetic proteins (BMPs) in the endocrine system have recently been revealed. The BMP system is composed of approximately 30 ligands and preferential combinations of type I and type II receptors. The BMP system not only induces bone formation but also plays unique tissue-specific roles in various organs. For instance, the ovarian BMP system is a physiological inhibitor of luteinization in growing ovarian follicles. In the ovary, the expression of oocyte-derived BMP-15 is critical for female reproduction. In the pituitary, BMP-4 is a key player for initial development of the anterior pituitary, while it is also functionally involved in some differentiated pituitary tumors, including prolactinoma and Cushing's disease. In the adrenal glands, BMP-6 and BMP-4 modulate aldosterone and catecholamine production, respectively, which contributes to a functional interaction between the cortex and medulla. In the present review, recent advances in BMP biology in the field of endocrinology are described and the possibility for clinical application of BMP activity is discussed.

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  • An in vivo role of bone morphogenetic protein-6 in aldosterone production by rat adrenal gland. Reviewed International journal

    Yoshinori Matsumoto, Fumio Otsuka, Kenichi Inagaki, Naoko Tsukamoto, Mariko Takano-Narazaki, Tomoko Miyoshi, Eri Nakamura, Kanako Ogura-Ochi, Masaya Takeda, Hirofumi Makino

    The Journal of steroid biochemistry and molecular biology   132 ( 1-2 )   8 - 14   2012.10

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    Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex. We previously reported the presence of a functional BMP system including BMP-6 in human adrenocortical cells. BMP-6 contributes to Ang II-induced aldosterone production by activating Smad signaling, in which endogenous BMP-6 action is negatively controlled by Ang II in vitro. In the present study, we examined the in vivo role of BMP-6 in regulation of aldosterone by neutralizing endogenous BMP-6 in rats treated with immunization against BMP-6. Three-week-old male rats were actively immunized with rat mature BMP-6 antigen conjugated with keyhole limpet hemocyanin (KLH). The immunization treatment had no effect on bilateral adrenal weight or its ratio to body weight. Urinary aldosterone excretion was time-dependently increased during the 8-week observation period in the control group. Of note, the level of urinary aldosterone excretion in BMP-6-KLH-immunized rats was significantly reduced compared to that in the control group, suggesting that endogenous BMP-6 contributes to the induction of aldosterone production in vivo. Moreover, the level of urinary aldosterone/creatinine after 8-week treatment was significantly lowered by treatment with BMP-6-KLH. In contrast, with chronic Ang II treatment, urinary aldosterone and creatinine-corrected values at 8 weeks were not significantly different between the two groups, suggesting that the effects of BMP-6-KLH were impaired under the condition of chronic treatment with Ang II. The mRNA levels of Cyp1162, but not those of Star, P450scc and 3 beta hsd2, were significantly decreased in adrenal tissues isolated from BMP-6-KLH-immunized rats after 8-week treatment. Furthermore, the ratio of plasma aldosterone level to corticosterone was significantly decreased by immunization with BMP-6-KLH. Collectively, the results indicate that endogenous BMP-6 is functionally linked to aldosterone synthesis by the zona glomerulosa in the adrenal cortex in vivo. (C) 2012 Elsevier Ltd. All rights reserved.

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  • Evaluation of weekly-reduction regimen of glucocorticoids in combination with cyclophosphamide for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis in Japanese patients. Reviewed International journal

    Yoshinori Matsumoto, Ken-Ei Sada, Fumio Otsuka, Mariko Takano, Noriko Toyota, Koichi Sugiyama, Hiroshi Wakabayashi, Tomoko Kawabata, Hirofumi Makino

    Rheumatology international   32 ( 10 )   2999 - 3005   2012.10

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    The current therapeutic regimen recommended by the European League against Rheumatism (EULAR) for anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is continuation of initially administered doses of glucocorticoids (GCs) in combination with cyclophosphamide (CYC) for 1 month followed by gradual tapering. Considering the adverse effects of GCs, another tapering regimen of GCs with CYC, which was characterized by tapering GCs weekly, was reported by the British Society of Rheumatology (weekly-reduction regimen). The aim of the present study is to evaluate the safety and efficacy of this weekly-reduction regimen for Japanese AAV patients in comparison with the monthly-reduction regimen recommended by the EULAR. We retrospectively reviewed medical records of adult patients newly diagnosed with AAV during the period from April 2000 to December 2010. The outcome measures were rates of remission, relapse, infection, and GC-induced diabetes mellitus during the first 12 months. Clinical data in the two groups and categorial variables with a possible relation to the outcomes were compared by using the t test and chi-square test, respectively. Twenty-four patients were enrolled in our study. All of the patients achieved remission, and the rates of relapse during the first 12 months were not statistically different between the two groups (P = 0.16). Patients treated with the weekly-reduction regimen were less liable to have infection (P = 0.03) and impaired glucose tolerance (P = 0.017), compared with those treated with the monthly-reduction regimen. A therapeutic strategy using the weekly-reduction regimen of GCs would be effective and would have fewer side effects than the monthly-reduction regimen.

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  • Pro-apoptotic effects of imatinib on PDGF-stimulated pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. International journal

    Kazufumi Nakamura, Satoshi Akagi, Aiko Ogawa, Kengo F Kusano, Hiromi Matsubara, Daiji Miura, Soichiro Fuke, Nobuhiro Nishii, Satoshi Nagase, Kunihisa Kohno, Hiroshi Morita, Takahiro Oto, Ryutaro Yamanaka, Fumio Otsuka, Aya Miura, Chikao Yutani, Tohru Ohe, Hiroshi Ito

    International journal of cardiology   159 ( 2 )   100 - 6   2012.8

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    BACKGROUND: Remodeling of the pulmonary artery by an inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) is problematic in the treatment of idiopathic pulmonary arterial hypertension (IPAH). Effective treatment that achieves reverse remodeling is required. The aim of this study was to assess the pro-apoptotic effects of imatinib, a platelet-derived growth factor (PDGF)-receptor tyrosine kinase inhibitor, on PASMCs obtained from patients with IPAH. METHODS: PASMCs were obtained from 8 patients with IPAH undergoing lung transplantation. Cellular proliferation was assessed by (3)H-thymidine incorporation. Pro-apoptotic effects of imatinib were examined using TUNEL and caspase-3,7 assays and using transmission electron microscopy. RESULTS: Treatment with imatinib (0.1 to 10 μg/mL) significantly inhibited PDGF-BB (10 ng/mL)-induced proliferation of PASMCs from IPAH patients. Imatinib (1 μg/mL) did not induce apoptosis in quiescent IPAH-PASMCs, but it had a pro-apoptotic effect on IPAH-PASMCs stimulated with PDGF-BB. Imatinib did not induce apoptosis in normal control PASMCs with or without PDGF-BB stimulation. PDGF-BB induced phosphorylation of Akt at 15 min, and Akt phosphorylation was inhibited by imatinib in IPAH-PASMCs. Akt-I-1/2 (1 μmol/L), an Akt inhibitor, in the presence of PDGF-BB significantly increased apoptotic cells compared with the control condition. Thus, Akt-I-1/2 could mimic the effects of imatinib on PASMCs. CONCLUSION: Imatinib has anti-proliferative and pro-apoptotic effects on IPAH-PASMCs stimulated with PDGF. The inhibitory effect of imatinib on Akt phosphorylation induced by PDGF plays an important role in the pro-apoptotic effect.

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  • Regulatory role of kit ligand-c-kit interaction and oocyte factors in steroidogenesis by rat granulosa cells. Reviewed International journal

    Tomoko Miyoshi, Fumio Otsuka, Eri Nakamura, Kenichi Inagaki, Kanako Ogura-Ochi, Naoko Tsukamoto, Masaya Takeda, Hirofumi Makino

    Molecular and cellular endocrinology   358 ( 1 )   18 - 26   2012.7

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    Although kit ligand (KL)-c-kit interaction is known to be critical for oogenesis and folliculogenesis, its role in ovarian steroidogenesis has yet to be elucidated. We studied the impact of KL-c-kit interaction in regulation of steroidogenesis using rat oocyte/granulosa cell co-culture. In the presence of oocytes, soluble KL suppressed FSH-induced estradiol production and aromatase mRNA expression without affecting FSH-induced progesterone production. The KL effect on steroidogenesis was interrupted by an anti-c-kit neutralizing antibody, suggesting that KL-c-kit interaction is involved in suppression of estrogen by granulosa cells through oocyte c-kit action. The cAMP-PKA pathway activity was not directly involved in the estrogen regulation by KL-c-kit action. It was of note that KL treatment increased the expression levels of oocyte-derived FGF-8, GDF-9 and BMP-6, while it reduced the expression levels of oocyte-derived BMP-15 in the oocyte-granulosa cell co-culture. Given the findings that FGF-8, but not GDF-9, BMP-6 or -15, suppressed FSH-induced estrogen production by granulosa cells, oocyte-derived FGF-8 is linked to suppression of FSH-induced estrogen production through the KL-c-kit interaction. Furthermore, the suppression of FSH-induced estrogen production by KL in the co-culture was reversed by a FGF receptor kinase inhibitor and the effect of the inhibitor was enhanced in combination with extracellular-domain protein of BMPRII, which interferes with BMP-15 and GDF-9 activities. Thus, the actions of endogenous oocyte factors including FGF-8 and BMP-15/GDF-9 were involved in the KL activity that inhibited FSH-induced estradiol production. Collectively, the results indicate that KL-c-kit interaction plays a role in estrogenic regulation through oocyte-granulosa cell communication. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

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  • Bone morphogenetic protein-3b (BMP-3b) inhibits osteoblast differentiation via Smad2/3 pathway by counteracting Smad1/5/8 signaling. Reviewed International journal

    Yoshinori Matsumoto, Fumio Otsuka, Jun Hino, Tomoko Miyoshi, Mariko Takano, Mikiya Miyazato, Hirofumi Makino, Kenji Kangawa

    Molecular and cellular endocrinology   350 ( 1 )   78 - 86   2012.3

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    Despite the involvement of BMP-3b (also called GDF-10) in osteogenesis, embryogenesis and adipogenesis, the functional receptors and intracellular signaling of BMP-3b have yet to be elucidated. In the present study, we investigated the cellular mechanism of BMP-3b in osteoblast differentiation using mouse myoblastic C2C12 cells. BMP-3b stimulated activin/TGF-β-responsive promoter activities. The stimulatory actions of BMP-3b on activin/TGF-β-responsive activities were suppressed by co-treatment with BMP-2. BMP-responsive promoter activities stimulated by BMP-2 were significantly inhibited by treatment with BMP-3b. BMP-3b suppressed the expression of osteoblastic markers including Runx2, osteocalcin and type-1 collagen induced by BMP-2, -4, -6 and -7. BMP-2-induced Smad1/5/8 phosphorylation and mRNA levels of the BMP target gene Id-1 were suppressed by co-treatment with BMP-3b, although BMP-3b failed to activate Smad1/5/8 signaling. Of interest, the BMP-3b suppression of BMP-2-induced Id-1 expression was not observed in cells overexpressing Smad4 molecules. On the other hand, BMP-3b directly activated Smad2/3 phosphorylation and activin/TGF-β target gene PAI-1 mRNA expression, while BMP-2 suppressed BMP-3b-induced Smad2/3 signal activation. BMP-2 inhibition of BMP-3b-induced PAI-1 expression was also reversed by overexpression of Smad4. Analysis using inhibitors for BMP-Smad1/5/8 pathways revealed that these BMP-3b effects were mediated via receptors other than ALK-2, -3 and -6. Furthermore, results of inhibitory studies using extracellular domains for BMP receptor constructs showed that the activity of BMP-3b was functionally facilitated by a combination of ALK-4 and ActRIIA. Collectively, BMP-3b plays an inhibitory role in the process of osteoblast differentiation, in which BMP-3b and BMP-2 are mutually antagonistic possibly by competing with the availability of Smad4.

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  • Enhanced expression of bone morphogenetic protein system in aldosterone-treated mouse kidneys. Reviewed International journal

    Jiro Suzuki, Fumio Otsuka, Yoshinori Matsumoto, Kenichi Inagaki, Tomoko Miyoshi, Masaya Takeda, Naoko Tsukamoto, Eri Nakamura, Kanako Ogura, Hirofumi Makino

    Hypertension research : official journal of the Japanese Society of Hypertension   35 ( 3 )   312 - 7   2012.3

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    Recent studies have shown that bone morphogenetic proteins (BMPs), particularly BMP-7, have an inhibitory role in the development of various renal diseases. We previously reported antagonistic effects of BMPs on renal mesangial cell proliferation induced by aldosterone (Aldo) in vitro. In the present study, we investigated in vivo roles of BMPs in Aldo-induced renal glomerular injury. BALB/c mice aged 6 weeks were treated with Aldo injection (5 mu g per day, intraperitoneally) and/or oral administration of high-salt (2%) water for 9 weeks. Systemic blood pressure, body weight, kidney weight and daily proteinuria were not significantly changed by Aldo and/or high-salt treatment. However, renal histological examination revealed increases in glomerular cellularity and glomerular diameter in the groups treated with Aldo injection and high-salt administration. Immunohistochemistry demonstrated expression of BMP-4 and -7 in the glomerular mesangial region. Aldo causes renal glomerular damage by stimulating mesangial cell proliferation and increasing extracellular matrix via the mineralocorticoid receptor (MR). MR messenger RNA (mRNA) expression in the renal cortex was transiently increased by 3-week treatment with Aldo and high-salt intake, but was decreased by 9-week treatment. Furthermore, the expression levels of BMP-4 and -7 mRNA were enhanced in the renal cortex treated with Aldo and high-salt administration. These findings suggest that the renal BMP system is activated by Aldo under the condition of high-salt exposure, which may have a key role in antagonizing glomerular damage in vivo. Hypertension Research (2012) 35, 312-317; doi:10.1038/hr.2011.186; published online 10 November 2011

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  • BMP action in the pituitary: its possible role in modulating somatostatin sensitivity in pituitary tumor cells. Reviewed International journal

    Fumio Otsuka, Naoko Tsukamoto, Tomoko Miyoshi, Yasumasa Iwasaki, Hirofumi Makino

    Molecular and cellular endocrinology   349 ( 2 )   105 - 10   2012.2

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    The existence of a functional bone morphogenetic protein (BMP) system in the pituitary has been recognized. Recent studies have provided evidence that BMPs elicit differential actions in the regulation of prolactin (PRL) and adrenocorticotropin (ACTH) release in lactotropinoma and corticotropinoma cells, respectively. BMPs play a key role in the modulation of somatostatin receptor (SSTR) sensitivity of lactosomatotrope cells in an autocrine/paracrine manner. In addition, SSTR action enhances BMP responsiveness in corticotrope cells. The functional link between BMP receptor signaling and SSTR actions may be crucial for individual tolerance to somatostatin analogs for controlling PRL and ACTH production. Adjustment of the endogenous SSTR sensitivity may be an effective strategy to inhibit the growth activity and hormonal productivity of intractable pituitary tumors.

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  • Interaction between gonadotropin-releasing hormone and bone morphogenetic protein-6 and -7 signaling in LβT2 gonadotrope cells. Reviewed International journal

    Masaya Takeda, Fumio Otsuka, Hiroaki Takahashi, Kenichi Inagaki, Tomoko Miyoshi, Naoko Tsukamoto, Hirofumi Makino, Mark A Lawson

    Molecular and cellular endocrinology   348 ( 1 )   147 - 54   2012.1

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    It is known that bone morphogenetic proteins (BMPs) regulate gonadotropin transcription and production by pituitary gonadotrope cells. However, the role of BMPs in gonadotropin-releasing hormone (GnRH)-induced FSH production remains uncertain. Here, we describe a functional link between BMP6 and BMP-7 signals and FSH transcriptional activity induced by GnRH using mouse gonadotrope L beta T2 cells. In L beta T2 cells, BMP-6 and BMP-7 increased mouse FSH beta-promoter activity in a concentration-dependent manner. The induction by BMP-6 and BMP-7 was inhibited by treatment with extracellular domains of ActRII but not BMPRII. These findings suggest that the type II receptor ActRII participates in BMP-induced FSH beta transcription regulation. Notably, BMP-6, but not BMP-7, enhanced GnRH-induced FSH beta-promoter activity in L beta T2 cells. Since GnRH stimulated MAPK phosphorylation in L beta T2 cells, a functional link between MAPK and FSH beta transcription was examined. Inhibition of the ERK pathway, but not that of p38 or SAPK/JNK signaling, suppressed GnRH-induced FSH beta transcription, suggesting that ERK is functionally involved in GnRH-induced FSH beta transcription. Co-treatment with BMP-7, but not with BMP-6, suppressed GnRH-induced MAPK phosphorylation in L beta T2 cells. Thus,, the difference between BMP-6 and BMP-7 in enhancing GnRH-induced FSH beta transcription may be due to the differential effects of BMP ligands on GnRH-induced ERK signaling. On the other hand, GnRH reduced Smad1/5/8 phosphorylation but increased Smad6/7 expression. These findings imply the presence of a functional link between GnRH action, MAPK signaling and the BMP system in pituitary gonadotropes for fine-tuning of FSH gene expression. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

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  • Peroxisome proliferator-activated receptor activity is involved in the osteoblastic differentiation regulated by bone morphogenetic proteins and tumor necrosis factor-α. Reviewed International journal

    Mariko Takano, Fumio Otsuka, Yoshinori Matsumoto, Kenichi Inagaki, Masaya Takeda, Eri Nakamura, Naoko Tsukamoto, Tomoko Miyoshi, Ken-ei Sada, Hirofumi Makino

    Molecular and cellular endocrinology   348 ( 1 )   224 - 32   2012.1

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    Recent studies have suggested possible adverse effects of thiazolidinediones on bone metabolism. However, the detailed mechanism by which the activity of PPAR affects bone formation has not been elucidated. Impaired osteoblastic function due to cytokines is critical for the progression of inflammatory bone diseases. In the present study, we investigated the cellular mechanism by which PPAR actions interact with osteoblast differentiation regulated by BMP and TNF-alpha using mouse myoblastic C2C12 cells. BMP-2 and -4 potently induced the expression of various bone differentiation markers including Runx2, osteocalcin, type-1 collagen and alkaline phosphatase (ALP) in C2C12 cells. When administered in combination with a PPAR alpha agonist (fenofibric acid) but not with a PPAR gamma agonist (pioglitazone), BMP-4 enhanced osteoblast differentiation through the activity of PPAR alpha. The osteoblastic changes induced by BMP-4 were readily suppressed by treatment with TNF-alpha. Interestingly, the activities of PPAR alpha and PPAR gamma agonists reversed the suppression by TNF-alpha of osteoblast differentiation induced by BMP-4. Furthermore, TNF-alpha-induced phosphorylation of MAPKs, NF kappa B, I kappa B and Stat pathways was inhibited in the presence of PPAR alpha and PPAR gamma agonists with reducing TNF-alpha receptor expression. In view of the finding that inhibition of SAPK/JNK. Stat and NF kappa B pathways reversed the TNF-alpha suppression of osteoblast differentiation, we conclude that these cascades are functionally involved in the actions of PPARs that antagonize TNF-alpha-induced suppression of osteoblast differentiation. It was further discovered that the PPAR alpha agonist enhanced BMP-4-induced Smad1/5/8 signaling through downregulation of inhibitory Smad6/7 expression, whereas the PPAR gamma agonist impaired this activity by suppressing BMPRII expression. On the other hand, BMPs increased the expression levels of PPAR alpha and PPAR gamma in the process of osteoblast differentiation. Thus, PPAR alpha actions promote BMP-induced osteoblast differentiation, while both activities of PPAR alpha and PPAR gamma suppress TNF-alpha actions. Collectively, our present data establishes that PPAR activities are functionally involved in modulating the interaction between the BMP system and TNF-alpha receptor signaling that is crucial for bone metabolism. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

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  • Mutual regulation of growth hormone and bone morphogenetic protein system in steroidogenesis by rat granulosa cells. Reviewed International journal

    Eri Nakamura, Fumio Otsuka, Kenichi Inagaki, Tomoko Miyoshi, Yoshinori Matsumoto, Kanako Ogura, Naoko Tsukamoto, Masaya Takeda, Hirofumi Makino

    Endocrinology   153 ( 1 )   469 - 80   2012.1

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    GH induces preantral follicle growth and differentiation with oocyte maturation. However, the effects of GH on ovarian steroidogenesis and the mechanisms underlying its effects have yet to be elucidated. In this study, we investigated the actions of GH on steroidogenesis by rat granulosa cells isolated from early antral follicles by focusing on the ovarian bone morphogenetic protein (BMP) system. We found that GH suppressed FSH-induced estradiol production with reduction in aromatase expression and, in contrast, GH increased FSH-induced progesterone level with induction of steroidogenic acute regulatory protein, side chain cleavage cytochrome P450, and 3 beta-hydroxysteroid dehydrogenase. The effects of GH on steroidogenesis by granulosa cells were enhanced in the presence of the BMP antagonist noggin. Coculture of GH with oocytes did not alter GH regulation of steroidogenesis. Steroid production induced by cAMP donors was not affected by GH treatment and the GH effects on FSH-induced steroid production were not accompanied by changes in cAMP synthesis, suggesting that GH actions were not directly mediated by the cAMP-protein kinase A pathway. GH exerted synergistic effects on MAPK activation elicited by FSH, which regulated FSH-induced steroidogenesis. In addition, GH-induced signal transducer and activator of transcription phosphorylation was involved in the induction of IGF-I expression. GH increased IGF-I, IGF-I receptor, and FSH receptor expression in granulosa cells, and inhibition of IGF-I signaling restored GH stimulation of FSH-induced progesterone production, suggesting that endogenous IGF-I is functionally involved in GH effects on progesterone induction. BMP inhibited IGF-I effects that increased FSH-induced estradiol production with suppression of expression of the GH/IGF-I system, whereas GH/IGF-I actions impaired BMP-Sma and Mad related protein 1/5/8 signaling through down-regulation of the expression of BMP receptors. Thus, GH acts to modulate estrogen and progesterone production differentially through endogenous IGF-I activity in granulosa cells, in which GH-IGF-I interaction leads to antagonization of BMP actions including suppression of FSH-induced progesterone production. Mutual balance between GH/IGF-I and BMP signal intensities may be a key for regulating gonadotropin-induced steroidogenesis in growing follicles. (Endocrinology 153: 469-480, 2012)

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  • Interactive Effects of Epidermal Growth Factor Receptor (EGFR) and Na+/Glucose Transporter 1 (SGLT-1) Inhibitors on Viability of Adrenocortical Tumor Cells.

    Takafumi Taguchi, Yasumasa Iwasaki, Mitsuru Nishiyama, Makoto Tsugita, Yoshinori Taniguchi, Mizuho Okazaki, Shuichi Nakayama, Toshihiro Takao, Fumio Otsuka, Yoshio Terada

    ENDOCRINE REVIEWS   31 ( 3 )   2010.6

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  • [Pulmonary arterial hypertension and BMP system abnormality].

    Fumio Otsuka

    Nihon rinsho. Japanese journal of clinical medicine   66 ( 11 )   2083 - 90   2008.11

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    Genetic analysis has uncovered that familial and idiopathic pulmonary arterial hypertension (PAH) is linked to germline mutations in BMP type II receptor (BMPRII). PAH is characterized by enhanced remodeling of pulmonary arteries due to arterial smooth muscle cell proliferation. BMPRII mutations contribute to abnormal mitotic responses to BMP ligands in pulmonary artery smooth muscle cells. Unbalanced Smad signaling induced by BMP and TGFbeta is functionally involved in the pathogenesis of PAH. BMPRII mutations also increase the susceptibility of endothelial cell apoptosis. The combination of increased endothelial injury and impaired suppression of smooth muscle cell proliferation is critical for the cellular pathogenesis of PAH. However, the detailed molecular mechanism leading to severe vascular remodeling caused by BMPRII mutations has yet to be elucidated.

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    Other Link: http://search.jamas.or.jp/link/ui/2008376655

  • Apparent mineralocorticoid excess manifested in an elderly patient with hypothyroidism. Reviewed International journal

    Kenichi Inagaki, Fumio Otsuka, Hiroyuki Otani, Chikage Sato, Tomoko Miyoshi, Toshio Ogura, Hirofumi Makino

    American journal of hypertension   20 ( 1 )   104 - 7   2007.1

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    The syndrome of apparent mineralocorticoid excess (AME) is characterized by persistent hypertension and hypokalemia, which is caused by impaired inactivation of cortisol (F) to cortisone (E). The thyroid hormone has been known to influence the F to E conversion leading to efficacious inactivation of F into E. However, there have been no reports regarding the clinical manifestation of secondary AME due to hypothyroidism. Here we report an elderly patient who manifested AME, showing persistent hypertension with hypokalemia induced by primary hypothyroidism. Maintenance of euthyroid conditions ameliorated the concurrent AME and restored adrenal secretion of aldosterone after the recovery of the F to E shuttle. This case report would broaden our clinical recognition regarding acquired AME in relation to thyroid dysfunction.

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  • [Primary pulmonary hypertension].

    Fumio Otsuka, Hirofumi Makino

    Nihon rinsho. Japanese journal of clinical medicine   63 Suppl 10   450 - 7   2005.10

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  • Differential effect of chronic inhibition of calcium channel and angiotensin II type 1-receptor on aldosterone synthesis in spontaneously hypertensive rats Reviewed

    F Otsuka, T Ogura, H Kataoka, M Kishida, M Takahashi, Y Mimura, T Yamauchi, H Makino

    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY   74 ( 3 )   125 - 136   2000.10

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    We have investigated the in vivo effect of chronic blockade of Ca2+-channels and angiotensin II type I (AT(1))-receptors on aldosterone (Aldo)-synthesis in the adrenal glands of spontaneously hypertensive rats (SHR). Male SHR were administered Ca2+-antagonist, amlodipine (10 mg/kg per day) or AT(1)-receptor-antagonist, TCV-116 (1 mg/kg per day) from 7 until 11 weeks of age. Systolic blood pressure (SBP) and heart rate (HR) were significantly higher in SHR than Wistar-Kyoto (WKY) rats. Both treatments resulted in equivalent and significant reduction in SEP in SHR. Aldo-secretion in SHR, which was significantly higher than in WKY rats, was profoundly suppressed by TCV-116 compared with amlodipine. Both treatments resulted in thickening of the tuna glomerulosa, which immunohistochemically contains Aldo, at the end of therapy. Competitive reverse transcription-polymerase chain reaction (RT-PCR) showed that CYP11A (P450scc) mRNA regulating the first step of Aldo-synthesis was significantly reduced from week 9 of age by amlodipine, and that CYP11A (P450aldo) mRNA regulating the last step of Aldo-synthesis was potently suppressed from 9 weeks of age by TCV-116. Our results indicate that chronic treatment with different antihypertensive agents directly modulates adrenocortical aldosterone synthesis in SHR in vivo via different mechanisms. (C) 2000 Elsevier Science Ltd. All rights reserved.

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  • Hiroo Hashimoto, Fumio Otsuka, Hiroko Yamasaki, Toru Okamoto, Tetsushi Aita, Norikuni Kawanaka, Masanaori Kawashima, Yoshitaka Morita, Naoki Kashihara, Masahiro Yamanura and Hirofumi Makino : A case manifesting systemic lupus erythematosus during the administration of bucillamine for rheumatoid Arthritis-Like symptoms.

    Clin. Rheumatol.   12   45-52   2000.1

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  • Toshio Ogura, Kazuo Tobe, Yukari Mimura, Fumio Otsuka, Takayoshi Yamauchi, Ayumi Imai, Chiaki Tsukamoto, Yoshiaki Iwasaki and Kazuharu Matsuura: Testosterone modulates serum leptin concentrations in a male patient with hypothalamic hypogonadism

    J. Endocrinol. Invest.   23   246-250   2000.1

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  • Fumio Otsuka, Zuxu Yao, Taek-hoo Lee, Shin Yamamoto, Gregory F. Erickson and Shunichi Shimasaki: Bone morphogenetic protein-15:identification of target cells and biological functions

    J. Biol. Chem.   275   39523-39528   2000.1

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