Faculty Profiles - OTSUKA Fumio

Papers - OTSUKA Fumio

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Markedly elevated serum level of presepsin in agranulocytosis with hematologic malignancy: A potential prognostic factor in a single-institution retrospective study after granulocyte transfusion. International journal

Takuya Fukumi, Keiko Fujii, Wataru Kitamura, Kazuhiro Ikeuchi, Naomi Asano, Akira Yamamoto, Hiroki Kobayashi, Takumi Kondo, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Ken-Ichi Matsuoka, Fumio Otsuka, Yoshinobu Maeda, Nobuharu Fujii

Laboratory medicine 2025.3

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

INTRODUCTION: No established criteria exist for assessing the effectiveness of granulocyte transfusion (GTX) or biomarkers for predicting fatal infections in neutropenia. This study aimed to assess whether a novel sepsis marker, presepsin (P-SEP), is a useful prognostic indicator during GTX. METHODS: We collected frozen serum from 8 patients who had undergone GTX between September 2022 and October 2023 and measured their P-SEP levels. We compared these results with clinical records and assessed the alterations before and after GTX and their association with prognosis. RESULTS: The post-transfusion neutrophil count increased in all cases. In 5 of 8 patients (62.5%), P-SEP levels were reduced 1 day after GTX. Pretransfusion P-SEP levels were statistically significantly lower in the group of patients who survived and overcame infection after transfusion (GTX-survived) than in the group of patients who did not survive (GTX-nonsurvived) (1493 pg/mL vs 6658 pg/mL, P =.04). Transfused cell counts and changes in P-SEP levels 1 day after GTX were better in the GTX-survived group than in the GTX-nonsurvived group, although the difference was not statistically significant. DISCUSSION: Presepsin is a biomarker that can be assessed in patients undergoing GTX for agranulocytosis. A clinically significant increase in P-SEP levels before GTX may indicate ineffective GTX and an unfavorable prognosis.

DOI： 10.1093/labmed/lmae118

Involvement of a Novel Variant of FGFR1 Detected in an Adult Patient with Kallmann Syndrome in Regulation of Gonadal Steroidogenesis. International journal

Yoshiaki Soejima, Yuki Otsuka, Marina Kawaguchi, Kohei Oguni, Koichiro Yamamoto, Yasuhiro Nakano, Miho Yasuda, Kazuki Tokumasu, Keigo Ueda, Kosei Hasegawa, Nahoko Iwata, Fumio Otsuka

International journal of molecular sciences 26 ( 6 ) 2025.3

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

Fibroblast growth factor receptor 1 (FGFR1), also known as KAL2, is a tyrosine kinase receptor, and variants of FGFR1 have been detected in patients with Kallmann syndrome (KS), which is a congenital developmental disorder characterized by central hypogonadism and anosmia. Herein, we report an adult case of KS with a novel variant of FGFR1. A middle-aged male was referred for a compression fracture of a lumbar vertebra. It was shown that he had severe osteoporosis, anosmia, gynecomastia, and a past history of operations for cryptorchidism. Endocrine workup using pituitary and gonadal stimulation tests revealed the presence of both primary and central hypogonadism. Genetic testing revealed a novel variant of FGFR1 (c.2197_2199dup, p.Met733dup). To identify the pathogenicity of the novel variant and the clinical significance for the gonads, we investigated the effects of the FGFR1 variant on the downstream signaling of FGFR1 and gonadal steroidogenesis by using human steroidogenic granulosa cells. It was revealed that the transfection of the variant gene significantly impaired FGFR1 signaling, detected through the downregulation of SPRY2, compared with that of the case of the forced expression of wild-type FGFR1, and that the existence of the variant gene apparently altered the expression of key steroidogenic factors, including StAR and aromatase, in the gonad. The results suggested that the novel variant of FGFR1 detected in the patient with KS was linked to the impairment of FGFR1 signaling, as well as the alteration of gonadal steroidogenesis, leading to the pathogenesis of latent primary hypogonadism.

DOI： 10.3390/ijms26062713

Is subclinical hypothyroidism associated with cardiovascular disease in the elderly? International journal

Koichiro Yamamoto, Yasuhiro Nakano, Yoshiaki Soejima, Atsuhito Suyama, Kohei Oguni, Kou Hasegawa, Fumio Otsuka

Endocrine connections 2025.3

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

Subclinical hypothyroidism (SCH) is diagnosed when thyroid function tests show that the serum thyrotropin (TSH) level is elevated and the serum free thyroxine (FT4) level is normal. SCH is mainly caused by Hashimoto's thyroiditis, the prevalence of which increases with aging. Recently, it has been revealed that SCH is associated with risk factors for cardiovascular diseases (CVDs), including atherosclerosis, dyslipidemia and hypertension, leading to cardiovascular morbidity and mortality. However, there are still controversies regarding the diagnosis and treatment of SCH in elderly patients. In this review, we present recent evidence regarding the relationship between SCH and CVD and treatment recommendations for SCH, especially in elderly patients. Studies have shown that SCH is associated with CVD and all-cause mortality. Patients aged less than 65 years showed significant associations of SCH with CVD risk and all-cause mortality, whereas patients aged 65 or older did not show such associations. It was shown that levothyroxine therapy was associated with lower all-cause mortality and cardiovascular mortality in younger SCH patients (<65-70 years) but not in SCH patients aged 65-70 years or older. In elderly SCH patients, levothyroxine treatment should be considered individually according to the patient's age, serum TSH level, hypothyroid symptoms, CVD risk, and other comorbidities. To further elucidate the impact of SCH on CVD in elderly patients, studies should be conducted using age-specific reference ranges of results of thyroid function tests, focusing on elderly patients, specific serum TSH levels, thyroid antibody status, and cardiovascular risk factors.

DOI： 10.1530/EC-24-0601

Course of General Fatigue in Patients with Post-COVID-19 Conditions Who Were Prescribed Hochuekkito: A Single-Center Exploratory Pilot Study. International journal

Kazuki Tokumasu, Nobuyoshi Matsuki, Yuki Otsuka, Yoko Sakamoto, Keigo Ueda, Yui Matsuda, Yasue Sakurada, Hiroyuki Honda, Yasuhiro Nakano, Toru Hasegawa, Ryosuke Takase, Daisuke Omura, Fumio Otsuka

Journal of clinical medicine 14 ( 4 ) 2025.2

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

Background: After the start of the COVID-19 pandemic, general fatigue in patients with long COVID and post-COVID-19 conditions (PCC) became a medical issue. Although there is a lack of evidence-based treatments, Kampo medicine (traditional Japanese medicine) has gained attention in Japan. At an outpatient clinic in Japan specializing in long COVID, 24% of all prescriptions were Kampo medicines, and 72% of Kampo medicine prescriptions were hochuekkito. However, there has been no prospective, quantitative study on the course of fatigue in patients with long COVID and PCC who were prescribed hochuekkito. The aim of this study was to clarify the course of fatigue in those patients. Methods: This study included patients aged 18 years or older with general fatigue who visited the long COVID specialized outpatient clinic at Okayama University Hospital and consented to participate after being prescribed hochuekkito. We reviewed the backgrounds of the patients, and we evaluated the patients' fatigue assessment scale in person or online. Results: Twenty patients were enrolled in this study from September to December in 2023. The average age of the patients was 42.9 years (SD: 15.8 years) and 12 patients (60%) were female. After hochuekkito administration, the fatigue assessment scale score decreased from 35.9 (SD: 5.9) at the initial visit to 31.2 (SD: 9.4) after 8 weeks, indicating a trend for improvement in fatigue (difference: 4.7; 95% CI: 0.5-8.9). Conclusions: A trend for improvement in fatigue was observed in patients with long COVID and PCC who were prescribed hochuekkito, indicating a potential benefit of hochuekkito for general fatigue in such patients. General fatigue in patients with long COVID or PCC can be classified as post-infectious fatigue syndrome and is considered a condition of qi deficiency in Kampo medicine, for which hochuekkito is appropriately indicated.

DOI： 10.3390/jcm14041391

Crowned Dens Syndrome Triggered by Dental Treatment. International journal

Satoru Morita, Yuki Otsuka, Yohei Masuda, Yoshiaki Soejima, Fumio Otsuka

Clinical case reports 13 ( 2 ) e70168 2025.2

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

Crowned dens syndrome (CDS) is an important yet often overlooked cause of fever and neck pain, frequently leading to unnecessary examinations and treatments and misdiagnosis as infectious diseases or rheumatic diseases. The mechanism of an acute attack of CDS is not clarified completely, while it is considered that severe systemic stress can trigger inflammation caused by calcium pyrophosphate crystals. We describe a case of CDS triggered by localized physical stress to the neck and emphasize the importance of considering this condition in cases of fever and neck pain following dental treatment.

DOI： 10.1002/ccr3.70168

Interrelationships Between Plasma Levels of Brain Natriuretic Peptide and Prolonged Symptoms Due to Long COVID. International journal

Yohei Masuda, Yuki Otsuka, Kazuki Tokumasu, Hiroyuki Honda, Yasue Sakurada, Yui Matsuda, Yasuhiro Nakano, Ryosuke Takase, Daisuke Omura, Toru Hasegawa, Keigo Ueda, Fumio Otsuka

Journal of clinical medicine 14 ( 3 ) 2025.1

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

Objectives: Evidence for the usefulness of biomarkers that aid in diagnosis, assessment of severity, and prediction of prognosis in patients with long COVID is limited. The aim of this study was to clarify the characteristics of brain natriuretic peptide (BNP) in long COVID. Methods: We conducted a retrospective observational study of patients who visited the COVID-19 aftercare outpatient clinic at Okayama University Hospital from February 2021 to April 2024. Results: A total of 428 patients were enrolled in this study, and the patients were divided into a group with normal BNP (n = 314, ≤18.4 pg/mL) and a group with increased BNP (n = 114, >18.4 pg/mL). The long COVID group with increased BNP had a higher proportion of females (44.3% vs. 73.7%, p < 0.01) and an older median age (38 vs. 51 years, p < 0.01). Fatigue and brain fog were commonly manifested in both groups, while dyspnea was a more frequent complaint in the group with increased BNP. Various symptoms including fatigue, palpitations, and taste and/or olfactory disorders were associated with elevated BNP (23 to 24 pg/mL). Memory impairment was also linked to higher BNP (OR: 2.36, p = 0.05). In long COVID patients, plasma BNP elevation appears to be more pronounced in females and is often related to cardiogenic factors, in which inflammatory responses are also involved. Conclusions: Plasma BNP measurement may be useful for evaluating the severity of long COVID, especially in female patients and those with respiratory symptoms and/or memory impairment.

DOI： 10.3390/jcm14030817

Efficacy in Japanese adults with growth hormone deficiency receiving weekly somapacitan or daily growth hormone: results from phase 3 REAL 1 trial. International journal

Fumio Otsuka, Michael Højby Rasmussen, Takaaki Endo, Claus Sværke, Shigeyuki Tahara, Gudmundur Johannsson

Frontiers in endocrinology 16 1534891 - 1534891 2025

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

INTRODUCTION: Somapacitan is a long-acting growth hormone (GH) derivative approved for once-weekly treatment of adult GH deficiency (AGHD). This study aimed to evaluate the efficacy and safety of somapacitan and daily GH in Japanese individuals with AGHD. METHODS: This subgroup study included the 34-week main period of the multinational, randomized, parallel-group, phase 3 trial, REAL 1 (NCT02229851). Participants received once-weekly somapacitan or daily GH (Norditropin®), both administered subcutaneously. Investigators and trial sites were blinded. A total of 36 Japanese GH-naïve individuals with AGHD were allocated to somapacitan or daily GH (excluding the placebo group of the global trial). Endpoints included change in truncal fat percentage to week 34 measured using dual-energy x-ray absorptiometry, as well as other body composition measures. Insulin-like growth factor I standard deviation score values were used for dose titration. RESULTS: In total, 36 Japanese individuals were included (18 and 18 in the somapacitan and daily GH group, respectively). 35 completed the main period (34 weeks). Mean (SD) change from baseline to week 34 in truncal fat percentage was -2.23 (2.50) %-points in the somapacitan group and -2.12 (4.21) %-points in the daily GH group. Other body composition measures also improved in both groups, including reduced visceral fat and increased lean body mass. Somapacitan was well tolerated, with a safety profile similar to daily GH. CONCLUSIONS: In Japanese treatment-naïve individuals with AGHD, once-weekly somapacitan demonstrated similar efficacy and safety to daily GH after 34 weeks of treatment. Somapacitan provides an effective alternative to daily GH in AGHD. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov, identifier NCT02229851.

DOI： 10.3389/fendo.2025.1534891

Clinical and microbiological characteristics of high-level daptomycin-resistant Corynebacterium species: A systematic scoping review. Reviewed International journal

Shinnosuke Fukushima, Hideharu Hagiya, Kazuyoshi Gotoh, Shuma Tsuji, Koji Iio, Hidemasa Akazawa, Osamu Matsushita, Fumio Otsuka

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 2024.12

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Corynebacterium species potentially develop high-level daptomycin resistance (HLDR) shortly after daptomycin (DAP) administration. We aimed to investigate the clinical and microbiological characteristics of HLDR Corynebacterium infections. METHODS: We first presented a clinical case accompanied by the results of a comprehensive genetic analysis of the isolate, and then performed a systematic scoping review. Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews, we searched for articles with related keywords, including "Corynebacterium", "Daptomycin", and "Resistance", in the MEDLINE and Web of Science databases from the database inception to October 25, 2024. Clinical case reports and research articles documenting the isolation of HLDR Corynebacterium species, defined by a minimum inhibitory concentration of DAP at ≥256 μg/mL, were deemed eligible for this review. RESULTS: Of 80 articles screened, seven case reports detailing eight cases of HLDR Corynebacterium infections, as well as five research articles, were included. C. striatum was the most common species (7/9 cases, 77.8%), and prosthetic device-associated infections accounted for 66.7% of the cases. Duration of DAP administration before the emergence of HLDR isolates ranged from 5 days to 3 months; three-quarters of the cases developed within 17 days. Three HLDR isolates were genetically confirmed to have an alteration in pgsA2. The majority of the patients were treated with either glycopeptides or linezolid, with favorable outcomes. In vitro experiments confirmed that C. striatum strains acquire the HLDR phenotype at higher rates (71% to 100%) within 24 hours of incubation, compared to other Corynebacterium strains CONCLUSION: DAP monotherapy, especially for prosthetic device-associated infections, can result in the development of HLDR Corynebacterium. Additional research is warranted to investigate the clinical implications of this potentially proliferating antimicrobial resistant pathogen.

DOI： 10.1016/j.jiac.2024.12.004

Clinical characteristics of female long COVID patients with menstrual symptoms: a retrospective study from a Japanese outpatient clinic. Reviewed International journal

Yasue Sakurada, Yui Matsuda, Kanon Motohashi, Toru Hasegawa, Yuki Otsuka, Yasuhiro Nakano, Kazuki Tokumasu, Koichiro Yamamoto, Naruhiko Sunada, Hiroyuki Honda, Hideharu Hagiya, Keigo Ueda, Fumio Otsuka

Journal of psychosomatic obstetrics and gynaecology 45 ( 1 ) 2305899 - 2305899 2024.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To elucidate the impact of long COVID on menstruation and mental health, medical records of patients with long COVID were evaluated. METHODS: Symptoms of long COVID, QOL, mental health, and related endocrine data were compared between two groups with and without menstrual disturbances. RESULTS: Of 349 female patients who visited our clinic between February 2021 and March 2023, 223 patients with long COVID (aged 18-50 years) were included. Forty-four (19.7%) of the patients had menstrual symptoms associated with long COVID. The patients with menstrual symptoms were older than those without menstrual symptoms (42.5 vs. 38 years). The percentage of patients with menstrual symptoms was higher during the Omicron phase (24%) than during the Preceding (13%) and Delta (12%) phases. Cycle irregularity was the most frequent (in 63.6% of the patients), followed by severe pain (25%), heavy bleeding (20.5%), perimenopausal symptoms (18.2%), and premenstrual syndrome (15.9%). Fatigue and depression were the most frequent complications. Scores for fatigue and for QOL were significantly worse in long COVID patients with menstrual symptoms. Results of endocrine examinations showed significantly increased cortisol levels in patients with menstrual complaints. CONCLUSION: Long COVID has an impact on menstrual conditions and on QOL related to menstrual conditions.

DOI： 10.1080/0167482X.2024.2305899

Oral calcium supplementation versus placebo in mitigating citrate reactions during apheresis: an open-label randomized control trial

Masaya Abe, Keiko Fujii, Nobuharu Fujii, Toshiharu Mitsuhashi, Takuya Fukumi, Yuichi Sumii, Maiko Kimura, Tomohiro Urata, Takumi Kondo, Fumio Otsuka, Yoshinobu Maeda

Hematology, Transfusion and Cell Therapy 2024.12

圧迫骨折と女性化乳房を契機に精査し、AGHDを合併した新規KAL2バリアントによるKallmann症候群と診断しえた1例

副島佳晃, 大塚勇輝, 川口満理奈, 大國皓平, 中野靖浩, 安田美帆, 徳増一樹, 植田圭吾, 長谷川高誠, 大塚文男

日本内分泌学会雑誌 100 ( 4 ) 1077 - 1077 2024.12

全身倦怠感を契機に発見され、可逆性の下垂体機能低下を呈した神経梅毒の1例

大國皓平, 中野靖浩, 副島佳晃, 須山敦仁, 山本紘一郎, 安田美帆, 長谷川功, 大塚文男

日本内分泌学会雑誌 100 ( 4 ) 1078 - 1078 2024.12

Clinical Characteristics of Persistent Hypophosphatasemia Uncovered in Adult Patients: A Retrospective Study at a Japanese Tertiary Hospital. Reviewed International journal

Shintaro Fujiwara, Yuki Otsuka, Masanori Furukawa, Akihito Higashikage, Fumio Otsuka

Journal of clinical medicine 13 ( 23 ) 2024.11

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Background: Hypophosphatasemia is often overlooked despite its potential to indicate underlying pathologies. The aim of this study was to determine the prevalence of persistent hypophosphatasemia in a large, urban, multi-specialty hospital population and characterize the clinical and laboratory findings in adult patients with this condition. Methods: In this retrospective observational study, the results of 424,434 alkaline phosphatase (ALP) tests in 50,136 patients aged ≥18 years that were performed at Okayama University Hospital between July 2020 and October 2023 were analyzed. Persistent hypophosphatasemia was defined as consistently low ALP levels (≤40 IU/L) for 28 days with a minimum recorded level of ≤35 IU/L. Results: Persistent hypophosphatasemia was detected in 273 patients (0.54% of the tested patients), and the patients with persistent hypophosphatasemia included a higher proportion of females (72.5% vs. 52.9% in the people without persistent hypophosphatasemia; chi-squared test, p < 0.01) and had a younger median age (51 years vs. 63 years; Mann-Whitney U test, p < 0.01) than those in the overall tested population. The common causes of persistent hypophosphatasemia were cancer (30%), glucocorticoid use (21%), and immunosuppressants (16%). Notably, 38 patients (14%) had no apparent cause for low ALP values. These patients were categorized on the basis of their clinical characteristics, with some patients presenting symptoms potentially related to adult hypophosphatasia. Conclusions: This study provides prevalence and insights into the causes and characteristics of persistent hypophosphatasemia in a Japanese tertiary care setting. While most cases were associated with known causes, patients with unexplained hypophosphatasemia and symptoms such as chronic pain, muscle weakness, and general fatigue could have adult hypophosphatasia. In such cases, comprehensive evaluation and further investigation for hypophosphatasia should be considered. Persistent hypophosphatasemia of undetermined etiology could be a crucial initial step in diagnostic algorithms for this condition.

DOI： 10.3390/jcm13237078

Human Papillomavirus vaccination awareness and uptake among healthcare students in Japan. Reviewed International journal

Madoka Shimbe, Yuki Otsuka, Hideharu Hagiya, Yoichi Yamada, Fumio Otsuka

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 2024.11

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The vaccination rate for HPV (Human Papillomavirus) has remained significantly low in Japan because of the administrative suspension of active recommendation. This study investigates the awareness and uptake of the HPV vaccine among healthcare students in Japan following the reinstatement of active recommendation for young women in April 2022. METHODS: A web-based survey was administered to 2567 healthcare students from Okayama and Shujitsu Universities in Japan in July 2023. The survey assessed participants' backgrounds, immunization status, awareness of vaccine recommendations, and knowledge of cervical cancer across various demographics, including sex, academic year, and department (Medicine, Health Science, Pharmaceutical, and Dentistry). RESULTS: The response rate was 36.3 % (933 students; 181 male, 739 female, and 13 unspecified gender). The overall immunization rate among female students was 55.6 %, with higher rates observed in medical (73.8 %) and dental (63.0 %) students. Awareness of the government's change in vaccine recommendation was notably high among female and senior male students. Over half of the female students (54.7 %) reported receiving vaccinations based on their parents' advice. Among those unvaccinated but interested in future immunization, concerns about adverse reactions (47.4 %) and challenges in scheduling vaccinations (29.1 %) were predominant. CONCLUSION: Healthcare students exhibited a higher HPV vaccination rate than the general population. Ongoing education to improve vaccine literacy is crucial for augmenting HPV vaccination rates in Japan.

DOI： 10.1016/j.jiac.2024.11.004

ブロスマブを高用量かつ長期投与中の腫瘍性骨軟化症の1例

中野靖浩, 越智可奈子, 山本紘一郎, 須山敦仁, 副島佳晃, 大國皓平, 長谷川功, 大塚文男

日本内分泌学会雑誌 100 ( 2 ) 678 - 678 2024.10

一過性の縮小を呈し悪性リンパ腫が疑われた左副腎偶発腫の1例

佐住洋祐, 中野靖浩, 加藤篤之, 須山敦仁, 大國皓平, 山本紘一郎, 安田美帆, 越智可奈子, 長谷川功, 本多寛之, 川合裕也, 藤井伸治, 大塚文男

日本内分泌学会雑誌 100 ( 2 ) 607 - 607 2024.10

Threat of MRSA bacteremia still matters: a propensity score matching analysis. Reviewed International journal

Shinnosuke Fukushima, Hideharu Hagiya, Naoki Kuninaga, Yuto Haruki, Haruto Yamada, Yoshitaka Iwamoto, Masayo Yoshida, Kota Sato, Yoshihisa Hanayama, Shuichi Tanaka, Tomoko Miyoshi, Yuki Otsuka, Keigo Ueda, Fumio Otsuka

Infection 2024.9

Trends in adverse effects of medical treatment in Paediatric populations in the United States: A global burden of disease study, 2000–2019 Reviewed

Shintaro Fujiwara, Emily Leibovitch, Ko Harada, Yoshito Nishimura, Russell Woo, Fumio Otsuka, Akshaya Srikanth Bhagavathula

Paediatric and Perinatal Epidemiology 2024.9

Publishing type：Research paper (scientific journal) Publisher：Wiley

Abstract

Background

Adverse effects of medical treatment (AEMT) pose significant risks to paediatric patients. However, the mortality trends associated with AEMT in this population have been unclear.

Objective

We aimed to clarify the trends in the incidence, disability‐adjusted life years (DALYs) and mortality rates of AEMT for children in the US from 2000 to 2019.

Methods

Data were retrieved from the Global Burden of Disease study 2019. We estimated age‐standardized incidence, DALYs and mortality rates of paediatric AEMT per 100,000 children in the US using a Bayesian meta‐regression model. We also analysed incidence, DALYs and mortality in different age groups, and employed Joinpoint regression models to assess the age‐ and sex‐specific trends.

Results

The number of deaths due to AEMT in children, the number of cases, and DALYs were 105.1, 551,076 and 145,555 in 2019, decreased by 37.5%, 6% and 28% from those in 2000, respectively. Age‐standardized mortality rates decreased across all age groups, while the incidence increased across all age groups with an average annual percentage change (AAPC) of 2.2% in those children <1 year and 4.5% in 5–9 years of age. The increases in DALYs over time was higher in children aged 1–4 years (AAPC: 0.51, 95% CI: 0.47, 0.62) and 5–9 years (AAPC: 0.33, 95% CI: 0.15, 0.50), with the 1–4 year age group being the highest.

Conclusion

The study reveals declining AEMT mortality but rising incidence and DALYs, emphasizing a disproportionate burden in <1, 1–4 and 5–9 years. To develop effective mitigation strategies, future research is warranted to identify the causes of increased AEMT in children, especially young males.

DOI： 10.1111/ppe.13116

A Case of Systemic Lupus Erythematosus Initially Presenting as Lupus Enteritis Triggered by Pregnancy Reviewed

Tomoko Miyoshi, Fumio Otsuka

JOURNAL OF HOSPITAL GENERAL MEDICINE 6 ( 6 ) 154 - 157 2024.9

COVID-19罹患後症状の女性患者にみられる月経異常とストレスの関係

櫻田泰江, 松田祐依, 長谷川徹, 大塚勇輝, 中野靖浩, 徳増一樹, 砂田匠彦, 本橋花音, 本多寛之, 植田圭吾, 大塚文男

日本病院総合診療医学会雑誌 20 ( 臨増2 ) 263 - 263 2024.9

出血性脳梗塞,肺塞栓,深部静脈血栓症を合併したCOVID-19の1例

長谷川功, 山本紘一郎, 中本健太, 平佑貴, 庵谷紘美, 中野靖浩, 萩谷英大, 大塚文男

日本病院総合診療医学会雑誌 20 ( 5 ) 289 - 294 2024.9

Language：Japanese Publisher：(一社)日本病院総合診療医学会

52歳男性。COVID-19発症7日後に経皮的動脈血酸素飽和度94%(リザーバー10L/分投与下),右眼球共同偏倚と左半側空間無視,左上下肢完全麻痺をきたし搬送された。単純CTでは頭部で右中大脳動脈領域低吸収域を認め,胸部では両側広範囲の末梢優位のすりガラス影を認めた。造影CTでは右下肺動脈と左大腿静脈・膝窩静脈に血栓を認め,脳梗塞と肺塞栓症・深部静脈血栓症を合併した重症COVID-19と診断した。経過中に出血性脳梗塞を発症するも救命し得た。脳梗塞・肺塞栓を合併したCOVID-19では出血性脳梗塞の発症を念頭に慎重なフォローが必要である。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J05937&link_issn=&doc_id=20241218260009&doc_link_id=10.60227%2Fjhgmwabun.20.5_289&url=https%3A%2F%2Fdoi.org%2F10.60227%2Fjhgmwabun.20.5_289&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

COVID-19罹患後症状の患者における就労状況への影響

松田祐依, 櫻田泰江, 大塚勇輝, 徳増一樹, 中野靖浩, 砂田匠彦, 本多寛之, 長谷川徹, 高瀬了輔, 大村大輔, 植田圭吾, 大塚文男

日本病院総合診療医学会雑誌 20 ( 臨増2 ) 263 - 263 2024.9

Cryptococcal prostatitis in an immunocompromised patient with tocilizumab and glucocorticoid therapy: A case report. Reviewed International journal

Kohei Oguni, Shinnosuke Fukushima, Hideharu Hagiya, Atsushi Kato, Atsuhito Suyama, Takehiro Iwata, Yoshia Miyawaki, Sawako Ono, Koji Iio, Fumio Otsuka

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 2024.8

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

Cryptococcus prostatitis is an uncommon manifestation of cryptococcal infection that occurs mostly in immunocompromised patients. Tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, has been associated with an increased risk of cryptococcal infections. However, there have been no documented cases of cryptococcal prostatitis in patients receiving tocilizumab therapy. We report a case of cryptococcal prostatitis in a 72-year-old man treated with glucocorticoids and tocilizumab for giant cell arteritis and granulomatosis with polyangiitis. The patient presented dysuria and his serum level of prostate-specific antigen was elevated. Magnetic resonance imaging revealed a prostate mass, and a prostate biopsy was performed, leading to a pathologic diagnosis of cryptococcal prostatitis. Fungal cultures for blood and urine were negative, while the cryptococcal antigen for both serum and urine showed positive results. There were no particular findings in the pulmonary and central nervous systems. The patient was successfully treated with oral fluconazole (400 mg/day) and was discharged. Although cryptococcal prostatitis is a rare entity, clinicians should note that an immunosuppressed patient may develop such a difficult-to-diagnose disease.

DOI： 10.1016/j.jiac.2024.08.009

Postgraduate Year Two Medical Residents' Awareness of Personal Development as a Physician during the Management of Inpatients: A Qualitative Study. Reviewed International journal

Kazuki Tokumasu, Haruo Obara, Takanobu Hirosawa, Hiroko Ogawa, Fumio Otsuka

Healthcare (Basel, Switzerland) 12 ( 16 ) 2024.8

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

Clinical experiences, helping relationships, and reflection are key factors for personal development for physicians. However, few studies have shown which experiences are important for personal growth and how medical residents specifically use their experiences for personal growth. The aim of this study was to identify from the medical residents' perspective which clinical experiences contribute to their personal development. We employed a qualitative design, conducting semi-structured interviews with ten postgraduate year two medical residents at a Japanese teaching hospital. The interviews were transcribed in interview memos, anonymized, and subjected to reflective thematic analysis to generate themes relevant to personal and professional development. Successful clinical experiences with autonomy and responsibility in clinical management were shown to be essential points for personal development as a physician. Autonomy in this study was the attitude of making one's own choices when managing patients. Responsibility was the obligation of the resident to take charge of a patient. Instructing junior trainees, appreciation received from patients, and approval granted by attending physicians reinforced their feelings of personal growth. The realization of what experiences and concepts influence medical residents' personal growth and development will make their professional development more effective.

DOI： 10.3390/healthcare12161621

Effectiveness of Sensing Gloves-Applied Virtual Reality Education System on Hand Hygiene Practice: A Randomised Controlled Trial. Reviewed International journal

Mahiro Izumi, Hideharu Hagiya, Yuki Otsuka, Yoshiaki Soejima, Shinnosuke Fukushima, Mitsunobu Shibata, Satoshi Hirota, Toshihiro Koyama, Fumio Otsuka, Akio Gofuku

American journal of infection control 2024.8

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

INTRODUCTION: We developed a virtual reality (VR) education system and evaluated its clinical utility for promoting hand hygiene practices. METHODS: This prospective, two-week, randomised controlled study conducted at Okayama University Hospital, Japan, from November 2023 to January 2024, involved 22 participants (18 medical students and four residents). A fully immersive 360° VR system (VIVE Pro Eye) using a head-mounted display and sensing gloves was used to develop three healthcare tasks in a virtual patient room-Environmental Cleaning, Gauze Exchange, and Urine Collection. After monitoring all participants' baseline usage data of portable hand-rubbing alcohol in the first week, we randomly assigned them into 1:1 groups (VR training and video lecture groups). The primary outcome was differences in hand-rubbed alcohol use before and after intervention. RESULTS: Before the intervention, alcohol use did not significantly differ between both groups. After the intervention, a significant increase in alcohol use was observed in the VR training group (median: 8.2 g vs. 16.2 g; p=0.019) but not in the video lecture group. CONCLUSION: Our immersive 360° VR education system enhanced hand hygiene practices. Infection prevention and control practitioners and digital technology experts must collaborate to advance the development of superior educational devices and content.

DOI： 10.1016/j.ajic.2024.08.003

Clinical and endocrine features of orthostatic intolerance detected in patients with long COVID. Reviewed International journal

Atsushi Kato, Kazuki Tokumasu, Koichiro Yamamoto, Yuki Otsuka, Yasuhiro Nakano, Hiroyuki Honda, Naruhiko Sunada, Yasue Sakurada, Yui Matsuda, Toru Hasegawa, Ryosuke Takase, Keigo Ueda, Fumio Otsuka

Scientific reports 14 ( 1 ) 17025 - 17025 2024.7

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Orthostatic intolerance (OI) is a key symptom of long COVID; however, the pathophysiology remains unknown. Among 688 long COVID patients who visited our clinic during the period from February 2021 to April 2023, 86 patients who were suspected of having OI and who underwent an active standing test (ST) were investigated to elucidate the clinical characteristics of OI in patients with long COVID. Of the 86 patients, 33 patients (38%) were ST-positive. Nausea and tachycardia in daily life were frequent complaints in the ST-positive group. The increase in heart rate (HR) during the ST was significantly greater during a 10-min period after standing in the ST-positive group (+ 30 bpm) than in the ST-negative group (+ 16 bpm). The initial increase in diastolic blood pressure (DBP) just after standing was significantly greater in the ST-positive group (+ 14 mmHg) than in the ST-negative group (+ 9 mmHg). Serum cortisol levels in the ST-positive patients aged over 20 years were higher and growth hormone levels in the patients under 20 years of age were lower than those in the ST-negative group. Autonomous nervous symptoms, transient DBP rise with increasing HR after standing, and endocrine dysfunctions are helpful for detecting OI related to long COVID.

DOI： 10.1038/s41598-024-67815-y

New Delhi Metallo-Beta-Lactamase Inhibitors: A Systematic Scoping Review. Reviewed International journal

Lutfun Nahar, Hideharu Hagiya, Kazuyoshi Gotoh, Md Asaduzzaman, Fumio Otsuka

Journal of clinical medicine 13 ( 14 ) 2024.7

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

Background/Objectives: Among various carbapenemases, New Delhi metallo-beta-lactamases (NDMs) are recognized as the most powerful type capable of hydrolyzing all beta-lactam antibiotics, often conferring multi-drug resistance to the microorganism. The objective of this review is to synthesize current scientific data on NDM inhibitors to facilitate the development of future therapeutics for challenging-to-treat pathogens. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews, we conducted a MEDLINE search for articles with relevant keywords from the beginning of 2009 to December 2022. We employed various generic terms to encompass all the literature ever published on potential NDM inhibitors. Results: Out of the 1760 articles identified through the database search, 91 met the eligibility criteria and were included in our analysis. The fractional inhibitory concentration index was assessed using the checkerboard assay for 47 compounds in 37 articles, which included 8 compounds already approved by the Food and Drug Administration (FDA) of the United States. Time-killing curve assays (14 studies, 25%), kinetic assays (15 studies, 40.5%), molecular investigations (25 studies, 67.6%), in vivo studies (14 studies, 37.8%), and toxicity assays (13 studies, 35.1%) were also conducted to strengthen the laboratory-level evidence of the potential inhibitors. None of them appeared to have been applied to human infections. Conclusions: Ongoing research efforts have identified several potential NDM inhibitors; however, there are currently no clinically applicable drugs. To address this, we must foster interdisciplinary and multifaceted collaborations by broadening our own horizons.

DOI： 10.3390/jcm13144199

Reliability and Validity of the Japanese Version of the Fatigue Assessment Scale. Reviewed

Kazuki Tokumasu, Nobuyoshi Matsuki, Hirohisa Fujikawa, Yoko Sakamoto, Fumio Otsuka

Internal medicine (Tokyo, Japan) 2024.7

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

Objective General fatigue is one of the most frequent chief complaints in primary care, and an accurate assessment of fatigue has a direct impact on a patient's quality of life and treatment decisions. The Fatigue Assessment Scale (FAS), a measure of general fatigue, is useful for assessing fatigue in diverse cultures and diseases. However, there has been no study showing the reliability and validity of the scale in the Japanese context. The present study assessed the reliability and validity of the Japanese version of the FAS. Methods This study was conducted on 649 patients with long COVID who had a high frequency of general fatigue. To test the structural validity of the FAS, the patients were randomly divided into two groups: one in which an exploratory factor analysis (EFA) was conducted and one in which a confirmatory factor analysis (CFA) was conducted. Cronbach's alpha was calculated to assess internal consistency reliability. Results As 58 patients had missing values, we analyzed the data of 591 patients. The EFA led to an FAS comprising two factors. The CFA showed an acceptable fit for this two-factor model. The internal consistency was found to be good (Cronbach's alpha =0.89). Conclusion This study verified the structural validity and internal consistency and reliability of the Japanese version of the FAS. The results indicate that the Japanese version of the FAS is useful for assessing general fatigue in patients with long COVID in Japan.

DOI： 10.2169/internalmedicine.4101-24

Importance of Blood Glucose Measurement for Predicting the Prognosis of Long COVID: A Retrospective Study in Japan. Reviewed International journal

Sho Yokoyama, Hiroyuki Honda, Yuki Otsuka, Kazuki Tokumasu, Yasuhiro Nakano, Yasue Sakurada, Yui Matsuda, Naruhiko Sunada, Toru Hasegawa, Ryosuke Takase, Daisuke Omura, Yoshiaki Soejima, Keigo Ueda, Masayuki Kishida, Fumio Otsuka

Journal of clinical medicine 13 ( 14 ) 2024.7

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Purpose: The present study aimed to clarify the effects of a hyperglycemic condition on the clinical consequences of long COVID. Methods: Among 643 patients who visited the outpatient clinic of our hospital from February 2021 to September 2023, long COVID patients were classified into a hyperglycemic (HG) group with casual blood glucose levels above 140 mg/dL and a normoglycemic (NG) group. The patients' backgrounds, clinical symptoms, health status including the QOL evaluation scale (EQ-5D-5L), self-rating depression scale (SDS), and F-scale questionnaire (FSSG), blood test data, and recovery periods were analyzed. Results: The NG group included 607 patients with long COVID and the HG group included 36 patients with long COVID. Patients in the HG group were older than those in the NG group (55 vs. 41 years; p < 0.001) and included a larger percentage of males (67% vs. 44%; p = 0.009). The HG group had a larger percentage of patients with moderate-to-severe conditions in the acute infection phase (28% vs. 12%; p = 0.008), a higher BMI (25 vs. 22 kg/m2; p < 0.001), higher blood pressure (138/81 vs. 122/72 mmHg; p < 0.001), and a larger percentage of patients with an alcohol drinking habit (53% vs. 34%; p = 0.031). Long COVID symptoms and self-rated scales were not differed between the two groups; however, the laboratory data showed that liver and renal functions and metabolic data were significantly worse in the HG group. Although there was no apparent difference between the two groups in duration from the infection to the first visit, the HG group had a significantly longer period of recovery from long COVID (median period of 421 vs. 294 days; p = 0.019). Conclusion: A hyperglycemic state associated with other lifestyle-related diseases is associated with the prolongation of recovery from long COVID.

DOI： 10.3390/jcm13144099

学生視点から得られた岡山大学病院総合内科・総合診療科における臨床実習教育の気づき質的研究

山本幸近, 徳増一樹, 大塚文男

医学教育 55 ( Suppl. ) 231 - 231 2024.7

コロナ禍における医学生のストレス知覚についての研究対面とオンラインのコミュニケーションによる違い(Medical students' stress perception on in-person/online communication during the COVID-19 pandemic)

徳増一樹, 西村義人, 坂本陽子, 小比賀美香子, 片岡仁美, 大塚文男

医学教育 55 ( Suppl. ) 223 - 223 2024.7

漢方医学への学習意欲向上プロセスの探索混合研究(Exploring the process of motivation for learning about Kampo medicine: A mixed method study)

徳増一樹, 植田圭吾, 松田祐依, 大塚勇輝, 川口満理奈, 大塚文男

医学教育 55 ( Suppl. ) 222 - 222 2024.7

医学生の医療面接における表情解析AIを用いた検討

越智可奈子, 三好智子, 大塚勇輝, 小崎吉訓, 山下範之, 伊野英男, 大塚文男

医学教育 55 ( Suppl. ) 292 - 292 2024.7

Changes in Working Situations of Employed Long COVID Patients: Retrospective Study in Japanese Outpatient Clinic. Reviewed International journal

Yui Matsuda, Yasue Sakurada, Yuki Otsuka, Kazuki Tokumasu, Yasuhiro Nakano, Naruhiko Sunada, Hiroyuki Honda, Toru Hasegawa, Ryosuke Takase, Daisuke Omura, Keigo Ueda, Fumio Otsuka

Journal of clinical medicine 13 ( 13 ) 2024.6

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Purpose: The present study aimed to uncover the impact of long COVID on the working situations of Japanese patients. Methods: Changes in the working situations of the patients who visited our long COVID clinic were evaluated from medical records for the aspects of physical status, quality of life (QOL), and mental conditions. Results: Of 846 long COVID patients who visited our clinic from February 2021 to December 2023, 545 employed patients aged between 18 and 65 years were included in this study. A total of 295 patients (54.1%) with long COVID (median age: 43 years, female: 55.6%) experienced changes in their working status. Those patients included 220 patients (40.4%) who took a leave of absence, 53 patients (9.7%) who retired, and 22 patients (4%) with reduced working hours. Most of the patients (93.2%) with changes in working conditions had mild disease severity in the acute phase of COVID-19. The majority of those patients with mild disease severity (58.8%) were infected in the Omicron-variant phase and included 65.3% of the female patients. The major symptoms in long COVID patients who had changes in their working situations were fatigue, insomnia, headache, and dyspnea. Scores indicating fatigue and QOL were worsened in long COVID patients who had changes in their working situations. In addition, 63.7% of the long COVID patients with changes in their working situations had decreases in their incomes. Conclusions: Changes in the working situation of long COVID patients who were employed had a negative impact on the maintenance of their QOL.

DOI： 10.3390/jcm13133809

Evaluation of ChatGPT-Generated Differential Diagnosis for Common Diseases With Atypical Presentation: Descriptive Research Reviewed

Kiyoshi Shikino, Taro Shimizu, Yuki Otsuka, Masaki Tago, Hiromizu Takahashi, Takashi Watari, Yosuke Sasaki, Gemmei Iizuka, Hiroki Tamura, Koichi Nakashima, Kotaro Kunitomo, Morika Suzuki, Sayaka Aoyama, Shintaro Kosaka, Teiko Kawahigashi, Tomohiro Matsumoto, Fumina Orihara, Toru Morikawa, Toshinori Nishizawa, Yoji Hoshina, Yu Yamamoto, Yuichiro Matsuo, Yuto Unoki, Hirofumi Kimura, Midori Tokushima, Satoshi Watanuki, Takuma Saito, Fumio Otsuka, Yasuharu Tokuda

JMIR Medical Education 10 e58758 - e58758 2024.6

Publishing type：Research paper (scientific journal) Publisher：JMIR Publications Inc.

Abstract

Background

The persistence of diagnostic errors, despite advances in medical knowledge and diagnostics, highlights the importance of understanding atypical disease presentations and their contribution to mortality and morbidity. Artificial intelligence (AI), particularly generative pre-trained transformers like GPT-4, holds promise for improving diagnostic accuracy, but requires further exploration in handling atypical presentations.

Objective

This study aimed to assess the diagnostic accuracy of ChatGPT in generating differential diagnoses for atypical presentations of common diseases, with a focus on the model’s reliance on patient history during the diagnostic process.

Methods

We used 25 clinical vignettes from the Journal of Generalist Medicine characterizing atypical manifestations of common diseases. Two general medicine physicians categorized the cases based on atypicality. ChatGPT was then used to generate differential diagnoses based on the clinical information provided. The concordance between AI-generated and final diagnoses was measured, with a focus on the top-ranked disease (top 1) and the top 5 differential diagnoses (top 5).

Results

ChatGPT’s diagnostic accuracy decreased with an increase in atypical presentation. For category 1 (C1) cases, the concordance rates were 17% (n=1) for the top 1 and 67% (n=4) for the top 5. Categories 3 (C3) and 4 (C4) showed a 0% concordance for top 1 and markedly lower rates for the top 5, indicating difficulties in handling highly atypical cases. The χ² test revealed no significant difference in the top 1 differential diagnosis accuracy between less atypical (C1+C2) and more atypical (C3+C4) groups (χ²₁=2.07; n=25; P=.13). However, a significant difference was found in the top 5 analyses, with less atypical cases showing higher accuracy (χ²₁=4.01; n=25; P=.048).

Conclusions

ChatGPT-4 demonstrates potential as an auxiliary tool for diagnosing typical and mildly atypical presentations of common diseases. However, its performance declines with greater atypicality. The study findings underscore the need for AI systems to encompass a broader range of linguistic capabilities, cultural understanding, and diverse clinical scenarios to improve diagnostic utility in real-world settings.

DOI： 10.2196/58758

Disseminated septic arthritis caused by Ureaplasma urealyticum in an immunocompromised patient with hypogammaglobulinemia after rituximab therapy. Reviewed International journal

Kohei Oguni, Shinnosuke Fukushima, Yuki Otsuka, Yoshiaki Soejima, Marina Kawaguchi, Yosuke Sazumi, Takumi Fujimori, Koji Iio, Noriyuki Umakoshi, Kazuki Yamada, Hideharu Hagiya, Fumio Otsuka

Infection 2024.6

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

PURPOSE: Ureaplasma urealyticum is a rare pathogen associated with septic arthritis that predominantly affects patients with hypogammaglobulinemia. Bacterial identification of fastidious organisms is challenging because they are undetectable by routine culture testing. To the best of our knowledge, this is the first report of septic arthritis induced by U. urealyticum infection in Japan. CASE DESCRIPTION: We describe the case of a 23-year-old Japanese female with secondary hypogammaglobulinemia (serum immunoglobulin level < 500 mg/dL), identified 8 years after treatment with rituximab. The patient presented with persistent fever and polyarthritis that were unresponsive to ceftriaxone and prednisolone. Contrast-enhanced computed tomography and gallium-67 scintigraphy revealed effusion and inflammation in the left sternoclavicular, hip, wrist, knee, and ankle joints. Although Gram staining and bacterial culture of the drainage fluid from the left hip joint were negative, the condition exhibited characteristics of purulent bacterial infection. The patient underwent empirical treatment with doxycycline, and her symptoms promptly resolved. Subsequent 16S ribosomal RNA (rRNA) gene sequencing of the joint fluid confirmed the presence of U. urealyticum, leading to the diagnosis of septic arthritis. Combination therapy with doxycycline and azithromycin yielded a favorable recovery from the inflammatory status and severe arthritic pain. CONCLUSION: This case highlights U. urealyticum as a potential causative agent of disseminated septic arthritis, particularly in patients with hypogammaglobulinaemia. The 16S rRNA gene analysis proved beneficial for identifying pathogens in culture-negative specimens, such as synovial fluid, in suspected bacterial infections.

DOI： 10.1007/s15010-024-02301-1

検体検査システムを利用したEDTA依存性偽性血小板減少症患者におけるFC管の採血忘れ防止策の構築と効果

平畑嵐紀, 青江伯規, 平松舞, 日野佳弥, 青江佐佳恵, 高橋孝英, 三宅雅之, 川下隆二, 東影明人, 大塚文男

日本検査血液学会雑誌 25 ( 学術集会 ) S215 - S215 2024.6

Benign adrenal cyst: A rare type of adrenal incidentaloma Reviewed

Koichiro Yamamoto, Kohei Oguni, Fumio Otsuka

Clinical Case Reports 12 ( 6 ) 2024.5

Authorship：Last author Publishing type：Research paper (scientific journal) Publisher：Wiley

Key Clinical Message

We present a patient with hypertension who developed a rare type of incidentaloma, a benign adrenal cyst. Benign adrenal cysts are typically large; however, most are nonfunctioning and asymptomatic, and they can be managed conservatively.

DOI： 10.1002/ccr3.8914

Optimization of Blood Culture in "Hospital without Infection Control Team or Microbiology Laboratories"

FUKUSHIMA Shinnosuke, HAGIYA Hideharu, TSUJI Kentaro, HIRAIWA Chihiro, OE Keishi, KITA Shinya, OTA Shigeru, TADA Ryuhei, MIYASAKA Ei, SUNAMI Hiroshi, OMOTE Shizuma, OTSUKA Fumio

Kansenshogaku Zasshi 98 ( 3 ) 306 - 310 2024.5

Authorship：Last author Language：Japanese Publisher：The Japanese Association for Infectious Diseases

The effectiveness of interventions by senior resident physicians to optimize blood culture examinations has rarely been reported. We compared the results of blood culture examinations performed before and after an intervention, which consisted of 1) holding a study session on blood culture, 2) informing the monthly contamination rate, 3) feeding back the blood culture results to the doctor who ordered the test, and 4) distributing the institutional manual. After the intervention, the contamination rate decreased from 7.7% to 2.4%, and the proportion of coagulase-negative staphylococci isolated decreased from 34.6% to 15.9%. Additional laboratory testing and antibiotic administration were ordered in 4 patients (30.8%) with suspected contamination. To reduce blood culture contamination, a multifaceted educational approach is essential. Our report highlights the fact that educational activities by senior residents could play a considerable role in promoting the optimization of blood culture examinations.

DOI： 10.11150/kansenshogakuzasshi.e23034

Adherence to and clinical utility of "quality indicators" for Staphylococcus aureus bacteremia: a retrospective, multicenter study. Reviewed International journal

Shinnosuke Fukushima, Hideharu Hagiya, Naoki Kuninaga, Yuto Haruki, Haruto Yamada, Yoshitaka Iwamoto, Masayo Yoshida, Kota Sato, Yoshihisa Hanayama, Shuichi Tanaka, Tomoko Miyoshi, Yuki Otsuka, Keigo Ueda, Fumio Otsuka

Infection 2024.5

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: We aimed to improve the prognosis, treatment, and management of Staphylococcus aureus bacteremia (SAB) by evaluating the association between adherence to quality indicators (QIs) and clinical outcomes in patients with their clinical outcomes. METHODS: We retrospectively collected clinical and microbiological data on hospitalized patients with SAB from 14 hospitals (three with > 600, two with 401-600, five with 201-400, and four with ≤ 200 beds) in Japan from January to December 2022. The SAB management quality was evaluated using the SAB-QI score (ranging from 0 to 13 points), which consists of 13 QIs (grouped into five categories) based on previous literature. RESULTS: Of the 4,448 positive blood culture episodes, 289 patients with SAB (6.5%) were enrolled. The SAB-QI scores ranged from 3 to 13, with a median score of 9 points. The SAB-QI score was highest in middle-sized hospitals with 401-600 beds. Adherence to each of the four QI categories (blood culture, echocardiography, source control, and antibiotic treatment) was significantly higher in survived cases than in fatal cases. Kaplan-Meier curves with log-rank tests demonstrated that higher adherence to SAB-QIs indicated a better prognosis. Logistic regression analysis revealed that age, methicillin resistance, multiple comorbidities (≥ 2), and low SAB-QI score were significantly associated with 30-day mortality in patients with SAB. CONCLUSIONS: Our study highlights that greater adherence to the SAB-QIs correlates with improved patient outcomes. Management of patients with SAB should follow these recommended indicators to maintain the quality of care, especially for patients with poor prognosticators.

DOI： 10.1007/s15010-024-02284-z

成人低アルカリフォスファターゼ血症の検出頻度とその特徴

藤原進太郎, 大塚勇輝, 古川雅規, 東影明人, 大塚文男

日本内分泌学会雑誌 100 ( 1 ) 351 - 351 2024.5

随時血糖高値によるCOVID-19罹患後症状および治療期間への影響

横山将, 本多寛之, 大塚勇輝, 徳増一樹, 砂田匠彦, 松田祐依, 櫻田泰江, 高瀬了輔, 植田圭吾, 大塚文男

日本内分泌学会雑誌 100 ( 1 ) 435 - 435 2024.5

後腹膜線維症49症例における臨床的特徴甲状腺機能に着目して

花山宜久, 安藤美穂, 大國皓平, 徳増一樹, 長谷川功, 萩谷英大, 大塚文男

日本内分泌学会雑誌 100 ( 1 ) 314 - 314 2024.5

若手総合診療医としてJMATでの能登派遣を振り返って災害医療に活かせる総合診療とは?

赤澤英将, 大塚勇輝, 藤原真治, 片岡仁美, 大塚文男

総合診療 34 ( 5 ) 560 - 563 2024.5

オトガイ部の生検から診断に至った全身性ALアミロイドーシスの1例

坂田伽奈子, 川上佳夫, 横山恵美, 森実真, 長谷川功, 中野靖浩, 大塚文男, 白藤宜紀

日本皮膚科学会雑誌 134 ( 6 ) 1711 - 1711 2024.5

Long COVIDに見られる起立性調節障害の臨床的特徴

加藤篤之, 徳増一樹, 山本紘一郎, 大塚勇輝, 副島佳晃, 須山敦仁, 大國皓平, 砂田匠彦, 松田祐依, 櫻田泰江, 植田圭吾, 大塚文男

日本内分泌学会雑誌 100 ( 1 ) 436 - 436 2024.5

随時血糖高値によるCOVID-19罹患後症状および治療期間への影響

横山将, 本多寛之, 大塚勇輝, 徳増一樹, 砂田匠彦, 松田祐依, 櫻田泰江, 高瀬了輔, 植田圭吾, 大塚文男

日本内分泌学会雑誌 100 ( 1 ) 435 - 435 2024.5

後腹膜線維症49症例における臨床的特徴甲状腺機能に着目して

花山宜久, 安藤美穂, 大國皓平, 徳増一樹, 長谷川功, 萩谷英大, 大塚文男

日本内分泌学会雑誌 100 ( 1 ) 314 - 314 2024.5

漢方医学への学習意欲向上プロセスの探索医学生の漢方教育×LongCOVIDプロジェクトを通して

徳増一樹, 植田圭吾, 大塚勇輝, 大塚文男

日本東洋医学雑誌 75 ( 別冊 ) 330 - 330 2024.5

日本における播種性クリプトコッカス症の疫学的特徴ならびに地域性・季節性およびトレンドの解析

赤澤英将, 福島伸乃介, 萩谷英大, 大塚文男

日本感染症学会総会・学術講演会・日本化学療法学会学術集会合同学会プログラム・抄録集 98回・72回 np193 - np193 2024.5

伝播性薬剤耐性HIVにより進行性多巣性白質脳症を発症した一例

川口満理奈, 萩谷英大, 大塚勇輝, 福島伸乃介, 大塚文男

日本感染症学会総会・学術講演会・日本化学療法学会学術集会合同学会プログラム・抄録集 98回・72回 np333 - np333 2024.5

黄色ブドウ球菌菌血症(SAB)に対する診療の質指標(Quality Indicator)に関する多施設研究

福島伸乃介, 萩谷英大, 大塚勇輝, 山田晴士, 岩本佳隆, 佐藤恒太, 大塚文男

日本感染症学会総会・学術講演会・日本化学療法学会学術集会合同学会プログラム・抄録集 98回・72回 np210 - np210 2024.5

Prostate abscess caused by ESBL-producing E. coli successfully treated with fosfomycin monotherapy. Reviewed International journal

Shinnosuke Fukushima, Yuki Otsuka, Hideharu Hagiya, Naoto Nishikawa, Fumio Otsuka

International journal of antimicrobial agents 107182 - 107182 2024.4

ISO15189の要求事項に適応した機材管理システムの構築と評価 Reviewed

三宅雅之, 飯尾耕治, 池田亮, 東影明人, 大塚文男

医学検査 73 ( 2 ) 316 - 322 2024.4

Authorship：Last author Language：Japanese Publisher：(一社)日本臨床衛生検査技師会

当院の検査部門は2007年7月にISO15189の認定を取得した。これまでISO15189の認定を維持管理してきたなかで,内部監査での機材管理に関連する不適合数が減少しないことが問題となった。そこで,機材管理を簡便かつ適切に行える機材管理システムの開発を行った。当院の医療用端末にインストールされているMicrosoft Accessを用いてリレーショナルデータベース(RDB)を独自に構築し,それに付属するVisual Basic for Applications(VBA)を用いてアプリケーション開発を行った。RDB構築にあたってISO15189の要求事項を過不足なく管理できることを意識し,なおかつ変更履歴を容易に確認できるようにするため一部のテーブルでは世代管理の仕組みを取り入れた。構築した機材管理システムは2019年6月から運用開始し,これまで複数回のバージョンアップを繰り返しながら稼動している。内部監査での機材管理に関連する不適合数では,機材管理システムを導入する以前の2013年度では13件あった不適合数が導入後の2022年度では7件まで減少した。機材管理システムを導入したことにより適切に機材管理できるようになったと考えられる。また,独自に開発したシステムであるためバグ修正や機能追加が容易であり,要求事項を満たし,かつ今の検査室にとって適切なシステムを維持しやすいと考えられた。(著者抄録)

副腎摘除後に血糖コントロールが著明に改善した高齢クッシング症候群の1例

長谷川功, 山本紘一郎, 大國皓平, 中野靖浩, 安田美帆, 本多寛之, 小比賀美香子, 片岡仁美, 大塚文男

糖尿病 67 ( Suppl.1 ) S - 299 2024.4

チルゼパチド導入が治療負担感軽減に有用と思われた若年肥満2型糖尿病男性の2例

本多寛之, 山本紘一郎, 大國皓平, 中野靖浩, 安田美帆, 長谷川功, 小比賀美香子, 片岡仁美, 大塚文男

糖尿病 67 ( Suppl.1 ) S - 336 2024.4

慢性甲状腺炎と副腎クリーゼを背景に発症した麻痺性イレウスにLT4静注が奏効した1例

中野靖浩, 大國皓平, 長谷川功, 越智可奈子, 大塚文男

日本内分泌学会雑誌 99 ( 5 ) 1288 - 1288 2024.4

腺腫様結節による甲状腺中毒症を呈したPlummer病の1例

加藤篤之, 大國皓平, 中野靖浩, 長谷川功, 越智可奈子, 大塚文男

日本内分泌学会雑誌 99 ( 5 ) 1295 - 1295 2024.4

チルゼパチド導入が治療負担感軽減に有用と思われた若年肥満2型糖尿病男性の2例

本多寛之, 山本紘一郎, 大國皓平, 中野靖浩, 安田美帆, 長谷川功, 小比賀美香子, 片岡仁美, 大塚文男

糖尿病 67 ( Suppl.1 ) S - 336 2024.4

A Case of Persistent Hiccups Induced by an Enlarging Hepatic Cyst Underneath the Diaphragm. Reviewed International journal

Wataru Ando, Yuki Otsuka, Fumio Otsuka

Cureus 16 ( 4 ) e58278 2024.4

Authorship：Last author Language：English

Although hiccups are regularly self-limited and rarely life-threatening, prolonged hiccups are bothersome, which can significantly decrease the quality of life. Here, we report a case of persistent hiccups coexisting with an enlarging liver cyst situated just below the diaphragm in a patient with autosomal dominant polycystic kidney disease (ADPKD). No other underlying etiologies related to the symptoms were suspected. The cyst was difficult to drain surgically and the patient continued with symptomatic treatment. Although rare, hepatic cysts should be considered a potential cause of prolonged hiccups in patients with ADPKD. We emphasize the significance of systematically excluding potential etiologies that cause prolonged hiccups and considering appropriate therapeutic interventions.

DOI： 10.7759/cureus.58278

高度のQT延長が副腎摘除術後に改善した原発性アルドステロン症の1例

高瀬了輔, 中野靖浩, 須山敦仁, 加藤篤之, 佐住洋祐, 長谷川功, 前川清明, 大塚文男

日本内分泌学会雑誌 99 ( 5 ) 1500 - 1500 2024.4

副腎摘除後に血糖コントロールが著明に改善した高齢クッシング症候群の1例

長谷川功, 山本紘一郎, 大國皓平, 中野靖浩, 安田美帆, 本多寛之, 小比賀美香子, 片岡仁美, 大塚文男

糖尿病 67 ( Suppl.1 ) S - 299 2024.4

腰椎圧迫骨折を契機に低アンドロゲン血症が判明した中年男性の1例

副島佳晃, 大塚勇輝, 川口満理奈, 大國晧平, 中野靖浩, 安田美帆, 徳増一樹, 植田圭吾, 大塚文男

日本内分泌学会雑誌 99 ( 5 ) 1500 - 1500 2024.4

NVX-CoV2373ワクチン投与後に血管浮腫様の眼瞼浮腫を生じた1例

松本真理, 川上佳夫, 三宅智子, 平井陽至, 森実真, 片岡仁美, 大塚文男

西日本皮膚科 86 ( 2 ) 198 - 198 2024.4

腰椎圧迫骨折を契機に低アンドロゲン血症が判明した中年男性の1例

副島佳晃, 大塚勇輝, 川口満理奈, 大國晧平, 中野靖浩, 安田美帆, 徳増一樹, 植田圭吾, 大塚文男

日本内分泌学会雑誌 99 ( 5 ) 1500 - 1500 2024.4

下垂体後葉ホルモンによる顆粒膜細胞のプロゲステロン合成調節と卵胞BMPの関与

山本紘一郎, 中野靖浩, 岩田菜穂子, 副島佳晃, 須山敦仁, 大塚文男

日本内分泌学会雑誌 99 ( 5 ) 1545 - 1545 2024.4

慢性甲状腺炎と副腎クリーゼを背景に発症した麻痺性イレウスにLT4静注が奏効した1例

中野靖浩, 大國皓平, 長谷川功, 越智可奈子, 大塚文男

日本内分泌学会雑誌 99 ( 5 ) 1288 - 1288 2024.4

腺腫様結節による甲状腺中毒症を呈したPlummer病の1例

加藤篤之, 大國皓平, 中野靖浩, 長谷川功, 越智可奈子, 大塚文男

日本内分泌学会雑誌 99 ( 5 ) 1295 - 1295 2024.4

Enhancing Medical Interview Skills through AI Simulated Patient Interactions: Non-Randomized Controlled Trial Reviewed

Akira Yamamoto, Masahide Koda, Hiroko Ogawa, Tomoko Miyoshi, Yoshinobu Maeda, Fumio Otsuka, Hideo Ino

JMIR Med Educ 10 ( e58753 ) 1 - 12 2024.3

Publisher：JMIR Publications Inc.

BACKGROUND<p>Medical interviewing is a critical skill in clinical practice, yet opportunities for practical training are limited in Japanese medical schools, necessitating urgent measures. Given advancements in AI technology, its application in the medical field is expanding. However, reports on its application in medical interviews in medical education are scarce.</p> OBJECTIVE<p>This study aimed to investigate whether medical students' interview skills could be improved by engaging with AI-simulated patients using large language models (LLMs), including the provision of feedback.</p> METHODS<p>A simulation program using LLMs was provided to 35 fourth-year medical students in Japan in 2023. As a control group, 110 fourth-year medical students from 2022 who did not participate in the intervention were selected. The primary outcome was the score on the pre-Clinical Clerkship Objective Structured Clinical Examination (pre-CC OSCE), a national standardized clinical skills examination, in medical interviewing. Secondary outcomes included surveys such as Simulation-Based Training Quality Assurance Tool (SBT-QA10).</p> RESULTS<p>The AI intervention group showed significantly higher scores on medical interviews than the control group (AI group vs. control group: median 28.0 vs. 27.0, p = 0.01). There was a trend of inverse correlation between the SBT-QA10 and pre-CC OSCE scores (regression coefficient -2.0 to -2.1). No significant safety concerns were observed.</p> CONCLUSIONS<p>Education through medical interviews using AI-simulated patients has demonstrated safety and a certain level of educational effectiveness, suggesting promising prospects for multifaceted applications in the field of medical education.</p>

DOI： 10.2196/preprints.58753

Calcium polystyrene sulfonate-induced rectal ulcer causing E. coli native-valve infective endocarditis. Reviewed

Shinnosuke Fukushima, Hideharu Hagiya, Hiroyuki Honda, Tomoharu Ishida, Ryohei Shoji, Kou Hasegawa, Fumio Otsuka

Clinical Journal of Gastroenterology 2024.3

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Escherichia coli-associated native-valve infective endocarditis is a rare disease that affects elderly patients with underlying risk factors such as diabetes mellitus, malignancy, and renal failure. Long-term use of calcium polystyrene sulfonate is a potential risk factor for gastrointestinal mucosal damage or even colorectal ulcers. Herein, we describe a fatal case of a 66-year-old Japanese man with diabetes mellitus and renal failure who was prescribed calcium polystyrene sulfonate (CPS) for 11 years and developed a CPS-induced rectal ulcer, leading to E. coli native-valve infective endocarditis. The patient was admitted to our hospital due to acute-onset impaired consciousness. As a result of the systemic investigation, he was diagnosed with E. coli bacteremia accompanied by multiple cerebral infarctions and an acute hemorrhagic rectal ulcer. Transesophageal echocardiography revealed a 20-mm vegetative structure on the mitral valve, resulting in a final diagnosis of E. coli-associated infective endocarditis. After rectal resection, mitral valve replacement surgery was performed; however, the patient died shortly after surgery. Pathological findings of the resected rectum showed deposition of a basophilic crystalline material suggesting the presence of CPS. Our case highlights the potential risk of colorectal ulcers in a long-term CPS user, which can trigger bacterial translocation and endocarditis as fatal complications.

DOI： 10.1007/s12328-024-01949-4

Idiopathic ventricular tachycardia detected after coronavirus disease 2019 Reviewed

Koichiro Yamamoto, Koji Nakagawa, Fumio Otsuka

Journal of General and Family Medicine 2024.3

Zinc deficiency is a potential risk factor for COVID-19 progression to pneumonia requiring oxygen therapy. Reviewed International journal

Koji Fujita, Kazuki Ocho, Tomoka Kadowaki, Takashi Yorifuji, Hideharu Hagiya, Fumio Otsuka

Journal of Infection and Chemotherapy 30 ( 10 ) 978 - 982 2024.3

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Various risk factors for developing severe coronavirus disease 2019 (COVID-19) have been reported. However, studies on the nutritional-related risk factors are limited. In this study, we investigated the effects of serum zinc deficiency on the severity of COVID-19. METHODS: The study included a total of 60 COVID-19 patients who were admitted to Tsuyama Chuo Hospital between March 2020 and April 2021. We divided the patients into two categories based on serum levels of zinc (normal and latent zinc deficiency vs. zinc deficiency [<60 μg/dL]) at the time of diagnosis. Severity of COVID-19 was defined as the most exaggerated disease status during admission. The associations between serum zinc deficiency and the severity of COVID-19 were examined using a logistic regression model adjusted for potential confounders. RESULTS: Patients who required oxygen therapy had a higher prevalence of comorbidities and poorer nutritional status, including zinc deficiency, than those who did not require oxygen therapy. Zinc deficiency was associated with an increased risk of COVID-19 severity, with an adjusted odds ratio of 7.29 (95% confidence interval: 1.70-31.18). This result remained significant in the sensitivity analyses conducted after adjusting for patient background factors. CONCLUSIONS: Zinc deficiency at the time of COVID-19 diagnosis is an independent risk factor for severe disease. Our findings need to be validated in external studies.

DOI： 10.1016/j.jiac.2024.03.007

Occult endocrine disorders newly diagnosed in patients with post-COVID-19 symptoms. Reviewed International journal

Yasuhiro Nakano, Naruhiko Sunada, Kazuki Tokumasu, Hiroyuki Honda, Yuki Otsuka, Yasue Sakurada, Yui Matsuda, Toru Hasegawa, Daisuke Omura, Kanako Ochi, Miho Yasuda, Hideharu Hagiya, Keigo Ueda, Fumio Otsuka

Scientific reports 14 ( 1 ) 5446 - 5446 2024.3

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Determination of long COVID requires ruling out alternative diagnoses, but there has been no report on the features of alternative diagnoses. This study was a single-center retrospective study of outpatients who visited our clinic between February 2021 and June 2023 that was carried out to determine the characteristics of alternative diagnoses in patients with post-COVID-19 symptoms. In a total of 731 patients, 50 patients (6.8%) were newly diagnosed with 52 diseases requiring medical intervention, and 16 (32%) of those 50 patients (2.2% of the total) were considered to have priority for treatment of the newly diagnosed disorders over long COVID treatment. The proportion of patients with a new diagnosis increased with advance of age, with 15.7% of the patients aged 60 years or older having a new diagnosis. Endocrine and metabolic diseases and hematological and respiratory diseases were the most common, being detected in eight patients (16%) each. Although 35 of the 52 diseases (67%) were related to their symptoms, endocrine and metabolic diseases were the least associated with specific symptoms. Other disorders that require attention were found especially in elderly patients with symptomatic long COVID. Thus, appropriate assessment and differentiation from alternative diagnoses are necessary for managing long COVID.

DOI： 10.1038/s41598-024-55526-3

【-え、ウソ!実は○○だった!?-"コモンディジーズ"の診断ピットフォール】(Pitfall 23)症状・所見は常に非特異的…!?

大塚勇輝, 大塚文男

総合診療 34 ( 3 ) 298 - 300 2024.3

先天性心疾患患者の移行期医療:成人循環器医の協力を得る方策成人先天性心疾患の診療の手助けとなる心エコー図検査

武本梨佳, 杜徳尚, 高谷陽一, 中山理絵, 赤木禎治, 中村一文, 笠原真悟, 大塚文男

日本循環器学会学術集会抄録集 88回 CS3 - 4 2024.3

病院総合診療医には新興感染症に備えた感染症危機管理教育が必要である全国97医療機関の調査より

藤原元嗣, 多胡雅毅, 平田理紗, 香月尚子, 大塚勇輝, 志水太郎, 佐々木陽典, 鋪野紀好, 和足孝之, 高橋宏瑞, 宇根一暢, 内藤俊夫, 大塚文男, 田妻進

日本病院総合診療医学会雑誌 20 ( 臨増1 ) 139 - 139 2024.3

病院総合診療医には新興感染症に備えた感染症危機管理教育が必要である全国97医療機関の調査より

藤原元嗣, 多胡雅毅, 平田理紗, 香月尚子, 大塚勇輝, 志水太郎, 佐々木陽典, 鋪野紀好, 和足孝之, 高橋宏瑞, 宇根一暢, 内藤俊夫, 大塚文男, 田妻進

日本病院総合診療医学会雑誌 20 ( 臨増1 ) 139 - 139 2024.3

SARS-CoV-2ワクチン接種後の持続的な副反応の特徴副反応外来における後向き観察研究

徳増一樹, 山下茉奈美, 砂田匠彦, 櫻田泰江, 山本紘一郎, 中野靖浩, 松田祐依, 大塚勇輝, 長谷川徹, 萩谷英大, 本多寛之, 大塚文男

日本病院総合診療医学会雑誌 20 ( 臨増1 ) 143 - 143 2024.3

コントロール不十分な糖尿病を伴う全身痛の鑑別プロセスから症状軽快を導けた一例

淺野晃太, 大塚勇輝, 副島佳晃, 川口満理奈, 大國皓平, 本多寛之, 長谷川功, 越智可奈子, 大塚文男

日本病院総合診療医学会雑誌 20 ( 臨増1 ) 182 - 182 2024.3

高齢女性の骨折・低カリウム血症を契機にPMAHの診断に至った1例

須山敦仁, 山本紘一郎, 加藤篤之, 副島佳晃, 佐住洋祐, 大國皓平, 中野靖浩, 大塚文男

日本病院総合診療医学会雑誌 20 ( 臨増1 ) 213 - 213 2024.3

Collection efficiency and safety of large-volume leukapheresis for the manufacturing of tisagenlecleucel. Reviewed International journal

Wataru Kitamura, Tomohiro Urata, Keiko Fujii, Takuya Fukumi, Kazuhiro Ikeuchi, Keisuke Seike, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Ken-Ichi Matsuoka, Fumio Otsuka, Yoshinobu Maeda, Nobuharu Fujii

Transfusion 2024.2

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

BACKGROUND: In patients with relapsed or refractory B cell acute lymphoblastic leukemia or B cell non-Hodgkin lymphoma (r/r B-ALL/B-NHL) with low CD3+ cells in the peripheral blood (PB), sufficient CD3+ cell yield in a single day may not be obtained with normal-volume leukapheresis (NVL). Large-volume leukapheresis (LVL) refers to the processing of more than three times the total blood volume (TBV) in a single session for PB apheresis; however, the efficiency and safety of LVL for manufacturing of tisagenlecleucel (tisa-cel) remain unclear. This study aimed to investigate the tolerability of LVL. STUDY DESIGN AND METHODS: We retrospectively collected data on LVL (≥3-fold TBV) and NVL (<3-fold TBV) performed for patients with r/r B-ALL/B-NHL in our institution during November 2019 and September 2023. All procedures were performed using a continuous mononuclear cell collection (cMNC) protocol with the Spectra Optia. RESULTS: Although pre-apheresis CD3+ cells in the PB were significantly lower in LVL procedures (900 vs. 348/μL, p < .01), all patients could obtain sufficient CD3+ cell yield in a single day with a comparably successful rate of final products (including out-of-specification) between the two groups (97.2% vs. 100.0%, p = 1.00). The incidence and severity of citrate toxicity (no patients with grade ≥ 3) during procedures was not significantly different between the two groups (22.2% vs. 26.1%, p = .43) and no patient discontinued leukapheresis due to any complications. CONCLUSION: LVL procedures using Spectra Optia cMNC protocol was well tolerated and did not affect the manufacturing of tisa-cel.

DOI： 10.1111/trf.17765

Penile cavernosal abscess after urethral injury Reviewed

Koichiro Yamamoto, Hiroyuki Honda, Kou Hasegawa, Hideharu Hagiya, Fumio Otsuka

Clinical Case Reports 12 ( 2 ) 2024.2

Authorship：Last author Publishing type：Research paper (scientific journal) Publisher：Wiley

Key Clinical Message

We present a patient catheterized for prostatic lesions who developed sepsis of urinary origin with a penile cavernosal abscess due to urethral injury caused by catheter ballooning. Urethral injury might lead to a life‐threatening penile abscess.

DOI： 10.1002/ccr3.8534

Characteristics of Functional Hyperthermia Detected in an Outpatient Clinic for Fever of Unknown Origin. Reviewed International journal

Kosuke Oka, Kazuki Tokumasu, Hideharu Hagiya, Fumio Otsuka

Journal of Clinical Medicine 13 ( 3 ) 889 2024.2

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Background: Functional hyperthermia (FH) is characterized by hyperthermia resulting from sympathetic hyperactivity rather than inflammation, and it is frequently overlooked by medical practitioners due to the absence of abnormalities in a medical examination. Although FH is an important differential diagnosis for fever of unknown origin (FUO), the literature on FUO cases in Japan lacks information on FH. In this study, we aimed to uncover the population of FH patients hidden in FUO cases. Methods: An outpatient clinic for FUO was established at Okayama University Hospital, and 132 patients were examined during the period from May 2019 to February 2022. Results: A diagnosis of FH was made in 31.1% of the FUO cases, and FH predominantly affected individuals in their third and fourth decades of life with a higher incidence in females (68.3%). The frequency of a history of psychiatric illness was higher in patients with FH than in patients with other febrile illnesses. Although the C-reactive protein (CRP) is generally negative in FH cases, some obese patients, with a body mass index ≥ 25 had slightly elevated levels of CRP but were diagnosed with FH. Conclusions: The results showed the importance of identifying FH when encountering patients with FUO without any organic etiology.

DOI： 10.3390/jcm13030889

【新型コロナ後遺症-これまでの対応と問題点】

大塚勇輝, 徳増一樹, 植田圭吾, 大塚文男

日本医事新報 ( 5208 ) 18 - 27 2024.2

Language：Japanese Publisher：(株)日本医事新報社

[1]はじめに・いわゆる「新型コロナ後遺症」にいまだ多くの患者が苦しみ,わが国を含む世界的な社会問題となっている。[2]呼称と定義・「新型コロナ後遺症」などの用語の定義は,医学的には統一されていない。・NIHの「PASC」,WHOの「PCC」という用語には定義が定められ,2023年には診断基準案の提案もなされた。[3]コロナ・アフターケア外来とは・罹患後慢性期にかけての症状の遷延に対し,専門外来であるコロナ・アフターケア(CAC)外来を開設した。・1日1～2人の新規患者を受け入れ,800人以上の患者を対面診療してきた。[4]疫学・CAC外来へは,デルタ株流行時に感染者の約1.5%,オミクロン株では感染者の0.1%程度が受診となった。・CAC外来の受診患者は若干女性が多く,30～50歳代が60%,10歳代など若年者が14%だが,70歳代以上の受診は比較的少ない。・オミクロン株に感染したと思われる症例では,95%の患者で急性期は軽症であったが,後遺症は残っている。[5]症状・症状は多彩であるが,倦怠感・易疲労感が最多で,ブレインフォグは,特にオミクロン株で増加していた。[6]病態とメカニズム・感染後の炎症と免疫応答,自己免疫反応,血栓・血管内皮障害,腸内細菌叢変化,自律神経・内分泌障害,ウイルス残存など,種々の仮説がある。・抑うつ指数,FT4,倦怠感スケール,血中コルチゾール値の間に正の相関がみられる。・捲怠感や味覚・嗅覚障害を随伴する患者では,それぞれ成長ホルモン低値,FT4高値,コルチゾール低値の傾向がある。[7]治療とマネジメント・漢方薬の処方のほか,亜鉛補充,急性期の抗ウイルス薬やメトホルミンの処方にも,一定の効果が認められる。・総合診療的なアプローチで,全人的なケアを心がけている。[8]今後の課題・終診とできるまでに日数を要するほか,対応可能な医師・施設も不足している。(著者抄録)

【入院時から始める退院調整】診療情報提供書の書き方と注意点入院診療とかかりつけ医をつなぐために

大塚勇輝, 川口満理奈, 大塚文男

レジデントノート 25 ( 16 ) 2894 - 2902 2024.2

Mutual Effects of Orexin and Bone Morphogenetic Proteins on Catecholamine Regulation Using Adrenomedullary Cells. Reviewed International journal

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

International journal of molecular sciences 25 ( 3 ) 2024.1

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Orexins are neuronal peptides that play a prominent role in sleep behavior and feeding behavior in the central nervous system, though their receptors also exist in peripheral organs, including the adrenal gland. In this study, the effects of orexins on catecholamine synthesis in the rat adrenomedullary cell line PC12 were investigated by focusing on their interaction with the adrenomedullary bone morphogenetic protein (BMP)-4. Orexin A treatment reduced the mRNA levels of key enzymes for catecholamine synthesis, including tyrosine hydroxylase (Th), 3,4-dihydroxyphenylalanie decarboxylase (Ddc) and dopamine β-hydroxylase (Dbh), in a concentration-dependent manner. On the other hand, treatment with BMP-4 suppressed the expression of Th and Ddc but enhanced that of Dbh with or without co-treatment with orexin A. Of note, orexin A augmented BMP-receptor signaling detected by the phosphorylation of Smad1/5/9 through the suppression of inhibitory Smad6/7 and the upregulation of BMP type-II receptor (BMPRII). Furthermore, treatment with BMP-4 upregulated the mRNA levels of OX1R in PC12 cells. Collectively, the results indicate that orexin and BMP-4 suppress adrenomedullary catecholamine synthesis by mutually upregulating the pathway of each other in adrenomedullary cells.

DOI： 10.3390/ijms25031585

Trends in the Incidence of Disseminated Cryptococcosis in Japan: A Nationwide Observational Study, 2015-2021. Reviewed International journal

Hidemasa Akazawa, Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

Mycopathologia 189 ( 1 ) 8 - 8 2024.1

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Cryptococcus species can cause severe disseminated infections in immunocompromised hosts. This study investigated the epidemiological features and trends in disseminated cryptococcosis in Japan. METHODS: We used publicly available Infectious Diseases Weekly Reports to obtain data on the incidence of disseminated cryptococcosis in Japan from 2015 to 2021. Patient information, including age, sex, and regional and seasonal data, were extracted. The Joinpoint regression program was used to determine the age-adjusted incidence rate (AAR) per 100,000 population, annual percentage change (APC), and average APC (AAPC). RESULTS: A total of 1047 cases of disseminated cryptococcosis were reported, of which those aged ≥ 70 years accounted for 68.8%. The AAR in men was significantly higher than that in women (median: 0.13 vs. 0.09: p = 0.0024). APC for the overall cases increased by 9.9% (95% confidence interval [95% CI] - 5.4-27.7) from 2015 to 2018 and then decreased by 3.3% (95% CI - 15.5-10.7) from 2018 to 2021. AAPC for the entire study period was 3.1% (95% CI - 1.5-8.0), indicating a possible increase in its number, although not statistically significant. In terms of regional distribution, the average AAR was highest in Shikoku District (0.17) and lowest in Hokkaido District (0.04). Northern Japan exhibited a significantly lower median AAR (median [interquartile range]: 0.06 [0.05, 0.08]) than the Eastern (0.12 [0.12, 0.13]), Western (0.11 [0.10, 0.13]), and Southern (0.14 [0.12, 0.15]) regions. No seasonal variation in incidence was observed. CONCLUSION: The prevalence of disseminated cryptococcosis has not increased in Japan. Geographically, the incidence is lower in Northern Japan. Further investigations that incorporate detailed clinical data are required.

DOI： 10.1007/s11046-023-00814-1

特集 -"体験型"臨床クイズで習得する!-フィジカル診断エクセレンス -❺内分泌･代謝-10年以上続く原因不明の全身痛

髙瀬了輔, 片岡仁美, 大塚文男

総合診療 34 ( 1 ) 37 - 40 2024.1

Influence of the coronavirus disease 2019 pandemic on the post-graduate career paths of medical students: a cross-sectional study Reviewed

Ayumu Nishimura, Tomoko Miyoshi, Fumio Otsuka, Akihiro Matsukawa

BMC Medical Education 24 ( 1 ) 2024.1

Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Background

The World Health Organization first declared the coronavirus disease 2019 (COVID-19) pandemic in March 2020 and announced the end of the emergency in May 2023. Additionally, the COVID-19 pandemic significantly impacted individuals globally, including medical students. Although the COVID-19 pandemic increased online education, it restricted clinical training, extracurricular activities, and interprovincial travel. Therefore, this study aimed to examine whether the COVID-19 pandemic influenced the choice of training hospitals and career paths among 3rd- to 6th-year medical students in Japan.

Methods

We developed a questionnaire comprising 21 multiple-choice and 1 open-ended questions, which was administered anonymously via online platforms. The survey targeted Japanese medical students to obtain insights into their preferences for training hospitals and career paths during the COVID-19 pandemic. Participants included 4th- to 6th-year medical students from 51 medical schools in Japan. The survey was conducted through student networks from 8 February 2022 to 20 March 2022.

Results

Overall, 507 medical students participated in the survey, with representation from various academic years as follows: 102 (20.1%), 134 (26.4%), 121 (23.9%), and 150 (29.6%) students from the 3rd, 4th, 5th, and 6th year, respectively. Of these, 338 (66.6%) students reported that the COVID-19 pandemic had influenced their choice of training hospitals. The degree of the influence varied based on the university region and the student year. However, most of the students (473, 93.3%) did not change their course for clinical, basic research, or administrative pathways due to the COVID-19 pandemic. Among the clinically oriented students, 391 (77.2%) did not change their preferred speciality.

Conclusions

The COVID-19 pandemic influenced medical students’ choice of training hospitals. Although many students believed that the pandemic would not change their career choices, our results indicate a potential subconscious trend to avoid internal medicine, which is the speciality most directly involved in treating patients with COVID-19.

DOI： 10.1186/s12909-023-05021-6

Other Link： https://link.springer.com/article/10.1186/s12909-023-05021-6/fulltext.html

A Mediastinum Tumor Presenting With Dysphagia Reviewed

Koichiro Yamamoto, Fumio Otsuka

JCEM Case Reports 2024.1

本邦の小児肥満有病率の10年間の推移 Joinpoint regressionを用いた小児肥満トレンド解析

藤原進太郎, 原田洸, 萩谷英大, 小山敏広, 長谷川高誠, 塚原宏一, 大塚文男

日本内分泌学会雑誌 99 ( 4 ) 1052 - 1052 2024.1

Development of virtual reality educational clips for improving hand hygiene compliance among healthcare providers: a pilot study Reviewed

Hideharu Hagiya, Shuichi Tanaka, Yuki Otsuka, Fumio Otsuka

Teaching and Learning in Nursing 19 ( 1 ) e17 - e20 2024.1

COVID-19流行が内分泌検査数に与えた変化 Reviewed

大塚勇輝, 古川雅規, 東影明人, 大塚文男

日本病院総合診療医学会雑誌 20 ( 1 ) 18 - 21 2024.1

成人成長ホルモン分泌不全症に関する医療者教育と総合診療科における実践 Reviewed

越智可奈子, 徳増一樹, 中野靖浩, 須山敦仁, 副島佳晃, 大塚勇輝, 安田美帆, 小比賀美香子, 大塚文男

日本病院総合診療医学会雑誌 20 ( 1 ) 7 - 17 2024.1

In vitro Activity of Cefmetazole and Flomoxef among Extended-Spectrum Beta-Lactamase producing Enterobacterales. Reviewed

Koji Iio, Hideharu Hagiya, Tsukasa Higashionna, Fumio Otsuka

New Microbiol. 348 - 353 2024.1

成人成長ホルモン分泌不全症に関する医療者教育と総合診療科における実践

越智可奈子, 徳増一樹, 中野靖浩, 須山敦仁, 副島佳晃, 大塚勇輝, 安田美帆, 小比賀美香子, 大塚文男

日本病院総合診療医学会雑誌 20 ( 1 ) 7 - 17 2024.1

Language：Japanese Publisher：(一社)日本病院総合診療医学会

成人成長ホルモン分泌不全症(AGHD)は下垂体前葉機能低下症の中で成長ホルモン(GH)不足により様々な代謝異常をきたす疾患である。治療にはGH製剤の自己注射を要することから,患者の予後改善にはAGHDの早期診断・治療とともに多職種連携や患者教育が重要である。本研究では,AGHD診療における多職種での医療連携や専門医の育成を目的とし,AGHDに関する講義や専攻医に対するAGHD患者のマネジメント指導において,その教育効果を検討した。まず多職種へのAGHD教育実践と効果の検討として,医師・看護師・検査技師・医薬情報担当者・医学生・看護学生・医療技術専門学生(作業療法学科・理学療法学科)に対してAGHDに関する講義を行い,講義前後でAGHDの理解度を評価する目的でアンケートを実施した。アンケート内容を(1)基礎的事項,(2)合併症に関する事項,(3)診断に関する事項,(4)治療・マネジメントに関する事項の4分野に分類して検討したところ,全職種において講義後の正答率が上昇し,各職種の正答率上昇率は分野ごとに違いを認めた。次に,内科専攻医に対してのAGHD診療の実践教育を内科専攻医4名に対して行い,AGHDの新規患者における診断・治療・GH自己注射指導およびマネジメント教育を実施し評価を行った。GH自己注射指導に関しては,自己注射練習用器材を用いて実践的トレーニングを行ったところ,全専攻医において診療能の向上を認めた。AGHD患者の診断やGH自己注射を含めた治療継続においては多職種連携や専門医育成などの医療者教育が非常に重要である。診療においては総合診療科における全人的・総合的診療の一環としての教育実践により,医療者のAGHD診療に対する理解が向上しており教育効果が示された。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J05937&link_issn=&doc_id=20240228380002&doc_link_id=%2Ffg3byoin%2F2024%2F002001%2F003%2F0007-0017%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Ffg3byoin%2F2024%2F002001%2F003%2F0007-0017%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

COVID-19流行が内分泌検査数に与えた変化

大塚勇輝, 古川雅規, 東影明人, 大塚文男

日本病院総合診療医学会雑誌 20 ( 1 ) 18 - 21 2024.1

Language：Japanese Publisher：(一社)日本病院総合診療医学会

新型コロナウイルス感染症(COVID-19)の流行に伴い医療へのアクセスが制限されたが,本邦において臨床検査に与えた影響については明らかとなっていない。2017年から2022年までの6年間に岡山大学病院において測定された内分泌検査測定件数を経年的に比較すると,入院・外来ともにCOVID-19禍の3年間ではそれ以前に比してACTH・Cortisol,GH・IGFIの測定件数は増加していた一方で,TSHや遊離T4,Renin活性(PRA)やAldosterone(Aldo)の件数は減少しており,特に外来における変化はTSH(平均値:19173件vs17512件),PRA(322件vs251件),Aldo(472件vs306件)と有意であった。内分泌疾患を有す,或いは疑われる患者に対する対面診療での測定依頼が減ったことや,倦怠感など機能低下で生じうる症状を呈する患者が増えたことがその要因ではないかと考察された。COVID-19の流行が少なくとも部分的に本邦での医療の質に影響を与えた可能性が示唆され,その要因分析が今後の課題と思われた。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J05937&link_issn=&doc_id=20240228380003&doc_link_id=%2Ffg3byoin%2F2024%2F002001%2F004%2F0018-0021%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Ffg3byoin%2F2024%2F002001%2F004%2F0018-0021%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Changes in the place of death before and during the COVID-19 pandemic in Japan. Reviewed International journal

Masashi Shibata, Yuki Otsuka, Hideharu Hagiya, Toshihiro Koyama, Hideyuki Kashiwagi, Fumio Otsuka

PloS one 19 ( 2 ) e0299700 2024

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: In the global aging, the coronavirus disease 2019 (COVID-19) pandemic may have affected the place of death (PoD) in Japan, where hospital deaths have dominated for decades. We analyzed the PoD trends before and during the COVID-19 pandemic in Japan. METHODS: This nationwide observational study used vital statistics based on death certificates from Japan between 1951 and 2021. The proportion of PoD; deaths at home, hospitals, and nursing homes; and annual percentage change (APC) were estimated using joinpoint regression analysis. Analyses were stratified by age groups and causes of death. RESULTS: After 2019, home deaths exhibited upward trends, while hospital death turned into downward trends. By age, no significant trend change was seen in the 0-19 age group, while hospital deaths decreased in the 20-64 age group in 2019. The trend change in home death in the ≥65 age group significantly increased since 2019 with an APC of 12.3% (95% confidence interval [CI]: 9.0 to 15.7), while their hospital death trends decreased by -4.0% (95% CI: -4.9 to -3.1) in 2019-2021. By cause of death, home death due to cancer and the old age increased since 2019 with an APC of 29.3% (95% CI: 25.4 to 33.2) and 8.8% (95% CI: 5.5 to 12.2), respectively. CONCLUSION: PoD has shifted from hospital to home during the COVID-19 pandemic in Japan. The majority of whom were older population with cancer or old age.

DOI： 10.1371/journal.pone.0299700

シリーズ「一目瞭然！目で診る症例」問題編

中本健太, 萩谷英大, 林瑠衣子, 大塚文男

日本内科学会雑誌 113 127 - 130 2024

「新型コロナウイルス感染症罹患後症状における睡眠障害の特徴と推移」 Reviewed

大塚文男, 砂田匠彦, 大塚勇輝, 徳増一樹, 本多寛之, 古川雅規

日本病院総合診療医学会雑誌 20(3) 129 - 134 2024

Functional interaction of Clock genes and bone morphogenetic proteins in the adrenal cortex. Reviewed International journal

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

Vitamins and hormones 124 429 - 447 2024

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The bone morphogenetic protein (BMP) system in the adrenal cortex plays modulatory roles in the control of adrenocortical steroidogenesis. BMP-6 enhances aldosterone production by modulating angiotensin (Ang) II-mitogen-activated protein kinase (MAPK) signaling, whereas activin regulates the adrenocorticotropin (ACTH)-cAMP cascade in adrenocortical cells. A peripheral clock system in the adrenal cortex was discovered and it has been shown to have functional roles in the adjustment of adrenocortical steroidogenesis by interacting with the BMP system. It was found that follistatin, a binding protein of activin, increased Clock mRNA levels, indicating an endogenous function of activin in the regulation of Clock mRNA expression. Elucidation of the interrelationships among the circadian clock system, the BMP system and adrenocortical steroidogenesis regulated by the hypothalamic-pituitary-adrenal (HPA) axis would lead to an understanding of the pathophysiology of adrenal disorders and metabolic disorders and the establishment of better medical treatment from the viewpoint of pharmacokinetics.

DOI： 10.1016/bs.vh.2023.05.002

Trends of correlations between serum levels of growth hormone and insulin-like growth factor-I in general practice. Reviewed International journal

Kohei Oguni, Koichiro Yamamoto, Yasuhiro Nakano, Yoshiaki Soejima, Atsuhito Suyama, Ryosuke Takase, Miho Yasuda, Kou Hasegawa, Fumio Otsuka

Frontiers in endocrinology 15 1381083 - 1381083 2024

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Serum levels of growth hormone (GH) and insulin-like growth factor (IGF)-I are crucial in the diagnosis and management of GH-related diseases. However, these levels are affected by nutritional and metabolic status. To elucidate the correlations between GH and IGF-I in various conditions, a retrospective analysis was performed for adult patients in which GH levels were examined by general practitioners during the period from January 2019 to December 2021. Of 642 patients, 33 patients were diagnosed with acromegaly, 21 were diagnosed with GH deficiency (GHD), and 588 were diagnosed with non-GH-related diseases (NGRD). In contrast to the positive correlations found between the levels of GH and IGF-I in patients with acromegaly (R=0.50; P<0.001) and patients with GHD (R=0.39; P=0.08), a negative correlation was found in the NGRD group (R=-0.23; P<0.001). In that group, the results of multivariable analysis showed that GH levels were predominantly influenced by gender and body mass index (BMI), whereas IGF-I levels were modulated by albumin in addition to age and GH. Of note, in the NGRD group, there was an enhanced negative correlation between GH and IGF-I under conditions of BMI < 22 and albumin < 4.0 g/dL (R=-0.45; P<0.001), and the negative correlation between GH and IGF-I was reinforced by excluding patients with other pituitary diseases and patients taking oral steroids (R=-0.51; P<0.001 and R=-0.59; P<0.001, respectively). Collectively, the results indicate that attention should be given to the presence of a negative correlation between serum levels of GH and IGF-I, especially in lean and low-nutritious conditions.

DOI： 10.3389/fendo.2024.1381083

What is the Definition of General Medicine and Generalists in Japan? [Letter]. Reviewed International journal

Yuya Yokota, Yuki Otsuka, Fumio Otsuka

International journal of general medicine 17 3465 - 3466 2024

Phase-dependent trends in the prevalence of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) related to long COVID: A criteria-based retrospective study in Japan. Reviewed International journal

Satoru Morita, Kazuki Tokumasu, Yuki Otsuka, Hiroyuki Honda, Yasuhiro Nakano, Naruhiko Sunada, Yasue Sakurada, Yui Matsuda, Yoshiaki Soejima, Keigo Ueda, Fumio Otsuka

PloS one 19 ( 12 ) e0315385 2024

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) related to COVID-19 have remained uncertain. To elucidate the clinical trend of ME/CFS induced by long COVID, we examined data for patients who visited our outpatient clinic established in a university hospital during the period from Feb 2021 to July 2023. METHODS: Long COVID patients were classified into two groups, an ME/CFS group and a non-ME/CFS group, based on three diagnostic criteria. RESULTS: The prevalence of ME/CFS in the long COVID patients was 8.4% (62 of 739 cases; female: 51.6%) and factors related to ME/CFS were severe illness, smoking and alcohol drinking habits, and fewer vaccinations. The frequency of ME/CFS decreased from 23.9% in the Preceding period to 13.7% in the Delta-dominant period and to 3.3% in the Omicron-dominant period. Fatigue and headache were commonly frequent complaints in the ME/CFS group, and the frequency of poor concentration in the ME/CFS group was higher in the Omicron period. Serum ferritin levels were significantly higher in female patients in the ME/CFS group infected in the Preceding period. In the ME/CFS group, the proportion of patients complaining of brain fog significantly increased from 22.2% in the Preceding period to 47.9% in the Delta period and to 81.3% in the Omicron period. The percentage of patients who had received vaccination was lower in the ME/CFS group than the non-ME/CFS group over the study period, whereas there were no differences in the vaccination rate between the groups in each period. CONCLUSION: The proportion of long COVID patients who developed ME/CFS strictly diagnosed by three criteria was lower among patients infected in the Omicron phase than among patients infected in the other phases, while the proportion of patients with brain fog inversely increased. Attention should be paid to the variant-dependent trends of ME/CFS triggered by long COVID (300 words).

DOI： 10.1371/journal.pone.0315385

Trends in childhood obesity in Japan: A nationwide observational study from 2012 to 2021. Reviewed International journal

Shintaro Fujiwara, Ko Harada, Hideharu Hagiya, Toshihiro Koyama, Kosei Hasegawa, Hirokazu Tsukahara, Fumio Otsuka

Clinical obesity e12636 2023.12

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

The persistent ascension of childhood obesity on a global scale constitutes a significant quandary. The prevalence of childhood obesity in Japan peaked in the early 2000s and has been reported to have declined since then, but recent data and its trend including the novel coronavirus disease 2019 (COVID-19) pandemic era are not available. Moreover, there is a dearth of studies examining the correlation between the trend in childhood obesity and exercise habits over the past decade. This study aims to examine the changes in the prevalence of obesity, physical fitness, and exercise habits over the past 10 years in Japanese children. We investigated the prevalence of childhood obesity in Japan, using the School Health Statistics Survey data from 2012 to 2021. The dataset has a sample size representative of children nationwide and includes variables for obesity, such as height, weight, and age. Data were classified into groups by sex and age (6-8, 9-11, and 12-14 years age). Children weighing 20% or more of the standard body weight are classified as obese. The annual percentage changes and average annual percentage changes were estimated using the joinpoint regression model. We also examined the trends in the physical fitness test score and exercise time. Average annual percentage changes of boys increased, especially in the 6- to 8-year age group (3.4%-4.6%). For girls, average annual percentage changes had increased in 6- to 8-year (2.5%-4.0%) and 9- to 11-year (0.9%-2.2%) age groups. Since the late 2010s, significantly increasing annual percentage changes were observed in 12- to 14-year age boys (6.7%-8.9%) and girls of many age groups (2.6%-8.6%). The physical fitness test score and exercise time showed decreasing trends since the late 2010s. Childhood obesity may have generally risen in Japan, in the last decade. Encouraging healthy eating and physical activity through school policies and curricula is necessary.

DOI： 10.1111/cob.12636

The effectiveness of simulation-based education combined with peer-assisted learning on clinical performance of first-year medical residents: a case-control study Reviewed

Taku Murakami, Akira Yamamoto, Hideharu Hagiya, Mikako Obika, Yasuhiro Mandai, Tomoko Miyoshi, Hitomi Kataoka, Fumio Otsuka

BMC Medical Education 23 ( 1 ) 2023.11

Authorship：Last author Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Background

Simulation-based education and peer-assisted learning (PAL) are both known as useful educational methods. Previous research has reported that combining these two methods are effective for training medical residents in short-term evaluation. This study was aimed to evaluate the middle- to long-term effects of simulation-based education combined with PAL on the performance of medical residents during emergency department duties.

Methods

This study was designed as a case-control study and conducted over three years at Okayama University Hospital in Japan. Postgraduate-year-one medical residents were assigned to three groups: a simulation group that received simulation-based education, a lecture group that received traditional lecture-based education, and a control group that received no such prior trainings. Prior training in emergency department duties using PAL was performed as an educational intervention for the simulation and lecture groups during the clinical orientation period. The residents’ medical knowledge was assessed by written examinations before and after the orientation. The performance of residents during their emergency department duties was assessed by self-evaluation questionnaires and objective-assessment checklists, following up with the residents for three months after the orientation period and collecting data on their 1st, 2nd, and 3rd emergency department duties. All the datasets collected were statistically analyzed and compared by their mean values among the three groups.

Results

A total of 75 residents were included in the comparative study: 27 in the simulation group, 24 in the lecture group, and 24 in the control group. The simulation and lecture groups obtained significantly higher written examination scores than the control group. From the self-evaluation questionnaires, the simulation group reported significantly higher satisfaction in their prior training than the lecture group. No significant differences were found in the emergency department performance of the residents among the three groups. However, when evaluating the improvement rate of performance over time, all three groups showed improvement in the subjective evaluation, and only the simulation and lecture groups showed improvement in the objective evaluation.

Conclusion

Simulation-based education combined with PAL is effective in improving the knowledge and satisfaction of medical residents, suggesting the possibility of improving work performance during their emergency department duties.

DOI： 10.1186/s12909-023-04798-w

Other Link： https://link.springer.com/article/10.1186/s12909-023-04798-w/fulltext.html

Characteristics of Persistent Symptoms Manifested after SARS-CoV-2 Vaccination: An Observational Retrospective Study in a Specialized Clinic for Vaccination-Related Adverse Events Reviewed

Kazuki Tokumasu, Manami Fujita-Yamashita, Naruhiko Sunada, Yasue Sakurada, Koichiro Yamamoto, Yasuhiro Nakano, Yui Matsuda, Yuki Otsuka, Toru Hasegawa, Hideharu Hagiya, Hiroyuki Honda, Fumio Otsuka

Vaccines 11 ( 11 ) 1661 - 1661 2023.10

Authorship：Last author Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Background: Although many adverse reactions after SARS-CoV-2 vaccination have been reported, there have been few comprehensive studies on persistent symptoms after SARS-CoV-2 vaccination. The aim of this study was to determine the clinical characteristics of patients with various persistent symptoms after SARS-CoV-2 vaccination. Methods: A retrospective descriptive study was performed for patients who visited a specialized clinic established at Okayama University Hospital to evaluate adverse events after SARS-CoV-2 vaccination during the period from April 2021 to March 2023. Results: Descriptive analysis was performed for 121 of 127 patients who visited the clinic during the study period, and separate analysis was performed for the other 6 patients who had serious complications, who required treatment with prednisolone, and who had persistent symptoms. The median [interquartile range] age of the patients was 48 years [31–64 years], and the patients included 44 males (36.4%) and 77 females (63.6%). The most frequent symptoms were sensory impairment (34 patients, 28.1%), general fatigue (30 patients, 24.8%), fever/low-grade fever (21 patients, 17.4%), and headache (21 patients, 17.4%). Serious complications included myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), sarcoidosis, aseptic meningitis, neuromyelitis optica spectrum disorders (NMOSDs), tendon adhesions, and idiopathic thrombocytopenia. Conclusions: Although causal relationships were not determined, 15 persistent symptoms after SARS-CoV-2 vaccination were characterized. All of the symptoms had onset from 12 hours to one week after vaccination, with 10 symptoms persisting for 6 months or longer. The most frequent symptom was sensory impairment.

DOI： 10.3390/vaccines11111661

Recognition and Practice of Hypopituitarism After Traumatic Brain Injury and Subarachnoid Hemorrhage in Japan: A Survey. Reviewed International journal

Shigeyuki Tahara, Fumio Otsuka, Takaaki Endo

Neurology and therapy 2023.10

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

INTRODUCTION: Individuals with traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH) are at a high risk of hypopituitarism, and should benefit from early diagnosis and management. However, data on awareness, attitudes, and practices of physicians treating hypopituitarism post-TBI/SAH are limited. The objectives of this study were to gain an understanding of the awareness of Japanese neurosurgeons and endocrinologists towards hypopituitarism post-TBI/SAH and the need for pituitary function assessments in these patients; and to assess the practices and perspectives of these specialists on screening patients with this condition. METHODS: An observational, cross-sectional study was performed that included a Web-based survey of practicing neurosurgeons managing ≥ 1 new patients with TBI/SAH per year or endocrinologists with ≥ 1 new patients per year with a history of TBI/SAH. RESULTS: Of the 316 respondents (201 neurosurgeons [male, 95.5%]; 115 endocrinologists [male, 77.4%]), 75.6% of neurosurgeons and 81.7% of endocrinologists were aware of the probable occurrence of hypopituitarism post-TBI/SAH, and 79% neurosurgeons and 93.8% endocrinologists considered pituitary function impairment after TBI/SAH to be either very important or important. Hypopituitarism after TBI/SAH was recognized as an important concern by both neurosurgeons (79%) and endocrinologists (93.8%). Although many respondents agreed that such patients remain undiagnosed and untreated, pituitary function assessment post-TBI/SAH has only been performed to a limited extent. The awareness that post-TBI/SAH hypopituitarism is often transient and can progress over several weeks or months was lower in neurosurgeons (46.8%) than in endocrinologists (66.1%). CONCLUSIONS: The level of awareness of hypopituitarism post-TBI/SAH was lower among Japanese neurosurgeons than among endocrinologists. Educational programs and detailed guidance for the diagnosis and treatment of hypopituitarism post-TBI/SAH are warranted.

DOI： 10.1007/s40120-023-00553-x

Relevance of complement immunity with brain fog in patients with long COVID. Reviewed International journal

Hideharu Hagiya, Kazuki Tokumasu, Yuki Otsuka, Naruhiko Sunada, Yasuhiro Nakano, Hiroyuki Honda, Masanori Furukawa, Fumio Otsuka

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 2023.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: This study aimed to elucidate the prevalence and clinical characteristics of patients with long COVID (coronavirus disease 2019), especially focusing on 50% hemolytic complement activity (CH50). METHODS: This retrospective observational study focused on patients who visited Okayama University Hospital (Japan) for the treatment of long COVID between February 2021 and March 2023. CH50 levels were measured using liposome immunometric assay (Autokit CH50 Assay, FUJIFILM Wako Pure Chemical Corporation, Japan); high CH50 was defined as ≥59 U/mL. Univariate analyses assessed differences in the clinical background, long COVID symptoms, inflammatory markers, and clinical scores of patients with normal and high CH50. Logistic regression model investigated the association between high CH50 levels and these factors. RESULTS: Of 659 patients who visited our hospital, 478 patients were included. Of these, 284 (59.4%) patients had high CH50 levels. Poor concentration was significantly more frequent in the high CH50 group (7.2% vs. 13.7%), whereas no differences were observed in other subjective symptoms (fatigue, headache, insomnia, dyspnea, tiredness, and brain fog). Multivariate analysis was performed on factors that could be associated with poor concentration, suggesting a significant relationship to high CH50 levels (adjusted odds ratio [aOR], 2.70; 95% confidence interval [CI], 1.33-5.49). Also, high CH50 was significantly associated with brain fog (aOR, 1.66; 95% CI, 1.04-2.66). CONCLUSIONS: High CH50 levels were frequently reported in individuals with long COVID, indicating a relationship with brain fog. Future in-depth research should examine the pathological role and causal link between complement immunity and the development of long COVID.

DOI： 10.1016/j.jiac.2023.10.016

Evaluating the efficiency and safety of large-volume leukapheresis using the Spectra Optia continuous mononuclear cell collection protocol for peripheral blood stem cell collection from healthy donors: A retrospective study. Reviewed International journal

Yuichi Sumii, Keiko Fujii, Takumi Kondo, Tomohiro Urata, Maiko Kimura, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken-Ichi Matsuoka, Fumio Otsuka, Yoshinobu Maeda, Nobuharu Fujii

Transfusion 2023.10

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

BACKGROUND: Large-volume leukapheresis (LVL) refers to processing of more than three volumes of blood in a single session for peripheral blood stem cell collection. Recently, continuous mononuclear cell collection (cMNC) protocol has been developed using the Spectra Optia system, which is a widely used apheresis device. LVL using the novel protocol has been investigated in patients. However, the efficiency and safety of LVL in healthy donors using this protocol has not been characterized. Therefore, this study aimed to evaluate the efficiency and tolerability of CD34+ collection of LVL with the cMNC protocol in healthy donors. STUDY DESIGN AND METHODS: We retrospectively collected data on LVL (>3 total blood volume) and normal-volume leukapheresis (NVL) performed in healthy donors between October 2019 and December 2021. All procedures were performed using the cMNC protocol. RESULTS: Although pre-apheresis CD34+ cell count was lesser in LVL (23.5 vs. 58.0/μL, p < .001), CD34+ collection efficiency was comparable between LVL and NVL (61.2% vs. 61.4%, p = .966). Platelet loss was significantly higher in LVL compared to NVL (38.0% vs. 29.4%, p < .001), with no correlation between attrition of platelet and processing blood volume. Moreover, the incidence of citrate toxicity during procedures was comparable between the two groups (31.6% vs. 21.4%, p = .322). All LVL procedures could be completed without any adverse events. CONCLUSION: Allogeneic LVL procedure using Spectra Optia cMNC protocol was well tolerated by the donors and resulted in efficient collection of CD34+ cells, which was comparable to that of NVL.

DOI： 10.1111/trf.17563

LETTER TO EDITOR: In the midst of a pandemic, significant event analysis may protect the well-being of healthcare professionals. Reviewed

Tomoko Miyoshi, Mikiko Iwatani and Fumio Otsuka

8 ( 4 ) 2023.10

Safety and usefulness of nebulized liposomal amphotericin B: Systematic scoping review. Reviewed International journal

Hideharu Hagiya, Yoshito Nishimura, Fumio Otsuka

Pulmonary pharmacology & therapeutics 82 102233 - 102233 2023.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Invasive fungal infections potentially result in fatal outcomes in immunocompromised hosts. Compared to intravenous administration, a nebulization therapy can achieve a high concentration of drug delivered in the respiratory tract, without a systematic absorption. We herein summarized the study findings on the safety and clinical utility of nebulized liposomal amphotericin B therapy. METHODS: According to the PRISMA Extension for Scoping Reviews, we performed a search on MEDLINE and EMBASE for articles with relevant keywords, including "inhaled liposomal amphotericin B″, "nebulized liposomal amphotericin B″, or "aerosolized liposomal amphotericin B″, from the inception of these databases to August 31, 2022. RESULTS: Of the 172 articles found, 27 articles, including 13 case reports, 11 observational studies, and 3 clinical trials, were selected. Generally, findings showed that nebulized liposomal amphotericin B treatment appeared to be safe and without severe adverse effects. We found an accumulated evidence for the safety, tolerability, and effectiveness of nebulized liposomal amphotericin B prophylaxis among lung transplantation recipients; however, a randomized controlled study has yet to be reported. Data on hemato-oncological patients are relatively scarce; however, a randomized controlled study suggested the prophylactic effect of nebulized liposomal amphotericin B on invasive pulmonary aspergillosis. Observational and randomized controlled studies to evaluate therapeutic efficacy of the nebulized liposomal amphotericin B therapy have not been performed. CONCLUSION: In conclusion, we found increasing evidence for the effectiveness of the inhalation therapy among patients after lung transplantation and with hemato-oncological diseases.

DOI： 10.1016/j.pupt.2023.102233

Clinical Characteristics of Retroperitoneal Fibrosis Patients at a Tertiary Hospital in Japan. Reviewed

Miho Ando, Yoshihisa Hanayama, Yoshito Nishimura, Hideharu Hagiya, Fumio Otsuka

Acta medica Okayama 77 ( 5 ) 527 - 536 2023.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Retroperitoneal fibrosis (RPF) is a rare cause of hydronephrosis and progressive renal dysfunction with unidentified origin. RPF is categorized into idiopathic RPF with/without immunoglobulin G4 (IgG4)-related disease (IgG4-RD), and secondary RPF. Identifying the underlying cause is challenging and often associated with delayed diagnosis or therapeutic interventions. We investigated RPF's clinical characteristics based on different etiologies and factors that may help distinguish the underlying causes. We analyzed the cases of 49 patients with RPF that was radiographically diagnosed at our institution (2008-2022). The cohort was 77.6% males; 75.5% had idiopathic RPF and 24.5% had secondary RPF. Among the idiopathic patients, 54.1% had IgG4-RD. The patients were likely to have abdominal pain, lower back pain/lumbago, and constitutional symptoms including generalized fatigue and fever. The idiopathic patients were likely to have higher serum IgG4 and IgG levels and lower serum C3 levels compared to secondary RPF. The IgG4-RPF patients were likely to have higher serum IgG4 levels and lower serum C-reactive protein, ferritin, and C3 levels compared to the idiopathic RPF patients without IgG4-RD. These findings might reflect underlying systemic inflammatory responses. Comprehensive laboratory testing, including serum inflammatory markers and immunological panels, is recommended for radiologically diagnosed RPF patients.

DOI： 10.18926/AMO/65975

一過性に口渇・多尿を生じた心因性多飲の1例

副島佳晃, 大塚勇輝, 川口満里奈, 大國皓平, 中野靖浩, 長谷川功, 大塚文男

日本内分泌学会雑誌 99 ( 2 ) 592 - 592 2023.10

Hypertension is the only clue for the discovery of adrenal rhabdomyosarcoma Reviewed

Koichiro Yamamoto, Fumio Otsuka

Hypertension Research 2023.9

Epidemiological Characteristics and Trends in the Incidence of Leptospirosis in Japan: A Nationwide, Observational Study from 2006 to 2021. Reviewed International journal

Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

The American journal of tropical medicine and hygiene 109 ( 3 ) 589 - 594 2023.9

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

During this age of climate change, the incidence of tropical diseases may change. This study compared the epidemiological characteristics and trends of leptospirosis in Japan between the endemic region, Okinawa, and the rest of the country. Infectious Diseases Weekly Reports were used to determine the numbers and crude incidence rates of leptospirosis. Data were stratified by sex, age, the estimated location of the infection, the notified regions, and the reporting month. A joinpoint regression analysis was performed to estimate the annual percentage change (APC). During the 16-year study period (2006-2021), 543 leptospirosis cases were reported, with male dominance (86.2%). Approximately half of these cases were reported from Okinawa (47.1%). The patients were relatively younger in Okinawa (20-29 years, 23.4%; 30-39 years, 20.7%) than outside Okinawa. The frequency of imported cases was significantly higher outside Okinawa (0.4% versus 14.3%). The incidences of leptospirosis in and outside Okinawa were apparently higher during the summer and typhoon seasons. The annual crude incidence ratios were 20-200 times higher in Okinawa than in the rest of the country. The average APCs for the entire study period in Okinawa and the rest of Japan were 1.6% (95% CI: -5.9 to 9.6) and -1.8% (95% CI: -7.8 to 4.6), respectively, without any particular trends. Collectively, the patient profile of leptospirosis differed between Okinawa (younger men) and outside Okinawa (middle- or older-aged men with a history of traveling abroad). The disease remains a neglected tropical disease; continuous surveillance with close monitoring is required.

DOI： 10.4269/ajtmh.23-0131

Case Report: Leptospirosis after a Typhoon Disaster Outside the Endemic Region, Japan. Reviewed International journal

Yukichika Yamamoto, Hideharu Hagiya, Ruiko Hayashi, Fumio Otsuka

The American journal of tropical medicine and hygiene 109 ( 3 ) 587 - 588 2023.9

Authorship：Last author Language：English

Leptospirosis is a zoonotic disease that primarily affects people in tropical and subtropical areas worldwide. Owing to the temperate climate of Japan, leptospirosis is not endemic across the country. Domestic cases of leptospirosis have been mainly reported in Okinawa and the southwestern subtropical islands, but not in the other regions. Here, we describe a case of leptospirosis that developed and was diagnosed outside the domestically endemic region. Notably, disease onset occurred shortly after the patient experienced a flood after a typhoon disaster. With global warming, the international prevalence of leptospirosis may change. Physicians outside currently endemic areas must be aware of this tropical disease.

DOI： 10.4269/ajtmh.23-0133

Task shifting of medical office works: A preliminary questionnaire survey for generalists. Reviewed

Yuki Otsuka, Hideharu Hagiya, Naruhiko Sunada, Fumio Otsuka

Journal of general and family medicine 24 ( 5 ) 317 - 319 2023.9

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

To reduce physician burden, task shifting of clerical work from physicians to medical assistants is being promoted; however, it depends on hospitals. A questionnaire survey was conducted among 40 general physicians at Okayama University Hospital in December 2022 to investigate physicians' preferences toward task shifting. Compared to other tasks, most physicians thought that ordering examinations (14, 47%), replying to referral letters (19, 63%), and prescriptions (21, 70%) and medical record entries (22, 73%) should not be task shifted. Physicians' controversial opinions on task shifting maybe the reason behind the slow progress in task shifting.

DOI： 10.1002/jgf2.641

Increased evidence for no benefit of contact precautions in preventing extended-spectrum β-lactamases-producing Enterobacteriaceae: Systematic scoping review Reviewed

Hideharu Hagiya, Fumio Otsuka

American Journal of Infection Control 51 ( 9 ) 1056 - 1062 2023.9

Super acute-onset disseminated BCG infection: A case report. Reviewed International journal

Ryosuke Takase, Hideharu Hagiya, Takumi Fujimori, Yukika Yokoyama, Koji Iio, Hiroyuki Honda, Kou Hasegawa, Fumio Otsuka

Journal of infection and chemotherapy 29 ( 9 ) 919 - 921 2023.9

Authorship：Last author Language：English

Intravesical Bacillus Calmette-Guérin (BCG) instillation is an established immunotherapy for superficial bladder cancer. Herein, we describe a case of disseminated BCG infection that developed immediately after the first BCG injection. A 76-year-old man diagnosed with non-invasive bladder cancer underwent intravesical BCG instillation; he developed high fever and systemic arthralgia later that night. General examination did not reveal any infectious sources, and a combination therapy of isoniazid, rifabutin, and ethambutol was initiated after collecting his blood, urine, bone marrow, and liver biopsy samples for mycobacterial cultures. Three weeks later, Mycobacterium bovis was detected in the urine and bone marrow samples, and pathological investigation of liver biopsy revealed multiple small epithelial granulomas with focal multinucleated giant cells, leading to a diagnosis of disseminated BCG infection. The patient recovered after long-term antimycobacterial therapy without remarkable sequelae. Most cases of disseminated BCG infection occur after several doses of BCG injections, and its onset reportedly varies among cases, ranging from a few days to several months. The present case was notable as disease onset was observed only a few hours after the first BCG injection. Although rare, development of disseminated BCG infection should be considered as a differential diagnosis in patients at any time after intravesical BCG instillation therapy.

DOI： 10.1016/j.jiac.2023.05.017

Interaction of Orexin and Bone Morphogenetic Proteins in Steroidogenesis by Human Adrenocortical Cells Reviewed

Yoshiaki Soejima, Nahoko Iwata, Ran Nishioka, Mako Honda, Yasuhiro Nakano, Koichiro Yamamoto, Atsuhito Suyama, Fumio Otsuka

International Journal of Molecular Sciences 24 ( 16 ) 12559 - 12559 2023.8

Authorship：Last author,　Corresponding author Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Orexins are neuropeptides that play important roles in sleep-wake regulation and food intake in the central nervous system, but their receptors are also expressed in peripheral tissues, including the endocrine system. In the present study, we investigated the functions of orexin in adrenal steroidogenesis using human adrenocortical H295R cells by focusing on its interaction with adrenocortical bone morphogenetic proteins (BMPs) that induce adrenocortical steroidogenesis. Treatment with orexin A increased the mRNA levels of steroidogenic enzymes including StAR, CYP11B2, CYP17, and HSD3B1, and these effects of orexin A were further enhanced in the presence of forskolin. Interestingly, orexin A treatment suppressed the BMP-receptor signaling detected by Smad1/5/9 phosphorylation and Id-1 expression through upregulation of inhibitory Smad7. Orexin A also suppressed endogenous BMP-6 expression but increased the expression of the type-II receptor of ActRII in H295R cells. Moreover, treatment with BMP-6 downregulated the mRNA level of OX1R, but not that of OX2R, expressed in H295R cells. In conclusion, the results indicate that both orexin and BMP-6 accelerate adrenocortical steroidogenesis in human adrenocortical cells; both pathways mutually inhibit each other, thereby leading to a fine-tuning of adrenocortical steroidogenesis.

DOI： 10.3390/ijms241612559

Feasibility of Flow Cytometry Analysis of Gastrointestinal Tract-Residing Lymphocytes in Hematopoietic Stem Cell Transplant Recipients. Reviewed

Masaya Iwamuro, Takumi Kondo, Daisuke Ennishi, Nobuharu Fujii, Ken-Ichi Matsuoka, Takahide Takahashi, Araki Hirabata, Takehiro Tanaka, Fumio Otsuka, Yoshinobu Maeda, Hiroyuki Okada

Acta medica Okayama 77 ( 4 ) 347 - 357 2023.8

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

The feasibility of lymphocyte isolation and flow cytometry using a single endoscopic biopsy specimen from the gastrointestinal tract of patients who have undergone hematopoietic stem cell transplantation has not been investigated. We acquired 51 endoscopic biopsy specimens from the gastrointestinal tract of 35 patients. We divided the flow cytometry samples into two groups: group A, successful lymphocyte isolation (n=24), and group B, incomplete isolation (n=27). We compared the backgrounds of the samples between the groups to reveal crucial elements in the successful isolation of lymphocytes residing in the gastrointestinal tract. Comparison between the groups revealed lymphocyte isolation success rates differed between biopsy sites. Isolation was most successful in samples from the duodenum (8/9, 88.9%), followed by the ileum (4/8, 50.0%), large intestine (4/11, 36.4%), and stomach (8/23, 34.8%). Tacrolimus was used more frequently in group B (92.6%) than in group A (62.5%) (p=0.015). Logistic regression analysis revealed that isolation from the duodenum or ileum was a significant factor for successful isolation, while tacrolimus use was not statistically significant. In conclusion, the duodenum and ileum are more suitable sites than the stomach and colorectum for acquiring samples for flow cytometry.

DOI： 10.18926/AMO/65740

Preoperative detection of functional somatostatin receptors in a patient with an insulinoma. Reviewed International journal

Kohei Oguni, Shinnosuke Fukushima, Yukichika Yamamoto, Kou Hasegawa, Hideharu Hagiya, Naoko Inoshita, Fumio Otsuka

Clinical case reports 11 ( 8 ) e7771 2023.8

Authorship：Last author Language：English

Octreotide is used in patients with insulinomas to treat hypoglycemia, and somatostatin receptor (SSTR) 2 expression is important for its efficacy. We report a case of insulinoma in a 50-year-old woman that responded to an octreotide test, showed accumulation in somatostatin scintigraphy, and was positive for SSTR2A on immunostaining.

DOI： 10.1002/ccr3.7771

COVID-19罹患を契機に発症したリウマチ性多発筋痛症の一例

高木桃李, 大塚勇輝, 副島佳晃, 川口満理奈, 大國皓平, 徳増一樹, 長谷川功, 本多寛之, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 166 - 166 2023.8

Covid-19流行時の予防、診療、感染制御に貢献する病院総合診療医～全国97の総合診療部門の解析

香月尚子, 多胡雅毅, 平田理紗, 大塚勇輝, 志水太郎, 佐々木陽典, 鋪野紀好, 和足孝之, 高橋宏端, 宇根一暢, 内藤俊夫, 大塚文男, 田妻進

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 169 - 169 2023.8

褥瘡を伴う胸髄損傷患者に発症した腰部化膿性脊椎炎の1例

森田悟, 加藤篤之, 須山敦仁, 佐藤啓介, 佐住洋祐, 大塚勇輝, 大國皓平, 大野洋平, 長谷川功, 本多寛之, 萩谷英大, 小田孔明, 今村竜太, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 180 - 180 2023.8

自動車運転中の失神・交通事故の原因精査に詳細な血糖測定が有用であった一例

佐藤啓介, 高瀬了輔, 森田悟, 加藤篤之, 須山敦仁, 佐住洋祐, 大塚勇輝, 大國皓平, 長谷川功, 本多寛之, 小比賀美香子, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 181 - 181 2023.8

当院総合内科・総合診療科における後腹膜線維症49症例の特徴の検討

花山宜久, 安藤美穂, 西村義人, 徳増一樹, 長谷川功, 萩谷英大, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 163 - 163 2023.8

Covid-19流行時の予防、診療、感染制御に貢献する病院総合診療医～全国97の総合診療部門の解析

香月尚子, 多胡雅毅, 平田理紗, 大塚勇輝, 志水太郎, 佐々木陽典, 鋪野紀好, 和足孝之, 高橋宏瑞, 宇根一暢, 内藤俊夫, 大塚文男, 田妻進

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 169 - 169 2023.8

眼内炎診療における病院総合医の役割

川口満理奈, 大塚勇輝, 副島佳晃, 安藤航, 高木桃李, 大國皓平, 長谷川功, 本多寛之, 萩谷英大, 小比賀美香子, 森田哲郎, 森實祐基, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 142 - 142 2023.8

病初期より関節リウマチの臨床像も有したリウマチ性多発筋痛症の一例

安藤航, 大塚勇輝, 副島佳晃, 川口満理奈, 大國皓平, 本多寛之, 長谷川功, 花山宜久, 勝山隆行, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 150 - 150 2023.8

MOCA-Jを用いたCOVID-19罹患後症状のブレインフォグの臨床的特徴の解明

長谷川徹, 大塚勇輝, 櫻田泰江, 徳増一樹, 砂田匠彦, 小西隆之, 中野靖浩, 本多寛之, 萩谷英大, 小比賀美香子, 植田圭吾, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 168 - 168 2023.8

病初期より関節リウマチの臨床像も有したリウマチ性多発筋痛症の一例

安藤航, 大塚勇輝, 副島佳晃, 川口満理奈, 大國皓平, 本多寛之, 長谷川功, 花山宜久, 勝山隆行, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 150 - 150 2023.8

眼内炎診療における病院総合医の役割

川口満理奈, 大塚勇輝, 副島佳晃, 安藤航, 高木桃李, 大國皓平, 長谷川功, 本多寛之, 萩谷英大, 小比賀美香子, 森田哲郎, 森實祐基, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 142 - 142 2023.8

自動車運転中の失神・交通事故の原因精査に詳細な血糖測定が有用であった一例

佐藤啓介, 高瀬了輔, 森田悟, 加藤篤之, 須山敦仁, 佐住洋祐, 大塚勇輝, 大國皓平, 長谷川功, 本多寛之, 小比賀美香子, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 181 - 181 2023.8

就学患者のCOVID-19罹患後症状とその社会的影響

櫻田泰江, 大塚勇輝, 徳増一樹, 砂田匠彦, 本多寛之, 中野靖浩, 松田祐依, 萩谷英大, 植田圭吾, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 168 - 168 2023.8

褥瘡を伴う胸髄損傷患者に発症した腰部化膿性脊椎炎の1例

森田悟, 加藤篤之, 須山敦仁, 佐藤啓介, 佐住洋祐, 大塚勇輝, 大國皓平, 大野洋平, 長谷川功, 本多寛之, 萩谷英大, 小田孔明, 今村竜太, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 180 - 180 2023.8

COVID-19罹患を契機に発症したリウマチ性多発筋痛症の一例

高木桃李, 大塚勇輝, 副島佳晃, 川口満理奈, 大國皓平, 徳増一樹, 長谷川功, 本多寛之, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 166 - 166 2023.8

当院総合内科・総合診療科における後腹膜線維症49症例の特徴の検討

花山宜久, 安藤美穂, 西村義人, 徳増一樹, 長谷川功, 萩谷英大, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 163 - 163 2023.8

不明熱診療にて遭遇した機能性高体温症とその臨床的特徴

岡浩介, 徳増一樹, 萩谷英大, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増2 ) 145 - 145 2023.8

Phase-dependent trends of male hypogonadism in long COVID patients. Reviewed

Naruhiko Sunada, Yuki Otsuka, Hiroyuki Honda, Kazuki Tokumasu, Fumio Otsuka

Endocrine journal 70 ( 7 ) 755 - 756 2023.7

Utility of Serum Ferritin for Predicting Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Patients with Long COVID. Reviewed International journal

Yukichika Yamamoto, Yuki Otsuka, Kazuki Tokumasu, Naruhiko Sunada, Yasuhiro Nakano, Hiroyuki Honda, Yasue Sakurada, Toru Hasegawa, Hideharu Hagiya, Fumio Otsuka

Journal of clinical medicine 12 ( 14 ) 2023.7

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The most common symptom of post-acute coronavirus disease 2019 (COVID-19) is fatigue, and it potentially leads to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); however, a specific prognosticator is lacking. We aimed to elucidate the clinical characteristics of patients who developed ME/CFS after COVID-19. METHODS: In this retrospective observational study, patients who visited Okayama University Hospital for long COVID between February 2021 and March 2022 were investigated. RESULTS: Of the 234 patients, 139 (59.4%) had fatigue symptoms. Fifty patients with fatigue symptoms (21.4%) met the criteria for ME/CFS (ME/CFS group), while the other 89 patients did not (non-ME/CFS group); 95 patients had no fatigue complaints (no-fatigue group). Although the patients' backgrounds were not significantly different between the three groups, the ME/CFS group presented the highest scores on the self-rating symptom scales, including the Fatigue Assessment Scale (FAS), EuroQol, and the Self-Rating Depression Scale (SDS). Furthermore, serum ferritin levels, which were correlated with FAS and SDS scores, were significantly higher in the ME/CFS group (193.0 μg/L, interquartile range (IQR): 58.8-353.8) than in the non-ME/CFS group (98.2 μg/L, 40.4-251.5) and no-fatigue group (86.7 μg/L, 37.5-209.0), and a high serum ferritin level was prominent in female patients. Endocrine workup further showed that the ME/CFS group had higher thyrotropin levels but lower growth hormone levels in serum and that insulin-like growth factor-I levels were inversely correlated with ferritin levels (R = -0.328, p < 0.05). CONCLUSIONS: Serum ferritin level is a possible predictor of the development of ME/CFS related to long COVID, especially in female patients.

DOI： 10.3390/jcm12144737

Angioedema‐like eyelid edema following the second NVX‐CoV2373 COVID‐19 vaccination Reviewed

Mari Matsumoto, Yoshio Kawakami, Tomoko Miyake, Yoji Hirai, Hitomi Kataoka, Fumio Otsuka, Shin Morizane

Journal of Cutaneous Immunology and Allergy 6 ( 5 ) 194 - 195 2023.7

A Case of Typhoid Fever Presenting with Non-G6PD Associated Hemolytic Anemia Reviewed

Shinnosuke Fukushima, Hideharu Hagiya, Hiroyuki Honda, Tomoharu Ishida, Kou Hasegawa, Fumio Otsuka

Journal of Travel Medicine 2023.7

Authorship：Last author Publishing type：Research paper (scientific journal) Publisher：Oxford University Press (OUP)

Typhoid fever is one of the representative febrile diseases in tropical and subtropical countries with poor hygiene. Among the anaemic conditions involving patients with typhoid fever, autoimmune hemolytic anaemia would be one of the potential causes in the absence of G6PD deficiency or intestinal haemorrhage

DOI： 10.1093/jtm/taad092

Endogenous panophthalmitis after colonoscopy Reviewed

Yukichika Yamamoto, Kohei Oguni, Hideharu Hagiya, Fumio Otuska

Internal and Emergency Medicine 2023.7

Antiviral effect and safety of nafamostat mesilate in patients with mild early-onset COVID-19: An exploratory multicenter randomized controlled clinical trial. Reviewed International journal

Shu Okugawa, Mahoko Ikeda, Kosuke Kashiwabara, Takashi Moritoyo, Takao Kohsaka, Toshio Shimizu, Hideharu Hagiya, Kou Hasegawa, Fumio Otsuka, Ayumi Miwa, Nobuhito Kisimoto, Ayako Mizoguchi, Akira Imamura, Kazuhiko Ikeuchi, Takeya Tsutsumi, Daisuke Jubishi, Hideki Hashimoto, Koh Okamoto, Sohei Harada, Jun-Ichiro Inoue, Yasuyuki Seto, Kyoji Moriya

International journal of antimicrobial agents 62 ( 3 ) 106922 - 106922 2023.7

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

OBJECTIVES: This study aimed to evaluate the antiviral effects and safety of nafamostat in early-onset patients with coronavirus disease 2019 (COVID-19). METHODS: In this exploratory multicenter randomized controlled trial, patients were assigned to three groups within 5 days of symptom onset, with 10 participants in each group: nafamostat at either 0.2 mg/kg/h or 0.1 mg/kg/h or a standard-of-care group. The primary endpoint was area under the curve for decrease in SARS-CoV-2 viral load in nasopharyngeal samples from baseline to day 6. RESULTS: Of the 30 randomized patients, 19 received nafamostat. Overall, 10 patients received low-dose nafamostat, 9 patients received high-dose nafamostat, and 10 received standard-of-care. The detected viruses were Omicron strains. The regression coefficient for area under the curve for decrease in viral load as the response variable and nafamostat dose per body weight as the explanatory variable showed a significant relationship of -40.1 (95% confidence interval, -74.1 to -6.2; p=0.022). Serious adverse events were not observed in either group. Phlebitis occurred in approximately 50% of patients treated with nafamostat. CONCLUSIONS: Nafamostat exerts virus load-reducing effects in patients with early-onset COVID-19.

DOI： 10.1016/j.ijantimicag.2023.106922

臨床実習前医学生におけるゾーニング実習の実践

越智可奈子, 萩谷英大, 小崎吉訓, 三好智子, 山下範之, 伊野英男, 成瀬恵治, 大塚文男, 松川昭博

医学教育 54 ( Suppl. ) 296 - 296 2023.7

成人成長ホルモン分泌不全症における医療者教育実践に関する検討

越智可奈子, 徳増一樹, 大塚勇輝, 中野靖浩, 小比賀美香子, 大塚文男

医学教育 54 ( Suppl. ) 296 - 296 2023.7

Acute arthritis caused by sarcoidosis. Reviewed

Rio Ogami, Yuki Otsuka, Kou Hasegawa, Kazuki Tokumasu, Mikako Obika, Masanori Fujii, Fumio Otsuka

Journal of general and family medicine 24 ( 4 ) 264 - 265 2023.7

Authorship：Last author Language：English

Here we report a case of sarcoidosis which demonstrated with bilateral ankle arthritis. We usually do not consider sarcoidosis routinely for the differential diagnosis of acute arthritis, however, up to 15 to 25% of sarcoidosis complicate arthritis, typically in ankle joints. Sarcoid arthritis is reported to occur mainly in young northern Europe women, whereas this case intimate that we should take sarcoidosis into account as the differential diagnosis of ankle arthralgia also among Asian men especially when combining upper respiratory symptoms.

DOI： 10.1002/jgf2.621

四肢と左臀部に皮下硬結を形成したExtensive Subcutaneous Sarcoidosisの1例

臼井真菜, 杉原悟, 立花宏太, 川上佳夫, 森実真, 中本健太, 大塚文男

日本皮膚科学会雑誌 133 ( 8 ) 1889 - 1889 2023.7

大学病院総合内科・総合診療科における臨床実習教育の学生視点の気づきとは質的研究

山本幸近, 徳増一樹, 大塚文男

医学教育 54 ( Suppl. ) 205 - 205 2023.7

Efficient granulocyte collection method using high concentrations of medium molecular weight hydroxyethyl starch Reviewed

Takumi Kondo, Keiko Fujii, Nobuharu Fujii, Yuichi Sumii, Tomohiro Urata, Maiko Kimura, Masayuki Matsuda, Shuntaro Ikegawa, Kana Washio, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken‐ichi Matsuoka, Fumio Otsuka, Yoshinobu Maeda

Transfusion 2023.6

Current Prevalence of Antimicrobial Resistance in Okayama from a National Database between 2018 and 2021. Reviewed

Shinnosuke Fukushima, Hideharu Hagiya, Kazuhiro Uda, Kazuyoshi Gotoh, Fumio Otsuka

Acta medica Okayama 77 ( 3 ) 255 - 262 2023.6

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Antimicrobial resistance is an emerging global threat that must be addressed using a multidisciplinary approach. This study aimed to raise awareness of high-level antimicrobial-resistant (AMR) pathogens in Japan by comparing their recent prevalences among prefectures, particularly Okayama. Data for the isolation proportions of meropenem-resistant Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, cefotaxime-resistant Escherichia coli and Klebsiella pneumoniae, and levofloxacin-resistant E. coli and K. pneumoniae were collected from the Japan Nosocomial Infections Surveillance, a national database sponsored by the Japanese Ministry of Health, Labour, and Welfare, between 2018 and 2021. The average isolated proportions of the seven AMR pathogens were higher in Okayama compared to other prefectures: the worst (19.9%) was meropenem-resistant P. aeruginosa, the sixth worst (57.2%) was methicillin-resistant S. aureus, the eighth worst (3.3%) was vancomycin-resistant E. faecium, the second (37.8%) and fifth worst (17.6%) were cefotaxime-resistant E. coli and K. pneumoniae, respectively, and the fourth (49.9%) and third worst (8.7%) were levofloxacin-resistant E. coli and K. pneumoniae, respectively. Our study highlights the notably high prevalences of representative AMR pathogens in Okayama, suggesting the need for fundamental infection prevention and control by healthcare professionals, promoting antimicrobial stewardship, and educating undergraduates and postgraduates in Okayama.

DOI： 10.18926/AMO/65490

Endocrinological Changes after Anamorelin Administration in Patients with Gastrointestinal Cancer. Reviewed

Sakiko Kuraoka, Masaya Iwamuro, Takuya Satomi, Tatsuhiro Yamazaki, Kenta Hamada, Yoshiyasu Kono, Hiromitsu Kanzaki, Hironari Kato, Fumio Otsuka, Hiroyuki Okada

Acta Medica Okayama 77 ( 3 ) 235 - 241 2023.6

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Changes in hormone levels in patients with cancer cachexia after anamorelin administration have not been fully investigated. This study aimed to determine how anamorelin affects the endocrine system in patients with gastrointestinal cancer and cachexia. We prospectively enrolled 13 patients and comprehensively investigated their body weight and levels of serum albumin, hemoglobin A1c (HbA1c), and hormones before (week 0) and 3 and 12 weeks after anamorelin administration. The variables were evaluated at week 3 in 9 patients and at week 12 in 5 patients. At week 3, anamorelin administration resulted in body weight gain and increased the levels of growth hormone and HbA1c, as well as insulin-like growth factor-1 standard deviation scores (IGF-1 SD scores). At the same time, negative correlations were observed between ΔIGF-1 SD score and Δthyroidstimulating hormone (TSH) and between ΔIGF-1 SD score and Δfree testosterone. ΔBody weight and ΔIGF-1 SD score correlated positively at week 12. These results suggest that TSH and free testosterone levels can be affected 3 weeks after anamorelin administration; however, those variables tend to return to a state of equilibrium, and anabolic effects of anamorelin appear in long-term (≥ 12 weeks) users.

DOI： 10.18926/AMO/65488

最先端医療の今内分泌視点から捉えたCOVID-19罹患後の倦怠感の機序とその解明

大塚勇輝, 徳増一樹, 大塚文男

Medical Science Digest 49 ( 7 ) 385 - 387 2023.6

Language：Japanese Publisher：(株)ニュー・サイエンス社

新型コロナウイルス感染症(COVID-19)罹患後症状(Post COVID-19 Condition:PCC)に悩む患者が多く存在し社会的問題となっている中で,その最多症状である「全身倦怠感」は鑑別すべき疾患も多く検査での可視化も難しい。一方でPCCに伴う倦怠感の重症度は症例によって大きく異なっており,倦怠感の客観的評価や予後予測に有用な指標を見出すことがPCC診療と研究における課題である。我々は2021年2月にいち早くPCCの専門外来であるコロナ・アフターケア外来を開設し多数のPCC患者の診療を行ってきた。そこで得られたデータをもとに科学研究費の助成も受けてPCCにおける倦怠感を内分泌の視点から考察を試み世界に向けた発信を目指しているところである。本稿ではそうした我々の取組みと得られつつある知見について概説する。(著者抄録)

Manifestation of Headache Affecting Quality of Life in Long COVID Patients. Reviewed International journal

Kana Fujita, Yuki Otsuka, Naruhiko Sunada, Hiroyuki Honda, Kazuki Tokumasu, Yasuhiro Nakano, Yasue Sakurada, Mikako Obika, Hideharu Hagiya, Fumio Otsuka

Journal of clinical medicine 12 ( 10 ) 2023.5

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Objectives: The present study aimed to elucidate the characteristics of long COVID patients with headaches. Methods: A single-center retrospective observational study was performed for long COVID outpatients who visited our hospital from 12 February 2021 to 30 November 2022. Results: A total of 482 long COVID patients, after excluding 6, were divided into two groups: the Headache group of patients with complaints of headache (113 patients: 23.4%) and the remaining Headache-free group. Patients in the Headache group were younger (median age: 37 years) than patients in the Headache-free group (42 years), while the ratio of females (56%) in the Headache group was nearly the same as that in the Headache-free group (54%). The proportion of patients in the Headache group who were infected in the Omicron-dominant phase (61%) was larger than the proportions of patients infected in the Delta (24%) and preceding (15%) phases, and that trend was significantly different from the trend in the Headache-free group. The duration before the first visit for long COVID was shorter in the Headache group (71 days) than in the Headache-free group (84 days). The proportions of patients in the Headache group with comorbid symptoms, including general fatigue (76.1%), insomnia (36.3%), dizziness (16.8%), fever (9.7%), and chest pain (5.3%) were larger than the proportions of patients in the Headache-free group, whereas blood biochemical data were not significantly different between the two groups. Interestingly, patients in the Headache group had significant deteriorations of scores indicating depression and scores for quality of life and general fatigue. In multivariate analysis, headache, insomnia, dizziness, lethargy, and numbness were shown to be involved in the quality of life (QOL) of long COVID patients. Conclusions: The manifestation of headaches related to long COVID was found to have a significant impact on social and psychological activities. Alleviation of headaches should be a priority for the effective treatment of long COVID.

DOI： 10.3390/jcm12103533

Furious lung abscess due to Parvimonas micra Reviewed

Shinnosuke Fukushima, Hideharu Hagiya, Hiromichi Naito, Fumio Otsuka

Respirology Case Reports 11 ( 6 ) 2023.5

Stimulatory effects of vasopressin on progesterone production and BMP signaling by ovarian granulosa cells Reviewed

Koichiro Yamamoto, Yasuhiro Nakano, Nahoko Iwata, Yoshiaki Soejima, Atsuhito Suyama, Toru Hasegawa, Fumio Otsuka

Biochemical and Biophysical Research Communications 2023.5

【医師の書類作成はじめの一歩診療情報提供書、診断書から院内の記録まで、効率的な"伝わる書類"の書きかた】電子カルテ時代の診療記録への心構え

大塚勇輝, 大塚文男

レジデントノート 25 ( 3 ) 420 - 424 2023.5

Susceptibility of ceftolozane/tazobactam against multidrug-resistant and carbapenem-resistant Pseudomonas aeruginosa. Reviewed International journal

Ayaka Kakehi, Hideharu Hagiya, Koji Iio, Takumi Fujimori, Mami Okura, Hiroshi Minabe, Yukika Yokoyama, Fumio Otsuka, Akihito Higashikage

The new microbiologica 46 ( 2 ) 213 - 215 2023.5

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

Ceftolozane (CTLZ) is a novel cephalosporin antibiotic that exhibits broad-spectrum activity against gram-negative pathogens, including Pseudomonas aeruginosa, especially when combined with tazobactam (TAZ). We examined the minimum inhibitory concentration (MIC) of CTLZ/TAZ for 21 multidrug-resistant P. aeruginosa (MDRP) and eight carbapenem-resistant P. aeruginosa (CRPA) strains isolated at Okayama University Hospital, Japan. Consequently, 81% (17/21) of the MDRP strains and 25% (2/8) of the CRPA strains were resistant to CTLZ/TAZ (MIC >8 μg/mL). All 18 blaIMP-positive strains showed resistance to CTLZ/TAZ, whereas the drug retained in vitro susceptibility in 54.5% (6/11 strains) of blaIMP-negative strains.

多発骨折を契機に発見され、社会的介入を要したビタミンD欠乏の1例

須山敦仁, 大塚勇輝, 中野靖浩, 松田祐依, 櫻田泰江, 小比賀美香子, 豊川達也, 大塚文男

日本内分泌学会雑誌 99 ( 1 ) 389 - 389 2023.5

後縦靱帯骨化症を合併し椎弓切除術を要した成人XLHの1例

山本紘一郎, 本多寛之, 大國皓平, 中野靖浩, 徳増一樹, 長谷川功, 長谷川高誠, 安原隆雄, 大塚文男

日本内分泌学会雑誌 99 ( 1 ) 330 - 330 2023.5

新型コロナウイルス後遺症診療において発見された内分泌代謝疾患

中野靖浩, 副島佳晃, 田中秀一, 大塚勇輝, 徳増一樹, 本多寛之, 長谷川功, 萩谷英大, 大塚文男

日本内分泌学会雑誌 99 ( 1 ) 323 - 323 2023.5

Case Series of Granulicatella Bacteremia: A Single-centered, Five-year Retrospective Study. Reviewed

Shinnosuke Fukushima, Hideharu Hagiya, Koji Iio, Hiroyuki Honda, Tomoharu Ishida, Hirokazu Nagaoka, Kou Hasegawa, Fumio Otsuka

Acta medica Okayama 77 ( 2 ) 203 - 207 2023.4

Authorship：Last author Language：English

Granulicatella species are rare, nutritionally variant streptococci that cause infective endocarditis. Their clinical and microbiological characteristics remain unknown. We reviewed five years of Granulicatella cases in our hospital database (Jan 2017-Jun 2022), finding 6 Granulicatella adiacens cases and 1 Granulicatella elegans case. Clinical backgrounds and bacteremia sources were diverse; 3 cases developed polymicrobial bacteremia. Antimicrobial testing showed non-susceptibility to penicillin G in 4 of 7 cases (57.1%), and high susceptibility to carbapenems and vancomycin in all cases. Determining optimal antibiotic therapy for Granulicatella infections is vital in this era of antimicrobial resistance.

DOI： 10.18926/AMO/65151

四肢と左臀部に生じたextensive subcutaneous sarcoidosisの1例

臼井真菜, 杉原悟, 立花宏太, 安富陽平, 川上佳夫, 中本健太, 大塚文男, 森実真

西日本皮膚科 85 ( 2 ) 109 - 112 2023.4

Language：Japanese Publisher：日本皮膚科学会-西部支部

71歳,女性。1年前に右膝と両側前腕に皮下硬結を自覚し,その後左臀部にも皮下硬結が出現した。右膝に20×10cm,左臀部に10×7cm,右前腕に10×7cm,左前腕に2個の7×5cmの板状皮下硬結がみられた。皮膚生検では皮下脂肪組織に非乾酪壊死性類上皮細胞肉芽腫を認め,sIL-2Rは1697.0U/mlと高値であった。胸部CTでは縦隔リンパ節の軽度腫大があり,Gaシンチグラフィーでは四肢と左臀部の皮下硬結部に高度な集積を認め,extensive subcutaneous sarcoidosisと診断した。膝関節屈曲制限が生じる懸念があったためプレドニゾロン25mg/day内服を開始したところ,皮下病変は速やかに縮小し,sIL-2Rは418.3U/mlまで低下した。皮下型サルコイドーシスではトラニラストやミノサイクリン内服で軽快する症例や,無治療で軽快する症例もあるが,本症例では,右膝部皮下病変の拡大による歩行障害が懸念されたため,ステロイド内服による治療を選択した。広範な皮下型病変を呈するサルコイドーシスでは,sIL-2Rや皮膚病変のサイズなどを総合的に評価し,病勢を検討することが必要である。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01003&link_issn=&doc_id=20230516250006&doc_link_id=10.2336%2Fnishinihonhifu.85.109&url=https%3A%2F%2Fdoi.org%2F10.2336%2Fnishinihonhifu.85.109&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Symptomatic Characteristics of Hypozincemia Detected in Long COVID Patients. Reviewed International journal

Yui Matsuda, Kazuki Tokumasu, Yuki Otsuka, Naruhiko Sunada, Hiroyuki Honda, Yasue Sakurada, Yasuhiro Nakano, Toru Hasegawa, Mikako Obika, Keigo Ueda, Fumio Otsuka

Journal of clinical medicine 12 ( 5 ) 2023.3

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: The aim of this study was to determine the characteristics of hypozincemia in long COVID patients. METHODS: This study was a single-center retrospective observational study for outpatients who visited the long COVID clinic established in a university hospital during the period from 15 February 2021 to 28 February 2022. Characteristics of patients with a serum zinc concentration lower than 70 μg/dL (10.7 μmol/L) were compared with characteristics of patients with normozincemia. RESULTS: In a total of 194 patients with long COVID after excluding 32 patients, hypozincemia was detected in 43 patients (22.2%) including 16 male patients (37.2%) and 27 female patients (62.8%). Among various parameters including the background characteristics of the patients and medical histories, the patients with hypozincemia were significantly older than the patients with normozincemia (median age: 50 vs. 39 years). A significant negative correlation was found between serum zinc concentrations and age in male patients (R = -0.39; p < 0.01) but not in female patients. In addition, there was no significant correlation between serum zinc levels and inflammatory markers. General fatigue was the most frequent symptom in both male patients with hypozincemia (9 out of 16: 56.3%) and female patients with hypozincemia (8 out of 27: 29.6%). Patients with severe hypozincemia (serum zinc level lower than 60 μg/dL) had major complaints of dysosmia and dysgeusia, which were more frequent complaints than general fatigue. CONCLUSIONS: The most frequent symptom in long COVID patients with hypozincemia was general fatigue. Serum zinc levels should be measured in long COVID patients with general fatigue, particularly in male patients.

DOI： 10.3390/jcm12052062

ペースメーカ留置を回避出来た粘液水腫性昏睡による洞不全症候群の1例

長谷川功, 原田洸, 山本紘一郎, 中野靖浩, 大塚文男

日本内分泌学会雑誌 98 ( 5 ) 1302 - 1302 2023.3

若年男性の橋本病による粘液水腫の1例

山本紘一郎, 本多寛之, 中野靖浩, 長谷川功, 大塚文男

日本内分泌学会雑誌 98 ( 5 ) 1303 - 1303 2023.3

ハンセン病に対する免疫抑制療法を背景に発症した播種性糞線虫症の1例

中本健太, 萩谷英大, 平佑貴, 庵谷紘美, 中野靖浩, 長谷川功, 大塚文男

感染症学雑誌 97 ( 2 ) 52 - 57 2023.3

Language：Japanese Publisher：(一社)日本感染症学会

症例は30歳代ネパール人男性で、下痢と嘔気を主訴とした。ハンセン病(LL型)と新型コロナウイルス感染症の既往があり、らい反応に対して長期間のステロイド製剤内服による免疫抑制療法を行っていた。各種検査所見より、糞線虫の過剰感染状態による播種性糞線虫症と診断した。栄養状態は不良で、寄生虫の消化管内過剰増殖に伴う腸管浮腫を認め、イベルメクチンは吸収不良で血中濃度が不十分であった。多臓器不全を併発したため集学的治療を行ったが第36病日に死亡した。日本では糞線虫症は稀であるが、インバウンドの増加に伴い播種性糞線虫症のリスクが増加する可能性があり、ステロイドの長期内服などで免疫抑制状態の可能性がある場合は寄生虫スクリーニングを行う必要があると考えられた。

【臨床検査で患者を救え!-知っておいてほしい疾患】重度で長期の甲状腺機能低下症

越智可奈子, 中野靖浩, 原田洸, 長谷川功, 大塚文男

臨床検査 67 ( 3 ) 246 - 253 2023.3

プラスミノーゲン欠乏症に腸管型ベーチェット病を合併し広範な皮膚粘膜病変を発症した一例

中土井崇人, 勝山恵理, 寺嶋悠也, 松本和也, 廣瀬啓, 志田原健太, 縄稚翔一, 浅野洋介, 片山祐, 宮脇義亜, 勝山隆行, 楢崎真理子, 松本佳則, 佐田憲映, 大塚文男, 和田淳

日本リウマチ学会総会・学術集会プログラム・抄録集 67回 795 - 795 2023.3

ハンセン病に対する免疫抑制療法を背景に発症した播種性糞線虫症の1例

中本健太, 萩谷英大, 平佑貴, 庵谷紘美, 中野靖浩, 長谷川功, 大塚文男

感染症学雑誌 97 ( 2 ) 52 - 57 2023.3

Language：Japanese Publisher：(一社)日本感染症学会

症例は30歳代ネパール人男性で、下痢と嘔気を主訴とした。ハンセン病(LL型)と新型コロナウイルス感染症の既往があり、らい反応に対して長期間のステロイド製剤内服による免疫抑制療法を行っていた。各種検査所見より、糞線虫の過剰感染状態による播種性糞線虫症と診断した。栄養状態は不良で、寄生虫の消化管内過剰増殖に伴う腸管浮腫を認め、イベルメクチンは吸収不良で血中濃度が不十分であった。多臓器不全を併発したため集学的治療を行ったが第36病日に死亡した。日本では糞線虫症は稀であるが、インバウンドの増加に伴い播種性糞線虫症のリスクが増加する可能性があり、ステロイドの長期内服などで免疫抑制状態の可能性がある場合は寄生虫スクリーニングを行う必要があると考えられた。

ビジュアルで見るプライマリ・ケア毒針毛による皮膚炎

大塚勇輝, 長岡寛和, 花山宜久, 大塚文男, 金森達也

日本プライマリ・ケア連合学会誌 46 ( 1 ) 33 - 34 2023.3

若年男性の橋本病による粘液水腫の1例

山本紘一郎, 本多寛之, 中野靖浩, 長谷川功, 大塚文男

日本内分泌学会雑誌 98 ( 5 ) 1303 - 1303 2023.3

Buruli ulcer caused by Mycobacterium ulcerans subsp. shinshuense: A case report. Reviewed International journal

Takumi Fujimori, Hideharu Hagiya, Koji Iio, Osamu Yamasaki, Yuji Miyamoto, Yoshihiko Hoshino, Ayaka Kakehi, Mami Okura, Hiroshi Minabe, Yukika Yokoyama, Fumio Otsuka, Akihito Higashikage

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 29 ( 5 ) 523 - 526 2023.2

Language：English

Buruli ulcer is the third most common mycobacterial infection worldwide and is mainly diagnosed in tropical regions. Globally, this progressive disease is caused by Mycobacterium ulcerans; however, Mycobacterium ulcerans subsp. shinshuense, an Asian variant, has been exclusively identified in Japan. Because of insufficient clinical cases, the clinical features of M. ulcerans subsp. shinshuense-associated Buruli ulcer remain unclear. A 70-year-old Japanese woman presented with erythema on her left backhand. The skin lesion deteriorated without an apparent etiology of inflammation, and she was referred to our hospital 3 months after disease onset. A biopsy specimen was incubated in 2% Ogawa medium at 30 °C. After 66 days, we detected small yellow-pigmented colonies, suggesting scotochromogens. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI Biotyper; Bruker Daltonics, Billerica, MA, USA) indicated that the organism was Mycobacterium pseudoshottsii or Mycobacterium marinum. However, additional PCR testing for the insertion sequence 2404 (IS2404) was positive, suggesting that the pathogen was either M. ulcerans or M. ulcerans subsp. shinshuense. Further examination by 16S rRNA sequencing analysis, focusing on nucleotide positions 492, 1247, 1288, and 1449-1451, we finally identified the organism as M. ulcerans subsp. shinshuense. The patient was successfully treated with 12 weeks of clarithromycin and levofloxacin treatment. Mass spectrometry is the latest microbial diagnostic method; however, it cannot be used to identify M. ulcerans subsp. shinshuense. To accurately detect this enigmatic pathogen and uncover its epidemiology and clinical characteristics in Japan, more accumulation of clinical cases with accurate identification of the causative pathogen is essential.

DOI： 10.1016/j.jiac.2023.02.009

Trends in the Incidence of Japanese Spotted Fever in Japan: A Nationwide, Two-Decade Observational Study from 2001-2020. Reviewed International journal

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

The American journal of tropical medicine and hygiene 2023.2

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

The worldwide spread of tick-borne diseases (TBDs) has become a public health concern. Therefore, this study aimed to clarify trends in the incidence of Japanese spotted fever (JSF), one of Japan's most prevalent TBDs. Weekly infectious disease reports were used to calculate the annual incidence rates (AIRs) of JSF. Data were stratified by age and sex, and joinpoint regression analysis was performed to estimate the annual percentage change (APC). AIR and APC were geographically compared among the 47 prefectures. A total of 3,453 JSF cases were observed from 2001 to 2020. The AIR per 100,000 population was 0.03 in 2001, which increased approximately 10-fold to 0.33 in 2020. The average APC (AAPC) during the study period was 12.3% (95% CI: 10.7-13.9). By age group, the incidence of JSF increased more rapidly among the older population: 11.5% (95% CI: 10.1-12.9) in those aged ≥ 65 years and 8.9% (95% CI: 6.4-11.5) in those aged < 50 years. Although the AIR over the past two decades was higher in climatically warm regions located in southwestern Japan and on the Pacific coast, increases in the AAPC were notable in colder regions located in eastern Japan. The incidence of JSF continues to increase in Japan, especially among older populations and in eastern prefectures, where the disease has not been previously diagnosed.

DOI： 10.4269/ajtmh.22-0487

Mediastinal Abscess Induced by Group B Streptococcus Reviewed

Kenta Nakamoto, Hideharu Hagiya, Ruiko Hayashi, Fumio Otsuka

Internal Medicine 62 ( 3 ) 491 - 492 2023.2

コロナ禍にCaSR作動薬で長期管理し得た原発性副甲状腺機能亢進症の一例

大上莉央, 大塚勇輝, 中野靖浩, 高瀬了輔, 山下茉奈美, 山本紘一郎, 長谷川功, 大塚文男

日本内分泌学会雑誌 98 ( 4 ) 1079 - 1079 2023.2

成人期にPHEX新規変異によるX染色体連鎖性低リン血症性骨軟化症と診断した1例

山本紘一郎, 本多寛之, 高瀬了輔, 中野靖浩, 徳増一樹, 長谷川功, 長谷川高誠, 大塚文男

日本内分泌学会雑誌 98 ( 4 ) 1080 - 1080 2023.2

臨床検査室におけるナノポアシーケンシング技術を用いた新型コロナウイルス感染症の疫学的解析実用化に向けての取り組み

飯尾耕治, 後藤和義, 萩谷英大, 小川寛人, 三好諒, 大塚文男, 東影明人

医学検査 72 ( 2 ) 248 - 255 2023.2

Prevalence of Inducible Macrolide, Lincosamide, and Streptogramin B (inducible MLSB) Resistance in Clindamycin-Susceptible Staphylococcus aureus at Okayama University Hospital. Reviewed

Lutfun Nahar, Hideharu Hagiya, Takahiro Nada, Koji Iio, Kazuyoshi Gotoh, Osamu Matsushita, Fumio Otsuka

Acta Medica Okayama 77 ( 1 ) 1 - 9 2023.2

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Inducible resistance to the macrolide, lincosamide, and streptogramin B (iMLSB) antibiotic family is a latent mechanism for antimicrobial resistance in Staphylococcus aureus. We here investigated the frequency and genotypic profiles of iMLSB resistance in clindamycin (CLDM)-susceptible S. aureus isolated in Okayama University Hospital from June 2020 to June 2021. We phenotypically screened the iMLSB resistance via D-zone test and performed PCR testing for the erythromycin ribosomal methylase (erm) genes: ermA and ermC. Among 432 CLDM-susceptible S. aureus isolates, 138 (31.9%) exhibited an iMLSB-resistance phenotype, with methicillinresistant S. aureus isolates (MRSA; 61 isolates: 58.6%) exhibiting higher positivity than methicillin-sensitive S. aureus isolates (MSSA; 77 isolates: 23.5%) (p<0.001). Male patients had a higher frequency of iMLSB resistance than females (OR [95%CI]: 1.8 [1.2-2.8]; p=0.007). Genotypically, ermA predominated in both MSSA (70.1%) and MRSA (86.9%) compared to ermC (14.3% in MSSA and 11.5% in MRSA). A single strain of MRSA possessed both ermA and ermC, while 12 (15.6%) MSSA isolates were negative for both ermA and ermC, suggesting the presence of other genetic mechanisms. Collectively, these results show that approximately 33% of CLDM-susceptible S. aureus isolates at our university hospital exhibited iMLSB resistance, predominantly caused by ermA in both MSSA and MRSA.

DOI： 10.18926/AMO/64355

不明熱の原因となるカンピロバクター菌血症の臨床的特徴に関する多施設後方研究

大塚勇輝, 萩谷英大, 高橋美砂, 福島伸乃介, 前田瑠璃, 砂田匠彦, 山田晴士, 岸田雅之, 藤田浩二, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増1 ) 214 - 214 2023.2

COVID-19罹患後症状と血清亜鉛濃度の関連

松田祐依, 徳増一樹, 大塚勇輝, 砂田匠彦, 本多寛之, 櫻田泰江, 中野靖浩, 長谷川徹, 萩谷英大, 小比賀美香子, 植田圭吾, 片岡仁美, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増1 ) 168 - 168 2023.2

COVID-19罹患後にME/CFSに移行する症例の臨床的特徴血清ferritinと内分泌系に注目した検討

山本幸近, 大塚勇輝, 徳増一樹, 萩谷英大, 砂田匠彦, 本多寛之, 中野靖浩, 櫻田泰江, 松田祐依, 長谷川徹, 長谷川功, 小比賀美香子, 植田圭吾, 片岡仁美, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増1 ) 173 - 173 2023.2

大腿骨頸部骨折を契機に発見されたビタミンD欠乏の1例

高瀬了輔, 本多寛之, 中野靖浩, 山本紘一郎, 大國皓平, 越智可奈子, 長谷川功, 三好智子, 花山宜久, 小川弘子, 森泰宏, 大塚文男

日本病院総合診療医学会雑誌 19 ( 臨増1 ) 223 - 223 2023.2

Trends in Long COVID Symptoms in Japanese Teenage Patients. Reviewed International journal

Yasue Sakurada, Yuki Otsuka, Kazuki Tokumasu, Naruhiko Sunada, Hiroyuki Honda, Yasuhiro Nakano, Yui Matsuda, Toru Hasegawa, Kanako Ochi, Hideharu Hagiya, Keigo Ueda, Hitomi Kataoka, Fumio Otsuka

Medicina (Kaunas, Lithuania) 59 ( 2 ) 2023.1

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Background: Since the start of the global pandemic of coronavirus disease 2019 (COVID-19), not only adults but also many children have suffered from it. However, the clinical characteristics of long COVID in children remain unclear. Methods: In this retrospective observational study conducted in a single facility, we reviewed the medical records of all long COVID patients who visited Okayama University Hospital from February 2021 to October 2022, and we compared the clinical characteristics of long COVID in teenagers (11 to 18 years of age) with those in adults. Results: Data for 452 long COVID patients including 54 teenagers (11.9%) were analyzed. Fatigue was the most frequent symptom in teenagers (55.6% of the patients) and also in adults. On the other hand, the percentage of teenagers who complained of headache, which was the second most frequent complaint, was significantly higher than the percentage of adults (35.2% vs. 21.9%, p < 0.05). A comparison of the frequencies of symptoms depending on the viral variant showed that fatigue and headache were predominant symptoms in the Omicron variant phase. Of the 50 teenagers who were enrolled in schools, 28 (56.0%) could not attend school due to long COVID symptoms. The most common symptoms as reasons for absence from school were fatigue (85.7% of the patients), headache (42.9%), and insomnia (32.1%). Conclusions: Attention should be paid to the symptoms of fatigue and headache in teenagers with long COVID.

DOI： 10.3390/medicina59020261

Tuberculous meningitis Reviewed

Shinnosuke Fukushima, Kazuki Ocho, Koji Fujita, Hideharu Hagiya, Fumio Otsuka

Clinical Case Reports 11 ( 1 ) 2023.1

Differences in Stress Perception of Medical Students Depending on In-Person Communication and Online Communication during the COVID-19 Pandemic: A Japanese Cross-Sectional Survey. Reviewed International journal

Kazuki Tokumasu, Yoshito Nishimura, Yoko Sakamoto, Mikako Obika, Hitomi Kataoka, Fumio Otsuka

International journal of environmental research and public health 20 ( 2 ) 2023.1

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Excessive psychological stress in medical students affects their mental health and causes problems such as burnout and depression. Furthermore, changes in the learning environment to online learning due to the COVID-19 pandemic have had a psychological effect on medical students. However, the relationships between medical students' perceived stress and different methods of communication, including in-person and online communication, remain unclear. The purpose of this study was to investigate the differences in stress perception of medical students depending on in-person communication and online communication during the COVID-19 pandemic. METHODS: This study was a cross-sectional study conducted from September to October in 2020. All of the students of Okayama University School of Medicine were asked to participate in a questionnaire survey. The explanatory variables were the frequency and length of communications with others (by in-person or online communication), empathy, and lifestyle. The main outcome measure was perceived stress. Subgroup analysis was conducted for students who preferred to be by themselves and students who preferred to study together and interact with other people. Univariate analysis and multivariate multiple regression analysis were conducted. Gender and grade, which have been shown to be associated with stress in previous studies, were used as covariates for multiple regression analysis. RESULTS: Valid responses to the questionnaire survey were received from 211 (29.4%) of the 717 students. There was no significant association between perceived stress and online communication, but the number of people with which students had in-person communication (1-2 people compared to 0 as a control, regression coefficient [B] = -4.4, 95% confidence interval [CI]; -7.8, -1.1, more than 10 people, B = -12, 95% CI: -18, -5.8) and the length of communication (more than 120 min, B = -4.5, 95% CI: -8.1, -0.92) were associated with a reduction in perceived stress. In subgroup analysis, the number of people with in-person communication and the length of communication had significant associations with stress reduction even in the group of students who had a preference for being by themselves. CONCLUSION: In-person communications rather than online communications were associated with a lower level of perceived stress. In subgroup analysis, this trend was statistically significant in the group of students who had a preference for being by themselves.

DOI： 10.3390/ijerph20021579

Clinical characteristics of Campylobacter bacteremia: a multicenter retrospective study. Reviewed International journal

Yuki Otsuka, Hideharu Hagiya, Misa Takahashi, Shinnosuke Fukushima, Ruri Maeda, Naruhiko Sunada, Haruto Yamada, Masayuki Kishida, Koji Fujita, Fumio Otsuka

Scientific reports 13 ( 1 ) 647 - 647 2023.1

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Campylobacter species are the pathogens of the intestinal tract, which infrequently cause bacteremia. To reveal the clinical characteristics of Campylobacter bacteremia, we performed a retrospective, multicenter study. Patients diagnosed with Campylobacter bacteremia in three general hospitals in western Japan between 2011 and 2021 were included in the study. Clinical, microbiological, and prognostic data of the patients were obtained from medical records. We stratified the cases into the gastroenteritis (GE) and fever predominant (FP) types by focusing on the presence of gastrointestinal symptoms. Thirty-nine patients (24 men and 15 women) were included, with a median age of 57 years and bimodal distribution between those in their 20 s and the elderly. The proportion of GE and FP types were 21 (53.8%) and 18 (46.2%), respectively. Comparing these two groups, there was no significant difference in patient backgrounds in terms of sex, age, and underlying diseases. Campylobacter jejuni was exclusively identified in the GE type (19 cases, 90.5%), although other species such as Campylobacter fetus and Campylobacter coli were isolated in the FP type as well. Patients with the FP type underwent intravenous antibiotic therapy more frequently (47.6% vs. 88.9%), and their treatment (median: 5 days vs. 13 days) and hospitalization (median: 7 days vs. 21 days) periods were significantly longer. None of the patients died during the hospitalization. In summary, we found that nearly half of the patients with Campylobacter bacteremia presented with fever as a predominant manifestation without gastroenteritis symptoms.

DOI： 10.1038/s41598-022-27330-4

Takayasu Arteritis Mimicking Phlegmon Reviewed

Yuki Taira, Yasuhiro Nakano, Yoshihisa Hanayama, Fumio Otsuka

Internal Medicine 62 ( 1 ) 149 - 149 2023.1

Oxytocin enhances progesterone production with upregulation of BMP-15 activity by granulosa cells Reviewed

Koichiro Yamamoto, Yasuhiro Nakano, Nahoko Iwata, Yoshiaki Soejima, Atsuhito Suyama, Toru Hasegawa, Fumio Otsuka

Biochemical and Biophysical Research Communications 646 103 - 109 2023.1

Late-Onset Neutropenia With Clozapine Associated With Lithium Carbonate–Related Hyperthyroidism Reviewed

Yuto Yamada, Masaki Fujiwara, Shuhei Tsujino, Satoru Edahiro, Shinji Sakamoto, Koichiro Yamamoto, Fumio Otsuka, Norihito Yamada, Manabu Takaki

Journal of Clinical Psychopharmacology 43 ( 1 ) 76 - 77 2023.1

Examining the association between vaccine reactogenicity and antibody titer dynamics after the third dose of BNT162b2 vaccine using a mixed-effects model Reviewed

Naomi Matsumoto, Hideharu Hagiya, Masanori Nakayama, Masanori Furukawa, Toshiharu Mitsuhashi, Soshi Takao, Fumio Otsuka, Takashi Yorifuji

Journal of Infection and Chemotherapy 29 ( 1 ) 39 - 42 2023.1

Antimicrobials in the Hospital are Unevenly Discontinued on Weekdays Reviewed

Hideharu Hagiya, Mika Uno, Tsukasa Higashionna, Hiroyuki Honda, Fumio Otsuka

Internal Medicine 2023

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Society of Internal Medicine

Objective Amid the global spread of antimicrobial resistance, antimicrobial stewardship should be further promoted in the clinical setting. Our previous study suggested an intra-week disproportion of discontinuation of broad-spectrum antibiotics. We therefore explored the generalization of this prescription trend by investigating the use of all intravenous antibiotics. Methods A retrospective, observational study. Patients Between January 1, 2018, and December 31, 2020, we collected data on the initiation and discontinuation of intravenous antimicrobials on each day of the week and on days after holidays at Okayama University Hospital, Japan. We compared the monthly antimicrobial prescription initiation and discontinuation using the Kruskal-Wallis test and Mann-Whitney U-test with Bonferroni correction as a post-hoc procedure. Results Data from 15,293 hospitalized cases were analyzed. The initiation of antimicrobials differed slightly among days of the week, although this trend was clinically insignificant. Compared with the initiations, antimicrobial discontinuations were disproportionately biased among the weekdays, tending to occur on Mondays (p <0.001) about twice as often as on other days. Similarly, antimicrobials were unevenly discontinued on the day after holidays compared to other days (p <0.001), with an approximately 2-fold difference. The use of antimicrobials in the hospital was thus unequally terminated on weekdays. Conclusion To further promote antimicrobial stewardship, clinicians should be aware of the influence of behavioral, environmental, and social factors on antimicrobial prescription, which is seemingly beyond medical indications.

DOI： 10.2169/internalmedicine.0707-22

Biofilm-associated candidal thrombophlebitis Reviewed

Shinnosuke Fukushima, Koichiro Yamamoto, Yasuhiro Nakano, Hideharu Hagiya, Fumio Otsuka

IDCases 31 e01733 - e01733 2023

Contributions of Japanese Hospitalists During the COVID-19 Pandemic and the Need for Infectious Disease Crisis Management Education for Hospitalists: An Online Cross-Sectional Study. Reviewed International journal

Masaki Tago, Risa Hirata, Naoko E Katsuki, Yuki Otsuka, Taro Shimizu, Yosuke Sasaki, Kiyoshi Shikino, Takashi Watari, Hiromizu Takahashi, Kazunobu Une, Toshio Naito, Fumio Otsuka, Rachel Thompson, Susumu Tazuma

Risk management and healthcare policy 16 1645 - 1651 2023

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

INTRODUCTION: Hospitalists in Japan have been at the forefront of the COVID-19 pandemic. However, contributions of Japanese hospitalists during the COVID-19 pandemic and hospitalists' awareness of crisis management education remain unclear. MATERIAL AND METHODS: We conducted a questionnaire survey to investigate the role of Japanese hospitalists during the COVID-19 pandemic. The questionnaire was conducted using email and Google Forms targeting the chairpersons of facilities certified by the Japanese Society of Hospital General Medicine (JSHGM). Members of the academic committee of the JSHGM and several hospitals conducted a narrative review and determined the questions for the survey in a discussion. RESULTS: We conducted descriptive statistics based on the responses of 97 hospitals that agreed to participate in this survey. In total, 91.8% of general medicine departments in the included hospitals were involved in the medical care of COVID-19 patients. Furthermore, in 73.2% of hospitals, hospitalists were involved in infection control for COVID-19 inside or outside the hospital. Our survey revealed that Japanese hospitalists were responsible for COVID-19 treatment in over 60% of hospitals and contributed to hospital management, infection control, and vaccination. In total, 79.4% of hospitals answered that "training of personnel who can provide practical care for emerging infectious diseases is necessary", 78.4% indicated that "the establishment of an infection control system in advance to prepare emerging infectious diseases in the hospital is necessary", and 74.2% stated that "the establishment of an educational system for responding to emerging infectious diseases is necessary.". CONCLUSION: In conclusion, during the pandemic, in addition to inpatient care, Japanese hospitalists provided outpatient care for COVID-19, which is the role of primary care physicians in other countries. Furthermore, Japanese hospitalists who experienced the COVID-19 pandemic expressed the need for personnel development and education to prepare for future emerging infectious disease pandemics.

DOI： 10.2147/RMHP.S422412

Ossification of the Posterior Longitudinal Ligament Caused by X-linked Hypophosphatemia Reviewed

JMA journal 2023

Cryptococcal Meningitis Developing in a Patient with Neurosarcoidosis Reviewed

Shinnosuke Fukushima, Hideharu Hagiya, Yukichika Yamamoto, Kohei Oguni, Kou Hasegawa, Fumio Otsuka

Internal Medicine 2023

Characteristics of Sleep Disturbance in Patients with Long COVID: A Retrospective Observational Study in Japan. Reviewed International journal

Naruhiko Sunada, Yasuhiro Nakano, Yuki Otsuka, Kazuki Tokumasu, Hiroyuki Honda, Yasue Sakurada, Yui Matsuda, Toru Hasegawa, Daisuke Omura, Kanako Ochi, Hideharu Hagiya, Keigo Ueda, Hitomi Kataoka, Fumio Otsuka

Journal of clinical medicine 11 ( 24 ) 2022.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: The objective of this study was to determine the clinical and endocrinological features of sleep disturbance in patients with long COVID. METHODS: This study was a single-center retrospective observational study for patients who visited the COVID-19 aftercare outpatient clinic (CAC) established in Okayama University Hospital in Japan during the period from 15 February 2021 to 29 July 2022. The long COVID patients were divided into two groups based on the presence or absence of sleep disturbance, and the clinical and laboratory characteristics of the patients were analyzed. RESULTS: Out of 363 patients with long COVID, after excluding 6 patients, 60 patients (16.5%) (55% males, median age of 38 years) complaining of sleep disturbance were compared with 303 patients (83.5%) (43% males, median age of 40 years) without sleep-related symptoms. Although there were no significant differences in clinical backgrounds and severities of COVID-19 between the two groups by the multivariate analysis, the percentage of long COVID patients with sleep disturbance was significantly increased among patients infected in the Omicron-dominant phase. In addition, the prevalence rate of sleep disturbance in patients when infected in the Omicron phase (24.8%) was two-times higher than that in patients infected in the Delta phase (12.8%). Of note, the percentages of patients with sleep disturbance who also complained of general fatigue, headache, concentration loss, anxiety, low-grade fever, and brain fog symptoms were higher than the percentages of patients without sleep disturbance who had the same complaints. Among the types of sleep disturbance, the percentage of patients who complained of loss of sleep induction (75%) was much higher than the percentage of patients with early-awakening sleep disturbance (6.7%), and many of the patients with mid-awakening types of insomnia had brain fog symptoms. Endocrine examinations revealed that long COVID patients with sleep disturbance had significantly higher levels of plasma adrenocorticotropin and lower levels of serum growth hormone, suggesting the presence of hypothalamic-pituitary stress. CONCLUSION: The prevalence of sleep disturbance has been increasing in long COVID patients infected in the Omicron phase with a certain clinical and endocrine trend.

DOI： 10.3390/jcm11247332

Key signs indicating mesenteric panniculitis Reviewed

Koichiro Yamamoto, Hiroyuki Honda, Hiroko Ogawa, Fumio Otsuka

Clinical Case Reports 10 ( 12 ) 2022.12

Detection of Enterobacter cloacae complex strain with a blaNDM-1-harboring plasmid from an elderly resident at a long-term care facility in Okayama, Japan Reviewed International journal

Kazuyoshi Gotoh, Hideharu Hagiya, Koji Iio, Haruto Yamada, Osamu Matsushita, Fumio Otsuka

Journal of Infection and Chemotherapy 28 ( 12 ) 1697 - 1699 2022.12

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

Amidst the global spread of antimicrobial resistance, New Delhi metallo-β-lactamase (NDM)-type carbapenemase-producing Enterobacterales (CPE) remain uncommon in Japan, and the detection of such highly drug-resistant organisms is limited to inbound cases. There is little evidence regarding the prevalence of NDM β-lactamase gene (blaNDM)-harboring CPE in the domestic community, especially in the provincial cities of Japan. Herein, we report the isolation of a blaNDM-1-harboring plasmid in Enterobacter cloacae complex strain isolated from an elderly woman without a history of traveling abroad who had resided in a long-term care facility in Okayama, Japan. The multidrug-resistant blaNDM-harboring CPE isolate was detected in a stool sample of the patient during routine screening at admission. We performed whole-genome sequencing analysis of the isolate using MiSeq (Illumina) and MinION (Oxford Nanopore Technologies) platforms. The isolate was identified as sequence type 171, which has predominantly been reported in the United States and China. The blaNDM-1 gene was encoded on the 46,161 bp IncX3 plasmid, with sequence similarity to plasmids of similar size isolated from individuals in China. Collectively, the genomic data suggest that an imported CPE isolate may have spread among healthy individuals in the regional area of Japan.

DOI： 10.1016/j.jiac.2022.08.019

Rhinogenic optic neuropathy with hemianopia caused by ethmoidal sinus mucocele. Reviewed International journal

Kosuke Oka, Wataru Ando, Hideharu Hagiya, Takaya Higaki, Fumio Otsuka

Clinical case reports 10 ( 12 ) e6696 2022.12

医療系学部教育でのIPE(Inter-professional Education:多職種連携教育)の実践を通した患者中心の医療の経験

三好智子, 岩室雅也, 花山宜久, 小川弘子, 小比賀美香子, 名倉弘哲, 大塚文男

医学教育 53 ( 6 ) 531 - 536 2022.12

Language：Japanese Publisher：(一社)日本医学教育学会

本研究では,医療系学生が小グループのIPEの実践を通して,患者中心のチーム医療を実践したと考えることができたかを検証した.医学科,薬学科,保健学科の臨床実習中の学部学生に対し,小グループで症例基盤型の臨床推論と治療・看護計画立案を行い,IPEに対するアンケートを行った.医学科生は臨床推論と治療計画立案が,薬学科生は治療の副作用対策を提案することが,看護学生は医療チームに必要な情報提供をすることが,医療チームとともに患者中心の医療が実践できたと感じていた.学部毎にチーム医療を実践したと考える項目が異なり,多学部合同IPEにはそれぞれの要素を組み込むことが重要である.(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00050&link_issn=&doc_id=20230117110006&doc_link_id=%2Fed9jmded%2F2022%2F005306%2F007%2F0531-0536%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fed9jmded%2F2022%2F005306%2F007%2F0531-0536%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Early-stage antibody kinetics after the third dose of BNT162b2 mRNA COVID-19 vaccination measured by a point-of-care fingertip whole blood testing Reviewed

Hideharu Hagiya, Yasuhiro Nakano, Masanori Furukawa, Naruhiko Sunada, Toru Hasegawa, Yasue Sakurada, Kou Hasegawa, Koichiro Yamamoto, Hiroko Ogawa, Takafumi Obara, Kouhei Ageta, Naomi Matsumoto, Rumi Matsuo, Tomoka Kadowaki, Akihito Higashikage, Takao Hikita, Takashi Yorifuji, Shinichi Toyooka, Yoshinobu Maeda, Yoshinori Yokokura, Fumio Otsuka, Masanori Nakayama

Scientific Reports 12 ( 1 ) 2022.11

Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Amid the Coronavirus Disease 2019 pandemic, we aimed to demonstrate the accuracy of the fingertip whole blood sampling test (FWT) in measuring the antibody titer and uncovering its dynamics shortly after booster vaccination. Mokobio SARS-CoV-2 IgM & IgG Quantum Dot immunoassay (Mokobio Biotechnology R&D Center Inc., MD, USA) was used as a point-of-care FWT in 226 health care workers (HCWs) who had received two doses of the BNT162b2 mRNA vaccine (Pfizer-BioNTech) at least 8 months prior. Each participant tested their antibody titers before and after the third-dose booster up to 14-days. The effect of the booster was observed as early as the fourth day after vaccination, which exceeded the detection limit (> 30,000 U/mL) by 2.3% on the fifth day, 12.2% on the sixth day, and 22.5% after the seventh day. Significant positive correlations were observed between the pre- and post-vaccination (the seventh and eighth days) antibody titers (correlation coefficient, 0.405; p < 0.001). FWT is useful for examining antibody titers as a point-of-care test. Rapid response of antibody titer started as early as the fourth day post-vaccination, while the presence of weak responders to BNT162b2 vaccine was indicated.

DOI： 10.1038/s41598-022-24464-3

Other Link： https://www.nature.com/articles/s41598-022-24464-3

Letter to the Editor From Yamamoto et al: “Whole Body, Whole Life, Whole Family: Patients’ Perspectives on X-Linked Hypophosphatemia” Reviewed

Koichiro Yamamoto, Daisuke Omura, Keiji Soga, Mikako Obika, Fumio Otsuka

Journal of the Endocrine Society 7 ( 1 ) 2022.11

Right-sided infective endocarditis with odontogenic infections Reviewed International journal

S Fukushima, K Fujita, H Hagiya, F Otsuka

QJM: An International Journal of Medicine 115 ( 11 ) 753 - 753 2022.11

A Wolff–Parkinson–White syndrome revealed by the event of heat stroke Reviewed International journal

S Tanaka, H Hagiya, F Otsuka

QJM: An International Journal of Medicine 115 ( 11 ) 760 - 761 2022.11

High frequency of extended-spectrum beta-lactamase-producing Enterobacteriaceae carriers at a Japanese long-term care hospital Reviewed International journal

Hideharu Hagiya, Yuji Onishi, Natsumi Shinohara, Mayumi Tokuyasu, Aki Imanishi, Shinnosuke Fukushima, Lutfun Nahar, Koji Iio, Fumio Otsuka

Journal of Infection and Chemotherapy 28 ( 11 ) 1578 - 1581 2022.11

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

INTRODUCTION: Long-term care hospitals (LTCHs) are at a high risk for the inflow and spread of antimicrobial resistance (AMR) pathogens. However, owing to limited laboratory resources, little is known about the extent to which AMR organisms are endemic. METHODS: We performed active surveillance for carbapenem-resistant Enterobacteriaceae (CRE) and extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) in newly admitted patients at Marugame Medical Center, a nearly 200-bedded LTCH located in Kagawa, Japan. From August to December 2021, we tested stool samples from patients wearing diapers and confirmed the genetic variants using specific PCR assays. We also collected clinical variables and compared them between AMR carriers and non-carriers. RESULTS: Stool samples were collected from 75 patients, with a median age of 84 years. CRE strain was not detected, but 37 strains of ESBL-E were isolated from 32 patients (42.7%). During the study period, 4.9% of in-hospital patients (37 per 756 patients) were identified to be ESBL-E carriers in the routine microbiological processing, suggesting that active surveillance detected approximately 9-fold more ESBL-E carriers. The blaCTX-M-9 group was the most common (38.5%), followed by the blaTEM (26.9%). The clinical backgrounds of the ESBL-E non-carriers and carriers were not significantly different. CONCLUSION: Our active screening demonstrated that nearly half of the patients hospitalized or transferred to a Japanese LTCH were colonized with ESBL-E. We highlight the enforcement of universal basic infection prevention techniques at LTCHs where patients carrying AMR pathogens gather.

DOI： 10.1016/j.jiac.2022.07.014

Trends in the incidence of syphilis in the middle‐aged and older adults in Japan: A nationwide observational study, 2009–2019 Reviewed

Misa Takahashi, Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

Geriatrics and Gerontology International 2022.11

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Wiley

AIM: Sexually transmitted infections remain a neglected area of research in geriatrics. However, in the global aging societies, sexual health among the middle-aged and older adults is an emerging public concern. High-income countries are facing a resurgence of syphilis cases among young generations, but little is known about its prevalence in older populations. We aimed to investigate the national trend of syphilis cases in Japan. METHODS: This nationwide observational study used the publicly-available database (2009-2019) to calculate crude and age-adjusted incidence rates of syphilis per 100 000 population by age, sex and clinical stage. We collected data from patients aged ≥50 years and performed joinpoint regression analysis to estimate long-term trends and average annual percentage changes (AAPCs). RESULTS: The total number of patients with syphilis increased about 8-fold from 165 in 2009 to 1280 in 2019. AAPCs of crude incidence rates significantly increased in every age category; 33.2% in 50-59 years, 23.8% in 60-69 years and 20.9% in ≥70 years. Age-adjusted incidence rates have surged at AAPCs of 28.7% in men and 23.1% in women, reaching 4.09 in men and 0.71 in women in 2019. By clinical stage, marked increases were observed in primary (AAPCs, 42.3% in men and 41.6% in women) and secondary syphilis (AAPCs, 24.9% in men and 24.2% in women). CONCLUSIONS: An up-toward trend of syphilis among people aged ≥50 years was observed. The importance of sexual health among older people should be highlighted in this aging Japanese society. Geriatr Gerontol Int 2022; ••: ••-••.

DOI： 10.1111/ggi.14500

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ggi.14500

Isolated unilateral absence of adult pulmonary artery Reviewed

Koichiro Yamamoto, Yasuhiro Nakano, Fumio Otsuka

Clinical Case Reports 10 ( 11 ) 2022.11

Increased CCR4+ and Decreased Central Memory CD4+ T Lymphocytes in the Background Gastric Mucosa of Patients Developing Gastric Cancer After Helicobacter pylori Eradication: An Exploratory Study. Reviewed International journal

Masaya Iwamuro, Takahide Takahashi, Araki Hirabata, Takehiro Tanaka, Fumio Otsuka, Horoyuki Okada

Cureus 14 ( 11 ) e31713 2022.11

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

The composition of lymphocytes in the gastric mucosa following the eradication of Helicobacter pylori (H. pylori) in patients with and without gastric cancer has not been compared. This study performed a single spot analysis of gastric mucosal lymphocytes after H. pylori eradication in patients with (n = 13) and without (n = 20) gastric cancer. Our comprehensive analysis of lymphocyte composition in the gastric mucosa revealed that: i) the proportion of CD8+/CD3+ cells was relatively higher in the peri-tumor mucosa than in the background mucosa; ii) the proportion of CCR4+/CD3+ cells was higher, and the ratio of CD62L+/CD3+CD4+ cells was relatively lower in the gastric mucosa of cancer patients than in non-cancer patients; and iii) the proportion of CD45RA-CD62L+/CD3+CD4+ cells, namely, the central memory CD4+ T-cell fraction, was lower in the gastric mucosa of cancer patients than in non-cancer patients. Although the exact mechanism of the altered proportions of CCR4+/CD3+ and central memory CD4+ cells in the gastric mucosa of patients with cancer is unknown, focusing on lymphocytes in the gastric mucosa might help improve our understanding of gastric cancer development after H. pylori eradication.

DOI： 10.7759/cureus.31713

男性2型糖尿病患者における血中アンドロゲン値とその意義

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

糖尿病 65 ( 11 ) 633 - 633 2022.11

Postprandial reactive hypoglycemia detected with premature ventricular contraction Reviewed

H Honda, S Tanaka, H Hagiya, F Otsuka

QJM: An International Journal of Medicine 115 ( 10 ) 675 - 676 2022.10

投稿 GM Report 専攻医から見た新専門医制度における総合診療専攻医の育成

大塚勇輝, 小比賀美香子, 大塚文男

総合診療 32 ( 10 ) 1274 - 1275 2022.10

Transitional Changes in Fatigue-Related Symptoms Due to Long COVID: A Single-Center Retrospective Observational Study in Japan Reviewed International journal

Yasuhiro Nakano, Yuki Otsuka, Hiroyuki Honda, Naruhiko Sunada, Kazuki Tokumasu, Yasue Sakurada, Yui Matsuda, Toru Hasegawa, Kanako Ochi, Hideharu Hagiya, Hitomi Kataoka, Keigo Ueda, Fumio Otsuka

Medicina 58 ( 10 ) 1393 - 1393 2022.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Background and Objectives: Changes in post COVID-19 condition (PCC) characteristics caused by viral variants have yet to be clarified. We aimed to characterize the differences between clinical backgrounds and manifestations in long COVID patients who were infected with the Delta variant and those who were infected with the Omicron variants. Materials and Methods: This study was a single-center retrospective observational study for patients who visited our COVID-19 aftercare outpatient clinic (CAC) established in Okayama University Hospital (Japan) during the period from 15 February 2021 to 15 July 2022. We classified the onset of COVID-19 in the patients into three groups, the preceding, Delta-dominant, and Omicron-dominant periods, based on the prevalent periods of the variants in our prefecture. Results: In a total of 353 patients, after excluding 8 patients, 110, 130, and 113 patients were classified into the preceding, Delta-dominant, and Omicron-dominant periods, respectively. Patients infected in the Omicron-dominant period had significantly fewer hospitalizations, milder illnesses, more vaccinations and earlier visit to the CAC than did patients infected in the Delta-dominant period. Patients infected in the Omicron-dominant period had significantly lower frequencies of dysosmia (12% vs. 45%, ** p < 0.01), dysgeusia (14% vs. 40%, ** p < 0.01) and hair loss (7% vs. 28%, ** p < 0.01) but had higher frequencies of fatigue (65% vs. 50%, * p < 0.05), insomnia (26% vs. 13%, * p < 0.05) and cough (20% vs. 7%, ** p < 0.01) than did patients infected in the Delta-dominant period. Conclusions: The transitional changes in long COVID symptoms caused by the two variants were characterized.

DOI： 10.3390/medicina58101393

Clinical and microbiological characteristics of polymicrobial bacteremia: a retrospective, multicenter study. Reviewed International journal

Shinnosuke Fukushima, Hideharu Hagiya, Koji Fujita, Shinya Kamiyama, Haruto Yamada, Masayuki Kishida, Fumio Otsuka

Infection 50 ( 5 ) 1233 - 1242 2022.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To clarify the clinical and microbial characteristics of polymicrobial bacteremia (PMB) to contribute to improvements in clinical diagnosis and effective early treatment. METHODS: This retrospective multicenter study used data from three acute-care hospitals in Okayama Prefecture, Japan, collected between January 2014 and March 2019. We reviewed the demographics, comorbidities, organisms isolated, infectious focus, and 30-day mortality of patients with PMB. RESULTS: Of the 7233 positive blood cultures, 808 (11.2%) were positive for more than one organism. Of the patients with bacteremia, 507 (7.0%) had PMB, of whom 65.3% were male. Infectious foci were identified in 78.3% of the cases, of which intra-abdominal infections accounted for 47.1%. A combination of Gram-positive cocci (GPC) (chain form) and Gram-negative rods (GNR) accounted for 32.9% of the cases, and GPC/GNR and GNR/GNR patterns were significantly associated with intra-abdominal infections. The 30-day mortality rate of patients with PMB was 18.1%, with a median of 7.5 days from diagnosis to death. The mortality in patients with an infectious focus identified was significantly lower than that in patients with an unknown focus (16.3% vs. 24.5%; p = 0.031). CONCLUSIONS: Intra-abdominal infections were the most common source of PMB, and were strongly associated with a Gram-staining combination pattern of GPC (chain form)/GNR. PMB cases with an unknown focus had a poorer prognosis, highlighting the importance of early diagnosis and appropriate treatment.

DOI： 10.1007/s15010-022-01799-7

新規PHEXバリアントを伴うXLHにブロスマブが奏効した1例

山本紘一郎, 本多寛之, 中野靖浩, 徳増一樹, 長谷川功, 長谷川高誠, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 591 - 591 2022.10

COVID-19罹患後症状における内分泌機能に関する検討

砂田匠彦, 本多寛之, 中野靖浩, 山本絋一郎, 徳増一樹, 櫻田泰江, 松田祐依, 長谷川徹, 大塚勇輝, 小比賀美香子, 花山宜久, 萩谷英大, 植田圭吾, 片岡仁美, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 628 - 628 2022.10

Kikuchi–Fujimoto disease manifesting bilateral lymphadenopathy Reviewed International journal

Akihiro Kawatsuki, Kosuke Oka, Hideharu Hagiya, Fumio Otsuka

Clinical Case Reports 10 ( 10 ) e6494 2022.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Wiley

Physicians should keep in mind that Kikuchi-Fujimoto disease can show bilateral lymphadenopathy like the present case.

DOI： 10.1002/ccr3.6494

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ccr3.6494

Candida dubliniensis fungemia in a patient with severe COVID-19: A case report Reviewed International journal

Ayaka Kakehi, Hideharu Hagiya, Koji Iio, Yasuhiro Nakano, Hiromi Ihoriya, Yuki Taira, Kenta Nakamoto, Kou Hasegawa, Akihito Higashikage, Fumio Otsuka

Journal of Infection and Chemotherapy 28 ( 10 ) 1433 - 1435 2022.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

Candida dubliniensis phenotypically mimics Candida albicans in its microbiological features; thus, its clinical characteristics have yet to be fully elucidated. Here we report the case of a 68-year-old Japanese man who developed C. dubliniensis fungemia during treatment for severe coronavirus disease 2019 (COVID-19). The patient was intubated and received a combination of immunosuppressants, including high-dose methylprednisolone and two doses of tocilizumab, as well as remdesivir, intravenous heparin, and ceftriaxone. A blood culture on admission day 11 revealed Candida species, which was confirmed as C. dubliniensis by mass spectrometry. An additional sequencing analysis of the 26S rDNA and ITS regions confirmed that the organism was 100% identical to the reference strain of C. dubliniensis (ATCC MYA-646). Considering the simultaneous isolation of C. dubliniensis from a sputum sample, the lower respiratory tract could be an entry point for candidemia. Although treatment with micafungin successfully eradicated the C. dubliniensis fungemia, the patient died of COVID-19 progression. In this case, aggressive immunosuppressive therapy could have caused the C. dubliniensis fungemia. Due to insufficient clinical reports on C. dubliniensis infection based on definitive diagnosis, the whole picture of the cryptic organism is still unknown. Further accumulation of clinical and microbiological data of the pathogen is needed to elucidate their clinical significance.

DOI： 10.1016/j.jiac.2022.07.007

Prevalence of medical factors related to aging among older car drivers: a multicenter, cross-sectional, descriptive study Reviewed International journal

Hideharu Hagiya, Ryosuke Takase, Hiroyuki Honda, Yasuhiro Nakano, Yuki Otsuka, Hitomi Kataoka, Mika Uno, Keigo Ueda, Misa Takahashi, Hiroko Ogawa, Yoshihisa Hanayama, Fumio Otsuka

BMC Geriatrics 22 ( 1 ) 792 - 792 2022.10

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

AIM: An increasing number of older adults in Japan are at an increased risk of road traffic crashes. This study aimed to investigate the prevalence of potential underlying medical factors that increase the risk of road traffic crashes among older people. METHODS: This cross-sectional observational study was conducted in 11 medical institutions in Japan using self-administered questionnaires and physical examination from January to May 2021. The background and social data, data on the use of nursing care insurance, and clinical data suggestive of polypharmacy, sarcopenia, cognitive impairment, and frailty/oral frailty were obtained. The prevalence of these factors was compared between everyday and occasional drivers. RESULTS: Data of 127 patients were collected; their median (interquartile range) age was 73 (70-78) years. Of the total participants, 82 were men (64.6%) and 45 were women (35.4%). There were 77 everyday drivers and 50 occasional drivers. Of these, 121 (95.3%) had not applied for nursing care insurance, but the numbers of those who required help 1 and 2 were 1 (0.8%) and 3 (2.4%), respectively. Prevalence of medical factors was as follows: polypharmacy, 27.6%; sarcopenia, 8.7%; dementia, 16.4%; frailty, 15.0%; and oral frailty, 54.3%; it was not significantly different between every day and occasional drivers. Intention to return the car license was significantly higher among the occasional drivers (2.6% vs. 14.0%; odds ratio: 6.7, 95% confidence interval: 1.2-70.6, p = 0.024). CONCLUSION: We uncovered the prevalence of medical factors that can be associated with road traffic crashes among Japanese older people aged ≥ 65 years in our community.

DOI： 10.1186/s12877-022-03490-w

RAS/BRAF解析においてPCR-rSSO法とNGS法の併用による補完性が示された大腸癌の二例

山本英喜, 重安邦俊, 柳井広之, 井上博文, 松岡博美, 青江伯規, 東影明人, 藤井敬子, 大塚文男, 草野展周, 平沢晃

日本臨床検査医学会誌 70 ( 補冊 ) 258 - 258 2022.10

異なる経過をたどった腎動脈狭窄を伴う高安動脈炎の2症例

武本梨佳, 内田治仁, 戸田洋伸, 岡本修吾, 竹内英実, 梅林亮子, 大塚文男, 伊藤浩, 和田淳

脈管学 62 ( Suppl. ) S195 - S195 2022.10

専攻医から見た新専門医制度における総合診療専攻医の育成

大塚勇輝, 小比賀美香子, 大塚文男

総合診療 32 ( 10 ) 1274 - 1275 2022.10

Weekly GH投与の有用性を認めた脂肪肝・糖尿病合併AGHDの3例

中野靖浩, 山本紘一郎, 高瀬了輔, 大國皓平, 長谷川功, 越智可奈子, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 622 - 622 2022.10

術前検査にて機能的SSTR発現が示唆されたインスリノーマの1例

大國皓平, 山本幸近, 福島伸乃介, 長谷川功, 井下尚子, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 614 - 614 2022.10

コロナ禍の若年男性に発症した著明な粘液水腫の1例

山本紘一郎, 本多寛之, 中野靖浩, 長谷川功, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 578 - 578 2022.10

中枢性尿崩症と眼瞼黄色腫から診断したErdheim-Chester病の3例

山本紘一郎, 高瀬了輔, 大國皓平, 中野靖浩, 岡浩介, 本多寛之, 長谷川功, 花山宜久, 小比賀美香子, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 569 - 569 2022.10

経過中にインスリノーマを認めた高齢2型糖尿病の1例

長岡寛和, 本多寛之, 斎藤光希, 田中秀一, 山本紘一郎, 石田智治, 長谷川功, 萩谷英大, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 620 - 620 2022.10

心室期外収縮を契機に判明した反応性低血糖の1例

本多寛之, 田中秀一, 中野靖弘, 長谷川功, 萩谷英大, 小比賀美香子, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 619 - 619 2022.10

RAS/BRAF解析においてPCR-rSSO法とNGS法の併用による補完性が示された大腸癌の二例

山本英喜, 重安邦俊, 柳井広之, 井上博文, 松岡博美, 青江伯規, 東影明人, 藤井敬子, 大塚文男, 草野展周, 平沢晃

日本臨床検査医学会誌 70 ( 補冊 ) 258 - 258 2022.10

経過中にインスリノーマを認めた高齢2型糖尿病の1例

長岡寛和, 本多寛之, 斎藤光希, 田中秀一, 山本紘一郎, 石田智治, 長谷川功, 萩谷英大, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 620 - 620 2022.10

Weekly GH投与の有用性を認めた脂肪肝・糖尿病合併AGHDの3例

中野靖浩, 山本紘一郎, 高瀬了輔, 大國皓平, 長谷川功, 越智可奈子, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 622 - 622 2022.10

術前検査にて機能的SSTR発現が示唆されたインスリノーマの1例

大國皓平, 山本幸近, 福島伸乃介, 長谷川功, 井下尚子, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 614 - 614 2022.10

心室期外収縮を契機に判明した反応性低血糖の1例

本多寛之, 田中秀一, 中野靖弘, 長谷川功, 萩谷英大, 小比賀美香子, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 619 - 619 2022.10

コロナ禍の若年男性に発症した著明な粘液水腫の1例

山本紘一郎, 本多寛之, 中野靖浩, 長谷川功, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 578 - 578 2022.10

新規PHEXバリアントを伴うXLHにブロスマブが奏効した1例

山本紘一郎, 本多寛之, 中野靖浩, 徳増一樹, 長谷川功, 長谷川高誠, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 591 - 591 2022.10

中枢性尿崩症と眼瞼黄色腫から診断したErdheim-Chester病の3例

山本紘一郎, 高瀬了輔, 大國皓平, 中野靖浩, 岡浩介, 本多寛之, 長谷川功, 花山宜久, 小比賀美香子, 大塚文男

日本内分泌学会雑誌 98 ( 2 ) 569 - 569 2022.10

異なる経過をたどった腎動脈狭窄を伴う高安動脈炎の2症例

武本梨佳, 内田治仁, 戸田洋伸, 岡本修吾, 竹内英実, 梅林亮子, 大塚文男, 伊藤浩, 和田淳

脈管学 62 ( Suppl. ) S195 - S195 2022.10

岡山大学病院中央採血室の待ち状況のYouTubeライブ配信について

東影明人, 青江伯規, 川下隆二, 藤井敬子, 山本英喜, 大塚文男

日本臨床検査医学会誌 70 ( 補冊 ) 166 - 166 2022.10

Collaboration between generalist and ENT physicians in COVID-19 Omicron variant-induced laryngitis Reviewed International journal

Yuki Otsuka, Kou Hasegawa, Yukichika Yamamoto, Asuka Sato, Ryotaro Omichi, Fumio Otsuka

Auris Nasus Larynx 50 ( 4 ) 652 - 653 2022.10

Effects of Yoga and Mindfulness Programs on Self-Compassion in Medical Professionals during the COVID-19 Pandemic: An Intervention Study Reviewed International journal

Tomoko Miyoshi, Hiromi Ida, Yoshito Nishimura, Soichiro Ako, Fumio Otsuka

International Journal of Environmental Research and Public Health 19 ( 19 ) 12523 - 12523 2022.9

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Stress among healthcare workers (HCWs) increased during the coronavirus disease 2019 pandemic. We aimed to determine whether a yoga and mindfulness program could alleviate burnout and other psychological and physical distress in HCWs, and how this might affect their empathy for patients. A weekly one-hour yoga and mindfulness program was conducted for three months in 2021. Participants were 18 consenting HCWs and, the final analysis included 13 participants. They responded to online questionnaires before and after the program. We measured salivary cortisol levels before and after the program on the first and last days. Self-measured pulse rates (PRs) were taken before and after each session, which decreased significantly in both cases (before, after the first program: 72, 65 bpm, p < 0.05; before, after the last program: 75, 66, p < 0.05), but salivary cortisol levels did not change. No significant changes were observed in Patient Health Questionnaire-9, Maslach Burnout Inventory, Sense of Coherence, Connor-Davidson Resilience Scale, Self-compassion Scale, or Jefferson Scale of Empathy. However, common humanity, a subscale of self-compassion, increased significantly (before the first program: 5.6, after the last program: 6.5, p < 0.05), and over-identification decreased significantly (7.9, 6.7, p < 0.01). Yoga and mindfulness programs may help improve the sense of common humanity and reduce over-identification in HCWs.

DOI： 10.3390/ijerph191912523

Secondary autoimmune hypothalamitis with severe memory impairment 7 years after the onset of diabetes insipidus due to lymphocytic hypophysitis: a case report Reviewed

Takahiro Asada, Shintaro Takenoshita, Mayuko Senda, Koichiro Yamamoto, Ryo Sasaki, Fumio Otsuka, Seishi Terada, Norihito Yamada

BMC Neurology 22 ( 1 ) 2022.9

Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Background

Autoimmune hypothalamitis is a very rare neuroendocrine disorder that causes central diabetes insipidus, headache, visual impairment, and sometimes cognitive impairment. Autoimmune hypothalamitis may occur in association with autoimmune hypophysitis, including lymphocytic hypophysitis, or in isolation. It is not known whether autoimmune hypothalamitis and autoimmune hypophysitis are consecutive diseases.

Case presentation

A 52-year-old woman developed autoimmune hypothalamitis 7 years after developing central diabetes insipidus due to lymphocytic hypophysitis, resulting in severe memory impairment. High-dose intravenous methylprednisolone therapy improved her cognitive function and decreased the size of the lesion.

Conclusion

This case presented a unique clinical course, with a long period of time between the onset of autoimmune hypopituitaritis and the development of autoimmune hypothalamitis.

DOI： 10.1186/s12883-022-02891-z

Other Link： https://link.springer.com/article/10.1186/s12883-022-02891-z/fulltext.html

Splenomegaly in silent endocarditis Reviewed

T Ishida, H Hagiya, Y Yamamoto, K Oguni, F Otsuka

QJM: An International Journal of Medicine 115 ( 9 ) 615 - 616 2022.9

Impact of the cervical cancer awareness months on public interest in Japan: A Google Trends analysis, 2012–2021 Reviewed International journal

Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

Scientific Reports 12 ( 1 ) 15391 - 15391 2022.9

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

The immunization and screening rates for human papillomavirus in Japan are lower than those in other countries. We aimed to evaluate the impact of cervical cancer awareness months on public attention using Google Trends analysis. Between 2012 and 2021, we analyzed the trends in relative search volumes (RSVs) for “Shikyuu-keigan” (cervical cancer in English) in Japan, during the cervical cancer awareness month (CCAM) in January and cervical cancer prevention awareness enhancement month (CCPAEM) in November. We performed a joinpoint regression analysis to identify a statistically significant trend change point. Additionally, we compared the mean RSVs of each awareness month with the rest of the year. Significant trend change points were observed, but none were found in CCAM and CCPAEM periods. Comparison of mean RSVs among CCAM, CCPAEM, and the rest of the months did not suggest any significant increases in RSVs during these awareness periods. In conclusion, CAM and CCPAEM did not raise public interest in cervical cancer in Japan. Although the results are based on internet users, the findings might suggest a need to develop a more effective and attractive approach to achieve the 90-70-90 targets of cervical cancer prevention by 2030.

DOI： 10.1038/s41598-022-19798-x

Other Link： https://www.nature.com/articles/s41598-022-19798-x

Idiopathic Plasmacytic Lymphadenopathy Forms an Independent Subtype of Idiopathic Multicentric Castleman Disease Reviewed

Asami Nishikori, Midori Nishimura, Yoshito Nishimura, Fumio Otsuka, Kanna Maehama, Kumiko Ohsawa, Shuji Momose, Naoya Nakamura, Yasuharu Sato

International Journal of Molecular Sciences 23 ( 18 ) 10301 - 10301 2022.9

Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease that is not related to KSHV/HHV8 infection. Currently, iMCD is classified into iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). The former has been established as a relatively homogeneous disease unit that has been recently re-defined, while the latter is considered to be a heterogeneous disease that could be further divided into several subtypes. In 1980, Mori et al. proposed the concept of idiopathic plasmacytic lymphadenopathy (IPL), a disease presenting with polyclonal hypergammaglobulinemia and a sheet-like proliferation of mature plasma cells in the lymph nodes. Some researchers consider IPL to be a part of iMCD-NOS, although it has not been clearly defined to date. This is the first paper to analyze iMCD-NOS clinicopathologically, to examine whether IPL forms a uniform disease unit in iMCD. Histologically, the IPL group showed prominent plasmacytosis and the hyperplasia of germinal centers, while the non-IPL group showed prominent vascularity. Clinically, the IPL group showed significant thrombocytosis and elevated serum IgG levels compared to the non-IPL group (p = 0.007, p < 0.001, respectively). Pleural effusion and ascites were less common in the IPL group (p < 0.001). The IPL group was more likely to have an indolent clinical course and a good response to the anti-IL-6 receptor antibody, while the non-IPL counterpart frequently required more aggressive medical interventions. Thus, the IPL group is a clinicopathologically uniform entity that forms an independent subtype of iMCD.

DOI： 10.3390/ijms231810301

[Central Nervous System and Psychiatric Complications in Long Coronavirus Disease 2019]. Reviewed

Hideharu Hagiya, Fumio Otsuka

No shinkei geka. Neurological surgery 50 ( 5 ) 1071 - 1077 2022.9

Language：Japanese

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has prevailed worldwide since early 2020 and has caused the global coronavirus disease 2019(COVID-19)pandemic. A considerable number of patients suffer from various sequela after SARS-CoV-2 infection, which is known as post COVID-19 condition(PCC). Amid the COVID-19 pandemic, we opened a COVID-19 aftercare clinic in February 2021 in Okayama University Hospital, where we specifically consult PCC patients. While examining such patients, three Cs are essential: complexity, continuity, and collaboration. Neurological and psychiatric manifestations are particularly important from the wide range of PCC symptoms. Indeed, a recent meta-analysis demonstrated that PCC patients suffer from brain fog(32%), memory loss(27%), attention disorder(22%), dyssomnia(31%), anxiety(23%), and depression(12%). The pathophysiology and treatment strategies for these conditions are yet to be developed, and further research is required. We have corroborated that endocrinological impairments may underlie the onset and deterioration of PCC. Through our continuous consultation at the COVID-19 aftercare clinic, we intend to conduct research on the pathophysiology of and treatment strategies for PCC.

DOI： 10.11477/mf.1436204667

Examining the association between vaccine reactogenicity and antibody titer dynamics after the third dose of BNT162b2 vaccine using a mixed-effects model Reviewed

Naomi Matsumoto, Hideharu Hagiya, Masanori Nakayama, Masanori Furukawa, Toshiharu Mitsuhashi, Soshi Takao, Fumio Otsuka, Takashi Yorifuji

Journal of Infection and Chemotherapy 2022.9

Gap between self-evaluation and actual hand hygiene compliance among health-care workers Reviewed International journal

Hideharu Hagiya, Ryosuke Takase, Yosuke Sazumi, Yoshito Nishimura, Hiroyuki Honda, Fumio Otsuka

Journal of Infection Prevention 23 ( 5 ) 239 - 242 2022.9

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：SAGE Publications

Hand hygiene (HH) compliance among health-care workers has not satisfactorily improved despite multiple educative approaches. Between October 2019 and February 2020, we performed a self-evaluation test and a direct observation for the compliance of the 5 Moments for Hand Hygiene program advocated by the World Health Organization at two Japanese hospitals. Average percentages of self-evaluated HH compliance were as follows: (i) 76.9% for “Before touching a patient,” (ii) 85.8% for “Before clean/aseptic procedures,” (iii) 95.9% for “After body fluid exposure/risk,” (iv) 84.0% for “After touching a patient,” and (v) 69.2% for “After touching patient surroundings.” On the other hand, actual HH compliance was 11.7% for “Before touching a patient” and 18.0% for “After touching a patient or patient surroundings.” The present study demonstrated a big gap between self-evaluation and actual HH compliance among nurses working at hospitals, indicating the need of further providing the education in infection prevention.

DOI： 10.1177/17571774221094160

Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/17571774221094160

Mutual Effects of Orexin and Bone Morphogenetic Proteins on Gonadotropin Expression by Mouse Gonadotrope Cells. Reviewed International journal

Yoshiaki Soejima, Nahoko Iwata, Nanako Nakayama, Shinichi Hirata, Yasuhiro Nakano, Koichiro Yamamoto, Atsuhito Suyama, Kohei Oguni, Takahiro Nada, Satoshi Fujisawa, Fumio Otsuka

International journal of molecular sciences 23 ( 17 ) 2022.8

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Orexin plays a key role in the regulation of sleep and wakefulness and in feeding behavior in the central nervous system, but its receptors are expressed in various peripheral tissues including endocrine tissues. In the present study, we elucidated the effects of orexin on pituitary gonadotropin regulation by focusing on the functional involvement of bone morphogenetic proteins (BMPs) and clock genes using mouse gonadotrope LβT2 cells that express orexin type 1 (OX1R) and type 2 (OX2R) receptors. Treatments with orexin A enhanced LHβ and FSHβ mRNA expression in a dose-dependent manner in the absence of GnRH, whereas orexin A in turn suppressed GnRH-induced gonadotropin expression in LβT2 cells. Orexin A downregulated GnRH receptor expression, while GnRH enhanced OX1R and OX2R mRNA expression. Treatments with orexin A as well as GnRH increased the mRNA levels of Bmal1 and Clock, which are oscillational regulators for gonadotropin expression. Of note, treatments with BMP-6 and -15 enhanced OX1R and OX2R mRNA expression with upregulation of clock gene expression. On the other hand, orexin A enhanced BMP receptor signaling of Smad1/5/9 phosphorylation through upregulation of ALK-2/BMPRII among the BMP receptors expressed in LβT2 cells. Collectively, the results indicate that orexin regulates gonadotropin expression via clock gene expression by mutually interacting with GnRH action and the pituitary BMP system in gonadotrope cells.

DOI： 10.3390/ijms23179782

Site-specific differences in T lymphocyte composition of the gastric mucosa after Helicobacter pylori eradication. Reviewed International journal

Masaya Iwamuro, Takahide Takahashi, Natsuki Watanabe, Makoto Abe, Hiroyuki Sakae, Yoshiyasu Kono, Hiromitsu Kanzaki, Takehiro Tanaka, Seiji Kawano, Fumio Otsuka, Yoshiro Kawahara, Hiroyuki Yanai, Hiroyuki Okada

Medicine 101 ( 34 ) e30241 2022.8

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

In our earlier work, we revealed that inflammation of the lesser curvature of the gastric body and antrum could constitute independent risk factors for gastric cancer development, while inflammation of the greater curvature was not. The aims of this study were as follows: first, to reveal the differences between T lymphocyte populations of the gastric antrum and the greater and lesser curvatures of the gastric body in patients after Helicobacter pylori eradication; second, to analyze the correlation between the composition of the stomach-resident T lymphocytes and time from H. pylori eradication; and third, to evaluate the sex differences in T lymphocyte subsets after H. pylori eradication. To investigate site-specific differences in stomach-resident T lymphocytes after H. pylori eradication, we performed flow cytometry analysis on samples taken from the gastric antrum, greater curvature of the gastric body, and lesser curvature of the gastric body of 20 patients. We also analyzed the correlation between the composition of the stomach-resident T lymphocytes and the time from H. pylori eradication. The lymphocyte subsets of the antrum and lesser curvature of the body were similar. In contrast, compared to those in the greater curvature of the gastric body, CD4+/CD3+ lymphocyte subsets (43.8 ± 19.4% vs 31.7 ± 14.6%) were elevated in the lesser curvature of the body, whereas CD8+/CD3+ (67.1 ± 21.3% vs 80.4 ± 12.0%), CD7+/CD3+ (91.2 ± 4.6% vs 93.7 ± 3.8%), CCR4+/CD3+ (7.7 ± 8.1% vs 10.4 ± 7.0%), CD45RA+/CD3+CD4+ (27.2 ± 24.8% vs 39.5 ± 20.8%), and CD45RA+/CD3+CD4- (14.2 ± 11.1% vs 18.7 ± 11.5) were lower. Linear regression analysis showed a negative correlation between the time after H. pylori eradication and CD4+/CD3+ (P < .05, R2 = 0.198). There were no significant differences between men and women with respect to the lymphocyte populations. These results indicate that there are site-specific differences in lymphocyte composition in the stomach after H. pylori eradication.

DOI： 10.1097/MD.0000000000030241

Tuberculous aortic aneurysm developed with miliary tuberculosis. Reviewed International journal

S Tanaka, H Hagiya, F Otsuka

QJM : monthly journal of the Association of Physicians 115 ( 8 ) 543 - 544 2022.8

Red blood cell depletion in small‐volume bone marrow processing using manipulation with third‐party red blood cells: A comparison of the performance of the COBE spectra and the spectra Optia systems Reviewed

Yuichi Sumii, Nobuharu Fujii, Keiko Fujii, Takumi Kondo, Tomohiro Urata, Maiko Kimura, Kana Washio, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken‐ichi Matsuoka, Fumio Otsuka, Yoshinobu Maeda

Transfusion 2022.8

Global public awareness of Castleman disease and TAFRO syndrome between 2015 and 2021: A Google Trends analysis Reviewed

Yoshito Nishimura, Midori Filiz Nishimura, David C. Fajgenbaum, Frits van Rhee, Yasuharu Sato, Fumio Otsuka

eJHaem 3 ( 3 ) 748 - 753 2022.8

Postprandial Reactive Hypoglycemia Detected with Premature Ventricular Contraction. Reviewed International journal

Hiroyuki Honda, Shuichi Tanaka, Hideharu Hagiya, Fumio Otsuka

QJM : monthly journal of the Association of Physicians 115 ( 10 ) 675 - 676 2022.7

Prevalence of psychological distress on public health officials amid COVID-19 pandemic. Reviewed International journal

Yoshito Nishimura, Tomoko Miyoshi, Hideharu Hagiya, Fumio Otsuka

Asian journal of psychiatry 73 103160 - 103160 2022.7

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: While the coronavirus disease 2019 (COVID-19) pandemic has led to increased burnout among frontline healthcare workers (HCWs), little research has been done regarding the potential psychological burden among public health officials who have worked tirelessly to tackle the pandemic from an administrative perspective. This study aimed to determine the prevalence of burnout, depression, and job-related stress in Japanese public health officers amid the COVID-19 pandemic. METHODS: We conducted an anonymous, self-administered web-based cross-sectional survey including basic demographics, work-related questions, the Maslach Burnout Inventory, Patient Health Questionnaire-9, Utrecht Work Engagement Scale-3, and Brief Job Stress Questionnaire. 100 public health officers working in the public health centers (PHCs) in Okayama, Japan, answered the survey in December 2021 when the 5th surge in the number of COVID-19 was over. RESULTS: The prevalence of burnout, depression, and job-related stress was 27%, 43%, and 62%, respectively. The multivariate logistic analysis demonstrated that females, public health nurses, and those who suffered from a lack of support from their workplaces were significantly associated with psychological distress. CONCLUSIONS: While we tend to focus on mitigation plans to help alleviate burnout of frontline HCWs, more focus is needed to help public health officers, and public health nurses, in particular, to alleviate their psychological distress and job-related stress to prevent further staff shortages and secure sustainable health systems.

DOI： 10.1016/j.ajp.2022.103160

Vancomycin MIC creep progresses in methicillin-resistant Staphylococcus aureus despite the national antimicrobial stewardship campaign: Single facility data in Japan. Reviewed International journal

Takumi Fujimori, Hideharu Hagiya, Koji Iio, Tsukasa Higashionna, Ayaka Kakehi, Mami Okura, Hiroshi Minabe, Yukika Yokoyama, Fumio Otsuka, Akihito Higashikage

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 28 ( 7 ) 918 - 922 2022.7

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

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of nosocomial and community infections, and vancomycin (VCM) is widely recommended as a first-line therapeutic drug. Minimum inhibitory concentrations (MICs) of VCM ≤2 μg/mL are defined as susceptible, but increases in these levels, known as "VCM MIC creep" have been reported. The aim of this study was to investigate VCM MIC creep during the promotion of a national antimicrobial stewardship campaign. METHODS: We collected data from 2013 to 2020 on S. aureus isolated at the clinical microbiology laboratory at Okayama University Hospital, Japan. We calculated the annual proportions of MRSA isolation rates by MIC levels for nosocomial and community samples and estimated annual percentage changes in the antimicrobial use density of the VCM. RESULTS: Of the 1,716 MRSA isolates, no strains showed intermediate or resistant ranges of VCM MIC levels. By 2020, the proportion of MRSA with an MIC of ≤0.5 μg/mL decreased to 35.4%, while that with an MIC of 1 μg/mL increased to 64.1% over time. The annual percentage changes of the VCM antimicrobial use density significantly increased without any trend change point (average 8.1%, p = 0.035). There was no clear correlation between the VCM AUD and annual proportion of nosocomial MRSA with MIC 1 μg/mL (correlation coefficient 0.48; p value = 0.24). CONCLUSION: We demonstrated a deteriorating situation of VCM MIC creep among MRSA strains isolated at our university hospital during the national antimicrobial stewardship campaign.

DOI： 10.1016/j.jiac.2022.03.017

Poor vaccine responsiveness towards third-dose mRNA vaccine of COVID-19 in Japanese older people Reviewed

Hideharu Hagiya, Takao Hikita, Tomohiro Habu, Masaki Asada, Takashi Yorifuji, Shinichi Toyooka, Fumio Otsuka, Masanori Nakayama

Journal of Infection 85 ( 4 ) 436 - 480 2022.7

Persistent methicillin-resistant Staphylococcus aureus bacteremia in an adult patient with Netherton's syndrome: A case report Reviewed

Misa Takahashi, Hideharu Hagiya, Shuichi Tanaka, Koichiro Yamamoto, Hiroyuki Honda, Kou Hasegawa, Fumio Otsuka

Journal of Infection and Chemotherapy 28 ( 7 ) 978 - 981 2022.7

Primary bone lymphoma presenting as fever of unknown origin Reviewed

Yuki Otsuka, Yasuhiro Nakano, Daisuke Omura, Kou Hasegawa, Fumio Otsuka

Journal of General and Family Medicine 23 ( 4 ) 280 - 281 2022.7

「哲学カフェ」は医師のどのような能力を涵養するか

小比賀美香子, 松川えり, 徳増一樹, 大塚文男

医学教育 53 ( Suppl. ) 145 - 145 2022.7

Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVID. Reviewed International journal

Kazuki Tokumasu, Hiroyuki Honda, Naruhiko Sunada, Yasue Sakurada, Yui Matsuda, Koichiro Yamamoto, Yasuhiro Nakano, Toru Hasegawa, Yukichika Yamamoto, Yuki Otsuka, Hideharu Hagiya, Hitomi Kataoka, Keigo Ueda, Fumio Otsuka

Medicina (Kaunas, Lithuania) 58 ( 7 ) 2022.6

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Background and Objectives: COVID-19 can be serious not only in the acute phase but also after the acute phase and some patients develop ME/CFS. There have been few studies on patients with long COVID in whom ME/CFS was diagnosed by physicians based on standardized criteria after examinations and exclusion diagnosis and not based on only subjective symptoms. The purpose of this study was to elucidate the detailed characteristics of ME/CFS in patients with long COVID. Materials and Methods: A retrospective descriptive study was performed for patients who visited a COVID-19 aftercare clinic established in Okayama University Hospital during the period was from February 2021 to April 2022. Results: Clinical data were obtained from medical records for 281 patients, and 279 patients who met the definition of long COVID were included. The overall prevalence rate of ME/CFS diagnosed by three sets of ME/CFS criteria (Fukuda, Canadian and IOM criteria) was 16.8% (48.9% in male and 51.1% in females). The most frequent symptoms in ME/CFS patients were general fatigue and post-exertional malaise (89.4% of the patients), headache (34.0%), insomnia (23.4%), dysosmia (21.3%) and dysgeusia (19.1%). Dizziness, chest pain, insomnia and headache were characteristic symptoms related to ME/CFS. The male to female ratio in ME/CFS patients was equal in the present study, although ME/CFS was generally more common in women in previous studies. Given that patients with ME/CFS had more severe conditions in the acute phase of COVID-19, the severity of the acute infectious state might be involved in the pathophysiology of ME/CFS. Conclusions: The prevalence rate of ME/CFS and the characteristic sequelae in the long COVID condition were revealed in this study.

DOI： 10.3390/medicina58070850

Clinical characteristics and outcomes of IgG4-positive marginal zone lymphoma: Systematic scoping review. Reviewed International journal

Yoshito Nishimura, Eric Andrew Wien, Midori Filiz Nishimura, Asami Nishikori, Yasuharu Sato, Fumio Otsuka

Pathology international 2022.6

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Immunoglobulin G4 (IgG4)-positive marginal zone lymphoma (MZL) is rare and undefined. It is unclear whether IgG4-positive MZLs have as favorable an outcome as MZLs in general. Also, correlation with IgG4-related disease (IgG4-RD) and IgG4-positive MZLs is unknown. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews, we searched MEDLINE and EMBASE for all peer-reviewed articles using keywords including"IgG4" and "marginal zone lymphoma" from their inception to February 20, 2022. Twenty-two articles, including six observational studies and 24 cases from 16 case reports and case series, were included. Only one study had a comparative group, and the other five were exploratory observational studies. IgG4-positive MZLs commonly occurred in males (83.3%). It primarily involved ocular adnexa (41.7%) and skin (29.2%). Only 29.2% had concurrent IgG4-RD, and no expiration was noted. While most cases were treated with excision, resection, or clinical observation, 21.7% received rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone as a first-line treatment. This systematic review summarizes the current understanding of the characteristics of IgG4-positive MZLs. While there seems to be IgG4-RD-related and de novo IgG4-positive MZLs, future research needs to clearly define MZL with polyclonal IgG4-positive cells and IgG4-producing lymphoma. Further studies are critical to clarifying long-term prognosis and optimal surveillance planning.

DOI： 10.1111/pin.13251

「筋痛性脳脊髄炎/慢性疲労症候群(ME/CFS)」岡山大学病院総合内科・総合診療科におけるME/CFS診療

片岡仁美, 大塚勇輝, 本多寛之, 砂田匠彦, 櫻田泰江, 松田祐依, 徳増一樹, 長谷川功, 小比賀美香子, 植田圭吾, 大塚文男

日本疲労学会誌 18 ( 1 ) 37 - 37 2022.6

Eyelid edema due to Cushing's syndrome Reviewed International journal

Koichiro Yamamoto, Kosuke Oka, Kou Hasegawa, Fumio Otsuka

Clinical Case Reports 10 ( 6 ) e05940 2022.6

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Wiley

Cushing's syndrome (CS) shows diverse signs such as centripetal obesity, moon face, and buffalo hump, which can complicate the diagnosis. Facial features including eyelid edema, as an underrecognized sign, can be diagnostic clues for an excess of corticoids in a CS patient.

DOI： 10.1002/ccr3.5940

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ccr3.5940

「筋痛性脳脊髄炎/慢性疲労症候群(ME/CFS)」岡山大学病院総合内科・総合診療科におけるME/CFS診療

片岡仁美, 大塚勇輝, 本多寛之, 砂田匠彦, 櫻田泰江, 松田祐依, 徳増一樹, 長谷川功, 小比賀美香子, 植田圭吾, 大塚文男

日本疲労学会誌 18 ( 1 ) 37 - 37 2022.6

胸鎖関節炎・頸部膿瘍を契機に診断した2型糖尿病の1例

中本健太, 本多寛之, 平佑貴, 庵谷紘美, 中野靖浩, 長谷川功, 萩谷英大, 小比賀美香子, 片岡仁美, 大塚文男

糖尿病 65 ( 6 ) 337 - 337 2022.6

維持透析中の2型糖尿病患者に発症したフルニエ壊疽の1例

庵谷紘美, 本多寛之, 平佑貴, 中本健太, 中野靖浩, 長谷川功, 萩谷英大, 小比賀美香子, 片岡仁美, 大塚文男

糖尿病 65 ( 6 ) 337 - 337 2022.6

医学生の自覚ストレスとコミュニケーションの関連横断研究

徳増一樹, 西村義人, 坂本陽子, 小比賀美香子, 片岡仁美, 大塚文男

日本プライマリ・ケア連合学会学術大会 13回 O - 90 2022.6

「筋痛性脳脊髄炎/慢性疲労症候群(ME/CFS)」漢方によるlong COVIDの倦怠感への対応

徳増一樹, 植田圭吾, 大塚勇輝, 本多寛之, 砂田匠彦, 櫻田泰江, 松田祐依, 片岡仁美, 大塚文男

日本疲労学会誌 18 ( 1 ) 37 - 37 2022.6

維持透析中の2型糖尿病患者に発症したフルニエ壊疽の1例

庵谷紘美, 本多寛之, 平佑貴, 中本健太, 中野靖浩, 長谷川功, 萩谷英大, 小比賀美香子, 片岡仁美, 大塚文男

糖尿病 65 ( 6 ) 337 - 337 2022.6

胸鎖関節炎・頸部膿瘍を契機に診断した2型糖尿病の1例

中本健太, 本多寛之, 平佑貴, 庵谷紘美, 中野靖浩, 長谷川功, 萩谷英大, 小比賀美香子, 片岡仁美, 大塚文男

糖尿病 65 ( 6 ) 337 - 337 2022.6

Application of Kampo Medicines for Treatment of General Fatigue Due to Long COVID. Reviewed International journal

Kazuki Tokumasu, Keigo Ueda, Hiroyuki Honda, Naruhiko Sunada, Yasue Sakurada, Yui Matsuda, Yasuhiro Nakano, Toru Hasegawa, Yuki Otsuka, Mikako Obika, Hideharu Hagiya, Hitomi Kataoka, Fumio Otsuka

Medicina (Kaunas, Lithuania) 58 ( 6 ) 2022.5

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Evidence regarding treatment for the acute phase of COVID-19 has been accumulating, but specific treatment for long COVID/post-COVID-19 condition has not yet been established. Treatment with herbal medicine might be one treatment option for long COVID, but there has been little research on the effectiveness of herbal medicine for long COVID. The aim of this study was to clarify the prescription patterns of Kampo medicines, which are herbal medicines that originated in China and were developed in Japan, for the treatment of general fatigue due to long COVID. A retrospective descriptive study was performed for patients who visited a COVID-19 aftercare clinic established in Okayama University Hospital during the period from Feb 2021 to Dec 2021 with a focus on symptoms accompanying general fatigue and prescriptions of Kampo medicine. Among the clinical data obtained from medical records of 195 patients, clinical data for 102 patients with general fatigue and accompanying symptoms were analyzed. The patients had various symptoms, and the most frequent symptoms accompanying general fatigue were dysosmia, dysgeusia, headache, insomnia, dyspnea, and hair loss. Prescriptions of Kampo medicine accounted for 24.1% of the total prescriptions (n = 609). The most frequently prescribed Kampo medicine was hochuekkito (71.6%) and other prescribed Kampo medicines were tokishakuyakusan, ryokeijutsukanto, juzentaihoto, hangekobokuto, kakkonto, ninjin'yoeito, goreisan, rikkunshito, and keishibukuryogan. Since the pathophysiology of general fatigue after an infectious disease is, in general, considered a qi deficiency in Kampo medicine, treatments with such compensation agents can be the major prescription as a complement for the qi. In conclusion, Kampo medicine can be one of the main pharmacological treatments for long COVID accompanying general fatigue.

DOI： 10.3390/medicina58060730

Characterization of Gastric Tissue-Resident T Cells in Autoimmune and Helicobacter pylori-Associated Gastritis Reviewed International journal

Daisuke Kametaka, Masaya Iwamuro, Takahide Takahashi, Araki Hirabata, Kenta Hamada, Yoshiyasu Kono, Hiromitsu Kanzaki, Seiji Kawano, Takehiro Tanaka, Fumio Otsuka, Yoshiro Kawahara, Hiroyuki Okada

Current Issues in Molecular Biology 44 ( 6 ) 2443 - 2452 2022.5

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

Data regarding the in-depth surface marker profiles of gastric tissue-resident lymphocytes in autoimmune and Helicobacter pylori-associated gastritis are lacking. In this study, we investigated potential differences in lymphocyte composition between these profiles. We enrolled patients with autoimmune (n = 14), active (current infection of H. pylori in the stomach; n = 10), and inactive gastritis (post-eradication of H. pylori; n = 20). Lymphocytes were isolated from the greater curvature of the stomach and lesser curvature of the body and analyzed using flow cytometry. The CD8+/CD3+ and CD4+/CD3+ ratios differed between the samples. Body CD4+/antrum CD4+, which is calculated by dividing the CD4+/CD3+ ratio in the body by that in the antrum, was significantly higher in autoimmune gastritis (3.54 ± 3.13) than in active (1.47 ± 0.41) and inactive gastritis (1.42 ± 0.77). Antrum CD8+/CD4+ in autoimmune gastritis (7.86 ± 7.23) was also higher than that in active (1.49 ± 0.58) and inactive gastritis (2.84 ± 2.17). The area under the receiver operating characteristic curve of antrum CD8+/CD4+ was 0.842, and the corresponding optimal cutoff point was 4.0, with a sensitivity of 71.4% and a specificity of 93.3%. We propose that an antrum CD8+/CD4+ ratio > 4.0 is a potential diagnostic marker for autoimmune gastritis.

DOI： 10.3390/cimb44060167

Call for correction: Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis. Reviewed International journal

Hideharu Hagiya, Yuki Otsuka, Fumio Otsuka

Journal of the neurological sciences 436 120232 - 120232 2022.5

Adrenal and Testicular Tumor Formation Due to 21-Hydroxylase Deficiency. Reviewed International journal

Koichiro Yamamoto, Hiroyuki Honda, Fumio Otsuka

The American journal of medicine 135 ( 5 ) e106 2022.5

Inconsistency of the "Sogo-Shinryo" department in Japanese hospitals. Reviewed

Yuki Otsuka, Mikako Obika, Fumio Otsuka

Journal of general and family medicine 23 ( 3 ) 201 - 202 2022.5

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

The inconsistency of Japanese names of "Sogo-Shinryo" departments is also a greater problem in this country, and we are afraid that it may cause anxiety to patients, residents, and students. As one of the "Sogo-Shinryo" departments in Japan, we want to provide them comprehensive learning environments regardless of the boundaries of academic cliques and societies, and, as a result, relieve them, foster general minds, and build their careers.

DOI： 10.1002/jgf2.522

Trends in sarcoidosis mortality rate in Japan from 2001 to 2020: A population-based study Reviewed International journal

Ko Harada, Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

Respiratory Medicine 196 106828 - 106828 2022.5

Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

BACKGROUND: The sarcoidosis mortality rate has increased over the years, which contributes to the health care burden. Although epidemiological studies of sarcoidosis mortality in aging societies are essential, none have been published since 1989 in Japan. METHODS: We aimed to investigate the trends in crude and age-adjusted sarcoidosis-associated mortality rates per 1,000,000 population in Japan from 2001 to 2020 using national death certificate data among older adults aged over 50 years. The data were analysed using the joinpoint regression models to estimate long-term trends and average annual percentage changes (AAPCs). RESULTS: A total of 3094 sarcoidosis-associated deaths were recorded from 2001 to 2020 in Japan; women constituted 65.3% of these, with a female:male ratio of 1.89. Nearly 80% of deaths were over the age of 65 years, of which 32% were over the age of 80 years. The trend in crude mortality of those aged ≥80 years markedly increased from 0.81 to 9.68 per 1,000,000 population in men and from 2.38 to 12.87 in women, respectively. The overall age-adjusted sarcoidosis mortality rate increased 2.46-fold during the study period, with an AAPC of 5.1%. CONCLUSIONS: This study revealed that sarcoidosis-associated deaths in Japan have significantly increased over the past two decades, especially among the older population with a female predominance. Given the rising mortality rate and susceptibility of the older population, sarcoidosis will require more attention from health care providers in terms of a multidisciplinary approach to address the specific needs of the older population.

DOI： 10.1016/j.rmed.2022.106828

Psychosis Induced by Hypothyroidism(Myxedema Psychosis): A Case Report and Review of the Literature Reviewed

124 ( 5 ) 293 - 299 2022.5

Processes of increasing medical residents' intrinsic motivation: a qualitative study. Reviewed International journal

Kazuki Tokumasu, Mikako Obika, Haruo Obara, Makoto Kikukawa, Yoshito Nishimura, Fumio Otsuka

International journal of medical education 13 115 - 123 2022.4

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Objectives: This study aimed to determine qualitatively how medical residents develop intrinsic motivation to learn and work in clinical training settings. Methods: This study was a descriptive qualitative study, which is widely used in healthcare research. We conducted a semi-structured interview aimed to explore key participants' in-depth experiences and perspectives regarding intrinsic motivation. The authors interviewed seven postgraduate Japanese medical residents. The transcripts were analyzed using the sequential and thematic qualitative data analysis technique steps for coding and theorization, which entails coding steps from open to selective, writing a storyline using the final selective codes, and offering theories. Results: External stimulations (a self-handle environment and a near-peer role model) triggered the medical residents' cognitive process (gap recognition, awareness, and internalization) to intrinsic motivation. The residents' awareness of autonomy, responsibility, and independence played a vital role in this process. Furthermore, a psychological feeling of competence also reinforced their intrinsic motivation. Positive feedback and approval from attending physicians and patients' gratitude promoted residents' sense of competence. Conclusions: We illustrated a process for increasing medical residents' intrinsic motivation. The intrinsic motivation was triggered by external stimulations (a self-handle environment and a near-peer role model), which caused the cognitive process: gap recognition, awareness of important attitudes as a doctor (autonomy, responsibility, and independence), and internalization. Since the first step of this process was an external factor, there are potential benefits of designing an appropriate training environment for increasing medical residents' intrinsic motivation.

DOI： 10.5116/ijme.6250.1017

Global public awareness of Castleman disease and TAFRO syndrome between 2015 and 2021: A Google Trends analysis Reviewed

Yoshito Nishimura, Midori Filiz Nishimura, David C. Fajgenbaum, Frits van Rhee, Yasuharu Sato, Fumio Otsuka

eJHaem 3 ( 3 ) 748 - 753 2022.4

Hormonal trends in patients suffering from long COVID symptoms. Reviewed

Naruhiko Sunada, Hiroyuki Honda, Yasuhiro Nakano, Koichiro Yamamoto, Kazuki Tokumasu, Yasue Sakurada, Yui Matsuda, Toru Hasegawa, Yuki Otsuka, Mikako Obika, Yoshihisa Hanayama, Hideharu Hagiya, Keigo Ueda, Hitomi Kataoka, Fumio Otsuka

Endocrine journal 69 ( 10 ) 1173 - 1181 2022.4

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Symptoms of long COVID are complex and long-lasting, and endocrine dysfunction might be involved in the underlying mechanisms. In this study, to clarify the hormonal characteristics of long COVID patients, laboratory data for patients who visited the outpatient clinic for long COVID were evaluated. A retrospective analysis was performed for patients who visited Okayama University Hospital during the period from Feb 2021 to Dec 2021 with focus on the interrelationships between major symptoms and endocrine data. Information and laboratory data were obtained from medical records for 186 patients. The patients had various symptoms, and the most frequent symptoms were general malaise, dysosmia/dysgeusia, hair loss, headache, dyspnea, and sleeplessness. Patients who were suffering from fatigue and dysosmia/dysgeusia were younger, while hair loss was more frequent in older and female patients. As for the characteristics of patients suffering from general fatigue, the scores of depression and fatigue were positively correlated with serum levels of cortisol and free thyroxin (FT4), respectively. Also, patients suffering from general fatigue had lower levels of serum growth hormone and higher levels of serum FT4, while patients with dysosmia/dysgeusia had a significantly lower level of serum cortisol. Serum thyrotropin (TSH) levels were higher and the ratios of FT4/TSH were lower in the initially severe cases, suggesting occult hypothyroidism. In addition, the ratios of plasma adrenocorticotropin to serum cortisol were decreased in patients with relatively high titers of serum SARS-CoV-2 antibody. Thus, hormonal changes seem to be, at least in part, involved in the persistent symptoms of long COVID.

DOI： 10.1507/endocrj.EJ22-0093

Late-Onset Hypogonadism in a Male Patient with Long COVID Diagnosed by Exclusion of ME/CFS. Reviewed International journal

Yoshiaki Soejima, Yuki Otsuka, Kazuki Tokumasu, Yasuhiro Nakano, Ko Harada, Kenta Nakamoto, Naruhiko Sunada, Yasue Sakurada, Kou Hasegawa, Hideharu Hagiya, Keigo Ueda, Fumio Otsuka

Medicina (Kaunas, Lithuania) 58 ( 4 ) 2022.4

Authorship：Last author Language：English

After the acute phase of COVID-19, some patients have been reported to have persistent symptoms including general fatigue. We have established a COVID-19 aftercare clinic (CAC) to provide care for an increasing number of these patients. Here, we report the case of a 36-year-old man who developed post-COVID fatigue after acute infection with SARS-CoV-2. In the acute phase of COVID-19, the patient's fever resolved within four days; however, general fatigue persisted for three months, and he visited our CAC 99 days after the initial infection. Examination revealed a high Aging Male's Symptoms (AMS) score of 44 and low free testosterone (FT) level of 5.5 pg/mL, which meet the Japanese criteria of late-onset hypogonadism (LOH) syndrome. Imaging studies revealed an atrophic pituitary in addition to fatty liver and low bone mineral density. Anterior pituitary function tests showed a low follicle-stimulating hormonelevel and delayed reaction of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation, indicating the possibility of hypothalamic hypogonadism in addition to primary hypogonadism seen in patients with post-COVID-19 conditions. After the initiation of Japanese traditional medicine (Kampo medicine: hochuekkito followed by juzentaihoto), the patient's symptoms as well as his AMS score and serum FT level were noticeably improved. Furthermore, follow-up tests of GnRH stimulation revealed improvements in LH responsiveness. Although many patients have been reported to meet the criteria of ME/CFS such as our case, we emphasize the possibility of other underlying pathologies including LOH syndrome. In conclusion, LOH syndrome should be considered a cause of general fatigue in patients with post-COVID-19 conditions and herbal treatment might be effective for long COVID symptoms due to LOH (264 words).

DOI： 10.3390/medicina58040536

Antimicrobial prescription practices for outpatients with uncomplicated cystitis in Japan. Reviewed International journal

Misa Takahashi, Hideharu Hagiya, Tsukasa Higashionna, Yasuhiro Nakano, Kota Sato, Yuto Haruki, Mai Haruki, Hiroyuki Honda, Hiroko Ogawa, Keigo Ueda, Fumio Otsuka

Scientific reports 12 ( 1 ) 5921 - 5921 2022.4

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

To promote antimicrobial stewardship, we studied antimicrobial prescription rates for uncomplicated cystitis, a common outpatient disease requiring antibiotic treatment. This multicenter retrospective study was performed from January 1, 2018, to December 31, 2020, in Japan, targeting outpatients aged ≥ 20 years whose medical records revealed International Classification of Diseases (ICD-10) codes suggesting uncomplicated cystitis (N300). The data of 1445 patients were collected and that of 902 patients were analyzed. The overall median patient age was 71 years and a proportion of those aged less than 50 years was 18.8% with a female dominance (82.6%). Antimicrobials were prescribed for 884 patients (98.0%) and a total of 623 patients (69.1%) were treated with broad-spectrum drugs, including fluoroquinolones (36.0%), third-generation cephalosporins (29.9%) and faropenem (3.1%). A logistic regression model revealed that the broad-spectrum agents were significantly prescribed for the older patients, male patients, and those who visited internists. Recurrence was observed in 37 (4.1%) cases, and the multivariate analysis suggested any of age, sex, or antimicrobial types were not associated with the recurrence. Collectively, approximately two-thirds of antimicrobials prescribed for uncomplicated cystitis were broad-spectrum agents. The present data would be an indicator for antimicrobial prescriptions in uncomplicated cystitis in Japan.

DOI： 10.1038/s41598-022-09946-8

Relationship between patients’ characteristics and efficacy of calcimimetics for primary hyperparathyroidism in the elderly

Koichiro Yamamoto, Yasuhiro Nakano, Kazuki Tokumasu, Hiroyuki Honda, Kou Hasegawa, Asuka Sato, Hiroko Ogawa, Mikako Obika, Yoshihisa Hanayama, Fumio Otsuka

Clinical Case Reports 10 ( 4 ) 2022.4

Cat scratch disease without a history of cat exposure International journal

Kosuke Oka, Yume Takagi, Hideharu Hagiya, Fumio Otsuka

Clinical Case Reports 10 ( 4 ) e04816 2022.4

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

A patient complaining of swelling and tenderness in her left axilla was diagnosed with cat scratch disease despite no apparent history of cat exposure. Zoonosis can occur even in the absence of cat exposure because cat flea Ctenocephalides felis is also the vector of the pathogen through the flea feces.

DOI： 10.1002/ccr3.4816

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ccr3.4816

Half-and-Half Toenails

Koichiro Yamamoto, Fumio Otsuka

Mayo Clinic Proceedings 97 ( 4 ) 652 - 652 2022.4

IFN-α投与が奏効したステロイド抵抗性Erdheim-Chester病の1例

庵谷紘美, 中野靖浩, 中本健太, 平佑貴, 山本紘一郎, 長谷川功, 三好智子, 小川弘子, 白羽英則, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 279 - 279 2022.4

COVID-19後遺症契機に発見された2型糖尿病の1例

田中秀一, 本多寛之, 山本絋一郎, 高橋美砂, 長谷川功, 小比賀美香, 片岡仁美, 大塚文男

糖尿病 65 ( Suppl.1 ) S - 268 2022.4

原発性副甲状腺機能亢進症に対するカルシウム受容体作動薬の効果と関連因子

山本紘一郎, 中野靖浩, 徳増一樹, 本多寛之, 長谷川功, 小比賀美香子, 三好智子, 小川弘子, 花山宜久, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 374 - 374 2022.4

重度の化膿性胸鎖関節炎から発見された2型糖尿病の1例

高瀬了輔, 本多寛之, 中本健太, 平佑貴, 庵谷紘美, 中野靖浩, 長谷川功, 萩谷英大, 小比賀美香子, 片岡仁美, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 363 - 363 2022.4

Cushing病術後にバセドウ病再燃と相対的副腎不全を来した1例

中野靖浩, 平佑貴, 中本健太, 庵谷紘美, 長谷川功, 大塚勇輝, 佐々木恵里佳, 岸田雅之, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 346 - 346 2022.4

体動困難を契機に発見され副腎クリーゼを発症したACTH単独欠損症の1例

中野靖浩, 中本健太, 平佑貴, 庵谷紘美, 長谷川功, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 336 - 336 2022.4

頭部外傷が契機と考えられる中枢性尿崩症の1例

山本紘一郎, 本多寛之, 田中秀一, 高橋美砂, 長谷川功, 中野靖浩, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 335 - 335 2022.4

肝硬変と多発骨折を契機に診断されたFGF23関連低リン血症性骨軟化症の1例

須山敦仁, 山本紘一郎, 田中秀一, 孫麗那, 高橋美砂, 中野靖浩, 本多寛之, 長谷川功, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 325 - 325 2022.4

経過中に難治性高血圧症を合併した血管型Ehlers-Danlos症候群の1例

長谷川功, 田中秀一, 山本紘一郎, 中野靖浩, 本多寛之, 萩谷英大, 冨田晃司, 戸田洋伸, 内田治仁, 平沢晃, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 322 - 322 2022.4

コロナ・アフターケア(CAC)外来における後遺症の特徴と抗体価との関連

櫻田泰江, 砂田匠彦, 大塚勇輝, 徳増一樹, 中野靖浩, 本多寛之, 松田祐依, 大村大輔, 長谷川功, 萩谷英大, 小比賀美香子, 植田圭吾, 片岡仁美, 古川雅規, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 301 - 301 2022.4

精巣副腎遺残腫瘍に関連し性腺機能低下を来した21-水酸化酵素欠損症の2例

山本紘一郎, 本多寛之, 中野靖浩, 徳増一樹, 長谷川功, 小比賀美香子, 花山宜久, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 401 - 401 2022.4

精巣副腎遺残腫瘍に関連し性腺機能低下を来した21-水酸化酵素欠損症の2例

山本紘一郎, 本多寛之, 中野靖浩, 徳増一樹, 長谷川功, 小比賀美香子, 花山宜久, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 401 - 401 2022.4

原発性副甲状腺機能亢進症に対するカルシウム受容体作動薬の効果と関連因子

山本紘一郎, 中野靖浩, 徳増一樹, 本多寛之, 長谷川功, 小比賀美香子, 三好智子, 小川弘子, 花山宜久, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 374 - 374 2022.4

頭部外傷が契機と考えられる中枢性尿崩症の1例

山本紘一郎, 本多寛之, 田中秀一, 高橋美砂, 長谷川功, 中野靖浩, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 335 - 335 2022.4

LβT2細胞におけるオレキシンとBMPによるゴナドトロピン分泌調節の検討

副島佳晃, 岩田菜穂子, 中山菜々子, 平田真一, 中野靖浩, 山本紘一郎, 須山敦仁, 灘隆宏, 藤澤諭, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 329 - 329 2022.4

肝硬変と多発骨折を契機に診断されたFGF23関連低リン血症性骨軟化症の1例

須山敦仁, 山本紘一郎, 田中秀一, 孫麗那, 高橋美砂, 中野靖浩, 本多寛之, 長谷川功, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 325 - 325 2022.4

コロナ・アフターケア外来における加齢性腺機能低下(LOH)症候群の潜在とその特徴

山本幸近, 大塚勇輝, 徳増一樹, 中野靖浩, 本多寛之, 櫻田泰江, 砂田匠彦, 大村大輔, 長谷川功, 萩谷英大, 小比賀美香子, 植田圭吾, 片岡仁美, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 292 - 292 2022.4

骨粗鬆症精査を契機に診断されたTurner症候群の1成人例

長谷川徹, 越智可奈子, 中野靖浩, 山本紘一郎, 小比賀美香子, 植田圭吾, 長谷川高誠, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 402 - 402 2022.4

LβT2細胞におけるオレキシンとBMPによるゴナドトロピン分泌調節の検討

副島佳晃, 岩田菜穂子, 中山菜々子, 平田真一, 中野靖浩, 山本紘一郎, 須山敦仁, 灘隆宏, 藤澤諭, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 329 - 329 2022.4

IFN-α投与が奏効したステロイド抵抗性Erdheim-Chester病の1例

庵谷紘美, 中野靖浩, 中本健太, 平佑貴, 山本紘一郎, 長谷川功, 三好智子, 小川弘子, 白羽英則, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 279 - 279 2022.4

Cushing病術後にバセドウ病再燃と相対的副腎不全を来した1例

中野靖浩, 平佑貴, 中本健太, 庵谷紘美, 長谷川功, 大塚勇輝, 佐々木恵里佳, 岸田雅之, 大塚文男

日本内分泌学会雑誌 98 ( 1 ) 254 - 254 2022.4

ADHDの薬物治療強化により減量と血糖コントロールの改善が得られた若年肥満男性の1例

本多寛之, 大塚文男

糖尿病 65 ( Suppl.1 ) S - 233 2022.4

Detection of Male Hypogonadism in Patients with Post COVID-19 Condition. International journal

Yukichika Yamamoto, Yuki Otsuka, Naruhiko Sunada, Kazuki Tokumasu, Yasuhiro Nakano, Hiroyuki Honda, Yasue Sakurada, Hideharu Hagiya, Yoshihisa Hanayama, Fumio Otsuka

Journal of clinical medicine 11 ( 7 ) 2022.3

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

The pathogenesis and prognosis of post COVID-19 condition have remained unclear. We set up an outpatient clinic specializing in long COVID in February 2021 and we have been investigating post COVID-19 condition. Based on the results of our earlier study showing that "general fatigue" mimicking myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the most common symptom in long COVID patients, a retrospective analysis was performed for 39 male patients in whom serum free testosterone (FT) levels were measured out of 61 male patients who visited our clinic. We analyzed the medical records of the patients' backgrounds, symptoms and laboratory results. Among the 39 patients, 19 patients (48.7%) met the criteria for late-onset hypogonadism (LOH; FT < 8.5 pg/mL: LOH group) and 14 patients were under 50 years of age. A weak negative correlation was found between age and serum FT level (r = -0.301, p = 0.0624). Symptoms including general fatigue, anxiety, cough and hair loss were more frequent in the LOH group than in the non-LOH group (FT ≥ 8.5 pg/mL). Among various laboratory parameters, blood hemoglobin level was slightly, but significantly, lower in the LOH group. Serum level of FT was positively correlated with the levels of blood hemoglobin and serum total protein and albumin in the total population, whereas these interrelationships were blurred in the LOH group. Collectively, the results indicate that the incidence of LOH is relatively high in male patients, even young male patients, with post COVID-19 and that serum FT measurement is useful for revealing occult LOH status in patients with long COVID.

DOI： 10.3390/jcm11071955

Low hematocrit reduces the efficiency of <scp>CD34</scp> ⁺ cell collection when using the Spectra Optia continuous mononuclear cell collection procedure

Takumi Kondo, Nobuharu Fujii, Keiko Fujii, Yuichi Sumii, Tomohiro Urata, Maiko Kimura, Masayuki Matsuda, Shuntaro Ikegawa, Kana Washio, Hideaki Fujiwara, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken‐ichi Matsuoka, Fumio Otsuka, Yoshinobu Maeda

Transfusion 2022.3

Hemothorax and Bloody Ascites Caused by Vascular Ehlers-Danlos Syndrome. International journal

Shuichi Tanaka, Hiroyuki Honda, Kou Hasegawa, Koji Tomita, Reimi Sogawa, Hideki Yamamoto, Takao Hiraki, Akira Hirasawa, Fumio Otsuka

The American journal of medicine 135 ( 7 ) e210-e211 2022.3

Idiopathic multicentric Castleman disease with positive antiphospholipid antibody: atypical and undiagnosed autoimmune disease?

Yoshito Nishimura, Asami Nishikori, Haruki Sawada, Torrey Czech, Yuki Otsuka, Midori Filiz Nishimura, Hiroki Mizuno, Naoki Sawa, Shuji Momose, Kumiko Ohsawa, Fumio Otsuka, Yasuharu Sato

Journal of clinical and experimental hematopathology : JCEH 2022.3

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

Idiopathic multicentric Castleman disease (iMCD) is a systemic disorder characterized by systemic inflammation and organ dysfunction associated with an increase in pro-inflammatory cytokines. Some patients with iMCD are positive for autoantibodies, although their significance and relationship with specific associated autoimmune diseases are unclear. This study retrospectively analyzed the clinicopathological features of iMCD patients focusing on autoantibodies. Among 63 iMCD patients in our database, 19 were positive for at least one autoantibody. Among the 19, we identified five with plasma cell type (PC)-iMCD lymph node histopathology and positive anti-phospholipid antibodies. These patients were likely to have thrombocytopenia, anasarca, fever, reticulin fibrosis or renal insufficiency, organomegaly (TAFRO) symptoms, and thrombotic events. The present study suggests that patients with undiagnosed or atypical autoimmune diseases, including anti-phospholipid syndrome (APS), were treated for iMCD. APS may present with thrombocytopenia or even multi-organ failure, which overlap with clinical presentations of iMCD. Due to differences in the treatment regimen and follow-up, recognition of the undiagnosed autoimmune disease process in those suspected of iMCD is essential. Our study highlights the importance of complete exclusion of differential diagnoses in patients with iMCD in their diagnostic workup.

DOI： 10.3960/jslrt.21038

初期研修医の卒後ローテーションにおける「感染症研修の必須化」に関するアンケート調査

萩谷英大, 徳増一樹, 小比賀美香子, 大塚文男

感染症学雑誌 96 ( 2 ) 61 - 64 2022.3

Trends in the amyloidosis mortality rate in <scp>J</scp> apan: A nationwide observational study from 1998 to 2019

Ko Harada, Hideharu Hagiya, Toshihiro Koyama, Fumio Otsuka

Geriatrics & Gerontology International 22 ( 3 ) 246 - 250 2022.3

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

AIM: Despite the increasing attention that has been paid to amyloidosis in recent years, there have been few reports on amyloidosis mortality and its trends worldwide. This study aimed to evaluate the trends in crude and age-adjusted amyloidosis-associated mortality rates in Japan from 1998 to 2019. METHODS: We used national Vital Statistics data among older adults aged over 50 years. The data were analyzed using the joinpoint regression program to estimate the long-term trends and average annual percentage changes (AAPCs). RESULTS: A total of 9158 amyloidosis-associated deaths were recorded from 1998 to 2019, of which 56.1% were in men. The crude mortality rate per 1 000 000 older adults aged over 80 years increased from 9.65 to 54.3 among men and from 7.02 to 22.1 among women during the study period. Overall, the AAPCs of age-adjusted amyloidosis-associated mortality rates increased significantly over the study period (1.8%, 95% confidence interval [CI], 1.0-2.7%). While the annual percentage change (APC) of age-adjusted mortality rates in women showed no significant change over the study period, the APC in men markedly increased in the 2013-2019 period (8.2%, 95% CI: 6.0-10.4%). CONCLUSIONS: This study revealed an increasing trend in mortality associated with amyloidosis, and in particular a marked increase in mortality among men over the past 6 years. Considering its high mortality rate and susceptibility to the effects of an increasing population of older adults, amyloidosis deserves more attention from healthcare providers to improve the understanding of diagnosis, clinical treatment, and healthcare planning. Geriatr Gerontol Int 2022; 22: 246-250.

DOI： 10.1111/ggi.14348

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/ggi.14348

卵胞ステロイド合成におけるNR5Aの役割とClock・BMPによる調節機序

須山敦仁, 岩田菜穂子, 副島佳晃, 中野靖浩, 山本紘一郎, 灘隆宏, 大塚文男

日本内分泌学会雑誌 97 ( 5 ) 1303 - 1303 2022.3

非機能性下垂体腺腫を伴った偽性クッシング症候群の1例

山本紘一郎, 花山宜久, 中野靖浩, 大村大輔, 本多寛之, 長谷川功, 大塚文男

日本内分泌学会雑誌 97 ( 5 ) 1262 - 1262 2022.3

不明熱の精査より診断した高齢特発性ACTH単独欠損症の1例

上枝礼佳, 山本紘一郎, 田中秀一, 孫麗那, 本多寛之, 長谷川功, 大塚文男

日本内分泌学会雑誌 97 ( 5 ) 1261 - 1261 2022.3

ゴナドトロープ細胞における時計遺伝子およびBMP分子の機能的役割

副島佳晃, 岩田菜穂子, 須山敦仁, 中野靖浩, 山本紘一郎, 大塚文男

日本内分泌学会雑誌 97 ( 5 ) 1247 - 1247 2022.3

潜在性甲状腺機能低下症の総合診療外来における検出とその特徴

高見優男, 山本紘一郎, 中野靖浩, 長谷川功, 大塚文男

日本内分泌学会雑誌 97 ( 5 ) 1143 - 1143 2022.3

コロナ・アフターケア外来から診断されたLOH症候群の1例

副島佳晃, 中野靖浩, 徳増一樹, 大塚勇輝, 櫻田泰江, 本多寛之, 中本健太, 長谷川功, 萩谷英大, 植田圭吾, 大塚文男

日本内分泌学会雑誌 97 ( 5 ) 1304 - 1304 2022.3

非機能性下垂体腺腫を伴った偽性クッシング症候群の1例

山本紘一郎, 花山宜久, 中野靖浩, 大村大輔, 本多寛之, 長谷川功, 大塚文男

日本内分泌学会雑誌 97 ( 5 ) 1262 - 1262 2022.3

不明熱の精査より診断した高齢特発性ACTH単独欠損症の1例

上枝礼佳, 山本紘一郎, 田中秀一, 孫麗那, 本多寛之, 長谷川功, 大塚文男

日本内分泌学会雑誌 97 ( 5 ) 1261 - 1261 2022.3

潜在性甲状腺機能低下症の総合診療外来における検出とその特徴

高見優男, 山本紘一郎, 中野靖浩, 長谷川功, 大塚文男

日本内分泌学会雑誌 97 ( 5 ) 1143 - 1143 2022.3

摂食調節ホルモンによる卵胞ステロイド合成への影響とその機序の検討

中野靖浩, 樫野千明, 長谷川徹, 岩田菜穂子, 副島佳晃, 須山敦仁, 山本紘一郎, 増山寿, 大塚文男

日本内分泌学会雑誌 97 ( 5 ) 1363 - 1363 2022.3

卵胞ステロイド合成におけるNR5Aの役割とClock・BMPによる調節機序

須山敦仁, 岩田菜穂子, 副島佳晃, 中野靖浩, 山本紘一郎, 灘隆宏, 大塚文男

日本内分泌学会雑誌 97 ( 5 ) 1303 - 1303 2022.3

ゴナドトロープ細胞における時計遺伝子およびBMP分子の機能的役割

副島佳晃, 岩田菜穂子, 須山敦仁, 中野靖浩, 山本紘一郎, 大塚文男

日本内分泌学会雑誌 97 ( 5 ) 1247 - 1247 2022.3

初期研修医の卒後ローテーションにおける「感染症研修の必須化」に関するアンケート調査

萩谷英大, 徳増一樹, 小比賀美香子, 大塚文男

感染症学雑誌 96 ( 2 ) 61 - 64 2022.3

Language：Japanese Publisher：(一社)日本感染症学会

初期研修医の卒後ローテーションにおける「感染症研修の必須化」に関する意識などを明らかにすることを目的に、岡山県内で初期研修プログラムを有する16の研修病院に所属する初期研修医(卒後1・2年)、および専攻医(卒後3・4・5年)を対象にウェブ・アンケートを行い、127名(男性64名、女性60名、無回答3名)より回答を得た。その結果、初期研修医制度における「感染症研修の必須化」(例:最低1ヵ月ローテーションするなど)について84名(66.1%)が賛成すると回答した。一方、18名(14.2%)は必須化に反対しており、その理由として、「ローテーション選択の自由度を損なうため」(15名)などが挙げられた。

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J00276&link_issn=&doc_id=20220406400006&doc_link_id=1390010292792199424&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390010292792199424&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

成人複雑先天性心疾患患者における両心室修復術後の腎内血行動態が臨床状態に及ぼす影響(Impact of Intrarenal Hemodynamics on Clinical Status in Adults with Complex Congenital Heart Disease after Biventricular Repair)

武本梨佳, 杜徳尚, 高谷陽一, 横濱ふみ, 中山理絵, 赤木禎治, 内田治仁, 大塚文男, 伊藤浩

日本循環器学会学術集会抄録集 86回 MPJ08 - 1 2022.3

Serial Changes of Long COVID Symptoms and Clinical Utility of Serum Antibody Titers for Evaluation of Long COVID. International journal

Yasue Sakurada, Naruhiko Sunada, Hiroyuki Honda, Kazuki Tokumasu, Yuki Otsuka, Yasuhiro Nakano, Yoshihisa Hanayama, Masanori Furukawa, Hideharu Hagiya, Fumio Otsuka

Journal of clinical medicine 11 ( 5 ) 2022.2

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

BACKGROUND: Various symptoms persist even after the acute symptoms in about one third of patients with COVID-19. In February 2021, we established an outpatient clinic in a university hospital for patients with long COVID and started medical treatment for sequelae that persisted one month or more after infection. METHODS: To determine the key factors that affect the onset and clinical course of sequelae, a retrospective analysis was performed at Okayama University Hospital (Japan) between February and July 2021. We focused on changes in the numbers of symptoms and the background of the patients during a three-month period from the first outpatient visit. We also examined the relationship with SARS-CoV-2 antibody titers. RESULTS: Information was obtained from medical records for 65 patients. The symptoms of sequelae were diverse, with more than 20 types. The most frequent symptoms were general malaise, dysosmia, dysgeusia, sleeplessness, and headache. These symptoms improved in about 60% of the patients after 3 months. Patients who required hospitalization and had a poor condition in the acute phase and patients who received oxygen/dexamethasone therapy had higher antibody titers at the time of consultation. Patients with antibody titers ≥200 U/mL showed significantly fewer improvements in long COVID symptoms in 1 month, but they showed improvements at 3 months after the first visit. CONCLUSION: Long COVID symptoms were improved at 3 months after the initial visit in more than half of the patients. Serum antibody titers were higher in patients who experienced a severe acute phase, but the serum antibody titers did not seem to be directly related to the long-term persistence of long COVID symptoms.

DOI： 10.3390/jcm11051309

Foramen of Winslow Hernia Ameliorating Conservatively.

Hiroyuki Honda, Hiroyuki Sakae, Hideharu Hagiya, Fumio Otsuka

Internal medicine (Tokyo, Japan) 61 ( 18 ) 2817 - 2818 2022.2

Adult-onset Mild Encephalitis/Encephalopathy with a Reversible Splenial Lesion Induced by MRSA Endocarditis International journal

Hideharu Hagiya, Fumio Otsuka

European Journal of Case Reports in Internal Medicine 9 ( 2 ) 003185 - 003185 2022.2

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

Background: Mild encephalitis/encephalopathy and a reversible splenial lesion (MERS) is a clinicoradiological syndrome with an unknown pathogenic mechanism, which usually involves children. Thus, adult-onset MERS is quite rare. Case presentation: A 71-year-old man, undergoing haemodialysis due to diabetes-induced chronic kidney disease, manifested a persistent fever and disorientation. Blood culture detected methicillin-resistant Staphylococcus aureus (MRSA), while echocardiography revealed vegetation in the aortic and mitral valves. Magnetic resonance imaging of the head revealed a fluid-attenuated inversion recovery-high, diffusion-weighted image-high lesion in the splenium of the corpus callosum, with a number of emboli. Accordingly, the patient was diagnosed with MERS induced by MRSA endocarditis. Discussion: Neurological impairment by MERS can be reversible. However, the differential diagnosis of the disease includes ischaemic lesions, multiple sclerosis, malignant lymphoma, acute disseminated encephalomyelitis, and posterior reversible encephalopathy. Clinicians should consider these diseases when MERS is suspected.

DOI： 10.12890/2022_003185

Clinical Utility of 4C Mortality Scores among Japanese COVID-19 Patients: A Multicenter Study. International journal

Kazuki Ocho, Hideharu Hagiya, Kou Hasegawa, Kouji Fujita, Fumio Otsuka

Journal of clinical medicine 11 ( 3 ) 2022.2

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

BACKGROUND: We analyzed data from COVID-19 patients in Japan to assess the utility of the 4C mortality score as compared with conventional scorings. METHODS: In this multicenter study, COVID-19 patients hospitalized between March 2020 and June 2021, over 16 years old, were recruited. The superiority for correctly predicting mortality and severity by applying the receiver operating characteristic (ROC) curve was compared. A Cox regression model was used to compare the length of hospitalization for each risk group of 4C mortality score. RESULTS: Among 206 patients, 21 patients died. The area under the curve (AUC) (95% confidential interval (CI)) of the ROC curve for mortality and severity, respectively, of 4C mortality scores (0.84 (95% CI 0.76-0.92) and 0.85 (95% CI 0.80-0.91)) were higher than those of qSOFA (0.66 (95% CI 0.53-0.78) and 0.67 (95% CI 0.59-0.75)), SOFA (0.70 (95% CI 0.55-0.84) and 0.81 (95% CI 0.74-0.89)), A-DROP (0.78 (95% CI 0.69-0.88) and 0.81 (95% CI 0.74-0.88)), and CURB-65 (0.82 (95% CI 0.74-0.90) and 0.82 (95% CI 0.76-0.88)). For length of hospitalization among survivors, the intermediate- and high- or very high-risk groups had significantly lower hazard ratios, i.e., 0.48 (95% CI 0.30-0.76)) and 0.23 (95% CI 0.13-0.43) for discharge. CONCLUSIONS: The 4C mortality score is better for estimating mortality and severity in COVID-19 Japanese patients than other scoring systems.

DOI： 10.3390/jcm11030821

Threat of Staphylococcus aureus Pneumonia in Severe COVID-19 Patients. International journal

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

Cureus 14 ( 2 ) e22486 2022.2

Language：English

Coronavirus disease 2019 (COVID-19) has been spreading worldwide with unprecedented rapidity. Staphylococcus aureus is reported to frequently cause bacterial complications in patients with COVID-19. We herein present two additional cases of S. aureus pneumonia involving such patients. The first case was an obese 48-year-old man without any particular underlying diseases. The second case was another patient, a 72-year-old man, with hypertension, dyslipidemia, and steatohepatitis. Both patients developed methicillin-susceptible S. aureus pneumonia in the clinical course of COVID-19, to which antibiotic therapy with cefazolin was effectively administered. Through these cases, we emphasize that S. aureus secondary infections should be well cared with a high degree of caution in a case of critically ill COVID-19 patients.

DOI： 10.7759/cureus.22486

Aging-related Characteristics of Subclinical Hypothyroidism Detected in General Practice.

Masao Takami, Koichiro Yamamoto, Yoshihisa Hanayama, Yasuhiro Nakano, Kou Hasegawa, Mikako Obika, Hideharu Hagiya, Masanori Furukawa, Fumio Otsuka

Acta medica Okayama 76 ( 1 ) 7 - 15 2022.2

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

Subclinical hypothyroidism (SCH) is diagnosed when serum thyrotropin (TSH) is elevated despite a normal thyroxine level and is known to increase the risk of metabolic disorders. This study was conducted to identify potential laboratory markers suspicious for latent SCH. We retrospectively reviewed 958 outpatients in whom thyroid functions had been examined. Eighty-five (9.1%) of the 939 analyzed subjects had SCH (73% females). In the SCH group, median serum TSH and FT4 levels were 5.04 μU/ml and 1.19 ng/dl, respectively, and auto-thyroid antibodies were detected in 53.8% of patients. SCH group patients were significantly older than patients in the euthyroid group, while there was no intergroup difference in BMI. However, 56.5% of the SCH patients were asymptomatic. In the SCH group, serum aspartate aminotransferase and low-density lipoprotein cholesterol (LDL-C) levels were significantly higher, and the estimated glomerular filtration rate (eGFR) was significantly lower than in the euthyroid group. Among patients less than 65 years of age, SCH patients tended to have lower eGFR and higher LDL-C than euthyroid patients. Age-dependent reductions of red blood cells and serum albumin were more prominent in the SCH than the euthyroid group. Biochemical changes with aging are useful as potential clues for suspecting latent SCH.

DOI： 10.18926/AMO/63203

ラット顆粒膜細胞による卵巣ステロイド合成におけるBMP-15が関与したグルココルチコイド作用(Involvement of BMP-15 in glucocorticoid actions on ovarian steroidogenesis by rat granulosa cells)

Kashino Chiaki, Hasegawa Toru, Kamada Yasuhiko, Masuyama Hisashi, Otsuka Fumio

日本産科婦人科学会雑誌 74 ( 臨増 ) S - 187 2022.2

右肩・上腕痛及び右手先の痺れから見つかった食道癌の一例

吉田純, 田中秀一, 山本紘一郎, 高橋美砂, 本多寛之, 長谷川功, 大塚文男

日本病院総合診療医学会雑誌 18 ( 臨増1 ) O - 002 2022.2

COVID-19後遺症状の診療において大学病院総合内科が果たせる役割

大塚勇輝, 徳増一樹, 中野靖浩, 本多寛之, 萩谷英大, 砂田匠彦, 櫻田泰江, 山本幸近, 大村大輔, 松田祐依, 長谷川功, 小比賀美香子, 植田圭吾, 片岡仁美, 大塚文男

日本病院総合診療医学会雑誌 18 ( 臨増1 ) N - 010 2022.2

右肩・上腕痛及び右手先の痺れから見つかった食道癌の一例

吉田純, 田中秀一, 山本紘一郎, 高橋美砂, 本多寛之, 長谷川功, 大塚文男

日本病院総合診療医学会雑誌 18 ( 臨増1 ) O - 002 2022.2

COVID-19後遺症状の診療において大学病院総合内科が果たせる役割

大塚勇輝, 徳増一樹, 中野靖浩, 本多寛之, 萩谷英大, 砂田匠彦, 櫻田泰江, 山本幸近, 大村大輔, 松田祐依, 長谷川功, 小比賀美香子, 植田圭吾, 片岡仁美, 大塚文男

日本病院総合診療医学会雑誌 18 ( 臨増1 ) N - 010 2022.2

Bull's Head Sign.

Koichiro Yamamoto, Hiroyuki Honda, Hideharu Hagiya, Fumio Otsuka

JMA journal 5 ( 1 ) 130 - 131 2022.1

Calcified spleen associated with Pneumocystis jirovecii infection

K Yamamoto, H Honda, H Hagiya, F Otsuka

QJM: An International Journal of Medicine 114 ( 12 ) 895 - 895 2022.1

Recovery From Alopecia After COVID-19. International journal

Yuki Otsuka, Yasuhiro Nakano, Hideharu Hagiya, Kazuki Tokumasu, Fumio Otsuka

Cureus 14 ( 1 ) e21160 2022.1

Language：English

Herein, we report a remarkable case of post-coronavirus disease 2019 (COVID-19) diffuse alopecia that gradually improved and recovered, and the hair volume returned approximately to the pre-infection level, seven months after the patient's first diagnosis of COVID-19. Approximately 20% of patients with COVID-19 develop alopecia a few months after the acute infection phase. Telogen effluvium is the major type of COVID-19 sequela secondary to physical or psychological distress. It is reversible and is expected to improve without any treatment, and it can be addressed by explaining to the patients their conditions, sharing medical information, and eliminating psychophysical stress by managing systemic complications.

DOI： 10.7759/cureus.21160

Enriched CD45RA⁻CD62L⁺ central memory T and decreased CD3⁺CD56⁺ natural killer T lymphocyte subsets in the rectum of ulcerative colitis patients

Masaya Iwamuro, Takahide Takahashi, Natsuki Watanabe, Takehiro Tanaka, Toshihiro Inokuchi, Sakiko Hiraoka, Fumio Otsuka, Hiroyuki Okada

International Journal of Immunopathology and Pharmacology 36 205873842110519 - 205873842110519 2022.1

Publishing type：Research paper (scientific journal) Publisher：SAGE Publications

Objectives

To investigate the distinctive features of lymphocytes promoting inflammation in ulcerative colitis.

Methods

We performed flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) and colorectal mucosa lymphocytes in ulcerative colitis patients ( n = 13) and control patients ( n = 5).

Results

CD62L⁺/CD3⁺CD4⁺ (35.7 ± 14.0% vs. 19.9 ± 6.4%) and CD62L⁺/CD3⁺CD4⁻ cells (17.1 ± 17.4% vs. 2.4 ± 3.9%) were higher in the rectum of ulcerative colitis patients than in control patients. Subpopulation analysis revealed that CD45RA⁻CD62L⁺/CD3⁺CD4⁺, that is, central memory T cell fraction in CD4⁺ T cells, was significantly increased in the rectum of ulcerative colitis, compared to that in control patients (23.3 ± 10.5% vs. 8.2 ± 4.0%). Comparison of rectum and colon samples in ulcerative colitis patients indicated that CD56⁺/CD3⁺ was decreased in the rectum compared to that in the colon (11.3 ± 12.5% vs. 21.3 ± 16.5%). The ratio of CD56⁺/CD3⁺ was also decreased in the rectum of active ulcerative colitis patients compared to that in ulcerative colitis patients at the endoscopic remission stages (2.8 ± 1.7% vs. 18.5 ± 13.3%).

Conclusion

We demonstrated that CD62L⁺ T lymphocytes, particularly the CD45RA⁻CD62L⁺ T cell subset that represents central memory T cells, were increased in the rectum of patients with ulcerative colitis. In addition, the CD56⁺/CD3⁺ subset (natural killer T cells) was decreased in the rectum compared to that of less inflamed colonic mucosa. These results suggest that the enrichment of central memory T lymphocytes and the reduction of natural killer T cells in the gut mucosa are involved in the pathogenesis of ulcerative colitis.

DOI： 10.1177/20587384211051982

Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/20587384211051982

Enriched CD45RA⁻CD62L⁺ central memory T and decreased CD3⁺CD56⁺ natural killer T lymphocyte subsets in the rectum of ulcerative colitis patients International journal

Masaya Iwamuro, Takahide Takahashi, Natsuki Watanabe, Takehiro Tanaka, Toshihiro Inokuchi, Sakiko Hiraoka, Fumio Otsuka, Hiroyuki Okada

International Journal of Immunopathology and Pharmacology 36 205873842110519 - 205873842110519 2022.1

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

Objectives

To investigate the distinctive features of lymphocytes promoting inflammation in ulcerative colitis.

Methods

We performed flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) and colorectal mucosa lymphocytes in ulcerative colitis patients ( n = 13) and control patients ( n = 5).

Results

CD62L⁺/CD3⁺CD4⁺ (35.7 ± 14.0% vs. 19.9 ± 6.4%) and CD62L⁺/CD3⁺CD4⁻ cells (17.1 ± 17.4% vs. 2.4 ± 3.9%) were higher in the rectum of ulcerative colitis patients than in control patients. Subpopulation analysis revealed that CD45RA⁻CD62L⁺/CD3⁺CD4⁺, that is, central memory T cell fraction in CD4⁺ T cells, was significantly increased in the rectum of ulcerative colitis, compared to that in control patients (23.3 ± 10.5% vs. 8.2 ± 4.0%). Comparison of rectum and colon samples in ulcerative colitis patients indicated that CD56⁺/CD3⁺ was decreased in the rectum compared to that in the colon (11.3 ± 12.5% vs. 21.3 ± 16.5%). The ratio of CD56⁺/CD3⁺ was also decreased in the rectum of active ulcerative colitis patients compared to that in ulcerative colitis patients at the endoscopic remission stages (2.8 ± 1.7% vs. 18.5 ± 13.3%).

Conclusion

We demonstrated that CD62L⁺ T lymphocytes, particularly the CD45RA⁻CD62L⁺ T cell subset that represents central memory T cells, were increased in the rectum of patients with ulcerative colitis. In addition, the CD56⁺/CD3⁺ subset (natural killer T cells) was decreased in the rectum compared to that of less inflamed colonic mucosa. These results suggest that the enrichment of central memory T lymphocytes and the reduction of natural killer T cells in the gut mucosa are involved in the pathogenesis of ulcerative colitis.

DOI： 10.1177/20587384211051982

Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/20587384211051982

Interest in Infectious Diseases specialty among Japanese medical students amidst the COVID-19 pandemic: A web-based, cross-sectional study. International journal

Hideharu Hagiya, Yuki Otsuka, Kazuki Tokumasu, Hiroyuki Honda, Yoshito Nishimura, Mikako Obika, Fumio Otsuka

PloS one 17 ( 4 ) e0267587 2022

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

INTRODUCTION: The emergence of the novel coronavirus disease of 2019 (COVID-19) has led to huge disruptions in the medical field and society. The significance of training and education for experts has been increasingly acknowledged in Japan, where the number of infectious disease (ID) specialists is reportedly insufficient. In this paper, we report the results of a web-based survey that was conducted to reveal the ways in which the COVID-19 pandemic has influenced medical students' awareness of ID specialists and future career choices. METHOD: This cross-sectional descriptive study was conducted in March 2021 and targeted 717 medical students belonging to Medical School of Okayama University, Japan. The questionnaire consisted of four questions meant to assess students' knowledge and future intentions of becoming ID specialists. RESULTS: We obtained 328 eligible questionnaires (response rate: 45.7%). Of 227 (69.2%) students who were aware of ID specialists, 99 (43.6%) answered that they came to know about them only after the pandemic, 12 (3.7%) answered that their interest in being an ID specialist arose during the pandemic, while 36 (11.0%) responded that they would rather not become ID specialists. At the time of the survey, 5 students (1.5%) were aiming to become ID specialists. CONCLUSION: We observed a very low rate of interest to be an ID specialist among medical students. The experience of the pandemic does not seem to have influenced Japanese medical students to choose ID as a specialty for their careers. Continuous efforts to increase the number of ID specialists are necessary in Japan as a countermeasure against the coming pandemic.

DOI： 10.1371/journal.pone.0267587

Fear of an unprecedented, invisible enemy: Difficulties experienced in establishing criteria for the release of COVID-19 patients from isolation in a Japanese University Hospital. International journal

Hideharu Hagiya, Kou Hasegawa, Fumio Otsuka

PloS one 17 ( 4 ) e0266853 2022

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

INTRODUCTION: The novel coronavirus disease 2019 (COVID-19) has emerged as a global pandemic, and the United States and European authorities established criteria for the release of COVID-19 patients from isolation in October 2020. However, a huge discrepancy exists between the hospital-discharge protocol for COVID-19 patients and the release of patients from in-hospital isolation. Our initially proposed criteria for in-hospital release from isolation was not adhered to by healthcare workers (HCWs) due to prevailing concerns regarding disease infectivity. Herein, we report difficulties encountered in attempting to establish a common understanding of the management of emerging infections. METHODS: We performed a Google Form-based questionnaire survey targeting HCWs from Okayama University Hospital, Japan, via e-mail on January 21-28, 2021. The anonymous investigation required respondents to provide information regarding their background as well as perceptions regarding the requirement, level of understanding, and readiness for developing release criteria. RESULTS: We obtained 150 eligible responses, including 57 (38.0%) from medical doctors and 53 (35.3%) from nurses. Most HCWs managing COVID-19 patients advocated for the implementation of the criteria, whereas those not working in that capacity did not (p<0.001). Over half of the HCWs indicated discomfort at seeing COVID-19 patients transitioning to general management even after meeting the criteria. CONCLUSIONS: It was challenging to establish a common understanding regarding the ideal criteria for in-hospital release of COVID-19 patients from isolation in our hospital. The dissemination of our experiences and multifaceted discussions with HCWs would be of great value as a countermeasure against the emergent pandemic.

DOI： 10.1371/journal.pone.0266853

Association between fever and antibody titer trends after a third dose of the mRNA-1273 vaccine

Naomi Matsumoto, Tomoka Kadowaki, Rumi Matsuo, Ayako Sasaki, Chikara Miyaji, Chigusa Higuchi, Masanori Nakayama, Yasue Sakurada, Hideharu Hagiya, Soshi Takao, Fumio Otsuka, Takashi Yorifuji

Journal of Epidemiology 32 ( 12 ) 567 - 569 2022

Possibility of endocrine dysfunction in post coronavirus disease 2019 (COVID-19) condition

Yuki Otsuka, Fumio Otsuka

Endocrine Journal 69 ( 11 ) 1357 - 1357 2022

Quality, as well as Quantity, of Universal Masking Matters amid the COVID-19 pandemic: A Comparison of Appropriate Masking between Healthcare Workers and Non-medical Personnel

Hideharu Hagiya, Hitoshi Osada, Hana Iguchi, Kotaro Takahashi, Kazuki Tokumasu, Mikako Obika, Fumio Otsuka

2022

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 77 ( 3 ) 857 - 858 2021.12

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

GH補充療法により脂肪肝の著明な改善を認めたAGHDの1例

高瀬了輔, 中野靖浩, 山本紘一郎, 越智可奈子, 本多寛之, 長谷川功, 三好智子, 小川弘子, 大塚文男

日本内分泌学会雑誌 97 ( 4 ) 951 - 951 2021.12

総合診療における甲状腺機能低下状態の潜在とその特徴

高見優男, 山本紘一郎, 花山宜久, 中野靖浩, 長谷川功, 小比賀美香子, 萩谷英大, 大塚文男

日本内分泌学会雑誌 97 ( 4 ) 961 - 961 2021.12

乳汁漏出の精査より判明したBigプロラクチンと性同一性障害の合併例

桜田泰江, 越智可奈子, 山本紘一郎, 古川雅規, 大塚文男

日本内分泌学会雑誌 97 ( 4 ) 953 - 953 2021.12

肺癌治療中の発熱を契機に発見されたペムブロリズマブによるirAEの1例

平仲凪, 山本紘一郎, 田中秀一, 孫麗那, 高橋美砂, 本多寛之, 長谷川功, 大塚文男

日本内分泌学会雑誌 97 ( 4 ) 951 - 951 2021.12

MEN1疑いの家族歴と上縦隔に進展する副甲状腺癌を認めた1例

大塚勇輝, 長谷川功, 原田洸, 西村義人, 岡浩介, 小野早和子, 枝園忠彦, 平沢晃, 大塚文男

日本内分泌学会雑誌 97 ( 4 ) 946 - 946 2021.12

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

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

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

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

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 69 ( 4 ) 417 - 425 2021.11

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

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

新型コロナウイルス感染症対策における慰労金交付事業の影響およびその評価

萩谷英大, 三好智子, 西村義人, 徳増一樹, 本多寛之, 長谷川功, 小比賀美香子, 頼藤貴志, 大塚文男

日本病院総合診療医学会雑誌 17 ( 6 ) 608 - 616 2021.11

Language：Japanese Publisher：(一社)日本病院総合診療医学会

新型コロナウイルス感染症対策の一環として,「新型コロナウイルス感染症対応従事者慰労金交付事業」が実施されたが,その影響・有効性に関するデータは乏しい。2021年4月26日〜5月31日に,岡山県・香川県・広島県の医療機関に勤務する職員を対象にウェブ・アンケートによる横断調査を実施した。1001名からの回答において,慰労金受給率は95.8%であり,59.5%は本事業に満足したと回答した。職種別満足度は,医師(60.8%),メディカルスタッフ(63.9%)に比べて看護職(46.3%)で低かった(p<0.001)。医療機関内職員のみならず,救急隊員,保健所職員,高齢者介護施設の職員も慰労金が支払われるべき業種として高率に理解を得た。慰労金交付事業は,医療従事者等の外的モチベーションとして概ね機能したと考えられるが,給付金額や対象者の選定に関しては検討の余地がある。(著者抄録)

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

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

【COVID-19-その診断と治療】倦怠感

大塚勇輝, 徳増一樹, 本多寛之, 萩谷英大, 大塚文男

カレントテラピー 39 ( 11 ) 1034 - 1039 2021.11

Language：Japanese Publisher：(株)ライフメディコム

新型コロナウイルス感染症(COVID-19)が最初に報告されてからおよそ1年半が経過したが、いまだ収束の兆しの見えない世界的流行のなかで「Long-COVID」ないし「post-acute sequelae of COVID-19(PASC)」と定義され、一般には「コロナ後遺症」として知られる、急性期以降に残存する症状に悩まされる患者が多く存在している。そのなかでも「倦怠感」は、最も多い症状として報告され、COVID-19罹患後に4割程度の患者が自覚すると言われている。倦怠感は視認できず検査での客観的評価も難しい症状である一方で、さまざまな要因が複雑に絡みあって生じており病態メカニズムも未解明なところが多く、診療に難渋する。われわれは2021年2月にLong-COVID/PASCを専門的に診療する「コロナ・アフターケア(COVID-19 aftercare:CAC)外来」を大学病院内にいち早く設立し、倦怠感などの症状に悩む患者の診療と研究・教育に取り組んできた。本稿ではそうしたわれわれの診療経験も踏まえ、診断や治療を行ううえでの対面診療の必要性や総合診療的アプローチの重要性についても触れながら、Long-COVID/PASCにおける倦怠感について概説する。(著者抄録)

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 50 ( 2 ) 141 - 147 2021.10

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

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

Temporal artery thickening in giant cell arteritis. International journal

Hiromi Ihoriya, Yasuhiro Nakano, Fumio Otsuka

BMJ case reports 14 ( 10 ) 2021.10

Radiologic features of Erdheim-Chester disease. International journal

Koichiro Yamamoto, Yasuhiro Nakano, Kou Hasegawa, Fumio Otsuka

Rheumatology (Oxford, England) 61 ( 7 ) e209 2021.10

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

Language：English Publishing type：Research paper (scientific journal) Publisher：BMJ PUBLISHING GROUP

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

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 41 ( 2 ) 331 - 333 2021.10

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

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.

DOI： 10.1016/j.ijid.2021.08.018

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

COVID-19外国人入院診療の実際

大塚勇輝, 萩谷英大, 中野靖浩, 大村大輔, 長谷川功, 大塚文男

日本医師会雑誌 150 ( 7 ) 1237 - 1241 2021.10

Language：Japanese Publisher：(公社)日本医師会

国際化を背景に、在日外国人も新型コロナウイルス感染症(COVID-19)に罹患しているが、本邦でその診療上の課題に関する文献はない。2020年2月からの1年間に岡山大学病院総合内科・総合診療科に入院した、外国人COVID-19患者全5人を対象として、患者背景や言語状況、入院中のトラブルや解決策について診療録から抽出した。全員が日本語の書字・読字が全く不能であり、うち1人は日常会話も困難で電話医療通訳サービスを要したが、担当医や看護師に加えて、国際診療支援センターや臨床栄養部、精神科などと連携することで隔離解除まで入院継続が可能であった。COVID-19では本人の希望に沿わない入院や予定外入院のため、通常の外国人診療に比して負担・課題が大きい。特に言語面での制約は、隔離管理下での意思疎通や同意書の取得などの面で障壁となることが明らかとなった。院内組織の連携と、病院を超えた情報共有による病軟な対応が重要である。(著者抄録)

Impact of the World Inflammatory Bowel Disease Day and Crohn’s and Colitis Awareness Week on Population Interest Between 2016 and 2020: Google Trends Analysis

Krixie Silangcruz, Author Orcid Image, Yoshito Nishimura, Author Orcid Image, Torrey Czech, Author Orcid Image, Nobuhiko Kimura, Author Orcid Image, Hideharu Hagiya, Author Orcid Image, Toshihiro Koyama, Author Orcid Image, Fumio Otsuka, Author Orcid Image

2021.10

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

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

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

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

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

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.

DOI： 10.7759/cureus.18070

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

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

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.

DOI： 10.1002/ccr3.4858

下咽頭癌肺転移に対するペンブロリズマブ投与中に発症したACTH単独欠損症の1例

山本紘一郎, 徳増一樹, 孫麗那, 岡浩介, 長谷川功, 大塚文男

ACTH RELATED PEPTIDES 32 18 - 20 2021.9

Language：Japanese Publisher：間脳・下垂体・副腎系研究会

70歳代、男性。下咽頭癌肺転移に対するペンブロリズマブの投与中に発熱や食思不振、嘔吐が持続し、精査目的で当科へ紹介となった。不明熱に対しての内分泌学的精査を施行し、ACTH単独欠損症(IAD)と診断され、ヒドロコルチゾン10mg/日の補充を開始したところ、症状・炎症反応の速やかな改善が得られた。病歴から本症例におけるIADの原因はペンブロリズマブによる免疫関連有害事象と考えられ、同薬剤の投与を中止することで、中止後も転移病変は縮小を維持している。

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

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

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.

DOI： 10.1097/MD.0000000000026931

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

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

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.

DOI： 10.7759/cureus.17398

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

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

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.

DOI： 10.7759/cureus.16918

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/62409

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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.

DOI： 10.1016/j.transci.2021.103147

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

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.

DOI： 10.1093/cid/ciaa810

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

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.

DOI： 10.1080/24725625.2020.1857022

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

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

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.

DOI： 10.1016/j.jiac.2021.03.018

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

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

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.

DOI： 10.7759/cureus.16643

Barium appendicitis. International journal

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

Clinical case reports 9 ( 7 ) e04583 2021.7

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

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.

DOI： 10.1002/ccr3.4583

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

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

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.

DOI： 10.1016/j.jiac.2021.05.001

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

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

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.

DOI： 10.1080/24725625.2021.1899444

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

ゴナドトロピン分泌調節における時計遺伝子およびBMPの関与

副島佳晃, 岩田菜穂子, 須山敦仁, 中野靖浩, 山本紘一郎, 大塚文男

日本内分泌学会雑誌 97 ( 3 ) 640 - 640 2021.7

NR5A1/NR5A2・ClockおよびBMPによる卵胞ステロイド合成調節メカニズムの検討

須山敦仁, 岩田菜穂子, 副島佳晃, 中野靖浩, 山本紘一郎, 大塚文男

日本内分泌学会雑誌 97 ( 3 ) 644 - 644 2021.7

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

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.

DOI： 10.1016/j.bbrc.2021.04.085

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

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

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

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.

DOI： 10.1002/ccr3.4305

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/62221

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

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

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.

DOI： 10.1002/ccr3.4333

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

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

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.

DOI： 10.1038/s41598-021-90441-x

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 2021.5

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

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.

DOI： 10.18926/AMO/62769

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ASSOC CLINICAL SCIENTISTS

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.

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

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

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.

DOI： 10.1002/ccr3.4095

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

どのように臨床研修医のモチベーションは上がるのか? プライマリ・ケア主体的診療の重要性

徳増一樹, 小比賀美香子, 尾原晴雄, 菊川誠, 大塚文男

日本プライマリ・ケア連合学会学術大会 12回 np637 - np637 2021.5

周期的発熱、及び腹痛精査中に診断された正中弓状靱帯圧迫症候群の1例

乃美優孝, 井口俊博, 青山祐樹, 竹井健介, 安富絵里子, 井川翔子, 大森正泰, 岡昌平, 竹内桂子, 山崎泰史, 衣笠秀明, 原田馨太, 平岡佐規子, 岡田裕之, 徳増一樹, 大塚文男, 矢野修也, 菊地覚次, 坂本真樹

日本消化器病学会中国支部例会プログラム・抄録集 115回 83 - 83 2021.5

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

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

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.

DOI： 10.3390/ijms22094553

Dysphagia Induced by Acromegalic Arthropathy.

Manami Fujita, Yasuhiro Nakano, Hiroyuki Sakae, Fumio Otsuka

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

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

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

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.

DOI： 10.1002/ccr3.3996

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/61909

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

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

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.

DOI： 10.1038/s41598-021-86431-8

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

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

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.

DOI： 10.3390/diagnostics11030460

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

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

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.

DOI： 10.3390/ijerph18052434

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

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

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

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

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.

DOI： 10.1002/jgf2.397

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

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

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.

DOI： 10.1002/ccr3.3843

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

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

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.

DOI： 10.1002/ccr3.3734

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

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

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.

DOI： 10.1507/endocrj.EJ20-0359

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

Language：English Publishing type：Research paper (scientific journal) Publisher：JMIR PUBLICATIONS, INC

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.

DOI： 10.2196/25232

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

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

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

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.

DOI： 10.1016/j.jiac.2020.09.024

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/61424

複数の基礎疾患を有した超高齢者COVID-19の一例

孫麗那, 藤田茉奈美, 山本紘一郎, 岡浩介, 山根真衣, 大塚勇輝, 高瀬了輔, 中野靖浩, 大村大輔, 榮浩行, 長谷川功, 萩谷英大, 大塚文男

日本病院総合診療医学会雑誌 17 ( 臨増1 ) 149 - 149 2021.2

COVID-19外国人患者の受入れで明らかとなった課題と病院総合医に求められる役割

大塚勇輝, 大村大輔, 李皓生, 藤田茉奈美, 山根真衣, 山本紘一郎, 孫麗那, 高瀬了輔, 中野靖浩, 岡浩, 榮浩行, 徳増一樹, 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 17 ( 臨増1 ) 109 - 109 2021.2

COVID-19外国人患者の受入れで明らかとなった課題と病院総合医に求められる役割

大塚勇輝, 大村大輔, 李皓生, 藤田茉奈美, 山根真衣, 山本紘一郎, 孫麗那, 高瀬了輔, 中野靖浩, 岡浩, 榮浩行, 徳増一樹, 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 17 ( 臨増1 ) 109 - 109 2021.2

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 98 ( e3 ) e183-e184 2021.1

Without a silhouette. International journal

Yosuke Sazumi, Kazuki Tokumasu, Hideharu Hagiya, Fumio Otsuka

Clinical case reports 9 ( 1 ) 574 - 575 2021.1

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

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.

DOI： 10.1002/ccr3.3469

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

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

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.

DOI： 10.1371/journal.pone.0259633

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/62776

Salivary gland enlargement manifested in recurred acromegaly

Koichiro Yamamoto, Kosuke Oka, Kou Hasegawa, Tomoko Miyoshi, Mikako Obika, Hiroko Ogawa, Hitomi Kataoka, Fumio Otsuka

JOURNAL OF HOSPITAL GENERAL MEDICINE 3 ( 1 ) 36 - 37 2021

Campylobacter jejuni enteritis mimicking colon cancer

Masayuki Kagota, Kosuke Oka, Hideharu Hagiya, Fumio Otsuka

JOURNAL OF HOSPITAL GENERAL MEDICINE 3 ( 6 ) 224 - 224 2021

Extreme Hyperferritinemia due to Alcoholic Liver Disease：Secondary Hemochromatosis

Koichiro Yamamoto, Yoshito Nishimura, Mai Yamane, Reina Son, Daisuke Omura, Kou Hasegawa, Youhei Marukawa, Fumio Otsuka

JOURNAL OF HOSPITAL GENERAL MEDICINE 3 ( 1 ) 33 - 35 2021

Electrocardiography diagnosed severe hypokalaemia in anorexia nervosa

Yuki Otsuka, Yasuhiro Nakano, Kazuki Tokumasu, Fumio Otsuka

JOURNAL OF HOSPITAL GENERAL MEDICINE 3 ( 2 ) 59 - 60 2021

Therapeutic Drug Monitoring for Aminoglycosides: Not Yet Readily Available in Japanese University Hospitals

Hideharu Hagiya, Fumio Otsuka

JMA Journal 5 ( 1 ) 127 - 129 2021

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

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

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.

DOI： 10.1002/ccr3.3367

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

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

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.

DOI： 10.1002/ccr3.3108

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/61205

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

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

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.

DOI： 10.1080/13685538.2019.1657083

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

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

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.

DOI： 10.1080/13685538.2019.1592151

Effects of somatostatin analogs on catecholamine biosynthesis regulated by corticosteroids and bone morphogenetic proteins in rat pheochromocytoma cells

Takahiro Nada, Motoshi Komatsubara, Nahoko Iwata, Yasuhiro Nakano, Fumio Otsuka

2020.12

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

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

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.

DOI： 10.3390/pathogens9120995

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

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

Ko Harada, Fumio Otsuka

Clinical case reports 8 ( 11 ) 2312 - 2313 2020.11

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

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

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.

DOI： 10.1002/ccr3.3124

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

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

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.

DOI： 10.1111/cen.14273

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

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

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

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.

DOI： 10.2169/internalmedicine.4651-20

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/60797

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

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

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.

DOI： 10.1016/j.scr.2020.101960

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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.

DOI： 10.1016/j.jsbmb.2020.105738

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

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

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.

DOI： 10.1016/j.jiac.2020.06.020

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

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

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.

DOI： 10.1016/j.jiac.2020.06.021

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

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

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.

DOI： 10.1038/s41598-020-72519-0

Hashimoto's thyroiditis and primary thyroid lymphoma. International journal

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

QJM : monthly journal of the Association of Physicians 0 ( 0 ) 691 - 692 2020.9

Bilateral massive empyema with bronchopleural fistula. International journal

Ko Harada, Hideharu Hagiya, Fumio Otsuka

Postgraduate medical journal 96 ( 1139 ) 573 - 573 2020.9

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

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

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.

DOI： 10.1002/ccr3.2986

Calcinosis Cutis. International journal

Ko Harada, Ei Miyasaka, Fumio Otsuka

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

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

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

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.

DOI： 10.1507/endocrj.EJ20-0024

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

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

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.

DOI： 10.2169/internalmedicine.4283-20

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

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

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.

DOI： 10.2169/internalmedicine.4337-19

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

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

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.

DOI： 10.1016/j.jiac.2020.03.004

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

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

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.

DOI： 10.1186/s12879-020-05193-2

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

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

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.

DOI： 10.1080/14397595.2019.1642291

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

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

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.

DOI： 10.1002/ccr3.2833

Macromolecules detected in highly increased serum luteinizing hormone

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

J. Endocrinol. Invest. 856 - 866 2020.6

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

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

Ko Harada, Fumio Otsuka

The American journal of medicine 133 ( 5 ) e192 2020.5

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ASSOC CLINICAL SCIENTISTS

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.

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

Malignant Lymphoma Developed in the Hypothalamus.

Ryosuke Takase, Yasuhiro Nakano, Fumio Otsuka

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

Gastrointestinal: Massive right pleural effusion caused by a pancreaticopleural fistula

K Tokumasu, K Harada, F Otsuka

J. Gastroenterol. Hepatol. 525 2020.4

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

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

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).

DOI： 10.3892/etm.2020.8538

Albright’s Hereditary Osteodystrophy

Ko Harada , Fumio Otsuka

QJM 2020.3

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

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

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

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.

DOI： 10.1111/trf.15664

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

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

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.

DOI： 10.1002/jgf2.296

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

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

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.

DOI： 10.1111/imj.14404

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/57950

繰り返しセルブロック標本を作製することにより原発性滲出性リンパ腫様リンパ腫と診断した1例

長谷井稜子, 佐住洋祐, 徳増一樹, 長谷川功, 萩谷英大, 藤井伸治, 花山宜久, 大塚文男

日本病院総合診療医学会雑誌 16 ( 臨増1 ) 166 - 166 2020.2

数年来,慢性疲労症候群として加療されていたACTH単独欠損症の1例

筒井ほのか, 徳増一樹, 原田洸, 安田美帆, 長谷川功, 萩谷英大, 花山宜久, 大塚文男

日本病院総合診療医学会雑誌 16 ( 臨増1 ) 113 - 113 2020.2

Panda and lambda sign' in sarcoidosis

K Harada, M Yasuda, F Otsuka

QJM 113 ( 1 ) 61 - 62 2020.1

Purple Urine Bag Syndrome.

Ko Harada, Chihiro Hiraiwa, Ei Miyasaka and Fumio Otsuka

J. Hosp. Gen. Med. 2020.1

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

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

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

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.

DOI： 10.1016/j.mex.2020.101095

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/57711

"Small Heart Syndrome" with Orthostatic Hypotension.

Ko Harada, Miho Yasuda, Fumio Otsuka

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/57370

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

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

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.

DOI： 10.1186/s13104-019-4578-4

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

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

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

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.

DOI： 10.1002/jgf2.267

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

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

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.

DOI： 10.1507/endocrj.EJ19-0067

FDG uptake in toxic multinodular goiter．

Ocho K, Hasegawa K, Otsuka F

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：INT JOURNAL MEDICAL EDUCATION-IJML

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.

DOI： 10.5116/ijme.5caf.53ad

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：JOHN WILEY & SONS LTD

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.

DOI： 10.1002/prp2.481

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

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

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.

DOI： 10.2169/internalmedicine.1361-18

Retention cysts due to latent pancreatic cancer．

Oka K, Horiguchi S, Obika M, Otsuka F

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

Cardiac Computed Tomography of Aortic Infective Endocarditis．

Harada K, Otsuka F

QJM 112 ( 5 ) 377 - 378 2019.5

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

Mesenteric follicular lymphoma. International journal

Yoshito Nishimura, Akira Yamamoto, Masahiro Takahara, Fumio Otsuka

Clinical case reports 7 ( 5 ) 1108 - 1109 2019.5

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

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.

DOI： 10.1002/ccr3.2148

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

Ko Harada, Fumio Otsuka

Postgraduate medical journal 95 ( 1123 ) 282 - 282 2019.5

Symptomatic Adrenal Myelolipoma.

Daisuke Omura, Yasuhiro Nakano, Ryosuke Takase, Fumio Otsuka

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

Renal intravascular lymphoma diagnosed by FDG-PET.

J. Hosp. Gen. Med. 2019.4

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

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

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

Peripartum cardiomyopathy with marked pulmonary edema: A case report．

Harada K, Otsuka F

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

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

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

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.

DOI： 10.1007/s00701-019-03818-3

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

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

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.

DOI： 10.1186/s12909-019-1509-y

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

Crowned Dens Syndrome Associated with Hyperuricemia.

Yuusaku Sugihara, Hiroko Ogawa, Fumio Otsuka

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

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

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

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.

DOI： 10.1016/j.peptides.2019.01.002

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

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

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.

DOI： 10.1007/s00441-018-2947-2

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

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

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.

DOI： 10.1507/endocrj.EJ18-0423

Diagnostic FDG PET/CT findings in polymyalgia rheumatica. International journal

Y Otsuka, K Harada, F Otsuka

QJM : monthly journal of the Association of Physicians 112 ( 2 ) 139 - 140 2019.2

Auricle Pain Due to Tophi.

Yasuhiro Nakano, Fumio Otsuka

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/56463

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

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

Hyperthyroidism with Selective Immunoglobulin A Deficiency.

Ko Harada, Fumio Otsuka

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

Actinomycosis-induced Trismus with Orbital Involvement.

Daisuke Omura, Kammei Rai, Nobuchika Kusano, Fumio Otsuka

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

Pleomorphic parotid adenoma with Graves’hyperthyroidism．

Ogura-Ochi K, Otsuka F

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

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

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

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

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.

DOI： 10.1002/ccr3.1901

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/56372

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/56378

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

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

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.

DOI： 10.2169/internalmedicine.1025-18

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

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

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.

DOI： 10.1507/endocrj.EJ18-0187

Photophobia in a Patient with Hashimoto's Thyroiditis.

Yoshito Nishimura, Fumio Otsuka

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/56242

The Esophagus on Sight: Ultrasonography in Achalasia.

Yoshito Nishimura, Yuusaku Sugihara, Fumio Otsuka

JMA journal 1 ( 1 ) 71 - 72 2018.9

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

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.

DOI： 10.1016/j.bbrc.2018.07.058

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

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

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.

DOI： 10.1002/jgf2.184

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

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

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.

DOI： 10.1002/jgf2.185

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

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

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.

DOI： 10.2169/internalmedicine.0063-17

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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.

DOI： 10.1016/j.jsbmb.2018.03.004

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

Fumio Otsuka

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

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

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.

DOI： 10.1002/rmb2.12089

Isolated Follicle-stimulating Hormone Deficiency Coincidentally Diagnosed by Hematospermia.

Satoshi Fujisawa, Fumio Otsuka

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

Unilateral Exophthalmos due to Lymphomatous Involvement.

Miho Yasuda, Masaya Iwamuro, Kosuke Kimura, Fumio Otsuka

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

RS3PE syndrome mimicking venous thrombosis

Nakano Y, Oka K, Horiguchi S and Otsuka F

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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.

DOI： 10.1016/j.jsbmb.2017.11.004

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

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

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.

DOI： 10.1507/endocrj.EJ17-0322

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

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

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.

DOI： 10.2169/internalmedicine.9250-17

Pneumatosis Cystoides Intestinalis

Yuusaku Sugihara, Keita Harada, Hiroko Ogawa, Fumio Otsuka, Hiroyuki Okada

Journal of Lung Health and Diseases 2018.2

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

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

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

DOI： 10.1159/000491862

Psoas abscess secondary to paravertebral inflammation. International journal

Yoshito Nishimura, Fumio Otsuka

IDCases 13 e00435 2018

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

Fumio Otsuka

Vitamins and hormones 107 137 - 153 2018

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER ACADEMIC PRESS INC

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.

DOI： 10.1016/bs.vh.2018.01.012

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

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

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.

DOI： 10.2169/internalmedicine.8671-16

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

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

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.

DOI： 10.1002/jgf2.119

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

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

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.

DOI： 10.1002/jgf2.123

Neck schwannoma mimicking a thyroid tumor.

Kosuke Oka, Masaya Iwamuro, Fumio Otsuka

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

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

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

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.

DOI： 10.2169/internalmedicine.9055-17

Regulation of gonadotropins by urocortin 2 in gonadotropic tumor LβT2 cells

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

Neuroscience Letters 660 63 - 67 2017.11

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

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

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

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

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

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.

DOI： 10.2169/internalmedicine.8216-16

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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.

DOI： 10.1016/j.jsbmb.2017.07.002

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

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

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.

DOI： 10.1016/j.peptides.2017.06.001

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 ( Suppl. Update ) 44 - 45 2017.6

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

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

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.

DOI： 10.1007/s12185-017-2204-6

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

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

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.

DOI： 10.3109/14397595.2014.1002163

A unique acromegalic osteoarthropathy: manubriosternal joint arthritis. International journal

Satoshi Fujisawa, Fumio Otsuka

Clinical case reports 5 ( 5 ) 725 - 726 2017.5

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

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.

DOI： 10.1002/ccr3.913

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/54977

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/54828

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

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

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.

DOI： 10.3390/jcm6010006

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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.

DOI： 10.1016/j.jsbmb.2016.06.002

Diffuse Large B-cell Lymphoma Involving the Skeletal Muscle

Ko Harada, Kosuke Kimura, Masaya Iwamuro, Fumio Otsuka

Internal Medicine 56 ( 10 ) 1269 - 1270 2017

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

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

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.

DOI： 10.2169/internalmedicine.56.6141

Hypertrophic Pachymeningitis Accompanying Scleritis

Kosuke Oka, Kazuki Ocho, Masaya Iwamuro, Fumio Otsuka

Internal Medicine 56 ( 17 ) 2383 - 2384 2017

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

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

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.

DOI： 10.2169/internalmedicine.56.7758

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

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

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

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

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

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER DIABETES ASSOC

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.

DOI： 10.2337/db15-1304

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

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

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

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.

DOI： 10.1016/j.peptides.2016.01.011

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

Multiple Organomegaly Exhibited in a Patient with Graves' Hyperthyroidism

Kazuki Ocho, Masaya Iwamuro, Fumio Otsuka

Internal Medicine 55 ( 18 ) 2737 - 2738 2016

Xanthoma of the Duodenum

Masaya Iwamuro, Takehiro Tanaka, Fumio Otsuka, Hiroyuki Okada

Internal Medicine 55 ( 19 ) 2899 - 2900 2016

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

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

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.

DOI： 10.2169/internalmedicine.55.4763

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

Invasive Intrasellar Plasmacytoma Mimicking Pituitary Adenoma. Reviewed

Terasaka T, Inagaki K, Otsuka F

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

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

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

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.

DOI： 10.2169/internalmedicine.55.6287

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

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

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

Language：English Publishing type：Research paper (scientific journal) Publisher：CANCER INTELLIGENCE LTD

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.

DOI： 10.3332/ecancer.2016.625

Hypoparathyroidism Solely Manifesting Otological Symptoms. Reviewed

Tokiko Urabe, Hideharu Hagiya, Eri Nakamura, Fumio Otsuka

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

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

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

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.

DOI： 10.14442/jgfm.16.4_292

Refractory chyluria due to filariasis. Reviewed International journal

Hideharu Hagiya, Fumio Otsuka

Infection 43 ( 6 ) 785 - 6 2015.12

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

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

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.

DOI： 10.1016/j.peptides.2015.09.007

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

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

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.

DOI： 10.1186/s13256-015-0737-y

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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.

DOI： 10.1016/j.jsbmb.2015.04.012

A Rare Cause of Esophageal Ulcers. Reviewed International journal

Masaya Iwamuro, Takao Tsuzuki, Fumio Otsuka

Gastroenterology 149 ( 1 ) 31 - 2 2015.7

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

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

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.

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

皮疹の再燃を繰り返しCD8陽性Terminally differentiated effector memory cellの増加を認めた薬剤性過敏症症候群(DIHS)の一例

青江伯規, 今田昌秀, 高橋孝英, 榊原佳奈枝, 日野佳弥, 狩山由貴, 渡部俊幸, 岡田健, 大塚文男

日本検査血液学会雑誌 16 ( 学術集会 ) S99 - S99 2015.6

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

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.

DOI： 10.1016/j.bbrc.2015.02.100

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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.

DOI： 10.1016/j.jsbmb.2014.12.007

Lemierre syndrome involving external jugular vein. Reviewed International journal

Hideharu Hagiya, Yuto Haruki, Fumio Otsuka

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

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

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.

DOI： 10.1002/ams2.61

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/53341

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

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

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

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.

DOI： 10.2169/internalmedicine.54.3397

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

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

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

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.

DOI： 10.2169/internalmedicine.54.4845

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

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

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.

DOI： 10.2169/internalmedicine.54.4998

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

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

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.

DOI： 10.2169/internalmedicine.54.4965

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

Language：English Publishing type：Research paper (scientific journal) Publisher：DOVE MEDICAL PRESS LTD

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.

DOI： 10.2147/IDR.S90726

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

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

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.

DOI： 10.2169/internalmedicine.54.4637

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

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

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.

DOI： 10.2169/internalmedicine.54.4956

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

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

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

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.

DOI： 10.2169/internalmedicine.54.3313

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

Relapsing Polychondritis Followed Up with FDG-PET. Reviewed

Hideharu Hagiya, Koichi Waseda, Fumio Otsuka

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

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

CT visualising infective vegetation. International journal

Hideharu Hagiya, Kou Hasegawa, Kikuko Asano, Fumio Otsuka

BMJ case reports 2014 2014.12

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

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

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.

DOI： 10.1002/ccr3.114

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

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

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.

DOI： 10.1016/j.jiac.2014.07.008

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

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

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

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.

DOI： 10.1016/j.avsg.2014.06.072

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

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

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

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.

DOI： 10.1002/ams2.64

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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.

DOI： 10.1016/j.jsbmb.2014.04.003

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

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

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.

DOI： 10.14814/phy2.12054

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

【市中感染型MRSAの動向と対処法】ST8/non-USA300株による全身播種性市中感染型MRSA感染症の1例

萩谷英大, 久恒順三, 森本直樹, 大塚文男, 菅井基行

化学療法の領域 30 ( 5 ) 779 - 787 2014.4

Language：Japanese Publisher：(株)医薬ジャーナル社

市中感染型メチシリン耐性黄色ブドウ球菌(CA-MRSA)は重症感染症を引き起こす起炎菌として知られているが、遺伝子的に多様であり、さまざまなタイプが世界中に分布している。本症例は、multilocus sequence type 8、IV型SCCmec(staphylococcal cassette chromosome mec)、III型コアグラーゼ陽性、Panton-Valentine leukocidinおよびarginine catabolic mobile element陰性の単一株により発症した全身播種性の重症CA-MRSA感染症のまれな一例である。筋骨格系を中心に全身に感染巣を形成しており、遺伝学的に同一のCA-MRSAを患者の異なる11部位より検出した。わが国におけるCA-MRSAの疫学および病原性は未解明である部分が多いが、本症例でもCA-MRSAの高病原性が示唆された。今後さらなる解析が期待される。(著者抄録)

本態性高血圧の初期治療における第一選択薬決定のアルゴリズム作成と有用性の検討

萱野由佳, 三好智子, 水島孝明, 花山宜久, 黒田真生, 尾上洋, 相良英憲, 座間味義人, 大塚文男, 名倉弘哲

Progress in Medicine 34 ( 3 ) 527 - 536 2014.3

Language：Japanese Publisher：(株)ライフ・サイエンス

本態性高血圧症は本邦において極めて患者数の多い疾患であり、その治療は食事・運動療法に加えて薬物治療が重要である。『高血圧治療ガイドライン2009』では、本態性高血圧に対する5種類の第一選択薬であるカルシウム拮抗薬、アンジオテンシンII受容体拮抗薬、アンジオテンシン変換酵素阻害薬、β遮断薬、利尿薬が提示されている。本態性高血圧の初期治療での薬剤選択に際して医師が考慮すべき事項は極めて煩雑であり、医師の処方薬決定を困難にしている。本研究では、本態性高血圧初期治療における処方決定に役立つためのアルゴリズムの作成を試みた。さらに、調査対象となる総合内科医師と保険薬剤師にアルゴリズムを配付し、一定の試用期間後にアルゴリズムの使用感に関する有用性の評価を実施したところ、本アルゴリズムは総合内科医師、保険薬剤師それぞれから高い評価を得た。また、医師の処方決定時の思考をおおむね反映していることが検証できた。したがって、作成したアルゴリズムは医師の処方決定の理解の手助けとなる可能性が示唆された。加えて、本アルゴリズムは薬剤師が処方解析を行ううえでもその有用性は高いと考えられた。(著者抄録)

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

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

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.

DOI： 10.1016/j.jiac.2013.10.001

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

DOI： 10.18926/AMO/52145

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

Lower Limb Infection in an Infant with Haemophilus influenzae Serotype b

Hideharu Hagiya, Fumio Otsuka

General Medicine 15 ( 1 ) 56 - 58 2014

Ceftriaxone-induced Biliary Sludge in a Patient with Uncontrolled Diabetes

Hideharu Hagiya, Kou Hasegawa, Kikuko Asano, Fumio Otsuka

Internal Medicine 53 ( 21 ) 2549 - 2550 2014

Calcium Oxalate Crystals in the Lungs

Hideharu Hagiya, Soichiro Fushimi, Junya Itakura, Fumio Otsuka

Internal Medicine 53 ( 17 ) 2025 - 2026 2014

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

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

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.

DOI： 10.2169/internalmedicine.53.0679

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

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

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.

DOI： 10.2169/internalmedicine.53.3098

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

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

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.

DOI： 10.2169/internalmedicine.53.2572

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

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

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.

DOI： 10.2169/internalmedicine.53.1995

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

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

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.

DOI： 10.2169/internalmedicine.53.2711

Actinomyces meyeri meningitis: the need for anaerobic cerebrospinal fluid cultures. Reviewed

Hideharu Hagiya, Fumio Otsuka

Internal medicine (Tokyo, Japan) 53 ( 1 ) 67 - 71 2014

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

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.

DOI： 10.2169/internalmedicine.53.0403

Epiglottic aphthous ulcers.

Hideharu Hagiya, Hiroyuki Hanakawa, Takayuki Katsuyama, Fumio Otsuka

Internal medicine (Tokyo, Japan) 53 ( 15 ) 1731 - 1731 2014

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

Triangle sign on neck MRI.

Kosuke Kimura, Hideharu Hagiya, Yoshihisa Hanayama, Fumio Otsuka

Internal medicine (Tokyo, Japan) 53 ( 9 ) 1035 - 6 2014

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

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

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

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.

DOI： 10.2169/internalmedicine.53.1746

Rhombencephalitis caused by Listeria monocytogenes.

Hideharu Hagiya, Fumio Otsuka

Internal medicine (Tokyo, Japan) 53 ( 6 ) 639 - 40 2014

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

Language：English Publishing type：Research paper (scientific journal) Publisher：BMJ PUBLISHING GROUP

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.

DOI： 10.1136/bmjopen-2013-003971

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

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.

DOI： 10.1016/j.mce.2013.07.009

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

Language：Japanese Publisher：(株)ライフ・サイエンス

薬理作用の異なる薬剤が多数処方される2型糖尿病治療域において、ガイドラインを適切に理解し薬剤の適正使用を行うことは、臨床経験の少ない研修医や新人薬剤師にとっては困難であり、煩雑な知識を要する。そこで、2型糖尿病初期治療の選択基準となるアルゴリズムを糖尿病診療ガイドラインなどに基づき作成し、その有効性について研修医、総合内科医師、薬剤師にアンケートを実施した。アルゴリズムの有用性に関する評価では、研修医と総合内科医師の間で有意差は認められなかった。一方、薬剤師では、「本アルゴリズムの使用により、医師の処方意図や患者背景について考えるきっかけとなりましたか」との質問に対して、経験年数が6年以上の薬剤師の値に比べ、経験年数が1〜5年の薬剤師の方が有意に高い値を示した。したがって、アルゴリズムを作成し治療選択基準を図式化することで、経験年数の少ない薬剤師の迅速な理解向上に寄与できることが示唆された。(著者抄録)

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

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.

DOI： 10.1016/j.mce.2013.05.010

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

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

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.

DOI： 10.1186/1743-422X-10-225

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

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.

DOI： 10.1016/j.bbrc.2013.04.002

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

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

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.

DOI： 10.1016/j.steroids.2013.02.011

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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.

DOI： 10.1016/j.jsbmb.2012.10.018

Rapid Progression of Graves' Ophthalmopathy Despite the Administration of Thiamazole

Takayuki Katsuyama, Masaya Takeda, Fumio Otsuka, Kishio Toma, Kenichi Inagaki, Ken-Ei Sada, Yukari Mimura, Toshio Ogura, Hirofumi Makino

Internal Medicine 52 ( 20 ) 2317 - 2320 2013

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

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

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.

DOI： 10.1186/2052-0492-1-10

Group A streptococcal meningitis in a patient with palmoplantar pustulosis. Reviewed

Hideharu Hagiya, Fumio Otsuka

Internal medicine (Tokyo, Japan) 52 ( 23 ) 2675 - 8 2013

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

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.

DOI： 10.2169/internalmedicine.52.0499

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

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

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.

DOI： 10.2169/internalmedicine.52.1033

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

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

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.

DOI： 10.2169/internalmedicine.52.0023

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

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

Multifunctional bone morphogenetic protein system in endocrinology.

Fumio Otsuka

Acta medica Okayama 67 ( 2 ) 75 - 86 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

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.

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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.

DOI： 10.1016/j.jsbmb.2012.04.004

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

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

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.

DOI： 10.1007/s00296-011-2136-z

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

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.

DOI： 10.1016/j.ijcard.2011.02.024

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

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.

DOI： 10.1016/j.mce.2012.02.011

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

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.

DOI： 10.1016/j.mce.2011.11.023

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

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

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

DOI： 10.1038/hr.2011.186

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

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.

DOI： 10.1016/j.mce.2011.10.017

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

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.

DOI： 10.1016/j.mce.2011.08.001

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

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

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.

DOI： 10.1016/j.mce.2011.08.027

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

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

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)

DOI： 10.1210/en.2011-1646

Risk Factors for Infection in Patients with Remitted Rheumatic Diseases Treated with Glucocorticoids

Yoshinori Matsumoto, Ken-ei Sada, Mariko Takano, Noriko Toyota, Ryutaro Yamanaka, Koichi Sugiyama, Hiroshi Wakabayashi, Tomoko Kawabata, Fumio Otsuka, Hirofumi Makino

Acta Medica Okayama 65 ( 5 ) 329 - 334 2011.10

Unique bioactivities of bone morphogenetic proteins in regulation of reproductive endocrine functions.

Fumio Otsuka, Kenichi Inagaki

Reproductive medicine and biology 10 ( 3 ) 131 - 142 2011.9

Language：English Publishing type：Research paper (scientific journal) Publisher：John Wiley and Sons Ltd

Remarkable progress has been made in understanding the mechanism by which growth factors and oocytes can regulate the development and function of granulosa cells. Insufficiency of two oocyte-specific growth factors, growth differentiation factor-9 and bone morphogenetic protein (BMP)-15, cause female infertility. Expression of mRNA and/or protein for the BMP system components, including ligands, receptors and intracellular signal transduction factors, was demonstrated in cell components of growing preantral follicles, and biofunctional experiments have further revealed many important roles of the BMP system in regulation of reproductive function. In this review, recent advances in studies on biological actions of BMPs in ovarian folliculogenesis and in related endocrine tissues are discussed. © 2011 Japan Society for Reproductive Medicine.

DOI： 10.1007/s12522-011-0082-9

Functional interaction of bone morphogenetic protein and growth hormone releasing peptide in adrenocorticotropin regulation by corticotrope cells

Naoko Tsukamoto, Fumio Otsuka, Tomoko Miyoshi, Kenichi Inagaki, Eri Nakamura, Tomohiro Terasaka, Masaya Takeda, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

Molecular and Cellular Endocrinology 344 ( 1-2 ) 41 - 50 2011.9

Functional interaction of fibroblast growth factor-8, bone morphogenetic protein and estrogen receptor in breast cancer cell proliferation

Hiroko Masuda, Fumio Otsuka, Yoshinori Matsumoto, Mariko Takano, Tomoko Miyoshi, Kenichi Inagaki, Tadahiko Shien, Naruto Taira, Hirofumi Makino, Hiroyoshi Doihara

Molecular and Cellular Endocrinology 343 ( 1-2 ) 7 - 17 2011.8

Rhabdomyosarcoma discovered in the adrenal region of an elderly hypertensive patient

Akihiro Katayama, Fumio Otsuka, Masaya Takeda, Tomoko Miyoshi, Eri Nakamura, Kenichi Inagaki, Takehiro Tanaka, Shinya Uehara, Hirofumi Makino

Hypertension Research 34 ( 6 ) 784 - 786 2011.6

Unexpected occurrence of adrenal Cushing’s syndrome in a patient with systemic lupus erythematosus

Akihiro Katayama, Fumio Otsuka, Katsuyuki Tanabe, Naoko Tsukamoto, Ryutaro Yamanaka, Yoshinori Matsumoto, Yasutomo Nasu, Hirofumi Makino

Hypertension Research 34 ( 5 ) 662 - 663 2011.5

Effects of eplerenone on nephrotic syndrome in a patient with renovascular hypertension

Jiro Suzuki, Fumio Otsuka, Kenichi Inagaki, Katsuyuki Tanabe, Naoko Tsukamoto, Tomoko Miyoshi, Eri Nakamura, Toshio Ogura, Isao Kumagai, Hirofumi Makino

Hypertension Research 34 ( 3 ) 404 - 406 2011.3

Integral role of GDF-9 and BMP-15 in ovarian function. International journal

Fumio Otsuka, Kirsten J McTavish, Shunichi Shimasaki

Molecular reproduction and development 78 ( 1 ) 9 - 21 2011.1

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

The oocyte plays an important role in regulating and promoting follicle growth, and thereby its own development, by the production of oocyte growth factors that predominantly act on supporting granulosa cells via paracrine signaling. Genetic studies in mice demonstrated critical roles of two key oocyte-derived growth factors belonging to the transforming growth factor-beta (TGF-beta) superfamily, growth and differentiation factor-9 (GDF-9) and bone morphogenetic protein-15 (BMP-15), in ovarian function. The identification of Bnip15 and Gdf9 gene mutations as the causal mechanism underlying the highly prolific or infertile nature of several sheep strains in a dosage-sensitive manner also highlighted the crucial role these two genes play in ovarian function. Similarly, large numbers of mutations in the GDF9 and BMP15 genes have been identified in women with premature ovarian failure and in mothers of dizygotic: twins. The purpose of this article is to review the genetic studies of GDF-9 and BMP-15 mutations identified in women and sheep, as well as describing the various knockout and overexpressing mouse models, and to summarize the molecular and biological functions that underlie the crucial role of these two oocyte factors in female fertility. Mol. Reprod. Dev.78: 9-21, 2011. (c) 2010 Wiley-Liss, Inc.

DOI： 10.1002/mrd.21265

Activities of bone morphogenetic proteins in prolactin regulation by somatostatin analogs in rat pituitary GH3 cells

Naoko Tsukamoto, Fumio Otsuka, Tomoko Miyoshi, Kenichi Inagaki, Eri Nakamura, Jiro Suzuki, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

Molecular and Cellular Endocrinology 332 ( 1-2 ) 163 - 169 2011.1

Systemic Lupus Erythematosus Complicated with Acute Myocardial Infarction and Ischemic Colitis

Yoshinori Matsumoto, Hiroshi Wakabayashi, Fumio Otsuka, Kentaro Inoue, Mariko Takano, Ken-ei Sada, Hirofumi Makino

Internal Medicine 50 ( 21 ) 2669 - 2673 2011

A Novel Antagonistic Effect of the Bone Morphogenetic Protein System on Prolactin Actions in Regulating Steroidogenesis by Granulosa Cells

Eri Nakamura, Fumio Otsuka, Kenichi Inagaki, Tomoko Miyoshi, Ryutaro Yamanaka, Naoko Tsukamoto, Jiro Suzuki, Toshio Ogura, Hirofumi Makino

Endocrinology 151 ( 11 ) 5506 - 5518 2010.11

Publishing type：Research paper (scientific journal) Publisher：The Endocrine Society

To investigate the mechanism by which prolactin (PRL) regulates follicular steroidogenesis in the ovary, we examined the functional roles of PRL in steroidogenesis using rat oocyte/granulosa cell coculture and focusing on the bone morphogenetic protein (BMP) system. The expression of long and short forms of PRL receptor (PRLR) were detected in both oocytes and granulosa cells, and PRL effectively up-regulated PRLR expression in granulosa cells in the presence of FSH. PRL suppressed FSH-induced estradiol production and increased FSH-induced progesterone production in granulosa cells. The PRL effects on FSH-induced progesterone were blocked by coculture with oocytes, implying roles of oocyte-derived factors in suppression of progesterone production in PRL-exposed granulosa cells. In accordance with the data for steroids, FSH-induced aromatase expression was suppressed by PRL, whereas FSH-induced steroidogenic acute regulatory protein, P450scc (P450 side-chain cleavage enzyme), and 3β-hydroxysteroid dehydrogenase type 2 levels were amplified by PRL. However, forskolin- and N6,O2-dibutyryl cAMP-induced steroid levels and FSH- and forskolin-induced cAMP were not affected by PRL, suggesting that PRL action on FSH-induced steroidogenesis was not due to cAMP-protein kinase A regulation. Treatment with a BMP-binding protein, noggin, facilitated PRL-induced estradiol reduction, and noggin increased PRL-induced progesterone production in FSH-treated granulosa cells cocultured with oocytes, suggesting that endogenous BMPs reduce progesterone but increase estradiol when exposed to high concentrations of PRL. PRL increased the expression of BMP ligands in oocyte/granulosa cell coculture and augmented BMP-induced phosphorylated mothers against decapentaplegic 1/5/8 signaling by reducing inhibitory phosphorylated mothers against decapentaplegic 6 expression through the Janus kinase/signal transducer and activator of transcription (STAT) pathway. In addition to STAT activation, PRL enhanced FSH-induced MAPK phosphorylation in granulosa cells, in which ERK activation was preferentially involved in suppression of FSH-induced estradiol. Furthermore, noggin treatment enhanced PRLR signaling including MAPK and STAT. Considering that BMPs suppressed PRLR in granulosa cells, it is likely that the BMP system in growing follicles plays a key role in antagonizing PRLR signaling actions in the ovary exposed to high concentrations of PRL.

DOI： 10.1210/en.2010-0265

ステロイドによる骨芽細胞分化および炎症性骨分化抑制への影響

松本佳則, 大塚文男, 高野真理子, 向井知之, 武田昌也, 三好智子, 稲垣兼一, 槇野博史

日本内分泌学会雑誌 86 ( 2 ) 408 - 408 2010.9

Roles of bone morphogenetic protein-6 in aldosterone regulation by adrenocortical cells.

Hiroyuki Otani, Fumio Otsuka, Kenichi Inagaki, Jiro Suzuki, Hirofumi Makino

Acta medica Okayama 64 ( 4 ) 213 - 8 2010.8

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Aldosterone production occurs in the adrenal cortex, and is regulated primarily by angiotensin II (Ang II), potassium and adrenocorticotropin (ACTH). In the presence of the aldosterone stimulators, steroidogenesis is further governed by local autocrine and/or paracrine factors in the adrenal cortex. We reported the presence of functional bone morphogenetic protein (BMP) system in the adrenal cortex and also demonstrated that BMP-6 increases Ang II-induced aldosterone production, which could be involved in the "aldosterone breakthrough" phenomenon. Aldosterone breakthrough is the phenomenon by which circulating aldosterone concentrations increase above pre-treatment levels after longterm therapy with ACE inhibitors or Ang II type 1 receptor antagonists (ARB). This phenomenon may lead to important clinical consequences since increased aldosterone in a high-salt state facilitates cardiovascular and renal damage in hypertensive patients. We found that long-term ARB treatment reverses the reduction of aldosterone synthesis by adrenocortical cells, thereby causing "cellular aldosterone breakthrough". The availability of BMP-6 in the adrenal cortex may be at least partly involved in the occurrence of cellular escape from aldosterone suppression under chronic treatment with ARB.

DOI： 10.18926/AMO/40128

Functional relationship between fibroblast growth factor-8 and bone morphogenetic proteins in regulating steroidogenesis by rat granulosa cells

Tomoko Miyoshi, Fumio Otsuka, Misuzu Yamashita, Kenichi Inagaki, Eri Nakamura, Naoko Tsukamoto, Masaya Takeda, Jiro Suzuki, Hirofumi Makino

Molecular and Cellular Endocrinology 325 ( 1-2 ) 84 - 92 2010.8

Estrogen and glucocorticoid regulate osteoblast differentiation through the interaction of bone morphogenetic protein-2 and tumor necrosis factor-α in C2C12 cells

Yoshinori Matsumoto, Fumio Otsuka, Mariko Takano, Tomoyuki Mukai, Ryutaro Yamanaka, Masaya Takeda, Tomoko Miyoshi, Kenichi Inagaki, Ken-ei Sada, Hirofumi Makino

Molecular and Cellular Endocrinology 325 ( 1-2 ) 118 - 127 2010.8

Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling

Misuzu Yamashita, Fumio Otsuka, Tomoyuki Mukai, Ryutaro Yamanaka, Hiroyuki Otani, Yoshinori Matsumoto, Eri Nakamura, Mariko Takano, Ken-ei Sada, Hirofumi Makino

Regulatory Peptides 162 ( 1-3 ) 99 - 108 2010.6

Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

Ryutaro Yamanaka, Fumio Otsuka, Kazufumi Nakamura, Misuzu Yamashita, Hiroyuki Otani, Masaya Takeda, Yoshinori Matsumoto, Kengo F Kusano, Hiroshi Ito, Hirofumi Makino

Hypertension Research 33 ( 5 ) 435 - 445 2010.5

Effects of Bone Morphogenetic Protein (BMP) on Adrenocorticotropin Production by Pituitary Corticotrope Cells: Involvement of Up-Regulation of BMP Receptor Signaling by Somatostatin Analogs

Naoko Tsukamoto, Fumio Otsuka, Tomoko Miyoshi, Ryutaro Yamanaka, Kenichi Inagaki, Misuzu Yamashita, Hiroyuki Otani, Masaya Takeda, Jiro Suzuki, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

Endocrinology 151 ( 3 ) 1129 - 1141 2010.3

Publishing type：Research paper (scientific journal) Publisher：The Endocrine Society

The mechanism by which somatostatin analogs suppress ACTH production by corticotropinomas has yet to be fully elucidated. We here studied the effects of somatostatin analogs on ACTH secretion using mouse corticotrope AtT20 cells focusing on the biological activity of bone morphogenetic proteins (BMPs). BMP ligands, receptors and Smads, and somatostatin receptors (SSTRs)-2, -3, and -5 were expressed in AtT20 cells. BMP-2, -4, -6, and -7 decreased basal ACTH production with BMP-4 effects being the most prominent. BMP-4 also inhibited CRH-induced ACTH production and proopiomelanocortin (POMC) transcription. However, the decrease in CRH-induced cAMP accumulation caused by BMP-4 was not sufficient to completely account for BMP-4 actions, indicating that ACTH suppression by BMPs was not directly linked to cAMP inhibition. CRH-activated ERK1/ERK2, p38-MAPK, stress-activated protein kinase/c-Jun NH2-terminal kinase, protein kinase C, and Akt pathways and CRH-induced ACTH synthesis was significantly decreased in the presence of U0126 or SB203580. Because BMPs attenuated CRH-induced ERK and p38 phosphorylation, it was suggested that BMP-4 suppresses ACTH production by inhibiting CRH-induced ERK and p38 phosphorylation. Somatostatin analogs octreotide and pasireotide (SOM230) significantly suppressed CRH-induced ACTH and cAMP production in AtT20 cells and reduced ERK and p38 phosphorylation. Notably, CRH-induced ACTH production was enhanced in the presence of noggin, a BMP-binding protein. The inhibitory effects of octreotide and SOM230 on CRH-induced ACTH production were also attenuated by noggin, implying that the endogenous BMP system plays a key role in inhibiting CRH-induced ACTH production by AtT20 cells. The findings that OCT and SOM230 up-regulated BMP-Smad1/Smad5/Smad8 signaling and ALK-3 and BMPRII and down-regulated inhibitory Smad6/7 establish that the activation of endogenous BMP system is functionally involved in the mechanism by which somatostatin analogs suppress CRH-induced ACTH production.

DOI： 10.1210/en.2009-1102

骨軟骨と滑膜 BMPによる骨芽細胞分化に対するTNF-αおよびsteroidの作用機序の検討

松本佳則, 大塚文男, 向井知之, 高野真理子, 山中龍太郎, 山下美鈴, 塚本尚子, 佐田憲映, 槇野博史

日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 54回・19回 526 - 526 2010.3

Multiple endocrine regulation by bone morphogenetic protein system.

Fumio Otsuka

Endocrine journal 57 ( 1 ) 3 - 14 2010.1

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

Bone morphogenetic proteins (BMPs) were originally identified with regard to their actions to regulate ectopic formation of bone and cartilage and early embryonic development. Subsequently, our research program has investigated a BMP system that exists in the mammalian ovary and plays roles in regulating numerous granulosa cell functions. BMP ligands including BMP-2, 4, -6, -7 and -15 were found to inhibit gondotropin-dependent progesterone synthesis by granulosa cells, which led to the hypothesis that BMPs are a physiological luteinization inhibitor in growing ovarian follicles during the follicular phase of the ovarian cycle. The physiological importance of the BMP system for normal mammalian reproduction has been further recognized by the discovery of aberrant reproductive phenotypes of female sheep and humans having mutated genes encoding BMP-15. Physiological roles of BMPs in the pituitary, hypothalamus, adrenal and other tissues have also been discovered. Here we discuss recent advances in the understanding of autocrine/paracrine actions of BMPs in the systemic regulation of endocrine function.

DOI： 10.1507/endocrj.K09E-310

Inhibitory Effects of Simvastatin on Platelet-derived Growth Factor Signaling in Pulmonary Artery Smooth Muscle Cells From Patients With Idiopathic Pulmonary Arterial Hypertension

Tetsuya Ikeda, Kazufumi Nakamura, Satoshi Akagi, Kengo Fukushima Kusano, Hiromi Matsubara, Hideki Fujio, Aiko Ogawa, Aya Miura, Daiji Miura, Takahiro Oto, Ryutaro Yamanaka, Fumio Otsuka, Hiroshi Date, Tohru Ohe, Hiroshi Ito

Journal of Cardiovascular Pharmacology 55 ( 1 ) 39 - 48 2010.1

Regulation of GNRH production by estrogen and bone morphogenetic proteins in GT1-7 hypothalamic cells

Hiroyuki Otani, Fumio Otsuka, Masaya Takeda, Tomoyuki Mukai, Tomohiro Terasaka, Tomoko Miyoshi, Kenichi Inagaki, Jiro Suzuki, Toshio Ogura, Mark A Lawson, Hirofumi Makino

Journal of Endocrinology 203 ( 1 ) 87 - 97 2009.10

Publishing type：Research paper (scientific journal) Publisher：Bioscientifica

Recent studies have shown that bone morphogenetic proteins (BMPs) are important regulators in the pituitary–gonadal endocrine axis. We here investigated the effects of BMPs on GNRH production controlled by estrogen using murine GT1-7 hypothalamic neuron cells. GT1-7 cells expressed estrogen receptor α (ERα; ESR1 as listed in MGI Database), ERβ (ESR2 as listed in MGI Database), BMP receptors, SMADs, and a binding protein follistatin. Treatment with BMP2 and BMP4 had no effect on Gnrh mRNA expression; however, BMP6 and BMP7 significantly increased Gnrh mRNA expression as well as GnRH production by GT1-7 cells. Notably, the reduction of Gnrh expression caused by estradiol (E₂) was restored by cotreatment with BMP2 and BMP4, whereas it was not affected by BMP6 or BMP7. E₂ activated extracellular signal-regulated kinase (ERK) 1/2 and stress-activated protein kinase/c-Jun NH₂-terminal kinase (SAPK/JNK) signaling but did not activate p38-mitogen-activated protein kinase (MAPK) signaling in GT1-7 cells. Inhibition of ERK1/ERK2 reversed the inhibitory effect of estrogen on Gnrh expression, whereas SAPK/JNK inhibition did not affect the E₂ actions. Expression levels of Erα and Erβ were reduced by BMP2 and BMP4, but were increased by BMP6 and BMP7. Treatment with an ER antagonist inhibited the E₂ effects on Gnrh suppression including reduction of E₂-induced ERK phosphorylation, suggesting the involvement of genomic ER actions in Gnrh suppression. BMP2 and BMP4 also suppressed estrogen-induced phosphorylation of ERK1/ERK2 and SAPK/JNK signaling, suggesting that BMP2 and BMP4 downregulate estrogen effects by attenuating ER–MAPK signaling. Considering that BMP6 and BMP7 increased the expression of α1E-subunit of R-type calcium channel (Cacna1e), which is critical for GNRH secretion, it is possible that BMP6 and BMP7 directly stimulate GNRH release by GT1-7 cells. Collectively, a newly uncovered interaction of BMPs and ER may be involved in controlling hypothalamic GNRH production and secretion via an autocrine/paracrine mechanism.

DOI： 10.1677/joe-09-0065

p38-Mitogen-Activated Protein Kinase Stimulated Steroidogenesis in Granulosa Cell-Oocyte Cocultures: Role of Bone Morphogenetic Proteins 2 and 4

Kenichi Inagaki, Fumio Otsuka, Tomoko Miyoshi, Misuzu Yamashita, Mina Takahashi, Junko Goto, Jiro Suzuki, Hirofumi Makino

Endocrinology 150 ( 4 ) 1921 - 1930 2009.4

Publishing type：Research paper (scientific journal) Publisher：The Endocrine Society

Roles of the p38-MAPK pathway in steroidogenesis were investigated using coculture of rat granulosa cells with oocytes. Activin and FSH readily phosphorylated p38 in granulosa cells. Activin effect on p38 phosphorylation was abolished by a selective activin receptor-like kinase-4, -5, and -7 inhibitor, SB431542. SB431542 decreased FSH-induced estradiol but had no effect on progesterone production with a marginal cAMP reduction, suggesting that endogenous activin is primarily involved in estradiol synthesis. FSH-induced p38 activation was not affected either by SB431542 or follistatin, suggesting that FSH activates p38 not through the endogenous activin. Bone morphogenetic protein (BMP)-2 and BMP-4 also enhanced FSH-induced p38 phosphorylation, which was augmented by oocyte action. A specific p38 inhibitor, SB203580, decreased FSH-induced estradiol production. However, FSH-induced cAMP accumulation was not changed by SB203580, suggesting that p38 activation is linked to estradiol synthesis independently of cAMP. BMP-2 and BMP-4 inhibited FSH- and forskolin (FSK)-induced progesterone and cAMP synthesis regardless of oocyte action. BMP-2, BMP-4, and activin increased FSH-induced estradiol production, which was enhanced in the presence of oocytes. In contrast to activin that enhanced FSK-induced estradiol, BMP-2 and BMP-4 had no effects on FSK-induced estradiol production, suggesting that BMP-2 and BMP-4 directly activate FSH-receptor signaling. Given that activin increased, but BMP-2 and BMP-4 decreased, FSH-induced cAMP, the effects of BMP-2 and BMP-4 on estradiol enhancement appeared to be diverged from the cAMP-protein kinase A pathway. Thus, BMP-2 and BMP-4 differentially regulate steroidogenesis by stimulating FSH-induced p38 and suppressing cAMP. The former is involved in estradiol production and enhanced by oocyte action, whereas the latter leads to reduction of progesterone synthesis.

DOI： 10.1210/en.2008-0851

Enhancement of aldosterone-induced catecholamine production by bone morphogenetic protein-4 through activating Rho and SAPK/JNK pathway in adrenomedullar cells

Junko Goto, Fumio Otsuka, Misuzu Yamashita, Jiro Suzuki, Hiroyuki Otani, Hiroko Takahashi, Tomoko Miyoshi, Yukari Mimura, Toshio Ogura, Hirofumi Makino

American Journal of Physiology-Endocrinology and Metabolism 296 ( 4 ) E904 - E916 2009.4

Publishing type：Research paper (scientific journal) Publisher：American Physiological Society

Here we investigated the effects of mineralocorticoid in the regulation of catecholamine biosynthesis using rat pheochromocytoma PC12 cells. Expression of mineralocorticoid receptor (MR) was confirmed in undifferentiated PC12 cells. Aldosterone stimulated dopamine production by PC12 cells without any increase in cAMP activity. Aldosterone-induced dopamine accumulation was enhanced in accordance with the increase in the rate-limiting enzyme tyrosine hydroxylase (TH). Blocking MR with eplerenone suppressed aldosterone-induced increases of TH mRNA and dopamine production. A glucocorticoid receptor (GR) antagonist, RU-486, attenuated dexamethasone- but not aldosterone-induced TH expression. Cycloheximide reduced both aldosterone- and dexamethasone-induced TH mRNA. A SAPK/JNK inhibitor, SP600125, suppressed aldosterone-induced TH mRNA expression; however, the aldosterone-induced TH expression was not affected by inhibition of ERK1/2, p38-MAPK, Rho-kinase, PI 3-kinase, and PKC. It was of note that cotreatment with eplerenone and SP600125 restored aldosterone-induced TH mRNA expression to basal levels. To investigate the involvement of bone morphogenetic protein (BMP) actions in aldosterone-induced catecholamine production, we examined the effects of BMP-4 and BMP-7, which are expressed in the adrenal medulla, on catecholamine biosynthesis. BMP-4 preferentially enhanced aldosterone-induced TH mRNA and dopamine production, although BMP-4 alone did not affect TH expression. The BMP-4 enhancement of aldosterone-induced TH expression was not observed in cells treated with eplerenone. BMP-4 did not affect MR expression of PC12 cells; however, it did enhance aldosterone-induced SAPK/JNK phosphorylation. Inhibition of SAPK/JNK or Rho suppressed BMP-4 enhancement of aldosterone-induced TH expression. Collectively, our findings demonstrate that aldosterone stimulates catecholamine biosynthesis in adrenomedullar cells via MR through genomic action and partly through nongenomic action by Rho-SAPK/JNK signaling, the latter of which is facilitated by BMP-4. A functional link between MR actions and endogenous BMP may be involved in the catecholamine production.

DOI： 10.1152/ajpendo.90840.2008

骨粗鬆症破骨細胞活性化に対するBMP-2の影響とsimvastatinの作用機序の検討

山下美鈴, 大塚文男, 向井知之, 山中龍太郎, 矢野隆介, 山村昌弘, 槇野博史

日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 53回・18回 283 - 283 2009.3

Adrenal ganglioneuroma accompanying catecholamine-producing adrenocortical cells

J. Goto, F. Otsuka, M. Omori, H. Makino

Journal of Endocrinological Investigation 32 ( 2 ) 192 - 192 2009.2

Effects of Growth Hormone Reduction in a Patient with Polycystic Ovary Syndrome Complicated with Acromegaly

Junko GOTO, Fumio OTSUKA, Kenichi INAGAKI, Naoko TSUKAMOTO, Jiro SUZUKI, Tomoko MIYOSHI, Toshio OGURA, Yasuhiko KAMADA, Hirofumi MAKINO

Endocrine Journal 56 ( 1 ) 157 - 160 2009

Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation

Mina Takahashi, Fumio Otsuka, Tomoko Miyoshi, Hiroyuki Otani, Junko Goto, Misuzu Yamashita, Toshio Ogura, Hirofumi Makino, Hiroyoshi Doihara

Journal of Endocrinology 199 ( 3 ) 445 - 455 2008.12

Publishing type：Research paper (scientific journal) Publisher：Bioscientifica

Estrogen is involved in the development and progression of breast cancer. Here, we investigated the effects of bone morphogenetic proteins (BMPs) on breast cancer cell proliferation caused by estrogen using human breast cancer MCF-7 cells. MCF-7 cells express estrogen receptors (ESR1 and ESR2), BMP receptors, and SMAD signaling molecules. Estradiol and membrane-impermeable estradiol stimulated MCF-7 cell proliferation. Estradiol also reduced mRNA levels of ESR1, aromatase, and steroid sulfatase. Treatment with BMPs and activin had no effects on MCF-7 cell proliferation. However, BMP2, BMP4, BMP6, BMP7, and activin suppressed estradiol-induced cell mitosis, with the effects of BMP6, BMP7, and activin being more prominent than those of BMP2 and BMP4. Activin decreased ESR1 mRNA expression, while BMP6 and BMP7 impaired steroid sulfatase expression in MCF-7 cells. Interestingly, SMAD1,5,8 activation elicited by BMP6 and BMP7, but not by BMP2 and BMP4, was preserved even under the exposure of a high concentration of estradiol. The difference of BMP responsiveness was likely due to the differential modulation of BMP receptor expression induced by estradiol. In this regard, estradiol decreased the expression levels of BMPR1A, BMPR1B, ACVR2A, and ACVR2B but did not affect ACVR1 and BMPRII, leading to the sustained effects of BMP6 and BMP7 in estrogen-treated MCF-7 cells. Estradiol rapidly activated MAPK phosphorylation including extracellular signal-regulated kinase 1/2, p38, and stress-activated protein kinase/c-Jun NH2-terminal kinase pathways and BMP6, BMP7, and activin preferentially inhibited estradiol-induced p38 phosphorylation. SB203580, a selective p38 MAPK inhibitor effectively suppressed estradiol-induced cell mitosis, suggesting that p38 MAPK plays a key role in estrogen-sensitive breast cancer cell proliferation. Thus, a novel interrelationship between estrogen and the breast cancer BMP system was uncovered, in which inhibitory effects of BMP6 and BMP7 on p38 signaling and steroid sulfatase expression were functionally involved in the suppression of estrogen-induced mitosis of breast cancer cells.

DOI： 10.1677/joe-08-0226

[Pulmonary arterial hypertension and BMP system abnormality].

Fumio Otsuka

Nihon rinsho. Japanese journal of clinical medicine 66 ( 11 ) 2083 - 90 2008.11

Language：Japanese

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.

Other Link： http://search.jamas.or.jp/link/ui/2008376655

Aldosterone Breakthrough Caused by Chronic Blockage of Angiotensin II Type 1 Receptors in Human Adrenocortical Cells: Possible Involvement of Bone Morphogenetic Protein-6 Actions

Hiroyuki Otani, Fumio Otsuka, Kenichi Inagaki, Jiro Suzuki, Tomoko Miyoshi, Yoshihiro Kano, Junko Goto, Toshio Ogura, Hirofumi Makino

Endocrinology 149 ( 6 ) 2816 - 2825 2008.6

Publishing type：Research paper (scientific journal) Publisher：The Endocrine Society

Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6, which is expressed in adrenocortical cells, enhances Ang II- but not potassium-induced aldosterone production in human adrenocortical cells. Accordingly, we examined the roles of BMP-6 in aldosterone breakthrough induced by long-term treatment with ARB. Ang II stimulated aldosterone production by adrenocortical cells. This Ang II stimulation was blocked by an ARB, candesartan. Interestingly, the candesartan effects on Ang II-induced aldosterone synthesis and CYP11B2 expression were attenuated in a course of candesartan treatment for 15 d. The impairment of candesartan effects on Ang II-induced aldosterone production was also observed in Ang II- or candesartan-pretreated cells. Levels of Ang II type 1 receptor mRNA were not changed by chronic candesartan treatment. However, BMP-6 enhancement of Ang II-induced ERK1/2 signaling was resistant to candesartan. The BMP-6-induced Smad1, -5, and -8 phosphorylation, and BRE-Luc activity was augmented in the presence of Ang II and candesartan in the chronic phase. Chronic Ang II exposure decreased cellular expression levels of BMP-6 and its receptors activin receptor-like kinase-2 and activin type II receptor mRNAs. Cotreatment with candesartan reversed the inhibitory effects of Ang II on the expression levels of these mRNAs. The breakthrough phenomenon was attenuated by neutralization of endogenous BMP-6 and activin receptor-like kinase-2. Collectively, these data suggest that changes in BMP-6 availability and response may be involved in the occurrence of cellular escape from aldosterone suppression under chronic treatment with ARB.

DOI： 10.1210/en.2007-1476

Involvement of bone morphogenetic protein-4 in GH regulation by octreotide and bromocriptine in rat pituitary GH3 cells

Tomoko Miyoshi, Fumio Otsuka, Hiroyuki Otani, Kenichi Inagaki, Junko Goto, Misuzu Yamashita, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

Journal of Endocrinology 197 ( 1 ) 159 - 169 2008.4

Publishing type：Research paper (scientific journal) Publisher：Bioscientifica

Here we investigated roles of the pituitary bone morphogenetic protein (BMP) system in modulating GH production regulated by a somatostatin analog, octreotide (OCT) and a dopamine agonist, bromocriptine (BRC) in rat pituitary somatolactotrope tumor GH3 cells. The GH3 cells were found to express BMP ligands, including BMP-4 and BMP-6; BMP type-1 and type-2 receptors (except the type-1 receptor, activin receptor-like kinase (ALK)-6); and Smad signaling molecules. Forskolin stimulated GH production in accordance with cAMP synthesis. BRC, but not OCT, suppressed forskolin-induced cAMP synthesis by GH3 cells. Individual treatment with OCT and BRC reduced forskolin-induced GH secretion. A low concentration (0.1 μM) of OCT in combination with BRC (1–100 μM) exhibited additive effects on reducing GH and cAMP production induced by forskolin. However, a high concentration (10 μM) of OCT in combination with BRC failed to suppress GH and cAMP production. BMP-4 specifically enhanced GH secretion and cAMP production induced by forskolin in GH3 cells. BRC, but not OCT, inhibited BMP-4-induced activation of Smad1,5,8 phosphorylation and Id-1 transcription and decreased ALK-3 expression. Of note, in the presence of a high concentration of OCT, the BRC effects suppressing BMP-4-Smad1,5,8 signaling were significantly impaired. In the presence of BMP-4, a high concentration of OCT also attenuated the BRC effects suppressing forskolin-induced GH and cAMP production. Collectively, a high concentration of OCT interferes with BRC effects by reducing cAMP production and suppressing BMP-4 signaling in GH3 cells. These findings may explain the mechanism of resistance of GH reduction to a combination therapy with OCT and BRC for GH-producing pituitary adenomas.

DOI： 10.1677/joe-07-0549

TNF-αによる骨芽細胞分化の抑制に対するSimvastatin作用の検討

山下美鈴, 大塚文男, 向井知之, 相田哲史, 山村昌弘, 槇野博史

日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 52回・17回 247 - 247 2008.4

Simvastatin antagonizes tumor necrosis factor-α inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway

Misuzu Yamashita, Fumio Otsuka, Tomoyuki Mukai, Hiroyuki Otani, Kenichi Inagaki, Tomoko Miyoshi, Junko Goto, Masahiro Yamamura, Hirofumi Makino

Journal of Endocrinology 196 ( 3 ) 601 - 613 2008.3

Publishing type：Research paper (scientific journal) Publisher：Bioscientifica

Recent studies have shown that the mevalonate pathway plays an important role in skeletal metabolism. Statins stimulate bone morphogenetic proteins-2 (BMP-2) production in osteoblasts, implicating a possible beneficial role for statins in promoting anabolic effects on bone. Here, we investigated the effects of a lipophilic simvastatin on osteoblast differentiation using mouse myoblast C2C12 cells, in the presence of tumor necrosis factor-α (TNF-α), an inflammatory cytokine that inhibits osteogenesis. The addition of TNF-α to C2C12 cells suppressed the BMP-2-induced expression of key osteoblastic markers including Runx2 and alkaline phosphatase (ALP) activity. Simvastatin had no independent effects on Runx2 and alkaline phosphatase activity; however, it reversed the suppressive effects of TNF-α. The ability of simvastatin to reverse TNF-α inhibition of BMP-induced Smad1,5,8 phosphorylation and Id-1 promoter activity suggests the involvement of Smad signaling pathway in simvastatin action. In addition, cDNA array analysis revealed that simvastatin increased expression levels of Smads in C2C12 cells exposed to TNF-α that also activated mitogen-activated protein kinase (MAPK) signaling pathways, including extracellular signal-regulated kinase 1/2 (ERK1/2), P38, and stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK). Simvastatin potently suppressed TNF-α-induced phosphorylation of ERK1/2 and SAPK/JNK by inhibiting TNF-α-induced membrane localization of Ras and RhoA. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) reversed the simvastatin effects on TNF-α-induced activation of Ras/Rho/MAPK pathways. FPP and GGPP also restored the simvastatin effects on TNF-α-induced suppression of Runx2 and ALP activity. In addition, simvastatin decreased the expression levels of TNF type-1 and -2 receptor mRNAs. Collectively, simvastatin supports BMP-induced osteoblast differentiation through antagonizing TNF-α-to-Ras/Rho/MAPK pathway and augmenting BMP-Smad signaling, suggesting a potential usage of statins to ameliorate inflammatory bone damage.

DOI： 10.1677/joe-07-0532

Other Link： https://joe.bioscientifica.com/downloadpdf/journals/joe/196/3/601.xml

A Rare Tumor in the Adrenal Region: Neuron-specific Enolase (NSE)-Producing Leiomyosarcoma in an Elderly Hypertensive Patient

Junko GOTO, Fumio OTSUKA, Ryo KODERA, Tomoko MIYOSHI, Masaru KINOMURA, Hiroyuki OTANI, Yukari MIMURA, Toshio OGURA, Hiroyuki YANAI, Yasutomo NASU, Hirofumi MAKINO

Endocrine Journal 55 ( 1 ) 175 - 181 2008

Effects of peroxisome proliferator-activated receptor activation on gonadotropin transcription and cell mitosis induced by bone morphogenetic proteins in mouse gonadotrope LβT2 cells

Masaya Takeda, Fumio Otsuka, Hiroyuki Otani, Kenichi Inagaki, Tomoko Miyoshi, Jiro Suzuki, Yukari Mimura, Toshio Ogura, Hirofumi Makino

Journal of Endocrinology 194 ( 1 ) 87 - 99 2007.7

Publishing type：Research paper (scientific journal) Publisher：Bioscientifica

Involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ ) activation and bone morphogenetic protein (BMP) signaling in regulating cell proliferation and hormonal production of pituitary tumors has been reported, although the underlying mechanism remains poorly understood. Here, we investigated regulatory roles of PPARα and PPARγ in gonadotropin transcription and cell mitosis modulated by pituitary activin/BMP systems using a mouse gonadotropinoma cell line Lβ T2, which expresses activin/BMP receptors, transcription factor Smads, PPARα , and PPARγ . In Lβ T2 cells, BMP signaling shown by Smad1/5/8 phosphorylation and Id-1 transcription was readily activated by BMPs. A PPARγ agonist, pioglitazone significantly reduced BMP-induced DNA synthesis by Lβ T2; whereas the PPARα agonist, fenofibric acid, did not. In accordance with the effects on cell mitosis, pioglitazone but not fenofibric acid significantly decreased BMP-induced Id-1-Luc activation. Neither fenofibric acid nor pioglitazone affected activin signaling detected by (CAGA)⁹-Luc activity. Both PPARα and PPARγ ligands directly suppressed transcriptional activities of FSHβ , LHβ , and GnRHR. Activation of PPARα and PPARγ increased mRNA levels of follistatin, but did not affect the expression of follistatin-related gene. Thus, PPAR agonists not only directly suppress gonadotropin transcription and BMP signaling, but also inhibit the biological actions of activins which facilitate gonadotropin transcription through upregulating follistatin expression. In addition, pioglitazone increased BMP ligands mRNA, but decreased activin-β B mRNA in Lβ T2 cells. Collectively, PPAR activation differentially regulates gonadotrope cell proliferation and gonadotropin transcription in a ligand-dependent manner.

DOI： 10.1677/joe-07-0138

Other Link： https://joe.bioscientifica.com/downloadpdf/journals/joe/194/1/1940087.xml

TNF-α inhibits BMP-induced osteoblast differentiation through activating SAPK/JNK signaling

Tomoyuki Mukai, Fumio Otsuka, Hiroyuki Otani, Misuzu Yamashita, Koji Takasugi, Kenichi Inagaki, Masahiro Yamamura, Hirofumi Makino

Biochemical and Biophysical Research Communications 356 ( 4 ) 1004 - 1010 2007.5

Antagonistic effects of bone morphogenetic protein-4 and -7 on renal mesangial cell proliferation induced by aldosterone through MAPK activation

Hiroyuki Otani, Fumio Otsuka, Kenichi Inagaki, Masaya Takeda, Tomoko Miyoshi, Jiro Suzuki, Tomoyuki Mukai, Toshio Ogura, Hirofumi Makino

American Journal of Physiology-Renal Physiology 292 ( 5 ) F1513 - F1525 2007.5

Publishing type：Research paper (scientific journal) Publisher：American Physiological Society

Aldosterone and angiotensin II (ANG II) contribute to the development and progression of renal damage. Here we investigated the effects of bone morphogenetic proteins (BMPs) on renal cell proliferation evoked by aldosterone and ANG II with mouse mesangial cells, which express mineralocorticoid receptors (MR), ANG II type 1 receptors, and BMP signaling molecules. Aldosterone and ANG II stimulated mesangial cell mitosis and activated ERK1/2 and SAPK/JNK signaling. These aldosterone effects were neutralized by the MR antagonist eplerenone and inhibition of transcription or translation, suggesting the involvement of genomic activation via MR. BMP-4 and BMP-7 stimulated Smad1, -5, -8 signaling more potently than BMP-2 and BMP-6, leading to suppression of mesangial cell mitosis and MR expression. MAPK inhibitors including U-0126 and SP-600125, but not SB-203580, suppressed aldosterone-induced cellular DNA synthesis, implying that ERK1/2 and SAPK/JNK pathways play crucial roles in mesangial cell proliferation. BMP-4 and BMP-7 inhibited phosphorylation of ERK1/2 and SAPK/JNK induced by aldosterone while activating p38 pathway, resulting in inhibition of aldosterone-induced cell mitosis. In contrast, aldosterone modulated the mesangial BMP system by decreasing expression of ALK-3, BMP-4, and BMP-7 while increasing inhibitory Smad6 expression. Thus novel functional cross talk between the mesangial BMP system and aldosterone signaling was uncovered, in which inhibition of MAPK signaling and MR expression by BMP-4 and BMP-7 may be involved in ameliorating renal damage due to mesangial proliferation caused by aldosterone.

DOI： 10.1152/ajprenal.00402.2006

バセドウ病ともやもや病を合併し経過中に脳梗塞を発症した1型糖尿病の1例

更井啓, 四方賢一, 大森一慶, 佐藤千景, 西下伸吾, 和田淳, 鈴木二郎, 大塚文男, 槇野博史, 山本久美子, 佐々原渉

糖尿病 50 ( 5 ) 356 - 356 2007.5

骨形成蛋白(BMP)により誘導される骨芽細胞分化に対する炎症性サイトカインTNF-αの抑制作用

大塚文男, 向井知之, 大谷寛之, 稲垣兼一, 三好智子, 後藤順子, 鈴木二郎, 三村由香里, 小倉俊郎, 槇野博史

日本内分泌学会雑誌 83 ( 1 ) 155 - 155 2007.4

BMPによる骨芽細胞の分化に及ぼすTNF-αの作用メカニズムの検討

向井知之, 大塚文男, 山下美鈴, 高杉幸司, 相田哲史, 槇野博史, 山村昌弘

日本リウマチ学会総会・学術集会・国際リウマチシンポジウムプログラム・抄録集 51回・16回 365 - 365 2007.4

Regulatory expression of bone morphogenetic protein-6 system in aldosterone production by human adrenocortical cells

Kenichi Inagaki, Fumio Otsuka, Jiro Suzuki, Hiroyuki Otani, Masaya Takeda, Yoshihiro Kano, Tomoko Miyoshi, Misuzu Yamashita, Toshio Ogura, Hirofumi Makino

Regulatory Peptides 138 ( 2-3 ) 133 - 140 2007.2

Differential Regulation of Steroidogenesis by Bone Morphogenetic Proteins in Granulosa Cells: Involvement of Extracellularly Regulated Kinase Signaling and Oocyte Actions in Follicle-Stimulating Hormone-Induced Estrogen Production

Tomoko Miyoshi, Fumio Otsuka, Kenichi Inagaki, Hiroyuki Otani, Masaya Takeda, Jiro Suzuki, Junko Goto, Toshio Ogura, Hirofumi Makino

Endocrinology 148 ( 1 ) 337 - 345 2007.1

Publishing type：Research paper (scientific journal) Publisher：The Endocrine Society

In the present study, we investigated the cellular mechanism by which oocytes and bone morphogenetic proteins (BMPs) govern FSH-induced steroidogenesis using rat primary granulosa cells. BMP-6 and BMP-7 both inhibited FSH- and forskolin (FSK)-induced progesterone synthesis and reduced cAMP synthesis independent of the presence or absence of oocytes. BMP-7 also increased FSH-induced estradiol production, and the response was further augmented in the presence of oocytes. In contrast, BMP-6 had no impact on estradiol synthesis regardless of the presence of oocytes. Because BMP-7 changed neither FSK- nor cAMP-induced estradiol production, the BMP-7 action was mediated through a FSH receptor signaling mechanism that was independent of cAMP-protein kinase A pathway. Treatment with FSH but not cAMP activated ERK1/2 phosphorylation in granulosa cells, which was further accelerated by oocytes. A specific ERK inhibitor, U0126, increased estradiol production and decreased FSH- and FSK-induced progesterone production and cAMP synthesis. This suggests that ERK activation is directly linked to inhibition of estradiol synthesis and amplification of cAMP. Moreover, FSH-induced ERK1/2 phosphorylation was inhibited by BMP-7 but not influenced by BMP-6. In contrast, BMP signaling including Smad1/5/8 phosphorylation and Id-1 transcription was up-regulated by FSH and oocytes in granulosa cells through inhibition of Smad6/7 expression. Collectively, oocytes enhance FSH-induced MAPK activation and BMP signaling in granulosa cells, which leads to differential regulation of steroidogenesis elicited by BMPs in the presence of FSH in developing follicles.

DOI： 10.1210/en.2006-0966

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

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

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.

DOI： 10.1016/j.amjhyper.2006.06.012

Primary Aldosteronism Caused by a Unilateral Adrenal Adenoma Accompanied by Autonomous Cortisol Secretion

Jiro SUZUKI, Fumio OTSUKA, Kenichi INAGAKI, Hiroyuki OTANI, Tomoko MIYOSHI, Tomohiro TERASAKA, Toshio OGURA, Masako OMORI, Yasutomo NASU, Hirofumi MAKINO

Hypertension Research 30 ( 4 ) 367 - 373 2007

Gastric Diverticulum Simulating Left Adrenal Incidentaloma in a Hypertensive Patient

Ryo KODERA, Fumio OTSUKA, Kenichi INAGAKI, Tomoko MIYOSHI, Toshio OGURA, Yasushi TANIMOTO, Tetsuro SEI, Hirofumi MAKINO

Endocrine Journal 54 ( 6 ) 969 - 974 2007

Mutual Regulation of Follicle-Stimulating Hormone Signaling and Bone Morphogenetic Protein System in Human Granulosa Cells1

Tomoko Miyoshi, Fumio Otsuka, Jiro Suzuki, Masaya Takeda, Kenichi Inagaki, Yoshihiro Kano, Hiroyuki Otani, Yukari Mimura, Toshio Ogura, Hirofumi Makino

Biology of Reproduction 74 ( 6 ) 1073 - 1082 2006.6

Involvement of Bone Morphogenetic Protein-6 in Differential Regulation of Aldosterone Production by Angiotensin II and Potassium in Human Adrenocortical Cells

Kenichi Inagaki, Fumio Otsuka, Jiro Suzuki, Yoshihiro Kano, Masaya Takeda, Tomoko Miyoshi, Hiroyuki Otani, Yukari Mimura, Toshio Ogura, Hirofumi Makino

Endocrinology 147 ( 6 ) 2681 - 2689 2006.6

Manifestation of Rheumatoid Arthritis after Transsphenoidal Surgery in a Patient with Acromegaly

Tomoko MIYOSHI, Fumio OTSUKA, Tomoko KAWABATA, Kenichi INAGAKI, Tomoyuki MUKAI, Masanori KAWASHIMA, Toshio OGURA, Masahiro YAMAMURA, Tetsuro SEI, Hirofumi MAKINO

Endocrine Journal 53 ( 5 ) 621 - 625 2006

Induction of tumour necrosis factor receptor-expressing macrophages by interleukin-10 and macrophage colony-stimulating factor in rheumatoid arthritis

Koji Takasugi, Masahiro Yamamura, Mitsuhiro Iwahashi, Fumio Otsuka, Jiro Yamana, Katsue Sunahori, Masanori Kawashima, Masao Yamada, Hirofumi Makino

Arthritis Research & Therapy 8 ( 4 ) R126 - R126 2006

Regulatory Roles of Bone Morphogenetic Proteins and Glucocorticoids in Catecholamine Production by Rat Pheochromocytoma Cells

Yoshihiro Kano, Fumio Otsuka, Masaya Takeda, Jiro Suzuki, Kenichi Inagaki, Tomoko Miyoshi, Manabu Miyamoto, Hiroyuki Otani, Toshio Ogura, Hirofumi Makino

Endocrinology 146 ( 12 ) 5332 - 5340 2005.12

Publishing type：Research paper (scientific journal) Publisher：The Endocrine Society

We here report a new physiological system that governs catecholamine synthesis involving bone morphogenetic proteins (BMPs) and activin in the rat pheochromocytoma cell line, PC12. BMP type I receptors, including activin receptor-like kinase-2 (ALK-2) (also referred to as ActRIA) and ALK-3 (BMPRIA), both type II receptors, ActRII and BMPRII, as well as the ligands BMP-2, -4, and -7 and inhibin/activin subunits were expressed in PC12 cells. PC12 cells predominantly secrete dopamine, whereas noradrenaline and adrenaline production is negligible. BMP-2, -4, -6, and -7 and activin A each suppressed dopamine and cAMP synthesis in a dose-dependent fashion. The BMP ligands also decreased 3,4-dihydroxyphenylalanine decarboxylase mRNA expression, whereas activin suppressed tyrosine hydroxylase expression. BMPs induced both Smad1/5/8 phosphorylation and Tlx2-Luc activation, whereas activin stimulated 3TP-Luc activity and p38 MAPK phosphorylation. ERK signaling was not affected by BMPs or activin. Dexamethasone enhanced catecholamine synthesis, accompanying increases in tyrosine hydroxylase and 3,4-dihydroxyphenylalanine decarboxylase transcription without cAMP accumulation. In the presence of dexamethasone, BMPs and activin failed to reduce dopamine as well as cAMP production. In addition, dexamethasone modulated mitotic suppression of PC12 induced by BMPs in a ligand-dependent manner. Furthermore, intracellular BMP signaling was markedly suppressed by dexamethasone treatment and the expression of ALK-2, ALK-3, and BMPRII was significantly inhibited by dexamethasone. Collectively, the endogenous BMP/activin system plays a key role in the regulation of catecholamine production. Controlling activity of the BMP system may be critical for glucocorticoid-induced catecholamine synthesis by adrenomedullar cells.

DOI： 10.1210/en.2005-0474

An Extra-adrenal Abdominal Pheochromocytoma Causing Ectopic ACTH Syndrome

F OTSUKA, T MIYOSHI, K MURAKAMI, K INAGAKI, M TAKEDA, K UJIKE, T OGURA, M OMORI, H DOIHARA, Y TANAKA

American Journal of Hypertension 18 ( 10 ) 1364 - 1368 2005.10

Essential Role of the Oocyte in Estrogen Amplification of Follicle-Stimulating Hormone Signaling in Granulosa Cells

Fumio Otsuka, R. Kelly Moore, Xia Wang, Shweta Sharma, Tomoko Miyoshi, Shunichi Shimasaki

Endocrinology 146 ( 8 ) 3362 - 3367 2005.8

Publishing type：Research paper (scientific journal) Publisher：The Endocrine Society

Abstract

The establishment of dominant ovarian follicles that are capable of ovulating fertilizable oocytes is a fundamental determinant of female fertility. This process is governed by pituitary gonadotropins as well as local ovarian factors. Within the follicle, estrogen acts in an autocrine/paracrine manner to enhance FSH action in the granulosa cells. These effects include the augmentation of P450aromatase expression and estradiol production. This feed-forward effect of estrogen is believed to play a key role in follicle dominance. Here we found the essential role of the oocyte in this physiological process using primary cultures of rat granulosa cells. In the presence, but not absence, of oocytes, estrogen amplified FSH-stimulated increases in mRNA expression of P450aromatase, FSH receptor, LH receptor, and inhibin α-, βA-, and βB-subunits as well as cAMP production. Thus, oocytes mediate the estrogen enhancement of FSH action in the granulosa cells. In comparison with FSH, cotreatment with estrogen and oocytes failed to amplify the stimulatory effects of forskolin or 8-bromoadenosine-cAMP on granulosa cell responses including P450aromatase mRNA expression and cAMP production, indicating that estrogen/oocytes amplify FSH action at a site upstream of adenylate cyclase. These findings support the novel conclusion that communication between the oocyte and granulosa cells plays a crucial role in mediating estrogen action during FSH-dependent folliculogenesis.

DOI： 10.1210/en.2005-0349

インスリン抵抗性と肥満を合併したバーター症候群の1例

村上和敏, 四方賢一, 和田淳, 大塚文男, 江口潤, 向井知之

糖尿病 48 ( 6 ) 464 - 464 2005.6

Functional roles of the bone morphogenetic protein system in thyrotropin signaling in porcine thyroid cells

Jiro Suzuki, Fumio Otsuka, Masaya Takeda, Kenichi Inagaki, Tomoko Miyoshi, Yukari Mimura, Toshio Ogura, Hiroyoshi Doihara, Hirofumi Makino

Biochemical and Biophysical Research Communications 327 ( 4 ) 1124 - 1130 2005.2

Octreotide effect on cluster headache in acromegaly patients

Fumio Otsuka, Satoshi Mizobuchi, Hirofumi Makino

EUROPEAN JOURNAL OF ENDOCRINOLOGY 152 2005

Abrupt Enlargement of Adrenal Incidentaloma: A Case of Isolated Adrenal Metastasis

Tomoko MIYOSHI, Fumio OTSUKA, Jiro SUZUKI, Kenichi INAGAKI, Yoshihiro KANO, Toshio OGURA, Katsuyuki KIURA, Takashi SAIKA, Hirofumi MAKINO

Endocrine Journal 52 ( 6 ) 785 - 788 2005

Periodic Secretion of Adrenocorticotropin in a Patient with Cushing's Disease Manifested during Pregnancy

Tomoko MIYOSHI, Fumio OTSUKA, Jiro SUZUKI, Kenichi INAGAKI, Masaya TAKEDA, Yoshihiro KANO, Tetsuji YAMASHITA, Toshio OGURA, Isao DATE, Yasushi TANAKA, Kozo HASHIMOTO, Hirofumi MAKINO

Endocrine Journal 52 ( 3 ) 287 - 292 2005

Effect of cabergoline treatment on Cushing’s disease caused by aberrant adrenocorticotropin-secreting macroadenoma

T. Miyoshi, F. Otsuka, M. Takeda, K. Inagaki, J. Suzuki, T. Ogura, I. Date, K. Hashimoto, H. Makino

Journal of Endocrinological Investigation 27 ( 11 ) 1055 - 1059 2004.12

Characterization of the Bone Morphogenetic Protein (BMP) System in Human Pulmonary Arterial Smooth Muscle Cells Isolated from a Sporadic Case of Primary Pulmonary Hypertension: Roles of BMP Type IB Receptor (Activin Receptor-Like Kinase-6) in the Mitotic Action

Masaya Takeda, Fumio Otsuka, Kazufumi Nakamura, Kenichi Inagaki, Jiro Suzuki, Daiji Miura, Hideki Fujio, Hiromi Matsubara, Hiroshi Date, Tohru Ohe, Hirofumi Makino

Endocrinology 145 ( 9 ) 4344 - 4354 2004.9

Aldosterone regulation for 18 years in a case of primary aldosteronism

Tomoko Miyoshi , Fumio Otsuka, Toshio Ogura, Jiro Suzuki, Kenichi Inagaki, Masaya Takeda, Masayuki Kishida, Yukari Mimura, Atsushi Nagai, Hirofumi Makino

American Journal of Hypertension 17 ( 6 ) 546 - 548 2004.6

Cholestatic jaundice: An unusual symptom of isolated adrenocorticotropin deficiency in adults

F. Otsuka, K. Yamamoto, N. Shimada, J. Kageyama, T. Ogura, H. Makino

Journal of Endocrinological Investigation 27 ( 4 ) 404 - 405 2004.4

Ovarian bone morphogenetic proteins in female reproduction

ShunichiShimasakiR.KellyMooreGregory, F.EricksonFumioOtsuka

International Congress Series 1266 241 - 247 2004.4

Recent trends of hyperuricemia and obesity in Japanese male adolescents, 1991 through 2002

Toshio Ogura, Kazuharu Matsuura, Yosuke Matsumoto, Yukari Mimura, Masayuki Kishida, Fumio Otsuka, Kazuo Tobe

Metabolism 53 ( 4 ) 448 - 453 2004.4

Novel Action of Activin and Bone Morphogenetic Protein in Regulating Aldosterone Production by Human Adrenocortical Cells

Jiro Suzuki, Fumio Otsuka, Kenichi Inagaki, Masaya Takeda, Toshio Ogura, Hirofumi Makino

Endocrinology 145 ( 2 ) 639 - 649 2004.2

Publishing type：Research paper (scientific journal) Publisher：The Endocrine Society

Abstract

We have uncovered a functional bone morphogenetic protein (BMP) and activin system complete with ligands (BMP-6 and activin βA/βB), receptors (activin receptor-like kinase receptors 2, 3, and 4; activin type-II receptor; and BMP type-II receptor), and the binding protein follistatin in the human adrenocortical cell line H295R. Administration of activin and BMP-6 to cultures of H295R cells caused concentration-responsive increases in aldosterone production. The mRNA levels of steroidogenic acute regulatory protein or P450 steroid side-chain cleavage enzyme, the rate-limiting steps of adrenocortical steroidogenesis, were enhanced by activin and BMP-6. Activin and BMP-6 also activated the transcription of steroidogenic acute regulatory protein as well as the late-step steriodogenic enzyme CYP11B2. Activin enhanced ACTH-, forskolin-, or dibutyryl-cAMP- but not angiotensin II (Ang II)-induced aldosterone production, whereas BMP-6 specifically augmented Ang II-induced aldosterone production. Activin and ACTH but not BMP-6 increased cAMP production. Follistatin, which inhibits activin actions by binding, suppressed basal and ACTH-induced aldosterone secretion but failed to affect the Ang II-induced aldosterone level. Furthermore, MAPK signaling appeared to be involved in aldosterone production induced by Ang II and BMP-6 because an inhibitor of MAPK activation, U0126, reduced the level of aldosterone synthesis stimulated by Ang II and BMP-6 but not activin. In addition, Ang II reduced the expression levels of BMP-6 but increased that of activin βB, whereas ACTH had no effect on these levels. Collectively, the present data suggest that activin acts to regulate adrenal aldosterone synthesis predominantly by modulating the ACTH-cAMP-protein kinase A signaling cascade, whereas BMP-6 works primarily by modulating the Ang II-MAPK cascade in human adrenal cortex in an autocrine/paracrine fashion.

DOI： 10.1210/en.2003-0968

The bone morphogenetic protein system in mammalian reproduction

S Shimasaki, RK Moore, F Otsuka, GF Erickson

ENDOCRINE REVIEWS 25 ( 1 ) 72 - 101 2004.2

Language：English Publisher：ENDOCRINE SOC

Using molecular, cellular, and genetic approaches, recent studies examining the role of the bone morphogenetic protein (BMP) family of growth factors in the reproductive system have led to significant breakthroughs in our understanding of mammalian reproduction and fertility. Gene expression studies have revealed that key components of the BMP system (ligands, receptors, signaling molecules, and binding proteins) exhibit coordinated spatial and temporal expression patterns in fundamental cell types throughout the reproductive system. Availability of recombinant BMPs has enabled functional studies that have demonstrated important biological activities of BMPs in controlling cellular proliferation, differentiation, and apoptosis in reproductive tissues. The physiological importance of the BMP system for mammalian reproduction has been further highlighted by the elucidation of the aberrant reproductive phenotypes of animals with naturally occurring mutations or targeted deletions of certain BMP family genes. Collectively, these studies have established the concept that the BMP system plays a crucial role in fertility in female and male mammals. The purpose of this article is to review the evidence underpinning the importance of the BMP system in mammalian reproduction.

DOI： 10.1210/er.2003-0007

An Aberrant ACTH-producing Ectopic Pituitary Adenoma in the Sphenoid Sinus

Jiro SUZUKI, Fumio OTSUKA, Toshio OGURA, Masayuki KISHIDA, Masaya TAKEDA, Takashi TAMIYA, Tatsuya NISHIOKA, Yasushi TANAKA, Kozo HASHIMOTO, Hirofumi MAKINO

Endocrine Journal 51 ( 1 ) 97 - 103 2004

Long-term Effects of Octreotide on Pituitary Gigantism: Its Analgesic Action on Cluster Headache

Fumio OTSUKA, Satoshi MIZOBUCHI, Toshio OGURA, Kenji SATO, Masataka YOKOYAMA, Hirofumi MAKINO

Endocrine Journal 51 ( 5 ) 449 - 452 2004

Effect of Etidronate on Intraosseous Meningioma

Kenichi INAGAKI, Fumio OTSUKA, Toshihiro MATSUI, Toshio OGURA, Hirofumi MAKINO

Endocrine Journal 51 ( 3 ) 389 - 390 2004

Skull Paget's Disease Developing into Chiari Malformation

Fumio OTSUKA, Kenichi INAGAKI, Jiro SUZUKI, Toshio OGURA, Hirofumi MAKINO

Endocrine Journal 51 ( 3 ) 391 - 392 2004

Reversible Pituitary Dysfunction in a Patient with Cushing's Syndrome Discovered as Adrenal Incidentaloma

Kenichi INAGAKI, Fumio OTSUKA, Tomoko MIYOSHI, Naomi WATANABE, Jiro SUZUKI, Toshio OGURA, Hirofumi MAKINO

Endocrine Journal 51 ( 2 ) 201 - 206 2004

Hypothyroidism associated with anti-human chorionic gonadotropin antibodies secondarily produced by gonadotropin therapy in a case of idiopathic hypothalamic hypogonadism

T. Ogura, Y. Mimura, Fumio Otsuka, M. Kishida, K. Yokota, J. Suzuki, A. Nagai, S. Hirakawa, H. Makino, K. Tobe

Journal of Endocrinological Investigation 26 ( 11 ) 1128 - 1135 2003.11

Involvement of activin/BMP system in development of human pituitary gonadotropinomas and nonfunctioning adenomas

Masaya Takeda, Fumio Otsuka, Jiro Suzuki, Masayuki Kishida, Toshio Ogura, Takashi Tamiya, Hirofumi Makino

Biochemical and Biophysical Research Communications 306 ( 4 ) 812 - 818 2003.7

Effect of Intracellular Interactions on the Processing and Secretion of Bone Morphogenetic Protein-15 (BMP-15) and Growth and Differentiation Factor-9

Wu Xiang Liao, R. Kelly Moore, Fumio Otsuka, Shunichi Shimasaki

Journal of Biological Chemistry 278 ( 6 ) 3713 - 3719 2003.2

Molecular Basis of Bone Morphogenetic Protein-15 Signaling in Granulosa Cells

R. Kelly Moore, Fumio Otsuka, Shunichi Shimasaki

Journal of Biological Chemistry 278 ( 1 ) 304 - 310 2003.1

A Lethal Complication, Acute Necrotizing Pancreatitis, of Turner's Syndrome with Primary Hyperparathyroidism

Masayuki Kishida, Fumio Otsuka, Yukari Mimura, Toshio Ogura, Hirofumi Makino

Endocrine Journal 50 ( 6 ) 835 - 836 2003

The role of bone morphogenetic proteins in ovarian function

S Shimasaki, RK Moore, GF Erickson, F Otsuka

REPRODUCTION 61,323-337 323 - 337 2003

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

Bone morphogenetic proteins (BMPs) represent the largest subclass of growth factors in the transforming growth factor beta (TGF-beta) superfamily. BMPs have proven to be multifunctional regulators of a wide variety of biological processes in numerous types of cell and tissue. The role of inhibins, activins and TGF-betas (which also belong to the TGF-beta superfamily) in reproduction has been studied extensively over the last 15 years. However, there were no reports on the role of BMPs in the mammalian ovary until 1999 when we reported an intrinsic ovarian BMP system replete with BMP ligands, receptors and novel biological functions. Since this report it has become clear that the BMP system plays an important role in the regulation of ovarian function, evidenced by the ability of BMPs to control granulosa cell proliferation and cytodifferentiation, as well as oocyte development. The physiological relevance of the BMP system has recently been highlighted by the discovery that genetic mutations in the BMP-15 ligand or the BMPtype IB receptor lead to critical aberrations in folliculogenesis and ovulation. This review provides a current overview of the rapidly emerging field of the BMP system in mammalian ovarian function.

Relationship between Adrenomedullin and Vasopressin-Aquaporin System under General Anesthesia

Toshio Ogura, Kiyoshi Morita, Mamoru Takeuchi, Fumio Otsuka, Tatsuo Iwasaki, Katsunori Oe, Kazuharu Matsuura, Kazuo Tobe, Yukari Mimura, Masayuki Kishida, Hirofumi Makino, Masahisa Hirakawa

Hormone Research in Paediatrics 59 ( 1 ) 30 - 34 2003

Publishing type：Research paper (scientific journal) Publisher：S. Karger AG

<i>Aim:</i> The roles of adrenomedullin (AM) in body fluid balance under general anesthesia were investigated. <i>Methods:</i> Time course changes in plasma osmolality, AM, arginine vasopressin (AVP), and urinary aquaporin 2 (AQP2) in 17 patients undergoing abdominal surgery under general anesthesia were examined. <i>Results:</i> Increases in plasma AM levels were observed in parallel with increases in the levels of urinary AQP2/creatinine (Cr) before induction and 90 and 180 min after initiation of anesthesia. Significant correlations between plasma AM and urinary AQP2/Cr (r = 0.62, p < 0.0001) as well as urinary AVP/Cr and AQP2/Cr (r = 0.60, p < 0.0001) were uncovered. Multivariate stepwise analysis identified plasma AM as the critical independent factor affecting urinary AQP2/Cr level. <i>Conclusion:</i> A novel correlation of AM and AQP2 which overlays an AVP-AQP2 system may play a key role in fluid homeostasis during general anesthesia.

DOI： 10.1159/000067933

Role of Bradykinin in Renoprotective Effects by Angiotensin II Type 1 Receptor Antagonist in Salt-Sensitive Hypertension.

Kazuaki YOKOTA, Masayuki KISHIDA, Toshio OGURA, Jiro SUZUKI, Fumio OTSUKA, Yukari MIMURA, Masaya TAKEDA, Yoshio NAKAMURA, Hirofumi MAKINO

Hypertension Research 26 ( 3 ) 265 - 272 2003

A Novel Function of Bone Morphogenetic Protein-15 in the Pituitary: Selective Synthesis and Secretion of FSH by Gonadotropes

Fumio Otsuka, Shunichi Shimasaki

Endocrinology 143 ( 12 ) 4938 - 4941 2002.12

A negative feedback system between oocyte bone morphogenetic protein 15 and granulosa cell kit ligand: Its role in regulating granulosa cell mitosis

Fumio Otsuka, Shunichi Shimasaki

Proceedings of the National Academy of Sciences 99 ( 12 ) 8060 - 8065 2002.6

Publishing type：Research paper (scientific journal) Publisher：Proceedings of the National Academy of Sciences

Although the existence of a regulatory paracrine feedback system between oocytes and follicular somatic cells has been postulated for some time, there has not yet been any definitive evidence that such a communication system exists. Herein we present a previously undescribed oocyte-granulosa cell (GC) feedback communication system involving an oocyte-derived factor, bone morphogenetic protein-15 (BMP-15) and a GC-derived factor, kit ligand (KL), both of which have been shown to be crucial regulators of female reproduction. We used a coculture system of rat oocytes and GCs and found that BMP-15 stimulates KL expression in GCs, whereas KL inhibits BMP-15 expression in oocytes, thus forming a negative feedback loop. Moreover, KL, like BMP-15, exhibited mitotic activity on GCs in the presence of oocytes. Because c-kit (KL receptor) is expressed in oocytes but not GCs, the oocytes must be involved in mediating the KL-induced GC mitosis. Furthermore, the blockage of c-kit signaling in oocytes by using a c-kit neutralizing antibody markedly suppressed BMP-15-induced GC mitosis, suggesting that the oocyte must play a role in the GC responses to BMP-15. In contrast, the c-kit antibody had no effect on the mitotic activities of two other known GC mitogens, activin-A and BMP-7. Altogether, this study presents direct evidence of a negative feedback system governed by oocyte-derived BMP-15 and GC-derived KL, and demonstrates that the mitotic activities of BMP-15 and KL for GCs depend on this oocyte–GC communication system. We hypothesize that the negative feedback system most likely plays a pivotal role in early folliculogenesis.

DOI： 10.1073/pnas.122066899

Role of ERK1/2 in the Differential Synthesis of Progesterone and Estradiol by Granulosa Cells

R.Kelly Moore, Fumio Otsuka, Shunichi Shimasaki

Biochemical and Biophysical Research Communications 289 ( 4 ) 796 - 800 2001.12

Follistatin Inhibits the Function of the Oocyte-Derived Factor BMP-15

Fumio Otsuka, R.Kelly Moore, Shun-ichiro Iemura, Naoto Ueno, Shunichi Shimasaki

Biochemical and Biophysical Research Communications 289 ( 5 ) 961 - 966 2001.12

Effect of Bone Morphogenetic Protein-7 on Folliculogenesis and Ovulation in the Rat1

Woo-Sik Lee, Fumio Otsuka, R. Kelly Moore, Shunichi Shimasaki

Biology of Reproduction 65 ( 4 ) 994 - 999 2001.10

Biological Function and Cellular Mechanism of Bone Morphogenetic Protein-6 in the Ovary

Fumio Otsuka, R. Kelly Moore, Shunichi Shimasaki

Journal of Biological Chemistry 276 ( 35 ) 32889 - 32895 2001.8

Chronic treatment with amlodipine modulates adrenocortical angiotensin II receptors in spontaneously hypertensive rats

Masayuki Kishida, Fumio Otsuka, Toshio Ogura, Hideo Kataoka, Yoshio Nakamura, Takayoshi Yamauchi, Masami Takahashi, Kazuaki Yokota, Yukari Mimura, Hirofumi Makino

Life Sciences 69 ( 1 ) 113 - 122 2001.5

Bone Morphogenetic Protein-15 Inhibits Follicle-stimulating Hormone (FSH) Action by Suppressing FSH Receptor Expression

Fumio Otsuka, Shin Yamamoto, Gregory F. Erickson, Shunichi Shimasaki

Journal of Biological Chemistry 276 ( 14 ) 11387 - 11392 2001.4

The role of nitric oxide and the renin-angiotensin system in salt-restricted Dahl rats

Hideo Kataoka, Fumio Otsuka, Toshio Ogura, Takayoshi Yamauchi, Masayuki Kishida, Masami Takahashi, Yukari Mimura, Hirofumi Makino

American Journal of Hypertension 14 ( 3 ) 276 - 285 2001.3

Coexistence of Graves' Disease and Struma Ovarii: Case Report and Literature Review.

YUKARI MIMURA, MASAYUKI KISHIDA, HISASHI MASUYAMA, NAOKO SUWAKI, JUNICHI KODAMA, FUMIO OTSUKA, HIDEO KATAOKA, TAKAYOSHI YAMAUCHI, TOSHIO OGURA, TAKAFUMI KUDO, HIROFUMI MAKINO

Endocrine Journal 48 ( 2 ) 255 - 260 2001

Japanese Family with Glucocorticoid-Remediable Aldosteronism Diagnosed by Long-Polymerase Chain Reaction.

Kazuaki YOKOTA, Toshio OGURA, Masayuki KISHIDA, Jiro SUZUKI, Fumio OTSUKA, Yukari MIMURA, Tetsuya OISHI, Makizo HIRATA, Kazuo TOBE, Hirofumi MAKINO

Hypertension Research 24 ( 5 ) 589 - 594 2001

Bone Morphogenetic Protein-15

Fumio Otsuka, Zuxu Yao, Taek-hoo Lee, Shin Yamamoto, Gregory F. Erickson, Shunichi Shimasaki

Journal of Biological Chemistry 275 ( 50 ) 39523 - 39528 2000.12

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

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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.

Effects of angiotensin-converting enzyme inhibitor and α1-adrenoceptor antagonist on hypertension induced in rats by long-term inhibition of nitric oxide production

M. Takahashi, F. Otsuka, T. Ogura, T. Yamauchi, H. Kataoka, M. Kishida, Y. Mimura, H. Makino

Clinical and Experimental Nephrology volume 126 - 132 2000.6

Testosterone modulates serum leptin concentrations in a male patient with hypothalamic hypogonadism

T. Ogura, K. Tobe, Y. Mimura, F. Otsuka, T. Yamauchi, A. Imai, C. Tsukamoto, Y. Iwasaki, K. Matsuura

Journal of Endocrinological Investigation 23 ( 4 ) 246 - 250 2000.4

Differential glomerular response to continuous infusion of vasopressin in spontaneously hypertensive rats and Wistar–Kyoto rats

Masayuki Kishida, Fumio Otsuka, Takayoshi Yamauchi, Toshio Ogura, Masami Takahashi, Hideo Kataoka, Yukari Mimura, Hirofumi Makino

Regulatory Peptides 87 ( 1-3 ) 25 - 32 2000.2

Serum leptin correlates with serum uric acid but not serum testosterone in non-obese male adolescents

T Ogura 1, K Matsuura, F Otsuka, A Imai, C Tsukamoto, Y Mimura, Y Iwasaki, K Tobe

Res. Commun. Mol. Pathol. Pharmacol. 107 ( 1-2 ) 55-64 - 64 2000.1

Language：English Publishing type：Research paper (scientific journal) Publisher：P J D PUBLICATIONS LTD

To identify the serum factors that affect circulating leptin levels, we measured the serum concentrations of leptin, testosterone (T), estradiol (E), serum alanine aminotransferase, total cholesterol and uric acid (UA) in healthy male adolescents (age, 18.3 +/- 0.1 years, n=96). We also measured body mass index (BMI), percent body fat and thickness of skin fold to assess the effect of body constitution on serum leptin level. Since serum concentration of leptin significantly correlated with BMI (r=0.820, p<0.001), we analyzed the relation-ship between leptin/BMI ratio (L/BMI) and serum parameters. Analysis of data of subjects with normal serum T level showed a significant inverse correlation between L/BMI and serum T levels (n=96, r=-0.294, p<0.005), but no such correlation was present among non-obese subjects (n=70) with BMI of +/- 20% of normal (22 kg/m(2)). There was no correlation between L/BMI and serum E level. Serum UA level significantly correlated with L/BMI in both the test group (n=96, r=0.520, p<0.001) and non-obese subjects (r=0.369, p<0.005). Stepwise multiple regression analysis showed that UA independently and significantly influenced serum leptin levels in both the test and control groups. Our results demonstrate that T weakly influences serum leptin concentration, and that UA concentrations strongly influences serum leptin in healthy male adolescents independent of their obesity level.

Pseudomalabsorption of Levothyroxine. A Case Report.

DAISUKE OGAWA, FUMIO OTSUKA, YUKARI MIMURA, AKIKO UENO, HIROO HASHIMOTO, MASAYUKI KISHIDA, TOSHIO OGURA, HIROFUMI MAKINO

Endocrine Journal 47 ( 1 ) 45 - 50 2000

Hyperthyroidism in a Patient with TSH-Producing Pituitary Adenoma Coexisting with Thyroid Papillary Adenocarcinoma.

MASAYUKI KISHIDA, FUMIO OTSUKA, HIDEO KATAOKA, KAZUAKI YOKOTA, TETSUYA OISHI, TAKAYOSHI YAMAUCHI, HIROYOSHI DOIHARA, TAKASHI TAMIYA, YUKARI MIMURA, TOSHIO OGURA, HIROFUMI MAKINO

Endocrine Journal 47 ( 6 ) 731 - 738 2000

Significant Gene Expression of Insulin-Like Growth Factor II and Proliferating Cell Nuclear Antigen in a Rapidly Growing Recurrent Pituitary ACTH-Secreting Adenoma

Kozo Hashimoto, Isao Nagano, Koichi Asaba, Mari Inoue, Tatsuya Nishioka, Toshihiro Takao, Takahito Nakajo, Takahisa Mori, Masahiro Kurisaka, Fumio Otsuka

Hormone Research in Paediatrics 54 ( 4 ) 198 - 202 2000

Publishing type：Research paper (scientific journal) Publisher：S. Karger AG

<i>Background:</i> We quantified the expression of various growth-related factors in an adrenocorticotropic hormone (ACTH)-secreting adenoma that had recurred very rapidly as invasive macroadenoma. <i>Methods/Results:</i> A 43-year-old woman underwent successful transsphenoidal surgery for Cushing’s disease. Seven years later, she was admitted to our ward for further endocrine examinations. In spite of a very high plasma ACTH level, the serum cortisol level was normal. Discrepancies between ACTH and cortisol levels were detected on the basis of diurnal rhythms, dexamethasone suppression tests, and corticotropin-releasing hormone test. The patient showed no clinical features of Cushing’s disease. Magnetic resonance imaging of the pituitary showed an almost empty sella, and no microadenoma was found. These results, along with those of Sephadex column gel filtration and high-performance liquid chromatography of plasma-immunoreactive ACTH, suggested that the patient’s residual corticotrophs secreted biologically inactive ACTH. Two years later, the patient suddenly developed diplopia and right abducens nerve palsy. She was slightly moonfaced and centrally obese. Her plasma ACTH and serum and urinary free cortisol levels were elevated, although discrepancies between ACTH and cortisol still existed. Magnetic resonance imaging revealed a large pituitary mass with suprasellar and cavernous sinus extensions. The tumor was excised, and the proopiomelanocortin gene and the expression of growth-related factors were analyzed. No mutations were found in the ACTH-coding region of the proopiomelanocortin gene. A significant expression of insulin-like growth factor II and proliferating cell nuclear antigen mRNAs was demonstrated. A high MIB-1 antibody labeling index was also detected in the adenoma tissue, suggesting high Ki-67 expression. <i>Conclusion:</i> These growth- and proliferation-related factors might be involved in the rapid growth and aggressiveness of this patient’s pituitary adenoma.

DOI： 10.1159/000053259

Chronic Treatment with Angiotensin II Type 1 Receptor Antagonist Suppresses Glomerular Activator Protein–1 Activity in Salt–Sensitive Hypertensive Rats

Fumio Otsuka, Toshio Ogura, Takayoshi Yamauchi, Minoru Sato, Hideo Kataoka, Jingo Kageyama, Hirofumi Makino

Kidney and Blood Pressure Research 23 ( 1 ) 35 - 41 2000

Publishing type：Research paper (scientific journal) Publisher：S. Karger AG

We examined the effects of angiotensin–converting enzyme inhibitor (ACEI) and angiotensin II type 1 receptor antagonist (AT1a) on the action of protooncogene c–fos in salt–sensitive hypertensive rats. Seven–week old Dahl salt–sensitive rats fed a high (8%)–salt diet were treated with ACEI, cilazapril (10 mg/kg) or AT1a, TCV–116 (1mg/ kg) every day for 6 weeks. The control animals were fed a low (0.3%)–salt diet. Systolic blood pressure gradually increased in high–salt–loaded rats and was higher than low–salt–treated rats throughout the study. However, both medications had no significant antihypertensive effect. After 6 weeks of therapy, glomerular mRNA and nuclear protein were extracted from the resected kidneys. Competitive reverse transcription–polymerase chain reaction showed a high level of glomerular c–fos mRNA in high–salt–loaded rats and that ACEI or AT1a treatment did not significantly change its level. Electrophoretic mobility shift assay demonstrated that treatment with AT1a significantly decreased the activator protein–1 (AP–1) binding activity in the glomerular nuclear extract compared to ACEI. Our findings suggest that, compared with ACEI treatment, long–term treatment with AT1a may contribute to attenuation of the glomerular injury in salt–sensitive hypertension by inhibiting AP–1 transcription activity independent of its antihypertensive effect.

DOI： 10.1159/000025952

Sevoflurane anaesthesia causes a transient decrease in aquaporin-2 and impairment of urine concentration

K Morita, F Otsuka, T Ogura, M Takeuchi, S Mizobuchi, T Yamauchi, H Makino, M Hirakawa

British Journal of Anaesthesia 83 ( 5 ) 734 - 739 1999.11

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

Sevoflurane anaesthesia is occasionally associated with polyuria, but the exact mechanism of this phenomenon has not been clarified. Aquaporin-2 (AQP2) is an arginine vasopressin (AVP)-regulated water channel protein localized to the apical region of renal collecting duct cells and is involved in the regulation of water permeability. To elucidate the effect of sevoflurane anaesthesia on urine concentration and AQP2, we have compared serum and urinary concentrations of AVP, AQP2 and osmolar changes during sevoflurane and propofol anaesthesia. General anaesthesia was induced with sevoflurane or propofol in 30 patients for a variety of major surgical procedures. Blood and urine samples were obtained from patients at baseline, and 90 and 180 min after induction of anaesthesia. AVP and AQP2 concentrations were measured by radioimmunoassay. In both groups, plasma and urinary concentrations of AVP increased similarly during anaesthesia although plasma osmolality remained unchanged. Although urinary AQP2 excretion in the propofol group increased together with changes in plasma and urinary AVP, urinary AQP2 was significantly lower at 90 min in the sevoflurane group. Urine osmolality in the sevoflurane group also showed a transient but significant decrease in parallel with suppression of AQP2. Our data suggest that sevoflurane anaesthesia transiently produced an impaired AQP2 response to an increase in intrinsic AVP.

DOI： 10.1093/bja/83.5.734

Quantitative analysis of growth-related factors in human pituitary adenomas

Fumio Otsuka, Takashi Tamiya, Takayoshi Yamauchi, Toshio Ogura, Takashi Ohmoto, Hirofumi Makino

Regulatory Peptides 83 ( 1 ) 31 - 38 1999.8

Long-term administration of adrenocorticotropin modulates the expression of IGF-I and TGF-β1mRNAs in the rat adrenal cortex

Fumio Otsuka, Toshio Ogura, Takayoshi Yamauchi, Hideo Kataoka, Masayuki Kishida, Nobuyuki Miyatake, Yukari Mimura, Jingo Kageyama, Hirofumi Makino

Growth Hormone & IGF Research 9 ( 1 ) 41 - 51 1999.2

The Effects of Intrinsic Vasopressin on Urinary Aquaporin-2 Excretion and Urine Osmolality During Surgery Under General Anesthesia

Fumio Otsuka, Kiyoshi Morita, Mamoru Takeuchi, Takayoshi Yamauchi, Toshio Ogura, Kyouichi Sekine, Masakazu Miura, Masahisa Hirakawa, Hirofumi Makino

Anesthesia & Analgesia 88 ( 1 ) 181 - 187 1999.1

An Elderly Patient with Transient Diabetes Insipidus Associated with Lymphocytic Infundibulo-Neurohypophysitis.

MASAMI TAKAHASHI, FUMIO OTSUKA, TOMOKO MIYOSHI, TOSHIO OGURA, HIROFUMI MAKINO

Endocrine Journal 46 ( 5 ) 741 - 746 1999

A case of idiopathic deep vein thrombosis improved with glucocorticoid therapy

F Otsuka, T Amano, H Uchida, T Ogura, H Makino

Haematologia (Budap) 29 ( 4 ) 305 - 312 1999

Giant Insulinoma in a Patient with Multiple Endocrine Neoplasia-Type I. A Case report.

HIDEO KATAOKA, FUMIO OTSUKA, TAKAYOSHI YAMAUCHI, MASAYUKI KISHIDA, MASAMI TAKAHASHI, TAKASHI TAMIYA, YUKARI MIMURA, TOSHIO OGURA, HIROFUMI MAKINO

Endocrine Journal 46 ( 3 ) 429 - 435 1999

Treatment with a Ca<sup>2+</sup> Channel Blocker, Barnidipine, Reduces Platelet-Derived Growth Factor B-Chain mRNA in Glomeruli of Spontaneously Hypertensive Rats

Masami Hashimoto, Takayoshi Yamauchi, Toshio Ogura, Tetsuya Oishi, Yukari Mimura, Fumio Otsuka, Naoki Kashihara, Hirofumi Makino

American Journal of Nephrology 19 ( 5 ) 615 - 621 1999

Publishing type：Research paper (scientific journal) Publisher：S. Karger AG

We investigated the effect of barnidipine hydrochloride, a Ca<sup>2+</sup> channel blocker, on the glomerular level of mRNA expression of platelet-derived growth factor (PDGF) B-chain and transforming growth factor (TGF)-β<sub>1</sub> in spontaneously hypertensive rats (SHR) with reverse transcription and polymerase chain reaction. Thirteen-week-old SHR were provided with food containing barnidipine (0.6 mg/g of food, average dose during treatment: 53 mg/kg of body mass/day) for 3 weeks. A stable reduction in systolic blood pressure relative to that of age-matched control SHR was recorded after week 1 of therapy. Although no renal histological changes were observed after 3 weeks of treatment with barnidipine, the level of expression of PDGF B-chain mRNA in glomeruli was significantly reduced relative to that in control SHR. The glomerular level of TGF-β<sub>1</sub> mRNA expression was not affected by the treatment. Treatment with barnidipine significantly reduced the excretion of urinary protein. Thus, the stable reduction in systemic blood pressure by barnidipine is associated with a reduction in PDGF B-chain mRNA expression in the glomerulus and reduction in urinary protein excretion in SHR.

DOI： 10.1159/000013511

Congenital Adrenal Hyperplasia With Normokalemic Periodic Paralysis

Fumio Otsuka, Toshio Ogura, Takayoshi Yamauchi, Hirofumi Makino

Archives of Neurology 55 ( 11 ) 1487 - 1487 1998.11

Renal c-fos expression induced by angiotensin II is enhanced in spontaneously hypertensive rats

Fumio Otsuka, Takayoshi Yamauchi, Toshio Ogura, Masami Takahashi, Jingo Kageyama, Hirofumi Makino

Life Sciences 63 ( 23 ) 2089 - 2095 1998.10

Hormonal characteristics of primary aldosteronism due to unilateral adrenal hyperplasia

Fumio Otsuka, F. Otsuka-Misunaga, S. Koyama, H. Yamanari, T. Ogura, T. Ohe, H. Makino

Journal of Endocrinological Investigation 21 ( 8 ) 531 - 536 1998.9

Cluster headache dependent upon octreotide injection

F Otsuka, J Kageyama, T Ogura, H Makino

Headache: The Journal of Head and Face Pain 38 ( 8 ) 629 - 631 1998.9

Effects of chronic inhibition of ACE and AT₁receptors on glomerular injury in Dahl salt-sensitive rats

Fumio Otsuka, Takayoshi Yamauchi, Hideo Kataoka, Yukari Mimura, Toshio Ogura, Hirofumi Makino

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 274 ( 6 ) R1797 - R1806 1998.6

Language：English Publishing type：Research paper (scientific journal) Publisher：American Physiological Society

To elucidate the contribution of the renin-angiontensin system (RAS) to glomerular injury in salt-sensitive hypertension, we investigated the chronic effects of the angiotensin I-converting enzyme inhibitor cilazapril and the angiotensin II type 1-receptor antagonist (AT_1a) TCV-116 in Dahl-Iwai rats. Dahl salt-sensitive (S) rats receiving 8% salt diet for 6 wk were simultaneously treated with cilazapril ( n = 6), TCV-116 ( n = 6), or saline ( n = 14). The 8% salt diet markedly increased systolic blood pressure (SBP), urinary protein, and N-acetyl-β-glucosaminidase (NAG) excretion compared with 0.3% salt-treated S ( n = 6) or salt-resistant ( n = 6) rats. Although neither cilazapril nor TCV-116 reduced the elevated SBP, TCV-116 significantly lowered urinary protein and NAG excretion. Histologically, 8% salt treatment in S rats induced progressive sclerotic and proliferative glomerular changes, which were ameliorated by both drugs. TCV-116 increased the glomerular diameter. Immunofluorescence demonstrated the increased level of type III collagen in the mesangium of 8% salt-treated S rats, which was completely reversed by TCV-116. Competitive RT-PCR of mRNA extracted from the glomeruli revealed that 8% salt treatment significantly increased the levels of proliferating cell nuclear antigen (PCNA) and platelet-derived growth factor B-chain and that TCV-116 significantly reduced the levels of PCNA and transforming growth factor-β1 (TGF-β1). Thus, although the chronic RAS-inhibition in salt-sensitive hypertension exerted a histologically renoprotective effect by both ways without lowering blood pressure, the RAS inhibition due to AT_1ahad more beneficial advantages of reducing proteinuria and attenuating the levels of glomerular TGF-β1 and extracellular matrix.

DOI： 10.1152/ajpregu.1998.274.6.r1797

Effect of continuous infusion of vasopressin on glomerular growth response in spontaneously hypertensive rats

Kazushi Harada, Toshio Ogura, Takayoshi Yamauchi, Fumio Otsuka, Yukari Mimura, Masami Hashimoto, Tetsuya Oishi, Hirofumi Makino

Regulatory Peptides 74 ( 1 ) 11 - 18 1998.4

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

Vasopressin (VP) is thought to play an important role in the presser and proliferative responses of renal glomeruli. We have utilized the spontaneously hypertensive rat (SHR) model to determine if glomerular proliferation is induced by chronic infusion of exogenous VP. SHR were continuously infused with 0.1 ng/kg/min VP (H-VP group), 1.0 ng/kg/min (H-VP group), or vehicle alone (control group) for fifteen days using osmotic minipumps, and the histological alterations and level of expression of platelet-derived growth factor B-chain (PDGF-B) and transforming growth factor (TGF)-beta 1 mRNA were determined. We observed no significant differences in systolic blood pressure, heart rate, serum electrolytes, protein and creatinine among the three groups of rats, but urine volume was found to be significantly decreased, and urine osmolality significantly increased, in the H-VP group. Kidney weight was significantly higher in the H-VP and L-VP groups than in the control group, and glomerular diameter was higher in the II-VP group. When we measured mesangial injury score and cellularity in the glomeruli of these animals, we observed VP dose-dependent proliferative changes. In the immunofluorescence study, although we did not find an obvious difference in depositions of collagen types III, IV and VI, alpha-smooth muscle actin and PDGF-B among the groups, the collagen type I and TGF-beta 1 increased in several glomeruli in the H-VP group. Reverse transcription polymerase chain reaction (RT-PCR) revealed no significant differences in the glomerular levels of PDGF-B mRNA among the three groups of rats, but the level of expression of TGF-beta 1 mRNA was significantly higher in the L-VP and H-VP groups than in the control group. These findings suggest that VP may contribute to glomerular proliferation, and that VP may exert its effects in part through the induction of TGF-beta 1 expression. These results also raise the possibility that blockade of VP receptors may be useful in the treatment of some forms of glomerular disease. (C) 1998 Published by Elsevier Science B.V.

DOI： 10.1016/s0167-0115(98)00009-3

Sheehan's syndrome of more than 30 years' duration: an endocrine and MRI study of 6 cases

Fumio Otsuka, Jingo Kageyama, Toshio ogura, Teruhiko Hattori, Hirofumi makino

Endocr. J. 45 451-458 1998.1

Renal AT1 receptor: autoradiographic localization and quantification in rat

N Asano, T Ogura, Y Mimura, M Kishida, H Kataoka, F Otsuka, T Yamauchi, H Makino

Res. Commun. Mol. Pathol. Pharmacol. 100 ( 2 ) 161-170 - 170 1998.1

Language：English Publishing type：Research paper (scientific journal) Publisher：P J D PUBLICATIONS LTD

To elucidate the precise localization of angiotensin II (Ang II) type 1 (AT(1)) receptor in the kidney, we utilized in vitro macro- and micro-autoradiography (ARG) of [H-3]-Ang II bindings to the Wistar rat kidney in the presence of L158,809, a specific non-peptide AT(1) receptor antagonist. Besides, we estimated the density of renal AT, receptors using the quantification of macro-ARG. The density of [H-3]-Ang II binding to renal tissue was concentration-dependent in both renal cortex and medulla Although the addition with 500 nM arginine vasopressin and 500 nM atrial natriuretic peptide had no effect on [H-3]-Ang II, the total binding of [H-3] Ang II completely displaced by the addition with 500 nM unlabeled Ang II or L-158,809. Macro-ARG revealed that the amount of both Ang II and AT, receptors in the renal medulla gready exceeded those in the renal cortex In the medulla, the density of these receptors was not localized on the outer medulla but was confirmed mainly to the inner medulla, especially to the inner zone and longitudinal bands. Since the density and localization of AT(1) receptors was consistent with that of total Ang II receptors, it appears that AT(1) receptors comprise most of the Ang II receptors in the kidney. Micro-ARG revealed that Ang II receptors were mainly located in the glomerulus and proximal tubules of the renal cortex, as well as on the circumferences of vessels and the vasa recta of the renal medulla. The present study established a method for ARO of AT(1) receptors in the kidney as well as a method for quantifying the macro-ARG.

Renal AT1 receptor: computerized quantification in spontaneously hypertensive rats and DOCA-salt rats

N Asano, T Ogura, Y Mimura, F Otsuka, M Kishida, M Hashimoto, T Yamauchi, H Makino

Res. Commun. Mol. Pathol. Pharmacol. 100 ( 2 ) 171-180 - 180 1998.1

Language：English Publishing type：Research paper (scientific journal) Publisher：P J D PUBLICATIONS LTD

To assess the involvement of angiotensin II (Ang II) in the regulation of blood pressure, we investigated the alterations of renal Ang II type 1 (AT(1)) receptors in two different models of hypertension; i.e., in spontaneously hypertensive rats (SHR) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats by using the method for quantification of in vitro macroautoradiography (ARG). In the SHR model, although the number of cortical AT(1) receptors equaled that of Wistar Kyoto (WKY) rats at 4 and 12 weeks of age, the number of medullary AT(1) receptors in the 4-week-old SHR animals was significantly lower than that in age-matched WKY rats, and increased by 12 weeks of age. The renal AT(1) receptor number in DOCA-salt hypertensive rats was significantly higher than that in control rats. The amount of these receptors also increased with age in both DOCA-salt hypertensive rats and control rats. These findings indicate that the development of medullary AT(1) receptors in early stages of hypertension in the SHR model differs from that in WKY rats or DOCA-salt hypertensive rats. This suggests that renal AT(1) receptors may contribute to the hypertension seen in the SHR group. The renal AT(1) receptors appear to be up-regulated in early stages of DOCA-salt-induced hypertension as well.

Reversible Hypothyroidism in Empty Sella Syndrome: A Case Report.

FUMIO OTSUKA, TOSHLO OGURA, NOBUHIKO HAYAKAWA, SEISHI HARADA, JINGO KAGEYAMA, HIROFUMI MAKINO

Endocrine Journal 45 ( 3 ) 385 - 391 1998

Cushing's Syndrome due to Unilateral Adrenocortical Hyperplasia.

Fumio OTSUKA, Toshio OGURA, Kazushi NAKAO, Nobuhiko HAYAKAWA, Yukari MIMURA, Takayoshi YAMAUCHI, Hirofumi MAKINO

Internal Medicine 37 ( 4 ) 385 - 390 1998

Hypocalcemia due to Spontaneous Infarction of Parathyroid Adenoma and Osteomalacia in a Patient with Primary Hyperparathyroidism.

FUMIO OTSUKA, TOSHIO OGURA, TORU SATO, NOBUHIKO HAYAKAWA, YUKARI MIMURA, MASAYUKI KISHIDA, TAKAYOSHI YAMAUCHI, HIROFUMI MAKINO

Endocrine Journal 45 ( 5 ) 617 - 623 1998

Pituitary Apoplexy Induced by a Combined Anterior Pituitary Test: Case Report and Literature Review.

FUMIO OTSUKA, JINGO KAGEYAMA, TOSHLO OGURA, HIROFUMI MAKINO

Endocrine Journal 45 ( 3 ) 393 - 398 1998

Sheehan's Syndrome of More Than 30 Years' Duration: An Endocrine and MRI Study of 6 Cases.

FUMIO OTSUKA, JINGO KAGEYAMA, TOSHIO OGURA, TERUHIKO HATTORI, HIROFUMI MAKINO

Endocrine Journal 45 ( 4 ) 451 - 458 1998

Effects of OPC-21268, a vasopressin V1-receptor antagonist, on expression of growth factors from glomeruli in spontaneously hypertensive rats

Fumio Otsuka, Toshio Ogura, Takayoshi Yamauchi, Tetsuya Oishi, Masami Hashimoto, Yukari Mimura, Hirofumi Makino

Regulatory Peptides 72 ( 2-3 ) 87 - 95 1997.10

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

To assess the chronic in vivo effects of OPC-21268, a vasopressin-Vl receptor antagonist, on renal injury, we investigated the mRNA expressions of platelet-derived growth factor (PDGF) B-chain, transforming growth factor (TGF)-beta 1 and proliferating cell nuclear antigen (PCNA) in the glomeruli of spontaneously hypertensive rats (SHR) treated with OPC-21268 for 3 weeks. SHR aged 10 weeks were given 2% NaCl in drinking water for 3 weeks. The OPC group was fed a 0.5% OPC-21268-containing diet for 3 weeks and the control group was given a normal diet. There were no significant changes in the time course of systolic blood pressure, heart rate, urine volume, or urinary sodium, protein and N-acetyl-beta-glucosaminidase (NAG) excretion between the two groups. Serum electrolytes, protein and creatinine levels also did not differ between the groups. The mRNA expressions of PDGF B-chain, TGF-beta 1 and PCNA in the glomerulus were examined using reverse transcriptase-polymerase chain reaction (RT-PCR) methods. The mRNA expressions of PDGF B-chain and PCNA among these were significantly suppressed in the OPC group. No significant differences in renal histology including the organ weights were found between the two groups; however, the glomerular size tended to be enlarged in the OPC group. These findings suggest that chronic V1-receptor blockade directly inhibits the glomerular proliferative injury of salt-loaded SHR at the established hypertension stage. (C) 1997 Elsevier Science Ireland Ltd.

DOI： 10.1016/s0167-0115(97)01041-0

Postanesthetic Polyuria Attributable to Central Diabetes Insipidus

Fumio Otsuka, Satoshi Mizobuchi, Kiyoshi Morita, Hideo Matsumoto, Toshio Ogura, Masahisa Hirakawa, Hirofumi Makino

Anesthesia & Analgesia 85 ( 4 ) 940 - 943 1997.10

In vitro Macro-and Microautoradiographic Localization of V1 and V2 Receptors in the Rat Kidney Using OPC-21268 and OPC-31260 Reviewed

Yukari Mimura, Toshio Ogura, Nobuhiko Hayakawa, Fumio Otsuka, Masami Hashimoto, Takayoshi Yamauchi, Hirofumi Makino, Norio Ogawa

Nephron 76 ( 3 ) 331 - 336 1997

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

To elucidate the precise localization of vasopressin(VP) Vj and V2 receptors in the kidney, we utilized in vitro macroautoradiography (macro-ARG) and microautoradiography (micro-ARG) of these receptors in Wistar rat kidneys.This was done by using OPC-21268 and OPC-31260, two newly developed selective Vi (OPC-21268) and V2 (OPC-31260)receptor antagonists. For macro-ARG, 10-μm kidney sections were incubated with Tris-HCl buffer containing [3H]-VP with or without unlabeled ligand (VP, OPC-21268, orOPC-31260) at 20°C for 40 min. These sections were then loaded intoX-ray cassettes with Hyperfilm-[3H] and exposed inthe dark for 2 months. The autoradiograms were quantitativelyanalyzed by using the research analysis system RAS 1,000
the V1 and V2 receptors were quantitated by inftracting the nonspecific binding (incubatedwith OPC-21268 and OPC-31260, respectively) from the total binding. To assess a more precise localization of the V1and V2 receptors, we also investigated the micro-ARG of the renal V1 and V2 receptorsby dipping the kidney section slides used for macro-ARG into a photographic emulsion and observing the receptors under light microscopy. [3H]-VP binding to the rat kidney was completely displaced by unlabeled excess VP, but not by unlabeled angiotensin II, indicating that [3H]-VP binding was specific for VP receptors. Computerized quantification showed that V2 receptors, visualized by OPC-31260, were the predominant type of VP receptor in the kidney. Conversely, V1receptors, visualized by OPC-21268, werefewer in number. V) receptors were partly localized to the glomerulus, cortical vessels, interstitial cells, and the medullary vessels. The V2receptors localized to the collecting ducts and medullary tubules. Our findings indicated that renal V1 and V2 receptors can be detected by in vitro macro- and micro-ARG by using OPC-21268 and OPC-31260. © 1997 S.Karger AG, Basel.

DOI： 10.1159/000190200

IDDM accompanied a growth hormone-producing pituitary adenoma: A case report Reviewed

Fumio Otsuka, Toshio Ogura, Takayoshi Yamauchi, Kenichi Shikata, Jingo Kageyama, Hirofumi Makino

Diabetes Care 20 ( 12 ) 1838 - 1841 1997

Language：English Publishing type：Research paper (scientific journal) Publisher：American Diabetes Association Inc.

CASE HISTORY - A 30-year-old Japanese man who presented with recurrent ketoacidosis caused by IDDM was found to have increased secretion of growth hormone (GH). On initial cranial magnetic resonance imaging (MRI), no pituitary lesion was detected
however, a pituitary microadenoma was found 2 years later during a repeat MRI. In spite of the hypersecretion of GH, serum IGF-I was dramatically suppressed. Transsphenoidal surgery was performed to resect the pituitary tumor that was histologically an acidophilic pituitary adenoma. Although the GH excess rapidly improved postoperatively, the IGF-I level remained low. Subsequent insulin therapy initiated 1 year after the operation elevated the serum IGF-I level to within the normal range. DISCUSSION - The first case of coexistent IDDM and a GH-producing pituitary adenoma suggests that patients with uncontrolled IDDM may develop GH hypersecretion. Furthermore, the low IGF-I levels may be closely associated with the GH excess and with the development or progression of GH-secreting pituitary adenomas.

DOI： 10.2337/diacare.20.12.1838

Manifestation of Primary Hyperthyroidism after Pituitary Adenomectomy: A Case Report.

FUMIO OTSUKA, TOSHIO OGURA, NOBUHIKO HAYAKAWA, YUKARI MIMURA, JINGO KAGEYAMA, HIROFUMI MAKINO

Endocrine Journal 44 ( 6 ) 887 - 893 1997

A Case of Primary Hyperparathyroidism Accompanying Multiple Myeloma.

FUMIO OTSUKA, NOBUHIKO HAYAKAWA, TOSHIO OGURA, HIDEO KATAOKA, MASANORI KAWASHIMA, YUKARI MIMURA, TAKAYOSHI YAMAUCHI, NAOKI KASHIHARA, JINGO KAGEYAMA, HIROFUMI MAKINO

Endocrine Journal 44 ( 1 ) 105 - 109 1997

Gestational Thyrotoxicosis Manifesting as Wernicke Encephalopathy: A Case Report.

FUMIO OTSUKA, KATSUHIKO TADA, TOSHIO OGURA, NOBUHIKO HAYAKAWA, YUKARI MIMURA, TAKAYOSHI YAMAUCHI, NANAKO INOUE, HIROFUMI MAKINO, TAKAFUMI KUDO

Endocrine Journal 44 ( 3 ) 447 - 452 1997

静脈疾患とリンパ管外科：深部静脈血栓症

柚木継二、末広晃太郎、内田發三、*大塚文男、天野哲基、槇野博史、太田善介

1997

Changes in urinary enzyme activity and histochemical findings in experimental tubular injury by gold sodium thiomalate

Toshio Ogura, Michio Takaoka, Takayoshi Yamauchi, Tetsuya Oishi, Yukari Mimura, Masami Hashimoto, Naoko Asano, Masahiro Yamamura, Fumio Otsuka, Hirofumi Makino, Zensuke Ota and Kayo Takahashi

J.Med. 27 41-55 1996.1

Syndrome of Inappropriate Secretion of Antidiuretic Hormone Following Intra-thoracic Cisplatin.

Fumio OTSUKA, Yoshiko HAYASHI, Toshio OGURA, Nobuhiko HAYAKAWA, Shuji IKEDA, Hirofumi MAKING, Zensuke OTA

Internal Medicine 35 ( 4 ) 290 - 294 1996

A Case of Schmidt Syndrome Accompanied by a Pituitary Adenoma.

FUMIO OTSUKA, TOSHIO OGURA, NOBUHIKO HAYAKAWA, MASAMI HASHIMOTO, HIROFUMI MAKINO, ZENSUKE OTA, JINGO KAGEYAMA

Endocrine Journal 43 ( 5 ) 495 - 502 1996

Manifestation of Subclinical Diabetes Insipidus due to Pituitary Tumor during Pregnancy.

MASAMI HASHIMOTO, TOSHIO OGURA, FUMIO OTSUKA, TAKAYOSHI YAMAUCHI, YUKARI MIMURA, NOBUHIKO HAYAKAWA, HIROFUMI MAKINO, ZENSUKE OTA, NORIKO SEKI, YUJI HIRAMATSU, NAOFUMI KUDO

Endocrine Journal 43 ( 5 ) 577 - 583 1996

Normotensive Bilateral Pheochromocytoma with Lindau Disease: Case Report.

FUMIO OTSUKA, TOSHIO OGURA, MINORU NAKAGAWA, NOBUHIKO HAYAKAWA, HIDEO KATAOKA, TETSUYA OISHI, HIROFUMI MAKINO

Endocrine Journal 43 ( 6 ) 719 - 723 1996

Diabetes insipidus with Behçet's disease

Fumio Otsuka, Tetsuki Amano, Toshio Ogura, Zensuke Ota

The Lancet 346 ( 8988 ) 1494 - 1495 1995.12

Effect of vasopressin V1- and V2-receptor stimulation on blood pressure in DOCA-salt hypertensive rats.

Mimura Yukari, Ogura Toshio, Yamauchi Takayoshi, Otsuka Fumio, Oishi Tetsuya, Harada Kazushi, Hashimoto Masami, Ota Zensuke

Acta Medica Okayama 49 ( 4 ) 187 - 194 1995.8

Language：English Publishing type：Research paper (scientific journal) Publisher：Okayama University Medical School

We recently reported that stimulation of the arginine vasopressin (AVP) V-1-receptor enhanced the pressor response in spontaneously hypertensive rats (SHR). In the present study, we investigated acute changes in systolic blood pressure (SBP) and heart rate (HR) after intravenous injections of AVP, OPC-21268 (a V-1-receptor antagonist), and OPC-31260 (a V-2-receptor antagonist), in anesthetized DOCA-salt hypertensive rats (DOCA) and age-matched sham-operated Wistar rats (control) to determine whether the pressor effect is specific to SHR or is present in other hypertensive animal models. SBP increased significantly in DOCA rats 9 min after injection of AVP 5 ng/kg without a concomitant increase in HR. Neither OPC-21268 3 mg/kg nor OPC-31260 3 mg/kg caused significant changes in SBP or HR. SBP tended to increase when AVP was administered after injection of OPC-31260. HR increased significantly 15 min after the combined treatment with OPC-31260 and AVP in DOCA rats compared with control rats. SBP did not change significantly when AVP was administered after injection of OPC-21268 in DOCA or control rats, but HR decreased significantly from 1 to 4 min after injection of AVP in DOCA rats. Our results suggest that V,-receptor stimulation does not enhance the pressor response in the DOCA rat, which is a model of volume-dependent hypertension, suggesting that the AVP system, especially V-1-receptor, is not as important in the development or maintenance of hypertension in DOCA rats as in SHR.

DOI： 10.18926/AMO/30375

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