Faculty Profiles - OTSUKA Fumio

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