Faculty Profiles - OTSUKA Fumio

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