Details of a Researcher - Tanaka, Mamoru

Papers - Tanaka, Mamoru

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Effects of maternal and fetal choline concentrations on the fetal growth and placental DNA methylation of 12 target genes related to fetal growth, adipogenesis, and energy metabolism

Nakanishi M., Funahashi N., Fukuoka H., Nammo T., Sato Y., Yoshihara H., Oishi H., Tanaka M., Yano T., Minoura S., Kato N., Yasuda K.

Journal of Obstetrics and Gynaecology Research (Journal of Obstetrics and Gynaecology Research) 47 ( 2 ) 734 - 744 2021.02

ISSN 13418076

© 2020 Japan Society of Obstetrics and Gynecology Aim: We performed a birth cohort study involving 124 mother–infant pairs to investigate whether placental DNA methylation is associated with maternal choline status and fetal development. Methods: Plasma choline concentration was assayed longitudinally in the 1st and 3rd trimesters and at term-pregnancy in mothers and cord blood. Placental DNA methylation was measured for 12 target candidate genes that are related to fetal growth, adipogenesis, lipid and energy metabolism, or long interspersed nuclear elements. Results: Higher maternal plasma and cord blood choline levels at term tended to associate with lower birthweight (r = −0.246, P < 0.013; r = −0.290, P < 0.002) and body mass index (BMI) at birth (r = 0.344, P < 1E−3; r = −0.360, P < 1E−3). The correlation between maternal plasma choline level and cord blood choline level was relatively modest (r = 0.049, P = 0.639). There was an inverse correlation between placental DNA methylation at the retinoid X receptor alpha (RXRA) gene and maternal plasma choline level (r = −0.188 to r = −0.452, P = 0.043 to P < 1E−3 at three points). RXRA methylation level was positively associated with birthweight and BMI at birth (r = 0.306, P = 0.001; r = 0.390, P < 1E−3). Further, RXRA methylation was inversely correlated with RXRA gene expression level (r = 0.333, P < 1E−3). Conclusion: Our results suggest that the association between maternal choline status and placental RXRA methylation represents a potential fetal programing mechanism contributing to fetal growth.

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Amniotic fluid stem cells as a novel strategy for the treatment of fetal and neonatal neurological diseases

Abe Y., Ochiai D., Sato Y., Otani T., Fukutake M., Ikenoue S., Kasuga Y., Tanaka M.

Placenta (Placenta) 104 247 - 252 2021.01

ISSN 01434004

© 2021 Elsevier Ltd Even in the context of modern medicine, infants with fetal and neonatal neurological diseases such as cerebral palsy and myelomeningocele suffer serious long-lasting impairment due to the irreversible neuronal damage. The promotion of neurologically intact survival in patients with perinatal intractable neurological diseases requires the development of novel strategies. One promising strategy involves the use of human amniotic fluid stem cells (hAFSCs), which have attracted much attention in recent years and are known to exert anti-inflammatory and neuroprotective effects. In recent years, the therapeutic effects of hAFSCs on fetal-neonatal neurological diseases have become evident as per intense research efforts by our group and others. Specifically, hAFSCs administered into the nasal cavity migrated to the brain and controlled local inflammation in a rodent model of neonatal hypoxic-ischemic encephalopathy. In contrast, hAFSCs administered intraperitoneally did not migrate to the brain; they rather formed spheroids in the abdominal cavity, resulting in the suppression of systemic inflammation (including in the brain) via the secretion of anti-inflammatory cytokines in concert with peritoneal macrophages in a rodent model of periventricular leukomalacia. Moreover, studies in a rat model of myelomeningocele suggested that hAFSCs administered in utero secreted hepatocyte growth factor and protected the exposed spinal cord during pregnancy. Importantly, autologous hAFSCs, whose use for fetal-neonatal treatment does not raise ethical issues, can be collected during pregnancy and prepared in sufficient numbers for therapeutic use. This article outlines the results of preclinical research on fetal stem cell therapy, mainly involving hAFSCs, in the context of perinatal neurological diseases.

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Mitochondrial replacement by genome transfer in human oocytes: Efficacy, concerns, and legality

Yamada M., Sato S., Ooka R., Akashi K., Nakamura A., Miyado K., Akutsu H., Tanaka M.

Reproductive Medicine and Biology (Reproductive Medicine and Biology) 20 ( 1 ) 53 - 61 2021.01

ISSN 14455781

© 2020 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine. Background: Pathogenic mitochondrial (mt)DNA mutations, which often cause life-threatening disorders, are maternally inherited via the cytoplasm of oocytes. Mitochondrial replacement therapy (MRT) is expected to prevent second-generation transmission of mtDNA mutations. However, MRT may affect the function of respiratory chain complexes comprised of both nuclear and mitochondrial proteins. Methods: Based on the literature and current regulatory guidelines (especially in Japan), we analyzed and reviewed the recent developments in human models of MRT. Main findings: MRT does not compromise pre-implantation development or stem cell isolation. Mitochondrial function in stem cells after MRT is also normal. Although mtDNA carryover is usually less than 0.5%, even low levels of heteroplasmy can affect the stability of the mtDNA genotype, and directional or stochastic mtDNA drift occurs in a subset of stem cell lines (mtDNA genetic drift). MRT could prevent serious genetic disorders from being passed on to the offspring. However, it should be noted that this technique currently poses significant risks for use in embryos designed for implantation. Conclusion: The maternal genome is fundamentally compatible with different mitochondrial genotypes, and vertical inheritance is not required for normal mitochondrial function. Unresolved questions regarding mtDNA genetic drift can be addressed by basic research using MRT.

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Differences in fetal fractional limb volume changes in normal and gestational diabetic pregnancies: an exploratory observational study

Akiba Y., Ikenoue S., Endo T., Kasuga Y., Ochiai D., Miyakoshi K., Ishii R., Yakubo K., Tanaka M.

BJOG: An International Journal of Obstetrics and Gynaecology (BJOG: An International Journal of Obstetrics and Gynaecology) 128 ( 2 ) 329 - 335 2021.01

ISSN 14700328

© 2020 Royal College of Obstetricians and Gynaecologists Objective: Fetal fractional limb volume has been proposed as a useful measure for quantifying fetal soft tissue development. The aim of this study was to investigate the growth of fractional arm volume (AVol) and fractional thigh volume (TVol) of fetuses with maternal gestational diabetes (GDM) compared with those of fetuses with normal glucose tolerance (NGT). We hypothesised fetal fractional limb volume would be larger in the GDM group than in the NGT group in late gestation. Design: Exploratory observational study. Setting: Saitama Municipal Hospital. Sample: A total of 165 (125 NGT and 40 GDM) singleton Japanese pregnant women. Methods: AVol and TVol were assessed between 20 and 37 weeks’ gestation as cylindrical limb volumes based on 50% of the fetal humeral or femoral diaphysis length. Women were diagnosed as GDM based on the criteria of the Japan Society of Obstetrics and Gynecology. Main outcome measures: AVol and TVol were compared between women with NGT and those with GDM at each gestational age period (2-week intervals from 20 to 37 weeks’ gestation). Results: Overall, 287 ultrasound scans were performed (NGT group, 205 scans; GDM group, 82 scans). There was no significant difference of AVol between the groups before 32 weeks’ gestation. AVol was significantly larger in the GDM group than in the NGT group after 32 weeks’ gestation (P < 0.05). TVol was not statistically different between the groups across gestation. Conclusions: Detection of variations in fetal AVol may provide greater insight into understanding the origins of altered fetal body proportion in GDM. Tweetable abstract: AVol, but not TVol, is significantly larger in fetuses with GDM than in those with NGT after 32 weeks’ gestation.

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Risk of preterm birth after the excisional surgery for cervical lesions: a propensity-score matching study in Japan

Miyakoshi K., Itakura A., Abe T., Kondoh E., Terao Y., Tabata T., Hamada H., Tanaka K., Tanaka M., Kanayama N., Takeda S.

Journal of Maternal-Fetal and Neonatal Medicine (Journal of Maternal-Fetal and Neonatal Medicine) 34 ( 6 ) 845 - 851 2021

ISSN 14767058

© 2019 Informa UK Limited, trading as Taylor & Francis Group. Introduction: There is a paucity of data on the risk of preterm birth subcategorized by gestational age in pregnancies after the pre-pregnancy excisional treatment for cervical lesions. In addition, little is known about the effect of prophylactic cerclage on the risk of preterm birth. The aim of this study was to investigate the risk of preterm birth stratified by gestational period and its reduction by the prophylactic cerclage in women with prior excisional surgery. Materials and methods: We retrospectively analyzed a cohort of singleton pregnancies in the Japan Perinatal Registry Network Database (2013–2014, n = 307,001). Cases included pregnancies after the surgery (i.e. conization and loop electrosurgical excision procedure). Controls comprised the propensity-score matched pregnancies without pre-pregnancy surgery. The main outcome was the occurrence of preterm birth. The effect of prophylactic cervical cerclage on the risk of preterm birth after the excisional surgery was also examined using cases. Results: In the propensity-score matched population (cases, n = 1389; controls, n = 1389), cases exhibited a higher risk of preterm birth and preterm prelabor rupture of membranes (PROM), compared with controls (preterm birth: 25.3 versus 10.6%; preterm PROM: 14.0 versus 3.5%: both p <.0001). Odds ratios (OR; 95% confidence interval [CI]) for preterm birth at 22–27 weeks, 28–31 weeks, 32–33 weeks, and 34–36 weeks were 3.4 [1.8–6.5], 4.6 [2.7–7.7], 2.2 [1.4–3.5], and 2.1 [1.6–2.7], respectively. The association was stronger for preterm PROM at earlier gestational age (22–27 weeks, 28–31 weeks, 32–33 weeks, and 34–36 weeks: 5.2 [2.3–11.8], 7.1 [3.4–15.0], 3.8 [1.7–8.3], and 3.9 [1.8–4.6], respectively). In cases, 171 underwent the prophylactic cervical cerclage. The occurrence of preterm birth and preterm PROM was comparable between those with and without the cerclage (28.7 versus 24.2, and 12.9 versus 13.3%, respectively). Conclusions: Pre-pregnancy excisional cervical surgery was associated with the increased risk of preterm birth, especially before 32 weeks of gestation. The prophylactic cerclage did not reduce the risk of preterm birth.

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Prophylactic therapy with human amniotic fluid stem cells improves long-term cognitive impairment in rat neonatal sepsis survivors

Abe Y., Ochiai D., Sato Y., Kanzaki S., Ikenoue S., Kasuga Y., Tanaka M.

International Journal of Molecular Sciences (International Journal of Molecular Sciences) 21 ( 24 ) 1 - 12 2020.12

ISSN 16616596

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. A systemic inflammatory response induces multiple organ dysfunction and results in poor long-term neurological outcomes in neonatal sepsis. However, there is no effective therapy for treating or preventing neonatal sepsis besides antibiotics and supportive care. Therefore, a novel strategy to improve neonatal sepsis-related morbidity and mortality is desirable. Recently, we reported that prophylactic therapy with human amniotic stem cells (hAFSCs) improved survival in a rat model of lipopolysaccharide (LPS)-induced neonatal sepsis through immunomodulation. Besides improving the mortality, increasing survival without major morbidities is an important goal of neonatal intensive care for neonatal sepsis. This study investigated long-term neurological outcomes in neonatal sepsis survivors treated with hAFSCs using the LPS-induced neonatal sepsis model in rats. We found that prophylactic therapy with hAFSCs improved spatial awareness and memory-based behavior in neonatal sepsis survivors at adolescence in rats. The treatment suppressed acute reactive gliosis and subsequently reduced astrogliosis in the hippocampal region over a long period of assessment. To the best of our knowledge, this is the first report that proves the concept that hAFSC treatment improves cognitive impairment in neonatal sepsis survivors. We demonstrate the efficacy of hAFSC therapy in improving the mortality and morbidity associated with neonatal sepsis.

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UDP-glucose, a cellular danger signal, and nucleotide receptor P2Y14 enhance the invasion of human extravillous trophoblast cells

Katakura S., Takao T., Arase T., Yoshimasa Y., Tomisato S., Uchida S., Masuda H., Uchida H., Tanaka M., Maruyama T.

Placenta (Placenta) 101 194 - 203 2020.11

ISSN 01434004

© 2020 The Authors Introduction: P2Y14, one of the P2Y purinergic G-protein coupled receptors, is expressed in a variety of cells and tissues. Its ligand, UDP-glucose (UDPG), is released from damaged and stress-stimulated cells and acts as a danger signal via P2Y14. Thus, P2Y14 plays an important role in immunological defense systems. Here, we aimed to elucidate the expression, localization, and role of P2Y14 in human trophoblasts and the placenta. Methods: Human chorionic villus and placental tissues were subjected to immunostaining for P2Y14 protein and an extravillous trophoblast (EVT) marker, HLA-G. We examined the expression of P2Y14 and the effect of UDPG on cell proliferation and invasion in an EVT cell line, HTR-8/SVneo, using an MTS assay and a Transwell assay, respectively. We tested the effect of UDPG on cell invasion in P2Y14-underexpressing HTR-8/SVneo clones established by the lentiviral introduction of shRNA for P2RY14 mRNA. Results: Immunostaining revealed that P2Y14 was exclusively expressed by EVTs. P2RY14 mRNA and P2Y14 protein were expressed in HTR-8/SVneo cells. UDPG did not affect cell proliferation but it did enhance invasion. Inhibition of P2Y14 and decreasing the expression of P2Y14 suppressed UDPG-mediated invasive activity. Conclusions: These results showed that EVT selectively expressed P2Y14 and that P2Y14 was positively involved in UDPG-enhanced EVT invasion. It suggests the possible existence of a danger signal-mediated physiological system at the fetomaternal interface where UDPG released from maternal tissues through destruction by EVT invasion may accelerate EVT invasion, allowing EVTs to undergo successful placentation and vascular remodeling.

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Universal screening for SARS-CoV-2 in asymptomatic obstetric patients in Tokyo, Japan

Ochiai D., Kasuga Y., Iida M., Ikenoue S., Tanaka M.

International Journal of Gynecology and Obstetrics (International Journal of Gynecology and Obstetrics) 150 ( 2 ) 268 - 269 2020.08

ISSN 00207292

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Prophylactic therapy with human amniotic fluid stem cells improved survival in a rat model of lipopolysaccharide-induced neonatal sepsis through immunomodulation via aggregates with peritoneal macrophages

Sato Y., Ochiai D., Abe Y., Masuda H., Fukutake M., Ikenoue S., Kasuga Y., Shimoda M., Kanai Y., Tanaka M.

Stem Cell Research and Therapy (Stem Cell Research and Therapy) 11 ( 1 ) 2020.07

© 2020 The Author(s). Background: Despite recent advances in neonatal care, sepsis remains a leading cause of mortality in neonates. Mesenchymal stem cells derived from various tissues, such as bone marrow, umbilical cord, and adipose tissue, have beneficial effects on adult sepsis. Although human amniotic fluid stem cells (hAFSCs) have mesenchymal stem cell properties, the efficacy of hAFSCs on neonatal sepsis is yet to be elucidated. This study aimed to investigate the therapeutic potential of hAFSCs on neonatal sepsis using a rat model of lipopolysaccharide (LPS)-induced sepsis. Methods: hAFSCs were isolated as CD117-positive cells from human amniotic fluid. Three-day-old rat pups were intraperitoneally treated with LPS to mimic neonatal sepsis. hAFSCs were administered either 3 h before or at 0, 3, or 24 h after LPS exposure. Serum inflammatory cytokine levels, gene expression profiles from spleens, and multiple organ damage were analyzed. hAFSC localization was determined in vivo. In vitro LPS stimulation tests were performed using neonatal rat peritoneal macrophages co-cultured with hAFSCs in a cell-cell contact-dependent/independent manner. Immunoregulation in the spleen was determined using a DNA microarray analysis. Results: Prophylactic therapy with hAFSCs improved survival in the LPS-treated rats while the hAFSCs transplantation after LPS exposure did not elicit a therapeutic response. Therefore, hAFSC pretreatment was used for all subsequent studies. Inflammatory cytokine levels were elevated after LPS injection, which was attenuated by hAFSC pretreatment. Subsequently, inflammation-induced damages in the brain, lungs, and liver were ameliorated. hAFSCs aggregated with peritoneal macrophages and/or transiently accumulated in the liver, mesentery, and peritoneum. Paracrine factors released by hAFSCs induced M1-M2 macrophage polarization in a cell-cell contact-independent manner. Direct contact between hAFSCs and peritoneal macrophages further enhanced the polarization. Microarray analysis of the spleen showed that hAFSC pretreatment reduced the expression of genes involved in apoptosis and inflammation and subsequently suppressed toll-like receptor 4 signaling pathways. Conclusions: Prophylactic therapy with hAFSCs improved survival in a rat model of LPS-induced neonatal sepsis. These effects might be mediated by a phenotypic switch from M1 to M2 in peritoneal macrophages, triggered by hAFSCs in a cell-cell contact-dependent/independent manner and the subsequent immunomodulation of the spleen.

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Impaired fetal growth in mothers with inadequate gestational weight gain: a retrospective study in Japanese uncomplicated pregnancy

Ikenoue S., Miyakoshi K., Kasuga Y., Ochiai D., Matsumoto T., Tanaka M.

Journal of Maternal-Fetal and Neonatal Medicine (Journal of Maternal-Fetal and Neonatal Medicine) 33 ( 13 ) 2227 - 2231 2020.07

ISSN 14767058

© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. Introduction: The average birth weight in Japan has gradually decreased and the number of low birth weight infant has increased over the last 30 years. Japanese pregnant women are characterized with lower prevalence of obesity than those in other developed countries, and maternal underweight before pregnancy is independently associated with low birth weight. However, the association between maternal inadequate gestational weight gain (GWG) and the risk of small for gestational age (SGA) in Japanese uncomplicated pregnant women has not been fully understood. This study aimed to examine the effect of maternal inadequate GWG on the risk of SGA in Japanese uncomplicated pregnancies. Methods: We retrospectively analyzed uncomplicated Japanese singleton pregnancies that delivered at term gestation in our institution from 2006 to 2016. The association between GWG and birth weight was analyzed by multiple linear regression. Potential confounding factors included maternal age, parity, prepregnancy BMI, and neonatal sex. The association between inadequate GWG and SGA was also examined by logistic regression. Results: A total of 3837 mother–neonate dyads were analyzed. Maternal GWG was 10.1 ± 3.7 kg (mean ± SD), and 2529 (66%) had inadequate GWG. After adjusting for confounding factors, GWG significantly correlated with birth weight (standardized β = 0.199, p <.001). Inadequate GWG increased the risk of delivering SGA neonate (adjusted odds ratio (aOR) = 1.97 [1.45–2.68], p <.001). This association was particularly pronounced in underweight (aOR = 2.95 [1.38–6.29], p =.005) and normal weight mothers (aOR = 1.79 [1.27–2.52], p =.001), and not in overweight/obese mothers (p =.115). Conclusion: Maternal GWG is associated with birth weight in Japanese women with uncomplicated singleton pregnancies. Inadequate GWG is an important risk factor of SGA, particularly in non-obese women. The present finding would potentially provide further evidence that promoting adequate gestational weight gain in Japanese underweight and normal weight mothers would reduce SGA, as well as metabolic dysfunction in later life.

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The impact of parental unaffected allele combination on the diagnostic outcome in the preimplantation genetic testing for myotonic dystrophy type 1 in Japanese ancestry

Senba H., Sueoka K., Sato S., Higuchi N., Mizuguchi Y., Sato K., Tanaka M.

Reproductive Medicine and Biology (Reproductive Medicine and Biology) 19 ( 3 ) 265 - 269 2020.07

ISSN 14455781

© 2020 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine. Purpose: The objective is to clarify the practical problem of the preimplantation genetic testing (PGT) for myotonic dystrophy type 1 (DM1) in Japanese subjects. Methods: For the 32 couples who consented to participate in PGT for DM1, CTG repeats number on the unaffected alleles was analyzed. Based on the allele combination, they were classified into 3 groups by the number of diagnostic allelic pattern; “full informative,” “semi informative,” and “noninformative.” According to the Japan Society of Obstetrics and Gynecology (JSOG) principle, PGT was performed using the direct diagnosis to the 288 embryos from the 17 couples who received the ethical approval from both our institution and JSOG. Results: In the 32 couples, the frequency of CTG repeats on the unaffected alleles showed bimodal distribution. The “full informative,” “semi informative,” and “noninformative” couples accounted for 46.9% (15/32 couples), 46.9% (15/32 couples) and 6.2% (2/32 couples), respectively. The transferable embryos accounted for 28.9% (33/114 embryos) in the “full informative” couples, although it was limited to 12.6% (22/174 embryos) in the “semi informative” couples. Conclusion: The loss of unaffected embryos which cannot be diagnosed as transferable was a clinically major problem and implied an increase in oocyte retrieval, especially for “semi informative” couples.

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Right aortic arch with an aberrant left subclavian artery: Sonographic features by HDlive Flow imaging

Endo T., Ochiai D., Tanaka M.

Cardiology in the Young (Cardiology in the Young) 30 ( 6 ) 892 - 893 2020.06

ISSN 10479511

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Transvaginal ultrasound features of the residual cervix in pregnancy after radical trachelectomy

Kasuga Y., Miyakoshi K., Tanaka M.

Journal of Medical Ultrasonics (Journal of Medical Ultrasonics) 47 ( 2 ) 335 - 337 2020.04

ISSN 13464523

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Impaired early phase insulin secretion associated with gestational diabetes mellitus in underweight women

Kasuga Y., Miyakoshi K., Saisho Y., Ikenoue S., Ochiai D., Tanaka M.

Journal of Maternal-Fetal and Neonatal Medicine (Journal of Maternal-Fetal and Neonatal Medicine) 2020

ISSN 14767058

© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group. Background: No reports have focused on the clinical and metabolic characteristics of gestational diabetes (GDM) in underweight women. The aim of this study is to investigate the clinical and metabolic features of underweight GDM (pregravid BMI, <18.5 kg/m2: U-GDM). Materials and methods: Women diagnosed with GDM were categorized based on their pre-pregnancy BMI as either underweight (n = 49) or normal weight (pregravid BMI, 18.5–25.0 kg/m2: n = 271: N-GDM). During the study period, GDM was diagnosed using the International Association of Diabetes in Pregnancy Study Group criteria. Women with multi-fetal pregnancies, fetal congenital anomalies, overt diabetes in pregnancy, and pre-gestational diabetes mellitus were excluded. Results: There were no notable differences in maternal age at delivery and the rate of nulliparous between the U-GDM and N-GDM groups. Regarding antepartum oral glucose tolerance test profiles, women with U-GDM exhibited significantly lower fasting plasma glucose (FPG) levels than those with N-GDM (p <.01). The Insulinogenic Index of women with U-GDM was significantly lower than that of women with N-GDM (p <.05). Conclusion: Impaired early phase insulin secretion was associated with GDM onset in underweight women.

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Changes in bone metabolic profile associated with pregnancy or lactation

Miyamoto T., Miyakoshi K., Sato Y., Kasuga Y., Ikenoue S., Miyamoto K., Nishiwaki Y., Tanaka M., Nakamura M., Matsumoto M.

Scientific Reports (Scientific Reports) 9 ( 1 ) 2019.12

© 2019, The Author(s). Calcium and nutrients are transferred from mothers to fetuses or infants during pregnancy or lactation, respectively, promoting metabolic changes in the mother, many uncharacterized. To evaluate these changes, we undertook two parallel studies. In one we analyzed fourteen clinical cases of vertebral fragility fractures, at or before three months after partum, in mothers who breastfed their infants. In the other, we enrolled 79 additional pregnant subjects, some who chose to breastfeed and others who did not, and analyzed changes in bone metabolic status starting between 34 and 36 weeks of gestation and ending one month after partum. In the larger group, bone-resorbing and bone-forming parameters such as serum TRACP5b and osteocalcin, respectively, significantly increased after partum. Among parameters that changed after partum, serum PTH and the bone-resorbing markers serum TRACP5b and urine NTX were significantly higher in mothers who only breastfed infants compared to mothers who fed infants formula or a mix of both. However, bone-forming parameters were comparable between breastfeeding and non-breast-feeding groups after partum, suggesting that elevated bone-resorption occurs only in the breastfeeding group. Radiographic analysis after partum demonstrated that no subject among the 79 analyzed showed vertebral fractures, even those who breastfed exclusively. Among fracture cases analyzed, subjects exhibited significantly lower bone mineral density than did non-fracture cases in breastfeeding-only subjects. We conclude that bone metabolic status significantly changes over the period between pregnancy and post-partum lactation, and that low bone mineral density seen in a small subset of breastfeeding-only cases likely causes post-partum vertebral fragility fractures.

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Ultrasound Findings of Varices at the Site of Uterovaginal Anastomosis in a Pregnant Woman After Radical Trachelectomy

Kasuga Y., Miyakoshi K., Tanaka M.

Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine (Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine) 38 ( 12 ) 3363 - 3364 2019.12

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Impact of Oxidative Stress on Age-Associated Decline in Oocyte Developmental Competence

Sasaki H., Hamatani T., Kamijo S., Iwai M., Kobanawa M., Ogawa S., Miyado K., Tanaka M.

Frontiers in Endocrinology (Frontiers in Endocrinology) 10 2019.11

© Copyright © 2019 Sasaki, Hamatani, Kamijo, Iwai, Kobanawa, Ogawa, Miyado and Tanaka. Reproductive capacity in women starts to decline beyond their mid-30s and pregnancies in older women result in higher rates of miscarriage with aneuploidy. Age-related decline in fertility is strongly attributed to ovarian aging, diminished ovarian reserves, and decreased developmental competence of oocytes. In this review, we discuss the underlying mechanisms of age-related decline in oocyte quality, focusing on oxidative stress (OS) in oocytes. The primary cause is the accumulation of spontaneous damage to the mitochondria arising from increased reactive oxygen species (ROS) in oocytes, generated by the mitochondria themselves during daily biological metabolism. Mitochondrial dysfunction reduces ATP synthesis and influences the meiotic spindle assembly responsible for chromosomal segregation. Moreover, reproductively aged oocytes produce a decline in the fidelity of the protective mechanisms against ROS, namely the ROS-scavenging metabolism, repair of ROS-damaged DNA, and the proteasome and autophagy system for ROS-damaged proteins. Accordingly, increased ROS and increased vulnerability of oocytes to ROS lead to spindle instability, chromosomal abnormalities, telomere shortening, and reduced developmental competence of aged oocytes.

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In Utero Amniotic Fluid Stem Cell Therapy Protects Against Myelomeningocele via Spinal Cord Coverage and Hepatocyte Growth Factor Secretion

Abe Y., Ochiai D., Masuda H., Sato Y., Otani T., Fukutake M., Ikenoue S., Miyakoshi K., Okano H., Tanaka M.

Stem Cells Translational Medicine (Stem Cells Translational Medicine) 8 ( 11 ) 1170 - 1179 2019.11

ISSN 21576564

© 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press Despite the poor prognosis associated with myelomeningocele (MMC), the options for prenatal treatments are still limited. Recently, fetal cellular therapy has become a new option for treating birth defects, although the therapeutic effects and mechanisms associated with such treatments remain unclear. The use of human amniotic fluid stem cells (hAFSCs) is ideal with respect to immunoreactivity and cell propagation. The prenatal diagnosis of MMC during early stages of pregnancy could allow for the ex vivo proliferation and modulation of autologous hAFSCs for use in utero stem cell therapy. Therefore, we investigated the therapeutic effects and mechanisms of hAFSCs-based treatment for fetal MMC. hAFSCs were isolated as CD117-positive cells from the amniotic fluid of 15- to 17-week pregnant women who underwent amniocentesis for prenatal diagnosis and consented to this study. Rat dams were exposed to retinoic acid to induce fetal MMC and were subsequently injected with hAFSCs in each amniotic cavity. We measured the exposed area of the spinal cord and hepatocyte growth factor (HGF) levels at the lesion. The exposed spinal area of the hAFSC-treated group was significantly smaller than that of the control group. Immunohistochemical analysis demonstrated a reduction in neuronal damage such as neurodegeneration and astrogliosis in the hAFSC-treated group. Additionally, in lesions of the hAFSC-treated group, HGF expression was upregulated and HGF-positive hAFSCs were identified, suggesting that these cells migrated to the lesion and secreted HGF to suppress neuronal damage and induce neurogenesis. Therefore, in utero hAFSC therapy could become a novel strategy for fetal MMC. Stem Cells Translational Medicine 2019;8:1170–1179.

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Zscan5b Deficiency Impairs DNA Damage Response and Causes Chromosomal Aberrations during Mitosis

Ogawa S., Yamada M., Nakamura A., Sugawara T., Nakamura A., Miyajima S., Harada Y., Ooka R., Okawa R., Miyauchi J., Tsumura H., Yoshimura Y., Miyado K., Akutsu H., Tanaka M., Umezawa A., Hamatani T.

Stem Cell Reports (Stem Cell Reports) 12 ( 6 ) 1366 - 1379 2019.06

ISSN 22136711

© 2019 The Authors Zygotic genome activation (ZGA) begins after fertilization and is essential for establishing pluripotency and genome stability. However, it is unclear how ZGA genes prevent mitotic errors. Here we show that knockout of the ZGA gene Zscan5b, which encodes a SCAN domain with C2H2 zinc fingers, causes a high incidence of chromosomal abnormalities in embryonic stem cells (ESCs), and leads to the development of early-stage cancers. After irradiation, Zscan5b-deficient ESCs displayed significantly increased levels of γ-H2AX despite increased expression of the DNA repair genes Rad51l3 and Bard. Re-expression of Zscan5b reduced γ-H2AX content, implying a role for Zscan5b in DNA damage repair processes. A co-immunoprecipitation analysis showed that Zscan5b bound to the linker histone H1, suggesting that Zscan5b may protect chromosomal architecture. Our report demonstrates that the ZGA gene Zscan5b is involved in genomic integrity and acts to promote DNA damage repair and regulate chromatin dynamics during mitosis. In this article, Yamada and colleagues show that Zscan5b deficiency increases DNA stress, compromises chromosomal structure during mitosis, and leads to the development of early-stage cancers. Zscan5b deficiency may offer a murine model of human chromosomal breakage syndromes.

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The orientation of a decellularized uterine scaffold determines the tissue topology and architecture of the regenerated uterus in rats

Miki F., Maruyama T., Miyazaki K., Takao T., Yoshimasa Y., Katakura S., Hihara H., Uchida S., Masuda H., Uchida H., Nagai T., Shibata S., Tanaka M.

Biology of Reproduction (Biology of Reproduction) 100 ( 5 ) 1215 - 1227 2019.05

ISSN 00063363

© 2019 The Author(s) 2019. Published by Oxford University Press on behalf of Society for the Study of Reproduction. A decellularized uterine scaffold (DUS) prepared from rats permits recellularization and regeneration of uterine tissues when placed onto a partially excised uterus and supports pregnancy in a fashion comparable to the intact uterus. The underlying extracellular matrix (ECM) together with an acellular, perfusable vascular architecture preserved in DUS is thought to be responsible for appropriate regeneration of the uterus. To investigate this concept, we examined the effect of the orientation of the DUS-preserving ECM and the vascular architecture on uterine regeneration through placement of a DUS onto a partially defective uterine area in the reversed orientation such that the luminal face of the DUS was outside and the serosal face was inside. We characterized the tissue structure and function of the regenerated uterus, comparing the outcome to that when the DUS was placed in the correct orientation. Histological analysis revealed that aberrant structures including ectopic location of glands and an abnormal lining of smooth muscle layers were observed significantly more frequently in the reversed group than in the correct group (70% vs. 30%, P < 0.05). Despite the changes in tissue topology, the uteri regenerated with an incorrectly oriented DUS could achieve pregnancy in a way similar to uteri regenerated with a correctly oriented DUS. These results suggest that DUS-driven ECM orientation determines the regenerated uterus structure. Using DUS in the correct orientation is preferable when clinically applied. The disoriented DUS may deteriorate the tissue topology leading to structural disease of the uterus even though the fertility potential is not immediately affected.

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Clinical and genetic characteristics of abnormal glucose tolerance in Japanese women in the first year after gestational diabetes mellitus

Kasuga Y., Miyakoshi K., Tajima A., Saisho Y., Ikenoue S., Ochiai D., Matsumoto T., Arata N., Hata K., Tanaka M.

Journal of Diabetes Investigation (Journal of Diabetes Investigation) 10 ( 3 ) 817 - 826 2019.05

ISSN 20401116

© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd Aims/Introduction: Risk factors of type 2 diabetes mellitus in Japanese women with recent gestational diabetes mellitus are unknown. The objective of the present study was to investigate the clinical and genetic characteristics associated with postpartum abnormal glucose tolerance in Japanese women with gestational diabetes mellitus. Materials and Methods: A total of 213 Japanese women with recent gestational diabetes mellitus who underwent a postpartum 2-h oral glucose tolerance test were investigated. The association between antepartum clinical characteristics and postpartum abnormal glucose tolerance (diabetes or prediabetes based on the Japan Diabetes Society criteria) was examined. Frequencies of 45 known type 2 diabetes mellitus-associated genetic variants were also compared between women with and without postpartum abnormal glucose tolerance. Results: A total of 59 women showed postpartum abnormal glucose tolerance (prediabetes, n = 51; diabetes, n = 8). Plasma glucose levels at 1 or 2 h, the insulinogenic index and the insulin secretion-sensitivity index-2 of the antepartum oral glucose tolerance test were independent of postpartum abnormal glucose tolerance risk factors (P = 0.006, P = 0.00002, P = 0.01 and P = 0.006, respectively). Four genetic variants (rs266729 [ADIPOQ], rs6017317 [HNF4A], rs5215 [KCNJ11] and rs7177055 [HMG20A]) showed a nominally significant association with postpartum abnormal glucose tolerance (P < 0.05, respectively). Among these, three were related to insulin secretion. Postpartum abnormal glucose tolerance risk significantly increased with increasing risk-allele number (P = 0.0005; odds ratio 1.91). Conclusions: Clinical features and genetic variants related to impaired insulin secretion are risk factors of postpartum abnormal glucose tolerance in Japanese women with recent gestational diabetes mellitus.

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Safe and easy technique for the laparoscopic application of Seprafilm® in gynecologic surgery

Ota K., Sato K., Ogasawara J., Takahashi T., Mizunuma H., Tanaka M.

Asian journal of endoscopic surgery (Asian journal of endoscopic surgery) 12 ( 2 ) 242 - 245 2019.04

© 2018 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd. INTRODUCTION: Laparoscopic surgery is a minimally invasive surgery, and the rate of postoperative adhesions is low. Although Seprafilm® helps to reduce adhesions, its application in the abdominal cavity during laparoscopic surgery is difficult because of its material. Therefore, we propose an easy method for applying this adhesion barrier. MATERIALS AND SURGICAL TECHNIQUE: The Seprafilm is cut into four equal pieces. The four pieces are stacked, firmly folded twice, and grasped with the forceps. The reducer sleeve is slid over the bundle of Seprafilm. The forceps with the reducer sleeve is inserted through a 12-mm trocar near the target area. The reducer sleeve is then slid down the forceps to uncover the Seprafilm. Finally, each piece of Seprafilm is applied over the suture area. In all cases, the Seprafilm was successfully applied to the intended target. There were no cases in which Seprafilm was incompletely applied or in which it could not be used because of moistening. The average application times of surgeon 1 and surgeon 2 were 4.8 min and 5.0 min, respectively; this difference was not significant. There were no postoperative complications in any case. DISCUSSION: It is safe and easy to use our simple technique to apply Seprafilm adhesion barrier laparoscopically. Further studies are warranted to prove Seprafilm's efficacy after such application.

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Distinctive subpopulations of the intestinal microbiota are present in women with unexplained chronic anovulation

Sasaki H., Kawamura K., Kawamura T., Odamaki T., Katsumata N., Xiao J.Z., Suzuki N., Tanaka M.

Reproductive BioMedicine Online (Reproductive BioMedicine Online) 38 ( 4 ) 570 - 578 2019.04

ISSN 14726483

© 2018 The Authors Research question: Do gut microbiota associate with the ovulatory cycle in women showing normogonadotrophic anovulation? In humans, the gut microbiota affects diverse physiological functions and dysbiosis (microbial imbalance) may lead to pathological syndromes. However, there is comparatively little information on the relevance of gut microbiota to reproductive functions in women. Here, a group of women with idiopathic chronic anovulation were examined, who do not exhibit any apparent endocrinological disorder, as they are suitable for investigating the relationship between intestinal bacteria and ovulatory disorders. Design: A prospective observational cohort study was performed on two groups of women who did not exhibit apparent endocrinological disorders but showed either irregular menstrual cycles (IMC group) or normal menstrual cycles (controls). The bacterial composition of faeces from rectal swabs from the women was analysed using next-generation sequencing based on bacterial 16SrRNA genes. Results: A metagenomic analysis indicated that the two groups of women had significant differences in 28 bacterial taxa in their faeces. Prevotella-enriched microbiomes were more abundant in the IMC group, whereas Clostridiales, Ruminococcus and Lachnospiraceae (butyrate-producing bacteria) were present at lower levels in the IMC group. Conclusions: Distinctive subpopulations of intestinal microbiota were identified in women with unexplained chronic anovulation. The results indicate that gut microbiota could be associated with ovarian functions.

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National survey of uterine rupture in Japan: Annual report of Perinatology Committee, Japan Society of Obstetrics and Gynecology, 2018

Makino S., Takeda S., Kondoh E., Kawai K., Takeda J., Matsubara S., Itakura A., Sago H., Tanigaki S., Tanaka M., Ikeda T., Kanayama N.

Journal of Obstetrics and Gynaecology Research (Journal of Obstetrics and Gynaecology Research) 45 ( 4 ) 763 - 765 2019.04

ISSN 13418076

© 2019 Japan Society of Obstetrics and Gynecology Aim: To clarify the frequency of occurrence of uterine rupture and its prognosis, a nationwide survey was performed. Methods: Cases of uterine rupture recorded for a period of 5 years were included. Results: There were 152 cases of uterine rupture with an incidence rate of 0.015%. The scarred uterine rupture cases were found to have a significantly earlier occurrence of uterine ruptures in comparison to the unscarred cases: unscarred 39.0 weeks, cesarean section 37.0 weeks, myomectomy 32 weeks and adenomyomectomy 30–32 weeks. And it became apparent that the frequency of hysterectomy, cerebral palsy and neonatal death were higher in the cases of uterine rupture during labor than before delivery. Among the cases of scarred uterine rupture, neonatal prognosis was poorer in cases of pregnancy after myomectomy or adenomyomectomy in comparison with postcesarean section cases. Conclusion: This survey revealed the current incidence of uterine rupture in Japan.

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Membrane protein CD9 is repositioned and released to enhance uterine function

Iwai M., Hamatani T., Nakamura A., Kawano N., Kanai S., Kang W., Yoshii N., Odawara Y., Yamada M., Miyamoto Y., Saito T., Saito H., Miyado M., Umezawa A., Miyado K., Tanaka M.

Laboratory Investigation (Laboratory Investigation) 99 ( 2 ) 200 - 209 2019.02

ISSN 00236837

© 2018, United States & Canadian Academy of Pathology. Tetraspanin CD9 is essential for sperm–egg fusion and also contributes to uterine repair through microexosome formation. Microexosomes share CD9 with exosomes and are released from eggs and uterine epithelial cells. However, the mechanism for the formation of microexosomes remains unknown. To address this issue, we examined membrane localization and extracellular release of CD9 proteins using uterine epithelial cells and secretions in mice and humans. In mice, CD9 localized predominantly on the basal region of the plasma membrane and relocated to the apical region upon embryo implantation. Furthermore, extracellular CD9 proteins were detected in uterine secretions of mice and women undergoing infertility treatment, but were below detectable levels in supernatants of pluripotent stem cells. Ultrastructural analysis demonstrated that membrane projections were shortened and the number of mitochondria was reduced in uterine epithelial cells lacking Cd9 genes. Our results suggest that CD9 repositioning and release affect both membrane structures and mitochondrial state in the uterus, and contribute to female fertility.

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Human amniotic fluid stem cells have a unique potential to accelerate cutaneous wound healing with reduced fibrotic scarring like a fetus

Fukutake M., Ochiai D., Masuda H., Abe Y., Sato Y., Otani T., Sakai S., Aramaki-Hattori N., Shimoda M., Matsumoto T., Miyakoshi K., Kanai Y., Kishi K., Tanaka M.

Human Cell (Human Cell) 32 ( 1 ) 51 - 63 2019.01

ISSN 09147470

© 2018, Japan Human Cell Society and Springer Japan KK, part of Springer Nature. Adult wound healing can result in fibrotic scarring (FS) characterized by excess expression of myofibroblasts and increased type I/type III collagen expression. In contrast, fetal wound healing results in complete regeneration without FS, and the mechanism remains unclear. Amniotic fluid cells could contribute to scar-free wound healing, but the effects of human amniotic fluid cells are not well characterized. Here, we determined the effect of human amniotic fluid stem cells (hAFS) on FS during wound healing. Human amniotic fluid was obtained by amniocentesis at 15–17 weeks of gestation. CD117-positive cells were isolated and defined as hAFS. hAFS (1 × 10 6 ) suspended in PBS or cell-free PBS were injected around wounds created in the dorsal region of BALB/c mice. Wound size was macroscopically measured, and re-epithelialization in the epidermis, granulation tissue area in the dermis and collagen contents in the regenerated wound were histologically analyzed. The ability of hAFS to engraft in the wound was assessed by tracking hAFS labeled with PKH-26. hAFS fulfilled the minimal criteria for mesenchymal stem cells. hAFS injection into the wound accelerated wound closure via enhancement of re-epithelialization with less FS. The process was characterized by lower numbers of myofibroblasts and higher expression of type III collagen. Finally, transplanted hAFS were clearly observed in the dermis until day 7 implying that hAFS worked in a paracrine manner. hAFS can function in a paracrine manner to accelerate cutaneous wound healing, producing less FS, a process resembling fetal wound healing.

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The neurorestorative effect of human amniotic fluid stem cells on the chronic phase of neonatal hypoxic–ischemic encephalopathy in mice

Otani T., Ochiai D., Masuda H., Abe Y., Fukutake M., Matsumoto T., Miyakoshi K., Tanaka M.

Pediatric Research (Pediatric Research) 85 ( 1 ) 97 - 104 2019.01

ISSN 00313998

© 2018, International Pediatric Research Foundation, Inc. Background: Hypoxic–ischemic encephalopathy (HIE) remains a major cause of cerebral palsy. Increasing evidence has suggested that mesenchymal stem cells have a favorable effect on HIE. However, the efficacy of human amniotic fluid stem cells (hAFS) for HIE, especially in the chronic phase, remains unclear. The aim of this study was to determine the neurorestorative effect of hAFS on the chronic phase of HIE. Methods: hAFS were isolated from AF cells as CD117-positive cells. HI was induced in 9-day-old mice. Animals intranasally received hAFS or phosphate‐buffered saline at 10 days post HI and were harvested for histological analysis after functional tests at 21 days post HI. We also implanted PKH26-positive hAFS to assess their migration to the brain. Finally, we determined gene expressions of trophic factors in hAFS co-cultured with HI brain extract. Results: hAFS improved sensorimotor deficits in HIE by gray and white matter restoration and neuroinflammation reduction followed by migration to the lesion. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), hepatocyte growth factor (HGF), and stromal cell-derived factor-1 (SDF-1) gene expressions in hAFS were elevated when exposed to HI-induced brain extract. Conclusion: hAFS induced functional recovery by exerting neurorestorative effects in HIE mice, suggesting that intranasal administration of hAFS could be a novel treatment for HIE, especially in the chronic phase.

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Chemotactic behavior of egg mitochondria in response to sperm fusion in mice

Iwai M., Harada Y., Miyabayashi R., Kang W., Nakamura A., Kawano N., Miyamoto Y., Yamada M., Hamatani T., Miyado M., Yoshida K., Saito H., Tanaka M., Umezawa A., Miyado K.

Heliyon (Heliyon) 4 ( 11 ) 2018.11

ISSN 24058440

© 2018 The Authors Mitochondria are the powerhouses of eukaryotic cells and their positioning contributes to fertilization and early developmental processes. We report that sperm fusion triggers Ca2+ oscillations and mitochondrial movement toward fused sperm (mitochondrial chemotaxis) in mouse eggs. Mitochondria functioned in Ca2+ storage and were colocalized with endoplasmic reticulum (ER) during Ca2+ oscillations. Mitochondria then moved toward the fused sperm. Sperm extracts lacking nuclei induced Ca2+ oscillations, but did not promote mitochondrial chemotaxis. Our results suggest that sperm fusion motivates Ca2+ oscillation-independent mitochondrial chemotaxis. This phenomenon indicates that egg mitochondria interact with sperm materials, presumably nuclear substances, and their network tethers egg and sperm nuclei at the early stage of zygote formation.

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Degradation of phosphate polymer polyP enhances lactic fermentation in mice

Nakamura A., Kawano N., Motomura K., Kuroda A., Sekiguchi K., Miyado M., Kang W., Miyamoto Y., Hanai M., Iwai M., Yamada M., Hamatani T., Saito T., Saito H., Tanaka M., Umezawa A., Miyado K.

Genes to Cells (Genes to Cells) 23 ( 10 ) 904 - 914 2018.10

ISSN 13569597

© 2018 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd In bacteria, a polymer of inorganic phosphate (Pi) (inorganic polyphosphate; polyP) is enzymatically produced and consumed as an alternative phosphate donor for adenosine triphosphate (ATP) production to protect against nutrient starvation. In vertebrates, polyP has been dismissed as a “molecular fossil” due to the lack of any known physiological function. Here, we have explored its possible role by producing transgenic (TG) mice widely expressing Saccharomyces cerevisiae exopolyphosphatase 1 (ScPPX1), which catalyzes hydrolytic polyP degradation. TG mice were produced and displayed reduced mitochondrial respiration in muscles. In female TG mice, the blood concentration of lactic acid was enhanced, whereas ATP storage in liver and brain tissues was reduced significantly. Thus, we suggested that the elongation of polyP reduces the intracellular Pi concentration, suppresses anaerobic lactic acid production, and sustains mitochondrial respiration. Our results provide an insight into the physiological role of polyP in mammals, particularly in females.

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Retrospective multicenter study of leaving the placenta in situ for patients with placenta previa on a cesarean scar

Miyakoshi K., Otani T., Kondoh E., Makino S., Tanaka M., Takeda S.

International Journal of Gynecology and Obstetrics (International Journal of Gynecology and Obstetrics) 140 ( 3 ) 345 - 351 2018.03

ISSN 00207292

© 2017 International Federation of Gynecology and Obstetrics Objective: To investigate maternal outcomes after leaving the placenta in situ for placenta accreta spectrum (PAS) disorders in patients with placenta previa on a cesarean delivery scar. Methods: The present retrospective study reviewed medical records from women with placenta previa on a cesarean scar underwent perinatal care at secondary- or tertiary-level perinatal centers in Japan between January 1, 2010, and December 31, 2014. Perinatal management was conducted based on each leading obstetrician's discretion. The primary outcome was success of the leaving the placenta in situ approach for PAS disorders (defined as preserving the uterus without hysterectomy). Results: Of 178 eligible centers, 126 (71%) participated in this study; data from 613 patients were included. Of these, 41 had the placenta left in situ owing to PAS disorders and follow-up data were available for 36 women. Leaving the placenta in situ was successful in 25 (69%) patients, with placental resorption occurring postpartum (median 89 days; range 6–510). Hysterectomy was performed for 11 patients, primarily owing to hemorrhage and/or infection (median 30 days; range 0–95 days, postpartum). Conclusion: Leaving the placenta in situ, with close postpartum follow-up for at least several months, could be a uterus-preserving option for patient with PAS disorders.

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Cover Image, Volume 176A, Number 1, January 2018

Ikenoue S., Miyakoshi K., Ishii T., Sato Y., Otani T., Akiba Y., Kasuga Y., Ochiai D., Matsumoto T., Ichihashi Y., Matsuzaki Y., Tachikawa K., Michigami T., Nishimura G., Ikeda K., Hasegawa T., Tanaka M.

American journal of medical genetics. Part A (American journal of medical genetics. Part A) 176 ( 1 ) 2018.01

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Discordant fetal phenotype of hypophosphatasia in two siblings

American Journal of Medical Genetics, Part A (American Journal of Medical Genetics, Part A) 176 ( 1 ) 171 - 174 2018.01

ISSN 15524825

© 2017 Wiley Periodicals, Inc. Hypophosphatasia (HPP) is an autosomal recessive metabolic disorder with impaired bone mineralization due to mutations in the ALPL gene. The genotype-phenotype correlation of this disorder has been widely described. Here, we present two affected siblings, whose fetal phenotypes were discordant. A 31-year-old Japanese woman, G0P0, was referred to our institution because of fetal micromelia. After obstetric counseling, the pregnancy was terminated at 21 weeks’ gestation. Post-mortem radiographs demonstrated severely defective mineralization of the skeleton. The calvarial, spinal, and tubular bones were mostly missing. Only the occipital bones, mandible, clavicles, ribs, one thoracic vertebra, ilia, and tibia were relatively well ossified. The radiological findings suggested lethal HPP. Genetic testing for genomic DNA extracted from the umbilical cord identified compound heterozygous mutations in the ALPL gene (c.532T>C, p.Y178H; c.1559delT, p.Leu520Argfs*86). c.532T>C was a novel variant showing no residual activity of the protein by the functional analysis. The parents were heterozygous carriers. In the next pregnancy, biometric values on fetal ultrasonography at 20 and 26 weeks’ gestation were normal. At 34 weeks, however, a small chest and shortening of distal long bones came to attention. The neonate delivered at 41 weeks showed serum ALP of <5U/L. Radiological examination showed only mild thoracic hypoplasia and metaphyseal mineralization defects of the long bones. ALP replacement therapy was introduced shortly after birth, and the neonate was discharged at day 22 without respiratory distress. Awareness of discordant fetal phenotypes in siblings with HPP precludes a diagnostic error, and enables early medical intervention to mildly affected neonates.

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Human amniotic fluid stem cells: Therapeutic potential for perinatal patients with intractable neurological disease

Ochiai D., Masuda H., Abe Y., Otani T., Fukutake M., Matsumoto T., Miyakoshi K., Tanaka M.

Keio Journal of Medicine (Keio Journal of Medicine) 67 ( 4 ) 57 - 66 2018

ISSN 00229717

© 2018 by The Keio Journal of Medicine. Mesenchymal stem cells (MSCs) have generated great interest in the fields of regenerative medicine and immunotherapy because of their unique biological properties. Among MSCs, amniotic fluid stem cells (AFS) have a number of characteristics that make them attractive candidates for tissue engineering and cell replacement strategies, particularly for perinatal medicine. If various neonatal conditions, including birth asphyxia, preterm birth, and congenital abnormalities, which result in long-lasting severe impairments, could be predicted during pregnancy, it would allow collection of small samples of amniotic fluid cells by amniocentesis. In vitro culture of these autologous AFS during pregnancy would make them available for use soon after birth. Hypoxic-ischemic encephalopathy (HIE) and myelomeningocele (MMC) are neonatal conditions that cause permanent neurological disability, for which the treatment options are extremely limited. Experiments using animal models of HIE and MMC and human clinical trials have demonstrated that MSCs, including AFS, have beneficial effects on the central nervous system through paracrine influences, indicating that autologous AFS treatment may be applicable for intractable neurological diseases, including HIE and MMC, during the perinatal period. In this review, we focus on recent research related to the therapeutic potential of AFS for perinatal neurological diseases such as HIE and MMC.

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Lower serum total bilirubin concentration is associated with higher prevalence of gestational diabetes mellitus in Japanese pregnant women

Nishimura T., Tanaka M., Saisho Y., Miyakoshi K., Tanaka M., Itoh H.

Endocrine Journal (Endocrine Journal) 65 ( 12 ) 1199 - 1208 2018

ISSN 09188959

©The Japan Endocrine Society. We aimed to clarify the pathophysiological significance of total bilirubin (TB) in gestational diabetes mellitus (GDM). This was a cross-sectional study that included 616 pregnant Japanese women (368 normal glucose tolerance [NGT] and 248 GDM). Serum TB concentration, homeostasis model assessment of insulin resistance (HOMA-IR), and other clinical parameters were compared in NGT and GDM women. TB concentration was also compared according to the number of abnormal OGTT values. Logistic regression analysis was used to evaluate the association between TB and GDM prevalence. A multiple linear regression model was used to evaluate the association between TB and HOMA-IR. TB concentrations were significantly lower in GDM women than in NGT women. This result did not change after adjustments for TB sampling timing were made. Out of 248 GDM women, the prevalences of 1-and 2/3-abnormal OGTT values (1-and 2/3-AV) GDM were 72.2% (n = 179) and 27.8% (n = 69), respectively. In the multiple comparisons, TB concentrations were significantly lower in women with 2/3-AV GDM than in women with NGT and 1-AV GDM. Multiple logistic regression analysis showed that TB was a significantly associated factor for 2/3-AV, but not for total GDM. HOMA-IR was significantly higher in GDM women than in NGT women. The univariate, but not multivariate, analysis showed that TB was a significantly associated factor for HOMA-IR. Our findings suggest that hypobilirubinemia may be involved in the pathogenesis of GDM.

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Successful Pregnancy After Sacrectomy Combined With Chemotherapy and Radiation for Ewing Sarcoma

Kakogawa Jun, Nako Takafumi, Kawamura Kazuhiro, Nakamura Shin, Mochiduki Ayako, Kanayama Naohiro, Tanaka Mamoru

Journal of Pediatric and Adolescent Gynecology 28 ( 3 ) e79 - e81 2015.06

ISSN 1083-3188

Ewing sarcoma is considered to have a poor prognosis. Recent advances in multidisciplinary management have resulted in a marked improvement in long-term survival. Case: We describe a case of successful pregnancy in a patient who underwent sacrectomy combined with multi-agent chemotherapy and radiotherapy for Ewing sarcoma. The patient was diagnosed with Ewing sarcoma of the sacrum at the age of 16. The ovaries were transposed, the uterus was shielded, and a gonadotropin-releasing hormone agonist was used during treatment to protect ovarian function. The patient spontaneously conceived at the age of 27. After an uneventful pregnancy, the patient delivered a healthy neonate at term by cesarean section. Summary and Conclusions: Successful pregnancy and delivery can be achieved after multi-modality treatment with pretreatment intervention for fertility preservation.

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Intracranial sonographic features demonstrating in utero development of hemorrhagic brain damage leading to schizencephaly-associated COL4A1 mutation

Matsumoto Tadashi, Miyakoshi Kei, Fukutake Marie, Ochiai Daigo, Minegishi Kazuhiro, Tanaka Mamoru

Journal of Medical Ultrasonics 2015.01

ISSN 1346-4523

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Analysis of late-onset ovarian insufficiency after ovarian surgery

Takae Seido, Kawamura Kazuhiro, Sato Yorino, Nishijima Chie, Yoshioka Nobuhito, Sugishita Yodo, Horage Yuki, Tanaka Mamoru, Ishizuka Bunpei, Suzuki Nao

PLoS ONE 9 ( 5 ) 2014.05

The primary objectives of the present study are to determine the period of onset of ovarian insufficiency after surgery and to confirm potential risk factors for ovarian insufficiency after surgery for the removal of benign ovarian cysts. Data were obtained from 75 patients who underwent surgery for benign ovarian cysts prior to the onset of ovarian insufficiency. Our analysis included 835 ovarian insufficiency patients who were referred to our institution from July 2003 to July 2013. Several epidemiological parameters of ovarian insufficiency after surgery (age at operation, period of onset of ovarian insufficiency, operation procedure, and pathological diagnosis) were investigated. Of the 835 patients who had ovarian insufficiency, 75 patients (9.0%) underwent ovarian surgery before the onset of ovarian insufficiency. Of those 75 patients, 66 patients (88.0%) underwent cystectomy. For the majority of the 75 patients the surgical indication was the presence of endometriotic cysts (57 patients; 76.0%). Twelve patients (16.0%) underwent multiple surgeries (all bilateral cystectomies). The mean age of the patients at the time of surgery was 27.8±5.5 years-old, and the mean period of onset of ovarian insufficiency was 5.8±3.8 years. In patients with cystectomy, the patient's age at the time of surgery and period of onset of ovarian insufficiency was well-correlated (coefficient of correlation; hemilateral endometriotic cystectomy: 20.64, bilateral endometriotic cystectomy: 20.61, and multiple endimetriotic cystectomy: 20.40). We found that cystectomy of endometriotic cysts is the potential risk factor for ovarian insufficiency after surgery, at times, the onset of ovarian insufficiency long after cystectomy. Therefore, it is important to monitor ovarian reserve for an extended period of time after ovarian surgery. It is particularly important to monitor ovarian reserve long-term for patients who wish to conceive in the future and to suggest a variety of infertility treatments appropriate for their ovarian reserve. © 2014 Takae et al.

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Compilation of copy number variants identified in phenotypically normal and parous Japanese women

Migita Ohsuke, Maehara Kayoko, Kamura Hiromi, Miyakoshi Kei, Tanaka Mamoru, Morokuma Seiichi, Fukushima Kotaro, Shimamoto Tomihiro, Saito Shigeru, Sago Haruhiko, Nishihama Keiichiro, Abe Kosei, Nakabayashi Kazuhiko, Umezawa Akihiro, Okamura Kohji, Hata Kenichiro

Journal of Human Genetics 59 ( 6 ) 326 - 331 2014

ISSN 1434-5161

With increasing public concern about infertility and the frequent involvement of chromosomal anomalies in miscarriage, analyses of copy number variations (CNVs) have been used to identify the genomic regions responsible for each process of childbearing. Although associations between CNVs and diseases have been reported, many CNVs have also been identified in healthy individuals. Like other types of mutations, phenotypically indefinite CNVs may have been retained and accumulated during anthropogenesis. Therefore to distinguish causative variants from other variants is a formidable task. Furthermore, because previous studies have predominantly focused on European and African populations, comprehensive detection of common Asian CNVs is eagerly awaited. Here, using a high-resolution genotyping array and samples from 411 Japanese women with normal parity without significant complications, we have compiled 1043 copy number variable regions. In total, the collected regions cover 164 Mb, or up to 0.5% of the genome. The copy number differences in these regions may be irrelevant not only to infertility but also to a wide range of diseases. The utility of this resource in reducing the candidate pathogenetic variants, especially in Japanese subjects, is also demonstrated. © 2014 The Japan Society of Human Genetics. All rights reserved.

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Fetal stomach paracentesis in combined duodenal and esophageal atresia

Kadohira Ikuko, Miyakoshi Kei, Shimojima Naoki, Matsumoto Tadashi, Minegishi Kazuhiro, Tanaka Mamoru, Kuroda Tatsuo, Yoshimura Yasunori

Journal of Medical Ultrasonics 41 ( 3 ) 397 - 400 2014

ISSN 1346-4523

Fetuses with concomitant duodenal atresia (DA) and esophageal atresia (EA) might develop in utero gastric rupture as well as neonatal respiratory complication due to dilated stomach and duodenum. Our patient with the typical "double bubble" appearance was highly suspected to have DA in the second trimester. Follow-up examinations revealed a massively dilated stomach and duodenum with a dilated distal esophagus, indicating concomitant DA and EA. With advancing pregnancy, the fetal abdomen progressively increased in size by retention of fluid in the closed loop of DA and EA. To avoid gastric perforation, prenatal stomach paracentesis using an ultrasound-guided needle was performed three times until delivery. A male neonate born at 37 weeks gestation showed no respiratory complication. Perinatal clinical features and operative findings revealed combined DA and EA (gross type A). He was successfully managed with duodenoduodenostomy, followed by esophago-esophagostomy. On fetal sonography, the marked "double bubble" appearance and the cystic structure presenting peristalsis-like movement above the diaphragm were indicative of concomitant DA and EA. Fetal stomach paracentesis could contribute to the improvement of perinatal outcomes in fetuses with this pathological condition. © 2014 The Japan Society of Ultrasonics in Medicine.

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Regulation of preimplantation embryo development in mice by FMS-like tyrosine kinase 3 ligand

Nishijima Chie, Kawamura Kazuhiro, Okamoto Naoki, Sato Yorino, Kawamura Nanami, Ishizuka Bunpei, Tanaka Mamoru, Suzuki Nao

Journal of Mammalian Ova Research 31 ( 1 ) 45 - 51 2014

ISSN 1341-7738

Successful development of preimplantation embryos is essential for reproduction. Growth factors secreted by reproductive tracts are important for the development of preimplantation embryos. FMS-like tyrosine kinase 3 (FLT3) is a tyrosine kinase receptor related to colony-stimulating factor-1 receptor and c-KIT, promoting preimplantation embryo development following their ligand binding. We found expression of FLT3 ligand transcripts in the oviducts and uteri of pregnant mice. The transcripts for its receptor, FLT3, were detectable throughout the early embryonic stages with an increase after the eight-cell stage. In contrast, the expression of FLT3 ligand was negligible after the morula stage, suggesting potential paracrine actions of FLT3 ligand produced by the reproductive tracts. Treatment with FLT3 ligand promoted the development of two-cell embryos to the morula and blastocyst stages in a dose-dependent manner with increases in cell proliferation, but not inhibition of cell survival. The effects of FLT3 ligand were blocked by a FLT3 receptor inhibitor, TCS359. Studies using specific inhibitors demonstrated the potential involvement of the PI3K pathway in mediating FLT3 ligand actions. Our findings suggest that the FLT3 ligand/FLT3 signaling system plays important paracrine roles during the development of preimplantation embryos. ©2014 Japan Society for Ova Research.

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Thrombomodulin improves maternal and fetal conditions in an experimental pre-eclampsia rat model

Shin Mihwa, Hino Hirofumi, Tamura Midori, Ishizuka Bunpei, Tanaka Mamoru, Suzuki Nao, Tateda Takeshi

Journal of Obstetrics and Gynaecology Research 40 ( 5 ) 1226 - 1234 2014

ISSN 1341-8076

Aim: The aim of this study was to investigate whether the consecutive administration of recombinant thrombomodulin (r-TM) for 4 days improves maternal and fetal conditions and physiological outcomes in an N'-nitro-L-arginine- methyl ester hydrochloride-induced and low-dose endotoxin-induced pre-eclampsia (PE). Methods: r-TM or saline was administrated i.v. to normal pregnant and experimental PE rats for 4 days. The maternal condition, vascular endothelial growth factor receptor-1 (VEGFR-1), fetal conditions, uteroplacental blood flow (UPBF), and oxygenation in the placenta and fetal brain was evaluated on gestational day 21. Results: Significant increases in the mean arterial blood pressure, VEGFR-1 values and fetal death rate were observed in PE rats compared with control rats, while maternal and fetal bodyweight and fetal brain weight were substantially lower. Hypoperfusion and hypo-oxygenation in both the placenta and fetal brain tissues occurred in PE rats. Although r-TM failed to improve hypertension and affect the differences in maternal bodyweight between the groups, r-TM significantly improved hypoperfusion and fetal and maternal conditions, including VEGFR-1 values (6.5 ± 4.0 vs 2.2 ± 2.7 ng/mL, PE vs PE with r-TM, respectively; P < 0.05). Although not significant, a decrease in the fetal death rate was observed in PE rats administrated r-TM (36.1 ± 17.6% vs 25.0 ± 23.8%, P = 0.077). Conclusion: The severe reductions in the UPBF and the placental oxygenation imply that regional hypoperfusion occurs in association with systemic mean arterial pressure. r-TM may be a candidate medical treatment for PE complications. © 2014 Japan Society of Obstetrics and Gynecology.

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N-Butyl Cyanoacrylate Is Very Effective for Massive Haemorrhage during the Perinatal Period

Igarashi Suguru, Izuchi Shinichirou, Ogawa Yukihisa, Yoshimathu Misako, Takizawa Kenji, Nakajima Yasuo, Tanaka Mamoru, Ishizuka Bunpei, Suzuki Nao

PLoS ONE 8 ( 10 ) 2013.10

Objective:The liquid embolic agent n-butyl cyanoacrylate (NBCA) is a tissue adhesive used as an immediate and permanent embolic agent when mixed with oil-based contrast medium. In this study, the preservation of fertility with TAE using NBCA for massive haemorrhage during pregnancy or the peripartum period and the utility of this therapy were investigated.Methods:Cases from January 2005 to October 2010 in which TAE was performed for massive haemorrhage in pregnant women, particularly during the peripartum period, were investigated.Results:TAE was performed in 27 pregnant women. The embolic agent used was GS only in five cases, NBCA only in 19 cases, and additional embolization with NBCA when the effect with GS was insufficient in three cases, one each of abruptio placentae, cervical pregnancy, and uterine atony.A comparison of mean blood loss when each embolic agent was used for haemostasis showed a significant difference between cases in which GS only was used and cases in which NBCA only was used. In a comparison of mean transfusion volume, a significant difference was seen between cases in which both GS and NBCA were used and cases in which NBCA only was used. In a postoperative follow-up survey, menses resumed in eight patients, including four patients who later became pregnant and three who delivered.Conclusions:TAE with NBCA, which has an embolic effect unrelated to clotting dysfunction for massive haemorrhage during the peripartum period, is a minimally invasive and very effective treatment method for patients with severe DIC. © 2013 Igarashi et al.

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Comparison of the right and left ventricular performance during the fetal development using velocity vector imaging

Kim Seon Hye, Miyakoshi Kei, Kadohira Ikuko, Tanaka Mamoru, Minegishi Kazuhiro, Matsumoto Tadashi, Yoshimura Yasunori

Early Human Development 89 ( 9 ) 675 - 681 2013.09

ISSN 0378-3782

Background: Studies on myocardial characteristics examined by speckle-tracking echocardiography are limited. Aims: To compare myocardial performance between the right and left ventricles during the fetal development using velocity vector imaging (VVI). Subjects and study design: Echocardiograms of 95 uncomplicated singleton fetuses (19-36. weeks pregnancy) were retrospectively analyzed by VVI to measure global longitudinal peak velocity, strain, and strain rate of both the right ventricle (RV) and left ventricle (LV). The regional values were calculated for three segments (base, mid, and apex) of the ventricular free wall and segment. Outcome measures: The VVI-derived measurements were examined for gestational age and compared between ventricles. Results: The global peak systolic and diastolic velocity values of both ventricles significantly increased over gestation examined, whereas the global systolic strain and strain rate were stable (RV: strain -. 22.6. ±5.0%, strain rate -. 2.6. ±. 0.7/s; LV: strain -. 21.5. ±. 5.6%, strain rate -. 2.5. ±. 0.7/s). Compared to the LV, the RV showed significantly higher global velocity in systole and diastole (P =0.001 for systole, P<. 0.001 for diastole). The global systolic velocity of the LV increased close to the RV toward term, whereas the RV was dominant in diastole throughout the examined gestation. Basal strain and strain rate in the RV were significantly greater than that of the LV, although there were no significant differences in the middle and apical values between ventricles. Conclusion: Our findings suggest the RV predominance of longitudinal contraction and dilatation, compared to the LV in uncomplicated fetuses. © 2013 Elsevier Ltd.

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Reproductive and obstetric outcomes after radical abdominal trachelectomy for early-stage cervical cancer in a series of 31 pregnancies.

Nishio Hiroshi, Fujii Takuma, Sugiyama Juri, Kuji Naoaki, Tanaka Mamoru, Hamatani Toshio, Miyakoshi Kei, Minegishi Kazuhiro, Tsuda Hiroshi, Iwata Takashi, Tanaka Kyoko, Fukuchi Takeshi, Takehara Yuji, Yoshimura Yasunori, Aoki Daisuke

Human reproduction (Oxford, England) 28 ( 7 ) 1793 - 1798 2013.07

What are the reproductive and obstetric outcomes in patients undergoing radical abdominal trachelectomy (RAT) for early-stage cervical cancer? When RAT was performed before a pregnancy achieved with fertility treatments, pregnancy rate of 36.2% was obtained and 71.4% of these women gave birth at ≥ 32 weeks of gestation. Reproductive and obstetric outcomes after radical vaginal trachelectomy (RVT) are well documented; however, these outcomes after RAT have not been well studied. This is a retrospective cohort study of patients at a single institution who underwent RAT and became pregnant. Reproductive and obstetric outcomes of 114 patients who had undergone RAT from September 2002 to December 2010 were investigated. Women of reproductive age with early-stage cervical cancer who wished to preserve their fertility were documented. Patients' median age was 33 years (25-40 years). A total of 31 pregnancies were achieved in 25 patients and 6 patients had 2 pregnancies. Eighteen of 25 patients (72.0%) had infertility problems; 17 patients conceived with IVF-embryo transfer and 1 patient with intrauterine insemination. The pregnancy rate among patients who wished to conceive was 36.2% (25/69). Among 31 pregnancies in 25 patients, 4 patients had first trimester miscarriage and 1 patient had second trimester miscarriage. Excluding the five patients who miscarried and the five ongoing pregnancies, all the 21 patients had deliveries by Cesarean section. Four patients had a preterm birth in the second trimester and 17 patients delivered in the third trimester. Of the 17 pregnancies that reached the third trimester, 2 (11.8%) were preterm births between 29 and 32 weeks, 11 (64.7%) were delivered between 32 and 37 weeks and 4 (23.5%) at ≥ 37 weeks of gestation. Because of the retrospective data collection, not all pregnancies may have been recorded. Prospective multicenter studies are needed to determine if the results shown in this retrospective cohort can be generalized to all patients with early-stage cervical cancer who wish to undergo the fertility-sparing RAT procedure.

Early second-trimester diagnosis of body stalk anomaly by fetal magnetic resonance imaging

Higuchi Takayuki, Sato Hiroaki, Iida Miho, Kim Seon Hye, Narimatsu Yoshiaki, Tanaka Mamoru

Japanese Journal of Radiology 31 ( 4 ) 289 - 292 2013.04

ISSN 1867-1071

We report a case of body stalk anomaly detected prenatally by fetal magnetic resonance imaging (MRI) at 14 weeks' gestation. A 29-year-old woman was followed during her first pregnancy. At 11-12 weeks' gestation, our sonographic images showed multiple fetal deformities. An abdominal wall defect was suspected. The exteriorized abdominal contents and the lower limb appeared within the extraembryonic celom with an intact amniotic membrane. Fetal MRI at 14 weeks' gestation confirmed a large anterior wall defect with herniation of the liver and bowel. In addition, abnormally rotated lower limb and scoliosis could be demonstrated. The fetus was prenatally diagnosed with body stalk anomaly, expected to be lethal in nature. The parents decided to terminate the pregnancy at 15 weeks' gestation. Prenatal diagnosis of body stalk anomaly is usually based on sonographic findings. As far as we are aware, this is the first case report of body stalk anomaly satisfactorily diagnosed by fetal MRI in the early second trimester. Fetal MRI scans should provide ground for a precise antenatal diagnosis of body stalk anomaly from early gestation. © 2013 Japan Radiological Society.

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Abnormal first-trimester fetal nuchal translucency and amniotic band syndrome

Higuchi Takayuki, Tanaka Mamoru, Kuroda Keiko, Yabuno Akira, Kim Seon Hye, Asai Satoshi, Iwata Sokichi, Miyakoshi Kei

Journal of Medical Ultrasonics 39 ( 3 ) 177 - 180 2012.07

ISSN 1346-4523

We report a case of amniotic band syndrome diagnosed prenatally by serial sonographic examinations. Our initial sonographic image showed a large fetal nuchal translucency (NT) at 12 weeks' gestation. Repeated fetal ultrasound images revealed an amniotic band and right upper limb anomaly. Fetal MRI at 19 weeks' gestation revealed right forearm hypoplasia and pseudosyndactyly. The fetus was prenatally diagnosed with amniotic band syndrome and was suspected of having severe functional impairment of the deformed limb. The parents decided to terminate the pregnancy at 21 weeks' gestation. In fetuses with aneuploidy and various structural and genetic abnormalities, the NT thickness is increased in the first trimester. As far as we are aware, this is the first case report of increased NT and limb anomaly associated with amniotic band syndrome. In chromosomally normal fetuses with increased NT, intensive sonographic follow-up should provide grounds for a precise antenatal diagnosis. © The Japan Society of Ultrasonics in Medicine 2012.

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Antepartum oral disposition index as a predictor of glucose intolerance postpartum

Saisho Yoshifumi, Miyakoshi Kei, Tanaka Mamoru, Matsumoto Tadashi, Minegishi Kazuhiro, Yoshimura Yasunori, Itoh Hiroshi

Diabetes Care 35 ( 4 ) 2012.04

ISSN 0149-5992

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Retrospective evaluation of intravenous fentanyl patient-controlled analgesia during labor

Hosokawa Yuki, Miyakoshi Kei, Morisaki Hiroshi, Tanaka Mamoru, Nakatsuka Itsuo, Yoshimura Yasunori, Hashiguchi Saori, Takeda Junzo

Journal of Anesthesia 26 ( 2 ) 219 - 224 2012.04

ISSN 0913-8668

Purpose Because the safety of intravenous fentanyl patient-controlled analgesia (iv-PCA) administered during labor remains unclear, we retrospectively examined the labor records from January 2005 to December 2007 in our institution, with a focus on both maternal and neonatal outcomes, as compared to no analgesia. Methods Parturients over 35 weeks of gestational age who received fentanyl iv-PCA (iv-PCA group) or no analgesia (control group) during labor were enrolled. The former group received iv-PCA through a pump programmed to give a loading dose of 0.05 mg fentanyl, followed by bolus injection of 0.02 mg fentanyl, with a lock-out interval of 5 min. This analgesia was initiated at the parturient's request and was discontinued before the second stage of labor, to ensure neonatal safety. During labor, both maternal and fetal heart rates, maternal pulse oximeter oxygen saturation (SpO ₂), respiratory rate, and sedation and nausea scores were continuously monitored, and the neonatal outcomes including umbilical arterial pH, Apgar scores, and other parameters were recorded. Results The data of 129 of the 143 parturients who received fentanyl iv-PCA were analyzed, while 697 parturients delivered without any analgesia during the 3-year study period. While iv-PCA prolonged the duration of labor and increased oxytocin use, no obvious maternal or neonatal complications of fentanyl use were recorded. Except for the significantly lower rate of emergency cesarean section in the iv-PCA group, both the maternal and neonatal outcomes were comparable between the groups. Conclusions As compared to no analgesia, fentanyl iv-PCA appears to be safe and clinically acceptable as analgesia during labor, particularly in nulliparous women. © 2011 Japanese Society of Anesthesiologists.

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Fetal growth and gestational hypertension in women classified as gestational diabetes mellitus defined by the new consensus criteria only

Matsumoto Tadashi, Miyakoshi Kei, Minegishi Kazuhiro, Tanaka Mamoru, Yoshimura Yasunori

Acta Obstetricia et Gynecologica Scandinavica 91 ( 2 ) 272 - 273 2012.02

ISSN 0001-6349

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Dreaming of fetal ICU

Tanaka Mamoru

Journal of Medical Ultrasonics 38 ( 2 ) 63 - 64 2011.04

ISSN 1346-4523

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Final diagnosis in patients with congenital cystic lung disease detected by fetal ultrasonography

Kuratsuji Gen, Hokuto Isamu, Higuchi Masataka, Koinuma Goro, Morikawa Yasuhide, Hoshino Ken, Tanaka Mamoru, Miyakoshi Kei, Ikeda Kazushige

Pediatrics International 53 ( 1 ) 131 - 132 2011.02

ISSN 1328-8067

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Pancreatic β-cell function in women with gestational diabetes mellitus defined by new consensus criteria

Miyakoshi Kei, Saisho Yoshifumi, Tanaka Mamoru, Shimada Akira, Itoh Hiroshi, Yoshimura Yasunori

Diabetes Care 34 ( 1 ) 2011.01

ISSN 0149-5992

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Midkine, a Heparin-Binding Growth Factor, Selectively Stimulates Proliferation of Definitive Zone Cells of the Human Fetal Adrenal Gland

Ishimoto, H. Muench, M. O. Higuchi, T. Minegishi, K.TANAKA MAMORUYoshimura, Y. Jaffe, R. B.

J Clin Endocrinol Metab 91 ( 10 ) 4050-4056 2006.08

Research paper (scientific journal), Joint Work, Accepted

Differential zonal expression and adrenocorticotropin regulation of secreted protein acidic and rich in cysteine (SPARC), a matricellular protein, in the midgestation human fetal adrenal gland: implications for adrenal development

Ishimoto, H. Ginzinger, D. G. Matsumoto, T. Hattori, Y. Furuya, M. Minegishi, K.TANAKA MAMORUYoshimura, Y. Jaffe, R. B.

J Clin Endocrinol Metab 91 ( 8 ) 3208-3214 2006.08

Research paper (scientific journal), Joint Work, Accepted

Prenatal diagnosis of hemifacial microsomia by magnetic resonance imaging

Hattori, Y. TANAKA MAMORU Matsumoto, T. Uehara, K. Ueno, K. Miwegishi, K. Ishimoto, H. Miyakoshi, K. Yoshimura, Y.

J Perinat Med 33 ( 1 ) 69-71 2005.01

Research paper (scientific journal), Joint Work, Accepted

H1FOO Is Coupled to the Initiation of Oocytic Growth.

TANAKA MAMORUKihara, M. Hennebold, J. D. Eppig, J. J. Viveiros, M. M. Emery, B. R. Carrell, D. T. Kirkman, N. J. Meczekalski, B. Zhou, J. Bondy, C. A. Becker, M. Schultz, R. M. Misteli, T. De La Fuente, R. King, G. J. Adashi, E. Y.

Biol Reprod 72 ( 1 ) 135-142 2005.01

Research paper (scientific journal), Joint Work, Accepted

Absent inner dynein arms in a fetus with familial hydrocephalus-situs abnormality

Kosaki, K. Ikeda, K. Miyakoshi, K. Ueno, M. Kosaki, R. Takahashi, D. Tanaka, M. Torikata, C. Yoshimura, Y. Takahashi, T.

Am J Med Genet 129 ( 3 ) 308-311 2004.09

Research paper (scientific journal), Joint Work

Pulmonary Hypoplasia: Prediction with Use of Ratio of MR Imaging-measured Fetal Lung Volume to US-estimated Fetal Body Weight

Tanigaki, S. Miyakoshi, K. Tanaka, M. Hattori, Y. Matsumoto, T. Ueno, K. Uehara, K. Nishimura, O. Minegishi, K. Ishimoto, H. Shinmoto, H. Ikeda, K. Yoshimura, Y.

Radiology 232 ( 3 ) 767-772 2004.09

Research paper (scientific journal), Joint Work, Accepted

Hypertensive disorders in Japanese women with gestational glucose intolerance

Miyakoshi, K. Tanaka, M. Matsumoto, T. Hattori, Y. Ueno, K. Teranishi, T. Minegishi, K. Ishimoto, H. Shimada, A. Yoshimura, Y.

Diabetes Res Clin Pract 64 ( 3 ) 201-205 2004.06

Research paper (scientific journal), Joint Work, Accepted

Rapid replacement of somatic linker histones with the oocyte-specific linker histone H1foo in nuclear transfer

Teranishi, T. TANAKA MAMORU Kimoto, S. Ono, Y. Miyakoshi, K. Kono, T. Yoshimura, Y.

Dev Biol 266 ( 1 ) 76-86 2004.02

Research paper (scientific journal), Joint Work, Accepted

Rapid replacement of somatic linker histones with the oocyte-specific linker histone H1foo in nuclear transfer

Teranishi, T. Tanaka, M. Kimoto, S. Ono, Y. Miyakoshi, K. Kono, T. Yoshimura, Y.

Dev Biol 266 ( 1 ) 76-86 2004.02

Research paper (scientific journal), Joint Work, Accepted

Massive hepatic infarction in preeclampsia: successful treatment with continuous hemodiafiltration and corticosteroid therapy

Miyakoshi, K. Tanaka, M. Ono, A. Ohno, R. Serita, T. Suzuki, H. Shinmoto, H. Morisaki, H. Yoshimura, Y.

J Perinat Med 32 ( 5 ) 453-455 2004

Research paper (scientific journal), Joint Work, Accepted

Fetal goitrous hypothyroidism followed by neonatal transient hyperthyroidism

Matsumoto Tadashi， Miyakoshi Kei， Kasai Kenji， Ishimoto Hitoshi， Tanaka Mamoru，　Ikeda Kazushige， Yoshimura Yasunori

Fetal Diagnosis and Therapy 18 459-462 2003.07

Research paper (scientific journal), Joint Work

難産を考える難産因子とその対策胎児付属物の異常

宮越　敬，田中　守，服部純尚，松本　直，吉村泰典

産科と婦人科 53 ( 7 ) 907-912 2003.07

Research paper (scientific journal), Joint Work

Checkmark fetal heart rate pattern associated with severe fetal hypoxia : A case report

Kashiwagi Satoshi， Miyakoshi Kei， Ishimoto Hitoshi， Tanaka Mamoru， Yoshimura Yasunori

Fetal Diagnosis and Therapy 18 237-239 2003.07

Research paper (scientific journal), Joint Work

The generation and characterization of an ovary-selective cDNA library

Tanaka Mamoru，　Hennebold Jon D.， Miyakoshi Kei， Teranishi Takahide， Ueno Kazunori，　Adashi Eli Y.

Molecular and Cellular Endocrinology 202 ( 39084 ) 67-69 2003.04

Research paper (scientific journal), Joint Work

''Cutoff value of 1 h,50 g glucose challenge test for screening of gestational diabetes mellitus in a Japanese population ''

Miyakoshi Kei， Tanaka Mamoru， Ueno Kazunori， Uehara Katsuhiko， Ishimoto Hitoshi， Yoshimura Yasunori

Diabetes Research and Clinical Practice 60 63-67 2003.04

Research paper (scientific journal), Joint Work

''Cutoff value of 1h,50 g glucose challenge test for screening of gestational diabetes mellitus in a Japanese population ''

Miyakoshi Kei， Tanaka Mamoru， Ueno Kazunori， Uehara Katsuhiko， Ishimoto Hitoshi， Yoshimura Yasunori

Diabetes Research and Clinical Practice 60 63-67 2003.04

Research paper (scientific journal), Joint Work

H1oo a pre-embryonic H1 linker histone in search of a function

Tanaka Mamoru，　Kihara Maki，　Meczekalski Blazej，　King Gretchen J.，　Adashi Eri Y.

Molecular and Cellular Endocrinology 202 ( 39084 ) 39211 2003.04

Research paper (scientific journal), Joint Work

Structure and expression of the human oocyte-specific histone H1 gene elucidated by direct RT-nested PCR of a single oocyte

Tanaka Yudai， Kato Shingo， Tanaka Mamoru， Kuji Naoaki， Yoshimura Yasunori

Biochemical and Biophysical Research Communications 304 351-357 2003

Research paper (scientific journal), Joint Work

Power and colour Doppler ultrasonography for the evaluation of the vasculature of the human corpus luteum

Miyazaki Toyohiko, Tanaka Mamoru, Miyakoshi Kei, Minegishi Kazuhiro, Kasai Kenji, Yoshimura Yasunori

Human Reproduction 13 ( 10 ) 2836-2841 1998.12

Research paper (scientific journal), Joint Work

Decidualized ovarian endometriosis mimicking malignancy

Miyakoshi Kei, Tanaka Mamoru, Gabionza Danilo, Takamatsu Kiyoshi, Miyazaki Toyohiko, Yuasa Yuji, Mukai Makio, Yoshimura Yasunori

American Journal of Roentgenology 171 1625-1626 1998.12

Research paper (scientific journal), Joint Work

Effect of danazol on the pregnancy rate in patients with unsuccessful in vitro fertilization-embryo transfer

Tei Chisei, Miyazaki Toyohiko, Kuji Naoaki, Tanaka Mamoru, Sueoka Kou, Yoshimura Yasunori

The Journal of Reproductive Medicine 43 ( 6 ) 541-546 1998.06

Research paper (scientific journal), Joint Work

Prenatal ultrasound diagnosis of small-bowel torsion

Miyakoshi Kei, Tanaka Mamoru, Miyazaki Toyohiko, Yoshimura Yasanori

Obstetrics and Gynecology 91 ( 5 ) 802-803 1998.05

Research paper (scientific journal), Joint Work

Role of β1 integrins in human endometrium and decidua during implantation

Yoshimura Yasunori, Miyakoshi Kei, Hamatani Toshio, Iwahashi Kazuhiro, Takahashi Jun, Kobayashi Noriko, Sueoka Kou, Miyazaki Toyohiko, Kuji Naoaki, Tanaka Mamoru

Hormone Research 50 ( Supp1 2 ) 46-55 1998.04

Research paper (scientific journal), Joint Work

Effects of infertility therapeutics on maternal infection resulting in premature rupture of the membranes

Kasai Kenji, Miyazaki Toyohiko, Minegishi Kazuhiro, Miyakoshi Kei, Tanaka Mamoru, Yoshimura Yasunori

Advances in Obstetrics and Perinatology 9 107-111 1998

Research paper (scientific journal), Joint Work

Effect of a delay in sampling on determination of umbilical arterial blood pH and gases

Tanaka Mamoru, Miyazaki Toyohiko, Miyakoshi Kei, Yoshimura Yasunori

Jpn J Obstet Gynecol Neonatal Hematol 7 ( 3 ) 88-93 1997.10

Research paper (scientific journal), Joint Work

Effects of a thromboxane synthetase inhibitor (OKY-046) in an ischemia─reperfusion model of intrauterine growth retardation in sprague-dawley rats

Tanaka Mamoru, Natori Michiya, Ishimoto Hitishi, Miyakoshi Kei, Miyazaki Toyohiko, Kobayashi Toshifumi, Yoshimura Yasunori

Biol Neonate 72 ( 3 ) 181-186 1997.09

Research paper (scientific journal), Joint Work

A retrospictive evaluation of maternal serum screening for the detection of fetal aneuploidy

Suzumori Kaoru, Tanemura Mitsuyo, Murakami Isamu, Natori Michiya, Tanaka Mamoru, Takagi Tsukasa, Satoh Akio

Prenat Diagn 17 ( 9 ) 861-866 1997.09

Research paper (scientific journal), Joint Work

Integrins and reproductive physiology : Expression and modulation in fertilization, embryogenesis, and implantation

Sueoka Kou, Shiokawa Shigetatsu, Miyazaki Toyohiko, Kuji Naoaki, Tanaka Mamoru, Yoshimura Yasunori

Fertil Steril 67 ( 5 ) 799-811 1997.05

Research paper (scientific journal), Joint Work

Role of oxygen-derived free radicals in fetal growth retardation induced by ishemia-reperfusion in rats

Ishimoto Hitoshi, Natori Michiya, Tanaka Mamoru, Miyazaki Toyohiko, Kobayashi Toshifumi, Yoshimura Yasunori

Am J Physiol 272 H701-H705 1997.02

Research paper (scientific journal), Joint Work

Insulin-like growth factor-I induces follicular development by stimulating ovarian production of angiotensin II

Kuji Naoaki, Miyazaki Toyohiko, Sueoka Kou, Tanaka Mamoru, Kiyokawa Kaoru, Kitaoka Yoshihisa, Yamauchi Jun, Hashiba Tsuyoshi, Nemoto Taiko, Kobayashi Toshifumi, Yoshimura Yasunori

Jpn J Fertil Steril 42 ( 1 ) 9-21 1997.01

Research paper (scientific journal), Joint Work

Role of oxygen-derived free radicals in fetal growth retardation induced by ischemia-reperfusion in rats

Ishimoto Hitoshi, Natori Michiya, Tanaka Mamoru, Miyazaki Toyohiko, Kobayashi Yoshifumi, Yoshimura Yasunori

Am J Physiol 272 701-705 1997

Research paper (scientific journal), Joint Work

Involvement of angiotensin II in the process of gonadotropin-induced ovulation in rabbits

Kuji Naoaki, Sueoka Kou, Miyazaki Toyohiko, Tanaka Mamoru, Oda Takahisa, Kobayashi Toshifumi, Yoshimura Yasunori

Biol Reprod 55 ( 5 ) 984-991 1996.11

Research paper (scientific journal), Joint Work

Interactions between insulin-like growth factor-I (IGF-I) and the renin-angiotensin system in follicular growth and ovulation

Yoshimura Yasunori, Aoki Nobumitsu, Sueoka kou, Miyazaki Toyohiko, Kuji Naoaki, Tanaka Mamoru, Kobayashi Toshifumi

J Clin Invest 98 ( 2 ) 308-316 1996.07

Research paper (scientific journal), Joint Work

Effects of insulin-like growth factor-I on follicle growth, oocyte maturation, and ovarian steroidogenesis and plasminogen activator activity in the rabbit

Yoshimura Yasunori, Ando Motoko, Nagamatsu Shinya, Iwashita Mitsutoshi, Adachi Tomoko, Sueoka Kou, Miyazaki Toyohiko, Kuji Naoaki, Tanaka Mamoru

Biol Reprod 55 ( 1 ) 152-160 1996.07

Research paper (scientific journal), Joint Work

A case of fetal bradycardia and sinusoid-like fetal heart rate pattern associated with maternal hypothermia

Tanaka M, Ikeda T, Suzuki T, Yakubo K, Fukuiya T

Fetal Diagn Ther 10 ( 3 ) 207-209 1995.05

Research paper (scientific journal), Joint Work

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