Research Achievements - Original paper -

Designing artificial circadian environments with multisensory cares for supporting preterm infants' growth in NICUs.

Takeshi Arimitsu, Rika Fukutomi, Mayuko Kumagai, Hayato Shibuma, Yoko Yamanishi, Kei-Ichi Takahashi, Hirotaka Gima, Yoshitaka Seto, Hiroyuki Adachi, Hirokazu Arai, Masakatsu Higuchi, Shohei Ohgi, Hidenobu Ohta

Frontiers in neuroscience ( Frontiers in Neuroscience )  17   1152959 - 1152959   2023.08  [Refereed]

Research paper (journal)  

Previous studies suggest the importance of stable circadian environments for fetuses to achieve sound physiology and intrauterine development. This idea is also supported by epidemiological and animal studies, in which pregnant females exposed to repeated shifting of light-dark cycles had increased rates of reproductive abnormalities and adverse pregnancy outcomes. In response to such findings, artificial circadian environments with light-dark (LD) cycles have been introduced to NICUs to promote better physical development of preterm infants. Such LD cycles, however, may not be fully effective for preterm infants who are less than 30 weeks gestational age (WGA) since they are too premature to be adequately responsive to light. Instead, circadian rhythmicity of incubated preterm infants less than 30 WGA may be able to be developed through stimulation of the non-visual senses such as touch and sound.

DOI PubMed

Association Between History of Psychiatric Disorder and Degree of Physical Injury Among Suicide Attempters: Secondary Data Analysis in a Japanese Rural Area.

Fumiya Tanji, Syohei Miyamoto, Atsushi Iwasawa, Hidenobu Ohta, Kyoichi Ono

Journal of primary care & community health ( Journal of Primary Care and Community Health )  14   21501319231212317 - 21501319231212317   2023  [Invited]

Research paper (journal)  

INTRODUCTION: While there may be differences in the choice of suicide methods between attempters with and those without a history of psychiatric disorders, it is not clear whether these differences predict the actual degree of physical injury. The present study aimed to investigate the association between the history of psychiatric disorder and the degree of physical injury among suicide attempters in a Japanese rural area. METHODS: We conducted a cross-sectional study analyzing secondary data of 806 suicide attempters from April 2012 to March 2022 obtained from a Japanese rural city. The exposure variable was a history of psychiatric disorders. The primary outcome was the degree of physical injury of suicide attempters: moderate and severe. We conducted a multivariate Poisson regression analysis to estimate the prevalence ratios (PRs) and 95% confidence intervals (CIs). RESULTS: Among 806 suicide attempters, a significant negative association between the history of psychiatric disorder and the degree of physical injury was observed (PR = 0.40; 95% CI, 0.28-0.59). Those with and without psychiatric disorders were more likely to choose low- and severe-lethality suicide methods such as drug or psychotropic overdoses and hanging or deep wrist injuries, respectively (P < .001). CONCLUSIONS: The present study highlights the importance of considering suicide attempters, both with and without psychiatric disorders, while formulating targeted suicide prevention strategies.

DOI PubMed

The shape of disposable diaper affects spontaneous movements of lower limbs in young infants.

Gima H, Teshima M, Tagami E, Sato T, Ohta H.

Sci Rep.   9 ( 1 ) 16176   2019.11  [Refereed]

Research paper (journal)   Domestic Co-author

DOI

アクティワッチ(小型照度・活動量計)による極低出生体重児の発達予後予測の可能性

下風 朋章, 太田 英伸, 兼次 洋介, 斎藤 朋子, 豊島 勝昭

日本新生児成育医学会雑誌 ( (公社)日本新生児成育医学会 )  31 ( 3 ) 744 - 744   2019.10

Research paper (journal)  

Combined effects of body position and sleep status on the cardiorespiratory stability of near-term infants

Yoshihisa Oishi, Hidenobu Ohta, Takako Hirose, Sachiko Nakaya, Keiji Tsuchiya, Machiko Nakagawa, Isao Kusakawa, Toshihiro Sato, Toshimasa Obonai, Hiroshi Nishida, Hitoshi Yoda

Scientific Reports ( Nature Publishing Group )  8 ( 1 ) 8845   2018.12

Research paper (journal)  

The purpose of this study was to determine the effects of body position (prone, supine and lateral) together with sleep status (wake and sleep) on the cardiorespiratory stability of near-term infants. A total of 53 infants (gestational age at birth 33.2 ± 3.5 weeks
birth weight 1,682 ± 521 g
gestational age at recording 38.6 ± 2.1 weeks
weight at recording: 2,273 ± 393 g) were monitored for 24 hours for clinically significant apnea (&gt
15 seconds), bradycardia (&lt
100 bpm), and oxygen desaturation (SpO2 &lt
90%) in alternating body positions (prone, supine and lateral) by cardiorespiratory monitors and 3-orthogonal-axis accelerometers. Sleep status of the infants was also continuously monitored by actigraphs. No apnea was observed. During wake, severe bradycardia was most frequently observed in the lateral position while, during sleep, severe bradycardia was most frequently observed in the supine position. Desaturation was most frequently observed in the supine and lateral positions during both wake and sleep. Our study suggests that the cardiorespiratory stability of infants is significantly compromised by both body position and sleep status. During both wake and sleep, prone position induces the most stable cardiorespiratory functions of near-term infants.

DOI PubMed

Entrainment of the Circadian Clock in Neural Stem Cells by Epidermal Growth Factor is Closely Associated with ERK1/2-mediated Induction of Multiple Clock-related Genes

Asuka Mogi, Ryo Yomoda, Syunya Kimura, Chisato Tsushima, Jun Takouda, Miho Sawauchi, Tomoko Maekawa, Hidenobu Ohta, Satoshi Nishino, Masatake Kurita, Nariyasu Mano, Noriko Osumi, Takahiro Moriya

Neuroscience ( Elsevier Ltd )  379   45 - 66   2018.05

Research paper (journal)  

The mitotic activity of certain tissues in the body is closely associated with circadian clock function. However, the effects of growth factors on the molecular clockwork are not fully understood. Stimulation of neural stem cells (NSCs) with epidermal growth factor (EGF), a well-known mitogen, is known to cause synchronized cell cycle progression with a period of approximately 24 h, closely associated with the Per2 gene expression rhythm. Here, we examined the effects of EGF on the molecular clockwork of NSCs. Treatment of cultured NSCs derived from embryonic mouse forebrain with EGF (20 ng/mL) caused a phase shift in the PER2::LUCIFERASE bioluminescence rhythm in a stimulation time-dependent manner. The EGF phase-response curve differed from that of forskolin (FK)—a well-known chemical resetting stimulus—both in the advance/delay ratio and stimulation time-dependency. PCR array analysis followed by quantitative PCR validation demonstrated that EGF treatment transiently induced multiple clock-related genes including Per1, Per2, Dec1, e4bp4, and Noct, whereas FK treatment induced a limited number of genes (Per1 and Dec1), suggesting that the mode of entrainment of NSC molecular clock was different for EGF and FK. EGF led to gene induction in the presence of cycloheximide, suggesting that de novo protein synthesis is unnecessary. Pretreatment with the MEK1/2 inhibitor U0126 significantly suppressed the acute induction of Per2, Dec1, and Noct by EGF and also abolished the EGF-induced phase shift of the PER2::LUCIFERASE rhythm in NSCs. These results suggest a unique effect of EGF on the molecular clockwork of NSCs.

DOI PubMed

Potential New Non-Invasive Therapy Using Artificial Oxygen Carriers for Pre-Eclampsia.

Ohta H, Kaga M, Li H, Sakai H, Okamura K, Yaegashi N

Journal of functional biomaterials   8 ( 3 )   2017.07

Research paper (journal)  

DOI PubMed

TSH and PRL, side-effect markers in aripiprazole treatment: Adjunctive aripiprazole-induced thyrotropin oversuppression in a young man with schizophrenia

Hidenobu Ohta, Satoru Inoue, Koichiro Hara, Akihiko Watanabe

BMJ Case Reports ( BMJ Publishing Group )  2017   2017

Research paper (journal)  

A 26-year-old Japanese man was admitted to our unit with exacerbated paranoid schizophrenia. Prior to his admission, daily administration of olanzapine had been sufficient to maintain a partial remission of his schizophrenia, but due to an exacerbation of his delusions, he had then also been prescribed aripiprazole, which had been followed by no improvement in symptoms and a gradual further exacerbation of auditory delusions. Physical examinations, brain MRI and neurophysiological assessment were unremarkable. Blood analysis, however, revealed extremely low thyroid-stimulating hormone (TSH) and prolactin-releasing hormone (PRL) concentration. Interestingly, after aripiprazole discontinuation, he returned to partial remission with an increase in plasma TSH and PRL concentration.

DOI PubMed

Daytime nap controls toddlers' nighttime sleep

Machiko Nakagawa, Hidenobu Ohta, Yuko Nagaoki, Rinshu Shimabukuro, Yoko Asaka, Noriko Takahashi, Takayo Nakazawa, Yousuke Kaneshi, Keita Morioka, Yoshihisa Oishi, Yuriko Azami, Mari Ikeuchi, Mari Takahashi, Michio Hirata, Miwa Ozawa, Kazutoshi Cho, Isao Kusakawa, Hitoshi Yoda

SCIENTIFIC REPORTS ( NATURE PUBLISHING GROUP )  6   27246   2016.06

Research paper (journal)  

Previous studies have demonstrated that afternoon naps can have a negative effect on subsequent nighttime sleep in children. These studies have mainly been based on sleep questionnaires completed by parents. To investigate the effect of napping on such aspects of sleep quality, we performed a study in which child activity and sleep levels were recorded using actigraphy. The parents were asked to attach actigraphy units to their child's waist by an adjustable elastic belt and complete a sleep diary for 7 consecutive days. 50 healthy young toddlers of approximately 1.5 years of age were recruited. There was a significant negative correlation between nap duration and both nighttime sleep duration and sleep onset time, suggesting that long nap sleep induces short nighttime sleep duration and late sleep onset time. We also found a significant negative correlation between nap timing and nighttime sleep duration and also a significant positive correlation between nap timing and sleep onset time, suggesting that naps in the late afternoon also lead to short nighttime sleep duration and late sleep onset. Our findings suggest that duration-controlled naps starting early in the afternoon can induce a longer nighttime sleep in full-term infants of approximately 1.5 years of age.

DOI PubMed

Influence of light exposure at nighttime on sleep development and body growth of preterm infants

Yosuke Kaneshi, Hidenobu Ohta, Keita Morioka, Itaru Hayasaka, Yutaka Uzuki, Takuma Akimoto, Akinori Moriichi, Machiko Nakagawa, Yoshihisa Oishi, Hisanori Wakamatsu, Naoki Honma, Hiroki Suma, Ryuichi Sakashita, Sei-ichi Tsujimura, Shigekazu Higuchi, Miyuki Shimokawara, Kazutoshi Cho, Hisanori Minakami

SCIENTIFIC REPORTS ( NATURE PUBLISHING GROUP )  6   21680   2016.02

Research paper (journal)  

Previous studies have demonstrated that a light-dark cycle has promoted better sleep development and weight gain in preterm infants than constant light or constant darkness. However, it was unknown whether brief light exposure at night for medical treatment and nursing care would compromise the benefits brought about by such a light-dark cycle. To examine such possibility, we developed a special red LED light with a wavelength of &gt; 675 nm which preterm infants cannot perceive. Preterm infants born at &lt; 36 weeks' gestational age were randomly assigned for periodic exposure to either white or red LED light at night in a light-dark cycle after transfer from the Neonatal Intensive Care Unit to the Growing Care Unit, used for supporting infants as they mature. Activity, nighttime crying and body weight were continuously monitored from enrolment until discharge. No significant difference in restactivity patterns, nighttime crying, or weight gain was observed between control and experimental groups. The data indicate that nursing care conducted at 3 to 4-hour intervals exposing infants to light for &lt; 15 minutes does not prevent the infants from developing circadian rest-activity patterns, or proper body growth as long as the infants are exposed to regular light-dark cycles.

DOI PubMed

Electrochemical analysis of optical switchable filter with a NiO thin film for high-performance incubators

K. Tajima, M. Nakagavva, Y. Oishi, H. Ohta

ECS Transactions ( Electrochemical Society Inc. )  75 ( 51 ) 1 - 7   2016

Research paper (journal)  

We report an optical switchable light filter fabricated from all solid-state materials for use in preterm infant incubators. The nickel oxide (NiO) thin film in the filter was fabricated by magnetron sputtering. The properties of the NiO thin film were also investigated. The optical switchable light filter also contained a W-Ir-0 thin film, because the widely used WO3 thin film shows an unsuitable EC color change to dark blue. The W-Ir-0 thin film did not absorb the longer wavelengths in the visible range, which is required for incubators. The optical switchable light filter containing the NiO thin film changed between pale yellow and dark yellow when a voltage was applied. The optical switching speed from the pale yellow to dark yellow state was around 60 s, and the reverse process was around 60 s. The fabrication of filters with a suitable color change for incubators requires further investigation.

DOI

Artificial oxygen carriers rescue placental hypoxia and improve fetal development in the rat pre-eclampsia model

Heng Li, Hidenobu Ohta, Yu Tahara, Sakiko Nakamura, Kazuaki Taguchi, Machiko Nakagawa, Yoshihisa Oishi, Yu-ichi Goto, Keiji Wada, Makiko Kaga, Masumi Inagaki, Masaki Otagiri, Hideo Yokota, Shigenobu Shibata, Hiromi Sakai, Kunihiro Okamura, Nobuo Yaegashi

SCIENTIFIC REPORTS ( NATURE PUBLISHING GROUP )  5   15271   2015.10

Research paper (journal)  

Pre-eclampsia affects approximately 5% of all pregnant women and remains a major cause of maternal and fetal morbidity and mortality. The hypertension associated with pre-eclampsia develops during pregnancy and remits after delivery, suggesting that the placenta is the most likely origin of this disease. The pathophysiology involves insufficient trophoblast invasion, resulting in incomplete narrow placental spiral artery remodeling. Placental insufficiency, which limits the maternal-fetal exchange of gas and nutrients, leads to fetal intrauterine growth restriction. In this study, in our attempt to develop a new therapy for pre-eclampsia, we directly rescued placental and fetal hypoxia with nano-scale size artificial oxygen carriers (hemoglobin vesicles). The present study is the first to demonstrate that artificial oxygen carriers successfully treat placental hypoxia, decrease maternal plasma levels of anti-angiogenic proteins and ameliorate fetal growth restriction in the pre-eclampsia rat model.

DOI PubMed

Correlation between umbilical cord hemoglobin and rate of jaundice requiring phototherapy in healthy newborns

Machiko Nakagawa, Yasushi Ishida, Yuko Nagaoki, Hidenobu Ohta, Rinshu Shimabukuro, Michio Hirata, Michiko Yamanaka, Isao Kusakawa

PEDIATRICS INTERNATIONAL ( WILEY-BLACKWELL )  57 ( 4 ) 626 - 628   2015.08

Research paper (journal)  

BackgroundDelay of umbilical cord clamping by at least 1min is recommended for newborns not requiring resuscitation in the International Liaison Committee On Resuscitation-Consensus on Science with Treatment Recommendations (ILCOR-CoSTR) 2010 guidelines. The delay in clamping improves iron status through early infancy but may increase the likelihood of jaundice requiring phototherapy. The present study investigated the relationship between umbilical cord hemoglobin and the rate of jaundice requiring phototherapy in healthy Japanese newborns.
MethodsCord hemoglobin was measured in healthy newborns and the rate of infants receiving phototherapy for jaundice and other data were obtained from medical records.
ResultsJaundice requiring phototherapy mostly occurred in association with high cord blood hemoglobin, which is increased by delayed cord clamping.
ConclusionsHigher cord hemoglobin may increase neonatal jaundice in newborns in Japan, therefore the present results support the Japan Resuscitation Council guideline 2010, which does not recommend delay of umbilical cord clamping by at least 1min, in contrast to the ILCOR guidelines.

DOI PubMed

Designing artificial environments for preterm infants based on circadian studies on pregnant uterus.

Shimpei Watanabe, Shizuko Akiyama, Takushi Hanita, Heng Li, Machiko Nakagawa, Yousuke Kaneshi, Hidenobu Ohta

Frontiers in endocrinology   4   113 - 113   2013.09

Research paper (journal)  

Using uterine explants from Per1::Luc rats and in situ hybridization, we recently reported that the circadian property of the molecular clock in the uterus and placenta is stably maintained from non-pregnancy, right through to the end stage of pregnancy under regular light-dark (LD) cycles. Despite long-lasting increases in progesterone during gestation and an increase in estrogen before delivery, the uterus keeps a stable Per1::Luc rhythm throughout the pregnancy. The study suggests the importance of stable circadian environments for fetuses to achieve sound physiology and intrauterine development. This idea is also supported by epidemiological and animal studies, in which pregnant females exposed to repeated shifting of the LD cycles have increased rates of reproductive abnormalities and adverse pregnancy outcomes. Leading from this, we introduced artificial circadian environments with controlled lighting conditions to human preterm infants by developing and utilizing a specific light filter which takes advantage of the unique characteristics of infants' developing visual photoreceptors. In spite of growing evidence of the physiological benefits of nighttime exposure to darkness for infant development, many Japanese Neonatal Intensive Care Units (NICUs) still prefer to maintain constant light in preparation for any possible emergencies concerning infants in incubators. To protect infants from the negative effects of constant light on their development in the NICU, we have developed a new device similar to a magic mirror, by which preterm infants can be shielded from exposure to their visible wavelengths of light even in the constant light conditions of the NICU while simultaneously allowing medical care staff to visually monitor preterm infants adequately. The device leads to significantly increased infant activity during daytime than during night time and better weight gains.

DOI PubMed

Controllable light filters using an all-solid-state switchable mirror with a Mg-Ir thin film for preterm infant incubators

Kazuki Tajima, Mika Shimoike, Heng Li, Masumi Inagaki, Hitomi Izumi, Misaki Akiyama, Yukiko Matsushima, Hidenobu Ohta

APPLIED PHYSICS LETTERS ( AMER INST PHYSICS )  102 ( 16 ) 161913-161913-4   2013.04

Research paper (journal)  

We have fabricated a controllable light filter using an all-solid-state switchable mirror incorporating a Mg-Ir thin film for use in preterm infant incubators. The solid-state switchable mirror device was fabricated by depositing a multilayer on a glass substrate. The mixed hydride of MgH2 and Mg6Ir2H11 created from the Mg-Ir thin film is red in the transparent state. The optical switching speeds between the reflective and transparent red states depended on applied voltage. The device showed three states, namely, reflective, black, and transparent red, due to the properties of the switchable mirror material. These results suggest that the material could be used as a controllable light filter for preterm infant incubators, since it eliminates the light wavelength that disturbs regular sleep-wake cycles of preterm infants. (C) 2013 AIP Publishing LLC. [http://dx.doi.org/10.1063/1.4801848]

DOI J-GLOBAL

Behavioral and cortical EEG evaluations confirm the roles of both CCKA and CCKB receptors in mouse CCK-induced anxiety

Heng Li, Hidenobu Ohta, Hitomi Izumi, Yoshiki Matsuda, Mika Seki, Takako Toda, Misaki Akiyama, Yukiko Matsushima, Yu-ichi Goto, Makiko Kaga, Masumi Inagaki

BEHAVIOURAL BRAIN RESEARCH ( ELSEVIER SCIENCE BV )  237   325 - 332   2013.01

Research paper (journal)  

This study investigated the roles of cholecystokinin (CCK)(A) and CCKB receptors on CCK-4-induced anxiety-like behaviors in mice through behavioral and neural evaluations. Anxiety-like behaviors in mice were induced by an intracerebroventricular (icy.) administration of CCK-4, which can bind to both CCKA and CCKB receptors. The effects of CCKA and CCKB receptor antagonists (devazepide and CI-988, respectively) were examined using mouse anxiety tests (elevated-plus maze and light-dark box) and also by examining neuronal activities through EEG monitoring and c-Fos immunohistochemistry in the cortex and amygdala. CCK-4 (3 mu g/kg of body weight i.c.v.) significantly induced mouse anxiety-like behaviors in the anxiety tests and also affected their EEG patterns with respect to pre-drug tracing, resulting in increase in spectral power in relative power distribution in the delta and theta bands (0.5-5 Hz frequency bands) and also in increase in c-Fos immunopositive neuron counts. These CCK-4 effects were completely suppressed by 1.0 mg/kg CCKB receptor antagonist, CI-988, while the same amount of CCKA receptor antagonist, devazepide was partly able to suppress the same effects. These findings indicated that not only CCKB receptors but also CCKA receptors in the brain play important roles in regulating anxiety-like behaviors in mice. The present study also proposed a possibility that cortical EEG is useful for assessing anxiety. (C) 2012 Elsevier B.V. All rights reserved.

DOI PubMed

Developmental change of visuo-spatial working memory in children: Quantitative evaluation through an Advanced Trail Making Test

Naomi Kokubo, Masumi Inagaki, Atsuko Gunji, Tomoka Kobayashi, Hidenobu Ohta, Osami Kajimoto, Makiko Kaga

BRAIN & DEVELOPMENT ( ELSEVIER SCIENCE BV )  34 ( 10 ) 799 - 805   2012.11

Research paper (journal)  

Aim: The present study aimed to investigate the developmental change in Visuo-Spatial Working Memory (VSWM) in typically developed children using a specially designed Advanced Trail Making Test for children (ATMT-C). Methods: We developed a new method for evaluating VSWM efficiency in children using a modified version ATMT to suit their shorter sustained attention. The ATMT-C consists of two parts; a number-based ATMT and a hiragana (Japanese phonogram)-based ATMT, both employing symbols familiar to young children. A total of 94 healthy participants (6-28 years of age) were enrolled in this study. Results: A non-linear developmental change of VSWM efficiency was observed in the results from the ATMT-C. In the number-based ATMT, children under 8 years of age showed a relatively rapid increase in VSWM efficiency while older children (9-12 years) had a more gradual increase in VSWM efficiency. Results from the hiragana-based ATMT-C showed a slightly delayed increase pattern in VSWM efficiency compared to the pattern from the number-based ATMT. There were no significant differences in VSWM efficiency for gender, handedness and test order. Interpretation: VSWM in children gradually matures in a non steady-state manner and there is an important stage for VSWM maturation before reaching 12 years of age. VSWM efficiency may also vary depending on developmental condition of its cognitive subsystems. (C) 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

DOI PubMed

Liposome-encapsulated hemoglobin (hemoglobin-vesicle) is not transferred from mother to fetus at the late stage of pregnancy in the rat model

Maiko Kaga, Heng Li, Hidenobu Ohta, Kazuaki Taguchi, Shigeru Ogaki, Hitomi Izumi, Masumi Inagaki, Shigeru Tsuchiya, Kunihiro Okamura, Masaki Otagiri, Hiromi Sakai, Nobuo Yaegashi

LIFE SCIENCES ( PERGAMON-ELSEVIER SCIENCE LTD )  91 ( 11-12 ) 420 - 428   2012.10

Research paper (journal)  

Aims: Liposome-encapsulated hemoglobin (hemoglobin vesicles: HbV; diameter 250 nm) is reconstructed from human hemoglobin and developed as an artificial oxygen carrier for use as a transfusion alternative. Previous studies using rodent models closely investigated the safety of daily repeated infusions (DRI) of HbV and reported that the reticuloendothelial system was physiologically capable of degrading HbV to maintain plasma clinical chemistry within normal ranges. The present study examined the effect of DRI of HbV on the pregnant rat mother and fetal development, focusing on placental transfer of HbV in pregnancy.
Main methods: Pregnant rats intravenously received HbV bolus injections at 2 ml/kg/day for the last 7 consecutive days till term. The cumulative infusion volume (14 ml/kg) was equal to 25% of the whole blood volume (56 ml/kg).
Key findings: Maternal DRI of HbV had no obvious side effects on the pregnant mother or on fetal development. Maternal vital signs, plasma clinical chemistry, and blood gas parameters were overall normal after DRI of HbV. In addition, maternal/fetal transfer of HbV was limited to the placenta and HbV did not reach the fetus. Histopathological examination with human hemoglobin antibody detected HbV accumulation in the maternal spleen, liver, kidney, and placenta, but not in the fetuses. These results were also confirmed by a pharmacokinetic study using I-125-labeled HbV.
Significance: This safety study of HbV use in the pregnant mother and fetus will contribute to a possible application of HbV as a potential treatment for fetal hypoxia by supplying oxygen through the placenta. Crown Copyright (c) 2012 Published by Elsevier Inc. All rights reserved.

DOI PubMed

Physiolgical capacity of the reticuloendothelial system for the degradation of hemoglobin-vesicles (artificial oxygen carriers) after massive intravenous doses by daily repeated infusion for 7 days in Pregnant rats and fetuses.

M. Kaga, H. Ohta, Y. Lee, R. Kamii, H. Yamamoto, S. Akiyama, S. Watanabe, T. Matsuda, Y. Kimura, S. Tsuchiya, H. Tei, L. Okamura, H. Sakai, N. Yaegashi

Life Sci.   91   420-428   2012

Research paper (journal)  

Antenatal Corticosteroids Promote Survival of Extremely Preterm Infants Born at 22 to 23 Weeks of Gestation

Rintaro Mori, Satoshi Kusuda, Masanori Fujimura

JOURNAL OF PEDIATRICS ( MOSBY-ELSEVIER )  159 ( 1 ) 110 - U137   2011.07

Research paper (journal)  

Objective To evaluate the effectiveness of antenatal corticosteroid (ACS) to improve neonatal outcomes for infants born at &lt;24 weeks of gestation.
Study design We performed a retrospective analysis of 11 607 infants born at 22 to 33 weeks of gestation between 2003 and 2007 from the Neonatal Research Network of Japan. We evaluated the gestational age effects of ACS administered to mothers with threatened preterm birth on several factors related to neonatal morbidity and mortality.
Results By logistic regression analysis, ACS exposure decreased respiratory distress syndrome and severe intraventricular hemorrhage in infants born between 24 and 29 weeks of gestation. Cox regression analysis revealed that ACS exposure was associated with a significant decrease in mortality of preterm infants born at 22 or 23 weeks of gestation (adjusted hazard ratio, 0.72; 95% Cl, 0.53 to 0.97; P = .03). This effect was also observed at 24 to 25 and 26 to 27 weeks of gestation and in the overall study population.
Conclusions ACS exposure improved survival of extremely preterm infants. ACS treatment should be considered for threatened preterm birth at 22 to 23 weeks of gestation. (J Pediatr 2011; 159:110-4).

DOI PubMed

The uterus sustains stable biological clock during pregnancy.

Shizuko Akiyama, Hidenobu Ohta, Shimpei Watanabe, Takahiro Moriya, Aya Hariu, Norimichi Nakahata, Hiroshi Chisaka, Tadashi Matsuda, Yoshitaka Kimura, Shigeru Tsuchiya, Hajime Tei, Kunihiro Okamura, Nobuo Yaegashi

The Tohoku journal of experimental medicine   221 ( 4 ) 287 - 98   2010.08

Research paper (journal)  

Maternal circadian information has been reported to play an important role in fetal physiology and development. Hormones and nutrition have been mainly investigated as circadian cues from mother to fetus. However, the influences of circadian properties of the pregnant reproductive organs on fetuses have not been fully investigated. To gain an insight on the circadian functions of the reproductive organs, we examined molecular clocks in the pregnant rat uterus and placenta. By using a Period1-luciferase (Per1-luc) rat, whose tissues express luciferase corresponding to activation of Period1, a "key clock gene", we examined the uterus clock during non-pregnancy, on embryonic day 12 (E12), and on E22 (the end of pregnancy) in a light-dark (LD) cycle and constant darkness (DD). By in situ hybridization we further explored Per1 mRNA rhythms in the placenta on E12 and E22. The uterus in vitro showed clear circadian Per1-luc rhythms both in and out of pregnancy, having peaks at around the time corresponding to dusk in LD. Likewise, in DD, the uterus in vitro had the same Per1-luc rhythms. The decidua in LD showed circadian Per1 mRNA rhythms, peaking during night 6 h after dusk, while the decidua in DD showed the same Per1 mRNA rhythms only on E22. In contrast, the labyrinth showed no circadian Per1 mRNA rhythms in LD or DD during pregnancy. These results suggest that the uterus and decidua, a maternally-originated tissue of the placenta, but not the labyrinth, a fetus-originated tissue of the placenta, can provide the fetus with circadian information.

DOI PubMed

Monitoring Preterm Infants' Vision Development with Light-Only Melanopsin is Functional

Takushi Hanita, Hidenobu Ohta, Tadashi Matsuda, Hiroshi Miyazawa

JOURNAL OF PEDIATRICS ( MOSBY-ELSEVIER )  155 ( 4 ) 596 - 596   2009.10

Research paper (journal)  

DOI PubMed

Maternal Feeding Controls Fetal Biological Clock

Hidenobu Ohta, Shanhai Xu, Takahiro Moriya, Masayuki Iigo, Tatsuya Watanabe, Norimichi Nakahata, Hiroshi Chisaka, Takushi Hanita, Tadashi Matsuda, Toshihiro Ohura, Yoshitaka Kimura, Nobuo Yaegashi, Shigeru Tsuchiya, Hajime Tei, Kunihiro Okamura

PLOS ONE ( PUBLIC LIBRARY SCIENCE )  3 ( 7 ) e2601   2008.07

Research paper (journal)  

Background: It is widely accepted that circadian physiological rhythms of the fetus are affected by oscillators in the maternal brain that are coupled to the environmental light-dark (LD) cycle.
Methodology/Principal Findings: To study the link between fetal and maternal biological clocks, we investigated the effects of cycles of maternal food availability on the rhythms of Per1 gene expression in the fetal suprachiasmatic nucleus (SCN) and liver using a transgenic rat model whose tissues express luciferase in vitro. Although the maternal SCN remained phase-locked to the LD cycle, maternal restricted feeding phase-advanced the fetal SCN and liver by 5 and 7 hours respectively within the 22-day pregnancy.
Conclusions/Significance: Our results demonstrate that maternal feeding entrains the fetal SCN and liver independently of both the maternal SCN and the LD cycle. This indicates that maternal-feeding signals can be more influential for the fetal SCN and particular organ oscillators than hormonal signals controlled by the maternal SCN, suggesting the importance of a regular maternal feeding schedule for appropriate fetal molecular clockwork during pregnancy.

DOI PubMed

Constant light disrupts the developing mouse biological clock

Hidenobu Ohta, Amanda C. Mitchell, Douglas G. McMahon

PEDIATRIC RESEARCH ( INT PEDIATRIC RESEARCH FOUNDATION, INC )  60 ( 3 ) 304 - 308   2006.09

Research paper (journal)  

The central biological clock of the brain, contained within the suprachiasmatic nuclei (SCN) of mammals, orchestrates an orderly "internal day" of physiology and behavior. The developing biological clock begins to respond to light at an early stage and a particular concern in humans is whether light exposure has disruptive effects on the developing biological clock of infants exposed to constant lighting conditions in neonatal intensive care units (NICUs). Worldwide, eighteen million, or 14%, of newborns estimated to be of low birth weight, are exposed to artificial lighting environments in hospital nurseries annually. Here, we have tested whether constant light (LL) exposure disrupts the developing biological clock of mice, using a circadian reporter transgenic mouse model in which the organization of the central biological clock can be assayed by real-time gene expression imaging. We now find that LL has both acute and long-term disruptive effects on developing biological clocks and that cyclic lighting conditions are critical for developing circadian clocks to coordinate their molecular circadian mechanisms. This suggests that, from the perspective of developing circadian organization in humans, cyclic light conditions in NICUs are likely to be most appropriate for infants.

DOI PubMed

Daily rhythmicity of large-conductance Ca2+-activated K+ currents in suprachiasmatic nucleus neurons

GR Pitts, H Ohta, DG McMahon

BRAIN RESEARCH ( ELSEVIER SCIENCE BV )  1071 ( 1 ) 54 - 62   2006.02

Research paper (journal)  

Neurons within the suprachiasmatic nucleus (SCN) comprise the master circadian pacemaker in mammals. These neurons exhibit circadian rhythms in spontaneous action potential frequency and in the transcription of core circadian clock genes, including Period1 (Per1). Targeted electrophysiological recordings from SCN neurons marked with a green fluorescent protein (GFP) reporter of Per1 gene transcription have previously indicated that K+ currents are critically involved in the expression of neurophysiological rhythmicity. The present study examined the role of large conductance, Ca2+-activated K+ channels (BK) in the daily rhythmicity of mouse SCN neurons. BK-mediated currents were examined in Per1::GFP neurons under voltage clamp using iberiotoxin, a specific BK channel blocker. BK current was a greater proportion of whole-cell outward currents during the night than during the day. Analysis of iberiotoxin difference currents also demonstrated that BK current amplitude and density were greater during the night and that the day/night difference in steady state amplitude was not due to altered inactivation. Single cell RT-PCR demonstrated the presence of the BK channel transcript, KCNMA1, in Per1-expressing neurons. In situ hybridization analysis further showed that KCNMA1 mRNA was rhythmically expressed in the SCN under light:dark (LD) conditions, peaking during the middle of the night phase. Acute inhibition of BK currents blunted the circadian rhythm SCN neuron spike frequency. These results establish that BK channel function is elevated at night, thus altering SCN neuron activity. (C) 2005 Elsevier B.V. All rights reserved.

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Constant light desynchronizes mammalian clock neurons

H Ohta, S Yamazaki, DG McMahon

NATURE NEUROSCIENCE ( NATURE PUBLISHING GROUP )  8 ( 3 ) 267 - 269   2005.03

Research paper (journal)  

Circadian organization can be disrupted by constant light, resulting in behavioral arrhythmicity or 'splitting' of rhythms of activity and rest. By imaging molecular rhythms of individual clock neurons in explanted mouse clock nuclei, we now find that constant light desynchronizes clock neurons but does not compromise their ability to generate circadian rhythms. Cellular synchrony within clock nuclei is disrupted during arrhythmicity, whereas neurons in the left and right clock nuclei cycle in antiphase during 'splitting.'

DOI PubMed

Characterization of genetically labeled catecholamine neurons in the mouse retina

DQ Zhang, JF Stone, TR Zhou, H Ohta, DG McMahon

NEUROREPORT ( LIPPINCOTT WILLIAMS & WILKINS )  15 ( 11 ) 1761 - 1765   2004.08

Research paper (journal)  

Mouse neurons were labeled transgenically with red fluorescent protein (RFP) driven by the tyrosine hydroxylase (TH) promoter and observed in living retinas and brain slices. Two types of retinal amacrine cells expressed TH::RFP. One type had large cell bodies, processes that ramified in SI of the inner plaxiform layer (IPL) and were TH immunoreactive, identifying them as dopaminergic neurons. A second type had smaller somas, ramified in S3 and lacked TH. Dopaminergic cells had large dendritic fields and exceptionally long axon-like processes, whereas type 2 cells were more compact. Neither cell type exhibited tracer coupling. Thus, murine retinal dopaminergic neurons exhibit functional anatomy similar to their primate counterparts and TH::RFP mice are useful for in situ characterization of catecholaminergic neurons.

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Periodic absence of nursing mothers phase-shifts circadian rhythms of clock genes in the suprachiasmatic nucleus of rat pups

H Ohta, S Honma, H Abe, K Honma

EUROPEAN JOURNAL OF NEUROSCIENCE ( BLACKWELL PUBLISHING LTD )  17 ( 8 ) 1628 - 1634   2003.04

Research paper (journal)  

Effects of absence of nursing mothers on the circadian pacemaker of their offspring were examined by measuring clock genes, the rat Per1 (rPer1) and rPer2 expression rhythms in the pup suprachiasmatic nuclei (SCN). Neonate rats born to mothers kept under a 12-h light : 12-h dark cycle (LD) were blinded immediately after birth and exposed to periodic maternal deprivation where pups were deprived of their mothers during the light phase of 12-h for the first week of life. At postnatal day 6, the periodic maternal deprivation completely phase- reversed the circadian rhythms in expression of the clock genes in the pup SCN and in spontaneous locomotor activity after the pups were weaned at postnatal day 21. The periodic maternal absence also altered the patterns of stress-related gene expressions such as corticotropine-releasing hormone, arginine vasopressin, and glucocorticoid receptor in particular brain areas of the mother-deprived pups at P6. These findings indicate that periodic absence of the nursing mother in the first week of life produces a resetting effect on the neonatal circadian clock and induces stress responses in the hypothalamus-pituitary-adrenal axis.

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Effects of nursing mothers on rPer1 and rPer2 circadian expressions in the neonatal rat suprachiasmatic nuclei vary with developmental stage

Hidenobu Ohta, Sato Honma, Hiroshi Abe, Ken-Ichi Honma

European Journal of Neuroscience ( 12 )  15 ( 12 ) 1953 - 1960   2002

Research paper (journal)  

The ability of nursing mothers to entrain the circadian pacemaker of rat pups was examined by measuring the rat Per1 (rPer1) and rPer2 expression levels in the suprachiasmatic nuclei (SCN). Newborn rats from mothers under a light-dark cycle (LD) were blinded immediately after birth and reared by foster mothers under either LD (LD blind pups) or reversed light-dark cycle (DL
DL blind pups). At postnatal day (P)6, small but significant phase differences were observed in the circadian gene expression rhythms of the SCN not only between the blind and sighted pups, but also between the two groups of blind pups, indicating the involvement of both free-running and maternal influence in phase-resetting the circadian rhythms of blind pups. However, from P6 to P13 the circadian rhythms of both LD and DL blind pups showed phase delays of similar extent, which suggests that the influence of nursing mothers was lost. From P13 to P20 (the day of weaning), the rPer1 and rPer2 rhythms phase-shifted in a different manner, the rPer2 rhythm being related more closely to the behavioural rhythm than was the rPer1. This finding suggests a differential influence of mothers on the rPer1 and rPer2 rhythms in the third week of life. It is concluded that the ability of nursing mothers to entrain pup circadian oscillation depends on the developmental stage.

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Continuous measurement of targeted promoter activity by a secreted bioluminescence reporter, Vargula hilgendorfii luciferase

Y Tanahashi, Y Ohmiya, S Honma, Y Katsuno, H Ohta, H Nakamura, K Honma

ANALYTICAL BIOCHEMISTRY ( ACADEMIC PRESS INC )  289 ( 2 ) 260 - 266   2001.02

Research paper (journal)  

The promoter activity of growth hormone (GH) was continuously monitored in rat pituitary adenoma cells (GH3) by a secreted bioluminescence reporter, Vargula hilgendorfii (Vh) luciferase. The sensitivity of the reporter was approximately 60-times higher than that of the firefly luciferase, GH3 cells were transfected with a plasmid containing a DNA sequence of the GH promoter (1.8 kb) and a full length of the Vh luciferase cDNA. Using the stable transformants, the Vh luciferase activity was monitored in the plate culture through the bioluminescence of Vh luciferase secreted into the culture medium. The reporter activity was well correlated with GH mRNA as well, as GH when the GH promoter activity was activated by thyroid hormone. To develop a continuous monitoring system of the promoter, the reporter activity was sequentially measured in the perfusion system. When the promoter activity of the stable transformants was suppressed by a transcription inhibitor, the reporter activity and GH in the perfusate were simultaneously decreased. The Vh luciferase reporter is a sensitive and convenient tool for continuous and prolonged measurement of promoter activity in living cell culture systems. (C) 2001 Academic Press.

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The observation of an ultradian rhythm of heart rate in low birth weight infants

H Ohta, K Cho, Y Matsumoto, T Matsuda, J Ohyu, S Fujimoto, K Honma

BIOLOGICAL RHYTHM RESEARCH ( TAYLOR & FRANCIS LTD )  30 ( 5 ) 545 - 554   1999.12

Research paper (journal)  

The relationship between ultradian rhythm of heart rate and schedules of body contact or feeding was studied in five low birth weight infants of conceptional ages of 34-36 weeks. The differential contribution of body contact and feeding to the formation of the ultradian rhythm of heart rate was evaluated by applying two different schedules of two- and three-hour periods for feeding with a single schedule of three hours for body contact during an observation period of seven days. A chi-square periodogram was used to calculate the period of ultradian rhythm. As a result, a three-hour ultradian rhythm of heart rates was detected in all subjects, which seems to correspond to either schedule of body contact or of feeding. However, no clear changes in the ultradian rhythm of heart rate were observed corresponding to changes in feeding schedules. The ultradian rhythm of heart: rate seems to correspond more to body contact than to feeding.

DOI

Toriello-Carey syndrome with endocardial fibroelastosis

H Ohta, M Masuno, J Kimura, K Imaizumi, Y Kuroki, S Yasui, N Aida, Y Tanaka

AMERICAN JOURNAL OF MEDICAL GENETICS ( WILEY-LISS )  87 ( 3 ) 271 - 272   1999.11

Research paper (journal)  

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