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Michigami T.,Research Institute for Maternal and Child Health
Contributions to Nephrology | Year: 2013

Phosphorus is involved in various biological processes including membrane integrity, maintenance and inheritance of genetic materials, energy metabolism, intracellular signaling and skeletal mineralization. In addition, accumulating evidences have indicated that alteration in the levels of extracellular inorganic phosphate (Pi) itself triggers signaling to regulate gene expression and cellular functions in some cell types. In bone cells such as osteoblasts and chondrocytes, extracellular Pi modulates cell proliferation, differentiation, mineralization and apoptosis. In extraskeletal tissues, extracellular Pi also exerts various effects. For example, increased extracellular Pi results in the calcification associated with the upregulation of osteoblast marker genes in vascular smooth muscle cells. As to the mechanistic aspects, it is suggested that an increase in extracellular Pi triggers signal transduction via the PiT1 type III sodium/phosphate (Na + /Pi) cotransporter and ERK1/2 pathway. Unicellular organisms such as bacteria and yeast sense the environmental Pi with a protein complex located in the plasma membrane, which regulates the expression of multiple genes involved in Pi uptake and metabolism to adapt to its availability. In mammals that are multicellular organisms, Pi availability should be sensed both at a cellular level to regulate the function of each cell and as a whole body to maintain the Pi homeostasis of the extracellular fluid. Although the responsiveness to the increased extracellular Pi suggests the existence of Pi-sensing mechanism in mammalian cells as well, it is unknown whether the sensing of Pi availability at a cellular level and that at a whole-body level share the same pathway or not. This chapter will review the findings regarding the regulation of various cellular functions by extracellular Pi, and also discuss the current concept on the mechanism for Pi-sensing. Copyright © 2013 S. Karger AG, Basel.

Kosho T.,Shinshu University | Okamoto N.,Research Institute for Maternal and Child Health
American Journal of Medical Genetics, Part C: Seminars in Medical Genetics | Year: 2014

Coffin-Siris syndrome (CSS) is a rare congenitalmalformation syndrome, recently found to be caused bymutations in several genes encoding components of the BAF complex. To date, 109 patients have been reported with their mutations: SMARCB1 (12%), SMARCA4 (11%), SMARCE1 (2%), ARID1A (7%), ARID1B (65%), and PHF6 (2%). We review genotype-phenotype correlation of all previously reported patients with mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A through reassessment of their clinical andmolecular findings. Cardinal features of CSS included variable degrees of intellectual disability (ID) predominantly affecting speech, sucking/feeding difficulty, and craniofacial (thick eyebrows, long eyelashes), digital (hypoplastic 5th fingers or toes, hypoplastic 5th fingernails or toenails), and other characteristics (hypertrichosis). In addition, patients withSMARCB1 mutations had severe neurodevelopmental deficits including severe ID, seizures, CNS structural abnormalities, and no expressive words as well as scoliosis. Especially, those with a recurrent mutation "p. Lys364del" represented strikingly similar phenotypes including characteristic facial coarseness. Patients with SMARCA4 mutations had less coarse craniofacial appearances and behavioral abnormalities. Patients with SMARCE1 mutations had a wide spectrum of manifestations fromsevere to moderate ID. Patients with ARID1A also had a wide spectrum of manifestations from severe ID and serous internal complications that could result in early death to mild ID. Mutations in SMARCB1, SMARCA4, and SMARCE1 are expected to exert dominant-negative or gain-of-function effects, whereas those in ARID1A are expected to exert loss-of-function effects. © 2014 Wiley Periodicals, Inc.

Ishii K.,Research Institute for Maternal and Child Health
Current Opinion in Obstetrics and Gynecology | Year: 2015

Purpose of review The purpose of this article is to investigate the perinatal outcomes of monoamniotic twins under current standards of prenatal management involving intensive fetal surveillance. Recent findings The incidence of perinatal mortality in monoamniotic twins has fallen over the last 2 decades. Umbilical cord entanglement has long been considered one of the main causes of poor outcome among monoamniotic twins; however, new evidence shows that it appears to be less important than prematurity and congenital anomalies. If intensive fetal surveillance is provided, the risk of perinatal mortality is acceptably low regardless of setting. In uncomplicated monoamniotic twin pregnancies, delivery at around 33 weeks of gestation might reduce the risk of neonatal adverse events without increasing the risk of perinatal death. Summary Perinatal outcome in monoamniotic twins improved if intensive fetal surveillance was performed under either outpatient or inpatient management. Planned delivery in uncomplicated monoamniotic twin pregnancies can be considered at around 33 weeks of gestation. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Kawai M.,Research Institute for Maternal and Child Health
Hormone Molecular Biology and Clinical Investigation | Year: 2013

Peroxisome proliferator-activated receptor-γ (PPARγ) is a critical factor for the reciprocal regulation of adipogenesis and osteogenesis. Because of their insulinsensitizing effect, PPARγ agonists, the thiazolidinediones (TZDs), have been widely used for the treatment of type 2 diabetes mellitus; however, the use of TZDs has also been revealed to cause bone loss and bone fractures. The nodal point of regulation of skeletal metabolism by PPARγ activation may reside in its role in cell fate determination of mesenchymal stem cells toward adipogenesis at the expense of osteogenesis. In addition, accumulating evidence demonstrates that PPARγ possesses a circadian expression profile and plays an important role in the skeletal and adipose metabolism regulated by the circadian clock network. Recently, we have shown that nocturnin, a circadian-regulated gene, enhances PPARγ activity, resulting in the suppression of osteogenesis and enhancement of adipogenesis, thus providing additional evidence of the link between circadian networks and PPARγ. In this review, we will focus on the emerging concept of PPARγ as a regulator for skeletal metabolism and summarize recent findings about one of the mechanisms on how PPARγ is connected to the circadian-regulatory system, which involves nocturnin.

Mori R.,University of Tokyo | Kusuda S.,Tokyo Womens Medical University | Fujimura M.,Research Institute for Maternal and Child Health
Journal of Pediatrics | Year: 2011

Objective: To evaluate the effectiveness of antenatal corticosteroid (ACS) to improve neonatal outcomes for infants born at <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% CI, 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. Copyright © 2011 Mosby Inc. All rights reserved.

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