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Kusuda S.,Tokyo Women's Medical University | Fujimura M.,Research Institute for Maternal and Child Health | Uchiyama A.,Tokyo Women's Medical University | Totsu S.,Tokyo Women's Medical University | Matsunami K.,Research Institute for Maternal and Child Health
Pediatric Research | Year: 2012

Background: although medical care for very-low-birthweight (VLBW) infants has improved over time, it is unclear how this has affected mortality and morbidity. To characterize these trends, a network database was analyzed. Methods: This is a cohort study of VLBW infants born from 2003 through 2008. results: Over the 6-y period, 19,344 infants were registered and analyzed. crude mortality rates among the infants at discharge decreased significantly (from 10.8 to 8.7%) during the study period. The greatest improvement in mortality was observed among infants with birth weights between 501 and 750 g (25.6-17.7 %). The odds ratio (OR) of mortality over year adjusted for potential confounders by a logistic regression model was 0.94 (95% confidence interval 0.92-0.97). significant increases were observed in some morbidities, including symptomatic patent ductus arteriosus with an OR of 1.11 (1.09-1.13); late-onset adrenal insufficiency, 1.21 (1.17-1.26); and necrotizing enterocolitis/intestinal perforation, 1.10 (1.01-1.12). however, the severe form of intraventricular hemorrhage, with an OR of 0.98 (0.92-0.99), decreased significantly. Risk-adjusted trends in other morbidities showed no significant change. conclusion: Mortality of VLBW infants decreased signifi-cantly over the 6-y study period. Decreasing morbidity is essential for further improvement in the outcomes in VLBW infants. © 2012 International Pediatric Research Foundation, Inc.


Ishii N.,Aiiku Hospital | Kono Y.,Jichi Medical University | Yonemoto N.,Translational Medical Center | Kusuda S.,Tokyo Women's Medical University | Fujimura M.,Research Institute for Maternal and Child Health
Pediatrics | Year: 2013

OBJECTIVE: To provide instructive information on death and neurodevelopmental outcomes of infants born at 22 and 23 weeks' gestational age. METHODS: The study cohort consisted of 1057 infants born at 22 to 25 weeks in the Neonatal Research Network, Japan. Neurodevelopmental impairment (NDI) at 36 to 42 months' chronological age was defined as any of the following: cerebral palsy, hearing impairment, visual impairment, and a developmental quotient ,70. A systematic review was performed by using databases of publications of cohort studies with neonatal and neurodevelopmental outcomes at 22 and 23 weeks. RESULTS: Numbers and incidences (%) of infants with death or NDI were 60 (80%) at 22 weeks and 156 (64%) at 23 weeks. In logistic regression analysis, gestational ages of 22 weeks (odds ratio [OR]: 5.40; 95% confidence interval [CI]: 2.48-11.76) and 23 weeks (OR: 2.14; 95% CI: 1.38-3.32) were associated with increased risk of death or NDI compared with 24 weeks, but a gestational age of 25 weeks (OR: 0.65; 95% CI: 0.45-0.95) was associated with decreased risk of death or NDI. In the systematic review, the medians (range) of the incidence of death or NDI in 8 cohorts were 99% (90%-100%) at 22 weeks and 98% (67%-100%) at 23 weeks. CONCLUSIONS: Infants born at 22 and 23 weeks' gestation were at higher risk of death or NDI than infants at born at 24 weeks. However, outcomes were improved compared with those in previous studies. There is a need for additional discussions on interventions for infants born at 22 or 23 weeks' gestation. Pediatrics 2013;132:62-71. Copyright © 2013 by the American Academy of Pediatrics.


Mori R.,University of Tokyo | Kusuda S.,Tokyo Women's 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.


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.


Michigami T.,Research Institute for Maternal and Child Health
Cellular and Molecular Life Sciences | Year: 2013

In vertebrates, most of the skeleton is formed through endochondral ossification. Endochondral bone formation is a complex process involving the mesenchymal condensation of undifferentiated cells, the proliferation of chondrocytes and their differentiation into hypertrophic chondrocytes, and mineralization. This process is tightly regulated by various factors including transcription factors, soluble mediators, extracellular matrices, and cell-cell and cell-matrix interactions. Defects of these factors often lead to skeletal dysplasias and short stature. Moreover, there is growing evidence that epigenetic and microRNA-mediated mechanisms also play critical roles in chondrogenesis. This review provides an overview of our current understanding of the regulators for the development of growth plate cartilage and their molecular mechanisms of action. A knowledge of the regulatory mechanisms underlying the proliferation and differentiation of chondrocytes will provide insights into future therapeutic options for skeletal disorders. © 2013 Springer Basel.


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.


Wada Y.,Research Institute for Maternal and Child Health | Tajiri M.,Research Institute for Maternal and Child Health | Tajiri M.,Japan Science and Technology Agency | Ohshima S.,Osaka Minami Medical Center
Journal of Proteome Research | Year: 2010

Profiling of oligosaccharide structures is widely utilized for both identification and evaluation of glycobiomarkers, and site-specific profiling of N-linked glycans of glycoproteins is conducted by mass spectrometry of glycopeptides, However, our knowledge of mucin-type O-glycans including site occupancy and profile variance, as well as attachment sites, is quite limited. Saccharide compositions and site-occupancy of O-glycans were calculated from the signal intensity of glycopeptide ions in the mass spectra and tandem mass spectra from electron transfer dissociation. The results for two major plasma glycoproteins, lgA1 and hemopexin, representing clustered and scattered O-glycan attachments, respectively, indicated that the variability in modifications among individuals is so small as to justify rigorous standards enabling reliable detection of disease-related alterations. Indeed, this method revealed a novel abnormality associated with rheumatoid arthritis: a significant decrease in the -acetylgalactosamine content of lgA1 O-glycans, indicating that the glycosylation abnormality is not limited to hypogalactosylation of lgG N-glycans in chronic inflammatory conditions. © 2010 Amarican Chemical Society.


Wada Y.,Research Institute for Maternal and Child Health | Kadoya M.,Research Institute for Maternal and Child Health | Okamoto N.,Research Institute for Maternal and Child Health
Glycobiology | Year: 2012

Apolipoprotein C-III (apoCIII) is a small glycoprotein with a single mucin-type core-1 oligosaccharide and is analyzed by isoelectric focusing (IEF) for the diagnosis of genetic defects in O-glycan biosynthesis such as congenital disorders of glycosylation. In the present study, mass spectrometry of apoCIII, after a simple procedure for sample preparation using a small amount of serum, was demonstrated to be a reliable alternative to IEF. It allows reproducible glycan profiling and detection of unglycosylated species. This method was applied to an autosomal recessive cutis laxa type-2 patient and demonstrated decreased site occupancy by O-glycosylation. © The Author 2012. Published by Oxford University Press. 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.

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