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DOI： 10.1007/s00535-024-02119-6

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DOI： 10.1253/circrep.CR-24-0061

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Language：English   Publisher：Japanese Journal of Ophthalmology  

Purpose: To assess the safety and efficacy of ripasudil for retinopathy of prematurity (ROP). Study design: Phase 1/2, multicenter, open-label, single-arm, 12-week clinical trial. Methods: Infants born with gestational age (GA) of ≤ 32 weeks or weight of ≤ 1500 g with zone I or II, ≥ stage 1, ROP in both eyes were enrolled. Ripasudil eye drops were administered to patients in both eyes. Phase 1 was a dose-escalation study (once daily for 1 week, then twice daily for 2 weeks); an additional dosing up to 9 weeks was allowed if no safety issues occurred. In phase 2, ripasudil was administered twice daily for up to 12 weeks. Adverse events were assessed. The proportion of patients with type 1 ROP progression, number of days for type 1 ROP progression, and progression to the most advanced ROP stage were estimated. Results: Twenty-four infants were enrolled (phase 1, n = 3; phase 2, n = 21). Nineteen and four patients experienced systemic and ocular adverse events, respectively. Efficacy endpoints were not different between the ripasudil and historical control groups. However, in the GA ≤ 27 weeks subgroup, fewer patients progressed to type 1 ROP in the ripasudil than in the historical control group (P = 0.09). In the GA ≤ 27 weeks subgroups, the 25th percentile for the number of days for type 1 ROP progression was 22 days in the historical control group and 44 days in the ripasudil group. Conclusion: Ripasudil was safe and inhibited/delayed type 1 ROP progression, especially in infants with short GA.

DOI： 10.1007/s10384-024-01100-3

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DOI： 10.2188/jea.JE20230207

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DOI： 10.1253/circj.CJ-23-0084

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DOI： 10.1111/den.14714

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DOI： 10.1097/BRS.0000000000005062

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DOI： 10.1007/s00535-024-02088-w

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DOI： 10.1038/s41598-024-59932-5

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DOI： 10.1007/s12928-024-00984-9

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DOI： 10.1002/ehf2.14550

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DOI： 10.1016/j.isci.2024.109121

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatric Blood and Cancer  

OBJECTIVE: CHARGE syndrome is a congenital malformation syndrome caused by heterozygous mutations in the CHD7 gene. Severe combined immunodeficiency (SCID) arises from congenital athymia called CHARGE/complete DiGeorge syndrome. While cultured thymus tissue implantation (CTTI) provides an immunological cure, hematopoietic cell transplantation (HCT) is an alternative option for immuno-reconstitution of affected infants. We aimed to clarify the clinical outcomes of patients with athymic CHARGE syndrome after HCT. METHODS: We studied the immunological reconstitution and outcomes of four patients who received non-conditioned unrelated donor cord blood transplantation (CBT) at Kyushu University Hospital from 2007 to 2022. The posttransplant outcomes were compared with the outcomes of eight reported patients. RESULTS: Four index cases received CBT 70-144 days after birth and had no higher than grade II acute graft-versus-host disease. One infant was the first newborn-screened athymic case in Japan. They achieved more than 500/μL naïve T cells with balanced repertoire 1 month post transplant, and survived more than 12 months with home care. Twelve patients including the index cases received HCT at a median 106 days after birth (range: 70-195 days). One-year overall survival rate was significantly higher in patients who underwent non-conditioned HCT than in those who received conditioned HCT (100% vs. 37.5%, p = .02). Nine patients died, and the major cause of death was cardiopulmonary failure. CONCLUSIONS: Athymic infants achieved a prompt reconstitution of non-skewing naïve T cells after non-conditioned CBT that led to home care in infancy without significant infections. Non-conditioned CBT is a useful bridging therapy for newborn-screened cases toward an immunological cure by CTTI.

DOI： 10.1002/pbc.30809

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DOI： 10.3390/cells13030279

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DOI： 10.1292/jvms.23-0239

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DOI： 10.1111/1756-185X.15009

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Language：Japanese   Publisher：(公社)日本小児科学会  

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OBJECTIVES: To determine the optimal management for early-onset thrombophilia (EOT), the genetic and clinical features of protein C (PC)-, protein S (PS)-, or antithrombin (AT)-deficient patients of ≤20 years of age were studied in Japan. METHODS/RESULTS: Clinical and genetic information of all genetically diagnosed cases was collected through the prospective, retrospective study, and literature review. One-hundred-one patients had PC (n = 55), PS (n = 29), or AT deficiency (n = 18). One overlapping case had PC- and PS-monoallelic variant. Fifty-five PC-deficient patients (54%) had 26 monoallelic or 29 biallelic variant(s), and 29 (29%) PS-deficient patients had 20 monoallelic or nine biallelic variant(s). None of the patients had AT-biallelic variants. The frequent low-risk allele p.K193del (PC-Tottori) was found in five patients with monoallelic (19%) but not 29 with biallelic variant(s). The most common low-risk allele p.K196E (PS-Tokushima) was found in five with monoallelic (25%) and six with biallelic variant(s) (67%). One exceptional de novo PC variant was found in 32 families with EOT. Only five parents had a history of thromboembolism. Thrombosis concurrently developed in three mother-newborn pairs (two PC deficiency and one AT deficiency). The prospective cohort revealed the outcomes of 35 patients: three deaths with PC deficiency and 20 complication-free survivors. Neurological complications were more frequently found in patients with PC-biallelic variants than those with PC-, PS-, or AT-monoallelic variants (73% vs. 24%, p = .019). CONCLUSIONS: We demonstrate the need for elective screening for EOT targeting PC deficiency in Japan. Early prenatal diagnosis of PC deficiency in mother-infant pairs may prevent perinatal thrombosis in them.

DOI： 10.1002/pbc.30824

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DOI： 10.1253/circj.CJ-23-0143

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DOI： 10.1038/s41440-023-01361-4

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DOI： 10.1016/j.ijcard.2023.131290

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DOI： 10.1016/j.amjcard.2023.10.011

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DOI： 10.1186/s40560-023-00697-w

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DOI： 10.1080/13416979.2023.2227820

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DOI： 10.1016/j.amjcard.2023.06.086

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Language：Japanese   Publisher：(公社)日本新生児成育医学会  

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DOI： 10.1177/17474930231175807

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DOI： 10.1172/jci.insight.161282

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Early Human Development  

INTRODUCTION: To establish actionable neonatal screening during the first month of life, we investigated critical diseases in seemingly healthy newborns discharged from birth hospitals. METHODS: This retrospective study enrolled previously healthy full-term infants who visited our hospital, a tertiary hospital in Japan, from home between 5 and 28 days after birth from 2009 to 2018. Infants with known perinatal or congenital diseases, positive newborn screening results, or accidental injuries were excluded. Data were collected from electronic medical records, including principal diagnosis, clinical details, and prognosis at 18 months of age. RESULTS: Ninety-seven (58 %) of 168 eligible neonates were admitted to the hospital, and 71 (42 %) were not. The median admission rate in patients with disease onset at ≤14 days after birth (80 %) was significantly higher than that in patients with disease onset at ≥15 days (42 %). Among 45 patients who received intensive medical care, 5 died and 10 developed neurodevelopmental sequelae. Four of 5 patients died by 100 days. Among 25 diseases treated in intensive care unit, 17 (68 %) diseases had a prevalence of <1 per 2000 live births. The commonly used diagnostic methods were imaging (n = 58, 35 %) and physical examination (n = 34, 20 %). CONCLUSION: Critical diseases due to rare and heterogeneous causes in ostensibly healthy newborns occurred predominantly in the first two weeks of life. Optimal newborn screening and health check-up protocols may benefit from the wide spectrum of life-threatening diseases occurring in home after birth.

DOI： 10.1016/j.earlhumdev.2023.105869

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BACKGROUND: Advanced perinatal medicine has decreased the mortality rate of preterm infants. Long-term neurodevelopmental outcomes of very-low-birth-weight infants (VLBWIs) remain to be investigated. METHODS: Participants were 124 VLBWIs who had in-hospital birth from 2007 to 2015. Perinatal information, developmental or intelligence quotient (DQ/IQ), and neurological comorbidities at ages 3 and 6 years were analyzed. RESULTS: Fifty-eight (47%) VLBWIs received neurodevelopmental assessments at ages 3 and 6 years. Among them, 15 (26%) showed DQ/IQ <75 at age 6 years. From age 3 to 6 years, 21 (36%) patients showed a decrease (≤-10), while 5 (9%) showed an increase (≥+10) in DQ/IQ scores. Eight (17%) with autism spectrum disorder or attention-deficit hyperactivity disorder (ASD/ADHD) showed split courses of DQ/IQ, including two with ≤-10 and one with +31 to their scores. On the other hand, all 7 VLBWIs with cerebral palsy showed DQ ≤35 at these ages. Magnetic resonance imaging detected severe brain lesions in 7 (47%) of those with DQ <75 and 1 (18%) with ASD/ADHD. CONCLUSIONS: VLBWIs show a broad spectrum of neurodevelopmental outcomes after 6 years. These divergent profiles also indicate that different risks contribute to the development of ASD/ADHD from those of cerebral palsy and epilepsy in VLBWIs. IMPACT: Very-low-birth-weight infants (VLBWIs) show divergent neurodevelopmental outcomes from age 3 to 6 years. A deep longitudinal study depicts the dynamic change in neurodevelopmental profiles of VLBWIs from age 3 to 6 years. Perinatal brain injury is associated with developmental delay, cerebral palsy and epilepsy, but not with ASD or ADHD at age 6 years.

DOI： 10.1038/s41390-023-02778-w

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DOI： 10.1016/j.jacasi.2023.06.004

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DOI： 10.1186/s12933-023-01915-3

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Publisher：東京医学社  

DOI： 10.24479/peri.0000001017

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00621&link_issn=&doc_id=20230803130024&doc_link_id=10.24479%2Fperi.0000001017&url=https%3A%2F%2Fdoi.org%2F10.24479%2Fperi.0000001017&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

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DOI： 10.1016/j.lungcan.2023.107264

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DOI： 10.1253/circj.CJ-22-0614

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Infection Control and Hospital Epidemiology  

To compare the culture sensitivities of MRSA detection, we collected 988 paired umbilical and nasal cultures from screened neonates. MRSA positivity rates were 79.1% from umbilicus and 41.9% from nares (P = .01). The umbilicus was a more useful culture site than the nares for surveillance of MRSA among neonates upon admission.

DOI： 10.1017/ice.2022.150

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DOI： 10.1016/j.jacasi.2023.02.002

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Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatrics and Neonatology  

BACKGROUND: The Edinburgh postnatal depression scale (EPDS) is commonly used in screening for major postpartum depression (PPD). We explored the clinical factors associated with score changes. METHODS: Mothers (n=1,287) who delivered a single live-born infant in Kokura Medical Center in Japan during 2018-2019 were analyzed. The EPDS-Japanese version was conducted at the first and fourth weeks after childbirth. Scores of ≥9 were considered to indicate an increased risk of PPD. RESULTS: The scores improved during the four-week period (5.03±0.12 to 3.79±0.10). Primiparity, Cesarean section (CS), and a low Apgar score were identified as initial risk factors, however, primiparity remained in the multivariate analysis (aOR 2.02, 95% CI 1.37-2.97). Age ≥35 years was associated with worsened scores (aOR 1.88, 95%CI 1.01-3.51), but CS improved (aOR 0.38, 95%CI 0.21-0.70). Primiparity, CS, and neonatal respiratory support were the initial risk factors, while infant anomaly was a late risk factor in mothers whose infants were admitted to the neonatal intensive care unit (NICU) (aOR 3.35, 95%CI 1.31-8.56). In mothers of infants with an NICU stay of ≥4 weeks, infant anomaly was associated with worsened scores (aOR 6.61, 95%CI 1.11-39.3), while respiratory support was associated with improved scores (aOR 0.09, 95%CI 0.01-0.65). Twenty-six mothrs with worsened scores received psychiatric support; three developed PPD. Two of the three were ≥35 years of age, neither of their infants had anomalies. CONCLUSION: Maternal aging and infant anomaly were risk factors for PPD. PPD occurred in mothers with worsened EPDS scores after mental care. Puerperants with worsening risk factors should be targeted to control PPD.

DOI： 10.1016/j.pedneo.2022.09.013

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DOI： 10.1016/j.jjcc.2022.11.011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Transfusion  

DOI： 10.1111/trf.17255

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Language：English   Publisher：Pediatric Blood and Cancer  

DOI： 10.1002/pbc.30047

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DOI： 10.1016/j.gie.2022.10.039

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Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

新生児期の血栓症は希少な事例と考えられてきたが、医療の高度化と疾患認識の広がりにより報告数が増加している。さらに、日本人小児の血栓性素因における遺伝性プロテインC欠乏症の重要性が示されてきた。今回私たちは新生児血栓症の全国調査を行い、遺伝性プロテインC欠乏症の遺伝学的効果と、遺伝学的検査の悉皆性を示すことができた。今後は調査対象を小児から成人に達するまでに拡大し、小児患者とその家族を血栓症から守る個別化医療の確立を目指す。(著者抄録)

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新生児期の血栓症は希少な事例と考えられてきたが、医療の高度化と疾患認識の広がりにより報告数が増加している。さらに、日本人小児の血栓性素因における遺伝性プロテインC欠乏症の重要性が示されてきた。今回私たちは新生児血栓症の全国調査を行い、遺伝性プロテインC欠乏症の遺伝学的効果と、遺伝学的検査の悉皆性を示すことができた。今後は調査対象を小児から成人に達するまでに拡大し、小児患者とその家族を血栓症から守る個別化医療の確立を目指す。(著者抄録)

Language：Japanese  

新生児期の血栓症は希少な事例と考えられてきたが、医療の高度化と疾患認識の広がりにより報告数が増加している。さらに、日本人小児の血栓性素因における遺伝性プロテインC欠乏症の重要性が示されてきた。今回私たちは新生児血栓症の全国調査を行い、遺伝性プロテインC欠乏症の遺伝学的効果と、遺伝学的検査の悉皆性を示すことができた。今後は調査対象を小児から成人に達するまでに拡大し、小児患者とその家族を血栓症から守る個別化医療の確立を目指す。(著者抄録)

Language：Japanese   Publisher：(公社)日本小児科学会  

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DOI： 10.1055/a-1876-7554

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DOI： 10.1111/cas.15645

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DOI： 10.1063/5.0136627

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DOI： 10.1371/journal.pone.0280753

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：English   Publisher：Pediatric Blood and Cancer  

DOI： 10.1002/pbc.29915

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DOI： 10.1016/j.lungcan.2022.11.018

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DOI： 10.1136/bmjno-2022-000370

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DOI： 10.1253/circj.CJ-22-0170

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DOI： 10.1097/MD.0000000000032330

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pediatric Pulmonology  

INTRODUCTION: Pulmonary agenesis is a complete absence of the pulmonary parenchyma, airways, and vasculature unilaterally or bilaterally. Although bilateral cases are lethal, the outcome of unilateral cases remains not well described. We performed a comprehensive literature review to assess the clinical features of pulmonary agenesis. METHODS: Four database sources were searched on October 10, 2021 and two cases were included from our institution. Studies related to the clinical impact of comorbidity and intervention on the survival outcome in pulmonary agenesis were included for full-text review. RESULTS: We identified 259 patients-with right-sided (59%), left-sided (34%), and bilateral agenesis (7%)-among 195 articles and our two cases. Additional anomalies included cardiovascular (40%), skeletal (30%), gastrointestinal (20%), tracheal (20%: all stenoses), and genitourinary (14%) anomalies. Fifty-seven (24%) individuals in unilateral pulmonary agenesis had isolated disease. Outcomes related to survival were not uniformly reported, but the 2-year overall survival rate of unilateral agenesis was 62% and no subsequent death was reported until 13 years of age. The right-sided agenesis was more frequently associated with tracheal stenosis (27% vs. 11%, p = 0.003) than the left-sided disease. A multivariable analysis indicated that tracheal stenosis (hazard ratio [HR]: 2.2, 95% confidence interval [CI]: 1.3-4.1, p = 0.003) and gastrointestinal anomalies (HR: 2.0, 95% CI: 1.1-3.3, p = 0.010) were prognostic factors for mortality. CONCLUSIONS: The poor prognostic factors were tracheal stenosis, right agenesis, and gastrointestinal anomalies. Treatment for these comorbidities is a key point for improving the survival of unilateral pulmonary agenesis.

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DOI： 10.1002/joa3.12714

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DOI： 10.1161/HYPERTENSIONAHA.122.19810

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DOI： 10.1253/circj.CJ-20-1212

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DOI： 10.1016/j.jacasi.2022.07.008

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DOI： 10.1111/den.14369

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DOI： 10.1016/j.gie.2022.04.1347

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DOI： 10.5056/jnm21254

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DOI： 10.1016/j.jjcc.2022.06.008

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DOI： 10.1111/ggi.14458

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DOI： 10.1164/rccm.202110-2302OC

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

Compared with the relatively well-investigated effects of childhood exposure to lead on neurocognitive deficits, those of prenatal exposure remain relatively inconclusive. We aimed to investigate the association between prenatal blood lead levels and neurodevelopmental delay during the first three years of life. From a prospective cohort of the Japan Environment and Children's Study, we analyzed a total of 80,759 children. The exposure factors were prenatal lead concentrations measured from maternal whole blood in the second/third trimesters and umbilical cord blood at birth. Neurodevelopment was assessed at 6, 12, 18, 24, 30, and 36 months old using a screening tool, the Ages and Stages Questionnaires, third edition (ASQ). The outcome measures were any suspected neurodevelopmental delay (sNDD) identified via the ASQ during the first (sNDD-1Y), second (sNDD-2Y), and third (sNDD-3Y) years of life. sNDD-1Y, 2Y, and 3Y were identified in 18.0%, 16.2%, and 17.2% of children, respectively. The geometric means of blood lead concentration in this study were much lower (0.62 μg/dL in maternal blood and 0.50 μg/dL in cord blood) than previously investigated levels. Multivariable regression models revealed that there were no associations between maternal blood lead and sNDD-1Y and 2Y and between cord blood lead and sNDD-1Y, 2Y, and 3Y. Although a higher maternal blood lead was associated with a reduced risk of sNDD-3Y (adjusted relative risk: 0.84, 95% confidence interval 0.75-0.94, per 1 increase in common logarithm of lead concentration), there were no dose-response relationships in the analysis using quintiles of lead concentrations. Using a large-scale data set, the present study demonstrated no convincing evidence for an inverse association between levels of prenatal blood lead and neurodevelopment in early childhood. Longitudinal measurements of prenatal and postnatal lead levels are needed to understand the relationship between lead exposure and neurocognitive development.

DOI： 10.1038/s41598-022-19509-6

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DOI： 10.1055/a-1753-9801

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DOI： 10.1016/j.geothermics.2022.102470

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DOI： 10.1055/a-1778-9730

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DOI： 10.1038/s41598-022-17964-9

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DOI： 10.1161/STROKEAHA.121.038285

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Language：Japanese   Publisher：(公社)日本小児科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Early Human Development  

INTRODUCTION: Infants with congenital diaphragmatic hernia (CDH) are at risk of neurodevelopmental disabilities. This study aimed to investigate the association between lung to thorax transverse area ratio (LTR) and neurodevelopmental outcomes at 3 years of age in fetuses with CDH. METHODS: We performed a retrospective study of infants with prenatally diagnosed isolated left-sided CDH born in Kyushu University Hospital between 2008 and 2016. We examined the association between prenatal ultrasound findings including LTR and development quotient (DQ) at 36 to 42 months of chronological age. RESULTS: We identified 34 live-born fetuses with isolated left-sided CDH, of which 30 survived and four died before discharge. The median LTR in the survivors was higher than in the non-survivors (p < 0.01). Among the survivors, 26 had available data on LTR (median 0.12, range 0.08-0.18) and overall DQ at 3 years of age (93, 61-112). Their median gestational age and birth weight were 37.6 (range 34.4-39.1) weeks and 2716 (2.256-3494) grams, respectively. There was no significant difference in overall DQ scores between the two groups divided according to the median LTR values (p = 0.62). LTR values were not associated with overall DQ scores after adjusting for gestational age (p = 0.39). In addition, no association was observed between LTR values and any subscale DQ scores. CONCLUSION: In fetuses with isolated left-sided CDH, prenatal LTR predicts the mortality but not neurodevelopmental outcomes at 3 years of age.

DOI： 10.1016/j.earlhumdev.2022.105598

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DOI： 10.1016/j.archger.2022.104661

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DOI： 10.1111/den.14197

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Language：Japanese   Publisher：(一社)日本周産期・新生児医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Therapeutic Drug Monitoring  

BACKGROUND: Teicoplanin is a glycopeptide antibiotic used for the treatment of methicillin-resistant Staphylococcus aureus infections. To ensure successful target attainment, therapeutic drug monitoring-informed dosage adjustment is recommended. However, it relies on the experience of the clinician and the frequency of drug measurements. This study aimed to design a new optimal dosing regimen of teicoplanin with a maintenance dosing strategy for neonates and children based on their physiological characteristics. METHODS: Data from teicoplanin-treated patients (n = 214) were collected from electronic medical records. Covariate analyses were performed using population pharmacokinetic (PK) modeling with 399 serum teicoplanin concentrations from 48 neonates and 166 children. Multiple PK simulations were conducted to explore optimal dosing regimens that would allow control of the trough concentration to the target of 15-30 mg/L quicker than the current standard regimen. RESULTS: Allometrically scaled body weight, postmenstrual age (PMA), renal function, and serum albumin were implemented as substantial covariates for teicoplanin clearance in a two-compartment PK model. Covariate analyses and comprehensive simulation assessments recommended the following modifications to the current regimen: 1) decreased dose for premature babies (PMA ≤ 28 weeks), 2) decreased dose for children with renal dysfunction, and 3) increased dose for children (0.5-11 years) with an estimated glomerular filtration rate of ≥90 mL/min/1.73 m2. CONCLUSIONS: This study leverages real-world clinical information and proposes new optimal dosing regimens for teicoplanin in neonates and children through PK modeling and simulation analyses, taking into account the age, including PMA, and renal function of patients.

DOI： 10.1097/FTD.0000000000000930

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Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

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Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

researchmap

Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

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DOI： 10.1111/den.14133

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PubMed

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DOI： 10.1292/jvms.21-0494

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PubMed

DOI： 10.1007/s00224-022-10070-3

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DOI： 10.5056/jnm21188

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DOI： 10.1093/ehjqcco/qcab025

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PubMed

Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

新生児単純ヘルペスウイルス(HSV)感染症は、主に垂直感染によって発症する重要な周産期感染症の一つである。臨床病型は表在型(SEM;skin, eye, and mouth)、中枢神経型(CNS;central nervous system)および全身型(Disseminated)の3つに分類され、それぞれ異なる症状と臨床経過を示す。1970年代以降、抗ウイルス薬の登場、またHSV-DNAを検出するPCR法の開発により、早期診断・治療が可能となり飛躍的に治療成績は改善した。しかし新生児医療が高度化した現代においても、全身型の新生児死亡率は29%、中枢神経型は65%以上に神経学的後遺症を残し、依然として予後不良の疾患である。本稿では新生児HSV感染症に対する治療指針と現在の課題について提示する。また新生児ヘルペス脳炎や新生児HSV関連血球貪食性リンパ組織球症といった重症例のリスク因子や治療戦略についても概説する。(著者抄録)

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Language：Japanese  

新生児単純ヘルペスウイルス(HSV)感染症は、主に垂直感染によって発症する重要な周産期感染症の一つである。臨床病型は表在型(SEM;skin, eye, and mouth)、中枢神経型(CNS;central nervous system)および全身型(Disseminated)の3つに分類され、それぞれ異なる症状と臨床経過を示す。1970年代以降、抗ウイルス薬の登場、またHSV-DNAを検出するPCR法の開発により、早期診断・治療が可能となり飛躍的に治療成績は改善した。しかし新生児医療が高度化した現代においても、全身型の新生児死亡率は29&#37;、中枢神経型は65&#37;以上に神経学的後遺症を残し、依然として予後不良の疾患である。本稿では新生児HSV感染症に対する治療指針と現在の課題について提示する。また新生児ヘルペス脳炎や新生児HSV関連血球貪食性リンパ組織球症といった重症例のリスク因子や治療戦略についても概説する。(著者抄録)

Language：English  

DOI： 10.1038/s41540-022-00213-0

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PubMed

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DOI： 10.1253/circj.CJ-21-0631

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PubMed

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DOI： 10.1253/circj.CJ-21-0180

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Perinatology  

OBJECTIVE: To examine erythroferrone (ERFE)-hepcidin iron regulation in premature infants under intensive care at risk of iron metabolic disorders. STUDY DESIGN: A retrospective cohort recruited 31 infants with a birth weight of <1500 g hospitalized in a tertiary center. Their hematological status was measured at birth and 2 and 4 weeks of life. RESULTS: ERFE was positively correlated with the reticulocyte hemoglobin content at 2 (r2 = 0.2374) and 4 weeks (r2 = 0.6005). An assumed negative correlation between ERFE and hepcidin was not determined during the neonatal period. Hepcidin was positively correlated with the leukocyte count (r2 = 0.3089) and ferritin (r2 = 0.7476) at birth and C-reactive protein (r2 = 0.3591) at 2 weeks and negatively correlated with the reticulocyte count (r2 = 0.2887) at 4 weeks. CONCLUSION: The vulnerability of the ERFE-hepcidin pathway within 4 weeks may contribute to iron imbalance in premature infants.

DOI： 10.1038/s41372-021-01184-6

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To clarify the incidence and genetic risk of neonatal-thromboembolism, we conducted a nationwide study exploring the impact of thrombophilia on neonatal-thromboembolism in Japan. STUDY DESIGN: A questionnaire survey was conducted for perinatal centers in Japan, focusing on the clinical expression, genotype, treatment, and outcome of patients who developed thromboembolism within 28 days of birth from 2014 to 2018. RESULTS: The estimated incidence of neonatal-thromboembolism was 0.39 cases per 10 000 live births. Intracranial lesions and purpura fulminans occurred in 66 and 5 of 77 patients, respectively. Fifty-eight (75.3&#37;) infants presented within 3 days after birth. Four (5.2&#37;) died, and 14 (18.2&#37;) survived with disability. At the diagnosis, <20&#37; plasma activity of protein C was noted in 16 infants, protein S (in 2), and antithrombin (in 1). Thirteen genetic tests identified 4 biallelic and 5 monoallelic protein C-variants but no protein S- or antithrombin-variants. Protein C-variants had purpura fulminans (P < .01), ocular bleeding (P < .01), positive-family history (P = .01), and death or disability (P = .03) more frequently than others. Protein C-variants were independently associated with disability (OR 5.74, 95&#37; CI 1.16-28.4, P = .03) but not death. Four biallelic variants had serious thrombotic complications of neurologic disability, blindness, and/or amputation. Three monoallelic variants survived without complications. The only protein C-variant death was an extremely preterm heterozygote infant. CONCLUSIONS: Monoallelic protein C-variants had a higher incidence of neonatal-thromboembolism than biallelic variants. Thrombophilia genetic testing should be performed in the setting of neonatal-thromboembolism and low protein C to identify the underlying genetic defect.

DOI： 10.1016/j.jpeds.2021.07.001

Language：English   Publishing type：Research paper (scientific journal)  

Trisomy 18 (T18) is one of the most commonly diagnosed aneuploidies leading to poor survival outcome. However, little is known about the dual risk of T18 and very low birth weight (VLBW, weighing <1500 g at birth). We aimed to investigate the survival and clinical features of VLBW infants with T18. In this observational cohort study, infants with T18 admitted to the neonatal intensive care unit in Kyushu University Hospital from 2000 to 2019 were eligible. Among 30 infants with T18 who were enrolled as study participants, 11 (37&#37;) were born with VLBW. VLBW infants had lower gestational age (34.4 vs. 39.4 weeks, p < 0.01) and a higher incidence of esophageal atresia (64&#37; vs. 11&#37;, p < 0.01) than non-VLBW infants. The proportions of patients who underwent any surgery (55&#37; vs. 5&#37;, p < 0.01) and positive pressure ventilation (82&#37; vs. 32&#37;, p = 0.02) were higher in VLBW than non-VLBW infants. One-year overall survival rate (45&#37; vs. 26&#37;, p = 0.32 by log-rank test) did not differ between the two groups. In conclusion, being born at VLBW may not be fatal for infants with T18 undergoing active interventions.

DOI： 10.1002/ajmg.a.62466

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To determine the neurodevelopmental outcomes of very-low-birth-weight infants (VLBWIs, birth weight <1,500 g) after 9 years of follow-up. METHODS: This study prospectively recruited 224 VLBWIs born from 2003 to 2009 in Kyushu University Hospital, Japan. Comorbidities of neurocognitive impairment, epilepsy, and autism spectrum disorder or attention-deficit hyperactivity disorder (ASD/ADHD) were assessed at age 3, 6, and 9 years. RESULTS: Neurodevelopmental profiles were obtained from 185 (83&#37;), 150 (67&#37;), and 119 (53&#37;) participants at age 3, 6, and 9 years, respectively. At age 9 years, 25 (21&#37;) VLBWIs showed intelligence quotient (IQ) <70, 11 (9&#37;) developed epilepsy, and 14 (12&#37;) had a diagnosis of ASD/ADHD. The prevalence of epilepsy was higher in children with an IQ <70 at age 9 years than in those with an IQ ≥70 (44&#37; vs 0&#37;). In contrast, ASD/ADHD appeared at similar frequencies in children with an IQ <70 (16&#37;) and ≥70 (11&#37;). Perinatal complications and severe brain lesions on MRI were considered common perinatal risks for developmental delay and epilepsy but not for ASD/ADHD. Male sex was identified as a unique risk factor for ASD/ADHD. CONCLUSION: These data suggest that VLBWIs showed a higher prevalence of developmental delay, epilepsy, and ASD/ADHD at age 9 years than the general population. Distinct mechanisms might be involved in the pathogenic process of ASD/ADHD from those of developmental delay and epilepsy.

DOI： 10.1212/CPJ.0000000000000920

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The association between a slower physical growth and poorer neurodevelopment has been established in infants born preterm or small for gestational age. However, this association is inconsistent in term-born infants, and detailed investigations in infancy, when intervention is most beneficial for improving outcomes, are lacking. We therefore examined this association separately by sex during the first year of life in term-born infants. METHODS: Using data collected until children reached 12 months old in an ongoing prospective cohort of the Japan Environment and Children's Study, we analyzed 44,264 boys and 42,541 girls with singleton term-birth. The exposure variables were conditional variables that disentangle linear growth from weight gain relative to linear growth, calculated from the length and weight at birth and 4, 7 and 10 months old. Neurodevelopmental delay was identified using the Japanese-translated version of Ages & Stages Questionnaires, third edition. RESULTS: A reduced risk of neurodevelopmental delay at 6 months old was observed in children with a higher birth weight (adjusted relative risks [aRRs]: 0.91 and 0.93, 95 &#37; confidence intervals [95 &#37; CIs]: 0.87-0.96 and 0.88-0.98 in boys and girls, respectively) and increased linear growth between 0 and 4 months old (aRRs: 0.85 and 0.87, 95 &#37; CIs: 0.82-0.88 and 0.83-0.91 in boys and girls, respectively). A reduced risk at 12 months was found in children with an increased linear growth between 0 and 4 months (aRRs: 0.92 and 0.90, 95 &#37; CIs: 0.87-0.98 and 0.84-0.96 in boys and girls, respectively), boys with an increased relative weight gain between 0 and 4 months (aRR: 0.90, 95 &#37; CI: 0.84-0.97), and girls with a higher birth weight (aRR: 0.89, 95 &#37; CI: 0.83-0.96). CONCLUSIONS: These results suggest that a slow physical growth by four months old may be a predictor of neurodevelopmental delay during infancy.

DOI： 10.1186/s12887-021-02815-9

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INTRODUCTION: Retinopathy of prematurity (ROP) is a vascular proliferative disorder that occurs in preterm infants. Existing treatments are only indicated in severe ROP cases due to the high invasiveness and the potential risk of irreversible side effects. We previously elucidated that ripasudil, a selective inhibitor of the Rho-associated protein kinase, has the ability to inhibit abnormal retinal neovascularisation in animal models. In addition, ripasudil eye drops (Glanatec ophthalmic solution 0.4&#37;) have been already used for the treatment of glaucoma. Since eye drop therapy is less invasive, early intervention for ROP is possible. The purpose of this phase I/II trial is to evaluate the safety and efficacy of ripasudil eye drops for preterm infants with ROP. METHODS AND ANALYSIS: This is a multicentre, open-label, single-arm phase I/II trial. To evaluate the safety and efficacy of ripasudil as much as possible, ripasudil will be administered to all enrolled preterm infants with zone I/II, stage 1, or worse ROP. The safety and efficacy of ripasudil in treated patients will be assessed in comparison to a historical control group. Because this is the first trial of ripasudil in preterm infants, a dose-escalation study (once daily for 1 week, then two times per day for 2 weeks) will be conducted in phase I. After obtaining approval from the independent data and safety monitoring board to continue the trial after the completion of phase I, phase II will be conducted. In phase II, ripasudil eye drops will be administered two times per day for 12 weeks. The primary endpoint in phase II is also safety. Efficacy and pharmacokinetics will be evaluated as secondary endpoints. ETHICS AND DISSEMINATION: This study protocol was approved by the institutional review board at each of the participating centres. Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT04621136 and jRCT2071200047.

DOI： 10.1136/bmjopen-2020-047003

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OBJECTIVE: To investigate recent trends in bronchopulmonary dysplasia (BPD) and its risk factors among extremely preterm infants. STUDY DESIGN: Demographic and clinical data were reviewed for 19 370 infants born at 22-27 weeks of gestation registered in the affiliated hospitals of the Neonatal Research Network of Japan between 2003 and 2016. We investigated the overall survival and prevalence of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age and risk factors for developing BPD among the survivors. RESULTS: Among 19 370 infants, 2244 (11.6&#37;) died by 36 weeks' postmenstrual age. The mortality rate decreased from 19.0&#37; (99&#37; CI, 15.7&#37;-22.8&#37;) in 2003 to 8.0&#37; (99&#37; CI, 6.2&#37;-10.3&#37;) in 2016. Among 17 126 survivors, BPD developed in 7792 (45.5&#37;) infants, and its proportion significantly increased from 41.4&#37; (99&#37; CI, 36.5&#37;-46.4&#37;) in 2003 to 52.0&#37; (99&#37; CI, 48.2&#37;-55.9&#37;) in 2016. A multivariable analysis of the survivors showed a positive association of BPD with ≥4 weeks' supplemental oxygen or invasive ventilation, birth weight <750 g, small for gestational age, ≥4 weeks' noninvasive positive pressure ventilation, chorioamnionitis, <26 weeks' gestational age, <20 cases per year of center patient volume, or treated patent ductus arteriosus. Although the median duration of invasive ventilation was shortened, the proportions of factors associated adversely with BPD generally showed increasing trends over time. CONCLUSIONS: The mortality rate of extremely preterm infants has decreased, but the rate of BPD has increased in survivors between 2003 and 2016. Despite the decreasing duration of invasive ventilation over time, increasing rates of BPD suggest that differences in the patient population or other management strategies influence the development of BPD.

DOI： 10.1016/j.jpeds.2020.11.041

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Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

This case series aimed to characterize the clinical features, management, and outcomes of apnea in infants with trisomy 18. Participants in this study were infants with trisomy 18 who were born alive and admitted to the neonatal intensive care unit in Kyushu University Hospital from 2000 to 2018. Retrospective analysis was performed on clinical data recorded in our department. Twenty-seven infants with trisomy 18 were admitted to our hospital during the study period, of which 25 (nine males, 16 females) were enrolled as eligible participants in this study. Among them, 14 started presenting with apnea from median 3.5 days of age (range 0–47d). In these infants with apnea, eight received respiratory support of positive pressure ventilation (PPV). The 1-year survival rate of infants in the PPV group was higher than that of non-PPV-supported infants (5 out of 8 vs 0 out of 6 infants). Five PPV-supported infants received a diagnosis of epilepsy, which was controlled by antiepileptic drugs. Postnatal respiratory intervention provides better prognosis in infants with trisomy 18. Improved survival leads to accurate diagnosis and treatment of apneic events in association with epilepsy. What this paper adds: Respiratory support is effective against apnea in infants with trisomy 18. Intervention with ventilation provides a higher chance of prolonged survival. Improved survival leads to the accurate diagnosis and treatment of epilepsy-associated apnea.

DOI： 10.1111/dmcn.14403

Language：Japanese  

母体は28歳の経産婦であった。在胎29週5日に胎児エコーで異常を指摘された。両腎は腫大のない高輝度エコーを呈し、羊水過少および肺低形成を認め、特徴的なエコー所見から先天性ネフローゼ症候群を疑った。出生時、両側瞳孔はピンホール状であり、胎児腎エコー所見と併せてPierson症候群を疑った。無尿が持続し、日齢9に腹膜透析(PD)カテーテルを留置し、日齢11にPDによる維持透析を開始した。遺伝子パネル解析でLAMB2のヘテロ接合体遺伝子変異を検出し、父母由来のアレル上に同様の変異を認め、Pierson症候群と確定診断した。両腎の正常～軽度腫大を呈する高輝度エコー像を示す疾患は、早期治療介入が必要な疾患が多く、重要な所見である。特徴的な腎外症状と組み合わせることにより、早期の診断・治療介入が可能になると考えられた。(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)  

Background: This study aimed to investigate the utility of transcutaneous (tc) measurements of partial pressure of oxygen (tcPO₂) and carbon dioxide (tcPCO₂) monitoring in neonatal intensive care units (NICUs) in Japan. Methods: At the end of 2016,we sent a survey questionnaire on tc monitoring to all 106 NICUs registered with the Japanese Neonatologist Association. The questions included usage, subjects, methods, management, and the practical usefulness of tc monitoring. Results: The questionnaire was returned by 69 NICUs (65.1&#37; of response rate). Seventeen institutions (24.6&#37;) measured both tcPCO₂ and tcPO₂, and 42 (60.9&#37;) measured tcPCO₂ alone. Transcutaneous PCO₂ or tcPO₂ monitoring was applied for “pre-viable” infants born at 22–23 weeks’ gestational age (18.6&#37; vs 23.5&#37;), and infants of <500 g birthweight (30.5&#37; vs 17.6&#37;). The tcPCO₂ and tcPO₂ monitoring was started at birth in 49.2&#37; and 70.6&#37; of the newborn infants, respectively. The temperature of the sensor was set at <38°C for tcPCO₂ in 54.3&#37; and >42°C for tcPO₂ in 58.9&#37; of NICUs. The accuracy for tcPO₂ was rated as good in 35.3&#37; or moderate in 64.7&#37;, of institutions but or for tcPCO₂ as 1.7&#37; or 93.2&#37;of institutions, respectively. Conclusion: Transcutaneous monitoring was widely, but limitedly, used for preterm infants. The lower temperature of the tcPCO₂ sensor compared to that reported in other developed countries might compromise the accuracy but increase the feasibility of tc monitoring in Japan.

DOI： 10.1111/ped.14107

Language：English   Publishing type：Research paper (scientific journal)  

Hemophagocytic lymphohistiocytosis (HLH) occurs in neonates with disseminated infection of herpes simplex virus (HSV). Little has been reported on the control of rapid HLH progression. We studied the cytokine profile and genetic basis of two index cases with divergent outcomes after early treatment of type 2 HSV infection. One survivor had fever and elevated serum levels of tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), interferon (IFN)-β, and IFN-γ at diagnosis. The other neonate had no fever or TNF-α production, but significant IL-6 or IFN responses during the treatment course, and died 19 days after birth. Among 16 reported cases of neonatal HSV-HLH including index cases, eight deceased neonates experienced significantly less fever at presentation (p = 0.028), lower platelet counts (p = 0.019), and lower ratios of soluble IL-2 receptor (sIL-2R) to ferritin levels (p = 0.044) than eight survivors. The 100-day overall survival rates were significantly higher in patients with fever (p = 0.004), > 100 × 10⁹/L of platelet counts (p = 0.035) or > 20 of sIL-2R/ferritin ratio at diagnosis (p = 0.004). The first febrile and cytokine responses to HSV infection predict the early outcome of neonatal HSV-HLH.

DOI： 10.1007/s12185-019-02738-3

Language：English   Publishing type：Research paper (scientific journal)  

Purpose The purpose of this study was to evaluate neurodevelopmental outcomes in 18-month old (corrected age) preterm infants who received an intravitreal bevacizumab (IVB) injection for the treatment of type 1 retinopathy of prematurity (ROP). Methods In this ten-year retrospective study, we reviewed the medical records of patients who underwent ROP screening at Kyushu University Hospital. Among the patients who received IVB or laser photocoagulation (LPC) for the treatment of type 1 ROP, we included infants whose neurodevelopmental examination (the Kyoto Scale of Psychological Development [KSPD]) results at 18 months corrected age were available. Then, the effect of IVB on the developmental quotient (DQ) in each KSPD domain (Postural-Movement, Cognitive-Adaptive, or Language-Social domain) or the overall DQ was investigated by performing linear regression analysis. Results Out of the 513 patients reviewed, 53 were included in the study. IVB and LPC were performed for 14 and 39 patients, respectively. Administration of IVB was significantly associated with neurodevelopmental delay in the Language-Social domain (p = 0.01). The observed association remained even after adjusting for gestational age and birth weight (p = 0.03). Conclusions Administration of IVB may introduce a risk of developmental impairment of interpersonal relationships, socializations, and/or verbal abilities of preterm children. We recommended that preterm infants who received IVB undergo a neurodevelopmental reassessment during their school years or in adulthood.

DOI： 10.1371/journal.pone.0230678

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Objective: To determine clinical features of very low birth weight infants (VLBWIs) who had developed epilepsy by age 3 years. Study design: Multicenter cohort study using the Neonatal Research Network of Japan database. We analyzed clinical variables of 8431 VLBWIs who had recorded data of neurological sequelae at age 3 years. Logistic regression identified the association between variables and development of epilepsy. Result: One hundred and forty-three (1.7&#37;) infants developed epilepsy, 683 (8.1&#37;) showed cerebral palsy (CP), and 1114 (13.2&#37;) had psychomotor delay. Epilepsy was associated with history of sepsis [adjusted odds ratio (AOR) 3.23], severe intraventricular hemorrhage (IVH; AOR 5.13), and cystic periventricular leukomalacia (PVL; AOR 12.7). Severe IVH and cystic PVL were also frequently associated with CP and psychomotor delay. Conclusion: Severe IVH and cystic PVL are strongly associated with development of epilepsy, as well as other neurological sequelae, and are potential critical therapeutic targets.

DOI： 10.1038/s41372-019-0494-7

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Background: To investigate the hematological features of infants with bronchopulmonary dysplasia (BPD) and their relationships with clinical severity. Methods: This prospective observational study enrolled 73 BPD patients from a total of 331 infants with a birth weight of <1500 g from 2005 to 2013. The clinical severity of BPD was defined by the duration of oxygen supplementation and positive pressure ventilation (PPV) in line with the diagnostic criteria of BPD. The hematological status and cytokine levels were surveyed from blood samples at birth and at 2 and 4 weeks of life. Results: Thirty-four (46.6&#37;) cases were classified as “moderate-to-severe” BPD. Small-for-gestational-age (SGA) was associated with the severity of BPD (OR: 5.05; 95&#37; CI: 1.45 to 17.2). The CRP level at 2 weeks (partial regression coefficient [rc]: 21.8; 4.01 to 39.7) and the neutrophil count at 4 weeks (0.005; 0.001 to 0.007) were positively correlated with the oxygenation period. The PPV period was found to be correlated with the CRP level at 2 weeks (27.2; 14.9 to 39.5), and the neutrophil count (0.003; 0.001 to 0.004) at 4 weeks. Conclusion: The aggravation of BPD was associated with both SGA at birth and inflammation during neonatal period.

DOI： 10.1016/j.pedneo.2018.11.007

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Objective: To investigate whether the development of postnatal, late-onset refractory hypotension, referred to as late-onset circulatory collapse, was associated with an increased risk of developing cerebral palsy (CP) at 3 years of age in extremely preterm infants. Methods: In this historical cohort study, infants who were born at 22-27 weeks of gestation from 2008 to 2012 in the Neonatal Research Network of Japan were eligible. The study sample consisted of 3474 infants (45.6&#37; of 7613 potentially eligible infants) who were evaluated at 36-42 months of age. Late-onset circulatory collapse was defined as a clinical diagnosis of late-onset circulatory collapse requiring treatment with corticosteroids. We compared the neurodevelopmental outcomes between infants with and without late-onset circulatory collapse. Results: Late-onset circulatory collapse was diagnosed in 666 of the infants studied. Infants with late-onset circulatory collapse had a higher incidence of CP than those without late-onset circulatory collapse (18.0&#37; vs 9.8&#37;; P < .01). In multivariable logistic analysis, late-onset circulatory collapse was independently associated with CP (aOR, 1.52; 95&#37; CI, 1.13-2.04) and developmental quotient score of <50 (OR, 1.83; 95&#37; CI, 1.23-2.72). Conclusions: Late-onset circulatory collapse may be a relatively common event occurring in extremely preterm infants and an independent risk factor for CP at 3 years of age.

DOI： 10.1016/j.jpeds.2019.05.033

Language：Japanese   Publishing type：Research paper (scientific journal)  

非免疫性胎児水腫の原因は多岐に渡るが、その成因が不明なものも2割程度存在する。母体のアンギオテンシン受容体拮抗薬(angiotensin II receptor blocker:ARB)内服による尿細管形成不全をきたした児(ARB fetopathy)が、妊娠後期にARBを中止後に胎児水腫を発症した。胎児心エコーでは右心不全の所見を認めた。出生後、浮腫が速やかに消失し、胎児水腫は母体要因である可能性が考えられた。母体および胎盤由来のレニン・アルドステロンが直接胎児に影響した可能性を疑ったが、出生後のレニン・アルドステロン値の推移からは否定的であった。元来妊娠中でレニン・アンギオテンシン・アルドステロン系(Renin-Angiotensin-Aldosterone System:RAAS)が亢進しており、ARBの中止という特異的な状況が加わり、母体でのNa、水再吸収が増加、母体・胎盤の浮腫から胎児の前負荷の増加につながり、右心不全、胎児水腫をきたしたのではないかと推測した。(著者抄録)

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Language：Japanese  

Language：Japanese  

新生児単純ヘルペスウィルス(HSV)感染症は主に産道感染によって新生児に発症する周産期感染症の重要な疾患の一つである。全身型、中枢神経型、表在型の3つの病型に分けられるが、特に全身型は新生児早期に発症し、一部ではHSV関連血球貪食性リンパ組織球症(HSV-HLH)に進展して、急激に致死的な経過をたどる予後不良な疾患である。救命のためには新生児HSV感染症を疑った時点で抗ウイルス薬の投与を開始することが、重症化の予防および生命予後の改善のために重要である。また新生児HSV-HLHに関しては高サイトカイン血症に基づいた重篤なDICの病態を合併していることから、適切な抗サイトカイン治療の選択も重要であると考えられる。しかしながら未だ新生児HSV-HLHの病態や治療に関する情報は乏しく、より良い診療のためには早期診断・治療の指針の確立が急務と考えられる。(著者抄録)

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Objective: The diagnosis of neonatal-onset protein C (PC) deficiency is challenging. This study aimed to establish the neonatal screening of heritable PC deficiency in Japan. Study design: We determined the changes in plasma activity levels of PC and protein S (PS) in healthy neonates, and studied newborn patients with PROC mutation in the Japanese registry. Result: Physiological PC and PS levels increased with wide range. The PC/PS-activity ratios converged after birth. The PC/PS-activity ratios of 19 patients with biallelic mutations, but not, 9 with monoallelic mutation, were lower than those of 13 without mutation. The logistic regression analyses established a formula including two significant variables of PC activity (cut-off < 10&#37;, odds ratio = 30.0) and PC/PS-activity ratio (cut-off < 0.35, odds ratio = 22.7), with 93&#37; sensitivity and 44&#37; specificity for determining patients with mutation(s). Conclusion: The PC/PS-activity ratio is an effective parameter for the genetic screening of neonatal-onset PC-deficiency in Japanese population.

DOI： 10.1038/s41372-018-0262-0

Language：English   Publishing type：Research paper (scientific journal)  

Objectives: Tracheostomy is indicated for very-low-birth-weight infants (VLBWIs) with prolonged respiratory problems during the perinatal period. The objective of this study is to clarify the epidemiology and risk factors in VLBWIs with tracheostomy after birth in Japan. Methods: A total of 40 806 VLBWIs were registered in the Neonatal Research Network of Japan database from 2003 to 2012. Among them, 34 674 infants (85&#37;) survived over 28 days after birth and were subjected to this study. The clinical variables at birth, outcomes at hospital discharge and associated factors for tracheostomy were examined. Results: The proportion of VLBWIs with tracheostomy did not increase during the study period (mean 36 cases per year, 0.93&#37;). The rate of in-hospital death over 28 days after birth did not differ between tracheostomized and non-tracheostomized infants (2/324, 0.6&#37; vs 314/34 350, 0.9&#37;). Tracheostomized infants more frequently had severe or moderate bronchopulmonary dysplasia (BPD) (75.5&#37; vs 26.0&#37;, P < 0.01) and longer hospitalization (229 days vs 83 days, P < 0.01) than non-tracheostomized infants. Tracheostomized patients showed higher comorbidities with hypoxic ischemic encephalopathy (odds ratio [OR] 10.98, P < 0.01), muscular disease (OR 10.95, P < 0.01), severe or moderate BPD (OR 7.79, P < 0.01), chromosomal abnormality (OR 4.43, P < 0.01) or sepsis (OR 1.78, P < 0.05) at hospital discharge than non-tracheostomized patients. Conclusion: We demonstrated the non-increasing rate in tracheostomy for VLBWIs and such cases were associated with an excellent survival in Japan. These data provide evidence that more attentive care must be practiced in order to reduce the pulmonary and neuromuscular burdens of VLBWIs at birth.

DOI： 10.1002/ppul.24200

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OBJECTIVES: To determine neurodevelopmental outcomes at 3 years of age in children born with a birth weight (BW) of ≤500 g. METHODS: Infants who were born with a BW of ≤500 g from 2003 to 2012 in the Neonatal Research Network of Japan and survived to discharge from the NICU were eligible in this study. The study population consisted of 460 children (56.7&#37; of 811 surviving infants) who were evaluated at 36 to 42 months of age. Neurodevelopmental impairment (NDI) was defined as having cerebral palsy, visual impairment, hearing impairment, or a developmental quotient score of <70. RESULTS: The overall proportion of NDI was 59.1&#37; (95&#37; confidence interval [CI]: 54.6&#37;-63.5&#37;). The trend revealed no significant change during the study period. In a multivariate modified Poisson regression analysis, NDI was associated with severe intraventricular hemorrhage (adjusted risk ratio [RR]: 1.42; 95&#37; CI: 1.19-1.68; P <.01), cystic periventricular leukomalacia (adjusted RR: 1.40; 95&#37; CI: 1.13-1.73; P <.01), severe necrotizing enterocolitis (adjusted RR: 1.31; 95&#37; CI: 1.07-1.60; P <.01), surgical ligation for patent ductus arteriosus (adjusted RR: 1.29; 95&#37; CI: 1.09-1.54; P <.01), and male sex (adjusted RR: 1.19; 95&#37; CI: 1.01-2.40; P =.04). CONCLUSIONS: This cohort showed that neurodevelopmental outcomes of infants with a BW of ≤500 g have not improved from 2003 to 2012. Multivariate analysis revealed that severe intracranial hemorrhage and cystic periventricular leukomalacia were the strongest risk factors for NDIs. Our data suggested that measures aimed at reducing neurologic morbidities will be important for improving outcomes of infants with a BW of ≤500 g.

DOI： 10.1542/peds.2017-4286

Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

母体は33歳で、妊娠6週時に一絨毛膜性二羊膜双胎妊娠と診断され、両児の体重、羊水量、中大脳動脈最高血流速度は正常範囲内であった。妊娠29週1日に分娩が進行して緊急帝王切開分娩となり、第1児は出生体重1234g、第2児は1002g、ヘモグロビン値は第1児が18.4g/dL、第2児が6.0g/dLであり、第1児が双胎間貧血多血Sequence受血児、第2児を供血児と診断した。第1児は部分交換輸血により合併症なく日齢58に退院した。第2児は出生後に濃厚赤血球輸血、非侵襲的陽圧換気を行い、日齢2より人工乳にて経腸栄養を開始したが、日齢10に新生児壊死性腸炎を発症した。緊急開腹手術にて壊死した小腸を45cm切除し人工肛門を造設した。術後7日より経腸栄養を再開し、116日後に人工肛門閉鎖術を実施した。閉鎖術後94日の消化管造影で短腸症候群と診断し、中心静脈栄養と低出生体重児用ミルクを用いた頻回授乳を併用し、日齢232に体重3324gで退院した。

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese   Publishing type：Research paper (scientific journal)  

2009年～2010年にNICUに入院しDubowitz神経学的評価を実施した低出生体重児42名(男24名、女18名)を、出生体重1500g未満(ハイリスク群)21名と出生体重1500g以上2500g未満(通常群)21名に分け、7～8年間の長期的な発達の経過を比較調査した。就学前6歳時点でフォロー継続できているのはハイリスク群19名、通常群7名であり、療育介入はハイリスク群10名、通常群3名であった。Dubowitz神経学的評価にてtotal scoreの平均値はハイリスク群・通常群ともに23.3点であり、27点未満はハイリスク群17名、通常群16名であった。そのうち運動発達障害を有するのはハイリスク群・通常群とも3例ずつであり、total scoreが27点以上で運動発達障害を有する者はいなかった。精神発達遅滞、発達障害を有する者はtotal scoreが27点未満・27点以上の両方に存在し、かつハイリスク群・通常群の両群に存在した。

Language：Japanese   Publishing type：Research paper (scientific journal)  

2009年～2010年に出生した低出生体重児42例のうち、就学先を把握できた24例を対象として、6歳時のWechsler Intelligence Scale of Children-IV(WISC-IV)、3歳時および1.5歳時の新版K式検査による発達検査と、新生児期のDubowitz神経学的評価を用いて、就学先による差違を後方視的に検討した。就学先は、通常学級14例(男児12例、女児2例)、支援学級・支援学校10例(男児3例、女児7例)であった。WISC-IVにおいて言語理解、知覚推理、ワーキングメモリー、処理速度、全検査の各項目において2群間で有意差を認めた。3歳時K式検査では姿勢-運動、認知-適応、言語-社会、全領域において、1.5歳時K式検査では認知-適応、言語-社会、全領域において2群間で有意差を認めた。Dubowitz評価ではtotalスコア・各スコアともに2群間で有意差は認めなかった。

Language：English  

Background: Transient abnormal myelopoiesis (TAM) is a neonatal preleukemic syndrome that occurs exclusively in neonates with Down syndrome (DS). Most affected infants spontaneously resolve, although some patients culminate in hepatic failure despite the hematological remission. It is impossible to determine the patients who are at high risk of progressive liver disease and leukemic transformation. The objective is to search for biomarkers predicting the development of hepatic failure in DS infants with TAM. Methods: Among 60 newborn infants with DS consecutively admitted to our institutions from 2003 to 2016, 41 infants with or without TAM were enrolled for the study. Twenty-two TAM-patients were classified into “progression group” (n = 7) that required any therapy and “spontaneous resolution group” (n = 15). Serum concentrations of chemokines (CXCL8, CXCL9, CXCL10, CCL2 and CCL5) and transforming growth factor (TGF)-β1 were measured at diagnosis of TAM for assessing the outcome of progressive disease. Results: Three patients developed leukemia during the study period (median, 1147 days; range, 33–3753). Three died of hepatic failure. All patients in the progression group were preterm birth <37 weeks of gestational age and were earlier than those in the spontaneous resolution group (median, 34.7 vs. 37.0 weeks, p < 0.01). The leukocyte counts and CXCL8 and CCL2 levels at diagnosis in the progression group were higher than those in the spontaneous resolution group (leukocyte: median, 81.60 vs. 27.30 × 10
⁹
/L, p = 0.01; CXCL8: 173.8 vs. 34.3 pg/ml, p < 0.01; CCL2: 790.3 vs. 209.8 pg/mL, p < 0.01). Multivariate analyses indicated that an increased CCL2 value was independently associated with the progression and CXCL8 with the death of liver failure, respectively (CCL2: standardized coefficient [sc], 0.43, p < 0.01; CXCL8: sc = −0.46, p = 0.02). Conclusion: High levels of circulating CXCL8 and CCL2 at diagnosis of TAM may predict progressive hepatic failure in DS infants.

DOI： 10.1016/j.pedneo.2018.09.005

Language：Japanese  

Language：English  

Objective To assess the short-term prognosis of Japanese infants with a birth weight (BW) of ≤500 g. Study design Demographic and clinical data were reviewed for 1473 live born infants with a BW ≤500 g at gestational age ≥22 weeks who were treated in the 204 affiliated hospitals of the Neonatal Research Network of Japan between 2003 and 2012. Results Survival to hospital discharge occurred in 811 of 1473 infants (55&#37;; 95&#37; CI 53&#37;-58&#37;). The survival rates of BW ≤300 g, 301-400 g, and 401-500 g were 18&#37; (95&#37; CI 10&#37;-31&#37;), 41&#37; (95&#37; CI 36&#37;-47&#37;), and 60&#37; (95&#37; CI 57&#37;-63&#37;), respectively. In a multivariable Cox proportional hazards analysis, antenatal corticosteroid use (adjusted hazard ratio: 0.68; 95&#37; CI 0.58-0.81; P <.01), cesarean delivery (0.69; 95&#37; CI 0.56-0.85; P <.01), advanced gestational age per week (0.94; 95&#37; CI 0.89-0.99; P =.02), BW per 100-g increase (0.55; 95&#37; CI 0.49-0.64; P <.01), Apgar score ≥4 at 5 minutes (0.51; 95&#37; CI 0.43-0.61; P <.01), and no major congenital abnormalities (0.38; 95&#37; CI 0.29-0.51; P <.01) were associated with survival to discharge. Despite the improved survival rate over the 10-year study period (from 40&#37; in 2003 [95&#37; CI 30&#37;-51&#37;] to 68&#37; in 2012 [95&#37; CI 61&#37;-75&#37;]), at least 1 severe morbidity was present in 81&#37;-89&#37; of the survivors. Conclusions Improvements in perinatal-neonatal medicine have improved the survival, but not the rate of major morbidities, of infants with a BW ≤500 g in Japan.

DOI： 10.1016/j.jpeds.2017.05.017

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Infants with Down syndrome (DS) are at risk of developing a transient abnormal myelopoiesis (TAM). TAM occasionally involves liver fibrosis, which can be fatal. The management of liver disease in TAM has not yet been established and is mainly supportive. We report an infant with DS and TAM who developed end-stage liver failure. Liver dysfunction progressed even after blast cells disappeared from the circulation. He underwent a living-donor liver transplantation at 56 days of life without surgical complications. The explanted liver showed atrophy and severe fibrosis without leukemic cell infiltration. The posttransplant course was favorable with no hematological abnormality. He is doing well 8 months after transplantation. To the best of our knowledge, this report is the first showing that liver transplantation might be a treatment option for TAM-related liver failure.

DOI： 10.1159/000474930

Language：Japanese  

Language：English  

Transient Hemi-Lower Limb Ischemia in the Newborn: Arterial Thrombosis or Persistent Sciatic Artery?
Neonatal thromboembolism occurs with various predispositions and triggers. Early diagnosis of the thrombosis is challenging and essential for the therapeutic interventions. We herein report two newborns who presented with transient hemi-lower limb ischemia due to (1) arterial thrombosis or (2) a persistent sciatic artery (PSA). The patient with arterial thrombosis showed elevations of fibrin degradation product and D-dimer and received antithrombin and heparin intravenously. The patient with PSA was immediately assessed by a contrast-enhanced computed tomography because of a transient ischemic episode with no evidence of hypercoagulability. Newborns suspected of having arterial thrombosis may need urgent surgical intervention along with thrombolytic and anticoagulant therapy to prevent organ ischemia and amputation of extremities. Conversely, some PSA cases have reportedly been treated conservatively. This vascular anomaly was previously reported as a cause of lower limb ischemia only in a newborn. PSA is a critical differential diagnosis of neonatal arterial thrombosis that needs urgent therapeutic intervention.

DOI： 10.1055/s-0037-1598044

Language：English  

Language：English  

Background: The substantial risk of iron overload is not routinely monitored in most of the neonatal intensive care units (NICUs) in Japan; however, blood transfusion is an essential strategy for successfully treating preterm low-birth-weight infants. Objective: The aim of this study was to investigate the iron status and clinical features of infants with a birth weight of <1,500 g, i.e. very-low-birth-weight infants (VLBWIs). Methods: This prospective observational study enrolled 176 (82.6&#37;) patients from a total of 213 VLBWIs admitted to our NICU from 2009 to 2014. Clinical information was collected including maternal records and infant morbidity and treatment. Management strategies including enteral iron supplementation, erythropoietin administration and blood transfusion were allowed according to the consensus in Japan. The hematological status was surveyed from birth to 12 postnatal weeks of age. The iron status was determined according to serum iron, unbound iron-binding capacity and serum ferritin. The definition of hyperferritinemia was set as a value of ≥500 ng/ml. Results: Twenty-four (13.6&#37;) infants displayed hyperferritinemia. A multiple logistic analysis selected 3 associated factors of hyperferritinemia: surgical ligation for patent ductus arteriosus, sepsis and moderate or severe states of bronchopulmonary dysplasia. We also verified that the value of ferritin was significantly correlated with those of aspartate transaminase, creatine kinase and C-reactive protein according to a multilinear regression analysis. After excluding the ferritin data of these outliers, we did not observe any factors associated with hyperferritinemia. Conclusions: Hyperferritinemia might be associated with oxygen radical diseases and susceptibility to infection.

DOI： 10.1159/000447991

Language：English   Publishing type：Research paper (scientific journal)  

Preterm low-birth-weight infants remain difficult to manage based on adequate laboratory tests. The aim of this study was to establish blood reference intervals (RIs) in those newborns who were admitted to and survived in the neonatal intensive care unit (NICU). A multicenter prospective study was conducted among all infants admitted to 11 affiliated NICUs from 2010 to 2013. The clinical information and laboratory data were registered in a network database designed for this study. The RIs for 26 items were derived using the parametric method after applying the latent abnormal values exclusion method. The influence of birth weight (BW) and gestational age (GA) on the test results was expressed in terms of the standard deviation ratio (SDR), as SDRBW and SDRGA, respectively. A total of 3189 infants were admitted during the study period; 246 were excluded due to a lack of blood sampling data, and 234 were excluded for chromosomal abnormalities (n = 108), congenital anomalies requiring treatment with surgical procedures (n = 76), and death or transfer to another hospital (n = 50). As a result, 2709 infants were enrolled in this study. Both the SDRGA and SDRBW were above 0.4 in the test results for total protein (TP), albumin (ALB), alanine aminotransferase (ALT), and red blood cells (RBC); their values increased in proportion to the BW and GA. We derived 26 blood RIs for infants who were admitted to NICUs. These RIs should help in the performance of proper clinical assessments and research in the field of perinatal-neonatal medicine.

DOI： 10.1371/journal.pone.0161439

Language：English   Publishing type：Research paper (scientific journal)  

Preterm low-birth-weight infants remain difficult to manage based on adequate laboratory tests. The aim of this study was to establish blood reference intervals (RIs) in those newborns who were admitted to and survived in the neonatal intensive care unit (NICU). A multicenter prospective study was conducted among all infants admitted to 11 affiliated NICUs from 2010 to 2013. The clinical information and laboratory data were registered in a network database designed for this study. The RIs for 26 items were derived using the parametric method after applying the latent abnormal values exclusion method. The influence of birth weight (BW) and gestational age (GA) on the test results was expressed in terms of the standard deviation ratio (SDR), as SDR_BW and SDR_GA, respectively. A total of 3189 infants were admitted during the study period; 246 were excluded due to a lack of blood sampling data, and 234 were excluded for chromosomal abnormalities (n = 108), congenital anomalies requiring treatment with surgical procedures (n = 76), and death or transfer to another hospital (n = 50). As a result, 2709 infants were enrolled in this study. Both the SDR_GA and SDR_BW were above 0.4 in the test results for total protein (TP), albumin (ALB), alanine aminotransferase (ALT), and red blood cells (RBC); their values increased in proportion to the BW and GA. We derived 26 blood RIs for infants who were admitted to NICUs. These RIs should help in the performance of proper clinical assessments and research in the field of perinatal-neonatal medicine.

DOI： 10.1371/journal.pone.0161439

Language：English   Publishing type：Research paper (scientific journal)  

Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.

DOI： 10.1038/ng.3569

Language：English   Publishing type：Research paper (scientific journal)  

Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.

DOI： 10.1038/ng.3569.

Language：English  

DOI： 10.1007/s00467-015-3309-x.

Language：English  

DOI： 10.4049/jimmunol.1500295.

Language：Japanese   Publishing type：Research paper (scientific journal)  

NICUに入院した神経学的評価が可能な低出生体重児42名(男児24名、女児18名、在胎週数中央値32週6日、出生体重中央値1564g)を対象に、1歳半時、3歳時の発達状況を調査した。新版K式発達検査(K式)で3歳まで追跡できたのは18名であった。K式全領域の発達指数(DQ)と有意な相関関係を認めたのは、1歳半時ではDubowitz神経学的評価法のToneとTotalであり、3歳児では同評価のToneとApgar score(5分)であった。特にToneは全領域DQや姿勢-運動DQだけでなく、1歳半時で認知-適応DQ、3歳時で言語-社会DQとも有意な相関関係を認めた。3歳時の全領域DQが70未満の7名ではToneのcolumn 2が多く、70以上の11名ではcolumn 4が多い傾向であった。NICU退院時のMRIで2名がPVLと診断され、Dubowitz Totalは14.5点と17点で42名中の最低点と次点であり、14.5点の児は1歳半時、3歳時ともK式で低値を示し、後に脳性麻痺と診断されていた。

Language：English  

Intrauterine fetal growth restriction (IUGR) and death (IUFD) are both serious problems in the perinatal medicine. Fetal vasculopathy is currently considered to account for a pathogenic mechanism of IUGR and IUFD. We previously demonstrated that an innate immune receptor, the nucleotide-binding oligomerization domain-1 (Nod1), contributed to the development of vascular inflammations in mice at postnatal stages. However, little is known about the deleterious effects of activated Nod1 signaling on embryonic growth and development. We report that administration of FK565, one of the Nod1 ligands, to pregnant C57BL/6 mice induced IUGR and IUFD. Mass spectrometry analysis revealed that maternally injected FK565 was distributed to the fetal tissues across placenta. In addition, maternal injection of FK565 induced robust increases in the amounts of CCL2, IL-6, and TNF proteins as well as NO in maternal, placental and fetal tissues. Nod1 was highly expressed in fetal vascular tissues, where significantly higher levels of CCL2 and IL-6 mRNAs were induced with maternal injection of FK565 than those in other tissues. Using Nod1-knockout mice, we verified that both maternal and fetal tissues were involved in the development of IUGR and IUFD. Furthermore, FK565 induced upregulation of genes associated with immune response, inflammation, and apoptosis in fetal vascular tissues. Our data thus provided new evidence for the pathogenic role of Nod1 in the development of IUGR and IUFD at the maternal-fetal interface.

DOI： 10.4049/jimmunol.1500295

Language：English  

Background: Cystatin C (Cys-C) is a more sensitive marker of renal function than creatinine (Cre) in pediatric and adult populations. However, the reference values of serum Cys-C for estimating glomerular filtration rates (eGFRs) in premature infants during the first year of life have not been sufficiently studied. Methods: In this prospective study, 481 blood samples were collected from 261 preterm infants with uncomplicated clinical courses during their first year of life. Infants were divided into three groups according to gestational age at birth: 27- 30 weeks, 31-33 weeks, and 34-36 weeks. Serum Cys-C and Cre levels were measured at 6-30 days, 3-5 months, 7- 9 months, and 12-14 months after birth and the eGFR was calculated using two previously published equations. Results: The median serum Cys-C levels were 1.776, 1.248, 1.037, and 0.960 mg/L at the first, second, third, and fourth measurement time-point, respectively, with the value significantly decreasing with age up to 12-14 months. Cys-C levels were independent of gestational age and gender. In contrast to Cys-C, serum Cre values declined rapidly up to 3-5 months, then remained constant up to 12-14 months. Using the Cys-C-based equation, the eGFR significantly increased with increasing age until approximately 1 year after birth; however, no such trend was noted using the equation based on Cys-C + Cre. Conclusions: Reference ranges for Cys-C in premature infants decline gradually over the first year after birth. Cys-C appears to be a more reliable marker than Cre for estimating GFR in preterm infants.

DOI： 10.1007/s00467-015-3309-x

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The early diagnosis of inherited thrombophilia in children is challenging because of the rarity and hemostatic maturation. METHODS: We explored protein C (PC), protein S (PS), and antithrombin (AT) deficiencies in 306 thromboembolic patients aged ≤20 y using the screening of plasma activity and genetic analysis. RESULTS: Reduced activities were determined in 122 patients (40&#37;). Low PC patients were most frequently found in the lowest age group (0-2 y, 45&#37;), while low PS or low AT patients were found in the highest age group (16-20 y; PS: 30&#37; and AT: 20&#37;). Genetic study was completed in 62 patients having no other causes of thromboembolism. Mutations were determined in 18 patients (8 PC, 8 PS, and 2 AT genes). Six of eight patients with PC gene mutation were found in age 0-2 y (75&#37;), while six of eight patients with PS gene mutation were in 7-20 y. Two AT gene-mutated patients were older than 4 y. Four PC-deficient and two PS-deficient patients carried compound heterozygous mutations. All but one PC gene-mutated patient suffered from intracranial thromboembolism, while PS/AT gene-mutated patients mostly developed extracranial venous thromboembolism. CONCLUSION: Stroke in low PC infants and deep vein thrombosis in low PS/AT school age children could be targeted for genetic screening of pediatric thrombophilias.

DOI： 10.1038/pr.2015.180.

Language：English   Publishing type：Research paper (scientific journal)  

Background:The early diagnosis of inherited thrombophilia in children is challenging because of the rarity and hemostatic maturation.Methods:We explored protein C (PC), protein S (PS), and antithrombin (AT) deficiencies in 306 thromboembolic patients aged ≤20 y using the screening of plasma activity and genetic analysis.Results:Reduced activities were determined in 122 patients (40&#37;). Low PC patients were most frequently found in the lowest age group (0-2 y, 45&#37;), while low PS or low AT patients were found in the highest age group (16-20 y; PS: 30&#37; and AT: 20&#37;). Genetic study was completed in 62 patients having no other causes of thromboembolism. Mutations were determined in 18 patients (8 PC, 8 PS, and 2 AT genes). Six of eight patients with PC gene mutation were found in age 0-2 y (75&#37;), while six of eight patients with PS gene mutation were in 7-20 y. Two AT gene-mutated patients were older than 4 y. Four PC-deficient and two PS-deficient patients carried compound heterozygous mutations. All but one PC gene-mutated patient suffered from intracranial thromboembolism, while PS/AT gene-mutated patients mostly developed extracranial venous thromboembolism.Conclusion:Stroke in low PC infants and deep vein thrombosis in low PS/AT school age children could be targeted for genetic screening of pediatric thrombophilias.

DOI： 10.1038/pr.2015.180

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Moyamoya disease (MMD) is a cerebrovascular disorder characterized by occlusive lesions of the circle of Willis. To date, both environmental and genetic factors have been implicated for pathogenesis of MMD. Allelic variations in RNF213 are known to confer the risk of MMD; however, functional roles of RNF213 remain to be largely elusive. We herein report that pro-inflammatory cytokines, IFNG and TNFA, synergistically activated transcription of RNF213 both in vitro and in vivo. Using various chemical inhibitors, we found that AKT and PKR pathways contributed to the transcriptional activation of RNF213. Transcriptome-wide analysis and subsequent validation with quantitative PCR supported that endogenous expression of cell cycle-promoting genes were significantly decreased with knockdown of RNF213 in cultured endothelial cells. Consistently, these cells showed less proliferative and less angiogenic profiles. Chemical inhibitors for AKT (LY294002) and PKR (C16) disrupted their angiogenic potentials, suggesting that RNF213 and its upstream pathways cooperatively organize the process of angiogenesis. Furthermore, RNF213 down-regulated expressions of matrix metalloproteases in endothelial cells, but not in fibroblasts or other cell types. Altogether, our data illustrate that RNF213 plays unique roles in endothelial cells for proper gene expressions in response to inflammatory signals from environments.

DOI： 10.1038/srep13191

Language：English   Publishing type：Research paper (scientific journal)  

Moyamoya disease (MMD) is a cerebrovascular disorder characterized by occlusive lesions of the circle of Willis. To date, both environmental and genetic factors have been implicated for pathogenesis of MMD. Allelic variations in RNF213 are known to confer the risk of MMD; however, functional roles of RNF213 remain to be largely elusive. We herein report that pro-inflammatory cytokines, IFNG and TNFA, synergistically activated transcription of RNF213 both in vitro and in vivo. Using various chemical inhibitors, we found that AKT and PKR pathways contributed to the transcriptional activation of RNF213. Transcriptome-wide analysis and subsequent validation with quantitative PCR supported that endogenous expression of cell cycle-promoting genes were significantly decreased with knockdown of RNF213 in cultured endothelial cells. Consistently, these cells showed less proliferative and less angiogenic profiles. Chemical inhibitors for AKT (LY294002) and PKR (C16) disrupted their angiogenic potentials, suggesting that RNF213 and its upstream pathways cooperatively organize the process of angiogenesis. Furthermore, RNF213 down-regulated expressions of matrix metalloproteases in endothelial cells, but not in fibroblasts or other cell types. Altogether, our data illustrate that RNF213 plays unique roles in endothelial cells for proper gene expressions in response to inflammatory signals from environments.

DOI： 10.1038/srep13191.

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DOI： 10.1515/jpm-2013-0192.

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Aim: To determine the factors affecting neonatal prognosis in preterm premature rupture of membranes (PPROM). Method: We conducted a case-control study involving 92 women between the years 2000 and 2010 diagnosed with PPROM between 25 and 31 weeks' gestation, who received antenatal steroids, and delivered between 26 and 31 weeks' gestation; a retrospective cohort study was conducted based on the results. We used data from four tertiary centers and compared the frequencies of neonatal neurologic deficits and neonatal deaths. Results: There was a difference between the two groups; specifically, the ND group (n = 18) consisted of patients whose infants had neurologic deficits and/or neonatal deaths and the neurologically normal (NN) group (n = 74) included NN neonates amongst the patients who had expectant management (94&#37; vs. 73&#37;, respectively). Multivariable analysis revealed that expectant management was independently associated with an increased risk for neonatal neurologic deficits and neonatal deaths (odds ratio, 16.14). All neonates with poor prognosis in the expectantmanagement group delivered within 14 days after PPROM. Conclusions: Expectant management within 14 days after PPROM is associated with poor neonatal outcomes. Decisions regarding an expectant strategy should be made carefully. An immediate, planned delivery after steroid administration should be considered to improve neonatal prognosis in patients who have PPROM after 26 weeks' gestation.

DOI： 10.1515/jpm-2013-0192

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Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease mostly occurring in preterm infants. The pathogenesis of BPD involves early inflammation and remodeling of the premature lung. Aim: To search for the novel predictive marker of BPD development, we studied serum levels of neutrophil gelatinase-associated lipocalin (NGAL), an innate immune mediator, in preterm infants. Methods: Serum NGAL concentrations at birth were measured by enzyme-linked immunosorbent assay. The reference levels were determined in 52 infants having no anomalies or inherited diseases. The levels and clinical variables were assessed in association with BPD. Results: Geometric means (95&#37;CI) of serum NGAL levels at birth of infants having no underlying diseases were 32.4 (22.1-47.5), 58.6 (47.9-71.8), and 126.2 (99.0-168.7) ng/mL for <. 31, 31-36 and >. 36 gestational weeks (GW), respectively (p. <. 0.001). These levels positively correlated with neutrophil (p. <. 0.0001) or monocyte counts (p. <. 0.0001). The median NGAL levels (307.8. ng/mL) and neutrophil counts (4141/μL) at birth of 16 preterm infants (<. 31. GW) who developed BPD were higher than those (42.9. ng/mL and 1357/μL) of 20 infants (<. 31. GW) who did not (p. <. 0.0001 and p=0.012), respectively. In multivariable analysis for 36 infants born less than 31. GW, higher NGAL levels (≥. 82. ng/mL) but not neutrophil counts at birth had a significant association with developing BPD (gestational-age adjusted odds ratio [OR]=37.45 [3.08-455.49], p. <. 0.01). Conclusions: High serum levels of NGAL at birth could be an early sensitive marker for BPD in preterm infants, because their levels were physiologically low.

DOI： 10.1016/j.earlhumdev.2012.12.011

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DOI： 10.1016/j.earlhumdev.2012.12.011.

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TNF receptor-associated periodic syndrome (TRAPS) is caused by mutations of TNFRSF1A gene and characterized by recurrent febrile episodes of prolonged duration and initial good response to steroids. Etanercept, a TNF blocker, has been used as a putative molecular-targeted agent for TRAPS, with some patients showing limited efficacy. Here, we report a patient with TRAPS who recovered from steroid dependency by etanercept and kept remission with a reduced dose of etanercept. The pathophysiology of TRAPS still remains to be elucidated and several hypotheses have been proposed. In the most recent hypothesis, the concerted action of wild-type and mutant TNF receptors plays an important role in provoking enhanced inflammation in TRAPS. The excellent response to etanercept in our patient suggested that there is heterogeneity in TRAPS patients in terms of the contribution of normal TNF signaling to autoinflammation.

DOI： 10.1111/j.1442-200X.2011.03525.x

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We present a case of triplets with intrauterine cytomegalovirus (CMV) infection, each of whom showed differential transmission, placental pathology, and postnatal outcome. The first- and second-born infants were both vigorous and asymptomatic at birth, although the first-, but not the second-born, triplet had a high copy number of CMV DNA in the peripheral blood (1.2 × 103 copy/mL). The third-born triplet suffered from symptomatic CMV infection with a high viral load (6.0 × 106 copy/mL). The triamniotic-trichorionic placentas were not fused to each other. The histopathologic analysis showed that CMVpositive cells were frequently found in the decidua, villi, and amnion of the third-born triplet's placenta but were limited and scattered in the decidua or villi but not amnion of the other 2 placentas. The third-born triplet underwent ganciclovir therapy. None of the infants had physical or auditory problems at 4 years of age, whereas the third-born triplet had been diagnosed with an autistic disorder. This observation exemplifies the preventive roles of the individual placentas of triplets with regard to virus infection, thus suggesting that developing CMV disease largely depends on the placental function.

DOI： 10.2350/11-05-1034-CR.1

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Background: Bronchopulmonary dysplasia (BPD) occurs in association with prenatal conditions predisposing infants to inflammation and remodeling of the premature lungs. Because of the lack of useful biomarkers for BPD, the gene expression of tracheal aspirate fluid (TAF) cells in premature infants was analyzed. Methods: Of 148 consecutive patients, 26 preterm infants (gestational age <34 weeks) were enrolled, who underwent assisted ventilation at birth for respiratory failure. Patients with congenital disorders were excluded. Half of these infants developed BPD. Interleukin (IL)-10, interferon (IFN)-γ, transforming growth factor (TGF)-β1, and platelet-derived growth factor (PDGF)-B mRNA of TAF cells were quantified on real-time polymerase chain reaction. Results: IL-10 (P < 0.01) and IFN-γ (P= 0.03) but not TGF-β1 or PDGF-B mRNA levels at birth were higher in BPD than in non-BPD infants. IL-10 expression differentiated BPD with the highest sensitivity (92&#37;) and specificity (77&#37;). IL-10 levels correlated with TGF-β1 (P= 0.03) and IFN-γ (P= 0.01), but not with PDGF-B levels. When BPD infants were classified according to comorbidity (group 1, six patients who suffered respiratory distress syndrome [RDS] but not chorioamnionitis [CAM]; group 2, five patients who had CAM but not RDS), PDGF-B levels were higher in group 2 (P= 0.01). High IL-10 expression was selected as a risk factor for BPD in infants who had CAM but not RDS (P= 0.01), although prolonged oxygen therapy was the most sensitive indicator for BPD (P < 0.01) on multivariate analysis. Conclusions: High IL-10 expression in TAF cells at birth could predict the evolution of BPD, but with less impact than oxygen requirement. PDGF might play a different role in the inflammatory process of premature lungs.

DOI： 10.1111/j.1442-200X.2011.03510.x

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鉄は、酸素を運搬するヘモグロビンの構成原子であるが、エネルギー産生、核酸合成などに必須の微量元素である。一方、この重金属は毒性のある活性酸素種の産生源でもあるため生体は厳密な制御機構を有している。鉄の恒常性を司るいくつかの因子は感染や炎症にも関わる分子であり、細胞内外における鉄代謝の仕組みが解明されつつある。新生児とくに低出生体重児は、鉄代謝機構が未熟なため、鉄欠乏と過剰に陥りやすく、神経障害、慢性肺疾患、および未熟児網膜症への影響が懸念されている。しかし、周産期における胎児・新生児の鉄代謝は未開拓の分野であり、輸血や鉄剤投与の方法に関して多くの議論がある。ここでは肝から産生される鉄代謝ホルモン、hepcidinを中心に新生児における鉄の恒常性維持機構について概説する。(著者抄録)

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We herein report a case study of a female newborn with multiple pituitary hormone deficiencies who presented with generalized seizures, hypoglycemia and hyperammonemia at 18 h after birth. In addition, we review the association of hyperammonemia in neonates with multiple pituitary hormone deficiencies reported in the previous literature. This unrecognized association should be taken into account for the early diagnosis and treatment of these patients.

DOI： 10.1038/jp.2010.143

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A novel SCN5A mutation associated with the linker between III and IV domains of Na _v 1.5 in a neonate with fatal long QT syndrome

DOI： 10.1016/j.ijcard.2009.04.023

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It is rare that coloboma, heart anomalies, choanal atresia, retarded growth and development, and genital and ear anomalies (CHARGE) syndrome patients have DiGeorge sequence showing severe immunodeficiency due to the defect of the thymus. Although the only treatment to achieve immunological recovery for these patients in countries where thymic transplantation is not ethically approved would be hematopoietic cell transplantation, long-term survival has not been obtained in most patients. On the other hand, it is still not clarified whether hypoparathyroidism is one of the manifestations of CHARGE syndrome. We observed a CHARGE syndrome patient with chromodomain helicase DNA-binding protein 7 mutation showing DiGeorge sequence including the defect of T cells accompanied with the aplasia of the thymus, severe hypoparathyroidism, and conotruncal cardiac anomaly. He received unrelated cord blood transplantation without conditioning at 4 months of age. Recovery of T cell number and of proliferative response against mitogens was achieved by peripheral expansion of mature T cells in cord blood without thymic output. Although he is still suffering from severe hypoparathyroidism, he is alive without serious infections for 10 months.

DOI： 10.1007/s00431-009-1126-6

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DOI： 10.1111/j.1442-200X.2010.03044.x

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A 12-year-old girl with aortic valvular stenosis underwent transcatheter balloon aortic valvuloplasty (BAV) using a femoral artery approach. Anticoagulation with heparin during the procedure was used. The patient noted sudden onset of concentric constriction of the visual field in the right eye 40 min after BAV. Brain magnetic resonance imaging and cervical ultrasound revealed no abnormality. Funduscopic examination showed white swelling around the macular region, indicating ischemia, consistent with central retinal artery occlusion (CRAO). CRAO should be recognized as a rare and serious complication associated with BAV even among the pediatric population. This requires careful evaluation of anticoagulation during the left heart procedures.

DOI： 10.1007/s00246-007-9181-0

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Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

新生児期の血栓症は希少な事例と考えられてきたが、医療の高度化と疾患認識の広がりにより報告数が増加している。さらに、日本人小児の血栓性素因における遺伝性プロテインC欠乏症の重要性が示されてきた。今回私たちは新生児血栓症の全国調査を行い、遺伝性プロテインC欠乏症の遺伝学的効果と、遺伝学的検査の悉皆性を示すことができた。今後は調査対象を小児から成人に達するまでに拡大し、小児患者とその家族を血栓症から守る個別化医療の確立を目指す。(著者抄録)

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Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

新生児期の血栓症は希少な事例と考えられてきたが、医療の高度化と疾患認識の広がりにより報告数が増加している。さらに、日本人小児の血栓性素因における遺伝性プロテインC欠乏症の重要性が示されてきた。今回私たちは新生児血栓症の全国調査を行い、遺伝性プロテインC欠乏症の遺伝学的効果と、遺伝学的検査の悉皆性を示すことができた。今後は調査対象を小児から成人に達するまでに拡大し、小児患者とその家族を血栓症から守る個別化医療の確立を目指す。(著者抄録)

Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

新生児単純ヘルペスウイルス(HSV)感染症は、主に垂直感染によって発症する重要な周産期感染症の一つである。臨床病型は表在型(SEM;skin, eye, and mouth)、中枢神経型(CNS;central nervous system)および全身型(Disseminated)の3つに分類され、それぞれ異なる症状と臨床経過を示す。1970年代以降、抗ウイルス薬の登場、またHSV-DNAを検出するPCR法の開発により、早期診断・治療が可能となり飛躍的に治療成績は改善した。しかし新生児医療が高度化した現代においても、全身型の新生児死亡率は29%、中枢神経型は65%以上に神経学的後遺症を残し、依然として予後不良の疾患である。本稿では新生児HSV感染症に対する治療指針と現在の課題について提示する。また新生児ヘルペス脳炎や新生児HSV関連血球貪食性リンパ組織球症といった重症例のリスク因子や治療戦略についても概説する。(著者抄録)

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Neurodevelopmental outcomes of high-risk preterm infants: A prospective study in single institute

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The management and outcomes of apnea in infants with trisomy 18

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九州における家族性血球貪食症候群(FHL)の現状

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