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BACKGROUND: Focal intestinal perforation (FIP) is a devastating complication of premature birth, and extremely low birth weight (ELBW) infants are at highest risk. This study aimed to evaluate the relationship of the superior mesenteric artery (SMA) and portal vein (PV) blood flow velocities to investigate the association between intestinal blood flow and FIP. In addition, the herbal formula Daikenchuto (TJ-100) is expected to improve intestinal blood flow disorders; therefore, we evaluated its effect. METHODS: We conducted a prospective cohort study of 15 ELBW infants from January 2020 to August 2021. Measured variables included birth weight, 5-minute Apgar score, time of oral feeding initiation, ductus arteriosus (PDA) closure (percent), diastolic and systolic blood pressure, SMA and PV blood flow velocity, and FIP onset data. Fifteen infants were divided into three groups: a non-surgery group (Group I; 6), a surgery group with FIP (Group II; 4), and a TJ-100 administration group (Group III; 5). The main outcome parameters included SMA and PV blood flow velocities with TJ-100. RESULTS: SMA and PV blood flow differed significantly for the SMA of Group I and the SMA and PV of Group III (P < 0.01, P = 0.01, and P = 0.04, respectively). There was a correlation between SMA and PV in Group III (P = 0.03). CONCLUSION: TJ-100 may increase SMA and PV blood flow and improve intestinal blood flow in ELBW infants at risk of FIP. Therefore, the effects of TJ-100 should undergo further study. [ABSTRACT FROM AUTHOR]

PURPOSE: Recently, the number of births using assisted reproductive technologies (ART) has increased. An associated increase in the incidence of congenital malformations in babies conceived using this technology has also been reported. Therefore, we aimed to investigate the rate of malformations in babies with neonatal surgical diseases, who were conceived using ART. MATERIALS AND METHODS: Between January 2007 and December 2016, 1737 patients were admitted to our hospital. We analyzed the incidence of congenital cardiac diseases, genetic anomalies, and congenital anomalies of the kidney and urinary tract (CAKUT) in neonates conceived by ART. The χ2 test and logistic regression analysis were used to assess the odds ratios (ORs) for congenital malformations. A P-value < 0.05 indicated statistical significance. RESULTS: The OR for CAKUT was 16.94 for the first-birth neonates conceived using ART, [P < 0.05, AUC (area under the curve) = 0.86]. However, for non-surgery neonates, the OR for CAKUT was 5.99 (P = 0.15, AUC = 0.87), compared to 32.27 (P < 0.05, AUC = 0.93) for parallel conditions in surgery-neonates. CONCLUSION: Neonates conceived using ART are prone to develop CAKUT, which will need surgical treatment. Therefore, more management is necessary for associated malformations in these babies, particularly in cases with CAKUT. [ABSTRACT FROM AUTHOR]

Background: Few studies have compared the efficacy and complications of dexmedetomidine (DEX) and fentanyl (FEN) in extremely preterm infants., Methods: We conducted a single-institution, retrospective controlled before and after study of preterm infants before 28 weeks of gestation admitted between April 2010 and December 2018 to compare the complications and efficacy of DEX and FEN for preterm infants. Patients were administered FEN prior to 2015 and DEX after 2015 as the first-line sedative. A composite outcome of death during hospitalization and developmental quotient (DQ) < 70 at a corrected age of 3 years was compared as the primary outcome. Secondary outcomes including postmenstrual weeks at extubation, days of age when full enteral feeding was achieved and additional sedation by phenobarbital (PB) were compared., Results: Sixty-six infants were enrolled into the study. The only perinatal factor that differed between the FEN (n = 33) and DEX (n = 33) groups was weeks of gestation. The composite outcome of death and DQ < 70 at a corrected age of 3 years were not significantly different. Postmenstrual weeks at extubation did not significantly differ between groups after adjustment for weeks of gestation and being small for gestational age. On the other hand, full feeding was significantly prolonged by DEX (p = 0.031). Additional sedation was less common in the DEX group (p = 0.044)., Conclusion: The composite outcome of death and DQ < 70 at a corrected age of 3 years were not significantly different by DEX or FEN for primary sedation. Prospective randomized controlled trials should examine the long-term effects on development., (© 2023 The Authors. Pediatrics International published by John Wiley & Sons Australia, Ltd on behalf of Japan Pediatric Society.)

Objectives: We aimed to investigate the psychosocial factors for postpartum depression as indicated by a high score of the Edinburgh Postnatal Depression Scale (EPDS), including marital relationship and social support. Relevant factors for antenatal depression were also analyzed., Methods: Thirty-five wife-and-husband pairs who visited University Hospital A for the wife's antenatal health check-up participated in a questionnaire survey using the Japanese version of the EPDS. Social support from the wife's husband, kins, and others including friends at the third trimester of pregnancy and 1 month after birth was assessed. The Marital Love Scale (MLS) was also used, and two marital relationship questions were asked regarding the husband's and wife's considerate actions toward each other during pregnancy. Binary logistic regression analysis was conducted to determine adjusted associations between higher EPDS scores (≥5 for postpartum depression and ≥7 for antenatal depression) and indicators for social support and marital relationships., Results: The most relevant factor for higher postpartum EPDS scores was a higher antenatal EPDS score, followed by the couple's poor communication skills (the wife did not feel any appreciation from her husband) during pregnancy and no support from the wife's husband during the postpartum period. The wife's poor marital communication skills and the husband's low MLS scores during pregnancy were associated (borderline significance) with the wife's higher antenatal EPDS scores., Conclusions: A good marital relationship before birth and support by the husband after birth may be important for preventing postpartum depression.

GATA4 is known to be a causative gene for congenital heart disease, but has also now been associated with disorders of sexual development (DSD). We here report a pathogenic variant of GATA4 in a 46,XY DSD patient with an atrial septal defect, identified by whole-exome sequencing to be c.487C>T (p.Pro163Ser). This mutation resulted in reduced transcriptional activity of the downstream gene. When we compared this transcriptional activity level with other GATA4 variants, those that had been identified in patients with cardiac defects and DSD showed less activity than those in patients with cardiac defect only. This suggests that the normal development of the heart requires more strict regulation of GATA4 transcription than testicular development. Further, when the different variants were co-expressed with wild-type, the transcriptional activities were consistently lower than would be expected from an additive effect, suggesting a dominant-negative impact of the variant via dimer formation of the GATA4 protein. Since these pathogenic GATA4 variants are occasionally identified in healthy parents, a threshold model of quantitative traits may explain the cardiac defect or DSD phenotypes that they cause., (© 2022 Japanese Teratology Society.)

Various mitochondrial diseases, including mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), are associated with heteroplasmic mutations in mitochondrial DNA (mtDNA). Herein, we refined a previously generated G13513A mtDNA-targeted platinum transcription activator-like effector nuclease (G13513A-mpTALEN) to more efficiently manipulate mtDNA heteroplasmy in MELAS-induced pluripotent stem cells (iPSCs). Introduction of a nonconventional TALE array at position 6 in the mpTALEN monomer, which recognizes the sequence around the m.13513G>A position, improved the mpTALEN effect on the heteroplasmic shift. Furthermore, the reduced expression of the new Lv-mpTALEN(PKLB)/R-mpTALEN(PKR6C) pair by modifying codons in their expression vectors could suppress the reduction in the mtDNA copy number, which contributed to the rapid recovery of mtDNA in mpTALEN-applied iPSCs during subsequent culturing. Moreover, MELAS-iPSCs with a high proportion of G13513A mutant mtDNA showed unusual properties of spontaneous, embryoid body-mediated differentiation in vitro , which was relieved by decreasing the heteroplasmy level with G13513A-mpTALEN. Additionally, drug-inducible, myogenic differentiation 1 (MYOD)-transfected MELAS-iPSCs (MyoD-iPSCs) efficiently differentiated into myosin heavy chain-positive myocytes, with or without mutant mtDNA. Hence, heteroplasmic MyoD-iPSCs controlled by fine-tuned mpTALENs may contribute to a detailed analysis of the relationship between mutation load and cellular phenotypes in disease modeling., Competing Interests: The authors declare no competing interests., (© 2020 The Authors.)

We report a patient with congenital complex pituitary hormone deficiency (CPHD) with intestinal malrotation and anal atresia. We identified a de novo heterozygous mutation, c.664T > G (p.Cys222Gly), in the FOXA2 gene in this individual. This missense mutation had the potential to affect the DNA binding properties of the FOXA2 protein based on a protein structure prediction. Since a CPHD patient with another missense mutation and one other case with an entire gene deletion have also been reported, we speculated that a haploinsufficiency of the FOXA2 gene might be a genetic etiology for this disorder. Phenotypic similarities and differences among these three cases are also discussed., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Craniofrontonasal syndrome (CFNS) is a very rare genetic disorder, the common physical malformations of which include coronal synostosis, widely spaced eyes, clefting of the nasal tip, and various skeletal anomalies. Mutations of EFNB1, which encodes a member of the ephrin family of transmembrane ligands for Eph receptor tyrosine kinases, is the cause of CFNS. Although familial CFNS cases have been reported, no studies in the literature describe familial cases of CFNS expressing bilateral cleft lip and palate. Here, we describe a Japanese family with three cases of CFNS expressing bilateral cleft lip and palate.

Background: We previously reported that perinatal dioxin exposure increased autistic traits in children living in dioxin-contaminated areas of Vietnam. In the present study, we investigated the impact of dioxin exposure on children's eating behavior, which is often altered in those with developmental disorders., Methods: A total of 185 mother-and-child pairs previously enrolled in a birth cohort in dioxin-contaminated areas participated in this survey, conducted when the children reached 3 years of age. Perinatal dioxin exposure levels in the children were estimated using dioxin levels in maternal breast milk after birth. Mothers were interviewed using the Children's Eating Behaviour Questionnaire (CEBQ). A multiple linear regression model was used to analyze the association between dioxin exposure and CEBQ scores, after controlling for covariates such as location, parity, maternal age, maternal education, maternal body mass index, family income, children's gestational age at delivery, and children's age at the time of the survey. A general linear model was used to analyze the effects of sex and dioxin exposure on CEBQ scores., Results: There was no significant association between most dioxin congeners or toxic equivalencies of polychlorinated dibenzo-p-dioxins/furans (TEQ-PCDDs/Fs) and CEBQ scores in boys, although significant associations between some eating behavior sub-scores and 1,2,3,4,6,7,8,9-octachlorodibenzofuran were observed. In girls, there was a significant inverse association between levels of TEQ-PCDFs and enjoyment of food scores and between levels of TEQ-PCDFs and TEQ-PCDDs/Fs and desire to drink scores. Two pentachlorodibenzofuran congeners and 1,2,3,6,7,8-hexachlorodibenzofuran were associated with a decreased enjoyment of food score, and seven PCDF congeners were associated with a decreased desire to drink score. The adjusted mean enjoyment of food score was significantly lower in children of both sexes exposed to high levels of TEQ-PCDFs. There was, however, a significant interaction between sex and TEQ-PCDF exposure in their effect on desire to drink scores, especially in girls., Conclusions: Perinatal exposure to dioxin can influence eating behavior in children and particularly in girls. A longer follow-up study would be required to assess whether emotional development that affects eating styles and behaviors is related to dioxin exposure.

Reduced heart rate (HR) variability in preterm infants compared with full-term infants suggests that autonomic cardiac control is developmentally delayed. However, the association between developmental changes in myocardial repolarization and gestational age remains unknown. This study investigated the association between the myocardial repolarization lability index, namely the QT variability index (QTVI) = log 10 [(QTv/QTm 2 )/(HRv/HRm 2 )], and the perinatal profile of healthy 1-month-old infants. We included 209 infants (143 boys and 87 girls; mean gestational weeks at birth, 38.6 ± 1.7) who were born in university hospitals between 2014 and 2015 without apparent cardiac disease. We compared the ECG variability indices in 28 infants born before 37 gestational weeks (mean gestational weeks at birth, 35.6 ± 1.1 as preterm) and 181 infants born at the average number of gestational weeks (mean gestational weeks at birth, 38.8 ± 1.1 as controls). There was a negative correlation between the QTVI and gestational weeks (r = - 0.460, p = 0.035). QTVI values in preterm infants were larger than those in the controls (0.01 ± 0.50 vs. -0.26 ± 0.48, p = 0.023). In conclusion, the QTVI is negatively correlated with gestational age. The QTVI can serve as an index of the maturity of the cardiac autonomic nervous system and myocardial depolarization.

Dioxin concentrations remain elevated in the environment and humans residing near the former US Air Force base in Bien Hoa city, South Vietnam. We recruited 210 mother-infant pairs for whom breast milk dioxin levels were reported in our previous study. Cord blood samples were collected from 162 mother-infant pairs. We selected 16 cord blood samples with a volume over 20mL and fat content of ≥0.03g. Toxic equivalent levels of polychlorinated dibenzodioxins and polychlorinated dibenzofurans (TEQ-PCDD/Fs) and concentrations of 17 congeners, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), in cord blood were measured and compared with levels in breast milk (Study 1). Levels of 2,3,7,8-TCDD and TEQ-PCDD/Fs in cord blood samples were highly and significantly correlated with those in breast milk samples in the same pairs. This suggests dioxins in breast milk reflect prenatal dioxin exposure. Estradiol (E2) and testosterone (TS) were measured in cord blood serum from 162 samples. Associations between dioxins in breast milk and cord blood sex hormones were analyzed by infant sex, after adjusting for confounding factors (Study 2). Increased levels of TEQ-PCDD/Fs in breast milk were associated with decreased cord blood TS in girls. In boys, a significant reduction of cord blood TS was observed in those exposed to 2,3,7,8-TCDD at high levels (≥5.5pg/g lipid). There was no significant association between E2 and dioxins in breast milk in either sex. These results suggest increased prenatal dioxin exposure is associated with decreased cord TS, but in boys, only high level of 2,3,7,8-TCDD influence cord blood TS., (Copyright © 2017. Published by Elsevier B.V.)

Background: This study was conducted to assess the transmissibility of rotavirus vaccine strains after rotavirus vaccination in a neonatal intensive care unit (NICU)., Methods: Pentavalent (RV5) or monovalent (RV1) rotavirus vaccine was administered to infants admitted to the NICU. Nineteen vaccinated infants and 49 unvaccinated infants whose beds were located in close proximity to the vaccinated infants were enrolled in this study. Dissemination and fecal shedding of vaccine viruses within the NICU were examined using real-time reverse transcription-polymerase chain reaction., Results: Shedding of the vaccine strain was detected in all 19 vaccinated infants. RV5 virus shedding started 1 day after the first vaccination and persisted for 8 days after the first vaccination, and viral shedding terminated by day 5 after administration of the second RV5 dose. The kinetics of RV1 virus shedding differed among vaccinated infants. The duration of RV1 virus shedding was longer after the first vaccination than after the second vaccination. In contrast to the vaccinated infants, no vaccine virus genomes were detected in any of the stool samples collected from the 49 unvaccinated infants., Conclusions: This study is direct evidence of no transmission of rotavirus vaccine strains between vaccinated infants and unvaccinated infants in close proximity within a NICU., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The QT variability index (QTVI) is a noninvasive index of repolarization lability that has been applied to subjects with cardiovascular disease. QTVI provides a ratio of normalized QT variability to normalized heart rate variability, and therefore includes an assessment of autonomic nervous activity. However, measurement of QT time is particularly difficult in children, who exhibit physiologically high heart rates compared with adults. In this study, we developed a set of standard values of J-point to Tpeak interval (JTp) for infants by age, and assessed the correlation of QTVI with the JTp variability index (JTpVI)., Methods: Subjects included 623 infants and children (0-7 years of age) without heart disease and 57 healthy university students. All subjects were divided into three groups by age. QTVI and JTpVI were calculated based on an electrocardiogram, and age-specific standard values, a gender-specific classification, and a standard growth curve were constructed., Results: JTpVI markedly decreased in infancy and slowly decreased thereafter, reaching adult values by school age. There was also a strong correlation of JTpVI with QTVI (r = .856)., Conclusions: JTp can be used to evaluate the variability of the repolarization time in healthy infants, and may be useful for detection of early repolarization abnormalities., (© 2017 Wiley Periodicals, Inc.)

Atrial septal defect is a common congenital heart disease. In patients with atrial septal defect, left-to-right shunting increases the right atrial and right ventricular preload. This pathological change affects sinus node automaticity and myocardial depolarization and repolarization, and has the potential to evoke arrhythmogenic substrates. We examined the effect of atrial septal defect on sinus node automaticity and myocardial repolarization by investigating the variability in the repolarization interval, namely the QT variability index (QTVI) and variability ratio (VR). This retrospective study included 38 patients (mean age, 2.2 ± 1.9 years; mean left-to-right shunt ratio, 2.1 ± 0.70) and 40 age-matched healthy control subjects evaluated from 2008 to 2015. QTVI was calculated using the ratio of the repolarization parameter variance to heart rate variance, and VR was calculated as the ratio of the standard deviation (SD) of QT intervals to the SD of RR intervals on electrocardiography. There was a significant difference in the SD of all normal RR intervals, heart rate variance, VR, and QTVI of control subjects or patients with low shunt ratio compared with patients with high shunt ratio (all P < 0.05). Linear regression analysis revealed strong positive correlations between the left-to-right shunt ratio and VR (r = 0.662, P < 0.0001) or QTVI (r = 0.808, P < 0.0001). These repolarization indices provide information on alteration of sinus node autonomic control and the pathophysiology of myocardial repolarization, and could be used as a noninvasive indicator of the shunt ratio in children with atrial septal defect.

Hypertension and brachydactyly syndrome (HTNB) with short stature is an autosomal-dominant disorder. Mutations in the PDE3A gene located at 12p12.2-p11.2 were recently identified in HTNB families. We found a novel heterozygous missense mutation c.1336T>C in exon 4 of the PDE3A gene in a Japanese family with multiple HTNB patients. This mutation was found to be completely linked to the family members who inherited this condition. The mutation, resulting in p.Ser446Pro, was located within the cluster region of reported mutations. This mutation may also affect the phosphodiesterase activity of PDE3A to reduce the cyclic AMP level in the cell and thereby influencing the development of limbs and the function of the cardiovascular system.

Background: In the present study, we report on a couple who underwent prenatal genetic diagnosis for autosomal recessive polycystic kidney disease (ARPKD)., Case Presentation: This healthy couple had previously had a healthy boy but had experienced two consecutive neonatal deaths due to respiratory distress resulting from pulmonary hypoplasia caused by oligohydramnios. The woman consulted our facility after she realized she was pregnant again. We promptly performed a carrier test for the PKHD1 gene by target exome sequencing of samples from the couple. A pathogenic mutation was identified only in the paternal allele (c.9008C>T, p.S3003F). The mutation was confirmed by Sanger sequencing of the DNA from formalin-fixed, paraffin-embedded, kidney tissue of the second neonate patient and was not found in the healthy sibling. We then performed haplotype analyses using microsatellite markers scattered throughout the PKHD1 gene. DNA from the amniocentesis was determined to belong to a carrier, and the couple decided to continue with the pregnancy, obtaining a healthy newborn. Subsequent detailed examination of the exome data suggested higher read depth at exons 45 and 46. Multiplex ligation-dependent probe amplification allowed identification of duplication of these two exons. This case suggests the potential usefulness of target exome sequencing in the prenatal diagnosis of the PKHD1 gene in ARPKD., Conclusions: This is the first report of intragenic duplication in the PKHD1 gene in ARPKD.

Kawasaki disease complicates with myocarditis and vasculitis. Even if myocarditis is asymptomatic, heterogeneity of ventricular repolarization may be increased in the acute phase. We evaluated whether the change in repolarization characteristics can be used as a predictor for myocarditis and coronary lesions. Enrolled 34 children who were treated with intravenous immunoglobulin therapy. There were no sequelae in the recovery phase in any subjects, including those who had transient coronary artery lesion. QT and the interval from the Tpeak to Tend (Tp-e) were determined. The Tp-e/QT ratios were compared between the acute and recovery phases and correlations with CRP level and body temperature were evaluated. A retrospective evaluation of Tp-e/QT as predictors of coronary dilation was also performed. Tp-e/QT in the acute phase correlated positively with body temperature and CRP level. In a comparison of patients with and without transient coronary artery lesion, Tp-e/QT was significantly higher in those with dilation. In conclusion, Tp-e/QT was strongly related to transient coronary dilation, in comparison with inflammatory indicators including fever and CRP level.