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To elucidate whether the survival and long-term neurodevelopmental outcomes of extremely preterm infants have improved in a Japanese tertiary center with an active treatment policy for infants born at 22-23 weeks of gestation.This single-centered retrospective cohort study enrolled EPI treated at Saitama Medical Center, Saitama Medical University, from 2003 to 2014. Patients with major congenital abnormalities were excluded. Primary outcomes were in-hospital survival and severe neurodevelopmental impairment (NDI) at six years of age, which was defined as having severe cerebral palsy, severe cognitive impairment, severe visual impairment, or deafness. We assessed the changes in primary outcomes between the first (Period 1; 2003-2008) and the second half (Period 2; 2009-2014) of the study period and evaluated the association between birth-year and primary outcomes using multivariate logistic regression models.Of the 403 eligible patients, 340 (84%) survived to discharge. Among 248 patients available at six years of age, 43 (14%) were classified as having severe NDI. Between the two periods, in-hospital survival improved from 155/198 (78%) to 185/205 (90%), but severe NDI increased from 11/108 (10%) to 32/140 (23%). In multivariate logistic regression models adjusted for gestational age, birthweight, sex, singleton birth, and antenatal corticosteroids, the adjusted odds ratio (95% confidence interval) of birth-year for in-hospital survival and severe NDI was 1.2 (1.1-1.3) and 1.1 (1.0-1.3), respectively.Mortality among EPI has improved over the past 12 years; nevertheless, no significant improvement was observed in the long-term neurodevelopmental outcomes.

Primitive myxoid mesenchymal tumor of infancy (PMMTI) is a rare soft tissue sarcoma in childhood. We present the case of a newborn male who experienced a severe hemorrhage in utero from the tumor on the scalp. He died at the age of 24 hours owing to hemorrhagic shock. The tumor was posthumously diagnosed as PMMTI. A literature search indicated that cases of severe hemorrhage from soft tissue sarcomas in utero or at birth are limited to infantile fibrosarcoma. This is the first case of PMMTI with massive hemorrhage. Clinicians must be aware of hemorrhagic complications of PMMTI.

In fetuses, the Eustachian valve directs oxygenated blood returning from the inferior vena cava into the left atrium via the foramen ovale. If too large, the Eustachian valve can restrict right ventricular inflow, as well as induce postnatal cyanosis via an interatrial right-to-left shunt. We report a fetal case of postnatal amelioration of the tricuspid valve and right ventricle hypoplasia, despite significant right ventricular hypoplasia associated with a large Eustachian valve. Application of an appropriate respiratory management regimen to help reduce pulmonary vascular resistance is of particular importance for the reversal of the right-to-left shunt via the foramen ovale and associated increases in right ventricular inflow.

We report a neonate with a successful percutaneous thrombectomy of a total thrombotic occlusion of the left pulmonary artery (LPA) after a surgical clipping for a patent ductus arteriosus (PDA). We suspected the compression of the LPA by the clipping and postoperative hemodynamic instability caused the LPA obstruction. After the surgical removal of the PDA clip and division of the PDA, we could safely retrieve the LPA thrombus with a non-hydrodynamic thrombectomy catheter for coronary arteries.

Many clinical trials have indicated that ibuprofen (IBU) has similar effects to indomethacin (IND) on the closure of patent ductus arteriosus (PDA) with fewer adverse effects. Owing to the scarce evidence on IBU use in Japan because of its recent approval we performed this observational study to compare the efficacy and safety of IBU with the efficiency and safety of IND.We included infants (gestational age30 weeks) with hemodynamically significant PDA under a prophylactic IND protocol for intraventricular hemorrhage who were treated with either IND (n = 30) or IBU (n = 30). We compared a PDA closing effect, changes in ultrasonography findings, and adverse effects between the groups.There was no significant difference in the rates of PDA closure in the first treatment course (IND vs IBU: 46.7% vs 50.0%, P = 0.796) and surgical closure (IND vs IBU: 20.0% vs 20.0%, P = 1.000) between the groups. Both groups showed significant oliguria (IND vs IBU: 30.0% vs 23.3%, P = 0.559) and increased serum creatinine levels after treatment. However, an increase in serum creatinine level by0.3 mg/dL, a criterion for acute kidney injury, was less frequent in the IBU group (35.7%) compared with that in the IND group (84.2%, P = 0.004). There were no significant differences in echocardiographic changes and jaundice and hypoglycemia incidence rates between the groups.Except for an increase in serum creatinine levels by0.3 mg/dL, which was less frequent with IBU, IBU had similar efficacy and safety as IND for preterm PDA. Ibuprofen and IND should be cautiously administered.

Neonatal hypoxic-ischaemic encephalopathy (HIE) is a serious condition; many survivors develop neurological impairments, including cerebral palsy and intellectual disability. Preclinical studies show that the systemic administration of umbilical cord blood cells (UCBCs) is beneficial for neonatal HIE. We conducted a single-arm clinical study to examine the feasibility and safety of intravenous infusion of autologous UCBCs for newborns with HIE. When a neonate was born with severe asphyxia, the UCB was collected, volume-reduced, and divided into three doses. The processed UCB was infused at 12–24, 36–48, and 60–72 hours after the birth. The designed enrolment was six newborns. All six newborns received UCBC therapy strictly adhering to the study protocol together with therapeutic hypothermia. The physiological parameters and peripheral blood parameters did not change much between pre- and postinfusion. There were no serious adverse events that might be related to cell therapy. At 30 days of age, the six infants survived without circulatory or respiratory support. At 18 months of age, neurofunctional development was normal without any impairment in four infants and delayed with cerebral palsy in two infants. This pilot study shows that autologous UCBC therapy is feasible and safe.

To establish the superiority of blood flow (BF)-based circulatory management over conventional blood pressure (BP)-based management strategies used for preventing intraventricular hemorrhage (IVH) in infants of very low birth weight (VLBW).We conducted a nonblinded, single-centered randomized trial with the aim to prevent IVH by managing BF. Infants with VLBW were assigned randomly to a BF-based group or BP-based (BP group) circulatory management group. The incidence of IVH was the outcome of interest. The IVH also data were compared among healthy patients and patients responsive and unresponsive to the intervention.A total of 219 and 220 infants with VLBW were assigned to the BF and BP groups, respectively. The IVH incidence rate was lower in the BF group, but the difference was not statistically significant (BF group, 6.8% vs BP group, 10.9%; P = .14). In 21% of patients of the BP group and 20% of the BF group, the intervention failed. In BF group, the IVH incidence rate was significantly greater in infants with unsuccessful intervention when compared with healthy individuals (6% vs 23%, P = .001). Multivariate logistic regression analysis revealed a correlation between low blood flow and IVH (aOR 3.24; 95% CI 1.49-7.08, P = .003) but not between low BP and IVH (P = .73).The BF management protocol did not significantly decrease the incidence of IVH. However, after further optimization, we speculate the treatment strategy holds promise in decreasing the incidence of IVH. Trial registration UMIN-CTR: UMIN000013296.

Dopamine is one of the most frequently used inotropic drugs in neonatal intensive care units (NICUs); however, it does not seem to improve outcomes in premature infants. Given that the ultimate aim of cardiovascular management is to stabilize and maintain organ perfusion, an understanding of dopamine's effects on organ blood flow will help in judging when to use dopamine and how to titrate the dosage. Such an approach can lead to improved outcomes. This study aimed to evaluate the effects of dopamine on peripheral perfusion in very-low-birth-weight (VLBW) infants within 72 h of birth.This prospective observational study identified and sampled 44 instances of initiation of dopamine treatment or increase in dopamine dose in 29 VLBW infants. Blood pressure, heart rate, and skin and subcutaneous blood flow were measured and compared before and after each instance.Blood pressure and skin and subcutaneous blood flow in the lower limbs increased after initiation of dopamine treatment or after dose increase.Dopamine increases blood pressure as well as skin and subcutaneous blood flow in VLBW infants despite its supposed vasoconstrictive action, indicating that it increases both perfusion pressure and blood flow and is devoid of overwhelming peripheral vasoconstrictive effects.

Congenital microcephaly with intracranial calcification is a rare condition presented in heterogeneous diseases. Here, we report the case of a 1-year-old boy with severe congenital microcephaly and diffuse calcification. Neuroimaging studies showed a diffuse simplified gyral pattern; a very thin cortex; ventricular dilatation; very small basal ganglia, thalamus, and brainstem; and cerebellar hypoplasia with diffuse calcification. Clinical features of intrauterine infections, such as neonatal jaundice, hepatomegaly, and thrombocytopenia, were not found. Serological tests, cultures, and polymerase chain reaction analysis were negative for viral infections. The etiology of pseudo–toxoplasmosis, rubella, cytomegalovirus, and herpes simplex syndrome is still unknown. This study describes the most severe form of pseudo–toxoplasmosis, rubella, cytomegalovirus, and herpes simplex syndrome reported to date, with the patient showing microcephaly and calcification or band-like intracranial calcification with simplified gyration and polymirogyria.

Charcot-Marie-Tooth disease type 1 (CMT1) is a heterogeneous disorder. Most CMT1 patients are associated with a duplication of 17p11.2-p12 (CMT1A duplication), but a small number of patients have mutations of peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), connexin 32 (Cx32) and early growth response 2 (EGR2) genes. In our previous study, we identified the responsible mutations in 72 of 128 Japanese CMT1 patients as CMT1A duplication in 40, PMP22 mutation in 6, MPZ mutation in 12 and Cx32 mutation in 14 patients. A total of 56 Japanese CMT1 patients with no identified mutations were screened for EGR2 mutation by denaturing gradient gel electrophoresis (DGGE). We detected a heterozygous Asp383Tyr mutation of EGR2 in one patient with severe CMT1, Dejerine-Sottas syndrome. EGR2 mutation is rare cause of CMT1 in Japan as in other nations. We were unable to identify the responsible mutation in 55 of 128 CMT1 patients and need further analysis to identify their candidate genes.

Kawasaki disease (KD) is a systemic vasculitis and occurs among Japanese children at a high incidence. Serum bilirubin and heme oxygenase-1 (HO-1) expression are known to play a significant role in the protection of vascular endothelial cells. Japanese have unique polymorphic distribution patterns of (TA)7 or G71R of the bilirubin UDP-glucuronosyltransferase (B-UGT) gene and of (GT)n repeats of the HO-1 gene. We investigated the relationship of KD susceptibility with these polymorphisms. There were no significant differences in the distribution of allele frequencies and genotypes of these polymorphisms between KD patients and controls. These polymorphisms are not associated with KD susceptibility.

Background Preterm infants have immature skin, which contributes to skin problems. Very little is known about postnatal changes in the skin, despite the clinical importance of this issue. Aim To assess temporal changes in skin water content in preterm infants. Study design A prospective observational study. Subjects Infants admitted to the neonatal intensive care unit were included in this study. Outcome measures Skin water content was measured at five different skin regions using dielectric methods at a depth of 1.5 mm. Skin water content was measured on postnatal day 1 in 101 infants, and the correlation between skin water content and gestational week was analyzed. Measurements were also made on postnatal days 2, 3, and 7, and every 7 days thereafter until the corrected age of 37 weeks in 87 of the 101 infants. Temporal changes were statistically analyzed after dividing participants into seven groups by gestational age. Results On postnatal day 1, skin water content correlated inversely with gestational age at all skin regions. Skin water content decreased significantly over time, converging to the level of term infants by the corrected age of 32–35 weeks. Conclusions Skin water content at a depth of 1.5 mm was related to corrected age and reached the level of term infants by the corrected age of approximately 32–35 weeks.

Recently, a few genetic abnormalities were identified in congenital central hypoventilation syndrome (CCHS or Ondine's curse). CCHS is often associated with other neurocristopathies, especially with Hirschsprung's disease (HSCR). Mutations of the genes involved in the receptor tyrosine kinase RET (REarranged during Transfection) (RET)-glial cell line-derived neurotrophic factor (GDNF) and/or endothelin 3 (EDN3)-endothelin receptor-B (EDNRB) signaling pathway have been found in some of HSCR patients. In this study, we analyzed candidates for HSCR, namely the RET, GDNF, EDN3 and EDNRB genes in three isolated CCHS patients to confirm the hypothesis that some CCHS patients have a common genetic abnormality with patients having HSCR or other neurocristopathies. We found a novel R114H mutation of the RET gene in one patient. The R114H mutation is unlikely to be a polymorphism and appears to be associated with CCHS. In addition, we also examined the HOX11L2 (RNX) gene, for which knock-out mice showed CCHS-like syndrome in these isolated CCHS patients and did not detected any mutation. Further cases should be analyzed for more candidates to clarify the pathophysiology of CCHS.

The molecular basis of double cortex syndrome was investigated in 2 male patients. Magnetic resonance imaging of the patients' heads showed diffuse subcortical band heterotopia, as is seen in female patients. We found a heterozygous mutation for Asp50Lys or Arg39Stop in both patients. Microsatellite polymorphism analysis revealed that both patients had inherited a single X chromosome from their mothers. Restriction enzyme analysis using DNA extracted from the hair roots of each patient showed four different patterns in the combination of cells carrying wild and mutant alleles, which strongly suggest somatic mosaicism. We conclude that somatic mosaic mutations in the doublecortin gene in male patients can cause subcortical band heterotopia, and that molecular analysis using hair roots is a useful method for detecting somatic mosaicism.

Cardiovascular instability immediately after birth is associated with intraventricular hemorrhage (IVH) in very-low-birth-weight (VLBW) infants. For circulatory management, evaluation of organ blood flow is important. In this study, the relationship between peripheral perfusion within 48 h after birth and IVH was evaluated in VLBW infants. In this prospective observational study involving 83 VLBW infants, forehead blood flow (FBF) and lower-limb blood flow (LBF) were measured for 48 h after birth using a laser Doppler flowmeter. Blood flow was compared between infants with and without IVH. Multivariate logistic regression analysis was performed to identify the risk factors for IVH. IVH developed in nine infants. In eight of these patients, IVH occurred after 24 h. LBF was lower in infants with IVH at 18 and 24 h and increased to the same level as that of infants without IVH at 48 h. Multivariate logistic regression analysis identified a correlation only between LBF and IVH at 18 h. These findings were consistent with the hypoperfusion–reperfusion theory, which states that IVH develops after reperfusion subsequent to hypoperfusion. We speculate that measurement of skin blood flow in addition to systemic and cerebral circulation may be helpful in predicting IVH.

Shwachman-Diamond syndrome (SDS) is a rare hereditary disorder characterized by pancreatic exocrine insufficiency, bone marrow dysfunction and skeletal changes. Recently, the cause of SDS was identified as mutations of Shwachman-Bodian-Diamond syndrome gene (SBDS) and most mutations are caused by gene conversion between SBDS and its highly homologous pseudogene. Clinical variations especially in skeletal and bone marrow abnormalities are well known in this syndrome. To study the relationship between SBDS mutation and its clinical features, we analyzed 9 Japanese patients including one sibling and detected the three different SBDS mutations in 7 patients: a mutation that disrupts the donor splice site of intron 2, deletes 8bp of the exon 2 and produces premature termination (258+2 T > C), a dinucleotide change that replaces a lysine at 62nd amino acid to a termination codon (183-184 TA > CT), and a 4-bp deletion that causes premature termination by frameshift (292-295 delAAAG). The 5 patients represent compound heterozygotes of the 258+2 T > C and 183-184 TA > CT mutations. One patient is a compound heterozygote of the 258+2 T > C and 292-295 delAAAG mutations, and in the remaining one case only a 258+2 T > C mutation could be detected. Thus, the 258+2 T > C and 183-184 TA > CT mutations are prevalent among Japanese patients. No mutations were found in two cases, despite the clinical features. Of the 7 patients with SBDS mutations, persistent hematologic abnormalities and skeletal changes were not observed in 3 and 2 patients, respectively. Notably, clinical variations are present even among the patients with the identical genotype: compound heterozygotes of the 258+2 T > C and 183-184 TA > CT mutations. Further study will be required to explain the clinical heterogeneity.

Congenital central hypoventilation syndrome (CCHS or Ondine’s curse; OMIM 209880) is a disorder characterized by an idiopathic failure of the automatic control of breathing. CCHS is frequently complicated with neurocristopathies such as Hirschsprung’s disease (HSCR). The genes involved in the RET-GDNF signaling and/or EDN3-EDNRB signaling pathways have been analyzed as candidates for CCHS; however, only a few patients have mutations of the RET, EDN3, and GDNF genes. Recently, mutations of the PHOX2B gene, especially polyalanine expansions, have been detected in two thirds of patients. We studied the RET, GDNF, GFRA1, PHOX2A, PHOX2B, HASH-1, EDN1, EDN3, EDNRB, and BDNF genes in seven patients with isolated CCHS and three patients with HSCR. We detected polyalanine expansions and a novel frameshift mutation of the PHOX2B gene in four patients and one patient, respectively. We also found several mutations of the RET, GFRA1, PHOX2A, and HASH-1 genes in patients with or without mutations of the PHOX2B gene. Our study confirmed the prominent role of mutations in the PHOX2B gene in the pathogenesis of CCHS. Mutations of the RET, GFRA1, PHOX2A, and HASH-1 genes may also be involved in the pathogenesis of CCHS. To make clear the pathogenesis of CCHS, the analysis of more cases and further candidates concerned with the development of the autonomic nervous system is required.

近年, 病院・診療室内における空気汚染が問題となり, 特に空気中細菌 (気菌) による院内感染が取りあげられ, その対策が積極的に推進されるようになってきた。そこで著者らは, 歯科診療室における空気汚染を把握するため, 気菌に着目し鶴見大学歯学部附属病院予防歯科診療室とその待合室において1年間にわたり, SY式ピンホールサンプラー法と落下法により気菌を測定し, また室内環境の測定をも行い次のような結果を得た。1) 室内気候は, 気温が23.3～28.4℃, 気湿が45～77%, 気流が0.06～0.20m/secであった。2) 在室人数は, 2～26人であった。3) 気菌コロニー数は, SY法では, 0.03～0.52個/l, 落下法では, 0.58～5.33個であった。4) 気菌コロニー数と気温, 気湿, 気流の間には, ほとんど相関はみられなかった。5) 気菌コロニー数と在室人数との間では, 相関係数はSY法で0.666, 落下法で0.590と高い正の相関が得られた。6) SY法と落下法との間における気菌コロニー数の相関係数は0.814と高い正の相関が得られた。