Sota Iwatani

Neurological outcomes in symptomatic congenital cytomegalovirus-infected infants after introduction of newborn urine screening and antiviral treatment

BACKGROUND Newborn screening for urinary cytomegalovirus (CMV) and early introduction of antiviral treatment are expected to improve neurological outcomes in symptomatic congenital CMV-infected infants. This cohort study prospectively evaluated neurological outcomes in symptomatic congenital CMV-infected infants following the introduction of hospital-based newborn urinary CMV screening and antiviral treatment. SUBJECTS/METHODS Following institutional review board approval and written informed consent from their parents, newborns were prospectively screened from 2009 to 2014 for urinary CMV-DNA by PCR within 1 week after birth at Kobe University Hospital and affiliated hospitals. CMV-positive newborns were further examined at Kobe University Hospital, and those diagnosed as symptomatic were treated with valganciclovir for 6 weeks plus immunoglobulin. Clinical neurological outcomes were evaluated at age ⩾12 months and categorized by the presence and severity of neurologic sequelae. RESULTS Urine samples of 6348 newborns were screened, with 32 (0.50%) positive for CMV. Of these, 16 were diagnosed with symptomatic infection and 12 received antiviral treatment. Four infants developed severe impairment (33%), three developed mild impairment (25%), and five developed normally (42%). CONCLUSIONS This is the first Japanese report of neurological assessments in infants with symptomatic congenital CMV infection who received early diagnosis and antiviral treatment. Urinary screening, resulting in early diagnosis and treatment, may yield better neurological outcomes in symptomatic congenital CMV-infected infants.

Disorders of bilirubin binding to albumin and bilirubin-induced neurologic dysfunction.

Bilirubin-induced neurologic dysfunction (BIND) is a syndrome of subtle bilirubin neurotoxic disorders. The risk for developing BIND in newborns usually increases with elevated serum/plasma concentrations of unconjugated bilirubin. This risk is further increased by disorders of bilirubin binding to albumin, which includes a reduction in serum albumin concentrations or in the bilirubin-binding capacity and affinity of albumin, and the presence of displacing substances or infection. Serum unbound bilirubin (UB) concentration may be an ideal marker that reflects changes in bilirubin binding to albumin. Kernicterus, the chronic and with the most severe manifestations beyond BIND, is diagnosed by the presence of motor impairments with athetosis, abnormal magnetic resonance imaging, and/or brainstem auditory-evoked potential findings during infancy and childhood. Preterm infants sometimes have acute bilirubin encephalopathy without marked hyperbilirubinemia, such that bilirubin neurotoxicity occurs at bilirubin thresholds lower than usually associated with kernicterus. Disorders of bilirubin binding to albumin may be associated with the clinical signs of neurological injury associated with the lower bilirubin levels observed in preterm infants.

Prevalence of small for gestational age (SGA) and short stature in children born SGA who qualify for growth hormone treatment at 3 years of age: Population-based study

To treat children born small for gestational age (SGA) with severe short stature, treatment with growth hormone (GH) has been approved in the USA, Europe, and Japan, but no population‐based studies have reported their prevalence. The aims of this study were to investigate the prevalence of SGA and short stature in children born SGA who qualify for GH treatment at 3 years of age in a Japanese population.

Extremely preterm infants small for gestational age are at risk for motor impairment at 3 years corrected age

BACKGROUND Few studies have targeted psychomotor development and associated perinatal risk factors in Japanese very low birth weight (VLBW) infants who are severely small for gestational age (SGA). DESIGN/SUBJECTS A single-center study was conducted in 104 Japanese VLBW infants who were born preterm, due to maternal, umbilical cord, or placental abnormalities, between 2000 and 2007. Psychomotor development as a developmental quotient (DQ) was assessed using the Kyoto Scale of Psychological Development at 3 years corrected age. Severely SGA was defined as birth weight or length below -2 standard deviation values of the mean values at the same gestation. VLBW infants were divided into 2 subgroups based on gestational age at birth: ⩾28 weeks (n=64) and <28 weeks (n=40). DQs of infants with severe SGA were compared with those of infants who were appropriate for gestational age (AGA). Factors associated with developmental disabilities in VLBW infants with severe SGA (n=23) were determined. RESULTS In the group born at ⩾28 weeks gestation, infants with severe SGA had normal DQ values and did not significantly differ from those with AGA. However, in the group born at <28 weeks gestation, severe SGA infants had significantly lower postural-motor DQ values than AGA infants. Gestational age <28 weeks was an independent factor for low postural-motor DQ, regardless of the cause of severe SGA or pregnancy termination. CONCLUSIONS Extremely preterm newborns with severe SGA are at risk of motor developmental disability at age 3 years.

Effect of hydrocortisone therapy on severe leaky lung syndrome in ventilated preterm infants

Background:  The aim of this study was (i) to determine the incidence and risk factors of severe leaky lung syndrome (sLLS), persistent pulmonary edema characterized by massive tracheal secretions and resistance to surfactant therapy, in extremely low gestational age newborns requiring ventilatory support; and (ii) to evaluate the effects of hydrocortisone (HC) therapy for sLLS on tracheal aspirate fluid (TAF) volume and β2‐microglobulin levels in TAF.

Fluorescent protein-based detection of unconjugated bilirubin in newborn serum

Increased serum levels of unconjugated bilirubin are associated with the development of brain damage in newborns. In current clinical settings, there are no methods for directly determining serum levels of unconjugated bilirubin. UnaG, a fluorescent protein from Japanese eel muscle that specifically binds to unconjugated bilirubin was used in this study. Linear regression analysis was carried out to compare unconjugated bilirubin levels measured by UnaG and conventional bilirubin oxidase methods. Unconjugated bilirubin levels in the serum of newborns who were untreated or treated with phototherapy were compared. Effects of interfering factors in the serum (conjugated bilirubin, hemoglobin, and lipid) on unconjugated bilirubin concentration measured by the UnaG method were also evaluated. Unconjugated bilirubin levels measured by the UnaG method were highly correlated with those determined by the bilirubin oxidase assay. Unconjugated bilirubin levels determined by bilirubin oxidase and UnaG assays were similar in serum samples containing conjugated bilirubin. The performance of the UnaG assay was unaffected by phototherapy and the presence of serum hemoglobin and lipid emulsion. These results demonstrate the clinical applicability of the UnaG method for direct measurement of unconjugated bilirubin levels in newborn serum.

Patterns of increases in interleukin-6 and C-reactive protein as predictors for white matter injury in preterm infants

The aim of this study was to determine whether patterns of increases in serum interleukin‐6 (IL‐6) and C‐reactive protein (CRP) levels at birth were associated with the development of white matter injury (WMI) in preterm infants with a fetal inflammatory response (FIR).

N-terminal pro-brain natriuretic peptide levels in monochorionic diamniotic twins with selective intrauterine growth restriction

Objective:To compare serum N-terminal pro-brain natriuretic peptide levels at birth between monochorionic diamniotic twins with and without selective intrauterine growth restriction.Study Design:Blood samples were collected from 73 monochorionic diamniotic twins without twin-to-twin transfusion syndrome. Two groups were studied on the basis of fetal ultrasonographic findings: 16 twins with and 57 twins without selective intrauterine growth restriction. Selective intrauterine growth restriction was defined as an estimated fetal weight below the 10th percentile in one twin at 18 to 26 weeks of gestation. Serum N-terminal pro-brain natriuretic peptide levels were measured.Result:Serum N-terminal pro-brain natriuretic peptide levels in monochorionic diamniotic twins with selective intrauterine growth restriction were significantly higher than in those without selective intrauterine growth restriction. Selective intrauterine growth restriction was independently associated with increased N-terminal pro-brain natriuretic peptide levels.Conclusion:N-terminal pro-brain natriuretic peptide levels at birth are elevated in monochorionic diamniotic twins with selective intrauterine growth restriction.

Current Situation of Treatment for Anaphylaxis in a Japanese Pediatric Emergency Center.

Objective Anaphylaxis is a systemic allergic reaction that sometimes requires prompt treatment with intramuscular adrenaline. The aim of the study was to investigate the current situation regarding anaphylaxis treatment in a representative pediatric primary emergency facility in Japan. Methods We retrospectively examined the medical records dating from April 2011 through March 2014 from Kobe Childrens Primary Emergency Medical Center, where general pediatricians work on a part-time basis. Clinical characteristics and current treatments for patients with anaphylaxis who presented to the facility were investigated. Furthermore, we compared the clinical characteristics between anaphylaxis patients given intramuscular adrenaline and those not given it. Results During the study period, 217 patients were diagnosed with anaphylaxis. The median Sampson grade at the time of visit was 2, and 90 patients (41%) were grade 4 or higher. No patients received self-intramuscular injected adrenaline before arrival at our emergency medical center because none of the patients had been prescribed it. Further treatment during the visit was provided to 128 patients (59%), with only 17 (8%) receiving intramuscular adrenaline. Patients given intramuscular adrenaline had significantly lower peripheral saturation of oxygen at the visit (P = 0.025) and more frequent transfer to a referral hospital (P < 0.001) than those not given intramuscular adrenaline. Conclusions Education for Japanese pediatric practitioners and patients is warranted, because no patients used self-intramuscular injected adrenaline as a prehospital treatment for anaphylaxis, and only severely affected patients who needed oxygen therapy or hospitalization received intramuscular adrenaline in a pediatric primary emergency setting.

Involvement of WNT Signaling in the Regulation of Gestational Age-Dependent Umbilical Cord-Derived Mesenchymal Stem Cell Proliferation

Mesenchymal stem cells (MSCs) are a heterogeneous cell population that is isolated initially from the bone marrow (BM) and subsequently almost all tissues including umbilical cord (UC). UC-derived MSCs (UC-MSCs) have attracted an increasing attention as a source for cell therapy against various degenerative diseases due to their vigorous proliferation and differentiation. Although the cell proliferation and differentiation of BM-derived MSCs is known to decline with age, the functional difference between preterm and term UC-MSCs is poorly characterized. In the present study, we isolated UC-MSCs from 23 infants delivered at 22–40 weeks of gestation and analyzed their gene expression and cell proliferation. Microarray analysis revealed that global gene expression in preterm UC-MSCs was distinct from term UC-MSCs. WNT signaling impacts on a variety of tissue stem cell proliferation and differentiation, and its pathway genes were enriched in differentially expressed genes between preterm and term UC-MSCs. Cell proliferation of preterm UC-MSCs was significantly enhanced compared to term UC-MSCs and counteracted by WNT signaling inhibitor XAV939. Furthermore, WNT2B expression in UC-MSCs showed a significant negative correlation with gestational age (GA). These results suggest that WNT signaling is involved in the regulation of GA-dependent UC-MSC proliferation.