Mild small-for-gestational-age as a non-negligible risk factor for short stature.

Risk of subsequent short stature remains unclear among mild small-for-gestational-age (SGA) infants with birthweight <10th percentile and ≥-2 standard deviations. In this multicenter cohort study in Japan, height was found to be <-2 standard deviations at 3 years old even in 18 % of mild-SGA infants.

Autonomic Nervous System in Preterm Very Low Birth Weight Neonates with Intraventricular Hemorrhage.

OBJECTIVE: Heart rate variability (HRV) indicates cardiac autonomic nerve activity and is influenced by brain damage during the neonatal period. We aimed to determine whether a correlation exists between the HRV of extremely preterm neonates and neurodevelopmental test scores. STUDY DESIGN: Electrocardiogram data of neonates were assessed and HRV patterns in extremely preterm neonates with severe intraventricular hemorrhage (IVH; n = 6) and those with no/mild IVH (n = 28) were compared. We analyzed the relationship between HRV and neurodevelopmental outcomes at 18 months (n = 21) and 3 years (n = 23) in extremely preterm neonates. RESULTS: HRV was significantly associated with IVH severity in extremely preterm neonates (p < 0.05). Neonates with severe IVH exhibited increased HR and decreased mean R-to-R interval (NN) compared with neonates with no/mild IVH. HRV parameters significantly decreased in the severe IVH group, but not in the no/mild IVH group, suggesting that both sympathetic and parasympathetic activities decreased in neonates with severe IVH. Additionally, decreased HR and increased NN were significantly related to impaired neurodevelopmental outcomes in the no/mild IVH group at corrected ages of 18 months and 3 years, respectively (all p < 0.05). CONCLUSION: HRV was significantly associated with IVH severity and neurodevelopmental outcome in extremely preterm neonates. HRV can distinguish extremely preterm neonates who subsequently had severe IVH from those who had no/low-grade IVH. HRV may identify extremely preterm neonates needing adjuvant neuroprotective interventions. These findings warrant further investigation in a larger population of extremely preterm neonates. KEY POINTS: · HRV was associated with IVH severity.. · HRV can predict subsequent severe IVH in extremely preterm neonates.. · HRV are predictive of neurodevelopmental outcomes in extremely premature neonates with low-grade IVH..

Neonatal sepsis and Kawasaki disease.

The purpose of this study is to clarify the relationship between neonatal sepsis and future development of Kawasaki disease (KD). We analyzed data from the National Hospital Organization Neonatal Intensive Care Unit (NHO-NICU) registry study in Japan. Participants in this study were children with a history of hospitalization in the NICU at the participating institutions from 2010 to 2014. A questionnaire was administered at age 3 years to obtain information about the patient's history of KD. There were 8275 infants who were eligible for this study. At 3 years of age, parents of 2161 children responded to the follow-up survey (follow-up rate, 26.1%). Multivariate logistic regression analysis adjusted for preterm birth, sex, use of antibiotics in the NICU, parity, and maternal smoking showed that children with neonatal sepsis were more likely to have a history of KD at 3 years of age (adjusted odds ratio [aOR]: 11.67, 95% confidence interval [CI]: 2.84-47.96). CONCLUSIONS: Among infants admitted to the NICU, neonatal sepsis might be associated with development of KD later in life. Further large studies are needed to elucidate the relationship between neonatal infections and KD development. WHAT IS KNOWN: • Preterm birth is known to be a risk factor for Kawasaki disease. •It is not yet known which factors related to preterm birth increase the risk of developing Kawasaki disease. WHAT IS NEW: •Neonatal sepsis is associated with an increased risk of subsequent development of Kawasaki disease. •Antibiotic use in the neonatal intensive care unit may also be an independent risk factor for subsequent development of Kawasaki disease.

A case of a renal abscess caused by Salmonella bareilly in a previously healthy boy.

BACKGROUND: Renal abscesses are relatively uncommon in children, and usually due to Gram-negative rods or Staphylococcus aureus, whereas abscesses caused by Salmonella are very rare. CASE PRESENTATION: We present the case of a previously healthy 10-year-old boy who had a renal abscess due to Salmonella bareilly. He responded well to treatment with antibiotics, and computed tomography (CT)-guided drainage of the abscess. His blood, urine and abscess aspirate cultures were sterile, but a broad-range 16S rDNA polymerase chain reaction (PCR) assay of the aspirate followed by analysis of four Salmonella genes (fliC, fliD, sopE2, and spaO) identified S. bareilly as the causative agent. CONCLUSION: To the best of our knowledge, this is the first report of renal abscess caused by S. bareilly.

Abnormal placental cord insertion, hypertensive disorders of pregnancy and birth length may be involved in development of hypospadias in male fetuses.

OBJECTIVES: Hypospadias is a congenital disease characterized by morphological abnormalities of the penis, including abnormal urethral opening and penile flexion, which cause urination disorders and/or sexual intercourse difficulty. Various factors have been suggested to cause this anomaly, but evidence concerning risk factors causing this anomaly is insufficient. We evaluated the etiology of hypospadias in Japan using the Common Database of the National Hospitals' Neonatal study group. STUDY DESIGN: We retrospectively evaluated 7,865 male neonates registered in the NICU Common Database of the National Hospitals' Neonatal study group. The subjects were divided into two groups by the presence (n = 43) or absence (n = 7,822) of hypospadias. Statistical analyses were performed to compare nominal variables between the groups by Fisher's direct establishment calculation method and logistic regression analyses. RESULTS: A univariate analysis showed significant between-group differences in hypertensive disorders in pregnancy (odds ratio [OR]: 4.02, 95% confidence interval [CI]: 1.95-7.90), placental weight <-1.28 standard deviation (SD; OR: 5.06, 95% CI: 2.45-10.32), abnormal placental cord insertion (OR: 4.7, 95% CI: 2.62-9.76), birth length <-2SD (OR: 10.56, 95% CI: 5.00-21.1) and birth weight <-2SD (OR: 8.17, 95% CI: 4.17-15.68). A multivariate analysis showed a significant between-group difference in hypertensive disorders of pregnancy (adjusted OR [AOR]: 2.30, 95% CI: 1.09-4.85), abnormal placental cord insertion (AOR: 3.69, 95% CI: 1.83-7.44) and birth length <-2SD (AOR: 3.44, 95% CI: 1.26-9.42). CONCLUSION: Abnormal placental cord insertion, hypertensive disorders of pregnancy and birth length may be involved in hypospadias development in male neonates in conjunction with placental dysfunction in early pregnancy.

Different pharmacoresistance of focal epileptic spasms, generalized epileptic spasms, and generalized epileptic spasms combined with focal seizures.

OBJECTIVE: Among standard treatments for infantile spasms, adrenocorticotropic hormone (ACTH) is reported as the best treatment, but ACTH is ineffective in one-half of the patients. To establish precision medicine, we examined pharmacoresistance of focal epileptic spasms (ES), generalized ES, and generalized ES combined with focal seizures, diagnosed based on the revised seizure classification of ILAE in 2017. METHODS: We conducted a retrospective nationwide study in Japan on the long-term seizure outcome of ES. Long-term seizure outcome was evaluated by seizure-free rate, seizure-free period, and Kaplan-Meier curve. Seizure-free was defined as seizure control for longer than 2 months. RESULTS: From the medical history of 501 patients, 325 patients had generalized ES only (GES group) at the start of the first treatment, 125 patients had generalized ES after focal seizure onset (FS-GES group), seven patients had focal ES after focal seizure onset (FS-FES group), and 24 patients had generalized ES combined with focal seizures after focal seizure onset (FS-GES + FS group). Seizure-free period of ES (generalized ES and focal ES) [mean (95% confidence interval)] was 2.7 (0.0-5.4) months in GES group, 1.1 (0.1-2.2) months in FS-GES group, 1.0 (0.2-1.9) months in FS-GES + FS group, and 0.1 (-0.2-0.5) months in FS-FES group. Seizure-free rate, seizure-free period, and Kaplan-Meier curve of generalized ES were almost the same in GES group and FS-GES group, with characteristics of superior response to ACTH. Mean seizure-free period of generalized ES combined with focal seizures was significantly shorter in FS-GES + FS group than in GES group. Mean seizure-free period of focal ES in FS-FES group was extremely short with exceedingly early relapse. SIGNIFICANCE: Pharmacoresistance was different in generalized ES, focal ES, and generalized ES combined with focal seizures. ES with focal features or with focal seizures may have focal lesions, thus consider surgical options earlier in the course.

Intelligence test at preschool-age predicts reading difficulty among school-aged very low birth weight infants in Japan.

OBJECTIVE: To elucidate whether the results of an intelligence test at preschool age are predictive of reading difficulty (RD) at school age among very low birth weight infants (VLBWI). METHODS: Subjects were 48 Japanese children whose birth weight was <1500 g and who regularly visited a follow-up clinic. All subjects completed the Wechsler Intelligence Scale for Children-III (WISC-III) during the last grade of kindergarten, and four reading tasks during the second to fourth grade of elementary school. All participants had a full-scale intelligence quotient score of 85 or higher. Subjects with a standard deviation reading time score greater than 2.0 in two or more tasks were considered to have RD. We evaluated the associations between each WISC-III score and RD using logistic regression analyses. Furthermore, we performed receiver operating characteristic (ROC) analysis to determine a cutoff WISC-III score predictive of RD. RESULTS: In the mutually-adjusted model, the adjusted odds ratio per 1 score increase of freedom from distractibility (FD) was 0.832 (95% confidence interval: 0.720-0.962). In the ROC analysis, an FD score of <95.5 was chosen as the cutoff value for predicting RD (sensitivity, 0.77; specificity, 0.74). CONCLUSION: The present study indicated that a lower FD score at preschool age, which was associated with deficits in verbal working memory and attention, is a risk factor for RD at school age among Japanese VLBWI. Further investigation is desired to clarify the cognitive deficits underlying RD in Japanese-speaking preterm children, and to establish appropriate interventions for these children.

CD3+ B-1a Cells as a Mediator of Disease Progression in Autoimmune-Prone Mice.

B-1a cells are distinguishable from conventional B cells, which are designated B-2 cells, on the basis of their developmental origin, surface marker expression, and functions. In addition to the unique expression of the CD5 antigen, B-1a cells are characterized by the expression level of CD23. Although B-1a cells are considered to be independent of T cells and produce natural autoantibodies that induce the clinical manifestations of autoimmune diseases, there is much debate on the role of B-1a cells in the development of autoimmune diseases. We examined the involvement of B-1a cells in autoimmune-prone mice with the lpr gene. MRL/lpr and B6/lpr mice exhibited lupus and lymphoproliferative syndromes because of the massive accumulation of CD3+CD4-CD8-B220+ T cells. Interestingly, the B220+CD23-CD5+ (B-1a) cell population in the peripheral blood and peritoneal cavity increased with age and disease progression. Ninety percent of B-1a cells were CD3 positive (CD3+ B-1a cells) and did not produce tumor necrosis factor alpha, interferon gamma, or interleukin-10. To test the possible involvement of CD3+ B-1a cells in autoimmune disease, we tried to eliminate the peripheral cells by hypotonic shock through repeated intraperitoneal injections of distilled water. The fraction of peritoneal CD3+ B-1a cells decreased, and symptoms of the autoimmune disease were much milder in the distilled water-treated MRL/lpr mice. These results suggest that CD3+ B-1a cells could be mediators of disease progression in autoimmune-prone mice.

Effects of the early administration of sivelestat sodium on bronchopulmonary dysplasia in infants: A retrospective cohort study.

BACKGROUND: Chorioamnionitis, or infiltration of the chorioamnion by neutrophils, is a risk factor associated with the development of bronchopulmonary dysplasia. Increased neutrophil elastase levels are observed in the tracheal aspirates of these patients. AIMS: To examine the effects of early administration of the selective neutrophil elastase inhibitor sivelestat, which is used to treat acute lung injury in adults, on bronchopulmonary dysplasia in extremely premature infants. STUDY DESIGN: Retrospective cohort study. SUBJECTS: This study included extremely low-birth-weight infants born at a gestational age<28weeks. Patients were divided into groups based on the receipt of sivelestat. OUTCOME MEASURES: The primary outcome was the rate of bronchopulmonary dysplasia-free survival at a postmenstrual age of 36weeks, and the secondary outcomes included various clinically significant factors of neonatal mortality and morbidity and adverse events. RESULTS: Of the 1031 included neonates, 124 (12.0%) were treated with sivelestat. Significant differences between the groups were noted for gestational age, delivery method, fetal number, the frequency of chorioamnionitis, immunoglobulin M levels, and WBC counts. No differences were identified concerning the bronchopulmonary dysplasia-free survival rate at a postmenstrual age of 36weeks (adjusted odds ratio for sivelestat to control, 0.83; 95% confidence interval=0.53-1.30). Secondary outcomes did not significantly differ between the groups. CONCLUSIONS: In extremely premature infants, early sivelestat use was not associated with an improved rate of survival without bronchopulmonary dysplasia at a postmenstrual age of 36weeks.

Reading difficulty in school-aged very low birth weight infants in Japan.

OBJECTIVE: To investigate the prevalence of and the perinatal risk factors related to reading difficulty in school-aged very low birth weight infants (VLBWI) with normal intelligence. METHODS: Subjects were 79 Japanese children in the second to fourth grade of elementary school who had been born at very low birth weight and who regularly visited a follow-up clinic at one of four hospitals. All members had a full-scale IQ score of 80 or higher. Perinatal information was obtained retrospectively from medical records. Each subject underwent four reading tasks, testing monomoratic syllable reading, word reading, non-word reading and short sentence reading. Subjects with an SD reading time score greater than 2.0 in two or more tasks were considered to have reading difficulty (RD). Furthermore we investigated the relations between RD and perinatal factors using logistic regression analysis adjusted for potential confounding factors. RESULTS: Twenty-five (31.6%) out of 79 subjects had RD. We discovered that treated retinopathy of prematurity (tRoP) was a significant risk factor (adjusted OR=5.80, 95% confidence interval=1.51-22.33). CONCLUSION: The rate of RD in school-aged VLBWI was higher than the estimated prevalence of dyslexia in Japan. Even in children with normal intelligence, long-term developmental follow-up including support for reading skills is necessary for VLBWI. Further investigation is desired to elucidate the relations between visual problems and RD in school-aged children.

Cord blood CD4(+)CD25(+) regulatory T cells fail to inhibit cord blood NK cell functions due to insufficient production and expression of TGF-beta1.

Although CD4(+)CD25(+) Treg (Treg) cells are known to modulate NK cell functions, the modulation mechanism of these cells in cord blood has not been fully clarified. The purpose of this study was to clarify the mechanism whereby cord blood Treg cells modulate cord NK cells. By performing various cultures of purified NK cells with or without autologous Treg cells, diminished inhibitory effects of cord Treg cells towards cord NK cell functions, including activation, cytokine production, and cytotoxicity, were observed. We also observed lower secretion of sTGF-beta1 and lower expression of mTGF-beta1 by cord Treg cells than by adult Treg cells. These data revealed the capability of adult Treg cells to suppress rhIL-2-stimulated NK cell function by TGF-beta1, both membrane-bound and soluble types. The reduced inhibitory capabilities of cord Treg cells compared with adult Treg cells is thought to be due to insufficient expression of TGF-beta1.

Blunted heart rate circadian rhythms in small for gestational age infants during the early neonatal period.

Infants born with intrauterine growth restriction are at increased risk for adverse cardiovascular outcomes in neonatal and later life. Although circadian rhythm is a prognostic marker of cardiovascular health, the concern over the circadian rhythm of these infants is rarely observed. To determine the influence of intrauterine growth retardation on the pattern of circadian rhythm, heart rate (HR) circadian rhythmicity was analyzed in 39 small for gestational age (SGA; birth weight and height below <-2.0 standard deviation score [SDS]) and 117 appropriate for gestational age (AGA; >-1.5 to <1.5 SDS) infants within 72 hours of birth using spectral analysis and cosinor analysis. Amplitude, midline estimating statistic of rhythm, and acrophase calculated from circadian rhythm were analyzed with clinical variables. A significant HR circadian rhythm was observed in 23.1% of the SGA and 24.8% of the AGA group without significant differences; however, SGA infants exhibited remarkable smaller amplitudes compared with AGA in all gestational age (GA) groups (p < 0.001). Amplitudes in AGA infants were positively correlated with the GA or body composition relevant variables (p < 0.001, respectively), but not SGA infants. The blunted HR circadian rhythmicity in SGA infants showed in this study might indicate the vulnerability to pathophysiological condition and could potentially refer to cardiovascular disease in later life.

Mission in Sukusuku cohort, Mie: a study focusing on the characteristics of participants and the mental health of the mothers raising children.

BACKGROUND: We carried out Sukusuku cohort, Mie (SCM), a long term cohort study of child development and investigated the feasibility and validity of this study. Then we focused on the characteristics of the enrolled families and verified the representativeness of the participants in SCM. METHODS: The characteristics of 185 families recruited from 3 hospitals were analyzed, and we verified the representativeness of these subjects. We also analyzed the factors that may influence the mental health of the mothers who are raising children. RESULTS: There were no significant differences between the subjects from the 3 hospitals in terms of the age distribution, academic background, occupation, and annual income of the participating families. At 42 months, the average developmental quotients for postural and motor, cognitive and adaptive, and speech and social development in the 140 infants were 98.6, 100.6, and 99.9, respectively. The overall developmental quotient for infants was 100.3 +/- 13.2; this score was within the standard range (55-132). The path-analysis model revealed that family function was an important factor influencing the mental health of mothers. CONCLUSIONS: The participant characteristics were thought to be generally representative, and we showed the validity and representativeness of the participants in this cohort study. The mental health analysis of mothers suggested that relieving mothers from child-rearing stress and maintaining family function were important for the maintenance and improvement of maternal mental health.

Mission in Sukusuku cohort, Mie: focusing on the feasibility and validity of methods for enrolling and retaining participants.

BACKGROUND: We investigated the feasibility and validity of and systematized the methods used to enroll and retain participants requiring long-term interdisciplinary collaborations. We carried out this study in the Sukusuku cohort, Mie (SCM), as one of the regional research site of Japan Children's Study (JCS). METHODS: A total of 467 families who were screened between December 1, 2004 and December 31, 2005, in the Mie-chuo Medical Center and 2 other hospitals; these families were deemed eligible for the study. Of these, a total of 185 families (39.6%) participated in the 4-month observation. Of these families, 5 dropped out at month 9 of the observation; 9, at month 18; 17, at month 30; and 5, at month 42. The retention rates at 9, 18, 30, and 42 months of observation were 97.3%, 92.4%, 83.2%, and 80.5%, respectively. Reinstatement to a previous job was the most common reason for dropouts. RESULTS: We observed that informative consultation notes during observation were beneficial for the retention of participants, and these notes also helped in improving communication between the study subjects and the evaluators during subsequent visits. CONCLUSIONS: In this study, we did not perform the standard checks for child development alone but also investigated the motivating influence of research partnerships with participants. Further, these visits help maintain the motivation levels of the participants and encourage them to contribute for social causes. The results present integration models that can be applied in future relevant longitudinal cohort studies in Japan.

Cerebral oxygenation responses during kangaroo care in low birth weight infants.

BACKGROUND: Kangaroo care (KC) has been widely using to improve the care of low birth weight infants. However, very little is known about cerebral hemodynamics responses in low birth weight infants during KC intervention. The objective of this study was to elucidate the response of cerebral hemodynamics during KC in low birth weight infants. METHODS: Near infrared spectroscopy measured regional cerebral oxygenation (rSO2), heart rate (HR), respiration rate (RR) measured by electrocardiogram, and percentages of oxygen saturation (SpO2) measured by pulse oxymetry was monitored in 16 preterm infants (< 1600 g) in three sessions: before, during, and after KC. Using power spectral analysis, total power (TP), low-frequency (LF, 0.02-0.20 Hz) and high-frequency (HF, 0.20-0.50 Hz) bands, the ratio of LF/HF were calculated and normalized as %LF or %HF = LF or HF/TP x 100 (%). RESULTS: Significant differences were not observed in the mean rSO2, HR, and SpO2 throughout sessions; however, the TP of these parameters was significantly decreased during KC and increased after KC (p < 0.001). The %LF of LrSO2 and RrSO2 was decreased during KC (p < 0.05) with decreased %HF in RrSO2 (p < 0.05). The %LF of HR was significantly increased during KC while %HF was decreased (p < 0.05). Mean and TP of RR was increased during KC (p < 0.01 respectively) with the increase of quiet sleep state (p < 0.05) and decreased after KC (p < 0.01). The %LF of RR was increased after KC (p < 0.05) with decreased %HF (p < 0.05); however, significant changes were not observed during KC. CONCLUSION: KC intervention appears to have influence on cerebral hemodynamics as well as cardiorespiratory parameters. The results of rSO2 and HR might be associated with quiet sleep states. The results of this study may indicate the contribution of KC intervention to the activation of central nervous system and brain function. Further study is needed to determine the underlying physiology responsible for these differences.

Emergence of physiological rhythmicity in term and preterm neonates in a neonatal intensive care unit.

BACKGROUND: Biological rhythmicity, particularly circadian rhythmicity, is considered to be a key mechanism in the maintenance of physiological function. Very little is known, however, about biological rhythmicity pattern in preterm and term neonates in neonatal intensive care units (NICU). In this study, we investigated whether term and preterm neonates admitted to NICU exhibit biological rhythmicity during the neonatal period. METHODS: Twenty-four-hour continuous recording of four physiological variables (heart rate: HR recorded by electrocardiogram; pulse rate: PR recorded by pulse oxymetry; respiratory rate: RR; and oxygen saturation of pulse oxymetry: SpO2) was conducted on 187 neonates in NICU during 0-21 days of postnatal age (PNA). Rhythmicity was analyzed by spectral analysis (SPSS procedure Spectra). The Fisher test was performed to test the statistical significance of the cycles. The cycle with the largest peak of the periodogram intensities was determined as dominant cycle and confirmed by Fourier analysis. The amplitudes and amplitude indexes for each dominant cycle were calculated. RESULTS: Circadian cycles were observed among 23.8% neonates in HR, 20% in PR, 27.8% in RR and 16% in SpO2 in 0-3 days of PNA. Percentages of circadian cycles were the highest (40%) at < 28 wks of gestational age (GA), decreasing with GA, and the lowest (14.3%) at > or = 37 wks GA within 3 days of PNA in PR and were decreased in the later PNA. An increase of the amplitude with GA was observed in PR, and significant group differences were present in all periods. Amplitudes and amplitude indexes were positively correlated with postconceptional age (PCA) in PR (p < 0.001). Among clinical parameters, oxygen administration showed significant association (p < 0.05) with circadian rhythms of PR in the first 3 days of life. CONCLUSION: Whereas circadian rhythmicity in neonates may result from maternal influence, the increase of amplitude indexes in PR with PCA may be related to physiological maturity. Further studies are needed to elucidate the effect of oxygenation on physiological rhythmicity in neonates.