Tear fluid cytokine analysis: a non-invasive approach for assessing retinopathy of prematurity severity.

PURPOSE: To determine whether there is a significant association between inflammatory cytokines in the tear fluid and the severity of Retinopathy of Prematurity (ROP). STUDY DESIGN: Retrospective cohort study. METHODS: The cytokine levels in tear fluids were determined in 34 eyes with ROP and 18 eyes without ROP. There were 15 eyes with severe ROP requiring treatment and 19 eyes with mild ROP not requiring treatment. For severe ROP eyes, tear fluids were collected before treatment. RESULTS: Significantly higher levels of CCL2 and vascular endothelial growth factor (VEGF) were detected in eyes with severe ROP compared to eyes with mild ROP and no ROP. When assessed for cytokine levels that discriminate each disease group, CCL2 showed a significant odds ratio of 1.76 for severity change (/quintile, P = 0.032, after adjusting for birth weight). Correlation analysis showed that birth weight correlated with IL-1α levels, and decreased weight gain increased IFN-γ levels. We next determined tear fluid cytokines which discriminate severe ROP using receiver operating characteristics' analysis. We found that combination of higher CCL2 levels, higher VEGF levels, and lower IFN-γ levels in the tear fluid had a stronger predictive value for severe ROP (area under curve, 0.85). CONCLUSION: The levels of CCL2, VEGF, and IFN-γ in tear fluid may serve as useful biomarkers for assessing the severity of ROP.

Risk of Transient Tachypnea of the Newborn following Elective Cesarean Section Increases at a Gestational Age of 37 Weeks Compared to That at ≥ 38 Weeks Despite the Exclusion of Pre-Existing Risk Factors for Neonatal Respiratory Disorders.

Background: Elective cesarean sections (ECSs) for early-term pregnancies at 37 weeks of gestational age (GA) aim to reduce the risk of emergency cesarean sections due to the onset of labor or rupture of membranes. However, resultant increases in neonatal respiratory disorders, including transient tachypnea of the newborn (TTN) have been observed. However, few studies have elucidated the associated risk factors. Consequently, we aimed to determine whether differences existed in the clinical outcomes between neonates delivered via ECS at 37 weeks and those delivered at ≥ 38 weeks of GA. Methods: A retrospective analysis was conducted on 259 neonates born via ECS at Tottori University Hospital, between January 2013 and December 2019, with birthweights ≥ 2500 g and GAs > 37 weeks. The neonates were categorized into two cohorts: births at 37 and at ≥ 38 weeks of GA (37-week and 38-week cohorts). The principal clinical outcomes included the appearance, pulse, grimace, activity, and respiration (Apgar) scores, need for positive-pressure ventilation, incidence of TTN, and length of hospital stay. Results: No statistically significant differences were observed in the indications for ECS, sex, or birthweight between the two cohorts. The 37-week cohort exhibited a lower 1-min Apgar score than did the 38-week cohort, with no statistically significant differences between the two cohorts, at 5 min. Statistically significant differences were not observed in the need for positive-pressure ventilation during initial resuscitation or length of hospital stay for patients with TTN between the two cohorts. Notably, the 37-week cohort exhibited a significantly higher incidence of TTN than did the 38-week cohort. Conclusion: ECSs at 37 weeks of GA exhibited an increased risk of TTN than ECSs at ≥ 38 weeks of GA. Strategic neonatal care and adequate preparation can mitigate this risk without affecting the length of hospital stay.

Retrospective Analysis of Neonatal Surgery at Tottori University over the Past Ten Years.

Background: In recent years, the number of neonatal surgeries has been on the rise despite the decline in the number of births, and we examined the actual trends and problems at Tottori University Hospital located in the Sanin region. Methods: Medical records were retrospectively searched for patients who underwent major surgery during the neonatal period (within 30 days of age) at the Tottori University Hospital over the past 10 years (Jan. 2011 to Dec. 2020). Results: Sixty-five cases were included. Early birth infants (< 37 gestational weeks) comprised 15 cases (23%) and low birth weight (< 2500 g) infants involved 27 cases (42%). In the latter half (2016-2020), early birth and low birth weight infants were significantly less than in the first half (2011-2015). The common diseases were anorectal malformation (14 cases), esophageal atresia (10), duodenal atresia (10), and diaphragmatic hernia (9). Prenatal diagnosis was obtained in 26 cases (40%), with high diagnostic rate obtained in duodenal atresia (100%), abdominal wall defect (100%), ileal atresia (75%), meconium peritonitis (67%), and diaphragmatic hernia (67%). Fifty-five cases (85%) were operated on within 7 days of age. Other major malformations were associated in 23 cases (35%). There were 6 deaths (9%), of which 3 cases were low birth weight infants with gastrointestinal perforation, 2 cases with severe chromosomal abnormalities (esophageal atresia, omphalocele), and 1 case with diaphragmatic hernia with severe pulmonary hypertension. Home medical care has been required with gastrostomy tube in 2 cases. Conclusion: Neonatal surgery at Tottori University has been well performed as required with acceptable results along with the progression of other perinatal care. However, further investigation for improvements in premature delivery or organ hypoplasia may be required.

Erratum for Hasegawa et al., "Retrospective Analysis of Neonatal Surgery at Tottori University over the Past Ten Years".

[This corrects the article DOI: 10.33160/yam.2023.11.003.].

Cord Blood from SGA Preterm Infants Exhibits Increased GLUT4 mRNA Expression.

BACKGROUND: Insulin and insulin-like growth factor (IGF) signaling plays an important role in prenatal and postnatal growth and glucose metabolism. Both small-for-gestational age (SGA) and preterm infants have abnormal growth and glucose metabolism. However, the underlying mechanism remains unknown. Recently, we showed that term SGA infants have abnormal insulin/IGF signaling in cord blood. In this study, we examined whether preterm infants show similar aberrations in cord blood insulin/IGF signaling. METHODS: A total of 41 preterm cord blood samples were collected. Blood glucose, insulin, IGF-1, and C-peptide concentrations were measured, and mRNA expression of IGF1R, INSR, IRS1, IRS2, and SLC2A4 (i.e., GLUT4) was analyzed by quantitative reverse-transcription PCR. RESULTS: This study included 34 appropriate-for-gestational age (AGA) and 7 SGA preterm neonates. No hyperinsulinemia or any differences in IGF1R or INSR mRNA expression were detected between the two groups. However, GLUT4 mRNA levels were increased in preterm SGA. Moreover, the expression level in hypoglycemic preterm SGA was significantly higher than that in hypoglycemic preterm AGA. IRS2 mRNA expression did not show a statistically significant difference between preterm SGA and AGA neonates. CONCLUSION: SGA preterm birth does not induce hyperinsulinemia; however, it modifies insulin/IGF signaling components such as GLUT4 in umbilical cord blood. Our study suggests that prematurity or adaptation to malnutrition alters the insulin/IGF signaling pathway.

De novo ATP1A3 variants cause polymicrogyria.

Polymicrogyria is a common malformation of cortical development whose etiology remains elusive. We conducted whole-exome sequencing for 124 patients with polymicrogyria and identified de novo ATP1A3 variants in eight patients. Mutated ATP1A3 causes functional brain diseases, including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP), and cerebellar ataxia, areflexia, pes cavus, optic nerve atrophy, and sensorineural deafness (CAPOS). However, our patients showed no clinical features of AHC, RDP, or CAPOS and had a completely different phenotype: a severe form of polymicrogyria with epilepsy and developmental delay. Detected variants had different locations in ATP1A3 and different functional properties compared with AHC-, RDP-, or CAPOS-associated variants. In the developing cerebral cortex of mice, radial neuronal migration was impaired in neurons overexpressing the ATP1A3 variant of the most severe patients, suggesting that this variant is involved in cortical malformation pathogenesis. We propose a previously unidentified category of polymicrogyria associated with ATP1A3 abnormalities.

Prenatal clinical manifestations in individuals with COL4A1/2 variants.

BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

Utilizing Video versus Direct Laryngoscopy to Intubate Simulated Newborns while Contained within the Incubator: A Randomized Crossover Study.

OBJECTIVE: The use of video laryngoscopy for intubating neonates in ergonomically challenging settings has not been studied well. We aimed to assess the usefulness of video laryngoscopy for experienced neonatologists to intubate neonatal manikins in incubators via side hand ports or head window. STUDY DESIGN: In this randomized crossover trial at three neonatal intensive care units in Japan, 27 neonatologists were randomized into two groups, namely, those intubating neonatal simulators using video laryngoscopy and then using direct laryngoscopy, or vice versa. The intubations were performed via hand ports or head window without opening top and side walls in incubators in two manikin positions (rotated 90° or unrotated). Glottis visualization (0-100%), success rate, intubation time, and ease of laryngoscopy (from 1 [very difficult] to 10 [very easy]) were compared between video laryngoscopy and direct laryngoscopy. Generalized linear models were used for the analyses. RESULTS: This study assessed 108 intubations performed by 27 neonatologists. The use of video laryngoscopy improved the glottis visualization by 14% (95% confidence interval, 7.4-20%; p < 0.01) and easiness scores of laryngoscopy by 0.8 (0.2-1.4; p < 0.01), but did not reduce the intubation time. CONCLUSION: Video laryngoscopy is useful for experienced neonatologists for intubating neonatal manikins in incubators without opening the top or side walls.

Increased IRS2 mRNA Expression in SGA Neonates: PCR Analysis of Insulin/IGF Signaling in Cord Blood.

CONTEXT: Hypoglycemia is the most common metabolic problem among small-for-gestational-age (SGA) neonates. However, the pathological mechanism and insulin/ insulin-like growth factor (IGF) signaling axis in neonates remain unknown. OBJECTIVE: To determine the insulin/IGF axis in neonates, we analyzed the messenger RNA (mRNA) expression of insulin/IGF signaling in fetal umbilical cord blood. SETTING: The Perinatal Medical Center of Tottori University Hospital. PARTICIPANTS: Fifty-two [42 appropriate-for-gestational-age (AGA) and 10 SGA] neonates. INTERVENTIONS: Immediately collected cord blood was placed into a PAXgene Blood RNA Tube. Total RNA from the blood was purified using reagents provided in the PAXgene Blood RNA Kit within 4 days, and reverse transcription polymerase chain reaction (PCR) was performed. MAIN OUTCOME MEASURE: Quantitative real-time PCR analysis was applied to evaluate the mRNA expression of insulin receptor (INSR), IGF-I receptor (IGF1R), insulin receptor substrate 1 (IRS1), IRS2, and glucose transporters (SLC2A2 and SLC2A4). ß-Actin was used as a control gene. RESULTS: Serum glucose and IGF-I levels in SGA neonates were significantly lower. The cord serum insulin levels were similar between AGA and SGA neonates. The IRS2 mRNA expression was significantly higher in SGA than in AGA neonates (P < 0.05). The IRS2 mRNA expression was significantly higher in hypoglycemic SGA neonates than in normoglycemic SGA neonates. CONCLUSIONS: We determined that intrauterine growth restriction induces increased IRS2 mRNA expression in cord blood, without hyperinsulinemia. The increased expression of IRS2 mRNA might be associated with abnormal glucose metabolism in SGA neonates. Our findings might lead to the elucidation of abnormal glucose metabolism in SGA neonates.

Approximate Entropy of Respiratory Movements in Human Newborns during Different Sleep States.

Previous studies have reported that the respiratory cycle of healthy newborns is more irregular during active sleep. This study aimed to apply non-linear analysis to examine the irregularity of respiratory movement in newborns at different sleep states. The respiratory movement signals from an abdominal band during quiet and active sleep were analyzed using approximate entropy (ApEn). The breathing interval of active sleep was significantly shorter than that of quiet sleep [1.30 (0.17) s vs. 1.58 (0.11) s; (P < 0.03)]. The ApEn of respiratory movements during active sleep were significantly larger than that during quiet sleep [0.785 (0.135) s vs. 0.678 (0.083) s; (P < 0.05)]. We found that the ApEn of respiratory movement in healthy newborns could detect irregularities in respiration during sleep.

Cutis laxa with frontoparietal cortical malformation: a novel type of congenital disorder of glycosylation.

This report describes a female infant with cutis laxa, short stature, microcephaly, wide anterior fontanel and bifrontal cortical malformation. Isoelectrofocusing of plasma transferrin and apolipoprotein C-III showed abnormal patterns suggesting defective N- and O-glycosylation. Together with recently reported patients, this patient represents a novel type of congenital disorder of glycosylation.