Amelioration of oxygen-induced retinopathy in neonatal mice with fetal growth restriction.

Introduction: With the aim of optimizing the balance of maintaining a safe oxygen saturation and reducing the risk of retinopathy of prematurity in human neonates with fetal growth restriction (FGR), the present study investigated the distinct effects of oxygen supplementation on the retinal neovasculature using a murine premature neonatal oxygen-induced retinopathy (OIR) model with or without fetal growth restriction. Methods: For comparison with normal birth-weight neonates, maternal low-protein diet-induced FGR neonates were subjected to fluctuating oxygen levels to generate oxygen-induced retinopathy. The retinal neovasculature was histologically evaluated, and comprehensive transcriptome analysis was conducted. Results: Compared to OIR neonates with normal birth weight, significant amelioration of the neovasculature, as indicated by decreases in the number of branch junctions, vascular distribution, maximal vascular radius and microaneurysm-like tufts, was observed in OIR mice with FGR. The results of retinal RNA-sequencing revealed downregulation of angiogenic factors that trigger pathological retinal neovascularization, such as the mitogen-activated protein kinase pathway and corresponding upstream signaling pathways in OIR mice with FGR. Conclusion: Our findings demonstrated that FGR neonates have a higher capacity for retinal oxygen stress, and the risk of OIR development is attenuated compared to that in mature neonates with normal birth weight.

Manifestation of recessive combined D-2-, L-2-hydroxyglutaric aciduria in combination with 22q11.2 deletion syndrome.

22q11.2 deletion syndrome is one of the most common human microdeletion syndromes. The clinical phenotype of 22q11.2 deletion syndrome is variable, ranging from mild to life-threatening symptoms, depending mainly on the extent of the deleted region. Brain malformations described in association with 22q11.2 deletion syndrome include polymicrogyria, cerebellar hypoplasia, megacisterna magna, and agenesis of the corpus callosum (ACC), although these are rare. We report here for the first time a patient who manifested combined D-2- and L-2-hydroxyglutaric aciduria as a result of a hemizygous mutation in SLC25A1 in combination with 22q11.2 deletion. The girl was diagnosed to have ACC shortly after birth and a deletion of 22q11.2 was identified by genetic analysis. Although the patient showed cardiac anomalies, which is one of the typical symptoms of 22q11.2 deletion syndrome, her rather severe phenotype and atypical face prompted us to search for additional pathogenic mutations. Three genes present in the deleted 22q11.2 region, SLC25A1, TUBA8, and SNAP29, which have been reported to be associated with brain malformation, were analyzed for the presence of pathogenic mutations. A frameshift mutation, c.18_24dup (p.Ala9Profs*82), was identified in the first exon of the remaining SLC25A1 allele, resulting in the complete loss of normal SLC25A1 function in the patient's cells. Our results support the notion that the existence of another genetic abnormality involving the retained allele on 22q11.2 should be considered when atypical or rare phenotypes are observed.

Installation of multiple automated external defibrillators to prevent sudden death in school-aged children.

BACKGROUND: Recently, a student died of idiopathic ventricular fibrillation in a school where an automated external defibrillator (AED) had been installed. The tragedy could not be prevented because the only AED in the school was installed in the teachers' office, far from the school ground where the accident took place. This prompted establishment of a multiple AED system in schools. The aim of this study was to analyze the efficacy of the multiple AED system to prevent sudden death in school-aged children. METHODS: Assumed accident sites consisted of the school ground, gymnasium, Judo and Kendo hall, swimming pool, and classrooms on the first and the fourth floor. Multiple AED were installed in the teachers' office, gymnasium, some classrooms, and also provided as a portable AED in a rucksack. The time from the accident site to the teachers' office for single AED, and from the accident site to the nearest AED for multiple AED, was calculated. RESULTS: The AED retrieval time was significantly shorter in 55 elementary schools and in 29 junior high schools when multiple AED were installed compared with single AED. Except for the classroom on the fourth floor, the number of people who took >120 s to bring the AED to the accident site was lower when multiple AED were installed compared with the single AED. CONCLUSION: Multiple AED provided in appropriate sites can reduce the time to reach the casualty and hence prevent sudden death in school-aged children.

Successful treatment by coil embolization for infantile hemangioma with Kasabach-Meritt syndrome of newborn.

Infantile hemangioma (IH) is the most common tumor of infancy, and it sometimes associated with Kasabach-Meritt syndrome (KMS) characterized by anemia, intraperitoneal hemorrhage secondary to rupture, coagulopathy, jaundice, and vascular malformations involving the brain, skin, gut, and other organs. Here, we report two newborn patients having IH with KMS at birth. The first patient had a giant hemangioma in the liver, which was successfully treated with i.v. corticosteroid and coil embolization. The second patient had a large hemangioma of the right axillary region, which was also successfully treated with i.v. corticosteroid, beta-blocker, coil embolization and local irradiation. All symptoms were controlled without any side-effects in both patients. According to these findings, combination therapy including coil embolization and corticosteroid is effective for IH patients with KMS. The indications for and timing of coil embolization should be determined further cases have been accumulated.

DGCR6 at the proximal part of the DiGeorge critical region is involved in conotruncal heart defects.

Cardiac anomaly is one of the hallmarks of DiGeorge syndrome (DGS), observed in approximately 80% of patients. It often shows a characteristic morphology, termed as conotruncal heart defects. In many cases showing only the conotruncal heart defect, deletion of 22q11.2 region cannot be detected by fluorescence in situ hybridization (FISH), which is used to detect deletion in DGS. We investigated the presence of genomic aberrations in six patients with congenital conotruncal heart defects, who show no deletion at 22q11.2 in an initial screening by FISH. In these patients, no abnormalities were identified in the coding region of the TBX1 gene, one of the key genes responsible for the phenotype of DGS. However, when copy number alteration was analyzed by high-resolution array analysis, a small deletion or duplication in the proximal end of DiGeorge critical region was detected in two patients. The affected region contains the DGCR6 and PRODH genes. DGCR6 has been reported to affect the expression of the TBX1 gene. Our results suggest that altered dosage of gene(s) other than TBX1, possibly DGCR6, may also be responsible for the development of conotruncal heart defects observed in patients with DGS and, in particular, in those with stand-alone conotruncal heart defects.

Procalcitonin as a marker of respiratory disorder in neonates.

BACKGROUND: Serum procalcitonin (PCT) increases in various respiratory disorders such as acute respiratory distress syndrome. Elevated PCT is also observed in healthy neonates. In this study, we investigated whether PCT is a good marker of respiratory disorder in neonates. METHODS: A total of 155 neonates with or without respiratory disorder, were eligible for the study. PCT was measured on electrochemiluminescence immunoassay. Each neonate was allocated to the non-respiratory disorder (control) group (n = 95), or a respiratory disorder group (n = 60). PCT was compared between the groups, and association with other markers, including C-reactive protein (CRP) and white blood cell (WBC) count, was analyzed. RESULTS: Of the 60 neonates in the respiratory disorder group, 39, 10, five, one, two, two, and one neonates had transient tachypnea of the newborn, respiratory distress syndrome, air leak syndrome, meconium aspiration syndrome, 18-trisomy, neonatal asphyxia, and congenital diaphragmatic hernia, respectively. Mean PCT, CRP and WBC count in the respiratory disorder group were 9.01 ng/mL, 0.26 mg/dL, and 16,100 cells/µL, respectively. The area under the curve obtained for PCT in distinguishing between the respiratory disorder and control groups was 0.85 (sensitivity, 66.7%; specificity, 93.0%; optimum cut-off, 3.73 ng/mL), that for CRP was 0.72 (sensitivity, 75.0%; specificity, 64.6%; optimum cut-off, 0.14 mg/dL), and for WBC it was 0.44 (sensitivity, 60.0%; specificity, 29.6%; optimum cut-off, 15,000 cells/µL). CONCLUSIONS: PCT is more susceptible, as a diagnostic parameter of infection, to the effect of respiratory disturbance than CRP and WBC.

Treatment with linezolid in a neonate with meningitis caused by methicillin-resistant Staphylococcus epidermidis.

UNLABELLED: Recent findings have focused on the possible role of linezolid (LZD) as a suitable candidate for the treatment of central nervous system infections. LZD treatment for meningitis has been sporadically reported in adults, but there are no reports in neonates or infants. We report a case of meningitis caused by methicillin-resistant Staphylococcus epidermidis (MRSE) in a neonatal girl. The patient had intraventricular hemorrhage on postnatal day 1 and was treated with ventricular drainage. Twenty-two days after drainage, the patient developed a fever and seizure. Although ampicillin and ceftriaxone were given empirically for meningitis, an increased cell count and protein were observed in cerebrospinal fluid (CSF). Vancomycin (VCM) was administered intravenously because MRSE was detected from CSF 2 days after the administration of ampicillin and ceftriaxone. However, intravenous administration of VCM did not show any effect. Subsequent treatment of LZD successfully reduced the cell count and protein in CSF. CONCLUSION: LZD may be a treatment option for neonates and infants for drain-associated meningitis caused by MRSE.

Pulmonary artery banding for neonates and early infants with low body weight.

Open heart surgery for infants with low body weight (BW) remains still a challenge. Pulmonary artery banding (PAB) is a useful surgical palliation for small neonates and early infants with excessive pulmonary blood flow who are unable to withstand a heart surgery. This study retrospectively reviewed neonates and infants who underwent PAB to assess the surgical results and the validity of our PAB. We selected 38 acyanotic infants and neonates and divided them into 2 groups: low BW (< 2.5 kg, n = 15, group L) and normal or high BW (≥ 2.5 kg, n = 23, group NH). The average BW at the time of PAB was 2.8 ± 1.1 kg (range, 1.2-5.8 kg), and the average age at the time of PAB was 41.8 ± 44.8 days (range, 2-151 days). Using a 3-mm-wide polyester tape, we tightened the main pulmonary artery to obtain the circumference of (19 mm + 1 mm for each kg of BW). There was no early death but one late death in each group. Postoperative BW continuously increased 1 month after PAB in both groups, although BW was significantly lower in group L than in group NH. Intracardiac repair (ICR) was accomplished in 31 patients (13 in group L and 18 in group NH) at average ages of 1.5 years, while the remaining 5 patients are awaiting ICR. In conclusion, PAB using our formula for the infants even weighing < 2.5 kg has low mortality and is effective as a bridge to ICR.

Total anomalous pulmonary venous drainage complicated by tracheoesophageal fistula.

We provided emergency treatment to a 1-day-old neonate (1600 g) with tracheoesophageal fistula (gross classification, type C) and total anomalous pulmonary venous drainage (infracardiac type) complicated by pulmonary venous obstruction. Emergency surgery was required because the tracheoesophageal fistula would have caused respiratory failure. Here we report the perioperative management techniques we used, including the surgical strategy.

Novel dominant-negative mutant of GATA3 in HDR syndrome.

HDR syndrome is an autosomal dominant disorder characterized by hypoparathyroidism, sensorineural deafness, and renal anomaly caused by mutation of the GATA3 gene located at chromosome 10p15. We report the case of a neonate with HDR syndrome and a novel GATA3 mutation. We performed genetic and functional analysis of GATA3 in this patient and identified a novel heterozygous 1516G> C missense mutation in exon 5, resulting in a cysteine-to-serine substitution at codon 321 (Cys321Ser). Mutated and wild-type GATA3 proteins were expressed at a similar level in vitro, indicating that the mutated GATA3 protein was stable. Luciferase assay revealed that the Cys321Ser-mutated GATA3 lacked transactivation activity due to loss of DNA-binding activity as confirmed by gel shift assay. Moreover, mutated GATA3 exerted a dominant-negative effect over the transactivation activity of wild-type GATA3. These findings indicate that not only haploinsufficiency of GATA3 but also the dominant-negative effect of Cys321Ser-mutated GATA3 might have been responsible for the HDR syndrome phenotype of our patient.

Use of a hand-made balloon-expandable covered stent for native coarctation of the aorta in an adult patient: a report of a first case in Japan.

In western countries, the use of a balloon-expandable covered stent is recommended for the treatment of native coarctation of the aorta (CoA) in adult patients because endovascular bare stents cannot completely prevent complications such as aneurysms or aortic rupture. However, such a product that is appropriate and officially approved is not available in Japan. We developed and used a handmade balloon-expandable covered stent in a 32-year-old patient with native CoA and achieved a good outcome. A Palmaz-Schatz stent (XL 10-series 4010; Johnson & Johnson, Warren, NJ, USA) was covered with an Ube woven-graft (WST series; 18 mm across; Ube Junken Medical, Tokyo, Japan). Because the stent shortens when dilated, one end of the graft was firmly sutured to one end of the stent, whereas the other end of the graft was stitched loosely to the other end of the stent so that it could slide along the struts of the stent to accommodate foreshortening. After meticulous in vitro simulations, the covered stent was implanted with right ventricular overdrive pacing. No complications were observed, and the pressure gradient disappeared. These results indicate that angioplasty using a balloon-expandable covered stent is highly safe and effective for correcting native CoA in adult patients and hopefully in children.

Successful stenting of the ductus venosus in 2 neonates with asplenia syndrome complicated by infracardiac type total anomalous pulmonary venous connection.

In the neonatal period, the surgical mortality of palliation is extremely high for asplenia syndrome complicated by single ventricle combined with total anomalous pulmonary venous connection (TAPVC). Recently, stent implantation for the pulmonary venous drainage route soon after birth has been used instead of surgery to prevent pulmonary venous occlusion and to maintain stable hemodynamics in the neonatal period or in early infancy. Here, we successfully implanted stents in the ductus venosus (DV) in 2 neonates with asplenia syndrome complicated by infracardiac type TAPVC. The first patient was a 3-day-old male neonate with severe cyanosis. Immediately after TAPVC was diagnosed, we implanted a stent in the DV. The second patient was a 0-day-old female neonate. She was diagnosed as TAPVC by fetal echocardiogram. After the scheduled delivery, a stent was successfully implanted. We believe that stent implantation in the DV in the neonatal period is effective and less invasive than surgery in patients with infracardiac type TAPVC.

Two-stage surgical repair for truncus arteriosus with unilateral absence of the left proximal pulmonary artery: translocation of the left pulmonary artery to the right pulmonary artery.

A two-stage surgical repair of a one-month-old infant with truncus arteriosus with unilateral absence of a proximal pulmonary artery (PA) with a closed ipsilateral ductus arteriosus was successfully performed. In the first palliation, translocation of the discontinuous, closed, and undeveloped PA to the adjacent area of the other PA was useful for making a pulmonary arterial confluence at timing of the subsequent radical operation.

Truncated KCNQ1 mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking defect.

We identified a novel mutation Ala178fs/105 missing S3-S6 and C-terminus portions of KCNQ1 channel. Ala178fs/105-KCNQ1 expressed in COS-7 cells demonstrated no current expression. Co-expression with wild-type (WT) revealed a dominant-negative effect, which suggests the formation of hetero-multimer by mutant and WT. Confocal laser microscopy displayed intracellular retention of Ala178fs/105-KCNQ1 protein. Co-expression of the mutant and WT also increased intracellular retention of channel protein compared to WT alone. Our findings suggest a novel mechanism for LQT1 that the truncated S1-S2 KCNQ1 mutant forms hetero-multimer and cause a dominant-negative effect due to trafficking defect.