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Costello syndrome (CS) is a rare genetic disorder characterized by distinctive facial appearance, cardiopulmonary complications, severe growth retardation, skin and skeletal defects, developmental delay, and tumor predisposition. CS is caused by heterozygous de novo mutations in the proto-oncogene HRAS, which is a component of the RAS/mitogen-activated protein kinase pathway. Herein, we reviewed the phenotypic and genetic features of 5 Korean patients who were genetically diagnosed with CS. Atrial tachycardia and polyhydramnios, which are important prenatal features for CS, were observed in 4 and 5 patients, respectively. The distinctive coarse facial appearances of the patients and presence of deep palmoplantar creases supported the clinical diagnosis of CS, which was confirmed by HRAS sequence analysis. Extremely poor postnatal growth was observed in all 5 patients. Further, all patients exhibited cardiac abnormalities; left ventricular hypertrophy and hypertrophic cardiomyopathy were observed in 3 patients. All 5 patients suffered from airway problems; 3 of them required intubation right after birth, and 2 of them received tracheostomy. One patient with a p.Gly12Ser mutation was diagnosed with retroperitoneal rhabdomyosarcoma alveolar type at the age of 5 years. Consistent with previous reports, both patients with p.Gly12Cys mutations died within the first year of life due to cardiopulmonary failure. Our study summarizes the characteristics of these 5 Korean patients with CS and, along with previous studies, provides clues for genotype-phenotype correlation in patients with CS. [ABSTRACT FROM AUTHOR]

Background: The long-term cardiovascular outcomes of pulmonary hypertension (PH) in preterm infants with bronchopulmonary dysplasia (BPD) are uncertain. Objectives: The purpose of this study was to assess outcomes of PH in prematurely born children diagnosed with moderate to severe BPD. Methods: We retrospectively reviewed the medical records of patients born before 32 weeks of gestation and diagnosed with moderate to severe BPD from June 2004 to April 2008. Patients were recruited for a cross-sectional study from August to October 2014 and underwent echocardiography. Results: Forty-two children were enrolled. Their mean gestational age and birth weight were 26.2 ± 1.7 weeks and 753.1 ± 172.5 g, respectively. Sixteen patients (38%) were diagnosed with PH at a mean age of 3.3 ± 1.6 months, and the PH improved after a median of 12.3 months (range 0.7-46.6). Cardiovascular function was reassessed at a mean age of 7.7 ± 0.9 years, at which time 1 patient was taking a medication for recurrent PH, and 12 (28.6%) patients exhibited elevated blood pressure. Conventional 2-dimensional and Doppler echocardiography indicated normal ventricular function in all children. However, right ventricular longitudinal strains were decreased in children with previous PH. Conclusions: Subclinical ventricular dysfunction was detectable using sensitive echocardiographic techniques in children with previous BPD-associated PH. Long-term follow-up and meticulous cardiovascular function assessment are required in this population. [ABSTRACT FROM AUTHOR]

Background: White matter injury (WMI) is the most common form of brain injury in preterm infants. It could be induced by a systemic inflammatory response in preterm infants. Objectives: We hypothesized that surgical necrotizing enterocolitis (surgNEC) results in more severe WMI than spontaneous intestinal perforation (SIP) on brain magnetic resonance imaging (MRI) at term-equivalent age (TEA). Methods: The medical records of 33 preterm infants born at less than 32 weeks of gestation who underwent surgery due to either NEC or SIP were reviewed retrospectively. White matter abnormality (WMA) on brain MRI was scored according to the diagnosis of surgNEC or SIP. Results: Nine patients were diagnosed with SIP and 24 with surgNEC. The median (range) gestational age of the SIP and surgNEC groups was 26+6 (23+3 -27+6) and 25+5 weeks (23+3 -31+2), respectively (p =0.454). There were no differences in 1- and 5-min Apgar scores, mode of delivery, use of antenatal steroids, histologic chorioamnionitis, or incidence of respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) between the two groups. Males were more prevalent in the surgNEC group (75.0 vs. 33.3%, p = 0.044), and the incidence of sepsis was higher in the surgNEC group than in the SIP group (75.0 vs. 33.3%, p = 0.044). Multivariate regression showed that the difference in WMA scores between the two groups remained significant (estimated difference = 2.418; 95% CI 0.107-4.729). Conclusion: In preterm infants at less than 32 weeks of gestation, those with surgNEC showed more severe WMI than infants with SIP on brain MRI at TEA. [ABSTRACT FROM AUTHOR]

Background: Preterm birth is known to be associated with risks of impaired nephrogenesis. Objectives: To determine the normal range of renal sizes at birth in preterm infants as well as their short-term postnatal renal growth, to assess the correlation between initial renal size and growth parameters at birth and to compare the initial and serial renal sizes between appropriate-for-gestational-age (AGA) and small-for-gestational-age (SGA) preterm infants. Methods: Initial ultrasonography (US) was prospectively performed in 125 preterm infants within the first 72 h of life and every 2 weeks thereafter until a postmenstrual age (PMA) of 37 weeks was reached. Correlation between renal size and growth parameters was investigated. Renal lengths of AGA and SGA preterm infants were compared with those of age-matched fetuses described in the literature. Results: The renal sizes at birth in preterm infants are presented. Multiple regression analysis showed the strongest correlation between initial renal size and birth weight (p < 0.0001). Initial renal lengths of AGA infants were not significantly different from those of age-matched fetuses at ≥30 weeks' gestational age (GA), whereas those of SGA infants were significantly smaller at ≥28 weeks' GA. Serial renal lengths of SGA infants were significantly smaller than fetal renal lengths at ≥30 weeks' GA. Conclusion: With US, the normal range of initial renal sizes of AGA preterm infants was defined according to GA. In contrast to AGA infants, SGA infants showed smaller initial renal sizes and no significant catch-up growth until a PMA of 37 weeks. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: In bronchopulmonary dysplasia (BPD), disrupted angiogenesis may result from an imbalance between pro- and anti-angiogenic factors triggered by inflammation, leading to the late development of pulmonary artery hypertension (PAH). Objectives: To investigate whether the levels of serum endostatin (as an anti-angiogenic factor) and angiopoietin-1 (AP-1; as a pro-angiogenic factor) in early life are associated with the development of PAH in preterm infants with severe BPD. Methods: In this prospective cohort study, the levels of serum endostatin and AP-1 were measured from 56 infants (gestational age <30 weeks or birth weight <1,250 g) including severe BPD with PAH ('PAH'; 15 infants) or without PAH ('non-PAH'; 22 infants) and no/mild BPD (19 infants) groups on days 1, 7, 14, and 28 of life. Results: The PAH group consistently underwent more aggressive respiratory management than the non-PAH group, over 1 month after birth. The endostatin level and the ratio of endostatin to AP-1 on day 7 of life were significantly higher in the PAH group than in the non-PAH group or no/mild BPD groups (median 146.6 vs. 102.4/108.0 ng/ml; 62.1 vs. 18.6/14.9). The ratio of endostatin to AP-1 on day 1 was also significantly higher in the PAH group than in the no/mild BPD group (median 31.8 vs. 11.3). Conclusions: An increased serum endostatin to AP-1 ratio may reflect impaired angiogenesis that may preclude the development of PAH. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Increased pro-inflammatory cytokines are suggested in the pathogenesis of necrotizing enterocolitis (NEC). The transcription factor, nuclear factor-κB (NF-κB), is a central regulator of inflammatory and immune responses, and recent rodent NEC models have shown that NF-κB may have a critical role in the disease processes that underlie NEC. Heat shock proteins have important functions in response to stress-related events in a variety of systems, including digestive organs. Objectives: We investigated whether heat shock pretreatment protects intestinal epithelial damage in the early NEC rat model. Methods: We generated human NEC-like lesions in neonatal rat ileum by administering oral endotoxin (10 mg/kg), intermittent 8% hypoxia, and hypertonic formula. Heat shock was administered by raising the chamber temperature to 42°C for 20 min, 3 h prior to endotoxin ingestion. Results: Heat shock pretreatment increased the expression of HSP70 in the ileal tissue and attenuated histological severity of early experimental NEC. NF-κB was activated in the ileal tissue of the NEC group and this activation was attenuated by heat shock pretreatment, which was determined by electrophoretic mobility shift assay and Western blot analysis of p50 in subcellular fractionated samples. Conclusions: Heat shock pretreatment reduced the incidence and severity of early experimental NEC in rats. A possible mechanism underlying this protective effect includes inhibition of NF-κB activation through increased HSP70 expression. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Granulocyte colony-stimulating factor (G-CSF) is known to mobilize endothelial progenitor cells (EPCs) from bone marrow. EPCs reportedly promote neovascularization and participate in the repair of lung structure in adult animals. Objective: We tested the hypothesis that G-CSF contributes to alveolar growth by increasing the production of angiogenic growth factor in the lungs of hyperoxia-exposed neonatal mice. Methods: Neonatal mice were exposed to hyperoxia (80%) or room air (RA) for 7 days and treated with G-CSF (50 μg/kg/day) or vehicle for 5 days. Blood was subjected to flow cytometry to gate for CD45dim/-/Sca-1+/CD133+/vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) to define the EPC population at day 7. Results: The percentage of EPCs in the peripheral blood and VEGF and VEGFR2 levels in the lungs of neonatal mice exposed to hyperoxia were significantly reduced compared to those of mice kept in RA. G-CSF significantly increased EPCs in the peripheral blood, and VEGF and VEGFR2 levels in the lungs of both mice exposed to hyperoxia and mice kept in RA. G-CSF restored alveolarization inhibited by hyperoxia without altering normal alveolarization under RA. Conclusion: G-CSF restored alveolarization inhibited by hyperoxia in the developing lungs and this alveolarization-enhancing effect of G-CSF is associated with mobilization of EPCs and upregulation of VEGF signaling. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Meconium obstruction (MO) of prematurity can result in increased morbidity or mortality and prolonged hospitalization if not diagnosed and treated appropriately. Objectives: The aims of our study were to identify the incidence and risk factors associated with MO and to review the treatment outcomes. Methods: A retrospective analysis was undertaken of 101 extremely low birth weight infants (ELBWIs) who were born between January 1, 2007, and April 1, 2009, at Seoul National University Hospital. Prenatal and neonatal factors were compared between the MO and control groups. The treatment outcomes were also reviewed. Results: Twenty-two (22%) patients were diagnosed as having MO. Eighteen of these patients (82%) had prenatal risk factors for MO. Respiratory distress syndrome was more prevalent in the MO group than in the control group (p = 0.001). Overall, 17 of the 22 patients (77%) were relieved with medical treatment and the rest underwent ileostomy. The times to full enteral feeding did not differ between the medically treated group and the control group. However, the surgically treated group required more time to achieve full enteral feeding, and some patients had persistent gastrointestinal problems. Conclusion: MO is not a rare condition in ELBWIs, and the majority of ELBWIs have prenatal risk factors. Medical management was effective, and medically manageable cases had good prognoses for subsequent feeding, whereas some surgically managed cases had persistent gastrointestinal problems. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Lung lavage with diluted surfactant has emerged as an innovative treatment for meconium aspiration syndrome (MAS). However, the treatment effect has not yet been fully established. Objective: To investigate the effects of surfactant lavage therapy for MAS by a systematic meta-analysis. Methods: Relevant studies were identified by database searches in MEDLINE (from 1950), EMBASE (from 1980), and CENTRAL, up to June 2010, and by additional hand searches. Meta-analyses were separately conducted for randomized controlled trials (RCTs) and non-randomized controlled studies (NRSs). Risk of bias was assessed and clinical as well as statistical heterogeneities were also investigated in explaining the potential bias. Results: Two RCTs (87 patients) and eight NRSs (178 patients) were identified. From the results of the meta-analysis of RCTs, surfactant lavage significantly decreased death or the need for extracorporeal membrane oxygenation (RR 0.34, 95% CI 0.11, 0.99). An interventional benefit was indicated for other outcomes, although it was not statistically significant based only on the two RCTs. Results from the analysis of outcomes from NRSs are consistent with those from RCTs and demonstrated a beneficial effect, which could be considered as supporting evidence. Conclusions: Lung lavage with diluted surfactant appeared to improve the clinical outcome in infants with MAS. Given that less than 100 infants were included in the two RCTs, the findings of this study may still be regarded as insufficient evidence. Further research will be needed to confirm the benefit as well as to refine the lavage technique. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Despite the potential importance of pulmonary artery hypertension (PAH) in preterm infants with bronchopulmonary dysplasia (BPD), little is known about the risk factors for PAH. Objectives: To investigate the risk factors for PAH in preterm infants with BPD. Methods: Infants diagnosed with BPD were assigned to the PAH group or non-PAH group except for infants with mild BPD who had no PAH. PAH was diagnosed on the basis of echocardiograms demonstrating elevated right ventricle pressure beyond the postnatal age of 2 months. Logistic regression analysis was done for the multivariate assessment of the risk factors for PAH in preterm infants with moderate or severe BPD. Results: A total of 98 infants among 145 infants with BPD were divided into a PAH group (n = 25) or non-PAH group (n = 73), while the remaining 47 infants had mild BPD with no PAH. Among the study patients, survival rate of the PAH group was significantly lower than that of the non-PAH group. Infants with PAH had more severe cases of BPD and underwent longer durations of oxygen therapy, conventional or high-frequency ventilation, and hospitalization compared to those without PAH. Low 5-min Apgar scores (≤6; relative risk (RR) 6.2; 95% confidence interval (CI) 1.4-28.0; p = 0.017) and oligohydramnios (RR 7.7; 95% CI 2.0-29.6; p = 0.030) were found to be significant risk factors for PAH according to multivariate analysis. Conclusions: The present study shows that oligohydramnios is a specific risk factor for PAH in preterm infants with moderate or severe BPD. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

AbstractBackground:The use of amplitude-integrated electroencephalography (aEEG) is increasing during the neonatal intensive care of preterm infants. Objective:This prospective study was designed to assess factors that affect the maturation of aEEG activity in preterm infants with a gestational age (GA) of 50). Results:The authors analyzed 207 recordings in 35 infants (GA 24–31 weeks, birth weight 440–1,980 g, postmenstrual age 25–38 weeks). At postmenstrual age 34–36 weeks, the aEEG total score was higher in preterm infants with a GA from 24 to 28 weeks than in less premature infants with a GA from 29 to 31 weeks (aEEG total score 12 vs. 10, p < 0.05). Logistic regression analysis revealed that the sleep-wake cycling was more prominent in infants with higher postnatal age (OR 3.32, 95 CI 2.40–4.59) or those receiving aminophylline (OR 3.28, 95 CI 1.06–10.08). Conclusions:The maturation of aEEG activity was found to be significantly correlated with postnatal age and with aminophylline use in clinically stable preterm infants. Most notably, aminophylline was found to be significantly associated with the degree of sleep-wake cycling as indicated by aEEG activity.Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

AbstractBackground:A considerable number of preterm infants may have been exposed to inflammation in utero and may be born with an inflamed lung. Objectives:To determine the impact of antenatal lung injury and inflammatory response on the pathogenesis of bronchopulmonary dysplasia (BPD) according to its clinical pattern, using KL-6 (as a lung injury marker) and C-reactive protein (CRP) (as a marker of inflammatory response). Methods:In this case-control study, a total of 74 infants (<32 weeks of gestation) including BPD with minimal early lung disease (‘atypical’; 21 infants), BPD with significant early lung disease (‘classic’; 29 infants) and the non-BPD (24 infants) groups underwent KL-6 and CRP in cord blood determinations. Results:The cord plasma KL-6 levels were significantly higher in the atypical and the total BPD groups than in the non-BPD group (median = 60.9 vs. 34.5 U/ml, p = 0.031; 43.5 vs. 34.5 U/ml, p = 0.02). However, the cord plasma CRP levels were not significantly different among the study groups. The cord plasma KL-6 levels in patients with atypical BPD were significantly higher in infants with moderate or severe BPD than in infants with mild BPD (median = 88.3 vs. 41.5 U/ml, p = 0.041) and were found to be significantly correlated with the duration of oxygen therapy (r = 0.502, p = 0.024). Conclusions:The present study shows that cord plasma KL-6, a specific lung injury marker, is increased and objectively reflects disease severity in atypical BPD.Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]