Secondary crest myofibroblast PDGFRα controls the elastogenesis pathway via a secondary tier of signaling networks during alveologenesis.

Postnatal alveolar formation is the most important and the least understood phase of lung development. Alveolar pathologies are prominent in neonatal and adult lung diseases. The mechanisms of alveologenesis remain largely unknown. We inactivated Pdgfra postnatally in secondary crest myofibroblasts (SCMF), a subpopulation of lung mesenchymal cells. Lack of Pdgfra arrested alveologenesis akin to bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. The transcriptome of mutant SCMF revealed 1808 altered genes encoding transcription factors, signaling and extracellular matrix molecules. Elastin mRNA was reduced, and its distribution was abnormal. Absence of Pdgfra disrupted expression of elastogenic genes, including members of the Lox, Fbn and Fbln families. Expression of EGF family members increased when Tgfb1 was repressed in mouse. Similar, but not identical, results were found in human BPD lung samples. In vitro, blocking PDGF signaling decreased elastogenic gene expression associated with increased Egf and decreased Tgfb family mRNAs. The effect was reversible by inhibiting EGF or activating TGFß signaling. These observations demonstrate the previously unappreciated postnatal role of PDGFA/PDGFRα in controlling elastogenic gene expression via a secondary tier of signaling networks composed of EGF and TGFß.

Progenitors of secondary crest myofibroblasts are developmentally committed in early lung mesoderm.

Development of the mammalian lung is predicated on cross-communications between two highly interactive tissues, the endodermally derived epithelium and the mesodermally derived pulmonary mesenchyme. While much attention has been paid for the lung epithelium, the pulmonary mesenchyme, partly due to lack of specific tractable markers remains under-investigated. The lung mesenchyme is derived from the lateral plate mesoderm and is the principal recipient of Hedgehog (Hh) signaling, a morphogenetic network that regulates multiple aspects of embryonic development. Using the Hh-responsive Gli1-cre(ERT2) mouse line, we identified the mesodermal targets of Hh signaling at various time points during embryonic and postnatal lung development. Cell lineage analysis showed these cells serve as progenitors to contribute to multiple lineages of mesodermally derived differentiated cell types that include parenchymal or interstitial myofibroblasts, peribronchial and perivascular smooth muscle as well as rare populations of cells within the mesothelium. Most importantly, Gli1-cre(ERT2) identified the progenitors of secondary crest myofibroblasts, a hitherto intractable cell type that plays a key role in alveolar formation, a vital process about which little is currently known. Transcriptome analysis of Hh-targeted progenitor cells transitioning from the pseudoglandular to the saccular phase of lung development revealed important modulations of key signaling pathways. Among these, there was significant downregulation of canonical WNT signaling. Ectopic stabilization of ß-catenin via inactivation of Apc by Gli1-cre(ERT2) expanded the Hh-targeted progenitor pools, which caused the formation of fibroblastic masses within the lung parenchyma. The Gli1-cre(ERT2) mouse line represents a novel tool in the analysis of mesenchymal cell biology and alveolar formation during lung development.

Serum Trace Element Levels and Their Correlation with Picky Eating Behavior, Development, and Physical Activity in Early Childhood.

Trace elements are vital components for healthy growth, development, and physical activity. The aim of this study was to investigate the relationship between trace element (iron, zinc, copper) deficiencies and picky eating behavior, development level, and physical activity level. This cross-sectional study involved 203 children aged 4-7 years; picky eating behavior, development level, and physical activity level were assessed through questionnaires. Zinc deficiency has the highest prevalence (37.4%); 67.5% of the children were assessed as picky eaters. Children with picky eating behaviors, poor development level, or poor physical activity level have significantly lower zinc levels, and higher prevalence of zinc deficiency. Pearson's correlation coefficient indicated a positive correlation between serum zinc level and development scores (r = 0.221, p = 0.002) and physical activity scores (r = 0.469, p < 0.001). In multivariate analysis, zinc deficiency independently related to picky eating (OR = 2.124, p = 0.037, CI = 1.042-4.312), developmental level (OR = 0.893, p = 0.022, CI = 0.810-0.984), and physical activity level (OR = 0.785, p < 0.001, CI = 0.700-0.879). In conclusion, the prevalence of zinc deficiency in children aged 4-7 was high, especially in picky eaters. Zinc deficiency was significantly associated with low development and poor physical activity in early childhood.

Characterization of group B Streptococcus colonization in full-term and Late-Preterm neonates in Taiwan.

BACKGROUND: Group B streptococcus (GBS) infections can be life-threatening in newborns. This study aimed to analyze GBS carriage status and genotypic diversity in healthy neonates after implementation of intrapartum antibiotic prophylaxis (IAP) in Taiwan. METHODS: Newborns carrying GBS were identified from a screen of 500 newborns and followed up until their cultures turned negative. Their mothers' GBS screening data were reviewed. Molecular methods, including capsular serotyping, multilocus sequence typing and pulsed-field gel electrophoresis (PFGE), were used to analyze GBS isolates. RESULTS: GBS colonization was detected at either the nose or anus in 11 of 500 healthy neonates (2.2%). In this group of 11 neonates, 4 had GBS serotypes II and III for 4-6 months, 1 had serotype V for 2 months, 6 had serotypes Ia, II, V, and VI for less than 1 month, and 1 had 2 different serotypes (serotypes V and II) at different times. The most prevalent serotype was II (33.3%), followed by Ia (25.0%), III (16.7%), V (16.7%), and VI (8.3%). The main sequence type was ST1 (50.0%), followed by ST19 (16.7%), ST23 (8.3%), ST24 (8.3%), ST103 (8.3%), and ST 231 (8.3%). All isolates were grouped into 5 PFGE clusters F, G, J, X, and Y, and all were susceptible to ß-lactam antimicrobial agents. CONCLUSIONS: GBS was carried in 2.2% (11/500) healthy newborns and persisted for 6 months in 3 neonates. This study makes clearer our understanding of GBS colonization, serotype distribution, and genotype distribution in healthy neonates.

Clinical aspects and molecular analysis of Chinese patients with Wiskott-Aldrich syndrome in Taiwan.

BACKGROUND: Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency, characterized by microthrombocytopenia, eczema and recurrent infections. More than 441 patient mutations have been described all over the world, mainly based on Caucasian and Japanese people. There have been few reported cases involving Chinese WAS patients. OBJECTIVE: We investigated Chinese WAS patients in Taiwan since 1980. METHODS: All WAS patients met the diagnosis criteria. Clinical manifestations, immunological functions, gene sequencing and the WAS protein (WASP) expression were analyzed. RESULTS: Eleven male Chinese WAS patients were enrolled, presenting as classic WAS phenotype, correlative to the expression level of WASP and the severity of infections. Seven patients had autoimmune disorders, encompassing autoimmune hemolysis in 4, lymphoproliferative disorders in 2 and ulcerative colitis in 1 patient. As well as prophylactic monthly intravenous immunoglobulin infusion, splenectomy was performed on 2 patients. Five patients received hematopoietic stem cell transplantation. The causes of mortality were mass bleeding, sepsis and Epstein Barr virus-associated lymphoproliferative disorders in 3 nontransplant patients and acute graft failure and cytomegalovirus pneumonitis in 2 transplant patients. Nine patients received genetic analysis and revealed 4 unique mutations. None had the X-linked thrombocytopenia phenotype. CONCLUSIONS: All of the recognized Chinese WAS patients had the classic phenotype. Most mutations involved exon 1 of the WASP gene and none had the X-linked thrombocytopenia phenotype. This may be attributable to genetic variation, although selection bias may exist.

A randomized pilot study comparing the role of PEEP, O2 flow, and high-flow air for weaning of ventilatory support in very low birth weight infants.

BACKGROUND: There is a lack of evidence to guide step-wise weaning of positive pressure respiratory support for premature infants. This study sought to compare the efficacy of three weaning protocols we designed to facilitate weaning of very low birth weight (VLBW, less than 1500 g) preterm infants from nasal continuous positive airway pressure (NCPAP) support. METHODS: This was a prospective, randomized, controlled trial of VLBW preterm infants who received positive pressure ventilatory support in our neonatal intensive care unit (NICU) from April 2008 through March 2009. When these infants were weaned to CPAP as their last step of respiratory support, they would be randomly assigned to one of the following three groups as their further weaning methods (M): (M1) CPAP group, (M2) O2 flow group, and (M3) air flow group. The time period they needed to wean off any kind of respiratory support, as well as the likelihood of developing relevant prematurity related morbidities, were compared among patients using different weaning modalities. RESULTS: 181 patients were enrolled in the study. Their gestational age (GA) and birth weight (BW) were 29.1 ± 2.5, 28.7 ± 2.4, 28.7 ± 2.4 (mean ± SD) weeks and 1142 ± 232, 1099 ± 234, 1083 ± 219 g, in M1, M2 and M3, respectively. The time (period) needed to wean off support was 16.0 ± 10.0 days (M1), 11.6 ± 6.4 days (M2), and 15.0 ± 8.9 days (M3), respectively (p = .033). Incidence of retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) were both significantly higher in the O2 flow group (p = .048). CONCLUSIONS: Although using low oxygen flow significantly shortens CPAP weaning time, it may increase risks of BPD and ROP, both known to be related to oxygen toxicity. Unless the infant has BPD and is O2-dependent, clinicians should consider using air flow or just splinting with no support at all when weaning NCPAP.

Prevalence and independent risk factors for hearing impairment among very low birth weight infants.

BACKGROUND: Although we've made big strides in perinatal and neonatal care, auditory handicap remains a serious complication in those who were born very premature. OBJECTIVES: The aim was to determine the prevalence and analyze possible risk factors of hearing impairment in very-low-birth-weight (VLBW) infants. MATERIALS AND METHODS: This was a retrospective study by reviewing medical records of all VLBW infants (BW ≤ 1500 g) admitted to NICU of Chang Gung Children's Hospital over 2 years period from Jan. 2010 to 2011. Brainstem auditory evoked potentials (BAEP) hearing screening was performed at 3 months postnatal corrective age and repeated if failed the 1st time, then refer to ENT doctor if BAEP confirmed abnormal. All VLBW infants examined for hearing impairment were included and data were retrieved retrospectively and analyzed for neonatal risk factors using logistic regression. RESULTS: Over the period, 309 VLBW infants were screened. Prevalence of uni- or bilateral hearing impairment was 3.9% (12/309; 95% CI 2.6-4.1). The mean corrective age on diagnosed of hearing impairment was 2.9 ± 1.1 (range 1-5) months. Mean gestational age was 27.9 weeks (SD 1.4) and mean birth weight was 1028 g (SD 180). By univariant analysis for hearing impairment, severe birth asphyxia, craniofacial anomalies, ventilator dependence, patent ductus arteriosus ligation, and use of postnatal ototoxins yielded good prediction of hearing impairment in this population. However, using multivariate analysis revealed that the only independent risk factors for hearing impairment were ototoxins (OR: 3.62; CI: 1.67-7.82), PDA ligation (OR: 4.96; CI: 2.34-10.52), craniofacial anomalies (OR: 3.42; CI: 1.70-6.88)and assisted prolonged use of oxygen at gestational age of >36 weeks (OR: 5.94; CI: 2.61-13.54). CONCLUSION: The incidence of hearing impairment among VLBW infants was 3.9%. Prolonged supplemental oxygen use is a marker for predicting hearing impairment; this requires detailed analysis of the pathophysiologic features, to reduce the prevalence of hearing impairment.

Prognostic factors and concomitant anomalies in neonatal gastric perforation.

OBJECTIVE: Neonatal gastric perforation is a rare and serious issue. This study aimed to highlight the vital clinical features and identify prognostic factors in such cases. DESIGN, SETTING, PATIENTS, INTERVENTIONS, AND MEASUREMENTS: Medical charts from January 1997 through December 2008 were reviewed retrospectively. Neonates with a diagnosis of gastric perforation were included. RESULTS: Thirteen patients were identified with a male:female ratio of 9:4. Five (38%) were preterm infants. The mortality rate was 30% (4/13), and the median age of onset was 3 days (range: 1-14 days). The most common presenting sign was abdominal distension, followed by respiratory distress and vomiting. Except for one patient in whom gastric perforation was diagnosed during surgical repair for gastroschisis, all patients had pneumoperitoneum on admission; 70% and 46% of patients had peritonitis and sepsis, respectively. Concomitant gastrointestinal (GI) tract anomalies or disorders included ischemic bowel/necrotizing enterocolitis (5 patients), intestinal malrotation (2), duodenal web (1), hiatal hernia (1), and gastroschisis (1), which necessitated secondary operations during hospitalization in 5 patients. Seven patients had leukopenia on admission, and 9 developed thrombocytopenia in the following 48 h. All patients who died presented with leukopenia on admission and thrombocytopenia in the following 48 h, yielding sensitivity and specificity rates of 100% and 67%, respectively. CONCLUSIONS: Neonatal gastric perforation is often concomitant with GI anomalies or inflammatory/infectious disease. Patients who were outborn and those with leucopenia, peritonitis, and thrombocytopenia development within 48 h were at risk for poor outcome.

Unusual Presentation of Renal Vein Thrombosis in a Preterm Infant.

Neonatal renal vein thrombosis is the most common vascular condition in the newborn kidney, which could lead to serious complication in infants undergoing intensive care. In this study, we report the case of a preterm infant with left renal vein and inferior vena cava thrombosis, presented with gross hematuria, thrombocytopenia, transient hypertension, and adrenal hemorrhage. Supportive care was offered instead of heparin therapy or thrombolytic agents. In conclusion, our case teaches that, despite the lack of a clinically obvious shock event, renal vein thrombosis should be considered in a macrohematuric newborn without renal failure.

Prevalence and morbidity of late preterm infants: current status in a medical center of Northern Taiwan.

BACKGROUND: "Late preterm" defines infants born at 34(0/7) through 36(6/7) weeks' gestation, which comprise a majority of preterm births. These infants were treated clinically as "near-term" in the past, but recent studies have implied increased morbidities that differentiate late preterm and term infants. The purpose of this study was to examine the prevalence and clinical complications that could be associated with late preterm birth, as compared to term. METHODS: This was a retrospective cohort study that reviewed infants born in a medical center in Northern Taiwan during a 2-year period between 2008 and 2009. Maternal obstetrical factors, neonatal demographic distributions, and neonatal complications were compared between full-term and late preterm deliveries. RESULTS: During the study period, there were 7998 live births in the institute, including 6507 term and 1491 preterm infants. Of the latter, there were 914 (61.3%) born after 34 weeks' gestation. The Neonatal Intensive Care Unit (NICU) (including a special care nursery) admission rate was higher in late preterm infants when compared to term (36% vs. 2%), and was 74%, 43%, and 21% in infants born at 34, 35, and 36 weeks' gestation, respectively. Compared with term infants, late-preterm infants had longer hospital stay if admitted to NICU (including special care nursery) (17 days vs. 10 days), and they were associated with increased risk of neonatal morbidities, including respiratory distress syndrome (2.6% vs. 0.02%), respiratory distress of other etiologies (16% vs. 2%), culture-proven sepsis (0.7% vs. 0.2%), hypoglycemia (3% vs. 0.4%), temperature instability (0.4% vs. 0.05%), feeding difficulty (2% vs. 0.4%), and hyperbilirubinemia needing phototherapy (14% vs. 3%). Late-preterm infants also had higher hospital readmission rate (4.4% vs. 2.3%, p<0.001) and neonatal mortality rate (0.3% vs. 0.08%, p=0.03). CONCLUSION: Late-preterm infants have increased risk of neonatal morbidities associated with organ immaturity. The results of this study emphasize the importance of judicious obstetrical decision-making when considering late preterm delivery, and the need to set up anticipatory clinical guidelines for the care of late preterm infants.

Analysis of incidence and risk factors of retinopathy of prematurity among very-low-birth-weight infants in North Taiwan.

BACKGROUND: Although significant advances have been made in perinatal care, retinopathy of prematurity (ROP) remains a serious complication in prematurely born individuals. There have been limited studies on ROP in Taiwan, and most of those existing reports are outdated. METHODS: This retrospective study included 252 very-low-birth-weight (VLBW) infants admitted to the neonatal intensive care unit of Chang Gung Children's Hospital over a 2-year period between July 2005 and June 2007. All infants were examined for ROP according to the guidelines published by the American Academy of Pediatrics. The relationship between clinical risk factors and the development of ROP was analyzed. RESULTS: Of the 252 VLBW infants, 216 met the screening criteria. Of the 216, 99 (45.8%) had ROP. Compared with neonates born at 29 weeks of gestational age (GA) or later, those very premature infants of ≤25 weeks' and 26-28 weeks' GA had increased odds ratios (OR) of 8.49 and 3.19, respectively, for the development of severe ROP. No ROP was detected in infants of greater than 33 weeks' GA. The simultaneous presence of a low GA, low birth weight (LBW), lower Apgar scores, hypotension, patent ductus arteriosus, septicemia, intraventricular hemorrhage, ventilator dependence, and use of postnatal steroids was associated with severe ROP. Using multiple logistic regression analyses for ROP, only maternal preeclampsia [OR, 2.52; confidence interval (CI), 1.32-4.7]; duration of mechanical ventilation (OR, 1.06; CI, 1.04-1.08); and LBW (OR, 2.62; CI, 1.370-3.375) predicted the development of threshold ROP. CONCLUSION: The incidence of ROP among VLBW infants was 45.8%; 19.0% had severe ROP. Infants of lower GAs and/or with LBW, whose mother had preeclampsia or who had a long duration of mechanical ventilation are at risk for the development of threshold ROP.

An extra-axial hemangioma mimicking a large prenatal brain tumor.

A rare case of a congenital brain tumor was diagnosed by sonography in a fetus at 37weeks' gestation. The ultrasound examination showed a large area of both increased echogenicity and echolucency in one hemisphere suggestive of brain tumor or hemorrhage. Extensive surgical removal of the tumor was performed and revealed an extremely rare histological type of hemangioma. We reported an interesting case of neonatal cavernous hemangioma, mimicking a large prenatal brain tumor and treated successively in neonatal period.