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1.  Novel FOXF1 deep intronic deletion causes lethal lung developmental disorder Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins 
Human mutation  2013;34(11):1467-1471.
Haploinsufficiency of FOXF1 causes an autosomal dominant neonatally lethal lung disorder, Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV). We identified novel 0.8-kb deletion within the 1.4-kb intron of FOXF1 in a deceased newborn diagnosed with ACDMPV. The deletion arose de novo on the maternal copy of the chromosome 16, and did not affect FOXF1 minigene splicing tested in lung fibroblasts. However, FOXF1 transcript level in the ACDMPV peripheral lung tissue was reduced by almost 40%. We found that, in an in vitro reporter assay, the FOXF1 intron exhibited moderate transcriptional enhancer activity, correlating with the presence of binding sites for expression regulators CTCF and CEBPB, whereas its truncated copy, that lost major CTCF and CEBPB binding sites, inhibited the FOXF1 promoter. Our data further emphasize the importance of testing the non-protein coding regions of the genome currently not covered by diagnostic chromosomal microarray analyses or whole exome sequencing.
PMCID: PMC4123314  PMID: 23943206
FOXF1; enhancer; splicing; intronic copy-number variants; CNV
2.  Antibiotic Exposure in the Newborn Intensive Care Unit and the Risk of Necrotizing Enterocolitis 
The Journal of pediatrics  2011;159(3):392-397.
To determine if duration of antibiotic exposure is an independent risk factor for necrotizing enterocolitis (NEC)
Study design
A retrospective, 2:1 control-case analysis was conducted comparing neonates with NEC to those without from 2000 through 2008. Controls were matched on gestational age, birth weight, and birth year. In each matched triad, demographic and risk factor data were collected from birth until the diagnosis of NEC in the case subject. Bivariate and multivariate analyses were utilized to assess associations between risk factors and NEC.
124 cases of NEC were matched with 248 controls. Cases were less likely to have respiratory distress syndrome (p=0.018) and more likely to reach full enteral feeding (p=0.028) than controls. Cases were more likely to have culture-proven sepsis (p<0.0001). Given the association between sepsis and antibiotic use, we tested for and found a significant interaction between the two variables (p=0.001). When neonates with sepsis were removed from the cohort, the risk of NEC increased significantly with duration of antibiotic exposure. Exposure for >10 days resulted in a nearly three-fold increase in the risk of developing NEC
Duration of antibiotic exposure is associated with an increased risk of NEC among neonates without prior sepsis.
PMCID: PMC3137655  PMID: 21489560
sepsis; antimicrobials; prematurity; neonates
3.  Case‐control analysis of endemic Serratia marcescens bacteremia in a neonatal intensive care unit 
Serratia marcescens is an opportunistic gram‐negative rod which typically infects compromised hosts.
To identify risk factors, signs, and outcomes associated with non‐epidemic S marcescens bacteremia in a neonatal intensive care unit (NICU).
The records of infants with S marcescens bacteremia while in the Yale‐New Haven Hospital NICU from 1980–2004 were reviewed. A matched case‐control study was performed by comparing each case of S marcescens to 2 uninfected controls and 2 cases of Escherichia coli bacteremia.
Twenty‐five sporadic cases of S marcescens bacteremia were identified. Eleven available isolates were determined to be different strains by pulse field gel electrophoresis. Infants with S marcescens bacteremia had median gestational age and birth weight of 28 weeks and 1235 grams, respectively. Compared to matched, uninfected controls, infants with S marcescens bacteremia were more likely to have had a central vascular catheter (OR = 4.33; 95% CI (1.41 to 13.36)) and surgery (OR = 5.67; 95% CI (1.81 to 17.37)), and had a higher overall mortality (44% vs 2%; OR = 38.50; 95% CI (4.57 to 324.47)). Compared to E coli matched controls, infants with S marcescens bacteremia had later onset of infection (median of 33 days of life vs 10; p<0.001), prolonged intubation (OR = 5.76; 95% CI (1.80 to 18.42)), and a higher rate of CVC (OR = 7.77; 95% CI (2.48 to 24.31)) use at the time of infection. A higher rate of meningitis (24% vs 7%; OR = 3.98; 95% CI (1.09 to 14.50)) was observed with S marcescens bacteremia compared to E coli.
S marcescens bacteremia occurs sporadically in the NICU, primarily in premature infants requiring support apparatus late in their hospital course. Associated meningitis is common and mortality high.
PMCID: PMC2675455  PMID: 17088342
4.  Early Onset Neonatal Sepsis: The Burden of Group B Streptococcal and E. coli Disease Continues 
Pediatrics  2011;127(5):817-826.
Guidelines for prevention of group B streptococcal (GBS) infection have successfully reduced early onset (EO) GBS disease. Study results suggest that Escherichia coli is an important EO pathogen.
To determine EO infection rates, pathogens, morbidity, and mortality in a national network of neonatal centers.
Infants with EO infection were identified by prospective surveillance at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Network centers. Infection was defined by positive culture results for blood and cerebrospinal fluid obtained from infants aged ≤72 hours plus treatment with antibiotic therapy for ≥5 days. Mother and infant characteristics, treatments, and outcomes were studied. Numbers of cases and total live births (LBs) were used to calculate incidence.
Among 396 586 LBs (2006–2009), 389 infants developed EO infection (0.98 cases per 1000 LBs). Infection rates increased with decreasing birth weight. GBS (43%, 0.41 per 1000 LBs) and E coli (29%, 0.28 per 1000 LBs) were most frequently isolated. Most infants with GBS were term (73%); 81% with E coli were preterm. Mothers of 67% of infected term and 58% of infected preterm infants were screened for GBS, and results were positive for 25% of those mothers. Only 76% of mothers with GBS colonization received intrapartum chemoprophylaxis. Although 77% of infected infants required intensive care, 20% of term infants were treated in the normal newborn nursery. Sixteen percent of infected infants died, most commonly with E coli infection (33%).
In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease. GBS remains the most frequent pathogen in term infants, and E coli the most significant pathogen in preterm infants. Missed opportunities for GBS prevention continue. Prevention of E coli sepsis, especially among preterm infants, remains a challenge.
PMCID: PMC3081183  PMID: 21518717
neonatal sepsis; group B streptococcal disease; Escherichia coli infection
5.  The Impact of Environmental and Genetic Factors on Neonatal Late-Onset Sepsis 
The Journal of pediatrics  2010;158(2):234-238.e1.
To assess the genetic contribution to late-onset sepsis in twins in the newborn intensive care unit (NICU).
Study design
A retrospective cohort analysis of twins born from 1994 to 2009 was performed on data collected from the NICUs at Yale University and the University of Connecticut. Sepsis concordance rates were compared between monozygotic and dizygotic twins. Mixed effects logistic regression (MELR) analysis was performed to determine the impact of selected non-genetic factors on late-onset sepsis. The influence of additive genetic and common and residual environmental effects were analyzed and quantified.
170 monozygotic and 665 dizygotic twin pairs were analyzed and sepsis identified in 8.9%. Mean gestational age and birth weight of the cohort was 31.1 weeks and 1637 grams, respectively. MELR determined birth weight (regression coefficient=−0.001; 95% CI: −0.003–0.000; p=0.028), respiratory distress syndrome (regression coefficient=1.769; 95% CI: 0.943–2.596; p<0.001) and duration of total parenteral nutrition (regression coefficient=0.041; 95% CI: 0.017–0.064; p<0.001) as significant non-genetic factors. Further analysis determined 49.0% (p=0.002) of the variance in liability to late-onset sepsis was due to genetic factors alone, and 51.0% (p=0.001) the result of residual environmental factors.
Our data support significant genetic susceptibility to late-onset sepsis in the NICU population.
PMCID: PMC3008342  PMID: 20850766
premature newborn; infection; twins
6.  Granulicatella adiacens and Early-Onset Sepsis in Neonate 
Emerging Infectious Diseases  2011;17(10):1971-1973.
PMCID: PMC3310662  PMID: 22000391
bacteria; infants; neonate; sepsis; streptococci; Granulicatella adiacens; granulicatella; letter
7.  Genetic Contribution to Patent Ductus Arteriosus in the Premature Newborn 
Pediatrics  2009;123(2):669-673.
The most common congenital heart disease in the newborn population, patent ductus arteriosus, accounts for significant morbidity in preterm newborns. In addition to prematurity and environmental factors, we hypothesized that genetic factors play a significant role in this condition.
The objective of this study was to quantify the contribution of genetic factors to the variance in liability for patent ductus arteriosus in premature newborns.
A retrospective study (1991–2006) from 2 centers was performed by using zygosity data from premature twins born at ≤36 weeks’ gestational age and surviving beyond 36 weeks’ postmenstrual age. Patent ductus arteriosus was diagnosed by echocardiography at each center. Mixed-effects logistic regression was used to assess the effect of specific covariates. Latent variable probit modeling was then performed to estimate the heritability of patent ductus arteriosus, and mixed-effects probit modeling was used to quantify the genetic component.
We obtained data from 333 dizygotic twin pairs and 99 monozygotic twin pairs from 2 centers (Yale University and University of Connecticut). Data on chorioamnionitis, antenatal steroids, gestational age, body weight, gender, respiratory distress syndrome, patent ductus arteriosus, necrotizing enterocolitis, oxygen supplementation, and bronchopulmonary dysplasia were comparable between monozygotic and dizygotic twins. We found that gestational age, respiratory distress syndrome, and institution were significant covariates for patent ductus arteriosus. After controlling for specific covariates, genetic factors or the shared environment accounted for 76.1% of the variance in liability for patent ductus arteriosus.
Preterm patent ductus arteriosus is highly familial (contributed to by genetic and environmental factors), with the effect being mainly environmental, after controlling for known confounders.
PMCID: PMC3161726  PMID: 19171636
neonate; patent ductus arteriosus; twins; genetic
8.  The Genetic Susceptibility to Respiratory Distress Syndrome 
Pediatric research  2009;66(6):693-697.
Previous studies to identify a genetic component to respiratory distress syndrome (RDS) have shown conflicting results. Our objectives were to evaluate and quantify the genetic contribution to RDS using data that comprehensively includes known environmental factors in a large sample of premature twins. Data from a retrospective chart review of twins born at ≤32 weeks gestational age were obtained from 2 neonatal units. Mixed effects logistic regression (MELR) analysis was used to assess the influence of several independent covariates on RDS. A zygosity analysis, including the effects of additive genetic and common and residual environmental (ACE) factors, was performed to estimate the genetic contribution. Results reveal that the 332 twin pairs had a mean gestational age of 29.5 weeks and birth weight of 1372 grams. MELR identified significant non-genetic covariates as male gender (p=0.04), birth weight (p<0.001), 5-minute Apgar score (p<0.001) and treating institution (p=0.001) as significant predictors for RDS. The ACE model was employed to estimate the genetic susceptibility to RDS by adjusting for the above factors. We found 49.7% (p=0.04) of the variance in liability to RDS was the result of genetic factors alone. We conclude that there is a significant genetic susceptibility to RDS in preterm infants.
PMCID: PMC2796284  PMID: 19687775
9.  COL4A1 Mutation in Preterm Intraventricular Hemorrhage 
The Journal of pediatrics  2009;155(5):743-745.
Intraventricular hemorrhage is a common complication of preterm infants. Mutations in the type IV procollagen gene, COL4A1, are associated with cerebral small vessel disease with hemorrhage in adults and fetuses. We report a rare variant in COL4A1 associated with intraventricular hemorrhage in dizygotic preterm twins. These results expand the spectrum of diseases attributable to mutations in type IV procollagens.
PMCID: PMC2884156  PMID: 19840616

Results 1-9 (9)