Necrotizing Enterocolitis Is Not Associated With Sequence Variants in Antioxidant Response Genes in Premature Infants.

Reactive oxygen species mediate intestinal injury in necrotizing enterocolitis (NEC), and yet the contribution of antioxidant response (ARE) gene polymorphisms to NEC risk remains unknown. Premature infants recruited in a multicenter study were genotyped for 6 ARE variants. Among 637 infants, 52 had NEC, and 22 developed surgical NEC. Gestational age <28 weeks (P < 0.02) and African American race (P = 0.03) were associated with NEC. The NFE2L2 (rs6721961), SOD2 (rs4880), GSTP1 (rs1695), NQO1 (rs1800566), GCLC (rs17883901), and HMOX1 (rs2071747) variants were not associated with medical or surgical NEC. This study does not support a role for common deleterious ARE variants in NEC.

Antioxidant response genes sequence variants and BPD susceptibility in VLBW infants.

BACKGROUND: Lung injury resulting from oxidative stress contributes to bronchopulmonary dysplasia (BPD) pathogenesis. Nuclear factor erythroid-2 related factor-2 (NFE2L2) regulates cytoprotective responses to oxidative stress by inducing enzymes containing antioxidant response elements (ARE). We hypothesized that ARE genetic variants will modulate susceptibility or severity of BPD in very-low-birth-weight (VLBW) infants. METHODS: Blood samples obtained from VLBW infants were used for genotyping variants in the SOD2, NFE2L2, GCLC, GSTP1, HMOX1, and NQO1 genes. SNPs were genotyped utilizing TaqMan probes (Applied Biosystems (ABI), Grand Island, NY), and data were analyzed using the ABI HT7900. Genetic dominance and recessive models were tested to determine associations between SNPs and BPD. RESULTS: In our cohort (n = 659), 284 infants had BPD; 135 of whom developed severe BPD. Presence of the hypomorphic NQO1 SNP (rs1800566) in a homozygous state was associated with increased BPD, while presence of the NFE2L2 SNP (rs6721961) was associated with decreased severe BPD in the entire cohort and in Caucasian infants. In regression models that adjusted for epidemiological confounders, the NQO1 and the NFE2L2 SNPs were associated with BPD and severe BPD, respectively. CONCLUSION: Genetic variants in NFE2L2-ARE axis may contribute to the variance in liability to BPD observed in preterm infants. These results require confirmation in independent cohorts.

Undetectable maternal serum uE3 and postnatal abnormal sterol and steroid metabolism in Antley-Bixler syndrome.

Antley-Bixler syndrome (ABS) is a rare condition characterized by radiohumeral synostosis, craniosynostosis, midface hypoplasia, bowing of the femora, multiple joint contractures, and urogenital defects. Several reports have implicated errors of steroid or sterol metabolism in the pathogenesis of ABS. Evidence for this has included association with maternal luteomas, fetal 21-hydroxylase deficiency, early pregnancy exposure to high-dose fluconazole, lanosterol 14-alpha-demethylase deficiency, and a unique urinary steroid profile consistent with apparent pregnene hydroxylation deficiency (APHD). We report two sibs with classic ABS. During both pregnancies, mid-trimester maternal serum screening demonstrated undetectable levels of uncongugated estriol (uE3). The brother had ambiguous genitalia and increased serum levels of progesterone and 17-alpha-hydroxyprogesterone. Postnatal tests performed on the sister demonstrated both the unique urinary steroid profile that defines APHD and evidence of impaired lanosterol 14-alpha-demethylase activity. Our results suggest that in at least some patients with ABS, the skeletal findings and altered steroidogenesis are not associated with genes specific to individual sterol or steroid pathways but rather are related to an element, such as NADPH cytochrome P450 reductase (CPR) or cytochrome b5 (CYb5), that is common to all of these pathways.

Intra-amniotic corticosteroids for preterm lung maturation in sheep.

OBJECTIVE: The purpose of this study was to compare efficacy on fetal lung maturation of intra-amniotic betamethasone or budesonide with the efficacy of maternal intramuscular betamethasone. STUDY DESIGN: Pregnant ewes received intra-amniotic betamethasone (0.5 mg/kg or 2 mg/kg fetal weight), intra-amniotic budesonide (0.5 mg/kg or 2 mg/kg), maternal intramuscular betamethasone (0.5 mg/kg maternal weight), intra-amniotic saline solution, or maternal saline solution. Lambs were delivered 2 or 7 days later, at 124 days of gestation for measurement of respiratory system compliance, ventilatory efficiency index, and surfactant levels. RESULTS: Lung function increased 2 days after maternal betamethasone, intra-amniotic betamethasone (2 mg/kg), and intra-amniotic budesonide (2 mg/kg) administration and 7 days after maternal betamethasone or intra-amniotic budesonide (2.0 mg/kg) administration. Lung function was not improved 7 days after intra-amniotic betamethasone (2.0 mg/kg) administration or 2 days after intra-amniotic betamethasone (0.5 mg/kg) or intra-amniotic budesonide (0.5 mg/kg) administration. Intra-amniotic corticosteroid administration increased fetal death and respiratory morbidity. CONCLUSION: Intra-amniotic corticosteroid administration improved preterm lung function, but the associated morbidity and mortality rates suggest that they are not suitable for clinical use.