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Neonatal systematic reviews that are continuously updated and rapidly made available can furnish important information about the safety and effectiveness of treatments still under scrutiny. Systematic reviews follow standard methods to assess the validity and combine the results of many clinical trials, and can provide meaningful guidance concerning the probable benefits and risks of a newly emerging therapy. Electronic publications, such as the Pediatrics electronic pages, supply a means to frequently update and widely distribute this important advance in evidence-based medical practice. By identifying still unanswered questions, these reviews can also facilitate new research., The article in this issue of Pediatrics electronic pages by Bhuta and Henderson-Smart[1] is an example of an important advance in the science of reviewing research. Readers who wish to [...]

Patients with spinal cord injury should receive a methylprednisolone infusion for at least 24 hours and preferably 48 hours if their treatment began 3 to 8 hours after injury. This was the conclusion of a study that compared a 24-hour infusion of methylprednisolone, a 48-hour infusion and a 48-hour infusion of tirilazad mesylate. The 48-hour infusion of methylprednisolone was most effective in improving motor function at 6 weeks and 6 months in those patients treated between 3 and 8 hours after injury., OBJECTIVE. -- To compare the efficacy of methylprednisolone administered for 24 hours with methyprednisolone administered for 48 hours or tirilazad mesylate administered for 48 hours in patients with acute spinal cord injury. Design. -- Double-blind, randomized clinical trial. Setting. -- Sixteen acute spinal cord injury centers in North America. Patients. -- A total of 499 patients with acute spinal cord injury diagnosed in National Acute Spinal Cord Injury Study (NASCIS) centers within 8 hours of injury. Intervention. -- All patients received an intravenous bolus of methylprednisolone (30 mg/kg) before randomization. Patients in the 24-hour regimen group (n= 166) received a methylprednislone infusion of 5.4 mg/kg per hour for 24 hours, those in the 48-hour regimen group (n= 167) received a methylprednisolone infusion of 5.4 mg/kg per hour for 48 hours, and those in the tirilazad group (n= 166) received a 2.5 mg/kg bolus infusion of tirilazad mesylate every 6 hours for 48 hours. Main Outcome Measures. -- Motor function change between initial presentation and at 6 weeks and 6 months after injury, and change in Functional Independence Measure (FIM) assessed at 6 weeks and 6 months. Results. -- Compared with patients treated with methylprednisolone for 24 hours, those related with methylprednisolone for 48 hours showed improved motor recovery at 6 weeks (P=.09) and 6 months (P=.07) after injury. The effect of the 48-hour methylprednisolone regimen was significant at 6 weeks (P=.04) and 6 months (P=.01) among patients whose therapy was initiated 3 to 8 hours after injury. Patients who received the 48-hour regimen and who started treatment at 3 to 8 hours were more likely to improve 1 full neurologic grade (P=.03) at 6 months, to show more improvement in 6-month FIM (P.08), and to have more severe sepsis and severe pneumonia than patients in the 24-hour methylprednisolone group and the tirilazad group, but other complications and mortality (P=.97) were similar. Patients treated with tirilazad for 48 hours showed motor recovery rates equivalent to patients who received methylprednisolone for 24 hours. Conclusion. -- Patients with acute spinal cord injury who receive methylprednisolone within 3 hours of injury should be maintained on the treatment regimen for 24 hours. When methylprednisolone is initiated 3 to 8 hours after injury, patients should be maintained on steroid therapy for 48 hours.

Abstract Background The x-ray cross complementing group 1 gene (XRCC1) is crucial to proper repair of DNA damage such as single-strand DNA breaks. A non-synonymous polymorphism in XRCC1, 399 G → A, has been shown to reduce effectiveness of such DNA repair and has been associated with the risk of certain cancers. The known risk for glioma from high dose ionizing radiation makes associations between this polymorphism and glioma of particular interest. Methods A systematic literature review and meta-analysis was conducted to explore the association between XRCC1 399 G → A and glioma. Subgroup analyses by grade, gender, genotyping method, country in which study was conducted, and study size were conducted when data were available and validity of the results were assessed by influence analyses and exploration of potential publication bias. Results Six studies were eligible for meta-analysis including data on 2,362 Caucasian glioma cases and 3,085 Caucasian controls. Pooled analysis yielded a significant association between the variant of interest and risk of glioma (OR = 1.17, 95% CI: 1.05-1.30) which was found to be disproportionately driven by a single study. Exclusion of this study, in an influence analysis, produced no statistically significant evidence of association with glioma (OR = 1.10, 95% CI: 0.98-1.23), and no evidence of publication bias. Conclusions This meta-analysis does not suggest a major role of the XRCC1 399 G → A polymorphism in influencing risk of glioma among Caucasians. Future studies should report data separately for glioma subtypes to permit stratified analyses for Grade III and Grade IV glioma and examine other polymorphisms in this gene.

Abstract Background Specific genetic contributions for preeclampsia (PE) are currently unknown. This genome-wide association study (GWAS) aims to identify maternal single nucleotide polymorphisms (SNPs) and copy-number variants (CNVs) involved in the etiology of PE. Methods A genome-wide scan was performed on 177 PE cases (diagnosed according to National Heart, Lung and Blood Institute guidelines) and 116 normotensive controls. White female study subjects from Iowa were genotyped on Affymetrix SNP 6.0 microarrays. CNV calls made using a combination of four detection algorithms (Birdseye, Canary, PennCNV, and QuantiSNP) were merged using CNVision and screened with stringent prioritization criteria. Due to limited DNA quantities and the deleterious nature of copy-number deletions, it was decided a priori that only deletions would be selected for assay on the entire case-control dataset using quantitative real-time PCR. Results The top four SNP candidates had an allelic or genotypic p-value between 10-5 and 10-6, however, none surpassed the Bonferroni-corrected significance threshold. Three recurrent rare deletions meeting prioritization criteria detected in multiple cases were selected for targeted genotyping. A locus of particular interest was found showing an enrichment of case deletions in 19q13.31 (5/169 cases and 1/114 controls), which encompasses the PSG11 gene contiguous to a highly plastic genomic region. All algorithm calls for these regions were assay confirmed. Conclusions CNVs may confer risk for PE and represent interesting regions that warrant further investigation. Top SNP candidates identified from the GWAS, although not genome-wide significant, may be useful to inform future studies in PE genetics.

It is difficult to successfully treat injuries to the spinal cord. The effectiveness and safety of the glucocorticoid drug methylprednisolone and the narcotic antagonist naloxone were examined in a randomized, controlled trial of 487 patients with spinal cord injuries. Ninety-five percent of the cases were treated within 14 hours after injury. Neurologic examinations were conducted on admission to the hospital, and at six weeks and six months after injury. Movement and sensory functions (the latter measured by the response to pinprick and light touch) were significantly improved in patients who were treated with methylprednisolone within eight hours of their injury, compared with patients treated with naloxone and a control group, who received a placebo or inactive substance. The degree of neurologic recovery was related to the severity of the injury, but improvement was seen in patients with various degrees of spinal cord damage. Patients treated with methylprednisolone eight or more hours after injury, or those who were treated with naloxone did not show any improvement in their movement or sensory functions; mortality and morbidity were the same in patients treated with methylprednisolone, naloxone, or placebo. Methylprednisolone is thought to inhibit the breakdown of cellular membranes. This study examines the neurologic changes that occurred after treatment, which should reflect the biologic changes in the spinal cord that lead to the patient's ability to recover during rehabilitation. These findings demonstrate that treatment with methylprednisolone improves the recovery of patients with spinal cord injuries, but must be given within eight hours of injury. (Consumer Summary produced by Reliance Medical Information, Inc.)

Abstract Background Polymorphisms in the endotoxin-mediated TLR4 pathway genes have been associated with asthma and atopy. We aimed to examine how genetic polymorphisms in innate immunity pathways interact with endotoxin to influence asthma risk in children. Methods In a previous analysis of 372 children from the Boston Home Allergens and the Connecticut Childhood Asthma studies, 7 SNPs in 6 genes (CARD15, TGFB1, LY96, ACAA1, DEFB1 and IFNG) involved in innate immune pathways were associated with asthma, and 5 SNPs in 3 genes (CD80, STAT4, IRAK2) were associated with eczema. We tested these SNPs for interaction with early life endotoxin exposure (n = 291), in models for asthma and eczema by age 6. Results We found a significant interaction between endotoxin and a SNP (rs156265) in ACAA1 (p = 0.0013 for interaction). Increased endotoxin exposure (by quartile) showed protective effects for asthma in individuals with at least one copy of the minor allele (OR = 0.39 per quartile increase in endotoxin, 95% CI 0.15 to 1.01). Endotoxin exposure did not reduce the risk of asthma in children homozygous for the major allele. Conclusion Our findings suggest that protective effects of endotoxin exposure on asthma may vary depending upon the presence or absence of a polymorphism in ACAA1.

Abstract Background Asthma is a phenotypically diverse disease with genetic susceptibility. A single nucleotide polymorphism (SNP) in the CD14 gene at position -260 (also known as -159) C>T has been inconsistently associated with asthma. The aim of this study was to estimate the combined likelihood of developing asthma given the CD14 -260C>T genotype. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic search and meta-analysis of the literature was conducted to estimate the association between this SNP and asthma. Planned subgroup analyses were performed to detect potential sources of heterogeneity from selected study characteristics. Post-hoc sensitivity analysis was performed to identify studies exerting excessive influence on among-study heterogeneity and combined effects. Results Meta-analysis of 23 studies yielded a non-significant overall association with high heterogeneity across studies. After restricting analysis to studies using atopic asthma and non-atopic non-asthma case-control phenotypes and excluding studies influencing heterogeneity, the genotype-specific odds ratios (ORs) suggested a codominant model. Carriers of the TT and CT genotypes were about 33% less likely (OR = 0.67, 95% CI: 0.54-0.84) and about 20% less likely (OR = 0.80, 95% CI: 0.66-0.95), respectively, to have atopic asthma compared to carriers of the CC genotype. Among-study heterogeneity may be explained by overly broad asthma phenotype definitions, gene-environment interactions, and gene-gene interactions. Conclusions A protective dose-response relationship between the CD14 -260T allele and atopic asthma susceptibility was observed. These results demonstrate the importance of precisely specified case-control groups as well as the need to assess interactions in the investigation of complex diseases such as asthma.

Abstract Background We examined the association between single nucleotide polymorphisms (SNPs) in loci encoding surfactant protein A (SFTPA) and risk of wheeze and persistent cough during the first year of life among a cohort of infants at risk for developing asthma. Methods Between September 1996 and December 1998, mothers of newborn infants were invited to participate if they had an older child with clinician-diagnosed asthma. Each mother was given a standardized questionnaire within 4 months of her infant's birth. Infant respiratory symptoms were collected during quarterly telephone interviews at 6, 9 and 12 months of age. Due to the association of SFTPA polymorphisms and race/ethnicity, analyses were restricted to 221 white infants for whom whole blood and respiratory data were available. Ordered logistic regression models were used to examine the association between respiratory symptom frequency and SFTPA haplotypes. Results The 6A allele haplotype of SFTPA1, with an estimated frequency of 6% among our study infants, was associated with an increased risk of persistent cough (OR 3.69, 95% CI 1.71, 7.98) and wheeze (OR 4.72, 95% CI 2.20, 10.11). The 6A/1A haplotype of SFTPA, found among approximately 5% of the infants, was associated with an increased risk of persistent cough (OR 3.20, 95% CI 1.39, 7.36) and wheeze (OR 3.25, 95% CI 1.43, 7.37). Conclusion Polymorphisms within SFTPA loci may be associated with wheeze and persistent cough in white infants at risk for asthma. These associations require replication and exploration in other ethnic/racial groups.

Abstract Background Otitis media is one of the most common infections of early childhood. Surfactant protein A functions as part of the innate immune response, which plays an important role in preventing infections early in life. This prospective study utilized a candidate gene approach to evaluate the association between polymorphisms in loci encoding SP-A and risk of otitis media during the first year of life among a cohort of infants at risk for developing asthma. Methods Between September 1996 and December 1998, women were invited to participate if they had at least one other child with physician-diagnosed asthma. Each mother was given a standardized questionnaire within 4 months of her infant's birth. Infant respiratory symptoms were collected during quarterly telephone interviews at 6, 9 and 12 months of age. Genotyping was done on 355 infants for whom whole blood and complete otitis media data were available. Results Polymorphisms at codons 19, 62, and 133 in SP-A1, and 223 in SP-A2 were associated with race/ethnicity. In logistic regression models incorporating estimates of uncertainty in haplotype assignment, the 6A4/1A5haplotype was protective for otitis media among white infants in our study population (OR 0.23; 95% CI 0.07,0.73). Conclusion These results indicate that polymorphisms within SP-A loci may be associated with otitis media in white infants. Larger confirmatory studies in all ethnic groups are warranted.