Early childhood health, growth, and neurodevelopmental outcomes after complete repair of total anomalous pulmonary venous connection at 6 weeks or younger

ObjectiveThis interprovincial inception cohort study explores early childhood outcomes and their operative and perioperative predictors after total anomalous pulmonary venous connection repair, simple (patent ductus arteriosus, atrial septal defect, or both) or complex (any associated major cardiac anomalies).MethodsFrom 1996 through 2004, a total of 41 consecutive neonates with total anomalous pulmonary venous connection underwent complete repair with deep hypothermic circulatory arrest. Multidisciplinary health and neurodevelopmental outcomes (Bayley Scales of Infant Development II [1993], Mental and Psychomotor Developmental Indices) were assessed at 18 to 24 months of age. Regression analyses explored potentially modifiable predictors of outcome.ResultsSurvival after simple total anomalous pulmonary venous connection repair was 31 of 32 (97%); that after complex repair was 3 of 9 (33%). Relative risk of death was higher for complex (21.3) and obstructive (8.4) total anomalous pulmonary venous connections. Those who died had longer deep hypothermic circulatory arrest times (P < .001). For 34 survivors, Mental Developmental Index was 87 ± 16 and Psychomotor Developmental Index was 89 ± 13. Among survivors, 24.6% of variability in Mental Developmental Index was explained by its linear relationship with socioeconomic status, whereas 35.5% of variability in Psychomotor Developmental Index was explained by its linear relationship with weight at surgery and highest plasma lactate level after surgery. North American native peoples made up 38% of survivors, a higher than expected number.ConclusionMean developmental scores were in the low average range of normative data. Socioeconomic factors predicted mental outcome. High postoperative lactate level on day 1 predicted low motor scores. Other potentially modifiable variables will need to be explored. Further epidemiologic study relating race to occurrence of total anomalous pulmonary venous connection is suggested. Early neurodevelopmental assessment is recommended

Crystal structure of the IL-2 signaling complex: Paradigm for a heterotrimeric cytokine receptor

IL-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits IL-2Rα, IL-2Rβ, and γ(c). Here, we describe the crystal structure of the trimeric assembly of the human IL-2 receptor ectodomains in complex with IL-2 at 3.0 Å resolution. The quaternary structure is consistent with a stepwise assembly from IL-2/IL-2Rα to IL-2/IL-2Rα/IL-2Rβ to IL-2/IL-2Rα/IL-2Rβ/γ(c). The IL-2Rα subunit forms the largest of the three IL-2/IL-2R interfaces, which, together with the high abundance of charge–charge interactions, correlates well with the rapid association rate and high-affinity interaction of IL-2Rα with IL-2 at the cell surface. Surprisingly, IL-2Rα makes no contacts with IL-2Rβ or γ(c), and only minor changes are observed in the IL-2 structure in response to receptor binding. These findings support the principal role of IL-2Rα to deliver IL-2 to the signaling complex and act as regulator of signal transduction. Cooperativity in assembly of the final quaternary complex is easily explained by the extraordinarily extensive set of interfaces found within the fully assembled IL-2 signaling complex, which nearly span the entire length of the IL-2Rβ and γ(c) subunits. Helix A of IL-2 wedges tightly between IL-2Rβ and γ(c) to form a three-way junction that coalesces into a composite binding site for the final γ(c) recruitment. The IL-2/γ(c) interface itself exhibits the smallest buried surface and the fewest hydrogen bonds in the complex, which is consistent with its promiscuous use in other cytokine receptor complexes