Hypoxia Disruption of Vertebrate CNS Pathfinding through EphrinB2 Is Rescued by Magnesium

The mechanisms of hypoxic injury to the developing human brain are poorly understood, despite being a major cause of chronic neurodevelopmental impairments. Recent work in the invertebrate Caenorhabditis elegans has shown that hypoxia causes discrete axon pathfinding errors in certain interneurons and motorneurons. However, it is unknown whether developmental hypoxia would have similar effects in a vertebrate nervous system. We have found that developmental hypoxic injury disrupts pathfinding of forebrain neurons in zebrafish (Danio rerio), leading to errors in which commissural axons fail to cross the midline. The pathfinding defects result from activation of the hypoxia-inducible transcription factor (hif1) pathway and are mimicked by chemical inducers of the hif1 pathway or by expression of constitutively active hif1α. Further, we found that blocking transcriptional activation by hif1α helped prevent the guidance defects. We identified ephrinB2a as a target of hif1 pathway activation, showed that knock-down of ephrinB2a rescued the guidance errors, and showed that the receptor ephA4a is expressed in a pattern complementary to the misrouting axons. By targeting a constitutively active form of ephrinB2a to specific neurons, we found that ephrinB2a mediates the pathfinding errors via a reverse-signaling mechanism. Finally, magnesium sulfate, used to improve neurodevelopmental outcomes in preterm births, protects against pathfinding errors by preventing upregulation of ephrinB2a. These results demonstrate that evolutionarily conserved genetic pathways regulate connectivity changes in the CNS in response to hypoxia, and they support a potential neuroprotective role for magnesium

Association between the concentration of fine particles in the atmosphere and acute respiratory diseases in children

ABSTRACT OBJECTIVE To analyze the association between fine particulate matter concentration in the atmosphere and hospital care by acute respiratory diseases in children. METHODS Ecological study, carried out in the region of Grande Vitória, Espírito Santo, in the winter (June 21 to September 21, 2013) and summer (December 21, 2013 to March 19, 2014). We assessed data of daily count for outpatient care and hospitalization by respiratory diseases (ICD-10) in children from zero to 12 years in three hospitals in the Region of Grande Vitória. For collecting fine particulate matter, we used portable samplers of particles installed in six locations in the studied region. The Generalized Additive Model with Poisson distribution, fitted for the effects of predictor covariates, was used to evaluate the relationship between respiratory outcomes and concentration of fine particulate matter. RESULTS The increase of 4.2 µg/m3 (interquartile range) in the concentration of fine particulate matter increased in 3.8% and 5.6% the risk of medical care or hospitalization, respectively, on the same day and with six-day lag from the exposure. CONCLUSIONS We identified positive association between outpatient care and hospitalizations of children under 12 years due to acute respiratory diseases and the concentration of fine particulate matter in the atmosphere