Background:Magnesium ion gates the N-methyl-D-aspartate (NMDA) receptor and may protect the brain from NMDA receptor-mediated asphyxial injury. The present study evaluated the neuroprotective role of magnesium in birth asphyxia.Material and Methods:Forty term neonates with severe birth asphyxia were randomized to either the study group or the control group. Neonates in the study group received magnesium sulfate in a dose of 250 mg/kg initially within half an hour of birth followed by 125 mg/kg at 24 and 48 h of birth. Cranial computed tomography (CT) scan and electroencephalography (EEG) were performed for all the babies. Denver II was used for developmental assessment at the age of 6 months.Results:Two babies in each group died of severe hypoxic ischemic encephalopathy. EEG abnormalities occurred in 43.75% of the cases in the control group compared with 31.25% in the study group. CT scan abnormalities were present in 62.5% of the control group compared with 37.5% of the cases in the study group. The Denver II assessment at 6 months revealed that there were five babies that were either abnormal or suspect in the control group compared with three in the study group.Conclusion:Magnesium is well tolerated and does appear to have beneficial effects in babies with severe asphyxia. More data is however needed and a large multicenter trial should be conducted.
Donohue syndrome (DS) is characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. To identify molecular defects contributing to metabolic dysregulation in DS in the undifferentiated state, we generated mesenchymal progenitor cells (MPCs) from induced pluripotent stem cells derived from a 4-week-old female with DS and a healthy newborn male (control). INSR mRNA and protein were significantly reduced in DS MPC (for β-subunit, 64% and 89% reduction, respectively, P < .05), but IGF1R mRNA and protein did not differ vs control. Insulin-stimulated phosphorylation of INSR or the downstream substrates insulin receptor substrate 1 and protein kinase B did not differ, but ERK phosphorylation tended to be reduced in DS (32% decrease, P = .07). By contrast, IGF-1 and insulin-stimulated insulin-like growth factor 1 (IGF-1) receptor phosphorylation were increased in DS (IGF-1, 8.5- vs 4.5-fold increase; INS, 11- vs 6-fold; P < .05). DS MPC tended to have higher oxygen consumption in both the basal state (87% higher, P =.09) and in response to the uncoupler carbonyl cyanide-p-triflouromethoxyphenylhydrazone (2-fold increase, P =.06). Although mitochondrial DNA or mass did not differ, oxidative phosphorylation protein complexes III and V were increased in DS (by 37% and 6%, respectively; P < .05). Extracellular acidification also tended to increase in DS (91% increase, P = .07), with parallel significant increases in lactate secretion (34% higher at 4 h, P < .05). In summary, DS MPC maintain signaling downstream of the INSR, suggesting that IGF-1R signaling may partly compensate for INSR mutations. However, alterations in receptor expression and pathway-specific defects in insulin signaling, even in undifferentiated cells, can alter cellular oxidative metabolism, potentially via transcriptional mechanisms.
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