High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates.

The vulnerability to infection of newborns is associated with a limited ability to mount efficient immune responses. High concentrations of adenosine and prostaglandins in the fetal and neonatal circulation hamper the antimicrobial responses of newborn immune cells. However, the existence of mechanisms counterbalancing neonatal immunosuppression has not been investigated. Remarkably, circulating levels of macrophage migration inhibitory factor (MIF), a proinflammatory immunoregulatory cytokine expressed constitutively, were 10-fold higher in newborns than in children and adults. Newborn monocytes expressed high levels of MIF and released MIF upon stimulation with Escherichia coli and group B Streptococcus, the leading pathogens of early-onset neonatal sepsis. Inhibition of MIF activity or MIF expression reduced microbial product-induced phosphorylation of p38 and ERK1/2 mitogen-activated protein kinases and secretion of cytokines. Recombinant MIF used at newborn, but not adult, concentrations counterregulated adenosine and prostaglandin E2-mediated inhibition of ERK1/2 activation and TNF production in newborn monocytes exposed to E. coli. In agreement with the concept that once infection is established high levels of MIF are detrimental to the host, treatment with a small molecule inhibitor of MIF reduced systemic inflammatory response, bacterial proliferation, and mortality of septic newborn mice. Altogether, these data provide a mechanistic explanation for how newborns may cope with an immunosuppressive environment to maintain a certain threshold of innate defenses. However, the same defense mechanisms may be at the expense of the host in conditions of severe infection, suggesting that MIF could represent a potential attractive target for immune-modulating adjunctive therapies for neonatal sepsis.

Exploring Brain Inhibition and Facilitation by Transcranial Magnetic Stimulation

Background and Question Paired-pulse TMS (Transcranial Magnetic Stimulation) paradigms allow explore motor cortex physiology. The Triple Stimulation Technique (TST) improves conventional TMS in quantifying cortico-spinal conduction. The objective of our study was to compare both methods in paired-pulse paradigms of inhibition and of facilitation. Method We investigated paired pulse paradigms of 2 ms (short intra-cortical inhibition) and of 10 ms intervals (intra cortical facilitation) in a randomized order in 22 healthy subjects applying conventional TMS and the TST protocol. Results Paired-pulse paradigms by both TMS and the TST yielded comparable results of short intra- cortical inhibition and intra cortical facilitation. However, the coefficient of variation was significantly smaller for SICI paradigm using TST. Conclusion These results suggest no greater sensitivity of the TST for quantifying inhibition and facilitation. The utility of TST to better quantify the individual amount of inhibition in SICI paradigms and its clinical utility need further studies.