GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis

Given that granulocyte macrophage colony-stimulating factor (GM-CSF) is identified as the key factor to endow auto-reactive Th cells with the potential to induce neuroinflammation in experimental autoimmune encephalomyelitis (EAE) models, the frequency and phenotype of GM-CSF-producing (GM-CSF+) Th cells in draining lymph nodes (dLNs) and spinal cord (SC) of Albino Oxford (AO) and Dark Agouti (DA) rats immunized for EAE were examined. The generation of neuroantigen-specific GM-CSF+ Th lymphocytes was impaired in dLNs of AO rats (relatively resistant to EAE induction) compared with their DA counterparts (susceptible to EAE) reflecting impaired CD4+ lymphocyte proliferation and less supportive of GM-CSF+ Th cell differentiation dLN cytokine microenvironment. Immunophenotyping of GM-CSF+ Th cells showed their phenotypic heterogeneity in both strains and revealed lower frequency of IL-17+ IFN-gamma+, IL-17+ IFN-gamma-, and IL-17-IFN-gamma+ cells accompanied by higher frequency of IL-17-IFN-gamma- cells among them in AO than in DA rats. Compared with DA, in AO rats was also found (i) slightly lower surface density of CCR2 (drives accumulation of highly pathogenic GM-CSF+ IFN-gamma+ Th17 cells in SC) on GM-CSF+ IFN-gamma+ Th17 lymphocytes from dLNs, and (ii) diminished CCL2 mRNA expression in SC tissue, suggesting their impaired migration into the SC. Moreover, dLN and SC cytokine environments in AO rats were shown to be less supportive of GM-CSF+ IFN-gamma+ Th17 cell differentiation (judging by lower expression of mRNAs for IL-1 beta, IL-6 and IL-23/p19). In accordance with the (i) lower frequency of GM-CSF+ Th cells in dLNs and SC of AO rats and their lower GM-CSF production, and (ii) impaired CCL2 expression in the SC tissue, the proportion of proinflammatory monocytes among peripheral blood cells and their progeny (CD45(hi) cells) among the SC CD11b+ cells were reduced in AO compared with DA rats. Collectively, the results indicate that the strain specificities in efficacy of several mechanisms controlling (auto) reactive CD4+ lymphocyte expansion/differentiation into the cells with pathogenic phenotype and migration of the latter to the SC contribute to AO rat resistance to EAE

Touch can change visual slant perception

Ernst MO, Banks MS, Bülthoff HH. Touch can change visual slant perception. Nature Neuroscience. 2000;3(1):69-73.The visual system uses several signals to deduce the three-dimensional structure of the environment, including binocular disparity, texture gradients, shading and motion parallax. Although each of these sources of information is independently insufficient to yield reliable three-dimensional structure from everyday scenes, the visual system combines them by weighting the available information; altering the weights would therefore change the perceived structure. We report that haptic feedback (active touch) increases the weight of a consistent surface-slant signal relative to inconsistent signals. Thus, appearance of a subsequently viewed surface is changed: the surface appears slanted in the direction specified by the haptically reinforced signal

Prescription Opioid Fatalities: Examining Why the Healer Could be the Culprit

© 2018, Springer International Publishing AG, part of Springer Nature. Prescription opioid use has increased rapidly in developed countries, as have fatalities and other related adverse events. This review examines the intrinsic characteristics of opioids, including their mechanisms of action and pharmacokinetic and pharmacodynamic properties, to determine how the use of a regonised pharmacological remedy for a medically confirmed ailment could result in an accidental fatality. Opioids trigger biological processes that inhibit their own therapeutic effect. Prolonged use of opioids can result in activation of pronociceptive systems, leading to opioid-induced hyperalgesia and tolerance, while opioid metabolites can antagonise the antinociceptive action of the parent drug, also leading to opioid-induced hyperalgesia and tolerance. Pain stimulates respiration and counteracts the respiratory depression effect of opioids. Analgesia from opioids leads to loss of this protective mechanism, leading to increased risk of death due to respiratory failure. Increased patient counseling during opioid prescribing and dispensing, and limiting prescription to short-term use in non-malignant pain, may decrease the adverse effects of opioids. The vast majority of patients who unintentionally experience serious adverse events from pharmaceutical opioids do not start out as drug seekers. Even opioid use within prescribing guidelines can place some patients at risk of death and may prevent patients from seeking help for prescription opioid dependence