Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2012
Randomized Controlled TrialNonconscious activation of placebo and nocebo pain responses.
The dominant theories of human placebo effects rely on a notion that consciously perceptible cues, such as verbal information or distinct stimuli in classical conditioning, provide signals that activate placebo effects. However, growing evidence suggest that behavior can be triggered by stimuli presented outside of conscious awareness. Here, we performed two experiments in which the responses to thermal pain stimuli were assessed. ⋯ Participants rated each pain stimulus on a numeric response scale, ranging from 0 = no pain to 100 = worst imaginable pain. Significant placebo and nocebo effects were found in both experiment 1 (using clearly visible stimuli) and experiment 2 (using nonconscious stimuli), indicating that the mechanisms responsible for placebo and nocebo effects can operate without conscious awareness of the triggering cues. This is a unique experimental verification of the influence of nonconscious conditioned stimuli on placebo/nocebo effects and the results challenge the exclusive role of awareness and conscious cognitions in placebo responses.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2012
Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain.
P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to the delivery of small-molecule drugs across the blood-brain barrier and into the CNS. Here we test a unique signaling-based strategy to overcome this obstacle. We used a confocal microscopy-based assay with isolated rat brain capillaries to map a signaling pathway that within minutes abolishes P-glycoprotein transport activity without altering transporter protein expression or tight junction permeability. ⋯ Administration of S1P, FTY720, or FTY729P increased brain uptake of three radiolabeled P-glycoprotein substrates, (3)H-verapamil (threefold increase), (3)H-loperamide (fivefold increase), and (3)H-paclitaxel (fivefold increase); blocking S1PR1 abolished this effect. Tight junctional permeability, measured as brain (14)C-sucrose accumulation, was not altered. Therefore, targeting signaling through S1PR1 at the blood-brain barrier with the sphingolipid-based drugs, FTY720 or FTY720P, can rapidly and reversibly reduce basal P-glycoprotein activity and thus improve delivery of small-molecule therapeutics to the brain.
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Rates of participation in organ donation programs are known to be powerfully influenced by the relevant default policy in effect ("opt-in" vs. "opt-out"). Three studies provide evidence that this difference in participation may occur in part because the requirement to opt-in or opt-out results in large differences in the meaning that individuals attach to participation. American participants in Study 1 rated participation as a significantly more substantial action when agreement was purportedly obtained under opt-in rather than opt-out conditions, and nonagreement as a greater abrogation of responsibility when that decision was made under opt-out rather than under opt-in conditions. ⋯ Study 3 required American participants to rate various actions that differ in the effort and self-sacrifice they demand. As predicted, the placement of organ donation on the resulting multidimensional scaling dimension differed significantly depending on whether it purportedly was made in an opt-in country (where it was considered roughly akin to giving away half of one's wealth to charity upon one's death) or an opt-out country (where it fell between letting others get ahead of one in line and volunteering some time to help the poor). We discuss the relationship between this change of meaning account and two other mechanisms-behavioral inertia and implicit norms-that we believe underlie the default effect in decision making and other effects of policies designed to influence decision-makers.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2012
Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation.
Inappropriate neutrophil activation contributes to the pathogenesis of acute lung injury (ALI). Apoptosis is essential for removal of neutrophils from inflamed tissues and timely resolution of inflammation. Resolvin E1 (RvE1) is an endogenous lipid mediator derived from the ω-3 polyunsaturated fatty acid eicosapentaenoic acid that displays proresolving actions. ⋯ In mice, RvE1 treatment enhanced the resolution of established neutrophil-mediated pulmonary injury evoked by intratracheal instillation or i.p. administration of live E. coli or intratracheal instillation of carrageenan plus myeloperoxidase via facilitating neutrophil apoptosis and their removal by macrophages. The actions of RvE1 were prevented by the pan-caspase inhibitor zVAD-fmk. These results identify a mechanism, promotion of phagocytosis-induced neutrophil apoptosis and mitigation of potent anti-apoptosis signals, by which RvE1 could enhance resolution of acute lung inflammation.
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Proc. Natl. Acad. Sci. U.S.A. · Sep 2012
Global economic potential for reducing carbon dioxide emissions from mangrove loss.
Mangroves are among the most threatened and rapidly disappearing natural environments worldwide. In addition to supporting a wide range of other ecological and economic functions, mangroves store considerable carbon. Here, we consider the global economic potential for protecting mangroves based exclusively on their carbon. ⋯ Given the recent range of market price for carbon offsets and the cost of reducing emissions from other sources, this finding suggests that protecting mangroves for their carbon is an economically viable proposition. Political-economy considerations related to the ability of doing business in developing countries, however, can severely limit the supply of offsets and increases their price per ton. We also find that although a carbon-focused conservation strategy does not automatically target areas most valuable for biodiversity, implementing a biodiversity-focused strategy would only slightly increase the costs.