Plos One
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Neutrophils detect bacterial constituents, including bacterial DNA (CpG DNA), which elicits innate immunity and prolongs the functional life span of neutrophils through suppression of apoptosis. Both the anti-apoptotic protein Mcl-1 and activation of NF-κB have been implicated in neutrophil survival, but there is no evidence that these are linked in neutrophils. We hypothesized that CpG DNA could simultaneously activate these pathways. ⋯ NF-κB inhibitors and the telomere-derived TLR9 inhibitory oligonucleotide 5'-TTT AGG GTT AGG GTT AGG G-3' markedly reduced Mcl-1 protein levels and subsequently abrogated suppression of apoptosis by CpG DNA. Furthermore, CpG DNA attenuated the decreases in Mcl-1 in both cell lysate and nucleus of neutrophils undergoing spontaneous apoptosis and increased Mcl-1 translocation to the mitochondria, leading to preservation of mitochondrial transmembrane potential. These results demonstrate that CpG DNA through toll-like receptor 9 links two survival signaling pathways by delaying apoptosis through induction of NF-κB-mediated Mcl-1 gene transcription and promoting Mcl-1 translocation to the mitochondria.
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Multicenter Study
The burden attributable to mental and substance use disorders as risk factors for suicide: findings from the Global Burden of Disease Study 2010.
The Global Burden of Disease Study 2010 (GBD 2010) identified mental and substance use disorders as the 5th leading contributor of burden in 2010, measured by disability adjusted life years (DALYs). This estimate was incomplete as it excluded burden resulting from the increased risk of suicide captured elsewhere in GBD 2010's mutually exclusive list of diseases and injuries. Here, we estimate suicide DALYs attributable to mental and substance use disorders. ⋯ Capturing the suicide burden attributable to mental and substance use disorders allows for more accurate estimates of burden. More consideration needs to be given to interventions targeted to populations with, or at risk for, mental and substance use disorders as an effective strategy for suicide prevention.
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Randomized Controlled Trial
Randomised controlled trials may underestimate drug effects: balanced placebo trial design.
It is an inherent assumption in randomised controlled trials that the drug effect can be estimated by subtracting the response during placebo from the response during active drug treatment. ⋯ Although this study examined placebo effects and not the whole placebo response as in randomised controlled trials, it does suggest that the additivity assumption may be incorrect, and that the estimated drug effects in randomised controlled trials may be underestimated, particularly in studies reporting large placebo responses. The implications for randomised controlled trials and systematic reviews need to be discussed.
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Besides reducing gastric acid secretion, proton pump inhibitors (PPIs) suppress Th2-cytokine-stimulated expression of an eosinophil chemoattractant (eotaxin-3) by esophageal epithelial cells through acid-independent, anti-inflammatory mechanisms. To explore acid-inhibitory and acid-independent, anti-inflammatory PPI effects in reducing esophageal eosinophilia, we studied eotaxin-3 expression by the proximal and distal esophagus of children with esophageal eosinophilia before and after PPI therapy. In vitro, we studied acid and bile salt effects on IL-13-stimulated eotaxin-3 expression by esophageal epithelial cells. ⋯ In children with esophageal eosinophilia, PPIs significantly decrease eotaxin-3 expression in the proximal but not the distal esophagus. In esophageal squamous cells, acid and bile salts decrease Th2 cytokine-stimulated eotaxin-3 secretion profoundly, possibly explaining the disparate PPI effects on the proximal and distal esophagus. In the distal esophagus, where acid reflux is greatest, a PPI-induced reduction in acid reflux (an effect that could increase eotaxin-3 secretion induced by Th2 cytokines) might mask the acid-independent, anti-inflammatory PPI effect of decreasing cytokine-stimulated eotaxin-3 secretion.
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Randomized Controlled Trial
Pronounced inflammatory response to endotoxaemia during nighttime: a randomised cross-over trial.
Circadian variation in bodily functions has been shown to impact health in acute and chronic medical conditions. Little is known about the relationship between circadian rhythm and sepsis in humans. We aimed to investigate circadian variations in the host response in a human endotoxaemia model. ⋯ A day-night difference in the acute phase response to endotoxaemia exists in healthy volunteers with a more pronounced inflammatory response during the night time. This circadian difference in the response to endotoxaemia may play an important role in the clinical setting and should be investigated further.