Exacerbation of CNS inflammation and neurodegeneration by systemic LPS treatment is independent of circulating IL-1β and IL-6

<p>Abstract</p> <p>Background</p> <p>Chronic neurodegeneration comprises an inflammatory response but its contribution to the progression of disease remains unclear. We have previously shown that microglial cells are primed by chronic neurodegeneration, induced by the ME7 strain of prion disease, to synthesize limited pro-inflammatory cytokines but to produce exaggerated responses to subsequent systemic inflammatory insults. The consequences of this primed response include exaggerated hypothermic and sickness behavioural responses, acute neuronal death and accelerated progression of disease. Here we investigated whether inhibition of systemic cytokine synthesis using the anti-inflammatory steroid dexamethasone-21-phosphate was sufficient to block any or all of these responses.</p> <p>Methods</p> <p>ME7 animals, at 18-19 weeks post-inoculation, were challenged with LPS (500 μg/kg) in the presence or absence of dexamethasone-21-phosphate (2 mg/kg) and effects on core-body temperature and systemic and CNS cytokine production and apoptosis were examined.</p> <p>Results</p> <p>LPS induced hypothermia and decreased exploratory activity. Dexamethasone-21-phosphate prevented this hypothermia, markedly suppressed systemic IL-1β and IL-6 secretion but did not prevent decreased exploration. Furthermore, robust transcription of cytokine mRNA occurred in the hippocampus of both ME7 and NBH (normal brain homogenate) control animals despite the effective blocking of systemic cytokine synthesis. Microglia primed by neurodegeneration were not blocked from the robust synthesis of IL-1β protein and endothelial COX-2 was also robustly synthesized. We injected biotinylated LPS at 100 μg/kg and even at this lower dose this could be detected in blood plasma. Apoptosis was acutely induced by LPS, despite the inhibition of the systemic cytokine response.</p> <p>Conclusions</p> <p>These data suggest that LPS can directly activate the brain endothelium even at relatively low doses, obviating the need for systemic cytokine stimulation to transduce systemic inflammatory signals into the brain or to exacerbate existing pathology.</p

Computer recommendations for an automatic approach and landing system for V/STOL aircraft. Volume 2 - Equations

Automatic approach and landing system for V/STOL aircraf

Delay Discounting is Associated with Treatment Response among Cocaine-Dependent Outpatients

Rationale—Delay discounting (DD) describes the rate at which reinforcers lose value as the temporal delay to their receipt increases. Steeper discounting has been positively associated with vulnerability to substance use disorders, including cocaine use disorders. Objectives—In the present study, we examined whether DD of hypothetical monetary reinforcers is associated with the duration of cocaine abstinence achieved among cocainedependent outpatients. Methods—Participants were 36 adults who were participating in a randomized controlled trial examining the efficacy of voucher-based contingency management (CM) using low-magnitude (N = 18) or high-magnitude (N = 18) voucher monetary values. Results—DD was associated with the number of continuous weeks of cocaine abstinence achieved, even after adjusting for treatment condition during the initial 12-week (t(33) = 2.48, p = .045) and entire recommended 24-week of treatment (t(33) = 2.40, p = .022). Participants who exhibited steeper discounting functions achieved shorter periods of abstinence in the Lowmagnitude voucher condition (12-week: t(16) = 2.48, p = .025; 24-week: t(16) = 2.68, p = .017), but not in the High-magnitude voucher condition (12-week: t(16) = 0.51, p = .618; 24-week: t(16) = 1.08, p = .298), although the interaction between DD and treatment condition was not significant (12-week: t(32) = −1.12, p = .271; 24-week: t(32) = −0.37, p = .712). Conclusions—These results provide further evidence on associations between DD and treatment response and extend those observations to a new clinical population (i.e., cocainedependent outpatients), while also suggesting that a more intensive intervention like the Highmagnitude CM condition may diminish this negative relationship between DD and treatment response