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Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light-dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.
INTRODUCTION - Recent studies on comatose survivors of cardiac arrest undergoing targeted temperature management (TTM) have shown similar outcomes at multiple target temperatures. However, details regarding core temperature variability during TTM and its prognostic implications remain largely unknown. We sought to assess the association between core temperature variability and neurological outcomes in patients undergoing TTM following cardiac arrest.
METHODS - We analyzed a prospectively collected cohort of 242 patients treated with TTM following cardiac arrest at a tertiary care hospital between 2007 and 2014. Core temperature variability was defined as the statistical variance (i.e. standard deviation squared) amongst all core temperature recordings during the maintenance phase of TTM. Poor neurological outcome at hospital discharge, defined as a Cerebral Performance Category (CPC) score>2, was the primary outcome. Death prior to hospital discharge was assessed as the secondary outcome. Multivariable logistic regression was used to examine the association between temperature variability and neurological outcome or death at hospital discharge.
RESULTS - A poor neurological outcome was observed in 147 (61%) patients and 136 (56%) patients died prior to hospital discharge. In multivariable logistic regression, increased core temperature variability was not associated with increased odds of poor neurological outcomes (OR 0.38, 95% CI 0.11-1.38, p=0.142) or death (OR 0.43, 95% CI 0.12-1.53, p=0.193) at hospital discharge.
CONCLUSION - In this study, individual core temperature variability during TTM was not associated with poor neurological outcomes or death at hospital discharge.
Copyright © 2017 Elsevier Inc. All rights reserved.
IMPORTANCE - To our knowledge, no evidence-based guidelines are available for the best medical management of blood pressure, blood glucose levels, and temperature in pediatric patients after arterial ischemic stroke.
OBJECTIVE - To determine the prevalence of abnormal blood pressure, blood glucose levels, and temperature in pediatric patients with acute arterial ischemic stroke and to explore any association between these measures and neurological outcome.
DESIGN, SETTING, AND PARTICIPANTS - We performed a retrospective review of children aged 29 days to 18 years with their first arterial ischemic stroke between January 2009 and December 2013 at a tertiary academic children's hospital. Ninety-eight children with stroke were identified by an International Classification of Diseases, Ninth Revision, code search and medical record review. Blood pressure, blood glucose, and temperature data were collected for 5 days after the stroke. Hypertension was defined as systolic blood pressure at or above the 95th percentile for age, sex, and height for 2 consecutive recordings and 2 consecutive days. Hypotension was defined as systolic and/or diastolic blood pressure below the fifth percentile for age, sex, and height for 2 consecutive recordings. Hyperglycemia was defined as a blood glucose level of 200 mg/dL or greater. Morbidity and mortality at 3 months were documented. Data analyses were performed from July 1, 2014, to December 31, 2015.
INTERVENTIONS OR EXPOSURES - Abnormal blood pressure, blood glucose levels, and fever in the setting of arterial ischemic stroke.
MAIN OUTCOMES AND MEASURES - The a priori outcome measure was poor clinical outcome, defined as a Pediatric Stroke Outcome Measure score of 1 or greater, which represents a moderate neurological deficit.
RESULTS - The median (interquartile range) age of the 98 children was 6.0 (0.6-14.3) years, and 58 (59.2%) were male. Hypertension was present in 64 (65.3%), hypotension in 67 (68.4%), hyperglycemia in 17 (18.1%), and fever in 37 (37.8%). The strongest association with poor neurological outcome was an infarct size of 4% or greater of brain volume (odds ratio, 5.6; 95% CI, 2.0-15.4; P = .001). Hyperglycemia was also independently associated with poor neurological outcome (odds ratio, 3.9; 95% CI, 1.2-12.4; P = .02). Hypertension and fever were not significantly associated with infarct size, poor outcome, or death. Hypertension was not documented in 24 of 87 surviving children (27.6%) at 3-month follow-up and was not associated with poor neurological outcome.
CONCLUSIONS AND RELEVANCE - Abnormalities of blood pressure, blood glucose levels, and temperature are prevalent in children with arterial ischemic stroke. Infarct volume and hyperglycemia were associated with poor neurological outcome but hypertension and fever were not. Prospective studies that systematically record blood pressure, blood glucose, and temperature data are required to further assess the associations between these potentially modifiable physiological parameters and pediatric stroke outcome.
IL-15 is currently undergoing clinical trials to assess its efficacy for treatment of advanced cancers. The combination of IL-15 with soluble IL-15Rα generates a complex termed IL-15 superagonist (IL-15 SA) that possesses greater biological activity than IL-15 alone. IL-15 SA is considered an attractive antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8(+) T (mCD8(+) T) lymphocytes. However, the adverse consequences of IL-15 SA treatment have not been defined. In this study, the effect of IL-15 SA on physiologic and immunologic functions of mice was evaluated. IL-15 SA caused dose- and time-dependent hypothermia, weight loss, liver injury, and mortality. NK (especially the proinflammatory NK subset), NKT, and mCD8(+) T cells were preferentially expanded in spleen and liver upon IL-15 SA treatment. IL-15 SA caused NK cell activation as indicated by increased CD69 expression and IFN-γ, perforin, and granzyme B production, whereas NKT and mCD8(+) T cells showed minimal, if any, activation. Cell depletion and adoptive transfer studies showed that the systemic toxicity of IL-15 SA was mediated by hyperproliferation of activated NK cells. Production of the proinflammatory cytokine IFN-γ, but not TNF-α or perforin, was essential to IL-15 SA-induced immunotoxicity. The toxicity and immunological alterations shown in this study are comparable to those reported in recent clinical trials of IL-15 in patients with refractory cancers and advance current knowledge by providing mechanistic insights into IL-15 SA-mediated immunotoxicity.
Copyright © 2015 by The American Association of Immunologists, Inc.
We evaluated the performance of time to clinical stability (TCS), a longitudinal outcome measure using 4 physiologic parameters (temperature, heart rate, respiratory rate, and use of supplemental oxygen), among children enrolled in a prospective study of pneumonia hospitalizations. We calculated the time from admission to normalization for each of the 4 parameters individually along with various combinations of these parameters (≥2 parameters). We assessed for agreement between the combined TCS measures and both hospital length of stay and an ordinal severity scale (nonsevere, severe, and very severe). Overall, 323 (96.7%) of 334 included children had ≥1 parameter abnormal on admission; 70 (21%) children had ≥1 parameter abnormal at discharge. For the 4 combined measures, median TCS decreased with increasing age. Increasing TCS was associated with both longer length of stay and increasing disease severity. The simplest combined measure incorporating only respiratory rate and need for supplemental oxygen performed similarly to more complex measures including additional parameters. Our study demonstrates that longitudinal TCS measures may be useful in children with pneumonia, both in clinical settings to assess recovery and readiness for discharge, and as an outcome measure in research and quality assessments. Additional study is needed to further validate our findings.
© 2015 Society of Hospital Medicine.
INTRODUCTION - The chemokine CXCL10 is produced during infection and inflammation to activate the chemokine receptor CXCR3, an important regulator of lymphocyte trafficking and activation. The goal of this study was to assess the contributions of CXCL10 to the pathogenesis of experimental septic shock in mice.
METHODS - Septic shock was induced by cecal ligation and puncture (CLP) in mice resuscitated with lactated Ringer's solution and, in some cases, the broad spectrum antibiotic Primaxin. Studies were performed in CXCL10 knockout mice and mice treated with anti-CXCL10 immunoglobulin G (IgG). Endpoints included leukocyte trafficking and activation, core body temperature, plasma cytokine concentrations, bacterial clearance and survival.
RESULTS - CXCL10 was present at high concentrations in plasma and peritoneal cavity during CLP-induced septic shock. Survival was significantly improved in CXCL10 knockout (CXCL10KO) mice and mice treated with anti-CXCL10 IgG compared to controls. CXCL10KO mice and mice treated with anti-CXCL10 IgG showed attenuated hypothermia, lower concentrations of interleukin-6 (IL-6) and macrophage inhibitory protein-2 (MIP-2) in plasma and lessened natural killer (NK) cell activation compared to control mice. Compared to control mice, bacterial burden in blood and lungs was lower in CXCL10-deficient mice but not in mice treated with anti-CXCL10 IgG. Treatment of mice with anti-CXCL10 IgG plus fluids and Primaxin at 2 or 6 hours after CLP significantly improved survival compared to mice treated with non-specific IgG under the same conditions.
CONCLUSIONS - CXCL10 plays a role in the pathogenesis of CLP-induced septic shock and could serve as a therapeutic target during the acute phase of septic shock.
Reports of methamphetamine-related emergency room visits suggest that elevated body temperature is a universal presenting symptom, with lethal overdoses generally associated with extreme hyperthermia. This review summarizes the available information on methamphetamine toxicity as it pertains to elevations in body temperature. First, a brief overview of thermoregulatory mechanisms is presented. Next, central and peripheral targets that have been considered for potential involvement in methamphetamine hyperthermia are discussed. Finally, future areas of investigation are proposed, as further studies are needed to provide greater insight into the mechanisms that mediate the alterations in body temperature elicited by methamphetamine.
Copyright © 2014 Elsevier Inc. All rights reserved.
Augmentation of endogenous cannabinoid (eCB) signaling represents an emerging approach to the treatment of affective disorders. Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid to form prostaglandins, but also inactivates eCBs in vitro. However, the viability of COX-2 as a therapeutic target for in vivo eCB augmentation has not been explored. Using medicinal chemistry and in vivo analytical and behavioral pharmacological approaches, we found that COX-2 is important for the regulation of eCB levels in vivo. We used a pharmacological strategy involving substrate-selective inhibition of COX-2 to augment eCB signaling without affecting related non-eCB lipids or prostaglandin synthesis. Behaviorally, substrate-selective inhibition of COX-2 reduced anxiety-like behaviors in mice via increased eCB signaling. Our data suggest a key role for COX-2 in the regulation of eCB signaling and indicate that substrate-selective pharmacology represents a viable approach for eCB augmentation with broad therapeutic potential.
Preclinical studies implicate a role for α₁-noradrenergic receptors in the effects of psychostimulants, including 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). The present study evaluated the effects of the α₁-noradrenergic receptor antagonist doxazosin on the acute pharmacodynamic and pharmacokinetic response to MDMA in 16 healthy subjects. Doxazosin (8 mg/d) or placebo was administered for 3 days before MDMA (125 mg) or placebo using a randomized, double-blind, placebo-controlled, 4-session, crossover design. Doxazosin reduced MDMA-induced elevations in blood pressure, body temperature, and moderately attenuated positive mood but enhanced tachycardia associated with MDMA. The results indicate that α₁-adrenergic receptors contribute to the acute cardiostimulant and to a minor extent possibly also to the thermogenic and euphoric effects of MDMA in humans.
BACKGROUND - Methamphetamine (METH) causes hyperthermia and dopaminergic neurotoxicity in the rodent striatum. METH interacts with σ receptors and σ receptor antagonists normally mitigate METH-induced hyperthermia and dopaminergic neurotoxicity. The present study was undertaken because in two experiments, pretreatment with σ receptor antagonists failed to attenuate METH-induced hyperthermia in mice. This allowed us to determine whether the ability of σ receptor antagonists (AZ66 and AC927) to mitigate METH-induced neurotoxicity depends upon their ability to modulate METH-induced hyperthermia.
METHODS - Mice were treated using a repeated dosing paradigm and body temperatures recorded. Striatal dopamine was measured one week post-treatment.
RESULTS - The data indicate that the ability of σ receptor antagonists to attenuate METH-induced dopaminergic neurotoxicity is linked to their ability to block METH-induced hyperthermia.
CONCLUSION - The ability of σ receptor antagonists to mitigate METH-induced hyperthermia may contribute to its neuroprotective actions.