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- Improved neurologic outcomes after cardiac arrest with combined administration of vasopressin, steroids, and epinephrine compared to epinephrine alone. [Journal Article]
- CJEM 2014 Apr 1; 16(0):1-4.
Clinical questionIs a vasopressin, steroid, and epinephrine (VSE) protocol for in-hospital cardiac arrest resuscitation associated with better survival to hospital discharge with favourable neurologic outcome compared to epinephrine alone?Article chosenMentzelopoulos S, Malachias S, Konstantopoulos D, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial.JAMA 2013;310:270-9.ObjectiveTo determine if a VSE protocol during cardiopulmonary resuscitation with hydrocortisone administration in patients with postresuscitative shock at 4 hours after return of spontaneous circulation would improve survival to hospital discharge with favourable neurologic outcome.
- MODULATION OF THE EXTINCTION OF FEAR LEARNING. [REVIEW]
- Brain Res Bull 2014 Apr 14.
We review recent work on extinction learning with emphasis on its modulation. Extinction is the learned inhibition of responding to previously acquired tasks. Like other forms of learning, it can be modulated by a variety of neurotransmitter systems and behavioral procedures. This bears on its use in the treatment of fear memories, particularly in posttraumatic stress disorder (PTSD), for which it is the treatment of choice, often under the name of exposure therapy. There have not been many laboratories interested in the modulation of extinction, but the available data, although not very abundant, are quite conclusive. Most studies on the nature of extinction and on its modulation have been carried out on fear motivated behaviors, possibly because of their applicability to the therapy of PTSD. A role for D-serine and the glycine site of NMDA receptors has been ascertained in two forms of extinction in the ventromedial prefrontal cortex, basolateral amygdala and dorsal hippocampus. The serine analog, D-cycloserine, has received clinical trials as an enhancer of extinction. The brain histaminergic system acting via H2 receptors, and the endocannabinoid system using CB1 receptors in the ventromedial prefrontal cortex, hippocampus and basolateral amygdala enhance extinction. Dopaminergic D1 and β-noradrenergic receptors also modulate extinction by actions on these three structures. Isolated findings suggest roles for on serotonin-1A, dopaminergic-D2 and α-and β noradrenergic receptors in extinction modulation. Importantly, behavioral tagging and capture mechanisms in the hippocampus have been shown to play a major modulatory role in extinction. In addition, extinction of at least one aversive task (inhibitory avoidance) can be made state dependent on peripheral epinephrine.
- Recent evidence on the management of bronchiolitis. [JOURNAL ARTICLE]
- Curr Opin Pediatr 2014 Apr 15.
Bronchiolitis is a common condition in children less than 2 years of age and is a leading cause of infant hospitalization. Although there is significant variability in testing and treatment of children with bronchiolitis, diagnostic testing rarely improves care, and no currently available pharmacologic options have been proven to provide meaningful benefits or improve outcomes.Beta-agonists continue to be used frequently despite evidence that they do not reduce hospital admissions or length of stay. In general, therapies initially considered promising were subsequently proven ineffective, a pattern seen in studies on corticosteroids, and more recently with nebulized racemic epinephrine and hypertonic saline. Recent research has improved our understanding of the viral epidemiology of bronchiolitis, with increasing recognition of viruses other than respiratory syncytial virus and better awareness of the role of viral coinfections. How these findings will translate into improved outcomes remains uncertain.Much of the emphasis of the last few decades of bronchiolitis clinical care and research has centered on the identification and testing of novel therapies. Future quality improvement efforts should focus more on the limitation of unnecessary testing and treatments. Future research should include identification of subgroups of children with bronchiolitis that may benefit from focused clinical interventions.
- Chemical sensing of neurotransmitters. [JOURNAL ARTICLE]
- Chem Soc Rev 2014 Apr 16.
In the past few decades, the development of chemosensors for neurotransmitters has emerged as a research area of significant importance, which attracted a tremendous amount of attention due to its high sensitivity and rapid response. This current review focuses on various neurotransmitter detection based on fluorescent or colorimetric spectrophotometry published for the last 12 years, covering biogenic amines (dopamine, epinephrine, norepinephrine, serotonin, histamine and acetylcholine), amino acids (glutamate, aspartate, GABA, glycine and tyrosine), and adenosine.
- Effects of prolonged exposure to hypobaric hypoxia on oxidative stress, inflammation and gluco-insular regulation: the not-so-sweet price for good regulation. [Journal Article]
- PLoS One 2014; 9(4):e94915.
The mechanisms by which low oxygen availability are associated with the development of insulin resistance remain obscure. We thus investigated the relationship between such gluco-insular derangements in response to sustained (hypobaric) hypoxemia, and changes in biomarkers of oxidative stress, inflammation and counter-regulatory hormone responses.After baseline testing in London (75 m), 24 subjects ascended from Kathmandu (1,300 m) to Everest Base Camp (EBC;5,300 m) over 13 days. Of these, 14 ascended higher, with 8 reaching the summit (8,848 m). Assessments were conducted at baseline, during ascent to EBC, and 1, 6 and 8 week(s) thereafter. Changes in body weight and indices of gluco-insular control were measured (glucose, insulin, C-Peptide, homeostasis model assessment of insulin resistance [HOMA-IR]) along with biomarkers of oxidative stress (4-hydroxy-2-nonenal-HNE), inflammation (Interleukin-6 [IL-6]) and counter-regulatory hormones (glucagon, adrenalin, noradrenalin). In addition, peripheral oxygen saturation (SpO2) and venous blood lactate concentrations were determined.SpO2 fell significantly from 98.0% at sea level to 82.0% on arrival at 5,300 m. Whilst glucose levels remained stable, insulin and C-Peptide concentrations increased by >200% during the last 2 weeks. Increases in fasting insulin, HOMA-IR and glucagon correlated with increases in markers of oxidative stress (4-HNE) and inflammation (IL-6). Lactate levels progressively increased during ascent and remained significantly elevated until week 8. Subjects lost on average 7.3 kg in body weight.Sustained hypoxemia is associated with insulin resistance, whose magnitude correlates with the degree of oxidative stress and inflammation. The role of 4-HNE and IL-6 as key players in modifying the association between sustained hypoxia and insulin resistance merits further investigation.
- Simultaneous voltammetric determination of dopamine and epinephrine in human body fluid samples using a glassy carbon electrode modified with nickel oxide nanoparticles and carbon nanotubes within a dihexadecylphosphate film. [JOURNAL ARTICLE]
- Analyst 2014 Apr 14.
A simple and highly selective electrochemical method was developed for the single or simultaneous determination of dopamine (DA) and epinephrine (EP) in human body fluids using a glassy carbon electrode modified with nickel oxide nanoparticles and carbon nanotubes within a dihexadecylphosphate film using square-wave voltammetry (SWV) or differential-pulse voltammetry (DPV). Using DPV with the proposed electrode, a separation of ca. 360 mV between the peak reduction potentials of DA and EP present in binary mixtures was obtained. The analytical curves for the simultaneous determination of dopamine and epinephrine showed an excellent linear response, ranging from 7.0 × 10(-8) to 4.8 × 10(-6) and 3.0 × 10(-7) to 9.5 × 10(-6) mol L(-1) for DA and EP, respectively. The detection limits for the simultaneous determination of DA and EP were 5.0 × 10(-8) mol L(-1) and 8.2 × 10(-8) mol L(-1), respectively. The proposed method was successfully applied in the simultaneous determination of these analytes in human body fluid samples of cerebrospinal fluid, human serum and lung fluid.
- Efficacy of Chest Compressions Directed by End-Tidal CO2 Feedback in a Pediatric Resuscitation Model of Basic Life Support. [Journal Article]
- J Am Heart Assoc 2014; 3(2):e000450.
End-tidal carbon dioxide (ETCO2) correlates with systemic blood flow and resuscitation rate during cardiopulmonary resuscitation (CPR) and may potentially direct chest compression performance. We compared ETCO2-directed chest compressions with chest compressions optimized to pediatric basic life support guidelines in an infant swine model to determine the effect on rate of return of spontaneous circulation (ROSC).Forty 2-kg piglets underwent general anesthesia, tracheostomy, placement of vascular catheters, ventricular fibrillation, and 90 seconds of no-flow before receiving 10 or 12 minutes of pediatric basic life support. In the optimized group, chest compressions were optimized by marker, video, and verbal feedback to obtain American Heart Association-recommended depth and rate. In the ETCO2-directed group, compression depth, rate, and hand position were modified to obtain a maximal ETCO2 without video or verbal feedback. After the interval of pediatric basic life support, external defibrillation and intravenous epinephrine were administered for another 10 minutes of CPR or until ROSC. Mean ETCO2 at 10 minutes of CPR was 22.7±7.8 mm Hg in the optimized group (n=20) and 28.5±7.0 mm Hg in the ETCO2-directed group (n=20; P=0.02). Despite higher ETCO2 and mean arterial pressure in the latter group, ROSC rates were similar: 13 of 20 (65%; optimized) and 14 of 20 (70%; ETCO2 directed). The best predictor of ROSC was systemic perfusion pressure. Defibrillation attempts, epinephrine doses required, and CPR-related injuries were similar between groups.The use of ETCO2-directed chest compressions is a novel guided approach to resuscitation that can be as effective as standard CPR optimized with marker, video, and verbal feedback.
- Effects of Potassium/Lidocaine-induced Cardiac Standstill During Cardiopulmonary Resuscitation in a Pig Model of Prolonged Ventricular Fibrillation. [JOURNAL ARTICLE]
- Acad Emerg Med 2014 Apr; 21(4):392-400.
Several studies in patients who underwent open heart surgery found that myocardial ischemic damage was reduced by potassium cardioplegia combined with lidocaine infusion. The authors evaluated the effects of potassium/lidocaine-induced cardiac standstill during conventional cardiopulmonary resuscitation (CPR) on myocardial injury and left ventricular dysfunction after resuscitation from prolonged ventricular fibrillation (VF) cardiac arrest in a pig model.Ventricular fibrillation was induced in 16 pigs, and circulatory arrest was maintained for 14 minutes. Animals were then resuscitated by standard CPR. Animals were randomized at the start of CPR to receive 20 mL of saline (control group) or 0.9 mEq/kg potassium chloride and 1.2 mg/kg lidocaine diluted to 20 mL (K-lido group).Seven animals in each group achieved return of spontaneous circulation (ROSC; p = 1.000). Four of the K-lido group animals (50%) achieved ROSC without countershock. Resuscitated animals in the K-lido group required fewer countershocks (p = 0.004), smaller doses of epinephrine (p = 0.009), and shorter durations of CPR (p = 0.004) than did the control group. The uncorrected troponin-I at 4 hours after ROSC was lower in the K-lido group compared with the control group (2.82 ng/mL, 95% confidence interval [CI] = 1.07 to 3.38 ng/mL vs. 6.55 ng/mL, 95% CI = 4.84 to 13.30 ng/mL; p = 0.025), although the difference was not significant after Bonferroni correction. The magnitude of reduction in left ventricular ejection fraction (LVEF) between baseline and 1 hour after ROSC was significantly lower in the K-lido group (26.5%, SD ± 6.1% vs. 39.1%, SD ± 6.8%; p = 0.004).In a pig model of untreated VF cardiac arrest for 14 minutes, resuscitation with potassium/lidocaine-induced cardiac standstill during conventional CPR tended to reduce myocardial injury and decreased the severity of postresuscitation myocardial dysfunction significantly.
- Activation of Hindbrain Neurons Is Mediated by Portal-Mesenteric Vein Glucosensors During Slow-Onset Hypoglycemia. [JOURNAL ARTICLE]
- Diabetes 2014 Apr 11.
Hypoglycemic detection at the portal-mesenteric vein (PMV) appears mediated by spinal afferents and is critical for the counter-regulatory response (CRR) to slow-onset, but not rapid-onset, hypoglycemia. Since rapid-onset hypoglycemia induces Fos protein expression in discrete brain regions, we hypothesized that denervation of the PMV or lesioning spinal afferents would suppress Fos expression in the dorsal medulla during slow-onset hypoglycemia, revealing a central nervous system reliance on PMV glucosensors. Rats undergoing PMV deafferentation via capsaicin, celiac-superior mesenteric ganglionectomy (CSMG), or total subdiaphragmatic vagotomy (TSV) were exposed to hyperinsulinemic-hypoglycemic clamps where glycemia was lowered slowly over 60-75 min. In response to hypoglycemia, control animals demonstrated a robust CRR along with marked Fos expression in the area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus. Fos expression was suppressed by 65-92% in capsaicin animals, as was epinephrine (74%), norepinephrine (33%), and glucagon (47%). CSMG also suppressed Fos expression and CRR during slow-onset hypoglycemia, whereas TSV failed to impact either. In contrast, CSMG failed to impact upon Fos expression or the CRR during rapid-onset hypoglycemia. Peripheral glucosensory input from the PMV is therefore required for activation of hindbrain neurons and the full CRR during slow-onset hypoglycemia.
- β2- and β3-adrenergic receptors drive COMT-dependent pain by increasing production of nitric oxide and cytokines. [JOURNAL ARTICLE]
- Pain 2014 Apr 10.
Decreased activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, contributes to pain in humans and animals. Previously, we demonstrated that development of COMT-dependent pain is mediated by both β2-and β3-adrenergic receptors (β2-and β3ARs). Here, we investigated molecules downstream of β2-and β3ARs driving pain in animals with decreased COMT activity. Based on evidence linking their role in pain and synthesis downstream of β2-and β3ARstimulation, we hypothesized that nitric oxide (NO) and pro-inflammatory cytokines drive COMT-dependent pain. To test this, we measured plasma NO derivatives and cytokines in rats receiving the COMT inhibitor OR486 in the presence or absence of the β2AR antagonist ICI118,551+β3AR antagonist SR59320A. We also assessed if the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) and cytokine neutralizing antibodies block the development of COMT-dependent pain. Results showed that animals receiving OR486 exhibited higher levels of NO derivatives, tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2) in a β2-and β3AR-dependent manner. Additionally, inhibition of NO synthases and neutralization of the innate immunity cytokines TNFα, IL-1β, and IL-6 blocked the development of COMT-dependent pain. Finally, we found that NO influences TNFα, IL-1β, IL-6 and CCL2levels, while TNFα and IL-6 influence NO levels. Altogether, these results demonstrate that β2-and β3ARs contribute to COMT-dependent pain, at least partly, by increasing NO and cytokines. Furthermore, they identify β2-and β3ARs, NO, and pro-inflammatory cytokines as potential therapeutic targets for pain patients with abnormalities in COMT physiology.