Ketamine analgesia for inflammatory pain in neonatal rats: a factorial randomized trial examining long-term effects

<p>Abstract</p> <p>Background</p> <p>Neonatal rats exposed to repetitive inflammatory pain have altered behaviors in young adulthood, partly ameliorated by Ketamine analgesia. We examined the relationships between protein expression, neuronal survival and plasticity in the neonatal rat brain, and correlated these changes with adult cognitive behavior.</p> <p>Methods</p> <p>Using Western immunoblot techniques, homogenates of cortical tissue were analyzed from neonatal rats 18–20 hours following repeated exposure to 4% formalin injections (F, N = 9), Ketamine (K, 2.5 mg/kg × 2, N = 9), Ketamine prior to formalin (KF, N = 9), or undisturbed controls (C, N = 9). Brain tissues from another cohort of rat pups (F = 11, K = 12, KF = 10, C = 15) were used for cellular staining with Fos immunohistochemistry or FluoroJade-B (FJB), followed by cell counting in eleven cortical and three hippocampal areas. Long-term cognitive testing using a delayed non-match to sample (DNMS) paradigm in the 8-arm radial maze was performed in adult rats receiving the same treatments (F = 20, K = 24, KF = 21, C = 27) in the neonatal period.</p> <p>Results</p> <p>Greater cell death occurred in F vs. C, K, KF in parietal and retrosplenial areas, vs. K, KF in piriform, temporal, and occipital areas, vs. C, K in frontal and hindlimb areas. In retrosplenial cortex, less Fos expression occurred in F vs. C, KF. Cell death correlated inversely with Fos expression in piriform, retrosplenial, and occipital areas, but only in F. Cortical expression of glial fibrillary acidic protein (GFAP) was elevated in F, K and KF vs. C. No significant differences occurred in Caspase-3, Bax, and Bcl-2 expression between groups, but cellular changes in cortical areas were significantly correlated with protein expression patterns. Cluster analysis of the frequencies and durations of behaviors grouped them as exploratory, learning, preparatory, consumptive, and foraging behaviors. Neonatal inflammatory pain exposure reduced exploratory behaviors in adult males, learning and preparatory behaviors in females, whereas Ketamine ameliorated these long-term effects.</p> <p>Conclusion</p> <p>Neuroprotective effects of Ketamine attenuate the impaired cognitive behaviors resulting from pain-induced cell death in the cortical and hippocampal fields of neonatal rats. This cell death was not dependent on the apoptosis associated proteins, but was correlated with glial activation.</p

What Are Normal Cortisol Values for Young Children?

Normative ranges for cortisol levels in children remain controversial, because of diurnal variations, effects of age, sex, stressful experiences before sampling (blood, saliva), intercurrent illnesses/immunizations, sample preparation and analytical methods. Measuring hair cortisol concentrations (HCC) is unaffected by diurnal variations or many of these factors, and presents a summative measure of chronic stress. Depending on hair growth rates, approximately 1 cm of hair represents cortisol release over the past month. HCC does not fluctuate frequently and therefore represents cumulative stress over time. It is vitally important to establish normative cortisol levels in children, so that both maladaptive and toxic stress levels can be measured. Pilot data from children in the CANDLE Study (Conditions Affecting Neurocognitive Development & Learning in Early childhood) were analyzed to identify the 25th, 50th and 75th percentiles for HCC in 1-4 year-old children. Significantly higher HCC were noted in black vs. white children at 1, 2, 3, and 4-years (P\u3c0.001, for all ages). When measuring HCC we must also study the biochemical composition of an individual’s hair, primarily its lipid content. This lipid content is significantly different depending on one’s racial background and may account for some of the observed racial differences in HCC (Robbins, 2012). Establishing age-, sex-, and race-specific normative levels for HCC are essential for investigating the cumulative effects of chronic stress or “allostatic load” across the lifespan. If the normative ranges for HCC can be established, both the causes and effects of maladaptive and toxic stress can be subsequently identified, prevented and/or treated

Development of the Family Poverty Index (FPI): A Novel Index to Measure Socioeconomic Status

The CANDLE Study aims to uncover factors experienced during pregnancy and early life that affect cognition, behavior, and health of children. External stressors and socioeconomic status (SES) influence the fetus through “prenatal programming”. However, comprehensive measures of SES do not exist, except those based on income and education. We selected 53 variables from the CANDLE study including annual household income, headcount, marital status, health insurance, parental occupation and education. Singular value decomposition imputation (SVDI), a principal components analysis approach unaffected by the 24.4% missing data in our variables, was applied to all 53 variables (Troyanskaya, 2001). All variables were distilled into 3 principal components explaining 93% of the variability. These components were combined to develop the Family Poverty Index (FPI, range 1-10). All subjects were separated into deciles based on FPI scores. Individuals with FPI=1 were the “poorest” with 79% individuals having annual incomes \u3c$15,000. Those with FPI=9 or 10 were “rich”, since most individuals (98.7$55,000. With FPI=1-3, 95% had Medicaid insurance and 4.8% had employer/private insurance, whereas with FPI=8-10, 86% had employer/private insurance and 11.8% had Medicaid. Other variables showed similar distributions across FPI categories. FPI appears to be a robust measure of SES in the CANDLE Study population. Further research should test the validity of the FPI in other datasets

Plasma biomarker analysis in pediatric ARDS: Generating future framework from a pilot randomized control trial of methylprednisolone: A framework for identifying plasma biomarkers related to clinical outcomes in pediatric ARDS

© 2016 Kimura, Saravia, Rovnaghi, Meduri, Schwingshackl, Cormier and Anand. Objective: Lung injury activates multiple pro-inflammatory pathways, including neutrophils, epithelial, and endothelial injury, and coagulation factors leading to acute respiratory distress syndrome (ARDS). Low-dose methylprednisolone therapy (MPT) improved oxygenation and ventilation in early pediatric ARDS without altering duration of mechanical ventilation or mortality. We evaluated the effects of MPT on biomarkers of endothelial [Ang-2 and soluble intercellular adhesion molecule-1 (sICAM-1)] or epithelial [soluble receptor for activated glycation end products (sRAGE)] injury, neutrophil activation [matrix metalloproteinase-8 (MMP-8)], and coagulation (plasminogen activator inhibitor-1). Design: Double-blind, placebo-controlled randomized trial. Setting: Tertiary-care pediatric intensive care unit (ICU). Patients: Mechanically ventilated children (0-18 years) with early ARDS. Interventions: Blood samples were collected on days 0 (before MPT), 7, and 14 during low-dose MPT (n = 17) vs. placebo (n = 18) therapy. The MPT group received a 2-mg/kg loading dose followed by 1 mg/kg/day continuous infusions from days 1 to 7, tapered off over 7 days; placebo group received equivalent amounts of 0.9% saline. We analyzed plasma samples using a multiplex assay for five biomarkers of ARDS. Multiple regression models were constructed to predict associations between changes in biomarkers and the clinical outcomes reported earlier, including P/F ratio on days 8 and 9, plateau pressure on days 1 and 2, PaCO 2 on days 2 and 3, racemic epinephrine following extubation, and supplemental oxygen at ICU discharge. Results: No differences occurred in biomarker concentrations between the groups on day 0. On day 7, reduction in MMP-8 levels (p = 0.0016) occurred in the MPT group, whereas increases in sICAM-1 levels (p = 0.0005) occurred in the placebo group (no increases in sICAM-1 in the MPT group). sRAGE levels decreased in both MPT and placebo groups (p \u3c 0.0001) from day 0 to day 7. On day 7, sRAGE levels were positively correlated with MPT group PaO 2 /FiO 2 ratios on day 8 (r = 0.93, p = 0.024). O 2 requirements at ICU transfer positively correlated with day 7 MMP-8 (r = 0.85, p = 0.016) and Ang-2 levels (r = 0.79, p = 0.036) in the placebo group and inversely correlated with day 7 sICAM-1 levels (r = -0.91, p = 0.005) in the MPT group. Conclusion: Biomarkers selected from endothelial, epithelial, or intravascular factors can be correlated with clinical endpoints in pediatric ARDS. For example, MPT could reduce neutrophil activation ([downwards double arrow]MMP-8), decrease endothelial injury (⇔sICAM-1), and allow epithelial recovery ([downwards double arrow]sRAGE). Large ARDS clinical trials should develop similar frameworks

The interaction between stress and chronic pain through the lens of threat learning

Stress and pain are interleaved at multiple levels - interacting and influencing each other. Both are modulated by psychosocial factors including fears, beliefs, and goals, and are served by overlapping neural substrates. One major contributing factor in the development and maintenance of chronic pain is threat learning, with pain as an emotionally-salient threat – or stressor. Here, we argue that threat learning is a central mechanism and contributor, mediating the relationship between stress and chronic pain. We review the state of the art on (mal)adaptive learning in chronic pain, and on effects of stress and particularly cortisol on learning. We then provide a theoretical integration of how stress may affect chronic pain through its effect on threat learning. Prolonged stress, as may be experienced by patients with chronic pain, and its resulting changes in key brain networks modulating stress responses and threat learning, may further exacerbate these impairing effects on threat learning. We provide testable hypotheses and suggestions for how this integration may guide future research and clinical approaches in chronic pain

Deficiency of the two-pore-domain potassium channel TREK-1 promotes hyperoxia-induced lung injury

Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins. Objectives: We previously reported the expression of the twoporedomain K+ channel TREK-1 in lung epithelial cells and proposed a role for this channel in the regulation of alveolar epithelial cytokine secretion. In this study, we focused on investigating the role of TREK-1 in vivo in the development of hyperoxia-induced lung injury. Design: Laboratory animal experiments. Setting: University research laboratory. Subjects: Wild-type and TREK-1-deficient mice. Interventions: Mice were anesthetized and exposed to 1) room air, no mechanical ventilation, 2) 95% hyperoxia for 24 hours, and 3) 95% hyperoxia for 24 hours followed by mechanical ventilation for 4 hours. Measurements and Main Results: Hyperoxia exposure accentuated lung injury in TREK-1-deficient mice but not controls, resulting in increase in lung injury scores, bronchoalveolar lavage fluid cell numbers, and cellular apoptosis and a decrease in quasi-static lung compliance. Exposure to a combination of hyperoxia and injurious mechanical ventilation resulted in further morphological lung damage and increased lung injury scores and bronchoalveolar lavage fluid cell numbers in control but not TREK-1-deficient mice. At baseline and after hyperoxia exposure, bronchoalveolar lavage cytokine levels were unchanged in TREK-1-deficient mice compared with controls. Exposure to hyperoxia and mechanical ventilation resulted in an increase in bronchoalveolar lavage interleukin-6, monocyte chemotactic protein-1, and tumor necrosis factor-á levels in both mouse types, but the increase in interleukin-6 and monocyte chemotactic protein-1 levels was less prominent in TREK-1-deficient mice than in controls. Lung tissue macrophage inflammatory protein-2, keratinocytederived cytokine, and interleukin-1β gene expression was not altered by hyperoxia in TREK-1-deficient mice compared with controls. Furthermore, we show for the first time TREK-1 expression on alveolar macrophages and unimpaired tumor necrosis factor-á secretion from TREK-1-deficient macrophages. Conclusions: TREK-1 deficiency resulted in increased sensitivity of lungs to hyperoxia, but this effect is less prominent if overwhelming injury is induced by the combination of hyperoxia and injurious mechanical ventilation. TREK-1 may constitute a new potential target for the development of novel treatment strategies against hyperoxiainduced lung injury

Clinical Profile Associated with Adverse Childhood Experiences: The Advent of Nervous System Dysregulation

Background: We report the prevalence of children with multiple medical symptoms in a pediatric neurology clinic, describe their symptom profiles, and explore their association with adverse childhood experiences (ACEs). Methods: We retrospectively reviewed 100 consecutive patients from an outpatient pediatric neurology clinic. Patients were included if they were ≥5 years old and reported ≥4 symptoms that were unexplained for ≥3-months. Symptom profiles across six functional domains were recorded: (1) executive dysfunction, (2) sleep disturbances, (3) autonomic dysregulation, (4) somatization, (5) digestive symptoms, and (6) emotional dysregulation. ACEs were scored for all patients. Results: Seventeen patients reported ≥4 medical symptoms. Somatization, sleep disturbances, and emotional dysregulation occurred in 100% patients, with executive dysfunction (94%), autonomic dysregulation (76%), and digestive problems (71%) in the majority. Forty-two children reported ≥1 ACE, but children with ≥4 symptoms were more likely to report ACEs compared to other children (88% vs. 33%; p &lt; 0.0001) and had a higher median total ACE score (3 vs. 1; p &lt; 0.001). Conclusions: Children with multiple medical symptoms should be screened for potential exposure to ACEs. A clinical profile of symptoms across multiple functional domains suggests putative neurobiological mechanisms involving stress and nervous system dysregulation that require further study

Ketamine analgesia for inflammatory pain in neonatal rats: a factorial randomized trial examining long-term effects-1

0.05.<p><b>Copyright information:</b></p><p>Taken from "Ketamine analgesia for inflammatory pain in neonatal rats: a factorial randomized trial examining long-term effects"</p><p>http://www.behavioralandbrainfunctions.com/content/4/1/35</p><p>Behavioral and Brain Functions : BBF 2008;4():35-35.</p><p>Published online 7 Aug 2008</p><p>PMCID:PMC2527299.</p><p></p

Ketamine analgesia for inflammatory pain in neonatal rats: a factorial randomized trial examining long-term effects-7

0.05.<p><b>Copyright information:</b></p><p>Taken from "Ketamine analgesia for inflammatory pain in neonatal rats: a factorial randomized trial examining long-term effects"</p><p>http://www.behavioralandbrainfunctions.com/content/4/1/35</p><p>Behavioral and Brain Functions : BBF 2008;4():35-35.</p><p>Published online 7 Aug 2008</p><p>PMCID:PMC2527299.</p><p></p