المؤلفون: Benipal, Simranjeet, Kuppermann, Nathan, Tancredi, Daniel J, Rivara, Frederick P, Wang, Jin, Nishijima, Daniel K

المصدر: American Journal of Physical Medicine & Rehabilitation. 101(5)

مصطلحات موضوعية: Allied Health and Rehabilitation Science, Health Sciences, Clinical Research, Neurosciences, Childhood Injury, Traumatic Head and Spine Injury, Rehabilitation, Unintentional Childhood Injury, Physical Injury - Accidents and Adverse Effects, Brain Disorders, Traumatic Brain Injury (TBI), Pediatric, Injuries and accidents, Good Health and Well Being, Brain Injuries, Traumatic, Child, Humans, Linear Models, Outcome Assessment, Health Care, Prospective Studies, Quality of Life, Brain Injuries, Traumatic, Pediatrics, Clinical Sciences, Human Movement and Sports Sciences, Clinical sciences, Allied health and rehabilitation science, Sports science and exercise

الوصف: AbstractA previous study demonstrated that the Pediatric Quality of Life Inventory, a health-related quality-of-life instrument consisting of physical and psychosocial domain scores, reliably differentiates between children with varying severities of traumatic brain injuries (N = 729) 3, 12, and 24 mos after injury. However, the Pediatric Quality of Life Inventory physical domain score alone may simplify evaluation outcomes in physical rehabilitation and clinical research when comparing different trauma interventions. Therefore, we performed a secondary analysis to evaluate and compare the discriminative capacity of traumatic brain injury severity for changes in the overall Pediatric Quality of Life Inventory or the Pediatric Quality of Life Inventory physical domain score alone. We used linear mixed models to assess the change of outcome scores from baseline compared with arm-injury controls. Somers' D was calculated to compare discriminatory capacity with injury severity as a predictor of change in Pediatric Quality of Life Inventory outcome scores. We found that traumatic brain injury severity in children can be differentiated by the Pediatric Quality of Life Inventory physical domain score alone. However, at all follow-up time points, traumatic brain injury severity had higher discriminatory capacity for changes in the overall Pediatric Quality of Life Inventory. Our results suggest that the overall Pediatric Quality of Life Inventory should be used preferentially in children with traumatic brain injuries, although further investigation of the physical domain is warranted in conditions where physical injuries may predominate.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/33j552dnTest

المؤلفون: Nishijima, Daniel K, Gosdin, Melissa, Naz, Hiba, Tancredi, Daniel J, Hewes, Hilary A, Myers, Sage R, Stanley, Rachel M, Adelson, P David, Burd, Randall S, Finkelstein, Yaron, VanBuren, John, Casper, T Charles, Kuppermann, Nathan, Network, the TIC-TOC Collaborators of the Pediatric Emergency Care Applied Research

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Physical Injury - Accidents and Adverse Effects, Clinical Research, Neurosciences, Brain Disorders, Clinical Trials and Supportive Activities, Pediatric, Good Health and Well Being, Child, Emergency Medicine, Female, Humans, Intracranial Hemorrhages, Male, Outcome Assessment, Health Care, Qualitative Research, Quality of Life, Randomized Controlled Trials as Topic, Surveys and Questionnaires, Children, Trauma, Tranexamic acid, Outcome measure, Consensus, Pediatric Quality of Life, TIC-TOC Collaborators of the Pediatric Emergency Care Applied Research Network, Emergency & Critical Care Medicine, Clinical sciences

الوصف: ObjectiveWe evaluated the acceptability of the Pediatric Quality of Life Inventory (PedsQL) and other outcomes as the primary outcomes for a pediatric hemorrhagic trauma trial (TIC-TOC) among clinicians.MethodsWe conducted a mixed-methods study that included an electronic questionnaire followed by teleconference discussions. Participants confirmed or rejected the PedsQL as the primary outcome for the TIC-TOC trial and evaluated and proposed alternative primary outcomes. Responses were compiled and a list of themes and representative quotes was generated.Results73 of 91 (80%) participants completed the questionnaire. 61 (84%) participants agreed that the PedsQL is an appropriate primary outcome for children with hemorrhagic brain injuries. 32 (44%) participants agreed that the PedsQL is an acceptable primary outcome for children with hemorrhagic torso injuries, 27 (38%) participants were neutral, and 13 (18%) participants disagreed. Several themes were identified from responses, including that the PedsQL is an important and patient-centered outcome but may be affected by other factors, and that intracranial hemorrhage progression assessed by brain imaging (among patients with brain injuries) or blood product transfusion requirements (among patients with torso injuries) may be more objective outcomes than the PedsQL.ConclusionsThe PedsQL was a well-accepted proposed primary outcome for children with hemorrhagic brain injuries. Traumatic intracranial hemorrhage progression was favored by a subset of clinicians. A plurality of participants also considered the PedsQL an acceptable outcome for children with hemorrhagic torso injuries. Blood product transfusion requirement was favored by fewer participants.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/87f3455vTest
https://escholarship.org/content/qt87f3455v/qt87f3455v.pdfTest

المؤلفون: Glaser, Nicole, Chu, Steven, Hung, Benjamin, Fernandez, Luis, Wulff, Heike, Tancredi, Daniel, ODonnell, Martha E

المصدر: BMJ Open Diabetes Research & Care. 8(2)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Diabetes, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Animals, Cytokines, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Diabetic Ketoacidosis, Humans, Hyperglycemia, Rats, diabetes mellitus, type 1, diabetic ketoacidosis, brain edema, Clinical sciences, Public health

الوصف: Cognitive decline is common in patients with type 1 diabetes and has been attributed to the effects of chronic hyperglycemia and severe hypoglycemia. Diabetic ketoacidosis (DKA) has only recently been suspected to be involved in causing cognitive decline. We hypothesized that DKA triggers both acute and chronic neuroinflammation, contributing to brain injury. We measured concentrations of cytokines, chemokines and matrix metalloproteinases (MMP) in serum and brain tissue lysates in juvenile rats during and after DKA (during acute DKA, 24 hours and 7 days after DKA), and compared these to healthy controls and hyperglycemic controls. We also measured cytokine, chemokine and MMP concentrations in serum and brain tissue of adult rats (70 days) that had experienced DKA as juveniles and compared these measurements to those of adult diabetic rats without exposure to DKA. During acute DKA in the juvenile rats, serum concentrations of CCL3, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and MMP-9 were significantly increased. Serum concentrations of IL-2 and IL-17A increased 7 days after DKA recovery. In brain tissue lysates, concentrations of CCL3, CCL5, interferon (IFN)-γ and MMP-9 were significantly elevated during acute DKA. In adult rats that had DKA as juveniles (28 days previously), serum concentrations of IL-1ß and brain concentrations of IL-10 and IL-12p70 were elevated in comparison to diabetic rats without prior DKA. Composite scores for highly correlated cytokines and chemokines (mean z-scores for IL-10, IL-1ß, TNF-α, IL-17A, IFN-γ, CXCL-1 and CCL5) were also significantly elevated in adult rats with prior DKA. These data confirm that DKA causes acute systemic inflammation and neuroinflammation in a rat model. Importantly, the neuroinflammatory response triggered by DKA is long-lasting, suggesting the possibility that DKA-induced chronic neuroinflammation could contribute to long-term cognitive decline in individuals with diabetes.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/07w7s856Test

المؤلفون: Dhir, Ashish, Bruun, Donald A, Guignet, Michelle, Tsai, Yi‐Hua, González, Eduardo, Calsbeek, Jonas, Vu, Joan, Saito, Naomi, Tancredi, Daniel J, Harvey, Danielle J, Lein, Pamela J, Rogawski, Michael A

المصدر: Annals of the New York Academy of Sciences. 1480(1)

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Agricultural, Veterinary and Food Sciences, Biomedical and Clinical Sciences, Brain Disorders, Neurosciences, Epilepsy, Neurodegenerative, Animals, Behavior, Animal, Drug Therapy, Combination, Electroencephalography, Isoflurophate, Male, Midazolam, Nitriles, Pregnanolone, Pyridones, Rats, Rats, Sprague-Dawley, Status Epilepticus, organophosphate nerve agent, status epilepticus, AMPA receptor antagonist, GABA(A)receptor positive allosteric modulator, neuroactive steroid, benzodiazepine, GABAA receptor positive allosteric modulator, General Science & Technology

الوصف: Combinations of midazolam, allopregnanolone, and perampanel were assessed for antiseizure activity in a rat diisopropylfluorophosphate (DFP) status epilepticus model. Animals receiving DFP followed by atropine and pralidoxime exhibited continuous high-amplitude rhythmical electroencephalography (EEG) spike activity and behavioral seizures for more than 5 hours. Treatments were administered intramuscularly 40 min after DFP. Seizures persisted following midazolam (1.8 mg/kg). The combination of midazolam with either allopregnanolone (6 mg/kg) or perampanel (2 mg/kg) terminated EEG and behavioral status epilepticus, but the onset of the perampanel effect was slow. The combination of midazolam, allopregnanolone, and perampanel caused rapid and complete suppression of EEG and behavioral seizures. In the absence of DFP, animals treated with the three-drug combination were sedated but not anesthetized. Animals that received midazolam alone exhibited spontaneous recurrent EEG seizures, whereas those that received the three-drug combination did not, demonstrating antiepileptogenic activity. All combination treatments reduced neurodegeneration as assessed with Fluoro-Jade C staining to a greater extent than midazolam alone, and most reduced astrogliosis as assessed by GFAP immunoreactivity but had mixed effects on markers of microglial activation. We conclude that allopregnanolone, a positive modulator of the GABAA receptor, and perampanel, an AMPA receptor antagonist, are potential adjuncts to midazolam in the treatment of benzodiazepine-refractory organophosphate nerve agent-induced status epilepticus.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8bf600d3Test

المؤلفون: Yuen, Natalie Y, Chechneva, Olga V, Chen, Yi-Je, Tsai, Yi-Chen, Little, Logan K, Dang, James, Tancredi, Daniel J, Conston, Jacob, Anderson, Steven E, O’Donnell, Martha E

المصدر: Cerebrovascular and Brain Metabolism Reviews. 39(9)

مصطلحات موضوعية: Brain Disorders, Stroke, Neurosciences, Diabetes, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Animals, Blood-Brain Barrier, Brain Edema, Cattle, Cell Line, Hyperglycemia, Infarction, Middle Cerebral Artery, Male, Rats, Rats, Sprague-Dawley, Sodium-Hydrogen Exchangers, Sodium-Potassium-Chloride Symporters, Streptozocin, Blood-brain barrier, brain edema, cerebral ischemia, hyperglycemia, sodium transporters, Blood–brain barrier

الوصف: Cerebral edema is exacerbated in diabetic ischemic stroke through poorly understood mechanisms. We showed previously that blood-brain barrier (BBB) Na-K-Cl cotransport (NKCC) and Na/H exchange (NHE) are major contributors to edema formation in normoglycemic ischemic stroke. Here, we investigated whether hyperglycemia-exacerbated edema involves changes in BBB NKCC and NHE expression and/or activity and whether inhibition of NKCC or NHE effectively reduces edema and injury in a type I diabetic model of hyperglycemic stroke. Cerebral microvascular endothelial cell (CMEC) NKCC and NHE abundances and activities were determined by Western blot, radioisotopic flux and microspectrofluorometric methods. Cerebral edema and Na in rats subjected to middle cerebral artery occlusion (MCAO) were assessed by nuclear magnetic resonance methods. Hyperglycemia exposures of 1-7d significantly increased CMEC NKCC and NHE abundance and activity. Subsequent exposure to ischemic factors caused more robust increases in NKCC and NHE activities than in normoglycemic CMEC. MCAO-induced edema and brain Na uptake were greater in hyperglycemic rats. Intravenous bumetanide and HOE-642 significantly attenuated edema, brain Na uptake and ischemic injury. Our findings provide evidence that BBB NKCC and NHE contribute to increased edema in hyperglycemic stroke, suggesting that these Na transporters are promising therapeutic targets for reducing damage in diabetic stroke.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8ht3652mTest

المؤلفون: Hertz-Picciotto, Irva, Schmidt, Rebecca J, Walker, Cheryl K, Bennett, Deborah H, Oliver, McKenzie, Shedd-Wise, Kristine M, LaSalle, Janine M, Giulivi, Cecilia, Puschner, Birgit, Thomas, Jennifer, Roa, Dorcas L, Pessah, Isaac N, Van de Water, Judy, Tancredi, Daniel J, Ozonoff, Sally

المصدر: Environmental Health Perspectives. 126(11)

مصطلحات موضوعية: Midwifery, Biomedical and Clinical Sciences, Health Sciences, Clinical Research, Pediatric, Behavioral and Social Science, Intellectual and Developmental Disabilities (IDD), Mental Health, Prevention, Perinatal Period - Conditions Originating in Perinatal Period, Neurosciences, Brain Disorders, Autism, Pediatric Research Initiative, Aetiology, 2.4 Surveillance and distribution, 2.2 Factors relating to the physical environment, 2.3 Psychological, social and economic factors, 2.1 Biological and endogenous factors, Reproductive health and childbirth, Mental health, Adult, Autism Spectrum Disorder, Biomarkers, California, Child, Preschool, Cohort Studies, Environmental Exposure, Ethnicity, Female, Humans, Infant, Longitudinal Studies, Male, Maternal Exposure, Neurodevelopmental Disorders, Pregnancy, Prospective Studies, Research Design, Environmental Sciences, Medical and Health Sciences, Toxicology, Biomedical and clinical sciences, Environmental sciences, Health sciences

الوصف: BackgroundUntil recently, environmental factors in autism spectrum disorder (ASD) were largely ignored. Over the last decade, altered risks from lifestyle, medical, chemical, and other factors have emerged through various study designs: whole population cohorts linked to diagnostic and/or exposure-related databases, large case-control studies, and smaller cohorts of children at elevated risk for ASD.ObjectivesThis study aimed to introduce the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) prospective study and its goals, motivate the enhanced-risk cohort design, describe protocols and main exposures of interest, and present initial descriptive results for the study population.MethodsFamilies having one or more previous child with ASD were contacted before or during a pregnancy, and once the woman became pregnant, were invited to enroll. Data and biological samples were collected throughout pregnancy, at birth, and until the child's third birthday. Neurodevelopment was assessed longitudinally. The study began enrolling in 2006 and is ongoing.ResultsAs of 30 June 2018, 463 pregnant mothers have enrolled. Most mothers ([Formula: see text]) were thirty years of age or over, including 7.9% who are fourty years of age or over. The sample includes 22% Hispanic and another 25% nonHispanic Black, Asian, or multiracial participants; 24% were born outside the United States. Retention is high: 84% of participants whose pregnancies did not end in miscarriage completed the study or are still currently active. Among children evaluated at 36 months of age, 24% met criteria for ASD, and another 25% were assessed as nonASD nontypical development.ConclusionFew environmental studies of ASD prospectively obtain early-life exposure measurements. The MARBLES study fills this gap with extensive data and specimen collection beginning in pregnancy and has achieved excellent retention in an ethnically diverse study population. The 24% familial recurrence risk is consistent with recent reported risks observed in large samples of siblings of children diagnosed with ASD. https://doi.org/10.1289/EHP535Test.

الوصول الحر: https://escholarship.org/uc/item/8m37f268Test

المؤلفون: Philippat, Claire, Barkoski, Jacqueline, Tancredi, Daniel J, Elms, Bill, Barr, Dana Boyd, Ozonoff, Sally, Bennett, Deborah H, Hertz-Picciotto, Irva

المصدر: International Journal of Hygiene and Environmental Health. 221(3)

مصطلحات موضوعية: Epidemiology, Public Health, Health Sciences, Mental Health, Endocrine Disruptors, Clinical Research, Neurosciences, Behavioral and Social Science, Pediatric, Prevention, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Autism, Mental health, Reproductive health and childbirth, Adult, Autism Spectrum Disorder, Case-Control Studies, Child, Preschool, Cohort Studies, Developmental Disabilities, Female, Humans, Male, Maternal Exposure, Organophosphates, Organophosphorus Compounds, Organothiophosphates, Pesticides, Pregnancy, Prenatal Exposure Delayed Effects, Risk, Sex Factors, Autism spectrum disorder, Biomarkers, Developmental concerns, Prenatal exposure, Prospective cohort, Organophosphate pesticides, Public Health and Health Services, Toxicology, Public health

الوصف: IntroductionOrganophosphates are widely used pesticides that have been shown to affect child neurodevelopment. Previous studies that explored their potential effects on Autism Spectrum Disorder (ASD) relied either on proxies of external exposure or on questionnaires completed by the parents to identify autism-like behaviors but did not provide a clinical diagnosis of ASD.AimsWe studied the associations between prenatal biologic markers for exposure to organophosphate pesticides and the risk of having a child with ASD or other developmental concerns (ODC).MethodWe analyzed 203 mother-child pairs of the ongoing MARBLES (Markers of Autism Risk in Babies - Learning Early Signs) mother-child cohort, which enrolls mothers who are either pregnant or planning a pregnancy and whose expected child has an elevated risk to develop ASD. Seven metabolites of organophosphate pesticides were assessed in repeated urine samples collected during pregnancy. At 36 months, children were assessed with intruments measuring cognitive function and adaptive behaviors, and with two gold-standard diagnostic instruments for ASD: the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised. Children were classified in one of the following groups: ASD (n = 46), ODC (n = 55) and typically developing (TD, n = 102).ResultsAfter adjustment for potential confounders, organophosphate metabolite concentrations were not associated with an increased risk of ASD or ODC when boys and girls were studied together. After stratification by sex, dimethylthiophosphate (DMTP) pregnancy concentration tended to be associated with an increased ASD risk among girls (OR for a doubling in the DMTP concentration: 1.64 (95%CI, 0.95; 2.82)) but not among boys (OR: 0.84, 95%CI: 0.63; 1.11).DiscussionThis is the first study of clinically confirmed diagnoses of ASD that utilized repeated measurements of organophosphate metabolites during pregnancy to explore the associations between these pesticides and ASD risk in children. The association we observed among girls, as well as the lack of association in boys, need to be replicated in further studies with similar design and larger sample size. In light of the higher baseline risk for ASD in this cohort, generalizability to children lacking a first degree relative affected by ASD is unknown.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/16n6f6spTest
https://escholarship.org/content/qt16n6f6sp/qt16n6f6sp.pdfTest

المؤلفون: Nishijima, Daniel K, Gaona, Samuel D, Waechter, Trent, Maloney, Ric, Blitz, Adam, Elms, Andrew R, Farrales, Roel D, Montoya, James, Bair, Troy, Howard, Calvin, Gilbert, Megan, Trajano, Renee P, Hatchel, Kaela M, Faul, Mark, Bell, Jeneita M, Coronado, Victor C, Vinson, David R, Ballard, Dustin W, Tancredi, Daniel J, Garzon, Hernando, Mackey, Kevin E, Shahlaie, Kiarash, Holmes, James F

المصدر: Journal of neurotrauma. 35(5)

مصطلحات موضوعية: anticoagulants, field triage, head injuries, older adults, Physical Injury - Accidents and Adverse Effects, Clinical Research, Hematology, Clinical Sciences, Neurosciences, Neurology & Neurosurgery

الوصف: Field triage guidelines recommend transport of head-injured patients on anticoagulants or antiplatelets to a higher-level trauma center based on studies suggesting a high incidence of traumatic intracranial hemorrhage (tICH). We compared the incidence of tICH in older adults transported by emergency medical services (EMS) with and without anticoagulation or antiplatelet use and evaluated the accuracies of different sets of field triage criteria to identify tICH. This was a prospective, observational study at five EMS agencies and 11 hospitals. Older adults (≥55 years) with head trauma and transported by EMS from August 2015 to September 2016 were eligible. EMS providers completed standardized data forms and patients were followed through emergency department (ED) or hospital discharge. We enrolled 1304 patients; 1147 (88%) received a cranial computed tomography (CT) scan and were eligible for analysis. Four hundred thirty-four (33%) patients had anticoagulant or antiplatelet use and 112 (10%) had tICH. The incidence of tICH in patients with (11%, 95% confidence interval [CI] 8%-14%) and without (9%, 95% CI 7%-11%) anticoagulant or antiplatelet use was similar. Anticoagulant or antiplatelet use was not predictive of tICH on adjusted analysis. Steps 1-3 criteria alone were not sensitive in identifying tICH (27%), whereas the addition of anticoagulant or antiplatelet criterion improved sensitivity (63%). Other derived sets of triage criteria were highly sensitive (>98%) but poorly specific (

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5pd4h6pqTest

المؤلفون: Goodrich, Amanda J, Volk, Heather E, Tancredi, Daniel J, McConnell, Rob, Lurmann, Fred W, Hansen, Robin L, Schmidt, Rebecca J

المصدر: Autism Research. 11(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Applied and Developmental Psychology, Clinical and Health Psychology, Neurosciences, Psychology, Pediatric, Intellectual and Developmental Disabilities (IDD), Clinical Research, Autism, Climate-Related Exposures and Conditions, Mental Health, Brain Disorders, Prevention, Reproductive health and childbirth, Mental health, Adult, Air Pollutants, Autism Spectrum Disorder, California, Case-Control Studies, Causality, Child, Preschool, Dietary Supplements, Female, Folic Acid, Humans, Male, Maternal Exposure, Mothers, Pregnancy, Prenatal Exposure Delayed Effects, Risk, autism, ASD, folic acid, air pollution, prenatal exposure, environmental exposure, Clinical Sciences, Developmental & Child Psychology, Applied and developmental psychology, Clinical and health psychology

الوصف: Independent studies report that periconceptional folic acid (FA) may decrease the risk of autism spectrum disorder (ASD) while exposure to air pollution may increase ASD risk. We examined the joint effects of gestational FA and air pollution exposures in association with ASD. We studied 346 ASD cases and 260 typically developing controls from the CHARGE case-control study. Self-reported FA intake for each month of pregnancy was quantified. Estimates of exposure to near roadway air pollution (NRP) and criteria air pollutant measures were assigned based on maternal residential history. Among mothers with high FA intake (>800 μg) in the first pregnancy month, exposure to increasing levels of all air pollutants, except ozone, during the first trimester was associated with decreased ASD risk, while increased ASD risk was observed for the same pollutant among mothers with low FA intake (≤800 μg). This difference was statistically significant for NO2 (e.g., NO2 and low FA intake: OR = 1.53 (0.91, 2.56) vs NO2 and high FA intake: OR = 0.74 (0.46, 1.19), P-interaction = 0.04). Mothers exposed to higher levels (≥ median) of any air pollutant during the first trimester of pregnancy and who reported low FA intake were at a higher ASD risk compared to mothers exposed to lower levels of that air pollutant and who reported high first month FA intake. Joint effects showed significant (alpha

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1cj5w467Test

المؤلفون: Glaser, Nicole, Little, Christopher, Lo, Weei, Cohen, Michael, Tancredi, Daniel, Wulff, Heike, O'Donnell, Martha

المصدر: Pediatric diabetes. 18(5)

مصطلحات موضوعية: Brain, Hippocampus, Corpus Striatum, Cerebral Cortex, Microglia, Animals, Encephalitis, Diabetic Ketoacidosis, Gliosis, Bumetanide, Pyrazoles, Glial Fibrillary Acidic Protein, Nerve Tissue Proteins, Anti-Inflammatory Agents, Non-Steroidal, Potassium Channel Blockers, Random Allocation, Female, Male, Sodium Potassium Chloride Symporter Inhibitors, Small-Conductance Calcium-Activated Potassium Channels, Biomarkers, CD11b Antigen, TRAM-34, bumetanide, cerebral edema, cerebral injury, diabetic ketoacidosis, Diabetes, Brain Disorders, Neurosciences, Paediatrics and Reproductive Medicine, Endocrinology & Metabolism

الوصف: BackgroundDiabetic ketoacidosis (DKA) causes brain injuries in children ranging from subtle to life-threatening. Previous studies suggest that DKA-related brain injury may involve both stimulation of Na-K-Cl cotransport and microglial activation. Other studies implicate the Na-K-Cl cotransporter and the Ca-activated K channel KCa3.1 in activation of microglia and ischemia-induced brain edema. In this study, we determined whether inhibiting cerebral Na-K-Cl cotransport or KCa3.1 could reduce microglial activation and decrease DKA-related inflammatory changes in the brain.MethodsUsing immunohistochemistry, we investigated cellular alterations in brain specimens from juvenile rats with DKA before, during and after insulin and saline treatment. We compared findings in rats treated with and without bumetanide (an inhibitor of Na-K-Cl cotransport) or the KCa3.1 inhibitor TRAM-34.ResultsGlial fibrillary acidic protein (GFAP) staining intensity was increased in the hippocampus during DKA, suggesting reactive astrogliosis. OX42 staining intensity was increased during DKA in the hippocampus, cortex and striatum, indicating microglial activation. Treatment with TRAM-34 decreased both OX42 and GFAP intensity suggesting a decreased inflammatory response to DKA. Treatment with bumetanide did not significantly alter OX42 or GFAP intensity.ConclusionsInhibiting KCa3.1 activity with TRAM-34 during DKA treatment decreases microglial activation and reduces reactive astrogliosis, suggesting a decreased inflammatory response.

الوصول الحر: https://escholarship.org/uc/item/7729c525Test