Contribution of mast cells to injury mechanisms in a mouse model of pediatric traumatic brain injury.

The cognitive and behavioral deficits caused by traumatic brain injury (TBI) to the immature brain are more severe and persistent than injuries to the adult brain. Understanding this developmental sensitivity is critical because children under 4 years of age of sustain TBI more frequently than any other age group. One of the first events after TBI is the infiltration and degranulation of mast cells (MCs) in the brain, releasing a range of immunomodulatory substances; inhibition of these cells is neuroprotective in other types of neonatal brain injury. This study investigates for the first time the role of MCs in mediating injury in a P7 mouse model of pediatric contusion-induced TBI. We show that various neural cell types express histamine receptors and that histamine exacerbates excitotoxic cell death in primary cultured neurons. Cromoglycate, an inhibitor of MC degranulation, altered the inflammatory phenotype of microglia activated by TBI, reversing several changes but accentuating others, when administered before TBI. However, without regard to the time of cromoglycate administration, inhibiting MC degranulation did not affect cell loss, as evaluated by ventricular dilatation or cleaved caspase-3 labeling, or the density of activated microglia, neurons, or myelin. In double-heterozygous cKit mutant mice lacking MCs, this overall lack of effect was confirmed. These results suggest that the role of MCs in this model of pediatric TBI is restricted to subtle effects and that they are unlikely to be viable neurotherapeutic targets. © 2016 Wiley Periodicals, Inc.

Association between functional gastrointestinal disorders and migraine in children and adolescents: a case-control study.

BACKGROUND: Functional gastrointestinal disorders and migraine are both common causes of medical attention. We have previously shown an association between migraine and infant colic. In this case-control study, we aimed to establish whether there is an association between migraine and other functional gastrointestinal disorders in children and adolescents. METHODS: We included children and adolescents aged 6-17 years presenting to the emergency department of four tertiary hospitals in France and Italy. Patients diagnosed with either migraine or tension-type headache by the hospital's paediatric neurologist were enrolled as cases. Patients presenting to the emergency department with minor trauma and no history of recurrent headache were enrolled as controls. Investigators masked to a patient's group allocation diagnosed functional gastrointestinal disorders using the Rome III diagnostic criteria. Univariable and multivariable analyses were done to identify specific disorders and baseline factors associated with migraines and tension-type headache. FINDINGS: Between Nov 1, 2014, and Jan 31, 2015, we enrolled 648 controls and 424 cases (257 patients with migraine and 167 with tension-type headache). 83 (32%) children and adolescents in the migraine group were diagnosed with functional gastrointestinal disorders compared with 118 (18%) in the control group (p<0·0001). Multivariable logistic regression showed a significant association between migraine and three gastrointestinal disorders: functional dyspepsia (odds ratio 10·76, 95% CI 3·52-32·85; p<0·0001), irritable bowel syndrome (3·47, 1·81-6·62; p=0·0002), and abdominal migraine (5·87, 1·95-17·69; p=0·002). By contrast, there was an inverse association between migraine and functional constipation (0·34, 0·14-0·84, p=0·02). 41 (25%) participants with tension-type headache had functional gastrointestinal disorders, which did not significantly differ from the prevalence of these disorders in the control group (p=0·07); no significant association was noted between any functional gastrointestinal disease and tension-type headaches. INTERPRETATION: Three abdominal-pain-related functional gastrointestinal disorders were associated with migraine in children and adolescents. These findings are of value to the diagnosis and management of these common diseases. Future studies should investigate whether antimigraine drugs are of benefit in functional gastrointestinal disorders. FUNDING: None.

Blood-brain barrier dysfunction in disorders of the developing brain.

Disorders of the developing brain represent a major health problem. The neurological manifestations of brain lesions can range from severe clinical deficits to more subtle neurological signs or behavioral problems and learning disabilities, which often become evident many years after the initial damage. These long-term sequelae are due at least in part to central nervous system immaturity at the time of the insult. The blood-brain barrier (BBB) protects the brain and maintains homeostasis. BBB alterations are observed during both acute and chronic brain insults. After an insult, excitatory amino acid neurotransmitters are released, causing reactive oxygen species (ROS)-dependent changes in BBB permeability that allow immune cells to enter and stimulate an inflammatory response. The cytokines, chemokines and other molecules released as well as peripheral and local immune cells can activate an inflammatory cascade in the brain, leading to secondary neurodegeneration that can continue for months or even years and finally contribute to post-insult neuronal deficits. The role of the BBB in perinatal disorders is poorly understood. The inflammatory response, which can be either acute (e.g., perinatal stroke, traumatic brain injury) or chronic (e.g., perinatal infectious diseases) actively modulates the pathophysiological processes underlying brain injury. We present an overview of current knowledge about BBB dysfunction in the developing brain during acute and chronic insults, along with clinical and experimental data.