Vibol Chhor

Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro

Highlight ► A unique catalogue of phenotype markers and neuronotoxic effects of polarised primary microglia, as a comparative tool to screen neurotherapies.

Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain

Activated microglia play a central role in the inflammatory and excitotoxic component of various acute and chronic neurological disorders. However, the mechanisms leading to their activation in the latter context are poorly understood, particularly the involvement of N‐methyl‐D‐aspartate receptors (NMDARs), which are critical for excitotoxicity in neurons. We hypothesized that microglia express functional NMDARs and that their activation would trigger neuronal cell death in the brain by modulating inflammation.

Clinical review: Initial management of blunt pelvic trauma patients with haemodynamic instability

Pelvic trauma can lead to severe, uncontrollable haemorrhage and death related to prolonged shock and multiple organ failure. Massive retroperitoneal haematoma should be assumed to be present in cases of post-traumatic haemodynamic instability associated with pelvic fracture in the absence of extrapelvic haemorrhagic lesions. This review describes the pathophysiology of retroperitoneal haematoma in trauma patient with blunt pelvic fracture, considering the roles of venous and arterial bleeding. Efficacy and safety of haemostatic procedures are also discussed, and particular attention is given to the efficacy of pelvic angiographic embolization and external pelvic fixation. A decision making algorithm is proposed for the treatment of trauma patients with pelvic fracture that takes haemodynamic status and associated lesions into account.

Neuroprotective Effects of Dexmedetomidine against Glutamate Agonist-induced Neuronal Cell Death Are Related to Increased Astrocyte Brain-derived Neurotrophic Factor Expression

Background:Brain-derived neurotrophic factor (BDNF) plays a prominent role in neuroprotection against perinatal brain injury. Dexmedetomidine, a selective agonist of &agr;2-adrenergic receptors, also provides neuroprotection against glutamate-induced damage. Because adrenergic receptor agonists can modulate BDNF expression, our goal was to examine whether dexmedetomidine’s neuroprotective effects are mediated by BDNF modulation in mouse perinatal brain injury. Methods:The protective effects against glutamate-induced injury of BDNF and dexmedetomidine alone or in combination with either a neutralizing BDNF antibody or an inhibitor of the extracellular signal-regulated kinase pathway (PD098059) were compared in perinatal ibotenate-induced cortical lesions (n = 10–20 pups/groups) and in mouse neuronal cultures (300 &mgr;M of ibotenate for 6 h). The effect of dexmedetomidine on BDNF expression was examined in vivo and in vitro with cortical neuronal and astrocyte isolated cultures. Results:Both BDNF and dexmedetomidine produced a significant neuroprotective effect in vivo and in vitro. Dexmedetomidine enhanced Bdnf4 and Bdnf5 transcription and BDNF protein cortical expression in vivo. Dexmedetomidine also enhanced Bdnf4 and Bdnf5 transcription and increased BDNF media concentration in isolated astrocyte cultures but not in neuronal cultures. Dexmedetomidine’s protective effect was inhibited with BDNF antibody (mean lesion size ± SD: 577 ± 148 &mgr;m vs. 1028 ± 213 &mgr;m, n = 14–20, P < 0.001) and PD098059 in vivo but not in isolated neuron cultures. Finally, PD098059 inhibited the increased release of BDNF induced by dexmedetomidine in astrocyte cultures. Conclusion:These results suggest that dexmedetomidine increased astrocyte expression of BDNF through an extracellular signal-regulated kinase-dependent pathway, inducing subsequent neuroprotective effects.

Poor performances of EuroSCORE and CARE score for prediction of perioperative mortality in octogenarians undergoing aortic valve replacement for aortic stenosis.

Background and objective Although results of cardiac surgery are improving, octogenarians have a higher procedure-related mortality and more complications with increased length of stay in ICU. Consequently, careful evaluation of perioperative risk seems necessary. The aims of our study were to assess and compare the performances of EuroSCORE and CARE score in the prediction of perioperative mortality among octogenarians undergoing aortic valve replacement for aortic stenosis and to compare these predictive performances with those obtained in younger patients. Methods This retrospective study included all consecutive patients undergoing cardiac surgery in our institution between November 2005 and December 2007. For each patient, risk assessment for mortality was performed using logistic EuroSCORE, additive EuroSCORE and CARE score. The main outcome measure was early postoperative mortality. Predictive performances of these scores were assessed by calibration and discrimination using goodness-of-fit test and area under the receiver operating characteristic curve, respectively. Results During this 2-year period, we studied 2117 patients, among whom 134/211 octogenarians and 335/1906 nonoctogenarians underwent an aortic valve replacement for aortic stenosis. When considering patients with aortic stenosis, discrimination was poor in octogenarians and the difference from nonoctogenarians was significant for each score (0.58, 0.59 and 0.56 vs. 0.82, 0.81 and 0.77 for additive EuroSCORE, logistic EuroSCORE and CARE score in octogenarians and nonoctogenarians, respectively, P < 0.05). Moreover, in the whole cohort, logistic EuroSCORE significantly overestimated mortality among octogenarians. Conclusion Predictive performances of these scores are poor in octogenarians undergoing cardiac surgery, especially aortic valve replacement. Risk assessment and therapeutic decisions in octogenarians should not be made with these scoring systems alone.

Role of microglia in a mouse model of paediatric traumatic brain injury.

Highlights • TBI in neonates leads to tissue loss and microglia/macrophage activation over several days.• Microglia/macrophage are predominantly of a reparatory/regenerative or immunomodulatory type after neonatal TBI.• Microglia/macrophage inhibition (using minocycline) after TBI is only transiently neuroprotective.

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.

HIP/PAP prevents excitotoxic neuronal death and promotes plasticity

Excitotoxicity plays a significant role in the pathogenesis of perinatal brain injuries. Among the consequences of excessive activation of the N‐methyl‐d‐aspartate (NMDA)‐type glutamate are oxidative stress caused by free radical release from damaged mitochondria, neuronal death and subsequent loss of connectivity. Drugs that could protect nervous tissue and support regeneration are attractive therapeutic options. The hepatocarcinoma intestine pancreas protein/pancreatitis‐associated protein I (HIP/PAP) or Reg3α, which is approved for clinical testing for the protection and regeneration of the liver, is upregulated in the central nervous system following injury or disease. Here, we examined the neuroprotective/neuroregenerative potential of HIP/PAP following excitotoxic brain injury.

Tree-based algorithm for prehospital triage of polytrauma patients

BACKGROUND There is a need for better allocation of medical resources in polytrauma, by optimizing both the over and undertriage rates. The goal of this study is to provide a new working definition for polytrauma based on the prediction of the need for specialized trauma care. METHODS This is a prospective, observational study, performed in a specialized trauma center in Paris. All consecutive patients admitted for a trauma at a major trauma center in Paris were included in the study. The primary outcome was the need for specialized trauma care as defined by the North American consensus. The explanatory variables included basic variables collected on scene. The modeling approach relied on recursive partitioning based decision trees. Its prediction performance was evaluated both internally and externally on a validation cohort, and compared to the MGAP (Mechanism, Glasgow coma scale, Age and Arterial pressure) score. MEASUREMENTS AND MAIN RESULTS 1160 patients were included in the analysis over a 3-year period (2012-2014), out of which 41% needed specialized trauma care as defined by the recent US guidelines. The decision tree outperformed the MGAP and reached an area under the receiver operating characteristic curve of 0.82 [0.79-0.84]. This optimal decision rule was associated with a sensitivity of 0.94 [0.92-0.96], a specificity of 0.48 [0.44-0.52]. A conservative decision rule (refer to a trauma center all patient with a predicted probability ≥0.34) would result in an undertriage rate of 5.7% and an overtriage of 52.3% (respectively 7% and 64% in the validation cohort). CONCLUSIONS Our tree-based decision algorithm is a user-friendly and reliable alternative to the preexisting scores, which offers good performance to predict the need for specialized trauma care.

Altered cytokine profiles in children with indeterminate quantiferon results and common infections

OBJECTIVES An increased rate of indeterminate quantiferon results (low IFN-γ release in the phytohemagglutinin-stimulated tube) has been reported in children with clinical signs compatible with tuberculosis but with the final diagnosis of infectious diseases different from tuberculosis. Here, we addressed the mechanisms involved and assessed potential alternative biomarkers to overcome indeterminate quantiferon results under these conditions. METHODS Cytokine concentrations were measured in residual plasma from quantiferon assays performed in immunocompetent children (cases, median age: 3 years 9 months) with indeterminate results and community acquired pneumonia (n = 7) or meningoencephalitis (n = 1). Controls were age-matched immunocompetent children with determinate quantiferon results (infected with mycobacterium tuberculosis, n = 7 or not, n = 8). RESULTS Lower IFN-γ expression in phytohemagglutinin-stimulated cultures from cases was accompanied by lower Th1 (IL-2, TNF-α, IP-10) and Th2 (IL-5, IL-13), but similar IL-10 secretion capacities as the controls. CONCLUSIONS A state of hyporesponsiveness that resembles the concept of immunoparalysis in severe infection was observed in children with milder infections. Though IP-10, IL-2, IL-5 and IL-13 were confirmed as promising alternative biomarkers for discriminating controls with and without tuberculosis in this study, defective induction of these biomarkers by phytohemagglutinin in cases precluded their usefulness in overcoming quantiferon indeterminate results in the above-mentioned clinical conditions.