Technical aspects of an impact acceleration traumatic brain injury rat model with potential suitability for both microdialysis and PtiO2 monitoring

This report describes technical adaptations of a traumatic brain injury (TBI) model-largely inspired by Marmarou-in order to monitor microdialysis data and PtiO2 (brain tissue oxygen) before, during and after injury. We particularly focalize on our model requirements which allows us to re-create some drastic pathological characteristics experienced by severely head-injured patients: impact on a closed skull, no ventilation immediately after impact, presence of diffuse axonal injuries and secondary brain insults from systemic origin...We notably give priority to minimize anaesthesia duration in order to tend to banish any neuroprotection. Our new model will henceforth allow a better understanding of neurochemical and biochemical alterations resulting from traumatic brain injury, using microdialysis and PtiO2 techniques already monitored in our Intensive Care Unit. Studies on efficiency and therapeutic window of neuroprotective pharmacological molecules are now conceivable to ameliorate severe head-injury treatment

Tirofiban, a Glycoprotein IIb/IIIa Antagonist, Has a Protective Effect on Decompression Sickness in Rats: Is the Crosstalk Between Platelet and Leukocytes Essential?

In its severest forms, decompression sickness (DCS) may extend systemically and/or induce severe neurological deficits, including paralysis or even death. It seems that the sterile and ischemic inflammatory phenomena are consecutive to the reaction of the bubbles with the organism and that the blood platelet activation plays a determinant role in the development of DCS. According to the hypotheses commonly put forward, the bubbles could either activate the platelets by direct contact or be the cause of abrasion of the vascular epithelium, which would expose the basal plate glycogen and then prompt the platelets to activate. The purpose of this study is to confirm anti-platelet drugs specific to GPIIb/IIIa integrin could prevent DCS, using a rat model. There is a significant difference concerning the incidence of the drug on the clinical status of the rats (p = 0.016), with a better clinical outcome for rats treated with tirofiban (TIR) compared with the control rats (p = 0.027), even if the three anti-GPIIb/IIIa agents used have limited respiratory distress. TIR limited the decrease in platelet counts following the hyperbaric exposure. TIR help to prevent from DCS. TIR is specific to GPIIb/IIIa whereas eptifibatide and abciximab could inhibit αVβ3 and αMβ2 involved in communication with the immune system. While inhibiting GPIIb/IIIa could highlight a platelet-dependent inflammatory pathway that improves DCS outcomes, we wonder whether inhibiting the αVβ3 and αMβ2 communications is not a wrong approach for limiting mortality in DCS

A New Role for TIMP-1 in Modulating Neurite Outgrowth and Morphology of Cortical Neurons

BACKGROUND:Tissue inhibitor of metalloproteinases-1 (TIMP-1) displays pleiotropic activities, both dependent and independent of its inhibitory activity on matrix metalloproteinases (MMPs). In the central nervous system (CNS), TIMP-1 is strongly upregulated in reactive astrocytes and cortical neurons following excitotoxic/inflammatory stimuli, but no information exists on its effects on growth and morphology of cortical neurons. PRINCIPAL FINDINGS:We found that 24 h incubation with recombinant TIMP-1 induced a 35% reduction in neurite length and significantly increased growth cones size and the number of F-actin rich microprocesses. TIMP-1 mediated reduction in neurite length affected both dendrites and axons after 48 h treatment. The effects on neurite length and morphology were not elicited by a mutated form of TIMP-1 inactive against MMP-1, -2 and -3, and still inhibitory for MMP-9, but were mimicked by a broad spectrum MMP inhibitor. MMP-9 was poorly expressed in developing cortical neurons, unlike MMP-2 which was present in growth cones and whose selective inhibition caused neurite length reductions similar to those induced by TIMP-1. Moreover, TIMP-1 mediated changes in cytoskeleton reorganisation were not accompanied by modifications in the expression levels of actin, betaIII-tubulin, or microtubule assembly regulatory protein MAP2c. Transfection-mediated overexpression of TIMP-1 dramatically reduced neuritic arbour extension in the absence of detectable levels of released extracellular TIMP-1. CONCLUSIONS:Altogether, TIMP-1 emerges as a modulator of neuronal outgrowth and morphology in a paracrine and autrocrine manner through the inhibition, at least in part, of MMP-2 and not MMP-9. These findings may help us understand the role of the MMP/TIMP system in post-lesion pre-scarring conditions

Highlighting of the interactions of MYD88 and NFKB1 SNPs in rats resistant to decompression sickness: toward an autoimmune response

Decompression sickness (DCS) with neurological disorders includes an inappropriate inflammatory response which degenerates slowly, even after the disappearance of the bubbles. There is high inter-individual variability in terms of the occurrence of DCS that could have been mastered by the selection and then the breeding of DCS-resistant rats. We hypothesized the selection of single-nucleotide polymorphisms (SNPs) linked to autoimmunity operated upon a generation of a DCS-resistant strain of rats. We used the candidate gene approach and targeted SNPs linked to the signaling cascade that directly regulates inflammation of innate immunity transiting by the Toll-like receptors. Twenty candidate SNPs were investigated in 36 standard rats and 33 DCS-resistant rats. For the first time, we identify a diplotype (i.e., with matched haplotypes)—when coinherited—that strengthens protection against DCS, which is not strictly homozygous and suggests that a certain tolerance may be considered. We deduced an ideal haplotype of six variants from it (MyD88_50-T, _49-A, _97-C coupled to NFKB_85-T, _69-T, _45-T) linked to the resistant phenotype. Four among the six identified variants are located in pre- and/or post-transcriptional areas regulating MyD88 or NFKB1 expression. Because of missense mutations, the other two variants induce a structural change in the NFKB1 protein complex including one damage alteration according to the Missense3D algorithm. In addition to the MyD88/NFKB1 haplotype providing rats with a strong resistance to DCS, this also highlights the importance that the immune response, here linked to the genetic heritage, can have in the development of DCS and offer a new perspective for therapeutic strategies

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Narcose à l'azote (modulation de la neurotransmission striatale chez le rat et implication des canaux potassiques TREK-1 chez la souris)

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Études métaboliques et neurochimiques du traumatisme crânien grave (modèle animal et aspects cliniques)

L'objectif de cette thèse était de mieux connaître les mécanismes liés au traumatisme crânien grave chez l'Homme. Pour cela, nous avons combiné deux techniques innovantes, la microdialyse intracérébrale et la mesure de la pression tissulaire en oxygène, permettant l'étude des lésions secondaires neurochimiques et métaboliques, directement au cœur du cerveau de patients traumatisés crâniens en Unités de Soins Intensifs. Ce monitorage nous a ainsi permis de vérifier l'efficacité neuroprotectrice réelle de protocoles thérapeutiques et de molécules pharmacologiques chez ces patients. Le modèle animal de traumatisme crânien, mis au point au cours de ce travail, et incluant le même monitorage spécifique, a caractérisé les altérations neurochimiques post-traumatiques ultra-précoces. L'utilisation d'un modèle humain de cerveau sain, au cours de gestes de biopsies tumorales per-opératoires, nous a par ailleurs permis de comparer deux protocoles d'anesthésie (sevoflurane, propofol)LYON1-BU.Sciences (692662101) / SudocSudocFranceF

Human recombinant tissue-plasminogen activator (alteplase): why not use the ‘human' dose for stroke studies in rats?

Since a pioneer work that has shown in vitro that the rat's fibrinolytic system is 10-fold less sensitive to recombinant tissue-plasminogen activator (rtPA) than the human system, most preclinical studies are performed with 10 instead of 0.9 mg/kg rtPA (the clinical dose in stroke patients). In this study, we compared the effects of these doses on mean time to reperfusion, reperfusion slope, brain infarct volume and edema in a rat model of thrombo-embolic stroke. Our data provide evidence that the dose of 0.9 mg/kg rtPA is as appropriate as that of 10 mg/kg for preclinical stroke studies in rodents