Fonctions exécutives chez les enfants d'âge préscolaire : lien avec la réussite scolaire ultérieure et association avec les comportements de type externalisés

La présente thèse de doctorat s'intéresse aux fonctions exécutives chez les enfants d'âge préscolaire. Les fonctions exécutives (FE) peuvent se définir comme étant un ensemble de processus mentaux hypothétiques permettant le contrôle conscient de la pensée et des actions afin de guider le comportement vers un but futur. La mémoire de travail, l'inhibition et la flexibilité sont considérée comme des composantes principales des FE et on s'intéresse de plus en plus au rôle de cet aspect de la cognition sur le développement humain. Cette thèse s'attarde au rôle des FE dans le rendement scolaire en début de scolarisation et au profil de FE des enfants ayant des comportements externalisés. Un devis longitudinal sur une année du développement des enfants a été utilisé et l'échantillon initial était composé d'enfants fréquentant des classes de maternelle régulières de la région de Montréal et de Sherbrooke. Un échantillon supplémentaire d'enfants présentant des problèmes de comportement ont été intégrés par la suite à l'échantillon initial. Les données ont été recueillies lors de séances de passation de tests auprès des enfants ainsi qu'à l'aide de questionnaires remplis par les parents et les enseignantes des enfants participants. Cette thèse comporte deux articles. Le premier article porte sur le rôle des FE dans le rendement scolaire en fin de première année du primaire. L'objectif consistait à vérifier si les différentes composantes des FE mesurées en maternelle permettaient de prédire de façon unique, c'est-à-dire en neutralisant l'effet de certaines variables (connaissances préscolaires, variables affectives et variables familiales), le rendement en mathématiques et en lecture-écriture en fin de première année du primaire. Les résultats suggèrent que les FE sont associées au rendement scolaire ultérieur. Cependant, seulement la mémoire de travail a permis de prédire de façon unique le rendement scolaire, et ce, seulement en mathématiques. La mémoire de travail et l'inhibition se sont montrées associées au rendement en lecture-écriture de façon indirecte, par les comportements externalisés de l'enfant. Le second article examine le profil de FE chez des enfants ayant des comportements externalisés. L'objectif principal consistait à comparer les FE d'enfants présentant des problèmes de comportements perturbateurs avec ou sans symptômes de trouble déficit de l'attention avec ou sans hyperactivité (TDAH) et des enfants d'un groupe contrôle. Les résultats indiquent que les enfants ayant des comportements perturbateurs sans symptômes de TDAH et les enfants ayant des comportements perturbateurs avec symptômes de TDAH présentent une faiblesse au plan de l'inhibition. Cependant, seulement les enfants ayant des comportements perturbateurs avec symptômes de TDAH ont montré une faiblesse au plan de la mémoire de travail, lorsque comparés à leur pairs normatifs. Pour conclure, la discussion générale porte sur les résultats des deux articles empiriques de la thèse selon les interprétations qui peuvent en être tirées et des implications théoriques et cliniques qui sont susceptibles d'en découler. Les différentes forces et limites inhérentes à cette recherche sont également abordées ainsi que des pistes de recherches futures.\ud ______________________________________________________________________________ \ud MOTS-CLÉS DE L’AUTEUR : Fonctions exécutives, inhibition, mémoire de travail, flexibilité, rendement scolaire, trouble déficit de l'attention avec/sans hyperactivité, troubles perturbateur

Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion.

The host responds to virus infection by activating type I interferon (IFN) signaling leading to expression of IFN-stimulated genes (ISGs). Dysregulation of the IFN response results in inflammatory diseases and chronic infections. In this study, we demonstrate that IFN regulatory factor 2 (IRF2), an ISG and a negative regulator of IFN signaling, influences alphavirus neuroinvasion and pathogenesis. A Sindbis virus strain that in wild-type (WT) mice only causes disease when injected into the brain leads to lethal encephalitis in Irf2-/- mice after peripheral inoculation. Irf2-/- mice fail to control virus replication and recruit immune infiltrates into the brain. Reduced B cells and virus-specific IgG are observed in the Irf2-/- mouse brains despite the presence of peripheral neutralizing antibodies, suggesting a defect in B cell trafficking to the central nervous system (CNS). B cell-deficient μMT mice are significantly more susceptible to viral infection, yet WT B cells and serum are unable to rescue the Irf2-/- mice. Collectively, our data demonstrate that proper localization of B cells and local production of antibodies in the CNS are required for protection. The work advances our understanding of host mechanisms that affect viral neuroinvasion and their contribution to immunity against CNS infections

Meta-analyses of the associations between disinhibited social engagement behaviors and child attachment insecurity or disorganization

Children with disinhibited social engagement disorder show reduced reticence with strangers, do not check back with their caregiver after venturing away, and may willingly leave with an unfamiliar adult. The recent DSM-5 has moved away from an attachment framework to understand disinhibited social engagement behavior (DSEB) due to studies indicating its presence in previously institutionalized children even after these children are adopted and show a selective, more secure attachment with their substitute caregiver (e.g. Chisholm et al., 1998). This meta-analysis aims to clarify the size of the associations between DSEB and attachment insecurity or disorganization. It also examines whether studies effect sizes differ according to various moderators (e.g., child age, type of attachment and DSEB measures). The results (k = 24) showed that the associations between DSEB and attachment insecurity (d = 0.48) or attachment disorganization (d = 0.47) were of small magnitude. There were no publication biases. As for moderator analyses on both attachment insecurity and disorganization, the effect sizes in studies using DSEB observational measures (respectively d = 0.63 and 0.57) were of moderate magnitude and stronger than those in studies not using an observational component (respectively d = 0.28 and 0.32). Given these small-to-moderate associations, attachment can be considered a relationship process associated with DSEB, and attachment-informed interventions could be potential tools to reduce DSEB in children. Nevertheless, given the sizable unshared portion of variance between DSEB and child attachment, future studies should examine other variables related to caregiving and noncaregiving contexts to further understand DSEB

Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures

During vertebrate angiogenesis, Notch regulates the cell-fate decision between vascular tip cells versus stalk cells. Canonical Notch signaling depends on sequential proteolytic events, whereby interaction of Notch with membrane-anchored ligands triggers proteolytic processing, first by Adam10 and then presenilins. This liberates the Notch intracellular domain, allowing it to enter the nucleus and activate Notch-dependent genes. Here we report that conditional inactivation of Adam10 in endothelial cells (A10ΔEC) recapitulates the increased branching and density of the retinal vasculature that is also caused by interfering with Notch signaling. Moreover, A10ΔEC mice have additional vascular abnormalities, including aberrant subcapsular hepatic veins, enlarged glomeruli, intestinal polyps containing endothelial cell masses, abnormal endochondral ossification, leading to stunted long bone growth and increased pathological neovascularization following oxygen-induced retinopathy. Our findings support a model in which Adam10 is a crucial regulator of endothelial cell-fate decisions, most likely because of its essential role in canonical Notch signaling.status: publishe

Targeting tumor vasculature to improve antitumor activity of T cells armed ex vivo with T cell engaging bispecific antibody

Background Success of T cell immunotherapy hinges on the tumor microenvironment (TME), and abnormal tumor vasculature is a hallmark of most solid tumors and associated with immune evasion. The efficacy of T cell engaging bispecific antibody (BsAb) treatment relies on the successful trafficking and cytolytic activity of T cells in solid tumors. Normalization of tumor vasculature using vascular endothelial growth factor (VEGF) blockades could improve efficacy of BsAb-based T cell immunotherapy.Methods Anti-human VEGF (bevacizumab, BVZ) or anti-mouse VEGFR2 antibody (DC101) was used as VEGF blockade, and ex vivo armed T cells (EATs) carrying anti-GD2, anti-HER2, or anti-glypican3 (GPC3) IgG-(L)-scFv platformed BsAb were used. BsAb-driven intratumoral T cell infiltration and in vivo antitumor response were evaluated using cancer cell line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) carried out in BALB-Rag2-/-IL-2R-γc-KO (BRG) mice. VEGF expression on human cancer cell lines was analyzed by flow cytometry, and VEGF levels in mouse serum were measured using VEGF Quantikine ELISA Kit. Tumor infiltrating lymphocytes (TILs) were evaluated using flow cytometry and by bioluminescence; both TILs and tumor vasculature were studied using immunohistochemistry.Results VEGF expression on cancer cell lines increased with seeding density in vitro. BVZ significantly reduced serum VEGF levels in mice. BVZ or DC101 increased high endothelial venules (HEVs) in the TME and substantially enhanced (2.1–8.1 fold) BsAb-driven T cell infiltration into neuroblastoma and osteosarcoma xenografts, which was preferential for CD8(+) TILs versus CD4(+) TILs, leading to superior antitumor effects in multiple CDX and PDX tumor models without added toxicities.Conclusions VEGF blockade using specific antibodies against VEGF or VEGFR2 increased HEVs in the TME and cytotoxic CD8(+) TILs, significantly improving the therapeutic efficacy of EAT strategies in preclinical models, supporting the clinical investigation of VEGF blockades to further enhance BsAb-based T cell immunotherapies

Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion.

The host responds to virus infection by activating type I interferon (IFN) signaling leading to expression of IFN-stimulated genes (ISGs). Dysregulation of the IFN response results in inflammatory diseases and chronic infections. In this study, we demonstrate that IFN regulatory factor 2 (IRF2), an ISG and a negative regulator of IFN signaling, influences alphavirus neuroinvasion and pathogenesis. A Sindbis virus strain that in wild-type (WT) mice only causes disease when injected into the brain leads to lethal encephalitis in Irf2-/- mice after peripheral inoculation. Irf2-/- mice fail to control virus replication and recruit immune infiltrates into the brain. Reduced B cells and virus-specific IgG are observed in the Irf2-/- mouse brains despite the presence of peripheral neutralizing antibodies, suggesting a defect in B cell trafficking to the central nervous system (CNS). B cell-deficient μMT mice are significantly more susceptible to viral infection, yet WT B cells and serum are unable to rescue the Irf2-/- mice. Collectively, our data demonstrate that proper localization of B cells and local production of antibodies in the CNS are required for protection. The work advances our understanding of host mechanisms that affect viral neuroinvasion and their contribution to immunity against CNS infections

Endoscopic spray cryotherapy for genitourinary malignancies: safety and efficacy in a porcine model

Objective: To examine the effects and safety of using endoscopic spray cryotherapy (ESC) on bladder, ureteral, and renal pelvis urothelium in a live porcine model. Subjects and methods: ESC treatments were systematically applied to urothelial sites in the bladder, ureter, and renal pelvis of eight female Yorkshire swine in a prospective trial. Freeze–thaw cycles ranged from 5 to 60 s/cycle for one to six cycles using a 7 French cryotherapy catheter. Tissue was evaluated histologically for treatment-related effects. Acute physiologic effects were evaluated with pulse oximetry, Doppler sonography, and postmortem findings. Results: In bladder, treatment depth was inconsistent regardless of dose, demonstrating urothelial necrosis in one, muscularis propria depth necrosis in two, and full thickness necrosis in all remaining samples. In ureter, full thickness necrosis was seen in all samples, even with the shortest spray duration (5 s/cycle for six cycles or 30 s/cycle for one cycle). Treatment to the renal pelvis was complicated by adiabatic gas expansion of liquid nitrogen to its gaseous state, resulting in high intraluminal pressures requiring venting to avoid organ perforation, even at the lowest treatment settings. At a planned dose of 5 s/cycle for six cycles of the first renal pelvis animal, treatment was interrupted by sudden and unrecoverable cardiopulmonary failure after three cycles. Repeated studies replicated this event. Ultrasound and immediate necropsy confirmed the creation of a large gaseous embolism and reproducible cardiopulmonary effects. Conclusion: ESC in a porcine urothelial treatment model results in full-thickness tissue necrosis in bladder, ureter, and renal pelvis at a minimal treatment settings of 5 s/cycle for six cycles. Adiabatic gas expansion may result in fatal pyelovenous gas embolism and collateral organ injury, as seen in both animals receiving treatment to the renal pelvis in this study. These results raise safety concerns for use of ESC as a treatment modality in urothelial tissues with current device settings