Validation de modalités d’imagerie innovantes de l’athérosclérose par cathéter intravasculaire bimodal combinant fluorescence (NIRF) et ultrasons (IVUS) couplé à l’injection locale de sondes moléculaires in vivo ciblant ICAM-1 et le collagène

Les maladies cardiovasculaires sont la principale cause de mortalité à l’échelle mondiale, dont la survenue de l’infarctus du myocarde et de la mort subite découle majoritairement de la rupture d’une plaque d’athérosclérose coronarienne vulnérable. Les modalités d’imagerie invasive contemporaines permettent d’analyser les caractéristiques anatomiques et morphologiques de la plaque d’athérome, mais ne révèlent aucune information sur la biologie de l’athérogenèse. Ainsi, l’identification des déterminant moléculaires et cellulaires définissant la plaque à haut risque de rupture est l’approche de choix afin d’améliorer nos connaissances sur la maladie coronarienne et pour l’optimisation des traitements actuels. L’objectif principal de ce projet de recherche visait à démontrer la faisabilité d’une technique d’imagerie moléculaire innovante par cathéter bimodal IVUS-NIRF couplé à l’utilisation de sondes d’imagerie ciblant spécifiquement l’inflammation (ICAM-1) et la composition de la plaque d’athérosclérose (fibres de collagène type-I non polymérisées) dans deux modèles animaux distincts de l’athérosclérose. Les résultats préliminaires contenus dans cette thèse décrivent une technique d’imagerie intravasculaire originale et novatrice permettant la détection in vivo par cathéter de biomarqueurs de l’inflammation et de la composition de la plaque d’athérosclérose à l’aide de traceurs moléculaires fluorescents spécifiques injectés en faible concentration au sein de plaques visualisées par IVUS. Permettant de discriminer avec précision le signal NIRF, le système d’imagerie par cathéter IVUS-NIRF exploité dans ce projet de recherche permet un multiplexage précis du signal NIRF suivant l’injection simultanée de sondes couplées à des fluorophores distincts, offrant la possibilité de cibler simultanément un panel de biomarqueurs à haut risque au sein d’une même plaque d’athérosclérose. Ainsi, cette application d’imagerie moléculaire in vivo est une stratégie prometteuse dont la translation en clinique permettrait d’identifier les processus biologiques clés impliqués dans l’instabilité de la plaque d’athérosclérose coronarienne humaine, un besoin à combler dans la pratique clinique.Cardiovascular disease is the leading cause of mortality worldwide, with the onset of myocardial infarction and sudden death resulting mainly from the rupture of a vulnerable coronary atherosclerotic plaque. Contemporary invasive imaging modalities enable analysis of anatomical and morphological characteristics of the atheroma plaque without providing information on the biology of atherosclerosis. Thus, the identification of molecular and cellular determinants defining high-risk plaques is a promising approach to improve our current knowledge of coronary heart disease and to optimize patient treatment. This research project aimed to demonstrate the feasibility of a novel molecular imaging technique using a custom bimodal intravascular ultrasound (IVUS) – near-infrared fluorescence (NIRF) catheter imaging system combined to local injection of labeled-specific imaging probes targeting both inflammation (ICAM-1) and plaque composition (unpolymerized type I collagen fibers) in two distinct atherosclerotic animal models. Preliminary results presented in this thesis describe an original and novel intravascular imaging technique for in vivo detection of inflammation and plaque morphology using specific fluorescent molecular tracers injected in low concentration in the vicinity of plaques visualized by IVUS. The bimodal IVUS-NIRF imaging catheter system used in this project enables accurate NIRF signal multiplexing following dual-injection of molecular probes coupled to distinct fluorophores, which might offer the possibility of targeting a panel of high-risk biomarkers simultaneously within in a single atherosclerotic plaque. Thus, this in vivo molecular imaging application is a promising strategy that could translate to future human studies with the purpose to identify key biological processes involved in human coronary atherosclerotic plaque instability, an unmet need in clinical practice

Étude des polymorphismes génétiques impliqués dans la résistance du virus de l'hépatite C au traitement

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal

Working Paper 08-08 - Welvaartsbinding van de sociale zekerheidsuitkeringen : een overzicht van de recente ontwikkelingen

Welfare programs, Social Security benefits

Near-Infrared Spectroscopy (NIRS): A Novel Tool for Intravascular Coronary Imaging

Acute coronary syndrome (ACS) arising from plaque rupture is the leading cause of mortality worldwide. Near-infrared spectroscopy (NIRS) combined with intravascular ultrasound (NIRS-IVUS) is a novel catheter-based intravascular imaging modality that provides a chemogram of the coronary artery wall, which enables the detection of lipid core and specific quantification of lipid accumulation measured as the lipid-core burden index (LCBI) in patients undergoing coronary angiography. Recent studies have shown that NIRS-IVUS can identify vulnerable plaques and vulnerable patients associated with increased risk of adverse cardiovascular events, whereas an increased coronary plaque LCBI may predict a higher risk of future cardiovascular events and periprocedural events. NIRS is a promising tool for the detection of vulnerable plaques in CAD patients, PCI-guidance procedures, and assessment of lipid-lowering therapies. Previous trials have evaluated the impact of statin therapy on coronary NIRS defined lipid cores, whereas NIRS could further be used as a surrogate end point of future ACS in phase II clinical trials evaluating novel anti-atheromatous drug therapies. Multiple ongoing studies address the different potential clinical applications of NIRS-IVUS imaging as a valuable tool for coronary plaque characterization and predictor of future coronary events in CAD patients

Synthesis, structural characterization, and chiroptical properties of planarly and axially chiral boranils

International audience2-Amino[2.2]paracyclophane reacts with salicylaldehyde or 2-hydroxyacetophenone to yield imines that then give access to a new series of boranils (8b–d) upon complexation with BF2. These novel boron-containing compounds display both planar and axial chiralities and were examined experimentally and computationally. In particular, their photophysical and chiroptical properties were studied and compared to newly prepared, simpler boranils (9a–d) exhibiting axial chirality only. Less sophisticated chiral architectures were shown to demonstrate overall stronger circularly polarized luminescence (CPL) activity

Finger creases lend a hand in Kabuki syndrome.

International audienceKabuki syndrome (KS) is a rare syndrome associating malformations with intellectual deficiency and numerous visceral, orthopedic, endocrinological, immune and autoimmune complications. The early establishment of a diagnostic of KS leads to better care of the patients and therefore prevents complications such as perception deafness, severe complications of auto-immune diseases or obesity. However, the diagnosis of KS remains difficult because based on the appreciation of facial features combined with other highly variable features. We describe a novel sign, namely the attenuation and/or congenital absence of the IPD crease of the third and fourth fingers associated with limitation of flexion of the corresponding joints, which seems to be specific of KS and could help the clinician to diagnose KS

Validating intravascular imaging with serial optical coherence tomography and confocal fluorescence microscopy

Atherosclerotic cardiovascular diseases are characterized by the formation of a plaque in the arterial wall. Intravascular ultrasound (IVUS) provides high-resolution images allowing delineation of atherosclerotic plaques. When combined with near infrared fluorescence (NIRF), the plaque can also be studied at a molecular level with a large variety of biomarkers. In this work, we present a system enabling automated volumetric histology imaging of excised aortas that can spatially correlate results with combined IVUS/NIRF imaging of lipid-rich atheroma in cholesterol-fed rabbits. Pullbacks in the rabbit aortas were performed with a dual modality IVUS/NIRF catheter developed by our group. Ex vivo three-dimensional (3D) histology was performed combining optical coherence tomography (OCT) and confocal fluorescence microscopy, providing high-resolution anatomical and molecular information, respectively, to validate in vivo findings. The microscope was combined with a serial slicer allowing for the imaging of the whole vessel automatically. Colocalization of in vivo and ex vivo results is demonstrated. Slices can then be recovered to be tested in conventional histology

Expanding the phenotype of the X-linked BCOR microphthalmia syndromes

Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia (‘Lenz’-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome (‘Lenz’) usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome

Retrospective French nationwide survey of childhood aggressive vascular anomalies of bone, 1988-2009

<p>Abstract</p> <p>Objective</p> <p>To document the epidemiological, clinical, histological and radiological characteristics of aggressive vascular abnormalities of bone in children.</p> <p>Study design</p> <p>Correspondents of the French Society of Childhood Malignancies were asked to notify all cases of aggressive vascular abnormalities of bone diagnosed between January 1988 and September 2009.</p> <p>Results</p> <p>21 cases were identified; 62% of the patients were boys. No familial cases were observed, and the disease appeared to be sporadic. Mean age at diagnosis was 8.0 years [0.8-16.9 years]. Median follow-up was 3 years [0.3-17 years]. The main presenting signs were bone fracture (n = 4) and respiratory distress (n = 7), but more indolent onset was observed in 8 cases. Lung involvement, with lymphangiectasies and pleural effusion, was the most frequent form of extraosseous involvement (10/21). Bisphosphonates, alpha interferon and radiotherapy were used as potentially curative treatments. High-dose radiotherapy appeared to be effective on pleural effusion but caused major late sequelae, whereas antiangiogenic drugs like alpha interferon and zoledrenate have had a limited impact on the course of pulmonary complications. The impact of bisphosphonates and alpha interferon on bone lesions was also difficult to assess, owing to insufficient follow-up in most cases, but it was occasionally positive. Six deaths were observed and the overall 10-year mortality rate was about 30%. The prognosis depended mainly on pulmonary and spinal complications.</p> <p>Conclusion</p> <p>Aggressive vascular abnormalities of bone are extremely rare in childhood but are lifethreatening. The impact of anti-angiogenic drugs on pulmonary complications seems to be limited, but they may improve bone lesions.</p

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old