Tomodensitométrie à temps de vol de photons

L'amélioration continuelle des technologies d'imagerie médicale supporte les spécialistes du milieu de la santé dans leur exploration des structures complexes du vivant autant pour la recherche que pour le diagnostic clinique. La tomodensitométrie (TDM) joue un rôle clé en radiologie grâce à son excellente résolution spatiale et à sa rapidité. Une des plus importantes considérations dans la conception de nouveaux systèmes de TDM est la réduction de la dose de radiations tout en maintenant la même qualité de l’image. Cette modalité d’imagerie médicale anatomique est actuellement limitée par un mauvais rapport contraste sur dose qui en fait, de loin, la plus importante contributrice aux expositions à de la radiation ionisante pour usage médical. La présence de collimateurs pour retirer les photons de rayons X qui ont diffusé dans le patient, réduit la sensibilité des détecteurs, ce qui entraîne l'utilisation d'une dose plus élevée que nécessaire. La détection des photons diffusés réduit le contraste, cause des artéfacts et génère des imprécisions dans l’image reconstruite. Ce phénomène est tout particulièrement problématique dans les scanners à faisceaux coniques où l’angle solide du système de détection favorise la détection d’un plus grand nombre de photons diffusés. Ce travail de recherche propose une nouvelle approche, la TDM par temps de vol de photons, pour identifier les photons qui ont diffusé et les retirer des données recueillies. Pour ce faire, il faut modifier le scanner TDM traditionnel pour y mettre une source de rayons X pulsée et un système de détection avec une bonne résolution temporelle qui doivent être synchronisés ensemble. La faisabilité de cette méthode a d’abord été étudiée par une série de simulations effectuées avec le logiciel GATE, puis une preuve de concept a été réalisée expérimentalement. Les résultats obtenus dans le cadre de ce travail de maîtrise démontrent une différence dans les mesures statistiques du temps de vol des photons diffusés et primaires. Cette différence est d'un ordre de grandeur suffisant pour être exploitée afin d'implémenter l'approche proposée. Pour un volume important, de la taille d'un abdomen humain, une réduction du bruit de diffusion de 296% à 4% est obtenue dans notre montage de simulation sans aucune gigue temporelle, ce qui permet d'augmenter le rapport contraste sur bruit de 110% ou de réduire la dose d'un facteur 4. Les artéfacts de coupe sont aussi réduits de 24,7% à 0,8% et l'imprécision de l'atténuation reconstruite est amélioré de -26,3% à 0,78%. Ces deux phénomènes empêchent actuellement, dans les scanners à faisceau conique commerciaux, de faire une comparaison quantitative de l'atténuation mesurée d'un patient à l'autre. Avec une gigue temporelle de 100 ps de largeur à mi-hauteur, 75% du bruit de diffusion peut être retiré avec cette technique. Cette preuve de concept permet de conclure que la TDM à temps de vol est une approche prometteuse pour la réduction du bruit de diffusion sans utiliser de collimateurs

Axon and myelin morphology in animal and human spinal cord

Characterizing precisely the microstructure of axons, their density, size and myelination is of interest for the neuroscientific community, for example to help maximize the outcome of studies on white matter (WM) pathologies of the spinal cord (SC). The existence of a comprehensive and structured database of axonal measurements in healthy and disease models could help the validation of results obtained by different researchers. The purpose of this article is to provide such a database of healthy SC WM, to discuss the potential sources of variability and to suggest avenues for robust and accurate quantification of axon morphometry based on novel acquisition and processing techniques. The article is organized in three sections. The first section reviews morphometric results across species according to range of densities and counts of myelinated axons, axon diameter and myelin thickness, and characteristics of unmyelinated axons in different regions. The second section discusses the sources of variability across studies, such as age, sex, spinal pathways, spinal levels, statistical power and terminology in regard to tracts and protocols. The third section presents new techniques and perspectives that could benefit histology studies. For example, coherent anti-stokes Raman spectroscopy (CARS) imaging can provide sub-micrometric resolution without the need for fixation and staining, while slide scanners and stitching algorithms can provide full cross-sectional area of SC. In combination with these acquisition techniques, automatic segmentation algorithms for delineating axons and myelin sheath can help provide large-scale statistics on axon morphometry

Detection of Multiple Pathways in the Spinal Cord White Matter Using Q-Ball Imaging

International audienceHigh angular resolution MRI such as q-ball imaging (QBI) allows to recover complex white matter architecture. We applied this technique to an ex vivo spinal cord of one cat using a 3T scanner, 100 directions and b-values varying from 1000 to 3000 s/mm2. As a result, QBI can retrieve crossing fibre information, where the diffusion tensor imaging approach is constrained to a single diffusion direction. To our knowledge, this is the first study demonstrating the benefits of QBI in observing longitudinal, commissural and dorso-ventral fibres in the spinal cord. It is a first step towards in vivo characterization of the healthy and injured spinal cord using high angular resolution diffusion imaging (HARDI) and QBI

Evaluation of q-ball metrics for assessing the integrity of the injured spinal cord

International audienceAssessment of spinal cord integrity following injury is crucial for evaluating the potential for functional rehabilitation [1]. Previous studies showed the benefits of diffusion tensor imaging (DTI) for the non-invasive characterization of the healthy and injured spinal cord [2]. However, biases related to the incapability of DTI to represent complex diffusion profiles suggested the use of less constraining techniques. Recently, we demonstrated that q-ball imaging (QBI) is capable of partly solving fiber crossing information in the intact spinal cord [3]. In this study, we extended the application of QBI in a model of cat partial spinal cord injury and we compared various QBI quantitative metrics to the ones used in DTI. We also proposed an original QBI-based metric to quantify the homogeneity of diffusion directions

Distinct Roles of Bcl-2 and Bcl-Xl in the Apoptosis of Human Bone Marrow Mesenchymal Stem Cells during Differentiation

Background: Adult mesenchymal stem cells (MSCs) can be maintained over extended periods of time before activation and differentiation. Little is known about the programs that sustain the survival of these cells. Principal Findings: Undifferentiated adult human MSCs (hMSCs) did not undergo apoptosis in response to different cell death inducers. Conversely, the same inducers can readily induce apoptosis when hMSCs are engaged in the early stages of differentiation. The survival of undifferentiated cells is linked to the expression of Bcl-Xl and Bcl-2 in completely opposite ways. Bcl-Xl is expressed at similar levels in undifferentiated and differentiated hMSCs while Bcl-2 is expressed only in differentiated cells. In undifferentiated hMSCs, the down-regulation of Bcl-Xl is associated with an increased sensitivity to apoptosis while the ectopic expression of Bcl-2 induced apoptosis. This apoptosis is linked to the presence of cytoplasmic Nur 77 in undifferentiated hMSCs. Significance: In hMSCs, the expression of Bcl-2 depends on cellular differentiation and can be either pro- or anti-apoptotic. Bcl-Xl, on the other hand, exhibits an anti-apoptotic activity under all conditions

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Role of Neuropilin in the antitumoral immune response of CD8+ T Lymphocytes

La compréhension récente des mécanismes impliqués dans l’échappement tumoral au système immunitaire est fondamentale. En effet, cela a permis le développement de nouvelles immunothérapies à l’origine de réponses prolongées chez les patients atteints par plusieurs types de cancers. Cependant, une majorité de patients répondent insuffisamment ou rechutent. Il est donc indispensable d’identifier les mécanismes de résistances aux immunothérapies, et de nouvelles cibles permettant d’augmenter l’activité de ces thérapeutiques.La Neuropiline-1 (Nrp1) est une glycoprotéine transmembranaire indispensable à de nombreux processus physiologiques tels que l’angiogénèse et la guidance axonale. Nous avons montré dans le laboratoire qu’elle était exprimée dans le système immunitaire, lors de la synapse immunologique puis sur les cellules T conventionnelles activées.L’objectif de ce travail était d’étudier le rôle de la Nrp1 dans la réponse anti tumorale des lymphocytes T CD8+ chez la souris et chez l’homme.Nous avons montré que la délétion de Nrp1 sur les cellules T CD8+ murines augmente la réponse anti tumorale et diminue la croissance tumorale. Les cellules T CD8+ murines délétées pour la Nrp1 ont des capacités effectrices augmentées. La Nrp1 ne pouvant pas signaliser de manière autonome, nous avons montré qu’elle forme un complexe avec PD-1 chez la souris et chez l’homme et qu’elle en module son activité. Enfin, nous avons observé un effet synergique entre l’inhibition de Nrp1 et de PD1 chez la souris, ouvrant la possibilité d’une efficacité clinique chez les patients.T follicular helper (Tfh) cells play an essential role in the development of antigen-specific B cell immunity. Tfh cells regulate the differentiation and survival of activated B cells outside and inside germinal centers (GC) of secondary lymphoid organs. They act through cognate contacts with antigen-presenting B cells, but there is no current marker to specifically identify those Tfh cells which productively interact with B cells. Here we show that neuropilin 1 (Nrp1), a cell surface receptor, is selectively expressed by a subset of Tfh cells in human secondary lymphoid organs. Nrp1 expression on Tfh cells correlates with B cell differentiation in vivo and in vitro, is transient, and can be induced upon co-culture with autologous memory B cells in a cell contact-dependent manner. Comparative analysis of ex vivo Nrp1+ and Nrp1- Tfh cells reveals gene expression modulation during activation. Finally, Nrp1 is expressed by malignant Tfh-like cells in a severe case of angioimmunoblastic T-cell lymphoma (AITL) associated with elevated terminal B cell differentiation. Thus, Nrp1 is a specific marker of Tfh cells cognate activation in humans, which may prove useful as a prognostic factor and a therapeutic target in neoplastic diseases associated with Tfh cells activity