Modeling the dynamics of oligodendrocyte precursor cells and the genesis of gliomas.

Oligodendrocyte precursor cells (OPCs) have remarkable properties: they represent the most abundant cycling cell population in the adult normal brain and they manage to achieve a uniform and constant density throughout the adult brain. This equilibrium is obtained by the interplay of four processes: division, differentiation or death, migration and active self-repulsion. They are also strongly suspected to be at the origin of gliomas, when their equilibrium is disrupted. In this article, we present a model of the dynamics of OPCs, first in a normal tissue. This model is based on a cellular automaton and its rules are mimicking the ones that regulate the dynamics of real OPCs. The model is able to reproduce the homeostasis of the cell population, with the maintenance of a constant and uniform cell density and the healing of a lesion. We show that there exists a fair quantitative agreement between the simulated and experimental parameters, such as the cell velocity, the time taken to close a lesion, and the duration of the cell cycle. We present three possible scenarios of disruption of the equilibrium: the appearance of an over-proliferating cell, of a deadless/non-differentiating cell, or of a cell that lost any contact-inhibition. We show that the appearance of an over-proliferating cell is sufficient to trigger the growth of a tumor that has low-grade glioma features: an invasive behaviour, a linear radial growth of the tumor with a corresponding growth velocity of less than 2 mm per year, as well a cell density at the center which exceeds the one in normal tissue by a factor of less than two. The loss of contact inhibition leads to a more high-grade-like glioma. The results of our model contribute to the body of evidence that identify OPCs as possible cells of origin of gliomas

Relationship between Plasma D-Dimer Concentration and Three-Dimensional Ultrasound Placental Volume in Women at Risk for Placental Vascular Diseases: A Monocentric Prospective Study

International audienceINTRODUCTION:The aim of this study was to correlate placental volumes deduced from three-dimensional ultrasound and virtual organ computer-aided analysis (VOCAL) software with systemic concentrations of D-dimer and soluble endothelial protein C receptor (sEPCR).METHODS:This was a monocentric experimental prospective study conducted from October 2008 to July 2009. Forty consecutive patients at risk of placental vascular pathology (PVP) recurrence or occurrence were included. Placental volumes were systematically measured three times (11-14, 16-18 and 20-22 weeks of gestation (WG)) by two independent sonographers. D-dimers and sEPCR plasma concentrations were measured using ELISA kits (Enzyme Linked ImmunoSorbent Assay).RESULTS:Eleven patients had a PVP. The plasma D-dimer level was positively correlated with placental volume (r = 0.45, p < 0.001). A smaller placental volume and placental quotient was evidenced in women who developed a PVP at the three gestational ages, and the difference was more pronounced during the third exam (20 WG). No obvious correlation could be demonstrated between the development of a PVP and the levels of D-dimer and sEPCR. There was no significant difference in the values of placental volumes measured by the two sonographers.CONCLUSION:The placenta growth could be a major determinant of the elevation of D-dimer during pregnancy. Consideration of placental volume could allow for modulation of the D-dimer concentrations for restoring their clinical interest

Evolution of the cell density versus time for cells with a fixed lifetime clock threshold.

<p>The proliferation parameter is λ = 0.05 per iteration and the lifetime threshold is <i>D</i> = 400 iterations. (a) The cells are represented by spheres whose color is correlated to the value of their lifetime clock: blue cells have been created recently and have a low lifetime clock, whereas red cells are close to the lifetime threshold. (b) Cell number versus time (average over 10 simulations, the error bars are smaller than the thickness of the line).</p

Properties of a glioma formed by the appearance of an over proliferating cell.

<p>(a) Normal (blue circles) and glioma (red circles) cell densities versus the distance to the center of space, for the glioma of <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005977#pcbi.1005977.g006" target="_blank">Fig 6</a>. Eight graphs corresponding to eight time points are represented from <i>t</i> = 0 (appearance of the first glioma cell, dark red and blue graphs), to <i>t</i> = 336 days (very light red and blue graphs), with a time interval of 42 days. (b) Temporal evolution of the mean radius of the glioma of <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005977#pcbi.1005977.g006" target="_blank">Fig 6</a>. (c) Temporal evolution of the total cell density, when an over proliferating cell appears at time <i>t</i> = 0. (d) Normal (blue lines) and tumoral (red lines) proliferating (plain curve) and disappearing (dashed curve) cell densities, in a 1 mm³ cube, where an over proliferating cell appears at time <i>t</i> = 0.</p

Total and proliferating cell densities in real gliomas.

<p>The graphs in (a) compare the mean total cell density (left) and the mean MIB-1 positive cell density (the MIB-1 positive cells are the cells that have entered the cell cycle, i.e. the proliferating cells) (right), inside (red bars) and outside (blue) real gliomas. The data come from 9 different patients, 22 samples inside the tumor (i.e. inside the signal abnormality on T2 MRI scans) and 16 samples ouside. In (b) left, a histological sample of a low-grade glioma, with a hematoxylin-eosin staining, displays a quasi-normal cell density. In (b), right, the same sample stained with the proliferation staining MIB-1, reveals a limited increase in the proliferating cell density compared to normal tissue. The detailed data have been published in [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005977#pcbi.1005977.ref011" target="_blank">11</a>].</p

Predictive value of premature atrial complex characteristics in pulmonary vein isolation for patients with paroxysmal atrial fibrillation

International audienceBackgroundPremature atrial complexes from pulmonary veins are the main triggers for atrial fibrillation in the early stages. Thus, pulmonary vein isolation is the cornerstone of catheter ablation for paroxysmal atrial fibrillation. However, the success rate remains perfectible.AimTo assess whether premature atrial complex characteristics before catheter ablation can predict pulmonary vein isolation success in paroxysmal atrial fibrillation.MethodsWe investigated consecutive patients who underwent catheter ablation for paroxysmal atrial fibrillation from January 2013 to April 2017 in two French centres. Patients were included if they were treated with pulmonary vein isolation alone, and had 24-hour Holter electrocardiogram data before catheter ablation available and a follow-up of ≥ 6 months. Catheter ablation success was defined as freedom from any sustained atrial arrhythmia recurrence after a 3-month blanking period following catheter ablation.ResultsOne hundred and three patients were included; all had an acute successful pulmonary vein isolation procedure, and 34 (33%) had atrial arrhythmia recurrences during a mean follow-up of 30 ± 15 months (group 1). Patients in group 1 presented a longer history of atrial fibrillation (71.9 ± 65.8 vs. 42.9 ± 48.4 months; P = 0.008) compared with those who were “free from arrhythmia” (group 2). Importantly, the daily number of premature atrial complexes before catheter ablation was significantly lower in group 1 (498 ± 1413 vs. 1493 ± 3366 in group 2; P = 0.028). A daily premature atrial complex cut-off number of < 670 predicted recurrences after pulmonary vein isolation (41.1% vs. 13.3%; sensitivity 88.2%; specificity 37.7%; area under the curve 0.635; P = 0.017), and was the only independent predictive criterion in the multivariable analysis (4-fold increased risk).ConclusionPreprocedural premature atrial complex analysis on 24-hour Holter electrocardiogram in paroxysmal atrial fibrillation may improve patient selection for pulmonary vein isolation.ContexteL’isolation des veines pulmonaires (IVP) est la pierre angulaire du traitement invasif de la fibrillation atriale paroxystique (FAP). Cependant, le taux de succès de cette procédure reste perfectible.ObjectifIdentifier si certaines caractéristiques des extrasystoles atriales (ESA) enregistrées sur le Holter électrocardiogramme de 24 heures précédant l’ablation constituent un facteur prédictif de succès de procédure.MéthodesTous les patients ayant eu une IVP seule pour une FAP ont été analysés entre janvier 2013 et avril 2017 au sein de deux centres français. Les critères d’inclusion étaient : les patients adressés pour une primo-ablation de FAP, disposant d’un Holter électrocardiogramme avant l’ablation, dont le suivi post-ablation était ≥ 6 mois. Le critère de jugement principal était la récidive d’une arythmie atriale après une période de blanking de 3 mois post-ablation.RésultatsCent trois patients ont été inclus, et 34 (33 %) ont récidivé après un suivi moyen de 30 ± 15 mois. Ces patients présentaient une histoire de FA plus ancienne (71,9 ± 65,8 mois vs 42,9 ± 48,4 mois; p = 0,008). Le nombre d’ESA total sur 24 heures pré-ablation était significativement plus important dans le groupe « non récidive » que dans le groupe « récidive » (1493 ± 3366 vs 498 ± 1413, respectivement; p = 0,028). Un seuil d’ESA < 670/24 heures prédisait la récidive post-IVP (sensibilité 88,2 %; spécificité 37,7 %; AUC 0,635; p = 0,017).ConclusionL’étude des ESA en pré-ablation peut potentiellement améliorer la sélection des patients pour l’ablation de FAP par IVP seule

Formation of a glioma by the appearance of an over proliferating cell.

<p>(a) Normal OPCs (blue) at equilibrium proliferate (<i>ρ</i> = 0.05/h) and differentiate, as described in the text. In (b), a newly created cell is characterized by an over-proliferating (<i>ρ</i> = 0.25/h) phenotype, in red (<i>t</i> = 0). The daughters of this abnormal cell keep the over-proliferating character. In (c) the system is represented at <i>t</i> = 1500 h = 62.5 days, the developing glioma appears in dark red; in (d) the system is represented at <i>t</i> = 3000 h = 125 days.</p

Comparison of the different scenarios of glioma appearance.

<p>(a) and (b), an immortal cell appears at time <i>t</i> = 0, (c) and (d), a cell without contact inhibition appears at time <i>t</i> = 0. (a) and (c) Temporal evolution of the total cell density. (b) and (d) Normal (blue lines) and tumoral (red lines) proliferating (plain curve) and disappearing (dashed curve) cell densities, in a 1 mm³ cube.</p

Model of an OPC and illustration of the proliferation/migration rules.

<p>(a) Schematic drawing of an OPC where the cell center and the filipodia are visible. The cell is modeled by a 100 <i>μ</i>m diameter sphere, represented by a dashed line drawn around the cell extensions. (b) A cell without overlap with other cells keeps moving with a constant velocity in the same direction. The direction of the motion changes only when the cell has overlaps with other cells. (c) The cell undergoes mitosis: a new cell is created and its center is placed at the distance <i>R</i> from the center of the first cell. (d) The two cells move in opposite direction in order to reduce the overlapping. After separation, they keep moving in the same direction, at a constant velocity.</p

Obstetrical and neonatal characteristics vary with birthweight in a cohort of 100 term newborns with symptomatic arterial ischemic stroke.

International audienceOBJECTIVES: Many questions remain regarding the mechanism of perinatal stroke. METHODS: In a series of 100 prospectively enrolled term neonates with symptomatic arterial ischemic stroke, we explored family antecedents, pregnancy and delivery conditions and clinical presenting features and distinguished features of the 50 larger infants with the remainder. Cardiac and cervical arterial imaging were performed in 70 and 51 cases. RESULTS: Previous fetal loss, first pregnancy, primiparity, twin-gestation, cesarean and traumatic delivery, neonatal distress, male sex and premature rupture of membranes were statistically more common than in the general population. Normal pregnancy proportion and mean birthweight were in the normal range, arguing against a vasculo-placental origin in the majority. Furthermore, there was an excess of large babies. The larger infants were more subject to suffer from acute perinatal events, with a trend for an excess of neonatal distress (p=0.065) and for more severe presenting features (p=0.027), while the lighter were more likely to have experienced longstanding obstetrical risk factors such as complicated pregnancy (p=0.047) and tobacco exposure (p=0.028). Cervical MR angiography showed an internal carotid occlusion in two babies, whereas echo-Doppler was always normal; in one case the two methods were discordant. Echocardiography was non-informative. INTERPRETATION: The data from this prospective cohort of neonates with stroke confirm that many obstetrical and perinatal factors are risk determinants. They also suggest that birthweight and gender may be biomarkers of two populations of neonates with different pathological mechanisms. MR angiography appears more sensitive than echo-Doppler for the exploration of the neonatal cervical vasculature