P2 receptors in atherosclerosis and postangioplasty restenosis

Atherosclerosis is an immunoinflammatory process that involves complex interactions between the vessel wall and blood components and is thought to be initiated by endothelial dysfunction [Ross (Nature 362:801–09, 1993); Fuster et al. (N Engl J Med 326:242–50, 1992); Davies and Woolf (Br Heart J 69:S3–S11, 1993)]. Extracellular nucleotides that are released from a variety of arterial and blood cells [Di Virgilio and Solini (Br J Pharmacol 135:831–42, 2002)] can bind to P2 receptors and modulate proliferation and migration of smooth muscle cells (SMC), which are known to be involved in intimal hyperplasia that accompanies atherosclerosis and postangioplasty restenosis [Lafont et al. (Circ Res 76:996–002, 1995)]. In addition, P2 receptors mediate many other functions including platelet aggregation, leukocyte adherence, and arterial vasomotricity. A direct pathological role of P2 receptors is reinforced by recent evidence showing that upregulation and activation of P2Y2 receptors in rabbit arteries mediates intimal hyperplasia [Seye et al. (Circulation 106:2720–726, 2002)]. In addition, upregulation of functional P2Y receptors also has been demonstrated in the basilar artery of the rat double-hemorrhage model [Carpenter et al. (Stroke 32:516–22, 2001)] and in coronary artery of diabetic dyslipidemic pigs [Hill et al. (J Vasc Res 38:432–43, 2001)]. It has been proposed that upregulation of P2Y receptors may be a potential diagnostic indicator for the early stages of atherosclerosis [Elmaleh et al. (Proc Natl Acad Sci U S A 95:691–95, 1998)]. Therefore, particular effort must be made to understand the consequences of nucleotide release from cells in the cardiovascular system and the subsequent effects of P2 nucleotide receptor activation in blood vessels, which may reveal novel therapeutic strategies for atherosclerosis and restenosis after angioplasty

Constitutive Model for Thermal Compaction of Clayey Geomaterials and Application to COx Claystone

International audienceClay formations present very favourable conditions for the long-term containment of radioactive waste due to their low hydraulic conductivity, high radionuclide retention capacity and limited fracturing in their natural state. But it is also due to the very low permeabilities of clays and claystone that drained conditions occur only at very slow temperature increases. The response is then partially drained or undrained with the consequence of thermal pressurisation induced by the thermal gradient. Furthermore, thermo-hydro-mechanical characterisations under drained and undrained conditions carried out on samples of the Callovo-Oxfordian (COx) clay formation and in situ experiments performed by Andra at the Meuse/Haute-Marne underground research laboratory (LS M/HM) have also highlighted the strongly coupled and complex thermo-hydro-mechanical processes of this material. In particular, the volume changes of the COx claystone, subjected to a temperature rise under a constant isotropic stress close to the in situ conditions of the LS M/HM laboratory in saturated and drained conditions, were highlighted. A behaviour comparable to that of over-consolidated clays depending on temperature is then experimentally observed, i.e. thermoelastic expansion followed by thermoplastic contraction: the transition temperature between these two volumetric deformation mechanisms would correspond to the maximum temperature value undergone by the COx claystone during its geological history. Based on the extensive literature on the thermomechanical behaviour of clays and clayey soils, recent thermo-hydro-mechanical tests conducted on COx samples, as well as the database on the instantaneous behaviour of COx claystone, a constitutive model for the thermomechanical behaviour of COx claystone is proposed, then implemented in a commercial computation code. The transverse isotropic elastic and then elastoplastic instantaneous behaviour (beyond the elastic limit) up to the peak strength of the COx claystone, thermoplastic and hydrostatic compactions are taken into account. The model is first validated on triaxial and hydrostatic paths. The simulation of one of the drained hydrostatic stress heating tests performed by Braun et al. verified that the proposed model was able to reproduce the thermal compaction phenomenon highlighted by the authors and to show its operational character

Effect of mechanical non-linearities on the thermal-hydraulic-mechanical response of a geological repository

International audienceIn France, the National Radioactive Waste Management Agency (Andra) oversees the study ofa disposal for intermediate-level long-lived (IL-LLW) and high-level activity radioactive waste(HLW) in a deep claystone formation (Callovo-Oxfordian claystone, COx) in the frameworkof Cigéo project. Several in situ and laboratory THM characterization studies have beenundertaken in this formation since 2000. In parallel, theoretical analyses, constitutive modelsand numerical modelings have been developed to describe different processes during the lifeof the disposal. This paper presents a regularized anisotropic elastoplastic and damage modelincluding both non-linear short and long terms response. The influence of damage andfracturation on the transport and viscous properties are considered. The proposed model wasimplemented with a regularization scheme based on the non-local implicit gradient in ComsolMultiphysics®. After validating the model on simple stress paths, its operational nature issuccessfully evidenced on the GCS drift for which the in situ observations are the mostchallenging to reproduce. It is shown that the model is able of reproducing the measured porepressure as well as the drift convergences. Importantly, the predicted extent of damaged zonesaround the drift is consistent with the in situ observations. Secondly, the proposed model isapplied to study the THM behavior of a HLW repository. The role of the non-linear behaviorof the COx claystone on the THM responses in the near and far fields, is herein highlighted inthe framework of a benchmarking exercise within the European program EURAD HITEC

Effect of short- and long-term nonlinear behaviour on the thermoporomechanical pressurisation in COx claystone

International audienceThis study focuses on assessing the effect of short- and long-term nonlinear deformation (plasticity and creep) on the thermo-hydro-mechanical (THM) responses of Callovo-Oxfordian (COx) claystone, considered as the host formation for the geological radioactive waste disposal in France, if it is licensed. The temperature increase due to heat emitted from the waste package induces a pore pressure rise in low permeability porous rocks such as the COx claystone, due to the difference in the thermal expansion coefficients between water and the argillaceous skeleton. This phenomenon has been evidenced by laboratory and in situ heating experiments. Recently, the key THM phenomena taking place around the high-level radioactive waste (HLW) repository based on the French concept, have been investigated using a thermoporoelasticity approach. In this paper, certain nonlinearities observed in the mechanical behaviour of the COx claystone have been considered in the evaluation of these THM processes. Three numerical simulations (thermoporoelastic, thermoporoelastoplastic and thermoporoelastoviscoplastic) are performed using Comsol Multiphysics code, in which the time-dependent behaviour of the COx is described by a power law whereas the elastoplastic behaviour is modelled by a strain hardening with a Hoek-Brown criterion and a non-associative flow rule. The role of elastoplastic and viscoplastic parts of deformations on the temperature, pore pressure and stresses time evolution in the far-field, is highlighted

A Bayesian network approach to the study of historical epidemiological databases: modelling meningitis outbreaks in the Niger

OBJECTIVE: To develop a tool for evaluating the risk that an outbreak of meningitis will occur in a particular district of the Niger after outbreaks have been reported in other, specified districts of the country. METHODS: A Bayesian network was represented by a graph composed of 38 nodes (one for each district in the Niger) connected by arrows. In the graph, each node directly influenced each of the "child" nodes that lay at the ends of the arrows arising from that node, according to conditional probabilities. The probabilities between "influencing" and "influenced" districts were estimated by analysis of databases that held weekly records of meningitis outbreaks in the Niger between 1986 and 2005. For each week of interest, each district was given a Boolean-variable score of 1 (if meningitis incidence in the district reached an epidemic threshold in that week) or 0. FINDINGS: The Bayesian network approach provided important and original information, allowing the identification of the districts that influence meningitis risk in other districts (and the districts that are influenced by any particular district) and the evaluation of the level of influence between each pair of districts. CONCLUSION: Bayesian networks offer a promising approach to understanding the dynamics of epidemics, estimating the risk of outbreaks in particular areas and allowing control interventions to be targeted at high-risk areas

Clustering mesoscale convective systems with laser-based water vapor delta O-18 monitoring in Niamey (Niger)

The isotopic composition of surface water vapor (delta(v)) has been measured continuously in Niamey along with the isotopic composition of event-based precipitation (delta(p)) since 2010. We investigate the evolution of water vapor and precipitation isotope ratios during rain events of the 2010, 2011, and 2012 monsoon periods. We establish a classification of rain systems into three types based on the delta(v) temporal evolution. We find that 51% of rain events (class A) exhibit a sharp decrease in delta O-18(v) in phase with the surface air temperature drop, leading to a depletion of water vapor by - 1.9% on average during rainfall. Twenty-nine percent of rain events (class B) show a similar decrease in delta O-18(v) in phase with the temperature drop but are characterized by a progressive enrichment of the vapor in the stratiform region, resulting in a depletion of water vapor by -1.2% on average during rainfall. The last 20% of the rain events (class C) are associated with a progressive increase in delta O-18(v) during rainfall (+0.8%). We also examine the temporal evolution of water vapor deuterium excess (d(v)) which shows a sharp increase as delta O-18(v) decreases, followed by a progressive decrease in the stratiform part for classes A and B. Using a basic box model, we examine for each class the respective roles that mesoscale subsidence and rain evaporation play on the evolution of delta O-18(v). We show that those two processes are dominant for class A, whereas other processes may exert a major role on delta O-18(v) for classes B and C

A Regularised Anisotropic Elastoplastic Damage and Viscoplastic Model and Its Hydromechanical Application to a Meuse/Haute-Marne URL Drift

International audienceClay formations are one of the options currently being considered for the storage of radioactive wastes worldwide. In France, the National Radioactive Waste Management Agency (Andra) operates the Meuse/Haute-Marne Underground Research Laboratory in the Callovo-Oxfordian (COx) clay formation to assess the feasibility and safety of an industrial radioactive waste repository. A good level of understanding of the thermo-hydromechanical behaviour of the host rock is paramount for the safety assessment. A new anisotropic elastoplastic damage and viscoplastic model is proposed to describe the hydromechanical behaviour of the COx claystone based on a large dataset of experimental evidence. The model is based on the Hoek and Brown criterion and considers recent findings of the COx hydromechanical behaviour. The key mechanisms considered are: plastic strain hardening prior to reaching the peak strength, a post-peak behaviour characterised by strain softening in the frame of continuum damage mechanics and a residual stage represented by a perfectly plastic behaviour. Time-dependent deformations are also included based on a creep model, which in this work is coupled with damage. The proposed model was implemented with a regularisation scheme based on the non-local implicit gradient in Comsol Multiphysics® with the purpose of performing THM modelling (1D, 2D and 3D) in the framework of the Cigéo project. The numerical implementation is first validated based on several simulations of creep tests at different deviatoric stress and triaxial compression tests at different confining pressures and angles between the loading direction and the bedding, α. Then, the GCS drift hydromechanical behaviour is simulated considering transverse isotropic conditions. It is shown that the model is capable of reproducing the measured peak of pore pressure in sensors near the GCS wall as well as the drift convergence. Importantly, the predicted extent of damaged zones around the drift is consistent with the in situ observations. The impact of damage on the time-dependent behaviour and the permeability was investigated numerically. It was found that the magnitude and anisotropy of drift convergence and the pore pressure drop are sensitive to this coupling and the best agreement was obtained when this effect was taken into account. Finally, the performance of the regularisation scheme is demonstrated with a set of simulations of the drift with different mesh refinements. It is concluded that the proposed model captures the key features of the hydromechanical behaviour of the COx claystone