White matter atlas of the human spinal cord with estimation of partial volume effect.

Template-based analysis has proven to be an efficient, objective and reproducible way of extracting relevant information from multi-parametric MRI data. Using common atlases, it is possible to quantify MRI metrics within specific regions without the need for manual segmentation. This method is therefore free from user-bias and amenable to group studies. While template-based analysis is common procedure for the brain, there is currently no atlas of the white matter (WM) spinal pathways. The goals of this study were: (i) to create an atlas of the white matter tracts compatible with the MNI-Poly-AMU template and (ii) to propose methods to quantify metrics within the atlas that account for partial volume effect. The WM atlas was generated by: (i) digitalizing an existing WM atlas from a well-known source (Gray's Anatomy), (ii) registering this atlas to the MNI-Poly-AMU template at the corresponding slice (C4 vertebral level), (iii) propagating the atlas throughout all slices of the template (C1 to T6) using regularized diffeomorphic transformations and (iv) computing partial volume values for each voxel and each tract. Several approaches were implemented and validated to quantify metrics within the atlas, including weighted-average and Gaussian mixture models. Proof-of-concept application was done in five subjects for quantifying magnetization transfer ratio (MTR) in each tract of the atlas. The resulting WM atlas showed consistent topological organization and smooth transitions along the rostro-caudal axis. The median MTR across tracts was 26.2. Significant differences were detected across tracts, vertebral levels and subjects, but not across laterality (right-left). Among the different tested approaches to extract metrics, the maximum a posteriori showed highest performance with respect to noise, inter-tract variability, tract size and partial volume effect. This new WM atlas of the human spinal cord overcomes the biases associated with manual delineation and partial volume effect. Combined with multi-parametric data, the atlas can be applied to study demyelination and degeneration in diseases such as multiple sclerosis and will facilitate the conduction of longitudinal and multi-center studies.

Framework for integrated MRI average of the spinal cord white and gray matter: the MNI-Poly-AMU template.

The field of spinal cord MRI is lacking a common template, as existing for the brain, which would allow extraction of multi-parametric data (diffusion-weighted, magnetization transfer, etc.) without user bias, thereby facilitating group analysis and multi-center studies. This paper describes a framework to produce an unbiased average anatomical template of the human spinal cord. The template was created by co-registering T2-weighted images (N = 16 healthy volunteers) using a series of pre-processing steps followed by non-linear registration. A white and gray matter probabilistic template was then merged to the average anatomical template, yielding the MNI-Poly-AMU template, which currently covers vertebral levels C1 to T6. New subjects can be registered to the template using a dedicated image processing pipeline. Validation was conducted on 16 additional subjects by comparing an automatic template-based segmentation and manual segmentation, yielding a median Dice coefficient of 0.89. The registration pipeline is rapid (~15 min), automatic after one C2/C3 landmark manual identification, and robust, thereby reducing subjective variability and bias associated with manual segmentation. The template can notably be used for measurements of spinal cord cross-sectional area, voxel-based morphometry, identification of anatomical features (e.g., vertebral levels, white and gray matter location) and unbiased extraction of multi-parametric data.

Unbinding transition from fluid membranes with associated polymers.

We consider two neighboring fluid membranes that are associated with long flexible polymers (proteins or other macromolecules). We are interested in two physical systems consisting of i) two adjacent membranes with end-grafted (or adsorbed) polymers (system I), or ii) two membranes confining a polymer solution (system II). In addition to the pure interactions between membranes, the presence of polymers gives rise to new induced mediated interactions, which are repulsive, for system I, and attractive, for system II. In fact, repulsive induced interactions are caused by the excluded-volume forces between grafted polymers, while attractive ones, by entropy loss, due to free motion of polymers between membranes. The main goal is a quantitative study of the unbinding transition thermodynamics that is drastically affected by the associated polymers. For system I, the repulsive polymer-mediated force delays this transition that can happen at low temperature. To investigate the unbinding phenomenon, we first present an exact mathematical analysis of the total potential that is the sum of the primitive and induced potentials. This mathematical study enables us to classify the total interaction potentials, in terms of all parameters of the problem. Second, use is made of the standard variational method to calculate the first moments of the membrane separation. Special attention is paid to the determination of the unbinding temperature. In particular, we discuss its dependence on the extra parameters related to the associated polymers, which are the surface coverage and the polymer layer thickness on each membrane (for system I) or the polymer density and the gyration radius of coils (for system II). Third, we compute the disjoining pressure upon membrane separation. Finally, we emphasize that the presence of polymers may be a mechanism to delay or to accentuate the appearance of the unbinding transition between fluid membranes.

Computation of the infrared active modes in single-walled boron nitride nanotube bundles.

In this work, the infrared active modes are computed for homogeneous bundles of single-walled boron nitride nanotubes (BBNNTs), using the so-called spectral moments method. The dependence of the wavenumber on these modes in terms of diameters, lengths, and numbers of tubes, is investigated. To this end, use is made of a Lennard-Jones potential for describing the van der Waals interactions between tubes in a bundle. We find that, for a finite homogeneous bundle, additional modes appear as a specific signature. Finally, these results are useful for the interpretation of the experimental infrared spectra of BBNNTs.

Primitive interactions between inclusions on a fluid membrane: the role of thermal fluctuations.

Consider a fluid membrane decorated by moving hard or soft inclusions. The aim of this work is a quantitative study of the influence of thermal fluctuations on the three-dimensional primitive forces between these inclusions. Integrating over all membrane fluctuations, we obtain a general form giving the modified primitive interactions upon the transverse distance. The established formalism enables us to obtain the modified expression of some standard interaction potentials. In particular, for power-like potentials, we found a modified expression featuring the Whittaker function. The present formalism may be extended to other primitive interaction potentials. Finally, the main conclusion is that, decorated fluid membranes may be regarded as effective two-dimensional colloidal solutions where inclusions interact via the computed effective interactions.

Critical microphase properties of crosslinked polymer blends with quenched random impurities.

We extend published works dealing with microphase separation in crosslinked polymer blends to the case where these are surrounded by random impurities. To study their influence on critical microphase properties, from a static and kinetics point of view, we first assume that the (real) disorder caused by impurities is quenched. Second, the replica theory is used to study such critical properties, upon the impurities concentration and their interaction strength. More precisely, we compute the spinodal temperature and structure factor. We find that the spinodal temperature is shifted towards its lower and higher values, for attractive and repulsive impurities, respectively. The obtained expression for the static structure factor suggests that, contrarily to repulsive impurities, the crosslinked mixture scatters better in the presence of attractive ones. Thereafter, the study is extended to kinetics of microphase separation, when the mixture is impregnated by small random impurities. Kinetics is investigated through the growth rate, and in particular, we demonstrate that the latter is increased by the presence of repulsive impurities. This is natural, since these play a stabilizer role. Finally, the discussion is extended to crosslinked polymer blends immersed in a good solvent, which induces drastic changes of the critical microphase properties.

Theory of microphase separation in crosslinked polymer blends immersed in a θ-solvent.

The aim of this work is a theoretical study of the effects of the solvent quality on the microphase separation in crosslinked polymer blends, from a static and kinetics point of view. More precisely, we assume that the crosslinked mixture is trapped in a θ-solvent. The static microphase properties are studied through the static structure factor. The latter is computed using an extended blob model, where the crosslinked unlike chains can be viewed as sequences of blobs. We demonstrate that the presence of the θ-solvent simply leads to a multiplicative renormalization of these properties, and the renormalization factors are powers of the overall monomer volume fraction. Second, we investigate the early kinetics of the microphase separation, via the relaxation rate, τ(q), which is a function of the wave number q (at fixed temperature and monomer volume fraction). We first show that the kinetics is entirely controlled by local motions of Rouse type, since the slow motions are frozen out by the presence of crosslinks. Using the blob model, we find an explicit form for the growth rate Ω(q) = τ(q)⁻¹, which depends, in addition to the wave number q , on the overall monomer volume fraction, Φ. Also, we discuss the effect of initial entanglements that are trapped when the system is crosslinked. In fact, these play the role of true reticulation points, and then, they quantitatively contribute to the microseparation phenomenon. Finally, the results are compared to their homologous relatively to the molten state and to the good solvent case. The main conclusion is that the quality of the solvent induces drastic changes of the microphase properties.

Cost effectiveness of two therapeutic regimens of infliximab in ankylosing spondylitis: economic evaluation within a randomised controlled trial.

OBJECTIVE: To determine the incremental cost-effectiveness ratios (ICERs) of two therapeutic regimens of infliximab for ankylosing spondylitis (AS). METHODS: 230 patients with active AS who were participating in a randomised controlled trial comparing two infliximab infusion modalities-every 6 weeks (Q6) and on demand (DEM)-were included in an economic evaluation within the trial. Data were collected by phone every 3 months for 1 year. Direct and indirect costs were calculated from a payer perspective. Health-related quality of life was assessed with a general health rating scale. ICERs were calculated for one 20% improvement (ASAS20), for one partial remission and for one quality-adjusted life year (QALY) gained. RESULTS: The Q6 regimen was significantly more efficacious than the DEM regimen but also more costly (euro22 388 vs euro17 596; p<0.001), because it required significantly more infliximab infusions per patient (8.4 vs 6.2). The ICERs of the Q6 to DEM regimen were euro15 841 for one ASAS20 response, euro23 296 for one partial remission and euro50 760 for one QALY gained. CONCLUSION: The administration of infliximab every 6 weeks is cost effective as compared with a DEM regimen; however, the ICER is close to the acceptability threshold of euro50 000 for one QALY gained. TRIAL REGISTRATION NUMBER: NCT 00439283.

Theory of microphase separation in charged crosslinked polymer blends with arbitrary charge distribution.

In this paper, we are interested in the phase behavior and scattering properties of charged crosslinked polymer blends in solution. The system undergoes a microphase separation, below some critical temperature. To study such a transition, use is made of the standard de Gennes theory based on an analogy with a dielectric medium. This analogy is extended to include the effects of the initial composition fluctuations in order to improve its agreement with experimental data in the small wave vector range. The excluded-volume interactions are explicitly introduced through the blob model. The charge effects on the phase behavior are examined, for any charge distribution of polyions and for any salt concentration. This completes a previous study which was concerned with the situation where only one species is charged. The early kinetics of microphase separation is discussed, and the charges contribution to the growth rate is also evaluated.

Critical dynamics of lateral and transversal phase separations in bilayer biomembranes and surfactants.

We consider bilayer biomembranes or surfactants made of two chemically incompatible amphiphile molecules, which may laterally or transversely phase separate into macrodomains, upon variation of some suitable parameter (temperature, lateral pressure, etc.). The purpose is an extensive study of the dynamics of both lateral and transverse phase separations, when the bilayer is suddenly cooled down from a high initial temperature towards a final one very close to the spinodal point. The critical dynamics are investigated through the partial dynamic structure factors of different species. Using a two-order parameter field theory, where the two fields are the composition fluctuations of one component in the leaflets of the bilayer, combined with an extended van Hove approach that is based on two coupled Langevin equations (with noise), we exactly compute these dynamic structure factors. We first find that the dynamics is governed by two time scales. The longest one, Tau, can be related to the thermal correlation length, Xi ~ Sigma|T - T(c)|(-1/2), by Tau ~ Xi(z), with the dynamic critical exponent z = 4, where Sigma is an atomic length scale, T the absolute temperature, and T(c) its critical value. The characteristic time Tau can be interpreted as the time required for the formation of the final macrophase domains. The second time scale is rather shorter, and can be viewed as the short time during which the unlike phospholipids execute local motion. Second, we demonstrate that the dynamic structure factors obey exact scaling laws, and depend on three lengths, namely the wavelength q(-1) (q is the wave vector modulus), the correlation length Xi, and a length scale R(t) ~ t(1/z) (z = 4) representing the size of macrophase domains at time t. Of course, the two lengths Xi and R(t) coincide at the final time Tau at which the bilayer reaches its final equilibrium state. Finally, the present work must be considered as a natural extension of our previously published one dealing with the study of lateral and transverse phase separations from a static point of view.

Field-theoretical Renormalization-Group approach to critical dynamics of crosslinked polymer blends.

We consider a crosslinked polymer blend that may undergo a microphase separation. When the temperature is changed from an initial value towards a final one very close to the spinodal point, the mixture is out equilibrium. The aim is the study of dynamics at a given time t, before the system reaches its final equilibrium state. The dynamics is investigated through the structure factor, S(q, t), which is a function of the wave vector q, temperature T, time t, and reticulation dose D. To determine the phase behavior of this dynamic structure factor, we start from a generalized Langevin equation (model C) solved by the time composition fluctuation. Beside the standard de Gennes Hamiltonian, this equation incorporates a Gaussian local noise, zeta. First, by averaging over zeta, we get an effective Hamiltonian. Second, we renormalize this dynamic field theory and write a Renormalization-Group equation for the dynamic structure factor. Third, solving this equation yields the behavior of S(q, t), in space of relevant parameters. As result, S(q, t) depends on three kinds of lengths, which are the wavelength q(-1), a time length scale R(t) approximately t(1/z), and the mesh size xi*. The scale R(t) is interpreted as the size of growing microdomains at time t. When R(t) becomes of the order of xi*, the dynamics is stopped. The final time, t*, then scales as t* approximately xi*z, with the dynamic exponent z = 6-eta. Here, eta is the usual Ising critical exponent. Since the final size of microdomains xi* is very small (few nanometers), the dynamics is of short time. Finally, all these results we obtained from renormalization theory are compared to those we stated in some recent work using a scaling argument.

Recent advances in adult T-cell leukemia therapy: focus on a new anti-transferrin receptor monoclonal antibody.

HTLV-I is an endemic retrovirus responsible for the adult T-cell leukemia/lymphoma (ATLL). This aggressive lymphoid proliferation is associated with a bad prognosis due to the resistance of HTLV-I-infected cells to most classical chemotherapeutic agents. Here we review recent advances in ATLL immunotherapy. We particularly focus on promising data from our group, characterizing a new mouse monoclonal antibody (mAb A24) against the human transferrin receptor (TfR-1). Monoclonal antibodies to target cell differentiation markers on ATLL cells have already been proposed as therapeutic agents. However, in clinical trials acute forms of ATLL were resistant to these immunotherapies. A24 binds TfR-1 (K(d) 2.7 nM) and competes with transferrin for receptor binding. It blocks the proliferation of malignant cells (TfR-1(high)), such as HTLV-I-infected T cells but not of resting cells. A24 induces TfR-1 endocytosis in lysosomal compartments where the receptor is degraded leading to intracellular iron deprivation. In HTLV-I-infected cells, A24 targets and induces apoptosis of both chronic and acute ATLL forms, independent of antibody aggregation, antibody-dependent cellular cytotoxicity and/or complement addition. The antibody efficacy was confirmed in animal models. We are currently developing strategies to use A24 in clinical trials.

[Chronic inflammatory disorders and reproduction]. / Rhumatisme inflammatoire chronique et procréation.

The desire of reproduction is a true challenge for the physicians in charge of patients with chronic inflammatory disorders such as rheumatoid arthritis or other connective tissue diseases. It requires: 1) the strict evaluation of the potential risks of flare of the rheumatic disease because of the pregnancy; 2) the assessment of risks on pregnancy outcome and fetus development; 3) the management of the different anti-rheumatic agents in order to maintain optimal control of disease activity and avoid any teratogenic problem. Besides this, it clearly appears that inflammatory rheumatic diseases may have an impact on patients' fertility, which may be explained by different mechanisms, physical, psychological, hormonal or immunological. Moreover, some treatments may directly affect fertility, which may justify specific managements in order to preserve gonadic functions.

Reconditioning in patients with rheumatoid arthritis.

UNLABELLED: Rheumatologists traditionally have recommended to rheumatoid arthritis (RA) patients that they avoid dynamic and weight-bearing exercises because of concerns about aggravating joint inflammation and accelerating joint damage in such patients. These restrictions may lead to inadequate levels of physical activity and deconditioning. OBJECTIVE: To review the literature on tolerance and benefits of conditioning training, including dynamic and weight-bearing activities in RA patients. MATERIALS AND METHODS: Medline and Cochrane databases were searched with the keywords RA, rehabilitation, physical therapy, exercise, reconditioning, and rest. RESULTS: Rest therapy is more deleterious than beneficial in most patients with RA and may lead to deconditioning. Dynamic and aerobic exercises do not aggravate joint inflammation and do not accelerate joint damage in such patients. The important goal of reconditioning patients with RA is the prevention of functional decline. Conditioning programs designed to prevent widespread morbidities in healthy subjects are attainable by most RA patients, but an individualized approach to exercise is required. CONCLUSION: RA patients need to be persuaded about the effectiveness and safety of moderate and even high-intensity exercise.

Phase separation between phospholipids and grafted polymer chains onto a fluctuating membrane.

We re-examine here the theoretical study of the phase separation between phospholipids and grafted long polymer chains onto a fluid membrane. The polymer chains are assumed to be anchored to the membrane by one extremity (anchor). The anchors are big amphiphile lipid molecules. The anchors and phospholipids forming the bilayer phase separate under the variation of a suitable parameter (temperature, pressure, membrane environment, ...). To investigate the demixtion transition, we elaborate a new approach that takes into account the membrane undulations. We show that these undulations have the tendency to induce additional attractive forces between anchors, and consequently, the separation transition is accentuated and occurs at high temperature. Quantitatively, we show that the membrane undulations contribute with an extra positive segregation parameter chi m > 0 , which scales as chi m approximately kappa(-2) , where kappa is the bending rigidity constant. Therefore, the attraction phenomenon between species of the same kind is significant only for those membranes of small bending rigidity constant. Finally, the study is extended to the case where the lengths of the anchored polymer chains are randomly distributed. To achieve calculations, we choose a length distribution of fractal form. The essential conclusion is that the polydispersity increases the size of domains alternatively rich in phospholipids and anchors.

Fatigue and rheumatoid arthritis.

Fatigue is a common complaint among patients with rheumatoid arthritis (RA) and is regarded as an extra-articular symptom of the disease. Little attention has been paid by health professional teams to the multidimensional nature of RA-related fatigue and its wide-ranging consequences for quality of life. Unlike normal tiredness, fatigue is chronic, typically not related to overexertion and poorly relieved by rest. The prevalence is high and several RA-related components have been reported as predictors of fatigue. RA-related fatigue appeared to be strongly associated with psychosocial factors. Fatigue assessment and management are complex because psychological and physiological factors may be involved. Several instruments that have been used in RA to assess fatigue. They have involved a self-reporting format. Some are brief, quantitative and symptom-focused questionnaires. Others provide a multidimensional assessment. DMARD therapy, especially anti-TNF decreased disease activity and alleviates fatigue. An additional direct effect is hypothetical. The non-pharmacological management includes behavioral therapy or self-management courses and physical exercise. Finally, the importance and relevance of fatigue as an outcome measure is becoming highlighted by research groups and should lead to improved management of fatigue in usual medical practice.

[Increase in right-to-left intracardiac shunt with non-invasive ventilation]. / Majoration d'un shunt intracardiaque droit-gauche sous ventilation non invasive.

INTRODUCTION: Hypoxia caused by an increase in right-to-left shunt has been reported in patients with patent foramen ovale treated with levels of positive end-expiratory pressures (PEEP) greater than 10 cmH2O. This phenomenon has not previously been described with non-invasive ventilation (NIV). CASE REPORT: A 23 year-old man with tetralogy of Fallot and a severe kyphoscoliosis was admitted at the hospital for chronic dyspnoea. Arterial blood gases on room air: pH 7.43, PaCO2 39 mmHg, PaO2 67 mmHg, HCO3- 25 mmol/l, SaO2 95%. Nocturnal oxymetry showed severe hypoxaemia resistant to oxygen. NIV with PEEP of 3 cm H2O was commenced. With ventilation, his oxygenation worsened. An echocardiogram performed during NIV showed an increase in the right-to-left interventricular gradient from 22 to 37 cmH2O, and of the right ventriculo-auricular gradient from 76 to 142 mmHg. Furthermore, his oxygen saturation decreased progressively from 95 to 85%. Following removal of NIV, the patient recovered in 15 minutes. DISCUSSION: We report an increased right-to-left intracardiac shunt in a patient with tetralogy of Fallot. Compression of pulmonary vessels and cardiac cavities induced by NIV may have been enhanced by a reduction in thoracic compliance related to kyphoscoliosis. Right-to-left shunt in patients with kyphoscoliosis may be a contra-indication to NIV.

Colloidal aggregation in polymer blends.

We consider here a low-density assembly of colloidal particles immersed in a critical polymer mixture of two chemically incompatible polymers. We assume that, close to the critical point of the free mixture, the colloids prefer to be surrounded by one polymer (critical adsorption). As result, one is assisted to a reversible colloidal aggregation in the nonpreferred phase, due the existence of a long-range attractive Casimir force between particles. This aggregation is a phase transition driving the colloidal system from dilute to dense phases, as the usual gas-liquid transition. We are interested in a quantitative investigation of the phase diagram of the immersed colloids. We suppose that the positions of particles are disordered, and the disorder is quenched and follows a Gaussian distribution. To apprehend the problem, use is made of the standard phi(4) theory, where the field phi represents the composition fluctuation (order parameter), combined with the standard cumulant method. First, we derive the expression of the effective free energy of colloids and show that this is of Flory-Huggins type. Second, we find that the interaction parameter u between colloids is simply a linear combination of the isotherm compressibility and specific heat of the free mixture. Third, with the help of the derived effective free energy, we determine the complete shape of the phase diagram (binodal and spinodal) in the (Psi,u) plane, with Psi as the volume fraction of immersed colloids. The continuous "gas-liquid" transition occurs at some critical point K of coordinates (Psi(c) = 0.5,u(c) = 2). Finally, we emphasize that the present work is a natural extension of that, relative to simple liquid mixtures incorporating colloids.