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.

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.

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 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.

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.

[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.

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.

Protein tyrosine kinases in activation signal of human basophils through the immunoglobulin E receptor type l.

Human basophils activated through high-affinity immunoglobulin E (IgE) receptors (Fc epsilon RI) are involved in the late phase of the allergic reaction. To investigate the possible involvement of protein-tyrosine kinases in this activation we used human acute basophilic leukemia (ABL) cells in culture as well as a pure population of normal basophils in vitro-derived from human bone marrow precursor cells (HBMB). ABL cells were 50-80% basophils at various stages of maturation as assessed by staining, morphology, ultrastructure, and flow cytometry analysis, and only basophils in ABL cells expressed Fc epsilon RI. Aggregation of Fc epsilon RI by IgE and anti-IgE, IgE and antigen, or anti-Fc epsilon RI monoclonal antibodies on ABL cells or on HBMB, led to increased tyrosine phosphorylation of 120-, 100-, 80-, 72-, 50- to 65-, and 38-kDa substrates. Tyrosine phosphorylations in ABL cells were in basophils because 1) they were detected after a 5-s stimulation, 2) they were observed under conditions where mediator release is minimal, i.e., in the absence of extracellular calcium, 3) hapten addition during antigen stimulation resulted in almost total disappearance of tyrosine phosphorylations within 30 s. There was correlation between histamine release and tyrosine phosphorylation in anti-IgE dose-responses and in dose-responses of the tyrosine kinase inhibitor genistein. The tyrosine kinase p72syk was detected in the cells. Stimulation of ABL cells for 1 min resulted in extracellular calcium-independent tyrosine phosphorylation and activation of p72syk. Therefore, tyrosine kinases are involved in the early steps of human Fc epsilon RI signaling in basophils. Tyrosine kinases and their substrates could represent new potential therapeutic targets to prevent the development of the allergic reaction.

The receptor with high affinity for IgE on rat mast cells is a functional receptor for rat IgG2a.

Rat mast cells express high-affinity receptors for IgE (Fc epsilon RI) and low-affinity receptors for IgG (Fc gamma R). In this study, the capacity of IgG to activate the rat basophilic leukemia (RBL-2H3) and rat peritoneal mast cells was investigated. Immune complexes formed with purified rat IgG and antigen as well as chemically cross-linked rat IgG induced histamine release from RBL-2H3 cells. This stimulation was inhibited by pre-incubation of the cells with saturating concentrations of monomeric IgE. With chemically cross-linked rat IgG of each subclass, only IgG2a stimulated histamine release from RBL-2H3 cells and this release was also inhibited by prior saturation of the Fc epsilon RI with monomeric IgE. Identical results were obtained with rat peritoneal mast cells. In binding experiments, IgE and cross-linked rat IgG2a bound to rat Fc epsilon RI transfected into CHO cells. Monomeric rat IgG2a, cross-linked rat IgG1, IgG2b, IgG2c and rabbit IgG did not bind to Fc epsilon RI. Stimulation of RBL-2H3 cells with aggregated IgG2a induced phosphorylation of tyrosines in the beta and gamma subunits of the Fc epsilon RI. Thus, although RBL-2H3 and rat peritoneal mast cells have Fc gamma R, the IgG-mediated stimulation of these cells for histamine release was by the Fc epsilon RI. Altogether, these data demonstrate that the rat Fc epsilon RI is a functional receptor with low affinity for rat IgG2a.

[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.

Vascular exclusion in surgery of the liver: experimental basis, technic, and clinical results.

Because liver exeresis and surgery for liver trauma still carry a great mortality by hemorrhage or air embolism due to suprahepatic or vena cava injuries, temporary vascular exclusion of the liver is considered. Based on hemodynamic, biologic, and anatomopathologic experimental and clinical data, a catheter was designed that allows isolation of the retro-and suprahepatic portions of the inferior vena cava and consequently vascular exclusion of the liver for 30 minutes. We report on seven patients in whom this technic was utilized (4 requiring hepatectomy and 3 traumatized), confirming the utility, ease, and efficacy of this method.

Statistical mechanics of a colloidal suspension in contact with a fluctuating membrane.

Surface effects are generally prevailing in confined colloidal systems. Here we report on dispersed nanoparticles close to a fluid membrane. Exact results regarding the static organization are derived for a dilute solution of nonadhesive colloids. It is shown that thermal fluctuations of the membrane broaden the density profile, but on average colloids are neither accumulated nor depleted near the surface. The radial correlation function is also evaluated, from which we obtain the effective pair potential between colloids. This entropically driven interaction shares many similarities with the familiar depletion interaction. It is shown to be always attractive with range controlled by the membrane correlation length. The depth of the potential well is comparable to the thermal energy, but depends only indirectly upon membrane rigidity. Consequences for the stability of the suspension are also discussed.

Computerized tomographical study of dorsal neck muscles for insertion of EMG wire electrodes.

A computerized tomographical (CT) study of the main dorsal neck muscles was performed on 60 subjects (30 males and 30 females) in order to quantify individual anatomical variations and to describe valid means of accurately inserting intramuscular wire electrodes in these deep and superimposed muscle layers. Depth and thickness of transverso-spinalis (TS), semispinalis capitis (SSC) and splenius capitis (SPL) muscles were measured on a cross-sectional image of the neck at the level of the fith cervical vertebrae. Thickness and depth were significantly greater in males than in females. SSC and SPL thicknesses were less than 10 mm in most subjects and their depths were highly variable depending on the subject's morphology. TS was thicker but its depth was also variable. This CT study clearly demonstrated that the interindividual variations of dorsal neck muscles are important and CT may provide a valid way to position wire electrodes accurately in most cervical muscles.

Arteriovenous fistulae of the internal iliac vessels.

Seven patients with arteriovenous fistulae of the internal iliac artery are reported. Ages varied from 6 to 50 years (mean 32 years). Cutaneous angiomata , leg oedema and pain was present in 4 cases each, bleeding in 2 cases whilst only one was asymptomatic. Only 1 patient had cardiac insufficiency. In six patients the lesion was a congenital malformation but in one it was posttraumatic. Arteriography both global and selective, intravenous pyelography and cardiac output are routine. Recently, pelvic computerised tomography has been most helpful. Embolization is recommended in all cases with surgery within 24 hours unless the lesion is very extensive and considered to be inoperable. Repeat embolization is used for recurrence or very extensive lesions. Results were good in five patients; in two patients the results were clinically good but control angiograms showed a recurrence.

Carotid artery surgery in patients over 70 years of age.

Between 1965 and 1979, 934 patients underwent 1,057 operations for extracranial carotid stenosis at this institute, and over a recent 30-month period 463 patients underwent 511 operations of this type. This number is equal to the total of operations performed during the years 1965-1976. The increase in the frequency of carotid artery surgery has been more marked in patients of over 70 years. The percentage of elderly patients has increased from 17.5% to 27% in the recent period. In the latter group of 511 operations, results were good in 93.17% of cases, while there was a mortality rate of 1.95% (1% of which were directly related to the surgery), in 1.95% the neurologic condition deteriorated and in 3.13% there was no change. In the first period the mortality rate for patients over 70 years of age was 7.69%. In the second it was 3.27% (1.63% of which were due to non-neurologic causes), 4.09% deteriorated, in 2.18% there was no change and good results were obtained in 90.46%.