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Paris Descartes University - Sorbonne Paris Cité , also known as "Paris V", is a public research university in Paris, France. It belongs to the leading academic alliance Sorbonne Paris Cité. It was established in order to succeed the medicine department of the world's second oldest academic institution, the University of Paris , shortly before the latter officially ceased to exist on December 31, 1970, as a consequence of the French cultural revolution of 1968, often referred to as "the French May". It is one of the best and the most prestigious French universities, mainly in the areas of medical science, biomedical science, law, computer science, economics and psychology.Headquartered in the historic École de Chirurgie in the 6th arrondissement of Paris, the university strongly focuses on medical science , biomedical science , social science , mathematics, computer science and law .A major pole of research and learning, Paris Descartes - Sorbonne Paris Cité is one of the most prestigious universities in France and the best one in its main domains. On that basis among others, it was rated by the 2013 QS World University Ranking 51-100th in Pharmacy and Pharmacology , 101-150th in Biological science , 100th in Medicine , 151-200th in Psychology , 151-200th in Linguistics , and 151-200th in Law .The University Paris Descartes supports a modern approach of social science on the basis of fieldwork, participant observation and ethnography . The dual master's degree in partnership with other important French academic institutions such as the École Normale Supérieure emphasizes opportunities offered as far as research is concerned.Faculty members have included eminent jurists, doctors and politicians. Wikipedia.


Wang A.,University of Texas Southwestern Medical Center | Batteux F.,University of Paris Descartes | Wakeland E.K.,University of Texas Southwestern Medical Center
Current Opinion in Immunology | Year: 2010

The SLAM/CD2 gene family encodes receptors that play important roles in regulating multiple cellular interactions in the adaptive and innate immune systems. Three members of this gene family, Ly108, Ly9, and CD84, exhibit polymorphisms that strongly influence susceptibility to systemic autoimmunity, notably in mice, but also in some human populations. Polymorphisms of Ly108 in mice strongly impact central tolerance in both B and T cell development, predominantly by modulating apoptosis, anergy, and cell-cycle progression. In addition, Ly108 and CD84, together with their downstream signaling adaptor SLAM-associated protein (SAP), have emerged as key players in B-T interactions during the formation of germinal centers. Interestingly, several independent lines of research have now associated variations in B-T interactions during germinal center formation with systemic autoimmunity, suggesting that susceptibility to systemic lupus erythematosus (SLE) may involve in part the impairment of this peripheral tolerance checkpoint. These new insights into the multiplicity of roles played by the SLAM/CD2 family and its potential importance in human autoimmunity positions the SLAM/CD2 family as an excellent target for immunotherapy. © 2010 Elsevier Ltd.


Dellinger F.,Telecom ParisTech | Delon J.,University of Paris Descartes | Gousseau Y.,Telecom ParisTech | Michel J.,French National Center for Space Studies | Tupin F.,Telecom ParisTech
IEEE Transactions on Geoscience and Remote Sensing | Year: 2015

The scale-invariant feature transform (SIFT) algorithm and its many variants are widely used in computer vision and in remote sensing to match features between images or to localize and recognize objects. However, mostly because of speckle noise, it does not perform well on synthetic aperture radar (SAR) images. In this paper, we introduce a SIFT-like algorithm specifically dedicated to SAR imaging, which is named SAR-SIFT. The algorithm includes both the detection of keypoints and the computation of local descriptors. A new gradient definition, yielding an orientation and a magnitude that are robust to speckle noise, is first introduced. It is then used to adapt several steps of the SIFT algorithm to SAR images. We study the improvement brought by this new algorithm, as compared with existing approaches. We present an application of SAR-SIFT to the registration of SAR images in different configurations, particularly with different incidence angles. © 2014 IEEE.


Donnet S.,University Dauphine | Foulley J.-L.,French National Institute for Agricultural Research | Samson A.,University of Paris Descartes
Biometrics | Year: 2010

Growth curve data consist of repeated measurements of a continuous growth process over time in a population of individuals. These data are classically analyzed by nonlinear mixed models. However, the standard growth functions used in this context prescribe monotone increasing growth and can fail to model unexpected changes in growth rates. We propose to model these variations using stochastic differential equations (SDEs) that are deduced from the standard deterministic growth function by adding random variations to the growth dynamics. A Bayesian inference of the parameters of these SDE mixed models is developed. In the case when the SDE has an explicit solution, we describe an easily implemented Gibbs algorithm. When the conditional distribution of the diffusion process has no explicit form, we propose to approximate it using the Euler-Maruyama scheme. Finally, we suggest validating the SDE approach via criteria based on the predictive posterior distribution. We illustrate the efficiency of our method using the Gompertz function to model data on chicken growth, the modeling being improved by the SDE approach. © 2009 INRA, Government of France.


Mallone R.,French Institute of Health and Medical Research | Mallone R.,University of Paris Descartes | Roep B.O.,Leiden University | Roep B.O.,National Diabetes Expert Center
Clinical Immunology | Year: 2013

After many efforts to improve and standardize assays for detecting immune biomarkers in type 1 diabetes (T1D), methods to identify and monitor such correlates of insulitis are coming of age. The ultimate goal is to use these correlates to predict disease progression before onset and regression following therapeutic intervention, which would allow performing smaller and shorter pilot clinical trials with earlier endpoints than those offered by preserved β-cell function or improved glycemic control. Here, too, progress has been made. With the emerging insight that T1D represents a heterogeneous disease, the next challenge is to define patient subpopulations that qualify for personalized medicine or that should be enrolled for immune intervention, to maximize clinical benefit and decrease collateral damage by ineffective or even adverse immune therapeutics. This review discusses the current state of the art, setting the stage for future efforts to monitor disease heterogeneity, progression and therapeutic intervention in T1D. © 2013 Elsevier Inc.


Touze E.,University of Paris Descartes
Current Vascular Pharmacology | Year: 2012

Carotid stenosis is frequent in the general population, especially in elderly people and is associated with a high risk of stroke and vascular events. In patients with asymptomatic carotid stenosis the overall annual risk of ipsilateral stroke has dramatically decreased over the past decades, due to improvement in medical management. Asymptomatic carotid stenosis is probably a better indicator of generalized atherosclerotic disease than of stroke risk, with an average risk of nonstroke death (mainly due to ischemic heart disease) generally higher than the risk of ipsilateral stroke. Management of risk factors, antiplatelet therapy, and statins are highly beneficial in these patients. Carotid surgery in patients with asymptomatic carotid stenosis is associated with a small absolute benefit compared to medical treatment. The prognosis of patients with symptomatic carotid stenosis is dramatically different from that of patients with asymptomatic carotid stenosis because the risk of stroke on medical treatment alone is very high and highest during the first few days and weeks. In these patients, endarterectomy is highly beneficial and the absolute benefit of is increased in patients with 70-99% stenosis, men, patients over 75 years, and in those treated within 2 weeks after the last event. The meta-analysis of the 3 major European trials comparing endarterectomy to stenting in symptomatic stenosis has shown an increased risk of perioperative risk of any stroke or death in the stenting group (74% increase in risk in patients treated with stenting). However, the risk of stroke or death after stenting and surgery were equivalent below the age of 70 whereas there was a two-fold increase in risk of stenting over endarterectomy above this age. Thus, surgery remains the first line method in most cases but stenting is potentially an alternative in young patients. © 2012 Bentham Science Publishers.


Rouzioux C.,University of Paris Descartes | Richman D.,University of California at San Diego
Current Opinion in HIV and AIDS | Year: 2013

PURPOSE OF REVIEW: The persistence of HIV within infected CD4 T cells is a major obstacle to eradication, and assessment of the strategies to reduce HIV reservoirs is one of the major challenges. Measuring HIV reservoirs accurately will be necessary to assess those strategies. The objective of this review is to present the most recent studies that may help to define the best markers to measure HIV reservoirs. RECENT FINDINGS: Recent findings have shown that multiple assays can be used to quantify the different analytes that reflect the HIV reservoirs. They have provided new insights, but lack of standardization has made cross-comparisons of data difficult. No single best assay for measuring HIV reservoirs has been identified and these assays often address different questions, such as the size of the reservoirs, the composition of the reservoirs, or the capacity of latent reservoirs to produce virus. A consensus on what values reflect robust conclusions will have to wait for the generation of additional results. SUMMARY: In conclusion, there is a compelling need for investigators to optimize assays and share protocol reagents and specimens to permit the validation, comparison, and standardization of techniques. There is an important need for validated, high-throughput, sensitive, and accurate assays that can detect changes in HIV reservoir size in order to assess the impact of candidate therapies. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.


Vauchelet N.,University of Paris Descartes
Journal of Statistical Physics | Year: 2010

A quantum-classical coupled system which models the diffusive transport of electrons partially confined in semiconductors nanostructures was presented in Ben Abdallah and Méhats (Proc. Edinb. Math. Soc. 49:513-549, 2006). In this model, electrons are assumed to behave like wave in the confinement direction and to have a classical behaviour in a diffusive regime in the transport direction parallel to the electron gas. It was formally derived from a kinetic system for partially quantized particles thanks to a diffusive limit when the mean free path becomes small with respect to the macroscopic length scale. This paper is devoted to the rigorous study of this limit for a transport in one dimension. In the transport direction, the motion of particles is described by a 1D Boltzmann equation. A Boltzmann-Schrödinger-Poisson system is then considered. Existence of renormalized solutions relying on the study of a quasistatic Schrödinger-Poisson system and on an entropy estimate is established. Its diffusive limit is then considered. © Springer Science+Business Media, LLC 2010.


Dupont C.,University of Paris Descartes
Pediatric Allergy and Immunology | Year: 2013

In a child that is allergic to milk, the natural next step, following the elimination diet, is the reintroduction of cow's milk. Several questions may arise. When feasible, this reintroduction has many benefits for the child and his family. However, the disease needs to be well defined by physicians and explained to parents. They need to understand that there are different types of allergy to cow's milk, specifically IgE- and non-IgE-mediated, and each of these may exhibit both a variable duration and frequently an incomplete recovery. Deciding where to first reintroduce cow's milk to a child who has previously followed a milk-free diet, whether it be at home or in a hospital, also frequently presents an issue. Following this first reintroduction, the progressive increase of milk into the diet needs to be managed properly, as not all children will go back to a normal dairy products intake. Recent studies show that most children with milk allergy tolerate products containing baked milk and that their consumption might speed up recovery. Hence, the purpose of the milk challenge in a child on a milk-free diet is becoming, even in a child still reactive to milk, the first step of gradual and individually adapted reintroduction of milk or dairy products. When reintroduction of cow's milk does not work, immunotherapy becomes an option, and this is carried out in specialized centers. © 2013 John Wiley & Sons A/S.


Jegatheesan P.,University of Paris Descartes
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2016

PURPOSE OF REVIEW: The high worldwide prevalence of nonalcoholic fatty liver disease (NAFLD) makes it a major public health issue. Amino acids offer a promising approach for its prevention, and several experimental studies highlight the nutritional importance of citrulline in this setting. The purpose of this review is to discuss the potential interest of citrulline in the prevention and treatment of NAFLD. RECENT FINDINGS: Current findings shed light on the role of the gut–liver, adipose tissue–liver, and muscle–liver axes in NAFLD progression. Recent experimental studies have produced evidence for a role of citrulline in controlling the pathophysiological mechanisms involved in NAFLD through its action on these three axes. Data are needed to distinguish between direct and indirect effects of citrulline on the liver and between a specific effect and a nitrogen supply-related effect. SUMMARY: Good level of experimental evidence suggests that citrulline supply may be associated with an attenuation of NAFLD development, but further human studies are now needed to support these findings. This review may help define novel strategies to control fatty liver diseases. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Pagnoux C.,University of Paris Descartes
Discovery medicine | Year: 2010

Churg-Strauss syndrome is a rare, small-sized vessel systemic necrotizing vasculitis that was first described in the early 1950s. Its most typical presentation consists of the appearance, in a patient with late-onset asthma, of vasculitic manifestations, like fever, cutaneous purpura and mononeuritis multiplex. In such a setting, the combination of blood eosinophilia and inflammatory syndrome is highly suggestive of the diagnosis, which can be further supported by the detection of antineutrophil cytoplasmic autoantibodies (ANCN), especially P-ANCA with anti-myeloperoxidase specificity, in almost 40% of the patients, and the presence of eosinophilic granulomas and/or necrotizing vasculitis in an affected-tissue biopsy. Although these disease hallmarks are now well-known, its pathophysiological mechanisms remain to be fully understood. Several gene polymorphisms and immune dysregulations are surely implicated, ranging from direct eosinophil toxicity to T- or even B-cell dysfunctions and, altogether, suggesting the existence of different disease stages and subsets according to the predominantly involved pathway. Only half the patients initially have severe life-threatening manifestations, like cardiac involvement, which require prompt aggressive treatments based on combined corticosteroids and immunosuppressants (mainly cyclophosphamide). Other less severe disease forms can usually be controlled with corticosteroids alone. Even though this current standardized therapy quite effectively and safely obtains remission, more than three-quarters of all the patients will remain corticosteroid-dependent, mostly because of residual asthma and/or eosinophilia. Hence, progress is needed in Churg-Strauss syndrome's therapeutic management, and better understanding of the complex disease mechanisms may aid such a quest.


Borst G.,University of Paris Descartes | Niven E.,University of Edinburgh | Logie R.H.,University of Edinburgh
Memory and Cognition | Year: 2012

Visual mental imagery and working memory are often assumed to play similar roles in high-order functions, but little is known of their functional relationship. In this study, we investigated whether similar cognitive processes are involved in the generation of visual mental images, in short-term retention of those mental images, and in short-term retention of visual information. Participants encoded and recalled visually or aurally presented sequences of letters under two interference conditions: spatial tapping or irrelevant visual input (IVI). In Experiment 1, spatial tapping selectively interfered with the retention of sequences of letters when participants generated visual mental images from aural presentation of the letter names and when the letters were presented visually. In Experiment 2, encoding of the sequences was disrupted by both interference tasks. However, in Experiment 3, IVI interfered with the generation of the mental images, but not with their retention, whereas spatial tapping was more disruptive during retention than during encoding. Results suggest that the temporary retention of visual mental images and of visual information may be supported by the same visual short-term memory store but that this store is not involved in image generation. © 2011 Psychonomic Society, Inc.


Platkiewicz J.,University of Paris Descartes
PLoS computational biology | Year: 2010

In central neurons, the threshold for spike initiation can depend on the stimulus and varies between cells and between recording sites in a given cell, but it is unclear what mechanisms underlie this variability. Properties of ionic channels are likely to play a role in threshold modulation. We examined in models the influence of Na channel activation, inactivation, slow voltage-gated channels and synaptic conductances on spike threshold. We propose a threshold equation which quantifies the contribution of all these mechanisms. It provides an instantaneous time-varying value of the threshold, which applies to neurons with fluctuating inputs. We deduce a differential equation for the threshold, similar to the equations of gating variables in the Hodgkin-Huxley formalism, which describes how the spike threshold varies with the membrane potential, depending on channel properties. We find that spike threshold depends logarithmically on Na channel density, and that Na channel inactivation and K channels can dynamically modulate it in an adaptive way: the threshold increases with membrane potential and after every action potential. Our equation was validated with simulations of a previously published multicompartemental model of spike initiation. Finally, we observed that threshold variability in models depends crucially on the shape of the Na activation function near spike initiation (about -55 mV), while its parameters are adjusted near half-activation voltage (about -30 mV), which might explain why many models exhibit little threshold variability, contrary to experimental observations. We conclude that ionic channels can account for large variations in spike threshold.


Van Marle A.J.,Catholic University of Leuven | Meliani Z.,University of Paris Descartes | Marcowith A.,Montpellier University
Astronomy and Astrophysics | Year: 2012

Context. Numerical models of the wind-blown bubble of massive stars usually only account for the wind of a single star. However, since massive stars are usually formed in clusters, it would be more realistic to follow the evolution of a bubble created by several stars. Aims. We develop a two-dimensional (2D) model of the circumstellar bubble created by two massive stars, a 40 M star and a 25 M star, and follow its evolution. The stars are separated by approximately 16 pc and surrounded by a cold medium with a density of 20 particles per cm 3. Methods. We use the MPI-AMRVAC hydrodynamics code to solve the conservation equations of hydrodynamics on a 2D cylindrical grid using time-dependent models for the wind parameters of the two stars. At the end of the stellar evolution (4.5 and 7.0 million years for the 40 and 25 M stars, respectively), we simulate the supernova explosion of each star. Results. Each star initially creates its own bubble. However, as the bubbles expand they merge, creating a combined, aspherical bubble. The combined bubble evolves over time, influenced by the stellar winds and supernova explosions. Conclusions. The evolution of a wind-blown bubble created by two stars deviates from that of the bubbles around single stars. In particular, once one of the stars has exploded, the bubble is too large for the wind of the remaining star to maintain and the outer shell starts to disintegrate. The lack of thermal pressure inside the bubble also changes the behavior of circumstellar features close to the remaining star. The supernovae are contained inside the bubble, which reflects part of the energy back into the circumstellar medium. © ESO, 2012.


Boudjemline Y.,University of Paris Descartes
Catheterization and Cardiovascular Interventions | Year: 2016

Objectives: To evaluate the safety, feasibility, and efficacy of the MVP™ microvascular plug(Covidien) for closure of vascular anomalies in patients with congenital heart diseases (CHD). Background: The MVP™ is a novel device with PTFE integrated. The device has been recently introduced in the radiological field and reported exclusively for neurological anomalies. Methods: All CHD patients receiving the device from April 2015 until July 2015 were included in the study and followed up clinically as well as by transthoracic echocardiography. Standard safety and follow-up such as vascular complications, embolization rate, and residual shunting were assessed. Results: Twelve patients with a median age of 2.6-years (0.03-12.6 years) and a mean weight of 13 kg (2.8-34.2 kg) were included. Devices were delivered from the femoral artery in 10 and from the femoral vein in 2 patients. Devices were used for closure of patent ductus arteriosus (PDA) closure (n=5), aorto-pulmonary collaterals or Blalock-Taussig shunt (n=5), veno-venous fistula (n=1), and coronary fistula (n=1). One device was retrieved before release due to inappropriate size estimation (PDA spasm). The PDA was successfully closed using a PDA device (Lifetech, Medtronic). Immediate angiographic evaluation showed minimal or no shunt in 90% (10/11 patients) and 100% occlusion rate after a mean follow-up of 3.2-months. There was no device embolization, hemolysis, or any other complication following closure. Conclusions: The delivery of new MVP™ micro vascular plug system (Covidien) is safe and effective in patients with CHD for closure of a variety of vascular abnormalities. The low profile of the device and the sheathless nature of the procedure make it particularly interesting for PDA closure in premature babies. © 2016 Wiley Periodicals, Inc.


Menasche P.,University of Paris Descartes
Journal of Thoracic and Cardiovascular Surgery | Year: 2016

There is accumulating evidence that the cardioprotective effects of stem cells are predominantly mediated by the release of a blend of factors, possibly clustered into extracellular vesicles, which harness endogenous repair pathways. The clinical translation of this concept requires the identification of the cell-secreted signaling biomolecules and an appropriate transfer method. The study by Wei and colleagues has addressed these 2 requirements by showing that the epicardial delivery of a collagen patch loaded with the cardiokine follistatin-like 1 improved left ventricular function in animal models of myocardial infarction. Beyond the choice of the factor and its vehicle, these data may open a new therapeutic path whereby the functionalization of biomaterials by bioactive compounds could successfully substitute for the current cell transplantation-based strategy. © 2016 The American Association for Thoracic Surgery.


Wang H.,University Pierre and Marie Curie | Noulet F.,University Pierre and Marie Curie | Edom-Vovard F.,University Pierre and Marie Curie | Le Grand F.,University of Paris Descartes | Duprez D.,University Pierre and Marie Curie
Developmental Cell | Year: 2010

Muscle progenitors, labeled by the transcription factor Pax7, are responsible for muscle growth during development. The signals that regulate the muscle progenitor number during myogenesis are unknown. We show, through in vivo analysis, that Bmp signaling is involved in regulating fetal skeletal muscle growth. Ectopic activation of Bmp signaling in chick limbs increases the number of fetal muscle progenitors and fibers, while blocking Bmp signaling reduces their numbers, ultimately leading to small muscles. The Bmp effect that we observed during fetal myogenesis is diametrically opposed to that previously observed during embryonic myogenesis and that deduced from in vitro work. We also show that Bmp signaling regulates the number of satellite cells during development. Finally, we demonstrate that Bmp signaling is active in a subpopulation of fetal progenitors and satellite cells at the extremities of muscles. Overall, our results show that Bmp signaling plays differential roles in embryonic and fetal myogenesis. © 2010 Elsevier Inc.


Guelfi J.-D.,University of Paris Descartes
Information Psychiatrique | Year: 2010

We are possibly on the eve, or at the threshold of major changes in the international classification of adult psychosis. The next published classification will be the DSM-V in May 2012, except for an additional delay; the classification of the WHO ICD-11 will only be published at the very earliest in 2014. The process of revision of the DSM-IV began in fact in 1999, that is to say even before the publication of the revised DSM-IV text. We briefly discuss the highly structured organization of the Herculean task that represents the preparation and development of DSM-V. As regards adult psychoses, although nothing has yet been definitely decided, the trends are discernible in the international literature over the past two years, which is summarized in this article.


Conley M.E.,Rockefeller University | Casanova J.-L.,Rockefeller University | Casanova J.-L.,Howard Hughes Medical Institute | Casanova J.-L.,University of Paris Descartes | Casanova J.-L.,Pediatric Hematology Immunology Unit
Current Opinion in Immunology | Year: 2014

Many patients with clinical and laboratory evidence of primary immunodeficiency do not have a gene specific diagnosis. The use of next generation sequencing, particularly whole exome sequencing, has given us an extraordinarily powerful tool to identify the disease-causing genes in some of these patients. At least 34 new gene defects have been identified in the last 4 years. These findings document the striking heterogeneity of the phenotype in patients with mutations in the same gene. In some cases this can be attributed to loss-of-function mutations in some patients, but gain-of-function mutations in others. In addition, the surprisingly high frequency of autosomal dominant immunodeficiencies with variable penetrance, and de novo mutations in disorders with a severe phenotype has been unmasked. © 2014 Elsevier Ltd.


Lamy J.-C.,University of Paris Descartes | Lamy J.-C.,University of Louisville | Boakye M.,University of Louisville | Boakye M.,Robley Rex Veterans Affairs Medical Center
Journal of Neurophysiology | Year: 2013

The brain-derived neurotrophic factor gene (BDNF) is one of many genes thought to influence neuronal survival, synaptic plasticity, and neurogenesis. A common single nucleotide polymorphism (SNP) of the BDNF gene due to valine-to-methionine substitution at codon 66 (BDNF Val66Met) in the normal population has been associated with complex neuronal phenotype, including differences in brain morphology, episodic memory, or cortical plasticity following brain stimulation and is believed to influence synaptic changes following motor learning task. However, the effect of this polymorphism on spinal plasticity remains largely unknown. Here, we used anodal transcutaneous spinal direct current stimulation (tsDCS), a novel noninvasive technique that induces plasticity of spinal neuronal circuits in healthy subjects. To investigate whether the susceptibility of tsDCS probes of spinal plasticity is significantly influenced by BDNF polymorphism, we collected stimulus-response curves of the soleus (Sol) H reflex before, during, at current offset, and 15 min after anodal tsDCS delivered at Th11 (2.5 mA, 15 min, 0.071 mA/cm2, and 64 mC/cm2) in 17 healthy, Met allele carriers and 17 Val homozygotes who were matched for age and sex. Anodal tsDCS induced a progressive leftward shift of recruitment curve of the H reflex during the stimulation that persisted for at least 15 min after current offset in Val/Val individuals. In contrast, this shift was not observed in Met allele carriers. Our findings demonstrate for the first time that the BDNF Val66Met genotype impacts spinal plasticity in humans, as assessed by tsDCS, and may be one factor influencing the natural response of the spinal cord to injury or disease. © 2013 the American Physiological Society.


Barbier M.,University of Paris Descartes
PloS one | Year: 2012

X-linked adrenoleukodystrophy (X-ALD) is characterized by marked phenotypic variation ranging from adrenomyeloneuropathy (AMN) to childhood cerebral ALD (CCALD). X-ALD is caused by mutations in the ABCD1 gene, but no genotype-phenotype correlation has been established so far and modifier gene variants are suspected to modulate phenotypes. Specific classes of lipids, enriched in very long-chain fatty acids that accumulate in plasma and tissues from X-ALD patients are suspected to be involved in the neuroinflammatory process of CCALD. CD1 proteins are lipid- antigen presenting molecules encoded by five CD1 genes in human (CD1A-E). Association studies with 23 tag SNPs covering the CD1 locus was performed in 52 patients with AMN and 87 patients with CCALD. The minor allele of rs973742 located 4-kb downstream from CD1D was significantly more frequent in AMN patients (χ 2 = 7.6; P = 0.006). However, this association was no longer significant after Bonferroni correction for multiple testing. The other polymorphisms of the CD1 locus did not reveal significant association. Further analysis of other CD1D polymorphisms did not detect stronger association with X-ALD phenotypes. Although the association with rs973742 warrants further investigations, these results indicate that the genetic variants of CD1 genes do not contribute markedly to the phenotypic variance of X-ALD.


Chauffier K.,University Pierre and Marie Curie | Salliot C.,University of Paris Descartes | Berenbaum F.,University Pierre and Marie Curie | Sellam J.,University Pierre and Marie Curie
Rheumatology | Year: 2012

Objectives: To assess the effect of biotherapies vs placebo on fatigue in two situations: inadequate response to conventional treatments (IR-DMARD) and inadequate response to anti-TNF (IR-anti-TNF) in RA. Methods: A systematic review of the literature and meta-analysis were performed. We included randomized controlled trials (RCTs) assessing the effect of biotherapies vs placebo on fatigue, in combination with DMARDs. Fatigue was measured using the functional assessment of chronic illness therapy-fatigue (FACIT-F) or short-form 36 (SF-36) vitality scores at baseline and at Week 24. The results were in effect size (ES) for each biotherapy (or class of biotherapy) vs placebo. An ES of <0.5 was considered as small, between 0.5 and 0.8 as moderate and >0.8 as important. Results: From the 763 published studies, 10 RCTs were included in the analysis: seven involved IR-DMARD RA and three IR-anti-TNF. Among the 3837 included patients with established RA, 1227 patients were treated with an anti-TNF, 420 with rituximab, 258 with abatacept, 205 with tocilizumab and 1727 received placebo. The overall ESs of all biotherapies vs placebo on fatigue were small (ES = 0.45; 95% CI 0.31, 0.58) as well as for anti-TNFs (ES = 0.36; 95% CI 0.21, 0.51). The ESs were small in IR-DMARD RA (ES = 0.38; 95% CI 0.30, 0.46), similar between anti-TNF and non-anti-TNF agents and moderate in IR-anti-TNF RA (ES = 0.57; 95% CI 0.27, 0.86). Conclusion: Few studies reported the impact of biotherapies on fatigue. The effect of biotherapies on fatigue in RA is small. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.


Teissandier D.,French National Center for Scientific Research | Delos V.,University of Paris Descartes
CAD Computer Aided Design | Year: 2011

Prompted by the development of algorithms for analysing geometric tolerancing, this article describes a method to determine the Minkowski sum for 3-dimensional polytopes. This method is based exclusively on intersection operations on normal cones, using the properties of the normal fan of a Minkowski sum obtained by common refinement of the normal fans of the operands. It can be used to determine from which vertices of the operands the vertices of the Minkowski sum derive. It is also possible to determine to which facets of the operands each facet of the Minkowski sum is oriented. The basic properties of the algorithms can be applied to n-polytopes. First, the main properties of the duality of normal cones and primal cones associated with the vertices of a polytope are described. Next, the properties of normal fans are applied to define the vertices and facets of the Minkowski sum of two polytopes. An algorithm is proposed, which generalises the method. Lastly, there is a discussion of the features of this algorithm, developed using the OpenCascade environment. © 2011 Elsevier Ltd. All rights reserved.


Dupont C.,University of Paris Descartes
Expert Review of Clinical Immunology | Year: 2014

Cow's milk protein allergy (CMPA) affect many organs, from mouth to gut, with, immediate and delayed reactions, including infantile colic, food protein induced enterocolitis syndrome, enteropathy, eosinophilic disorders, among which infantile proctocolitis, and "dysmotility" disturbances, gastro-esophageal reflux and constipation. Diagnosis follows usual steps, careful history taking and medical examination, before starting an elimination diet, for diagnosis and treatment. Beyond, laboratory tests may help, but definitive conclusion will arise from the oral food challenge. The double-blind-placebo-controlled-food challenge, the "gold standard", is needed in clinical research. The food challenge includes the progressive at-home reintroduction of milk, all the more needed since most cases of CMPA in infants are delayed: in clinical practice, diagnosing CMPA is more than saying if the child reacts to cow's milk. One has to define the syndrome the child is suffering from, the risk implied, the best replacement formula. When tolerance develops, a second diagnostic procedure allows seeing if the child has outgrown his disease and, if not, what is the expected outcome and which type of food is best adapted: small amounts of milk, or transformed forms, such as baked milk. Primary care practice is adapted to non-IgE mediated CMPA. When CMPA is part of multiple food allergies or of an eosinophilic disorder, referral centers will perform multiple allergy testing, endoscopic procedures and complex dietary guidance. © 2014 Informa UK Ltd.


Lallement R.,University of Paris Descartes
Astronomische Nachrichten | Year: 2012

Charge-transfer (CT) X-ray emission may occur at interfaces between a partially neutral gas and gas possessing high ions, provided there is a relative motion between those two phases. The CTX surface brightness from distant objects must be taken into account if it is not far below other "classical" emission sources, especially the thermal emission from the hot phase. I discuss those conditions and potential spectroscopic or photometric diagnostics. I also mention potential indirect effects of the CT reactions by means of pickup ion production, acceleration and subsequent modification of interface and plasma properties. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Schulz C.,Kings College London | Perdiguero E.G.,Kings College London | Chorro L.,Kings College London | Szabo-Rogers H.,Kings College London | And 9 more authors.
Science | Year: 2012

Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia - cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.


Jensen D.M.,University of Chicago | Pol S.,University of Paris Descartes
Liver International | Year: 2012

An association between variations at the IL28B gene locus and HCV clearance (spontaneous recovery or sustained virological response under pegylated interferon (PEG-IFN) and ribavirin (RBV) has been extensively described. In genotype 1-infected patients, the new direct antiviral agents (DAA) including the two approved protease inhibitors boceprevir and telaprevir, in association with the PEG-IFN/RBV combination is the new standard of care making it necessary to redefine the interest of the IL28B genotype in the decision to treat and how to treat genotype 1-infected patients. In treatment-naïve patients, IL28B status can certainly identify those with a high probability of achieving SVR with response guided therapy and probably in whom the duration of treatment can be markedly reduced. In experienced patients, the impact of IL28B genotypes is limited and cancelled by early viral kinetics. However, the decision to initiate or withhold therapy remains a clinical one. In summary, although it was a major milestone in the treatment of patients with PEG-IFN/RBV, IL28B polymorphism testing entered the clinical arena almost 10 years too late. © 2012 John Wiley & Sons A/S.


Wolfsheimer S.,University of Paris Descartes | Hartmann A.K.,Carl von Ossietzky University
Physical Review E - Statistical, Nonlinear, and Soft Matter Physics | Year: 2010

We study the distribution of the minimum free energy (MFE) for the Turner model of pseudoknot free RNA secondary structures over ensembles of random RNA sequences. In particular, we are interested in those rare and intermediate events of unexpected low MFEs. Generalized ensemble Markov-chain Monte Carlo methods allow us to explore the rare-event tail of the MFE distribution down to probabilities such as 10-70 and to study the relationship between the sequence entropy and structural properties for sequence ensembles with fixed MFEs. Entropic and structural properties of those ensembles are compared with natural RNA of the same reduced MFE (z score). © 2010 The American Physical Society.


Glutamate is the most important excitatory neurotransmitter of the nervous system, critically needed for the brain’s development and function. Glutamate has also a signaling role in peripheral organs. Herein, we discuss glutamate receptors (GluRs) and glutamate-induced direct effects on human T cells. T cells are the most important cells of the adaptive immune system, crucially needed for eradication of all infectious organisms and cancer. Normal, cancer and autoimmune human T cells express functional ionotropic and metabotropic GluRs. Different GluR subtypes are expressed in different T cell subtypes, and in resting vs. activated T cells. Glutamate by itself, at low physiological 10-8M to 10-5M concentrations and via its several types of GluRs, activates many key T cell functions in normal human T cells, among them adhesion, migration, proliferation, intracellular Ca2+ fluxes, outward K+ currents and more. Glutamate also protects activated T cells from antigen-induced apoptotic cell death. By doing all that, glutamate can improve substantially the function and survival of resting and activated human T cells. Yet, glutamate’s direct effects on T cells depend dramatically on its concentration and might be inhibitory at excess pathological 10-3M glutamate concentrations. The effects of glutamate on T cells also depend on the specific GluRs types expressed on the target T cells, the T cell’s type and subtype, the T cell’s resting or activated state, and the presence or absence of other simultaneous stimuli besides glutamate. Glutamate also seems to play an active role in T cell diseases. For example, glutamate at several concentrations induces or enhances significantly very important functions of human T-leukemia and T-lymphoma cells, among them adhesion to the extracellular matrix, migration, in vivo engraftment into solid organs, and the production and secretion of the cancer- associated matrix metalloproteinase MMP-9 and its inducer CD147. Glutamate induces all these effects via activation of GluRs highly expressed in human T-leukemia and T-lymphoma cells. Glutamate also affects T cellmediated autoimmune diseases. With regards to multiple sclerosis (MS), GluR3 is highly expressed in T cells of MS patients, and upregulated significantly during relapse and when there is neurological evidence of disease activity. Moreover, glutamate or AMPA (10-8M to 10-5M) enhances the proliferation of autoreactive T cells of MS patients in response to myelin proteins. Thus, glutamate may play an active role in MS. Glutamate and its receptors also seem to be involved in autoimmune rheumatoid arthritis and systemic lupus erythematosus. Finally, T cells can produce and release glutamate that in turn affects other cells, and during the contact between T cells and dendritic cells, the latter cells release glutamate that has potent effects on the T cells. Together, these evidences show that glutamate has very potent effects on normal, and also on cancer and autoimmune pathological T cells. Moreover, these evidences suggest that glutamate and glutamatereceptor agonists might be used for inducing and boosting beneficial T cell functions, for example, T cell activity against cancer and infectious organisms, and that glutamate- receptor antagonists might be used for preventing glutamate-induced activating effects on detrimental autoimmune and cancerous T cells. © Springer-Verlag Wien 2014.


Leger D.,University of Paris Descartes | Beck F.,French Institute of Health and Medical Research | Richard J.-B.,French Institute of Health and Medical Research | Godeau E.,University Paul Sabatier
PLoS ONE | Year: 2012

Restricted sleep duration among young adults and adolescents has been shown to increase the risk of morbidities such as obesity, diabetes or accidents. However there are few epidemiological studies on normal total sleep time (TST) in representative groups of teen-agers which allow to get normative data. Purpose: To explore perceived total sleep time on schooldays (TSTS) and non schooldays (TSTN) and the prevalence of sleep initiating insomnia among a nationally representative sample of teenagers. Methods: Data from 9,251 children aged 11 to 15 years-old, 50.7% of which were boys, as part of the cross-national study 2011 HBSC were analyzed. Self-completion questionnaires were administered in classrooms. An estimate of TSTS and TSTN (week-ends and vacations) was calculated based on specifically designed sleep habits report. Sleep deprivation was estimated by a TSTN - TSTS difference >2 hours. Sleep initiating nsomnia was assessed according to International classification of sleep disorders (ICSD 2). Children who reported sleeping 7 hours or less per night were considered as short sleepers. Results: A serious drop of TST was observed between 11 yo and 15 yo, both during the schooldays (9 hours 26 minutes vs. 7 h 55 min.; p<0.001) and at a lesser extent during week-ends (10 h 17 min. vs. 9 h 44 min.; p<0.001). Sleep deprivation concerned 16.0% of chidren aged of 11 yo vs. 40.5% of those of 15 yo (p<0.001). Too short sleep was reported by 2.6% of the 11 yo vs. 24.6% of the 15 yo (p<0.001). Conclusion: Despite the obvious need for sleep in adolescence, TST drastically decreases with age among children from 11 to 15 yo which creates significant sleep debt increasing with age. © 2012 Leger et al.


Bamias A.,National and Kapodistrian University of Athens | Pignata S.,Italian National Cancer Institute | Pujade-Lauraine E.,University of Paris Descartes
Critical Reviews in Oncology/Hematology | Year: 2012

Ovarian cancer is the leading cause of death from gynecological cancers. Primary treatment of advanced ovarian cancer (FIGO stages III and IV) until recently consisted of cytoreductive surgery and paclitaxel/carboplatin chemotherapy. The results of two randomized studies, showing prolongation of progression-free survival (PFS) by the addition of the anti-VEGF monoclonal antibody, bevacizumab, led to the approval of this agent for first-line treatment of this disease and indicate that angiogenesis is a promising therapeutic target. Angiogenesis is essential for oncogenesis but also the viability and expansion of ovarian cancer. Specifically, VEGF is involved in the formation of ascites and has a direct effect on ascites tumor cells as well as an immunosuppressive function. Apart from VEGF, PDGF, FGF and angiopoietins present a therapeutic interest. We are reviewing the results of published clinical studies using anti-angiogenic factors in advanced ovarian cancer. © 2012 Elsevier Ireland Ltd.


Mignani S.,University of Paris Descartes | El Kazzouli S.,Euro-Mediterranean University | Bousmina M.M.,Euro-Mediterranean University | Bousmina M.M.,Hassan II Academy of Science and Technology | Majoral J.-P.,CNRS Coordination Chemistry
Chemical Reviews | Year: 2014

The progress made in the inhibition of protein-protein interactions (PPIs) by use of dendrimers as drugs is studied. Specific protein-protein molecular recognition is critical for cellular function, programmed cell death, signal transduction, and viral self-assembly. These PPI signatures suggest that large ligands may be required to compete effectively with one of the two interfacial areas and suggest the inappropriateness of the druglike small-molecule approach. Two main different strategies have been used for their identification of PPI, screening, including in silico screening, and drug design approaches, including nanoparticles for protein surface recognition. As already proposed by Lipinski and Hopkins, one of the foremost challenges facing drug discovery is the identification and development of specific chemical areas. Dendritic polymers are often referred to as artificial globular proteins, based on their closely matched size and contours of important proteins and bioassemblies and their electrophoretic properties and other biomimetic properties.


Lapillonne A.,University of Paris Descartes | Lapillonne A.,Baylor College of Medicine | Groh-Wargo S.,Case Western Reserve University | Lozano Gonzalez C.H.,Academia Mexicana de Pediatria | Uauy R.,University of Chile
Journal of Pediatrics | Year: 2013

Long-chain polyunsaturated fatty acids (LCPUFAs) are of nutritional interest because they are crucial for normal development of the central nervous system and have potential long-lasting effects that extend beyond the period of dietary insufficiency. Here we review the recent literature and current recommendations regarding LCPUFAs as they pertain to preterm infant nutrition. In particular, findings that relate to fetal accretion, LCPUFA absorption and metabolism, effects on development, and current practices and recommendations have been used to update recommendations for health care providers. The amounts of long-chain polyunsaturated fatty acids (LCPUFAs) used in early studies were chosen to produce the same concentrations as in term breast milk. This might not be a wise approach for preterm infants, however, particularly for very and extremely preterm infants, whose requirements for LCPUFAs and other nutrients exceed what is normally provided in the small volumes that they are able to tolerate. Recent studies have reported outcome data in preterm infants fed milk with a docosahexaenoic acid (DHA) content 2-3 times higher than the current concentration in infant formulas. Overall, these studies show that providing larger amounts of DHA supplements, especially to the smallest infants, is associated with better neurologic outcomes in early life. We emphasize that current nutritional management might not provide sufficient amounts of preformed DHA during the parenteral and enteral nutrition periods and in very preterm/very low birth weight infants until their due date, and that greater amounts than used routinely likely will be needed to compensate for intestinal malabsorption, DHA oxidation, and early deficit. Research should continue to address the gaps in knowledge and further refine adequate intake for each group of preterm infants.


Lapillonne A.,University of Paris Descartes | Lapillonne A.,Baylor College of Medicine | Griffin I.J.,University of California at Davis
Journal of Pediatrics | Year: 2013

Preterm birth continues to contribute disproportionately to neonatal morbidity and subsequent physical and neurodevelopmental disabilities. Epidemiologic studies have described additional long-term health consequences of preterm birth such as an increased risk of hypertension and insulin resistance in adult life. It is not known whether the influence of infant and childhood growth rates and early nutrition on long-term outcomes is the same or different among preterm infants and neonates with intrauterine growth restriction. Our goal is to review the effects of fetal growth, postnatal growth, and early nutrition on long-term cardiovascular and metabolic outcomes in preterm infants. Present evidence suggests that even brief periods of relative undernutrition during a sensitive period of development have significant adverse effects on later development. Our review suggests that growth between birth and expected term and 12-18 months post-term has no significant effect on later blood pressure and metabolic syndrome, whereas reduced growth during hospitalization significantly impacts later neurodevelopment. In contrast, growth during late infancy and childhood appears to be a major determinant of later metabolic and cardiovascular well being, which suggests that nutritional interventions during this period are worthy of more study. Our review also highlights the paucity of well-designed, controlled studies in preterm infants of the effects of nutrition during hospitalization and after discharge on development, the risk of developing hypertension, or insulin resistance.


The pharmacokinetics and pharmacodynamics of the main antifungal drugs used for invasive fungal infections (amphotéricin B, flucytosine, triazole compounds, echinocandins) have been more or less completely investigated in the paediatric population. This article reviews the pharmacokinetic profiles of these drugs in children, with a focus on the age-related changes. The concentration/efficacy relationships that were evidenced in children are also described. © 2011 Elsevier Masson SAS.


Bargy F.,University of Paris Descartes
Fetal Diagnosis and Therapy | Year: 2014

Introduction: The development of gastroschisis remains an area of controversy. Various theories have been proposed, but none has ever been supported by a thorough embryological study. Material and Methods: We herein report anatomical and microscopic observations of the developing abdominal wall and cord of embryos and fetuses, along with clinical features of gastroschisis. Results: It appears that the developing cord normally has two parts, a firm left-sided part formed by the vessels and urachus, and a thin right-sided pouch covering the intestinal loops (the 'physiological umbilical hernia'), which could rupture, giving the basis of gastroschisis. Discussion: Gastroschisis could be the result of amniotic damage, possibly from some as yet unidentified toxin. Further bowel damage can be explained by the subsequent mesenteric injury. © 2014 S. Karger AG, Basel.


Suspected allergic reactions to drugs and biological substances (anti-infectious drugs and antipyretics, non opioid analgesics and nonsteroidal anti-inflammatory drugs especially) are reported in 5 to 12% of children. Most frequent reactions are morbilliform/maculopapular rashes, urticaria and angioedema. Other cutaneous and respiratory reactions, and severe allergic and non-allergic anaphylactic reactions are rare. The results of studies based on allergological tests and/or microbiological/serological tests strongly suggest that, except for a few types of reactions (anaphylactic and/or immediate reactions, potentially harmful toxidermias) and for very specific drugs (i.e. latex and myorelaxants), most reactions to commonly used drugs and biological substances in children do not result from drug hypersensitivity, but are rather a consequence of the infectious and/or inflammatory diseases for which the drugs have been prescribed. Non-immediate reactions may also result from complex interactions between drugs, immune system and "danger signals" provided or induced by infectious and/or inflammatory diseases. Diagnosis is based above all on a detailed analysis of clinical history, skin tests (if validated), and challenge tests (if indicated). At present, the diagnostic and predictive values of in vitro tests exploring immediate (specific IgE determination, histamine and leukotriene release tests, basophil activation test) and non-immediate type (lymphocyte activation tests, and cytokine assays in the supernatant of activated blood mononuclear cells) of drug hypersensitivity are not validated. © 2011 Elsevier Masson SAS.


Nault J.-C.,UMR 1162 | Nault J.-C.,University of Paris Descartes | Nault J.-C.,University of Paris 13 | Villanueva A.,Liver Cancer Research Program
Clinical Cancer Research | Year: 2015

Hepatocellular carcinoma is a highly heterogeneous disease both at the molecular and clinical levels. Intratumor morphologic and genetic heterogeneity adds a new level of complexity in our understanding of liver carcinogenesis, and it is likely an important determinant of primary and secondary resistance to targeted therapies. © 2015 American Association for Cancer Research.


Carling D.,Clinical Science Center | Viollet B.,French Institute of Health and Medical Research | Viollet B.,French National Center for Scientific Research | Viollet B.,University of Paris Descartes
Cell Metabolism | Year: 2015

The recent exciting advances in our understanding of the regulation of the energy sensor AMP-activated protein kinase (AMPK), together with renewed appreciation of its importance in maintaining cellular function, brought together leading scientists at a recent FASEB-sponsored meeting in September 2014. Here, we report some of the highlights of this conference. © 2015 Elsevier Inc.


The early identification of patients who are unlikely to respond to intravenous recombinant tissue plasminogen activator (IV-tPA) could help select candidates for additional intra-arterial therapy or add-on antithrombotic drugs during the acute stage of stroke. Given that very early neurological improvement (VENI) is a reliable surrogate of early recanalization, we assessed the clinical and magnetic resonance imaging predictors of lack of VENI. We reviewed consecutive ischemic stroke patients with middle cerebral artery occlusion and treated within 4.5 hours by IV-tPA between 2003 and 2012 in our center, where magnetic resonance imaging is systematically implemented as first-line diagnostic workup. Lack of VENI was defined as a <40% decrease in baseline National Institutes of Health Stroke Scale (NIHSS) score 1 hour after start of IV-tPA. Poor outcome was defined as a 3-month modified Rankin scale ≥2. Associations between lack of VENI and potential determinants were assessed in logistic regression models. In all, 186 patients were included (median baseline NIHSS score, 16; median onset to treatment time, 155 minutes). One hundred forty-three patients (77%) had no VENI. The variables significantly associated with lack of VENI in multivariable analysis were baseline NIHSS (OR, 1.08; 95% CI, 1.01 to 1.16 per 1-point increase; P=0.03), onset to treatment time >120 minutes (OR, 2.94; 95% CI, 1.31 to 6.63; P=0.009) and diffusion weighted imaging--Alberta Stroke Programme Early CT Score ≤5 (OR, 3.60; 95% CI, 1.14 to 11.35; P=0.03). Patients without VENI were more likely to have a modified Rankin Scale ≥2 than those without VENI (68% versus 24%; OR, 5.01; 95% CI, 2.12 to 11.82) and less likely to have recanalization after 24 hours (OR, 0.41; 95% CI, 0.19 to 0.88). Lack of VENI provides an early estimate of 3-month outcome and recanalization after IV-tPA. Baseline NIHSS, onset to treatment time, and diffusion weighted imaging--Alberta Stroke Programme Early CT Score could help to predict lack of VENI and, in turn, might help early selection of candidates for complementary reperfusion strategies.


Houvet P.,University of Paris Descartes
Orthopaedics & traumatology, surgery & research : OTSR | Year: 2013

Work-related musculoskeletal disorders (WRMSDs) of the upper limb have become a serious concern in many countries and have been steadily progressing for several decades. The cause of WRMSDs is assumed to be the direct consequence of repetitiveness, extreme postures, and intensive efforts in a problematic psychosocial environment. Therapy should therefore associate the occupational physician and the regulatory bodies. It may be necessary to modify the individual workstation and to reorganize the company. Such upper limb pathologies may be surgically treated but the results are often delayed and poorer when compared to the general population. Copyright © 2013 Elsevier Masson SAS. All rights reserved.


Sharman J.E.,Menzies Research Institute | Laurent S.,University of Paris Descartes
Journal of Human Hypertension | Year: 2013

Blood pressure (BP) is conventionally measured by cuff at the brachial artery as an indication of pressure experienced by the organs. However, individual variation in pulse pressure amplification means that brachial cuff BP may be a poor representation of true central BP. Estimation of central BP is now possible using non-invasive methods that are amenable for widespread use. This paper reviews the evidence regarding the potential value of central BP in hypertension management. The major lines of evidence that support the use of central BP as a clinical tool include the: (1) major discrepancies in central BP among people with similar brachial BP; (2) independent relationship of central BP with end-organ damage; (3) independent relationship of central BP with cardiovascular (CV) events and mortality; (4) differential central and brachial BP responses to antihypertensive medications and; (5) improvements in end-organ damage after therapy more strongly relate to central than brachial BP. Despite all this, important evidence gaps relating to clinical use of central BP need fulfilling. These include the lack of central BP reference values and randomized, controlled studies to determine if: (1) central BP can help with diagnostic/therapeutic decisions and; (2) CV outcome is improved by targeting therapy towards lowering central BP levels. Additional challenges such as standardization of central BP methods, and understanding which patients are most likely to benefit from central BP monitoring also need to be determined. Overall, the future for central BP as a worthwhile clinical instrument appears positive, but there is much to be done. © 2013 Macmillan Publishers Limited.


Roche N.,University of Paris Descartes | Chavannes N.H.,Leiden University | Miravitlles M.,Hospital Universitari Vall dHebron
Respiratory Research | Year: 2013

Chronic obstructive pulmonary disease (COPD) symptoms in the morning, including dyspnea and sputum production, affect patients' quality of life and limit their ability to carry out even simple morning activities. It is now emerging that these symptoms are associated with increased risk of exacerbations and work absenteeism, suggesting that they have a more profound impact on patients than previously thought. The development of validated patient-reported outcome (PRO) questionnaires to capture patients' experience of COPD symptoms in the morning is, therefore, vital for establishing effective and comprehensive management strategies. Although it is well established that long-acting bronchodilators are effective in improving COPD symptoms, the limited available data on their impact on morning symptoms and activities have been obtained with non-validated PRO questionnaires. In this review, we discuss the impact of COPD symptoms in the morning and available tools used to evaluate them, and highlight specific gaps that need to be addressed to develop standardized instruments able to meet regulatory requirement. We also present available evidence on the effect of pharmacological therapies on morning symptoms. © 2013 Roche et al.; licensee BioMed Central Ltd.


Our interest, since a number of years, has focalized on the worldwide rapid expansion of the aging population, accompanied by a progressive increase of age-related pathologies. Most of these concern connective tissues, that are rich in extracellular matrix (ECM), such as osteoarticular, cardiovascular and pulmonary diseases. Therefore age-related modifications of connective tissues become of increasing importance for the understanding of these diseases. In this article, we shall recapitulate some of our (and others') experiments on fibronectin, an important matrix glycoprotein mediating cell-matrix interactions. We studied the effect of age on fibronectin biosynthesis and also the effect of UV-radiation. Both conditions, age and radiation, produce a significant increase of fibronectin biosynthesis. Some results, when in vitro aging of skin fibroblasts was studied, exhibited also a passage-dependent regulation of fibronectin biosynthesis. A few studies, quoted in this review, were reported about the effect of age on integrin expression and function. An important finding was that novel biological fragments of fibronectin have proteolytic activities, pro-inflammatory activity in articular tissues, enhance malignant transformation as well as other activities. Proteolytic activity also increases with age-dependent increase of fibronectin fragmentation. This process exhibits positive feedback properties, forming a vicious circle, possibly important for the age-dependent aggravation of connective tissue diseases. Besides these observations, the recent demonstration of fibronectin elasticity suggests its implication in novel biological regulation as for instance mechano-transduction. © 2012 Société de Biologie.


Aubourg P.,University of Paris Descartes | Wanders R.,University of Amsterdam
Handbook of Clinical Neurology | Year: 2013

The peroxisomal disorders represent a group of genetic diseases in man in which there is an impairment in one or more peroxisomal functions. The peroxisomal disorders are subdivided into three subgroups comprising: (1) the peroxisome biogenesis disorders (PBDs); (2) the single peroxisomal (enzyme-) protein deficiencies; and (3) the single peroxisomal substrate transport deficiencies. The PBD group comprises four different disorders that include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). ZS, NALD, and IRD are clearly distinct from RCDP and are usually referred to as the Zellweger spectrum with ZS being the most severe, and IRD the less severe disorder, with sometimes onset in adulthood. The single peroxisomal enzyme deficiency group comprises seven different disorders, of which D-bifunctional protein and phytanoyl-CoA hydroxylase (adult Refsum disease) deficiencies are the most frequent. The single peroxisomal substrate transport deficiency group consists of only one disease, X-linked adrenoleukodystrophy. It is the purpose of this chapter to describe the current state of knowledge about the clinical, biochemical, cellular, and molecular aspects of peroxisomal diseases, and to provide guidelines for their post- and prenatal diagnosis. Therapeutic interventions are mostly limited to X-linked adrenoleukodystrophy. © 2013 Elsevier B.V.


Le Heuzey J.Y.,University of Paris Descartes
Thrombosis Research | Year: 2012

The incidence and prevalence of atrial fibrillation are quickly increasing, mainly due to the ageing of the population. Atrial fibrillation is, to date, a problem of public health. Atrial fibrillation is associated to a five-fold risk of stroke, which may be identified by score risks, such as CHADS2 score. The classical antithrombotic treatment of atrial fibrillation is based on vitamin K antagonists. Trials made in the 90's have clearly shown that vitamin K antagonists were able to decrease stroke risk by about 60%. New oral anticoagulants are now available on the market to treat patients with atrial fibrillation. These drugs are Dabigatran which has demonstrated an interest in the RE-LY trial. Two doses may be prescribed, 110 mg bid and 150 mg bid. Anti Xa have also demonstrated an interest: Rivaroxaban in the ROCKET AF trial and Apixaban in the AVERROES (versus aspirin) and ARISTOTLE trials. In the future these drugs will have a major place in the armamentarium used to treat patients with atrial fibrillation. In all these trials a decrease in intra cranial haemorrhages has been demonstrated. In the everyday practice it will be necessary to be very cautious in patients with impaired renal function, as all these drugs are eliminated by kidneys. © 2012 Elsevier Ltd.


Nakamori M.,University of Rochester | Gourdon G.,University of Paris Descartes | Thornton C.A.,University of Rochester
Molecular Therapy | Year: 2011

Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the gene DMPK. The expansion is highly unstable in somatic cells, a feature that may contribute to disease progression. The RNA expressed from the mutant allele exerts a toxic gain of function, due to the presence of an expanded CUG repeat (CUG exp). This RNA dominant mechanism is amenable to therapeutic intervention with antisense oligonucleotides (ASOs). For example, CAG-repeat ASOs that bind CUG exp RNA are beneficial in DM1 models by altering the protein interactions or metabolism of the toxic RNA. Because CUG exp RNA has been shown to aggravate instability of expanded CTG repeats, we studied whether CAG-repeat ASOs may also affect this aspect of DM1. In human cells the instability of (CTG) 800 was suppressed by addition of CAG-repeat ASOs to the culture media. In mice that carry a DMPK transgene the somatic instability of (CTG) 800 was suppressed by direct injection of CAG-repeat ASOs into muscle tissue. These results raise the possibility that early intervention with ASOs to reduce RNA or protein toxicity may have the additional benefit of stabilizing CTG:CAG repeats at subpathogenic lengths. © The American Society of Gene & Cell Therapy.


Motzer R.J.,Sloan Kettering Cancer Center | Escudier B.,Institute Gustave Roussy | Tomczak P.,University Medyczny | Hutson T.E.,Sammons Cancer Center | And 10 more authors.
The Lancet Oncology | Year: 2013

Background: In a phase 3 trial comparing the efficacy and safety of axitinib versus sorafenib as second-line treatment for metastatic renal cell carcinoma, patients given axitinib had a longer progression-free survival (PFS). Here, we report overall survival and updated efficacy, quality of life, and safety results. Methods: Eligible patients had clear cell metastatic renal cell carcinoma, progressive disease after one approved systemic treatment, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1. 723 patients were stratified by ECOG PS and previous treatment and randomly allocated (1:1) to receive axitinib (5 mg twice daily; n=361) or sorafenib (400 mg twice daily; n=362). The primary endpoint was PFS assessed by a masked, independent radiology review committee. We assessed patient-reported outcomes using validated questionnaires. Baseline characteristics and development of hypertension on treatment were studied as prognostic factors. Efficacy was assessed in the intention-to-treat population, and safety was assessed in patients who received at least one dose of the study drug. This ongoing trial is registered on ClinicalTrials.gov, number NCT00678392. Findings: Median overall survival was 20·1 months (95% CI 16·7-23·4) with axitinib and 19·2 months (17·5-22·3) with sorafenib (hazard ratio [HR] 0·969, 95% CI 0·800-1·174; one-sided p=0·3744). Median investigator-assessed PFS was 8·3 months (95% CI 6·7-9·2) with axitinib and 5·7 months (4·7-6·5) with sorafenib (HR 0·656, 95% CI 0·552-0·779; one-sided p<0·0001). Patient-reported outcomes scores were similar in the treatment groups at baseline, were maintained during treatment, but decreased at end-of-treatment. Common grade 3 or higher treatment-related adverse events were hypertension (60 [17%]), diarrhoea (40 [11%]), and fatigue (37 [10%]) in 359 axitinib-treated patients and hand-foot syndrome (61 [17%]), hypertension (43 [12%]), and diarrhoea (27 [8%]) in 355 sorafenib-treated patients. In a post-hoc 12-week landmark analysis, median overall survival was longer in patients with a diastolic blood pressure of 90 mm Hg or greater than in those with a diastolic blood pressure of less than 90 mm Hg: 20·7 months (95% CI 18·4-24·6) versus 12·9 months (10·1-20·4) in the axitinib group (p=0·0116), and 20·2 months (17·1-32·0) versus 14·8 months (12·0-17·7) in the sorafenib group (one-sided p=0·0020). Interpretation: Although overall survival, a secondary endpoint for the study, did not differ between the two groups, investigator-assessed PFS remained longer in the axitinib group compared with the sorafenib group. These results establish axitinib as a second-line treatment option for patients with metastatic renal cell carcinoma. Funding: Pfizer Inc. © 2013 Elsevier Ltd.


Szinte M.,University of Paris Descartes
Journal of vision | Year: 2012

Different attention and saccade control areas contribute to space constancy by remapping target activity onto their expected post-saccadic locations. To visualize this dynamic remapping, we used a technique developed by Honda (2006) where a probe moved vertically while participants made a saccade across the motion path. Observers do not report any large excursions of the trace at the time of the saccade that would correspond to the classical peri-saccadic mislocalization effect. Instead, they reported that the motion trace appeared to be broken into two separate segments with a shift of approximately one-fifth of the saccade amplitude representing an overcompensation of the expected retinal displacement caused by the saccade. To measure the timing of this break in the trace, we introduced a second, physical shift that was the same size but opposite in direction to the saccade-induced shift. The trace appeared continuous most frequently when the physical shift was introduced at the midpoint of the saccade, suggesting that the compensation is in place when the saccade lands. Moreover, this simple linear shift made the combined traces appear continuous and linear, with no curvature. In contrast, Honda (2006) had reported that the pre- and post-saccadic portion of the trace appeared aligned and that there was often a small, visible excursion of the trace at the time of the saccade. To compare our results more directly, we increased the contrast of our moving probe in a third experiment. Now some observers reported seeing a deviation in the motion path but the misalignment remained present. We conclude that the large deviations at the time of saccade are generally masked for a continuously moving target but that there is nevertheless a residual misalignment between pre- and post-saccadic coordinates of approximately 20% of the saccade amplitude that normally goes unnoticed.


Hsu Y.-F.,University of Paris Descartes | Waszak F.,CNRS Laboratory of Physiology of Perception
International Journal of Psychophysiology | Year: 2012

Priming can reflect the stimulus-driven retrieval of output-related memory traces, commonly referred to as stimulus-response associations. The purpose of the current study was to investigate which aspects of the output exactly are preserved in these traces using electroencephalography (EEG). We orthogonally manipulated the repetition of action and classification whilst participants performed one of the two semantic tasks according to the cue. We found no evidence of stimulus-action associations but significant effects relevant to the retrieval of stimulus-classification associations in participants' accuracy and RT. Event-related potential (ERP) and oscillatory analysis further revealed a classification-related modulation at around 200. ms after stimulus onset, which appeared much earlier than the one reported in previous studies. These classification effects possibly indicate the modification of memory traces which requires the dynamic interaction of temporal and frontal cortices. The finding of classification effects across behavioural and EEG data suggested that the formation of stimulus-classification traces is rather spontaneous and may be dominant in single trial stimulus-response binding. © 2012 Elsevier B.V.


Gavard J.,French National Center for Scientific Research | Gavard J.,French Institute of Health and Medical Research | Gavard J.,University of Paris Descartes
Cell Adhesion and Migration | Year: 2014

The endothelium forms a selective semi-permeable barrier controlling bidirectional transfer between blood vessel and irrigated tissues. This crucial function relies on the dynamic architecture of endothelial cell-cell junctions, and in particular, VE-cadherin-mediated contacts. VE-cadherin indeed chiefly organizes the opening and closing of the endothelial barrier, and is central in permeability changes. In this review, the way VE-cadherin-based contacts are formed and maintained is first presented, including molecular traits of its expression, partners, and signaling. In a second part, the mechanisms by which VE-cadherin adhesion can be disrupted, leading to cell-cell junction weakening and endothelial permeability increase, are described. Overall, the molecular basis for VE-cadherin control of the endothelial barrier function is of high interest for biomedical research, as vascular leakage is observed in many pathological conditions and human diseases. © 2014 Landes Bioscience.


Nichols J.D.,University of Leicester | Cowley S.W.H.,University of Leicester | Lamy L.,University of Paris Descartes
Geophysical Research Letters | Year: 2010

We present observations of the oscillation of the dawn-dusk locations of Saturn's northern and southern UV auroral ovals obtained using the Hubble Space Telescope during the 2009 equinoctial campaign. We determine the dawn-dusk locations of the centers of the southern and northern auroral ovals from the mean of the dawnward and duskward extents of the emission, and order the computed locations by the phases of the respective SKR oscillations for each hemisphere. We show that statistically significant ∼1-2 oscillations of the dawn-dusk location of the auroral ovals are evident, with the duskward displacement being in lagging quadrature with the SKR power. These results, the first to indicate that the location of the northern auroral oval oscillates, show that the cause of the oscillation is an external magnetospheric current system, and the sense of the oscillations is consistent with the expected displacement caused by magnetic perturbations observed throughout Saturn's magnetosphere. © 2010 by the American Geophysical Union.


Ruemmele F.M.,University of Paris Descartes | Ruemmele F.M.,French Institute of Health and Medical Research
Current Opinion in Gastroenterology | Year: 2010

Purpose of review: Inflammatory bowel diseases (IBD) comprise a heterogeneous group of distinct intestinal disorders. Here, we discuss the concept of childhood-onset IBD as separate disease forms within a larger multifactorial disease category. Recent findings: There are excellent epidemiological data indicating that the incidence of pediatric IBD, mainly Crohn's disease, is still increasing over the last decades, with indicators of more extensive and more severe disease presentations in children compared to adults, also reflected by higher levels of humoral immune responses. Recent genetic scans allowed to identify particular susceptibility genes for pediatric IBD forms, such as IL27 or probably DcR3. Early postnatal onset forms of IBD might reflect monogenetic causes, as suggested with the finding of IL10 signaling defects that may define a new form of IBD. Summary: There are good epidemiological, genetic and clinical data to distinguish different forms of IBD, particularly forms starting early in life. Profound insights in the molecular basis of immune dysregulation in IBD have been gained over the last few years. These recent discoveries will nourish and substantially stimulate the future search for precise cause(s) responsible for life-long intestinal inflammation and it will help to explain the still ongoing rise in incidence in childhood IBD. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Bonnichon D.,University of Paris Descartes
Evolution Psychiatrique | Year: 2011

The teenager's suicide attempt takes place in adolescent process. Sexuality is key point in this process. Gender differences in teenager's suicide are proved, but not explicated. We want to consider these gender differences in order to understand the girl propensy to attempt suicide. The specific aspects of girl's psychosexual development are analysed. The adolescence returns œdipal fantasy and rivalry conflict. For both, girls and boys, it is the same thing. But the girl rivalry conflict goes with an important ambivalence. It causes her anxiety of being attacked inside his body, but also anxiety of losing love. The girl's suicide attempt, often medicinal, attacks the internal body. These teenagers give themselves the dreaded retaliations. By this way, they avoid the anxiety of losing love. © 2010 Elsevier Masson SAS.


Houillier P.,University of Paris Descartes | Houillier P.,French Institute of Health and Medical Research
Current Opinion in Nephrology and Hypertension | Year: 2013

PURPOSE OF REVIEW: Changes in extracellular calcium concentration affect several functions of the renal tubule. The calcium-sensing receptor (CaSR), initially identified in the parathyroid gland cells, is also expressed in the kidney and was assumed to mediate all effects of extracellular calcium on the renal tubule. The purpose of this review is to critically review the evidence supporting this assumption. RECENT FINDINGS: Recent results confirm that, in the kidney, the CaSR is mainly expressed in the thick ascending limb of the loop of Henle. There, it is involved in the control of calcium reabsorption, independently of its action on parathyroid hormone secretion, through an effect on the paracellular pathway permeability. Although extracellular calcium affects transports other than that of calcium, the direct evidence that CaSR is involved in these effects is still lacking in many instances. SUMMARY: As the CaSR in the kidney controls calcium reabsorption and excretion and subsequently affects blood calcium concentration, agonists and antagonists of the CaSR could be used to control blood calcium concentration in patients who have lost their ability to regulate parathyroid hormone secretion. In addition, more work is needed to further decipher the molecular mechanisms through which CaSR determines calcium transport in the loop of Henle.


Seghatchian J.,Hill International | Samama M.M.,University of Paris Descartes
Transfusion and Apheresis Science | Year: 2012

Massive transfusion (MT) is an empiric mode of treatment advocated for uncontrolled bleeding and massive haemorrhage, aiming at optimal resuscitation and aggressive correction of coagulopathy. Conventional guidelines recommend early administration of crystalloids and colloids in conjunction with red cells, where the red cell also plays a critical haemostatic function. Plasma and platelets are only used in patients with microvascular bleeding with PT/APTT values >1.5 times the normal values and if PLT counts are below 50×109/L. Massive transfusion carries a significant mortality rate (40%), which increases with the number of volume expanders and blood components transfused. Controversies still exist over the optimal ratio of blood components with respect to overall clinical outcomes and collateral damage. While inadequate transfusion is believed to be associated with poor outcomes but empirical over transfusion results in unnecessary donor exposure with an increased rate of sepsis, transfusion overload and infusion of variable amounts of some biological response modifiers (BRMs), which have the potential to cause additional harm. Alternative strategies, such as early use of tranexamic acid are helpful. However in trauma settings the use of warm fresh whole blood (WFWB) instead of reconstituted components with a different ratio of stored components might be the most cost effective and safer option to improve the patient's survival rate and minimise collateral damage. This manuscript, after a brief summary of standard medical intervention in massive transfusion focuses on the main characteristics of various substances currently available to overcome massive transfusion coagulopathy. The relative levels of some BRMs in fresh and aged blood components of the same origin are highlighted and some myths and unresolved issues related to massive transfusion practice are discussed. In brief, the coagulopathy in MT is a complex phenomenon, often complicated by chronic activation of coagulation, platelets, complement and vascular endothelial cells, where haemolysis, microvesiculation, exposure of phosphatidyl serine positive cells, altered red cells with reduced adhesive proteins and the presence of some BRM, could play a pivotal role in the coagulopathy and untoward effects. The challenges of improving the safety of massive transfusion remain as numerous and as varied as ever. The answer may reside in appropriate studies on designer whole blood, combined with new innovative tools to diagnosis a coagulopathy and an evidence based mode of therapy to establish the optimal survival benefit of patients, always taking into account the concept of harm reduction and reduction of collateral damage. © 2012 Elsevier Ltd.


Soussi T.,Karolinska Institutet | Soussi T.,Paris-Sorbonne University | Soussi T.,French Institute of Health and Medical Research | Soussi T.,University of Paris Descartes | Wiman K.G.,Karolinska Institutet
Cell Death and Differentiation | Year: 2015

The standard classification used to define the various cancer genes confines tumor protein p53 (TP53) to the role of a tumor suppressor gene. However, it is now an indisputable fact that many p53 mutants act as oncogenic proteins. This statement is based on multiple arguments including the mutation signature of the TP53 gene in human cancer, the various gains-of-function (GOFs) of the different p53 mutants and the heterogeneous phenotypes developed by knock-in mouse strains modeling several human TP53 mutations. In this review, we will shatter the classical and traditional image of tumor protein p53 (TP53) as a tumor suppressor gene by emphasizing its multiple oncogenic properties that make it a potential therapeutic target that should not be underestimated. Analysis of the data generated by the various cancer genome projects highlights the high frequency of TP53 mutations and reveals that several p53 hotspot mutants are the most common oncoprotein variants expressed in several types of tumors. The use of Muller's classical definition of mutations based on quantitative and qualitative consequences on the protein product, such as 'amorph', 'hypomorph', 'hypermorph' 'neomorph' or 'antimorph', allows a more meaningful assessment of the consequences of cancer gene modifications, their potential clinical significance, and clearly demonstrates that the TP53 gene is an atypical cancer gene. © 2015 Macmillan Publishers Limited.


Guillemin F.,University of Paris Descartes | Guillemin F.,University of Lorraine
Current Opinion in Rheumatology | Year: 2012

Purpose: Producing descriptive epidemiology data is essential to understand the burden of rheumatic diseases (prevalence) and their dynamic in the population (incidence). Important considerations: No matter how simple such indicators may look, the correct collection of data and the appropriate interpretation of the results face several challenges: distinguishing indicators, facing the costs of obtaining data, using appropriate definition, identifying optimal sources of data, choosing among many survey methods, dealing with estimates precision, and standardizing results. Summary: This study describes the underlying methodological difficulties to be overcome so as to make descriptive indicators reliable and interpretable. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Fontaine H.,University of Paris Descartes
Clinics and research in hepatology and gastroenterology | Year: 2011

Around 50% of hepatitis C virus (HCV)-positive patients infected with genotype 1 are nonresponders to the combination of pegylated interferon (pegIFN) and ribavirin, including relapsers, and partial and null responders and, as such, are exposed to the risk of progression to cirrhosis and its complications, resulting in HCV-related morbidity and mortality. Repeat treatment using the same combination in such patients results in <5% viral eradication and there are no therapeutic prospects for patients who fail, as maintenance therapy has not proved efficacious. The triple association of direct-acting antivirals specific of HCV, and especially the first-generation protease inhibitors boceprevir and telaprevir, increases this percentage to around 65%, with variations according to the previous response to therapy of patients (85% of relapsers, 50% of partial responders and 30% of null responders). These encouraging results extend the therapeutic indications and costs of therapy during virological follow-up, and influence the rules of discontinuation. Information on the management of these new molecules also allows a larger number of patients to be cured and reduces the occurrence of viral resistance. Thus, the aim of the present review is to summarize the efficacy of the triple association of pegIFN, ribavirin and telaprevir or boceprevir in treatment-experienced patients who failed to respond to dual pegIFN and ribavirin therapy. Copyright © 2011 Elsevier Masson SAS. All rights reserved.


Bahi-Buisson N.,University of Paris Descartes | Guerrini R.,University of Florence
Handbook of Clinical Neurology | Year: 2013

Malformations of cortical development (MCD) represent a major cause of developmental disabilities and severe epilepsy. Advances in imaging and genetics have improved the diagnosis and classification of these conditions. Up to now, eight genes have been involved in different types of MCD. Lissencephaly-pachygyria and subcortical band heterotopia (SBH) represent a malformative spectrum resulting from mutations of either LIS1 or DCX genes. LIS1 mutations cause a more severe malformation in the posterior brain regions. DCX mutations usually cause anteriorly predominant lissencephaly in males and SBH in female patients. Additional forms are X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia associated with mutations of the ARX gene. Lissencephaly with cerebellar hypoplasia (LCH) encompass heterogeneous disorders named LCH types a to d. LCHa is related to mutation in LIS1 or DCX, LCHb with mutation of the RELN gene, and LCHd could be related to the TUBA1A gene.Polymicrogyria encompasses a wide range of clinical, etiological, and histological findings. Among several syndromes, recessive bilateral fronto-parietal polymicrogyria has been associated with mutations of the GPR56 gene. Bilateral perisylvian polymicrogyria has been associated with mutations in the SRPX2 gene in a few individuals and with linkage to chromosome Xq28 in a some other families.X-linked bilateral periventricular nodular heterotopia (PNH) consists of PNH with focal epilepsy in females and prenatal lethality in males. Filamin A (FLNA) mutations have been reported in some families and in sporadic patients. It is possible to infer the most likely causative gene by brain imaging studies and other clinical findings. © 2013 Elsevier B.V.


Puechal X.,systemIC | Puechal X.,University of Paris Descartes
Annals of the Rheumatic Diseases | Year: 2013

Whipple's disease is a chronic, systemic infection caused by Tropheryma whipplei. Gene amplification, isolation and DNA sequencing of T whipplei have extended our knowledge of this pathogen, which is now recognised as a ubiquitous commensal bacterium. The spectrum of signs associated with T whipplei has now been extended beyond the classic form, which affects middle-aged men, and begins with recurrent arthritis followed several years later by digestive problems associated with other diverse clinical signs. Children may present an acute primary infection, but only a small number of people with a genetic predisposition subsequently develop authentic Whipple's disease. This bacterium may also cause localised chronic infections with no intestinal symptoms: endocarditis, central nervous system involvement, arthritis, uveitis and spondylodiscitis. An impaired TH1 immune response is seen. T whipplei replication in vitro is dependent on interleukin 16 and is accompanied by the apoptosis of host cells, facilitating dissemination of the bacterium. In patients with arthritis, PCR with samples of joint fluid, saliva and stools has become the preferred examination for diagnosis. Immunohistochemical staining is also widely used for diagnosis. Treatment is based on recent microbiological data, but an immune reconstitution syndrome and recurrence remain possible. The future development of serological tests for diagnosis and the generalisation of antigen detection by immunohistochemistry should make it possible to obtain a diagnosis earlier and thus to decrease the morbidity, and perhaps also the mortality, associated with this curable disease which may, nonetheless, be fatal if diagnosed late or in an extensive systemic form.


Tsopra R.,University of Paris 13 | Jais J.-P.,University of Paris Descartes | Venot A.,University of Paris 13 | Duclos C.,University of Paris 13
Journal of the American Medical Informatics Association | Year: 2014

Context: It is important to consider the way in which information is presented by the interfaces of clinical decision support systems, to favor the adoption of these systems by physicians. Interface design can focus on decision processes (guided navigation) or usability principles. Objective: The aim of this study was to compare these two approaches in terms of perceived usability, accuracy rate, and confidence in the system. Materials and methods: We displayed clinical practice guidelines for antibiotic treatment via two types of interface, which we compared in a crossover design. General practitioners were asked to provide responses for 10 clinical cases and the System Usability Scale (SUS) for each interface. We assessed SUS scores, the number of correct responses, and the confidence level for each interface. Results: SUS score and percentage confidence were significantly higher for the interface designed according to usability principles (81 vs 51, p=0.00004, and 88.8% vs 80.7%, p=0.004). The percentage of correct responses was similar for the two interfaces. Discussion/conclusion: The interface designed according to usability principles was perceived to be more usable and inspired greater confidence among physicians than the guided navigation interface. Consideration of usability principles in the construction of an interface-in particular 'effective information presentation', 'consistency', 'efficient interactions', 'effective use of language', and 'minimizing cognitive load'-seemed to improve perceived usability and confidence in the system.


Guillevin L.,University of Paris Descartes
Best Practice and Research: Clinical Rheumatology | Year: 2013

Infections, mainly viral, are the cause of some vasculitides, like polyarteritis nodosa (hepatitis B virus) or mixed cryoglobulinemia (hepatitis C virus), and it has been hypothesized that others might be due to infectious agents (HIV, EBV, parvovirus.). Among etiologies of vasculitis, the responsibility of a Burkholderia-like strain has been recently demonstrated as the cause of giant-cell arteritis. On the other hand, patients frequently develop infections, mainly as a consequence of steroids, immunosuppressants and most immunomodulating treatments prescribed to treat vasculitides. Infections occur when patients receive steroids and immunosuppressants, especially in the long term. They are more frequently observed in elderly patients or in patients with poor general condition. Infection risk is not reduced when biotherapies are prescribed to induce or maintain remission. Patients, considered at higher risk for infections, should be followed closely and their immunological status monitored periodically. We recommend especially to monitor neutrophiles, lymphocytes and if needed CD3-, CD4- and CD8-cell counts in patients receiving steroids and cyclophosphamide or other cytotoxic agents. In patients treated with rituximab, CD19 and gammaglobulins should be monitored regularly. Prophylaxis are needed in patients at risk to develop infections. © 2012 Elsevier Ltd. All rights reserved.


Baiz N.,French Institute of Health and Medical Research | Baiz N.,University Pierre and Marie Curie | Dargent-Molina P.,French Institute of Health and Medical Research | Dargent-Molina P.,University Pierre and Marie Curie | And 4 more authors.
Journal of Allergy and Clinical Immunology | Year: 2014

Background: There is increasing evidence of the effect of maternal vitamin D intake during pregnancy on the risk of asthma and allergic outcomes in offspring. However, studies on the relationship between cord levels of 25-hydroxyvitamin D (25[OH]D) and asthma and allergic diseases are very few. Objective: Our aim was to investigate the associations between cord serum 25(OH)D levels and asthma, wheezing, allergic rhinitis, and atopic dermatitis in the offspring from birth to 5 years. Methods: Cord blood samples were collected at birth and analyzed for 25(OH)D levels in 239 newborns from the Etude des Déterminants pré et post natals du développement et de la santé de l′Enfant (EDEN) birth cohort. The children were followed up until age 5 years by using International Study of Asthma and Allergies in Childhood-based symptom questionnaires. Results: The median cord serum level of 25(OH)D was 17.8 ng/mL (interquartile range, 15.1 ng/mL). By using multivariable-adjusted logistic regression models, a significant inverse association was observed between cord serum 25(OH)D levels and risk of transient early wheezing and early- and late-onset atopic dermatitis, as well as atopic dermatitis, by the ages of 1, 2, 3, and 5 years. We found no association between cord serum 25(OH)D levels and asthma and allergic rhinitis at age 5 years. Conclusions: Cord serum 25(OH)D levels were inversely associated with the risk of transient early wheezing and atopic dermatitis by the age of 5 years, but no association was found with asthma and allergic rhinitis. © 2013 American Academy of Allergy, Asthma & Immunology.


De Witt Hamer P.C.,VU University Amsterdam | Moritz-Gasser S.,Montpellier University Hospital Center | Gatignol P.,University of Paris Descartes | Duffau H.,Montpellier University Hospital Center | Duffau H.,Montpellier University
Human Brain Mapping | Year: 2011

Human brain pathways required for language processing are poorly known. A new white matter tract in humans, the middle longitudinal fascicle, has recently been anatomically determined by diffusion tensor imaging and suggested to be essential for language. Our aim is to determine the importance of the middle longitudinal fascicle for language processing. This study is based on 8 patients with glioma resection at least involving the superior temporal gyrus of the left dominant hemisphere. Language is systematically examined pre- and postoperatively at 3 months. Intraoperative electrostimulation is used to map cortical and subcortical structures as functional boundaries of the glioma resection, including those essential for language processing. The resections are extensive (on average 62 ml, ranging from 21 to 111 ml) and include a large part of the middle longitudinal fascicle in all patients. Intraoperatively, no interference with picture naming is observed by electrostimulation of the middle longitudinal fascicle, while in all patients the inferior fronto-occipital fascicle is identified by eliciting semantic paraphasia as functional boundary. Postoperatively, no new permanent language deficits are detected by systematic language examination. Therefore, we suggest that the middle longitudinal fascicle may participate but is not essential for language processing. © 2010 Wiley-Liss, Inc.


Amthor H.,University Pierre and Marie Curie | Amthor H.,University of Paris Descartes | Hoogaars W.M.H.,Leiden University
Current Gene Therapy | Year: 2012

Since the discovery of the myostatin/ActRIIB signaling pathway 15 years ago, numerous strategies were developed to block its inhibitory function during skeletal muscle growth. Accumulating evidence demonstrates that abrogation of myostatin/ActRIIB signaling ameliorates pathology and function of dystrophic muscle in animal models for Duchenne muscular dystrophy (DMD). Therapeutic trials in healthy man and muscular dystrophy patients suggest feasibility of blockade strategies for potential clinical use. However, many key questions on the effect of myostatin/ActRIIB blockade remain unresolved; such as the underlying molecular mechanism that triggers muscle growth, the effect on muscle regeneration and adult muscle stem cell regulation and whether it causes long term metabolic alterations. Current therapeutic strategies aim to systemically abrogate myostatin/ActRIIB signaling. Although this ensures widespread effect on musculature, it also interferes with ActRIIB signaling in other tissues than skeletal muscle, thereby risking adverse effects. This review discusses current knowledge on myostatin/ActRIIB signaling and its potential value as a therapeutic target for DMD. © 2012 Bentham Science Publishers.


Flor P.J.,University of Regensburg | Acher F.C.,University of Paris Descartes
Biochemical Pharmacology | Year: 2012

Group-III metabotropic glutamate receptors (mGluRs) comprise four structurally related brain and retinal G protein-coupled receptors (GPCRs), mGluR4, mGluR6, mGluR7 and mGluR8, which receive much attention as promising targets for nervous system drugs. In particular, activation of mGluR4 is a major focus for the development of new therapeutics in Parkinson's disease, while mGluR7 activation is considered a potential approach for future treatments of specific psychiatric conditions. The first generation group-III mGluR agonists, e.g. l-AP4 and l-SOP, are characterized by an essential phosphonate functional group, which became a major limitation for the development of systemically active, potent and receptor subtype-selective drugs. Recently however, two approaches emerged in parallel providing resolution to this constraint: in silico high-throughput screening of chemical libraries against a 3D-model of the mGluR4 extracellular domain identified a hit that was optimized into a series of potent and subtype-selective orthosteric agonists with drug-like properties and novel chemotype structures; secondly, high-throughput random screening of chemical libraries against recombinantly expressed group-III receptors identified diverse chemical sets of allosteric agonists and positive modulators, which are drug-like, display selectivity for mGluR4, mGluR7, or mGluR8 and act via novel pharmacological sites. Here, we illustrate new scientific insights obtained via the use of those strategies. Also, we compare advantages and disadvantages of both approaches to identify the desired group-III mGluR activators and we conclude with suggestions how to employ those discovery strategies with success for the identification, optimization, and development of clinical drug candidates; this may have important implications for the entire field of GPCR research. © 2012 Elsevier Inc.


Shi D.D.,Princeton University | Trigo F.F.,University of Paris Descartes | Semmelhack M.F.,Princeton University | Wang S.S.-H.,Princeton University
Journal of the American Chemical Society | Year: 2014

Photoactivatable "caged" neurotransmitters allow optical control of neural tissue with high spatial and temporal precision. However, the development of caged versions of the chief vertebrate inhibitory neurotransmitter, γ-amino butyric acid (GABA), has been limited by the propensity of caged GABAs to interact with GABA receptors. We describe herein the synthesis and application of a practically useful doubly caged GABA analog, termed bis-α-carboxy-2-nitrobenzyl-GABA (bis-CNB-GABA). Uncaging of bis-CNB-GABA evokes inward GABAergic currents in cerebellar molecular layer interneurons with rise times of 2 ms, comparable to flash duration. Response amplitudes depend on the square of flash intensity, as expected for a chemical two-photon uncaging effect. Importantly, prior to uncaging, bis-CNB-GABA is inactive at the GABAA receptor, evoking no changes in holding current in voltage-clamped neurons and showing an IC50 of at least 2.5 mM as measured using spontaneous GABAergic synaptic currents. Bis-CNB-GABA is stable in solution, with an estimated half-life of 98 days in the light. We expect that bis-CNB-GABA will prove to be an effective tool for high-resolution chemical control of brain circuits. © 2014 American Chemical Society.


De Ziegler D.,University of Paris Descartes | Meldrum D.R.,Reproductive Partners Medical Group la Jolla
Fertility and Sterility | Year: 2015

Training in reproductive endocrinology (REI) and its male variant, andrology, has been profoundly influenced by the central role captured by assisted reproductive technologies (ART). The marked differences in financial, regulatory, and societal/ethical restrictions on ART in different countries of the world also prominently influence the clinical management of infertility. Training should strive for comprehensive teaching of all medically indicated procedures, even if only to optimize cross-border care. Better international standardization of infertility practices and training would benefit worldwide infertility care and should be promoted by international societies.


Uhl J.-F.,University of Paris Descartes | Uhl J.-F.,The Surgical Center | Gillot C.,The Surgical Center
Phlebology | Year: 2012

The aim of this paper is to demonstrate the location of the venous foot pump using an anatomical study. Four hundred cadaveric feet were injected with green neoprene latex followed by a dissection. A coloured segmentation of the venous system was achieved. The Lejars' concept of the venous sole of the foot is incorrect: the true blood venous reservoir of the foot is located deeply in the plantar veins, between the plantar muscles. The medial and mostly lateral plantar veins converge into the plexus shaped calcaneal crossroad, where the blood is ejected upwards into the two posterior tibial veins. In addition, the several medial perforators of the foot directly connect the deep system (medial plantar veins) to the superficial venous system (medial marginal vein). This forms a true 'medial functional unit' which is unique in the limb given its directional flow is from deep to superficial. In conclusion, the plantar veins play an important role in the physiology of the venous return since a venous reservoir of 25 mL of blood is mobilized upwards with each step during walking. Therefore, the impairment of the foot pump by a static foot disorder should be considered as an important risk factor for chronic venous disease, and should be evaluated and corrected in any patient with venous insufficiency.


Cutaneous squamous cell carcinoma (cSCC) is a frequent side-effect of vemurafenib treatment. The main aim of this study was to identify the clinical risk factors associated with the development of cSCC in melanoma patients treated with vemurafenib. We carried out a retrospective study, including 63 consecutive melanoma patients treated with vemurafenib for BRAF-mutant metastatic melanoma in an oncodermatological department. Clinical and follow-up data were collected and analysed, and a comparison of the subgroups who did and did not develop cSCC was performed. A total of 42.9% of patients (n=27) treated with vemurafenib developed one or more cSCC. Patients with cSCC were significantly older (P=0.01). Clear eyes were also associated with a higher risk of developing cSCC (odds ratio=3.50; 95% confidence interval: 1.08–12.43). Three patients developed cSCC more than 1 year after the initiation of treatment (12, 16 and 18 months, respectively). Clinicians should be vigilant in older patients undergoing vemurafenib therapy as well as patients with clear eyes as they seem to be at increased risk of developing cSCC, even late after the initiation of treatment. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Gavard J.,French National Center for Scientific Research | Gavard J.,French Institute of Health and Medical Research | Gavard J.,University of Paris Descartes
Cell Adhesion and Migration | Year: 2013

The endothelium forms a selective semi-permeable barrier controlling bidirectional transfer between blood vessel and irrigated tissues. This crucial function relies on the dynamic architecture of endothelial cell-cell junctions, and in particular, VE -cadherin-mediated contacts. VE -cadherin indeed chiefly organizes the opening and closing of the endothelial barrier, and is central in permeability changes. In this review, the way VE -cadherin-based contacts are formed and maintained is first presented, including molecular traits of its expression, partners, and signaling. In a second part, the mechanisms by which VE -cadherin adhesion can be disrupted, leading to cell-cell junction weakening and endothelial permeability increase, are described. Overall, the molecular basis for VE -cadherin control of the endothelial barrier function is of high interest for biomedical research, as vascular leakage is observed in many pathological conditions and human diseases. © 2013 Landes Bioscience.


Ludvigsson J.,Linkoping University | Krisky D.,Diamyd Medical | Casas R.,Linkoping University | Battelino T.,University of Ljubljana | And 8 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixedmeal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P = 0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.) Copyright © 2012 Massachusetts Medical Society.


Wicart P.,University of Paris Descartes
Orthopaedics and Traumatology: Surgery and Research | Year: 2012

Pes cavus, defined as a high arch in the sagittal plane, occurs in various clinical situations. A cavus foot may be a variant of normal, a simple morphological characteristic, seen in healthy individuals. Alternatively, cavus may occur as a component of a foot deformity. When it is the main abnormality, direct pes cavus should be distinguished from pes cavovarus. In direct pes cavus, the deformity occurs only in the sagittal plane (in the forefoot, hindfoot, or both). Direct pes cavus may be related to a variety of causes, although neurological diseases predominate in posterior pes cavus. Pes cavovarus is a three-dimensional deformity characterized by rotation of the calcaneopedal unit (the foot minus the talus). This deformity is caused by palsy of the intrinsic foot muscles, usually related to Charcot-Marie-Tooth disease. The risk of progression during childhood can be eliminated by appropriate conservative treatment (orthosis to realign the foot). Extra-articular surgery is indicated when the response to orthotic treatment is inadequate. Muscle transfers have not been proven effective. Triple arthrodesis (talocalcanear, talonavicular, and calcaneocuboid) accelerates the mid-term development of osteoarthritis in the adjacent joints and should be avoided. © 2012.


Robert L.,University of Paris Descartes
Pathologie Biologie | Year: 2015

Hyaluronan (hyaluronic acid, HA) is a ubiquitous linear polysaccharide endowed with some exceptional physicochemical properties such as strong hydration and viscoelasticity that depend on the size of the molecule. It plays a variety of important physiological roles in tissue hydration and mechanical protection, for example in the umbilical cord, skin and most other tissues. Since its large scale preparation and the invention by E.A.Balazs of the preparation of its non-inflammatory fraction (NIF-NaHA), there have been several important medical and cosmetic applications, most notably of viscosurgery for eye operation, intra-articular injections for osteoarthritis and also for wrinkle filling on the face, as well as for drug administration. Its concentration in tissues is decreasing with age, source of loss of function and structure of tissues. The purpose of this review is to present a succinct overview of the essential properties of hyaluronan and its medical and esthetic applications. © 2014 Elsevier Masson SAS.


Larmarange J.,University of Paris Descartes | Bendaud V.,UNAIDS
AIDS | Year: 2014

Objectives: A better understanding of the subnational variations could be paramount to the efficiency and effectiveness of the response to the HIV epidemic. The purpose of this study is to describe the methodology used to produce the first estimates at second subnational level released by UNAIDS.Methods: We selected national population-based surveys with HIV testing and survey clusters geolocation, conducted in 2008 or later. A kernel density estimation approach (prevR) with adaptive bandwidths was used to generate a surface of HIV prevalence. This surface was combined with LandScan global population distribution grid to estimate the spatial distribution of people living with HIV (PLWHIV). Finally, results were adjusted to national UNAIDS's published estimates and merged per second subnational administrative unit. An indicator of the quality of the estimates was computed for each administrative unit.Results: These estimates combine two complementary approaches: The prevR method, focusing on spatial variations of HIV prevalence, as well as national estimates published by UNAIDS, taking into account trends of HIV prevalence over time. Seventeen country reports have been produced. However, quality of the estimates at second subnational level is highly heterogonous between countries, depending on the number of units and the survey sampling size. In some countries, estimates at second subnational level are very uncertain and should be interpreted with caution.Conclusion: These estimates at second subnational level constitute a first step to help countries to better understand their HIV epidemic and to inform programming at lower geographical levels. Further developments are needed to better match local needs. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Novak J.,Charles University | Novak J.,French Institute of Health and Medical Research | Lehuen A.,French Institute of Health and Medical Research | Lehuen A.,University of Paris Descartes
Cytokine | Year: 2011

iNKT cells, CD1d dependent natural killer T cells are a unique population of T cells. The capacity of iNKT cells to produce regulatory cytokines first provided an indication of their regulatory potential. Later on, in experimental models as well as in patients afflicted with an auto-immune disease, such as Type 1 diabetes mellitus, multiple sclerosis, and systemic lupus erythematosus along with others, a deficit in iNKT cell number was observed, suggesting the role these cells may possibly have in the prevention of auto-immune diseases. More importantly, experimental strategies which focused on increasing the volume or stimulation of iNKT cells in laboratory animals, demonstrated an improved level of protection against the development of auto-immune diseases. This article reviews the mechanism of protection against autoimmunity by iNKT cells, discusses the obstacles against and indications for the potential use of iNKT cell manipulation in the treatment of human auto-immune diseases. © 2010 Elsevier Ltd.


Flavone-8-acetic acid (FAA) has been proved to be a potent vascular-disrupting agent in mice. Unfortunately, FAA did not produce any anticancer activity in clinical trials. Previously, we had reported that FAA is metabolized by mouse microsomes into six metabolites, whereas it was poorly metabolized by human microsomes, with fewer metabolites formed in lesser amounts. Especially, 6-OH-FAA was not formed by human microsomes. In this work, two major available metabolites, 4′-OH-FAA and 6-OH-FAA, were tested and compared with the parent compound FAA for their potential antivascular activities in vitro. The ability of the products to induce morphological changes, disrupt preformed capillaries of EA.hy926 endothelial cells and inhibit tubulin polymerization in vitro was assessed. The action mechanism was determined using the RhoA and Rac1 inhibitors. At 25 µg/ml, 6-OH-FAA induced morphological changes and membrane blebbing, whereas 300 µg/ml of FAA and 4′-OH-FAA slightly changed the morphology without inducing membrane blebbing. At 300 µg/ml, 6-OH-FAA produced morphological changes that were 2.1–6.9-fold greater than that produced by FAA and 4′-OH-FAA, an effect that was consistent with its much greater inhibitory effect on tubulin polymerization compared with FAA and 4′-OH-FAA. 6-OH-FAA significantly disrupted the EA.hy926 cell capillaries. 6-OH-FAA activities were prevented in EA.hy926 cells pretreated with RhoA, but not Rac1, inhibitor. In this short communication we report for the first time that, in vitro, 6-OH-FAA, a mouse-specific FAA metabolite, exhibits significantly stronger antivascular activities compared with FAA and 4′-OH-FAA, which are mediated through the RhoA kinase pathway. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Esterle L.,University of Paris Descartes | Mathieu-Fritz A.,University Paris Est Creteil
International Journal of Medical Informatics | Year: 2013

Teleconsultations in medicine are encouraged by authorities and decision-makers to improve access to specialty services for isolated patients. For elderly patients in geriatric hospitals, they thus avoid trips to consult with specialists. However, teleconsultation can modify clinical practice and it may be abandoned for reasons not related to technical issues. Qualitative research on the impact of teleconsultation on medical practice and organisation are thus crucial for an understanding of the changes it can generate. Methods: We used qualitative methods to analyse the impact on professional work practices and care organisation of an initially experimental and then permanent teleconsultation system using a video conference system set up between a geriatric hospital and a tertiary care hospital. Sixty-six teleconsultations (56 during the experimental phase and 10 when the system was in routine use) were observed and ten semi-structured interviews were carried out with the actors in the teleconsultations. Results: Our study shows that the uses of teleconsultation affected work practices of both the consulted specialist and the geriatrician who participated in the consultation alongside the patient. The interactions of specialists with the patient were more difficult than in a face-to-face setting and delegation of the clinical examination of the patient depended on a specific form of cooperation and on trust in the person doing the examination. New kinds of relationships between health professionals contributed to sharing and transmission of knowledge between practitioners. While teleconsultations established alliances between geriatricians and specialists, they none-the-less called for a certain humility on the part of geriatricians. In order for these relationships to become routine and to facilitate interaction among participants, the project manager carried out important work during the experimental phase of the teleconsultations by organising these interactions. Finally, the teleconsultations went through several local reorganisations, especially within the geriatric hospital. These included changes in the geriatrician's schedule and the added presence of an assistant knowledgeable in telemedicine. Conclusions: Specialists found the system used for teleconsultation between a geriatric hospital and a tertiary care hospital to be suitable for their consultations. The main advantage brought about by the teleconsultation system studied resulted from its collaborative nature, which created relationships between health professionals. This resulted in improved care for elderly patients. However, using the system required effort on the part of both the specialists and the geriatricians. Adapting to the system was facilitated by coordination work carried out by the project manager during the experimental phase that created a favourable context for cooperation between actors, allowing diagnoses to be made at a distance. Finally, teleconsultations do not appear suitable for all specialties, by reason of the limits imposed on the delegation of tasks, or to all situations. They require setting up new forms of organisation that must be encouraged by decision-makers. © 2013 Elsevier Ireland Ltd.


Majumder S.,University of Calcutta | Mondal S.,University of Calcutta | Lemoine P.,University of Paris Descartes | Mohanta S.,University of Calcutta
Dalton Transactions | Year: 2013

The work in this paper presents the syntheses, characterization, catecholase activity, and electrospray ionization mass spectroscopic (ESI-MS positive) study of three mixed-valence dinuclear CoIIICoII complexes of composition [CoIIICoIIL(N3) 3]·CH3CN (1), [CoIIICo IIL(OCN)3]·CH3CN (2), and [Co IIICoIIL(μ-CH3COO)2](ClO 4) (3), derived from a tetraimino diphenolate macrocyclic ligand H2L, obtained on [2 + 2] condensation of 4-ethyl-2,6-diformylphenol and 2,2′-dimethyl-1,3-diaminopropane. While 1 and 2 are diphenoxo-bridged, 3 is a heterobridged bis(μ-phenoxo)bis(μ-acetate) system. Utilizing 3,5-di-tert-butyl catechol (3,5-DTBCH2) as the substrate, the catecholase activity of all the three complexes has been checked in methanol/acetonitrile/N,N-dimethyl formamide. While 2 and 3 are inactive, complex 1 shows catecholase activity with turnover numbers of 482.16 h -1 and 45.38 h-1 in acetonitrile and methanol, respectively. Electrospray ionization mass (ESI-MS positive) spectra of complexes 1-3 have been recorded in acetonitrile solutions and the positive ions have been well characterized. The ESI-MS positive spectrum of complex 1 in the presence of 3,5-DTBCH2 has also been recorded and, interestingly, two positive ions [CoIIICoIIL(N3) 2(3,5-DTBCH-)H]+ and [CoIICo IIL(μ-3,5-DTBCH2-)Na]+ have been identified. © The Royal Society of Chemistry 2013.


Rotig A.,University of Paris Descartes
Revue Neurologique | Year: 2014

Oxidative phosphorylation, i.e. ATP synthesis by the oxygen-consuming respiratory chain (RC), supplies most organs and tissues with a readily usable energy source, and is already fully functioning before birth. This means that, in theory, RC deficiency can give rise to any symptom in any organ or tissue at any age and with any mode of inheritance, due to the twofold genetic origin of RC components (nuclear DNA and mitochondrial DNA). It has long been erroneously believed that RC disorders originate from mutations of mtDNA as, for some time, only mutations or deletions of mtDNA could be identified. However, the number of disease-causing mutations in nuclear genes is now steadily growing. These genes not only encode the various subunits of each complex, but also the ancillary proteins involved in the different stages of holoenzyme biogenesis, including transcription, translation, chaperoning, addition of prosthetic groups and assembly of proteins, as well as the various enzymes involved in mtDNA metabolism. © 2014 Elsevier Masson SAS. All rights reserved.


Uhl J.F.,The Surgical Center | Uhl J.F.,University of Paris Descartes
Phlebology | Year: 2012

The aim of multislice helical computed tomography venography (CTV) is to provide a precise, global and three-dimensional (3D) anatomical depiction of the venous network of the lower limbs. A multislice and multidetector spiral CT acquisition of the lower limbs with contrast injection of the dorsal foot produces about 1000 slices in 30 seconds. Dedicated volume-rendering software can compute a realistic and interactive 3D model of the venous system in realtime. This new tool furnishes an accurate 3D representation of the whole venous system of the lower limb with a realistic 3D model of the limbs, providing a road map of the varicose networks complementary to the duplex ultrasound (DUS). CTV allows a complete morphological study of the deep veins, including the detection of anatomical variations and proximal venous obstruction, not easily detectable by DUS. In the case of deep vein thrombosis, it has been shown to be a good diagnostic tool, well correlated with sonography. It also demonstrates, in some cases, haemodynamic patterns which are not available by DUS, particularly for perforator veins and congenital vascular malformations. The use of virtual reality techniques enables a complete anatomical study of both deep and superficial veins including a virtual dissection of the limbs. CTV is also a great educational tool to learn anatomy of the venous system and a powerful research tool to improve our knowledge of venous anatomy.


Data accumulated rapidly over the last decades on genes involved in regulating longevity in several animal models, from yeast to mice. Extrapolation to humans is however a risky enterprise for reasons to be discussed. Aging, age-dependent decline of functions appear however to be independently regulated mainly by post-genetic mechanisms. Little is known on the interactions between genetic and post-genetic processes. A few examples will be discussed, essentially in relation with the Maillard reaction. Age-related diseases, cardiovascular, respiratory, osteo-articular, increase in frequency and severity with age as do also age-related dementias. It is tempting to speculate on the relationship between the mechanisms of longevity, aging and the onset and evolution of these diseases. A better understanding of such relations might accelerate the elaboration of preventive measures and possibly also curative interventions. © 2011 Elsevier Masson SAS and European Union Geriatric Medicine Society.


Jeyabalan J.,Royal Veterinary College | Shah M.,Royal Veterinary College | Viollet B.,University of Paris Descartes | Chenu C.,Royal Veterinary College
Journal of Endocrinology | Year: 2012

There is increasing evidence that osteoporosis, similarly to obesity and diabetes, could be another disorder of energy metabolism. AMP-activated protein kinase (AMPK) has emerged over the last decade as a key sensing mechanism in the regulation of cellular energy homeostasis and is an essential mediator of the central and peripheral effects of many hormones on the metabolism of appetite, fat and glucose. Novel work demonstrates that the AMPK signaling pathway also plays a role in bone physiology. Activation of AMPK promotes bone formation in vitro and the deletion of α or β subunit of AMPK decreases bone mass in mice. Furthermore, AMPK activity in bone cells is regulated by the same hormones that regulate food intake and energy expenditure through AMPK activation in the brain and peripheral tissues. AMPK is also activated by antidiabetic drugs such as metformin and thiazolidinediones (TZDs), which also impact on skeletal metabolism. Interestingly, TZDs have detrimental skeletal side effects, causing bone loss and increasing the risk of fractures, although the role of AMPK mediation is still unclear. These data are presented in this review that also discusses the potential roles of AMPK in bone as well as the possibility for AMPK to be a future therapeutic target for intervention in osteoporosis. © 2012 Society for Endocrinology.


Meijer A.J.,University of Amsterdam | Lorin S.,University Paris - Sud | Blommaart E.F.,University of Amsterdam | Codogno P.,University of Paris Descartes
Amino Acids | Year: 2015

Amino acids not only participate in intermediary metabolism but also stimulate insulin-mechanistic target of rapamycin (MTOR)-mediated signal transduction which controls the major metabolic pathways. Among these is the pathway of autophagy which takes care of the degradation of long-lived proteins and of the elimination of damaged or functionally redundant organelles. Proper functioning of this process is essential for cell survival. Dysregulation of autophagy has been implicated in the etiology of several pathologies. The history of the studies on the interrelationship between amino acids, MTOR signaling and autophagy is the subject of this review. The mechanisms responsible for the stimulation of MTOR-mediated signaling, and the inhibition of autophagy, by amino acids have been studied intensively in the past but are still not completely clarified. Recent developments in this field are discussed. © 2014 The Author(s).


Although frequent and severe, envenomations represent a neglected public health problem in most of the developing countries. Access to antivenoms is poor, mainly in Sub-Saharan Africa, and remains a major concern to World Health Organization (WHO). Since 2007, WHO committed international experts to propose guidelines aiming to improve the manufacture, quality control, registration and use of antivenoms. These guidelines, which will published soon, should promote access to antivenoms, and their use by health services, leading in the short term to a significant decrease of snakebite morbidity and mortality. © 2010 Société de Biologie.


Billard J.-M.,University of Paris Descartes
Journal of Pharmaceutical and Biomedical Analysis | Year: 2015

Experimental evidences now indicate that memory formation relies on the capacity of neuronal networks to manage long-term changes in synaptic communication. This property is driven by N-methyl-. d-aspartate receptors (NMDAR), which requires the binding of glutamate but also the presence of the co-agonist d-serine at the glycine site. Defective memory function and impaired brain synaptic plasticity observed in aging are rescued by partial agonist acting at this site suggesting that this gating process is targeted to induce age-related cognitive defects. This review aims at compelling recent studies characterizing the role of d-serine in changes in functional plasticity that occur in the aging hippocampus since deficits are rescued by d-serine supplementation. The impaired efficacy of endogenous d-serine is not due to changes in the affinity to glycine-binding site but to a decrease in tissue levels of the amino acid resulting from a weaker expression of the producing enzyme serine racemase (SR). Interestingly, neither SR expression, d-serine levels, nor NMDAR activation is affected in aged LOU/C rats, a model of healthy aging in which memory deficits do not occur. These old animals do not develop oxidative stress suggesting that the d-serine-related pathway could be targeted by the age-related accumulation of reactive oxygen species. Accordingly, senescent rats chronically treated with the reducing agent N-acetyl-cysteine to prevent oxidative damage, show intact NMDAR activation linked to preserved d-serine levels and SR expression.These results point to a significant role of d-serine in age-related functional alterations underlying hippocampus-dependent memory deficits, at least within the CA1 area since the amino acid does not appear as critical in changes affecting the dentate gyrus. © 2015 Elsevier B.V.


Touboul D.,CNRS Natural Product Chemistry Institute | Gaudin M.,CNRS Natural Product Chemistry Institute | Gaudin M.,University of Paris Descartes
Bioanalysis | Year: 2014

Alzheimer's disease (AD) is a progressive brain disease that leads to an irreversible loss of neurons and cognition. It is the most common cause of dementia and can be considered as a major public health problem. At the histological level, AD is characterized by senile plaques and neurofibrillary tangles. Numerous studies involving genomic, transcriptomic and proteomic approaches have been published in order to understand the molecular mechanisms involved in AD, and to find new biomarkers. Metabolomics, and in particular lipidomics, have recently offered new possibilities due to the development of robust and sensitive analytical methods, such as LC-MS. This review aims to illustrate how lipidomics can help understand the biological mechanisms inherent to AD and how lipids can be considered as relevant biomarkers of AD at early stages. © 2014 Future Science Ltd.


Elabidi H.,University of Carthage | Sahal-Brechot S.,University of Paris Descartes
European Physical Journal D | Year: 2011

Using their dependence on the upper level ionization potential and the rest core charge of the emitter, electron impact line widths of several highly charged ions have been recently predicted. For most of them, neither theoretical nor experimental data are available (Mg VII, Na VII, Al VIII, Na VIII, Mg IX, Al X, Mg X, Al XI, Si XI, Ti XI, Cr XIII, Cr XIV, Fe XV, Fe XVI, Ni XVIII and Fe XXIII). The aim of this work is to check the above dependence and systematic trends of line widths by using quantum calculations. The comparison between the quantum results and the predicted ones shows that for the same element, the agreement is better for lower ionization degrees. © 2010 EDP Sciences, SIF, Springer-Verlag Berlin Heidelberg.


Provenzi E.,University of Paris Descartes
International Journal of Geometric Methods in Modern Physics | Year: 2016

The space of perceived colors, before acquiring an industrial interest, has received a systematic theoretical attention from philosophers, physicists and mathematicians. The research about this topic is still active nowadays. In this paper, it will be presented a critical overview of a model based on differential geometry proposed by H. L. Resnikoff in 1974. It will be shown that, while some fundamental and elegant ideas behind this model can be still used as a guiding principle, some other parts of the model must be updated to comply with the modern findings about color perception. © 2016 World Scientific Publishing Company


Teulier C.,University of Paris Descartes | Sansom J.K.,University of Michigan | Muraszko K.,University of Michigan | Ulrich B.D.,University of Michigan
Journal of Neurophysiology | Year: 2012

Previous research has described kinetic characteristics of treadmill steps in very stable steppers, in crosssectional designs. In this study we examined, longitudinally, muscle activation patterns during treadmill stepping, without practice, in 12 healthy infants at 1, 6, and 12 mo of age. We assessed lateral gastrocnemius, tibialis anterior, rectus femoris, and biceps femoris as infants stepped on a treadmill during twelve 20-s trials. Infants showed clear changes in kinematics, such as increased step frequency, increased heel contact at touchdown, and more flat-footed contact at midstance. Electromyographic data showed high variability in muscle states (combinations), with high prevalence of all muscles active initially, reducing with age. Agonist-antagonist muscle coactivation also decreased as age increased. Probability analyses showed that across step cycles, the likelihood a muscle was on at any point tended to be <50%; lateral gastrocnemius was the exception, showing an adultlike pattern of probability across ages. In summary, over time, healthy infants produce a wide variety of muscle activation combinations and timings when generating stepping patterns on a treadmill, even if some levels of muscle control arose with time. However, the kinematic stability improved much more clearly than the underlying kinetic strategies. We conclude that although innate control of limb movement improves as infants grow, explore, and acquire functional movement, stepping on a treadmill is a novel and unpracticed one. Hence, developing stable underlying neural activations will only arise as functional practice ensues, similarly to that observed for other functional movements in infancy. © 2012 the American Physiological Society.


Goldberg M.,University of Paris Descartes
Advances in dental research | Year: 2011

Differences between pulp repair and regeneration guide different strategic options. After mild carious dentin lesions, odontoblasts and Hoehl's cells are implicated in the formation of reactionary dentin. Reparative dentin formation and/or pulp regeneration after partial degradation is under the control of pulp progenitors. A series of questions arise from recent researches on tissue engineering. In this series of questions, we compare the therapeutic potential of pluripotent embryonic and adult stem cells, both being used in cell-based dental therapies. Crucial questions arise on the origin of stem cells and the localization of niches of progenitors in adult teeth. Circulating progenitor cells may also be candidate for promoting pulp regeneration. Then, we focus on strategies allowing efficient progenitors recruitment. Along this line, we compare the potential of embryonic stem cells versus adult stem cells. Re-programming adult pulp cells to become induced pluripotent stem cells constitute another option. Genes, transcription factors and growth factors may be used to stimulate the differentiation cascade. Extracellular matrix molecules or some bioactive specific domains after enzymatic cleavage may also contribute to the formation of an artificial pulp and ultimately to its mineralization.


Briet M.,University of Paris Descartes | Schiffrin E.L.,McGill University
Current Hypertension Reports | Year: 2013

Essential hypertension is associated with large and small vascular remodeling that impacts cardiovascular prognosis. Longitudinal follow-up of hypertensive patients has shown that large arterial stiffness decreases partly independently of blood pressure reduction, suggesting specific pharmacological effects of antihypertensive therapy. Inhibitors of the renin-angiotensin- aldosterone system are among the agents that have been shown to affect vascular remodeling to a greater degree. Lifestyle modifications, including exercise and weight reduction, also improve large and small vascular remodeling. New antihypertensive drugs, including neprilysin inhibitors associated with an angiotensin receptor blocker, aldosterone synthase inhibitors and new devices such as renal denervation and baroreceptor stimulation, may exert beneficial effects on vascular remodeling and are currently under evaluation. © 2012 Springer Science+Business Media New York.


Tirlet G.,University of Paris Descartes
The European journal of esthetic dentistry : official journal of the European Academy of Esthetic Dentistry | Year: 2013

Enamel white spot lesions are frequent and can impact patients' quality of life. The most conservative treatment in such cases is microabrasion, a technique that presents some drawbacks. The proposed strategy is not based on the elimination of dysplastic enamel, but on masking the lesion by infiltrating the porous subsurface enamel with a hydrophobic resin that has a refraction index closer to that of sound enamel, after permeating the non-porous surface enamel through hydrochloric acid erosion. Erosion-infiltration approaches have been proposed to treat initial caries, but this report suggests extending it to two novel indications: fluorosis and traumatic hypo-mineralization lesions. Four cases were treated by erosion infiltration following the original protocol. They were followed up clinically at several intervals during a period of 19 months of clinical service. The clinical results, although not perfect, satisfied the patients entirely. Erosion infiltration could be a promising alternative for minimally invasive treatment in similar situations.


Piolino P.,University of Paris Descartes
Current Alzheimer research | Year: 2013

The Self-reference effect (SRE) on long-term episodic memory and autonoetic consciousness has been investigated in young adults, scarcely in older adults, but never in Alzheimer's patients. Is the functional influence of Selfreference still present when the individual's memory and identity are impaired? We investigated this issue in 60 young subjects, 41 elderly subjects, and 28 patients with Alzheimer's disease, by using 1) an incidental learning task of personality traits in three encoding conditions, inducing variable degrees of depth of processing and personal involvement, 2) a 2- minute retention interval free recall task, and 3) a 20-minute delayed recognition task, combined with a remember-know paradigm. Each recorded score was corrected for errors (intrusions in free recall, false alarms in recognition, and false source memory in remember responses). Compared with alternative encodings, the Self-reference significantly enhanced performance on the free recall task in the young group, and on the recognition task both in the young and older groups but not in the Alzheimer group. The most important finding in the Alzheimer group is that the Self-reference led the most often to a subjective sense of remembering (especially for the positive words) with the retrieval of the correct encoding source. This Self-reference recollection effect in patients was related to independent subjective measures of a positive and definite sense of Self (measured by the Tennessee Self Concept Scale), and to memory complaints in daily life. In conclusion, these results demonstrated the power and robustness of the Self-reference effect on recollection in long-term episodic memory in Alzheimer's disease, albeit the retrieval is considerably reduced. These results should open new perspectives for the development of rehabilitation programs for memory deficits.


Garnier J.,University of Paris Descartes | Papanicolaou G.,Stanford University
Inverse Problems | Year: 2010

We analyze the resolution of imaging functionals that migrate the cross-correlation matrices of passive sensor arrays. These matrices are obtained by cross-correlating signals emitted by ambient noise sources and recorded by the passive sensor array. They contain information about reflectors in the surrounding medium. Therefore, travel time or Kirchhoff migration of the cross-correlations can, under favorable circumstances, produce images of such reflectors. However, migration should be carried out appropriately depending on the type of illumination provided by the ambient noise sources. We present here a detailed resolution analysis of these functionals in a homogeneous medium. Resolution depends on the sensor array diameter, the distance from the array to the reflector and the central frequency, as is the case in active array imaging. When imaging with passive sensor arrays and ambient noise, resolution also depends on the space and time coherence of the noise sources because it determines an effective noise bandwidth. © 2010 IOP Publishing Ltd.


Campbell N.D.,Rensselaer Polytechnic Institute | Lovell A.M.,University of Paris Descartes
Annals of the New York Academy of Sciences | Year: 2012

This paper traces the early 21st century success of the agonist-antagonist buprenorphine and the combination drug buprenorphine with naloxone within the broader quest to develop addiction therapeutics that began in the 1920s as the search for a nonaddictive analgesic. Drawing on archival research, document analysis, and interviews with contemporary actors, this paper situates the social organization of laboratory-based and clinical research within the domestic and international confluence of several issues, including research ethics, drug regulation, public attitudes, tensions around definitions of drug addiction, and the evolving roles of the pharmaceutical industry. The fervor that drove the champions of buprenorphine must be understood in relation to (1) the material work of research and pharmaceutical manufacturing; (2) the symbolic role of buprenorphine as a solution to numerous problems with addiction treatment evident by the mid-1970s; the destigmatization and individualization of addicts as patients; and (3) the complex configurations of public and private partnerships. © 2012 New York Academy of Sciences.


Vaiman D.,University of Paris Descartes
Biomedical Journal | Year: 2015

Recurrent pregnancy loss, defined as a pregnancy failure occurring before 24 weeks of gestation more than two or three times according to most definitions, is a fertility defect encountered in 1-5% of the patients. This defect is of course of multifactorial origin. Among the possible origins of recurrent pregnancy loss are uterine structural defaults, defective ploidy control of the embryo, defective immunological dialog between the embryo (or the fetus) and the uterus sometimes in relation with immunological disorders (such as autoimmune diseases), thrombophilia, and free radical metabolism imbalance. Numerous studies attempted to correlate variants of genes supposed to be intervening in the different facets of the early maternal-fetal or maternal-embryonic dialog, and eventually modify the outcome of fertilization, leading to success or failure of post-implantation development. The objective of the present review is to portray the major genes and gene polymorphisms studied for their putative association with recurrent pregnancy loss. Most of these genes have been studied as candidate genes for which strong biological arguments were put forward as to their putative involvement in recurrent pregnancy loss. They were mostly studied by genetic analysis, often in various populations of different ethnic origins, throughout the world. Some of these studies were available only in English as abstracts and were nevertheless used if the information was given with enough detail. With the space being too short to depict all the available literature, different major pathways releva nt to the scientific question are presented without any attempt to hide the fact that discordant views often aroused for a given gene.


Chapelle C.,University of Paris Descartes
Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association | Year: 2014

PURPOSE: To assess the efficacy of low-molecular-weight heparin (LMWH) venous thromboprophylaxis in patients with transient reduced mobility in the non-major orthopaedic setting.METHODS: A meta-analysis was conducted using data from all available randomized trials comparing LMWH with placebo or no prophylactic treatment in patients with leg immobilization for fracture or soft-tissue injury of the lower limb or in patients undergoing knee arthroscopy. The primary endpoint was the incidence of major venous thromboembolic events (VTEs), including asymptomatic proximal deep-vein thrombosis, symptomatic VTEs, and VTE-related death. The Mantel-Haenszel method was used to generate the summary statistics for the overall effect of LMWH.RESULTS: Fourteen studies were included (4,726 patients). The weighted rate of major VTEs was estimated to be 2.9% (95% confidence interval [CI], 2.2% to 3.7%) without LMWH prophylaxis. Overall, a significant 68% reduction in the risk of major VTEs was observed with LMWH prophylaxis (relative risk [RR], 0.32; 95% CI, 0.20 to 0.51; P < .001). The treatment effect was not modified by the clinical setting, that is, distal lower limb injury (7 studies; 1,711 patients; RR, 0.42; 95% CI, 0.20 to 0.86) or knee arthroscopy (6 studies; 2,428 patients; RR, 0.27; 95% CI, 0.15 to 0.49). A nonsignificant 35% increase in the risk of major bleeding was observed in the LMWH prophylaxis group (RR, 1.35; 95% CI, 0.53 to 3.47).CONCLUSIONS: This meta-analysis indicates potential efficacy of LMWH in preventing thromboembolic events in patients with reduced mobility in the non-major orthopaedic setting compared with placebo or no treatment. However, the decision of whether to implement LMWH prophylaxis in each specific setting should also take into account the risk of VTEs in the absence of prophylaxis, the potential adverse effects of LMWH, and the cost.LEVEL OF EVIDENCE: Level II, meta-analysis of Level II studies or Level I studies with inconsistent results. Copyright © 2014 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.


Paris M.,LOreal | Rouleau M.,University of Nice Sophia Antipolis | Puceat M.,University of Paris Descartes | Aberdam D.,University of Nice Sophia Antipolis
Cell Death and Differentiation | Year: 2012

Since the discovery of the TP63 gene in 1998, many studies have demonstrated that ΔNp63, a p63 isoform of the p53 gene family, is involved in multiple functions during skin development and in adult stemprogenitor cell regulation. In contrast, TAp63 studies have been mostly restricted to its apoptotic function and more recently as the guardian of oocyte integrity. TAp63 endogenous expression is barely detectable in embryos and adult (except in oocytes), presumably because of its rapid degradation and the lack of antibodies able to detect weak expression. Nevertheless, two recent independent studies have demonstrated novel functions for TAp63 that could have potential implications to human pathologies. The first discovery is related to the protective role of TAp63 on premature aging. TAp63 controls skin homeostasis by maintaining dermal and epidermal progenitorstem cell pool and protecting them from senescence, DNA damage and genomic instability. The second study is related to the role of TAp63, expressed by the primitive endoderm, on heart development. This unexpected role for TAp63 has been discovered by manipulation of embryonic stem cells in vitro and confirmed by the severe cardiomyopathy observed in brdm2 p63-null embryonic hearts. Interestingly, in both cases, TAp63 acts in a cell-nonautonomous manner on adjacent cells. Here, we discuss these findings and their potential connection during development. © 2012 Macmillan Publishers Limited All rights reserved.


Malmqvist E.,University of Paris Descartes
Bioethics | Year: 2014

This paper challenges the view that bans on kidney sales are unjustifiably paternalistic, that is, that they unduly deny people the freedom to make decisions about their own bodies in order to protect them from harm. I argue that not even principled anti-paternalists need to reject such bans. This is because their rationale is not hard paternalism, which anti-paternalists repudiate, but soft paternalism, which they in principle accept. More precisely, I suggest that their rationale is what Franklin Miller and Alan Wertheimer call 'group soft paternalism'. Group soft paternalistic policies restrict the freedom of autonomous individuals, not for their own good (hard paternalism), but as an unavoidable consequence of seeking to protect other, non-autonomous individuals from harms that they have not voluntarily chosen (soft paternalism). Group soft paternalism supports prohibiting kidney sales on three conditions: (1) that such sales are potentially harmful to vendors, (2) that many vendors would suffer impaired autonomy, and (3) that distinguishing between autonomous and non-autonomous vendors and interfering only with the latter is unfeasible. I provide reasons for thinking that these conditions will often hold. © 2012 John Wiley & Sons Ltd.


Leach S.,University of Paris Descartes
Chemical Physics | Year: 2012

The heats of formation of molecular ions are often not known to better than 10 or 20 kJ/mol. The present study on nitrogenous compounds adopts the graphical approach of Holmes and Lossing [8] which relates cation heats of formation to cation size. A study of methyl substitution in formamides and acetamides is followed by an examination of heat of formation data on carbon-site and nitrogen-site methyl substitution in immonium, amine, imine, ammonium and amino cations. The results provide tests of the validity of this graphical method and also suggest investigating or re-investigating the ionization energies and the heats of formation of several of the molecules studied. © 2011 Elsevier B.V. All rights reserved.


Dekeuwer C.,Jean Moulin University Lyon 3 | Bateman S.,University of Paris Descartes
Medicine, Health Care and Philosophy | Year: 2013

This article presents the results of a study that investigates the way in which carriers of a mutation on the BRCA1 or the BRCA2 gene, associated with a high risk of breast and ovarian cancer, make their reproductive decisions. Using semi-structured interviews, the study explored the way in which these persons reflected on the acceptability of taking the risk of transmitting this mutation to the next generation, the arguments they used in favor or against taking that risk, and in the light of these arguments, their opinion on the acceptability of preimplantation genetic diagnosis (PGD) as a reproductive option. The findings suggest that when carriers are planning to have a(nother) child, they are mainly concerned by the risk of transmitting 'much more than a gene': essentially painful experiences not only with respect to health, such as undergoing cancer surveillance or combatting one's own illness, but also with regards to family life, such as witnessing the illness and death of a close relative, encountering difficulties in finding a partner or reconsidering one's plans to have a family. As for opinions concerning the acceptability of PGD as a reproductive option, opinions about personal recourse were varied but all expressed the understanding that PGD should be made available to those persons who consider it their best option. © 2011 Springer Science+Business Media B.V.


Ong A.C.M.,University of Sheffield | Ong A.C.M.,Sheffield Kidney Institute | Devuyst O.,University of Zurich | Devuyst O.,Catholic University of Louvain | And 2 more authors.
The Lancet | Year: 2015

Autosomal dominant polycystic kidney disease is the most common inherited kidney disease and accounts for 7-10% of all patients on renal replacement therapy worldwide. Although first reported 500 years ago, this disorder is still regarded as untreatable and its pathogenesis is poorly understood despite much study. During the past 40 years, however, remarkable advances have transformed our understanding of how the disease develops and have led to rapid changes in diagnosis, prognosis, and treatment, especially during the past decade. This Review will summarise the key findings, highlight recent developments, and look ahead to the changes in clinical practice that will likely arise from the adoption of a new management framework for this major kidney disease. © 2015 Elsevier Ltd.


Ohayon M.M.,Stanford University | Mahowald M.W.,University of Minnesota | Dauvilliers Y.,French Institute of Health and Medical Research | Krystal A.D.,Duke University | Leger D.,University of Paris Descartes
Neurology | Year: 2012

Objective: To assess the prevalence and comorbid conditions of nocturnal wandering with abnormal state of consciousness (NW) in the American general population. Methods: Cross-sectional study conducted with a representative sample of 19,136 noninstitutionalized individuals of the US general population 18 years old. The Sleep-EVAL expert system administered questions on life and sleeping habits; health; and sleep, mental, and organic disorders (DSM-IV-TR; International Classification of Sleep Disorders, version 2; International Classification of Diseases-10). Results: Lifetime prevalence of NW was 29.2% (95% confidence interval [CI] 28.5%-29.9%). In the previous year, NW was reported by 3.6% (3.3%-3.9%) of the sample: 1% had 2 or more episodes per month and 2.6% had between 1 and 12 episodes in the previous year. Family history of NW was reported by 30.5% of NW participants. Individuals with obstructive sleep apnea syndrome (odds ratio [OR] 3.9), circadian rhythm sleep disorder (OR 3.4), insomnia disorder (OR 2.1), alcohol abuse/dependence (OR 3.5), major depressive disorder (MDD) (OR 3.5), obsessivecompulsive disorder (OCD) (OR 3.9), or using over-The-counter sleeping pills (OR 2.5) or selective serotonin reuptake inhibitor (SSRI) antidepressants (OR 3.0) were at higher risk of frequent NW episodes (2 times/month). Conclusions: With a rate of 29.2%, lifetime prevalence ofNWis high. SSRIs were associated with an increased risk of NW. However, these medications appear to precipitate events in individuals with a prior history of NW. Furthermore, MDD and OCD were associated with significantly greater risk of NW, and this was not due to the use of psychotropic medication. These psychiatric associations imply an increased risk due to sleep disturbance. Copyright © 2012 by AAN Enterprises, Inc.


Collins T.,University of Paris Descartes
Journal of Vision | Year: 2010

Executing sequences of memory-guided movements requires combining sensory information with information about previously made movements. In the oculomotor system, extraretinal information must be combined with stored visual information about target location. The use of extraretinal signals in oculomotor planning can be probed in the double-step task. Using this task and a multiple-step version, the present study examined whether an extraretinal signal was used on every trial, whether its metrics represented desired or actual eye displacement, and whether it was best characterized as a direct estimate of orbital eye position or a vector representation of eye displacement. The results show that accurate information, including saccadic adaptation, about the first saccade is used to plan the second saccade. Furthermore, with multiple saccades, endpoint variability increases with the number of saccades. Controls ruled out that this was due to the perceptual or memory requirements of storing several target locations. Instead, each memory-guided movement depends on an internal copy of an executed movement, which may present a small discrepancy with the actual movement. Increasing the number of estimates increases the variability because this small discrepancy accumulates over several saccades. Such accumulation is compatible with a corollary discharge signal carrying metric information about saccade vectors. © ARVO.


BACKGROUND:: This study was designed to assess the feasibility of dual closed-loop titration of propofol and remifentanil guided solely by the Bispectral Index (BIS) monitor in pediatric and adolescent patients during anesthesia.METHODS:: Children undergoing elective surgery in this single-blind randomized study were allocated into the closed-loop (auto) or manual (manual) group. Primary outcome was the percentage of time with the BIS in the range 40 to 60 (BIS40–60). Secondary outcomes were the percentage of deep (BIS<40) anesthesia and drug consumption. Data are presented as median (interquartile range) or number (%).RESULTS:: Twenty-three patients (12 [10 to 14] yr) were assigned to the auto group and 19 (14 [7 to 14] yr) to the manual group. The closed-loop controller was able to provide induction and maintenance for all patients. The percentage of time with BIS40–60 was greater in the auto group (87% [75 to 96] vs. 72% [48 to 79]; P = 0.002), with a decrease in the percentage of BIS<40 (7% [2 to 17] vs. 21% [11 to 38]; P = 0.002). Propofol (2.4 [1.9 to 3.3] vs. 1.7 [1.2 to 2.8] mg/kg) and remifentanil (2.3 [2.0 to 3.0] vs. 2.5 [1.2 to 4.3] μg/kg) consumptions were similar in auto versus manual groups during induction, respectively. During maintenance, propofol consumption (8.2 [6.0 to 10.2] vs. 7.9 [7.2 to 9.1] mg kg h; P = 0.89) was similar between the two groups, but remifentanil consumption was greater in the auto group (0.39 [0.22 to 0.60] vs. 0.22 [0.17 to 0.32] μg kg min; P = 0.003). Perioperative adverse events and length of stay in the postanesthesia care unit were similar.CONCLUSION:: Intraoperative automated control of hypnosis and analgesia guided by the BIS is clinically feasible in pediatric and adolescent patients and outperformed skilled manual control. © 2014 American Society of Anesthesiologists, Inc.


Burgel P.-R.,University of Paris Descartes
European Respiratory Review | Year: 2011

This review article is a summary of a seminar organised by the European Respiratory Society on "The role of small airways in obstructive airway diseases" which was held in October 2010 in Amsterdam, the Netherlands. The aims of the seminar were to identify important questions related to small airways involvement in asthma and chronic obstructive pulmonary disease (COPD), and to discuss future approaches based on current and evolving knowledge. Data obtained by pathological and physiological measurements in small airways and their relevance to clinical manifestations and therapeutics in asthma and COPD were reviewed. It was concluded that our knowledge on the roles of small airways in asthma and COPD is limited. Studies of large numbers of well-characterised subjects using multiple methods (genetic characterisation, cell biology and physiology, imaging) and integration of the data using mathematical models are suggested to be of interest. The availability of these techniques coupled with our ability to better target inhaled molecules to small airways provide a unique opportunity for a reappraisal of the relevance of small airways in chronic airway diseases. © ERS 2011.


Gorea A.,University of Paris Descartes
Journal of Physiology Paris | Year: 2011

The last decade underwent a revival of interest in the perception of time and duration. The present short essay does not compete with the many other recent reviews and books on this topic. Instead, it is meant to emphasize the notion that humans (and most likely other animals) have at their disposal more than one time measuring device and to propose that they use these devices jointly to appraise the passage of time. One possible consequence of this conjecture is that the same physical duration can be judged differently depending on the reference 'clock' used in any such judgment. As this view has not yet been tested empirically, several experimental manipulations susceptible to directly test it are suggested. Before, are summarized a number of its latent precursors, namely the relativity of perceived duration, current trends in modeling time perception and its neural and pharmacological substrate, the experimental literature supporting the existence of multiple 'clocks' and a selected number of experimental manipulations known to induce time perception illusions which together with many others are putatively accountable in terms of alternative clock readings. © 2011 Elsevier Ltd.


Toutain S.,University of Paris Descartes
Drug and Alcohol Review | Year: 2010

Introduction and Aims. In spite of the implemented policies warning of the dangers of alcohol consumption for pregnant women, many women still continue drinking during pregnancy. This article focuses on the question of the representations of alcohol consumption during pregnancy in France. Design and Methods. A qualitative approach based on discussions with 42 pregnant women in three Internet chat groups in 2007 was used for our study. Results. The recommendation for total abstinence is often misunderstood by women, as are the consequences of drinking for the unborn babies. Besides, these Internet users do not seem to know much about the consequences of alcohol consumption for unborn babies. Finally, their sources of information are varied (written, oral, television, Internet, professionals of health, family networks and friends); however, their mothers remain the most credible source for them. Discussion and Conclusion. Alcohol consumption during pregnancy already constitutes a real taboo for the heath care professionals in France. It is extremely urgent and imperative that they recommend total abstinence during pregnancy, in order to avoid any irreversible consequences for the unborn babies. [Toutain S. What women in France say about alcohol abstinence during pregnancy. Drug Alcohol Rev 2009]. © 2009 Australasian Professional Society on Alcohol and other Drugs.


Goffinet F.,University of Paris Descartes
Annales Francaises d'Anesthesie et de Reanimation | Year: 2010

In France, the incidence of PE is estimated to range between 1 and 3% in the nuliparous and between 0.5 and 1.5% in the multiparous women. Factors associated with the development of PE are ofvarious types. Studies conducted on families affected by PE suggest the existence of a genetic component to the disease, even though the association between PE and certain genes, allotypes and polymorphisms are still under scrutiny. The hypotheses suggesting an immunological mechanism is supported by several arguments. Indeed, being nuliparous, changing partner, insemination with donor semen are factors associated with the development of PE whereas pre-exposition to the father's sperm bears protection.Some factors qualified as physiological are also associated with the occurrence of PE although no clear pathophysiological explanation can be put forward. These are being a mother of African descent, an increase in the mothers' age or herself being born prematurely.Some gestational incidents are also associated with the occurrence of PE: multiparity, a congenital defect affecting the foetus, UTI.Similarly, some pre-existing conditions ofthe mother are associated with PE, i.e. chronic hypertension, kidney disease, obesity and diabetes mellitus.Several well designed epidemiological studies confirm that tobacco consumption is itself associated with a 20 to 50% reduction in the development of PE, although being itself associated with an increase in other vascular gestational complications such as retroplacental haemorrhage and IUGR.Living conditions and stress, especially at work are also associated with the occurrence of PE.All these identified risk factors by far do not account for all the reported cases of PE and do not bear sufficient positive or negative predictive value. © 2010 Elsevier Masson SAS.


Gompel A.,University of Paris Descartes | Burger H.,Institute of Medical Research
Climacteric | Year: 2015

The incidence of ovarian cancer is tenfold lower than that of breast cancer. The goal of the recently published meta-analysis by Beral and colleagues, using 'individual participant datasets from 52 epidemiological studies', was to provide an updated assessment of the effect of menopausal hormone therapy (MHT) on ovarian cancer risk. The relative risk generated from the cited prospective studies was significantly increased but the relative risk from the retrospective studies was not. This is quite unusual since retrospective studies usually display higher levels of relative risk. No further increase was observed with increasing duration. Moreover, a number of the studies could not be adjusted for important ovarian cancer risk factors. From the metaanalysis, it can be calculated that the absolute excess risk of 5 years of MHT for a 50-year-old UK woman is 1 in 10 000 per year, indicating a very low risk. We conclude that this meta-analysis mostly reflects the previously published data from the Million Women Study, from which the majority of this new publication is derived. © 2015 International Menopause Society.


Ruse N.D.,University of British Columbia | Sadoun M.J.,University of Paris Descartes
Journal of Dental Research | Year: 2014

Advances in digital impression technology and manufacturing processes have led to a dramatic paradigm shift in dentistry and to the widespread use of computer-aided design/computer-aided manufacturing (CAD/CAM) in the fabrication of indirect dental restorations. Research and development in materials suitable for CAD/CAM applications are currently the most active field in dental materials. Two classes of materials are used in the production of CAD/CAM restorations: glass-ceramics/ceramics and resin composites. While glass-ceramics/ceramics have overall superior mechanical and esthetic properties, resin-composite materials may offer significant advantages related to their machinability and intra-oral reparability. This review summarizes recent developments in resin-composite materials for CAD/CAM applications, focusing on both commercial and experimental materials. © International & American Associations for Dental Research.


Fulda S.,Goethe University Frankfurt | Kroemer G.,French Institute of Health and Medical Research | Kroemer G.,Institute Gustave Roussy | Kroemer G.,University of Paris Descartes
Antioxidants and Redox Signaling | Year: 2011

Significance: Mitochondria exert vital functions during normal physiology and are also centrally involved in the regulation of various modes of cell death. Thus, engaging the mitochondrial apoptosis pathway presents an attractive possibility to activate lethal effectors in cancer cells. Recent Advances: Compounds that directly target mitochondria offer the advantage to initiate mitochondrial outer membrane permeabilization independently of upstream signal transduction elements that are frequently impaired in human cancers. As a consequence, mitochondrion-targeted agents may bypass some forms of drug resistance. Critical Issues: An ever-increasing number of compounds, including natural compounds and rationally designed drugs, has been shown to directly act on mitochondria. Future Directions: Forthcoming insights into the fine regulation of mitochondrial apoptosis will likely open future perspectives for cancer drug development. © Copyright 2011, Mary Ann Liebert, Inc. 2011.


Schlichtholz P.,Polish Academy of Sciences | Houssais M.-N.,University of Paris Descartes
Journal of Geophysical Research: Oceans | Year: 2011

Hydrographic data and atmospheric reanalysis from 1982 to 2005 are used to show a strong link of the Atlantic water temperature (AWT) anomalies observed in the transition zone between the Norwegian Atlantic current and the West Spitsbergen current in summer to the surface heat flux (SHF) anomalies observed over the Barents Sea open water in the preceding late winter. A mechanism proposed for this link is formation of ocean temperature anomalies in a deep mixed layer and their subsequent westward export by a branch of Atlantic water recirculating in the western Barents Sea. The SHF anomalies over the Barents Sea are due to advection of temperature and humidity by anomalous winds across the Arctic ice edge and do not strongly depend on the North Atlantic oscillation (NAO). Correlations of up to about 0.9 between the AWT anomalies and indices of atmospheric variability over the Barents Sea open prospects for seasonal AWT predictability. It is also shown that the wind-forcing responsible for positive AWT anomalies is involved in a cyclonic perturbation of the atmospheric circulation over the Nordic Seas. This perturbation generates, through influence on the sea ice distribution, a lobe of SHF anomalies in the marginal ice zone (MIZ) on the eastern (Barents Sea) and western (Greenland Sea) sides of the Nordic Seas which has the opposite sign to the open water lobe. In contrast to the Barents Sea MIZ, the diabatic heating of the atmosphere by upward SHF anomalies in the Greenland Sea MIZ competes with cold advection. Copyright 2011 by the American Geophysical Union.


Meyrier A.,Service de Nephrologie | Meyrier A.,University of Paris Descartes
Seminars in Nephrology | Year: 2011

Focal segmental glomerulosclerosis (FSGS) is not a disease but a clinicopathologic entity. The term FSGS itself is a misnomer because its lesions are not always focal, segmental, or sclerotic. Its clinical expression also widely varies and is nonspecific. Confronted with such diversity, one cannot but translate the title of this contribution into a unifying version focusing on the podocyte, initial culprit, or victim of multiple processes leading to FSGS. Some have been identified in human glomerulopathies and/or in animal or cell culture models, and are classified as secondary. Genetic forms, nonsyndromic or syndromic, have adduced a wealth of knowledge on the slit diaphragm architecture and explain the reason for their steroid resistance. Others, mostly expressed by a nephrotic syndrome, will be considered as idiopathic until the offending factor(s) that affect the molecular array of the slit diaphragm filtration barrier are identified and counteracted. Recent research has lead to suggesting that FSGS is not a T-cell-driven autoimmune glomerulopathy. Thus, treatments considered as etiologic, including glucocorticoids and calcineurin inhibitors, are in fact endowed with a mode of action on podocytes that suggests that drugs used such as immunosuppressors also might be considered as antiproteinuric agents. © 2011 Elsevier Inc.


Fligny C.,University of Paris Descartes
Contributions to nephrology | Year: 2011

The identification of patients at increased risk for chronic kidney disease offers the potential to prevent or delay end-stage renal disease and the associated cardiovascular events. Data from recently completed controlled clinical trials of endothelin (ET) receptor blockers confirmed their potent antiproteinuric effect after a number of preclinical studies. A spectrum of proteinuric glomerular diseases results from podocyte abnormalities and, in return, impact podocyte structure and function. Because podocytes are cells in the glomerulus that form a crucial component of the glomerular filtration barrier, contributing to size selectivity and maintaining a large filtration surface, we focus on evidence that suggest ET-1 may promote podocyte injury thereby aggravating albumin urinary loss and alteration of the glomerular microvasculature. Systematic confrontation of animal models and studies in human subjects should help decipher pathophysiological mechanisms whereby the local renal ET system promotes podocyte injury and chronic kidney disease in specific pathophysiological contexts. Current evidence suggests that more experimental and clinical attention should be paid to conditions with increased vascular or endocapillary ET-1 production on the one hand, and in diseases with altered podocyte phenotype and survival such as focal segmental glomerulosclerosis and crescentic glomerulonephritis on the other. These conclusions may assist clinicians in creating optimal clinical trials for patients at increased risk for or with overt chronic kidney disease. Copyright © 2011 S. Karger AG, Basel.


Baud V.,University of Paris Descartes
Current topics in microbiology and immunology | Year: 2011

NF-κB transcription factors are critical regulators of many biological processes such as innate and adaptive immune responses, inflammation, cell proliferation and programmed cell death. This versatility necessitates a highly complex and tightly coordinated control of the signaling pathways leading to their activation. Here, we review the role of proteolysis in the regulation of NF-κB activity, more specifically the contribution of the well-known ubiquitin-proteasome system and the involvement of proteolytic activity of caspases and calpains.


Mangin J.-F.,LNAO | Mangin J.-F.,French Institute of Health and Medical Research | Jouvent E.,LNAO | Cachia A.,University of Paris Descartes
Current Opinion in Neurology | Year: 2010

Purpose of review: Study of the variability of the cortical mantle thickness is now a key issue in neuroimaging. Here we describe a more recent trend aiming at the study of the variability of the cortical folding morphology. Recent findings: Computerized three-dimensional versions of gyrification index and other morphometric features dedicated to the folding patterns are modified in psychiatric syndromes and neurologic disorders. These observations provide new insights into the mechanisms involved in abnormal development or abnormal aging. Summary: Quantification of the folding morphology will contribute to the global endeavor aiming at building biomarkers from neuroimaging data, with a specific focus on developmental diseases. © 2010 Wolters Kluwer Health | Lippincott Williams and Wilkins.


Chamak B.,University of Paris Descartes
Neuropsychiatrie de l'Enfance et de l'Adolescence | Year: 2013

The controversies about French autism care services receive heavy media coverage. The parents' associations of autistic children, who obtained that autism became " The Great National Cause for 2012" , heap criticism on psychoanalysis and promote behavioural methods. The notion of French scandal is taken up by most of the media. Only few of them adopt a more moderate attitude and take into account the fieldwork of professionals aiming to help families and children. The shortage of public services, the first aim of the mobilization for the parents' associations in the 1960-1990s, is relegated to the background. The co-construction of public problems by the media and the associations is analyzed to better understand how public opinion is built. © 2012 Elsevier Masson SAS.


Leblois A.,University of Paris Descartes
Journal of Physiology Paris | Year: 2013

Dysfunction of the dopaminergic system leads to motor, cognitive, and motivational symptoms in brain disorders such as Parkinson's disease. The basal ganglia (BG) are involved in sensorimotor learning and receive a strong dopaminergic signal, shown to play an important role in social interactions. The function of the dopaminergic input to the BG in the integration of social cues during sensorimotor learning remains however largely unexplored. Songbirds use learned vocalizations to communicate during courtship and aggressive behaviors. Like language learning in humans, song learning strongly depends on social interactions. In songbirds, a specialized BG-thalamo-cortical loop devoted to song is particularly tractable for elucidating the signals carried by dopamine in the BG, and the function of dopamine signaling in mediating social cues during skill learning and execution. Here, I review experimental findings uncovering the physiological effects and function of the dopaminergic signal in the songbird BG, in light of our knowledge of the BG-dopamine interactions in mammals. Interestingly, the compact nature of the striato-pallidal circuits in birds led to new insight on the physiological effects of the dopaminergic input on the BG network as a whole. In singing birds, D1-like receptor agonist and antagonist can modulate the spectral variability of syllables bi-directionally, suggesting that social context-dependent changes in spectral variability are triggered by dopaminergic input through D1-like receptors. As variability is crucial for exploration during motor learning, but must be reduced after learning to optimize performance, I propose that, the dopaminergic input to the BG could be responsible for the social-dependent regulation of the exploration/exploitation balance in birdsong, and possibly in learned skills in other vertebrates. © 2012 Elsevier Ltd.


Delclaux C.,University of Paris Descartes
Revue Francaise d'Allergologie | Year: 2013

Exercise-induced bronchospasm depends on the level of ventilation and the weather conditions (temperature, humidity). It can thus occur often in high level athletes without a history of asthma. Bronchospasm occurring during or after exercise in an asthmatic patient is known as exercise-induced asthma. Its functional expression, a decrease in FEV1, seems almost constant in asthmatic patients who are able to perform strenuous exercise, but its clinical expression is less frequent, in about one-third of these patients. Exercise-induced asthma is rarely an isolated phenomenon; when it is such, the diagnosis should be one of exclusion, especially in adults. Its pathophysiology depends on thermal and osmotic interactions in the inspired air in the lower airways, associated with an inflammatory response involving leukotrienes. Prevention of exercised-induced asthma is based on administration of montelukast or a short-acting beta-agonist, although the latter appears to be the less effective. These preventive treatments have demonstrated only a partial effect on the decrease of the FEV1 and the symptoms of the bronchospasm, their limited efficacy thus not completely preventing exercise-induced asthma. © 2013 Elsevier Masson SAS.


Girard J.,University of Paris Descartes
Medecine des Maladies Metaboliques | Year: 2013

Kidney plays an important role in glucose homeostasis, both in the postabsorptive and postprandial period. Kidney produce glucose by gluconeogenesis in the renal cortex and use glucose for covering energy needs of the medulla. Kidney participes also to the reabsorption of filtered glucose in order the terminal urine was devoided of glucose, as long as blood glucose did not exceed 180 mg/dl. Reabsorption of glucose is mediated by sodium-glucose cotransporters (SGLT1 and SGLT2) expressed in S1 and S3 segments of proximal tubule. SGLT2 is the main sodium-glucose cotransporter responsible for 90% of glucose reabsorption. In type 2 diabetics (T2D), renal gluconeogenesis and glucose utilisation are increased by 30%. Surprisingly, renal glucose reabsorption is increased, participating to worsening of hyperglycemia. This results from the increase in the renal threshold of glucose reabsorption (220 mg/dl) and from an overexpression of SGLT2 in response to hyperglycemia and of cytokine secretion. The administration of SGLT2 inhibitors to T2D patients induced a decreased in the renal threshold of glucose reabsorption (80 mg/dl) and strongly reduced kidney glucose reabsorption. The inhibitors of SGLT2 are the only antidiabetic molecules able to correct the excessive renal glucose reabsorption in T2D patients and thus to contribute, by an original mechanism to the lowering of blood glucose level. © 2013 - Elsevier Masson SAS - Tous droits réservés.


Safar M.E.,University of Paris Descartes | Plante G.E.,Universite de Sherbrooke | Mimran A.,Montpellier University Hospital Center
American Journal of Hypertension | Year: 2015

Classical studies indicate that the contribution of kidneys to hypertension is almost exclusively related to the association between mean arterial pressure (MAP) and vascular resistance. Recent reports including estimates of glomerular filtration rate (GFR) have shown that pulse pressure (PP) and pulse wave velocity, 2 major indices of arterial stiffness, now emerge as significant predictors of cardiovascular risk and age-associated decline in GFR. Such findings are mainly observed in patients with hypertension and renal failure and in atherosclerotic subjects undergoing coronary angiography. In such patients, amplification of PP between ascending and terminal aorta at the renal site is constantly increased over 10 mm Hg (P < 0.001), whereas MAP level remains continuously unmodified. This PP amplification is significantly associated with presence of proteinuria. Furthermore, increases in plasma creatinine and aortic stiffness are independently and positively correlated (P < 0.001) both in cross-sectional and longitudinal studies. All these relationships associating PP, arterial stiffness, and renal function are mainly observed in patients 60 years of age or older. Furthermore, in renal transplant patients and their donors, subjects have been recruited for evaluations of arterial stiffness and posttransplant decline in GFR. Determinants of GFR decline were evaluated 1 and 9 years after transplantation. The first year GFR decline was related to smoking and acute rejection, whereas the later was significantly and exclusively associated with donor age and aortic stiffness. Thus, in hypertensive humans, the observed association between PP and GFR suggests that the 2 parameters are substantially mediated by arterial stiffness, not exclusively by vascular resistance. © American Journal of Hypertension, Ltd 2014. All rights reserved.


Puget S.,University of Paris Descartes
Frontiers in Endocrinology | Year: 2012

The surgical management of craniopharyngiomas in children remains one of the more controversial topics in pediatric neurosurgery. Theoretically, the benign histology implies that total surgical excision would be sufficient to provide a cure. It has been widely established however, that in certain cases total excision may lead to unacceptable hypothalamic injury. The therapeutic goals for pediatric craniopharyngiomas therefore, require not just cure of the disease but also preservation of function. Over the last 15years, there has been a growing worldwide advocacy for less extensive resection and for the utilization of multi-modality therapy to limit morbidity. With this in mind, risk-adapted strategies designed to preserve hypothalamic structures have been developed. The preliminary results of these strategies appear to be encouraging. However, the long-term clinical outcome in terms of post irradiation complications and management of relapses is currently unknown. © 2012 Puget.


For patients with metastatic castration-resistant prostate cancer (mCRPC), the current standard of care is chemotherapy involving the tubulin-binding taxane docetaxel. However, as the tumor cells become resistant to docetaxel-based therapy, disease progression is inevitable, and until recently there was no further available treatment beyond palliative care. In June 2010, cabazitaxel, a next-generation taxane, was approved by the US FDA for the treatment of mCRPC that has progressed after docetaxel therapy. This article describes the background and rationale of cabazitaxel's development and the clinical study program that led to its FDA approval, focusing on the Phase III TROPIC trial that demonstrated the efficacy of cabazitaxel plus prednisone in the treatment of mCRPC. Future development of this therapy and others under investigation is discussed. © 2011 Future Medicine Ltd.


Due to its highly specific metabolism, citrulline (CIT) is now recognized as a biomarker of functional intestinal mass. In the stressed and septic critically ill patient, plasma CIT is often very low at ∼10 μmol/L (normal range: 38±8 μmol/L). These abnormal values are difficult to interpret as patients may present increased CIT recycling into arginine and/or arginine depletion. Additionally, multiple organ failure may further make this issue complex. Experimental studies in rodent models of sepsis have raised promising results, particularly regarding gut microcirculation, which now need to be confirmed by ongoing randomized clinical trials. © SRLF et Springer-Verlag France 2013.


Collet M.,University of Paris Descartes
European Journal of Human Genetics | Year: 2015

Acyl-CoA dehydrogenase family, member 9 (ACAD9) mutation is a frequent, usually fatal cause of early-onset cardiac hypertrophy and mitochondrial respiratory chain complex I deficiency in early childhood. We retrospectively studied a series of 20 unrelated children with cardiac hypertrophy and isolated complex I deficiency and identified compound heterozygosity for missense, splice site or frame shift ACAD9 variants in 8/20 patients (40%). Age at onset ranged from neonatal period to 9 years and 5/8 died in infancy. Heart transplantation was possible in 3/8. Two of them survived and one additional patient improved spontaneously. Importantly, the surviving patients later developed delayed-onset neurologic or muscular symptoms, namely cognitive impairment, seizures, muscle weakness and exercise intolerance. Other organ involvement included proximal tubulopathy, renal failure, secondary ovarian failure and optic atrophy. We conclude that ACAD9 mutation is the most frequent cause of cardiac hypertrophy and isolated complex I deficiency. Heart transplantation in children surviving neonatal period should be considered with caution, as delayed-onset muscle and brain involvement of various severity may occur, even if absent prior to transplantation.European Journal of Human Genetics advance online publication, 16 December 2015; doi:10.1038/ejhg.2015.264. © 2015 Macmillan Publishers Limited


Huang Y.-M.,Lanzhou University | Moisan L.,University of Paris Descartes | Ng M.K.,Hong Kong Baptist University | Zeng T.,Hong Kong Baptist University
IEEE Transactions on Image Processing | Year: 2012

Multiplicative noise removal is a challenging image processing problem, and most existing methods are based on the maximum a posteriori formulation and the logarithmic transformation of multiplicative denoising problems into additive denoising problems. Sparse representations of images have shown to be efficient approaches for image recovery. Following this idea, in this paper, we propose to learn a dictionary from the logarithmic transformed image, and then to use it in a variational model built for noise removal. Extensive experimental results suggest that in terms of visual quality, peak signal-to-noise ratio, and mean absolute deviation error, the proposed algorithm outperforms state-of-the-art methods. © 2012 IEEE.


Monk B.J.,Arizona Cancer Center | Pujade-Lauraine E.,University of Paris Descartes | Burger R.A.,The Surgical Center
Annals of Oncology | Year: 2013

Angiogenesis plays a fundamental role in the pathogenesis of ovarian cancer. Vascular endothelial growth factor (VEGF) expression has been associated with the development of malignant ascites and tumor progression. Bevacizumab (Avastin. ®; Genentech, South San Francisco, CA, USA), a humanized anti-VEGF monoclonal antibody, is the most widely studied antiangiogenesis agent across tumor types and specifically in epithelial ovarian cancer (EOC). With the recent reporting of four consecutive positive randomized trials adding bevacizumab to chemotherapy in the treatment of both front-line (GOG 218 and ICON7) and recurrent EOC ['platinum-resistant' (AURELIA Trial) or 'platinum-sensitive' (OCEANS Trial)], the most debatable question today is thus not IF we should treat ovarian cancer patients with bevacizumab, but WHEN. As bevacizumab is active in both settings, it seems appropriate to carefully consider this clinical controversy: 'what is the optimal setting for bevacizumab treatment?' A fine balance of efficacy, toxicity, quality of life, and symptom control is the main crux of this controversy. The cost effectiveness of bevacizumab in EOC is also controversial. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Herrel A.,University of Paris Descartes | Bonneaud C.,French National Center for Scientific Research
Journal of Experimental Biology | Year: 2012

Trade-offs are thought to impose barriers to phenotypic diversification and may limit the evolutionary responses of organisms to environmental changes. In particular, locomotor trade-offs between endurance or maximal exertion capacity and burst performance capacity have been observed in some species and may constrain the ability of organisms to disperse. Here, we tested for the presence of locomotor trade-offs between maximal exertion and burst performance capacity in an aquatic frog, the tropical clawed frog (Xenopus tropicalis). Given the importance of overland dispersal for this species, we focused on terrestrial exertion capacity (time and distance jumped until exhaustion) and tested whether it trades-off with aquatic burst performance capacity (maximum instantaneous velocity and acceleration), which is likely to be relevant in the context of predator escape and prey capture. Our data show that in both sexes, individuals with longer hindlimbs display higher endurance. Additionally, in females forelimb length was positively correlated with aquatic burst performance capacity and negatively correlated with terrestrial exertion. Trade-offs between endurance and burst performance capacity were detected, but were significant in males only. Finally, males and females differ in morphology and performance. Our data suggest that trade-offs are not universal and may be driven by sex-dependent selection on locomotor capacity. Moreover, our results suggest that locomotor trade-offs may result in sex-biased dispersal under selection for improved endurance capacity as is expected under habitat fragmentation scenarios. © 2012. Published by The Company of Biologists Ltd.


Kim J.,University of California at San Diego | Kundu M.,St. Jude Childrens Hospital | Viollet B.,University of Paris Descartes | Guan K.L.,University of California at San Diego
Nature Cell Biology | Year: 2011

Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling. © 2011 Macmillan Publishers Limited. All rights reserved.


Background: The effects of low-frequency conditioning stimulation (LFS, 900 pulses at 1 Hz) of glutamatergic afferents in CA1 hippocampal area using slices from two different strains of adult (3-5 month-old) and aged (23-27 month-old) rats were reinvestigated regarding the discrepancies in the literature concerning the expression of long-term depression (LTD) in the aging brain. Methodology/Principal Findings: N-methyl-D-aspartate receptor (NMDA-R) dependent LTD was examined in both adult (n = 21) and aged (n = 22) Sprague-Dawley rats. While equivalent amounts of LTD could be obtained in both ages, there was significant variability depending upon the time between the slices were made and when they were tested. LTD was not apparent if slices were tested within 3 hours of dissection. The amount of LTD increased over the next three hours but more in adult than in aged rats. This age-related impairment was abolished by exogenous D-serine, thus reflecting the reduced activation of the NMDA-R glycine-binding site by the endogenous agonist in aged rats. Then, the amount of LTD reached asymptote at 5-7 hours following dissection. Similar temporal profiles of LTD expression were seen in young and aged Wistar rats. Conclusions/Significance: Taken together, these results sound a cautionary note regarding the existence of an experimental "window of opportunity" for studying the effects of aging on LTD expression in hippocampal slice preparation. © 2010 Jean-marie Billard.


Tharaux P.L.,University of Paris Descartes
Contributions to nephrology | Year: 2011

Sickle cell disease (SCD), the first 'molecular disease' to be identified, has been well characterized as a single amino acid molecular disorder of hemoglobin leading to its pathological polymerization, with resulting red cell rigidity that causes poor microvascular blood flow, with consequent tissue ischemia and infarction. Thus, the manifestations of SCD chronic renal disease have long been considered clinical manifestations of an obstructive vasculopathy of the arterial and capillary microcirculation. Recently, accumulating evidence have indicated that blood vessel functions are affected by SCD, involving abnormal vascular tone and activated endothelium. These abnormalities are particularly prominent in the kidney where specific biochemical conditions in the medulla and papilla favor change in endothelial phenotype and in tubular phenotype that, in turn, may promote dysfunction and destruction of this organ through active endothelin (ET)-1 production and signals. High ET-1 urinary output in SCD subjects at steady state may reflect increased tubular activation of ET-1 production acting on the collecting duct thereby favoring the constant hyposthenuria. Chronically, augmented ET-1 concentrations in the SCD kidney would further aggravate ischemia and sickling through actions on vasa recta and red blood cells. The kidneys suffer multiple ischemic hits during SCD as consequences of vasos-occlusive crisis (VOC). Blockade of ET receptors unraveled the major vasoconstrictive role of ET-1 in the pathophysiology of VOC, stressing the pivotal role of abnormal endothelial phenotype in this hemoglobinopathy and opening potential new therapeutic options. At last, indirect evidence suggest that ET-1 may be involved in the progression of chronic glomerulosclerosis affecting a number of patients. In fact, sickle cell nephropathy is an emerging severe disease that requires pathophysiological studies and development of specific therapies. Copyright © 2011 S. Karger AG, Basel.


Papagiakoumou E.,French Institute of Health and Medical Research | Papagiakoumou E.,University of Paris Descartes
Biology of the Cell | Year: 2013

Brain intricacies and the difficulty that scientists encounter in revealing its function with standard approaches such as electrical stimulation of neurons have led to the exploration of new tools that enable the study of neural circuits in a remote and non-invasive way. To this end, optogenetics has initialised a revolution for neuroscience in the last decade by enabling simultaneous monitoring and stimulation of specific neuronal populations in intact brain preparations through genetically targeted expression of light sensitive proteins and molecular photoswitches. In addition to ongoing molecular probe development and optimisation, novel optical techniques hold immense potential to amplify and diversify the utility of optogenetic methods. Importantly, by improving the spatio-temporal resolution of light stimulation, neural circuits can be photoactivated in patterns mimicking endogenous physiological processes. The following synopsis addresses the possibilities and limitations of optical stimulation methods applied to and developed for activation of neuronal optogenetic tools. Advances in molecular engineering and the bloom of optogenetics facilitated the realisation of studies towards the understanding of neural circuits function. To this direction, great effort has been made to also develop illumination tools that provide better specificity than standard wide-field illumination. Here, optical methods that have been used so far in optogenetics are reviewed and the challenges that need to satisfy are discussed.© 2013 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.


Chatenoud L.,University of Paris Descartes
Methods in molecular biology (Clifton, N.J.) | Year: 2011

Evidence has been accumulated to show that the forkhead/winged-helix transcription factor Foxp3 is a good marker for specialized CD4+ T cells that regulate immune responses to self as well as to a variety of foreign antigens including infectious or tumor antigens, alloantigens, allergens, and commensal antigens. It is now well established that CD4+CD25+Foxp3+ regulatory T cells encompass two categories of lymphocytes that are distinct in their origin, antigen specificity, as well as the stimuli driving their differentiation and homeostasis. Natural CD4+CD25+Foxp3+ regulatory T cells are an independent lineage generated in the thymus through major histocompatibility class II molecules-dependent MHC class high avidity interactions with their T cell receptor. They are specific for self-antigens. Adaptive or induced CD4+CD25+Foxp3+ regulatory T cells stem from mature CD4+CD25-Foxp3-precursors at the periphery following adequate stimulation. They have been shown to develop in vivo following suboptimal antigen stimulation, in situations characterized by chronic inflammation (autoimmunity, allergy, immune responses to tumors and transplants) and also as physiological actors of the mucosal immune system. Although major progress has been accomplished over the last years in our understanding of the central role of CD4+CD25+Foxp3+ regulatory T cells in the control of immune responses, major issues are still elusive. In particular, there are still no reliable phenotypic or functional markers that make it possible to distinguish between natural and induced CD25+Foxp3+ regulatory T cells.


Chopin A.,University of Paris Descartes
Journal of vision | Year: 2011

Two sets of dots moving in opposite directions are usually seen as two transparent surfaces. Deciding which surface is in front of the other is bistable and observers exhibit strong biases to see one particular motion direction in front. Surprisingly, biases are dependent on stimulus orientation in a persistent, idiosyncratic, and irrelevant manner. We investigated here whether this preferred direction is arbitrarily fixed or can instead be updated from the context. Observers performed two tasks alternately. One task was to report the surface seen in front in a transparent motion stimulus. The other task was a visual search for a slow dot. Unknown to the observers, we systematically paired the target dot with one surface direction in an attempt to make that surface appear preferentially in front. This manipulation was sufficient to change the observer's preferred direction for the surface seen in front. Attentional explanations did not account for the results. Observers modified their idiosyncratic preference in motion transparency depth rivalry only because it was useful to perform well in an auxiliary task.


Ollero M.,University of Paris Descartes
Methods in molecular biology (Clifton, N.J.) | Year: 2011

Lipid analysis has been a crucial source of information in cystic fibrosis (CF). New methodologies for qualitative and quantitative lipidomics allow evaluation of a large number of samples, of special interest in patient screening for diagnostic and prognostic biological markers, as well as in cell physiology. In this chapter, two new complementary approaches are described: matrix-assisted laser desorption coupled to time of flight (MALDI-TOF-ClinProTools™) and liquid chromatography coupled to ion trap mass spectrometry (LC-MS( n )). MALDI-TOF-ClinProTools™ offers a large unbiased screening for the discovery of potential lipid alterations in diseased patients. LC-MS( n ) represents a state-of-the-art lipidomic tool for the identification and quantification of such alterations. The combination of both may open new perspectives in the quest for lipids participating in CF pathogenesis, therapy targets, and biomarkers.


Gaucher S.,University of Paris Descartes
Journal of visceral surgery | Year: 2013

Nowadays, in France, development of the ambulatory surgery has stalled. This is probably related to the fact that ambulatory surgery is restricted by the law to the "day surgery" in 12 hours, and only 17 procedures are referenced for this surgery. Thus, conventional hospitalization remained the rule after surgery. In January 2010, our university general surgery unit was restructured. It evolved from a conventional unit to a predominantly ambulatory unit. Otherwise, our unit adjoins a hotel, even inside our institution, which accommodates patients, patient visitors and tourists. The aim of this retrospective study was to compare the postoperative accommodation modalities between two groups of patients. The first group consisted of patients admitted before January 2010, at the time of conventional activity, whereas the second group consisted of patients admitted after January 2010 in a restructured unit. Inclusion of patients admitted from April 1, 2008 to March 31, 2009 (conventional hospitalization period) and from April 1, 2010 to March 31, 2011 (ambulatory management period), scheduled for one single surgical procedure excluding emergency. A total of 360 patients were retained: 229 for the conventional period and 131 for the ambulatory period, with a median age of 55 (range 15-87). No statistically significant difference was noted between the two groups as concerned median age, gender or ASA status. The number of postoperative nights varied significantly between the two groups with a mean of 3.8 nights (median three nights, range 0-32) for the conventional period versus 0.4 nights (median 0 night, range 0-10) for the ambulatory period (P<0.0001 by the unadjusted Mann-Whitney test and P<0.0001 by the Wald test [with adjustment]). Our results show that it is clearly possible to distinguish the need for care of the need for accommodation and significantly reduce postoperative conventional accommodation. They also raise the question of extending the legal period of 12 hours to 24 hours in order to expand the list of the referenced procedures. Copyright © 2013 Elsevier Masson SAS. All rights reserved.


Ding J.,Schepens Eye Research Institute | Sackmann-Sala L.,University of Paris Descartes | Kopchick J.J.,Ohio University
Proteomics | Year: 2013

Growth hormone (GH) is a protein secreted by the anterior pituitary and circulates throughout the body to exert important actions on growth and metabolism. GH stimulates the secretion of insulin-like growth factor-I (IGF-I) that mediates some of the growth promoting actions of GH. The GH/IGF-I axis has recently been recognized as important in terms of longevity in organisms ranging from Caenorhabditis elegans to mice. For example, GH transgenic mice possess short lifespans while GH receptor null (GHR-/-) mice have extended longevity. Thus, the actions of GH (or IGF-I) or lack thereof impact the aging process. In this review, we summarize the proteomic analyses of plasma and white adipose tissue in these two mouse models of GH action, i.e. GH transgenic and GHR-/- mice. At the protein level, we wanted to establish novel plasma biomarkers of GH action as a function of age and to determine differences in adipose tissue depots. We have shown that these proteomic approaches have not only confirmed several known physiological actions of GH, but also resulted in novel protein biomarkers and targets that may be indicative of the aging process and/or new functions of GH. These results may generate new directions for GH and/or aging research. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Safar M.E.,University of Paris Descartes
Artery Research | Year: 2011

Blood pressure variability (BPV) is defined by the standard deviation of a given sample of population of normotensive or hypertensive subjects. Recent studies have suggested that this parameter might constitute a cardiovascular risk factor. Reduction of blood pressure variability could be an important purpose of anti-hypertensive treatment, as suggested from experimental studies. In a double-blind controlled investigation, the thiazide compound indapamide was compared to placebo, to the angiotensin blocker candesartan and to the calcium-entry blocker amlodipine for 12 weeks treatment. The 3 drugs reduced significantly and identically blood pressure. Only indapamide and amlodipine reduced significantly BPV. This study was the first to demonstrate the interest of BPV in the setting of a double-blind, placebo controlled, trial. © 2011 Association for Research into Arterial Structure and Physiology.


Machado-Pinilla R.,Yeshiva University | Liger D.,University Paris - Sud | Leulliot N.,University of Paris Descartes | Meier U.T.,Yeshiva University
RNA | Year: 2012

The AAA+ ATPases pontin and reptin function in a staggering array of cellular processes including chromatin remodeling, transcriptional regulation, DNA damage repair, and assembly of macromolecular complexes, such as RNA polymerase II and small nucleolar (sno) RNPs. However, the molecular mechanism for all of these AAA+ ATPase associated activities is unknown. Here we document that, during the biogenesis of H/ACA RNPs (including telomerase), the assembly factor SHQ1 holds the pseudouridine synthase NAP57/dyskerin in a viselike grip, and that pontin and reptin (as components of the R2TP complex) are required to pry NAP57 from SHQ1. Significantly, the NAP57 domain captured by SHQ1 harbors most mutations underlying X-linked dyskeratosis congenita (X-DC) implicating the interface between the two proteins as a target of this bone marrow failure syndrome. Homing in on the essential first steps of H/ACA RNP biogenesis, our findings provide the first insight into the mechanism of action of pontin and reptin in the assembly of macromolecular complexes. Copyright © 2012 RNA Society.


Andrikopoulos V.,University of Stuttgart | Benbernou S.,University of Paris Descartes | Papazoglou M.P.,University of Tilburg
IEEE Transactions on Software Engineering | Year: 2012

In an environment of constant change and variation driven by competition and innovation, a software service can rarely remain stable. Being able to manage and control the evolution of services is therefore an important goal for the Service-Oriented paradigm. This work extends existing and widely adopted theories from software engineering, programming languages, service-oriented computing, and other related fields to provide the fundamental ingredients required to guarantee that spurious results and inconsistencies that may occur due to uncontrolled service changes are avoided. The paper provides a unifying theoretical framework for controlling the evolution of services that deals with structural, behavioral, and QoS level-induced service changes in a type-safe manner, ensuring correct versioning transitions so that previous clients can use a versioned service in a consistent manner. © 2012 IEEE.


Rapp T.,University of Paris Descartes
Social Science and Medicine | Year: 2014

It is surprising to observe that the number of patients receiving a late diagnosis for Alzheimer's disease (AD) remains high even in countries promoting early diagnosis campaigns. We explore the impact of family history and family support on the risks of receiving a delayed diagnosis. We use French data of 1131 patients diagnosed between 1991 and 2005. We find that the presence of AD history in the family increased the risks of receiving a delayed diagnosis. This was true especially when AD history involved brothers, sisters and other relatives (uncles or cousins). The presence of an informal caregiver at the time of the first warning signs reduced the risks of receiving a late diagnosis, regardless of the informal caregiver concerned (spouse, son, daughter etc.). We identify several opportunities for early detection campaigns. Families with history of disease should be targeted. Campaigns should also target isolated patients, who do not benefit from informal care. Our results underline the importance of improving the diagnosis access for old patients and for men. © 2014 Elsevier Ltd.


Dupont B.,University of Paris Descartes
Journal de Mycologie Medicale | Year: 2010

Intravenous micafungin is an echinocandin antifungal agent, its mode of action is the inhibition of synthesis of 1,3-β-d-glucan, an essential cell wall component in many fungi. It is active in vitro against all Candida spp. and against Aspergillus spp. In large randomized clinical trials, micafungin was shown effective in oesophageal candidiasis and non inferior to fluconazole, in candidemia and invasive candidiasis and non inferior to liposomal amphotericin B or caspofungin and as prophylactic treatment of fungal infections in hematopoietic stem cell transplant recipients, superior to fluconazole. Efficacy was demonstrated in paediatric patients including neonates and premature children. Efficacy was established against invasive aspergillosis in non-randomized clinical trials. Tolerance was satisfactory, similar to fluconazole or caspofungin and better than liposomal amphotericin B. Drug-drug interactions are mild and limited (sirolimus, itraconazole and nifédipine). © 2010 Elsevier Masson SAS.


Touboul D.,CNRS Natural Product Chemistry Institute | Laprevote O.,CNRS Natural Product Chemistry Institute | Laprevote O.,University of Paris Descartes | Brunelle A.,CNRS Natural Product Chemistry Institute
Current Opinion in Chemical Biology | Year: 2011

Time-Of-Flight Secondary Ion Mass Spectrometry is compared to other mass spectrometry imaging techniques, and recent improvements of the experimental methods, driven by biological and biomedical applications, are described and discussed. This review shows that this method that can be considered as a micrometric molecular histology is particularly efficient for obtaining images of various lipid species at the surface of a tissue sample, without sample preparation, and with a routine spatial resolution of 1 μm or less. © 2011 Elsevier Ltd.


Safar M.E.,University of Paris Descartes | Nilsson P.M.,Lund University
Journal of Hypertension | Year: 2013

BACKGROUND: In the nineteenth century, prior to the introduction of the cuff sphygmomanometer, stiffening of arteries was recognized as an indicator of vascular ageing and cardiovascular risk. Through the twentieth century, views on vascular ageing came to focus on brachial blood pressures and on occlusive atherosclerotic disease. Such focus deflected attention from primary ageing changes, represented by stiffening and dilation of the proximal aorta. AIM: This review emphasizes the cushioning function of elastic arteries, principally the aorta, now when life expectancy largely exceeds 80 years providing new challenges for medical treatment in the very old. METHODS AND RESULTS: First, life expectancy has increased significantly for both sexes and is particularly prolonged after menopause. Second, phenotypic changes are noticed such as that the age-related increase of waist circumference and hyperlipidemia is markedly slowed, whereas the concomitant rise in C-reactive protein is enhanced and hyperglycaemia develops in many patients. Third, the systolic, diastolic and pulse pressures rise with age is attenuated or even stopped, as is the degree of arterial stiffness. Finally, in very old patients, the main causes of death are cardiovascular, including cardiac deaths, which differ markedly by causation in men (due to lowered ejection fraction) and women (due to arrhythmia disorders). Deaths associated with renal impairment are observed in both sexes. CONCLUSION: No simple linear relationships exist between all these phenotypic variables and the ageing process. Treatment goals of hypertension and diabetes mellitus remain difficult to predict from such data. Prevention of cardiovascular risk in the very old is thus influenced by limited evidence and important ethical considerations. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.


Witzel C.,University of Paris Descartes | Gegenfurtner K.R.,Justus Liebig University
Journal of Vision | Year: 2015

This study investigates the impact of language on color perception. By categorical facilitation, we refer to an aspect of categorical perception, in which the linguistic distinction between categories affects color discrimination beyond the low-level, sensory sensitivity to color differences. According to this idea, discrimination performance for colors that cross a category border should be better than for colors that belong to the same category when controlling for lowlevel sensitivity. We controlled for sensitivity by using colors that were equally discriminable according to empirically measured discrimination thresholds. To test for categorical facilitation, we measured response times and error rates in a speeded discrimination task for suprathreshold stimuli. Robust categorical facilitation occurred for five out of six categories with a group of inexperienced observers, namely for pink, orange, yellow, green, and purple. Categorical facilitation was robust against individual variations of categories or the laterality of target presentation. However, contradictory effects occurred in the blue category, most probably reflecting the difficulty to control effects of sensory mechanisms at the green-blue boundary. Moreover, a group of observers who were highly familiar with the discrimination task did not show consistent categorical facilitation in the other five categories. This trained group had much faster response times than the inexperienced group without any speed-accuracy tradeoff. Additional analyses suggest that categorical facilitation occurs when observers pay attention to the categorical distinction but not when they respond automatically based on sensory feed-forward information. © 2015 ARVO.


Ruskone-Fourmestraux A.,HOpital Saint Antoine | Audouin J.,University of Paris Descartes
Best Practice and Research: Clinical Gastroenterology | Year: 2010

Primary gastrointestinal involvement of mantle cell lymphoma (MCL) is rare with a frequency reported between 4 and 9% of all gastrointestinal B-cell non-Hodgkin lymphomas. It was first described and so-called as multiple lymphomatous polyposis (MLP). Its clinical presentation is usually characteristic, with multiple lymphomatous polyps involving several digestive tract segments and a marked tendency towards extra-intestinal spread. The constant and typical phenotypic features of the small cleaved tumour cells, characterised as CD20+, CD5+ CD23- with a t(11;14) (q13;q32) and cyclin D1 overexpression on immunochemistry, allow MLP to be considered as the gastrointestinal counterpart of peripheral nodal MCL. They both share a very poor outcome. Response to intensive chemotherapy regimens usually results in regression of macroscopic and sometimes microscopic lesions but remissions are short and median survival from 3 to 4 years. Prognosis has been significantly improved since in younger patients, intensive front-line immunochemotherapy with autologous stem cell transplantation has been proposed. Earlier diagnosis with further studies integrating novel agents are still required to determine the optimal treatment with less toxicity. © 2010 Elsevier Ltd. All rights reserved.


Cavanagh P.,University of Paris Descartes | Anstis S.,University of California at San Diego
Vision Research | Year: 2013

When an object moves back and forth, its trajectory appears significantly shorter than it actually is. The object appears to stop and reverse well before its actual reversal point, as if there is some averaging of location within a window of about 100 ms (Sinico et al., 2009). Surprisingly, if a bar is flashed at the physical end point of the trajectory, right on top of the object, just as it reverses direction, the flash is also shifted - grabbed by the object - and is seen at the perceived endpoint of the trajectory rather than the physical endpoint. This can shift the perceived location of the flash by as much as 2 or 3 times its physical size and by up to several degrees of visual angle. We first show that the position shift of the flash is generated by the trajectory shortening, as the same shift is seen with or without the flash. The flash itself is only grabbed if it is presented within a small spatiotemporal attraction zone around the physical end point of the trajectory. Any flash falling in that zone is pulled toward the perceived endpoint. The effect scales linearly with speed, up to a maximum, and is independent of the contrast of the moving stimulus once it is above 5%. Finally, we demonstrate that this position shift requires attention. These results reveal a new "flash grab" effect in the family of motion-induced position shifts. Although it most resembles the flash drag effect, it differs from this in the following ways: (1) it has a different temporal profile, (2) it requires attention, (3) it is about 10 times larger. © 2013 Elsevier Ltd.


Matteini L.,University of Paris Descartes | Landi S.,University of Florence | Velli M.,Jet Propulsion Laboratory | Hellinger P.,Academy of Sciences of the Czech Republic
Journal of Geophysical Research: Space Physics | Year: 2010

Using numerical simulations in a hybrid regime, we studied the evolution of large-amplitude Alfvn waves subject to modulational and decay instabilities, including the effects of ion kinetics. We considered both a monochromatic and incoherent spectrum of waves, different wave polarizations and amplitudes, and different plasma regimes, ranging from β < 1 to β > 1. We found in all cases that ion dynamics affects the instability evolution and saturation; as a feedback, wave-particle interactions provide a nonlinear trapping of resonant particles that importantly change the properties of the ion velocity distribution functions. In particular, we observed a proton acceleration along the magnetic field and in some cases the formation of a parallel velocity beam traveling faster than the rest of the distribution. For the range of parameters used in our simulations, the fundamental ingredient in generating an ion beam is observed to be the parallel electric field carried by the density fluctuations driven by the ion-acoustic modes generated by the parametric instabilities. Copyright © 2010 by the American Geophysical Union.


Irtan S.,University of Paris Descartes
The lancet oncology | Year: 2013

Ovarian transposition was the first procedure proposed to preserve fertility in girls with cancer and is indicated for patients with tumours requiring pelvic radiation at doses of 42·0-58·4 Gy, much higher doses than those that can induce loss of ovarian function (4-20 Gy). Ovarian transposition is usually done after neoadjuvant chemotherapy and is completed by minimally invasive surgery or open surgery in case of concomitant resection of the abdominal tumour. According to the type of tumour, the ovaries are moved and placed in the paracolic gutters when the radiation field reaches the midline (for medulloblastoma or urogenital rhabdomyosarcoma), contralaterally to the tumour (for pelvic sarcomas), or in line with the iliac crests (for Hodgkin's lymphoma). However, in 10-14% of cases the procedure can fail to protect the ovaries. Although few long-term results in adults are available, normal hormonal function and pregnancies have been reported in a few long-term follow-up studies. In view of the continued development of fertility preservation techniques, ovarian transposition should be discussed at a multidisciplinary meeting at the time of cancer diagnosis. Copyright © 2013 Elsevier Ltd. All rights reserved.


Doly S.,University of Paris Descartes
Molecular Psychiatry | Year: 2015

Endoplasmic reticulum (ER) release and cell-surface export of many G protein-coupled receptors (GPCRs) are tightly regulated. For gamma-aminobutyric acid (GABA)B receptors of GABA, the major mammalian inhibitory neurotransmitter, the ligand-binding GB1 subunit is maintained in the ER by unknown mechanisms in the absence of hetero-dimerization with the GB2 subunit. We report that GB1 retention is regulated by a specific gatekeeper, PRAF2. This ER resident transmembrane protein binds to GB1, preventing its progression in the biosynthetic pathway. GB1 release occurs upon competitive displacement from PRAF2 by GB2. PRAF2 concentration, relative to that of GB1 and GB2, tightly controls cell-surface receptor density and controls GABAB function in neurons. Experimental perturbation of PRAF2 levels in vivo caused marked hyperactivity disorders in mice. These data reveal an unanticipated major impact of specific ER gatekeepers on GPCR function and identify PRAF2 as a new molecular target with therapeutic potential for psychiatric and neurological diseases involving GABAB function.Molecular Psychiatry advance online publication, 2 June 2015; doi:10.1038/mp.2015.72. © 2015 Macmillan Publishers Limited


Vinckier F.,University of Paris Descartes
Molecular Psychiatry | Year: 2015

A state of pathological uncertainty about environmental regularities might represent a key step in the pathway to psychotic illness. Early psychosis can be investigated in healthy volunteers under ketamine, an NMDA receptor antagonist. Here, we explored the effects of ketamine on contingency learning using a placebo-controlled, double-blind, crossover design. During functional magnetic resonance imaging, participants performed an instrumental learning task, in which cue-outcome contingencies were probabilistic and reversed between blocks. Bayesian model comparison indicated that in such an unstable environment, reinforcement learning parameters are downregulated depending on confidence level, an adaptive mechanism that was specifically disrupted by ketamine administration. Drug effects were underpinned by altered neural activity in a fronto-parietal network, which reflected the confidence-based shift to exploitation of learned contingencies. Our findings suggest that an early characteristic of psychosis lies in a persistent doubt that undermines the stabilization of behavioral policy resulting in a failure to exploit regularities in the environment.Molecular Psychiatry advance online publication, 9 June 2015; doi:10.1038/mp.2015.73. © 2015 Macmillan Publishers Limited


Marie I.,University of Rouen | Mouthon L.,University of Paris Descartes | Mouthon L.,French Institute of Health and Medical Research
Autoimmunity Reviews | Year: 2011

Because polymyositis and dermatomyositis (PM/DM) are uncommon conditions, few randomized placebo controlled studies have been performed in these patients. The first line of therapy consists in high-dose oral prednisone, prescribed at 1. mg/kg/day, then progressively tapered based on patients' clinical response. In patients who do not improve with corticosteroids alone, methotrexate is added, the therapeutic effect of which being observed within 8. weeks. If PM/DM patients are refractory to corticosteroids and methotrexate, intravenous immunoglobulins can be added. In patients who fail to respond to this therapeutic strategy, it is crucial to make sure that the correct diagnosis has been made and we strongly recommend to perform a new muscle biopsy in order to exclude other myopathies. If the diagnosis of PM/DM is confirmed, a number of therapeutic agents may be proposed, including mycophenolate mofetil and rituximab. Importantly, TNF-α antagonists should not be considered in PM/DM patients, as these agents have been shown to favor exacerbation of interstitial lung disease and myositis and increase the risk of severe pyogenic and opportunistic infections in PM/DM patients. © 2011 Elsevier B.V.


Chalumeau M.,University of Paris Descartes
The Cochrane database of systematic reviews | Year: 2013

Acetylcysteine and carbocysteine are the most commonly prescribed mucolytic drugs in Brazil and many European and African countries. To our knowledge, no systematic review has been published on their efficacy and safety for acute upper and lower respiratory tract infections (RTIs) in children without chronic broncho-pulmonary disease. The objective was to assess the efficacy and safety and to establish a benefit-risk ratio of acetylcysteine and carbocysteine as symptomatic treatments for acute upper and lower RTIs in paediatric patients without chronic broncho-pulmonary disease. We searched CENTRAL (2013, Issue 2), MEDLINE (1966 to February week 3, 2013), EMBASE (1980 to March 2013), Micromedex (2010), Pascal (1987 to 2004) and Science Citation Index (1974 to March 2013). To study efficacy, we used randomised controlled trials (RCTs) comparing the use of acetylcysteine or carbocysteine versus placebo, either alone or as an add-on therapy. To study safety, we used trials comparing acetylcysteine or carbocysteine versus active treatment or no treatment and case reports. In this review update two review authors (YD, MC), with help from a colleague, extracted data and assessed trial quality. We performed a subgroup analysis of children younger than two years of age. We included six trials involving 497 participants to study efficacy. They showed some benefit (e.g. reduction of cough at day seven) from mucolytic agents, although differences were of little clinical relevance. No conclusion was drawn about the subgroup of infants younger than two years because data were unavailable. Thirty-four studies, including the previous six trials involving 2064 children, were eligible to study safety. Overall safety was good but very few data were available to evaluate safety in infants younger than two years. However, 59 cases of paradoxically increased bronchorrhoea observed in infants were reported to the French pharmacovigilance system. The results have to be interpreted with caution because they are based on a limited number of participants included in studies whose methodological quality is questionable. Acetylcysteine and carbocysteine seem to have a limited efficacy and appear to be safe in children older than two years. These results should take into consideration the fact that acetylcysteine and carbocysteine are prescribed for self limiting diseases (for example, acute cough, bronchitis). Given strong concerns about safety, these drugs should only be used for acute upper and lower RTIs in the context of a RCT with regards to children younger than two years.


Bahi-buisson N.,University of Paris Descartes | Dulac O.,Hopital Necker Enfants Malades
Handbook of Clinical Neurology | Year: 2013

Epilepsies associated with inborn errors of metabolism (IEM) represent a major challenge. Seizures rarely dominate the clinical presentation, which is more frequently associated with other neurological symptoms, such as hypotonia and/or cognitive disturbances. Although epilepsy in IEM can be classified in various ways according to pathogenesis, age of onset, or electroclinical presentation, the most pragmatic approach is determined by whether they are accessible to specific treatment or not.The main potentially treatable causes comprise vitamin B6 (pyridoxine deficiency), biotine, and GLUT1 deficiency (GLUT1DS) syndromes. Folinic acid-dependent seizures are allelic with pyridoxine dependency.Incompletely treatable IEMs include pyridoxal phosphate, serine, and creatine deficiencies.The main IEMs that present with epilepsy but offer no specific treatment are nonketotic hyperglycinemia, mitochondrial disorders, sulfite oxidase deficiency, ceroid-lipofuscinosis, Menkes disease, and peroxisomal disorders. © 2013 Elsevier B.V.


Aubourg P.,University of Paris Descartes
Handbook of Clinical Neurology | Year: 2013

Though heavily hyped in the early 1990s as the answer to many genetic diseases, gene therapy has largely failed to live up to its promises up to now. The scientific challenges of conveying replacement genes into the brain have prevented it from having an impact on more than a handful of conditions. In addition, gene therapy has been beset by safety problems. During the last 5 years, new vectors and techniques have started to resolve not only safety issues that once held gene therapy back but also markedly to improve efficient gene delivery within the brain and even the spinal cord. Brain gene therapy will not be suitable for every neurological disease, but considerable progress made in the field means we can now envisage that CNS gene therapy will be able to treat many neurological conditions that are not obviously treatable in any other way. © 2013 Elsevier B.V.


Dignat-George F.,French Institute of Health and Medical Research | Dignat-George F.,Center Hospitalier University Conception | Boulanger C.M.,French Institute of Health and Medical Research | Boulanger C.M.,University of Paris Descartes
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2011

Endothelial microparticles (EMP) are complex vesicular structures shed from activated or apoptotic endothelial cells. They play a remarkable role in coagulation, inflammation, endothelial function, and angiogenesis and thus disturb the vascular homeostasis, contributing to the progression of vascular diseases. As a cause or a consequence, elevated levels of EMP were found in plasma from patients with vascular diseases, where they serve as a surrogate marker of endothelial function. More recent data challenged the presumed deleterious role of EMP because they could promote cell survival, exert antiinflammatory effects, counteract coagulation processes, or induce endothelial regeneration. This review focuses on the ambivalent role of EMP in vascular homeostasis. © 2011 American Heart Association. All rights reserved.


Buades A.,University of Paris Descartes | Coll B.,University of the Balearic Islands | Morel J.-M.,Ecole Normale Superieure de Cachan
Communications of the ACM | Year: 2011

The search for efficient image denoising methods is still a valid challenge at the crossing of functional analysis and statistics. In spite of the sophistication of the recently proposed methods, most algorithms have not yet attained a desirable level of applicability. All show an outstanding performance when the image model corresponds to the algorithm assumptions but fail in general and create artifacts or remove image fine structures. The main focus of this paper is, first, to define a general mathematical and experimental methodology to compare and classify classical image denoising algorithms and, second, to describe the nonlocal means (NL-means) algorithm6 introduced in 2005 and its more recent extensions. The mathematical analysis is based on the analysis of the "method noise," defined as the difference between a digital image and its denoised version. NL-means, which uses image self-similarities, is proven to be asymptotically optimal under a generic statistical image model. The denoising performance of all considered methods are compared in four ways: mathematical, asymptotic order of magnitude of the method noise under regularity assumptions; perceptual-mathematical, the algorithms artifacts and their explanation as a violation of the image model; perceptual-mathematical, analysis of algorithms when applied to noise samples; quantitative experimental, by tables of L2 distances of the denoised version to the original image. © 2011 ACM.


Shirvani H.,University of Paris Descartes
Sub-cellular biochemistry | Year: 2012

The regulated export of nascent G protein coupled receptors (GPCRs) from intracellular stores is an emerging concept with important implications in cell biology and pharmacology. This phenomenon requires a complex network of interactions between GPCRs with either chaperones and escort proteins or gatekeepers, which are respectively involved in the progression of GPCRs along the biosynthetic pathway to the plasma membrane or in their retention in intracellular compartments. The regulated export of GPCRs is also controlled by external stimuli and might represent an adaptive mechanism to specific physiological constraints, such as the sustained activation of the CCR5 chemokine receptor in the context of chemotaxis.


Duron E.,University of Paris Descartes | Hanon O.,Hopital Broca
Journal of Alzheimer's Disease | Year: 2010

Chronic hypertension is associated with an increased risk of both vascular dementia and Alzheimer's disease (AD). In this context, the role of anti-hypertensive therapy for the prevention and delay of cognitive decline and dementia is of central importance. Most longitudinal studies have shown a significant inverse association between anti-hypertensive therapies and dementia incidence and for some of these, particularly in AD. Seven randomized, double blind placebo-controlled trials have evaluated the benefit of antihypertensive treatments on cognition. Three of them found positive results in term of prevention of dementia (SYST-EUR) or cognitive decline (PROGRESS, HOPE). Others disclosed non-significant results (MRC, SHEP, SCOPE, HYVET-COG). This discrepancy emphasizes the difficulty to perform such trials: the follow-up has to be long enough to disclose a benefit, a large number of patients is needed for these studies, and because of ethical reasons some anti-hypertensive treatments are often prescribed in the placebo group. Results of the two more recent meta-analyses are inconsistent, possibly due to methodological issues. Antihypertensive treatments could be beneficial to cognitive function by lowering blood pressure and/or by specific neuroprotective effect. Three main antihypertensive subclasses have been associated with a beneficial effect on cognitive function beyond blood pressure reduction (calcium channel blockers, angiotensin converting enzyme inhibitor, angiotensin-AT1-receptor-blockers). Further long-term randomized trials, designed especially to assess a link between antihypertensive therapy and cognitive decline or dementia are therefore needed with cognition as the primary outcome. A low blood pressure threshold that could be deleterious for cognitive function should also be determined. © 2010 - IOS Press and the authors.


Bayry J.,University of Paris Descartes
Indian Journal of Virology | Year: 2014

CD4+CD25+FoxP3+ regulatory T cells (Tregs) are critical for immune homeostasis and tolerance. However, because of their capacity to suppress antigen presenting cells (APC), T and B cells, Tregs could also inhibit protective immune responses to viruses and vaccines. Several viruses have been shown to exploit Tregs to evade immune response. By modulating APC and in particular by weakening the functions of dendritic cells such as their ability to secrete polarizing cytokines and expression of co-stimulatory molecules, viruses could support differentiation and expansion of Tregs. Of note, as a proof of concept, depletion of Tregs significantly enhanced the protective immune response to viruses and vaccines suggesting that Tregs are viable targets to enhance immunogenicity of vaccines. As Treg depletion or inhibition of their functions could lead to deleterious autoimmune and inflammatory disorders, any Treg-based approach for vaccination should not aim at depletion of Tregs and inhibition of their functions should be transient. Recent studies have targeted the interaction between CCR4 expressed on Tregs and its ligands CCL22 and CCL17 to inhibit transiently the recruitment of Tregs at the site of immunization. Importantly, use of CCR4 antagonists as 'molecular adjuvants' in vivo in experimental models, amplified cellular and humoral immune responses when injected in combination with various vaccine antigens. The significant adjuvant activity observed in diverse models without noticeable side effects provided strong evidence that CCR4 is a sustainable target for rational adjuvant design. © 2013 Indian Virological Society.


Langlois J.,University of Paris Descartes
International orthopaedics | Year: 2013

Zirconia was introduced in the 1980s for total hip arthroplasty (THA) with the expectation of lower polyethylene wear. The purpose of this prospective study was to evaluate the results of a continuous series of total hip arthroplasties combining a zirconia head with polyethylene socket at a minimum eight-year follow-up. We performed an open prospective clinical trial in 1997. Our study involved 51 consecutive patients (55 hips) with a mean age of 52.5 ± 12 years (range, 25-76 years). All patients had a Charnley-Kerboull all-cemented hip replacement. A 22-mm stabilised yttrium tetragonal polycrystalline zirconia head (Y-TZP) was used in association with moderately cross-linked and annealed polyethylene. Clinical and radiological outcomes were assessed yearly. A survival analysis was performed using revision for any reason as the end-point. At a minimum eight-year follow-up, 12 patients (13 hips) were lost to follow-up (mean 26.8 months), two patients (two hips) had died, and six patients (six hips) were revised. The remaining 31 patients (34 hips) were alive and had not been revised on either the femoral or acetabular side at a mean follow-up of 117.1 months (range, 96-150 months). Mean functional score at last follow-up was 17.7. Mean linear head penetration was 0.23 mm/year. More than 90% of the remaining hips had signs of periprosthetic osteolysis. Five stems were loosened. The survival at eight years was 87.3% (95% IC: 76.7-97.8). This study confirms earlier short-terms results, and demonstrates that zirconia should no longer be used in THA.


Daifotis A.G.,MacroGenics | Koenig S.,MacroGenics | Chatenoud L.,University of Paris Descartes | Herold K.C.,Yale University
Clinical Immunology | Year: 2013

Two humanized, anti-CD3 mAbs with reduced FcR binding, teplizumab and otelixizumab, have been evaluated in over 1500 subjects, ages 7-45, with new and recently diagnosed T1D with a range of intravenous doses (3-48. mg) and regimens (6-14. days, single or repeat courses). In general, studies that used adequate dosing demonstrated improvement in stimulated C-peptide responses and reduced need for exogenous insulin for two years and even longer after diagnosis. Drug treatment causes a transient reduction in circulating T cells, but the available data suggest that the mechanism of action may involve induction of regulatory mechanisms. The adverse effects of anti-CD3 treatment are infusion-related and transient. The studies have identified significant differences in efficacy among patient groups suggesting that a key aspect for development of this immune therapy is identification of the demographic, metabolic, and immunologic features that distinguish subjects who are most likely to show beneficial clinical responses. © 2013 Elsevier Inc.


Ricquier D.,University of Paris Descartes
International Journal of Obesity | Year: 2010

Brown adipose tissue is generally referred to as a specialized adipose tissue, as it presents many features of an adipose tissue. However, its specific morphology, innervation, vascularization and body location, as well as its unique physiological role in regulatable thermogenesis, highlight its peculiarity. Whereas the mechanism for energy dissipation by brown adipocytes as heat was elucidated several years ago, recent work has advanced our knowledge of these cells in terms of precursors, cell lineage and transcriptional regulators. The discovery of a proximity at the developmental level between brown adipocytes and myocytes will influence future research on human brown adipocytes with the aim of facilitating the burning of fatty acids in order to prevent or alleviate certain metabolic diseases. © 2010 Macmillan Publishers Limited All rights reserved.


Amar L.,University of Paris Descartes | Eisenhofer G.,TU Dresden
Clinical Endocrinology | Year: 2015

Phaeochromocytomas and paragangliomas (PPGLs) are revealed by acute cardiovascular complications involving end-organ damage in up to 20% of cases, a presentation associated with particularly high risk for mortality. Among such cases, PPGLs should be considered in patients with unexplained left ventricular failure, multi-organ failure, hypertensive crises or shock. The diagnosis of PPGL commonly relies on measurements of metanephrines in plasma or urine. However, acute critical illness is usually associated with sympathoadrenal activation. Thus, levels of metanephrines in patients in an acute emergency or intensive care setting, whether treated or not with vasoactive drugs, usually cannot be used to reliably diagnose PPGL. Delays in provision of diagnostic test results, particularly when these require 24-h urine collections, may also be incompatible for any need for rapid decisions on patient management or therapeutic interventions. The acute emergency situation therefore represents one exception to the rule where imaging studies to search for a PPGL may be undertaken without biochemical evidence of a catecholamine-producing tumour. © 2015 John Wiley & Sons Ltd.


OBJECTIVES:: Cardiac magnetic resonance (CMR) is potentially more useful than Doppler ultrasound for quantifying ascending aortic flow velocity in the presence of complex flow patterns. Our aim was to characterize flow velocity wave patterns in the ascending aortic with age and their use with central (carotid) pressure waves to estimate ascending aortic impedance as left ventricular (LV) load and interpret vascular/ventricular interaction. METHODS:: Ascending aortic flow velocity was measured noninvasively, using velocity-encoded CMR, in 50 healthy patients (21–70 years) by averaging flow velocities across the aortic cross-section. Pressure waves were measured noninvasively by carotid tonometry as a surrogate of aortic pressure. Impedance was determined in modulus and phase from corresponding harmonics of pressure and flow velocity waves. RESULTS:: With increasing age, ascending aortic peak flow velocity decreased from 67?±?18?cm/s in younger persons (≤50 years) to 48?±?13?cm/s in older persons (>50 years) (P?


Reynard L.N.,Northumbria University | Bui C.,Northumbria University | Bui C.,University of Paris Descartes | Syddall C.M.,Northumbria University | Loughlin J.,Northumbria University
Human Genetics | Year: 2014

GDF5 encodes an extracellular signalling molecule that is essential for normal skeletal development. The rs144383 C to T SNP located in the 5′UTR of this gene is functional and has a pleiotropic effect on the musculoskeletal system, being a risk factor for knee-osteoarthritis (OA), congenital hip dysplasia, lumbar disc degeneration and Achilles tendon pathology. rs143383 exerts a joint-wide effect on GDF5 expression, with expression of the OA-associated T allele being significantly reduced relative to the C allele, termed allelic expression imbalance. We have previously reported that the GDF5 locus is subject to DNA methylation and that allelic imbalance of rs143383 is mediated by SP1, SP3 and DEAF1 transcriptional repressors. In this study, we have assayed GDF5 methylation in normal and osteoarthritic cartilage, and investigated the effect of methylation on the allelic imbalance of rs143383. We observed demethylation of the GDF5 5′UTR in OA knee cartilage relative to both OA (p = 0.009) and non-OA (p = 0.001) hip cartilage, with the most significant demethylation observed at the highly conserved +37 CpG site located 4 bp upstream of rs143383. Methylation modulates the level and direction of allelic imbalance of rs143383, with methylation of the +37 CpG dinucleotide within the SP1/SP3 binding site having an allele-specific effect on SP1 and SP3 binding. Furthermore, methylation attenuated the repressive effects of SP1, SP3 and DEAF1 on GDF5 promoter activity. This data suggest that the differential methylation of the +37 CpG site between osteoarthritic hip and knee cartilage may be responsible for the knee-specific effect of rs143383 on OA susceptibility. © 2014 The Author(s).


Woodruff P.G.,University of California at San Francisco | Agusti A.,University of Barcelona | Roche N.,University of Paris Descartes | Singh D.,University of Manchester | And 2 more authors.
The Lancet | Year: 2015

Chronic obstructive pulmonary disease (COPD) is a common, complex, and heterogeneous disorder that is responsible for substantial and growing morbidity, mortality, and health-care expense worldwide. Of imperative importance to decipher the complexity of COPD is to identify groups of patients with similar clinical characteristics, prognosis, or therapeutic needs, the so-called clinical phenotypes. This strategy is logical for research but might be of little clinical value because clinical phenotypes can overlap in the same patient and the same clinical phenotype could result from different biological mechanisms. With the goal to match assessment with treatment choices, the latest iteration of guidelines from the Global Initiative for Chronic Obstructive Lung Disease reorganised treatment objectives into two categories: to improve symptoms (ie, dyspnoea and health status) and to decrease future risk (as predicted by forced expiratory volume in 1 s level and exacerbations history). This change thus moves treatment closer to individualised medicine with available bronchodilators and anti-inflammatory drugs. Yet, future treatment options are likely to include targeting endotypes that represent subtypes of patients defined by a distinct pathophysiological mechanism. Specific biomarkers of these endotypes would be particularly useful in clinical practice, especially in patients in which clinical phenotype alone is insufficient to identify the underlying endotype. A few series of potential COPD endotypes and biomarkers have been suggested. Empirical knowledge will be gained from proof-of-concept trials in COPD with emerging drugs that target specific inflammatory pathways. In every instance, specific endotype and biomarker efforts will probably be needed for the success of these trials, because the pathways are likely to be operative in only a subset of patients. Network analysis of human diseases offers the possibility to improve understanding of disease pathobiological complexity and to help with the development of new treatment alternatives and, importantly, a reclassification of complex diseases. All these developments should pave the way towards personalised treatment of patients with COPD in the clinic. © 2015 Elsevier Ltd.


Savino W.,Oswaldo Cruz Foundation | Dardenne M.,University of Paris Descartes
Proceedings of the Nutrition Society | Year: 2010

The thymus gland, where T lymphocyte development occurs, is targeted in malnutrition secondary to protein energy deficiency. There is a severe thymic atrophy, resulting from massive thymocyte apoptosis (particularly affecting the immature CD4 +CD8 + cell subset) and decrease in cell proliferation. The thymic microenvironment (the non-lymphoid compartment that drives intrathymic T-cell development) is also affected in malnutrition: morphological changes in thymic epithelial cells were found, together with a decrease of thymic hormone production, as well as an increase of intrathymic contents of extracellular proteins. Profound changes in the thymus can also be seen in deficiencies of vitamins and trace elements. Taking Zn deficiency as an example, there is a substantial thymic atrophy. Importantly, marginal Zn deficiency in AIDS subjects, children with diarrhoea and elderly persons, significantly impairs the host's immunity, resulting in an increased risk of opportunistic infections and mortality; effects that are reversed by Zn supplementation. Thymic changes also occur in acute infectious diseases, including a severe thymic atrophy, mainly due to the depletion of CD4 +CD8 + thymocytes, decrease in thymocyte proliferation, in parallel to densification of the epithelial network and increase in the extracellular matrix contents, with consequent disturbances in thymocyte migration and export. In conclusion, the thymus is targeted in several conditions of malnutrition as well as in acute infections. These changes are related to the impaired peripheral immune response seen in malnourished and infected individuals. Thus, strategies inducing thymus replenishment should be considered as adjuvant therapeutics to improve immunity in malnutrition and/or acute infectious diseases. © 2010 The Author.


Billard J.-M.,University of Paris Descartes
Amino Acids | Year: 2012

Far from our initial view of D-amino acids as being limited to invertebrates, they are now considered active molecules at synapses of mammalian central and peripheral nervous systems, capable of modulating synaptic communication within neuronal networks. In particular, experimental data accumulated in the last few decades show that through the regulation of glutamatergic neurotransmission, D-serine influences the functional plasticity of cerebral circuitry throughout life. In addition, the modulation of NMDA-R-dependent signalling by D-aspartate has been demonstrated by pharmacological studies and after the targeted deletion of the D-aspartate-degrading enzyme. Considering the major contribution of the glutamatergic system to a wide range of neurological disorders such as schizophrenia, Alzheimer's disease and amyotrophic lateral sclerosis, an improved understanding of the mechanisms of D-amino-acid-dependent neuromodulation will certainly offer new insights for the development of relevant strategies to treat these neurological diseases. © 2012 Springer-Verlag.


This article analyzes the controversy raised among psychiatrists by the law of the 30 June 1975 in favor of disabled people in France in the second half of the 1970s. This controversy played a major role in stabilizing definitions and representations of categories of disability and mental disorder, which still bear a strong influence on today's French debates upon "handicap psychique". The first part of the article shows how the controversy emerged within the reform dynamics that dominated French health and social policies in the 1960s and 1970s. The second part examines the specific debate concerning a project of nursing homes for long-term mentally disordered people that took place within this controversy in order to show how it contributed to the redefinition of psychiatric chronicity. © 2012 Association ALTER. Published by Elsevier Masson SAS. All rights reserved.


Non-opioid analgesics, antipyretics and nonsteroidal anti-inflammatory drugs are widely used, but suspected allergic reactions to these drugs are rare, especially in children. Most frequent reactions are cutaneous (urticaria, angioedema) and respiratory (rhinitis, asthma). Other reactions (anaphylaxis, potentially harmful toxidermias) are rare. In a few patients, reactions may result from a specific (allergic) hypersensitivity, with positive responses in prick and intradermal tests (anaphylaxis, immediate urticaria and/or angioedema) and in intradermal and patch tests (non-immediate reactions). However, most reactions result from a non-specific (non-allergic) hypersensitivity (intolerance), with a frequent cross-reactivity between the various families of analgesics, antipyretics and nonsteroidal anti-inflammatory drugs, including paracetamol. Based on a convincing clinical history and/or positive responses in challenge tests, intolerance to non-opioid analgesics, antipyretics and nonsteroidal anti-inflammatory drugs has been diagnosed in 13 to 50% of the patients with allergic-like reactions to these drugs. Risk factors are a personal atopy and age. Prevention is based on administration of other (families of) analgesics, antipyretics and nonsteroidal anti-inflammatory drugs in patients with allergic hypersensitivity to these drugs. In patients with non-allergic hypersensitivity, prevention is based on administration of drugs with a low cyclo-oxygenase-1 inhibitory activity (if tolerated). Desensitization is efficient in patients with respiratory reactions, but does not work in patients with mucocutaneous reactions and anaphylaxis. © 2012 Elsevier Masson SAS.


Leach S.,University of Paris Descartes
Journal of Physical Chemistry A | Year: 2013

A relation between the heat of formation of molecular ions and cation size is used to study the effects of methyl substitution on a series of species containing oxygen. These include methanol, the hydroxymethyl radical, formaldehyde and related isomers, acetaldehyde and related isomers, ketene, formic acid, and acetic acid. This size-dependent relation is found to be valid in most cases, enabling a choice to be made among conflicting reported ion and neutral heat of formation values, but it holds much less well in methyl-substituted formaldehyde and its carbene isomers. The cations formed in methanol, hydroxymethyl, hydroxycarbene, and formic acid by methyl substitution at carbon sites were found to be more stable than those substituted at oxygen sites. Suggestions are made for investigating or reinvestigating the ionization energies and the heats of formation of several of the molecules studied in cases where multiple choices are available in the literature or where our analysis suggests that more reliable values are needed. © 2013 American Chemical Society.


Vouhe P.R.,University of Paris Descartes
Seminars in Thoracic and Cardiovascular Surgery | Year: 2011

The population of adults with congenital heart disease (CHD) (commonly called grown-ups with congenital heart disease or GUCH) is increasing steadily and exceeds the population of children with CHD already. The specificities of GUCH surgery are multiple and include (1) variety of the anatomo-clinical situations (defects repaired during childhood, malformations either nonoperated or palliated, nonreparable defects), (2) usual multiorgan involvement, and (3) many technical differences related to cardiopulmonary bypass, myocardial protection, and surgical technique. The surgical indications should be taken after a precise evaluation of the risk/benefit ratio on an individual basis; a balanced attitude should be kept between unwise interventionism and excessive waiting policy. It is now agreed that GUCH surgery should be performed in specialized centers with large patient volumes and expertise of both surgical and medical disciplines. Much remains to be done to implement these recommendations and to accumulate experience and evidence-based information to provide optimal outcome. © 2011 Elsevier Inc.


Farkhooi F.,Free University of Berlin | Van Vreeswijk C.,University of Paris Descartes
Physical Review Letters | Year: 2015

We develop a framework in which the activity of nonlinear pulse-coupled oscillators is posed within the renewal theory. In this approach, the evolution of the interevent density allows for a self-consistent calculation that determines the asynchronous state and its stability. This framework can readily be extended to the analysis of systems with more state variables and provides a population density treatment to evolve them in their thermodynamical limits. To demonstrate this we study a nonlinear pulse-coupled system, where couplings are dynamic and activity dependent. We investigate its stability and numerically study the nonequilibrium behavior of the system after the bifurcation. We show that this system undergoes a supercritical Hopf bifurcation to collective synchronization. © 2015 American Physical Society. © 2015 American Physical Society.


Konstantinides S.V.,Johannes Gutenberg University Mainz | Konstantinides S.V.,Democritus University of Thrace | Barco S.,Johannes Gutenberg University Mainz | Lankeit M.,Johannes Gutenberg University Mainz | Meyer G.,University of Paris Descartes
Journal of the American College of Cardiology | Year: 2016

Pulmonary embolism (PE) remains a major contributor to global disease burden. Risk-adapted treatment and follow-up contributes to a favorable outcome. Age-adjusted cutoff levels increase D-dimer specificity and may decrease overuse of imaging procedures and overdiagnosis of PE. Primary systemic fibrinolysis has an unfavorable risk-benefit ratio in intermediate-risk PE; catheter-directed techniques are an option for patients with hemodynamic decompensation and high bleeding risk. New oral anticoagulant agents are effective and safe alternatives to standard anticoagulation regimens. Recent trial data do not support insertion of cava filters in patients who can receive anticoagulant treatments. Remaining areas of uncertainty include the therapeutic implications of subsegmental PE, the optimal diagnostic approach to the pregnant patient with suspected PE, and the efficacy and safety of new oral anticoagulant agents in patients with cancer. Campaigns to increase awareness combined with strategies to implement guideline recommendations will be crucial steps towards further optimizing management of acute PE. © 2016 American College of Cardiology Foundation.


Bonnaire C.,University of Paris Descartes
Encephale | Year: 2012

Introduction: Actually, there are many different and varied new ways to take part in gambling activities such as gambling via the Internet, mobile phone and interactive television. Among these media, the rise in Internet gambling activity has been very rapid. Nevertheless, few empirical studies have been carried out on the psychosocial effects of Internet gambling. While there is no conclusive evidence that Internet gambling is more likely than other gambling media to cause problem gambling, there are a number of factors that make online activities like Internet gambling potentially seductive and/or addictive. Such factors include anonymity, convenience, escape, dissociation/immersion, accessibility, event frequency, interactivity, disinhibition, simulation, and asociability. It would also appear that virtual environments have the potential to provide short-term comfort, excitement and/or distraction. Background: The introduction of the Internet to gambling activities changes some of the fundamental situational and structural characteristics. The major change is that gambling activities are bought into the home and workplace environment. Thus, Internet gambling can become an in-house or work activity. One of the major concerns relating to those changes and the increase in gambling opportunities is the potential rise in the number of problem and pathological gamblers. Addictions always result from an interaction and interplay between many factors but in the case of gambling, it could be argued that technology and technological advance can themselves be an important contributory factor as we saw in examining the salient factors in Internet gambling. It is difficult to determine the prevalence of online (problem or not) gamblers, as it is obviously a figure that changes and has changed relatively quickly over the past decade. Nevertheless, the rate of Internet gambling is increasing and some recent studies using self-selected samples suggest, for example, that the prevalence of problem gambling among student Internet gamblers is relatively high for students who gamble on the Internet in general. Literature findings: Some recent studies have focused on the type of online games. For example, one specific form of online gambling online poker, is one of the fastest growing forms of online gambling. It appears that problem online poker players are more likely to swap genders when playing online, and play more frequently for longer periods of time. Thus, problem gamblers may be losing time but winning money. This result has a big implication for problem gambling criteria. Indeed, some data suggest that online poker may be producing a new type of problem gambler where the main negative consequence is loss of time (rather than loss of money). Conclusion: All these findings underline the need for better Internet gambling legislation. Indeed, the potential for excessive gambling and the lack of safeguards for vulnerable populations (e.g. adolescents and problem gamblers) raise the need for developing social responsibility tools. Harm-minimisation strategies are fundamental to facilitate gambling in a responsible manner, that is, to promote gambling within a player's means so they do not spent excessive time or money gambling, which cause the individual problems. Some research, but still few, examines the efficacy of responsible gambling strategies like pop-up messages. © 2011 L'Encéphale, Paris.


Marcouyeux A.,University of Paris Descartes | Fleury-Bahi G.,University of Nantes
Environment and Behavior | Year: 2011

Studies on place identity show positive relationships between the evaluation of a place and mechanisms involved in place identification. However, individuals also identify with places of low social prestige (places that bear a negative social image). Few authors investigate the nature of place identity processes in this case. The goal of this study is to highlight the specific connections between the three components of place identification, place attachment, place dependence, and group identity, which depend on the social evaluation of the environmental context (negative vs. positive image). The author uses self-administered questionnaires to interview 542 high-school students, to collect data on the basis of these three dimensions of their high school place identity, and their evaluation of their high school's image. Results show positive relationships between the students' evaluation of his or her high-school's image and his or her place identity. However, findings show that some students reported strong place identification even though they had rated their high school as having low social prestige (negative image). Findings also show that such place identification occurred through strong attachment ties, which were a strong influence. © 2011 SAGE Publications.


Segad M.,Chemical Center | Jonsson B.,Chemical Center | Akesson T.,Chemical Center | Cabane B.,University of Paris Descartes
Langmuir | Year: 2010

Ca/Na montmorillonite and natural Wyoming bentonite (MX-80) have been studied experimentally and theoretically. For a clay system in equilibrium with pure water, Monte Carlo simulations predict a large swelling when the clay counterions are monovalent, while in presence of divalent counterions a limited swelling is obtained with an aqueous layer between the clay platelets of about 10 Å. This latter result is in excellent agreement with X-ray scattering data, while dialysis experiments give a significantly larger swelling for Ca montmorillonite in pure water. Obviously, there is one "intra- lamellar" and a second "extra-lamellar" swelling. Montmorillonite in contact with a salt reservoir containing both Na+ and Ca 2+ counterions will only show a modest swelling unless the Na + concentration in the bulk is several orders of magnitude larger than the Ca2+ concentration. The limited swelling of clay in presence of divalent counterions is a consequence of ion?ion correlations, which reduce the entropic repulsion as well as give rise to an attractive component in the total osmotic pressure. Ion?ion correlations also favor divalent counterions in a situation with a competition with monovalent ones. A more fundamental result of ion?ion correlations is that the osmotic pressure as a function of clay sheet separation becomes nonmonotonic, which indicates the possibility of a phase separation into a concentrated and a dilute clay phase, which would correspond to the "extra-lamellar" swelling found in dialysis experiments. This idea also finds support in the X-ray scattering spectra, where sometimes two peaks corresponding to different lamellar spacings appear. © 2010 American Chemical Society.


Chiron C.,University of Paris Descartes
Handbook of Clinical Neurology | Year: 2013

Surgery of focal epilepsies in childhood has largely benefited from the recent advances of the noninvasive functional imaging techniques, particularly SPECT which presurgically contributes to the localization of the seizure onset zone, in order to select the patients, decide the optimal placement of intracranial electrodes, and plan the resection. Peri-ictal SPECT (ictal and postictal) proved especially useful when video-EEG is not contributory, when MRI looks normal or shows multiple abnormalities, or in cases of discrepant findings within the presurgery workup. Because of a poor temporal resolution, peri-ictal SPECT must be coupled with video-EEG. Multimodal imaging so-called SISCOM (peri-ictal - interictal SPECT subtraction image superimposed on MRI) increases the sensitivity of peri-ictal SPECT by about 70% and makes it a good predictor of seizure-free outcome after surgery. In addition, interictal SPECT occasionally provides some interesting results regarding functional cortical maturation and learning disorders in childhood. © 2013 Elsevier B.V.


Ribeil J.A.,University of Paris Descartes
TheScientificWorldJournal | Year: 2013

In humans, β -thalassemia dyserythropoiesis is characterized by expansion of early erythroid precursors and erythroid progenitors and then ineffective erythropoiesis. This ineffective erythropoiesis is defined as a suboptimal production of mature erythrocytes originating from a proliferating pool of immature erythroblasts. It is characterized by (1) accelerated erythroid differentiation, (2) maturation blockade at the polychromatophilic stage, and (3) death of erythroid precursors. Despite extensive knowledge of molecular defects causing β -thalassemia, less is known about the mechanisms responsible for ineffective erythropoiesis. In this paper, we will focus on the underlying mechanisms leading to premature death of thalassemic erythroid precursors in the bone marrow.


Silvestre J.-S.,University of Paris Descartes
Thrombosis Research | Year: 2012

Pro-angiogenic cell therapy has emerged as a promising option to treat patients with acute myocardial infarction or with critical limb ischemia. Exciting pre-clinical studies have prompted the initiation of numerous clinical trials based on administration of stem/progenitor cells with pro-angiogenic potential. Most of the clinical studies performed so far have used bone marrow-derived or peripheral blood-derived mononuclear cells and showed, overall, a modest but significant benefit on tissue remodeling and function in patients with ischemic diseases. These mixed results pave the way for the development of strategies to overcome the limitation of autologous cell therapy and to propose more efficient approaches. Such strategies include pretreatment of cells with activators to augment cell recruitment and survival in the ischemic target area and/or the improvement of cell functions such as their paracrine ability to release proangiogenic factors and vasoactive molecules. In addition, efforts should be directed towards stimulation of both angiogenesis and vessel maturation, the development of a composite product consisting of stem/progenitor cells encapsulated in a biomaterial and the use of additional sources of regenerative cells. © 2012 Elsevier Ltd.


Tharaux P.-L.,French Institute of Health and Medical Research | Tharaux P.-L.,University of Paris Descartes | Huber T.B.,University Hospital Freiburg | Huber T.B.,Albert Ludwigs University of Freiburg
Seminars in Nephrology | Year: 2012

Podocytes are highly specialized epithelial cells that line the urinary surface of the glomerular capillary tuft. To maintain kidney filtration, podocytes oppose the high intraglomerular hydrostatic pressure, form a molecular sieve, secrete soluble factors to regulate other glomerular cell types, and provide synthesis and maintenance of the glomerular basement membrane. Impairment of any of these functions after podocyte injury results in proteinuria and possibly renal failure. Loss of glomerular podocytes is a key feature for the progression of renal diseases, and detached podocytes can be retrieved in the urine of patients with progressive glomerular diseases. Thus, the concept of podocyte loss as a hallmark of progressive glomerular disease has been widely accepted. However, the nature of events that promote podocyte detachment and whether detachment is preceded by any kind of podocyte cell death, such as apoptosis, necroptosis, or necrosis, still remains unclear and is discussed in this review. © 2012 Elsevier Inc.


Bahi-Buisson N.,University of Paris Descartes
Handbook of Clinical Neurology | Year: 2013

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting females that has an incidence of 1:10. 000 female births, one of the most common genetic causes of severe mental retardation in females. Development is apparently normal for the first 6-18 months until fine and gross motor skills and social interaction are lost, and stereotypic hand movements develop. Progression and severity of the classical form of RTT are most variable, and there are a number of atypical variants, including congenital, early onset seizure, preserved speech variant, and " forme fruste." Mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) involve most of the classical RTT patients. Mutations in cyclin-dependent kinase like 5 (CDKL5) and FoxG1 genes have been identified in the early onset seizure and the congenital variants respectively.Management of RTT is mainly symptomatic and individualized. It focuses on optimizing each patient's abilities. A dynamic multidisciplinary approach is most effective, with specific attention given to epileptic and nonepileptic paroxysmal events, as well as scoliosis, osteoporosis, and the development of spasticity, which can have a major impact on mobility, and to the development of effective communication strategies for these severely disabled individuals. © 2013 Elsevier B.V.


Mignani S.,University of Paris Descartes | Majoral J.-P.,CNRS Coordination Chemistry
New Journal of Chemistry | Year: 2013

It is well documented that dendrimers were described as one of the most tunable nanomaterials both for therapeutic applications and diagnostics. This concise review surveys the different types of both non-targeted and targeted drug-encapsulated dendrimers and dendrimer-drug conjugates in oncology. In addition, progress in biocompatible dendritic architectures is discussed as it relates to the development of anti-cancer agents through in vitro and in vivo studies. In particular, we present relevant examples of these nanodevices to treat aggressive cancers such as colon and brain tumors. This review concludes with a brief survey of perspectives for clinical translation. © 2013 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.


Fagon J.-Y.,University of Paris Descartes
Critical Care | Year: 2011

Evaluation of a new biomarker from bronchoalveolar fluid, the Clara cell protein 10, adds data to the search for a diagnostic marker for ventilator-associated pneumonia (VAP). For more than 15 years, investigators tried to identify such a marker for predicting or diagnosing VAP. Unfortunately, the results of a number of these studies are disappointing. For optimal management of critically ill, ventilated patients with clinical suspicion of VAP, clinicians need accurate microbiological information to decide to treat in case of confirmed infection and to guide the initial choice of antibiotic therapy with identification of the responsible pathogen(s). Thus, today, the potential advantages of biomarkers are to improve the rapidity and performance of current diagnostic procedures and to reduce antibiotic exposure and selective pressure. © 2011 BioMed Central Ltd.


Lambert F.M.,University of Paris Descartes | Combes D.,French National Center for Scientific Research | Simmers J.,French National Center for Scientific Research | Straka H.,Ludwig Maximilians University of Munich
Current Biology | Year: 2012

Background: Self-generated body movements require compensatory eye and head adjustments in order to avoid perturbation of visual information processing. Retinal image stabilization is traditionally ascribed to the transformation of visuovestibular signals into appropriate extraocular motor commands for compensatory ocular movements. During locomotion, however, intrinsic "efference copies" of the motor commands deriving from spinal central pattern generator (CPG) activity potentially offer a reliable and rapid mechanism for image stabilization, in addition to the slower contribution of movement-encoding sensory inputs. Results: Using a variety of in vitro and in vivo preparations of Xenopus tadpoles, we demonstrate that spinal locomotor CPG-derived efference copies do indeed produce effective conjugate eye movements that counteract oppositely directed horizontal head displacements during undulatory tail-based locomotion. The efference copy transmission, by which the extraocular motor system becomes functionally appropriated to the spinal cord, is mediated by direct ascending pathways. Although the impact of the CPG feedforward commands matches the spatiotemporal specificity of classical vestibulo-ocular responses, the two fundamentally different signals do not contribute collectively to image stabilization during swimming. Instead, when the CPG is active, horizontal vestibulo-ocular reflexes resulting from head movements are selectively suppressed. Conclusions: These results therefore challenge our traditional understanding of how animals offset the disruptive effects of propulsive body movements on visual processing. Specifically, our finding that predictive efference copies of intrinsic, rhythmic neural signals produced by the locomotory CPG supersede, rather than supplement, reactive vestibulo-ocular reflexes in order to drive image-stabilizing eye adjustments during larval frog swimming, represents a hitherto unreported mechanism for vertebrate ocular motor control. © 2012 Elsevier Ltd. All rights reserved.


Fumagalli S.,Metabolic Diseases Institute | Fumagalli S.,University of Paris Descartes | Ivanenkov V.V.,Metabolic Diseases Institute | Teng T.,Metabolic Diseases Institute | And 3 more authors.
Genes and Development | Year: 2012

Impairment of ribosome biogenesis leads to p53 induction and cell cycle arrest, a checkpoint involved in human disease. Induction of p53 is attributed to the binding and inhibition of human double minute 2 (Hdm2) by a subset of ribosomal proteins (RPs): RPS7, RPL5, RPL11, and RPL23. However, we found that only RPL11 or RPL5, in a mutually dependent manner, elicit this response. We show that depletion of RPS7 or RPL23, like depletion of other RPs, except for RPL11 and RPL5, induces a p53 response and that the effects of RPS7 and RPL23 on p53 induction reported earlier may be ascribed to inhibition of global translation. Moreover, we made the surprising observation that codepletion of two essential RPs, one from each subunit, but not the same subunit, leads to suprainduction of p53. This led to the discovery that the previously proposed RPL11-dependent mechanism of p53 induction, thought to be caused by abrogation of 40S biogenesis and continued 60S biogenesis, is still operating, despite abrogation of 60S biogenesis. This response leads to both a G1 block and a novel G2/M block not observed when disrupting either subunit alone. Thus, induction of p53 is mediated by distinct mechanisms, with the data pointing to an essential role for ribosomal subunits beyond translation. © 2012 by Cold Spring Harbor Laboratory Press.


Aims: This article explores the subjective and objective effects of new data collection technologies concerning our bodies on the awareness of bodily self-care. Methods: The article is divided into four parts: after an overview of the new technological background of in vivo captors, we set out three arguments in the present debate concerning the interest shown by our contemporaries for knowledge of their living bodies, the dangers of new bio-controls of this data via profiling, and the reflexive uses of self-care. Results: The self-tracking techniques range from the recording of data to clinical profiling, depending on the health objectives and treatments. We show how the appropriation of knowledge on the living body upsets our perceptions of the body as such, but also raises the question of the ownership of this data in the light of its availability on different networks. Discussion: The discussion contrasts a post-Foucault reading of the control of bodies by an integrated bio-power implementing remote surveillance of the health of individuals, and a reading based on the empowerment of the subject who uses the data on his living body to define a conscious use of that body. Conclusion: The technical osmosis is two-fold - on the one hand it fuels the belief in a direct communication with one's living body, and on the other it feeds the confusion between the living body, its technological measures and the awareness of bodily experiences. © 2015 Published by Elsevier Masson SAS.


Verdon B.,University of Paris Descartes
Rorschachiana | Year: 2011

Since the 1950s, the growing interest of clinicians in using projective tests to study normal or pathological aging processes has led to the creation of several thematic tests for older adults. This development reflects their authors' belief that the TAT is not suitable to the concerns and anxieties of elderly persons. The new material thus refers explicitly to situations related to age; it aims to enable older persons to express needs they cannot verbalize during consultations. The psychodynamic approach to thematic testing is based on the differentiation between the pictures' manifest and latent content, eliciting responses linked to mental processes and issues the respondent is unaware of. The cards do not necessarily have to show aging characters to elicit identification: The situations shown in the pictures are linked to loss, rivalry, helplessness, and renunciation, all issues elderly respondents can identify with and that lead them to express their mental fragilities and resources. The article first explains the principles underlying four of these thematic tests, then develops several examples of stories told for card 3BM of the TAT, thus showing the effectiveness of this tool for the understanding and differentiation of loss-related issues facing older men and women.


Hovnanian A.,University of Paris Descartes | Hovnanian A.,French Institute of Health and Medical Research
Journal of Investigative Dermatology | Year: 2013

In this issue, Woodley et al. report restoration of anchoring fibril formation and dermal-epidermal adherence in a murine model of recessive dystrophic epidermolysis bullosa (RDEB) by intravenous injection of recombinant human type VII collagen. This work follows a previous report by the same group of the surprising capability of intradermally injected type VII collagen protein to reverse RDEB, and it opens new therapeutic avenues. © 2013 The Society for Investigative Dermatology.


Weil D.,University of Paris Descartes | Hollien J.,University of Utah
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2013

Localization of both mRNAs and mRNA decay factors to internal membranes of eukaryotic cells provides a means of coordinately regulating mRNAs with common functions as well as coupling organelle function to mRNA turnover. The classic mechanism of mRNA localization to membranes is the signal sequence-dependent targeting of mRNAs encoding membrane and secreted proteins to the cytoplasmic surface of the endoplasmic reticulum. More recently, however, mRNAs encoding proteins with cytosolic or nuclear functions have been found associated with various organelles, in many cases through unknown mechanisms. Furthermore, there are several types of RNA granules, many of which are sites of mRNA degradation; these are frequently found associated with membrane-bound organelles such as endosomes and mitochondria. In this review we summarize recent findings that link organelle function and mRNA localization to mRNA decay. This article is part of a Special Issue entitled: RNA Decay mechanisms. © 2013 Elsevier B.V.


Lopez-Otin C.,University of Oviedo | Blasco M.A.,Telomeres and Telomerase Group | Partridge L.,Max Planck Institute for Biology of Ageing | Partridge L.,University College London | And 4 more authors.
Cell | Year: 2013

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. © 2013 Elsevier Inc.


Dimopoulos Y.,University of Cyprus | Hashmi M.A.,University Pierre and Marie Curie | Moraitis P.,University of Paris Descartes
Knowledge-Based Systems | Year: 2012

Planning is a fundamental issue in multi-agent systems. In this work we focus on the coordination of multiple agents in two different settings. In the first, agents are able to attain individual goals that are necessary for the achievement of a global common goal. As the agents share the same environment, they need to find a coordinated course of action that avoids harmful (or negative) interactions, and benefit from positive interactions, whenever this is possible. In the second setting some of the agents may need the assistance of other agents to achieve their individual goals. This is the case where some of the actions of the plan of an agent may be executed by another agent who will play the role of the assistant. We formalize these two problems in a more general way than in previous works, and present a coordination algorithm which generates optimal solutions in the case of two agents. In this algorithm, agents use μ-SATPLAN as the underlying planner for generating individual and joint consistent plans. This planner is an extension of the classical SATPLAN planner, that tackles negative and positive interactions and, therefore, multi-agent planning. We also present an algorithm that solves the assistance problem. The underlying algorithm is again μ-SATPLAN, and is used for the generation of individual (based on assistance) and joint consistent plans. Finally experimental results on multi-agent versions of problems taken from International Planning Competitions demonstrate the effectiveness of μ-SATPLAN and the coordination algorithm. © 2011 Elsevier B.V. All rights reserved.


Attwell D.,University College London | Buchan A.M.,University of Oxford | Charpak S.,University of Paris Descartes | Lauritzen M.,Copenhagen University | And 2 more authors.
Nature | Year: 2010

Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches. © 2010 Macmillan Publishers Limited. All rights reserved.


Largeron M.,University of Paris Descartes
European Journal of Organic Chemistry | Year: 2013

The catalytic oxidation of amines to imines is of intense current interest, owing to the importance of imines as pivotal intermediates in the synthesis of fine chemicals and numerous biologically active compounds. Whereas considerable efforts had been made to develop efficient methods for the oxidation of secondary amines to imines, little attention had until recently been given to the oxidation of primary amines, probably because the generated imines are intermediate products that are easily dehydrogenated to nitriles. A surge of activity in this area originated with the discovery of new catalytic systems that allow the oxidation of primary amines to imines under green conditions. This microreview focuses on the major achievements during the last five years. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Landi S.,University of Florence | Matteini L.,University of Florence | Pantellini F.,University of Paris Descartes
Astrophysical Journal | Year: 2012

We present numerical simulations of the solar wind using a fully kinetic model which takes into account the effects of particle's binary collisions in a quasi-neutral plasma in spherical expansion. Starting from an isotropic Maxwellian velocity distribution function for the electrons, we show that the combined effect of expansion and Coulomb collisions leads to the formation of two populations: a collision-dominated cold and dense population almost isotropic in velocity space and a weakly collisional, tenuous field-aligned and antisunward drifting population generated by mirror force focusing in the radially decreasing magnetic field. The relative weights and drift velocities for the two populations observed in our simulations are in excellent agreement with the relative weights and drift velocities for both core and strahl populations observed in the real solar wind. The radial evolution of the main moments of the electron velocity distribution function is in the range observed in the solar wind. The electron temperature anisotropy with respect to the magnetic field direction is found to be related to the ratio between the collisional time and the solar wind expansion time. Even though collisions are found to shape the electron velocity distributions and regulate the properties of the strahl, it is found that the heat flux is conveniently described by a collisionless model where a fraction of the electron thermal energy is advected at the solar wind speed. This reinforces the currently largely admitted fact that collisions in the solar wind are clearly insufficient to force the electron heat flux obey the classical Spitzer-Härm expression where heat flux and temperature gradient are proportional to each other. The presented results show that the electron dynamics in the solar wind cannot be understood without considering the role of collisions. © 2012. The American Astronomical Society. All rights reserved..


Garrel V.,Subaru Telescope | Guyon O.,Subaru Telescope | Baudoz P.,University of Paris Descartes
Publications of the Astronomical Society of the Pacific | Year: 2012

We propose a new algorithm dramatically enhancing the efficiency of the lucky imaging technique for AO-corrected images in the visible range. It is achieved by a selection based on the relative strength of signal for each spatial frequency in the Fourier domain, making a more efficient use of information contained in each frame. Realistic simulations show that our algorithm allows us to reach the diffraction limit in the visible range on an AO-equipped 8 m telescope and enhances the Strehl ratio of an AO long exposure by a factor of up to 4. It outperforms the lucky imaging technique at an equivalent selection ratio. The fraction of selected data in simulation is also boosted from two to eight times for a given Strehl-ratio performance. © 2012. The Astronomical Society of the Pacific. All rights reserved.


Bachmann M.F.,University of Zurich | Bachmann M.F.,University of Oxford | Whitehead P.,University of Paris Descartes
Vaccine | Year: 2013

With the effective control of infectious diseases in many parts of the world, chronic, non-communicable diseases have become the major cause of death and disability. Monoclonal antibodies (mAbs) have become an important class of drugs for the treatment of such diseases. Nevertheless, mAbs suffer from major shortcomings in a chronic setting: most notably, generation of anti-antibodies and high cost of goods. Here, we discuss a novel approach to treat chronic diseases based on active rather than passive immunization and contrast the 2 treatment modalities to highlight their respective advantages and disadvantages. © 2013 .


Polak M.,University of Paris Descartes
Hormone Research in Paediatrics | Year: 2011

Background: Advances in prenatal imaging techniques and in fetal hormonology now allow for identification of disorders of thyroid function in the fetus. These can potentially be treated in utero by giving drugs to the mother. Aims: This review examines the feasibility of in utero treatment of fetal thyroid disorders, either indirectly by treating the mother or by giving the necessary drugs directly to the fetus. Methodologies: In women with Graves' disease, autoimmune fetal hyperthyroidism can generally be treated in a noninvasive way by optimizing treatment of the mother, such as by increasing the dose of antithyroid drugs. For goitrous fetal hypothyroidism leading to hydramnios, repeated intra-amniotic injections of thyroxine have been reported to decrease the size of the fetal thyroid. Results: Experience with such procedures is limited but positive. The risk that direct in utero treatment of the fetus may provoke premature labor or cause infection should be carefully evaluated. Conclusions: Follow-up of the efficacy and the possible long-term consequences of medical interventions to normalize thyroid function of the fetus are of great importance. Specialized care of the fetus should be provided by skilled teams with extensive experience in prenatal care. © 2011 S. Karger AG, Basel.


Blancard C.,CEA DAM Ile-de-France | Blancard C.,University of Paris Descartes | Cosse P.,CEA DAM Ile-de-France | Faussurier G.,CEA DAM Ile-de-France
Astrophysical Journal | Year: 2012

An opacity model (OPAS) combining detailed configuration and level accounting treatments has been developed to calculate radiative opacity of plasmas in local thermodynamic equilibrium. The model is presented and used to compute spectral opacities of a solar mixture. Various density-temperature couples have been considered from the solar center up to the vicinity of the radiative/convective zone interface. For a given solar thermodynamic path, OPAS calculations are compared to Opacity Project (OP) and OPAL data. Rosseland mean opacity values are in very good agreement over all the considered solar thermodynamic path, while OPAS and OP spectral opacities of each element may vary considerably. Main sources of discrepancy are discussed. © 2012. The American Astronomical Society. All rights reserved.


Drape J.L.,University of Paris Descartes
Orthopaedics & traumatology, surgery & research : OTSR | Year: 2013

Functional magnetic resonance imaging (MRI) improves tissue characterisation and staging of bone and soft-tissue tumours compared to the information usually supplied by structural imaging. Perfusion MRI, diffusion MRI, and in-phase/opposed-phase MRI can be performed in everyday practice. Nuclear magnetic resonance (NMR) spectroscopic imaging is a challenging technique that is available only in specialised centres. Tumour characterisation can benefit from perfusion MRI with dynamic gadolinium injection and enhancement time-intensity curve analysis or from diffusion MRI. Highly cellular malignant tumours restrict diffusion and consequently decrease the apparent diffusion coefficient (ADC). With some tumours, tissue heterogeneity or the presence of a myxoid component can hinder this evaluation. Chronic hematoma can be distinguished from haemorrhagic sarcoma. Perfusion and diffusion MRI contribute to the evaluation of tumour spread, in particular by differentiating oedema from tumour tissue. Another advantage of perfusion MRI and ADC mapping is the early identification of good responders to chemotherapy. The use of NMR spectroscopy remains limited. Evaluation of the choline peak can help to differentiate benign and malignant tumours. All available functional MRI techniques have limitations and leave some overlap between benign and malignant tumours. Functional MRI can be used only as an adjunctive imaging modality to complement morphological imaging. Copyright © 2012 Elsevier Masson SAS. All rights reserved.


Briet M.,University of Paris Descartes | Schiffrin E.L.,McGill University
Journal of Vascular Research | Year: 2013

Aldosterone exerts direct effects on the vascular system by inducing oxidative stress, inflammation, hypertrophic remodeling, fibrosis, and endothelial dysfunction. Aldosterone exerts its effects through genomic and nongenomic pathways in a mineralocorticoid receptor (MR)-dependent or independent manner. Other aldosterone receptors such as GPR30 have been identified. A tight relation exists between the aldosterone and angiotensin II pathways, as well as with the endothelin-1 system. There is a correlation between plasma levels of aldosterone and cardiovascular risk. Recently, an increasing body of evidence has underlined the importance of aldosterone in cardiovascular complications associated with the metabolic syndrome, such as arterial remodeling and endothelial dysfunction. Blockade of MR is an increasingly used evidence-based therapy for many forms of cardiovascular disease, including hypertension, heart failure, chronic kidney disease, and diabetes mellitus. © 2012 S. Karger AG, Basel.


Yuan J.,Harvard University | Kroemer G.,French Institute of Health and Medical Research | Kroemer G.,Institute Gustave Roussy | Kroemer G.,University of Paris Descartes
Genes and Development | Year: 2010

A canonical regulatory pathway involving the members of the Bcl-2 and caspase families has been established to regulate developmental apoptosis in nematodes and flies. However, mutant mice that have major deficiencies in this apoptosis pathway show only relatively minor developmental defects. Recent revelations indicate that multiple mechanisms are involved in regulating cell death during mammalian development, tissue homeostasis, and pathological cell loss. Here, we critically evaluate the evidence demonstrating the existence of alternative cell death mechanisms, including apoptosis of lower organisms in the absence of canonical apoptosis mediators, autophagic cell death, necroptosis, elimination by shedding, keratinocyte death by cornification, and cell-cell cannibalism by entosis. The physiological relevance of alternative cell death mechanisms as primary and backup mechanisms is discussed. © 2010 by Cold Spring Harbor Laboratory Press.


Tissier F.,University of Paris Descartes | Tissier F.,French National Center for Scientific Research
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2010

Most adrenocortical tumors are benign; adrenocortical carcinomas are rare but their prognosis is poor and their therapeutics are sparse. In most adrenocortical tumors, the morphological approach in particular by Weiss system, brings sufficient elements to establish the differential diagnosis between a benign and a malignant tumor. But some tumors of Weiss score of 2 or 3 can raise problems: are they benign, malignant or are they of uncertain malignant potential? On the other hand, some Weiss criteria are difficult to evaluate as, for example, sinusoidal invasion. These observations led to the development of other approaches, in particular genetic approaches. These genetics findings already have repercussions for the patients in the development of molecular markers for diagnosis and prognosis and in the future they could help in the development of new morphological approaches, in particular immunohistochemical approaches. © 2010 Elsevier Ltd. All rights reserved.


Menasche P.,University of Paris Descartes
Current Opinion in Molecular Therapeutics | Year: 2010

Peripheral arterial disease remains an often devastating condition, particularly in patients with diabetes, because of the high rate of functional disability, amputation and death. For those patients for whom conventional endovascular or surgical revascularization procedures have been unsuccessful, new options are eagerly awaited, among which cell therapy has gained increasing interest. Most clinical trials of cell therapy have used multiple intramuscular injections of bone marrow-derived mononuclear cells that have yielded encouraging suggestions of efficacy. The prevailing opinion is that the benefits of cell therapy are not a result of the structural integration of grafted cells within new vessels, but of the paracrine activation of angiogenesis, arteriogenesis and vasculogenesis pathways by the cytokines, chemokines and growth factors released from such cells. An analysis of cell therapy clinical trial outcomes has also identified several key issues that need to be addressed, including the optimal cell type, source and dosing, the most effective route for cell transfer, and methods for enhancing survival of the cellular graft. Finally, because of the strong placebo effect that may confound interpretation of outcome measures, rigorously randomized controlled trials are mandatory in order to assess more thoroughly whether cell therapy will be beneficial for patients with peripheral arterial disease. © 2010 Thomson Reuters (Scientific) Ltd.


Irigaray P.,Cancer Research Center | Belpomme D.,Cancer Research Center | Belpomme D.,University of Paris Descartes
Carcinogenesis | Year: 2010

Exogenous chemical carcinogenesis is an extremely complex multifactorial process during which gene-environment interactions involving chronic exposure to exogenous chemical carcinogens (ECCs) and polymorphisms of cancer susceptibility genes add further complexity. We describe the properties and molecular mechanisms of ECCs that contribute to induce and generate cancer. A basic and specific property of many lipophilic organic ECCs including polycyclic aromatic hydrocarbons and polyhalogenated aromatic hydrocarbons is their ability to bioaccumulate in the adipose tissue from where they may be released in the blood circulation and target peripheral tissues for carcinogenesis. Many organic ECCs are procarcinogens and consequently need to be activated by the cytochrome P450 (CYP) system and/or other enzymes before they can adduct DNA and proteins. Because they contribute not only to the cocarcinogenic and promoting effects of many aromatic pollutants but also to their mutagenic effects, the aryl hydrocarbon receptor-activating and the inducible CYP systems are central to exogenous chemical carcinogenesis. Another basic property of ECCs is their ability to induce stable and bulky DNA adducts that cannot be simply repaired by the different repair systems. In addition, following ECC exposure, mutagenesis may also be caused indirectly by free-radical production and by epigenetic alterations. As a result of complex molecular interplays, direct and/or indirect mutagenesis may especially account for the carcinogenic effects of many exogenous metals and metalloids. Because of these molecular properties and action mechanisms, we conclude that ECCs could be major contributors to human cancer, with obviously great public health consequences. © The Author 2009. Published by Oxford University Press.


Chatenoud L.,University of Paris Descartes
Cold Spring Harbor perspectives in medicine | Year: 2012

Type 1 diabetes is an autoimmune disease, hence the rationale for immunotherapy to halt disease progression. Based on knowledge gained from other autoimmune diseases and from transplantation, the first immunointervention trials used immunosuppressive drugs, e.g., cyclosporin, in patients with recently diagnosed type 1 diabetes. Although remarkable, the effect vanished following drug withdrawal. Efforts were then devoted to devise strategies to induce/restore self-tolerance and avoid chronic immunosuppression. Various approaches were identified from work in spontaneous models of autoimmune diabetes, including the use of β-cell autoantigens and monoclonal antibodies directed at relevant immune molecules such as costimulatory ligands, T-cell receptor molecules such as CD3, and B cells. Phase II and phase III trials were launched, results of which are now available. Although the endeavor is challenging, the experience gained indicates that immunotherapy appears as the real hope of inducing long-term remission of the disease provided the treatment is started early and that protocols are adapted based on lessons from the past.


Chatenoud L.,University of Paris Descartes
Nature Reviews Endocrinology | Year: 2010

Type 1 diabetes mellitus (T1DM) is a prototypic organ-specific autoimmune disease that results from selective destruction of insulin-secreting Β-cells by immune-mediated inflammation (insulitis), that is, the infiltration of pancreatic islets by autoreactive CD4+ and CD8 + T lymphocytes. Current treatment is substitutivechronic use of exogenous insulinwhich, in spite of considerable advances, is still associated with constraints and lack of effectiveness over the long-term in relation to the prevention of vascular and neurological complications. Finding a cure for T1DM is an important medical health challenge, as the disease's incidence is steadily increasing in industrialized countries and projections of future prevalence are alarming. Crucially, as T1DM mainly affects children and young adults, any candidate immune therapy must be safe and avoid chronic use of immunosuppressants that promote sustained depression of immune responses. The ideal approach would, therefore, involve induction or, in the case of established T1DM, restoration of immune tolerance to target autoantigens. This Review presents, in particular, two strategies that are still in clinical development but hold great promise. These strategies are focused on the use of candidate autoantigens and anti-CD3 monoclonal antibodies. © 2010 Macmillan Publishers Limited.


Barouki R.,University of Paris Descartes
Biochimie | Year: 2010

Understanding the mechanisms of long-term toxicities of chemicals is challenging. The present review discusses evidence suggesting that the biological adaptation to acute xenobiotic exposure could lead in the long run to toxic side effects. Upon acute exposure, hydrophobic xenobiotics are sequestered in the adipose tissue, which consequently protects other organs. However, this could also lead to the persistence of these xenochemicals and to a chronic low level internal exposure. The intrinsic properties of the xenobiotic detection and metabolism systems could also account for long-term toxicity. Indeed, hydrophobic xenochemicals are metabolized into more hydrophilic compounds; the first step of this pathway consists in the "activation" of the parent compound into a more reactive intermediate by cytochromes P450 activity. Those intermediates can be extremely reactive with DNA and proteins and thus could lead to toxic side effects that may become significant over time. Furthermore, recent evidence suggests that xenobiotic receptors also display endogenous functions. It is likely that repeated exposure to xenobiotics disrupts those endogenous functions with possibly dire cellular consequences. Altogether, The hypothesis presented here proposes that one mechanism for long-term toxicity stems from cumulative side effects due to the repeated activity of adaptive pathways triggered by acute intoxication. © 2010 Elsevier Masson SAS.


Rotig A.,University of Paris Descartes
Diabetes and Metabolism | Year: 2010

Oxidative phosphorylation - ATP synthesis by the oxygen-consuming respiratory chain (RC) - supplies most organs and tissues with a readily usable energy source, and is already fully functioning at birth. This means that, in theory, RC deficiency can give rise to any symptom in any organ or tissue at any age and with any mode of inheritance, due to the two-fold genetic origin of RC components (nuclear DNA and mitochondrial DNA). It has long been erroneously believed that RC disorders originate from mutations of mtDNA as, for some time, only mutations or deletions of mtDNA could be identified. However, the number of disease-causing mutations in nuclear genes is now steadily growing. These genes not only encode the various subunits of each complex, but also the ancillary proteins involved in the different stages of holoenzyme biogenesis, including transcription, translation, chaperoning, addition of prosthetic groups and assembly of proteins, as well as the various enzymes involved in mtDNA metabolism. © 2010 Elsevier Masson SAS. All rights reserved.


Gabory A.,French National Institute for Agricultural Research | Jammes H.,French National Institute for Agricultural Research | Dandolo L.,University of Paris Descartes
BioEssays | Year: 2010

The H19 gene produces a non-coding RNA, which is abundantly expressed during embryonic development and down-regulated after birth. Although this gene was discovered over 20 years ago, its function has remained unclear. Only recently a role was identified for the non-coding RNA and/or its microRNA partner, first as a tumour suppressor gene in mice, then as a trans-regulator of a group of co-expressed genes belonging to the imprinted gene network that is likely to control foetal and early postnatal growth in mice. The mechanisms underlying this transcriptional or post-transcriptional regulation remain to be discovered, perhaps by identifying the protein partners of the full-length H19 RNA or the targets of the microRNA. This first in vivo evidence of a functional role for the H19 locus provides new insights into how genomic imprinting helps to control embryonic growth. © 2010 Wiley Periodicals, Inc.


Rothenbuhler A.,University of Paris Descartes | Stratakis C.A.,Section on Endocrinology and Genetics
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2010

Carney complex (CNC) is a rare multiple familial neoplasia syndrome that is characterized by multiple types of skin tumors and pigmented lesions, endocrine neoplasms, myxomas and schwannomas and is inherited in an autosomal dominant manner. Clinical and pathologic diagnostic criteria are well established. Over 100 pathogenic variants in the regulatory subunit type 1A (RI-A) of the cAM