Paris, France

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.

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Institute Curie, French National Center for Scientific Research, French Institute of Health, Medical Research, Assistance Publique Hopitaux De Paris and University of Paris Descartes | Date: 2016-07-29

A composition that can be used as a vaccine containing means for targeting at least one antigen to dendritic cells and as adjuvants a granulocyte macrophage colony stimulating factor and a CpG oligodeoxynucleotide and/or a CpG-like oligodeoxynucleotide. This composition can used to treat cancers, infectious diseases caused by bacterial, viral, fungal, parasitic or protozoan infections, allergies and/or autoimmune diseases.

French Institute of Health, Medical Research, French National Center for Scientific Research, Genethon, University of Paris Descartes, École Nationale Supérieure de Chimie de Paris, University of Évry Val d'Essonne and Assistance Publique Hopitaux De Paris | Date: 2016-09-16

The present invention relates to a method for treating a Leber congenital amaurosis in a patient harbouring the mutation c.2991+1655 A>G in the CEP290 gene, comprising the step of administering to said patient at least one antisense oligonucleotide complementary to nucleic acid sequence that is necessary for preventing splicing of the cryptic exon inserted into the mutant c.2291+1655 A>G CEP290 mRNA

French Institute of Health, Medical Research, University of Paris Descartes, Fondation Imagine, Assistance Publique Hopitaux De Paris Aphp, French National Center for Scientific Research, University Grenoble Alpes, French Atomic Energy Commission and University of Burgundy | Date: 2015-02-18

The present invention relates to methods and pharmaceutical compositions for the treatment of diseases mediated by the NRP-1/OBR complex signaling pathway. In particular, the present invention relates to a method for treating a disease selected from the group consisting of cancers, obesity and obesity related diseases, anorexia, autoimmune diseases and infectious diseases in a subject in need thereof comprising administering the subject with a therapeutically effective amount of an antagonist of the NRP-1/OBR signaling pathway.

French Institute of Health, Medical Research, University of Paris Descartes and Assistance Publique Hopitaux De Paris Aphp | Date: 2015-04-29

The present invention relates to methods and pharmaceutical compositions for treating vaso-occlusive crises. In particular, the present invention relates to a method of treating a vaso-occlusive crisis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of agent capable of degrading, destabilizing or depleting the blood-borne extracellular DNA from the blood of the subject.

Institute Pasteur Paris, French National Center for Scientific Research, University of Paris Descartes and Assistance Publique Hopitaux De Paris | Date: 2016-10-12

The present invention relates to polynucleotides enabling the rapid, simple and specific detection of Group B Streptococcus highly-virulent ST-17 clones. The present invention also relates to the polypeptides encoded by said polynucleotides, as well as to antibodies directed or raised against said polypeptides. The present invention also relates to kits and methods for the specific detection of Group B Streptococcus highly-virulent ST-17 clones, using the polynucleotides, the polypeptides or the antibodies according to the invention.

Institute Curie and University of Paris Descartes | Date: 2015-04-21

An in vitro method for determining whether a patient has, or is at risk of having or developing an autoimmune disease or for assessing the severity or predicting the outcome of an autoimmune disease, comprising a step of detecting or quantifying in a biological sample obtained from said patient an immune anti-IL2 response, peptides specifically recognised by anti-IL2 antibodies or IL-2-specific T cells of T1D, systemic lupus erythematosus, rheumatoid arthritis, Sjgrens syndrome and autoimmune polymyositis patients, and pharmaceutical compositions.

Institute Pasteur Paris and University of Paris Descartes | Date: 2017-01-11

The application relates to Listerin monocytogenes, more particularly to the determination of the clone to which a L. monocytogenes isolate belongs. The means of the application involve primers and/or probes, more particularly multiplex primers. The means of the application are notably useful to assess the invasivity that said L. monocytogenes isolate might show in a human being.

OBJECTIVES:: The objective of the study was to assess the efficacy of reduced sufentanil doses for postoperative analgesia following surgical ductal closure in extremely premature infants. METHODS:: This was a retrospective, single-center, cohort study comparing 2 sufentanil dosing regimens used between 2001 and 2010 and included all infants born at <28 weeks of gestation with surgical ductal closure. Sufentanil doses were reduced in 2007 as a standard of care. Time was divided into 3 epochs to distinguish the effects of practice changes over time from the effects of sufentanil dose change: epoch 1 (2001 to 2004), epoch 2 (May 2005 to 2007), and epoch 3 (June 2007 to 2010). RESULTS:: A total of 109 of 114 eligible infants were analyzed (mean [±SD], gestational age: 25.1 [±1.1] wk; mean [±SD], birth weight: 756 [±144] g). Median sufentanil doses were significantly higher during epochs 1 and 2 (0.1 to 0.2 µg/kg/h) than during epoch 3 (0.03 to 0.04 µg/kg/h) (P<0.0001). EDIN (Echelle de Douleur et d’Inconfort du Nouveau-né) pain scores were mostly ≤4 throughout the study period and their changes over time were not contemporaneous with the reduction in sufentanil doses; they were lower during epoch 1 versus epochs 2 and 3 (P<0.0001) and comparable between epochs 2 and 3. Midazolam doses and paracetamol use were not higher during epoch 3 as compared with epochs 1 and 2. No difference in opioid-related adverse events was observed between the 3 epochs. CONCLUSION:: Our study supports the use of low continuous intravenous sufentanil doses, consistent with morphine doses currently recommended in this population. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Jasseron C.,University of Paris Descartes
Transplantation | Year: 2017

BACKGROUND: The cardiac allocation system in France is currently based on urgency and geography. Medical urgency is defined by therapies without considering objective patient mortality risk factors. This study aimed to develop a waitlist mortality risk score from commonly available candidate variables. METHODS: The study included all patients, aged 16 years or older, registered on the national registry CRISTAL for first single-organ heart transplantation between January 2010 and December 2014. This population was randomly divided in a 2:1 ratio into derivation and validation cohorts. The association of variables at listing with 1-year waitlist death or delisting for worsening medical condition was assessed within the derivation cohort. The predictors were used to generate a candidate risk score (CRS). Validation of the CRS was performed in the validation cohort. Concordance probability estimation (CPE) was used to evaluate the discriminative capacity of the models. RESULTS: During the study period, 2333 patients were newly listed. The derivation (n=1 555) and the validation cohorts (n=778) were similar. Short-term mechanical circulatory support, natriuretic peptide decile, glomerular filtration rate and total bilirubin level were included in a simplified model and incorporated into the score. The CPE of the CRS was 0.73 in the derivation cohort and 0.71 in the validation cohort. The correlation between observed and expected 1-year waitlist mortality in the validation cohort was 0.87. CONCLUSIONS: The candidate risk score provides an accurate objective prediction of waitlist mortality. It is currently being used to develop a modified cardiac allocation system in France. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Leroy F.,University of Paris Descartes | Lamotte d'Incamps B.,University of Paris Descartes | Imhoff-Manuel R.D.,University of Paris Descartes | Zytnicki D.,University of Paris Descartes
eLife | Year: 2014

In amyotrophic lateral sclerosis (ALS) the large motoneurons that innervate the fast-contracting muscle fibers (F-type motoneurons) are vulnerable and degenerate in adulthood. In contrast, the small motoneurons that innervate the slow-contracting fibers (S-type motoneurons) are resistant and do not degenerate. Intrinsic hyperexcitability of F-type motoneurons during early postnatal development has long been hypothesized to contribute to neural degeneration in the adult. Here, we performed a critical test of this hypothesis by recording from identified F- and S-type motoneurons in the superoxide dismutase-1 mutant G93A (mSOD1), a mouse model of ALS at a neonatal age when early pathophysiological changes are observed. Contrary to the standard hypothesis, excitability of F-type motoneurons was unchanged in the mutant mice. Surprisingly, the S-type motoneurons of mSDO1 mice did display intrinsic hyperexcitability (lower rheobase, hyperpolarized spiking threshold). As S-type motoneurons are resistant in ALS, we conclude that early intrinsic hyperexcitability does not contribute to motoneuron degeneration.

Ornitz D.M.,University of Washington | Legeai-Mallet L.,University of Paris Descartes
Developmental Dynamics | Year: 2017

Autosomal dominant mutations in fibroblast growth factor receptor 3 (FGFR3) cause achondroplasia (Ach), the most common form of dwarfism in humans, and related chondrodysplasia syndromes that include hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD). FGFR3 is expressed in chondrocytes and mature osteoblasts where it functions to regulate bone growth. Analysis of the mutations in FGFR3 revealed increased signaling through a combination of mechanisms that include stabilization of the receptor, enhanced dimerization, and enhanced tyrosine kinase activity. Paradoxically, increased FGFR3 signaling profoundly suppresses proliferation and maturation of growth plate chondrocytes resulting in decreased growth plate size, reduced trabecular bone volume, and resulting decreased bone elongation. In this review, we discuss the molecular mechanisms that regulate growth plate chondrocytes, the pathogenesis of Ach, and therapeutic approaches that are being evaluated to improve endochondral bone growth in people with Ach and related conditions. Developmental Dynamics 246:291–309, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Guillon M.,University of Paris Descartes
Optics InfoBase Conference Papers | Year: 2016

Superresolution imaging of optical vortices in a high-NA speckle pattern. We imaged optical vortices thanks to STED microscopy. We identified their charges, we observed creation and annihilation of vortices of opposite charges and demonstrated the ability of vortices to confine fluorescence to sub-diffraction dimensions. © OSA 2016. © OSA 2016.

L'Honneur A.-S.,University of Paris Descartes | Rozenberg F.,University of Paris Descartes
Virologie | Year: 2016

JC virus (JCV) is an ubiquitous human polyomavirus which causes persistent infections. The biological cycle of JCV in its host is incompletely known. Most infected individuals remain asymptomatic lifelong despite occasional viral urinary shedding. In some cases of immune depression, JCV may reactivate, gain access to the central nervous system, infect and harm glial cells involved in myelin production, leading to a fatal demyelinating disease called progressive multifocal leukoencephalopathy (PML). PML cases have recently increased in patients receiving monoclonal antibody therapies - in particular multiple sclerosis patients treated with natalizumab - raising a new interest in the pathophysiology of JCV infection. The tropism of JCV for glial cells has been associated with various mutations and rearrangements in the non-coding control region (NCCR) of JCV genome, a regulator of viral expression. Several hypotheses have taken into account this hypervariability to explain the pathogenesis of JCV infection.

Levrero M.,French Institute of Health and Medical Research | Levrero M.,Italian Institute of Technology | Levrero M.,University of Rome La Sapienza | Zucman-Rossi J.,French Institute of Health and Medical Research | And 3 more authors.
Journal of Hepatology | Year: 2016

Hepatitis B virus (HBV) contributes to hepatocellular carcinoma (HCC) development through direct and indirect mechanisms. HBV DNA integration into the host genome occurs at early steps of clonal tumor expansion and induces both genomic instability and direct insertional mutagenesis of diverse cancer-related genes. Prolonged expression of the viral regulatory protein HBx and/or altered versions of the preS/S envelope proteins dysregulates cell transcription and proliferation control and sensitizes liver cells to carcinogenic factors. Accumulation of preS1 large envelope proteins and/or preS2/S mutant proteins activates the unfold proteins response, that can contribute to hepatocyte transformation. Epigenetic changes targeting the expression of tumor suppressor genes occur early in the development of HCC. A major role is played by the HBV protein, HBx, which is recruited on cellular chromatin and modulates chromatin dynamics at specific gene loci. Compared with tumors associated with other risk factors, HBV-related tumors have a higher rate of chromosomal alterations, p53 inactivation by mutations and overexpression of fetal liver/hepatic progenitor cells genes. The WNT/β-catenin pathway is also often activated but HBV-related tumors display a low rate of activating β-catenin mutations. HBV-related HCCs may arise on non-cirrhotic livers, further supporting the notion that HBV plays a direct role in liver transformation by triggering both common and etiology specific oncogenic pathways in addition to stimulating the host immune response and driving liver chronic necro-inflammation. © 2016 European Association for the Study of the Liver

Debru A.,University of Paris Descartes
History of Medicine | Year: 2015

Galen was a philosopher and physician who paid particular attention to the importance of anatomy. After all, anatomical demonstrations could be used to address such issues as the localization of the various parts of the soul, like the hegemonikon. These demonstrations, in turn, served as a means of refuting opposing theories like those of the stoics. What’s more, one can find a number of similarities between Galen’s philosophical approach and his anatomical practice, including his method and use of analysis, guided observation, differentiation of parts, etc. For instance, his theoretical preference for the concept of the tripartite soul, each part possessing specific properties and interaction dispositions, was reflected in his practical activities. Also, a comparison between two of his late treatises, De motibus obscuris and De moribus, reveals a continuity between his approach to anatomo-physiology and his moral philosophy. Moving beyond dichotomies between the rational and irrational parts of the soul or between voluntary and involuntary movement, both treatises reveal Galen’s new preference for thinking in terms of interactions in both anatomo-physiology and in moral philosophy in order to overcome some difficulties of interpretation related to strict dichotomies. He appears more and more interested in forging new tools to approach the complexity of biological and psychological actions and behaviors. © Armelle Debru.

Guettier C.,Safran | Lucas F.,University of Paris Descartes
Knowledge Engineering Review | Year: 2016

Unmanned Aerial Vehicles (UAV) represent a major advantage in defense, disaster relief and first responder applications. UAV may provide valuable information on the environment if their Command and Control (C2) is shared by different operators. In a C2 networking system, any operator may request and use the UAV to perform a remote sensing operation. These requests have to be scheduled in time and a consistent navigation plan must be defined for the UAV. Moreover, maximizing UAV utilization is a key challenge for user acceptance and operational efficiency. The global planning problem is constrained by the environment, targets to observe, user availability, mission duration and on-board resources. This problem follows previous research works on automatic mission Planning & Scheduling for defense applications. The paper presents a full constraint-based approach to simultaneously satisfy observation requests, and resolve navigation plans. © 2017 Cambridge University Press.

Matic I.,University of Paris Descartes | Matic I.,French National Center for Scientific Research
Periodicum Biologorum | Year: 2016

Organisms live in constantly changing environments in which the nature, severity and frequency of environmental stresses are highly variable. Organisms possess multiple strategies for coping with environmental fluctuations. One such strategy is the modulation of mutation rates as a function of the degree of adaptation to the environment. When adaptation is limited by the available genetic variability, natural selection favors cells that have higher mutation rates in the bacterial populations. High mutation rates can be advantageous because they increase the probability that beneficial mutations will be generated. Constitutive mutator alleles are carried to high frequency through hitchhiking with beneficial mutations they generate. However, once adaptation is achieved, deleterious mutations that are generated by constitutive mutator alleles reduce the cellular fitness. For this reason, the possibility of adapting the mutation rate to environmental conditions is interesting from an evolutionary point of view. Stress-induced mutagenesis enables rapid adaptation to complex environmental challenges without compromising bacterial fitness because it reduces the overall cost of a high mutation rate. Here, we review the molecular mechanisms involved in the control of modulation of mutation rates in bacteria. © 2016, Croatian Society of Natural Sciences. All rights reserved.

Lucon E.,University of Paris Descartes
Journal of Statistical Physics | Year: 2017

The aim of the paper is to establish a large deviation principle (LDP) for the empirical measure of mean-field interacting diffusions in a random environment. The point is to derive such a result once the environment has been frozen (quenched model). The main theorem states that a LDP holds for every sequence of environment satisfying appropriate convergence condition, with a rate function that does not depend on the disorder and is different from the rate function in the averaged model. Similar results concerning the empirical flow and local empirical measures are provided. © 2017 Springer Science+Business Media New York

Jin C.,Central China Normal University | Jin S.-W.,University of Paris Descartes
Proceedings of SPIE - The International Society for Optical Engineering | Year: 2017

Multi-label image annotation (MIA) has been widely studied during recent years and many MIA schemes have been proposed. However, the most existing schemes are not satisfactory. In this paper, an improved multiple kernel learning (IMKL) method of support vector machine (SVM) is proposed to improve the classification accuracy of SVM, then a novel MIA scheme based on IMKL is presented, which uses the discriminant loss to control the number of top semantic labels, and the feature selection approach is also used for improving the performance of MIA. The experiment results show that proposed MIA scheme achieves higher the performance than the existing other MIA schemes, its performance is satisfactory for large image dataset. © 2017 SPIE.

Salah A.,University of Paris Descartes | Nadif M.,University of Paris Descartes
Data Mining and Knowledge Discovery | Year: 2017

Collaborative filtering (CF) is a widely used technique to guide the users of web applications towards items that might interest them. CF approaches are severely challenged by the characteristics of user-item preference matrices, which are often high dimensional and extremely sparse. Recently, several works have shown that incorporating information from social networks—such as friendship and trust relationships—into traditional CF alleviates the sparsity related issues and yields a better recommendation quality, in most cases. More interestingly, even with comparable performances, social-based CF is more beneficial than traditional CF; the former makes it possible to provide recommendations for cold start users. In this paper, we propose a novel model that leverages information from social networks to improve recommendations. While existing social CF models are based on popular modelling assumptions such as Gaussian or Multinomial, our model builds on the von Mises–Fisher assumption which turns out to be more adequate, than the aforementioned assumptions, for high dimensional sparse data. Setting the estimate of the model parameters under the maximum likelihood approach, we derive a scalable learning algorithm for analyzing data with our model. Empirical results on several real-world datasets provide strong support for the advantages of the proposed model. © 2017 The Author(s)

Grementieri L.,University of Paris Descartes | Provenzi E.,University of Paris Descartes
Proceedings of SPIE - The International Society for Optical Engineering | Year: 2017

Many ancient paintings, in particular frescoes, have some parts ruined by time and events. Sometimes one or more non-negligible regions are completely lost, leaving a blank that is called by restaurateurs a â€lacuna'. The general restoration philosophy adopted in these cases is to paint the interior part of the lacuna with an achromatic or non-neutral uniform color carefully selected in order to minimize its overall perception. In this paper, we present a computational model, based on a well-established variational theory of color perception, that may facilitate the job of a restaurateur by providing both achromatic and non-neutral colors which minimize the local contrast with the surrounding parts of the fresco. © 2017 SPIE.

Goulet O.,University of Paris Descartes | Lambe C.,University of Paris Descartes
Current Opinion in Organ Transplantation | Year: 2017

The incidence of cholestatic liver disease (CLD) in pediatric patients suffering intestinal failure (IF) is not well established. Due to persistent portal inflammation, about 20% of these patients will progress to end-stage intestinal failure associated liver disease (IFALD) leading to liver transplant or death. Purpose of review Premature babies as well as infants with short bowel syndrome (SBS) and repeated sepsis (catheter or small intestinal bacterial overgrowth related) are at risk of developing CLD. Clinical data in SBS infants focused on intravenous lipid emulsion (ILE) as an important factor of CLD. Recent findings Compared to the last generation of composite ILE containing fish oil (FO), soybean oil (SO) based ILE, have marked differences in term of oil source, omega-3 fatty acids (FAs) composition, vitamin E (atocopherols) and plant sterols contents, that may explain CLD and CLD reversal. Randomized controlled trials and meta-analysis allow the following recommendations. Summary In pediatric patients with developing or established CLD or IFALD, potential causes should be explored and pure SO ILE should be avoided. A reduction of the ILE dosage and/or the use of the new composite FO based ILE, may be recommended along with the treatment and management of other risk factors. The 10% pure FO ILE should not be used as a sole provision of IV lipids in paediatric patients on total PN but can only serve as a short-term rescue treatment. © Copyright 2017 Wolters Kluwer Health, Inc. All rights reserved.

Jacob L.,University of Paris Descartes | Kostev K.,IMS Health
Clinical Microbiology and Infection | Year: 2017

Objectives: The goal of this study was to analyse patients' compliance with vaccination against tick-borne encephalitis (TBE) virus in Germany. Methods: The present study included 7266 patients from 638 general practices and 4194 patients from 114 paediatric practices. Patients were included if they had received the first dose of one of two vaccines against TBE virus (FSME-Immune® and Encepur®). The immunization schedule of these vaccines consisted of three injections. Patients were considered compliant if they received the second and third doses at the recommended time or within a period of ±25% around the recommended time (tolerance period). Results: Of the recruited patients, 28% received both the second and the third injections within the tolerance period. Individuals treated in paediatric practices had a higher likelihood of receiving vaccine doses within the tolerance period compared with individuals treated in general practices (OR 2.15; 95% CI 1.92-2.41). Moreover, patients <18 years old were more likely to be compliant than patients >65 years old (OR 1.22; 95% CI 1.02-1.46), whereas patients aged between 18 and 30 years were least likely to be compliant (OR 0·77; 95% CI 0.61-0.96). Conclusions: Compliance with vaccination against the TBE virus was low. This compliance was significantly associated with age and the type of practices in which patients were treated. © 2017 European Society of Clinical Microbiology and Infectious Diseases.

Duval R.,University of Paris Descartes | Duplais C.,French National Institute for Agricultural Research
Natural Product Reports | Year: 2017

Covering: 1985 up to the end of 2016 Fluorescence is a remarkable property of many natural products in addition to their medicinal and biological values. Herein, we provide a review on these peculiar secondary metabolites to stimulate prospecting of them as original fluorescent tracers, endowed with unique photophysical properties and with applications in most fields of biology. The compounds are spectrally categorized (i.e. fluorescing from violet to the near infra-red) and further structurally classified within each category. Natural products selected for their high impact in modern fluorescence-based biological studies are highlighted throughout the article. Finally, we discuss aspects of chemical ecology where fluorescent natural products might have key evolutionary roles and thus open new research directions in the field. © 2017 The Royal Society of Chemistry.

Hamdidouche I.,University of Paris Descartes
Journal of Hypertension | Year: 2017

Adherence to treatment is now well recognized as a crucial key in the effectiveness of antihypertensive drugs; however, it is often overlooked in the management of hypertension because methodology to assess it is partly unreliable and limits its use in clinical practice. The available evidence suggests that nonadherence is highly prevalent in a chronic asymptomatic condition such as hypertension. It may undermine benefits expected from antihypertensive agents and therefore, may negatively impact cardiovascular, cerebrovascular and renal outcomes. In this review, we discuss the methodological issues related to the measurement of drug adherence in a research setting and clinical practice, the prevalence and the impact of drug nonadherence on blood pressure control and thus in apparent resistant hypertension, and on cardiovascular, cerebrovascular and renal outcomes. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

BACKGROUND AND PURPOSE—: Primary angiitis of the central nervous system remains challenging. To report an overview and pictorial review of brain magnetic resonance imaging findings in adult primary angiitis of the central nervous system and to determine the distribution of parenchymal, meningeal, and vascular lesions in a large multicentric cohort. METHODS—: Adult patients from the French COVAC cohort (Cohort of Patients With Primary Vasculitis of the Central Nervous System), with biopsy or angiographically proven primary angiitis of the central nervous system and brain magnetic resonance imaging available at the time of diagnosis were included. A systematic imaging review was performed blinded to clinical data. RESULTS—: Sixty patients met inclusion criteria. Mean age was 45 years (±12.9). Patients initially presented focal deficit(s) (83%), headaches (53%), cognitive disorder (40%), and seizures (38.3%). The most common magnetic resonance imaging finding observed in 42% of patients was multiterritorial, bilateral, distal acute stroke lesions after small to medium artery distribution, with a predominant carotid circulation distribution. Hemorrhagic infarctions and parenchymal hemorrhages were also frequently found in the cohort (55%). Acute convexity subarachnoid hemorrhage was found in 26% of patients and 42% demonstrated pre-eminent leptomeningeal enhancement, which is found to be significantly more prevalent in biopsy-proven patients (60% versus 28%; P=0.04). Seven patients had tumor-like presentations. Seventy-seven percent of magnetic resonance angiographic studies were abnormal, revealing proximal/distal stenoses in 57% and 61% of patients, respectively. CONCLUSIONS—: Adult primary angiitis of the central nervous system is a heterogenous disease, with multiterritorial, distal, and bilateral acute stroke being the most common pattern of parenchymal lesions found on magnetic resonance imaging. Our findings suggest a higher than previously thought prevalence of hemorrhagic transformation and other hemorrhagic manifestations. © 2017 American Heart Association, Inc.

News Article | May 3, 2017

A new genetic fingerprinting technique is the first to show the huge diversity of the malaria parasite, one of nature’s most persistent and successful human pathogens. The technique validates a previously untestable “strain hypothesis” that was proposed more than 20 years ago and opens up new ways of thinking about how to tackle this cunning killer. Key to that understanding is changing the way we think about malaria—that it is not so much like the measles and more like the flu. As reported in the Proceedings of the National Academy of Sciences, researchers collected blood samples from 641 children, aged 1 to 12 years from Bakoumba, a village in Gabon, West Africa and the genetic fingerprints of parasites from 200 infected children. Remarkably, every child was infected with malaria parasites that had a different fingerprint from the parasites in every other child. In 1994, Professors Sunetra Gupta and Karen Day, both then working at Imperial College London and later the University of Oxford, proposed that the malaria transmission system may be organized into a set of strains based on diversity of the genes that code for the surface coat of the parasite. If true, this strain diversity could explain why people can be re-infected with malaria many times over. It has taken until now for Day and colleagues to develop and optimize the mathematical and laboratory techniques to finally address the hypothesis. The malaria parasite is a single-celled microorganism (known as a Plasmodium) that infects red blood cells and is transferred from human to human via mosquitoes. It has been infecting people for tens of thousands of years, and, according to the World Health Organization, in 2015, nearly half of the world’s population remained at risk of malaria. Over the past 20 years, Day’s team has developed a way to genetically fingerprint malaria parasites from small amounts of blood based on what are called var genes. Every parasite has approximately 60 of these var genes but only uses one at a time and can switch between the one it uses. The genes encode proteins that coat the surface of the red blood cells that the parasite infects. The var genes are significant because they determine the ability of the parasite to disguise itself from the human immune system, and contribute to the virulence of the disease. If the genes that encode the surface coat overlap between two parasites, such as you would expect in siblings that would share a maximum of 50 percent of their genes, then when someone is re-infected, the immune system will recognize these malaria parasites and quickly purge them if they have seen the parent infections. But if there is little or no overlap in these genes, then the immune system won’t recognize the malaria parasite as readily, leading to chronic infection. The study shows that “the parasite has evolved this enormous diversity with limited overlap between the sets of var genes likely so it can keep re-infecting the same humans,” says Day, now a professor of population science and dean of science at the University of Melbourne. Coauthor Mercedes Pascual, an ecologist and professor at the University of Chicago, describes this as “the parasites forming niches by diversifying. They compete with each other for hosts, and distance themselves from each other to invade the same population of humans, a limited resource.” Current malaria control programs don’t target the diversity of the parasite, Day says. “With malaria, we attack something that is conserved between all strains, but the problem is if you don’t get rid of all of the malaria parasites with current strategies, you have this enormous diversity that can allow the system to bounce back quickly to pre-control levels. The resilience of the system is coming from the diversity, so you’ve got to monitor how approaches to control attack diversity and not just the parasite per se.” Interestingly, the theory of malaria control is based on malaria having no diversity and being like measles. You contract measles once and have lifelong immunity, whereas you can get malaria or the flu many times because there are multiple strains circulating. “Malaria is like flu, but our fingerprinting results show that it is way more complicated,” Day says. By analyzing the var genes, researchers came up with a unique identifier, or fingerprint, for each malaria strain that they call a var code. “Looking down the microscope you would have said all of the infections look the same, but when we did the fingerprinting genetically with this variant antigen gene system, we could see that every child had a different parasite fingerprint, and importantly, each fingerprint was highly unrelated to all other fingerprints,” Day says. This unrelatedness was a surprise, Day says. “Malaria has sex as part of its lifecycle, every time it goes through a mosquito. And so, because the malaria parasite mates you would expect to find related parasites that we might call parents, siblings, cousins, and aunts and uncles in the population.” “Even with very high levels of sex between parasites, their competition for available hosts can be so intense, that really only very unrelated parasites would be fit enough to survive and here we have a structure where highly related parasites were not detected,” says Yael Artzy-Randrup, a theoretical ecologist from the University of Amsterdam, and a coauthor of the study. “Malaria is similar to flu in that humans can be infected multiple times by different malaria parasite variants. However, in contrast to the flu, the situation with malaria is much more complex. With malaria, at any given point of time there is a high diversity of variants coexisting even in very small human populations, while in flu, variants usually replace each other, and people will only be infected by one variant at a time.” After waiting 20 years to get their results, the researchers suffered a setback in 2012 when Hurricane Sandy cut the power to Day’s laboratory at New York University, destroying samples that represented months of work. The team was eventually able to recover and continue its work. Once the team had assembled all the data, they had to assure their scientific peers—many of whom were skeptical of the strain hypothesis—that the pattern of diversity and unrelatedness they were seeing was not just through random chance. Researchers tested the results using statistical and computational techniques inspired by the analysis of complex systems in ecology, such as communities of species in ecosystems. They found that the system was non-random, and the relatives were absent from the population. The project is connected to a central question in ecology: what is the structure of diversity? “We are asking this question for the ensemble of parasites within a population of Plasmodium falciparum, but it can also be asked for the ensemble of tree species in a rainforest,” Pascual says. “It is an exciting time for bringing together quantitative analyses and deep sampling of biological systems in the field. “Our findings indicate that the enormous diversity of the parasite is structured and that we need to consider the implications of this structure for intervention, and possibly develop a different way to model transmission in malaria altogether.” Additional researchers from the University of Melbourne, the University of Chicago, New York University, the University of Michigan, the University of Amsterdam, the University of Montpellier, and the University of Paris Descartes are coauthors of the study.

Delestree N.,University of Paris Descartes | Manuel M.,University of Paris Descartes | Iglesias C.,University of Paris Descartes | Zytnicki D.,University of Paris Descartes
Journal of Physiology | Year: 2014

In amyotrophic lateral sclerosis (ALS), an adult onset disease in which there is progressive degeneration of motoneurones, it has been suggested that an intrinsic hyperexcitability of motoneurones (i.e. an increase in their firing rates), contributes to excitotoxicity and to disease onset. Here we show that there is no such intrinsic hyperexcitability in spinal motoneurones. Our studies were carried out in an adult mouse model of ALS with a mutated form of superoxide dismutase 1 around the time of the first muscle fibre denervations. We showed that the recruitment current, the voltage threshold for spiking and the frequency-intensity gain in the primary range are all unchanged in most spinal motoneurones, despite an increased input conductance. On its own, increased input conductance would decrease excitability, but the homeostasis for excitability is maintained due to an upregulation of a depolarizing current that is activated just below the spiking threshold. However, this homeostasis failed in a substantial fraction of motoneurones, which became hypoexcitable and unable to produce sustained firing in response to ramps of current. We found similar results both in lumbar motoneurones recorded in anaesthetized mice, and in sacrocaudal motoneurones recorded in vitro, indicating that the lack of hyperexcitability is not caused by anaesthetics. Our results suggest that, if excitotoxicity is indeed a mechanism leading to degeneration in ALS, it is not caused by the intrinsic electrical properties of motoneurones but by extrinsic factors such as excessive synaptic excitation. © 2014 The Physiological Society.

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.

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.

Galluzzi L.,University of Paris Descartes | Galluzzi L.,Institute Gustave Roussy | Kepp O.,Institute Gustave Roussy | Kepp O.,French Institute of Health and Medical Research | And 4 more authors.
Nature Reviews Molecular Cell Biology | Year: 2012

Throughout more than 1.5 billion years of obligate endosymbiotic co-evolution, mitochondria have developed not only the capacity to control distinct molecular cascades leading to cell death but also the ability to sense (and react to) multiple situations of cellular stress, including viral infection. In addition, mitochondria can emit danger signals that alert the cell or the whole organism of perturbations in homeostasis, hence promoting the induction of cell-intrinsic or systemic adaptive responses, respectively. As such, mitochondria can be considered as master regulators of danger signalling. © 2012 Macmillan Publishers Limited. All rights reserved.

Ludvigsson J.,Linköping University | Krisky D.,Diamyd Medical | Casas R.,Linköping 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; number, NCT00723411.) Copyright © 2012 Massachusetts Medical Society.

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.

Donnet S.,University of Paris 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.

Dumont A.,University of Paris Descartes | Dumont A.,University of Montréal | Fournier P.,University of Montréal | Abrahamowicz M.,McGill University | And 2 more authors.
The Lancet | Year: 2013

Summary Background Maternal mortality is higher in west Africa than in most industrialised countries, so the development and validation of effective interventions is essential. We did a trial to assess the effect of a multifaceted intervention to promote maternity death reviews and onsite training in emergency obstetric care in referral hospitals with high maternal mortality rates in Senegal and Mali. Methods We did a pragmatic cluster-randomised controlled trial, with hospitals as the units of randomisation and patients as the unit of analysis. 46 public first-level and second-level referral hospitals with more than 800 deliveries a year were enrolled, stratified by country and hospital type, and randomly assigned to either the intervention group (n=23) or the control group with no external intervention (n=23). All women who delivered in each of the participating facilities during the baseline and post-intervention periods were included. The intervention, implemented over a period of 2 years at the hospital level, consisted of an initial interactive workshop and quarterly educational clinically-oriented and evidence-based outreach visits focused on maternal death reviews and best practices implementation. The primary outcome was reduction of risk of hospital-based mortality. Analysis was by intention-to-treat and relied on the generalised estimating equations extension of the logistic regression model to account for clustering of women within hospitals. This study is registered with, number ISRCTN46950658. Findings 191â€̂167 patients who delivered in the participating hospitals were analysed (95â€̂931 in the intervention groups and 95â€̂ 236 in the control groups). Overall, mortality reduction in intervention hospitals was significantly higher than in control hospitals (odds ratio [OR] 0·85, 95% CI 0·73-0·98, p=0·0299), but this effect was limited to capital and district hospitals, which mainly acted as first-level referral hospitals in this trial. There was no effect in second-level referral (regional) hospitals outside the capitals (OR 1·02, 95% CI 0·79-1·31, p=0·89). No hospitals were lost to follow-up. Concrete actions were implemented comprehensively to improve quality of care in intervention hospitals. Interpretation Regular visits by a trained external facilitator and onsite training can provide health-care professionals with the knowledge and confidence to make quality improvement suggestions during audit sessions. Maternal death reviews, combined with best practices implementation, are effective in reducing hospital-based mortality in first-level referral hospitals. Further studies are needed to determine whether the benefits of the intervention are generalisable to second-level referral hospitals. Funding Canadian Institutes of Health Research. © 2013 Elsevier Ltd.

Locker N.,University of Surrey | Chamond N.,University of Paris Descartes | Sargueil B.,University of Paris Descartes
Nucleic Acids Research | Year: 2011

Translation initiation on HIV genomic RNA relies on both cap and Internal Ribosome Entry Site (IRES) dependant mechanisms that are regulated throughout the cell cycle. During a unique phenomenon, the virus recruits initiation complexes through RNA structures located within Gag coding sequence, downstream of the initiation codon. We analyzed initiation complexes paused on the HIV-2 gag IRES and revealed that they contain all the canonical initiation factors except eIF4E and eIF1. We report that eIF3 and the small ribosomal subunit bind HIV RNA within gag open reading frame. We thus propose a novel two step model whereby the initial event is the formation of a ternary eIF3/40S/IRES complex. In a second step, dependent on most of the canonical initiation factors, the complex is rearranged to transfer the ribosome on the initiation codons. The absolute requirement of this large structure for HIV translation defines a new function for a coding region. Moreover, the level of information compaction within this viral genome reveals an additional level of evolutionary constraint on the coding sequence. The conservation of this IRES and its properties in rapidly evolving viruses suggest an important role in the virus life cycle and highlight an attractive new therapeutic target. © The Author(s) 2010. Published by Oxford University Press.

Lapillonne A.,University of Paris Descartes | Lapillonne A.,Baylor College of Medicine | Lapillonne A.,Necker Hospital | 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.

Nikolayev V.S.,CEA Grenoble | Nikolayev V.S.,University of Paris Descartes
Physics of Fluids | Year: 2010

The dynamics of the triple gas-liquid-solid contact line is analyzed for the case where the gas is the saturated vapor corresponding to the liquid. For partial wetting conditions, a nonstationary contact line problem where the contact line motion is caused by evaporation or condensation is treated. It is shown that the Navier slip condition alone is not sufficient to relax the hydrodynamic contact line singularity: the Marangoni term is equally important when the heat transfer is involved. The transient heat conduction inside the heater is accounted for. A multiscale problem of drop evaporation with freely moving contact line is solved in the lubrication approximation as an illustration of the proposed approach. © 2010 American Institute of Physics.

Zitvogel L.,French Institute of Health and Medical Research | Zitvogel L.,Institute Gustave Roussy | Zitvogel L.,University Paris - Sud | Galluzzi L.,University of Paris Descartes | And 5 more authors.
Immunity | Year: 2013

Conventional chemotherapeutics and targeted antineoplastic agents have been developed based on the simplistic notion that cancer constitutes a cell-autonomous genetic or epigenetic disease. However, it is becoming clear that many of the available anticancer drugs that have collectively saved millions of life-years mediate therapeutic effects by eliciting de novo or reactivating pre-existing tumor-specific immune responses. Here, we discuss the capacity of both conventional and targeted anticancer therapies to enhance the immunogenic properties of malignant cells and to stimulate immune effector cells, either directly or by subverting the immunosuppressive circuitries that preclude antitumor immune responses in cancer patients. Accumulating evidence indicates that the therapeutic efficacy of several antineoplastic agents relies on their capacity to influence the tumor-host interaction, tipping the balance toward the activation of an immune response specific for malignant cells. We surmise that the development of successful anticancer therapies will be improved and accelerated by the immunological characterization of candidate agents. © 2013 Elsevier Inc.

Boissonnas C.C.,University of Paris Descartes | Jouannet P.,University of Paris Descartes | Jammes H.,French National Institute for Agricultural Research
Fertility and Sterility | Year: 2013

Objective: To provide a link between epigenetics and male subfertility at the DNA, histone-protamine, and RNA levels and its consequences on fertilization and embryo development. Design: Review of the relevant literature. Setting: University-based clinical and research laboratories. Patient(s): Fertile and infertile men. Intervention(s): None. Main Outcome Measure(s): Critical review of the literature. Result(s): Epigenetic markers can be modified in infertile patients. Epigenetic modifications include methylation loss or gain on the global level and on imprinted genes, high levels of histone retention in spermatozoa, and deficiencies in some transcripts involved in spermatogenesis. Interestingly, these abnormalities are all linked together, because DNA methylation maintenance depends on DNA histone-protamine configuration which itself is stabilized by spermatozoal RNAs. Conclusion(s): The paternal genome has long been considered to be silent and passive in embryo formation. The epigenetic processes associated with the paternal DNA genome highlights its importance in male fertility as well as for embryo development. ©2013 by American Society for Reproductive Medicine.

Amalberti R.,HAS and La Prevention Medicale | Brami J.,University of Paris Descartes
BMJ Quality and Safety | Year: 2012

Background: The role of time management in safe and efficient medicine is important but poorly incorporated into the taxonomies of error in primary care. This paper addresses the lack of time management, presenting a framework integrating five time scales termed 'Tempos' requiring parallel processing by GPs: the disease's tempo (unexpected rapid evolutions, slow reaction to treatment); the office's tempo (day-to-day agenda and interruptions); the patient's tempo (time to express symptoms, compliance, emotion); the system's tempo (time for appointments, exams, and feedback); and the time to access to knowledge. The art of medicine is to control all of these tempos in parallel and simultaneously. Method: Two qualified physicians reviewed a sample of 1046 malpractice claims from one liability insurer to determine whether a medical injury had occurred and, if so, whether it was due to one or more tempo-related problems. 623 of these reports were analysed in greater detail to identify the prevalence and characteristics of claims and related time management errors. Results: The percentages of contributing factors were as follows: disease tempo, 37.9%; office tempo, 13.2%; patient tempo, 13.8%; out-of-office coordination tempo, 22.6%; and GP's access to knowledge tempo, 33.2%. Conclusion: Although not conceptualised in most error taxonomies, the disease and patient tempos are cornerstones in risk management in primary care. Traditional taxonomies describe events from an analytical perspective of care at the system level and offer opportunities to improve organisation, process, and evidence-based medicine. The suggested classification describes events in terms of (unsafe) dynamic control of parallel constraints from the carer's perspective, namely the GP, and offers improvement on how to self manage and coordinate different contradictory tempos and day-to-day activities. Further work is needed to test the validity and usefulness of this approach.

Kroemer G.,U848 | Kroemer G.,University of Paris Descartes | Kroemer G.,University Paris - Sud | Galluzzi L.,Institute Gustave Roussy | And 7 more authors.
Annual Review of Immunology | Year: 2013

Depending on the initiating stimulus, cancer cell death can be immunogenic or nonimmunogenic. Immunogenic cell death (ICD) involves changes in the composition of the cell surface as well as the release of soluble mediators, occurring in a defined temporal sequence. Such signals operate on a series of receptors expressed by dendritic cells to stimulate the presentation of tumor antigens to T cells. We postulate that ICD constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies. Hence, suboptimal regimens (failing to induce ICD), selective alterations in cancer cells (preventing the emission of immunogenic signals during ICD), or defects in immune effectors (abolishing the perception of ICD by the immune system) can all contribute to therapeutic failure. We surmise that ICD and its subversion by pathogens also play major roles in antiviral immune responses. © Copyright 2013 by Annual Reviews. All rights reserved.

Marino G.,French Institute of Health and Medical Research | Marino G.,Institute Gustave Roussy | Marino G.,University Paris - Sud | Madeo F.,University of Graz | And 3 more authors.
Current Opinion in Cell Biology | Year: 2011

Although autophagy has frequently been viewed as a cell death mechanism in the mammalian system, it is now considered as indispensable for the homeostasis of cells, tissues, and organisms. Basal or stress-induced autophagy plays essential and diverse roles in a variety of tissues, due to its cytoprotective properties. In this review, we briefly discuss the different homeostatic functions of autophagy that have been finely dissected in mammals through the generation and characterization of animal models with tissue-specific autophagic alterations. In addition, and given the importance of constitutive autophagy in neuronal tissues, we describe in more detail the specific roles of autophagy in the central nervous system (CNS). Finally, we discuss the contribution of autophagy malfunctions to the development of several common neurological disorders and the potential benefits of pharmacologically induced autophagy for the avoidance of neurodegeneration. © 2010 Elsevier Ltd.

Vitale I.,French Institute of Health and Medical Research | Vitale I.,University Paris - Sud | Galluzzi L.,French Institute of Health and Medical Research | Galluzzi L.,University Paris - Sud | And 5 more authors.
Nature Reviews Molecular Cell Biology | Year: 2011

The improper distribution of chromosomes during mitosis compromises cellular functions and can reduce cellular fitness or contribute to malignant transformation. As a countermeasure, higher eukaryotes have developed strategies for eliminating mitosis-incompetent cells, one of which is mitotic catastrophe. Mitotic catastrophe is driven by a complex and poorly understood signalling cascade but, from a functional perspective, it can be defined as an oncosuppressive mechanism that precedes (and is distinct from) apoptosis, necrosis or senescence. Accordingly, the disruption of mitotic catastrophe precipitates tumorigenesis and cancer progression, and its induction constitutes a therapeutic endpoint. © 2011 Macmillan Publishers Limited. All rights reserved.

Bouillaud F.,University of Paris Descartes | Blachier F.,French National Institute for Agricultural Research
Antioxidants and Redox Signaling | Year: 2011

Sulfide is a molecule with toxicity comparable to that of cyanide. It inhibits mitochondrial cytochrome oxidase at submicromolar concentrations. However, at even lower concentrations, sulfide is a substrate for the mitochondrial electron transport chain in mammals, and is comparable to succinate. This oxidation involves a sulfide quinone reductase. Sulfide is thus oxidized before reaching a toxic concentration, which explains why free sulfide concentrations are very low in mammals, even though sulfide is constantly released as a result of cellular metabolism. It has been suggested that sulfide has signaling properties in mammals like two other gases, NO and CO, which are also cytochrome oxidase inhibitors. The oxidation of sulfide by mitochondria creates further complexity in the description/use of sulfide signaling in mammals. In fact, in the many studies reported in the literature, the sulfide concentrations that have been used were well within the range that affects mitochondrial activity. This review focuses on the relevance of sulfide bioenergetics to sulfide biology and discusses the case of colonocytes, which are routinely exposed to higher sulfide concentrations. Finally, we offer perspectives for future studies on the relationship between the two opposing aspects of this Janus-type molecule, sulfide. © Copyright 2011, Mary Ann Liebert, Inc.

Cerf-Bensussan N.,University of Paris Descartes | Cerf-Bensussan N.,French National Institute for Agricultural Research | Gaboriau-Routhiau V.,University of Paris Descartes | Gaboriau-Routhiau V.,French National Institute for Agricultural Research
Nature Reviews Immunology | Year: 2010

The mammalian intestine is home to a complex community of trillions of bacteria that are engaged in a dynamic interaction with the host immune system. Determining the principles that govern host-microbiota relationships is the focus of intense research. Here, we describe how the intestinal microbiota is able to influence the balance between pro-inflammatory and regulatory responses and shape the host's immune system. We suggest that improving our understanding of the intestinal microbiota has therapeutic implications, not only for intestinal immunopathologies but also for systemic immune diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Bidard F.-C.,University of Paris Descartes | Pierga J.-Y.,University of Paris Descartes | Soria J.-C.,French Institute of Health and Medical Research | Thiery J.P.,IMCB A STAR | And 2 more authors.
Nature Reviews Clinical Oncology | Year: 2013

In the context of metastatic disease, preclinical models have been used primarily to decipher different steps of the metastatic cascade. Numerous molecular processes operate in these model systems, but none of these has been successfully translated to the clinic. We discuss some of the successes and failures of preclinical models in metastasis research and suggest some of the clues for more clinically relevant research. These potential avenues of research include: the use of adequate statistical methods and well-annotated cohorts in biomarker discovery; an objective assessment of the level of evidence provided by each biomarker; the development of robust molecular or cellular surrogates of metastasis in patients; and original designs for clinical trials. © 2013 Macmillan Publishers Limited. All rights reserved.

Viriot Durandal J.-P.,University of Franche Comte | Viriot Durandal J.-P.,University of Paris Descartes
Gerontologist | Year: 2013

Like in other advanced industrial countries, in France, demographic aging has become a widely debated research and policy topic. This article offers a brief overview of major aging-related trends in France. The article describes France's demographics of aging, explores key policy matters, maps the institutional field of French social gerontology research, and, finally, points to several emerging issues about aging. In France, these issues include active and healthy aging, the improvement of knowledge on specific vulnerable segments of the elderly population, and the adaptation of the urban landscape and infrastructure to an aging population. At the broadest level, one of the key points formulated in this article is that in France, aging research is dominated by the state, yet it is scattered and compartmentalized, posing a crucial challenge in an era dominated by European and other international networks and coordination efforts in aging policy and knowledge. © 2012 © The Author 2012. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.

Senovilla L.,French Institute of Health and Medical Research | Galluzzi L.,University of Paris Descartes | Kroemer G.,University of Paris Descartes
Current Opinion in Immunology | Year: 2014

Tumors are not immunologically silent but evolve and respond to therapy in the context of a continuous, bi-directional interaction with the host immune system. In line with this notion, several clinically successful chemotherapeutics have been shown to mediate antineoplastic effects as they (re)activate an anticancer immune response that is generally executed by lymphoid cells. Myeloid cells play a central role in this process, not only because they critically regulate the activity of T and B lymphocytes, but also because they exert direct tumoricidal effects, at least in some settings. Here, we discuss the impact of various myeloid cell populations, including macrophages, dendritic cells and myeloid-derived suppressor cells, on the efficacy of anticancer chemotherapy. © 2014 Elsevier Ltd.

Vandenabeele P.,Ghent University | Galluzzi L.,French Institute of Health and Medical Research | Galluzzi L.,University Paris - Sud | Vanden Berghe T.,Ghent University | And 3 more authors.
Nature Reviews Molecular Cell Biology | Year: 2010

For a long time, apoptosis was considered the sole form of programmed cell death during development, homeostasis and disease, whereas necrosis was regarded as an unregulated and uncontrollable process. Evidence now reveals that necrosis can also occur in a regulated manner. The initiation of programmed necrosis, 'necroptosis', by death receptors (such as tumour necrosis factor receptor 1) requires the kinase activity of receptor-interacting protein 1 (RIP1; also known as RIPK1) and RIP3 (also known as RIPK3), and its execution involves the active disintegration of mitochondrial, lysosomal and plasma membranes. Necroptosis participates in the pathogenesis of diseases, including ischaemic injury, neurodegeneration and viral infection, thereby representing an attractive target for the avoidance of unwarranted cell death. © 2010 Macmillan Publishers Limited. All rights reserved.

Kroemer G.,French Institute of Health and Medical Research | Kroemer G.,Institute Gustave Roussy | Kroemer G.,University of Paris Descartes | Marino G.,French Institute of Health and Medical Research | And 2 more authors.
Molecular Cell | Year: 2010

Autophagy is a tightly regulated pathway involving the lysosomal degradation of cytoplasmic organelles or cytosolic components. This pathway can be stimulated by multiple forms of cellular stress, including nutrient or growth factor deprivation, hypoxia, reactive oxygen species, DNA damage, protein aggregates, damaged organelles, or intracellular pathogens. Both specific, stimulus-dependent and more general, stimulus-independent signaling pathways are activated to coordinate different phases of autophagy. Autophagy can be integrated with other cellular stress responses through parallel stimulation of autophagy and other stress responses by specific stress stimuli, through dual regulation of autophagy and other stress responses by multifunctional stress signaling molecules, and/or through mutual control of autophagy and other stress responses. Thus, autophagy is a cell biological process that is a central component of the integrated stress response. © 2010 Elsevier Inc.

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.

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.

Chamond N.,University of Paris Descartes | Locker N.,University of Surrey | Sargueil B.,University of Paris Descartes
Biochemical Society Transactions | Year: 2010

Lentiviruses, the prototype of which is HIV-1, can initiate translation either by the classical cap-dependent mechanism or by internal recruitment of the ribosome through RNA domains called IRESs (internal ribosome entry sites). Depending on the virus considered, the mechanism of IRES-dependent translation differs widely. It can occur by direct binding of the 40S subunit to the mRNA, necessitating a subset or most of the canonical initiation factors and/or ITAF (IRES trans-acting factors). Nonetheless, a common feature of IRESs is that ribosomal recruitment relies, at least in part, on IRES structural determinants. Lentiviral genomic RNAs present an additional level of complexity, as, in addition to the 5′-UTR (untranslated region) IRES, the presence of a new type of IRES, embedded within Gag coding region was described recently. This IRES, conserved in all three lentiviruses examined, presents conserved structural motifs that are crucial for its activity, thus reinforcing the link between RNA structure and function. However, there are still important gaps in our understanding of the molecular mechanism underlying IRES-dependent translation initiation of HIV, including the determination of the initiation factors required, the dynamics of initiation complex assembly and the dynamics of the RNA structure during initiation complex formation. Finally, the ability of HIV genomic RNA to initiate translation through different pathways questions the possible mechanisms of regulation and their correlation to the viral paradigm, i.e. translation versus encapsidation of its genomic RNA. ©The Authors Journal compilation ©2010 Biochemical Society.

Hughes G.,University of Essex | Waszak F.,University of Paris Descartes | Waszak F.,CNRS Laboratory of Physiology of Perception
Neuropsychologia | Year: 2014

Our perception is fundamentally influenced by the way that we interact with the world. In particular, sensory events that are consistent with our planned actions are attenuated, both in terms of their phenomenology, and their neural response. Previous research in this domain has focused on simple-featured stimuli such as Gabor patches or sine wave tones, with attenuation normally occurring at early stages of sensory processing. In the current study we investigated this phenomenon using more ecologically valid stimuli that would likely involve higher-level visual predictions. More specifically, we trained participants to associate different actions with the presentation of a face or a house. By recording ERPs we could utilise the modularity of face processing to determine the locus of sensory attenuation for these high-level stimuli, as well as identify content-specific brain activity related to the prediction itself. In contrast to previous studies using low-level stimuli, we observed attenuation at later stages of visual processing, suggesting that higher-level predictions result in high-level prediction errors. We additionally observed significant differences over visual brain regions during action preparation dependent on whether participants were predicting to see a house or a face, perhaps reflecting preactivation of the predicted action effects. Furthermore, the degree to which participants showed evidence of preactivation, was correlated with the magnitude of their P2 attenuation. Taken together, these findings provide new insight into motor prediction and its influence on perception. © 2014 Elsevier Ltd.

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 cAMP-dependant proteine kinase (PRKAR1A) have been detected in approximately 60% of CNC patients, most leading to R1A haploinsufficiency. Other CNC-causing genes remain to be identified. Recent studies provided some genotype-phenotype correlations in CNC patients carrying PRKAR1A-inactivating mutations, which provide useful information for genetic counseling and/or prognosis; however, CNC remains a disease with significant clinical heterogeneity. Recent mouse and in vitro studies have shed light into how R1A haploinsufficiency causes tumors. PRKAR1A defects appear to be weak tumorigenic signals for most tissues; Wnt signaling activation and cell cycle dysregulation appear to be important mediators of the tumorigenic effect of a defective R1A. © 2010 Elsevier Ltd. All rights reserved.

Hermsdorfer J.,TU Munich | Hermsdorfer J.,Hospital Munich Bogenhausen | Li Y.,TU Munich | Randerath J.,University of Oregon | And 2 more authors.
Cortex | Year: 2013

Studying the characteristics of movements performed under different action conditions may foster the understanding of disturbed tool use in apraxia and may enhance the knowledge about the links between states of action representations.We registered hand and arm movements during a hammering action executed under three task conditions: pantomime, demonstration with the hammer only, and actual execution with hammer and nail. Various movement parameters were calculated to characterize the kinematic aspects of the hammering movements. An apraxia score that reflects conceptual errors was derived from video-evaluation of pantomiming. Twenty-three patients with left brain damage (LBD), 10 patients with right brain damage (RBD), and 19 control subjects were tested. Patients performed with the non-paretic ipsilesional hand.Four apraxic LBD patients failed to perform the task due to severe conceptual errors. The remaining LBD patients frequently produced movements that were slower, shorter, and less vertical than those of control subjects in all task conditions. Lesion analyses for the LBD patients suggested that inferior frontal areas were particularly responsible for impaired performance. RBD patients performed normally in most kinematic task aspects. Although the conditions differed characteristically in geometry and kinematics, correlations of performance measures indicated that individual patterns in patients as well as in control subjects were stable across the conditions.Performance stability across conditions and the overlapping neural network both support the concept of a general action prototype that is adapted flexibly to environmental constraints. Findings in patients show that LBD can affect the execution of an actual hammering action also in the absence of conceptual errors. It remains to be shown however whether conceptual errors and abnormalities of movement kinematics have a common cause or are two independent manifestations of damage to the motor-dominant brain. © 2011 Elsevier Ltd.

Parvaneh N.,Tehran University of Medical Sciences | Casanova J.-L.,Rockefeller University | Casanova J.-L.,University of Paris Descartes | Notarangelo L.D.,Harvard University | And 2 more authors.
Journal of Allergy and Clinical Immunology | Year: 2013

The characterization of primary immunodeficiencies (PIDs) in human subjects is crucial for a better understanding of the biology of the immune response. New achievements in this field have been possible in light of collaborative studies; attention paid to new phenotypes, infectious and otherwise; improved immunologic techniques; and use of exome sequencing technology. The International Union of Immunological Societies Expert Committee on PIDs recently reported on the updated classification of PIDs. However, new PIDs are being discovered at an ever-increasing rate. A series of 19 novel primary defects of immunity that have been discovered after release of the International Union of Immunological Societies report are discussed here. These new findings highlight the molecular pathways that are associated with clinical phenotypes and suggest potential therapies for affected patients. © 2013 American Academy of Allergy, Asthma & Immunology.

Ma Y.,French Institute of Health and Medical Research | Ma Y.,Institute Gustave Roussy | Ma Y.,University of Paris Descartes | Galluzzi L.,Institute Gustave Roussy | And 6 more authors.
Immunity | Year: 2013

Autophagy constitutes a mechanism for the sequestration and lysosomal degradation of various cytoplasmic structures, including damaged organelles and invading microorganisms. Autophagy not only represents an essential cell-intrinsic mechanism to protect against internal and external stress conditions but also shapes cellular immunity. Recent evidence indicates that autophagic responses in antigen-donor cells affect the release of several cytokines and "danger signals." Thus, especially when it precedes cell death, autophagy alerts innate immune effectors to elicit cognate immune responses. Autophagy is also important for the differentiation, survival, and activation of myeloid and lymphoid cells. Accordingly, inherited mutations in autophagy-relevant genes are associated with immune diseases, whereas oncogenesis-associated autophagic defects promote the escape of developing tumors from immunosurveillance. Here, we discuss the regulation of autophagy in the course of cellular immune responses and emphasize its impact on the immunogenicity of antigen-donor cells and on the activity of antigen-presenting cells and T lymphocytes. © 2013 Elsevier Inc.

Siddiqi I.,University of Paris Descartes | Vincent N.,University of Paris Descartes
Pattern Recognition | Year: 2010

We propose an effective method for automatic writer recognition from unconstrained handwritten text images. Our method relies on two different aspects of writing: the presence of redundant patterns in the writing and its visual attributes. Analyzing small writing fragments, we seek to extract the patterns that an individual employs frequently as he writes. We also exploit two important visual attributes of writing, orientation and curvature, by computing a set of features from writing samples at different levels of observation. Finally we combine the two facets of handwriting to characterize the writer of a handwritten sample. The proposed methodology evaluated on two different data sets exhibits promising results on writer identification and verification. © 2010 Elsevier Ltd. All rights reserved.

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.

De Montalembert M.,Hopital Necker Enfants Malades | De Montalembert M.,University of Paris Descartes
British Journal of Haematology | Year: 2014

Summary: Advances achieved over the last three decades have transformed sickle cell disease (SCD) from a fatal childhood disease to a long-term chronic condition. Consequently, patients must transition from paediatric to adult care. The transition is a high-risk period associated with increases in hospital admissions and death. The factors underlying this increased risk include not only characteristics of the disease itself, with the accumulation of disabilities and progression of organ damage, but also psychological factors and a frequent paucity of adult-care resources for SCD. Leaving the familiar paediatric team causes marked anxiety in many patients. The transition of care coincides with the many other transitions that characterize the emotional, social and academic development of adolescents. The shift from protection by parents and physicians to independent self-management may be difficult. Finally, young adults may have limited access to health insurance. In recent years, many medical groups have suggested the development of transitioning programmes combining transition schedules, printed and web-based materials, and, in some cases, transition-dedicated physicians, nurses and psychologists. Transition must begin early, involve both the paediatric and the adult team, direct appropriate attention to the parents and occur over a period of several years. Evaluations of these programmes are urgently needed. © 2013 John Wiley & Sons Ltd.

Dumas F.,University of Paris Descartes | Dumas F.,Cochin Hotel Dieu Broca Hospital | Cariou A.,University of Paris Descartes | Cariou A.,Cochin Hotel Dieu Broca Hospital | Rea T.D.,University of Washington
Journal of the American College of Cardiology | Year: 2012

Objectives: The aim of the study was to assess the influence of percutaneous coronary intervention (PCI) and therapeutic hypothermia (TH) on long-term prognosis. Background: Although hospital care consisting of TH and/or PCI in particular patients resuscitated following out-of-hospital cardiac arrest (OHCA) can improve survival to hospital discharge, there is little evidence regarding how these therapies may impact long-term prognosis. Methods: We performed a cohort investigation of all persons >18 years of age who suffered nontraumatic OHCA and were resuscitated and discharged alive from the hospital between January 1, 2001, and December 31, 2009, in a metropolitan emergency medical service (EMS) system. We reviewed EMS and hospital records, state death certificates, and the national death index to determine clinical characteristics and vital status. Survival analyses were conducted using Kaplan-Meier estimates and multivariable Cox regression. Analyses of TH were restricted to those patients who were comatose at hospital admission. Results: Of the 5,958 persons who received EMS-attempted resuscitation, 1,001 (16.8%) were discharged alive from the hospital. PCI was performed in 384 of 1,001 (38.4%), whereas TH was performed in 241 of 941 (25.6%) persons comatose at hospital admission. Five-year survival was 78.7% among those treated with PCI compared with 54.4% among those not receiving PCI and 77.5% among those treated with TH compared with 60.4% among those not receiving TH (both p < 0.001). After adjustment for confounders, PCI was associated with a lower risk of death (hazard ratio [HR]: 0.46 [95% confidence interval [CI]: 0.34 to 0.61]; p < 0.001). Likewise, TH was associated with a lower risk of death (HR: 0.70 [95% CI: 0.50 to 0.97]; p = 0.04). Conclusions: The findings suggested that effects of acute hospital interventions for post-resuscitation treatment extend beyond hospital survival and can positively influence prognosis following the arrest hospitalization. © 2012 American College of Cardiology Foundation.

Galluzzi L.,French Institute of Health and Medical Research | Galluzzi L.,University of Paris Descartes | Galluzzi L.,University Pierre and Marie Curie | Pietrocola F.,French Institute of Health and Medical Research | And 7 more authors.
Cell | Year: 2014

Macroautophagy (herein referred to as autophagy) is an evolutionarily conserved mechanism of adaptation to adverse microenvironmental conditions, including limited nutrient supplies. Several sensors interacting with the autophagic machinery have evolved to detect fluctuations in key metabolic parameters. The signal transduction cascades operating downstream of these sensors are highly interconnected to control a spatially and chronologically coordinated autophagic response that maintains the health and function of individual cells while preserving organismal homeostasis. Here, we discuss the physiological regulation of autophagy by metabolic circuitries, as well as alterations of such control in disease. © 2014 Elsevier Inc.

Agundez M.,University of Paris Descartes | Cernicharo J.,CSIC - National Institute of Aerospace Technology | Guelin M.,Institute Of Radioastronomie Millimetrique
Astrophysical Journal Letters | Year: 2010

Amechanism based on the penetration of interstellar ultraviolet photons into the inner layers of clumpy circumstellar envelopes (CSEs) around asymptotic giant branch stars is proposed to explain the non-equilibrium chemistry observed in such objects. We show through a simple modeling approach that in CSEs with a certain degree of clumpiness or with moderately low mass loss rates (a few 10-7M⊙ yr-1) a photochemistry can take place in the warm and dense inner layers, inducing important changes in the chemical composition. In carbon-rich objects water vapor and ammonia would be formed with abundances of 10-8-10-6 relative to H 2, while in oxygen-rich envelopes ammonia and carbon-bearing molecules such as HCN and CS would form with abundances of 10 -9-10-7 relative to H2. The proposed mechanism would explain the recent observation of warm water vapor in the carbon-rich envelope IRC+10216 with the Herschel Space Observatory and predict that H 2O should be detectable in other carbon-rich objects. © 2010 The American Astronomical Society. All rights reserved.

Marino G.,French Institute of Health and Medical Research | Marino G.,University of Paris Descartes | Niso-Santano M.,French Institute of Health and Medical Research | Niso-Santano M.,University of Paris Descartes | And 4 more authors.
Nature Reviews Molecular Cell Biology | Year: 2014

Autophagy and apoptosis control the turnover of organelles and proteins within cells, and of cells within organisms, respectively, and many stress pathways sequentially elicit autophagy, and apoptosis within the same cell. Generally autophagy blocks the induction of apoptosis, and apoptosis-associated caspase activation shuts off the autophagic process. However, in special cases, autophagy or autophagy-relevant proteins may help to induce apoptosis or necrosis, and autophagy has been shown to degrade the cytoplasm excessively, leading to 'autophagic cell death'. The dialogue between autophagy and cell death pathways influences the normal clearance of dying cells, as well as immune recognition of dead cell antigens. Therefore, the disruption of the relationship between autophagy and apoptosis has important pathophysiological consequences. © 2014 Macmillan Publishers Limited.

Berger R.M.F.,University of Groningen | Beghetti M.,University of Geneva | Humpl T.,University of Toronto | Raskob G.E.,The University of Oklahoma Health Sciences Center | And 5 more authors.
The Lancet | Year: 2012

Background: Paediatric pulmonary hypertension, is an important cause of morbidity and mortality, and is insufficiently characterised in children. The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry is a global, prospective study designed to provide information about demographics, treatment, and outcomes in paediatric pulmonary hypertension. Methods: Consecutive patients aged 18 years or younger at diagnosis with pulmonary hypertension and increased pulmonary vascular resistance were enrolled in TOPP at 31 centres in 19 countries from Jan 31, 2008, to Feb 15, 2010. Patient and disease characteristics, including age at diagnosis and at enrolment, sex, ethnicity, presenting symptoms, pulmonary hypertension classification, comorbid disorders, medical and family history, haemodynamic indices, and functional class were recorded. Follow-up was decided by the patients' physicians according to the individual's health-care needs. Findings: 362 of 456 consecutive patients had confirmed pulmonary hypertension (defined as mean pulmonary artery pressure ≥25 mm Hg, pulmonary capillary wedge pressure ≤12 mm Hg, and pulmonary vascular resistance index ≥3 WU/m -2). 317 (88) patients had pulmonary arterial hypertension (PAH), which was idiopathic [IPAH] or familial [FPAH] in 182 (57), and associated with other disorders in 135 (43), of which 115 (85) cases were associated with congenital heart disease. 42 patients (12) had pulmonary hypertension associated with respiratory disease or hypoxaemia, with bronchopulmonary dysplasia most frequent. Finally, only three patients had either chronic thromboembolic pulmonary hypertension or miscellaneous causes of pulmonary hypertension. Chromosomal anomalies, mainly trisomy 21, were reported in 47 (13) of patients with confirmed disease. Median age at diagnosis was 7 years (IQR 3-12); 59 (268 of 456) were female. Although dyspnoea and fatigue were the most frequent symptoms, syncope occurred in 31 (57 of 182) of patients with IPAH or FPAH and in 18 (eight of 45) of those with repaired congenital heart disease; no children with unrepaired congenital systemic-to-pulmonary shunts had syncope. Despite severe pulmonary hypertension, functional class was I or II in 230 of 362 (64) patients, which is consistent with preserved right-heart function. Interpretation: TOPP identifies important clinical features specific to the care of paediatric pulmonary hypertension, which draw attention to the need for paediatric data rather than extrapolation from adult studies. Funding: Actelion Pharmaceuticals. © 2012 Elsevier Ltd.

Galluzzi L.,University of Paris Descartes | Galluzzi L.,Gustave Roussy Comprehensive Cancer Center | Bravo-San Pedro J.M.,Gustave Roussy Comprehensive Cancer Center | Bravo-San Pedro J.M.,French Institute of Health and Medical Research | And 3 more authors.
Nature Cell Biology | Year: 2014

In a majority of pathophysiological settings, cell death is not accidental-it is controlled by a complex molecular apparatus. Such a system operates like a computer: it receives several inputs that inform on the current state of the cell and the extracellular microenvironment, integrates them and generates an output. Thus, depending on a network of signals generated at specific subcellular sites, cells can respond to stress by attemptinwg to recover homeostasis or by activating molecular cascades that lead to cell death by apoptosis or necrosis. Here, we discuss the mechanisms whereby cellular compartments-including the nucleus, mitochondria, plasma membrane, endoplasmic reticulum, Golgi apparatus, lysosomes, cytoskeleton and cytosol-sense homeostatic perturbations and translate them into a cell-death-initiating signal. © 2014 Macmillan Publishers Limited. All rights reserved.

Pranke I.M.,University of Paris Descartes | Sermet-Gaudelus I.,University of Paris Descartes
International Journal of Biochemistry and Cell Biology | Year: 2014

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride (Cl-) channel. Mutations of its gene lead to the disease of cystis fibrosis (CF) among which the most common is the deletion of phenylalanine at position 508 (Phe508del). CFTR is a multi-domain glycoprotein whose biosynthesis, maturation and functioning as an anion channel involve multi-level post-translational modifications of CFTR molecules and complex folding processes to reach its native, tertiary conformation. Only 20-40% of the nascent chains achieve folded conformation, while the remaining molecules are targeted for degradation by endoplasmic reticulum, lysosomes, or autophagy. A large number of mutations causing CF impair processing of CFTR. Growing knowledge of CFTR biosynthesis has enabled understanding the cellular basis of CF and has brought to light various potential targets for novel, promising therapies. This article is part of a Directed Issue entitled: Cystic fibrosis: From o-mics to cell biology, physiology, and therapeutic advances. © 2014 Elsevier Ltd.

Schnupf P.,French Institute of Health and Medical Research | Gaboriau-Routhiau V.,French Institute of Health and Medical Research | Gaboriau-Routhiau V.,French National Institute for Agricultural Research | Gaboriau-Routhiau V.,University of Paris Descartes | And 9 more authors.
Nature | Year: 2015

The gut microbiota plays a crucial role in the maturation of the intestinal mucosal immune system of its host1,2. Within the thousand bacterial species present in the intestine, the symbiont segmented filamentous bacterium (SFB) is unique in its ability to potently stimulate the post-natal maturation of the B- and T-cell compartments and induce a striking increase in the small-intestinal Th17 responses3-5. Unlike other commensals, SFB intimately attaches to absorptive epithelial cells in the ileum and cells overlying Peyer's patches6,7. This colonization does not result in pathology; rather, it protects the host from pathogens4. Yet, little is known about the SFB-host interaction that underlies the important immunostimulatory properties of SFB, because SFB have resisted in vitro culturing for more than 50 years. Here we grow mouse SFB outside their host in an SFB-host cell co-culturing system. Single-celled SFB isolated from monocolonized mice undergo filamentation, segmentation, and differentiation to release viable infectious particles, the intracellular offspring, which can colonize mice to induce signature immune responses. In vitro, intracellular offspring can attach to mouse and human host cells and recruit actin. In addition, SFB can potently stimulate the upregulation of host innate defence genes, inflammatory cytokines, and chemokines. In vitro culturing thereby mimics the in vivo niche, provides new insights into SFB growth requirements and their immunostimulatory potential, and makes possible the investigation of the complex developmental stages of SFB and the detailed dissection of the unique SFB-host interaction at the cellular and molecular levels. © 2015 Macmillan Publishers Limited. All rights reserved.

Husky M.M.,University of Paris Descartes | Guignard R.,National Institute for Health Promotion and Health Education INPES | Beck F.,National Institute for Health Promotion and Health Education INPES | Michel G.,University of Bordeaux Segalen
Journal of Affective Disorders | Year: 2013

Background Data from large nationally representative samples are needed to provide the empirical foundation to inform health policies for the prevention of suicide risk and risk behaviors in men and women. Methods Data were extracted from the 2010 Health Barometer, a large telephone survey on a representative sample of the general population aged 15-85 years living in France (n=27,653), carried out by the National Institute for Health Promotion and Health Education. Data were collected between October 2009 and July 2010. A computer-assisted telephone interview (CATI) system was used. Results Overall, 3.9% of respondents aged 15 to 85 reported past year suicidal ideation, and 0.5% reported a suicide attempt in that time period. Increased rates of risky sexual behavior are associated with ideation and attempt in both men and women, after controlling for sociodemographic variables. Homosexuality or bisexuality are associated with suicidal ideation for both men and women, but not with attempts. Substance misuse, physical and sexual assaults are strongly associated with suicidal symptoms for both men and women. Early first experiences with sex, tobacco, and alcohol are associated with suicidal symptoms though somewhat differentially for men and women. Limitations Cross-sectional survey. Conclusion The findings underscore associations between suicidal thoughts and behaviors and risk behaviors such as unprotected sex and substance use in men and women throughout the lifespan. These associations highlight the need for preventive strategies such as screening for risk behaviors in order to identify men and women particularly at risk for suicidal behavior. © 2013 Elsevier B.V.

University of Paris Descartes, Assistance Publique Hopitaux De Paris and French National Institute for Agricultural Research | Date: 2013-02-28

A combination product includes as active substances, at least an inhibitor of the HMG-CoA-reductase enzyme and citrulline, or a bioequivalent compound thereof, for treating excess weight or obesity and/or the accumulation of body fat. A cosmetic treatment method for improving or slimming the figure and/or for stimulating the loss of excess weight and/or of cellulite and/or for limiting the accumulation thereof, includes the administration of a combination product including as active substances, at least an inhibitor of the HMG-CoA-reductase enzyme or a physiologically acceptable salt thereof, and citrulline, or a bioequivalent compound thereof, or one of theirs analogues, and the renewal of the administration until the expected cosmetic effect is obtained. The combination product such as previously defined for improving or slimming the figure and/or for stimulating the loss of excess weight and/or of cellulite and/or for limiting the accumulation thereof is also described.

Agency: European Commission | Branch: H2020 | Program: RIA | Phase: SC1-PM-04-2016 | Award Amount: 9.99M | Year: 2017

Sudden cardiac arrest (SCA) causes ~20% of all deaths in Europe. SCA is lethal within minutes if left untreated and survival rates are presently only 5-20%. Therefore, there is a large medical need to improve SCA prevention and treatment. Designing effective individualized prevention and treatment strategies requires knowledge on genetic and environmental risk factors. So far, these efforts have been hampered by the lack of sufficiently large study cohorts of SCA patients with detailed information. Obtaining SCA patient samples is challenging as the condition happens suddenly and unexpectedly. In this project, leading European scientific teams which have created large relevant population cohorts, mostly dedicated to SCA research, join forces to fully exploit available data towards improving SCA management. This will be done by: - Building an unique and growing database of >100.000 (DNA) samples including >20.000 SCA patient samples, by combining existing European databases and infrastructures. - Identifying risk factors (inherited, acquired, environmental) and first-response treatment strategies that may explain the differences in SCA occurrence and survival between European countries - Collaborating with professional networks, such as the European Heart Rhythm Association, and European Resuscitation Council, to translate the outcomes into changes in clinical practice and influencing European health policies on SCA management.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.2.4.4-2 | Award Amount: 3.79M | Year: 2012

The current approach to diagnosis and management of the rare disease systemic sclerosis (SSc) is based on American College of Rheumatology criteria with low sensitivity and few validated recommendations for the therapy of the disease and its manifold organ manifestations. To overcome these shortcomings, the DeSScipher project will use the multinational, prospective and open EUSTAR (Scleroderma Trials and Research group of the European League Against Rheumatism) SSc cohort based on the established MEDSonline database which covers >30 data items and will evolve into a multimodular tool to answer step-by-step all immanent questions in a long-term setting according to the nature of the disease. The resulting progress will address functionally disabling manifestations affecting the hands (digital ulcers and arthritis), and compare the efficacy and safety of off-label drugs in the treatment of vital organ manifestations. Specifically, the DeSScipher project will evaluate (i) the utility of a combination of easy-to-perform clinical and laboratory investigations in combination with capillaroscopy for identifying SSc patients at risk for the development of digital ulcers at an early stage (ii) the prevention and treatment of digital ulcers and hand arthritis in order to improve long-term disability and quality of life, (iii) the efficacy of different immunosuppressive agents in attenuating or inhibiting pulmonary fibrosis, (iv) the optimal treatment options for reducing morbidity and mortality of pulmonary hypertension and severe heart disease in SSc. Based on the results of these observational trials, the DeSScipher project will develop evidence-based clinical guidelines for the future management of adult and juvenile SSc to be disseminated widely and rapidly to physicians and patients. Novel outcome measures will also be provided as a basis for future clinical trials.

Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2011.2.2.1-2 | Award Amount: 24.91M | Year: 2012

The goal of this proposal (INMiND) is to carry out collaborative research on molecular mechanisms that link neuroinflammation with neurodegeneration in order to identify novel biological targets for activated microglia, which may serve for both diagnostic and therapeutic purposes, and to translate this knowledge into the clinic. The general objectives of INMiND are: (i) to identify novel mechanisms of regulation and function of microglia under various conditions (inflammatory stimuli; neurodegenerative and -regenerative model systems); (ii) to identify and implement new targets for activated microglia, which may serve for diagnostic (imaging) and therapeutic purposes; (iii) to design new molecular probes (tracers) for these novel targets and to implement and validate them in in vivo model systems and patients; (iv) to image and quantify modulated microglia activity in patients undergoing immune therapy for cognitive impairment and relate findings to clinical outcome. Within INMiND we bring together a group of excellent scientists with a proven background in efficiently accomplishing common scientific goals (FP6 project DiMI,, who belong to highly complementary fields of research (from genome-oriented to imaging scientists and clinicians), and who are dedicated to formulate novel image-guided therapeutic strategies for neuroinflammation related neurodegenerative diseases. The strength of this proposal is that, across Europe, it will coordinate research and training activities related to neuroinflammation, neurodegeneration/-regeneration and imaging with special emphasis on translating basic mechanisms into clinical applications that will provide health benefits for our aging population. With its intellectual excellence and its crucial mass the INMiND consortium will play a major role in the European Research Area and will gain European leadership in the creation of new image-guided therapy paradigms in patients with neurodegenerative diseases.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.1-1 | Award Amount: 8.10M | Year: 2013

Colorectal cancer (CRC) is the 3rd most common cancer in Europe, and with approximately 200,000 deaths per year, it remains the 2nd most common cause of cancer death. More than half of all CRC patients develop distant metastases and have 5-year overall survival (OS) of less than 5% because of ineffective treatments. Increased understanding of cancer biology, coupled with the implementation of omics-based approaches, has revealed that cancer must be considered a heterogeneous disease. Historically, one-size-fits-all approaches have been standard practice in CRC treatment, but with the increased understanding of the molecular/genetic heterogeneity of CRC, it is clear that novel treatments must be developed and tested in selected subgroups to maximize the benefit of these new developments. MErCuRIC is a multicentre phase Ib/II clinical trial which will assess a novel therapeutic strategy (combined treatment of a MEK inhibitor PD-0325901 with a MET inhibitor PF-02341066) to combat metastasis, improve survival and change current clinical practice for CRC patients with KRAS mutant (MT) and KRAS wild type (WT) (with aberrant c-MET) tumours. The consortium will go beyond the current state-of-the-art by (i) employing a novel treatment strategy targeting the biology of the disease and by (ii) using next generation sequencing (NGS) and xenopatients to identify CRC patient subgroups who will maximally benefit from this novel treatment strategy.

Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-1.2-4 | Award Amount: 15.50M | Year: 2008

Cell therapy can be defined as the transplantation of living cells for the treatment of medical disorders. Three different principles underlie the increasing interest in cell therapy. 1. Transplanted cells used as an active drug 2. Transplanted cells used to replace damaged and degenerated tissue. 3. Cells used as a drug delivery vehicle. Promising results have been obtained in pre-clinical and clinical studies, however, success rates have been variable and clinical benefits have been limited. A major issue is the fact that the mechanisms by which cell therapy works in the different disease areas, are still poorly understood. The ability to non-invasively monitor the fate and modes of action of transplanted cells over time is mandatory. The development of relevant imaging tools will lead to a better understanding of how cell therapy works, the possibility of response monitoring in patients, and sufficient safety of the treatment.. ENCITE will provide tools to allow this by developing; New imaging methods to improve the spatio-temporal tracking of labelled cells Dual- and multimodality imaging procedures to cross-validate each individual approach New contrast agents and procedures that will improve the sensitivity and specificity of cellular labelling Combining of molecular biology for the generation of molecular and cellular imaging reporters with multimodal imaging techniques Novel cell and animal reporter systems detecting the location and function of individual cells and small cell subsets within the target organ Cellular labelling that does not interfere with cellular functions and therapeutic efficacy Methods for quantitative assessment to generate reliable biomarkers of the cell fate and therapeutic effects Cell homing for therapeutic delivery to target organs The tools and methodologies developed will be validated in 5 key disease areas; Neurological, Cardiovascular, Musculoskeletal, Diabetes and Cancer.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.3.1-2 | Award Amount: 7.84M | Year: 2013

Antimicrobial resistance is arguably the most significant challenge facing the EU health care system. The unnecessary use of antibiotics is a key driver in the development of antibiotic resistance. Cystic Fibrosis (CF) represents a unique disease model to study bacterial resistance and to explore therapeutic strategies for same, as chronic lung infection overlaps with acute lung exacerbations caused by a multitude of organisms that traditionally evolve various mechanisms of resistance. With time, chronic polymicrobial infection develops, with the most dominant infecting organism being Pseudomonas aeruginosa, which is also important in other infections including wounds, burns and patients with medical devices, making it an important clinical target for the EU. In CF infections, empiric intravenous antibiotics are usually given for two weeks. Recurrent infections and treatments result in increasing antimicrobial resistance, and alterations in pathogen host interactions in the lung and gut flora. Next-generation DNA sequencing technology now offers DNA-based personalised diagnostics and treatment strategies. Enhancing our knowledge of the microbiome allows the use of stratified targeted antibacterial therapy that can be compared with standard empirical antibacterial therapy currently used. We believe this will reduce antibiotic usage, optimize dosage and duration startegies as the therapy will be tailored to the actual individual patient needs. Cystic Fibrosis Microbiome-determined Antimicrobial Therapy Trial in Exacerbations: Results Stratified (CF MATTERS) will provide a randomized multi-centre controlled trial of microbiome-derived antimicrobial treatments versus current empirical therapy. Simultaneously parallel human host-pathogen interaction studies in sputa, human gut microflora analysis and evaluation of murine exacerbation models will be performed. This will improve prescription practice and decrease antimicrobial usage and resistance.

Agency: European Commission | Branch: FP7 | Program: CP | Phase: ENV.2013.6.4-1 | Award Amount: 14.89M | Year: 2013

Assessing individual exposure to environmental stressors and predicting health outcomes implies that both environmental exposures and epi/genetic variations are reliably measured simultaneously. HEALS (Health and Environment-wide Associations based on Large population Surveys) brings together in an innovative approach a comprehensive array of novel technologies, data analysis and modeling tools that support efficiently exposome studies. The general objective of HEALS is the refinement of an integrated methodology and the application of the corresponding analytical and computational tools for performing environment-wide association studies in support of EU-wide environment and health assessments. The exposome represents the totality of exposures from conception onwards, simultaneously identifying, characterizing and quantifying the exogenous and endogenous exposures and modifiable risk factors that predispose to and predict diseases throughout a persons life span. The HEALS approach brings together and organizes environmental, socio-economic, exposure, biomarker and health effect data; in addition, it includes all the procedures and computational sequences necessary for applying advanced bioinformatics coupling thus effective data mining, biological and exposure modeling so as to ensure that environmental exposure-health associations are studied comprehensively. The overall approach will be verified and refined in a series of population studies across Europe including twin cohorts, tackling different levels of environmental exposure, age windows of exposure, and socio-economic and genetic variability. The HEALS approach will be applied in a pilot environment and health examination survey of children including singletons and sets of twins with matched singletons (each twins pair having also a matched singleton) covering ten EU Member States (the EXHES Study). The lessons learned will be translated into scientific advice towards the development of protocols and guidelines for the setting up of a larger European environment and health examination survey.

Agency: European Commission | Branch: FP7 | Program: CP | Phase: ICT-2011.9.11 | Award Amount: 1.99M | Year: 2013

Humanoid robots will become important machines to support mankind if they develop similar capabilities as humans have. One of those capabilities is to orient in space and to extract the relevant information from its environment. A common approach has been to build a spatiotopic map of the external world, so called an internal world model. However, since the sensors, such as the eyes (cameras) are attached to the body an updating problem occurs: After any action the input changes and additional information about the position of the eyes or the posture or the position in the external world is required to map a new sensory input into an existing map of the world. As this position about sensors is not error free, internal world models are not always reliable.\nHowever, a large body of information suggests that humans do not maintain full maps of their external world. They are rather very sparse and evidence suggests that we extract the important information from the world just on time and only keep track of a few relevant aspects in a scene by means of attentive and memory processes. Humans rather know how to retrieve the necessary information rather than representing all information in an internal world model. Thus, we aim to explore how humans solve the necessary updating and by which mechanisms they keep track of important aspects and extract the relevant information from the environment. This will be done by a combination of experimental investigations and computational modelling and by the integration of the developed modules leading to a human-like neural model of spatial orientation and attention in the context of eye, head and body movements. The model will be demonstrated as neuroware for a virtual human acting in a virtual reality.

Agency: European Commission | Branch: FP7 | Program: CP-CSA | Phase: Fission-2013-3.1.1 | Award Amount: 10.26M | Year: 2013

Within the OPERRA project, it is proposed that the MELODI Association, as a well-advanced network, takes the lead in establishing the necessary structures able to manage the long-term European research programmes in radiation protection, also taking advantage of the valuable experience gathered through the DoReMi network of excellence. Whilst in fields adjacent to low-dose risk research (radioecology, nuclear emergency management) scientific issues would continue to be hosted by the sister associations, Alliance and NERIS, these associations are encouraged to join MELODI to establish an umbrella structure as equal partners. OPERRA will exploit the synergies of EURATOM and other EC programmes considering the most relevant joint program areas and mechanisms for funding joint activities. The project will also strengthen the links with national funding programs as well as the European education and training structures. Also, it will take steps towards a greater involvement of those new Member States who could benefit from increased participation in the radiation research programmes. Finally, OPERRA will take steps to further integrate the joint use of infrastructures in European countries, and to develop and facilitate an easier access to research infrastructures. The final objective of this project is to build up an umbrella coordination structure that has the capacity in a legal and logistical sense to administer future calls for research in radiation protection as a whole (including low-dose risk, radioecology, nuclear emergency management, and also research activities related to the medical uses of ionizing radiation) on behalf of the European Commission. OPERRA will prepare the organisation for a first competitive call by the end of 2013 for projects in low-dose risk research and a second competitive call in 2014 for broader projects in radiation protection research, subject to the approval of EC services, with the support of Go-between administrator operator and an external advisory entity.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.1.4-1 | Award Amount: 8.01M | Year: 2013

In renal allograft recipients, 10-year graft survival has not improved over the past decades. Histological examination of graft biopsies has long been the gold standard to confirm graft injuries, but biopsies are invasive and histological grading is not very robust. There is thus a need for robust, non-invasive methods to predict and diagnose acute and chronic graft lesions, to improve patient treatment, quality of life and long-term graft survival. Also, there is an unmet need for better understanding of the immune and non-immune mechanisms of interstitial fibrosis /tubular atrophy and graft loss. Combining all the skills required to build upon previous findings, BIOMARGIN will offer such opportunities in renal transplantation by integrating several omics approaches (mRNA, miRNA, peptides, proteins, lipids and metabolites) in blood, graft tissue and urine, in a well thought out, multistage discovery-to-validation translational programme, following the highest European ethics and regulatory requirements, as well as quality controls and quality assessments at all clinical and analytical steps. It is probably one of the first programmes to pursue such an integrated and systematic research approach. BIOMARGIN aims to: (i) discover, select and validate blood and/or urine biomarkers of renal allograft lesions in adult and pediatric kidney transplant recipients; (ii) provide renal transplant physicians with non-invasive, robust diagnostic tests and interpretation algorithms enabling closer, more accurate, more predictive and/or less invasive monitoring of transplanted patients; (iii) help to avoid or diminish the use of biopsies and improve patient treatment, quality of life and long-term graft survival; (iv) help understand the mechanisms involved in the allograft injury processes which, combined with mass spectrometry imaging should offer pathologists new molecular targets and tools for renal graft biopsy analysis.

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.

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.

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).

Law K.J.H.,University of Warwick | Kevrekidis P.G.,University of Massachusetts Amherst | Tuckerman L.S.,University of Paris Descartes
Physical Review Letters | Year: 2010

We report the numerical realization of robust two-component structures in 2D and 3D Bose-Einstein condensates with nontrivial topological charge in one component. We identify a stable symbiotic state in which a higher-dimensional bright soliton exists even in a homogeneous setting with defocusing interactions, due to the effective potential created by a stable vortex in the other component. The resulting vortex-bright-solitons, generalizations of the recently experimentally observed dark-bright solitons, are found to be very robust both in the homogeneous medium and in the presence of external confinement. © 2010 The American Physical Society.

Schulz C.,King's College London | Perdiguero E.G.,King's College London | Chorro L.,King's College London | Szabo-Rogers H.,King's 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.

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.

Anderson M.S.,University of California at San Francisco | Casanova J.-L.,Rockefeller University | Casanova J.-L.,Howard Hughes Medical Institute | Casanova J.-L.,French Institute of Health and Medical Research | And 2 more authors.
Immunity | Year: 2015

Autoimmunity is often familial, suggesting that inborn genetic variations might underlie its development. Curiously, autoimmunity has long been thought to be typically polygenic. Contrary to this prediction and consistent with growing discoveries of monogenic autoimmunity, Oftedal etal. discovered heterozygous dominant-negative AIRE mutations in patients with certain forms of autoimmunity. © 2015 Elsevier Inc.

Katlama C.,University Pierre and Marie Curie | Deeks S.G.,University of California at San Francisco | Autran B.,University Pierre and Marie Curie | Martinez-Picado J.,Autonomous University of Barcelona | And 8 more authors.
The Lancet | Year: 2013

Antiretroviral therapy for HIV infection needs lifelong access and strict adherence to regimens that are both expensive and associated with toxic effects. A curative intervention will be needed to fully stop the epidemic. The failure to eradicate HIV infection during long-term antiretroviral therapy shows the intrinsic stability of the viral genome in latently infected CD4T cells and other cells, and possibly a sustained low-level viral replication. Heterogeneity in latently infected cell populations and homoeostatic proliferation of infected cells might affect the dynamics of virus production and persistence. Despite potent antiretroviral therapy, chronic immune activation, inflammation, and immune dysfunction persist, and are likely to have important effects on the size and distribution of the viral reservoir. The inability of the immune system to recognise cells harbouring latent virus and to eliminate cells actively producing virus is the biggest challenge to finding a cure. We look at new approaches to unravelling the complex virus-host interactions that lead to persistent infection and latency, and discuss the rationale for combination of novel treatment strategies with available antiretroviral treatment options to cure HIV. Copyright © 2013 Elsevier B.V.

Azzi S.,University of Paris Descartes | Azzi S.,University Paris - Sud
Oncogene | Year: 2014

Kaposi sarcoma (KS) and primary effusion lymphoma (PEL) are two pathologies associated with KS herpes virus (KSHV/HHV-8) infection. KSHV genome contains several oncogenes, among which, the viral G-protein-coupled receptor (vGPCR open reading frame 74) has emerged as a major factor in KS pathogenicity. Indeed, vGPCR is a constitutively active receptor, whose expression is sufficient to drive cell transformation in vitro and tumour development in mice. However, neither the role of vGPCR in KSHV-infected B-lymphocytes nor the molecular basis for its constitutive activation is well understood. Here, we show that vGPCR expression contributes to nuclear factor-κB (NF-κB)-dependent cellular survival in both PEL cells and primary B cells from HIV-negative KS patients. We further identified within vGPCR an AP2 consensus binding motif, Y326GLF, that directs its localization between the plasma membrane and clathrin-coated vesicles. The introduction of a mutation in this site (Y326A) increased NF-κB activity and proinflammatory cytokines production. This correlated with exacerbated morphological rearrangement, migration and proliferation of non-infected monocytes. Collectively, our work raises the possibility that KSHV-infected B-lymphocytes use vGPCR to impact ultimately the immune response and communication within the tumour microenvironment in KSHV-associated pathologies.

Kroon F.,Leiden University | Landewe R.,Atrium Medical | Dougados M.,University of Paris Descartes | Dougados M.,Cochin Hospital | van der Heijde D.,Leiden University
Annals of the Rheumatic Diseases | Year: 2012

Objectives: The aim was to compare continuous and on-demand NSAID treatment with respect to their ability to suppress radiographic progression in subgroups of patients with high/elevated CRP-levels, ESR, ASDAS-levels or BASDAI-levels in comparison to patients with normal levels. Methods: Post-hoc analyses were performed in a randomized trial comparing continuous and on-demand NSAID treatment. Relevant high/elevated subgroups were created based on time-averaged (ta) CRP (>5mg/L), ta-ESR (>12mm/hr), ta-BASDAI (>4), ta-ASDAS-CRP (>2.1) and ta-ASDAS-ESR (>2.1). Subgroups were further split according to NSAID-use (continuous vs. on-demand). Radiological progression was presented in probability plots. Statistical interactions were tested using multiple and logistic regression analysis. Differences in radiological progression were analysed using the Chi-square and Mann-Whitney U test. Results: 150 participants randomized to either the continuous-treatment group (n=76), or the on-demand group (n=74) had complete radiographs and were included. The effect of slowing radiological progression with continuous NSAID therapy was more pronounced in patients with elevated ta-CRP-levels, elevated ta-ESR, high ta-ASDAS-CRP or high ta-ASDAS-ESR versus patients with low/normal values. No such effect was found for participants with high vs. low BASDAI. Also, in participants with elevated ta-ESR (irrespective of treatment), there appeared to be a higher rate of structural progression than in participants with normal ta-ESR. Regression analyses showed that continuous NSAID treatment neutralizes the negative effect of inflammation (high ta-ESR). Conclusions: Patients with elevated acute phase reactants seem to benefit most from continuous treatment with NSAIDs. Continuous NSAID-therapy in patients with elevated acute phase reactants may lead to an improved benefit-risk-ratio of these drugs. Copyright Article author (or their employer) 2012.

Tartour E.,Hopital Europeen Georges Pompidou | Tartour E.,University of Paris Descartes | Zitvogel L.,French Institute of Health and Medical Research | Zitvogel L.,University Paris - Sud
The Lancet Respiratory Medicine | Year: 2013

Lung cancer is the most common cause of cancer-related mortality worldwide and a therapeutic challenge. Recent success with antibodies blocking immune checkpoints in non-small-cell lung cancers (NSCLC) highlights the potential of immunotherapy for lung cancer treatment, and the need for trials of combination regimens of immunotherapy plus chemotherapy that lead to immunogenic cell death. Here, we review the development of immunogenic cytotoxic compounds, vaccines, and antibodies in NSCLC, in view of their integration into personalised oncology. © 2013 Elsevier Ltd.

Zhang Y.,University of Paris Descartes | Zhang Y.,Shanghai JiaoTong University | Agnoletti D.,University of Paris Descartes | Safar M.E.,University of Paris Descartes | Blacher J.,University of Paris Descartes
Hypertension | Year: 2011

To investigate the effect of different antihypertensive agents on blood pressure (BP) variability (BPV) and the underlying mechanism, we analyzed the ambulatory BP monitoring data of 577 patients before and after 3-month antihypertensive treatment, in the Natrilix SR Versus Candesartan and Amlodipine in the Reduction of Systolic Blood Pressure in Hypertensive Patients (X-CELLENT) Study, a multicenter, multinational, randomized, double-blind, placebo-controlled study with 4 parallel treatment arms (placebo, candesartan, indapamide sustained release, and amlodipine). Within-subject mean and SD of 24-hour BP, weighted by time interval between consecutive readings, were calculated in 3 time frames (daytime, nighttime, and 24 hours) to evaluate BP and BPV. The mean 24-hour heart rate (HR) and HR variability were calculated with the same algorithms. We found that the 3 antihypertensive drugs had a similar BP-lowering effect (P<0.001 for all), but amlodipine (P<0.007) and indapamide sustained release (P<0.04) were the only agents associated with a significantly decreased BPV after 3-month treatment. On the other hand, the major determinants of BPV at baseline were age, mean BP, and the corresponding HR variability. However, the reduction in BPV by amlodipine was significantly associated with the reduction in BP (P<0.006) and the reduction in HR variability (P<0.02), whereas the corresponding reduction by indapamide sustained release was only associated with the reduction in HR variability at night (P=0.004). In summary, 3-month amlodipine or indapamide sustained release treatment was associated with a significant reduction in BPV, and the mechanism of those reductions was possibly attributable to lowering BP or ameliorating the autonomic nervous system regulation or both. The combination of the 2 agents might help to optimize such properties. © 2011 American Heart Association, Inc.

De Wit M.P.T.,Medical Center | Smolen J.S.,Medical University of Vienna | Smolen J.S.,Hietzing Hospital | Gossec L.,University of Paris Descartes | Van Der Heijde D.M.F.M.,Leiden University
Annals of the Rheumatic Diseases | Year: 2011

To transcribe the treat-to-target (T2T) recommendations into a version that can be easily understood by patients. A core group of physicians and patients involved in the elaboration of the T2T recommendations produced a draft version of the T2T recommendations in lay language. This version was discussed, changed and reworded during a 1-day meeting with nine patients with rheumatoid arthritis (RA) from nine different European countries. Finally, the level of agreement with the translation and with the content of the recommendations was assessed by the patient participants. The project resulted in a patient version of the T2T recommendations. The level of agreement with the translation and the content was high. The group discussion revealed a number of potentialbarriers for the implementation of the recommendations in clinical practice, such as inequalities in arthritis healthcare provision across Europe. An accurate version of the T2T recommendations that can be easily understood by patients is available and can improve the shared decision process in the management of RA.

Lorin S.,University Paris - Sud | Hamai A.,University of Paris Descartes | Mehrpour M.,University of Paris Descartes | Codogno P.,University of Paris Descartes
Seminars in Cancer Biology | Year: 2013

The modulation of macroautophagy is now recognized as one of the hallmarks of cancer cells. There is accumulating evidence that autophagy plays a role in the various stages of tumorigenesis. Depending on the type of cancer and the context, macroautophagy can be tumor suppressor or it can help cancer cells to overcome metabolic stress and the cytotoxicity of chemotherapy. Recent studies have shed light on the role of macroautophagy in tumor-initiating cells, in tumor immune response cross-talk with the microenvironment. This review is intended to provide an up-date on these aspects, and to discuss them with regard to the role of the major signaling sub-networks involved in tumor progression (Beclin 1, MTOR, p53 and RAS) and in regulating autophagy. © 2013 Elsevier Ltd.

Molnar M.,Basque Center on Cognition | Gervain J.,University of Paris Descartes | Carreiras M.,Basque Center on Cognition | Carreiras M.,University of the Basque Country
Infancy | Year: 2014

Language rhythm determines young infants' language discrimination abilities. However, it is unclear whether young bilingual infants exposed to rhythmically similar languages develop sensitivities to cross-linguistic rhythm cues to discriminate their dual language input. To address this question, 3.5-month-old monolingual Basque, monolingual Spanish and bilingual Basque-Spanish infants' language discrimination abilities (across low-pass filtered speech samples of Basque and Spanish) have been tested using the visual habituation procedure. Although falling within the same rhythmic class, Basque and Spanish exhibit significant differences in their distributions of vocalic intervals (within-rhythmic class variation). All infant groups in our study successfully discriminated between the languages, although each group exhibited a different pattern. Monolingual Spanish infants succeeded only when they heard Basque during habituation, suggesting that they were influenced by native language recognition. The bilingual and the Basque monolingual infants showed no such asymmetries and succeeded irrespective of the language of habituation. Additionally, bilingual infants exhibited longer looking times in the test phase as compared with monolinguals, reflecting that bilingual infants attend to their native languages differently than monolinguals. Overall, results suggest that bilingual infants are sensitive to within-rhythm acoustic regularities of their native language(s) facilitating language discrimination and hence supporting early bilingual acquisition. © International Society on Infant Studies (ISIS).

Desbuquois B.,University of Paris Descartes | Carre N.,University of Paris Descartes | Carre N.,University Paris - Sud | Burnol A.-F.,University of Paris Descartes
FEBS Journal | Year: 2013

The effects of insulin and type 1 insulin-like growth factor (IGF-1) on metabolism, growth and survival are mediated by their association with specific receptor tyrosine kinases, which results in both receptor and substrate phosphorylation. Phosphotyrosine residues on receptors and substrates provide docking sites for signaling proteins containing SH2 (Src homology 2) domains, including molecular adaptors. This review focuses on the regulation of insulin/IGF-1 signaling and action by two adaptor families with a similar domain organization: the growth factor receptor-bound proteins Grb7/10/14 and the SH2B proteins. Both Grb10/14 and SH2B1/B2 associate with the activation loop of insulin/IGF-1 receptors through their SH2 domains, but association of Grb10/14 also involves their unique BPS domain. Consistent with Grb14 binding as a pseudosubstrate to the kinase active site, insulin/IGF-induced activation of receptors and downstream signaling pathways in cultured cells is inhibited by Grb10/14 adaptors, but is potentiated by SH2B1/B2 adaptors. Accordingly, Grb10 and Grb14 knockout mice show improved insulin/IGF sensitivity in vivo, and, for Grb10, overgrowth and increased skeketal muscle and pancreatic β-cell mass. Conversely, SH2B1-depleted mice display insulin and IGF-1 resistance, with peripheral depletion leading to reduced adiposity and neuronal depletion leading to obesity through associated leptin resistance. Grb10/14 and SH2B1 adaptors also modulate insulin/IGF-1 action by interacting with signaling components downstream of receptors and exert several tissue-specific effects. The identification of Grb10/14 and SH2B1 as physiological regulators of insulin signaling and action, together with observations that variants at their gene loci are associated with obesity and/or insulin resistance, highlight them as potential therapeutic targets for these conditions. Grb10/14 and SH2B1 are SH2 domain containing adapters which associate with insulin/IGF1 receptors and act as negative and positive regulators, respectively, of insulin/IGF1 signaling. Here, we review the molecular determinants of their interaction with receptors and the consequences of their overexpression and depletion in cells and mice, and discuss the potential role of altered adapter gene function in insulin resistance highlight them as potential therapeutic targets for these conditions.© 2012 The Authors Journal compilation.

Belec L.,University of Paris Descartes | Kourtis A.P.,Centers for Disease Control and Prevention
Advances in Experimental Medicine and Biology | Year: 2012

The UNAIDS estimated that more than 370,000 (230,000-510,000) children were infected by human immunodeficiency virus (HIV) type 1 through mother-to-child transmission (MTCT) worldwide in 2009, with the majority (>90%) occurring in sub-Saharan Africa (a drop of 24% from 5 years earlier) [1]. The majority of MTCT occurs during pregnancy and birth. In addition, postnatal transmission of HIV from HIV-infected mother to her child through prolonged breastfeeding is well recognized, and may account for one-third to half of new infant HIV infections worldwide [2-10]. While studies of maternal or infant antiretroviral prophylaxis during the period of breastfeeding have shown substantial potential for reduction of infant HIV infections [11-14], postnatal virus transmissions may continue to occur even in the setting of optimal antiretroviral prophylaxis. Therefore, development of immunologic strategies to reduce HIV transmission via breast milk remains important to improving survival of infants born to HIV-infected mothers in the developing world. © 2012 Springer Science+Business Media New York.

Pallud J.,Sainte Anne Hospital | Pallud J.,University of Paris Descartes | Capelle L.,Pitie Salpetriere University Hospital | Huberfeld G.,Pitie Salpetriere University Hospital | Huberfeld G.,French Institute of Health and Medical Research
Epilepsia | Year: 2013

Gliomas are the most frequent primary brain tumors and most glioma patients have seizures. The origin and mechanisms of human glioma-related epilepsy are multifactorial and an intermix of oncologic and neuronal processes. In this brief review, we show that the infiltrated peritumoral neocortex appears to be the key structure for glioma- related epileptic activity, which depends on the interactions between the tumor per se and the surrounding brain. We shed light on the underlying mechanisms from two different "tumorocentric" and "epileptocentric" approaches, with a special emphasis on the glioma-related glutamatergic and γ-aminobutyric acid (GABA)ergic changes leading to epileptogenicity. Because gliomas use the neurotransmitter glutamate as a "tumor growth factor" to enhance glioma cell proliferation and invasion with neurotoxic, proinvasive, and proliferative effects, glutamate homeostasis is impaired, with elevated extracellular glutamate concentrations. Such excitatory effects contribute to the generation of epileptic activity in the peritumoral neocortex. GABAergic signaling is also involved both in tumor growth and in paradoxical excitatory effects mediated by alterations in neuronal and tumor cell Cl- homeostasis related to cotransporter changes. Local excitability may also be affected by an increase in extracellular K+ concentration, the alkalization of peritumoral neocortex, and alterations of gapjunction functioning. Finally, the tumor itself may mechanically affect locally neuronal behavior, connections, and networks. Better understanding of glioma-related oncologic and epileptologic processes are crucial for development of combined therapeutic strategies, but so far, the surgical management of gliomas should comprise a maximally safe surgical resection encompassing peritumoral neocortex. © 2013 International League Against Epilepsy.

Storck S.,University of Paris Descartes | Aoufouchi S.,University Paris - Sud | Weill J.-C.,University of Paris Descartes | Reynaud C.-A.,University of Paris Descartes
Current Opinion in Immunology | Year: 2011

Post-rearrangement diversification of the antibody repertoire relies on a DNA editing factor, the cytidine deaminase AID. How B lymphocytes avoid generalized mutagenesis while expressing high levels of AID remained a long-standing question. Genome-wide studies of AID targeting combined to the discovery of several co-factors controlling its recruitment and its local activity shed new light on this enigma. © 2011 Elsevier Ltd.

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.

Girard P.,Institute Mutualiste Montsouris | Meyer G.,University of Paris Descartes | Parent F.,University Paris - Sud | Mismetti P.,Jean Monnet University
Thrombosis and Haemostasis | Year: 2014

Up to 15% of all patients with venous thromboembolism (VTE) receive an inferior vena cava filter, and prophylactic placements are increasing. To determine whether current use of filters is based on robust evidence, a global review of the recent (2001-2012) literature on filters was undertaken. The MEDLINE database was searched for articles related to filters appearing during the period 2001-2012, updating a prior search of literature from 1975-2001. All retrieved articles were analysed, classified into predetermined categories and compared to the prior analysis; randomised and large (>100 patients with a filter) comparative non-randomised clinical studies were read in full. The 651 articles, vs 568 in the period 1975-2000, consisted mainly of retrospective series (37.8%), case reports (31.7%), reviews (14.7%, vs 6.7%, p<0.001), animal and/or in vitro studies (7.5%, vs 12.9%, p=0.002), and prospective series or trials (4.9%, vs 7.4%, p=0.07). Of 4 new randomised trials (RCT), none were designed to test the efficacy of the device; to date, only one RCT has attempted to ascertain efficacy, occurring during the period 1975-2000. Eleven large non-randomised studies compared clinical outcomes of patients with and without filters, in VTE patients (n=5) or prophylactic indications (n=6); two studies found statistically significant relationships between filter use and lower mortality rates, though none could demonstrate a causal relationship. Hence, the plethoric literature on filters parallels growing experience with these devices, but still fails to provide reliable evidence that filter use improves relevant clinical outcomes. No indication for filter placement is based on appropriate scientific evidence. © Schattauer 2014.

Verga D.,University Paris - Sud | Hamon F.,University Paris - Sud | Poyer F.,University Paris - Sud | Bombard S.,University of Paris Descartes | Teulade-Fichou M.-P.,University Paris - Sud
Angewandte Chemie - International Edition | Year: 2014

We have developed a straightforward synthetic pathway to a set of six photoactivatable G-quadruplex ligands with a validated G4-binding motif (the bisquinolinium pyridodicarboxamide PDC-360A) tethered through various spacers to two different photo-cross-linking groups: benzophenone and an aryl azide. The high quadruplex-versus-duplex selectivity of the PDC core was retained in the new derivatives and resulted in selective alkylation of two well-known G-quadruplexes (human telomeric G4 and oncogene promoter c-myc G4) under conditions of harsh competition. The presence of two structurally different photoactivatable functions allowed the selective alkylation of G-quadruplex structures at specific nucleobases and irreversible G4 binding. The topology and sequence of the quadruplex matrix appear to influence strongly the alkylation profile, which differs for the telomeric and c-myc quadruplexes. The new compounds are photoactive in cells and thus provide new tools for studying G4 biology. Catch me if you can: A readily accessible set of photoactivatable G-quadruplex (G4) ligands with a bisquinolinium core showed high G4-versus-duplex selectivity. Alkylation under UV/Vis irradiation occurred at G4 nucleobases located in either the loops or the external G-quartets (see picture), depending on the cross-linker and the topology of the quadruplex. These probes might be used to irreversibly trap G4 structures for the study of G4 biology. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Kroemer G.,French Institute of Health and Medical Research | Kroemer G.,University of Paris Descartes | Perfettini J.-L.,Cell Death and Aging Team | Perfettini J.-L.,French Institute of Health and Medical Research | Perfettini J.-L.,University Paris - Sud
Cell Research | Year: 2014

Cell-in-cell structures, also referred to as 'entosis', are frequently found in human malignancies, although their prognostic impact remains to be defined. Two articles recently published in Cell Research report the stimulation of entosis by one prominent oncogene, Kras, as well as by one class of tumor suppressors, namely epithelial cadherins E and P, illustrating the complex regulation of this biological process. © 2014 IBCB, SIBS, CAS.

Casanova J.-L.,Rockefeller University | Casanova J.-L.,University of Paris Descartes | Holland S.,National Institute of Allergy and Infectious Diseases | Notarangelo L.,Harvard University
Immunity | Year: 2012

Inborn errors of the genes encoding two of the four human JAKs (JAK3 and TYK2) and three of the six human STATs (STAT1, STAT3, and STAT5B) have been described. We review the disorders arising from mutations in these five genes, highlighting the way in which the molecular and cellular pathogenesis of these conditions has been clarified by the discovery of inborn errors of cytokines, hormones, and their receptors, including those interacting with JAKs and STATs. The phenotypic similarities between mice and humans lacking individual JAK-STAT components suggest that the functions of JAKs and STATs are largely conserved in mammals. However, a wide array of phenotypic differences has emerged between mice and humans carrying biallelic null alleles of JAK3, TYK2, STAT1, or STAT5B. Moreover, the high degree of allelic heterogeneity at the human JAK3, TYK2, STAT1, and STAT3 loci has revealed highly diverse immunological and clinical phenotypes, which had not been anticipated. © 2012 Elsevier Inc..

Trono D.,Ecole Polytechnique Federale de Lausanne | Van Lint C.,Free University of Colombia | Rouzioux C.,University of Paris Descartes | Verdin E.,Gladstone | And 3 more authors.
Science | Year: 2010

HIV infection can persist in spite of efficacious antiretroviral therapies. Although incomplete inhibition of viral replication may contribute to this phenomenon, this is largely due to the early establishment of a stable reservoir of latently infected cells. Thus, life-long antiviral therapy may be needed to control HIV. Such therapy is prone to drug resistance and cumulative side effects and is an unbearable financial burden for regions of the world hit hardest by the epidemic. This review discusses our current understanding of HIV persistence and the limitations of potential approaches to eradicate the virus and accordingly pleads for a joint multidisciplinary effort toward two highly related goals: the development of an HIV prophylactic vaccine and the achievement of long-term drug-free remissions in HIV-infected individuals.

Carlin L.M.,King's College London | Stamatiades E.G.,King's College London | Auffray C.,University of Paris Descartes | Hanna R.N.,La Jolla Institute for Allergy and Immunology | And 7 more authors.
Cell | Year: 2013

The functions of Nr4a1-dependent Ly6Clow monocytes remain enigmatic. We show that they are enriched within capillaries and scavenge microparticles from their lumenal side in a steady state. In the kidney cortex, perturbation of homeostasis by a TLR7-dependent nucleic acid "danger" signal, which may signify viral infection or local cell death, triggers Gαi-dependent intravascular retention of Ly6Clow monocytes by the endothelium. Then, monocytes recruit neutrophils in a TLR7-dependent manner to mediate focal necrosis of endothelial cells, whereas the monocytes remove cellular debris. Prevention of Ly6Clow monocyte development, crawling, or retention in Nr4a1-/-, Itgal-/-, and Tlr7host-/-BM+/+ and Cx3cr1-/- mice, respectively, abolished neutrophil recruitment and endothelial killing. Prevention of neutrophil recruitment in Tlr7host+/+BM-/- mice or by neutrophil depletion also abolished endothelial cell necrosis. Therefore, Ly6C low monocytes are intravascular housekeepers that orchestrate the necrosis by neutrophils of endothelial cells that signal a local threat sensed via TLR7 followed by the in situ phagocytosis of cellular debris. © 2013 Elsevier Inc.

Seror R.,University Paris - Sud | Seror R.,University of Paris Descartes | Seror R.,Lille 2 University of Health and Law | Seror R.,Nimes University Hospital Center | Seror R.,Center Hospitalier Valenciennes
Annals of the rheumatic diseases | Year: 2014

OBJECTIVES: To evaluate the effect of adding a 10-week treatment of adalimumab to a standardised treatment with corticosteroids on the ability to taper more rapidly corticosteroid doses in patients with newly diagnosed giant cell arteritis (GCA).METHODS: Patients included in this double-blind, multicentre controlled trial were randomly assigned to receive a 10-week subcutaneous treatment of adalimumab 40 mg every other week or placebo in addition to a standard prednisone regimen (starting dose 0.7 mg/kg per day). The primary endpoint was the percentage of patients in remission on less than 0.1 mg/kg of prednisone at week 26. Analysis was performed by intention to treat (ITT).RESULTS: Among the 70 patients enrolled (adalimumab, n=34; placebo, n=36), 10 patients did not receive the scheduled treatment, seven in the adalimumab and three in the placebo group. By ITT, the number of patients achieving the primary endpoint was 20 (58.9%) and 18 (50.0%) in the adalimumab and placebo arm, respectively (p=0.46). The decrease in prednisone dose and the proportion of patients who were relapse free did not differ between the two groups. Serious adverse events occurred in five (14.7%) patients on adalimumab and 17 (47.2%) on placebo, including serious infections in three patients on adalimumab and five on placebo. Two patients died in the placebo arm (septic shock and cancer) and one in the adalimumab group (pneumonia).CONCLUSIONS: In patients with newly diagnosed GCA, adding a 10-week treatment of adalimumab to prednisone did not increase the number of patients in remission on less than 0.1 mg/kg of corticosteroids at 6 months.CLINICAL TRIAL REGISTRATION NUMBER: NCT00305539. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to

Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.3.2-6 | Award Amount: 10.15M | Year: 2008

The elicitation of broadly neutralising antibodies (Nab) remains the primary and most challenging goal in HIV-1 vaccine development. Although a few anti-HIV-1 monoclonal antibodies with broadly neutralising capability have been isolated from infected individuals, none of the immunization strategies thus far explored has proven effective in inducing similar antibodies. Objective of this application is the development of a variety of next-generation HIV-1 envelope-based immunogens that in combination with new adjuvant formulations are capable of eliciting high-titer broadly Nab responses. Our strategy will be based on one side on the identification and cloning of envelopes that have successfully elicited broad Nabs in their natural hosts, focusing on HIV-1 strains derived from patients with high-titered broad Nabs in their sera; on the other side, we will introduce rational modifications into these and promising HIV-env based immunogens that are already under development by NGINs partners, with the aim of exposing cryptic conserved neutralization epitopes and permitting their efficient presentation to the immune system. HIV-1 envelopes will be expressed in viral vectors or as trimeric (gp150) soluble proteins and screened for their immunogenicity and antigenicity in rabbits. A selection of envelopes with highest antigenicity will be expressed as trimeric envelope-complexes on the surface of virosomes or virus-like particles (VLP), to further improve immunogenicity. New immunogens will be evaluated in prime-boost regimens in rabbits using novel effective adjuvant formulations. Immunogen/adjuvant combinations that prove most effective in eliciting broadly Nabs both systemically and at the mucosal level will be evaluated in non-human primates for their immunogenicity and efficacy upon challenge with live heterologous virus. Finally, formulations that will elicit protective immunity in non-human primates will be forwarded for proof-of-principle testing in humans.

Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: NMP.2013.1.4-2 | Award Amount: 12.85M | Year: 2013

The thermal properties of nanostructured materials are of fundamental importance to modern technology, but at present reproducible metrological definitions, tools and methods do not exist. This is because the mechanisms of heat transport at the nanoscale are entirely different to those at the macro scale. The project will place nanothermal metrology on a solid basis by an integrated physics-based experimental and modelling effort to: Define a common terminology for nanothermal measurement Realise standard materials and devices for measurement and calibration of nanothermal measurements Develop new instruments and methods for traceable nanothermal measurement Develop calibrated and validated thermal models covering the range from atomic to macro-scale Apply these tools to selected representative industrial problems Assess the tools for suitability for adoption as potential standards of measurement including their traceability and reproducibility The objectives will be achieved by a team comprising physicists, materials scientists, modellers, instrumentalists, microscopists, industrial partners (including SMEs and OEMs) and National Measurement Institutes. The outputs of QUANTIHEAT will be embodied in highly characterised reference samples, calibration systems, measurement tools, numerical modelling tools, reference measurements and documented procedures. The availability of calibrated numerical modelling tools will facilitate the rapid digital thermal design of new nanosystems without the need for extensive prototyping. Their validation against experiment over all length scales will provide a solid basis for the deployment of new nanostructured materials, devices and structures having optimised performance without the need for excessively conservative design. Standardization is a key driver of industrial and scientific progress: QUANTIHEAT is expected to constitute a de-facto standard for a key area of physical measurement at the nanoscale worldwide.

French Institute of Health, Medical Research, University of Paris Descartes and University Paris - Sud | Date: 2012-10-29

The present invention relates to the treatment and the diagnosis of atherosclerosis, in particular to a miRNA for use in the treatment and the diagnosis of atherosclerosis.

University of Paris Descartes and University Paris - Sud | Date: 2015-04-14

The invention relates to an in vitro method for detecting systemic scleroderma (SSc) and/or pulmonary arterial hypertension (PAH), or a risk of developing SSc or PAH, which comprises determining the presence and/or the amount of antibodies in a biological sample originating from a patient.

French Institute of Health, Medical Research, Institute Gustave Roussy, Assistance Publique Hopitaux De Paris, Center Henri Becquerel, University of Paris Descartes, University Pierre, Marie Curie and University Paris - Sud | Date: 2016-06-08

The present invention concerns an in vitro method for diagnosing a myeloid tumour or a lymphoid tumour in a subject, which comprises the step of analyzing a biological sample from said subject by (i) detecting the presence of a mutation in the Ten Eleven Translocation protein family member 2 gene (TET2) coding for the polypeptide having the sequence SEQ ID NO: 2, and/or (ii) analyzing the expression of the TET2 gene; wherein the detection of such a TET2 mutation, of the absence of expression of TET2 or of the expression of a truncated TET2 is indicative of a subject developing or predisposed to develop a myeloid tumour or a lymphoid tumour.

University Paris - Sud, University of Paris Descartes and Assistance Publique Hopitaux De Paris | Date: 2010-01-15

The present invention relates to the use of a composition including of at least a mutated antithrombin

Agency: European Commission | Branch: FP7 | Program: MC-IRSES | Phase: FP7-PEOPLE-2010-IRSES | Award Amount: 434.70K | Year: 2011

The ChemBioFight project aims towards the exploration of natural resources to the discovery of bioactive therapeutic molecules against leishmania and Chagas disease. This will be accomplished through the establishment of an extended scientific network between European and South American research entities. Already assembled, highly diverse chemical libraries will be employed for the determination of active natural scaffolds leading to the focused collection of biomaterial (plants, marine organisms, fungi, endophytes) from local diversity hot-spots. Automated, high throughput and advanced techniques will be incorporated for the extraction process as well as the isolation and identification of natural products. Sophisticated approaches as metabolomics and chemical profiling will contribute to the discovery of novel active compounds and will be used to conduct dereplication procedures. Semi-synthetic derivatives of lead compounds will be also produced aiming to the optimization of favorable biological properties via medicinal chemistry aspects. In every step of the proposed work flow, the obtained samples (extracts, isolated compounds, synthetic derivatives) will be evaluated in vitro and/or in vivo for their antileishmanial and antitrypanosomal activity. Within the aforementioned context, an extensive net of secondements, both with educational and experimental attributes, will be established. Core scientific knowledge is expected to be produced and exchanged, with the prospect of creating partnerships with future scientific potential. All partners will participate in the dissemination procedure through teaching activities, workshops and international conferences, leading overall to mutual transfer of know-how. Finally, all procedures will be effectively monitored from a management team ensuring effectiveness and prompt objective achievement.

Agency: European Commission | Branch: FP7 | Program: MC-IAPP | Phase: FP7-PEOPLE-IAPP-2008 | Award Amount: 1.06M | Year: 2009

OLITEC is a collaborative research project between academic community (Universities of Athens-Greece and Paris Descartes-France) and industry (Hitex-France, Lavipharm-Greece and Frutarom-Switzerland) focusing in the advance of new technologies and the development of new products from the olive tree with therapeutic or preventive potential (phytomedicines, food supplement). The main scientific and technological objectives of this project are: a) to develop extraction methods based on the combination of emerging new technologies (Supercritical Fluid Extraction, Adsorption Resin Technology, Accelerated Solvent Extraction and Microwave Associated Extraction) for the preparation of enriched extracts from olive tree leaves, b) to study the chemical composition of the extracts and their variation, depending on the extraction processes, the botanical origin c) to identify bioactive small molecules from the highly complex extract matrix with modern techniques , d) To investigate the preparation of oleocanthal (and analogues) using chemical and/or biotechnological transformations, e) to evaluate the biological activity of the pure isolated compounds and of the extracts, in terms of anti-inflammatory and cancer chemopreventive activity, by direct effect or through anti-angiogenic or neo-vascular disrupting processes, f) to study the transdermal formulation of the bioactive compounds and extracts and to scale up the best process for the preparation of transdermal products, and g) to study the feasibility of the development of a new commercial product and design the next steps of OLITEC results exploitation.. The final outcome of OLITEC project will be The optimized production in pilot scale of extracts enriched in oleuropein (>50%), the optimized production of oleocanthal (or its analogues) the development of new transdermal pharmaceutical forms based on the active compounds and Documentation on the anticancer and anti-inflammatory activity of the products

Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-EJD | Phase: MSCA-ITN-2015-EJD | Award Amount: 3.86M | Year: 2016

Our aim is to create, in Europe, an innovative and ambitious multidisciplinary intersectoral joint doctoral training programme, dedicated to Methods in Research on Research (MIROR) in the field of clinical research. Research on Research, is an emerging new scientific discipline that aims to reduce waste in research and increase research value. Waste in research represents tens of billions of Euros spent each year on studies that are redundant, flawed in their design, never published or poorly reported. The public is the main victim of this waste and reducing waste and increasing value of research represents a major societal challenge. Our proposal involving 15 early-stage researchers, aims to 1) prepare students for envisioning the future challenges in clinical research and find innovative solutions to face them, 2) train students to go well beyond the state-of-the-art in their research, 3) help students think differently, taking advantage of the multidisciplinary expertise and intercultural diversity of the network, 4) teach students how to move from research to action and convert knowledge and idea into a product, and 5) help students develop skills to match the public and private sector needs and create new professional opportunities. MIROR will bring together 7 world-class research teams in various disciplines (computer sciences, applied mathematics, biostatistics, bioinformatics, clinical epidemiology, psychology, social sciences and translational medicine) from 6 different European countries; 6 non-academic partners involved in diverse sectors, and 4 major academic partners. We will tackle several steps of a clinical research project (planning, conduct, reporting and the peer-review); various study designs (observational studies, randomised trials, systematic reviews); various study questions (therapeutic, diagnostic, and prognostic evaluation) using various methods (meta-epidemiologic studies, qualitative studies, experimental studies, simulations etc).

Agency: European Commission | Branch: H2020 | Program: RIA | Phase: ICT-29-2016 | Award Amount: 4.70M | Year: 2016

Cardiovascular disease (CVD), more specifically, vulnerable plaque rupture, remains the major cause of death for people at middle age. The CVENT consortium will revolutionize screening, diagnosis and monitoring of CVD by means of a compact photoacoustic imaging (PAI) system for vulnerable plaque imaging. In the carotid arteries feeding the brain, vulnerable plaque rupture initiates cerebrovascular ischemic attacks. The state-of-the-art decision-making approach for a high-risk surgical intervention to avoid plaque rupture is based on stenosis severity alone, measured with ultrasound (US) imaging. However, this does not distinguish between vulnerable (rupture-prone) and stable (harmless) plaques, leading to severe overtreatment. Consequently, there is a worldwide unmet and urgent clinical need for functional information to enable in-depth diagnosis of carotid plaque vulnerability, avoiding cardiovascular events (CVENT) and reducing overtreatment risk. The objective of the CVENT consortium is the development of a portable multimodal and multiwavelength PAI system with a 3 cm imaging depth, for diagnosis and monitoring of carotid plaque vulnerability. The combination of high optical contrast of PAI and the high resolution of US will be used to identify plaque vulnerability markers, typically lipid pools and intra-plaque haemorrhage. Improved diagnosis of carotid plaque vulnerability will lead to a significant reduction in CVD-related disability and mortality. Simultaneously, by stratifying patients into high and low risk groups, overtreatment is reduced, leading to better allocation of healthcare funds. The CVENT consortium unites leading research groups, clinicians, industrial partners, and their expertise on R&D and a focus on exploitation, creating a breakthrough in carotid plaque vulnerability diagnosis. CVENT will bring together leading experts in the field of CVD, functional US imaging and PAI, introducing clinically applied PAI into the vascular medical arena.

University of Paris Descartes, French National Center for Scientific Research, French Institute of Health, Medical Research, Laboratoire Mabio International and University Paris - Sud | Date: 2015-12-16

The invention related to a device for cultivating cells comprising:- a lower part comprising at least two lower compartments, a lower wall separating the two lower compartments, and a semi-porous membrane covering the lower compartments, the semi-porous membrane comprising an upper surface intended to receive the cells;- a first upper part and a second upper part intended to be fitted onto the lower part, in order to obtain selectively:- a first configuration of the device wherein the first upper part is fitted onto the lower part, the first upper part forming an upper compartment wherein a culture medium can flow, in order to apply shear stress to the cells;- a second configuration of the device wherein the second upper part is fitted onto the lower part, the second upper part comprising at least two upper compartments, a wall separating the two upper compartments, and injection openings for injecting a substance to be tested in each upper compartment, the wall of the second upper part facing the wall of the lower element and being in contact with the semi-porous membrane so as to prevent a leakage of the injected substance from an upper compartment to another.

Agency: European Commission | Branch: FP7 | Program: CP | Phase: ICT-2007.5.3 | Award Amount: 9.27M | Year: 2008

ARTreat targets at providing a patient-specific computational model of the cardiovascular system, used to improve the quality of prediction for the atherosclerosis progression and propagation into life-threatening events that need to be treated accordingly. ARTreat will provide a three-level patient model describing the 3d arterial tree anatomy, the patient-specific blood flow and blood particle dynamics and the biological processes that lead to the creation and progression of atherosclerotic plaques. ARTreat will apply the developed patient-specific model on two main applications: the clinical decision support and the training. ARTreat will produce two decision support tools to assist clinical cardiologists into providing personalized treatment selection and real-time, on- the-fly advice during invasive interventions, such stent positioning. The aim is to minimize future therapy costs, by providing higher than even possible personalized treatment support. The same patient-specific model will also be used to develop a real-case simulator training, which will support realistic hands-on skill development training to clinical cardiologists. Finally, ARTreat is coupled with advanced clinical support tools for plaque characterization, and the discovery of new knowledge; associations among heterogeneous data, that can improve the predictive power of the patient-model. It thus supports the medical expert into programming the accumulated knowledge into the existing model and generating an adaptive patient-specific computational tool. Key market players AGFA and SORIN will exploit the ARTreat applications to provide new sophisticated solutions to their product range, while all academic and ITcompany partners will accumulate significant experience on the new generation patient-specific healthcare services.

Agency: European Commission | Branch: FP7 | Program: CSA-SA | Phase: HEALTH.2011.4.1-2 | Award Amount: 556.63K | Year: 2011

Full information about completed and ongoing clinical trials is the indispensable base for decision making about medical therapies and diagnostic procedures by patients and doctors. Equally, researchers and research organisations, ethics boards, governments and health system agencies, courts for social justice, pharmaceutical companies and all professional groups of the health care system are dependent on unbiased information. Research projects have consistently shown that for approximately 50% of all launched trials results or reasons for their failure are never published. Not only pharmaceutical industry, but also researchers and their organisations, ethics boards and scientific journals are actively contributing to the general failure to come close to a 100% publication rate. An obvious reason is the complexity of the system as well as the limitation of resources, giving ample space for all stakeholders to avoid appropriate changes and draw attention to deficiencies outside their responsibility. This project is based on the assumption that the existence of broad publication bias with seriously harmful impact has been accepted by all stakeholders and does not require further evidence. The current knowledge on publication bias and its impact will be summarized by systematic reviews of the relevant literature, with emphasis on the situation in the EU. OPEN focuses on the investigation of attitudes and handling of stakeholders involved in the whole knowledge translation process. Surveys, case studies and analyses of policies to reduce publication bias will be conducted to describe the current views and practice of stakeholders who are involved in knowledge translation. These results will be brought together to describe the status quo. Based on those insights recommendations will be derived to reduce publication bias and thus foster the provision of relevant results from clinical trials to citizens and organisations in the EU.

Agency: European Commission | Branch: H2020 | Program: RIA | Phase: FETOPEN-1-2014 | Award Amount: 3.48M | Year: 2016

This project aims to develop a new paradigm to build open-ended learning robots called `Goal-based Open-ended Autonomous Learning (GOAL). GOAL rests upon two key insights. First, to exhibit an autonomous open-ended learning process, robots should be able to self-generate goals, and hence tasks to practice. Second, new learning algorithms can leverage self-generated goals to dramatically accelerate skill learning. The new paradigm will allow robots to acquire a large repertoire of flexible skills in conditions unforeseeable at design time with little human intervention, and then to exploit these skills to efficiently solve new user-defined tasks with no/little additional learning. This innovation will be essential in the design of future service robots addressing pressing societal needs. The project will develop the GOAL paradigm by pursuing three main objectives: (1) advance our understanding of how goals are formed and underlie skill learning in children; (2) develop innovative computational architectures and algorithms supporting (2a) the self-generation of useful goals based on user/task independent mechanisms such as intrinsic motivations, and (2b) the use of such goals to efficiently and autonomously build large repertoires of skills; (3) demonstrate the potential of GOAL with a series of increasingly challenging demonstrators in which robots will autonomously develop complex skills and use them to solve difficult challenges in real-life scenarios. The interdisciplinary project consortium is formed by leading international roboticists, computational modelers, and developmental psychologists working with complementary approaches. This will allow the project to greatly advance our understanding of the fundamental principles of open-ended learning and to produce a breakthrough in the field of autonomous robotics by producing for the first time robots that can autonomously accumulate complex skills and knowledge in a truly open-ended way.

Nabbout R.,Necker Infants Maladies Hospital | Nabbout R.,French Institute of Health and Medical Research | Nabbout R.,University of Paris Descartes
Epilepsia | Year: 2013

Idiopathic hemiconvulsion hemiplegia and epilepsy syndrome (IHHE) and febrile infection- related epilepsy syndrome (FIRES) are rare epileptic syndromes characterized by the occurrence of status epilepticus in a previously healthy child during or closely after a febrile episode. In both syndromes, there is no evidence of central nervous system infection (encephalitis) and the etiology remains unclear. Treatment is disappointing, particularly in FIRES, except for a response to ketogenic diet (KD) in half of patients. In IHHS, children develop hemispheric brain atrophy with contralateral hemiplegia, epilepsy, and a variable degree of cognitive deficit. Patients with FIRES develop refractory epilepsy with severe cognitive deficit affecting the temporal and frontal lobe functions. The role of inflammation is hypothesized with a vicious circle involving inflammation and seizure activity facilitated by brain maturation putting them under the concept of acute encephalopathy with inflammation-mediated status epilepticus. © 2013 International League Against Epilepsy.

Chassoux F.,Sainte Anne Hospital | Chassoux F.,Center Hospitalier Sainte Anne | Daumas-Duport C.,Sainte Anne Hospital | Daumas-Duport C.,University of Paris Descartes
Epilepsia | Year: 2013

Dysembryoplastic neuroepithelial tumors (DNTs) belong to the surgically treatable long-term epilepsy-associated group of tumors. Based on cortical specimens provided through epilepsy surgery at Sainte-Anne hospital, three histologic subtypes (simple, complex, and nonspecific) have been described. Electroclinical data, imaging, intralesional recordings (stereo- electroencephalography [EEG]) and histologic correlations have been recently reviewed in order to assess the relationship between the epileptogenic zone (EZ), the tumor, and associated focal cortical dysplasia (FCD), and to determine optimal strategy for curing epilepsy. Based on a large series (78 patients, 50 male, aged 3-54 years, temporal location 73%, nonspecific forms 68%), we found similar electroclinical data in all DNT subtypes, and demonstrated that magnetic resonance imaging (MRI) features allow differentiation of histologic subtypes. Type 1 (cystic/polycystic-like) always corresponded to complex or simple forms, whereas type 2 (nodular-like) and type 3 (dysplastic-like) corresponded to nonspecific forms. It is notable that we demonstrated intrinsic epileptogenicity in all cases, but found that the EZ differed significantly according to MRI subtype, colocalizing with the tumor in type 1 MRI, including perilesional cortex in type 2 MRI, and involving extensive areas in type 3 MRI. The main prognostic factors for favorable outcome (83% of seizure-free patients) were complete tumor and EZ removal, short epilepsy duration, and lack of cortico-subcortical damage. According to these findings, surgical resection may be restricted to the tumor in type 1 MRI but should be more extensive in other MRI subtypes, especially in type 3 MRI. This MRI-based scheme may be helpful for optimal resection in epilepsy due to DNTs. In addition, we emphasize that early surgery is crucial in curing epilepsy. © 2013 International League Against Epilepsy.

Assistance Publique Hopitaux De Paris, French Institute of Health, Medical Research, Institute for Radiological Protection, Nuclear Safety and University of Paris Descartes | Date: 2014-07-09

The present invention relates to the use of gingival fibroblasts-derived products to reduce hair loss and promote hair growth. Specifically, the invention relates to a product derived from gingival fibroblasts to be used in the treatment or prevention of alopecia, as well as in the promotion of natural hair growth and/or in the control of natural hair loss.

Assistance Publique Hopitaux De Paris Aphp, University of Paris Descartes, University Pierre, Marie Curie, University Paris Diderot, University Paris - Sud and Institute Gustave Roussy | Date: 2014-10-03

The present invention provides novel methods for the modulation of autophagy and the treatment of autophagy-related diseases, including cancer, neurodegenerative diseases, liver diseases, muscle diseases and pancreatitis.

French Institute of Health, Medical Research, University of Paris Descartes and University Paris - Sud | Date: 2015-06-25

The present invention relates to the treatment and the diagnosis of atherosclerosis, in particular to a miRNA for use in the treatment and the diagnosis of atherosclerosis.

French Institute of Health, Medical Research, French National Center for Scientific Research, University of Paris Descartes, Fondation Image, University Paris - Sud, Assistance Publique Hopitaux De Paris Aphp and University Paris Diderot | Date: 2013-08-02

The present disclosure relates to antagonists of transferrin receptor and compositions and methods of use of said antagonists for treating pathological disorders such as thalassemia disorders

Tazarourte K.,Center Hospitalier Melun | Riou B.,University Pierre and Marie Curie | Tremey B.,Center Medico Chirurgical Ambroise Pare | Samama C.-M.,University of Paris Descartes | And 2 more authors.
Critical Care | Year: 2014

Introduction: In vitamin K antagonist (VKA)-treated patients with severe hemorrhage, guidelines recommend prompt VKA reversal with prothrombin complex concentrate (PCC) and vitamin K. The aim of this observational cohort study was to evaluate the impact of guideline concordant administration of PCC and vitamin K on seven-day mortality.Methods: Data from consecutive patients treated with PCC were prospectively collected in 44 emergency departments. Type of hemorrhage, coagulation parameters, type of treatment and seven-day mortality mortality were recorded. Guideline-concordant administration of PCC and vitamin K (GC-PCC-K) were defined by at least 20 IU/kg factor IX equivalent PCC and at least 5 mg of vitamin K performed within a predefined time frame of eight hours after admission. Multivariate analysis was used to assess the effect of appropriate reversal on seven-day mortality in all patients and in those with intracranial hemorrhage (ICH).Results: Data from 822 VKA-treated patients with severe hemorrhage were collected over 14 months. Bleeding was gastrointestinal (32%), intracranial (32%), muscular (13%), and " other" (23%). In the whole cohort, seven-day mortality was 13% and 33% in patients with ICH. GC-PCC-K was performed in 38% of all patients and 44% of ICH patients. Multivariate analysis showed a two-fold decrease in seven-day mortality in patients with GC-PCC-K (odds ratio (OR) = 2.15 (1.20 to 3.88); P = 0.011); this mortality reduction was also observed when only ICH was considered (OR = 3.23 (1.53 to 6.79); P = 0.002).Conclusions: Guideline-concordant VKA reversal with PCC and vitamin K within eight hours after admission was associated with a significant decrease in seven-day mortality. © 2014 Tazarourte et al.; licensee BioMed Central Ltd.

Keniry A.,Babraham Institute | Oxley D.,Babraham Institute | Monnier P.,University of Paris Descartes | Kyba M.,University of Minnesota | And 4 more authors.
Nature Cell Biology | Year: 2012

The H19 large intergenic non-coding RNA (lincRNA) is one of the most highly abundant and conserved transcripts in mammalian development, being expressed in both embryonic and extra-embryonic cell lineages, yet its physiological function is unknown. Here we show that miR-675, a microRNA (miRNA) embedded in H19's first exon, is expressed exclusively in the placenta from the gestational time point when placental growth normally ceases, and placentas that lack H19 continue to grow. Overexpression of miR-675 in a range of embryonic and extra-embryonic cell lines results in their reduced proliferation; targets of the miRNA are upregulated in the H19 null placenta, including the growth-promoting insulin-like growth factor 1 receptor (Igf1r) gene. Moreover, the excision of miR-675 from H19 is dynamically regulated by the stress-response RNA-binding protein HuR. These results suggest that H19's main physiological role is in limiting growth of the placenta before birth, by regulated processing of miR-675. The controlled release of miR-675 from H19 may also allow rapid inhibition of cell proliferation in response to cellular stress or oncogenic signals. © 2012 Macmillan Publishers Limited. All rights reserved.

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.

Ong A.C.M.,University of Sheffield | Ong A.C.M.,Sheffield Teaching Hospitals NHS Foundation Trust | Devuyst O.,University of Zürich | 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.

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, 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.

Lecuit M.,Institute Pasteur Paris | Lecuit M.,French Institute of Health and Medical Research | Lecuit M.,University of Paris Descartes | Lecuit M.,Necker Enfants Malades University Hospital | And 2 more authors.
Trends in Microbiology | Year: 2013

The human virome is the viral component of the microbiome. Its composition, and interindividual and temporal variability are not precisely known. Its impact on human health has received less attention than that of the bacterial microbiome, but is likely to be equally important, both in homeostasis and disease. Here we review the recent advances in this field and the questions that arise in the context of our rapidly increasing knowledge regarding the composition and function of the human virome. With the ever-extending use of next-generation sequencing (NGS) on a variety of clinical samples, rapid progress on the composition of the human virome and its impact upon human health are to be expected in the coming years. © 2013.

Gazzard B.,Chelsea and Westminster Hospital | Duvivier C.,University of Paris Descartes | Zagler C.,Hohe Otto Wagner Hospital | Castagna A.,Fondazione San Raffaele | Hill A.,University of Liverpool
AIDS | Year: 2011

Background: The Study of Etravirine Neuropsychiatric Symptoms versus Efavirenz (SENSE) trial compared etravirine with efavirenz in treatment-naive patients. The primary endpoint was neuropsychiatric adverse events up to week 12; HIV RNA suppression at week 48 was a secondary endpoint. Methods: Patients with HIV RNA more than 5000copies/ml were randomized to etravirine 400mg once daily (n=79) or efavirenz (n=78), plus two nucleoside analogues. HIV RNA less than 50copies/ml at week 48 was analysed using the time to loss of virological response (TLOVR) algorithm. Drug resistance at treatment failure and safety endpoints were also evaluated. Results: At baseline, the median CD4 + cell count was 302cells/μl and HIV RNA was 4.8log10copies/ml. In the intent to treat TLOVR analysis at week 48, 60 of 79 (76%) patients on etravirine versus 58 of 78 (74%) on efavirenz had HIV RNA less than 50copies/ml. In the on-treatment analysis, 60 of 65 (92%) taking etravirine had HIV RNA les than 50copies/ml versus 58 of 65 (89%) for efavirenz: etravirine showed noninferior efficacy versus efavirenz in both analyses (P<0.05). Four patients had virological failure in the etravirine arm: none developed resistance to nucleoside analogues or nonnucleosides. Seven patients had virological failure in the efavirenz arm: three developed treatment-emergent resistance to nucleoside analogues and/or nonnucleosides. At the week 48 visit, the percentage with ongoing neuropsychiatric adverse events was 6.3% for etravirine and 21.5% for efavirenz (P=0.011). Conclusion: First-line treatment with etravirine 400mg once daily and two nucleoside reverse transcriptase inhibitors (NRTIs) led to similar rates of HIV RNA suppression, compared with efavirenz and two NRTIs. None of the patients with virological failure in the etravirine arm developed resistance to nonnucleosides. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Hezode C.,University Paris Est Creteil | Asselah T.,University Paris Diderot | Reddy K.R.,University of Pennsylvania | Hassanein T.,Southern California Liver Centers and Southern California Research Center | And 10 more authors.
The Lancet | Year: 2015

Summary Background Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. Methods In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18-70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10 000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12). Analysis was by intention to treat. This study is registered with, number NCT01685203. Findings Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91·6-100]) in the ribavirin-containing regimen and 90·9% (40/44 [95% CI 78·3-97·5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference -9·16% [95% CI -19·61 to 1·29]; p=0·086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92·7-100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia. Interpretation An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection. Funding AbbVie. © 2015 Elsevier Ltd.

Ramos O.,CNRS Physics Laboratory | Ramos O.,University of Paris Descartes
Tectonophysics | Year: 2010

Through the analysis of the correlation functions in simulations of an earthquake model, the critical properties of the system are studied. Simulations are performed in a more realistic modification of the Olami-Feder-Christensen model of earthquakes and result in uncorrelated avalanches distributed following a power-law with weak signs of foreshocks and aftershocks. The spatial autocorrelation function of the system and other structural variables are computed in every step of the simulation. The spatial autocorrelation between points separated from each other by a constant distance equal to 1/4 and 1/8 of the linear size of the system shows large variations, temporally correlated with the time series of avalanche size; i.e., spatial correlation values are in average very high before a large earthquake, very small after a large earthquake and they evolve between these two states. However, the temporal average of the spatial autocorrelation over the whole simulation shows values close to zero, result that is in contradiction with the idea that the correlation length is of the same order as the linear size of the system (diverging in an infinite system), which is the main signature of a critical scenario. By averaging the autocorrelation in smaller time windows, the critical properties of temporal states can be used as an indication of upcoming catastrophic events. The structural variables are also correlated with the occurrence of large avalanches, suggesting the possibility of monitoring these variables in order to achieve prediction. © 2009 Elsevier B.V.

Biffi A.,San Raffaele Scientific Institute | Aubourg P.,University of Paris Descartes | Cartier N.,University of Paris Descartes
Human Molecular Genetics | Year: 2011

Leukodystrophies (LDs) refer to a group on inherited diseases in which molecular abnormalities of glial cells are responsible for exclusive or predominant defects in myelin formation and/or maintenance within the central and, sometimes, the peripheral nervous system. For three of them [X-linked adrenoleukodystrophy (X-ALD), metachromatic (MLD) and globoid cell LDs], a gene therapy strategy aiming at transferring the disease gene into autologous hematopoietic stem cells (HSCs) using lentiviral vectors has been developed and has already entered into the clinics for X-ALD and MLD. Long-term follow-up has shown that HSCs gene therapy can arrest the devastating progression of X-ALD. Brain gene therapy relying upon intracerebral injections of adeno-associated vectors is also envisaged for MLD. The development of new gene therapy viral vectors allowing targeting of the disease gene into oligodendrocytes or astrocytes should soon benefit other forms of LDs. © The Author 2011. Published by Oxford University Press. All rights reserved.

Baudry A.,University of Paris Descartes | Mouillet-Richard S.,University of Paris Descartes | Schneider B.,University of Paris Descartes | Launay J.-M.,Hoffmann-La Roche | And 2 more authors.
Science | Year: 2010

The serotonin transporter (SERT) ensures the recapture of serotonin and is the pharmacological target of selective serotonin reuptake inhibitor (SSRI) antidepressants. We show that SERT is a target of microRNA-16 (miR-16). miR-16 is expressed at higher levels in noradrenergic than in serotonergic cells; its reduction in noradrenergic neurons causes de novo SERT expression. In mice, chronic treatment with the SSRI fluoxetine (Prozac) increases miR-16 levels in serotonergic raphe nuclei, which reduces SERT expression. Further, raphe exposed to fluoxetine release the neurotrophic factor S100β, which acts on noradrenergic cells of the locus coeruleus. By decreasing miR-16, S100β turns on the expression of serotonergic functions in noradrenergic neurons. Based on pharmacological and behavioral data, we propose that miR-16 contributes to the therapeutic action of SSRI antidepressants in monoaminergic neurons.

Lewin S.R.,Alfred Hospital | Lewin S.R.,Monash University | Lewin S.R.,Burnet Institute | Rouzioux C.,Laboratory of Virology | Rouzioux C.,University of Paris Descartes
AIDS | Year: 2011

Combination antiretroviral therapy (cART) has led to a major reduction in HIV-related mortality and morbidity; however, HIV can still not be cured. Achieving either a functional cure (long-term control of HIV in the absence of cART) or a sterilizing cure (elimination of all HIV-infected cells) remains a major challenge. The most significant barrier to cure is the establishment of a latent or 'silent' infection in resting CD4 T cells. Several randomized clinical trials have demonstrated that treatment intensification with additional antiretrovirals has little impact on latent reservoirs. Some potential other approaches that may reduce the latent reservoir include very early initiation of cART and the use of agents that could reverse latent infection. Drugs such as histone deacetylase inhibitors, currently used and licensed for the treatment of some cancers; methylation inhibitors; cytokines such as IL-7 or activators of nuclear factor kappa B (NF-κB) such as prostratin, show promising activity in reversing latency in vitro when used either alone or in combination. Alternate strategies include using gene therapy to modify expression of CCR5 and therefore make cells resistant to HIV. This review will primarily focus on the advantages and disadvantages of methods currently being used to quantify persistent virus ex vivo in patients receiving cART and strategies aimed at cure that are being tested in vitro or in early clinical development. In addition, we discuss key issues that need to be addressed to successfully move laboratory research to clinical trials aimed at curing HIV. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Weinreb J.C.,Yale University | Barentsz J.O.,Radboudumc | Choyke P.L.,U.S. National Institutes of Health | Cornud F.,University of Paris Descartes | And 8 more authors.
European Urology | Year: 2016

The Prostate Imaging - Reporting and Data System Version 2 (PI-RADS™ v2) is the product of an international collaboration of the American College of Radiology (ACR), European Society of Uroradiology (ESUR), and AdMetech Foundation. It is designed to promote global standardization and diminish variation in the acquisition, interpretation, and reporting of prostate multiparametric magnetic resonance imaging (mpMRI) examination, and it is based on the best available evidence and expert consensus opinion. It establishes minimum acceptable technical parameters for prostate mpMRI, simplifies and standardizes terminology and content of reports, and provides assessment categories that summarize levels of suspicion or risk of clinically significant prostate cancer that can be used to assist selection of patients for biopsies and management. It is intended to be used in routine clinical practice and also to facilitate data collection and outcome monitoring for research. © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Armstrong A.J.,Duke University | Eisenberger M.A.,Johns Hopkins University | Halabi S.,Duke University | Oudard S.,University of Paris Descartes | And 4 more authors.
European Urology | Year: 2012

Context: We have recently witnessed a rapid increase in the number of effective systemic agents for men with metastatic castration-resistant prostate cancer (CRPC), including novel hormonal therapies (abiraterone acetate and MDV3100), immunotherapies (sipuleucel-T), chemotherapies (cabazitaxel), and bone microenvironment targeting agents (denosumab, radium 223). Given the increasing complexity of treatment decisions for this disease, major research and clinical priorities are (1) finding biomarkers that enable an understanding of the natural history and complex biology of this heterogeneous malignancy, (2) defining predictive biomarkers that identify men most likely to benefit from a given therapy, and (3) identifying biomarkers of early response or progression to optimize outcomes. Objective: In this review, we discuss existing and potential biomarkers in CRPC and how they may currently inform prognosis, aid in treatment selection (predictive value), and relate to survival outcomes (surrogacy). Evidence acquisition: PubMed-based literature searches and abstracts through September 2011 provided the basis for this literature review as well as expert opinion. Evidence synthesis: We address blood and urine-based biomarkers such as prostate-specific antigen, lactate dehydrogenase, total and bone alkaline phosphatase and other bone turnover markers, hemoglobin, and circulating tumor cells in the context of prognosis, prediction, and patient selection for therapy. Given the inherent problems associated with defining progression-free survival in CRPC, the importance of biomarker development and the needed steps are highlighted. We place the discussion of biomarkers within the context of the design/intent of a trial and mechanism of action of a given systemic therapy. We discuss novel biomarker development and the pathway for surrogate or predictive biomarkers to become credentialed as useful tests that inform therapeutic decisions. Conclusions: A greater understanding of biomarkers in CRPC permits a more personalized approach to care that maximizes benefit and minimizes harm and can inform clinical trials tailored to men most likely to derive benefit. © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Grassi A.,University of Pennsylvania | Perduca V.,University of Paris Descartes
Advances in Theoretical and Mathematical Physics | Year: 2013

We study elliptically fibered K3 surfaces, with sections, in toric Fano 3-folds which satisfy certain combinatorial properties relevant to F-theory/heterotic duality. We show that some of these conditions are equivalent to the existence of an appropriate notion of a Weierstrass model adapted to the toric context. Moreover, we show that if in addition other conditions are satisfied, there exists a toric semistable degeneration of the elliptic K3 surface which is compatible with the elliptic fibration and F-theory/Heterotic duality. © 2013 International Press.

Megerlin F.,University of Paris Descartes | Megerlin F.,University of California at Berkeley | Lopert R.,George Washington University | Lopert R.,Therapeutic Goods Administration | And 2 more authors.
Health Affairs | Year: 2013

Biologics are medicines derived from a biological source. Their high prices and rapid uptake have raised hopes that with the gradual expiration of patents on the first generations of biologics, the advent of lower-cost follow-on products known as biosimilars will help "bend the cost curve." Although biosimilars have been available since 2006 within the European Union and are expected to save $15-$44 billion by 2020, the Food and Drug Administration (FDA) has yet to finalize the necessary regulatory processes for their approval in the United States. The European experience suggests, however, that once these are in place, the US biosimilar market may well emerge as bimodal: Initially, modestly discounted biosimilars deemed noninterchangeable with the original products will compete to become the initial treatment of choice in new patients. Subsequently, a second market may be anticipated for those products able to meet the FDA's higher standard for "interchangeability." In that market, discounts may be more dramatic. © 2013 Project HOPE-The People-to-People Health Foundation, Inc.

Baeten D.,University of Amsterdam | Sieper J.,Charité - Medical University of Berlin | Braun J.,Rheumazentrum Ruhrgebiet | Baraliakos X.,Rheumazentrum Ruhrgebiet | And 8 more authors.
New England Journal of Medicine | Year: 2015

Background: Secukinumab is an anti-interleukin-17A monoclonal antibody that has been shown to control the symptoms of ankylosing spondylitis in a phase 2 trial. We conducted two phase 3 trials of secukinumab in patients with active ankylosing spondylitis. Methods: In two double-blind trials, we randomly assigned patients to receive secukinumab or placebo. In MEASURE 1, a total of 371 patients received intravenous secukinumab (10 mg per kilogram of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8. In MEASURE 2, a total of 219 patients received subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline; at weeks 1, 2, and 3; and every 4 weeks starting at week 4. At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg. The primary end point was the proportion of patients with at least 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16. Results: In MEASURE 1, the ASAS20 response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for both comparisons with placebo); in MEASURE 2, the rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for the 150-mg dose and P = 0.10 for the 75-mg dose). The significant improvements were sustained through 52 weeks. Infections, including candidiasis, were more common with secukinumab than with placebo during the placebo-controlled period of MEASURE 1. During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn's disease were 0.7, 0.9, and 0.7 cases per 100 patientyears, respectively, in secukinumab-treated patients. Conclusions: Secukinumab at a subcutaneous dose of 150 mg, with either subcutaneous or intravenous loading, provided significant reductions in the signs and symptoms of ankylosing spondylitis at week 16. Secukinumab at a subcutaneous dose of 75 mg resulted in significant improvement only with a higher intravenous loading dose. Copyright © 2015 Massachusetts Medical Society. All rights reserved.

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.

Gligorov J.,University Pierre and Marie Curie | Doval D.,Rajiv Gandhi Cancer Institute and Research Center | Bines J.,Instituto Nacional Of Cancer | Alba E.,Hospital Universitario Regional rgen Of La Victoria | And 8 more authors.
The Lancet Oncology | Year: 2014

Background: Longer duration of first-line chemotherapy for patients with metastatic breast cancer is associated with prolonged overall survival and improved progression-free survival. We investigated capecitabine added to maintenance bevacizumab after initial treatment with bevacizumab and docetaxel in this setting. Methods: We did this open-label randomised phase 3 trial at 54 hospitals in Brazil, China, Egypt, France, Hong Kong, India, Italy, Poland, Spain, and Turkey. We enrolled patients with HER2-negative measurable metastatic breast cancer; each received three to six cycles of first-line bevacizumab (15 mg/kg) and docetaxel (75-100 mg/m2) every 3 weeks. Progression-free patients were randomly assigned with an interactive voice-response system by block (size four) randomisation (1:1) to receive either bevacizumab and capecitabine or bevacizumab only (bevacizumab 15 mg/kg on day 1; capecitabine 1000 mg/m2 twice per day on days 1-14, every 3 weeks) until progression, stratified by oestrogen receptor status (positive vs negative), visceral metastases (present vs absent), response status (stable disease vs response vs non-measurable), and lactate dehydrogenase concentration (≤1.5 vs >1.5×upper limit of normal). Neither patients nor investigators were masked to allocation. The primary endpoint was progression-free survival (from randomisation) in the intention-to-treat population. This trial is registered with, NCT00929240. Findings: Between July 16, 2009, and March 7, 2011 (when enrolment was prematurely terminated), 284 patients received initial bevacizumab and docetaxel; 185 (65%) were randomly assigned (91 to bevacizumab and capecitabine versus 94 to bevacizumab only). Progression-free survival was significantly longer in the bevacizumab and capecitabine group than in the bevacizumab only group (median 11.9 months [95% CI 9.8-15.4] vs 4.3 months [3.9-6.8]; stratified hazard ratio 0.38 [95% CI 0.27-0.55]; two-sided log-rank p<0.0001), as was overall survival (median 39.0 months [95% CI 32.3-not reached] vs 23.7 months [18.5-31.7]; stratified HR 0.43 [95% CI 0.26-0.69]; two-sided log-rank p=0.0003). Results for time to progression were consistent with those for progression-free survival. 78 (86%) patients in the bevacizumab and capecitabine group and 72 (77%) in the bevacizumab only group had an objective response. Clinical benefit was recorded in 92 (98%) patients in the bevacizumab alone group and 90 (99%) in the bevacizumab and capecitabine group. Mean change from baseline in global health score did not differ significantly between groups. Grade 3 or worse adverse events during the maintenance phase were more common with bevacizumab and capecitabine than with bevacizumab only (45 [49%] of 91 patients vs 25 [27%] of 92 patients). The most common grade 3 or worse events were hand-foot syndrome (28 [31%] in the bevacizumab and capecitabine group vs none in the bevacizumab alone group), hypertension (eight [9%] vs three [3%]), and proteinuria (three [3%] vs four [4%]). Serious adverse events were reported by ten (11%) patients in the bevacizumab and capecitabine group and seven (8%) patients in the bevacizumab only group. Interpretation: Despite prematurely terminated accrual and the lack of information about post-progression treatment, both progression-free survival and overall survival were significantly improved with bevacizumab and capecitabine compared with bevacizumab alone as maintenance treatment. These results might inform future maintenance trials and current first-line treatment strategies for HER2-negative metastatic breast cancer. Funding: F Hoffmann-La Roche. © 2014 Elsevier Ltd.

French Institute of Health, Medical Research, University of Paris Descartes and Assistance Publique Hopitaux De Paris Aphp | Date: 2013-07-12

The present invention relates to a method for predicting the survival time of a patient suffering from a solid cancer comprising i) determining in a tumor sample obtained from the patient the gene expression level of at least 7 genes selected from the group consisting of CCR2, CD3D, CD3E, CD3G, CD8A, CXCL10, CXCL11, GZMA, GZMB, GZMK, GZMM, IL15, IRF1, PRF1, STAT1, CD69, ICOS, CXCR3, STAT4, CCL2, and TBX21, ii) comparing every expression level determined at step i) with their predetermined reference value and iii) providing a good prognosis when all expression levels determined at step i) are higher than their predetermined reference values, or providing a bad prognosis when all expression levels determined at step i) are lower than their predetermined reference values or providing an intermediate prognosis when at least one expression level determined value is higher than its predetermined value. The method is also particularly suitable for predicting the responsiveness of the patient to a treatment.

B.R.A.H.M.S. Gmbh, University of Paris Descartes and Assistance Publique Hopitaux De Paris | Date: 2012-07-02

The invention relates to a method for the determination of the time from onset of atrial fibrillation to presentation in a patient comprising the steps of: providing a sample of a bodily fluid of said patient, determining the level of proANP (SEQ ID NO: 1) or fragments thereof in said sample, correlating the level of proANP or fragments thereof to the time from the onset of atrial fibrillation to presentation of said patient, wherein said fragments have a length of at least 6 amino acid residues.

French National Center for Scientific Research, University of Paris Descartes, Hospices Civils De Lyon and University Claude Bernard Lyon 1 | Date: 2013-02-01

The present invention relates to the field of medicine, in particular of research and diagnosis. It relates more particularly to a novel tool for detecting antibodies in a biological sample originating from a mammal. This tool, which is in the form of a protein chip, can be used in screening for new targets of interest involved in the occurrence of an autoimmune disease, in particular of a disease affecting the nervous system of a mammal, and also in the diagnosis or the monitoring of the progression of such an autoimmune disease. The invention also relates to a method for producing such a tool and also to kits comprising it and enabling its use.

French National Center for Scientific Research, University of Rennes 1 and University of Paris Descartes | Date: 2010-02-19

The invention relates to trisubstituted or tetrasubstituted imidazo[4,5b]pyridines, to their uses as well as to a process for manufacturing them. The compounds of the invention are imidazo[4,5b]pyridines. The first general synthesis of 3,5,7 imidazo[4,5b]pyridines is disclosed in the description. The invention founds application, in particular, in the pharmaceutical field.

Agency: European Commission | Branch: H2020 | Program: CSA | Phase: ISSI-1-2015 | Award Amount: 3.94M | Year: 2016

Our project, Doing-It-Together Science, DITOs, represents a step change in European public engagement with science and innovation. We propose moving from a model in which scientific research, innovation, and problem-solving is mainly driven by scientific/professional institutions to one based on active public participation and capacity building with various levels and strategies of engagement in the scientific process. At the core of our ethos is a recognition of peoples existing expertise and the different ways people want to and do engage in science and technology. The project is aimed at elevating public engagement with science across Europe from passive engagement with the process of developing science to an active one. Citizen Science and Do It Yourself (DIY) scientific efforts demonstrate that this is possible, and our aim is to ensure that the European Research Area will become leader in deep public engagement that is afforded by these advances. As a Coordination and Support Action, this project will support and build upon DIY, grassroots, and frugal innovation initiatives so that in the short and medium term we sustain localised capacity building and in the long term the effects of these grassroots efforts channel to policy makers at different levels, from external advice to societal inputs, regarding appropriate research and innovation policies. The proposal includes the participation of policy bodies (European Citizen Science Association, DE), SMEs (Tekiu, UK; Eutema, AT), Universities (University College London, UK; Universite Paris Descartes, FR; University of Genve, CH), Science galleries and public spaces (Royal Belgian Institute of Natural Sciences, BE; Medialab-Prado, E; Kersnikova Institution, SL) and NGOs (Meritum Association, PL; Waag Society, NL).

Agency: European Commission | Branch: FP7 | Program: CP | Phase: ICT-2007.2.2 | Award Amount: 3.89M | Year: 2009

The goal of the proposed study is to equip a highly biomimetic robot hand-arm system with the agility, robustness and versatility that are hallmarks of the human motor system by understanding and mimicking the variable stiffness paradigms that are so effectively employed by the human CNS. A key component of the study will be the anatomically accurate musculoskeletal modelling of the human arm and hand. The project will develop novel methodologies to comprehend how the human arm can adapt its impedance, e.g. by changing the co-contraction level or by adapting the reflex gains. The impedance of the arm and of the hand will be investigated using powerful robot manipulators capable of imposing force perturbations. The existing closed-loop system identification techniques will be extended with non-linear time-variant techniques which can identify the behaviour during reaching and grasping tasks. The grasp force modulation and hand muscle activity correlations will be learned for use on the robotic system. Finally, optimization techniques gleaned and validated on the detailed biophysical model will be transferred to the variable impedance actuation of the novel biomorphic robotic system The central question that this proposal focuses on for both the human and robotic arm is: how is stiffness used to enhance performance?; and this project represents one of the first attempts where targeted modelling studies will go the full circle by exploiting these results for optimal control of an embodied, high dimensional, variable impedance robotic system.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.2.1.2-1 | Award Amount: 3.90M | Year: 2012

With the arrival of new colorectal cancer (CRC) therapeutics targeting specific cell signalling pathways, such as anti-EGFR therapy, personalised cancer treatment is at the door step of clinical practise. This progress in drug development contrasts strikingly with current clinical practice, where decision making depends largely on clinical factors such as tumour staging and age of patient, with the success of such treatments being largely unpredictable. 5-FU-based chemotherapy represents the main stay of CRC therapy. DNA damaging agents such as 5-FU and anti-EGFR therapy seek to induce tumour regression through induction of apoptosis or sensitization to apoptosis. Dysfunctional apoptosis is well recognized as a key contributing factor in chemotherapy resistance. The aim of the APODECIDE consortium is to develop systems medicine tools that predict treatment responses in CRC patients to 5-FU-based chemotherapy and anti-EGFR therapy, based on a systems analysis of apoptosis and EGFR signalling pathways. Based on previous clinical proof-of-concept studies that demonstrated the unique potential of such approaches in predicting tumour resistance, the APO-DECIDE consortium aims to deliver new clinical decision making tools that enable personalised medicine approaches and smart clinical trials design in the future. The SMEs will benefit from the project through the development of systems-based combinatorial biomarkers adapted to formalin fixed paraffin-embedded material, the routine material used in clinical histopathology, hence providing a unique opportunity for marketing and exploitation. SMEs and their academic partners will also develop computational whole body models reflecting drug pharmacodynamics and pharmacokinetics in patient cohorts, providing a unique market niche in the field clinical oncology.

French National Center for Scientific Research, French Institute of Health, Medical Research, University Claude Bernard Lyon 1 and University of Paris Descartes | Date: 2010-03-11

A compound of formula (I), or a pharmaceutically acceptable salt thereof, where R_(1 )is a (C_(1)-C_(6))alkyl or (C_(3)-C_(6))cycloalkyl group; R_(2 )is a (C_(1)-C_(6))alkyl, (C_(3)-C_(6))cycloalkyl, (C_(1)-C_(6))alkenyl, (C_(1)-C_(6))fluoroalkyl, (C_(1)-C_(3))fluoroalkoxy, or (C_(1)-C_(6))alkoxy(C_(1)-C_(6))alkyl group, substituted: (i) with one to three hydroxyl groups, or (ii) with an NR_(a)R_(b )group, where R_(a )and R_(b )are independently a hydrogen atom or a (C_(1)-C_(3))alkyl group; or a pyrrolidinylmethyl group substituted with one to three hydroxyl groups; R_(9 )is the same as R_(2 )or hydrogen; the R_(2 )and R_(9 )groups independently being substitutable with an OCOR_(3 )group, where R_(3 )is a natural or unnatural amino acid derivative or a piperidyl group; alternatively, R_(2 )and R_(9 )together form a heterocyclic compound; X and Y are independently a substitutable phenyl or heteroaryl group, the heteroaryl group being a thienyl, pyridyl, pyrimidinyl, thiazolyl, pyrrolyl, or furanyl group; and R_(6 )is a hydrogen or a (C_(1)-C_(3))alkyl group.

Institute Pasteur Paris, University of Paris Descartes, Assistance Publique Hopitaux De Paris, PathoQuest and National Veterinary School of Alfort | Date: 2013-04-19

The present invention relates to the use of the measure of anelloviral load for the determination of immunosuppression. More precisely, the present invention provides a method for characterizing the immunosuppressed or non-immunosuppressed status of a subject, comprising the steps of determining the anelloviral load from a biological sample of the said subject, and determining from the said comparison the immunosuppressed or non-immunosuppressed status. The determination of the immunosuppressed status of the subject can then be used to design or adapt a therapeutic treatment.

French Institute of Health, Medical Research, University of Paris Descartes, University Pierre, Marie Curie and Assistance Publique Hopitaux De Paris Aphp | Date: 2014-06-20

The present invention relates to method and pharmaceutical compositions for preventing glucocorticoid-induced corneal or skin thinning. In particular, the present invention relates to a mineralocorticoid receptor antagonist for topical use in a method for preventing or reducing glucocorticoid-induced corneal or skin thinning in a subject in need thereof. The invention also relates to a topical pharmaceutical composition comprising an amount of at least one glucocorticoid and an amount of at least one mineralocorticoid receptor antagonist or inhibitor of MR expression for use in a method for treating an inflammatory skin disease or an inflammatory disease of the cornea or of the anterior segment of the eye in a subject in need thereof.

University of Paris Descartes and Assistance Publique Hopitaux De Paris Aphp | Date: 2014-05-28

The invention relates to the diagnosis of HIV-associated nephropathy (HIVAN) based on determining the expression level of HIV nucleic acids (HIV RNA and/or DNA) in combination with the renal function of a patient. The invention also relates to a method for distinguishing between HIVAN and non-HIVAN kidney disease in a patient based on the expression level of urinary HIV nucleic acids.

French Institute of Health, Medical Research, University of Paris Descartes, Assistance Publique Hopitaux De Paris Aphp, Foundation Imagine and French National Center for Scientific Research | Date: 2014-11-18

The present invention relates to methods and pharmaceutical compositions for the treatment of beta-thalassemias. In particular, the present invention relates to an XPO1 inhibitor for use in a method for treating beta-thalassemia in a subject in need thereof.

Biovaxim Ltd and University of Paris Descartes | Date: 2016-03-30

The present invention relates to pharmaceutical compositions comprising a mixture of a specific HIV antigen and a non-pathogenic living bacterium. Said specific HIV antigen comprises one or more epitopes from Gag and/or Pol proteins and is preferably under a particulate form. Said bacterium is preferably Lactobacillus plantarum. These compositions are useful for preventing and/or treating an HIV disease in humans.

Free University of Colombia, French National Center for Scientific Research, University of Rennes 1 and University of Paris Descartes | Date: 2013-03-28

This invention relates to the direct grafting of a calixarene mostly onto the surface of a material, as well as to a grafting process, and certain calixarene intermediates useful for carrying the grafting process.

French Institute of Health, Medical Research, Foundation Imagine, University of Paris Descartes and Assistance Publique Hopitaux De Paris Aphp | Date: 2014-11-07

A method, an apparatus, and a computer program product for wireless communication are provided. The apparatus determines an observed bit rate based on uplink transmissions of the UE, estimates an available link capacity for the UE, selects an estimate factor, and estimates available uplink throughput for future uplink transmissions of the UE as a function of the observed bit rate, the estimated available link capacity, and the estimate factor.

Slade D.,University of Paris Descartes | Radman M.,University of Paris Descartes | Radman M.,Mediterranean Institute for Life Sciences
Microbiology and Molecular Biology Reviews | Year: 2011

Deinococcus radiodurans is a robust bacterium best known for its capacity to repair massive DNA damage efficiently and accurately. It is extremely resistant to many DNA-damaging agents, including ionizing radiation and UV radiation (100 to 295 nm), desiccation, and mitomycin C, which induce oxidative damage not only to DNA but also to all cellular macromolecules via the production of reactive oxygen species. The extreme resilience of D. radiodurans to oxidative stress is imparted synergistically by an efficient protection of proteins against oxidative stress and an efficient DNA repair mechanism, enhanced by functional redundancies in both systems. D. radiodurans assets for the prevention of and recovery from oxidative stress are extensively reviewed here. Radiation- and desiccation-resistant bacteria such as D. radiodurans have substantially lower protein oxidation levels than do sensitive bacteria but have similar yields of DNA double-strand breaks. These findings challenge the concept of DNA as the primary target of radiation toxicity while advancing protein damage, and the protection of proteins against oxidative damage, as a new paradigm of radiation toxicity and survival. The protection of DNA repair and other proteins against oxidative damage is imparted by enzymatic and nonenzymatic antioxidant defense systems dominated by divalent manganese complexes. Given that oxidative stress caused by the accumulation of reactive oxygen species is associated with aging and cancer, a comprehensive outlook on D. radiodurans strategies of combating oxidative stress may open new avenues for antiaging and anticancer treatments. The study of the antioxidation protection in D. radiodurans is therefore of considerable potential interest for medicine and public health. Copyright © 2011, American Society for Microbiology. All Rights Reserved.

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.

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.

Nessar R.,University of Paris Descartes | Cambau E.,University Paris Diderot | Reyrat J.M.,University of Paris Descartes | Murray A.,Institute Pasteur Paris | And 2 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2012

The intrinsic and acquired resistance of Mycobacterium abscessus to commonly used antibiotics limits the chemotherapeutic options for infections caused by these mycobacteria. Intrinsic resistance is attributed to a combination of the permeability barrier of the complex multilayer cell envelope, drug export systems, antibiotic targets with low affinity and enzymes that neutralize antibiotics in the cytoplasm. To date, acquired resistance has only been observed for aminoglycosides and macrolides, which is conferred by mutations affecting the genes encoding the antibiotic targets (rrs and rrl, respectively). Here we summarize previous and recent findings on the resistance of M. abscessus to antibiotics in light of what has been discovered for other mycobacteria. Since we can now distinguish three groups of strains belonging to M. abscessus (M. abscessus sensu stricto, Mycobacterium massiliense and Mycobacterium bolletii), studies on antibiotic susceptibility and resistance should be considered according to this new classification. This review raises the profile of this important pathogen and highlights the work needed to decipher the molecular events responsible for its extensive chemotherapeutic resistance. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. 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.

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.

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.

Wise R.A.,Johns Hopkins University | Anzueto A.,University of Texas Health Science Center at San Antonio | Cotton D.,Boehringer Ingelheim Pharmaceuticals | Dahl R.,University of Southern Denmark | And 7 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo. METHODS: In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a oncedaily dose of 2.5 μg or 5 μg, as compared with tiotropium HandiHaler at a oncedaily dose of 18 μg. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 μg or 2.5 μg vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 μg vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease. RESULTS: During a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 μg vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups. CONCLUSIONS: Tiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 μg in patients with COPD. Copyright © 2013 Massachusetts Medical Society.

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.

Robin A.,University of Witwatersrand | Moisan L.,University of Paris Descartes | Le Hegarat-Mascle S.,CNRS Fundamental Electronics Institute
IEEE Transactions on Pattern Analysis and Machine Intelligence | Year: 2010

This paper presents a new method for unsupervised subpixel change detection using image series. The method is based on the definition of a probabilistic criterion capable of assessing the level of coherence of an image series relative to a reference classification with a finer resolution. In opposition to approaches based on an a priori model of the data, the model developed here is based on the rejection of a nonstructured modelcalled a-contrario modelby the observation of structured data. This coherence measure is the core of a stochastic algorithm which automatically selects the image subdomain representing the most likely changes. A theoretical analysis of this model is led to predict its performances, in particular regarding the contrast level of the image as well as the number of change pixels in the image. Numerical simulations are also presented that confirm the high robustness of the method and its capacity to detect changes impacting more than 25 percent of a considered pixel under average conditions. An application to land-cover change detection is then provided using time series of satellite images. © 2006 IEEE.

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.

Gompel A.,University of Paris Descartes | Santen R.J.,University of Virginia
Climacteric | Year: 2012

Ten years after the publication of the first Women's Health Initiative (WHI) report, a substantial decrease in hormone replacement therapy (HRT) has been observed world-wide. Fear of developing breast cancer represents one of the reasons for an important shift toward alternatives for treatment of menopause symptoms or abstention from therapy altogether. Many publications in the scientific and lay press have emphasized the magnitude of the relative risk of breast cancer but have not focused on excess or attributable risk. Since the original report of the WHI study, new information has been published on risk factors for breast cancer related to hormone therapy use. Accordingly, we believe it important to review current data and examine excess rather than relative or absolute risk. A balanced perspective on excess risk determined from existing data suggests that the benefits of HRT for quality of life can outweigh the risks in management of a large number of postmenopausal women. In addition, alternative strategies for relief of menopausal symptoms are not as effective as HRT in treating the climacteric symptoms. © 2012 International Menopause Society.

Laurent S.,University of Paris Descartes | Laurent S.,French Institute of Health and Medical Research | Schlaich M.,Baker IDI Heart and Diabetes Institute | Esler M.,Baker IDI Heart and Diabetes Institute
The Lancet | Year: 2012

Successful treatment of hypertension is difficult despite the availability of several classes of antihypertensive drug, and the value of strategies to combat the effect of adverse lifestyle behaviours on blood pressure. In this paper, we discuss two promising therapeutic alternatives for patients with resistant hypertension: novel drugs, including new pharmacological classes (such as vasopeptidase inhibitors and aldosterone synthase inhibitors) and new molecules from present pharmacological classes with additional properties in blood-pressure or metabolism pathways; and new procedures and devices, including stimulation of arterial baroreceptors and catheter-based renal denervation. Although several pharmacological targets have been discovered with promising preclinical results, the clinical development of novel antihypertensive drugs has been more difficult and less productive than expected. The effectiveness and safety of new devices and procedures should be carefully assessed in patients with resistant hypertension, thus leading to a new era of outcome trials and evidence-based guidelines.

Epstein J.,University of Paris Descartes | Santo R.M.,University of Sao Paulo | Guillemin F.,University of Paris Descartes
Journal of Clinical Epidemiology | Year: 2015

Abstract Objectives The aim of cross-cultural adaptation (CCA) of a questionnaire is to achieve equivalence between the original and adapted questionnaire. Here, we aimed to review the state of the art in CCA methods. Study Design and Setting We reviewed cross-disciplinary bibliographic databases for articles on methods and guidelines for CCA of questionnaires. Articles were first selected by their abstract and title, and then, we retrieved full-text English articles. References of selected articles were searched for additional relevant studies. Results We identified 31 guidelines and found no consensus in CCA methods. Most methods included use of committees, focus groups, and back translations. Evidence for the best methods is lacking, although clues indicate that back translation may not be mandatory. Conclusion Several methods are available for CCA of questionnaires. According to experts only, most would achieve comparable results, and choosing one is a matter of preference and logistic. More evidence is needed to support recommendations. Adaptation and validation of a questionnaire are two different processes that should be distinguished and undertaken with care. © 2015 Elsevier Inc. All rights reserved.

Elez M.,University of Paris Descartes | Radman M.,University of Paris Descartes | Radman M.,Mediterranean Institute for Life Sciences | Matic I.,University of Paris Descartes
Nucleic Acids Research | Year: 2012

Mismatch repair (MMR) is an evolutionarily conserved DNA repair system, which corrects mismatched bases arising during DNA replication. MutS recognizes and binds base pair mismatches, while the MutL protein interacts with MutS-mismatch complex and triggers MutH endonuclease activity at a distal-strand discrimination site on the DNA. The mechanism of communication between these two distal sites on the DNA is not known. We used functional fluorescent MMR proteins, MutS and MutL, in order to investigate the formation of the fluorescent MMR protein complexes on mismatches in real-time in growing Escherichia coli cells. We found that MutS and MutL proteins co-localize on unrepaired mismatches to form fluorescent foci. MutL foci were, on average, 2.7 times more intense than the MutS foci co-localized on individual mismatches. A steric block on the DNA provided by the MutHE56A mutant protein, which binds to but does not cut the DNA at the strand discrimination site, decreased MutL foci fluorescence 3-fold. This indicates that MutL accumulates from the mismatch site toward strand discrimination site along the DNA. Our results corroborate the hypothesis postulating that MutL accumulation assures the coordination of the MMR activities between the mismatch and the strand discrimination site. © 2012 The Author(s).

De Bandt J.-P.,Paris Observatory | Waligora-Dupriet A.-J.,University of Paris Descartes | Butel M.-J.,University of Paris Descartes
Current Opinion in Clinical Nutrition and Metabolic Care | Year: 2011

Purpose of Review: The gut microbiota is a very complex ecosystem which interacts extensively with the host, influencing multiple metabolic and physiological functions. Several diseases have been shown to be associated with specific alterations in gut microbiota. It is more and more underscored as playing a major role in the development of insulin resistance and inflammation associated with excess weight gain. Recent Findings: Recent studies in obese patients have shown perturbations in gut microbiota with a weight gain-associated increase in the Firmicutes/Bacteroidetes ratio ameliorated by various attempts at inducing weight loss. Summary: Intestinal microbiota may contribute to the development of inflammation and insulin resistance by two main mechanisms. First, gut microbiota might facilitate energy harvest from the gut leading via perturbation in energy homeostasis to fat deposition and increased adipokine production and plasma free fatty acid levels both contributing to insulin resistance and inflammation. Alternatively, it can initiate an inflammatory process either originating from the intestine or generated at the peripheral level via endotoxin leakage into the blood from the intestine, both leading secondarily to insulin resistance. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Colnot C.,University of Paris Descartes | Zhang X.,University of Rochester | Tate M.L.K.,Case Western Reserve University
Journal of Orthopaedic Research | Year: 2012

While century old clinical reports document the periosteum's remarkable regenerative capacity, only in the past decade have scientists undertaken mechanistic investigations of its regenerative potential. At a Workshop at the 2012 Annual Meeting of Orthopaedic Research Society, we reviewed the molecular, cellular, and tissue scale approaches to elucidate the mechanisms underlying the periosteum's regenerative potential as well as translational therapies engineering solutions inspired by its remarkable regenerative capacity. The entire population of osteoblasts within periosteum, and at endosteal and trabecular bone surfaces within the bone marrow, derives from the embryonic perichondrium. Periosteal cells contribute more to cartilage and bone formation within the callus during fracture healing than do cells of the bone marrow or endosteum, which do not migrate out of the marrow compartment. Furthermore, a current healing paradigm regards the activation, expansion, and differentiation of periosteal stem/progenitor cells as an essential step in building a template for subsequent neovascularization, bone formation, and remodeling. The periosteum comprises a complex, composite structure, providing a niche for pluripotent cells and a repository for molecular factors that modulate cell behavior. The periosteum's advanced, "smart" material properties change depending on the mechanical, chemical, and biological state of the tissue. Understanding periosteum development, progenitor cell-driven initiation of periosteum's endogenous tissue building capacity, and the complex structure-function relationships of periosteum as an advanced material are important for harnessing and engineering ersatz materials to mimic the periosteum's remarkable regenerative capacity. © 2012 Orthopaedic Research Society.

Witko-Sarsat V.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | Witko-Sarsat V.,University of Paris Descartes | Pederzoli-Ribeil M.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | Pederzoli-Ribeil M.,University of Paris Descartes | And 3 more authors.
Trends in Immunology | Year: 2011

Recently, unexpected biological features of polymorphonuclear neutrophils have been revealed. In addition to their pivotal role in the defence against pathogens, neutrophils display a high degree of plasticity and contribute to control of adaptive immune responses. An emerging aspect of neutrophils is their ability to modulate their survival in response to both intrinsic and extrinsic factors. This review focuses on recent advances that have uncovered proliferating cell nuclear antigen (PCNA) and other cell cycle regulatory proteins as novel players regulating neutrophil survival. A better understanding of the mechanisms involved in neutrophil fate might pave the way for the identification of new anti-inflammatory molecules. © 2011 Elsevier Ltd.

Le Bertre T.,Paris Observatory | Matthews L.D.,Massachusetts Institute of Technology | Gerard E.,University of Paris Descartes | Libert Y.,Grenoble Institute of Technology
Monthly Notices of the Royal Astronomical Society | Year: 2012

We report the detection of the Hi line at 21cm in the direction of α Orionis (α Ori) with the Nançay Radiotelescope and with the Very Large Array. The observations confirm the previous detection of Hi emission centred on α Ori, but additionally reveal for the first time a quasi-stationary detached shell of neutral atomic hydrogen ∼4arcmin in diameter (0.24 pc at a distance of 200pc). The detached shell appears elongated in a direction opposite to the star's space motion. A simple model shows that this detached atomic gas shell can result from the collision of the stellar wind from α Ori with the local interstellar medium (ISM). It implies that α Ori has been losing matter at a rate of ∼1.2×10 -6M ⊙yr -1 for the past 8×10 4 yr. In addition, we report the detection of atomic hydrogen associated with the far-infrared arc located 6arcmin north-east of α Ori, which has been suggested to trace the bow shock resulting from the motion of the star through the ISM. We also report the detection by the Galaxy Evolution Explorer of a far-ultraviolet counterpart to this arc. © 2012 The Authors Monthly Notices of the Royal Astronomical Society © 2012 RAS.

Pagani L.,Paris Observatory | Roueff E.,University of Paris Descartes | Lesaffre P.,Ecole Normale Superieure de Paris
Astrophysical Journal Letters | Year: 2011

Interstellar dark clouds are the sites of star formation. Their main component, dihydrogen, exists under two states, ortho and para. H2 is supposed to form in the ortho:para ratio (OPR) of 3:1 and to subsequently decay to almost pure para-H2 (OPR ≤ 0.001). Only if the H2 OPR is low enough, will deuteration enrichment, as observed in the cores of these clouds, be efficient. The second condition for strong deuteration enrichment is the local disappearance of CO, which freezes out onto grains in the core formation process. We show that this latter condition does not apply to DCO+, which, therefore, should be present all over the cloud. We find that an OPR ≥ 0.1 is necessary to prevent DCO+ large-scale apparition. We conclude that the inevitable decay of ortho-H2 sets an upper limit of 6 million years to the age of starless molecular clouds under usual conditions. © 2011. The American Astronomical Society. All rights reserved..

Abrao M.S.,University of Sao Paulo | Petraglia F.,University of Siena | Falcone T.,Cleveland Clinic | Keckstein J.,Villach Hospital | And 2 more authors.
Human Reproduction Update | Year: 2015

Background: Deep endometriosis invading the bowel constitutes a major challenge for the gynecologist. In addition to the greater impact on pain, the high incidence of surgical morbidity involved with bowel endometriosis poses a therapeutic dilemma for the surgeon. Intestinal involvement by deep endometriotic nodules has been estimated to occur in 8-12% of women with endometriosis. Individual and clinical factors, pre-operative morphologic characteristics from imaging, surgical considerations and impact on quality of life are critical variables that should be considered in determining the best therapeutic strategy for a patient with deep endometriosis involving the sigmoid and/or the rectum. Pre-operative planning is fundamental for defining the optimal therapeutic strategy; patient counseling of treatment options, and when surgery is indicated, involvement of a multidisciplinary surgical team is required. Methods: The PubMed and Cochrane database were searched for all original and review articles published in English, French and Italian, until June 2014. Search terms included 'deep endometriosis', 'surgical and clinical approach', 'bowel disease', 'quality of life', 'management of deep endometriosis'. Special attention was paid to articles comparing features of discoid and segmental resection. Results: The rationale for the best therapeutic options for patients with deep endometriosis has been shown and an evidence-based treatment algorithm for determining when and which surgical intervention may be required is proposed. In deciding the best treatment option for patients with deep endometriosis involving the sigmoid and rectum, it is important to understand how the different clinical factors and preoperative morphologic imaging affect the algorithm. Surgery is not indicated in all patients with deep endometriosis, but, when surgery is chosen, a complete resection by the most appropriate surgical team is required in order to achieve the best patient outcome. Conclusion: In women with deep endometriosis, surgery is the therapy of choice for symptomatic patients when deep lesions do not improve with a medical treatment. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2009-2.4.4-1 | Award Amount: 9.25M | Year: 2010

Leukodystrophies (LDs) are inherited rare neurodegenerative diseases of the white matter and its main component, the myelin, that are affecting predominantly children. Severity of the disease is related to the axonal dysfunction due to myelin deficiency or destruction. Despite the achievement of remarkable advances made in the past decade, there is no current curative therapy. The development of therapeutic approaches for myelin repair and neuroprotection constitutes the main objective of the LeukoTreat project. Indeed LDs constitute prototypic pathologies to tackle myelin formation/destruction issues as well as glial cells dysfunctions in neurodegeneration. The global aim is to promote the development of therapeutic strategies for the largest number of LD affected patients and further applications to more common white matter disorders and finally neurodegenerative diseases. For this purpose, the project will combine the expertise of (i) recognized European research teams in the field of White Matter diseases (COST Myelinet), (ii) high-technology SMEs, (iii) experts in medical ethics and (iv) LD patients and families associations. To develop efficient therapies, the LeukoTreat project is based on 5 complementary approaches consisting in: (i) collecting information on the epidemiology, the natural history, the genotype/phenotype correlation of LDs for at least 500 patients; (ii) validating/identifying biomarkers for therapeutic decisions/follow up to isolate new therapeutic targets; (iii) developing pharmacological strategies with the ultimate objective to launch at least 4 pharmacological clinical trials during 5 years following the project; (iv) developing innovative gene and cell therapies with the ultimate objective to launch at least 3 clinical trials during the next 5 years; (v) tackling ethical impacts of the proposed therapeutic challenges by integrating the participation of patients driven by a well-experienced research team strongly skilled in ethics

French National Center for Scientific Research, University of Paris Descartes, French Institute of Health, Medical Research and École Nationale Supérieure de Chimie de Paris | Date: 2015-01-15

The present invention relates to 4-azapodophyllotoxin analogs of formula (I) in which X, R_(1), R_(2), R_(3), R_(4 )and Ar are as defined in claim 1, preferably a pharmaceutically acceptable salt thereof, optionally in the form of a solvate, a composition comprising said analogs, their use as medicament, in particular for the treatment of cancer, and a process for their preparation.

IntegraGen, French Institute of Health, Medical Research, French National Center for Scientific Research, Assistance Publique Hopitaux De Paris and University of Paris Descartes | Date: 2012-11-23

The present invention relates to a method for predicting whether a patient with a cancer is likely to respond to an epidermal growth factor receptor (EGFR) inhibitor, which method comprises determining the expression level hsa-miR-31-3p miRNA in a sample of said patient. The invention also relates to therapeutic uses of an EGFR inhibitor in a patient predicted to respond to said EGFR inhibitor.

IntegraGen, French Institute of Health, Medical Research and University of Paris Descartes | Date: 2013-09-23

The present invention relates to the technical field of liver diseases, their classification and diagnosis. It provides a new method for classifying a liver sample between non-hepatocellular sample; hepatocellular carcinoma (HCC) sample with further classification into one of subgroups G1 to G6; focal nodule dysplasia (FNH) sample; hepatocellular adenoma (HCA) sample with further classification into HNF1A mutated HCA, inflammatory HCA, catenin mutated HCA or other HCA sample; and other benign liver sample, based on determination in vitro of genes expression profiles and analysis of the expression profile using algorithms calibrated with reference samples. The invention also provides kits for the classification of liver samples, and methods of treatment of liver disease in a subject based on a preliminary classification of a liver sample of said subject.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: SiS.2012.1.1.1-1 | Award Amount: 2.24M | Year: 2013

The GREAT project will develop an empirically based and theoretically sound model of the role of responsible research and innovation governance. The project will explore the dynamics of participation in research and innovation, and investigate the characteristics of responsible practices. It will investigate the nature of new partnerships among various stakeholders, researchers and policymakers that are developing within innovation networks and the influence that these developments have on knowledge production and policy. This will be done a. by determining the characteristics of research and innovation b. involving diverse groupings and c. determining the social processes involved in responsible research and innovation practices. In doing so, the GREAT project will address all three issues requested in the call: a. It will explore the knowledge and research potential of multi-stakeholder approaches in research; b. it will investigate how responsible innovation is involved in research processes and c. it will use this knowledge to inform policy makers on how to integrate responsible innovation in further research activities.

French Institute of Health, Medical Research, French National Center for Scientific Research, Genethon, University of Paris Descartes, École Nationale Supérieure de Chimie de Paris, University of Évry Val d'Essonne and Assistance Publique Hopitaux De Paris | Date: 2014-11-18

The present invention relates to a method for treating a Leber congenital amaurosis in a patient harbouring the mutation c.2991+1655 A>G in the CEP290 gene, comprising the step of administering to said patient at least one antisense oligonucleotide complementary to nucleic acid sequence that is necessary for preventing splicing of the cryptic exon inserted into the mutant c.2291+1655 A>G CEP290 mRNA

Agency: European Commission | Branch: FP7 | Program: MC-ITN | Phase: PEOPLE-2007-1-1-ITN | Award Amount: 1.88M | Year: 2008

The proposed Initial Training Network for Lateralized Attention Networks (ITN-LAN) brings together 6 research teams with established international reputations and, more importantly, is founded on well established collaborations. The long-term scientific objectives of the proposed ITN-LAN are: (1) To validate and standardize a behavioural battery for assessing the attentional networks of the two cerebral hemispheres and their interaction, (2) To study its neurophysiological correlates using EEG/ERP, fMRI, NIRS and TMS, (3) To assess methods for modulating the attention networks in each hemisphere and their interaction using: (i) biofeedback of the participants own ongoing EEG or fMRI, (ii) TMS to generate selective virtual lesions of hemispheric attentional networks. The focus of the current proposal is to assess critically and rigorously the effectiveness of biofeedback in modulating attention, a goal which has both basic and applied aspects. Common to both aspects is our ability to harness cortical plasticity in the service of ameliorating not only acquired, but also congenital attention deficits. The clinical application has commercial potential and this will be pursued by the industry associated partner (Bio-Keshev). The proposed ITN-LAN offers a comprehensive range of research methods and theories in attention research. First, we cover ALL the non-invasive research methods applied in this field, and second, we look at attention processes at all levels, from sensory to frontal cortex regions, from childhood to old age, and from normal performance to acquired and developmental disorders. We ask to fund 312 person-months, mostly (92%) ESR. One of the centres is located in a less-favoured region. We are privileged to have Prof. Michael Posner as our consultant, being an eminent researcher in the field of attention.

Agency: European Commission | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2012-ITN | Award Amount: 3.01M | Year: 2013

Visual perception provides us with a richly detailed representation of the surrounding world, enabling us to make subtle judgements of 1) 3D shape, 2) the material properties of objects, and 3) the flow of illumination within a scene. Together, these three factors determine the intensity of a surface in the image. Estimating scene properties is crucial for guiding action and making decisions like whether food is edible. Visual look and feel also plays a key role in industrial design, computer graphics and other industries. Despite this, little is known about how we visually estimate the physical properties of objects and illumination. Previous research has mainly focussed on one or two of the three causal factors independently, and from the viewpoint of a specific discipline. By contrast, in PRISM we take an integrative approach, to understand how the brain creates a richly detailed representation of the world by looking at how all three factors interact simultaneously. PRISM is radically interdisciplinary, uniting experts from psychology, neuroscience, computer science and physics to understand both the analysis and synthesis of shape, shading and materials. PRISM is intersectoral by uniting researchers from seven leading Universities and two industrial partners, enabling impact in basic research, technology and the creative industries. Through research projects, cross-discipline visits, and structured Course Modules delivered through local and network-wide training events, we will endow PRISM fellows with an unusually broad overview and the cross-sector skills they need to become future leaders in European research and development. Thus, by delivering early-career training embedded in a cutting-edge research programme, we aim to 1) springboard the next generation of interdisciplinary researchers on perceptual representations of 3D scenes and 2) cement long-term collaborations between sectors to enhance European perception research and its applications.

Agency: European Commission | Branch: H2020 | Program: MSCA-RISE | Phase: MSCA-RISE-2015 | Award Amount: 2.18M | Year: 2016

EXANDAS project aims to apply emerging and cutting edge technologies in the field of Natural Product Chemistry in order to fully and efficiently exploit the therapeutic potential of medicinal and aromatic processing waste and by-products. New opportunities for the generation of innovative products with high added value in the field of cosmeceuticals and food supplements are expected to be generated while current environmental challenges will be addressed. The cornerstone of EXANDAS project is the development of novel processes based on eco-friendly technologies for the efficient extraction, purification and transformation of active ingredients, as well as the complete chemical characterization and biological evaluation of produced extracts and pure compounds that can be commercially exploited. Optimization and scaling up of these procedures, as well as formulation using emerging technologies will lead to the development of novel final products. A diverse group of experts, leaders in their scientific and technological fields, comprising six academic groups and six SMEs partners from four EU Member States and three Third Countries will join forces and exchange know-how through an extended secondments scheme to advance Research & Innovation. Using the experience of the academic partners in phytochemistry and natural product chemistry, as well as the practical experience of the SMEs in large scale processing of plant material and development of innovative final products, transfer of scientific knowledge, best practices and know-how, training courses and workshops will take place. Overall, the implementation of the EXANDAS project aspires to develop a successful and sustainable international and intersectoral collaboration model, that will contribute to the innovation potential of Europe for the most effective exploitation of natural resources and the development of novel cosmeceuticals and food supplements.

Beghetti M.,University of Geneva | Galie N.,University of Bologna | Bonnet D.,University of Paris Descartes
Congenital Heart Disease | Year: 2012

The decision whether to repair congenital heart defects in patients with raised pulmonary vascular resistance to alleviate pulmonary hypertension is a complex one. The degree of pulmonary vascular disease is of paramount importance. Operating on patients with pulmonary vascular resistance above a certain threshold runs the risk of postoperative persistent pulmonary hypertension and a worse long-term prognosis. This review focuses on patients deemed "borderline inoperable" or "inoperable" due to pulmonary vascular disease and asks whether they can be "converted to an operable status" with pulmonary arterial hypertension-specific drugs that potentially modify the pulmonary vascular lesions and resistance. © 2012 Wiley Periodicals, Inc.

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.

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.

Boutouyrie P.,University of Paris Descartes | Vermeersch S.J.,Ghent University
European Heart Journal | Year: 2010

Aims Carotid-femoral pulse wave velocity (PWV), a direct measure of aortic stiffness, has become increasingly important for total cardiovascular (CV) risk estimation. Its application as a routine tool for clinical patient evaluation has been hampered by the absence of reference values. The aim of the present study is to establish reference and normal values for PWV based on a large European population. Methods and results We gathered data from 16 867 subjects and patients from 13 different centres across eight European countries, in which PWV and basic clinical parameters were measured. Of these, 11 092 individuals were free from overt CV disease, non-diabetic and untreated by either anti-hypertensive or lipid-lowering drugs and constituted the reference value population, of which the subset with optimal/normal blood pressures (BPs) (n = 1455) is the normal value population. Prior to data pooling, PWV values were converted to a common standard using established conversion formulae. Subjects were categorized by age decade and further subdivided according to BP categories. Pulse wave velocity increased with age and BP category; the increase with age being more pronounced for higher BP categories and the increase with BP being more important for older subjects. The distribution of PWV with age and BP category is described and reference values for PWV are established. Normal values are proposed based on the PWV values observed in the non-hypertensive subpopulation who had no additional CV risk factors. Conclusion The present study is the first to establish reference and normal values for PWV, combining a sizeable European population after standardizing results for different methods of PWV measurement. ©2010 The Author.

Gerardin P.,University of Birmingham | Gerardin P.,University of Paris Descartes | Gerardin P.,French Institute of Health and Medical Research | Kourtzi Z.,University of Birmingham | Mamassian P.,University of Paris Descartes
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

In perceiving 3D shape from ambiguous shading patterns, humans use the prior knowledge that the light is located above their head and slightly to the left. Although this observation has fascinated scientists and artists for a long time, the neural basis of this "light from above left" preference for the interpretation of 3D shape remains largely unexplored. Combining behavioral and functional MRI measurements coupled with multivoxel pattern analysis, we show that activations in early visual areas predict best the light source direction irrespective of the perceived shape, but activations in higher occipitotemporal and parietal areas predict better the perceived 3D shape irrespective of the light direction. These findings demonstrate that illumination is processed earlier than the representation of 3D shape in the visual system. In contrast to previous suggestions, we propose that prior knowledge about illumination is processed in a bottom-up manner and influences the interpretation of 3D structure at higher stages of processing.

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.

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.

Truchetet M.-E.,University of Geneva | Allanore Y.,University of Paris Descartes | Montanari E.,University of Geneva | Chizzolini C.,University of Geneva | Brembilla N.C.,University of Geneva
Annals of the Rheumatic Diseases | Year: 2012

Objective: Among pleiotropic effects, the capacity of prostaglandin I 2 (PGI2) analogues to affect adaptive immunity remains poorly characterised. The purpose of this study was to assess whether PGI 2 analogues could affect T helper (Th) cell responses in patients with systemic sclerosis (SSc) and healthy donors (HD). Methods: Peripheral blood mononuclear cells (PBMC) were obtained from 33 patients with SSc and 29 HD. Cytokine levels in PBMC and monocyte/CD4 T cell cultures were quantified by immunoassays. The frequencies of interleukin (IL)-17A, IL-22, interferon γ (IFNγ) and IL-4-producing CD4 T cells were assessed by multiparametric flow cytometry. Selective receptor antagonists, cytokine blocking antibodies and signalling protein inhibitors were used to identify the receptors and signalling pathways mediating PGI2 analogue effects. Results: Th17 and Th22 cells were more abundant in individuals with SSc than in HD. PGI2 analogues (iloprost, treprostinil and beraprost) significantly increased IL-17A and IL-22 in vitro while decreasing IFNγ production both in SSc and HD PBMC. These effects relied on the specific expansion of Th17 and Th22 and inhibition of Th1 cells. The enhanced Th17 cell responses depended on increased IL-23 production by monocytes, involved the IP prostacyclin receptor and required protein kinase A activation. Importantly, in vivo administration of iloprost in individuals with SSc presenting with digital ulcers resulted in a significant increase in the frequency of Th17 cells. Conclusions: These findings demonstrate that PGI2 analogues affect Th cell differentiation/expansion programmes, favouring Th17 and inhibiting Th1 cell responses in SSc. The impact of these changes on the disease course needs to be taken into consideration and further exploited to improve SSc.

Cavalcante J.L.,Ford Motor Company | Cavalcante J.L.,Cleveland Clinic | Lima J.A.C.,Johns Hopkins University | Redheuil A.,University of Paris Descartes | And 2 more authors.
Journal of the American College of Cardiology | Year: 2011

The aorta stiffens with aging, a process that is accelerated by arterial hypertension. Decreased arterial compliance is one of the earliest detectable manifestations of adverse structural and functional changes within the vessel wall. The use of different imaging techniques optimized for assessment of vascular elasticity and quantification of luminal and vessel wall parameters allows for a comprehensive and detailed view of the vascular system. In addition, several studies have also documented the prognostic importance of arterial stiffness (AS) in various populations as an independent predictor of cardiovascular morbidity and all-cause mortality. Measurement of AS by applanation tonometry with pulse-wave velocity has been the gold-standard method and is well-validated in large populations as a strong predictor of adverse cardiovascular outcomes. Because aortic stiffness depends on the prevailing blood pressure, effective antihypertensive treatment is expected to reduce it in proportion to the blood pressure reduction. Nevertheless, drugs lowering blood pressure might differ in their effects on structure and function of the arterial walls. This review paper not only will discuss the current understanding and clinical significance of AS but also will review the effects of various pharmacological and nonpharmacological interventions that can be used to preserve the favorable profile of a more compliant and less stiff aorta. © 2011 American College of Cardiology Foundation.

Dupont C.,University of Paris Descartes | Campagne A.,General Practitioner | Constant F.,Nestlé
Clinical Gastroenterology and Hepatology | Year: 2014

Background and Aims: Little is known about the effects of natural mineral water on constipation in adults. We assessed the effect of a magnesium sulfate-rich natural mineral water (Hépar; Nestlé Waters, Issy-les-Moulineaux, France) on gastrointestinal transit in constipated women. Methods: We performed a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of Hépar in outpatients with functional constipation (based on the Rome III criteria). The study included 244 female patients, age 18 to 60 years, identified by 62 general practitioners throughout France. After a washout period, subjects drank 1.5 L natural low-mineral water daily (control, n= 77), 0.5 L Hépar and 1 L natural low-mineral water daily (Hépar 0.5 group, n=85), or 1 L Hépar and 0.5 L natural low-mineral water daily (Hépar 1 group, n= 82) for 4 weeks. We collected information on the number and types of stools, abdominal pain, rescue medications, adverse events, and volume of water consumed. Results: We observed no significant effect at week 1. At week 2, constipation was reduced in 21.1% of patients in the control group, in 30.9% in the Hépar 0.5 group (P= .099 vs controls), and in 37.5% in the Hépar 1 group (P= .013 vs controls). The Hépar 1 group also had a decreased number of hard or lumpy stools (Bristol scale, P= .030 vs baseline) and a substantial decrease in the use of rescue medication (P= .034 vs controls). Patient responses correlated with magnesium sulfate concentrations. Safety was very good; there were no serious adverse events among patients who drank Hépar. Conclusions: In a controlled trial, daily consumption of 1 L Hépar reduced constipation and hard or lumpy stools in a greater percentage of women with functional constipation than natural low-mineral water, as early as the second week of treatment. © 2014 AGA Institute.

Chippaux J.-P.,IRD Montpellier | Chippaux J.-P.,University of Paris Descartes
Journal of Venomous Animals and Toxins Including Tropical Diseases | Year: 2014

The tremendous outbreak of Ebola virus disease occurring in West Africa since the end of 2013 surprises by its remoteness from previous epidemics and dramatic extent. This review aims to describe the 27 manifestations of Ebola virus that arose after its discovery in 1976. It provides an update on research on the ecology of Ebola viruses, modes of contamination and human transmission of the disease that are mainly linked to close contact with an infected animal or a patient suffering from the disease. The recommendations to contain the epidemic and challenges to achieve it are reminded. © 2014 Chippaux; licensee BioMed Central Ltd.

Kaveri S.V.,French Institute of Health and Medical Research | Kaveri S.V.,University Pierre and Marie Curie | Kaveri S.V.,University of Paris Descartes | Kaveri S.V.,Impact Lab
Autoimmunity Reviews | Year: 2012

Antibodies present in healthy conditions in the absence of deliberate immunization or infections are called natural antibodies. A significant proportion of natural antibody pool is believed to interact with self-antigens, and thus is called natural autoantibodies. Natural autoantibodies belong to IgG, IgM and IgA subclasses, and are encoded by V(D)J genes in germline configuration and bind to self molecules with varying affinities. In addition to serving in first line defense mechanism, natural antibodies participate in the homeostasis of the immune system. Intravenous immunoglobulin (IVIg) is a therapeutic preparation that contains substantial amount of natural antibodies exclusively of IgG subclass. In addition to its role in protection against pathogens in primary and secondary immunodeficiency patients, IVIg exerts a number of immunoregulatory functions through its interaction with innate and adaptive immune system and thereby imposing immune homeostasis. © 2012 Elsevier B.V.

Madeo F.,University of Graz | Pietrocola F.,French Institute of Health and Medical Research | Pietrocola F.,University of Paris Descartes | Eisenberg T.,University of Graz | And 3 more authors.
Nature Reviews Drug Discovery | Year: 2014

Caloric restriction, be it constant or intermittent, is reputed to have health-promoting and lifespan-extending effects. Caloric restriction mimetics (CRMs) are compounds that mimic the biochemical and functional effects of caloric restriction. In this Opinion article, we propose a unifying definition of CRMs as compounds that stimulate autophagy by favouring the deacetylation of cellular proteins. This deacetylation process can be achieved by three classes of compounds that deplete acetyl coenzyme A (AcCoA; the sole donor of acetyl groups), that inhibit acetyl transferases (a group of enzymes that acetylate lysine residues in an array of proteins) or that stimulate the activity of deacetylases and hence reverse the action of acetyl transferases. A unifying definition of CRMs will be important for the continued development of this class of therapeutic agents.

Castel P.-H.,University of Paris Descartes | Sass L.,Rutgers University
Philosophy, Psychiatry and Psychology | Year: 2015

This paper aims to show why a systematic history of obsessive and compulsive symptoms (today called OCD) offers more than a special chapter in the history of psychiatry. It opens a window on the genesis of the Western individual by casting new light on the functions of self-restraint, self-control, and the self-monitoring of intentions and moral feelings (guilt, anxiety), as well as on the formation of a sense of individual autonomy and ‘interiority.’ Such a project aligns with Norbert Elias’s notion of the ‘civilizing process,’ but is distinct from Foucault’s views on madness and normalcy. I finally consider contemporary cognitive and behavioral treatments of OCD in light of their participation in this historical process. The efficacy of such treatments might be explained, in large measure, as deriving from their reliance on, and implicit fostering of, contemporary cultural ideals of autonomy. © 2015 by The Johns Hopkins University Press.

Giraud V.,Service de Pneumologie | Allaert F.-A.,British Petroleum | Roche N.,University of Paris Descartes
Respiratory Medicine | Year: 2011

Poor inhaler technique is frequent in asthma, but its long-term consequences have been seldom assessed. Pharmacists are ideally positioned to teach inhaler technique. This prospective observational study evaluated the feasibility of inhaler training by pharmacists in patients receiving inhaled corticosteroids by pressurised metered-dose inhaler (pMDI) or breath-actuated MDI. In parallel, the relationships between inhaler technique, adherence, and asthma control, and their modulation one month after training were assessed. Of 727 patients receiving training at pharmacies (n = 123), 61% were prescribed a pMDI; 35%, an Autohaler ®; and 5%, an Easi-Breathe ® inhaler. Poor asthma control (Asthma Control Questionnaire score ≥1.5) at baseline was significantly (p < 0.05) and independently associated with poor inhaler technique and poor self-reported adherence (Morisky score ≥3). The percentage of patients with optimal inhaler technique rose from 24% before to 79% after training (p < 0.001). Median training session length was 6 min. At 1 month, mean (SD) ACQ score had improved from a baseline score of 1.8 (1.2) to 1.4 (1.1), (p < 0.001). Importantly, greater change was observed in patients with improved inhaler technique versus those without. Similar results were observed for Morisky score. Inhaler technique is associated with adherence and influences asthma control. Inhaler training by pharmacists is feasible and seams to improve inhaler technique, asthma control and adherence. © 2011 Elsevier Ltd. All rights reserved.

Flateau C.,University Pierre and Marie Curie | Flateau C.,Lille University of Science and Technology | Le Loup G.,University Pierre and Marie Curie | Le Loup G.,IRD Montpellier | And 2 more authors.
The Lancet Infectious Diseases | Year: 2011

Despite recent changes in the epidemiology of HIV infection and malaria and major improvements in their control, these diseases remain two of the most important infectious diseases and global health priorities. As they have overlapping distribution in tropical areas, particularly sub-Saharan Africa, any of their clinical, diagnostic, and therapeutic interactions might have important effects on patient care and public health policy. The biological basis of these interactions is well established. HIV infection induces cellular depletion and early abnormalities of CD4+ T cells, decreases CD8+ T-cell counts and function (cellular immunity), causes deterioration of specific antigen responses (humoral immunity), and leads to alteration of innate immunity through impairment of cytolytic activity and cytokine production by natural killer cells. Therefore, HIV infection affects the immune response to malaria, particularly premunition in adolescents and adults, and pregnancy-specific immunity, leading to different patterns of disease in HIV-infected patients compared with HIV-uninfected patients. In this systematic review, we collate data on the effects of HIV on malaria and discuss their therapeutic consequences. HIV infection is associated with increased prevalence and severity of clinical malaria and impaired response to antimalarial treatment, depending on age, immunodepression, and previous immunity to malaria. HIV also affects pregnancy-specific immunity to malaria and response to intermittent preventive treatment. Co-trimoxazole (trimethoprim-sulfamethoxazole) prophylaxis and antiretroviral treatment reduce occurrence of clinical malaria; however, these therapies interact with antimalarial drugs, and new therapeutic guidelines are needed for concomitant use. © 2011 Elsevier Ltd.

Marie I.,University of Rouen | Hatron P.Y.,Lille University of Science and Technology | Dominique S.,University of Rouen | Cherin P.,Hopital Pitie Salpetriere | And 2 more authors.
Arthritis and Rheumatism | Year: 2011

Objective This study was undertaken to assess the characteristics and outcome of interstitial lung disease (ILD) in polymyositis/dermatomyositis (PM/DM) and to determine variables predictive of ILD deterioration in PM/DM. Methods Among 348 consecutive patients with PM/DM, 107 patients with ILD were identified by medical records search in 4 medical centers. All patients underwent pulmonary function tests (PFTs) and pulmonary high-resolution computed tomography (HRCT) scan. Results ILD onset preceded PM/DM clinical manifestations in 20 patients, was identified concurrently with PM/DM in 69 patients, and occurred after PM/DM onset in 18 patients. Patients with ILD could be divided into 3 groups according to their presenting lung manifestations: patients with acute lung disease (n = 20), patients with progressive-course lung signs (n = 55), and asymptomatic patients with abnormalities consistent with ILD evident on PFTs and HRCT scan (n = 32). We observed that 32.7% of the patients had resolution of pulmonary disorders, whereas 15.9% experienced ILD deterioration. Factors that predicted a poor ILD prognosis were older age, symptomatic ILD, lower values of vital capacity and diffusing capacity for carbon monoxide, a pattern of usual interstitial pneumonia on HRCT scan and lung biopsy, and steroid-refractory ILD. The mortality rate was higher in patients with ILD deterioration than in those without ILD deterioration (47.1% versus 3.3%). Conclusion Our findings indicate that ILD results in high morbidity in PM/DM. Our findings also suggest that more aggressive therapy may be required in PM/DM patients presenting with factors predictive of poor ILD outcome. © 2011 by the American College of Rheumatology.

Agency: European Commission | Branch: FP7 | Program: CP | Phase: ICT-2011.8.1 | Award Amount: 4.31M | Year: 2012

Citizen Cyberlab will research and evaluate on-line collaborative environments and software tools that stimulate creative learning in the context of Citizen Cyberscience. Beyond helping scientists execute laborious tasks, Citizen Cyberscience projects enable citizens to learn about science and take part in the more creative aspects of research. Little is known about the learning and creativity processes stimulated by such projects, even though millions of volunteers participate. Even less is known about how to optimize those processes. Citizen Cyberlab will pioneer open source platforms and tools that enable and enhance learning and creativity in Citizen Cyberscience, using four pilot projects as testbeds, including a particle physics game by CERN, and collaborative disaster mapping by the UN Institute for Training and Research. Pioneers in extreme citizen science at University College London will develop a community learning pilot, leading proponents of open science at Universit Paris Descartes will develop a hands-on crowdsourcing pilot in synthetic biology. Platforms and tools developed at Imperial College focus on virtualization of software and device-independent environments that enhance creative learning opportunities by reducing barriers to citizen participation. These pilots, platforms and tools will be evaluated by experts in educational technology and human-computer interaction at University of Geneva and UCL, with a focus on studying and evaluating learning processes and growth in creativity.. This research will produce new understanding of creative learning behaviours, anchored in real-world examples of Citizen Cyberscience. Citizen Cyberlab emphasizes direct participation of citizens at all stages of evaluation and research, in particular via the successful ThinkCamp events developed by The Mobile Collective. Citizen Cyberlab results will be sustained and exploited beyond the project lifetime by the Citizen Cyberscience Centre based at CERN.

French Institute of Health, Medical Research, University of Paris Descartes, French National Center for Scientific Research, Assistance Publique Hopitaux De Paris, University Paris Diderot and Imagine | Date: 2015-09-03

The present invention relates to the treatment or prevention of skeletal disorders, in particular skeletal diseases, developed by patients that display abnormal increased activation of the fibroblast growth factor receptor 3 (FGFR3), in particular by expression of a constitutively activated mutant of FGFR3.

University of Paris Descartes, French National Center for Scientific Research, Institute Curie and Institute Gustave Roussy | Date: 2013-04-17

The present invention provides a novel method for the selection of serum biomarkers of epigenetic alterations, particularly of global hypomethylation, and the use of said biomarkers in a method for screening, diagnosing and following a pathology associated to epigenetic alterations of cell in an individual, such as placental-related pathology or cancer. The present invention also relates to a method of detecting a predisposition to placental-related pathology or cancer based on the presence or the level of said biomarker in a serum or plasma sample of said patient. The present invention also relates to a method for predicting and following the effect of drugs targeting epigenetic modifications and in particular the effect of demethylating agents. The present invention is directed to a kit comprising such serum biomarkers of epigenetic alterations, particularly of global hypomethylation.

Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2014-ETN | Award Amount: 3.85M | Year: 2015

PredictAble aims to train a new generation of young scientists at the crossroads between academic research, technological development in the private sector and clinical practice to pioneer an interdisciplinary approach to language related developmental disorders, like specific language impairment (SLI) and developmental dyslexia (DD). The innovative and timely research program will enhance the understanding of the cognitive mechanisms that underlie developmental disorders of spoken and written language by pooling international experts from academia and the private sector. For the first time, PredictAble applies a truly multidisciplinary and cross-linguistic perspective with a unique and novel combination of cutting-edge approaches and techniques for studying mono- and bilingual children. Thus, PredictAble will provide young researchers with an excellent foundation for making scientific progress in this area, in collaboration with technology development and the transfer of research outcomes to applicants in the private sector and the health sector/clinical practice. Highly recognized experts in the area of language acquisition in very young mono- and bilingual children will work together on the acquisition of spoken and written language in a cross-linguistic approach. The complementarity of the different languages in PredictAble will make it possible to identify language-specific and cross-linguistically valid effects. In cooperation with technological partners from the private sector, PredictAble will optimize recently developed technologies in the area of developmental cognitive neuroscience to render them suitable for use with very young children and as diagnostic tools to detect early risks for language-related impairments.

News Article | February 23, 2017

PARIS and NEW YORK, Feb. 23, 2017 (GLOBE NEWSWIRE) -- Quantum Genomics (Alternext - FR0011648971 - ALQGC), a biopharmaceutical company with the mission of developing new therapies for unmet medical needs in the field of cardiovascular diseases, today presented its financial calendar for 2017: In 2017, Quantum Genomics will also take part in major international conferences: Quantum Genomics is pleased to announce that it recently joined the national Pass French Tech program of the 2016-2017 selection, intended for hyper-growth companies. The primary mission of this program is to provide services to these companies that specifically respond to the issues associated with hyper-growth, including providing access to funding and furthering their international development. To achieve this, the program relies on the services of French organisations such as Bpifrance (innovation bank), the Direction Générale des Entreprises (corporations management committee), Business France (international development), the Compagnie Française d'Assurance pour le Commerce Extérieur (export insurance), the Institut National de la Propriété Industrielle (patents institute), the Association Française des Pôles de Compétitivité (competitiveness clusters association) and the Association Française des Investisseurs pour la Croissance (association of investors for growth). Quantum Genomics is a biopharmaceutical company with the mission of developing new therapies for unmet medical needs in the field of cardiovascular diseases, especially hypertension and heart failure. The Company is developing a new therapeutic approach based on BAPAI (Brain Aminopeptidase A Inhibition). This is the result of more than 20 years of academic research in the laboratories of the Collège de France, INSERM, CNRS and the University of Paris Descartes. Quantum Genomics is listed on the Alternext market in Paris (ISIN code FR0011648971, Ticker ALQGC). The Company has offices in Paris, France, and New York, NY, USA. For more information, please visit

Bova C.,University Hospital of Cosenza | Sanchez O.,University of Paris Descartes | Prandoni P.,University of Padua | Lankeit M.,University of Mainz | And 3 more authors.
European Respiratory Journal | Year: 2014

The identification of normotensive patients with acute pulmonary embolism (PE) at high risk of adverse PE-related clinical events (i.e. intermediate-risk group) is a major challenge. We combined individual patient data from six studies involving 2874 normotensive patients with PE. We developed a prognostic model for intermediate-risk PE based on the clinical presentation and the assessment of right ventricular dysfunction and myocardial injury. We used a composite of PE-related death, haemodynamic collapse or recurrent PE within 30 days of follow-up as the main outcome measure. The primary outcome occurred in 198 (6.9%) patients. Predictors of complications included systolic blood pressure 90-100 mmHg (adjusted odds ratio (aOR) 2.45, 95% CI 1.50-3.99), heart rate ≥110 beats per min (aOR 1.87, 95% CI 1.31-2.69), elevated cardiac troponin (aOR 2.49, 95% CI 1.71-3.69) and right ventricular dysfunction (aOR 2.28, 95% CI 1.58-3.29). We used these variables to construct a multidimensional seven-point risk index; the odds ratio for complications per one-point increase in the score was 1.55 (95% CI 1.43-1.68; p<0.001). The model identified three stages (I, II and III) with 30-day PE-related complication rates of 4.2%, 10.8% and 29.2%, respectively. In conclusion, a simple grading system may assist clinicians in identifying intermediate-risk PE. Copyright ©ERS 2014.

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.

Pierrot-Deseilligny C.,University Pierre and Marie Curie | Souberbielle J.-C.,University of Paris Descartes
Brain | Year: 2010

The role of hypovitaminosis D as a possible risk factor for multiple sclerosis is reviewed. First, it is emphasized that hypovitaminosis D could be only one of the risk factors for multiple sclerosis and that numerous other environmental and genetic risk factors appear to interact and combine to trigger the disease. Secondly, the classical physiological notions about vitamin D have recently been challenged and the main new findings are summarized. This vitamin could have an important immunological role involving a number of organs and pathologies, including autoimmune diseases and multiple sclerosis. Furthermore, human requirements for this vitamin are much higher than previously thought, and in medium-or high-latitude countries, they might not be met in the majority of the general population due to a lack of sunshine and an increasingly urbanized lifestyle. Thereafter, the different types of studies that have helped to implicate hypovitaminosis D as a risk factor for multiple sclerosis are reviewed. In experimental autoimmune encephalomyelitis, vitamin D has been shown to play a significant immunological role. Diverse epidemiological studies suggest that a direct chain of causality exists in the general population between latitude, exposure to the sun, vitamin D status and the risk of multiple sclerosis. New epidemiological analyses from France support the existence of this chain of links. Recently reported immunological findings in patients with multiple sclerosis have consistently shown that vitamin D significantly influences regulatory T lymphocyte cells, whose role is well known in the pathogenesis of the disease. Lastly, in a number of studies on serum levels of vitamin D in multiple sclerosis, an insufficiency was observed in the great majority of patients, including at the earliest stages of the disease. The questionable specificity and significance of such results is detailed here. Based on a final global analysis of the cumulative significance of these different types of findings, it would appear likely that hypovitaminosis D is one of the risk factors for multiple sclerosis. © 2010 The Author(s).

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..

Agut H.,University Pierre and Marie Curie | Agut H.,French Institute of Health and Medical Research | Agut H.,Hopitaux Universitaires Pitie Salpetriere Charles Foix | Bonnafous P.,University Pierre and Marie Curie | And 5 more authors.
Clinical Microbiology Reviews | Year: 2015

Human herpesvirus 6 (HHV-6) is a widespread betaherpesvirus which is genetically related to human cytomegalovirus (HCMV) and now encompasses two different species: HHV-6A and HHV-6B. HHV-6 exhibits a wide cell tropism in vivo and, like other herpesviruses, induces a lifelong latent infection in humans. As a noticeable difference with respect to other human herpesviruses, genomic HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6) in about 1% of the general population. Although it is infrequent, this may be a confounding factor for the diagnosis of active viral infection. The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Many active HHV-6 infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. However, the virus may be the cause of serious diseases, particularly in immunocompromised individuals. As emblematic examples of HHV-6 pathogenicity, exanthema subitum, a benign disease of infancy, is associated with primary infection, whereas further virus reactivations can induce severe encephalitis cases, particularly in hematopoietic stem cell transplant recipients. Generally speaking, the formal demonstration of the causative role of HHV-6 in many acute and chronic human diseases is difficult due to the ubiquitous nature of the virus, chronicity of infection, existence of two distinct species, and limitations of current investigational tools. The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active HHV-6 infections, but the indications for treatment, as well as the conditions of drug administration, are not formally approved to date. There are still numerous pending questions about HHV-6 which should stimulate future research works on the pathophysiology, diagnosis, and therapy of this remarkable human virus. © 2015, American Society for Microbiology. All Rights Reserved.

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.

Meeus L.,University of Florence | Meeus L.,Catholic University of Leuven | Saguan M.,University of Paris Descartes
Renewable Energy | Year: 2011

In the current context of a decarbonizing electricity system, grid innovation is needed to deal with the main challenges of integrating distributed generation, demand and storage, and large-scale renewable energy sources. Grid companies however have disincentives to innovate under the conventional regulatory framework, and if they do innovate, they are confronted with grid users that have disincentives to participate in the innovation. This paper analyzes three empirical cases where state of the art regulatory frameworks have been successful at stimulating grid innovation. The main lesson learned from the cases is that there is experience with addressing the disincentive of grid companies to innovate, but the participation of grid users in the innovation is much more an open issue. © 2010 Elsevier Ltd.

Foretz M.,French Institute of Health and Medical Research | Foretz M.,French National Center for Scientific Research | Foretz M.,University of Paris Descartes | Guigas B.,Leiden University | And 5 more authors.
Cell Metabolism | Year: 2014

Metformin is currently the first-line drug treatment for type 2 diabetes. Besides its glucose-lowering effect, there is interest in actions of the drug of potential relevance to cardiovascular diseases and cancer. However, the underlying mechanisms of action remain elusive. Convincing data place energy metabolism at the center of metformin's mechanism of action in diabetes and may also be of importance in cardiovascular diseases and cancer. Metformin-induced activation of the energy-sensor AMPK is well documented, but may not account for all actions of the drug. Here, we summarize current knowledge about the different AMPK-dependent and AMPK-independent mechanisms underlying metformin action. © 2014 Elsevier Inc.

Sieper J.,Charité - Medical University of Berlin | Porter-Brown B.,Roche Holding AG | Thompson L.,Roche Holding AG | Harari O.,Roche Holding AG | Dougados M.,University of Paris Descartes
Annals of the Rheumatic Diseases | Year: 2014

Objectives BUILDER-1 and BUILDER-2 aimed to assess the efficacy and safety of tocilizumab (TCZ) in patients with ankylosing spondylitis (AS). Methods BUILDER-1 was a two part, phase II-III parallel-group trial in patients with AS naive to antitumour necrosis factor (aTNF) treatment. Patients in part 1 received TCZ 8 mg/kg or placebo for 12 weeks. In part 2 (beginning after part 1 enrolment ended), newly enrolled patients received TCZ 4 or 8 mg/kg or placebo for 24 weeks. The same treatment arms were used in BUILDER-2, a phase III study in aTNF-inadequate responders. The primary endpoint for both studies was the proportion of patients achieving 20% improvement in the Assessments in Axial SpondyloArthritis international Society (ASAS). Secondary and exploratory endpoints included ASAS40 response rates, Bath Ankylosing Spondylitis Disease Activity Index improvement, changes in joint counts, enthesitis score and C reactive protein (CRP). Results 102 patients were randomised in BUILDER-1 part 1; 99 (48 TCZ, 51 placebo) completed 12 weeks. Week 12 ASAS20 response rates were 37.3% and 27.5% in the TCZ and placebo arms, respectively (p=0.2823). Secondary and exploratory endpoints did not differ between treatment arms. CRP levels declined with TCZ treatment, suggesting adequate IL-6 receptor blockade. As a result, BUILDER-1 part 2 and BUILDER-2 were terminated. TCZ safety results were consistent with previous observations in rheumatoid arthritis, except for a cluster of anaphylactic and hypersensitivity events at Bulgarian study sites. No apparent explanation for this clustering could be found. Conclusions BUILDER-1 failed to demonstrate TCZ efficacy in treating aTNF-naive patients with AS.

Baker M.,Telecom ParisTech | Bernard F.-X.,University of Paris Descartes | Dumez-Feroc I.,University of Poitiers
Journal of Computer Assisted Learning | Year: 2012

We present an analysis of a longitudinal case study whose aim was to understand the processes of integration of a face-to-face and networked collaborative learning technology and pedagogy into a secondary school history-geography classroom. Students carried out a sequence of argumentative tasks relating to sustainable development, including argument generation, sharing and elaboration, debate using a computer-mediated communication, and organization of arguments in a shared diagram. Students' interactions and diagrams were analysed in terms of degree and quality of argumentativity, as well as catachresis ('getting round' the software to perform a non-prescribed task). Results run counter to positive systems of ideas and values concerning collaborative learning and its technological mediation in that the scenario did not meet its pedagogical aims, having to be abandoned before its planned end. We discuss possible explanations for this 'failure story' in terms of the articulation between everyday, technology-related and educational discourse genres, with their associated social milieux, as well as the social structure of the classroom. The relevance of these aspects for future attempts to integrate such technologies is discussed. In conclusion, we discuss a vision of learning that takes into account students who do not accept to play the educational game. © 2011 Blackwell Publishing Ltd.

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.

Church S.E.,French Institute of Health and Medical Research | Church S.E.,University of Paris Descartes | Church S.E.,University Pierre and Marie Curie | Galon J.,French Institute of Health and Medical Research | And 2 more authors.
Immunity | Year: 2015

Predicting cancer patients' response to therapy is essential for curing disease and improving quality of life. Garraway and colleagues demonstrate that the frequency and number of neoantigens, non-synonymous mutations, and adaptive immune genes, but not the assessment of individual recurrent neoantigens or mutations, predicts patient responses to immunotherapy. © 2015 Elsevier Inc.

Ferre S.,U.S. National Institutes of Health | Casado V.,University of Barcelona | Casado V.,Research Center Biomedica en Red sobre Enfermedades Neurodegenerativas | Devi L.A.,Mount Sinai School of Medicine | And 9 more authors.
Pharmacological Reviews | Year: 2014

Most evidence indicates that, as for family C G protein-coupled receptors (GPCRs), family A GPCRs form homo- and heteromers. Homodimers seem to be a predominant species, with potential dynamic formation of higher-order oligomers, particularly tetramers. Although monomeric GPCRs can activate G proteins, the pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein may provide a main functional unit, and oligomeric entities can be viewed as multiples of dimers. It still needs to be resolved if GPCR heteromers are preferentially heterodimers or if they are mostly constituted by heteromers of homodimers. Allosteric mechanisms determine a multiplicity of possible unique pharmacological properties of GPCR homomers and heteromers. Some general mechanisms seemto apply, particularly at the level of ligand-binding properties. In the frame of the dimer-cooperativity model, the two-state dimer model provides the most practical method to analyze ligand-GPCR interactions when considering receptor homomers. In addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to different intrinsic efficacy of ligands for different signaling pathways (functional selectivity). This gives a rationale for the use of GPCR oligomers, and particularly heteromers, as novel targets for drug development. Herein, we review the functional and pharmacological properties of GPCR oligomers and provide some guidelines for the application of discrete direct screening and highthroughput screening approaches to the discovery of receptor-heteromer selective compounds.

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.

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.

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.

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.

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.

Galon J.,French Institute of Health and Medical Research | Galon J.,University of Paris Descartes | Galon J.,University Pierre and Marie Curie | Angell H.,French Institute of Health and Medical Research | And 5 more authors.
Immunity | Year: 2013

Numerous analyses of large patient cohorts identified specific patterns of immune activation associated with patient survival. We established these as the immune contexture, encompassing the type, functional orientation, density, and location of adaptive immune cells within distinct tumor regions. Based on the immune contexture, a standardized, powerful immune stratification system, the Immunoscore, was delineated. The immune contexture is characterized by immune signatures also observed in association with the broader phenomenon of immune-mediated, tissue-specific destruction. We defined these as the immunologic constant of rejection. Predictive, prognostic, and mechanistic immune signatures overlap, and a continuum of intratumor immune reactions exists. The balance between tumor cell growth and elimination may be tippedupon a crescendo induced by immune manipulations aimed at enhancing naturally occurring immunosurveillance. Here, we propose a broader immunological interpretation of these three concepts-immune contexture, Immunoscore, and immunologic constant of rejection-that segregates oncogenic processes independently of their tissue origin. © 2013 Elsevier Inc.

Angell H.,French Institute of Health and Medical Research | Angell H.,University of Paris Descartes | Angell H.,University Pierre and Marie Curie | Galon J.,French Institute of Health and Medical Research | And 2 more authors.
Current Opinion in Immunology | Year: 2013

The inherent complexity of multifactorial diseases such as cancer renders the process of patient prognosis and prediction of response to therapy extremely difficult. Many markers, signatures, and methods have been described to evaluate the prognosis of cancer patients, yet very few translate into the clinic. Systems biology approaches have facilitated analysis of the complex interaction between tumors and the host-immune response, and allowed the definition of the immune contexture. Here we review the potential of the immune contexture, quantified by the Immunoscore, to provide a statistically strong parameter for prognosis. Finally we introduce the concept that the host-immune reaction could be the critical element in determining response to therapy. The effect on the immune response could be the underlying factor behind many of the predictive markers. © 2013 Elsevier Ltd.

Fridman W.H.,French Institute of Health and Medical Research | Fridman W.H.,University Pierre and Marie Curie | Fridman W.H.,University of Paris Descartes | Fridman W.H.,Georges Pompidou European Hospital | And 11 more authors.
Nature Reviews Cancer | Year: 2012

Tumours grow within an intricate network of epithelial cells, vascular and lymphatic vessels, cytokines and chemokines, and infiltrating immune cells. Different types of infiltrating immune cells have different effects on tumour progression, which can vary according to cancer type. In this Opinion article we discuss how the context-specific nature of infiltrating immune cells can affect the prognosis of patients. © 2012 Macmillan Publishers Limited. 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.

Martinelli P.,French National Center for Scientific Research | Martinelli P.,University of Paris Descartes | Sperduti M.,French National Center for Scientific Research | Sperduti M.,University of Paris Descartes | And 2 more authors.
Human Brain Mapping | Year: 2013

The self has been the topic of philosophical inquiry for centuries. Neuropsychological data suggest that the declarative self can be fractionated into three functionally independent systems processing personal information at several levels of abstraction, including episodic memories of one's own life (episodic autobiographical memory, EAM), semantic knowledge of facts about one's own life (semantic autobiographical memory, SAM), and semantic summary representations of one's personal identity (conceptual self, CS). Our proposal here was to present a comprehensive description of the neural networks underpinning self-representations. To this aim, we performed three meta-analyses, one each for EAM, SAM, and CS, using the activation likelihood estimation (ALE) method. We expected a shift from posterior to anterior structures associated with the incrementally increasing level of abstraction of self-representations. The key finding was that EAM predominantly activates posterior and limbic regions including hippocampus. SAM is associated with anterior activations and also posterior and limbic activations in a lesser degree than EAM. CS mainly recruits medial prefrontal structures. Interestingly, medial prefrontal cortex is activated irrespective of the level of abstraction, but a more caudal part is recruited during CS, while SAM and EAM activate more rostral portions. To conclude, in line with the previous proposals, our results corroborate the idea that the declarative self is not monolithic but a multidimensional construct comprising distinct representations at different levels of abstraction. © 2012 Wiley Periodicals, Inc.

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.

Amar L.,University of Paris Descartes | Plouin P.-F.,University of Paris Descartes | Steichen O.,University Pierre and Marie Curie
Orphanet Journal of Rare Diseases | Year: 2010

Surgically correctable forms of primary aldosteronism are characterized by unilateral aldosterone hypersecretion and renin suppression, associated with varying degrees of hypertension and hypokalemia. Unilateral aldosterone hypersecretion is caused by an aldosterone-producing adenoma (also known as Conn's adenoma and aldosteronoma), primary unilateral adrenal hyperplasia and rare cases of aldosterone-producing adrenocortical carcinoma. In these forms, unilateral adrenalectomy can cure aldosterone excess and hypokalemia, but not necessarily hypertension. The prevalence of primary aldosteronism in the general population is not known. Its prevalence in referred hypertensive populations is estimated to be between 6 and 13%, of which 1.5 to 5% have an aldosterone-producing adenoma or primary unilateral adrenal hyperplasia. Taking into account referral biases, the prevalence of surgically correctable primary aldosteronism is probably less than 1.5% in the hypertensive population and less than 0.3% in the general adult population. Surgically correctable primary aldosteronism is sought in patients with hypokalemic, severe or resistant forms of hypertension. Recent recommendations suggest screening for primary aldosteronism using the aldosterone to renin ratio. Patients with a raised ratio then undergo confirmatory suppression tests. The differential diagnosis of hypokalemic hypertension with low renin includes mineralocorticoid excess, with the mineralocorticoid being cortisol or 11-deoxycorticosterone, apparent mineralocorticoid excess, pseudo-hypermineralocorticoidism in Liddle syndrome or exposure to glycyrrhizic acid. Once the diagnosis is confirmed, adrenal computed tomography is performed for all patients. If surgery is considered, taking into consideration the clinical context and the desire of the patient, adrenal vein sampling is performed to detect whether or not aldosterone hypersecretion is unilateral. Laparoscopic surgery for unilateral aldosterone hypersecretion is associated with a morbidity of about 8%, with most complications being minor. It generally results in the normalization of aldosterone secretion and kalemia, and in a large decrease in blood pressure, but normotension without treatment is only achieved in half of all cases. Normotension following adrenalectomy is more frequent in young patients with recent hypertension than in patients with long-standing hypertension or a family history of hypertension. © 2010 Amar et al; licensee BioMed Central Ltd.

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.

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.

Fautrel B.,University Pierre and Marie Curie | Combe B.,Montpellier University Hospital Center | Rincheval N.,Institut Universitaire de France | Dougados M.,University of Paris Descartes
Annals of the Rheumatic Diseases | Year: 2012

Background: In 2010, new classification criteria for rheumatoid arthritis (RA) were developed. Objective: To assess agreement between 1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria and the potential source of discordance, based on ESPOIR cohort data. Methods: 813 early arthritis patients were included in ESPOIR between 2002 and 2005. Between-criteria agreement was based on the κ coefficient. Discordance was explored by logistic regression. Results: Data for 811 patients were available, with their main characteristics as follows: women 77%, swollen joint count 7.2, tender joint count 8.4, disease activity score in 28 joints 5.2, rheumatoid factor 46%, anticitrullinated protein antibody (ACPA) 39%, structural damage 22%. At baseline, 579 (71.4%) patients met the 1987 ACR criteria and 641 (79.0%) the 2010 criteria. Agreement at baseline was discordant for 168 patients: 115 satisfied the 2010 criteria and 53 the 1987 criteria. Concordance between the two sets was fair, with a κ coefficient of 0.45 and 0.42 at baseline and year 2, respectively. The main sources of discordance were the number and symmetry of joint involvement, as well as ACPA status. Conclusion: 2010 ACR/EULAR criteria identified more patients with RA than did 1987 criteria. The 2010 criteria failed to identify RA patients with symmetrical seronegative arthritis and limited joint involvement.

Hein E.,University of Paris Descartes | Hein E.,French National Center for Scientific Research | Moore C.M.,University of Iowa
Journal of Experimental Psychology: Human Perception and Performance | Year: 2012

We live in a dynamic environment in which objects change location over time. To maintain stable object representations the visual system must determine how newly sampled information relates to existing object representations, the correspondence problem. Spatiotemporal information is clearly an important factor that the visual system takes into account when solving the correspondence problem, but is feature information irrelevant as some theories suggest? The Ternus display provides a context in which to investigate solutions to the correspondence problem. Two sets of three horizontally aligned disks, shifted by one position, were presented in alternation. Depending on how correspondence is resolved, these displays are perceived either as one disk "jumping" from one end of the row to the other (element motion) or as a set of three disks shifting back and forth together (group motion). We manipulated a feature (e.g., color) of the disks such that, if features were taken into account by the correspondence process, it would bias the resolution of correspondence toward one version or the other. Features determined correspondence, whether they were luminance-defined or not. Moreover, correspondence could be established on the basis of similarity, when features were not identical between alternations. Finally, the stronger the feature information supported a certain correspondence solution the more it dominated spatiotemporal information. © 2012 American Psychological Association.

Pierrot-Deseilligny C.,University Pierre and Marie Curie | Souberbielle J.-C.,University of Paris Descartes
Therapeutic Advances in Neurological Disorders | Year: 2013

The contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis (MS) is reviewed. Among the multiple recently discovered actions of vitamin D, an immunomodulatory role has been documented in experimental autoimmune encephalomyelitis and in humans. This action in the peripheral immune system is currently the main known mechanism through which vitamin D might influence MS, but other types of actions could be involved within the central nervous system. Furthermore, vitamin D insufficiency is widespread in temperate countries and in patients with MS at the earliest stages of the disease, suggesting that the deleterious effects related to vitamin D insufficiency may be exerted in these patients. In fact, many genetic and environmental risk factors appear to interact and contribute to MS. In genetics, several human leukocyte antigen (HLA) alleles (more particularly HLA-DRB1*1501) could favour the disease whereas some others could be protective. Some of the genes involved in vitamin D metabolism (e.g. CYP27B1) also play a significant role. Furthermore, three environmental risk factors have been identified: past Epstein-Barr virus infection, vitamin D insufficiency and cigarette smoking. Interactions between genetic and environmental risk or protective factors may occur during the mother's pregnancy and could continue during childhood and adolescence and until the disease is triggered in adulthood, therefore possibly modulating the MS risk throughout the first decades of life. Furthermore, some clinical findings already strongly suggest that vitamin D status influences the relapse rate and radiological lesions in patients with MS, although the results of adequately powered randomized clinical trials using vitamin D supplementation have not yet been reported. While awaiting these incontrovertible results, which might be long in coming, patients with MS who are currently in vitamin D insufficiency should be supplemented, at least for their general health status, using moderate doses of the vitamin. © The Author(s), 2013.

Poupeau A.,French Institute of Health and Medical Research | Postic C.,French Institute of Health and Medical Research | Postic C.,French National Center for Scientific Research | Postic C.,University of Paris Descartes
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2011

There is a worldwide epidemic of obesity and type 2 diabetes, two major public health concerns associated with alterations in both insulin and glucose signaling pathways. Glucose is not only an energy source but also controls the expression of key genes involved in energetic metabolism, through the glucose-signaling transcription factor, Carbohydrate Responsive Element Binding Protein (ChREBP). ChREBP has emerged as a central regulator of de novo fatty acid synthesis (lipogenesis) in response to glucose under both physiological and physiopathological conditions. Glucose activates ChREBP by regulating its entry from the cytosol to the nucleus, thereby promoting its binding to carbohydrate responsive element (ChoRE) in the promoter regions of glycolytic (L-PK) and lipogenic genes (ACC and FAS). We have previously reported that the inhibition of ChREBP in liver of obese ob/ob mice improves the metabolic alterations linked to obesity, fatty liver and insulin-resistance. Therefore, regulating ChREBP activity could be an attractive target for lipid-lowering therapies in obesity and diabetes. However, before this is possible, a better understanding of the mechanism(s) regulating its activity is needed. In this review, we summarize recent findings on the role and regulation of ChREBP and particularly emphasize on the cross-regulations that may exist between key nuclear receptors (LXR, TR, HNF4α) and ChREBP for the control of hepatic glucose metabolism. These novel molecular cross-talks may open the way to new pharmacological opportunities. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease. © 2011 Elsevier B.V.

Gentric G.,French Institute of Health and Medical Research | Gentric G.,French National Center for Scientific Research | Gentric G.,University of Paris Descartes | Desdouets C.,French Institute of Health and Medical Research | And 2 more authors.
American Journal of Pathology | Year: 2014

Polyploidy (alias whole genome amplification) refers to organisms containing more than two basic sets of chromosomes. Polyploidy was first observed in plants more than a century ago, and it is known that such processes occur in many eukaryotes under a variety of circumstances. In mammals, the development of polyploid cells can contribute to tissue differentiation and, therefore, possibly a gain of function; alternately, it can be associated with development of disease, such as cancer. Polyploidy can occur because of cell fusion or abnormal cell division (endoreplication, mitotic slippage, or cytokinesis failure). Polyploidy is a common characteristic of the mammalian liver. Polyploidization occurs mainly during liver development, but also in adults with increasing age or because of cellular stress (eg, surgical resection, toxic exposure, or viral infections). This review will explore the mechanisms that lead to the development of polyploid cells, our current state of understanding of how polyploidization is regulated during liver growth, and its consequence on liver function. © 2014 American Society for Investigative Pathology.

Chazaud B.,French Institute of Health and Medical Research | Chazaud B.,French National Center for Scientific Research | Chazaud B.,University of Paris Descartes
Immunobiology | Year: 2014

Macrophages, and more broadly inflammation, have been considered for a long time as bad markers of tissue homeostasis. However, if it is indisputable that macrophages are associated with many diseases in a deleterious way, new roles have emerged, showing beneficial properties of macrophages during tissue repair and regeneration. This discrepancy is likely due to the high plasticity of macrophages, which may exhibit a wide range of phenotypes and functions depending on their environment. Therefore, regardless of their role in immunity, macrophages play a myriad of roles in the maintenance and recovery of tissue homeostasis. They take a major part in the resolution of inflammation. They also exert various effects of parenchymal cells, including stem and progenitor cell, of which they regulate the fate. In the present review, few examples from various tissues are presented to illustrate that, beyond their specific properties in a given tissue, common features have been described that sustain a role of macrophages in the recovery and maintenance of tissue homeostasis. © 2013 Elsevier GmbH.

Phin N.,Public Health England | Phin N.,University of Chester | Parry-Ford F.,Public Health England | Harrison T.,Public Health England | And 6 more authors.
The Lancet Infectious Diseases | Year: 2014

Legionnaires' disease is an important cause of community-acquired and hospital-acquired pneumonia. Although uncommon, Legionnaires' disease continues to cause disease outbreaks of public health significance. The disease is caused by any species of the Gram-negative aerobic bacteria belonging to the genus Legionella; Legionella pneumophila serogroup 1 is the causative agent of most cases in Europe. In this Review we outline the global epidemiology of Legionnaires' disease, summarise its diagnosis and management, and identify research gaps and priorities. Early clinical diagnosis and prompt initiation of appropriate antibiotics for Legionella spp in all patients with community-acquired or hospital-acquired pneumonias is a crucial measure for management of the disease. Progress in typing and sequencing technologies might additionally contribute to understanding the distribution and natural history of Legionnaires' disease, and inform outbreak investigations. Control of Legionnaires' disease outbreaks relies on rapid ascertainment of descriptive epidemiological data, combined with microbiological information to identify the source and implement control measures. Further research is required to define the actual burden of disease, factors that influence susceptibility, key sources of infection, and differences in virulence between strains of Legionella species. Other requirements are improved, specific, sensitive, and rapid diagnostic tests to accurately inform management of Legionnaires' disease, and controlled clinical trials to ascertain the optimum antibiotics for treatment. © 2014 Elsevier Ltd.

Subar D.,Royal Blackburn Hospital | Gobardhan P.D.,Amphia Hospital | Gayet B.,University of Paris Descartes
Best Practice and Research: Clinical Gastroenterology | Year: 2014

Pancreatic surgery was reported as early as 1898. Since then significant developments have been made in the field of pancreatic resections. In addition, advances in laparoscopic surgery in general have seen the description of this approach in pancreatic surgery with increasing frequency. Although there are no randomized controlled trials, several large series and comparative studies have reported on the short and long term outcome of laparoscopic pancreatic surgery. Furthermore, in the last decade published systematic reviews and meta-analyses have reported on cost effectiveness and outcomes of these procedures. © 2013 Elsevier Ltd. All rights reserved.

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.

Samuel M.A.,University of Paris Descartes | Samuel M.A.,Massachusetts Eye and Ear Infirmary
Nature neuroscience | Year: 2014

Age-related decreases in neural function result in part from alterations in synapses. To identify molecular defects that lead to such changes, we focused on the outer retina, in which synapses are markedly altered in old rodents and humans. We found that the serine/threonine kinase LKB1 and one of its substrates, AMPK, regulate this process. In old mice, synaptic remodeling was accompanied by specific decreases in the levels of total LKB1 and active (phosphorylated) AMPK. In the absence of either kinase, young adult mice developed retinal defects similar to those that occurred in old wild-type animals. LKB1 and AMPK function in rod photoreceptors where their loss leads to aberrant axonal retraction, the extension of postsynaptic dendrites and the formation of ectopic synapses. Conversely, increasing AMPK activity genetically or pharmacologically attenuates and may reverse age-related synaptic alterations. Together, these results identify molecular determinants of age-related synaptic remodeling and suggest strategies for attenuating these changes.

Irtan S.,University of Paris Descartes | Orbach D.,University Pierre and Marie Curie | Helfre S.,University Pierre and Marie Curie | Sarnacki 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. © 2013 Elsevier Ltd.

Georgelin T.,University Pierre and Marie Curie | Bombard S.,University of Paris Descartes | Siaugue J.-M.,University Pierre and Marie Curie | Cabuil V.,University Pierre and Marie Curie
Angewandte Chemie - International Edition | Year: 2010

Direct delivery: Multifunctionalized magnetic nanoparticles, which are highly stable and positively charged, induce strong interactions with cells and nuclei, thus confining bleomycin (BLM) close to its DNA target (see picture; PEG=polyethylene glycol). Grafted BLM can induce significant damage in DNA and cancerous cells. © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Savard S.,Georges Pompidou European Hospital | Amar L.,Georges Pompidou European Hospital | Amar L.,University of Paris Descartes | Plouin P.-F.,Georges Pompidou European Hospital | And 3 more authors.
Hypertension | Year: 2013

A higher risk of cardiovascular events has been reported in patients with primary aldosteronism (PA) than in otherwise similar patients with essential hypertension (EH). However, the evidence is limited by small sample size and potential confounding factors. We, therefore, compared the prevalence of cardiovascular events in 459 patients with PA diagnosed in our hypertension unit from 2001 to 2006 and 1290 controls with EH. PA cases and EH controls were individually matched for sex, age (±2 years), and office systolic blood pressure (±10 mm Hg). Patients with PA and EH differed significantly in duration of hypertension, serum potassium, plasma aldosterone and plasma renin concentrations, aldosterone-to-renin ratio, and urinary aldosterone concentration (P<0.001 for all comparisons). The prevalence of electrocardiographic and echocardiographic left ventricular hypertrophy was about twice higher in patients with PA even after adjustment for hypertension duration. PA patients also had a significantly higher prevalence of coronary artery disease (adjusted odds ratio, 1.9), nonfatal myocardial infarction (adjusted odds ratio, 2.6), heart failure (adjusted odds ratio, 2.9), and atrial fibrillation (adjusted odds ratio, 5.0). The risks associated with PA were similar across levels of serum potassium and plasma aldosterone. To conclude, patients with PA are more likely to have had a cardiovascular complication at diagnosis than otherwise similar patients with EH. Target organ damage and complications disproportionate to blood pressure should be considered as an additional argument for suspecting PA in a given individual and possibly for broadening the scope of screening at the population level. © 2013 American Heart Association, Inc.

Fernandez I.,University of Paris Descartes | Touraine P.,University Pierre and Marie Curie | Goffin V.,University of Paris Descartes
Journal of Neuroendocrinology | Year: 2010

The involvement of prolactin in human tumourogenesis has been long debated. The reason is that the evidence supporting the role of circulating prolactin in promoting breast cancer was mainly obtained using rodent models, whereas most of the studies performed in human species in the 1980s have remained inconclusive. Things have now started to change because two alternative mechanisms of prolactin actions in tumour growth have emerged since the beginning of the 21st Century. The first involves locally-produced prolactin, which acts by an autocrine/paracrine mechanism. Genetically-modified mouse models have demonstrated the tumourigenic potential of local prolactin on the prostate and the mammary gland, and arguments are now emerging in humans also. The second mechanism involves genetic variants of the receptor. Although no genetic disorder has been reported for prolactin or its receptor, a variant of the prolactin receptor exhibiting constitutive activity has been recently identified in patients presenting with breast tumours, suggesting that sustained prolactin signalling may participate in breast tumourogenesis. Recent data regarding these two nonclassical mechanisms of prolactin action are discussed. Finally, we address the question of their inhibition in future cancer therapy, both in light of other findings that have revealed novel actions of prolactin in breast cancer cells, and with respect to the compounds currently available to target prolactin receptor signalling. © 2010 The Authors. Journal Compilation © 2010 Blackwell Publishing Ltd.

Scharfmann R.,University of Paris Descartes | Rachdi L.,University of Paris Descartes | Ravassard P.,University Pierre and Marie Curie
Stem Cells Translational Medicine | Year: 2013

It is well-established that insulin-producing pancreatic beta cells are central in diabetes. In type 1 diabetes, beta cells are destroyed by an autoimmune mechanism, whereas in type 2 diabetes, there is a decrease in functional beta-cell mass. In this context, studying beta cells is of major importance. Beta cells represent only 1% of total pancreatic cells and are found dispersed in the pancreatic gland. During the past decades, many tools and approaches have been developed to study rodent beta cells that efficiently pushed the field forward. However, rodent and human beta cells are not identical, and our knowledge of human beta cells has not progressed as quickly as our understanding of rodent beta cells. We believe that one of the reasons for this inefficient progress is the difficulty of accessing unlimited sources of functional human pancreatic beta cells. The main focus of this review concerns recent strategies to generate new sources of human pancreatic beta cells. © AlphaMed Press.

Traiffort E.,French National Center for Scientific Research | O'Regan S.,University of Paris Descartes | Ruat M.,French National Center for Scientific Research
Molecular Aspects of Medicine | Year: 2013

The Na+-independent, high affinity choline carrier system proposed to supply choline for the synthesis of cell membrane phospholipids was recently associated with SLC44 family members (SLC44A1-5) also called choline-like transporter family. SLC44A1 is widely expressed throughout the nervous system in both neurons and oligodendrocytes, while SLC44A2-4 are mainly detected in peripheral tissues. The subcellular localization of the proteins was mainly addressed for SLC44A1 through the development of specific antibodies. SLC44A1 is detected in both the plasma and mitochondrial membranes where the protein is able to transport choline at high affinity and in a Na +-independent manner. The physiological relevance of SLC44A1 as a choline carrier is indicated by its likely involvement in membrane synthesis for cell growth or repair, and also by its role in phospholipid production for the generation of lung surfactant. Moreover, an autoimmune disease has been related to the blockade of SLC44A2 function, which results in the alteration of hair cells in the inner ear and leads to autoimmune hearing loss. In the alloimmune syndrome called transfusion-related acute lung injury, antibodies to SLC44A2 cause a deleterious aggregation of granulocytes. Therefore transporters of the SLC44 family represent attractive and promising targets for therapeutic and diagnostic applications regarding both immune and degenerative diseases. © 2012 Elsevier Ltd. All rights reserved.

Eladari D.,University of Paris Descartes | Eladari D.,University Pierre and Marie Curie | Chambrey R.,University of Paris Descartes | Chambrey R.,University Pierre and Marie Curie | Peti-Peterdi J.,University of Southern California
Annual Review of Physiology | Year: 2012

The distal nephron plays a critical role in the renal control of homeostasis. Until very recently most studies focused on the control of Na +, K +, and water balance by principal cells of the collecting duct and the regulation of solute and water by hormones from the renin-angiotensin-aldosterone system and by antidiuretic hormone. However, recent studies have revealed the unexpected importance of renal intercalated cells, a subtype of cells present in the connecting tubule and collecting ducts. Such cells were thought initially to be involved exclusively in acid-base regulation. However, it is clear now that intercalated cells absorb NaCl and K + and hence may participate in the regulation of blood pressure and potassium balance. The second paradigm-challenging concept we highlight is the emerging importance of local paracrine factors that play a critical role in the renal control of water and electrolyte balance. Copyright © 2012 by Annual Reviews. All rights reserved.

Benmerah A.,French Institute of Health and Medical Research | Benmerah A.,French National Center for Scientific Research | Benmerah A.,University of Paris Descartes
Current Opinion in Cell Biology | Year: 2013

Cilia are fascinating highly conserved organelles shared by very different organisms from unicellular eukaryotes to vertebrates where they are involved in motility and sensory functions. In vertebrates, the function of the primary cilium, a unique nonmotile cilium found at the surface of most cell types during development, remained mysterious during 40 years until its crucial function in the control of key signaling cascades during development and its involvement in complex genetic disorders now called ciliopathies were uncovered. Recent studies have focused on a specific membrane domain found at the base of primary cilia in most cell types which was already mentioned in the first descriptions of these cilia but did not raise much interest during 50 years. This membrane domain, the 'ciliary pocket', also found at the base of some motile cilia, may act as a platform for cilia-associated vesicular trafficking and as an interface with the actin cytoskeleton but also likely in additional important functions which remain to be discovered. © 2012 Elsevier Ltd.

Ostojic S.,Columbia University | Ostojic S.,University Pierre and Marie Curie | Brunel N.,University of Paris Descartes
PLoS Computational Biology | Year: 2011

Neurons transform time-varying inputs into action potentials emitted stochastically at a time dependent rate. The mapping from current input to output firing rate is often represented with the help of phenomenological models such as the linearnonlinear (LN) cascade, in which the output firing rate is estimated by applying to the input successively a linear temporal filter and a static non-linear transformation. These simplified models leave out the biophysical details of action potential generation. It is not a priori clear to which extent the input-output mapping of biophysically more realistic, spiking neuron models can be reduced to a simple linear-nonlinear cascade. Here we investigate this question for the leaky integrate-andfire (LIF), exponential integrate-and-fire (EIF) and conductance-based Wang-Buzsáki models in presence of background synaptic activity. We exploit available analytic results for these models to determine the corresponding linear filter and static non-linearity in a parameter-free form. We show that the obtained functions are identical to the linear filter and static nonlinearity determined using standard reverse correlation analysis. We then quantitatively compare the output of the corresponding linear-nonlinear cascade with numerical simulations of spiking neurons, systematically varying the parameters of input signal and background noise. We find that the LN cascade provides accurate estimates of the firing rates of spiking neurons in most of parameter space. For the EIF and Wang-Buzsáki models, we show that the LN cascade can be reduced to a firing rate model, the timescale of which we determine analytically. Finally we introduce an adaptive timescale rate model in which the timescale of the linear filter depends on the instantaneous firing rate. This model leads to highly accurate estimates of instantaneous firing rates. © 2011 Ostojic, Brunel.

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.

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.

Nejad A.B.,Ap Hp Service University Of Psychiatrie Of Ladulte Et Du Sujet Age | Nejad A.B.,University Pierre and Marie Curie | Fossati P.,University Pierre and Marie Curie | Lemogne C.,Ap Hp Service University Of Psychiatrie Of Ladulte Et Du Sujet Age | And 2 more authors.
Frontiers in Human Neuroscience | Year: 2013

Major depression is associated with a bias toward negative emotional processing and increased self-focus, i.e., the process by which one engages in self-referential processing. The increased self-focus in depression is suggested to be of a persistent, repetitive and self-critical nature, and is conceptualized as ruminative brooding. The role of the medial prefrontal cortex in self-referential processing has been previously emphasized in acute major depression. There is increasing evidence that self-referential processing as well as the cortical midline structures play a major role in the development, course, and treatment response of major depressive disorder. However, the links between self-referential processing, rumination, and the cortical midline structures in depression are still poorly understood. Here, we reviewed brain imaging studies in depressed patients and healthy subjects that have examined these links. Self-referential processing in major depression seems associated with abnormally increased activity of the anterior cortical midline structures. Abnormal interactions between the lateralized task-positive network, and the midline cortical structures of the default mode network, as well as the emotional response network, may underlie the pervasiveness of ruminative brooding. Furthermore, targeting this maladaptive form of rumination and its underlying neural correlates may be key for effective treatment. © 2013 Nejad, Fossatiand Lemogne.

Carroll K.C.,University of Louisville | Viollet B.,French Institute of Health and Medical Research | Viollet B.,French National Center for Scientific Research | Viollet B.,University of Paris Descartes | Suttles J.,University of Louisville
Journal of Leukocyte Biology | Year: 2013

AMPK is a serine/threonine kinase that regulates energy homeostasis and metabolic stress in eukaryotes. Previous work from our laboratory, as well as by others, has provided evidence that AMPKα1 acts as a negative regulator of TLR-induced inflammatory function. Herein, we demonstrate that AMPKα1-deficient macrophages and DCs exhibit heightened inflammatory function and an enhanced capacity for antigen presentation favoring the promotion of Th1 and Th17 responses. Macrophages and DCs generated from AMPKα1-deficient mice produced higher levels of proinflammatory cytokines and decreased production of the anti-inflammatory cytokine IL-10 in response to TLR and CD40 stimulation as compared with WT cells. In assays of antigen presentation, AMPKα1 deficiency in the myeloid APC and T cell populations contributed to enhanced IL-17 and IFN-γ production. Focusing on the CD154-CD40 interaction, we found that CD40 stimulation resulted in increased phosphorylation of ERK1/2, p38, and NF-κB p65 and decreased activation of the anti-inflammatory Akt-GSKΒ3-CREB pathway in DCs deficient for AMPKα 1. Our data demonstrate that AMPKα 1 serves to attenuate LPS and CD40-mediated proinflammatory activity of myeloid APCs and that AMPKα 1 activity in both APC and T cells contributes to T cell functional polarization during antigen presentation. © Society for Leukocyte Biology.

Gonzalez-Gomez N.,University of Paris Descartes | Nazzi T.,University of Paris Descartes | Nazzi T.,French National Center for Scientific Research
Journal of Speech, Language, and Hearing Research | Year: 2013

Purpose: In this study, the authors explored whether Frenchlearning infants use nonadjacent phonotactic regularities in their native language, which they learn between the ages of 7 and 10 months, to segment words from fluent speech. Method: Two groups of 20 French-learning infants were tested using the head-turn preference procedure at 10 and 13 months of age. In Experiment 1, infants were familiarized with 2 passages: 1 containing a target word with a frequent nonadjacent phonotactic structure and the other containing a target word with an infrequent nonadjacent phonotactic structure in French. During the test phase, infants were presented with 4 word lists: 2 containing the target words presented during familiarization and 2 other control words with the same phonotactic structure. In Experiment 2, the authors retested infants' ability to segment words with the infrequent phonotactic structure. Results: Ten- and 13-month-olds were able to segment words with the frequent phonotactic structure, but it is only by 13 months, and only under the circumstances of Experiment 2, that infants could segment words with the infrequent phonotactic structure. Conclusion: These results provide new evidence showing that infant word segmentation is influenced by prior nonadjacent phonotactic knowledge. © American Speech-Language-Hearing Association.

van Endert P.,French Institute of Health and Medical Research | van Endert P.,University of Paris Descartes | van Endert P.,French National Center for Scientific Research
Immunological Reviews | Year: 2016

Cross-presentation of internalized antigens by dendritic cells requires efficient delivery of Major Histocompatibility Complex (MHC) class I molecules to peptide-loading compartments. Strong evidence suggests that such loading can occur outside of the endoplasmic reticulum; however, the trafficking pathways and sources of class I molecules involved are poorly understood. Examination of non-professional, non-phagocytic cells has revealed a clathrin-independent, Arf6-dependent recycling pathway likely traveled by internalized optimally loaded (closed) class I molecules. Some closed and all open MHC class I molecules travel to late endosomes to be degraded but might also partly be re-loaded with peptides and recycled. Studies of viral interference revealed pathways in which class I molecules are directed to degradation in lysosomes upon ubiquitination at the surface, or upon AP-1 and HIV-nef-dependent misrouting from the Golgi network to lysosomes. While many observations made in non-professional cells remain to be re-examined in dendritic cells, available evidence suggests that both recycling and neo-synthesized class I molecules can be loaded with cross-presented peptides. Recycling molecules can be recruited to phagosomes triggered by innate signals such as TLR4 ligands, and may therefore specialize in loading with phagocytosed antigens. In contrast, AP-1-dependent accumulation at, or trafficking through, a Golgi compartment of newly synthesized molecules appears to be important for cross-presentation of soluble proteins and possibly of long peptides that are processed in the so-called vacuolar pathway. However, significant cell biological work will be required to confirm this or any other model and to integrate knowledge on MHC class I biochemistry and trafficking in models of CD8+ T-cell priming by dendritic cells. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Parpaleix A.,French Institute of Health and Medical Research | Parpaleix A.,French National Center for Scientific Research | Parpaleix A.,University of Paris Descartes | Houssen Y.G.,French Institute of Health and Medical Research | And 5 more authors.
Nature Medicine | Year: 2013

Two-photon phosphorescence lifetime microscopy (2PLM) has been used recently for depth measurements of oxygen partial pressure (PO2) in the rodent brain. In capillaries of olfactory bulb glomeruli, 2PLM has also allowed simultaneous measurements of PO2 and blood flow and revealed the presence of erythrocyte-associated transients (EATs), which are PO 2 gradients that are associated with individual erythrocytes. We investigated the extent to which EAT properties in capillaries report local neuronal activity. We find that at rest, PO2 at EAT peaks overestimates the mean PO2 by 35 mm Hg. PO2 between two EAT peaks is at equilibrium with, and thus reports, PO2 in the neuropil. During odor stimulation, there is a small PO2 decrease before functional hyperemia, showing that the initial dip in PO2 is present at the level of capillaries. We conclude that imaging oxygen dynamics in capillaries provides a unique and noninvasive approach to map neuronal activity. © 2013 Nature America, Inc. All rights reserved.