Institute for Research and Innovation in Biomedicine IRIB

Sotteville-lès-Rouen, France

Institute for Research and Innovation in Biomedicine IRIB

Sotteville-lès-Rouen, France
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El Amki M.,French Institute of Health and Medical Research | El Amki M.,Institute for Research and Innovation in Biomedicine IRIB | Dubois M.,French Institute of Health and Medical Research | Dubois M.,Institute for Research and Innovation in Biomedicine IRIB | And 23 more authors.
Molecular Neurobiology | Year: 2017

Subarachnoid hemorrhage (SAH) is a devastating disease with high mortality and morbidity. Long-term cognitive and sensorimotor deficits are serious complications following SAH but still not well explained and described in mouse preclinical models. The aim of our study is to characterize a well-mastered SAH murine model and to establish developing pathological mechanisms leading to cognitive and motor deficits, allowing identification of specific targets involved in these long-term troubles. We hereby demonstrate that the double blood injection model of SAH induced long-lasting large cerebral artery vasospasm (CVS), microthrombosis formation and cerebral brain damage including defect in potential paravascular diffusion. These neurobiological alterations appear to be associated with sensorimotor and cognitive dysfunctions mainly detected 10 days after the bleeding episode. In conclusion, this characterized model of SAH in mice, stressing prolonged neurobiological pathological mechanisms and associated sensitivomotor deficits, will constitute a validated preclinical model to better decipher the link between CVS, long-term cerebral apoptosis and cognitive disorders occurring during SAH and to allow investigating novel therapeutic approaches in transgenic mice. © 2017 Springer Science+Business Media New York


Medrinal C.,University of Rouen | Medrinal C.,Institute for Research and Innovation in Biomedicine IRIB | Medrinal C.,Groupe Hospitalier du Havre | Combret Y.,Groupe Hospitalier du Havre | And 9 more authors.
BMJ Open Respiratory Research | Year: 2017

Introduction: Early rehabilitation has become widespread practice for patients in intensive care; however, the prevalence of intensive care unit-acquired weakness remains high and the majority of physiotherapy is carried out in bed. Several inbed rehabilitation methods exist, but we hypothesise that techniques that provoke muscle contractions are more effective than passive techniques. Methods: A randomised, controlled cross-over study will be carried out to evaluate and compare the effectiveness of early rehabilitation techniques on cardiac output (CO) in sedated patients in intensive care. 20 intubated and sedated patients will undergo 4 10 min rehabilitation sessions. 2 sessions will involve ‘passive’ techniques based on mobilisations and inbed cycle ergometry and 2 involving electrostimulation of the quadriceps muscle and Functional Electrical Stimulation-cycling (FES-cycling). The primary outcome is CO measured by Doppler ultrasound. The secondary outcomes are right ventricular function, pulmonary systolic arterial pressure, muscle oxygenation and minute ventilation during exercise. Results and conclusion: Approval has been granted by our Institutional Review Board (Comité de Protection des Personnes Nord-Ouest 3). The results of the trial will be presented at national and international meetings and published in peer-reviewed journals. © 2017, BMJ Publishing Group. All rights reserved.


Combret Y.,Pierre Mendès-France University | Prieur G.,Groupe Hospitalier du Havre | Le Roux P.,Groupe Hospitalier du Havre | Medrinal C.,University of Rouen | And 2 more authors.
Minerva Anestesiologica | Year: 2017

INTRODUCTION: Non-invasive ventilation (NIV) is a common treatment for bronchiolitis. However, consensus concerning its efficacy is lacking. The aim of this systematic review was to assess NIV effectiveness to reduce respiratory distress. Secondary objectives were to summarize the effects of NIV, identify predictive factors for failure and describe settings and applications. EVIDENCEACQUISITION: Literature searches were conducted in MEDLINE/PubMed, PEDro, Cochrane, EMBASE, CINAHL, Web of Science, UpToDate, and SuDoc from 1990 to April 2015. Randomized controlled trials, controlled non-randomized trials and prospective studies of NIV(continuous positive airway pressure [CPAP], bi-level CPAP, or neurally-adjusted ventilator assist) for bronchiolitis in infants younger than 2 years were included. EVIDENCESYNTHESIS: Fourteen studies were included, for a total of 379 children. Of these, 357 were treated with NIV as first intention. Respiratory distress, heart rate, respiratory rate and respiratory effort improved (P<0.05). Results were inconclusive regarding prevention of endotracheal intubation. Few adverse events were reported. NIVreduced carbon dioxide pressure (pCO2) in 10 studies. Two randomized controlled studies reported a decrease of 7 mmHg in pCO2 (P<0.05). Predictive factors of NIV failure were apneas, high pCO2, young age, low weight, elevated heart rate and high pediatric risk of mortality score. NIV is mostly administered through a nasal mask, nasal cannula or helmet, with an initial expiratory positive airway pressure of 7 cmH2O. CONCLUSIONS: NIVshows promising results for the reduction of respiratory distress in acute viral bronchiolitis, as shown in several recent studies. However, there is a lack of robust studies to confirm this. © 2017 EDIZIONIMINERVAMEDICA.


Castel H.,French Institute of Health and Medical Research | Castel H.,Institute for Research and Innovation in Biomedicine IRIB | Desrues L.,French Institute of Health and Medical Research | Desrues L.,Institute for Research and Innovation in Biomedicine IRIB | And 10 more authors.
Frontiers in Endocrinology | Year: 2017

The urotensinergic system was previously considered as being linked to numerous physiopathological states, including atherosclerosis, heart failure, hypertension, pre-eclampsia, diabetes, renal disease, as well as brain vascular lesions. Thus, it turns out that the actions of the urotensin II (UII)/G protein-coupled receptor UT system in animal models are currently not predictive enough in regard to their effects in human clinical trials and that UII analogs, established to target UT, were not as beneficial as expected in pathological situations. Thus, many questions remain regarding the overall signaling profiles of UT leading to complex involvement in cardiovascular and inflammatory responses as well as cancer. We address the potential UT chemotactic structural and functional definition under an evolutionary angle, by the existence of a common conserved structural feature among chemokine receptorsopioïdergic receptors and UT, i.e., a specific proline position in the transmembrane domain-2 TM2 (P2.58) likely responsible for a kink helical structure that would play a key role in chemokine functions. Even if the last decade was devoted to the elucidation of the cardiovascular control by the urotensinergic system, we also attempt here to discuss the role of UII on inflammation and migration, likely providing a peptide chemokine status for UII. Indeed, our recent work established that activation of UT by a gradient concentration of UII recruits Gai/o and Ga13 couplings in a spatiotemporal way, controlling key signaling events leading to chemotaxis. We think that this new vision of the urotensinergic system should help considering UT as a chemotactic therapeutic target in pathological situations involving cell chemoattraction. © 2017 Castel, Desrues, Joubert, Tonon, Prézeau, Chabbert, Morin and Gandolfo.


Legrand R.,University of Rouen | Lucas N.,University of Rouen | Breton J.,University of Rouen | Azhar S.,University of Rouen | And 5 more authors.
European Neuropsychopharmacology | Year: 2016

Stimulation of feeding is necessary for treatment of pathological conditions of chronic malnutrition due to anorexia. Ghrelin, a hunger hormone, is one of the candidate for pharmacological treatments of anorexia, but because of its instability in plasma has limited efficacy. We previously showed that plasmatic IgG protect ghrelin from degradation and that IgG from obese subjects and mice may increase ghrelin's orexigenic effect. In this study we tested if ghrelin alone or combined with IgG may improve feeding in chronically food-restricted mice with or without physical activity-based anorexia (ABA) induced by free access to a running wheel. Mice received a single daily intraperitoneal injection of ghrelin (1. nM) together or not with total IgG (1. nM) from obese ob/ob or lean mice before access to food during 8 days of 3. h/day feeding time. We found that both ghrelin and ghrelin combined with IgG from obese, but not lean mice, prevented ABA, however, they were not able to diminish body weight loss. Physical activity was lower during the feeding period and was increased shortly after feeding in mice receiving ghrelin together with IgG from obese mice. In food-restricted mice without ABA, ghrelin treatments did not have significant effects on food intake. Thus, this study supports pharmacological use of ghrelin or ghrelin combined with IgG from obese animals for treatment of anorexia accompanied by elevated physical activity. The utility of combining ghrelin with protective IgG should be further determined in animal models of anorexia with unrestricted access to food. © 2016 Elsevier B.V. and ECNP.


Dumont L.,University of Rouen | Dumont L.,Institute for Research and Innovation in Biomedicine IRIB | Arkoun B.,University of Rouen | Arkoun B.,Institute for Research and Innovation in Biomedicine IRIB | And 10 more authors.
Andrology | Year: 2015

Testicular tissue cryopreservation offers the hope of preserved future fertility to pre-pubertal boys with cancer before exposition to gonadotoxic treatments. The objective of this study was to compare controlled slow freezing (CSF) with five vitrification techniques for cryopreservation of murine pre-pubertal testicular tissue and to evaluate the best protocol that could provide a successful completion of spermatogenesis after in vitro maturation. Testicular tissue from 24 mice at 6.5 days post-partum (dpp) was used to compare several vitrification protocols with one another, as well as with a CSF protocol. Toxicity test using additional 12 mice was performed for all cryopreservation solutions. Fresh tissue (FT) from six mice was used as a control. Once the optimal vitrification protocol was selected [the modified solid surface vitrification No. 1 (mSSV1)], testes from 18 mice were cultured in vitro for 30 days with (i) fresh, (ii) slow-frozen/thawed and (iii) vitrified/warmed tissues. Testes from six mice at 36.5 dpp were used as controls. At day 30 of in vitro culture, germ cells of the seminiferous tubules showed a high ability to proliferate and elongated spermatids were observed after both freezing techniques, confirming the successful completion of in vitro spermatogenesis. However, after mSSV1, the morphological alterations and the percentage of pyknotic seminiferous tubules were lower than CSF (4.67 ± 0.53 vs. 10.1 ± 1.12 and 22.7 ± 2.83% vs. 37.3 ± 4.24% respectively). Moreover, the number of flagellated spermatozoa produced per mg of tissue was higher for mSSV1 than for CSF (35 ± 3 vs. 9 ± 4 cells), with amounts of secreted testosterone during the culture close to those of FT. The mSSV1 protocol resulted in success rates better than CSF in maintaining testicular tissue structure, tubular morphology and tissue functions not solely for immediate frozen/thawed tissues but also after a long-term in vitro culture. © 2015 American Society of Andrology and European Academy of Andrology.


Mareschal S.,French Institute of Health and Medical Research | Mareschal S.,University of Rouen | Mareschal S.,Institute for Research and Innovation in Biomedicine IRIB | Dubois S.,French Institute of Health and Medical Research | And 8 more authors.
Bioinformatics | Year: 2014

Summary: Thanks to its free licensing and the development of initiatives like Bioconductor, R has become an essential part of the bioinformatics toolbox in the past years and is more and more confronted with genomically located data. While separate solutions are available to manipulate and visualize such data, no R package currently offers the efficiency required for computationally intensive tasks such as interactive genome browsing. The package proposed here fulfills this specific need, providing a multilevel interface suitable for most needs, from a completely interfaced genome browser to low-level classes and methods. Its time and memory efficiency have been challenged in a human dataset, where it outperformed existing solutions by several orders of magnitude. Availability and implementation: R sources and packages are freely available at the CRAN repository and dedicated Web site: http://bioinformatics.ovsa.fr/Rgb. Distributed under the GPL 3 license, compatible with most operating systems (Windows, Linux, Mac OS) and architectures. © The Author 2014.


Guernet A.,French Institute of Health and Medical Research | Guernet A.,Institute for Research and Innovation in Biomedicine IRIB | Mungamuri S.K.,Mount Sinai School of Medicine | Cartier D.,French Institute of Health and Medical Research | And 20 more authors.
Molecular Cell | Year: 2016

Intratumor genetic heterogeneity underlies the ability of tumors to evolve and adapt to different environmental conditions. Using CRISPR/Cas9 technology and specific DNA barcodes, we devised a strategy to recapitulate and trace the emergence of subpopulations of cancer cells containing a mutation of interest. We used this approach to model different mechanisms of lung cancer cell resistance to EGFR inhibitors and to assess effects of combined drug therapies. By overcoming intrinsic limitations of current approaches, CRISPR-barcoding also enables investigation of most types of genetic modifications, including repair of oncogenic driver mutations. Finally, we used highly complex barcodes inserted at a specific genome location as a means of simultaneously tracing the fates of many thousands of genetically labeled cancer cells. CRISPR-barcoding is a straightforward and highly flexible method that should greatly facilitate the functional investigation of specific mutations, in a context that closely mimics the complexity of cancer. © 2016 Elsevier Inc.


Coly P.-M.,French Institute of Health and Medical Research | Coly P.-M.,Institute for Research and Innovation in Biomedicine IRIB | Perzo N.,French Institute of Health and Medical Research | Perzo N.,Institute for Research and Innovation in Biomedicine IRIB | And 18 more authors.
Autophagy | Year: 2016

Chemotactic migration is a fundamental behavior of cells and its regulation is particularly relevant in physiological processes such as organogenesis and angiogenesis, as well as in pathological processes such as tumor metastasis. The majority of chemotactic stimuli activate cell surface receptors that belong to the G protein-coupled receptor (GPCR) superfamily. Although the autophagy machinery has been shown to play a role in cell migration, its mode of regulation by chemotactic GPCRs remains largely unexplored. We found that ligand-induced activation of 2 chemotactic GPCRs, the chemokine receptor CXCR4 and the urotensin 2 receptor UTS2R, triggers a marked reduction in the biogenesis of autophagosomes, in both HEK-293 and U87 glioblastoma cells. Chemotactic GPCRs exert their anti-autophagic effects through the activation of CAPNs, which prevent the formation of pre-autophagosomal vesicles from the plasma membrane. We further demonstrated that CXCR4- or UTS2R-induced inhibition of autophagy favors the formation of adhesion complexes to the extracellular matrix and is required for chemotactic migration. Altogether, our data reveal a new link between GPCR signaling and the autophagy machinery, and may help to envisage therapeutic strategies in pathological processes such as cancer cell invasion. © 2016 Taylor & Francis


Legrand R.,University of Rouen | Legrand R.,Institute for Research and Innovation in Biomedicine IRIB | Lucas N.,University of Rouen | Lucas N.,Institute for Research and Innovation in Biomedicine IRIB | And 12 more authors.
European Neuropsychopharmacology | Year: 2016

Stimulation of feeding is necessary for treatment of pathological conditions of chronic malnutrition due to anorexia. Ghrelin, a hunger hormone, is one of the candidate for pharmacological treatments of anorexia, but because of its instability in plasma has limited efficacy. We previously showed that plasmatic IgG protect ghrelin from degradation and that IgG from obese subjects and mice may increase ghrelin's orexigenic effect. In this study we tested if ghrelin alone or combined with IgG may improve feeding in chronically food-restricted mice with or without physical activity-based anorexia (ABA) induced by free access to a running wheel. Mice received a single daily intraperitoneal injection of ghrelin (1 nM) together or not with total IgG (1 nM) from obese ob/ob or lean mice before access to food during 8 days of 3 h/day feeding time. We found that both ghrelin and ghrelin combined with IgG from obese, but not lean mice, prevented ABA, however, they were not able to diminish body weight loss. Physical activity was lower during the feeding period and was increased shortly after feeding in mice receiving ghrelin together with IgG from obese mice. In food-restricted mice without ABA, ghrelin treatments did not have significant effects on food intake. Thus, this study supports pharmacological use of ghrelin or ghrelin combined with IgG from obese animals for treatment of anorexia accompanied by elevated physical activity. The utility of combining ghrelin with protective IgG should be further determined in animal models of anorexia with unrestricted access to food. © 2016 Elsevier B.V. and ECNP.

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