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738 results on '"Toutain A"'

1. Next generation phenotyping for diagnosis and phenotype–genotype correlations in Kabuki syndrome

Author

Quentin Hennocq, Marjolaine Willems, Jeanne Amiel, Stéphanie Arpin, Tania Attie-Bitach, Thomas Bongibault, Thomas Bouygues, Valérie Cormier-Daire, Pierre Corre, Klaus Dieterich, Maxime Douillet, Jean Feydy, Eva Galliani, Fabienne Giuliano, Stanislas Lyonnet, Arnaud Picard, Thantrira Porntaveetus, Marlène Rio, Flavien Rouxel, Vorasuk Shotelersuk, Annick Toutain, Kevin Yauy, David Geneviève, Roman H. Khonsari, and Nicolas Garcelon

Subjects
Medicine, Science
Abstract

Abstract The field of dysmorphology has been changed by the use Artificial Intelligence (AI) and the development of Next Generation Phenotyping (NGP). The aim of this study was to propose a new NGP model for predicting KS (Kabuki Syndrome) on 2D facial photographs and distinguish KS1 (KS type 1, KMT2D-related) from KS2 (KS type 2, KDM6A-related). We included retrospectively and prospectively, from 1998 to 2023, all frontal and lateral pictures of patients with a molecular confirmation of KS. After automatic preprocessing, we extracted geometric and textural features. After incorporation of age, gender, and ethnicity, we used XGboost (eXtreme Gradient Boosting), a supervised machine learning classifier. The model was tested on an independent validation set. Finally, we compared the performances of our model with DeepGestalt (Face2Gene). The study included 1448 frontal and lateral facial photographs from 6 centers, corresponding to 634 patients (527 controls, 107 KS); 82 (78%) of KS patients had a variation in the KMT2D gene (KS1) and 23 (22%) in the KDM6A gene (KS2). We were able to distinguish KS from controls in the independent validation group with an accuracy of 95.8% (78.9–99.9%, p

Published
2024
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2. Targeted dosing for susceptible heteroresistant subpopulations may improve rational dosage regimen prediction for colistin in broiler chickens

Author

Andrew Mead, Pierre-Louis Toutain, Pascal Richez, and Ludovic Pelligand

Subjects
Medicine, Science
Abstract

Abstract The dosage of colistin for the treatment of enteric E. coli in animals necessitates considering the heteroresistant (HR) nature of the targeted inoculum, described by the presence of a major susceptible population (S1, representing 99.95% of total population) mixed with an initial minor subpopulation of less susceptible bacteria (S2). Herein, we report the 1-compartment population pharmacokinetics (PK) of colistin in chicken intestine (jejunum and ileum) and combined it with a previously established pharmacodynamic (PD) model of HR in E. coli. We then computed probabilities of target attainment (PTA) with a pharmacodynamic target (AUC24h/MIC) that achieves 50% of the maximal kill of bacterial populations (considering inoculums of pure S1, S2 or HR mixture of S1 + S2). For an MIC of 1 mg/L, PTA > 95% was achieved with the registered dose (75,000 IU/kg BW/day in drinking water) for the HR mixture of S1 + S2 E. coli, whether they harboured mcr or not. For an MIC of 2 mg/L (ECOFF), we predicted PTA > 90% against the dominant susceptible sub-population (S1) with this clinical dose given (i) over 24 h for mcr-negative isolates or (ii) over 6 h for mcr-positive isolates (pulse dosing). Colistin clinical breakpoint S ≤ 2 mg/L (EUCAST rules) should be confirmed clinically.

Published
2023
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3. Diagnosis of autism spectrum disorder based on functional brain networks and machine learning

Author

Caroline L. Alves, Thaise G. L. de O. Toutain, Patricia de Carvalho Aguiar, Aruane M. Pineda, Kirstin Roster, Christiane Thielemann, Joel Augusto Moura Porto, and Francisco A. Rodrigues

Subjects
Medicine, Science
Abstract

Abstract Autism is a multifaceted neurodevelopmental condition whose accurate diagnosis may be challenging because the associated symptoms and severity vary considerably. The wrong diagnosis can affect families and the educational system, raising the risk of depression, eating disorders, and self-harm. Recently, many works have proposed new methods for the diagnosis of autism based on machine learning and brain data. However, these works focus on only one pairwise statistical metric, ignoring the brain network organization. In this paper, we propose a method for the automatic diagnosis of autism based on functional brain imaging data recorded from 500 subjects, where 242 present autism spectrum disorder considering the regions of interest throughout Bootstrap Analysis of Stable Cluster map. Our method can distinguish the control group from autism spectrum disorder patients with high accuracy. Indeed the best performance provides an AUC near 1.0, which is higher than that found in the literature. We verify that the left ventral posterior cingulate cortex region is less connected to an area in the cerebellum of patients with this neurodevelopment disorder, which agrees with previous studies. The functional brain networks of autism spectrum disorder patients show more segregation, less distribution of information across the network, and less connectivity compared to the control cases. Our workflow provides medical interpretability and can be used on other fMRI and EEG data, including small data sets.

Published
2023
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4. Executive functioning in adolescents and adults with Silver-Russell syndrome.

Author

Mélissa Burgevin, Agnès Lacroix, Fanny Ollivier, Karine Bourdet, Régis Coutant, Bruno Donadille, Laurence Faivre, Sylvie Manouvrier-Hanu, Florence Petit, Christel Thauvin-Robinet, Annick Toutain, Irène Netchine, and Sylvie Odent

Subjects
Medicine, Science
Abstract

Silver-Russell syndrome (SRS) is a rare imprinting disorder characterized by prenatal and postnatal growth retardation. The two principal causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (UPD(7)mat). Knowledge of the neuropsychological profile of SRS remains sparse and incomplete even if several difficulties related to attention and learning have been reported both in the literature and by patients with SRS. These difficulties could be the result of troubles in different cognitive domains, but also of executive dysfunction. Nevertheless, executive functioning has never been investigated, even though executive functions play an essential role in psychological development, and are extensively involved in daily life. The present study explored the executive functioning of individuals with SRS due to UPD(7)mat or 11p15 LOM. A battery of executive tasks assessing cognitive flexibility, inhibitory control, and working memory, together with a task assessing sustained attention, was administered to 19 individuals with SRS (13-39 years) and 19 healthy controls. The Behavior Rating Inventory of Executive Function was also completed by the participants' families. The results showed that participants with SRS had similar performance (z-scores) to our controls, in a context of normal intellectual efficiency. Group comparisons with Bayesian statistics showed a single difference between the 11p15 LOM and control groups: the completion time for part A of the Trail Making Test appeared to be longer in the 11p15 LOM group than in the control group. However, at the clinical level, several participants with SRS had clinically significant scores on various measures of EFs. Thus, the cognitive phenotype of SRS did not appear to be characterized by executive dysfunction, but individuals with SRS could be at high risk of developing executive dysfunction or attention-deficit/hyperactivity disorder. These results provide new insights into the neuropsychological profile of individuals with SRS.

Published
2023
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5. Confined placental mosaicism revisited: Impact on pregnancy characteristics and outcome.

Author

Jérôme Toutain, Damien Goutte-Gattat, Jacques Horovitz, and Robert Saura

Subjects
Medicine, Science
Abstract

We wanted to re-evaluate the influence of confined placental mosaicism subtypes (type 2 and type 3) on pregnancy characteristics and outcome.From July 2009 to December 2015, 5512 chorionic villus samplings were performed in our Fetal Medicine Center. Conventional karyotyping was performed after long-term and short-term cultured villi to define type 2 or type 3 confined placental mosaicisms. Karyotype after amniocentesis was performed to exclude true fetal mosaicism, when appropriate. Pregnancy characteristics and outcomes were collected and compared to a control population.Thirty-six (0.65%) confined placental mosaicisms were observed (13 type 2 and 23 type 3). Nuchal translucency was not increased for type 2 and type 3 confined placental mosaicisms. Pregnancy characteristics and outcomes were comparable between type 2 confined placental mosaicisms and the control population. In type 3 confined placental mosaicisms, median first trimester serum pregnancy-associated plasma protein A was lower than for the control population (p

Published
2018
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6. Medication control of flunixin in racing horses: Possible detection times using Monte Carlo simulations

Author

Kanichi Kusano, Fumio Sato, Masayuki Yamada, Kentaro Fukuda, Yohei Minamijima, Taisuke Kuroda, Pierre-Louis Toutain, Shun-ichi Nagata, Shozo Yamashita, Atsutoshi Kuwano, Norihisa Tamura, Hiroshi Mita, and Motoi Nomura

Subjects
Flunixin, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Monte Carlo method, Horse, Drug administration, General Medicine, Urine, Withdrawal time, Clonixin, Animal science, Tandem Mass Spectrometry, medicine, Animals, Female, Statistical analysis, Horses, Multiple administration, business, Monte Carlo Method, Chromatography, Liquid, medicine.drug
Abstract

Background For medication control in several jurisdictions, withdrawal time is the period of refrain from racing after drug administration. It is set by adding a safety period to an experimental detection time. However, there are no reports of statistical analyses of detection time for the determination of withdrawal time in flunixin meglumine-treated horses. Objective To analyse the population pharmacokinetics of flunixin in horses through the generation of a dataset for detection time statistical analysis and predictions via Monte Carlo simulation. Study design Experimental study. Methods Drug plasma and urine concentrations following single intravenous (i.v.) administration of flunixin 1.1 mg/kg bodyweight (BW) in 10 horses and multiple administration of q 24 h for 5 days in 10 horses were measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Data were modelled using a nonlinear mixed effect model followed by Monte Carlo simulation. Irrelevant plasma concentration (IPC) and irrelevant urine concentration (IUC) were calculated using the Toutain approach. Detection times were obtained considering the time after the last administration for selected quantiles of 5000 hypothetical horses under the International Screening Limit (ISL) proposed by the International Federation of Horseracing Authorities (plasma: 1 ng/ml, urine; 100 ng/ml) RESULTS: For a regimen of 1.1 mg/kg BW q 24 h, the IPC and IUC values were 2.0 and 73.0 ng/ml, respectively. Detection times in plasma above the ISL for 90% of simulated horses were estimated as 74 h after a single 1.1 mg/kg dose administration, 149 h and 199 h after multiple doses over 5 days at either 24- or 12-h intervals, respectively. Corresponding detection times in urine were 46 h, 68 h and 104 h, respectively. Main limitation Only female horses were investigated. Conclusions Statistical detection times for different flunixin meglumine regimens indicated a delay of detection time in plasma after multiple administrations under ISL.

Published
2021
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7. Accelerated genome sequencing with controlled costs for infants in intensive care units: a feasibility study in a French hospital network

Author

Robert Olaso, Adeline Prost, Anne-Sophie Denommé-Pichon, Magali Gorce, Anne Boland, Mélanie Fradin, Magalie Barth, Mathilde Nizon, Antonio Vitobello, Dominique Bonneau, Bertrand Isidor, Christel Thauvin-Robinet, Frédéric Tran Mau-Them, Victor Couturier, Caroline Racine, Céline Besse, Marie Vincent, Bertrand Fin, Yline Capri, Alban Ziegler, Ange-Line Bruel, Yannis Duffourd, Christophe Philippe, P. Callier, Sébastien Moutton, Aurore Garde, Médéric Jeanne, Annick Toutain, Sophie Nambot, Delphine Bacq-Daian, Charlotte Poë, Emilie Tisserant, Aurélien Juven, Julien Van-Gils, Tiffany Busa, Laurent Pasquier, Sabine Sigaudy, Arthur Sorlin, Thibaud Jouan, Philippine Garret, Corinne Chantegret, Julian Delanne, Cyril Flamant, Alinoë Lavillaureix, Clement Prouteau, Paul Rollier, Laurence Faivre, and Jean-François Deleuze

Subjects
Protocol (science), Hospital network, medicine.medical_specialty, business.industry, Infant, Newborn, Infant, Pilot Projects, Context (language use), Disease, Hospitals, Article, Intensive Care Units, Intensive care, Genetics, medicine, Etiology, Feasibility Studies, Humans, Prospective Studies, Duration (project management), Child, Intensive care medicine, business, Genetics (clinical), Blood sampling
Abstract

Obtaining a rapid etiological diagnosis for infants with early-onset rare diseases remains a major challenge. These diseases often have a severe presentation and unknown prognosis, and the genetic causes are very heterogeneous. In a French hospital network, we assessed the feasibility of performing accelerated trio-genome sequencing (GS) with limited additional costs by integrating urgent requests into the routine workflow. In addition to evaluating our capacity for such an approach, this prospective multicentre pilot study was designed to identify pitfalls encountered during its implementation. Over 14 months, we included newborns and infants hospitalized in neonatal or paediatric intensive care units with probable genetic disease and in urgent need for etiological diagnosis to guide medical care. The duration of each step and the pitfalls were recorded. We analysed any deviation from the planned schedule and identified obstacles. Trio-GS was performed for 37 individuals, leading to a molecular diagnosis in 18/37 (49%), and 21/37 (57%) after reanalysis. Corrective measures and protocol adaptations resulted in a median duration of 42 days from blood sampling to report. Accelerated trio-GS is undeniably valuable for individuals in an urgent care context. Such a circuit should coexist with a rapid or ultra-rapid circuit, which, although more expensive, can be used in particularly urgent cases. The drop in GS costs should result in its generalized use for diagnostic purposes and lead to a reduction of the costs of rapid GS.

Published
2021
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8. Performance evaluation of the fully automated random‐access multiparameter Sysmex CN‐6000 hemostasis analyzer at a core laboratory with a high sample throughput

Author

Isabelle Martin-Toutain, Corinne Frere, Yasmine Bourti, Mayssa Gaaloul, Manon Lejeune, Jean-Pierre Delorme, and Guillaume Nguyen

Subjects
Prothrombin time, Hemostasis, Spectrum analyzer, Materials science, medicine.diagnostic_test, Sample (material), Coefficient of variation, Biochemistry (medical), Clinical Biochemistry, Hematology, General Medicine, Fibrinogen, Turnaround time, Prothrombin Time, medicine, Humans, Partial Thromboplastin Time, Blood Coagulation Tests, Laboratories, Throughput (business), medicine.drug, Biomedical engineering
Abstract

INTRODUCTION We aimed to evaluate the performance of the fully automated multiparameter CN-6000 hemostasis analyzer. METHODS Performance evaluation of the CN-6000 analyzer was conducted for 10 tests including prothrombin time (PT), activated partial prothrombin time (aPTT), fibrinogen level, anti-Xa activity, and antithrombin activity using a unique portfolio of liquid ready-to-use reagents. Precision, sample and reagent carryovers, throughput, and sample turnaround time (STAT) function were prospectively assessed. Results from 343 samples (normal subjects, critically ill patients, patients receiving anticoagulants, subjects with high or low fibrinogen levels, and patients with decreased levels of factor II, V, VII, and X) were compared to those obtained on the STA-R Max 2® analyzer using dedicated reagents. RESULTS Total precision (coefficient of variation) was below 7% for all parameters in both normal and pathological ranges. For all analyzed parameters, results obtained on the CN-6000 were strongly correlated with those obtained on the STA-R Max 2®analyzer. Agreement between both instruments was excellent for all assays. The CN-6000 demonstrated a 30% higher throughput compared to the STA-R Max 2® (258 vs 185 tests per hour for a panel of tests including PT, aPTT, fibrinogen, factor V, anti-Xa, and D-Dimer). STAT turnaround time for critical care samples testing was

Published
2021
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9. CRISPR-Cas9 globin editing can induce megabase-scale copy-neutral losses of heterozygosity in hematopoietic cells

Author

Jean-Marc Blouin, F. Prat, J. Rosier, Jean-Philippe Merlio, J. Bouron, Emmanuel Richard, Cécile Ged, Julian Boutin, Isabelle Lamrissi-Garcia, Aurélie Bedel, Sandrine Dabernat, François Moreau-Gaudry, G. Cullot, J. Toutain, Caroline Rooryck, Perrine Pennamen, Véronique Guyonnet-Dupérat, D. Cappellen, Samuel Amintas, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Association Française contre les Myopathies, ANR-21-CE18-0002,CRISPR-genotox,Génotoxicité induite par CRISPR-CAS9(2021), Admin, Oskar, and Génotoxicité induite par CRISPR-CAS9 - - CRISPR-genotox2021 - ANR-21-CE18-0002 - AAPG2021 - VALID

Subjects
CRISPR-Cas9 genome editing, Genetic enhancement, Science, General Physics and Astronomy, Gene Expression, Loss of Heterozygosity, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Loss of heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Genome editing, Insulin-Like Growth Factor II, medicine, CRISPR, Humans, Globin, Cells, Cultured, 030304 developmental biology, Sequence Deletion, Genetics, Gene Editing, 0303 health sciences, Multidisciplinary, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Chromosomes, Human, Pair 11, Chromosome, General Chemistry, DNA Methylation, medicine.disease, Hematopoietic Stem Cells, Uniparental disomy, 3. Good health, Telomere, Globins, Targeted gene repair, HEK293 Cells, 030220 oncology & carcinogenesis, RNA, Long Noncoding, CRISPR-Cas Systems, Chromosome Deletion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

CRISPR-Cas9 is a promising technology for gene therapy. However, the ON-target genotoxicity of CRISPR-Cas9 nuclease due to DNA double-strand breaks has received little attention and is probably underestimated. Here we report that genome editing targeting globin genes induces megabase-scale losses of heterozygosity (LOH) from the globin CRISPR-Cas9 cut-site to the telomere (5.2 Mb). In established lines, CRISPR-Cas9 nuclease induces frequent terminal chromosome 11p truncations and rare copy-neutral LOH. In primary hematopoietic progenitor/stem cells, we detect 1.1% of clones (7/648) with acquired megabase LOH induced by CRISPR-Cas9. In-depth analysis by SNP-array reveals the presence of copy-neutral LOH. This leads to 11p15.5 partial uniparental disomy, comprising two Chr11p15.5 imprinting centers (H19/IGF2:IG-DMR/IC1 and KCNQ1OT1:TSS-DMR/IC2) and impacting H19 and IGF2 expression. While this genotoxicity is a safety concern for CRISPR clinical trials, it is also an opportunity to model copy-neutral-LOH for genetic diseases and cancers., CRISPR-Cas9 generates double-strand breaks, which pose a threat to genome integrity. Here the authors show loss of heterozygosity in edited hematopoietic progenitor cells.

Published
2021
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10. Extracorporeal Membrane Oxygenation Induces Early Alterations in Coagulation and Fibrinolysis Profiles in COVID-19 Patients with Acute Respiratory Distress Syndrome

Author

Guillaume Lebreton, Ania Nieszkowska, Corinne Frere, Marc Pineton de Chambrun, Isabelle Martin-Toutain, Guillaume Hékimian, Manon Lejeune, Paul Masi, Juliette Chommeloux, Matthieu Schmidt, Charles-Edouard Luyt, Alain Combes, Nicolas Bréchot, Cyrielle Desnos, and Pascal Leprince

Subjects
Adult, Male, ARDS, medicine.medical_specialty, medicine.medical_treatment, Hemorrhage, 030204 cardiovascular system & hematology, Fibrinogen, law.invention, 03 medical and health sciences, Extracorporeal Membrane Oxygenation, 0302 clinical medicine, Von Willebrand factor, law, Internal medicine, von Willebrand Factor, Fibrinolysis, medicine, Extracorporeal membrane oxygenation, Humans, Prospective Studies, Blood Coagulation, Respiratory Distress Syndrome, biology, business.industry, COVID-19, 030208 emergency & critical care medicine, Hematology, Middle Aged, medicine.disease, Intensive care unit, Coagulation, biology.protein, Cardiology, Female, Median body, business, medicine.drug
Abstract

Hemostatic changes induced by extracorporeal membrane oxygenation (ECMO) support have been yet poorly documented in coronavirus-19 (COVID-19) patients who have a baseline complex hypercoagulable state. In this prospective monocentric study of patients with severe acute respiratory distress syndrome (ARDS) rescued by ECMO, we performed longitudinal measurements of coagulation and fibrinolysis markers throughout the course of ECMO support in 20 COVID-19 and 10 non-COVID-19 patients. Blood was sampled before and then 24 hours, 7, and 14 days after ECMO implantation. Clinical outcomes were prospectively assessed until discharge from the intensive care unit or death. The median age of participants was 47 (35–56) years, with a median body mass index of 30 (27–35) kg/m2, and a Sepsis-related Organ Failure Assessment score of 12 (8–16). Baseline levels of von Willebrand factor, fibrinogen, factor VIII, prothrombin F1 + 2, thrombin–antithrombin, D-dimer, and plasminogen activator inhibitor-1 (PAI-1) were elevated in both COVID-19 and non-COVID-19 ARDS patients, indicating that endothelial activation, endogenous thrombin generation, and fibrinolysis shutdown occur in all ARDS patients before ECMO implantation. From baseline to day 7, thrombin generation (prothrombin F1 + 2, p

Published
2021
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11. Kinetic disposition of diazepam and its metabolites after intravenous administration of diazepam in the horse: Relevance for doping control

Author

Diane C. Broussou, Elodie Lallemand, M. Düe, Astrid Meuly, Helma Röttgen, Ina Schenk, Mario Thevis, Henrike Lagershausen, Béatrice B. Roques, Pierre-Louis Toutain, Marc Machnik, Center for Preventive Doping Research, Innovations Thérapeutiques et Résistances (InTheRes), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, German Equestrian Federation, Partenaires INRAE, Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and The Royal Veterinary College

Subjects
040301 veterinary sciences, medicine.drug_class, [SDV]Life Sciences [q-bio], Metabolite, Nordazepam, 0403 veterinary science, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, medicine, Animals, Horses, ComputingMilieux_MISCELLANEOUS, Active metabolite, Doping in Sports, Pharmacology, Benzodiazepine, Diazepam, Chromatography, General Veterinary, Temazepam, 04 agricultural and veterinary sciences, 3. Good health, Oxazepam, chemistry, Administration, Intravenous, 030217 neurology & neurosurgery, Chromatography, Liquid, medicine.drug
Abstract

In horses, the benzodiazepine diazepam (DIA) is used as sedative for pre-medication or as an anxiolytic to facilitate horse examinations. As the sedative effects can also be abused for doping purposes, DIA is prohibited in equine sports. DIA is extensively metabolized to several active metabolites such as nordazepam, temazepam and oxazepam (OXA). For veterinarians, taking into account the detection times of DIA and its active metabolites is needed for minimizing the risk of an anti-doping rule violation. Therefore, a pharmacokinetic study on 6 horses was conducted using a single intravenous (IV) dose of 0.2 mg/kg DIA Plasma and urine samples were collected at specified intervals until 16 and 26 days post-administration, respectively. Samples were analysed by a sensitive liquid chromatography-electrospray ionization/tandem mass spectrometry method. DIA showed a triphasic elimination pattern in the horse. The mean plasma clearance of DIA was 5.9 ml/min/kg, and the plasma elimination half-life in the terminal phase was 19.9 h. Applying the Toutain model approach, an effective plasma concentration of DIA was estimated at 24 ng/ml, and irrelevant plasma concentration (IPC) and irrelevant urine concentration (IUC) were computed to 0.047 and 0.1 ng/ml, respectively. The detection time according to the European Horserace Scientific Liaison Committee (EHSLC), that is the time for which observed DIA plasma concentrations of all investigated horses were below the IPC was 10 days. Using Monte Carlo Simulations, it was estimated that concentrations of DIA in plasma would fall below the IPC 18 days after the DIA administration for 90% of horses. However, in the present study, a single administration of DIA could be detected for 24 days in urine via the presence of OXA, its dominant metabolite.

Published
2021
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12. Infection-stage adjusted dose of beta-lactams for parsimonious and efficient antibiotic treatments: A Pasteurella multocida experimental pneumonia in mice.

Author

Maleck V Vasseur, Marlene Z Lacroix, Pierre-Louis Toutain, Alain Bousquet-Melou, and Aude A Ferran

Subjects
Medicine, Science
Abstract

In this study, the impact of infection stage on clinically and microbiologically efficacious doses and on antibiotic consumption was assessed during a naturally evolving infectious disease, using an original mouse model of pulmonary infection produced by air-borne contamination. When Pasteurella multocida was administered as pathogenic agent to immunocompetent mice, 60% of the animals exhibited clinical symptoms of pneumonia 2 to 4 days after bacterial contamination of the lungs. Two beta-lactam antibiotics were evaluated: amoxicillin and cefquinome, a fourth generation cephalosporin developed for food animals. First, a pharmacokinetic study was performed in infected mice to determine the exposure to amoxicillin or cefquinome required to treat clinically affected animals, based on the targeted values of PK/PD indices for beta-lactams. We then confirmed that these doses resulted in a 100% clinical cure rate in animals exhibiting clinical signs of infection and harboring a high pathogenic inoculum. More interestingly, we also showed that the same 100% clinical cure could be obtained in our model with 10-fold lower doses in animals at pre-patent stages of infection i.e. when harboring a low pathogenic inoculum. At the group level, antimicrobial drug consumption was reduced by treating animals at an early stage of the infection course with a pre-patent tailored dose. These results suggest that early treatment with a dose suitably adjusted to the stage of infection might help to reduce both overall antibiotic consumption and resistance selection pressure in the animals and in the environment.

Published
2017
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13. Clinical and neuroimaging findings in 33 patients with <scp>MCAP</scp> syndrome: A survey to evaluate relevant endpoints for future clinical trials

Author

Florence Petit, Fabienne Giuliano, Juliette Mazereeuw-Hautier, Marjolaine Willems, Christel Thauvin-Robinet, Patricia Blanchet, Laurence Faivre, Elodie Gautier, Anne-Claire Bursztejn, Renaud Touraine, Annick Toutain, Frederico Di Rocco, Maxime Luu, Patrick Edery, Arthur Sorlin, Jean-Luc Alessandri, Nicolas Chassaing, Alice Goldenberg, Christine Chiaverini, Fanny Morice-Picard, Aurore Garde, Stéphanie Arpin, Massimiliano Rossi, Marc Bardou, Claire Nicolas, Gilles Morin, Jenny Cornaton, Cyril Mignot, Christophe Philippe, V. Carmignac, Rodolphe Dard, Joelle Roume, Michèle Mathieu-Dramard, Philippe Khau Van Kien, Pierre Vabres, Didier Lacombe, Diane Doummar, Lucile Pinson, Christine Coubes, Laurent Guibaud, Olivia Boccara, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), and Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Cutis marmorata, Adolescent, Class I Phosphatidylinositol 3-Kinases, Neuroimaging, Context (language use), Skin Diseases, Vascular, 030105 genetics & heredity, Cohort Studies, Young Adult, 03 medical and health sciences, Genetics, Polymicrogyria, medicine, Humans, PROS, Abnormalities, Multiple, Telangiectasis, Megalencephaly, Child, MCAP syndrome, Genetics (clinical), Chiari malformation, Clinical Trials as Topic, business.industry, Macrocephaly, PIK3CA, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Clinical trial, 030104 developmental biology, Child, Preschool, Postnatal macrocephaly, Female, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Forecasting, Ventriculomegaly
Abstract

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.

Published
2021
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14. Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth

Author

Damien Haye, Sandrine Vonwill, Rolph Pfundt, Annick Toutain, Stephan C. Collins, Joost Kummeling, Sylviane Marouillat, Marie-Pierre Moizard, Médéric Jeanne, Dévina C. Ung, Binnaz Yalcin, Frédéric Laumonnier, Nora Chelloug, Tjitske Kleefstra, Marie-Laure Vuillaume, Valerie E. Vancollie, and Christel Wagner

Subjects
0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], biology, 030305 genetics & heredity, Neurogenesis, Hippocampus, Hippocampal formation, medicine.disease, Phenotype, Cell biology, 03 medical and health sciences, Histone, Neurodevelopmental disorder, 22q11 Deletion Syndrome, Genetics, biology.protein, medicine, Haploinsufficiency, Genetics (clinical), 030304 developmental biology
Abstract

Item does not contain fulltext The 22q11.2 deletion syndrome (22q11DS) is associated with a wide spectrum of cognitive and psychiatric symptoms. Despite the considerable work performed over the past 20 years, the genetic etiology of the neurodevelopmental phenotype remains speculative. Here, we report de novo heterozygous truncating variants in the HIRA (Histone cell cycle regulation defective, S. Cerevisiae, homolog of, A) gene associated with a neurodevelopmental disorder in two unrelated patients. HIRA is located within the commonly deleted region of the 22q11DS and encodes a histone chaperone that regulates neural progenitor proliferation and neurogenesis, and that belongs to the WD40 Repeat (WDR) protein family involved in brain development and neuronal connectivity. To address the specific impact of HIRA haploinsufficiency in the neurodevelopmental phenotype of 22q11DS, we combined Hira knock-down strategies in developing mouse primary hippocampal neurons, and the direct study of brains from heterozygous Hira(+/-) mice. Our in vitro analyses revealed that Hira gene is mostly expressed during neuritogenesis and early dendritogenesis stages in mouse total brain and in developing primary hippocampal neurons. Moreover, shRNA knock-down experiments showed that a twofold decrease of endogenous Hira expression level resulted in an impaired dendritic growth and branching in primary developing hippocampal neuronal cultures. In parallel, in vivo analyses demonstrated that Hira(+/-) mice displayed subtle neuroanatomical defects including a reduced size of the hippocampus, the fornix and the corpus callosum. Our results suggest that HIRA haploinsufficiency would likely contribute to the complex pathophysiology of the neurodevelopmental phenotype of 22q11DS by impairing key processes in neurogenesis and by causing neuroanatomical defects during cerebral development.

Published
2021
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15. Rational dosage regimens for cephalothin and cefazolin using pharmacokinetics and pharmacodynamics analysis in healthy horses

Author

Taisuke Kuroda, Pierre-Louis Toutain, Yuki Enoki, Kentaro Fukuda, Hiroshi Mita, Masahiro Kaimachi, Kazuaki Matsumoto, Norihisa Tamura, Yuto Suzuki, Kazuaki Taguchi, Hidekazu Niwa, Alain Bousquet-Mélou, Yohei Minamijima, Yoshinori Kasashima, Japan Racing Association, Laboratory of Racing Chemistry, Equine Research Institute, Faculty of Pharmacy Tokyo, Royal Veterinary College [London], University of London [London], Innovations Thérapeutiques et Résistances (InTheRes), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Staphylococcus aureus, Dose, 040301 veterinary sciences, medicine.drug_class, [SDV]Life Sciences [q-bio], gram positive infection, Cephalosporin, Cefazolin, Microbial Sensitivity Tests, Pharmacology, 0403 veterinary science, Pharmacokinetics, Tandem Mass Spectrometry, Cephalothin, Medicine, Animals, Horses, ComputingMilieux_MISCELLANEOUS, biology, business.industry, 0402 animal and dairy science, Horse, 04 agricultural and veterinary sciences, General Medicine, biology.organism_classification, 040201 dairy & animal science, Blood proteins, Experimental and Basic Research Studies, 3. Good health, horse, Anti-Bacterial Agents, Regimen, Streptococcus zooepidemicus, General Article, business, medicine.drug, Chromatography, Liquid
Abstract

Background First-generation cephalosporins have good activity against gram-positive bacteria and are extensively used in horses. There are few reports of pharmacokinetics and pharmacodynamics (PK/PD) analysis of cephalosporins in horses. Objective To optimise the dosages of the two first-generation cephalosporins cephalothin (CET) and cefazolin (CEZ) in horses using PK/PD concepts. Study design Experimental study with single administration. Methods Drug plasma concentrations following a single intravenous (i.v.) administration of 22 mg/kg bodyweight (bwt) CET in 12 horses and of 10 mg/kg bwt CEZ in six horses were measured using LC-MS/MS. Data were modelled using a nonlinear mixed effect modelling followed by Monte Carlo simulations. Minimum inhibitory concentrations (MICs) against Streptococcus zooepidemicus and Staphylococcus aureus isolated from horses were determined by the microbroth dilution method. Results The percentages of CET and CEZ binding to serum proteins were 19.9% ± 8.4% and 15.2% ± 8.5% respectively. For both CET and CEZ, the MIC90 against S. zooepidemicus was 0.12 mg/L and against S. aureus was 0.5 mg/L. For CET, to achieve a probability of target attainment (PTA) of 90% for a PK/PD target of a free serum plasma concentration exceeding the MIC90 for 40% of the dosing interval, an empirical CET dosage regimen of 22 mg/kg bwt q8h and 22 mg/kg bwt q4h i.v. administration were required for S. zooepidemicus and S. aureus respectively. For CEZ, the corresponding dosage regimens were 10 mg/kg bwt q12h and 10 mg/kg bwt q8h. Main limitations Small sample size only in healthy horses. Conclusions For CET, more frequent administration than that currently recommended (22 mg/kg bwt q6-12h) is required to empirically control S. aureus infection in horses. For CEZ, less frequent administration compared to the dosage regimen currently proposed (10-22 mg/kg bwt q6h) could control S. zooepidemicus and S. aureus infections in horses.

Published
2021
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16. Dynamic interactions between cephalexin and macrophages on different Staphylococcus aureus inoculum sizes: a tripartite in vitro model

Author

Claudine Zemirline, Séverine Boullier, Aude A. Ferran, Alain Bousquet-Mélou, Pierre-Louis Toutain, Elodie Lallemand, Innovations Thérapeutiques et Résistances (InTheRes), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CEVA Santé Animale, Royal Veterinary College, and INTHERES-Innovations Thérapeutiques et Résistances, École Nationale Vétérinaire de Toulouse, 31076 Toulouse, France.

Subjects
Staphylococcus aureus, [SDV]Life Sciences [q-bio], Microbial Sensitivity Tests, Biology, medicine.disease_cause, Models, Biological, Microbiology, 03 medical and health sciences, Immune system, medicine, Macrophage, Animals, Killing curves, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Cephalexin, Innate immune system, lcsh:Veterinary medicine, General Veterinary, 030306 microbiology, Macrophages, Pathogenic bacteria, General Medicine, Staphylococcal Infections, Antimicrobial, biology.organism_classification, In vitro, Immunity, Innate, Anti-Bacterial Agents, Mice, Inbred C57BL, Host-Pathogen Interactions, lcsh:SF600-1100, Female, Bacteria, Research Article
Abstract

Background The bactericidal activity of an antimicrobial drug is generally assessed by in vitro bacterial time-kill experiments which do not include any components of the immune system, even though the innate immunity, the primary host defence, is probably able to kill a large proportion of pathogenic bacteria in immunocompetent patients. We developed an in vitro tripartite model to investigate the joint action of C57Bl/6 murine bone-marrow-derived macrophages and cephalexin on the killing of Staphylococcus aureus. Results By assessing the bactericidal effects on four bacterial inoculum sizes, we showed that macrophages can cooperate with cephalexin on inoculum sizes lower than 106 CFU/mL and conversely, protect S. aureus from cephalexin killing activity at the highest inoculum size. Cell analysis by flow cytometry revealed that macrophages were rapidly overwhelmed when exposed to large inoculums. Increasing the initial inoculum size from 105 to 107 CFU/mL increased macrophage death and decreased their ability to kill bacteria from six hours after exposure to bacteria. The addition of cephalexin at 16-fold MIC to 105 and 106 CFU/mL inoculums allowed the macrophages to survive and to maintain their bactericidal activity as if they were exposed to a small bacterial inoculum. However, with the highest inoculum size of 107 CFU/mL, the final bacterial counts in the supernatant were higher with macrophages plus cephalexin than with cephalexin alone. Conclusions These results suggest that if the bacterial population at the infectious site is low, as potentially encountered in the early stage of infection or at the end of an antimicrobial treatment, the observed cooperation between macrophages and cephalexin could facilitate its control.

Published
2021
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17. Determination of the pharmacokinetic‐pharmacodynamic cut‐off values of marbofloxacin in horses to support the establishment of a clinical breakpoint for antimicrobial susceptibility testing

Author

Alain Bousquet-Mélou, Pierre‐Louis Toutain, Elodie Lallemand, Marc Schneider, Cyrielle Triboulloy, Farid El Garch, Peter Damborg, Diane C. Broussou, Aude A. Ferran, Innovations Thérapeutiques et Résistances (InTheRes), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Vétoquinol, Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, University of Copenhagen = Københavns Universitet (KU), and The Royal Veterinary College, Hawkshead Campus

Subjects
Streptococcus equi, PK/PD cut-off, medicine.drug_class, [SDV]Life Sciences [q-bio], Antibiotics, Population, Microbial Sensitivity Tests, Pharmacology, Gram-Positive Bacteria, medicine.disease_cause, monte carlo simulations, 03 medical and health sciences, 0302 clinical medicine, Anti-Infective Agents, Pharmacokinetics, Marbofloxacin, Gram-Negative Bacteria, medicine, Animals, Horses, 030212 general & internal medicine, education, antimicrobial susceptibility testing, 0303 health sciences, education.field_of_study, 030306 microbiology, business.industry, Broth microdilution, Horse, General Medicine, horse, Anti-Bacterial Agents, Staphylococcus aureus, population pharmacokinetic, business, Fluoroquinolones, medicine.drug
Abstract

Background Marbofloxacin (MBX), a fluoroquinolone (FQ), is considered as a critical antibiotic requiring antimicrobial susceptibility testing (AST) for prudent use. No clinical breakpoint (CBP) currently exists to interpret the results of such tests in horses. Objectives To compute PK/PD cut-offs (PK/PDCO ) that is one of the three minimum inhibitory concentrations (MICs) considered establishing a CBP for antimicrobial susceptibility test interpretation. Study design A meta-analysis conducted by combining five sets of previously published pharmacokinetic data, obtained in clinical and nonclinical settings. Methods Horses (n = 131) received MBX intravenously at doses of either 2 or 10 mg/kg BW. They were richly sampled (five or six samples per horse). A population model was built to generate a virtual population of 5000 MBX disposition curves by Monte Carlo simulations (MCS) over 24 hours. The selected PK/PD index was the ratio of Area Under the free plasma concentration-time Curve divided by the MIC (fAUC/MIC). The PK/PDCO , which is the highest MIC for which 90% of horses can achieve an a priori selected critical value for the numerical value of the PK/PD index, was established for Gram-positive and Gram-negative bacteria for a dose of 2 mg/kg. Results The PK/PDCO of MBX in horses was 0.125 mg/L for Gram-positive pathogens and 0.0625 mg/L for Gram-negative pathogens. MBX MICs determined by broth microdilution for 54 Escherichia coli and 189 Streptococcus equi isolates are reported. Main limitation No clinical data are taken into account in the determination of a PK/PDco . Conclusion The computed PK/PDco predicts that MBX may be efficacious in horses to treat infections associated with Enterobacteriaceae but unlikely to those involving Staphylococcus aureus or Streptococcus equi.

Published
2020
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18. Why Were More Than 200 Subjects Required to Demonstrate the Bioequivalence of a New Formulation of Levothyroxine with an Old One?

Author

Jean-Louis Montastruc, Pierre-Louis Toutain, Alain Bousquet-Mélou, Aude A. Ferran, Peter Lees, Peggy Gandia, Didier Concordet, Toutain, Pierre-Louis, Innovations Thérapeutiques et Résistances (InTheRes), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CHU Toulouse [Toulouse], and Royal Veterinary College, University of London

Subjects
Pharmacology, Actuarial science, Computer science, [SDV]Life Sciences [q-bio], Pharmacology toxicology, Levothyroxine, Guideline, Bioequivalence, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, Current Opinion, 030220 oncology & carcinogenesis, medicine, Pharmacology (medical), Equivalence (measure theory), medicine.drug
Abstract

At the request of French Regulatory Authorities, a new formulation of Levothyrox® was licensed in France in 2017, with the objective of avoiding the stability deficiencies of an existing licensed formulation. Before launching the new formulation, an average bioequivalence (ABE) trial was conducted, having enrolled 204 subjects and selected for interpretation a narrow a priori bioequivalence range of 0.90–1.11. Bioequivalence was concluded. In a previous publication, we questioned the ability of an ABE trial to guarantee the switchability within patients of the new and old levothyroxine formulations. It was suggested that the two formulations should be compared using the conceptual framework of individual bioequivalence. The present paper is a response to those claiming that, despite the fact that ABE analysis does not formally address the switchability of the two formulations, future patients will nevertheless be fully protected. The basis for this claim is that the ABE study was established in a large trial and analyzed using a stringent a priori acceptance interval of equivalence. These claims are questionable, because the use of a very large number of subjects nullifies the implicit precautionary intention of the European guideline when, for a Narrow Therapeutic Index drug, it recommends shortening the a priori acceptance interval from 0.80–1.25 to 0.90–1.11.

Published
2019
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19. CUGC for Simpson-Golabi-Behmel syndrome (SGBS)

Author

Frédéric Brioude, Edouard Cottereau, Marie-Pierre Moizard, Annick Toutain, Marie-Laure Vuillaume, Alessandra Baumer, Anita Rauch, University of Zurich, and Toutain, Annick

Subjects
Heart Defects, Congenital, Male, 2716 Genetics (clinical), 10039 Institute of Medical Genetics, 610 Medicine & health, Disease, Biology, Gigantism, 03 medical and health sciences, Glypicans, 1311 Genetics, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Genetic Testing, Gene, Genetics (clinical), Genetic testing, 0303 health sciences, medicine.diagnostic_test, 030305 genetics & heredity, Chromosome, Arrhythmias, Cardiac, Genetic Diseases, X-Linked, Simpson–Golabi–Behmel syndrome, medicine.disease, Phenotype, Clinical Utility Gene Card, Mutation, Clinical validity, 570 Life sciences, biology, Female
Abstract

Name of the disease (synonyms) Simpson-Golabi-Behmel syndrome (SGBS). OMIM# OF THE DISEASE: 312870. Name of the analysed genes or dna/chromosome segments GPC3. OMIM# OF THE GENE(S): 300037. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the GPC3 gene(s) in ⊠ diagnostic, ☐ predictive and ⊠ prenatal settings and for ⊠ risk assessment in relatives.

Published
2019
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20. Resveratrol Improved Flow-Mediated Outward Arterial Remodeling in Ovariectomized Rats with Hypertrophic Effect at High Dose.

Author

Marie Petit, Anne-Laure Guihot, Linda Grimaud, Emilie Vessieres, Bertrand Toutain, Marie-Claude Menet, Valérie Nivet-Antoine, Jean-François Arnal, Laurent Loufrani, Vincent Procaccio, and Daniel Henrion

Subjects
Medicine, Science
Abstract

OBJECTIVES:Chronic increases in blood flow in resistance arteries induce outward remodeling associated with increased wall thickness and endothelium-mediated dilatation. This remodeling is essential for collateral arteries growth following occlusion of a large artery. As estrogens have a major role in this remodeling, we hypothesized that resveratrol, described as possessing phytoestrogen properties, could improve remodeling in ovariectomized rats. METHODS:Blood flow was increased in vivo in mesenteric arteries after ligation of adjacent arteries in 3-month old ovariectomized rats treated with resveratrol (5 or 37.5 mg/kg per day: RESV5 or RESV37.5) or vehicle. After 2 weeks arterial structure and function were measured in vitro in high flow (HF) and normal flow (NF) arteries isolated from each rat. RESULTS:Arterial diameter was greater in HF than in NF arteries in ovariectomized rats treated with RESV5 or RESV37.5, not in vehicle-treated rats. In mice lacking estrogen receptor alpha diameter was equivalent in HF and NF arteries whereas in mice treated with RESV5 diameter was greater in HF than in NF vessels. A compensatory increase in wall thickness and a greater phenylephrine-mediated contraction were observed in HF arteries. This was more pronounced in HF arteries from RESV37.5-treated rats. ERK1/2 phosphorylation, involved in hypertrophy and contraction, were higher in RESV37.5-treated rats than in RESV5- and vehicle-treated rats. Endothelium-dependent relaxation was greater in HF than in NF arteries in RESV5-treated rats only. In HF arteries from RESV37.5-treated rats relaxation was increased by superoxide reduction and markers of oxidative stress (p67phox, GP91phox) were higher than in the 2 other groups. CONCLUSION:Resveratrol improved flow-mediated outward remodeling in ovariectomized rats thus providing a potential therapeutic tool in menopause-associated ischemic disorders. This effect seems independent of the estrogen receptor alpha. Nevertheless, caution should be taken with high doses inducing excessive contractility and hypertrophy in association with oxidative stress in HF arteries.

Published
2016
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21. A Novel Analog Reasoning Paradigm: New Insights in Intellectually Disabled Patients.

Author

Aurore Curie, Amandine Brun, Anne Cheylus, Anne Reboul, Tatjana Nazir, Gérald Bussy, Karine Delange, Yves Paulignan, Sandra Mercier, Albert David, Stéphanie Marignier, Lydie Merle, Bénédicte de Fréminville, Fabienne Prieur, Michel Till, Isabelle Mortemousque, Annick Toutain, Eric Bieth, Renaud Touraine, Damien Sanlaville, Jamel Chelly, Jian Kong, Daniel Ott, Behrouz Kassai, Nouchine Hadjikhani, Randy L Gollub, and Vincent des Portes

Subjects
Medicine, Science
Abstract

BACKGROUND:Intellectual Disability (ID) is characterized by deficits in intellectual functions such as reasoning, problem-solving, planning, abstract thinking, judgment, and learning. As new avenues are emerging for treatment of genetically determined ID (such as Down's syndrome or Fragile X syndrome), it is necessary to identify objective reliable and sensitive outcome measures for use in clinical trials. OBJECTIVE:We developed a novel visual analogical reasoning paradigm, inspired by the Progressive Raven's Matrices, but appropriate for Intellectually Disabled patients. This new paradigm assesses reasoning and inhibition abilities in ID patients. METHODS:We performed behavioural analyses for this task (with a reaction time and error rate analysis, Study 1) in 96 healthy controls (adults and typically developed children older than 4) and 41 genetically determined ID patients (Fragile X syndrome, Down syndrome and ARX mutated patients). In order to establish and quantify the cognitive strategies used to solve the task, we also performed an eye-tracking analysis (Study 2). RESULTS:Down syndrome, ARX and Fragile X patients were significantly slower and made significantly more errors than chronological age-matched healthy controls. The effect of inhibition on error rate was greater than the matrix complexity effect in ID patients, opposite to findings in adult healthy controls. Interestingly, ID patients were more impaired by inhibition than mental age-matched healthy controls, but not by the matrix complexity. Eye-tracking analysis made it possible to identify the strategy used by the participants to solve the task. Adult healthy controls used a matrix-based strategy, whereas ID patients used a response-based strategy. Furthermore, etiologic-specific reasoning differences were evidenced between ID patients groups. CONCLUSION:We suggest that this paradigm, appropriate for ID patients and developmental populations as well as adult healthy controls, provides an objective and quantitative assessment of visual analogical reasoning and cognitive inhibition, enabling testing for the effect of pharmacological or behavioural intervention in these specific populations.

Published
2016
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22. Heparin-induced thrombocytopenia in COVID-19 patients with severe acute respiratory distress syndrome requiring extracorporeal membrane oxygenation: two case reports

Author

Guillaume Hékimian, Guillaume Lebreton, Corinne Frere, Alain Combes, Isabelle Martin-Toutain, Frank Bidar, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service d'Hématologie Biologique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Chirurgie cardiaque et thoracique [CHU Pitié-Salpêtrière], Gestionnaire, Hal Sorbonne Université, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Adult, Male, medicine.medical_specialty, ARDS, [SDV]Life Sciences [q-bio], medicine.medical_treatment, 0206 medical engineering, Biomedical Engineering, Medicine (miscellaneous), 02 engineering and technology, 030204 cardiovascular system & hematology, Argatroban, law.invention, Biomaterials, 03 medical and health sciences, Extracorporeal Membrane Oxygenation, 0302 clinical medicine, law, Heparin-induced thrombocytopenia, Coagulopathy, Extracorporeal membrane oxygenation, Humans, Medicine, Intensive care medicine, Respiratory Distress Syndrome, Heparin, business.industry, Anticoagulants, COVID-19, Middle Aged, medicine.disease, Thrombocytopenia, 020601 biomedical engineering, Intensive care unit, Thrombosis, 3. Good health, [SDV] Life Sciences [q-bio], Intensive Care Units, surgical procedures, operative, Female, Cardiology and Cardiovascular Medicine, business, Complication, medicine.drug
Abstract

International audience; Veno-venous (VV) extracorporeal membrane oxygenation (ECMO) is increasingly used in Coronavirus disease-19 (COVID-19) patients with the most severe forms of acute respiratory distress syndrome (ARDS). Its use is associated with a significant hemostatic challenge, especially in COVID- 19 patients who have been demonstrated to otherwise present a COVID-19-associated coagulopathy. The systematic use of unfractionated heparin therapy to prevent circuit thrombosis is warranted during ECMO support. The clinical presentation and management of heparin-induced thrombocytopenia, which is a rare but life-threatening complication of heparin therapy, has not been described in those patients yet. We report herein two cases of laboratory-confirmed HIT in COVID-19 patients with severe ARDS admitted to our intensive care unit for VV-ECMO support and the successful use of argatroban as an alternative therapy. We also provide a brief literature review of best evidence for managing such patients. The diagnosis and management of HIT is particularly challenging in COVID-19 patients receiving ECMO support. An increased awareness is warranted in those patients who already present a procoagulant state leading to higher rates of thrombotic events which can confuse the issues. Argatroban seems to be an appropriate and safe therapeutic option in COVID-19 patients with HIT while on VV-ECMO.

Published
2020
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23. Systemic Inflammatory Response Syndrome Is a Major Contributor to COVID-19–Associated Coagulopathy

Author

Isabelle Martin-Toutain, Juliette Chommeloux, Alain Combes, Nicolas Bréchot, Charles Edouard Luyt, Ania Nieszkowska, Corinne Frere, Matthieu Schmidt, Guillaume Hékimian, Guillaume Lebreton, Marc Pineton de Chambrun, Cyrielle Desnos, Manon Lejeune, and Paul Masi

Subjects
medicine.medical_specialty, biology, Coronavirus disease 2019 (COVID-19), business.industry, 030204 cardiovascular system & hematology, biology.organism_classification, Single Center, medicine.disease, Systemic inflammatory response syndrome, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Internal medicine, Pandemic, medicine, Coagulopathy, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, Prospective cohort study, business, Betacoronavirus, Cohort study
Published
2020
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24. Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals

Author

Margot, Henri, Boursier, Guilaine, Duflos, Claire, Sanchez, Elodie, Amiel, Jeanne, Andrau, Jean-Christophe, Arpin, Stéphanie, Brischoux-Boucher, Elise, Boute, Odile, Burglen, Lydie, Caille, Charlotte, Capri, Yline, Collignon, Patrick, Conrad, Solène, CORMIER-DAIRE, Valerie, Delplancq, Geoffroy, Dieterich, Klaus, Dollfus, Hélène, Fradin, Mélanie, Faivre, Laurence, Fernandes, Helder, Francannet, Christine, Gatinois, Vincent, Gérard, Marion, Goldenberg, Alice, Ghoumid, Jamal, Grotto, Sarah, Guerrot, Anne-Marie, Guichet, Agnès, Isidor, Bertrand, Jacquemont, Marie-Line, Julia, Sophie, Philip, K, Legendre, Marine, Le Quan Sang, K., Leheup, Bruno, Lyonnet, Stanislas, Magry, Virginie, Manouvrier, Sylvie, Martin, Dominique, Morel, Godelieve, Munnich, Arnold, Naudion, Sophie, Odent, Sylvie, Perrin, Laurence, Petit, Florence, Philip, Nicole, Rio, Marlène, Robbe, Julie, Rossi, Massimiliano, Sarrazin, Elisabeth, Toutain, Annick, Van Gils, Julien, Vera, Gabriella, Verloes, Alain, Weber, Sacha, Whalen, Sandra, Sanlaville, Damien, Lacombe, Didier, Aladjidi, Nathalie, Geneviève, David, Khau Van Kien, Philippe, Van Gils, Julie, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris Descartes - Paris 5 (UPD5), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Robert Debré Paris, Hôpital Robert Debré, Service de Génétique Médicale, Hôpital intercommunal de Font-Pré, Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Muscle et Pathologies, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de génétique clinique, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], CHU Bordeaux [Bordeaux], Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Maladies Rénales Héréditaires, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hydrosciences Montpellier (HSM), Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence car i b é en des maladies rares neuromusculaires et neurologiques adultes et enfant (CERCA), Hôpital Pierre Zobda Quitman-CHU Fort-de-France, U 1211 Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (MRGM), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire régional de télédétection, Institut de Recherche pour le Développement (IRD), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hémato-oncologie Pédiatrique, CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), AOM 07-090, Ministère de la Santé et des Services sociaux, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), gerard, marion, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Male, [SDV.GEN] Life Sciences [q-bio]/Genetics, Vitiligo, Severity of Illness Index, Hypogammaglobulinemia, 0302 clinical medicine, Prevalence, Medicine, KDM6A, Registries, Child, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Immunodeficiency, Histone Demethylases, 0303 health sciences, Genetic disorder, KMT2D, Middle Aged, Thrombocytopenic purpura, Neoplasm Proteins, 3. Good health, DNA-Binding Proteins, Vestibular Diseases, Child, Preschool, Female, Autoimmune hemolytic anemia, Adult, medicine.medical_specialty, Adolescent, Primary Immunodeficiency Diseases, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Autoimmune Diseases, Young Adult, 03 medical and health sciences, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Humans, Abnormalities, Multiple, Genetic Association Studies, Aged, 030304 developmental biology, Autoimmune disease, [SDV.GEN]Life Sciences [q-bio]/Genetics, Kabuki syndrome, business.industry, Infant, Newborn, Infant, medicine.disease, Hematologic Diseases, immunity, Dermatology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Face, Mutation, business, 030217 neurology & neurosurgery
Abstract

Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype–phenotype correlations in KS individuals from a registry. Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.

Published
2020
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25. Topical ophthalmic atropine in horses, pharmacokinetics and effect on intestinal motility

Author

F. Dalin, M. Domberg, C Stenlund, Mikael Hedeland, Ulf Bondesson, Lena Ström, Carl Ekstrand, Pierre-Louis Toutain, Swedish University of Agricultural Sciences (SLU), National Veterinary Institute [Uppsala] (SVA), Department of Medicinal Chemistry, Uppsala University, Sweden, Uppsala University, Innovations Thérapeutiques et Résistances (InTheRes), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), The Royal Veterinary College, University of London, Hawkshead Campus, Hatfield AL9 7TA, UK., and Department of Biomedicine and Veterinary Public Health

Subjects
Atropine, Male, Colic, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 0403 veterinary science, ComputingMilieux_MISCELLANEOUS, Volume of distribution, Other Veterinary Science, education.field_of_study, lcsh:Veterinary medicine, 04 agricultural and veterinary sciences, General Medicine, Farmakologi och toxikologi, 3. Good health, Anesthesia, Injections, Intravenous, Female, Systemic exposure, Half-Life, Research Article, medicine.drug, Side effect, 040301 veterinary sciences, Population, Biological Availability, Pharmacology and Toxicology, Pharmacokinetics, medicine, Animals, Horses, education, Plasma disposition, General Veterinary, Equine, business.industry, 0402 animal and dairy science, Parasympatholytics, Eye drop, 040201 dairy & animal science, Bioavailability, Pharmacodynamics, lcsh:SF600-1100, Ophthalmic Solutions, Gastrointestinal Motility, business
Abstract

Background Topical ophthalmic atropine sulfate is an important part of the treatment protocol in equine uveitis. Frequent administration of topical atropine may cause decreased intestinal motility and colic in horses due to systemic exposure. Atropine pharmacokinetics are unknown in horses and this knowledge gap could impede the use of atropine because of the presumed risk of unwanted effects. Additional information could therefore increase safety in atropine treatment. Results Atropine sulfate (1 mg) was administered in two experiments: In part I, atropine sulfate was administered intravenously and topically (manually as eye drops and through a subpalpebral lavage system) to six horses to document atropine disposition. Blood-samples were collected regularly and plasma was analyzed for atropine using UHPLC-MS/MS. Atropine plasma concentration was below lower limit of quantification (0.05 μg/L) within five hours, after both topical and IV administration. Atropine data were analyzed by means of population compartmental modeling and pharmacokinetic parameters estimated. The typical value was 1.7 L/kg for the steady-state volume of distribution. Total plasma clearance was 1.9 L/h‧kg. The bioavailability after administration of an ophthalmic preparation as an eye drop or topical infusion were 69 and 68%, respectively. The terminal half-life was short (0.8 h). In part II, topical ophthalmic atropine sulfate and control treatment was administered to four horses in two dosing regimens to assess the effect on gastro-intestinal motility. Borborygmi-frequency monitored by auscultation was used for estimation of gut motility. A statistically significant decrease in intestinal motility was observed after administration of 1 mg topical ophthalmic atropine sulfate every three hours compared to control, but not after administration every six hours. Clinical signs of colic were not observed under any of the treatment protocols. Conclusions Taking the plasma exposure after topical administration into consideration, data and simulations indicate that eye drops administrated at a one and three hour interval will lead to atropine accumulation in plasma over 24 h but that a six hour interval allows total washout of atropine between two topical administrations. If constant corneal and conjunctival atropine exposure is required, a topical constant rate infusion at 5 μg/kg/24 h offers a safe alternative.

Published
2021
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26. [Assisted reproductive technology outcomes of infertile men carrying balanced chromosomal rearrangements or Y-chromosome microdeletions - Retrospective study]

Author

Hélène Lheureux, Julian Poquet, Lucie Chansel-Debordeaux, Bérénice Doray, Joffrey Mons, and Jérôme Toutain

Subjects
Male, medicine.medical_specialty, Reproductive Techniques, Assisted, Y chromosome microdeletion, medicine.medical_treatment, Clinical pregnancy, Sex Chromosome Disorders of Sex Development, Chromosomal rearrangement, Male infertility, Primary outcome, Pregnancy, Medicine, Humans, Infertility, Male, Sex Chromosome Aberrations, Azoospermia, Retrospective Studies, Gynecology, Assisted reproductive technology, Chromosomes, Human, Y, business.industry, Karyotype, Retrospective cohort study, General Medicine, medicine.disease, Case-Control Studies, Female, Chromosome Deletion, business
Abstract

The aim of this study was to evaluate the ART outcomes for infertile males carrying a balanced structural chromosomal rearrangement or a Y-chromosome microdeletion, and to compare the results with a control group. The primary outcome was the clinical pregnancy rate. A retrospective case-control study has been carried out in the ART departments of the university hospitals of Bordeaux and la Reunion. Results of karyotypes and Y-chromosome microdeletions analysis of infertile men with sperm concentration lower than 5 millions/mL have been extracted from the softwares Jfiv® (Bordeaux) and MediFirst® (la Reunion). The clinical pregnancy rate for carriers of balanced chromosomal rearrangements and Y-chromosome microdeletions was 28% and 43% respectively. The clinical pregnancy rate for the controls was 24% (non-significant difference). According to this study, balanced chromosomal rearrangements and Y-chromosome microdeletions are not found to affect the clinical pregnancy rate in conventional ART. Further larger scale studies are required to confirm these results.

Published
2021

27. Thrombophilia Associated with Anti-DFS70 Autoantibodies.

Author

Julien Marlet, Annick Ankri, Jean-Luc Charuel, Pascale Ghillani-Dalbin, Amélie Perret, Isabelle Martin-Toutain, Julien Haroche, Zahir Amoura, Lucile Musset, and Makoto Miyara

Subjects
Medicine, Science
Abstract

Anti-DFS70 antibodies are the most frequent antinuclear antibodies (ANA) found in healthy individuals. We assessed the clinical significance of the presence of anti-DFS70 antibodies.We defined a group of patients (n = 421) with anti-DFS70 antibodies and a group of patients (n = 63) with a history of idiopathic arterial and/or venous thrombotic disease and/or obstetric complication (i.e. ≥ 3 miscarriages, fetal death or premature birth with eclampsia). Anti-DFS70 antibodies prevalence was also assessed in a cohort of 300 healthy blood donors.The prevalence of thrombotic disease and/or obstetric complication in the 421 patients with anti-DFS70 antibodies was 13.1% (n = 55) and the prevalence of connective tissue disease was 19% (n = 80). Among the 63 patients with a history of thrombosis and/or obstetric complications, 7 (11.1%) had anti-DFS70 antibodies and among the latter, 5 had no common thrombophilic factor. In contrast, the prevalence of anti-DFS70 antibodies was of 3.0% (9 out of 300) in healthy donors. Finally, the Activated Partial Thromboplastin Time (aPTT) ratio of patients with a history of thrombosis and anti-DFS70 antibodies was lower than the aPTT ratio of other patients, suggesting that thrombotic patients with anti-DFS70 antibodies may have a hypercoagulable state.We described here for the first time an immune procoagulant state involving anti-DFS70 antibodies.

Published
2015
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28. Bacterial Species-Specific Activity of a Fluoroquinolone against Two Closely Related Pasteurellaceae with Similar MICs: Differential In Vitro Inoculum Effects and In Vivo Efficacies.

Author

Guillaume Lhermie, Farid El Garch, Pierre-Louis Toutain, Aude A Ferran, and Alain Bousquet-Mélou

Subjects
Medicine, Science
Abstract

We investigated the antimicrobial activity of a fluoroquinolone against two genetically close bacterial species belonging to the Pasteurellaceae family. Time-kill experiments were used to measure the in vitro activity of marbofloxacin against two strains of Mannheimia haemolytica and Pasteurella multocida with similar MICs. We observed that marbofloxacin was equally potent against 105 CFU/mL inocula M. haemolytica and P. multocida. However, an inoculum effect was observed with P. multocida, meaning that marbofloxacin activity was decreased against a 108 CFU/mL inoculum, whereas no inoculum effect was observed with M. haemolytica. Marbofloxacin activity was also tested in a lung infection model with immunocompromised mice intratracheally infected with 109 CFU of each bacteria. At the same dose, the clinical and bacteriological outcomes were much better for mice infected with M. haemolytica than for those infected with P. multocida. Moreover, bacteriological eradication was obtained with a lower marbofloxacin dose for mice infected with M. haemolytica. Our results suggest that the differential in vivo marbofloxacin efficacy observed with the two bacterial species of similar MIC could be explained by a differential inoculum effect. Consequently, MICs determined on 105 CFU inocula were not predictive of the differences in antibiotic efficacies against high bacterial inocula of closely related bacterial strains. These results could stimulate further investigations on bacterial species-specific antibiotic doses in a clinical setting.

Published
2015
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30. Brain Asymmetry in Pain Affective Modulation

Author

Raphael Silva do Rosário, Miguel A. Muñoz, Thaise Graziele L. de O. Toutain, José Garcia Vivas Miranda, Guzmán Alba, and Eduardo Pondé de Sena

Subjects
Male, medicine.medical_specialty, Brain Mapping, medicine.diagnostic_test, Brain activity and meditation, business.industry, Left Brain Hemisphere, Emotions, Brain, Pain, Electroencephalography, General Medicine, Audiology, Stimulus (physiology), Affective modulation, Homophily, Lateralization of brain function, Anesthesiology and Pain Medicine, medicine, Brain asymmetry, Humans, Female, Neurology (clinical), business
Abstract

Objective The aim of this study was to characterize the dynamic brain networks underlying the affective modulation of pleasant, unpleasant, and neutral image perception due to painful stimulations in healthy subjects. Methods Forty volunteers, 20 men and 20 women, participated in this study. Brain activity was recorded by 64-channel electroencephalography. After data cleaning, brain functional networks were built through the use of the motif synchronization method. Results We found that increased cerebral connectivity in the left hemisphere under the pain condition broke the connection symmetry. Both women and men showed homophilic connections (intrahemispheric), but women were more homophilic than men. The pain condition increased homophily in the left hemisphere, and emotions could modulate pain. The frontal, central, and left temporal regions showed homophilic variation, depending on the emotional stimulus. Conclusions Pain and emotions altered brain activity. There was increased connectivity and homophily in the left brain hemisphere for the painful experience. The emotions modulated brain activity in the pain condition. Overall, the brain presented homophilic characteristics; homophily changed, depending on emotion or pain. The left brain hemisphere seems to be related to pain processing.

Published
2021

31. Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder

Author

Sylviane Marouillat, Marie-Laure Vuillaume, Thomas Smol, Rose-Anne Thépault, Lyse Ruaud, Sarah Grotto, Jamal Ghoumid, Nicolas Chatron, Annick Toutain, Marianne Till, Alain Verloes, Manon Dixneuf, Valérie Chune, Gaetan Lesca, Frédéric Laumonnier, Nathalie Couque, Bénédicte Gérard, Martine Raynaud, Judith Halewa, Dévina C. Ung, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, ANR-20-CE17-0006,ASDecode,Approches translationnelles pour la caractérisation de la voie PTCHD1 impliquée dans les troubles neurodéveloppementaux(2020), Laumonnier, Frédéric, Approches translationnelles pour la caractérisation de la voie PTCHD1 impliquée dans les troubles neurodéveloppementaux - - ASDecode2020 - ANR-20-CE17-0006 - AAPG2020 - VALID, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Male, [SDV]Life Sciences [q-bio], Mutation, Missense, autism spectrum disorder, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, functional analyses, PTCHD1 (patched domain containing 1) gene, 03 medical and health sciences, Mice, in vitro cellular models, subcellular localization, Genetics, medicine, Missense mutation, Animals, Humans, Gene, Genetics (clinical), Research Articles, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Endoplasmic reticulum, 030305 genetics & heredity, Cell Membrane, Membrane Proteins, Subcellular localization, medicine.disease, In vitro, Transmembrane protein, Amino acid, [SDV] Life Sciences [q-bio], chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, intellectual disability, missense variants, Research Article
Abstract

The X‐linked PTCHD1 gene, encoding a synaptic membrane protein, has been involved in neurodevelopmental disorders with the description of deleterious genomic microdeletions or truncating coding mutations. Missense variants were also identified, however, without any functional evidence supporting their pathogenicity level. We investigated 13 missense variants of PTCHD1, including eight previously described (c.152G>A,p.(Ser51Asn); c.217C>T,p.(Leu73Phe); c.517A>G,p.(Ile173Val); c.542A>C,p.(Lys181Thr); c.583G>A,p.(Val195Ile); c.1076A>G,p.(His359Arg); c.1409C>A,p.(Ala470Asp); c.1436A>G,p.(Glu479Gly)), and five novel ones (c.95C>T,p.(Pro32Leu); c.95C>G,p.(Pro32Arg); c.638A>G,p.(Tyr213Cys); c.898G>C,p.(Gly300Arg); c.928G>C,p.(Ala310Pro)) identified in male patients with intellectual disability (ID) and/or autism spectrum disorder (ASD). Interestingly, several of these variants involve amino acids localized in structural domains such as transmembrane segments. To evaluate their potentially deleterious impact on PTCHD1 protein function, we performed in vitro overexpression experiments of the wild‐type and mutated forms of PTCHD1‐GFP in HEK 293T and in Neuro‐2a cell lines as well as in mouse hippocampal primary neuronal cultures. We found that six variants impaired the expression level of the PTCHD1 protein, and were retained in the endoplasmic reticulum suggesting abnormal protein folding. Our functional analyses thus provided evidence of the pathogenic impact of missense variants in PTCHD1, which reinforces the involvement of the PTCHD1 gene in ID and in ASD., Thirteen missense variants in the PTCHD1 gene associated with X‐linked neurodevelopmental disorder were investigated to address their potentially deleterious impact. Their overexpression in various cell lines (HEK293T, Neuro‐2a) and in primary neuronal cultures revealed abnormal protein stability and impaired subcellular localization, thus providing further evidence for the significant impact of PTCHD1 genetic alterations in intellectual disability and in autism spectrum disorder.

Published
2021
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32. Heterozygous HMGB1 loss-of-function variants are associated with developmental delay and microcephaly

Author

Laurence Faivre, Natáliya Tkachenko, Celia Azevedo Soares, Annick Toutain, Marlène Rio, Anne Boland, Kendra Engleman, Eléonore Viora-Dupont, Kévin Uguen, Cédric Le Maréchal, Yang Cao, Sophie Rondeau, Kilannin Krysiak, Jean-François Deleuze, Caroline Benech, Frédéric Tran Mau-Them, Sylvie Odent, Jorge L. Granadillo, Dominique Bonneau, Claude Férec, Ibrahim Elsharkawi, Séverine Audebert-Bellanger, Julie Neidich, Stéphane Bézieau, Brigitte Gilbert-Dussardier, Elena Repnikova, Sylvia Redon, Shivarajan Manickavasagam Amudhavalli, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universidade do Porto = University of Porto, Centro Hospitalar do Porto, Children's Mercy Hospital [Kansas City], Université Paris-Saclay, Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade do Porto, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, Heterozygote, Microcephaly, Adolescent, DNA Copy Number Variations, Language delay, [SDV]Life Sciences [q-bio], Karyotype, Inheritance Patterns, chemical and pharmacologic phenomena, 030105 genetics & heredity, Biology, dysmorphic features, loss of function mutation, 03 medical and health sciences, Exome Sequencing, Intellectual disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, HMGB1 Protein, Child, Gene, Genetic Association Studies, In Situ Hybridization, Fluorescence, Genetics (clinical), Loss function, HMGB1, Facies, Exons, developmental disabilities, Microdeletion syndrome, medicine.disease, Phenotype, 030104 developmental biology, Child, Preschool, Female, Haploinsufficiency
Abstract

International audience; 13q12.3 microdeletion syndrome is a rare cause of syndromic intellectual disability. Identification and genetic characterization of patients with 13q12.3 microdeletion syndrome continues to expand the phenotypic spectrum associated with it. Previous studies identified four genes within the approximately 300 Kb minimal critical region including two candidate protein coding genes: KATNAL1 and HMGB1. To date, no patients carrying a sequence-level variant or a single gene deletion in HMGB1 or KATNAL1 have been described. Here we report six patients with loss-of-function variants involving HMGB1 and who had phenotypic features similar to the previously described 13q12.3 microdeletion syndrome cases. Common features included developmental delay, language delay, microcephaly, obesity and dysmorphic features. In silico analyses suggest that HMGB1 is likely to be intolerant to loss-of-function, and previous in vitro data are in line with the role of HMGB1 in neurodevelopment. These results strongly suggest that haploinsufficiency of the HMGB1 gene may play a critical role in the pathogenesis of the 13q12.3 microdeletion syndrome.

Published
2021
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33. Author response for 'Heterozygous HMGB1 loss‐of‐function variants are associated with developmental delay and microcephaly'

Author

Natáliya Tkachenko, Stéphane Bézieau, Shivarajan M. Amudhavalli, Sylvia Redon, Cédric Le Maréchal, Sylvie Odent, Claude Férec, Ibrahim Elsharkawi, Annick Toutain, Frédéric Tran Mau-Them, Julie Neidich, Brigitte Gilbert-Dussardier, Kilannin Krysiak, Jean-Francois Deleuze, Marlène Rio, Séverine Audebert-Bellanger, Sophie Rondeau, Celia Azevedo Soares, Caroline Benech, Dominique Bonneau, Eléonore Viora-Dupont, Kevin Uguen, Jorge L. Granadillo, Anne Boland, Yang Cao, Elena Repnikova, Laurence Faivre, and Kendra Engleman

Subjects
Genetics, Microcephaly, medicine, Biology, medicine.disease, Loss function
Published
2021
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34. Response to Letter: ‘Reply to 'High frequency of antiphospholipid antibodies in critically ill COVID‐19 patients: a link with hypercoagulability?'’

Author

Corinne Frere, A. Mathian, Guillaume Hékimian, Makoto Miyara, M. Pineton De Chambrun, Isabelle Martin-Toutain, Z. Amoura, and Alain Combes

Subjects
0301 basic medicine, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Critical Illness, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), education, 030204 cardiovascular system & hematology, Virus diseases, 03 medical and health sciences, 0302 clinical medicine, Internal Medicine, Humans, Thrombophilia, Medicine, In patient, Intensive care medicine, biology, SARS-CoV-2, business.industry, Critically ill, COVID-19, 030104 developmental biology, Antibodies, Antiphospholipid, biology.protein, Antibody, business
Abstract

We read with great interest the comment by Suarez-Perez et al. on our article.[1] We share their concerns regarding the need for a cautious interpretation of antiphospholipid antibodies (aPLA) positivity in patients with coronary virus disease 2019 (COVID-19). Herein, we would like to add further insights in the discussion.

Published
2020
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35. High frequency of antiphospholipid antibodies in critically ill COVID‐19 patients: a link with hypercoagulability?

Author

Guillaume Hékimian, Z. Amoura, A. Mathian, Makoto Miyara, M. Pineton De Chambrun, Corinne Frere, Isabelle Martin-Toutain, and Alain Combes

Subjects
0301 basic medicine, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), macromolecular substances, 030204 cardiovascular system & hematology, Fibrinogen, Systemic inflammation, Gastroenterology, SARS‐CoV‐2, 03 medical and health sciences, 0302 clinical medicine, COVID‐19, Internal medicine, antiphospholipid antibody, Internal Medicine, medicine, Letters to the Editor, Letter to the Editor, thrombosis, medicine.diagnostic_test, biology, business.industry, Retrospective cohort study, medicine.disease, Pulmonary embolism, Pneumonia, 030104 developmental biology, biology.protein, medicine.symptom, Antibody, business, medicine.drug, Partial thromboplastin time
Abstract

Coronavirus disease 2019 (COVID‐19) is associated with both severe systemic inflammation and a prothrombotic state, as reflected by significant increases in fibrinogen and D‐dimers levels that have been associated with poor prognosis and high rates of severe pulmonary embolism. A recent report suggested a role for antiphospholipid antibodies (aPLA) in the thrombotic manifestations associated with severe COVID‐19. As we also recently noticed unexplained lengthening of activated partial thromboplastin time (aPTT) in some critically ill COVID‐19 patients, we explored our patients for aPLA positivity.

Published
2020
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36. Hereditary sensory autonomic neuropathy type II: Report of two novel mutations in the FAM134B gene

Author

de Becdelievre, Alix, Falcão de Campos, Catarina, Vidailhet, Marie, Toutain, Annick, Becdelièvre, Alix, Funalot, Benoît, Bonello‐Palot, Nathalie, Stojkovic, Tanya, Institut Mondor de Recherche Biomédicale (IMRB), and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)

Subjects
Pathology, medicine.medical_specialty, Sensory axonal neuropathy, business.industry, General Neuroscience, Osteomyelitis, medicine.medical_treatment, Dysautonomia, Sensory system, medicine.disease, Phenotype, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Nociception, Amputation, 030220 oncology & carcinogenesis, Sensation, medicine, Neurology (clinical), medicine.symptom, business, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

Hereditary sensory autonomic neuropathy (HSAN) type II is a rare, autosomal recessive, and early onset sensory neuropathy, characterized by severe and progressive sensation impairment, leading to ulcero-mutilating complications. FAM134B gene, also known as RETREG1 gene, mutations have been reported to be associated to HSAN-IIB. We report four patients from two unrelated families who developed during childhood a sensory axonal neuropathy with variable severity and pronounced nociception impairment. Complications such as recurrent ulcerations, osteomyelitis, and osteonecrosis leading to distal amputation were noticed. Dysautonomia was mild or even absent in our group of patients. Additionally, either clinical or neurophysiological motor impairment was not uncommon. Presence of upper motor neuron signs was also a distinctive feature in two related patients. After extensive workup, two novel homozygous mutations in the FAM134B gene were identified. This report expands the clinical and genetic spectrum of HSAN type II and emphasizes the phenotype variability even within the same family.

Published
2019
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37. Fryns type mesomelic dysplasia of the upper limbs caused by inverted duplications of the HOXD gene cluster

Author

Richard Redon, Pierre Lindenbaum, Denis Duboule, Flavie Diguet, Annaig Briand, André Mégarbané, Christian Bonnard, Caroline Schluth-Bolard, Cédric Le Caignec, Damien Sanlaville, Marie-Laure Vuillaume, Olivier Pichon, Benoît de Courtivron, Pierre-Antoine Rollat-Farnier, Marta Sanchez-Castro, and Annick Toutain

Subjects
Male, family, translocation, Mesomelic Dysplasia, breakpoints, Locus (genetics), hierarchy, Biology, Article, 03 medical and health sciences, Loss of Function Mutation, Gene Duplication, expression, Gene duplication, Genetics, medicine, Humans, Limb development, Upper Extremity Deformities, Congenital, Enhancer, Gene, domains, time, Cells, Cultured, Genetics (clinical), kantaputra type, Homeodomain Proteins, Bone Diseases, Developmental, 0303 health sciences, 030305 genetics & heredity, Infant, medicine.disease, Phenotype, HOXD13, Dysplasia, Multigene Family, Female
Abstract

The HoxD cluster is critical for vertebrate limb development. Enhancers located in both the telomeric and centromeric gene deserts flanking the cluster regulate the transcription of HoxD genes. In rare patients, duplications, balanced translocations or inversions misregulating HOXD genes are responsible for mesomelic dysplasia of the upper and lower limbs. By aCGH, whole-genome mate-pair sequencing, long-range PCR and fiber fluorescent in situ hybridization, we studied patients from two families displaying mesomelic dysplasia limited to the upper limbs. We identified microduplications including the HOXD cluster and showed that microduplications were in an inverted orientation and inserted between the HOXD cluster and the telomeric enhancers. Our results highlight the existence of an autosomal dominant condition consisting of isolated ulnar dysplasia caused by microduplications inserted between the HOXD cluster and the telomeric enhancers. The duplications likely disconnect the HOXD9 to HOXD11 genes from their regulatory sequences. This presumptive loss-of-function may have contributed to the phenotype. In both cases, however, these rearrangements brought HOXD13 closer to telomeric enhancers, suggesting that the alterations derive from the dominant-negative effect of this digit-specific protein when ectopically expressed during the early development of forearms, through the disruption of topologically associating domain structure at the HOXD locus.

Published
2019
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38. Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies

Author

Mélanie Fradin, Nicolas Sadoul, Xavier Waintraub, Didier Klug, Albert Hagège, Pascal Sabouraud, Arnaud Isapof, Julien Durigneux, Olivier Lascols, Pascal Laforêt, Armelle Magot, Ivana Dabaj, Eloi Marijon, Camille Vatier, Pascal Cintas, Emmanuelle Salort, Bénédicte Gaborit, Antoine Muchir, Xavier Ferrer, Pascale Richard, Corinne Metay, Stéphane Boulé, Sarah Leonard-Louis, Philippe Mabo, V. Tiffreau, Caroline Stalens, Jitendra K. Vohra, Stéphane Schaeffer, Khadija Chikhaoui, Eric Bieth, Sandra Mercier, Pierre Ambrosi, Aleksandra Nadaj-Pakleza, Michèle Mayer, Katja Zeppenfeld, Gisèle Bonne, Véronique Manel, Jean-Marc Davy, Guilhem Sole, Ghassan Moubarak, Nicolas Lamblin, Klaus Dieterich, Christophe Meune, Abdallah Fayssoil, Arnaud Lazarus, Philippe Maury, Karim Wahbi, Philippe Petiot, Isabelle Jéru, Annick Toutain, Corinne Vigouroux, Ana Ferreiro, Maud Michaud, H.M. Bécane, Bruno Eymard, Thomas D. Gossios, Marie-Christine Vantyghem, Saurabh Kumar, Estelle Gandjbakhch, Yann Péréon, T. Thompson, Marie-Christine Minot-Myhié, Anthony Behin, Frédéric Sacher, Philippe Charron, Nicolas Combes, Julien Praline, Dominique Babuty, Emmanuelle Lagrue, Usha B. Tedrow, Jean-Marc Sellal, Florence Petit, Perry M. Elliott, Frédéric Anselme, Philippe Chevalier, Frederic Taithe, Christine Barnerias, Vincent Laugel, Andoni Echaniz-Laguna, Raphaël P. Martins, Alexander F.A. Androulakis, Rabah Ben Yaou, Franck Boccara, Ulrike Walther-Louvier, Tanya Stojkovic, Françoise Bouhour, Annachiara De Sandre-Giovannoli, Susana Quijano-Roy, Françoise Chapon, Jean-Noël Trochu, Céline Tard, Anne Rollin, Jean-Marie Cuisset, Denis Duboc, Raphaël Porcher, Catherine Sarret, Jonathan M. Kalman, Florence Demurger, Damien Bonnet, Christine Francannet, Neal K. Lakdawala, Romain Eschalier, Fabien Labombarda, Kostantinos Savvatis, Raul Juntas Morales, Isabelle Desguerre, Nicolas Lévy, Anne-Claire Brehin, Service de Cardiologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Rouen, Normandie Université (NU), St Bartholomew's Hospital (London), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Association française contre les myopathies (AFM-Téléthon), IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Service de Cardiologie B, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hôpital Ambroise Paré [AP-HP], William Harvey Research Institute, Barts and the London Medical School, Biostatistique et épidemiologie clinique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Filière Neuromusculaire (FILNEMUS), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université de Caen Normandie (UNICAEN), Laboratoire d'Informatique Scientifique et Industrielle (LISI), Université de Poitiers-Ecole Nationale Supérieure de Mécanique et d'Aérotechnique [Poitiers] (ISAE-ENSMA), Hôpital Raymond Poincaré [AP-HP], CHU Lille, Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Aix Marseille Université (AMU), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Pasteur [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), The Royal Melbourne Hospital, Leiden University Medical Center (LUMC), Universiteit Leiden, Service de neurologie pédiatrique [CHU Necker], Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Hôpital Privé Le Bois Ramsay Santé [Lille], Service de génétique [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Roger Salengro [Lille], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire [Grenoble] (CHU), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Clermont-Ferrand, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Bordeaux], Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie cadiovasculaire et thoracique [Rouen], Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Service de cardiologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Trousseau [APHP], Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Strasbourg, Clinique Ambroise Paré [Centres Médico-Chirurgicaux Ambroise Pré, Pierre Cherest, Hartmann], Hôpital Cochin [AP-HP], Hospices Civils de Lyon (HCL), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Lorraine (UL), Service de neurologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Laboratoire d'étude de la motricité humaine - EA 3608 (LEMH), Université de Lille, Droit et Santé, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montréal (UdeM), Laboratoire Génie des procédés papetiers (LGP2 ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), The Heart Hospital [London], University College of London [London] (UCL), This study was funded by grants from the AFM-Téléthon (French Alliance against Myopathies), which was not involved in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication. Some of this work was undertaken at University College London (United Kingdom) and St. Bartholomew’s Hospital (London, United Kingdom), which received a portion of funding from the United Kingdom Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], CHU Bordeaux [Bordeaux]-Université Bordeaux Segalen - Bordeaux 2, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie et maladies vasculaires, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP]-Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies rares neuromusculaires Aquitaine-Grand Sud Ouest, CHU Bordeaux [Bordeaux], Laboratoire d'Informatique Scientifique et Industrielle (LISI / ENSMA), LISI-ENSMA, Service de Biochimie-Génétique [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Cardiologie A, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Endocrinologie et Métabolisme, Unité de Cardiologie et Soins Intensifs, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Centre de Référence M3C Malformations Cardiaques Congénitales Complexes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Hôpital neurologique, Centre Hospitalier Universitaire de Lille (CHU de Lille), Service Neurologie Pédiatrique, Service de Neuropédiatrie, INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Département de Neurologie, Hôpital Civil de Strasbourg, Groupe Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, CHU - HÔTEL-DIEU Clermont-Ferrand, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Centre recherche en CardioVasculaire et Nutrition (C2VN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Clinique Ambroise Paré, CHU Cochin [AP-HP], Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hopital Neurologique-Hôpital Femme Mère Enfant, Department of Medicine, Columbia University [New York]-College of Physicians and Surgeons, Service de neurologie, Hospices Civils de Lyon (HCL)-Hôpital de la Croix-Rousse [CHU - HCL], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Hôpital de Rangueil, Institut Pascal - Clermont Auvergne (IP), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), laboratoire d'étude de la motricité humaine (LEMH EA3608), Université de Montréal - UdeM (CANADA), Laboratoire Génie des procédés papetiers (LGP2), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Myologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Genomic Institute for Diabetes - FR 3508 (EGID), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Hôpital Purpan [Toulouse], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut de Myologie, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Tachycardia, medicine.medical_specialty, implantable, Accurate estimation, Ventricular Tachyarrhythmias, Validation Studies as Topic, 030204 cardiovascular system & hematology, tachycardia, Sudden death, LMNA, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, death, Physiology (medical), Internal medicine, defibrillators, medicine, Humans, In patient, 030212 general & internal medicine, sudden, [SDV.GEN]Life Sciences [q-bio]/Genetics, Prediction score, business.industry, Defibrillators, Implantable, ventricular, Tachycardia, Ventricular, Cardiology, Female, medicine.symptom, Cardiomyopathies, Cardiology and Cardiovascular Medicine, business
Abstract

Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator–treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0–7.2] and 5.1 [2.0–9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711–0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642–0.959), and the calibration slope was 1.082 (95% CI, 0.643–1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03058185.

Published
2019
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39. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

Author

Philippe M. Campeau, Katherine Agre, Vernon R. Sutton, Kirsty McWalter, Bertrand Isidor, Øystein L. Holla, Anna Lehman, Megha Desai, Jonathan Berg, Stéphane Bézieau, Rolph Pfundt, Jennifer Tarpinian, Jennifer B. Humberson, Holly A.F. Stessman, Madeleine R. Geisheker, Emma Bedoukian, Shalini N. Jhangiani, Marine I. Murphree, Annapurna Poduri, Anne-Sophie Denommé-Pichon, Christian Gilissen, Yaping Yang, Eliane Beauregard-Lacroix, Claude Férec, Francesca Filippini, Anne Guimier, Daryl A. Scott, Stephen Sanders, Julie C. Sapp, Ralitza H. Gavrilova, Slavé Petrovski, Ann Nordgren, Sylvia Redon, Ernie M.H.F. Bongers, Shelagh Joss, Jill A. Rosenfeld, Wallid Deb, Ingrid M. Wentzensen, Usha Kini, Vandana Shashi, Mindy H. Li, Stanislas Lyonnet, Thomas Garcia, Øyvind L. Busk, Christoffer Nellåker, Amber Begtrup, Brigitte Gilbert-Dussardier, Thomas Besnard, Francois V. Bolduc, Patrick R. Blackburn, Justine Rousseau, Frédéric Bilan, Eric W. Klee, Christopher T. Gordon, Pavel N. Pichurin, Peggy Kulch, Kevin P. Lally, Laurie Robak, Arnaud Picard, Kristian Tveten, Meredith Park, Sébastien Küry, Jaya Punetha, Moira Blyth, Asbjørg Stray-Pedersen, Jacqueline Harris, Erin L. Heinzen, Nicholas Stong, Cara M. Skraban, Julie S. Cohen, Aida Telegrafi, Xenia Latypova, Zeynep Coban Akdemir, Jacob Zyskind, Caitlin Troyer, Xiang-Jiao Yang, Tuula Rinne, Leslie G. Biesecker, Jennifer E. Posey, Kyle Retterer, Jeanne Amiel, Rui Xiao, Magnus Nordenskjöld, Tammie Dewan, Jennifer A. Sullivan, Charlotte von der Lippe, Evan E. Eichler, Anna Lindstrand, Dominique Bonneau, Yuri A. Zarate, Elaine H. Zackai, Fayth M. Kalb, Daniel H. Lowenstein, Shiri Avni, Benjamin Cogné, Jennifer J. Johnston, Kerri H. Whitlock, Catherine Shain, Séverine Audebert-Bellanger, Malin Kvarnung, Oana Caluseriu, David Goldstein, Annick Toutain, Andres Hernandez-Garcia, Brina Daniels, Sophie Ehresmann, James R. Lupski, Julie McGaughran, Ashley H Ebanks, Kévin Uguen, Marine Legendre, Sylvie Odent, Richard Redon, Erica H. Gerkes, Xiaofei Song, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Sainte Justine [Montréal], Université du Québec à Montréal = University of Québec in Montréal (UQAM), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Mayo Clinic [Rochester], University of California [San Francisco] (UCSF), University of California, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement Français du Sang Bretagne, EFS, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Johns Hopkins University School of Medicine [Baltimore], Kennedy Krieger Institute [Baltimore], Chapel Allerton Hospital, University of British Columbia (UBC), University of Dundee, Rush University Medical Center [Chicago], Oxford University Hospitals NHS Trust, Queen Elizabeth University Hospital (Glasgow), Trondheim University, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Virginia [Charlottesville], Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania [Philadelphia], National Human Genome Research Institute (NHGRI), Harvard Medical School [Boston] (HMS), Karolinska University Hospital [Stockholm], Duke University Medical Center, University of Groningen [Groningen], University of Arkansas for Medical Sciences (UAMS), McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Phoenix Children's Hospital, Columbia University [New York], University of Southern Queensland (USQ), Telemark Hospital Trust [Skien, Norway], University of Washington [Seattle], Oslo University Hospital [Oslo], Children’s Hospital of Philadelphia (CHOP ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Radboud University Medical Center [Nijmegen], Ann & Robert H. Lurie Children's Hospital of Chicago, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Alberta, Boston Children's Hospital, McGill University Health Center [Montreal] (MUHC), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Creighton University Medical School [Omaha, NE, USA], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), National Institute of Neurological Disorders and Stroke, K08 HG008986, National Human Genome Research Institute, BC Children’s Hospital Foundation, Genome British Columbia, Fonds de Recherche du Québec - Santé, Canadian Institutes of Health Research, Center for Individualized Medicine, Mayo Clinic, Health Regional Agency from Poitou-Charentes, French Ministry of Health, RC14_0107, HUGODIMS, NS053998, The Epilepsy Phenome/Genome Project, NS077303, Epi4K, Duke Genome Sequencing Clinic, NINDS R35 NS105078, National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, HG200328 12, intramural research program of the NHGRI, Dart NeuroScience, Kids Brain Health Network, Mining for Miracles, UM1 HG006542, National Heart, Lung, and Blood Institute, CIM Investigative and Functional Genomics Program, R01MH101221, National Institute of Mental Health, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Virginia, University of Pennsylvania, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), CCSD, Accord Elsevier, Faculteit Medische Wetenschappen/UMCG, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
CHROMATIN, Male, 0301 basic medicine, Autism, Sequence Homology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Medical and Health Sciences, 0302 clinical medicine, SCHIZOPHRENIA, Gene expression, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, de novo variants, Genetics (clinical), Pediatric, Genetics & Heredity, Genetics, biology, neurodevelopmental disorders, histone acetylation, Adaptor Proteins, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Biological Sciences, Prognosis, Phenotype, Chromatin, Mental Health, Histone, intellectual disability, Child, Preschool, Female, REGULATOR, congenital malformations, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], BRAIN-DEVELOPMENT, Adult, Adolescent, Histone acetyltransferase complex, Intellectual and Developmental Disabilities (IDD), Mutation, Missense, Deciphering Developmental Disorders study, autism spectrum disorder, KAT6B, RNAI SCREEN, Young Adult, 03 medical and health sciences, CAUSES Study, Rare Diseases, Intellectual Disability, Report, COFACTOR, medicine, RUBINSTEIN-TAYBI-SYNDROME, Humans, Amino Acid Sequence, Autistic Disorder, Preschool, Gene, Genetic Association Studies, Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Rubinstein–Taybi syndrome, Signal Transducing, Neurosciences, Infant, medicine.disease, TRRAP, Brain Disorders, SELF-RENEWAL, 030104 developmental biology, DE-NOVO MUTATIONS, Mutation, biology.protein, Missense, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 202928.pdf (Publisher’s version ) (Open Access) Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

Published
2019
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40. LIMK2-1 is a Hominidae-Specific Isoform of LIMK2 Expressed in Central Nervous System and Associated with Intellectual Disability

Author

Sylviane Marouillat, Rose-Anne Thépault, Frédéric Laumonnier, Annick Toutain, Patrick Vourc'h, H. Cubéros, Béatrice Vallée, Hélène Bénédetti, Martine Raynaud, Christian R. Andres, Frédérique Bonnet-Brilhault, Julie Tastet, University Medical Center [Utrecht], Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Equipe neurogénétique et neurométabolomique, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), German Aerospace Center (DLR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)

Subjects
Central Nervous System, Models, Molecular, 0301 basic medicine, Gene isoform, Neurite, [SDV]Life Sciences [q-bio], Neuronal Outgrowth, Phosphatase, Central nervous system, Mutation, Missense, Sequence Homology, Biology, Lim kinase, Mice, 03 medical and health sciences, 0302 clinical medicine, Intellectual Disability, Intellectual disability, medicine, Animals, Protein Isoforms, Missense mutation, Coding region, Genetic Predisposition to Disease, Amino Acid Sequence, Cells, Cultured, Neurons, General Neuroscience, Lim Kinases, Hominidae, medicine.disease, Rats, Cell biology, 030104 developmental biology, medicine.anatomical_structure, 030217 neurology & neurosurgery
Abstract

International audience; LIMK2 is involved in neuronal functions by regulating actin dynamics. Different isoforms of LIMK2 are described in databanks. LIMK2a and LIMK2b are the most characterized. A few pieces of evidence suggest that LIMK2 isoforms might not have overlapping functions. In this study, we focused our attention on a less studied human LIMK2 isoform, LIMK2-1. Compared to the other LIMK2 isoforms, LIMK2-1 contains a supplementary C-terminal phosphatase 1 inhibitory domain (PP1i). We found out that this isoform was hominidae-specific and showed that it was expressed in human fetal brain and faintly in adult brain. Its coding sequence was sequenced in 173 patients with sporadic non-syndromic intellectual disability (ID), and we observed an association of a rare missense variant in the PP1i domain (rs151191437, p.S668P) with ID. Our results also suggest an implication of LIMK2-1 in neurite outgrowth and neurons arborization which appears to be affected by the p.S668P variation. Therefore our results suggest that LIMK2-1 plays a role in the developing brain, and that a rare variation of this isoform is a susceptibility factor in ID.

Published
2019
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41. Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Author

Kees E. P. van Roozendaal, Molka Kammoun, Michael Field, Andreas Dufke, Joris Vermeesch, Annick Toutain, Hao Hu, Theresa Mihalic Mosher, Joep P.M. Geraedts, Hans-Hilger Ropers, Peter White, Jan Liebelt, Sungjin Moon, Vera M. Kalscheuer, Joost Gribnau, Bas de Hoon, Germán Rodríguez Criado, Marie Shaw, Ute Grasshoff, Stefan A. Haas, Benjamin J. Kelly, Lynne Hobson, Marjan De Rademaeker, Christelle Golzio, Suzanna G.M. Frints, Olaf Riess, Claudia S. Bauer, Eric Haan, Nicholas Katsanis, Peter Bauer, Karen W. Gripp, Renee Carroll, Jozef Gecz, Jean Pierre Fryns, Cristina Gontan, Aysegul Ozanturk, Eveline Rentmeester, Martine Raynaud, Scott E. Hickey, Daniel C. Koboldt, Sylvie Manouvrier-Hanu, Lucinda Murray, Koen Devriendt, Christopher Schroeder, Kathryn Friend, Developmental Biology, Obstetrics & Gynecology, MUMC+: DA KG Bedrijfsbureau (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, MUMC+: DA KG Lab Centraal Lab (9), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Duke University [Durham], Hospital Universitario Virgen del Rocío [Sevilla], University of Tübingen, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hunter Genetics, Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Nationwide Children's Hospital, Ohio State University [Columbus] (OSU), University Hospitals Leuven [Leuven], Nemours/Alfred I. du Pont Hospital for Children, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, University of Adelaide, Women’s and Children’s Hospital [Adelaide], SA Pathology [Adelaide, SA, Australia], Vrije Universiteit Brussel (VUB), South Australian Health and Medical Research Institute [ Adelaide] (SAHMRI), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), univOAK, Archive ouverte, Reproduction and Genetics, Clinical sciences, and Medical Genetics

Subjects
Male, 0301 basic medicine, X-linked intellectual disability, PROTEIN, [SDV.GEN] Life Sciences [q-bio]/Genetics, FUNCTIONAL-ACTIVITY, Mice, 0302 clinical medicine, Genes, X-Linked, X Chromosome Inactivation, RNF12, Missense mutation, TRANSCRIPTION, Child, Zebrafish, Genetics, Middle Aged, Phenotype, Pedigree, Ubiquitin ligase, Psychiatry and Mental health, medicine.anatomical_structure, Child, Preschool, Female, Adult, Conduct Disorder, Adolescent, Ubiquitin-Protein Ligases, NPAS3, Biology, 03 medical and health sciences, Cellular and Molecular Neuroscience, Intellectual Disability, medicine, Ring finger, Animals, Humans, Molecular Biology, Transcription factor, RLIM, [SDV.GEN]Life Sciences [q-bio]/Genetics, CHROMOSOME INACTIVATION, MUTATIONS, Infant, Newborn, Ubiquitination, Wild type, Zebrafish Proteins, medicine.disease, biology.organism_classification, HEK293 Cells, 030104 developmental biology, Mutation, Mental Retardation, X-Linked, biology.protein, LIM COFACTORS, 030217 neurology & neurosurgery, Transcription Factors, GENE UBE2A CAUSE
Abstract

RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes co-segregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

Published
2019
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42. CytoProcessorTM: A New Cervical Cancer Screening System for Remote Diagnosis

Author

Matthieu Toutain, Joëlle Depardon, Arnaud Renouf, Incarnation Garcia, Romain Brixtel, Carole Ferreri, Yann Caillot, Cyril Bazin, François Saunier, Marie-Claire Mathieu, Elizabeth Faris Crowell, Jérôme Vaussanvin, and Boris Lesner

Subjects
medicine.medical_specialty, education.field_of_study, Histology, Cervical screening, business.industry, Population, Digital pathology, Papanicolaou stain, General Medicine, Papanicolaou Test, 030224 pathology, medicine.disease, Pathology and Forensic Medicine, 03 medical and health sciences, Squamous intraepithelial lesion, 0302 clinical medicine, 030220 oncology & carcinogenesis, Medicine, Radiology, Medical diagnosis, business, education, Virtual slide
Abstract

Background: Current automated cervical cytology screening systems still heavily depend on manipulation of glass slides. We developed a new system called CytoProcessorTM (DATEXIM, Caen, France), which increases sensitivity and takes advantage of virtual slide technology to simplify the workflow and save worker time. We used an approach based on artificial intelligence to identify abnormal cells among the tens of thousands in a cervical preparation. Objectives: We set out to compare the diagnostic sensitivity and specificity of CytoProcessorTM and the ThinPrep Imaging System (HOLOGIC, Marlborough, MA, USA). Methods: A representative population of 1,352 cases was selected from the routine workflow in a private laboratory. Diagnoses were established using the ThinPrep Imaging System and CytoProcessorTM. All discordances were resolved by a consensus committee. Results: Compared to the ThinPrep Imaging System, CytoProcessorTM significantly improves diagnostic sensitivity without compromising specificity. The sensitivity of detection of “atypical squamous cells of undetermined significance (ASC-US) and more severe” and “low-grade squamous intraepithelial lesion and more severe” was significantly higher using CytoProcessorTM. Considering that cases with a truth diagnosis of ASC-US or more severe required clinical follow-up, 1.5% of the cases (21/1,360) would have been missed if the CytoProcessorTM diagnosis had been used for clinical decision-making. In contrast, 4% of the cases (54/1,360) were missed when the ThinPrep Imaging System diagnosis was used for clinical decision-making. There were 2.6 times fewer false negatives using CytoProcessorTM. The CytoProcessorTM workflow was 1.5 times faster in terms of worker time. Conclusions: CytoProcessorTM is the first of a new generation of automated screening systems, demonstrating improved sensitivity and yielding significant gains in processing time. In addition, the fully digital nature of slide presentation in CytoProcessorTM allows the remote diagnosis of Papanicolaou tests for the first time.

Published
2019
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43. Holding thermal receipt paper and eating food after using hand sanitizer results in high serum bioactive and urine total levels of bisphenol A (BPA).

Author

Annette M Hormann, Frederick S Vom Saal, Susan C Nagel, Richard W Stahlhut, Carol L Moyer, Mark R Ellersieck, Wade V Welshons, Pierre-Louis Toutain, and Julia A Taylor

Subjects
Medicine, Science
Abstract

Bisphenol A (BPA) is an endocrine disrupting environmental contaminant used in a wide variety of products, and BPA metabolites are found in almost everyone's urine, suggesting widespread exposure from multiple sources. Regulatory agencies estimate that virtually all BPA exposure is from food and beverage packaging. However, free BPA is applied to the outer layer of thermal receipt paper present in very high (∼20 mg BPA/g paper) quantities as a print developer. Not taken into account when considering thermal paper as a source of BPA exposure is that some commonly used hand sanitizers, as well as other skin care products, contain mixtures of dermal penetration enhancing chemicals that can increase by up to 100 fold the dermal absorption of lipophilic compounds such as BPA. We found that when men and women held thermal receipt paper immediately after using a hand sanitizer with penetration enhancing chemicals, significant free BPA was transferred to their hands and then to French fries that were eaten, and the combination of dermal and oral BPA absorption led to a rapid and dramatic average maximum increase (Cmax) in unconjugated (bioactive) BPA of ∼7 ng/mL in serum and ∼20 µg total BPA/g creatinine in urine within 90 min. The default method used by regulatory agencies to test for hazards posed by chemicals is intra-gastric gavage. For BPA this approach results in less than 1% of the administered dose being bioavailable in blood. It also ignores dermal absorption as well as sublingual absorption in the mouth that both bypass first-pass liver metabolism. The elevated levels of BPA that we observed due to holding thermal paper after using a product containing dermal penetration enhancing chemicals have been related to an increased risk for a wide range of developmental abnormalities as well as diseases in adults.

Published
2014
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44. Family Outbreak of Shiga Toxin–producing Escherichia coli O123:H–, France, 2009

Author

Lisa A. King, Ingrid Filliol-Toutain, Patricia Mariani-Kurkidjian, Véronique Vaillant, Christine Vernozy-Rozand, Sarah Ganet, Nathalie Pihier, Patrick Niaudet, and Henriette de Valk

Subjects
Shiga toxin–producing Escherichia coli O123:H–, Escherichia coli, disease outbreaks, foodborne diseases, zoonoses, ground beef, Medicine, Infectious and parasitic diseases, RC109-216
Published
2010
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45. Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

Author

Stéphane Bézieau, Médéric Jeanne, Anne Sophie Denommé-Pichon, Jason Laufman, William B. Dobyns, Sébastien Küry, Judith Halewa, Elliott H. Sherr, Dominique Bonneau, Julie Vogt, Sophie Blesson, Hélène Demory, Jérôme Honnorat, Helene Cox, Séverine Audebert-Bellanger, Marie Laure Vuillaume, Sylviane Marouillat, Estelle Colin, Avgi Andreou, Emanuela Argilli, Bertrand Isidor, Bernhard Lohkamp, Miroslava Hancarova, Rajesh Khanna, Davit Babikyan, Sarka Bendova, Kimberly A. Aldinger, Aubin Moutal, Saskia M. Maas, Marjon van Slegtenhorst, Annick Toutain, Sylvie Odent, Rose Anne Thépault, Natella Kostandyan, Eleina M. England, Zdenek Sedlacek, Richard Redon, M. Mahdi Motazacker, Frédéric Laumonnier, Brigitte Gilbert-Dussardier, Grazia M.S. Mancini, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University of Arizona, Amsterdam UMC - Amsterdam University Medical Center, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Birmingham Women's and Children's NHS Foundation Trust, University of Akron, Yerevan State Medical University after Mkhitar Heratsi, Charles University [Prague] (CU), Center for Integrative Brain Research, University of Washington [Seattle], University of California [Los Angeles] (UCLA), University of California (UC), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institutet [Stockholm], National Human Genome Research Institute, Ministry of Health of the Czech Republic, DGOS, Wellcome Trust, Chard-Hutchinson, Xavier, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Amsterdam UMC, University of California, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Genetics, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Human Genetics, ANS - Cellular & Molecular Mechanisms, ANS - Complex Trait Genetics, and ACS - Pulmonary hypertension & thrombosis

Subjects
Models, Molecular, Male, 0301 basic medicine, Hydrolases, [SDV]Life Sciences [q-bio], Hippocampal formation, Medical and Health Sciences, 0302 clinical medicine, Neurodevelopmental disorder, Tubulin, Models, Neurotrophic factors, Cerebellum, Intellectual disability, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, dendrite branching, Genetics (clinical), de novo missense variants, Pediatric, Genetics & Heredity, DPYSL5, Biological Sciences, [SDV] Life Sciences [q-bio], corpus callosum agenesis, Mental Health, Child, Preschool, Neurological, Female, Microtubule-Associated Proteins, Adult, Neurite, Intellectual and Developmental Disabilities (IDD), primary neuronal cultures, Mutation, Missense, Biology, Young Adult, 03 medical and health sciences, Rare Diseases, Mediator, Report, Intellectual Disability, Genetics, medicine, Humans, Preschool, Corpus Callosum Agenesis, brain malformation, Neurosciences, Molecular, medicine.disease, neurodevelopmental disorder, Brain Disorders, 030104 developmental biology, Neurodevelopmental Disorders, Mutation, Missense, Agenesis of Corpus Callosum, Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

Published
2021
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46. A Large Impact of Obesity on the Disposition of Ivermectin, Moxidectin and Eprinomectin in a Canine Model: Relevance for COVID-19 Patients

Author

Alain Bousquet-Mélou, Isabelle Bargues, Jean-François Sutra, Pierre-Louis Toutain, Anne Lespine, Innovations Thérapeutiques et Résistances (InTheRes), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and The Royal Veterinary College, Hawkshead Campus

Subjects
0301 basic medicine, obesity, Calorie, [SDV]Life Sciences [q-bio], 030231 tropical medicine, 030106 microbiology, RM1-950, Pharmacology, Loading dose, ivermectin, 03 medical and health sciences, chemistry.chemical_compound, canine model, 0302 clinical medicine, Ivermectin, Pharmacokinetics, Medicine, Pharmacology (medical), Original Research, Volume of distribution, business.industry, urogenital system, COVID-19, dosage regimen, medicine.disease, Obesity, 3. Good health, Moxidectin, chemistry, embryonic structures, Lean body mass, moxidectin, Therapeutics. Pharmacology, business, pharmacokinetics, medicine.drug
Abstract

Ivermectin (IVM) and moxidectin (MOX) are used extensively as parasiticides in veterinary medicine. Based on in vitro data, IVM has recently been proposed for the prevention and treatment of COVID-19 infection, a condition for which obesity is a major risk factor. In patients, IVM dosage is based on total body weight and there are no recommendations to adjust dosage in obese patients. The objective of this study was to establish, in a canine model, the influence of obesity on the clearance and steady-state volume of distribution of IVM, MOX, and a third analog, eprinomectin (EPR). An experimental model of obesity in dogs was based on a high calorie diet. IVM, MOX, and EPR were administered intravenously, in combination, to a single group of dogs in two circumstances, during a control period and when body weight had been increased by 50%. In obese dogs, clearance, expressed in absolute values (L/day), was not modified for MOX but was reduced for IVM and EPR, compared to the initial control state. However, when scaled by body weight (L/day/kg), plasma clearance was reduced by 55, 42, and 63%, for IVM, MOX and EPR, respectively. In contrast, the steady-state volume of distribution was markedly increased, in absolute values (L), by obesity. For IVM and MOX, this obese dog model suggests that the maintenance doses in the obese subject should be based on lean body weight rather than total weight. On the other hand, the loading dose, when required, should be based on the total body weight of the obese subject.

Published
2021
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47. Multimodal evaluation of hypoxia in brain metastases of lung cancer and interest of hypoxia image-guided radiotherapy

Author

Aurélien Corroyer-Dulmont, Cécile Perrio, Didier Divoux, Guénaëlle Levallet, Méziane Ibazizène, Stéphane Guillouet, Jérôme Levallet, Samuel Valable, Jade Fantin, Jérôme Toutain, Louisa Barré, Elise Letissier, Sylvain Teulier, Françoise Chapon, Nicola R. Sibson, Sébastien Serres, Céline Bazille, Laurent Chatre, Myriam Bernaudin, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Service de pneumologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Département de Pathologie [CHU Caen], School of Life Sciences, University of Nottingham, UK (UON), Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford [Oxford], Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Oncology [Oxford, UK] (CRUK/MRC), and University of Oxford

Subjects
Cancer microenvironment, medicine.medical_specialty, Lung Neoplasms, Cancer therapy, [SDV]Life Sciences [q-bio], Science, medicine.medical_treatment, Article, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, medicine, Pimonidazole, Animals, Humans, Registries, Lung cancer, 030304 developmental biology, Aged, 0303 health sciences, Multidisciplinary, Tumor hypoxia, Radiotherapy, business.industry, Brain Neoplasms, Hypoxia (medical), Middle Aged, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Rats, Radiation therapy, CNS cancer, 030220 oncology & carcinogenesis, Cancer research, Medicine, Tumor Hypoxia, Neurosurgery, medicine.symptom, business, Immunostaining, Radiotherapy, Image-Guided
Abstract

Lung cancer patients frequently develop brain metastases (BM). Despite aggressive treatment including neurosurgery and external-radiotherapy, overall survival remains poor. There is a pressing need to further characterize factors in the microenvironment of BM that may confer resistance to radiotherapy (RT), such as hypoxia. Here, hypoxia was first evaluated in 28 biopsies from patients with non‑small cell lung cancer (NSCLC) BM, using CA-IX immunostaining. Hypoxia characterization (pimonidazole, CA-IX and HIF-1α) was also performed in different preclinical NSCLC BM models induced either by intracerebral injection of tumor cells (H2030-Br3M, H1915) into the cortex and striatum, or intracardial injection of tumor cells (H2030-Br3M). Additionally, [18F]-FMISO-PET and oxygen-saturation-mapping-MRI (SatO2-MRI) were carried out in the intracerebral BM models to further characterize tumor hypoxia and evaluate the potential of Hypoxia-image-guided-RT (HIGRT). The effect of RT on proliferation of BM ([18F]-FLT-PET), tumor volume and overall survival was determined. We showed that hypoxia is a major yet heterogeneous feature of BM from lung cancer both preclinically and clinically. HIGRT, based on hypoxia heterogeneity observed between cortical and striatal metastases in the intracerebrally induced models, showed significant potential for tumor control and animal survival. These results collectively highlight hypoxia as a hallmark of BM from lung cancer and the value of HIGRT in better controlling tumor growth.

Published
2021
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48. A Combined Study with 18F-FDG and 11C-Methionine Dynamic PET for the Grading of Brain Gliomas

Author

N Vikhrova, D Kalaeva, Toutain J, Valable S, A Postnov, Derlon J, Konakova T, Clerck Nd, Usachev D, I Pronin, NN Burdenko Neurosurgical Institute (NNBNI), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Republican Research and Practical Center of Neurology and Neurosurgery, and University of Antwerp (UA)

Subjects
18 F-FDG, Pathology, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], PET-CT, 11c methionine, Brain gliomas, Text mining, Glioma grading, Medicine, 11C-Methionine, business, Grading (tumors), metabolism
Abstract

Purpose: Conventional MRI based on contrast enhancement and T2/FLAIR is often not sufficient in differentiating grade II from grade III and grade III from grade IV diffuse gliomas. Here we assessed advanced metabolic imaging using two well characterized PET tracers, namely 18F-FDG and 11C-Methionine.Methods: In this prospective study, 39 patients were enrolled with diffuse gliomas of grades II, III or IV underwent dynamic [18F]-FDF-PET and [11C]-Methionine. The first minutes were taken into accountResults: The use of 11C- Methionine provided significant differences between the different histologic subgroups with a higher number of parameters than did the use of 18 F-FDG. The most informative parameter is T/Np (T/N at the peak of the first maximum) with 11C- Methionine.Conclusion: The study of the first minute passage of 18F-FDG and/or 11C- Methionine through the tumor and healthy tissues in brain gliomas could not only allow improving the identification of the different glioma grades, but also to shorten the time spent by the patients under the camera. In case of using one tracer, methionine still would be the best choice. Otherwise, the use of 18F-FDG and SUVр (SUV at the peak of the first maximum) would provide results likely comparable to methionine T/N index.

Published
2021

49. Critical role of Aquaporin-1 and telocytes in infantile hemangioma response to propranolol beta blockade

Author

Sandra Oucherif, Marie-Laure Jullie, Benoit Rousseau, Sabrina Lacomme, Alain Taieb, Hamid Reza Rezvani, François Moisan, Christine Léauté-Labrèze, Marc Bonneu, Stéphane Claverol, Jerome Toutain, Maya Loot, P. Kaulanjan-Checkmodine, Thierry Couffinhal, Sorilla Prey, Léa Dousset, Etienne Gontier, and Muriel Cario-André

Subjects
0301 basic medicine, Stromal cell, Proteome, Angiogenesis, Adrenergic beta-Antagonists, Propranolol, Hemangioma, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Neoplastic Syndromes, Hereditary, Cell Line, Tumor, medicine, Animals, Humans, Hemangioma, Capillary, Telocytes, Receptor, Tube formation, Matrigel, Multidisciplinary, Aquaporin 1, Neovascularization, Pathologic, business.industry, Biological Sciences, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, Receptors, Adrenergic, beta-2, business, medicine.drug
Abstract

Propranolol, a nonselective β-adrenergic receptor (ADRB) antagonist, is the first-line therapy for severe infantile hemangiomas (IH). Since the incidental discovery of propranolol efficacy in IH, preclinical and clinical investigations have shown evidence of adjuvant propranolol response in some malignant tumors. However, the mechanism for propranolol antitumor effect is still largely unknown, owing to the absence of a tumor model responsive to propranolol at nontoxic concentrations. Immunodeficient mice engrafted with different human tumor cell lines were treated with anti-VEGF bevacizumab to create a model sensitive to propranolol. Proteomics analysis was used to reveal propranolol-mediated protein alteration correlating with tumor growth inhibition, and Aquaporin-1 (AQP1), a water channel modulated in tumor cell migration and invasion, was identified. IH tissues and cells were then functionally investigated. Our functional protein association networks analysis and knockdown of ADRB2 and AQP1 indicated that propranolol treatment and AQP1 down-regulation trigger the same pathway, suggesting that AQP1 is a major driver of beta-blocker antitumor response. Examining AQP1 in human hemangioma samples, we found it exclusively in a perivascular layer, so far unrecognized in IH, made of telocytes (TCs). Functional in vitro studies showed that AQP1-positive TCs play a critical role in IH response to propranolol and that modulation of AQP1 in IH-TC by propranolol or shAQP1 decreases capillary-like tube formation in a Matrigel-based angiogenesis assay. We conclude that IH sensitivity to propranolol may rely, at least in part, on a cross talk between lesional vascular cells and stromal TCs.

Published
2021
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50. Pediatric Acute B-Cell Lymphoblastic Leukemia Developing Following Recent SARS-CoV-2 Infection

Author

Noémie Wagner, Frederic Baleydier, Fabienne Toutain, Arnaud G L'Huillier, Anne-Marie Calza, Charlotte Leclercq, Céline Lironi, Marc Ansari, and Geraldine Blanchard-Rohner

Subjects
Male, Pancytopenia, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), B-Cell Lymphoblastic Leukemia, medicine.disease_cause, Virus, EBV, Acute lymphocytic leukemia, hemic and lymphatic diseases, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, medicine, Humans, Pediatrics, Perinatology, and Child Health, Child, Coronavirus, Pediatric, Leukemi, ddc:618, business.industry, SARS-CoV-2, COVID-19, Hematology, Exanthema, medicine.disease, Prognosis, Rash, Cutaneous, Oncology, Pediatrics, Perinatology and Child Health, Immunology, Etiology, medicine.symptom, business
Abstract

Coronavirus disease-2019 in children has been linked to various clinical presentation, from paucisymptomatic cutaneous eruptions, to multisystemic inflammatory syndrome. We report the case of an 8-year-old boy who presented with persistent fever and pancytopenia, associated to a skin rash. An extensive etiological workup showed a positive serology for severe acute respiratory syndrome coronavirus 2 and Epstein-Barr virus. A few weeks later, type B acute lymphocytic leukemia was diagnosed. This case underlines the polymorphic appearance of coronavirus disease-2019 and the need for critical appraisal.

Published
2021
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