High-throughput microfluidic blood testing to phenotype genetically linked platelet disorders: an aid to diagnosis.

Linking the genetic background of patients with bleeding diathesis and altered platelet function remains challenging. We aimed to assess how a multiparameter microspot-based measurement of thrombus formation under flow can help identify patients with a platelet bleeding disorder. For this purpose, we studied 16 patients presenting with bleeding and/or albinism and suspected platelet dysfunction and 15 relatives.

Nicotinamide Mononucleotide Administration Prevents Doxorubicin-Induced Cardiotoxicity and Loss in Physical Activity in Mice.

Doxorubicin (Doxo) is a widely used antineoplastic drug with limited clinical application due to its deleterious dose-related side effects. We investigated whether nicotinamide mononucleotide (NMN) could protect against Doxo-induced cardiotoxicity and physical dysfunction in vivo. To assess the short- and long-term toxicity, two Doxo regimens were tested, acute and chronic.

Nicotinamide Mononucleotide Administration Triggers Macrophages Reprogramming and Alleviates Inflammation During Sepsis Induced by Experimental Peritonitis.

Peritonitis and subsequent sepsis lead to high morbidity and mortality in response to uncontrolled systemic inflammation primarily mediated by macrophages. Nicotinamide adenine dinucleotide (NAD+) is an important regulator of oxidative stress and immunoinflammatory responses. However, the effects of NAD+ replenishment during inflammatory activation are still poorly defined.

GATA1 pathogenic variants disrupt MYH10 silencing during megakaryopoiesis.

Background: GATA1 is an essential transcription factor for both polyploidization and megakaryocyte (MK) differentiation. The polyploidization defect observed in GATA1 variant carriers is not well understood.

Objective: To extensively phenotype two pedigrees displaying different variants in the GATA1 gene and determine if GATA1 controls MYH10 expression levels, a key modulator of MK polyploidization.

Safety evaluation after acute and sub-chronic oral administration of high purity nicotinamide mononucleotide (NMN-C®) in Sprague-Dawley rats.

β-nicotinamide mononucleotide (NMN) is a natural molecule intermediate in the biosynthesis of nicotinamide adenine dinucleotide (NAD). Preclinical evidences point to the beneficial effect of NMN administration on several age-related conditions. The present work aimed at studying mutagenicity, and genotoxicity, acute oral toxicity and subchronic oral toxicity of a high purity synthetic form of NMN (NMN-C®) following the OECD guidelines.

Simplification of syllable structure in childhood apraxia of speech: a 2-year follow-up French case study.

Although Childhood Apraxia of Speech (CAS) has been extensively investigated in the clinical literature, most of the findings regarding impairments in the production of syllable structure, recorded within this population, have been mainly focused on English. The main purpose of this two-year follow-up case study was, therefore, to examine whether syllable complexity may be considered as a robust indicator in CAS and whether it can explain the persistence of errors and, if so, at what age. This was tested in a boy followed up annually from age 5 to 7 who was administered a narrative task.

TicagRelor Or Clopidogrel in severe or terminal chronic kidney patients Undergoing PERcutaneous coronary intervention for acute coronary syndrome: The TROUPER trial.

Chronic kidney disease (CKD) is associated with an increased risk of acute coronary syndrome (ACS) and cardiovascular death. CKD patients suffering from ACS are exposed to an increased risk of thrombotic recurrences and a higher bleeding rate than patients with normal renal function. However, CKD patients are excluded or underrepresented in clinical trials.

Syllable duration changes during babbling: a longitudinal study of French infant productions.

At the babbling stage, the syllable does not have the temporal characteristics of adult syllables because of the infant's limited oro-motor skills. This research aims to further our knowledge of syllable duration and temporal variability and their evolution with age as an indicator of the development of articulatory skills. The possible impact of syllable position, as well as that of type of intrasyllabic associations and intersyllabic articulatory changes on these parameters has also been tested.

RasGRP2 Structure, Function and Genetic Variants in Platelet Pathophysiology.

RasGRP2 is calcium and diacylglycerol-regulated guanine nucleotide exchange factor I that activates Rap1, which is an essential signaling-knot in "inside-out" αIIbβ3 integrin activation in platelets. Inherited platelet function disorder caused by variants of RASGRP2 represents a new congenital bleeding disorder referred to as platelet-type bleeding disorder-18 (BDPLT18). We review here the structure of RasGRP2 and its functions in the pathophysiology of platelets and of the other cellular types that express it.

Rehabilitation of speech disorders following glossectomy, based on ultrasound visual illustration and feedback.

Intraoral surgery for tongue cancer usually induces speech disorders that have a negative impact on communication and quality of life. Studies have documented the benefit of tongue ultrasound imaging as a visual articulatory feedback for speech rehabilitation. This study aims to assess specifically the complementary contribution of visual feedback to visual illustration (i.

Subcellular localization of Rap1 GTPase activator CalDAG-GEFI is orchestrated by interaction of its atypical C1 domain with membrane phosphoinositides.

Background: The small GTPase Rap1 and its guanine nucleotide exchange factor, CalDAG-GEFI (CDGI), are critical for platelet function and hemostatic plug formation. CDGI function is regulated by a calcium binding EF hand regulatory domain and an atypical C1 domain with unknown function.

Objective: Here, we investigated whether the C1 domain controls CDGI subcellular localization, both in vitro and in vivo.

Platelet CD40 ligand and bleeding during P2Y12 inhibitor treatment in acute coronary syndrome.

Antiplatelet therapy through inhibition of the adenosine diphosphate (ADP)/P2Y12 pathway is commonly used in the treatment of acute coronary syndrome (ACS). Although efficient in preventing platelet activation and thrombus formation, it increases the risk of bleeding complications. In patients with ACS receiving platelet aggregation inhibitors, that is, P2Y12 blockers (n = 923), we investigated the relationship between plasma and platelet-associated CD40L levels and bleeding events (n = 71).

A Novel Rapid Method of Red Blood Cell and Platelet Permeabilization and Staining for Flow Cytometry Analysis.

Background: Flow cytometry essentially focuses on surface-expressed proteins, with few protocols being devoted to intracellular components. We evaluated a two-step procedure using new formaldehyde-free permeabilization and staining reagents that allow the staining of platelets and red blood cells (RBCs) from whole blood.

Methods: Citrated blood was treated with the new staining protocol (NSP) or control reagent (phosphate-buffered solution bovine serum albumin) and stained with antibodies against surface or intracellular markers.

Increased levels of the megakaryocyte and platelet expressed cysteine proteases stefin A and cystatin A prevent thrombosis.

Increased platelet activity occurs in type 2 diabetes mellitus (T2DM) and such platelet dysregulation likely originates from altered megakaryopoiesis. We initiated identification of dysregulated pathways in megakaryocytes in the setting of T2DM. We evaluated through transcriptomic analysis, differential gene expressions in megakaryocytes from leptin receptor-deficient mice (db/db), exhibiting features of human T2DM, and control mice (db/+).

Phenotype analysis and clinical management in a large family with a novel truncating mutation in , the CalDAG-GEFI encoding gene.

Background: Genetic variants in the gene encoding calcium and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) represent a new inherited bleeding disorder linked to major defects of platelet aggregation and activation of αIIbβ3 integrin. They are of major interest as CalDAG-GEFI is receiving attention as a potential target for antiplatelet therapy for prevention and treatment of cardiovascular disorders including arterial thrombosis and atherosclerosis.

Objectives: To better understand the phenotypical and clinical profiles of patients with CalDAG-GEFI deficiency.

Macrothrombocytopenia and dense granule deficiency associated with FLI1 variants: ultrastructural and pathogenic features.

Congenital macrothrombocytopenia is a family of rare diseases, of which a significant fraction remains to be genetically characterized. To analyze cases of unexplained thrombocytopenia, 27 individuals from a patient cohort of the Bleeding and Thrombosis Exploration Center of the University Hospital of Marseille were recruited for a high-throughput gene sequencing study. This strategy led to the identification of two novel variants (c.

Germline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34+ progenitors.

Variants in ETV6, which encodes a transcription repressor of the E26 transformation-specific family, have recently been reported to be responsible for inherited thrombocytopenia and hematologic malignancy. We sequenced the DNA from cases with unexplained dominant thrombocytopenia and identified six likely pathogenic variants in ETV6, of which five are novel. We observed low repressive activity of all tested ETV6 variants, and variants located in the E26 transformation-specific binding domain (encoding p.

Role of eNOS- and NOX-containing microparticles in endothelial dysfunction in patients with obesity.

Objective: To explore the pathophysiological profile of patients who have obesity and to investigate the potential role of circulating microparticles (MPs) in endothelial dysfunction in patients who have obesity.

Methods: The inflammatory and oxidative status and the cutaneous microvascular blood flow were characterized in 69 patients with android obesity and 46 subjects with normal weight (controls) by using laser Doppler flowmetry. Circulating MP levels were measured by flow cytometry, and endothelial nitric oxide synthase (eNOS) and NADPH oxidase (NOX) expression in MPs was investigated by Western blotting.

Reliability of the Language ENvironment Analysis system (LENA™) in European French.

In this study, we examined the accuracy of the Language ENvironment Analysis (LENA) system in European French. LENA is a digital recording device with software that facilitates the collection and analysis of audio recordings from young children, providing automated measures of the speech overheard and produced by the child. Eighteen native French-speaking children, who were divided into six age groups ranging from 3 to 48 months old, were recorded about 10-16 h per day, three days a week.

CD28 deletion improves obesity-induced liver steatosis but increases adiposity in mice.

Background/objectives: Lymphocytes have a critical role in visceral adipose tissue (AT) inflammation. The CD28 costimulatory molecule is required for lymphocyte activation and for the development of a functional regulatory T cells (Tregs) compartment; however, its role during obesity is unknown.

Methods: During diet-induced obesity, we investigated the effects of selective interference with CD28 signaling using knockout mice (Cd28KO) and a CTLA4-Ig fusion protein inhibiting CD28-B7 interactions.

Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort.

We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbβ3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real-time PCR.