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Avec l'apparition de nouvelles techniques minimalement invasives, la chirurgie des hernies ventrales connaît depuis une dizaine d'années de profonds remaniements. Elles ont en commun d'intégrer les concepts fondamentaux de reconstruction pariétale de la chirurgie ouverte à une voie d'abord laparoscopique, dans le but de réduire les taux de complication du site opératoire et de permettre une réhabilitation accélérée. La diffusion des systèmes d'assistance robotique en chirurgie de la paroi facilite l'accès à ce type de procédure et permet d'envisager leur application dans des cas de plus en plus complexes. Les techniques de relaxation pariétale permettent la fermeture sans tension d'orifices herniaires larges. Elles sont maintenant aussi réalisées par voie minimalement invasive et de manière moins délabrante. Même si la place exacte de l'ensemble de ces techniques doit encore être mieux définie en fonction du type de hernie, ces prises en charge laparoscopiques ou robot-assistées semblent déjà permettre une récupération postopératoire plus rapide.

Background Podocalyxin (PODXL) is a highly sialylated adhesion glycoprotein that plays an important role in podocyte's physiology. Recently, missense and nonsense dominant variants in the PODXL gene have been associated with focal segmental glomerulosclerosis (FSGS), a leading cause of nephrotic syndrome and kidney failure. Their histologic description, however, was superficial or absent. Methods We performed exome sequencing on a three‐generation family affected by an atypical glomerular nephropathy and characterized the disease by light and electron microscopy. Results The disease was characterized by FSGS features and glomerular basement membrane duplication. Six family members displayed chronic proteinuria, ranging from mild manifestations without renal failure, to severe forms with end‐stage renal disease. Exome sequencing of affected twin sisters, their affected mother, healthy father, and healthy maternal uncle revealed a new nonsense variant cosegregating with the disease (c.1453C>T, NM_001018111) in the PODXL gene, which is known to be expressed in the kidney and to cause nephropathy when mutated. The variant is predicted to lead to a premature stop codon (p.Q485*) that results in the loss of the intracytoplasmic tail of the protein. Conclusion This is the first description of a peculiar association combining a PODXL stop‐gain variant and both FSGS and membranoproliferative glomerulonephritis features, described by light and electron microscopy., This study describes the association of a genetic Podocalyxin (PODXL) variant with a familial glomerular nephropathy characterized by focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis features. This finding expands the phenotypic spectrum associated to PODXL variants and highlights the importance to screen the PODXL gene for deleterious variants in similar disease forms.

Major surgery is associated with an increased risk of venous thromboembolism (VTE), thus the application of mechanical or pharmacologic prophylaxis is recommended. The incidence of VTE in patients with inherited platelet disorders (IPD) undergoing surgical procedures is unknown and no information on the current use and safety of thromboprophylaxis, particularly of low-molecular-weight-heparin in these patients is available. Here we explored the approach to thromboprophylaxis and thrombotic outcomes in IPD patients undergoing surgery at VTE-risk participating in the multicenter SPATA study. We evaluated 210 surgical procedures carried out in 155 patients with well-defined forms of IPD (VTE-risk: 31% high, 28.6% intermediate, 25.2% low, 15.2% very low). The use of thromboprophylaxis was low (23.3% of procedures), with higher prevalence in orthopedic and gynecological surgeries, and was related to VTE-risk. The most frequently employed thromboprophylaxis was mechanical and appeared to be effective, as no patients developed thrombosis, including patients belonging to the highest VTE-risk classes. Low-molecular-weight-heparin use was low (10.5%) and it did not influence the incidence of post-surgical bleeding or of antihemorrhagic prohemostatic interventions use. Two thromboembolic events were registered, both occurring after high VTE-risk procedures in patients who did not receive thromboprophylaxis (4.7%). Our findings suggest that VTE incidence is low in patients with IPD undergoing surgery at VTE-risk and that it is predicted by the Caprini score. Mechanical thromboprophylaxis may be of benefit in patients with IPD undergoing invasive procedures at VTE-risk and low-molecular-weight-heparin should be considered for major surgery. Fil: Paciullo, Francesco. Università di Perugia; Italia Fil: Bury, Loredana. Università di Perugia; Italia Fil: Noris, Patrizia. Universita Degli Studi Di Pavia; Italia Fil: Falcinelli, Emanuela. Università di Perugia; Italia Fil: Melazzini, Federica. Universita Degli Studi Di Pavia; Italia Fil: Orsini, Sara. Università di Perugia; Italia Fil: Zaninetti, Carlo. Universita Degli Studi Di Pavia; Italia Fil: Abdul-Kadir, Rezan. Colegio Universitario de Londres; Reino Unido Fil: Obeng-Tuudah, Deborah. Colegio Universitario de Londres; Reino Unido Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Fabris, Fabrizio. Azienda Ospedaliera Di Padova; Italia Fil: Rivera, Jose. Hospital Universitario Morales Meseguery; España. Universidad de Murcia; España Fil: Lozano, Maria Luisa. Hospital Universitario Morales Meseguery; España. Universidad de Murcia; España Fil: Butta, Nora. Instituto de Investigacion del Hospital de la Paz.; España Fil: Favier, Remi. Armand Trousseau Children’s Hospital; Francia Fil: Cid, Ana Rosa. Hospital Universitario y Politecnico La Fe; España Fil: Fouassier, Marc. CHU de Nantes; Francia Fil: Podda, Gian Marco. Università degli Studi di Milano; Italia Fil: Santoro, Cristina. Università degli studi di Roma "La Sapienza"; Italia Fil: Grandone, Elvira. Istituto Nazionale di Ricovero e Cura a Carattere Scientifico "Saverio de Bellis"; Italia. Moscow State Medical University; Rusia Fil: Henskens, Yvonne. Maastricht University Medical Centre; Países Bajos Fil: Nurden, Paquita. Hospital Universitario Morales Meseguery; España. Universidad de Murcia; España Fil: Zieger, Barbara. Albert Ludwigs University of Freiburg; Alemania Fil: Cuker, Adam. University of Pennsylvania; Estados Unidos Fil: Devreese, Katrien. University of Ghent; Bélgica Fil: Tosetto, Alberto. Ospedale San Bortolo; Italia Fil: de Candia, Erica. Università Cattolica del Sacro Cuore; Italia. Istituto Nazionale di Ricovero e Cura a Carattere Scientifico "Saverio de Bellis"; Italia Fil: Dupuis, Arnaud. Université de Strasbourg; Francia Fil: Miyazaki, Koji. Kitasato University; Japón Fil: Othman, Maha. Queens University; Canadá Fil: Gresele, Paolo. Università di Perugia; Italia

GPVI, a major platelet activation receptor for collagen and fibrin, is considered as a particularly promising safe antithrombotic target. In this study, we show that human GPVI signals upon platelet adhesion to fibrinogen. Full spreading of human platelets on fibrinogen is abolished in platelets from GPVI-deficient patients suggesting that fibrinogen activates platelets through GPVI. While mouse platelets fail to spread on fibrinogen, human-GPVI-transgenic mouse platelets show full spreading and increased Ca2+ signalling through the tyrosine kinase Syk. Direct binding of fibrinogen to human GPVI was shown by surface plasmon resonance and by increased adhesion of human GPVI-transfected Rbl-2H3 cells to fibrinogen relative to mock-transfected cells. Blockade of human GPVI with the Fab of the monoclonal antibody 9O12 impairs platelet aggregation on preformed platelet aggregates in flowing blood independent of collagen and fibrin exposure. These results demonstrate that human GPVI binds to immobilized fibrinogen and show that this contributes to platelet spreading and platelet aggregation under flow.

Inherited platelets disorders (IPD) are pathologies associated with heterogeneous bleedingphenotypes. They are due to functional platelets deficiency that may come with morphological abnormalities and/or thrombocytopenia. Available diagnosis tools are used to link a functional deficiency to a protein defect and in some instances to a specific genetic mutation. However, in 2015 at least 50% of IPD are still not identified. In this context, the haemostasis laboratory of the EFS Alsace together with INSERM UMR S949 team are working to diagnose and characterize these pathologies. Thus, we found three new P2Y12 receptor variants in three different families. The mutation p.His187Gln has been fully characterized on blood fresh platelets coming from one patient and in an appropriate cellular model. The reproduction of the two other mutations (p.Tyr259Cys and p.Phe95Ser) is currently ongoing. We also studied a family in which three members are carrying a delta storage pool disease. The full exome sequencing analysis leads us to suspect the involvement of the nucleotides transporter VNUT in this pathology., Les thrombopathies congénitales sont des pathologies au phénotype hémorragique hétérogène dues à des anomalies fonctionnelles des plaquettes sanguines parfois associées à des anomalies morphologiques et/ou à une thrombopénie. Les outils diagnostic disponibles permettent de corréler une anomalie fonctionnelle plaquettaire à un déficit protéique voire à une mutation d’un gène spécifique. Cependant, en 2015, au moins 50% des thrombopathies restent non étiquetées. Dans ce contexte, le laboratoire d’hémostase de l’EFS Alsace et l’unité INSERM UMR S949 travaillent de concert à l’identification et à la caractérisation de ces pathologies. Ainsi, nous avons mis en évidence trois nouvelles mutations du récepteur P2Y12 dans trois familles différentes. La mutation p.His187Gln a été entièrement caractérisée sur des plaquettes fraiches du patient et dans un modèle cellulaire adapté. La reproduction des deux autres mutations (p.Tyr259Cys et p.Phe95Ser) est en cours. Nous avons par ailleurs identifié une famille dont trois membres sont atteints d’une maladie du pool vide non syndromique et nous suspectons grâce au séquençage d’exome effectué que le transporteur de nucléotides VNUT est impliqué dans la pathologie.

Inherited platelets disorders (IPD) are pathologies associated with heterogeneous bleedingphenotypes. They are due to functional platelets deficiency that may come with morphological abnormalities and/or thrombocytopenia. Available diagnosis tools are used to link a functional deficiency to a protein defect and in some instances to a specific genetic mutation. However, in 2015 at least 50% of IPD are still not identified. In this context, the haemostasis laboratory of the EFS Alsace together with INSERM UMR S949 team are working to diagnose and characterize these pathologies. Thus, we found three new P2Y12 receptor variants in three different families. The mutation p.His187Gln has been fully characterized on blood fresh platelets coming from one patient and in an appropriate cellular model. The reproduction of the two other mutations (p.Tyr259Cys and p.Phe95Ser) is currently ongoing. We also studied a family in which three members are carrying a delta storage pool disease. The full exome sequencing analysis leads us to suspect the involvement of the nucleotides transporter VNUT in this pathology.; Les thrombopathies congénitales sont des pathologies au phénotype hémorragique hétérogène dues à des anomalies fonctionnelles des plaquettes sanguines parfois associées à des anomalies morphologiques et/ou à une thrombopénie. Les outils diagnostic disponibles permettent de corréler une anomalie fonctionnelle plaquettaire à un déficit protéique voire à une mutation d’un gène spécifique. Cependant, en 2015, au moins 50% des thrombopathies restent non étiquetées. Dans ce contexte, le laboratoire d’hémostase de l’EFS Alsace et l’unité INSERM UMR S949 travaillent de concert à l’identification et à la caractérisation de ces pathologies. Ainsi, nous avons mis en évidence trois nouvelles mutations du récepteur P2Y12 dans trois familles différentes. La mutation p.His187Gln a été entièrement caractérisée sur des plaquettes fraiches du patient et dans un modèle cellulaire adapté. La reproduction des deux autres mutations (p.Tyr259Cys et p.Phe95Ser) est en cours. Nous avons par ailleurs identifié une famille dont trois membres sont atteints d’une maladie du pool vide non syndromique et nous suspectons grâce au séquençage d’exome effectué que le transporteur de nucléotides VNUT est impliqué dans la pathologie.

The Ikaros transcription factor is crucial for many aspects of hematopoiesis. Loss of function mutations in IKZF1, the gene encoding Ikaros, have been implicated in adult and pediatric B cell acute lymphoblastic leukemia (B-ALL). These mutations result in haploinsufficiency of the Ikaros gene in approximately half of the cases. The remaining cases contain more severe or compound mutations that lead to the generation of dominant-negative proteins or complete loss of function. All IKZF1 mutations are associated with a poor prognosis. Here we review the current genetic, clinical and mechanistic evidence for the role of Ikaros as a tumor suppressor in B-ALL.