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Le Kremlin-Bicêtre, France

Deplaine G.,Institute Pasteur Paris | Deplaine G.,French National Center for Scientific Research | Deplaine G.,University Pierre and Marie Curie | Safeukui I.,Institute Pasteur Paris | And 24 more authors.
Blood | Year: 2011

Retention of poorly deformable red blood cells (RBCs) by the human spleen has been recognized as a critical determinant of pathogenesis in hereditary spherocytosis, malaria, and other RBC disorders. Using an ex vivo perfusion system, we had previously shown that retention of Plasmodium falciparum - infected RBCs (Pf-RBCs) occur in the splenic red pulp, upstream from the sinus wall. To experimentally replicate the mechanical sensing of RBCs by the splenic microcirculation, we designed a sorting device where a mixture of 5- to 25-μm-diameter microbeads mimics the geometry of narrow and short interendothelial splenic slits. Heated RBCs, Pf-RBCs, and RBCs from patients with hereditary spherocytosis were retained in the microbead layer, without hemolysis. The retention rates of Pf-RBCs were similar in microbeads and in isolated perfused human spleens. These in vitro results directly confirm the importance of the mechanical sensing of RBCs by the human spleen. In addition, rigid and deformable RBC subpopulations could be separated and characterized at the molecular level, and the device was used to deplete a stored RBC population from its subpopulation of rigid RBCs. This experimental approach may contribute to a better understanding of the role of the spleen in the pathogenesis of inherited and acquired RBC disorders. © 2011 by The American Society of Hematology. Source

Saliba G.,Bellevue Medical Center | Kamouh W.,Kremlin Bicetre Hospital | Fontanet A.,Institute Pasteur Paris | Le Bras J.,National malaria reference Center | Le Bras J.,University of Paris Descartes
Pathologie Biologie | Year: 2011

Objectives: To identify independent risk factors of severe falciparum malaria among travelers to endemic regions. Materials and methods: A retrospective study on imported malaria into metropolitan France. The World's Health Organization severity criteria were used to classify malarial episodes. Results: Nine hundred and twenty-one malarial cases were studied; 81 were severe. Independent risk factors of severe malaria were aged above 40 years, high level of parasitized erythrocytes (more than 4%), parasite acquisition in the south-eastern asian region, infection with a chloroquine resistant Plasmodium falciparum (P. falciparum) phenotype and a self administered antimalarial treatment. Conclusion: This study points out two particularly interesting results: severe malaria is significantly associated with the infection by a chloroquine resistant P. falciparum phenotype and with the parasite's acquisition in the south-eastern asian region. © 2010 Elsevier Masson SAS. Source

Simkin D.,University of Nice Sophia Antipolis | Simkin D.,Rosalind Franklin University of Medicine and Science | Lena I.,University of Nice Sophia Antipolis | Landrieu P.,Kremlin Bicetre Hospital | And 5 more authors.
Journal of Physiology | Year: 2011

Myotonia is an intrinsic muscular disorder caused by muscle fibre hyperexcitability, which produces a prolonged time for relaxation after voluntary muscle contraction or internal mechanical stimulation. Missense mutations in skeletal muscle genes encoding Cl - or Na + channels cause non-dystrophic myotonias. Mutations of the SCN4A gene that encodes the skeletal voltage-gated Na + channel Nav1.4 can produce opposing phenotypes leading to hyperexcitable or inexcitable muscle fibres. Nav1.4 mutations result in different forms of myotonias that can be found in adults. However, the recently reported myotonic manifestations in infants have been shown to be lethal. This was typically the case for children suffering from severe neonatal episodic laryngospasm (SNEL). A novel Nav1.4 channel missense mutation was found in these children that has not yet been analysed. In this study, we characterize the functional consequences of the new A799S Na + channel mutation that is associated with sodium channel myotonia in newborn babies. We have used mammalian cell expression and patch-clamp techniques to monitor the channel properties. We found that the A799S substitution changes several biophysical properties of the channel by causing a hyperpolarizing shift of the steady-state activation, and slowing the kinetics of fast inactivation and deactivation. In addition, the single channel open probability was dramatically increased, contributing hence to a severe phenotype. We showed that substitutions at position 799 of the Nav1.4 channel favoured the channel open state with sustained activity leading to hyperexcitability of laryngeal muscles that could be lethal during infancy. © 2011 The Authors. Journal compilation © 2011 The Physiological Society. Source

Malouf G.G.,University Paris Diderot | Malouf G.G.,University of Houston | Brugieres L.,CNRS Gustave Roussy Institute | Le Deley M.-C.,University Paris - Sud | And 9 more authors.
Cancer | Year: 2012

BACKGROUND: The purpose of the current study was to describe pure and mixed fibrolamellar hepatocellular carcinoma (FL-HCC). METHODS: Consecutive patients with pure and mixed FL-HCC were identified from a central pathological review using Edmondson's criteria. Clinical, pathological, and epigenetic characteristics of patients who underwent curative surgery were evaluated. Overall and disease-free survival as well as patterns of disease recurrence were examined. Methylation levels of L1 retrotransposon (LINE-1) repetitive elements and Ras association domain family 1A gene (RASSF1) promoter were also assessed using pyrosequencing. RESULTS: Forty of 53 patients with a median age of 22 years (range, 9 years-;65 years) met the criteria for analysis. Central pathological review found that 30 patients (75%) had pure and 10 patients (25%) had mixed FL-HCC. Pure FL-HCC typically occurred in patients aged < 30 years. These patients often presented with lymph node metastasis at the time of diagnosis and frequently experienced extrahepatic recurrences (n = 16). Conversely, mixed FL-HCC appeared to resemble to classic HCC, occurring in patients aged > 40 years and frequently involving the liver as the primary site of disease recurrence. With a median follow-up of 7.8 years, the median overall survival from the time of diagnosis in all patients was 6.4 years (range, 3.2 years-12 years). Multivariate analysis found that the risk of death was increased in patients with higher American Joint Committee on Cancer disease stages (P =.003) and those with mixed FL-HCC (P =.03). Methylation analysis of LINE-1 repetitive elements and RASSF1 promoter revealed different methylation levels between pure and mixed FL-HCC, suggesting a different epigenetic background. CONCLUSIONS: Pure and mixed FL-HCC display distinct clinical presentations and epigenetic backgrounds leading to different prognoses and as such may be regarded as separate clinical entities. Copyright © 2012 American Cancer Society. Source

Vialle R.,Ecole de Chirurgie de lAssistance Publique | Vialle R.,University Pierre and Marie Curie | Lacroix C.,Kremlin Bicetre Hospital | Harding I.,Frenchay Hospital | And 2 more authors.
Spinal Cord | Year: 2010

Study design:Experimental animal study.Objective:To evaluate motor and sensitive axonal regrowth after multiple intercosto-lumbar neurotizations in a sheep model.Setting:France.Methods:Fifteen sheep were separated into three groups. Five sheep had multiple intercosto-lumbar neurotizations and a spinal cord lesion, five sheep were neurotized without any spinal cord lesion and five sheep had a spinal cord lesion without any neurotizations. Six months after the initial surgery, histological study of the neurotized roots was performed.Results:The length of the three rerouted intercostal nerves was sufficient in the 10 sheep to perform an intercosto-lumbar neurotization in good conditions. Eight sheep out of the 15 had postoperative complications responsible for the animal's death in five cases. Histological cross-sections of all the neurotized L2, L3 and L4 roots showed numerous myelinated regenerated axons. Dorsal root ganglions of neurotized roots showed both large and small neurons with normal nucleus and cytoplasm. The fluorescent retrograde labeling of 18 roots revealed labeled motor neurons in five cases.Conclusions:This study demonstrates the technical feasibility of intercosto-lumbar neurotizations in a big mammalian model. Intercostal nerve harvesting and rerouting was successfully performed in all the cases. Our histological results proved, in all the animals studied, the ability of motor and sensitive neurons to regenerate through the neurotization area. In the context of the future clinical application of strategies aimed at promoting axonal regeneration after severe spinal cord injury, the present data suggest that multiple intercosto-lumbar neurotization could be helpful to promote lower limb muscular strength recovery after spinal cord injuries. © 2010 International Spinal Cord Society. Source

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