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Lemaire M.,Yale University | Fremeaux-Bacchi V.,Assistance Publique Hopitaux de Paris | Schaefer F.,University of Heidelberg | Choi M.,Yale University | And 29 more authors.
Nature Genetics | Year: 2013

Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase É) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid-containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS. © 2013 Nature America, Inc. All rights reserved.

Coghill D.R.,University of Dundee | Banaschewski T.,University of Heidelberg | Lecendreux M.,Hopital University Robert Debre | Zuddas A.,University of Cagliari | And 7 more authors.
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2014

Objective In this phase 3 extension study, the long-term maintenance of efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) was evaluated using a randomized-withdrawal study design. Method European and US patients (6-17 years; N = 276) with ADHD were entered into a 26-week open-label trial of LDX treatment. Those who completed the open-label period (n = 157) were randomized 1:1 to their optimized dose of LDX (30, 50, or 70 mg per day) or placebo for a 6-week randomized-withdrawal period (RWP). The primary efficacy measure was the proportion of patients meeting treatment failure criteria (≥50% increase in ADHD Rating Scale IV total score and ≥2-point increase in Clinical Global Impressions-Severity of Illness [CGI-S] score, compared with RWP start point). Safety and tolerability were also evaluated. Results During the RWP (LDX, n = 78; placebo, n = 79), significantly fewer patients receiving LDX met treatment failure criteria (15.8%) compared with those receiving placebo (67.5%; difference = -51.7%; 95% confidence interval = -65.0, -38.5; p <.001). Most treatment failures occurred at or before the week 2 visit after randomization. Treatment-emergent adverse events were reported in 39.7% and 25.3% of patients receiving LDX and placebo, respectively, during the RWP. Conclusions These data demonstrate the maintenance of efficacy of LDX during long-term treatment in children and adolescents with ADHD. The rapid return of symptoms on LDX withdrawal demonstrates the need for continuing treatment. The safety profile of LDX was consistent with that of other stimulants. Clinical trial registration information - Double-Blind, Placebo-Controlled, Randomized Withdrawal, Extension, Safety and Efficacy Study of LDX in Children and Adolescents Aged 6-17; http://clinicaltrials.gov; NCT00784654.

Da Costa L.,Hopital University Robert Debre
Blood | Year: 2013

In this issue of Blood Garçon et al describe successful derivation of induced pluripotent stem cells (iPSs) from fibroblasts of Diamond Blackfan anemia (DBA) patients with 2 distinct ribosomal defects. Using these cells the authors showed that they not only exhibit defective erythropoiesis but also globally impaired hematopoiesis affecting multipotent progenitors. © 2013 by The American Society of Hematology.

Quoc E.B.,Hopital University Robert Debre
Revue Francophone d'Orthoptie | Year: 2014

Meridian amblyopia or amblyopia induced by astigmatism is a unilateral or bilateral amblyopia resulting from a significant astigmatism that was not corrected during the sensitive period of visual development: unilateral meridian amblyopia is possible with a 0.75 diopter cylindrical anisotropy; bilateral meridian amblyopia is possible in the case of bilateral astigmatism of more than 2 diopters. An oblique axis of astigmatism is more amblyogenic than an orthogonal axis. The prevalence of meridian amblyopia is difficult to assess because the spherical factors are often associated with cylindrical factors, but an asymmetrical astigmatism is clearly a risk factor for amblyopia. Meridian amblyopia would be the consequence notably of a bias in the selectivity in orientation of visual neurones. Treatment of meridian amblyopia resides in total optical correction of the cylindrical ametropia and of the spherical ametropia as well as occlusion of the healthy eye. © 2014 Elsevier Masson SAS. All rights reserved.

Deschenes G.,Hopital University Robert Debre | Dossier C.,Hopital University Robert Debre
Medecine Therapeutique Pediatrie | Year: 2015

Idiopathic nephrotic syndrome is a worldwide disease, the only sign of which is massive proteinuria, subsequently marked by increased renal albumin clearance by a factor of between 1,000 and 10,000. The only lesion is an eradication of podocyte arborisation, which is visible exclusively under ultrastructural microscopy. These alterations are functional and regress completely after a few days of treatment with prednisone. The current hypothesis is that nephrotic syndrome is not a primary kidney disease but an immune disease for which the kidney is the functional and exclusive target. Immune system abnormalities are global and either affect humoral or cellular immunity, as well as bone marrow progenitor cells. The link between the immune system and the glomerular wall is likely to be a soluble circulating glomerular factor, although this has not yet been identified. The involvement of immunoglobulin, in reality, an auto-antibody, is plausible but so far unclear. The epidemiology of the disease in the Paris area suggests that environmental factors, in particular viral infections, also play a major role in triggering the immune mechanisms of disease.

Deschenes G.,Hopital University Robert Debre | Peuchmaur M.,Hopital University Robert Debre | Dossier C.,Hopital University Robert Debre
Medecine Therapeutique Pediatrie | Year: 2015

Steroid resistance manifests in hereditary diseases of the glomerular wall and steroid-resistant forms of idiopathic nephrotic syndrome which are of immune in origin. The assessment of a child with steroid-resistant nephrotic syndrome should include a genetic analysis. For patients with steroid-resistant idiopathic nephritic syndrome, focal segmental glomerulosclerosis is present in half the initial renal biopsies, but this has no formal prognostic value. The other half have minimal glomerular lesions. First-line treatment involves prolonged prednisone administration combined with a calcineurin antagonist, typically cyclosporine, and more recently tacrolimus. Response to treatment is the only prognostic factor. All patients with no response to first-line immunosuppressive therapy progress to end-stage renal disease (ESRD) within months. Patients with ESRD are treated with renal replacement therapy at least six months after the bilateral nephrectomy to prevent post-transplant complications associated with chronic nephrotic syndrome, particularly the risk of early renal graft thrombosis. The prognosis following renal transplantation is largely determined by the recurrence of nephrotic syndrome associated with the renal graft.

Deschenes G.,Hopital University Robert Debre | Dossier C.,Hopital University Robert Debre
Medecine Therapeutique Pediatrie | Year: 2015

Mutation in genes leading to hereditary nephrotic syndrome exclusively affect proteins in the glomerular wall. In 80% of patients, mutation is identified in the following five genes: nephrin, podocin, phospholipase-C, WT1, and laminin 2. Hereditary nephrotic syndrome manifests as four different clinical forms: (1) congenital nephrotic syndrome present at birth or the first few weeks of life; (2) steroid-resistant nephrotic syndrome commencing between one and ten years, which cannot be differentiated from idiopathic steroid-resistant nephrotic syndrome; (3) syndromic nephrotic syndrome; and (4) chronic proteinuria that starts in childhood and gradually progresses to nephrotic syndrome in adulthood. All these forms exhibit progression to end-stage renal disease (ESRD).

More than 90% of children with idiopathic nephrotic syndrome (INS) experience remission with steroid treatment. However, 80% experience relapses and around 60% require long-term corticotherapy to remain in remission. Prolonged use of corticotherapy leads to a number of side effects and in order to avoid them, immune modulators or immune suppressors may be prescribed. Traditionally, cyclosporine and cyclophosphamide have been used as immunosuppressive treatment strategies in such cases, but toxicity limits their use. For more than 10 years, numerous clinical reports have demonstrated the efficacy of mycophenolate mofetil (MMF) in steroid-dependent nephrotic syndrome (NS). Due to the lack of nephrotoxicity, cyclosporine is now considered only in the event of MMF treatment failure. More recently, rituximab has emerged as a new treatment option in cases of calcineurin inhibitor dependency. However, while treatment of the primary course of INS is well established, steroid-dependent NS management continues to pose challenges and there is a need to define appropriate treatment depending on patients' individual characteristics.

Dossier C.,Hopital University Robert Debre | Deschenes G.,Hopital University Robert Debre
Medecine Therapeutique Pediatrie | Year: 2015

Nephrotic syndrome is invariably the clinical and biological expression of glomerular kidney disease, with the exception of isolated cases of bilateral renal vein thrombosis in the neonatal period. Upon presentation at the emergency room, diagnosis is fairly straightforward, but requires precise knowledge of the biological definition. Aetiological orientation depends on the patient's age, and renal biopsy is a formal indication in all patients under the age of one and over the age of ten. Between the ages of one and ten, initial treatment with oral prednisone for four weeks is a diagnostic test for idiopathic nephritic syndrome.

Bucci M.P.,University Paris Diderot | Melithe D.,University Paris Diderot | Ajrezo L.,University Paris Diderot | Bui-Quoc E.,Hopital University Robert Debre | Gerard C.-L.,Hopital University Robert Debre
Frontiers in Human Neuroscience | Year: 2014

Dual task is known to affect postural stability in children. We explored the effect of visual tasks on postural control in thirty dyslexic children. A selected group of thirty chronological age-matched non-dyslexic children (mean age: 9.92 ± 0.35 years) and a group of thirty reading age-matched non-dyslexic children (mean reading age: 7.90 ± 0.25 years) were chosen for comparison. All children underwent ophthalmologic and optometric evaluation. Eye movements were recorded by a video-oculography system (EyeBrain® T2) and postural sway was recorded simultaneously by a force platform (TechnoConept®). All children performed fixations, pursuits, pro- and anti-saccades tasks. Dyslexic children showed significantly poor near fusional vergence ranges (convergence and divergence) with respect to the non-dyslexic children groups. During the postural task, quality of fixation and anti-saccade performance in dyslexic children were significantly worse compared to the two non-dyslexic children groups. In contrast, the number of catch-up saccades during pursuits and the latency of pro- and anti-saccades were similar in the three groups of children examined. Concerning postural quality, dyslexic children were more unstable than chronological age-matched non-dyslexic children group. For all three groups of children tested we also observed that executing saccades (pro- and anti-saccades) reduced postural values significantly in comparison with fixation and pursuit tasks. The impairment in convergence and divergence fusional capabilities could be due to an immaturity in cortical structures controlling the vergence system. The poor oculomotor performance reported in dyslexic children suggested a deficit in allocating visual attention and their postural instability observed is in line with the cerebellar impairment previously reported in dyslexic children. Finally, pro- or anti-saccades reduce postural values compared to fixation and pursuit tasks in all groups of children tested, suggesting a different influence of visual tasks on postural control according to their attentional demand. © 2014 Bucci, Mélithe, Ajrezo, Bui-Quoc and Gérard.

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