The three stages of epilepsy in patients with CDKL5 mutations

Mutations in the X-linked cyclin-dependent kinase-like 5 ( CDKL5 ) gene are responsible for a severe encephalopathy with early epilepsy. So far, the electroclinical phenotype remains largely unknown and no clear genotype–phenotype correlations have been established.
Purpose: To characterize the epilepsy associated with CDKL5 mutations and to look for a relationship between the genotype and the course of epilepsy.
Methods : We retrospectively analyzed the electroclinical phenotypes of 12 patients aged from 2.5 to 19 years diagnosed with pathogenic CDKL5 mutations and one patient with a novel intronic sequence variation of uncertain pathogenicity and examined whether the severity of the epilepsy was linked to the type and location of mutations.
Results : The epilepsy course reveals three successive stages: (Stage I) early epilepsy (onset 1–10 weeks) with normal interictal electroencephalogram (EEG) (10/13) despite frequent convulsive seizures; (Stage II) epileptic encephalopathy with infantile spasms (8/8) and hypsarrhythmia (8/8). At the age of evaluation, seven patients were seizure free and six had developed refractory epilepsy (stage III) with tonic seizures and myoclonia (5/6).
  Interestingly, the patients carrying a CDKL5 mutations causing a truncation of the catalytic domain tended to develop a more frequent refractory epilepsy than patients with mutations located downstream (4/6, 66.6% versus 1/6, 16%) although, these trends are not yet significant.
Discussion : Our data contribute to a better definition of the epileptic phenotype in CDKL5 mutations, and might give some clues to a potential relationship between the phenotype and the genotype in these patients.     

Prevalence and consequences of nonadherence to hemodialysis regimens.

Adherence to fluid restrictions and dietary and medication guidelines as well as attendance at prescribed hemodialysis sessions of a hemodialysis regimen are essential for adequate management of end-stage renal disease. A literature review was conducted to determine the prevalence and consequences of nonadherence to the different aspects of a hemodialysis regimen and the methodological obstacles in research on nonadherence. Nonadherence to the prescribed regimen is a common problem in hemodialysis and is associated with increased morbidity and mortality. Research on nonadherence is associated with 2 major obstacles: inconsistencies in definitions and invalid measurement methods. Further research is needed to validate measurement methods and to establish clinically relevant operational definitions of nonadherence.     

Anorexie mentale : bases rationnelles pour l’hospitalisation en milieu psychiatrique

Hospitalisation in a psychiatry ward is one of the oldest treatments for anorexia nervosa (AN); however the therapeutic modalities and indications for inpatient care have evolved considerably over the last century. In this article, we will present the clinical arguments from the international literature that are used to determine the type of treatment ward in which patients with AN should be hospitalised. Then we will discuss our belief that ideally, all patients with AN needing hospitalisation should cared for in a specialised psychiatry department, even though patients are usually hospitalised because of somatic manifestations of the disorder. Finally, in order to illustrate our point, we present the example of our treatment program at the “Institut Mutualiste Montsouris” before concluding.     

Fluorescent labeling of degradable poly(lactide-co-glycolide) for cellular nanoparticles tracking in living cells

Fluorescent-labeled aliphatic polyesters are essential materials for in vitro and in vivo studies of the behavior of these biodegradable polymers in interaction with cells or in a body. In particular, the direct cellular localization of drug delivery systems based on these materials allows better understanding of the internalization mechanism and determination of the pharmacokinetics. Polylactide-co-glycolide (PLGA) is a rapidly degradable copolymer widely used in pharmaceutics and nanomedecine. It was prepared by ring-opening polymerization of lactide and glycolide in order to obtain a well-defined material to investigate conditions allowing the covalent linkage of a fluorescent dye (fluorescein) while preserving the macromolecular characteristics of the polymer. The success of the functionalization was ascertained by proton nuclear magnetic resonance (1H NMR), size-exclusion chromatography (SEC) and fluorescence spectroscopy.     

First report of infection with community-acquired methicillin-resistant Staphylococcus aureus in South America

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has recently emerged in the southwestern Pacific, North America, and Europe. These S. aureus isolates frequently shared some genetic characteristics, including the SCCmec type IV and lukS-lukF genes. In this paper we show that typical CA-MRSA isolates have spread to South America (Brazil).     

Similar delivery rates in a selected group of patients, for day 2 and day 5 embryos both cultured in sequential medium: a randomized study

BACKGROUND: The existence of a real benefit of blastocyst transfer is still a matter of debate. The aim of this study was to compare, in a prospective randomized trial, the outcome of day 2 and day 5 transfer of human embryos cultured in an 'in-house' sequential medium. METHODS: A total of 193 cycles from 171 patients with less than four previous IVF cycles, <39 years old and with four or more zygotes on day 1, were randomly allocated to day 2 (94 cycles) or day 5 (99 cycles) transfer. Zygotes were kept in fertilization medium until 18 h post-fertilization and then placed in a 'glucose-free' cleavage medium. Embryos allocated for day 5 transfer were placed in a blastocyst medium 66 h post-fertilization. Two or three embryos were replaced according to the morphology. RESULTS: A mean (+/- SEM) number of 2.1 +/- 0.4 and 1.9 +/- 0.3 embryos were replaced on day 2 and day 5 (P < 0.001) respectively. Delivery rates per transfer were 44.1 and 37.1% [P = not significant (NS)], implantation rates were 31.4 and 29.4% (NS) and multiple delivery rates 22 and 36% (NS) for day 2 and day 5 groups respectively. Ten patients (10.1%) had no blastocysts available for transfer. CONCLUSIONS: No clear benefits were observed using blastocyst transfer for patients aged <39 years who had had less than four previous IVF cycle attempts.     

T cell long-term hyporesponsiveness follows antigen receptor engagement and results from defective signal transduction

T cell receptor (TCR)-mediated stimulation of T hybridomas leads to cell activation and lymphokine production that is followed by a long-term hyporesponsiveness. To investigate the biochemical events involved in the induction and maintenance of this antigen receptor hyporesponsiveness or anergy, we have expressed a G protein/PLCβ1-coupled muscarinic subtype 1 acetylcholine receptor in a murine T cell hybrid. Transfected cells were capable of responding to both muscarinic agonists and TCR ligands by inducing interleukin-2 secretion that was sensitive to cyclosporin A and dexamethasone. Both receptors induced tyrosine kinase (TK) activity, but muscarinic stimulation did not affect tyrosine phosphorylation of PLCγ1, nor did the TK inhibitor, herbimycin, block muscarinic receptor-mediated calcium mobilization. These data indicate that in T cells, the muscarinic receptor mediates T cell effector functions by regulating a TK-independent proximal pathway which later converges with the TCR pathway. Using these cells, we have explored the long-term consequences of T cell stimulation via antigen or muscarinic receptors. Our results show that hyporesponsiveness specifically follows TCR engagement and appears to result from a defect in the early signal transduction initiated by TCR cross-linking. A study of TCR-mediated signaling supports this model by showing that tyrosine phosphorylation and calcium mobilization are deficient in hyporesponsive T cells.     

Identification of a novel candidate gene for non-syndromic autosomal recessive intellectual disability: the WASH complex member SWIP

High-throughput sequencing has greatly facilitated the elucidation of genetic disorders, but compared with X-linked and autosomal dominant diseases, the search for genetic defects underlying autosomal recessive diseases still lags behind. In a large consanguineous family with autosomal recessive intellectual disability (ARID), we have combined homozygosity mapping, targeted exon enrichment and high-throughput sequencing to identify the underlying gene defect. After appropriate single-nucleotide polymorphism filtering, only two molecular changes remained, including a non-synonymous sequence change in the SWIP [Strumpellin and WASH (Wiskott-Aldrich syndrome protein and scar homolog)-interacting protein] gene, a member of the recently discovered WASH complex, which is involved in actin polymerization and multiple endosomal transport processes. Based on high pathogenicity and evolutionary conservation scores as well as functional considerations, this gene defect was considered as causative for ID in this family. In line with this assumption, we could show that this mutation leads to significantly reduced SWIP levels and to destabilization of the entire WASH complex. Thus, our findings suggest that SWIP is a novel gene for ARID.     

Heat Shock and Proinflammatory Stressors Induce Differential Localization of Heat Shock Proteins in Human Monocytes

Heat shock (HS) proteins (HSP) are a family of molecular chaperones induced by environmental stresses such as oxidative injury, and contribute to protection from and adaptation to cellular stress. We investigated in human monocytes the expression and subcellular distribution of hsp70 and hsc70 after HS and inflammation-related stresses leading to generation of reactive oxygen species by these cells, such as the phorbol ester PMA and erythrophagocytosis (Eø). By combining immunofluorescent staining and Western blot on subcellular fractions, we found that all three stress factors resulted in an increased hsp70 expression, however the subcellular distribution pattern was different depending on the type of stress. While HS induced a rapid translocation of hsp70 into the nucleus, no nuclear translocation of hsp70 was observed after PMA or Eø. Neither of the examined stresses induced membrane expression of hsp70. The observed differences in subcellular distribution pattern might relate to distinct regulation and specific functions of hsp70 in inflammation.