IL1 receptor accessory protein like,a protein involved in X-linked mental retardation,interacts with Neuronal Calcium Sensor-1 and regulates exocytosis

Previously, human genetics-based approaches allowed us to show that mutations in the IL-1 receptor accessory protein-like gene (IL1RAPL) are responsible for a non-specific form of X-linked mental retardation. This gene encodes a predicted protein of 696 amino acids that belongs to a novel class of the IL-1/Toll receptor family. In addition to the extracellular portion consisting of three Ig-like domains and the intracellular TIR domain characteristic of the IL-1/Toll receptor family, IL1RAPL contains a specific 150 amino acid carboxy terminus that has no significant homology with any protein of known function. In order to begin to elucidate the function of this IL-1/Toll receptor-like protein, we have assessed the effect of recombinant IL1RAPL on the binding affinity of type I IL-1R for its ligands IL-1alpha and beta and searched for proteins interacting with the specific carboxy terminus domain of IL1RAPL. Our results show that IL1RAPL is not a protein receptor for IL-1. In addition we present here the identification of Neuronal Calcium Sensor-1 (NCS-1) as an IL1RAPL interactor. Remarkably, although NCS-1 and its non-mammalian homologue, frequenin, are members of a highly conserved EF-hand Ca(2+) binding protein family, our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.     

A method for studying social security records in epidemiology. Use in a study on the prognosis of chronic bronchitis (author's transl)]

A method is presented to study, in an epidemiological research, the social security records. This study is based upon records of workers affiliated to the french social security general system. To obtain data which may be compared, it was necessary to take the legislation as a basis; this legislation gives the data which must be in the records. A study of laws and rules has been done to find out these data in the medical record and in the administrative one. A questionnaire is presented. This basic questionnaire should be modified according to the precise objectives of each study and to the characteristics of the population sample. To illustrate this method, some results of a study of chronic bronchitis risk factors are presented in the second part. These results concern 950 men, born in France, aged 30 to 59 in 1960 an still alive in 1972. The study of the long reductions of the ability to work, happened from 1960 to 1971, confirm the disabling character of the group "chronic bronchitis, asthma, emphysema, respiratory insufficiency" which follows immediately cardiovascular and rheumatic diseases. The total number of beneficiaries of the social security is already very important and the whole population will be soon concerned. The use of the social security records as data source could give very interesting informations about morbidity. So, it is possible to study representative samples of the general population or of some particular groups, which has up to now, been done only in a slight extent.     

Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A)

We have recently reported a missense mutation in exon 4 of the tubulin alpha 1A (Tuba1a) gene in a hyperactive N-ethyl-N-nitrosourea (ENU) induced mouse mutant with abnormal lamination of the hippocampus. Neuroanatomical similarities between the Tuba1a mutant mouse and mice deficient for Doublecortin (Dcx) and Lis1 genes, and the well-established functional interaction between DCX and microtubules (MTs), led us to hypothesize that mutations in TUBA1A (TUBA3, previous symbol), the human homolog of Tuba1a, might give rise to cortical malformations. This hypothesis was subsequently confirmed by the identification of TUBA1A mutations in two patients with lissencephaly and pachygyria, respectively. Here we report additional TUBA1A mutations identified in six unrelated patients with a large spectrum of brain dysgeneses. The de novo occurrence was shown for all mutations, including one recurrent mutation (c.790C>T, p.R264C) detected in two patients, and two mutations that affect the same amino acid (c.1205G>A, p.R402H; c.1204C>T, p.R402C) detected in two other patients. Retrospective examination of MR images suggests that patients with TUBA1A mutations share not only cortical dysgenesis, but also cerebellar, hippocampal, corpus callosum, and brainstem abnormalities. Interestingly, the specific high level of Tuba1a expression throughout the period of central nervous system (CNS) development, shown by in situ hybridization using mouse embryos, is in accordance with the brain-restricted developmental phenotype caused by TUBA1A mutations. All together, these results, in combination with previously reported data, strengthen the relevance of the known interaction between MTs and DCX, and highlight the importance of the MTs/DCX complex in the neuronal migration process.     

Epileptic phenotypes in children with respiratory chain disorders

Purpose: Epilepsy is a commonly reported but rarely described clinical hallmark of mitochondrial respiratory chain defects (RCDs) with encephalopathy. Methods: From 1990–2006 we collected data about 56 children with RCD (single, n = 24 or multiple, n = 20 mitochondrial complex deficiencies; mtDNA mutation, n = 11; mtDNA depletion n = 10 of 21; and nuclear gene mutation n = 11). Epileptic features were reviewed retrospectively. Results: First seizures were frequently (47 patients, 82.5%) preceded by failure to thrive, psychomotor delay, ataxia, or multisystemic dysfunction. Sixty percent of the patients had several seizure types. Six age‐related epilepsy phenotypes could be identified: status epilepticus complicating neonatal multivisceral deficiency (2 patients), neonatal myoclonic encephalopathy (3 patients), infantile spasms (8 patients), refractory or recurrent status epilepticus (21 patients), epilepsia partialis continua (4 patients), and myoclonic epilepsy (18 patients). Except for infantile spasms, epilepsy was difficult to control in most patients (95%). Valproate was administered to 25 patients, one of whom developed acute liver failure 6 days later. Twenty‐two patients (45%) died, half of them within 9 months from the onset of epilepsy. Discussion: In RCD, epilepsy is not only difficult to control but its occurrence often indicates a severe turn in the course of the disease. For one‐third of the patients, classical biochemical measures failed to reveal any abnormality and RCD could be detected in the liver only.     

Psychotropic medications and the risk of fracture: a meta-analysis.

BACKGROUND: Older adults throughout the developed world are at significant risk of osteoporotic fractures. Many studies have examined the relationship between the use of psychotropic medications and the risk of fractures, but these studies have reported conflicting results. PURPOSE: To resolve discrepancies, we carried out a meta-analysis to assess the risk of fractures among users of several classes of psychotropic drugs. DATA SOURCES: We retrieved studies published in any language by systematically searching MEDLINE, LILACS, EMBASE and ISI Proceedings databases and by manually examining the bibliographies of the articles retrieved electronically as well as those of recent reviews. STUDY SELECTION: We included 98 cohort and case-control studies, published in 46 different articles, that reported relative risk (RR) estimates and confidence intervals (CIs) or sufficient data to calculate these values. DATA SYNTHESIS: Study-specific RRs were weighted by the inverse of their variance to obtain fixed- and random effects pooled estimates. The random effects RR of fractures was 1.34 (95% CI 1.24, 1.45) for benzodiazepines (23 studies), 1.60 (95% CI 1.38, 1.86) for antidepressants (16 studies), 1.54 (95% CI 1.24, 1.93) for non-barbiturate antiepileptic drugs (13 studies), 2.17 (95% CI 1.35, 3.50) for barbiturate antiepileptic drugs (five studies), 1.59 (1.27, 1.98) for antipsychotics (12 studies), 1.15 (95% CI 0.94, 1.39) for hypnotics (13 studies) and 1.38 (95% CI 1.15, 1.66) for opioids (six studies). For non-specified psychotropic drugs (10 studies), the pooled RR was 1.48 (95% CI 1.41, 1.59). LIMITATIONS: Main concerns were the potential for residual confounding and for publication bias. CONCLUSION: Globally, the increase in the risk of fractures among psychotropic drug users is moderate. Further research is needed, especially to examine high-risk populations and newer medications. Future studies should be prospective and emphasise control of confounding bias.