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Vauthier V.,French Institute of Health and Medical Research | Vauthier V.,French National Center for Scientific Research | Vauthier V.,University of Paris Descartes | Jaillard S.,French National Center for Scientific Research | And 10 more authors.
Molecular Genetics and Metabolism | Year: 2012

Context: The genomic organization of the LEPR gene is complex and generates three independent transcripts whose respective functions are still poorly understood. Methods/results: We describe here a 7-year old patient with a homozygous 80. kb deletion in the chromosomal 1p31.3 region with early onset obesity, mental retardation and epilepsy. The deleted region comprises the proximal promoter and exons 1 and 2 of the LEPR gene and exons 5 to 19 of the DNAJC6 gene. The deletion leads to the deficiency of all canonical OB-R isoforms but maintains the B219 OB-R short isoforms controlled by the preserved second LEPR promoter. The DNAJC6 gene encodes auxilin-1, a protein required for clathrin-dependent recycling of synaptic vesicles in neurons that is possibly at the origin of the mental retardation and epilepsy phenotype. The obese phenotype and the absence of signaling-competent OB-R are consistent with previously reported individuals with OB-R deficiency. The deletion eliminates an additional transcript of the LEPR gene that encodes endospanin-1, a protein that has been genetically and biochemically linked to OB-R function. Conclusions: Our study confirms the phenotype of individuals with OB-R deficiency and postulates the effects of auxilin-1 deficiency (mental retardation/epilepsy) and endospanin-1 deficiency (OB-R specific functions) in humans. © 2012 Elsevier Inc. Source


Righini M.,University of Geneva | Jobic C.,French Institute of Health and Medical Research | Boehlen F.,University of Geneva | Broussaud J.,Center hospitalier Bretagne Atlantique | And 4 more authors.
Haematologica | Year: 2013

The assessment of clinical probability represents an important step in the diagnostic strategy of patients with suspected deep vein thrombosis. The recently derived LEFt clinical prediction rule for pregnant women combines three variables: symptoms in the left leg (L), calf circumference difference of 2 centimeters or over (E for edema) and first trimester presentation (Ft) but is lacking an external validation. The LEFt rule was computed among pregnant women with suspected deep vein thrombosis who were included in a multicenter prospective diagnostic management outcome study. We calculated the proportion of women and the prevalence of deep vein thrombosis in each probability group, along with the diagnostic performances of the LEFt rule. All variables needed to compute the rule could be retrieved in 157 of the 167 pregnant women with suspected deep vein thrombosis. The prevalence of confirmed deep vein thrombosis was 13 of 157 (8.3%). The LEFt rule was negative in 46 (29%) women. A deep vein thrombosis was diagnosed in 13 of 111 (11.7%, 95% Confidence Interval (CI): 8.3-20.9%) of women with at least one of the LEFt criteria, as compared with none of 46 (0.0%, 95%CI: 0.0-7.9%) of women with none of the LEFt criteria. These results suggest that a negative LEFt rule accurately identifies pregnant women in whom the proportion of confirmed deep vein thrombosis appears to be very low. The rule should not be used as stand-alone test for excluding DVT during pregnancy, but might rather be implemented in a diagnostic strategy in association with D-dimer measurement and compression ultrasonography. The original trial was registered at clinicaltrials.gov (NCT 00740454). © 2013 Ferrata Storti Foundation. Source


Kott E.,University Pierre and Marie Curie | Legendre M.,University Pierre and Marie Curie | Copin B.,University Pierre and Marie Curie | Papon J.-F.,French Institute of Health and Medical Research | And 27 more authors.
American Journal of Human Genetics | Year: 2013

Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive respiratory disorder resulting from defects of motile cilia. Various axonemal ultrastructural phenotypes have been observed, including one with so-called central-complex (CC) defects, whose molecular basis remains unexplained in most cases. To identify genes involved in this phenotype, whose diagnosis can be particularly difficult to establish, we combined homozygosity mapping and whole-exome sequencing in a consanguineous individual with CC defects. This identified a nonsense mutation in RSPH1, a gene whose ortholog in Chlamydomonas reinhardtii encodes a radial-spoke (RS)-head protein and is mainly expressed in respiratory and testis cells. Subsequent analyses of RSPH1 identified biallelic mutations in 10 of 48 independent families affected by CC defects. These mutations include splicing defects, as demonstrated by the study of RSPH1 transcripts obtained from airway cells of affected individuals. Wild-type RSPH1 localizes within cilia of airway cells, but we were unable to detect it in an individual with RSPH1 loss-of-function mutations. High-speed-videomicroscopy analyses revealed the coexistence of different ciliary beating patterns - cilia with a normal beat frequency but abnormal motion alongside immotile cilia or cilia with a slowed beat frequency - in each individual. This study shows that this gene is mutated in 20.8% of individuals with CC defects, whose diagnosis could now be improved by molecular screening. RSPH1 mutations thus appear as a major etiology for this PCD phenotype, which in fact includes RS defects, thereby unveiling the importance of RSPH1 in the proper building of CCs and RSs in humans. © 2013 The American Society of Human Genetics. Source


Le Floc'h M.,Center hospitalier Bretagne Atlantique
Medecine Palliative | Year: 2012

In palliative care services, we meet patients who are waiting for death, for whom death is already there. These are bodies in suspense, watched and locked up in a death sentence. Everything about their relations with others appears to be closed, at the risk of being a tragedy. It's a strange place, a strange time for a meeting where, at a time when everything seems to be passing away, something unexpected can appear. It's an unexpected event that will reveal desire. © 2011 Elsevier Masson SAS. Source


A semi-structured survey conducted among caregivers of a regional hospital in France reveals a confusion between anxiolysis and sedation in some situations of terminal illness. Analysis of the results reveals that this confusion is due to the difficulty in clearly identifying anxiety, the absence of a reassessment of treatment and finally from a trivialization of vigilance disorders at the end of life. Added the difficulty of the notion of refractory symptom and of modulation of sedation's depth. Furthermore the molecule used for sedation has also an indication as anxiolytic and has, for some caregivers, a symbolic connotation of " serene end of life" , as its name suggests, " hypno-well" , good sleep. All this contributes to the confusion. These findings lead to proposals for trainings, tools, places of listening and exchanges. The reflection about the use of a single molecule for two different indications, anxiolysis and sedation, seems to be useful. © 2011 Elsevier Masson SAS. Source

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