Altered splicing in hematological malignancies reveals a tissue-specific translational block of the Src-family tyrosine kinase fyn brain isoform expression.
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Alternative Splicing↗
Biomedical subjects
C Picard
Publications and source records attributed to C Picard.
Melanocortin 1 receptor (MC1R) gene variants may increase the risk of melanoma in France independently of clinical risk factors and UV exposure.
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Adult↗
Clinical criteria for the diagnosis of bullous pemphigoid: a reevaluation according to immunoblot analysis of patient sera.
BACKGROUND: We previously proposed a set of 4 clinical criteria for the diagnosis of bullous pemphigoid (BP) that consisted of age greater than 70 years, absence of atrophic scars, absence of mucosal involvement and absence of predominant bullous lesions on the neck and head. These results have been challenged because direct immunoelectron microscopy (IEM), which was used as the standard diagnostic criterion in our initial study, does not identify the different antigens of the basement membrane zone. OBJECTIVE: To reassess the validity of these clinical criteria for the diagnosis of BP using immunoblot analysis of patient sera as the main diagnostic criterion, in order to precisely identify the antigens recognized by patient sera. METHODS: One hundred and eighty-nine sera from patients with various subepidermal autoimmune blistering diseases (AIBDs) were tested by immunoblotting using dermal and epidermal extracts. IEM was used as a complementary diagnostic procedure in a few patients whose serum recognized BPAG2 exclusively or was negative in immunoblotting. RESULTS: 142 patients (75%) had at least 3 of the 4 clinical diagnostic criteria. Sera from patients who lacked the set of BP clinical criteria were more frequently immunoblot negative (34%) than sera from patients who had the criteria (18%; p = 0.025). BPAG1 was more frequently recognized by sera from patients with the set of BP clinical criteria (78%) than by sera from patients without the criteria (45%; p = 5.10(-4)). In contrast, BPAG2 was recognized by a great number of sera from patients who lacked the criteria of BP (71%), which was in accordance with the presence of numerous patients with cicatricial pemphigoid in this group. Among patients with various subepidermal AIBDs, the diagnosis of BP could be made with a sensitivity of 86%, a specificity of 90% and an excellent prognostic positive value over 95%, if 3 of these clinical criteria were present. CONCLUSION: These results confirm the interest of this set of clinical criteria for the rapid diagnosis of BP.
Aged↗
[New hereditary immunodeficiencies and genetic predisposition to infective diseases in children].
Since 10 years severe pediatric infections which were idiopathic have now molecular explanation, because new primary immunodeficiencies responsible of these severe infections were identified. These children presented a new kind of hereditary immunodeficiency with severe and/or recurrent infections caused by only one microorganisms family, in opposition to other patients with "classic" primary immunodeficiency. Standard immunologic explorations for example white blood counts, lymphocyte counts, vaccine serology, immunoglobulin levels and complement were normal. However, these children presented a vulnerability, sometimes lethal, caused by one type of microorganism. The aim of this review is to describe 3 new syndromes with a genetic predisposition of infectious diseases: IL-12-IFN gamma axis deficiency (Mendelian susceptibility to mycobacterial disease), STAT1 deficiency (predisposition to viral disease) and NEMO and IRAK-4 deficiencies (predisposition to infections caused by pyogenic bacteria).
Child↗
Interaction with simian Hck tyrosine kinase reveals convergent evolution of the Nef protein from simian and human immunodeficiency viruses despite differential molecular surface usage.
Simian and human immunodeficiency virus type 1 (SIV and HIV-1) Nef proteins are thought to use different molecular surfaces to mediate the protein-protein interactions required for their otherwise similar functions. This genetically separable function suggests convergent evolution of primate lentiviruses and/or structural differences between human and nonhuman primate cellular target proteins. However, such comparative molecular analyses have not been undertaken so far using the respective natural host-derived cellular targets. We cloned simian Src family kinase Hck and analyzed structurally and biochemically its interaction with SIV Nef.
Amino Acid Sequence↗
[Mucoviscidosis in adults].
FROM CHILDREN TO ADULTS: Mucoviscidosis, a genetic autosomal recessive disease, is not only a paediatric disease, but with the progress in therapy, has become a disease of adults. Today, median survival of patients is of 30 years and, in France, more than one third of patients are adults. CLINICAL SYMPTOMS IN ADULTS: Are predominantly respiratory, with dilatation of the bronchi and characteristic colonization flora. Chronic bronchial Pseudomonas aeruginosa colonisation is frequently encountered in adults. It develops in successive episodes towards chronic respiratory failure. Other than this typical form, diagnosed in the first years of life, the discovery of the CFTR (Cystic Fibrosis Transmembrane conductance Regulator) gene and its mutations permits diagnosis of mucoviscidosis in patients presenting with mild, or even monosymptomatic forms of the disease. Today, diagnosis of mucoviscidosis relies on the association of characteristic organ damage and an abnormality in CFTR (sweat test and/or difference in nasal potential) or the revelation of gene mutations on each allele. REGARDING TREATMENT: Respiratory failure is the core of daily therapeutic efforts. Respiratory physical therapy, effort re-education and muscle exercising are essential. Antibiotherapy is aimed at treating, spacing out or preventing the infectious exacerbations, in order to stall the functional degradation. Repeated, sequential cycles of intravenous infusions of antibiotics are required in P. aeruginosa chronic bronchial colonization. Treatment of the primary pyocyanic colonisation and inhaled antiobiotherapy appear promising. Pulmonary transplantation is a recognized and efficient therapeutic in advanced stages of respiratory failure. The discomfort and time the patient has to spend on daily treatments requires regular monitoring, to improve compliance and to improve the quality of life of these patients.
Adult↗
Inherited disorders of IL-12- and IFNgamma-mediated immunity: a molecular genetics update.
In the last 6 years, considerable advances have been made in the molecular analysis of a rare clinical syndrome: Mendelian susceptibility to mycobacterial disease (MSMD). Infection with poorly virulent environmental non-tuberculous mycobacteria (NTM) or vaccination with bacillus Calmette-Guerin (BCG) may cause disseminating and even fatal disease in individuals suffering from this syndrome. Mutations in five genes (IFNGR1, IFNGR2, STAT1, IL12B and IL12RB1) have been shown to be responsible for MSMD and further allelic heterogeneity accounts for the existence of nine distinct inherited disorders. All of these disorders are caused by impaired IFNgamma-mediated immunity. These results have important medical and biological implications. In this report, we update the disease-causing mutations reported in the literature.
Adult↗
Effect of granisetron on radiation-induced alterations of colonic motility and fluid absorption in rats.
BACKGROUND: Radiation-induced diarrhoea is attributed to both mucosal injury and alterations of intestinal motility. Previous reports have indicated that 5-hydroxytryptamine is released following irradiation, which may contribute to these changes. AIMS: To investigate the effects of granisetron (5-hydroxytryptamine type-3 receptor antagonist) on colonic motility, fluid absorption and 5-hydroxytryptamine colonic content following abdominal irradiation (10 Gy) in rats. METHODS: In vivo measurements of motility and fluid absorption in the proximal and distal colon, respectively, diarrhoea score and 5-hydroxytryptamine tissue levels were performed 3 and 7 days after abdominal irradiation. The effects of post-irradiation granisetron (0.3 mg/kg subcutaneously) were also evaluated. RESULTS: Colonic motility and fluid/Na(+) absorption were reduced 3 and 7 days after irradiation. All rats developed diarrhoea (3 days) concomitant with increased colonic mucosal 5-hydroxytryptamine levels. Granisetron prevented diarrhoea, attenuated decreased colonic motility and reduced 5-hydroxytryptamine levels on day 3, although fluid absorption was only slightly improved. On day 7, colonic motility and fluid/Na(+) absorption were restored in granisetron-dosed animals. CONCLUSIONS: These results indicate that radiation-induced diarrhoea involves alterations of both colonic motility and fluid/Na(+) absorption. 5-Hydroxytryptamine could be one of the mediators implicated in these alterations, as post-irradiation dosage with a 5-hydroxytryptamine type-3 receptor antagonist improved colonic motility and prevented diarrhoea on day 3.
Animals↗
[Revascularization of atherosclerotic stenosis of the renal artery. Indications and results].
RISKS: Atherosclerotic renal artery stenosis typically occurs in high risk patients with coexistent vascular disease elsewhere. Patients with atherosclerotic renal artery stenosis may develop progressive renal failure but have a much higher risk of dying with a stroke or a myocardial infarction than of progressing to end-stage renal disease. REVASCULARIZATION RESULTS: Recent controlled trials comparing medication to revascularization have shown that only a minority of such patients can expect hypertension cure, whereas trials designed to document the ability of revascularization to prevent progressive renal failure are not yet available. Percutaneous renal artery angioplasty is the first choice because it is simpler than and as effective as surgical reconstruction. INDICATIONS: Revascularization should be undertaken in patients with atherosclerotic renal artery stenosis and resistant hypertension or heart failure, and probably in those with rapidly deteriorating renal function or with an increase in plasma creatinine levels during angiotensin-converting enzyme inhibition. Older age, long history of hypertension and a kidney size less than 8 cm are associated with little chance of blood pressure improvement or kidney function recovery. PRACTICAL ATTITUDE: With or without revascularization, medical therapy using antihypertensive agents, statins and aspirin is necessary in almost all cases. Blood pressure and plasma creatinine concentration should be measured every three months. Kidney size and renal artery patency should be assessed yearly.
Arteriosclerosis↗
The tyrosine kinase Hck is an inhibitor of HIV-1 replication counteracted by the viral vif protein.
The virus infectivity factor (Vif) protein facilitates the replication of human immunodeficiency virus type 1 (HIV-1) in primary lymphocytes and macrophages. Its action is strongly dependent on the cellular environment, and it has been proposed that the Vif protein counteracts cellular activities that would otherwise limit HIV-1 replication. Using a glutathione S-transferase pull-down assay, we identified that Vif binds specifically to the Src homology 3 domain of Hck, a tyrosine kinase from the Src family. The interaction between Vif and the full-length Hck was further assessed by co-precipitation assays in vitro and in human cells. The Vif protein repressed the kinase activity of Hck and was not itself a substrate for Hck phosphorylation. Within one single replication cycle of HIV-1, Hck was able to inhibit the production and the infectivity of vif-deleted virus but not that of wild-type virus. Accordingly, HIV-1 vif- replication was delayed in Jurkat T cell clones stably expressing Hck. Our data demonstrate that Hck controls negatively HIV-1 replication and that this inhibition is suppressed by the expression of Vif. Hck, which is present in monocyte-macrophage cells, represents the first identified cellular inhibitor of HIV-1 replication overcome by Vif.
Amino Acid Sequence↗
Diffuse large B-cell non-Hodgkin's lymphoma in a patient with autoimmune lymphoproliferative syndrome.
Mutations of Fas or Fas ligand genes result in the autoimmune lymphoproliferative syndrome (ALPS) in humans. We report here a diffuse large B-cell non-Hodgkin's lymphoma occurring in a man with ALPS. Fas-mediated lymphocyte apoptosis was defective in vitro, owing to a mutation within the death domain of the Fas molecule. High-dose methotrexate and doxorubicin-based chemotherapy led to complete remission of lymphoma.
Adult↗
Intestinal and colonic motor alterations associated with irradiation-induced diarrhoea in rats.
Localized application of ionizing radiation to the gastrointestinal tract frequently elicits responses, which include diarrhoea. The origin of this symptom is not clear but has been attributed to loss of epithelial integrity, together with alterations in motility and increased secretion. The purpose of this study was to examine whether a 10 Gy abdominal gamma irradiation leads to an inflammatory reaction, and to compare intestinal and colonic motility in controls and abdominally irradiated rats 1, 3 and 7 days after irradiation, using an electromyographic technique. The motility parameters analysed were the frequency and velocity of propagation of migrating myoelectric complexes (MMC) in the jejunum and colonic spike activity (long spike bursts; LSB) per 10 min in fasted rats. The MMC frequency was significantly reduced on days 1 and 7 after irradiation and the MMC pattern was markedly disrupted on day 3. The frequency of colonic LSB was significantly reduced on days 1, 3 and 7. Mouth to anus transit was significantly accelerated on day 3 only and diarrhoea was observed at this time. Myeloperoxidase activity in the jejunum and colon was also increased on this day only. It is concluded that irradiation-induced diarrhoea occurs contemporaneously with disruption of MMC in the small intestine.
Animals↗
Absence of protective role of afferent nerves in early intestinal mucosal alterations induced by abdominal irradiation in rats.
PURPOSE: To assess the early effects of primary afferent nerve suppression by systemic treatment with the neurotoxin capsaicin in an acute model of abdominal irradiation in rats (10Gy, gamma). MATERIALS AND METHODS: Changes in myeloperoxidase (MPO) activity, calcitonin gene-related peptide (CGRP) tissue content, number of mast cells and apoptotic cells were determined in jejunum and ileum in four groups of rat male Wistar (vehicle sham-irradiated, vehicle irradiated, capsaicin sham-irradiated and capsaicin irradiated) at 1 and 3 days post-irradiation. RESULTS: In vehicle irradiated rats, CGRP was significantly increased from the first day after irradiation in jejunal mucosa; MPO activity increased in both segments at day 3 but not at day 1 after irradiation; the number of detectable mucosal mast cells dropped to nearly zero on days 1 and 3, while the apoptotic cells in the intestinal mucosa were significantly increased at day 1. Similar results were obtained for mast cells and apoptosis in capsaicin irradiated rats as compared to capsaicin sham-irradiated rats, while MPO activity was significantly increased and CGRP concentration in jejunal mucosa significantly decreased from the first day in these rats in comparison with capsaicin sham-irradiated rats. CONCLUSIONS: Intestinal sensory innervation seems not to have a major protective role against a radiation-induced intestinal inflammatory reaction.
Animals↗
Impaired interferon gamma-mediated immunity and susceptibility to mycobacterial infection in childhood.
Mendelian susceptibility to poorly virulent mycobacteria such as bacillus Calmette-Guerin (BCG) and environmental nontuberculous mycobacteria is a clinically heterogeneous syndrome. The clinical features of affected children cover a continuous spectrum from disseminated lethal bacillus Calmette-Guerin infection to local recurrent nontuberculous mycobacterial infection. Different types of mutations in four genes (IFNGR1, IFNGR2, IL12B, IL12RB1) have revealed both allelic and nonallelic heterogeneity and result in eight different disorders whose common pathogenic pathway is impaired interferon gamma (IFNgamma) mediated immunity. The severity of the clinical phenotype depends on the genotype. Complete IL-12 p40 and IL-12 receptor beta1 deficiencies and partial IFNgamma receptor 1 (IFNgammaR1) and IFNgammaR2 deficiencies generally lead to curable infections at various ages, and antibiotics supplemented with IFNgamma if required are likely to be effective. Complete IFNgammaR1 and IFNgammaR2 deficiencies predispose to overwhelming infection in early childhood, which may respond to antibiotics but relapse when antibiotics are discontinued. Rapid discrimination between complete IFNgammaR1 and IFNgammaR2 deficiency and other defects, therefore, is an important diagnostic step for planning clinical management.
Child↗
Recurrent Mycobacterium avium osteomyelitis associated with a novel dominant interferon gamma receptor mutation.
Mycobacterium avium causes infections in immunocompromised individuals. Recurrent infection with this organism has been associated with a deletion at the 818 residue of the interferon-gamma receptor (IFN-gammaR). This mutation produces a truncated receptor without an intracytoplasmic tail, resulting in diminished signaling. We describe a substitution at the 832 residue of the IFN-gammaR causing a similar truncated receptor in a 7-year-old girl with recurrent M avium osteomyelitis.
Antibodies, Monoclonal↗
High levels of interferon gamma in the plasma of children with complete interferon gamma receptor deficiency.
We have found that children with complete interferon gamma (IFNgamma) receptor deficiency, unlike patients with other genetic defects predisposing them to mycobacterial diseases, have very high levels of IFNgamma in their plasma. This unexpected observation provides a simple and accurate diagnostic method for complete IFNgamma receptor deficiency in children with clinical disease caused by bacille Calmette-Guérin vaccines or environmental nontuberculous mycobacteria.
BCG Vaccine↗
HIV-2 and SIV nef proteins target different Src family SH3 domains than does HIV-1 Nef because of a triple amino acid substitution.
The nef gene is required for optimal viral spread of human and simian immunodeficiency viruses. However, the molecular mechanisms underlying the action of the Nef proteins may not be identical for all viral families. Here we investigate the interaction between the Nef protein of human and simian immunodeficiency viruses and SH3 domains from Src family kinases. Using the yeast two-hybrid system and immunoblotting we show that, in contrast to HIV-1 Nef, SIV and HIV-2 Nef poorly interact with Hck SH3 but bind to Src and Fyn SH3 domains. The molecular basis of these differences in SH3 targeting was revealed by sequence analysis and homology modeling of the putative SH3-Nef structures. Three amino acids (Trp-113, Thr-117, and Gln-118) that localize in a "hydrophobic pocket" implicated in SH3 binding of HIV-1 Nef, are systematically substituted in SIV/HIV-2 alleles (by Tyr, Glu, and Glu, respectively). We demonstrate that site-directed mutagenesis of these residues in SIV(mac239) Nef suffices to restore Hck SH3 binding and co-immunoprecipitation with full-length Hck from transfected cells. Our findings identify fundamental mechanistic differences in targeting of Src family kinases by HIV and SIV Nef. The herein described mechanism of SH3 selection by Nef via a "pocket" proximal to the canonical proline-rich motif may be a common feature for SH3 recognition by their natural ligands.
Amino Acid Sequence↗
A conformational study of the xyloglucan oligomer, XXXG, by NMR spectroscopy and molecular modeling.
A structural study of the XXXG xyloglucan heptasaccharide (X = alpha-D-Xylp(1 --> 6)-beta-D-Glcp and G = beta-D-Glcp) isolated from apple fruit has been undertaken with nmr and molecular mechanics methods. Quantitative 400 MHz nmr data including nuclear Overhauser effect spectroscopy (NOESY) volumes were recorded at both 6 and 20 degrees C. In spite of severe overlapping of resonances, it was possible to estimate summed NOEs for the majority of the anomeric and glucosyl methylene protons. An ensemble-average population of preferred geometries has been established with the CICADA conformational searching algorithm associated with the MM3 force field. Comparison of the theoretical data obtained by back-calculation of the NOESY volumes from the ensemble-average distance matrix program and motional models based on the Stokes-Einstein-Debye relation satisfactorily reproduce the experimental data. Conformational averaging about the mainchain glycosidic linkages includes both the syn and anti conformers and a minor gauche-gauche population is highly probable. The theoretical data overestimate the syn preference of the Glc(c) --> Glc(b) linkage as well as the Glc(c) GT rotamer population. Finally, both the motional models and the conformational search indicate a fairly rigid backbone and greater flexiblity for the xylose side chains.
Carbohydrate Conformation↗