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Biomedical subjects

E Fournier

Publications and source records attributed to E Fournier.

At least 19 recordsLinked to original sources

Linkage analysis of a complex pedigree with severe bipolar disorder, using a Markov chain Monte Carlo method.

Recently developed algorithms permit nonparametric linkage analysis of large, complex pedigrees with multiple inbreeding loops. We have used one such algorithm, implemented in the package SimWalk2, to reanalyze previously published genome-screen data from a Costa Rican kindred segregating for severe bipolar disorder. Our results are consistent with previous linkage findings on chromosome 18 and suggest a new locus on chromosome 5 that was not identified using traditional linkage analysis.

Algorithms

The role of the Shc phosphotyrosine interaction/phosphotyrosine binding domain and tyrosine phosphorylation sites in polyoma middle T antigen-mediated cell transformation.

The phosphotyrosine interaction (PI)/phosphotyrosine binding (PTB) domain of Shc binds specific tyrosine-phosphorylated motifs found on activated growth factor receptors and proteins such as polyoma virus middle T antigen (MT). Phenylalanine 198 (Phe198) has been identified as a crucial residue involved in the interaction of the Shc PI/PTB with phosphopeptides. In NIH 3T3 cells expressing MT, p52 Shc carrying the F198V mutation is weakly phosphorylated and does not bind MT or Grb2. Overexpression of the PI/PTB domain alone as Shc amino acids 1-238 acted in a dominant interfering fashion blocking MT-induced transformation. However, expression of a slightly longer construct, Shc 1-260, which encompasses Tyr239/Tyr240, a novel Shc tyrosine phosphorylation site, did not block transformation. This was found to be due to the ability of Shc 1-260 to become tyrosine-phosphorylated and bind Grb2. Furthermore, full-length Shc in which Tyr239/Tyr240 had been mutated to phenylalanine did not become tyrosine-phosphorylated or bind Grb2 but did inhibit colony formation in soft agar. Conversely, p52 Shc carrying a mutation in the other tyrosine phosphorylation site, Tyr317, became heavily tyrosine-phosphorylated, bound Grb2, and gave rise to colonies in soft agar.

3T3 Cells

Relationships between storage and secretion of hepatic lipids in two breeds of geese with different susceptibility to liver steatosis.

Susceptibility to liver steatosis was studied in Landes and Poland geese, which are hyper- and hyporesponsive, respectively, to overfeeding. Plasma lipoproteins were characterized at different stages of the overfeeding process, whereas fatty liver composition was determined after completion of overfeeding and slaughtering. Before overfeeding, plasma lipoprotein profile was typical of birds in both breeds, except that very low density lipoproteins (VLDL) were low in triglyceride (approximately 30%). Moreover, high-density lipoprotein (HDL) concentration was higher in the Poland geese (6.44 vs 4.97 g/L). During overfeeding, hepatic lipogenesis was increased, and fatty liver resulted from accumulation of primarily triglyceride (approximately 95% of lipid content), but also of all other lipids. This accumulation was significantly greater in the Landes geese for all lipids but phospholipid. Thus, the liver weight was 100% higher in this breed (1,005 g vs 485 g), whereas lipid release during sterilization was twofold higher (26.3 vs 7.5%). Parallel, plasma concentration and triglyceride content of hepatic lipoproteins, VLDL and HDL, increased about one- to twofold, this effect being greater in the Poland geese. Therefore, channeling of triglyceride towards secretion rather than in situ storage may be responsible for the hyporesponsiveness of this breed to overfeeding. In both breeds, and especially in the Landes geese, a relative deficiency in phospholipid synthesis together with an enhanced secretion may be limiting factors of hepatocyte hypertrophia and, therefore, of steatosis.

Animals

[Receptors for factors of the VEGF (Vascular Endothelial Growth Family)].

Growth factors of the VEGF (vascular endothelial growth factor) family comprises 4 well characterized members that play a crucial role in the biology of blood vessels. They interact with 3 high affinity tyrosine kinase receptors (FLT1/VEGFR1, FLK1/KDR/VEGFR2, FLT4/VEGFR3). VEGF/VEGFR interactions have essential functions in blood vessel formation during development, specific phases of adult life, and in some pathological processes with neo-vascularization such as tumor growth.

Adult

A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees.

Bipolar mood disorder (BP) is a debilitating syndrome characterized by episodes of mania and depression. We designed a multistage study to detect all major loci predisposing to severe BP (termed BP-I) in two pedigrees drawn from the Central Valley of Costa Rica, where the population is largely descended from a few founders in the 16th-18th centuries. We considered only individuals with BP-I as affected and screened the genome for linkage with 473 microsatellite markers. We used a model for linkage analysis that incorporated a high phenocopy rate and a conservative estimate of penetrance. Our goal in this study was not to establish definitive linkage but rather to detect all regions possibly harboring major genes for BP-I in these pedigrees. To facilitate this aim, we evaluated the degree to which markers that were informative in our data set provided coverage of each genome region; we estimate that at least 94% of the genome has been covered, at a predesignated threshold determined through prior linkage simulation analyses. We report here the results of our genome screen for BP-I loci and indicate several regions that merit further study, including segments in 18q, 18p, and 11p, in which suggestive lod scores were observed for two or more contiguous markers. Isolated lod scores that exceeded our thresholds in one or both families also occurred on chromosomes 1, 2, 3, 4, 5, 7, 13, 15, 16, and 17. Interesting regions highlighted in this genome screen will be followed up using linkage disequilibrium (LD) methods.

Bipolar Disorder

Use of linkage disequilibrium approaches to map genes for bipolar disorder in the Costa Rican population.

Linkage disequilibrium (LD) analysis provides a powerful means for screening the genome to map the location of disease genes, such as those for bipolar disorder (BP). As described in this paper, the population of the Central Valley of Costa Rica, which is descended from a small number of founders, should be suitable for LD mapping; this assertion is supported by reconstruction of extended haplotypes shared by distantly related individuals in this population suffering low-frequency hearing loss (LFHL1), which has previously been mapped by linkage analysis. A sampling strategy is described for applying LD methods to map genes for BP, and clinical and demographic characteristics of an initially collected sample are discussed. This sample will provide a complement to a previously collected set of Costa Rican BP families which is under investigation using standard linkage analysis.

Adult

Interaction with the phosphotyrosine binding domain/phosphotyrosine interacting domain of SHC is required for the transforming activity of the FLT4/VEGFR3 receptor tyrosine kinase.

The FLT4 gene encodes two isoforms of a tyrosine kinase receptor, which belongs to the family of receptors for vascular endothelial growth factor. As the result of an alternative processing of primary mRNA transcripts, the long isoform differs from the short isoform by an additional stretch of 65 amino acid residues located at the C terminus and containing three tyrosine residues, Tyr1333, Tyr1337, and Tyr1363. Only the long isoform is endowed with a transforming capacity in fibroblasts. We show that this activity is related to the capacity of the tyrosine 1337-containing sequence to interact with the phosphotyrosine binding domain of the SHC protein. This demonstrates that a functional property of this newly described domain includes relay of mitogenic signals. In addition, it shows that the same receptor can mediate different functions through the optional binding of the phosphotyrosine binding domain and that the alternative use of this domain is sufficient to direct the signal toward different pathways.

Adaptor Proteins, Signal Transducing

Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23.

Manic depressive illness, or bipolar disorder (BP), is characterized by episodes of elevated mood (mania) and depression. We designed a multistage study in the genetically isolated population of the Central Valley of Costa Rica to identify genes that promote susceptibility to severe BP (termed BPI), and screened the genome ot two Costa Rican BPI pedigrees (McInnes et al., submitted). We considered only individuals who fulfilled very stringent diagnostic criteria for BPI to be affected. The strongest evidence for a BPI locus was observed in 18q22-q23. We tested 16 additional markers in this region and seven yielded peak lod scores over 1.0. These suggestive lod scores were obtained over a far greater chromosomal length (about 40 cM) than in any other genome region. This localization is supported by marker haplotypes shared by 23 of 26 BPI affected individuals studied. Additionally, marker allele frequencies over portions of this region are significantly different in the patient sample from those of the general Costa Rican population. Finally, we performed an analysis which made use of both the evidence for linkage and for association in 18q23, and we observed significant lod scores for two markers in this region.

Alleles

A clinical and neurophysiological study of a patient with an extensive transection of the spinal cord sparing only a part of one anterolateral quadrant.

In 1976, Noordenbos and Wall studied sensory functions in a woman with a surgically verified T3 spinal cord transection which spared only a part of the left anterolateral quadrant, We re-investigated this unique case 18 years after the lesion and included a comparable sensory examination, MRI of the spinal cord, somatosensory evoked potentials, PET-activation study during hand and foot vibration and analysis of flexion reflex modulation during the Jendrassik manoeuvre. Our results show that the residual anterolateral quadrant contains ascending pathways carrying a wide range of sensory information as well as descending pathways modulating flexion reflex activity at the spinal level. Moreover, the changes in sensory functions and the unique pattern of cortical activation suggest a functional reorganization of the connectivity between the periphery and the cerebral cortex. Changes of facilitation and/or of inhibition at different levels of the somatosensory system may account for these longterm plastic changes.

Evoked Potentials, Somatosensory

Mutation at tyrosine residue 1337 abrogates ligand-dependent transforming capacity of the FLT4 receptor.

In humans, the FLT4 gene encodes two isoforms of a tyrosine kinase receptor, which differ in their carboxy terminal regions. As compared to the short form, the long form has an additional stretch of 65 amino acids containing three tyrosine residues (Y1333, Y1337 and Y1363). Once expressed in fibroblast cells, only the long form is able to elicit both anchorage-independent growth in a soft agar assay and tumors in nude mice, and thus appears endowed with a potential ligand-dependent transforming capacity. Replacement of tyrosine 1337 by phenylalanine abrogates the transforming capacity of the long form. This residue was identified as a potential autophosphorylation site, and a docking site for a substrate important in the signal transduction specific of the long FLT4 isoform. We demonstrate that the GRB2 and SHC cytoplasmic substrates are involved in FLT4 signal transduction. SHC interaction could be crucial to FLT4-mediated transforming activity associated with the long isoform. Finally, trancripts for the two forms are detected in tissues positive for FLT4 gene expression.

3T3 Cells

[Incidents and side effects of metallic orthopedic and odontologic prostheses].

Sensitization and immune disorders from metallic prostheses are very unusual although most of them were metal-metal structures (nickel, cobalt or chromium alloys) during decades. Recent technical modifications; the use of new metal (titan-vanadium), of aluminum or ceramic prostheses eliminate these side effects; The clinical diseases may be regional (eczema, dermatitis, vascularitis) or general (diffuse dermatitis, itching). Some very rare systemic diseases have been described but their relation with the prosthesis is often uncertain. The positive patch tests are good indicators of the sensitization but their high prevalence of metal sensitization in the normal population excludes a safe diagnosis. The best demonstration remains the complete recovery of the disease after removal of the prosthesis.

Biocompatible Materials

Effects of occupational lead exposure on motor and somatosensory evoked potentials.

In order to objectivate the effects of inorganic lead compounds on the nervous system, 17 men occupationally exposed have been recorded for Motor Electric Potentials (MEPs) of the abductor policis brevis muscles with transcranial, cervical root and peripheral electrical stimulations, for Somatosensory Evoked Potentials (SEPs) of median and tibial posterior nerves, and for Electromyography (EMG). Considering each subject, 16 out of the 17 lead exposed ones exhibited electrophysiological abnormalities, occurring at both peripheral and central levels for the somatosensory as well as for the motor systems. As compared to a normal control group, the lead exposed one showed decreased sensory and motor peripheral conduction velocities, increased motor central conduction time, and delayed cortical P22 SEPs component that could be interpreted as a sensory-motor cortical dysfunction. The respective contributions of MEPs and SEPs are compared to clinical, biological and EMG examinations in the evaluation of the neurotoxic effects of inorganic lead compounds.

Adult

[A fatal case of viper bite in an adult in France].

Vipera bites in France are supposed to be benign. We report here, the case of a snake bite with fatal outcome due to hypoxemia and shock, occurring in a young woman without previous disease. This case could lead to reevaluate the indication of antivenomous serotherapy in the severe envenomations. However the tolerance of the new serums has to the confirmed.

Adult

[Lymphocyte phenylvaleric acid hydroxylase activity (L-PVH), a new marker of peripheral neurotoxicity].

A reduction in the level of a new enzymatic assay--a phenyl valerate hydrolase (PVH)--has been found during the clinical evolution of toxic neuropathies (as almitrine-bismetilate ones) as well as alcoholic or diabetic neuropathies. The substrate and the enzymatic function are different from those used by M.K. Johnson for NTE. The method follows procedures comparable to NTE (differential determination after inhibition by paraoxon and by paraoxon plus mipafox or DFP). It may be useful to test possible neurotoxicity of drugs and chemicals.

Adult

[Non-auditory responses to noise. Objective estimation. Experimental and individual analyses].

The physiological reactions to a strong noise are immediate and transitory: start, arousal reactions, postural oculo-cephalo-motor response, cardiovascular reactions with tachycardia and peripheral vasoconstriction, mydriasis. The chronic reactions to an occupational permanent noise are mostly a state of fatigue, lowering of the psychotechnic ability, aggressivity, transitory tachycardia and elevation of blood pressure, mainly diastolic. The best argument in favour of a correlation between these reactions and the noise is their reversibility with the cessation of the nuisance. The non-auditive responses to noise--including blood pressure variation--described for stimuli of moderate intensity considered as environmental nuisances are less evident. Among inhabitants of a town the neurophysiological examination of the modifications due to different demonstrate the evident perturbation of the sleep organisation: difficulties to fall asleep, need of a complementary rest. The epidemiological inquiries in noisy zones indicate however that, within a common population, 10% of the subjects feel very uncomfortable, but that 30% of them declare to be normal. The revendications and the trials against the factors of noise let us recommend to associate the efforts of physicians and of physiologists to those of acousticians experts. The different sonometric assays, the methods used in order to decide if a noise is a nuisance are described and should be widely used to demarcate very quiet territories (climatic areas) and sectors to be improved.

Hearing Loss, Noise-Induced

[Vasospastic angina with angiographically normal coronary vessels of iatrogenic origin. Apropos of 2 cases].

Two cases of angina pectoris, induced by methylergometrine (Methergin) and by an association of ergotamine tartrate (Gynergene) and methysergide (Desernil) respectively, are reported. In both patients, angiography revealed spontaneous spasm in a coronary system free from any significant atheromatous stenosis. In the second case, a test administration of i.v. Methergin, administered during calcium-channel antagonist treatment a few days after the "guilty" drugs had been stopped was found to be negative. The outcome was favorable in both cases: the angina disappeared and the base-line and exercise ECG returned to normal. The hypothesis of coronary spasm induced by the treatment was adopted in both cases. In this context, the major iatrogenic etiologies of vasospastic angina are recalled, together with the prophylactic and therapeutic measures they call for.

Adult