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Biomedical subjects

E Fournier

Publications and source records attributed to E Fournier.

At least 37 records · Page 2Linked to original sources
PubMed2001

Genome screening for linkage disequilibrium in a Costa Rican sample of patients with bipolar-I disorder: a follow-up study on chromosome 18.

Linkage disequilibrium (LD) methods offer great promise for mapping complex traits, but have thus far been applied sparingly. In this paper we describe an LD mapping study of severe bipolar disorder (BP-I) in the genetically isolated population of the Central Valley of Costa Rica. This study provides the first complete screen of a chromosome for a complex trait using LD mapping and presents the first application of a new LD mapping statistic (ancestral haplotype reconstruction (AHR)) that evaluates haplotype sharing among affected individuals. The results of this chromosome-wide analysis are instructive for genome-wide LD mapping in isolated populations. Furthermore, the analysis continues to support a possible BP-I locus on 18pter, suggested by previous analyses in this population. Evidence for a possible BP-I locus on 18q12.2 is also described.

Bipolar Disorder↗
PubMed2001

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↗
PubMed2000

Further evidence for a central reorganisation of synaptic connectivity in patients with hypoglossal-facial anastomosis in man.

In normal subjects, electrical stimulation of trigeminal mucosal afferents (lingual nerve - V3) can elicit a short latency (12.5+/-0. 3 ms; mean+/-S.D.) reflex response in the ipsilateral genioglossus muscle (Maisonobe et al., Reflexes elicited from cutaneous and mucosal trigeminal afferents in normal human subjects. Brain Res. 1998;810:220-228). In the present study on patients with hypoglossal-facial (XII-VII) nerve anastomoses, we were able to record similar R1-type blink reflex responses in the orbicularis oculi muscles, following stimulation of either supraorbital nerve (V1) or lingual nerve (V3) afferents. However, these responses were not present in normal control subjects. Voluntary swallowing movements produced clear-cut facilitations of the R1 blink reflex response elicited by stimulation of V1 afferents. In a conditioning-test procedure with a variable inter-stimulus interval, the R1 blink reflex response elicited by supraorbital nerve stimulation was facilitated by an ipsilateral mucosal conditioning stimulus in the V3 region. This facilitatory effect was maximal when the two stimuli (conditioning and test) were applied simultaneously. This effect was not observed on the R1 component of the blink reflex in the normal control subjects. These data strongly suggest that in patients with XII-VII anastomoses, but not in normal subjects, both cutaneous (V1) and mucosal (V3) trigeminal afferents project onto the same interneurones in the trigeminal principal sensory nucleus. This clearly supports the idea that peripheral manipulation of the VIIth and the XIIth nerves induces a plastic change within this nucleus.

Adult↗
PubMed2000

Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains.

Pleckstrin homology (PH) domains are protein modules of around 120 amino acids found in many proteins involved in cellular signaling. Certain PH domains drive signal-dependent membrane recruitment of their host proteins by binding strongly and specifically to lipid second messengers produced by agonist-stimulated phosphoinositide 3-kinases (PI 3-Ks). We describe X-ray crystal structures of two different PH domains bound to Ins(1,3,4,5)P4, the head group of the major PI 3-K product PtdIns(3,4,5)P3. One of these PH domains (from Grp1) is PtdIns(3,4,5)P3 specific, while the other (from DAPP1/PHISH) binds strongly to both PtdIns(3,4,5)P3 and its 5'-dephosphorylation product, PtdIns(3,4)P2. Comparison of the two structures provides an explanation for the distinct phosphoinositide specificities of the two PH domains and allows us to predict the 3-phosphoinositide selectivity of uncharacterized PH domains.

Adaptor Proteins, Signal Transducing↗
PubMed2000

ERBIN: a basolateral PDZ protein that interacts with the mammalian ERBB2/HER2 receptor.

The ERBB receptors have a crucial role in morphogenesis and oncogenesis. We have identified a new PDZ protein we named ERBIN (ERBB2 interacting protein) that acts as an adaptor for the receptor ERBB2/HER2 in epithelia. ERBIN contains 16 leucine-rich repeats (LRRs) in its amino terminus and a PDZ (PSD-95/DLG/ZO-1) domain at its carboxy terminus, and belongs to a new PDZ protein family. The PDZ domain directly and specifically interacts with ERBB2/HER2. ERBIN and ERBB2/HER2 colocalize to the lateral membrane of human intestinal epithelial cells. The ERBIN-binding site in ERBB2/HER2 has a critical role in restricting this receptor to the basolateral membrane of epithelial cells, as mutation of the ERBIN-binding site leads to the mislocalization of the receptor in these cells. We suggest that ERBIN acts in the localization and signalling of ERBB2/HER2 in epithelia.

Adaptor Proteins, Signal Transducing↗
PubMed2000

[True neurological thoracic outlet syndrome].

The thoracic outlet syndrome (TOS) encompasses various clinical entities affecting the neurovascular bundle crossing the thoracic outlet. Unfortunately, this term often proves to be confusing because many of these entities have little in common beyond their known or presumed lesion site. Neurogenic TOS (true TOS) is caused by compression of the lower trunk in the brachial plexus, the cervical ribs or fibrous band. This syndrome is extremely rare. We consider that this neurological form of TOS is a clearly defined neurological syndrome. We report 10 patients with true TOS. All were females. Stating the onset was difficult because symptoms were progressive and insidious. Pain was the most frequently reported symptom. Sensory deficit was slight or absent. All patients showed unilateral severe atrophy of the thenar muscles. Wasting and weakness developed later. A reduced amplitude of ulnar and median compound muscle action potential associated with a normal amplitude of median sensory nerve action and a reduced amplitude of ulnar sensory nerve action potential were indicative of a chronic axon loss in the lower trunk of the brachial plexus. In all cases, we performed medial antebrachial cutaneous sensory nerve action potential, a C8-T1 innervated nerve. The absence of the medial antebrachial cutaneous sensory nerve action potential in 9 patients and a reduction in amplitude of 50 p. 100 compared to the unaffected side in the other patient, indicated the diagnostic value of this easy and reproductible test. It confirmed a C8-T1 post-ganglionic radicular lesion or a lower brachial plexus neuropathy. Radiography showed a rudimentary bilateral cervical rib or an elongated C7 transverse process in all cases. Surgery was performed in the affected side in 7 patients and in each case the lower part of the brachial plexus was found to be stretched and angulated over a fibrous band, which was removed. Pain was relieved after 1 to 4 weeks. A minimal motor improvement was observed after one year. Electrophysiological results were unchanged.

Adult↗
PubMed2000

[Periodic hypokalemic paralysis as the manifestation of Graves' disease: clinical and electrophysiological study].

A 30-year-old Vietnamese man experienced severe weakness of four limbs revealing hypokalaemia. Tachycardia and goiter allowed to diagnose a Graves' disease. Thyrotoxic hypokaliemic periodic paralysis is a rare complication of hyperthyroidism in western populations. Electromyogram performed after resolution of the paralysis episodes revealed marked abnormalities of the muscular excitability. Duration of compound muscular action potential was markedly increased after a brief exercise. This increase might indicate a delayed repolarization of muscle fibres.

Adult↗
PubMed1999

Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF receptor 3 signaling.

The VEGFR3/FLT4 receptor, which is involved in vasculogenesis and angiogenesis, binds and phosphorylates SHC proteins on tyrosine residues. SHC contains two phosphotyrosine interaction domains: a PTB (Phosphotyrosine Binding) and a SH2 (Src Homology 2) domain. Previous studies have shown that SHC proteins are phosphorylated on Y239/Y240 and Y313 (Y317 in humans) by tyrosine kinases such as the EGF and IL3 receptors. We have investigated which of the SHC tyrosine residues are targeted by the VEGFR3/ FLT4 kinase and the role of the SHC PTB and SH2 domains in this process. Our results show that Y239/ Y240 and Y313 are simultaneously phosphorylated by the kinase, creating GRB2 binding sites. Mutation of SHC PTB, but not SH2, domain interferes with the SHC phosphorylation by VEGFR3/FLT4. Soft agar assay experiments revealed that the VEGFR3/FLT4 transforming capacity is increased by the mutation of Y239/Y240 to phenylalanines in SHC, suggesting that these two residues mediate an inhibitory signal for cell growth. Mutation of the two phosphorylation sites increases this effect, suggesting that they have a synergistic role.

Cell Line↗
PubMed1999

Measuring interstate variations in drug problems.

This article describes the Drug Problem Index (DPI), a composite index measuring the interstate severity of drug abuse problems. The DPI's components (drug-coded mortality, drug-defined arrest, and drug-treatment client rates) were selected because they were linked closely with drug abuse, data were available for all states, and there was published evidence of their validity. The variables were reliable, and their convergent validity was estimated in a multi-trait, multi-method matrix. We found evidence consistent with the DPI's construct validity in its relations with other consequences of drug abuse. The DPI correlated significantly with the Block Grant drug need index but not with model estimates of drug dependence based on the National Household Survey.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Electrophysiological diagnosis of motor neuron disease and pure motor neuropathy.

Motor neuron disease (MND) is a group of disorders in which there is degeneration of upper and lower motor neurons to a variable degree. Amyotrophic lateral sclerosis is the most frequent form of the disease, presenting with both upper and lower motor neuron involvement. Frequently, especially in the early stages of the disease, only lower motor neuron signs are present. In these conditions, some pure motor neuropathies may resemble MND. The diagnosis is of importance because some of these motor neuropathies are "dysimmune" disorders and may respond to immune therapies. In such diseases the multifocal motor neuropathy with conduction block appears to be the more frequent. In MND and pure motor neuropathies, the electrophysiological examination is the most decisive test. In MND, it is of diagnostic importance. In addition, it is useful in the assessment of disease severity and progression, in the evaluation of therapeutic trials and in the understanding of etiopathogenesis of the disease. In pure motor neuropathies, the presence of conduction block leads to immune treatment with good response in more than 50% of the cases.

Diagnosis, Differential↗
PubMed1999

SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor.

The FLT3 receptor tyrosine kinase and its ligand, FL, regulate the development of hematopoietic stem cells and early B lymphoid progenitors. FL has a strong capacity to boost production of dendritic and natural killer cells in vivo, thereby providing a new and promising tool for anti-cancer immunotherapy. Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313. SHC possesses two phosphotyrosine-binding domains: an amino-terminal phosphotyrosine binding (PTB) and a carboxy-terminal Src Homology 2 (SH2) domain. Neither is required for SHC phosphorylation, but the PTB domain is necessary and sufficient for SHC binding to the SH2 containing inositol phosphatase (SHIP). Overexpression of SHC increases the level of SHIP phosphorylation on tyrosines in response to FLT3 activation, suggesting that SHC availability is a limiting step for SHIP phosphorylation. This effect is observed only if the SHC PTB domain is functional. Interestingly, SHC overexpression in FLT3-activatable Ba/F3 cells limits FLT3-dependent cell growth and this effect requires tyrosine 313. Taken together, the present data show that SHC can antagonize cell proliferation induced by FLT3 stimulation and regulate phosphorylation of the SHIP negative regulator. In addition, our study provides the structural bases for SHC phosphorylation and formation of the SHC/SHIP complex.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Assessing the feasibility of linkage disequilibrium methods for mapping complex traits: an initial screen for bipolar disorder loci on chromosome 18.

Linkage disequilibrium (LD) analysis has been promoted as a method of mapping disease genes, particularly in isolated populations, but has not yet been used for genome-screening studies of complex disorders. We present results of a study to investigate the feasibility of LD methods for genome screening using a sample of individuals affected with severe bipolar mood disorder (BP-I), from an isolated population of the Costa Rican central valley. Forty-eight patients with BP-I were genotyped for markers spaced at approximately 6-cM intervals across chromosome 18. Chromosome 18 was chosen because a previous genome-screening linkage study of two Costa Rican families had suggested a BP-I locus on this chromosome. Results of the current study suggest that LD methods will be useful for mapping BP-I in a larger sample. The results also support previously reported possible localizations (obtained from a separate collection of patients) of BP-I-susceptibility genes at two distinct sites on this chromosome. Current limitations of LD screening for identifying loci for complex traits are discussed, and recommendations are made for future research with these methods.

Bipolar Disorder↗
PubMed1998

Reflexes elicited from cutaneous and mucosal trigeminal afferents in normal human subjects.

It has been shown that in patients in whom the central stump of the hypoglossal nerve has been anastomosed to the peripheral stump of a lesioned facial nerve, supraorbital nerve stimulation can elicit a short-latency reflex (12.5+/-0.6 ms; mean+/-S.D.) in facial muscles similar to the R1 disynaptic blink reflex response, but not followed by an R2 blink reflex component46. Thus in addition to replacing the facial neurons at peripheral synapses, these hypoglossal nerves contribute to a trigemino-hypoglossal reflex. The aim of this work was to study the type of reflex activities which can be elicited in both facial and tongue muscles by electrical stimulation of cutaneous (supraorbital nerve) or mucosal (lingual nerve) trigeminal (V) afferents in normal subjects. The results show that although stimulation of cutaneous V1 afferents elicits the well-known double component (R1-R2) blink reflex response in the orbicularis oculi muscles, it does not produce any detectable reflex response in the genioglossus muscle, even during experimental paradigms designed to facilitate the reflex activity. Conversely, stimulation of mucosal V3 afferents can elicit a single reflex response of the R1 type in the genioglossus muscle but not in the orbicularis oculi muscles, even during experimental paradigms designed to facilitate the reflex activity. These data are discussed in terms of two similar but separate circuits for the R1 responses of cutaneous (blink reflex) and mucosal (tongue reflex) origins. They suggest that in patients with hypoglossal-facial (XII-VII) nerve anastomosis, the short-latency trigemino-'hypoglossal-facial' reflex of the R1 blink reflex type observed in facial muscles following supraorbital nerve stimulation could be due to changes in synaptic effectiveness of the central connectivity within the principal trigeminal nucleus where both cutaneous and mucosal trigeminal afferents project.

Adult↗
PubMed1998

Electrophysiological determination of the site involved in generating abnormal muscle responses in hemifacial spasm.

In patients with hemifacial spasm (HFS), abnormal muscle responses due to abnormal cross-transmission are observed in facial muscles. However, the site in the facial nerve responsible for the cross-transmission remains a matter of controversy. We have developed a model in which by considering the electrophysiological parameters involved in producing the abnormal muscle response, we can determine the site of the abnormal cross-transmission within the facial nerve. This model was applied to HFS patients with three different etiologies: idiopathic, post-Bell's palsy, and post-XII-VII anastomosis. Our data show that: in idiopathic HFS, the cross-transmission may occur in the facial nerve at the level of the pontocerebellar angle; in post-Bell's palsy, it is inside the petrous bone; and in XII-VII anastomosis, it must be in the extracranial part of the facial nerve. The possible mechanisms for this cross talk are discussed in terms of ephaptic transmission or of a central hyperexcitability in the facial motor nucleus.

Adult↗
PubMed1998

A third human CBL gene is on chromosome 19.

CBL genes encode cytoplasmic proteins involved in signal transduction downstream of a number of receptors including tyrosine kinases, cytokine receptors, and T-cell or B-cell receptors. They seem to be transducers associated with negative regulation of signals, and, as such, may be potential tumor suppressors. Using a probe derived from an expressed sequence tag, we isolated a cosmid containing part of a new CBL gene, CBLc, related to the two characterized paralogous genes CBLa and CBLb. Using the cosmid in fluorescence in situ hybridization of human metaphase chromosomes, we localized the CBLc gene to band 13.2 of chromosome 19. We show that the 19q12.2-13.3 region where CBLc is located shows paralogy with two other regions of the human genome, 3q22-q27 and 11q22-q24 where CBLb and CBLa are located, respectively. Genes from several other families are located in these regions.

Chromosome Mapping↗
PubMed1997

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↗
PubMed1997

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↗