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Biomedical subjects

A Vincent

Publications and source records attributed to A Vincent.

At least 145 records · Page 8Linked to original sources
PubMed1998

Antibodies affecting ion channel function in acquired neuromyotonia, in seropositive and seronegative myasthenia gravis, and in antibody-mediated arthrogryposis multiplex congenita.

A new autoimmune disease affecting the neuromuscular junction has been defined. Acquired neuromyotonia is associated with antibodies to voltage-gated potassium channels that act, at least in part, by reducing potassium channel function with resulting neuronal hyperactivity. This condition is quite frequently associated with thymoma and, in many cases, antibodies to acetylcholine receptors are present as well as antibodies to VGKC. Improvements in techniques and the availability of cloned DNA and recombinant forms of the AChR subunits have led to new observations concerning the specificity and roles of antibodies in myasthenia gravis. The transfection of a cell line with the epsilon subunit means that we can now accurately compare antibodies reactive with adult and fetal human AChR. This may help to determine the relationship between AChR subunit expression in different tissues and the induction of antibodies that bind specifically to the two forms, as well as to clarify the role of antibodies to fetal or adult AChR in causing ocular muscle symptoms. Serum antibodies from a few mothers with obstetric histories of recurrent arthrogryposis multiplex congenita in their babies specifically inhibit the function of fetal AChR. These observations not only explain the cause of some cases of arthrogryposis multiplex congenita, but also suggest that other fetal-specific antibodies might be responsible for other fetal or neonatal conditions. An animal model has been established to enable us to investigate the role of maternal serum factors in causing such disorders. Seronegative MG has been the subject of many studies from our laboratory over the last ten years. The transience of the effects of SNMG plasmas on AChR function strongly suggests that the plasma antibodies do not bind directly to the AChR, but inhibit function by some indirect mechanism. They do not appear to act via the cAMP-dependent protein kinase pathway, and studies are in progress to investigate the involvement of other second messenger systems.

Adult↗
PubMed1998

Autoimmunity in paraneoplastic neurological disorders.

Antibodies to neuronal antigens are found in a range of different neurological disorders, both central and peripheral, and often indicate the presence of particular underlying tumours. This conference and workshop was an opportunity to discuss the clinical associations of these antibodies, the relevance of new antibody specificities, and to establish protocols for their detection.

Antibodies↗
PubMed1998

XCoe2, a transcription factor of the Col/Olf-1/EBF family involved in the specification of primary neurons in Xenopus.

BACKGROUND: Primary neurogenesis in Xenopus is a model for studying the control of neural cell fate decisions. The specification of primary neurons appears to be driven by transcription factors containing a basic region and a helix-loop-helix (HLH) motif: expression of Xenopus neurogenin-related-1 (X-ngnr-1) defines the three prospective domains of primary neurogenesis, and expression of XNeuroD coincides with neuronal differentiation. The transition between neuronal competence and stable commitment to a neuronal fate remains poorly characterised, however. RESULTS: Drosophila Collier and rodent early B-cell factor/olfactory-1 define a family of HLH transcription factors containing a previously unknown type of DNA-binding domain. We isolated an orthologous gene from Xenopus, Xcoe2, which is expressed in precursors of primary neurons. Xcoe2 is transcribed after X-ngnr-1 and before XNeuroD. Overexpression of a dominant-negative mutant of XCoe2 prevented neuronal differentiation. Conversely, overexpressed wild-type Xcoe2 could promote ectopic differentiation of neurons, in both the neural plate and the epidermis. In contrast to studies with X-ngnr-1 or XNeuroD, the supernumerary neurons induced by Xcoe2 appeared in a 'salt-and-pepper' pattern, resulting from the activation of X-Delta1 expression and feedback regulation by lateral inhibition. CONCLUSIONS: XCoe2 may play a pivotal role in the transcriptional cascade that specifies primary neurons in Xenopus embryos: by maintaining Delta-Notch signalling, XCoe2 stabilises the higher neural potential of selected progenitor cells that express X-ngnr-1, ensuring the transition between neural competence and irreversible commitment to a neural fate; and it promotes neuronal differentiation by activating XNeuroD expression, directly or indirectly.

Amino Acid Sequence↗
PubMed1998

Acquired neuromyotonia in a patient with spinal epidural abscess.

We report a case of acquired neuromyotonia in a patient with Staphylococcus aureus septicemia and a spinal epidural abscess. Autoantibodies to voltage-gated potassium channels, which are associated with acquired neuromyotonia, were present during the patient's acute illness but became undetectable on clinical recovery. The spinal epidural abscess may have triggered the production of these specific autoantibodies, resulting in clinically and electromyographically detectable neuromyotonia.

Abscess↗
PubMed1998

IL-12 is involved in the induction of experimental autoimmune myasthenia gravis, an antibody-mediated disease.

IL-12 has been shown to be involved in the pathogenesis of Th1-mediated autoimmune diseases, but its role in antibody-mediated autoimmune pathologies is still unclear. We investigated the effects of exogenous and endogenous IL-12 in experimental autoimmune myasthenia gravis (EAMG). EAMG is an animal model for myasthenia gravis, a T cell-dependent, autoantibody-mediated disorder of neuromuscular transmission caused by antibodies to the muscle nicotinic acetylcholine receptor (AChR). Administration of IL-12 with Torpedo AChR (ToAChR) to C57BL/6 (B6) mice resulted in increased ToAChR-specific IFN-gamma production and increased anti-ToAChR IgG2a serum antibodies compared with B6 mice primed with ToAChR alone. These changes were associated with earlier and greater neurophysiological evidence of EAMG in the IL-12-treated mice, and reduced numbers of AChR. By contrast, when IL-12-deficient mice were immunized with ToAChR, ToAChR-specific Th1 cells and anti-ToAChR IgG2a serum antibodies were reduced compared to ToAChR-primed normal B6 mice, and the IL-12-deficient mice showed almost no neurophysiological evidence of EAMG and less reduction in AChR. These results indicate an important role of IL-12 in the induction of an antibody-mediated autoimmune disease, suggest that Th1-dependent complement-fixing IgG2a anti-AChR antibodies are involved in the pathogenesis of EAMG, and help to account for the lack of correlation between anti-AChR levels and clinical disease seen in many earlier studies.

Animals↗
PubMed1998

Acquired slow-channel syndrome: a form of myasthenia gravis with prolonged open time of the acetylcholine receptor channel.

A 32-year-old female presented with a 2-year history of fluctuating generalized weakness including extraocular, bulbar, and limb muscles, suggesting myasthenia gravis, but with poor response to pyridostigmine and unusual electromyographic findings. After rest, power increased on repeated maximal contractions, followed by progressive weakness. There were decremental responses at low-frequency stimulation, but incremental responses at high frequencies, and single stimuli evoked repetitive compound muscle action potentials. Plasmapheresis was ineffective. In a conventional assay, antibodies against acetylcholine receptors (AChRs) were borderline. However, in an assay using cells expressing mainly adult-type human AChRs, the patient's serum was positive. Thymectomy revealed a hyperplastic thymus. An intercostal muscle specimen revealed small miniature end-plate potentials, 0.22+/-0.02 mV instead of 0.56+/-0.05 mV in controls. The number of 125I-alpha-bungarotoxin binding sites was normal. The decay time constant of end-plate potentials was increased from 5.3+/-0.6 msec in controls to 23+/-3.6 msec in the patient. Ultrastructurally, there was no destruction of the end plate. Transfer of the patient's plasma to mice in vivo produced similar physiological changes in their diaphragms. We conclude that the patient has an immune-mediated disorder, in which an antibody specific to the adult form of the AChRs alters the channel properties, reducing total current and slowing the closure. We propose the name "acquired slow-channel syndrome" for this variant of myasthenia gravis.

Adult↗
PubMed1998

Conservation of read-through transcription of the Drosophila serendipity genes during evolution is gratuitous.

The Drosophila melanogaster serendipity (sry) genes sry alpha and sry beta, which code for unrelated proteins and functions, are transcribed both as monocistronic (sry alpha, srv beta) and dicistronic (sry beta-sry alpha) polyadenylated transcripts, the three types of transcripts being differentially expressed throughout development. We show here that, while the sry gene cluster is conserved in two other distantly related Drosophila species, sry beta-sry alpha dicistronic transcription is observed in one of them, Drosophila pseudoobscura but not in the other, Drosophila virilis, indicating that this mode of transcription is not subject to selection during evolution. Sequence comparison of the intergenic sry beta-sry alpha region suggests that sry, beta-sry alpha read-through transcription results from interference between initiation of transcription at the sry alpha promoter and 3' processing of the upstream sry beta transcript. From these and previous analyses, we propose that read-through transcription at the sry locus reflects its clustered gene organisation but is functionally gratuitous. This conclusion is supported by the autonomous rate of evolutionary sequence divergence shown by each individual sry gene.

Animals↗
PubMed1998

Molecular cloning of Zcoe2, the zebrafish homolog of Xenopus Xcoe2 and mouse EBF-2, and its expression during primary neurogenesis.

Xcoe2 is a recently identified HLH transcription factor of the Xenopus primary neurogenesis pathway, which is necessary downstream of Neurogenin to stabilize neuroblast determination (Dubois, L. et al., 1998. Curr. Biol. 8, 199-209). We report here the embryonic expression pattern of Zcoe2, its zebrafish homolog. As observed for Xcoe2, Zcoe2 is strongly expressed in a subset of the neurogenin1- (ngn1-) positive primary neuroblasts of the spinal cord. In the anterior neural plate, in contrast, Zcoe2 is expressed earlier and more widely than ngn1. This pattern is strongly maintained in the presumptive mesencephalon and rhombomeres 1-4 until the 2-3-somite stage. This expression of Zcoe2 in the brain anlage calls for a re-analysis in zebrafish of the functional relationship demonstrated in Xenopus between Coe2 and Neurogenin factors. At later stages, Zcoe2 is expressed in early forming neurons of the anterior brain and is a marker of the olfactory placodes.

Animals↗