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A Vincent

Publications and source records attributed to A Vincent.

At least 73 records · Page 4Linked to original sources
PubMed2001

Presynaptic neuronal antigens expressed by a small cell lung carcinoma cell line.

Small cell lung carcinoma (SCLC) is a tumour of neuroendocrine origin often found in association with autoimmune paraneoplastic neurological disorders. We established a SCLC cell line from a woman with Lambert-Eaton myasthenic syndrome (LEMS) who developed antibodies to both the P/Q-type voltage-gated calcium channels (VGCC) and the muscle acetycholine receptor (AChR). We used a range of techniques to establish which neuronal antigens were expressed in her tumour cell line. The results show that many proteins involved in exocytosis are present in the SCLC cells, and that depolarisation-dependent release of [(3)H]-serotonin is linked to calcium influx through P/Q-type VGCCs. In addition, some of the subunits encoding the AChR and both agrin and ARIA, molecules released from the motor nerve during development, were expressed. These results suggest that many potential antigenic targets are present in SCLC, and indicate a surprising 'motor nerve terminal'-like characteristic of this line.

Autoantibodies↗
PubMed2001

Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients.

BACKGROUND: Antibodies to glutamic acid decarboxylase (GAD-Ab) are described in patients with insulin-dependent (type 1) diabetes mellitus (IDDM), in stiff-man syndrome, and, recently, in a few patients with cerebellar ataxia. OBJECTIVES: To show a link between GAD-Ab and some patients with cerebellar ataxia and to clarify their clinical and immunologic profiles. METHODS: Serum samples were selected from 9000 samples of 4 laboratories. The selection criterion was an immunohistochemical pattern compatible with GAD-Ab that was confirmed by radioimmunoassay. We identified 22 patients with stiff-man syndrome and 14 with cerebellar ataxia and GAD-Ab. RESULTS: Thirteen of the 14 patients with cerebellar ataxia and GAD-Ab were women, and 11 had late-onset IDDM. Patients did not have clinical or radiologic evidence of brainstem involvement. Ten patients had oligoclonal IgG bands in the cerebrospinal fluid, and intrathecal GAD-Ab synthesis was observed in 5 of the 6 patients studied. The level of GAD-Ab of these patients was similar to those with stiff-man syndrome and significantly higher than those with IDDM or with polyendocrine autoimmunity (P<.001). However, the GAD-Ab levels of 6 of the 9 patients with polyendocrine autoimmunity overlapped with those of patients with cerebellar ataxia. CONCLUSIONS: These results suggest a link between high level of GAD-Ab and some cases of cerebellar ataxia, particularly women with IDDM. If high serum levels of GAD-Ab are detected, the cerebrospinal fluid should be evaluated for the presence of oligoclonal IgG bands and intrathecal synthesis of GAD-Ab to further prove an autoimmune origin of the syndrome.

Adult↗
PubMed2001

Anti-Yo antibodies and cerebellar degeneration in a man with adenocarcinoma of the esophagus.

Serum antibodies to the Yo antigen are usually associated with paraneoplastic cerebellar degeneration arising in female patients with gynecological or breast malignancy and are rarely associated with other tumors. We report a male patient who presented with paraneoplastic cerebellar degeneration and anti-Yo antibodies following removal of an esophageal adenocarcinoma. This is only the third report of anti-Yo antibodies occurring in a male patient. The Yo antigen was expressed by the esophageal tumor but not in a frontal lobe cerebral metastasis identified at postmortem. Interestingly, CD8+ T-cell infiltration was also found in the tumor, but not in the metastasis, consistent with down-regulation of Yo expression by the tumor cells leading to evasion from immune-mediated tumor surveillance.

Adenocarcinoma↗
PubMed2001

Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis.

Antibodies to muscle acetylcholine receptors, to other muscle antigens, and to some cytokines are found in the majority of patients with thymic tumors (thymomas) and myasthenia gravis (MG). The role of the tumor in initiating autoimmunity, however, is unclear; in particular, it is not known whether the thymoma exports mature and long-lived T cells, which could provide help for antibody production in the periphery. Here, we quantified recently exported thymic T cells using the approach of measuring episomal DNA fragments [T-cell receptor excision circles (TRECs)], generated by T-cell receptor gene rearrangement. Compared to values in healthy individuals (n = 10) or in patients with late-onset MG (n = 8), TREC levels were significantly raised in both the CD4+ and CD8+ peripheral blood compartments of patients with thymoma and MG (n = 14, p = 0.002 and p = 0.0004 compared to healthy controls) but only in the CD8+ compartment of the three patients with thymoma without MG (p = 0.4 and p = 0.01 for CD4+ and CD8+). TREC levels decreased following thymectomy to values similar to controls but were substantially raised in patients who had developed tumor recurrence (n = 6, p = 0.04 and p = 0.02 for CD4+ and CD8+); this was associated with increased antibodies to interferon-alpha and interleukin-12 in the one case studied serially. Collectively, these results support the hypothesis that the neoplastic thymoma tissue itself can generate and export mature, long-lived T cells and that these T cells reflect the thymic pathology and are likely to be related to the associated autoimmune diseases. The results also provide a new approach for early diagnosis of thymoma recurrence.

Adult↗
PubMed2001

Potassium channel antibodies in two patients with reversible limbic encephalitis.

Limbic encephalitis (LE) is often associated with lung, thymic, or testicular tumours and antibodies to Hu, CV2, or Ma2 (Ta) antigens. In these cases, it generally has a poor prognosis. Here we describe two patients with symptoms of LE, negative for typical paraneoplastic antibodies, in whom antibodies to voltage-gated potassium channels (VGKC) were detected retrospectively in serial serum samples. Patient 1 had a thymoma recurrence, but in patient 2 no tumour has been detected in the years following presentation. Plasma exchange was effective in reducing VGKC antibody levels, with substantial improvement in mental symptoms in patient 1. In patient 2, the VGKC antibodies fell spontaneously over two years, with almost complete recovery of mental function. Although neither patient had obvious neuromyotonia at presentation, both showed excessive secretions. We suggest that patients with limbic symptoms and excessive secretions should be tested for VGKC antibodies, and, if they are present, prompt and effective immunosuppressive treatment should be considered.

Aged↗
PubMed2001

The COE--Collier/Olf1/EBF--transcription factors: structural conservation and diversity of developmental functions.

One major conclusion of studies in Developmental Biology during the last two decades is that, despite profound anatomical differences, the building of vertebrate and arthropod bodies relies on the same fundamental molecular networks, including conserved cell signalling and transcription-regulatory cascades. Rodent Early B-Cell Factor/Olfactory-1 and Drosophila Collier belong to a recently defined, novel family of transcription factors, the Collier/Olf1/EBF (COE) proteins which have a unique DNA-binding domain. Early investigations revealed that, despite their high degree of sequence identity, the different vertebrate and invertebrate COE proteins play a variety of developmental roles. We review here the current evidence for this diversity of COE functions, including in the specification and differentiation of various neuronal populations. We also discuss the existence of an evolutionarily conserved pathway linking Notch signalling and COE regulatory functions in various developmental decisions.

Amino Acid Sequence↗
PubMed2001

Stiff-person syndrome: autoimmunity and the central nervous system.

Stiff-person syndrome (SPS) is a rare disease of severe progressive muscle stiffness in the spine and lower extremities with superimposed muscle spasms triggered by external stimuli. Patients with SPS are often referred for psychiatric evaluation and the psychiatrist may be the first to diagnosis SPS. Psychosocial stressors often precede the first manifestations of the disease; depression, anxiety, and alcohol abuse are comorbid illnesses. The identification of an association with antibodies to glutamic acid decarboxylase (GAD) was invaluable for definitively establishing a pathological basis for the disease; antibodies to amphiphysin and gephyrin are also found in cases of SPS but at much lower frequencies. Whether the antibodies inhibit GAD activity in vivo, target GAD-expressing neurons for immune-mediated destruction, are part of a wider immune process, or are merely a marker for destruction of GAD-expressing neurons by an independent neurodegenerative process is not yet clear. Both electromyography and the detection of GAD antibodies are useful in establishing a diagnosis of SPS. Treatment of SPS includes the use of immunomodulating therapies (plasmapheresis and intravenous immunoglobulins) and symptomatic treatment with benzodiazepines and baclofen. The use of tricyclic antidepressants and rapid withdrawal from therapy should be avoided.

Journal Article↗
PubMed2001

Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies.

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction. In approximately 80% of patients, auto-antibodies to the muscle nicotinic acetylcholine receptor (AChR) are present. These antibodies cause loss of AChR numbers and function, and lead to failure of neuromuscular transmission with muscle weakness. The pathogenic mechanisms acting in the 20% of patients with generalized MG who are seronegative for AChR-antibodies (AChR-Ab) have not been elucidated, but there is evidence that they also have an antibody-mediated disorder, with the antibodies directed towards another, previously unidentified muscle-surface-membrane target. Here we show that 70% of AChR-Ab-seronegative MG patients, but not AChR-Ab-seropositive MG patients, have serum auto-antibodies against the muscle-specific receptor tyrosine kinase, MuSK. MuSK mediates the agrin-induced clustering of AChRs during synapse formation, and is also expressed at the mature neuromuscular junction. The MuSK antibodies were specific for the extracellular domains of MuSK expressed in transfected COS7 cells and strongly inhibited MuSK function in cultured myotubes. Our results indicate the involvement of MuSK antibodies in the pathogenesis of AChR-Ab-seronegative MG, thus defining two immunologically distinct forms of the disease. Measurement of MuSK antibodies will substantially aid diagnosis and clinical management.

Autoantibodies↗
PubMed2001

Effect of the atrial blanking time on the detection of atrial fibrillation in dual chamber pacing.

Patients with paroxysmal atrial fibrillation (PAF) and dual chamber pacemakers frequently have short postventricular atrial blanking times and sensitive atrial sensing thresholds used to provide reliable detection and mode switching during AF. However, short atrial blanking times increase the risk of atrial sensing of ventricular far-field signals. We evaluated if the length of the atrial blanking time influences the detection of AF. The study included ten patients with a VDDR (n = 7) or DDDR system (n = 3), who presented with AF at 18 follow-up visits. Bipolar atrial sensing was programmed to the most sensitive value. Atrial blanking times were programmed from 100 to 200 ms in 25-ms steps in each patient. Using marker annotation, the following parameters were measured at ten consecutive ventricular beats: VAF = the interval between ventricular stimulus and first sensing of AF; AFS = the number of atrial-sensed events between two ventricular events; and XAF = the interpolated number of atrial-sensed events during atrial blanking time. The intervals between ventricular events and between atrial-sensed event markers showed no significant differences for the five blanking times tested. There was no significant influence of the atrial blanking time onto the measured parameters (least square means +/- standard error) with VAF between 281 +/- 12 and 300 +/- 12 ms (P = NS), AFs between 3.4 +/- 0.2 and 3.6 +/- 0.2 beats (P = NS) and XAF between 1.84 +/- 0.12 and 2.03 +/- 0.12 beats (P = NS). At ventricular rates < 100/min, the atrial sensing of AF in dual chamber pacemakers demonstrated no evidence for deterioration by an increase of the atrial blanking time from 100 to 200 ms. Thus, the risk of ventricular far-field sensing may be reduced without compromising atrial sensing.

Aged↗
PubMed2001

Morvan's syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels.

Morvan's 'fibrillary chorea' or Morvan's syndrome is characterized by neuromyotonia (NMT), pain, hyperhydrosis, weight loss, severe insomnia and hallucinations. We describe a man aged 76 years with NMT, dysautonomia, cardiac arrhythmia, lack of slow-wave sleep and abnormal rapid eye movement sleep. He had raised serum antibodies to voltage-gated K(+) channels (VGKC), oligoclonal bands in his CSF, markedly increased serum norepinephrine, increased serum cortisol and reduced levels and absent circadian rhythms of prolactin and melatonin. The neurohormonal findings and many of the clinical features were very similar to those in fatal familial insomnia, a hereditary prion disease that is associated with thalamic degenerative changes. Strikingly, however, all symptoms in our MFC patient improved with plasma exchange. The patient died unexpectedly 11 months later. At autopsy, there was a pulmonary adenocarcinoma, but brain pathology showed only a microinfarct in the hippocampus and no thalamic changes. The NMT and some of the autonomic features are likely to be directly related to the VGKC antibodies acting in the periphery. The central symptoms might also be due to the direct effects of VGKC antibodies, or perhaps of other autoantibodies still to be defined, on the limbic system with secondary effects on neurohormone levels. Alternatively, changes in secretion of neurohormones in the periphery might contribute to the central disturbance. The relationship between VGKC antibodies, neurohormonal levels, autonomic, limbic and sleep disorders requires further study.

Aged↗
PubMed2001

End-plate gamma- and epsilon-subunit mRNA levels in AChR deficiency syndrome due to epsilon-subunit null mutations.

Acetylcholine receptor (AChR) deficiency is the most common of the congenital myasthenic syndromes (CMS). Typically, the number of AChRs, measured by alpha-bungarotoxin binding, is reduced to 10-30% of normal levels, the miniature end-plate potentials are correspondingly reduced, and there are morphological changes at the motor end-plates. The majority of these syndromes are due to either missense or frameshift mutations within the gene encoding the adult-specific epsilon-subunit. These are often null mutations, but some mutant epsilon-subunits can be incorporated, at low levels, into functional AChRs in transfected cell lines. It is not clear, therefore, whether upregulation of the mutant epsilon-subunit mRNA could generate sufficient AChR to support neuromuscular transmission, albeit at a reduced level. Conversely, it might be that the mutant epsilon-subunit transcripts are subject to mRNA surveillance and 'nonsense-mediated' loss, leading to reduced epsilon-subunit mRNA expression. In either case, it is thought that neuromuscular transmission may be provided partly or entirely by incorporation of the foetal-specific gamma-subunit into end-plate AChR. gamma-Subunit mRNA is expressed at low levels in normal human muscle, but might be upregulated in CMS. The study of mRNA levels for AChR subunits should improve our understanding of genotype-phenotype relationships in CMS. Here we have defined homozygous epsilon-subunit mutations in four unrelated families with AChR deficiency and studied the steady-state levels of mRNA for AChR subunits at the motor end-plates by in situ hybridization. Although we demonstrated that each mutation would lead to almost complete absence of surface adult AChR expression, we detected similar robust expression of alpha- and epsilon-subunit mRNAs at end-plates of patient and control muscles, suggesting that mRNA transcripts for the epsilon-subunit are neither upregulated nor degraded preferentially. Interestingly, we were unable to detect any increase in gamma-subunit mRNA expression at CMS end-plates. Transgenic mice lacking the epsilon-subunit die 2-3 months after birth, suggesting that alpha(2)betadelta(2) pentamers cannot sustain neuromuscular transmission. Therefore, we tentatively conclude that the persistent low level expression of the gamma-subunit, which is present in normal human muscles as well as in AChR deficiency syndromes, is sufficient to enable patients with epsilon-subunit null alleles to survive.

Adult↗
PubMed2001

Myasthenia gravis: diagnostic and management dilemmas.

This review focuses on the diagnostic tests that may help to confirm myasthenia in patients without acetylcholine receptor antibodies, including the newly discovered anti-muscle-specific receptor tyrosine kinase antibody and other investigations. We discuss management dilemmas, particularly those that revolve around treatments whose efficacy is questionable or unproved, such as thymectomy. We review the important issue of how treatments are assessed, and examine future treatment trial designs.

Humans↗
PubMed2001

Effects of exposure to high temperature and feeding level on regional blood flow and oxidative capacity of tissues in piglets.

To determine to what extent exposure to high ambient temperature and feeding level affect tissue energy metabolism in piglets, regional blood flow and oxidative capacity of tissues were evaluated in sixteen 21.8 +/- 2.8 kg pigs. At 5 weeks of age, littermates were divided into three groups and acclimated to the treatment for 25 days. One group was reared at 33 degrees C and fed ad libitum (33AL, n = 6) while the other two groups were maintained at 23 degrees C and either pair-fed on the basis of the food consumption of their 33AL littermates (23PF, n = 5), or fed ad libitum (23AL, n = 5). Regional blood flow was determined in conscious pigs by injection of coloured microspheres, which were recovered in different tissues after slaughter. Activities of cytochrome oxidase and cytochrome aa(3) content were measured in tissue homogenates of heart, longissimus dorsi and rhomboideus muscles, liver and small intestine. There was decreased blood flow to internal adipose tissue (42 %) and increased blood flow to peripheral tissues (skin, 44 %) and tissues implicated in respiratory evaporative heat loss (diaphragm, 45 %, lungs, 59 %) at 33 degrees C compared to 23 degrees C, which can be viewed as an effective mechanism for increasing heat loss at high temperature. In addition, the concomitant decrease in blood flow (49 %) and slight reduction of oxidative capacities in both muscles at 33 degrees C might contribute to the reduction in thermogenesis, but these effects were also observed when the feeding level was reduced at thermal neutrality (23PF group). In the viscera (intestine, liver), blood flow was decreased in the two groups on a restricted food intake (about 50 % of 23AL), independently of environmental temperature. The results suggest that most of the mechanisms associated with the reduction in energy expenditure during warm acclimation are related to the adaptive reduction in food intake. Experimental Physiology (2001) 86.1, 83-91.

Acclimatization↗
PubMed2001

Acetylcholine receptor delta subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita.

Limitation of movement during fetal development may lead to multiple joint contractures in the neonate, termed arthrogryposis multiplex congenita. Neuromuscular disorders are among the many different causes of reduced fetal movement. Many congenital myasthenic syndromes (CMSs) are due to mutations of the adult-specific epsilon subunit of the acetylcholine receptor (AChR), and, thus, functional deficits do not arise until late in gestation. However, an earlier effect on the fetus might be predicted with some defects of other AChR subunits. We studied a child who presented at birth with joint contractures and was subsequently found to have a CMS. Mutational screening revealed heteroallelic mutation within the AChR delta subunit gene, delta 756ins2 and delta E59K. Expression studies demonstrate that delta 756ins2 is a null mutation. By contrast, both fetal and adult AChR containing delta E59K have shorter than normal channel activations that predict fast decay of endplate currents. Thus, delta E59K causes dysfunction of fetal as well as the adult AChR and would explain the presence of joint contractures on the basis of reduced fetal movement. This is the first report of the association of AChR gene mutations with arthrogryposis multiplex congenita. It is probable that mutations that severely disrupt function of fetal AChR will underlie additional cases.

Action Potentials↗
PubMed2001

Gender differences in the effect of genistein on vascular smooth muscle cells: a possible cardioprotective effect?

OBJECTIVE: Isoflavones are a class of phytoestrogens found abundantly in soybeans. They share structural similarity to 17-beta-estradiol, bind to the estrogen receptors alpha and beta, and produce estrogenic or antiestrogenic effects. Atherosclerosis is an inflammatory-mediated fibroproliferative response to injury to the arterial wall. Vascular smooth muscle cells (VSMCs) are the prominent cells in the atherosclerotic plaque. VSMCs contain estrogen receptors and, at physiologic concentrations, 17-beta-estradiol-inhibited proliferation of VSMCs from sexually mature female pigs. We determined if genistein inhibited proliferation and altered matrix protein production in VSMCs from coronary arteries of sexually mature pigs. METHODS: The effect of genistein on cell proliferation was assessed by thymidine incorporation. The effect of genistein on matrix protein production in VSMCs was assessed by Western blot analysis. RESULTS AND CONCLUSION: We demonstrate gender-specific effects in the proliferation of coronary artery vascular smooth muscle cells obtained from a sexually mature pig model treated with genistein at physiologically relevant concentrations. There were no differences in the amount of estrogen receptor proteins between the genders, suggesting that nongenomic mechanisms may be responsible for these effects. Genistein also upregulated matrix protein expression, which may be related to the formation of the atherosclerotic plaque. Overall, these results suggest possible cardioprotection by genistein.

Analysis of Variance↗
PubMed2000

Differential expression and subcellular localization of murine BRCA1 and BRCA1-delta 11 isoforms in murine and human cell lines.

BRCA1 mutations are involved in breast and ovarian cancer predisposition in humans. The biological functions of the murine BRCA1 gene have been extensively studied but little is known about murine BRCA1 proteins. To better characterize these proteins, we have cloned the full-length murine BRCA1 cDNA and a splice variant deleted of exon 11, BRCA1-delta 11, by RT-PCR method. Three polyclonal antibodies raised against various parts of murine BRCA1 were used in our study: D16, M20 and 5MO, which were generated in our laboratory. This allowed us to analyze the expression and subcellular localization of both isoforms in murine and human cell lines by immunoblotting, immunoprecipitation, cell fractionation and immunofluorescence. Endogenous BRCA1 was detected in murine cell lines but not splice variant BRCA1-delta 11, whereas both ectopically expressed murine isoforms were detected in transfected human Bosc 23 cells. Subcellular fractionation and immunofluorescence results showed that the BRCA1 protein was mainly located in the nucleus, whereas BRCA1-delta 11 was preferentially cytoplasmic. The conservation of exon 11 splicing and the differential subcellular localization of BRCA1 and BRCA1-delta 11 in human and mouse suggest that these proteins could play distinct roles and that they could differentially act in the pathological mechanisms leading to the development of breast and ovarian cancer. The characterization of the murine BRCA1 proteins and antibodies will be useful to further study BRCA1 functions in murine models.

3T3 Cells↗
PubMed2000

Differentiation of electrical excitability in motoneurons.

Investigation of the differentiation of electrical properties of motoneurons has been stimulated by the importance of these neurons for embryonic behavior and facilitated by their experimental accessibility. In this review, we examine the development of different patterns of excitability and their functions, and discuss the emergence of repetitive firing and localization of ion channels in axons and dendrites. Finally, we summarize studies of the role of extrinsic factors in differentiation. These changes associated with differentiation of young motoneurons may presage those occurring later in the context of plasticity in the mature nervous system.

Action Potentials↗