RESUMEN
In this paper, using polymerase chain reaction (PCR), we demonstrated the occurrence of hybrid genes formed by interlocus recombination between T cell receptor gamma (TCR-gamma) variable (V) regions and TCR-beta joining (J) regions in the peripheral blood lymphocytes (PBL) from normal individuals and patients with ataxia-telangiectasia (AT). Sequence analysis of the PCR-derived hybrid genes confirmed that site-specific V gamma-J beta recombination had occurred and showed that 10 of 23 genomic hybrid genes maintained a correct open reading frame. By dilution analysis, the frequency of these hybrid genes was 8 +/- 1/10(5) cells in normal PBL and 587 +/- 195/10(5) cells in AT PBL. These frequencies and the approximately 70-fold difference between the normal and AT samples are consistent with previous cytogenetic data examining the occurrence of an inversion of chromosome 7 in normal and AT PBL. We also demonstrated expression of these hybrid genes by PCR analysis of first-strand cDNA prepared from both normal and AT PBL. Sequence analysis of the PCR-amplified transcripts showed that, in contrast to the genomic hybrid genes, 19 of 22 expressed genes maintained a correct open reading frame at the V-J junction and correctly spliced the hybrid V-J exon to a TCR-beta constant region, thus allowing translation into a potentially functional hybrid TCR protein. Another type of hybrid TCR transcript was found in a which a rearranged TCR-gamma V-J exon was correctly spliced to a TCR-beta constant region. This form of hybrid gene may be formed by trans-splicing. These hybrid TCR genes may serve to increase the repertoire of the immune response. In addition, studies of their mechanism of formation and its misregulation in AT may provide insight into the nature of the chromosomal instability syndrome associated with AT. The mechanism underlying hybrid gene formation may be analogous to the mechanism underlying rearrangements between putative growth-affecting genes and the antigen receptor loci, which are associated with AT lymphocyte clones and lymphoid malignancies.
Asunto(s)
Ataxia Telangiectasia/genética , Cromosomas Humanos Par 7 , Genes , Linfocitos/inmunología , Receptores de Antígenos de Linfocitos T/genética , Recombinación Genética , Ataxia Telangiectasia/inmunología , Secuencia de Bases , Southern Blotting , Clonación Molecular , ADN/genética , ADN/aislamiento & purificación , Humanos , Datos de Secuencia Molecular , Hibridación de Ácido Nucleico , Sondas de Oligonucleótidos , Reacción en Cadena de la Polimerasa/métodos , ARN/genética , Valores de ReferenciaRESUMEN
Studies performed during these last 30 years have had a major impact on the understanding of carcinogenesis. They have opened a new field: cancer genetic predisposition. At the present time, most of the cancer predispositions linked to the alteration of one gene, associated with a high risk of cancer and with a specific phenotype have been identified. About 70 genes have been identified and have led to genetic testing. The indication of genetic testing, the management of at risk patients require the establishment of guidelines. The next challenge is the identification of cancer susceptibility genes associated with low risk or modifying the effect of treatment.
Asunto(s)
Neoplasias/genética , Transformación Celular Neoplásica/genética , Predicción , Genes Relacionados con las Neoplasias , Genes Supresores de Tumor , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Mutación , Síndromes Neoplásicos Hereditarios/genética , Oncogenes , RiesgoRESUMEN
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.
Asunto(s)
Antineoplásicos/farmacología , Biomarcadores de Tumor , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Ensayos Analíticos de Alto Rendimiento , Leucemia Prolinfocítica de Células T/genética , Mutación , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Ciclo Celular/genética , Línea Celular Tumoral , Aberraciones Cromosómicas , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Quinasas Janus/metabolismo , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Leucemia Prolinfocítica de Células T/metabolismo , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Oxazoles/farmacología , Fenotipo , Inhibidores de Proteínas Quinasas/farmacología , Factores de Transcripción STAT/metabolismo , Tiazoles/farmacologíaRESUMEN
T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Daño del ADN , Epigénesis Genética , Leucemia Prolinfocítica de Células T/genética , Proteínas Proto-Oncogénicas/genética , Adulto , Anciano , Animales , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica/métodos , Células HEK293 , Humanos , Estimación de Kaplan-Meier , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Leucemia Prolinfocítica de Células T/metabolismo , Masculino , Ratones Transgénicos , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
BACKGROUND: Chromosome rearrangements are frequently involved in the generation of hematopoietic tumors. One type of T-cell leukemia, T-cell prolymphocytic leukemia, is consistently associated with chromosome rearrangements characterized by the juxtaposition of the TCRA locus on chromosome 14q11 and either the TCL1 gene on 14q32.1 or the MTCP1 gene on Xq28. The TCL1 gene is preferentially expressed in cells of early lymphoid lineage; its product is a 14 kDa protein (p14TCL1), expressed in the cytoplasm. p14TCL1 has strong sequence similarity with one product of the MTCP1 gene, p13MTCP1 (41% identical and 61% similar). The functions of the TCL1 and MTCP1 genes are not known yet. They have no sequence similarity to any other published sequence, including those of well-documented oncogene families responsible for leukemia. In order to gain a more fundamental insight into the role of this particular class of oncogenes, we have determined the three-dimensional structure of p14TCL1. RESULTS: The crystal structure of p14TCL1 has been determined at 2.5 A resolution. The structure was solved by molecular replacement using the solution structure of p13MTCP1, revealing p14TCL1 to be an all-beta protein consisting of an eight-stranded antiparallel beta barrel with a novel topology. The barrel consists of two four-stranded beta-meander motifs, related by a twofold axis and connected by a long loop. This internal pseudo-twofold symmetry was not expected on basis of the sequence alone, but structure-based sequence analysis of the two motifs shows that they are related. The structures of p13MTCP1 and p14TCL1 are very similar, diverging only in regions that are either flexible and/or involved in crystal packing. p14TCL1 forms a tight crystallographic dimer, probably corresponding to the 28 kDa species identified in solution by gel filtration experiments. CONCLUSIONS: Structural similarities between p14TCL1 and p13MTCP1 suggest that their (unknown) function may be analogous. This is confirmed by the fact that these proteins are implicated in analogous diseases. Their structure does not show similarity to other oncoproteins of known structure, confirming their classification as a novel class of oncoproteins.
Asunto(s)
Proteínas de Unión al ADN/química , Estructura Secundaria de Proteína , Proteínas Proto-Oncogénicas/química , Factores de Transcripción/química , Secuencia de Aminoácidos , Cristalografía por Rayos X , Dimerización , Humanos , Leucemia Prolinfocítica , Leucemia de Células T , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas Recombinantes de FusiónRESUMEN
BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.
Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad/genética , Mutación , Neoplasias Ováricas/genética , Femenino , Humanos , Persona de Mediana EdadRESUMEN
The t(X;14)(q28;q11.2) translocation is associated with mature T-cell proliferations. Recently this translocation has been shown to implicate the MTCP-1/c6.1B gene on chromosome Xq28, leading to aberrant or overexpressed MTCP-1 transcripts. The potential coding role of this gene was made uncertain by the lack of a long open reading frame in its major transcripts. However, a short 204 bases open reading frame is potentially coding for a 68 amino-acid protein. Here, we show that this open reading frame sequence and the deduced product are well conserved in mouse. A 8 kD protein (p8), which corresponds to the predicted molecular weight was revealed in transient transfectants and in cell lines by Western blotting, using a rabbit antiserum. This product was absent in lymphoblastoid cell lines with deletions of the MTCP-1/c6.1B locus. A dramatic overexpression of p8 was found in leukemic cells from a patient with a t(X;14). This small protein was localized in the cytoplasm by immunofluorescence. In conclusion, MTCP-1 encodes for a cytoplasmic 8 kD product. Its potential role in leukemogenesis is supported by its overexpression in leukemia with t(X;14), but its function remains unknown.
Asunto(s)
Cromosomas Humanos Par 14 , Leucemia de Células T/genética , Proteínas de Neoplasias/genética , Translocación Genética , Cromosoma X , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Citoplasma/metabolismo , ADN Complementario , Humanos , Sueros Inmunes , Leucemia de Células T/metabolismo , Ratones , Datos de Secuencia Molecular , Oncogenes , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/inmunología , Células Tumorales CultivadasRESUMEN
T-cell lymphoproliferative diseases are often associated with recurrent chromosomal translocations involving T cell receptor genes (TCR) and genes that are thought to play a role in the pathogenesis of these diseases. Whereas numerous such genes have already been identified in acute T cell leukemias, no candidate gene has yet been identified to play a role in the heterogeneous group of T cell proliferations with a mature phenotype. We here report the molecular cloning of two examples of the rare but recurrent t(X;14) translocation. The first translocation was associated with a benign clonal proliferation in an ataxia telangiectasia patient and the second with a T cell prolymphocytic leukemia. Both translocations implicated the TCR alpha/delta locus and a common breakpoint region on chromosome Xq28. A previously unidentified gene, abnormally transcribed in both T cell proliferations, was characterized in the immediate proximity of the breakpoints. This Xq28 gene has no homology with known sequences, uses a complex alternative splicing pattern and demonstrates two short open reading frames. This gene, named MTCP-1 (Mature T Cell Proliferation-1) is the first candidate gene potentially involved in the leukemogenic process of mature T cell proliferations.
Asunto(s)
Trastornos Linfoproliferativos/genética , Proteínas Proto-Oncogénicas/genética , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Translocación Genética , Cromosoma X , Empalme Alternativo , Secuencia de Aminoácidos , Ataxia Telangiectasia/genética , Secuencia de Bases , Cromosomas Humanos Par 14 , Expresión Génica , Genes , Humanos , Leucemia Prolinfocítica/genética , Datos de Secuencia Molecular , ARN Mensajero/genética , Mapeo Restrictivo , Linfocitos T/citologíaRESUMEN
The MTCP1 gene is involved in the t(X;14)(q28;q11) translocation associated with T-cell prolymphocytic leukemia and related conditions. This gene is unusual in that it codes for two distinct proteins: a small mitochondrial protein, p8MTCP1, and a putative oncogenic protein, p13MTCP1. Scarcity of material from t(X;14)-associated proliferations and very low levels of mRNA expression have so far prevented a thorough description of p13MTCP1-encoding transcripts. Here, we characterize two additional t(X;14) bearing leukemias allowing this analysis. In one case, with a breakpoint located 5' to the MTCP1 gene, the level of transcription of previously described p13MTCP1-encoding transcripts is enhanced. In the second case, with a breakpoint within the MTCP1 intron I, an alternative transcription initiation site is demonstrated in the tumor cells at 229 bp upstream to exon II. The identification of this internal promoter, together with the similarity between TCL1 and MTCP1 genomic structures, allow us to propose a model in which the duplication of an ancestral gene was followed by the insertion of one copy within the intron of a p8-encoding gene, accounting for the unusual feature of the MTCP1 gene.
Asunto(s)
Leucemia de Células T/genética , Transcripción Genética , Translocación Genética , Anciano , Secuencia de Bases , División Celular/genética , Femenino , Humanos , Leucemia Prolinfocítica/genética , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteínas Proto-Oncogénicas/genética , Linfocitos T/fisiologíaRESUMEN
An unusually small (8 kD) protein (p8MTCP-1) is coded by the putative oncogene MTCP-1 (also called c6.1B), involved in the translocation t(X;14)(q28;q11) associated with some mature T-cell proliferations. Here, we show by subcellular fractionation and by confocal microscopy that this protein is located in the mitochondria. This localization orientates toward a role of p8MTCP-1 in the mitochondrial metabolism which may be relevant for the oncogenic process.
Asunto(s)
Mitocondrias/metabolismo , Secuencia de Aminoácidos , Técnica del Anticuerpo Fluorescente , Humanos , Microscopía Confocal , Datos de Secuencia Molecular , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas/genética , Homología de Secuencia de AminoácidoRESUMEN
MTCP1 (for Mature-T-Cell Proliferation) is the first gene unequivocally identified in the group of uncommon leukemias with a mature phenotype. The three-dimensional solution structure of the human p8(MTCP1) protein encoded by the MTCP1 oncogene was determined by homonuclear proton two-dimensional NMR methods at 600 MHz. After sequence specific assignments, a total of 931 distance restraints and 57 dihedral restraints were collected. The location of the three previously unassigned disulfide bridges was determined from preliminary DIANA structures, using a statistical analysis of intercystinyl distances. The solution structure of p8(MTCP1) is presented as a set of 30 DIANA structures, further refined by restrained molecular dynamics using a simulated annealing protocol with the AMBER force field. The r.m.s.d. values with respect to the mean structure for the backbone and all heavy atoms for a family of 30 structures are 0.73(+/-0.28) and 1.17(+/-0.23) A, when the structured core of the protein (residues 5 to 63) is considered. The solution structure of p8(MTCP1) reveals an original scaffold consisting of three alpha helices, associated with a new cysteine motif. Two of the helices are covalently paired by two disulfide bridges, forming an alpha-hairpin which resembles an antiparallel coiled-coil. The third helix is oriented roughly parallel to the plane defined by the alpha-antiparallel motif and its axis forms an angle of approximately 60 degrees with respect to the main axis of this motif.
Asunto(s)
Cisteína/química , Conformación Proteica , Simulación por Computador , Cristalografía por Rayos X , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular/métodos , Oncogenes , Estructura Secundaria de Proteína , Proteínas Proto-Oncogénicas/químicaRESUMEN
Uveal melanoma is genetically one of the simplest malignant tumors in adults. Initiation of these tumors is dependent of an oncogenic mutation in the GNAQ or GNA11 genes present in almost all cases. The nature of second mutational events is of major interest as it monosomy 3, gain of 8q and BAP1 inactivation are associated with unfavorable prognosis while SF3BI or EIF1AX are of good prognosis. Despite their common lineage, cutaneous and uveal melanomas are distinct diseases, implicating different oncogenic pathways and contrasting mutational landscapes. Even if uveal melanoma is a simple tumor, it is also one of the deadliest tumors in adults. There is a major clinical need for drugs targeting either the downstream pathways of Gαq and Gα11 or the biological cell functions dysregulated by BAP1 loss of function.
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Predisposición Genética a la Enfermedad/genética , Melanoma/genética , Neoplasias de la Úvea/genética , Adulto , Transformación Celular Neoplásica/genética , Deleción Cromosómica , Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 8/genética , Análisis Mutacional de ADN , Factor 1 Eucariótico de Iniciación/genética , Subunidades alfa de la Proteína de Unión al GTP/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Melanoma/mortalidad , Melanoma/terapia , Fosfoproteínas/genética , Pronóstico , Factores de Empalme de ARN , Ribonucleoproteína Nuclear Pequeña U2/genética , Factores de Riesgo , Neoplasias Cutáneas/genética , Tasa de Supervivencia , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genética , Neoplasias de la Úvea/mortalidad , Neoplasias de la Úvea/terapiaAsunto(s)
Antineoplásicos Alquilantes/farmacología , Bencimidazoles/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Leucemia de Células T/patología , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis/efectos de los fármacos , Humanos , Leucemia de Células T/genética , Mutación , Proteína p53 Supresora de Tumor/genéticaRESUMEN
INTRODUCTION: T-cell prolymphocytic leukemia is a rare form of mature leukemia which occurs in adults and in younger patients suffering ataxia telangiectasia. Among others, complex chromosome aberrations of chromosome 12 have been described in this disease. We searched for deletions of the 12p13 region as the result of these chromosome rearrangements. MATERIAL AND METHODS: Paired leukemic and non-leukemic cells were obtained from a series of 21 patients suffering T-cell prolymphocytic leukemia. Loss of heterozygosity was searched for by microsatellite typing using a fluorescent automated laser DNA sequencer to analyze the amplification products. Proteins were analyzed by Western blot. Southern blot analysis of one patient was conducted. RESULTS AND CONCLUSION: Loss of heterozygosity of the 12p13 region, including the ETV6 and CDKN1B genes, was detected in nine of these 21 cases (43%). Western and Southern blot analyses of one case demonstrated a biallelic deletion which did not include ETV6. Taken together, our results defined a minimal region of deletion of less than one Mb flanked by the markers b312C2T7 and D12S320, excluding ETV6 as a candidate gene. Deletion of the 12p13 region is thus a highly recurrent genetic event in T-cell prolymphocytic leukemia.
Asunto(s)
Centrómero/genética , Deleción Cromosómica , Cromosomas Humanos Par 12 , Proteínas de Unión al ADN/genética , Leucemia Prolinfocítica/genética , Leucemia de Células T/genética , Pérdida de Heterocigocidad , Proteínas Represoras/genética , Mapeo Cromosómico , ADN de Neoplasias/sangre , ADN de Neoplasias/aislamiento & purificación , Marcadores Genéticos , Humanos , Repeticiones de Microsatélite , Fosfoproteínas/genética , Proteínas Proto-Oncogénicas c-ets , Mapeo Restrictivo , Transcripción Genética , Proteína ETS de Variante de Translocación 6RESUMEN
Advanced atherosclerosis in the form of fibro-fatty intimal plaques has been produced in the rabbit aorta and oral vasculature (labial, lingual, gingival, palatal, periodontal and alveolar arteries) by dietary means. The animals were fed a hypercholesteremic diet and a normocholesteremic diet on alternate months for two years. In the aorta and in many of the oral vessels, the formation of the intimal atheromas was paralleled by a degeneration of the tunica media. The lingual arteries rivaled the aorta and coronary arteries in vulnerability to the diet-induced arteriopathies.
Asunto(s)
Enfermedades de la Aorta/etiología , Arteriosclerosis/etiología , Dieta Aterogénica , Boca/irrigación sanguínea , Animales , Aorta/patología , Enfermedades de la Aorta/patología , Arterias/patología , Arteriosclerosis/patología , Colesterol/sangre , Tejido Elástico/patología , Femenino , Masculino , ConejosRESUMEN
Twelve histologically-confirmed periapical granulomas were evaluated by conventional immunologic rosette assays for the presence of T-lymphocytes and complement receptor-bearing lymphocytes. A technique for dispersing the granuloma cells into suspensions was adopted to facilitate performance of the assays which were not applicable to tissue sections. Differential cell counts by an acridine orange vital dye method disclosed that the cell suspensions contained 30% macrophages, 44% lymphocytes, 15% plasma cells, and 12% neutrophils. Complement receptor-bearing cells comprised 17.9%, and T cells comprised 34.5% of the unseparated inflammatory cells. This study provides the first direct evidence of a predominance of thymic-derived lymphocytes in the lymphocyte compartment of the periapical granuloma. Analysis of the data shows that cell-mediated immunity most likely plays a role in the pathogenesis of the periapical granuloma.
Asunto(s)
Granuloma Periapical/patología , Linfocitos T/patología , Recuento de Células , Humanos , Recuento de Leucocitos , Macrófagos/patología , Monocitos/patología , Neutrófilos/patología , Células Plasmáticas/patologíaRESUMEN
Subjects were 70 Wistar rats showing either low preference for aversive alcohol solutions or a high preference induced by hypothalamic stimulation. Experiments 1 and 2 showed that a large lithium chloride injection.(3 meq/kg) suppressed alcohol intake only if alcohol was tasted. Pairing lithium contiguously with water or intubed alcohol failed to reduce subsequent alcohol intake despite the concurrent presence of high serum lithium levels. In Experiments 3 and 4 a series of seven lithium injections increased rather than decreased alcohol intake if lithium was allowed to accumulate in the blood and brain during alcohol exposure while the transitory sickness associated with each injection was prevented from association with the taste of alcohol. When sickness was allowed to occur during alcohol exposure a suppression of intake resulted after two injections. Contrary to current interpretations these results suggest that the suppression of voluntary alcohol intake by acute and chronic lithium administration is due to a learned taste aversion rather than to a pharmacological mechanism specific to alcohol;
Asunto(s)
Consumo de Bebidas Alcohólicas/efectos de los fármacos , Litio/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Conducta de Elección , Depresión Química , Estimulación Eléctrica , Litio/sangre , Masculino , Ratas , Factores de TiempoRESUMEN
Using HEp2 cells to study antinuclear antibodies has resulted in the discovery of the anti-centromere antibody which is thought to separate the CREST syndrome from progressive systemic sclerosis (scleroderma). This antibody seems to be exceptional in healthy subjects and are in patients with connective tissue diseases, except for scleroderma. It has also been found in CREST syndrome associated with other diseases, such as primary cirrhosis and neoplasias. In our study, the sensitivity of the anti-centromere antibody was 89.1% and its specificity 92.3% which shows that it is worth looking for.