Assuntos
Azatioprina/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/genética , Eritema Nodoso/genética , Imunossupressores/efeitos adversos , Pirofosfatases/genética , Adulto , Biópsia , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Urticária Crônica/tratamento farmacológico , Eritema Nodoso/induzido quimicamente , Eritema Nodoso/diagnóstico , Eritema Nodoso/patologia , Feminino , Humanos , Testes de Função Hepática , Polimorfismo de Nucleotídeo Único , Pele/efeitos dos fármacos , Pele/patologiaRESUMO
BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse drug reaction. However, its histopathological features have not been well defined. OBJECTIVES: To identify the clinicohistopathological findings of DRESS, and analyse the cutaneous histopathological changes observed in DRESS compared with those observed in maculopapular exanthema (MPE). METHODS: In a retrospective study, conducted at Chang Gung Memorial Hospital (Taiwan) between 2001 and 2011, we compared the clinicohistopathological features of 32 patients with probable/definite DRESS (defined by the RegiSCAR scoring system) with those of 17 patients with MPE. RESULTS: The major pathological changes observed in patients with DRESS included dyskeratosis (97%), epidermal spongiosis (78%), interface vacuolization (91%), perivascular lymphocytic infiltration (97%) and eosinophilic infiltration (72%). Many pathological features were common to both MPE and DRESS. However, severe dyskeratosis, epidermal spongiosis and severe interface vacuolization were significantly more prominent in cases of DRESS (P < 0·05). The presence of severe dyskeratosis was significantly associated with the clinical severity of renal impairment (P = 0·01). CONCLUSIONS: The severe dyskeratosis detected in patients with DRESS may correlate with a greater extent of systemic involvement compared with that noted in MPE. However, the histopathological changes associated with DRESS are not entirely specific.
Assuntos
Síndrome de Hipersensibilidade a Medicamentos/patologia , Pele/patologia , Biópsia , Diagnóstico Diferencial , Humanos , Ceratose/etiologia , Ceratose/patologia , Nefropatias/etiologia , Hepatopatias/etiologia , Estudos RetrospectivosRESUMO
Transcriptional silencing in the yeast Saccharomyces cerevisiae occurs at HML and HMR mating-type loci and telomeres and requires the products of the silent information regulator (SIR) genes. Recent evidence suggests that the silencer- and telomere-binding protein Rap1p initiates silencing by recruiting a complex of Sir proteins to the chromosome, where they act in some way to modify chromatin structure or accessibility. A single allele of the SUM1gene (SUM1-1) which restores silencing at HM loci in strains mutant for any of the four SIR genes was identified a number of years ago. However, conflicting genetic results and the lack of other alleles of SUM1 made it difficult to surmise the wild-type function of SUM1 or the manner in which the SUM1-1 mutation restores silencing in sir mutant strains. Here we report the cloning and characterization of the SUM1 gene and the SUM1-1 mutant allele. Our results indicate that SUM1-1 is an unusual altered-function mutation that can bypass the need for SIR function in HM silencing and increase repression at telomeres. A sum1 deletion mutation has only minor effects on silencing in SIR strains and does not restore silencing in sir mutants. In addition to its effect on transcriptional silencing, the SUM1-1 mutation (but not a sum1 deletion) increases the rate of chromosome loss and cell death. We suggest several speculative models for the action of SUM1-1 in silencing based on these and other data.
Assuntos
Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica , Proteínas de Membrana/fisiologia , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Telômero/fisiologia , Sequência de Aminoácidos , Sequência de Bases , Cromossomos/ultraestrutura , Clonagem Molecular , Genes Dominantes , Genes Fúngicos , Genes Supressores , Dados de Sequência Molecular , RNA Mensageiro/genética , Proteínas Repressoras , Mapeamento por Restrição , Transcrição GênicaRESUMO
Mutational replacements of specific residues in the GTP-binding pocket of the 21-kDa ras proteins (p21ras) reduce their GTPase activity. To test the possibility that the cognate regions of G protein alpha chains participate in GTP binding and hydrolysis, we compared signaling functions of normal and mutated alpha chains (termed alpha s) of Gs, the stimulatory regulator of adenylyl cyclase. alpha s chains were expressed in an alpha s-deficient S49 mouse lymphoma cell line, cyc-. alpha s in which leucine replaces glutamine 227 (corresponding to glutamine 61 of p21ras) constitutively activates adenylyl cyclase and reduces the kcat for GTP hydrolysis more than 100-fold. There is a smaller reduction in GTPase activity in another mutant in which valine replaces glycine 49 (corresponding to glycine 12 of p21ras). This mutant alpha s is a poor activator of adenylyl cyclase. Moreover, the glycine 49 protein, unlike normal alpha s, is not protected against tryptic cleavage by hydrolysis resistant GTP analogs; this finding suggests impairment of the mutant protein's ability to attain the active (GTP-bound) conformation. We conclude that alpha s residues near glutamine 227 and glycine 49 participate in binding and hydrolysis of GTP, although the GTP binding regions of alpha s and p21ras are not identical.