RESUMO
The deficiency of complement C5 is rare and frequently associated with severe and recurrent infections, especially caused by Neisseria spp. We observed the absence of component C5 in the serum of 3 siblings from a Brazilian family with history of consanguinity. The patients had suffered from recurrent episodes of meningitis and other less severe infections. Sera from these patients were unable to mediate hemolytic activity either by the classical or alternative pathways and presented extremely low levels of C5 protein (1.3, 0.9 and 1.0 microg/ml-normal range: 45-190 microg/ml). Hemolytic activity could be restored by the addition of purified C5 to deficient serum. Sequencing of sibling C5 cDNA revealed a homozygous 153 bp deletion that corresponds precisely to exon 30. The parents carried the same deletion but only in one allele. Sequencing of the corresponding region in the genomic DNA revealed a C to G substitution within intron 30 and, most significantly, the substitution of GAG(4028) for GAA(4028) at the 3' end of exon 30 which is most likely responsible for skipping of exon 30. The resulting in-frame deletion in the C5 mRNA codes for a mutant C5 protein lacking residues 1289-1339. These residues map to the CUB and C5d domains of the C5 alpha chain. This deletion is expected to produce a non-functional and unstable C5 protein which is more susceptible to degradation.
Assuntos
Complemento C5/química , Complemento C5/genética , Éxons/genética , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Adolescente , Adulto , Indígena Americano ou Nativo do Alasca/genética , Sequência de Bases , Western Blotting , Brasil , Criança , Análise Mutacional de DNA , DNA Complementar/genética , Feminino , Hemólise , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Linhagem , Estabilidade Proteica , Estrutura Terciária de ProteínaRESUMO
The genus Xanthomonas is a diverse and economically important group of bacterial phytopathogens, belonging to the gamma-subdivision of the Proteobacteria. Xanthomonas axonopodis pv. citri (Xac) causes citrus canker, which affects most commercial citrus cultivars, resulting in significant losses worldwide. Symptoms include canker lesions, leading to abscission of fruit and leaves and general tree decline. Xanthomonas campestris pv. campestris (Xcc) causes black rot, which affects crucifers such as Brassica and Arabidopsis. Symptoms include marginal leaf chlorosis and darkening of vascular tissue, accompanied by extensive wilting and necrosis. Xanthomonas campestris pv. campestris is grown commercially to produce the exopolysaccharide xanthan gum, which is used as a viscosifying and stabilizing agent in many industries. Here we report and compare the complete genome sequences of Xac and Xcc. Their distinct disease phenotypes and host ranges belie a high degree of similarity at the genomic level. More than 80% of genes are shared, and gene order is conserved along most of their respective chromosomes. We identified several groups of strain-specific genes, and on the basis of these groups we propose mechanisms that may explain the differing host specificities and pathogenic processes.
Assuntos
Genoma Bacteriano , Plantas/microbiologia , Xanthomonas/genética , Xanthomonas/fisiologia , Ordem dos Genes/genética , Interações Hospedeiro-Parasita , Dados de Sequência Molecular , Filogenia , Regulon/genética , Origem de Replicação/genética , Especificidade da Espécie , Virulência/genética , Xanthomonas/classificação , Xanthomonas/patogenicidade , Xanthomonas campestris/genética , Xanthomonas campestris/patogenicidade , Xanthomonas campestris/fisiologiaRESUMO
The in vitro Ca(2+) regulation of the actomyosin Mg(2+)-ATPase at physiological ratios of actin, tropomyosin, and troponin occurs only in the presence of troponin T. We have previously demonstrated that a polypeptide corresponding to the first 191 amino acids of troponin T (TnT-(1-191)) activates the actomyosin Mg(2+)-ATPase in the presence of tropomyosin. In order to further characterize this activation domain, we constructed troponin T fragments corresponding to residues 1-157 (TnT-(1-157)), 1-76 (TnT-(1-76)), 77-157 (TnT-(77-157)), 77-191 (TnT-(77-191)), and 158-191 (TnT-(158-191)). Assays using these fragments demonstrated the following: (a) residues 1-76 do not bind to tropomyosin or actin; (b) residues 158-191 bind to actin cooperatively but not to tropomyosin; (c) the sequence 77-157 is necessary for troponin interaction with residue 263 of tropomyosin; (d) TnT-(77-191) on its own activates the actomyosin ATPase activity as described previously for TnT-(1-191). TnT-(1-157), TnT-(1-76), TnT-(77-157), TnT-(158-191), and combinations of TnT-(158-191) with TnT-(1-157) or TnT-(77-157) showed no effect on the ATPase activity. We conclude that the activation of actomyosin ATPase activity is mediated by a direct interaction between amino acids 77 and 191 of troponin T, tropomyosin, and actin.
Assuntos
Actinas/metabolismo , Miosinas/metabolismo , Troponina T/química , Troponina T/metabolismo , Actinas/química , Animais , Sítios de Ligação , ATPase de Ca(2+) e Mg(2+)/metabolismo , Sinalização do Cálcio , Galinhas , Dicroísmo Circular , Ativação Enzimática , Cinética , Músculo Esquelético/metabolismo , Mutagênese Sítio-Dirigida , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Conformação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Tropomiosina/metabolismoRESUMO
We have introduced tryptophan codons at different positions of the chicken alpha-tropomyosin cDNA (Monteiro, P. B., Lataro, R. C., Ferro, J. A., and Reinach, F. C. (1994) J. Biol. Chem. 269, 10461-10466) and employed a trp auxotrophic Escherichia coli strain to express the proteins in media containing either normal tryptophan, 5-hydroxytrptophan, or 7-azatryptophan. The fluorescence of these latter two tryptophan analogues is excitable at 312-315 nm at which the natural fluorescence of other thin filament proteins (actin, troponin) is not excited. The recombinant tropomyosins have tryptophans or analogues located at amino acid positions 90, 101, 111, 122, or 185 of the protein, all on the external surface of the tropomyosin coiled-coil (positions "c" or "f" of the hydrophobic heptad repeat). The first four mutations are located within the third actin-binding zone of tropomyosin, a region not expected to interact directly with troponin or with neighboring tropomyosin molecules in muscle thin filaments, while position 185 is located in a region that has been implicated in interactions with the globular domain of troponin. The fluorescence intensity of the mutant containing 5-hydroxytryptophan at position 122 (5OH122W) is sensitive to actin binding and sensitive to Ca2+-binding to thin filaments reconstituted with troponin. Assuming that the globular domain of troponin binds to a site between residues 150 and 190 of tropomyosin, the distance between the troponin-binding site and the fluorescent probes at position 122 can be estimated to be 4.2-10.2 nm. While X-ray diffraction and electron micrograph reconstitution studies have provided evidence of Ca2+-induced changes in tropomyosin's interactions in the thin filament, their resolution was not sufficient to distinguish between changes involving the whole tropomyosin molecule or only that region directly interacting with troponin. Here we provide a clear demonstration that Ca2+-binding to troponin results in a conformational change in a region of tropomyosin outside the troponin binding site which is probably associated with a changed interaction with actin.
Assuntos
5-Hidroxitriptofano/química , Cálcio/metabolismo , Proteínas Recombinantes/química , Tropomiosina/química , Troponina/metabolismo , 5-Hidroxitriptofano/genética , 5-Hidroxitriptofano/metabolismo , Actinas/química , Actinas/metabolismo , Actomiosina/química , Actomiosina/metabolismo , Substituição de Aminoácidos/genética , Animais , Sítios de Ligação/genética , Galinhas , Mutagênese Sítio-Dirigida , Miosinas/antagonistas & inibidores , Conformação Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Espectrometria de Fluorescência , Tropomiosina/genética , Tropomiosina/metabolismo , Troponina/química , Triptofano/análogos & derivados , Triptofano/genéticaAssuntos
Mutagênese Sítio-Dirigida , Plasmídeos/genética , Animais , Células COS/citologia , Células COS/metabolismo , Complemento C4/genética , Enzimas de Restrição do DNA , Vetores Genéticos/genética , Humanos , Ácidos Nucleicos Heteroduplexes/genética , Reação em Cadeia da Polimerase , Polinucleotídeo 5'-Hidroxiquinase , Proteínas Recombinantes de Fusão/genéticaRESUMO
The contraction of skeletal muscle is regulated by Ca2+ binding to troponin C, which results in an internal reorganization of the interactions within the troponin-tropomyosin complex. Troponin T is necessary for Ca2+-dependent inhibition and activation of actomyosin. Troponin T consists of an extended NH2-terminal domain that interacts with tropomyosin and a globular COOH-terminal domain that interacts with tropomyosin, troponin I, and troponin C. In this study we used recombinant troponin T and troponin I fragments to delimit further the structural and regulatory interactions with the thin filament. Our results show the following: (i) the NH2-terminal region of troponin T activates the actomyosin ATPase in the presence of tropomyosin; (ii) the interaction of the globular domain of troponin T with the thin filament blocks ATPase activation in the absence of Ca2+; and (iii) the COOH-terminal region of the globular domain anchors the troponin C-troponin I binary complex to troponin T through a direct Ca2+-independent interaction with the NH2-terminal region of troponin I. This interaction is required for Ca2+-dependent activation of the actomyosin ATPase activity. Based on these results we propose a refined model for the troponin complex and its interaction with the thin filament.
Assuntos
Miosinas/metabolismo , Troponina C/metabolismo , Troponina I/metabolismo , Troponina/metabolismo , Animais , Sítios de Ligação , Cálcio/metabolismo , Galinhas , Ativação Enzimática , Contração Muscular , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Mutagênese Sítio-Dirigida , Ligação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Troponina/química , Troponina/genética , Troponina TRESUMO
The thioester bond in complement components C3 and C4 and the protease inhibitor alpha2-macroglobulin have traditionally been thought of as fulfilling the dual roles of mediating covalent attachment and maintaining the native conformational states of these molecules. We previously reported that several human C3 thioester-region mutants, including variants E1012Q and C1010A, in the latter of which thioester-bond formation is precluded, display an unexpected phenotype. Despite the lack of a thioester bond in these mutants, they appear to adopt a native-like conformation as suggested by the finding that they are cleavable by the classical pathway C3 convertase, C4b2a, whereas the C3b-like C3(H2O) species is not. Subsequently, a species referred to as C3(NH3)* was described which potentially could account for the observations with the above mutants. C3(NH3)* is a transient species formed on aminolysis of native C3 that can spontaneously re-form the thioester bond. Importantly, it has a mobility on cation-exchange HPLC that is distinct from both native C3 and C3(H2O), but like the native molecule, it is cleavable by an alternative-pathway C3 convertase. In this study we showed by using cation-exchange HPLC as an additional conformational probe that C3 C1010A and E1012Q mutant proteins did not resemble C3(NH3)*. Instead they displayed a chromatographic behaviour that was indistinguishable from that of native C3. To assess the general applicability of these observations, we engineered the equivalent mutations into human C4, specifically C4 C1010A and C4 E1012Q. As expected, thioester-bond formation did not occur in either of these C4 mutants, but in contrast with the results with C3 we found no evidence for the formation of a stable native-like conformation in either C4 mutant, as assessed using cleavability by C1s as the conformational probe. A possible interpretation of our data is that the adoption of the native conformational state during biosynthesis of C3 and C4 is an energetically permissible process, even if it is not locked in via thioester-bond formation. Whereas this conformational state is stable in mature C3, it is unstable in mature C4, perhaps reflecting the additional post-translational cleavage of C4 before its secretion.
Assuntos
Complemento C3/química , Complemento C4/química , Conformação Proteica , Compostos de Sulfidrila/química , Substituição de Aminoácidos/genética , Animais , Cromatografia Líquida de Alta Pressão , Complemento C3/biossíntese , Complemento C3/genética , Complemento C4/biossíntese , Complemento C4/genética , Cisteína/genética , Ésteres , Expressão Gênica , Ácido Glutâmico/genética , Humanos , Camundongos , Mutagênese Sítio-Dirigida , Plasmocitoma , Transfecção , Células Tumorais CultivadasRESUMO
During Musca domestica vitellogenesis a protein is preferentially synthesized by the female fat body and accumulates in the haemolymph but not in the ovaries. This protein, designated nonvitellogenic female protein (NVFP), was purified and shown to be a hexamer with an M(r) = 430 kDa, and subunits of M(r) = 70 kDa. The hexamer dissociates into subunits when the pH is elevated from 7.0 to 9.0. Two cDNA clones, F0 and F2, were isolated and analysed. The 2.2 kb F2 clone has an open reading frame that encodes a conceptual translation product that has similarity to the Drosophila melanogaster LSP-2 hexamerin. Recombinant protein from the F2-cDNA is recognized by a specific anti-NVFP serum. The temporal pattern of mRNA expression of the gene represented by the F2 clone follows that determined for the synthesis of NVFP. The data support the conclusion that NVFP is an hexamerin specific to the adult stage of Musca domestica.
Assuntos
Moscas Domésticas/genética , Proteínas de Insetos/genética , Sequência de Aminoácidos , Animais , Anticorpos/imunologia , Sequência de Bases , Clonagem Molecular , DNA Complementar , Escherichia coli , Feminino , Moscas Domésticas/metabolismo , Proteínas de Insetos/imunologia , Proteínas de Insetos/isolamento & purificação , Dados de Sequência Molecular , Coelhos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/isolamento & purificação , Homologia de Sequência de Aminoácidos , VitelogêneseRESUMO
Skeletal muscle contraction is regulated by a complex of five polypeptides which are stably associated with the actin filament. This complex consists of two proteins: troponin with three subunits (TnC; TnI and TnT) and tropomyosin (a dimer of two chains). Using deletion mutants of TnC, TnI and TnT we determined that each of these polypeptides can be divided into at least two domains. One domain is responsible for the regulatory properties of the protein. Its interaction with the other components of the system change upon calcium binding to TnC. A second domain present in each of these proteins is responsible for the stable association of the complex to the actin filament. The interactions among this second set of domains is not influenced by calcium binding to TnC. The structural interactions are: 1) interactions between the C-domain of TnC with the N-domain of TnI; 2) interactions of the N-domain of TnI with the C-terminal domain of TnT and 3) interactions between the N-domain of TnT (T1) and actin/tropomyosin.
Assuntos
Citoesqueleto de Actina/metabolismo , Músculo Esquelético/metabolismo , Troponina/metabolismo , Animais , Dimerização , Modelos Moleculares , Mutagênese Sítio-Dirigida , Conformação Proteica , Deleção de Sequência , Tropomiosina/metabolismo , Troponina/genética , Troponina C/genética , Troponina C/metabolismo , Troponina I/genética , Troponina I/metabolismo , Troponina TRESUMO
The changes in the serum thyroid autoantibodies, antithyroglobulin (TgAb) and antithyroid-peroxidase (TPOAb), lipid profile, and thyroid volume following L-thyroxine (L-T4) therapy is still a controversial matter. We studied 23 patients with goiter due to Hashimoto's thyroiditis; 10 had clinical hypothyroidism (CH) and 13 had subclinical hypothyroidism (SH). Both groups received L-T4 (2.0 to 2.5 micrograms/kg/day) for a median period of 6 months. Serum concentration of TgAb (normal value: < 200 mUI/mL) and TPOAb (normal value: < 150 mUI/mL) were measured by a sensitive IRMA using 125I protein-A. Thyroid volume was determined by ultrasound (normal value: 8-14 mL). At the end of the observation period the median serum TSH concentration decreased significantly in both groups (42.9 to 0.55 in CH and 2.4 to 0.74 mU/L in SH patients) and serum FT4I levels increased only in the CH group (0.87 to 2.1; p < 0.05). Serum TgAb concentration did not change in SH patients (72 to 218 mUI/mL) but declined in CH patients (364.5 to 75 mU/mL; p < 0.05). TPOAb levels also fell in the CH group (871 to 194 mUI/mL; p < 0.05) and no significant change was noted in SH patients (260 to 116 mUI/mL). Further, a significant correlation was obtained between TSH and either TPOAb concentration (rs = 0.569, p < 0.01) or thyroid volume (rs = 0.488, p < 0.05) in the CH group but not in SH patients (rs = 0.232, NS). LDL-cholesterol was higher in the CH (159.4 mg/dL) compared with the SH group (116 mg/dL). Moreover, only in the CH patients was there a significant fall in total cholesterol (224.5 to 165.5 mg/dL, p < 0.05) and in LDL-cholesterol (159.4 to 104.3 mg/dL, p < 0.05) values. The thyroid volume decreased in all patients with CH and in 77% (10/13) of SH patients and a significant median in the thyroid volume decrease was found (39.7% of initial volume in the CH group and 80.9% in SH patients; p < 0.01). The influence of L-T4 on both thyroid autoantibody levels and thyroid volume might be explained by reduction of antigenic substance through a decreased stimulation of thyroid tissue by circulating TSH as was seen in CH but not in SH patients. The benefits of the administration of L-T4 replacement therapy in SH patients due to Hashimoto's thyroiditis remain to be clarified.
Assuntos
Autoanticorpos/sangue , Lipídeos/sangue , Glândula Tireoide/imunologia , Glândula Tireoide/patologia , Tireoidite Autoimune/tratamento farmacológico , Tiroxina/uso terapêutico , Adolescente , Adulto , Idoso , LDL-Colesterol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tireoglobulina/imunologia , Glândula Tireoide/diagnóstico por imagem , Tireoidite Autoimune/diagnóstico por imagem , Tireoidite Autoimune/imunologia , Tireotropina/sangue , Tiroxina/administração & dosagem , Tiroxina/sangue , UltrassonografiaRESUMO
In a wide variety of cellular settings, from organelle transport to muscle contraction, Ca2+ binding to members of the EF hand family of proteins controls the interaction between actin and different myosins that are responsible for generating movement. In vertebrate skeletal and cardiac muscle the Ca(2+)-binding protein troponin C (TnC) is one subunit of the ternary troponin complex which, through its association with actin and tropomyosin on the thin filament, inhibits the actomyosin interaction at submicromolar Ca2+ concentrations and stimulates the interaction at micromolar Ca2+ concentrations. Because TnC does not interact directly with actin or tropomyosin, the Ca(2+)-binding signal must be transmitted to the thin filament via the other two troponin subunits: troponin I (TnI), the inhibitory subunit, and troponin T (TnT), the tropomyosin-binding subunit. Thus, the troponin complex is a Ca(2+)-sensitive molecular switch and the structures of and interactions between its components have been of great interest for many years. Although the crystal structure of TnC has been known for almost a decade, the molecular structures of TnI and TnT are not known and therefore convincing models of the organization of the troponin complex and the Ca(2+)-induced changes in its structure have not been forthcoming. Recent advances on a wide variety of fronts including 1) the bacterial expression and characterization of mutants of TnC, TnI, and TnT; 2) cross-linking and fluorescence studies; and 3) the determination of the crystal and nuclear magnetic resonance structures of synthetic and recombinant troponin fragments and complexes between EF hand proteins and their target peptides have provided new insights into the nature of the interactions between troponin subunits. This review discusses these recent advances with the aim of critically assessing molecular models of the nature of the Ca(2+)-induced structural transition in troponin.
Assuntos
Contração Muscular/fisiologia , Troponina/metabolismo , Actomiosina/metabolismo , Sequência de Aminoácidos , Animais , Cálcio/metabolismo , Modelos Biológicos , Dados de Sequência Molecular , Sarcômeros/ultraestrutura , Tropomiosina/metabolismo , Troponina C , Troponina IRESUMO
Calcium binding to regulatory sites located in the NH2-terminal domain of troponin C (TnC) induces a conformational change that blocks the inhibitory action of troponin I (TnI) and triggers muscle contraction. We used deletion mutants of TnI in conjunction with a series of TnC mutants to understand the structural and functional relationship between different TnI regions and TnC domains. Our results indicate that TnI is organized into structural and regulatory regions which interact in an antiparallel fashion with the corresponding structural and regulatory regions of TnC. Functional studies show that the COOH-terminal region of TnI, when linked to the inhibitory region (TnI103-182) can regulate actomyosin ATPase. A TnI lacking the first 57 amino acids (TnId57) has been shown to have similar properties (Sheng, Z., Pan, B.-S., Miller, T. E., and Potter, J. D. (1992) J. Biol. Chem. 267, 25407-25413). Regulation was not observed with the COOH-terminal region alone (TnI120-182), with the NH2-terminal region alone (TnI1-98), or with the NH2-terminal linked to the inhibitory region (TnI1-116). Binding studies show that the NH2-terminal region of TnI interacts with the COOH-terminal domain of TnC in the presence of Ca2+ or Mg2+ and that the inhibitory plus COOH-terminal region of TnI (TnI103-182) interacts with the NH2-terminal domain of TnC in a Ca(2+)-dependent manner. Based on these results we propose a model for the Ca(2+)-induced conformational change. In our model the NH2-terminal domain of TnI is anchored strongly to the COOH-terminal domain of TnC in the absence and presence of Ca2+ while the inhibitory and COOH-terminal regions of TnI switch between actin-tropomyosin in the absence of Ca2+ to binding sites in both NH2- and COOH-terminal domains of TnC in the presence of Ca2+.
Assuntos
Músculos/metabolismo , Miosinas/metabolismo , Deleção de Sequência , Troponina/química , Troponina/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Cálcio/metabolismo , Cálcio/farmacologia , Galinhas , Cinética , Magnésio/metabolismo , Dados de Sequência Molecular , Peso Molecular , Mutagênese Sítio-Dirigida , Oligodesoxirribonucleotídeos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/isolamento & purificação , Fragmentos de Peptídeos/farmacologia , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Mapeamento por Restrição , Troponina/isolamento & purificação , Troponina C , Troponina IRESUMO
The value of the criteria used to anticipate the outcome of treatment of Graves' hyperthyroid patients with methimazole (MMI) remains controversial. We have reported that high MMI doses combined with T3 administration was correlated with higher remission rates. In this study, we used the lowest MMI dose able to control the hyperthyroidism, keeping the free T4 index (FT4I) values below the normal range throughout treatment, and compared the results with patients treated with a high MMI regimen. Both groups received T3. We also evaluated the usefulness of goiter size, serum thyroid-stimulating antibody (TSAb: adenylate cyclase stimulation in human thyroid membrane), thyroglobulin (Tg) levels, and the T3 suppressibility of 24 h RAIU as prognostic markers for the outcome of Graves' disease therapy. Twenty-four Graves' hyperthyroid patients were treated with high MMI dose (mean +/- SD 60 +/- 19, range 40-120 mg daily), and 25 patients received low MMI dose (17 +/- 4.3, 5-20 mg daily). T3, 75 micrograms daily, was given to both groups of patients for 15 +/- 4 (13-22) months of treatment. After cessation of drug therapy, 31 patients (63%) remained euthyroid for 18 +/- 3 (13-49) months of follow-up, 15 (62.5%) and 16 (64%) patients in the high and low dose groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Autoanticorpos/sangue , Doença de Graves/tratamento farmacológico , Metimazol/uso terapêutico , Tireoglobulina/sangue , Glândula Tireoide/metabolismo , Tri-Iodotironina/uso terapêutico , Adulto , Quimioterapia Combinada , Feminino , Humanos , Imunoglobulinas Estimuladoras da Glândula Tireoide , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/imunologia , Tri-Iodotironina/sangueRESUMO
The authors studied 389 Graves' hyperthyroid patients receiving either high propylthiouracil (PTU) or methimazole (MMI) daily doses or low doses to evaluate whether adverse effects were related to the thionamide drugs or its daily dose regimen. Group 1 patients (n = 286) received high PTU (728 +/- 216 mg/day, n = 92) or MMI (60 +/- 19 mg/day, n = 94) doses, and group 2 patients (n = 103) were treated with low PTU (255 +/- 85 mg/day, n = 39) or MMI (23 +/- 10 mg/day, n = 64) doses. Major adverse effects were observed in 11 (2.8%) patients. Of these, four (1.0%) had agranulocytosis, two (0.5%) were granulocytopenic and five (1.3%) had hepatotoxicity. Agranulocytosis occurred in two patients from each group, 0.7% and 1.9%, respectively from group 1 and group 2. There was no significant difference between the groups or the types of thionamide. There also was no correlation with the patients' age. All of the patients were hyperthyroid, and its onset occurred in the first to third month of treatment. Full recovery was achieved in all cases after drug withdrawal. Four of 5 patients with hepatotoxicity were treated with high PTU doses, and one patient received low MMI doses (p less than .05). All patients were euthyroid. Arthralgias, skin rash and gastric intolerance, the minor adverse effects of thionamides studied, were observed in 52 (13.4%) of the patients. Although no significant differences were found, most of the patients experiencing side effects were from group 1 an received MMI therapy. These adverse effects did not demand drug withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Doença de Graves/tratamento farmacológico , Hipertireoidismo/tratamento farmacológico , Metimazol/efeitos adversos , Propiltiouracila/efeitos adversos , Adolescente , Adulto , Idoso , Agranulocitose/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas , Criança , Relação Dose-Resposta a Droga , Toxidermias , Humanos , Articulações/efeitos dos fármacos , Metimazol/administração & dosagem , Pessoa de Meia-Idade , Dor/induzido quimicamente , Propiltiouracila/administração & dosagem , Gastropatias/induzido quimicamenteRESUMO
The TSH effect on slice and the incubation medium cyclic AMP levels and T3 and T4 released from 8 autonomously functioning thyroid nodules (AFTN) and their respective perinodular (PN) tissues were examined. The thyroid slices were incubated in Eagle's Medium containing TSH (5 to 100 mU/ml) for 60 min and 300 min for tissue cyclic AMP generation and for cyclic AMP, T3 and T4 release, respectively. Basal cyclic AMP levels were not different either in AFTN and in PN slices or into the incubation medium. In both tissues TSH produced a similar cyclic AMP generation. In contrast, cyclic AMP released into the incubation medium was significantly higher in AFTN than in PN tissues, after TSH stimulation. Basal T3 values and TSH-stimulated T3 release in AFTN were not different from PN tissue. However, basal T4 levels were significantly higher in AFTN than in PN tissue as well as T4 released in response to TSH. In addition, T3/T4 ratio was lower in AFTN than in PN tissues. The cyclic AMP released into the incubation medium correlated with both T3 and T4 release in PN tissue but in the AFTN tissue no correlations were found. These findings suggest that the adenylate cyclase-cyclic AMP system is more sensitive to TSH-stimulation in AFTN when compared with PN tissue and that AFTN tissue has a preferential T4 secretion.