RESUMO
Pseudoephedrine is a sympathomimetic α- and ß-adrenergic receptor agonist that causes vasoconstriction and reduction in edema throughout the nasal passages. Coronary vasospasm associated with pseudoephedrine has been reported in the literature. We discuss the case of a patient with new-onset atrial fibrillation receiving metoprolol for rate control on a background of pseudoephedrine use for allergic rhinitis leading to acute myocardial infarction from multivessel coronary vasospasm. This case illustrates the importance of understanding the pharmacology of potential drug-drug interactions when managing patients with acute cardiovascular syndromes.
Assuntos
Asma/tratamento farmacológico , Fibrilação Atrial/tratamento farmacológico , Vasoespasmo Coronário , Metoprolol , Infarto do Miocárdio , Nitroglicerina/administração & dosagem , Pseudoefedrina , Antiarrítmicos/administração & dosagem , Antiarrítmicos/efeitos adversos , Asma/complicações , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Angiografia Coronária/métodos , Vasoespasmo Coronário/induzido quimicamente , Vasoespasmo Coronário/diagnóstico por imagem , Eletrocardiografia/métodos , Feminino , Humanos , Metoprolol/administração & dosagem , Metoprolol/efeitos adversos , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Pseudoefedrina/administração & dosagem , Pseudoefedrina/efeitos adversos , Resultado do Tratamento , Vasodilatadores/administração & dosagemRESUMO
There have been no reports of successful resuscitation using nitroglycerin (NTG) for cardiac arrest due to definitive coronary vasospasm. A 42-year-old female was brought to the Emergency Department in ventricular fibrillation after being found collapsed with the consumption of misoprostol. NTG, a potent coronary arterial dilator, not typically used in the management of cardiac arrest, was administered after 27 min of resuscitation efforts following advanced cardiac life support. NTG aided in the return of spontaneous circulation during a ventricular fibrillation cardiac arrest in the setting of prostaglandin use.
RESUMO
Multiple sclerosis (MS) is a central nervous system inflammatory disorder with evidence of peripheral immune dysregulation. Abnormalities of the immune suppressive cytokine TGF-ß have been reported, but not fully defined, in MS. Through a pathway-focused expression profiling of the peripheral blood, we found abnormalities of TGF-ßRII, SMAD4 and SMAD7 expression in subjects with MS, and reduction in the levels of TGF-ß regulated genes, indicating an overall reduction in TGF-ß signaling in MS. The response to exogenous TGF-ß was intact, however, indicating an extrinsic defect of TGF-ß signaling in MS. These results indicate that TGF-ß control is diminished in MS.
Assuntos
Esclerose Múltipla/sangue , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/sangue , Adulto , Western Blotting , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Proteína Smad7/sangue , Proteína Smad7/genética , Proteína Smad7/imunologia , Transcrição Gênica , Fator de Crescimento Transformador beta1/genéticaRESUMO
BACKGROUND: HTLV-I is the causal agent of adult T cell leukemia (ATLL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Biomarkers are needed to diagnose and/or predict patients who are at risk for HAM/TSP or ATLL. Therefore, we investigated using luciferase immunoprecipitation technology (LIPS) antibody responses to seven HTLV-I proteins in non-infected controls, asymptomatic HTLV-I-carriers, ATLL and HAM/TSP sera samples. Antibody profiles were correlated with viral load and examined in longitudinal samples. RESULTS: Anti-GAG antibody titers detected by LIPS differentiated HTLV-infected subjects from uninfected controls with 100% sensitivity and 100% specificity, but did not differ between HTLV-I infected subgroups. However, anti-Env antibody titers were over 4-fold higher in HAM/TSP compared to both asymptomatic HTLV-I (P < 0.0001) and ATLL patients (P < 0.0005). Anti-Env antibody titers above 100,000 LU had 75% positive predictive value and 79% negative predictive value for identifying the HAM/TSP sub-type. Anti-Tax antibody titers were also higher (P < 0.0005) in the HAM/TSP compared to the asymptomatic HTLV-I carriers. Proviral load correlated with anti-Env antibodies in asymptomatic carriers (R = 0.76), but not in HAM/TSP. CONCLUSION: These studies indicate that anti-HTLV-I antibody responses detected by LIPS are useful for diagnosis and suggest that elevated anti-Env antibodies are a common feature found in HAM/TSP patients.
Assuntos
Anticorpos Anti-HTLV-I/sangue , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Imunoprecipitação/métodos , Paraparesia Espástica Tropical/imunologia , Doenças da Medula Espinal/imunologia , Portador Sadio , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Paraparesia Espástica Tropical/diagnóstico , Paraparesia Espástica Tropical/virologia , Doenças da Medula Espinal/diagnóstico , Doenças da Medula Espinal/virologia , Carga Viral , Proteínas Virais/imunologiaRESUMO
Most PRKAR1A tumorigenic mutations lead to nonsense mRNA that is decayed; tumor formation has been associated with an increase in type II protein kinase A (PKA) subunits. The IVS6+1G>T PRKAR1A mutation leads to a protein lacking exon 6 sequences [R1 alpha Delta 184-236 (R1 alpha Delta 6)]. We compared in vitro R1 alpha Delta 6 with wild-type (wt) R1 alpha. We assessed PKA activity and subunit expression, phosphorylation of target molecules, and properties of wt-R1 alpha and mutant (mt) R1 alpha; we observed by confocal microscopy R1 alpha tagged with green fluorescent protein and its interactions with Cerulean-tagged catalytic subunit (C alpha). Introduction of the R1 alpha Delta 6 led to aberrant cellular morphology and higher PKA activity but no increase in type II PKA subunits. There was diffuse, cytoplasmic localization of R1 alpha protein in wt-R1 alpha- and R1 alpha Delta 6-transfected cells but the former also exhibited discrete aggregates of R1 alpha that bound C alpha; these were absent in R1 alpha Delta 6-transfected cells and did not bind C alpha at baseline or in response to cyclic AMP. Other changes induced by R1 alpha Delta 6 included decreased nuclear C alpha. We conclude that R1 alpha Delta 6 leads to increased PKA activity through the mt-R1 alpha decreased binding to C alpha and does not involve changes in other PKA subunits, suggesting that a switch to type II PKA activity is not necessary for increased kinase activity or tumorigenesis.
Assuntos
Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Mutação , Invasividade Neoplásica/genética , Neoplasias/genética , Animais , Células COS , Forma Celular/genética , Células Cultivadas , Chlorocebus aethiops , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Deleção de Genes , Células HeLa , Humanos , Ligação Proteica , Subunidades Proteicas/metabolismo , RNA Mensageiro/metabolismo , Distribuição Tecidual , TransfecçãoRESUMO
PURPOSE: Since the identification of PRKAR1A mutations in Carney complex, substitutions and small insertions/deletions have been found in approximately 70% of the patients. To date, no germ-line PRKAR1A deletion and/or insertion exceeded a few base pairs (up to 15). Although a few families map to chromosome 2, it is possible that current sequencing techniques do not detect larger gene changes in PRKAR1A -- mutation-negative individuals with Carney complex. EXPERIMENTAL DESIGN: To screen for gross alterations of the PRKAR1A gene, we applied Southern hybridization analysis on 36 unrelated Carney complex patients who did not have small intragenic mutations or large aberrations in PRKAR1A, including the probands from two kindreds mapping to chromosome 2. RESULTS: We found large PRKAR1A deletions in the germ-line of two patients with Carney complex, both sporadic cases; no changes were identified in the remaining patients, including the two chromosome-2-mapping families. In the first patient, the deletion is expected to lead to decreased PRKAR1A mRNA levels but no other effects on the protein; the molecular phenotype is predicted to be PRKAR1A haploinsufficiency, consistent with the majority of PRKAR1A mutations causing Carney complex. In the second patient, the deletion led to in-frame elimination of exon 3 and the expression of a shorter protein, lacking the primary site for interaction with the catalytic protein kinase A subunit. In vitro transfection studies of the mutant PRKAR1A showed impaired ability to bind cyclic AMP and activation of the protein kinase A enzyme. The patient bearing this mutation had a more-severe-than-average Carney complex phenotype that included the relatively rare psammomatous melanotic schwannoma. CONCLUSIONS: Large PRKAR1A deletions may be responsible for Carney complex in patients that do not have PRKAR1A gene defects identifiable by sequencing. Preliminary data indicate that these patients may have a different phenotype especially if their defect results in an expressed, abnormal version of the PRKAR1A protein.
Assuntos
Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Deleção de Genes , Neoplasia Endócrina Múltipla/genética , Linhagem Celular , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Éxons , HumanosRESUMO
CONTEXT: Primary pigmented nodular adrenocortical disease, associated with Carney complex, is caused by mutations in PRKAR1A (mt-PRKAR1A), a gene that codes for the regulatory subunit type 1alpha (RIalpha) of cAMP-dependent protein kinase (PKA). PRKAR1A inactivation is associated with dysregulated PKA activity that is thought to result in tumorigenesis. mt-PRKAR1A-bearing lymphocytes from Carney complex patients exhibit enhanced cell proliferation associated with increased expression of the MAPK ERK1/2 pathway. OBJECTIVE: The objective of the study was to determine how PKA and its subunits and ERK1/2 and their molecular partners change in the presence of PRKAR1A mutations in adrenocortical tissue. DESIGN: PKA activity and subunit expression, ERK1/2, other immunoassays, and immunohistochemistry on adrenocortical samples from patients with germline normal or mt-PRKAR1A were analyzed. RESULTS: Increased cAMP-stimulated total kinase activity was associated with mt-PRKAR1A. PKA subunit expression analysis in mt-PRKAR1A tissues, by quantitative mRNA assay and immunoblotting, showed a 2.4-fold (P = 0.02) and 1.8-fold (P = 0.09) decrease in RIalpha's message and protein, respectively, and increases in other PKA subunits. Immunoassays showed 2-fold (P = 0.03) and 6-fold (P = 0.03) decreases in baseline ERK1/2, with corresponding increases in phosphorylated (p) ERK1/2 in mt-PRKAR1A samples. B-raf kinase, p-MEK1/2, and p-c-Myc, but not p-Akt/protein kinase B, were significantly increased. Immunohistochemistry studies supported these data. CONCLUSIONS: mt-PRKAR1A causes increased total cAMP-stimulated kinase activity, likely the result of up-regulation of other PKA subunits caused by down-regulation of RIalpha, as seen in human lymphocytes and mouse animal models. These changes, associated with enhanced MAPK activity, may be, in part, responsible for the proliferative signals that result in primary pigmented nodular adrenocortical disease.
Assuntos
Córtex Suprarrenal/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Mutação , Transdução de Sinais/fisiologia , Adulto , Criança , Pré-Escolar , AMP Cíclico/fisiologia , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico , Proteínas Quinases Dependentes de AMP Cíclico/análise , Proteínas Quinases Dependentes de AMP Cíclico/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Sistema de Sinalização das MAP Quinases , Masculino , Pessoa de Meia-Idade , Fosforilação , Proteínas Proto-Oncogênicas c-akt/fisiologia , RNA Mensageiro/análiseRESUMO
Mutations of the human type Ialpha regulatory subunit (RIalpha) of cyclic AMP-dependent protein kinase (PKA; PRKAR1A) lead to altered kinase activity, primary pigmented nodular adrenocortical disease, and tumors of the thyroid and other tissues. To bypass the early embryonic lethality of Prkar1a(-/-) mice, we established transgenic mice carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline-responsive promoter. Down-regulation of Prkar1a by up to 70% was achieved in transgenic mouse tissues and embryonic fibroblasts, with concomitant changes in kinase activity and increased cell proliferation, respectively. Mice developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia, and other features reminiscent of primary pigmented nodular adrenocortical disease, histiocytic and epithelial hyperplasias, lymphomas, and other mesenchymal tumors. These were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIbeta protein levels. This mouse provides a novel, useful tool for the investigation of cyclic AMP, RIalpha, and PKA functions and confirms the critical role of Prkar1a in tumorigenesis in endocrine and other tissues.
Assuntos
Neoplasias do Córtex Suprarrenal/enzimologia , Transtornos Linfoproliferativos/enzimologia , Proteínas/fisiologia , Neoplasias da Glândula Tireoide/enzimologia , Adenoma/enzimologia , Adenoma/genética , Neoplasias do Córtex Suprarrenal/genética , Animais , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico , DNA Antissenso/genética , Regulação para Baixo , Éxons , Feminino , Transtornos Linfoproliferativos/genética , Mesoderma/enzimologia , Mesoderma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Gravidez , Regiões Promotoras Genéticas , Proteínas/genética , Tetraciclina/farmacologia , Neoplasias da Glândula Tireoide/genética , Transativadores/genéticaRESUMO
Mice with complete inactivation of the type Ialpha regulatory subunit (RIalpha) of cyclic (c) AMP-dependent protein kinase (PKA) (coded by the Prkar1a gene) die early in embryonic life. To bypass the early embryonic lethality of Prkar1a-/- mice, we established transgenic mice carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline-responsive promoter. Mice developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia, and other features reminiscent of PPNAD, and histiocytic and epithelial hyperplasias, lymphomas, and other mesenchymal tumors. This mouse provides a useful tool for the investigation of cAMP, RIalpha, and PKA functions and confirms Prkar1a's critical role in tumorigenesis in endocrine and other tissues.