RESUMEN
OBJECTIVES: The objective of this study was to examine the association between the use of statins and the risk of newly diagnosed dementia in an elderly population. DESIGN, SETTING AND PARTICIPANTS: Random samples of 1,000,000 individuals covered by the National Health Insurance in Taiwan were included in the analysis. All participants were 65 years or older without dementia and either did or did not start treatment with statins from 1 August 1997 to 31 December 2010. Patients with established dementia before the start of treatment were excluded. Baseline characteristics were matched (by propensity score) in those who did and did not receive statins. RESULTS: A total of 57,669 subjects were included in the analysis with approximately 12 years of follow-up. Propensity score matching identified 2003 patients who received statins and another 2003 patients who did not with comparable baseline characteristics. Adjusted hazard ratios (HRs) for dementia were significantly inversely associated with total or daily equivalent statin dosage (total accumulated dose: HRs 0.829, 0.720 and 0.385 from T1 to T3 vs. control, P < 0.001 for trend; mean daily dose: HRs 0.667, 0.798 and 0.503 from T1 to T3 vs. control, P < 0.001). The results remained robust after propensity adjustment. CONCLUSION: Independent of traditional risk factors, there was a decrease in newly diagnosed cases of dementia in elderly patients who had received a high total or daily dose of statins. The more potent statins (e.g. atorvastatin and rosuvastatin) seemed to be particularly effective in the prevention of dementia.
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Demencia/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Anciano , Demencia/epidemiología , Femenino , Humanos , Masculino , Puntaje de Propensión , Sistema de Registros , Factores de Riesgo , Taiwán/epidemiologíaRESUMEN
OBJECTIVES: In a large population-based cohort, the level of C-reactive protein (CRP) in patients at baseline predicts an increased risk of future development of atrial fibrillation (AF). The mechanism of this increased risk is unknown. Furthermore, both the molecular effects of CRP on atrial myocytes and fibroblasts and whether genetic variants in the CRP gene predispose to AF are also unknown. METHODS: A genetic association study between CRP gene polymorphisms and AF was performed in two independent populations (I: 100 AF patients and 101 controls; II: 348 AF patients and 356 controls), with functional studies to elucidate the mechanism of association. RESULTS: Three polymorphisms (T-861C, A-821G and C-390A/C-390T) were found in the 1-kb promoter of CRP. A triallelic polymorphism (C-390A/C-390T) captured all haplotype information and determined the CRP gene promoter activity and the plasma CRP level, and was in nearly complete linkage disequilibrium with G1059C polymorphism in exon 2. The -390A variant was associated with a higher CRP gene promoter activity, a higher plasma CRP level and a higher risk of AF. Patients with AF also had a higher plasma CRP level than controls. CRP significantly increased the inward L-type calcium current in atrial myocytes with no changes in other ionic currents. CRP did not affect the expressions of type I alpha 1 (COL1A1), type III alpha 1 (COL3A1) and type 1 alpha 2 (COL1A2) procollagens in atrial fibroblasts. CONCLUSION: A CRP gene promoter triallelic polymorphism was associated with CRP gene promoter activity, determined the plasma level of CRP, and predicted the risk of AF. The mechanism of this may be via augmention of calcium influx by CRP in atrial myocytes, but not because of atrial fibrosis.
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Fibrilación Atrial/genética , Proteína C-Reactiva/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Fibrilación Atrial/sangre , Proteína C-Reactiva/análisis , Canales de Calcio Tipo L/fisiología , Estudios de Casos y Controles , Estudios de Cohortes , Exones , Femenino , Fibroblastos/fisiología , Genotipo , Haplotipos , Atrios Cardíacos/citología , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Miocitos Cardíacos/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Medición de RiesgoRESUMEN
BACKGROUND AND AIMS: The association between inflammation and left ventricular (LV) diastolic dysfunction in continuous ambulatory peritoneal dialysis (CAPD) and non-CAPD patients is not established. The objective of this study was to test the above association and whether inflammation interacts with CAPD to increase LV diastolic dysfunction risks. METHODS AND RESULTS: 120 subjects with normal creatinine levels and 101 CAPD patients were recruited. Echocardiographic parameters were assessed in all patients. The participants were classified as having LV diastolic dysfunction by echocardiographic findings including mitral inflow E/A ratio < 1, deceleration time > 220 cm/s, or decreased peak annular early diastolic velocity in tissue Doppler imaging. Blood was sampled at the baseline for measurement of inflammation markers, including tissue necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Subjects with LV diastolic dysfunction had higher proinflammation cytokines levels in both groups. Inflamed markers correlated significantly with echocardiography parameters for LV diastolic dysfunction in patients receiving CAPD. In a multivariate regression analysis adjusting for all the factors associated with LV diastolic dysfunction, inflammation is still significantly associated with left ventricular diastolic dysfunction (TNF-alpha, OR: 2.6, 95% CI: 2.0-3.35, p < 0.001; IL-6, OR: 1.26, 95% CI: 1.25-1.26, p = 0.01). In addition, the interaction of CAPD and inflammation significantly contributed to the development of LV diastolic dysfunction (CAPD∗ TNF-α: OR: 1.45, 95% CI: 1.13-1.79, P = 0.004). CONCLUSION: We found inflammation plays a vital role for LV diastolic dysfunction especially in CAPD patients. A synergistic effect between CAPD and inflammation, especially TNF-α, would further aggravate LV diastolic dysfunction.
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Inflamación/fisiopatología , Interleucina-6/sangre , Diálisis Peritoneal Ambulatoria Continua , Factor de Necrosis Tumoral alfa/sangre , Disfunción Ventricular Izquierda/fisiopatología , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Casos y Controles , Creatinina/sangre , Ecocardiografía Doppler/métodos , Femenino , Humanos , Inflamación/complicaciones , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo , Disfunción Ventricular Izquierda/complicacionesRESUMEN
The objective of this study was to evaluate the effects of angiotensin-converting enzyme (ACE) inhibitors and pharmacogenetic interaction on the survival of the patients with diastolic heart failure (DHF). A total of 285 subjects with DHF confirmed by echocardiography were recruited in the period between 1995 and 2003. Baseline characteristics (age, sex, prior history, medication, and echocardiographic findings) and genetic polymorphisms (ACE gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen (AGT) gene; and A1166C polymorphisms of the angiotensin II type I receptor (AT1R)) were collected and matched (by propensity score) in those who received and those who did not receive ACE inhibitors. The patients were followed up to 10 years. Kaplan-Meier curves and Cox regression models were used to demonstrate the survival trend. The 85 patients who received ACE inhibitors and the other 85 patients who did not were found to have comparable baseline characteristics and polymorphism distribution. Prescription of ACE inhibitors was associated with a significant decrease in overall mortality (hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.24-0.83; P=0.01), and a lower rate of cardiovascular events at 4000 days (HR, 0.53; 95% CI, 0.32-0.90; P=0.02). In addition, ACE I/D gene D allele was associated with higher overall mortality as compared with the I allele (HR, 2.04; P=0.003). This effect was diminished in those who received ACE inhibitors. The use of ACE inhibitor was associated with a significant decrease in long-term mortality and cardiovascular events in the patients with DHF. Genetic variants in the renin-angiotensin system genes were also associated, but their effects could be modified by the use of ACE inhibitors.
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Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Insuficiencia Cardíaca Diastólica/genética , Peptidil-Dipeptidasa A/genética , Receptores de Angiotensina/genética , Anciano , Femenino , Estudios de Seguimiento , Eliminación de Gen , Insuficiencia Cardíaca Diastólica/tratamiento farmacológico , Insuficiencia Cardíaca Diastólica/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutagénesis Insercional , Polimorfismo Genético , Pronóstico , Puntaje de Propensión , Estudios Prospectivos , Sistema Renina-Angiotensina/genéticaRESUMEN
This double-blind, active- and randomized-controlled study compared the efficacy and safety of a fixed-dose combination of valsartan/hydrochlorothiazide 80 mg/12.5 mg once daily (n = 32) with amlodipine monotherapy 5 mg once daily (n = 33) for 8 weeks in patients with mild to moderate hypertension. Non-inferiority of valsartan/hydrochlorothiazide to amlodipine was demonstrated by comparable reductions in sitting systolic blood pressure (SBP), sitting diastolic blood pressure (DBP), and daytime, night-time and 24-h SBP and DBP on ambulatory blood pressure monitoring. Between-group comparisons of adverse events and changes in laboratory parameters did not reach statistical significance, except for uric acid which showed a significant increase in the valsartan/hydrochlorothiazide group compared with the amlodipine group, but was still below the laboratory's upper limit of normal. In conclusion, the use of the fixed-dose combination of valsartan/hydrochlorothiazide 80 mg/12.5 mg once daily as a starting regimen in patients with mild to moderate hypertension was shown to have non-inferior efficacy and comparable safety for daily practice compared with amlodipine 5 mg once daily monotherapy.
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Amlodipino/uso terapéutico , Antihipertensivos/uso terapéutico , Hidroclorotiazida/efectos adversos , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Tetrazoles/efectos adversos , Tetrazoles/uso terapéutico , Valina/análogos & derivados , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Hidroclorotiazida/administración & dosificación , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Valina/efectos adversos , Valina/uso terapéutico , ValsartánRESUMEN
BACKGROUND: Diastolic heart failure (DHF) refers to an abnormality of diastolic distensibility, filling or relaxation of the left ventricle. The genetic study of DHF is scarce in the literature. The association of renin-angiotensin system (RAS) and DHF are well known. We hypothesized that RAS genes might be the susceptible genes for DHF and conducted a case-control study to prove the hypothesis. MATERIALS AND METHODS: A total of 1452 consecutive patients were analysed and 148 patients with a diagnosis of DHF confirmed by echocardiography were recruited. We had two control populations. The first controls consisted of 286 normal subjects while the second were 148 matched controls selected on a 1-to-1 basis by age, sex, hypertension, diabetes and medication use. The angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism; multilocus polymorphisms of the angiotensinogen gene; and the A1166C polymorphisms of the angiotensin II type I receptor (AT(1)R) gene were genotyped. RESULTS: In a single-locus analysis, the odds ratios (ORs) for DHF were significant with the ACE DD genotype and the AT(1)R 1166 CC plus AC genotype. In addition, the concomitant presence of ACE DD and AT(1)R 1166 CC/AC genotypes synergistically increased the predisposition to DHF. CONCLUSIONS: Genetic variants in the RAS genes may determine an individual's risk to develop DHF. There is also a synergistic gene-gene interaction between the RAS genes in the development of DHF.
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Angiotensina II/genética , Insuficiencia Cardíaca Diastólica/genética , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético , Sistema Renina-Angiotensina/genética , Anciano , Estudios de Casos y Controles , Ecocardiografía , Femenino , Eliminación de Gen , Predisposición Genética a la Enfermedad/genética , Genotipo , Insuficiencia Cardíaca Diastólica/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Mutagénesis Insercional/genéticaRESUMEN
While the current epigenetic drug development is still largely restricted to target DNA methylome, emerging evidence indicates that histone methylome is indeed another major epigenetic determinant for gene expression and frequently deregulated in acute myeloid leukaemia (AML). The recent advances in dissecting the molecular regulation and targeting histone methylome in AML together with the success in developing lead compounds specific to key histone methylation-modifying enzymes have revealed new opportunities for effective leukaemia treatment. In this article, we will review the emerging functions of histone methyltransferases and histone demethylases in AML, especially MLL-rearranged leukaemia. We will also examine recent preclinical and clinical studies that show significant promises of targeting these histone methylation-modifying enzymes for AML treatment.
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Antineoplásicos/farmacología , Epigénesis Genética/efectos de los fármacos , Histona Demetilasas/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Histonas/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Acetilación , Animales , Antineoplásicos/uso terapéutico , Estudios Clínicos como Asunto , Metilación de ADN/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Histona Demetilasas/metabolismo , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Terapia Molecular Dirigida , Unión Proteica , Transducción de Señal/efectos de los fármacos , Resultado del TratamientoRESUMEN
Essentials We studied the C-reactive protein (CRP) gene on stroke risk in atrial fibrillation (AF) patients. 725 patients with CRP triallelic polymorphism genotype were followed-up for more than 10 years. Patients with the A-390/T-390 allele of the CRP gene were more likely to get ischemic stroke. The triallelic polymorphism of the CRP is related to ischemic stroke in AF patients. SUMMARY: Background Little evidence is available regarding the impact of genetic polymorphisms on the risk of thromboembolic stroke in patients with atrial fibrillation (AF). An increasing body of evidence is demonstrating that inflammatory responses play an important role in the pathophysiology of AF. Objectives To investigate the effect of genetic polymorphisms of the C-reactive protein (CRP) gene on the incidence of thromboembolic stroke in patients with AF. Methods A total of 725 AF patients were longitudinally followed up for > 10 years; this is the largest and longest AF follow-up cohort with genetic data. CRP promoter triallelic polymorphisms (C-390A and C-390T) were genotyped, and CRP levels were divided into four quartiles. Results Patients with higher CRP levels were more likely to develop thromboembolic stroke than those with lower CRP levels (P<0.001, log-rank test for comparison of four quartiles). After adjustment for conventional risk factors, patients with higher CRP levels were more likely to develop thromboembolic stroke than those in the lowest CRP quartile (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.08-4.81; the lowest CRP quartile was the reference group). Patients carrying the A-390 or T-390 allele had higher CRP levels (3.35 ± 2.71 mg L-1 versus 2.43 ± 2.00 mg L-1 ), and were more likely to develop thromboembolic stroke, even after adjustment for conventional risk factors (HR 2.07, 95% CI 1.23-3.48). Conclusion The CRP triallelic polymorphism and the CRP level are associated with the risk of incident thromboembolic stroke in patients with AF.
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Fibrilación Atrial/genética , Proteína C-Reactiva/genética , Polimorfismo Genético , Accidente Cerebrovascular/genética , Tromboembolia/genética , Anciano , Fibrilación Atrial/sangre , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/epidemiología , Proteína C-Reactiva/metabolismo , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Estimación de Kaplan-Meier , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Fenotipo , Regiones Promotoras Genéticas , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Sistema de Registros , Factores de Riesgo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Taiwán/epidemiología , Tromboembolia/sangre , Tromboembolia/diagnóstico , Tromboembolia/epidemiología , Factores de TiempoRESUMEN
The effects of increases in intracellular adenosine 3':5'-cyclic monophosphate (cyclic AMP) on bradykinin (BK)-induced generation of inositol phosphates (IPs) and Ca2+ mobilization were investigated in canine cultured tracheal smooth muscle cells (TSMCs). Pretreatment of TSMCs with either forskolin or dibutyryl cyclic AMP attenuated BK-stimulated responses. The inhibitory effects of these agents produced both a depression of the maximal response and a shift to the right of the concentration-response curves of BK. The water-soluble forskolin analogue L-858051, 7-deacetyl-7 beta-(r-N-methylpiperazino)-butyryl forskolin, significantly attenuated BK-stimulated IPs accumulation, while 1,9-dideoxy forskolin, an inactive forskolin, had little effect on IPs response. Moreover, SQ-22536, 9-(tetrahydro-2-furanyl)-9-H-purin-6-amine, an inhibitor of adenylate cyclase, and both H-89, N-(2-aminoethyl)-5-isoquinolinesulfonamide, and HA-1004, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide, inhibitors of cyclic AMP-dependent protein kinase (PKA), reversed the ability of forskolin to attenuate BK-stimulated IPs accumulation. The KD and Bmax, values of the BK receptor for [3H]BK binding were not significantly changed by forskolin treatment for 30 min and 4 h. The AlF4(-)-induced IPs accumulation was attenuated by forskolin, indicating that G protein(s) are directly activated by AlF4- and uncoupled to phospholipase C by forskolin treatment. These results suggest that activation of cyclic AMP/PKA might inhibit the BK-stimulated PI breakdown and consequently reduce the [Ca2+]i increases or inhibit independently both responses, which is distal to the BK receptor in canine cultured TSMCs.
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Bradiquinina/farmacología , Calcio/metabolismo , Colforsina/farmacología , Músculo Liso/metabolismo , Tráquea/metabolismo , Adenina/análogos & derivados , Adenina/farmacología , Inhibidores de Adenilato Ciclasa , Adenilil Ciclasas/fisiología , Compuestos de Aluminio/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Bradiquinina/metabolismo , Bucladesina/farmacología , Permeabilidad de la Membrana Celular/efectos de los fármacos , Células Cultivadas , Colforsina/análogos & derivados , AMP Cíclico/fisiología , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Perros , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Femenino , Fluoruros/farmacología , Fosfatos de Inositol/metabolismo , Masculino , Receptores de Bradiquinina/metabolismo , Saponinas/farmacología , Transducción de Señal/fisiología , Tráquea/citologíaRESUMEN
Regulation of the increase in inositol 1,4,5-trisphosphate (IP3) production and intracellular Ca2+ concentration ([Ca2+]i) by protein kinase C (PKC) was investigated in cultured canine tracheal smooth muscle cells (TSMCs). Stimulation of TSMCs by endothelin-1 (ET-1) led to IP3 formation and caused an initial transient peak followed by a sustained elevation of [Ca2+]i in a concentration-dependent manner. Pretreatment of TSMCs with phorbol 12-myristate 13-acetate (PMA, 1 microM) for 30 min blocked the ET-1-induced IP3 formation and Ca2+ mobilization. However, this inhibition was reduced after incubating the cells for 8 h with PMA. Following preincubation, ET-1-induced Ca2+ mobilization recovered with time and reached the same extent of control cells within 48 h. The concentrations of PMA that gave half-maximal inhibition (-logEC50) of ET-1-induced IP3 formation and increase in [Ca2+]i were 8.6 and 8.4 M, respectively. Prior treatment of TSMCs with staurosporine (1 microM), a PKC inhibitor, inhibited the ability of PMA to attenuate ET-1-induced responses, suggesting that the inhibitory effect of PMA is mediated through the activation of PKC. In parallel with the effect of PMA on the ET-1-induced IP3 formation and Ca2+ mobilization, a change of PKC activity was observed in TSMCs. PMA rapidly decreased PKC activity in the cytosol of TSMCs, while increasing it transiently in the membranes within 30 min. Thereafter the membrane-associated PKC activity decreased and persisted for at least 24 h of PMA treatment. Taken together, these results suggest that activation of PKC may inhibit the phosphoinositide hydrolysis and consequently attenuate the [Ca2+]i increase or inhibit independently both responses. The PMA-induced inhibition of responses to ET-1 was associated with an increase in membranous PKC activity.
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Calcio/metabolismo , Endotelinas/farmacología , Inositol 1,4,5-Trifosfato/metabolismo , Músculo Liso/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Tráquea/metabolismo , Alcaloides/farmacología , Animales , Células Cultivadas , Diglicéridos/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Interacciones Farmacológicas , Hidrólisis , Contracción Muscular/fisiología , Músculo Liso/citología , Músculo Liso/efectos de los fármacos , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Transducción de Señal , Estaurosporina , Tráquea/citología , Tráquea/efectos de los fármacosRESUMEN
Reports of the association of Chlamydia pneumoniae (C. pneumoniae) infection with coronary artery disease (CAD) are scarce in the Oriental population. We therefore conducted a case-control study to explore this issue in Taiwan. There were 242 consecutive subjects (166 men and 76 women) who underwent cardiac catheterization at the National Taiwan University Hospital Cardiac Catheterization Laboratory. Patients with CAD (n = 156) had > or = 1 coronary artery lesion of > 50% diameter stenosis on angiography. Controls (n = 86) had no demonstrable CAD angiographically. Antibodies to C. pneumoniae were tested by using an enzyme-linked immunosorbent assay. The prevalence of antibodies to C. pneumoniae was as follows: immunoglobulin-G (IgG), 50% (122 of 242 patients); immunoglobulin-A (IgA), 72% (176 of 242 patients); and either IgG or IgA, 79% (192 of 242 patients ). The odds ratio (OR) for CAD with either IgG or IgA was 1.4 (95% confidence interval [CI] 0.7 to 2.7, p = 0.31). After adjusting for the known CAD risk factors, the OR decreased to 0.8 (95% CI 0.3 to 2.1, p = 0.60). The OR for unstable angina or acute myocardial infarction with the presence of either IgG or IgA was 0.5 (95% CI 0.2 to 1.1, p = 0.08) and 0.4 ( 95% CI 0.1 to 1.0, p = 0.049) after adjusting for other risk factors. These results suggest a high prevalence of C. pneumoniae infection in Taiwan. However, C. pneumoniae infection is not associated with angiographically documented CAD, and, in contrast, is a negative predictor for the development of acute coronary syndromes.
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Angina Inestable/microbiología , Infecciones por Chlamydophila/epidemiología , Chlamydophila pneumoniae , Enfermedad Coronaria/microbiología , Infarto del Miocardio/microbiología , Anciano , Angina Inestable/epidemiología , Estudios de Casos y Controles , Angiografía Coronaria , Enfermedad Coronaria/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Prevalencia , Estudios Seroepidemiológicos , TaiwánRESUMEN
1. A direct [3H]-bradykinin ([3H]-BK) binding assay has been used to characterize the BK receptors in canine cultured tracheal epithelial cells (TECs). Based on receptor binding assay, TECs have specific, saturable, high-affinity binding sites for [3H]-BK. 2. The specific [3H]-BK binding was time- and temperature-dependent. Equilibrium of association of [3H]-BK with the BK receptors was attained within 30 min at room temperature and 1 h at 4 degrees C, respectively. 3. Analysis of binding isotherms yielded an apparent equilibrium dissociation constant (KD) of 1.5 +/- 0.2 nM and a maximum receptor density (Bmax) of 53.2 +/- 5.2 fmol mg-1 protein. The Hill coefficient for [3H]-BK binding was 1.00 +/- 0.02. The association (K1) and dissociation (K-1) rate constants were (7.6 +/- 1.1) x 10(6) M-1 min-1 and (9.2 +/- 1.5) x 10 M-3 min-1, respectively. KD, calculated from the ratio of K-1 and K1, was 1.2 +/- 0.3 nM, a value close to that calculated from Scatchard plots of binding isotherms. 4. Neither a B1 receptor selective agonist (des-Arg9-BK, 0.1 nM - 10 microM) nor antagonist ([Leu8, des-Arg9]-BK, 0.1 nM - 10 microM) significantly inhibited [3H]-BK binding to TECs, which excludes the presence of B1 receptors in canine TECs. 5. The specific binding of [3H]-BK to canine TECs was inhibited by the B2 receptor selective antagonists ([D-Arg0, Hyp3, Thi5, D-Tic7, Oic8]-BK (Hoe 140, 0.1 nM-10 microM) and [D-Arg0, Hyp3, Thi5.8, D-Phe7]-BK, 0.1 nM - 10 microM) and agonists (BK and kallidin, 0.1 nM-10 microM) with a best fit by a one-binding site model. The order of potency for the inhibition of [3H]-BK binding was kallidin = BK = Hoe 140 > [D-Arg0, Hyp3, Thi5,8, D-Phe7]-BK. 6. BK and kallidin significantly induced concentration-dependent accumulation of IPs with a half-maximal response (EC50) at 17.6 +/- 3.5 and 26.6 +/- 5.3 nM, respectively, while the B1-selective agonist, des-Arg9-BK did not stimulate IPs accumulation and the B1-selective antagonist [Leu8, des-Arg9]-BK did not inhibit BK-induced IPs accumulation. Two B2-selective antagonists, Hoe 140 and [D-Arg0, Hyp3, Thi5,8, D-Phe7]-BK, inhibited BK-stimulated IPs accumulation with apparent pKB values of 8.8 +/- 0.3 and 7.0 +/- 0.3, respectively. 7. It is concluded that the pharmacological characteristics of the BK receptors in canine cultured TECs are primarily of the B2 receptor subtype which might regulate the function of tracheal epithelium through the activation of this receptor subtype coupling to PI hydrolysis.
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Receptores de Bradiquinina/efectos de los fármacos , Receptores de Bradiquinina/fisiología , Tráquea/efectos de los fármacos , Tráquea/ultraestructura , Animales , Unión Competitiva , Bradiquinina/metabolismo , Células Cultivadas , Perros , Epitelio/ultraestructura , Femenino , Hidrólisis , Cinética , Masculino , Fosfatidilinositoles/metabolismo , Ensayo de Unión Radioligante , Receptores de Bradiquinina/metabolismo , Especificidad por Sustrato , Tráquea/metabolismo , TritioRESUMEN
The contribution of the pedunculopontine nucleus to exploratory locomotion was investigated in rats. Locomotor activity recorded in a standard open-field apparatus was increased more than two-fold when wooden panels were inserted. This novelty-elicited locomotion was reduced significantly when procaine was injected bilaterally into the pedunculopontine nucleus but not when procaine was injected bilaterally into the mediodorsal thalamus, a second major projection site of the subpallidal area. These results support observations from earlier studies implicating hippocampal-accumbens-subpallidal-pedunculopontine projections in exploratory locomotion.
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Conducta Exploratoria/fisiología , Globo Pálido/fisiología , Puente/fisiología , Núcleos Talámicos/fisiología , Animales , Masculino , Ratas , Ratas EndogámicasRESUMEN
In urethane-anesthetized rats discharges of neurons of substantia nigra, pars compacta (SNC) were recorded extracellularly after natural somatic sensory stimulation and electrical stimulation of peripheral sensory nerves. (1) Among different modalities of somatic sensory stimulation tested, noxious stimuli were effective in reducing spontaneous discharges of SNC neurons. The inhibition appeared with a concomitant increase of spike amplitude. The same inhibitory effect was obtained by stimulating the sciatic nerve (SC) repetitively. In response to single shock stimulation of the SC the inhibition occurred at an average latency of 39.6 msec (S.E. 1.6 msec) and lasted for 221.6 msec on average (S.E. 10.8 msec). (2) The SC-induced inhibition of SNC neurons failed to reliably block ortho- and antidromic discharges evoked from the caudate nucleus (Cd). (3) In rats with the Cd lesioned the SC-induced inhibition was longer lasting than in controls. When the Cd was stimulated concurrently with SC stimulation, the inhibition from the SC was weakened. (4) In a majority of SNC neurons, their inhibition by SC stimulation, their inhibition by SC stimulation was antagonized by intravenous injection of haloperidol.
Asunto(s)
Núcleo Caudado/fisiología , Inhibición Neural , Nociceptores/fisiología , Sustancia Negra/fisiología , Animales , Dopamina/metabolismo , Estimulación Eléctrica , Potenciales Evocados/efectos de los fármacos , Haloperidol/farmacología , Masculino , Mecanorreceptores/fisiología , Inhibición Neural/efectos de los fármacos , Neuronas/fisiología , Ratas , Nervio Ciático/fisiologíaRESUMEN
Recordings were made of the electrical activity of neurons in the subpallidal area of urethane-anesthetized rats. Output neurons from the subpallidal area to the pedunculopontine nucleus were identified by antidromic activation. The inputs to subpallidal neurons to single-pulse stimulation of the amygdala and hippocampus were investigated. More than two-thirds of the subpallidal neurons antidromically activated by pedunculopontine stimulation were inhibited by hippocampal stimulation and activated by amygdala stimulation. Subpallidal neurons not antidromically activated by pedunculopontine stimulation also responded to stimulation of the amygdala and hippocampus but no differential effects were observed. The relation of these findings to limbic influences on locomotor activity is discussed.
Asunto(s)
Amígdala del Cerebelo/fisiología , Globo Pálido/fisiología , Hipocampo/fisiología , Tegmento Mesencefálico/fisiología , Potenciales de Acción , Animales , Estimulación Eléctrica , Masculino , Vías Nerviosas/fisiología , Ratas , Ratas EndogámicasRESUMEN
Neuronal activities of the substantia nigra pars compacta (SNC) are known to be inhibited by noxious stimuli. Extracellular recording of spontaneous firing of SNC neurons were made to investigate how such inhibition would be influenced by treatment with 5,7-dihydroxytryptamine (5,7-DHT) or p-chlorophenylalanine (PCPA) or by IV injection of the serotonin antagonist, cyproheptadine. Noxious stimuli were produced by tail pinching (TP) and tail heating (HW). In 5,7-DHT-treated experiment, the inhibition indices were 62.8 +/- 4.4 (TP) and 63.4 +/- 4.6 (HW)% for vehicle-treated control, then the inhibition indices were 26.3 +/- 2.6 (TP) and 27.8 +/- 2.9 (HW)% for 5,7-DHT-treated animals. As to the PCPA-treated experiment, the inhibition indices were 63.1 +/- 2.6 (TP) and 64.8 +/- 2.5 (HW)% for saline control rats, while the inhibition indices were 30.3 +/- 1.6 (TP) and 30.1 +/- 1.6 (HW)% for the PCPA-treated ones. Furthermore, in another observation, the firing rates of SNC neurons were reduced from the saline (control) level by 53.2 +/- 2.12 and 52.1 +/- 2.07% during the application of stimulation of TP and HW, respectively. Following the intravenous injection of cyproheptadine, the firing rates of those were reduced by only 6.71 +/- 1.38 and 4.38 +/- 1.79% for TP and HW, respectively. That is, the TP- and HW-induced inhibition were attenuated about 47% by the injection of cyproheptadine. The results strongly suggested that the serotonergic mechanism would be involved in the mediation of the inhibition of SNC neurons by noxious stimuli.
Asunto(s)
Inhibición Neural/efectos de los fármacos , Dolor/metabolismo , Serotonina/fisiología , Sustancia Negra/metabolismo , 5,7-Dihidroxitriptamina/farmacología , Animales , Estimulación Eléctrica , Fenclonina/farmacología , Inyecciones Intraventriculares , Masculino , Dolor/fisiopatología , Ratas , Ratas Endogámicas , Serotonina/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiopatologíaRESUMEN
Extracellular nucleotides, acting through P2-purinoceptors, have been implicated in the regulation of ion transport in epithelia, including Madin-Darby canine kidney (MDCK) cells. In this study, experiments were conducted to characterize the P2-purinoceptor subtype on MDCK cells responsible for stimulating inositol phosphate (IP) accumulation using a range of nucleotide analogues. In Ca2+- and Mg2+-free Krebs-Henseleit solution (KHS), ATP, UTP, and ATPgammaS caused an increase in IP accumulation as a function of concentration with comparable kinetics. The order of potency for the nucleotide analogues was UTP = ATPgammaS > ATP = 2-chloro ATP (Cl-ATP) >> alpha,beta-methylene ATP (alpha,beta-MeATP) = 2-methylthio ATP (2MeSATP). Selective agonists for P1-, P2X- and P2Y-purinoceptors, such as N6-cyclopentyl adenosine, AMP, alpha,beta-MeATP, and 2MeSATP, had little effect. Stimulation of MDCK cells with maximally effective concentrations of ATP and UTP showed no additive effect and furthermore, ATP, UTP, and ATPgammaS induced cross-desensitization of the IP response, suggesting that ATP and UTP act upon a common nucleotide receptor, i.e. a P2U-purinoceptor. In Ca2+- and Mg2+-containing KHS, the concentration-response curves of ATP, UTP, and ATPgammaS were shifted to the right of those obtained in Ca2+- and Mg2+-free buffer, and asymptotic maxima were not reached, indicating that ATP4- and not MgATP2- or CaATP2- was the active agonist. Pretreatment of MDCK cells with pertussis toxin (PTX) inhibited ATP- and UTP-induced IP accumulation in a concentration-dependent fashion but did not completely abolish the IP accumulation, indicating that a PTX-sensitive G protein was partially involved in the IP response. In conclusion, ATP- and UTP-stimulated IP accumulation in MDCK cells appears to be mediated through the activation of P2U-purinoceptors coupled to a G protein that is partially sensitive to PTX. A form of nucleotide uncomplexed with divalent ions such as ATP4- seems to be the preferential agonist form for the purinoceptors on MDCK cells.
Asunto(s)
Riñón/metabolismo , Fosfatidilinositoles/metabolismo , Receptores Purinérgicos P2/fisiología , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/farmacología , Animales , Células Cultivadas , Perros , Hidrólisis , Técnicas In Vitro , Riñón/citología , Riñón/efectos de los fármacos , Toxina del Pertussis , Agonistas del Receptor Purinérgico P2 , Receptores Purinérgicos P2/clasificación , Uridina Trifosfato/farmacología , Factores de Virulencia de Bordetella/farmacologíaRESUMEN
The effects of electrical stimulation of prefrontal cortex upon neurons of substantia nigra (pars compacta) in anesthetized rats were mostly inhibition without antidromic excitation. By studying nigral neurons in which the inhibition from caudate-putamen was antagonized by iontophoretic bicuculline, it was found in only half of them that the same drug also antagonized the inhibition from prefrontal cortex.
Asunto(s)
Lóbulo Frontal/fisiología , Inhibición Neural , Sustancia Negra/fisiología , Animales , Bicuculina/farmacología , Núcleo Caudado/fisiología , Estimulación Eléctrica , Masculino , Inhibición Neural/efectos de los fármacos , Putamen/fisiología , RatasRESUMEN
A complete two-handed technique for laparoscopic appendectomy is described. From April 1992 to July 1994, 100 patients with suspected acute appendicitis were selected to undergo this approach. This technique allows the surgeon to manipulate instruments with both hands for dissecting, transecting and removing the appendix. The appropriate placement of three cannulas in the lower abdominal midline makes this technique possible. Monopolar cautery is used to dissect the mesoappendix and to cauterize the appendicular vessels. Two ligatures are placed at the junction of the appendix with the cecum. The appendix is clamped at its base by ratchet forceps and is extracted along with the forceps immediately after transection. None of the patients selected for this procedure required conversion to open appendectomy. Postoperative complications occurred in four patients, two with umbilical wound infections and two with intra-abdominal abscesses; 12 patients had perforated appendicitis. The results of this study suggest that a complete two-handed laparoscopic appendectomy can be safely and successfully accomplished in patients with suspected acute appendicitis.
Asunto(s)
Apendicectomía/métodos , Laparoscopía/métodos , Enfermedad Aguda , Adolescente , Adulto , Anciano , Apendicitis/cirugía , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Neural connections from the hippocampus and nucleus accumbens to the subpallidal area have been implicated by behavioral observation. The locomotor activity recorded in an automated activity cage increased substantially after the bilateral injection of carbachol, a cholinergic agonist, into the dentate gyrus of the hippocampus, and this increase of activity was reduced significantly after the injection of glutamate antagonist into the nucleus accumbens. On the other hand, this hyperactivity elicited by the injection of carbachol was also reduced by the injection of GABA into the subpallidal area. In another observation, increased locomotor activity was recorded following the injection of dopamine into the nucleus accumbens. However, the increase of locomotor activity induced by dopamine was attenuated by the injection of GABA into the subpallidal area. These observations suggest that neural connections from hippocampus and nucleus accumbens to the subpallidal region may contribute to locomotor activity.