RESUMEN
Different patterns in the incidence of road accidents are revealed when considering areas with increased levels of urbanization. To understand these patterns, road accident data from England and Wales is explored. In particular, the data are used to (i) generate time series for comparison of the incidence of road accidents in urban as opposed to rural areas, (ii) analyse the relationship between the number of road accidents and the population size of a set of urban areas, and (iii) model the likelihood of suffering an accident in an urban area and its dependence with population size. It is observed that minor and serious accidents are more frequent in urban areas, whereas fatal accidents are more likely in rural areas. It is also shown that, generally, the number of accidents in an urban area depends on population size superlinearly, with this superlinear behaviour becoming stronger for lower degrees of severity. Finally, given an accident in an urban area, the probability that the accident is fatal or serious decreases with population size and the probability that it is minor, increases sublinearly. These findings promote the question as to why such behaviours exist, the answer to which will lead to more sustainable urban policies.
RESUMEN
El estado dippers es un factor de riesgo independiente en los pacientes hipertensos (Risers-R-) Non-dippers-ND-> Dippers-D>Dippers extremos-DE). Se evaluó el efecto de la nueva nifedipina en microgránulos (NMG) una vez al día en la disminución de la presión arterial nocturna medida a través del MAPA con Mobil-o-Graph-CE0434-(I.E.MGmbh-Cockerillstr. 69 D-Stolberg. Germany). Se incluyeron pacientes hipertensos (PAS mayor igual 140 y/o PAD mayor igual 90 mmHg, medidas con esfigmomanómetro de Hg) que recibieron de 30 a 60 mgrs/día de NMG, en un estudio prospectivo abierto comparativo y cruzado en time-doses 8 am ó 8 pm; que luego de 6 semanas de tratamiento mantuvieran PAS < 140 mmHg. Se reclutaron 73 pacientes. 40 pacientes (54.8 por ciento), mantuvieron su estado: NDn = 22 (disminución de la PAS nocturna entre 0 y 10 por ciento), D n= 16 (disminución de PAS nocturna entre 10 y 20 por ciento) y Rn = 2 (incremento de la PAS nocturna). Los otros 33 pacientes (45.2 por ciento) modificaron su estado: cinco: 3D y 2ND cambiaron a DE (disminución de la PAS nocturna > 20 por ciento), once: 2DE y 9ND se transformaron en D, catorce: 6R, 1DE y 7D hacia ND y 3D cambiaron a R. No hubo diferencias significativas en el cambio de estado dippers en ambos grupos (30 ó 60 mgrs), 17 pacientes mejoraron su estado (9ND y 2DE) se transformaron en D y 6R pasaron a ND; 16 pacientes dipper se mantuvieron. Estos resultados sugieren que la NMG ofrece en el 45 por ciento de los pacientes estudiados un beneficio independiente de la reducción de la presión arterial, manteniendo o mejorando el estado dippers ofreciendo una mejor predicción en la disminución de eventos cardiovasculares y del pronóstico de los accidentes cerebrovasculares
Asunto(s)
Humanos , Masculino , Femenino , Hipertensión/complicaciones , Hipertensión/terapia , Nifedipino , Presión Sanguínea , Farmacología , Terapéutica , VenezuelaRESUMEN
Bryostatin-1 (Bryo-1), a protein kinase C modulator with antineoplastic activity, may exert some of its antitumor activity through activation of the immune response. Studies in tumor-bearing hosts have indicated that the T cell response, particularly IFN-gamma production, is impaired. To evaluate whether Bryo-1 plus IL-2 may affect the activation pattern of T cells, we investigated the expression of IFN-gamma mRNA and protein in human primary T cells. Northern blot analysis and ELISAs demonstrated that Bryo-1 and IL-2 synergized to induce both IFN-gamma mRNA and protein expression. This synergistic induction was seen within 3 h of treatment and with as little as 10 U/ml IL-2 and 1.0 ng/ml Bryo-1. In vitro transcription assays revealed that Bryo-1 plus IL-2 induced transcriptional activation of the IFN-gamma gene. Furthermore, mRNA stability studies indicated that this treatment also enhanced the IFN-gamma mRNA half-life. Both CD4(+) and CD8(+) T cells responded to the treatment with IFN-gamma expression. The induction of the IFN-gamma expression was decreased by a specific p38 mitogen-activated protein kinase inhibitor, but not by a protein kinase C inhibitor. Our results demonstrate for the first time that Bryo-1 in combination with IL-2 control IFN-gamma gene expression at both the transcriptional and post-transcriptional levels through a p38 mitogen-activated protein kinase-dependent process. Given the pivotal role that IFN-gamma plays in the orchestration of an effective Th1 type of response, our results suggest that Bryo-1 plus IL-2 may be a valuable combined therapy for cancer treatment.
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Interferón gamma/biosíntesis , Interleucina-2/farmacología , Lactonas/farmacología , Neoplasias/tratamiento farmacológico , Linfocitos T/efectos de los fármacos , Brioestatinas , Cicloheximida/farmacología , Dexametasona/farmacología , Sinergismo Farmacológico , Humanos , Interferón gamma/genética , Interleucina-13/biosíntesis , Interleucina-2/administración & dosificación , Interleucina-4/biosíntesis , Lactonas/administración & dosificación , Macrólidos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/fisiología , Neoplasias/inmunología , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/fisiología , ARN Mensajero/análisis , Linfocitos T/metabolismo , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
The activating properties of IL-2 and the structure of the IL-2R on human monocytes are well characterized. However, relatively little is known about the biochemical mechanisms involved in IL-2 signal transduction in these cells. We investigated the role of protein tyrosine kinases (PTKs) in the activation of monocytes by IL-2. Incubation of monocytes with the PTK inhibitor herbimycin A (HA) resulted in the dose-dependent suppression of IL-2-induced monocyte tumoricidal activity. This inhibition was rather potent, as a concentration of HA as low as 0.5 microM caused a complete abrogation of cytolytic activity. Furthermore, HA markedly suppressed the ability of IL-2 to induce IL-1 beta, TNF-alpha, IL-6, and IL-8 mRNA expression and protein secretion by monocytes. Anti-phosphotyrosine immunoblotting demonstrated that IL-2 induced a rapid and time-dependent increase in tyrosine phosphorylation of several cellular proteins of molecular masses ranging from 35 to 180 kDa. Interestingly, IL-2 caused a significant up-regulation of the constitutive levels of hck PTK mRNA and protein relative to medium-treated cells as well as an increase in p59hck tyrosine phosphorylation. Finally, we demonstrated by in vitro kinase assay that the specific activity of p59hck PTK was also induced by IL-2 in monocytes. Thus, these data show that the activation of PTKs is required for the triggering of monocyte effector and secretory functions by IL-2 and strongly suggest that p59hck is a key participant in IL-2 signaling in human monocytes.
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Interleucina-2/fisiología , Activación de Linfocitos/inmunología , Monocitos/inmunología , Monocitos/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal/inmunología , Antibióticos Antineoplásicos/farmacología , Benzoquinonas , Células Cultivadas , Citocinas/antagonistas & inhibidores , Citocinas/biosíntesis , Células HT29 , Humanos , Inflamación/inmunología , Inflamación/prevención & control , Interleucina-2/farmacología , Interfase/inmunología , Janus Quinasa 1 , Janus Quinasa 3 , Lactamas Macrocíclicas , Activación de Macrófagos/efectos de los fármacos , Activación de Macrófagos/inmunología , Monocitos/efectos de los fármacos , Monocitos/enzimología , Fosforilación , Fosfotirosina/metabolismo , Proteínas Tirosina Quinasas/biosíntesis , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/fisiología , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-hck , Quinonas/farmacología , ARN Mensajero/biosíntesis , Rifabutina/análogos & derivados , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología , Familia-src Quinasas/biosíntesis , Familia-src Quinasas/genéticaRESUMEN
BACKGROUND: The mechanisms that determine chronic left ventricular dysfunction in coronary artery disease (in particular, critical reductions in coronary artery blood flow leading to hibernating myocardium) may affect the ability of the myocardium to respond to inotropic stimulation with dobutamine. This study was designed to investigate the relationship between resting myocardial blood flow and contractile reserve in patients with coronary artery disease and chronic left ventricular dysfunction. METHODS AND RESULTS: Twenty-three patients (21 men and 2 women; age 61 +/- 9 years) underwent transesophageal echocardiography during infusion of dobutamine (2.5 microg/kg to 40 microg/kg per minute) and positron emission tomography (PET) with 150-water (9 patients) or 13N-ammonia (14 patients). Systolic wall thickening at each dose of dobutamine and resting myocardial blood flow were quantitatively analyzed in 8 anatomically matched regions at mid-ventricular level. Myocardial regions with preserved contraction had higher blood flow compared with regions with basal dyssynergy (0.99 +/- 0.3 vs 0.65 +/- 0.3 mL/min/gm; P < .0001). Among myocardial regions with preserved resting contraction, no relation was observed between blood flow and the response to dobutamine (r = 0.06). In contrast, among myocardial regions with diminished resting contraction, a significant correlation was observed between resting blood flow and contractile reserve (r = 0.53; P < .0001). The maximum increase in percent systolic wall thickening with dobutamine was 32.8% +/- 14% in regions with normal blood flow, 21.5% +/- 17% in regions with mildly to moderately reduced blood flow, and 10.7% +/- 10% in regions with severely reduced blood flow (P < .0001). CONCLUSIONS: These findings emphasize the importance of resting myocardial blood flow for the preservation of contractile reserve in patients with coronary artery disease and left ventricular dysfunction. Because a positive inotropic response to dobutamine is more likely to occur in dyssynergic regions with preserved rather than reduced myocardial blood flow, regional perfusion may determine in which circumstances dobutamine echocardiography contributes to the assessment of myocardial viability.
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Circulación Coronaria , Enfermedad Coronaria/fisiopatología , Contracción Miocárdica , Disfunción Ventricular Izquierda/fisiopatología , Enfermedad Crónica , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/diagnóstico por imagen , Dobutamina , Ecocardiografía Transesofágica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Descanso , Estimulación Química , Tomografía Computarizada de Emisión , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/diagnóstico por imagenRESUMEN
B7-2 is a costimulatory molecule expressed on professional antigen-presenting cells that provides T cells with a critical signal resulting in T-cell activation. Interferon-gamma (IFN-gamma) enhances B7-2 protein expression in monocytic cells. However, the molecular mechanisms controlling the enhanced expression of B7-2 are poorly understood. Northern blot and flow cytometry analysis revealed that human monocytes and the human monocytic cell line MonoMac6 (MM6) constitutively expressed B7-2 mRNA and protein and IFN-gamma treatment further enhanced the expression of both molecules. The ability of IFN-gamma to enhance B7-2 mRNA was evident at the dose of 31 U/mL and reached plateau levels at 500 U/mL. The effects of IFN-gamma on B7-2 mRNA expression were time dependent and occurred within 3 hours of treatment and increased through 24 hours. In vitro transcription assays and mRNA stability experiments showed that IFN-gamma increases both transcriptional activity and the stability of B7-2 mRNA. Treatment of MM6 cells with cycloheximide showed that de novo protein synthesis was not required for the IFN-gamma-enhanced expression of B7-2 mRNA. Overall, these studies show for the first time that IFN-gamma-enhanced expression of B7-2 protein in human monocytic cells is controlled at the gene level through a dual mechanism involving transcriptional and posttranscriptional mechanisms.
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Antígenos CD/biosíntesis , Antivirales/farmacología , Interferón gamma/farmacología , Glicoproteínas de Membrana/biosíntesis , Monocitos/fisiología , Antígenos CD/genética , Antígeno B7-2 , Células Cultivadas , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Glicoproteínas de Membrana/genética , Procesamiento Postranscripcional del ARN/efectos de los fármacos , Transcripción GenéticaRESUMEN
The pore-forming protein perforin is preferentially expressed in NK and cytotoxic T cells. To investigate the molecular regulation of human perforin gene transcription, the activity of the human perforin promoter was analyzed in human NK and T cell lines using various promoter fragments linked to a luciferase reporter gene. A core promoter was identified within 55 bp upstream of the transcription start site. This promoter region contains a guanine/cytosine box and has basal activity in YT, Kit225-k6, and Jurkat cells. A strong enhancer activity was identified between positions -1136 and -1076, a region that includes a STAT-like element. This enhancer region was active in YT cells, which have constitutive perforin expression and activated STAT3 protein, but not in Kit225-k6 or Jurkat cells, which do not have constitutive perforin expression. Mutation of the STAT binding site resulted in a dramatic down-regulation of promoter activity. Electrophoretic mobility shift assays, using a probe containing the STAT element of the perforin promoter, indicated that this element can bind STAT3 from YT cells. Moreover, the STAT element was shown to bind STAT5a/b induced by IL-2 as well as STAT1alpha induced by IL-6 in human NK cells. Together, these results suggest that STAT proteins play a key role in perforin gene transcription and provide a model by which cytokines can regulate perforin gene expression.
Asunto(s)
Proteínas de Unión al ADN/fisiología , Glicoproteínas de Membrana/genética , Proteínas de la Leche , Regiones Promotoras Genéticas , Transactivadores/fisiología , Sitios de Unión , Línea Celular , Elementos de Facilitación Genéticos , Regulación de la Expresión Génica , Humanos , Perforina , Proteínas Citotóxicas Formadoras de Poros , Factor de Transcripción STAT3 , Factor de Transcripción STAT5 , Activación Transcripcional , Proteínas Supresoras de TumorRESUMEN
Coronary artery endothelial dysfunction has been proposed as a cause of myocardial ischemia and symptoms in patients with angina-like chest pain despite normal coronary angiograms, especially those with ischemic-appearing ST-segment depression during exercise (syndrome X). We measured coronary vasomotor responses to acetylcholine (3 to 300 microg/min) in 42 patients (27 women and 15 men) with effort chest pain and normal coronary angiograms who also had normal electrocardiograms and echocardiograms at rest. All patients underwent treadmill exercise testing and measurement of systolic wall thickening responses to dobutamine (40 microg/kg/min) during transesophageal echocardiography. There were no differences in the acetylcholine-stimulated epicardial coronary diameter (+5+/-13% vs +1+/-13%, p=0.386) and flow (+179+/-90% vs +169+/-96%, p=0.756), or in the systolic wall thickening responses (+134+/-65% vs +118+/-57%, p=0.445) from baseline values in the 12 syndrome X patients compared with the 30 patients with negative exercise test results. In patients in the lowest quartile of coronary flow responses to acetylcholine, dobutamine increased systolic wall thickening by 121+/-73%; 3 had ischemic-appearing ST-segment depression during this stress. This contractile response to dobutamine was no different than the increase in systolic wall thickening (129+/-48%, p=0.777) in patients in the highest quartile of coronary flow responses, 3 of whom also had ischemic-appearing ST-segment depression during this stress. Thus, coronary endothelial dysfunction in the absence of coronary artery disease does not account for ischemic-appearing ST-segment depression in patients with chest pain despite normal coronary angiograms. Further, coronary endothelial dysfunction is not associated with myocardial contractile responses to stress consistent with myocardial ischemia.
Asunto(s)
Vasos Coronarios/fisiopatología , Electrocardiografía , Endotelio Vascular/fisiopatología , Función Ventricular Izquierda/fisiología , Acetilcolina , Adulto , Velocidad del Flujo Sanguíneo , Cardiotónicos , Angiografía Coronaria , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/efectos de los fármacos , Dobutamina , Ecocardiografía Transesofágica , Endotelio Vascular/diagnóstico por imagen , Endotelio Vascular/efectos de los fármacos , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Angina Microvascular/diagnóstico por imagen , Angina Microvascular/fisiopatología , Contracción MiocárdicaRESUMEN
Gender bias favoring female resistance to picornavirus disease is not seen in ICR Swiss mice following infection with the MM strain of encephalomyocarditis virus (EMCV) (causing encephalitis and death) as it is with D variant of EMCV (causing diabetes in males). To define this difference, an in vitro virus-infected splenocyte culture system was used to explore virus effects on lymphoid cells. Infected and sham-infected splenocyte cultures, prepared from both genders of mice and infected with either virus variant, were examined for immunoregulatory cytokines in the first 24 h of infection using ELISA or bioassays. Disease resistance was associated with increased levels of interferon-y (IFN-gamma) and undetectable levels of interleukin-10 (IL-10) by 12 h postinfection in splenocytes from ICR Swiss females infected with EMCV-D. Disease susceptibility was associated with high levels of IL-10 at 12 h after infection of spleen cells from ICR Swiss males infected with EMCV-D or from both genders infected with EMCV-MM. This information was used to protect susceptible mice against picornavirus disease (either diabetes or death) by giving them an inducer of IFN-alpha/beta, to induce natural killer (NK)-like cells to produce high levels of IFN-gamma and rat monoclonal anti-IL-10 to neutralize the effects of mouse IL-10.
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Adyuvantes Inmunológicos/biosíntesis , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Infecciones por Picornaviridae/metabolismo , Animales , Células Cultivadas , Diabetes Mellitus Experimental/prevención & control , Femenino , Predisposición Genética a la Enfermedad , Antígenos de Histocompatibilidad Clase II/biosíntesis , Inductores de Interferón/uso terapéutico , Masculino , Ratones , Ratones Endogámicos ICR , Infecciones por Picornaviridae/genética , Poli I-C/uso terapéutico , Bazo/citología , Bazo/efectos de los fármacos , Bazo/metabolismo , Factores de TiempoRESUMEN
Forty-four patients with coronary artery disease and left ventricular dysfunction underwent transesophageal echocardiography with dobutamine infusion to investigate the relation between basal contractile function and inotropic reserve. No significant relation was observed between basal percent systolic thickening or diastolic thickness and the maximum increase in contractile function in response to dobutamine, thus emphasizing the heterogenity of the mechanisms by which coronary stenoses may affect contraction at rest and inotropic reserve in these patients.
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Cardiotónicos/farmacología , Enfermedad Coronaria/fisiopatología , Dobutamina/farmacología , Contracción Miocárdica/efectos de los fármacos , Miocardio/patología , Disfunción Ventricular Izquierda/fisiopatología , Anciano , Enfermedad Crónica , Enfermedad Coronaria/complicaciones , Ecocardiografía Transesofágica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sístole , Disfunción Ventricular Izquierda/complicacionesRESUMEN
Se evaluaron 4500 historias de pacientes a los que se les realizó recto-sigmoidoscopia en la unidad de Endoscopia del Hospital de Clínicas Caracas como parte de una evaluación médica preventiva entre Julio de 1995 y Abril de 1997. Se examina la incidencia de algunas patologías colorectales, como la presencia de pólipos, divertículos, entre otras, así como su relación con la edad y el sexo de los pacientes. En este estudio se demuestra que la recto
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Humanos , Masculino , Femenino , Medicina Preventiva , Recto , Sigmoidoscopía , VenezuelaRESUMEN
Interleukin (IL)-4 is an immunomodulatory cytokine produced by a number of cell types including T cells, basophils, and mast cells. This pleiotropic cytokine has a number of immunoregulatory functions; however, the molecular mechanisms controlling the transcription of this gene are not yet completely understood. Several studies have implicated a possible autoregulatory mechanism for its own expression. Here, we have identified a Stat-6-responsive element (Stat-6RE) in the promoter of the human IL-4 gene. Utilizing electrophoretic mobility shift analysis, we have demonstrated the presence of two specific IL-4-responsive DNA-protein complexes in nuclear extracts of both human Th1 and Th2 clones. Phytohemagglutinin-blasted peripheral blood T cells also generated an inducible complex in response to stimulation with IL-4 and the IL-4-like cytokine IL-13. Transient transfection of the murine pre-B cell line BA/F3 stably transfected with the full-length human IL-4 receptor alpha chain demonstrated the ability of multicopy Stat-6RE to initiate transcription from a heterologous promoter upon IL-4 or IL-13 stimulation. These results indicate a possible autocrine mechanism for the regulation of IL-4 gene transcription through the Stat-6RE as well as a possible mechanism for IL-13 regulation of the human IL-4 promoter.
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Interleucina-4/genética , Regiones Promotoras Genéticas , Transactivadores/genética , Animales , Secuencia de Bases , Línea Celular , Cloranfenicol O-Acetiltransferasa/genética , Regulación de la Expresión Génica , Genes Reporteros , Humanos , Interleucina-13/farmacología , Interleucina-4/farmacología , Ratones , Oligodesoxirribonucleótidos/genética , Factor de Transcripción STAT6 , Transducción de Señal , Células TH1/inmunología , Células Th2/inmunología , TransfecciónRESUMEN
OBJECTIVES: The present study sought to determine whether myocardial contractile abnormalities accompany the development of chest pain in patients with normal coronary angiograms. BACKGROUND: The mechanism of chest pain in patients with angina despite a normal coronary arteriogram is controversial. Although previous studies postulated the existence of coronary microvascular dysfunction, others failed to find evidence of myocardial ischemia, and recent studies have demonstrated abnormal cardiac sensitivity in these patients that can lead to chest pain on a nonischemic basis. METHODS: Seventy patients (26 men and 44 women, mean age 49 +/- 10 years) with angina-like chest pain and angiographically normal coronary arteries underwent exercise treadmill testing, radionuclide angiography at rest and during exercise, thallium stress testing and transesophageal dobutamine stress echocardiography. The results of exercise treadmill testing and stress echocardiography were compared with those obtained in 26 normal control subjects (19 men and 7 women, mean age 56 +/- 7 years). RESULTS: Abnormalities consistent with myocardial ischemia were noted in 31% of the patients during exercise treadmill testing, in 16% during exercise radionuclide angiography and in 18% during thallium stress testing. The findings of the radionuclide studies were not concordant with one another and were not related to the presence of repolarization changes during exercise testing. During infusion of dobutamine, chest pain developed in 59 patients (84%) and in none of the control subjects (p < 0.0001); repolarization changes occurred in 22 patients (34%) and in 2 control subjects (8%) (p < 0.04). None of the patients or the control subjects developed regional wall motion abnormalities with dobutamine. The quantitative myocardial contractile response to dobutamine was similar in patients and control subjects, with an 80% power to detect a 25% difference in systolic wall thickening at the maximal dose of dobutamine. CONCLUSIONS: There was no agreement in the results of noninvasive tests in our patients. Despite the frequent provocation of chest pain and electrocardiographic abnormalities with dobutamine, the patients demonstrated a quantitatively normal myocardial contractile response without development of wall motion abnormalities. These observations strongly suggest that myocardial ischemia is not the cause of chest pain in patients with a normal coronary arteriogram.
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Dolor en el Pecho/fisiopatología , Angiografía Coronaria , Ecocardiografía Transesofágica , Contracción Miocárdica , Adulto , Anciano , Cardiotónicos , Dolor en el Pecho/etiología , Dobutamina , Electrocardiografía , Prueba de Esfuerzo , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Stress echocardiography has become an accepted methodology for the evaluation of coronary artery disease. One potential advantage of dobutamine over other stressors used with echocardiography is the possibility of assessing the ischemic threshold. However, whether this measurement correlates with indices associated with adverse outcome has not been established. METHODS AND RESULTS: One hundred four patients (91 men and 13 women; age, 61 +/- 9 years) with coronary artery disease were studied with transesophageal echocardiography during infusion of dobutamine 2.5 to 40 microgram/kg per minute. When regional dyssnergy developed, the dobutamine ischemic threshold (the dose of dobutamine at which induced regional wall motion abnormalities were first detected) was identified. The dobutamine stress echocardiogram was abnormal in 90 patients (sensitivity, 87%). The dobutamine ischemic threshold was 25.4 +/- 11.2 micrograms/kg per minute in patients with single-vessel disease, 14.4 +/- 7.9 in patients with two-vessel disease, and 9.1 +/- 7.9 in patients with three-vessel disease (P < .0001). The dobutamine ischemic threshold correlated with the ejection fraction response to exercise measured by radionuclide angiography: Patients with low ischemic threshold had a mean fall in ejection fraction, and patients with high ischemic threshold or normal tests had a mean increase in ejection fraction. CONCLUSIONS: In patients with coronary artery disease, the ischemic threshold measured during dobutamine stress echocardiography correlates with both the number of stenosed vessels and the left ventricular ejection fraction response to exercise. Because these variables are associated with poor prognosis, these findings provide further support regarding the utility of dobutamine stress echocardiography in the clinical evaluation of patients with chronic coronary artery disease.
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Cardiotónicos , Enfermedad Coronaria/diagnóstico por imagen , Dobutamina , Ecocardiografía Transesofágica , Angiografía Coronaria , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/fisiopatología , Prueba de Esfuerzo , Femenino , Imagen de Acumulación Sanguínea de Compuerta , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/fisiopatología , Variaciones Dependientes del Observador , Pronóstico , Sensibilidad y Especificidad , Volumen Sistólico/fisiologíaRESUMEN
BACKGROUND: Both thallium scintigraphy and dobutamine echocardiography have been used to assess myocardial viability. However, thallium uptake and the inotropic response to dobutamine are expressions of different cellular phenomena. The present study was undertaken to investigate the relation between the two methods in patients with chronic coronary artery disease and left ventricular dysfunction to derive insights into the mechanisms related to myocyte viability. METHODS AND RESULTS: Thirty patients (28 men and 2 women; age, 59 +/- 10 years) with chronic coronary artery disease and impaired left ventricular systolic function at rest (mean ejection fraction, 32 +/- 9%) were included in the study. Patients underwent transesophageal echocardiography during incremental doses of dobutamine from 2.5 to a maximum of 40 micrograms.kg-1.min-1 and single photon emission computed tomographic thallium scintigraphy using a stress-redistribution-reinjection protocol. The left ventricle was divided into 16 segments for analysis of echocardiographic and thallium images. Segmental myocardial contractile function was graded as normal, hypokinesis, akinesis, or dyskinesis at each incremental dose of dobutamine. Thallium uptake in each myocardial segment was graded on a 5-point scale from 0 (absent) to 2 (normal) for each of the stress, redistribution, and reinjection images. A segment was considered viable if the assigned thallium score was 1 or higher (normal uptake or only mild to moderate defect) in any of the stress, redistribution, or reinjection images. Among 472 myocardial segments available for analysis, 311 had resting wall motion abnormalities, of which 56% (173/311) showed contractile improvement with dobutamine (usually first observed at < or = 10 micrograms.kg-1.min-1) and 84% (262/311) were considered viable by thallium scintigraphy (P < .0001). Of the 262 segments considered viable by thallium, 167 (64%) had a contractile improvement with dobutamine; in contrast, only 6 of the 49 segments (12%) considered nonviable by thallium had a positive dobutamine response (P < .0001). Furthermore, a positive inotropic response to dobutamine was significantly related to the magnitude of thallium uptake: the proportion of segments with a positive dobutamine response rose with increasing magnitude of thallium uptake (P < .001). The disagreement between the two tests was related primarily to segments considered viable by thallium that did not show contractile improvement with dobutamine. CONCLUSIONS: These findings demonstrate the existence of a relation between thallium uptake and the inotropic response to dobutamine in patients with chronic coronary artery disease and left ventricular dysfunction. However, the proportion of segments showing a positive response to dobutamine is significantly lower than those with thallium uptake, suggesting that the cellular mechanisms responsible for a positive inotropic response to adrenergic stimulation require a higher degree of myocyte functional integrity than those responsible for thallium uptake.
Asunto(s)
Enfermedad Coronaria/diagnóstico , Dobutamina , Ecocardiografía Transesofágica , Corazón/diagnóstico por imagen , Contracción Miocárdica/efectos de los fármacos , Radioisótopos de Talio , Tomografía Computarizada de Emisión de Fotón Único , Disfunción Ventricular Izquierda/diagnóstico , Enfermedad Coronaria/fisiopatología , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Contracción Miocárdica/fisiología , Estimulación Química , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
BACKGROUND: We previously reported that 6 to 12 weeks of dual-chamber (DDD) pacing results in clinical and hemodynamic improvement in obstructive hypertrophic cardiomyopathy (HCM). This study examines the long-term results of DDD pacing in obstructive HCM. METHODS AND RESULTS: DDD devices were implanted in 84 patients (mean age, 49 +/- 16 years) with obstructive HCM and severe drug-refractory symptoms. At a mean follow-up of 2.3 +/- 0.8 years (maximum, 3.5 years), the New York Heart Association (NYHA) functional class had improved significantly (1.6 +/- 0.6 versus 3.2 +/- 0.5, P < .00001). Symptoms were eliminated in 28 patients (33%), improved in 47 patients (56%), but remained unchanged in 7 patients (8%). Two patients died suddenly (97% cumulative 3-year survival rate). In 74 patients with significant left ventricular outflow tract (LVOT) obstruction at rest, the LVOT gradients were significantly reduced at follow-up (27 +/- 31 versus 96 +/- 41 mm Hg, P < .00001). Symptoms and provokable LVOT gradients were also reduced in all 10 patients without significant resting but with provokable LVOT obstruction. Persistence of the LVOT obstruction and symptoms was attributed to inability to pre-excite the interventricular septum (n = 8) and onset of atrial fibrillation (n = 7). Fifty patients had two cardiac catheterization evaluations, 3 +/- 1 and 16 +/- 4 months after implantation of a pacemaker. In this subgroup, the NYHA functional class improved from 3.2 +/- 0.5 at baseline to 1.8 +/- 0.7 at the initial evaluation (P < .00001), but with a further significant improvement at the second evaluation: 1.4 +/- 0.6, P < .001. This symptomatic improvement was associated with progressive reduction of LVOT gradient at the two evaluations: baseline, 100 +/- 47 mm Hg; first evaluation, 41 +/- 36 mm Hg (P < .0001); and second evaluation, 29 +/- 34 mm Hg (P < .01). Despite the presence of left bundle branch block, DDD pacing reduced LVOT obstruction significantly in 15 patients (LVOT gradient, baseline 89 +/- 36 mm Hg versus 18 +/- 26 mm Hg at follow-up, P < .0001). There was a weak but significant correlation between the reduction in LVOT gradients accomplished by AV pacing before implantation of DDD device and the eventual reduction in LVOT gradients recorded at the follow-up evaluation (r = .38, P = .0017). Echocardiography demonstrated significant thinning of the anterior septum and distal anterior LV wall in the absence of deterioration of LV systolic function. CONCLUSIONS: (1) Although most of the improvement of symptoms and hemodynamic indexes occurs during the first few months of DDD pacing, further changes are often observed a year later; (2) DDD pacing is associated with an excellent prognosis in a subgroup of severely disabled patients, many of whom present with syncope or presyncope; (3) baseline pacing studies are not essential to identify patients who may benefit from pacing; (4) preexisting left bundle branch block is compatible with severe LVOT obstruction, and DDD pacing is also beneficial in this subgroup; (5) DDD pacing reduces both resting and provokable LVOT obstruction; (6) additional therapy, for example, radiofrequency ablation of the AV node, may be necessary in some patients either to preexcite the interventricular septum or to control atrial fibrillation; and (7) although LV hypertrophy has been considered a primary feature of HCM, pacing appears to reverse LV wall thickness in a significant subset of adult HCM patients.
Asunto(s)
Estimulación Cardíaca Artificial/métodos , Cardiomiopatía Hipertrófica/fisiopatología , Cardiomiopatía Hipertrófica/terapia , Hemodinámica , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/terapia , Adolescente , Adulto , Anciano , Niño , Ecocardiografía , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Marcapaso Artificial , Pronóstico , Programas Informáticos , Disfunción Ventricular Izquierda/fisiopatología , Obstrucción del Flujo Ventricular Externo/fisiopatologíaRESUMEN
OBJECTIVES: The present study was undertaken to determine the safety, feasibility and diagnostic accuracy of transesophageal dobutamine stress echocardiography for the evaluation of patients with known or suspected coronary artery disease. BACKGROUND: Dobutamine stress echocardiography has proved to be a valuable method for detecting and prognosticating ischemic heart disease. In addition, it may provide accurate information about myocardial viability in patients with systolic dysfunction. However, in some patients the technique may be limited by poor myocardial imaging with the conventional transthoracic approach. METHODS: Seventy-six patients (62 men, 14 women; mean age +/- SD 60 +/- 10 years) who underwent coronary angiography were included in the study. Transesophageal stress echocardiograms were performed after withdrawal of antianginal medications for > or = 48 h. Dobutamine was infused at a starting dose of 2.5 micrograms/kg body weight per min and was increased by 5-micrograms/kg per min increments every 5 min to a maximum of 40 micrograms/kg per min. Two-dimensional views were acquired at each stage and digitized for subsequent analysis. The left ventricle was divided into 16 segments, and each segment was assigned to a major coronary artery with the use of a model of regional distribution of coronary perfusion. RESULTS: Sixty-two of the 76 patients had angiographic evidence of coronary artery disease. New or worsening regional wall motion abnormalities developed during dobutamine infusion in 55 of these 62 patients and in none of the 14 patients with normal coronary arteries (sensitivity 89%, specificity 100%, overall accuracy 91%). Regional wall motion abnormalities in the distribution of more than one major coronary artery were seen in 3 of the 25 patients with single-vessel coronary artery disease and in 30 of the 37 patients with multivessel disease (p < 0.0001). The test was successfully completed in 73 (96%) of the 76 patients; it was discontinued in the remaining 3 patients because of intolerance to the probe. No major complications occurred in any patient. Minor complications developed in seven patients but did not affect the diagnostic accuracy of the test. CONCLUSIONS: Transesophageal dobutamine stress echocardiography is a safe, feasible and accurate method for assessing coronary artery disease. Its use should be considered in patients who have a suboptimal ultrasound window, and it provides an excellent tool for clinical investigations based on ultrasound imaging of the myocardium.
Asunto(s)
Enfermedad Coronaria/diagnóstico por imagen , Dobutamina , Ecocardiografía Transesofágica/métodos , Angiografía Coronaria , Enfermedad Coronaria/epidemiología , Prueba de Esfuerzo , Estudios de Factibilidad , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Disfunción Ventricular Izquierda/diagnóstico por imagenRESUMEN
In severe heart failure many deaths are sudden and are presumed to be due to ventricular arrhythmias. The GESICA trial evaluated the effect of low-dose amiodarone on two-year mortality in patients with severe heart failure. Our prospective multicentre trial included 516 patients on optimal standard treatment for heart failure. Patients were randomised to 300 mg/day amiodarone (260) or to standard treatment (256). Intention-to-treat analysis showed 87 deaths in the amiodarone group (33.5%) compared with 106 in the control group (41.4%) (risk reduction 28%; 95% CI 4%-45%; log rank test p = 0.024). There were reductions in both sudden death (risk reduction 27%; p = 0.16) and death due to progressive heart failure (risk reduction 23%; p = 0.16). Fewer patients in the amiodarone group died or were admitted to hospital due to worsening heart failure (119 versus 149 in the control group; risk reduction 31%; 95% CI 13-46%; p = 0.0024). The decrease in mortality and hospital admission was present in all subgroups examined and independent of the presence of non-sustained ventricular tachycardia. Side-effects were reported in 17 patients (6.1%); amiodarone was withdrawn in 12. Low-dose amiodarone proved to be an effective and reliable treatment, reducing mortality and hospital admission in patients with severe heart failure independently of the presence of complex ventricular arrhythmias.
Asunto(s)
Amiodarona/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Amiodarona/efectos adversos , Amiodarona/farmacocinética , Muerte Súbita Cardíaca/etiología , Femenino , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de RiesgoRESUMEN
Splenocyte cultures from female ICR Swiss mice produced greater interferon (IFN) levels, particularly IFN-gamma, than did cultures from males by 12 h post-infection (pi) with the D variant of encephalomyocarditis virus (EMCV-D). This early IFN-gamma is produced by natural killer (NK)-like cells and is dependent on plastic adherent cells and IFN-alpha/beta. In this study, we evaluated the significance of this observation on the innate resistance of ICR Swiss females to EMCV-D-mediated disease. Treatment of females with rabbit anti-mouse IFN-alpha/beta serum rendered them susceptible to the diabetogenicity of EMCV-D. Although sera from both sexes of ICR Swiss mice exhibited peak IFN levels day 3 pi, IFN-gamma was present in the sera of males at only 1 day pi and in the sera of females at days 1-3 pi. Females cleared virus from the circulation by day 2 pi, 1 day earlier than did males. Flow cytometric evaluations of lymphoid cell phenotypes in spleens and pancreata of infected mice revealed that percentages of L3T4+ cells were significantly decreased only in spleens from males at day 1 pi and were diminished along with Ly2+ cells in pancreata of males at 7 days pi, suggesting that T-cell responses were impaired in virus-infected males.