RESUMEN
Ancient DNA is transforming our ability to reconstruct historical patterns and mechanisms shaping modern diversity and distributions. In particular, molecular data from extinct Holocene island faunas have revealed surprising biogeographic scenarios. Here, we recovered partial mitochondrial (mt) genomes for 1300-1400 year old specimens (n = 2) of the extinct "horned" crocodile, Voay robustus, collected from Holocene deposits in southwestern Madagascar. Phylogenetic analyses of partial mt genomes and tip-dated timetrees based on molecular, fossil, and stratigraphic data favor a sister group relationship between Voay and Crocodylus (true crocodiles). These well supported trees conflict with recent morphological systematic work that has consistently placed Voay within Osteolaeminae (dwarf crocodiles and kin) and provide evidence for likely homoplasy in crocodylian cranial anatomy and snout shape. The close relationship between Voay and Crocodylus lends additional context for understanding the biogeographic origins of these genera and refines competing hypotheses for the recent extinction of Voay from Madagascar.
Asunto(s)
Caimanes y Cocodrilos/genética , Evolución Biológica , ADN Antiguo/análisis , Extinción Biológica , Fósiles , Genómica/métodos , Animales , Madagascar , Paleontología , FilogeniaRESUMEN
PURPOSE: Vulnerable atherosclerotic plaques are structurally weak and prone to rupture, presumably due to local oxidative stress. Redox active iron is linked to oxidative stress and the aim of this study was to investigate the distribution of Fe(III) in carotid plaques and its relation to vulnerability for rupture. METHODS: Atherosclerotic plaques from 10 patients (three asymptomatic and seven symptomatic) were investigated. Plaque vulnerability was classified using ultrasound and immunohistochemistry and correlated to Fe(III) measured by electron paramagnetic resonance spectroscopy. RESULTS: Large intra-plaque Fe(III) variations were found. Plaques from symptomatic patients had a higher Fe(III) concentration as compared with asymptomatic plaques (0.36 ± 0.21 vs. 0.06 ± 0.04 nmol Fe(III)/mg tissue, P < 0.05, in sections adjoining narrowest part of the plaques). All but one plaque from symptomatic patients showed signs of cap rupture. No plaque from asymptomatic patients showed signs of cap rupture. There was a significant increase in cap macrophages in plaques from symptomatic patients compared with asymptomatic patients (31 ± 11% vs. 2.3 ± 2.3%, P < 0.01). CONCLUSION: Fe(III) distribution varies substantially within atherosclerotic plaques. Plaques from symptomatic patients had significantly higher concentrations of Fe(III), signs of cap rupture and increased cap macrophage activity.
Asunto(s)
Aterosclerosis/diagnóstico , Aterosclerosis/metabolismo , Estenosis Carotídea/diagnóstico , Estenosis Carotídea/metabolismo , Espectroscopía de Resonancia por Spin del Electrón/métodos , Hierro/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Distribución Tisular , Ultrasonografía/métodosRESUMEN
Shared behavioural, morphological and physiological characteristics are indicative of the evolution of extant birds from nonavian maniraptoran dinosaurs. One such shared character is the presence of uncinate processes and respiratory structures in extant birds. Recent research has suggested a respiratory role for these processes found in oviraptorid and dromaeosaurid dinosaurs. By measuring the geometry of fossil rib cage morphology, we demonstrate that the mechanical advantage, conferred by uncinate processes, for movements of the ribs in the oviraptorid theropod dinosaur, Citipati osmolskae, basal avialan species Zhongjianornis yangi, Confuciusornis sanctus and the more derived ornithurine Yixianornis grabaui, is of the same magnitude as found in extant birds. These skeletal characteristics provide further evidence of a flow-through respiratory system in nonavian theropod dinosaurs and basal avialans, and indicate that uncinate processes are a key adaptation facilitating the ventilation of a lung air sac system that diverged earlier than extant birds.
Asunto(s)
Evolución Biológica , Aves/anatomía & histología , Aves/fisiología , Fósiles , Animales , Dinosaurios/anatomía & histología , Dinosaurios/fisiología , Extinción Biológica , Filogenia , RespiraciónRESUMEN
Acetaminophen, a popular analgesic and antipyretic, has been found to be effective against neuronal cell death in in vivo and in vitro models of neurological disorders. Acute neuronal death has been attributed to loss of mitochondrial permeability transition coupled with mitochondrial dysfunction. The potential impact of acetaminophen on acute injury from cerebral ischemia-reperfusion has not been studied. We investigated the effects of acetaminophen on cerebral ischemia-reperfusion-induced injury using a transient global forebrain ischemia model. Male Sprague-Dawley rats received 15mg/kg of acetaminophen intravenously during ischemia induced by hypovolemic hypotension and bilateral common carotid arterial occlusion, which was followed by reperfusion. Acetaminophen reduced tissue damage, degree of mitochondrial swelling, and loss of mitochondrial membrane potential. Acetaminophen maintained mitochondrial cytochrome c content and reduced activation of caspase-9 and incidence of apoptosis. Our data show that acetaminophen reduces apoptosis via a mitochondrial-mediated mechanism in an in vivo model of cerebral ischemia-reperfusion. These findings suggest a novel role for acetaminophen as a potential stroke therapeutic.
Asunto(s)
Acetaminofén/farmacología , Isquemia Encefálica/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Daño por Reperfusión/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Enfermedades de las Arterias Carótidas/tratamiento farmacológico , Enfermedades de las Arterias Carótidas/metabolismo , Enfermedades de las Arterias Carótidas/patología , Caspasa 9/metabolismo , Citocromos c/metabolismo , Modelos Animales de Enfermedad , Hipotensión/tratamiento farmacológico , Hipotensión/metabolismo , Hipotensión/patología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Dilatación Mitocondrial/efectos de los fármacos , Dilatación Mitocondrial/fisiología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Factores de TiempoRESUMEN
We examined the expression of interleukin (IL)-1beta, IL-6 and tumour necrosis factor (TNF) alpha in mice lacking microsomal prostaglandin E synthase-1 (mPGES-1), which neither produce prostaglandin E(2), nor mount a febrile response upon immune challenge. Intraperitoneal lipopolysaccharide (LPS) injection resulted in a strongly induced expression of all three cytokines in the brain and viscera, similar to wild-type animals. Several brain regions additionally showed modest induction of receptors for these cytokines in both genotypes. Telemetric recordings of body temperature showed that the mPGES-1 deficient mice remained afebrile upon LPS challenge, in contrast to the prominent fever displayed by the wild-type mice. These data demonstrate that LPS-induced cytokine expression occurs independently of prostaglandin E(2), and imply that endogenously expressed IL-1beta, IL-6, and TNFalpha are not pyrogenic per se, supporting the role of prostaglandin E(2) as the final and obligatory mediator of LPS-induced fever.
Asunto(s)
Encéfalo/metabolismo , Citocinas/metabolismo , Lipopolisacáridos/administración & dosificación , Animales , Temperatura Corporal , Citocinas/genética , Dinoprostona/biosíntesis , Fiebre/metabolismo , Oxidorreductasas Intramoleculares/genética , Oxidorreductasas Intramoleculares/metabolismo , Hígado/metabolismo , Pulmón/metabolismo , Ratones , Ratones Endogámicos DBA , Ratones Noqueados , Prostaglandina-E Sintasas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Vísceras/efectos de los fármacos , Vísceras/metabolismoRESUMEN
During neuronal development, neurons form elaborate dendritic arbors that receive signals from axons. Additional studies are needed to elucidate the factors regulating the establishment of dendritic patterns. Our work explored possible roles played by nitric oxide synthase 1 adaptor protein (NOS1AP; also known as C-terminal PDZ ligand of neuronal nitric oxide synthase or CAPON) in dendritic patterning of cultured hippocampal neurons. Here we report that the long isoform of NOS1AP (NOS1AP-L) plays a novel role in regulating dendrite outgrowth and branching. NOS1AP-L decreases dendrite number when overexpressed at any interval between day in vitro (DIV) 0 and DIV 12, and knockdown of NOS1AP-L results in increased dendrite number. In contrast, the short isoform of NOS1AP (NOS1AP-S) decreases dendrite number only when overexpressed during DIV 5-7. Using mutants of NOS1AP-L, we show that neither the PDZ-binding domain nor the PTB domain is necessary for the effects of NOS1AP-L. We have functionally narrowed the region of NOS1AP-L that mediates this effect to the middle amino acids 181-307, a region that is not present in NOS1AP-S. Furthermore, we performed a yeast two-hybrid screen and identified carboxypeptidase E (CPE) as a binding partner for the middle region of NOS1AP-L. Biochemical and cellular studies reveal that CPE mediates the effects of NOS1AP on dendrite morphology. Together, our results suggest that NOS1AP-L plays an important role in the initiation, outgrowth, and maintenance of dendrites during development.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Tipificación del Cuerpo/fisiología , Carboxipeptidasa H/metabolismo , Dendritas/fisiología , Hipocampo/citología , Neuronas/fisiología , Proteínas Adaptadoras Transductoras de Señales/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Western Blotting , Tipificación del Cuerpo/genética , Células COS , Carboxipeptidasa H/genética , Técnicas de Cultivo de Célula , Chlorocebus aethiops , ADN Complementario , Dendritas/metabolismo , Regulación hacia Abajo/fisiología , Vectores Genéticos , Proteínas Fluorescentes Verdes/química , Humanos , Inmunohistoquímica , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Mutación , Neuronas/metabolismo , Plásmidos , ARN Interferente Pequeño , Ratas , Transducción de Señal/fisiología , Regulación hacia Arriba/fisiologíaRESUMEN
Actin and microtubules (MT) are targets of numerous molecular pathways that control neurite outgrowth. To generate a neuronal protrusion, coordinated structural changes of the actin and MT cytoskeletons must occur. Neurite formation occurs when actin filaments (F-actin) are destabilized, filopodia are extended, and MTs invade filopodia. This process results in either axon or dendrite formation. Axonal branching involves interplay between F-actin and MTs, with F-actin and MTs influencing polymerization, stabilization, and maintenance of each other. Our knowledge of the mechanisms regulating development of the axon, however, far eclipses our understanding of dendritic development and branching. The two classes of neurites, while fundamentally similar in their ability to elongate and branch, dramatically differ in growth rate, orientation of polarized MT bundles, and mechanisms that initiate branching. In this review, we focus on how F-actin, MTs, and proteins that link the two cytoskeletons coordinate to specifically initiate dendritic events.
Asunto(s)
Actinas/fisiología , Proteínas del Citoesqueleto/metabolismo , Dendritas/fisiología , Dendritas/ultraestructura , Microtúbulos/fisiología , Axones/fisiología , Axones/ultraestructura , Polaridad Celular/fisiología , Dinaminas/metabolismo , Cinesinas/metabolismo , Microtúbulos/metabolismo , Microtúbulos/ultraestructura , Miosinas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/fisiología , Proteínas de Unión al GTP rho/metabolismoRESUMEN
Here we report our ongoing investigation of the cardiovascular effects of acetaminophen, with emphasis on oxidation-induced canine myocardial dysfunction. The objective of the current study was to investigate whether acetaminophen could attenuate exogenous H(2)O(2)-mediated myocardial dysfunction in vivo. Respiratory, metabolic, and hemodynamic indices such as left ventricular function (LVDP and +/-dP/dt(max)), and percent ectopy were measured in anesthetized, open-chest dogs during intravenous administration of 0.88 mM, 2.2 mM, 6.6 mM H(2)O(2). Following 6.6 mM H(2)O(2), tissue from the left ventricle was harvested for electron microscopy. Left ventricular function did not vary significantly between vehicle and acetaminophen groups under baseline conditions. Acetaminophen-treated dogs regained a significantly greater fraction of baseline function after high concentrations of H(2)O(2) than vehicle-treated dogs. Moreover, the incidence of H(2)O(2)-induced ventricular arrhythmias was significantly reduced in the acetaminophen-treated group. Percent ectopy following 6.6 mM concentrations of H(2)O(2) was 1 +/- 0.3 vs. 0.3 +/- 0.1 (P < 0.05) for vehicle- and acetaminophen-treated dogs, respectively. Additionally, electron micrograph images of left ventricular tissue confirmed preservation of tissue ultrastructure in acetaminophen-treated hearts when compared to vehicle. We conclude that, in the canine myocardium, acetaminophen is both functionally cardioprotective and antiarrhythmic against H(2)O(2)-induced oxidative injury.
Asunto(s)
Acetaminofén/farmacología , Analgésicos no Narcóticos/farmacología , Cardiomiopatías/inducido químicamente , Cardiomiopatías/prevención & control , Peróxido de Hidrógeno/efectos adversos , Animales , Presión Sanguínea/efectos de los fármacos , Cardiomiopatías/fisiopatología , Perros , Relación Dosis-Respuesta a Droga , Electrocardiografía , Corazón/efectos de los fármacos , Corazón/fisiopatología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/ultraestructura , Peróxido de Hidrógeno/farmacología , Masculino , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Our laboratory has previously reported that acetaminophen confers functional cardioprotection following cardiac insult, including ischemia/reperfusion, hypoxia/reoxygenation, and exogenous peroxynitrite administration. In the present study, we further examined the mechanism of acetaminophen-mediated cardioprotection following ischemia/reperfusion injury. Langendorff-perfused guinea pig hearts were exposed to acute treatment with acetaminophen (0.35 mM) or vehicle beginning at 15 min of a 30-min baseline stabilization period. Low-flow global myocardial ischemia was subsequently induced for 30 min followed by 60 min of reperfusion. At the completion of reperfusion, hearts were homogenized and separated into cytosolic and mitochondrial fractions. Mitochondrial swelling and mitochondrial cytochromec release were assessed and found to be significantly and completely reduced in acetaminophen- vs. vehicle-treated hearts following reperfusion. In a separate group of hearts, ventricular myocytes were isolated and subjected to fluorescence-activated cell sorting. Acetaminophen-treated hearts showed a significant decrease in late stage apoptotic myocytes compared with vehicle-treated hearts following injury (58 +/- 1 vs. 81 +/- 5%, respectively). These data, together with electron micrograph analysis, suggest that acetaminophen mediates cardioprotection, in part, via inhibition of the mitochondrial permeability transition pore and subsequent apoptotic pathway.
Asunto(s)
Acetaminofén/farmacología , Apoptosis/efectos de los fármacos , Fármacos Cardiovasculares/farmacología , Mitocondrias Cardíacas/efectos de los fármacos , Proteínas de Transporte de Membrana Mitocondrial/efectos de los fármacos , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Acetaminofén/uso terapéutico , Animales , Fármacos Cardiovasculares/uso terapéutico , Separación Celular , Citocromos c/metabolismo , Citometría de Flujo , Cobayas , Hemodinámica/efectos de los fármacos , Técnicas In Vitro , Masculino , Microscopía Electrónica , Mitocondrias Cardíacas/enzimología , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/ultraestructura , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Dilatación Mitocondrial/efectos de los fármacos , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/ultraestructura , Factores de TiempoAsunto(s)
Enfermedad Coronaria/terapia , Atención a la Salud/normas , Angioplastia Coronaria con Balón/estadística & datos numéricos , Consultores , Enfermedad Coronaria/mortalidad , Desfibriladores Implantables/provisión & distribución , Atención a la Salud/organización & administración , Ecocardiografía/estadística & datos numéricos , Gastos en Salud/estadística & datos numéricos , Accesibilidad a los Servicios de Salud/organización & administración , Accesibilidad a los Servicios de Salud/normas , Encuestas Epidemiológicas , Fuerza Laboral en Salud , Humanos , Cuerpo Médico de Hospitales/provisión & distribución , Marcapaso Artificial/provisión & distribución , Stents/provisión & distribución , Reino UnidoRESUMEN
The peroxynitrite-mediated activation of matrix metalloproteinase-2 (MMP-2) and subsequent cleavage of troponin I (TnI) in ventricular myocytes is a detrimental effect of ischemia/reperfusion injury. We hypothesized that acetaminophen, an effective antioxidant against peroxynitrite, would attenuate activation of MMP-2 and improve cardiac mechanical function. Isolated, perfused guinea pig hearts (Langendorff) were treated with either acetaminophen [0.35 mmol/l] or its vehicle and administered a bolus injection of peroxynitrite (6 microM) after reaching steady state function. Hemodynamic, metabolic, and mechanical effects were recorded, and coronary effluent concentrates or supernatant from heart homogenates were subjected to Western blotting and gelatin zymography. Hemodynamic and metabolic data showed no difference between acetaminophen- and vehicle-treated hearts. Mechanical data revealed that treatment with acetaminophen preserved contractile function (particularly diastolic function) after peroxynitrite administration. For example, 5 min after administration of peroxynitrite percent baseline -dP/dt(max) was 10+/-3% and -4+/-7% (P<0.05) in acetaminophen- and vehicle-treated hearts, respectively. Western blotting and gel zymography revealed higher 72 kDa (pro-MMP-2) proteolytic activity in heart homogenates of vehicle-treated versus acetaminophen-treated hearts. In addition, Western blotting of heart homogenates showed increased degradative products of TnI in vehicle-treated versus acetaminophen-treated hearts. We conclude that acetaminophen is cardioprotective, at least in part, by attenuating peroxynitrite-activated, MMP-2-mediated cleavage of TnI.
Asunto(s)
Acetaminofén/farmacología , Analgésicos no Narcóticos/farmacología , Metaloproteinasa 2 de la Matriz/metabolismo , Miocardio/metabolismo , Ácido Peroxinitroso/farmacología , Troponina I/metabolismo , Animales , Cobayas , Masculino , Miocardio/citología , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Perfusión/métodosRESUMEN
For over 50 years, acetaminophen (paracetamol) has been a staple in industrialized and non-industrialized countries for the treatment of pain and fever. Although its precise mechanisms of action are not known, the drug generates dose-dependent reduction in circulating prostaglandins, inhibits myeloperoxidase and the oxidation of lipoproteins, and appears to confer cardioprotection by blocking the effects of hydroxyl radical, peroxynitrite, and hydrogen peroxide. The drug might inhibit cyclooxygenase, although its ultimate target(s) is (are) still unclear. Sadly, since most investigations of acetaminophen have focused on its analgesic/antipyretic properties and hepatotoxicity, the effects of the drug on other mammalian organ systems, including the heart and circulation, have been ignored. Recently, work in our laboratory has shown acetaminophen to have a protective role in the injured mammalian myocardium. The cardioprotection was first observed in isolated, perfused guinea pig hearts subjected to ischemia-reperfusion injury. Hearts pretreated with acetaminophen recovered greater ventricular function and exhibited improved myofibrillar ultrastructure when compared to vehicle-treated hearts. More recent in vitro investigations have suggested protective roles for acetaminophen in barbiturate-induced arrhythmogenesis and myocardial hypoxia-reoxygenation injury. We have also extended our work to the in vivo arena. There, we found that acetaminophen reduced infarct size in dogs exposed to 60 minutes regional myocardial ischemia and 180 minutes reperfusion. We invite and encourage readers of this review to repeat/duplicate our experiments. Such work is needed to either challenge or support our findings. Further, more clinically-relevant work depends on these basic and related translational experiments.
Asunto(s)
Acetaminofén/farmacología , Acetaminofén/uso terapéutico , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Animales , Humanos , Isquemia Miocárdica/tratamiento farmacológico , Miocardio/metabolismoRESUMEN
BACKGROUND: Thrombolysis is still the first line of treatment for acute myocardial infarction in the United Kingdom. In a significant proportion of these patients thrombolytic therapy fails to restore patency of the occluded artery or is followed by early re-infarction. The best management of this group of patients is not clear although repeat doses of thrombolysis are commonly administered especially in the district general hospitals that do not have access to invasive facilities. We performed a retrospective clinical study to determine the outcome of repeat thrombolysis for acute myocardial infarction in patients with failed initial thrombolysis or early re-infarction. METHODS: Ninety-two patients who received two or more doses of thrombolysis for acute myocardial infarction were compared with 98 contemporary similar patients who received only one dose of thrombolysis. Case notes of all patients were examined for retrospective analysis. Main outcome measures were death, heart failure and need for in-hospital revascularization. RESULTS: Compared to the group thrombolysed once, in the rethrombolysed group there were significantly more deaths at 30 days (p=0.0016), more heart failure (with lower mean ejection fraction), more cardiac arrests as well as more frequent coronary angiography and percutaneous coronary interventions (PCIs). The incidence of haemorrhage in the two groups did not differ. CONCLUSIONS: The need for repeat thrombolysis identifies a group of patients with a high risk of early complications. Although repeat thrombolysis is safe, these patients then need close monitoring with a view to early intervention. For such patients admitted to district general hospitals without interventional facilities early referral to a tertiary center should be considered.
Asunto(s)
Fibrinolíticos/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Terapia Trombolítica/métodos , Enfermedad Aguda , Femenino , Hospitales de Distrito , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/mortalidad , Infarto del Miocardio/fisiopatología , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
We investigated the effects of 0.35-mM acetaminophen and its vehicle on isolated, perfused guinea pig hearts made hypoxic and subsequently reoxygenated. Hearts were allowed 30 min postinstrumentation to reach baseline, steady-state values, and then were exposed to 6 min of hypoxia (5% O(2), 5% CO(2), balance N(2)) followed by 36 min of reoxygenation (95% O(2), 5% CO(2)). We recorded hemodynamic, metabolic, and mechanical data in addition to assessing ultrastructure and the capacity of coronary venous effluent to reduce reactive oxygen species. We found that acetaminophen-treated hearts retained a greater fraction of mechanical function during hypoxia and reoxygenation. For example, the average percentage change from baseline of left ventricular developed pressure in acetaminophen- and vehicle-treated hearts at 6 min reoxygenation was 9 +/- 2% and -8 +/- 5% (P < 0.05), respectively. In addition, electron micrographs revealed greater preservation of myofibrillar ultrastructure in acetaminophen-treated hearts. Biochemical analyses revealed the potential of coronary effluent from acetaminophen-treated hearts to significantly neutralize peroxynitrite-dependent chemiluminescence in all recorded time periods. During early reoxygenation, the percentage inhibition of peroxynitrite-mediated chemiluminescence was 56 +/- 10% in vehicle-treated hearts and 99 +/- 1% in acetaminophen-treated hearts (P < 0.05). We conclude that acetaminophen has previously unreported cardioprotective properties in the nonischemic, hypoxic, and reoxygenated myocardium mediated through the reduction of reactive oxygen species.
Asunto(s)
Acetaminofén/farmacología , Cardiotónicos/farmacología , Corazón/efectos de los fármacos , Hipoxia/tratamiento farmacológico , Miocardio/patología , Animales , Cobayas , Hipoxia/patología , Microscopía Electrónica de Transmisión , Contracción Miocárdica/efectos de los fármacos , Miocardio/ultraestructura , Técnicas de Cultivo de Órganos , Ácido Peroxinitroso/metabolismoRESUMEN
The hypothesis that acetaminophen can reduce necrosis during myocardial infarction was tested in male dogs. Two groups were studied: vehicle- (n=10) and acetaminophen-treated (n=10) dogs. All dogs were obtained from the same vendor, and there were no significant differences in their ages (18 +/- 2 mo), weights (24 +/- 1 kg), or housing conditions. Selected physiological data, e.g., coronary blood flow, nonspecific collateral flow, epicardial temperature, heart rate, systemic mean arterial pressure, left ventricular developed pressure, the maximal first derivative of left ventricular developed pressure, blood gases, and pH, were collected at baseline and during regional myocardial ischemia and reperfusion. There were no significant differences in coronary blood flow, nonspecific collateral flow, epicardial temperature, heart rate, systemic mean arterial pressure, or blood gases and pH between the two groups at any of the three time intervals, even though there was a trend toward improved function in the presence of acetaminophen. Infarct size, the main objective of the investigation, was markedly and significantly reduced by acetaminophen. For example, when expressed as a percentage of ventricular wet weight, infarct size was 8 +/- 1 versus 3 +/- 1%(P <0.05) in vehicle- and acetaminophen-treated hearts, respectively. When infarct size was expressed as percentage of the area at risk, it was 35 +/- 3 versus 13 +/- 2% (P <0.05) in vehicle- and acetaminophen-treated groups, respectively. When area at risk was expressed as percentage of total ventricular mass, there were no differences in the two groups. Results reveal that the recently reported cardioprotective properties of acetaminophen in vitro can now be extended to the in vivo arena. They suggest that it is necessary to add acetaminophen to the growing list of pharmaceuticals that possess cardioprotective efficacy in mammals.
Asunto(s)
Acetaminofén/farmacología , Cardiotónicos/farmacología , Infarto del Miocardio/patología , Animales , Circulación Colateral/efectos de los fármacos , Circulación Coronaria/efectos de los fármacos , Perros , Electrocardiografía , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Masculino , Microscopía Electrónica , Infarto del Miocardio/fisiopatología , Miofibrillas/ultraestructura , Necrosis , Función Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Most patients with heart failure due to left ventricular systolic dysfunction (LVSD) secondary to coronary artery disease (CAD) have evidence of myocardium in jeopardy (reversible ischaemia and/or stunning hibernation). It is not known whether revascularisation in such cases is safe or beneficial. AIMS: To determine whether revascularisation will improve the survival of patients with LVSD and heart failure secondary to CAD and myocardium in jeopardy. METHODS: This is a randomised controlled trial comparing revascularisation or not, in addition to optimal medical therapy with ACE inhibitors, beta-blockers, aldosterone antagonists and an anti-thrombotic agent. Patients must have heart failure requiring treatment with diuretics, a left ventricular ejection fraction <35% and evidence of coronary disease. Myocardial viability and ischaemia are assessed by a broad range of techniques including stress echocardiography and nuclear imaging. All imaging tests are reviewed in core laboratories to ensure uniform reporting. Any conventional revascularisation technique is permitted. The primary outcome measure is all cause mortality. Symptoms, quality of life and health economic issues will also be explored. Assuming an annual mortality of 10% in the control group and allowing for substantial cross-over rates, a study of 800 patients followed for 5 years has 80% power with an alpha of 0.05 (two-sided) to show a 25% reduction in mortality with revascularisation. RESULTS: At the time of writing 180 patients have been screened for inclusion, 111 have consented to participate and 70 have been randomised. The results of viability testing are awaited in 22 patients. Twenty-six patients had been investigated for myocardial viability and/or by angiography prior to consent, as part of the routine practice in that cardiology department. Of 68 patients who have completed assessment only after consent, 47 (69%) were included. The principal reason for drop-out between consent and randomisation was lack of evidence of myocardial ischaemia or hibernation. CONCLUSION: The HEART trial will help to determine whether investigation of myocardial ischaemia and/or viability with a view to revascularisation should become part of the routine care of patients with heart failure due to LVSD and CAD.
Asunto(s)
Insuficiencia Cardíaca/cirugía , Revascularización Miocárdica , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/mortalidad , Enfermedad de la Arteria Coronaria/cirugía , Estudios de Seguimiento , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/mortalidad , Humanos , Proyectos de Investigación , Análisis de Supervivencia , Resultado del Tratamiento , Reino Unido , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/mortalidad , Disfunción Ventricular Izquierda/cirugíaRESUMEN
The operator of radiation exposure during coronary angiography varies between different centres. The purpose of this study was to explore whether radiation dose was lower during cardiologist- or radiographer-controlled radiation exposure and to determine if the grade of cardiologist performing angiography influenced radiation dose. Patients were randomly allocated either to cardiologist- or radiographer-controlled radiation exposure during coronary angiography. Screening time and radiation dose during fluoroscopy and image acquisition, measured by dose-area product meter, were recorded. Mean radiation dose during cardiologist-controlled radiation exposure (n=176) of 15.6 Gy cm(2) (95% confidence interval (CI), 14.4-16.8) was significantly lower than that produced by the radiographer-controlled group (n=192) of 17.3 Gy cm(2) (95% CI, 16.2-18.6) (p<0.044). There was no significant difference in screening times produced by the two groups of radiation exposure operators. The difference in radiation dose produced by the two operator groups was principally owing to exposure produced at image acquisition. Irrespective of radiation exposure operator, consultant cardiologists produced significantly lower screening times and radiation doses compared with registrars. During routine coronary angiography, radiographer-controlled radiation exposure does not reduce screening time or radiation dose. Senior cardiologists produce the lowest radiation doses during coronary angiography when they are responsible for radiation exposure.