RESUMEN
Murine macrophages are endowed with nicotinamide adenine dinucleotide splitting activity that is markedly higher than that of other cells, tissues, or organs of the mouse. This enzyme therefore can be used as a biochemical marker for distinguishing macrophages from other cells of the lymphoreticular system and from polymorphonuclear leukocytes.
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Macrófagos/enzimología , NAD+ Nucleosidasa/metabolismo , Animales , Líquido Ascítico/enzimología , Linfocitos B/enzimología , Plaquetas/enzimología , Médula Ósea/enzimología , Humanos , Ganglios Linfáticos/enzimología , Ratones , Monocitos/enzimología , Neutrófilos/enzimología , Bazo/enzimología , Linfocitos T/enzimología , Distribución TisularRESUMEN
Although substantial information has accumulated over the past decade, many gaps remain in our understanding of the regulation of contractility and modulation of inotropic responsiveness in the developing heart. There are several important problems facing investigators in the field of developmental cardiology. Responses often differ among species and the human correlates to many of the animal studies remain to be defined. In many instances, the supply of tissues is limited and difficult to obtain consistently. Furthermore, comparable experiments may be nearly impossible to perform in human fetal and neonatal myocardium. Interpretation of results from developmental studies using various animal species and a number of different experimental models is further complicated by the complexity of normal developmental processes. Numerous changes are occurring simultaneously in neurohumoral influences, cardiac ultrastructure, protein synthesis, gene expression, and metabolism. Comprehensive integration of the impact of these and other factors on overall contractile performance and inotropic responsiveness requires a multifaceted approach incorporating a variety of techniques. Results from pharmacological experiments must be placed into perspective with available knowledge of relevant morphological, physiological, and biochemical status at the precise age in the particular species in which the experiments are performed. A thorough understanding of developmental cardiology is of more than simple academic interest. Basic knowledge of the regulation of contractile function during development will obviously have important therapeutic applications in the immature heart. Moreover, results from future developmental studies directed toward characterising myocardial gene expression, modulation of specific effector systems, and regulation of excitation-contraction coupling are ultimately likely to contribute to the design of therapeutic strategies for both congenital and acquired heart disease.
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Cardiotónicos/farmacología , Corazón/crecimiento & desarrollo , Contracción Miocárdica/efectos de los fármacos , Animales , Corazón/embriología , Humanos , Estimulación QuímicaRESUMEN
OBJECTIVES: Expression of the cardiac Na(+)-Ca2+ exchanger (NCX) is high at birth and declines rapidly to adult levels by approximately 21 days in rabbits. The aim was to evaluate the role of thyroid hormone in regulating cardiac NCX expression. METHODS: Adult New Zealand White rabbits were made hypothyroid by treatment with propylthiouracil or hyperthryoid by administration of sigma-thyroxine. Hypothyroidism was induced in immature rabbits by exposure to propylthiouracil from gestational day 25 through the first 21 days after birth. NCX steady-state mRNA levels were quantitated using Northern slot blots with poly(A+) RNA isolated from ventricular myocardium of treated and age-matched euthyroid animals. As a control, steady-state levels of cardiac sarco(endo)plasmic reticulum calcium ATPase (SERCA2a) were measured in each group. Thyroid status was confirmed with serum T4, ventricular weight and body weight measurements. Immunoreactive NCX protein levels were assessed using Western blots. RESULTS: Compared with euthyroid controls, NCX steady-state mRNA levels increased to 189 +/- 20% in hypothyroid adults and decreased to 55 +/- 15% in hyperthyroid adults. Opposite effects were observed for SERCA2a expression (58 +/- 7% in hypothyroidism and 130 +/- 15% in hyperthyroidism). In hypothyroid 21-day-old rabbits, NCX steady-state mRNA levels were elevated to 205 +/- 30% of age-matched euthyroid controls. SERCA2a levels were unaffected in the immature animals, possibly due to inability to reduce thyroid levels sufficiently to affect SERCA2a expression in this model. Changes in NCX mRNA levels produced comparable changes in immunoreactive NCX protein levels. CONCLUSIONS: Thyroid hormone reciprocally regulates NCX and SERCA2a expression in the ventricles of adult rabbits. Hypothyroidism resulted in sustained high levels of NCX expression in 21-day-old rabbits. These results suggest that the postnatal thyroid hormone surge is important for the normal down-regulation of cardiac NCX expression during the first 3 weeks after birth in developing rabbits.
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Antiportadores/metabolismo , Calcio/metabolismo , Miocardio/metabolismo , Sodio/metabolismo , Tiroxina/fisiología , Animales , Northern Blotting , ATPasas Transportadoras de Calcio/metabolismo , Propiltiouracilo/farmacología , ARN Mensajero/análisis , Conejos , Retículo Sarcoplasmático/enzimología , Intercambiador de Sodio-Calcio , Tiroxina/farmacologíaRESUMEN
The Ca(2+)-binding protein, K(+) channel-interacting protein 1 (KChIP1), modulates Kv4 channels. We show here that KChIP1 affects Kv4.1 and Kv4.2 currents differently. KChIP1 slows Kv4.2 inactivation but accelerates the Kv4.1 inactivation time course. Kv4.2 activation is shifted in a hyperpolarizing direction, whereas a depolarizing shift occurs for Kv4.1. On the other hand, KChIP1 increases the current amplitudes and accelerates recovery from inactivation of both currents. An involvement of the Kv4 N-terminus in these differential effects is demonstrated using chimeras of Kv4.2 and Kv4.1. These results reveal a novel interaction of KChIP1 with these two Kv4 members. This represents a mechanism to further increase the functional diversity of K(+) channels.
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Proteínas de Unión al Calcio/fisiología , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/fisiología , Animales , Proteínas de Unión al Calcio/genética , Electrofisiología , Proteínas de Interacción con los Canales Kv , Oocitos/fisiología , Canales de Potasio Shal , Transfección , Xenopus laevisRESUMEN
We have identified and cloned a new member of the mammalian tandem pore domain K+ channel subunit family, TWIK-originated similarity sequence, from a human testis cDNA library. The 939 bp open reading frame encodes a 313 amino acid polypeptide with a calculated Mr of 33.7 kDa. Despite the same predicted topology, there is a relatively low sequence homology between TWIK-originated similarity sequence and other members of the mammalian tandem pore domain K+ channel subunit family group. TWIK-originated similarity sequence shares a low (< 30%) identity with the other mammalian tandem pore domain K+ channel subunit family group members and the highest identity (34%) with TWIK-1 at the amino acid level. Similar low levels of sequence homology exist between all members of the mammalian tandem pore domain K+ channel subunit family. Potential glycosylation and consensus PKC sites are present. Northern analysis revealed species and tissue-specific expression patterns. Expression of TWIK-originated similarity sequence is restricted to human pancreas, placenta and heart, while in the mouse, TWIK-originated similarity sequence is expressed in the liver. No functional currents were observed in Xenopus laevis oocytes or HEK293T cells, suggesting that TWIK-originated similarity sequence may be targeted to locations other than the plasma membrane or that TWIK-originated similarity sequence may represent a novel regulatory mammalian tandem pore domain K+ channel subunit family subunit.
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Canales de Potasio de Dominio Poro en Tándem , Canales de Potasio/genética , Testículo/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , ADN Complementario , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , ARN Mensajero , Homología de Secuencia de Aminoácido , Xenopus laevisRESUMEN
Four hours after acute ingestion of 400 to 1,200 mg of propranolol by a healthy, 3-year-old boy, his plasma concentration of propranolol was 2,289 ng/ml. The only pharmacologic effect observed was a diminished heart rate response to crying and activity. In a second case, a 4-year-old boy on chronic propranolol therapy for renovascular hypertension had a hypoglycemic seizure when solid food was refused for three days because of an oral wound. The hypoglycemia was easily managed with intravenous glucose, and there were no sequelae. The first case alludes to the safety of propranolol in a healthy child even with very high plasma concentrations. The second case suggests the necessity of anticipating and avoiding hypoglycemia that can develop in children on chronic propranolol therapy when caloric intake is impaired.
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Propranolol/efectos adversos , Preescolar , Ingestión de Energía , Humanos , Hipoglucemia/etiología , MasculinoRESUMEN
The ratio of left ventricular to right ventricular stroke counts measured by radionuclide angiography has been used in adults to estimate the severity of left-sided valvular regurgitation. The validation of this technique in children for assessment of right and left ventricular volume overload is reported herein. Radionuclide stroke count ratios in 60 children aged 0.5 to 19 years (mean 11) were determined. Based on their diagnoses, the patients were divided into 3 groups: (1) normal--40 patients with no shunts or valvular regurgitation, (2) left ventricular volume overload--13 patients with mitral or aortic regurgitation, or both, and (3) right ventricular volume overload--7 patients, 2 with severe tricuspid regurgitation, 3 with atrial septal defects, and 2 with total anomalous pulmonary venous drainage. The radionuclide stroke count ratio clearly differentiated these groups (p less than 0.05): normal patients had a stroke count ratio of 1.04 +/- 0.17 (mean +/- 1 standard deviation), the left ventricular volume overload group had a stroke count ratio of 2.43 +/- 0.86, and the right ventricular volume overload group had a stroke count ratio of 0.44 +/- 0.17. In 22 of our 60 patients, radionuclide stroke count ratios were compared with cineangiographic stroke volume ratios, resulting in a correlation coefficient of 0.88. It is concluded that radionuclide ventriculography is an excellent tool for qualitative and quantitative assessment of valvular regurgitation in children.
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Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Cardiopatías Congénitas/diagnóstico por imagen , Corazón/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Adolescente , Niño , Preescolar , Eritrocitos , Defectos del Tabique Interatrial/diagnóstico por imagen , Humanos , Lactante , Radioisótopos , Cintigrafía , Volumen Sistólico , Tetralogía de Fallot/diagnóstico por imagen , Transposición de los Grandes Vasos/diagnóstico por imagenRESUMEN
Our results demonstrate that (a) the Kir2.1 gene encodes a native K+ channel protein with a 21-pS conductance; (b) this channel has an important role in the genesis of adult ventricular 1K1; and (c) the contribution of Kir2.1 channel proteins to 1K1 changes during development. The lack of contribution of Kir2.1 to fetal 1K1 channels is interesting from the point of view of possible future generation of knockout mice lacking Kir2.1, since cardiac abnormalities would not be expected to result in fetal lethality. These observations provide further support for a generalized hypothesis that different genes may code for 1K1 channel proteins at various developmental stages. However, the effects of these AS-oligos must first be examined on native 1K1 channels in cardiac myocytes before definite conclusions can be reached.
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Ventrículos Cardíacos/metabolismo , Canales de Potasio de Rectificación Interna , Canales de Potasio/genética , Potasio/metabolismo , Animales , Células Cultivadas , Desarrollo Embrionario y Fetal , Regulación del Desarrollo de la Expresión Génica/genética , Ventrículos Cardíacos/embriología , Ratones , Oligonucleótidos Antisentido/farmacología , Oocitos/metabolismo , Canales de Potasio/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ribonucleasas/metabolismo , XenopusRESUMEN
The presumed limited growth potential of saphenous vein grafts has led many authorities to discourage their use in young children. We documented excellent growth and patency of a saphenous vein graft 13 years after operation in a 7-year-old child with coronary artery obstruction caused by Kawasaki disease.
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Puente de Arteria Coronaria , Síndrome Mucocutáneo Linfonodular/cirugía , Vena Safena/trasplante , Factores de Edad , Estatura , Peso Corporal , Niño , Circulación Colateral , Enfermedad Coronaria/etiología , Enfermedad Coronaria/cirugía , Vasos Coronarios/patología , Estudios de Seguimiento , Humanos , Masculino , Síndrome Mucocutáneo Linfonodular/complicaciones , Vena Safena/crecimiento & desarrollo , Grado de Desobstrucción VascularRESUMEN
BACKGROUND: Heparin-coated circuits reduce the inflammatory response to cardiopulmonary bypass in adult patients; however, little is known about its effects in the pediatric population. Two studies were performed to assess this technology's impact on inflammation and clinical outcomes. METHODS: In a pilot study, complement and interleukins were measured in 19 patients who had either uncoated cardiopulmonary bypass circuits or heparin-bonded circuits. Subsequently, 23 additional patients were studied in a randomized fashion. Respiratory function and blood product utilization were recorded. RESULTS: In the pilot study, heparin-bonded circuit patients had less complement 3a (p < 0.001) and interleukin-8 (p < 0.05) compared with uncoated cardiopulmonary bypass circuit patients. The randomized study revealed that the heparin-bonded circuit was associated with reduced complement 3a (p = 0.02). Multiple variable analysis revealed that the following postoperative variables were increased with bypass time (p = 0.01) and diminished with heparin-bonded circuits: interleukins (p = 0.01), peak airway pressures (p = 0.05), and prothrombin time (p = 0.03). CONCLUSIONS: Heparin-bonded circuits significantly reduce cytokines and complement during cardiopulmonary bypass and lower interleukin levels postbypass; they were also associated with improved pulmonary and coagulation function. Heparin-bonded circuits ameliorate the systemic inflammatory response in pediatric patients from cardiopulmonary bypass.
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Puente Cardiopulmonar , Fibrinolíticos/administración & dosificación , Heparina/administración & dosificación , Preescolar , Materiales Biocompatibles Revestidos , Complemento C3a/análisis , Complemento C5a/análisis , Femenino , Humanos , Lactante , Interleucina-1/sangre , Interleucina-6/sangre , Interleucina-8/sangre , Masculino , Proyectos Piloto , Estudios Prospectivos , Propiedades de SuperficieRESUMEN
The impact of left ventricular hypertension on coronary flow patterns in adult patients has been well described. In contrast, few reports exist regarding the association of right coronary flow abnormalities with right ventricular hypertension. The observation of myocardial infarcts, right ventricular hypertension, and abnormal coronary flow pattern-as well as its normalization with relief of right ventricular hypertension-lends support to a causal relation between ventricular hypertension and coronary flow abnormalities.
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Circulación Coronaria , Vasos Coronarios/fisiopatología , Cardiopatías Congénitas/fisiopatología , Infarto del Miocardio/fisiopatología , Sístole , Función Ventricular Derecha , Presión Ventricular , Arterias , Ecocardiografía Doppler , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/diagnóstico por imagen , Humanos , Lactante , Infarto del Miocardio/complicaciones , Infarto del Miocardio/diagnóstico por imagenRESUMEN
We used continuous intraoperative transesophageal echocardiography (TEE) monitoring to detect intraoperative myocardial ischemia in children after they had been weaned from cardiopulmonary bypass for cardiac surgery. Three pediatric patients are described here to illustrate the usefulness of such TEE monitoring in surgical procedures involving coronary arteries. The indications for intraoperative TEE monitoring and a simplified scheme for immediate qualitative interpretation are discussed.
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Procedimientos Quirúrgicos Cardíacos , Ecocardiografía Transesofágica , Complicaciones Intraoperatorias/diagnóstico por imagen , Monitoreo Intraoperatorio , Isquemia Miocárdica/diagnóstico por imagen , Adolescente , Insuficiencia de la Válvula Aórtica/cirugía , Anomalías de los Vasos Coronarios/cirugía , Vasos Coronarios/cirugía , Femenino , Humanos , Recién Nacido , Masculino , Transposición de los Grandes Vasos/cirugíaRESUMEN
Poloxamer 188 is a synthetic surfactant that reduces the viscosity of whole blood without hemodilution. It is postulated that poloxamer 188 would improve outcome if administered during retransfusion following hemorrhage. Rabbits were anesthetized and instrumented for 3 hours of hemodynamic monitoring. After stabilization, blood was withdrawn over a 5 minute period to reduce mean arterial pressure to 35 mmHg (4.7 kPa). Following a 60 minute shock period, animals were randomly assigned to 1 of 5 experimental groups (n = 8 in each): (1) Shock (no retransfusion); (2) Transfusion (retransfusion of autologous shed blood); (3) Volume (retransfusion with autologous blood and infusion of an additional volume of normal saline equivalent to the volume of poloxamer 188 given in the next 2 experimental groups); (4) Low and (5) High drug (i.v. bolus of 200 mg/kg of poloxamer 188 over 5 minutes at retransfusion, followed by a continuous infusion of poloxamer 188 at 50 mg/kg/hr in the Low drug group and 200 mg/kg/hr in the High drug group). All animals in a surgery Control group (n = 6) remained stable during the 3 hour monitoring period. In contrast, none of the animals in the Shock group remained alive, confirming this to be a relevant model of trauma and severe hemorrhagic shock. There were significantly more animals surviving at the end of the monitoring period in the two groups that received poloxamer 188 (numbers of animals alive after 3 hours = 7 of 8 in the High group and 6 of 8 in the Low group) compared to the Transfusion (4 of 8) and Volume (2 of 8) groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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Poloxaleno/farmacología , Choque Hemorrágico/tratamiento farmacológico , Animales , Transfusión de Sangre Autóloga , Relación Dosis-Respuesta a Droga , Hemodinámica , Concentración de Iones de Hidrógeno , Masculino , Poloxaleno/administración & dosificación , Conejos , Choque Hemorrágico/mortalidad , Choque Hemorrágico/terapia , Análisis de Supervivencia , Factores de TiempoRESUMEN
For the most part of this the century heart failure syndrome was understood as a pump failure disorder with hemodynamic consequences stemming from the same myocardial dysfunction. In addition supply and demand theories were used to explain the nature of symptoms. As a result, therapeutic strategies were directed at correcting the abnormal hemodynamic conditions and normalizing the delivery of the much needed nutrients. Improvement of cardiac pump function with inotropic drugs and abnormal circulatory conditions with afterload and preload modifications became therapeutic goals and standards of care. However, while vasodilators and inotropic drugs immediately improved symptoms, hemodynamics and functional status, in the long term they either did not affect or worsen the natural history of heart failure. In pediatrics, this is further complicated by the lack of large scale trials addressing issues pertinent to the particularities that affect heart failure in children. In the late 1980s and 1990s heart failure has evolved into a more complex, multiple and interactive pathophysiologic disorder. Today not only the abnormal hemodynamics but also the biological disorders are pharmacologic targets. The reversal or slowing of myocardial maladaptation has become one of the most important therapeutic goals. With this end in mind therapeutic strategies may seem counterintuitive and paradoxical, such as the use of beta-blockers. This review will address the current thinking and therapeutic modalities used today in the treatment of heart failure syndrome in the adult population. We also discuss some of the issues why we think that these principles can be extrapolated to the pediatric population.
RESUMEN
Clinical experience indicates that infants and young children respond to a variety of cardiovascular pharmacological and physiological interventions differently than adults. What is less clear, however, are the cellular and molecular mechanisms that contribute to these age-related differences. Based largely upon results from animal models, it is apparent that developmental changes occur in numerous pathways and proteins involved in the regulation of contractile function and in the determinants of inotropic responsiveness. The purposes of this review are to provide a brief overview of cardiac excitation-contraction and to illustrate some of the important age-related differences in the mechanisms involved in calcium regulation in the heart. This scientific foundation may help to explain certain clinical observations in the very young. Furthermore, it is hoped that a better understanding of the fundamental processes involved in controlling cardiac contractile function will stimulate additional research in the search for more specific, rational and age-appropriate cardiovascular therapeutics.