RESUMEN
The chemo-immunotherapy (CIT) and chemo-adoptive immunotherapy (CAIT) regimens tested in the past decade are summarized. From them we have learned a great deal about the interactions between various chemotherapeutic agents, immune modulating agents and effector cells. The most commonly reported result in multi-modality experiments with CAIT has been a synergistic enhancement in antitumor activity. Clinical trials usually demonstrated improvement in patient quality of life, an extension of survival time, and occasional complete regression of tumor. In many animal models, this enhancement often meant the complete regression and apparent cure of tumor in the animal. One mechanism by which this synergistic enhancement takes place appears to be a suppression of tumor-associated suppressor T cell activity by the chemotherapeutic agents, thereby inducing enhanced cytolytic activity against tumor by the adoptively transferred, activated effector cells. In CAIT the most commonly used drug has been cyclophosphamide. In CIT a wide variety of chemotherapy agents have been used but none of the clinical trials made use of cyclophosphamide. Thus, direct comparisons are not possible. Suggestive of the intricate regulatory processes involved, many CIT studies indicate a synergy only when specific doses of chemotherapy and immunotherapy agents are given, and in a specific sequence. CIT has become less toxic, is being handled on a cost-effective outpatient basis, while maintaining similar objective response rates to earlier inpatient treatments. In the future, CAIT and CIT will probably have an increasing role in the management of patients with specific cancers.
Asunto(s)
Inmunoterapia Adoptiva/métodos , Neoplasias Experimentales/terapia , Neoplasias/terapia , Animales , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Predicción , Humanos , Sistema Inmunológico/fisiología , Linfocitos Infiltrantes de Tumor/inmunologíaRESUMEN
Effects of acute tissue potassium depletion on cellular energy metabolism are poorly understood. To examine this issue, we performed the following studies in an isovolumic isolated perfused heart preparation. Perfusion of isolated hearts with media lacking potassium (K = 0 mmol/l) for 30 min resulted in ventricular fibrillation, rapid decreases in creatine phosphate (PCr) and ATP, and increases in Pi. During reinstitution of normal perfusate potassium, hearts did not resume normal contractions, and no increases in tissue ATP were observed. However, some normalization of PCr and Pi were noted during reinstitution of normal perfusate. Perfusion with media containing K = 2 mmol/l caused significant but less dramatic decreases in tissue ATP concentrations than perfusion with media containing K = 0 mmol/l. Reduction of perfusate calcium from 1.2 (normal) to 0.6 mmol/l in media containing K = 0 mmol/l attenuated the fall in ATP seen with media containing K = 0 mmol/l. Conversely, increasing perfusate calcium to 2.4 mmol/l in media containing K = 2 mmol/l markedly worsened the fall in tissue ATP seen in media containing K = 2 mmol/l. In this subgroup (K = 2 mmol/l, Ca = 2.4 mmol/l), ventricular fibrillation developed approximately one-half of the time. However, no differences in the rate of ATP fall were observed between those hearts that fibrillated and those that did not. During perfusion with media containing K = 0 mmol/l, nuclear magnetic resonance (NMR)-visible tissue potassium concentrations fell rapidly and dramatically. Significant but less severe reductions in NMR-visible potassium were seen during perfusion with media containing K = 2 mmol/l. With K = 2 mmol/l perfusate, the rate of cellular potassium loss was influenced by perfusate calcium concentration. When cardiac mitochondria were examined after perfusion with media containing K = 0 mmol/l, evidence for calcium loading as well as respiratory dysfunction was noted. These data indicate that reductions in perfusate potassium caused dramatic reductions in tissue ATP and NMR-visible potassium concentrations. The abnormal energy metabolism that results from acute cellular potassium depletion appears to be due, at least in part, to impaired energy production by cardiac mitochondria that become calcium loaded.
Asunto(s)
Hipopotasemia/metabolismo , Miocardio/metabolismo , Acidosis/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Calcio/metabolismo , Metabolismo Energético , Técnicas In Vitro , Membranas Intracelulares/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Mitocondrias Cardíacas/metabolismo , Perfusión , Ratas , Ratas Sprague-Dawley , Valores de ReferenciaRESUMEN
In this study, the physiological and metabolic effects of Carbicarb administered as an isotonic (150 mmol/L Na[n[]I+) or hypertonic (1 mol/L Na[n[]I+) solution over 2 minutes in the acidotic isolated heart were compared. Physiological monitoring as well as 31P and 23Na nuclear magnetic resonance spectroscopy were performed. Both isotonic and hypertonic Carbicarb induced comparable dose-dependent increases in intracellular pH as well as decreases in inorganic phosphate and increases in creatine phosphate concentrations, which were sustained for 20 minutes. However, immediate functional improvement was greater in hearts receiving isotonic Carbicarb. Metabolic acidosis conditions resulted in a 27% increase in cytosolic sodium by 30 minutes (P < .05). In this setting, hypertonic Carbicarb induced a large transient increase in cytosolic sodium, whereas isotonic Carbicarb caused immediate and sustained decreases in cytosolic sodium. These data suggest that isotonic Carbicarb may have more beneficial effects on cardiac function than hypertonic Carbicarb. These effects may be related to associated changes in cytosolic sodium.
Asunto(s)
Acidosis/tratamiento farmacológico , Carbonatos/uso terapéutico , Frecuencia Cardíaca/efectos de los fármacos , Soluciones Hipertónicas/uso terapéutico , Soluciones Isotónicas/uso terapéutico , Miocardio/metabolismo , Bicarbonato de Sodio/uso terapéutico , Acidosis/sangre , Acidosis/diagnóstico , Acidosis/metabolismo , Acidosis/fisiopatología , Animales , Análisis de los Gases de la Sangre , Carbonatos/farmacología , Citosol/química , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Concentración de Iones de Hidrógeno/efectos de los fármacos , Soluciones Hipertónicas/farmacología , Técnicas In Vitro , Soluciones Isotónicas/farmacología , Espectroscopía de Resonancia Magnética , Miocardio/química , Consumo de Oxígeno/efectos de los fármacos , Fosfatos/análisis , Fosfocreatina/análisis , Ratas , Ratas Sprague-Dawley , Sodio/análisis , Bicarbonato de Sodio/farmacologíaRESUMEN
Intracellular sodium (Nai) concentrations rose immediately and progressively during ischemia in the isolated heart. The intracellular double quantum filtered sodium coherence (DQ) intensity also increased during ischemia. However, when normalized for Nai, the DQ intensity began to fall after 40 min of ischemia, and remained depressed during reperfusion.
Asunto(s)
Espectroscopía de Resonancia Magnética , Isquemia Miocárdica/metabolismo , Sodio/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Calcio/metabolismo , Citoplasma/metabolismo , Reperfusión Miocárdica , Fosfatos/metabolismo , Fosfocreatina/metabolismo , Fósforo , Ratas , Ratas Sprague-Dawley , Sodio/análisis , Factores de TiempoRESUMEN
An outbreak of chlamydia infection affecting seven people from a small town in Grampian is described. The origin of the outbreak seemed to be a local pet shop. The difficulties of diagnosis and tracing the connections with the pet shop are discussed. The clinical histories of the seven patients are described including those of the two who died.
Asunto(s)
Trazado de Contacto , Brotes de Enfermedades , Psitacosis/epidemiología , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , EmbarazoRESUMEN
Evaluation of the double-quantum filter for sodium was performed on several sample series of bovine serum albumin in water. Both single-quantum (1Q) and double-quantum (2Q) measurements were obtained. The quality of the 2Q filter was found to be quite sensitive to pulse width setting. Ordinary 1Q measurements of sodium in albumin-containing solutions show 100% visibility. At high ionic strengths, the 2Q albumin results confirm earlier conclusions demonstrating the tendency for the albumin molecule to unfold under a variety of influences. At physiological sodium concentrations, the magnitude of the 2Q/1Q ratio is controlled not only by the concentration of albumin, but also by the solution pH. Non-zero, double-quantum signals were observed in physiological samples consisting of essentially intracellular material (packed red blood cells) as well as in extracellular material (plasma and urine). Measurements in human urine showed no 2Q signal. However, high-concentration NaCl solutions did produce real, measurable 2Q signals. Therefore, the 2Q filter does not measure intracellular sodium exclusively. Although packed red blood cells gave the highest 2Q/1Q ratio (8.5 x 10(-3), plasma gave a very considerable 2Q/1Q ratio (2.3 x 10(-3). Because of its relatively high extracellular concentration, extracellular sodium may give a greater absolute 2Q signal than intracellular sodium in unmodified tissue samples. Based on these data, we conclude that a 2Q filter will not provide a useful measurement of intracellular sodium in in vivo tissue samples.