RESUMEN
Obesity increases the risk of developing multiple myeloma (MM). Adiponectin is a cytokine produced by adipocytes, but paradoxically decreased in obesity, that has been implicated in MM progression. Herein, we evaluated how prolonged exposure to adiponectin affected the survival of MM cells as well as putative signaling mechanisms. Adiponectin activates protein kinase A (PKA), which leads to decreased AKT activity and increased AMP-activated protein kinase (AMPK) activation. AMPK, in turn, induces cell cycle arrest and apoptosis. Adiponectin-induced apoptosis may be mediated, at least in part, by the PKA/AMPK-dependent decline in the expression of the enzyme acetyl-CoA-carboxylase (ACC), which is essential to lipogenesis. Supplementation with palmitic acid, the preliminary end product of fatty acid synthesis, rescues MM cells from adiponectin-induced apoptosis. Furthermore, 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), an ACC inhibitor, exhibited potent antiproliferative effects on MM cells that could also be inhibited by fatty acid supplementation. Thus, adiponectin's ability to reduce survival of MM cells appears to be mediated through its ability to suppress lipogenesis. Our findings suggest that PKA/AMPK pathway activators, or inhibitors of ACC, may be useful adjuvants to treat MM. Moreover, the antimyeloma effect of adiponectin supports the concept that hypoadiponectinemia, as occurs in obesity, promotes MM tumor progression.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Adiponectina/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Mieloma Múltiple/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Adipoquinas/metabolismo , Adiponectina/deficiencia , Adiponectina/metabolismo , Animales , Apoptosis , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Ácidos Grasos/química , Furanos/química , Humanos , Lipogénesis , Errores Innatos del Metabolismo/metabolismo , Ratones , Mieloma Múltiple/tratamiento farmacológico , Obesidad/metabolismo , Transducción de SeñalRESUMEN
A Partnership Program between USAF Medical Center, Wright-Patterson (WPAFB) and Miami Valley Hospital (MVH), Dayton, Ohio, was created through CHAMPUS to provide cardiac surgical services for eligible patients. During the first year of this program, 82 patients underwent 89 percutaneous transluminal coronary angioplasty (PTCA) procedures. Sixty-one patients underwent cardiac surgery at WPAFB, 50 were referred to MVH due to ineligibility or other reasons, and five were referred to other military or civilian hospitals. The program has been successful with low morbidity and mortality (3%). Cost savings for PTCAs was $241,853 and for cardiac surgery was $462,046.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos/estadística & datos numéricos , Hospitales Comunitarios/organización & administración , Hospitales Militares/organización & administración , Procedimientos Quirúrgicos Cardíacos/economía , Planes de Asistencia Médica para Empleados , Hospitales Comunitarios/estadística & datos numéricos , Hospitales Militares/estadística & datos numéricos , Humanos , Ohio , Afiliación OrganizacionalRESUMEN
Direct mechanical ventricular actuation (DMVA) is a non-blood-contacting method of biventricular cardiac massage which may be applied expediently for total circulatory support. The purpose of this study was to assess the feasibility of DMVA application for patients suffering refractory cardiac arrest. Following informed consent, DMVA was applied in 22 patients. Vascular access for hemodynamic monitoring was possible in only 12 patients, whose outcomes serve as the basis for this report. The mean age of the patients was 48.2 +/- 4.2 years (seven men; five women). The average time from witnessed cardiac arrest to DMVA application was 81 +/- 9 minutes. Application took less than two minutes from the time of skin incision and resulted in immediate hemodynamic improvement. Systolic and diastolic blood pressures averaged 78 +/- 4 and 41 +/- 4 mm Hg, respectively, with a mean cardiac output of 3.14 +/- 0.18 L/min during a mean of 228 +/- 84 minutes of circulatory support (range, 25 minutes to 18 hours). In selected cases the device was temporarily removed for 2 to 3 minutes and open-chest cardiac massage (OCCM) performed at similar compression rates. DMVA increased arterial pressures 65 percent and cardiac output 190 percent compared to OCCM. Initial arterial pH (7.12 +/- 0.04) improved by the time the device was removed (7.24 +/- 0.05). Serum lactate levels decreased from 18.0 +/- 2.3 mumol/L to 14.9 +/- 2.9 mumol/L. Four patients were successfully defibrillated: two had inadequate cardiac function and died within 1 h, and two were successfully resuscitated, but later died from cardiac failure and respiratory insufficiency. Another patient regained normal neurologic function during DMVA and was successfully bridged to cardiopulmonary bypass for emergent coronary artery bypass grafting, but died later from myocardial infarction. There were only two complications: (1) a cardiac laceration during pericardiotomy (1/22 patients); and (2) a ventricular rupture during OCCM (1/22). No complication resulted from the device. We found DMVA to be a feasible method for acute cardiovascular stabilization in victims suffering refractory cardiac arrest. Human clinical trials employing earlier DMVA application are required to determine its resuscitative potential.