RESUMEN
Over the past 8 years, the National Institutes of Health (NIH) budget appropriation has lost purchasing power, with erosion of the benefits of the doubling of the budget less than a decade ago. For the first time in 40 years, the NIH appropriation in fiscal year 2011 was 1% less than in the previous year. The National Heart, Lung, and Blood Institute (NHLBI) has been closely managing its funds to protect its core functions: support and conduct of research, and training of biomedical research scientists. Rigorous evaluations of funding mechanisms, management of clinical studies, set-aside programs and funding guidelines are designed to help the Institute, in consultation with its advisory council, to minimize the long-term impact of extreme resource limitations on the advance and conduct of science. This report describes some recent actions taken by the NHLBI to maximize support for investigator-initiated research, maintain a balanced portfolio, and provide as much support as possible for established and early-stage investigators.
Asunto(s)
Investigación Biomédica/economía , National Heart, Lung, and Blood Institute (U.S.)/economía , National Heart, Lung, and Blood Institute (U.S.)/organización & administración , Apoyo a la Investigación como Asunto/organización & administración , Investigación Biomédica/tendencias , Presupuestos/tendencias , Guías como Asunto , Humanos , National Heart, Lung, and Blood Institute (U.S.)/tendencias , Apoyo a la Investigación como Asunto/tendencias , Pequeña Empresa/economía , Pequeña Empresa/tendencias , Estados UnidosRESUMEN
Efforts to enhance therapy for children and adults with sickle cell disease (SCD) have proven more challenging than might have been predicted from the fact that an understanding of the underlying pathogenesis antedated that of many other diseases for which good treatments presently exist. The multi-organ injury that occurs with SCD certainly contributes to this clinical reality. Research over decades indicates that the primary defect in hemoglobin that results in polymerization of the protein under low oxygen conditions and resultant cellular deformity of the red blood cell initiates a complex downstream pathogenesis associated with vascular injury and organ ischemia. Deciphering this in a manner that informs successful therapies that improve all target organs continues to challenge hematologists. The National Heart, Lung and Blood Institute (NHLBI) is dedicated to support research across the basic science, translational and clinical spectrum to achieve these clinical outcomes. The following provides a brief summary of the research strategies which NHLBI is presently supporting and will support in the future to enhance care and ultimately, to effect cure of this hemoglobin disease that causes such suffering to those who inherit this monogenic disease.
Asunto(s)
Anemia de Células Falciformes/terapia , Investigación Biomédica/tendencias , Adulto , Niño , Humanos , National Institutes of Health (U.S.) , Estados UnidosAsunto(s)
Salud Global , Salud Mental/estadística & datos numéricos , Humanos , Trastornos Mentales/economía , Trastornos Mentales/epidemiología , Trastornos Mentales/prevención & control , Trastornos Relacionados con Sustancias/economía , Trastornos Relacionados con Sustancias/epidemiología , Organización Mundial de la SaludAsunto(s)
Investigación Biomédica/tendencias , Protección a la Infancia , Atención a la Salud , Pediatría/tendencias , Nacimiento Prematuro/mortalidad , Calidad de Vida , Niño , Humanos , Lactante , Mortalidad Infantil/tendencias , Recién Nacido , National Institutes of Health (U.S.) , Tasa de Supervivencia , Estados UnidosAsunto(s)
Investigación Biomédica/economía , Protección a la Infancia , National Institutes of Health (U.S.)/economía , Apoyo a la Investigación como Asunto/economía , Niño , Preescolar , Departamentos de Hospitales/economía , Hospitales Pediátricos/economía , Humanos , Pediatría/economía , Apoyo a la Investigación como Asunto/tendencias , Estados UnidosAsunto(s)
Donantes de Sangre/estadística & datos numéricos , Seguridad de la Sangre/tendencias , Control de Enfermedades Transmisibles/tendencias , Enfermedades Transmisibles Emergentes/sangre , Enfermedades Transmisibles Emergentes/epidemiología , Animales , Donantes de Sangre/provisión & distribución , Seguridad de la Sangre/historia , Seguridad de la Sangre/métodos , Transfusión Sanguínea/historia , Control de Enfermedades Transmisibles/métodos , Enfermedades Transmisibles Emergentes/prevención & control , Enfermedades Transmisibles Emergentes/transmisión , Congresos como Asunto , Historia del Siglo XXI , Humanos , National Heart, Lung, and Blood Institute (U.S.)/organización & administración , Reacción a la Transfusión , Estados Unidos/epidemiologíaAsunto(s)
National Heart, Lung, and Blood Institute (U.S.)/economía , Evaluación de Programas y Proyectos de Salud/economía , Apoyo a la Investigación como Asunto/economía , Humanos , National Heart, Lung, and Blood Institute (U.S.)/tendencias , Evaluación de Programas y Proyectos de Salud/tendencias , Apoyo a la Investigación como Asunto/tendencias , Estados UnidosRESUMEN
OBJECTIVE: A favorable incidence and severity of graft-vs-host disease is observed in patients transplanted with banked, unrelated, HLA-mismatched umbilical cord blood (UCB) grafts, while the incidence of malignant relapse remains low. CTLA-4 mediates negative T-cell signaling and may contribute to the development of allogeneic tolerance. In this study, we compared protein and mRNA expression of CTLA-4 in stimulated UCB and adult peripheral blood T cells. MATERIALS AND METHODS: T cells were isolated from UCB and adult peripheral blood and stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. Cells were immunostained and analyzed by flow cytometry for both surface and intracellular expression of CTLA-4 in the presence and absence of cyclosporin A, and kinetics of CTLA-4 expression compared. CTLA-4 mRNA expression was measured using quantitative real-time polymerase chain reaction. NFAT1 protein levels were measured by Western blot analysis. RESULTS: These studies demonstrate reduced surface and intracellular expression of CTLA-4 in stimulated UCB T cells compared to adult controls. Furthermore, reduced CTLA-4 protein expression in UCB T cells was noted to be in part transcriptionally regulated, as CTLA-4 mRNA levels also were significantly lower. Reduced CLTA-4 expression by UCB T cells followed the kinetics of delayed and reduced expression of the transcription factor NFAT1 by UCB T lymphocytes during primary stimulation. Moreover, cyclosporin A, which is known to modulate NFAT activation, reduced CTLA-4 protein expression in adult and UCB T cells. CONCLUSION: Reduced expression of the key regulatory proteins CTLA-4 and NFAT-1 may contribute to favorable UCB T lymphocyte allogeneic responses.
Asunto(s)
Antígenos de Diferenciación/biosíntesis , Sangre Fetal/citología , Inmunoconjugados , Proteínas Nucleares , ARN Mensajero/biosíntesis , Linfocitos T/metabolismo , Abatacept , Adulto , Envejecimiento/inmunología , Antígenos CD , Antígenos de Diferenciación/genética , Antígeno CTLA-4 , División Celular/efectos de los fármacos , Ciclosporina/farmacología , Proteínas de Unión al ADN/metabolismo , Citometría de Flujo , Regulación de la Expresión Génica/efectos de los fármacos , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Tolerancia Inmunológica , Inmunosupresores/farmacología , Recién Nacido , Activación de Linfocitos , Factores de Transcripción NFATC , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética , Linfocitos T/efectos de los fármacos , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
The clinical challenges confronting patients with human immunodeficiency virus (HIV) have shifted from acquired immunodeficiency syndrome (AIDS)-related illnesses to chronic diseases, such as coronary artery disease, chronic lung disease, and chronic anemia. With the growing burden of HIV-related heart, lung, and blood (HLB) disease, the National Heart, Lung, and Blood Institute (NHLBI) recognizes it must stimulate and support HIV-related HLB research. Because HIV offers a natural, accelerated model of common pathological processes, such as inflammation, HIV-related HLB research may yield important breakthroughs for all patients with HLB disease. This paper summarizes the cardiovascular recommendations of an NHLBI Working Group, Advancing HIV/AIDS Research in Heart, Lung, and Blood Diseases, charged with identifying scientific priorities in HIV-related HLB disease and developing recommendations to promote multidisciplinary collaboration among HIV and HLB investigators. The working group included multidisciplinary sessions, as well as HLB breakout sessions for discussion of disease-specific issues, with common themes about scientific priorities and strategies to stimulate HLB research emerging in all 3 groups.
Asunto(s)
Investigación Biomédica/organización & administración , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/terapia , Infecciones por VIH/complicaciones , Infecciones por VIH/terapia , National Heart, Lung, and Blood Institute (U.S.) , Protocolos Clínicos , Prioridades en Salud , Humanos , Estados UnidosRESUMEN
Monogenic deficiency diseases provide unique opportunities to define the contributions of individual molecules to human physiology and to identify pathologies arising from their dysfunction. Here we describe a deficiency disease in two human siblings that presented with severe bleeding, frequent infections and osteopetrosis at an early age. These symptoms are consistent with but more severe than those reported for people with leukocyte adhesion deficiency III (LAD-III). Mechanistically, these symptoms arose from an inability to activate the integrins expressed on hematopoietic cells, including platelets and leukocytes. Immortalized lymphocyte cell lines isolated from the two individuals showed integrin activation defects. Several proteins previously implicated in integrin activation, including Ras-associated protein-1 (RAP1) and calcium and diacylglycerol-regulated guanine nucleotide exchange factor-1 (CALDAG-GEF1), were present and functional in these cell lines. The genetic basis for this disease was traced to a point mutation in the coding region of the KINDLIN3 (official gene symbol FERMT3) gene. When wild-type KINDLIN-3 was expressed in the immortalized lymphocytes, their integrins became responsive to activation signals. These results identify a genetic disease that severely compromises the health of the affected individuals and establish an essential role of KINDLIN-3 in integrin activation in humans. Furthermore, allogeneic bone marrow transplantation was shown to alleviate the symptoms of the disease.