Evidence against dopamine D1/D2 receptor heteromers.

Hetero-oligomers of G-protein-coupled receptors have become the subject of intense investigation, because their purported potential to manifest signaling and pharmacological properties that differ from the component receptors makes them highly attractive for the development of more selective pharmacological treatments. In particular, dopamine D1 and D2 receptors have been proposed to form hetero-oligomers that couple to Gαq proteins, and SKF83959 has been proposed to act as a biased agonist that selectively engages these receptor complexes to activate Gαq and thus phospholipase C. D1/D2 heteromers have been proposed as relevant to the pathophysiology and treatment of depression and schizophrenia. We used in vitro bioluminescence resonance energy transfer, ex vivo analyses of receptor localization and proximity in brain slices, and behavioral assays in mice to characterize signaling from these putative dimers/oligomers. We were unable to detect Gαq or Gα11 protein coupling to homomers or heteromers of D1 or D2 receptors using a variety of biosensors. SKF83959-induced locomotor and grooming behaviors were eliminated in D1 receptor knockout (KO) mice, verifying a key role for D1-like receptor activation. In contrast, SKF83959-induced motor responses were intact in D2 receptor and Gαq KO mice, as well as in knock-in mice expressing a mutant Ala(286)-CaMKIIα that cannot autophosphorylate to become active. Moreover, we found that, in the shell of the nucleus accumbens, even in neurons in which D1 and D2 receptor promoters are both active, the receptor proteins are segregated and do not form complexes. These data are not compatible with SKF83959 signaling through Gαq or through a D1/D2 heteromer and challenge the existence of such a signaling complex in the adult animals that we used for our studies.

Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation.

A decrease in dopamine D2 receptor (D2R) binding in the striatum is one of the most common findings in disorders that involve a dysregulation of motivation, including obesity, addiction and attention deficit hyperactivity disorder. As disruption of D2R signaling in the ventral striatum--including the nucleus accumbens (NAc)--impairs motivation, we sought to determine whether potentiating postsynaptic D2R-dependent signaling in the NAc would improve motivation. In this study, we used a viral vector strategy to overexpress postsynaptic D2Rs in either the NAc or the dorsal striatum. We investigated the effects of D2R overexpression on instrumental learning, willingness to work, use of reward value representations and modulation of motivation by reward associated cues. Overexpression of postsynaptic D2R in the NAc selectively increased motivation without altering consummatory behavior, the representation of the value of the reinforcer, or the capacity to use reward associated cues in flexible ways. In contrast, D2R overexpression in the dorsal striatum did not alter performance on any of the tasks. Thus, consistent with numerous studies showing that reduced D2R signaling impairs motivated behavior, our data show that postsynaptic D2R overexpression in the NAc specifically increases an animal's willingness to expend effort to obtain a goal. Taken together, these results provide insight into the potential impact of future therapeutic strategies that enhance D2R signaling in the NAc.

[The approach to hypercholesterolemia in health strategies and plans in Spain: present situation and future proposals].

BACKGROUND: Cardiovascular diseases (CVD) are a major cause of death worldwide and Hypercholesterolemia (HC) is an important cardiovascular risk factor. In Spain, approximately 25% of middle-aged adults suffer from HC. Our objective was to analyse current health strategies and plans in Spain related to CVD and HC in order to define possible future courses of action to bring about better control from a health management and policy perspective. METHODS: The study was observational and descriptive. In the first step, a literature review was carried out, followed by six semi structured interviews. In the second step, a group of 12 experts in the field identified existing barriers to HC control and suggested ways to reduce premature mortality due to CVD. RESULTS: A total of 51 documents were identified, of which 43% referred to HC. There was a high variability at the regional level in the implementation of measures and initiatives for the control of HC. Barriers that were identified were : trivialization of HC, lack of active participation by key stakeholders, lack of understanding of the impact of HC, existing care models and pathways, and short-term health policies that limit the provision of resources for HC care and control. CONCLUSION: Despite the considerable medical and socioeconomic burden of CVD and HC in Spain, the importance of HC is not reflected in health policies. There is a lack of HC control measures, even when they are shown to be highly feasible and beneficial. This article proposes specific measures to improve control of this issue.

Abordaje de la hipercolesterolemia en planes y estrategias de saluden España: estado actual y propuestas de futuro / The approach to hypercholesterolemia in health strategies and plans in Spain: present situation and future proposals

Fundamento: Las enfermedades cardiovasculares (ECV)son la principal causa de muerte a nivel mundial y la hipercolesterolemia (HC) es un importante factor de riesgo cardiovascular (FRCV). En España, aproximadamente un25% de los adultos de mediana edad presentan hipercolesterolemia. Nuestro objetivo fue analizar las estrategias y planes de salud existentes en España respecto a las ECVy a la HC, y definir líneas de actuación para su controldesde la gestión y política sanitaria. Material y métodos: Estudio observacional, descriptivo.En la primera fase se revisó la literatura y se realizaronseis entrevistas semiestructuradas; en una segunda fase,12 expertos identificaron las barreras existentes y propusieron estrategias para reducir la mortalidad prematura por las ECV.Resultados: Se identificaron 51 documentos de planificación, el 43% hacían referencia a la HC. Se detectó una altavariabilidad en la implementación de iniciativas a nivel autonómico para el control de la HC. Las barreras identificadas para explicar estos resultados fueron: banalización de la HC, falta de participación activa de agentes clave, desconocimiento del impacto de la HC, el modelo de atención y los circuitos asistenciales existentes, y las políticas sanitarias a corto plazo y con escasa dedicación de recursos a la HC.Conclusiones: A pesar del impacto en salud y socioeconómico de las ECV y de la HC en España, el peso de la HC en las políticas de salud no parece corresponderse con esa relevancia. Faltan medidas para su abordaje, pese a la evidencia de su efectividad. Este estudio propone medidas concretas para avanzar en su control.(AU)

Background: Cardiovascular diseases (CVD) are a major cause of death worldwide and Hypercholesterolemia (HC) is an important cardiovascular risk factor. In Spain,approximately 25% of middle-aged adults suffer from HC.Our objective was to analyse current health strategiesand plans in Spain related to CVD and HC in order todefine possible future courses of action to bring aboutbetter control from a health management and policy perspective.Methods: The study was observational and descriptive.In the first step, a literature review was carried out, followed by six semi structured interviews. In the second step, a group of 12 experts in the field identified existing barriers to HC control and suggested ways to reduce premature mortality due to CVD. Results: A total of 51 documents were identified, of which 43% referred to HC. There was a high variability at the regional level in the implementation of measures and initiatives for the control of HC. Barriers that were identified were : trivialization of HC, lack of active participation bykey stakeholders, lack of understanding of the impact ofHC, existing care models and pathways, and short-termhealth policies that limit the provision of resources forHC care and control. Conclusion: Despite the considerable medical and socioeconomic burden of CVD and HC in Spain, the importance of HC is not reflected in health policies. There is a lack of HC control measures, even when they are shown to be highly feasible and beneficial. This article proposes specific measures to improve control of this issue.(AU)

Generation of a mouse monoclonal TSH receptor antibody with stimulating activity.

A Balb/c mouse was subjected to genetic immunization with a cDNA construct encoding the human thyrotropin receptor (TSHr). The immune response of the mouse resulted in the production of immunoglobulins recognizing the TSHr in three different assays: (1) flow immunocytometry (FACS) with CHO cells expressing the receptor; (2) receptor-dependent stimulation of cAMP production in the same cell line; and (3) competition with labeled TSH for binding to the receptor. One thousand hybridomas were generated from the spleen of the mouse and their supernatants were screened. A single monoclonal, IRI-SAb1, scored positive in all three assays and was studied further. It stimulated 13-fold cAMP production in TSHr-expressing CHO cells, with an EC50 in the low nanomolar range. When compared with bovine TSH, IRI-SAb1 behaved as a partial agonist. Contrary to the expectation from the characteristic of autoantibodies of Graves' patients, IRI-SAb1 recognized a linear epitope, which was localized in a segment encompassing the first 281 residues of the receptor.

Glomerulonefritis membranoproliferativa (GNMP): correlaciones clínico-patológicas y terapéuticas / Membranoproliferative glomerulonephritis: clinical-pathological and therapeutic correlations

La GNMP, una entidad crónica y progresiva, frecuente en niños y adultos, produce insuficiencia renal terminal en un número significativo de pacientes. Estudios inmunohistopatológicos permiten distinguir las variedades 1 y 2 y posiblemente una tercera, cuyas manifestaciones clínicas particularmente en el niño menor son indistinguibles y en algunos enfermos semejan una GN difusa aguda de etiología estreptocócica o un síndrome nefrótico idiopático. En estos casos se requieren determinaciones seriadas del complemento sérico (C3 y C4) y biopsia renal para el diagnóstico diferencial clínico y tipificación histológica. Debido a su progresividad, se han ensayado numerosos regímenes terapéuticos. En la actualidad, los estudios que demuestran la participación de las plaquetas y de las células mononucleares en el proceso destructivo glomerular proporcionan un trasfondo racional para el empleo de medicaciones inhibidoras de la agregación y activación plaquetaria (aspirina y dipridamol) y antiinflamatorios de alta potencia como la prednisona. Estas substancias, usadas en conjunto diariamente y en forma alternada, respectivamente, en regímenes prolongados (3 a 5 años o más) e iniciados a los pocos meses de hecho el diagnóstico parecen haber logrado un control efectivo de la progresión de la glomerulopatía sin grandes efectos nocivos debidos al tratamiento. Su uso combinado ha aumentado significativamente la sobrevida de pacientes pediátricos y adultos en series clínicas publicadas recientemente. Es nuestra convicción que el tratamiento combinado descrito (aspirina-dipridamol-prednisona) es la terapia de elección en la GNMP independientemente de su tipo histológico y que otros tratamientos o la ausencia de este no es justificable

Coagulación intravascular diseminada inducida en la rata: efecto sobre la concentración plasmática de fibronectina / Disseminated intravascular coagulation induced in rats: effect on plasma concentration of fibronectin

La inducción de coagulación intravascular diseminada (CID) o una reacción semejante a la CID por una sola inyección de una substancia polianiónica: polianetol sulfonato (Liquoid) produjo microtrombosis renal y pulmonar. Las concentraciones plasmáticas de fibronectina (Fn) disminuyeron en 63% (P 0.01) en los primeros 15 min. que siguieron a la inyección y se mantuvieron disminuídos por lo menos 90 min., sugiriendo que, in vivo, el polianión interviene en la coprecipitación del Fibrógeno-Fibronectina ya que cuando las concentraciones circulantes de Fn son bajas aumentan la localización de Fibrinógeno I125 en los riñones y pulmones después de inyectar liquoid. En la microvasculatura renal y pulmonar se encontraron trombos que contenían fibrinógeno, fibrina, Fn., y antígeno relacionado con el factor VIII (VIII ag). Los estudios de inmuno emborronamiento mostraron cantidades significativas de productos de degradación de la Fn. Los estudios "in vitro" sugieren que el liquoid altera la movilidad electroforética pero no la detección de la Fn por inmunodifusión. De esta manera la reacción semejante a CID inducida por el polianión agrega y secuestra Fn en los microtrombos y resulta en fragmentación molecular de ésta. Como la Fn es importante para la función retículoendotelial es razonable suponer que la reducción de su concentración y su degradación asociada con la CID puedan contribuir significativamente a las alteraciones histopatológicas mediadas por la coagulopatía de consumo

Nuevos conceptos acerca del síndrome hemolítico urémico / New concepts about hemolytic-uremic syndrome

El síndrome hemolítico urémico (SHU) es heterogéneo en su etiología, fisiopatología, tratamiento y diagnóstico. En esta presentación se analizan algunos aspectos de su epidemiología, clínica e inmunopatología. La distribución del SHU es universal, pero en Argentina, sur de Europa, Sudáfrica y oeste de USA se detecta con mayor frecuencia que en el resto de los países. Los estudios inmunopatológicos muestran lesiones angiopáticas trombóticas consistentes en alteración generalizada del epitelio capilar y arteriolar. Entre los factores que aparentemente participan en la génesis del síndrome se analizan la disminución de los niveles de prostaglandina PGT2, del factor de von Willebrand y las toxinas de origen microbiano. La diálisis es una de las herramientas más útiles en el manejo del SHU. A pesar de los actuales conocimientos, todavía se requiere más investigación para conocer los mecanismos íntimos del síndrome