Effect of primary care availability and health insurance coverage on risk and cost of Preventable Hospitalizations in Harris County

Preventable Hospitalizations (PHs) are hospitalizations that can be avoided with appropriate and timely care in the ambulatory setting and hence are closely associated with primary care access in a community. Increased primary care availability and health insurance coverage may increase primary care access, and consequently may be significantly associated with risks and costs of PHs. Objective. To estimate the risk and cost of preventable hospitalizations (PHs); to determine the association of primary care availability and health insurance coverage with the risk and costs of PHs, first alone and then simultaneously; and finally, to estimate the impact of expansions in primary care availability and health insurance coverage on the burden of PHs among non-elderly adult residents of Harris County. Methods. The study population was residents of Harris County, age 18 to 64, who had at least one hospital discharge in a Texas hospital in 2008. The primary independent variables were availability of primary care physicians, availability of primary care safety net clinics and health insurance coverage. The primary dependent variables were PHs and associated hospitalization costs. The Texas Health Care Information Collection (THCIC) Inpatient Discharge data was used to obtain information on the number and costs of PHs in the study population. Risk of PHs in the study population, as well as average and total costs of PHs were calculated. Multivariable logistic regression models and two-step Heckman regression models with log-transformed costs were used to determine the association of primary care availability and health insurance coverage with the risk and costs of PHs respectively, while controlling for individual predisposing, enabling and need characteristics. Predicted PH risk and cost were used to calculate the predicted burden of PHs in the study population and the impact of expansions in primary care availability and health insurance coverage on the predicted burden. Results. In 2008, hospitalized non-elderly adults in Harris County had 11,313 PHs and a corresponding PH risk of 8.02%. Congestive heart failure was the most common PH. PHs imposed a total economic burden of $84 billion at an average of $7,449 per PH. Higher primary care safety net availability was significantly associated with the lower risk of PHs in the final risk model, but only in the uninsured. A unit increase in safety net availability led to a 23% decline in PH odds in the uninsured, compared to only a 4% decline in the insured. Higher primary care physician availability was associated with increased PH costs in the final cost model (β=0.0020; p<0.05). Lack of health insurance coverage increased the risk of PH, with the uninsured having 30% higher odds of PHs (OR=1.299; p<0.05), but reduced the cost of a PH by 7% (β=-0.0668; p<0.05). Expansions in primary care availability and health insurance coverage were associated with a reduction of about $1.6 million in PH burden at the highest level of expansion. Conclusions. Availability of primary care resources and health insurance coverage in hospitalized non-elderly adults in Harris County are significantly associated with the risk and costs of PHs. Expansions in these primary care access factors can be expected to produce significant reductions in the burden of PHs in Harris County.^

Exposure to nonsteroidal anti-inflammatory drugs and weight loss and hospitalization in non-small cell lung cancer patients

Background. Cancer cachexia is a common syndrome complex in cancer, occurring in nearly 80% of patients with advanced cancer and responsible for at least 20% of all cancer deaths. Cachexia is due to increased resting energy expenditure, increased production of inflammatory mediators, and changes in lipid and protein metabolism. Non-steroidal anti-inflammatory drugs (NSAIDs), by virtue of their anti-inflammatory properties, are possibly protective against cancer-related cachexia. Since cachexia is also associated with increased hospitalizations, this outcome may also show improvement with NSAID exposure. ^ Design. In this retrospective study, computerized records from 700 non-small cell lung cancer patients (NSCLC) were reviewed, and 487 (69.57%) were included in the final analyses. Exclusion criteria were severe chronic obstructive pulmonary disease, significant peripheral edema, class III or IV congestive heart failure, liver failure, other reasons for weight loss, or use of research or anabolic medications. Information on medication history, body weight and hospitalizations was collected from one year pre-diagnosis until three years post-diagnosis. Exposure to NSAIDs was defined if a patient had a history of being treated with NSAIDs for at least 50% of any given year in the observation period. We used t-test and chi-square tests for statistical analyses. ^ Results. Neither the proportion of patients with cachexia (p=0.27) nor the number of hospitalizations (p=0.74) differed among those with a history of NSAID use (n=92) and those without (n=395). ^ Conclusions. In this study, NSAID exposure was not significantly associated with weight loss or hospital admissions in patients with NSCLC. Further studies may be needed to confirm these observations.^

Significado de la pérdida de peso en pacientes hospitalizados

La pérdida involuntaria de peso es un predictor independiente de morbimortalidad, especialmente en ancianos, pacientes con cáncer, SIDA y postoperatorios. Con el objeto de determinar la significación clínica de la pérdida de peso en pacientes internados, se estudiaron 100 pacientes. La edad media fue de 57.6 años (DS±11.04); 38% mayores de 65 años y 62% hombres. La permanencia hospitalaria media fue de 13 días, superior a la media del servicio (7,3 días). El 61% pertenecían a clase social baja y 25% eran desocupados. En el 100% fue involuntaria y en ninguno fue causa de hospitalización. Tenían hiporexia 61 pacientes y 57 malnutrición. El IMC fue inferior a 20 en el 50% de los casos. La causa fue determinada en el 70% y en 72% se relacionó con la enfermedad de base, en 27% con trastornos alimentarios y con fármacos en 1%. Las etiologías más frecuentes fueron: neoplasias (34 pacientes), enfermedades crónicas (24), TBC (3) y SIDA (3). El 46% desarrollaron infecciones nosocomiales y el 100% tenían comórbidas (alcoholismo 26%, depresión 22%, diabetes 20%, EPOC 11%, insuficiencia cardiaca, cirrosis y demencia 8% c/u e insuficiencia renal 6%). La mortalidad fue del 18% y las causas más frecuentes fueron sepsis severa, fallo multiorgánico y neoplasias. Conclusiones: La pérdida significativa de peso en el paciente hospitalizado se caracterizó por ser involuntaria, asociada a clase social baja, a malnutrición, a alta taza de comorbilidad, a predisposición a infecciones nosocomiales, secundaria a enfermedades crónicas, neoplasias, tuberculosis y SIDA y a una tasa de mortalidad elevada.

La Ordenación del Territorio en las Ciudades Globales Europeas: El caso de Madrid

En la Comunidad de Madrid el modelo de ocupación del territorio en las dos últimas décadas ha obedecido a factores de oferta del mercado y no a las necesidades de la población, ello provoca un consumo de suelo y de recursos que conducen a una sobrexplotación insostenible. Las metrópolis globales están experimentando rápidas e intensas transformaciones, basadas en los paradigmas emergentes de la globalización, la gobernanza, la metropolizacion y la dispersión de las actividades en el territorio y a través de ellos se abordan los planes de Londres, París y las tentativas de Madrid. La globalización provoca la pérdida de soberanía de las administraciones publicas y la competitividad entre las ciudades globales en Europa, Londres, Paris y Madrid, son centros de poder, de concentración y crecimiento donde se produce la dualización del espacio y donde la desigualdad participa de la restructuración urbana, concentración de pobreza frente a espacios de la nueva clase emergente en donde dominan los sectores de servicios y las tecnologías de la información. Frente al desarrollo urbano neoliberal de regulación a través del mercado y basada en criterios de eficiencia de la Nueva Gestión Pública, se vislumbra la posibilidad de que la sociedad se administre a si misma por medio de acciones voluntarias y responsables que promuevan los intereses colectivos mediante el reconocimiento de su propia identidad, introduciendo el concepto de gobernanza. Frente, a la explotación del territorio por parte de la sociedad extractiva que genera corrupcion, se propone un modelo de cooperación público-privada basado en la confianza mutua, un marco regulador estable, la transparencia y la información a cuyo flujo más homogéneo contribuirán sin duda las TICs. En todo este proceso, las regiones metropolitanas en Europa se erigen como motores del crecimiento, donde los límites administrativos son superados, en un territorio cada vez más extendido y donde los gobiernos locales tienen que organizarse mediante un proceso de cooperación en la provisión de servicios que ayuden a evitar los desequilibrios territoriales. El fenómeno de la dispersión urbana en desarrollos de baja densidad, los centros comerciales periféricos, la expulsión hacia la periferia de las actividades de menor valor añadido y la concentración de funciones directivas en el centro, conducen a una fragmentación del territorio en islas dependientes del automóvil y a procesos de exclusión social por la huida de las rentas altas y la expulsión de las rentas bajas de los centros urbanos. Se crean fragmentos monofuncionales y discontinuos, apoyados en las autovías, lugares carentes de identidad y generadores de despilfarro de recursos y una falta de sostenibilidad ambiental, económica y social. El estudio de la cultura de la planificación en Europa ayuda a comprender los diferentes enfoques en la ordenación del territorio y el proceso de convergencia entre las diferentes regiones. Los documentos de la UE se basan en la necesidad de la competitividad para el crecimiento europeo y la cohesión social y en relación al territorio en los desarrollos policéntricos, la resolución del dualismo campo-ciudad, el acceso equilibrado a las infraestructuras, la gestión prudente de la naturaleza, el patrimonio y el fomento de la identidad. Se proponen dos niveles de estudio uno actual, los últimos planes de Londres y Paris y el otro la evolución de las tentativas de planes en la Región madrileña siempre en relación a los paradigmas emergentes señalados y su reflejo en los documentos. El Plan de Londres es estratégico, con una visión a largo plazo, donde se confiere un gran interés al proceso, al papel del alcalde como líder y su adaptación a las circunstancias cambiantes, sujeto a las incertidumbres de una ciudad global. El desarrollo del mismo se concibe a través de la colaboración y cooperación entre las administraciones y actores. La estructura del documento es flexible, establece orientaciones y guías indicativas, para la redacción de los planes locales, no siendo las mismas vinculantes y con escasa representación grafica. El Plan de París es más un plan físico, similar al de otros centros europeos, trabaja sobre los sectores y sobre los territorios, con información extensa, con características de “Plan Latino” por la fuerza de la expresión gráfica, pero al mismo tiempo contiene una visión estratégica. Es vinculante en sus determinaciones y normativas, se plantea fomentar, pero también prohibir. Ambos planes tratan la competitividad internacional de sus centros urbanos, la igualdad social, la inclusión de todos los grupos sociales y la vivienda como una cuestión de dignidad humana. Londres plantea la gobernanza como cooperación entre sector público-privado y la necesaria cooperación con las regiones limítrofes, en París las relaciones están más institucionalizadas resaltando la colaboración vertical entre administraciones. Ambos plantean la densificación de nodos servidos por transporte público, modos blandos y el uso los TODs y la preservación de la infraestructura verde jerarquizada, la potenciación de la red azul y la mejora del paisaje de las periferias. En las “tentativas” de planes territoriales de Madrid se constata que estuvieron sujetas a los ciclos económicos. El primer Documento las DOT del año 1984, no planteaba crecimiento, ni económico ni demográfico, a medio plazo y por ello no proponía una modificación del modelo radio concéntrico. Se trataba de un Plan rígido volcado en la recuperación del medio rural, de la ciudad, el dimensionamiento de los crecimientos en función de las dotaciones e infraestructuras existentes. Aboga por la intervención de la administración pública y la promoción del pequeño comercio. Destaca el desequilibrio social en función de la renta, la marginación de determinados grupos sociales, el desequilibrio residencia/empleo y la excesiva densidad. Incide en la necesidad de viviendas para los más desfavorecidos mediante el alquiler, la promoción suelo público y la promoción del ferrocarril para dar accesibilidad al espacio central. Aboga por el equipamiento de proximidad y de pequeño tamaño, el tratamiento paisajístico de los límites urbanos de los núcleos y el control de las actividades ilegales señalando orientaciones para el planeamiento urbano. Las Estrategias (1989) contienen una visión: la modificación del modelo territorial, mediante la intervención pública a través de proyectos. Plantea la reestructuración económica del territorio, la reconversión del aparato productivo, la deslocalización de actividades de escaso valor añadido y una mayor ubicuidad de la actividad económica. Incide en la difusión de la centralidad hacia el territorio del sur, equilibrándolo con el norte, tratando de recomponer empleo y residencia, integrando al desarrollo económico las periferias entre sí y con el centro. Las actuaciones de transporte consolidarían las actuaciones, modificando el modelo radio concéntrico facilitando la movilidad mediante la red de cercanías y la intermodalidad. El plan se basaba en el liderazgo del Consejero, no integrando sectores como el medio ambiente, ni estableciendo un documento de seguimiento de las actuaciones que evaluara los efectos de las políticas y su aportación al equilibrio territorial, a través de los proyectos realizados. El Documento Preparatorio de las Bases (1995), es más de un compendio o plan de planes, recoge análisis y propuestas de los documentos anteriores y de planes sectoriales de otros departamentos. Presenta una doble estructura: un plan físico integrador clásico, que abarca los sectores y territorios, y recoge las Estrategias previas añadiendo puntos fuertes, como el malestar urbano y la rehabilitación el centro. Plantea la consecución del equilibrio ambiental mediante el crecimiento de las ciudades existentes, la vertebración territorial basada en la movilidad y en la potenciación de nuevas centralidades, la mejora de la habitabilidad y rehabilitación integral del Centro Urbano de Madrid, y la modernización del tejido productivo existente. No existe una idea-fuerza que aglutine todo el documento, parte del reconocimiento de un modelo existente concentrado y congestivo, un centro urbano dual y dos periferias al este y sur con un declive urbano y obsolescencia productiva y al oeste y norte con una dispersión que amenaza al equilibrio medioambiental. Señala como aspectos relevantes, la creciente polarización y segregación social, la deslocalización industrial, la aparición de las actividades de servicios a las empresas instaladas en las áreas metropolitanas, y la dispersión de las actividades económicas en el territorio por la banalización del uso del automóvil. Se plantea el reto de hacer ciudad de la extensión suburbana y su conexión con el sistema metropolitano, mediante una red de ciudades integrada y complementaria, en búsqueda de un mayor equilibrio y solidaridad territorial. Las Bases del PRET (1997) tenían como propósito iniciar el proceso de concertación en que debe basarse la elaboración del Plan. Parte de la ciudad mediterránea compacta, y diversa, y de la necesidad de que las actividades económicas, los servicios y la residencia estén en proximidad, resolviéndolo mediante una potente red de transporte público que permitiese una accesibilidad integrada al territorio. El flujo de residencia hacia la periferia, con un modelo ajeno de vivienda unifamiliar y la concentración del empleo en el centro producen desequilibrio territorial. Madrid manifiesta siempre apostó por la densificación del espacio central urbanizado, produciendo su congestión, frente al desarrollo de nuevos suelos que permitieran su expansión territorial. Precisa que es necesario preservar los valores de centralidad de Madrid, como generador de riqueza, canalizando toda aquella demanda de centralidad, hacia espacios más periféricos. El problema de la vivienda no lo ve solo como social, sino como económico, debido a la pérdida de empleos que supone su paralización. Observa ya los crecimientos residenciales en el borde de la region por el menor valor del suelo. Plantea como la política de oferta ha dado lugar a un modelo de crecimiento fragmentado, desequilibrado, desestructurado, con fuertes déficits dotacionales y de equipamiento, que inciden en la segregación espacial de las rentas, agravando el proceso de falta de identidad morfológica y de desarraigo de los valores urbanos. El plan señalaba que la presión sobre el territorio creaba su densificación por las limitaciones de espacio, Incidía en limitar el peso de la intervención pública, no planteando propuestas de cooperación público-privado. La mayor incoherencia estriba en que los objetivos eran innovadores y coinciden en su mayoría con las propuestas estudiadas de Londres o Paris, pero se intentan implementar a través de un cambio hacia un modelo reticulado homogéneo, expansivo sobre el territorio, que supone un consumo de suelo y de infraestructuras para solucionar un problema inexistente, la gestión de la densidad. Durante las dos últimas décadas en ausencia de un plan regional, la postura neoliberal fue la de un exclusivo control de legalidad del planeamiento, los municipios entraron en un proceso de competencia para aprovechar las iniciales ventajas económicas de los crecimientos detectados, que proporcionaban una base económica “sólida” a unos municipios con escasos recursos en sus presupuestos municipales. La legislación se modifica a requerimiento de grupos interesados, no existiendo un marco estable. Se pierde la figura del plan no solo a nivel regional, si no en los sectores y el planeamiento municipal donde los municipios tiende a basarse en modificaciones puntuales con la subsiguiente pérdida del modelo urbanístico. La protección ambiental se estructura mediante un extenso nivel de figuras, con diversidad de competencias que impide su efectiva protección y control. Este proceso produce un despilfarro en la ocupación del suelo, apoyada en las infraestructuras viarias, y un crecimiento disperso y de baja densidad, cada vez más periférico, produciéndose una segmentación social por dualización del espacio en función de niveles de renta. Al amparo del boom inmobiliario, se produce una falta de política social de vivienda pública, más basada en la dinamización del mercado con producción de viviendas para rentas medias que en políticas de alquiler para determinados grupos concentrándose estas en los barrios desfavorecidos y en la periferia sur. Se produce un incremento de la vivienda unifamiliar, muchas veces amparada en políticas públicas, la misma se localiza en el oeste principalmente, en espacios de valor como el entorno del Guadarrama o con viviendas más baratas por la popularización de la tipología en la frontera de la Región. El territorio se especializa a modo de islas monofuncionales, las actividades financieras y de servicios avanzados a las empresas se localizan en el norte y oeste próximo, se pierde actividad industrial que se dispersa más al sur, muchas veces fuera de la región. Se incrementan los grandes centros comerciales colgados de las autovías y sin población en su entorno. Todo este proceso ha provocado una pérdida de utilización del transporte público y un aumento significativo del uso del vehículo privado. En la dos últimas décadas se ha producido en la región de Madrid desequilibrio territorial y segmentación social, falta de implicación de la sociedad en el territorio, dispersión del crecimiento y un incremento de los costes ambientales, sociales y económicos, situación, que solo, a través del uso racional del territorio se puede reconducir, apoyado en una planificación integrada sensible y participativa. ABSTRACT In Madrid the model of land occupation in the past two decades has been driven by market supply factors rather than the needs of the population. This results in a consumption of land and resources that leads to unsustainable overexploitation. Addressing this issue must be done through sensitive and participatory integrated planning. Global cities are experiencing rapid and intense change based on the emerging paradigms of globalization, governance, metropolization and the dispersion of activities in the territory. Through this context, a closer look will be taken at the London and Paris plans as well as the tentative plans of Madrid. Globalization causes the loss of state sovereignty and the competitiveness among global cities in Europe; London, Paris and Madrid. These are centres of power, concentration and growth where the duality of space is produced, and where inequality plays a part in urban restructuration. There are concentrated areas of poverty versus areas with a new emerging class where the services sector and information technologies are dominant. The introduction of ICTs contributes to a more homogeneous flow of information leading, us to the concept of governance. Against neoliberal urban development based on free market regulations and efficiency criteria as established by the “New Public Management”, emerge new ways where society administers itself through voluntary and responsible actions to promote collective interests by recognizing their own identity. A new model of public-private partnerships surfaces that is based on mutual trust, transparency, information and a stable regulatory framework in light of territorial exploitation by the “extractive society” that generates corruption. Throughout this process, European metropolitan regions become motors of growth where administrative boundaries are overcome in an ever expanding territory where government is organized through cooperative processes to provide services that protect against regional imbalances. Urban sprawl or low-density development as seen in peripheral shopping centres, the off-shoring of low added-value activities to the periphery, and the concentration of business and top management functions in the centre, leads to a fragmentation of the territory in automobile dependent islands and a process of social exclusion brought on by the disappearance of high incomes. Another effect is the elimination of low income populations from urban centres. In consequence, discontinuous expansions and mono-functional places that lack identity materialize supported by a highway network and high resource consumption. Studying the culture of urban planning in Europe provides better insight into different approaches to spatial planning and the process of convergence between different regions. EU documents are based on the need of competitiveness for European growth and social cohesion. In relation to polycentric development territory they are based on a necessity to solve the dualism between field and city, balanced access to infrastructures, prudent management of nature and solidifying heritage and identity Two levels of study unfold, the first being the current plans of London and Île-de-France and the second being the evolution of tentative plans for the Madrid region as related to emerging paradigms and how this is reflected in documents. The London Plan is strategic with a long-term vision that focuses on operation, the role of the mayor as a pivotal leader, and the adaptability to changing circumstances brought on by the uncertainties of a global city. Its development is conceived through collaboration and cooperation between governments and stakeholders. The document structure is flexible, providing guidance and indicative guidelines on how to draft local plans so they are not binding, and it contains scarce graphic representation. The Plan of Paris takes on a more physical form and is similar to plans of other European centres. It emphasizes sectors and territories, using extensive information, and is more characteristic of a “Latin Plan” as seen in its detailed graphic expression. However, it also contains a strategic vision. Binding in its determinations and policy, it proposes advancement but also prohibition. Both plans address the international competitiveness of urban centres, social equality, inclusion of all social groups and housing as issues of human dignity. London raises governance and cooperation between public and private sector and the need for cooperation with neighbouring regions. In Paris, the relations are more institutionalized highlighting vertical collaboration between administrations. Both propose nodes of densification served by public transportation, soft modes and the use of TOD, the preservation of a hierarchical green infrastructure, and enhancing the landscape in urban peripheries. The tentative territorial plans for the Madrid region provide evidence that they were subject to economic cycles. The first document of master guidelines (1984) does not address either economic or demographic growth in the mid term and therefore does not propose the modification of the radio-concentric model. It is a rigid plan focused on rural and urban recovery and the dimensioning of growth that depends on endowments and infrastructures. It advocates government intervention and promotes small business. The plan emphasizes social imbalance in terms of income, marginalization of certain social groups, the imbalance of residence/employment and excessive density. It stresses the need for social rent housing for the underprivileged, promotes public land, and the supports rail accessibility to the central area. It backs facilities of proximity and small size, enhancing the landscaping of city borders, controlling illegal activities and draws out guidelines for urban planning. The strategies (1989) contain a vision: Changing the territorial model through public intervention by means of projects. They bring to light economic restructuring of territory, the reconversion of the productive apparatus, relocation of low value-added activities, and greater ubiquity of economic activity. They also propose the diffusion of centrality towards southern territories, balancing it with the north in an attempt to reset employment and residence that integrates peripheral economic development both in the periphery and the centre. Transport would consolidate the project, changing the radius-concentric model and facilitating mobility through a commuter and inter-modality network. The plan derives itself from the leadership of the minister and does not integrate sectors such as environment. It also does not incorporate the existence of a written document that monitors performance to evaluate the effects of policies and their contribution to the territorial balance. The Preparatory Document of the Bases, (1995) is more a compendium, or plan of plans, that compiles analysis and proposals from previous documents and sectorial plans from other departments. It has a dual structure: An integrating physical plan covering the sectors and territories that includes the previous strategies while adding some strengths. One such point is the urban discomfort and the rehabilitation of the centre. It also poses the achievement of environmental balance through the growth of existing cities, the territorial linking based on mobility, strengthening new centres, improving the liveability and comprehensive rehabilitation of downtown Madrid, and the modernization of the existing production network. There is no one powerful idea that binds this document. This is due to the recognition of an existing concentrate and congestive model, a dual urban centre, two eastern and southern suburbs suffering from urban decay, and an obsolescent productive north and west whose dispersion threatens the environmental balance. Relevant aspects the document highlights are increasing polarization and social segregation, industrial relocation, the emergence of service activities to centralized companies in metropolitan areas and the dispersion of economic activities in the territory by the trivialization of car use. It proposes making the city from the suburban sprawl and its connection to the metropolitan system through a network of integrated and complementary cities in search of a better balance and territorial solidarity. The Bases of PRET (1997) aims to start the consultation process that must underpin the development of the plan. It stems from a compact and diverse Mediterranean city along with the need for economic activities, services and residences that are close. To resolve the issue, it presents a powerful network of public transport that allows integrated accessibility to the territory. The flow of residence to the periphery based on a foreign model of detached housing and an employment concentration in the centre produces territorial imbalance. Madrid always opted for the densification of the central space, producing its congestion, against the development of new land that would allow its territorial expansion. The document states that the necessity to preserve the values of the housing problem is not only viewed as social, but also economic due to the loss of jobs resulting from their paralysis. It notes the residential growth in the regional border due to the low price of land and argues that the policy of supply has led to a fragmented model of growth that is unbalanced, unstructured, with strong infrastructure and facility deficits that affect the spatial segregation of income and aggravate the lack of morphological identity, uprooting urban values. The pressure on the territory caused its densification due to space limitation; the proposed grid model causes land consumption and infrastructure to solve a non-problem, density. Focusing on limiting the weight of public intervention, it does not raise proposals for public-private cooperation. The biggest discrepancy is that the targets were innovative and mostly align with the proposals in London and Paris. However, it proposes to be implemented through a shift towards a uniform gridded model that is expansive over territory. During the last two decades, due to the absence of a regional plan, a neoliberal stance held exclusive control of the legality of urban planning. The municipalities entered a competition process to take advantage of initial economic benefits of such growth. This provided a “solid” economic base for some municipalities with limited resources in their municipal budgets. The law was amended without a legal stable framework at the request of stakeholders. The character of the plan is lost not only regionally, but also in the sectors and municipal planning. This tends to be based on specific changes with the loss of an urban model. Environmental protection is organized through an extensive number of protection figures with diverse competencies that prevent its effective protection. This process squanders the use of the land, backed by increasing road infrastructure, dispersed occupations with low-density growth causing a social segmentation due to space duality based on income levels. During the housing boom, there is a reduction in social public housing policy mostly due to a boost in the market of housing production for average incomes than in rental policies for needy social groups that focus on disadvantaged neighbourhoods and southern suburbs. As a result, there is an increase in single-family housing, often protected by public policy. This is located primarily in the west in areas of high environmental value such as Guadarrama. There is also cheaper housing due to the popularization of typology in the border region. There, territory works as a mono-functional islands. Financial activities and advanced services for companies are located to the north and west where industrial activity is lost as it migrates south, often outside the region. The number of large shopping centres hanging off the highway infrastructure with little to no surrounding population increases. This process leads to the loss of dependency on public transport and a significant increase in the use of private vehicles. The absence of regional planning has produced more imbalance, more social segmentation, more dispersed growth and a lot of environmental, social and economic costs that can only be redirected through rational territorial.

Rem : a los dos lados del espejo = (Rem at both sides of the mirror)

Cuando se trata de Rem Koolhaas, su espejo no refleja una sola imagen sino múltiples, es un prisma poliédrico. Su espejo nos devuelve el Rem mediático, el intelectual, el conceptualizador, el constructor, el analista, el periodista, el actor... En el caso de esta investigación, fijamos el punto de mira en el Rem COMUNICADOR. “Rem a los dos lados del espejo” se enmarca en una investigación sobre los medios de comunicación de arquitectura, su reflejo en la producción arquitectónica y viceversa. Se trata de llegar a discernir si comunicación y producción arquitectónica colisionan y confluyen en el caso de grandes comunicadores como Rem Koolhaas, si el mensaje y el medio transmisor adquieren las mismas cualidades. Centrándose en la figura de Rem Koolhaas, la tesis aborda la evolución de su faceta comunicativa y las transformaciones sucesivas en el campo de la comunicación arquitectónica, en paralelo a su evolución conceptual a lo largo de su trayectoria. La investigación, por tanto, no se centra tanto en su componente teórica o en la práctica arquitectónica de OMA, sino en la exposición de su producción al mundo, especialmente a través de sus ensayos y libros. “Delirious New York” y “SMLXL” son un reflejo del momento conceptual en que se inscriben, y contienen mucha información sobre los referentes gráficos que irremediablemente han influido en su composición. Especialmente, la aparición de “SMLXL” supuso un revulsivo para el mundo de la comunicación arquitectónica, porque puso el foco sobre la importancia de dejar atrás un discurso narrativo linea y unifocal, para afrontar la comunicación barajando múltiples variables, y aproximaciones, en un proceso similar al desarrollo de un proyecto de arquitectura. Presenta un diseño muy novedoso y una edición extremadamente cuidada, que atiende a parámetros mucho más ambiciosos que los meramente narrativos. Profundiza en la necesidad de una temática global, planteando cuál es la aproximación más apropiada para cada uno de los proyectos que describe, transmitiendo al lector una percepción más allá de lo estrictamente visual, más próximo a lo sensorial. Además, su enorme repercusión a nivel internacional y el gran interés que despertó (no solamente entre los arquitectos, sino también entre diseñadores gráficos, publicistas, personas provenientes de todo tipo de tendencias artísticas y público en general), provocó la globalización del fenómeno de las publicaciones arquitectónicas y puso de manifiesto la importancia de la comunicación como una disciplina en sí misma, dentro de la producción arquitectónica en la era actual. A pesar de la importancia de “SMLXL” a todos los niveles, la presente tesis plantea que, donde realmente se culmina esa experiencia comunicativa, es en “Content”, al incluir nuevos parámetros relacionados con la fusión conceptual de continente y contenido. Es en esta publicación donde el objeto de la comunicación y la expresión de la misma se convierten en un único elemento, que se rige por leyes similares. En este caso, la ley fundamental es la aplicación hasta sus máximas consecuencias de la “cultura de la congestión”, tanto en el mensaje como en el medio, generando lo que hemos convenido en denominar “comunicación congestiva”. Esta concepción deviene en que necesariamente se materialice como un producto efímero, desechable, casi virtual, porque responde a las condiciones de un momento muy concreto y específico y fuera de ese contexto pierde su significación.. La “cultura de la congestión” empieza a surgir en los planteamientos de Koolhaas en la Architectural Association School of Architecture de Londres, bajo la tutela de Elia Zenghelis. Posteriormente se desarrolla en su manifiesto retroactivo sobre Manhattan, “Delirious New York”, donde declara la guerra abierta al urbanismo del movimiento moderno y afirma que la ciudad realmente contemporánea es aquella que es fruto de un desarrollo no planificado, hiperdensa y posible gracias a los avances tecnológicos de su era. Finalmente comienza a materializarse en la Diploma Unit 9 de la AA, donde entra como profesor en 1975, dejando una huella indeleble en las generaciones posteriores de arquitectos que pasaron dicha unidad. Rem Koolhaas es ante todo un intelectual y por ello, todo el constructo teórico sobre la metrópolis comienza a reflejarse en su obra a través de OMA desde el comienzo de su producción. Podemos decir a grandes rasgos que su carrera está marcada por dos hitos históricos fundamentales que determinan tres etapas diferenciadas en su producción. En sus primeros años de profesión, Koolhaas sigue fascinado por la metrópolis urbana y la aplicación del método paranoico crítico a su producción arquitectónica. Es un arquitecto profundamente surrealista. Entiende este método como una estrategia de conocimiento y aproximación al mundo que le rodea: “dejar salir el inconsciente pero sostenerlo con las muletas de la racionalidad”. Pero lo que en realidad le interesa es su aplicación a la gran escala, el “Bigness”, y por ello, participa en proyectos muy ambiciosos de los que surgen conceptos que, más allá de resultar premiados o no, han dejado una huella ideológica en el devenir de la arquitectura. Entre estos proyectos, cabe destacar su propuesta para el Parque de la Villette o la Très Grande Bibliotèque de París. Sus proyectos de esta época destilan una gran carga conceptual, que devienen en unos interiores sorprendentes pero una apariencia exterior sobria o incluso podríamos decir "povera", por el uso de materiales efímeros, poco habituales en la macro-arquitectura hasta ese momento. Súbitamente, en 1997, explotó el denominado “Efecto Bilbao”, de la mano de Frank Gehry (1). El Museo Guggenheim de Bilbao, con su espectacularidad, sus formas pregnantes e imposibles, impacta al mundo. Nace la era de la “Arquitectura del Espectáculo”; la transformación de la ciudad a través de ICONOS que actúen como nodos de atracción y concentración en torno a los cuales supuestamente se revitaliza la actividad económica, cultural y sociopolítica de la ciudad, como si a través de un único gesto se pudieran regenerar todos los tejidos internos de la urbe. Rem Koolhaas comprende rápidamente que la aproximación a la ciudad ha cambiado y, sobre todo, el mercado. En el mundo de la globalización, la única manera de llegar a materializar el “Bigness”, es encerrando sus ejercicios intelectuales en formas pregnantes, bellas, icónicas, espectaculares. Koolhaas encuentra su marca personal en la estética “Stealth”, proveniente de los aviones de combate facetados para evitar los radares, elaborados en los años 80. De esta época surgen proyectos como la Casa da Música de Oporto o la Biblioteca de Seattle; ambos edificios son iconos facetados, de belleza pregnante, que dejan una huella indeleble en la ciudad y provocan, al igual que el Guggenheim, un cierto efecto de recuperación y revitalización en el entorno en que se asientan, al menos de manera temporal. En cualquier caso, Koolhaas nunca abandona los ejercicios meramente teóricos, pero segrega su actividad en dos: OMA produce aquello que tiene vocación de ser construido y se rige por los parámetros del mercado global y AMO, la otra cara del espejo de Rem, aplica el pensamiento arquitectónico a campos no explorados, sin la dependencia de agentes externos, pudiendo permitirse ser un laboratorio puramente experimental. En este escenario, llega el 11 de septiembre de 2001 y el ataque a las Torres Gemelas de Nueva York tiene efectos devastadores a todos los niveles, significando, en un período de tiempo sorprendentemente corto, un cambio en el orden mundial. Rem Koolhaas da entonces un giro de 180 grados, dirige su mirada hacia China, donde entiende que sus aportaciones tienen un beneficio social más directo que en occidente. (2) Para presentar al mundo su nuevo cambio de rumbo y la creación del “Think Tank” AMO, plantea una gran exposición en la NeueGallerie de Berlín bajo el título de “Content”, experiencia paralela a la edición del libro con el mismo título, que inicialmente nace como “catálogo de la exposición, pero que internamente siempre se concibió como el documento más trascendente en el estudio desde “SMLXL”. Sin embargo, en muchos aspectos se trata de su opuesto: una publicación con formato revista, de tapa blanda, con paginado muy fino, formato de "folleto de supermercado" y contenido hiperdenso. Es un experimento efímero, fugaz, ligero, barato, de “usar y tirar”. De hecho, está fuera de stock, ya no se edita. Probablemente Rem Koolhaas desaprobaría que se hiciera una investigación que pusiera el foco sobre el mismo, porque diez años después de su publicación seguramente opine que su vigencia ha caducado. Sin embargo, muestra con una claridad meridiana el estado conceptual y vital de OMA en el momento de su publicación y representa, además un verdadero hito en la comunicación arquitectónica, un punto de no retorno, el máximo exponente de lo que hemos denominado “comunicación congestiva”. La presente tesis plantea que “Content” contiene la esencia de la mayor aportación de Rem Koolhaas al mundo de la arquitectura: la transformación profunda y definitiva de la comunicación arquitectónica mediante la convergencia del estado conceptual y la transmisión del mismo. Su legado arquitectónico y conceptual ha marcado a todas las generaciones posteriores de manera indeleble. Sus ensayos, sus teorías, sus proyectos y sus edificaciones ya pertenecen a la historia de la arquitectura, sin ninguna duda. Pero es su revisión del concepto de la comunicación en arquitectura lo que ha tenido y tendrá un reflejo inmediato en las generaciones futuras, no solamente en la comunicación sino en su arquitectura, a través de un intercambio biyectivo. El planteamiento a futuro sería determinar qué sucede tras “Content”, tras la hiperdensidad máxima, tras la cultura de la congestión visual; qué es lo que propone Koolhaas y qué se va a plantear también en el mundo de la comunicación arquitectónica. Para ello, estudiaremos en profundidad sus últimos proyectos relacionados con la comunicación, como su propuesta para la Biennale de Arquitectura de Venecia de 2014, su intensa investigación sobre el “Metabolismo” en “Project Japan: Metabolism Talks...”, o la dirección de sus últimos planteamientos territoriales. En los últimos tiempos Rem Koolhaas habla de “Preservación”, de “Sobriedad”, de “Esencialismo”, de “Performance”... El autor intelectual de la cultura de la congestión habla ahora de la “low density”...como no podía ser de otra manera en la otra cara del espejo. En definitiva, el color blanco como suma de todos los colores, todas las longitudes de onda del espectro visible recibidas al tiempo. ABSTRACT When talking about Rem Koolhaas, the mirror does not only reflect one but numerous images: it is nothing but a polyhedral prism. His mirror gives us the image of Rem the media celebrity, the intellectual, the conceptualizer, the builder, the analyst, the journalist, the actor... This research sets the spotlight on Rem the COMMUNICATOR. "Rem on both sides of the mirror" belongs to a research on architectural media, its influence on the architectural production and vice versa. It is aimed at getting to discern whether communication and architectural production collide and converge in the case of great communicators such as Rem Koolhaas, and whether the message and transmission media acquire the same features. Focusing on the figure of Rem Koolhaas, this thesis addresses the evolution of his communicative facet and the successive transformations in the field of architectural communication, parallel to the conceptual evolution he underwent throughout his career. Therefore, this research is not so much focused on his theoretical component or on the OMA’s architectural practice, but on the exhibition of his production to the world, especially through his essays and books. "Delirious New York" and "SMLXL" hold up a mirror to the conceptual moment they are part of, and contain a great deal of information about the graphic references that have inevitably influenced his work. Specially, the launch of "SMLXL" was a salutary shock for the architectural communication world, since it set the spotlight on the importance of leaving a linear and unifocal narrative behind in order to face communication considering multiple variables and approaches, based on a process similar to the development of an architectural project. It offers a very innovative design and an extremely careful editing, which deals with parameters much more ambitious than those merely narrative. It explores the need for a global subject and suggests the most appropriate approach for each of the projects described, giving the reader a closer insight to the sensory that goes beyond what’s strictly visual. In addition, its huge international impact and the great interest shown, not only by architects but also by graphic designers, publishers, people from all kinds of artistic trends and the general public, led to the globalisation of the architectural publications phenomenon and brought the importance of communication as a discipline in itself, within the architectural production in the age at hand, to light. Despite the importance of "SMLXL" at all levels, this thesis suggests that the communication experience really culminates in "Content", for it includes new conceptual parameters associated with the container-content conceptual fusion. It is in this book where the purpose of communication and the expression of such become a single element, ruled by similar laws. In this particular case, the fundamental law is to implement the "culture of congestion" to its extreme consequences in both the message and the media, leading to what we have agreed to refer to as "congestive communication”. This concept leads to its inevitable materialisation into an ephemeral, disposable, almost virtual product, because it meets the conditions of a very concrete and specific time, and outside that context it loses its significance. The "culture of congestion" emerged in Koolhaas’ approaches under the guidance of Elia Zenghelis, in the Architectural Association School of Architecture of London. Subsequently, his retroactive manifesto on Manhattan, "Delirious New York" developed it, waging an all-out war against the modern movement urbanism and maintaining that the really contemporary cities are those hyperdense ones that rise as a result of an unplanned development and thanks to the typical technological advances of their time. Finally it began to materialise in the Diploma Unit 9 of the AA, in which he started lecturing in 1975, leaving an indelible mark on subsequent generations of architects who passed that unit. First and foremost, Rem Koolhaas is an intellectual and, therefore, all the theoretical construct in the metropolis began to be reflected in his work through OMA since the beginnings of his production. Broadly speaking, we can say that his career is influenced by two essential historic events, which determine three different stages in his production. In the early years of his career, Koolhaas was still fascinated by the urban metropolis and the implementation of the paranoiac-critical method to his architectural production. He was then a deeply surreal architect. He understood this method as a knowledge strategy and an approach to the world around him: "let the subconscious out but hold it with the crutches of reasonableness”. However, he was actually interested in its implementation on a broad scale, the "Bigness", and therefore, he took part in ambitious projects that led to the accrual of concepts that, beyond being rewarded, left an ideological impression on the evolution of architecture. These projects included his proposal for the Parc de la Villette or the Très Grande Bibliotèque in Paris. The projects he carried out during this period showed a great conceptual background, which evolved into surprising interiors but a sober, or even "povera", exterior appearance, thanks to the use of ephemeral materials that were atypical in the macro-architecture field until that moment. Suddenly, in 1997, the so-called "Bilbao effect" boomed thanks to Frank Gehry (1). The Guggenheim Museum of Bilbao amazed the world with its spectacular nature and its pregnant and impossible shapes. It was the beginning of the era of “The architecture of spectacle”: the transformation of the city through ICONS that would act as nodes of attraction and gathering, around which the economic, cultural and socio-political activity of the city was supposed to be revitalized, as if through a single gesture all internal tissues of the city could be rebuilt. Rem Koolhaas quickly realized that the approach to the city, and especially to the global market, had changed. In the world of globalisation, the only way to get to materialise such "Bigness" was by keeping his intellectual exercises in pregnant, beautiful, iconic and spectacular shapes. Koolhaas found his personal brand in the Stealth aesthetic, resulting from the eighties American combat aircrafts whose shape was faceted in order to avoid radars. Projects such as the Casa da Música in Porto or the Seattle Library date from this period; both buildings are faceted icons of pregnant beauty that left an indelible mark on the city and caused, like the Guggenheim, some degree of recovery and revitalization on the environment in which they were based, at least temporarily. In any case, Koolhaas never gave the merely theoretical exercises up, but he segregated his work in two: OMA produced what was destined to be built and ruled by the parameters of the global market and AMO, Rem’s other side of the mirror, applied the architectural thought in unexplored fields, notwithstanding external agents and being able to work as a purely experimental laboratory. In light of this backdrop, September 11th 2001 came and the attacks on the Twin Towers in New York had devastating effects at all levels, leading to a change in the world order, in a surprisingly short period of time. Rem Koolhaas made a 180° turn directing his vision towards China, where he believed his contributions would have a more direct social benefit than in the Western world. (2) In order to introduce his new course of direction and the creation of the AMO "Think Tank", he planned a major exhibition in the Neue Nationalgalerie of Berlin under the title "Content", in parallel with edition of the book with the same title, which was at first the "exhibition catalog” but, deep down, was always conceived as the most important document of the Office since "SMLXL". However, in many ways it was just the opposite: a publication characterised by its magazine format, soft cover, very fine paging, "supermarket brochure" form and hyperdense content. It was an ephemeral, brief, light, cheap and "disposable" experiment. In fact, it is currently out of stock and out of print. Rem Koolhaas would probably disapprove of a research that sets the spotlight on him, for he would probably say that his validity has expired given that it has been ten years since its publication. However, it shows OMA’s conceptual and vital status at the time of its publication with crystalline clarity and it is also a true milestone in architectural communication. A point of no return. The epitome of the so-called "congestive communication ". This thesis suggests that "Content" contains the essence of Rem Koolhaas’ greatest contribution to the world of architecture: the deep and definitive transformation of architectural communication through the convergence of the conceptual state and the transmission thereof. His architectural and conceptual legacy has left an indelible mark on all subsequent generations. There is no doubt his essays, theories, projects and buildings already belong to the history of architecture. But it is his review on the concept of communication in architecture that has had and shall have an immediate influence on future generations, not only in their communication but also in their architecture, through a bijective exchange. Future approaches should try to determine what happens after "Content", after the maximum hyperdensity, after the visual culture of congestion; what shall Koolhaas suggest as well as what shall happen in the world of architectural communication. To this end, we shall study his latest communication-related projects, such as the design of the Venetian Architecture Biennale in 2014, his intensive research on the "Metabolism" in "Project Japan: Metabolism Talks ...", or the course of his latest territorial approaches in depth. Most recently, Rem Koolhaas has talked about "Preservation", "Sobriety" of "Essentialism", "Performance", etc. The mastermind of the culture of congestion now speaks of the "low density"... as it could not be otherwise, on the other side of the mirror. Summarizing, the white color as the sum of all colors; all wavelengths of the visible spectrum received at the same time.

Restoration of β-adrenergic signaling in failing cardiac ventricular myocytes via adenoviral-mediated gene transfer

Cardiovascular gene therapy is a novel approach to the treatment of diseases such as congestive heart failure (CHF). Gene transfer to the heart would allow for the replacement of defective or missing cellular proteins that may improve cardiac performance. Our laboratory has been focusing on the feasibility of restoring β-adrenergic signaling deficiencies that are a characteristic of chronic CHF. We have now studied isolated ventricular myocytes from rabbits that have been chronically paced to produce hemodynamic failure. We document molecular β-adrenergic signaling defects including down-regulation of myocardial β-adrenergic receptors (β-ARs), functional β-AR uncoupling, and an up-regulation of the β-AR kinase (βARK1). Adenoviral-mediated gene transfer of the human β2-AR or an inhibitor of βARK1 to these failing myocytes led to the restoration of β-AR signaling. These results demonstrate that defects present in this critical myocardial signaling pathway can be corrected in vitro using genetic modification and raise the possibility of novel inotropic therapies for CHF including the inhibition of βARK1 activity in the heart.

Quantitative high performance liquid chromatography/tandem mass spectrometric analysis of the four classes of F2-isoprostanes in human urine

Isoprostanes (iPs) are free radical catalyzed prostaglandin isomers. Analysis of individual isomers of PGF2α—F2-iPs—in urine has reflected lipid peroxidation in humans. However, up to 64 F2-iPs may be formed, and it is unknown whether coordinate generation, disposition, and excretion of F2-iPs occurs in humans. To address this issue, we developed methods to measure individual members of the four structural classes of F2-iPs, using liquid chromatography/tandem mass spectrometry (LC/MS/MS), in which sample preparation is minimized. Authentic standards of F2-iPs of classes III, IV, V, and VI were used to identify class-specific ions for multiple reaction monitoring. Using iPF2α-VI as a model compound, we demonstrated the reproducibility of the assay in human urine. Urinary levels of all F2-iPs measured were elevated in patients with familial hypercholesterolemia. However, only three of eight F2-iPs were elevated in patients with congestive heart failure, compared with controls. Paired analyses by GC/MS and LC/MS/MS of iPF2α-VI in hypercholesterolemia and of 8,12-iso-iPF2α-VI in congestive heart failure were highly correlated. This approach will permit high throughput analysis of multiple iPs in human disease.

Nonmuscle myosin II-B is required for normal development of the mouse heart

We used targeted gene disruption in mice to ablate nonmuscle myosin heavy chain B (NMHC-B), one of the two isoforms of nonmuscle myosin II present in all vertebrate cells. Approximately 65% of the NMHC-B−/− embryos died prior to birth, and those that were born suffered from congestive heart failure and died during the first day. No abnormalities were detected in NMHC-B+/− mice. The absence of NMHC-B resulted in a significant increase in the transverse diameters of the cardiac myocytes from 7.8 ± 1.8 μm (right ventricle) and 7.8 ± 1.3 μm (left ventricle) in NMHC-B+/+ and B+/− mice to 14.7 ± 1.1 μm and 13.8 ± 2.3 μm, respectively, in NMHC-B−/− mice (in both cases, P < 0.001). The increase in size of the cardiac myocytes was seen as early as embryonic day 12.5 (4.5 ± 0.2 μm for NMHC-B+/+ and B+/− vs. 7.2 ± 0.6 μm for NMHC-B−/− mice (P < 0.01)). Six of seven NMHC-B−/− newborn mice analyzed by serial sectioning also showed structural cardiac defects, including a ventricular septal defect, an aortic root that either straddled the defect or originated from the right ventricle, and muscular obstruction to right ventricular outflow. Some of the hearts of NMHC-B−/− mice showed evidence for up-regulation of NMHC-A protein. These studies suggest that nonmuscle myosin II-B is required for normal cardiac myocyte development and that its absence results in structural defects resembling, in part, two common human congenital heart diseases, tetralogy of Fallot and double outlet right ventricle.

Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A

Natriuretic peptides, produced in the heart, bind to the natriuretic peptide receptor A (NPRA) and cause vasodilation and natriuresis important in the regulation of blood pressure. We here report that mice lacking a functional Npr1 gene coding for NPRA have elevated blood pressures and hearts exhibiting marked hypertrophy with interstitial fibrosis resembling that seen in human hypertensive heart disease. Echocardiographic evaluation of the mice demonstrated a compensated state of systemic hypertension in which cardiac hypertrophy and dilatation are evident but with no reduction in ventricular performance. Nevertheless, sudden death, with morphologic evidence indicative in some animals of congestive heart failure and in others of aortic dissection, occurred in all 15 male mice lacking Npr1 before 6 months of age, and in one of 16 females in our study. Thus complete absence of NPRA causes hypertension in mice and leads to cardiac hypertrophy and, particularly in males, lethal vascular events similar to those seen in untreated human hypertensive patients.

Bepridil opens the regulatory N-terminal lobe of cardiac troponin C

Cardiac troponin C (cTnC) is the calcium-dependent switch for contraction in heart muscle and a potential target for drugs in the therapy of congestive heart failure. This calmodulin-like protein consists of two lobes connected by a central linker; each lobe contains two EF-hand domains. The regulatory N-terminal lobe of cTnC, unlike that of skeletal troponin C (sTnC), contains only one functional EF-hand and does not open fully upon the binding of Ca2+. We have determined the crystal structure of cTnC, with three bound Ca2+ ions, complexed with the calcium-sensitizer bepridil, to 2.15-Å resolution. In contrast to apo- and 3Ca2+-cTnC, the drug-bound complex displays a fully open N-terminal lobe similar to the N-terminal lobes of 4Ca2+-sTnC and cTnC bound to a C-terminal fragment of cardiac troponin I (residues 147–163). The closing of the lobe is sterically hindered by one of the three bound bepridils. Our results provide a structural basis for the Ca2+-sensitizing effect of bepridil and reveal the details of a distinctive two-stage mechanism for Ca2+ regulation by troponin C in cardiac muscle.

Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy

The signal transducer and activator of transcription (STAT) 3, a transcriptional factor downstream of several cytokines, is activated by Janus kinase families and plays a pivotal role in cardiac hypertrophy through gp130. To determine the physiological significance of STAT3 in vivo, transgenic mice with cardiac-specific overexpression of the Stat3 gene (STAT3-TG) were generated. STAT3-TG manifested myocardial hypertrophy at 12 wk of age with increased expression of the atrial natriuretic factor (ANF), β-myosin heavy chain (MHC), and cardiotrophin (CT)-1 genes. The animals were injected i.p. with 15 mg/kg doxorubicin (Dox), an antineoplastic drug with restricted use because of its cardiotoxicity. The survival rates after 10 days were 25% (5/20) for control littermates (WT), but 80% (16/20) for STAT3-TG (P < 0.01). WT showed increased expression of β-MHC and ANF mRNAs in the hearts 1 day after Dox treatment; this expression peaked at 3 days, suggesting that the WT suffered from congestive heart failure. Although the expression of these mRNAs was elevated in STAT3-TG hearts before Dox treatment, no additional increase was observed after the treatment. Dox administration significantly reduced the expression of the cardiac α-actin and Stat3 genes in WT hearts but not in STAT3-TG. These results provide direct evidence that STAT3 transduces not only a hypertrophic signal but also a protective signal against Dox-induced cardiomyopathy by inhibiting reduction of cardiac contractile genes and inducing cardiac protective factors.

A new endogenous natriuretic factor: LLU-alpha.

For over three decades, renal physiology has sought a putative natriuretic hormone (third factor) that might control the body's pool of extracellular fluid, an important determinant in hypertension, congestive heart failure, and cirrhosis. In our search for this hormone, we have isolated several pure natriuretic factors from human uremic urine that would appear, alone or in combination, to mark a cluster of phenomena previously presumed to be that of a single "natriuretic hormone." This paper reports the purification, chemical structure, and total synthesis of the first of these compounds, LLU-alpha, which proved to be 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman, presumably a metabolite of gamma-tocopherol. Both natural LLU-alpha and synthetic material are identical (except for optical activity) with respect to structure and biological activity. It appears that the natriuretic activity of LLU-alpha is mediated by inhibition of the 70 pS K+ channel in the apical membrane of the thick ascending limb of the kidney.

Avaliação comparativa dos efeitos do anlodipino e da pimobendana na insuficiência valvar crônica de mitral em cães

A insuficiência valvar crônica de mitral (IVCM) é a principal cardiopatia de cães, correspondendo a 75-85% dos casos de cardiopatias. É causada pela degeneração mixomatosa da valva mitral (endocardiose de mitral) sendo, então, uma doença degenerativa adquirida e que pode ocasionar a insuficiência cardíaca congestiva (ICC). Pode acometer qualquer raça de cão, mas é mais frequentemente observada nas raças de pequeno porte, dentre as quais, Poodle miniatura, Spitz Alemão, Dachshund, Yorkshire Terrier, Chihuahua e Cavalier King Charles Spaniel. Na endocardiose de mitral, o volume sanguíneo regurgitado causa sobrecarga do lado esquerdo do coração, devido ao aumento das pressões atrial e ventricular esquerdas, seguida de dilatação e hipertrofia dessas cavidades cardíacas. A elevação da pressão ventricular esquerda pode causar hipertensão pulmonar, congestão e, em estágios avançados, edema pulmonar. A doença pode evoluir assintomática, enquanto que naqueles casos que evoluem para insuficiência cardíaca congestiva (ICC) os sintomas mais usuais são: tosse, intolerância ao exercício, dispneia e síncope. Em 2009 o colégio americano de medicina interna veterinária (American College of Veterinary Internal Medicine -ACVIM) elaborou diretrizes para o tratamento da IVCM, tendo por base a classificação funcional adaptada do American College of Cardiology. Neste trabalho foram utilizados os fármacos anlodipino e pimobendana em associação a outros usualmente indicados no tratamento da ICC em cães, segundo consenso de 2009, indicados no tratamento da ICC em cães. Dois grupos (A e B) de cães, cada um constituído por 10 pacientes com IVCM em estágio C, foram tratados com furosemida e maleato de enalapril, sendo que os animais do grupo A receberão pimobendana e os do grupo B, anlodipino. Os animais foram avaliados em diferentes momentos (T0, T30, T60) observando-se as alterações nos exames ecodopplercardiográfico e eletrocardiográfico, bem como de pressão arterial sistólica

Evaluación de la calidad de vida relacionada con la salud mediante las láminas Coop-Wonca en una población de hemodiálisis

Ante la necesidad de disponer de instrumentos que permitan medir calidad de vida relacionada con la salud (CVRS) de una manera ágil y rápida, nos planteamos estudiar, en un grupo de pacientes en hemodiálisis, las propiedades de medición de las láminas Coop-Wonca con el objetivo de establecer si reúnen las condiciones para su uso rutinario en este tipo de pacientes. Métodos: Estudio transversal en 163 pacientes de hemodiálisis (106 varones y 57 mujeres) procedentes de 3 centros. Para medir la CVRS de la población estudiada se ha utilizado la versión validada española de las láminas Coop-Wonca completa. Este cuestionario comprende nueve dimensiones de función y bienestar de un único ítem: 1.– Forma física; 2.–Sentimientos; 3.–Actividades cotidianas; 4.–Actividades sociales; 5.–Cambio en el estado de salud; 6.–Estado de salud; 7.–Dolor; 8.–Apoyo social; y 9.–Calidad de vida en general. Las posibles respuestas se puntúan de 1 a 5, siendo las puntuaciones mayores las que reflejan una peor salud percibida. El instrumento permite la obtención de un índice (Coop total) que es un sumatorio de las puntuaciones de todas las dimensiones salvo la 5 (Cambio en el estado de salud). Resultados: El tiempo medio de cumplimentación del cuestionario fue inferior a 5 minutos. Las láminas resultaron fácilmente comprensibles para los pacientes y la autoadministración de las mismas no planteó problemas. Las puntuaciones más altas (peor CVRS) se obtuvieron en las dimensiones «forma física» (3,66 ± 0,8) y «estado de salud» (3,43 ± 0,8), y la menor (mejor CVRS) en la dimensión «actividades sociales» (1,98 ± 1,3). Entre los principales factores asociados a un peor estado de salud percibida figuran el sexo (mujer), la comorbilidad (presencia de diabetes y/o hepatopatía), la situación laboral (pensionista) y el medio de transporte (taxi-ambulancia). Un mayor tiempo en hemodiálisis se asoció a peores puntuaciones en las dimensiones «calidad de vida en general» y «Dolor». Los pacientes que se trasladaban en taxi o ambulancia presentaban peores puntuaciones en las dimensiones «Forma física», «Actividades cotidianas» y «Estado de salud». Una mayor se asoció a peor puntuación en «Forma física». Un número elevado de fármacos prescritos (más de seis) se asoció a peor puntuación en las dimensiones «Forma física», «Actividades sociales» y «Apoyo social». Los varones, los viudos y los solteros puntuaron peor en «Apoyo social». Los pacientes con mayor nivel de estudios mostraron puntuaciones más altas (peor CVRS) en la dimensión «Forma física». Conclusiones: Las láminas Coop-Wonca podrían ser un buen instrumento de medida de CVRS en los pacientes de hemodiálisis, por la rapidez de su cumplimentación y por ser de fácil comprensión lo que favorece la autoadministración que evita el posible sesgo del entrevistador. Todo ello favorecería su uso rutinario como indicador par valorar la evolución en el tiempo de la CVRS de los pacientes en hemodiálisis. No obstante, se precisan estudios ulteriores que permitan evaluar en mayor profundidad las propiedades psicométricas del instrumento en este tipo de pacientes.

Multifaceted Role of Heme during Severe Plasmodium falciparum Infections in India

Several immunomodulatory factors are involved in malaria pathogenesis. Among them, heme has been shown to play a role in the pathophysiology of severe malaria in rodents, but its role in human severe malaria remains unclear. Circulating levels of total heme and its main scavenger, hemopexin, along with cytokine/chemokine levels and biological parameters, including hemoglobin and creatinine levels, as well as transaminase activities, were measured in the plasma of 237 Plasmodium falciparum-infected patients living in the state of Odisha, India, where malaria is endemic. All patients were categorized into well-defined groups of mild malaria, cerebral malaria (CM), or severe noncerebral malaria, which included acute renal failure (ARF) and hepatopathy. Our results show a significant increase in total plasma heme levels with malaria severity, especially for CM and malarial ARF. Spearman rank correlation and canonical correlation analyses have shown a correlation between total heme, hemopexin, interleukin-10, tumor necrosis factor alpha, gamma interferon-induced protein 10 (IP-10), and monocyte chemotactic protein 1 (MCP-1) levels. In addition, canonical correlations revealed that heme, along with IP-10, was associated with the CM pathophysiology, whereas both IP-10 and MCP-1 together with heme discriminated ARF. Altogether, our data indicate that heme, in association with cytokines and chemokines, is involved in the pathophysiology of both CM and ARF but through different mechanisms.