G-CSF induced arteriogenesis in humans: molecular insights into a randomized controlled trial

AIMS Recent data have demonstrated the feasibility of therapeutic induction of coronary collateral growth (arteriogenesis); however, mechanisms of action of such therapeutic collateral stimulation in humans are unknown. The aim of this study was to evaluate potential mechanisms, especially the involvement of arteriogenesis-relevant genes. METHODS AND RESULTS A total of 52 patients were randomized into two groups: subcutaneous G-CSF (10 μg/kg; n=26) or placebo (n=26). Before and after this 2-week treatment, collateral-flow index (CFI) was determined by simultaneous measurement of mean aortic, distal coronary occlusive and central venous pressure. CD34+ endothelial progenitor cells (EPC) and monocytes were quantified before, during and after treatment; gene-expression analysis of monocytes was performed with real-time polymerase chain reaction (RT-PCR). G-CSF lead to a significant increase of EPC and monocytes (4.8 and 2.6 fold, p < 0.05); for both cell types, the extent of increase correlated with CFI increase (r=0.23 and 0.14, p < 0.05). G-CSF also induced a change in gene expression of pro-and anti-arteriogenic genes in monocytes. Among nine assessed genes, three were found to be differentially regulated (IL8, JAK2, and PNPLa4; p < 0.05). CONCLUSIONS The mechanism of induction of collateral growth by G-CSF is related to an increase of EPC and of peripheral monocytes. It also leads to a change toward a pro-arteriogenic gene expression in peripheral monocytes.

BPM software and process modelling languages in practice

IT has turned out to be a key factor for the purposes of gaining maturity in Business Process Management (BPM). This book presents a worldwide investigation that was conducted among companies from the ‘Forbes Global 2000’ list to explore the current usage of software throughout the BPM life cycle and to identify the companies’ requirements concerning process modelling. The responses from 130 companies indicate that, at the present time, it is mainly software for process description and analysis that is required, while process execution is supported by general software such as databases, ERP systems and office tools. The resulting complex system landscapes give rise to distinct requirements for BPM software, while the process modelling requirements can be equally satisfied by the most common languages (BPMN, UML, EPC).

The secretome of endothelial progenitor cells promotes brain endothelial cell activity through PI3-kinase and MAP-kinase

BACKGROUND Angiogenesis and vascular remodelling are crucial events in tissue repair mechanisms promoted by cell transplantation. Current evidence underscores the importance of the soluble factors secreted by stem cells in tissue regeneration. In the present study we investigated the effects of paracrine factors derived from cultured endothelial progenitor cells (EPC) on rat brain endothelial cell properties and addressed the signaling pathways involved. METHODS Endothelial cells derived from rat brain (rBCEC4) were incubated with EPC-derived conditioned medium (EPC-CM). The angiogenic response of rBCEC4 to EPC-CM was assessed as effect on cell number, migration and tubular network formation. In addition, we have compared the outcome of the in vitro experiments with the effects on capillary sprouting from rat aortic rings. The specific PI3K/AKT inhibitor LY294002 and the MEK/ERK inhibitor PD98059 were used to study the involvement of these two signaling pathways in the transduction of the angiogenic effects of EPC-CM. RESULTS Viable cell number, migration and tubule network formation were significantly augmented upon incubation with EPC-CM. Similar findings were observed for aortic ring outgrowth with significantly longer sprouts. The EPC-CM-induced activities were significantly reduced by the blockage of the PI3K/AKT and MEK/ERK signaling pathways. Similarly to the outcome of the rBCEC4 experiments, inhibition of the PI3K/AKT and MEK/ERK pathways significantly interfered with capillary sprouting induced by EPC-CM. CONCLUSION The present study demonstrates that EPC-derived paracrine factors substantially promote the angiogenic response of brain microvascular endothelial cells. In addition, our findings identified the PI3K/AKT and MEK/ERK pathways to play a central role in mediating these effects.

Current developments in the use of stem cell for therapeutic neovascularisation: is the future therapy "cell-free"?

The plasticity and self-regenerative properties of stem cells have opened new avenues in regenerative medicine. Greater understanding of the biology of stem cells is followed by growing expectations of a rapid translation into alternative therapeutic options. Recent preclinical studies and clinical trials employing stem and progenitor cells from different sources have shown encouraging results. However, their underlying mechanisms are still poorly understood, the potential adverse effects and the discrepancy in efficacy remain to be further investigated. Their essential role in vessel regeneration has made endothelial progenitor cells (EPC) a suitable candidate for therapeutic applications aiming at tissue revascularisation. Recent evidence suggests that EPC contribute to neovascularisation not only by direct participation in tissue homeostasis but mainly via paracrine mechanisms. In future, novel therapeutic strategies could be based on EPC paracrine factors or synthetic factors, and replace cell transplantation.

Endothelial progenitor cells as a biological marker of peripheral artery disease.

The role of endothelial progenitor cells (EPCs) in peripheral artery disease (PAD) remains unclear. We hypothesized that EPC mobilization and function play a central role in the development of endothelial dysfunction and directly influence the degree of atherosclerotic burden in peripheral artery vessels. The number of circulating EPCs, defined as CD34(+)/KDR(+) cells, were assessed by flow cytometry in 91 subjects classified according to a predefined sample size of 31 non-diabetic PAD patients, 30 diabetic PAD patients, and 30 healthy volunteers. Both PAD groups had undergone endovascular treatment in the past. As a functional parameter, EPC colony-forming units were determined ex vivo. Apart from a broad laboratory analysis, a series of clinical measures using the ankle-brachial index (ABI), flow-mediated dilatation (FMD) and carotid intima-media thickness (cIMT) were investigated. A significant reduction of EPC counts and proliferation indices in both PAD groups compared to healthy subjects were observed. Low EPC number and pathological findings in the clinical assessment were strongly correlated to the group allocation. Multivariate statistical analysis revealed these findings to be independent predictors of disease appearance. Linear regression analysis showed the ABI to be a predictor of circulating EPC number (p=0.02). Moreover, the functionality of EPCs was correlated by linear regression (p=0.017) to cIMT. The influence of diabetes mellitus on EPCs in our study has to be considered marginal in already disease-affected patients. This study demonstrated that EPCs could predict the prevalence and severity of symptomatic PAD, with ABI as the determinant of the state of EPC populations in disease-affected groups.

Caracterización y cuantificación de células progenitoras endoteliales de ratas espontáneamente hipertensas alimentadas con fructosa

Objetivo: Examinar cómo se ve afecta la participación de las células progenitoras endoteliales (CPE) por la resistencia a la insulina (IR) asociada a un modelo experimental de síndrome metabólico (SM), generado por la administración crónica de fructosa a ratas espontáneamente hipertensas. Material y métodos: Ratas WKY y SHR, macho, distribuidas en 4 grupos (n=8 c/u): WKY: controles; FFR: WKY recibiendo fructosa en agua de bebida al 10 % (v/v) durante 6 semanas; SHR; FFHR: SHR recibiendo fructosa en agua de bebida al 10 % (v/v) durante 6 semanas. Al finalizar el protocolo se determinó: presión arterial sistólica, variables bioquímicas, índice HOMA, cuantificación por citometría de flujo de los niveles de CPE en sangre periférica y en médula ósea, inmunofluorescencia en cultivo celular, para identificar los marcadores CD34 y VEGFR-2, recuento de colonias de CPE y actividad de NAD(P)H-oxidasa en tejido aórtico. Resultados: Se confirmó el modelo experimental en base a las variables metabólicas analizadas. Se observó una disminución en los niveles de CPE; en sangre periférica y médula ósea, la que se hace más importante en los grupos de animales tratados con fructosa. En estos también hay menor número de colonias de CPE desarrolladas en cultivo celular y presentan un aumento en los niveles de estrés oxidativo, estimado por la actividad de NAD(P)H oxidasa. Conclusión: el SM causado por la administración crónica de fructosa en FFHR ha demostrado generar una disminución en los niveles de CPE, así como en su capacidad funcional. Los mecanismos intracelulares que producen este fenómeno podrían estar desencadenados por el grado de IR que presenta este modelo experimental.

Enseñar biología desde la perspectiva de la enseñanza para la comprensión : El sistema circulatorio, un delivery en mi cuerpo

En el marco del proceso de capacitación e innovación pedagógica centrado en la Enseñanza para la comprensión (EpC) que se está implementando en el Colegio Nacional Rafael Hernández, se llevó a cabo una propuesta para la enseñanza de la Biología en tercer año. El enfoque tuvo en cuenta el modelo de EpC y la perspectiva sistémica Los contenidos seleccionados apuntaron a integrar los sistemas digestivo, respiratorio, circulatorio y excretor y el proceso de homeostasis. El eje central fue el sistema circulatorio. El tópico generativo: "El sistema circulatorio un delivery en mi cuerpo", se construyó suponiendo que una analogía de la vida cotidiana podría representar una forma clara y motivadora de pensar los aspectos funcionales del sistema circulatorio y su conexión con los otros sistemas del cuerpo estudiados en la asignatura. El hilo conductor orientó y ayudó a expresar el sentido de lo que se quería enseñar: "Los alumnos comprenderán el cuerpo humano como una Unidad constituida por una serie de sistemas en continua interacción.". En torno a éste eje se plantearon Metas de Comprensión: aquellos conceptos, procesos, habilidades que esperábamos que los estudiantes comprendieran. Los alumnos se mostraron muy interesados y en la clase lograron responder a múltiples interrogantes que promovieron la apropiación significativa de los contenidos. Utilizando un lenguaje cotidiano, se fue introduciendo el vocabulario específico, para favorecer el acceso a los nuevos contenidos .En un muy buen clima de trabajo se lograron las metas propuestas. La secuencia didáctica aplicada fue evaluada favorablemente por especialistas externos.

Enseñar biología desde la perspectiva de la enseñanza para la comprensión : El sistema circulatorio, un delivery en mi cuerpo

En el marco del proceso de capacitación e innovación pedagógica centrado en la Enseñanza para la comprensión (EpC) que se está implementando en el Colegio Nacional Rafael Hernández, se llevó a cabo una propuesta para la enseñanza de la Biología en tercer año. El enfoque tuvo en cuenta el modelo de EpC y la perspectiva sistémica Los contenidos seleccionados apuntaron a integrar los sistemas digestivo, respiratorio, circulatorio y excretor y el proceso de homeostasis. El eje central fue el sistema circulatorio. El tópico generativo: "El sistema circulatorio un delivery en mi cuerpo", se construyó suponiendo que una analogía de la vida cotidiana podría representar una forma clara y motivadora de pensar los aspectos funcionales del sistema circulatorio y su conexión con los otros sistemas del cuerpo estudiados en la asignatura. El hilo conductor orientó y ayudó a expresar el sentido de lo que se quería enseñar: "Los alumnos comprenderán el cuerpo humano como una Unidad constituida por una serie de sistemas en continua interacción.". En torno a éste eje se plantearon Metas de Comprensión: aquellos conceptos, procesos, habilidades que esperábamos que los estudiantes comprendieran. Los alumnos se mostraron muy interesados y en la clase lograron responder a múltiples interrogantes que promovieron la apropiación significativa de los contenidos. Utilizando un lenguaje cotidiano, se fue introduciendo el vocabulario específico, para favorecer el acceso a los nuevos contenidos .En un muy buen clima de trabajo se lograron las metas propuestas. La secuencia didáctica aplicada fue evaluada favorablemente por especialistas externos.

Tanque de almacenamiento de GNL para la ampliación de la planta de regasificación de Barcelona

ENAGAS tiene la intención de ampliar el Terminal de Regasificación de GNL que tiene en el puerto de Barcelona. El presente Proyecto Básico define las instalaciones de uno de los Tanques de almacenamiento de GNL que se van a construir dentro del Alcance de dicha ampliación, con el suficiente detalle como para permitir a ENAGAS acometer las tareas previas a la ejecución del proyecto, a saber: 1. Planificar y presupuestar la fase de ejecución 2. Solicitar los Permisos y Autorizaciones necesarias de los Organismos competentes 3. Lanzar la Petición de Ofertas para el concurso llave en mano del EPC. Los trabajos de Ingeniería contenidos en el Proyecto Básico son los siguientes: Antecedentes y Datos básicos, Criterios de diseño, Descripción de instalaciones, Cálculos estructurales, Planos del Tanque de GNL, Definición de equipos y materiales a utilizar, Plan de ejecución del proyecto, Especificaciones técnicas para Ingeniería, Compras y Construcción, Paquete para Petición de Ofertas del EPC, Condiciones técnicas particulares, Programa de ejecución y Presupuesto de inversiones. ABSTRACT ENAGAS is expanding its LNG Regasification Terminal located in Barcelona Port (Spain). This Document reports the Front End Engineering and Design (FEED) works undertaken in relation to one of the LNG Storage Tanks to be built within the scope of that expansion. The Project FEED hereby presented comprehensively defines the LNG Storage Tank so as to allow ENAGAS to perform next stages of the Works, namely: 1. Plan and budget the Project Execution phase 2. Request Regulatory authorizations 3. Invite Contractors to bid for the LNG Tank EPC. Main components of the FEED Document contents are as follow:Background and Basic Data, Design Criteria, Description of LNG Tank elements, Engineering Calculations, LNG Tank Drawings, Equipment and Materials definition, Project Execution Plan (PEP), Technical Conditions, EPC Invitation to Tender (ITT) package, Execution Schedule and Cost Estimate.

Tecnología y competitividad en la economía mundial. Factores e indicadores clave de actuación

Durante los últimos 30 años se han creado una gran cantidad de índices e indicadores para evaluar la práctica totalidad de los países bajo distintas premisas. La tesis parte de un análisis detallado de más de un centenar de estos índices diferenciados entre los enfocados al desarrollo y los enfocados a la competitividad económica (véase Módulo I anexo) y tras esto, dentro del estudio teórico nos hemos centrado en 35 indicadores relacionados con la tecnología (capítulo 3, apartado 3.3.). La justificación, el objetivo de la investigación y la estructura de la tesis se presenta en el capítulo 2. Respecto a la metodología, tal y como se plantea en la hipótesis (apartado 2.2.), se presentan los criterios de selección de seis grupos de países (EP, EPC, EC, ECI, EI y EM)1, que se van a evaluar. Posteriormente se plantea el Protocolo de Cálculo para el total de grupos seleccionados dentro de los periodos 2005-2006 y 2007-2008 y se realiza una profunda evaluación estadística como se plantea dentro de la coherencia estadística explicada en el apartado 3.4.4.5. (también se dispone de los cálculos dentro de los Módulos II, III, IV y V anexos). Tras la metodología establecemos la construcción de un índice sintético NRI(A) y, tras esto, estudiamos las relaciones así como la interpretación de los resultados (capítulo 4, apartado 4.1.). Una vez obtenidos los resultados realizamos la validación de los mismos para el periodo 2007-2015 (capítulo 4 - apartado 4.2. – y los Módulos VI y VII anexos). En el capítulo 5, evaluamos el nivel de preparación tecnológico y su relación con la competitividad para los seis grupos de países (véase desde los apartados 5.1.y 5.2.). Dentro de cada uno de los seis grupos de países, sabemos las variables que cualitativamente tienen que priorizarse para mejorar el nivel de preparación tecnológica de los mismos. Estas variables inicialmente son sesenta y ocho – año 2007-08 –, y al final de la implementación del método se reducen notablemente. Estas variables finales, llamadas Indicadores Clave de Actuación (ICA), se agrupan – vía análisis factorial – en Factores Clave de Actuación que nos simplifican lo planteado. Para cada grupo de países se realizan los conglomerados de acuerdo a sus valores dentro de las ICAs en busca de singularidades y se ha llevado a cabo un análisis minucioso en función de los Indicadores Clave de Actuación. La Tesis, plantea científicamente como podemos evaluar el nivel de preparación tecnológica y su relación con la competitividad, desde un índice sintético creado NRI(A), que contempla únicamente Indicadores Clave de Actuación (variables seleccionadas) a partir de las variables originales del Network Readiness Index (NRI(R)) . Por último se plantea dentro de las conclusiones, capítulo 6, diferentes líneas de investigación, desarrollando dos de ellas que se pueden encontrar en el Modulo VIII anexo. Por un lado presentamos una línea de investigación centrada en 29 economías africanas (EA) de las que disponemos información fidedigna y por otro lado una segunda línea en la que nos centramos en la evaluación de España respecto a sus naciones coetáneas. La principal voluntad de la presente tesis doctoral, es simplificar la evaluación del nivel de preparación tecnológica y la relación de esta con la competitividad a partir de la creación de un índice sintético propio NRI(A). ABSTRACT - During the last 30 years, many institutions have been evaluating and endless range of variables in practically all of the world´s economies. This Thesis is the product of a detail analysis of more than one hundred indicators / index, which we have divided into two parts: those focused on development and those focused on economic competitiveness (see module I annex). Secondly, in our theoretical research we have concentrated on those indicators, which are related to technology (chapters 3, section 3.3). The selection criteria of the six economic groups to be evaluated are included in our methodology, as mentioned in the hypothesis (see section 2.2.). Subsequently the calculation procedure is also presented for all of the groups selected between the periods 2005-2006 and 2007-2008. Next, we perform a statistical study, which is presented accordingly in the segment dealing with statistics, section 3.4.4.5. The calculations are provided in modules I, II, III, IV and V annex. After the methods segment of the Thesis, we develop our argument, in which we presented the explanation of the relations as well as the interpretation of the results. Also at the chapter 4 you can find the result validation from 2007 till 2015. Finally in chapters 6, we evaluate the conclusions for the six economic groups (see section 6.2.). The Thesis scientifically explains the way in which we evaluate economic competitiveness in 135 countries from a standpoint of strictly technological variables. Six groups of countries are evaluated, being divided by criteria, which homogenize the economies under review. We recognize that the variables of each economic group should be prioritized in order to better their competitiveness. Initially the group consisted of 68 variables, a number which was considerably reduced after the implementation of our methodology. Likewise, these final variables, dubbed “key performance indicators”, were grouped into factors (key performance factors), which greatly simplify the prioritization process. At the same time, conglomerates have been created for each economic group according to their value concerning the selected variables. A detailed country – by – country analysis of their positioning in each of the six groups was conducted for each of the mathematically selected key performance indicators. Finally, at the Conclusion we introduce new research lines and between them we focus on two research lines in which ones we are working with (see chapter 6). We basically try to apply the multivariable analysis method, the factorial analysis and the conglomerates to designed and implemented our method first in a geographically group of countries (Africa) and secondly to evaluate and develop the public policies for Spain for the development of its competitively, comparing Spain to his coetaneous countries in Europe (see Module VIII). The main objective of this Doctoral Thesis is to noticeably simplify the comparison of the Network Readiness Index and its relation with the economic competitiveness of the countries using a new synthetic index design by us.

1 + 1 = 3? EU-US voting cohesion in the United Nations General Assembly. EU Diplomacy Paper 07/2012, September 2012

This paper investigates the factors that explain the voting cohesion of the United States (US) and the European Union (EU) on foreign policy issues in the United Nations General Assembly (UNGA). It is often argued that the EU and the US are simply too different to cooperate within international organizations and thus to vote the same way, for example, in the UNGA. However, there is still a lack of research on this point and, more importantly, previous studies have not analyzed which factors explain EU-US voting cohesion. In this paper, I try to fill this gap by studying voting cohesion from 1980 until 2011 on issues of both ‘high’ politics (security) and ‘low’ politics (human rights) not only as regards EU-US voting cohesion, but also concerning voting cohesion among EU member states. I test six hypotheses derived from International Relations theories, and I argue that EU-US voting cohesion is best explained by the topic of the issue voted upon, whether an issue is marked as ‘important’ by the US government, and by the type of resolution. On the EU level, the length of Union membership and transaction costs matter most.

All Roads Lead to Rome: Background, Context and Legacy of the Treaty on the European Community. Jean Monnet/Robert Schuman Paper Series Special Issue 3, August 2012

From the Introduction. The rejection by the French National Assembly of the ill-fated European Defense Community (EDC) Treaty in August 30, 1954, together with the automatic shelving of the equally faulty European Political Community (EPC) proposal, put an end, at least for the time being, to any form of political and military union of the existing Western Europe on a supranational level. The times were difficult in Europe and the international atmosphere was cloudy. The end of the Korean War coincided with the insistence of the Soviets to stick to a policy of détente, leading to the suppression of the Hungarian rebellion. France was facing opposition to her colonial presence in Indochina, as well as in North Africa. But the crisis of Suez prompted the French government to distance itself from the British and the United States. The defeat of the EDC and EPC was not going to be the end of the story and the dream inaugurated by Monnet and Schuman in 1950. It was not long before plans in favor of a European re-launch were taking shape. 1

Missing a generation in EU politics. FutureLab Europe, April 2014

The European Union has always struggled to build a strong relation with its electorate and the results of the 2009 European elections showed that turnout is still declining but also significantly lower than in national elections. The percentage of young people that voted in these elections was even lower, with an average of 29% for the age group 18-24 and 36% for the age group 25-36. To investigate this further, FutureLab Europe carried out an online survey, asking young Europeans about their attitude towards the EU and the upcoming EP elections, with the results presented here in the report: ‘Missing a generation in EU politics’.

Social cohesion in Europe after the crisis

In the last few years, Europe has been forced to re-think its socio-economic model. Social indicators speak for themselves. Real household income declined significantly between 2008 and 2012, employment rates are lower and the number of people in poverty saw a steady rise with a growing divergence between EU countries. In the eurozone, cuts in public spending and internal devaluation have been the main tools to aim at a correction of unsustainable fiscal positions and a strengthening of competitiveness. It has carried a heavy social price tag. Outside of the eurozone, austerity has also been the prevailing policy, seen as inevitable to avoid economic instability. The crisis has not hit everyone equally. The general losses have been high, but there have also been some quite important redistributive effects. With all the difficulties of defining and measuring 'fairness', it is clear that the adjustment has not been equitable. Apart from issues of market failure, there have been direct increases of inequality within each of the member states. Higher poverty rates have been observed, rises in inequalities between higher and lower income earners as well as intergenerational inequalities between age groups. Long-term consequences are only beginning to surface in the public debate as the most immediate pressures of the crisis are slowly overcome. In this report, the authors first of all look at the results of the survey we have carried out in seven European countries and review perceptions of the socio-economic model. Subsequently, they assess the importance of the social dimension in the broader context of the European growth model. The authors discuss the impact of the structural challenges of globalisation, demography and technological change. They then review the EU’s performance in the crisis. Finally, the authors make a number of recommendations on how to bridge the gap between Europeans‘ expectations and reality.