El patrimonio constitucional europeo: su asimilación por el orden jurídico comunitario (análisis específico del patrimonio europeo de los derechos fundamentales)

La creación de las Comunidades europeas se realizó mediante un Tratado internacional negociado y aprobado por los representantes de los Estados miembros y sucesivamente modificado siguiendo los procedimientos por ellos establecidos. Así, desde la perspectiva del instrumento elegido para crear esta organización, la convergencia de las Comunidades europeas con las organizaciones internacionales "clásicas" es absoluta. Una aproximación a la naturaleza jurídica de la UE, a sus características, funciones, estructura, a las relaciones existentes entre el orden jurídico comunitario y los órdenes jurídicos de los Estados miembros... permite apreciar claramente que el proceso de integración europea va más allá de los objetivos que caracterizan una organización internacional "clásica".Tras algo más de 50 años de constitucionalización informal del orden jurídico comunitario, en nuestros días esta organización se enfrenta a los retos políticos y jurídicos que genera la constitucionalización del orden jurídico comunitario. En este sentido, la "Convención sobre el futuro de Europa" ha aceptado este reto. No es la primera vez que una transformación de este tipo se intenta, ahora bien, en estos momentos -próximos a una nueva ampliación-, la transformación resulta absolutamente indispensable. La conclusión final de mi investigación es la siguiente: hasta ahora en el orden comunitario se ha producido una "constitucionalización" de facto, por la vía de la modificación de los Tratados. Pero, tras el Tratado de Maastricht de 1992, el proceso de profundización de la UE, que actualmente no sólo incluye las libertades fundamentales sino también políticas tan relevantes como la moneda común, la política exterior o la inmigración y el asilo, etc., debería acompañarse de una "constitucionalización" formal que permita un cambio constitucional profundo. Hasta ahora, la mutación constitucional de la UE no ha podido desarrollarse globalmente teniendo en cuenta todos sus contenidos y consecuencias, en una palabra, coherentemente. Esta circunstancia ha provocado aún un mayor déficit democrático y una menor transparencia del sistema. En este marco, la alternativa propuesta por nuestra investigación es clara: el mejor medio de afrontar una real y coherente transformación constitucional de la UE es utilizando el adecuado instrumento legal para conseguirlo: una real y formal Constitución.The European Communities were created by international Treaties negotiated and approved by the representatives of each Member State and successively modified following procedures established in their own Treaties. Therefore, from the perspective of the legal instrument chosen to create this organisation, the convergence of the European Communities with the "classical" international organisations is absolute. An approach to the legal nature of the European Union, its characteristic notes, their functions, structure, the relations between the EC legal order and the legal orders of the Member States... allows to appreciate clearly that the process of European Integration goes beyond the objectives that characterise a "classical" international organisation. After more than 50 years of informal constitutionalisation of the EU legal order, nowadays this organisation has to be confront with the political and juridical challenges that generate a formal constitutionalisation of the EU structure. So, the "Convention on the future of Europe" has accepted the challenge to change the EU institutional structure. It is not the first time that such a transformation is trying by the European Union, but at present -near a new enlargement to the East and Central Europe-, the transformation become absolutely indispensable. The final conclusion of my dissertation is that: up to now the EU system has proceed with a factual "constitutionalisation" of its legal order using the traditional way of amending treaties. But clearly after Maastricht Treaty (1992), the process of deepening of the European Union that nowadays include not only the fundamental liberties but also policies as relevant as the common currency, the foreign policy or the immigration, visa and asylum etc. should have a formal "constitutionalisation" that permit a deeply constitutional change. Up to now, the practical constitutional mutation of the EU couldn't be done as a whole taking care of all its contents and consequences, coherently in a word. That provokes still more democratic deficit and less transparency in the system. In this framework, the alternative for this Ph.D. thesis is clear, the best way to confront a real and coherent constitutional transformation of the EU is using the adequate legal instrument to do it: a real, a formal Constitution

Noninvasive referencing of intraocular tumors for external beam radiation therapy using optical coherence tomography: a proof of concept.

PURPOSE External beam radiation therapy is currently considered the most common treatment modality for intraocular tumors. Localization of the tumor and efficient compensation of tumor misalignment with respect to the radiation beam are crucial. According to the state of the art procedure, localization of the target volume is indirectly performed by the invasive surgical implantation of radiopaque clips or is limited to positioning the head using stereoscopic radiographies. This work represents a proof-of-concept for direct and noninvasive tumor referencing based on anterior eye topography acquired using optical coherence tomography (OCT). METHODS A prototype of a head-mounted device has been developed for automatic monitoring of tumor position and orientation in the isocentric reference frame for LINAC based treatment of intraocular tumors. Noninvasive tumor referencing is performed with six degrees of freedom based on anterior eye topography acquired using OCT and registration of a statistical eye model. The proposed prototype was tested based on enucleated pig eyes and registration accuracy was measured by comparison of the resulting transformation with tilt and torsion angles manually induced using a custom-made test bench. RESULTS Validation based on 12 enucleated pig eyes revealed an overall average registration error of 0.26 ± 0.08° in 87 ± 0.7 ms for tilting and 0.52 ± 0.03° in 94 ± 1.4 ms for torsion. Furthermore, dependency of sampling density on mean registration error was quantitatively assessed. CONCLUSIONS The tumor referencing method presented in combination with the statistical eye model introduced in the past has the potential to enable noninvasive treatment and may improve quality, efficacy, and flexibility of external beam radiotherapy of intraocular tumors

Recommendations for the Implementation of the Self-Administration of Alpha-1 Antitrypsin

María Torres-Durán,1 José Luis López-Campos,2,3 Myriam Calle Rubio,4 Carmen Montero-Martínez,5 Ana Priegue Carrera,6 Rosanel Amaro Rodríguez,7 Miriam Barrecheguren,8 María Ángeles Barrio Guirado,9 Francisco Javier Callejas-González,10 Francisco Casas-Maldonado,11 Layla Diab-Cáceres,12 Pilar García-Meseguer,9 José María Hernández-Pérez,13 Lourdes Lázaro-Asegurado,14 Cristina Martínez-González,15 Carlos Martínez Rivera,16 Francisco Javier Michel,17 José-Bruno Montoro-Ronsano,18 Raquel Sánchez,19 Marta Ortiz-Pica,20 Isabel Parra,21 José Pablo Quintero García,22 María del Rosario Ruiz-Serrano-de la Espada,23 Begoña Tortajada-Goitia,24 Marc Miravitlles8 1Pneumology Department, Hospital Álvaro Cunqueiro, NeumoVigo I+i Research Group, IIS Galicia Sur, Vigo, Spain; 2Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain; 3Medical and Surgery Unit for Respiratory Diseases, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/Universidad de Sevilla, Seville, Spain; 4Pneumology Department, Research Institute of Hospital Clínico San Carlos (IdISSC), Department of Medicine, Faculty of Medicine, University Complutense of Madrid, Madrid, Spain; 5Pneumology Department, Hospital Universitario de A Coruña, A Coruña, Spain; 6Nursing Unit, Hospital Álvaro Cunqueiro, Pontevedra, Spain; 7Pneumology Department, Hospital Clínic, Barcelona, Spain; 8Pneumology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 9Nursung Unit, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 10Pneumology Department, Complejo Hospitalario Universitario de Albacete, Albacete, Spain; 11Pneumology Department, Hospital Universitario Clínico San Cecilio, Granada, Spain; 12Pneumology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; 13Pneumology Department, Hospital Universitario Nuestra Señora de La Candelaria, Santa Cruz de Tenerife, Tenerife, Spain; 14Pneumology Department, Complejo Asistencial Universitario de Burgos, Burgos, Spain; 15Instituto de Investigación Sanitaria del Principado de Asturias (FINBA-ISPA) Oviedo, Oviedo, Spain; 16Pneumology Department, Hospital Universitario Germans Trías I Pujol, Institut d’investigació Germans Trias i Pujol (IGTP), Badalona, Spain; 17Pneumology Department, Hospital Universitario Donostia, Donostia, Spain; 18Hospital Pharmacy Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 19Pneumology Department, Hospital Universitario Basurto, Bilbao, Spain; 20Nursing Unit, Hospital Clínico San Carlos, Madrid, Spain; 21Pneumology Department, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; 22Hospital Pharmacy Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain; 23Nursing Unit, Hospital Universitario Virgen del Rocío, Sevilla, Spain; 24Hospital Pharmacy Department, Hospital Costa del Sol, Málaga, SpainCorrespondence: María Torres-Durán, Tel +34986811111, Email [email protected]: Administration of exogenous alpha-1 antitrypsin (AAT) is the only specific therapy for the management of pulmonary morbidity in patients with AAT deficiency. It requires weekly or biweekly intravenous infusions, which may impact patient independence and quality of life. Self-administration of AAT therapy is an alternative to reduce the burden for patients who require AAT therapy. We presented herein experts’ recommendations for the implementation of a program for the self-administration of AAT.Methods: This project was conducted using a modified nominal group technique and was undertaken in two online meetings involving the participation of 25 experts: specialists in pulmonology (n=17), nurses (n=5) and hospital pharmacists (n=3).Results: The following issues were discussed, and several recommendations were agreed upon on the following topics: a) patient profile and clinical evaluation, establishing selection criteria that should include clinical as well as social criteria; b) role of health care professionals, suggested roles for specialists in pulmonology, nurses, and hospital pharmacists; c) training by the nurse, including recommendations before initiating the training and the content of the training sessions; and d) logistic issues and follow-up, adherence, and patient support.Conclusion: We expect this proposal to increase awareness of this therapeutic alternative and facilitate the implementation of self-administration programs, thus contributing to optimizing the patient experience with AAT therapy. Further research on the outcomes of these programs, especially from the patient perspective, will also help to improve their design and implementation.Keywords: alpha-1 antitrypsin deficiency, disease burden, augmentation therapy, self-administratio

The Schistosoma mansoni Cytochrome P450 (CYP3050A1) Is Essential for Worm Survival and Egg Development

Schistosomiasis affects millions of people in developing countries and is responsible for more than 200,000 deaths annually. Because of toxicity and limited spectrum of activity of alternatives, there is effectively only one drug, praziquantel, available for its treatment. Recent data suggest that drug resistance could soon be a problem. There is therefore the need to identify new drug targets and develop drugs for the treatment of schistosomiasis. Analysis of the Schistosoma mansoni genome sequence for proteins involved in detoxification processes found that it encodes a single cytochrome P450 (CYP450) gene. Here we report that the 1452 bp open reading frame has a characteristic heme-binding region in its catalytic domain with a conserved heme ligating cysteine, a hydrophobic leader sequence present as the membrane interacting region, and overall structural conservation. The highest sequence identity to human CYP450s is 22%. Double stranded RNA (dsRNA) silencing of S. mansoni (Sm)CYP450 in schistosomula results in worm death. Treating larval or adult worms with antifungal azole CYP450 inhibitors results in worm death at low micromolar concentrations. In addition, combinations of SmCYP450-specific dsRNA and miconazole show additive schistosomicidal effects supporting the hypothesis that SmCYP450 is the target of miconazole. Treatment of developing S. mansoni eggs with miconazole results in a dose dependent arrest in embryonic development. Our results indicate that SmCYP450 is essential for worm survival and egg development and validates it as a novel drug target. Preliminary structure-activity relationship suggests that the 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-1-ol moiety of miconazole is necessary for activity and that miconazole activity and selectivity could be improved by rational drug design