Sistema Integrado de Gestión Académica

El Sistema Integrado de Gestión Académica consiste en una plataforma software modular orientada a apoyar la labor del profesorado en la gestión docente de las asignaturas impartidas por el Departamento de Mecánica de la Escuela Técnica Superior de Ingeniería y Diseño Industrial de la Universidad Politécnica de Madrid. Durante los últimos 5 años se ha trabajado en la creación de esta plataforma que se encuentra ahora en su recta final. Es necesario aclarar que toda la plataforma desde su inicio ha sido creada por el mismo autor y que debido al tiempo disponible para la realización del TFG, éste se ha centrado en realizar mejoras sobre lo ya desarrollado y en implementar uno de los módulos. El trabajo desarrollado comienza con un estudio de plataformas educativas online. Se han valorado las alternativas de Moodle y ATutor como posibles soluciones a los requisitos planteados llegando a la conclusión de que era necesario realizar un desarrollo a medida. La plataforma consta de 3 módulos principales:  Plataforma de Gestión Docente en Internet (PGDNet)  Aplicación de Notas (AdN)  Plataforma de Entrega de Prácticas Académicas (PEPA) PGDNet está orientado a la realización de pruebas de evaluación online. El profesor tiene a su alcance un conjunto de opciones que le permiten la creación de actividades y ejercicios de diferente índole, gestionar alumnos y establecer periodos de evaluación. El sistema recoge los resultados y corrige automáticamente permitiendo además exportar los resultados, manteniendo de esta manera la compatibilidad con otros sistemas informáticos de la UPM. PGDNet ofrece además un servicio de correo electrónico para realizar comunicaciones con grupos predefinidos de alumnos, un gestor documental enlazado con las diferentes actividades y un gestor de encuestas programable a medida. AdN se integra en la plataforma como un sistema para la gestión de calificaciones y permite mantener un historial del alumno. Las materias pueden dividirse en diferentes evaluaciones con un determinado peso sobre la calificación final. La nota total se calcula en tiempo real y de forma automática. El alumno puede entrar a consultar sus calificaciones en cualquier momento. El módulo ofrece a los profesores acceso simultáneo a introducir las calificaciones e importar notas guardadas de convocatorias pasadas. PEPA es el nuevo módulo que se añade a la plataforma y el que concentra los esfuerzos de desarrollo de este TFG. Se trata de un sistema de entrega de prácticas online que permite al profesor centralizar la recogida de documentación para su posterior corrección. PEPA dispone de un sistema de plantillas de respuestas fijas utilizadas en los laboratorios que son corregidas de forma automática en la entrega. Los 3 módulos se complementan entre sí compartiendo datos y permitiendo realizar importaciones y exportaciones de información con las aplicaciones actuales de Secretaría de alumnos como puede ser la introducción de listas de alumnos.---ABSTRACT---Academic Management Framework (Sistema Integrado de Gestión Académica) is a module‐oriented software application that aims to help teachers from ETSIDI Department from UPM to manage all information related to graduate courses. The software, which has been in continuous developing during the last 5 years, is now about to be finished. It must be pointed out the fact that the entire application has been designed and implemented by the same author. However, due to time schedule restrictions in this TFG (spanish acronym for “Graduation Project”), it has been focused on developing a few improvements in the software already implemented and creating a specific new module. In the beginning, this TFG includes an educational software comparative study. Moodle and ATutor have been selected as plausible assembled solutions that would fit the requirements given. Nonetheless, the conclusion ends up with rejecting both possibilities and moving the project towards a custom‐developed software. The application is divided in 3 modules:  Network Based Academic Management Platform (Plataforma de Gestión Docente en Internet ‐ PGDNet)  Evaluation Aid Tool (Aplicación de Notas ‐ AdN)  Academic Lab‐Work Delivery Platform (Plataforma de Entrega de Prácticas Académicas ‐ PEPA) PGDNet main purpose is handling online tests for students. There are a bunch of tools available for teachers that allow them to create activities and different types of exercises, manage students and set examination schedules. The system gathers the results and marks exercises automatically. Moreover, the teacher is able to export this information which is compatible with other UPM systems. PGDNet offers a mail service, a document management system and a survey application among others. AdN adds new features to the system. It helps teachers to manage student marks by keeping a history over the years. Subjects can be divided into little parts with a different weight in the final mark. Eventually, the mark is automatically calculated and published. The application can be accessed by both students and teachers simultaneously. This module is also ready to import old marks into the current course and allow all teachers to fill in the results at the same time. PEPA, which is a new module added from scratch, concentrate this TFG efforts. It consists of a practice delivery system that gathers all student documentation in a single site for easy correction. Besides, PEPA deploys an answer template repository for laboratory training. Students fill the templates and PEPA corrects them automatically on sending. These 3 modules are integrated in a single system that allows them to share data and import information such as student lists from the Administration Department.

Inter-organizational information systems adoption for service innovation in building sector

The building sector has experienced a significant decline in recent years in Spain and Europe as a result of the financial crisis that began in 2007. This drop accompanies a low penetration of information and communication technologies in inter-organizational oriented business processes. The market decrease is causing a slowdown in the building sector, where only flexible small and medium enterprises (SMEs) survive thanks to specialization and innovation in services, which allow them to face new market demands. Inter-organizational information systems (IOISs) support innovation in services, and are thus a strategic tool for SMEs to obtain competitive advantage. Because of the inherent complexity of IOIS adoption, this research extends Kurnia and Johnston's (2000) theoretical model of IOIS adoption with an empirical model of IOIS characterization. The resultant model identifies the factors influencing IOIS adoption in SMEs in the building sector, to promote further service innovation for competitive and collaborative advantages. An empirical longitudinal study over six consecutive years using data from Spanish SMEs in the building sector validates the model, using the partial least squares technique and analyzing temporal stability. The main findings of this research are the four ways an IOIS might contribute to service innovation in the building sector. Namely: a) improving client interfaces and the link between service providers and end users; b) defining a specific market where SMEs can develop new service concepts; c) enhancing the service delivery system in traditional customer?supplier relationships; and d) introducing information and communication technologies and tools to improve information management.

El análisis de la construcción sin pérdidas (Lean Construction) y su relación con el Project & Construction Management : propuesta de regulación en España y su inclusión en la ley de la ordenación de la edificación

El presente trabajo se basa en la filosofía de la Construcción sin Pérdidas (“Lean Construction”), analizando la situación de esta filosofía en el sector de la edificación en el contexto internacional y español, respondiendo las siguientes preguntas: 1. ¿Cómo surge el “Lean Construction”? 2. ¿Cuáles son sus actividades, funciones y cometidos? 3. ¿Existe regulación del ¨Lean Construction” en otros países? 4. ¿Existe demanda del ¨Lean Construction” en España? 5. ¿Existe regulación del ¨Lean Construction” en España? 6. ¿Cómo debería ser la regulación ¨Lean Construction” en España? 7. ¿Cuál es la relación del “Lean Construction” con el “Project & Construction Management”? 8. ¿Cómo debería ser la regulación de “Lean Construction” en España considerando su relación con el “Project & Construction Management”? Las preguntas indicadas las hemos respondido detalladamente en el presente trabajo, a continuación se resume las respuestas a dichas preguntas: 1. El “Lean Construction” surge en agosto de 1992, cuando el investigador finlandés Lauri Koskela publicó en la Universidad de Stanford el reporte TECHNICAL REPORT N° 72 titulado “Application of the New Production Philosophy to Construction”. Un año más tarde el Dr. Koskela invitó a un grupo de especialistas en construcción al primer workshop de esta materia en Finlandia, dando origen al International Group for Lean Construction (IGLC) lo que ha permitido extender la filosofía a EEUU, Europa, América, Asia, Oceanía y África. “Lean Construction” es un sistema basado en el enfoque “Lean Production” desarrollado en Japón por Toyota Motors a partir de los años cincuenta, sistema que permitió a sus fábricas producir unidades con mayor eficiencia que las industrias americanas, con menores recursos, en menor tiempo, y con un número menor de errores de fabricación. 2. El sistema “Lean Construction” busca maximizar el valor y disminuir las pérdidas de los proyectos generando una coordinación eficiente entre los involucrados, manejando un proyecto como un sistema de producción, estrechando la colaboración entre los participantes de los proyectos, capacitándoles y empoderándoles, fomentando una cultura de cambio. Su propósito es desarrollar un proceso de construcción en el que no hayan accidentes, ni daños a equipos, instalaciones, entorno y comunidad, que se realice en conformidad con los requerimientos contractuales, sin defectos, en el plazo requerido, respetando los costes presupuestados y con un claro enfoque en la eliminación o reducción de las pérdidas, es decir, las actividades que no generen beneficios. El “Last Planner System”, o “Sistema del Último Planificador”, es un sistema del “Lean Construction” que por su propia naturaleza protege a la planificación y, por ende, ayuda a maximizar el valor y minimizar las pérdidas, optimizando de manera sustancial los sistemas de seguridad y salud. El “Lean Construction” se inició como un concepto enfocado a la ejecución de las obras, posteriormente se aplicó la filosofía a todas las etapas del proyecto. Actualmente considera el desarrollo total de un proyecto, desde que nace la idea hasta la culminación de la obra y puesta en marcha, considerando el ciclo de vida completo del proyecto. Es una filosofía de gestión, metodologías de trabajo y una cultura empresarial orientada a la eficiencia de los procesos y flujos. La filosofía “Lean Construction” se está expandiendo en todo el mundo, además está creciendo en su alcance, influyendo en la gestión contractual de los proyectos. Su primera evolución consistió en la creación del sistema “Lean Project Delivery System”, que es el concepto global de desarrollo de proyectos. Posteriormente, se proponen el “Target Value Design”, que consiste en diseñar de forma colaborativa para alcanzar los costes y el valor requerido, y el “Integrated Project Delivery”, en relación con sistemas de contratos relacionales (colaborativos) integrados, distintos a los contratos convencionales. 3. Se verificó que no existe regulación específica del ¨Lean Construction” en otros países, en otras palabras, no existe el agente con el nombre específico de “Especialista en Lean Construction” o similar, en consecuencia, es un agente adicional en el proyecto de la edificación, cuyas funciones y cometidos se pueden solapar con los del “Project Manager”, “Construction Manager”, “Contract Manager”, “Safety Manager”, entre otros. Sin embargo, se comprobó la existencia de formatos privados de contratos colaborativos de Integrated Project Delivery, los cuales podrían ser tomados como unas primeras referencias para futuras regulaciones. 4. Se verificó que sí existe demanda del ¨Lean Construction” en el desarrollo del presente trabajo, aunque aún su uso es incipiente, cada día existe más interesados en el tema. 5. No existe regulación del ¨Lean Construction” en España. 6. Uno de los objetivos fundamentales de esta tesis es el de regular esta figura cuando actúe en un proyecto, definir y realizar una estructura de Agente de la Edificación, según la Ley de Ordenación de la Edificación (LOE), y de esta manera poder introducirla dentro de la Legislación Española, protegiéndola de eventuales responsabilidades civiles. En España existe jurisprudencia (sentencias de los tribunales de justicia españoles) con jurisdicción civil basada en la LOE para absolver o condenar a agentes de la edificación que son definidos en los tribunales como “gestores constructivos” o similares. Por este motivo, en un futuro los tribunales podrían dictaminar responsabilidades solidarias entre el especialista “Lean Construction” y otros agentes del proyecto, dependiendo de sus actuaciones, y según se implemente el “Lean Project Delivery System”, el “Target Value Design” y el “Integrated Project Delivery”. Por otro lado, es posible que el nivel de actuación del especialista “Lean Construcción” pueda abarcar la gestión del diseño, la gestión de la ejecución material (construcción), la gestión de contratos, o la gestión integral de todo el proyecto de edificación, esto último, en concordancia con la última Norma ISO 21500:2012 o UNE-ISO 21500:2013 Directrices para la dirección y gestión de proyectos. En consecuencia, se debería incorporar adecuadamente a uno o más agentes de la edificación en la LOE de acuerdo a sus funciones y responsabilidades según los niveles de actuación del “Especialista en Lean Construction”. Se propone la creación de los siguientes agentes: Gestor del Diseño, Gestor Constructivo y Gestor de Contratos, cuyas definiciones están desarrolladas en este trabajo. Estas figuras son definidas de manera general, puesto que cualquier “Project Manager” o “DIPE”, gestor BIM (Building Information Modeling), o similar, puede actuar como uno o varios de ellos. También se propone la creación del agente “Gestor de la Construcción sin Pérdidas”, como aquel agente que asume las actuaciones del “gestor de diseño”, “gestor constructivo” y “gestor de contratos” con un enfoque en los principios del Lean Production. 7. En la tesis se demuestra, por medio del uso de la ISO 21500, que ambos sistemas son complementarios, de manera que los proyectos pueden tener ambos enfoques y ser compatibilizados. Un proyecto que use el “Project & Construction Management” puede perfectamente apoyarse en las herramientas y técnicas del “Lean Construction” para asegurar la eliminación o reducción de las pérdidas, es decir, las actividades que no generen valor, diseñando el sistema de producción, el sistema de diseño o el sistema de contratos. 8. Se debería incorporar adecuadamente al agente de la edificación “Especialista en Lean Construction” o similar y al agente ¨Especialista en Project & Construction Management” o DIPE en la Ley de Ordenación de la Edificación (LOE) de acuerdo a sus funciones y responsabilidades, puesto que la jurisprudencia se ha basado para absolver o condenar en la referida Ley. Uno de los objetivos fundamentales de esta tesis es el de regular la figura del “Especialista en Lean Construction” cuando actúa simultáneamente con el DIPE, y realizar una estructura de Agente de la Edificación según la LOE, y de esta manera protegerlo de eventuales responsabilidades solidarias. Esta investigación comprueba que la propuesta de definición del agente de edificación DIPE, según la LOE, presentada en la tesis doctoral del Doctor Manuel Soler Severino es compatible con las nuevas definiciones propuestas. El agente DIPE puede asumir los roles de los diferentes gestores propuestos en esta tesis si es que se especializa en dichas materias, o, si lo estima pertinente, recomendar sus contrataciones. ABSTRACT This work is based on the Lean Construction philosophy; an analysis is made herein with regard to the situation of this philosophy in the building sector within the international and Spanish context, replying to the following questions: 1. How did the concept of Lean Construction emerge? 2. Which are the activities, functions and objectives of Lean Construction? 3. Are there regulations on Lean Construction in other countries? 4. Is there a demand for Lean Construction in Spain? 5. Are there regulations on Lean Construction in Spain? 6. How should regulations on Lean Construction be developed in Spain? 7. What is the relationship between Lean Construction and the Project & Construction Management? 8. How should regulations on Lean Construction be developed in Spain considering its relationship with the Project & Construction Management? We have answered these questions in detail here and the replies are summarized as follows: 1. The concept of Lean Construction emerged in august of 1992, when Finnish researcher Lauri Koskela published in Stanford University TECHNICAL REPORT N° 72 entitled “Application of the New Production Philosophy to Construction”. A year later, Professor Koskela invited a group of construction specialists to Finland to the first workshop conducted on this matter; thus, the International Group for Lean Construction (IGLC) was established, which has contributed to extending the philosophy to the United States, Europe, the Americas, Asia, Oceania, and Africa. Lean Construction is a system based on the Lean Production approach, which was developed in Japan by Toyota Motors in the 1950s. Thanks to this system, the Toyota plants were able to produce more units, with greater efficiency than the American industry, less resources, in less time, and with fewer manufacturing errors. 2. The Lean Construction system aims at maximizing the value of projects while reducing waste, producing an effective coordination among those involved; it manages projects as a production system, enhancing collaboration between the parties that participate in the projects while building their capacities, empowering them, and promoting a culture of change. Its purpose is to develop a construction process free of accidents, without damages to the equipment, facilities, environment and community, flawless, in accordance with contractual requirements, within the terms established, respecting budgeted costs, and with a clear approach to eliminating or reducing waste, that is, activities that do not generate benefits. The Last Planner System is a Lean Construction system, which by its own nature protects planning and, therefore, helps to maximize the value and minimize waste, optimizing substantially the safety and health systems. Lean Construction started as a concept focused on the execution of works, and subsequently the philosophy was applied to all the stages of the project. At present it considers the project’s total development, since the time ideas are born until the completion and start-up of the work, taking into account the entire life cycle of the project. It is a philosophy of management, work methodologies, and entrepreneurial culture aimed at the effectiveness of processes and flows. The Lean Construction philosophy is extending all over the world and its scope is becoming broader, having greater influence on the contractual management of projects. It evolved initially through the creation of the Lean Project Delivery System, a global project development concept. Later on, the Target Value Design was developed, based on collaborative design to achieve the costs and value required, as well as the Integrated Project Delivery, in connection with integrated relational (collaborative) contract systems, as opposed to conventional contracts. 3. It was verified that no specific regulations on Lean Construction exist in other countries, in other words, there are no agents with the specific name of “Lean Construction Specialist” or other similar names; therefore, it is an additional agent in building projects, which functions and objectives can overlap those of the Project Manager, Construction Manager, Contract Manager, or Safety Manager, among others. However, the existence of private collaborative contracts of Integrated Project Delivery was confirmed, which could be considered as first references for future regulations. 4. There is a demand for Lean Construction in the development of this work; even though it is still emerging, there is a growing interest in this topic. 5. There are no regulations on Lean Construction in Spain. 6. One of the main objectives of this thesis is to regulate this role when acting in a project, and to define and develop a Building Agent structure, according to the Building Standards Law (LOE by its acronym in Spanish), in order to be able to incorporate it into the Spanish law, protecting it from civil liabilities. In Spain there is jurisprudence in civil jurisdiction based on the LOE to acquit or convict building agents, which are defined in the courts as “construction managers” or similar. For this reason, courts could establish in the future joint and several liabilities between the Lean Construction Specialist and other agents of the project, depending on their actions and based on the implementation of the Lean Project Delivery System, the Target Value Design, and the Integrated Project Delivery. On the other hand, it is possible that the level of action of the Lean Construction Specialist may comprise design management, construction management and contract management, or the integral management of the entire building project in accordance with the last ISO 21500:2012 or UNE-ISO 21500:2013, guidelines for the management of projects. Accordingly, one or more building agents should be appropriately incorporated into the LOE according to their functions and responsibilities and based on the levels of action of the Lean Construction Specialist. The creation of the following agents is proposed: Design Manager, Construction Manager, and Contract Manager, which definitions are developed in this work. These agents are defined in general, since any Project Manager or DIPE, Building Information Modeling (BIM) Manager or similar, may act as one or as many of them. The creation of the Lean Construction Manager is also proposed, as the agent that takes on the role of the Design Manager, Construction Manager and Contract Manager with a focus on the Lean Production principles. 7. In the thesis it is demonstrated that through the implementation of the ISO 21500, both systems are supplementary, so projects may have both approaches and be compatible. A project that applies the Project & Construction Management may perfectly have the support of the tools, techniques and practices of Lean Construction to ensure the elimination or reduction of losses, that is, those activities that do not generate value, thus designing the production system, the design system, or the contract system. 8. The Lean Construction Specialist or similar and the Specialist in Project & Construction Management should be incorporated appropriately into the LOE according to their functions and responsibilities, since jurisprudence has been based on such Law to acquit or convict. One of the main objectives of this thesis is the regulate the role of the Lean Construction Specialist when acting simultaneously with the DIPE, and to develop a structure of the building agent, according to the LOE, and in this way protect such agent from joint and several liabilities. This research proves that the proposal to define the DIPE building agent, according to the LOE, and presented in the doctoral dissertation of Manuel Soler Severino, Ph.D. is compatible with the new definitions proposed. The DIPE agent may assume the roles of the different managers proposed in this thesis if he specializes in those topics or, if deemed pertinent, recommends that they be engaged.

Interleukin 12 and B7-1 costimulatory molecule expressed by an adenovirus vector act synergistically to facilitate tumor regression

Stimulation of antitumor immune mechanisms is the primary goal of cancer immunotherapy, and accumulating evidence suggests that effective alteration of the host–tumor relationship involves immunomodulating cytokines and also the presence of costimulatory molecules. To examine the antitumor effect of direct in vivo gene transfer of murine interleukin 12 (IL-12) and B7-1 into tumors, we developed an adenovirus (Ad) vector, AdIL12–B7-1, that encodes the two IL-12 subunits in early region 1 (E1) and the B7-1 gene in E3 under control of the murine cytomegalovirus promoter. This vector expressed high levels of IL-12 and B7-1 in infected murine and human cell lines and in primary murine tumor cells. In mice bearing tumors derived from a transgenic mouse mammary adenocarcinoma, a single intratumoral injection with a low dose (2.5 × 107 pfu/mouse) of AdIL12–B7-1 mediated complete regression in 70% of treated animals. By contrast, administration of a similar dose of recombinant virus encoding IL-12 or B7-1 alone resulted in only a delay in tumor growth. Interestingly, coinjection of two different viruses expressing either IL-12 or B7-1 induced complete tumor regression in only 30% of animals treated at this dose. Significantly, cured animals remained tumor free after rechallenge with fresh tumor cells, suggesting that protective immunity had been induced by treatment with AdIL12–B7-1. These results support the use of Ad vectors as a highly efficient delivery system for synergistically acting molecules and show that the combination of IL-12 and B7-1 within a single Ad vector might be a promising approach for in vivo cancer therapy.

Ablation of P/Q-type Ca2+ channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the α1A-subunit

The Ca2+ channel α1A-subunit is a voltage-gated, pore-forming membrane protein positioned at the intersection of two important lines of research: one exploring the diversity of Ca2+ channels and their physiological roles, and the other pursuing mechanisms of ataxia, dystonia, epilepsy, and migraine. α1A-Subunits are thought to support both P- and Q-type Ca2+ channel currents, but the most direct test, a null mutant, has not been described, nor is it known which changes in neurotransmission might arise from elimination of the predominant Ca2+ delivery system at excitatory nerve terminals. We generated α1A-deficient mice (α1A−/−) and found that they developed a rapidly progressive neurological deficit with specific characteristics of ataxia and dystonia before dying ≈3–4 weeks after birth. P-type currents in Purkinje neurons and P- and Q-type currents in cerebellar granule cells were eliminated completely whereas other Ca2+ channel types, including those involved in triggering transmitter release, also underwent concomitant changes in density. Synaptic transmission in α1A−/− hippocampal slices persisted despite the lack of P/Q-type channels but showed enhanced reliance on N-type and R-type Ca2+ entry. The α1A−/− mice provide a starting point for unraveling neuropathological mechanisms of human diseases generated by mutations in α1A.

Tissue-engineered cells producing complex recombinant proteins inhibit ovarian cancer in vivo

Techniques of tissue engineering and cell and molecular biology were used to create a biodegradable scaffold for transfected cells to produce complex proteins. Mullerian Inhibiting Substance (MIS) causes regression of Mullerian ducts in the mammalian embryo. MIS also causes regression in vitro of ovarian tumor cell lines and primary cells from ovarian carcinomas, which derive from Mullerian structures. In a strategy to circumvent the complicated purification protocols for MIS, Chinese hamster ovary cells transfected with the human MIS gene were seeded onto biodegradable polymers of polyglycolic acid fibers and secretion of MIS confirmed. The polymer-cell graft was implanted into the right ovarian pedicle of severe combined immunodeficient mice. Serum MIS in the mice rose to supraphysiologic levels over time. One week after implantation of the polymer-cell graft, IGROV-1 human tumors were implanted under the renal capsule of the left kidney. Growth of the IGROV-1 tumors was significantly inhibited in the animals with a polymer-cell graft of MIS-producing cells, compared with controls. This novel MIS delivery system could have broader applications for other inhibitory agents not amenable to efficient purification and provides in vivo evidence for a role of MIS in the treatment of ovarian cancer.

Evaluating the federal role in financing health-related research

This paper considers the appropriate role for government in the support of scientific and technological progress in health care; the information the federal government needs to make well-informed decisions about its role; and the ways that federal policy toward research and development should respond to scientific advances, technology trends, and changes in the political and social environment. The principal justification for government support of research rests upon economic characteristics that lead private markets to provide inappropriate levels of research support or to supply inappropriate quantities of the products that result from research. The federal government has two basic tools for dealing with these problems: direct subsidies for research and strengthened property rights that can increase the revenues that companies receive for the products that result from research. In the coming years, the delivery system for health care will continue to undergo dramatic changes, new research opportunities will emerge at a rapid pace, and the pressure to limit discretionary federal spending will intensify. These forces make it increasingly important to improve the measurement of the costs and benefits of research and to recognize the tradeoffs among alternative policies for promoting innovation in health care.

Systemic gene therapy: biodistribution and long-term expression of a transgene in mice.

We have investigated the in vivo efficacy of a systemic gene transfer method, which combines a liposomal delivery system (DLS liposomes) with episomally replicative DNA plasmids to effect long-term expression of a transgene in cells. A single i.v. injection of a plasmid DNA vector containing the luciferase gene as a marker was administered with the DLS liposomes in BALB/c mice. The luciferase gene and its product were found in all mouse tissues tested as determined by PCR analysis and immunohistochemistry. Luciferase activity was also detected in all tissues tested and was present in lung, liver, spleen, and heart up to 3 months postinjection. In contrast to the nonepisomal vectors tested (pRSV-luc and pCMVintlux), human papovavirus (BKV)-derived episomal vectors showed long-term transgene expression. We found that these episomal vectors replicated extrachromosomally in lung 2 weeks postinjection. Results indicated that transgene expression in specific tissues depended on the promoter element used, DNA/liposome formulation, dose of DNA per injection, and route of administration.

Injetor intravascular de CO2: estudo in vivo de viabilidade inicial do dispositivo e de qualidade de imagem

INTRODUÇÃO: Durante procedimentos endovasculares, estão presentes os riscos relacionados ao uso dos contrastes iodados, tais como a nefropatia por contraste, uma vez que é fundamental o emprego de um meio de contraste para a obtenção das imagens radiológicas vasculares. A injeção intravascular de gás CO2 purificado é reconhecidamente uma alternativa relativamente mais segura ao contraste iodado, contudo, seu manuseio artesanal pode também trazer dificuldades técnicas e riscos aos pacientes. Para contemplar estas questões, foi desenvolvido o protótipo de um injetor intravascular de CO2 medicinal, microprocessado, dedicado à obtenção de imagens angiográficas. OBJETIVOS: Realizar os testes de viabilidade técnica inicial do protótipo em modelo in vivo. MÉTODOS: Realizar a angioplastia da artéria renal esquerda de 10 porcos, divididos em 2 grupos: Grupo 1 (n=5) injeção de contraste iodado, Grupo 2 (n=5) injeção de CO2 através do protótipo. Monitorização clínica e laboratorial dos animais no pré, intra e pós-operatório, com exames de função renal na véspera e 48h após os procedimentos e 3 gasometrias arteriais seriadas no intra-operatório. Observação clínica foi mantida por 48h no pós- operatório. RESULTADOS: Os procedimentos de angioplastia com CO2 foram realizados com sucesso técnico de 100%, sem necessidade de complementação com injeção de contraste iodado no Grupo 2. Não foram identificadas falhas no protótipo em funcionamento. Não foram identificadas alterações clínicas ou radiológicas sugestivas de contaminação por ar ambiente do sistema de CO2 e nem alterações laboratoriais nos animais. As imagens angiográficas obtidas no Grupo 2 foram consideradas, numa avaliação subjetiva, relativamente inferiores às imagens obtidas no Grupo 1. DISCUSSÃO: A qualidade inferior de imagem no Grupo 2 pode ser atribuída ao equipamento de fluoroscopia utilizado, com software desatualizado em relação aos equipamentos atuais, que incluem pré-configurações para angiografia com CO2; no entanto, ainda assim todos os procedimentos propostos no Grupo 2 foram realizados com sucesso técnico, o que nos leva a classificar as imagens deste grupo 2 como satisfatórias. O manuseio do aparelho mostrou-se ágil e eficiente, com a programação dos parâmetros sendo realizada com facilidade através do visor \"touch screen\", comparativamente superior ao método artesanal de injeção de CO2 com seringas em selo d\'água. CONCLUSÕES: O protótipo do aparelho injetor intravascular de CO2 funcionou de forma adequada durante os testes e as imagens obtidas permitiram a compleição com sucesso dos procedimentos. Portanto, os resultados positivos obtidos sugerem que o equipamento é tecnicamente viável

Nanopartículas lipídicas sólidas e vesículas cataniônicas contendo ftalocianina de cloro alumínio aplicadas nos processos fotodinâmicos

O trabalho apresentado foi realizado em duas etapas independentes e baseou-se no estudo de diferentes sistemas nanométricos para viabilizar a aplicação da ftalocianina de cloro alumínio (ClAlPc) na terapia fotodinâmica (TFD) para o tratamento do câncer de pele do tipo melanoma. O fármaco fotossensibilizante (FS) utilizado apresenta propriedades físico-químicas que lhe permitem exercer sua atividade fotodinâmica com excelência, sem a interferência do cromóforo endógeno melanina existente nas células melanocíticas. Para driblar sua elevada hidrofobicidade, ClAlPc foi encapsulada em sistemas nanométricos para administração em meio fisiológico. Inicialmente nanopartículas lipídicas sólidas (NLS) foram desenvolvidas por emulsificação direta, após um estudo de elaboração do diagrama de fases. O compritol foi o lipídio sólido escolhido para compor as NLS, com diferentes concentrações de ClAlPc. Todas as formulações desenvolvidas foram devidamente caracterizadas, com tamanho médio entre 100 e 200 nm, baixa polidispersão, potencial zeta adequadamente negativo (~|30| mV), drug loading de ClAlPc entre 76-94% (com pequena redução após 24 meses) e alta eficiência de encapsulação (E.E.). A morfologia arredondada das nanopartículas foi confirmada por microscopia eletrônica de transmissão e de força atômica. A estabilidade das NLS foi de 24 meses. A avaliação da cristalinidade do lipídio revelou a integração da ClAlPc à matriz lipídica da NLS, presença de estruturas polimórficas e grau de cristalinidade adequado, sem alterações após 24 meses. Nos estudos de difusão in vitro, observou-se que ftalocianina encapsulada nas NLS acumulam-se preferencialmente na epiderme e derme do que no estrato córneo, sem traços de permeação do ativo. Foi confirmado o caráter biocompatível das NLS sobre fibroblastos NIH-3T3. A ftalocianina encapsulada nas NLS não foi tóxica na linhagem de melanoma B16-F10 na ausência de luz, porém, apresentou excelente efeito fototóxico (0,75 ?g mL-1 de ClAlPc nanoencapsulada e irradiação entre 0,5 e 2,0 J cm-2), com redução da viabilidade celular de 87%. O segundo sistema de veiculação estudado foram as vesículas cataniônicas (VesCat), que se formam espontaneamente em água com o tensoativo TriCat 12. A obtenção das vesículas contendo ClAlPc envolve uma etapa adicional, para remoção de solvente orgânico, que foi aprimorada, reduzindo o tempo de produção em 55%. As VesCat/ClAlPc obtidas mantiveram suas propriedades físico-químicas e morfologia arredondada (confirmada por microscopia eletrônica de varredura), drug loading de 47% e alta E.E. Os resultados comprovaram que a aplicação desses dois sistemas nanométricos é altamente eficiente para aplicação da TFD no tratamento do câncer de pele do tipo melanoma ou outras doenças cutâneas, apresentando características favoráveis para avanços nos estudos de fase clínica e pré-clínica.

Preparação, caracterização e propriedades de lipossomas contendo o ácido -ciano-4-hidroxicinâmico e o agente fotossenbilizador AICIPc: um novo sistema carreador específico com ação sinérgica aplicado a terapia fotodinâmica

Ftalocianina de alumínio-cloro (AlClPc) é um fotossensibilizador de segunda geração em terapia fotodinâmica (TFD) caracterizado por seu caráter anfifílico e tendência de auto-agregação em meio aquoso, o que prejudica seu potencial de aplicação. O aCHC é um substrato de transportadores de monocarboxilato (MCT) superexpresso em células de MCF-7. Objetivando a solubilização da AlClPc e aumento de internalização em tecidos neoplásicos nos propomos aqui o uso de DSPC e DOPC em diferentes proporções para formar vesículas lipidicas mistas (LV) na presença de aCHC como sistemas veiculadores de fármaco. Lv foi preparado pelo método de injeção etanólica e formou vesículas de dimensões nanométricas (aproximadamente 100 nm) com bom índice de polidispersão, valores negativos de potencial zeta e estáveis em meio aquoso por mais de 50 dias. AlClPc se complexou com o fosfato das LV o que conferiu uma localização interfacial às moléculas de AlClPc como demonstrado pelos resultados de supressão de fluorescência. Medidas de anisotropia, fluorescência estática e resolvida no tempo corroboram com estes resultados e demonstram que a auto-agregação da AlClPc ocorre mesmo em lipossomas. Entretanto, a veiculação da AlClPc por LV em carcinoma de células escamosas oral (OSCC) levou a um processo de desagregação demonstrado por (FLIM). Este incrível comportamento é novo e aumenta o conhecimento científico sobre o mecanismo intracelular de ação de fotossensibilizadores em TFD. Em TFD, ambos os sistemas LVIII+AlClPc e LVIII+AlClPc+aCHC não apresentaram toxicidade no escuro no período de incubação de 3 h com as concentrações de lipídios, AlClPc e aCHC iguais a 0,15 mmol/L, 0,5 umol/L e 10,0 umol/L, respectivamente. De maneira inesperada, o sistema LVIII+AlClPc foi mais eficiente em TFD que o sistema LVIII+AlClPc+aCHC, devido ao caráter antioxidante do aCHC. Estes resultados abrem uma nova perspectiva do potencial uso de LV-AlClPc para o tratamento fotodinâmico.

The measurement of nicotine in human plasma by high-performance liquid chromatography-electrospray-tandem mass spectrometry

The authors describe a reverse-phase high-performance liquid chromatography-electrospray-tandem mass spectrometry method for the measurement of nicotine in human plasma. Samples (500 muL) with added deuterium-labeled d(3)-nicotine as an internal standard (IS) were treated with a 2-step process of ether extraction (6 mL) followed by back-extraction into 0.1% formic acid (50 muL). Chromatography was performed on a phenyl Novapak column with a mobile phase consisting of 50% 10 mM ammonium fortriate (pH 3.3) and acetonitrile (50:50, vol/vol). A flow rate of 0.2 mL/min resulted in a total analysis time of 5 minutes per sample. Mass spectrometric detection was by selected reactant monitoring (nicotine m/z 163.2 --> 130.2; IS m/z 166.2 --> 87.2). The assay was linear from 0.5 to 100 mug/L (r > 0.993, n = 9). The accuracy and imprecision of the method for quality control sampleswere 87.5% to 113% and < 10.2%, respectively. Interday accuracy and imprecision at the limit of quantification (0.5 mug/L) was 113% and 7.2% (n = 4). The process efficiency for nicotine in plasma was > 75%. The method described has good process efficiency, stabilized nicotine, avoided concentration steps, and most importantly minimized potential contamination. Further, we have established that water-based standards and controls are interchangeable with plasma-based samples. This method was used successfully to measure the pharmacokinetic profiles of subjects involved in the development of an aerosol inhalation drug delivery system.

The International Consortium on Mental Health Policy and Services: objectives, design and project implementation

The concept of the burden of disease, introduced and estimated for a broad range of diseases in the World Bank report of 1993 illustrated that mental and neurological disorders not only entail a higher burden than cancer, but are responsible, in developed and developing countries, for more than 15% of the total burden of all diseases. As a consequence, over the past decade, mental disorders have ranked increasingly highly on the international agenda for health. However, the fact that mental health and nervous system disorders are now high on the international health agenda is by no means a guarantee that the fate of patients suffering from these disorders in developing countries will improve. In most developing countries the treatment gap for mental and neurological disorders is still unacceptably high. To address this problem, an international network of collaborating institutions in low-income countries has been set up. The establishment and the achievements of this network-the International Consortium on Mental Health Policy and Services-are reported. Sixteen institutions in developing countries collaborate (supported by a small number of scientific resource centres in industrialized nations) in projects on applied mental health systems research. Over a two-year period, the network produced the key elements of a national mental health policy; provided tools and methods for assessing a country's current mental health status (context, needs and demands, programmes, services and care and outcomes); established a global network of expertise, i.e., institutions and experts, for use by countries wishing to reform their mental health policy, services and care; and generated guidelines and examples for upgrading mental health policy with due regard to the existing mental health delivery system and demographic, cultural and economic factors.

Increased adjuvant activity of minimal CD8 T cell peptides incorporated into lipid-core-peptides

A problem facing the use of subunit peptide and protein vaccines is their inability to stimulate protective immune responses. Many different approaches have been utilized to overcome this inefficient immune activation. The approach we have taken is to modify the vaccine antigen so that it now has adjuvant properties. To do this, multiple copies of minimal CD8 T cell epitopes were attached to a poly lysine lipid core. These constructs are known as lipid-core-peptides (LCP). The research presented here examines the adjuvant activity of LCP. Using mouse models, we were able to show that LCP were indeed able to activate antigen-presenting cells in vitro and to activate cytotoxic T-cell responses in vivo. More importantly, LCP were able to stimulate the development of a protective antitumour immune response.

Gastrointestinal transit in the common brushtail possum measured by gamma scintigraphy

This paper reports an example of the application of pharmaceutical technology to wildlife management, specifically the design of an oral delivery system for the common brushtail possum in New Zealand. Designing an oral delivery system requires a knowledge of the time taken for particulates to reach target sites within the gastrointestinal tract (GIT). The transit time for fluid and indigestible particles of two different size ranges was determined in the common brushtail possum (Trichosurus vulpecula). Technetium-labelled (Tc-99m) anion exchange resin particles (75-125 or 500-700 mu m diameter) or solution (Tc-99m-labelled diethylenetriamine pentaacetic acid, Tc-99m-DTPA) was administered orally. At predetermined times after dosing (3, 6, 12, 24 or 32 h), the distribution of radioactivity throughout excised gastrointestinal tracts was determined by gamma scintigraphy. The transit profile was similar for the three formulations investigated. Unlike other closely related hindgut fermenting marsupials, there was no evidence to support the presence of a colonic separating mechanism in the common brushtail possum. Gastrointestinal transit was independent of body mass, gender and time of day that the dose is given. To target the hindgut for oral delivery of protein and peptide biocontrol agents, the formulation Would need to protect the bioactive for approximately 12 h prior to release. (c) 2005 Elsevier B.V. All rights reserved.