Consentimiento informado comunitario en investigación con seres humanos

Marianela Barcia: Profesora Adjunta de la Unidad Académica de Bioética. Facultad de Medicina. Universidad de la República.-- Lucía de Pena: Ex-Asistente (int.) de la Unidad Académica de Bioética. Facultad de Medicina. Universidad de la República.--Silvia Giménez: Ex-Asistente (int.) de la Unidad Académica de Bioética. Facultad de Medicina. Universidad de la República.-- Claudia Morosi: Profesora Adjunta (int.) de la Unidad Académica de Bioética. Facultad de Medicina. Universidad de la República.-- Sebastián Toledo: Asistente (int.) de la Unidad Académica de Bioética. Facultad de Medicina. Universidad de la República.En el presente trabajo se aborda el problema de la significación del consentimiento informado comunitario (CIC) en investigación como práctica dirigida a proteger los aspectos colectivos y culturales de las comunidades. Se pone en discusión, el concepto de consentimiento informado con la dimensión colectiva. Partiendo de un concepto polisémico como es el de “comunidad”, se busca analizar los principales problemas éticos en las investigaciones realizadas en el ámbito comunitario, en cuanto al reconocimiento o no de la mismas, y los derechos a ser protegidos desde lo colectivo. El consentimiento informado, como instrumento, proviene desde la dimensión individual, relacionado al principio de autonomía y libertad, por lo que es pertinente destacar que el consentimiento informado comunitario no revoca ni sustituye bajo ninguna circunstancia el consentimiento individual pero sí lo complementa desde una dimensión contextualizada y colectiva. Se desarrolla una descripción y análisis de la normativa nacional e internacional vigente para ver en qué medida las mismas amparan y promueven el respeto de los derechos de las comunidades en las investigaciones. Se intenta valorar la importancia del consentimiento informado comunitario como forma de revertir relaciones sociales de gran asimetría de poder

In vivo mature immunological synapses forming SMACs mediate clearance of virally infected astrocytes from the brain

The microanatomy of immune clearance of infected brain cells remains poorly understood. Immunological synapses are essential anatomical structures that channel information exchanges between T cell–antigen-presenting cells (APC) during the priming and effector phases of T cells' function, and during natural killer–target cell interactions. The hallmark of immunological synapses established by T cells is the formation of the supramolecular activation clusters (SMACs), in which adhesion molecules such as leukocyte function-associated antigen 1 segregate to the peripheral domain of the immunological synapse (p-SMAC), which surrounds the T cell receptor–rich or central SMAC (c-SMAC). The inability so far to detect SMAC formation in vivo has cast doubts on its functional relevance. Herein, we demonstrate that the in vivo formation of SMAC at immunological synapses between effector CD8+ T cells and target cells precedes and mediates clearance of virally infected brain astrocytes

JUEGOS TRADICIONALES COMO MEDIO DE DESARROLLO PSICOMOTOR PARA LOS NIÑOS DE QUINTO AÑO BÁSICO DE LA ESCUELA "12 DE OCTUBRE" DE LA CIUDAD DE MANTA.

CADA REGIÓN O PAÍS, TIENEN MANIFESTACIONES CULTURALES QUE LE PERMITEN PRESERVAR SU IDENTIDAD A TRAVÉS DE LAS GENERACIONES, UNA DE ESAS MANIFESTACIONES SON LOS JUEGOS TRADICIONALES, LOS CUALES NO SÓLO CONTRIBUYEN A MANTENER EL ACERVO CULTURAL DE UNA REGIÓN, SINO QUE LE PERMITEN A SUS PRACTICANTES, GENERALMENTE NIÑOS, CONOCER UN POCO MÁS ACERCA DE LAS RAÍCES Y PRESERVAR LA CULTURA...EL DESARROLLO PSICOMOTOR REPRESENTA UNA SERIE DE ETAPAS Y RETOS QUE DESDE EL DESARROLLO EVOLUTIVO DE LOS NIÑOS APORTA A SU ÓPTIMO CRECIMIENTO, SIN EMBARGO PARA SU DESARROLLO NO SE TOMA EN CUENTA LOS JUEGOS TRADICIONALES Y SUS VENTAJAS, ES POR ELLO QUE EL OBJETIVO DE ESTA INVESTIGACIÓN FUE "ANALIZAR LOS JUEGOS TRADICIONALES COMO MEDIO DE DESARROLLO PSICOMOTOR PARA LOS NIÑOS DE QUINTO AÑO BÁSICO DE LA ESCUELA "12 DE OCTUBRE" DE LA CIUDAD DE MANTA"

Consentimiento informado comunitario en investigación con seres humanos

En el presente trabajo se aborda el problema de la significación del consentimiento informado comunitario (CIC) en investigación como práctica dirigida a proteger los aspectos colectivos y culturales de las comunidades. Se pone en discusión, el concepto de consentimiento informado con la dimensión colectiva. Partiendo de un concepto polisémico como es el de “comunidad”, se busca analizar los principales problemas éticos en las investigaciones realizadas en el ámbito comunitario, en cuanto al reconocimiento o no de la mismas, y los derechos a ser protegidos desde lo colectivo. El consentimiento informado, como instrumento, proviene desde la dimensión individual, relacionado al principio de autonomía y libertad, por lo que es pertinente destacar que el consentimiento informado comunitario no revoca ni sustituye bajo ninguna circunstancia el consentimiento individual pero sí lo complementa desde una dimensión contextualizada y colectiva. Se desarrolla una descripción y análisis de la normativa nacional e internacional vigente para ver en qué medida las mismas amparan y promueven el respeto de los derechos de las comunidades en las investigaciones. Se intenta valorar la importancia del consentimiento informado comunitario como forma de revertir relaciones sociales de gran asimetría de poder

Regulatable Gene Expression Systems for Gene Therapy Applications: Progress and Future Challenges

Gene therapy aims to revert diseased phenotypes by the use of both viral and nonviral gene delivery systems. Substantial progress has been made in making gene transfer vehicles more efficient, less toxic, and nonimmunogenic and in allowing long-term transgene expression. One of the key issues in successfully implementing gene therapies in the clinical setting is to be able to regulate gene expression very tightly and consistently as and when it is needed. The regulation ought to be achievable using a compound that should be nontoxic, be able to penetrate into the desired target tissue or organ, and have a half-life of a few hours (as opposed to minutes or days) so that when withdrawn or added (depending on the regulatable system used) gene expression can be turned “on” or “off” quickly and effectively. Also, the genetic switches employed should ideally be nonimmunogenic in the host. The ability to switch transgenes on and off would be of paramount importance not only when the therapy is no longer needed, but also in the case of the development of adverse side effects to the therapy. Many regulatable systems are currently under development and some, i.e., the tetracycline-dependent transcriptional switch, have been used successfully for in vivo preclinical applications. Despite this, there are no examples of switches that have been employed in a human clinical trial. In this review, we aim to highlight the main regulatable systems currently under development, the gene transfer systems employed for their expression, and also the preclinical models in which they have been used successfully. We also discuss the substantial challenges that still remain before these regulatable switches can be employed in the clinical setting

Adenoviral Mediated Gene Transfer into the Dog Brain In Vivo

OBJECTIVE: Glioblastoma multiforme (GBM) is a devastating brain tumor for which there is no cure. Adenoviral-mediated transfer of conditional cytotoxic (herpes simplex virus [HSV] 1-derived thymidine kinase [TK]) and immunostimulatory (Fms-like tyrosine kinase 3 ligand [Flt3L]) transgenes elicited immune-mediated long-term survival in a syngeneic intracranial GBM model in rodents. However, the lack of a large GBM animal model makes it difficult to predict the outcome of therapies in humans. Dogs develop spontaneous GBM that closely resemble the human disease; therefore, they constitute an excellent large animal model. We assayed the transduction efficiency of adenoviral vectors (Ads) encoding beta-galactosidase (betaGal), TK, and Flt3L in J3T dog GBM cells in vitro and in the dog brain in vivo. METHODS: J3T cells were infected with Ads (30 plaque-forming units/cell; 72 h) encoding betaGal (Ad-betaGal), TK (Ad-TK), or Flt3L (Ad-Flt3L). We determined transgene expression by immunocytochemistry, betaGal activity, Flt3L enzyme-linked immunosorbent assay, and TK-induced cell death. Ads were also injected intracranially into the parietal cortex of healthy dogs. We determined cell-type specific transgene expression and immune cell infiltration. RESULTS: Adenoviral-mediated gene transfer of HSV1-TK, Flt3L, and betaGal was detected in dog glioma cells in vitro (45% transduction efficiency) and in the dog brain in vivo (10-mm area transduced surrounding each injection site). T cells and macrophages/activated microglia infiltrated the injection sites. Importantly, no adverse clinical or neuropathological side effects were observed. CONCLUSION: We demonstrate effective adenoviral-mediated gene transfer into the brain of dogs in vivo and support the use of these vectors to develop an efficacy trial for canine GBM as a prelude to human trials

Flt3L and TK gene therapy eradicate multifocal glioma in a syngeneic glioblastoma model

The disseminated characteristics of human glioblastoma multiforme (GBM) make it a particularly difficult tumor to treat with long-term efficacy. Most preclinical models of GBM involve treatment of a single tumor mass. For therapeutic outcomes to translate from the preclinical to the clinical setting, induction of an antitumor response capable of eliminating multifocal disease is essential. We tested the hypothesis that expression of Flt3L (human soluble FMS-like tyrosine kinase 3 ligand) and TK (herpes simplex virus type 1–thymidine kinase) within brain gliomas would mediate regression of the primary, treated tumor mass and a secondary, untreated tumor growing at a distant site from the primary tumor and the site of therapeutic vector injection. In both the single-GBM and multifocal-GBM models used, all saline-treated control animals succumbed to tumors by day 22. Around 70% of the animals bearing a single GBM mass treated with an adenovirus expressing Flt3L (AdFlt3L) and an adenovirus expressing TK (AdTK + GCV) survived long term. Approximately 50% of animals bearing a large primary GBM that were implanted with a second GBM in the contralateral hemisphere at the same time the primary tumors were being treated with AdFlt3L and AdTK also survived long term. A second multifocal GBM model, in which bilateral GBMs were implanted simultaneously and only the right tumor mass was treated with AdFlt3L and AdTK, also demonstrated long-term survival. While no significant difference in survival was found between unifocal and multifocal GBM–bearing animals treated with AdFlt3L and AdTK, both treatments were statistically different from the saline-treated control group (p < 0.05). Our results demonstrate that combination therapy with AdFlt3L and AdTK can eradicate multifocal brain tumor disease in a syngeneic, intracranial GBM model

Regulatable Gutless Adenovirus Vectors Sustain Inducible Transgene Expression in the Brain in the Presence of an Immune Response against Adenoviruses

In view of recent serious adverse events and advances in gene therapy technologies, the use of regulatable expression systems is becoming recognized as indispensable adjuncts to successful clinical gene therapy. In the present work we optimized high-capacity adenoviral (HC-Ad) vectors encoding the novel tetracycline-dependent (TetOn)-regulatory elements for efficient and regulatable gene expression in the rat brain in vivo. We constructed two HC-Ad vectors encoding β-galactosidase (β-gal) driven by a TetOn system containing the rtTAS(s)M2 transactivator and the tTS(Kid) repressor under the control of the murine cytomegalovirus (mCMV) (HC-Ad-mTetON-β-Gal) or the human CMV (hCMV) promoter (HC-Ad-hTetON-β-Gal). Expression was tightly regulatable by doxycycline (Dox), reaching maximum expression in vivo at 6 days and returning to basal levels at 10 days following the addition or removal of Dox, respectively. Both vectors achieved higher transgene expression levels compared to the expression from vectors encoding the constitutive mCMV or hCMV promoter. HC-Ad-mTetON-β-Gal yielded the highest transgene expression levels and expressed in both neurons and astrocytes. Antivector immune responses continue to limit the clinical use of vectors. We thus tested the inducibility and longevity of HC-Ad-mediated transgene expression in the brain of rats immunized against adenovirus by prior intradermal injections of RAds. Regulated transgene expression from HC-Ad-mTetON-β-Gal remained active even in the presence of a significant systemic immune response. Therefore, these vectors display two coveted characteristics of clinically useful vectors, namely their regulation and effectiveness even in the presence of prior immunization against adenovirus