Analysis of the transcriptional activity of endogenous NFAT5 in primary cells using transgenic NFAT-luciferase reporter mice

Background: The transcription factor NFAT5/TonEBP regulates the response of mammalian cells to hypertonicity. However, little is known about the physiopathologic tonicity thresholds that trigger its transcriptional activity in primary cells. Wilkins et al. recently developed a transgenic mouse carrying a luciferase reporter (9xNFAT-Luc) driven by a cluster of NFAT sites, that was activated by calcineurin-dependent NFATc proteins. Since the NFAT site of this reporter was very similar to an optimal NFAT5 site, we tested whether this reporter could detect the activation of NFAT5 in transgenic cells.Results: The 9xNFAT-Luc reporter was activated by hypertonicity in an NFAT5-dependent manner in different types of non-transformed transgenic cells: lymphocytes, macrophages and fibroblasts. Activation of this reporter by the phorbol ester PMA plus ionomycin was independent of NFAT5 and mediated by NFATc proteins. Transcriptional activation of NFAT5 in T lymphocytes was detected at hypertonic conditions of 360–380 mOsm/kg (isotonic conditions being 300 mOsm/kg) and strongly induced at 400 mOsm/kg. Such levels have been recorded in plasma in patients with osmoregulatory disorders and in mice deficient in aquaporins and vasopressin receptor. The hypertonicity threshold required to activate NFAT5 was higher in bone marrow-derived macrophages (430 mOsm/kg) and embryonic fibroblasts (480 mOsm/kg). Activation of the 9xNFAT-Luc reporter by hypertonicity in lymphocytes was insensitive to the ERK inhibitor PD98059, partially inhibited by the PI3-kinase inhibitor wortmannin (0.5 μM) and the PKA inhibitor H89, and substantially downregulated by p38 inhibitors (SB203580 and SB202190) and by inhibition of PI3-kinase-related kinases with 25 μM LY294002. Sensitivity of the reporter to FK506 varied among cell types and was greater in primary T cells than in fibroblasts and macrophages.Conclusion: Our results indicate that NFAT5 is a sensitive responder to pathologic increases in extracellular tonicity in T lymphocytes. Activation of NFAT5 by hypertonicity in lymphocytes was mediated by a combination of signaling pathways that differed from those required in other cell types. We propose that the 9xNFAT-Luc transgenic mouse model might be useful to study the physiopathological regulation of both NFAT5 and NFATc factors in primary cells.

Le financement des hôpitaux suisses par APDRGs

Dans le cadre du projet de modification du financement des hôpitaux, les partenaires de deux des plus grands cantons suisses - Vaud (Lausanne) et Zürich - ont décidé d'expérimenter le mode de système de paiement par cas traité dès le mois de janvier 2002, en utilisant la classification "All patient diagnosis related groups" (APDRGs). Pourquoi a t-on choisi les APDRGs? Ce système de classification des patients est-il adapté au contexte helvétique? Quelles en sont les caractéristiques? Quelles précautions doit-on prendre pour limiter les risques attendus? Quelles adaptations implique ce nouveau financement pour les différents acteurs?

Mass casualty incidents with multiple burn victims: rationale for a Swiss burn plan.

INTRODUCTION: Mass casualty incidents involving victims with severe burns pose difficult and unique problems for both rescue teams and hospitals. This paper presents an analysis of the published reports with the aim of proposing a rational model for burn rescue and hospital referral for Switzerland. METHODS: Literature review including systematic searches of PubMed/Medline, reference textbooks and journals as well as landmark articles. RESULTS: Since hospitals have limited surge capacities in the event of burn disasters, a special approach to both prehospital and hospital management of these victims is required. Specialized rescue and care can be adequately met and at all levels of needs by deploying mobile burn teams to the scene. These burn teams can bring needed skills and enhance the efficiency of the classical disaster response teams. Burn teams assist with both primary and secondary triage, contribute to initial patient management and offer advice to non-specialized designated hospitals that provide acute care for burn patients with Total Burn Surface Area (TBSA) <20-30%. The main components required for successful deployments of mobile burn teams include socio-economic feasibility, streamlined logistical implementation as well as partnership coordination with other agencies including subsidiary military resources. CONCLUSIONS: Disaster preparedness plans involving burn specialists dispatched from a referral burn center can upgrade and significantly improve prehospital rescue outcome, initial resuscitation care and help prevent an overload to hospital surge capacities in case of multiple burn victims. This is the rationale behind the ongoing development and implementation of the Swiss burn plan.

La huella del futuro. El cine y el pensamiento y la imagen y el fantasma

Se tratará en este trabajo, primero, de caracterizar un tipo de imagen capaz deromper con los yugos con los que la contemporaneidad somete la imaginación a partir de la obra de cineastas particularmente sensibles a este problema, como Werner Herzog y Wim Wenders. Una vez hecho esto, analizaremos la fuente de dicha imagen para así poder invocarla, como si de verdaderas hechicerías o chamanismos se tratase, teniendo en cuenta las nuevas tecnologías y atendiendo a algunos de quienes han sabido extraer de ellas sus poderes más ocultos, sobre todo Jean-Luc Godard y David Lynch. Por último, será a través del cine de Claire Denis y de una cierta idea del cuerpo como ahondaremos en el acontecimiento de la nueva imagen capaz de sacar al sistema de sus goznes y relanzar al cine y al pensamiento hacia un futuro incierto; incierto como es todo auténtico futuro.

Cuerpos abiertos, cineastas del corte. Una introducción al corte como dispositivo

La figuración del cuerpo en el cine ha sido también la figuración de su apertura, de la visualización de lo interno como un universo misterioso y siniestro. Pocos cineastas han vuelto su mirada hacia lo que esconde la piel de sus personajes. Se tratará de poner en escena una constelación de cineastasque han hecho del corte el instrumento para hacer visible lo invisible de lo humano: David Lynch, Georges Franju, Alfred Hitchcok y Marina de Van. Asimismo, el corte es un elemento que define la imagen del cine, en tanto que es capaz de unir y sumar dos imágenes para formar un cuerpo. La idea delcorte y el intervalo como aquello único en Jean-Luc Godard se estudiará a partir de “Pasión”, una película considerada como filme intersticial en su corpus cinematográfico y filme nuclear en su voluntad de ver aquello que aún no se ve.

Cost-effectiveness of opportunistic versus organised mammography screening in Switzerland

BACKGROUND: Various centralised mammography screening programmes have shown to reduce breast cancer mortality at reasonable costs. However, mammography screening is not necessarily cost-effective in every situation. Opportunistic screening, the predominant screening modality in several European countries, may under certain circumstances be a cost-effective alternative. In this study, we compared the cost-effectiveness of both screening modalities in Switzerland. METHODS: Using micro-simulation modelling, we predicted the effects and costs of biennial mammography screening for 50-69 years old women between 1999 and 2020, in the Swiss female population aged 30-70 in 1999. A sensitivity analysis on the test sensitivity of opportunistic screening was performed. RESULTS: Organised mammography screening with an 80% participation rate yielded a breast cancer mortality reduction of 13%. Twenty years after the start of screening, the predicted annual breast cancer mortality was 25% lower than in a situation without screening. The 3% discounted cost-effectiveness ratio of organised mammography screening was euro11,512 per life year gained. Opportunistic screening with a similar participation rate was comparably effective, but at twice the costs: euro22,671-24,707 per life year gained. This was mainly related to the high costs of opportunistic mammography and frequent use of imaging diagnostics in combination with an opportunistic mammogram. CONCLUSION: Although data on the performance of opportunistic screening are limited, both opportunistic and organised mammography screening seem effective in reducing breast cancer mortality in Switzerland. However, for opportunistic screening to become equally cost-effective as organised screening, costs and use of additional diagnostics should be reduced.

Los títulos de crédito como marco de la obra fílmica. Análisis en Un americano en París, West Side Story y El desprecio

Este trabajo de investigación plantea un paralelismo entre los marcos en pintura y lostítulos de crédito en cine. Se analizan los créditos de tres películas (Un americano en París, West Side Story y El desprecio) según sus características de indicación, frontera, límite, umbral al imaginario y marco de actividad. Las películas a las que acompañan pertenecen, a su vez, a diferentes medios de producción y jerarquía, aspectos tecnológicos, áreas estéticas y estructuras de emisión y recepción. Los tres marcos son, a su vez, marcos-objeto, marcos-límite, marcos-ventana y marcos-espejo. Se leen de manera centrípeta, entre dos mundos y desde fuera del marco. Para ello se parte de una metodología transdisciplinar basada en la hermenéutica, el análisis crítico de los textos audiovisuales, los estudios sobrela imagen y el marco como objeto social.

La creación imposible. Poética de las ficciones sobre el fracaso artístico desde la modernidad

La intención de este trabajo ha sido el estudio hermenéutico de films que, a partir de la Modernidad cinematográfica occidental, muestran el proceso de un fracaso artístico autoconsciente, mediante el inacabamiento de un relato de ficción emprendido por el protagonista de la diégesis, quien suele actuar como alter ego del autor real. Se ha pretendido justificar históricamente la aparición de este motivo, así como señalar las características cualitativas que lo diferencian de su tradición, que también se ha rastreado tanto en cine como en literatura. Además, se han agrupado temáticamente las cuestiones estéticas aludidas mediante estos fracasos artísticos ficticios, entre los que se ha procurado establecer relaciones de significado.La metodología utilizada ha sido el comparatismo hermenéutico entre diversos films, así como entre películas y obras literarias con que se han observado correspondencias, que se han contrastado con textos de Teoría y Crítica. La principal cuestión a dilucidar ha sido el discernimiento de las causas del fracaso artístico mostrado en los films y textos del corpus, tanto como hallar una justificación estética a su proliferación.Así, se ha observado que estas películas aparecen a partir de un momento concreto, la década de los sesenta; que tienen dos precedentes claros en Fellini 8 ½ y en Le mépris y que durante la Postmodernidad el esquema narrativo de la creación fracasada ha sido aún más productivo para desarrollar cuestiones estéticas, siempre en un tipo de cine autorial.

Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice.

In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤ 500 ms) of radiation delivered at ultrahigh dose rate (≥ 40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤ 0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc(+) orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-β (transforming growth factor-β) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administration of systemic TNF-α (tumor necrosis factor-α) before irradiation. In contrast, FLASH was as efficient as CONV in the repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.