1,144 research outputs found
Estudio de los mecanismos dependientes e independientes de uniones adherentes que regulan la función de barrera endotelial durante la inflamación
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 19-05-2017Esta tesis tiene embargado el acceso al texto completo hasta el 19-11-2018El endotelio vascular constituye la capa más interna de los vasos sanguíneos y separa el
torrente circulatorio del tejido subyacente. Durante la inflamación, la función de barrera del
endotelio queda comprometida por la acción conjunta de mediadores inflamatorios y
células del sistema inmune. Por otro lado, para que este aumento de permeabilidad no se
torne deletéreo, existen mecanismos que restringen su alcance en el tiempo y en el espacio,
lo cual permite el mantenimiento de la integridad endotelial. Sin embargo, estos fenómenos
pueden alterarse, dando lugar a patologías de componente inflamatorio. En efecto, la
disfunción endotelial es una de las principales causas de la aparición de enfermedades
inflamatorias crónicas de gran prevalencia en nuestra sociedad.
En esta tesis hemos investigado los mecanismos dependientes e independientes de las
uniones intercelulares que median la alteración de la permeabilidad endotelial en un
contexto inflamatorio inducido por una exposición persistente a la citoquina inflamatoria
TNF. Primero, hemos descubierto que la GTPasa RhoB se expresa en vasos pequeños en
tejidos de pacientes con enfermedades inflamatorias, aquellos donde la función de barrera
está más comprometida, y además aumenta sus niveles en respuesta a TNF en células
endoteliales microvasculares. Hemos probado que RhoB juega un papel específico en el
retraso de la recuperación de la función de barrera independientemente de las uniones
adherentes en células endoteliales tanto microvasculares como vasculares. En efecto, dicha
GTPasa inhibe la actividad y altera la localización de Rac1, limitándose así la formación de
protrusiones de membrana. Por otro lado, TNF también altera la permeabilidad endotelial
por mecanismos dependientes de las uniones adherentes. En este contexto, hemos
demostrado en células de vasos grandes –HUVEC- que TNF incrementa la degradación de
VE-cadherina a través del proteasoma. Sin embargo, esta degradación es compensada por
un aumento de la síntesis de VE-cadherina por la vía NF-κβ, a través del factor de
transcripción Ets1. Esto resulta en una aceleración de la tasa de reemplazamiento de VEcadherina
que correlaciona con un aumento de la permeabilidad endotelial, manteniéndose
sin embargo constantes los niveles de superficie de dicha proteína, lo que preserva la
integridad de este endotelio vascular. El mantenimiento de la expresión de VE-cadherina
en células expuestas a TNF es mediado por BST-2, proteína que también se induce en
respuesta a esta citoquina, la cual cicla entre un compartimento endosomal y la superficie
celular y regula positivamente los niveles de Ets1, lo que sugiere que podría funcionar
como un sensor de los niveles de VE-cadherina. De hecho, la expresión de BST-2 es
necesaria para la recuperación de la función de barrera tras la terminación del estímulo
inflamatorio inducido por TNF. Finalmente, en el contexto de la infección del endotelio
con Neisseria meningitidis, BST-2 también incrementa su expresión y se relocaliza junto con
VE-cadherina en la superficie endotelial en contacto con las colonias bacterianas, lo que
sugiere una posible implicación en la reorganización de las uniones intercelulares provocada
por esta infección.
Con todo, nuestros resultados indican que, por un lado, TNF incrementa la expresión de
proteínas que debilitan la barrera endotelial, puesto que limitan la capacidad de reformación
de ésta en un contexto inflamatorio. Por otro, TNF también induce un programa
transcripcional compensatorio que preserva la integridad del endotelio en células
endoteliales de vasos grandes y contribuye a la recuperación de la homeostasis vascular
durante la inflamación
Micrometeoroid Events in LISA Pathfinder
The zodiacal dust complex, a population of dust and small particles that
pervades the Solar System, provides important insight into the formation and
dynamics of planets, comets, asteroids, and other bodies. Here we present a new
set of data obtained using a novel technique: direct measurements of momentum
transfer to a spacecraft from individual particle impacts. This technique is
made possible by the extreme precision of the instruments flown on the LISA
Pathfinder spacecraft, a technology demonstrator for a future space-based
gravitational wave observatory that operated near the first Sun-Earth Lagrange
point from early 2016 through Summer of 2017. Using a simple model of the
impacts and knowledge of the control system, we show that it is possible to
detect impacts and measure properties such as the transferred momentum (related
to the particle's mass and velocity), direction of travel, and location of
impact on the spacecraft. In this paper, we present the results of a systematic
search for impacts during 4348 hours of Pathfinder data. We report a total of
54 candidates with momenta ranging from 0.2 to
230. We furthermore make a comparison of these candidates
with models of micrometeoroid populations in the inner solar system including
those resulting from Jupiter-family comets, Oort-cloud comets, Hailey-type
comets, and Asteroids. We find that our measured population is consistent with
a population dominated by Jupiter-family comets with some evidence for a
smaller contribution from Hailey-type comets. This is in agreement with
consensus models of the zodiacal dust complex in the momentum range sampled by
LISA Pathfinder.Comment: 22 pages, 14 figures, accepted in Ap
Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory
The Auger Engineering Radio Array (AERA) is part of the Pierre Auger
Observatory and is used to detect the radio emission of cosmic-ray air showers.
These observations are compared to the data of the surface detector stations of
the Observatory, which provide well-calibrated information on the cosmic-ray
energies and arrival directions. The response of the radio stations in the 30
to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of
the incoming electric field. For the latter, the energy deposit per area is
determined from the radio pulses at each observer position and is interpolated
using a two-dimensional function that takes into account signal asymmetries due
to interference between the geomagnetic and charge-excess emission components.
The spatial integral over the signal distribution gives a direct measurement of
the energy transferred from the primary cosmic ray into radio emission in the
AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air
shower arriving perpendicularly to the geomagnetic field. This radiation energy
-- corrected for geometrical effects -- is used as a cosmic-ray energy
estimator. Performing an absolute energy calibration against the
surface-detector information, we observe that this radio-energy estimator
scales quadratically with the cosmic-ray energy as expected for coherent
emission. We find an energy resolution of the radio reconstruction of 22% for
the data set and 17% for a high-quality subset containing only events with at
least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO
Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy
We measure the energy emitted by extensive air showers in the form of radio
emission in the frequency range from 30 to 80 MHz. Exploiting the accurate
energy scale of the Pierre Auger Observatory, we obtain a radiation energy of
15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV
arriving perpendicularly to a geomagnetic field of 0.24 G, scaling
quadratically with the cosmic-ray energy. A comparison with predictions from
state-of-the-art first-principle calculations shows agreement with our
measurement. The radiation energy provides direct access to the calorimetric
energy in the electromagnetic cascade of extensive air showers. Comparison with
our result thus allows the direct calibration of any cosmic-ray radio detector
against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI.
Supplemental material in the ancillary file
Measurement of the cosmic ray spectrum above eV using inclined events detected with the Pierre Auger Observatory
A measurement of the cosmic-ray spectrum for energies exceeding
eV is presented, which is based on the analysis of showers
with zenith angles greater than detected with the Pierre Auger
Observatory between 1 January 2004 and 31 December 2013. The measured spectrum
confirms a flux suppression at the highest energies. Above
eV, the "ankle", the flux can be described by a power law with
index followed by
a smooth suppression region. For the energy () at which the
spectral flux has fallen to one-half of its extrapolated value in the absence
of suppression, we find
eV.Comment: Replaced with published version. Added journal reference and DO
Nomenclature, Diagnosis and Management of Drug-induced Autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report.
Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarizes the major topics discussed at a joint International Conference held between Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and often resolve spontaneously after stopping the culprit drug whereas patients with AIH mostly need long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements such as Khat and Tinospora cordifolia have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow a precise diagnosis and similarly, there is no single feature which is diagnostic of AIH. A management algorithm is proposed. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterization of this condition
Dynamics of disease characteristics and clinical management of critically ill COVID-19 patients over the time course of the pandemic: an analysis of the prospective, international, multicentre RISC-19-ICU registry.
BACKGROUND
It remains elusive how the characteristics, the course of disease, the clinical management and the outcomes of critically ill COVID-19 patients admitted to intensive care units (ICU) worldwide have changed over the course of the pandemic.
METHODS
Prospective, observational registry constituted by 90 ICUs across 22 countries worldwide including patients with a laboratory-confirmed, critical presentation of COVID-19 requiring advanced organ support. Hierarchical, generalized linear mixed-effect models accounting for hospital and country variability were employed to analyse the continuous evolution of the studied variables over the pandemic.
RESULTS
Four thousand forty-one patients were included from March 2020 to September 2021. Over this period, the age of the admitted patients (62 [95% CI 60-63] years vs 64 [62-66] years, p < 0.001) and the severity of organ dysfunction at ICU admission decreased (Sequential Organ Failure Assessment 8.2 [7.6-9.0] vs 5.8 [5.3-6.4], p < 0.001) and increased, while more female patients (26 [23-29]% vs 41 [35-48]%, p < 0.001) were admitted. The time span between symptom onset and hospitalization as well as ICU admission became longer later in the pandemic (6.7 [6.2-7.2| days vs 9.7 [8.9-10.5] days, p < 0.001). The PaO2/FiO2 at admission was lower (132 [123-141] mmHg vs 101 [91-113] mmHg, p < 0.001) but showed faster improvements over the initial 5 days of ICU stay in late 2021 compared to early 2020 (34 [20-48] mmHg vs 70 [41-100] mmHg, p = 0.05). The number of patients treated with steroids and tocilizumab increased, while the use of therapeutic anticoagulation presented an inverse U-shaped behaviour over the course of the pandemic. The proportion of patients treated with high-flow oxygen (5 [4-7]% vs 20 [14-29], p < 0.001) and non-invasive mechanical ventilation (14 [11-18]% vs 24 [17-33]%, p < 0.001) throughout the pandemic increased concomitant to a decrease in invasive mechanical ventilation (82 [76-86]% vs 74 [64-82]%, p < 0.001). The ICU mortality (23 [19-26]% vs 17 [12-25]%, p < 0.001) and length of stay (14 [13-16] days vs 11 [10-13] days, p < 0.001) decreased over 19 months of the pandemic.
CONCLUSION
Characteristics and disease course of critically ill COVID-19 patients have continuously evolved, concomitant to the clinical management, throughout the pandemic leading to a younger, less severely ill ICU population with distinctly different clinical, pulmonary and inflammatory presentations than at the onset of the pandemic
Post-Franco Theatre
In the multiple realms and layers that comprise the contemporary Spanish theatrical landscape, “crisis” would seem to be the word that most often lingers in the air, as though it were a common mantra, ready to roll off the tongue of so many theatre professionals with such enormous ease, and even enthusiasm, that one is prompted to wonder whether it might indeed be a miracle that the contemporary technological revolution – coupled with perpetual quandaries concerning public and private funding for the arts – had not by now brought an end to the evolution of the oldest of live arts, or, at the very least, an end to drama as we know it
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