Factors that trigger emergency physicians to contact a poison centre: findings from a Swiss study.

OBJECTIVE Poison centres offer rapid and comprehensive support for emergency physicians managing poisoned patients. This study investigates institutional, case-specific and poisoning-specific factors which influence the decision of emergency physicians to contact a poison centre. METHODS Retrospective, consecutive review of all poisoning-related admissions to the emergency departments (EDs) of a primary care hospital and a university hospital-based tertiary referral centre during 2007. Corresponding poison centre consultations were extracted from the poison centre database. Data were matched and analysed by logistic regression and generalised linear mixed models. RESULTS 545 poisonings were treated in the participating EDs (350 (64.2%) in the tertiary care centre, 195 (35.8%) in the primary care hospital). The poison centre was consulted in 62 (11.4%) cases (38 (61.3%) by the tertiary care centre and 24 (38.7%) by the primary care hospital). Factors significantly associated with poison centre consultation included gender (female vs male) (OR 2.99; 95% CI 1.69 to 5.29; p<0.001), number of ingested substances (>1 vs 1) (OR 2.84; 95% CI 1.65 to 4.9; p<0.001) and situation (accidental vs intentional) (OR 2.76; 95% CI 1.05 to 7.25; p=0.039). In contrast, age, medical history and hospital size did not influence poison centre consultation. Poison centre consultation was significantly higher during the week, and significantly less during night shifts. The poison centre was consulted significantly more when patients were admitted to intensive care units (OR 5.81; 95% CI 3.25 to 10.37; p<0.001). Asymptomatic and severe versus mild cases were associated with more frequent consultation (OR 4.48; 95% CI 1.78 to 11.26; p=0.001 and OR 2.76; 95% CI 1.42 to 5.38; p=0.003). CONCLUSIONS We found low rates of poison centre consultation by emergency physicians. It appears that intensive care unit admission and other factors reflecting either complexity or uncertainty of the clinical situation are the strongest predictors for poison centre consultation. Hospital size did not influence referral behaviour.

The Salmonella pathogenicity island (SPI)-2 and SPI-1 type III secretion systems allow Salmonella serovar typhimurium to trigger colitis via MyD88-dependent and MyD88-independent mechanisms.

Salmonella typhimurium can colonize the gut, invade intestinal tissues, and cause enterocolitis. In vitro studies suggest different mechanisms leading to mucosal inflammation, including 1) direct modulation of proinflammatory signaling by bacterial type III effector proteins and 2) disruption or penetration of the intestinal epithelium so that penetrating bacteria or bacterial products can trigger innate immunity (i.e., TLR signaling). We studied these mechanisms in vivo using streptomycin-pretreated wild-type and knockout mice including MyD88(-/-) animals lacking an adaptor molecule required for signaling via most TLRs. The Salmonella SPI-1 and the SPI-2 type III secretion systems (TTSS) contributed to inflammation. Mutants that retain only a functional SPI-1 (M556; sseD::aphT) or a SPI-2 TTSS (SB161; DeltainvG) caused attenuated colitis, which reflected distinct aspects of the colitis caused by wild-type S. typhimurium: M556 caused diffuse cecal inflammation that did not require MyD88 signaling. In contrast, SB161 induced focal mucosal inflammation requiring MyD88. M556 but not SB161 was found in intestinal epithelial cells. In the lamina propria, M556 and SB161 appeared to reside in different leukocyte cell populations as indicated by differential CD11c staining. Only the SPI-2-dependent inflammatory pathway required aroA-dependent intracellular growth. Thus, S. typhimurium can use two independent mechanisms to elicit colitis in vivo: SPI-1-dependent and MyD88-independent signaling to epithelial cells and SPI-2-dependent intracellular proliferation in the lamina propria triggering MyD88-dependent innate immune responses.

Reciprocity as a trigger of social cooperation in contemporary immigration societies?

While the system stabilizing function of reciprocity is widely acknowledged, much less attention has been paid to the argument that reciprocity might initiate social cooperation in the first place. This paper tests Gouldner’s early assumption that reciprocity may act as a ‘starting mechanism’ of social cooperation in consolidating societies. The empirical test scenario builds on unequal civic engagement between immigrants and nationals, as this engagement gap can be read as a lack of social cooperation in consolidating immigration societies. Empirical analyses using survey data on reciprocal norms and based on Bayesian hierarchical modelling lend support for Gouldner’s thesis, underlining thereby the relevance of reciprocity in today’s increasingly diverse societies: individual norms of altruistic reciprocity elevate immigrants’ propensity to volunteer, reducing thereby the engagement gap between immigrants and natives in the area of informal volunteering. In other words, compliance with altruistic reciprocity may trigger cooperation in social strata, where it is less likely to occur. The positive moderation of the informal engagement gap through altruistic reciprocity turns out to be most pronounced for immigrants who are least likely to engage in informal volunteering, meaning low, but also high educated immigrants.

The granulocyte orphan receptor CEACAM4 is able to trigger phagocytosis of bacteria.

Human granulocytes express several glycoproteins of the CEACAM family. One family member, CEACAM3, operates as a single-chain phagocytic receptor, initiating the detection, internalization, and destruction of a limited set of gram-negative bacteria. In contrast, the function of CEACAM4, a closely related protein, is completely unknown. This is mainly a result of a lack of a specific ligand for CEACAM4. By generating chimeric proteins containing the extracellular bacteria-binding domain of CEACAM3 and the transmembrane and cytoplasmic part of CEACAM4 (CEACAM3/4) we demonstrate that this chimeric receptor can trigger efficient phagocytosis of attached particles. Uptake of CEACAM3/4-bound bacteria requires the intact ITAM of CEACAM4, and this motif is phosphorylated by Src family PTKs upon receptor clustering. Furthermore, SH2 domains derived from Src PTKs, PI3K, and the adapter molecule Nck are recruited and associate directly with the phosphorylated CEACAM4 ITAM. Deletion of this sequence motif or inhibition of Src PTKs blocks CEACAM4-mediated uptake. Together, our results suggest that this orphan receptor of the CEACAM family has phagocytic function and prompt efforts to identify CEACAM4 ligands.

Circulating tumor cells as trigger to hematogenous spreads and potential biomarkers to predict the prognosis in ovarian cancer.

Despite several improvements in the surgical field and in the systemic treatment, ovarian cancer (OC) is still characterized by high recurrence rates and consequently poor survival. In OC, there is still a great lack of knowledge with regard to cancer behavior and mechanisms of recurrence, progression, and drug resistance. The OC metastatization process mostly occurs via intracoelomatic spread. Recent evidences show that tumor cells generate a favorable microenvironment consisting in T regulatory cells, T infiltrating lymphocytes, and cytokines which are able to establish an "immuno-tolerance mileau" in which a tumor cell can become a resistant clone. When the disease responds to treatment, immunoediting processes and cancer progression have been stopped. A similar inhibition of the immunosuppressive microenvironment has been observed after optimal cytoreductive surgery as well. In this scenario, the early identification of circulating tumor cells could represent a precocious signal of loss of the immune balance that precedes cancer immunoediting and relapse. Supporting this hypothesis, circulating tumor cells have been demonstrated to be a prognostic factor in several solid tumors such as colorectal, pancreatic, gastric, breast, and genitourinary cancer. In OC, the role of circulating tumor cells is still to be defined. However, as opposed to healthy women, circulating tumor cells have been demonstrated in peripheral blood of OC patients, opening a new research field in OC diagnosis, treatment monitoring, and follow-up.

Depolarization-dependent synaptic potentiation and hyperexcitability induced by a Ca2+-independent trigger

Despite vast research efforts since Cajal's seminal thoughts on the adaptation of the nervous system, researchers have only recently begun to understand the diversity of forms of neuronal plasticity and its mechanisms. All known forms of activity-dependent neuronal plasticity utilize alterations in [Ca 2+]i as a signal of changes in the membrane voltage. Ca 2+ sensors trigger modifications in excitability or synaptic strength that last from seconds to weeks and presumably years. Intriguingly, Kunjilwar et al., (unpublished observations) discovered in peripheral sensory axons of Aplysia that the induction of depolarization-dependent long-term axonal hyperexcitability does not require Ca2+ transients. Here we show that induction of depolarization-dependent intermediate-term and long-term synaptic potentiation in Aplysia occurs in conditions that prevent Ca2+ entry through voltage-gated channels and elevation of [Ca2+]i. We found that the intermediate-term synaptic potentiation induced under conditions expected to prevent Ca 2+ transients is associated with increased excitability of sensory neuron axons near presynaptic terminals, suggesting that the synaptic potentiation involves a presynaptic locus. The Ca2+-independent intermediate- and long-term synaptic potentiation appeared similar to previously reported Ca2+-dependent modifications in Aplysia. ^

A new analog trigger system for the Cherenkov Telescope array

La astronomía de rayos γ estudia las partículas más energéticas que llegan a la Tierra desde el espacio. Estos rayos γ no se generan mediante procesos térmicos en simples estrellas, sino mediante mecanismos de aceleración de partículas en objetos celestes como núcleos de galaxias activos, púlsares, supernovas, o posibles procesos de aniquilación de materia oscura. Los rayos γ procedentes de estos objetos y sus características proporcionan una valiosa información con la que los científicos tratan de comprender los procesos físicos que ocurren en ellos y desarrollar modelos teóricos que describan su funcionamiento con fidelidad. El problema de observar rayos γ es que son absorbidos por las capas altas de la atmósfera y no llegan a la superficie (de lo contrario, la Tierra será inhabitable). De este modo, sólo hay dos formas de observar rayos γ embarcar detectores en satélites, u observar los efectos secundarios que los rayos γ producen en la atmósfera. Cuando un rayo γ llega a la atmósfera, interacciona con las partículas del aire y genera un par electrón - positrón, con mucha energía. Estas partículas secundarias generan a su vez más partículas secundarias cada vez menos energéticas. Estas partículas, mientras aún tienen energía suficiente para viajar más rápido que la velocidad de la luz en el aire, producen una radiación luminosa azulada conocida como radiación Cherenkov durante unos pocos nanosegundos. Desde la superficie de la Tierra, algunos telescopios especiales, conocidos como telescopios Cherenkov o IACTs (Imaging Atmospheric Cherenkov Telescopes), son capaces de detectar la radiación Cherenkov e incluso de tomar imágenes de la forma de la cascada Cherenkov. A partir de estas imágenes es posible conocer las principales características del rayo γ original, y con suficientes rayos se pueden deducir características importantes del objeto que los emitió, a cientos de años luz de distancia. Sin embargo, detectar cascadas Cherenkov procedentes de rayos γ no es nada fácil. Las cascadas generadas por fotones γ de bajas energías emiten pocos fotones, y durante pocos nanosegundos, y las correspondientes a rayos γ de alta energía, si bien producen más electrones y duran más, son más improbables conforme mayor es su energía. Esto produce dos líneas de desarrollo de telescopios Cherenkov: Para observar cascadas de bajas energías son necesarios grandes reflectores que recuperen muchos fotones de los pocos que tienen estas cascadas. Por el contrario, las cascadas de altas energías se pueden detectar con telescopios pequeños, pero conviene cubrir con ellos una superficie grande en el suelo para aumentar el número de eventos detectados. Con el objetivo de mejorar la sensibilidad de los telescopios Cherenkov actuales, en el rango de energía alto (> 10 TeV), medio (100 GeV - 10 TeV) y bajo (10 GeV - 100 GeV), nació el proyecto CTA (Cherenkov Telescope Array). Este proyecto en el que participan más de 27 países, pretende construir un observatorio en cada hemisferio, cada uno de los cuales contará con 4 telescopios grandes (LSTs), unos 30 medianos (MSTs) y hasta 70 pequeños (SSTs). Con un array así, se conseguirán dos objetivos. En primer lugar, al aumentar drásticamente el área de colección respecto a los IACTs actuales, se detectarán más rayos γ en todos los rangos de energía. En segundo lugar, cuando una misma cascada Cherenkov es observada por varios telescopios a la vez, es posible analizarla con mucha más precisión gracias a las técnicas estereoscópicas. La presente tesis recoge varios desarrollos técnicos realizados como aportación a los telescopios medianos y grandes de CTA, concretamente al sistema de trigger. Al ser las cascadas Cherenkov tan breves, los sistemas que digitalizan y leen los datos de cada píxel tienen que funcionar a frecuencias muy altas (≈1 GHz), lo que hace inviable que funcionen de forma continua, ya que la cantidad de datos guardada será inmanejable. En su lugar, las señales analógicas se muestrean, guardando las muestras analógicas en un buffer circular de unos pocos µs. Mientras las señales se mantienen en el buffer, el sistema de trigger hace un análisis rápido de las señales recibidas, y decide si la imagen que hay en el buér corresponde a una cascada Cherenkov y merece ser guardada, o por el contrario puede ignorarse permitiendo que el buffer se sobreescriba. La decisión de si la imagen merece ser guardada o no, se basa en que las cascadas Cherenkov producen detecciones de fotones en píxeles cercanos y en tiempos muy próximos, a diferencia de los fotones de NSB (night sky background), que llegan aleatoriamente. Para detectar cascadas grandes es suficiente con comprobar que más de un cierto número de píxeles en una región hayan detectado más de un cierto número de fotones en una ventana de tiempo de algunos nanosegundos. Sin embargo, para detectar cascadas pequeñas es más conveniente tener en cuenta cuántos fotones han sido detectados en cada píxel (técnica conocida como sumtrigger). El sistema de trigger desarrollado en esta tesis pretende optimizar la sensibilidad a bajas energías, por lo que suma analógicamente las señales recibidas en cada píxel en una región de trigger y compara el resultado con un umbral directamente expresable en fotones detectados (fotoelectrones). El sistema diseñado permite utilizar regiones de trigger de tamaño seleccionable entre 14, 21 o 28 píxeles (2, 3, o 4 clusters de 7 píxeles cada uno), y con un alto grado de solapamiento entre ellas. De este modo, cualquier exceso de luz en una región compacta de 14, 21 o 28 píxeles es detectado y genera un pulso de trigger. En la versión más básica del sistema de trigger, este pulso se distribuye por toda la cámara de forma que todos los clusters sean leídos al mismo tiempo, independientemente de su posición en la cámara, a través de un delicado sistema de distribución. De este modo, el sistema de trigger guarda una imagen completa de la cámara cada vez que se supera el número de fotones establecido como umbral en una región de trigger. Sin embargo, esta forma de operar tiene dos inconvenientes principales. En primer lugar, la cascada casi siempre ocupa sólo una pequeña zona de la cámara, por lo que se guardan muchos píxeles sin información alguna. Cuando se tienen muchos telescopios como será el caso de CTA, la cantidad de información inútil almacenada por este motivo puede ser muy considerable. Por otro lado, cada trigger supone guardar unos pocos nanosegundos alrededor del instante de disparo. Sin embargo, en el caso de cascadas grandes la duración de las mismas puede ser bastante mayor, perdiéndose parte de la información debido al truncamiento temporal. Para resolver ambos problemas se ha propuesto un esquema de trigger y lectura basado en dos umbrales. El umbral alto decide si hay un evento en la cámara y, en caso positivo, sólo las regiones de trigger que superan el nivel bajo son leídas, durante un tiempo más largo. De este modo se evita guardar información de píxeles vacíos y las imágenes fijas de las cascadas se pueden convertir en pequeños \vídeos" que representen el desarrollo temporal de la cascada. Este nuevo esquema recibe el nombre de COLIBRI (Concept for an Optimized Local Image Building and Readout Infrastructure), y se ha descrito detalladamente en el capítulo 5. Un problema importante que afecta a los esquemas de sumtrigger como el que se presenta en esta tesis es que para sumar adecuadamente las señales provenientes de cada píxel, estas deben tardar lo mismo en llegar al sumador. Los fotomultiplicadores utilizados en cada píxel introducen diferentes retardos que deben compensarse para realizar las sumas adecuadamente. El efecto de estos retardos ha sido estudiado, y se ha desarrollado un sistema para compensarlos. Por último, el siguiente nivel de los sistemas de trigger para distinguir efectivamente las cascadas Cherenkov del NSB consiste en buscar triggers simultáneos (o en tiempos muy próximos) en telescopios vecinos. Con esta función, junto con otras de interfaz entre sistemas, se ha desarrollado un sistema denominado Trigger Interface Board (TIB). Este sistema consta de un módulo que irá montado en la cámara de cada LST o MST, y que estará conectado mediante fibras ópticas a los telescopios vecinos. Cuando un telescopio tiene un trigger local, este se envía a todos los vecinos conectados y viceversa, de modo que cada telescopio sabe si sus vecinos han dado trigger. Una vez compensadas las diferencias de retardo debidas a la propagación en las fibras ópticas y de los propios fotones Cherenkov en el aire dependiendo de la dirección de apuntamiento, se buscan coincidencias, y en el caso de que la condición de trigger se cumpla, se lee la cámara en cuestión, de forma sincronizada con el trigger local. Aunque todo el sistema de trigger es fruto de la colaboración entre varios grupos, fundamentalmente IFAE, CIEMAT, ICC-UB y UCM en España, con la ayuda de grupos franceses y japoneses, el núcleo de esta tesis son el Level 1 y la Trigger Interface Board, que son los dos sistemas en los que que el autor ha sido el ingeniero principal. Por este motivo, en la presente tesis se ha incluido abundante información técnica relativa a estos sistemas. Existen actualmente importantes líneas de desarrollo futuras relativas tanto al trigger de la cámara (implementación en ASICs), como al trigger entre telescopios (trigger topológico), que darán lugar a interesantes mejoras sobre los diseños actuales durante los próximos años, y que con suerte serán de provecho para toda la comunidad científica participante en CTA. ABSTRACT -ray astronomy studies the most energetic particles arriving to the Earth from outer space. This -rays are not generated by thermal processes in mere stars, but by means of particle acceleration mechanisms in astronomical objects such as active galactic nuclei, pulsars, supernovas or as a result of dark matter annihilation processes. The γ rays coming from these objects and their characteristics provide with valuable information to the scientist which try to understand the underlying physical fundamentals of these objects, as well as to develop theoretical models able to describe them accurately. The problem when observing rays is that they are absorbed in the highest layers of the atmosphere, so they don't reach the Earth surface (otherwise the planet would be uninhabitable). Therefore, there are only two possible ways to observe γ rays: by using detectors on-board of satellites, or by observing their secondary effects in the atmosphere. When a γ ray reaches the atmosphere, it interacts with the particles in the air generating a highly energetic electron-positron pair. These secondary particles generate in turn more particles, with less energy each time. While these particles are still energetic enough to travel faster than the speed of light in the air, they produce a bluish radiation known as Cherenkov light during a few nanoseconds. From the Earth surface, some special telescopes known as Cherenkov telescopes or IACTs (Imaging Atmospheric Cherenkov Telescopes), are able to detect the Cherenkov light and even to take images of the Cherenkov showers. From these images it is possible to know the main parameters of the original -ray, and with some -rays it is possible to deduce important characteristics of the emitting object, hundreds of light-years away. However, detecting Cherenkov showers generated by γ rays is not a simple task. The showers generated by low energy -rays contain few photons and last few nanoseconds, while the ones corresponding to high energy -rays, having more photons and lasting more time, are much more unlikely. This results in two clearly differentiated development lines for IACTs: In order to detect low energy showers, big reflectors are required to collect as much photons as possible from the few ones that these showers have. On the contrary, small telescopes are able to detect high energy showers, but a large area in the ground should be covered to increase the number of detected events. With the aim to improve the sensitivity of current Cherenkov showers in the high (> 10 TeV), medium (100 GeV - 10 TeV) and low (10 GeV - 100 GeV) energy ranges, the CTA (Cherenkov Telescope Array) project was created. This project, with more than 27 participating countries, intends to build an observatory in each hemisphere, each one equipped with 4 large size telescopes (LSTs), around 30 middle size telescopes (MSTs) and up to 70 small size telescopes (SSTs). With such an array, two targets would be achieved. First, the drastic increment in the collection area with respect to current IACTs will lead to detect more -rays in all the energy ranges. Secondly, when a Cherenkov shower is observed by several telescopes at the same time, it is possible to analyze it much more accurately thanks to the stereoscopic techniques. The present thesis gathers several technical developments for the trigger system of the medium and large size telescopes of CTA. As the Cherenkov showers are so short, the digitization and readout systems corresponding to each pixel must work at very high frequencies (_ 1 GHz). This makes unfeasible to read data continuously, because the amount of data would be unmanageable. Instead, the analog signals are sampled, storing the analog samples in a temporal ring buffer able to store up to a few _s. While the signals remain in the buffer, the trigger system performs a fast analysis of the signals and decides if the image in the buffer corresponds to a Cherenkov shower and deserves to be stored, or on the contrary it can be ignored allowing the buffer to be overwritten. The decision of saving the image or not, is based on the fact that Cherenkov showers produce photon detections in close pixels during near times, in contrast to the random arrival of the NSB phtotons. Checking if more than a certain number of pixels in a trigger region have detected more than a certain number of photons during a certain time window is enough to detect large showers. However, taking also into account how many photons have been detected in each pixel (sumtrigger technique) is more convenient to optimize the sensitivity to low energy showers. The developed trigger system presented in this thesis intends to optimize the sensitivity to low energy showers, so it performs the analog addition of the signals received in each pixel in the trigger region and compares the sum with a threshold which can be directly expressed as a number of detected photons (photoelectrons). The trigger system allows to select trigger regions of 14, 21, or 28 pixels (2, 3 or 4 clusters with 7 pixels each), and with extensive overlapping. In this way, every light increment inside a compact region of 14, 21 or 28 pixels is detected, and a trigger pulse is generated. In the most basic version of the trigger system, this pulse is just distributed throughout the camera in such a way that all the clusters are read at the same time, independently from their position in the camera, by means of a complex distribution system. Thus, the readout saves a complete camera image whenever the number of photoelectrons set as threshold is exceeded in a trigger region. However, this way of operating has two important drawbacks. First, the shower usually covers only a little part of the camera, so many pixels without relevant information are stored. When there are many telescopes as will be the case of CTA, the amount of useless stored information can be very high. On the other hand, with every trigger only some nanoseconds of information around the trigger time are stored. In the case of large showers, the duration of the shower can be quite larger, loosing information due to the temporal cut. With the aim to solve both limitations, a trigger and readout scheme based on two thresholds has been proposed. The high threshold decides if there is a relevant event in the camera, and in the positive case, only the trigger regions exceeding the low threshold are read, during a longer time. In this way, the information from empty pixels is not stored and the fixed images of the showers become to little \`videos" containing the temporal development of the shower. This new scheme is named COLIBRI (Concept for an Optimized Local Image Building and Readout Infrastructure), and it has been described in depth in chapter 5. An important problem affecting sumtrigger schemes like the one presented in this thesis is that in order to add the signals from each pixel properly, they must arrive at the same time. The photomultipliers used in each pixel introduce different delays which must be compensated to perform the additions properly. The effect of these delays has been analyzed, and a delay compensation system has been developed. The next trigger level consists of looking for simultaneous (or very near in time) triggers in neighbour telescopes. These function, together with others relating to interfacing different systems, have been developed in a system named Trigger Interface Board (TIB). This system is comprised of one module which will be placed inside the LSTs and MSTs cameras, and which will be connected to the neighbour telescopes through optical fibers. When a telescope receives a local trigger, it is resent to all the connected neighbours and vice-versa, so every telescope knows if its neighbours have been triggered. Once compensated the delay differences due to propagation in the optical fibers and in the air depending on the pointing direction, the TIB looks for coincidences, and in the case that the trigger condition is accomplished, the camera is read a fixed time after the local trigger arrived. Despite all the trigger system is the result of the cooperation of several groups, specially IFAE, Ciemat, ICC-UB and UCM in Spain, with some help from french and japanese groups, the Level 1 and the Trigger Interface Board constitute the core of this thesis, as they have been the two systems designed by the author of the thesis. For this reason, a large amount of technical information about these systems has been included. There are important future development lines regarding both the camera trigger (implementation in ASICS) and the stereo trigger (topological trigger), which will produce interesting improvements for the current designs during the following years, being useful for all the scientific community participating in CTA.