Heavy Ion Carcinogenesis and Human Space Exploration

Prior to the human exploration of Mars or long duration stays on the Earth s moon, the risk of cancer and other diseases from space radiation must be accurately estimated and mitigated. Space radiation, comprised of energetic protons and heavy nuclei, has been show to produce distinct biological damage compared to radiation on Earth, leading to large uncertainties in the projection of cancer and other health risks, while obscuring evaluation of the effectiveness of possible countermeasures. Here, we describe how research in cancer radiobiology can support human missions to Mars and other planets

Intracranial injection of dengue virus induces interferon stimulated genes and CD8(+) T cell infiltration by sphingosine kinase 1 independent pathways

We have previously reported that the absence of sphingosine kinase 1 (SK1) affects both dengue virus (DENV) infection and innate immune responses in vitro. Here we aimed to define SK1-dependancy of DENV-induced disease and the associated innate responses in vivo. The lack of a reliable mouse model with a fully competent interferon response for DENV infection is a challenge, and here we use an experimental model of DENV infection in the brain of immunocompetent mice. Intracranial injection of DENV-2 into C57BL/6 mice induced body weight loss and neurological symptoms which was associated with a high level of DENV RNA in the brain. Body weight loss and DENV RNA level tended to be greater in SK1-/- compared with wildtype (WT) mice. Brain infection with DENV-2 is associated with the induction of interferon-β (IFN-β) and IFN-stimulated gene (ISG) expression including viperin, Ifi27l2a, IRF7, and CXCL10 without any significant differences between WT and SK1-/- mice. The SK2 and sphingosine-1-phosphate (S1P) levels in the brain were unchanged by DENV infection or the lack of SK1. Histological analysis demonstrated the presence of a cellular infiltrate in DENV-infected brain with a significant increase in mRNA for CD8 but not CD4 suggesting this infiltrate is likely CD8+ but not CD4+ T-lymphocytes. This increase in T-cell infiltration was not affected by the lack of SK1. Overall, DENV-infection in the brain induces IFN and T-cell responses but does not influence the SK/S1P axis. In contrast to our observations in vitro, SK1 has no major influence on these responses following DENV-infection in the mouse brain.Wisam H. Al-Shujairi, Jennifer N. Clarke, Lorena T. Davies, Mohammed Alsharifi, Stuart M. Pitson, Jillian M. Car

Blocking in human causal learning is affected by outcome assumptions manipulated through causal structure

Additivity-related assumptions have been proven to modulate blocking in human causal learning. Typically, these assumptions are manipulated by means of pretraining phases (including exposure to different outcome magnitudes), or through explicit instructions. In two experiments, we used a different approach that involved neither pretraining nor instructional manipulations. Instead, we manipulated the causal structure in which the cues were embedded, thereby appealing directly to the participants’ prior knowledge about causal relations and how causes would add up to yield stronger outcomes. Specifically, in our "different-system" condition, the participants should assume that the outcomes would add up, whereas in our "same-system" condition, a ceiling effect would prevent such an assumption. Consistent with our predictions, Experiment 1 showed that, when two cues from separate causal systems were combined, the participants did expect a stronger outcome on compound trials, and blocking was found, whereas when the cues belonged to the same causal system, the participants did not expect a stronger out- come on compound trials, and blocking was not observed. The results were partially replicated in Experiment 2, in which this pattern was found when the cues were tested for the second time. This evidence supports the claim that prior knowledge about the nature of causal relations can affect human causal learning. In addition, the fact that we did not manipulate causal assumptions through pretraining renders the results hard to account for with associative theories of learning

Análisis de la endotoxemia en el postoperatorio de cirugía cardiaca

Desde el inicio de la cirugía cardiaca, el desarrollo de nuevas técnicas quirúrgicas, los avances en los métodos de circulación extracorpórea (CEC) y los tratamientos en cuidados intensivos hacen que la mortalidad de estos pacientes haya disminuido de casi el 100% hasta un 5-6% en la actualidad. No obstante, estas cifras se mantienen estables durante los últimos años. La respuesta inflamatoria asociada a la CEC es un proceso que puede llegar a desarrollar complicaciones mayores incluyendo insuficiencia respiratoria, shock, fracaso renal e incluso fracaso multiorgánico. La cirugía con CEC provoca cambios sistémicos importantes que inician el proceso de SIRS. Entre ellos se encuentra la hipoperfusión esplénica, que podría producir daños en la mucosa intestinal alterando la permeabilidad de la barrera favoreciendo así la traslocación bacteriana y la endotoxemia. La endotoxina es un lipopolisacárido de la pared celular de las BGN y es reconocido como un importante estímulo para el desarrollo del SIRS. Su presencia en pacientes sometidos a CEC ha sido ampliamente reconocida, pero la magnitud de la endotoxemia así como su correlación con la evolución clínica y la aparición de complicaciones varía ampliamente entre los estudios. Según algunos estudios, la concentración sistémica de endotoxinas se correlaciona estrechamente con el grado de disfunción cardiovascular, duración de la cirugía, tiempo de CEC, tiempo de isquemia y necesidad de aminas vasoactivas, lo que se podría resumir en todas aquellas situaciones que potencialmente podrían favorecer una situación de hipopefusión esplácnica. Existen diferentes técnicas para detectar la presencia de la endotoxemia. Tradicionalmente, se había cuantificado la cantidad de endotoxina mediante un análisis in vitro denominado lisado de Amebocitos del Limulus Polyphemus (LAL), pero este test nunca ha sido aprobado por la FDA pasa su uso en sangre. Esto ha motivado el descubrimiento de un nuevo test llamado ensayo de actividad de endotoxina (EAA) (Spectral Diagnostics, Toronto, ON, Canadá), que consta de un kit de prueba rápida de quimioluminiscencia inmunodiagnóstica que se puede realizar en menos de 1 hora, aprobado por la FDA para su realización en líquidos biológicos como es la sangre. Los objetivos marcados del estudio fueron detectar la presencia de endotoxemia en el postoperatorio de cirugía cardiaca utilizando un nuevo método diagnóstico así como establecer los factores de riesgo de presentar endotoxemia y establecer la implicación pronóstica de esta. El estudio se ha realizado en la Unidad de Cuidados Intensivos del Hospital Germans Trías i Pujol, Badalona. Incluimos un total de 107 pacientes, la mayoría varones (69%), con una edad media de 66 años (36-87). El 38% tenían DM, 71% HTA y un 12% vasculopatía periférica. La mediana del EuroSCORE I fue de 7 (0-16). Solo 24 pacientes presentaron endotoxemia alta (≥0,4EA). La duración mediana de la CEC fue de 95 min (24-300) con un tiempo de isquemia (ClAo) de 72 min (17-175). El 37% de los pacientes requirieron transfusión de concentrados de hematíes. Los resultados de nuestro estudio indican que en el postoperatorio de cirugía cardiaca existe endotoxemia al menos en grado moderado y que esta puede tener utilidad en la detección de aquellos pacientes que pueden presentar infección postoperatoria precoz. Como factor de riesgo de endotoxemia, hemos observado que aquellos pacientes con vasculopatía periférica y los que requieren trasfusión de mayor cantidad de concentrados de hematíes durante la intervención son los que presentan mayor riesgo de presentar endotoxemia en el postoperatorio inmediato.Since the beginning of cardiac surgery, development of new surgical techniques, advances in methods of cardiopulmonary bypass (CPB) and intensive care treatments, mortality has decreased from almost 100% to 5- 6% today. However, these figures have remained stable in recent years. The inflammatory response to CPB has been implicated in many of the postoperative clinical problems that often occur in these patients including respiratory failure, postoperative shock states, renal failure and multiple organ dysfunction syndrome. These systemic changes may be due to many different mechanisms. One mechanism, is attributed to splanchnic hypoperfusion that might cause harm to the intestinal mucosa by altering the barrier's permeability, thus favouring bacterial translocation and endotoxemia. Endotoxin is a lipopolysaccharide in the membrane of GNB and is known to be one of the most potent activators known of innate immunity and the inflammatory response in humans. In patients subjected to cardiac surgery, transient endotoxemia has been shown in many occasions, which seems to be closely related to extracorporeal circulation, but the magnitude of endotoxemia and their correlation with clinical evolution and the development of complications vary widely between studies. According to some studies, systemic endotoxin concentration is closely correlated with the degree of cardiovascular dysfunction, duration of CPB, ischemic time and need for vasoactive amines, which can be summarized in all situations that could potentially favor a situation of splanchnic hypoperfusion. There are different techniques to detect the presence of endotoxemia. The amount of endotoxin has traditionally been quantified by the analysis known as "Limulus amebocyte lysate" (LAL), but this test has never been approved by the FDA for clinical use in humans. This has led to the discovery of a new test called endotoxin activity assay (EAA) (Spectral Diagnostics, Toronto, ON, Canada), comprising a rapid chemiluminiscent immunodiagnostic test kit that can be performed in less than 1 hour, approved by the FDA for its realization in biological fluids such as it is blood. The purpose of the study was to assess the prevalence of endotoxemia related to CPB in a cohort of patients undergoing cardiac surgery, using the EAA test. There was also investigated the criteria for high risk of endotoxemia and the association between endotoxemia and the development of adverse clinical events including length of stay and mortality. The study was performed in the Intensive Care Unit of Germans Trias i Pujol Hospital, in Badalona. A total of 107 patients were enrolled. Of these 107 patients, the median age was 66 years (36-87), most were males (69%), 38% had DM, 71% HTA and 12% peripheral vascular disease. Median EuroSCORE I was 7 (0-6). Only 23 patients had EAA ≥0,4 EA. Median CBP time was 95 (24-300) and isquemic time 68 (17-175) minutes. 37% required blood transfusion. The results of the study indicate that in postoperative cardiac surgery there is endotoxemia at least in moderate degree, and that the presence of endotoxemia is significantly related to early postoperative infection. As a risk factor, we found that patients with peripheral vascular disease and transfused more than 2 during surgery are those with increased risk of endotoxemia