Itaconate modulates tricarboxylic acid and redox metabolism to mitigate reperfusion injury.

ObjectivesCerebral ischemia/reperfusion (IR) drives oxidative stress and injurious metabolic processes that lead to redox imbalance, inflammation, and tissue damage. However, the key mediators of reperfusion injury remain unclear, and therefore, there is considerable interest in therapeutically targeting metabolism and the cellular response to oxidative stress.MethodsThe objective of this study was to investigate the molecular, metabolic, and physiological impact of itaconate treatment to mitigate reperfusion injuries in in vitro and in vivo model systems. We conducted metabolic flux and bioenergetic studies in response to exogenous itaconate treatment in cultures of primary rat cortical neurons and astrocytes. In addition, we administered itaconate to mouse models of cerebral reperfusion injury with ischemia or traumatic brain injury followed by hemorrhagic shock resuscitation. We quantitatively characterized the metabolite levels, neurological behavior, markers of redox stress, leukocyte adhesion, arterial blood flow, and arteriolar diameter in the brains of the treated/untreated mice.ResultsWe demonstrate that the "immunometabolite" itaconate slowed tricarboxylic acid (TCA) cycle metabolism and buffered redox imbalance via succinate dehydrogenase (SDH) inhibition and induction of anti-oxidative stress response in primary cultures of astrocytes and neurons. The addition of itaconate to reperfusion fluids after mouse cerebral IR injury increased glutathione levels and reduced reactive oxygen/nitrogen species (ROS/RNS) to improve neurological function. Plasma organic acids increased post-reperfusion injury, while administration of itaconate normalized these metabolites. In mouse cranial window models, itaconate significantly improved hemodynamics while reducing leukocyte adhesion. Further, itaconate supplementation increased survival in mice experiencing traumatic brain injury (TBI) and hemorrhagic shock.ConclusionsWe hypothesize that itaconate transiently inhibits SDH to gradually "awaken" mitochondrial function upon reperfusion that minimizes ROS and tissue damage. Collectively, our data indicate that itaconate acts as a mitochondrial regulator that controls redox metabolism to improve physiological outcomes associated with IR injury

Analytical and numerical solutions of the potential and electric field generated by different electrode arrays in a tumor tissue under electrotherapy

<p>Abstract</p> <p>Background</p> <p>Electrotherapy is a relatively well established and efficient method of tumor treatment. In this paper we focus on analytical and numerical calculations of the potential and electric field distributions inside a tumor tissue in a two-dimensional model (2D-model) generated by means of electrode arrays with shapes of different conic sections (ellipse, parabola and hyperbola).</p> <p>Methods</p> <p>Analytical calculations of the potential and electric field distributions based on 2D-models for different electrode arrays are performed by solving the Laplace equation, meanwhile the numerical solution is solved by means of finite element method in two dimensions.</p> <p>Results</p> <p>Both analytical and numerical solutions reveal significant differences between the electric field distributions generated by electrode arrays with shapes of circle and different conic sections (elliptic, parabolic and hyperbolic). Electrode arrays with circular, elliptical and hyperbolic shapes have the advantage of concentrating the electric field lines in the tumor.</p> <p>Conclusion</p> <p>The mathematical approach presented in this study provides a useful tool for the design of electrode arrays with different shapes of conic sections by means of the use of the unifying principle. At the same time, we verify the good correspondence between the analytical and numerical solutions for the potential and electric field distributions generated by the electrode array with different conic sections.</p

Evaluating a bilingual education program in Spain: the impact beyond foreign language learning

We evaluate a program that introduced bilingual education in English and Spanish in primary education in some public schools of the Madrid region in 2004. Under this program students not only study English as a foreign language but also some subjects (at least Science, History and Geography) are taught in English. Spanish and Mathematics are taught only in Spanish. The first class receiving full treatment finished Primary education in June 2010 and they took the standardized test for all 6th grade students in Madrid on the skills considered "indispensable" at that age. This test is our measure of the outcome of primary education to evaluate the program. We have to face a double self-selection problem. One is caused by schools who decide to apply for the program, and a second one caused by students when choosing school. We take several routes to control for these selection problems. The main route to control for self-selected schools is to take advantage of the test being conducted in the same schools before and after the program was implemented in 6th grade. To control for students self-selection we combine the use of several observable characteristics (like parents' education and occupation) with the fact that most students were already enrolled at the different schools before the program was announced. Our results indicate that there is a clear negative effect on learning the subject taught in English for children whose parents have less than upper secondary education, and no clear effect for anyone on mathematical and reading skills, which were taught in Spanish

Intravital Microscopy of the Mouse Brain Microcirculation using a Closed Cranial Window

This experimental model was designed to assess the mouse pial microcirculation during acute and chronic, physiological and pathophysiological hemodynamic, inflammatory and metabolic conditions, using in vivo fluorescence microscopy. A closed cranial window is placed over the left parieto-occipital cortex of the mice. Local microcirculation is recorded in real time through the window using epi and fluorescence illumination, and measurements of vessels diameters and red blood cell (RBC) velocities are performed. RBC velocity is measured using real-time cross-correlation and/or fluorescent-labeled erythrocytes. Leukocyte and platelet adherence to pial vessels and assessment of perfusion and vascular leakage are made with the help of fluorescence-labeled markers such as Albumin-FITC and anti-CD45-TxR antibodies. Microcirculation can be repeatedly video-recorded over several days. We used for the first time the close window brain intravital microscopy to study the pial microcirculation to follow dynamic changes during the course of Plasmodium berghei ANKA infection in mice and show that expression of CM is associated with microcirculatory dysfunctions characterized by vasoconstriction, profound decrease in blood flow and eventually vascular collapse

Trustors’ Disregard for Trustees Deciding Intuitively or Reflectively: Three Experiments on Time Constraints

Human decisions in the social domain are modulated by the interaction between intuitive and reflective processes. Requiring individuals to decide quickly or slowly triggers these processes and is thus likely to elicit different social behaviors. Meanwhile, time pressure has been associated with inefficiency in market settings and market regulation often requires individuals to delay their decisions via cooling-off periods. Yet, recent research suggests that people who make reflective decisions are met with distrust. If this extends to external time constraints, then forcing individuals to delay their decisions may be counterproductive in scenarios where trust considerations are important. In three Trust Game experiments (total n = 1,872), including within- and between-subjects designs, we test whether individuals trust more someone who is forced to respond quickly (intuitively) or slowly (reflectively). We find that trustors do not adjust their behavior (or their beliefs) to the trustee’s time conditions. This seems to be an appropriate response because time constraints do not affect trustees’ behavior, at least when the game decisions are binary (trust vs. don’t trust; reciprocate vs. don’t reciprocate) and therefore mistakes cannot explain choices. Thus, delayed decisions per se do not seem to elicit distrust

Polyethylene Glycol Camouflaged Earthworm Hemoglobin.

Nearly 21 million components of blood and whole blood and transfused annually in the United States, while on average only 13.6 million units of blood are donated. As the demand for Red Blood Cells (RBCs) continues to increase due to the aging population, this deficit will be more significant. Despite decades of research to develop hemoglobin (Hb) based oxygen (O2) carriers (HBOCs) as RBC substitutes, there are no products approved for clinical use. Lumbricus terrestris erythrocruorin (LtEc) is the large acellular O2 carrying protein complex found in the earthworm Lumbricus terrestris. LtEc is an extremely stable protein complex, resistant to autoxidation, and capable of transporting O2 to tissue when transfused into mammals. These characteristics render LtEc a promising candidate for the development of the next generation HBOCs. LtEc has a short half-life in circulation, limiting its application as a bridge over days, until blood became available. Conjugation with polyethylene glycol (PEG-LtEc) can extend LtEc circulation time. This study explores PEG-LtEc pharmacokinetics and pharmacodynamics. To study PEG-LtEc pharmacokinetics, hamsters instrumented with the dorsal window chamber were subjected to a 40% exchange transfusion with 10 g/dL PEG-LtEc or LtEc and followed for 48 hours. To study the vascular response of PEG-LtEc, hamsters instrumented with the dorsal window chamber received multiple infusions of 10 g/dL PEG-LtEc or LtEc solution to increase plasma LtEc concentration to 0.5, then 1.0, and 1.5 g/dL, while monitoring the animals' systemic and microcirculatory parameters. Results confirm that PEGylation of LtEc increases its circulation time, extending the half-life to 70 hours, 4 times longer than that of unPEGylated LtEc. However, PEGylation increased the rate of LtEc oxidation in vivo. Vascular analysis verified that PEG-LtEc showed the absence of microvascular vasoconstriction or systemic hypertension. The molecular size of PEG-LtEc did not change the colloid osmotic pressure or blood volume expansion capacity compared to LtEc, due to LtEc's already large molecular size. Taken together, these results further encourage the development of PEG-LtEc as an O2 carrying therapeutic

Humans’ (Incorrect) Distrust of Reflective Decisions

Recent experiments suggest that social behavior may be shaped by the time available for decision making. It is known that fast decision making relies more on intuition whereas slow decision making is affected by reflective processes. Little is known, however, about whether people correctly anticipate the effect of intuition vs. reflection on others’ decision making. This is important in everyday situations where anticipating others’ behavior is often essential. A good example of this is the extensively studied Trust Game where the trustor, by sending an amount of money to the trustee, runs the risk of being exploited by the trustee’s subsequent action. We use this game to study how trustors’ choices are affected by whether trustees are externally forced to respond quickly or slowly. We also examine whether trustors’ own tendency to stop and reflect on their intuitions (as measured by the Cognitive Reflection Test) moderates how they anticipate the effect of reflection on the behavior of trustees. We find that the least reflective trustors send less money when trustees are forced to respond “reflectively” rather than “intuitively”, but we also argue that this is a wrong choice. In general, no group, including the ones with the largest number of reflective individuals, is good at anticipating the (positive) effect of forced delay on others’ trustworthiness

Replacing the Transfusion of 1-2 Units of Blood with Plasma Expanders that Increase Oxygen Delivery Capacity: Evidence from Experimental Studies.

At least a third of the blood supply in the world is used to transfuse 1-2 units of packed red blood cells for each intervention and most clinical trials of blood substitutes have been carried out at this level of oxygen carrying capacity (OCC) restoration. However, the increase of oxygenation achieved is marginal or none at all for molecular hemoglobin (Hb) products, due to their lingering vasoactivity. This has provided the impetus for the development of "oxygen therapeutics" using Hb-based molecules that have high oxygen affinity and target delivery of oxygen to anoxic areas. However it is still unclear how these oxygen carriers counteract or mitigate the functional effects of anemia due to obstruction, vasoconstriction and under-perfusion. Indeed, they are administered as a low dosage/low volume therapeutic Hb (subsequently further diluted in the circulatory pool) and hence induce extremely small OCC changes. Hyperviscous plasma expanders provide an alternative to oxygen therapeutics by increasing the oxygen delivery capacity (ODC); in anemia they induce supra-perfusion and increase tissue perfusion (flow) by as much as 50%. Polyethylene glycol conjugate albumin (PEG-Alb) accomplishes this by enhancing the shear thinning behavior of diluted blood, which increases microvascular endothelial shear stress, causes vasodilation and lowering peripheral vascular resistance thus facilitating cardiac function. Induction of supra-perfusion takes advantage of the fact that ODC is the product of OCC and blood flow and hence can be maintained by increasing either or both. Animal studies suggest that this approach may save a considerable fraction of the blood supply. It has an additional benefit of enhancing tissue clearance of toxic metabolites