Bench-to-bedside review: Carbon monoxide – from mitochondrial poisoning to therapeutic use

Carbon monoxide (CO) is generated during incomplete combustion of carbon-containing compounds and leads to acute and chronic toxicity in animals and humans depending on the concentration and exposure time. In addition to exogenous sources, CO is also produced endogenously by the activity of heme oxygenases (HOs) and the physiological significance of HO-derived CO has only recently emerged. CO exerts vasoactive, anti-proliferative, anti-oxidant, anti-inflammatory and anti-apoptotic effects and contributes substantially to the important role of the inducible isoform HO-1 as a mediator of tissue protection and host defense. Exogenous application of low doses of gaseous CO might provide a powerful tool to protect organs and tissues under various stress conditions. Experimental evidence strongly suggests a beneficial effect under pathophysiological conditions such as organ transplantation, ischemia/reperfusion, inflammation, sepsis, or shock states. The cellular and molecular mechanisms mediating CO effects are only partially characterized. So far, only a few studies in humans are available, which, however, do not support the promising results observed in experimental studies. The protective effects of exogenous CO may strongly depend on the pathological condition, the mode, time point and duration of application, the administered concentration, and on the target tissue and cell. Differences in bioavailability of endogenous CO production and exogenous CO supplementation might also provide an explanation for the lack of protective effects observed in some experimental and clinical studies. Further randomized, controlled clinical studies are needed to clarify whether exogenous application of CO may turn into a safe and effective preventive and therapeutic strategy to treat pathophysiological conditions associated with inflammatory or oxidative stress

Simulations and experiments on the ignition probability in turbulent premixed bluff-body flames

The ignition characteristics of a premixed bluff-body burner under lean conditions were investigated experimentally and numerically with a physical model focusing on ignition probability. Visualisation of the flame with a 5 kHz OH* chemiluminescence camera confirmed that successful ignitions were those associated with the movement of the kernel upstream, consistent with previous work in non-premixed systems. Performing many separate ignition trials at the same spark position and flow conditions resulted in a quantification of the ignition probability P_ign, which was found to decrease with increasing distance downstream of the bluff body and a decrease in equivalence ratio. Flows corresponding to flames close to the blow-off limit could not be ignited, although such flames were stable if reached from a richer already ignited condition. A detailed comparison with the local Karlovitz number and the mean velocity showed that regions of high P_ign are associated with low Ka and negative bulk velocity (i.e. towards the bluff body), although a direct correlation was not possible. A modelling effort that takes convection and localised flame quenching into account by tracking stochastic virtual flame particles, previously validated for non-premixed and spray ignition, was used to estimate the ignition probability. The applicability of this approach to premixed flows was first evaluated by investigating the model’s flame propagation mechanism in a uniform turbulence field, which showed that the model reproduces the bending behaviour of the S_T -versus-u' curve. Then ignition simulations of the bluff-body burner were carried out. The ignition probability map was computed and it was found that the model reproduces all main trends found in the experimental study.M.P. Sitte gratefully acknowledges financial support from the Gates Cambridge Trust. The experiments were carried out by E. Bach who was a Masters student from Karlsruhe Institute of Technology visiting the University of Cambridge in 2011.This is the final version of the article. It first appeared from Taylor & Francis via http://dx.doi.org/10.1080/13647830.2016.115575

Topological descriptors for 3D surface analysis

We investigate topological descriptors for 3D surface analysis, i.e. the classification of surfaces according to their geometric fine structure. On a dataset of high-resolution 3D surface reconstructions we compute persistence diagrams for a 2D cubical filtration. In the next step we investigate different topological descriptors and measure their ability to discriminate structurally different 3D surface patches. We evaluate their sensitivity to different parameters and compare the performance of the resulting topological descriptors to alternative (non-topological) descriptors. We present a comprehensive evaluation that shows that topological descriptors are (i) robust, (ii) yield state-of-the-art performance for the task of 3D surface analysis and (iii) improve classification performance when combined with non-topological descriptors.Comment: 12 pages, 3 figures, CTIC 201

Mesenchymal stem cell-based therapy for ischemic stroke

Ischemic stroke represents a major, worldwide health burden with increasing incidence. Patients affected by ischemic strokes currently have few clinically approved treatment options available. Most currently approved treatments for ischemic stroke have narrow therapeutic windows, severely limiting the number of patients able to be treated. Mesenchymal stem cells represent a promising novel treatment for ischemic stroke. Numerous studies have demonstrated that mesenchymal stem cells functionally improve outcomes in rodent models of ischemic stroke. Recent studies have also shown that exosomes secreted by mesenchymal stem cells mediate much of this effect. In the present review, we summarize the current literature on the use of mesenchymal stem cells to treat ischemic stroke. Further studies investigating the mechanisms underlying mesenchymal stem cells tissue healing effects are warranted and would be of benefit to the field

The Directed Dominating Set Problem: Generalized Leaf Removal and Belief Propagation

A minimum dominating set for a digraph (directed graph) is a smallest set of vertices such that each vertex either belongs to this set or has at least one parent vertex in this set. We solve this hard combinatorial optimization problem approximately by a local algorithm of generalized leaf removal and by a message-passing algorithm of belief propagation. These algorithms can construct near-optimal dominating sets or even exact minimum dominating sets for random digraphs and also for real-world digraph instances. We further develop a core percolation theory and a replica-symmetric spin glass theory for this problem. Our algorithmic and theoretical results may facilitate applications of dominating sets to various network problems involving directed interactions.Comment: 11 pages, 3 figures in EPS forma

Mirroring everyday clinical practice in clinical trial design: a new concept to improve the external validity of randomized double-blind placebo-controlled trials in the pharmacological treatment of major depression

Background: Randomized, double-blind, placebo-controlled trials constitute the gold standard in clinical research when testing the efficacy of new psychopharmacological interventions in the treatment of major depression. However, the blinded use of placebo has been found to influence clinical trial outcomes and may bias patient selection. Discussion: To improve clinical trial design in major depression so as to reflect clinical practice more closely we propose to present patients with a balanced view of the benefits of study participation irrespective of their assignment to placebo or active treatment. In addition every participant should be given the option to finally receive the active medication. A research agenda is outlined to evaluate the impact of the proposed changes on the efficacy of the drug to be evaluated and on the demographic and clinical characteristics of the enrollment fraction with regard to its representativeness of the eligible population. Summary: We propose a list of measures to be taken to improve the external validity of double-blind, placebocontrolled trials in major depression. The recommended changes to clinical trial design may also be relevant for other psychiatric as well as medical disorders in which expectations regarding treatment outcome may affect the outcome itself

Re-construction of action awareness depends on an internal model of action-outcome timing.

The subjective time of an instrumental action is shifted towards its outcome. This temporal binding effect is partially retrospective, i.e., occurs upon outcome perception. Retrospective binding is thought to reflect post-hoc inference on agency based on sensory evidence of the action - outcome association. However, many previous binding paradigms cannot exclude the possibility that retrospective binding results from bottom-up interference of sensory outcome processing with action awareness and is functionally unrelated to the processing of the action - outcome association. Here, we keep bottom-up interference constant and use a contextual manipulation instead. We demonstrate a shift of subjective action time by its outcome in a context of variable outcome timing. Crucially, this shift is absent when there is no such variability. Thus, retrospective action binding reflects a context-dependent, model-based phenomenon. Such top-down re-construction of action awareness seems to bias agency attribution when outcome predictability is low

Flavor SU(3) symmetry and QCD factorization in B→PPB \to PP and PVPV decays

Using flavor SU(3) symmetry, we perform a model-independent analysis of charmless $\bar B_{u,d} (\bar B_s) \to PP, ~PV$ decays. All the relevant topological diagrams, including the presumably subleading diagrams, such as the QCD- and EW-penguin exchange diagrams and flavor-singlet weak annihilation ones, are introduced. Indeed, the QCD-penguin exchange diagram turns out to be important in understanding the data for penguin-dominated decay modes. In this work we make efforts to bridge the (model-independent but less quantitative) topological diagram or flavor SU(3) approach and the (quantitative but somewhat model-dependent) QCD factorization (QCDF) approach in these decays, by explicitly showing how to translate each flavor SU(3) amplitude into the corresponding terms in the QCDF framework. After estimating each flavor SU(3) amplitude numerically using QCDF, we discuss various physical consequences, including SU(3) breaking effects and some useful SU(3) relations among decay amplitudes of $\bar B_s \to PV$ and $\bar B_d \to PV$.Comment: 47 pages, 3 figures, 28 table

Can We Really Prevent Suicide?

Every year, suicide is among the top 20 leading causes of death globally for all ages. Unfortunately, suicide is difficult to prevent, in large part because the prevalence of risk factors is high among the general population. In this review, clinical and psychological risk factors are examined and methods for suicide prevention are discussed. Prevention strategies found to be effective in suicide prevention include means restriction, responsible media coverage, and general public education, as well identification methods such as screening, gatekeeper training, and primary care physician education. Although the treatment for preventing suicide is difficult, follow-up that includes pharmacotherapy, psychotherapy, or both may be useful. However, prevention methods cannot be restricted to the individual. Community, social, and policy interventions will also be essentia

Deletion of the GABAA α2-subunit does not alter self dministration of cocaine or reinstatement of cocaine seeking

Rationale GABAA receptors containing α2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the α2-subunit results in an absence of sensitisation to cocaine. Objective We investigated the reinforcing properties of cocaine in GABAA α2-subunit knockout (KO) mice using an intravenous self-administration procedure. Methods α2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg). Results No differences were found in acquisition of lever pressing for milk. All genotypes acquired self-administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose-dependent increase in lever pressing during the cue presentation, KO mice did not. Conclusions Despite a reported absence of sensitisation, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the α2-subunit may be involved in modulating the “energising” aspect of cocaine’s effects on reward-seeking