Translational perspectives on perfusion-diffusion mismatch in ischemic stroke

Magnetic resonance imaging has tremendous potential to illuminate ischemic stroke pathophysiology and guide rational treatment decisions. Clinical applications to date have been largely limited to trials. However, recent analyses of the major clinical studies have led to refinements in selection criteria and improved understanding of the potential implications for the risk vs. benefit of thrombolytic therapy. In parallel, preclinical studies have provided complementary information on the evolution of stroke that is difficult to obtain in humans due to the requirement for continuous or repeated imaging and pathological verification. We review the clinical and preclinical advances that have led to perfusion–diffusion mismatch being applied in phase 3 randomized trials and, potentially, future routine clinical practice

Chemosensitization as a Means to Augment Commercial Antifungal Agents

Antimycotic chemosensitization and its mode of action are of growing interest. Currently, use of antifungal agents in agriculture and medicine has a number of obstacles. Foremost of these is development of resistance or cross-resistance to one or more antifungal agents. The generally high expense and negative impact, or side effects, associated with antifungal agents are two further issues of concern. Collectively, these problems are exacerbated by efforts to control resistant strains, which can evolve into a treadmill of higher dosages for longer periods. This cycle in turn, inflates cost of treatment, dramatically. A further problem is stagnation in development of new and effective antifungal agents, especially for treatment of human mycoses. Efforts to overcome some of these issues have involved using combinations of available antimycotics (e.g., combination therapy for invasive mycoses). However, this approach has had inconsistent success and is often associated with a marked increase in negative side effects. Chemosensitization by natural compounds to increase effectiveness of commercial antimycotics is a somewhat new approach to dealing with the aforementioned problems. The potential for safe natural products to improve antifungal activity has been observed for over three decades. Chemosensitizing agents possess antifungal activity, but at insufficient levels to serve as antimycotics, alone. Their main function is to disrupt fungal stress response, destabilize the structural integrity of cellular and vacuolar membranes or stimulate production of reactive oxygen species, augmenting oxidative stress and apoptosis. Use of safe chemosensitizing agents has potential benefit to both agriculture and medicine. When co-applied with a commercial antifungal agent, an additive or synergistic interaction may occur, augmenting antifungal efficacy. This augmentation, in turn, lowers effective dosages, costs, negative side effects and, in some cases, countermands resistance

Designing and evaluating complex interventions to improve health care

Complex interventions are “built up from a number of components, which may act both independently and interdependently.”1 2 Many health service activities should be considered as complex. Evaluating complex interventions can pose a considerable challenge and requires a substantial investment of time. Unless the trials illuminate processes and mechanisms they often fail to provide useful information. If the result is negative, we are left wondering whether the intervention is inherently ineffective (either because the intervention was inadequately developed or because all similar interventions are ineffective), whether it was inadequately applied or applied in an inappropriate context, or whether the trial used an inappropriate design, comparison groups or outcomes. If there is a positive effect, it can be hard to judge how the results of the trial might be applied to a different context (box 1)

Antifungal activity of redox-active benzaldehydes that target cellular antioxidation

<p>Abstract</p> <p>Background</p> <p>Disruption of cellular antioxidation systems should be an effective method for control of fungal pathogens. Such disruption can be achieved with redox-active compounds. Natural phenolic compounds can serve as potent redox cyclers that inhibit microbial growth through destabilization of cellular redox homeostasis and/or antioxidation systems. The aim of this study was to identify benzaldehydes that disrupt the fungal antioxidation system. These compounds could then function as chemosensitizing agents in concert with conventional drugs or fungicides to improve antifungal efficacy.</p> <p>Methods</p> <p>Benzaldehydes were tested as natural antifungal agents against strains of <it>Aspergillus fumigatus</it>, <it>A. flavus</it>, <it>A. terreus </it>and <it>Penicillium expansum</it>, fungi that are causative agents of human invasive aspergillosis and/or are mycotoxigenic. The yeast <it>Saccharomyces cerevisiae </it>was also used as a model system for identifying gene targets of benzaldehydes. The efficacy of screened compounds as effective chemosensitizers or as antifungal agents in formulations was tested with methods outlined by the Clinical Laboratory Standards Institute (CLSI).</p> <p>Results</p> <p>Several benzaldehydes are identified having potent antifungal activity. Structure-activity analysis reveals that antifungal activity increases by the presence of an <it>ortho</it>-hydroxyl group in the aromatic ring. Use of deletion mutants in the oxidative stress-response pathway of <it>S. cerevisiae </it>(<it>sod1</it>Δ, <it>sod2</it>Δ, <it>glr1</it>Δ) and two mitogen-activated protein kinase (MAPK) mutants of <it>A. fumigatus </it>(<it>sakA</it>Δ, <it>mpkC</it>Δ), indicates antifungal activity of the benzaldehydes is through disruption of cellular antioxidation. Certain benzaldehydes, in combination with phenylpyrroles, overcome tolerance of <it>A. fumigatus </it>MAPK mutants to this agent and/or increase sensitivity of fungal pathogens to mitochondrial respiration inhibitory agents. Synergistic chemosensitization greatly lowers minimum inhibitory (MIC) or fungicidal (MFC) concentrations. Effective inhibition of fungal growth can also be achieved using combinations of these benzaldehydes.</p> <p>Conclusions</p> <p>Natural benzaldehydes targeting cellular antioxidation components of fungi, such as superoxide dismutases, glutathione reductase, <it>etc</it>., effectively inhibit fungal growth. They possess antifungal or chemosensitizing capacity to enhance efficacy of conventional antifungal agents. Chemosensitization can reduce costs, abate resistance, and alleviate negative side effects associated with current antifungal treatments.</p

Autonomous space processor for orbital debris

This work continues to develop advanced designs toward the ultimate goal of a GETAWAY SPECIAL to demonstrate economical removal of orbital debris utilizing local resources in orbit. The fundamental technical feasibility was demonstrated last year through theoretical calculations, quantitative computer animation, a solar focal point cutter, a robotic arm design and a subscale model. During this reporting period, several improvements are made in the solar cutter, such as auto track capabilities, better quality reflectors and a more versatile framework. The major advance has been in the design, fabrication and working demonstration of a ROBOTIC ARM that has several degrees of freedom. The functions were specifically tailored for the orbital debris handling. These advances are discussed here. Also a small fraction of the resources were allocated towards research in flame augmentation in SCRAMJETS for the NASP. Here, the fundamental advance was the attainment of Mach numbers up to 0.6 in the flame zone and a vastly improved injection system; the current work is expected to achieve supersonic combustion in the laboratory and an advanced monitoring system

Enhancing food security in an era of global climate change

The goal of the workshop was to build a more strategic and integrated perspective on the threats and opportunities latent in the food / climate issue, and to discuss the hard challenges of moving forward toward common goals in a private, off-the-record setting. An executive session convened by the John F. Kennedy School of Government at Harvard University and the Venice International University on June 6-9, 2010 attracted more than 25 of the world’s leading experts from the fields of policy, science, and business to San Servolo Island for an intensive three day session (see text for a list of the participants). The discussions were off-the-record, with each participant present in his or her own capacity, rather than representing an organization. The session was one in a series on Grand Challenges of the Sustainability Transition organized by the Sustainability Science Program at Harvard University with the generous support of the Italy’s Ministry for Environment, Land and Sea. This particular session was held in cooperation with the new Mega Program on Climate Change, Agriculture and Food Security being developed by the Consultative Group on International Agricultural Research (CGIAR) and the Earth System Science Partnership. This summary report of the session is our synthesis of the main points and arguments that emerged from the discussions. It does not represent a consensus document, since no effort was made at the Session to arrive at a single consensus view. Rather, we report here on what we heard to be the major themes discussed at the session. Any errors or misrepresentations remain solely our responsibility

Targeting the Oxidative Stress Response System of Fungi with Redox-Potent Chemosensitizing Agents

The cellular antioxidant system is a target in the antifungal action of amphotericin B (AMB) and itraconazole (ITZ), in filamentous fungi. The sakAΔ mutant of Aspergillus fumigatus, a mitogen-activated protein kinase (MAPK) gene deletion mutant in the antioxidant system, was found to be more sensitive to AMB or ITZ than other A. fumigatus strains, a wild type and a mpkCΔ mutant (a MAPK gene deletion mutant in the polyalcohol sugar utilization system). Complete fungal kill (≥99.9%) by ITZ or AMB was also achieved by much lower dosages for the sakAΔ mutant than for the other strains. It appears msnA, an Aspergillus ortholog to Saccharomyces cerevisiae MSN2 (encoding a stress-responsive C2H2-type zinc-finger regulator) and sakA and/or mpkC (upstream MAPKs) are in the same stress response network under tert-butyl hydroperoxide (t-BuOOH)-, hydrogen peroxide (H2O2)- or AMB-triggered toxicity. Of note is that ITZ-sensitive yeast pathogens were also sensitive to t-BuOOH, showing a connection between ITZ sensitivity and antioxidant capacity of fungi. Enhanced antifungal activity of AMB or ITZ was achieved when these drugs were co-applied with redox-potent natural compounds, 2,3-dihydroxybenzaldehyde, thymol or salicylaldehyde, as chemosensitizing agents. We concluded that redox-potent compounds, which target the antioxidant system in fungi, possess a chemosensitizing capacity to enhance efficacy of conventional drugs

Design studies of large aperture, high-resolution Earth science microwave radiometers compatible with small launch vehicles

High-spatial-resolution microwave radiometer sensing from space with reasonable swath widths and revisit times favors large aperture systems. However, with traditional precision antenna design, the size and weight requirements for such systems are in conflict with the need to emphasize small launch vehicles. This paper describes tradeoffs between the science requirements, basic operational parameters, and expected sensor performance for selected satellite radiometer concepts utilizing novel lightweight compactly packaged real apertures. Antenna, feed, and radiometer subsystem design and calibration are presented. Preliminary results show that novel lightweight real aperture coupled with state-of-the-art radiometer designs are compatible with small launch systems, and hold promise for high-resolution earth science measurements of sea ice, precipitation, soil moisture, sea surface temperature, and ocean wind speeds

Enhancing Food Security in an Era of Global Climate Change: An Executive Session on Grand Challenges of the Sustainability Transition

The goal of the workshop was to build a more strategic and integrated perspective on the threats and opportunities latent in the food / climate issue, and to discuss the hard challenges of moving forward toward common goals in a private, off-the-record setting. An executive session convened by the John F. Kennedy School of Government at Harvard University and the Venice International University on June 6-9, 2010, attracted more than 25 of the world's leading experts from the fields of policy, science, and business to San Servolo Island for an intensive three- day session (see text for a list of the participants). The discussions were off-the-record, with each participant present in his or her own capacity, rather than representing an organization. The session was one in a series on Grand Challenges of the Sustainability Transition organized by the Sustainability Science Program at Harvard University with the generous support of the Italy’s Ministry for Environment, Land and Sea. This particular session was held in cooperation with the new Mega Program on Climate Change, Agriculture and Food Security being developed by the Consultative Group on International Agricultural Research (CGIAR) and the Earth System Science Partnership. This summary report of the session is our synthesis of the main points and arguments that emerged from the discussions. It does not represent a consensus document, since no effort was made at the session to arrive at a single consensus view. Rather, we report here on what we heard to be the major themes discussed at the session. Any errors or misrepresentations remain solely our responsibility

A Phase I Trial of Aminolevulinic Acid-Photodynamic Therapy for Treatment of Oral Leukoplakia

Background Photodynamic therapy with aminolevulinic acid (ALA PDT) for oral leukoplakia has shown promising effects in regression of oral leukoplakia. Although ALA has been extensively studied and is an ideal photosensitizer, the optimal light dose for treatment of oral leukoplakia has not been determined. We conducted a phase I study to determine MTD and DLT of PDT in patients treated with ALA for leukoplakia. Methods Patients with histologically confirmed oral leukoplakia received a single treatment of ALA PDT in cohorts with escalating doses of light (585 nm). Clinical, histologic, and biologic markers were assessed. Results Analysis of 11 participants is reported. No significant toxicity from ALA PDT was observed in patients who received ALA with a light dose of up to 4 J/cm2. One participant experienced transient grade 3 transaminase elevation due to ALA. One participant had a partial clinical response 3 months after treatment. Biologic mucosal risk markers showed no significant associations. Determination of MTD could not be accomplished within a feasible timeframe for completion of the study. Conclusions ALA PDT could be safely administered with a light dose up to 4 J/cm2 and demonstrated activity. Larger studies are needed to fully elucidate the MTD and efficacy of ALA-PDT