An old dream revitalised: preconditioning strategies to protect surgical flaps from critical ischaemia and ischaemia-reperfusion injury

The prevention of ischaemia and the adequate restitution of blood flow to ischaemic tissue are pivotal to halt the progression of cellular injury associated with decreased oxygen and nutrient supply. Accordingly, the search for novel strategies which aim at preventing ischaemia-reperfusion-induced tissue damage is still of major interest in flap surgery. Preconditioning represents an elegant approach to render the tissue more resistant against deleterious ischaemic insults. For many decades, 'surgical delay' has been the standard method of tissue preconditioning. During the last 10 years, ischaemic preconditioning was added to the repertoire of plastic surgeons to protect flaps from ischaemic necrosis. The invasiveness and expenditure of time of these procedures, however, have always been major drawbacks, hindering a wide distribution in clinical practice. Consequently, the motivation has all along been to further refine and simplify protective strategies. Recent experimental studies have now shown that efficient protection from ischaemic necrosis can also be achieved by remote preconditioning or pretreatment with chemical agents and growth factors, which mimic the action of surgical delay and ischaemic preconditioning. In addition, the local application of unspecific stressors, including both heating and cooling, have been shown to effectively improve flap microcirculation and, thus, tissue survival. In view of successful translational research, it is now time that the efficacy of these novel preconditioning procedures is proven in prospective randomised clinical trials.

Clinical trials in head injury

Secondary brain damage, following severe head injury is considered to be a major cause for bad outcome. Impressive reductions of the extent of brain damage in experimental studies have raised high expectations for cerebral neuroprotective treatment, in the clinic. Therefore multiple compounds were and are being evaluated in trials. In this review we discuss the pathomechanisms of traumatic brain damage, based upon their clinical importance. The role of hypothermia, mannitol, barbiturates, steroids, free radical scavengers, arachidonic acid inhibitors, calcium channel blockers, N-methyl-D-aspartate (NMDA) antagonists, and potassium channel blockers, will be discussed. The importance of a uniform strategic approach for evaluation of potentially interesting new compounds in clinical trials, to ameliorate outcome in patients with severe head injury, is proposed. To achieve this goal, two nonprofit organizations were founded: the European Brain Injury Consortium (EBIC) and the American Brain Injury Consortium (ABIC). Their aim lies in conducting better clinical trials, which incorporate lessons learned from previous trials, such that the succession of negative, or incomplete studies, as performed in previous years, will cease.

Creep and shrinkage behavior of ultra high-performance concrete under compressive loading with varying curing regimes

This Ultra High Performance Concrete research involves observing early-age creep and shrinkage under a compressive load throughout multiple thermal curing regimes. The goal was to mimic the conditions that would be expected of a precast/prestressing plant in the United States, where UHPC beams would be produced quickly to maximize a manufacturing plant’s output. The practice of steam curing green concrete to accelerate compressive strengths for early release of the prestressing tendons was utilized (140°F [60°C], 95% RH, 14 hrs), in addition to the full thermal treatment (195°F [90°C], 95% RH, 48 hrs) while the specimens were under compressive loading. Past experimental studies on creep and shrinkage characteristics of UHPC have only looked at applying a creep load after the thermal treatment had been administered to the specimens, or on ambient cured specimens. However, this research looked at mimicking current U.S. precast/prestressed plant procedures, and thus characterized the creep and shrinkage characteristics of UHPC as it is thermally treated under a compressive load. Michigan Tech has three moveable creep frames to accommodate two loading criteria per frame of 0.2f’ci and 0.6f’ci. Specimens were loaded in the creep frames and moved into a custom built curing chamber at different times, mimicking a precast plant producing several beams throughout the week and applying a thermal cure to all of the beams over the weekend. This thesis presents the effects of creep strain due to the varying curing regimes. An ambient cure regime was used as a baseline for the comparison against the varying thermal curing regimes. In all cases of thermally cured specimens, the compressive creep and shrinkage strains are accelerated to a maximum strain value, and remain consistent after the administration of the thermal cure. An average creep coefficient for specimens subjected to a thermal cure was found to be 1.12 and 0.78 for the high and low load levels, respectively. Precast/pressed plants can expect that simultaneously thermally curing UHPC elements that are produced throughout the week does not impact the post-cure creep coefficient.

Diesel spray mixing limited vaporization with non-ideal and multi-component fuel thermophysical property effects

Internal combustion engines are, and will continue to be, a primary mode of power generation for ground transportation. Challenges exist in meeting fuel consumption regulations and emission standards while upholding performance, as fuel prices rise, and resource depletion and environmental impacts are of increasing concern. Diesel engines are advantageous due to their inherent efficiency advantage over spark ignition engines; however, their NOx and soot emissions can be difficult to control and reduce due to an inherent tradeoff. Diesel combustion is spray and mixing controlled providing an intrinsic link between spray and emissions, motivating detailed, fundamental studies on spray, vaporization, mixing, and combustion characteristics under engine relevant conditions. An optical combustion vessel facility has been developed at Michigan Technological University for these studies, with detailed tests and analysis being conducted. In this combustion vessel facility a preburn procedure for thermodynamic state generation is used, and validated using chemical kinetics modeling both for the MTU vessel, and institutions comprising the Engine Combustion Network international collaborative research initiative. It is shown that minor species produced are representative of modern diesel engines running exhaust gas recirculation and do not impact the autoignition of n-heptane. Diesel spray testing of a high-pressure (2000 bar) multi-hole injector is undertaken including non-vaporizing, vaporizing, and combusting tests, with sprays characterized using Mie back scatter imaging diagnostics. Liquid phase spray parameter trends agree with literature. Fluctuations in liquid length about a quasi-steady value are quantified, along with plume to plume variations. Hypotheses are developed for their causes including fuel pressure fluctuations, nozzle cavitation, internal injector flow and geometry, chamber temperature gradients, and turbulence. These are explored using a mixing limited vaporization model with an equation of state approach for thermopyhysical properties. This model is also applied to single and multi-component surrogates. Results include the development of the combustion research facility and validated thermodynamic state generation procedure. The developed equation of state approach provides application for improving surrogate fuels, both single and multi-component, in terms of diesel spray liquid length, with knowledge of only critical fuel properties. Experimental studies are coupled with modeling incorporating improved thermodynamic non-ideal gas and fuel

Computational prediction of the influence of crosslink distribution on the thermo-mechanical properties of epoxies

Experimental studies on epoxies report that the microstructure consists of highly crosslinked localized regions connected with a dispersed phase of low crosslink density. The various thermo-mechanical properties of epoxies might be affected by the crosslink distribution. But as experiments cannot report the exact number of crosslinked covalent bonds present in the structure, molecular dynamics is thus being used in this work to determine the influence of crosslink distribution on thermo-mechanical properties. Molecular dynamics and molecular mechanics simulations are used to establish wellequilibrated molecular models of EPON 862-DETDA epoxy system with a range of crosslink densities and various crosslink distributions. Crosslink distributions are being varied by forming differently crosslinked localized clusters and then by forming different number of crosslinks interconnecting the clusters. Simulations are subsequently used to predict the volume shrinkage, thermal expansion coefficients, and elastic properties of each of the crosslinked systems. The results indicate that elastic properties increase with increasing levels of overall crosslink density and the thermal expansion coefficient decreases with overall crosslink density, both above and below the glass transition temperature. Elastic moduli and coefficients of linear thermal expansion values were found to be different for systems with same overall crosslink density but having different crosslink distributions, thus indicating an effect of the epoxy nanostructure on physical properties. The values of thermo-mechanical properties for all the crosslinked systems are within the range of values reported in literature.

Gene expression in cultured endometrium from women with different outcomes following IVF

Estradiol and progesterone are crucial for the acquisition of receptivity and the change in transcriptional activity of target genes in the implantation window. The aim of this study was to differentiate the regulation of genes in the endometrium of patients with recurrent implantation failure (IF) versus those who became pregnant after in vitro fertilization (IVF) treatment. Moreover, the effect of embryo-derived factors on endometrial transcriptional activity was studied. Nine women with known IVF outcome (IF, M, miscarriage, OP, ongoing pregnancy) and undergoing hysteroscopy with endometrial biopsy were enrolled. Biopsies were taken during the midluteal phase. After culture in the presence of embryo-conditioned IVF media, total RNA was extracted and submitted to reverse transcription, target cDNA synthesis, biotin labelling, fragmentation and hybridization using the Affymetrix Human Genome U133A 2.0 Chip. Differential expression of selected genes was re-analysed by quantitative PCR, in which the results were calculated as threshold cycle differences between the groups and normalized to Glyceraldehyde phosphate dehydrogenase and beta-actin. Differences were seen for several genes from endometrial tissue between the IF and the pregnancy groups, and when comparing OP with M, 1875 up- and 1807 down-regulated genes were returned. Real-time PCR analysis confirmed up-regulation for somatostatin, PLAP-2, mucin 4 and CD163, and down-regulation of glycodelin, IL-24, CD69, leukaemia inhibitory factor and prolactin receptor between Op and M. When the different embryo-conditioned media were compared, no significant differential regulation could be demonstrated. Although microarray profiling may currently not be sensitive enough for studying the effects of embryo-derived factors on the endometrium, the observed differences in gene expression between M and OP suggest that it will become an interesting tool for the identification of fertility-relevant markers produced by the endometrium.

DEVELOPMENT OF CONFOCAL IMAGING TECHNIQUES FOR PROBING INTERFACIAL DYNAMICS IN MICROSCALE, GAS-LIQUID, TWO-PHASE FLOW

Micro-scale, two-phase flow is found in a variety of devices such as Lab-on-a-chip, bio-chips, micro-heat exchangers, and fuel cells. Knowledge of the fluid behavior near the dynamic gas-liquid interface is required for developing accurate predictive models. Light is distorted near a curved gas-liquid interface preventing accurate measurement of interfacial shape and internal liquid velocities. This research focused on the development of experimental methods designed to isolate and probe dynamic liquid films and measure velocity fields near a moving gas-liquid interface. A high-speed, reflectance, swept-field confocal (RSFC) imaging system was developed for imaging near curved surfaces. Experimental studies of dynamic gas-liquid interface of micro-scale, two-phase flow were conducted in three phases. Dynamic liquid film thicknesses of segmented, two-phase flow were measured using the RSFC and compared to a classic film thickness deposition model. Flow fields near a steadily moving meniscus were measured using RSFC and particle tracking velocimetry. The RSFC provided high speed imaging near the menisci without distortion caused the gas-liquid interface. Finally, interfacial morphology for internal two-phase flow and droplet evaporation were measured using interferograms produced by the RSFC imaging technique. Each technique can be used independently or simultaneously when.

The feasibility of non-viral gene transfer to the diaphragm in vivo

Gene transfer using electroporation is an essential method for the study of developmental biology, especially to understand the internal control of degeneration and apoptosis of the muscle cells that occurs earlier and quicker than the usual degeneration process occurring by aging. Such experimental studies may have a role in developing new strategies for treating patients suffering from inherited primary myopathies such as Duchenne muscular dystrophy (DMD). The present study was designed to evaluate the feasibility of electroporation mediated transfer of reporter genes to the diaphragm in vivo. This is the first report of gene transfer of naked plasmid DNA into the diaphragm muscle in vivo using electroporation. Our results showed that in vivo gene transfer of naked plasmid DNA into the diaphragm muscle using electroporation is feasible.

ABO blood group incompatible haematopoietic stem cell transplantation and xenograft rejection

The current organ shortage in transplantation medicine stimulates the exploration of new strategies to expand the donor pool including the utilisation of living donors, ABO-incompatible grafts, and xenotransplantation. Preformed natural antibodies (Ab) such as anti-Gal or anti-A/B Ab mediate hyperacute graft rejection and thus represent a major hurdle to the employment of such strategies. In contrast to solid organ transplantation (SOT), ABO blood group incompatibilities are of minor importance in haematopoietic stem cell transplantation (HSCT). Thus, ABO incompatible HSCT may serve as an in vivo model to study carbohydrate antigen (Ag)-mismatched transplantations such as ABO-incompatible SOT or the effect of preformed Ab against Gal in xenotransplantation. This mini-review summarises our clinical and experimental studies performed with the support of the Swiss National Science Foundation program on Implants and Transplants (NFP-46). Part 1 describes data on the clinical outcome of ABO-incompatible HSCT, in particular the incidence of several immunohaematological complications, acute graft-versus-host-disease (GvHD), and the overall survival. Part 2 summarises the measurements of anti-A/B Ab in healthy blood donors and ABO-incompatible HSCT using a novel flow cytometry based method and the potential mechanisms responsible for the loss of anti-A/B Ab observed following minor ABO-incompatible HSCT, ie the occurrence of humoral tolerance. Part 3 analyses the potential of eliminating Gal expression as well as specific complement inhibitors such as dextran sulfate and synthetic tyrosine analogues to protect porcine endothelial cells from xenoreactive Ab-mediated damage in vitro and in a hamster-to-rat heart transplantation model. In conclusion, due to similarities of the immunological hurdles of ABO incompatible transplantations and xenotransplantation, the knowledge obtained from both fields might lead to new strategies to overcome humoral rejection in transplantation.

Compliance of the L5-S1 spinal unit: a comparative study between an unconstrained and a partially constrained system

A comparison between an unconstrained and a partially constrained system for in vitro biomechanical testing of the L5-S1 spinal unit was conducted. The objective was to compare the compliance and the coupling of the L5-S1 unit measured with an unconstrained and a partially constrained test for the three major physiological motions of the human spine. Very few studies have compared unconstrained and partially constrained testing systems using the same cadaveric functional spinal units (FSUs). Seven human L5-S1 units were therefore tested on both a pneumatic, unconstrained, and a servohydraulic, partially constrained system. Each FSU was tested along three motions: flexion-extension (FE), lateral bending (LB) and axial rotation (AR). The obtained kinematics on both systems is not equivalent, except for the FE case, where both motions are similar. The directions of coupled motions were similar for both tests, but their magnitudes were smaller in the partially constrained configuration. The use of a partially constrained system to characterize LB and AR of the lumbosacral FSU decreased significantly the measured stiffness of the segment. The unconstrained system is today's "gold standard" for the characterization of FSUs. The selected partially constrained method seems also to be an appropriate way to characterize FSUs for specific applications. Care should be taken using the latter method when the coupled motions are important.

International cooperation in ambient computing education

Funded by the US-EU Atlantis Program, the International Cooperation in Ambient Computing Education Project is establishing an international knowledge-building community for developing a broader computer science curriculum aimed at preparing students for real-world problems in a multidisciplinary, global world. The project is collaboration among Troy University (USA), University of Sunderland (UK), FernUniversität in Hagen (Germany), Universidade do Algarve (Portugal), University of Arkansas at Little Rock (USA) and San Diego State University (USA). The curriculum will include aspects of social science, cognitive science, human-computer interaction, organizational studies, global studies, and particular application areas as well as core computer science subjects. Programs offered at partner institutions will form trajectories through the curriculum. A degree will be defined in terms of combinations of trajectories which will satisfy degree requirements set by accreditation organizations. This is expected to lead to joint- or dual-degree programs among the partner institutions in the future. This paper describes the goals and activities of the project and discusses implementation issues.

Impacts of changing climate and land use on vegetation dynamics in a Mediterranean ecosystem: insights from paleoecology and dynamic modeling

Forests near the Mediterranean coast have been shaped by millennia of human disturbance. Consequently, ecological studies relying on modern observations or historical records may have difficulty assessing natural vegetation dynamics under current and future climate. We combined a sedimentary pollen record from Lago di Massacciucoli, Tuscany, Italy with simulations from the LandClim dynamic vegetation model to determine what vegetation preceded intense human disturbance, how past changes in vegetation relate to fire and browsing, and the potential of an extinct vegetation type under present climate. We simulated vegetation dynamics near Lago di Massaciucoli for the last 7,000 years using a local chironomid-inferred temperature reconstruction with combinations of three fire regimes (small infrequent, large infrequent, small frequent) and three browsing intensities (no browsing, light browsing, and moderate browsing), and compared model output to pollen data. Simulations with low disturbance support pollen-inferred evidence for a mixed forest dominated by Quercus ilex (a Mediterranean species) and Abies alba (a montane species). Whereas pollen data record the collapse of A. alba after 6000 cal yr bp, simulated populations expanded with declining summer temperatures during the late Holocene. Simulations with increased fire and browsing are consistent with evidence for expansion by deciduous species after A. alba collapsed. According to our combined paleo-environmental and modeling evidence, mixed Q. ilex and A. alba forests remain possible with current climate and limited disturbance, and provide a viable management objective for ecosystems near the Mediterranean coast and in regions that are expected to experience a mediterranean-type climate in the future.

Say on Pay: ein Überblick über Gestaltungsoptionen, ökonomische Konsequenzen und Erkenntnisse aus Empirie und Laborexperimenten

Unter dem Stichwort Say on Pay (SoP) haben in den letzen Jahren die meisten Länder der EU und die USA den Aktionären Abstimmungsrechte im Zusammenhang mit der Vergütung des Top-Managements eingeräumt. Zwischen den einzelnen Ländern bestehen jedoch erhebliche Unterschiede hinsichtlich der konkreten Ausgestaltung des SoP. Dieser Beitrag diskutiert die Wirkungen unterschiedlicher Gestaltungsoptionen des SoP auf die Anreizgestaltung und den Nutzen des Managements und der Aktionäre im Rahmen eines einfachen linearen Agency Modells. Dabei erweisen sich das vorvertragliche bindende SoP und das bedingt verpflichtende, nachvertragliche bindende SoP gegenüber den anderen untersuchten Varianten als überlegen. Während das konsultative SoP an seiner mangelnden Durchsetzbarkeit leidet, bietet das nachvertragliche bindende SoP Anreize für opportunistisches Verhalten auf Seiten der Aktionäre und führt deshalb zu Wohlfahrtsverlusten. In Ergänzung der Modellanalyse wird ein Überblick über die wichtigsten empirischen und experimentellen Studien zum Thema SoP gegeben und deren Inhalt im Lichte der Modellergebnisse diskutiert. Most countries of the European Union as well as the US recently introduced shareholder votes on the remuneration of executives, also referred to as “Say on Pay” (SoP). Interestingly, legislators in different jurisdictions opted for quite dissimilar voting right regimes. We provide an overview of the main regulatory approaches and discuss the potential impact of variations in SoP design on the structure of compensation contracts and the utility of shareholders and executives. We find that pre-contractual SoP and conditional post-contractual SoP with binding consequences are in the best interest of shareholders. By contrast, advisory SoP typically suffers from lacking enforceability. We also find that post-contractual SoP with binding consequences results in efficiency losses because it fuels moral hazard on the part of shareholders. We complement the theoretical analysis with a discussion of recent empirical and experimental studies on Say on Pay.

Group size adjustment to ecological demand in a cooperative breeder

Environmental factors can determine which group size will maximize the fitness of group members. This is particularly important in cooperative breeders, where group members often serve different purposes. Experimental studies are yet lacking to check whether ecologically mediated need for help will change the propensity of dominant group members to accept immigrants. Here, we manipulated the perceived risk of predation for dominant breeders of the cooperatively breeding cichlid fish Neolamprologus pulcher to test their response to unrelated and previously unknown immigrants. Potential immigrants were more readily accepted if groups were exposed to fish predators or egg predators than to herbivorous fish or control situations lacking predation risk. Our data are consistent with both risk dilution and helping effects. Egg predators were presented before spawning, which might suggest that the fish adjust acceptance rates also to a potential future threat. Dominant group members of N. pulcher apparently consider both present and future need of help based on ecological demand. This suggests that acceptance of immigrants and, more generally, tolerance of group members on demand could be a widespread response to ecological conditions in cooperatively breeding animals.