Detailed characterization of a long-term rodent model of critical illness and recovery

Objective: To characterize a long-term model of recovery from critical illness, with particular emphasis on cardiorespiratory, metabolic, and muscle function. Design: Randomized controlled animal study. Setting: University research laboratory. Subjects: Male Wistar rats. Interventions: Intraperitoneal injection of the fungal cell wall constituent, zymosan or n-saline. Measurements and Main Results: Following intervention, rats were followed for up to 2 weeks. Animals with zymosan peritonitis reached a clinical and biochemical nadir on day 2. Initial reductions were seen in body weight, total body protein and fat, and muscle mass. Leg muscle fiber diameter remained subnormal at 14 days with evidence of persisting myonecrosis, even though gene expression of regulators of muscle mass (e.g., MAFbx, MURF1, and myostatin) had peaked on days 2–4 but normalized by day 7. Treadmill exercise capacity, forelimb grip strength, and in vivo maximum tetanic force were also reduced. Food intake was minimal until day 4 but increased thereafter. This did not relate to appetite hormone levels with early (6 hr) rises in plasma insulin and leptin followed by persisting subnormal levels; ghrelin levels did not change. Serum interleukin-6 level peaked at 6 hours but had normalized by day 2, whereas interleukin-10 remained persistently elevated and high-density lipoprotein cholesterol persistently depressed. There was an early myocardial depression and rise in core temperature, yet reduced oxygen consumption and respiratory exchange ratio with a loss of diurnal rhythmicity that showed a gradual but incomplete recovery by day 7. Conclusions: This detailed physiological, metabolic, hormonal, functional, and histological muscle characterization of a model of critical illness and recovery reproduces many of the findings reported in human critical illness. It can be used to assess putative therapies that may attenuate loss, or enhance recovery, of muscle mass and function

How can developing countries harness biotechnology to improve health?

<p>Abstract</p> <p>Background</p> <p>The benefits of genomics and biotechnology are concentrated primarily in the industrialized world, while their potential to combat neglected diseases in the developing world has been largely untapped. Without building developing world biotechnology capacity to address local health needs, this disparity will only intensify. To assess the potential of genomics to address health needs in the developing world, the McLaughlin-Rotman Centre for Global Health, along with local partners, organized five courses on Genomics and Public Health Policy in the developing world. The overall objective of the courses was to collectively explore how to best harness genomics to improve health in each region. This article presents and analyzes the recommendations from all five courses.</p> <p>Discussion</p> <p>In this paper we analyze recommendations from 232 developing world experts from 58 countries who sought to answer how best to harness biotechnology to improve health in their regions. We divide their recommendations into four categories: science; finance; ethics, society and culture; and politics.</p> <p>Summary</p> <p>The Courses' recommendations can be summarized across the four categories listed above:</p> <p>Science</p> <p>- Collaborate through national, regional, and international networks</p> <p>- Survey and build capacity based on proven models through education, training, and needs assessments</p> <p>Finance</p> <p>- Develop regulatory and intellectual property frameworks for commercialization of biotechnology</p> <p>- Enhance funding and affordability of biotechnology</p> <p>- Improve the academic-industry interface and the role of small and medium enterprise</p> <p>Ethics, Society, Culture</p> <p>- Develop public engagement strategies to inform and educate the public about developments in genomics and biotechnology</p> <p>- Develop capacity to address ethical, social and cultural issues</p> <p>- Improve accessibility and equity</p> <p>Politics</p> <p>- Strengthen understanding, leadership and support at the political level for biotechnology</p> <p>- Develop policies outlining national biotechnology strategy</p> <p>These recommendations provide guidance for all those interested in supporting science, technology, and innovation to improve health in the developing world. Applying these recommendations broadly across sectors and regions will empower developing countries themselves to harness the benefits of biotechnology and genomics for billions who have long been excluded.</p

Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites

Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter μ, the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, μ was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery

Heavy-to-light baryonic form factors at large recoil

We analyze heavy-to-light baryonic form factors at large recoil and derive the scaling behavior of these form factors in the heavy quark limit. It is shown that only one universal form factor is needed to parameterize Lambda_b to p and Lambda_b to Lambda matrix elements in the large recoil limit of light baryons, while hadronic matrix elements of Lambda_b to Sigma transition vanish in the large energy limit of Sigma baryon due to the space-time parity symmetry. The scaling law of the soft form factor eta(P^{\prime} \cdot v), P^{\prime} and v being the momentum of nucleon and the velocity of Lambda_b baryon, responsible for Lambda_b to p transitions is also derived using the nucleon distribution amplitudes in leading conformal spin. In particular, we verify that this scaling behavior is in full agreement with that from light-cone sum rule approach in the heavy-quark limit. With these form factors, we further investigate the Lambda baryon polarization asymmetry alpha in Lambda_b to Lambda gamma and the forward-backward asymmetry A_{FB} in Lambda_b to Lambda l^{+} l^{-}. Both two observables (alpha and A_{FB}) are independent of hadronic form factors in leading power of 1/m_b and in leading order of alpha_s. We also extend the analysis of hadronic matrix elements for Omega_b to Omega transitions to rare Omega_b to Omega gamma and Omega_b to Omega l^{+} l^{-} decays and find that radiative Omega_b to Omega gamma decay is probably the most promising FCNC b to s radiative baryonic decay channel. In addition, it is interesting to notice that the zero-point of forward-backward asymmetry of Omega_b to Omega l^{+} l^{-} is the same as the one for Lambda_b to Lambda l^{+} l^{-} to leading order accuracy provided that the form factors \bar{\zeta}_i (i=3, 4, 5) are numerically as small as indicated from the quark model.Comment: 19 page

Correlation functions quantify super-resolution images and estimate apparent clustering due to over-counting

We present an analytical method to quantify clustering in super-resolution localization images of static surfaces in two dimensions. The method also describes how over-counting of labeled molecules contributes to apparent self-clustering and how the effective lateral resolution of an image can be determined. This treatment applies to clustering of proteins and lipids in membranes, where there is significant interest in using super-resolution localization techniques to probe membrane heterogeneity. When images are quantified using pair correlation functions, the magnitude of apparent clustering due to over-counting will vary inversely with the surface density of labeled molecules and does not depend on the number of times an average molecule is counted. Over-counting does not yield apparent co-clustering in double label experiments when pair cross-correlation functions are measured. We apply our analytical method to quantify the distribution of the IgE receptor (Fc{\epsilon}RI) on the plasma membranes of chemically fixed RBL-2H3 mast cells from images acquired using stochastic optical reconstruction microscopy (STORM) and scanning electron microscopy (SEM). We find that apparent clustering of labeled IgE bound to Fc{\epsilon}RI detected with both methods arises from over-counting of individual complexes. Thus our results indicate that these receptors are randomly distributed within the resolution and sensitivity limits of these experiments.Comment: 22 pages, 5 figure

The Precursors and Products of Justice Climates: Group Leader Antecedents and Employee Attitudinal Consequences

Drawing on the organizational justice, organizational climate, leadership and personality, and social comparison theory literatures, we develop hypotheses about the effects of leader personality on the development of three types of justice climates (e.g., procedural, interpersonal, and informational), and the moderating effects of these climates on individual level justice- attitude relationships. Largely consistent with the theoretically-derived hypotheses, the results showed that leader (a) agreeableness was positively related to procedural, interpersonal and informational justice climates, (b) conscientiousness was positively related to a procedural justice climate, and (c) neuroticism was negatively related to all three types of justice climates. Further, consistent with social comparison theory, multilevel data analyses revealed that the relationship between individual justice perceptions and job attitudes (e.g., job satisfaction, commitment) was moderated by justice climate such that the relationships were stronger when justice climate was high

What do hospital decision-makers in Ontario, Canada, have to say about the fairness of priority setting in their institutions?

BACKGROUND: Priority setting, also known as rationing or resource allocation, occurs at all levels of every health care system. Daniels and Sabin have proposed a framework for priority setting in health care institutions called 'accountability for reasonableness', which links priority setting to theories of democratic deliberation. Fairness is a key goal of priority setting. According to 'accountability for reasonableness', health care institutions engaged in priority setting have a claim to fairness if they satisfy four conditions of relevance, publicity, appeals/revision, and enforcement. This is the first study which has surveyed the views of hospital decision makers throughout an entire health system about the fairness of priority setting in their institutions. The purpose of this study is to elicit hospital decision-makers' self-report of the fairness of priority setting in their hospitals using an explicit conceptual framework, 'accountability for reasonableness'. METHODS: 160 Ontario hospital Chief Executive Officers, or their designates, were asked to complete a survey questionnaire concerning priority setting in their publicly funded institutions. Eight-six Ontario hospitals completed this survey, for a response rate of 54%. Six close-ended rating scale questions (e.g. Overall, how fair is priority setting at your hospital?), and 3 open-ended questions (e.g. What do you see as the goal(s) of priority setting in your hospital?) were used. RESULTS: Overall, 60.7% of respondents indicated their hospitals' priority setting was fair. With respect to the 'accountability for reasonableness' conditions, respondents indicated their hospitals performed best for the relevance (75.0%) condition, followed by appeals/revision (56.6%), publicity (56.0%), and enforcement (39.5%). CONCLUSIONS: For the first time hospital Chief Executive Officers within an entire health system were surveyed about the fairness of priority setting practices in their institutions using the conceptual framework 'accountability for reasonableness'. Although many hospital CEOs felt that their priority setting was fair, ample room for improvement was noted, especially for the enforcement condition

Investigating human audio-visual object perception with a combination of hypothesis-generating and hypothesis-testing fMRI analysis tools

Primate multisensory object perception involves distributed brain regions. To investigate the network character of these regions of the human brain, we applied data-driven group spatial independent component analysis (ICA) to a functional magnetic resonance imaging (fMRI) data set acquired during a passive audio-visual (AV) experiment with common object stimuli. We labeled three group-level independent component (IC) maps as auditory (A), visual (V), and AV, based on their spatial layouts and activation time courses. The overlap between these IC maps served as definition of a distributed network of multisensory candidate regions including superior temporal, ventral occipito-temporal, posterior parietal and prefrontal regions. During an independent second fMRI experiment, we explicitly tested their involvement in AV integration. Activations in nine out of these twelve regions met the max-criterion (A &lt; AV &gt; V) for multisensory integration. Comparison of this approach with a general linear model-based region-of-interest definition revealed its complementary value for multisensory neuroimaging. In conclusion, we estimated functional networks of uni- and multisensory functional connectivity from one dataset and validated their functional roles in an independent dataset. These findings demonstrate the particular value of ICA for multisensory neuroimaging research and using independent datasets to test hypotheses generated from a data-driven analysis