Can we learn from the pathogenetic strategies of group A hemolytic streptococci how tissues are injured and organs fail in post-infectious and inflammatory sequelae?

The purpose of this review-hypothesis is to discuss the literature which had proposed the concept that the mechanisms by which infectious and inflammatory processes induce cell and tissue injury, in vivo, might paradoxically involve a deleterious synergistic ‘cross-talk’, among microbial- and host-derived pro-inflammatory agonists. This argument is based on studies of the mechanisms of tissue damage caused by catalase-negative group A hemolytic streptococci and also on a large body of evidence describing synergistic interactions among a multiplicity of agonists leading to cell and tissue damage in inflammatory and infectious processes. A very rapid cell damage (necrosis), accompanied by the release of large amounts of arachidonic acid and metabolites, could be induced when subtoxic amounts of oxidants (superoxide, oxidants generated by xanthine-xanthine oxidase, HOCl, NO), synergized with subtoxic amounts of a large series of membrane-perforating agents (streptococcal and other bacterial-derived hemolysins, phospholipases A 2 and C, lysophosphatides, cationic proteins, fatty acids, xenobiotics, the attack complex of complement and certain cytokines). Subtoxic amounts of proteinases (elastase, cathepsin G, plasmin, trypsin) very dramatically further enhanced cell damage induced by combinations between oxidants and the membrane perforators. Thus, irrespective of the source of agonists, whether derived from microorganisms or from the hosts, a triad comprised of an oxidant, a membrane perforator, and a proteinase constitutes a potent cytolytic cocktail the activity of which may be further enhanced by certain cytokines. The role played by non-biodegradable microbial cell wall components (lipopolysaccharide, lipoteichoic acid, peptidoglycan) released following polycation- and antibiotic-induced bacteriolysis in the activation of macrophages to release oxidants, cytolytic cytokines and NO is also discussed in relation to the pathophysiology of granulomatous inflammation and sepsis. The recent failures to prevent septic shock by the administration of only single antagonists is disconcerting. It suggests, however, that since tissue damage in post-infectious syndromes is caused by synergistic interactions among a multiplicity of agents, only cocktails of appropriate antagonists, if administered at the early phase of infection and to patients at high risk, might prevent the development of post-infectious syndromes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72535/1/j.1574-695X.1999.tb01357.x.pd

Real-time volume rendering and tractography visualization on the web

In the field of computer graphics, Volume Rendering techniques allow the visualization of 3D datasets, and specifically, Volume Ray-Casting renders images from volumetric datasets, typically used in some scientific areas, such as medical imaging -- This article aims to describe the development of a combined visualization of tractography and volume rendering of brain T1 MRI images in an integrated way -- An innovative web viewer for interactive visualization of neuro-imaging data has been developed based on WebGL -- This recently developed standard enables the clients to use the web viewer on a wide range of devices, with the only requirement of a compliant web-browser -- As the majority of the rendering tasks take place in the client machine, the effect of bottlenecks and server overloading are minimized -- The web application presented is able to compete with desktop tools, even supporting high graphical demands and facing challenges regarding performance and scalability -- The developed software modules are available as open source code and include MRI volume data and tractography generated by the Diffusion Toolkit, and connectivity data from the Connectome Mapping Toolkit -- Our contribution for the Volume Web Viewer implements early ray termination step according to the tractography depthmap, combining volume images and estimated white matter fibers -- Furthermore, the depthmap system extension can be used for visualization of other types of data, where geometric and volume elements are displayed simultaneousl

Research Directions in the Clinical Implementation of Pharmacogenomics: An Overview of US Programs and Projects

Response to a drug often differs widely among individual patients. This variability is frequently observed not only with respect to effective responses but also with adverse drug reactions. Matching patients to the drugs that are most likely to be effective and least likely to cause harm is the goal of effective therapeutics. Pharmacogenomics (PGx) holds the promise of precision medicine through elucidating the genetic determinants responsible for pharmacological outcomes and using them to guide drug selection and dosing. Here we survey the US landscape of research programs in PGx implementation, review current advances and clinical applications of PGx, summarize the obstacles that have hindered PGx implementation, and identify the critical knowledge gaps and possible studies needed to help to address them

A research agenda to support the development and implementation of genomics-based clinical informatics tools and resources.

OBJECTIVE: The Genomic Medicine Working Group of the National Advisory Council for Human Genome Research virtually hosted its 13th genomic medicine meeting titled Developing a Clinical Genomic Informatics Research Agenda . The meeting\u27s goal was to articulate a research strategy to develop Genomics-based Clinical Informatics Tools and Resources (GCIT) to improve the detection, treatment, and reporting of genetic disorders in clinical settings. MATERIALS AND METHODS: Experts from government agencies, the private sector, and academia in genomic medicine and clinical informatics were invited to address the meeting\u27s goals. Invitees were also asked to complete a survey to assess important considerations needed to develop a genomic-based clinical informatics research strategy. RESULTS: Outcomes from the meeting included identifying short-term research needs, such as designing and implementing standards-based interfaces between laboratory information systems and electronic health records, as well as long-term projects, such as identifying and addressing barriers related to the establishment and implementation of genomic data exchange systems that, in turn, the research community could help address. DISCUSSION: Discussions centered on identifying gaps and barriers that impede the use of GCIT in genomic medicine. Emergent themes from the meeting included developing an implementation science framework, defining a value proposition for all stakeholders, fostering engagement with patients and partners to develop applications under patient control, promoting the use of relevant clinical workflows in research, and lowering related barriers to regulatory processes. Another key theme was recognizing pervasive biases in data and information systems, algorithms, access, value, and knowledge repositories and identifying ways to resolve them

Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits

Automatic Data Restructuring

Data restructuring is often an integral but non-trivial part of information processing, especially when the data structures are fairly complicated. This paper describes the underpinnings of a program, called the Restructurer, that relieves the user of the "thinking and coding" process normally associated with writing procedural programs for data restructuring. The process is accomplished by the Restructurer in two stages. In the first, the differences in the input and output data structures are recognized and the applicability of various transformation rules analyzed. The result is a plan for mapping the specified input to the desired output. In the second stage, the plan is executed using embedded knowledge about both the target language and run-time efficiency considerations. The emphasis of this paper is on the planning stage. The restructuring operations and the mapping strategies are informally described and explained with mathematical formalism. The notion of solution of a set of instantiated forms with respect to an output form is then introduced. Finally, it is shown that such a solution exists if and only if the Restructurer produces one