The GTN patch: a simple and effective new approach to cardioprotection?

This is a post-peer-review, pre-copyedit version of an article published in Basic Research in Cardiology . The final authenticated version is available online at: https://doi.org/10.1007/s00395-018-0681-2There remains a significant un-met need to reduce the extent of myocardial injury caused by ischaemia and reperfusion injury in patients experiencing an ST-elevation MI. Although nitric oxide is central to many cardioprotective strategies currently undergoing investigation, cardioprotection from the delivery of nitrates/nitrites has been inconsistently observed. The route of administration appears to be a critical variable. The glyceryl trinitrate (GTN) patch is commonly used as a simple and practical means of delivering nitric oxide to patients with ischaemic heart disease, but whether acute cardioprotection can be achieved by application of a GTN patch has not been investigated before. Here, we use a mouse model to demonstrate that a GTN patch is highly cardioprotective when applied immediately prior to 40 min occlusion of the left anterior coronary artery followed by 2 h reperfusion, reducing infarct size from 54 ± 4% in control mice, to 28 ± 4% (P < 0.001, N = 7). The degree of protection was similar to that achieved with a standard remote ischaemic preconditioning protocol. Furthermore, and of greater potential clinical relevance, a GTN patch was also protective when applied well after the initiation of ischaemia and 15 min prior to reperfusion (28 ± 4 vs 59 ± 4%; P < 0.01, N = 5). Confirmatory experiments verified the expected effect increase in plasma nitrite levels and decrease in blood pressure. The simplicity and rapidity of GTN patch application (easily applied in an ambulance or cardiac catheterization laboratory), and low cost (potentially relevant to low-income countries), make it attractive for further investigation.NIHR Biomedical Research Council (SD), British Heart Foundation PG/15/52/31598 (SD, DH) and the The Hatter Foundation

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Text as Observational Data

Quantitative research has traditionally been focused on estimating the parameters by which different variables are related, with an emphasis on establishing causal relationships. It is well known that any study using observational data has to overcome fundamental challenges to its internal validity and precisely elucidate the reasoning and assumptions made about the counterfactual. In this chapter, we address this crucial concern in the context of the new wealth of textual observational data now available for quantitative approaches to legal studies. We also discuss at a high level the opportunities made possible by these new data, as well as the methodological considerations raised by the use of quantitative techniques in a domain heretofore dominated by qualitative approaches

Analyse der Smog-Situation in Stuttgart Januar 1982

TIB Hannover: RN 9332 (4) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

The Deep Structure of Deliberate Ignorance: Mapping the Terrain

This chapter explores the “deep structure” of deliberate ignorance, defined as an individual’s or collective’s intentional choice to create a short- or long-term barrier to information for the individual or collective who made the choice. This definition is used to identify clear cases while acknowledging that the key terms of the definition (deliberate and ignorance) admit of ambiguity. It is argued that the frequency, forms, and functions of deliberate ignorance may vary across individuals as well as domains of information. Potential causal variables are suggested (e.g., the utility of the information, the nature of the information environment, the level of relevant parties who initiate and are affected by deliberate ignorance, and the legal, ethical, and social context within which deliberate ignorance occurs) and possible consequences are explored for the actors who engage in deliberate ignorance. Finally, the potential time course of deliberate ignorance is discussed within an episode of deliberate ignorance itself, across life-span development as well as cultural and biological evolutionary time

ZBTB7B (Th-POK) Regulates the Development of IL-17-Producing CD1d-Restricted Mouse NKT Cells

The research outputs in this collection have been funded in whole or in part by the National Health and Medical Research Council (NHMRC)Published VersionCopyright © 2012 by The American Association of ImmunologistsCD1d-dependent NKT cells represent a heterogeneous family of effector T cells including CD4(+)CD8(-) and CD4(-)CD8(-) subsets that respond to glycolipid Ags with rapid and potent cytokine production. NKT cell development is regulated by a unique combination of factors, however very little is known about factors that control the development of NKT subsets. In this study, we analyze a novel mouse strain (helpless) with a mis-sense mutation in the BTB-POZ domain of ZBTB7B and demonstrate that this mutation has dramatic, intrinsic effects on development of NKT cell subsets. Although NKT cell numbers are similar in Zbtb7b mutant mice, these cells are hyperproliferative and most lack CD4 and instead express CD8. Moreover, the majority of ZBTB7B mutant NKT cells in the thymus are retinoic acid-related orphan receptor γt positive, and a high frequency produce IL-17 while very few produce IFN-γ or other cytokines, sharply contrasting the profile of normal NKT cells. Mice heterozygous for the helpless mutation also have reduced numbers of CD4(+) NKT cells and increased production of IL-17 without an increase in CD8(+) cells, suggesting that ZBTB7B acts at multiple stages of NKT cell development. These results reveal ZBTB7B as a critical factor genetically predetermining the balance of effector subsets within the NKT cell population

ZBTB7B (Th-POK) regulates the development of IL-17 -producing-CD1d-restricted mouse NKT cells

CD1d-dependent NKT cells represent a heterogeneous family of effector T cells including CD4+CD8- and CD4-CD8- subsets that respond to glycolipid Ags with rapid and potent cytokine production. NKT cell development is regulated by a unique combination of factors, however very little is known about factors that control the development of NKT subsets. In this study, we analyze a novel mouse strain (helpless) with a mis-sense mutation in the BTB-POZ domain of ZBTB7B and demonstrate that this mutation has dramatic, intrinsic effects on development of NKT cell subsets. Although NKT cell numbers are similar in Zbtb7b mutant mice, these cells are hyperproliferative and most lack CD4 and instead express CD8. Moreover, the majority of ZBTB7B mutant NKT cells in the thymus are retinoic acid-related orphan receptor γt positive, and a high frequency produce IL-17 while very few produce IFN-γ or other cytokines, sharply contrasting the profile of normal NKT cells. Mice heterozygous for the helpless mutation also have reduced numbers of CD4+ NKT cells and increased production of IL-17 without an increase in CD8+ cells, suggesting that ZBTB7B acts at multiple stages of NKT cell development. These results reveal ZBTB7B as a critical factor genetically predetermining the balance of effector subsets within the NKT cell population.NHMRC (National Health and Medical Research Council of Australia

ATP11C is critical for the internalization of phosphatidylserine and differentiation of B lymphocytes

Subcompartments of the plasma membrane are believed to be critical for lymphocyte responses, but few genetic tools are available to test their function. Here we describe a previously unknown X-linked B cell-deficiency syndrome in mice caused by mutations in Atp11c, which encodes a member of the P4 ATPase family thought to serve as &apos;flippases&apos; that concentrate aminophospholipids in the cytoplasmic leaflet of cell membranes. Defective ATP11C resulted in a lower rate of phosphatidylserine translocation in pro-B cells and much lower pre-B cell and B cell numbers despite expression of pre-rearranged immunoglobulin transgenes or enforced expression of the prosurvival protein Bcl-2 to prevent apoptosis and abolished pre-B cell population expansion in response to a transgene encoding interleukin 7. The only other abnormalities we noted were anemia, hyperbilirubinemia and hepatocellular carcinoma. Our results identify an intimate connection between phospholipid transport and B lymphocyte function.X1171sciescopu