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

Forum Selling Abroad

Judges decide cases. Do they also try to influence which cases they decide? Clearly plaintiffs “shop” for the most attractive forum, but do judges try to attract cases by “selling” their courts? Some American judges actively try to enlarge their influence by making their courts attractive to plaintiffs, a phenomenon known as “forum selling.” This article shows that forum selling occurs outside the U.S. as well, focusing on Germany, a country that is often held up as the paragon of the civil law approach to adjudication. As in the U.S., German courts attract cases primarily through the pro-plaintiff manipulation of procedure, including the routine issuance of ex parte injunctions in press cases and refusal to stay patent infringement proceedings when the patent’s validity is challenged in another forum. A critical difference between forum selling in Germany and the U.S. is that court administrators are more actively involved in Germany. As state officials, German court administrators have the incentive to consider the effect of caseloads on government revenue and the local economy, and they use their power to allocate judges to particular kinds of cases in order to make their courts attractive. They also use their power over promotion, case allocation, and resources to reward judges who succeed in attracting cases. Based on an extensive set of interviews with attorneys, judges and court officials, this article describes evidence of forum selling in German patent, press, and antitrust law. It also analyzes how German courts compete internationally with courts from other countries

Forum Selling Abroad

Judges decide cases. Do they also try to influence which cases they decide? Clearly plaintiffs “shop” for the most attractive forum, but do judges try to attract cases by “selling” their courts? Some American judges actively try to enlarge their influence by making their courts attractive to plaintiffs, a phenomenon known as “forum selling.” This article shows that forum selling occurs outside the U.S. as well, focusing on Germany, a country that is often held up as the paragon of the civil law approach to adjudication. As in the U.S., German courts attract cases primarily through the pro-plaintiff manipulation of procedure, including the routine issuance of ex parte injunctions in press cases and refusal to stay patent infringement proceedings when the patent’s validity is challenged in another forum. A critical difference between forum selling in Germany and the U.S. is that court administrators are more actively involved in Germany. As state officials, German court administrators have the incentive to consider the effect of caseloads on government revenue and the local economy, and they use their power to allocate judges to particular kinds of cases in order to make their courts attractive. They also use their power over promotion, case allocation, and resources to reward judges who succeed in attracting cases. Based on an extensive set of interviews with attorneys, judges and court officials, this article describes evidence of forum selling in German patent, press, and antitrust law. It also analyzes how German courts compete internationally with courts from other countries

Analyse der Smog-Situation in Stuttgart Januar 1982

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

Linagliptin treatment is associated with altered cobalamin (VitB12) homeostasis in mice and humans

Abstract Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used for the treatment of type 2 diabetes, with additional beneficial effects for the kidney. Treatment of mice with linagliptin revealed increased storage of cobalamin (Cbl, Vitamin B12) in organs if a standard Cbl diet (30 µg Cbl/kg chow) is given. In order to translate these findings to humans, we determined methylmalonic acid (MMA), a surrogate marker of functional Cbl homeostasis, in human plasma and urine samples (n = 1092) from baseline and end of trial (6 months after baseline) of the previously completed MARLINA-T2D clinical trial. We found that individuals with medium Cbl levels (MMA between 50 and 270 nmol/L for plasma, 0.4 and 3.5 µmol/mmol creatinine for urine, at baseline and end of trial) exhibited higher MMA values at the end of study in placebo compared with linagliptin. Linagliptin might inhibit the N-terminal degradation of the transcobalamin receptor CD320, which is necessary for uptake of Cbl into endothelial cells. Because we demonstrate that linagliptin led to increased organ levels of Cbl in mice, sustained constant medium MMA levels in humans, and inhibited CD320 processing by DPP-4 in-vitro, we speculate that linagliptin promotes intra-cellular uptake of Cbl by prolonging half-life of CD320

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

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