Acute hyperglycemic exacerbation of lung ischemia-reperfusion injury is mediated by receptor for advanced glycation end-products signaling

The effects of acute hyperglycemia on lung ischemia-reperfusion (IR) injury and the role of receptor for advanced glycation end-products (RAGE) signaling in this process are unknown. The objective of this study was twofold: (1) evaluate the impact of acute hyperglycemia on lung IR injury; and (2) determine if RAGE signaling is a mechanism of hyperglycemia-enhanced IR injury. We hypothesized that acute hyperglycemia worsens lung IR injury through a RAGE signaling mechanism. C57BL/6 wild-type (WT) and RAGE knockout (RAGE (-/-)) mice underwent sham thoracotomy or lung IR (1-h left hilar occlusion and 2-h reperfusion). Acute hyperglycemia was established by dextrose injection 30 minutes before ischemia. Lung injury was assessed by measuring lung function, cytokine expression in bronchoalveolar lavage fluid, leukocyte infiltration, and microvascular permeability via Evans blue dye. Mean blood glucose levels doubled in hyperglycemic mice 30 minutes after dextrose injection. Compared with IR in normoglycemic mice, IR in hyperglycemic mice significantly enhanced lung dysfunction, cytokine expression (TNF-α, keratinocyte chemoattractant, IL-6, monocyte chemotactic protein-1, regulated upon activation, normal T cell expressed and secreted), leukocyte infiltration, and microvascular permeability. Lung injury and dysfunction after IR were attenuated in normoglycemic RAGE (-/-) mice, and hyperglycemia failed to exacerbate IR injury in RAGE (-/-) mice. Thus, this study demonstrates that acute hyperglycemia exacerbates lung IR injury, whereas RAGE deficiency attenuates IR injury and also prevents exacerbation of IR injury in an acute hyperglycemic setting. These results suggest that hyperglycemia-enhanced lung IR injury is mediated, at least in part, by RAGE signaling, and identifies RAGE as a potential, novel therapeutic target to prevent post-transplant lung IR injury.     

Review article: A primer for clinical researchers in the emergency department: Part VI. Measuring what matters: Core outcome sets in emergency medicine research

In this series we address important topics for clinicians who participate in research as part of their work in the ED. The overarching goal of clinical research is to improve care and determine which treatment is best. Yet, defining and measuring outcomes – what is ‘best’ – can be one of the most difficult steps in the design of a study, in particular when answers to research questions cannot be captured in simple binary results. This article addresses how to choose outcome measures and highlights the increasingly important concept of core outcome sets.     

A cross-sectional survey of complementary and alternative medicine use by children and adolescents attending the University Hospital of Wales

Background  

A high prevalence of CAM use has been documented worldwide in children and adolescents with chronic illnesses. Only a small number of studies, however, have been conducted in the United Kingdom. The primary aim of this study was to examine the use of CAM by children and adolescents with a wide spectrum of acute and chronic medical problems in a tertiary children's hospital in Wales.     

Synthesis of tritiated tuftsin and macrophage inhibitory tripeptide via acetylenic intermediates

Acetylenic analogues of tuftsin (Thr-Dah-Pro-Arg) and of a macrophage inhibitory tripeptide (Thr-Dah-Pro) have been synthesized by conventional procedures in solution (Dah = 2,6-diamino-4-hexynoic acid). These acetylenic derivatives are intermediates for the preparation of structurally unmodified, tritiated peptides. Catalytic tritiation of Thr-Dah-Pro-Arg and of Thr-Dah-Pro has afforded the radioactive tetra- and tripeptides with specific activities of 11.4 Ci/mmol and 37 Ci/mmol, respectively.     

Inhibition of in vitro adherence of antibody-coated red cells to monocytes by the dialyzable leukocyte extract

The red cell-monocyte assay (RMA), which has been used to evaluate the clinical significance of red cell (RBC) antibodies, was employed to test the effect of the dialyzable leukocyte extract (DLE) on in vitro adherence to monocytes of human RBCs coated with alloantibodies or autoantibodies. The total association index (TAI) of the RMA, expressing the number of RBCs adhering to or phagocytosed by 100 monocytes, indicated a potent inhibitory activity of DLE in the test system. TAI values of 100.4 +/- 20.1 (mean +/- SD) in the control sample, consisting of RBCs coated in vitro with anti-D, dropped to 4.0 +/- 2.1 when DLE was present in the assay medium at a concentration of 0.5 U per mL. Similar results were obtained with RBCs coated with IgG antibodies in vivo. The inhibition was dose dependent and was associated with a thermolabile component of DLE. This study establishes that DLE can modulate monocyte function by inhibiting the recognition of IgG sensitized red cells.     

Update on elotuzumab,a novel anti-SLAMF7 monoclonal antibody for the treatment of multiple myeloma

ABSTRACT

Introduction: In 2015, 4 new drugs were approved for the treatment of patients with multiple myeloma who experience drug resistance and relapsing disease, offering potential for improved patient outcomes. Given the mortality, morbidity, and projected rise in the incidence of multiple myeloma, more effective, novel therapies and treatment combinations are needed for patients at each stage of the disease.

Areas covered: Here, the authors examine published data regarding the development and clinical investigation of elotuzumab, a SLAMF7-targeted monoclonal antibody, for treatment of patients with multiple myeloma. The clinical efficacy, safety, and tolerability of elotuzumab treatment are summarized.

Expert opinion: Elotuzumab, a first-in-class immunostimulatory monoclonal antibody, is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received 1–3 prior therapies. Elotuzumab has the potential for use in patients in the upfront setting, in combination with other backbone regimens, as well as maintenance therapy. Trials demonstrate clinical benefit of adding elotuzumab to conventional lenalidomide and dexamethasone therapy, without additive toxicity. Data suggest that elotuzumab may provide clinical benefit in combination with proteasome inhibitors. Elotuzumab combination therapy is currently under further evaluation in the relapsed/refractory and newly diagnosed settings.