Novel mode for neutrophil protease cathepsin G-mediated signaling: membrane shedding of epidermal growth factor is required for cardiomyocyte anoikis

Neutrophils are thought to orchestrate myocardial remodeling during the early progression to cardiac failure through the release of reactive oxygen species, antimicrobial peptides, and proteases. Although neutrophil activation may be beneficial at early stages of disease, excessive neutrophil infiltration can induce cardiomyocyte death and tissue damage. The neutrophil-derived serine protease cathepsin G (Cat.G) has been shown to induce neonatal rat cardiomyocyte detachment and apoptosis by anoikis. However, the involved signaling mechanisms for Cat.G are not well understood. This study identifies epidermal growth factor receptor (EGFR) transactivation as a mechanism whereby Cat.G induces signaling in cardiomyocytes. Cat.G induced a rapid and transient increase in EGFR tyrosine phosphorylation, and inhibition of EGFR kinase activity, either with AG1478 or by expression of kinase inactive EGFR mutants (EGFR-CD533), markedly attenuated EGFR downstream signaling and myocyte anoikis induced by Cat.G. Consistent with this effect of EGFR, high level expression of wild-type EGFR was sufficient to promote myocyte apoptosis. We also found that matrix metalloproteinase-dependent membrane shedding of heparin-binding EGF was involved in Cat.G signaling and that membrane type 1 matrix metalloproteinase activation may constitute a potential target that entails matrix metalloproteinase activation induced by Cat.G. The paradoxical proapoptotic effect of EGFR appeared to be dependent on protein tyrosine phosphatase SHP2 (Src homology domain 2-containing tyrosine phosphatase 2) activation and focal adhesion kinase downregulation. These results show that Cat.G-induced cardiomyocyte apoptosis involves an increase in EGFR-dependent activation of SHP2 that promotes focal adhesion kinase dephosphorylation and subsequent cardiomyocyte anoikis.     

Myocardial function in general and regional left ventricular ischaemia in dogs at control and high aortic blood pressure.

End-diastolic dilation and reduced systolic shortening are the characteristic dimensional changes during myocardial ischaemia. Elevation of systolic aortic blood pressure by 5.3 kPa (40 mm Hg) normalized shortening and reduced myocardial dilatation when the tissue rendered ischaemic by coronary artery occlusion was less than 20% of the left ventricle. However, when the ischaemic lesion was more extensive, an adverse effect of raising aortic blood pressure was observed.     

Combinations of self‐reported rhinitis,conjunctivitis, and asthma predicts IgE sensitization in more than 25,000 Danes

BackgroundAllergic rhinitis (AR), allergic conjunctivitis (AC), and asthma composing multiple phenotypes and improved understanding of these phenotypes and their respective risk factors are needed.ObjectivesThe objective of this study was to define the prevalence of AR, AC, and asthma and their association with allergen‐specific immunoglobulin E (sIgE) sensitization in a large cohort of blood donors and identify risk factors.MethodsFrom the nationwide population‐based Danish Blood Donor Study, 52,976 participants completed an electronic questionnaire including AR, AC, asthma, allergic predisposition, and childhood residence. Of these, 25,257 were additionally tested for sIgE to inhalation allergens (Phadiatop).ResultsThe prevalence of sIgE sensitization, AR, AC, and asthma was 30%, 19%, 15%, and 9%, respectively. The youngest birth cohorts had the highest prevalence of sIgE sensitization and symptoms of asthma, AR, and AC, and for asthma, they apparently experienced symptoms at an earlier age. The sIgE sensitization was positively associated with male sex. The sIgE seroprevalence was higher in participants with both AR and AC (ARC) than in participants with either AR or AC. Allergic predisposition and sIgE sensitization increased the risk of the diseases, while farm upbringing was associated with reduced prevalence of ARC, however, only in sIgE sensitized participants.ConclusionBirth year, childhood residence, sIgE sensitization, and allergic predisposition were associated with asthma, AR, and AC prevalence. Individuals with self‐reported ARC represent a primarily sIgE‐positive phenotype, while those with either AR or AC represent more diverse phenotypes.     

Effect of AndoSan(™) on expression of adhesion molecules and production of reactive oxygen species in human monocytes and granulocytes in vivo

Abstract Background. Oral intake (60 ml daily) over 12 days in eight healthy volunteers of an immunostimulatory extract based on the medicinal mushroom Agaricus blazei Murill (AbM (AndoSan(?))), reduced the monocyte and granulocyte release of mainly proinflammatory cytokines in vivo, suggesting an anti-inflammatory effect. In this foremost in vivo study, the aim was to examine the effect of such AndoSan(?) consumption on the expression of adhesion molecules CD11b, CD11c and CD62L and production of reactive oxygen species (ROS) in leukocytes. Methodology/Principal findings. As shown by flow cytometry, there was a significant increase of CD62L expression on monocytes and granulocytes from before (day 0) compared with 12 days after daily AndoSan(?) consumption. However, only minor alterations and no clear trend in the expression of CD11b and CD11c were detected. Intracellular ROS (mainly superoxide ion) were significantly reduced in these cells from days 0 to 12. Conclusions/Significance. These results support that oral intake of AndoSan(?) exhibits an anti-inflammatory effect in humans in vivo.     

Treatment of Acute Achilles Tendon Rupture in Scandinavia Does Not Adhere to Evidence-based Guidelines: A Cross-sectional Questionnaire-based Study of 138 Departments

The best treatment of acute Achilles tendon rupture has been discussed for decades. During the past half decade, evidence has increased in favor of nonoperative treatment and dynamic and weightbearing rehabilitation. We hypothesized that the treatment strategies would show great variation and that adherence to evidence-based recommendations would not be as good as desired. The purpose of the present study was to investigate how acute Achilles tendon rupture is treated in Scandinavia. A questionnaire was distributed to all orthopedic departments treating acute Achilles tendon ruptures in Denmark, Sweden, Norway, and Finland. The questionnaire was returned by 138 of 148 departments (response rate 93%). Two-way tables with Fisher’s exact test were used for statistical analysis. In Denmark, Norway, Sweden, and Finland, 19 of 23 (83%), 44 of 48 (92%), 26 of 40 (65%), and 8 of 27 (30%) departments recommended surgical treatment (p < .001). Dynamic rehabilitation was used significantly less often in Denmark (5 of 23 [22%]), Norway (17 of 45 [38%]), and Sweden (11 of 40 [28%]) than in Finland (15 of 26 [58%]; p = .015). A significant difference was found among the countries in the educational level of the performing surgeons (p < .001). Surgical treatment was the treatment of choice in Danish, Norwegian, and Swedish hospitals regardless of the increasing evidence favoring nonoperative treatment. Although increasing evidence has favored dynamic rehabilitation, it has gained limited use across Scandinavia. Weightbearing was used in most hospitals. Surgery was performed by junior surgeons in most hospitals across Scandinavia. Treatment algorithms showed considerable variation and often did not adhere to the clinical evidence.     

Fridge: Focused fine‐tuning of ridge regression for personalized predictions

Statistical prediction methods typically require some form of fine‐tuning of tuning parameter(s), with K‐fold cross‐validation as the canonical procedure. For ridge regression, there exist numerous procedures, but common for all, including cross‐validation, is that one single parameter is chosen for all future predictions. We propose instead to calculate a unique tuning parameter for each individual for which we wish to predict an outcome. This generates an individualized prediction by focusing on the vector of covariates of a specific individual. The focused ridge—fridge—procedure is introduced with a 2‐part contribution: First we define an oracle tuning parameter minimizing the mean squared prediction error of a specific covariate vector, and then we propose to estimate this tuning parameter by using plug‐in estimates of the regression coefficients and error variance parameter. The procedure is extended to logistic ridge regression by using parametric bootstrap. For high‐dimensional data, we propose to use ridge regression with cross‐validation as the plug‐in estimate, and simulations show that fridge gives smaller average prediction error than ridge with cross‐validation for both simulated and real data. We illustrate the new concept for both linear and logistic regression models in 2 applications of personalized medicine: predicting individual risk and treatment response based on gene expression data. The method is implemented in the R package fridge.