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3.
Cardiovasc Res ; 2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32282914

RESUMO

Endothelial cells (EC) are sentinels of cardiovascular health. Their function is reduced by the presence of cardiovascular risk factors, and is regained once pathological stimuli are removed. In this European Society for Cardiology Position Paper we describe endothelial dysfunction as a spectrum of phenotypic states and advocate further studies to determine the role of EC subtypes in cardiovascular disease. We conclude that there is no single ideal method for measurement of endothelial function. Techniques to measure coronary epicardial and microvascular function are well established but they are invasive, time-consuming and expensive. Flow-mediated dilatation (FMD) of the brachial arteries provides a non-invasive alternative but is technically challenging and requires extensive training and standardization. We therefore propose that a consensus methodology for FMD is universally adopted to minimize technical variation between studies, and that reference FMD values are established for different populations of healthy individuals and patient groups. Newer techniques to measure endothelial function that are relatively easy to perform, such as finger plethysmography and the retinal flicker test, have the potential for increased clinical use provided a consensus is achieved on the measurement protocol used. We recommend further clinical studies to establish reference values for these techniques and to assess their ability to improve cardiovascular risk stratification. We advocate future studies to determine whether integration of endothelial function measurements with patient-specific epigenetic data and other biomarkers can enhance the stratification of patients for differential diagnosis, disease progression and responses to therapy.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32290712

RESUMO

There are a number of physical restrictions that develop in the course of amyotrophic lateral sclerosis (ALS). While loss of speech and motor control may be partially compensated by the support of assistive devices, swallowing difficulty and respiratory insufficiency require medical interventions (percutaneous endoscopic gastrostomy, noninvasive, and invasive ventilation). Based on the data collected within the NEEDSinALS study, we found major differences in personal satisfaction with the financing, healthcare provision, medical infrastructure, and regulations of German and Polish ALS patients, despite minor differences in economic burden caused by the disease. In order to explain this phenomenon, we thoroughly reviewed the legal basis, structure and organization of the healthcare systems in Germany and Poland to determine the range of obstacles in the everyday lives of patients and their caregivers that are attempting to attain an assistive device or care after the start of medical interventions.

5.
J Am Coll Cardiol ; 75(15): 1788-1800, 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32299591

RESUMO

BACKGROUND: miR-21 is a central regulator of cardiac fibrosis, and its inhibition in small-animal models has been shown to be an effective antifibrotic strategy in various organs, including the heart. Effective delivery of therapeutic antisense micro-ribonucleic acid (antimiR) molecules to the myocardium in larger organisms is challenging, though, and remains to be established for models of chronic heart failure. OBJECTIVES: The aims of this study were to test the applicability and therapeutic efficacy of local, catheter-based delivery of antimiR-21 in a pig model of heart failure and determine its effect on the cardiac transcriptomic signature and cellular composition. METHODS: Pigs underwent transient percutaneous occlusion of the left coronary artery and were followed up for 33 days. AntimiR-21 (10 mg) was applied by intracoronary infusion at days 5 and 19 after the injury. Cardiac function was assessed in vivo, followed by histological analyses and deep ribonucleic acid sequencing (RNA-seq) of the myocardium and genetic deconvolution analysis. RESULTS: AntimiR-21 effectively suppressed the remodeling-associated increase of miR-21. At 33 days after ischemia/reperfusion injury, LNA-21-treated hearts exhibited reduced cardiac fibrosis and hypertrophy and improved cardiac function. Deep RNA-seq revealed a significant derepression of the miR-21 targetome in antimiR-21-treated myocardium and a suppression of the inflammatory response and mitogen-activated protein kinase signaling. A genetic deconvolution approach built on deep RNA-seq and single-cell RNA-seq data identified reductions in macrophage and fibroblast numbers as the key cell types affected by antimiR-21 treatment. CONCLUSIONS: This study provides the first evidence for the feasibility and therapeutic efficacy of miR-21 inhibition in a large animal model of heart failure.

6.
Eur Heart J ; 41(12): 1227-1230, 2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32198920
7.
Cells ; 9(2)2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32075106

RESUMO

The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.

9.
Anesth Analg ; 130(5): 1389-1395, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32058448

RESUMO

BACKGROUND: Cardiothoracic surgery is associated with major blood loss and allogeneic transfusion of red blood cell concentrates. To minimize allogeneic red blood cell (RBC) transfusion, intraoperative cell salvage has been effectively used for years. The objective of this study was to evaluate the impact of cell salvage on blood coagulation factors. METHODS: We enrolled 30 patients scheduled for cardiac surgery in a prospective single-center observational cohort study at an academic hospital. Blood samples from the cell salvage system were obtained from both the reservoir and the processed red blood cell concentrate. Coagulation factors, fibrinogen, antithrombin and von Willebrand activity, and antigen were assessed before and after cell salvage. Statistical analysis was performed using Wilcoxon matched-pairs signed rank test. RESULTS: Our results revealed a significant decrease of fibrinogen (P < .001), coagulation factors II (P = .004), factors VII, X, and XIII (P < .001), and all other measured coagulation factor concentrations/activities in the processed red blood cell concentrate, when compared to the concentrations/activities of the reservoir. CONCLUSIONS: The results of the present study revealed a significant reduction of coagulation factor concentrations/activities by the washing process. Therefore, physicians need to consider adequate management of coagulation in patients with major blood loss and the need of large volumes of RBC transfusion.

10.
EMBO Rep ; 21(4): e47852, 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32080959

RESUMO

Chemokines and galectins are simultaneously upregulated and mediate leukocyte recruitment during inflammation. Until now, these effector molecules have been considered to function independently. Here, we tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability to bind galectin-1 and galectin-3, we identified several interacting pairs, such as CXCL12 and galectin-3. Based on NMR and MD studies of the CXCL12/galectin-3 heterodimer, we identified contact sites between CXCL12 ß-strand 1 and Gal-3 F-face residues. Mutagenesis of galectin-3 residues involved in heterodimer formation resulted in reduced binding to CXCL12, enabling testing of functional activity comparatively. Galectin-3, but not its mutants, inhibited CXCL12-induced chemotaxis of leukocytes and their recruitment into the mouse peritoneum. Moreover, galectin-3 attenuated CXCL12-stimulated signaling via its receptor CXCR4 in a ternary complex with the chemokine and receptor, consistent with our structural model. This first report of heterodimerization between chemokines and galectins reveals a new type of interaction between inflammatory mediators that can underlie a novel immunoregulatory mechanism in inflammation. Thus, further exploration of the chemokine/galectin interactome is warranted.

11.
Platelets ; : 1-7, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32046562

RESUMO

Reticulated Platelets (RPs) are large, RNA-rich, prothrombotic and hyperactive platelets known to be elevated in high-risk populations such as diabetics and patients with acute coronary syndrome. High levels of RPs correlate with mortality and adverse cardiovascular events in patients with coronary artery disease as well as with an insufficient antiplatelet response to thienopyridines and aspirin after percutaneous coronary interventions, making them an appealing drug target. However, processing of platelets is challenging and no specific marker for RPs exists. Until now, the gold standard laboratory-based method to study them is based on the flow cytometric measurement of their cell size and their RNA-content with the fluorescent dye Thiazole Orange (TO). Nevertheless, standardized protocols for staining and processing of RPs are missing and the existing techniques were not applied for cell sorting. We provide here a structured and reproducible method to detect, isolate and collect RPs from peripheral blood by RNA-specific staining with TO implementing several platelet inhibitors as well as magnetic labeling allowing sufficient cell recovery and deep biological investigation of these platelets.

12.
Nat Immunol ; 21(2): 135-144, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31932813

RESUMO

The antimicrobial functions of neutrophils are facilitated by a defensive armamentarium of proteins stored in granules, and by the formation of neutrophil extracellular traps (NETs). However, the toxic nature of these structures poses a threat to highly vascularized tissues, such as the lungs. Here, we identified a cell-intrinsic program that modified the neutrophil proteome in the circulation and caused the progressive loss of granule content and reduction of the NET-forming capacity. This program was driven by the receptor CXCR2 and by regulators of circadian cycles. As a consequence, lungs were protected from inflammatory injury at times of day or in mouse mutants in which granule content was low. Changes in the proteome, granule content and NET formation also occurred in human neutrophils, and correlated with the incidence and severity of respiratory distress in pneumonia patients. Our findings unveil a 'disarming' strategy of neutrophils that depletes protein stores to reduce the magnitude of inflammation.


Assuntos
Ritmo Circadiano/imunologia , Inflamação/metabolismo , Neutrófilos/metabolismo , Pneumonia/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Animais , Degranulação Celular/imunologia , Grânulos Citoplasmáticos/imunologia , Grânulos Citoplasmáticos/metabolismo , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Humanos , Inflamação/imunologia , Camundongos , Neutrófilos/imunologia , Pneumonia/complicações , Pneumonia/imunologia , Proteoma/imunologia , Proteoma/metabolismo , Síndrome do Desconforto Respiratório do Adulto/imunologia
14.
Thromb Haemost ; 120(1): 184-190, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31931536
15.
Artigo em Inglês | MEDLINE | ID: mdl-31925451

RESUMO

OBJECTIVE: The aim of this prospective randomised trial was to assess the impact of the team-based learning approach on basic musculoskeletal ultrasound skills in comparison to both peer-assisted and conventional teaching and to examine the influence of gender and learning style on learning outcomes. METHODS: In this prospective randomised trial, we randomly assigned 88 students to 3 groups: team-based learning (n = 19), peer-assisted learning (n = 36) and conventional teaching (n = 33). Pre-existing knowledge was assessed using a multiple-choice (MC) exam. Student performance after completing the course was measured using an Objective Structured Clinical Examination (OSCE) and a second MC exam. Students were asked to complete Kolb's Learning Style Inventory and to evaluate the course. RESULTS: There was a significant gain in theoretical knowledge for all students (p < 0.001). The team-based learning groups' performance proved to be significantly superior on the OSCE (p = 0.001). As gender had no significant effect on practical or theoretical performance, learning style was linked to differences in the practical outcome. An evaluation showed overall satisfaction with the course and with the respective teaching methods. CONCLUSION: Team-based learning proved to be superior to peer-assisted and conventional teaching of musculoskeletal ultrasound skills.

16.
J Pharm Sci ; 109(1): 161-168, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31408634

RESUMO

Antibody conjugates, in particular antibody-drug conjugates (ADCs), are a fast-growing area in research and in the pharmaceutical industry. The covalent attachment of an antibody to a chemical moiety can be an effective measure for drug targeting or can also positively impact pharmacokinetics of small molecular compounds by serum half-life extension. Stability, physicochemical properties, and degradation pathways of biotherapeutics or small molecule therapeutics are often not totally known and understood. However, ADCs represent a hybrid of small molecular and macromolecular components, and their properties are still not fully understood and described. This review discusses the alteration of the physicochemical properties of antibodies upon conjugation of chemical moieties to its surface and the resulting impact on ADC stability.

17.
Atherosclerosis ; 292: 23-30, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31733453

RESUMO

BACKGROUND AND AIMS: IKKα is an important regulator of gene expression. As IKKα kinase inactivity in bone marrow-derived cells does not affect atherosclerosis, we here investigate the impact of a whole body-IKKα kinase inactivity on atherosclerosis. METHODS: Apolipoprotein E (Apoe)-deficient mice homozygous for an activation-resistant Ikkα-mutant (IkkαAA/AAApoe-/-) and Ikkα+/+Apoe-/- controls received a Western-type diet. Atherosclerotic lesion size and cellular content were analyzed using histology and immunofluorescence. Vascular protein expression and IKKα kinase activity were quantified by Luminex multiplex immuno-assay and ELISA. RESULTS: A vascular site-specific IKKα expression and kinase activation profile was revealed, with higher total IKKα protein levels in aortic root but increased IKKα phosphorylation, representing activated IKKα, in the aortic arch. This was associated with a vascular site-specific effect of IkkαAA/AA knock-in on atherosclerosis: in the aortic root, IkkαAA/AA knock-in decreased lesion size by 22.0 ±â€¯7.7% (p < 0.01), reduced absolute lesional smooth muscle cell numbers and lowered pro-atherogenic MMP2. In contrast, IkkαAA/AA knock-in increased lesion size in the aortic arch by 43.7 ±â€¯20.1% (p < 0.001), increased the abundance of lesional smooth muscle cells in brachiocephalic artery as main arch side branch and elevated MMP2. A similar profile was observed for MMP3. No effects were observed on necrotic core or collagen deposition in atherosclerotic lesions, nor on absolute lesional macrophage numbers. CONCLUSIONS: A non-activatable IKKα kinase differentially affects atherosclerosis in aortic root vs. aortic arch/brachiocephalic artery, associated with a differential vascular IKKα expression and kinase activation profile as well as with a vascular site-dependent impact on lesional smooth muscle cell accumulation and protein expression profiles.

20.
Int J Cardiol ; 299: 249-253, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31409515

RESUMO

BACKGROUND: ATP-binding cassette A1 (ABCA1) and G1 (ABCG1) mediate cholesterol efflux from lipid-laden macrophages, thus promoting anti-atherosclerotic outcomes. The mechanism(s) linking treatment with statins and ABCA1/ABCG1 in human atherosclerosis are not fully understood and require further investigation. Therefore, we studied whether short-term treatment with low- or high-dose rosuvastatin may affect ABCA1 and ABCG1 expression in human atherosclerotic plaques. METHODS: Seventy patients with severe stenosis of the internal carotid artery were randomized to receive low (10 mg/day) or high (40 mg/day) dose rosuvastatin for 12 weeks before elective endarterectomy. As controls, we analyzed a reference group of 10 plaques from subjects with hypercholesterolemia but not receiving statin treatment and an additional set of 11 plaques collected from normocholesterolemic patients. On atherosclerotic plaques, ABCA1 and ABCG1 expression was evaluated at RNA level by qPCR and at protein level by immunoblotting and immunohistochemistry. RESULTS: Both rosuvastatin doses were associated with lower plaque ABCA1 mRNA levels and with a trend toward reduction for ABCG1. However, ABCA1 protein was paradoxically higher in patients treated with high-dose rosuvastatin and was associated with lower levels of miR-33b-5p, a microRNA known as a regulator of ABCA1. Multivariate analyses showed that the effect is cholesterol-independent. Finally, no effects were found for ABCG1 protein. CONCLUSIONS: High-dose rosuvastatin increases macrophage ABCA1 protein levels in human atherosclerotic plaque despite mRNA reduction in a mechanism unrelated to plasma cholesterol reduction and potentially involving miR-33b-5p. This pathway may reflect an additional feature contributing to the anti-atherosclerotic effect for high-dose rosuvastatin. TRIAL REGISTRATION: ISRCTN16590640.

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