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  1. Article ; Online: Thromboinflammation: From Atherosclerosis to COVID-19.

    Wagner, Denisa D / Heger, Lukas A

    Arteriosclerosis, thrombosis, and vascular biology

    2022  Volume 42, Issue 9, Page(s) 1103–1112

    Abstract: The activating interplay of thrombosis and inflammation (thromboinflammation) has been established as a major underlying pathway, driving not only cardiovascular disease but also autoimmune disease and most recently, COVID-19. Throughout the years, ... ...

    Abstract The activating interplay of thrombosis and inflammation (thromboinflammation) has been established as a major underlying pathway, driving not only cardiovascular disease but also autoimmune disease and most recently, COVID-19. Throughout the years, innate immune cells have emerged as important modulators of this process. As the most abundant white blood cell in humans, neutrophils are well-positioned to propel thromboinflammation. This includes their ability to trigger an organized cell death pathway with the release of decondensed chromatin structures called neutrophil extracellular traps. Decorated with histones and cytoplasmic and granular proteins, neutrophil extracellular traps exert cytotoxic, immunogenic, and prothrombotic effects accelerating disease progression. Distinct steps leading to extracellular DNA release (NETosis) require the activities of PAD4 (protein arginine deiminase 4) catalyzing citrullination of histones and are supported by neutrophil inflammasome. By linking the immunologic function of neutrophils with the procoagulant and proinflammatory activities of monocytes and platelets, PAD4 activity holds important implications for understanding the processes that fuel thromboinflammation. We will also discuss mechanisms whereby vascular occlusion in thromboinflammation depends on the interaction of neutrophil extracellular traps with ultra-large VWF (von Willebrand Factor) and speculate on the importance of PAD4 in neutrophil inflammasome assembly and neutrophil extracellular traps in thromboinflammatory diseases including atherosclerosis and COVID-19.
    MeSH term(s) Atherosclerosis/metabolism ; COVID-19 ; Extracellular Traps/metabolism ; Histones/metabolism ; Humans ; Inflammasomes/metabolism ; Inflammation/metabolism ; Neutrophils/metabolism ; Thromboinflammation ; Thrombosis/etiology ; Thrombosis/metabolism ; von Willebrand Factor/metabolism
    Chemical Substances Histones ; Inflammasomes ; von Willebrand Factor
    Language English
    Publishing date 2022-07-08
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1221433-4
    ISSN 1524-4636 ; 1079-5642
    ISSN (online) 1524-4636
    ISSN 1079-5642
    DOI 10.1161/ATVBAHA.122.317162
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1705: Show issues Location:
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  2. Article ; Online: Accuracy of Event Rate and Effect Size Estimation in Major Cardiovascular Trials: A Systematic Review.

    Olivier, Christoph B / Struß, Lasse / Sünnen, Nathalie / Kaier, Klaus / Heger, Lukas A / Westermann, Dirk / Meerpohl, Joerg J / Mahaffey, Kenneth W

    JAMA network open

    2024  Volume 7, Issue 4, Page(s) e248818

    Abstract: Importance: For the design of a randomized clinical trial (RCT), estimation of the expected event rate and effect size of an intervention is needed to calculate the sample size. Overestimation may lead to an underpowered trial.: Objective: To ... ...

    Abstract Importance: For the design of a randomized clinical trial (RCT), estimation of the expected event rate and effect size of an intervention is needed to calculate the sample size. Overestimation may lead to an underpowered trial.
    Objective: To evaluate the accuracy of published estimates of event rate and effect size in contemporary cardiovascular RCTs.
    Evidence review: A systematic search was conducted in MEDLINE for multicenter cardiovascular RCTs associated with MeSH (Medical Subject Headings) terms for cardiovascular diseases published in the New England Journal of Medicine, JAMA, or the Lancet between January 1, 2010, and December 31, 2019. Identified trials underwent abstract review; eligible trials then underwent full review, and those with insufficiently reported data were excluded. Data were extracted from the original publication or the study protocol, and a random-effects model was used for data pooling. This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. The primary outcome was the accuracy of event rate and effect size estimation. Accuracy was determined by comparing the observed event rate in the control group and the effect size with their hypothesized values. Linear regression was used to determine the association between estimation accuracy and trial characteristics.
    Findings: Of the 873 RCTs identified, 374 underwent full review and 30 were subsequently excluded, resulting in 344 trials for analysis. The median observed event rate was 9.0% (IQR, 4.3% to 21.4%), which was significantly lower than the estimated event rate of 11.0% (IQR, 6.0% to 25.0%) with a median deviation of -12.3% (95% CI, -16.4% to -5.6%; P < .001). More than half of the trials (196 [61.1%]) overestimated the expected event rate. Accuracy of event rate estimation was associated with a higher likelihood of refuting the null hypothesis (0.13 [95% CI, 0.01 to 0.25]; P = .03). The median observed effect size in superiority trials was 0.91 (IQR, 0.74 to 0.99), which was significantly lower than the estimated effect size of 0.72 (IQR, 0.60 to 0.80), indicating a median overestimation of 23.1% (95% CI, 17.9% to 28.3%). A total of 216 trials (82.1%) overestimated the effect size.
    Conclusions and relevance: In this systematic review of contemporary cardiovascular RCTs, event rates of the primary end point and effect sizes of an intervention were frequently overestimated. This overestimation may have contributed to the inability to adequately test the trial hypothesis.
    MeSH term(s) Humans ; Cardiovascular Diseases ; Randomized Controlled Trials as Topic/standards ; Randomized Controlled Trials as Topic/statistics & numerical data ; Research Design/standards ; Sample Size
    Language English
    Publishing date 2024-04-01
    Publishing country United States
    Document type Journal Article ; Systematic Review ; Research Support, Non-U.S. Gov't
    ISSN 2574-3805
    ISSN (online) 2574-3805
    DOI 10.1001/jamanetworkopen.2024.8818
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Inhibition of protein arginine deiminase 4 prevents inflammation-mediated heart failure in arthritis.

    Heger, Lukas A / Schommer, Nicolas / Fukui, Shoichi / Van Bruggen, Stijn / Sheehy, Casey E / Chu, Long / Rajagopal, Sridharan / Sivanandhan, Dhanalakshmi / Ewenstein, Bruce / Wagner, Denisa D

    Life science alliance

    2023  Volume 6, Issue 10

    Abstract: Rheumatoid arthritis is a prototypic inflammatory condition with affected patients being at greater risk of incident heart failure (HF). Targeting innate immune cell function in the pathogenesis of HF bears the potential to guide the development of ... ...

    Abstract Rheumatoid arthritis is a prototypic inflammatory condition with affected patients being at greater risk of incident heart failure (HF). Targeting innate immune cell function in the pathogenesis of HF bears the potential to guide the development of future therapies. A collagen-induced arthritis (CIA) model in DBA/1 J mice was used to generate arthritis. Mice with CIA developed concentric hypertrophic myocardial remodeling, left ventricular (LV) diastolic dysfunction, and HF with elevated plasma B-type natriuretic peptide levels but preserved LV ejection fraction. Key features of HF in CIA were increased infiltration of activated neutrophils, deposition of neutrophil extracellular traps in the myocardium, and increased tissue levels of the proinflammatory cytokine IL-1β. Specific inhibition of protein arginine deiminase 4 (PAD4) by an orally available inhibitor (JBI-589), administered after the onset of clinical arthritis, prevented HF with reduced neutrophil infiltration. We identify PAD4-mediated neutrophil activation and recruitment as the key thromboinflammatory pathway driving HF development in arthritis. Targeting PAD4 may be a viable therapeutic approach for the prevention of HF secondary to chronic inflammation.
    MeSH term(s) Mice ; Animals ; Protein-Arginine Deiminase Type 4 ; Mice, Inbred DBA ; Heart Failure/etiology ; Heart Failure/prevention & control ; Inflammation ; Arthritis
    Chemical Substances Protein-Arginine Deiminase Type 4 (EC 3.5.3.15)
    Language English
    Publishing date 2023-07-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2575-1077
    ISSN (online) 2575-1077
    DOI 10.26508/lsa.202302055
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Extracellular Vesicles Are Associated With Outcome in Veno-Arterial Extracorporeal Membrane Oxygenation and Myocardial Infarction.

    Siegel, Patrick M / Bender, Ileana / Chalupsky, Julia / Heger, Lukas A / Rieder, Marina / Trummer, Georg / Wengenmayer, Tobias / Duerschmied, Daniel / Bode, Christoph / Diehl, Philipp

    Frontiers in cardiovascular medicine

    2021  Volume 8, Page(s) 747453

    Abstract: Background: ...

    Abstract Background:
    Language English
    Publishing date 2021-11-04
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2781496-8
    ISSN 2297-055X
    ISSN 2297-055X
    DOI 10.3389/fcvm.2021.747453
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Complement system component dysregulation is a distinctive feature of COVID-19 disease: a prospective and comparative analysis of patients admitted to the emergency department for suspected COVID-19 disease.

    Gauchel, Nadine / Rieder, Marina / Krauel, Krystin / Goller, Isabella / Jeserich, Maren / Salzer, Ulrich / Venhoff, Ana Cecilia / Baldus, Niklas / Pollmeier, Luisa / Wirth, Luisa / Kern, Winfried / Rieg, Siegbert / Busch, Hans-Jörg / Hofmann, Maike / Bode, Christoph / Duerschmied, Daniel / Lother, Achim / Heger, Lukas A

    Journal of thrombosis and thrombolysis

    2021  Volume 53, Issue 4, Page(s) 788–797

    Abstract: The complement system (CS) plays a pivotal role in Coronavirus disease 2019 (COVID-19) pathophysiology. The objective of this study was to provide a comparative, prospective data analysis of CS components in an all-comers cohort and COVID-19 patients. ... ...

    Abstract The complement system (CS) plays a pivotal role in Coronavirus disease 2019 (COVID-19) pathophysiology. The objective of this study was to provide a comparative, prospective data analysis of CS components in an all-comers cohort and COVID-19 patients. Patients with suspected COVID-19 infection admitted to the Emergency department were grouped for definite diagnosis of COVID-19 and no COVID-19 accordingly. Clinical presentation, routine laboratory and von Willebrand factor (vWF) antigen as well as CS components 3, 4 and activated 5 (C5a) were assessed. Also, total complement activity via the classical pathway (CH50) was determined. Levels of calprotectin in serum were measured using an automated quantitative lateral flow assay. We included 80 patients in this prospective trial. Of those 19 (23.7%) were tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with COVID-19 had higher levels of CS components 5a and 4 (54.79 [24.14-88.79] ng/ml vs. 35 [23.15-46.1] ng/ml; p = 0.0433 and 0.3772 [± 0.1056] g/L vs. 0.286 [0.2375-0.3748] g/L; p = 0.0168). COVID-19 patients had significantly higher levels of vWF antigen when compared to the control group (288.3 [± 80.26] % vs. 212 [151-320] %; p = 0.0469). There was a significant correlation between CS C3 and 5a with vWF antigen (r
    MeSH term(s) COVID-19/diagnosis ; Emergency Service, Hospital ; Humans ; Immunologic Factors ; Leukocyte L1 Antigen Complex ; Prospective Studies ; SARS-CoV-2 ; von Willebrand Factor/analysis
    Chemical Substances Immunologic Factors ; Leukocyte L1 Antigen Complex ; von Willebrand Factor
    Language English
    Publishing date 2021-12-14
    Publishing country Netherlands
    Document type Clinical Trial ; Journal Article
    ZDB-ID 1230645-9
    ISSN 1573-742X ; 0929-5305
    ISSN (online) 1573-742X
    ISSN 0929-5305
    DOI 10.1007/s11239-021-02617-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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