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  1. Article ; Online: Myeloid Extracellular Vesicles: New Players in Indirect Lung Injury.

    Mahida, Rahul Y / Matthay, Michael A

    American journal of respiratory cell and molecular biology

    2022  Volume 68, Issue 2, Page(s) 121–123

    MeSH term(s) Humans ; Acute Lung Injury ; Respiratory Distress Syndrome ; Extracellular Vesicles ; Myeloid Cells
    Language English
    Publishing date 2022-10-06
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 1025960-0
    ISSN 1535-4989 ; 1044-1549
    ISSN (online) 1535-4989
    ISSN 1044-1549
    DOI 10.1165/rcmb.2022-0380ED
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Extracellular Vesicles: A New Frontier for Research in Acute Respiratory Distress Syndrome.

    Mahida, Rahul Y / Matsumoto, Shotaro / Matthay, Michael A

    American journal of respiratory cell and molecular biology

    2020  Volume 63, Issue 1, Page(s) 15–24

    Abstract: Recent research on extracellular vesicles (EVs) has provided new insights into pathogenesis and potential therapeutic options for acute respiratory distress syndrome (ARDS). EVs are membrane-bound anuclear structures that carry important intercellular ... ...

    Abstract Recent research on extracellular vesicles (EVs) has provided new insights into pathogenesis and potential therapeutic options for acute respiratory distress syndrome (ARDS). EVs are membrane-bound anuclear structures that carry important intercellular communication mechanisms, allowing targeted transfer of diverse biologic cargo, including protein, mRNA, and microRNA, among several different cell types. In this review, we discuss the important role EVs play in both inducing and attenuating inflammatory lung injury in ARDS as well as in sepsis, the most important clinical cause of ARDS. We discuss the translational challenges that need to be overcome before EVs can also be used as prognostic biomarkers in patients with ARDS and sepsis. We also consider how EVs may provide a platform for novel therapeutics in ARDS.
    MeSH term(s) Animals ; Biomarkers/metabolism ; Cell Communication/physiology ; Extracellular Vesicles/metabolism ; Humans ; MicroRNAs/metabolism ; RNA, Messenger/metabolism ; Respiratory Distress Syndrome/metabolism
    Chemical Substances Biomarkers ; MicroRNAs ; RNA, Messenger
    Language English
    Publishing date 2020-02-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1025960-0
    ISSN 1535-4989 ; 1044-1549
    ISSN (online) 1535-4989
    ISSN 1044-1549
    DOI 10.1165/rcmb.2019-0447TR
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Raised FGF23 Correlates to Increased Mortality in Critical Illness, Independent of Vitamin D

    Thein, Onn Shaun / Ali, Naeman Akbar / Mahida, Rahul Y. / Dancer, Rachel C. A. / Ostermann, Marlies / Amrein, Karin / Martucci, Gennaro / Scott, Aaron / Thickett, David R. / Parekh, Dhruv

    Biology (Basel). 2023 Feb. 14, v. 12, no. 2

    2023  

    Abstract: Background: Fibroblast Growth Factor (FGF23) is an endocrine hormone classically associated with the homeostasis of vitamin D, phosphate, and calcium. Elevated serum FGF23 is a known independent risk factor for mortality in chronic kidney disease (CKD) ... ...

    Abstract Background: Fibroblast Growth Factor (FGF23) is an endocrine hormone classically associated with the homeostasis of vitamin D, phosphate, and calcium. Elevated serum FGF23 is a known independent risk factor for mortality in chronic kidney disease (CKD) patients. We aimed to determine if there was a similar relationship between FGF23 levels and mortality in critically ill patients. Methods: Plasma FGF23 levels were measured by ELISA in two separate cohorts of patients receiving vitamin D supplementation: critical illness patients (VITdAL-ICU trial, n = 475) and elective oesophagectomy patients (VINDALOO trial, n = 76). Mortality data were recorded at 30 and 180 days or at two years, respectively. FGF23 levels in a healthy control cohort were also measured (n = 27). Results: Elevated FGF23 (quartile 4 vs. quartiles 1–3) was associated with increased short-term (30 and 180 day) mortality in critical illness patients (p < 0.001) and long-term (two-year) mortality in oesophagectomy patients (p = 0.0149). Patients who died had significantly higher FGF23 levels than those who survived: In the critical illness cohort, those who died had 1194.6 pg/mL (range 0–14,000), while those who survived had 120.4 pg/mL (range = 15–14,000) (p = 0.0462). In the oesophagectomy cohort, those who died had 1304 pg/mL (range = 154–77,800), while those who survived had 644 pg/mL (range = 179–54,894) (p < 0.001). This was found to be independent of vitamin D or CKD status (critical illness p = 0.3507; oesophagectomy p = 0.3800). FGF23 levels in healthy controls were similar to those seen in oesophagectomy patients (p = 0.4802). Conclusions: Elevated baseline serum FGF23 is correlated with increased mortality in both the post-oesophagectomy cohort and the cohort of patients with critical illness requiring intensive care admission. This was independent of vitamin D status, supplementation, or CKD status, which suggests the presence of vitamin D-independent mechanisms of FGF23 action during the acute and convalescent stages of critical illness, warranting further investigation.
    Keywords blood serum ; calcium ; fibroblast growth factors ; homeostasis ; kidney diseases ; mortality ; phosphates ; risk factors ; vitamin D
    Language English
    Dates of publication 2023-0214
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article ; Online
    ZDB-ID 2661517-4
    ISSN 2079-7737
    ISSN 2079-7737
    DOI 10.3390/biology12020309
    Database NAL-Catalogue (AGRICOLA)

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  4. Article ; Online: CD14-positive extracellular vesicles in bronchoalveolar lavage fluid as a new biomarker of acute respiratory distress syndrome.

    Mahida, Rahul Y / Price, Joshua / Lugg, Sebastian T / Li, Hui / Parekh, Dhruv / Scott, Aaron / Harrison, Paul / Matthay, Michael A / Thickett, David R

    American journal of physiology. Lung cellular and molecular physiology

    2022  Volume 322, Issue 4, Page(s) L617–L624

    Abstract: Recent studies have indicated that extracellular vesicles (EVs) may play a role in the pathogenesis of acute respiratory distress syndrome (ARDS). EVs have been identified as potential biomarkers of disease severity and prognosis in other pulmonary ... ...

    Abstract Recent studies have indicated that extracellular vesicles (EVs) may play a role in the pathogenesis of acute respiratory distress syndrome (ARDS). EVs have been identified as potential biomarkers of disease severity and prognosis in other pulmonary diseases. We sought to characterize the EV phenotype within bronchoalveolar lavage (BAL) fluid of patients with ARDS, and to determine whether BAL EV could be used as a potential biomarker in ARDS. BAL was collected from patients with sepsis with and without ARDS, and from esophagectomy patients postoperatively (of whom a subset later developed ARDS during hospital admission). BAL EVs were characterized with regard to size, number, and cell of origin. Patients with sepsis-related ARDS had significantly higher numbers of CD14
    MeSH term(s) Biomarkers ; Bronchoalveolar Lavage Fluid ; Extracellular Vesicles ; Humans ; Respiratory Distress Syndrome ; Sepsis/diagnosis
    Chemical Substances Biomarkers
    Language English
    Publishing date 2022-03-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1013184-x
    ISSN 1522-1504 ; 1040-0605
    ISSN (online) 1522-1504
    ISSN 1040-0605
    DOI 10.1152/ajplung.00052.2022
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Dexamethasone impairs the expression of antimicrobial mediators in lipopolysaccharide-activated primary macrophages by inhibiting both expression and function of interferon β.

    O'Neil, John D / Bolimowska, Oliwia O / Clayton, Sally A / Tang, Tina / Daley, Kalbinder K / Lara-Reyna, Samuel / Warner, Jordan / Martin, Claire S / Mahida, Rahul Y / Hardy, Rowan S / Arthur, J Simon C / Clark, Andrew R

    Frontiers in immunology

    2023  Volume 14, Page(s) 1190261

    Abstract: Glucocorticoids potently inhibit expression of many inflammatory mediators, and have been widely used to treat both acute and chronic inflammatory diseases for more than seventy years. However, they can have several unwanted effects, amongst which ... ...

    Abstract Glucocorticoids potently inhibit expression of many inflammatory mediators, and have been widely used to treat both acute and chronic inflammatory diseases for more than seventy years. However, they can have several unwanted effects, amongst which immunosuppression is one of the most common. Here we used microarrays and proteomic approaches to characterise the effect of dexamethasone (a synthetic glucocorticoid) on the responses of primary mouse macrophages to a potent pro-inflammatory agonist, lipopolysaccharide (LPS). Gene ontology analysis revealed that dexamethasone strongly impaired the lipopolysaccharide-induced antimicrobial response, which is thought to be driven by an autocrine feedback loop involving the type I interferon IFNβ. Indeed, dexamethasone strongly and dose-dependently inhibited the expression of IFNβ by LPS-activated macrophages. Unbiased proteomic data also revealed an inhibitory effect of dexamethasone on the IFNβ-dependent program of gene expression, with strong down-regulation of several interferon-induced antimicrobial factors. Surprisingly, dexamethasone also inhibited the expression of several antimicrobial genes in response to direct stimulation of macrophages with IFNβ. We tested a number of hypotheses based on previous publications, but found that no single mechanism could account for more than a small fraction of the broad suppressive impact of dexamethasone on macrophage type I interferon signaling, underlining the complexity of this pathway. Preliminary experiments indicated that dexamethasone exerted similar inhibitory effects on primary human monocyte-derived or alveolar macrophages.
    MeSH term(s) Mice ; Animals ; Humans ; Lipopolysaccharides/pharmacology ; Interferon-beta/pharmacology ; Proteomics ; Macrophages ; Glucocorticoids/pharmacology ; Dexamethasone/pharmacology ; Anti-Infective Agents/pharmacology
    Chemical Substances Lipopolysaccharides ; Interferon-beta (77238-31-4) ; Glucocorticoids ; Dexamethasone (7S5I7G3JQL) ; Anti-Infective Agents
    Language English
    Publishing date 2023-10-24
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1190261
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  6. Article: Raised FGF23 Correlates to Increased Mortality in Critical Illness, Independent of Vitamin D.

    Thein, Onn Shaun / Ali, Naeman Akbar / Mahida, Rahul Y / Dancer, Rachel C A / Ostermann, Marlies / Amrein, Karin / Martucci, Gennaro / Scott, Aaron / Thickett, David R / Parekh, Dhruv

    Biology

    2023  Volume 12, Issue 2

    Abstract: Background: Fibroblast Growth Factor (FGF23) is an endocrine hormone classically associated with the homeostasis of vitamin D, phosphate, and calcium. Elevated serum FGF23 is a known independent risk factor for mortality in chronic kidney disease (CKD) ... ...

    Abstract Background: Fibroblast Growth Factor (FGF23) is an endocrine hormone classically associated with the homeostasis of vitamin D, phosphate, and calcium. Elevated serum FGF23 is a known independent risk factor for mortality in chronic kidney disease (CKD) patients. We aimed to determine if there was a similar relationship between FGF23 levels and mortality in critically ill patients.
    Methods: Plasma FGF23 levels were measured by ELISA in two separate cohorts of patients receiving vitamin D supplementation: critical illness patients (VITdAL-ICU trial,
    Results: Elevated FGF23 (quartile 4 vs. quartiles 1-3) was associated with increased short-term (30 and 180 day) mortality in critical illness patients (
    Conclusions: Elevated baseline serum FGF23 is correlated with increased mortality in both the post-oesophagectomy cohort and the cohort of patients with critical illness requiring intensive care admission. This was independent of vitamin D status, supplementation, or CKD status, which suggests the presence of vitamin D-independent mechanisms of FGF23 action during the acute and convalescent stages of critical illness, warranting further investigation.
    Language English
    Publishing date 2023-02-14
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2661517-4
    ISSN 2079-7737
    ISSN 2079-7737
    DOI 10.3390/biology12020309
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Impaired alveolar macrophage 11β-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDS.

    Mahida, Rahul Y / Lax, Siân / Bassford, Christopher R / Scott, Aaron / Parekh, Dhruv / Hardy, Rowan S / Naidu, Babu / Matthay, Michael A / Stewart, Paul M / Cooper, Mark C / Perkins, Gavin D / Thickett, David R

    Frontiers in immunology

    2023  Volume 14, Page(s) 1159831

    Abstract: Background: Acute Respiratory Distress Syndrome (ARDS) is a devastating pulmonary inflammatory disorder, commonly precipitated by sepsis. Glucocorticoids are immunomodulatory steroids that can suppress inflammation. Their anti-inflammatory properties ... ...

    Abstract Background: Acute Respiratory Distress Syndrome (ARDS) is a devastating pulmonary inflammatory disorder, commonly precipitated by sepsis. Glucocorticoids are immunomodulatory steroids that can suppress inflammation. Their anti-inflammatory properties within tissues are influenced by their pre-receptor metabolism and amplification from inactive precursors by 11β-hydroxysteroid dehydrogenase type-1 (HSD-1). We hypothesised that in sepsis-related ARDS, alveolar macrophage (AM) HSD-1 activity and glucocorticoid activation are impaired, and associated with greater inflammatory injury and worse outcomes.
    Methods: We analysed broncho-alveolar lavage (BAL) and circulating glucocorticoid levels, AM HSD-1 reductase activity and Receptor for Advanced Glycation End-products (RAGE) levels in two cohorts of critically ill sepsis patients, with and without ARDS. AM HSD-1 reductase activity was also measured in lobectomy patients. We assessed inflammatory injury parameters in models of lung injury and sepsis in HSD-1 knockout (KO) and wild type (WT) mice.
    Results: No difference in serum and BAL cortisol: cortisone ratios are shown between sepsis patients with and without ARDS. Across all sepsis patients, there is no association between BAL cortisol: cortisone ratio and 30-day mortality. However, AM HSD-1 reductase activity is impaired in patients with sepsis-related ARDS, compared to sepsis patients without ARDS and lobectomy patients (0.075 v 0.882 v 0.967 pM/hr/10
    Conclusions: AM HSD-1 reductase activity does not shape total BAL and serum cortisol: cortisone ratios, however impaired HSD-1 autocrine signalling renders AMs insensitive to the anti-inflammatory effects of local glucocorticoids. This contributes to the decreased efferocytosis, increased BAL RAGE concentrations and mortality seen in sepsis-related ARDS. Upregulation of alveolar HSD-1 activity could restore AM function and improve clinical outcomes in these patients.
    MeSH term(s) Animals ; Mice ; 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics ; 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism ; Glucocorticoids ; Hydrocortisone ; Cortisone ; Macrophages, Alveolar/metabolism ; Receptor for Advanced Glycation End Products ; Pneumonia ; Hydroxysteroid Dehydrogenases/metabolism ; Anti-Inflammatory Agents ; Respiratory Distress Syndrome ; Sepsis/complications
    Chemical Substances 11-beta-Hydroxysteroid Dehydrogenase Type 1 (EC 1.1.1.146) ; Glucocorticoids ; Hydrocortisone (WI4X0X7BPJ) ; Cortisone (V27W9254FZ) ; Receptor for Advanced Glycation End Products ; Hydroxysteroid Dehydrogenases (EC 1.1.-) ; Anti-Inflammatory Agents
    Language English
    Publishing date 2023-04-27
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1159831
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Specific Inhibition of Orai1-mediated Calcium Signalling Resolves Inflammation and Clears Bacteria in an Acute Respiratory Distress Syndrome Model.

    Ahmad, Saira / Wrennall, Joe A / Goriounova, Alexandra S / Sekhri, Malika / Iskarpatyoti, Jason A / Ghosh, Arunava / Abdelwahab, Sabri H / Voeller, Alexis / Rai, Mani / Mahida, Rahul Y / Krajewski, Krzysztof / Ignar, Diane M / Greenbaum, Alon / Moran, Timothy P / Tilley, Stephen L / Thickett, David R / Sassano, M Flori / Tarran, Robert

    American journal of respiratory and critical care medicine

    2023  Volume 209, Issue 6, Page(s) 703–715

    Abstract: Rationale: ...

    Abstract Rationale:
    MeSH term(s) Humans ; Mice ; Animals ; Calcium Channels/metabolism ; Calcium Channels/pharmacology ; Calcium/metabolism ; HEK293 Cells ; Methicillin-Resistant Staphylococcus aureus/metabolism ; Calcium Signaling ; Inflammation/drug therapy ; Lung/metabolism ; Respiratory Distress Syndrome/drug therapy ; Pneumonia, Bacterial/drug therapy ; ORAI1 Protein/metabolism ; ORAI1 Protein/pharmacology
    Chemical Substances Calcium Channels ; Calcium (SY7Q814VUP) ; ORAI1 Protein ; Orai1 protein, mouse
    Language English
    Publishing date 2023-11-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1180953-x
    ISSN 1535-4970 ; 0003-0805 ; 1073-449X
    ISSN (online) 1535-4970
    ISSN 0003-0805 ; 1073-449X
    DOI 10.1164/rccm.202308-1393OC
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Assessment of Alveolar Macrophage Dysfunction Using an

    Mahida, Rahul Y / Scott, Aaron / Parekh, Dhruv / Lugg, Sebastian T / Belchamber, Kylie B R / Hardy, Rowan S / Matthay, Michael A / Naidu, Babu / Thickett, David R

    Frontiers in medicine

    2021  Volume 8, Page(s) 737859

    Abstract: Background: ...

    Abstract Background:
    Language English
    Publishing date 2021-09-29
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2775999-4
    ISSN 2296-858X
    ISSN 2296-858X
    DOI 10.3389/fmed.2021.737859
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  10. Article ; Online: Acute respiratory distress syndrome is associated with impaired alveolar macrophage efferocytosis.

    Mahida, Rahul Y / Scott, Aaron / Parekh, Dhruv / Lugg, Sebastian T / Hardy, Rowan S / Lavery, Gareth G / Matthay, Michael A / Naidu, Babu / Perkins, Gavin D / Thickett, David R

    The European respiratory journal

    2021  Volume 58, Issue 3

    MeSH term(s) Humans ; Macrophages, Alveolar ; Phagocytosis ; Respiratory Distress Syndrome
    Language English
    Publishing date 2021-09-09
    Publishing country England
    Document type Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 639359-7
    ISSN 1399-3003 ; 0903-1936
    ISSN (online) 1399-3003
    ISSN 0903-1936
    DOI 10.1183/13993003.00829-2021
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