ABSTRACT
OBJECTIVE: Specific protocols for anticoagulation for children on ECMO vary across institutions, with most using a continuous infusion of unfractionated heparin. The goal of this study is to aid clinician's decision on the best measure of heparin anticoagulation test; which would be the one that correlates well with heparin activity and helps in predicting hemorrhagic and thrombotic complications. DATA SOURCES: A comprehensive search of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus was conducted from each database's inception to 07/13/2018. STUDY SELECTION: Studies evaluating children (<18â¯years) treated with ECMO and evaluating ACT, aPTT, TEG and Anti-Xa in any language were included. DATA EXTRACTION: Two reviewers selected and appraised studies independently, and abstracted data. RESULTS: We included 19 studies (759 patients, mean age 19.8â¯months). Meta-analysis showed strong correlation between heparin dosing and anti-Xa. Additionally, there was not a strong correlation between laboratory tests and complications (hemorrhagic and thrombosis), or mortality. CONCLUSION: Based on current evidence, Anti-Xa is the only laboratory test that shows strong correlation with heparin infusion dose and seems like the most suitable test for monitoring of anticoagulation with heparin in children on ECMO.
Subject(s)
Anticoagulants/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Adolescent , Anticoagulants/pharmacology , Child , Child, Preschool , Extracorporeal Membrane Oxygenation , Female , Heparin, Low-Molecular-Weight/pharmacology , Humans , Infant , MaleABSTRACT
The C. elegans genes ced-2, ced-5, and ced-10, and their mammalian homologs crkII, dock180, and rac1, mediate cytoskeletal rearrangements during phagocytosis of apoptotic cells and cell motility. Here, we describe an additional member of this signaling pathway, ced-12, and its mammalian homologs, elmo1 and elmo2. In C. elegans, CED-12 is required for engulfment of dying cells and for cell migrations. In mammalian cells, ELMO1 functionally cooperates with CrkII and Dock180 to promote phagocytosis and cell shape changes. CED-12/ELMO-1 binds directly to CED-5/Dock180; this evolutionarily conserved complex stimulates a Rac-GEF, leading to Rac1 activation and cytoskeletal rearrangements. These studies identify CED-12/ELMO as an upstream regulator of Rac1 that affects engulfment and cell migration from C. elegans to mammals.
Subject(s)
Adaptor Proteins, Signal Transducing , Caenorhabditis elegans Proteins , Caenorhabditis elegans/physiology , Carrier Proteins/metabolism , Cell Movement/physiology , Cytoskeletal Proteins , Helminth Proteins/metabolism , Phagocytosis/physiology , Proto-Oncogene Proteins , rac GTP-Binding Proteins/metabolism , Amino Acid Sequence , Animals , Animals, Genetically Modified , Apoptosis Regulatory Proteins , Caenorhabditis elegans/cytology , Caenorhabditis elegans/genetics , Carrier Proteins/chemistry , Carrier Proteins/genetics , Cell Line , Cell Surface Extensions/metabolism , Cytoskeleton/metabolism , Flow Cytometry , Genes, Helminth , Genes, Reporter , Gonads/growth & development , Helminth Proteins/genetics , Humans , Male , Mice , Microscopy, Fluorescence , Molecular Sequence Data , Protein Kinases/metabolism , Proteins/metabolism , Proto-Oncogene Proteins c-crk , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Sequence Alignment , Signal Transduction/physiology , Tissue DistributionABSTRACT
The Ran guanosine triphosphatase (GTPase) controls nucleocytoplasmic transport, mitotic spindle formation, and nuclear envelope assembly. These functions rely on the association of the Ran-specific exchange factor, RCC1 (regulator of chromosome condensation 1), with chromatin. We find that RCC1 binds directly to mononucleosomes and to histones H2A and H2B. RCC1 utilizes these histones to bind Xenopus sperm chromatin, and the binding of RCC1 to nucleosomes or histones stimulates the catalytic activity of RCC1. We propose that the docking of RCC1 to H2A/H2B establishes the polarity of the Ran-GTP gradient that drives nuclear envelope assembly, nuclear transport, and other nuclear events.
Subject(s)
Cell Cycle Proteins , Chromatin/metabolism , DNA-Binding Proteins/metabolism , Guanine Nucleotide Exchange Factors , Histones/metabolism , Nuclear Proteins , Nucleosomes/metabolism , Active Transport, Cell Nucleus , Animals , Catalysis , Cell Nucleus/metabolism , Chickens , DNA/metabolism , Dimerization , Guanosine Diphosphate/metabolism , Guanosine Triphosphate/metabolism , HeLa Cells , Humans , Male , Nuclear Envelope/metabolism , Recombinant Fusion Proteins/metabolism , Spermatozoa , Xenopus Proteins , Xenopus laevis , ran GTP-Binding Protein/metabolismABSTRACT
RCC1, the only known guanine-nucleotide exchange factor for the Ran GTPase, is an approximately 45-kD nuclear protein that can bind chromatin. An important question concerns how RCC1 traverses the nuclear envelope. We now show that nuclear RCC1 is not exported readily in interphase cells and that the import of RCC1 into the nucleoplasm is extremely rapid. Import can proceed by at least two distinct mechanisms. The first is a classic import pathway mediated by basic residues within the NH(2)-terminal domain (NTD) of RCC1. This pathway is dependent upon both a preexisting Ran gradient and energy, and preferentially uses the importin-alpha3 isoform of importin-alpha. The second pathway is not mediated by the NTD of RCC1. This novel pathway does not require importin-alpha or importin-beta or the addition of any other soluble factor in vitro; however, this pathway is saturable and sensitive only to a subset of inhibitors of classical import pathways. Furthermore, the nuclear import of RCC1 does not require a preexisting Ran gradient or energy. We speculate that this second import pathway evolved to ensure that RCC1 never accumulates in the cytoplasm.
