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Seoul, South Korea

Kim J.-H.,National Health Insurance Service Ilsan Hospital | Shim J.-K.,Yonsei University | Song J.-W.,Yonsei University | Song Y.,Yonsei University | And 2 more authors.
Critical Care

Introduction: Recombinant human erythropoietin (EPO) is known to provide organ protection against ischemia-reperfusion injury through its pleiotropic properties. The aim of this single-site, randomized, case-controlled, and double-blind study was to investigate the effect of pre-emptive EPO administration on the incidence of postoperative acute kidney injury (AKI) in patients with risk factors for AKI undergoing complex valvular heart surgery. Methods: We studied ninety-eight patients with preoperative risk factors for AKI. The patients were randomly allocated to either the EPO group (n = 49) or the control group (n = 49). The EPO group received 300 IU/kg of EPO intravenously after anesthetic induction. The control group received an equivalent volume of normal saline. AKI was defined as an increase in serum creatinine >0.3 mg/dl or >50% from baseline. Biomarkers of renal injury were serially measured until five days postoperatively. Results: Patient characteristics and operative data, including the duration of cardiopulmonary bypass, were similar between the two groups. Incidence of postoperative AKI (32.7% versus 34.7%, P = 0.831) and biomarkers of renal injury including cystatin C and neutrophil gelatinase-associated lipocalin showed no significant differences between the groups. The postoperative increase in interleukin-6 and myeloperoxidase was similar between the groups. None of the patients developed adverse complications related to EPO administration, including thromboembolic events, throughout the study period. Conclusions: Intravenous administration of 300 IU/kg of EPO did not provide renal protection in patients who are at increased risk of developing AKI after undergoing complex valvular heart surgery.Trial registration: Clinical Trial.gov, NCT01758861. © 2013 Kim et al.; licensee BioMed Central Ltd. Source

Chatterjee C.,National University of Singapore | Kumar S.,National University of Singapore | Kumar S.,Biomedical Science Institute | Chakraborty S.,National University of Singapore | And 5 more authors.

Background: The putative needle complex subunit AscF forms a ternary complex with the chaperones AscE and AscG in the type III secretion system of Aeromonas hydrophila so as to avoid premature assembly. Previously, we demonstrated that the C-terminal region of AscG (residues 62-116) in the hetero-molecular chaperone, AscE-AscG, is disordered and susceptible to limited protease digestion. Methodology/Principal Findings: Here, we report the crystal structure of the ordered AscG1-61 region in complex with AscE at 2.4 Å resolution. Helices α2 and α3 of AscE in the AscE-AscG1-61 complex assumes a helix-turn-helix conformation in an anti-parallel fashion similar to that in apo AscE. However, in the presence of AscG, an additional N-terminal helix α1 in AscE (residues 4-12) is observed. PscG or YscG in the crystal structures of PscE-PscF-PscG or YscE-YscF-YscG, respectively, assumes a typical tetratricopeptide repeat (TPR) fold with three TPR repeats and one C-terminal capping helix. By comparison, AscG in AscE-AscG1-61 comprises three anti-parallel helices that resembles the N-terminal TPR repeats in the corresponding region of PscG or YscG in PscE-PscF-PscG or YscE-YscF-YscG. Thermal denaturation of AscE-AscG and AscE-AscG1-61 complexes demonstrates that the C-terminal disordered region does not contribute to the thermal stability of the overall complex. Conclusion/Significance: The N-terminal region of the AscG in the AscE-AscG complex is ordered and assumes a structure similar to those in the corresponding regions of PscE-PscG-PscF or YscE-YscF-YscG complexes. While the C-terminal region of AscG in the AscE-AscG complex is disordered and will assume its structure only in the presence of the substrate AscF. We hypothesize that AscE act as a chaperone of the chaperone to keep AscG in a stable but partially disordered state for interaction with AscF. © 2011 Chatterjee et al. Source

Receptor tyrosine kinases couple a wide variety of extracellular cues to cellular responses. The class III subfamily comprises the platelet-derived growth factor receptor, c-Kit, Flt3 and c-Fms, all of which relay cell proliferation signals upon ligand binding. Accordingly, mutations in these proteins that confer ligand-independent activation are found in a subset of cancers. These mutations cluster in the juxtamembrane (JM) and catalytic tyrosine kinase domain (TKD) regions. In the case of acute myeloid leukemia (AML), the juxtamembrane (named ITD for internal tandem duplication) and TKD Flt3 mutants differ in their spectra of clinical outcomes. Although the mechanism of aberrant activation has been largely elucidated by biochemical and structural analyses of mutant kinases, the differences in disease presentation cannot be attributed to a change in substrate specificity or signaling strength of the catalytic domain. This review discusses the latest literature and presents a working model of differential Flt3 signaling based on mis-localized juxtamembrane autophosphorylation, to account for the disease variation. This will have bearing on therapeutic approaches in a complex disease such as AML, for which no efficacious drug yet exists. © 2011 Higher Education Press and Springer-Verlag Berlin Heidelberg. Source

Bustamante M.L.,Biomedical Science Institute | Bustamante M.L.,University of Chile | Lees A.,University College London

Manganism has captured the imagination of neurologists for more than a century because of its similarities to Parkinson disease and its indirect but seminal role in the "l-dopa miracle." We present unpublished footage of the original case series reported in Neurology® in 1967 by Mena and Cotzias depicting the typical neurologic signs of manganism in 4 Chilean miners and their response to high doses of l-dopa. © 2015 American Academy of Neurology. Source

Blocki A.,National University of Singapore | Blocki A.,Biomedical Science Institute | Wang Y.,National University of Singapore | Koch M.,National University of Singapore | And 7 more authors.
Stem Cells and Development

Pericytes play a crucial role in angiogenesis and vascular maintenance. They can be readily identified in vivo and isolated as CD146 +CD34- cells from various tissues. Whether these and other markers reliably identify pericytes in vitro is unclear. CD146 +CD34- selected cells exhibit multilineage potential. Thus, their perivascular location might represent a stem cell niche. This has spurred assumptions that not only all pericytes are mesenchymal stromal cells (MSCs), but also that all MSCs can act as pericytes. Considering this hypothesis, we developed functional assays by confronting test cells with endothelial cultures based on matrigel assay, spheroid sprouting, and cord formation. We calibrated these assays first with commercial cell lines [CD146+CD34- placenta-derived pericytes (Pl-Prc), bone marrow (bm)MSCs and fibroblasts]. We then functionally compared the angiogenic abilities of CD146+CD34-selected bmMSCs with CD146 - selected bmMSCs from fresh human bm aspirates. We show here that only CD146+CD34- selected Pl-Prc and CD146 +CD34- selected bmMSCs maintain endothelial tubular networks on matrigel and improve endothelial sprout morphology. CD146 - selected bmMSCs neither showed these abilities, nor did they attain pericyte function despite progressive CD146 expression once passaged. Thus, cell culture conditions appear to influence expression of this and other reported pericyte markers significantly without correlation to function. The newly developed assays, therefore, promise to close a gap in the in vitro identification of pericytes via function. Indeed, our functional data suggest that pericytes represent a subpopulation of MSCs in bm with a specialized role in vascular biology. However, these functions are not inherent to all MSCs. © Mary Ann Liebert, Inc. Source

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