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Ed in blood, and has the substanceAs seen in Table 1, the most common predicate in the final network is LOCATION_OF with 26 instances. This represents 22 of the 209 total edges. The predicate PREDISPOSES, which is a clear indicator of biomarker potential, is significantly lower at 12 edges (5.7 ). The semantic type Amino Acid, Peptide, or Protein was by far most common with 13 out of the 49 nodes (26.5 ) asCairelli et al. Journal of Biomedical Semantics (2015) 6:Page 8 ofFigure 6 Visualization of substance predication network. The network contains 49 nodes and 1021 edges. Multiple Staurosporine edges between a pair of nodes are represented as a single edge for visual simplicity; therefore edge labels are not included. Abbreviations: FGF2 = fibroblast growth factor 2, NGFs = nerve growth factors, BDNF = brain-derived neurotrophic factor, NaCl = sodium chloride, APP = amyloid-beta precursor protein, SOD = superoxide dismutase, NSE = neuron specific enolase, GFAP = glial fibrillary acidic protein, TBI = traumatic brain injury, IL6 = interleukin 6, NE = norepinephrin, DA = dopamine, SHAM = salicylhydroxamic acid.seen in Table 2. This semantic type was also dominant within the subset of substance nodes (Table 3) with 8 of the 17 (47.1 ).Evaluation of biomarker potentialThe results of the substance verification in Table 4 provide an estimate of level of interest for further research as a member in a biomarker panel. In general, the substances show evidence of change in TBI in the literature, with two exceptions: amyloid betaprotein precursor and calpain. (Although calpain itself does not appear in the literature, the calpainderived NH2-terminal fragment of -spectrin fragment does [67]). Timing and degree of change may also be an issue regarding the effectiveness of some substances as mTBI biomarkers. Reduced levels of calcium appear to return to normal within as little as 4 hours of trauma [68]. Glutamate levels increase in cerebral spinal fluid but there is no evidence for measurable changes in blood [69-72]. And a conflict exists in the literature for melatonin. One study reports a decrease in serum melatonin after TBI [73] while another reports no change in blood but an increase in cerebral spinal fluid [74].Discussion Most substances identified in this study as worthy of consideration as mTBI biomarkers fall into four general categories: previously studied biomarkers (amyloid beta-protein precursor, brain-derived neurotrophic factor, fibroblast growth factor 2, glial fibrillary acidic protein, neuron-specific enolase, S100b); neurotransmitters (glutamate, dopamine, norepinephrine); inflammation and cell injury markers (interleukin-6, calpain breakdown products, malondialdehyde, superoxide dismutase); and ubiquitous substances (glucose, lactate, calcium). Although all of the resulting substances were reviewed in depth during the methodology, the following illustrate the information contained in the resulting mTBI biomarker network and the information retrieved during the validation process. These examples suggest possible implications for clinical practice retrieved directly from the research literature.GlutamateThe well-known association between glutamate and TBI is present in PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/17139194 the network as Glutamate ASSOCIATED_ WITH Traumatic Brain Injury (PMID 17014847), but relationships that focus on interconnectedness withCairelli et al. Journal of Biomedical Semantics (2015) 6:Page 9 ofTable 1 Predication frequency in final networkFGFLOCATION_OF ASSOCIATED_WITH.