Dataset Information

Detection of structural and metabolic changes in traumatically injured hippocampus by quantitative differential proteomics.

ABSTRACT: Traumatic brain injury (TBI) is a complex and common problem resulting in the loss of cognitive function. In order to build a comprehensive knowledge base of the proteins that underlie these cognitive deficits, we employed unbiased quantitative mass spectrometry, proteomics, and bioinformatics to identify and quantify dysregulated proteins in the CA3 subregion of the hippocampus in the fluid percussion model of TBI in rats. Using stable isotope 18O-water differential labeling and multidimensional tandem liquid chromatography (LC)-MS/MS with high stringency statistical analyses and filtering, we identified and quantified 1002 common proteins, with 124 increased and 76 decreased. The ingenuity pathway analysis (IPA) bioinformatics tool identified that TBI had profound effects on downregulating global energy metabolism, including glycolysis, the Krebs cycle, and oxidative phosphorylation, as well as cellular structure and function. Widespread upregulation of actin-related cytoskeletal dynamics was also found. IPA indicated a common integrative signaling node, calcineurin B1 (CANB1, CaNB?, or PPP3R1), which was downregulated by TBI. Western blotting confirmed that the calcineurin regulatory subunit, CANB1, and its catalytic binding partner PP2BA, were decreased without changes in other calcineurin subunits. CANB1 plays a critical role in downregulated networks of calcium signaling and homeostasis through calmodulin and calmodulin-dependent kinase II to highly interconnected structural networks dominated by tubulins. This large-scale knowledge base lays the foundation for the identification of novel therapeutic targets for cognitive rescue in TBI.

SUBMITTER: Wu P

PROVIDER: S-EPMC3941921 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Detection of structural and metabolic changes in traumatically injured hippocampus by quantitative differential proteomics.

Wu Ping P Zhao Yingxin Y Haidacher Sigmund J SJ Wang Enyin E Parsley Margaret O MO Gao Junling J Sadygov Rovshan G RG Starkey Jonathan M JM Luxon Bruce A BA Spratt Heidi H Dewitt Douglas S DS Prough Donald S DS Denner Larry L

Journal of neurotrauma 20120920 9

Traumatic brain injury (TBI) is a complex and common problem resulting in the loss of cognitive function. In order to build a comprehensive knowledge base of the proteins that underlie these cognitive deficits, we employed unbiased quantitative mass spectrometry, proteomics, and bioinformatics to identify and quantify dysregulated proteins in the CA3 subregion of the hippocampus in the fluid percussion model of TBI in rats. Using stable isotope 18O-water differential labeling and multidimensiona ...[more]

PMID: 22757692

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Project description:BackgroundIn trauma-exposed adults, the relationship between an individual's socioeconomic position (SEP) and post-traumatic stress disorder (PTSD) has been well demonstrated. One potential mechanism by which the stress associated with lower SEPs may impact trauma outcomes is through changes in neurocognition. In both healthy and clinical samples, area-level factors also appear to be independently related to neurocognition. Far less is known about how neighborhood socioeconomic disadvantage, may impact cognition in traumatically-injured adults. The current study employed hierarchical linear modeling to longitudinally investigate whether neighborhood disadvantage was associated with neurocognitive functioning in five domains: processing speed, sustained attention, controlled attention, cognitive flexibility, and response inhibition.MethodsOne-hundred and ninety-five socioeconomically diverse traumatically-injured subjects (mean age = 32.8, 52.8% female) were recruited from an Emergency Department. Two-weeks, three-months, and six-months post-trauma, participants completed self-report measures and a computerized test battery to evaluate neurocognition. An Area Deprivation Index (ADI) score, a measure of a neighborhood's socioeconomic disadvantage, was derived from each participants' home address.ResultsGreater neighborhood disadvantage was significantly related to lower scores in all domains. Results of hierarchical linear models revealed neighborhood disadvantage was significantly associated with processing speed, controlled attention, cognitive flexibility, and response inhibition across time, even after adjusting for individual annual household income, baseline PTSD symptoms, and previous adverse life experiences. This relationship was stable for all domains except sustained attention, which varied across time.ConclusionThese findings indicate neighborhood disadvantage contributes uniquely to neurocognitive functioning and, for the majority of domains, these contributions are stable across time. The relationship between area-level variables and cognitive function may underlie individual vulnerability to developing psychiatric disorders. Future work should continue to examine the interaction between socioenvironmental stressors and PTSD symptoms longitudinally.

Project description:BackgroundHospital-acquired conditions (HACs) are increasingly scrutinized as markers of hospital quality and are subject to increasing regulatory and financial pressure. Despite this, there is little evidence that HACs are associated with poor outcomes in traumatically injured patients, or that lower HAC rates are a marker of a better quality of care. Our study compares mortality rates in hospitals with high versus low rates of HAC. Our hypothesis is that high HAC trauma centers have higher mortality.MethodsThe latest editions of the National Trauma Data Bank (NTDB) containing facility identification keys (2011 to 2015) were combined. The HACs targeted by the Centers for Medicare and Medicaid Services (CMS) Hospital-Acquired Condition Reduction Program (HACRP) were identified. Hospital-acquired conditions per 1000 patient-days were calculated for individual trauma centers, and these facilities were stratified into quartiles by HAC rate. Propensity score matching was used to match patients admitted to hospitals in the highest versus the lowest quartiles.ResultsComplete data was available for 3,510,818 patients; 58,296 (1.67%) developed HACs recorded in the NTDB. Good performing centers had a mean of 0.84 HACs per 1000 patient-days compared to 7.82 at poor-performing centers. After propensity matching, patients treated at good performing centers had higher mortality of 1.22% versus 1.02% at poor-performing centers (p<0.001). The facility characteristics most over-represented in the poor performing quartile were: University (45.19% vs 10.59%, p<0.001), American College of Surgeons (ACS) Level I Status (31.85% vs 2.24%, p<0.001), and bed size > 600 (28.15% vs 5.5%, p<0.001).ConclusionInjured patients treated at poor-performing centers (high HAC) have reduced mortality relative to good performing centers (low HAC). Large academic centers were overwhelmingly represented in the poor-performing quartile. Hospital-acquired conditions may be markers of a non-modifiable underlying patient and facility characteristics rather than markers of poor hospital quality.

Dataset Information

Detection of structural and metabolic changes in traumatically injured hippocampus by quantitative differential proteomics.

Publications

Detection of structural and metabolic changes in traumatically injured hippocampus by quantitative differential proteomics.

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