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- Creator:
- Stringer, Kathleen A.
- Description:
- These data were produced from the survival analysis of the pre-treatment metabolomics data generated from the Phase II clinical trial of L-carnitine treatment for septic shock (the RACE trial - see https://clinicaltrials.gov/ct2/show/NCT01665092). The results based on respective acetylcarnitine or valine concentration are presented (pdf). The csv files contain the at risk numbers from the Kaplan-Meier survival analysis. These findings described in our manuscript: Pharmacometabolomics Identifies Candidate Predictor Metabolites of an L-carnitine Treatment Mortality Benefit in Septic Shock. and All of the metabolomics data are available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org which is supported by NIH grant U2C-DK119886 and where it has been assigned Project ID (accession number ST001319). The data can be accessed directly via its Project DOIs: (DOI: http://dx.doi.org/10.21228/M8VX0Z).
- Keyword:
- sepsis, septic shock, survival, mortality, metabolomics, and pharmacometabolomics
- Citation to related publication:
- Puskarich, M. A., Jennaro, T. S., Gillies, C. E., Evans, C. R., Karnovsky, A., McHugh, C. E., Flott, T. L., Jones, A. E., Stringer, K. A., & Investigators, O. behalf of the R. T. (2021). Pharmacometabolomics Identifies Candidate Predictor Metabolites of an L-carnitine Treatment Mortality Benefit in Septic Shock. (Preprint) https://doi.org/10.1101/2021.01.28.21250687 and Puskarich MA, Jennaro TS, Gillies CE, et al; the RACE Trial Investigators. Pharmacometabolomics identifies candidate predictor metabolites of an L-carnitine treatment mortality benefit in septic shock. Clin Transl Sci. 2021; 14: 2288–2299. https://doi.org/10.1111/cts.13088
- Discipline:
- Health Sciences
-
- Creator:
- Jean Nemzek and Chris Fry
- Description:
- After an initial acclimation period at standard temperatures, mice were randomly placed in static cages (3-5 mice/cage) in specialized climate chambers (Powerscientific, Pipersville, PA). Chamber temperatures were set to either 22°C or 30°C with relative humidity set to 30%. After 7 days, groups of mice (n=10/group) were euthanized without further manipulations to establish the effects of ambient temperature on select markers of inflammation including cell counts and cytokine concentrations in plasma and peritoneal lavage fluid. Spleen cells were harvested for total counts and in vitro stimulation. Additional groups of mice exposed to either 22°C or 30°C underwent cecal ligation and puncture surgery to induce polymicrobial peritonitis, then returned to their assigned housing temperature. Survival was monitored for 7 days after surgery. In a separate cohort of mice, inflammatory responses at 6 hours after surgery were examined in the systemic (blood) and local (peritoneal lavage) compartments. the experiment was repeated with mice implanted with a thermistor to monitor body temperature over 72 hours.
- Keyword:
- sepsis, ambient temperature, and inflammation
- Citation to related publication:
- Chan G, et al. Impact of thermoneutral acclimation on a murine model of polymicrobial peritonitis. Under review.
- Discipline:
- Health Sciences
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- Creator:
- Stringer, Kathleen
- Description:
- Organ-specific metabolic pathways, including those related to mitochondrial metabolism, could provide insight to mechanisms underlying sepsis-induced organ dysfunction. However, it remains unclear if metabolic changes precede or if they result from organ dysfunction. We determined if blood levels of the mitochondrial metabolites acetylcarnitine and L-carnitine correlate with organ-specific signals of sepsis-induced dysfunction. To achieve this goal, we performed a series of translational analyses of two cohorts of human sepsis and experiments using a murine model of polymicrobial sepsis. We evaluated the association between mitochondrial metabolites and clinical indices of organ function. We found that in the blood of patients with sepsis or septic shock, metabolic indices of dysfunctional mitochondrial beta-oxidation that were correlated with clinical measures of renal and liver dysfunction. The relevance of these findings was corroborated in an experimental model that showed distinct patterns of change in organ metabolism that correlated with the blood acetylcarnitine to L-carnitine ratio. In addition, sepsis-induced changes in organ metabolism were distinct in the liver and kidney highlighting the unique energy economies of each organ. Importantly, these metabolic changes preceded histological evidence of cellular apoptosis. In conclusion, sepsis-induced disruption in blood levels of specific metabolites could serve as more reliable indicators of early organ dysfunction than those we presently use. These early metabolite signals provide mechanistic insights to altered metabolism that may hold the key to timely identification of impending organ dysfunction. This could lead to strategies directed at the prevention of sepsis-induced organ failure.
- Keyword:
- sepsis, organ dysfunction, and biomarker discovery
- Citation to related publication:
- pending
- Discipline:
- Science