The results of this preliminary study, which were not readily apparent from the parent clinical trial, show a unique metabolite profile of l-carnitine responders and introduce pharmacometabolomics as a viable strategy for informing l-carnitine responsiveness. The approach taken in this study represents a concrete example for the application of precision medicine to sepsis therapeutics that warrants further study.
Serum is a common sample of convenience for metabolomics studies. Its processing time can be lengthy and may result in the loss of metabolites including those of red blood cells (RBC). Unlike serum, whole blood (WB) is quickly processed, minimizing the influence of variable hemolysis while including RBC metabolites. To determine differences between serum and WB metabolomes, both sample types, collected from healthy volunteers, were assayed by 1H-NMR spectroscopy. A total of 34 and 50 aqueous metabolites were quantified from serum and WB, respectively. Free hemoglobin (Hgb) levels in serum were measured and the correlation between Hgb and metabolite concentrations was determined. All metabolites detected in serum were at higher concentrations in WB with the exception of acetoacetate and propylene glycol. The 18 unique metabolites of WB included adenosine, AMP, ADP and ATP, which are associated with RBC metabolism. The use of serum results in the underrepresentation of a number of metabolic pathways including branched chain amino acid degradation and glycolysis and gluconeogenesis. The range of free Hgb in serum was 0.03-0.01 g/dL and 8 metabolites were associated (p ≤ 0.05) with free Hgb. The range of free Hgb in serum samples from 18 sepsis patients was 0.02-0.46 g/dL. WB and serum have unique aqueous metabolite profiles but the use of serum may introduce potential pathway bias. Use of WB for metabolomics may be particularly important for studies in diseases like sepsis in which RBC metabolism is altered and mechanical and sepsis-induced hemolysis contributes to variance in the metabolome.
Prolonged (8 weeks) oral administration of clofazimine results in a profound pharmacodynamic response- bioaccumulation in macrophages (including Kupffer cells) as intracellular crystal-like drug inclusions (CLDIs) with an associated increase in interleukin-1 receptor antagonist production. Notably, CLDI formation in Kupffer cells concomitantly occurs with the formation of macrophage-centric granulomas. Accordingly, we sought to understand the impact of these events on host metabolism using 1H-nuclear magnetic resonance metabolomics. Mice received a clofazimine - or vehicle-enriched (sham) diet for at least 8 weeks. At two weeks, the antimicrobial activity of clofazimine was evident by changes in urine metabolites. From 2 to 8 weeks, there was a striking change in metabolite levels indicative of a reorientation of host energy metabolism paralleling the onset of CLDI and granuloma formation. This was evidenced by a progressive reduction in urine levels of metabolites involved in one-carbon metabolism with corresponding increases in whole blood, and changes in metabolites associated with lipid, nucleotide and amino acid metabolism, and glycolysis. Although clofazimine-fed mice ate more, they gained less weight than control mice. Together, these results indicate that macrophage sequestration of clofazimine as CLDIs and granuloma formation is accompanied by a profound metabolic disruption in energy homeostasis and one-carbon metabolism.
Study Objective To illustrate the potential of metabolomics to identify novel biomarkers of illness severity in a child with fatal necrotizing pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA). Design Case report with two control groups and a metabolomics analysis. Patients An infant with fatal MRSA pneumonia, four children with influenza pneumonia (pneumonia control group), and seven healthy children with no known infections (healthy control group). Measurements and Main Results Urine samples were collected from all children. Metabolites were identified and quantified by using 1H-nuclear magnetic resonance spectrometry. Normalized metabolite concentration data from children with influenza pneumonia and healthy controls were compared by using an unpaired Student's t test. To identify differentiating metabolites of MRSA pneumonia, the fold change of each metabolite was calculated by dividing each urine metabolite concentration of the patient with fatal MRSA pneumonia by the median urine concentration values of the same metabolite of the patients with influenza pneumonia and healthy controls, respectively. Metscape (http://metscape.ncibi.org/), a bioinformatics tool, was used for data visualization and interpretation. Urine metabolite concentrations previously identified as associated with sepsis in children (e.g., 3-hydroxybutyrate, carnitine, and creatinine) were higher in the patient with fatal MRSA pneumonia compared with those of patients with influenza pneumonia and healthy controls. The concentrations of additional metabolites—acetone, acetoacetate, choline, fumarate, glucose and 3-aminoisobutyrate—were more than 25-fold higher in the patient with MRSA pneumonia than those of patients with influenza pneumonia and healthy controls. Conclusion These metabolic changes in the urine preceded the clinical severe sepsis phenotype, which suggests that detection of the extent of metabolic disruption can aid in the early identification of a sepsis phenotype in advance of clinical diagnosis. These data also support the utility of metabolomics for the development of clinical assays for the identification of patients with pediatric pneumonia at high risk for deterioration.
Anticipating the location of a temporarily obscured target—what Piaget (the construction of reality in the child. Basic Books, New York, 1954) called ‘‘objectpermanence’’—is a critical skill, especially in hunters of mobile prey. Previous research with bottlenose dolphins found they could predict the location of a target that had been visibly displaced into an opaque container, but not one that was first placed in an opaque container and then invisibly displaced to another container. We tested whether, by altering the task to involve occlusion rather than containment, these animals could show more advanced object permanence skills. We projected dynamic visual displays at an underwater-viewing window and videotaped the animals’ head moves while observing these displays. In Experiment 1, the animals observed a small black disk moving behind occluders that shifted in size, ultimately forming one large occluder. Nine out of ten subjects ‘‘tracked’’ the presumed movement of the disk behind this occluder on their first trial—and in a statistically significant number of subsequent trials—confirming their visible displacement abilities. In Experiment 2, we tested their invisible displacement abilities. The disk first disappeared behind a pair of moving occluders, which then moved behind a stationary occluder. The moving occluders then reappeared and separated, revealing that the disk was no longer behind them. The subjects subsequently looked to the correct stationary occluder on eight of their ten first trials, and in a statistically significant number of subsequent trials. Thus, by altering the stimuli to be more ecologically valid, we were able to show that the dolphins could indeed succeed at an invisible displacement task.
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