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Pediatric Multi-Organ Dysfunction Syndrome: Analysis by an Untargeted "Shotgun" Lipidomic Approach Reveals Low-Abundance Plasma Phospholipids and Dynamic Recovery over 8-Day Period, a Single-Center Observational Study.
Leimanis-Laurens, ML, Ferguson, K, Wolfrum, E, Boville, B, Sanfilippo, D, Lydic, TA, Prokop, JW, Rajasekaran, S
Nutrients. 2021;(3)
Abstract
Lipids are molecules involved in metabolism and inflammation. This study investigates the plasma lipidome for markers of severity and nutritional status in critically ill children. Children with multi-organ dysfunction syndrome (MODS) (n = 24) are analyzed at three time-points and cross-referenced to sedation controls (n = 4) for a total of N = 28. Eight of the patients with MODS, needed veno-arterial extracorporeal membrane oxygenation (VA ECMO) support to survive. Blood plasma lipid profiles are quantified by nano-electrospray (nESI), direct infusion high resolution/accurate mass spectrometry (MS), and tandem mass spectrometry (MS/MS), and compared to nutritional profiles and pediatric logistic organ dysfunction (PELOD) scores. Our results show that PELOD scores were not significantly different between MODS and ECMO cases across time-points (p = 0.66). Lipid profiling provides stratification between sedation controls and all MODS patients for total lysophosphatidylserine (lysoPS) (p-value = 0.004), total phosphatidylserine (PS) (p-value = 0.015), and total ether-linked phosphatidylethanolamine (ether-PE) (p-value = 0.03) after adjusting for sex and age. Nutrition intake over time did not correlate with changes in lipid profiles, as measured by caloric and protein intake. Lipid measurement in the intensive care environment shows dynamic changes over an 8-day pediatric intensive care unit (PICU) course, suggesting novel metabolic indicators for defining critically ill children.
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Plasma Phospholipid Fatty Acids and Coronary Heart Disease Risk: A Matched Case-Control Study within the Women's Health Initiative Observational Study.
Liu, Q, Matthan, NR, Manson, JE, Howard, BV, Tinker, LF, Neuhouser, ML, Van Horn, LV, Rossouw, JE, Allison, MA, Martin, LW, et al
Nutrients. 2019;(7)
Abstract
BACKGROUND AND AIMS The association of fatty acids with coronary heart disease (CHD) has been examined, mainly through dietary measurements, and has generated inconsistent results due to measurement error. Large observational studies and randomized controlled trials have shown that plasma phospholipid fatty acids (PL-FA), especially those less likely to be endogenously synthesized, are good biomarkers of dietary fatty acids. Thus, PL-FA profiles may better predict CHD risk with less measurement error. METHODS We performed a matched case-control study of 2428 postmenopausal women nested in the Women's Health Initiative Observational Study. Plasma PL-FA were measured using gas chromatography and expressed as molar percentage (moL %). Multivariable conditional logistic regression was used to calculate odds ratios (95% CIs) for CHD associated with 1 moL % change in PL-FA. RESULTS Higher plasma PL long-chain saturated fatty acids (SFA) were associated with increased CHD risk, while higher n-3 polyunsaturated fatty acids (PUFA) were associated with decreased risk. No significant associations were observed for very-long-chain SFA, monounsaturated fatty acids (MUFA), PUFA n-6 or trans fatty acids (TFA). Substituting 1 moL % PUFA n-6 or TFA with an equivalent proportion of PUFA n-3 were associated with lower CHD risk. CONCLUSIONS Higher plasma PL long-chain SFA and lower PUFA n-3 were associated with increased CHD risk. A change in diet by limiting foods that are associated with plasma PL long-chain SFA and TFA while enhancing foods high in PUFA n-3 may be beneficial in CHD among postmenopausal women.
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Serum lipidomics reveals early differential effects of gastric bypass compared with banding on phospholipids and sphingolipids independent of differences in weight loss.
Kayser, BD, Lhomme, M, Dao, MC, Ichou, F, Bouillot, JL, Prifti, E, Kontush, A, Chevallier, JM, Aron-Wisnewsky, J, Dugail, I, et al
International journal of obesity (2005). 2017;(6):917-925
Abstract
BACKGROUND/OBJECTIVES Circulating phospholipids and sphingolipids are implicated in obesity-related comorbidities such as insulin resistance and cardiovascular disease. How bariatric surgery affects these important lipid markers is poorly understood. We sought to determine whether Roux-en-Y gastric bypass (RYGB), which is associated with greater metabolic improvement, differentially affects the phosphosphingolipidome compared with adjustable gastric banding (AGB). SUBJECTS/METHODS Fasting sera were available from 59 obese women (body mass index range 37-51 kg m-2; n=37 RYGB and 22 AGB) before surgery, then at 1 (21 RYGB, 12 AGB) and 3 months follow-up (19 RYGB, 12 AGB). HPLC-MS/MS was used to quantify 131 lipids from nine structural classes. DXA measurements and laboratory parameters were also obtained. The associations between lipids and clinical measurements were studied with P-values adjusted for the false discovery rate (FDR). RESULTS Both surgical procedures rapidly induced weight loss and improved clinical profiles, with RYGB producing better improvements in fat mass, and serum total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and orosomucoid (FDR <10%). Ninety-three (of 131) lipids were altered by surgery-the majority decreasing-with 29 lipids differentially affected by RYGB during the study period. The differential effect of the surgeries remained statistically significant for 20 of these lipids after adjusting for differences in weight loss between surgery types. The RYGB signature consisted of phosphatidylcholine species not exceeding 36 carbons, and ceramides and sphingomyelins containing C22 to C25 fatty acids. RYGB also led to a sustained increase in unsaturated ceramide and sphingomyelin species. The RYGB-specific lipid changes were associated with decreases in body weight, total and LDL-C, orosomucoid and increased HOMA-S (FDR <10%). CONCLUSIONS Concomitant with greater metabolic improvement, RYGB induced early and sustained changes in phosphatidylcholines, sphingomyelins and ceramides that were independent of greater weight loss. These data suggest that RYGB may specifically alter sphingolipid metabolism, which, in part, could explain the better metabolic outcomes of this surgical procedure.
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Perivascular Perfusion on Contrast-Enhanced Ultrasound (CEUS) Is Associated with Inflammation in Patients with Acute Deep Vein Thrombosis.
Kaspar, M, Imfeld, S, Partovi, S, Aschwanden, M, Baldi, T, Dikkes, A, Vogt, DR, Tsakiris, DA, Staub, D
Thrombosis and haemostasis. 2017;(11):2146-2155
Abstract
Background Inflammatory processes of the venous wall in acute deep vein thrombosis (DVT) play a role in thrombus formation and resolution. However, direct evaluation of the perivascular inflammation is currently not feasible. Objective To assess perivascular perfusion in acute proximal DVT using contrast-enhanced ultrasound (CEUS) reflecting perivenous inflammation and its association with systemic inflammatory markers in a single-centre, prospective observational study. Patients/Methods Twenty patients with proximal DVT underwent CEUS imaging in the thrombosed and contralateral popliteal vein at baseline and after 2 weeks and 3 months. Perfusion was quantified by measuring peak enhancement (PE) and wash-in rate (WiR) in a perivenous region after bolus injection of the contrast agent. High-sensitive C-reactive protein (hsCRP) and interleukin-6 (IL-6) were determined at the time of each CEUS imaging. Results PE and WiR were significantly higher in the thrombosed compared with the unaffected leg at baseline (1,007 vs. 34 au and 103 vs. 4 au/s) and 2-week follow-up (903 vs. 35 au and 70 vs. 4 au/s). Compared with baseline, PE and WiR in the thrombosed leg significantly decreased to 217 au and 18 au/s at 3-month follow-up.At baseline, hsCRP and IL-6 were elevated at 20.1 mg/mL and 8.2 pg/mL and decreased significantly to 2.8 mg/mL and 2.6 pg/mL at 2-week follow-up, remaining low after 3 months. There was a weak association between the level of inflammatory markers and the CEUS parameters at baseline on the thrombosed leg. Conclusion Elevated perivascular perfusion assessed by CEUS imaging is associated with the inflammatory response in acute DVT.
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Longitudinal Associations of Phospholipid and Cholesteryl Ester Fatty Acids With Disorders Underlying Diabetes.
Johnston, LW, Harris, SB, Retnakaran, R, Zinman, B, Giacca, A, Liu, Z, Bazinet, RP, Hanley, AJ
The Journal of clinical endocrinology and metabolism. 2016;(6):2536-44
Abstract
CONTEXT Specific serum fatty acid (FA) profiles predict the development of incident type 2 diabetes; however, limited longitudinal data exist exploring their role in the progression of insulin sensitivity (IS) and β-cell function. OBJECTIVE To examine the longitudinal associations of the FA composition of serum phospholipid (PL) and cholesteryl ester (CE) fractions with IS and β-cell function over 6 years. DESIGN The Prospective Metabolism and Islet Cell Evaluation (PROMISE) cohort is a longitudinal observational study, with clinic visits occurring every 3 years. Three visits have been completed, totaling 6 years of follow-up. SETTING Individuals (n = 477) at risk for diabetes recruited from the general population in London and Toronto, Canada. MAIN OUTCOME MEASURES Values from an oral glucose tolerance test were used to compute 1/HOMA-IR and the Matsuda index for IS, the insulinogenic index over HOMA-IR, and the insulin secretion-sensitivity index-2 for β-cell function. Thin-layer chromatograph and gas chromatograph quantified FA. Generalized estimating equations were used for the analysis. RESULTS IS and β-cell function declined by 8.3-19.4% over 6 years. In fully adjusted generalized estimating equation models, PL cis-vaccenate (18:1n-7) was positively associated with all outcomes, whereas γ-linolenate (GLA; 18:3n-6) and stearate (18:0) were negatively associated with IS. Tests for time interactions revealed that PL eicosadienoate (20:2n-6) and palmitate (16:0) and CE dihomo-γ-linolenate (20:3n-6), GLA, and palmitate had stronger associations with the outcomes after longer follow-up. CONCLUSIONS In a Canadian population at risk for diabetes, we found that higher PL stearate and GLA and lower cis-vaccenic acid predicted consistently lower IS and β-cell function over 6 years.
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Reliability, repeatability, and reproducibility of pulmonary transit time assessment by contrast enhanced echocardiography.
Herold, IH, Saporito, S, Bouwman, RA, Houthuizen, P, van Assen, HC, Mischi, M, Korsten, HH
Cardiovascular ultrasound. 2016;:1
Abstract
BACKGROUND The aim of this study is to investigate the inter and intra-rater reliability, repeatability, and reproducibility of pulmonary transit time (PTT) measurement in patients using contrast enhanced ultrasound (CEUS), as an indirect measure of preload and left ventricular function. METHODS Mean transit times (MTT) were measured by drawing a region of interest (ROI) in right and left cardiac ventricle in the CEUS loops. Acoustic intensity dilution curves were obtained from the ROIs. MTTs were calculated by applying model-based fitting on the dilution curves. PTT was calculated as the difference of the MTTs. Eight raters with different levels of experience measured the PTT (time moment 1) and repeated the measurement within a week (time moment 2). Reliability and agreement were assessed using intra-class correlations (ICC) and Bland-Altman analysis. Repeatability was tested by estimating the variance of means (ANOVA) of three injections in each patient at different doses. Reproducibility was tested by the ICC of the two time moments. RESULTS Fifteen patients with heart failure were included. The mean PTT was 11.8 ± 3.1 s at time moment 1 and 11.7 ± 2.9 s at time moment 2. The inter-rater reliability for PTT was excellent (ICC = 0.94). The intra-rater reliability per rater was between 0.81-0.99. Bland-Altman analysis revealed a bias of 0.10 s within the rater groups. Reproducibility for PTT showed an ICC = 0.94 between the two time moments. ANOVA showed no significant difference between the means of the three different doses F = 0.048 (P = 0.95). The mean and standard deviation for PTT estimates at three different doses was 11.6 ± 3.3 s. CONCLUSIONS PTT estimation using CEUS shows a high inter- and intra-rater reliability, repeatability at three different doses, and reproducibility by ROI drawing. This makes the minimally invasive PTT measurement using contrast echocardiography ready for clinical evaluation in patients with heart failure and for preload estimation.
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Plasma trimethylamine N-oxide concentration is associated with choline, phospholipids, and methyl metabolism.
Obeid, R, Awwad, HM, Rabagny, Y, Graeber, S, Herrmann, W, Geisel, J
The American journal of clinical nutrition. 2016;(3):703-11
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Abstract
BACKGROUND Elevated plasma concentrations of the gut bacteria choline metabolite trimethylamine N-oxide (TMAO) are associated with atherosclerosis. However, the determinants of TMAO in humans require additional assessment. OBJECTIVE We examined cardiometabolic risk factors and pathways associated with TMAO concentrations in humans. DESIGN A total of 283 individuals (mean ± SD age: 66.7 ± 9.0 y) were included in this observational study. Plasma concentrations of trimethylamine, TMAO, choline, lipids, phospholipids, and methyl metabolites were measured. RESULTS Study participants were divided into 4 groups by median concentrations of TMAO and choline (4.36 and 9.7 μmol/L, respectively). Compared with the group with TMAO and choline concentrations that were less than the median (n = 82), the group with TMAO and choline concentrations that were at least the median (n = 83) was older and had lower high-density lipoprotein (HDL) cholesterol, phospholipids, and methylation potential, higher creatinine, betaine, S-adenosylhomocysteine (SAH), and S-adenosylmethionine (SAM), and higher percentages of men and subjects with diabetes. The difference in plasma TMAO concentrations between men and women (7.3 ± 10.0 compared with 5.4 ± 5.6 μmol/L, respectively) was NS after adjustment for age and creatinine (P = 0.455). The TMAOtrimethylamine ratio was higher in men (P < 0.001). Diabetes was associated with significantly higher plasma TMAO concentration (8.6 ± 12.2 compared with 5.4 ± 5.2 μmol/L) even after adjustments. Sex and diabetes showed an interactive effect on trimethylamine concentrations (P = 0.010) but not on TMAO concentrations (P = 0.950). Positive determinants of TMAO in a stepwise regression model that applied to the whole group were SAH, trimethylamine, choline, and female sex, whereas plasma phosphatidylcholine was a negative determinant. CONCLUSIONS High TMAO and choline concentrations are associated with an advanced cardiometabolic risk profile. Diabetes is related to higher plasma TMAO concentrations but also to alterations in interrelated pathways such as lipids, phospholipids, and methylation. Elevated plasma TMAO concentrations likely reflect a specific metabolic pattern characterized by low HDL and phospholipids in addition to hypomethylation. This trial was registered at clinicaltrials.gov as NCT02586181 and NCT02588898.
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HDL mimetic CER-001 targets atherosclerotic plaques in patients.
Zheng, KH, van der Valk, FM, Smits, LP, Sandberg, M, Dasseux, JL, Baron, R, Barbaras, R, Keyserling, C, Coolen, BF, Nederveen, AJ, et al
Atherosclerosis. 2016;:381-388
Abstract
BACKGROUND AND AIMS Infusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients. METHODS CER-001 was radiolabeled with the long-lived positron emitter zirconium-89 ((89)Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of (89)Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001. RESULTS One hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p < 0.001). Using serial PET/CT imaging, we showed that arterial uptake of CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p < 0.001). Plaque TBRmax correlated with local plaque contrast enhancement (r = 0.56; p = 0.019) as assessed by CE-MRI. CONCLUSIONS Infusion of HDL mimetic CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis. CLINICAL TRIAL REGISTRATION Netherlands Trial Registry - NTR5178. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5178.
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Effects of obesity and gestational diabetes mellitus on placental phospholipids.
Uhl, O, Demmelmair, H, Segura, MT, Florido, J, Rueda, R, Campoy, C, Koletzko, B
Diabetes research and clinical practice. 2015;(2):364-71
Abstract
Gestational diabetes mellitus (GDM) is associated with adverse effects in the offspring. The composition of placental glycerophospholipids (GPL) is known to be altered in GDM and might reflect an aberrant fatty acid transfer across the placenta and thus affect the foetal body composition. The aim of this study was to investigate possible effects of obesity and GDM, respectively, on placental GPL species composition. We investigated molecular species of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS) in term placentas from controls (lean non-diabetic, body-mass-index [BMI] 18-24.9k g/m(2), n=31), obese non-diabetics (BMI ≥30 kg/m(2), n=17) and lean diabetics (n=15), using liquid chromatography - triple quadrupole mass spectrometry. PE(16:0/22:6) and PE(18:0/20:4) were increased in GDM and decreased species were PC(18:0/20:3), PC(18:1/20:3) and PS(18:0/18:2). A consistent difference between BMI related changes and changes caused by GDM was not observed. Arachidonic acid percentages of cord blood correlated with placental PC(16:0/20:4), whereas foetal docosahexaenoic acid correlated to placental PE species. Furthermore, a positive correlation of placental weight was found to levels of PE containing arachidonic acid. We demonstrated that obesity and GDM are associated with decreased dihomo-gamma-linolenic acid and increased arachidonic acid and docosahexaenoic acid contents of placental GPL, with unknown consequences for the foetus. PC(16:0/20:4) was identified as the major component for the supply of arachidonic acid to the foetal circulation, whereas PE containing arachidonic acid was found to be associated to the placental and infant growth.