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1.
Transverse signal decay under the weak field approximation: Theory and validation.
Berman, AJL, Pike, GB
Magnetic resonance in medicine. 2018;(1):341-350
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Abstract
PURPOSE To derive an expression for the transverse signal time course from systems in the motional narrowing regime, such as water diffusing in blood. This was validated in silico and experimentally with ex vivo blood samples. METHODS A closed-form solution (CFS) for transverse signal decay under any train of refocusing pulses was derived using the weak field approximation. The CFS was validated via simulations of water molecules diffusing in the presence of spherical perturbers, with a range of sizes and under various pulse sequences. The CFS was compared with more conventional fits assuming monoexponential decay, including chemical exchange, using ex vivo blood Carr-Purcell-Meiboom-Gill data. RESULTS From simulations, the CFS was shown to be valid in the motional narrowing regime and partially into the intermediate dephasing regime, with increased accuracy with increasing Carr-Purcell-Meiboom-Gill refocusing rate. In theoretical calculations of the CFS, fitting for the transverse relaxation rate (R2 ) gave excellent agreement with the weak field approximation expression for R2 for Carr-Purcell-Meiboom-Gill sequences, but diverged for free induction decay. These same results were confirmed in the ex vivo analysis. CONCLUSION Transverse signal decay in the motional narrowing regime can be accurately described analytically. This theory has applications in areas such as tissue iron imaging, relaxometry of blood, and contrast agent imaging. Magn Reson Med 80:341-350, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
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Absorption and Safety With Sustained Use of RELiZORB Evaluation (ASSURE) Study in Patients With Cystic Fibrosis Receiving Enteral Feeding.
Stevens, J, Wyatt, C, Brown, P, Patel, D, Grujic, D, Freedman, SD
Journal of pediatric gastroenterology and nutrition. 2018;(4):527-532
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Abstract
OBJECTIVES Pancreatic insufficiency (PI) and malabsorption of fats lead to reduced caloric intake, inability to maintain weight, and increased gastrointestinal symptoms. Thus, enteral nutrition (EN) is used in patients with cystic fibrosis (CF) and poor nutritional status. The current study evaluated safety, tolerability, and improvement of fatty acid (FA) status in red blood cell (RBC) membranes, a marker of long-term FA absorption, with an in-line digestive cartridge (RELiZORB) that hydrolyzes fat in enteral formula. METHODS Patients with CF receiving EN participated in a multicenter, 90-day open-label study during which RELiZORB was used with overnight EN. The primary endpoint was change over time in RBC uptake of docosahexaenoic acid (DHA)+ eicosapentaenoic acid (EPA). Gastrointestinal symptoms were collected to evaluate safety and tolerability. Several clinical and anthropometric parameters were also assessed throughout the study. RESULTS A total of 36 subjects completed the study with a mean age of 13.8 years, body mass index of 17.7 and 6.2 years mean use of overnight EN. Fat absorption significantly improved as shown by increased RBC levels of DHA+EPA, improved ω-6/ω-3 ratio, and increased plasma levels of DHA+EPA. RELiZORB use was not associated with any unanticipated adverse events. CONCLUSIONS RELiZORB use was found to be safe, well tolerated, and resulted in increased levels of FAs in RBCs and plasma. This is the first prospective study to show EN can improve FA abnormalities in CF. Because improvement in omega-3 levels has been shown to help pulmonary and inflammatory status as well as anthropometric parameters in CF, RELiZORB may have important long-term therapeutic benefits in patients with CF.
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Response of Red Blood Cell Folate to Supplementation in Nonpregnant Women is Predictable: A Proposal for Personalized Supplementation.
Obeid, R, Schön, C, Wilhelm, M, Shrestha, RP, Pilz, S, Pietrzik, K
Molecular nutrition & food research. 2018;(4)
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SCOPE We modeled red blood cell (RBC)-folate response to supplementation and developed personalized folate supplementation concepts. METHODS AND RESULTS The changes of RBC-folate were modeled in a time- (4 or 8 weeks) and dose- (400 or 800 μg d-1 folate) dependent manner. Post-supplementation RBC-folate levels were predicted from folate-loading capacities (= measured RBC-folate - [baseline RBC-folate × RBC-survival]). The prediction equations were validated in 119 participants. The median increase of RBC-folate was higher in the 800 μg d-1 than in the 400 μg d-1 group (275 vs 169 nmol L-1 after 4 weeks, and 551 vs 346 nmol L-1 after 8 weeks). Medians (interquartile range) of RBC-folate loading were (4 weeks: 299 (160) vs 409 (237) nmol L-1 ) and (8 weeks: 630 (134) versus 795 (187) nmol L-1 ) in the 400 and 800 μg d-1 group, respectively. The individual measured and predicted RBC-folate values (after 4 weeks/400 μg d-1 = 25 + 1.27 × baseline RBC-folate) and (after 4 weeks/800 μg d-1 = 65 + 1.41 × baseline RBC-folate) did not differ significantly. The measured and predicted concentrations showed high agreement in the validation cohort. CONCLUSIONS The models can guide nutritional recommendations in women when baseline RBC-folate concentrations are measured and the time to pregnancy between 4 and 8 weeks.
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Is gestational diabetes mellitus in obese women predicted by oxidative damage in red blood cells?
León-Reyes, G, Guzmán-Grenfell, AM, Medina-Navarro, R, Montoya-Estrada, A, Moreno-Eutimio, MA, Fuentes-García, S, Perichart Perera, O, Muñoz-Manrique, C, Espino Y Sosa, S, Hicks G, JJ, et al
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2018;(11):995-1000
Abstract
Obesity in pregnant women has been associated with an increased risk of maternal complications, including gestational diabetes mellitus (GDM), a process that is related to oxidative stress (OS). To evaluate the biomarkers of OS in red blood cells (RBCs), we assigned 80 pregnant women to one of three groups: control (n = 28), overweight (n = 26) and obese (n = 26). Then, we measured in plasma, the levels of glucose, triacylglycerol (TAG), insulin, free fatty acids (FFAs), leptin and cytokines (e.g. interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-alpha]) and OS biomarkers, such as lipohydroperoxides (LHP), malondialdehyde (MDA) and protein carbonylation (PC) in RBCs. We found significant positive correlations between OS biomarkers, body mass index (BMI) and pregnancy progression. Seven (26.9%) obese women who were diagnosed with GDM at 24-28 weeks of pregnancy showed significantly increased concentrations of FFAs, insulin, leptin, TNF-alpha and biomarkers of OS measured at 12-13 weeks of gestation. We propose to quantify LHP, MDA and PC in membranes of erythrocytes as possible markers to diagnose GDM from weeks 12-14.
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Investigations on the role of hemoglobin in sulfide metabolism by intact human red blood cells.
Bianco, CL, Savitsky, A, Feelisch, M, Cortese-Krott, MM
Biochemical pharmacology. 2018;:163-173
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Abstract
In addition to their role as oxygen transporters, red blood cells (RBCs) contribute to cardiovascular homeostasis by regulating nitric oxide (NO) metabolism via interaction of hemoglobin (Hb) with nitrite and NO itself. RBCs were proposed to also participate in sulfide metabolism. Although Hb is known to react with sulfide, sulfide metabolism by intact RBCs has not been characterized so far. Therefore we explored the role of Hb in sulfide metabolism in intact human RBCs. We find that upon exposure of washed RBCs to sulfide, no changes in oxy/deoxyhemoglobin (oxy/deoxyHb) are observed by UV-vis and EPR spectroscopy. However, sulfide reacts with methemoglobin (metHb), forming a methemoglobin-sulfide (metHb-SH) complex. Moreover, while metHb-SH is stable in cell-free systems even in the presence of biologically relevant thiols, it gradually decomposes to produce oxyHb, inorganic polysulfides and thiosulfate in intact cells, as detected by EPR and mass spectrometry. Taken together, our results demonstrate that under physiological conditions RBCs are able to metabolize sulfide via intermediate formation of a metHb-SH complex, which subsequently decomposes to oxyHb. We speculate that decomposition of metHb-SH is preceded by an inner-sphere electron transfer, forming reduced Hb (which binds oxygen to form oxyHb) and thiyl radical (a process we here define as "reductive sulfhydration"), which upon release, gives rise to the oxidized products, thiosulfate and polysulfides. Thus, not only is metHb an efficient scavenger and regulator of sulfide in blood, intracellular sulfide itself may play a role in keeping Hb in the reduced oxygen-binding form and, therefore, be involved in RBC physiology and function.
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Human erythrocytes release ATP by a novel pathway involving VDAC oligomerization independent of pannexin-1.
Marginedas-Freixa, I, Alvarez, CL, Moras, M, Leal Denis, MF, Hattab, C, Halle, F, Bihel, F, Mouro-Chanteloup, I, Lefevre, SD, Le Van Kim, C, et al
Scientific reports. 2018;(1):11384
Abstract
We previously demonstrated that the translocase protein TSPO2 together with the voltage-dependent anion channel (VDAC) and adenine nucleotide transporter (ANT) were involved in a membrane transport complex in human red blood cells (RBCs). Because VDAC was proposed as a channel mediating ATP release in RBCs, we used TSPO ligands together with VDAC and ANT inhibitors to test this hypothesis. ATP release was activated by TSPO ligands, and blocked by inhibitors of VDAC and ANT, while it was insensitive to pannexin-1 blockers. TSPO ligand increased extracellular ATP (ATPe) concentration by 24-59% over the basal values, displaying an acute increase in [ATPe] to a maximal value, which remained constant thereafter. ATPe kinetics were compatible with VDAC mediating a fast but transient ATP efflux. ATP release was strongly inhibited by PKC and PKA inhibitors as well as by depleting intracellular cAMP or extracellular Ca2+, suggesting a mechanism involving protein kinases. TSPO ligands favoured VDAC polymerization yielding significantly higher densities of oligomeric bands than in unstimulated cells. Polymerization was partially inhibited by decreasing Ca2+ and cAMP contents. The present results show that TSPO ligands induce polymerization of VDAC, coupled to activation of ATP release by a supramolecular complex involving VDAC, TSPO2 and ANT.
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Kinetic and stoichiometric constraints determine the pathway of H2O2 consumption by red blood cells.
Orrico, F, Möller, MN, Cassina, A, Denicola, A, Thomson, L
Free radical biology & medicine. 2018;:231-239
Abstract
Red blood cells (RBC) are considered as a circulating sink of H2O2, but a significant debate remains over the role of the different intraerythocyte peroxidases. Herein we examined the kinetic of decomposition of exogenous H2O2 by human RBC at different cell densities, using fluorescent and oxymetric methods, contrasting the results against a mathematical model. Fluorescent measurements as well as oxygen production experiments showed that catalase was responsible for most of the decomposition of H2O2 at cell densities suitable for both experimental settings (0.1-10 × 1010 cell L-1), since sodium azide but not N-ethylmaleimide (NEM) inhibited H2O2 consumption. Oxygen production decreased at high cell densities until none was detected above 1.1 × 1012 cell L-1, being recovered after inhibition of the thiol dependent systems by NEM. This result underlined that the consumption of H2O2 by catalase prevail at RBC densities regularly used for research, while the thiol dependent systems predominate when the cell density increases, approaching the normal number in blood (5 × 1012 cell L-1). The mathematical model successfully reproduced experimental results and at low cell number it showed a time sequence involving Prx as the first line of defense, followed by catalase, with a minor role by Gpx. The turning points were given by the total consumption of reduced Prx in first place and reduced GSH after that. However, Prx alone was able to account for the added H2O2 (50 µM) at physiological RBC density, calling attention to the importance of cell density in defining the pathway of H2O2 consumption and offering an explanation to current apparently conflicting results in the literature.
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Intra-individual variability of long-chain fatty acids (C12-C24) in plasma and red blood cells.
Yuzyuk, T, Lozier, B, Schwarz, EL, Viau, K, Kish-Trier, E, De Biase, I
Prostaglandins, leukotrienes, and essential fatty acids. 2018;:30-38
Abstract
Long-chain fatty acids (LCFA) play key roles in mammalian cells as sources of energy, structural components and signaling molecules. Given their importance in numerous physiological processes, the roles of LCFAs in health and disease have been extensively investigated. In the majority of studies, correlations are established using a single measurement in plasma or red blood cells (RBCs). Although a few studies have reported on reproducibility of individual fatty acid measurements, the comprehensive analysis of intra-individual LCFA variability has not been performed. Therefore, our goal was to determine intra-individual variability for the 22 most abundant LCFAs in both plasma and RBC samples collected from healthy individuals on a regular diet after overnight fasting. The measurements of LCFAs in RBCs were consistent throughout the course of study reflecting long-term nutritional status. In contrast, the results in plasma showed considerable LCFA intra-individual variability, even between fatty acids of the same type. Plasma intra-individual variability for omega-3 alpha-linolenic and eicosapentaenoic acids in some participants were >40% whereas the variability of docosahexaenoic acid was consistently <12.8%. Omega-6 linoleic and arachidonic acids also showed low variability in plasma. The results suggest that some LCFAs have less variability and would be more reliable as biomarkers. Reliability of biomarkers can have a profound impact on the research outcomes. Intra-individual variability of LCFAs should be taken into consideration in designing, conducting and interpreting results of clinical studies.
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Elastohydrodynamic Lift at a Soft Wall.
Davies, HS, Débarre, D, El Amri, N, Verdier, C, Richter, RP, Bureau, L
Physical review letters. 2018;(19):198001
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We study experimentally the motion of nondeformable microbeads in a linear shear flow close to a wall bearing a thin and soft polymer layer. Combining microfluidics and 3D optical tracking, we demonstrate that the steady-state bead-to-surface distance increases with the flow strength. Moreover, such lift is shown to result from flow-induced deformations of the layer, in quantitative agreement with theoretical predictions from elastohydrodynamics. This study thus provides the first experimental evidence of "soft lubrication" at play at small scale, in a system relevant, for example, to the physics of blood microcirculation.
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Maternal DHA Status during Pregnancy Has a Positive Impact on Infant Problem Solving: A Norwegian Prospective Observation Study.
Braarud, HC, Markhus, MW, Skotheim, S, Stormark, KM, Frøyland, L, Graff, IE, Kjellevold, M
Nutrients. 2018;(5)
Abstract
Docosahexaenoic acid (DHA, 22:6, n-3) is a long-chain polyunsaturated fatty acid necessary for normal brain growth and cognitive development. Seafood and dietary supplements are the primary dietary sources of DHA. This study addresses the associations between DHA status in pregnant women and healthy, term-born infant problem-solving skills assessed using the Ages and Stages Questionnaire. The fatty acid status of maternal red blood cells (RBCs) was assessed in the 28th week of gestation and at three months postpartum. The infants’ fatty acid status (RBC) was assessed at three, six, and twelve months, and problem-solving skills were assessed at six and twelve months. Maternal DHA status in pregnancy was found to be positively associated with infants’ problem-solving skills at 12 months. This association remained significant even after controlling for the level of maternal education, a surrogate for socio-economic status. The infants’ DHA status at three months was associated with the infants’ problem solving at 12 months. The results accentuate the importance for pregnant and lactating women to have a satisfactory DHA status from dietary intake of seafood or other sources rich in DHA.