Arterial Plasma Research Articles

Effect of acute dietary nitrate supplementation on sympathetic vasoconstriction at rest and during exercise.

Dietary nitrate ( ) supplementation has been shown to reduce resting blood pressure. However, the mechanism responsible for the reduction in blood pressure has not been identified. Dietary supplementation may increase nitric oxide (NO) bioavailability, and NO has been shown to inhibit sympathetic vasoconstriction in resting and contracting skeletal muscle. Therefore, the purpose of this study was to investigate the hypothesis that acute dietary supplementation would attenuate sympathetic vasoconstrictor responsiveness at rest and during exercise. In a double-blind randomized crossover design, 12 men (23 ± 5 yr) performed a cold-pressor test (CPT) at rest and during moderate- and heavy-intensity alternate-leg knee-extension exercise after consumption of rich beetroot juice (~12.9 mmol ) or a -depleted placebo (~0.13 mmol ). Venous blood was sampled before and 2.5 h after the consumption of beetroot juice for the measurement of total plasma nitrite/ [NOx]. Beat-by-beat blood pressure was measured by Finometer. Leg blood flow was measured at the femoral artery via Doppler ultrasound, and leg vascular conductance (LVC) was calculated. Sympathetic vasoconstrictor responsiveness was calculated as the percentage decrease in LVC in response to the CPT. Total plasma [NOx] was greater (P < 0.001) in the (285 ± 120 µM) compared with the placebo (65 ± 30 µM) condition. However, mean arterial blood pressure and plasma catecholamines were not different (P > 0.05) between and placebo conditions at rest or during moderate- and heavy-intensity exercise. Sympathetic vasoconstrictor responsiveness (Δ% LVC) was not different (P > 0.05) between and placebo conditions at rest ( : -33 ± 10%; placebo: -35 ± 11%) or during moderate ( : -18 ± 8%; placebo: -20 ± 10%)- and heavy ( : -12 ± 8%; placebo: -11 ± 9%)-intensity exercise. These data demonstrate that acute dietary supplementation does not alter sympathetic vasoconstrictor responsiveness at rest or during exercise in young healthy males. NEW & NOTEWORTHY Dietary nitrate may increase nitric oxide bioavailability, and nitric oxide has been shown to attenuate sympathetic vasoconstriction in resting and contracting skeletal muscle and enhance functional sympatholysis. However, the effect of dietary nitrate on sympathetic vasoconstrictor responsiveness is unknown. Acute dietary nitrate supplementation did not alter blood pressure or sympathetic vasoconstrictor responsiveness at rest or during exercise in young healthy males.

Sustained hypoxemia in late gestation potentiates hepatic gluconeogenic gene expression but does not activate glucose production in the ovine fetus.

Fetal hypoxemia is associated with pregnancy conditions that cause an early activation of fetal glucose production. However, the independent role of hypoxemia to activate this pathway is not well understood. We hypothesized that fetal hypoxemia would activate fetal glucose production by decreasing umbilical glucose uptake and increasing counter-regulatory hormone concentrations. We induced hypoxemia for 9 days with maternal tracheal N2 gas insufflation to reduce maternal and fetal arterial Po2 by ~20% (HOX) compared with fetuses from ewes receiving intratracheal compressed air (CON). At 0.9 of gestation, fetal metabolic studies were performed (n = 7 CON, 11 HOX). Umbilical blood flow rates, net fetal oxygen and glucose uptake rates, and fetal arterial plasma glucose concentrations were not different between the two groups. Fetal glucose utilization rates were lower in HOX versus CON fetuses but not different from umbilical glucose uptake rates, demonstrating the absence of endogenous glucose production. In liver tissue, mRNA expression of gluconeogenic genes G6PC (P < 0.01) and PCK1 (P = 0.06) were six- and threefold greater in HOX fetuses versus CON fetuses. Increased fetal norepinephrine and cortisol concentrations and hepatic G6PC and PCK1 expression were inversely related to fetal arterial Po2. These findings support a role for fetal hypoxemia to act with counter-regulatory hormones to potentiate fetal hepatic gluconeogenic gene expression. However, in the absence of decreased net fetal glucose uptake rates and plasma glucose concentrations, hypoxemia-induced gluconeogenic gene activation is not sufficient to activate fetal glucose production.

Plasma hormone concentrations associated with early embryo mortality in heifers

Results of a detailed study involving 18 pregnant, 17 cyclic and 12 inseminated but non-pregnant Holstein heifers indicated the following. (1) Jugular plasma progesterone concentrations were higher (P less than 0.05) in pregnant than in cyclic or in inseminated--non-pregnant animals from Days 10 through 18. (2) Jugular plasma progesterone concentrations of inseminated--non-pregnant animals could be related to heifers in which (a) fertilization may not have occurred (N = 5); (b) embryonic death may have occurred between Days 6 and 9 (N = 5); and (c) embryo mortality may have occurred shortly before Day 18 (N = 2). (3) Jugular plasma oestradiol concentrations were higher (P less than 0.05) in pregnant than in cyclic animals between Days 10 and 18; the oestrogen values of the inseminated--non-pregnant animals resembled those of the pregnant animals. (4) The steroid-synthesizing capabilities of incubated luteal tissues from inseminated--non-pregnant heifers more closely resembled those of tissues from pregnant animals than those of cyclic animals. (5) At Day 18 PGF concentrations in endometrial and luteal tissues and ovarian arterial plasma did not differ among the 3 groups. (6) PGF and progesterone concentrations of luteal tissues were negatively correlated (r = -0.77, P less than 0.05) in cyclic animals and positively correlated (r = 0.73, P less than 0.05) in pregnant animals, implying a luteotrophic effect of PGF in pregnant animals. These results suggested a luteotrophic effect of the embryo, beginning as early as Day 10 of pregnancy, and the results of further experiments suggested that (i) homogenates and extracts of Day 18 bovine embryos contain one or more substances capable of stimulating progesterone synthesis in dispersed bovine luteal cell preparations; (ii) the luteotrophic activity was proportional to the protein contents of the embryo homogenates; and (iii) the luteotrophic activity was heat labile and was removed from homogenates by dialysis, indicating a structure of one or more relatively small molecules.

Effect of oxidative stress in rostral ventrolateral medulla on sympathetic hyperactivity after traumatic brain injury.

Sympathetic hyperactivity occurs in a subgroup of patients after traumatic brain injury (TBI). The rostral ventrolateral medulla (RVLM) is a key region for the activity of sympathetic nervous system. Oxidative stress in the RVLM is proved to be responsible for the increased level of sympathetic activity in animal models of hypertension and heart failure. In this study, we investigated whether oxidative stress in the RVLM contributed to the development of sympathetic hyperactivity after TBI in rats. Model of diffuse axonal injury was induced using Sprague-Dawley rats, and level of mean arterial pressure (MAP) and plasma Norepinephrine (NE) was measured to evaluate the sympathetic activity. For the assessment of oxidative stress, expression of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) in the RVLM was determined. Microinjection of Tempol into the RVLM was performed to determine the effect of oxidative stress on sympathetic hyperactivity. According to the results, TBI led to elevated MAP and plasma NE in rats. It also induced a significantly increased level of ROS, MDA production and decreased level of SOD in the RVLM. The sympathetic activity, ROS, and MDA in the RVLM decreased significantly after microinjection of Tempol. Therefore, the present results suggested that oxidative stress in the RVLM was involved in the development of sympathetic hyperactivity following TBI.

Elevated plasma homocysteine and cysteine are associated with endothelial dysfunction across menopausal stages in healthy women.

Hyperhomocysteinemia is associated with endothelial dysfunction and increased cardiovascular disease (CVD). We determined whether elevated homocysteine (Hcy) and markers of Hcy metabolism were associated with the previously reported endothelial dysfunction across stages of the menopause transition. Brachial artery flow-mediated dilation (FMD) and plasma concentrations of Hcy, cysteine, and methionine were measured in healthy women (n = 128) 22-70 yr of age categorized as premenopausal (n = 35), perimenopausal (early: n = 16; late: n = 21), and postmenopausal (early: n = 21; late: n = 35). Dietary intake of micronutrients involved in Hcy metabolism (e.g., vitamins B6, B12, folate) was assessed in a subpopulation of women. Hcy and cysteine concentrations were progressively higher, and methionine was progressively lower across menopausal stages (all P < 0.005). The higher Hcy and cysteine concentrations correlated with lower circulating estradiol levels (r = -0.49 and -0.50, respectively, both P < 0.001). FMD was inversely correlated with Hcy (r = -0.25, P = 0.004) and cysteine (r = -0.39, P < 0.001) and positively correlated with methionine concentrations (r = 0.25, P = 0.005). Dietary intake of vitamins B6 and B12 (both P < 0.05) were lower in postmenopausal women. Vitamin B12 intake correlated with FMD (r = 0.22, P = 0.006). These data suggest that declines in estradiol across stages of the menopause transition may lead to elevations in Hcy and cysteine that may contribute to endothelial dysfunction in postmenopausal women. Future studies should examine whether targeting Hcy metabolism during the perimenopausal to early postmenopausal period with interventions, including diet, attenuates or reverses the decline in endothelial function in women. NEW & NOTEWORTHY Declines in circulating estradiol across the stages of the menopausal transition may lead to elevations in Hcy and cysteine concentrations that may contribute to endothelial dysfunction. Abnormalities in the Hcy metabolic pathways, possibly related to dietary deficiencies of vitamins B12 and B6 and folate, may contribute to elevations in Hcy and cysteine concentrations. Findings also suggest that higher cysteine levels may be more damaging to the vascular endothelium than Hcy.

Analysis of capillary microsamples obtained from a skin-prick to measure vancomycin concentrations as a valid alternative to conventional sampling: A bridging study

A bridging study is presented to investigate the applicability of measuring vancomycin concentrations obtained by finger-prick. A total of 25 paired plasma samples, collected from finger prick as capillary microsampling and arterial plasma samples collected from an indwelling cannula as conventional sampling, were obtained from critically ill patients receiving vancomycin. The maximum concentration (Cmax) and the minimum concentration (Cmin) measured were 66.2 mg/L and 29.7 mg/L for capillary microsampling and 78.9 mg/L, 25.6 mg/L for conventional sampling, respectively. The area under the concentration-time curve from 0 to 6 h (AUC0-6h) ranged between 94.8 and 269 mg/L.h for capillary microsampling and from 106 and 303 mg/L.h for conventional sampling. The comparative study conducted was assessed using three different statistical approaches: Bland-Altman and Passing-Bablok regression analyses and the USFDA criterion for the incurred sample reanalysis. The results of this analysis revealed no significant bias and a strong correlation between both sampling methods, with 95% of the calculated concentrations from the paired plasma samples laying within 20% of difference of the mean. This bridging study verifies that capillary microsampling may serve as an alternative to conventional sampling techniques to support clinical applications for measuring vancomycin concentrations in plasma.

Assessment of Simplified Methods for Quantification of 18F-FDHT Uptake in Patients with Metastatic Castration-Resistant Prostate Cancer.

18F-fluorodihydrotestosterone (18F-FDHT) PET/CT potentially provides a noninvasive method for assessment of androgen receptor expression in patients with metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to assess simplified methods for quantifying 18F-FDHT uptake in mCRPC patients and to assess effects of tumor perfusion on these 18F-FDHT uptake metrics. Methods: Seventeen mCRPC patients were included in this prospective observational multicenter study. Test and retest 30-min dynamic 18F-FDHT PET/CT scans with venous blood sampling were performed in 14 patients. In addition, arterial blood sampling and dynamic 15O-H2O scans were obtained in a subset of 6 patients. Several simplified methods were assessed: Patlak plots; SUV normalized to body weight (SUVBW), lean body mass (SUVLBM), whole blood (SUVWB), parent plasma activity concentration (SUVPP), area under the parent plasma curve (SUVAUC,PP), and area under the whole-blood input curve (SUVAUC,WB); and SUVBW corrected for sex hormone-binding globulin levels (SUVSHBG). Results were correlated with parameters derived from full pharmacokinetic 18F-FDHT and 15O-H2O. Finally, the repeatability of individual quantitative uptake metrics was assessed. Results: Eighty-seven 18F-FDHT-avid lesions were evaluated. 18F-FDHT uptake was best described by an irreversible 2-tissue-compartment model. Replacing the continuous metabolite-corrected arterial plasma input function with an image-derived input function in combination with venous sample data provided similar Ki results (R2 = 0.98). Patlak Ki and SUVAUC,PP showed an excellent correlation (R2 > 0.9). SUVBW showed a moderate correlation to Ki (R2 = 0.70, presumably due to fast 18F-FDHT metabolism. When calculating SUVSHBG, correlation to Ki improved (R2 = 0.88). The repeatability of full kinetic modeling parameters was inferior to that of simplified methods (repeatability coefficients > 36% vs. < 28%, respectively). 18F-FDHT uptake showed minimal blood flow dependency. Conclusion:18F-FDHT kinetics in mCRPC patients are best described by an irreversible 2-tissue-compartment model with blood volume parameter. SUVAUC,PP showed a near-perfect correlation with the irreversible 2-tissue-compartment model analysis and can be used for accurate quantification of 18F-FDHT uptake in whole-body PET/CT scans. In addition, SUVSHBG could potentially be used as an even simpler method to quantify 18F-FDHT uptake when less complex scanning protocols and accuracy are required.

Cardiac output during exercise is related to plasma atrial natriuretic peptide but not to central venous pressure in humans.

What is the central question of this study? Is cardiac output during exercise dependent on central venous pressure? What is the main finding and its importance? The increase in cardiac output during both rowing and running is related to preload to the heart, as indicated by plasma atrial natriuretic peptide, but unrelated to central venous pressure. The results indicate that in upright humans, central venous pressure reflects the gravitational influence on central venous blood rather than preload to the heart. We evaluated the increase in cardiac output (CO) during exercise in relationship to central venous pressure (CVP) and plasma arterial natriuretic peptide (ANP) as expressions of preload to the heart. Seven healthy subjects (four men; mean ± SD: age 26±3years, height 181± 8cm and weight 76±11kg;) rested in sitting and standing positions (in randomized order) and then rowed and ran at submaximal workloads. The CVP was recorded, CO (Modelflow) calculated and arterial plasma ANP determined by radioimmunoassay. While sitting, (mean±SD) CO was 6.2±1.6lmin-1 , plasma ANP 70±10pgml-1 and CVP 1.8±1.1mmHg, and when standing decreased to 5.9±1.0lmin-1 , 63±10 pgml-1 and -3.8±1.2mmHg, respectively (P<0.05). Ergometer rowing elicited an increase in CO to 22.5±5.5lmin-1 as plasma ANP increased to 156±11 pgml-1 and CVP to 3.8±0.9mmHg (P<0.05). Likewise, CO increased to 23.5±6.0lmin-1 during running, albeit with a smaller (P<0.05) increase in plasma ANP, but with little change in CVP (-0.9±0.4mmHg). The increase in CO in response to exercise is related to preload to the heart, as indicated by plasma ANP, but unrelated to CVP. The results indicate that in upright humans, CVP reflects the gravitational influence on central venous blood rather than preload to the heart.

Preclinical Evaluation and Nonhuman Primate Receptor Occupancy Study of 18F-JNJ-64413739, a PET Radioligand for P2X7 Receptors.

The P2X7 receptor is an adenosine triphosphate-gated ion channel, which is abundantly expressed in glial cells within the central nervous system and in the periphery. P2X7 receptor activation leads to the release of the proinflammatory cytokine IL-1β in the brain, and antagonism of the P2X7 receptor is a novel therapeutic strategy to dampen adenosine triphosphate-dependent IL-1β signaling. PET ligands for the P2X7 receptor will not only be valuable to assess central target engagement of drug candidates but also hold promise as surrogate markers of central neuroinflammation. Herein we describe the in vitro and in vivo evaluation of 18F-JNJ-64413739, an 18F-labeled PET ligand for imaging the P2X7 receptor in the brain. Methods: P2X7 receptor affinity and specificity, pharmacokinetics, metabolic stability, blood-brain barrier permeability, and off-target binding of JNJ-64413739 were evaluated in a series of in vitro, ex vivo, and in vivo assays. 18F-JNJ-64413739 was radiolabeled via a one-step nucleophilic aromatic substitution. The tracer was also studied in rhesus macaques, and PET images were analyzed with an arterial plasma input function-based Logan graphical analysis. Results: The potency (half-maximal inhibitory concentration) of the P2X7 receptor antagonist JNJ-64413739 is 1.0 ± 0.2 nM and 2.0 ± 0.6 nM at the recombinant human and rat P2X7 receptor, respectively, and the binding affinity is 2.7 nM (rat cortex binding assay) and 15.9 nM (human P2X7 receptor). In nonhuman primate PET imaging studies, dose-dependent receptor occupancy of JNJ-54175446 was observed in 2 rhesus monkeys. At a 0.1 mg/kg dose (intravenous) of JNJ-54175446, the receptor occupancy was calculated to be 17% by Logan graphical analysis, whereas a dose of 2.5 mg/kg yielded a receptor occupancy of 60%. Conclusion: The preclinical evaluation of 18F-JNJ-64413739 demonstrates that the tracer engages the P2X7 receptor. Reproducible and dose-dependent receptor occupancy studies with the P2X7 receptor antagonist JNJ-54175446 were obtained in rhesus monkeys. This novel PET tracer exhibits in vitro and in vivo characteristics suitable for imaging the P2X7 receptor in the brain and warrants further studies in humans.

Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.

Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF. We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events. We identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk. The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

Reduced skeletal-muscle perfusion and impaired ATP release during hypoxia and exercise in individuals with type 2 diabetes.

Plasma ATP is a potent vasodilator and is thought to play a role in the local regulation of blood flow. Type 2 diabetes is associated with reduced tissue perfusion. We aimed to examine whether individuals with type 2 diabetes have reduced plasma ATP concentrations compared with healthy control participants (case-control design). We measured femoral arterial and venous plasma ATP levels with the intravascular microdialysis technique during normoxia, hypoxia and one-legged knee-extensor exercise (10W and 30W) in nine participants with type 2 diabetes and eight control participants. In addition, we infused acetylcholine (ACh), sodium nitroprusside (SNP) and ATP into the femoral artery to assess vascular function and ATP signalling. Individuals with type 2 diabetes had a lower leg blood flow (LBF; 2.9 ± 0.1l/min) compared with the control participants (3.2 ± 0.1l/min) during exercise (p < 0.05), in parallel with lower venous plasma ATP concentration (205 ± 35 vs 431 ± 72nmol/l; p < 0.05). During systemic hypoxia, LBF increased from 0.35 ± 0.04 to 0.54 ± 0.06l/min in control individuals, whereas it did not increase (0.25 ± 0.04 vs 0.31 ± 0.03l/min) in the those with type 2 diabetes and was lower than in the control individuals (p < 0.05). Hypoxia increased venous plasma ATP levels in both groups (p < 0.05), but the increase was higher in control individuals (90 ± 26nmol/l) compared to those with type 2 diabetes (18 ± 5nmol/l). LBF and vascular conductance were lower during ATP (0.15 and 0.4μmolmin-1 [kg leg mass]-1) and ACh (100μgmin-1 [kg leg mass]-1) infusion in individuals with type 2 diabetes compared with the control participants (p < 0.05), whereas there was no difference during SNP infusion. These findings demonstrate that individuals with type 2 diabetes have lower plasma ATP concentrations during exercise and hypoxia compared with control individuals, and this occurs in parallel with lower blood flow. Moreover, individuals with type 2 diabetes have a reduced vasodilatory response to infused ATP. These impairments in the ATP system are both likely to contribute to the reduced tissue perfusion associated with type 2 diabetes. ClinicalTrials.gov NCT02001766.

Mammary gland utilization of amino acids and energy metabolites differs when dairy cow rations are isoenergetically supplemented with protein and fat

Mammary gland utilization of AA and other metabolites in response to supplemental energy from protein (PT) and supplemental energy from fat (FT) was tested in a 2 × 2 factorial arrangement using a randomized complete block design. Fifty-six Holstein-Friesian dairy cows were adapted during a 28-d control period to a basal total mixed ration consisting of 34% grass silage, 33% corn silage, 5% grass hay, and 28% concentrate on a dry matter (DM) basis. Experimental rations were fed for 28 d immediately following the control period and consisted of (1) low protein, low fat (LP/LF), (2) high protein, low fat (HP/LF), (3) low protein, high fat (LP/HF), and (4) high protein, high fat (HP/HF). To obtain the high-protein (HP) and high-fat (HF) diets, intake of the basal ration was restricted and supplemented isoenergetically [net energy (MJ/d) basis] with 2.0 kg/d rumen-protected protein (soybean + rapeseed, 50:50 mixture on a DM basis) and 0.68 kg/d hydrogenated palm fatty acids on a DM basis. Arterial and venous blood samples were collected on d 28 of both periods. Isoenergetic supplements (MJ/d) of protein and fat independently and additively increased milk yield, PT increased protein yield, and FT increased fat yield. A PT × FT interaction affected arterial concentration of all essential AA (EAA) groups, where they increased in response to PT by a greater magnitude at the LF level (on average 35%) compared with the HF level (on average 14%). Mammary gland plasma flow was unaffected by PT or FT. Supplementation with PT tended to decrease mammary clearance of total EAA and decreased group 1 AA clearance by 19%. In response to PT, mammary uptake of total EAA and group 2 AA increased 12 and 14%, respectively, with significantly higher uptake of Arg, Ile, and Leu. Energy from fat had no effect on mammary clearance or uptake of any AA group. The mammary gland uptake:milk protein output ratio was not affected by FT, whereas PT increased this ratio for EAA and group 2 AA. Arterial plasma insulin concentration decreased in response to FT, in particular on the HP/HF diet, as indicated by a PT × FT interaction. Arterial concentrations of nonesterified fatty acids, triacylglycerol, and long-chain fatty acids increased in response to FT, and concentrations of β-hydroxybutyrate and acetate decreased in response to FT only at the HP level. Mammary clearance and uptake of triacylglycerol and long-chain fatty acids increased in response to FT. Energy from PT and FT increased lactose yield despite no change in arterial glucose concentration or mammary glucose uptake. Mammary-sequestered glucose with PT or FT was used in the same amount for lactose synthesis, and a positive net mammary glucose balance was found across all treatments. Results presented here illustrate metabolic flexibility of the mammary gland in its use of aminogenic versus lipogenic substrates for milk synthesis.

Peripheral Insulin Extraction in Non-Diabetic Subjects and Type 2 Diabetes Mellitus Patients.

Insulin has to be transported across the capillary endothelium to stimulate muscle glucose uptake. We investigated insulin uptake from the peripheral circulation in non-diabetic (ND) individuals and in type 2 diabetes (T2D) patients. Single-center cross-sectional study involving 40 ND (age 65±11 years) and 30 T2D patients (age 67±8 years). Thirty-six participants were studied in the fasted state (22 ND subjects and 14 T2D patients termed NDF and T2DF) and 34 participants 1-h following a glucose challenge (18 ND subjects and 16 T2D patients indicated as NDG and T2DG). Main outcome measure was fractional extraction (FE) of insulin (FEins) and glucose using the forearm balance method. In NDF, FEins was 18 (10-26) % at lower insulin levels (63 51-80] pmol/l), while in NDG at higher insulin levels (776 [543-1176] pmol/l), FEins was 9 (4-16) % (p = 0.01 vs. NDF). In NDF only, a negative correlation was observed between FEins and arterial plasma insulin load (rho = - 0.575;p = 0.006) and fasting plasma glucose levels (rho = - 0.551;p = 0.01). In T2DF FEins was 6 (1-19) % and not different from FEins in T2DG (10 2-14) %), and was not associated to fasting glucose. FEins tended to be higher in NDF compared to T2DF (p = 0.07). We propose that in ND individuals, besides passive diffusion, an active high-affinity pathway with limited capacity around lower physiologic insulin levels exists for insulin transendothelial transport, contributing to glycemic control. In T2D patients, this mechanism of peripheral insulin uptake is diminished or even absent. Modulation of insulin extraction from the circulation may be a novel target to improve glucose metabolism in T2D.

Plasma and milk fatty acid profiles in goats fed diets supplemented with oils from soybean, linseed or fish

This study aimed to evaluate the effect of polyunsaturated fatty acids (FA) sources (soybean oil, linseed oil and fish oil) on apparent nutrient digestibility, milk composition, and the FA profile in the arterial blood plasma and the milk from dairy goats. Four multiparous Saanen goats were assigned to receive the experimental diets: control diet (no additional oil, with 425 g/kg DM of corn), or a diet substituting 20 g/kg DM of corn by either soybean oil (SO), linseed oil (LO) or fish oil (FO), which were arranged in a 4 × 4 Latin square design. The goats were housed in individual tie stalls, where they received diets containing 400 g/kg DM of corn silage and 600 g/kg DM of concentrate. The corn substitution by FAs sources did not affect apparent nutrient digestibility and milk composition (macro compounds). The oil sources changed the plasma and milk fatty acids profile differently. The plasma concentration of vaccenic and rumenic acids were strongly increased (P < 0.05) (about 500%) in diet containing FO, similarly the content of vaccenic and rumenic acids in the milk were also strongly increased (P < 0.05) (about 540 and 1380%, respectively) using FO, as well as the incorporation of EPA and DHA in the milk. The SO and LO treatments were able to change the profile of several FA in the arterial blood plasma; however, only linoleic and linolenic acids were increased (P < 0.05) in milk, respectively. Changes in plasma and milk FA were observed by adding FO, making the goats’ milk nutritionally healthier for the human diet because FO strongly increased the rumenic and vaccenic acids, EPA and DHA content. The SO and LO led to a few changes in milk FA profile.

In vivo assessment of neuroinflammation in progressive multiple sclerosis: a proof of concept study with [18F]DPA714 PET

BackgroundOver the past decades, positron emission tomography (PET) imaging has become an increasingly useful research modality in the field of multiple sclerosis (MS) research, as PET can visualise molecular processes, such as neuroinflammation, in vivo. The second generation PET radioligand [18F]DPA714 binds with high affinity to the 18-kDa translocator-protein (TSPO), which is mainly expressed on activated microglia. The aim of this proof of concept study was to evaluate this in vivo marker of neuroinflammation in primary and secondary progressive MS.MethodsAll subjects were genotyped for the rs6971 polymorphism within the TSPO gene, and low-affinity binders were excluded from participation in this study. Eight patients with progressive MS and seven age and genetic binding status matched healthy controls underwent a 60 min dynamic PET scan using [18F]DPA714, including both continuous on-line and manual arterial blood sampling to obtain metabolite-corrected arterial plasma input functions.ResultsThe optimal model for quantification of [18F]DPA714 kinetics was a reversible two-tissue compartment model with additional blood volume parameter. For genetic high-affinity binders, a clear increase in binding potential was observed in patients with MS compared with age-matched controls. For both high and medium affinity binders, a further increase in binding potential was observed in T2 white matter lesions compared with non-lesional white matter. Volume of distribution, however, did not differentiate patients from healthy controls, as the large non-displaceable compartment of [18F]DPA714 masks its relatively small specific signal.ConclusionThe TSPO radioligand [18F]DPA714 can reliably identify increased focal and diffuse neuroinflammation in progressive MS when using plasma input-derived binding potential, but observed differences were predominantly visible in high-affinity binders.

Association between coronary artery atherosclerosis and plasma glucose levels assessed by dual-source computed tomography.

To assess the association between coronary artery atherosclerosis (CAA) and plasma glucose parameters in a randomly selected cohort of asymptomatic, community-dwelling, Chinese adults by dual-source computed tomography (DSCT). We randomly selected participants and classified them into three groups based on their plasma glucose levels: normal glucose regulation (NGR), pre-diabetes, and diabetes mellitus (DM). The participants underwent DSCT, and those identified with CAA were divided into four groups according to the severity of their coronary artery stenosis. We analyzed the composition of plaques in all coronary artery segments according to the American Heart Association's (AHA) guidelines. We compared the severity of coronary artery stenosis and the plaque composition with plasma glucose parameters among participants. Out of a total of 335 participants, 118 were found to have CAA. The prevalence of CAA was highest (P value for trend =0.031) in the diabetic group (67.7%) followed by the pre-diabetic group (35.1%) then the NGR group (27.7%). Both calcified and mixed plaques were found in the coronary arteries of the diabetic group while mixed and non-calcified plaques predominated in the pre-diabetic and the NGR groups. When data from all subjects with CAA were analyzed, blood glucose parameters, fasting plasma glucose (FPG), 2-hr postprandial plasma glucose (PPG), and hemoglobin A1c (HbA1c), exhibited a positive correlation with the severity of coronary stenosis (P<0.05). Multivariable logistic regression models indicated a significantly higher risk of CAA among the diabetic patients. Triglyceride levels were positively correlated with the blood glucose parameters among the three groups while LDL-C was elevated in the DM group but not in the pre-diabetic group compared to the NGR group. The severity of CAA exhibited a direct correlation with the blood glucose parameters, FPG, PPG, and HbA1c. DSCT can accurately detect the presence and distribution of CAA in asymptomatic, community-dwelling subjects. DSCT is a useful screening tool for coronary artery disease (CAD).

The association of fatty acid desaturase gene polymorphisms on long-chain polyunsaturated fatty acid composition in Indonesian infants

ABSTRACTBackgroundAdequate availability of long-chain polyunsaturated fatty acids (LC-PUFAs) is important for human health from pregnancy to adulthood. Previous studies on fatty acid desaturase (FADS) gene single-nucleotide polymorphisms (SNPs) have been performed predominantly in Western populations and showed that FADS SNPs had a marked impact on LC-PUFA composition in blood and tissues.ObjectivesWe aimed to investigate the influence of fetal FADS genotypes on LC-PUFA composition in umbilical artery plasma lipids in Indonesian infants.DesignWe performed a cross-sectional study to assess for these associations.ResultsA total of 12 cord plasma n–6 (ω-6) and n–3 (ω-3) fatty acids were analyzed for associations with 18 FADS gene cluster SNPs from 390 women with single parturition from the Indonesian Prospective Study of Atopic Dermatitis in Infants (ISADI). Fetal FADS genotypes influenced cord plasma LC-PUFA composition, but, in contrast to previous studies from Western populations, the quantitatively predominant SNPs were associated with lower LC-PUFA content.ConclusionTo our knowledge, this study was the first in South East Asia on FADS genotypes and arterial cord blood fatty acids to show an association between fetal LC-PUFA composition and fetal FADS SNPs. The FADS genotype distribution differs markedly between different geographical populations. This trial was registered at clinicaltrials.gov as NCT02401178.

Differences in Amino Acid Loss Between High-Efficiency Hemodialysis and Postdilution and Predilution Hemodiafiltration Using High Convection Volume Exchange—A New Metabolic Scenario? A Pilot Study

The objective of the study was to quantify the loss of total amino acids (TAAs), nonessential amino acids, essential amino acids, and branched chain amino acids (BCAAs) produced by high-efficiency hemodialysis (HEHD), postdilution hemodiafiltration (HDFpost), and predilution hemodiafiltration (HDFpre) using high ultrafiltration volumes; and to define the specific AA losses registered in HEHD, HDFpost, and HDFpre; to identify a potential metabolic and nutritional decline into protein energy wasting; to compare AA analysis of arterial blood samples taken from healthy controls and patients with end-stage renal disease undergoing hemodialysis. Identical dialysis monitors, membranes, and dialysate/infusate were used to homogenize extracorporeal body influence. Ten patients were recruited and randomized to receive treatment with HEHD, HDFpost, and HDFpre it was used on-line dialytic water methodologies (OL); patients' AA arterial concentrations were measured at the start and on completion of dialysis; TAA from the dialyzer filter was calculated, and baseline levels were subsequently compared with findings obtained 1year later. Finally, the results obtained were compared with the data from a study of 8 healthy volunteers conducted using bioimpedance analysis and laboratory blood tests to assess nutritional status. A higher convective dose results in a higher weekly loss of TAA, nonessential AAs, essential AAs, and BCAAs (HEHD: 15.7g; HDFpost-OL: 16.1g; HDFpre-OL: 16.3g, P<.01). After 12months, the same hemodialys patients showed a reduced body and water intracellular mass and reduced phase angle. Arterial concentrations of TAAs and BCAAs were lower than those detected in healthy subjects (P<.01). The study shows that the AA losses in dialytic liquid are greater after high exchange volume HDF techniques, especially HDFpre. The AA losses are not metabolically compensated, so these increase the derangements of predialytic arterial plasma AA levels. Both AA losses and arterial AA perturbations further worsened body composition already after 12months of additional dialysis.

A Unified Framework for Plasma Data Modeling in Dynamic Positron Emission Tomography Studies.

Full quantification of dynamic positron emission tomography (PET) data requires the knowledge of tracer concentration in the arterial plasma. However, its accurate measurement is challenging due to the presence of radiolabeled metabolites and measurement noise. Mathematical models are fitted to the plasma data for both radiometabolite correction and data denoising. However, the models used are generally not physiologically informed and not consistently applied across studies even when quantifying the kinetics of the same radiotracer, introducing methodological variability affecting the results interpretation. The aim of this study was to develop and validate a unified framework for the arterial data modeling to achieve an accurate and fully automated description of the plasma tracer kinetics. The proposed pipeline employs basis pursuit techniques for estimating both radiometabolites and parent concentration models from the raw plasma measurements, allowing the resulting algorithm to be both robust and flexible to the different quality of data available. The pipeline was tested on four PET tracers ([11C]PBR28, [11C]MePPEP, [11C]WAY-100635, and [11C]PIB) with continuous and discrete blood sampling. Compared to the standard procedure, the pipeline provided similar fit of the parent fraction but yielded a better description of the total plasma radioactivity, which in turn allowed a more accurate fit of the tissue PET data. The new method showed superior fits compared to the standard pipeline, for both continuous and discrete arterial sampling protocol, yielding to better description of PET data. The proposed pipeline has the potential to standardize the blood data modeling in dynamic PET studies given its robustness, flexibility and easiness of use.

Enterically delivered insulin tregopil exhibits rapid absorption characteristics and a pharmacodynamic effect similar to human insulin in conscious dogs.

Current therapy fails to emulate rapid (first-phase) insulin release in relation to a meal, a key defect in types 1 and 2 diabetes. We aimed to quantify the pharmacokinetic (PK) and pharmacodynamic (PD) profile of insulin tregopil, an enterically-absorbed insulin analog that restores the normal distribution of insulin between the hepatic portal and peripheral circulations. The PK and PD profiles of insulin tregopil were studied in overnight-fasted, catheterized, conscious canines using four approaches: (1) equimolar intraportal infusions of tregopil vs human insulin; (2) escalating doses of oral tregopil; (3) identical, consecutive enteric doses of tregopil; and (4) comparison of oral tregopil to inhaled and subcutaneous human insulin administration. Equimolar intraportal infusions of tregopil and human insulin resulted in very similar PK profiles and PD profiles were nearly identical. Enteric delivery of tregopil brought about rapid absorption with tmax = 20 minutes in most cases. Median tmax was 20 minutes for oral tregopil and inhaled insulin and 88 minutes for subcutaneous human insulin. The time required for arterial plasma insulin levels to return to baseline was approximately 90, 210 and 360 minutes for oral tregopil, inhaled insulin and subcutaneous insulin, respectively. Enterically delivered tregopil is rapidly absorbed and restores a portal-to-peripheral vascular distribution. These characteristics should improve postprandial hyperglycaemia in types 1 and 2 diabetes.