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BACKGROUND - Disturbances in vitamin D metabolism are common in patients with end-stage renal disease and may contribute to vascular dysfunction.
STUDY DESIGN - Cross-sectional.
SETTING & PARTICIPANTS - We evaluated 558 of 602 participants at baseline of the Hemodialysis Fistula Maturation (HFM) Study, a 7-center prospective cohort study of a cohort of patients with chronic kidney disease awaiting arteriovenous fistula (AVF) creation surgery.
FACTOR - 4 vitamin D metabolites measured with liquid chromatography-tandem mass spectroscopy from samples obtained within 4 weeks prior to AVF surgery.
OUTCOMES - Vasodilator functions and measurements of arterial stiffness.
MEASUREMENTS - Trained HFM Study personnel measured brachial artery flow-mediated dilation, nitroglycerin-mediated dilation, and carotid-femoral and carotid-radial pulse wave velocities (PWVs) prior to AVF creation. We evaluated associations after basic adjustment for sex, age, and clinical site and more fully adjusted additionally for baseline education, smoking, body mass index, diabetes, dialysis status, and medication use.
RESULTS - Mean participant age was 55±13 (SD) years and 65% were receiving maintenance dialysis. None of the vitamin D metabolites were significantly associated with flow-mediated dilation, carotid-femoral PWV, or carotid-radial PWV in basic or fully adjusted analyses. Higher serum concentrations of bioavailable vitamin D and 1,25-dihydroxyvitamin D were associated with 0.62% and 0.58% greater nitroglycerin-mediated dilation values, respectively, in basic models; however, these associations were no longer statistically significant with full adjustment. There were no significant associations of vitamin D metabolites with carotid-femoral or carotid-radial PWV in fully adjusted analyses.
LIMITATIONS - Cross-sectional ascertainment of vitamin D metabolites and vascular functions late during the course of kidney disease.
CONCLUSIONS - Serum concentrations of vitamin D metabolites are not associated with vasodilator functions or vascular stiffness at baseline in a cohort study of patients with chronic kidney disease awaiting AVF creation surgery. Laboratory measurements of vitamin D metabolites are unlikely to provide useful information regarding vascular functions in this setting.
Copyright © 2017 National Kidney Foundation, Inc. All rights reserved.
AIMS/HYPOTHESIS - Insulin resistance is frequently associated with hypertension and type 2 diabetes. The cytochrome P450 (CYP) arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. However, the direct contribution of endogenous EET production on insulin sensitivity has not been previously investigated. In this study, we tested the hypothesis that endogenous CYP2C-derived EETs alter insulin sensitivity by analysing mice lacking CYP2C44, a major EET producing enzyme, and by testing the association of plasma EETs with insulin sensitivity in humans.
METHODS - We assessed insulin sensitivity in wild-type (WT) and Cyp2c44 mice using hyperinsulinaemic-euglycaemic clamps and isolated skeletal muscle. Insulin secretory function was assessed using hyperglycaemic clamps and isolated islets. Vascular function was tested in isolated perfused mesenteric vessels. Insulin sensitivity and secretion were assessed in humans using frequently sampled intravenous glucose tolerance tests and plasma EETs were measured by mass spectrometry.
RESULTS - Cyp2c44 mice showed decreased glucose tolerance (639 ± 39.5 vs 808 ± 37.7 mmol/l × min for glucose tolerance tests, p = 0.004) and insulin sensitivity compared with WT controls (hyperinsulinaemic clamp glucose infusion rate average during terminal 30 min 0.22 ± 0.02 vs 0.33 ± 0.01 mmol kg min in WT and Cyp2c44 mice respectively, p = 0.003). Although glucose uptake was diminished in Cyp2c44 mice in vivo (gastrocnemius R 16.4 ± 2.0 vs 6.2 ± 1.7 μmol 100 g min, p < 0.01) insulin-stimulated glucose uptake was unchanged ex vivo in isolated skeletal muscle. Capillary density was similar but vascular K-induced relaxation was impaired in isolated Cyp2c44 vessels (maximal response 39.3 ± 6.5% of control, p < 0.001), suggesting that impaired vascular reactivity produces impaired insulin sensitivity in vivo. Similarly, plasma EETs positively correlated with insulin sensitivity in human participants.
CONCLUSIONS/INTERPRETATION - CYP2C-derived EETs contribute to insulin sensitivity in mice and in humans. Interventions to increase circulating EETs in humans could provide a novel approach to improve insulin sensitivity and treat hypertension.
PURPOSE - To compare cerebrovascular reactivity (CVR) and CVR lagtimes in flow territories perfused by vessels with vs. without proximal arterial wall disease and/or stenosis, separately in patients with atherosclerotic and nonatherosclerotic (moyamoya) intracranial stenosis.
MATERIALS AND METHODS - Atherosclerotic and moyamoya patients with >50% intracranial stenosis and <70% cervical stenosis underwent angiography, vessel wall imaging (VWI), and CVR-weighted imaging (n = 36; vessel segments evaluated = 396). Angiography and VWI were evaluated for stenosis locations and vessel wall lesions. Maximum CVR and CVR lagtime were contrasted between vascular territories with and without proximal intracranial vessel wall lesions and stenosis, and a Wilcoxon rank-sum was test used to determine differences (criteria: corrected two-sided P < 0.05).
RESULTS - CVR lagtime was prolonged in territories with vs. without a proximal vessel wall lesion or stenosis for both patient groups: moyamoya (CVR lagtime = 45.5 sec ± 14.2 sec vs. 35.7 sec ± 9.7 sec, P < 0.001) and atherosclerosis (CVR lagtime = 38.2 sec ± 9.1 sec vs. 35.0 sec ± 7.2 sec, P = 0.001). For reactivity, a significant decrease in maximum CVR in the moyamoya group only (maximum CVR = 9.8 ± 2.2 vs. 12.0 ± 2.4, P < 0.001) was observed.
CONCLUSION - Arterial vessel wall lesions detected on noninvasive, noncontrast intracranial VWI in patients with intracranial stenosis correlate on average with tissue-level impairment on CVR-weighted imaging.
LEVEL OF EVIDENCE - 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1167-1176.
© 2017 International Society for Magnetic Resonance in Medicine.
Automated software improves the accuracy and reliability of blood velocity, vessel diameter, blood flow, and shear rate ultrasound measurements, but existing software offers limited flexibility to customize and validate analyses. We developed FloWave.US-open-source software to automate ultrasound blood flow analysis-and demonstrated the validity of its blood velocity (aggregate relative error, 4.32%) and vessel diameter (0.31%) measures with a skeletal muscle ultrasound flow phantom. Compared with a commercial, manual analysis software program, FloWave.US produced equivalent in vivo cardiac cycle time-averaged mean (TAMean) velocities at rest and following a 10-s muscle contraction (mean bias <1 pixel for both conditions). Automated analysis of ultrasound blood flow data was 9.8 times faster than the manual method. Finally, a case study of a lower extremity muscle contraction experiment highlighted the ability of FloWave.US to measure small fluctuations in TAMean velocity, vessel diameter, and mean blood flow at specific time points in the cardiac cycle. In summary, the collective features of our newly designed software-accuracy, reliability, reduced processing time, cost-effectiveness, and flexibility-offer advantages over existing proprietary options. Further, public distribution of FloWave.US allows researchers to easily access and customize code to adapt ultrasound blood flow analysis to a variety of vascular physiology applications.
Copyright © 2016 the American Physiological Society.
BACKGROUND AND PURPOSE - Clinical measurements of cerebral perfusion have been increasingly performed with multiecho dynamic susceptibility contrast-MR imaging techniques due to their ability to remove confounding T1 effects of contrast agent extravasation from perfusion quantification. However, to this point, the extra information provided by multiecho techniques has not been used to improve the process of estimating the arterial input function, which is critical to accurate perfusion quantification. The purpose of this study is to investigate methods by which multiecho DSC-MRI data can be used to automatically avoid voxels whose signal decreases to the level of noise when calculating the arterial input function.
MATERIALS AND METHODS - Here we compare postprocessing strategies for clinical multiecho DSC-MR imaging data to test whether arterial input function measures could be improved by automatically identifying and removing voxels exhibiting signal attenuation (truncation) artifacts.
RESULTS - In a clinical pediatric population, we found that the Pearson correlation coefficient between ΔR2* time-series calculated from each TE individually was a valuable criterion for automated estimation of the arterial input function, resulting in higher peak arterial input function values while maintaining smooth and reliable arterial input function shapes.
CONCLUSIONS - This work is the first to demonstrate that multiecho information may be useful in clinically important automatic arterial input function estimation because it can be used to improve automatic selection of voxels from which the arterial input function should be measured.
© 2016 by American Journal of Neuroradiology.
BACKGROUND - Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in disorders of serum phosphorus concentration and vitamin D. The role of FGF23 in vascular calcification remains controversial.
METHODS - Relationships between FGF23 and coronary artery calcified atherosclerotic plaque (CAC), aortoiliac calcified plaque (CP), carotid artery CP, volumetric bone mineral density (vBMD), albuminuria, and estimated glomerular filtration rate (eGFR) were determined in 545 African Americans with type 2 diabetes (T2D) and preserved kidney function in African American-Diabetes Heart Study participants. Generalized linear models were fitted to test associations between FGF23 and cardiovascular, bone, and renal phenotypes, and change in measurements over time, adjusting for age, gender, African ancestry proportion, body mass index, diabetes duration, hemoglobin A1c, blood pressure, renin-angiotensin-system inhibitors, statins, calcium supplements, serum calcium, and serum phosphate.
RESULTS - The sample was 56.7% female with a mean (SD) age of 55.6 (9.6) years, diabetes duration of 10.3 (8.2) years, eGFR 90.9 (22.1) ml/min/1.73 m2, urine albumin:creatinine ratio (UACR) 151 (588) (median 13) mg/g, plasma FGF23 161 (157) RU/ml, and CAC 637 (1,179) mg. In fully adjusted models, FGF23 was negatively associated with eGFR (p < 0.0001) and positively associated with UACR (p < 0.0001) and CAC (p = 0.0006), but not with carotid CP or aortic CP. Baseline FGF23 concentration did not associate with changes in vBMD or CAC after a mean of 5.1 years follow-up.
CONCLUSIONS - Plasma FGF23 concentrations were independently associated with subclinical coronary artery disease, albuminuria, and kidney function in the understudied African American population with T2D. Findings support relationships between FGF23 and vascular calcification, but not between FGF23 and bone mineral density, in African Americans lacking advanced nephropathy.
© 2016 S. Karger AG, Basel.
BACKGROUND AND PURPOSE - The safety of using adult-sized neuroendovascular devices in the smaller pediatric vasculature is not known. In this study we measure vessel diameters in the cervical and cranial circulation in children to characterize when adult-approved devices might be compatible in children.
METHODS - For 54 children without vasculopathy (mean age 9.5±4.9 years (range 0.02-17.8), 20F/34M) undergoing catheter angiography, the diameters of the large vessels in the cervical and cranial circulation (10 locations, 611 total measurements) were assessed by three radiologists. Mean±SD diameter was calculated for the following age groups: 0-6 months, 1, 2, 3, 4, 5-9, 10-14, and 15-18 years. To compare with adult sizes, each vessel measurement was normalized to the respective region mean diameter in the oldest age group (15-18 years). Normalized measurements were compared with age and fitted to a segmented regression.
RESULTS - Vessel diameters increased rapidly from 0 to 5 years of age (slope=0.069/year) but changed minimally beyond that (slope=0.005/year) (R(2)=0.2). The regression model calculated that, at 5 years of age, vessels would be 94% of the diameter of the oldest age group (compared with 59% at birth). In addition, most vessels in children under 5, while smaller, were still potentially large enough to be compatible with many adult devices.
CONCLUSIONS - The growth curve of the cervicocerebral vasculature displays rapid growth until age 5, at which point most children's vessels are nearly adult size. By age 5, most neuroendovascular devices are size-compatible, including thrombectomy devices for stroke. Under 5 years of age, some devices might still be compatible.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. These findings provide a systematic understanding of the cellular and biological consequences of human genetic variation and of the heterogeneity of such effects among a diverse set of human tissues.
Copyright © 2015, American Association for the Advancement of Science.