The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
High-resolution C NMR spectroscopy of hyperpolarized succinate-1-C-2,3-d is reported in vitro and in vivo using a clinical-scale, biplanar (80cm-gap) 48.7mT permanent magnet with a high homogeneity magnetic field. Non-localized C NMR spectra were recorded at 0.52MHz resonance frequency over the torso of a tumor-bearing mouse every 2s. Hyperpolarized C NMR signals with linewidths of ∼3Hz (corresponding to ∼6ppm) were recorded in vitro (2mL in a syringe) and in vivo (over a mouse torso). Comparison of the full width at half maximum (FWHM) for C NMR spectra acquired at 48.7mT and at 4.7T in a small-animal MRI scanner demonstrates a factor of ∼12 improvement for the C resonance linewidth attainable at 48.7mT compared to that at 4.7T in vitro. C hyperpolarized succinate-1-C resonance linewidths in vivo are at least one order of magnitude narrower at 48.7mT compared to those observed in high-field (≥3T) studies employing HP contrast agents. The demonstrated high-resolution C in vivo spectroscopy could be useful for high-sensitivity spectroscopic studies involving monitoring HP agent uptake or detecting metabolism using HP contrast agents with sufficiently large C chemical shift differences.
Copyright © 2017 Elsevier Inc. All rights reserved.
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.
BACKGROUND - Intimal hyperplasia remains the primary cause of vein graft failure for the 1 million yearly bypass procedures performed using human saphenous vein (HSV) grafts. This response to injury is caused in part by the harvest and preparation of the conduit. The use of Brilliant Blue FCF (FCF) restores injury-induced loss of function in vascular tissues possibly via inhibition of purinergic receptor signaling. This study investigated whether pretreatment of the vein graft with FCF prevents intimal hyperplasia.
METHODS - Cultured rat aortic smooth muscle cells (A7r5) were used to determine the effect of FCF on platelet-derived growth factor-mediated migration and proliferation, cellular processes that contribute to intimal hyperplasia. The effectiveness of FCF treatment during the time of explantation on preventing intimal hyperplasia was evaluated in a rabbit jugular-carotid interposition model and in an organ culture model using HSV.
RESULTS - FCF inhibited platelet-derived growth factor-induced migration and proliferation of A7r5 cells. Treatment with FCF at the time of vein graft explantation inhibited the subsequent development of intimal thickening in the rabbit model. Pretreatment with FCF also prevented intimal thickening of HSV in organ culture.
CONCLUSIONS - Incorporation of FCF as a component of vein graft preparation at the time of explantation represents a potential therapeutic approach to mitigate intimal hyperplasia, reduce vein graft failure, and improve outcome of the autologous transplantation of HSV.
Copyright © 2016. Published by Elsevier Inc.
Veins used as grafts in heart bypass or as access points in hemodialysis exhibit high failure rates, thereby causing significant morbidity and mortality for patients. Interventional or revisional surgeries required to correct these failures have been met with limited success and exorbitant costs, particularly for the US Centers for Medicare & Medicaid Services. Vein stenosis or occlusion leading to failure is primarily the result of neointimal hyperplasia. Systemic therapies have achieved little long-term success, indicating the need for more localized, sustained, biomaterial-based solutions. Numerous studies have demonstrated the ability of external stents to reduce neointimal hyperplasia. However, successful results from animal models have failed to translate to the clinic thus far, and no external stent is currently approved for use in the US to prevent vein graft or hemodialysis access failures. This review discusses current progress in the field, design considerations, and future perspectives for biomaterial-based external stents. More comparative studies iteratively modulating biomaterial and biomaterial-drug approaches are critical in addressing mechanistic knowledge gaps associated with external stent application to the arteriovenous environment. Addressing these gaps will ultimately lead to more viable solutions that prevent vein graft and hemodialysis access failures.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
OBJECTIVE - Despite patent vein bypass grafts, some patients with critical limb ischemia (CLI) receive major amputations. We analyzed the predictive factors leading to major amputation in the presence of patent lower extremity bypass (LEB) grafts.
METHODS - Data from the Project of Ex-Vivo vein graft Engineering via Transfection III (PREVENT III), a large prospective randomized trial of 1404 patients who underwent LEB with vein graft for CLI, were queried for outcomes. The primary outcome was major amputation with patent (PMA) LEB compared with patients with patent LEB who achieved limb salvage (PLS). The population excluded those who received amputation for occluded grafts. A Cox proportional hazard model identified independent predictors.
RESULTS - Of 1404 LEB patients, 162 (11.5%) had major amputation: 89 (6.3%) with patent and 73 (5.2%) with occluded LEB. For PMA, 21 of 89 (23.6%) developed critical stenosis and 11 of 21 (52.4%) were revised. For PLS, 460 of 1242 (37.0%) developed critical stenosis and 351 of 460 (76.3%) were revised. Predictive patient factors included having preoperative gangrene (vs rest pain; hazard ratio [HR], 3.504; 95% confidence interval [CI], 1.533-8.007; P = .0029), diabetes (HR, 1.800; 95% CI, 1.006-3.219; P = .0477), black (vs white) race (HR, 1.779; 95% CI, 1.051-3.011; P = .0321), baseline creatinine clearance <25 mL/min (vs >65 mL/min; HR, 1.759; 95% CI, 1.016-3.048; P = .0439), prior history of coronary artery bypass grafting (HR, 1.702; 95% CI, 1.080-2.683; P = .0221), and lower baseline activity quality of life score (HR, 1.401; 95% CI, 1.105-1.778; P = .0054). Postoperative wound factors included gangrenous changes (HR, 5.830; 95% CI, 1.647-20.635; P = .0063), surgical wound necrosis (HR, 5.319; 95% CI, 1.478-19.146; P = .0105), deep (vs superficial) wound infection (HR, 3.815; 95% CI, 1.220-11.927; P = .0213), and wound healing abnormally (HR, 3.754; 95% CI, 1.061-13.278; P = .0402). Associated postoperative consequences leading to PMA included having recurrent CLI symptoms (HR, 2.915; 95% CI, 1.816-4.681; P < .0001), a severe (vs mild) adverse event (HR, 2.751; 95% CI, 1.391-5.443; P = .0036), fewer percutaneous revisions (HR, 2.425; 95% CI, 1.573-3.740; P < .0001), discharge on low-molecular-weight heparin (HR, 2.087; 95% CI, 1.309-3.326; P = .0020), and decreasing days to critical stenosis/occlusion/revision/amputation (HR, 1.010; 95% CI, 1.007-1.012; P < .0001).
CONCLUSIONS - Whereas a patent vein graft is important to all vascular surgeons, additional factors should be considered in trying to attain limb salvage for patients with CLI. These factors include intervening surgically before CLI has progressed to a state of gangrene or limited activity and optimizing nutrition, diabetes control, cardiac conditions, and activity level. Revision offers hope for clinical improvement but may be delayed when there is no graft lesion identified. The absence of a graft lesion to revise may also portend amputation despite a patent graft because of nongraft-related factors such as infection. Finally, the experience of a severe (vs mild) adverse event may also result in limb loss despite a patent graft. Systematic efforts to reduce severe adverse events among patients may also lead to increased limb salvage.
Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare, lethal cause of neonatal respiratory failure and persistent pulmonary hypertension. We present a presumptive prenatal diagnosis of ACDMPV based on chorionic villus sampling of a FOXF1 mutation in a fetus with extra-pulmonary anomalies often associated with ACDMPV.
Copyright © 2016 Elsevier Inc. All rights reserved.
Insulin-like growth factor-1 receptor (IGF-1R) can regulate vascular homeostasis and endothelial function. We studied the role of IGF-1R in oxidative stress-induced endothelial dysfunction. Unilateral ureteral obstruction (UUO) was performed in wild-type (WT) mice and mice with endothelial cell (EC)-specific IGF-1R knockout (KO). After UUO in endothelial IGF-1R KO mice, endothelial barrier dysfunction was more severe than in WT mice, as seen by increased inflammatory cell infiltration and vascular endothelial (VE)-cadherin phosphorylation. UUO in endothelial IGF-1R KO mice increased interstitial fibroblast accumulation and enhanced extracellular protein deposition as compared with the WT mice. Endothelial barrier function measured by transendothelial migration in response to hydrogen peroxide (H2O2) was impaired in ECs. Silencing IGF-1R enhanced the influence of H2O2 in disrupting the VE-protein tyrosine phosphatase/VE-cadherin interaction. Overexpression of IGF-1R suppressed H2O2-induced endothelial barrier dysfunction. Furthermore, by using the piggyBac transposon system, we expressed IGF-1R in VE cells in mice. The expression of IGF-1R in ECs also suppressed the inflammatory cell infiltration and renal fibrosis induced by UUO. IGF-1R KO in the VE-cadherin lineage of bone marrow cells had no significant effect on the UUO-induced fibrosis, as compared with control mice. Our results indicate that IGF-1R in the endothelium maintains the endothelial barrier function by stabilization of the VE-protein tyrosine phosphatase/VE-cadherin complex. Decreased expression of IGF-1R impairs endothelial function and increases the fibrosis of kidney disease.
Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Monophosphoryl lipid A (MPLA) is a TLR4 agonist that is used as an immunomodulator in human vaccines; additionally, it has been shown to be protective in models of sepsis. As endothelial cells regulate inflammation, we hypothesized that MPLA would decrease activation of human umbilical vein endothelial cells (HUVECs) to LPS. We studied HUVECs challenged with LPS (100 ng/ml), MPLA (0.001-100 µg/ml) or a combination. Secretion of IL-6, RANTES (CCL5) and IP-10 (CXCL10) were assessed by ELISA. Activation of MAPK phosphorylation and cytokine transcription were assessed by Western blot analysis and PCR, respectively. MPLA alone was a weak stimulator of myeloid differentiation primary response protein 88-dependent IL-6 and did not induce TIR-domain-containing adapter-inducing IFN-β (TRIF)-dependent chemokine responses. MPLA significantly reduced LPS-mediated IL-6 production. This inhibitory effect was also conferred for the TRIF-dependent chemokines RANTES and IP-10. Inhibition of LPS-mediated activation by MPLA was associated with reduced p38 phosphorylation and mRNAs encoding inflammatory cytokines. MPLA inhibition of LPS signaling appeared to be at the level of the TLR4 receptor, acting as a receptor antagonist with weak agonistic properties. This study provides evidence of a novel mechanism for the inhibitory effect of MPLA on LPS-induced endothelial activation.
© The Author(s) 2014.
BACKGROUND - Pulmonary veno-occlusive disease is caused by excessive cell proliferation and fibrosis, which obliterate the lumen of pulmonary venules, leading to pulmonary hypertension, right ventricular failure, and death. This condition has no effective treatment and a 5-year survival of <5%. Understanding the mechanism of this disease and designing effective therapies are urgently needed.
METHODS AND RESULTS - We show that mice with homozygous deletion of the Ets transcription factor Erg die between embryonic day 16.5 and 3 months of age as a result of pulmonary veno-occlusive disease, capillary hemorrhage, and pancytopenia. We demonstrate that Erg binds to and serves as a transcriptional activator of the G-protein-coupled receptor gene Aplnr, the expression of which is uniquely specific for venous endothelium and that knockout of either Erg or Aplnr results in pulmonary venule-specific endothelial proliferation in vitro. We show that mice with either homozygous-global or endothelium-directed deletion of Aplnr manifest pulmonary veno-occlusive disease and right heart failure, detectable at 8 months of age. Levels of pulmonary ERG and APLNR in patients with pulmonary veno-occlusive disease undergoing lung transplantation were significantly lower than those of control subjects.
CONCLUSIONS - Our results suggest that ERG and APLNR are essential for endothelial homeostasis in venules in the lung and that perturbation in ERG-APLNR signaling is crucial for the development of pulmonary veno-occlusive disease. We identify this pathway as a potential therapeutic target for the treatment of this incurable disease.
© 2014 American Heart Association, Inc.