bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 546: Physiologic Variations Between Hemoglobin Levels in Capillary and Venous Blood
Authors: Murphy William G , Browne Susan , Segurado Ricardo , Gallagher Brigid , Tong Emma , Murphy Ciaran , Grant Timothy 
Published: July 2021

A complex relationship exists between venous hemoglobin level and thrombosis risk. The hemoglobin content of capillary blood varies in healthy individuals in relation to that of venous blood with sex, age, season of the year, and venous hemoglobin level. (Murphy WG, et al. Blood 2010;116:2861-2). To study further the dynamics of this relationship, venous and capillary (finger pulp blood) hemoglobin levels were compared in 462 frequent blood donors with hereditary hemochromatosis. A linear mixed effects model was fitted to compare capillary hemoglobin with the difference between the venous and capillary hemoglobin. Random slopes and intercepts for each donor were modelled to account for inter-individual variability. A linear mixed effects model was fitted to hemoglobin levels over cumulative time since first donation for each person in separate analyses for capillary and venous hemoglobin levels. Random intercepts and random slopes were modelled within individuals. For each change of 1g/dL in capillary hemoglobin, the difference between venous and capillary hemoglobin changed by -0.694 g/dL, significantly different from zero (p<0.001), indicating a dynamic relationship between the two compartments.
After venesection capillary hemoglobin rose by a mean of 0.496 mg/dL/day, (p<0.001) and venous hemoglobin by 0.113 mg/dL/day (p=0.019). The recovery rate for capillary hemoglobin between venesections was 4.39 times faster than for venous hemoglobin [t(4798)=2.743; p=0.006].
These data indicate that healthy individuals preserve venous hemoglobin at the expense of capillary hemoglobin as the red cell mass rises and falls, and that the capillary space buffers the venous hemoglobin level from changes in red cell mass. Since this space occupies > 10% of the intravascular volume (Chaplin H, et al. JCI 1953:32;1309-16) we estimate that 27% or more of a decrease or increase in red cell mass is accommodated by changes in hemoglobin level of capillary blood relative to the venous hemoglobin level.
The mechanisms underlying these dynamics, such as NO-induced vasodilation by deoxyhemoglobin and modulation of the Fåhraeus effect, remain to be elucidated; however their implications for the relationship between hemoglobin level and thrombosis may be considerable.
Abstract 10: Randomized, Double-Blind, Placebo-Controlled Single Ascending Dose Pharmacokinetic and Pharmacodynamic Study of PRT064445, a Universal Antidote for Factor Xa Inhibitors
Authors: Crowther Mark , Kitt Michael , McClure Matthew , Sinha Uma , Lu Genmin , Karbarz Mark , Hutchaleelaha Athiwat , Barron Lee , Mathur Vandana , Curnutte John 
Published: July 2021

Background
Direct factor Xa inhibitors [fXaI] have superior anticoagulant efficacy and/or safety relative to warfarin and LMWH but are limited by lack of a specific antidote to reverse anticoagulation during episodes of serious bleeding or before surgery. PRT064445 [PRT] is a modified, human recombinant fXa that is catalytically inactive but retains high-affinity binding to direct fXaI and heparin- antithrombin III complexes. It competes with native fXa for fXaI drugs, thus reversing direct and indirect fXaI-mediated anticoagulation.

Methods
In this phase I, first-in-man double-blind study, 32 healthy volunteers were randomized (6:2) within dosing cohorts to a single IV bolus of PRT (30 mg, 90 mg, 300 mg, or 600 mg) or placebo and followed for 28 days. Anti-fXa activity was assayed in vitro by adding exogenous rivaroxaban (50 ng/mL) to subject plasma samples.

Results

The terminal t1/2 was ~6 hours. AUC and Cmax increased disproportionately relative to dose. In the presence of PRT, thrombin generation and anti-fXa activity of rivaroxaban (
Figure
) were reversed in a dose-dependent manner. There were no thrombotic AEs or deaths. There was 1 serious AE (pneumonia) and 3 non-serious infusion-related reactions without anaphylaxis [90 mg (2) and placebo (1)]. One unplanned pregnancy occurred ~10 days post-treatment, followed shortly by a spontaneous abortion. Prothrombin fragment 1 + 2, thrombin-antithrombin complex, and D-dimer transiently increased with dose; other coagulation parameters including PT, aPTT, ACT and platelet activity were unchanged.

Conclusions
PRT is a promising universal antidote for fXaI. A Phase 2 trial evaluating PRT reversal of several fXaI is ongoing.
Abstract 171: Acute Sagittal Sinus Thrombosis in an Elderly Patient with Chronic Idiopathic Thrombocytopenic Purpura
Authors: Wu Huimin , Paulino Robert , Shi Qi , Samavedam Sandhya , Pallekonda Indupriya , Khaira Rajni , Irukulla Pavan 
Published: July 2021

INTRODUCTION
Chronic idiopathic thrombocytopenic purpura (ITP) is classified as a bleeding disorder that involves autoimmune platelet destruction. Cerebral venous sinus thrombosis in association with chronic ITP is rarely reported in medical literature.

CASE PRESENTATION

A 70-year-old female with a history of chronic ITP, on prednisone, and coronary artery disease presented with a four-day history of vomiting and diarrhea. Platelet count at the time of admission was 25×10
9
/L. She was treated with i.v normal saline. Platelets fell to 12×10
9
/L and intravenous immunoglobulin (IVIG) was started. Six days later, the patient developed confusion and right sided weakness. Repeat platelet count was 13x10
9
/L. MRI of the brain showed bilateral cortical infarcts suggesting sagittal vein involvement. MRV confirmed thrombosis of the posterior portion of the sagittal sinus. Bone marrow aspirates and core biopsy done to rule out other hematological disorders showed tri-lineage hematopoiesis with adequate marrow megakaryocytes. Hypercoagulable work up was unremarkable. ITP was treated with rituximab and romiplostim. Repeat MRV after 2 weeks showed no new thrombosis or hemorrhage.

DISCUSSION
ITP is occasionally associated with venous thrombosis. The paradoxical occurrence of venous thrombosis in the setting of ITP is poorly understood. Previous data postulates that platelet destruction releases humoral factors and microparticles, which may increase thrombotic events by the activation of thrombin and other coagulation factors. Other possible mechanisms include endothelial damage by autoantibodies directed against antigens on platelets and endothelial cells. More recently, reports have described IVIG-induced arterial and venous thrombotic complications. Treatment of thrombosis in the setting of ITP is complex and requires in-depth risk/benefit assessment. Our case highlights the dilemma of stroke treatment and prevention predicated on antiplatelet therapies for patients with ITP. Additional studies on chronic ITP associated with thrombosis are needed to establish preventive and treatment guidelines.
Abstract 190: Epigenetic Modifications of Pro-inflammatory Gene Expression in Macrophages by a Demethylase Enzyme, JMJD3, May Promote Chronic Inflammation in Type 2 Diabetic (T2D) Wounds
Authors: Gallagher Katherine A , Joshi Amrita , Carson William , Coleman Dawn , Henke Peter , Hogaboam Cory , Burant Charles , Kunkel Steven 
Published: July 2021

Introduction
Type 2 diabetic(T2D) wounds are characterized by chronic inflammation, maintained by an exaggerated M1(pro-inflammatory) macrophage phenotype response. We seek to define a link between epigenetic modifications of bone marrow(BM) cells in T2D and dysregulated macrophages in wounds. We hypothesized that a chromatin modifying demethylase enzyme, JMJD3, is responsible for the decrease in H3K27me3 repressive methylation at the IL-12 gene promoter and thus drives an M1 macrophage phenotype in T2D wounds.

Methods
BM/adipose tissue(AT)/wounds were harvested from 30 diet-induced obese mice(DIO)(MG= 350g/DL) and 30 matched(WT) controls. For chromatin immunoprecipitation(ChIP) analysis, cells were isolated via ferromagnetic columns(CD34+,CD11b+). ChIP to detect histone methylation at the promoter regions of JMJD3 and IL-12(key M1 macrophage gene) was performed and RNA analysis was done with standard primers.

Results
JMJD3 mRNA in the BM is significantly increased in the DIO versus WT. ChIP showed increased H3K4me3(gene expression mark) in CD34+ progenitor cells and a corresponding decrease in H3K27me3(repressive mark) in monocytes at the promoter region of JMJD3. These changes correspond with the decrease in H3K27me3 seen at the IL-12 promoter in macrophages(CD11b+) from AT/T2D wounds.

Conclusions
Epigenetic changes initiated by JMJD3 in BM progenitor cells result in changes in histone methylation at the IL-12 promoter favoring an M1 phenotype in macrophages and thus contributes to the chronic inflammation seen in T2D wounds and AT. Whether manipulation of epigenetic enzymes could reduce chronic inflammation in T2D wounds requires further work.
Abstract 219: Agxt2 Plays Important Role in Regulation of Urine Adma Levels After Acute Adma Loading in Mice
Authors: Rodionov Roman N , Martens-Lobenhoffer Jens , Brilloff Silke , Hohenstein Bernd , Weiss Norbert , Bode-Böger Stefanie M 
Published: July 2021

Background

Multiple epidemiological studies demonstrated increased levels of an endogenous inhibitor of nitric oxide synthases asymmetric dimethylarginine (ADMA) in cardiovascular diseases. In addition to the well characterized pathway of ADMA hydrolysis by dimethylarginine dimethylaminohydrolase (DDAH) ADMA can also be metabolized through an alternative pathway by alanine:glyoxylate aminotransferase 2 (AGXT2), which converts ADMA to α-keto-δ-(N,N-dimethylguanidino)valeric acid (DMGV). The goal of this study was to better characterize the role of AGXT2 pathway in metabolism of ADMA
in vivo
using a recently developed assay for detection of DMGV in biological samples.

Methods
ADMA (250 μmol x kg-1 x d-1) was infused in C57/BL6 mice for 3 days using osmotic minipumps implanted intraperitoneally. We performed bilateral nephrectomy in some of the mice 24 hours before the end of ADMA infusion and sample collection. Urine was collected for 24 hours in metabolic cages. Blood was collected by cardiac puncture. Measurements of ADMA and DMGV were performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results
Intraperitoneal infusion of ADMA for 3 days resulted in an increase in plasma ADMA levels from 0.46±0.045 to 1.57±0.40 μM (p<0.05) and in urine ADMA levels from 36.4±3.4 to 188.6±31.5 μmol / mmol creatinine (p<0.05). Elevation of ADMA concentration coincided with elevation of plasma DMGV levels from 0.21±0.025 to 0.61±0.14 μM (p<0.05) and urine DMGV levels from 41.4±3.2 to 162.5±32.9 μmol / mmol creatinine (p<0.05). Bilateral nephrectomy in the mice, which underwent ADMA infusion, lead to a 1.7 fold increase in plasma ADMA levels and a 17.6 fold increase in DMGV levels compared with the mice from the sham group.

Conclusions
Infusion of ADMA leads to increased flux through the AGXT2 pathway of ADMA metabolism in vivo. The observation that each 1 μmol / mmol creatinine increase in ADMA level in urine leads to a ~1 μmol / mmol creatinine increase in urine DMGV level suggests that AGXT2 is a major enzyme regulating ADMA levels in urine. The marked increase in DMGV levels in the mice lacking both kidneys suggests significant extrarenal production of DMGV in addition to absent renal excretion.
Abstract 236: Local Wall Thickness in Finite Element Models Improves Prediction of Abdominal Aortic Aneurysm Growth
Authors: Shang Eric K , Nathan Derek P , Fairman Ronald M , Woo Edward Y , Wang Grace J , Gorman Robert C , Gorman Joseph H , Jackson Benjamin M 
Published: July 2021

Objective
Growing evidence suggests that peak wall stress (PWS) derived from finite element analysis (FEA) of abdominal aortic aneurysms (AAAs) predicts clinical outcomes better than diameter alone. Prior models assume uniform wall thickness (UWT). We hypothesize that inclusion of locally variable wall thickness (VWT) into FEA of AAAs will improve the ability to predict clinical outcomes.

Methods
Patients with AAAs (n=26) undergoing radiologic surveillance were identified. Custom MATLAB algorithms generated UWT and VWT aortic geometries from CTA images, which were subsequently loaded with systolic blood pressure using FEA. PWS and aneurysm growth (as a proxy for rupture risk and the need for repair) were examined.

Results
The average radiologic follow-up time was 22.0±13.6 months and the average aneurysm growth rate was 2.8±1.7 mm/year. PWS in VWT models significantly differed from PWS in UWT models (238±68 vs 212±73 kPa, P=0.025). In our sample, initial aortic diameter was not found to be correlated with aneurysm growth (r=0.26, P=0.19). A stronger correlation was found between aneurysm growth and PWS derived from VWT models as compared to PWS from UWT models (r=0.86 vs r=0.58, P=0.032 by Fisher’s r to Z transformation). The three panels in the figure demonstrate the correlation between aneurysm growth rate and (1) initial diameter, (2) PWS using UWT model, and (3) PWS using VWT model, respectively.

Conclusion
The inclusion of locally variable wall thickness significantly improved the correlation between PWS and aneurysm growth. Aortic wall thickness should be incorporated into future FEA models to accurately predict clinical outcomes.
Abstract 243: Adiponectin Inhibits Angiotensin II-induced Abdominal Aortic Aneurysm Formation
Authors: Vorkapic Emina , Wågsäter Dick , Van Stijn Caroline , Kim Jason , Eriksson Per , Tangirala Rajendra 
Published: July 2021

BACKGROUND
Abdominal aortic aneurysms (AAA) are characterized by inflammation, loss of smooth muscle cells (SMC) and degradation of extracellular matrix in the vessel wall. Adiponectin, an adipokine produced by adipose tissue, exerts profound anti-inflammatory and anti-atherogenic effects on vascular cells. However, the role of adiponectin on AAA has not been studied. We investigated the impact of increased plasma adiponectin levels on angiotensin II (AngII)-induced AAA formation in mice.

METHOD AND RESULTS

Male low-density lipoprotein receptor-deficient (LDLR
-/-
) mice fed on a high-fat diet were infused with AngII (25 mg/kg/min) for 8 weeks to induce AAA. Mice infused with saline was used as controls. A recombinant adenoviral vector encoding mouse adiponectin (Ad-APN) was injected intravenously to induce adiponectin expression. A recombinant adenovirus expressing green fluorescence protein (GFP) was used as a control (Ad-GFP). Eight weeks after injection, plasma adiponectin levels were 10-fold higher (253.9±59.0 μg/mL) in Ad-APN mice compared to Ad-GFP mice (25.2±3.8 μg/mL, P<0.001). Aortic diameter was significantly reduced in Ad-APN mice compared to Ad-GFP mice (60% reduction). This was accompanied by decreased frequency and size of abdominal atherosclerotic lesions in Ad-APN mice compared to Ad-GFP mice. Histologically, elastin was degraded in all AngII-infused mice compared to saline-infused mice. However elastin was more preserved in Ad-APN mice compared to Ad-GFP mice (P<0.05). Gene expression analysis of the abdominal aorta revealed a decrease of CD3e (P<0.05) but no profound changes in inflammatory genes, IL-6, TNF-α and CD68. Decreased mRNA expression of the SMC marker SM22α was observed in all AngII-infused mice compared to saline-infused mice. Expression of SM22α was two-fold higher in the abdominal aorta in Ad-APN mice than in Ad-GFP mice (P<0.05).

CONCLUSION

These results provide first evidence that adiponectin overexpression significantly inhibits AngII-induced AAA formation in LDLR
-/-
mice. The protective actions of adiponectin appear to be mediated, in part, through preservation of SMC content and elastin in the vascular wall. The mechanisms of adiponectin inhibiting AAA formation deserve further attention.
Abstract 249: Delayed Gene Transfer Increases Transgene Expression in Vein Grafts
Authors: Du Liang , Zhang Jingwan , Clowes Alexander , Dichek David 
Published: July 2021

Background
Autogenous vein grafts are effective therapies for obstructive arterial disease. However, their long-term utility is limited by stenosis and occlusion. Genetic engineering of veins that prevents intimal hyperplasia and atherosclerosis could significantly improve the clinical utility of vein grafts. We recently reported that a helper-dependent adenoviral vector (HDAd) reduces atherosclerosis 4 wks after gene transfer in fat-fed rabbits and can express a therapeutic transgene (apo AI) in normal rabbit carotids for at least 48 wks. Use of HDAd for vein graft gene therapy will depend on achievement of similarly high and persistent transgene expression in grafted veins.

Hypothesis
We tested the hypothesis that Ad-mediated transgene expression in grafted veins (at an early time point) can be increased by varying the timing of gene transfer.

Methods
Rabbit external jugular veins were transduced by exposure to a beta galactosidase (b-gal)-expressing Ad: in situ either without (a) or with (b) immediate arterial grafting; c) ex vivo with grafting after overnight incubation with Ad; d) in vivo immediately after grafting and e) in vivo 4 wks after grafting (n = 6 - 19 veins/group). Transgene expression was measured in veins removed 3 d after Ad exposure by PCR quantitation of b-gal mRNA and by en-face planimetry of blue-stained area.

Results
B-gal transgene expression was higher in ungrafted veins than in veins grafted immediately after gene transfer (84 ± 17 vs 9.4 ± 2.0 arbitrary units (AU); P < 0.0001). Overnight incubation of veins with Ad increased gene expression ex vivo by 10-fold but neither this nor performing vector infusion immediately after grafting improved gene expression (11 ± 4.7 and 9.1 ± 1.8 AU; P > 0.9 for both vs immediately grafted veins). Delaying gene transfer until 4 wks after grafting significantly increased gene expression, to a level equivalent to transgene expression in ungrafted veins (61 ± 11 AU; P = 0.3 vs ungrafted veins). En face planimetry yielded similar results.

Conclusions
Exposure of a transduced vein to arterial blood flow is associated with significant loss of transgene expression. Transgene expression in grafted veins is significantly higher when gene transfer is performed 4 wks after exposure of the vein to arterial blood flow.
Abstract 286: Loss of Smad3 Exacerbates Abdominal Aortic Aneurysm Formation With Enhanced Inflammation in an Experimental Mouse Model
Authors: Dai Xiaohua , Arora Anandita , Shen Jianbin , Jiang Hong , Li Li 
Published: July 2021

Introduction
Abdominal aortic aneurysm (AAA) is a complex vascular disease that causes more than 10,000 deaths each year in the United States. Extensive studies have been performed in search of pharmaceutical treatment but surgical repair still remains the most effective treatment. TGF-β signaling is an important mechanism in the pathogenesis of aneurysms; however, there is debate as to whether its role is protective or destructive. Smad3 is a major intracellular mediator of the canonical pathway of TGF-β signaling.

Hypothesis
We hypothesize that Smad3-mediated TGF-β signal pathway plays important roles in the pathogenesis of AAA.

Methods
To test this hypothesis, we analyze the effects of loss of Smad3 on aneurysm formation in the calcium chloride induced AAA model using Smad3 knockout mice.

Results
Three weeks after calcium chloride treatment, the abdominal aorta displayed increased dilation, forming aneurysms. Histology and immunohistochemistry analyses show increased cell proliferation and enhanced inflammatory cell infiltration in the media and adventitia of the vessel wall. This was accompanied by elastic fibers degradation, increased MMPs expression and reduced expression of smooth muscle markers. Further analysis showed that the expression and nuclear localization of Smad2 and Smad4 was significantly increased.

Conclusions
These results demonstrate that Smad3-mediated TGF-β signaling plays a protective role in the pathogenesis of AAA and Smad2/Smad4 upregulation is not sufficient to compensate for the loss of Smad3 in this experimental model.
Abstract 289: High Density Lipoproteins Augment Hypoxia-Induced Angiogenesis via Regulation of Post-translational Modification of HIF-1a
Authors: Tan Joanne T , Prosser Hamish C , Vanags Laura Z , Monger Steven A , Ng Martin K , Bursill Christina A 
Published: July 2021

Background
Angiogenesis plays a critical role in tissue neovascularization in response to ischemia, particularly following myocardial infarction (MI). High-density lipoproteins (HDL) are associated with improved survival following MI, suggesting that it may play a role in hypoxia-induced angiogenic regulation. We have shown previously that in hypoxia, HDL augments angiogenesis and HIF-1α/VEGF expression. HIF-1α is post-translationally regulated by prolyl hydroxylases (PHDs 1-3), which target HIF-1α for degradation following hydroxylation. Furthermore, Siah ubiquitin ligases (Siah1 and Siah2) promote the degradation of PHDs. We aimed to determine if HDL augments HIF-1α/VEGF via modulation of PHDs and Siahs.

Methods
Human coronary artery endothelial cells were pre-incubated with PBS (control) or reconstituted HDL (rHDL) for 24 h then subjected to normoxic or hypoxic conditions for 6 h. To determine the importance of Siah1 and Siah2 in the HDL-induced modulation of the HIF-1α/VEGF pathway, a siRNA knockdown approach was used.

Results
Pre-incubation with rHDL inhibited the hypoxia-induced increases in PHD2 and PHD3 levels (32% and 45% respectively, p<0.05) while Siah1 and Siah2 mRNA levels were increased (58% and 88% respectively, p<0.05) with rHDL pre-incubation. Following siRNA knockdown of Siah1 and Siah2, HDL lost its ability to induce the expression of HIF-1α (11% reduction, p<0.05) and VEGF (18% reduction, p<0.05). Augmentation of tubulogenesis by HDL was attenuated in Siah siRNA-transfected cells (55% in siSiah1; 40% in siSiah2, p<0.05). Siah knockdown also abrogated HDL inhibition of hypoxia-mediated induction of PHD2 and PHD3 (p<0.05). PI3K and Akt are upstream regulators of HIF-1α/VEGF and also regulate Siahs. Specific inhibition of the PI3K/Akt pathway revealed that it plays a key role in HDL-induced elevations in Siah1 and Siah2 (37% and 20% reduction respectively, p<0.05) as well as HIF-1α and VEGF (65% and 15% reduction respectively, p<0.05).

Conclusion
In conclusion, HDL augments the HIF-1α/VEGF pathway by regulation of post-translational modification of HIF-1α via the PI3K/Siah/PHD pathway. HDL induced augmentation of angiogenesis in hypoxia may have implications for preventing ischemic injury following MI.