bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beneficial effect of colchicine in an animal model of atherosclerosis
Authors: Cecconi A , Vilchez-Tschischke J.P , Mateo J , Sanchez-Gonzalez J , Espana S , Fernandez-Jimenez R , Lopez-Melgar B , Fernandez Friera L , Lopez-Martin G.J , Fuster V , Ruiz-Cabello J , Ibanez B 
Published: November 2020

Abstract

Background
Atherosclerosis is a chronic inflammatory disease and colchicine demonstrated clinical benefits in the treatment of stable coronary artery disease.

Purpose
Our aim was to assess the anti-inflammatory effects of colchicine on atherosclerotic vascular disease.

Methods
Atherosclerosis was induced in the abdominal aorta of 20 rabbits with high-cholesterol diet and balloon endothelial denudation. The study protocol lasted 36 weeks. After 18 weeks rabbits were randomized to receive either colchicine or placebo. Two animals died in each group. At randomization and at the end of the study, all animals underwent MRI and positron 18F-FDG PET/CT. In this post-hoc subgroup analyses, animals of each group in the first quartile of cholesterol levels were excluded. For MRI plaque volume values were expressed as Normalized Wall Index (NWI) and for 18F-FDG PET/CT values were expressed as mean maximum standard uptake (meanSUVmax). Statistical comparisons were made by using the Mann-Whitney U test for unpaired data and Wilcoxon signed-rank test for paired data.

Results
Results are summarized in Table 1. Animals with higher levels of cholesterol (6 per group) showed significant differences in favor to colchicine group, both as NWI at the end of the protocol 0.47 (IQR 0.05) in the colchicine group versus 0.52 (IQR 0.03) in the placebo; p=0.01] and as relative increase in meanSUVmax [−4.0% (IQR 30.1) in the colchicine group versus 35.1 (IQR 59.0) in the placebo; p 0.041] (Figure 1).

Conclusions
Colchicine may stabilize atherosclerotic plaque by reducing inflammatory activity and plaque burden.
Figure 1

Funding Acknowledgement
Type of funding source: Public grant(s) – EU funding. Main funding source(s): This work was supported by a grant from the Sociedad Española de Cardiología and a grant from the Carlos III Institute of Health of Spain and Fondo Europeo de Desarrollo Regional (FEDER, “Una manera de hacer Europa”)
Maternal high-fat diet promotes calcified atherosclerotic plaque formation in adult offspring by enhancing transformation of vascular smooth muscle cells to osteochondrocytic-like phenotype
Authors: Miyawaki D , Yamada H , Kubota H , Sugimoto T , Saburi M , Wakana N , Matoba S 
Published: November 2020

Abstract

Background and objective
Maternal high-fat diet (HFD) has been shown to modulate vascular function and remodeling in adult offspring. Atherosclerotic vascular calcification is closely associated with the onset of cardiovascular event. We therefore investigated the impact of maternal HFD on calcification of atherogenic plaques.

Methods and results
Eight-week-old female apo-E−/− mice (C57BL/6) were fed an HFD or a normal diet (ND) one week prior to mating, and the diet was continued throughout gestation and lactation. Offspring of both groups were fed a high-cholesterol diet (HCD) from 8 weeks of age. Ex vivo osteogenic activity of aortic root and aortic arch was analyzed using in vivo imaging system (IVIS) with OsteoSense 680. Sixteen-week-old male offspring of HFD-fed dams (O-HFD) showed a 1.4-fold increase in fluorescent intensity compared with those of ND-fed dams (O-ND) (p&lt;0.05). Likewise, female O-HFD showed a significantly increased osteogenic activity in aortic arch (154%, p&lt;0.05). Percentages of plaque area and oil red O-positive area were comparable between O-ND and O-HFD of both genders, suggesting that augmented osteogenic activity in O-HFD is not dependent on the plaque size. To investigate the underlying mechanism of augmented calcified plaque formation in O-HFD, vascular smooth muscle cells (VSMCs) of thoracic aorta form 8-week-old male offspring were primarily cultured and VSMCs calcification was induced by treatment with calcification media supplemented with phosphate (2.6 mM). Alizarin-red-positive area upon 10 days stimulation showed a 3.4-fold increase in VSMCs from O-HFD compared with that from O-ND (p&lt;0.01). Consistently, western blotting analysis revealed that expression level of osteocalcin was significantly higher in O-HFD than O-ND, suggesting that osteochondrocytic transformation of VSMCs is augmented in O-HFD.

Conclusion
Our findings demonstrate that maternal HFD accelerates the development of atherogenic calcification independent of plaque size. In vitro transformation to osteochondrocytic-like cells is enhanced in VSMCs from offspring of HFD-fed dams. Inhibition of VSMCs skewing toward osteochondrocytic-like cells could be a potential therapeutic target for preventing the development of atherosclerotic vascular calcification.

Funding Acknowledgement
Type of funding source: None
Molecular structure analysis of ascending aorta aneurysm upon atherosclerosis
Authors: Mamarelis I , Mamareli V , Kyriakidou M , Tanis O , Mamareli C , Kotoulas S , Subramaniyan Parimalam S , Packirisamy M , Badilescu S , Anastassopoulou J , Kotoulas C , Theophanides T 
Published: November 2020

Abstract

Background
The atherosclerotic ascending aorta could represent a potential source of emboli or could be an indicator of atherosclerosis in general with high mortality. The mechanism of aneurysm formation and atherosclerosis of the ascending aorta at the molecular level has not yet been clarified. To approach the mechanism of ascending aortic lesions and mineralization at a molecular level, we used the non-destructive FT-IR, Raman spectroscopy, SEM and Hypermicroscope.

Methods
Six ascending aorta biopsies were obtained from patients who underwent aortic valve replacement (AVR) cardiac surgery. CytoViva (einst inc) hyperspectral microscope was used to obtain the images of ascending aorta. The samples were dissolved in hexane on a microscope glass plate. The FT-IR and Raman spectra were recorded with Nicolet 6700 thermoshintific and micro-Raman Reinshaw (785nm, 145 mwatt), respectively. The architecture of ascending aorta biopsies was obtained by using scanning electron microscope (SEM of Fei Co) without any coating.

Results
FT-IR and Raman spectra showed changes arising from the increasing of lipophilic environment and aggregate formation (Fig. 1). The band at 1744 cm–1 is attributed to aldehyde CHO mode due to oxidation of lipids. The shifts of the bands of the amide I and amide II bands to lower are associated with protein damage, in agreement with SEM data. The bands at about 1170–1000 cm–1 resulted from the C-O-C of advanced glycation products as result of connecting tissues fragmentations and polymerization. The spectroscopic data were analogous with the lesions observed with SEM and hypermicroscopic images.

Conclusions
The present innovate molecular structure analysis showed that upon ascending aorta aneurysm development an excess of lipophilic aggregate formation and protein lesions, changing the elasticity of the aorta's wall. The released Ca2+ interacted mostly with carbonate-terminal of cellular protein chains accelerated the ascending aorta calcifications.
Figure 1. FT-IR and Raman spectra

Funding Acknowledgement
Type of funding source: None
A novel three-dimensional visualization system revealed an essential adaptive angiogenic response during the early phase of pulmonary hypertension
Authors: Fujiwara T , Takeda N , Hatano M , Nishimura S , Komuro I 
Published: November 2020

Abstract

Background
Pulmonary hypertension (PH) is characterized by increased pulmonary vascular resistance and right heart failure with progressive narrowing or occlusion of the pulmonary artery. However, the assessment of vascular remodeling is mostly limited to averaged increases in wall thickening, and even the role of vascular endothelial growth factor (VEGF), remains incompletely understood; Although abundantly expressed VEGF is expected to elicit angio-obliteration and the knockout of hypoxia inducible factor (HIF) prevents PH in mice, VEGF inhibitor Sugen exacerbates hypoxia (Hx)-induced PH model, which is referred to as VEGF paradox.

Purpose
To analyze three-dimensional (3D) spatiotemporal changes of pulmonary microstructure and function, which reflect the disease activity and lead to resolve the paradox.

Methods and results
We developed a novel 3D visualization system of microstructural networks in whole mouse organ with single-cell resolution, using combined tissue clearing technique called CUBIC and multiphoton excitation microscope. The system enabled the simultaneous 3D evaluation of microvascular structure, invaded macrophages and fibrosis with effective penetration of several mm (whole organ). Three-dimensional observations of PH mice models including Hx, Sugen/Hx, and human-like Alk1+/− hereditary PH models, revealed that not only inward (negative) microvessel remodeling with stenosis, but also marked elongation of microvascular ECs, was evident except Sugen/Hx model at the early phase, which had not been detected by 2D histological sections. Comparable transcriptome analysis revealed that PGC1α, which regulates HIF-independent VEGF expression and angiogenesis, plays an important role in the characteristic response for mitochondrial and microvascular maintenance. PGC1α was up-regulated in the early phage in Hx and Alk1+/− PH models with microvascular angiogenetic change, whereas Sugen/Hx-model did not increase PGC1α expression and did not show microvascular remodeling. Furthermore pulmonary ECs-specific PGC1α-deficient mice exacerbated Hx-PH model with decreased VEGF expression and microvessel density, and administration of Baicalin, a flavonoid enhancing PGC1α expression, ameliorated Hx-PH model with increased VEGF expression.

Conclusions
The 3D visualization system disclosed an unexpected change of angiogenic microvascular structure in the early phage of PH, which is regulated by EC PGC1α. Microvascular angiogenesis which is induced by up-regulation in PGC1α -VEGF pathway is a crucial factor for compensation of PH in the early phase, which provides a potential novel therapeutic target for PH.
Figure 1

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSJP
Treating ApoE−/− mice with Toll-like receptor 7 ligand lead to expansion of marginal zone B cells, reduced plasma cholesterol and decreased atherosclerosis
Authors: Paulsson-Berne G , Karadimou G , Gistera A , Gallina A , Centa M , Salagianni M , Andreakos E , Hansson G.K , Malin S , Olofsson P 
Published: November 2020

Abstract

Background
The interplay between innate and adaptive immunity is involved in the cause of the life-threatening events in atherosclerosis, such as myocardial infarction and stroke. We have previously shown that higher levels of Toll-like receptor 7 (TLR7) expression in human atherosclerotic lesions are correlated to better patient outcome, emphasizing the role of the innate pattern recognizing receptors in the pathogenesis of atherosclerosis.

Purpose
Firstly, to investigate if activation of the innate immune receptor TLR7 in vivo in experimental atherosclerosis is a potential way to reduce disease and secondly to identify pathways upon TLR7 ligation treatment.

Methods
Apolipoprotein E (ApoE−/−) deficient mice with established disease were injected intraperitoneal with a TLR7 ligand. Local effects were evaluated by characterization of atherosclerotic lesions. Systemic effects of the treatment were investigated by immune composition analysis in the spleen and by plasma measurements

Results
In vivo treatment of ApoE−/−mice with TLR7 ligand arrested atherosclerotic lesion development in the aortic root. Moreover, in the lesions of the treated mice we detected decrease in necrotic area and decrease in accumulation of apoptotic cells. In the spleen we detected an expansion of marginal zone B cells accompanied with an increase in IgM antibodies against oxidized low-density lipoprotein (oxLDL). The treated mice had reduced plasma cholesterol levels.

Conclusions
In vivo administration of TLR7 ligand ameliorated the atherosclerotic burden in old ApoE−/− mice. Our findings indicate that TLR7 ligation is involved in control of inflammatory responses in atherosclerosis, suggesting that TLR7 is a potential therapeutic target. Further analysis is needed in order to elucidate the underlying mechanisms by which TLR7 exerts its protective role.

Funding Acknowledgement
Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Swedish Heart-Lung Foundation
IgG1 antibodies against phosphorylcholine are associated with protection in SLE and atherosclerosis: potential underlying mechanisms
Authors: Frostegard J , Steen J , Fiskesund R , Frostegard A.G , Rahman M , Lundstrom S , Thiagarajan D 
Published: November 2020

Abstract

Background
The risk of cardiovascular disease (CVD) and atherosclerosis is very high in SLE. This is a clinical problem, and could also shed light on immunity and atherosclerosis in general. IgM antibodies against phosphorylcholine (anti-PC) may be protective in atherosclerosis, cardiovascular disease (CVD) and systemic lupus erythematosus (SLE). We here study IgG1 and IgG2 anti-PC, with focus on atherosclerosis and SLE.

Methods
We determined anti-PC by ELISA in 116 SLE-patients and 110 age- and sex-matched controls. For functional studies, we used three in-house generated, fully human monoclonal IgG1 anti-PC (A01, D05, E01). Apoptosis was induced in Jurkat T-cells and pre-incubated with A01, D05, E01 or isotype control IgG1 and effects on efferocytosis by human macrophages studied. Anti-PC peptide/protein characterization was determined using a proteomics de novo sequencing approach.

Results
IgG1 but not IgG2 anti-PC levels were higher among SLE patients (p=0.02). IgG1 anti-PC was negatively associated with SLICC and SLEDAI (OR: 2,978 CI: 0.876–10.098, OR: 5.108 CI 1.3 20.067 respectively) and negatively associated with CVD, atherosclerotic plaques and echolucent (potentially vulnerable plaques) but the association for the two former was not significant after controlling for confounders. D05 had maximum effect on macrophage efferocytosis efficiency, followed by A01 and E01. The monoclonal antibodies showed differential binding specificity to PC and PC associated neo-epitopes. Peptide analysis showed difference in the CDR3 region of the three anti-PC IgG1 clones which are crucial for recognition of PC on apoptotic cell surface and other neo-epitopes.

Conclusion
Anti-PC IgG1 is negatively associated with disease activity, and disease damage in SLE, but the negative association with CVD is also dependent on confounding risk factors. One potential underlying mechanism could be increased clearance of dead cells.

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swedish Heart and Lung Foundation, Reumatikerfonden
Neutrophil extracellular traps induce MCP-1 release from endothelial cells at the plaque rupture site in acute myocardial infarction
Authors: Ondracek A , Hofbauer T.M , Mangold A , Scherz T , Seidl V , Lang I.M 
Published: November 2020

Abstract

Introduction
Leukocyte-mediated inflammation is crucial in acute myocardial infarction (AMI). We recently observed that neutrophil extracellular traps (NETs) are increased at the culprit site, promoting activation and differentiation of fibrocytes, cells with mesenchymal and leukocytic properties. Fibrocyte migration is mediated by monocyte chemoattractant protein (MCP)-1 and C-C chemokine receptor type 2 (CCR2). We investigated the interplay between NETs, fibrocyte function, and MCP-1 in AMI.

Methods
Culprit site and femoral blood of AMI patients was drawn during percutaneous coronary intervention. We characterized CCR2 expression of fibrocytes by flow cytometry. MCP-1 and the NET marker citrullinated histone H3 (citH3) were measured by ELISA. Fibrocytes were treated in vitro with MCP-1. Human coronary arterial endothelial cells (hCAECs) were stimulated with isolated NETs, and MCP-1 was measured by ELISA and qPCR. The influence of MCP-1 on NET formation in vitro was assessed using isolated neutrophils.

Results
We have included 50 consecutive AMI patients into the study. NETs and concentrations of MCP-1 were increased at the CLS. NET stimulation of hCAECs induced MCP-1 on mRNA and protein level. Increasing MCP-1 gradient was associated with fibrocyte accumulation at the site of occlusion. In the presence of higher MCP-1 these fibrocytes expressed proportionally less CCR2 than peripheral fibrocytes. In vitro, MCP-1 dose-dependently decreased fibrocyte CCR2 and reduced ex vivo NET release of healthy donor neutrophils.

Conclusions
NETs induce endothelial MCP-1 release, presumably promoting a chemotactic gradient for leukocyte and fibrocyte migration. MCP-1 mediated inhibition of NET formation could point to a negative feedback loop. These data will shed light on vascular healing.

Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund
‘You cannot touch taxes easily’: making the case for tobacco taxation in India
Authors: Rao Seshadri Shreelata , Kaulgud Radhika , Jha Prabhat 
Published: November 2020

AbstractIndia represents over 1.3 billion people with &gt;100 million adult smokers. The catastrophic health costs of smoking are staggering; and estimates show that even modest increases in taxes on cigarettes and bidis would both raise substantial revenues for the government and save ∼69 million years of healthy life over the next four decades. Karnataka represents a good example of tobacco control efforts and their impact. This case study examines the factors that have contributed to tobacco control policy in Karnataka based on 23 semi-structured interviews with key informants engaged in tobacco policymaking and decision-making, tobacco control/taxation research and advocacy. Their narratives indicate that: (i) Domestic taxation policy is complicated by the complex tax structure and centralized control over taxation with the introduction of Goods and Services Tax; (ii) Implementation of legal frameworks is a challenge, due to conflicts with powerful industry and farmer lobbies. A vigorous civil society backed by the Courts is necessary to garner political support; (iii) Action on taxation is hampered by weak leadership and mixed messaging; and (iv) There is a need for innovative policy solutions to promote both demand- and supply-side measures for tobacco control. Tobacco control advocates need to recognize the political economy of tobacco control and generate strong, reliable and scientifically sound evidence to support their arguments. Working for incremental ‘wins’ in terms of more stringent application of existing legal frameworks can make a substantial difference even in contexts where enhancing tobacco taxes is a challenge. Promoting multisectoral action is critical, at both policy and the ground levels, by expanding ownership and responsibility for tobacco control to sectors beyond health. Finally, the health sector needs to recommit to its role as a champion for tobacco control. Failure to do so would amount to a failure on multiple fronts—public health, economic, fiscal and ethical.
Mycobacterium tuberculosis complex and human coadaptation: a two-way street complicating host susceptibility to TB
Authors: Uren Caitlin , Hoal Eileen G , Möller Marlo 
Published: November 2020

Abstract
For centuries, the Mycobacterium tuberculosis complex (MTBC) has infected numerous populations, both human and non-human, causing symptomatic tuberculosis (TB) in some hosts. Research investigating the MTBC and how it has evolved with its host over time is sparse and has not resulted in many significant findings. There are even fewer studies investigating adaptation of the human host susceptibility to TB and these have largely focused on genome-wide association and candidate gene association studies. However, results emanating from these association studies are rarely replicated and appear to be population specific. It is, therefore, necessary to relook at the approach taken to investigate the relationship between the MTBC and the human host. Understanding that the evolution of the pathogen is coupled to the evolution of the host might be the missing link needed to effectively investigate their relationship. We hypothesize that this knowledge will bolster future efforts in combating the disease.
Lq-error estimates for approximation of irregular functionals of random vectors
Authors: Taguchi Dai , Tanaka Akihiro , Yuasa Tomooki 
Published: November 2020

AbstractIn Avikainen (2009, On irregular functionals of SDEs and the Euler scheme. Finance Stoch., 13, 381–401) the author showed that, for any $p,q \in [1,\infty )$, and any function $f$ of bounded variation in $\mathbb{R}$, it holds that $ \mathbb{E}[|f(X)-f(\widehat{X})|^{q}] \leq C(p,q) \mathbb{E}[|X-\widehat{X}|^{p}]^{\frac{1}{p+1}} $, where $X$ is a one-dimensional random variable with a bounded density, and $\widehat{X}$ is an arbitrary random variable. In this article we will provide multi-dimensional versions of this estimate for functions of bounded variation in $\mathbb{R}^{d}$, Orlicz–Sobolev spaces, Sobolev spaces with variable exponents and fractional Sobolev spaces. The main idea of our arguments is to use the Hardy–Littlewood maximal estimates and pointwise characterizations of these function spaces. We apply our main results to analyze the numerical approximation for some irregular functionals of the solution of stochastic differential equations.
In vitrosusceptibility ofMycobacterium abscessuscomplex and feasibility of standardizing treatment regimens
Authors: Chew Ka Lip , Octavia Sophie , Go Joelle , Ng Sally , Tang Yit Er , Soh Patsy , Yong Joy , Jureen Roland , Lin Raymond Tzer Pin , Yeoh Siang Fei , Teo Jeanette 
Published: November 2020

AbstractObjectivesTo determine the in vitro susceptibility of members of the Mycobacterium abscessus complex to routinely tested antibiotics and to an extended antibiotic panel.MethodsNon-duplicate isolates for which susceptibility testing results were available were included in this study. Retrospective laboratory records were reviewed, including tigecycline susceptibility results, and testing was performed with additional drugs, including vancomycin, dalbavancin, telavancin, oritavancin, rifabutin, delafloxacin, eravacycline, clofazimine and bedaquiline using broth microdilution (Sensititre, Thermo Fisher).ResultsA total of 218 M. abscessus complex isolates were included for retrospective review, of which 151 were respiratory isolates. Of these 218 isolates, 211 were available for additional testing with the extended antibiotic panel. Of these, 146 were respiratory isolates. One isolate had a vancomycin MIC of 2 mg/L and MICs of all other isolates were &gt;8 mg/L. All isolates had MICs of &gt;8 mg/L for oritavancin, dalbavancin and telavancin. One isolate had a delafloxacin MIC of 4 mg/L and MICs of all other isolates were &gt;8 mg/L. The MIC50/MIC90s of rifabutin, tigecycline, eravacycline, clofazimine and bedaquiline were 16/32, 0.5/1, 0.12/0.25, 0.12/0.25 and 0.06/0.12 mg/L, respectively.ConclusionsIn vitro activity was demonstrated for clofazimine, bedaquiline and eravacycline, indicating potential for inclusion as standardized therapy for M. abscessus complex infections.