lesion formation
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Author(s):  
Kars Neven ◽  
Vincent J.H.M. Driel ◽  
Aryan Vink ◽  
Bastiaan C. du Pré ◽  
Harry Wessel ◽  
...  

2021 ◽  
Author(s):  
Omar El Bounkari ◽  
Chunfang Zan ◽  
Jonas Wagner ◽  
Elina Bugar ◽  
Priscila Bourilhon ◽  
...  

Atherosclerosis is the underlying cause of cardiovascular diseases (CVDs) such as myocardial infarction and ischemic stroke. It is a lipid-triggered chronic inflammatory condition of the arterial vascular wall that is driven by various inflammatory pathways including atherogenic cytokines and chemokines. D-dopachrome tautomerase (D-DT), also known as macrophage migration inhibitory factor-2 (MIF-2), belongs to the MIF protein family, which is best known for its pathogenic role in a variety of inflammatory and immune conditions including CVDs. While MIF is well known as a promoter of atherogenic processes, MIF-2 has not been studied in atherosclerosis. Here, we investigated atherosclerosis in hyperlipidemic Mif-2-/-Apoe-/- mice and studied the role of MIF-2 in various atherogenic assays in vitro. We found that global Mif-2 deficiency as well as its pharmacological blockade by 4-CPPC protected against atherosclerotic lesion formation and vascular inflammation in models of early and advanced atherogenesis. On cellular level, MIF-2 promoted monocyte migration in 2D and 3D and monocyte arrest on aortic endothelial monolayers, promoted B-cell chemotaxis in vitro and B-cell homing in vivo, and increased macrophage foam cell formation. Dose curves and direct comparison in a 3D migration set-up suggest that MIF-2 may be a more potent chemokine than MIF for monocytes and B cells. We identify CXCR4 as a novel receptor for MIF-2. The evidence relies on a CXCR4 inhibitor, CXCR4 internalization experiments, MIF-2/CXCR4 binding studies by yeast-CXCR4 transformants, and fluorescence spectroscopic titrations with a soluble CXCR4 surrogate. Of note, Mif-2-/- Apoe-/- mice exhibited decreased plasma cholesterol and triglyceride levels, lower body weights, smaller livers, and profoundly reduced hepatic lipid accumulation compared to Apoe-/- mice. Mechanistic experiments in Huh-7 hepatocytes suggest that MIF-2 regulates the expression and activation of sterol-regulatory element binding protein-1 and -2 (SREBP-1, SREBP-2) to induce lipogenic downstream genes such as FASN and LDLR, while it attenuated the activation of the SREBP inhibiting AMPK pathway. Studies using receptor Inhibitors showed that SREBP activation and hepatic lipoprotein uptake by MIF-2 is mediated by both CXCR4 and CD74. Lastly and in line with a combined role of MIF-2 in vascular inflammation and hepatic lipid accumulation, MIF-2 was found to be profoundly upregulated in unstable human carotid plaques, underscoring a critical role for MIF-2 in advanced stages of atherosclerosis. Together, these data identify MIF-2 as a novel atherogenic chemokine and CXCR4 ligand that not only promotes lesion formation and vascular inflammation but also strongly affects hepatic lipogenesis in an SREBP-mediated manner, possibly linking atherosclerosis and hepatic steatosis.


2021 ◽  
Author(s):  
Julia Stokes ◽  
Rebecca Bornstein ◽  
Katerina James ◽  
Kyung Yeon Park ◽  
Kira Spencer ◽  
...  

Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of Leigh syndrome. Directly depleting leukocytes with a colony-stimulating factor 1 receptor (CSF1R) inhibitor dramatically attenuates disease, including complete prevention of CNS lesion formation and substantial extension of survival. Leukocyte depletion rescues a range of symptoms including hyperlactemia, seizures, respiratory function, and neurologic symptoms. These data provide a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement directly drives disease. These findings have significant implication for the mechanisms of disease resulting from mitochondrial dysfunction, and may lead to novel therapeutic strategies.


2021 ◽  
Vol 22 (21) ◽  
pp. 11429
Author(s):  
Paolo Custurone ◽  
Luca Di Bartolomeo ◽  
Natasha Irrera ◽  
Francesco Borgia ◽  
Domenica Altavilla ◽  
...  

Vitiligo is a chronic autoimmune dermatosis of which the pathogenesis remains scarcely known. A wide variety of clinical studies have been proposed to investigate the immune mediators which have shown the most recurrency. However, such trials have produced controversial results. The aim of this review is to summarize the main factors involved in the pathogenesis of vitiligo, the latest findings regarding the cytokines involved and to evaluate the treatments based on the use of biological drugs in order to stop disease progression and achieve repigmentation. According to the results, the most recurrent studies dealt with inhibitors of IFN-gamma and TNF-alpha. It is possible that, given the great deal of cytokines involved in the lesion formation process of vitiligo, other biologics could be developed in the future to be used as adjuvants and/or to entirely replace the treatments that have proven to be unsatisfactory so far.


Author(s):  
Francesca Fasolo ◽  
Hong Jin ◽  
Greg Winski ◽  
Ekaterina Chernogubova ◽  
Jessica Pauli ◽  
...  

Background: Long noncoding RNAs (lncRNAs) are important regulators of biological processes involved in vascular tissue homeostasis and disease development. The current study assessed the functional contribution of the lncRNA Myocardial Infarction Associated Transcript ( MIAT ) to atherosclerosis and carotid artery disease. Methods: We profiled differences in RNA transcript expression in patients with advanced carotid artery atherosclerotic lesions from the Biobank of Karolinska Endarterectomies (BiKE). The lncRNA MIAT was identified as the most upregulated non-coding RNA transcript in carotid plaques compared to non-atherosclerotic control arteries, which was confirmed by quantitative real time PCR (qRT-PCR) and in situ hybridization. Results: Experimental knockdown of MIAT , utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) not only markedly decreased proliferation and migration rates of cultured human carotid artery smooth muscle cells (SMCs), but also increased their apoptosis. Mechanistically, MIAT regulated SMC proliferation via the EGR1-ELK1-ERK pathway. MIAT is further involved in SMC phenotypic transition to proinflammatory macrophage-like cells through binding to the promoter region of KLF4 and enhancing its transcription. Studies using Miat −/− and Miat −/− ApoE −/− mice as well as Yucatan LDLR −/− mini-pigs confirmed the regulatory role of this lncRNA in SMC de- and trans-differentiation and advanced atherosclerotic lesion formation. Conclusions: The lncRNA MIAT is a novel regulator of cellular processes in advanced atherosclerosis that controls proliferation, apoptosis, and phenotypic transition of SMCs as well as the pro-inflammatory properties of macrophages.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Soo Young Park ◽  
Rajinder Singh-Moon ◽  
Haiqiu Yang ◽  
Deepak Saluja ◽  
Christine Hendon

AbstractThere are currently limited means by which lesion formation can be confirmed during radiofrequency ablation procedures. The purpose of this study was to evaluate the use of NIRS-integrated RFA catheters for monitoring irrigated lesion progression, ex vivo and in vivo. Open-irrigated NIRS-ablation catheters with optical fibers were fabricated to sample tissue diffuse reflectance. Spectra from 44 irrigated lesions and 44 non-lesion sites from ex vivo swine hearts (n = 15) were used to train and evaluate a predictive model for lesion dimensions based on key spectral features. Additional studies were performed in diluted blood to assess NIRS signatures of catheter-tissue contact status. Finally, the potential of NIRS-RFA catheters for guiding lesion delivery was evaluated in a set of in vivo pilot studies conducted in healthy pigs (n = 4). Model predictions for lesion depth (R = 0.968), width (R = 0.971), and depth percentage (R = 0.924) correlated well with measured lesion dimensions. In vivo deployment in preliminary trials showed robust translational consistency of contact discrimination (P < 0.0001) and lesion depth parameters (< 3% error). NIRS empowered catheters are well suited for monitoring myocardial response to RF ablation and may provide useful intraprocedural feedback for optimizing treatment efficacy alongside current practices.


2021 ◽  
pp. 135245852110449
Author(s):  
Matthias Bussas ◽  
Sophia Grahl ◽  
Viola Pongratz ◽  
Achim Berthele ◽  
Christiane Gasperi ◽  
...  

Background: Lesions of brain white matter (WM) and atrophy of brain gray matter (GM) are well-established surrogate parameters in multiple sclerosis (MS), but it is unclear how closely these parameters relate to each other. Objective: To assess across the whole cerebrum whether GM atrophy can be explained by lesions in connecting WM tracts. Methods: GM images of 600 patients with relapsing-remitting MS (women = 68%; median age = 33.0 years, median expanded disability status scale score = 1.5) were converted to atrophy maps by data from a healthy control cohort. An atlas of WM tracts from the Human Connectome Project and individual lesion maps were merged to identify potentially disconnected GM regions, leading to individual disconnectome maps. Across the whole cerebrum, GM atrophy and potentially disconnected GM were tested for association both cross-sectionally and longitudinally. Results: We found highly significant correlations between disconnection and atrophy across most of the cerebrum. Longitudinal analysis demonstrated a close temporal relation of WM lesion formation and GM atrophy in connecting fibers. Conclusion: GM atrophy is associated with WM lesions in connecting fibers. Caution is warranted when interpreting group differences in GM atrophy exclusively as differences in early neurodegeneration independent of WM lesion formation.


PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257050
Author(s):  
Nándor Szegedi ◽  
Zoltán Salló ◽  
Péter Perge ◽  
Katalin Piros ◽  
Vivien Klaudia Nagy ◽  
...  

Introduction Our pilot study aimed to evaluate the role of local impedance drop in lesion formation during pulmonary vein isolation with a novel contact force sensing ablation catheter that records local impedance as well and to find a local impedance cut-off value that predicts successful lesion formation. Materials and methods After completing point-by-point radiofrequency pulmonary vein isolation, the success of the applications was evaluated by pacing along the ablation line at 10 mA, 2 ms pulse width. Lesions were considered successful if loss of local capture was achieved. Results Out of 645 applications, 561 were successful and 84 were unsuccessful. Compared to the unsuccessful ablation points, the successful applications were shorter (p = 0.0429) and had a larger local impedance drop (p<0.0001). There was no difference between successful and unsuccessful applications in terms of mean contact force (p = 0.8571), force-time integral (p = 0.0699) and contact force range (p = 0.0519). The optimal cut-point for the local impedance drop indicating successful lesion formation was 21.80 Ohms on the anterior wall [AUC = 0.80 (0.75–0.86), p<0.0001], and 18.30 Ohms on the posterior wall [AUC = 0.77 (0.72–0.83), p<0.0001]. A local impedance drop larger than 21.80 Ohms on the anterior wall and 18.30 Ohms on the posterior wall was associated with an increased probability of effective lesion creation [OR = 11.21, 95%CI 4.22–29.81, p<0.0001; and OR = 7.91, 95%CI 3.77–16.57, p<0.0001, respectively]. Conclusion The measurement of the local impedance may predict optimal lesion formation. A local impedance drop > 21.80 Ohms on the anterior wall and > 18.30 Ohms on the posterior wall significantly increases the probability of creating a successful lesion.


2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Krzysztof Ficek ◽  
Jolanta Rajca ◽  
Jerzy Cholewiński ◽  
Agnieszka Racut ◽  
Paweł Gwiazdoń ◽  
...  

Abstract Background Cyclops lesion is the second most common cause of extension loss after anterior cruciate ligament reconstruction. This study focused on the correlation between the anatomy of the intercondylar notch and the incidence of cyclops lesion. To determine whether the size and shape of the intercondylar notch are related to cyclops lesion formation following anterior cruciate ligament reconstruction according to magnetic resonance imaging (MRI) findings. Methods One hundred twenty-five (125) patients were retrospectively evaluated. The notch width index (NWI) and notch shape index (NSI) were measured based on coronal and axial MRI sections in patients diagnosed with cyclops syndrome (n = 25), diagnosed with complete anterior cruciate ligament (ACL) tears (n = 50), and without cyclops lesions or ACL ruptures (n = 50). Results Imaging analysis results showed that the cyclops and ACL groups had lower mean NWI and NSI values than the control group. Significant between-group differences were found in NSI (p = 0.0140) based on coronal cross-sections and in NWI (p = 0.0026) and NSI (p < 0.0001) based on axial sections. Conclusions The geometry of the intercondylar notch was found to be associated with the risk of cyclops lesion formation and ACL rupture.


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