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Browsing by Subject "Vascular system injuries"
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Item Dual Anti-Inflammatory and Anti-Angiogenic Action of miR-15a in Diabetic Retinopathy.(Elsevier, 2016-09) Wang, Qi; Navitskaya, Svetlana; Chakravarthy, Harshini; Huang, Chao; Kady, Nermin; Lydic, Todd A.; Chen, Y. Eugene; Yin, Ke-Jie; Powell, Folami Lamoke; Martin, Pamela M.; Grant, Maria B.; Busik, Julia V.; Department of Ophthalmology, IU School of MedicineActivation of pro-inflammatory and pro-angiogenic pathways in the retina and the bone marrow contributes to pathogenesis of diabetic retinopathy. We identified miR-15a as key regulator of both pro-inflammatory and pro-angiogenic pathways through direct binding and inhibition of the central enzyme in the sphingolipid metabolism, ASM, and the pro-angiogenic growth factor, VEGF-A. miR-15a was downregulated in diabetic retina and bone marrow cells. Over-expression of miR-15a downregulated, and inhibition of miR-15a upregulated ASM and VEGF-A expression in retinal cells. In addition to retinal effects, migration and retinal vascular repair function was impaired in miR-15a inhibitor-treated circulating angiogenic cells (CAC). Diabetic mice overexpressing miR-15a under Tie-2 promoter had normalized retinal permeability compared to wild type littermates. Importantly, miR-15a overexpression led to modulation toward nondiabetic levels, rather than complete inhibition of ASM and VEGF-A providing therapeutic effect without detrimental consequences of ASM and VEGF-A deficiencies.Item Establishing a core outcome set for blunt cerebrovascular injury: an EAST modified Delphi method consensus study(BMJ, 2023-06-15) Ziesmann, Markus; Byerly, Saskya; Yeh, Daniel Dante; Boltz, Melissa; Gelbard, Rondi; Haut, Elliott R.; Smith, Jason W.; Stein, Deborah M.; Zarzaur, Ben L.; Bensard, Denis D.; Biffl, Walter L.; Boyd, April; Brommeland, Tor; Burlew, Clay Cothren; Fabian, Timothy; Lauerman, Margaret; Leichtle, Stefan; Moore, Ernest E.; Timmons, Shelly; Vogt, Kelly; Nahmias, Jeffry; Surgery, School of MedicineObjectives: Our understanding of blunt cerebrovascular injury (BCVI) has changed significantly in recent decades, resulting in a heterogeneous description of diagnosis, treatment, and outcomes in the literature which is not suitable for data pooling. Therefore, we endeavored to develop a core outcome set (COS) to help guide future BCVI research and overcome the challenge of heterogeneous outcomes reporting. Methods: After a review of landmark BCVI publications, content experts were invited to participate in a modified Delphi study. For round 1, participants submitted a list of proposed core outcomes. In subsequent rounds, panelists used a 9-point Likert scale to score the proposed outcomes for importance. Core outcomes consensus was defined as >70% of scores receiving 7 to 9 and <15% of scores receiving 1 to 3. Feedback and aggregate data were shared between rounds, and four rounds of deliberation were performed to re-evaluate the variables not achieving predefined consensus criteria. Results: From an initial panel of 15 experts, 12 (80%) completed all rounds. A total of 22 items were considered, with 9 items achieving consensus for inclusion as core outcomes: incidence of postadmission symptom onset, overall stroke incidence, stroke incidence stratified by type and by treatment category, stroke incidence prior to treatment initiation, time to stroke, overall mortality, bleeding complications, and injury progression on radiographic follow-up. The panel further identified four non-outcome items of high importance for reporting: time to BCVI diagnosis, use of standardized screening tool, duration of treatment, and type of therapy used. Conclusion: Through a well-accepted iterative survey consensus process, content experts have defined a COS to guide future research on BCVI. This COS will be a valuable tool for researchers seeking to perform new BCVI research and will allow future projects to generate data suitable for pooled statistical analysis with enhanced statistical power.Item Role of Acid Sphingomyelinase in Shifting the Balance Between Proinflammatory and Reparative Bone Marrow Cells in Diabetic Retinopathy(Wiley, 2016-04) Chakravarthy, Harshini; Navitskaya, Svetlana; O'reilly, Sandra; Gallimore, Jacob; Mize, Hannah; Beli, Eleni; Wang, Qi; Kady, Nermin; Huang, Chao; Blanchard, Gary J.; Grant, Maria B.; Busika, Julia V.; Ophthalmology, School of MedicineThe metabolic insults associated with diabetes lead to low-grade chronic inflammation, retinal endothelial cell damage, and inadequate vascular repair. This is partly due to the increased activation of bone marrow (BM)-derived proinflammatory monocytes infiltrating the retina, and the compromised function of BM-derived reparative circulating angiogenic cells (CACs), which home to sites of endothelial injury and foster vascular repair. We now propose that a metabolic link leading to activated monocytes and dysfunctional CACs in diabetes involves upregulation of a central enzyme of sphingolipid signaling, acid sphingomyelinase (ASM). Selective inhibition of ASM in the BM prevented diabetes-induced activation of BM-derived microglia-like cells and normalized proinflammatory cytokine levels in the retina. ASM upregulation in diabetic CACs caused accumulation of ceramide on their cell membrane, thereby reducing membrane fluidity and impairing CAC migration. Replacing sphingomyelin with ceramide in synthetic membrane vesicles caused a similar decrease in membrane fluidity. Inhibition of ASM in diabetic CACs improved membrane fluidity and homing of these cells to damaged retinal vessels. Collectively, these findings indicate that selective modulation of sphingolipid metabolism in BM-derived cell populations in diabetes normalizes the reparative/proinflammatory cell balance and can be explored as a novel therapeutic strategy for treating diabetic retinopathy.Item Treatment of asymptomatic blunt cerebrovascular injury (BCVI): a systematic review(BMJ, 2021-04-26) Murphy, Patrick B.; Severance, Sarah; Holler, Emma; Menard, Laura; Savage, Stephanie; Zarzaur, Ben L.; Surgery, School of MedicineBackground: The management of asymptomatic blunt cerebrovascular injury (BCVI) with respect to stroke prevention and vessel healing is challenging. Objectives: The aim of this systematic review was to determine if a specific treatment results in lower stroke rates and/or improved vessel healing in asymptomatic BCVI. Data sources: An electronic literature search of MEDLINE, EMBASE, Cochrane Library, CINAHL, SCOPUS, Web of Science, and ClinicalTrials.gov performed from inception to March 2020. Study eligibility criteria: Studies were included if they reported on a comparison of any treatment for BCVI and stroke and/or vessel healing rates. Participants and interventions: Adult patients diagnosed with asymptomatic BCVI(s) who were treated with any preventive medication or procedure. Study appraisal and synthesis methods: All studies were systematically reviewed and bias was evaluated by the Newcastle-Ottawa Scale. No meta-analysis was performed secondary to significant heterogeneity across studies in patient population, screening protocols, and treatment selection. The main outcomes were stroke and healing rate. Results: Of 8781 studies reviewed, 19 reported on treatment effects for asymptomatic BCVI and were included for review. Any choice of medical management was better than no treatment, but no specific differences between choice of medical management and stroke outcomes were found. Vessel healing was rare and the majority of healed vessels were following low-grade injuries. Limitations: Majority of the included studies were retrospective and at high risk of bias. Conclusions or implications of key findings: Asymptomatic BCVI should be treated medically using a consistent, local protocol. High-quality studies on the effect of individual antithrombotic agents on stroke rates and vessel healing for asymptomatic BCVI are required.