The importance of intracranial atherosclerotic disease (ICAD) as a cause of stroke is underscored as compared to that of extracranial carotid stenosis and nonvalvular atrial fibrillation. Recent ...large clinical trials of ICAD, which evaluated the effectiveness of anticoagulation and stenting to prevent thromboembolism and restore hemodynamic compromise, failed to reduce major vascular events in patients with ICAD. These trials showed the importance of optimal control of risk factors to reduce major vascular events in these patients. Recent advances in risk factors for ICAD are summarized, together with possible reasons for race-ethnic differences in the prevalence of ICAD. In addition, the failure of the major clinical trials of ICAD may be caused by limitations in the understanding of ICAD. Unlike in patients with extracranial carotid stenosis or atrial fibrillation, stroke associated with ICAD occurs in association with various stroke mechanisms such as in situ thrombotic occlusion, artery-to-artery embolism, hemodynamic insufficiency, and branch occlusion. In clinical trials of ICAD, patients with all these types of ICAD were included. However, treatment effects may differ among the different types of ICAD. Treatment strategies might be selected based on clinical features (including the time after onset) and serologic and neuroimaging biomarkers (including diffusion-weighted image pattern and plaque images). Additional clinical trials considering these features are needed.
Moyamoya disease is a rare cause of stroke, radiologically characterised by progressive stenosis of the terminal portion of the internal carotid arteries and compensatory capillary collaterals. The ...discovery that RNF213, which encodes an unconventional E3 ubiquitin ligase, is the major susceptibility gene for moyamoya disease in people from east Asia has opened new avenues for investigation into the mechanisms of disease and potential treatment targets. The Arg4810Lys variant of the gene is most strongly associated with moyamoya disease, but the penetrance is lower than 1%, suggesting a synergistic relationship with additional environmental and genetic risk factors. White people carry less common non-Arg4810Lys variants of RNF213, which partly explains the lower prevalence of moyamoya disease in European countries and in the USA than in east Asian countries. Several monogenic moyamoya syndromes possess the radiological characteristics of moyamoya disease and have been associated with multiple genes and pathways involved in moyamoya angiopathy pathogenesis. Further clarification of the genetic and environmental factors that contribute to the emergence of moyamoya angiopathy could enable development of new treatment strategies for moyamoya disease.
Microvesicles (MVs) released by cells are involved in a multitude of physiological events as important mediators of intercellular communication. MVs derived from mesenchymal stem cells (MSCs) contain ...various paracrine factors from the cells that primarily contribute to their therapeutic efficacy observed in numerous clinical trials. As nano-sized and bi-lipid layered vesicles retaining therapeutic potency equivalent to that of MSCs, MSC-derived MVs have been in focus as ideal medicinal candidates for regenerative medicine, and are preferred over MSC infusion therapy with their improved safety profiles. However, technical challenges in obtaining sufficient amounts of MVs have limited further progress in studies and clinical application. Of the multiple efforts to reinforce the therapeutic capacity of MSCs, few studies have reportedly examined the scale-up of MSC-derived MV production. In this study, we successfully amplified MV secretion from MSCs compared to the conventional culture method using a simple and efficient 3D-bioprocessing method. The MSC-derived MVs produced in our dynamic 3D-culture contained numerous therapeutic factors such as cytokines and micro-RNAs, and showed their therapeutic potency in in vitro efficacy evaluation. Our results may facilitate diverse applications of MSC-derived MVs from the bench to the bedside, which requires the large-scale production of MVs.
Purpose
Deep sedation for endoscopic retrograde cholangiopancreatography (ERCP) can be challenging in elderly patients in the prone position. This study investigated the effect of a high flow nasal ...oxygen (HFNO) delivery system on oxygenation in this procedure compared with that of conventional nasal cannula oxygen administration.
Methods
A prospective randomized trial was conducted using HFNO and conventional nasal cannula in patients undergoing ERCP in the prone position. For each patient, the lowest oxygen saturation (SpO
2
), the incidence of hypoxemia defined as an SpO
2
below 90%, and interruptions due to airway interventions were recorded during the procedure.
Results
The lowest mean (standard deviation) SpO
2
recorded during the procedure was higher in the HFNO group than in the conventional control group 99.8 (0.6)%
vs
95.1 (7.3)%; mean difference, 4.7%; 95% confidence interval, 2.3% to 7.1%;
P
Group x Time
< 0.001. While the lowest SpO
2
during the procedure was lower than the baseline SpO
2
in the control group, the lowest SpO
2
during the procedure was higher than the baseline SpO
2
in the HFNO group. Hypoxemia occurred only in the control group (
n
= 7; 19%;
P
= 0.01). Procedural interruptions, including discontinuation of sedation, patient stimulation, and jaw thrusting, occurred only in the control group (
n
= 9 25%,
n
= 10 28%, and
n
= 10 28% cases, respectively;
P
= 0.001 for each).
Conclusion
In contrast to conventional nasal cannula, high flow nasal oxygen provided adequate oxygenation without causing procedural interruptions during ERCP, suggesting that HFNO may be used as a standard oxygen delivery method during these procedures.
Trial registration
www.ClinicalTrials.gov
(NCT03872674); registered 11 March 2019.
Stroke is the leading cause of physical disability among adults. Stem cells such as mesenchymal stem cells (MSCs) secrete a variety of bioactive substances, including trophic factors and ...extracellular vesicles (EVs), into the injured brain, which may be associated with enhanced neurogenesis, angiogenesis, and neuroprotection. EVs are circular membrane fragments (30 nm-1 μm) that are shed from the cell surface and harbor proteins, microRNAs, etc. Since 2013 when it was first reported that intravenous application of MSC-derived EVs in a stroke rat model improved neurological outcomes and increased angiogenesis and neurogenesis, many preclinical studies have shown that stem cell-derived EVs can be used in stroke therapy, as an alternative approach to stem cell infusion. Although scientific research regarding MSC-derived EV therapeutics is still at an early stage, research is rapidly increasing and is demonstrating a promising approach for patients with severe stroke. MSC therapies have already been tested in preclinical studies and clinical trials, and EV-mediated therapy has unique advantages over cell therapies in stroke patients, in terms of biodistribution (overcoming the first pass effect and crossing the blood-brain-barrier), cell-free paradigm (avoidance of cell-related problems such as tumor formation and infarcts caused by vascular occlusion), whilst offering an off-the-shelf approach for acute ischemic stroke. Recently, advances have been made in the understanding of the function and biogenesis of EVs and EVs therapeutics for various diseases. This review presents the most recent advances in MSC-derived EV therapy for stroke, focusing on the application of this strategy for stroke patients.
To test whether autologous modified mesenchymal stem cells (MSCs) improve recovery in patients with chronic major stroke.
In this prospective, open-label, randomized controlled trial with blinded ...outcome evaluation, patients with severe middle cerebral artery territory infarct within 90 days of symptom onset were assigned, in a 2:1 ratio, to receive preconditioned autologous MSC injections (MSC group) or standard treatment alone (control group). The primary outcome was the score on the modified Rankin Scale (mRS) at 3 months. The secondary outcome was to further demonstrate motor recovery.
A total of 39 and 15 patients were included in the MSC and control groups, respectively, for the final intention-to-treat analysis. Mean age of patients was 68 (range 28-83) years, and mean interval between stroke onset to randomization was 20.2 (range 5-89) days. Baseline characteristics were not different between groups. There was no significant difference between the groups in the mRS score shift at 3 months (
= 0.732). However, secondary analyses showed significant improvements in lower extremity motor function in the MSC group compared to the control group (change in the leg score of the Motricity Index,
= 0.023), which was notable among patients with low predicted recovery potential. There were no serious treatment-related adverse events.
IV application of preconditioned, autologous MSCs with autologous serum was feasible and safe in patients with chronic major stroke. MSC treatment was not associated with improvements in the 3-month mRS score, but we did observe leg motor improvement in detailed functional analyses.
This study provides Class III evidence that autologous MSCs do not improve 90-day outcomes in patients with chronic stroke.
NCT01716481.
One-quarter to one-third of ischemic strokes have no established mechanism after standard diagnostic evaluation and are classified as embolic stroke of undetermined source (ESUS). Failure of ...randomized trials to demonstrate a benefit of direct oral anticoagulants over aspirin for the treatment of ESUS as a single homogeneous entity has led to renewed interest by stroke experts to divide ESUS into subgroups. Emerging data suggest that active cancer, which is present in 5% to 10% of patients with ESUS, is a distinct and important subgroup of ESUS with unique clinical characteristics, underlying pathophysiologies, and treatment and prognostic considerations. Furthermore, the prevalence of cancer-related ESUS is expected to increase as patients with cancer, even those with distant metastases, survive longer due to improvements in cancer treatments. In this topical review, we examine the epidemiological link between ESUS and cancer, the clinical features and potential mechanistic underpinnings of ESUS with cancer (with a focus on novel biomarkers and their relationship to recurrent stroke and other thromboembolic events), and the potential treatment strategies for cancer-related ESUS. We include a critical appraisal of existing data and ongoing or planned clinical trials of different antithrombotic approaches. As cancer-related ESUS is a dynamic disease with variable course, we recommend close collaboration between neurologists and oncologists to develop individualized management plans.
Stem cell-based therapy is a promising approach for treating a variety of disorders, including acute brain insults and neurodegenerative diseases. Stem cells such as mesenchymal stem cells (MSCs) ...secrete extracellular vesicles (EVs), circular membrane fragments (30 nm-1 μm) that are shed from the cell surface, carrying several therapeutic molecules such as proteins and microRNAs. Because EV-based therapy is superior to cell therapy in terms of scalable production, biodistribution, and safety profiles, it can be used to treat brain diseases as an alternative to stem cell therapy. This review presents evidences evaluating the role of stem cell-derived EVs in stroke, traumatic brain injury, and degenerative brain diseases, such as Alzheimer's disease and Parkinson' disease. In addition, stem cell-derived EVs have better profiles in biocompatibility, immunogenicity, and safety than those of small chemical and macromolecules. The advantages and disadvantages of EVs compared with other strategies are discussed. Even though EVs obtained from native stem cells have potential in the treatment of brain diseases, the successful clinical application is limited by the short half-life, limited targeting, rapid clearance after application, and insufficient payload. We discuss the strategies to enhance the efficacy of EV therapeutics. Finally, EV therapies have yet to be approved by the regulatory authorities. Major issues are discussed together with relevant advances in the clinical application of EV therapeutics. BMB Reports 2022; 55(1): 20-29.
Polypharmacy is common in patients with atrial fibrillation (AF), making these patients vulnerable to the occurrence of potential drug-drug interactions (DDIs). We assessed the risk of ischemic ...stroke and major bleeding in the context of concomitant treatment with potential DDIs in patients with AF prescribed direct oral anticoagulants (DOACs). Using the common data model (CDM) based on an electronic health record (EHR) database, we included new users of DOACs from among patients treated for AF between January 2014 and December 2017 (n = 1938). The median age was 72 years, and 61.8% of the patients were males, with 28.2% of the patients having a CHA
DS
-VASc score in category 0-1, 49.4% in category 2-3, and 22.4% in category ≥ 4. The CHA
DS
-VASc score was significantly associated with ischemic stroke occurrence and hospitalization for major bleeding. Multiple logistic regression analysis showed that increased risk of ischemic stroke and hospitalization for major bleeding was associated with the number of DDIs regardless of comorbidities: ≥ 2 DDIs was associated with ischemic stroke (OR = 18.68; 95% CI, 6.22-55.27, P < 0.001) and hospitalization for major bleeding (OR = 5.01; 95% CI, 1.11-16.62, P < 0.001). DDIs can cause reduced antithrombotic efficacy or increased risk of bleeding in AF patients prescribed DOACs.
Collaterals sustain the penumbra before recanalization and offset infarct growth, yet the influence of baseline collateral flow on recanalization after endovascular therapy remains relatively ...unexplored.
We analyzed consecutive patients who received endovascular therapy for acute cerebral ischemia from 2 distinct study populations. We assessed the relationship between pretreatment collateral grade and vascular recanalization (Thrombolysis In Myocardial Ischemia TIMI scale). In addition, we assessed infarct growth on serial MRI.
A total of 222 patients was included, 138 from the United States and 84 from South Korea. Complete revascularization occurred in 14.1% (11 of 78) patients with poor pretreatment collateral grades, whereas it was observed in 25.2% (26 of 103) patients with good collaterals and 41.5% (17 of 41) patients with excellent collaterals (P<0.001). This relationship was consistently observed in both study populations, although the mode of endovascular therapy was different between them. After adjustment for other factors, including mode of endovascular therapy, prior use of intravenous tissue plasminogen activator, and site of occlusion, pretreatment collateral grade was independently associated with recanalization. When revascularization was achieved, greater infarct growth occurred in patients with poor collaterals than in those with good collaterals (P=0.012).
Our data indicate that angiographic collateral grade determines the recanalization rate after endovascular revascularization therapy. When therapeutic revascularization was achieved, beneficial effects were not observed in patients with poor collaterals. Angiographic collateral grade may therefore help guide treatment decision-making in acute cerebral ischemia.
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