Use of mesenchymal stem cell therapy in COVID-19 related strokes

Co ronavirus disease 2019(COVID-19) has affected a broad demographics,eliciting a more significant effect on specific groups such as males,African Americans,and Hispanic minorities.Treatment of COVID-19 often requires antiviral drugs or monoclonal antibodies.However,immunotherapies such as mesenchymal stem cells and mesenchymal stem cells-derived exosomal vesicles should be evaluated as treatment options for COVID-19.Mesenchymal stem cell thera py offe rs regenerative,anti-inflammatory,and immunomodulato ry properties that can speed up the recovery from COVID-19.Mesenchymal stem cell therapy can also benefit COVID-19 patients who suffer from stro kes,as COVID-19 increases the risk of strokes due to increased cytokines and clotting facto rs.Most stroke cases that occur in COVID-19 patients are ischemic strokes.Therefo re,with the help of mesenchymal stem cell therapy and mesenchymal stem cells-derived exosomes,COVID-19-induced stroke patients might benefit from dual-ended treatment.The o bjective of this review was to discuss COVID-19 and stroke incidence and the available treatment options.

Persistent dysexecutive syndrome after pneumococcal meningitis complicated by recurrent ischemic strokes:A case report

Meningitis is a possible complication of pneumococcal infection concerning acute otitis media and sinusitis.It might compromise cognitive function,both for the infection itself and the vascular events that sometimes follow the acute phase.CASE SUMMARY Here we describe the case of a 32-year-old female patient admitted to the emergency room due to extensive pneumococcal meningitis as a consequence of sinus outbreak.She presented with extensive laminar ischemic damage in the acute phase,resulting in severe cognitive and behavioural impairment.Four years of follow-up,through neuropsychological assessments and neuroradiological investigations,demonstrated the presence of subsequent vascular events,3 months and 2 years after onset.CONCLUSION The case is discussed in light of scientific knowledge of the long-term outcomes of this pathology in order to potentially improve diagnosis and promote better outcomes.

Impact of Strokes: The Burden of Care, Post-CVA Fatigue & Caregiver Role Strain

Strokes and cerebral vascular accidents (CVAs) and related disease events are an unfortunate circumstance that inflicts individuals around the world and impacts people every day as individuals and their caregivers. The consequences of these strokes or CVA events are life-changing for all those involved. As a result of long-term disability related to strokes, the caregiver may undergo many emotional, psychological, and physical factors that impact their daily lives. There is a relatively short period of time to react to the necessary change and as a result there may be differences in coping associated with these unexpected health circumstances. Many stoke victims experience motor, cognitive, emotional, and psycho-social deficits and their caregivers may not be prepared for these abrupt life altering effects. The impact for caregivers, factors impacting strokes, and solutions for care will be addressed in the paper. Evidence suggests that post fatigue stroke (PFS) may be triggered by a dysfunction of the stress system. Family caregivers with a low level of social engagement may be more likely to perceived stress, and increased risk for caregiver role strain.

Locating Parent Lightning Strokes of Sprites Observed over a Mesoscale Convective System in Shandong Province,China

In this paper, we report the location results for the parent lightning strokes of more than 30 red sprites observed over an asymmetric mesoscale convective system(MCS) on 30 July 2015 in Shandong Province, China, with a long-baseline lightning location network of very-low-frequency/low-frequency magnetic field sensors. The results show that almost all of these cloud-to-ground(CG) strokes are produced during the mature stage of the MCS, and are predominantly located in the trailing stratiform region, which is similar to analyses of sprite-productive MCSs in North America and Europe. Comparison between the location results for the sprite-producing CG strokes and those provided by the World Wide Lightning Location Network(WWLLN) indicates that the location accuracy of WWLLN for intense CG strokes in Shandong Province is typically within 10 km, which is consistent with the result based on analysis of 2838 sprite-producing CG strokes in the continental United States. Also, we analyze two cases where some minor lightning discharges in the parent flash of sprites can also be located, providing an approach to confine the thundercloud region tapped by the sprite-producing CG strokes.

Denoising of Chinese calligraphy tablet images based on run-length statistics and structure characteristic of character strokes

In this paper, a novel approach is proposed for denoising of Chinese calligraphy tablet documents. The method includes two phases: First, a partial differential equations (PDE) based the total variation model and Otsu thresholding method are used to preprocess the calligraphy document image. Second, a new method based on run-length statistics and structure charac- teristics of Chinese characters is proposed to remove some random and ant-like noises. This includes the optimal threshold se- lection from histogram of run-length probability density, and improved Hough transform algorithm for line shape noise detection and removal. Examples are given in the paper to demonstrate the proposed method.

Recurrent ischemic strokes in a young celiac woman with MTHFR gene mutation

Celiac disease(CD) is frequently associated with neurological disorders,but very few reports concern the association with ischemic stroke.A 26-year-old woman affected by CD with secondary amenorrhea,carrier of a homozygous 5,10-methylenetetrahydrofolate reductase mutation with hyperhomocysteinemia,was affected by two occipital ischemic strokes within a period of 5 mo.At the time of the second stroke,while she was being treated with folic acid,acetylsalicylic acid and a gluten-free diet,she had left hemianopsia,left hemiparesthesias,and gait imbalance.Brain magnetic resonance imaging showed a subacute right occipital ischemic lesion,which was extended to the dorsal region of the right thalamus and the ipsilateral thalamocapsular junction.Antitransglutaminase and deamidated gliadin peptide antibodies were no longer present,while antinuclear antibodies,antineuronal antibodies and immune circulating complexes were only slightly elevated.Since the patient was taking folic acid,her homocysteine levels were almost normal and apparently not sufficient alone to explain the clinical event.A conventional cerebral angiography showed no signs of vasculitis.Finally,rare causes of occipital stroke in young patients,such as Fabry's disease and mitochondrial myopathy,encephalomyopathy,lactic acidosis and stroke-like symptoms,were also excluded by appropriate tests.Thus,the most probable cause for the recurrent strokes in this young woman remained CD,although the mechanisms involved are still unknown.The two main hypotheses concern malabsorption(with consequent deficiency of vitamins known to exert neurotrophic and neuroprotective effects) and immunemediated mechanisms.CD should be kept in mind in the differential diagnosis of ischemic stroke in young patients.

Treating blood pressure to prevent strokes: The age factor

The importance of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP), on the incidence of coronary heart disease (CHD) and stroke are known. However, the importance of blood pressure (BP)-age shifts regarding the stroke incidence is not clearly known. The BP changes with the advancement of age from the predominance of DBP in the young to the predominance of SBP in the old. This change is due to the stiffening of the large arteries as a result of the aging process and the replacement of the elastic fibers with collagen fibers. This change results in the loss of compliance and the elastic recoil of these vessels leading to increase in pulse wave velocity, central SBP and widening of pulse pressure leading to an increased incidence of CHD and strokes. It has been demonstrated epidemiologically that the SBP rises linearly with age, whereas the DBP rises up to the age of 45-50 years, and then begins to decline after the age of 60 years leading to a progressive widening of PP. Several studies have shown an inverse relationship between DBP and CHD, whereas no such relationship has been demonstrated for stroke. However, a recent study showed an inverse relationship with DBP and stroke when it dropped below 71 mmHg in subjects 50 years of age or older. In contrast, there was a positive association between BP and stroke when both SBP and DBP were ≥ 71 mmHg. These findings suggest that intreating systolic hypertension in the elderly to reduce stroke risk, attention should be paid on the potential harm of low DBP and the widening of PP regarding CHD and stroke. The implications of BP shifts with age and the potential risks of low DBP regarding the risk of stroke will be discussed in this concise review.

Silent brain infarctions and leuko-araiosis in Chinese patients with first-ever acute lacunar strokes

We report on silent brain infarction (SBI) and leuko- araiosis (LA) of 23 patients with clinically diagnosed “first-ever” acute ischemic lacunar stroke. The lacunar syndromes were pure motor hemiparesis (10), pure sensory syndrome (2), ataxic hemiparesis (3), dysarthria clumsy hand syndrome (3), and sensory- motor deficit (5). Nineteen out of the 23 patients presented with completed strokes on arrival to the hospital, and 4 (17%) developed evolving-stroke within 24 hours of stroke onset. A lacune corresponded to the acute stroke could be found in all patients on brain magnetic resonance imaging (MRI), and in 18 (78%) on brain computed tomography (CT). MRI showed additional subclinical or asymptomatic “silent brain infarctions or lacunes” (SBI) in 19 (83%) of 23 patients, and leuko-araiosis (LA) of moderate to severe degree (> grade 2) was present in 61% of patients although dementia was absent. Hypertension is the risk factor in 78% of cases followed by diabetes mellitus, smoking, and elevated plasma cholesterol level. Independence of the types of lacunar syndromes, patients with hypertension and diabetes mellitus are associated with high grade LA. None with normal blood pressure and plasma glucose had grade 3 or grade 4 LA (p < 0.05). In conclusion, evolving-stroke occurs in one- fifth of patients with “first-ever” lacunar infarct within the first 24 hours of stroke onset. SBI was found in 83% of cases. Hypertension and diabetes mellitus are associated with additional SBI and high grade LA. The severity of leuko-araiosis per se dictates the cerebrovascular risks.

Additional Treatment Modality to Improve Outcomes in Myocardial Infarctions and Strokes

In 1974, in Nature, we hypothesized that removal of cytokines can be effective in the treatment of certain inflammatory diseases, e.g., rheumatoid arthritis (RA). We call this approach anticytokino-therapy. Later it was shown that neutralization of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interferon alpha (IFN-α), interferon gamma (IFN-γ), and interleukin 6 (IL-6), leads to a good therapeutic effect. Anticytokinotherapy is currently used around the world for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, and other Th-1-mediated inflammatory diseases. Pro-inflammatory cytokines have also been found in other conditions (myocardial infarctions, strokes, chronic pain syndromes, etc.). This leads us to believe that hyper- production of pro-inflammatory cytokines forms a basis of a variety of pathological conditions and represents a uniform response of the organism to a wide variety of insults in any part of the body. Thus, we propose to add monoclonal antibodies to (or other blockers of) pro-inflammatory cytokines to the treatment regimens for myocardial infarctions, strokes, and possibly other Th-1-mediated diseases.

Transthoracic echocardiographic and clinical predictors in first versus recurrent ischemic strokes

Recurrent strokes are more likely to be disabling or fatal than first ever strokes. The aim of the study is to evaluate transthoracic echocardiographic (TTE) and clinical predictors in patients with first versus those with recurrent ischemic strokes. A prospective observational comparative study of 217 patients admitted with ischemic strokes who were in sinus rhythm. Two groups of patients were simultaneously enrolled. The first group was 110 patients with first ischemic stroke and the second was 107 patients with recurrent ischemic stroke. TTE was done for all patients. Both echocardiographic and clinical risk factors were compared between both groups. Logistic regression analysis identified predictors for recurrent strokes. Among clinical risk factors hypertension, hyperlipidemia, family history of atherosclerotic vascular disease, prior coronary artery disease, peripheral vascular disease, and chronic kidney disease were significantly higher in recurrent stroke group. Multivariate logistic analysis identified age (OR, 1.03;95% CI, 1.01 - 1.07), hypertension (OR, 2.25;95% CI, 1.03 - 4.92), and hyperlipidemia (OR, 2.73;95% CI, 1.40 - 5.35), as predictors for recurrent ischemic strokes. Left ventricular diastolic dysfunction, left ventricular hypertrophy (LVH) and aortic sclerosis were significantly more common in the recurrent stroke group compared to the first stroke group. However, in multivariate logistic analysis only LVH (OR, 3.50;95% CI, 1.69 - 7.23), was identified as a predictor for recurrent strokes. Older age, hypertension, hyperlipidemia and left ventricular hypertrophy are significant predictors of recurrent ischemic strokes in patients with sinus rhythm. Those patients need more aggressive lipid lowering therapy and optimal blood pressure control.

A New Method for Chinese Character Strokes Recognition

In this paper, the problem of stroke recognition has been studied, and the strategies and the algorithms related to the problem are proposed or developed. Based on studying some current methods for Chinese characters strokes recognition, a new method called combining trial is presented. The analysis and results of experiments showed that the method has the advantage of high degree of steadiness.

Ferroptosis and endoplasmic reticulum stress in ischemic stroke

Ferroptosis is a form of non-apoptotic programmed cell death,and its mechanisms mainly involve the accumulation of lipid peroxides,imbalance in the amino acid antioxidant system,and disordered iron metabolism.The primary organelle responsible for coordinating external challenges and internal cell demands is the endoplasmic reticulum,and the progression of inflammatory diseases can trigger endoplasmic reticulum stress.Evidence has suggested that ferroptosis may share pathways or interact with endoplasmic reticulum stress in many diseases and plays a role in cell survival.Ferroptosis and endoplasmic reticulum stress may occur after ischemic stroke.However,there are few reports on the interactions of ferroptosis and endoplasmic reticulum stress with ischemic stroke.This review summarized the recent research on the relationships between ferroptosis and endoplasmic reticulum stress and ischemic stroke,aiming to provide a reference for developing treatments for ischemic stroke.

Machine learning applications in stroke medicine:advancements,challenges,and future prospectives

Stroke is a leading cause of disability and mortality worldwide,necessitating the development of advanced technologies to improve its diagnosis,treatment,and patient outcomes.In recent years,machine learning techniques have emerged as promising tools in stroke medicine,enabling efficient analysis of large-scale datasets and facilitating personalized and precision medicine approaches.This abstract provides a comprehensive overview of machine learning’s applications,challenges,and future directions in stroke medicine.Recently introduced machine learning algorithms have been extensively employed in all the fields of stroke medicine.Machine learning models have demonstrated remarkable accuracy in imaging analysis,diagnosing stroke subtypes,risk stratifications,guiding medical treatment,and predicting patient prognosis.Despite the tremendous potential of machine learning in stroke medicine,several challenges must be addressed.These include the need for standardized and interoperable data collection,robust model validation and generalization,and the ethical considerations surrounding privacy and bias.In addition,integrating machine learning models into clinical workflows and establishing regulatory frameworks are critical for ensuring their widespread adoption and impact in routine stroke care.Machine learning promises to revolutionize stroke medicine by enabling precise diagnosis,tailored treatment selection,and improved prognostication.Continued research and collaboration among clinicians,researchers,and technologists are essential for overcoming challenges and realizing the full potential of machine learning in stroke care,ultimately leading to enhanced patient outcomes and quality of life.This review aims to summarize all the current implications of machine learning in stroke diagnosis,treatment,and prognostic evaluation.At the same time,another purpose of this paper is to explore all the future perspectives these techniques can provide in combating this disabling disease.

Mitochondrial transplantation confers protection against the effects of ischemic stroke by repressing microglial pyroptosis and promoting neurogenesis

Transferring healthy and functional mitochondria to the lateral ventricles confers neuroprotection in a rat model of ischemia-reperfusion injury.Autologous mitochondrial transplantation is also beneficial in pediatric patients with cardiac ischemia-reperfusion injury.Thus,transplantation of functional exogenous mitochondria may be a promising therapeutic approach for ischemic disease.To explore the neuroprotective effect of mitochondria transplantation and determine the underlying mechanism in ischemic stroke,in this study we established a photo-thrombosis-induced mouse model of focal ischemia and administered freshly isolated mitochondria via the tail vein or to the injury site(in situ).Animal behavior tests,immunofluorescence staining,2,3,5-triphenyltetrazolium chloride(TTC)staining,mRNA-seq,and western blotting were used to assess mouse anxiety and memory,cortical infarct area,pyroptosis,and neurogenesis,respectively.Using bioinformatics analysis,western blotting,co-immunoprecipitation,and mass spectroscopy,we identified S100 calcium binding protein A9(S100A9)as a potential regulator of mitochondrial function and determined its possible interacting proteins.Interactions between exogenous and endogenous mitochondria,as well as the effect of exogenous mitochondria on recipient microglia,were assessed in vitro.Our data showed that:(1)mitochondrial transplantation markedly reduced mortality and improved emotional and cognitive function,as well as reducing infarct area,inhibiting pyroptosis,and promoting cortical neurogenesis;(2)microglial expression of S100A9 was markedly increased by ischemic injury and regulated mitochondrial function;(3)in vitro,exogenous mitochondria enhanced mitochondrial function,reduced redox stress,and regulated microglial polarization and pyroptosis by fusing with endogenous mitochondria;and(4)S100A9 promoted internalization of exogenous mitochondria by the microglia,thereby amplifying their pro-proliferation and anti-inflammatory effects.Taken together,our findings show that mitochondrial transplantation protects against the deleterious effects of ischemic stroke by suppressing pyroptosis and promoting neurogenesis,and that S100A9 plays a vital role in promoting internalization of exogenous mitochondria.

Immune regulation of the gut-brain axis and lung-brain axis involved in ischemic stroke

Local ischemia often causes a series of inflammatory reactions when both brain immune cells and the peripheral immune response are activated.In the human body,the gut and lung are regarded as the key reactional targets that are initiated by brain ischemic attacks.Mucosal microorganisms play an important role in immune regulation and metabolism and affect blood-brain barrier permeability.In addition to the relationship between peripheral organs and central areas and the intestine and lung also interact among each other.Here,we review the molecular and cellular immune mechanisms involved in the pathways of inflammation across the gut-brain axis and lung-brain axis.We found that abnormal intestinal flora,the intestinal microenvironment,lung infection,chronic diseases,and mechanical ventilation can worsen the outcome of ischemic stroke.This review also introduces the influence of the brain on the gut and lungs after stroke,highlighting the bidirectional feedback effect among the gut,lungs,and brain.

Activation of endogenous neurogenesis and angiogenesis by basic fibroblast growth factor-chitosan gel in an adult rat model of ischemic stroke

Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.

Ferroptosis:a potential therapeutic target for stroke

Ferroptosis is a form of regulated cell death characterized by massive iron accumulation and iron-dependent lipid peroxidation,differing from apoptosis,necroptosis,and autophagy in several aspects.Ferroptosis is regarded as a critical mechanism of a series of pathophysiological reactions after stroke because of iron overload caused by hemoglobin degradation and iron metabolism imbalance.In this review,we discuss ferroptosis-related metabolisms,important molecules directly or indirectly targeting iron metabolism and lipid peroxidation,and transcriptional regulation of ferroptosis,revealing the role of ferroptosis in the progression of stroke.We present updated progress in the intervention of ferroptosis as therapeutic strategies for stroke in vivo and in vitro and summarize the effects of ferroptosis inhibitors on stroke.Our review facilitates further understanding of ferroptosis pathogenesis in stroke,proposes new targets for the treatment of stroke,and suggests that more efforts should be made to investigate the mechanism of ferroptosis in stroke.

Succinylation modification:a potential therapeutic target in stroke

Stroke is a leading cause of mortality and disability worldwide.Ischemic cell death triggered by the compromised supply of blood oxygen and glucose is one of the major pathophysiology of strokeinduced brain injury.Impaired mitochondrial energy metabolism is observed minutes after stroke and is closely associated with the progression of neuropathology.Recently,a new type of posttranslational modification,known as lysine succinylation,has been recognized to play a significant role in mitochondrial energy metabolism after ischemia.However,the role of succinylation modification in cell metabolism after stroke and its regulation are not well understood.We aimed to review the effects of succinylation on energy metabolism,reactive oxygen species generation,and neuroinflammation,as well as Sirtuin 5 mediated desuccinylation after stroke.We also highlight the potential of targeting succinylation/desuccinylation as a promising strategy for the treatment of stroke.The succinylation level is dynamically regulated by the nonenzymatic or enzymatic transfer of a succinyl group to a protein on lysine residues and the removal of succinyl catalyzed by desuccinylases.Mounting evidence has suggested that succinylation can regulate the metabolic pathway through modulating the activity or stability of metabolic enzymes.Sirtuins,especially Sirtuin 5,are characterized for their desuccinylation activity and have been recognized as a critical regulator of metabolism through desuccinylating numerous metabolic enzymes.Imbalance between succinylation and desuccinylation has been implicated in the pathophysiology of stroke.Pharmacological agents that enhance the activity of Sirtuin 5 have been employed to promote desuccinylation and improve mitochondrial metabolism,and neuroprotective effects of these agents have been observed in experimental stroke studies.However,their therapeutic efficacy in stroke patients should be validated.

Astrocytic endothelin-1 overexpression impairs learning and memory ability in ischemic stroke via altered hippocampal neurogenesis and lipid metabolism

Vascular etiology is the second most prevalent cause of cognitive impairment globally.Endothelin-1,which is produced and secreted by endothelial cells and astrocytes,is implicated in the pathogenesis of stroke.However,the way in which changes in astrocytic endothelin-1 lead to poststroke cognitive deficits following transient middle cerebral artery occlusion is not well understood.Here,using mice in which astrocytic endothelin-1 was overexpressed,we found that the selective overexpression of endothelin-1 by astrocytic cells led to ischemic stroke-related dementia(1 hour of ischemia;7 days,28 days,or 3 months of reperfusion).We also revealed that astrocytic endothelin-1 overexpression contributed to the role of neural stem cell proliferation but impaired neurogenesis in the dentate gyrus of the hippocampus after middle cerebral artery occlusion.Comprehensive proteome profiles and western blot analysis confirmed that levels of glial fibrillary acidic protein and peroxiredoxin 6,which were differentially expressed in the brain,were significantly increased in mice with astrocytic endothelin-1 overexpression in comparison with wild-type mice 28 days after ischemic stroke.Moreover,the levels of the enriched differentially expressed proteins were closely related to lipid metabolism,as indicated by Kyoto Encyclopedia of Genes and Genomes pathway analysis.Liquid chromatography-mass spectrometry nontargeted metabolite profiling of brain tissues showed that astrocytic endothelin-1 overexpression altered lipid metabolism products such as glycerol phosphatidylcholine,sphingomyelin,and phosphatidic acid.Overall,this study demonstrates that astrocytic endothelin-1 overexpression can impair hippocampal neurogenesis and that it is correlated with lipid metabolism in poststroke cognitive dysfunction.