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1.
J Stroke Cerebrovasc Dis ; 30(8): 105919, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1253283

ABSTRACT

BACKGROUND: The characteristics and pathophysiological mechanisms involved in acute ischemic stroke in patients with COVID-19 infection have not been fully clarified. We prospectively studied the phenotypic and etiological features of acute stroke occurring in COVID-19 infection. PATIENTS & METHODS: Within nine months starting from April-2020, the presence of COVID-19 infection was determined by thoracic CT and SARS-CoV-2 PCR in all acute stroke cases managed in a single tertiary center. Consecutive and prospective data on vascular risk factors/comorbidities, in-hospital quality metrics, discharge outcomes, etiological subclassification and blood markers of thrombosis / inflammation were compared in 44 COVID-19 positive cases (37 acute ischemic stroke, 5 TIA, 2 intracerebral hematoma) and 509 COVID-19 negative patients (355 ischemic, 105 TIA, 44 hematoma and 5 stroke mimic). RESULTS: COVID-19 positive patients had more severe strokes, delayed hospital admission, longer hospital stay, higher mortality rates, but had similar vascular risk factors/comorbidities frequency, thrombolysis/thrombectomy utilization rates, metrics, and stroke etiological subtype. They had significantly higher CRP, fibrinogen, ferritin, leukocyte count and lower lymphocyte count. No difference was detected in aPTT, INR, D-dimer, platelet, hemoglobin, homocysteine levels and ANA, anti-dsDNA antibody and ENA panel positivity rates. Anti-phospholipid antibodies have been studied in 70% of COVID-19 positive and all cryptogenic patients, but were never found positive. Tests for coagulation factor levels and hereditary thrombophilia did not show major thrombophilia in any of the stroke patients with COVID-19. CONCLUSION: We documented that there is no significant difference in etiological spectrum in acute stroke patients with COVID-19 infection. In addition, cryptogenic stroke and antiphospholipid antibody positivity rates did not increase.


Subject(s)
COVID-19/complications , Hemorrhagic Stroke/etiology , Ischemic Attack, Transient/etiology , Ischemic Stroke/etiology , Aged , Aged, 80 and over , Biomarkers/blood , Blood Coagulation , COVID-19/diagnosis , COVID-19/therapy , COVID-19/virology , Case-Control Studies , Female , Hemorrhagic Stroke/diagnosis , Hemorrhagic Stroke/therapy , Humans , Inflammation Mediators/blood , Ischemic Attack, Transient/diagnosis , Ischemic Attack, Transient/therapy , Ischemic Stroke/diagnosis , Ischemic Stroke/therapy , Male , Middle Aged , Prognosis , Prospective Studies , Risk Assessment , Risk Factors
2.
Stem Cells ; 39(7): 904-912, 2021 07.
Article in English | MEDLINE | ID: covidwho-1126519

ABSTRACT

We have shown previously that transplanted bone marrow mononuclear cells (BM-MNC), which are a cell fraction rich in hematopoietic stem cells, can activate cerebral endothelial cells via gap junction-mediated cell-cell interaction. In the present study, we investigated such cell-cell interaction between mesenchymal stem cells (MSC) and cerebral endothelial cells. In contrast to BM-MNC, for MSC we observed suppression of vascular endothelial growth factor uptake into endothelial cells and transfer of glucose from endothelial cells to MSC in vitro. The transfer of such a small molecule from MSC to vascular endothelium was subsequently confirmed in vivo and was followed by suppressed activation of macrophage/microglia in stroke mice. The suppressive effect was absent by blockade of gap junction at MSC. Furthermore, gap junction-mediated cell-cell interaction was observed between circulating white blood cells and MSC. Our findings indicate that gap junction-mediated cell-cell interaction is one of the major pathways for MSC-mediated suppression of inflammation in the brain following stroke and provides a novel strategy to maintain the blood-brain barrier in injured brain. Furthermore, our current results have the potential to provide a novel insight for other ongoing clinical trials that make use of MSC transplantation aiming to suppress excess inflammation, as well as other diseases such as COVID-19 (coronavirus disease 2019).


Subject(s)
Cell Communication , Gap Junctions , Human Umbilical Vein Endothelial Cells/metabolism , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Stroke , Allografts , Animals , COVID-19/metabolism , COVID-19/pathology , Gap Junctions/metabolism , Gap Junctions/pathology , Human Umbilical Vein Endothelial Cells/pathology , Humans , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/pathology , Mice , SARS-CoV-2/metabolism , Stroke/metabolism , Stroke/pathology , Stroke/therapy
3.
Brain Behav Immun ; 94: 458-462, 2021 05.
Article in English | MEDLINE | ID: covidwho-1091937

ABSTRACT

BACKGROUND: The newly emerged severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a worldwide pandemic of human respiratory disease. Angiotensin-converting enzyme (ACE) 2 is the key receptor on lung epithelial cells to facilitate initial binding and infection of SARS-CoV-2. The binding to ACE2 is mediated via the spike glycoprotein present on the viral surface. Recent clinical data have demonstrated that patients with previous episodes of brain injuries are a high-risk group for SARS-CoV-2 infection. An explanation for this finding is currently lacking. Sterile tissue injuries including stroke induce the release of several inflammatory mediators that might modulate the expression levels of signaling proteins in distant organs. Whether systemic inflammation following brain injury can specifically modulate ACE2 expression in different vital tissues has not been investigated. METHODS: For the induction of brain stroke, mice were subjected to a surgical procedure for transient interruption of blood flow in the middle cerebral artery for 45 min and sacrificed after 1 and 3 days for analysis of brain, lung, heart, and kidney tissues. Gene expression and protein levels of ACE2, ACE, IL-6 and IL1ß were measured by quantitative PCR and Western blot, respectively. The level of soluble ACE2 in plasma and bronchial alveolar lavage (BAL) was measured using an immunoassay. Immune cell populations in lymphoid organs were analyzed by flow cytometry. Post-stroke pneumonia in mice was examined by bacterial cultures from lung homogenates and whole blood. RESULTS: Strikingly, 1 day after surgery, we observed a substantial increase in the protein levels of ACE2 in the lungs of stroke mice compared to sham-operated mice. However, the protein levels of ACE2 were found unchanged in the heart, kidney, and brain of these animals. In addition, we found increased transcriptional levels of alveolar ACE2 after stroke. The increased expression of ACE2 was significantly associated with the severity of behavioral deficits after stroke. The higher protein levels of alveolar ACE2 persisted until 3 days of stroke. Interestingly, we found reduced levels of soluble ACE2 in plasma but not in BAL in stroke-operated mice compared to sham mice. Furthermore, stroke-induced parenchymal and systemic inflammation was evident with the increased expression of IL-6 and IL-1ß. Reduced numbers of T-lymphocytes were present in the blood and spleen as an indicator of sterile tissue injury-induced immunosuppression. CONCLUSIONS: We demonstrate specific augmented alveolar ACE2 levels and inflammation in murine lungs after experimental stroke. These pre-clinical findings suggest that patients with brain injuries may have increased binding affinity to SARS-CoV-2 in their lungs which might explain why stroke is a risk factor for higher susceptibility to develop COVID-19.


Subject(s)
COVID-19 , Stroke , Animals , Humans , Lung , Mice , Peptidyl-Dipeptidase A/genetics , SARS-CoV-2
4.
Brain Behav Immun ; 91: 649-667, 2021 01.
Article in English | MEDLINE | ID: covidwho-1064858

ABSTRACT

For the last two decades, researchers have placed hopes in a new era in which a combination of reperfusion and neuroprotection would revolutionize the treatment of stroke. Nevertheless, despite the thousands of papers available in the literature showing positive results in preclinical stroke models, randomized clinical trials have failed to show efficacy. It seems clear now that the existing data obtained in preclinical research have depicted an incomplete picture of stroke pathophysiology. In order to ameliorate bench-to-bed translation, in this review we first describe the main actors on stroke inflammatory and immune responses based on the available preclinical data, highlighting the fact that the link between leukocyte infiltration, lesion volume and neurological outcome remains unclear. We then describe what is known on neuroinflammation and immune responses in stroke patients, and summarize the results of the clinical trials on immunomodulatory drugs. In order to understand the gap between clinical trials and preclinical results on stroke, we discuss in detail the experimental results that served as the basis for the summarized clinical trials on immunomodulatory drugs, focusing on (i) experimental stroke models, (ii) the timing and selection of outcome measuring, (iii) alternative entry routes for leukocytes into the ischemic region, and (iv) factors affecting stroke outcome such as gender differences, ageing, comorbidities like hypertension and diabetes, obesity, tobacco, alcohol consumption and previous infections like Covid-19. We can do better for stroke treatment, especially when targeting inflammation following stroke. We need to re-think the design of stroke experimental setups, notably by (i) using clinically relevant models of stroke, (ii) including both radiological and neurological outcomes, (iii) performing long-term follow-up studies, (iv) conducting large-scale preclinical stroke trials, and (v) including stroke comorbidities in preclinical research.


Subject(s)
Stroke Rehabilitation/methods , Stroke/immunology , Stroke/physiopathology , Animals , Brain Ischemia/drug therapy , Comorbidity , Disease Models, Animal , Humans , Immunity/immunology , Immunity/physiology , Inflammation/immunology , Neuroprotection/immunology , Neuroprotection/physiology , Outcome Assessment, Health Care , Reperfusion/methods , Reperfusion/trends
5.
J Stroke Cerebrovasc Dis ; 30(3): 105549, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-988561

ABSTRACT

INTRODUCTION: COVID-19 is a multi-system infection which predominantly affects the respiratory system, but also causes systemic inflammation, endothelialitis and thrombosis. The consequences of this include renal dysfunction, hepatitis and stroke. In this systematic review, we aimed to evaluate the epidemiology, clinical course, and outcomes of patients who suffer from stroke as a complication of COVID-19. METHODS: We conducted a systematic review of all studies published between November 1, 2019 and July 8, 2020 which reported on patients who suffered from stroke as a complication of COVID-19. RESULTS: 326 studies were screened, and 30 studies reporting findings from 55,176 patients including 899 with stroke were included. The average age of patients who suffered from stroke as a complication of COVID-19 was 65.5 (Range: 40.4-76.4 years). The average incidence of stroke as a complication of COVID-19 was 1.74% (95% CI: 1.09% to 2.51%). The average mortality of stroke in COVID-19 patients was 31.76% (95% CI: 17.77% to 47.31%). These patients also had deranged clinical parameters including deranged coagulation profiles, liver function tests, and full blood counts. CONCLUSION: Although stroke is an uncommon complication of COVID-19, when present, it often results in significant morbidity and mortality. In COVID-19 patients, stroke was associated with older age, comorbidities, and severe illness.


Subject(s)
COVID-19/complications , Stroke/etiology , COVID-19/epidemiology , Humans , Incidence , Predictive Value of Tests , Prognosis , Stroke/epidemiology , Treatment Outcome
6.
Neuromolecular Med ; 23(1): 184-198, 2021 03.
Article in English | MEDLINE | ID: covidwho-871558

ABSTRACT

Ergothioneine (ET) is a naturally occurring antioxidant that is synthesized by non-yeast fungi and certain bacteria. ET is not synthesized by animals, including humans, but is avidly taken up from the diet, especially from mushrooms. In the current study, we elucidated the effect of ET on the hCMEC/D3 human brain endothelial cell line. Endothelial cells are exposed to high levels of the cholesterol oxidation product, 7-ketocholesterol (7KC), in patients with cardiovascular disease and diabetes, and this process is thought to mediate pathological inflammation. 7KC induces a dose-dependent loss of cell viability and an increase in apoptosis and necrosis in the endothelial cells. A relocalization of the tight junction proteins, zonula occludens-1 (ZO-1) and claudin-5, towards the nucleus of the cells was also observed. These effects were significantly attenuated by ET. In addition, 7KC induces marked increases in the mRNA expression of pro-inflammatory cytokines, IL-1ß IL-6, IL-8, TNF-α and cyclooxygenase-2 (COX2), as well as COX2 enzymatic activity, and these were significantly reduced by ET. Moreover, the cytoprotective and anti-inflammatory effects of ET were significantly reduced by co-incubation with an inhibitor of the ET transporter, OCTN1 (VHCL). This shows that ET needs to enter the endothelial cells to have a protective effect and is unlikely to act via extracellular neutralizing of 7KC. The protective effect on inflammation in brain endothelial cells suggests that ET might be useful as a nutraceutical for the prevention or management of neurovascular diseases, such as stroke and vascular dementia. Moreover, the ability of ET to cross the blood-brain barrier could point to its usefulness in combatting 7KC that is produced in the CNS during neuroinflammation, e.g. after excitotoxicity, in chronic neurodegenerative diseases, and possibly COVID-19-related neurologic complications.


Subject(s)
Antioxidants/pharmacology , COVID-19/complications , Endothelial Cells/drug effects , Ergothioneine/pharmacology , Ketocholesterols/toxicity , Nervous System Diseases/prevention & control , Neuroprotective Agents/pharmacology , Antioxidants/pharmacokinetics , Apoptosis/drug effects , Biological Transport , Blood-Brain Barrier , Brain/blood supply , Brain/cytology , Cell Line , Cholesterol/metabolism , Claudin-5 , Cyclooxygenase 2/biosynthesis , Cyclooxygenase 2/genetics , Cytokines/biosynthesis , Cytokines/genetics , Drug Evaluation, Preclinical , Ergothioneine/pharmacokinetics , Humans , Microvessels/cytology , Nervous System Diseases/etiology , Neuroprotective Agents/pharmacokinetics , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type III/metabolism , Organic Cation Transport Proteins , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Symporters , Zonula Occludens-1 Protein
7.
J Stroke Cerebrovasc Dis ; 29(8): 104989, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-622312

ABSTRACT

OBJECTIVE: Identify clinical and radiographic features of venous infarct as a presenting feature of COVID-19 in the young. BACKGROUND: SARS-CoV-2 infection causes hypercoagulability and inflammation leading to venous thrombotic events (VTE). Although elderly patients with comorbidities are at higher risk, COVID-19 may also cause VTE in a broader patient population without these risks. Neurologic complications and manifestations of COVID-19, including neuropathies, seizures, strokes and encephalopathy usually occur in severe established cases of COVID-19 infection who primarily present with respiratory distress. CASE DESCRIPTION: Case report of a 29-year-old woman, with no significant past medical history or comorbidities, presenting with new onset seizures. Further questioning revealed a one-week history of headaches, low-grade fever, mild cough and shortness of breath, diagnosed as COVID-19. Imaging revealed a left temporoparietal hemorrhagic venous infarction with left transverse and sigmoid sinus thrombosis treated with full dose anticoagulation and antiepileptics. CONCLUSION: Although elderly patients with comorbidities are considered highest risk for COVID-19 neurologic complications, usually when systemic symptoms are severe, this case report emphasizes that young individuals are at risk for VTE with neurologic complications even when systemic symptoms are mild, likely induced by COVID-19 associated hypercoagulable state.


Subject(s)
Betacoronavirus/pathogenicity , Brain Infarction/virology , Coronavirus Infections/virology , Pneumonia, Viral/virology , Sinus Thrombosis, Intracranial/virology , Venous Thrombosis/virology , Adult , Age Factors , Anticoagulants/therapeutic use , Anticonvulsants/therapeutic use , Brain Infarction/diagnostic imaging , Brain Infarction/drug therapy , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Female , Host Microbial Interactions , Humans , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Risk Factors , SARS-CoV-2 , Sinus Thrombosis, Intracranial/diagnostic imaging , Sinus Thrombosis, Intracranial/drug therapy , Treatment Outcome , Venous Thrombosis/diagnostic imaging , Venous Thrombosis/drug therapy
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