Current Neurovascular Research - Volume 17, Issue 5, 2020

Background: The precise cellular behaviors of calcification, including its molecular and genetic activities, have not yet been fully established for carotid plaques. Objective: We sought specific genes with tissue-specific differential methylation associated with carotid calcification status. Methods: We classified eight plaques from carotid endarterectomy patients as high- or low-calcified based on their Agatston calcium scores. We analyzed differential DNA methylation and performed bioinformatics data mining. Results: A high correlation of average methylation levels (β-values) in promoter regions between high- and low-calcified plaque groups was observed. A principal component analysis of DNA methylation values in promoters of specimens revealed two independent clusters for high- and lowcalcified plaques. Volcano plots for methylation differences in promoter regions showed that significantly hypomethylated probes were more frequently found for high-calcified plaques than more methylated probes. Differential hypomethylation of receptor activity-modifying protein 1 (RAMP1) in high-calcified plaques was commonly extracted in both the promoter region and the cytosinephosphate- guanine (CpG) island shore region, where differential methylation had been reported to be more tissue-specific. Kyoto Encyclopedia of Genes and Genomes pathway analysis annotated a pathway associated with vascular smooth muscle contraction in the differentially methylated genes of the promoter and CpG island shore regions in high-calcified plaques. Conclusion: Among the extracted differentially methylated genes, hypomethylated genes were more dominant than more methylated genes. The augmentation of RAMP1 by hypomethylation may contribute to the enhancement of anti-atherosclerotic effects and hence stability in high-calcified plaques. These results contribute to our understanding of the genetic signatures associated with calcification status and cellular activity in carotid plaques.

Objective: The aim of this investigation was to examine the association between the serum homocysteine (Hcy) level and the distal single small subcortical infarction (dSSSI). Methods: Consecutive patients were prospectively recruited in a registered hospital-based ischemic stroke database. Baseline characteristics and risk factors of single small subcortical infarction (SSSI), including the serum Hcy level, were assessed. The SSSI located in the lenticulostriate artery (LSA) territory was divided into proximal single small subcortical infarction (pSSSI) and dSSSI based on a standard template on axial diffusion-weighted imaging (DWI). The association between the serum Hcy level and dSSSI was analysed by multivariate logistic regression analysis. Results: Out of 3,247 patients, a total of 572 patients were included in the final analysis. We found that dSSSI had a higher serum Hcy level than pSSSI. Elevated Hcy level was independently correlated with dSSSI. Compared with the lowest quartile, the upper quartiles of Hcy level were independently associated with dSSSI, the odds ratio for the second quartile was 1.748 (95%CI 1.019 to 3.000), 1.824 (95% CI 1.060 to 3.140) for the third quartile, and 2.010 (95% CI 1.155 to 3.497) for the fourth quartile. The restricted cubic spline showed that the higher level of Hcy, the greater risk of developing dSSSI. Conclusion: The dSSSI shows higher serum Hcy level than pSSSI. Elevated serum Hcy is more closely related to dSSSI. In the future, the effectiveness of Hcy-lowering therapy for dSSSI needs to be explored by further clinical studies.

Background: Gait impairment after stroke is considered as a loss of cerebral function but is also the result of dysfunctional cerebral signals travelling to the spinal motor centres. A therapeutic option to restore disturbed cerebral network activity is deep brain stimulation (DBS). Methods: A promising target for neuromodulation might be the pedunculopontine tegmental nucleus (PPTg), which contributes to the initiation and control of gait. To test this hypothesis, we trained eighteen rats to cross a horizontal ladder and a wooden beam before inflicting a photothrombosis in the right sensorimotor cortex and implanting a stimulating electrode in the ipsilateral PPTg. Results: Continuous high-frequency DBS (130 Hz; amplitude 55 ± 5 μA) of rats for 10 days yielded no significant improvement of skilled walking when examined with the ladder rung walking test and beam walking test compared to sham-stimulation. Conclusion: In contrast to DBS of the cuneiform nucleus, PPTg-stimulation improves neither control of gait nor balance after stroke.

Aims: To investigate the role of autophagy in the tight junction of human brain endothelial cells during hypoxia and ischemia. Background: Endothelial cells play an important role in the initiation, progression and recovery from ischemic stroke. The role of autophagy on human brain endothelial cells (HBECs) subjected to oxygen-glucose deprivation (OGD) is not fully elucidated. Objective: The objective of this study was to investigate the effect of autophagy on HBECs during OGD. Methods: HBECs were cultured in a 96-well plate and underwent 4 hours of OGD. For drug treatment, 3-Methyladenine (3-MA) (5mmol/L), an inhibitor of autophagy, was added at the start of OGD. Cell viability and cytotoxicity were tested by cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays. Morphological changes in cells were examined by immunofluorescence microscopy. The protein expression of light chain 3 (LC3) was measured. Autophagosomes and endothelial cell tight junctions were observed using transmission electron microscopy. Results: The results showed that OGD induced serious damage to HBECs. Cell viability was decreased significantly and LDH release increased significantly (p<0.05) following OGD. 3-MA protected HBECs from damage. Immunostaining further confirmed these results. Since 3-MA is an inhibitor of autophagy, we chose to examine alterations in the amount of LC3, a marker of autophagy. The ratios of LC3-II to LC3-I were significantly lower in the 3-MA treated OGD group than in the non-3-MA treated OGD group (p<0.05). Electron microscopy showed that 3-MA inhibited the formation of autophagolysosomes and revealed that the tight junction ultrastructure of HBECs, which was destroyed by OGD, was significantly protected by treatment with 3-MA. Conclusion: Autophagy is a key response to oxygen-glucose deprivation stress and its detrimental effects are closely related to the destruction of tight junctions of human brain endothelial cells. Strategies to inhibit autophagy could help to preserve tight junctions.

Background: Haptoglobin (Hp) binds to and facilitates clearance of heme. Compared with HP 1-1 and 1-2 genotypes, HP 2-2 has a weaker binding affinity and has been linked with increased inflammation and vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Objective: This study aims to assess levels of inflammatory cytokines in the context of different HP genotypes. Methods: Patients were enrolled among those presenting with spontaneous aneurysmal SAH. Blood was drawn at four time points; <24 hours (T1), 24-48 hours (T2), 3-5 days (T3), and 6-8 days (T4). Blood was analyzed for levels of 41 cytokines at each time point, as well as for HP genotypes. These data were analyzed using mixed-effect models to assess the association between HP genotypes and cytokine levels. The modified Rankin Scale (mRS) score was obtained at discharge, 3 months, and 6 months. Results: Fifty-seven patients were enrolled. Compared with HP 1-1 and 1-2, subjects encoding HP 2-2 had elevated levels of the following cytokines at all time points: FLT3L, IFNγ, IL-17A, TGFα, and VEGF-A. Elevations were also seen at some time points for IL-8, CSF2, FGF2, IL-7, IL-12p70, and TNFα. This study was not powered to detect differences in the functional outcome; however, there were no significant differences in dichotomized mRS scores between patients with HP 1-1/1-2 or HP 2-2. Conclusion: Our findings indicate that HP 2-2 genotype leads to increased proinflammatory cytokine levels compared with HP 1-1/1-2 genotypes. These data may provide guidance for further studies seeking to identify testable markers for functional prognosis or targets for treatment.

Objective: An increased leukocyte count is positively associated with poor outcomes and all-cause mortality in coronary heart disease, cancer, and ischemic stroke. The role of leukocyte count in acute ischemic stroke (AIS) remains important. We aimed to investigate the association between admission leukocyte count before thrombolysis with recombinant tissue plasminogen activator (rt-PA) and 3-month outcomes in AIS patients. Methods: This retrospective study included consecutive AIS patients who received intravenous (IV) rt-PA within 4.5 h of symptom onset between January 2016 to December 2018. We assessed outcomes, including short-term hemorrhagic transformation (HT), 3-month mortality, and functional independence (modified Rankin Scale [mRS] score of 0-2 or 0-1). Results: Among 579 patients who received IV rt-PA, 77 (13.3%) exhibited HT at 24 h, 43 (7.4%) died within 3 months, and 211 (36.4%) exhibited functional independence (mRS score: 0-2). Multivariable logistic regression revealed admission leukocyte count as an independent predictor of good and excellent outcomes at 3 months. Each 1-point increase in admission leukocyte count increased the odds of poor outcomes at 3 months by 7.6% (mRS score: 3-6, odds ratio [OR]: 1.076, 95% confidence interval [CI]: 1.003-1.154, p=0.041) and 7.8% (mRS score: 2-6, OR: 1.078, 95% CI: 1.006-1.154, p=0.033). Multivariable regression analysis revealed no association between HT and 3-month mortality. Admission neutrophil and lymphocyte count were not associated with 3-- month functional outcomes or 3-month mortality. Conclusion: A lower admission leukocyte count independently predicts good and excellent outcomes at 3 months in AIS patients undergoing rt-PA treatment.

Objective: Post-operative chronic post-thoracotomy pain (CPTP) has been linked to restrictions in mobility and daily activities. However, its potential causes and optimal therapy have not been well characterized. Here, the purpose of this study was to investigate the role of Toll-like receptor 4 (TLR4) in CPTP rats and its underlying mechanism. Methods: Initially, rat models of CPTP were established. Then, the mechanical withdrawal threshold (MWT) was measured after intrathecal injection of TLR4 antagonist (LPS-RS), TLR4 agonist (LPS-PG), or caspase-1 inhibitor (Ac-YVAD-CMK) in CPTP rats. Levels of TNF-α, IL-6 and IL-1β in the spinal dorsal horn (SDH) were measured by ELISA. TLR4 and caspase-1 were located by immunofluorescence double staining. TLR4 and caspase-1 levels were assessed by qRT-PCR and Western blot. Results: TLR4 and caspase-1 were up-regulated in SDH of CPTP rats. Compared with Sham and non-CPTP groups, MWT was effectively decreased while TNF-α, IL-6 and IL-1β in SDH were increased in CPTP group. Moreover, intrathecal injection of TLR4 antagonist or caspase-1 inhibitor significantly elevated MWT expression and reduced levels of TNF-α, IL-6 and IL-1β in SDH. Additionally, high expression of TLR4 promoted mechanical hyperalgesia and inflammatory response, while intrathecal injection of a mixture of caspase-1 inhibitor and TLR4 agonist reversed the alleviation of caspase-1 inhibitor on the mechanical hyperalgesia and inflammatory response. TLR4 and caspase-1 were co-located in neurons. Conclusion: TLR4 aggravated CPTP in rats by mediating activation of caspase-1 in SDH.

Objective: Prognostic significance of inflammatory response has been reported in various diseases. The objective of this study was to analyze the association between inflammation- based scores and the prognosis of patients who underwent neuro-intervention for aneurysmal subarachnoid hemorrhage (SAH). Methods: Inflammation-based scores such as neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and monocyte to high-density lipoprotein cholesterol (HDL-C) ratio (MHR) were analyzed for aneurysmal SAH patients who underwent endovascular intervention. Unfavorable functional outcome was defined as a modified Rankin Scale (mRS) score of 3-6. Receiver operating characteristic (ROC) curve analysis was performed to identify cut-off values of inflammation- based scores for predicting unfavorable functional outcome. Logistic regression analyses were performed to explore the relationship between inflammation-based scores and the prognosis of patients. Results: A total of 498 patients were enrolled. Optimal cutoff values of inflammation-based scores of NLR, LMR, and MHR for unfavorable functional outcome were 5.7, 4.2, and 1.5, respectively (p < 0.001, < 0.001, and 0.004, respectively). In multivariate analysis, NLR value ≥ 5.7 (odds ratio [OR] 1.92, 95% CI 1.42-3.42; P = 0.008), LMR value < 4.2 (OR 1.74, 95% CI 1.48-2.98; P = 0.018), and MHR value ≥ 1.5 (OR 1.44, 95% CI 1.22-2.82; P = 0.040) were independently associated with unfavorable functional outcome. Conclusion: Inflammation based scores were associated with functional outcome after endovascular intervention for aneurysmal SAH. Higher NLR and MHR with lower LMR could predict unfavorable outcomes of aneurysmal SAH patients who underwent endovascular intervention.

Background: Stroke is associated with cerebral ischemia/reperfusion (I/R) injury. Ischemic postconditioning (IPoC) reduces cerebral ischemic injury in rats and offers neuroprotection. The central histaminergic pathway possesses a crucial role in the pathogenesis of cerebral I/R, but its neuroprotective role in IPoC is still unidentified. Objective: This research explored the role of the histaminergic in IPoC during cerebral I/R injury in the rat. Methods: Global cerebral ischemia/reperfusion (GCI/R) injury in Wistar albino rats was induced by occluding the bilateral carotid arteries for 10 minutes, followed by reperfusion. IPoC was provided by giving three episodes of I/R post GCI (10 min), after which of reperfusion was permitted. Inclined- beam-walk, hanging-wire, lateral-push, and rota-rod tests were employed to assess motor functions, and Morris water maze (MWM) was used to assess spatial learning as well as memory in animals. Cerebral oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione- GSH), inflammatory markers (myeloperoxidase-MPO), acetylcholinesterase activity- AChE, infarct size, and histopathological changes were also assessed. L-histidine and chlorpheniramine were used as histaminergic agonists and antagonists. Results: I/R animals showed a reduction in memory and motor function, and an increase in cerebral oxidative stress, inflammation, AChE activity, infarct size and histopathological changes. Episodes of IPoC post-ischemia attenuated the deleterious effects of I/R injury. Pretreatment (30 min before cerebral ischemia) with L-histidine mimicked the neuroprotective effects of IPoC. However, neuroprotection produced by IPoC was abolished by pretreatment with chlorpheniramine (histaminergic- H1 receptor antagonist). Conclusion: IPoC may provide neuroprotection against cerebral I/R induced brain injury by modulating the histaminergic-H1-receptor pathway.

Purpose: The aim of this study was to evaluate whether the VNTR intron 4b/4a variant in the eNOS gene is associated with type 2 diabetes mellitus (T2DM) and DPN. Methods: A total of 598 subjects were enrolled in the study. eNOS VNTR 4b/4a variant was genotyped by polymerase chain reaction (PCR) method. Results: eNOS VNTR intron 4b/4b genotype and b allele increased in patients with both DPN and T2DM compared healthy controls (p=0.0005, OR:1.94, p= 0.000002, OR:4.10, respectively). 4a/4b genotype was more prevalent in controls than in DPN and T2DM patients (p=0.00008, OR:0.46; p=0.000004, OR:0.24, respectively). eNOS VNTR b allele was more common in DPN patients and T2DM patients compared with controls (p=0.007, p=0.00002, respectively). Conclusion: The eNOS VNTR “4b/4b” homozygous genotype and hence “4b”allele as a genetic risk factor for T2DM and DPN, which may serve as a useful marker of increased susceptibility to the risk of these disorders.

Aim: The study has been commenced to discover the potential of sodium dependent glucose co-transporters (SGLT) in neuroprotective mechanism of ischemic postconditioning (iPoCo) in diabetic and non-diabetic mice. Methods: Cerebral ischemic injury in mice was induced by bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 hr. For iPoCo, three episodes of carotid artery reperfusion and occlusion of 10 sec each were instituted immediately after BCAO, followed by 24 hr reperfusion. Learning and memory were evaluated using the Morris water maze test. Motor coordination was assessed using rotarod test, inclined beam walking test, neurological severity score (NSS), and lateral push response. Glutathione and Thiobarbituric acid reactive species level was quantified to evaluate the oxidative stress; the cholinergic activity of the brain was estimated in terms of acetylcholinestrase activity, and the levels of myeloperoxidase were measured as inflammation marker. Cerebral infarct size was evaluated using triphenyltetrazolium chloride staining. Fasting blood glucose levels of animals were taken before and 6 hr after the surgical procedure. Results: BCAO resulted in impairment of memory and motor coordination and biochemical alterations along with a marked rise in cerebral infarct size and NSS. iPoCo diminished the deadly effect of BCAO in non-diabetic mice; however, it failed to abolish the deleterious effects of ischemia- reperfusion injury in diabetic mice. Pretreatment of Phlorizin (SGLT-inhibitor) potentiated the neuroprotective effects of iPoCo in non-diabetics and restored the protective effect of iPoCo in diabetic mice. Conclusion: It may be concluded that the neuroprotective effect of iPoCo is abolished in diabetic mice, and SGLT plays an important role in neuroprotection.

Objective: The study aimed to investigate the relationship between serum interleukin-33 (IL-33) concentrations and poststroke depression (PSD) in patients with acute ischemic stroke (AIS). Methods: Serum IL-33 concentrations were determined using an enzyme-linked immunosorbent assay. Patients were assigned to the PSD group after a six-month follow-up if their score on the 17- item Hamilton Rating Scale for Depression was ≥7 or to the non-PSD group if their score was <7. IL-33 was used to predict the risk of PSD using multivariate logistic regression analysis, while a receiver operating characteristic (ROC) curve was used to analyze the accuracy of PSD prediction. In addition, the modified Rankin scale (mRS) was used for follow-up scoring six months after disease onset. Results: A total of 151 AIS patients and 40 healthy controls were included in this study. ROC curve results showed that the area under the curve was 0.684 (95% confidence interval: 0.594-0.774,=0.001) for IL-33 as a predictor of PSD. When the IL-33 concentration was ≤71.85 ng/L, prediction sensitivity and specificity were 77.5% and 57.3%, respectively. Multivariate logistic regression analysis showed that IL-33 concentration of ≤71.85 ng/L was an independent predictor of PSD (95% CI: 1.129-7.515, P=0.027). The follow-up mRS data showed that serum IL-33 is a protective prognosis factor in patients with AIS (95% CI: 0.954-0.997, P=0.024). Conclusion: Serum IL-33 is an independent predictor of PSD and a protective prognosis factor in patients with AIS.

Background: Due to the scarcity of longitudinal data, the morphologic development of intracranial aneurysms (IAs) during their natural history remains poorly understood. However, longitudinal information can often be inferred from cross-sectional datasets as demonstrated by anatomists’ use of geometric morphometrics to build evolutionary trees, reconstructing species inter-relationships based on morphologic landmarks. Objective: We adopted these tools to analyze cross-sectional image data and infer relationships between IA morphologies. Methods: On 3D reconstructions of 52 middle cerebral arteries (MCA) IAs (9 ruptured) and 10 IAfree MCAs (baseline geometries), 7 semi-automated landmarks were placed at the proximal parent artery and maximum height. From these, 64 additional landmarks were computationally generated to create a 71-landmark point cloud of 213 xyz coordinates. This data was normalized by Procrustes transformation and used in the principal component analysis, hierarchical clustering, and phylogenetic analyses. Results: Principal component analysis showed separation of IA-free MCA geometries and grouping of ruptured IAs from unruptured IAs. Hierarchical clustering delineated a cluster of only unruptured IAs that were significantly smaller and more spherical than clusters that had ruptured IAs. Phylogenetic classification placed ruptured IAs more distally in the tree than unruptured IAs, indicating greater shape derivation. Groups of unruptured IAs were observed, but ruptured IAs were invariably found in mixed lineages with unruptured IAs, suggesting that some pathways of shape change may be benign while others are more associated with rupture. Conclusion: Geometric morphometric analyses of larger datasets may indicate particular pathways of shape change leading toward aneurysm rupture versus stabilization.

Objective: Recently, a few studies have shown that non-traditional lipid parameters are associated with the hemorrhagic transformation (HT) and the clinical outcome of ischemic stroke. However, the role of non-traditional lipid parameters in ischemic stroke patients treated with intravenous thrombolysis remains unclear. Thus, we aimed to assess the associations of non-traditional lipid parameters with HT and clinical outcome after thrombolysis in ischemic stroke patients. Methods: This study consecutively included 763 ischemic stroke patients treated with intravenous thrombolysis. Non-traditional lipid parameters included non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol to HDL-C ratio (TC/HDL-C), triglyceride to HDL-C ratio (TG/ HDL-C), and low-density lipoprotein cholesterol to HDL-C ratio (LDL-C/HDL-C). Receiver operating characteristic (ROC) curves and multivariate logistic regression analyses were used to investigate the associations between the four non-traditional lipid parameters and HT and poor outcome after thrombolysis. Results: Of 763 patients, 78 (10.2%) had HT and 281 (36.8%) had poor outcome. The ROC curves showed that the optimum cut-off points of the non-HDL-C, TC/HDL-C, TG/HDL-C, and LDL/HDL-C for predicting HT and poor outcome were 2.99 and 2.01, 4.05 and 3.66, 0.82 and 1.02, as well as 2.67 and 2.71, respectively. Multivariate logistic regression analyses showed that the TC/HDL-C <4.05 (adjusted odds ratio [OR]=1.727, 95% confidence interval [CI]: 1.008-2.960), TG/HDL-C <0.82 (adjusted OR=2.064, 95% CI: 1.241-3.432), and LDL/HDL-C <2.67 (adjusted OR=1.935, 95% CI: 1.070-3.501) were positively associated with the risk of HT, while the non-HDL-C <2.99 (adjusted OR=0.990, 95% CI: 0.583-1.680) was not related to the risk of HT. In addition, the non-HDL-C <2.01, TC/HDL-C <3.66, TG/HDL-C <1.02, and LDL/HDL-C <2.71 were associated with an increased risk of poor outcome, with adjusted ORs of 2.340 (95% CI: 1.150-4.764), 1.423 (95% CI: 1.025-1.977), 1.539 (95% CI: 1.102-2.151), and 1.608 (95% CI: 1.133-2.283). Conclusion: Low TC/HDL-C, TG/HDL-C, and LDL/HDL-C, but not non-HDL-C, were associated with an increased risk of HT after thrombolysis. In addition, low non-HDL-C, TC/HDL-C, TG/HDL-C, and LDL/HDL-C were associated with an increased risk of poor outcome in ischemic stroke patients with intravenous thrombolysis.

Background: We investigated the association between elevated total homocysteine (tHcy) levels upon hospital admission and short-term in-hospital outcomes, including pneumonia in acute ischemic stroke (AIS) patients. Methods: A total of 2,084 AIS patients enrolled from December 2013 to May 2014 across 22 hospitals in Suzhou city were included in the present study. We divided patients into four groups according to their level of admission tHcy: quartile (Q1) (<9.70 umol/L), Q2 (9.70-12.3 umol/L), Q3 (12.3-16.9 umol/L), and Q4 (≥16.9 umol/L). Logistic regression models were used to estimate the effect of tHcy on the short-term outcomes, including in-hospital pneumonia, all-cause in-hospital mortality, and poor outcome upon discharge (modified Rankin Scale score ≥3) in AIS patients. Results: The risk of in-hospital pneumonia was significantly higher in patients with the highest tHcy level (Q4) compared to those with the lowest tHcy level (Q1) (adjusted odds ratio [OR] 1.55; 95% confidence interval [CI], 1.03-2.33; P-trend =0.019). The highest tHcy level (Q4) was associated with a 3.35-fold and 1.50-fold increase in the risk of in-hospital mortality (OR 3.35; 95% CI, 1.11-10.13; P-trend =0.015) and poor outcome upon discharge (OR 1.50; 95% CI, 1.06-2.12; Ptrend =0.044) in comparison to Q1 after adjustment for potential covariates including pneumonia. Conclusion: Having a high admission tHcy level was independently associated with in-hospital pneumonia, in-hospital mortality, and poor outcome upon discharge in AIS patients.

Background: Since the introduction of endovascular methods to treat cerebral aneurysms, several technical advances have allowed a greater number of aneurysms to be treated endovascularly as opposed to open surgical clipping. These include flow diverting stents, which do not utilize coils and instead treat aneurysms by acting as an “internal bypass.” We sought to investigate whether flow diversion is replacing coiling at our institution. Methods: A retrospective chart review on five years of data was conducted to investigate the possible increasing use of flow diversion devices compared to traditional simple or stent-assisted coiling. Results: Over five years, the population revealed a trend toward an increased proportion of female patients, increased frequency of basilar tip and internal carotid artery (ICA) aneurysm location, increased hospital volume, and increased volume of patients treated by dual-trained neurosurgeons over interventional radiologists. Patients were stratified by aneurysm location and statistically significant differences were observed. Flow diversion devices were used with increasing frequency when treating aneurysms arising from the proximal internal carotid artery (Odds ratio (OR)=1.24, 95% CI: 1.02-1.50; p = 0.03), and middle cerebral artery (OR=2.60, 95% CI: 1.38-4.88; p = 0.003). Distal internal carotid artery aneurysm location came close to achieving statistical significance (OR=1.3, 95% CI: 0.99-1.72; p = 0.063). Conclusion: In our single center experience at Houston Methodist Hospital, flow diversion devices are being used more frequently for aneurysms arising from the proximal ICA, MCA, and likely distal ICA (though this third location barely failed to achieve statistical significance.

Acute Ischemic Stroke (AIS) is currently the most frequently reported neurological complication of Coronavirus disease 2019 (COVID-19). This article will elaborate the clinical features of inpatients with COVID-19 and AIS and the pathophysiological mechanism of AIS under the background of COVID-19. Through a detailed search of relevant studies, we found that the incidence of AIS among COVID-19 patients varied from 0.9% to 4.6%, and AIS has been observed in many people without an underlying disease and cardiovascular risk factors as well as young people. The National Institute of Health Stroke Scale (NIHSS) score of COVID-19 patients with AIS was higher than historical AIS patients, and the proportion of large vessel occlusion (LVO) was about 64.2%. COVID-19 patients with AIS generally have high levels of D-D dimer, fibrinogen, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), suggesting systemic hyperinflammatory and hypercoagulable state. The pooled mortality of COVID-19 patients with AIS was 38% and the mortality of LVO patients is higher (45.9%). Compared with COVID-19-negative AIS patients in the same period in 2020 and 2019, COVID-19 patients with AIS had a worse prognosis.

Metabolic disorders that include diabetes mellitus present significant challenges for maintaining the welfare of the global population. Metabolic diseases impact all systems of the body and despite current therapies that offer some protection through tight serum glucose control, ultimately such treatments cannot block the progression of disability and death realized with metabolic disorders. As a result, novel therapeutic avenues are critical for further development to address these concerns. An innovative strategy involves the vitamin nicotinamide and the pathways associated with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and clock genes. Nicotinamide maintains an intimate relationship with these pathways to oversee metabolic disease and improve glucose utilization, limit mitochondrial dysfunction, block oxidative stress, potentially function as antiviral therapy, and foster cellular survival through mechanisms involving autophagy. However, the pathways of nicotinamide, SIRT1, mTOR, AMPK, and clock genes are complex and involve feedback pathways as well as trophic factors such as erythropoietin that require a careful balance to ensure metabolic homeostasis. Future work is warranted to gain additional insight into these vital pathways that can oversee both normal metabolic physiology and metabolic disease.

A pericyte-centered theory suggesting that embolisms occurring within the microvasculature of a neurovascular unit that can result in either parenchymal hemorrhage or intravascular congestion is presented here. Dysfunctional microvascular pericytes are characterized by their location in the neurovascular unit, either on the arteriole or venule side. Pathophysiological and pathological changes caused by coronavirus disease 2019 (COVID-19) include pulmonary hypertension, edema, focal hemorrhage, microvascular congestion, and thrombosis. In this paper, the application of the pericytes-centered hypothesis to COVID-19 has been presented by proposing the concept of a pulmonary neurovascular unit (pNVU). The application of this concept implies that human lungs contain approximately 300 million pNVUs. This concept of existing local regulation of microvascular blood flow is supported by the observation of pathophysiology in pulmonary embolism and in acute high-altitude illness. The autonomic control seen in these three disease states matches blood flow with oxygen supply in each pNVU to maintain physiological blood oxygen saturation level. This paper illustrates how the malfunction of microvascular pericytes may cause focal hemorrhage, edema or microvascular congestion and thrombosis. A bypass existing in each pNVU would autonomically deviate blood flow from a COVID-19-affected pNVU to other healthy pNVUs. This action would prevent systemically applied medicines from reaching the therapeutic threshold in COVID-19-affected pNVUs. While testing this hypothesis with experimental evidence is urgently needed, supporting therapy aimed at improving microcirculation or rebuilding the physiological function of microvascular pericytes is recommended as a potentially effective treatment of COVID 19.