Neuroinflammation is initiated in response to ischemic stroke, generally with the hallmarks of microglial activation and collateral brain injury contributed by robust inflammatory effects. Triggering ...receptor expressed on myeloid cells (TREM)-1, an amplifier of the innate immune response, is a critical regulator of inflammation. This study identified that microglial TREM-1 expression was upregulated following cerebral ischemic injury. After pharmacologic inhibition of TREM-1 with synthetic peptide LP17, ischemia-induced infarction and neuronal injury were substantially alleviated. Moreover, blockade of TREM-1 can potentiate cellular proliferation and synaptic plasticity in hippocampus, resulting in long-term functional improvement. Microglial M1 polarization and neutrophil recruitment were remarkably abrogated as mRNA levels of M1 markers, chemokines, and protein levels of myeloperoxidase and intracellular adhesion molecule-1 (ICAM-1) were decreased by LP17. Mechanistically, both in vivo and in vitro, we delineated that TREM-1 can activate downstream pro-inflammatory pathways, CARD9/NF-κB, and NLRP3/caspase-1, through interacting with spleen tyrosine kinase (SYK). In addition, TREM-1-induced SYK initiation was responsible for microglial pyroptosis by elevating levels of gasdermin D (GSDMD), N-terminal fragment of GSDMD (GSDMD-N), and forming GSDMD pores, which can facilitate the release of intracellular inflammatory factors, in microglia. In summary, microglial TREM-1 receptor yielded post-stroke neuroinflammatory damage via associating with SYK.
Social distance, quarantine, pathogen testing, and other preventive strategies implemented during CO-VID-19 pandemic may negatively influence the management of acute ischemic stroke (AIS).
The ...current study aimed to evaluate the impacts of COVID-19 pandemic on treatment delay of AIS in China.
This study included patients with AIS admitted in 2 hospitals in Jiangsu, China. Patients admitted before and after the COVID-19 pandemic outbreak (January 31, 2020, as officially announced by the Chinese government) were screened to collect sociodemographic data, medical history information, and symptom onset status from clinical medical records and compared for pre- (measured as onset-to-door time ODT) and posthospital delay (measured as door-to-needle time DNT). The influencing factors for delayed treatment (indicated as onset-to-needle time >4.5 h) were analyzed with multivariate logistic regression analysis.
A total of 252 patients were included, of which 153 (60.7%) were enrolled before and 99 (39.3%) after the COVID-19 pandemic. ODT increased from 202 min (interquartile range IQR 65-492) before to 317 min (IQR 75-790) after the COVID-19 pandemic (p = 0.001). DNT increased from 50 min (IQR 40-75) before to 65 min (IQR 48-84) after the COVID-19 pandemic (p = 0.048). The proportion of patients with intravenous thrombolysis in those with AIS was decreased significantly after the pandemic (15.4% vs. 20.1%; p = 0.030). Multivariate logistic regression analysis indicated that patients after COVID-19 pandemic, lower educational level, rural residency, mild symptoms, small artery occlusion, and transported by other means than ambulance were associated with delayed treatment.
COVID-19 pandemic has remarkable impacts on the management of AIS. Both pre- and posthospital delays were prolonged significantly, and proportion of patients arrived within the 4.5-h time window for intravenous thrombolysis treatment was decreased. Given that anti-COVID-19 measures are becoming medical routines, efforts are warranted to shorten the delay so that the outcomes of stroke could be improved.
Background & Aims The association between dietary fiber intake and gastric cancer risk has been investigated by many studies, with inconclusive results. We conducted a meta-analysis of case-control ...and cohort studies to analyze this association. Methods Relevant studies were identified by searching PubMed and Embase through October 2012. We analyzed 21 articles, which included 580,064 subjects. Random-effects models were used to estimate summary relative risks. Dose-response, subgroup, sensitivity, meta-regression, and publication bias analyses were performed. Results The summary odds ratios of gastric cancer for the highest, compared with the lowest, dietary fiber intake was 0.58 (95% confidence interval, 0.49−0.67) with significant heterogeneity among studies ( P < .001, I2 = 62.2%). Stratified analysis for study design, geographic area, source and type of fiber, Lauren’s classification, publication year, sample size, and quality score of study yielded consistent results. Dose-response analysis associated a 10-g/day increment in fiber intake with a significant (44%) reduction in gastric cancer risk. Sensitivity analysis restricted to studies with control for conventional risk factors produced similar results, and omission of any single study had little effect on the combined risk estimate. Conclusions In a meta-analysis, we show that dietary fiber intake is associated inversely with gastric cancer risk; the effect probably is independent of conventional risk factors. The direction of the protective association of dietary fiber was consistent among all studies, but the absolute magnitude was less certain because of heterogeneity among the studies. Further studies therefore are required to establish this association.
Previous randomised trials have shown an overwhelming benefit of mechanical thrombectomy for treating patients with stroke caused by large vessel occlusion of the anterior circulation. Whether ...endovascular treatment is beneficial for vertebrobasilar artery occlusion remains unknown. In this study, we aimed to investigate the safety and efficacy of endovascular treatment of acute strokes due to vertebrobasilar artery occlusion.
We did a multicentre, randomised, open-label trial, with blinded outcome assessment of thrombectomy in patients presenting within 8 h of vertebrobasilar occlusion at 28 centres in China. Patients were randomly assigned (1:1) to endovascular therapy plus standard medical therapy (intervention group) or standard medical therapy alone (control group). The randomisation sequence was computer-generated and stratified by participating centres. Allocation concealment was implemented by use of sealed envelopes. The primary outcome was a modified Rankin scale (mRS) score of 3 or lower (indicating ability to walk unassisted) at 90 days, assessed on an intention-to-treat basis. The primary safety outcome was mortality at 90 days. Secondary safety endpoints included the rates of symptomatic intracranial haemorrhage, device-related complications, and other severe adverse events. The BEST trial is registered with ClinicalTrials.gov, NCT02441556.
Between April 27, 2015, and Sept 27, 2017, we assessed 288 patients for eligibility. The trial was terminated early after 131 patients had been randomly assigned (66 patients to the intervention group and 65 to the control group) because of high crossover rate and poor recruitment. In the intention-to-treat analysis, there was no evidence of a difference in the proportion of participants with mRS 0–3 at 90 days according to treatment (28 42% of 66 patients in the intervention group vs 21 32% of 65 in the control group; adjusted odds ratio OR 1·74, 95% CI 0·81–3·74). Secondary prespecified analyses of the primary outcome, done to assess the effect of crossovers, showed higher rates of mRS 0–3 at 90 days in patients who actually received the intervention compared with those who received standard medical therapy alone in both per-protocol (28 44% of 63 patients with intervention vs 13 25% of 51 with standard therapy; adjusted OR 2·90, 95% CI 1·20–7·03) and as-treated (36 47% of 77 patients with intervention vs 13 24% of 54 with standard therapy; 3·02, 1·31–7·00) populations. The 90-day mortality was similar between groups (22 33% of 66 patients in the intervention vs 25 38% of 65 in the control group; p=0·54) despite a numerically higher prevalence of symptomatic intracranial haemorrhage in the intervention group.
There was no evidence of a difference in favourable outcomes of patients receiving endovascular therapy compared with those receiving standard medical therapy alone. Results might have been confounded by loss of equipoise over the course of the trial, resulting in poor adherence to the assigned study treatment and a reduced sample size due to the early termination of the study.
Jiangsu Provincial Special Program of Medical Science.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
As a common etiology for ischemic stroke, atherosclerotic carotid stenosis has been targeted by vascular surgery since 1950s. Compared with carotid endarterectomy, carotid angioplasty and stenting ...(CAS) is almost similarly efficacious and less invasive. These advantages make CAS an alternative in treating carotid stenosis. However, accumulative evidences suggested that the long-term benefit-risk ratio of CAS may be decreased or even neutralized by the complications related to in-stent restenosis (ISR). Therefore, investigating the mechanisms and identifying the influential factors of ISR are of vital importance for improving the long-term outcomes of CAS. As responses to intrinsic and extrinsic injuries, intimal hyperplasia and vascular smooth muscle cell proliferation have been regarded as the principle mechanisms for ISR development. Due to the lack of consensus-based definition and consistent follow-up protocol, the reported incidences of ISR after CAS varied widely among studies. These variations made the inter-study comparisons of ISR largely illogical. To eliminate restenosis after CAS, both surgery and endovascular procedures have been attempted with promising results. For preventing ISR, drug-eluting stents and antiplatelets have been proposed as potential solutions.
Background and purpose
Data on procedure time (PT) for mechanical thrombectomy (MT) are scarce. Moreover, the relationship among PT, postprocedural hemorrhagic transformation (HT), and functional ...outcomes in MT patients remains unclear. We investigated whether postprocedural HT mediated the relationship between PT and functional outcomes in patients with stent-retriever thrombectomy.
Methods
We retrospectively analyzed consecutive patients who underwent MT at two comprehensive stroke centers. PT was defined as the time from puncture to first successful recanalization or to abortion of the procedure if successful recanalization was not achieved. A favorable outcome was defined as a 90-day modified Rankin Scale score of 0–2. HT was classified using the European Cooperative Acute Stroke Study definition.
Results
Among 283 patients (mean age, 67.2 ± 11.9 years; male, 53.7%), 124 (43.8%) patients had a favorable outcome and 27 (9.5%) patients experienced symptomatic intracranial hemorrhage (sICH). Whether in the overall cohort or in the successful recanalization cohort, extended PT was an independent predictor for a poor outcome (per 30 min: OR 1.433, 95% CI 1.062–1.865,
p
= 0.019; OR 1.522, 95% CI 1.062–2.159,
p
= 0.020, respectively) and sICH (per 30 min: OR 1.391, 95% CI 1.030–1.865,
p
= 0.029; OR 1.716, 95% CI 1.161–2.648,
p
= 0.009, respectively). Moreover, postprocedural HT might partially explain the worse function outcomes in patients with an extended PT (the regression coefficient was changed by 28.2% and 28.1%, respectively).
Conclusions
The PT is an independent predictor for 90-day outcomes in stent-retriever thrombectomy patients. Postprocedural HT was partially responsible for the worse outcome in patients who experienced a longer PT.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive treatment for ischemic stroke. Astrocytes regulation has been suggested as one mechanism for rTMS effectiveness. But how rTMS ...regulates astrocytes remains largely undetermined. There were neurotoxic and neuroprotective phenotypes of astrocytes (also denoted as classically and alternatively activated astrocytes or A1 and A2 astrocytes) pertaining to pro- or anti-inflammatory gene expression. Pro-inflammatory or neurotoxic polarized astrocytes were induced during cerebral ischemic stroke. The present study aimed to investigate the effects of rTMS on astrocytic polarization during cerebral ischemic/reperfusion injury.
Three rTMS protocols were applied to primary astrocytes under normal and oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Cell survival, proliferation, and phenotypic changes were assessed after 2-day treatment. Astrocytes culture medium (ACM) from control, OGD/R, and OGD/R + rTMS groups were mixed with neuronal medium to culture neurons for 48 h and 7 days, in order to explore the influence on neuronal survival and synaptic plasticity. In vivo, rats were subjected to middle cerebral artery occlusion (MCAO), and received posterior orbital intravenous injection of ACM collected from different groups at reperfusion, and at 3 days post reperfusion. The apoptosis in the ischemic penumbra, infarct volumes, and the modified Neurological Severity Score (mNSS) were evaluated at 1 week after reperfusion, and cognitive functions were evaluated using the Morris Water Maze (MWM) tests. Finally, the 10 Hz rTMS was directly applied to MCAO rats to verify the rTMS effects on astrocytic polarization.
Among these three frequencies, the 10 Hz protocol exerted the greatest potential to modulate astrocytic polarization after OGD/R injury. Classically activated and A1 markers were significantly inhibited by rTMS treatment. In OGD/R model, the concentration of pro-inflammatory mediator TNF-α decreased from 57.7 to 23.0 рg/mL, while anti-inflammatory mediator IL-10 increased from 99.0 to 555.1 рg/mL in the ACM after rTMS treatment. The ACM collected from rTMS-treated astrocytes significantly alleviated neuronal apoptosis induced by OGD/R injury, and promoted neuronal plasticity. In MCAO rat model, the ACM collected from rTMS treatment decreased neuronal apoptosis and infarct volumes, and improved cognitive functions. The neurotoxic astrocytes were simultaneously inhibited after rTMS treatment.
Inhibition of neurotoxic astrocytic polarization is a potential mechanism for the effectiveness of high-frequency rTMS in cerebral ischemic stroke.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Functions of astrocytes in the rehabilitation after ischemic stroke, especially their impacts on inflammatory processes, remain controversial. This study uncovered two phenotypes of astrocytes, of ...which one was helpful, and the other harmful to anoxic neurons after brain ischemia.
We tested the levels of inflammatory factors including TNF-a, IL-6, IL-10, iNOS, IL-1beta, and CXCL10 in primary astrocytes at 0 h, 6 h, 12 h, 24 h, and 48 h after OGD, grouped the hypoxia astrocytes into iNOS-positive (iNOS(+)) and iNOS-negative (iNOS(-)) by magnetic bead sorting, and then co-cultured the two groups of cells with OGD-treated neurons for 24 h. We further verified the polarization of astrocytes in vivo by detecting the co-localization of iNOS, GFAP, and Iba-1 on MCAO brain sections. Lentivirus overexpressing LCN2 and LCN2 knockout mice (#024630. JAX, USA) were used to explore the role of LCN2 in the functional polarization of astrocytes. 7.0-T MRI scanning and the modified Neurological Severity Score (mNSS) were used to evaluate the neurological outcomes of the mice.
After oxygen-glucose deprivation (OGD), iNOS mRNA expression increased to the peak at 6 h in primary astrocytes, but keep baseline expression in LCN2-knockout astrocytes. In mice with transient middle cerebral artery occlusion (tMCAO), LCN2 was proved necessary for astrocyte classical activation. In LCN2 knockout mice with MCAO, no classically activated astrocytes were detected, and smaller infarct volumes and better neurological functions were observed.
The results indicated a novel pattern of astrocyte activation after ischemic stroke and lipocalin-2 (LCN2) plays a key role in polarizing and activating astrocytes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background:Carotid angioplasty and stenting (CAS) is emerging as an alternative treatment for carotid stenosis, but neointimal hyperplasia (NIH) remains a drawback of this treatment strategy. This ...study aimed to evaluate the effect of variations of carotid bifurcation geometry on local hemodynamics and NIH.Methods and Results:Hemodynamic and geometric effects on NIH were compared between 2 groups, by performing computational fluid dynamics (CFD) simulations both on synthetic models and patient-specific models. In the idealized models, multiple regression analysis revealed a significant negative relationship between internal carotid artery (ICA) angle and the local hemodynamics. In the patient-derived models, which were reconstructed from digital subtraction angiography (DSA) of 25 patients with bilateral CAS, a low time-average wall shear stress (TAWSS) and a high oscillatory shear index (OSI) were often found at the location of NIH. Larger difference values of the OSI percentage area (10.56±20.798% vs. −5.87±18.259%, P=0.048) and ECA/CCA diameter ratio (5.64±12.751% vs. −3.59±8.697%, P=0.047) were detected in the NIH-asymmetric group than in the NIH-symmetric group.Conclusions:Changes in carotid bifurcation geometry can make apparent differences in hemodynamic distribution and lead to bilateral NIH asymmetry. It may therefore be reasonable to consider certain geometric variations as potential local risk factors for NIH.
BACKGROUND AND PURPOSE—In 1960s, a stroke belt with high stroke mortality was discovered in the southeast United States. In China, where stroke is the leading cause of death, we aimed to determine ...whether a focal region of high stroke incidence (stroke belt) exits and, if so, the possible causal and modifiable factors.
METHODS—We systematically reviewed all studies of stroke incidence in China between 1980 and 2010, and included those which met our criteria for a high-quality study. Criteria for a provincial region of high stroke incidence were ranking in the top one third of all provinces for stroke incidence and ranking of more than one third of prefectural regions within the province in the top two sevenths of all prefectural regions for stroke incidence. We also reviewed regional distribution of major vascular risk factors, socioeconomic status, and demographic profiles in China.
RESULTS—Nine eligible studies provided data on the incidence of stroke in 32 of 34 provincial regions of China (with Hong Kong and Macao as exceptions) and 52% of the 347 prefectural regions. Nine provincial regions (Heilongjiang, Tibet, Jilin, Liaoning, Xinjiang, Hebei, Inner Mongolia, Beijing, and Ningxia) met our criteria for a region of high stroke incidence and constitute a stroke belt in north and west China. The incidence of stroke in the stroke belt was 236.2 per 100 000 population compared with 109.7 in regions outside the belt (rate ratio, 2.16; 95% confidence interval, 2.10–2.22). The mean population prevalence of hypertension and overweight (body mass index, >25) was greater in the stroke belt than that in other regions (15.3% versus 10.3%, P<0.001; 21.1% versus 12.3%, P=0.013, respectively). The prevalence of hypertension and overweight also correlated significantly with regional stroke incidence (R=0.642, P<0.001; R=0.438, P=0.014, respectively, by Spearman rank correlation).
CONCLUSIONS—A stroke belt of high stroke incidence exists in 9 provincial regions of north and west China. The stroke belt may be caused, at least in part, by a higher population prevalence of hypertension and excess body weight. Lowering blood pressure and body weight in the stroke belt may reduce the geographic disparity in stroke risk and incidence in China.
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