Clinical Reasoning: A 30-Year-Old Woman Presenting With Rapidly Progressive Dementia and Extreme Hypoglycorrhachia.

A 30-year-old woman presented with rapidly progressive dementia 1 month after the coronavirus disease 2019 infection. Repeated CSF analysis showed extreme hypoglycorrhachia, while cultures, metagenomic next-generation sequencing, and cytopathology testing of CSF were negative. Laboratory investigations for possible etiologies revealed elevated blood ammonia and cancer antigen 125. Brain MRI demonstrated bilateral symmetric diffuse cortical lesions with mild hyperintensity on T1-weighted image and postcontrast enhancement. A more thorough history and specific examinations subsequently indicated an underlying etiology. This case provides an approach for evaluating young patients with rapidly progressive dementia, extreme hypoglycorrhachia, and diffuse CNS lesions, highlighting the importance of considering a broad differential diagnosis.

Impact of leukoaraiosis on the infarct growth rate and clinical outcome in acute large vessel occlusion stroke after endovascular thrombectomy.

INTRODUCTION: As a marker of chronic cerebral small vessel disease, leukoaraiosis (LA) was reported to impact the recruitment of collaterals in acute ischemic stroke (AIS). We intended to explore the impact of LA on the infarct growth rate (IGR) and clinical outcome by impaired collateral development in AIS patients with large vessel occlusion (LVO) who underwent endovascular thrombectomy (EVT). PATIENTS AND METHODS: Two hundred thirty-six AIS patients who underwent EVT were retrospectively reviewed. The severity of LA was graded using the Fazekas scale with non-contrast CT. IGR was calculated by the acute core volume on CT perfusion divided by the time from stroke onset to imaging. The collateral status after LVO was assessed using the ASITN/SIR collateral scale. The clinical outcomes after EVT were evaluated using a modified Rankin Scale (mRS). The Alberta stroke program early CT score (ASPECTS), the National Institutes of Health Stroke Scale (NIHSS) score at admission, and the modified treatment in cerebral infarction (mTICI) score after EVT were also included. Correlations between those factors were analyzed. RESULTS: Patients with severe LA had significantly larger core volume on CTP (p = 0.022) and lower collateral grade (p < 0.001). Faster IGR was significantly associated with higher LA severity (adjusted odds ratio [aOR]: 1.53; 95% CI: 1.02-2.33; p = 0.046), higher NIHSS (aOR: 1.04; 95% CI: 1.00-1.09; p = 0.032) and impaired collaterals (aOR: 2.26; 95% CI: 1.27-4.03; p = 0.005). In mediation analysis, collaterals explained 33% of the effect of LA on fast IGR. There was correlation between the severity of LA and mRS (p = 0.007). DISCUSSION AND CONCLUSION: The increasing severity of LA is associated with impaired collateral status and fast infarct growth. These findings suggest that LA may become a predictive imaging biomarker for the likelihood of progression of tissue injury and clinical outcome after EVT in acute large vessel occlusion stroke.

ChemR23 signaling ameliorates brain injury via inhibiting NLRP3 inflammasome-mediated neuronal pyroptosis in ischemic stroke.

BACKGROUND: Inflammatory response has been recognized as a pivotal pathophysiological process during cerebral ischemia. ChemR23 signaling is involved in the pathophysiology of various inflammatory diseases. Nevertheless, the role of ChemR23 signaling in ischemic stroke remains largely unknown. METHODS: Permanent ischemic stroke mouse model was accomplished by middle cerebral artery occlusion (MCAO). Resolvin E1 (RvE1) or chemerin-9 (C-9), the agonists of ChemR23, were administered by intracerebroventricular (i.c.v) injection before MCAO induction. Then, analysis of neurobehavioral deficits and brain sampling were done at Day 1 after MCAO. The brain samples were further analyzed by histological staining, immunofluorescence, RNA sequencing, ELISA, transmission electron microscope, and western blots. Furthermore, oxygen-glucose deprivation (OGD) was employed in SH-SY5Y to mimic MCAO in vitro, and ChemR23 signaling pathway was further studied by overexpression of ChemR23 or administration of related agonists or antagonists. Analysis of cell death and related pathway markers were performed. RESULTS: ChemR23 expression was upregulated following MCAO. Under in vitro and in vivo ischemic conditions, ChemR23 deficiency or inhibition contributed to excessive NLRP3-mediated maturation and release of IL-1ß and IL-18, as well as enhanced cleavage of GSDMD-N and neuronal pyroptosis. These influences ultimately aggravated brain injury and neuronal damage. On the other hand, ChemR23 activation by RvE1 or C-9 mitigated the above pathophysiological abnormalities in vivo and in vitro, and overexpression of ChemR23 in SH-SY5Y cells also rescued OGD-induced neuronal pyroptosis. Blockade of NLRP3 mimics the protective effects of ChemR23 activation in vitro. CONCLUSION: Our data indicated that ChemR23 modulates NLRP3 inflammasome-mediated neuronal pyroptosis in ischemic stroke. Activation of ChemR23 may serve as a promising potential target for neuroprotection in cerebral ischemia.

Excessive apoptosis of Rip1-deficient T cells leads to premature aging.

In mammals, the most remarkable T cell variations with aging are the shrinking of the naïve T cell pool and the enlargement of the memory T cell pool, which are partially caused by thymic involution. However, the mechanism underlying the relationship between T-cell changes and aging remains unclear. In this study, we find that T-cell-specific Rip1 KO mice show similar age-related T cell changes and exhibit signs of accelerated aging-like phenotypes, including inflammation, multiple age-related diseases, and a shorter lifespan. Mechanistically, Rip1-deficient T cells undergo excessive apoptosis and promote chronic inflammation. Consistent with this, blocking apoptosis by co-deletion of Fadd in Rip1-deficient T cells significantly rescues lymphopenia, the imbalance between naïve and memory T cells, and aging-like phenotypes, and prolongs life span in T-cell-specific Rip1 KO mice. These results suggest that the reduction and hyperactivation of T cells can have a significant impact on organismal health and lifespan, underscoring the importance of maintaining T cell homeostasis for healthy aging and prevention or treatment of age-related diseases.

Meta-analysis on clinical outcomes of suprapapillary versus transpapillary stent insertion in malignant biliary obstruction.

BACKGROUND/AIMS: Endoscopic biliary stenting is an essential treatment for malignant biliary obstruction (MBO). However, the optimal location for the placement of metal stents (MS) or plastic stents (PS) during the management of MBO, whether above (suprapapillary) or across (transpapillary) the sphincter of Oddi (SO), has not been thoroughly evaluated. This meta-analysis aims to compare the clinical outcomes associated with endoscopic retrograde cholangiopancreatography (ERCP)-guided biliary stents placed above and across the SO in patients with MBO. METHODS: A comprehensive search of electronic databases was carried out to identify studies published from inception to April 2022. The clinical outcomes examined including stent patency, stent occlusion, and overall adverse events (AEs) such as cholangitis, post-ERCP pancreatitis (PEP), cholecystitis, stent migration, and bleeding. The selection of a random-effects model or fixed-effects model was based on the presence of heterogeneity. RESULTS: A total of 12 articles involving 751 patients were analyzed. The findings showed that the suprapapillary approach had longer stent patency compared to the transpapillary approach (mean difference: 38.58; 95% confidence interval 16.02-61.14, P < 0.0001). Additionally, the suprapapillary approach was associated with a lower risk of stent occlusion and overall AEs (P = 0.04, P = 0.002, respectively), particularly in the incidence of PEP (P = 0.009). The incidence of cholangitis, cholecystitis, stent migration, and bleeding were similar between the suprapapillary and transpapillary approaches. The subgroup analyses indicated that suprapillary PS had a significant decrease in the incidence of stent occlusion and longer stent patency, while suprapillary MS had a significant decrease in the incidence of overall AEs and PEP than the transpapillary approach. CONCLUSION: Compared with the transpapillary approach, the suprapapillary stent had superiority in longer stent patency, lower rates of stent occlusion and overall AEs, and notably, a lower incidence of PEP. The incidence of cholangitis, cholecystitis, stent migration, and bleeding were similar between the suprapapillary and transpapillary approaches. Further large-scale randomized controlled studies are needed to confirm our findings. REGISTRATION NO: CRD42022336435.

Core overestimation of CT perfusion in patients with cardiac insufficiency who had a stroke is mediated by impaired collaterals.

BACKGROUND: We hypothesized that left ventricular systolic dysfunction (LVSD) would lead to an ischemic core overestimation in patients with acute ischemic stroke (AIS), and impaired collateral status might partly mediate this effect. OBJECTIVE: A pixel-based analysis of CT perfusion (CTP) and follow-up CT was undertaken to investigate the optimum CTP thresholds for the ischemic core if overestimation was found. METHODS: A total of 208 consecutive patients with AIS with large vessel occlusion in the anterior circulation, who received initial CTP evaluation and successful reperfusion, were retrospectively analyzed and divided into an LVSD (left ventricular ejection fraction (LVEF) ratio <50%; n=40) and a normal cardiac function (LVEF≥50%; n=168) group. Ischemic core overestimation was considered when the CTP-derived core was larger than the final infarct volume. We investigated the relationship between cardiac function, probability for core overestimation, and collateral scores using mediation analysis. A pixel-based analysis was undertaken to define the optimum CTP thresholds for ischemic core. RESULTS: LVSD was independently associated with impaired collaterals (aOR=4.28, 95% CI 2.01 to 9.80, P<0.001) and core overestimation (aOR=2.52, 95% CI 1.07 to 5.72, P=0.030). In mediation analysis, the total effect on core overestimation is composed of the direct effect of LVSD (+17%, P=0.034) and the mediated indirect effect of collateral status (+6%, P=0.020). Collaterals explained 26% of the effect of LVSD on core overestimation. Compared with relative cerebral blood flow (rCBF) thresholds of <35%, <30%, and <20%, a rCBF <25% cut-off point had the highest correlation (r=0.91) and best agreement (mean difference 3.2±7.3 mL) with the final infarct volume to determine the CTP-derived ischemic core in patients with LVSD. CONCLUSIONS: LVSD increased the possibility of ischemic core overestimation on baseline CTP, partly due to impaired collateral status, and a stricter rCBF threshold should be considered.

Thrombus Enhancement Sign May Differentiate Embolism From Arteriosclerosis-Related Large Vessel Occlusion.

BACKGROUND AND PURPOSE: To evaluate whether the thrombus enhancement sign (TES) can be used to differentiate embolic large vessel occlusion (LVO) from in situ intracranial atherosclerotic stenosis (ICAS)-related LVO in the anterior circulation of patients with acute ischemic stroke (AIS). METHODS: Patients with LVO in the anterior circulation who underwent both non-contrast computed tomography (CT) and CT angiography and mechanical thrombectomy were retrospectively enrolled. Both embolic LVO (embo-LVO) and in situ ICAS-related LVO (ICAS-LVO) were confirmed by two neurointerventional radiologists after reviewing the medical and imaging data. TES was assessed to predict embo-LVO or ICAS-LVO. The associations between occlusion type and TES, along with clinical and interventional parameters, were investigated using logistic regression analysis and a receiver operating characteristic curve. RESULTS: A total of 288 patients with AIS were included and divided into an embo-LVO group (n=235) and an ICAS-LVO group (n=53). TES was identified in 205 (71.2%) patients and was more frequently observed in those with embo-LVO, with a sensitivity of 83.8%, specificity of 84.9%, and area under the curve (AUC) of 0.844. Multivariate analysis showed that TES (odds ratio [OR], 22.2; 95% confidence interval [CI], 9.4-53.8; P<0.001) and atrial fibrillation (OR, 6.6; 95% CI, 2.8-15.8; P<0.001) were independent predictors of embolic occlusion. A predictive model that included both TES and atrial fibrillation yielded a higher diagnostic ability for embo-LVO, with an AUC of 0.899. CONCLUSION: TES is an imaging marker with high predictive value for identifying embo- and ICAS-LVO in AIS and provides guidance for endovascular reperfusion therapy.

Effects of predictive nursing intervention on cognitive impairment and neurological function in ischemic stroke patients.

BACKGROUND: Ischemic stroke is a clinical emergency caused by insufficient intracranial blood supply, which eventually leads to brain tissue necrosis and neurological impairment. Predictive nursing intervention has achieved impressive success in the nursing of multiple surgeries. However, the role of predictive nursing intervention in the care of patients with ischemic stroke remains unclear. METHODS: This study was a randomized controlled trial. Based on the inclusion and exclusion criteria, 126 patients were randomly assigned into two groups, namely the control group and the predictive nursing intervention group. Both groups were treated with thrombolytic therapy with alteplase. The patients in the control group were given routine nursing intervention and the predictive nursing intervention group received additional predictive care. Neurologic functions and cognitive impairment were evaluated by National Institutes of Health Stroke Scale (NIHSS), Fugl-Meyer assessment (FMA), Montreal cognitive assessment (MoCA), and mini-mental state examination (MMSE) scales, respectively. Door-to-Needle Times, venous thromboembolism (VTE)-related parameters, and complications were recorded. RESULTS: Predictive nursing intervention significantly shortened the Door-to-Needle Times and enhanced the peak/average femoral venous blood flow and femoral venous diameter. In addition, predictive nursing intervention improved the NIHSS, FMA, MMSE, and MoCA scores and remarkably reduced the recurrence of ischemic stroke, deep vein thrombosis and gingival bleeding. CONCLUSION: Predictive nursing intervention is beneficial to improve the effects of thrombolytic therapy in patients with ischemic stroke, which improves the neurological, cognitive and motor functions of patients, and reduces the occurrence of complications, suggesting an important clinical application value.

Impact of high-sensitivity troponin elevation and dynamic changes on 90-day mortality in patients with acute ischemic stroke after mechanical thrombectomy: results from an observational cohort.

BACKGROUND: A study was undertaken to evaluate the impact of high-sensitivity cardiac troponin I (hs-cTnI) elevation and hs-cTnI dynamic changes on 90-day mortality in patients with acute ischemic stroke (AIS) treated with mechanical thrombectomy (MT). METHODS: Patients with AIS receiving MT were included in the study. Sixty hours after AIS onset, hs-cTnI levels were measured before and after MT to determine elevated and dynamic changes. Patients were stratified into either normal or hs-cTnI elevation groups according to the pre-MT hs-cTnI cut-off value of 0.03 ng/L. hs-cTnI dynamic changes were defined as an increase or decrease of more than 20% pre-MT and post-MT, and at least one hs-cTnI level >0.03 ng/L. Multivariate Cox regression models were used to investigate the association between hs-cTnI elevation, hs-cTnI dynamic changes, and 90-day mortality in patients with AIS after MT. RESULTS: A total of 423 patients with AIS after MT were included in our final analysis, of whom only 72 (17%) showed hs-cTnI elevation. Post-MT hs-cTnI retesting was performed in 354 patients, and 90 (25.4%) patients presented with hs-cTnI dynamic changes. 119 patients died within 90 days. After adjusting for potential confounding factors, the Cox regression model showed that patients with hs-cTnI dynamic changes, rather than hs-cTnI elevation, were associated with 90-day mortality (p<0.05). Compared with the hs-cTnI non-dynamic changes, these results showed that a statistical association was present between rising hs-cTnI dynamic changes and 90-day mortality (p>0.05). CONCLUSIONS: hs-cTnI dynamic changes, dominated by the rising pattern rather than hs-cTnI elevation, were independent factors associated with 90-day mortality in patients with AIS after MT, especially in elderly subjects.

Thrombus enhancement sign on CT angiography is associated with the first pass effect of stent retrievers.

BACKGROUND: The thrombus enhancement sign (TES) is thought to be associated with the source of the stroke and thrombus composition. We investigated whether this imaging sign along with other thrombus characteristics could be used to predict the successful first pass effect (FPE) of mechanical thrombectomy. METHODS: 246 consecutive patients with acute ischemic stroke in the anterior circulation with large vessel occlusion who underwent thrombectomy with a stent retriever and clot collection were included. Patients were divided into FPE (modified Thrombolysis in Cerebral Infarction (mTICI) grade 2c or 3)/non-FPE (mTICI 0-2b) and modified FPE (mFPE) (mTICI 2b-3)/non-mFPE (mTICI 0-2a) groups based on flow restoration after the first pass. TES presence, thrombus density, thrombus length, clot burden score, and thrombus composition were compared. The association between FPE and imaging biomarkers, along with clinical and interventional parameters, was investigated by univariate and multivariate analysis. RESULTS: FPE was achieved in 85 (34.6%) patients. TES presence was significantly lower in the FPE group (64.7% vs 80.7% in the non-FPE group, p=0.008) and mFPE group (69.1% vs 81.0% in the non-mFPE group, p=0.039). Histopathological examination revealed that TES (+) thrombi contained a higher fibrin/platelet proportion (50.9% vs 46.9% in TES (-) thrombi, p=0.029) and fewer erythrocytes (43.3% vs 47.3% in TES (-) thrombi, p=0.030). Thrombus characteristics, namely shorter thrombus length (p=0.032), higher erythrocyte proportions (p=0.026), and less fibrin/platelets (p=0.014), were confirmed in patients with FPE. In multivariable analysis, TES was the only independent predictor of FPE failure (OR 0.51, 95% CI 0.28 to 0.94; p=0.031). CONCLUSIONS: TES was independently associated with first pass angiographic failure in patients treated with a stent retriever.

Analyses on safety and efficacy of non-standard dose of r-tPA in intravenous thrombolysis-treated AIS patients.

Background: Intravenous 0.9 mg/kg recombinant tissue plasminogen activator (r-tPA) is one of the most effective treatments in acute ischemic stroke patients. Practically, the dose of r-tPA is still a topic that is constantly being discussed. Methods: For this observational study, data were obtained from 537 patients who received r-tPA thrombolysis at Shanghai Sixth People's Hospital stroke center over 5 years (2014-2019). Patients were divided into two groups: a non-standard dose group (0.6 mg/kg ≤ dose < 0.9 mg/kg) and a standard dose group (0.9 mg/kg). Different outcomes were observed: efficacy: 3 months mRS 0-1 (3m-mRS0-1); safety: symptomatic intracranial hemorrhage within 24 h (24h-sICH) and 3 months mortality (3m-death). We also observed the effect of r-tPA dose coefficient on outcomes in different age groups and baseline National Institute of Health stroke scale (NIHSS) score subgroups. Results: There were 265 patients who gave the standard dose treatment and 272 gave the nonstandard dose. There was no significant difference between the non-standard dose group and the standard dose group in 3m-mRS0-1, 3m-death, and 24h-sICH (p = 0.567, 0.327, and 0.415, respectively). The dose coefficient presents a significant negative correlation (p = 0.034, B = -4.290) with 3m-death in NIHSS < 16 sub-group. Door-to-needle time (DNT) is the most important independent outcome-influential factor (MIOIF) in the NIHSS ≥16 sub-group. The diabetes history and baseline NIHSS score were the MIOIF in the age ≥80-year sub-group. Conclusions: The non-standard dose group (0.6 mg/kg ≤ dose < 0.9 mg/kg) shows no difference in safety and effectiveness than the standard dose group (0.9 mg/kg) in our study. The standard dose should be considered first according to current evidence and Guidelines, but the non-standard dose (0.6 mg/kg ≤ dose < 0.9 mg/kg) might be an option in the actual diagnosis and treatment process considering the patient's clinical profile and financial condition.

No sex difference was found in the safety and efficacy of intravenous alteplase before endovascular therapy.

Background and purpose: Prior studies on sex disparities were post-hoc analyses, had limited treatment modalities, and had controversial findings. Our study aimed to examine whether sex difference modifies the effect of intravenous alteplase before endovascular therapy. Methods: We conducted a multicenter prospective cohort study of 850 eligible patients with acute ischemic stroke who underwent endovascular therapy. A propensity score was utilized as a covariate to achieve approximate randomization of alteplase pretreatment. The baseline characteristics of women and men were compared. Logistic regression with interaction terms, adjusted for potential confounders, was used to investigate the effect of sex on the prognosis of bridging therapy. Results: In comparison to men, women were older [78.00 (70.00-84.00) vs. 67 (61.00-74.00), P < 0.001], had more atrial fibrillation (61.4 vs. 35.2%, P < 0.001), had a lower ASPECTS [10.00 (8.00-10.00) vs. 10 (9.00-10.00), P = 0.0047], and had a higher NIHSS score [17.00 (14.00-20.00) vs. 16 (13.00-19.00), P = 0.005]. Women tended to receive less bridging therapy (26.3 vs. 33%, P = 0.043) and more retrieval attempts [2.00 (1.00-2.00) vs. 1 (1.00-2.00), P = 0.026]. There was no sex difference in functional independence at 90 days after bridging therapy (OR 0.968, 95% CI 0.575-1.63), whereas men benefited more after EVT alone (OR 0.654, 95% CI 0.456-0.937). There were no sex-treatment interactions observed regardless of the location of the occlusion. There were no significant sex differences in all safety outcomes. Conclusion: Our study could not confirm that sex modifies the treatment effect of intravenous alteplase before endovascular therapy. At the same time, we advocate for women to seek timely medical treatment.

Caspase-8 Blocks Receptor-Interacting Protein Kinase-1 Kinase-Independent Necroptosis during Embryogenesis.

Caspase-8 (Casp8) suppresses receptor-interacting protein kinase-3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL)-dependent necroptosis, demonstrated by the genetic evidence that deletion of Ripk3 or Mlkl prevented embryonic lethality of Casp8-deficient mice. However, the detailed mechanisms by which Casp8 deficiency triggers necroptosis during embryonic development remain unclear. In this article, we show that Casp8 deletion caused formation of the RIPK1-RIPK3 necrosome in the yolk sac, leading to vascularization defects, prevented by MLKL and RIPK3 deficiency, or RIPK3 RHIM mutant (RIPK3 V448P), but not by the RIPK1 kinase-dead mutant (RIPK1 K45A). In addition, Ripk1K45A/K45ACasp8 -/- mice died on embryonic day 14.5, which was delayed to embryonic day 17.5 by ablation of one allele in Ripk1 and was completely rescued by ablation of Mlkl Our results revealed an in vivo role of RIPK3 RHIM and RIPK1K45A scaffold-mediated necroptosis in Casp8 deficiency embryonic development and suggested that the Casp8-deficient yolk sac might be implicated in identifying novel regulators as an in vivo necroptotic model.

Potential Factors Predicting Histopathologically Upgrade Discrepancies between Endoscopic Forceps Biopsy of the Colorectal Low-Grade Intraepithelial Neoplasia and Endoscopic Resection Specimens.

Background: It was gradually accepted that endoscopic fragment biopsy (EFB) diagnosis cannot accurately guarantee the absence of higher-grade neoplasms within the lesion of the digestive tract. There are no well-established predictors for histopathologically upgrade discrepancies between EFB diagnosing colorectal low-grade intraepithelial neoplasia (LGIN) and endoscopic resection (ER) specimens. Methods: A total of 918 colorectal LGINs was histopathologically diagnosed by EFB, including 162 cases with upgrade discrepancy and 756 concordant cases. We compared clinicopathological data of EFB and ER specimens between these two groups. Multivariate analysis was performed to identify predictors for this upgrade histopathology. Results: The predominant upgrade discrepancy of LGINs diagnosed by EFB was upgrades to high-grade dysplasia (114/918, 12.4%), followed by upgrades to intramucosal carcinoma (33/918, 3.6%), submucosal adenocarcinoma (10/918, 1.1%), and advanced adenocarcinoma (5/918, 0.5%). NSAID history (OR 4.83; 95% CI, 2.27-10.27; p < 0.001), insufficient EFB number (OR 2.99; 95% CI, 1.91-4.68; p < 0.001), maximum diameter ≥ 1.0 cm (OR 6.18; 95% CI, 1.32-28.99; p = 0.021), lobulated shape (OR 2.68; 95% CI, 1.65-4.36; p < 0.001), erythema (OR 2.42; 95% CI, 1.50-3.91; p < 0.001), erosion (OR 7.12; 95% CI, 3.91-12.94; p < 0.001), surface unevenness (OR 2.31; 95% CI, 1.33-4.01; p = 0.003), and distal location of the target adenoma (OR 3.29; 95% CI, 1.68-6.41; p < 0.001) were associated with the histologically upgrade discrepancies. Conclusion: NSAID history, insufficient EFB number, adenoma size and location, and abnormal macroscopic patterns are potential predictors for upgrade histopathology of LGINs diagnosed by EFBs. The standardization of EFB number and advanced imaging techniques could minimize the risk of neglecting the potential of this upgrade histopathology.

Systemic Glycemic Variation Predicts Mortality of Acute Ischemic Stroke After Mechanical Thrombectomy: A Prospective Study Using Continuous Glucose Monitoring.

Objective: We investigated the association of glycemic variation with the clinical outcomes of large vessel occlusion (LVO) induced acute ischemic stroke (AIS) after mechanical thrombectomy (MT). Methods: We recruited consecutive ischemic patients with stroke. Glucose levels were assessed through continuous glucose monitoring in 70 patients with AIS who had undergone MT. Metrics including percentages of time of glucose levels above the range, the hypoglycemic range, and the time within the range, coefficient of variation, standard deviation (SD), mean of daily differences, mean amplitude of glycemic excursion, largest amplitude of glycemic excursion, high blood glucose index, and low blood glucose index. The outcomes of this observational study were in-hospital mortality, neurological improvement during hospitalization, functional independence, and mortality at follow-up (3 months). The associations of the blood glucose metrics with outcomes were analyzed. Results: The average period of glucose monitoring was 3.5 days, and serum glucose was recorded 728 times after MT for each person. The glycemic variation expressed in SDs was independently associated with in-hospital mortality [odds ratio (OR): 2.8, 95% confidence interval (CI): 1.276-6.145, p = 0.01] and the 3-month mortality (OR: 2.107, 95% CI: 1.013-4.382, p = 0.046) after adjusting for potential confounders. There was no association of glycemic variation with the 3-month clinical functional independence. Conclusions: Increased systemic glycemic variation was associated with higher odds of mortality of LVO-AIS after MT. Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=21016, identifier: ChiCTR-OOC-17012378.

Ubiquitin-binding domain in ABIN1 is critical for regulating cell death and inflammation during development.

ABIN1 is a polyubiquitin-binding protein known to regulate NF-κB activation and cell death signaling. Mutations in Abin1 can cause severe immune diseases in human, such as psoriasis, systemic lupus erythematosus, and systemic sclerosis. Here, we generated mice that disrupted the ubiquitin-binding domain of ABIN1 (Abin1UBD/UBD) died during later embryogenesis owing to TNFR1-mediated cell death, similar to Abin1-/- mice. Abin1UBD/UBD cells were rendered sensitive to TNF-α-induced apoptosis and necroptosis as the inhibition of ABIN1UBD and A20 recruitment to the TNF-RSC complex leads to attenuated RIPK1 deubiquitination. Accordingly, the embryonic lethality of Abin1UBD/UBD mice was rescued via crossing with RIPK1 kinase-dead mice (Ripk1K45A/K45A) or the co-deletion of Ripk3 and one allele of Fadd, but not by the loss of Ripk3 or Mlkl alone. Unexpectedly, Abin1UBD/UBD mice with the co-deletion of Ripk3 and both Fadd alleles died at E14.5. This death was caused by spontaneous RIPK1 ubiquitination-dependent multiple inflammatory cytokines over production and could be rescued by the co-deletion of Ripk1 or Tnfr1 combined with Ifnar. Collectively, these data demonstrate the importance of the ABIN1 UBD domain, which mediates the ABIN1-A20 axis, at limiting RIPK1 activation-dependent cell death during embryonic development. Furthermore, our findings reveal a previously unappreciated ubiquitin pathway that regulates RIPK1 ubiquitination by FADD/Casp8 to suppress spontaneous IKKε/TBK1 activation.

Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia.

Caspase-8 is an initiator of death receptor-induced apoptosis and an inhibitor of RIPK3-MLKL-dependent necroptosis. In addition, caspase-8 has been implicated in diseases such as lymphoproliferation, immunodeficiency, and autoimmunity in humans. Although auto-cleavage is indispensable for caspase-8 activation, its physiological functions remain poorly understood. Here, we generated a caspase-8 mutant lacking E385 in auto-cleavage site knock-in mouse (Casp8ΔE385/ΔE385). Casp8ΔE385/ΔE385 cells were expectedly resistant to Fas-induced apoptosis, however, Casp8ΔE385/ΔE385 cells could switch TNF-α-induced apoptosis to necroptosis by attenuating RIPK1 cleavage. More importantly, CASP8(ΔE385) sensitized cells to RIPK3-MLKL-dependent necroptosis through promoting complex II formation and RIPK1-RIPK3 activation. Notably, Casp8ΔE385/ΔE385Ripk3-/- mice partially rescued the perinatal death of Ripk1-/- mice by blocking apoptosis and necroptosis. In contrast to the Casp8-/-Ripk3-/- and Casp8-/-Mlkl-/- mice appearing autoimmune lymphoproliferative syndrome (ALPS), both Casp8ΔE385/ΔE385Ripk3-/- and Casp8ΔE385/ΔE385Mlkl-/- mice developed transplantable lymphopenia that could be significantly reversed by RIPK1 heterozygosity, but not by RIPK1 kinase dead mutation. Collectively, these results demonstrate previously unappreciated roles for caspase-8 auto-cleavage in regulating necroptosis and maintaining lymphocytes homeostasis.

Activation of ERK-Drp1 signaling promotes hypoxia-induced Aß accumulation by upregulating mitochondrial fission and BACE1 activity.

Hypoxia is a risk factor for Alzheimer's disease (AD). Besides, mitochondrial fission is increased in response to hypoxia. In this study, we sought to investigate whether hypoxia-induced mitochondrial fission plays a critical role in regulating amyloid-ß (Aß) production. Hypoxia significantly activated extracellular signal-regulated kinase (ERK), increased phosphorylation of dynamin-related protein 1 (Drp1) at serine 616, and decreased phosphorylation of Drp1 at serine 637. Importantly, hypoxia triggered mitochondrial dysfunction, elevated ß-secretase 1 (BACE1) and γ-secretase activities, and promoted Aß accumulation in HEK293 cells transfected with ß-amyloid precursor protein (APP) plasmid harboring the Swedish and Indiana familial Alzheimer's disease mutations (APPSwe/Ind HEK293 cells). Then, we investigated whether the ERK inhibitor PD325901 and Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1) would attenuate hypoxia-induced mitochondrial fission and Aß generation in APPSwe/Ind HEK293 cells. PD325901 and Mdivi-1 inhibited phosphorylation of Drp1 at serine 616, resulting in reduced mitochondrial fission under hypoxia. Furthermore, hypoxia-induced mitochondrial dysfunction, BACE1 activation, and Aß accumulation were downregulated by PD325901 and Mdivi-1. Our data demonstrate that hypoxia induces mitochondrial fission, impairs mitochondrial function, and facilitates Aß generation. The ERK-Drp1 signaling pathway is partly involved in the hypoxia-induced Aß generation by regulating mitochondrial fission and BACE1 activity. Therefore, inhibition of hypoxia-induced mitochondrial fission may prevent or slow the progression of AD.

Mechanical thrombectomy injury to the arterial wall: A comparison between catheter aspiration and stent retriever.

PURPOSE: To compare the extent of arterial wall damage when SR and CA were used for treatment of AIS models to evaluate their efficacy and safety. METHODS: A thrombin-induced thrombus was pre-injected into the right distal external carotid-maxillary artery (ECMA) in 12 dogs to create an acute thrombus occlusion model and were randomly divided into the SR group (n = 6; received SR treatment) and CA group (n = 6; received CA treatment). Device safety was also assessed by five passages through the normal left ECMA using each device. Device manipulation-related damage to arterial walls, final flow restoration, recanalization time and complications were recorded. RESULTS: Sixteen retriever and 10 aspiration attempts were performed in the SR and CA groups. Reperfusion time was significantly reduced in the CA group (17.83 ±â€¯1.96 vs. 28.33 ±â€¯3.26 in the SR group; P = 0.02). Stent retriever thrombectomy resulted in an increased risk of endothelium denudation (1.17 ±â€¯0.24 in SR group vs. 0.42 ±â€¯0.15 in CA group; P = 0.01) and reduced frequency of vessel vasospasm (0.67 ±â€¯0.14 in SR group vs. 0.25 ±â€¯0.13 in CA group; P = 0.04). Injury score and thrombus deposition were similar between the two groups (P > 0.05). TICI 2b/3 flow restoration values of the right ECMA were 100 % in both groups. Device-related complications, including dissection (P = 0.21), side branch influence (P = 0.24), and distal thromboembolism (P = 1.00), did not differ between the two groups. CONCLUSION: Both devices had similar efficacy and caused minimal arterial wall damage in our dog models. SR was more likely to cause endothelium denudation, while CA had a greater risk of vasospasm.

Arterial wall injury and miRNA expression induced by stent retriever thrombectomy under stenotic conditions in a dog model.

BACKGROUND: Acute ischemic stroke can be caused by in situ stenotic vessel occlusion. In the present study, we compared the extent of arterial wall damage and miRNA expression following stent retriever use under normal and stenotic conditions. METHODS: The stent retriever procedure was simulated in three dogs by the creation of four stenoses on each side of the common carotid artery (CCA) to allow five stent passages. Device safety was also assessed in normal control models by five passages through both CCAs. Device manipulation-related damage to the arterial walls was evaluated and compared between groups by angiography and pathological analysis. Real-time PCR was used to evaluate the differences in the expression of miRNAs between the two groups. RESULTS: Twenty-four stenoses were created in three model dogs, and the mean stenosis rate was 65.58%±18.95%. Angiography revealed greater vasospasm in the stenotic group than in the non-stenotic group (1.17±0.17 vs 0.5±0.23; P=0.04). Pathological examination revealed that SR passage through the stenotic lumen caused higher injury scores (1.63±0.19 vs 0.25±0.09 for the non-stenotic lumen; P<0.001), more endothelial denudation (1.79±0.13 vs 0.58±0.13 for the non-stenotic lumen; P<0.001), and increased thrombus deposition (0.71±0.14 vs 0±0 for the non-stenotic lumen; P<0.001). miR21-3p, miR29-3p, and miR26a were upregulated in stenotic vessels compared with non-stenotic vessels after SR thrombectomy (P<0.001). CONCLUSION: In our model dogs, SR thrombectomy resulted in more severe tissue damage to the arterial wall under stenotic conditions than under non-stenotic conditions. The damage may have resulted from upregulation of miR21-3p, miR29-3p, and miR26a expression.