Early neurological deterioration in acute ischemic stroke patients after intravenous thrombolysis with alteplase predicts poor 3-month functional prognosis - data from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China).

BACKGROUND: We aimed to investigate the risk factors of early neurological deterioration (END) after intravenous thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) and the relationship between END and poor 3-month functional outcomes. METHODS: Patients who accepted intravenous recombinant rt-PA were enrolled continuously. END was defined as an increase in National Institute of Health Stroke (NIHSS) score ≥ 4 points or death within 24 hours after intravenous thrombolysis. The modified Rankin Scale (mRS) score was recorded to evaluate the functional outcome of stroke, and the poor 3-month prognosis was defined as an mRS score ≥ of 3. Univariate and multivariate analyses were used to analyze the risk factors of END. The relation between END and 3-month functional outcome was analyzed by multivariate logistic regression analysis. RESULTS: A total of 1107 patients (mean age, 63.42 ± 11.33 years; 673 males) were included in the final analysis, and 81(7.32%) patients had END. In multivariate analysis, the serum glucose level was significantly associated with END; the odds ratio was 1.10 (95% CI 1.03 to 1.18, p = 0.004). The multivariate logistic analysis showed END has a notable association with the poor 3-month functional recovery even after adjusting for confounding factors; the adjusted OR was 8.25 (95% CI 3.77 to 18.03, p < 0.0001). CONCLUSIONS: The initial serum glucose level might be an independent risk factor of END, and END might predict a poor 3-month prognosis.

A New Target of the Four-Herb Chinese Medicine for Wound Repair Promoted by Mitochondrial Metabolism Using Protein Acetylation Analysis.

BACKGROUND Wound healing is a dynamic and complex process that is regulated by a variety of factors and pathways. This study sought to identify the mechanisms of the four-herb Chinese medicine ANBP in enhancing wound repair. MATERIAL AND METHODS By comparing the group treated with ANBP for 6 h (Z6h) with the corresponding control group (C6h), we used the new high-throughput differential acetylation proteomics method to explore the mechanism of ANBP treatment and analyse and identify new targets of ANBP for promoting wound healing. RESULTS ANBP promoted skin wound healing in mice; the wound healing process was accelerated and the wound healing time was shortened (P<0.05). The upregulated proteins were distributed mostly in the mitochondria to nuclear respiratory chain complexes and cytoplasmic vesicles. The dominant pathways for upregulated proteins were fatty acid metabolism, pyruvate metabolism, and tricarboxylic acid cycle. Pdha1 was upregulated with the most acetylation sites, while the downregulated Ncl, and Pfkm were most acetylated. CONCLUSIONS The findings from our study showed that ANBP improved cell aerobic respiration through enhanced glycolysis, pyruvic acid oxidative decarboxylation, and the Krebs cycle to produce more ATP for energy consumption, thus accelerating wound repair of skin.

Intraluminal Thrombus and Outcomes of Patients With Acute Large Vessel Occlusive Stroke Undergoing Endovascular Treatment.

BACKGROUND AND PURPOSE: Intraluminal thrombus (ILT) is an emerging imaging marker in acute ischemic stroke. We aimed to investigate the association of ILT with outcomes of acute large vessel occlusion (LVO) patients receiving endovascular treatment. METHODS: Acute LVO stroke patients who underwent endovascular treatment within 24 hours, in a prospective, nationwide registry were enrolled. Pretreatment digital subtraction angiography was reviewed for the presence of ILT. The primary outcome was 90-day functional dependence (modified Rankin Scale scores, 3-6). Secondary outcomes included 24-hour LVO, 90-day death, and symptomatic intracranial hemorrhage. RESULTS: Among 711 patients enrolled, 75 (10.5%) with ILT were less likely to have 90-day functional dependence compared with those without ILT (adjusted odds ratio, 0.53 [95% CI, 0.31-0.90]; P=0.021). The same trend was found among those with successful reperfusion (modified Thrombolysis in Cerebral Infarction 2b-3; P=0.008) but not in those without successful reperfusion (P=0.107). Presence of ILT was also independently associated with a lower rate of 24-hour LVO (adjusted odds ratio 0.34 [95% CI, 0.13-0.89]; P=0.028). However, those with or without ILT had similar risks of symptomatic intracranial hemorrhage and 90-day death. CONCLUSIONS: Among acute LVO patients receiving endovascular treatment, pretreatment ILT-positive patients may have a better 90-day functional outcome (versus ILT-negative) but similar risk of death and symptomatic intracranial hemorrhage. The possibly favorable effect of ILT patients remained in those with successful reperfusion. Registration: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR1900022154.

Capacitive Pressure Sensor Combining Dual Dielectric Layers with Integrated Composite Electrode for Wearable Healthcare Monitoring.

Foot activity can reflect numerous physiological abnormalities in the human body, making gait a valuable metric in health monitoring. Research on flexible sensors for gait monitoring has focused on high sensitivity, wide working range, fast response, and low detection limit, but challenges remain in areas such as elasticity, antibacterial activity, user-friendliness, and long-term stability. In this study, we have developed a novel capacitive pressure sensor that offers an ultralow detection limit of 1 Pa, wide detection ranges from 1 Pa to 2 MPa, a high sensitivity of 0.091 kPa-1, a fast response time of 71 ms, and exceptional stability over 6000 cycles. This sensor not only has the ability of accurately discriminating mechanical stimuli but also meets the requirements of elasticity, antibacterial activity, wearable comfort, and long-term stability for gait monitoring. The fabrication method of a dual dielectric layer and integrated composite electrode is simple, cost-effective, stable, and amenable to mass production. Thereinto, the introduction of a dual dielectric layer, based on an optimized electrospinning network and micropillar array, has significantly improved the sensitivity, detection range, elasticity, and antibacterial performance of the sensor. The integrated flexible electrodes are made by template method using composite materials of carbon nanotubes (CNTs), two-dimensional titanium carbide Ti3C2Tx (MXene), and polydimethylsiloxane (PDMS), offering synergistic advantages in terms of conductivity, stability, sensitivity, and practicality. Additionally, we designed a smart insole that integrates the as-prepared sensors with a miniature instrument as a wearable platform for gait monitoring and disease warning. The developed sensor and wearable platform offer a cutting-edge solution for monitoring human activity and detecting diseases in a noninvasive manner, paving the way for future wearable devices and personalized healthcare technologies.

Cost-effective core@shell structured zero-valent iron nanoparticles @ magnetic (nZVI@Fe3O4) for Cr(vi) removal from aqueous solutions: preparation by disproportionation of Fe(ii).

Nanoscale zero-valent iron (nZVI) and its composites are known for their excellent ability to remove Cr(vi), but their preparation can be expensive due to the reduction processes. This study presents a cost-effective method to prepare core@shell structured nZVI@Fe3O4 nanocomposites using a novel Fe(ii) disproportionation reaction. The nZVI@Fe3O4 was thoroughly characterized using various techniques, including FESEM, HRTEM, EDS, XPS, XRD, FTIR, and VSM. Batch experiments were performed to evaluate the removal efficiency of nZVI@Fe3O4 in eliminating Cr(vi) ions from aqueous solutions, while classical models were employed to investigate the influencing factors associated with the removal process. The results showed that a 0.7 mg per ml NaOH solution reacted with Fe(ii) at 150 °C for 0.5 h could be used to prepare nZVI@Fe3O4 composites efficiently and inexpensively. nZVI@Fe3O4 was able to remove more than 99% of Cr(vi) from both simulated Cr(vi) solutions and real electroplating wastewater, and the recovery and preparation could be easily performed using external magnets to separate it from the solution. At pH 6.0, the maximum adsorption capacity (qmax) for Cr(vi) reached 58.67 mg g-1. The reaction mechanism was discussed from the perspective of electron transfer. Overall, the results suggest that nZVI@Fe3O4, an efficient adsorbent prepared using an environmentally friendly and inexpensive Fe(ii) disproportionation reaction, is a promising option for the treatment of Cr(vi) from industrial wastewater and other contaminated water sources.

Perspectives on effect of spleen in ischemic stroke.

Despite decades of research, stroke therapies are limited to recanalization therapies that can only be used on <10% of stroke patients; the vast majority of stroke patients cannot be treated by these methods. Even if recanalization is successful, the outcome is often poor due to subsequent reperfusion injury. A major damage mechanism operating in stroke is inflammatory injury due to excessive pro-inflammatory cascades. Many studies have shown that, after stroke, splenic inflammatory cells, including neutrophils, monocytes/macrophages, and lymphocytes, are released and infiltrate the brain, heightening brain inflammation, and exacerbating ischemia/reperfusion injury. Clinical studies have observed spleen contraction in acute stroke patients where functional outcome improved with the gradual recovery of spleen volume. These observations are supported by stroke animal studies that have used splenectomy- or radiation-induced inhibition of spleen function to show spleen volume decrease during the acute phase of middle cerebral artery occlusion, and transfer of splenocytes to stroke-injured brain areas. Thus, activation and release of splenic cells are upstream of excessive brain inflammation in stroke. The development of reversible means of regulating splenic activity offers a therapeutic target and potential clinical treatment for decreasing brain inflammation and improving stroke outcomes.

Combined Association of Low-Density Lipoprotein Cholesterol Levels and Systolic Blood Pressure to the Outcome of Intracerebral Hemorrhage: Data from the China Stroke Center Alliance.

Limited data were available about the combined impact of systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) levels on intracerebral hemorrhage (ICH) prognosis. The objective of this study is to explore whether the relationship between LDL-C and ICH outcomes was modified by SBP levels in a Chinese population. From August 1, 2015, to July 31, 2019, 75,443 ICH patients enrolled from the Chinese Stroke Center Alliance program were included in our study. Patients were divided into LDL-C levels of <70 mg/dL, 70-100 mg/dL, and ≥100 mmol/L. SBP was stratified as <140 mmHg, 140-180 mmHg, and ≥180 mmHg. The primary outcome was the occurrence of hematoma expansion (HE), and the second outcome was in-hospital mortality. Correlation between LDL-C levels and SBP on ICH outcomes were assessed by logistic regression. 6,116 (8.1%) and 1,576 (2.1%) patients suffered HE and in-hospital mortality. Compared with the ≥100 mg/dL group, patients with LDL-C concentrations under 70 mg/dL had a 19% and 24% increase in the relative risk of HE (crude OR 1.19, 95% CI 1.11-1.28) and in-hospital mortality (crude OR 1.24, 95% CI 1.08-1.42). When SBP was added as a stratification variable, the above-mentioned association was attenuated in patients under a threshold SBP of 140 mmHg (P > 0.05). However, no statistical interaction was detected between SBP and LDL-C levels. Lower LDL-C levels (<70 mg/dL) are related to a higher risk of HE and in-hospital mortality confined to ICH patients with elevated SBP (≥140 mmHg).

Endovascular treatment with or without intravenous alteplase for acute ischaemic stroke due to basilar artery occlusion.

BACKGROUND AND PURPOSE: It remains controversial if endovascular treatment (EVT) can improve the outcome of patients with acute basilar artery occlusion (BAO). This study aims to compare the functional outcomes between EVT with and without intravenous thrombolysis (IVT) first in patients who had acute ischaemic stroke (AIS) due to BAO. METHODS: Patients who had AIS with BAO who underwent EVT within 24 hours of onset were enrolled in this multicentre cohort study, and the efficacy and safety were compared between IVT+EVT and direct EVT. The primary outcome was 90-day functional independence. All outcomes were assessed with adjusted OR (aOR) from the multivariable logistic regression. In addition, a meta-analysis was performed on all recently published pivotal studies on functional independence after EVT in patients with BAO. RESULTS: Of 310 enrolled patients with BAO, 241 (78%) were treated with direct EVT and 69 (22%) with IVT+EVT. Direct EVT was associated with a worse functional outcome (aOR, 0.46 (95% CI 0.24 to 0.85), p=0.01). IVT+EVT was associated with a lower percentage of patients who needed ≥3 passes of stent retriever (10.14% vs 20.75%). The meta-analysis regression revealed a potential positive correlation between bridging with IVT first and functional independence (r=0.14 (95% CI 0.05 to 0.24), p<0.01). CONCLUSIONS: This study showed that compared with direct EVT, EVT with IVT first was associated with better functional outcomes in patients with BAO treated within 24 hours of onset. The meta-analysis demonstrated similar favourable efficacy of IVT first followed by EVT in patients with BAO.

Matrix metallopeptidase 9 and placental growth factor may correlate with collateral status based on whole-brain perfusion combined with multiphase computed tomography angiography.

OBJECTIVE: The aim of this study was to find out the relationship between serum biomarkers and cerebral collateral status in acute ischemic stroke with cerebral large artery atherosclerosis. METHODS: We enrolled patients with ischemic stroke due to large artery atherosclerosis within 7 days of symptom onset, age 18-80 years, from August 2016 to December 2017. Twelve biomarkers representing different pathophysiological mechanisms were tested after admission. Whole-brain perfusion combined with multiphase computed tomography angiography was performed to assess cerebral collateral structure and function. RESULTS: Fifty-two patients completed the test of candidate biomarkers and recruited in this study. The mean age was 55.0 (11.1) years, 42 (80.8%) patients were male, 20 (38.5%) had poor collateral, 36 (69.2%) patients had anterior circulation stenosis or occlusion. Compared with poor collateral group, the level of MMP-9 (135,475.00 pg/ml vs. 103,612.00 pg/ml, p = 0.040) and PGF (5.75 pg/ml vs. 3.46 pg/ml, p = 0.046) was significantly higher in good collateral group. The adjusted OR (95%CI) of MMP-9 and PGF were 5.533 (1.10-27.74, p = 0.038), 7.73 (1.41-42.39, p = 0.018), respectively. sTie-2 level had a positive correlation with proportion of Tmax 4-6 (r = 0.302, p = 0.033) and HMW-KGN had negative correlation with proportion of Tmax 6-8 (r = -0.338, p = 0.02). After adjustment, the correlation of sTie-2 level and proportion of Tmax 4-6 was statistically significant (p = 0.003), and correlation of HMW-KGN and Tmax6-8 was not statistically significant (p = 0.056). DISCUSSION: Serum PGF and MMP-9 levels may correlate with collateral status based on MP-CTA in acute ischemic stroke patients with cerebral large artery atherosclerosis. Higher PGF and MMP-9 concentration associated with good collateral status.

Association Between CST3 Gene Polymorphisms and Large-Artery Atherosclerotic Stroke.

Objective: Cystatin C, a marker of atherosclerosis, is encoded by CST3. We aimed to evaluate whether two single-nucleotide polymorphisms (SNPs) of CST3 are correlated with large-artery atherosclerotic stroke (LAAS) and prognosis. Methods: This subgroup analysis of the Third China National Stroke Registry (CNSR-III) enrolled acute ischemic stroke (AIS) patients within 7 days from August 2015 to March 2018 in China. rs13038305 and rs911119 of CST3 were selected based on the strong association with cystatin C concentration. Results: Two loci of CST3 (rs13038305 and rs911119) were analyzed in 3,833 ischemic stroke patients. Carriers of T allele in rs13038305 and C allele in rs911119 tend to have lower serum cystatin C levels (p < 0.05). Compared with C/C as a reference in rs13038305, odds ratio (OR) of T/T was 0.486, 95% CI 0.237-0.994, p = 0.048. Per C allele of rs13038305 also showed an increased level of low-density lipoprotein cholesterol (LDL-C), ß (95% CI) was 1.335 (1.008-1.250), p = 0.044. No correlation was found between the selected SNPs and stroke prognosis (functional outcome, recurrence, and mortality). Conclusions: Carriers of the T allele in rs13038305 tend to have a lower proportion of LAAS. rs13038305 and rs911119 polymorphisms were likely to affect cystatin C concentration independently of kidney function.

Serum Cystatin C Predicts Stroke Clinical Outcomes at 1 Year Independent of Renal Function.

Objective: Serum cystatin C (CysC) is a sensitive marker of renal function to predict cardiovascular diseases. We aimed to investigate the predictive value of CysC for clinical outcomes independent of renal function in patients with acute ischemic stroke (AIS). Methods: We measured serum CysC levels in 10,256 AIS patients from Third China National Stroke Registry (CNSR-III). The primary outcome was a combination of all-cause mortality and major disability (modified Rankin scale score, 3-6). Secondary outcomes included stroke recurrence and combined vascular events at 1 year. Outcomes were analyzed using logistic regression and Cox proportional hazards models, respectively. Results: The median CysC of included patients was 0.95 mg/l (interquartile range, 0.83-1.10 mg/l). A U-shaped association was observed between CysC and primary outcome (all-cause mortality or major disability) [quartile (Q)1 vs. Q2: adjusted odds ratio (aOR) 1.29, 95% CI 1.06-1.58, p = 0.012; Q3 vs. Q2: aOR 1.12, 95% CI 0.93-1.35, p = 0.242; Q4 vs. Q2: aOR 1.35, 95% CI 1.10-1.65, p = 0.004]. A similar trend also existed in "preserved renal function" patients. Adding CysC to a model containing conventional risk factors improved the model performance with integrated discrimination improvement (IDI) of 0.13% (p = 0.016) and net reclassification index (NRI) of 13.10% (p <0.001) for primary outcome. No significant association was observed for stroke recurrence or combined vascular event rate in different CysC quartiles. Conclusions: CysC showed a U-shaped correlation with 1-year stroke clinical outcome, suggesting that serum CysC may not only be a simple candidate marker of renal function.

Adverse Outcomes Associated With Higher Mean Blood Pressure and Greater Blood Pressure Variability Immediately After Successful Embolectomy in Those With Acute Ischemic Stroke, and the Influence of Pretreatment Collateral Circulation Status.

Background To investigate whether collateral status could modify the associations between post-thrombectomy blood pressure (BP) measures and outcomes. Methods and Results Patients with anterior-circulation large-vessel-occlusion successfully recanalized in a multicenter endovascular thrombectomy registry were enrolled. Pretreatment collateral status was graded and dichotomized (good/poor) in angiography. Maximum, minimum, and mean systolic BP (SBP) and BP variability (assessed by the SD, coefficient of variation) during the initial 24 hours after endovascular thrombectomy were obtained. The primary outcome was unfavorable 90-day outcome (modified Rankin Scale score 3-6). Secondary outcomes included symptomatic intracranial hemorrhage and 90-day mortality. Adjusted odds ratios (aOR) of BP parameters over the outcomes were obtained in all patients and in patients with good/poor collaterals. Among 596 patients (mean age 66 years; 59.9% males), 302 (50.7%) patients had unfavorable 90-day outcome. In multivariable analyses, higher mean SBP (aOR, 1.59 per 10 mm Hg increment; 95% CI, 1.26-2.02; P<0.001), mean SBP >140 mm Hg (versus ≤120 mm Hg; aOR, 4.27; 95% CI, 1.66-10.97; P=0.002), and higher SBP SD (aOR, 1.08 per 1-SD increment; 95% CI, 1.01-1.16; P=0.02) were respectively associated with unfavorable 90-day outcome in patients with poor collateral but not in those with good collateral. A marginal interaction between SBP coefficient of variation tertiles and collaterals on 90-day functional outcome (P for interaction, 0.09) was observed. A significant interaction between SBP coefficient of variation tertiles and collaterals on 90-day mortality (P for interaction, 0.03) was observed. Conclusions Higher postprocedural BP is associated with 90-day unfavorable outcomes after successful endovascular thrombectomy in patients with poor collateral. Registration URL: https://www.chictr.org.cn; Unique identifier: ChiCTR1900022154.

DPP-4 inhibitors promote proliferation and migration of rat brain microvascular endothelial cells under hypoxic/high-glucose conditions, potentially through the SIRT1/HIF-1/VEGF pathway.

BACKGROUND: Vascular disease in diabetes, for example, stroke, presents a significant public health burden. Recently, the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin has been found to counteract stroke among diabetic patients, showing great promise in drug repurposing and indication expansion. However, the molecular basis of this protection mechanism remains unknown. METHODS: The expression and localization of DPP-4 in rat brain microvascular endothelial cells (rBMVECs) were assessed with immunofluorescent staining and Western blotting. The effects of DPP-4 inhibitors on cell proliferation and migration of rBMVECs were determined using MTT and transwell assays, separately. The influence of DPP-4 inhibition on the expression of molecular markers (eg, VEGF, eNOS, HIF-1α. SIRT1) was examined at both mRNA and protein levels with qRT-PCR and Western blotting, individually. RESULTS: DPP-4 inhibitors (40 nmol/L linagliptin, 30 µmol/L berberine) offer protection from hypoxia/high glucose induced impairments in the proliferation and migration of rBMVECs. Treatment with DPP-4 inhibitors counteracted the attenuating effects of hypoxic/high-glucose conditions on the expression of VEGF, eNOS, HIF-1α, and SIRT1, which can be completely eliminated by the inhibition of SIRT1 with 1 mmol/L nicotinamide. CONCLUSIONS: The protection of rBMVECs from hypoxia/high-glucose induced impairment by DPP-4 inhibitors may be mediated by the SIRT1/HIF-1α/VEGF pathway.

Using the synthesized peptide HAYED (5) to protect the brain against iron catalyzed radical attack in a naturally senescence Kunming mouse model.

Alzheimer's disease (AD) is a progressive neurodegenerative disease of the brain. It cannot be cured currently, and those suffering from AD place a great burden on their caregivers and society. AD is characterized by high levels of iron ions in the brain, which catalyze radicals that damage the neurons. Knowing that the Aß42 peptide precipitates iron by binding iron ions at amino acid residues D1, E3, H11, H13, and H14, we synthesized a 5-repeat (HAYED) sequence peptide. By treating iron-stressed SH-SY5Y cells with it and injecting it into the cerebrospinal fluid (CSF) of naturally senescence Kunming mouse, which displaying AD-similar symptoms such as learning and memory dysfunction, neuron degeneration and high level of iron in brain, we found that HAYED (5) decreased the iron and radical levels in the cell culture medium and in the CSF. Specially, the synthesized peptide prevented cell and brain damage. Furthermore, functional magnetic resonance imaging (fMRI), Morris water maze and passive avoidance tests demonstrated that the peptide ameliorated brain blood-oxygen metabolism and slowed cognitive loss in the experimental senescence mice, and clinical and blood tests showed that HAYED (5) was innoxious to the kidney, the liver and blood and offset the AD-associated inflammation and anemia.