Neurological Improvement by One-Thirds Is Associated With Early Recanalization in Stroke With Large Vessel Occlusion.

BACKGROUND: A proportion of large vessel occlusion strokes demonstrate early recanalization, obviating the initial intention to proceed to endovascular thrombectomy. Neurological improvement is a possible surrogate marker for reperfusion. We aimed to determine the optimal threshold of neurological improvement, as defined by the National Institutes of Health Stroke Scale (NIHSS), which best associates with early recanalization. METHODS: We retrospectively analyzed consecutive patients with large vessel occlusion transferred from primary stroke centers to a tertiary comprehensive stroke center in Melbourne, Australia, for possible endovascular thrombectomy from January 2018 to December 2022. Absolute and percentage changes in NIHSS between transfer, as well as other definitions of neurological improvement, were compared using receiver operating characteristic curve analysis for association with recanalization as defined by the absence of occlusion in the internal carotid artery, middle cerebral artery (M1 or M2 segments), or basilar artery on repeat vascular imaging. RESULTS: Six hundred and fifty-four transferred patients with large vessel occlusion were included in the analysis: mean age was 68.8±14.0 years, 301 (46.0%) were women, and 338 (52%) received intravenous thrombolytics. The proportion of extracranial internal carotid artery, intracranial internal carotid artery, M1, proximal M2, and basilar artery occlusion was 18.8%, 13.6%, 48.3%, 15.0%, and 4.3%, respectively, on initial computed tomography angiogram. Median NIHSSprimary stroke center and NIHSScomprehensive stroke center scores were 15 (interquartile range, 9-18) and 13 (interquartile range, 8-19), respectively. Early recanalization occurred in 82 (13%) patients. NIHSS reduction of ≥33% was the best tradeoff between sensitivity (64%) and specificity (83%) for identifying recanalization. NIHSS reduction of ≥33% had the highest discriminative ability to predict recanalization (area under the curve, 0.735) in comparison with other definitions of neurological improvement. CONCLUSIONS: One-third neurological improvement between the primary hospital and tertiary center was the best predictor of early recanalization.

Triglyceride-glucose index and triglyceride to high-density lipoprotein cholesterol ratio as potential cardiovascular disease risk factors: an analysis of UK biobank data.

BACKGROUND: The triglyceride-glucose (TyG) index and triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, two simple surrogate indicators of insulin resistance, have been demonstrated to predict cardiovascular disease (CVD). However, very few studies have investigated their associations with CVD in European populations. METHODS: A total of 403,335 participants from the UK Biobank with data for TyG index and TG/HDL-C ratio and free from CVD at baseline were included. Cox models were applied to evaluate the association between TyG index and TG/HDL-C ratio and incident CVD. Mediation analyses were performed to evaluate the contribution of prevalent diabetes, hypertension, and dyslipidemia to observed associations. RESULTS: During a median follow-up of 8.1 years, 19,754 (4.9%) individuals developed CVD, including 16,404 (4.1%) cases of CHD and 3976 (1.0%) cases of stroke. The multivariable-adjusted hazard ratios of total CVD in higher quartiles versus the lowest quartiles were 1.05, 1.05, and 1.19, respectively, for TyG index, and 1.07, 1.13, and 1.29, respectively, for TG/HDL-C ratio. There were significant trends toward an increasing risk of CVD across the quartiles of TyG index and TG/HDL-C ratio. In mediation analyses, dyslipidemia, type 2 diabetes, and hypertension explained 45.8%, 27.0%, and 15.0% of TyG index's association with CVD, respectively, and 40.0%, 11.8%, and 13.3% of TG/HDL-C ratio's association with CVD, respectively. CONCLUSIONS: Elevated baseline TyG index and TG/HDL-C ratio were associated with a higher risk of CVD after adjustment for the well-established CVD risk factors. These associations were largely mediated by greater prevalence of dyslipidemia, type 2 diabetes, and hypertension.

Prognostic significance of plasma SDF-1 in acute ischemic stroke patients with diabetes mellitus: the CATIS trial.

BACKGROUND AND OBJECTIVES: Evidence on the associations between baseline stromal cell-derived factor (SDF)-1 and clinical outcomes in acute ischemic stroke patients is lacking. The present study aimed to examine the relationship between plasma SDF-1 levels and clinical outcomes based on a large multicenter study of the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). METHODS: Secondary analysis was conducted among 3,255 participants from the CATIS trial with a baseline measurement of plasma SDF-1 levels. We evaluated the associations between plasma SDF-1 levels and one-year recurrent stroke, cardiovascular events, and all-cause mortality using Cox regression models. We further investigated the prognostic effect of SDF-1 on clinical outcomes in patients with different characteristics. RESULTS: Higher plasma SDF-1 levels were not associated with recurrent stroke, cardiovascular events, and all-cause mortality at one-year after ischemic stroke (all P trend ≥ 0.05). There were significant interactions between plasma SDF-1 levels and history of diabetes mellitus on recurrent stroke (P = 0.005), cardiovascular events (P = 0.007) and all-cause mortality (P = 0.04) at one year. In patients with diabetes mellitus, plasma SDF-1 was significantly associated with an increased risk of recurrent stroke and cardiovascular events after adjustment for confounders. For example, 1-SD higher log-SDF-1 was associated with a hazard ratio (95% confidence interval) of 1.65 (1.18-2.32) for recurrent stroke and 1.47 (1.08-1.99) for the cardiovascular events, but not all-cause mortality 1.36 (0.96-1.93) at one year. However, there were no associations between plasma SDF-1 and clinical outcomes in patients without diabetes mellitus (all P > 0.05). The addition of plasma SDF-1 to the conventional risk factors model significantly improved the risk prediction of all outcomes. Similarly, findings between elevated SDF-1 levels and two-year outcomes were found only in patients with diabetes mellitus. CONCLUSIONS: Elevated plasma SDF-1 was significantly associated with an increased risk of recurrent stroke and cardiovascular events only in ischemic patients with diabetes mellitus.

Plasma homeostatic chemokines CCL19 and CCL21 and the prognosis of ischemic stroke in two Chinese prospective cohorts.

BACKGROUND: The homeostatic chemokines CCL19 and CCL21 are involved in carotid plaque vulnerability and post-ischemic neuroinflammatory responses. This study aimed to examine the prognostic values of CCL19 and CCL21 in ischemic stroke. METHODS: Plasma CCL19 and CCL21 were measured in 4483 ischemic stroke patients from two independent cohorts of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) and IIPAIS (Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke), and participants were followed up at 3 months after stroke. The primary outcome was the composite outcome of death or major disability. The associations of CCL19 and CCL21 levels with the primary outcome were examined. RESULTS: In CATIS, multivariable-adjusted odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 compared with the lowest quartiles were 2.06 and 2.62, respectively. In IIPAIS, odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 were 2.81 and 2.78 compared with the lowest quartiles, respectively. In the pooled analysis of the two cohorts, odds ratios of the primary outcome associated with the highest quartiles of CCL19 and CCL21 were 2.24 and 2.66, respectively. Similar findings were observed in the analysis with major disability, death, and the composite outcome of death or cardiovascular events as the secondary study outcomes. Adding CCL19 and CCL21 to conventional risk factors significantly improved risk reclassification and discrimination for adverse outcomes. CONCLUSIONS: Both CCL19 and CCL21 levels were independently associated with adverse outcomes within 3 months after ischemic stroke and should be further investigated for risk stratification and potential therapeutic targets of ischemic stroke.

Lipoprotein(a) and functional outcome of acute ischemic stroke when discordant with low-density lipoprotein cholesterol.

BACKGROUND: Several studies have indicated that residual cardiovascular risk might be associated with elevated lipoprotein(a) [Lp(a)] even in the setting of controlled low-density lipoprotein cholesterol (LDL-C). We aimed to prospectively examine the association between Lp(a) and unfavorable functional outcome among patients with acute ischemic stroke when Lp(a) and LDL-C were discordant. METHODS: Based on samples from the Infectious Factors, Inflammatory Markers and Prognosis of Acute Ischemic Stroke study, 973 patients with baseline plasma Lp(a) levels were included. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale score of 3-6) at 6 months. Logistic regression models were used to estimate the risk for the primary outcome. Discordance analyses were performed, using difference in percentile units (>10 units), to detect the relative risk when Lp(a) and LDL-C were discordant. RESULTS: In total, 201 (20.7%) participants experienced major disability or death at 6 months. The multivariable-adjusted odds ratio (OR) for the highest quartile was 1.88 [95% confidence interval (CI): 1.16-3.04] compared with the lowest quartile. Each 1-SD higher log-Lp(a) was associated with a 23% increased risk (95% CI: 2%-47%) for the primary outcome. Compared with the concordant group, the high Lp(a)/low LDL-C discordant group was associated with increased risk for the primary outcome (adjusted OR: 1.59, 95% CI: 1.01-2.52). CONCLUSIONS: Elevated plasma Lp(a) levels were associated with increased risk of major disability and death at 6 months. Discordantly high Lp(a)/low LDL-C was associated with an unfavorable functional outcome, supporting the predictive potential of plasma Lp(a) after ischemic stroke, especially when discordant with LDL-C. Key messages What is already known on this topic Previous studies have indicated that a positive association between increased lipoprotein(a) [Lp(a)] and cardiovascular disease risk remained even in patients who achieved controlled low-density lipoprotein cholesterol (LDL-C) levels. The findings of studies exploring the association between Lp(a) and unfavorable clinical outcomes of stroke were inconsistent, and whether Lp(a) can predict the risk of unfavorable functional outcome in stroke patients when Lp(a) and LDL-C levels are discordant remains unknown. What this study adds Elevated plasma Lp(a) levels were associated with increased risk of major disability and death at 6 months beyond LDL-C levels in acute ischemic stroke patients. How this study might affect research, practice, or policy The combination of LDL-C-lowering therapies and Lp(a)-lowering therapies may have better clinical efficacy for patients with ischemic stroke, and it is of great clinical interest to further explore this possibility in dedicated randomized trials.

Circulating choline pathway nutrients and depression after ischemic stroke.

BACKGROUND AND PURPOSE: Choline pathway nutrients, including choline and betaine, are reported to exert antidepressant effects. However, there is little population-based evidence on the relationships between circulating choline and betaine and poststroke depression (PSD). We aimed to prospectively explore the associations between plasma choline and betaine and depression after ischemic stroke. METHODS: This study was based on the China Antihypertensive Trial in Acute Ischemic Stroke. A total of 612 participants with plasma choline and betaine concentrations were included in the analysis. The study outcome was depression 3 months after ischemic stroke. Logistic regression models were performed to estimate the relationships between plasma choline and betaine and the risk of PSD. Risk reclassification and calibration of models with choline or betaine were analyzed. RESULTS: Patients with PSD had lower choline and betaine levels than those without PSD (p < 0.05). Compared with tertile 1, the multivariable-adjusted odds ratios (95% CIs) for tertile 3 of choline and betaine were 0.54 (0.35-0.83) and 0.59 (0.38-0.92), respectively. Per 1 SD increase in choline or betaine was associated with a 25% (95% CI 9%-37%) or an 19% (95% CI 3%-32%) decreased risk of PSD, respectively. Furthermore, the addition of choline or betaine to the established risk factors model improved the risk reclassification for PSD, as shown by an increase in the net reclassification index and integrated discrimination improvement (all p < 0.05). CONCLUSIONS: Patients with elevated levels of choline and betaine had a lower risk of depression after acute ischemic stroke, suggesting the protective significance of choline pathway nutrients for PSD.

Multivitamin/mineral supplementation and the risk of cardiovascular disease: a large prospective study using UK Biobank data.

PURPOSE: Despite the widespread use of multivitamin/mineral supplements, the effects of multivitamin/mineral on cardiovascular disease (CVD) remain inconclusive. We aimed to prospectively investigate how multivitamin/mineral use is associated with CVD. METHODS: This population-based cohort study included 465,278 men and women who participated in the UK Biobank and were free from CVD at baseline. Participants were enrolled between 2006 and 2010 and followed-up until the end of 2018. Data on supplement use including multivitamin/mineral were collected using self-reported questionnaires. Cox proportional hazards models were used to estimate the hazard ratios of CVD events in relation to multivitamin/mineral use. RESULTS: During the follow-up, we identified 25,772 cases of CVD events, 4754 cases of CVD mortality, 18,728 cases of coronary heart disease, 6726 cases of myocardial infarction, and 4561 cases of stroke. The multivariable-adjusted hazard ratios associated with multivitamin/mineral use were 0.96 (95% CI: 0.93, 0.99) for CVD events, 0.92 (0.86, 1.00) for CVD mortality, 0.96 (0.93, 0.99) for coronary heart disease, and 0.92 (0.86, 0.97) for myocardial infarction. Subgroup analysis suggested that multivitamin/mineral use was associated with a significantly lower risk of CVD events in participants aged < 60 years and in former and current smokers (P for interaction ≤ 0.01). Sensitivity analyses showed no substantial change in the results when we excluded participants who developed CVD events during the first 2 years of follow-up. CONCLUSION: Multivitamin/mineral supplementation was associated with very modest reductions in CVD events. Age and smoking might modify these associations.

Plasma l-carnitine and risks of cardiovascular events and recurrent stroke after ischemic stroke: A nested case-control study.

BACKGROUND AND AIMS: l-Carnitine was suggested to prevent the progression of atherosclerosis, myocardial and neurologic injury, and exhibited cardioprotective effects. However, epidemiological data on circulating l-carnitine and risks of cardiovascular events in the setting of stroke is rare. We aimed to explore the relationships between plasma l-carnitine and cardiovascular events and stroke recurrence after ischemic stroke in a nested case-control study. METHODS AND RESULTS: A total of 323 cardiovascular events (including 264 recurrent strokes) and 323 matched controls (free of recurrent cardiovascular events) were included. Study outcomes included cardiovascular events and recurrent stroke after ischemic stroke. Plasma l-carnitine concentrations were measured by ultra-high-performance LC-MS/MS. Conditional logistic regression models were used to estimate odds ratios (ORs) of stroke outcomes. Plasma l-carnitine was inversely associated with cardiovascular events (OR = 0.69, 95% CI: 0.57-0.84 per SD) and recurrent stroke (OR = 0.72, 95% CI: 0.58-0.88 per SD) after adjusting for established risk confounders. Compared with the lowest tertile of l-carnitine, adjusted ORs of cardiovascular events and recurrent stroke for participants in the highest tertiles were 0.35 (95% CI: 0.21-0.57) and 0.36 (95% CI: 0.21-0.62), respectively. In addition, l-carnitine provided incremental predictive ability beyond established risk factors, shown by increase in C statistics, net reclassification improvement and integrated discrimination improvement. CONCLUSIONS: Higher l-carnitine levels were associated with lower risks of cardiovascular events and recurrent stroke after ischemic stroke. Our findings provided evidence supporting plasma l-carnitine as a potential prognostic marker in risk discrimination and stratification in patients with ischemic stroke. TRIAL REGISTRATION: Clinicaltrials.gov as NCT01840072. URL: https://www. CLINICALTRIALS: gov.

Choline Pathway Nutrients and Metabolites and Cognitive Impairment After Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Choline metabolism was suggested to play pathophysiological roles in nervous system and atherosclerosis development. However, little is known about the impacts of choline pathway nutrients and metabolites on poststroke cognitive impairment. We aimed to prospectively investigate the relationships between circulating choline, betaine, and trimethylamine N-oxide with cognitive impairment among acute ischemic stroke patients. METHODS: We derived data from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). Plasma choline, betaine, and trimethylamine N-oxide concentrations at baseline were measured in 617 participants. Cognitive impairment was evaluated using the Mini-Mental State Examination and the Montreal Cognitive Assessment. Reclassification and calibration of models with choline-related biomarkers were evaluated. RESULTS: Plasma choline and betaine were inversely associated with cognitive impairment. Compared with the lowest tertile, adjusted odds ratios of Mini-Mental State Examination-defined cognitive impairment for participants in the highest tertiles of choline and betaine were 0.59 (95% CI, 0.39-0.90) and 0.60 (95% CI, 0.39-0.92), respectively. In addition, both choline and betaine offered incremental predictive ability over the basic model with established risk factors, shown by increase in net reclassification improvement and integrated discrimination improvement. There were similar significant relationships between choline and betaine with cognitive impairment as defined by the Montreal Cognitive Assessment. However, plasma trimethylamine N-oxide was only associated with cognitive impairment evaluated using the Mini-Mental State Examination; the adjusted odds ratio was 1.33 (95% CI, 1.04-1.72) for each 1-SD increment of trimethylamine N-oxide. CONCLUSIONS: Patients with higher choline and betaine levels had lower risk of cognitive impairment after ischemic stroke, supporting promising prognostic roles of choline pathway nutrients for poststroke cognitive impairment.

Association between serum matrix metalloproteinase-9 and poor prognosis in acute ischemic stroke patients: The role of dyslipidemia.

BACKGROUND AND AIMS: Whether the prognostic value of matrix metalloproteinase-9 (MMP-9) is modified by patients' dyslipidemia status is unknown. The aim of present study was to evaluate the prognostic effect of MMP-9 among ischemic stroke patients stratified by dyslipidemia status. METHODS AND RESULTS: MMP-9 levels were measured for 2977 acute ischemic stroke patients from 26 participating hospitals across China, and data of clinical outcomes within one year after ischemic stroke was collected. The primary outcome was a composite outcome of major disability and death at one year after stroke onset, and secondary outcomes were major disability, death, vascular events and recurrent stroke. The association between MMP-9 and primary outcome was appreciably modified by dyslipidemia status (Pinteraction = 0.048). After multivariate adjustment, increased MMP-9 level was associated with increased risk of primary outcome at one year after ischemic stroke in the patients with dyslipidemia (odds ratio, 1.34; 95% confidence interval, 1.06-1.79), but not in those without dyslipidemia (odds ratio, 1.23; 95% confidence interval, 0.90-1.68). Increased MMP-9 was also significantly associated with major disability, death and vascular events in the patients with dyslipidemia but not in those without dyslipidemia (P for interaction < 0.05 for all). CONCLUSION: Increased MMP-9 was associated with poor prognosis within one-year after stroke only in patients with dyslipidemia, suggesting that the prognostic value of MMP-9 be modified by dyslipidemia status of ischemic stroke patients. Further prospective study from other populations and randomized clinical trials are needed to verify our findings and clarify the potential mechanisms.

Serum tissue inhibitor of metalloproteinase-1 and risk of cognitive impairment after acute ischaemic stroke.

The expression of tissue inhibitor metalloproteinase-1 (TIMP-1) significantly increased after acute cerebral ischaemia and involved in neurodegeneration. The purpose was to prospectively investigate the relationship between serum TIMP-1 with post-stroke cognitive impairment. Our participants were from an ancillary study of China Antihypertensive Trial in Acute Ischemic Stroke. 598 ischaemic stroke patients from seven participating hospitals were included. Cognitive impairment was evaluated using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) at 3 months. 316 (52.84%) or 384 (64.21%) participants had cognitive impairment according to MMSE or MoCA, respectively. Compared with the first quartile of TIMP-1, the multivariate-adjusted odds ratios (95% confidence intervals) for the highest quartile were 1.80 (1.09-2.97) for cognitive impairment defined by MMSE and 2.55 (1.49-4.35) by MoCA. Multiple-adjusted spline regression models showed linear associations between TIMP-1 concentrations and cognitive impairment (P value for linearity < 0.01). The addition of TIMP-1 to models including conventional factors improved reclassification for cognitive impairment, as shown by net reclassification index or integrated discrimination improvement (P < 0.05). Participants with both higher TIMP-1 and matrix metalloproteinase-9 levels simultaneously had highest risk of cognitive impairment. Higher serum TIMP-1 levels were associated with increased risk of cognitive impairment after acute ischaemic stroke, independently of established risk factors.

Serum Matrix Metalloproteinase-9 Is Associated With Depression After Acute Ischemic Stroke.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9), a key determinant of extracellular matrix degradation, might cause cerebral damage after stroke and be involved in the development of depressive symptoms. This study aimed to evaluate the association of serum MMP-9 levels and post-stroke depression (PSD).Methods and Results:Serum MMP-9 levels were determined in 558 acute ischemic stroke patients from 7 hospitals comprising the China Antihypertensive Trial in Acute Ischemic Stroke. We assessed depression status using the 24-item Hamilton Depression Rating Scale and defined PSD as a cutoff score of 8. Logistic regression was performed to estimate the risk of PSD associated with serum MMP-9. Discrimination and reclassification for PSD by MMP-9 were analyzed. A total of 222 (39.8%) stroke patients were categorized as PSD within 3 months. Serum MMP-9 concentrations were higher among PSD patients than those without PSD (658.8 vs. 485.7 ng/mL; P<0.001). The multiple-adjusted odds ratio (95% confidence interval) for the highest MMP-9 quartile compared with the lowest quartile was 4.36 (2.49-7.65) for PSD, and 1 standard deviation higher log-MMP-9 was associated with 68% (37-106%) increased odds of PSD. Adding MMP-9 to the conventional risk factors model substantially improved discrimination and reclassification for PSD (all P<0.05). CONCLUSIONS: Elevated serum MMP-9 levels in the acute phase of ischemic stroke were associated with increased risk of PSD, suggesting an important prognostic role of MMP-9 for PSD.

Cytotoxicity and genotoxicity of nanosilver in stable GADD45α promoter-driven luciferase reporter HepG2 and A549 cells.

OBJECTIVES: The intense commercial application of silver nanoparticles (AgNPs) has been raising concerns about their potential adverse health effects to human. This study aimed to explore the potency of AgNPs to induce GADD45α gene, an important stress sensor, and its relationships with the cytotoxicity and genotoxicity elicited by AgNPs. METHODS: Two established HepG2 and A549 cell lines containing the GADD45α promoter-driven luciferase reporter were treated with increasing concentrations of AgNPs for 48 hours. After the treatment, transcriptional activation of GADD45α indicated by luciferase activity, cell viability, cell cycle arrest, and levels of genotoxicity were determined. The uptake and intracellular localization of AgNPs, cellular Ag doses as well as Ag+ release were also detected. RESULTS: AgNPs could activate GADD45α gene at the transcriptional level as demonstrated by the dose-dependent increases in luciferase activity in both the reporter cells. The relative luciferase activity was greater than 12× the control level in HepG2-luciferase cells at the highest concentration tested where the cell viability decreased to 17.0% of the control. These results was generally in accordance with the positive responses in cytotoxicity, cell cycle arrest of Sub G1 and G2/M phase, Olive tail moment, micronuclei frequency, and the cellular Ag content. CONCLUSIONS: The cytotoxicity and genotoxicity of AgNPs seems to occur mainly via particles uptake and the subsequent liberation of ions inside the cells. And furthermore, the GADD45α promoter-driven luciferase reporter cells, especially the HepG2-luciferase cells, could provide a new and valuable tool for predicting nanomaterials genotoxicity in humans.

Development of HSPA1A promoter-driven luciferase reporter gene assays in human cells for assessing the oxidative damage induced by silver nanoparticles.

The exponential increase in the total number of engineered nanoparticles in consumer products requires novel tools for rapid and cost-effective toxicology screening. In order to assess the oxidative damage induced by nanoparticles, toxicity test systems based on a human HSPA1A promoter-driven luciferase reporter in HepG2, LO2, A549, and HBE cells were established. After treated with heat shock and a group of silver nanoparticles (AgNPs) with different primary particle sizes, the cell viability, oxidative damage, and luciferase activity were determined. The time-dependent Ag(+) ions release from AgNPs in cell medium was also evaluated. Our results showed that heat shock produced a strong time-dependent induction of relative luciferase activity in the four luciferase reporter cells. Surprisingly, at 4h of recovery, the relative luciferase activity was >98× the control level in HepG2-luciferase cells. Exposure to different sizes of AgNPs resulted in activation of the HSPA1A promoter in a dose-dependent manner, even at low cytotoxic or non-cytotoxic doses. The smaller (5nm) AgNPs were more potent in luciferase induction than the larger (50 and 75nm) AgNPs. These results were generally in accordance with the oxidative damage indicated by malondialdehyde concentration, reactive oxygen species induction and glutathione depletion, and Ag(+) ions release in cell medium. Compared with the other three luciferase reporter cells, the luciferase signal in HepG2-luciferase cells is obviously more sensitive and stable. We conclude that the luciferase reporter cells, especially the HepG2-luciferase cells, could provide a valuable tool for rapid screening of the oxidative damage induced by AgNPs.

Oxidative stress and mitochondrial injury-mediated cytotoxicity induced by silver nanoparticles in human A549 and HepG2 cells.

OBJECTIVES: Considering the increasing applications of silver nanoparticles (AgNPs) in food- and cosmetic-related products worldwide, the aim of this study was to investigate the potential adverse health effects induced by AgNPs exposure in terms of cytotoxicity, oxidative stress, and mitochondrial injury in human A549 and HepG2 cells. METHODS: After a 48 h AgNPs treatment, the cell viability was measured by MTT assay. Oxidative damage was determined by assays of malondialdehyde (MDA), 8-epi-PGF2α and 8-hydroxy-2'-deoxyguanosine (8-oxo-dG). The protein expression of HSPA1A and HO-1 was analyzed by western blot analysis. Mitochondrial membrane potential (MMP) was detected by using JC-1 as fluorescent probes. The uptake and intracellular localization of AgNPs was measured by transmission electron microscopy (TEM), and cellular AgNPs was determined by inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: A dose-dependent decrease in cell viability after AgNPs treatment was observed, which was associated correspondingly with oxidative damage as indicated by increases in MDA amount, 8-epi-PGF2α and 8-oxo-dG levels, HSPA1A and HO-1 expression, as well as mitochondrial injury as indicated by decreased MMP. The cellular uptake of AgNPs measured by ICP-MS analysis was correlated correspondingly with the oxidative damage and mitochondrial injury. CONCLUSIONS: The dose-dependent cytotoxicity induced by AgNPs may result from an interaction of oxidative stress, DNA damage and mitochondrial injury in A549 and HepG2 cells. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1691-1699, 2016.

Alcohol drinking modified the effect of plasma YKL-40 levels on stroke-specific mortality of acute ischemic stroke.

OBJECTIVES: Our study aimed to evaluate the association between plasma human cartilage glycoprotein-39 (YKL-40) and stroke-specific mortality at two years in acute ischemic stroke patients according to the drinking status and amount of alcohol consumption. We further investigated the effect of the interaction between these conditions and YKL-40 levels on the outcome. METHODS: We measured plasma YKL-40 levels in 3267 participants from the China Antihypertensive Trial in Acute Ischemic Stroke. Outcome data on stroke-specific mortality were collected at two years after stroke onset. RESULTS: During the two years of follow-up, 208 (6.4 %) patients, including 44 drinkers and 164 nondrinkers, died of stroke-specific causes. The patients in the highest quartile of YKL-40 had a 3.52-fold (95 % CI: 1.15-10.76, P for trend = 0.006) risk of stroke-specific mortality compared with those in the lowest quartile among drinkers. However, no significant association between YKL-40 and the outcome was observed among nondrinkers (HR: 1.18, 95 % CI: 0.75-1.86, P for trend = 0.08). Alcohol drinking modified the effect of YKL-40 on the outcome (P for interaction = 0.04). Subgroup analyses revealed that each 1-unit increase in log-transformed YKL-40 was associated with a 72 % greater risk of stroke-specific mortality for light drinkers. This association was amplified with a 226 % increased risk of the outcome among heavy drinkers. CONCLUSIONS: Elevated YKL-40 levels were associated with an increased risk of stroke-specific mortality at two years among drinkers with ischemic stroke. Drinking status substantially modified the effect of plasma YKL-40 levels on the outcome. This effect was amplified with the increased amount of alcohol consumption. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01840072.

One-Year Disability Trajectories and Long-Term Cardiovascular Events, Recurrent Stroke, and Mortality After Ischemic Stroke.

BACKGROUND: Patients with stroke are often affected by varying degrees of functional disability and have different evolution patterns in functional disability. However, little is known about the predictive usefulness of disability changes after stroke. We aimed to describe 1-year disability trajectories and to assess the associations of longitudinal disability trajectories with 24-month clinical outcomes after ischemic stroke. METHODS AND RESULTS: A total of 3533 patients with ischemic stroke from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) were studied. Distinct trajectories of disability were identified by the group-based trajectory model, as measured by modified Rankin Scale score within 12 months. Cox proportional hazards regression models were used to examine the associations of disability trajectories with 24-month cardiovascular events and all-cause mortality. We identified 4 distinct disability trajectories: no significant disability (562 participants [15.9%]), slight disability to recovery (1575 participants [44.6%]), severe to moderate disability (1087 participants [30.8%]), and persistent severe disability (309 participants [8.7%]). Compared with no significant disability trajectory, the multivariable adjusted hazard ratios (95% CIs) of patients within the persistent heavy-severe trajectory were 2.63 (1.20-5.76) for cardiovascular events, 2.55 (1.12-5.79) for recurrent stroke, and 6.10 (2.22-16.72) for all-cause mortality; notably, the hazard ratios (95% CIs) for patients within the severe to moderate disability trajectory were 1.99 (1.01-3.94) for cardiovascular events and 1.85 (1.03-3.33) for the composite outcome of cardiovascular events and all-cause mortality. CONCLUSIONS: Functional disability trajectories within 12 months after stroke onset were associated with the risk of 24-month adverse outcomes. Patients with persistent severe disability or severe to moderate disability had higher risk of cardiovascular events and all-cause mortality. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

Efficacy of Immediate Antihypertensive Treatment in Patients With Acute Ischemic Stroke With Different Blood Pressure Genetic Variants.

BACKGROUND: It remains unclear whether blood pressure (BP) genetic variants could modify the efficacy of immediate antihypertensive treatment after acute ischemic stroke. We conducted a secondary analysis of the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) to investigate the effect of early antihypertensive treatment on clinical outcomes among patients with acute ischemic stroke according to 5 BP-associated genetic variants. METHODS: The CATIS randomized 4071 patients with acute ischemic stroke with elevated systolic BP to receive antihypertensive treatment or discontinue all antihypertensive agents during hospitalization. Randomization was conducted centrally and was stratified by participating hospitals and use of antihypertensive medications. Five BP-associated single nucleotide polymorphisms (rs16849225, rs17030613, rs1173766, rs6825911, and rs35444 in FIGN-GRB14, ST7L-CAPZA1, NPR3, ENPEP, and near TBX3, respectively) were genotyped among 2590 patients. The primary outcome was a combination of death and major disability at 14 days or hospital discharge. A weighted BP genetic risk score was constructed by the 5 single nucleotide polymorphisms. RESULTS: At 14 days or hospital discharge, the primary outcome was not significantly different between antihypertensive treatment and control groups based on genotype subgroups for all 5 single nucleotide polymorphisms (all P>0.05 for interaction). In addition, the BP genetic risk score did not modify the effect of antihypertensive treatment. The odds ratios (95% CIs) for the primary outcome were 0.95 (0.71-1.26), 1.08 (0.80-1.44), and 0.91 (0.69-1.22) in patients with low, intermediate, and high BP genetic risk score, respectively (P=0.88 for interaction). CONCLUSIONS: Early antihypertensive treatment had a neutral effect on clinical outcomes among patients with acute ischemic stroke according to 5 BP-associated genetic variants. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

Effect of Immediate Antihypertensive Treatment on Clinical Outcomes in Acute Ischemic Stroke Patients With Different Renal Function Status.

BACKGROUND: It remains unclear whether different blood pressure management strategies should be administered for acute stroke patients with or without impaired renal function. We conducted a secondary analysis of the CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke) to investigate the effect of early antihypertensive treatment among patients with acute ischemic stroke according to the baseline renal function assessed by estimated glomerular filtration rates (eGFR). METHODS: The CATIS trial randomly assigned 4071 acute ischemic stroke patients with systolic blood pressure between 140 and 220 mm Hg to receive antihypertensive treatment or to discontinue all antihypertensive medications during hospitalization. A primary outcome (composite outcome of death and major disability) and secondary outcomes were compared between antihypertensive treatment and control groups by baseline renal function levels of eGFR values of <60, 60 to 89, and ≥90 mL/min per 1.73 m2. RESULTS: At day 14 or hospital discharge, the primary outcome was not significantly different between the antihypertensive treatment and control groups in each subgroup stratified by renal function status (P=0.98 for homogeneity), and the odds ratios (95% CIs) were 1.23 (0.76-2.02) in patients with eGFR <60 mL/min per 1.73 m2, 0.94 (0.75-1.19) in patients with eGFR values of 60-89 mL/min per 1.73 m2, and 1.04 (0.88-1.24) in patients with eGFR ≥90 mL/min per 1.73 m2, respectively. In addition, early antihypertensive treatment was not associated with secondary clinical outcomes by baseline renal function (P>0.05 for all homogeneity). CONCLUSIONS: Early antihypertensive treatment had a neutral effect on clinical outcomes in ischemic stroke patients with different renal function status. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique Identifier: NCT01840072.

The relationship between neurological function trajectory, assessed by repeated NIHSS measurement, and long-term cardiovascular events, recurrent stroke, and mortality after ischemic stroke.

BACKGROUND: Clinically significant changes in neurological deficits frequently occur after stroke onset, reflecting further neurological injury or neurological improvement. However, the National Institutes of Health Stroke Scale (NIHSS) score is only evaluated once in most studies, usually at stroke onset. Utilizing repeated measures of NIHSS scores to identify different trajectories of neurological function may be more informative and provide more useful predictive information. We determined the association of neurological function trajectories with long-term clinical outcomes after ischemic stroke. METHODS: A total of 4025 participants with ischemic stroke from the China Antihypertensive Trial in Acute Ischemic Stroke were included. Patients were recruited from 26 hospitals across China between August 2009 and May 2013. A group-based trajectory model was used to identify distinct neurological function trajectories, as measured by NIHSS at admission, 14 days or hospital discharge, and 3 months. Study outcomes were cardiovascular events, recurrent stroke, and all-cause mortality during 3-24 months after ischemic stroke onset. Cox proportional hazards models were used to examine the associations of neurological function trajectories with outcomes. RESULTS: We identified three distinct subgroups of NIHSS trajectories: persistent severe (persistent high NIHSS scores during the 3-month follow-up), moderate (NIHSS scores started at around 5 and gradually reduced), and mild (NIHSS scores always below 2). The three trajectory groups had different clinical profiles and different risk of stroke outcomes at 24-month follow-up. Compared to the mild trajectory group, patients in the persistent severe trajectory group had a higher risk of cardiovascular events (multivariable-adjusted hazard ratios (95% confidence intervals) = 1.77 (1.10-2.86)), recurrent stroke (1.82 (1.10-3.00)), and all-cause mortality (5.64 (3.37-9.43)). Those with moderate trajectory had an intermediate risk: 1.45 (1.03-2.04) for cardiovascular events and 1.52 (1.06-2.19) for recurrent stroke. CONCLUSION: Longitudinal neurological function trajectories derived from repeated NIHSS measurements during the first 3 months after stroke provide additional predictive information and are associated with long-term clinical outcomes. The trajectories characterized by persistent severe and moderate neurological impairment were associated with increased risk of subsequent cardiovascular events.