Predictors of futile recanalization after endovascular treatment of acute ischemic stroke.

OBJECTIVE: Endovascular therapy (EVT) is the most successful treatment for patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) in the anterior circulation. However, futile recanalization (FR) seriously affects the prognosis of these patients. The aim of this study was to investigate predictors of FR after EVT in patients with AIS. METHOD: Patients diagnosed with AIS due to anterior circulation LVO and receiving EVT between June 2020 and October 2022 were prospectively enrolled. FR after EVT was defined as a poor 90-day prognosis (modified Rankin Scale [mRS] score ≥ 3) despite achieving successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] classification of 2b-3). All included patients were categorized into control group (mRS score < 3) and FR group (mRS score ≥ 3). Demographic characteristics, comorbidities (hypertension, diabetes, atrial fibrillation, smoking, etc.), stroke-specific data (NIHSS score, ASPECT score and site of occlusion), procedure data (treatment type [direct thrombectomy vs. bridging thrombectomy], degree of vascular recanalization [mTICI], procedure duration time and onset-recanalization time), laboratory indicators (lymphocytes count, neutrophils count, monocytes count, C-reactive protein, neutrophil-to-lymphocyte ratio [NLR], monocyte-to-high-density lipoprotein ratio [MHR], lymphocyte-to-monocyte ratio [LMR], lymphocyte-to-C-reactive protein ratio [LCR], lymphocyte-to-high-density lipoprotein ratio[LHR], total cholesterol and triglycerides.) were compared between the two groups. Multivariate logistic regression analysis was performed to explore independent predictors of FR after EVT. RESULTS: A total of 196 patients were included in this study, among which 57 patients were included in the control group and 139 patients were included in the FR group. Age, proportion of patients with hypertension and diabetes mellitus, median NIHSS score, CRP level, procedure duration time, neutrophil count and NLR were higher in the FR group than in the control group. Lymphocyte count, LMR, and LCR were lower in the FR group than in the control group. There were no significant differences in platelet count, monocytes count, total cholesterol, triglycerides, HDL, LDL, gender, smoking, atrial fibrillation, percentage of occluded sites, onset-recanalization time, ASPECT score and type of treatment between the two groups. Multivariate logistic regression analysis demonstrated that NLR was independently associated with FR after EVT (OR = 1.37, 95%CI = 1.005-1.86, P = 0.046). CONCLUSION: This study demonstrated that high NLR was associated with a risk of FR in patients with AIS due to anterior circulation LVO. These findings may help clinicians determine which patients with AIS are at higher risk of FR after EVT. Our study can provide a theoretical basis for interventions in the aforementioned population.

Intensive Ambulance-Delivered Blood-Pressure Reduction in Hyperacute Stroke.

BACKGROUND: Treatment of acute stroke, before a distinction can be made between ischemic and hemorrhagic types, is challenging. Whether very early blood-pressure control in the ambulance improves outcomes among patients with undifferentiated acute stroke is uncertain. METHODS: We randomly assigned patients with suspected acute stroke that caused a motor deficit and with elevated systolic blood pressure (≥150 mm Hg), who were assessed in the ambulance within 2 hours after the onset of symptoms, to receive immediate treatment to lower the systolic blood pressure (target range, 130 to 140 mm Hg) (intervention group) or usual blood-pressure management (usual-care group). The primary efficacy outcome was functional status as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days after randomization. The primary safety outcome was any serious adverse event. RESULTS: A total of 2404 patients (mean age, 70 years) in China underwent randomization and provided consent for the trial: 1205 in the intervention group and 1199 in the usual-care group. The median time between symptom onset and randomization was 61 minutes (interquartile range, 41 to 93), and the mean blood pressure at randomization was 178/98 mm Hg. Stroke was subsequently confirmed by imaging in 2240 patients, of whom 1041 (46.5%) had a hemorrhagic stroke. At the time of patients' arrival at the hospital, the mean systolic blood pressure in the intervention group was 159 mm Hg, as compared with 170 mm Hg in the usual-care group. Overall, there was no difference in functional outcome between the two groups (common odds ratio, 1.00; 95% confidence interval [CI], 0.87 to 1.15), and the incidence of serious adverse events was similar in the two groups. Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common odds ratio, 0.75; 95% CI, 0.60 to 0.92) but an increase among patients with cerebral ischemia (common odds ratio, 1.30; 95% CI, 1.06 to 1.60). CONCLUSIONS: In this trial, prehospital blood-pressure reduction did not improve functional outcomes in a cohort of patients with undifferentiated acute stroke, of whom 46.5% subsequently received a diagnosis of hemorrhagic stroke. (Funded by the National Health and Medical Research Council of Australia and others; INTERACT4 ClinicalTrials.gov number, NCT03790800; Chinese Trial Registry number, ChiCTR1900020534.).

Predictive role of neutrophil-to-platelet ratio in futile recanalization of patients after endovascular therapy.

Aim: To explore the association between the neutrophil-to-platelet ratio (NPR) and futile recanalization (FR) in patients with acute ischemic stroke due to large vascular occlusions after endovascular therapy (EVT). Methods: FR after EVT was defined as a poor 90-day prognosis (modified Rankin scale [mRS] score ≥3) despite successful reperfusion (modified thrombolysis in cerebral infarction grade 2b-3). Patients were divided into high NPR (>35; n = 115) and low NPR (≤35; n = 81) groups. Results: The FR rate was significantly higher in the high NPR group than low NPR group (81.74 vs 55.56%; p = 0.000). NPR was independently associated with FR (odds ratio: 2.107; 95% CI: 1.017-4.364; p = 0.045). Conclusion: High NPR was associated with the risk of FR in patients with acute ischemic stroke due to large vascular occlusions.

Predictive Role of Pre-Thrombolytic Neutrophil-Platelet Ratio on Hemorrhagic Transformation After Intravenous Thrombolysis in Acute Ischemic Stroke.

To investigate the predictive role of the neutrophil-platelet ratio (NPR) before intravenous thrombolysis (IVT) on hemorrhagic transformation (HT) in patients with acute ischemic stroke (AIS). AIS patients treated with IVT without endovascular therapy between June 2019 and February 2023 were included. Patients were divided into high NPR (>35) and low NPR (≤35) groups according to the optimal threshold NPR value for identifying high-risk patients before IVT. The baseline data and the incidence of HT and symptomatic intracranial hemorrhage (sICH) were compared between the two groups. The predictive role of the NPR and other related factors on HT after IVT was analyzed by multivariate logistic regression. A total of 247 patients were included, with an average age of 67.5 ± 12.4 years. Post-thrombolytic HT was observed in 18.6% of the patients, and post-thrombolytic sICH was observed in 1.2% of the patients. There were 69 patients in the high NPR group and 178 patients in the low NPR group. The incidence of HT in the high NPR group was significantly higher than that in the low NPR group (30.4% vs 16.3%, P < .05). The incidence of sICH was significantly higher in the high NPR group than in the low NPR group (14.5% vs 1.7%, P < .001). Multivariate logistic regression analysis showed that NPR > 35 was positively correlated with HT (odds ratio (OR) = 3.236, 95% confidence interval (CI): 1.481-7.068, P = .003) and sICH (OR = 13.644, 95% CI: 2.392-77.833, P = .003). A high NPR (>35) before IVT may be a predictor of HT in AIS patients. This finding may help clinicians make clinical decisions before IVT in AIS patients.

Cerebral blood volume index can predict the long-term prognosis after endovascular thrombectomy in patients with acute ischemic stroke due to large vessel occlusion.

Long-term prognosis and factors influencing endovascular therapy (EVT) remain unclear. This study aimed to investigate the association between computed tomography perfusion (CTP) parameters and long-term prognosis of patients with acute ischemic stroke (AIS) treated with EVT. Patients with AIS due to large vessel occlusion treated with EVT were prospectively included for a 1-year follow-up. All patients and their data were grouped based on the hypoperfusion intensity ratio (HIR, ＜0.3 vs. ≥ 0.3) and cerebral blood volume (CBV) index (＞0.7 vs. ≤ 0.7). The primary outcome was favorable prognosis, defined as a modified Rankin Scale (mRS) score of 0-2. Multivariate logistic regression was used to analyze factors influencing long-term favorable prognosis. Of 69 patients included, 35 (50.7 %) achieved mRS 0-2 at one year. A favorable prognosis was observed predominantly in patients with higher CBV index (75.0 % vs. 34.1 %, p= 0.001) and lower HIR (72.0 % vs. 38.6 %, p=0.008). In the multivariate logistic regression, CBV index (odds ratio (OR) = 4.362; 95 % confidence interval (CI): 1.052, 18.082; p = 0.042), baseline National Institutes of Health Stroke Scale (NIHSS) score (OR = 0.913; 95 % CI: 0.836, 0.997; p = 0.044), and symptomatic intracranial hemorrhage (sICH) (OR = 0.089; 95 % CI: 0.009, 0.925; p = 0.043) were independently associated with a long-term favorable prognosis. The CBV index may serve as a predictor of the long-term prognosis of patients treated with EVT. The novel finding is that the baseline NIHSS score and sICH were associated with long-term prognosis.

Direct Thrombectomy versus Bridging Thrombectomy within 6 Hours of Stroke Onset: A Prospective Cohort Study on Cognitive and Physical Function Outcomes.

PURPOSE: To evaluate the physical and cognitive functions of patients with stroke who underwent either direct or bridging thrombectomy within 6 hours of stroke onset. MATERIALS AND METHODS: Patients with large vessel occlusion in anterior circulation treated with direct (direct group) or bridging thrombectomy (bridging group) were prospectively analyzed between June 2020 and February 2022. The efficacy outcome was the 3-month modified Rankin Scale (mRS) score, the safety outcome was symptomatic intracranial hemorrhage (sICH), and cognitive function was assessed using the Clinical Dementia Rating (CDR) scale at 6 months after stroke. RESULTS: A total of 125 patients (direct group, n = 75; bridging group, n = 50) who had completed follow-up at 3 months by telephone call were included. No significant differences were observed between the direct and bridging groups in terms of an mRS score of 0-2 (25.3% vs 22.0%, respectively; P = .83), an mRS score of 0-3 (37.3% vs 44.0%, respectively; P = .58), sICH (17.3% vs 14.0%, respectively; P = .80), or 3-month all-cause mortality (36.3% vs 30.0%, respectively; P = .34). Sixty-nine patients (direct group, n = 38; bridging group, n = 31) completed the CDR assessment at 6 months after stroke. There was no significant difference in poststroke dementia, defined as a CDR score of ≥1 point between the direct group (42.1%) and bridging group (22.6%) (P = .12). Ordinal regression analyses showed that the CDR score at 6 months was not associated with treatment type (direct thrombectomy vs bridging thrombectomy). CONCLUSIONS: With regard to physical and cognitive functions at 3 and 6 months, direct thrombectomy was comparable with bridging thrombectomy in patients who were treated within 6 hours of stroke onset.

Predictive role of pre-thrombolytic hs-CRP on the safety and efficacy of intravenous thrombolysis in acute ischemic stroke.

PURPOSE: To investigate the predictive role of pre-thrombolytic high sensitivity C-reactive protein (hs-CRP) on the safety and efficacy of intravenous thrombolysis in patients with acute ischemic stroke (AIS). METHODS: Patients with AIS who underwent intravenous thrombolysis with recombinant plasminogen activator (rtPA) or urokinase without endovascular therapy from June 2019 to June 2022 were retrospectively analysed. All patients were grouped into two groups (high or low hs-CRP group) according to the median value of hs-CRP before intravenous thrombolysis. The baseline NIHSS, NIHSS changes before and after thrombolysis (ΔNIHSS), the rate of good thrombolysis response (NIHSS decreased ≥ 2 points from baseline), the rate of any intracranial hemorrhage, age, sex, hypertension, diabetes, uric acid and platelet count were compared between the two groups. Logistic regression analysis was performed to identify possible prognostic factors for a good thrombolysis response. RESULTS: A total of 212 patients were included in the analysis, with a mean age of 66.3 ± 12.5 years. In total, 145 patients received rtPA, and 67 patients received urokinase. Patients were divided into a high hs-CRP group (> 1.60 mg/L) and a low hs-CRP group (≤ 1.60 mg/L) according to the median hs-CRP level (1.60 mg/L). The ΔNIHSS of the high hs-CRP group was significantly smaller than that of the low hs-CRP group (0 [-1 ~ 0] vs. -1 [-2 ~ 0], P < 0.05). The good rate of thrombolysis response in the high hs-CRP group was significantly lower than that in the low hs-CRP group (21.9% vs. 36.5%, P < 0.05). Similar results were shown in the rtPA subgroup between the high and low hs-CRP groups but not in the urokinase subgroup. Logistic regression analysis showed that hs-CRP > 1.60 mg/L was negatively correlated with a good thrombolysis response rate (OR = 0.496, 95% CI = 0.266-0.927, P = 0.028). CONCLUSION: hs-CRP > 1.6 mg/L may serve as a poor prognosis predictive factor for patients with AIS receiving intravenous thrombolysis. However, due to the small sample size of this study, further studies are needed to verify our results.

Associations of Serum Antimicrobial Peptide LL-37 with Longitudinal Cognitive Decline and Neurodegeneration Among Older Adults with Memory Complaints.

BACKGROUND: A potential role of the antimicrobial peptide LL-37, which is upregulated after infection, in the pathogenesis of Alzheimer's disease (AD) was identified. However, the clinical relevance of LL-37 in AD is not clear yet. OBJECTIVE: This study aims to investigate the association of circulating LL-37 with longitudinal cognitive decline and neurodegeneration among older adults with memory complaints. METHODS: This cohort study recruited 357 older adults with memory complaints. Participants were followed-up for two years and the cognitive functions were assessed using the Mini-Mental State Examination (MMSE). Serum LL-37, pTau181, and tTau levels were determined at baseline. Associations of baseline LL-37 with longitudinal cognitive decline and change of neurodegenerative biomarkers were analyzed. RESULTS: No difference was found in the slope of longitudinal cognitive decline during follow-up between the low and high LL-37 group, adjusting for age, sex, education, body mass index, APOE ɛ4 carrier status, comorbidities, and baseline MMSE scores (difference in slope: 0.226, 95% CI: -0.169 to 0.621). Higher LL-37 levels were associated with longitudinal cognitive decline, as indicated by a decrease of MMSE scores of 3 points or above during follow-up (OR = 2.11, 95% CI: 1.32 to 3.38). The high LL-37 group had larger slopes of the increase in neurofilament light (difference in slope: 3.759, 95% CI: 2.367 to 5.152) and pTau181 (difference in slope: 0.325, 95% CI: 0.151 to 0.499) than the low LL-37 group. CONCLUSION: These findings support an association of the antimicrobial peptide LL-37 with AD from a clinical perspective.

Novel compound heterozygous mutations of LAMA2-limb-girdle muscular dystrophy: A case report and literature review.

The laminin α2 (LAMA2) gene pathogenic variants can lead to limb-girdle muscular dystrophy (known as LGMDR23), which is rarely reported and characterized by proximal weakness in the limbs. We present the case of a 52-year-old woman who gradually developed weakness in both lower extremities since the age of 32 years. Magnetic resonance imaging (MRI) brain showed symmetrical sphenoid wings-like white matter demyelination in bilateral lateral ventricles. Electromyography showed quadriceps muscle damage on the bilateral lower extremity. Next-generation sequencing (NGS) found two loci variations in the LAMA2 gene, i.e., c.2749 + 2dup and c.8689C>T. This case highlights the importance of considering LGMDR23 in patients presenting with weakness and white matter demyelination on MRI brain and further expands the gene variants spectrum of LGMDR23.

Anti-CASPR2 encephalitis in a liver posttransplant patient receiving immune-suppression and lenvatinib: a case report and literature review.

It has been assumed that patients with strict immunosuppressive treatment after solid organ transplantation have only marginal risk in developing autoimmune encephalitis. We reported a woman in her late 40 s who presented with generalized convulsions and loss of consciousness. After detailed history review, neuropsychological tests, metagenomic next-generation sequencing of serum and cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) brain, and electroencephalogram, she was diagnosed as anti-CASPR2 encephalitis based on the positive anti-CASPR2 auto-antibody in serum and CSF. The patient underwent liver transplantation and has taken lenvatinib for 2 months, in addition to tacrolimus, mycophenotale mofetil, and entecavir administered for half a year. This case was the first report of anti-CASPR2 encephalitis in post-organ transplantation patients. Together with the reports of other encephalitis cases in organ transplantation, it warns the possibility of developing immune-oriented encephalitis in patients undergoing immunosuppression, especially in combination with other treatments of immunomodulatory activity.

Cerebral blood volume index may be a predictor of independent outcome of thrombectomy in stroke patients with low ASPECTS.

INTRODUCTION: To evaluate the predictors for efficacy and safety of patients with acute ischemic stroke (AIS) and Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) ＜6 undergoing endovascular therapy (EVT). METHODS: This study retrospectively analyzed consecutive patients presented between December 2020 and December 2021 with large vessel occlusions (LVO) within the anterior circulation and an ASPECTS ＜6, followed by EVT. The efficacy outcome was 90-day functional independence, defined as modified Rankin Scale (mRS) score 0-3. The primary safety outcome was symptomatic intracranial hemorrhage (sICH). Secondary safety outcomes included 90-day all-cause mortality and 24-hour any ICH. RESULTS: A total of 22 patients were included. The percentage of patients with mRS 0-3 at 90 days was 36.4% (8/22). The occurrence of sICH was 22.7% (5/22). The occurrence of any ICH was 45.5% (10/22). The 90-day all-cause mortality was 36.4% (8/22). Median (interquartile range, IQR) cerebral blood volume (CBV) index was 0.5 (0.4-0.7). CBV index in mRS 0-3 group (n = 8) was higher than mRS 4-5 group (n = 14) (P＜0.05). There was no significant difference of age, gender, comorbidities, baseline National Institutes of Health Stroke Scale (NIHSS) score, mismatch ratio, CBV index, interval between stroke onset and re-perfusion, good re-perfusion rate between sICH group (n = 5) and non-sICH group (n = 17). CONCLUSIONS: AIS patients with low ASPECTS can still benefit from EVT and gain good functional outcome, especial those had higher CBV index on pre-EVT computed tomography perfusion (CTP). Further studies with larger sample size are needed to validate our findings.

Different Doses of Intravenous Tissue-Type Plasminogen Activator for Acute Ischemic Stroke: A Network Meta-Analysis.

Background: This study aims to assess the efficacy and safety of different doses of intravenous tissue-type plasminogen activator (tPA) for acute ischemic stroke (AIS) by adopting a network meta-analysis (NMA). Methods: Studies comparing different doses of tPA in AIS were identified by retrieving electronic databases. NMAs of outcome measures included favorable functional outcome with a modified Rankin scale score (mRS) of 0 or 1 at 3 months after treatment (3M-FF), the functional independence with a mRS of 0, 1, or 2 at 3 months (3M-FI), symptomatic intracranial hemorrhage (sICH) and 3-month all-cause mortality (3M-M). Symptomatic intracranial hemorrhage (sICH) and 3-month all-cause mortality (3M-M) were assessed. Probability-based ranking and surface under cumulative ranking (SUCRA) were performed to identify the best dose of tPA. Inconsistency was evaluated by node-splitting analysis and a loop-specific approach. Publication bias was analyzed by funnel plots. Results: A total of 14 studies were included in the quantitative synthesis. The NMA results revealed no difference among low (<0.7 mg/kg), moderate (0.8 mg/kg), and standard (0.9 mg/kg) doses of tPA with regard to efficacy and safety. The SUCRAs of 3M-FF and 3M-FI showed that the standard dose ranked first, the moderate dose ranked second, and the low dose ranked third. The SUCRA of sICH showed that the standard dose ranked first (78.1%), the low dose ranked second (61.0%), and the moderate dose ranked third (11.0%). The SUCRAs of 3-month mortality showed that the standard dose ranked first (73.2%), the moderate dose ranked second (40.8%), and the low dose ranked third (36.1%). No significant inconsistency was shown by node-splitting analysis and no publication bias was shown in funnel plots. Conclusion: Lower dose tPA was comparable to the standard dose with regard to efficacy and safety. Based on the SUCRA results and American Heart Association/American Stroke Association (AHA/ASA) guidelines, the standard dose was still the optimal selection for AIS.

Mitochondrial-Derived Vesicles Protect Cardiomyocytes Against Hypoxic Damage.

Myocardial ischemia is a condition with insufficient oxygen supporting the heart tissues, which may result from myocardial infarction or trauma-induced hemorrhagic shock. In order to develop better preventive and therapeutic strategies for myocardial ischemic damage, it is important that we understand the mechanisms underlying this type of injury. Mitochondrial-derived vesicles (MDVs) have been proposed as a novel player in maintaining mitochondrial quality control. This study aimed to investigate the role and possible mechanisms of MDVs in ischemia/hypoxia-induced myocardial apoptosis. H9C2 cardiomyocytes were used for the cellular experiments. A 40% fixed blood volume hemorrhagic shock rat model was used to construct the acute general ischemic models. MDVs were detected using immunofluorescence staining with PDH and TOM20. Exogenous MDVs were reconstituted in vitro from isolated mitochondria under different hypoxic conditions. The results demonstrate that MDV production was negatively correlated with cardiomyocyte apoptosis under hypoxic conditions; exogenous MDVs inhibited hypoxia-induced cardiomyocyte apoptosis; and MDV-mediated protection against hypoxia-induced cardiomyocyte apoptosis was accomplished via Bcl-2 interactions in the mitochondrial pathway. This study provides evidence that MDVs protect cardiomyocytes against hypoxic damage by inhibiting mitochondrial apoptosis. Our study used a novel approach that expands our understanding of MDVs and highlights that MDVs may be part of the endogenous response to hypoxia designed to mitigate damage. Strategies that stimulate cardiomyocytes to produce cargo-specific MDVs, including Bcl-2 containing MDVs, could theoretically be helpful in treating ischemic/hypoxic myocardial injury.

Resuscitation Fluids in Septic Shock: A Network Meta-Analysis of Randomized Controlled Trials.

The aim of this study was to assess the efficacy and safety of various resuscitation fluids in septic shock by adopting a network meta-analysis (NMA). Randomized controlled trials (RCTs) comparing resuscitation fluids in septic shock were carried out by retrieving electronic databases. NMAs of 28-day mortality, 90-day mortality, incidence of acute kidney injury (AKI), and the need for renal replacement therapy (RRT) were conducted using the STATA 15.0 software. Probability-based ranking and surface under cumulative ranking (SUCRA) were performed to identify the optimal resuscitation fluid. Inconsistencies were evaluated by node-splitting analysis and a loop-specific approach. Furthermore, publication bias was analyzed by funnel plots. A total of 13 RCTs were enrolled in the analysis. The NMA results revealed that no significant differences were detected in the outcomes of 28-day mortality and 90-day mortality among various resuscitation fluids. The SUCRAs (the first indicates the best) of 28-day mortality showed that the hypertonic sodium chloride/hydroxyethyl starch 40 solution ranked the highest (93.8%), followed by the balanced solution (BS) (69.6%), and albumin (61.9%). On the other hand, the SUCRAs of 90-day mortality revealed that gelatin (GEL) ranked the highest (75.1%), followed by BS (55.1%), and NS (52.4%). The NMA results of AKI demonstrated that high-molecular-weight hydroxyethyl starch (H-HES) was associated with increased risk of AKI in comparison with GEL, BS, and L-HES. The SUCRAs of AKI showed that GEL ranked the highest (74.4%), followed by NS (64.9%), and BS (58.3%). In addition, the NMA results of RRT revealed that H-HES was associated with an increased need for RRT in comparison with BS and NS, and L-HES was associated with increased need of RRT in comparison with BS. The SUCRAs of RRT revealed that NS ranked the highest (91.6%), followed by BS (74.4%) and L-HES (36.1%). No significant inconsistencies were shown by the node-splitting analysis and no publication bias was demonstrated in the funnel plots. In conclusion, BS was determined as the preferred resuscitation fluid for septic shock. Moreover, the use of GEL requires further evaluation. H-HES was associated with a significant risk of AKI and RRT, whereas L-HES with an increased need for RRT compared with BS. Thus, both resuscitation fluids should be avoided for septic shock.

Role of Tumor Necrosis Factor-α in vascular hyporeactivity following endotoxic shock and its mechanism.

BACKGROUND: Vascular hyporeactivity plays an important role in organ dysfunction induced by endotoxic shock. Given that cytokine, such as TNF-α, plays an important role in endotoxic shock, the aim of the present study is to investigate the role of Tumor Necrosis Factor (TNF)-α in vascular hyporeactivity following endotoxic shock and the mechanisms. METHODS: Lipopolysaccharide (LPS) (1 mg/kg) injection was used for replicating the endotoxic shock model in the rabbit. The changes in the level of TNF-α in plasma in the rabbits model and the contractile response of superior mesenteric arteries (SMA) to norepinephrine (NE) and Ca were observed. The mechanisms in TNF-α-induced vascular hyporeactivity were further explored. RESULTS: The levels of TNF-α in plasma were gradually increased after 1 hour of LPS administration and reached the peak at 6 hours. The contractile responses of SMA to NE were decreased at 1 hour of LPS and lowest at 6 hour. TNF-α (200 ng/mL) incubation decreased contractile response of SMA to NE significantly. Further studies found that calcium desensitization participated in the occurrence of TNF-α-induced vascular hyporeactivity, the changes were consistent with the changes of vascular reactivity, calcium sensitivities were decreased significantly at 1 hour, 2 hours, 4 hours, and 6 hours after LPS injection. TNF-α (200 ng/mL) incubation could significantly reduce the contractile response of SMA to Ca. The activity of Rho-kinase and the changes of myosin light chain 20 (MLC20) phosphorylation level were significantly decreased at 6 hours following LPS administration, and TNF-α (200 ng/mL) incubation led to a decrease of Rho-kinase and MLC20 phosphorylation. Arginine vasopressin significantly antagonized TNF-α (200 ng/mL)-induced the decrease of the vascular reactivity and calcium sensitivity. CONCLUSION: TNF-α is involved in vascular hyporeactivity after endotoxic shock. Calcium desensitization plays an important role in TNF-α-induced vascular hyporeactivity after endotoxic shock. Rho-kinase/MLC20 phosphorylation pathway takes part in the regulation of calcium desensitization and vascular hyporeactivity induced by TNF-α. Arginine vasopressin is beneficial to endotoxic shock in TNF-α-induced vascular hyporeactivity.

The critical role of ABCG1 and PPARγ/LXRα signaling in TLR4 mediates inflammatory responses and lipid accumulation in vascular smooth muscle cells.

Toll-like receptor 4 (TLR4) plays critical roles in vascular inflammation, lipid accumulation and atherosclerosis development. However, the mechanisms underlying these processes are still not well established, especially in vascular smooth muscle cells (VSMCs). ATP-binding cassette transporter G1 (ABCG1) is one of the key genes mediating inflammation and cellular lipid accumulation. The function of TLR4 in regulating the expression of ABCG1 and the underlying molecular mechanisms remain to be elucidated. In this study, we cultured VSMCs from the thoracic aortas of mice and treated the cells with 50 µg/ml oxidized low-density lipoprotein (oxLDL) to activate TLR4 signaling. We observed that activating TLR4 with oxLDL induced inflammatory responses and lipid accumulation in VSMCs. The expression of peroxisome proliferator-activated receptor gamma (PPARγ), liver X receptor alpha (LXRα) and ABCG1 was inhibited by TLR4 activation. However, these effects could be reversed by knocking out TLR4. PPARγ activation by rosiglitazone rescued LXRα and ABCG1 expression and reduced TLR4-induced inflammation and lipid accumulation. Silencing PPARγ expression with a specific small interfering RNA (siRNA) inhibited LXRα and ABCG1 expression and, importantly, enhanced TLR4-induced inflammation and lipid accumulation. In conclusion, ABCG1 expression was down-regulated by TLR4, which induces inflammation and lipid accumulation in VSMCs via PPARγ/LXRα signaling. These findings indicate a novel molecular mechanism underlying TLR4-induced inflammation and lipid accumulation.

PPARγ Inhibits VSMC Proliferation and Migration via Attenuating Oxidative Stress through Upregulating UCP2.

Increasing evidence showed that abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are common event in the pathophysiology of many vascular diseases, including atherosclerosis and restenosis after angioplasty. Among the underlying mechanisms, oxidative stress is one of the principal contributors to the proliferation and migration of VSMCs. Oxidative stress occurs as a result of persistent production of reactive oxygen species (ROS). Recently, the protective effects of peroxisome proliferator-activated receptor γ (PPARγ) against oxidative stress/ROS in other cell types provide new insights to inhibit the suggests that PPARγ may regulate VSMCs function. However, it remains unclear whether activation of PPARγ can attenuate oxidative stress and further inhibit VSMC proliferation and migration. In this study, we therefore investigated the effect of PPARγ on inhibiting VSMC oxidative stress and the capability of proliferation and migration, and the potential role of mitochondrial uncoupling protein 2 (UCP2) in oxidative stress. It was found that platelet derived growth factor-BB (PDGF-BB) induced VSMC proliferation and migration as well as ROS production; PPARγ inhibited PDGF-BB-induced VSMC proliferation, migration and oxidative stress; PPARγ activation upregulated UCP2 expression in VSMCs; PPARγ inhibited PDGF-BB-induced ROS in VSMCs by upregulating UCP2 expression; PPARγ ameliorated injury-induced oxidative stress and intimal hyperplasia (IH) in UCP2-dependent manner. In conclusion, our study provides evidence that activation of PPARγ can attenuate ROS and VSMC proliferation and migration by upregulating UCP2 expression, and thus inhibit IH following carotid injury. These findings suggest PPARγ may represent a prospective target for the prevention and treatment of IH-associated vascular diseases.

Association between serum uric acid levels and cerebral white matter lesions in Chinese individuals.

PURPOSE/AIM OF THE STUDY: We aimed to evaluate the association between serum uric acid (SUA) levels and cerebral white matter lesions (WMLs) in Chinese individuals. MATERIAL AND METHODS: We prospectively identified patients aged 50 years and older in neurology department from July 2014 to March 2015. Both periventricular WMLs (P-WMLs) and deep WMLs (D-WMLs) were identified on magnetic resonance imanging (MRI) scans and the severity was graded using the Fazekas method. Multivariate logistic regression analyses were performed to examine the association between SUA and WMLs. RESULTS: A total of 480 eligible participants were enrolled in this study. SUA level in severe group was much higher than that in mild group (for P-WMLs: 320.21 ± 79.97 vs. 286.29 ± 70.18, p = 0.000; for D-WMLs: 314.71 ± 74.74 vs. 290.07 ± 74.04, p = 0.031). Subgroup analyses showed that higher SUA level was associated with higher severity of P-WMLs in women, but not in male patients. Multivariate logistic regression analyses showed that SUA was still associated with increased risk of higher severity of P-WMLs (OR = 1.003, 95% = 1.000-1.006), but not D-WMLs. CONCLUSION: Elevated SUA level was independently associated with greater odds of higher severity of P-WMLs, particularly in women.

Cinnamaldehyde prevents endothelial dysfunction induced by high glucose by activating Nrf2.

BACKGROUND/AIMS: It is well documented that hyperglycemia-induced oxidative stress is an important causative factor of endothelial dysfunction. Cinnamaldehyde (CA) is a key flavor compound in cinnamon essential oil that can enhance the antioxidant defense against reactive oxygen species (ROS) by activating NF-E2-related factor 2 (Nrf2), which has been shown to have a cardiovascular protective effect, but its role in endothelial dysfunction induced by high glucose is unknown. METHODS: Dissected male C57BL/6J mouse aortic rings and HUVECs were cultured in normal glucose(NG 5.5 mM) or high glucose(HG 30.0 mM) DMEM treatment with or without CA (10 µM). RESULTS: Treatment with CA protected the endothelium relaxation, inhibited ROS generation and preserved nitric oxide (NO) levels in the endothelium of mouse aortas treated with high glucose . CA up-regulated Nrf2 expression, promoted its translocation to the nucleus'and increased HO-1, NQO1, Catalase and Gpx1 expression under high glucose condition. The increased level of nitrotyrosine in HUVECs under high glucose was also attenuated by treatment with CA. Dihydroethidium (DHE) and DAF-2DA staining indicated that CA inhibited the ROS generation and preserved the NO levels in HUVECs, but these effects were reversed by Nrf2-siRNA in high glucose conditions. CONCLUSION: Our results indicated that CA protected endothelial dysfunction under high glucose conditions and this effect was mediated by Nrf2 activation and the up-regulation of downstream target proteins. CA administration may represent a promising intervention in diabetic patients who are at risk for vascular complications.