Journal of Investigative Medicine最新文献

Background: Melatonin protects against ischaemic stroke in diabetic animal models, though the mechanisms involving brain and peripheral immune responses remain underexplored. We aimed to clarify how melatonin interacts with these immune responses to protect against stroke in diabetic mice.

Methods: Type 1 diabetes mellitus (T1DM) was induced in mice using streptozotocin. RNA sequencing of brain tissue and peripheral blood mononuclear cells (PBMCs) was performed 24 hours poststroke. Inflammatory responses were evaluated 72 hours after ischaemia/reperfusion.

Results: Melatonin reduced infarction and improved neurological function in T1DM mice. In the ischaemic brain, melatonin downregulated inflammatory factor expression, with bioinformatics identifying 62 differentially expressed genes (DEGs) related to inflammation and 11 associated with inflammasomes. Western blotting confirmed reductions in NLRP3, HMGB1 and Cleaved Caspase-1 expression. Flow cytometry showed reduced infiltration of CD8+T cells and neutrophils. Melatonin decreased IL-6, IL-1β and IL-4 levels. In PBMCs, RNA sequencing revealed 939 DEGs following melatonin treatment. Kyoto Encyclopaedia of Genes and Genomes analysis indicated that downregulated DEGs were involved in metabolic pathways, and upregulated DEGs were enriched in the Jak-STAT signalling pathway. GO analysis showed that downregulated DEGs were enriched in the cytosol, and upregulated DEGs related to macromolecule modification. Protein-protein interaction analysis revealed that melatonin affected 38 inflammation-associated genes linked to key cytokines (Il6, Il1b, Ifng, Il4). Flow cytometry indicated melatonin increased CD8+T cells, monocytes and neutrophils in the blood, suggesting a reversal of immunosuppression. Multiplex cytokine assays showed melatonin decreased IL-6 and IFN-γ levels.

Conclusion: Poststroke melatonin therapy reduces ischaemic brain damage in T1DM mice by modulating central and peripheral inflammatory responses.

Background: We aimed to investigate the relationships between metabolic syndrome (MetS) and its severity score (Metsss) with asymptomatic intracranial arterial stenosis (aICAS) while also assessing the additional effect of high-sensitivity C reactive protein (hsCRP).

Methods: This cross-sectional study included 2390 individuals who underwent health examinations at our centre from June 2019 to August 2023. Participants received physical examinations, laboratory tests and magnetic resonance angiography evaluations. MetS was defined by the modified acknowledged criteria and quantified by Metsss. Logistic regression, interaction analysis and mediation analysis were employed.

Results: Among the 2390 participants, 135 (5.65%) had aICAS, and 726 (30.40%) had MetS. After adjusting for confounders, MetS was significantly associated with aICAS (OR: 1.68, 95% CI: 1.16 to 2.43, p=0.006). The prevalence of aICAS increased significantly from 3.6% to 8.6% as the number of MetS components increased. Higher quartiles of Metsss also significantly increased aICAS risk (P for trend <0.001). After multivariable adjustment, MetS (p=0.001) and elevated Metsss (p<0.001) were only associated with posterior circulation aICAS (vs anterior). Furthermore, participants with both MetS and elevated hsCRP levels had a greater risk for aICAS (OR: 2.32, 95% CI: 1.36 to 3.96, p=0.002). hsCRP mediated the association between MetS and alCAS in participants ≤65 years old.

Conclusions: MetS and Metsss were independently associated with the risk of aICAS. The mediating effect of hsCRP on the relationship between MetS and aICAS appears to be age-dependent. These findings offer valuable insights into clinical decision making of aICAS and further improve the primary stroke prevention.

Vascular dementia (VaD) is the second leading cause of dementia after Alzheimer's disease (AD). In comparison to AD, there is a decline in the incidence of VaD due to recent improvements in cardiovascular risk factors. Brain hypoperfusion and hypoxia due to vascular pathologies have been postulated as the primary disease mechanism of VaD. However, other factors such as neuroinflammation may also contribute to the development of VaD. Non-modifiable and modifiable risk factors have been attributed to VaD. The clinical features overlapping between AD and VaD create significant challenges for physicians. Newly developed biomarkers may potentially help differentiate VaD from other forms of dementia. Unlike AD, there is no Food and Drug Administration-approved drug or device for treating VaD. Current treatment options mainly target symptoms rather than slowing the development or progression of VaD. There are ongoing research studies testing the efficacy of various therapeutic strategies for VaD. In this narrative review, we will summarise current findings on epidemiology, attributed risk factors and disease mechanisms, as well as emphasise the importance of optimising lifestyle modifications and comorbid condition management in preventing or slowing down the development of VaD. Finally, current therapies and ongoing research studies of novel therapeutic interventions such as stem-cell therapy and neuromodulation are highlighted.

Objective: Limited evidence is available regarding the risk-benefit ratio of thrombolytic therapy in patients with stroke and renal impairment complications, particularly for the drug tenecteplase. Therefore, we examined the association of impaired renal function with the safety and efficacy of intravenous thrombolytic treatment (IVT) in patients with acute ischaemic stroke (AIS).

Methods: A post hoc analysis of a randomised controlled trial (ClinicalTrials gov. NCT04797013) was conducted. Participants who received IVT with tenecteplase and alteplase (0.25 and 0.9 mg/kg, respectively) within 4.5 hours of symptoms onset were categorised based on their estimated glomerular filtration rate as follows: (1) ≥90 mL/min/1.73 m²,normal renal function; (2) 60-89 mL/min/1.73 m², mildly decreased renal function; and (3) <60 mL/min/1.73 m², moderately to severely decreased renal function. Patients stratified based on the normal renal function were used as the references. The primary efficacy and safety outcome were the percentage of patients achieving a modified Rankin Scale score of 0-1 at 90 days and the symptomatic intracranial haemorrhage (sICH) occurrence within 36 hours, respectively.

Results: In intravenous tenecteplase-treated patients, mildly decreased renal function (OR 3.10; 95% CI: 1.41 to 6.78) and moderately to severely decreased renal function (OR: 8.03; 95% CI: 2.76 to 23.38) showed an association with a higher risk of all-cause mortality but not with sICH incidence compared with normal renal function. Among patients administered intravenous alteplase, those with a moderate-to-severe decrease in renal function exhibited an elevated risk of sICH (adjusted OR: 10.01; 95% CI: 1.61 to 62.15) and all-cause mortality (adjusted OR: 4.54; 95% CI: 1.48 to 13.91). Comparative treatment effects between tenecteplase and alteplase according to renal function grades showed no heterogeneity.

Conclusions: A significant correlation was noted between kidney dysfunction and unfavourable outcomes in individuals with AIS who received treatment with either tenecteplase or alteplase.

Background: Stroke remains a major global health challenge, with China experiencing a significant burden due to its high incidence and severe outcomes. Reperfusion therapies, such as intravenous thrombolysis and endovascular thrombectomy, have shown substantial benefits in improving early outcomes for ischaemic stroke. Recent clinical trials have validated the safety and efficacy of a broader range of thrombolytic agents and expanded the eligible patient populations for both intravenous thrombolysis and mechanical thrombectomy. This guideline aims to provide the latest evidence-based insights in the field of reperfusion therapy.

Methods: The Chinese Stroke Association (CSA) established a writing group to develop updated guidelines on reperfusion therapy for acute ischaemic stroke. A comprehensive search of MEDLINE (via PubMed) was conducted up to 30 September 2024. Experts in the field of stroke engaged in extensive discussions, both online and offline, to evaluate the latest evidence. Each recommendation was graded using the CSA's class of recommendation and level of evidence in the Guideline Development Manual of the CSA.

Results: This guideline, reviewed and approved by the CSA Guidelines Writing Group, outlines the criteria for patient selection for thrombolysis and thrombectomy and summarises the latest evidence on various thrombolytic drug options to support decision-making in reperfusion therapy. Additionally, the guideline includes green channel flow charts for intravenous thrombolysis and mechanical thrombectomy, designed to assist clinicians in optimising their clinical decisions.

Conclusion: This guideline updates the latest advancements in the field of reperfusion therapy for acute ischaemic stroke. It is anticipated that future clinical research will further advance areas such as innovative thrombolytic agents, expanded indications for thrombolysis and mechanical thrombectomy.

Objective: Sacral dural arteriovenous fistula (SDAVF) is a rare spinal vascular malformation and often misdiagnosed or even mistreated. This study delved into the clinical characteristics, vascular architecture and treatment results of SDAVF, with the goal of enhancing upcoming diagnostic and therapeutic methodologies.

Methods: From March 2014 to March 2022, consecutive patients with SDAVF were retrospectively analysed. The data on demographics, symptom resolution, angioarchitectural features and postoperative course were studied. Spinal cord function was evaluated by modified Aminoff-Logue scale.

Results: A total of 36 patients with 36 SDAVFs were enrolled, 12 of whom were misdiagnosed on their initial visit. The SDAVFs were located at S1 in 24 (66.7%), S2 in 10 (27.8%) and S3 in 2 (5.6%) cases, respectively. The primary feeding arteries included lateral sacral artery (LSA) of internal iliac artery (31/36, 86.1%), the branches of external iliac artery (2/36, 5.6%) and median artery (3/36, 8.3%), most of which are straight. Venae terminalisis is the sole drainage vein, flowing back into perimedullary venous network. Endovascular embolisation is the main therapy method for 30 cases, while the other 6 cases were treated with microsurgical fistulectomy. MRI tests showed that the abnormal vascular signals around the medulla disappeared, and the spinal cord oedema was alleviated in the majority of cases (32/36, 88.9%). Six patients, who all were treated by endovascular embolisation at first time, had residual or recurrent and two of them were performed by microsurgical fistulectomy again. All patients by microsurgical fistulectomy had no residual or recurrent during follow-up. According to the spinal cord functional assessment, the Aminoff-Logue score was significantly decreased (Z=-3.449, p=0.001) postoperatively.

Conclusion: The misdiagnosis rate of SDAVF is very high. The most feeding artery of SDAVF came from the LSA, which was thicker and more straight, making it easier for microcatheters to reach the fistula site. So, endovascular embolism has become the first choice of treatment with minimal invasion, and safe and effective results.

Background and purpose: Symptomatic internal carotid artery stenosis (sCAS) is an essential cause of transient ischaemic attack (TIA) or minor stroke. We aimed to evaluate whether the superiority of aspirin-ticagrelor over aspirin-clopidogrel varies between patients with sCAS or not.

Methods: This was a post-hoc analysis of the High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II (CHANCE-2) trial, all of which were CYP2C19 loss-of-function alleles carriers. The primary exposures of interest were the treatment group and sCAS status. The primary efficacy endpoint was the new stroke assessed within 90 days.

Results: A total of 5920 (92.3%) from 6412 were analysed, including 197 (3.3%) with sCAS and 5723 (96.7%) without sCAS. Stroke recurrence occurred in 13 (12.15%) and 11 (12.22%) patients with sCAS who received aspirin-ticagrelor and aspirin-clopidogrel, respectively (adjusted HR, 1.04; 95% CI, 0.46 to 2.36; p=0.930). Among patients without sCAS, there were 158 cases (5.52%) of new strokes in the aspirin-ticagrelor group and 222 cases (7.76%) in the aspirin-clopidogrel group (HR, 0.70; 95% CI, 0.57 to 0.86; p=0.0006). The treatment-by-sCAS subtype was not significant (p=0.405).

Conclusions: Genotype-guided dual antiplatelet treatment with aspirin-ticagrelor may be beneficial for preventing recurrent strokes in patients without sCAS; however, it appears less effective in those with sCAS. No significant interaction was found between the treatment and sCAS subtypes.

Trial registration number: NCT04078737.

Background: Research data regarding the correlation between elevated oxidised low-density lipoprotein (oxLDL) cholesterol concentrations and unfavourable clinical outcomes in individuals experiencing minor acute ischaemic cerebrovascular events or transient ischaemic attack (TIA) with presumed atherosclerotic aetiology are still limited.

Methods: This investigation incorporated a cohort of 5814 participants derived from the Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis clinical trial. The core laboratory conducted blinded measurements of baseline plasma oxLDL concentrations. Multivariable Cox regression analyses were employed to assess the correlations between oxLDL levels and adverse clinical events. The principal endpoint for efficacy assessment was defined as the occurrence of stroke within a 90-day follow-up period. Additional secondary endpoints encompassed composite vascular events during the same observation window. The main safety endpoint assessed was the occurrence of bleeding events of moderate to severe intensity.

Results: The final analytical cohort comprised 5814 patients included in the final analysis. The mean age was 63.7±9.6 years, and 36.0% were female. The average concentration of circulating oxLDL was 36.62 µg/dL. Elevated oxLDL concentrations demonstrated a potential correlation with heightened stroke risk (T3 vs T1: HR 1.39, 95% CI 1.04 to 1.85), ischaemic stroke (T3 vs T1: HR 1.31, 95% CI 0.98 to 1.76) and composite vascular events (T3 vs T1: HR 1.36, 95% CI 1.02 to 1.81) within 90 days. An increased concentration of oxLDL demonstrated a significant association with elevated susceptibility to moderate and severe haemorrhagic events (T3 vs T1: HR 3.61, 95% CI 1.26 to 10.34) within 90 days.

Conclusion: Increased concentrations of oxLDL demonstrated an independent correlation with both stroke recurrence and the occurrence of moderate-to-severe haemorrhagic events in individuals presenting with acute minor ischaemic stroke or TIA at elevated risk, accompanied by intracranial or extracranial atherosclerotic lesions.

Background: The increased permeability of the blood-brain barrier (BBB) is a critical contributor to the high mortality following ischaemic stroke. However, the mechanisms regulating BBB integrity remain poorly understood. Leucine-rich repeat-containing 8A (LRRC8A) is a chloride channel critical for cellular volume homeostasis and plays a key role in regulating neuronal injury during ischaemia. However, its impact on BBB function is currently unclear.

Methods: A transient middle cerebral artery occlusion model was established to investigate the impact of LRRC8A on BBB integrity. Laser speckle contrast imaging was used to monitor cortical blood flow. Primary mouse and human brain microvascular endothelial cells (m/hBMVECs) were subjected to oxygen-glucose deprivation (OGD) and re-oxygenation for varying durations. Patch-clamp recordings were performed to measure volume-regulated chloride currents. Immunostaining was conducted to evaluate protein expression. Cell permeability was evaluated with transwell assay.

Results: LRRC8A deletion in endothelial cells ameliorates the infarct area and mitigates BBB leakage. Ischaemia dramatically upregulates the expression of LRRC8A in endothelial cells, concurrently downregulating tight junction proteins. OGD exposure augments the VRCC current mediated by LRRC8A in BMVECs. In contrast, inhibiting LRRC8A promotes the expression of ZO-1 and VE-cadherin, thereby preserving the integrity of endothelial cells. With-no-lysine kinase 1 (WNK1) inhibition contributes to LRRC8A-induced BBB damage post-ischaemic stroke. Eupatorin, a newly identified LRRC8A inhibitor, exerts neuroprotective effects against ischaemic stroke.

Conclusions: LRRC8A in BMVECs plays a pivotal role in modulating BBB integrity, a process regulated by WNK1. As an LRRC8A inhibitor, Eupatorin holds the potential for ischaemic stroke therapy.

Background: Cognitive decline is a significant concern for stroke survivors, affecting their quality of life and increasing their burden on the healthcare system. DL-3-n-butylphthalide (butylphthalide) has shown efficacy in the short-term treatment of various cognitive impairments. This study evaluated the efficacy of butylphthalide in preventing cognitive decline over a 12-month period in patients with ischaemic stroke.

Methods: This prospective following-up study involved patients newly diagnosed with ischaemic stroke between 1 month and 6 months after stroke onset and not in the acute phase. Patients were assigned to either the butylphthalide or control group. Cognitive function was assessed using the mini-mental state examination (MMSE) at baseline and at the 12-month follow-up. Statistical analyses included t-tests, χ² tests and multivariate regression analyses.

Results: Butylphthalide was negatively associated with the MMSE D-value (β=-0.122; 95% CI -1.932 to -0.298; p=0.003) and the MMSE D-value percentage (β=-0.117; 95% CI -0.057 to -0.011; p=0.004). A multivariate analysis indicated that butylphthalide treatment was negatively associated with both changes in orientation and language score. Additionally, the incidence of cognitive decline was significantly lower in the butylphthalide group (OR, 0.612; p=0.020) than the control group. An age of ≥60 years and lower educational level were identified as risk factors for lower cognitive score and cognitive decline.

Conclusion: This study demonstrated that butylphthalide is effective in preventing cognitive decline in patients with ischaemic stroke. These findings have significant implications for clinical practice, suggesting that butylphthalide could be incorporated into standard post-stroke care regimens to improve patient outcomes and reduce the healthcare burden. Additional multicentre double-blind trials are recommended to confirm these results in diverse populations.