Correlation between lipoprotein(a) and recurrent ischemic events post-cerebral vascular stent implantation.

BACKGROUND AND AIM: The association of Lipoprotein(a) (Lp[a]) with recurrent ischemic events in stented patients remains uncertain. So, this research aimed to investigate the impact of elevated Lp(a) levels on the occurrence of ischemic events in this specific patient population. METHODS: Totally 553 patients who underwent intracranial or extracranial artery stent implantation were included. Baseline data were collected and postoperative ischemic outcomes were followed up. Cox regression analysis was used to investigate the association between Lp(a) and outcomes, while accounting for confounding factors. Finally, we established prediction models based on nomogram. RESULTS: Of total 553 patients, a number of 107 (19.3%) experienced outcomes. These included 46 cases (34.7%) in group with elevated Lp(a) levels (>30 mg/dL) and 61 cases (18.4%) in non-elevated group (χ2=6.343, p=0.012). The group with elevated Lp(a) was 1.811 times more likely to experience ischemic events than the non-elevated group, each 1 mg/dL increase in Lp(a) resulted in a 1.008-fold increase in the recurrence rate of ischemic events. In addition, sex (male), previous history of coronary heart disease, decreased albumin, elevated very low density lipoprotein cholesterol and poorly controlled risk factors (including blood pressure and blood sugar) were also associated with a high risk of recurrent ischemic events after stent implantation. CONCLUSION: Lp(a) elevation was a significant risk factor for ischemic events in symptomatic patients who underwent intracranial or extracranial artery stenting.

Identification of a ferroptosis-related gene pair biomarker with immune infiltration landscapes in ischemic stroke: a bioinformatics-based comprehensive study.

BACKGROUND: Ischemic stroke (IS) is a principal contributor to long-term disability in adults. A new cell death mediated by iron is ferroptosis, characterized by lethal aggregation of lipid peroxidation. However, a paucity of ferroptosis-related biomarkers early identify IS until now. This study investigated potential ferroptosis-related gene pair biomarkers in IS and explored their roles in immune infiltration. RESULTS: In total, we identified 6 differentially expressed ferroptosis-related genes (DEFRGs) in the metadata cohort. Of these genes, 4 DEFRGs were incorporated into the competitive endogenous RNA (ceRNA) network, including 78 lncRNA-miRNA and 16 miRNA-mRNA interactions. Based on relative expression values of DEFRGs, we constructed gene pairs. An integrated scheme consisting of machine learning algorithms, ceRNA network, and gene pair was proposed to screen the key DEFRG biomarkers. The receiver operating characteristic (ROC) curve witnessed that the diagnostic performance of DEFRG pair CDKN1A/JUN was superior to that of single gene. Moreover, the CIBERSORT algorithm exhibited immune infiltration landscapes: plasma cells, resting NK cells, and resting mast cells infiltrated less in IS samples than controls. Spearman correlation analysis confirmed a significant correlation between plasma cells and CDKN1A/JUN (CDKN1A: r = - 0.503, P < 0.001, JUN: r = - 0.330, P = 0.025). CONCLUSIONS: Our findings suggested that CDKN1A/JUN could be a robust and promising gene-pair diagnostic biomarker for IS, regulating ferroptosis during IS progression via C9orf106/C9orf139-miR-22-3p-CDKN1A and GAS5-miR-139-5p/miR-429-JUN axes. Meanwhile, plasma cells might exert a vital interplay in IS immune microenvironment, providing an innovative insight for IS therapeutic target.

The prediction of asymptomatic carotid atherosclerosis with electronic health records: a comparative study of six machine learning models.

BACKGROUND: Screening carotid B-mode ultrasonography is a frequently used method to detect subjects with carotid atherosclerosis (CAS). Due to the asymptomatic progression of most CAS patients, early identification is challenging for clinicians, and it may trigger ischemic stroke. Recently, machine learning has shown a strong ability to classify data and a potential for prediction in the medical field. The combined use of machine learning and the electronic health records of patients could provide clinicians with a more convenient and precise method to identify asymptomatic CAS. METHODS: Retrospective cohort study using routine clinical data of medical check-up subjects from April 19, 2010 to November 15, 2019. Six machine learning models (logistic regression [LR], random forest [RF], decision tree [DT], eXtreme Gradient Boosting [XGB], Gaussian Naïve Bayes [GNB], and K-Nearest Neighbour [KNN]) were used to predict asymptomatic CAS and compared their predictability in terms of the area under the receiver operating characteristic curve (AUCROC), accuracy (ACC), and F1 score (F1). RESULTS: Of the 18,441 subjects, 6553 were diagnosed with asymptomatic CAS. Compared to DT (AUCROC 0.628, ACC 65.4%, and F1 52.5%), the other five models improved prediction: KNN + 7.6% (0.704, 68.8%, and 50.9%, respectively), GNB + 12.5% (0.753, 67.0%, and 46.8%, respectively), XGB + 16.0% (0.788, 73.4%, and 55.7%, respectively), RF + 16.6% (0.794, 74.5%, and 56.8%, respectively) and LR + 18.1% (0.809, 74.7%, and 59.9%, respectively). The highest achieving model, LR predicted 1045/1966 cases (sensitivity 53.2%) and 3088/3566 non-cases (specificity 86.6%). A tenfold cross-validation scheme further verified the predictive ability of the LR. CONCLUSIONS: Among machine learning models, LR showed optimal performance in predicting asymptomatic CAS. Our findings set the stage for an early automatic alarming system, allowing a more precise allocation of CAS prevention measures to individuals probably to benefit most.

Clinical implications of Girdin protein expression in glioma.

OBJECTIVE: To investigate the expression status of Girdin in glioma and the relationship between Girdin expression and the biological behavior of glioma. MATERIALS AND METHODS: The expression status of Girdin in glioma from 560 cases was evaluated by RT-PCR, Western Blot and immunohistochemistry. The relationship between Girdin expression and clinic-pathological parameters as well as prognosis was also studied. RESULTS: The expression of Girdin in high grade glioma was significantly higher than low grade glioma. After universal analysis, the expression of Girdin protein is closely related to KPS score, extent of resection, Ki67 and WHO grade, but it was not related to sex and age. Finally, extent of resection, Ki67 and WHO grade were indentified to be related to the Girdin protein expression in logistic regression. Interestingly, we found that the expression of Girdin is significantly related to the distant metastasis of glioma. After COX regression analysis, KPS score, Extent of resection, Ki67, WHO grade as well as Girdin were observed to be independent prognostic factors. CONCLUSIONS: Girdin is differential expressed in the glioma patients and closely related to the biological behavior of Glioma. Finally, Girdin was found to be a strong predictor for the post-operative prognosis.

A Novel De Novo TUBB3 Variant Causing Developmental Delay, Epilepsy and Mild Ophthalmological Symptoms in a Chinese Child.

Heterozygous missense mutations in TUBB3 have been implicated in various neurological disorders encompassing either isolated congenital fibrosis of the extraocular muscles type 3 (CFEOM3) or complex cortical dysplasia with other brain malformations 1 (CDCBM1). The description of seizures in patients with TUBB3 mutations is rare. Here, we reported a patient who had febrile seizures before and focal seizure this time, which was diagnosed as epilepsy in combination with an abnormal EEG. MRI showed hypoplastic corpus callosum. Mutation analysis showed a novel de novo heterozygous variant of the TUBB3 gene (NM_006086), c.763G > A (p.V255I). The patient had global developmental delay, photophobia and elliptic pupils, but lacking extraocular muscle involvement and malformations of cortical development, which might be a less severe phenotype of TUBB3 mutations. This is the first report of elliptic pupils in a patient with TUBB3 mutations and expands the spectrum of TUBB3 phenotypes. It indicates that the phenotypic range of TUBB3 mutations might exist on more of a continuum than as a discrete entity, with severity ranging from mild to severe. Further studies are needed to elucidate the complete spectrum of TUBB3-related phenotypes.

Correlation between microalbuminuria and atherosclerotic intracranial and extracranial arterial stenosis in patients with cerebral infarction.

BACKGROUND AND AIMS: Microalbuminuria (MAU) reflects the generalized vascular endothelial dysfunction. Whether MAU has correlation with atherosclerotic intracranial and extracranial arterial stenosis in cerebral infarction patients is not known and is explored in the present investigation. METHODS: We enrolled 255 cerebral infarction patients hospitalized at the department of neurology. All patients underwent digital subtraction angiography (DSA) to evaluate the severity and distribution of intracranial and extracranial arterial stenosis. MAU was expressed as the urine albumin-to-creatinine ratio (UACR). We collected basic information, medical history reviews and laboratory results of each participant. The multivariate logistic regression analysis was utilized to analyze the risk factors for severity and distribution of cerebral arterial stenosis. RESULTS: The prevalence of MAU in patients with cerebral infarction was 39.2%, patients with MAU had older age, lower blood uric acid, higher systolic blood pressure (SBP), higher prevalence of hypertension and diabetes (p < 0.05) and higher incidence of atherosclerotic intracranial and extracranial arterial stenosis (χ2 = 5.900, p = 0.015). In multiple logistic regression analysis for intracranial and extracranial arterial stenosis more than 50% or occlusion groups, UACR (OR 1.088 95%CI 1.012-1.170p = 0.022), male (OR 2.196 95%CI 1.085-4.442p = 0.029) as well as SBP (OR 5.870 95%CI 1.026-1.048p = 0.015) showed statistical significance. But UACR had no correlation with the distribution of intracranial and extracranial artery stenosis after adjusting for all potential confounders. CONCLUSIONS: Microalbuminuria was an independent risk factor for intracranial and extracranial arterial stenosis more than 50% or occlusion.

Investigating the AC079305/DUSP1 Axis as Oxidative Stress-Related Signatures and Immune Infiltration Characteristics in Ischemic Stroke.

Background: Oxidative stress (OS) and immune inflammation play complex intersections in the pathophysiology of ischemic stroke (IS). However, a competing endogenous RNA- (ceRNA-) based mechanism linked to the intersections in IS has not been explored. We aimed to identify potential OS-related signatures and analyze immune infiltration characteristics in IS. Methods: Three datasets (GSE22255, GSE110993, and GSE140275) from the GEO database were extracted. Differentially expressed long noncoding RNAs, microRNAs, and messenger RNAs (DElncRNAs, DEmiRNAs, and DEmRNAs) between IS patients and controls were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were explored. Moreover, a triple ceRNA network was constructed to reveal transcriptional regulation mechanisms. A comprehensive strategy among least absolute shrinkage and selection operator (LASSO) regression, DEmRNAs, uprelated DEmRNAs, and OS-related genes was adopted to select the best signature. Then, we evaluated and verified the discriminant ability of the signature via receiver operating characteristic (ROC) analysis. Immune infiltration characteristics were explored via the CIBERSORT algorithm. Moreover, the best signature was verified via qPCR and western blot methods in rat brain tissues and PC12 cells. Results: 11 DEmRNAs were identified totally. Enrichment analysis showed that the DEmRNAs were primarily concentrated in MAPK-associated biological processes and immune or inflammation-involved pathways. DUSP1 was identified as the best signature with an area under the ROC curve of 73.5% (95%CI = 57.02-89.98, sensitivity = 95%, and specificity = 60%) in GSE22255 and 100.0% (95%CI = 100.00-100.00, sensitivity = 100%, and specificity = 100%) in GSE140275. Importantly, we also identified the AC079305/DUSP1 axis in the ceRNA network. Immune infiltration showed that resting mast cells infiltrate less in IS patients compared with controls. And DUSP1 was negatively correlated with resting mast cells (r = -0.703, P < 0.01), whereas it was positively correlated with neutrophils (r = 0.339, P < 0.05). Both in vivo and in vitro models confirmed the upregulated expression of DUSP1 and the downregulated expression of miR-429. Conclusion: This study identified the ceRNA-based AC079305/DUSP1 axis as a promising OS-related signature for IS. Immune infiltrating cells, especially mast cells, may exert a pivotal role in IS progression. Pharmacological agents targeting signatures, their receptors, or mast cells may shed a novel light on therapeutic targets for IS.

Combination of High-Density Lipoprotein Cholesterol and Lipoprotein(a) as a Predictor of Collateral Circulation in Patients With Severe Unilateral Internal Carotid Artery Stenosis or Occlusion.

BACKGROUND AND PURPOSE: Collateral circulation is considered an important factor affecting the risk of stroke, but the factors that affect collateral circulation remain unclear. This study was performed to identify the factors associated with collateral circulation, especially blood lipids. METHODS: The study involved patients who had undergone digital subtraction angiography and were confirmed as having severe unilateral stenosis or occlusion of the internal carotid artery (ICA). We classified the collateral circulation status of each patient as good (Grade 3 or 4) or poor (Grade 0, 1, or 2) according to the grading system of the American Society of Interventional and Therapeutic Neuroradiology/American Society of Interventional Radiology. We collected data on patients' characteristics and identified the factors that affect collateral circulation. RESULTS: This study included 212 patients. The multivariate logistic regression analysis showed that the high-density lipoprotein cholesterol (HDL-C) concentration and a complete anterior half of the circle of Willis were independent protective factors for good collateral circulation, whereas elevated lipoprotein(a) [Lp(a)] and serum creatinine concentrations were independent risk factors for good collateral circulation. The area under the receiver operating characteristics curve (AUC) was 0.68 (95% confidence interval [CI], 0.61-0.76) for HDL-C and 0.69 (95% CI, 0.62-0.76) for Lp(a). A binary logistic regression model analysis of the joint factor of HDL-C and Lp(a) yielded an AUC of 0.77 (95% CI, 0.71-0.84). CONCLUSIONS: In patients with severe unilateral ICA stenosis or occlusion, the combination of HDL-C and Lp(a) is a useful predictor of collateral circulation.

Dynorphin A (1-8) inhibits oxidative stress and apoptosis in MCAO rats, affording neuroprotection through NMDA receptor and κ-opioid receptor channels.

The contents of Dynorphin A(1-8) decreased gradually in ischemic cortices in rats and an intracerebroventricular administration of synthetic Dynorphin A(1-8) reduced the volume of cerebral infarction in our previous research. However, the specific protective mechanism is unclear and Dynorphin A(1-8) is unlikely to cross the blood-brain barrier (BBB) by noninvasive oral or intravenous administration as a macromolecule neuropeptide. In this study, intranasal administration was used to middle cerebral artery occlusion(MCAO) rats to assessed the therapeutic effects of Dynorphin A(1-8) by evaluating behavior, volume of cerebral infarct, cerebral edema ratio, histological observation. Then apoptosis neuron rate was detected by TUNEL staining. Immunohistochemical staining was carried out to explore the alteration of Bcl-2, Bax and Caspase-3. Finally, κ-opioid receptor antagonist and N-methyl-d-aspartate(NMDA) receptor antagonist were used to explore its possible mechanism. We found that MCAO rats under intranasal administration of Dynorphin A(1-8) showed better behavioral improvement, higher extent of Bcl-2, activity of SOD along with much lower level of infarction volume, brain water content, number of cell apoptosis, extent of Bax and Caspase-3, and concentration of MDA compared with those in MCAO model group and intravenous Dynorphin A(1-8) group. Administration of nor-BNI or MK-801 reversed these neuroprotective effects of intranasal Dynorphin A(1-8). In summary, Dynorphin A(1-8), with advantages of intranasal administration, could be effectively delivered to central nervous system(CNS). Dynorphin A(1-8) inhibited oxidative stress and apoptosis against cerebral ischemia/reperfusion injury, affording neuroprotection through NMDA receptor and κ-opioid receptor channels.

TPEN Attenuates Neural Autophagy Induced by Synaptically-released Zinc Translocation and Improves Histological Outcomes after Traumatic Brain Injury in Rats.

OBJECTIVES: Previous studies have demonstrated that the inhibition of autophagy could reduce traumatic brain injury (TBI)-induced cell injury and attenuate behavioural outcomes. Meanwhile, synaptically released zinc translocation is found in the hippocampus of rats, and excessive release of chelatable zinc from excitatory synaptic vesicles is involved in the pathophysiological processes of TBI. We speculated that the release of zinc is closely connected with autophagy and that treatment with the zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN) could attenuate autophagy and thus improve histologic outcomes after TBI in rats. METHODS: Rats were randomly divided into three groups: sham group, CCI+vehicle group and CCI+TPEN group. TPEN (20 mg/kg/12 h, i.p) or vehicle (DMSO) was injected into the rats immediately after TBI, then given twice a day until the animals were sacrificed. Morphological changes associated with autophagy were tested by TEM. Zinc autometallography staining was used to evaluate chelatable zinc accumulation. Western blot analysis was used to detect protein expression. RESULTS: In our study, we found that treatment with TPEN reduced zinc translocation, reduced excitotoxicity and also partially reduced levels of LC3-II, Beclin1 and the ratio of Beclin-1/Bcl-2 in injured hippocampal neurons of rats, partially improving histologic outcomes after TBI. CONCLUSION: These data show that the zinc chelator TPEN plays a protective role in TBI, suggesting the possible involvement of autophagy.