Re-Exploring the Inflammation-Related Core Genes and Modules in Cerebral Ischemia.

The genetic transcription profile of brain ischemic and reperfusion injury remains elusive. To address this, we used an integrative analysis approach including differentially expressed gene (DEG) analysis, weighted-gene co-expression network analysis (WGCNA), and pathway and biological process analysis to analyze data from the microarray studies of nine mice and five rats after middle cerebral artery occlusion (MCAO) and six primary cell transcriptional datasets in the Gene Expression Omnibus (GEO). (1) We identified 58 upregulated DEGs with more than 2-fold increase, and adj. p < 0.05 in mouse datasets. Among them, Atf3, Timp1, Cd14, Lgals3, Hmox1, Ccl2, Emp1, Ch25h, Hspb1, Adamts1, Cd44, Icam1, Anxa2, Rgs1, and Vim showed significant increases in both mouse and rat datasets. (2) Ischemic treatment and reperfusion time were the main confounding factors in gene profile changes, while sampling site and ischemic time were not. (3) WGCNA identified a reperfusion-time irrelevant and inflammation-related module and a reperfusion-time relevant and thrombo-inflammation related module. Astrocytes and microglia were the main contributors of the gene changes in these two modules. (4) Forty-four module core hub genes were identified. We validated the expression of unreported stroke-associated core hubs or human stroke-associated core hubs. Zfp36 mRNA was upregulated in permanent MCAO; Rhoj, Nfkbiz, Ms4a6d, Serpina3n, Adamts-1, Lgals3, and Spp1 mRNAs were upregulated in both transient MCAO and permanent MCAO; and NFKBIZ, ZFP3636, and MAFF proteins, unreported core hubs implicated in negative regulation of inflammation, were upregulated in permanent MCAO, but not in transient MCAO. Collectively, these results expand our knowledge of the genetic profile involved in brain ischemia and reperfusion, highlighting the crucial role of inflammatory disequilibrium in brain ischemia.

HLA in Alzheimer's Disease: Genetic Association and Possible Pathogenic Roles.

Alzheimer's disease (AD) is commonly considered as the most prominent dementing disorder globally and is characterized by the deposition of misfolded amyloid-ß (Aß) peptide and the aggregation of neurofibrillary tangles. Immunological disturbances and neuroinflammation, which result from abnormal immunological reactivations, are believed to be the primary stimulating factors triggering AD-like neuropathy. It has been suggested by multiple previous studies that a bunch of AD key influencing factors might be attributed to genes encoding human leukocyte antigen (HLA), whose variety is an essential part of human adaptive immunity. A wide range of activities involved in immune responses may be determined by HLA genes, including inflammation mediated by the immune response, T-cell transendothelial migration, infection, brain development and plasticity in AD pathogenesis, and so on. The goal of this article is to review the recent epidemiological findings of HLA (mainly HLA class I and II) associated with AD and investigate to what extent the genetic variations of HLA were clinically significant as pathogenic factors for AD. Depending on the degree of contribution of HLA in AD pathogenesis, targeted research towards HLA may propel AD therapeutic strategies into a new era of development.

Diffusion-weighted imaging-documented bilateral small embolic stroke involving multiple vascular territories may indicate occult cancer: A retrospective case series and a brief review of the literature.

Diffusion-weighted imaging (DWI) MRI is very sensitive for detecting small embolic brain infarctions. Stroke as the first manifestation of cancer is extremely rare. We performed a retrospective study to identify the clinical and DWI features of patients with acute ischemic stroke as the first manifestation of occult cancer. A total of five patients in our hospital from January 2017 to May 2019 were analyzed. We also reviewed the literature and seven case series (16 patients) were included. Most of these patients were aged in their sixties and lung cancer was the most common type of occult cancer. Patients showed various presentations of ischemic stroke. All of the patients showed small multiple lesions on DWI that involved mostly the anterior or both anterior and posterior territories. The lesions were mostly in both the supratentorium and infratentorium, with the mechanisms of embolic and watershed infarcts. These features were useful for identifying the causes of embolic stroke. Therefore, patients with small bilateral embolic stroke, especially those involved in multiple vascular territories, should be examined for concealed malignancy.

Levetiracetam Reduces Early Inflammatory Response After Experimental Intracerebral Hemorrhage by Regulating the Janus Kinase 2 (JAK2)-Signal Transducer and Activator of Transcription 3 (STAT3) Signaling Pathway.

BACKGROUND Levetiracetam (LEV) is an antiepileptic drug that promotes recovery of neurological function by alleviating inflammatory reactions. However, it is not known whether it can improve secondary brain injury after intracerebral hemorrhage (ICH). The aim of this study was to determine whether LEV can reduce early inflammatory response after ICH in rats. MATERIAL AND METHODS An in vitro model of early inflammation was created by treating microglia cells with lipopolysaccharide (LPS). After exposure to various concentrations of LEV, the expression levels of NF-kappaB and STAT3 and inflammatory factors such as interleukin (IL)-1ß and tumor necrosis factor (TNF)-alpha in microglia were detected. In vivo, autologous blood was used to induce the rat ICH model. The effects of LEV on post-cerebral hemorrhagic inflammatory response were examined using neurobehavioral tests, FJC staining, brain water content testing, and analysis of protein expression levels of NF-kappaB, JAK2, STAT3, and inflammatory factors. RESULTS LEV treatment significantly reduced the expression of inflammatory factors and protein expression levels of NF-kappaB and STAT3 in LPS-treated microglia cells (P<0.05). In male Sprague-Dawley (SD) rats, LEV treatment markedly decreased the volume of hematoma and the number of degenerative neurons (P<0.05). It also improved the neurological function and relieved brain edema. The protein expression levels of NF-kappaB, JAK2, and STAT3 were significantly lower in the ICH+LEV group than in the control group (P<0.05). CONCLUSIONS Our study suggests that treatment with LEV alleviates early inflammatory responses induced by ICH. Mechanistically, LEV inhibited the JAK2-STAT3 signaling pathway and reduced neuronal injury around the hematoma, and ameliorated brain edema, all of which promoted recovery of nerve function after hemorrhage.

Thrombotic thrombocytopenic purpura with reversible splenial lesion syndrome: a case report.

BACKGROUND: Reversible splenial lesion syndrome (RESLES) is known to cause severe psychiatric symptoms but is also a very rare clinical disease in which the specific aetiology is unknown. According to current reports, there are major causes of the disease, including viral or bacterial infection, epilepsy, anti-epileptic drug withdrawal, high-altitude cerebral oedema, and metabolic disorders such as hypoglycaemia and hypernatraemia. In this article, we report a patient with thrombotic thrombocytopenic purpura (TTP) who presented with RESLES. CASE PRESENTATION: A 34-year-old female patient who presented with fever and progression of disorder of consciousness was eventually diagnosed with RESLES based on brain imaging. Moreover, clinical features and peripheral smears demonstrating schistocytes and thrombocytopenia confirmed a diagnosis of TTP. RESLES can be improved by plasma exchange therapy. CONCLUSION: This rare case highlights the occurrence of RESLES as a presenting feature of the expanding list of unusual neurological manifestations of TTP.

Efficacy of perioperative anticonvulsant prophylaxis in seizure-naïve glioma patients: A meta-analysis.

The efficacy of perioperative seizure prophylaxis in seizure-naïve glioma patients is still controversial. Thus we conducted this meta-analysis to assess the effectiveness of perioperative prophylactic antiepileptic drugs (AEDs) on postoperative seizures in seizure-naïve glioma for the first time. We systematically searched PubMed, Embase, Weipu (VIP) and Chinese National Knowledge Infrastructure (CNKI) until July 5, 2019 for eligible studies. Fixed or random model was used to calculate the odds ratios in STATA 12.0 software. Subgroup analyses of early postoperative seizure, late postoperative seizure, high-grade glioma (WHOIII-IV) and phenytoin (PHT) or phenobarbital (PB) prophylaxis were conducted. Altogether 1143 seizure-naïve glioma patients from 9 studies were included in this meta-analysis, containing 643 prophylaxed and 503 non-prophylaxed patients. No significant association was detected between perioperative seizure prophylaxis and postoperative seizure occurrence in glioma patients without preoperative seizure history (OR = 0.91, 95% CI = 0.65-1.26, P = 0.56). Perioperative AED prophylaxis showed no significant benefit to postoperative seizures when stratified by early postoperative seizure(within the first postoperative week), late postoperative seizure (after the first postoperative week), high-grade glioma and PHT or PB prophylaxis (all P > 0.05). Current evidence indicated that perioperative seizure prophylaxis did not reduce the occurrence of postoperative seizure in seizure-naïve glioma patients. The pros and cons of perioperative seizure prophylaxis should be considered before the start of perioperative AEDs treatment.

Effect of anti-microbial-coated central venous catheter on catheter-associated deep venous thrombosis / 临床麻醉学杂志

Objective To evaluate the effect of anti-microbia-l coated central venous catheter (CVC),compared with routine CVC,on catheter-associated deep venous thrombosis (CADVT). Methods A total of 1 359 patients,aged 26-82 years,ASA physical status Ⅰ-Ⅲ,undergoing internal jugular,axillary-subclavian,or femoral vein CVC catheterization during January to June of 2017,were retrospectively reviewed.The patients were divided into intoanti-microbial-coated CVC group (group A)and routine CVC group (group B).Gender,age,ASA class,pre-operative risk of thrombus (Caprini score),CVC site,surgical site,ultrasound-guided catheterization,and anticoagu-lation therapy,CADVT and the degree,as well as the other adverse events were recorded.Results A total of 938 patients were successfully matched.There were 323 (34.4%)articipants diagnosed with CADVT with bedside point-of-care ultrasound,in which 172 cases (36.7%)in group A and 151 (32.2%)in group B.There was no statistical significance of CADVT and the degree between the two groups.The subgroup analysis results indicated that the patients using anti-microbial-coated CVC with high risk of thrombus (Caprini score ≥ 5 points)(OR 1.34,95% C I 1.01-1.78),undergoing catheterization according to anatomical landmark (OR 1.69,95% C I 1.04-2.74),and not-receiving anticoagulation therapy (OR 1.39,95% C I 1.01-1.92)had an increased risk of CADVT compared with those using routine CVC.A significantly decreased incidence of catheter-associated infection in group A was observed compared with group B (0.9% vs 4.1%,P<0.05).Conclusion Anti-micro-bial-coated CVC does not increase the incidence of CADVT.

Strong Association of Lipid Metabolism Related MicroRNA Binding Sites Polymorphisms with the Risk of Late Onset Alzheimer's Disease.

Although altered lipid metabolism has been extensively implicated in the pathogenesis of late onset Alzheimer's disease (LOAD) through cell biological and epidemiological studies, genetic studies linking lipid metabolism and LOAD are still not well understood. MicroRNAs (miRNAs) exert posttranscriptional down-regulation and their target sequence on the 3' untranslated regions (3'UTR) may be altered by single nucleotide polymorphisms (SNPs). We therefore explore whether the six loci in Clusterin gene (CLU) (rs9331949), Lipoprotein lipase gene (LPL) (rs1059507, rs3200218, rs3208305, rs3735964) and Low-density lipoprotein receptor related protein 6 (LRP6) (rs2160525) could modulate LOAD risk through the alteration of miRNA binding sites. We performed a case-control study of 2338 unrelated subjects (984 cases and 1354 age- and gender-matched controls) in the Northern Han Chinese. We found that the minor C allele in rs9331949 significantly increased the risk of LOAD (P<0.001, OR=1.31, 95% CI=1.14-1.51), even after adjusting for multiple testing. Logistic analysis identified the rs9331949 polymorphism was still strongly associated with LOAD, even in Apolipoprotein E (APOE) ε4 allele noncarrier subgroups. However, the other five loci were not significantly associated with LOAD after Bonferroni adjustment. In conclusion, we have identified that the locus (rs9331949) located in the binding site of 3' UTR of CLU has a strong association with LOAD rather than loci in LPL and LRP6. However, additional independent replication is required for further validation.

The Role of MAPT in Neurodegenerative Diseases: Genetics, Mechanisms and Therapy.

Microtubule-associated protein tau (MAPT) is a gene responsible for encoding tau protein, which is tightly implicated in keeping the function of microtubules and axonal transport. Hyperphosphorylated tau protein participates in the formation of neurofibrillary tangles (NFTs), which characterize many neurodegenerative disorders termed tauopathies. Genome-wide association studies (GWAS) have demonstrated numerous single nucleotide polymorphisms (SNPs) located in MAPT associated with various neurodegenerative diseases. Thus, it has been presumed that MAPT plays a crucial role in pathogenesis of neurodegeneration via affecting the structure and function of tau. Here, we review the advanced studies to summarize the biochemical properties of MAPT and its encoded protein, as well as the genetics and epigenetics of MAPT in neurodegeneration. Finally, given the potential mechanisms of MAPT to neurodegeneration pathogenesis, targeting MAPT and tau might present significant treatments of MAPT mutation-related neurodegeneration. Affirmatively, the identification of MAPT is extremely beneficial for improving our understanding of the pathogenesis of various neurodegenerative diseases and developing the mechanism-based therapies.

The Role of Cdk5 in Alzheimer's Disease.

Alzheimer's disease (AD) is known as the most fatal chronic neurodegenerative disease in adults along with progressive loss of memory and other cognitive function disorders. Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (Cdks), is reported to intimately associate with the process of the pathogenesis of AD. Cdk5 is of vital importance in the development of CNS and neuron movements such as neuronal migration and differentiation, synaptic functions, and memory consolidation. However, when neurons suffer from pathological stimuli, Cdk5 activity becomes hyperactive and causes aberrant hyperphosphorylation of various substrates of Cdk5 like amyloid precursor protein (APP), tau and neurofilament, resulting in neurodegenerative diseases like AD. Deregulation of Cdk5 contributes to an array of pathological events in AD, ranging from formation of senile plaques and neurofibrillary tangles, synaptic damage, mitochondrial dysfunction to cell cycle reactivation as well as neuronal cell apoptosis. More importantly, an inhibition of Cdk5 activity with inhibitors such as RNA inference (RNAi) could protect from memory decline and neuronal cell loss through suppressing ß-amyloid (Aß)-induced neurotoxicity and tauopathies. This review will briefly describe the above-mentioned possible roles of Cdk5 in the physiological and pathological mechanisms of AD, further discussing recent advances and challenges in Cdk5 as a therapeutic target.

The impacts of information-sharing mechanisms on spatial market formation based on agent-based modeling.

There has been an increasing interest in the geographic aspects of economic development, exemplified by P. Krugman's logical analysis. We show in this paper that the geographic aspects of economic development can be modeled using multi-agent systems that incorporate multiple underlying factors. The extent of information sharing is assumed to be a driving force that leads to economic geographic heterogeneity across locations without geographic advantages or disadvantages. We propose an agent-based market model that considers a spectrum of different information-sharing mechanisms: no information sharing, information sharing among friends and pheromone-like information sharing. Finally, we build a unified model that accommodates all three of these information-sharing mechanisms based on the number of friends who can share information. We find that the no information-sharing model does not yield large economic zones, and more information sharing can give rise to a power-law distribution of market size that corresponds to the stylized fact of city size and firm size distributions. The simulations show that this model is robust. This paper provides an alternative approach to studying economic geographic development, and this model could be used as a test bed to validate the detailed assumptions that regulate real economic agglomeration.