Dual selective sensor for exosomes in serum using magnetic imprinted polymer isolation sandwiched with aptamer/graphene oxide based FRET fluorescent ignition.

The selective and sensitive detection of cancerous exosomes in serum is critical for early disease diagnosis and improved prognosis. Previous exosome-related research has been limited by a lack of well-understanding in exosomes as well as the challenging background interference of body fluid. Molecularly imprinted polymers (MIPs) and nucleic acid aptamers can be regarded as the two alternatives to antibodies. When using imprinted polymer technology, comprehensive and precise information about the target constituents is not required. In this study, a novel kind of dual selective fluorescent nanosensor for the poorly characterized exosomes was constructed by integrating magnetic MIP selective exosome capture sandwiched with an aptamer/graphene oxide fluorescence resonance energy transfer system (FRET) based selective 'turn-on' exosome labeling heterogeneously. The overall strategy performance was successively evaluated using lysozyme and exosomes as targets. Good linearity and high sensitivity achieved were demonstrated. The LOD of exosomal detection in serum was 2.43 × 106 particles/mL, lower than other immunology based detection methods. The discrimination between serum from breast cancer patients and healthy people was also primarily studied. In conclusion, the developed sensor with outstanding selectivity, high detection sensitivity, simplicity, low cost, and wide applicability for known or unknown targets present significant potential in challenging clinical diagnosis.

Dysregulated CD40 and CD40 ligand expression in anti-N-methyl-d-aspartate receptor encephalitis.

Anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) is a B cell- and antibody-mediated autoimmune disease which may be regulated by CD40/CD40L signaling pathway. we enrolled anti-NMDARE patients and measured the serum CD40 and CD40L concentrations. The serum concentration of CD40 was decreased, while CD40L was increased in anti-NMDARE patients compared with that of healthy controls. The concentrations of CD40 and CD40L were both elevated in the acute stage of anti-NMDARE and were reduced during remission. Serum CD40L levels were positively correlated with serum CD40 levels. These results revealed that the CD40/CD40L signaling pathway might contribute to the pathogenesis of anti-NMDARE.

Association of serum Gasdermin D with anti-N-methyl-D-aspartate receptor encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease of the central nervous system. Gasdermin D (GSDMD) is associated with autoimmune disorders and neuroinflammatory disorders, but its role in anti-NMDAR encephalitis is unclear. In this study, we measured serum levels of GSDMD in 42 patients with anti-NMDAR encephalitis and 25 healthy controls. Of the 42 patients, 17 had follow-up evaluation of GSDMD levels and modified Rankin scale (mRS) scores at 3 months. Association of GSDMD with anti-NMDAR encephalitis and its clinical parameters were evaluated. Serum GSDMD levels were significantly higher in patients with anti-NMDAR encephalitis than in healthy controls (p = 0.002, padjusted  = 0.009), especially in males (p = 0.001, padjusted  = 0.022). This was also evident in patients with severe impairment (mRS >3 vs mRS ≤3; p < 0.001). Serum GSDMD was associated with mRS before and after adjustment for age and gender (r = 0.440 and 0.430, p = 0.004 and 0.006, respectively) as well as serum CH50 (r = -0.419 and -0.426, p = 0.011 and 0.012, respectively). Furthermore, 3-month follow-up evaluation revealed that after treatment, anti-NMDAR encephalitis patients had significantly decreased serum GSDMD levels (p = 0.007) and significantly decreased mRS scores (p = 0.002) compared with before treatment. Furthermore, the changes in mRS scores were negatively associated with changes in GSDMD levels, although the associations were not significant (r = -0.222, p = 0.393). Our findings show that serum GSDMD levels are elevated in anti-NMDAR encephalitis and are associated with disease prognosis.

Long-term safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis: Results from the TOWER extension study.

BACKGROUND: In the phase 3 TOWER core study (NCT00751881), the efficacy and safety of teriflunomide compared with placebo were demonstrated in patients with relapsing forms of multiple sclerosis (RMS). Here, the long-term safety and efficacy outcomes from the TOWER extension study (NCT00751881) are reported. METHODS: All patients who entered the extension (N = 751) were assigned to teriflunomide 14 mg and assessed for long-term safety and efficacy. RESULTS: Of 751 patients in the TOWER extension study, 253, 265, and 233 patients received placebo/teriflunomide 14 mg, teriflunomide 7 mg/14 mg, and teriflunomide 14 mg/14 mg, respectively. Median teriflunomide exposure was 4.25 years (maximum 6.3 years). The overall frequency of adverse events (AEs) was comparable across treatment groups, but a higher proportion of patients in the teriflunomide 7 mg/14 mg (12.4%) and 14 mg/14 mg (12.4%) groups had serious AEs compared with the placebo/teriflunomide 14 mg group (6.4%). Alanine aminotransferase increase and hair thinning occurred at a higher frequency in the placebo/teriflunomide 14 mg group (11.2% and 14.3%, respectively) compared with the teriflunomide 7 mg/14 mg (3.0% and 4.5%, respectively) and 14 mg/14 mg groups (5.2% and 4.3%, respectively). The incidences of AEs of interest (hematologic and hepatic effects, peripheral neuropathy, hypertension, and malignancy) were low and comparable across treatment arms. Disability worsening and adjusted annualized relapse rates were low and stable over time, and mean Expanded Disability Status Scale scores were unchanged over time, for all treatment groups. CONCLUSION: In the TOWER extension study, the efficacy of teriflunomide 14 mg was maintained in patients with RMS. No new or unexpected AEs were observed with teriflunomide treatment, supporting a safety profile in the extension that was consistent with the core trial. These findings support the positive benefit:risk profile of teriflunomide as a long-term immunomodulatory therapy.

The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke.

BACKGROUND: Preserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important component of the BBB, promote BBB breakdown in subjects with AIS by secreting inflammatory factors. The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) protects the BBB and reduces brain inflammation from cerebral ischemia, and GLP-1R is expressed on astrocytes. However, the effect of Ex-4 on astrocytes in subjects with AIS remains unclear. METHODS: In the present study, we investigated the effect of Ex-4 on astrocytes cultured under oxygen-glucose deprivation (OGD) plus reoxygenation conditions and determined whether the effect influences bEnd.3 cells. We used various methods, including permeability assays, western blotting, immunofluorescence staining, and gelatin zymography, in vitro and in vivo. RESULTS: Ex-4 reduced OGD-induced astrocyte-derived vascular endothelial growth factor (VEGF-A), matrix metalloproteinase-9 (MMP-9), chemokine monocyte chemoattractant protein-1 (MCP-1), and chemokine C-X-C motif ligand 1 (CXCL-1). The reduction in astrocyte-derived VEGF-A and MMP-9 was related to the increased expression of tight junction proteins (TJPs) in bEnd.3 cells. Ex-4 improved neurologic deficit scores, reduced the infarct area, and ameliorated BBB breakdown as well as decreased astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic brain tissues from rats subjected to middle cerebral artery occlusion. Ex-4 reduced the activation of the JAK2/STAT3 signaling pathway in astrocytes following OGD. CONCLUSION: Based on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.

Neutralization of interleukin-9 ameliorates experimental stroke by repairing the blood-brain barrier via down-regulation of astrocyte-derived vascular endothelial growth factor-A.

Astrocytes mediate the destruction of the blood-brain barrier (BBB) during ischemic stroke (IS). IL-9 is a pleiotropic cytokine that we previously found to be highly expressed in peripheral blood mononuclear cells from patients with IS, and the presence of IL-9 receptors on astrocytes has been reported in the literature. Here, we detected the effect of IL-9 on astrocytes using an anti-IL-9-neutralizing antibody to treat rats with experimental stroke. Supernatants from astrocytes treated with or without oxygen-glucose deprivation and/or IL-9 were incubated with bEnd.3 cell monolayers after blocking the IL-9 receptor on the endothelium. Immunofluorescence staining and Western blot analyses were conducted to observe the change in tight junction proteins (TJPs) in bEnd.3 cells as well as the level of VEGF-A and possible signal pathways in astrocytes. We also applied middle cerebral artery occlusion (MCAO) models to determine the effect of anti-IL-9-neutralizing antibodies on IS. As a result, astrocyte-conditioned medium treated with IL-9 aggravated the disruption of the BBB accomplished by the degradation of TJPs in endothelial cells. In addition, IL-9 increased the level of VEGF-A in astrocytes, and blocking the effect of VEGF-A reversed the breakdown of the BBB. In the MCAO model, anti-IL-9-neutralizing antibody reduced the infarct volume and BBB destruction. Mechanistically, the anti-IL-9-neutralizing antibody repaired the damaged TJPs (zonula occludens 1, occludin, and claudin-5) and induced a decrease in VEGF-A expression in ischemic lateral brain tissue. In contrast, a local injection of recombinant murine IL-9 to the brain resulted in a marked up-regulation of VEGF-A in the striatum. In conclusion, anti-IL-9-neutralizing antibody can reduce the severity of IS partially by alleviating the destruction of the BBB via down-regulation of astrocyte-derived VEGF-A. This finding suggests that targeting IL-9 or VEGF-A could provide a new direction for the treatment of IS.-Tan, S., Shan, Y., Lin, Y., Liao, S., Zhang, B., Zeng, Q., Wang, Y., Deng, Z., Chen, C., Hu, X., Peng, L., Qiu, W., Lu, Z. Neutralization of IL-9 ameliorates experimental stroke by repairing the blood-brain barrier via down-regulation of astrocyte-derived vascular endothelial growth factor-A.

HLA class II allele DRB1*16:02 is associated with anti-NMDAR encephalitis.

BACKGROUND AND OBJECTIVE: Aetiology and pathogenesis of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the most common autoimmune encephalitis, is largely unknown. Since an association of the disease with the human leucocyte antigen (HLA) has not been shown so far, we here investigated whether anti-NMDAR encephalitis is associated with the HLA locus. METHODS: HLA loci of 61 patients with anti-NMDAR encephalitis and 571 healthy controls from the Chinese Han population were genotyped and analysed for this study. RESULTS: Our results show that the DRB1*16:02 allele is associated with anti-NMDAR encephalitis (OR 3.416, 95% CI 1.817 to 6.174, p=8.9×10-5, padj=0.021), with a higher allele frequency in patients (14.75%) than in controls (4.82%). This association was found to be independent of tumour formation. Besides disease susceptibility, DRB1*16:02 is also related to the clinical outcome of patients during treatment, where patients with DRB1*16:02 showed a lower therapeutic response to the treatment than patients with other HLA alleles (p=0.033). Bioinformatic analysis using HLA peptide-binding prediction algorithms and computational docking suggested a close relationship between the NR1 subunit of NMDAR and the DRB1*16:02. CONCLUSIONS: This study for the first time demonstrates an association between specific HLA class II alleles and anti-NMDAR encephalitis, providing novel insights into the pathomechanism of the disease.

Serum Bilirubin and Albumin in Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

BACKGROUND AND OBJECTIVE: Low serum levels of bilirubin and albumin are associated with multiple autoimmune diseases, but their role in anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is unknown. METHODS: Serum bilirubin and albumin levels were evaluated in 60 patients with anti-NMDAR encephalitis, 50 cryptococcal encephalitis, and 145 healthy controls (CTLs). Of the 60 anti-NMDAR encephalitis patients, 30 had a follow-up evaluation at 3 months after admission. RESULTS: Serum bilirubin and albumin levels were both significantly lower in anti-NMDAR encephalitis than in CTLs, and serum bilirubin levels were significantly lower in anti-NMDAR encephalitis than in cryptococcal encephalitis. Serum bilirubin levels were significantly lower in patients with psychiatric symptoms, with severe impairment, and with limited responses to treatment than those without psychiatric symptoms, with mild impairment, and with favorable responses to treatment, respectively. A follow-up evaluation of 30 patients revealed that the modified Rankin Scale scores were significantly decreased after treatment. Serum bilirubin significantly associated with serum albumin, and plasma hemoglobin. CONCLUSIONS: Our results revealed for the first time an association between the serum levels of bilirubin in the anti-NMDAR encephalitis. Further studies investigating the role of bilirubin and albumin in anti-NMDAR encephalitis are required.

Cerebrospinal Fluid Level of Soluble CD27 Is Associated with Disease Severity in Neuromyelitis Optica Spectrum Disorder.

OBJECT: CD27 belongs to the tumor necrosis factor receptor family and is constitutively expressed on T cells. The concentration of cerebrospinal fluid (CSF) soluble (s)CD27 is elevated in patients with multiple sclerosis (MS). However, whether the level of CSF sCD27 is elevated in neuromyelitis optica spectrum disorder (NMOSD) remains unknown. The aim of this study was to measure the CSF concentration of sCD27 and to determine its relationship with NMOSD disease activity. METHODS: CSF CXCL13 was measured by ELISA in neuromyelitis optica (NMO) (n = 31) and MS (n = 23) patients and in controls (CTLs) (n = 22). RESULTS: The concentration of sCD27 was higher in the NMO group than in the MS (p = 0.082) and CTL (p = 0.002) groups, and there was a positive correlation with CSF IL-6 (p = 0.000) and a negative correlation with IL-10 (p = 0.073). In the NMO group, patients with higher sCD27 concentrations exhibited worse disease disability in their CSF (p = 0.006). Moreover, the sCD27 concentrations had a significantly positive correlation with the level of CSF total protein (p = 0.030). Furthermore, the patients positive for AQP4-IgG (n = 26) seemed to have higher levels of sCD27 in their CSF (p = 0.069) than those negative for AQP4-IgG (n = 5). CONCLUSIONS: We revealed that the level of CSF sCD27 was elevated in NMOSD and correlated with NMOSD disease activity.

Brain Immunohistopathology in a Patient with Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy.

BACKGROUND: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a novel meningoencephalomyelitis. However, the pathogenesis of this disease is unclear. We therefore examined a brain biopsy from a patient with autoimmune GFAP astrocytopathy by immunohistopathology. METHODS: We examined brain biopsy sections from a patient with autoimmune GFAP astrocytopathy using hematoxylin and eosin (HE) and Luxol fast blue (LFB) staining, and immunostaining with antibodies for CD4, CD8, CD3, CD20, CD68, CD138, Neu-N, GFAP, myelin oligodendrocyte glycoprotein (MOG), and aquaporin-4 (AQP4). RESULTS: HE staining revealed extensive inflammatory cells (marked lymphocytes) around brain vessels, and LFB showed no signs of demyelination or axon loss. Immunohistochemical analysis showed CD3+ and CD4+ T cells cuffing around brain vessels, accompanied by CD8+ T cells, CD20+ B cells, and CD138+ plasma cells, while some macrophages (CD68+) were scattered throughout the brain parenchyma. There was no loss of AQP4 or MOG expression in this patient, while GFAP was abundantly expressed. CONCLUSIONS: These findings suggest that inflammatory cells, including T cells, B cells, plasma cells, and macrophages, are involved in autoimmune GFAP astrocytopathy. Demyelination and astrocyte loss may not necessarily occur in this disease.

Exacerbation of oxygen-glucose deprivation-induced blood-brain barrier disruption: potential pathogenic role of interleukin-9 in ischemic stroke.

Interleukin (IL)-9 exerts a variety of functions in autoimmune diseases. However, its role in ischemic brain injury remains unknown. The present study explored the biological effects of IL-9 in ischemic stroke (IS). We recruited 42 patients newly diagnosed with IS and 22 age- and sex-matched healthy controls. The expression levels of IL-9 and percentages of IL-9-producing T cells, including CD3+CD4+IL-9+ and CD3+CD8+IL-9+ cells, were determined in peripheral blood mononuclear cells (PBMCs) obtained from patients and control individuals. We also investigated the effects of IL-9 on the blood-brain barrier (BBB) following oxygen-glucose deprivation (OGD) and the potential downstream signaling pathways. We found that patients with IS had higher IL-9 expression levels and increased percentages of IL-9-producing T cells in their PBMCs. The percentages of CD3+CD4+IL-9+ and CD3+CD8+IL-9+ T cells were positively correlated with the severity of illness. In in vitro experiments using bEnd.3 cells, exogenously administered IL-9 exacerbated the loss of tight junction proteins (TJPs) in cells subjected to OGD plus reoxygenation (RO). This effect was mediated via activation of IL-9 receptors, which increased the level of endothelial nitric oxide synthase (eNOS), as well as through up-regulated phosphorylation of signal transducer and activator of transcription 1 and 3 and down-regulated phosphorylated protein kinase B/phosphorylated phosphatidylinositol 3-kinase signaling. These results indicate that IL-9 has a destructive effect on the BBB following OGD, at least in part by inducing eNOS production, and raise the possibility of targetting IL-9 for therapeutic intervention in IS.

Serum uric acid and anti-N-methyl-d-aspartate receptor encephalitis.

BACKGROUND: Uric acid (UA) levels are associated with autoimmune and neurodegenerative disorders, but their relationship with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is unknown. METHODS: UA levels were evaluated in 58 patients with anti-NMDAR encephalitis, and 58 age- and sex-matched healthy controls (CTLs). Follow-up evaluations of 30 out of the 58 patients with anti-NMDAR encephalitis were conducted 3 months after admission. Modified Rankin scale (mRS) scores and clinical and cerebrospinal fluid parameters were evaluated in all anti-NMDAR encephalitis patients. RESULTS: Serum UA levels were significantly lower in patients with anti-NMDAR encephalitis than those in CTLs (p < 0.001), and this was especially evident in patients with severe impairments (mRS ≥ 4 vs. <4, p = 0.004) or with limited response to treatment (vs. favourable outcome, p = 0.002). Follow-up evaluations revealed that serum UA levels normalized after treatment, with significantly increased serum UA levels (p < 0.001), and that mRS scores were significantly lower (p < 0.001) than those before treatment. In addition, serum UA levels were significantly associated with mRS scores (r = -0.463, p < 0.001). CONCLUSION: Our results showed that serum UA levels in patients with anti-NMDAR encephalitis are reduced during attacks compared with those in CTLs, are normalized after treatment, and are associated with disease severity.

Immune characteristics study of AG490, a signal pathway inhibitor, in EAE model mice.

Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination, axonal damage and progressive neurologic dysfunction in central nervous system (CNS). Many evidences show that B cells play an important role in the pathogenesis of MS. Follicular helper T cells (Tfh) secrete IL-21 to prompt the proliferation and differentiation of B cells in germinal center (GC) through clonal proliferation, somatic hypermutation, antibody class switching, antibody affinity maturation process. AG490 is a synthetic inhibitor to JAK-STAT signal pathway, which has been studied in inflammatory, tumor and autoimmune diseases. In the present study, the experimental mice were divided into 3 groups, vehicle group and AG490 group were given MOG35-55 to induce EAE model, from the third day after immunization, the mice were given vehicle or AG490 by intraperitoneal injection every other day. All mice were assessed clinical scores after immunization. On twentieth day, all mice were sacrificed, HE staining and solochrome cyanine staining were performed to evaluate inflammatory cells infiltration and demyelination, spleen sections were stained with PNA-FITC to analyze the difference in germinal center. Compared with vehicle group, the incidence of AG490 group was deceased, onset time was delayed, the severity was significantly reduced. The inflammatory cells and demyelination in AG490 group were lower than those in vehicle group. Immunofluorescence showed the fluorescence intensity of AG490 group was significantly lower than in the vehicle group, but higher than that of control group.

Risk factors, topographic patterns and mechanism analysis of intracranial atherosclerotic stenosis ischemic stroke.

BACKGROUND: The association between topographic patterns, risk factors and stroke mechanisms of ICAS in first-ever stroke remains unknown. METHODS: A large sample sized retrospective study was performed on first-ever ICAS ischemic stroke using DWI and MRA. RESULTS: Hypertension (60.92%), cigarette smoking (26.82%), MCA (76.65%) and multiple vessels (65.37%) stenosis, were the major factors favoring different mechanisms. Subcortical lesions were the most occurring topographic patterns (41.4%). The common mechanism was LBO (66.3%). Statistical analysis showed a significant relationship between lesion patterns and mechanisms (r = 0.384, P = 0.001). Single mechanism had the higher apoB/apoAI ratio (P = 0.005) and levels of plasma apoB (P = 0.007) compared with multiple mechanisms. The anterior circulation stroke were more multiple mechanisms as compared to the posterior circulation stroke (P = 0.001). LBO was more prevalent in posterior circulation stroke than in anterior circulation stroke (P = 0.001). CONCLUSIONS: The topographic patterns of ischemic lesions is helpful in early identification of different mechanisms of ICAS. Monitoring apoB and apoB/apoA1 may help to predict the mechanism of stroke with ICAS. The prevalence of mechanisms differ between anterior and posterior circulation stroke with ICAS.

Low serum vitamin D levels and anti-N-methyl-d-aspartate receptor encephalitis: A case-control study.

BACKGROUND: Low vitamin D levels are associated with autoimmunity, but the relationship with anti-N-Methyl-d-aspartate receptor (anti-NMDAR) encephalitis is unknown. METHODS: 25(OH) D levels and clinical and cerebrospinal fluid parameters were evaluated in 30 patients with anti-NMDAR encephalitis and compared with 90 age-, sex-, and season-matched healthy controls. RESULTS: 25(OH)D levels were lower in patients with anti-NMDAR encephalitis compared to controls (43.89 ± 17.91 vs 64.24 ± 24.38 nmol/L, p < 0.001), especially for females (vs males, p = 0.008), aged ≤30 years (vs > 30 years, p = 0.002), severe impairment (mRS ≥ 5) (vs mRS < 5, p = 0.018), and limited treatment responses (vs favorable treatment, p = 0.02). Serum 25(OH)D levels were associated with age (r = 0.393, p = 0.032), and mRS (r = -0.417, p = 0.022). CONCLUSIONS: Our data showed that serum 25(OH)D levels were reduced in patients with anti-NMDAR encephalitis.

Serum concentration of CD40L is elevated in inflammatory demyelinating diseases.

It is believed that auto-inflammatory activity, including cellular and humoral immunity responses, especially T cell-B cell collaboration, is one of the most important components of the pathogenesis of inflammatory demyelinating disease. CD40L is critical for T cell-B cell collaboration. Actually, serum CD40L levels have been shown to increase in MS. In the present study, serum CD40L levels were measured by an enzyme-linked immunosorbent assay (ELISA) in NMO (n=27) and MS (n=19) patients and controls (n=14). We revealed elevation of CD40L in NMO patients, and discovered a correlation between CD40L and humoral immunity in inflammatory demyelinating disease.

Involvement of the optic nerve in mutated CSF1R-induced hereditary diffuse leukoencephalopathy with axonal spheroids.

BACKGROUND: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration and caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. Involvement of the optic nerves in hereditary diffuse leukoencephalopathy is rare. CASE PRESENTATION: We report the case of a 30-year-old Chinese woman with HDLS, who carried a heterozygous c.2345 G > A (p.782Arg > His) mutation in exon 18 of CSF1R. She developed a gradual decline in motor ability, as well as cognitive and visual function, over the course of 4 months. Brain T2 fluid-attenuated inversion recovery-weighted magnetic resonance imaging revealed high signal lesions in the bilateral frontoparietal and periventricular deep white matter. Optical coherence tomography showed that the right peripapillary retinal nerve fiber layer was atrophic in the temporal quadrant while the left peripapillary retinal nerve fiber layer was thin in the temporal superior quadrant. CONCLUSIONS: A diagnosis of HDLS should be considered in patients with white matter lesions and optic nerves injury upon magnetic resonance imaging that mimics progressive multiple sclerosis.

Linear lesions may assist early diagnosis of neuromyelitis optica and longitudinally extensive transverse myelitis, two subtypes of NMOSD.

PURPOSE: To investigate the relationship between linear lesions (LL) and the development of longitudinally extensive spinal cord lesions (LESCL) in Chinese patients with neuromyelitis optica or longitudinally extensive transverse myelitis. METHOD: The clinical records of 143 patients with these conditions were reviewed. Forty-one patients with LL were divided into three groups according to the order of appearance of LL and LESCL (simultaneously [n=10], LL first [n=26], or LESCL first [n=5]). The remaining 102 patients without LL were used as a control group. RESULTS: Patients who developed LL first demonstrated a lower annualized relapse rate than those in the simultaneous group (1.00 [0.23-10.00] vs. 4.38 [0.60-6.67], p=0.017) and the control group (1.00 [0.23-10.00] vs. 2.00 [0.24-10.00], p=0.007). Among all patients with LL, there were significantly more who developed them before LESCL than those who developed them after LESCL (p<0.001) or at the same time (p=0.008). The mean time before the appearance of LESCL was 9.0months (2-35months) in the 'LL-first' group, which was shorter than that in the control group (12months [1-60months], p=0.010). The rate of positivity for anti-aquaporin 4 IgG antibodies was higher in patients with LL compared with controls (90.24% vs. 64.71%, p=0.002). CONCLUSION: LL may be a precursor to LESCL and assist early diagnosis of neuromyelitis optica and longitudinally extensive transverse myelitis.

Predictors associated with stroke after coronary artery bypass grafting: a systematic review.

BACKGROUND: Stroke is a major cause of morbidity and mortality after coronary artery bypass grafting (CABG). The purpose of this systematic review was to evaluate the predictors of perioperative stroke after CABG. METHODS: We reviewed the published literature on prognostic factors for perioperative stroke after CABG in articles using multivariate regression models. The statistical validity of prognostic models and a qualitative synthesis were performed. RESULTS: We identified 14 studies. The methodological quality of study reporting was variable. Overall, the incidence of stroke after CABG was 1.1-5.7%. About 37-59% of strokes occurred early (intraoperatively). No validated stroke outcome scale was used to assess morbidity and mortality in any of the included studies. Advanced age, prior (before CABG) cerebrovascular disease/stroke, prior carotid artery stenosis, prior peripheral vascular disease, prior unstable angina, and prolonged cardiopulmonary bypass time were found to be the most consistent independent predictors of perioperative stroke after CABG. Postoperative atrial fibrillations were found to be the most consistent independent variables associated with postoperative stroke after CABG. No association was found with hypercholesterolemia, prior myocardial infarct, and smoking. Other risk factors, such as gender, prior hypertension, diabetes mellitus, congestive heart failure, and chronic renal failure, showed inconsistent results. CONCLUSIONS: Seven variables (advanced age, prior cerebrovascular disease/stroke, prior carotid artery stenosis, prior peripheral vascular disease, prior unstable angina, prolonged cardiopulmonary bypass time, and postoperative atrial fibrillation), representing and high atherosclerotic burden, were found to be associated with more perioperative stroke events. Stroke assessment scales should be included to enable a detailed description of stroke morbidity post CABG. Lessons learned from the present study should also help to improve the quality and relevance of future studies on prognostic factors in stroke after CABG.

[Correlation of AQP4 gene polymorphism with NMO clinical phenotypes and its underlying mechanism].

OBJECTIVE: To explore the correlation between aquaporin-4 (AQP4) gene single nucleotide polymorphism (SNP) and clinical phenotypes of neuromyelitis optica (NMO) and its underlying mechanism. METHODS: Eight SNPs in AQP4 gene regulatory region were selected and genotyped for 208 anti-AQP4 autoantibodies (NMO-IgG) seropositive cases during January 2010 to January 2014 and 204 healthy subjects. Then the correlation was further analysed between genotypes and NMO phenotypes. And the effect of microRNA (miRNA) on the expression of AQP4 gene was examined by dual-luciferase reporter technique. RESULTS: The A/T genotype of rs1058424 (50.61% vs 70.45%, OR = 0.430, 95% CI 0.210-0.880) and C/T (50.00% vs 68.18%, OR = 0.467, 95%CI 0.231-0.994) genotype of rs3763043 in 3'-UTR were correlated with longitudinal extensive transverse myelitis; the A/T genotype of rs1058424 (46.72% vs 66.28%, OR = 0.525, 95% CI 0.276-0.999) and A/C genotype of rs335929 (45.08% vs 58.14%, OR = 0.527, 95% CI 0.281-0.987) in 3'-UTR as well as C/T genotype of rs151244 (50.82% vs 69.77%, OR = 0.450, 95% CI 0.230-0.881) in promoter 0 region were correlated with optic neuritis. The polymorphism of rs6508459 in 3'-UTR and rs3763040 in intron region were correlated with concurrent systemic autoimmune diseases (P = 0.012 and 0.023 respectively).miRNA 323-3p could regulate AQP4 gene expression.However, variation in SNP rs1058424 failed to affect this regulation. CONCLUSION: SNP in 3'-UTR of AQP4 gene may be associated with NMO phenotypes.miRNA 323-3p may participate in the pathogenesis of NMO by binding to certain SNP sites in 3'-UTR of AQP4 gene and regulating its expression.