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Unacylated ghrelin (UAG), the unacylated form of ghrelin, accounts for 80%-90% of its circulation. Accumulated studies have pointed out that UAG may be used to treat metabolic disorders. This study aimed to investigate the effect of intestinal perfusion of UAG on metabolically associated fatty liver disease (MAFLD) induced by a high-fat diet and its possible mechanisms. Neuronal retrograde tracking combined with immunofluorescence, central administration of a glucagon-like peptide-1 receptor (GLP-1R) antagonist, and hepatic vagotomy was performed to reveal its possible mechanism involving a central glucagon-like peptide-1 (GLP-1) pathway. The results showed that intestinal perfusion of UAG significantly reduced serum lipids, aminotransferases, and food intake in MAFLD rats. Steatosis and lipid accumulation in the liver were significantly alleviated, and lipid metabolism-related enzymes in the liver were regulated. UAG upregulated the expression of GLP-1 receptor (GLP-1R) in the paraventricular nucleus (PVN) and GLP-1 in the nucleus tractus solitarii (NTS), as well as activated GLP-1 neurons in the NTS. Furthermore, GLP-1 fibers projected from NTS to PVN were activated by the intestinal perfusion of UAG. However, hepatic vagotomy and GLP-1R antagonists delivered into PVN before intestinal perfusion of UAG partially attenuated its alleviation of MAFLD. In conclusion, intestinal perfusion of UAG showed a therapeutic effect on MAFLD, which might be related to its activation of the GLP-1 neuronal pathway from NTS to PVN. The present results provide a new strategy for the treatment of MAFLD. NEW & NOTEWORTHY Intestinal perfusion of UAG, the unacylated form of ghrelin, has shown promising potential for treating MAFLD. This study unveils a potential mechanism involving the central GLP-1 pathway, with UAG upregulating GLP-1R expression and activating GLP-1 neurons in specific brain regions. These findings propose a novel therapeutic strategy for MAFLD treatment through UAG and its modulation of the GLP-1 neuronal pathway.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system primarily mediated by CD4 + T helper cells. This study investigated the dynamic changes of natural killer (NK) cells and follicular T helper (Tfh) cells and their associations in relapsing-remitting MS patients. The findings revealed inverse relationships between NK cells and CD4 + T cells or Tfh cells. Specifically, CD56 dim NK cells, not CD56 bright NK cells, were negatively correlated with CD4 + T cells and Tfh cells. However, no significant correlations were found between NK cells and sNfL levels or EDSS scores. The ratio of CD56 dim NK cells to circulating Tfh (cTfh) cells demonstrated superior discriminatory ability in distinguishing relapsing MS patients from healthy controls (HCs) and remitting patients, as determined by receiver operating characteristic (ROC) analysis. Following treatment with immunosuppressants or disease-modifying therapies (DMTs), a significant increase in the CD56 dim NK/cTfh ratio was observed. These findings suggest that the CD56 dim NK/cTfh ratio holds promise as a prognostic indicator for clinical relapse and treatment response in MS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objective: This study aims to evaluate the short-term safety of inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in Chinese patients with central nervous system inflammatory demyelinating diseases (CNS IDDs)., Methods: A web-based survey was conducted among patients with CNS IDDs from April 15 to 19, 2022 in China. In total, 645 patients with CNS IDDs were identified, including 425 patients with multiple sclerosis (MS), 194 with neuromyelitis optica spectrum disorder (NMOSD), and 26 with other CNS IDDs. The questionnaire consisted of demographic data, clinical records, history of SARS-CoV-2 vaccination, and vaccination-related symptoms within one month after vaccination. The demographic data, clinical information, and relapse rates between vaccinated and non-vaccinated patients were compared., Results: Among 645 patients with CNS IDDs, 78 were vaccinated and 567 were non-vaccinated with the vaccination rate of 12.1 %. Compared to non-vaccinated group, a lower percentage of patients on DMDs therapy (41.0 % vs. 71.8 %, P  < 0.001) and an increased proportion of patients with other vaccination in past 3 years (17.9 % vs. 4.8 %, P  < 0.001) were observed in vaccinated group. Six patients experienced a relapse within 30 days of a vaccination. Additionally, vaccine-associated relapse rates in vaccinated patients did not significantly differ from these in non-vaccinated patients among 2020, 2021, and from January 1 to October 1, 2022., Conclusions: No increased risk of vaccination-associated relapses among Chinese patients with CNS IDDs indicated that inactivated SARS-CoV-2 vaccines appear to be safe for this population., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Objective: To address a novel lower-dose rituximab (RTX) therapy strategy based on our clinical experience and assess its efficacy and safety in neuromyelitis optica spectrum disorder (NMOSD)., Methods: A multicenter, open-label, self-controlled, prospective follow-up study. Totally, 108 NMOSD patients were enrolled and a lower-dose RTX strategy was applied including 100 mg weekly for 3 weeks and then reinfusions every 6 months. Annualized relapse rate (ARR), the expanded disability status scale (EDSS) score and length of spinal cord lesions were included to evaluate the efficacy. Side effects were recorded to assess the safety profile., Results: Of 108 patients, 80 (74.1%) initiated low-dose RTX therapy immediately after acute attack treatment and 33 (30.6%) initiated it after the first attack. During a median treatment period of 35.5 (22.0-48.8) months, significant decreases were observed in median ARR (1.1 [0.8-2.0] versus 0 [0-0.2], p < 0.001), EDSS score (3.5 [2.5-4.0] versus 2.0 [1.0-3.0], p < 0.001) and spinal cord lesion segments (5.0 [4.0-8.0] versus 3.0 [1.0-6.0], p < 0.001). The cumulative risk of relapses significantly decreased during the post- versus pre-RTX period (HR 0.238, 95%CI 0.160-0.356, p < 0.001) and on early therapy initiated within 24 months after disease onset versus delayed therapy (HR 0.506, 95%CI 0.258-0.994, p = 0.041). No serious side effects were recorded and all the subjects did not discontinue treatment due to RTX-related side effects., Conclusion: Our research provided evidence supporting the lower-dose RTX strategy in treating NMOSD and reopened the issues of optimal dosage and therapy initiation timing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Ren, Lu, Liu, Li, Wu, Xu, Wu, Lei, Ma, Zhao, Bai, Li and Guo.)

Background and Objectives: Existing evidence indicates anti-GABA B receptor encephalitis (GABA B R-E) seems to occur more commonly later in life, yet the age-associated differences in clinical features and outcomes are not well determined. This study aims to explore the demographic, clinical characteristics, and prognostic differences between late-onset and early-onset GABA B R-E and identify predictors of favorable long-term outcomes., Methods: This is an observational retrospective study conducted in 19 centers from China. Data from 62 patients with GABA B R-E were compared between late-onset (aged 50 years or older) and early-onset (younger than 50 years) groups and between groups with favorable outcomes (modified Rankin scale (mRS) ≤ 2) and poor outcomes (mRS >2). Logistic regression analyses were applied to identify factors affecting long-term outcomes., Results: Forty-one (66.1%) patients experienced late-onset GABA B R-E. A greater proportion of males, a higher mRS score at onset, higher frequencies of ICU admission and tumors, and a higher risk of death were demonstrated in the late-onset group than in the early-onset group. Compared with poor outcomes, patients with favorable outcomes had a younger onset age, a lower mRS score at onset, lower frequencies of ICU admission and tumors, and a greater proportion with immunotherapy maintenance for at least 6 months. On multivariate regression analysis, age at onset (OR, 0.849, 95% CI 0.739-0.974, p = 0.020) and the presence of underlying tumors (OR, 0.095, 95% CI 0.015-0.613, p = 0.013) were associated with poorer long-term outcomes, whereas immunotherapy maintenance for at least 6 months was associated with favorable outcomes (OR, 10.958, 95% CI 1.469-81.742, p = 0.020)., Discussion: These results demonstrate the importance of risk stratification of GABA B R-E according to age at onset. More attention should be paid to older patients especially with underlying tumors, and immunotherapy maintenance for at least 6 months is recommended to achieve a favorable outcome., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Rituximab (RTX) is an extensively used off-label drug for multiple sclerosis (MS), whereas the induction and maintenance regimens vary widely among studies. Few data are available on efficacy and safety of repeated low-dose RTX therapy in MS patients., Objective: This study aimed to evaluate the efficacy and safety of repeated low-dose RTX therapy for relapsing-remitting MS (RRMS), the most common form of MS affecting approximately 85% of patients., Methods: Nine RRMS patients were enrolled and the medical records were retrospectively reviewed. RTX at 100 mg per week for three consecutive weeks was used as induction therapy. Maintenance therapy was reinfusions of RTX at 100 mg every 6 months during the first year, followed by 100 mg every 6 to 12 months. Main outcome measures included annualized relapse rate (ARR), expanded disability status scale (EDSS) score, and T2 lesion burden on MRI for evaluating the efficacy of low-dose RTX regimen. Meanwhile, adverse events (AEs) were recorded to assess the safety of repeated RTX infusions., Results: All patients were females with an average onset age of 25.4 ± 6.7 years. The median disease duration before the first RTX infusion was 56 (range, 3-108) months and the median follow-up period was 30 (range, 15-40) months. No relapses were recorded in all patients after RTX therapy. Repeated low-dose RTX therapy resulted in a dramatic reduction of median ARR (pre-RTX vs post-RTX, 1.1 vs 0, p = 0.012), median EDSS score (2.0 vs 0, p = 0.007), and the number of T2 lesions on MRI (35.6 ± 18.0 vs 29.4 ± 18.1, p = 0.001). A total of 35 episodes of AEs occurred during repeated low-dose RTX therapy, and all of them were mild and transient., Conclusion: Repeated low-dose RTX therapy is cost-effective for RRMS patients and shows a good safety profile. It may be a promising option for those having no access or poor response to first-line disease-modified drugs (DMDs), particularly in low- or middle-income countries., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Monocytes in peripheral blood and sciatic nerves play vital roles in immune-mediated neuropathies such as Guillain-Barré syndrome (GBS). Different subpopulations of monocytes, including classical and non-classical, exhibit distinct functions as well as phenotypic conversion potentials. However, the mechanisms underlying their development during immune-mediated neuropathy remain unclear. Notch signaling participates in monocyte differentiation and function. In this study, we used a myeloid-specific Notch signaling activation transgenic mouse (NIC cA ) and investigated the role of Notch signaling in monocytes during experimental autoimmune neuritis (EAN) in a mouse model of GBS. Clinical score assessment and histopathological examination revealed that sciatic nerve injury was attenuated in NIC cA EAN mice compared to that in control mice. Flow cytometry and immunofluorescence staining suggested that increasing Ly6C lo monocytes in the peripheral blood and nerve tissue might contribute to the alleviation of neuritis in NIC cA mice. Meanwhile, an in vitro study suggested that bone marrow-derived monocytes from NIC cA mice are more inclined toward Ly6C lo cells than Ly6C hi cells. Differential expression of monocyte development-associated genes was detected in NIC cA and wild-type mice using RNA sequencing. The expression of Nr4a1 is upregulated remarkably when Notch signaling is activated. Treatment with Nr4a1 antagonist on NIC cA mice-derived monocytes compromise their Ly6C lo tendency. Consistently, a relationship between monocyte conversion and disease severity was observed in blood samples from patients with GBS. In conclusion, our current study showed that monocyte conversion modulated by Notch signaling plays an essential role in the EAN mouse model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Eugenol, an active ingredient of many medicinal aromatic plants, has been proved to have the hypolipidemic effect, but its potential mechanism of action is still unknown. This study aimed to investigate whether eugenol regulates liver lipid accumulation in high-fat diet (HFD) induced nonalcoholic fatty liver disease (NAFLD) rats via the gut-brain-liver axis involving glucagon-like peptide-1 (GLP-1). Hepatic vagotomy was performed in NAFLD rats to determine the role of eugenol in regulating hepatic lipid accumulation via vagus nerve. The results showed that after eight weeks of eugenol administration in NAFLD rats, serum total cholesterol (TC), triglyceride (TG) and hepatic TG decreased. However, eugenol showed no significant effect on the increased food intakes and weight gain caused by the HFD. Eugenol promoted the secretion of GLP-1 into the blood, increased GLP-1 receptor (GLP-1R) expression in the duodenum, liver, arcuate nucleus (ARC) and paraventricular nucleus (PVN), increased c-fos expression in the nucleus tractus solitarii (NTS), and promoted ZO-1 and occludin expression in duodenum. Furthermore, steatosis and lipid accumulation were significantly alleviated. Hepatic vagotomy partially attenuated the improvement of eugenol in hepatic lipid accumulation in NAFLD rats. In conclusion, eugenol regulates hepatic lipid metabolism via a gut-brain-liver axis involving in GLP-1, providing a new strategy for the treatment of NAFLD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) has been considered a diagnostic marker for patients with demyelinating disease, termed "MOG-IgG associated disorder" (MOGAD). Recently, the coexistence of MOG-IgG and other neuronal or glial antibodies has attracted extensive attention from clinicians. In this article, we systematically review the characteristics of MOG-IgG-related antibody coexistence syndrome., Methods: Two authors independently searched PubMed for relevant studies published before October 2021. We also manually searched the references of each related article. The appropriateness of the included studies was assessed by reading the titles, abstracts, and full texts if necessary., Results: Thirty-five relevant publications that met our inclusion criteria were finally included, of which fourteen were retrospective studies and twenty-one were case reports. A total of 113 patients were reported to show the coexistence of MOG-IgG and neuronal or glial antibodies. Additionally, 68.14% of patients were double positive for MOG-IgG and N-Methyl-D-Aspartate Receptor-IgG (NMDAR-IgG), followed by 23.01% of patients who were double positive for MOG-IgG and aquaporin4-IgG (AQP4-IgG). Encephalitis was the predominant phenotype when MOG-IgG coexisted with NMDAR-IgG, probably accompanied by imaging features of demyelination. Patients with dual positivity for MOG-IgG and AQP4-IgG experienced more severe disease and more frequent relapses. The coexistence of MOG-IgG and antibodies other than NMDAR-IgG and AQP4-IgG was extremely rare, and the clinical presentations were diverse and atypical. Except for patients who were double positive for MOG-IgG and AQP4-IgG, most patients with multiple antibodies had a good prognosis., Conclusions: MOG-IgG may coexist with neuronal or glial antibodies. Expanded screening for neuronal or glial antibodies should be performed in patients with atypical clinical and radiological features., Competing Interests: The authors declare no conflict of interest.

Objectives: Diabetic gastroparesis (DGP) is one of the main complications of diabetes, and more than half of diabetes cases are accompanied by gastroparesis. This study aims to explore the effect of Atractylodes chinensis volatile oil (ACVO) on DGP rats., Materials and Methods: The rats were injected with STZ combined with a high-sugar and high-fat diet in an irregular manner to establish the DGP model. ACVO at different doses (9.11 mg/kg, 18.23 mg/kg, and 36.45 mg/kg) were given by intragastric administration. A mixture of cisapride and metformin was used as the positive control. At the end of the experiment, gastric emptying and intestinal propulsion were determined. Then the tissue samples and blood were taken from each group for serum analysis, western blot and immunopathological examination., Results: After treatment with ACVO, body weight increased and blood glucose decreased when compared with rats in the DGP group. Gastric emptying and intestinal propulsion were accelerated, and gastric acid secretion increased. The serum insulin-like growth factor-1 (IGF-1) level was increased. Protein expressions and positive cells of IGF-1 receptor (IGF-1R), acetylcholine transferase (CHAT), and stem cell factors (SCF) in the stomach were significantly increased determined by western blot and immunofluorescence staining. The morphology and the number of interstitial cells of Cajal (ICCs) in the stomach were restored, determined by hematoxylin and eosin staining and immunohistochemical staining, respectively., Conclusion: ACVO effectively alleviated DGP in rats, and its mechanism may be related to the up-regulation of IGF-1/IGF-1R signaling., Competing Interests: None of the authors has personal or financial conflicts of interest.

Background and Aim: Guillain-Barré syndrome (GBS) is one of the most common causes of acute flaccid paralysis. A timely assessment of this disease condition and its treatments are of vital importance to patients diagnosed with GBS. The purpose of this study is to investigate the variation trend of neutrophils along with disease courses and assess the prognostic value of serum low-density neutrophils (LDNs) in the acute-onset and recurrence of GBS., Methods: A total of 176 GBS patients were recruited. Patients were evaluated with Medical Research Council (MRC) sum score and the Hughes Functional Grading Scale score upon admission. Peripheral blood samples were collected for routine testing. Flow cytometry analysis was performed to identify LDNs. All patients were followed up to collect disease condition data., Results: The total neutrophil ratios and counts were significantly higher in patients with acute-onset GBS compared to healthy controls (HCs). These counts/ratios decreased during remission and re-elevated in recurrent GBS patients. However, no correlation was observed between the total neutrophil counts/ratios and the MRC sum score. The LDNs collected from different GBS courses were identified using flow cytometry. The counts and ratios were significantly higher in acute-onset GBS and recurrent GBS compared to HCs and patients in remission. The LDN counts/ratios displayed a negative correlation with the MRC sum scores in acute-onset GBS and recurrent GBS., Conclusion: Our findings suggest that LDN counts/ratios are positively correlated with the acute-onset and recurrence of GBS and its severity. Therefore, LDNs might serve as an accessible prognostic indicator for disease progression monitoring., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Objective: To explore the effect of individualized blood pressure (BP)-lowering treatment on the outcomes of elderly patients with severe intracerebral hemorrhage (ICH)., Methods: We performed an exploratory analysis of Controlling Hypertension After Severe Cerebrovascular Event (CHASE) trial, which was a multicenter, randomized, controlled clinical trial. Patients with severe ischemic or hemorrhagic stroke (defined as GCS ≤ 12 or NIHSS ≥ 11) were randomized into individualized versus standard BP-lowering treatment in CHASE trial. In this exploratory analysis, patients with severe ICH were included. The primary outcome was the percentage of patients with 90-day functional independence defined as modified Rankin Scale (mRS) ≤2., Results: We included 242 patients with severe ICH in the present analysis, consisting of 142 patients aged <65 years and 100 patients aged ≥65 years. There were significant differences between patients aged ≥65 years and <65 years in the proportion of functional independence (47.9% vs. 15.0%, P < 0.001) and good outcome (73.9% vs. 50.0%, P < 0.001) at day 90. In patients aged ≥65 years, the adjusted individualized BP-lowering treatment had an unequivocal effect on the functional independence at day 90 (21.6% vs. 8.2%, odds ratio [OR]: 4.309, 95% confidence interval [CI]: 1.040-17.859, P = 0.044) and improved the neurological deficits at discharge (∆ NIHSS ≥ 4: 64.7% vs. 34.7%, OR: 4.300, 95% CI: 1.599-11.563, P = 0.004)., Interpretation: Compared with the younger counterparts, the elderly patients (≥65 years) with acute severe ICH might benefit more from individualized BP-lowering treatment., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: The stroke induced by ischemia of brain remains high incidence and death rate. The study wanted to confirm the effects of Quaking 6 (QKI 6) on the protection role in neurons of rat model of cerebral ischemia/reperfusion injury (CIRI)., Material and Methods: The rat model with CIRI induced by middle cerebral artery occlusion was well established and rat neurons were isolated to characterize the effects of QKI 6 mediated by sirtuin 1 (SIRT1) on synthesis of triglyceride in neuron and neuronal apoptosis via activation of SIRT1-peroxisome proliferater-activated receptor (PPAR)γ- peroxisome proliferator-activated receptor coactivator (PGC)-1α signaling pathway., Results: The expression levels of SIRT1 or QKI 6, and acetylation level of QKI 6 were decreased in neurons of rat model with CIRI. QKI 6 deacetylated and mediated by SIRT1 that contributed to suppressing the progression of neuronal apoptosis in rat through promoting synthesis of triglyceride in vivo and in vitro via SIRT1-PPARγ-PGC-1α signaling pathway, then inhibiting CIRI., Conclusions: Our results demonstrated SIRT1 deacetylates QKI 6, the RNA-binding protein, that affects significantly the synthesis of triglyceride in neurons of CIRI rat model. Moreover, it activated transcription factor peroxisome proliferator-activated receptorγ coactivator-1α (PGC-1α) through post-transcriptional regulation of the expression of PPARγ, and further enhanced synthesis of triglyceride, thereby restrained the progression of neural apoptosis and CIRI., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: The optimal blood pressure lowering target in the acute phase of severe stroke is uncertain. Our aim was to compare the efficacy and safety of individualized blood pressure lowering with standard blood pressure lowering in severe stroke., Methods: Five-hundred consecutive patients with acute severe stroke and elevated BP were recruited from 26 Chinese hospitals. Eligible patients were randomized into an individualized blood pressure lowering group (with 10-15% reduction in systolic blood pressure from admission level or standard blood pressure lowering group (with a target SBP of <200 mm Hg in acute ischemic stroke and <180 mm Hg in intracerebral hemorrhage). The primary outcome was the proportion of patients with a poor functional outcome at day 90 of enrolment., Results: Of 483 participants included in the analysis, 242 received individualized blood pressure lowering treatment and 241 received standard treatment. The primary outcome event was observed in 71.1% of the participants in the individualized treatment group and in 73.4% of the standard treatment group (odds ratio with individualized treatment for primary outcome, 0.75; 95% confidence interval, 0.47 to 1.19; p  = 0.222). The rates of serious adverse events in the two groups were similar (27.7% vs. 28.2%)., Conclusions: In patients with acute severe stoke, individualized blood pressure lowering treatment did not significantly reduce the rate of three-month death or dependence., Trial Registration: Clinicaltrials.gov, NCT02982655. Registered in 5 December 2016, https://clinicaltrials.gov/ct2/show/NCT02982655.

The influence of blood pressure variability (BPV) on outcomes in patients with severe stroke is still largely unsettled. Using the data of CHASE trial, the authors calculated the BPV during the acute phase and subacute phase of severe stroke, respectively. The primary outcome was to investigate the relationship between BPV and 90-day modified Rankin scale (mRS) ≥ 3. The BPV was assessed by eight measurements including standard deviation (SD), mean, maximum, minimum, coefficient of variation (CV), successive variation (SV), functional successive variation (FSV), and average real variability (ARV). Then, the SD of SBP was divided into quintiles and compared the quintile using logistic regression in three models. The acute phase included 442 patients, and the subacute phase included 390 patients. After adjustment, six measurements of BPV during the subacute phase rather than acute phase were strongly correlated with outcomes including minimum (odds ratio [OR]: 0.83, 95% confidence interval [CI]: 0.69-0.99, p = .037), SD (OR: 1.10, 95% CI: 1.03-1.17, p = .007), CV (OR: 1.12, 95% CI: 1.03-1.23, p = .012), ARV (OR: 1.13, 95% CI: 1.05-1.20, p < .001), SV (OR: 1.09, 95% CI: 1.04-1.15, p = .001), and FSV (OR: 1.12, 95% CI: 1.05-1.19, p = .001). In the logistic regression, the highest fifth of SD of SBP predicted poor outcome in all three models. In conclusion, the increased BPV was strongly correlated with poor outcomes in the subacute phase of severe stroke, and the magnitude of association was progressively increased when the SD of BP was above 12., (© 2020 Wiley Periodicals LLC.)

Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been considered to be closely relevant to an inflammatory demyelinating disease of the central nervous system (CNS). Glial fibrillary acidic protein (GFAP) immunoglobulin G (IgG) has been identified as a biomarker for a novel autoimmune astrocytopathy. However, coexistence of MOG-IgG and GFAP-IgG is extremely unusual and only one patient has been described with simultaneous presence of MOG-IgG in serum and GFAP-IgG in cerebrospinal fluid (CSF). Herein, we reported the first case of overlapping syndrome of MOG-IgG-associated disease (MOG-AD) and autoimmune GFAP astrocytopathy in whom MOG-IgG and GFAP-IgG were detected both in serum and CSF. A 20-year-old male patient was referred to our department with the presentation of decreased vision, diplopia and weakness of right limb with unknown reasons. Magnetic resonance imaging (MRI) revealed multiple intracranial lesions presenting hypointensity on T1-weighted images, hyperintensity on T2-weighted and FLAIR images and patchy contrast enhancement. MOG-IgG and GFAP-IgG were detected both in serum and CSF, and the titers of both antibodies fluctuated with the severity of disease. Treatment strategy employing intravenous methylprednisolone pulse therapy followed by oral prednisone with slow tapering resulted in an improvement of his symptoms and a sustained remission. Coexistence of MOG-IgG and GFAP-IgG with distinct underlying pathogeneses necessitates the recommendations to screen all recognized pathogenic antibodies against CNS antigens when an autoimmune disease is suspected, since it shows great significance for definite diagnosis of disease and treatment strategy options.

Background: It is well demonstrated that immunosuppressants can reduce, but not eliminate the risk of generalized development in ocular myasthenia gravis (OMG). In this study, we aimed to explore the predictive factors of generalized conversion of OMG patients who received immunosuppressive treatments., Methods: OMG patients under immunosuppressive treatments in Tangdu Hospital from June 2008 to June 2012 were retrospectively reviewed. Baseline clinical characteristics were documented. Patients were followed up regularly by face-to-face interview and the main outcome measure was generalized conversion. The logistic regression analysis was performed to determine the predictive factors of generalization of OMG., Results: Two hundred twenty-three eligible OMG patients completed the final follow-up visit and 38 (17.0%) progressed to generalized MG (GMG) at a median time to generalization of 0.9 year. Patients with adult onset and positive repetitive nerve stimulation (RNS) of facial or axillary nerve had higher conversion rate than those with juvenile onset and negative RNS (p = 0.001; p = 0.019; p = 0.015, respectively). Adult-onset patients converted earlier than juvenile-onset OMG patients (p = 0.014). Upon multivariate logistic regression analysis, age of onset (Odds ratio [OR] 1.023, 95% confidence interval [CI] 1.006-1.041, p = 0.007) and positive facial nerve RNS (OR 2.826, 95%CI 1.045-5.460, p = 0.038) were found to be positively associated with generalized development. Moreover, an obviously negative association was found for disease duration (OR 0.603, 95%CI 0.365-0.850, p = 0.019)., Conclusions: Age of onset, disease duration and facial nerve RNS test can predict generalized conversion of OMG under immunosuppressive therapy. Adult-onset, shorter disease duration and facial nerve RNS-positive OMG patients have a higher risk of generalized development.

Neuromyelitis optica (NMO), also known as Devic's disease, is a classical autoimmune disorder of the central nervous system (CNS). The relapsing-remitting disease course contributes to application of a variety of immunosuppressants to prevent further relapses after high-dose methylprednisolone pulse therapy for acute attacks. Azathioprine is one of the most widely used immunosuppressive drugs during the remission stage of NMO due to its good efficacy and favorable side-effect profile. Even if, enough attention should be paid to some rare but devastating adverse events, such as pellagra. Herein, we reported that a well-nourished patient experienced serious pellagra while receiving oral azathioprine for treating her NMO. Moreover, literature on azathioprine-induced pellagra was reviewed to raise concerns regarding patient safety., (Copyright © 2018. Published by Elsevier B.V.)

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) have been proved to be T cell-mediated autoimmune diseases. Recent researches indicate that humoral immunity is also involved in the pathogenesis of these disorders. T follicular helper (Tfh) cells are critical for B cell differentiation and antibody production. However, the role of Tfh cells in MS and EAE remains unclear. Here, we found elevated frequencies of CD4 + CXCR5 + PD-1 + Tfh-like cells in both MS patients and EAE. In EAE mice, Tfh-like cells, together with B cells, were found in the ectopic lymphoid structures in spinal cords. Moreover, Tfh-like cells promoted the antibody production via IL-21/IL-21R and CD40 ligand/CD40 interaction and the synergy effect of STAT3 and non-canonical NF-κB signaling pathway inside B cells. Moreover, adoptive transfer of Tfh-like cells could increase the severity and delay the remission of EAE. In conclusion, our data indicate that Tfh-like cells contribute to the pathogenesis of EAE.

Objectives: Multiple sclerosis (MS) is the most prevalent autoimmune disease of the central nervous system, and is characterized by inflammation and myelin damage. The immune system initiates the autoimmune response, although the mechanisms of neuronal damage have not been elucidated. The purpose of the present study was to investigate autoreactive CD4+ and CD8 + T lymphocytes, in conjunction with other inflammatory cells and cytokines in active MS lesions., Methods: EAE animal models was established by plantar injections of MBP (200 μg per rat). Purified CD4+ or CD8+ T-cells were isolated from heparinized peripheral blood (EAE animals and control animals) via negative selection. To examine effects of presence of autoreactive CD4+ and CD8+ T lymphocytes, we carried out ELISA, Western blot analysis and TUNEL. In addition, we examined the direct effects of various factors on neuronal cell death using MTT assay., Results: The data revealed that CD8+ T-cells were more toxic to neurons compared to CD4+ T-cells, in both the MBP and EAE conditions. Bax was greater increased when neurons were co-cultured with CD8+ T-cells in the MBP group. There is a significant increase in IL-17 secretion by CD4+ T-cells in both the MBP group and EAE group. Neuronal viability were affected by Perforin (1.5 μg/mL)., Conclusion: The present study extends previous research by demonstrating the role of CD8+ T-cells in MS and supports perforin secretion by CD8+ T-cells as a potential therapeutic factor. Furthermore, we determined that CD4 + T-cells can enhance CD8 + T-cell neuronal cytotoxicity via induction of intense inflammation.

Myasthenia gravis (MG) is a kind of chronic autoimmune disease which can weaken patients' motor function and, furthermore, produce negative impact on the health-related quality of life (HRQoL). The primary purpose of this research was to evaluate factors that might affect the HRQoL of MG patients. A cross-sectional clinical research was carried out including 188 successive patients with MG. Myasthenia Gravis Foundation of America (MGFA) classification and Quantitative Myasthenia Gravis (QMG) score were applied to assess the severity of the disease. The Medical Outcome Survey 36-Item Short-Form Health Survey (SF-36) was used to estimate the HRQoL. Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) were utilized to measure the depression and anxiety symptom. Factors may influence the HRQoL of MG patients include age, educational level, occupation, the situation of the thymus, the type of MG and generalized myasthenia gravis (GMG), the severity of the disease and the psychological disorder. Higher QMG and HARS scores were two significant factors that can prognosticate lower Physical Composite Score (PCS) and Mental Composite Score (MCS), while older age was just a significant factor which has prognostic value for lower PCS. The results of this research may have a potential guiding significance for the clinical treatment strategy and improve the quality of life in patients with MG consequently. In addition to the treatment of physical symptoms, the psychological symptoms such as anxiety and depression should be concerned as well.

Objective: The primary objective was to evaluate the efficacy and safety of droxidopa as add-on therapy in improving stiffness, tremors and other motor functions and activities of daily living for moderate-to-severe Parkinson's disease (PD)., Methods: PD patients, above Hoehn-Yahr III (including Hoehn-Yahr III), were randomly assigned to drug therapy (droxidopa 600 mg/day for 8 weeks) or placebo. Efficacy indicators were the Unified Parkinson's Disease Rating Scale (UPDRS) part I, II, III subscale, Clinical Global Impression (CGI) rating score, and individual symptom scores (e.g. stiffness, tremors), to evaluate motor function and activities of daily life., Results: There are 109 patients in the droxidopa group, and 110 in the placebo group, at baseline, there were no differences between the two groups for age, body weight, disease severity and previous drugs therapy. At days 14 and 57 of droxidopa add on treatment, UPDRS-II scores reflecting activities of daily life and UPDRS-III scores reflecting motor functions were significantly different compared to the pre-treatment baseline scores (P < 0.01), UPDRS- II and UPDRS-III scores at day 14 and day 57 were also significantly different (P < 0.01) between the two groups. Individual motor symptoms such as stiffness, resting tremor, and alternate hand motion were also significantly improved with droxidopa on days 14 and 57 of treatment (P < 0.01 vs placebo), showing that droxidopa is effective in improving rigidity, tremor and alternate motion of hand., Conclusions: Droxidopa was effective as symptomatic adjunct therapy, improved significantly motor function and activities of daily living, benefited patients with signs of tremor and Stiffness., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To explore the change in the number and role of Gr-1⁺ CD11b⁺ myeloid-derived suppressor cells (MDSCs) in experimental autoimmune encephalomyelitis (EAE)., Methods: Totally 30 healthy female C57BL/6 mice were randomly divided into two groups: EAE-induced group (n=15) and control group (n=15). EAE was induced by immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55), and pathological changes in spinal cords were revealed by HE staining and Luxol fast blue (LFB) staining. The number of Gr-1⁺ CD11b⁺ MDSCs in spleens and spinal cords of the two groups was respectively compared by flow cytometry and immunofluorescent staining. The effect of Gr-1⁺ CD11b⁺ MDSCs from EAE mice on the proliferation of CD4⁺ T cells and CD8⁺ T cells was evaluated by in vitro co-culture system., Results: Twelve of 15 immunized mice (80%) developed EAE. HE staining showed an extensive infiltration of inflammatory cells in the spinal cords of the EAE mice. LFB staining revealed multiple demyelinated lesions in the above inflammatory infiltration. The immunofluorescent histochemistry suggested that many Gr-1⁺ CD11b⁺ MDSCs were present in spinal cords of the EAE mice, but no positive cells were observed in the control group. The mass of spleen in the EAE mice was significantly higher than that of the control mice [(146.5 ± 12.4) mg vs (67.2 ± 8.7) mg, P<0.01], and the proportion of splenic Gr-1⁺ CD11b⁺ MDSCs in EAE mice significantly increased (P<0.01 vs controls). Consistent with the results of immunofluorescent staining, a significantly increased proportion of Gr-1⁺ CD11b⁺ MDSCs in spinal cords of EAE mice was observed with flow cytometry. In vitro co-culture analysis revealed that Gr-1⁺ CD11b⁺ MDSCs from spinal cords of the EAE mice markedly suppressed the proliferation of CD4⁺ T cells and CD8⁺ T cells., Conclusion: EAE induces an expansion and aggregation of Gr-1⁺ CD11b⁺ MDSCs in spleens and spinal cords. These cells suppress T cell proliferation in vitro and are involved in the immunoregulation of EAE.

Follicular helper CD4+ T (TFH) cells are the specialized providers of B cell help in germinal centers (GCs). Formation of GCs in thymi is the primary thymi characteristic in MG patients. TFH cells are involved in the pathogenic process of many autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis and autoimmune thyroid disease. The role thymic TFH cells played in MG with thymoma has not been elucidated. Here, we analyzed surface markers CXCR5, Bcl-6, ICOS and IL-21 on TFH cells in thymus derived from thymoma patients with ocular MG (OMG), generalized MG (GMG) or without MG using immunohistochemical staining, immunofluorescence, western blotting, and real-time PCR analysis. We show that clinical severity of MG is correlated with higher mRNA expression of the four markers. Indeed, results show higher expression of all four markers in thymoma with GMG patients compared with both OMG and non-MG patients. We found no significant difference in the expression of CXCR5, Bcl-6 and ICOS in OMG compared with non-MG patients. Regression analysis shows a positive correlation between thymic CXCR5, BCL-6, ICOS and IL-21 levels and quantitative MG score (QMGS) in GMG patients. In addition, we found no significant correlation between TFH cell expression and QMGS in OMG patients. Our findings show that higher expression of TFH cells in the thymoma is related to the clinical severity of MG and suggests a role in the pathogenesis of MG. However, the real source of these TFH cells is still uncertain and needs further study., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This study investigated the relationship between N5,N10-methylene tetrahydrofolic acid reductase (MTHFR) polymorphisms, smoking, and vascular dementia (VD). Polymerase chain reaction-restriction fragment length polymorphism analysis was used to analyze the frequency of the C/T polymorphism at position 677 of the MTHFR gene in 304 VD patients and 300 control patients with nondementia cerebral infarction. The CC, CT, and TT genotype frequencies of the MTHFR gene were 43.42%, 32.57%, and 24.01%, respectively, in the VD group, and 50.67%, 32.00%, and 17.33%, respectively, in the control group. The T allele frequency was significantly higher in the VD group than in the control group (P < .05). Among patients who smoked, the relative risk of VD in patients with the TT genotype and T allele was higher than in the control group (P < .05). Therefore, the smoking group with the T allele has the highest risk of VD, and synergy appears to exist between the MTHFR gene polymorphisms and smoking in susceptibility to VD.

Differential expressions of immune molecules have been shown in the thymi with pathological results, including myasthenia gravis (MG). CD25 is an activation marker expressed on T cells. CXCL13 mediates the homing and motility of B cells in secondary lymphoid tissues. Herein, we investigated the expressions of CD25 and CXCL13 in the thymi of thymic hyperplasia patients with MG or with non-MG. A total of 34 thymic hyperplasia patients with MG (20 generalized MG (GMG) and 14 ocular MG (OMG) and six thymic hyperplasia patients without MG were enrolled and analyzed using immunohistochemical staining and real-time polymerase chain reaction for CD25 and CXCL13. Our study demonstrated a higher expression of both CD25 and CXCL13 in hyperplastic thymi with OMG or GMG compared to those with non-MG. According to the immunohistochemical results, we observed that CD25 expression was significantly lower in atrophic thymi and non-MG hyperplastic thymi, compared with that in infant thymi (P = 0.002 and 0.005, respectively). In contrast to CD25 expression, we did not observe differential expression of CXCL13 among three control groups. And a similar CD25 mRNA expression was found in real-time polymerase chain reaction (PCR) results. We observed that both hyperplastic thymi with OMG or GMG expressed significantly higher levels of CD25 than those with non-MG (P = 0.007 and 0.001, respectively). And an increase of CD25 expression was observed in hyperplastic thymi with GMG compared to those with OMG (P = 0.030). Similarly, CXCL13 expression was significantly higher in hyperplastic thymi with GMG or with OMG than those with non-MG (P = 0.001 and 0.050, respectively). No significant CXCL13 expression difference was found between hyperplastic thymi with GMG and those with OMG (P > 0.05). The real-time PCR results showed a similar tendency of CD25 mRNA expression among the thymi of non-MG, OMG, and GMG patients, but the difference did not reach significance (P > 0.05). An obvious increased expression of CXCL13 was found in hyperplastic thymi with GMG patients, compared to those with non-MG and OMG patients (P = 0.003 and 0.071, respectively). There was no difference found between hyperplastic thymi with non-MG and with OMG. Regression analysis showed a positive correlation between thymic CD25 level and MG symptom severity (F = 28.240; P = 0.000, r = 0.523). Similarly, a positive correlation was found between thymic CXCL13 expression and MG disease severity (F = 36.093; P = 0.000, r = 0.671). Taken together, our findings suggest CD25 and CXCL13 participate in the pathogenesis of MG and may influence the clinical symptoms of MG.

Background: Increasing evidence supports a link between expressions of CD4, CD25, Foxp3, and CXCL13 in thymic hyperplasia with myasthenia gravis (MG) patients. Herein, we investigated the expressions of these molecules in thymoma patients with ocular MG (OMG) or generalized MG (GMG)., Methods: A total of 58 thymoma patients with MG (23 GMG and 35 OMG) and 73 thymoma patients without MG were analyzed using immunohistochemistry for CD4, CD25, Foxp3 and CXCL13., Results: OMG was more frequent than GMG in late-onset thymoma males (P=0.037), but no difference was observed in females (P=0.128). There was no significant difference of Foxp3 expression among all types of thymoma from patients with OMG and Non-MG. Compared to patients with OMG, a decreased Foxp3 expression was seen in types AB, B1 and B2 thymoma with GMG, with the decrease in the former two types reaching significance (P=0.001, 0.043, respectively). However, a significantly increased expression of CXCL13 was observed in types B1 and B2 thymoma patients with GMG (P=0.027, 0.048, respectively, compared to those with OMG). Furthermore, the CXCL13 expression in type AB thymoma patients with GMG was higher than those with Non-MG (P=0.003).There were no differences among expressions of CD4, CD25, Foxp3, and CXCL13 in type A and B3 thymoma patients, regardless of with OMG, GMG or Non-MG., Conclusion: Differential expressions of Foxp3 and CXCL13 in various types of thymoma patients with OMG or GMG might suggest the differential immunological processes underlying the two subtype of MG., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Diabetes mellitus is associated with adverse complications in many organ systems including the brain. Accumulating evidence indicates that diabetes, regardless of its type, impairs adult neurogenesis in the dentate gyrus (DG) of the hippocampus (HPC). However, the effects of the disease on neurogenesis in the subventricular zone (SVZ) are not well established. We induced diabetes in male NOD/SCID (non-obese diabetic/severe combined immunodeficiency) mice and C57BL/6 mice with a single intraperitoneal injection of streptozotocin (STZ). On day 7 or day 21 after STZ injection mice received the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) for labeling of proliferative cells. Mice were sacrificed 24h later and brain coronal sections were stained with anti-BrdU antibodies. Neural stem/progenitor cell (NSC/NPC) proliferation, as revealed by BrdU-labeled cells, was markedly decreased in the subgranular zone of the DG in STZ-treated diabetic mice. A similar reduction of NSC/NPC proliferation was seen in the SVZ. Reduced DG and SVZ cell proliferation was also found in diabetic NOD mice, a model of spontaneous diabetes, and the reduction was attenuated by bilateral adrenalectomy (Adx). Adx did not alter blood glucose or insulin levels in either prediabetic or diabetic NOD mice, but Adx partly increased mRNA levels of hippocampal and SVZ brain-derived neurotrophic factor (BDNF), a crucial regulator of NSC/NPC proliferation. Moreover, NOD and NOD/SCID mice showed a more rapid reduction of NSC/NPC proliferation than C57BL/6 mice in response to diabetes. Thus, we conclude that diabetes inhibits cell proliferation in both the SVZ and HPC, and inhibition was associated with elevated glucocorticoid levels and reduced BDNF expression., (Copyright © 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

It has been reported that autoimmune inflammatory processes in human multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), may induce an alteration in neurogenesis. Studies with transgenic EAE mice have demonstrated an enhancement of neurogenesis in the subventricular zone (SVZ). In contrast, a reduction of stem cell proliferation in the same region has been observed by Pluchino et al. [Brain 2008;131:2564-2578] in myelin oligodendrocyte glycoprotein (MOG)-induced EAE mice. We immunized female C57BL/6 mice with MOG 35-55 peptide and successfully developed chronic/nonremitting EAE, which is believed to be analogous to the progressive form of MS. On day 21 postimmunization, coronal brain sections were collected and stained with anti-5-bromo-2'-deoxyuridine (BrdU) antibody. By counting the number of BrdU-labeled cells, we demonstrated that the neural stem/progenitor cell (NSC/NPC) proliferation decreased in the SVZ, which basically confirms the study of Pluchino et al. on the changes in the SVZ. A reduction of NSC/NPC proliferation also occurred in the hippocampal subgranular zone of the dentate gyrus. The hippocampus is well known to be an important region involved in learning and memory; thus, our finding may offer a possible explanation for the cognitive impairment in human chronic MS., (Copyright © 2009 S. Karger AG, Basel.)

A 21-year-old woman, who experienced manual strangulation, developed delayed parkinsonism associated with a selective symmetric basal ganglia lesion. The patient had recovered completely one year after early combination therapy. This case emphasizes the need for greater attention in detecting early brain injuries in those afflicted with strangulation so as to provide optimal management.

Parry-Romberg syndrome (PRS) is a rare clinical entity of unknown etiology, generally characterized by a slow and progressive atrophy that affects 1 side of the face. A variety of neurologic abnormalities have been shown to coexist with PRS. However, few studies regarding pyramidal tract involvement in this disorder have been reported. We report a unique case, in which the patient presented with bilateral pyramidal tract insult and an unusual sequence of disease onset and progression. This case suggests a rarer variant of PRS, and the neurologic findings indicate that the underlying essential neural degeneration may contribute to the processing of pyramidal tract insult or this syndrome.

Brown-Vialetto-Van Laere (BVVL) syndrome is a rare disorder with clinical features that include progressive bilateral sensorineural deafness and a variety of cranial nerve impairments. Respiratory compromise has been observed in most familial and sporadic cases; however, few studies have been published regarding sleep-disordered breathing in this syndrome. We report the unique case of a 16-year-old girl with the clinical features of BVVL syndrome who presented with bilateral sensorineural hearing loss and then progressively developed paralysis of the 7th and 9th-12th cranial nerves. More importantly, she presented with the unusual feature of severe sleep-disordered breathing. A polysomnographic study showed evidence of dominant central sleep apnea, and the majority of apneic episodes more likely occurred in stage 2 during NREM sleep. The central sleep apnea was associated with rapid respiratory deterioration and death. This report raises the fact that a patient with BVVL syndrome may present with severe sleep-disordered breathing as a life-threatening condition, which emphasizes the need for greater attention to the early detection of potential sleep-disordered breathing in these afflicted with the BVVL syndrome for optimal clinical management.