Intestinal perfusion of unacylated ghrelin alleviated metabolically associated fatty liver disease in rats via a central glucagon-like peptide-1 pathway.

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.

Notch signaling dependent monocyte conversion alleviates immune-mediated neuropathies by regulating RBP-J/NR4A1 axis.

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 (NICcA) 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 NICcA EAN mice compared to that in control mice. Flow cytometry and immunofluorescence staining suggested that increasing Ly6Clo monocytes in the peripheral blood and nerve tissue might contribute to the alleviation of neuritis in NICcA mice. Meanwhile, an in vitro study suggested that bone marrow-derived monocytes from NICcA mice are more inclined toward Ly6Clo cells than Ly6Chi cells. Differential expression of monocyte development-associated genes was detected in NICcA and wild-type mice using RNA sequencing. The expression of Nr4a1 is upregulated remarkably when Notch signaling is activated. Treatment with Nr4a1 antagonist on NICcA mice-derived monocytes compromise their Ly6Clo 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.

Eugenol alleviated nonalcoholic fatty liver disease in rat via a gut-brain-liver axis involving glucagon-like Peptide-1.

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.

Prediction of generalization of ocular myasthenia gravis under immunosuppressive therapy in Northwest China.

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.

Neuroprotective effects of a chromatin modifier on ischemia/reperfusion neurons: implication of its regulation of BCL2 transactivation by ERα signaling.

An understanding of the molecular mechanisms involved in the regulation of estrogen receptor alpha (ERα)-mediated neuroprotective effects is valuable for the development of therapeutic strategy against neuronal ischemic injury. Here, we report the upregulated expression of metastasis-associated protein 1 (MTA1), a master chromatin modifier and transcriptional regulator, in the murine middle cerebral artery occlusion (MCAO) model. Inhibition of MTA1 expression by in vivo short interfering RNA treatment potentiated neuronal apoptosis in a caspase-3-dependent manner and thereafter aggravated MCAO-induced neuronal damage. Mechanistically, the pro-survival effects of MTA1 required the participation of ERα signaling. We also provide in vitro evidence that MTA1 enhances the binding of ERα with the BCL2 promoter upon ischemic insults via recruitment of HDAC2 together with other unidentified coregulators, thus promoting the ERα-mediated transactivation of the BCL2 gene. Collectively, our results suggest that the augmentation of endogenous MTA1 expression during neuronal ischemic injury acts additionally to an endocrinous cascade orchestrating intimate interactions between ERα and BCL2 pathways and operates as an indispensable defensive mechanism in response to neuronal ischemia/reperfusion stress. Future studies in this field will shed light on the modulation of the complicated neuroprotective effects by estrogen signaling.

Quality of life in 188 patients with myasthenia gravis in China.

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.

The ratio of circulating CD56dim NK cells to follicular T helper cells as a promising predictor for disease activity of relapsing-remitting multiple sclerosis.

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, CD56dim NK cells, not CD56bright 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 CD56dim 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 CD56dim NK/cTfh ratio was observed. These findings suggest that the CD56dim NK/cTfh ratio holds promise as a prognostic indicator for clinical relapse and treatment response in MS.

Efficacy and safety of repeated low-dose rituximab therapy in relapsing-remitting multiple sclerosis: A retrospective case series study.

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.

Short-term safety of inactivated SARS-Cov-2 vaccines in Chinese patients with central nervous system inflammatory demyelinating diseases.

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.

Rituximab at lower dose for neuromyelitis optica spectrum disorder: a multicenter, open-label, self-controlled, prospective follow-up study.

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.

Late-Onset Anti-GABAB Receptor Encephalitis: Clinical Characteristics and Outcomes Differing From Early-Onset Patients.

BACKGROUND AND OBJECTIVES: Existing evidence indicates anti-GABAB receptor encephalitis (GABABR-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 GABABR-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 GABABR-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 GABABR-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 GABABR-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.

Atractylodes chinensis volatile oil up-regulated IGF-1 to improve diabetic gastroparesis in rats.

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.

Coexistence of Myelin Oligodendrocyte Glycoprotein Immunoglobulin G and Neuronal or Glial Antibodies in the Central Nervous System: A Systematic Review.

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.

Association between serum low-density neutrophils and acute-onset and recurrent Guillain-Barré syndrome.

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.

QKI 6 ameliorates CIRI through promoting synthesis of triglyceride in neuron and inhibiting neuronal apoptosis associated with SIRT1-PPARγ-PGC-1α axis.

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.

Case Report: Prominent Brainstem Involvement in Two Patients With Anti-CASPR2 Antibody-Associated Autoimmune Encephalitis.

Anti-contactin-associated protein-like 2 (CASPR2) antibody-associated autoimmune encephalitis is commonly characterized by limbic encephalitis with clinical symptoms of mental and behavior disorders, cognitive impairment, deterioration of memory, and epilepsy. The classical lesions reported are located at the medial temporal lobe or hippocampus, whereas prominent brainstem lesions have not been addressed to date. Herein, we reported two patients mimicking progressive brainstem infarction with severe neurological manifestations. On brain magnetic resonance imaging (MRI), prominent brainstem lesions were noted, although multifocal lesions were also shown in the juxtacortical and subcortical white matters, basal ganglia, hippocampus, and cerebellar hemisphere. Unexpectedly and interestingly, both cases had detectable CASPR2 antibodies in sera, and an exclusive IgG1 subclass was documented in the further analysis. They were treated effectively with aggressive immunosuppressive therapies including corticosteroids, intravenous immunoglobulin G, and rituximab, with the first case achieving a rapid remission and the other undergoing a slow but gradual improvement. To the best of our knowledge, this is the first report on prominent brainstem involvement with definite MRI lesions in anti-CASPR2 antibody-associated autoimmune encephalitis, which helps to expand the clinical spectrum of this rare autoimmune disease and update the lesion patterns in the CNS.

Controlling Hypertension After Severe Cerebrovascular Event (CHASE): A randomized, multicenter, controlled study.

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.

Hypertension management in elderly with severe intracerebral hemorrhage.

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.

Blood pressure variability and outcome in acute severe stroke: A post hoc analysis of CHASE-A randomized controlled trial.

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.

Decreased neural stem/progenitor cell proliferation in mice with chronic/nonremitting experimental autoimmune encephalomyelitis.

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.