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Abstract Background Clinical nurses frequently face the necessity of working night shifts, often with insufficient opportunities for timely sleep recovery, which may negatively impact autonomic nervous system regulation. The aim of this study was to evaluate changes in heart rate variability (HRV) after the six-minute walk test (6MWT) in nurses post-night shift and to explore the impact of night shift work on cardiac autonomic regulation. Methods Thirty-five female nurses, with a mean age of 28.7 years (range 21.0–37.0 years), participated in this study. On the first and second mornings after a night shift, the nurses performed the 6MWT. During the test, electrocardiogram (ECG) signals, blood pressure, and walking distance were recorded simultaneously. Results Compared with the second postshift morning, on the first postshift morning, nurses presented higher ratings of perceived exertion (RPE), higher Borg scale scores, and a slower pulse rate before and after the 6MWT but covered a shorter walking distance. Additionally, HRV indicators such as the SDNN, RMSSD, pNN50, TP, VLF, LF, and HF were all higher on the first postshift morning. Regarding the amplitude of cardiac autonomic nervous regulation, variations in the RMSSD and pNN50 were both greater during the 6MWT on the first postshift morning, although there was no significant difference in post-6MWT recovery. Conclusions Night shifts appear to increase the activity of the autonomic nervous system in nurses on the first postshift morning and exert a greater inhibitory effect on parasympathetic activity during the 6MWT. Therefore, it is important to ensure timely recovery sleep and improve autonomic regulation after working night shifts. Keywords Heart rate variability; Night shift; Autonomic nervous system; Six-minute walk test; Nurses. Trial registration This study was retrospectively registered in the Clinicaltrials.gov. Registration Date: August 1, 2024. Clinicaltrials.gov ID: NCT06542510.

BackgroundIntracerebral hemorrhage (ICH) is the most lethal and devastating subtype of stroke. Basal ganglia hemorrhage and thalamic hemorrhage are the most common types of ICH, accounting for 50–70% of all ICH cases, leading to disability and death, and it involves the posterior limb of the internal capsule to varying degrees. In this study, we investigated the impact of varying degrees of the involvement of the posterior limb of the internal capsule on the prognosis of patients with basal ganglia and thalamic ICH and assessed whether it improves the predictive accuracy of the max-ICH score, an existing scale for ICH functional outcome.MethodsThis is a multicenter, retrospective, observational study. We graded the involvement of the posterior limb of the internal capsule according to the degree of compression and injury (called iICH, ranging from 0 to 4). An unfavorable outcome was defined as a 90-day modified Rankin Scale (mRS) of > 2. Multivariate logistic regression analysis was used to identify independent risk factors associated with unfavorable prognosis. The discrimination was verified using receiver operating characteristic curve (ROC) analysis, while the calibration was verified by the Hosmer-Lemeshow test.ResultsOf the 305 patients included, 188 from Nanfang Hospital were assigned to the development cohort, and 117 from Heyuan People's Hospital and Huadu District People's Hospital were assigned to the validation cohort. In the development cohort, iICH was identified as an independent factor of a 90-day unfavorable outcome, and the area under the ROC (AUC) was 0.774. When combined with the iICH, the AUC of max-ICH was significantly elevated from 0.816 to 0.866. Comparable results were found in the validation cohort.ConclusionsIncreased involvement of the posterior limb of the internal capsule is associated with a worse outcome in patients with basal ganglia and thalamic ICH.

AbstractBackground Whether minor ischemic stroke (MIS) patients can benefit from intravenous thrombolysis (IVT) remains controversial. The association between the efficacy of IVT and baseline National Institute of Health Stroke Scale (NIHSS) score is unclear in MIS, while the association in moderate and severe stroke is known. This study aimed to explore the effect of IVT in patients with MIS and analyze its efficacy in patients with different baseline NIHSS scores.Methods Patients with a NIHSS score ≤5 within 4.5 h of stroke onset were screened in 32 centers. Patients with and without IVT were matched to a ratio of 1:1 with propensity scores. An excellent outcome was defined as a modified Rankin Scale (mRS) score ≤1 at three months after stroke onset. Safety outcomes included mortality and symptomatic intracranial hemorrhage (sICH). Multivariate analysis was used to compute the adjusted odds ratio (OR) for excellent outcomes. The effect of IVT was further analyzed in subgroups according to the baseline NIHSS score.Results Of the 23,853 screened, 3336 patients with MIS who arrived at the hospital within 4.5 h of onset were included. The 1163 patients treated with IVT were matched with 1163 patients without IVT. IVT in minor strokes generated an adjusted OR of 1.38 (95% CI: 1.09–1.75, p = 0.009) for excellent outcomes. There were no significant differences in mortality (0.17% vs. 0.09%, p = 1.000) and sICH (0.69% vs. 0.86%, p = 0.813) between patients with and without IVT. Subgroup analysis showed that there was no significant effect of IVT in the baseline NIHSS 0-1 or 2-3 subgroups, with adjusted OR of 0.816 (95% CI 0.437–1.53, p = 0.525) and1.22 (95% CI 0.845–1.77, p = 0.287), respectively. In patients with NIHSS score of 4–5, IVT was significantly effective, with an adjusted OR of 1.53 (95% CI 1.02–2.30, p = 0.038).Conclusion IVT can improve MIS outcomes. The risks of sICH and mortality did not increase, especially in patients with NIHSS scores 4 to 5, who could benefit from IVT significantly.

Stroke is a significant health concern impacting society and the health care system. Reperfusion therapy for acute ischemic stroke and standard rehabilitative therapies may not always be effective at improving post-stroke neurological function, and developing alternative strategies is particularly important. Vagus nerve stimulation (VNS) is a treatment option currently approved by the Food and Drug Administration (FDA) for intractable epilepsy, refractory depression, primary headache disorders, obesity, and moderate to severe upper-limb motor dysfunction in chronic ischemic stroke patients. Moreover, VNS has demonstrated potential efficacy in various conditions, including autoimmune diseases, disorders of consciousness, Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, stroke, and other diseases. Although the popularity and application of VNS continue to increase rapidly, the field generally lacks a consensus on the optimal stimulation parameters. The stimulation parameters for VNS are directly related to the clinical outcome, and determining the optimal stimulation conditions for VNS has become an essential concern in its clinical application. This review summarizes the current evidence on VNS for stroke in preclinical models and clinical trials in humans, paying attention to the current types and stimulation parameters of VNS, highlighting the mechanistic pathways involved in the beneficial effects of VNS, critically evaluating clinical implementation challenges and proposing some suggestions for its future research directions. Achieving safe and effective clinical transformation of VNS requires further animal and clinical studies to determine the optimal stimulation parameters and therapeutic mechanisms.

Aberrant expression of cyclin-dependent kinase 5 (Cdk5) has been reported in pituitary adenomas. However, the role of Cdk5 in the tumorigenesis remains unclear. We show that prenatal p25-activated Cdk5 phosphorylates minichromosome maintenance protein 2 (Mcm2), enhancing minichromosome maintenance (MCM) family proteins and driving intermediate lobe-located melanotrope-originated pituitary tumorigenesis. In a mouse model with CaMKII promoter-driven transgenic induction of p25, we observed intermediate lobe-originated pituitary adenoma producing non-functional proopiomelanocortin (POMC)-derived peptides under persistent p25 overexpression. Single-cell RNA sequencing revealed Mcm2 may play an important role during tumor progression. Subsequently, Mcm2 was identified as a potential phosphorylated substrate of Cdk5, mediating the tumorous proliferation of melanotrope cells. Silencing Cdk5 or Mcm2 suppressed cell proliferation and colony formation in the 293T cell lines. Therefore, our findings provide a new mouse model of intermediate lobe-originated pituitary adenoma induced by p25/Cdk5 and unveil a previously unappreciated role of Cdk5 and Mcm2 in pituitary adenoma tumorigenesis.

Stroke-related sarcopenia (SRS) is characterized by progressive systemic muscle loss and decreased function and is thought to be primarily affected by catabolic-anabolic imbalance, but there is a lack of specific treatment. Our study evaluated whether β-hydroxybutyrate (BHB) improves SRS through regulation in protein synthesis and proteolysis. BHB reduced infarct volume, increased muscle mass and muscle fiber cross-sectional area. Delayed administration of BHB, when the infarct volume was stable, improved the balance beam score and time of rotarod and the above SRS indicators. Mechanistically, BHB increased the total contents of H3K9bhb in gastrocnemius muscles of tMCAO mice and enhanced the endogenous binding of H3K9bhb with Foxo3a promoter in response to the transcription inhibition of Foxo3a. Our study indicated BHB alleviated SRS, which was partly mediated by H3K9bhb, and then inhibited FOXO3a. BHB also promoted protein synthesis, muscle regeneration and proliferation to maintain protein metabolic homeostasis and ultimately ameliorated SRS.

Objective This study was based on the network pharmacology to explore the mechanisms whereby Tribulus terrestris affects vitiligo. Methods The screening criteria for oral bioavailability (OB) and drug-likeness (DL) were set as OB≥30% and DL≥0.18, respectively. The databases of Traditional Chinese Medicine Systems Pharmacology and analysis platforms of OMIM, Swiss Target Prediction and GeneCards were used to screen out target genes of main active ingredients of Tribulus terrestris and construct an "active ingredients-target" network using Cytoscape 3.9.1 software. Then the target genes of the main active ingredients of Tribulus terrestris and the target genes of vitiligo were intersected to construct a "disease-pathway-target-component-drug" network. In addition, the intersection targets were respectively imported into the STRING platform to construct Protein-Protein Interaction (PPI) Networks, and into the DAVID database for GO and KEGG pathway enrichment analyses. The structure of small molecules of key drug components and vitiligo-related protein structure were searched on PubChem and PBD. After setting up receptors and ligands, the molecular docking of these two was performed. Results Through screening, we identified 12 active ingredients, including kaempferol, terrestramide, isorhamnetin, sitosterol, which possibly affect 71 targets. PPI network analysis showed ten major targets, including AKT1, TNF, ESR1, PPARG, HPGDS, CASP3, and PTGS2. These targets were involved in many biological processes, such as apoptosis, peptide serine phosphorylation, and cell response to reactive oxygen species, through various signaling pathways, including apoptosis, tumor necrosis factor and reactive oxygen species signaling. Molecular docking results showed that the main active components such as kaverol and isorhamnetin were stably bound to the core targets, such as AKT1, TNF and ESR1, the core components regulating key targets. Conclusion Tribulus terrestris may improve vitiligo through regulating inflammation, apoptosis, immune function and oxidative stress.

Cytoprotection has emerged as an effective therapeutic strategy for mitigating brain injury following acute ischemic stroke (AIS). The sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel plays a pivotal role in brain edema and neuroinflammation. However, the practical use of the inhibitor glyburide (GLB) is hindered by its low bioavailability. Additionally, the elevated reactive oxygen species (ROS) after AIS exacerbate SUR1-TRPM4 activation, contributing to irreversible brain damage. To overcome these challenges, GLB and superoxide dismutase (SOD) were embedded in a covalent organic framework (COF) with a porous structure and great stability. The resulting S/G@COF demonstrated significant improvements in survival and neurological functions. This was achieved by eliminating ROS, preventing neuronal loss and apoptosis, suppressing neuroinflammation, modulating microglia activation, and ameliorating blood-brain barrier (BBB) disruption. Mechanistic investigations revealed that S/G@COF concurrently activated the Wnt/β-catenin signaling pathway while suppressing the upregulation of SUR1-TRPM4. This study underscores the potential of employing multi-target therapy and drug modification in cytoprotective strategies for ischemic stroke.

PURPOSE: Through three neurocritical care unit (NCCU) surveys in China, we tried to understand the development status of neurocritical care and clarify its future development. METHODS: Using a cross-sectional survey method and self-report questionnaires, the number and quality of NCCUs were investigated through three steps: administering the questionnaire, sorting the survey data, and analyzing the survey data. RESULTS: At the second and third surveys, the number of NCCUs (76/112/206) increased by 47% and 84%, respectively. The NCCUs were located in tertiary grade A hospitals or teaching hospitals (65/100/181) in most provinces (24/28/29). The numbers of full-time doctors (359/668/1337) and full-time nurses (904/1623/207) in the NCCUs increased, but the doctor–bed ratio and nurse–bed ratio were still insufficient (0.4:1 and 1.3:1). CONCLUSION: In the past 20 years, the growth rate of NCCUs in China has accelerated, while the allocation of medical staff has been insufficient. Although most NCCU hospital bed facilities and instruments and equipment tend to be adequate, there are obvious defects in some aspects of NCCUs.

Abstract Background Plasmodium berghei has been used as a preferred model for studying human malaria, but only a limited number of disease-associated genes of P. berghei have been reported to date. Identification of new disease-related genes as many as possible will provide a landscape for better understanding the pathogenesis of P. berghei. Methods Network module analysis method was developed and applied to identify disease-related genes in P. berghei genome. Sequence feature identification, gene ontology annotation, and T-cell epitope analysis were performed on these genes to illustrate their functions in the pathogenesis of P. berghei. Results 33,314 genes were classified into 4,693 clusters. 4,127 genes shared by six malaria parasites were identified and are involved in many aspects of biological processes. Most of the known essential genes belong to shared genes. A total of 63 clusters consisting of 405 P. berghei genes were enriched in rodent malaria parasites. These genes participate in various stages of parasites such as liver stage development and immune evasion. Combination of these genes might be responsible for P. berghei infecting mice. Comparing with P. chabaudi, none of the clusters were specific to P. berghei. P. berghei lacks some proteins belonging to P. chabaudi and possesses some specific T-cell epitopes binding by class-I MHC, which might together contribute to the occurrence of experimental cerebral malaria (ECM). Conclusions We successfully identified disease-associated P. berghei genes by network module analysis. These results will deepen understanding of the pathogenesis of P. berghei and provide candidate parasite genes for further ECM investigation.

Objective To analyze the active ingredients of Xiaoyao Pill and its molecular mechanisms in the treatment of chloasma. Methods The active ingredients of Xiaoyao Pill, its target proteins and the targets related to human chloasma were searched through BATMAB-TCM database, GeneCards database, CTD database and GEO database, and the network diagram of active ingredient-disease targets was constructed. STRING database was used to construct protein interaction network, followed by GO and KEGG enrichment analysis. Finally, the active ingredients and common targets were verified by molecular docking. Results Xiaoyao Pill contained many key active ingredients such as angelica, 1-methyl-2-dodecyl-4-quinolone, ergotamine, palmitic acid, behenic acid, azelaic acid, and retinol, which possibly regulated expression of proteins related to core genes such as AKT1, INS, TNF, TP53, IL1B, KCNA1, PPARG, and JUN, resulting in the improvement of melasma. KEGG enrichment analysis revealed that the pathways involved in the action of Xiaoyao Pill included neuroactive ligand-receptor interactions, retrograde endocannabinoid signaling, dopaminergic synapses, CAMP signaling, nonalcoholic fatty liver disease, and gonadotropin-releasing hormone secretion. Molecular docking showed that the binding energies of TNF-ergotamine, IL1B-ergotamine, PPARG-ergotamine and JUN-ergotamine were all

Background: Generalized convulsive status epilepticus (GCSE) is one of the most challenging life-threatening neurological emergencies. If GCSE becomes super-refractory, it is associated with significant mortality. Although aggressive management of prolonged status epilepticus was conducted, the mortality has not decreased since the late 1990s. Objectives: The present study aimed to explore the risk factors for progression to super-refractory in patients with generalized convulsive status epilepticus (GCSE). Moreover, we illustrated the risk factors for mortality in GCSE patients. Design: An observational retrospective cohort study. Methods: We conducted a retrospective study of patients with GCSE admitted to our neurocritical unit, in Guangzhou, China, from October 2010 to February 2021. The data of sociodemographic information, etiology, laboratory results, treatment, and prognosis were collected and analyzed. Results: A total of 106 patients were enrolled; 51 (48%) of them developed super-refractory status epilepticus (SRSE). Multivariate logistic regression analysis demonstrated that patients with autoimmune encephalitis ( p = 0.015) and intracranial infection ( p = 0.019) are likely to progress to SRSE. The in-hospital mortality was 11.8% and 9.1% for patients in the SRSE and non-SRSE groups, respectively ( p = 0.652). Multivariate logistic regression analysis showed that neutrophil-to-lymphocyte ratios (NLR) at admission were independently associated with in-hospital mortality. Up to 31.4% of SRSE patients and 29.1% of non-SRSE patients died within 6 months after discharge ( p = 0.798). Multivariate logistic regression analysis showed that plasma exchange (PE) was a protective factor for 6-month mortality. A high NLR at discharge was a risk factor for 6-month mortality. Conclusion: In the current study, about 48% of GCSE patients progressed to SRSE. Regarding etiology, autoimmune encephalitis or intracranial infection was prone to SRSE. No significant differences were observed in the in-hospital and 6-month mortality between SRSE and non-SRSE groups. Multivariate logistic regression analysis showed that NLR at admission and discharge was an independent predictor of in-hospital and 6-month mortality, respectively. Moreover, PE significantly reduced the 6-month mortality.

Summary: Background: Glibenclamide alleviates brain edema and improves neurological outcomes in experimental models of stroke. We aimed to assess whether glibenclamide improves functional outcomes in patients with acute ischemic stroke treated with recombinant tissue plasminogen activator (rtPA). Methods: In this randomized, double-blind, placebo-controlled trial, patients with acute ischemic stroke were recruited to eight academic hospitals in China. Patients were eligible if they were aged 18–74 years, presented with a symptomatic anterior circulation occlusion with a deficit on the NIHSS of 4–25, and had been treated with rtPA within 4.5 h of symptom onset. We used web-based randomization (1:1) to allocate eligible participants to the glibenclamide or placebo group, stratified according to endovascular treatment and baseline stroke severity. Glibenclamide or placebo was taken orally or via tube feeding at a loading dose of 1.25 mg within 10 h after symptom onset, followed by 0.625 mg every 8 h for 5 days. The primary outcome was the proportion of patients with good outcomes (modified Rankin Scale of 0–2) at 90 days, assessed in all randomly assigned patients who had been correctly diagnosed and had begun study medication. The study is registered with ClinicalTrials.gov, NCT03284463, and is closed to new participants. Findings: Between January 1, 2018, and May 28, 2022, 305 patients were randomly assigned, of whom 272 (142 received glibenclamide and 130 received placebo) were included in the primary efficacy analysis. 103 (73%) patients in the glibenclamide group and 94 (72%) in the placebo group had a good outcome (adjusted risk difference 0.002, 95% CI −0.098 to 0.103; p = 0.96). 12 (8%) patients allocated to glibenclamide and seven (5%) patients allocated to placebo died from any cause at 90 days (p = 0.35). The number and type of adverse events were similar between the two groups. There were no drug-related adverse events and no drug-related deaths. Interpretation: The addition of glibenclamide to thrombolytic therapy did not increase the proportion of patients who achieved good outcomes after stroke compared with placebo, but it did not lead to any safety concerns. Funding: Southern Medical University and Nanfang Hospital.

Neuroinflammation plays a key role in the pathogenesis of post-cardiac arrest (CA) brain injury. Innate immune cells sense a variety of danger signals through pattern-recognition receptors and evoke rapidly after ischemic challenge, triggering inflammatory responses and amplifying brain damage. A programmed cell death (PCD) pathway is activated after ischemic and/or inflammatory stimuli, leading to the elimination of the damaged cells. However, PCD also regulates inflammatory responses flexibly. The present review aimed to summarize the mechanisms of inflammatory responses, including the biology of immune cells, the innate immune recognition that initiates the inflammation, and the immunomodulatory effects of PCD following CA. Promising therapeutic approaches of targeting inflammatory responses to alleviate brain injury and improve neurological outcomes after CA are also reviewed.

Objectives Neutrophil-to-lymphocyte ratio (NLR) is a simple parameter implying the inflammatory status. We aimed to explore the association of brain-dead donor NLR change with delayed graft function (DGF) in kidney transplant recipients.Methods We retrospectively analyzed the data on 102 adult brain-dead donors and their corresponding 199 kidney transplant recipients (2018 − 2021). We calculated ΔNLR by subtracting the NLR before evaluating brain death from the preoperative NLR. Increasing donor NLR was defined as ΔNLR > 0.Results Forty-four (22%) recipients developed DGF after transplantation. Increasing donor NLR was significantly associated with the development of DGF in recipients (OR 2.8, 95% CI 1.2 − 6.6; p = .018), and remained significant (OR 2.6, 95% CI 1.0 − 6.4; p = .040) after adjustment of confounders including BMI, hypertension, diabetes, and the occurrence of cardiac arrest. When acute kidney injury (AKI) was included in the multivariable analysis, increasing donor NLR lost its independent correlation with DGF, while AKI remained an independent risk factor of recipient DGF (OR 4.5, 95% CI 2.7 − 7.6; p

Objective To explore the association of hub genes and immune infiltration with acne pathogenesis by integrating and analyzing multi-chip data. Methods Gene microarray datasets were obtained from the GEO database, and differentially expressed genes (DEGs) in the acne phenotype-related gene module were screened using the "limma" R package and weighted gene co-expression network analysis (WGCNA). Moreover, GO functional enrichment and KEGG pathway analysis were performed. STRING online database and Cytoscape software were used to construct protein interaction network and to screen hub genes. Analysis of immune cell infiltration and correlation of hub genes with immune cell infiltration were based on the CIBERSORT algorithm. Results A total of 154 DEGs were screened. The DEGs associated with signaling receptor binding, cytokine activity and chemokine receptor binding were mainly enriched in pathways such as viral protein interaction with cytokine and cytokine receptors, cytokine-cytokine receptor interactions, chemokine signaling, NF-κB signaling and IL-17 signaling. The PPI network was constructed with 139 nodes and 1 597 edges, identifying two hub genes (CCR5, CXCL8). Among the 22 infiltrating immune cells, lesional site exhibited more neutrophils, activated mast cells, activated dendritic cells and activated CD4 memory T cells, but fewer regulatory T cells, resting dendritic cells and resting mast cells, in comparison to normal controls. Conclusion Changes in hub genes and immune cell infiltration, as identified by bioinformatics methods, may play an important role in the pathogenesis of acne.

Abstract Background Brain injury is the main cause of high mortality and disability after successful cardiopulmonary resuscitation (CPR) from sudden cardiac arrest (CA). The transient receptor potential M4 (TRPM4) channel is a novel target for ameliorating blood–brain barrier (BBB) disruption and neuroinflammation. Herein, we tested whether flufenamic acid (FFA), which is reported to block TRPM4 with high potency, could confer neuroprotection against brain injury secondary to CA/CPR and whether its action was exerted by blocking the TRPM4 channel. Methods Wild-type (WT) and Trpm4 knockout (Trpm4 −/− ) mice subjected to 10-min CA/CPR were randomized to receive FFA or vehicle once daily. Post-CA/CPR brain injuries including neurologic deficits, survival rate, histological damage, edema formation, BBB destabilization and neuroinflammation were assessed. Results In WT mice subjected to CA/CPR, FFA was effective in improving survival and neurologic outcome, reducing neuropathological injuries, attenuating brain edema, lessening the leakage of IgG and Evans blue dye, restoring tight junction protein expression and promoting microglia/macrophages from the pro-inflammatory subtype toward the anti-inflammatory subtype. In comparison to WT mice, Trpm4 −/− mice exhibited less neurologic deficiency, milder histological impairment, more BBB integrity and more anti-inflammatory microglia/macrophage polarization. As expected, FFA did not provide a benefit of superposition compared with vehicle in the Trpm4 −/− mice after CA/CPR. Conclusions FFA mitigates BBB breach and modifies the functional status of microglia/macrophages, thereby improving survival and neurologic deficits following CA/CPR. The neuroprotective effects occur at least partially by interfering with the TRPM4 channel in the neurovascular unit. These results indicate the significant clinical potential of FFA to improve the prognosis for CA victims who are successfully resuscitated.

Background and purposeSeveral reported cases of autoimmune conditions such as anti-NMDAR encephalitis and neuromyelitis optica (AQP4) have been considered to be potentially secondary to Treponema pallidum infection. Since the role of immune impairment in neurosyphilis is unclear, in this retrospective study, we examined the correlation of the immune impairment in patients with neurosyphilis with their clinical characteristics and outcomes.MethodsClinical information was collected from patients with neurosyphilis in our center from January 2019 to December 2021. Cerebrospinal fluid (CSF) samples were subjected to indirect immunofluorescence tissue-based assay (IIF-TBA) on mouse brain sections and cell-based assay (CBA). The clinical characteristics and treatment outcomes of TBA-positive and-negative patients were compared.ResultsA total number of 81 patients diagnosed with neurosyphilis were included. The results of the CBA tests showed that three cases had anti-NMDAR, AQP4, or GAD65 antibodies, respectively. By TBA test, 38 patients (38/81, 46.9%) had positive immunostains, including staining of neuronal cells in 21 cases (21/38, 55.3%), glial cells in 11 cases (11/38, 28.9%), and neuronal and glial cells in six cases (6/38, 15.8%). We then compared the clinical characteristics and treatment outcomes between the TBA-positive and-negative patients and found that TBA-positive staining was significantly correlated with syphilis antibody titers (p = 0.027 for serum and p = 0.006 for CSF) and head MRI abnormalities (p

ObjectiveTo understand the varieties, evaluation, treatment, and prognosis of severe neurological diseases using the third NCU survey in China.DesignA cross-sectional questionnaire study. The study was completed in three main steps: filling in the questionnaire, sorting out the survey data, and analyzing the survey data.ResultsOf 206 NCUs, 165 (80%) provided relatively complete information. It was estimated that 96,201 patients with severe neurological diseases were diagnosed and treated throughout the year, with an average fatality rate of 4.1%. The most prevalent severe neurological disease was cerebrovascular disease (55.2%). The most prevalent comorbidity was hypertension (56.7%). The most prevalent complication was hypoproteinemia (24.2%). The most common nosocomial infection was hospital-acquired pneumonia (10.6%). The GCS, APACHE II, EEG, and TCD were the most commonly used (62.4–95.2%). The implementation rate of the five nursing evaluation techniques reached 55.8–90.9%. Routinely raising the head of the bed by 30°, endotracheal intubation and central venous catheterization were the mostprevalent treatment strategies (97.6, 94.5, and 90.3%, respectively). Traditional tracheotomy, invasive mechanical ventilation and nasogastric tube feeding (75.8, 95.8, and 95.8%, respectively) were more common than percutaneous tracheotomy, non-invasive mechanical ventilation and nasogastric tube insertion (57.6, 57.6, and 66.7%, respectively). Body surface hypothermia brain protection technology was more commonly used than intravascular hypothermia technology (67.3 > 6.1%). The rates of minimally invasive hematoma removal and ventricular puncture were only 40.0 and 45.5%, respectively.ConclusionIn addition to traditional recognized basic life assessment and support technology, it is necessary to the use of promote specialized technology for neurological diseases, according to the characteristics of critical neurological diseases.

Abstract Background The serum orexin A level was significantly lower among patients with acute ischemic stroke (AIS) and negatively related to the volume of the infarction, but the relationship between serum orexin A and prognosis of AIS was still unclear. We aimed to clarify the association between serum orexin A and the short‐term neurological improvement in patients with mild to moderate AIS. Methods We consecutively enrolled patients with first ever mild to moderate AIS admitted to hospital within 48 h from symptom onset in this prospective observational study. The serum orexin A concentrations were determined on the second morning since the admission. The short‐term neurological improvement was defined as more than 1 point decrease in the National Institute of Health Stroke Scale score within 7 days after admission. Results We detected increased serum orexin A level in mild to moderate AIS patients with early onset of stroke‐related insomnia (33.44 vs 18.66 pg/ml, p = .004) as well as in patients with short‐term neurological improvement compared to those without improvement (31.78 vs 16.24 pg/ml, p = .038). The serum orexin A level was positively associated with the short‐term neurological improvement after adjusting for sleep condition and other related variables. Conclusion Serum orexin A might be a useful biomarker for the assessment of early prognosis in patients with mild to moderate AIS.

ObjectiveThis study aimed to develop a diagnostic model of multi-kinematic parameters for patients with amnestic mild cognitive impairment (aMCI).MethodIn this cross-sectional study, 94 older adults were included (33 cognitively normal, CN; and 61 aMCI). We conducted neuropsychological battery tests, such as global cognition and cognitive domains, and collected gait parameters by an inertial-sensor gait analysis system. Multivariable regression models were used to identify the potential diagnostic variables for aMCI. Receiver operating characteristic (ROC) curves were applied to assess the diagnostic accuracy of kinematic parameters in discriminating aMCI from healthy subjects.ResultsMultivariable regression showed that multi-kinematic parameters were the potential diagnostic variables for aMCI. The multi-kinematic parameter model, developed using Timed Up and Go (TUG) time, stride length, toe-off/heel stride angles, one-leg standing (OLS) time, and braking force, showed areas under ROC (AUC), 0.96 [95% confidence interval (CI), 0.905–0.857]; sensitivity, 0.90; and specificity, 0.91. In contrast, a single kinematic parameter’s sensitivity was 0.26–0.95 and specificity was 0.21–0.90. Notably, the separating capacity of multi-kinematic parameters was highly similar to Montreal Cognitive Assessment (MoCA; AUC: 0.96 vs. 0.95). Compared to cognitive domain tests, the separating ability was comparable to Auditory Verbal Learning Test (AVLT) and Boston Naming Test (BNT; AUC: 0.96 vs. 0.97; AUC: 0.96 vs. 0.94).ConclusionWe developed one diagnostic model of multi-kinematic parameters for patients with aMCI in Foshan.

BackgroundDeafness-dystonia-optic neuronopathy (DDON) syndrome, a condition that predominantly affects males, is caused by mutations in translocase of mitochondrial inner membrane 8A (TIMM8A)/deafness dystonia protein 1 (DDP1) gene and characterized by progressive deafness coupled with other neurological abnormalities. In a previous study, we demonstrated the phenotype of male mice carrying the hemizygous mutation of Timm8a1-I23fs49X. In a follow-up to that study, this study aimed to observe the behavioral changes in the female mutant (MUT) mice with homologous mutation of Timm8a1 and to elucidate the underlying mechanism for the behavioral changes.Materials and methodsHistological analysis, transmission electron microscopy (EM), Western blotting, hearing measurement by auditory brainstem response (ABR), and behavioral observation were compared between the MUT mice and wild-type (WT) littermates.ResultsThe weight of the female MUT mice was less than that of the WT mice. Among MUT mice, both male and female mice showed hearing impairment, anxiety-like behavior by the elevated plus maze test, and cognitive deficit by the Morris water maze test. Furthermore, the female MUT mice exhibited coordination problems in the balance beam test. Although the general neuronal loss was not found in the hippocampus of the MUT genotype, EM assessment indicated that the mitochondrial size showing as aspect ratio and form factor in the hippocampus of the MUT strain was significantly reduced compared to that in the WT genotype. More importantly, this phenomenon was correlated with the upregulation of translation of mitochondrial fission process protein 1(Mtfp1)/mitochondrial 18 kDa protein (Mtp18), a key fission factor that is a positive regulator of mitochondrial fission and mitochondrial size. Interestingly, significant reductions in the size of the uterus and ovaries were noted in the female MUT mice, which contributed to significantly lower fertility in the MUT mice.ConclusionTogether, a homologous mutation in the Timm8a1 gene caused the hearing impairment and psychiatric behavioral changes in the MUT mice; the latter phenotype might be related to a reduction in mitochondrial size regulated by MTP18.

ObjectivesThis study aimed to primarily examine the association between memory deficit and increased fall risk, second, explore the underlying neuroanatomical linkage of this association in the elderly with aMCI and mild AD.MethodsIn this cross-sectional study, a total of 103 older adults were included (55 cognitively normal, CN; 48 cognitive impairment, CI, elderly with aMCI, and mild AD). Memory was assessed by the Auditory Verbal Learning Test (AVLT). Fall risk was evaluated by the Timed Up and Go (TUG) Test, heel strike angles, and stride speed, which were collected by an inertial-sensor-based wearable instrument (the JiBuEn™ gait analysis system). Brain volumes were full-automatic segmented and quantified using AccuBrain® v1.2 from three-dimensional T1-weighted (3D T1W) MR images. Multivariable regression analysis was used to examine the extent of the association between memory deficit and fall risk, the association of brain volumes with memory, and fall risk. Age, sex, education, BMI, and HAMD scores were adjusted. Sensitivity analysis was conducted.ResultsCompared to CN, participants with aMCI and mild AD had poorer cognitive performance (p < 0.001), longer TUG time (p = 0.018), and smaller hippocampus and medial temporal volumes (p = 0.037 and 0.029). In the CI group, compared to good short delayed memory (SDM) performance (AVLT > 5), the elderly with bad SDM performance (AVLT ≤ 3) had longer TUG time, smaller heel strike angles, and slower stride speed. Multivariable regression analysis showed that elderly with poor memory had higher fall risk than relative good memory performance among cognitive impairment elderly. The TUG time increased by 2.1 s, 95% CI, 0.54∼3.67; left heel strike angle reduced by 3.22°, 95% CI, −6.05 to −0.39; and stride speed reduced by 0.09 m/s, 95% CI, −0.19 to −0.00 for the poor memory elderly among the CI group, but not found the association in CN group. In addition, serious medial temporal atrophy (MTA), small volumes of the frontal lobe and occipital lobe were associated with long TUG time and small heel strike angles; small volumes of the temporal lobe, frontal lobe, and parietal lobe were associated with slow stride speed.ConclusionOur findings suggested that memory deficit was associated with increased fall risk in the elderly with aMCI and mild AD. The association might be mediated by the atrophy of medial temporal, frontal, and parietal lobes. Additionally, increased fall risk, tested by TUG time, heel stride angles, and stride speed, might be objective and convenient kinematics markers for dynamic monitoring of both memory function and fall risk.

Abstract Background Brain injury is the leading cause of death and disability in survivors of cardiac arrest, where neuroinflammation is believed to play a pivotal role, but the underlying mechanism remains unclear. Pyroptosis is a pro-inflammatory form of programmed cell death that triggers inflammatory response upon infection or other stimuli. This study aims to understand the role of microglial pyroptosis in post-cardiac arrest brain injury. Methods Sprague-Dawley male rats underwent 10-min asphyxial cardiac arrest and cardiopulmonary resuscitation or sham-operation. Flow cytometry analysis, Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), co-immunoprecipitation, and immunofluorescence were used to evaluate activated microglia and CD11b-positive leukocytes after cardiac arrest and assess inflammasome activation and pyroptosis of specific cellular populations. To further explore the underlying mechanism, MCC950 or Ac-YVAD-cmk was administered to block nod-like receptor family protein 3 (NLRP3) or caspase-1, respectively. Results Our results showed that, in a rat model, successful resuscitation from cardiac arrest resulted in microglial pyroptosis and consequential inflammatory infiltration which was mediated by the activation of NLRP3 inflammasome. Targeting NLRP3 and caspase-1, the executor of pyroptosis, with selective inhibitors MCC950 and Ac-YVAD-cmk treatment significantly prevented microglial pyroptosis, reduced infiltration of leukocytes, improved neurologic outcome, and alleviated neuro-pathological damages after cardiac arrest in modeling rats. Conclusions This study demonstrates that microglial pyroptosis mediated by NLRP3 inflammasome is critically involved in the pathogenesis of post-cardiac arrest brain injury and provides a new therapeutic strategy.

Abstract Background Thrombolysis with recombinant tissue plasminogen activator (rtPA) improves outcome for patients with acute ischemic stroke (AIS), but many of them still have substantial disability. Glibenclamide (US adopted name, glyburide), a long-acting sulfonylurea, shows promising result in treating AIS from both preclinical and clinical studies. This study investigates the safety and efficacy of glibenclamide combined with rtPA in treating AIS patients. Methods This is a prospective, randomized, double-blind, placebo-controlled, multicenter trial with an estimated sample size of 306 cases, starting in January 2018. Patients aged 18 to 74 years, presented with a symptomatic anterior circulation occlusion with a deficit on the NIHSS of 4 to 25 points and treated with intravenous rtPA within the first 4.5 h of their clinical onsets, are eligible for participation in this study. The target time from the onset of symptoms to receive the study drug is of 10 h. Subjects are randomized 1: 1 to receive glibenclamide or placebo with a loading dose of 1.25 mg, followed by 0.625 mg every 8 h for total 5 days. The primary efficacy endpoint is 90-day good outcome, measured as modified Rankin Scale of 0 to 2. Safety outcomes are all-cause 30-day mortality and early neurological deterioration, with a focus on cardiac- and glucose-related serious adverse events. Discussion This study will provide valuable information about the safety and efficacy of oral glibenclamide for AIS patients treated with rtPA. This would bring benefits to a large number of patients if the agent is proved to be effective. Trial registration The trial was registered on September 14th 2017 at www.clinicaltrials.gov having identifier NCT03284463 . Registration was performed before recruitment was initiated.

Abstract Background Endovascular therapy (EVT) is increasingly used to improve cerebral reperfusion after moderate-to-severe acute ischemic stroke (AIS). However, the influence of hemodynamic factors on clinical outcome is still unclear after EVT. Dynamic cerebral autoregulation (dCA) is an important brain reserve mechanism and is impaired after AIS. This study aimed to explore the role of dCA in predicting the outcome of AIS patients after EVT. Methods AIS patients with severe stenosis/occlusion of unilateral middle cerebral artery (MCA) or internal carotid and treatment with EVT were enrolled to receive dCA examinations at the 24 h, 72 h and 7th day after stroke onset. Healthy volunteers were also recruited as controls. DCA was recorded from spontaneous fluctuations of blood pressure and MCA flow velocity. Transfer function analysis was used to derive dCA parameters, including phase difference (PD) and coherence in the low-frequency range (0.06–0.12 Hz). The clinical outcome was measured using the modified Rankin Scale (mRS) at 90 days after onset. Multivariate logistic regression was performed to reveal the correlation between dCA and clinical outcomes. The receiver operation characteristics (ROC) curve was performed to determine the cut-off point of PD. Results A total of 62 AIS patients and 77 healthy controls were included. Compared with controls, dCA were impaired bilaterally till to 7th day after onset in patients, presenting as much lower PD value on the ipsilateral side. During follow-up, we found that PD on the ipsilateral side at 24 h after onset was significantly lower in patients with unfavourable outcome (n = 41) than those with favourable outcome (n = 21), even after adjustment of confounding factors (p = 0.009). ROC curve analysis revealed that PD

Background and PurposeAn increasing number of autoimmune encephalitis (AE)-associated autoantibodies have been successfully characterized. However, many cases of AE remain unexplained on account of unknown antibodies. The aim of the present study was to identify a novel antibody against collapsin response mediator protein 2 (CRMP2) in suspected AE patients.MethodsA patient’s serum and cerebrospinal fluid samples tested negative for known AE antibodies; however, strong immunolabel signals were observed in the neuronal cytoplasm of the cortex, hippocampus, and Purkinje cells on rat brain sections. Immunoprecipitation from the rat brain protein lysate, followed by mass spectrometry analysis, was used to identify the targeting antigen. Western blotting and cell-based assay with antigen-overexpressing HEK293T cells were used for antibody specificity, epitope, IgG subtype determination, and retrospective study.ResultsAn antibody against CRMP2, a synaptic protein involved in axon guidance, was identified. The immunostains of the patient’s samples on rat brain sections were eliminated by pre-absorption with HEK293T cells overexpressing CRMP2. The samples specifically immunoreacted with CRMP2, but not with CRMP1, CRMP3, CRMP4, and CRMP5. The C-terminus of CRMP2 with 536 amino acids contained the epitope for antibody binding. The subtype analysis showed that the anti-CRMP2 antibody was IgG4. Furthermore, a screening of 46 patients with neurological disoders and neuro-cytoplasm immunostainings on rat brain sections resulted in the identification of anti-CRMP2 antibodies in a case of encephalomyelitis. The two patients responded well to immunotherapies.ConclusionsThis study discovered that a novel anti-CRMP2 antibody was associated with suspected AE and thus should be included in the testing list for AE.

Status epilepticus (SE) is a neurological emergency usually accompanied by acute cerebral edema and long-term cognitive impairment, and is characterized by neurodegeneration and aberrant hyperphosphorylated tau protein (p-tau) aggregation. The glia-lymphatic (glymphatic) system plays a central role in facilitating the clearance of metabolic waste from the brain, but its relationship with cerebral edema and cognitive dysfunction after SE is unclear. We hypothesized that cerebral edema after SE might impair glymphatic system function through compression, thus leading to impaired removal of metabolic waste, and ultimately affecting long-term cognitive function. Our results showed that glymphatic system function was temporarily impaired, as evidenced by 2-photon imaging, MRI enhancement, imaging of brain sections, and astrocytic water channel aquaporin 4 (AQP4) protein polarization. The severity of cerebral edema on MRI correlated well with glymphatic system dysfunction within 8 days following SE. Moreover, when cerebral edema was alleviated by glibenclamide treatment or genetic deletion of Trpm4, post-SE glymphatic system function recovered earlier, along with fewer p-tau–deposited neurons and neuronal degeneration and better cognitive function. These findings suggest that SE-induced cerebral edema may cause glymphatic system dysfunction and render the post-SE brain vulnerable to p-tau aggregation and neurocognitive impairment.

Abstract Increasing evidence indicates that immune system dysfunction affects anti‐N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis. This study aims to investigate the relationship between adhesion molecules and the pathophysiology in anti‐NMDAR encephalitis. Soluble forms of Intercellular adhesion molecule‐1 (sICAM‐1), vascular adhesion molecule‐1 (sVCAM‐1), and L‐selectin (sL‐selectin), were measured in the CSF and serum of 26 participants with anti‐NMDAR encephalitis, 11 patients with schizophrenia and 22 patients with noninflammatory disorders. CSF levels of sICAM‐1, sVCAM‐1 and sL‐selectin were significantly elevated in the anti‐NMDAR encephalitis group. sVCAM‐1 levels were positively associated with modified Rankin scale score in anti‐NMDAR encephalitis patients at the onset and 3‐month follow‐up.

Abstract Background Despite the essential functions of the intestinal microbiota in human physiology, little has been reported about the microbiome in neurocritically ill patients. This investigation aimed to evaluate the characteristics of the gut microbiome in neurocritically ill patients and its changes after admission. Furthermore, we investigated whether the characteristics of the gut microbiome at admission were a risk factor for death within 180 days. Methods This prospective observational cohort study included neurocritically ill patients admitted to the neurological intensive care unit of a large university-affiliated academic hospital in Guangzhou. Faecal samples were collected within 72 h after admission (before antibiotic treatment) and serially each week. Healthy volunteers were recruited from a community in Guangzhou. The gut microbiome was monitored via 16S rRNA gene sequence analysis, and the associations with the clinical outcome were evaluated by a Cox proportional hazards model. Results In total, 98 patients and 84 age- and sex-matched healthy subjects were included in the analysis. Compared with healthy subjects, the neurocritically ill patients exhibited significantly different compositions of intestinal microbiota. During hospitalization, the α-diversity and abundance of Ruminococcaceae and Lachnospiraceae decreased significantly over time in patients followed longitudinally. The abundance of Enterobacteriaceae was positively associated with the modified Rankin Scale at discharge. In the multivariate Cox regression analysis, Christensenellaceae and Erysipelotrichaceae were associated with an increased risk of death. The increases in intestinal Enterobacteriales and Enterobacteriaceae during the first week in the neurological intensive care unit were associated with increases of 92% in the risk of 180-day mortality after adjustments. Conclusions This analysis of the gut microbiome in 98 neurocritically ill patients indicates that the gut microbiota composition in these patients differs significantly from that in a healthy population and that the magnitude of this dysbiosis increases during hospitalization in a neurological intensive care unit. The gut microbiota characteristics seem to have an impact on patients’ 180-day mortality. Gut microbiota analysis could hopefully predict outcome in the future.

Abstract Background and Purpose Intracranial atherosclerotic stenosis (ICAS) is the most common cause of ischemic stroke (IS) and is associated with stroke recurrence. It results in IS due to a variety of mechanisms. However, the influence of brain reserve mechanism on different stroke mechanism is still unclear. Cerebral autoregulation (CA) is an important brain reserve mechanism and is impaired after IS. This study aimed to explore the impaired pattern of CA and assess the association between CA and stroke risk factors in different stroke mechanism caused by ICAS. Methods IS patients with ICAS (50%–99% stenosis/occlusion) in middle cerebral artery (MCA) or internal carotid artery were enrolled to receive CA examinations within 7 days after onset. Healthy volunteers were also recruited as controls. CA was recorded from spontaneous fluctuations of blood pressure and MCA flow velocity. Transfer function analysis was used to derive CA parameters, including phase difference (PD) and coherence in the low‐frequency range (0.06–0.12 Hz). Results A total of 89 IS patients and 90 healthy controls were included. Compared with controls, CA was impaired ipsilaterally in patients with parent artery atherosclerosis occluding penetrating artery (POPA) while CA was bilaterally impaired in other stroke mechanisms. And CA on ipsilateral hemisphere was correlated with hypertension/hyperlipidemia in patients with POPA (r = −0.481, p = .008; r = −0.484, p = .008). While CA on ipsilateral hemisphere was correlated with perfusion parameter including the arterial spin‐labeling (ASL) parameter cerebral blood flow (CBF) (r = 0.893, p = .007) and collateral circulation status the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) (r = 0.610, p = .021) in patients with hypoperfusion mechanism. Conclusion In IS patients, CA was impaired heterogeneously and was correlated with different risk factors in varied stroke mechanism. CA can be as an informative determinant of stroke risk in patients with ICAS and to help improving individualized treatment strategies in the presence of ischemic stroke caused by ICAS.

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune neurological disorder. Osteopontin (OPN) is a secreted multifunctional phosphorylated glycoprotein that regulates various autoimmune and inflammatory diseases, but its diagnostic and prognostic values in anti-NMDAR encephalitis patients remain elusive. This retrospective study aimed to determine the levels of OPN and related cytokines in cerebrospinal fluid (CSF) of anti-NMDAR encephalitis patients and to assess their influence on disease severity so as to evaluate their efficacy as biomarkers for diagnosis and prognosis. CSF samples from 33 anti-NMDAR encephalitis, 13 viral encephalitis, and 21 controls were collected. All CSF were tested for levels of OPN and inflammation-associated cytokines [interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α] via ELISA. In addition, 15 anti-NMDAR encephalitis patients without follow-up relapse were re-examined for these four parameters 3 months later. The clinical status was evaluated by modified Rankin Scale (mRS) scores. Results showed that the CSF levels of these cytokines were increased in anti-NMDAR encephalitis patients compared to controls but not viral encephalitis patients. Their levels were decreased in remission compared with that in acute stage. Moreover, CSF OPN positively correlated with IL-6, white blood cell (WBC) counts, and C-reactive protein (CRP) levels in anti-NMDAR encephalitis patients. However, no associations were found between OPN or related cytokines and mRS scores in acute stage in anti-NMDAR encephalitis patients. Overall, CSF OPN and related cytokines were increased when anti-NMDAR encephalitis patients are in acute stage and decreased in remission, suggesting the underlying neuro-inflammatory process in this disease. However, they are not qualified with diagnostic or prognostic value.

Introduction Anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is an autoimmune-mediated disease that is common in young female patients with ovarian teratomas. With appropriate immunotherapy, most patients achieve a good prognosis. Nevertheless, some patients may be refractory to first- and second-line immunotherapy, thus alternative treatments are required for these patients. Case presentation: We present a case of anti-NMDA receptor encephalitis with ovarian teratoma. After the prompt removal of the teratoma and intense immunotherapy was administered, including an intravenous methylprednisolone pulse, intravenous immunoglobin, plasmapheresis, immunoadsorption, intravenous cyclophosphamide, and rituximab, the patient’s neurologic status did not improve. Bilateral salpingo-oophorectomy was then conducted, and intrathecal injection of methotrexate (MTX) and dexamethasone (DXM) was performed. The patient’s neurological symptoms improved dramatically, and she achieved a good prognosis after 23 months. Conclusions Intrathecal injection of MTX and DXM may be beneficial for treatment of refractory cases of anti-NMDA receptor encephalitis. Additional research is required to elucidate the mechanisms of intrathecal treatment with this therapy.

Abstract Objective To explore the predictive value of serum creatinine (Cr) to cystatin C (CysC) ratio in neurocritically ill patients. Methods We conducted a retrospectively observational study of adult patients admitted to a neurocritical care unit (NCU) between Jan 2013 and Jan 2017. Patients were excluded if

PurposeThe application of metagenomic next-generation sequencing (mNGS) in the diagnosis of tuberculous meningitis (TBM) remains poorly characterized. Here, we retrospectively analyzed data from patients with TBM who had taken both mNGS and conventional tests including culture of Mycobacterium tuberculosis (MTB), polymerase chain reaction (PCR) and acid-fast bacillus (AFB) stain, and the sensitivity and specificity of these methods were compared.MethodsWe retrospectively recruited TBM patients admitted to the hospital between December 2015 and October 2018. The first collection of cerebrospinal fluid (CSF) samples underwent both mNGS and conventional tests. In addition, patients with bacterial/cryptococcal meningitis or viral meningoencephalitis were mNGS positive controls, and a patient with auto-immune encephalitis was an mNGS negative control.ResultsTwenty three TBM patients were classified as 12 definite and 11 clinical diagnoses, which were based on clinical manifestations, pathogen evidence, CSF parameters, brain imaging, and treatment response. The mNGS method identified sequences of Mycobacterium tuberculosis complex (MBTC) from 18 samples (18/23, 78.26%). In patients with definite TBM, the sensitivity of mNGS, AFB, PCR, and culture to detect MTB in the first CSF samples were 66.67, 33.33, 25, and 8.33%, respectively. The specificity of each method was 100%. Among the four negative mNGS cases (4/23, 17.39%), three turned out positive by repeated AFB stain. The agreement of mNGS with the total of conventional methods was 44.44% (8/18). Combination of mNGS and conventional methods increased the detection rate to 95.65%. One patient was diagnosed as complex of TBM and cryptococcal meningitis, in which AFB stain and cryptococcal antigen enzyme immunoassay were positive and the DNA of Cryptococcus neoformans was detected by mNGS.ConclusionOur study indicates that mNGS is an alternative method to detect the presence of mycobacterial DNA in CSF samples from patients with TBM and deserves to be applied as a front-line CSF test.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is accepted as an autoimmune disorder of the central nervous system (CNS). NLR family pyrin domain containing 3 (NLRP3) inflammasome, a potent innate inflammatory mediator, can activate IL-1β and induce the migration of T helper cell into CNS. However, the possible role of NLRP3 inflammasome in the pathogenesis of anti-NMDAR encephalitis remains unclear. This study aims to determine the levels of NLRP3 and related cytokines (IL-1β, IL-6, and IL-17) in the cerebrospinal fluid (CSF) of anti-NMDAR encephalitis patients and to assess whether NLRP3 influences the clinical outcomes of this disease. Twenty-five patients with anti-NMDAR encephalitis, 12 viral meningoencephalitis patients and 26 controls with non-inflammatory neurological diseases were recruited. CSF NLRP3 inflammasome, IL-1β, IL-6, and IL-17 were measured by enzyme-linked immunosorbent assay. Thirteen out of 25 patients were re-examed for the concentrations of NLRP3 and cytokines 6 months later. Our results showed significant increases of CSF NLRP3 inflammasome, IL-1β, IL-6, and IL-17 in anti-NMDAR encephalitis patients. There were positive correlations between CSF NLRP3 inflammasome and cytokines in anti-NMDAR encephalitis patients. There was also a positive correlation between maximum modified Rankin Scale (mRS) scores and CSF NLRP3 inflammasome in anti-NMDAR encephalitis patients. During follow-up, the decrease of mRS was positively correlated with the decrease of CSF NLRP3 inflammasomes. These results suggested that the level of CSF NLRP3 inflammasome could represent the severity of anti-NMDAR encephalitis and the reduction of CSF NLRP3 inflammasome could act as an indicator for the prognosis of this disease.

BackgroundCD138 (also known as syndecan-1) is an important component of endothelial cell glycocalyx, and it is reportedly involved in negative regulation of various inflammatory processes. The clinical implications of circulating and cerebrospinal fluid (CSF) soluble CD138 (sCD138) in patients with Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis remain unclear.ObjectiveThe aim of the current study was to investigate associations between serum and CSF sCD138 levels in anti-NMDAR encephalitis patients.MethodsThe participants enrolled in the study included 27 with anti-NMDAR encephalitis, 11 with viral meningoencephalitis, and 22 controls. At acute stage and 3 to 6-month follow-up time-points, sCD138, tumor necrosis factor-α, matrix metalloproteinase-2, and matrix metalloproteinase-9 in serum and CSF were measured in all participants via enzyme-linked immunosorbent assays.ResultsSerum and CSF levels of sCD138 were significantly increased in patients with anti-NMDAR encephalitis. Furthermore, after 3–6 months of follow-up CSF sCD138 levels were significantly decreased in anti-NMDAR encephalitis patients. Changes in sCD138 levels were significantly associated with amelioration of modified Rankin Scale scores in patients with anti-NMDAR encephalitis.ConclusionIn anti-NMDAR encephalitis patients, high circulating, and CSF sCD138 is associated with inflammation and poor clinical prognosis. The present study suggests that sCD138 may be an informative biomarker of inflammation in anti-NMDAR encephalitis.

Objective: Gut microbiota is a newly identified risk factor for stroke, and there are no large prospective studies linking the baseline gut microbiome to long-term risk of stroke. We present here the correlation between the gut microbiota and stroke risk in people with no prior stroke history.Methods: A total of 141 participants aged ≥60 years without prior history of stroke were recruited and divided into low-risk, medium-risk, and high-risk groups based on known risk factors and whether they were suffering from chronic diseases. The composition of their gut microbiomes was compared using 16S rRNA gene amplicon next-generation-sequencing and Quantitative Insights into Microbial Ecology (QIIME) analysis. Levels of fecal short-chain fatty acids were measured using gas chromatography.Results: We found that opportunistic pathogens (e.g., Enterobacteriaceae and Veillonellaceae) and lactate-producing bacteria (e.g., Bifidobacterium and Lactobacillus) were enriched, while butyrate-producing bacteria (e.g., Lachnospiraceae and Ruminococcaceae) were depleted, in the high-risk group compared to the low-risk group. Butyrate concentrations were also lower in the fecal samples obtained from the high-risk group than from the low-risk group. The concentrations of other short-chain fatty acids (e.g., acetate, propionate, isobutyrate, isovalerate, and valerate) in the gut were comparable among the three groups.Conclusion: Participants at high risk of stroke were characterized by the enrichment of opportunistic pathogens, low abundance of butyrate-producing bacteria, and reduced concentrations of fecal butyrate. More researches into the gut microbiota as a risk factor in stroke should be carried out in the near future.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune inflammatory brain disease that can develop a variety of neuropsychiatric presentations. However, the underlying nature of its inflammatory neuronal injury remains unclear. Mitochondrial DNA (mtDNA) is recently regarded as a damage-associated molecular pattern molecule (DAMP) that can initiate an inflammatory response. In the presenting study, we aimed to evaluate the levels of cell-free mtDNA in cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis and to determine a potential role of cell-free mtDNA in the prognosis of anti-NMDAR encephalitis. A total of 33 patients with NMDAR encephalitis and 17 patients with other non-inflammatory disorders as controls were included in this study. The CSF levels of cell-free mtDNA were measured by quantitative polymerase chain reaction (qPCR). Cytokines including interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNF-α) were measured by ELISA. The modified Rankin scale (mRS) score was evaluated for neurologic disabilities. Our data showed that the CSF levels of cell-free mtDNA and inflammation-associated cytokines were significantly higher in the patients with anti-NMDAR encephalitis compared with those in controls. Positive correlations were detected between the CSF levels of cell-free mtDNA and mRS scores of patients with anti-NMDAR encephalitis at both their admission and 6-month follow up. These findings suggest that the CSF level of cell-free mtDNA reflects the underlying neuroinflammatory process in patients with anti-NMDAR encephalitis and correlates with their clinical mRS scores. Therefore, cell-free mtDNA may be a potential prognostic biomarker for anti-NMDAR encephalitis.

Background: Innate immune response to neuronal death is one of the key events of the pathogenesis of ischemic brain injury. Interleukin-1 receptor-associated kinase (IRAK)-M, encoded by gene Irak3, negatively regulates toll-like receptor signaling by interacting with the MyD88–IRAK-4–IRAK-1 complex and blocking the phosphorylation and dissociation of IRAK-1. Its function in the ischemic stroke is unknown.Objective: This study aims to investigate whether IRAK-M deficiency could exacerbate neuroinflammation and neurovascular injuries during cerebral ischemia and reperfusion.Methods: Male C57BL/6 mice and Irak3 knockout mice were subjected to 45 min of middle cerebral artery occlusion and 4 or 24 h of reperfusion. Transcription of Irak3 gene was evaluated by quantitative real-time PCR (qRT-PCR). Then, infarct volume, neurological score, brain water content, and Evans blue leakage were compared between knock-out and wild-type mice after reperfusion. Through the observation of gross brain specimen after cerebral ischemia, the incidence of hemorrhage transformation was compared between KO and WT mice. To explore underlying signaling pathways involved in IRAK-M deficiency, major proinflammatory cytokines and NF-κB signaling were measured by qRT-PCR and Western blot.Results: The expression of IRAK-M peaked at 1 h after reperfusion, and then gradually decreased within the first 24 h, which was abolished by blocking the expression of hypoxia induced factor 1α. IRAK-M deficiency increased infarct volume, brain edema, the incidence of hemorrhage transformation, and the permeability of blood–brain barrier. In addition, the NF-κB-mediated expressions of proinflammatory cytokines and the activation of microglia in the ipsilateral brain from knock-out mice were much higher than those in wild-type littermates.Conclusion: IRAK-M deletion exacerbates neurovascular damages which are related to the pronounced activation of NF-κB signaling and neuroinflammatory responses during cerebral ischemia-reperfusion in mice. Our study indicates that IRAK-M has neuroprotective effect and has potential to facilitate the development of new pharmaceuticals that reduce neurovascular complications.

Background and Purpose: The 40-Hz steady state response (SSR) reflects early sensory processing and has the potential to differentiate disease severity. This study aims to evaluate the predictive value of 40-Hz SSRs on the prognosis of patients with large hemispheric infarction (LHI).Methods: We conducted a retrospective study in patients with LHI admitted to the neurological intensive care unit (NICU) of Nanfang Hospital, Southern Medical University, Guangzhou, China, between June 2008 and December 2014. Forty-hertz SSRs were recorded within 72 h of onset and categorized into 3 grades. The correlation between 40-Hz SSR grading and clinical outcome was examined.Results: Of the 97 eligible participants, 41 (42.3%) died within 30 days and 68 (70.1%) exhibited a poor outcome (modified Rankin Scale of 5 and 6) at 90 days after the onset of LHI. We found that 40-Hz SSRs correlated significantly with NIHSS scores at admission and patient outcome. Moreover, Grade III 40-Hz SSR (bilateral sine waves that either disappeared or were not clearly identifiable) had a specificity of 97% and a positive predictive value of 94% in predicting 90-days poor outcome; Grade III 40-Hz SSR also had a specificity of 91% and a positive predictive value of 74% in predicting 30-days mortality.Conclusions: 40-Hz SSR could be used as a simple and specific method in predicting poor prognosis after LHI.

Objective: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis predominantly affects children and young women; the disease can have a multistage presentation and exhibit a wide variety of neuropsychiatric features. This study aimed to investigate the profile of YKL-40 (Chitinase 3-like 1) in anti-NMDAR encephalitis patients and evaluate its association with modified Rankin Scale (mRS) scores and expression of inflammatory cytokines.Methods: A total of 66 patients were enrolled in this study, 33 with anti-NMDAR encephalitis, 13 with viral meningitis and 20 with non-inflammatory neurological disease. Patients were evaluated to determine mRS scores at disease onset and at the 3 month follow-up; cerebrospinal fluid (CSF) samples were collected in the meantime. CSF levels of YKL-40 and cytokines (TNF-α, IL-6, IL-10) were measured by enzyme-linked immunosorbent assay.Results: CSF levels of YKL-40 and inflammatory cytokines (TNF-α, IL-6, IL-10) were all more highly elevated in patients with anti-NMDAR encephalitis at the acute stage of disease compared with the controls. Levels of CSF YKL-40 were correlated with levels of IL-6 both at disease onset and at the 3 month follow-up. Changes in YKL-40 levels were significantly correlated with improved mRS scores in patients with anti-NMDAR encephalitis.Conclusion: Our study suggests that CSF levels of YKL-40 in patients with anti-NMDAR encephalitis were increased and correlated with clinical mRS scores. This may be reflective of the underlying neuroinflammatory process. YKL-40 demonstrates potential as a possible biomarker for the prognosis of anti-NMDAR encephalitis.

Background and Purpose: This study aims to explore the cause and predictive value of hyperchloremia in critically ill stroke patients.Materials and Methods: We conducted a retrospective study of a prospectively collected database of adult patients with first-ever acute ischemic stroke (AIS) or intracerebral hemorrhage (ICH) admitted to the neurointensive care unit (NICU) of a university-affiliated hospital, between January 2013 and December 2016. Patients were excluded if admitted beyond 72 h from onset, if they required neurocritical care for less than 72 h, and were treated with hypertonic saline within 72 h or had creatinine clearance less than 15 mL/min.Results: Of 405 eligible patients, the prevalence of hyperchloremia ([Cl−] ≥ 110 mmol/L) was 8.6% at NICU admission ([Cl−]0) and 17.0% within 72 h ([Cl−]max). Thirty-eight (9.4%) patients had new-onset hyperchloremia and 110 (27.1%) had moderate increase in chloride (Δ[Cl−] ≥ 5 mmol/L; Δ[Cl−] = [Cl−]max − [Cl−]0) in the first 72 h after admission, which were found to be determined by the sequential organ failure assessment score in multivariate logistic regression analysis. Neither total fluid input nor cumulative fluid balance had significant association with such chloride disturbance. New-onset hyperchloremia and every 5 mmol/L increment in Δ[Cl−] were both associated with increased odds of 30-day mortality and 6-month poor outcome, although no independent significance was found in multivariate models.Conclusion: Hyperchloremia tends to occur in patients more severely affected by AIS and ICH. Although no independent association was found, new-onset hyperchloremia and every 5 mmol/L increment in Δ[Cl−] were related to poorer outcome in critically ill AIS and ICH patients.Subject terms: clinical studies, intracranial hemorrhage, ischemic stroke, mortality/survival, quality and outcomes.

Background Sudden cardiac arrest (CA) often results in severe injury to the brain, and neuroprotection after CA has proved to be difficult to achieve. Herein, we sought to investigate the effects of metformin pretreatment on brain injury secondary to CA and cardiopulmonary resuscitation. Methods and Results Rats were subjected to 9‐minute asphyxial CA after receiving daily metformin treatment for 2 weeks. Survival rate, neurologic deficit scores, neuronal loss, AMP‐activated protein kinase (AMPK), and autophagy activation were assessed at indicated time points within the first 7 days after return of spontaneous circulation. Our results showed that metformin pretreatment elevated the 7‐day survival rate from 55% to 85% and significantly reduced neurologic deficit scores. Moreover, metformin ameliorated CA‐induced neuronal degeneration and glial activation in the hippocampal CA1 region, which was accompanied by augmented AMPK phosphorylation and autophagy activation in affected neuronal tissue. Inhibition of AMPK or autophagy with pharmacological inhibitors abolished metformin‐afforded neuroprotection, and augmented autophagy induction by metformin treatment appeared downstream of AMPK activation. Conclusions Taken together, our data demonstrate, for the first time, that metformin confers neuroprotection against ischemic brain injury after CA/cardiopulmonary resuscitation by augmenting AMPK‐dependent autophagy activation.

BackgroundWe previously have shown that glibenclamide (GBC), a sulfonylurea receptor 1–transient receptor potential M4 (SUR1‐TRPM4) channel inhibitor, improves survival and neurological outcome after asphyxial cardiac arrest and cardiopulmonary resuscitation (ACA/CPR). Here, we further compare the efficacy of GBC with target temperature management (TTM) and determine whether the efficacy of GBC is affected by TTM. Methods and ResultsMale Sprague‐Dawley rats (n=213) subjected to 10‐minute ACA/CPR were randomized to 4 groups after return of spontaneous circulation (ROSC): normothermia control (NT); GBC; TTM; and TTM+GBC. Survival, neurodeficit scores, histological injury, as well as the expressions of SUR1 and TRPM4 were evaluated. The 7‐day survival rate was 34.4% (11 of 32) in the NT group, 65% (13 of 20) in the GBC group, 50% (10 of 20) in the TTM group, and 70% (14 of 20) in the TTM+GBC group. Rats that received either GBC, TTM alone, or in combination showed less neurological deficit than NT control at 24, 48, and 72 hours and 7 days after ROSC. Moreover, TTM or GBC ameliorated neuronal degeneration and glial activation in the hippocampal CA1 region with similar efficacy, whereas the combination of them had a trend toward better effect. The subunits of SUR1‐TRPM4 heterodimers were both strongly upregulated after ACA/CPR and expressed in multiple types of brain cells, but partly suppressed by TTM. ConclusionsGBC is comparable to TTM in improving survival and neurological outcome after ACA/CPR. When GBC is given along with TTM, less histological injury tended to be achieved.

BACKGROUND: Prediction of extubation failure, particularly in neurocritical patients, is unique and controversial. We conducted a systematic review and meta-analysis to identify the risk factors for extubation failure in these patients. METHODS: A literature search of databases (MEDLINE, EMBASE, the Cochrane Library, and Web of Science) was performed up to August of 2013 to identify trials that evaluated extubation failure predictors. Included trials were either prospective or retrospective cohort studies. RESULTS: Nine studies involving 928 participants were included. The systematic review and meta-analysis revealed that the following were predictive for extubation failure: pneumonia, atelectasis, mechanical ventilation of >24 h, a low Glasgow Coma Scale score (7-9T) (OR = 4.96, 95% CI = 1.61-15.26, P = 0.005), the inability to follow commands (OR = 2.07, 95% CI = 1.15-3.71, P = 0.02), especially the command to close the eyes, thick secretion, and no intact gag reflex. Meanwhile, the following were not predictive for extubation failure: sex, secretion volume, coughing upon suctioning, and the inability to follow one command among showing two fingers, wiggling the toes, or coughing on command. Additionally, some traditional weaning parameters were shown to poorly predict extubation failure in neurocritical patients. CONCLUSIONS: Besides pneumonia, atelectasis, and the duration of mechanical ventilation, other factors that should be taken into consideration in the prediction of extubation failure when neurocritical patients are weaned from tracheal intubation include neurologic abilities (Glasgow Coma Scale score and following commands), the secretion texture, and the presence of a gag reflex.

Type 2 episodic ataxia (EA2) is the most common subtype among a group of rare hereditary syndromes characterized by recurrent attacks of ataxia. More than 60 mutations and several gene rearrangements due to large deletions in CACNA1A gene have been reported so far for the cause of EA2. Because CACNA1A gene is a large gene containing 47 exons and there is no hot spot mutation, direct sequencing will be a challenge in clinical genetic testing. In this study, we used next generation sequencing technology to identify a novel nonsense mutation of CACNA1A (p.Tyr1957Ter, NP_001120693.1) resulting in truncated protein without 305 amino acids in the c-terminus. Sanger sequencing confirmed the heterozygous mutation of CACNA1A in a Chinese family with 11 affected individuals. Affected individuals experienced recurrent attacks with or without nystagmus, dysarthria, seizure, myokymia, dystonia, weakness, blurred vision, visual field defects, diplopia, migraine, dizziness, nausea and vomiting, sweating and abdominal pain. This is the first report of EA2 in a Chinese family that carries a novel mutation in CACNA1A gene and had abdominal pain as a novel phenotype associated with EA2.

During the COVID-19 epidemic, the treatment of critically ill patients has been increasingly difficult and challenging. During the epidemic, some patients with neurological diseases also have COVID-19, which could be misdiagnosed and cause silent transmission and nosocomial infection. Such risk is high in a neurological intensive care unit (NCU). Therefore, prevention and control of epidemic in critically ill patients is of utmost importance. The principle of NCU care should include comprehensive screening and risk assessment, weighing risk against benefits and reducing the risk of COVID-19 transmission while treating patients as promptly as possible.