A multicenter, randomized, open-label, phase 2 clinical study of telitacicept in adult patients with generalized myasthenia gravis.

BACKGROUND AND PURPOSE: This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle-specific kinase antibodies and were receiving standard-of-care therapy. METHODS: Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard-of-care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. RESULTS: Twenty-nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. CONCLUSION: Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial.

miR-127-5p regulates FAIM2-mediated cell apoptosis and participates in cerebral ischemia-reperfusion injury.

Mechanical thrombectomy (MT) has become an effective re-airway method for cerebral ischemia-reperfusion injury (CI/RI). However, at present, there are few studies on the impact of MT therapy on the prognosis of CI/RI patients at home and abroad. Therefore, this paper aims to analyze the relevant factors affecting the prognosis of CI/RI patients after MT therapy. The main regulatory miRNAs during CI/RI in patients with MT were screened and studied. Serums were obtained from 80 patients (moderate to severe stroke) who underwent MT. Clinical information was recorded using a unified standard questionnaire. According to the modified Rankin Scale, the patients were divided into a good prognosis group and a poor prognosis group. The clinical data were compared respectively, and univariate and multivariate Logistic regression analysis was performed. ROC curves were drawn, and Kaplan-Merier method determined whether different NIHSS scores at admission had any difference in the in-hospital survival rate of CI/RI patients treated with MT. miRNAs in serum were detected and screened out. Cell and animal models were established, in which miRNAs and apoptotic molecules were detected. miRNA target genes were predicted, and the mechanism of miRNA regulation of apoptosis was verified. Gender, smoking, drinking, diabetes, hypertension, hyperlipidemia, age, and alcohol consumption suggested no difference in the two groups. The rates of smoking history, diabetes, hypertension, and hyperlipidemia in the poor prognosis group were higher than those in the good prognosis group. Smoking and diabetes were independent risk factors for poor prognosis. miR-127-5p expression in CI/RI patients with poor prognosis was higher than that in those with good prognosis. miR-127-5p expression was also elevated in both cell and animal models. Cell apoptosis was weakened after miR-127-5p knockdown, and tissue infarction in animal models was also reduced. FAIM2 was a target gene of miR-127-5p. silencing FAIM2 enhanced apoptosis after miR-127-5p knockdown. miR-127-5p/FAIM2 axis can be a new strategy to treat and prevent brain injury in CI/RI patients treated with MT.

Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke: The ARAMIS Randomized Clinical Trial.

Importance: Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown. Objective: To investigate whether dual antiplatelet therapy (DAPT) is noninferior to intravenous thrombolysis among patients with minor nondisabling acute ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded end point, noninferiority randomized clinical trial included 760 patients with acute minor nondisabling stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5, with ≤1 point on the NIHSS in several key single-item scores; scale range, 0-42). The trial was conducted at 38 hospitals in China from October 2018 through April 2022. The final follow-up was on July 18, 2022. Interventions: Eligible patients were randomized within 4.5 hours of symptom onset to the DAPT group (n = 393), who received 300 mg of clopidogrel on the first day followed by 75 mg daily for 12 (±2) days, 100 mg of aspirin on the first day followed by 100 mg daily for 12 (±2) days, and guideline-based antiplatelet treatment until 90 days, or the alteplase group (n = 367), who received intravenous alteplase (0.9 mg/kg; maximum dose, 90 mg) followed by guideline-based antiplatelet treatment beginning 24 hours after receipt of alteplase. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score of 0 or 1 (range, 0-6), at 90 days. The noninferiority of DAPT to alteplase was defined on the basis of a lower boundary of the 1-sided 97.5% CI of the risk difference greater than or equal to -4.5% (noninferiority margin) based on a full analysis set, which included all randomized participants with at least 1 efficacy evaluation, regardless of treatment group. The 90-day end points were assessed in a blinded manner. A safety end point was symptomatic intracerebral hemorrhage up to 90 days. Results: Among 760 eligible randomized patients (median [IQR] age, 64 [57-71] years; 223 [31.0%] women; median [IQR] NIHSS score, 2 [1-3]), 719 (94.6%) completed the trial. At 90 days, 93.8% of patients (346/369) in the DAPT group and 91.4% (320/350) in the alteplase group had an excellent functional outcome (risk difference, 2.3% [95% CI, -1.5% to 6.2%]; crude relative risk, 1.38 [95% CI, 0.81-2.32]). The unadjusted lower limit of the 1-sided 97.5% CI was -1.5%, which is larger than the -4.5% noninferiority margin (P for noninferiority <.001). Symptomatic intracerebral hemorrhage at 90 days occurred in 1 of 371 participants (0.3%) in the DAPT group and 3 of 351 (0.9%) in the alteplase group. Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke presenting within 4.5 hours of symptom onset, DAPT was noninferior to intravenous alteplase with regard to excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03661411.

Clinical effects of continuous theta burst stimulation for generalized anxiety disorder and a mechanism involving α oscillations: a randomized controlled trial.

BACKGROUND: Continuous theta burst stimulation (cTBS) is a much more rapid protocol than low-frequency repetitive transcranial magnetic stimulation (rTMS), but no clinical trial has yet investigated the efficacy and mechanisms of cTBS for the treatment of generalized anxiety disorder. The purpose of this study was to compare the clinical effects and α oscillations induced by cTBS versus 1 Hz rTMS as predictors of response, and to assess the underlying mechanisms of the therapeutic effects of cTBS in patients with generalized anxiety disorder. METHODS: We randomly allocated 120 patients with generalized anxiety disorder to receive cTBS (n = 41), 1 Hz rTMS (n = 40) or sham cTBS (n = 39) over the right dorsolateral prefrontal cortex; we also included healthy controls (n = 30) to compare neurophysiological data. We analyzed changes in Hamilton Anxiety Rating Scale scores and α oscillations (frequency and power) at baseline, post-treatment and 1-month follow-up. RESULTS: After 20 sessions of treatment, patients' anxiety had improved and α power had increased in the cTBS and 1 Hz rTMS groups. However, at 1-month follow-up the cTBS group had significantly more responders and remitters, and higher α oscillations than the 1 Hz rTMS group (post hoc analysis: cTBS > rTMS > sham). At baseline, α frequency was inversely correlated with psychological symptom scores on the Hamilton Anxiety Rating Scale (r = -0.613, p < 0.001); post-treatment, this correlation was present only in the cTBS group (r = -0.685, p < 0.001). LIMITATIONS: Electroencephalography data were limited to the α band. CONCLUSION: Our findings provide evidence for the clinical use of cTBS, a novel brain stimulation protocol. Its therapeutic effects may be the result of increasing α frequency, thereby improving the psychological symptoms of generalized anxiety disorder.

Relapsing MOG-IgG-associated diseases coexisting with anti-NMDAR encephalitis: a case report and literature review.

BACKGROUND: In recent years, an overlapping syndrome, MNOS, of MOG encephalomyelitis and NMDARE has been clinically identified. In these diseases, both MOG-Ab and NMDAR-Ab are positive. Previous studies were almost case reports and incomprehensive which focused on this kind of overlapping syndrome in adults. METHODS: We reported a rare case of MNOS. In addition, we reviewed the clinical characteristics, diagnosis, and treatment of MNOS in adults by consulting relevant literature. RESULTS: The patient initially presented with CNS demyelination symptoms followed by recurrent encephalitis, concomitant anti-MOG, and NMDAR antibodies. His symptoms improved significantly after initiating hormonal therapy. We searched previous MNOS case reports and 17 adult MNOS cases were retrieved. The previous history of all patients was unremarkable. Most of these patients (72.2%, 13/18) first developed NMDR encephalitis-related symptoms, such as cognitive behavior abnormalities, cognitive decline, and epilepsy. Some patients (16.7%, 3/18) first developed MOG-related demyelinating symptoms, such as visual deterioration, walking instability, and dizziness. The most common site of new brain lesions was the supratentorial region. In the acute phase, MNOS patients were sensitive to hormone therapy. During the follow-up, 72.2% (13/18) of the patients relapsed, with a median interval of 12.25 months. Immunotherapy was still effective after recurrence, and no deaths were reported. CONCLUSIONS: (1) The clinical manifestations of MNOS are atypical, sometimes like MOG encephalomyelitis, sometimes like NMDARE, sometimes both of the characteristic clinical manifestations are present. (2) Immunotherapy is the primary treatment of patients with MNOS. (3) MNOS are prone to recurrence, and serum MOG and tumor markers should be monitored.

JNK/c-Jun-driven NLRP3 inflammasome activation in microglia contributed to retinal ganglion cells degeneration induced by indirect traumatic optic neuropathy.

BACKGROUND: Indirect traumatic optic neuropathy (ITON) is a major cause of permanent loss of vision after blunt head trauma. Neuroinflammation plays a crucial role in neurodegenerative diseases. The present study concentrated on JNK/c-Jun-driven NLRP3 inflammasome activation in microglia during the degeneration of retinal ganglion cells (RGCs) in ITON. METHODS: An impact acceleration (IA) model was employed to induce ITON, which could produce significant neurodegeneration in the visual system. Pharmacological approaches were employed to disrupt JNK and to explore whether JNK and the microglial response contribute to RGC death and axonal degeneration. RESULTS: Our results indicated that the ITON model induced significant RGC death and axonal degeneration and activated JNK/c-Jun signaling, which could further induce the microglial response and NLRP3 inflammasome activation. Moreover, JNK disruption is sufficient to suppress NLRP3 inflammasome activation in microglia and to prevent RGC death and axonal degeneration. CONCLUSIONS: ITON could promote JNK/c-Jun signaling, which further activates the NLRP3 inflammasome in microglia and contributes to the degeneration of axons and death of RGCs. JNK inhibition is able to suppress the inflammatory reaction and improve RGC survival. Although further work is needed to determine whether pharmacological inhibition of the NLRP3 inflammasome can prevent ITON, our findings indicated that such intervention could be promising for translational work.

Guillain-Barré syndrome following bacterial meningitis: a case report and literature review.

BACKGROUND: We reported a case of an adult that presented Guillain-Barré syndrome (GBS) after bacterial meningitis which was secondary to chronic suppurative otitis media (CSOM). To our knowledge, this is the first case involving an adult presenting with GBS following bacterial meningitis. CASE PRESENTATION: A 46-year man with type 2 diabetes and otitis media (OM) suffered with fever, headache, and vomiting for 6 days. The patient's neck stiffness was obvious and the Kernig and Brudzinski signs were produced. The result of cerebrospinal fluid (CSF) analysis and cytological examination of the CSF supported the diagnose of bacterial meningitis. On day 17 the patient felt numbness in both hands and feet, which gradually progressed to weakness of the limbs. Bladder dysfunction occurred, which required catheterization. The patient showed a tetraparesis with emphasis on the legs. The deep tendon reflexes of limbs were absent. The patient had peripheral hypalgesia and deep sensory dysfunction. The symptoms were possibly a result of GBS. Nerve conduction study showed that the F wave latency of the upper and lower limbs was prolonged, particularly the lower limbs. 8 days later the repeated nerve conduction study showed a low compound muscle action potential (3.3 mV) with a normal distal motor latency (14.2 ms) and a low motor nerve conduction velocity (34.3 m/s) in the tibial nerve. The patient still required assistance when walking 3 months after onset. CONCLUSIONS: GBS following bacterial meningitis is rare and limbs weakness in patients with bacterial meningitis was usually considered because of weakness. This case should serve as a reminder for clinical doctors that when a patient with bacterial meningitis complains about limbs numbness or weakness, GBS should be considered, especially when the patient had diabetes mellitus (DM) history.

Nε-(carboxymethyl)-lysine, White Matter, and Cognitive Function in Diabetes Patients.

OBJECTIVE: To study the relationship of Nε-(carboxymethyl)-lysine level (CML) with microstructure changes of white matter (WM), and cognitive impairment in patients with type 2 diabetes mellitus (T2DM) and to discuss the potential mechanism underlying T2DM-associated cognitive impairment. METHODS: The study was performed in T2DM patients (n=22) with disease course ≥5 years and age ranging from 65 to 75 years old. A control group consisted of 25 sex- and age-matched healthy volunteers. Fractional anisotropy (FA) of several WM regions was analyzed by diffusion tensor imaging scan. Plasma CML levels were measured by enzyme-linked immunosorbent assay, and cognitive function was assessed by Mini-Mental State Examination and Montreal cognitive assessment (MoCA). RESULTS: The total Mini-Mental State Examination score in the patient group (25.72±3.13) was significantly lower than the control group (28.16±2.45) (p<0.05). In addition, the total MoCA score in the patient group (22.15±3.56) was significantly lower than the control group 25.63±4.12) (p<0.01). In the patient group, FA values were significantly decreased in the corpus callosum, cingulate fasciculus, inferior fronto-occipital fasciculus, parietal WM, hippocampus, and temporal lobes relative to corresponding regions of healthy controls (p<0.05). Plasma CML level was negatively correlated with average FA values in the global brain (r=-0.58, p<0.01) and MoCA scores (r=-0.47, p<0.05). CONCLUSIONS: In T2DM, WM microstructure changes occur in older patients, and elevations in CML may play a role in the development of cognitive impairment.

A new method for evaluation of motor injury after acute brain ischemic damage.

PURPOSE: Motor impairment is an important index for assessing the extent of brain injury. The present study uses a new method, the movement capture analysis (MOCA) system, for assessing motor damage after acute ischemia. MATERIALS AND METHODS: Forty rats were divided into four groups: standard ischemia, sham-operated, Dizocilpine (MK-801), and Ginkgo biloba extract (GBE) groups. Brain ischemia was induced using the temporary right middle cerebral artery occlusion model. Longa score and MOCA were used to assess motor injury one day after ischemia. Infarct volume was delineated with 2% 2,3,5-triphenyltetrazolium chloride (TTC) staining. The correlation of infarct volume with Longa score and MOCA data was calculated. RESULTS: Compared with the sham-operated group (0.10 ± 0.31), Longa scores of MK-801 (2.33 ± 0.73), GBE (1.80 ± 0.58), and standard (2.88 ± 0.83) groups showed a statistical difference (p < 0.05); however, it was unable to discern the difference between MK-801 and standard groups. MOCA was able to clearly discern the differences in motor disparity among the four groups, standard (1.00 ± 0.19), sham-operated group (0.17 ± 0.02), MK-801 (0.79 ± 0.08), GBE (0.38 ± 0.05) (p < 0.05). Both MK-801 (18.03 ± 0.96%) and GBE (10.82 ± 1.93%) treatment reduced infarct size compared with the standard ischemia group (25.88 ± 1.16%) (p < 0.05). The MOCA data showed a more significant correlation with infarct size than Longa score (r = 0.85:0.53). CONCLUSIONS: MOCA system proved to be more sensitive than the Longa score. It may potentially be more accurate method for behavioral evaluation in clinical trials.

[Research of Outlier Samples Elimination Methods for Near-Infrared Spectral Analysis of Blood Glucose].

For the near-infrared (NIR) spectral analysis of the concentration of blood glucose, the calibration accuracy can be affected because of the existing of outlier samples. In this research, a Monte-Carlo cross validation (MCCV) method is constructed for eliminating outlier samples. The human blood plasma experiment in vitro and the human body experiment in vivo were introduced to evaluate the MCCV method for its application effect in NIR spectral analysis of blood glucose. And the uninformative sample elimination method based on modified uninformative variable elimination (MUVE-USE) was employed in this study for the comparison with MCCV. The results indicated that, like the MUVE-USE method, the outlier samples elimination method based on MCCV could be used to eliminate the outlier samples which came from gross errors (such as bad sample) or system errors (such as baseline drift). In addition, the outlier samples from the random errors of uncertain causes which affect model accuracy can be eliminated simultaneously by MCCV. The elimination of multiple outlier samples is beneficial to the improvement of prediction accuracy of calibration model.

Targeted induction of apoptosis in glioblastoma multiforme cells by an MRP3-specific TRAIL fusion protein in vitro.

Single-chain Fv fragments (scFvs) consist of the variable heavy-chain (VH) and variable light-chain (VL) domains, which are the smallest immunoglobulin fragments containing the whole antigen-binding site. Human soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) proves to acquire a potent pro-apoptotic activity only after selective binding to a predefined tumor cell surface antigen and has no off-target effects towards normal cells. Glioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor and overexpresses human multidrug resistance protein 3 (MRP3). In this study, we designed a novel fusion protein, termed scFvM58-sTRAIL, in which the MRP3-specific scFv antibody M58 was genetically fused to the N-terminus of human soluble TRAIL (sTRAIL). The recombinant scFvM58-sTRAIL fusion protein, expressed in Escherichia coli, was purified by chromatography and tested for cytotoxicity. scFvM58-sTRAIL showed a significant apoptosis-inducing activity towards MRP3-positive GBM cells in vitro. The pro-apoptotic activity of scFvM58-sTRAIL towards GBM cells was strongly inhibited in the presence of the parental scFvM58 antibody, suggesting that cytotoxic activity is MRP3-restricted. In a control experiment with MRP3-negative Jurkat cells, scFvM58-sTRAIL did not induce apparent apoptosis. In addition, through target antigen-restricted binding, scFvM58-sTRAIL was capable of activating not only TRAIL-R1 but also TRAIL-R2. In conclusion, our results suggest that fusion protein scFvM58-sTRAIL with specificity for MRP3 is a highly selective therapeutic agent and may provide an alternative therapy for human GBM.

Isobavachalcone alleviates ischemic stroke by suppressing HDAC1 expression and improving M2 polarization.

Ischemic stroke is a serious cerebrovascular condition. Isobavachalcone (ISO) has been documented to exhibit an anti-inflammatory effect across a variety of diseases; however, its protective impact on ischemic stroke remains unexplored. In this study, we evaluated the influence of ISO in both transient middle cerebral artery occlusion/reperfusion (tMCAO/R) rat models and oxygen-glucose deprivation/reperfusion (OGD/R) cell models. We observed that pretreatment with 50 mg/kg ISO diminished the volume of brain infarction, reduced brain edema, and ameliorated neurological deficits in rats. A reduction in Nissl bodies was noted in the tMCAO/R group, which was reversed following treatment with 50 mg/kg ISO. TUNEL/NeuN double staining revealed a decrease in TUNEL-positive cells in tMCAO/R rats treated with ISO. Furthermore, ISO treatment suppressed the expression of cleaved caspase-3 and BAX, while elevating the expression of BCL-2 in tMCAO/R rats. The levels of CD86 and iNOS were elevated in tMCAO/R rats; conversely, ISO treatment enhanced the expression of CD206 and Arg-1. Additionally, the expression of TNF-α, IL-6, and IL-1ß was elevated in tMCAO/R rats, whereas ISO treatment counteracted this effect. ISO treatment also increased the expression of TGF-ß and IL-10 in the ischemic penumbra of tMCAO/R rats. It was found that ISO treatment hindered microglial M1 polarization and favored M2 polarization. Histone Deacetylase 1 (HDAC1) is the downstream target protein of ISO, with ISO treatment resulting in decreased HDAC1 expression in both tMCAO/R rats and OGD/R-induced cells. Overexpression of HDAC1 was shown to promote microglial M1 polarization and inhibit M2 polarization in OGD/R+ISO cells. Overall, ISO treatment mitigated brain damage following ischemic stroke by promoting M2 polarization and attenuated ischemic injury by repressing HDAC1 expression.

The efficacy of targeted therapy combined with radiotherapy and temozolomide-based chemotherapy in the treatment of glioma: A systemic review and meta-analysis of phase II/III randomized controlled trials.

Background: Glioma is the most common intracranial tumor, accounting for about half of the primary intracranial tumors, with the characteristics of hidden onset and high mortality. Even after surgery, radiotherapy and chemotherapy, the prognosis of glioma is not ideal. Targeted therapy has developed rapidly in the treatment of other malignant tumors, which is also an important direction in the research and development of new therapies for glioma. So far, targeting combined with radiotherapy and chemotherapy have been used as the treatment of glioma in many clinical trials, but the role of targeted combined radiotherapy and chemotherapy in the treatment of glioma is still controversial. The purpose of this study was to evaluate the efficacy of targeted therapy combined with radiotherapy and temozolomide (TMZ)-based chemotherapy in the treatment of glioma. Methods: Phase II or phase III clinical trials involving targeted therapy combined with radiotherapy and chemotherapy and temozolomide-based radiotherapy and chemotherapy for gliomas were searched using PubMed, Embase and Web of Science databases, and a comprehensive meta-analysis was conducted. The primary outcome was overall survival time (OS) and progression-free survival time (PFS), and the secondary outcome was adverse reaction. The time-to-event data is summarized as hazard ratio (HR), and the binary results are summarized as odds ratio (OR). Two researchers conducted literature screening, data extraction and quality evaluation according to inclusion and exclusion criteria. Stata16.0 software was used for analysis, random effect model was used for data merging, and forest map was used for display. Results: A total of 11 eligible literatures and 12 prospective randomized controlled clinical trials of 1284 cases were included in the meta-analysis. The results showed that compared with radiotherapy and chemotherapy alone, targeted drugs combined with temozolomide-based radiotherapy and chemotherapy could significantly improve OS in phase II trial, but there was no improvement in Phase III trial, and PFS of newly diagnosed glioma patients was improved (HR=0.82(0.71-0.94) 95%CI, p =0.005). The PFS of the third phase of the experiment also improved. Compared with radiotherapy and chemotherapy alone, there was no statistically significant increase in adverse events in targeted combined radiotherapy and chemotherapy group. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022326012.

Novel compound heterozygous missense variants in TOE1 gene associated with pontocerebellar hypoplasia type 7.

BACKGROUND: Pontocerebellar hypoplasia type 7(PCH7)is a neurodegenerative disease related to autosomal recessive variants in the target of EGR1 (TOE1)gene. Biallelic mutation in the TOE1 gene causes global developmental delay, cognitive and psychomotor impairment, hypotonia, breathing abnormalities, and gonadal abnormalities. This study examined the clinical and genetic features of a 2-year-old patient carrying novel compound heterozygous variants in the TOE1 gene, mutations of previously reported 14 PCH7 patients were reviewed. METHODS: Clinical data of the 2-year-old patient were captured. Trio- whole exome sequencing (Trio-WES) was performed to identify pathogenic variants. Sanger sequencing was further used to verify the variants. In silico analysis was performed to explain the pathogenicity. RESULTS: Herein, we described the clinical features of the 2-year-old patient diagnosed with PCH7 caused by mutations in the TOE1gene. The kid was presenting with global development delay and gonadal abnormalities. Brain imaging revealed hypoplasia of the cerebellum and pons with ambiguous genitalia. Trio-WES revealed novel compound heterozygous missense variants in TOE1gene (c.911C > T p.S304L, c.161C > T p.A54V). Multiple in silico tools predicted the deleterious effects of the mutations. CONCLUSION: The novel compound heterozygous missense mutation in the TOE1 gene identified in the proband broadened the genotypic and phenotypic spectrum of disorders associated with PCH7. Our findings provide critical information for the differential diagnosis of rare neurodevelopment disorders and genetic counselling.

Generation of an induced pluripotent stem cell lines NSHDMUi001-A from patients with type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is common in China, and its aetiology and pathogenesis are still unclear. We reprogrammed pEP4EO2SEN2K and pEP4EO2SET2K, pCEP4-M2L was electrotransfected in T2DM patients with pEP4EO2SEN2K, and pCEP4-M2L was electrotransfected in T2DM patients expressing the OCT4, SOX2, NANOG, LIN28, c-MYC, KLF4, and SV40LT transcription factors to obtain induced pluripotent stem cells (iPSCs). The obtained iPSCs have been verified to have pluripotency, normal karyotype and differentiation potential; therefore, these cells can be used in the study of disease pathophysiology and drug development to create new therapeutic targets for T2DM and associated central nervous system damage.

Prefrontal cortical hemodynamics and functional network organization during Tai Chi standing meditation: an fNIRS study.

Introduction: Tai Chi standing meditation (Zhan Zhuang, also called pile standing) is characterized by meditation, deep breathing, and mental focus based on theories of traditional Chinese medicine. The purpose of the present study was to explore prefrontal cortical hemodynamics and the functional network organization associated with Tai Chi standing meditation by using functional near-infrared spectroscopy (fNIRS). Methods: Twenty-four channel fNIRS signals were recorded from 24 male Tai Chi Quan practitioners (54.71 ± 8.04 years) while standing at rest and standing during Tai Chi meditation. The general linear model and the SPM method were used to analyze the fNIRS signals. Pearson correlation was calculated to determine the functional connectivity between the prefrontal cortical sub-regions. The small world properties of the FC networks were then further analyzed based on graph theory. Results: During Tai Chi standing meditation, significantly higher concentrations of oxygenated hemoglobin were observed in bilateral dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), frontal eye field (FEF), and pre-motor cortex (PMC) compared with the values measured during standing rest (p < 0.05). Simultaneously, significant decreases in deoxygenated hemoglobin concentration were observed in left VLPFC, right PMC and DLPFC during Tai Chi standing meditation than during standing rest (p < 0.05). Functional connectivity between the left and right PFC was also significantly stronger during the Tai Chi standing meditation (p < 0.05). The functional brain networks exhibited small-world architecture, and more network hubs located in DLPFC and VLPFC were identified during Tai Chi standing meditation than during standing rest. Discussion: These findings suggest that Tai Chi standing meditation introduces significant changes in the cortical blood flow and the brain functional network organization.

Monocyte to high-density lipoprotein ratio predicts clinical outcomes after acute ischemic stroke or transient ischemic attack.

AIMS: The monocyte to high-density lipoprotein cholesterol ratio (MHR) has emerged as a novel inflammatory biomarker of atherosclerotic cardiovascular disease. However, it has not yet been identified whether MHR can predict the long-term prognosis of ischemic stroke. We aimed to investigate the associations of MHR levels with clinical outcomes in patients with ischemic stroke or transient ischemic attack (TIA) at 3 months and 1 year. METHODS: We derived data from the Third China National Stroke Registry (CNSR-III). Enrolled patients were divided into four groups by quartiles of MHR. Multivariable Cox regression for all-cause death and stroke recurrence and logistic regression for the poor functional outcome (modified Rankin Scale score 3-6) were used. RESULTS: Among 13,865 enrolled patients, the median MHR was 0.39 (interquartile range, 0.27-0.53). After adjustment for conventional confounding factors, the MHR level in quartile 4 was associated with an increased risk of all-cause death (hazard ratio [HR], 1.45; 95% confidence interval [CI], 1.10-1.90), and poor functional outcome (odd ratio [OR], 1.47; 95% CI, 1.22-1.76), but not with stroke recurrence (HR, 1.02; 95% CI, 0.85-1.21) at 1 year follow-up, compared with MHR level in quartile 1. Similar results were observed for outcomes at 3 months. The addition of MHR to a basic model including conventional factors improved predictive ability for all-cause death and poor functional outcome validated by the C-statistic and net reclassification index (all p < 0.05). CONCLUSIONS: Elevated MHR can independently predict all-cause death and poor functional outcome in patients with ischemic stroke or TIA.

Up-regulation of microglial cathepsin C expression and activity in lipopolysaccharide-induced neuroinflammation.

BACKGROUND: Cathepsin C (Cat C) functions as a central coordinator for activation of many serine proteases in inflammatory cells. It has been recognized that Cat C is responsible for neutrophil recruitment and production of chemokines and cytokines in many inflammatory diseases. However, Cat C expression and its functional role in the brain under normal conditions or in neuroinflammatory processes remain unclear. Our previous study showed that Cat C promoted the progress of brain demyelination in cuprizone-treated mice. The present study further investigated the Cat C expression and activity in lipopolysaccharide (LPS)-induced neuroinflammation in vivo and in vitro. METHODS: C57BL/6 J mice were intraperitoneally injected with either 0.9% saline or lipopolysaccharide (LPS, 5 mg/kg). Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to analyze microglial activation, TNF-α, IL-1ß, IL-6, iNOS mRNAs expressions and cellular localization of Cat C in the brain. Nitrite assay was used to examine microglial activation in vitro; RT-PCR and ELISA were used to determine the expression and release of Cat C. Cat C activity was analyzed by cellular Cat C assay kit. Data were evaluated for statistical significance with paired t test. RESULTS: Cat C was predominantly expressed in hippocampal CA2 neurons in C57BL/6 J mice under normal conditions. Six hours after LPS injection, Cat C expression was detected in cerebral cortical neurons; whereas, twenty-four hours later, Cat C expression was captured in activated microglial cells throughout the entire brain. The duration of induced Cat C expression in neurons and in microglial cells was ten days and three days, respectively. In vitro, LPS, IL-1ß and IL-6 treatments increased microglial Cat C expression in a dose-dependent manner and upregulated Cat C secretion and its activity. CONCLUSIONS: Taken together, these data indicate that LPS and proinflammatory cytokines IL-1ß, IL-6 induce the expression, release and upregulate enzymatic activity of Cat C in microglial cells. Further investigation is required to determine the functional role of Cat C in the progression of neuroinflammation, which may have implications for therapeutics for the prevention of neuroinflammation-involved neurological disorders in the future.

Joint High Level of Oxidized Low-Density Lipoprotein and High-Sensitivity C-Reactive Protein are Associated With Recurrent Stroke and Poor Functional Outcome in Minor Stroke or Transient Ischemic Attack.

Background Oxidized low-density lipoprotein (oxLDL) and hs-CRP (high-sensitivity C-reactive protein) plays an important role in cardiovascular diseases though inflammation and oxidative stress, etc. However, evidence on their combined effects on stroke prognosis is still limited. We aimed to explore the joint association of oxLDL and hs-CRP with outcomes of minor stroke or transient ischemic attack. Methods and Results A subgroup of 3019 patients from the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) were analyzed. Baseline oxLDL and hs-CRP levels were measured. The primary outcome was any stroke within 90 days. The secondary outcomes included any stroke within 1 year, and ischemic stroke, combined vascular events, and poor functional outcomes (modified Rankin Scale 2-6 or 3-6) at 90 days and 1 year. Vascular events outcomes were analyzed with Cox proportional hazards and poor functional outcomes with logistic models. Elevated oxLDL (>28.81 µg/dL) and hs-CRP (>4.20 mg/L) was observed in 624 (20.67%) of the 3019 patients. Patients with oxLDL >28.81 µg/dL and hs-CRP >4.20 mg/L had a higher risk of recurrent stroke within 90 days (adjusted hazard ratio, 1.52; 95% CI, 1.17-1.97), compared with those with oxLDL ≤28.81 µg/dL and hs-CRP ≤4.20 mg/L, after adjusting relevant confounding factors (P=0.002). Similar results were observed for secondary outcomes (P<0.05 for all). Conclusions In patients with minor stroke or transient ischemic attack, joint high levels of oxLDL and hs-CRP was associated with increased risk of recurrent stroke, combined vascular events, and poor functional outcome.

Efficacy and Safety of Recombinant Human Prourokinase in Acute Ischemic Stroke: A Phase IIa Randomized Clinical Trial.

Recombinant human prourokinase (rhPro-UK) is a novel thrombolytic that has been approved to treat patients with acute myocardial infarction. However, the safety and efficacy of intravenous rhPro-UK in patients with acute ischemic stroke (AIS) has not been well established. We aimed to investigate the safety and preliminary efficacy of rhPro-UK in patients with AIS in a multi-center phase IIa trial setting. One hundred nineteen patients within 4.5 h of AIS onset were enrolled in this randomized, open-label, 23-center phase IIa clinical trial. Patients were randomly assigned to 35 mg (n = 40) or 50 mg (n = 39) intravenous rhPro-UK or 0.9 mg/kg recombinant tissue plasminogen activator (r-tPA; n = 40). The primary endpoint was functional independence defined as a modified Rankin scale (mRS) score of 0 or 1 at 90 days. The secondary outcome was early neurological improvement defined as a reduction of ≥ 4 points on the National Institutes of Health Stroke Scale (NIHSS) score from baseline to 24 h after drug administration. Safety endpoints included death due to any cause, symptomatic intracerebral hemorrhage (sICH), and other serious adverse events (SAEs). The proportion of patients with an mRS score of ≤ 1 at 90 days did not differ significantly among three groups (35 mg rhPro-UK: 55.56% vs. 50 mg rhPro-UK: 57.89% vs. vs. r-tPA: 52.63%; P = 0.92). The rates of treatment response, referring to early neurological improvement, were similar among these three groups (36.11% vs. 31.58% vs. 28.95%, respectively; P = 0.85). There was no difference in mortality at 90 days or in the rate of other SAEs among the three groups. One patient in the 50 mg rhPro-UK group suffered sICH. While neither the primary efficacy outcomes nor safety profile differed significantly among the low, high rhPro-UK and control groups, it is a logical step to further test the low-dose rhPro-UK group versus the control group in a well-powered phase III study.Trial Registration: http://www.chictr.org.cn . Identifier: ChiCTR1800016519. Date of registration: June 6 2018.