Early-onset Parkinson's disease with mutations in both the PRKN gene and the APOB gene: A case report. / PRKNåŸºå› åˆå¹¶APOBåŸºå› çªå˜çš„æ—©å‘åž‹å¸•é‡‘æ£®ç— 1例.

The incidence rate of Parkinson's disease ranks the second among degenerative diseases of the nervous system, only lower than Alzheimer's disease. Early-onset Parkinson's disease (EPOD) refers to Parkinson's disease with initial symptoms appearing before the age of 50. EOPD is associated with certain genetic mutations and has distinct clinical features. This study reports a case of EOPD with mutations in both the PRKN and the APOB genes. The patient presented with the initial symptom of unstable walking at the age of 28, followed by bradykinesia, limb tremors, masked face, shuffling gait, and cogwheel rigidity in both upper limbs. The blood lipid test showed total cholesterol of 6.48 mmol/L and low-density lipoprotein cholesterol of 4.13 mmol/L. Genetic testing showed a deletion in exon 5 and a point mutation [c.850G>C(p.Gly284Arg)] in exon 7 of the PRKN gene, as well as a point mutation [c.10579C>T(p.Arg3527Trp)] in exon 26 of the APOB gene. Based on these clinical manifestations and examination results, the patient was diagnosed with EOPD. The compound heterozygous mutations in the PRKN gene, as well as the combined mutations in the PRKN and APOB genes, are both reported for the first time, expanding the spectrum of genetic mutations associated with EOPD.

Curcumin-primed olfactory mucosa-derived mesenchymal stem cells mitigate cerebral ischemia/reperfusion injury-induced neuronal PANoptosis by modulating microglial polarization.

BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury often leads to neuronal death through persistent neuroinflammatory responses. Recent research has unveiled a unique inflammatory programmed cell death mode known as PANoptosis. However, direct evidence for PANoptosis in ischemic stroke-induced neuronal death has not been established. Although it is widely thought that modulating the balance of microglial phenotypic polarization in cerebral I/R could mitigate neuroinflammation-mediated neuronal death, it remains unknown whether microglial polarization influences PANoptotic neuronal death triggered by cerebral I/R. Our prior study demonstrated that curcumin (CUR) preconditioning could boost the neuroprotective properties of olfactory mucosa-derived mesenchymal stem cells (OM-MSCs) in intracerebral hemorrhage. Yet, the potential neuroprotective capacity of curcumin-pretreated OM-MSCs (CUR-OM-MSCs) on reducing PANoptotic neuronal death during cerebral I/R injury through modulating microglial polarization is uncertain. METHODS: To mimic cerebral I/R injury, We established in vivo models of reversible middle cerebral artery occlusion (MCAO) in C57BL/6 mice and in vitro models of oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 neurons and BV2 microglia. RESULTS: Our findings indicated that cerebral I/R injury caused PANoptotic neuronal death and triggered microglia to adopt an M1 (pro-inflammatory) phenotype both in vivo and in vitro. Curcumin pretreatment enhanced the proliferation and anti-inflammatory capacity of OM-MSCs. The CUR-OM-MSCs group experienced a more pronounced reduction in PANoptotic neuronal death and a better recovery of neurological function than the OM-MSCs group. Bioinformatic analysis revealed that microRNA-423-5p (miRNA-423-5p) expression was obviously upregulated in CUR-OM-MSCs compared to OM-MSCs. CUR-OM-MSCs treatment induced the switch to an M2 (anti-inflammatory) phenotype in microglia by releasing miRNA-423-5p, which targeted nucleotide-binding oligomerization domain 2 (NOD2), an upstream regulator of NF-kappaB (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways, to attenuate PANoptotic neuronal death resulting from cerebral I/R. CONCLUSION: This results provide the first demonstration of the existence of PANoptotic neuronal death in cerebral I/R conditions. Curcumin preconditioning enhanced the ameliorating effect of OM-MSCs on neuroinflammation mediated by microglia polarization via upregulating the abundance of miRNA-423-5p. This intervention effectively alleviates PANoptotic neuronal death resulting from cerebral I/R. The combination of curcumin with OM-MSCs holds promise as a potentially efficacious treatment for cerebral ischemic stroke in the future.

The role of short-chain fatty acids in central nervous system diseases: A bibliometric and visualized analysis with future directions.

Background: Short-chain fatty acids (SCFAs) are thought to play a key role in the microbe-gut-brain axis and involve in the pathogenesis of a variety of neurological diseases. This study aimed to identify research hotspots and evolution trends in SCFAs in central nervous diseases (CNS) and examine current research trends. Methods: The bibliometric analysis was performed using CiteSpace, and the results were visualized via network maps. Results: From 2002 to 2022, 480 publications in the database met the criteria. On the country level, China produced the highest number of publications, while the United States had the highest centrality. On the institutional level, University College Cork contributed to the most publications, and John F. Cryan from this university was the key researcher with considerable academic influence. The article, the role of short-chain fatty acids in microbiota-gut-brain, written by Boushra Dalile et al., in 2019 was the most cited article. Furthermore, the journal Nutrients had the maximum number of publications, while Plos One was the most cited journal. "Gut microbiome", "SCFAs", and "central nervous system" were the three most frequent keywords. Among them, SCFAs had the highest centrality. "Animal model" was the keyword with the highest burst strength, with the latest burst keywords being "social behavior", "pathogenesis", and "insulin sensitive". In addition, the research topics on SCFAs in CNS diseases from 2002 to 2022 mainly focused on following aspects: SCFAs plays a key role in microbe-gut-brain crosstalk; The classification and definition of SCFAs in the field of CNS; Several CNS diseases that are closely related to SCFAs research; Mechanism and translational studies of SCFAs in the CNS diseases. And the hotspots over the past 5 years have gradually increased the attention to the therapeutic potential of SCFAs in the CNS diseases. Conclusion: The research of SCFAs in CNS diseases is attracting growing attention. However, there is a lack of cooperation between countries and institutions, and additional measures are required to promote cooperation. The current evidence for an association between SCFAs and CNS diseases is preliminary and more work is needed to pinpoint the precise mechanism. Moreover, large-scale clinical trials are needed in the future to define the therapeutic potential of SCFAs in CNS diseases.

Application of Neuroimaging for the Prediction of Hemorrhagic Transformation after Intravenous Thrombolysis in Acute Ischemic Stroke.

BACKGROUND: Ischemic stroke is a common cerebrovascular disease with high morbidity, disability, and mortality worldwide. Currently, recombinant tissue plasminogen activator is the main intravenous thrombolysis agent for the treatment of acute ischemic stroke within 4.5 h after onset. Hemorrhagic transformation (HT) is the most serious complication of intravenous thrombolysis, which can significantly aggravate clinical poor prognosis. Therefore, it is important to early predict the risk of post-thrombolysis HT in patients with acute ischemic stroke. SUMMARY: Recently, several studies have reported that neuroimaging techniques have potential value in predicting HT after intravenous thrombolysis in patients with acute ischemic stroke. The corresponding neuroimaging parameters may be effective predictors of HT after intravenous thrombolysis. In this review, we summarized and discussed the application of neuroimaging techniques and related parameters in predicting HT after intravenous thrombolysis. KEY MESSAGES: Recognizing and understanding the predictive performance of neuroimaging parameters for HT may help assess the risk of HT after intravenous thrombolysis in patients with acute ischemic stroke and make an appropriate treatment decision.

Association between fibrinogen-to-albumin ratio and hemorrhagic transformation after intravenous thrombolysis in ischemic stroke patients.

BACKGROUND AND PURPOSE: Hemorrhagic transformation (HT) is the most serious complication of intravenous thrombolysis in ischemic stroke patients. Inflammation plays a critical role in the pathological progression of HT. This study was to explore the relationship between fibrinogen-to-albumin ratio (FAR), a novel systemic inflammation biomarker, and HT after intravenous thrombolysis in patients with ischemic stroke. METHODS: This retrospective study enrolled ischemic stroke patients who underwent intravenous thrombolysis between Jan 2017 to May 2022. The characteristic data of all patients at admission were retrospectively collected. The univariate and multivariate logistic regression analyses were performed to evaluate the correlation between FAR and HT after intravenous thrombolysis. The optimal cut-off value of FAR for predicting HT was determined by the receiver operating characteristic curve. RESULTS: A total of 363 ischemic stroke patients were enrolled in the present study. Sixty-two patients had HT after intravenous thrombolysis. In multivariate regression analysis, FAR was significantly associated with HT (odds ratio [OR], 1.105; 95% confidential interval [CI], 1.029-1.186, P = 0.006). The receiver operating characteristic curve analysis indicated FAR predicts HT after intravenous thrombolysis with an AUC of 0.613 (95%CI, 0.530-0.695; P = 0.005) and an optimal cut-off value of 0.101. The correlation between FAR and HT after intravenous thrombolysis was still observed when patients were stratified according to FAR levels. A higher FAR level was independently related to the occurrence of HT after adjusting for the potential confounding factors. CONCLUSION: Higher FAR level was independently associated with HT after intravenous thrombolysis in patients with ischemic stroke.

A novel nomogram to predict hemorrhagic transformation in ischemic stroke patients after intravenous thrombolysis.

Background: Hemorrhagic transformation (HT) is the most serious complication of ischemic stroke patients after intravenous thrombolysis and leads to a poor clinical prognosis. This study aimed to determine the independent predictors associated with HT in stroke patients with intravenous thrombolysis and to establish and validate a nomogram that combines with predictors to predict the probability of HT after intravenous thrombolysis in patients with ischemic stroke. Method: This study enrolled ischemic stroke patients with intravenous thrombolysis from December 2016 to June 2022. All the patients were divided into training and validation cohorts. The nomogram was composed of the significant predictors for HT in the training cohort as obtained by the multivariate logistic regression analysis. The area under the receiver operating characteristic curve was used to assess the discriminative performance of the nomogram. The calibration performance of the nomogram was assessed by the Hosmer-Lemeshow goodness-of-fit test and calibration plots. Decision curve analysis was used to test the clinical validity of the nomogram. Results: A total of 394 patients with intravenous thrombolysis were enrolled in the study. In the training cohort (n = 257), 45 patients had HT after intravenous thrombolysis. Multivariate logistic regression analysis demonstrated early infarct signs (OR, 7.954; 95% CI, 3.553-17.803; P < 0.001), NIHSS scores (OR, 1.110; 95% CI, 1.054-1.168; P < 0.001), uric acid (OR, 0.993; 95% CI, 0.989-0.997; P = 0.001), and albumin-to-globulin ratio (OR, 0.109; 95% CI, 0.023-0.508; P = 0.005) were independent predictors for HT and constructed the nomogram. In the training and validation cohorts, the AUC of the nomogram was 0.859 and 0.839, respectively. The Hosmer-Lemeshow goodness-of-fit test and calibration plot showed good concordance between predicted and observed probability in the training and validation cohorts. Decision curve analysis indicated that the nomogram was significantly useful for predicting HT in the training and further confirmed in the validation cohort. Conclusion: This study proposes a novel and practical nomogram based on early infarct signs, NIHSS scores, uric acid, and albumin-to-globulin ratio that can well predict the probability of HT after intravenous thrombolysis in patients with ischemic stroke.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy in Association With Concomitant Diseases: Identification and Management.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare, heterogeneous, but treatable autoimmune-mediated peripheral neuropathy characterized by demyelination. CIDP can occur independently or simultaneously with a variety of diseases such as diabetes, monoclonal gammopathy of undetermined significance (MGUS), connective tissue disease, and HIV. It is important to identify CIDP and specific peripheral neuropathies caused by these diseases; this review aims to summarize the CIDP literatures related to diabetes, MGUS, SLE, and HIV, and to be helpful for the management of such patients.

Reversible Toxic Encephalopathy Involving the Cerebellum and Subcortical White Matter Attributed to Capecitabine.

Capecitabine is an anticancer drug related to 5-fluorouracil (5-FU) that is used to treat multiple cancers. Little is known about the central nervous system toxicity of capecitabine owing to the low frequency of occurrence. In this report we describe a rare case of capecitabine-related toxic encephalopathy involving the cerebellum and subcortical white matter. A review of the literature showed that most reported cases have shown excellent recovery within a few days of capecitabine termination. Whether uridine triacetate is a reasonable treatment choice for patients with life-threatening toxic encephalopathy depends on the availability of reliable clinical data. Prescreening for dihydropyrimidine dehydrogenase genotype variants and detection of 5-FU degradation rate prior to capecitabine treatment may become an effective way to avoid toxic reactions by regulating the therapeutic dose for each patient, which remains to be investigated and needs more clinical data to support.

Mesenchymal stem cells-derived therapies for subarachnoid hemorrhage in preclinical rodent models: a meta-analysis.

BACKGROUND: Mesenchymal stem cells (MSCs) and MSCs-derived extracellular vesicles (EVs) have emerged as potential novel therapies for subarachnoid hemorrhage (SAH). However, their effects remain incompletely understood. We aim to comprehensively evaluate the effect of MSCs-derived therapies in rodent models of SAH. METHODS: We searched PubMed, EMBASE, and Web of Science up to September 2021 to identify studies that reported the effects of MSCs or MSCs-derived EVs in a rodent SAH model. Neurobehavioral score was extracted as the functional outcome, and brain water content was measured as the histopathological outcome. A random-effects model was used to calculate the standardized mean difference (SMD) and confidence interval (CI). RESULTS: Nine studies published from 2018 to 2021 met the inclusion criteria. Studies quality scores ranged from 5 to 10, with a mean value of 7.22. Our results revealed an overall positive effect of MSCs and MSCs-derived EVs on the neurobehavioral score with a SMD of - 2.21 (95% CI - 3.14, - 1.08; p < 0.0001). Meanwhile, we also found that MSCs and MSCs-derived EVs reduced brain water content by a SMD of - 2.09 (95% CI - 2.99, - 1.19; p < 0.00001). Significant heterogeneity among studies was observed, further stratified and sensitivity analyses did not identify the source of heterogeneity. CONCLUSIONS: Our results suggested that MSCs-derived therapies prominently improved functional recovery and reduced brain edema in the rodent models of SAH. Notably, the limitations of small sample size should be considered when interpreting the results, and large animal studies and human trials are needed for further investigation.

OM-MSCs Alleviate the Golgi Apparatus Stress Response following Cerebral Ischemia/Reperfusion Injury via the PEDF-PI3K/Akt/mTOR Signaling Pathway.

The mechanism of Golgi apparatus (GA) stress responses mediated by GOLPH3 has been widely studied in ischemic stroke, and the neuroprotection effect of olfactory mucosa mesenchymal stem cells (OM-MSCs) against cerebral ischemia/reperfusion injury (IRI) has been preliminarily presented. However, the exact role of OM-MSCs in the GA stress response following cerebral IRI remains to be elucidated. In the present study, we used an oxygen-glucose deprivation/reoxygenation (OGD/R) model and reversible middle cerebral artery occlusion (MCAO) model to simulate cerebral IRI in vitro and in vivo. Our results showed that the level of GOLPH3 protein, reactive oxygen species (ROS), and Ca2+ was upregulated, SPCA1 level was downregulated, and GA fragmentation was increased in ischemic stroke models, and OM-MSC treatment clearly ameliorated these GA stress responses in vitro and in vivo. Subsequently, the knockdown of PEDF in OM-MSCs using PEDF-specific siRNA further demonstrated that secretion of PEDF in OM-MSCs protected OGD/R-treated N2a cells and MCAO rats from GA stress response. Additionally, rescue experiment using specific pathway inhibitors suggested that OM-MSCs could promote the phosphorylation of the PI3K/Akt/mTOR pathway, thereby mitigating OGD/R-induced GA stress response and excessive autophagy. In conclusion, OM-MSCs minimized the GA stress response following cerebral IRI, at least partially, through the PEDF-PI3K/Akt/mTOR pathway.

The Efficacy of Mesenchymal Stem Cell Therapies in Rodent Models of Multiple Sclerosis: An Updated Systematic Review and Meta-Analysis.

Studies have demonstrated the potential of mesenchymal stem cell (MSC) administration to promote functional recovery in preclinical studies of multiple sclerosis (MS), yet the effects of MSCs on remyelination are poorly understood. We wished to evaluate the therapeutic effects of MSCs on functional and histopathological outcomes in MS; therefore, we undertook an updated systematic review and meta-analysis of preclinical data on MSC therapy for MS. We searched mainstream databases from inception to July 15, 2021. Interventional studies of therapy using naïve MSCs in in vivo rodent models of MS were included. From each study, the clinical score was extracted as the functional outcome, and remyelination was measured as the histopathological outcome. Eighty-eight studies published from 2005 to 2021 met the inclusion criteria. Our results revealed an overall positive effect of MSCs on the functional outcome with a standardized mean difference (SMD) of -1.99 (95% confidence interval (CI): -2.32, -1.65; p = 0.000). MSCs promoted remyelination by an SMD of -2.31 (95% CI: -2.84, -1.79; p = 0.000). Significant heterogeneity among studies was observed. Altogether, our meta-analysis indicated that MSC administration improved functional recovery and promoted remyelination prominently in rodent models of MS.

Strategies to Improve the Efficiency of Transplantation with Mesenchymal Stem Cells for the Treatment of Ischemic Stroke: A Review of Recent Progress.

Cerebral ischemia is a common global disease that is characterized by a loss of neurological function and a poor prognosis in many patients. However, only a limited number of treatments are available for this condition at present. Given that the efficacies of these treatments tend to be poor, cerebral ischemia can create a significant burden on patients, families, and society. Mesenchymal stem cell (MSC) transplantation treatment has shown significant potential in animal models of ischemic stroke; however, the specific mechanisms underlying this effect have yet to be elucidated. Furthermore, clinical trials have yet to yield promising results. Consequently, there is an urgent need to identify new methods to improve the efficiency of MSC transplantation as an optimal treatment for ischemic stroke. In this review, we provide an overview of recent scientific reports concerning novel strategies that promote MSC transplantation as an effective therapeutic approach, including physical approaches, chemical agents, traditional Chinese medicines and extracts, and genetic modification. Our analyses showed that two key factors need to be considered if we are to improve the efficacy of MSC transplantation treatments: survival ability and homing ability. We also highlight the importance of other significant mechanisms, including the enhanced activation of MSCs to promote neurogenesis and angiogenesis, and the regulation of permeability in the blood-brain barrier. Further in-depth investigations of the specific mechanisms underlying MSC transplantation treatment will help us to identify effective methods that improve the efficiency of MSC transplantation for ischemic stroke. The development of safer and more effective methods will facilitate the application of MSC transplantation as a promising adjuvant therapy for the treatment of poststroke brain damage.

GATA3 improves the protective effects of bone marrow-derived mesenchymal stem cells against ischemic stroke induced injury by regulating autophagy through CREG.

BACKGROUND: Bone marrow-derived mesenchymal stem cells (BMSCs) transplantation has been demonstrated to benefit functional recovery after ischemic stroke, however, the low survival rate of BMSCs in ischemic microenvironment largely limits its use. METHODS: Rat BMSCs (rBMSCs) were isolated from SD rats and treated with oxygen glucose deprivation/reoxygenation (OGD) to mimic ischemic microenvironment in vitro. Expression of mRNAs and proteins were assessed by qRT-PCR and western blot, respectively. Cell viability was detected using MTT. ROS level was evaluated by DCFH-DA Assay Kit. TUNEL and flow cytometry analysis were adopted to detect cell apoptosis. Immunofluorescence analysis was used to examine LC3 expression. Dual-luciferase reporter and ChIP assays were employed to determine the interaction between CREG and GATA3. Middle cerebral artery occlusion (MCAO) model was established to mimic ischemic stroke in vivo. TTC staining was used to measure the infarcts area in the brain of MCAO rats. Nissl staining was used to examine the quantity of neurons, and mNSS test was applied to compare behavioral functions of animals. RESULTS: The rBMSCs were successfully isolated from SD rats. OGD exposure decreased the expression of GATA3 in rBMSCs, GATA3 overexpression alleviated OGD-induced cell injury and enhanced autophagy. Treatment with autophagy inhibitor (3-MA) abolished the protective effects of GATA3 against OGD-induced cell injury. GATA3 targeted the promoter of CREG and positively regulated its expression. The protective effect of GATA3 overexpression on autophagy during OGD exposure was reversed by CREG knockdown. Moreover, GATA3 overexpression improved the therapeutic effects of BMSCs transplantation on ischemic stroke in vivo. CONCLUSION: Our results indicated that GATA3 overexpression improved the therapeutic effects of rBMSCs transplantation against ischemic stroke induced injury by regulating autophagy through CREG.

Exosomes From miR-19b-3p-Modified ADSCs Inhibit Ferroptosis in Intracerebral Hemorrhage Mice.

Objectives: Effective treatments for intracerebral hemorrhage (ICH) are limited until now. Ferroptosis, a novel form of iron-dependent cell death, is implicated in neurodegeneration diseases. Here, we attempted to investigate the impact of exosomes from miR-19b-3p-modified adipose-derived stem cells (ADSCs) on ferroptosis in ICH. Methods: Collagenase was used to induce a mouse model of ICH and hemin was used to induce ferroptosis in cultured neurons. Exosomes were isolated from mimic NC- or miR-19b-3p mimic-transfected ADSCs (ADSCs-MNC-Exos or ADSCs-19bM-Exos, respectively) and then administered to ICH mice or hemin-treated neurons. ICH damage was evaluated by assessing the neurological function of ICH mice and cell viability of neurons. Ferroptosis was evaluated in mouse brains or cultured neurons. The interaction between miR-19b-3p and iron regulatory protein 2 (IRP2) 3'-UTR was analyzed by performing luciferase reporter assay. Results: Ferroptosis occurred in ICH mice, which also exhibited decreased miR-19b-3p and increased IRP2 expression. IRP2 was a direct target of miR-19b-3p, and IRP2 expression was repressed by ADSCs-19bM-Exos. Importantly, ADSCs-19bM-Exos effectively attenuated hemin-induced cell injury and ferroptosis. Moreover, ADSCs-19bM-Exos administration significantly improved neurologic function and inhibited ferroptosis in ICH mice. Conclusion: Exosomes from miR-19b-3p-modified ADSCs inhibit ferroptosis in ICH mice.

A Systematic Review and Meta-Analysis of Autoantibodies for Diagnosis and Prognosis in Patients With Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

Objectives: To review the available evidence on sensitivity and specificity of anti-NF155 antibody detection in diagnosing a specific subset of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and to calculate the frequencies of different autoantibodies to paranodal proteins. Background: Diagnosis of CIDP relies on clinical and neurophysiologic criteria and lacks useful diagnostic biomarkers. A subset of CIDP patients exhibit atypical clinical phenotypes and impaired response to conventional treatments. These patients were reported as having autoantibodies targeting paranodal protein neurofascin isoform 155 (NF155), contactin-1 (CNTN1), and contactin-associated protein-1 (CASPR1). Here, we conducted a meta-analysis to summarize evidence on the diagnostic and prognostic value of these autoantibodies, especially for anti-NF155 antibody. Methods: We searched the following electronic bibliographic databases: PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science. Eligible studies provided information to calculate the frequencies of anti-NF155 antibody and anti-CNTN1 antibody, the sensitivity and specificity of anti-NF155 antibody, and the incidence of improvement and deterioration among anti-NF155 antibody seropositive CIDP patients. Heterogeneity was assessed using Q and I 2 statistics. Results: The pooled frequency of anti-NF155 autoantibody across 14 studies was 7% [95% confidence interval (CI): 0.05-0.10] with high heterogeneity; the overall pooled sensitivity and specificity of anti-NF155 antibody for the diagnosis of a specific subgroup of CIDP patients were 0.45 (95% CI: 0.29-0.63) and 0.93 (95% CI: 0.86-0.97), respectively. Conclusions: For diagnosing of a specific subset of CIDP characterized by poor response to intravenous immunoglobulin (IVIg), we found a moderate sensitivity and a high specificity. The anti-NF155 antibody test should be used as a confirmatory test rather than a screening test. Systematic Review Registration: PROSPERO, identifier: CRD42020203385 and CRD42020190789.

A systematic review of the correlation between serum asymmetric dimethylarginine, carotid atherosclerosis and ischaemic stroke.

OBJECTIVE: To investigate the correlation between serum asymmetric dimethylarginine (ADMA) and the risk of ischaemic stroke and carotid atherosclerosis in adults. METHODS: We systematically searched PubMed, EMBASE, Web of Science and other databases for relevant studies on serum ADMA and ischaemic stroke or carotid atherosclerosis, which were published from December 1980 to December 2019. The quality of the included studies was evaluated according to the Cochrane system evaluation standard. The difference in serum ADMA level between ischaemic stroke and control group was selected as the effect size (standardized mean difference, SMD). The pooled analysis was performed using Review Manager (V.5.3). RESULTS: According to the selection criteria, thirteen studies were included in the meta-analysis after screening. Nine studies compared ADMA levels between the ischaemic stroke group and healthy control group, involving a total of 1315 and 880 subjects in the two groups, respectively. Pooled effect sizes were calculated using the random-effects model due to the high heterogeneity (I2  = 93%, P < .00001). The level of serum ADMA in patients with ischaemic stroke was significantly higher than that in healthy people (SDM = 0.69, 95% CI [0.32, 1.06], P = .0002). Seven of the thirteen articles compared ADMA levels between the carotid arteriosclerosis group and the healthy control group, with 559 and 330 subjects in the two groups, respectively. The random-effects model was applied due to the high heterogeneity (I2  = 91%, P < .00001). The level of serum ADMA in patients with carotid arteriosclerosis was significantly higher than that in healthy people (SDM = 1.03, 95% CI [0.49, 1.57], P = .0002). CONCLUSION: The serum ADMA may be related to ischaemic stroke, and it is a risk factor for carotid atherosclerosis.

Current Developments in Cell Replacement Therapy for Parkinson's Disease.

Parkinson's disease (PD) is characterized by tremor, rigidity, and bradykinesia. PD is caused mainly by depletion of the nigrostriatal pathway. Conventional medications such as levodopa are highly effective in the early stage of PD; however, these medications fail to prevent the underlying neurodegeneration. Cell replacement therapy (CRT) is a strategy to achieve long-term motor improvements by preventing or slowing disease progression. Replacement therapy can also increase the number of surviving dopaminergic neurons, an outcome confirmed by positron emission tomography and immunostaining. Several promising cell sources offer authentic and functional dopaminergic replacement neurons. These cell sources include fetal ventral mesencephalic tissue, embryonic stem cells (ESCs), neural stem cells (NSCs), mesenchymal stem cells (MSCs) from various tissues, induced pluripotent stem cells (iPSCs), and induced neural cells. To fully develop the potential of CRT, we need to recognize the advantages and limitations of these cell sources. For example, although fetal ventral midbrain is efficacious in some patients, its ethical issues and the existence of graft-induced dyskinesias (GID) have prevented its use in large-scale clinical applications. ESCs have reliable isolation protocols and the potential to differentiate into dopaminergic progenitors. iPSCs and induced neural cells are suitable for autologous grafting. Here we review milestone improvements and emerging sources for cell-based PD therapy to serve as a framework for clinicians and a key reference to develop replacement therapy for other neurological disorders.

Oxidative Stress, Inflammation, and Autophagy: Potential Targets of Mesenchymal Stem Cells-Based Therapies in Ischemic Stroke.

Ischemic stroke is a leading cause of death worldwide; currently available treatment approaches for ischemic stroke are to restore blood flow, which reduce disability but are time limited. The interruption of blood flow in ischemic stroke contributes to intricate pathophysiological processes. Oxidative stress and inflammatory activity are two early events in the cascade of cerebral ischemic injury. These two factors are reciprocal causation and directly trigger the development of autophagy. Appropriate autophagy activity contributes to brain recovery by reducing oxidative stress and inflammatory activity, while autophagy dysfunction aggravates cerebral injury. Abundant evidence demonstrates the beneficial impact of mesenchymal stem cells (MSCs) and secretome on cerebral ischemic injury. MSCs reduce oxidative stress through suppressing reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation and transferring healthy mitochondria to damaged cells. Meanwhile, MSCs exert anti-inflammation properties by the production of cytokines and extracellular vesicles, inhibiting proinflammatory cytokines and inflammatory cells activation, suppressing pyroptosis, and alleviating blood-brain barrier leakage. Additionally, MSCs regulation of autophagy imbalances gives rise to neuroprotection against cerebral ischemic injury. Altogether, MSCs have been a promising candidate for the treatment of ischemic stroke due to their pleiotropic effect.

Remote clinical training practice in the neurology internship during the COVID-19 pandemic.

Background: During the current COVID-19 pandemic, offline clinical education was mandated to suspend at the neurology department of many teaching hospitals globally, yet there is insufficient evidence regarding the preferred practice and methods for online neurology intern training course.Objective: The investigation aimed to examine whether the online neurology training course based on Small Private Online Course (SPOC) and blending learning mode can achieve a good effect and cater for interns from different medical programs and whether the learning group size affects the teaching effect.Design: The subjects were 92 students enrolled in the neurology internship at the Second Xiangya Hospital of China from 9 March to 9 August 2020. After completing the online course, the final scores and evaluation results were compared among different groups of interns, and their preference to distinct contents of the course was analyzed. Statistical analysis was performed using the SPSS program (version 22.0).Results: Our online course received consistent positive recognition from the interns. Ninety-nine percent of the interns recommended incorporating the online course into the conventional offline training program after the pandemic. There was no significant difference between interns from different programs concerning the final scores and course evaluation. A smaller learning group size (<15 students) could achieve a better teaching effect than a larger group size (p < 0.05). The interns preferred interactive discussions, and course contents that they can get practice and feedback from, rather than video watching and didactic lectures.Conclusions: The online neurology intern training course based on SPOC and blending learning mode is worthy of popularization in a large student base. The teaching effect of an online intern training program may be improved by limiting the group size to less than 15 students and encouraging more interactive discussion, more practice and feedback.

The Application of Tirofiban in the Endovascular Treatment of Acute Ischemic Stroke: A Meta-Analysis.

OBJECTIVE: The purpose of this meta-analysis is to evaluate the safety and efficacy of tirofiban during endovascular treatment (EVT) for acute ischemic stroke (AIS) patients. METHODS: We systematically searched PubMed, Embase, Web of Science, and CENTRAL (Cochrane Central Register of Controlled Trials) databases for randomized controlled trials and cohort studies (published before May 1, 2020; no language restrictions) comparing tirofiban administration to blank control during EVT in patients with AIS. Our primary end points were the 3-month functional outcome, recanalization rate, symptomatic intracerebral hemorrhage, and 3-month mortality. RESULTS: The incidence of 3-month modified Rankin Scale (mRS) 0-2 score of the tirofiban group was higher than that of the control group (odds ratio [OR] = 1.27, 95% CI [1.09, 1.48], p = 0.002) with heterogeneity (I2 = 34%, p = 0.11). Data pooled from the 6 studies describing the details of retriever stent in EVT revealed that tirofiban was associated with higher incidence of 3-month mRS 0-2 score (OR = 1.48, 95% CI [1.11, 1.96], p = 0.007). The recanalization rate was higher in the tirofiban group compared to the control group (OR = 1.66, 95% CI [1.16, 2.39], p = 0.006). There were no statistically significant differences in the incidence of symptomatic intracranial hemorrhage (OR = 0.97, 95% CI [0.73, 1.31], p = 0.86) and intracranial hemorrhage (OR = 1.08, 95% CI [0.59, 1.97], p = 0.80) between tirofiban and non-tirofiban group. Besides, the tirofiban administration was associated with lower mortality (OR = 0.75, 95% CI [0.62, 0.91], p = 0.003). CONCLUSIONS: The application of tirofiban in EVT of AIS may improve functional outcomes and reduce mortality at 3 months. Besides, tirofiban does not seem to increase the risk of symptomatic intracranial hemorrhage and intracranial hemorrhage, either in the anterior or posterior circulation stroke.