Identification of a de novo splicing mutation in the CSF1R gene in a Chinese patient with hereditary diffuse leukoencephalopathy with spheroids.

OBJECTIVE: To report a de novo splicing mutation in the CSF1R gene in a patient with hereditary diffuse leukoencephalopathy with spheroids (HDLS). METHODS: A 42-year-old Chinese woman with constant weakness on her left lower extremity was recruited in the current study. Detail medical history and clinical characteristics were reviewed. Brain magnetic resonance imaging (MRI), whole-exome sequencing, and Sanger sequencing were performed with bioinformatics analysis. RESULTS: The Chinese HDLS patient with no HDLS family history exhibited a de novo splicing mutation (c.1754-10 T > A) in the CSF1R gene. This mutation was located at the splice site of intron 12 and resulted in the skipping of exon 13 from the CSF1R mRNA. This finding constitutes the first de novo splicing mutation ever reported in HDLS. Furthermore, MRI abnormalities had been reported at least 6 months prior to the onset of the patient's clinical phenotype. CONCLUSION: Our study indicates that the diagnosis of HDLS should be considered even in the absence of a family history and can help deepen the clinical and genetic understanding of HDLS.

Differential value of intima thickness in ischaemic stroke due to large-artery atherosclerosis and small-vessel occlusion.

No study has examined the differential value of arterial intima thickness in the subtypes of acute ischaemic stroke. This study aimed to assess whether intima thickness of carotid artery (CIT), radial artery (RIT) and dorsalis pedis artery (PIT) have an independent and additive value in differentiating ischaemic stroke subtypes due to large-artery atherosclerosis (LAA) or small-vessel occlusion (SVO). One hundred and sixty-one patients with LAA and 79 patients with SVO were recruited. CIT, RIT and PIT were measured with a 24-MHz ultrasound transducer. Binary logistic regression analysis was used to evaluate the differential values of the different parameters in the two subtypes. ROC curve analyses were plotted to compare the differential performance of different parameters and the combination model. Both RIT and PIT were substantially thicker in LAA than in SVO stroke patients. RIT and carotid intima-media thickness had similar performances in differentiating stroke subtypes. Introduction of RIT to traditional atherosclerotic associated risk factors had a marginal satisfactory differential performance for LAA and SVO stroke patients (AUC 0.775). RIT is a promising parameter for LAA and SVO subgroup classification. The combination of RIT and traditional risk factors might be a promising tool for differentiating ischaemic stroke subgroups.

The efficacy and safety of antiepileptics in the prophylaxis of pediatric migraine: the meta-analysis of randomized controlled trials.

BACKGROUND: Migraine is the most common primary headache among children and adolescents. The aim of this meta-analysis was to evaluate the efficacy and safety of antiepileptic drugs in the prevention of pediatric migraine. METHODS: PubMed, Cochrane Library, EMBASE and Chinese National Knowledge Infrastructure (CNKI) databases were searched for eligible published RCTs from January 1970 to June 2020. Migraine frequency and ≥50% response rate were measured as the efficacy outcomes. We used "Risk of Bias" tool for quality assessment and RevMan5.3 software for statistical analysis. RESULTS: Four articles containing 7 RCTs with 794 participants compared the efficacy of AEDs with placebo. Four RCTs assessed topiramate vs. placebo and 3 RCTs evaluated divalproex sodium extended-release (DVPX ER) vs. placebo. The results demonstrated that children receiving antiepileptic drugs had a significant advantage in remitting the mean monthly migraine days compared to those who received placebo, with an MD of -0.48 (n=930, 95% CI: -0.84 to -0.12, Z=2.60, P=0.009). Topiramate significantly reduced monthly migraine days (MD =-0.70, n=489, 95% CI: -1.16 to -0.25, Z=3.01, P=0.003) but failed to improve the ≥50% response rate (MD =-1.50, n=489, 95% CI: 0.70 to 3.22, Z=1.05, P=0.30). DVPX ER did not significantly reduce monthly headache frequency (n=441, 95% CI: -0.70 to 0.47, Z=0.38, P=0.70) or improve the ≥50% response rate (n=441, 95% CI: 0.59 to 1.25, Z=0.82, P=0.41) compared with placebo. Topiramate and DVPX ER were related to higher rates of side effects and adverse reactions. DISCUSSION: Topiramate can reduce monthly headache days in children and adolescents with migraine. However, it failed to improve the ≥50% response rate. DVPX ER showed no difference from placebo in the prophylactic treatment pediatric migraine. Side effects seemed to be more frequent in topiramate and DVPX ER treated children but generally well-tolerated.

Neural stem cell-conditioned medium ameliorates Aß25-35-induced damage in SH-SY5Y cells by protecting mitochondrial function.

Inhibition of amyloid ß (Aß)-induced mitochondrial damage is considered crucial for reducing the pathological damage in Alzheimer's disease (AD). We evaluated the effect of neural stem cell-conditioned medium (NSC-CDM) on Aß25-35-induced damage in SH-SY5Y cells. An in vitro model of AD was established by treating SH-SY5Y cells with 40 µM Aß25-35 for 24 h. SH-SY5Y cells were divided into control, Aß25-35 (40 µM), Aß25-35 (40 µM) + NSC-CDM, and Aß25-35 (40 µM) + neural stem cell-complete medium (NSC-CPM) groups. Cell viability was detected by CCK-8 assay. Apoptosis, reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) were detected by flow cytometry. Malondialdehyde content was detected by ELISA assay. Western blot analysis was used to detect cytochrome c release and apoptosis-related proteins. Transmission electron microscopy was used to observe mitochondrial morphology. Cell viability significantly decreased and apoptosis significantly increased in SH-SY5Y cells treated with Aß25-35, and both effects were rescued by NSC-CDM. In addition, NSC-CDM reduced ROS production and significantly inhibited the reduction of MMP caused by Aß25-35. Furthermore, NSC-CDM ameliorated Aß25-35-induced reduction in Bcl-2 expression levels and increased the expression levels of cytochrome c, caspase-9, caspase-3, and Bax. Moreover, Aß25-35 induced the destruction of mitochondrial ultrastructure and this effect was reversed by NSC-CDM. Collectively, our findings demonstrated the protective effect of NCS-CDM against Aß25-35-induced SH-SY5Y cell damage and clarified the mechanism of action of Aß25-35 in terms of mitochondrial maintenance and mitochondria-associated apoptosis signaling pathways, thus providing a theoretical basis for the development of novel anti-AD treatments.

The Diagnostic Value of Radial and Carotid Intima Thickness Measured by High-Resolution Ultrasound for Ischemic Stroke.

BACKGROUND: No study has examined intima thickness of the carotid artery and peripheral arteries in subjects with acute ischemic stroke due to large-artery atherosclerosis (LAAS). The aim of this study was to test whether carotid intima thickness (CIT), radial intima thickness (RIT), and dorsalis pedis intima thickness (PIT) are closely associated to atherosclerotic risk factors and whether they possess independent and additive value for differentiating LAAS stroke. METHODS: One hundred and two patients with LAAS stroke and 104 age- and gender-matched control subjects were enrolled. CIT, RIT, and PIT were measured using a 24-MHz, high-resolution ultrasound system. Multivariate linear regression was performed to determine associations between ultrasonic parameters and risk factors. Binary logistic regression was used to evaluate the diagnostic value of different parameters. Receiver operating characteristic curves were plotted to compare the performance of several diagnostic models. RESULTS: CIT ([36.97 ± 11.27] × 10-2 vs [23.68 ± 5.12] × 10-2 mm, P < .001) and RIT ([15.40 ± 3.62] × 10-2 vs [11.06 ± 2.22] × 10-2 mm, P < .001) were significantly thicker in patients with LAAS stroke than in control subjects. CIT and RIT were associated with traditional risk factors for atherosclerosis, including age, systolic blood pressure, and serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, homocysteine, and glucose. CIT had incremental diagnostic value to traditional risk factors for LAAS stroke (area under the curve, 0.945 vs 0.860; P = .006). The addition of CIT and RIT to traditional risk factors had the best diagnostic performance (area under the curve, 0.961). CONCLUSIONS: Measurement of CIT, RIT, and PIT is feasible and reliable using newly developed ultrasound techniques. CIT and RIT were associated with traditional risk factors for atherosclerosis and exhibited incremental value to traditional risk factors for differentiating patients with LAAS stroke from control subjects.

Retraction: Neural stem cell conditioned medium alleviates Aß25-35 damage to SH-SY5Y cells through the PCMT1/MST1 pathway.

On behalf of the coauthors and with much regret, I must retract our publication entitled "Neural stem cell conditioned medium alleviates Aß25-35 damage to SH-SY5Y cells through the PCMT1/MST1 pathway" published on European Journal of Histochemistry 2020;64(s2):3135 for the following reasons: In Figure 1A, the data of 20 µM Aß25-35 for different time were confused with the data of 30 µM Aß25-35 for different time. In Figure 2, the differential expression of PCMT1 is poor in repeatability. The authors need to revise the experimental design and steps to verify it again, re-do the experiment and conduct a more in-depth study. Dr. Congcong Sun Department of Neurology Qilu Hospital Cheeloo College of Medicine Shandong University China.

Immunoproteasome is up-regulated in rotenone-induced Parkinson's disease rat model.

The study was to investigate whether immunoproteasome (i-proteasome) and its downstream pathway are related to the pathogenesis of Parkinson's disease (PD). Rats were treated with rotenone showed significant weight loss and dyskinesia, which is consistent with the degeneration of TH-positive neurons and the activation of Iba-1-positive microglia/macrophages. Two major catalytic subunits of i-proteasome (PSMB9 and PSMB8) were seldom expressed in rat substantia nigra (SN) under normal condition, but they were significantly up-regulated with the release of TNF-α and IFN-γ after exposure to rotenone. In addition, compared with control group, the antigen presentation-related proteins antigen peptide transporter (TAP) 1, TAP2, major histocompatibility complex (MHC)-I and MHC-II levels were significantly up-regulated in rotenone group, which was in line with the accumulation of α-syn. These findings suggested that i-proteasome and antigen presentation pathways (related proteins) were upregulated by rotenone in a PD rat model.

Paclitaxel and quercetin co-loaded functional mesoporous silica nanoparticles overcoming multidrug resistance in breast cancer.

Multidrug resistance (MDR) in tumor has long been considered a major factor in the failure of tumor chemotherapy. P-glycoprotein (P-gp)-mediated drug efflux plays a significant role in the MDR of tumor. Herein, paclitaxel (PTX) and P-gp inhibitor quercetin (QC) co-loaded and chondroitin sulfate (ChS)-coated mesoporous silica nanoparticles (MSNs) (MSNs-ChS@PQ) were developed to reverse MDR in breast cancer and improve chemotherapy efficacy. The dual drug-loaded nanoparticles (NPs) showed a nanoscale size of ∼ 227.2 nm and redox-responsive drug release property. In vitro cell experiments showed that NPs exhibited CD44 receptor-mediated active targeting in MCF-7/ADR cells. The dual drug-loaded NPs had lower IC50 value, higher apoptosis rate, obvious G2M phase arrest as well as stronger microtubule destruction in MCF-7/ADR cells compared to PTX-loaded NPs, suggesting that QC addition, significantly, improved the sensitivity of MCF-7/ADR cells to PTX. Further study found that QC-loaded NPs down-regulated the expression of P-gp. Notably, the dual drug-loaded NPs exhibited tumor-targeting ability, prolonged tumor retention time and effective anti-tumor effect without obvious toxicity to normal tissues in vivo. Taken together, our research provides a viable approach to overcome MDR in breast cancer.

Neural stem cell conditioned medium alleviates Aß25-35 damage to SH-SY5Y cells through the PCMT1/MST1 pathway.

Alzheimer's disease (AD) is a progressive, neurodegenerative disease. Accumulating evidence suggests that protein isoaspartate methyltransferase 1 (PCMT1) is highly expressed in brain tissue (substantia nigra, blue plaque, paraventricular nucleus). In this study, we investigated the effect of neural stem cell conditioned medium alleviates Aß25-35 damage to SH-SY5Y cells by PCMT1/MST1 pathway. Results demonstrated that Aß25-35 significantly decreased the cell viability in time and dose dependent manner. However, Neural stem cell-complete medium (NSC-CPM) or NSC-CDM had inhibitory effect on toxicity when fibrillation of Aß25-35 occurred in their presence and NSC-CDM had a better inhibitor result. An increase of the PCMT1 expression levels was found in Aß25-35 + NSC-CDM group. sh-PCMT1 significantly reduced the PCMT1, the cell viability and inhibited the protective effect; induced apoptosis and increased the expression of p-MST1. Overexpression of PCMT1 group reversed the effect of Aß25-35 inhibited the cell viability and Aß25-35 induced the apoptosis. In conclusion, NSC-CDM corrects the damage of Aß25-35 to cells by increasing PCMT1, reducing MST phosphorylation.

Peripheral Humoral Immune Response Is Associated With the Non-motor Symptoms of Parkinson's Disease.

BACKGROUND: Non-motor symptoms are common in Parkinson's disease (PD) and can even be used as part of the supportive criteria for diagnosis. Chronic inflammation is involved in every stage of PD. Disorders of the immune system affect the peripheral blood. Whether the humoral immune response is associated with the non-motor symptoms of PD remains unknown. METHODS: Mann-Whitney tests and Bonferroni correction were used to compare the serum levels of IgG, IgA, IgM, C3, and C4 between 180 sporadic PD patients and 187 healthy controls. Multiple regression models were conducted to assess the associations among these indicators of humoral immunity and the clinical features of PD patients. RESULTS: Male PD patients had lower levels of C3 and C4 than healthy controls [0.87 (0.22) vs. 0.96 (0.19); 0.19 (0.06) vs. 0.22 (0.07), respectively, Pc < 0.01] and lower levels of C3 than female PD patients [0.87 (0.22) vs. 1.02 (0.23), Pc < 0.01]. Patients suffering from attention/memory problems had significantly lower levels of IgA and C3 than those without these problems [1.92 (1.21) vs. 2.57 (0.76); 0.89 (0.24) vs. 0.97 (0.24), respectively, Pc < 0.04]. In addition, serum IgG levels were negatively associated with mood/cognition problem scores and were positively associated with gastrointestinal tract problem scores (adjusted R 2 = 0.063, F = 1.805, p = 0.038). Serum C3 levels were negatively associated with being male, age, and sleep/fatigue problem scores (adjusted R 2 = 0.123, F = 2.678, p = 0.001). CONCLUSION: The peripheral humoral immune response might be correlated with the non-motor symptoms of PD.

The Synergistic Neuroprotective Effects of Combined Rosuvastatin and Resveratrol Pretreatment against Cerebral Ischemia/Reperfusion Injury.

BACKGROUND: It is well accepted that both rosuvastatin and resveratrol exert neuroprotective effects on cerebral ischemia/reperfusion injury through some common pathways. Resveratrol has also been demonstrated to protect against cerebral ischemia/reperfusion injury through enhancing autophagy. Thus, we hypothesized that combined rosuvastatin and resveratrol pretreatment had synergistic effects on cerebral ischemia/reperfusion injury. MATERIALS AND METHODS: Adult male Sprague Dawley rats receiving middle cerebral artery occlusion surgery as animal model of cerebral ischemia/reperfusion injury were randomly assigned to 4 groups: control, resveratrol alone pretreatment, rosuvastatin alone pretreatment, and combined rosuvastatin and resveratrol pretreatment. Rosuvastatin (10 mg/kg) or resveratrol (50 mg/kg) was administrated once a day for 7 days before cerebral ischemia onset. RESULTS: We found that combined rosuvastatin and resveratrol pretreatment not only significantly decreased the neurologic defective score, cerebral infarct volume, the levels of caspase-3, and Interleukin-1ß (IL-1ß) but also significantly increased the ratios of Bcl-2/Bax and LC3II/LC3I, as well as the level of Becline-1, compared with resveratrol alone or rosuvastatin alone pretreatment group. Rosuvastatin alone pretreatment significantly increased the ratio of LC3II/LC3I and the level of Beclin-1. However, there were no significant differences in the neurologic defective score, cerebral infarct volume, the levels of caspase-3, IL-1ß, and Beclin-1, and the ratios of Bcl-2/Bax and LC3II/LC3I between resveratrol pretreatment group and rosuvastatin pretreatment group. CONCLUSIONS: Synergistically enhanced antiapoptosis, anti-inflammation, and autophagy activation might be responsible for the synergistic neuroprotective effects of combining rosuvastatin with resveratrol on cerebral ischemia/reperfusion injury.

Agrypnia excitata and obstructive apnea in a patient with fatal familial insomnia from China: A case report.

RATIONALE: Fatal familial insomnia (FFI) linked to a D178N/129M haplotype mutation in the PRNP gene is the most common genetic prion disease in the Han Chinese population. Here, we describe a Han Chinese patient with FFI who exhibited agrypnia excitata and obstructive apnea. PATIENT CONCERNS: A 46-year-old man displayed involuntary movements during sleep time, snoring, autonomic nervous system dysfunction, cognitive deficit, brainstem symptoms, myoclonus and ataxia in order within 8 months. The electroencephalogram (EEG) and Magnetic Resonance Imaging (MRI) revealed abnormal changes but without the typical prion disease signs. DIAGNOSES: After the conduction of Polysomnogram (PSG) and gene detection of PRNP, the patient was diagnosed as FFI. Three others exhibiting the same clinical manifestations were observed in the large family. INTERVENTIONS: The patient responded temporally well to drugs that strengthening the function of mitochondria. OUTCOMES: Sudden death occurred after 3 month ever since the diagnoses. The total disease course was 11 months. LESSONS: The insomnia in FFI is complex, agrypnia excitata and obstructive apnea can also be indicators for FFI. Polysomnogram is necessary for recognizing the sleep loss when the symptom of insomia is not typical. Improving energy metabolism may be a potential treatment for it.

Carotid endarterectomy versus carotid angioplasty for stroke prevention: a systematic review and meta-analysis.

BACKGROUND: This meta-analysis aimed to evaluate the efficacy of carotid endarterectomy (CE) compared with carotid angioplasty (CA) in preventing stroke. Whether the use of CE is more efficient in preventing stroke than CA is a matter of debate. METHODS: Data were gathered from randomized controlled trials to evaluate the effect of CE compared with CA on the risk of stroke. Electronic searches in PubMed, Embase, and the Cochrane Library were performed to identify studies till November 2014. Only randomized controlled trials performed on patients who received either CE or CA for stroke prevention were included. RESULTS: Nine relevant trials (n = 7163) that met the inclusion criteria were identified. In a pooled analysis, CE resulted in 35 % reduction in relative risk (RR) for short-term stroke [RR, 0.65; 95 % confidence interval (CI): 0.47-0.89; P = 0.007)] and 22 % reduction in RR for long-term stroke (RR, 0.78; 95 % CI: 0.66-0.93; P = 0.006) relative to CA. However, CE also increased the risk of 30-day myocardial infarction by 114 % compared with CA (RR, 2.14; 95 % CI: 1.30-3.53; P = 0.003). Sensitivity analyses suggested that CE might influence the risk of 30-day major vascular events and 1-year major vascular events compared with CA. CONCLUSIONS: CE could reduce the risk of stroke (whether short term or long term), but resulted in a relative increase in the risk of myocardial infarction. This study might guide appropriate judgments about treatment approach. It also provided evidence to justify general guidelines for patients with carotid artery stenosis.

Significance of decreased serum interleukin-10 levels in the progression of cerebral infarction.

Anti-inflammatory cytokine and its serological detection may have an important role in the process of cardiovascular and cerebrovascular diseases. We investigated whether serum interleukin-10 (IL-10) is associated with cerebral infarction or not in the general population. Identified comprehensive searching was performed covering PubMed, EMBASE, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine, and China National Knowledge Infrastructure databases. Two reviewers extracted data and assessed studies independently. Information was extracted separately and classed into Asians and Caucasians. Summary standardized mean differences (SMDs) with 95 % confidence intervals (CI) were used with the utilization of Z test. Nine studies ranged from 2003 to 2014 were collected for meta-analysis. Results identified a negative association between serum IL-10 levels and cerebral infarction (SMD = 1.80, 95 % CI 0.79-2.81, P < 0.001). Country-subgroup analysis showed that low IL-10 level may be the main risk factor for cerebral infarction in India (SMD = 1.44, 95 % CI 1.13-1.75, P < 0.001) and Croatia (SMD = 2.96, 95 % CI 2.48-3.44, P < 0.001). In the ethnicity-stratified subgroup analysis, serum IL-10 levels were negatively correlated with cerebral infarction in Asians (SMD = 2.52, 95 % CI 0.47-4.57, P = 0.016), while not in Caucasians (P > 0.05). The lower serum IL-10 concentration was significantly associated with an increased likelihood of cerebral infarction in this meta-analysis. More prospective studies should be conducted to provide stronger evidence justifying the use of IL-10 as new biomarker to identify a predisposition toward cerebral infarction.

Poor outcome of experimental ischemic stroke in type 2 diabetic rats: impaired circulating endothelial progenitor cells mobilization.

BACKGROUND: It is well accepted that type 2 diabetic mellitus (T2DM) results in the poor outcome of ischemic stroke. However, the mechanisms by which T2DM causes aggravated cerebral ischemic/reperfusion (I/R) injury are not clear. Recently, endothelial progenitor cells (EPCs) are considered to be related with the outcome of ischemic stroke. More importantly, T2DM can affect the function of circulating EPCs. This study tried to investigate whether T2DM worsens the cerebral I/R injury via affecting circulating EPCs. METHODS: We used high-fat diet-fed and low-dose streptozotocin-treated male rats receiving middle cerebral artery occlusion surgery as animal model of focal cerebral I/R injury with T2DM (diabetic operated). And the rats were divided into 4 groups: normal sham, diabetic sham, normal operated, and diabetic operated. We measured the circulating EPCs counts and the levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) in peripheral plasma of 4 groups. RESULTS: We found that diabetic rats subjected to I/R exhibited significantly severe deterioration in neurologic deficits compared with nondiabetic counterparts, which manifested higher infarct volume and cell apoptosis as well as lower neurologic defective score. There was no significant difference on the plasma glucose of groups before cerebral I/R injury compared with that of the groups posterior to cerebral I/R injury despite cerebral I/R injury had the tendency to increase the plasma glucose no matter in the presence or the absence of T2DM. In addition, there were the marked downregulation of circulating EPCs counts and the levels of VEGF and eNOS in diabetic rats before the cerebral I/R injury. Despite I/R injury without T2DM, there was a significant increase in the circulating EPCs counts, the circulating EPCs counts in I/R injury with T2DM group were significantly decreased compared with those in the other 3 groups. We also observed that the level of eNOS was significantly improved by I/R injury without considering the presence of T2DM. CONCLUSIONS: Thus, our present study suggested that it might be the impaired EPCs mobilization into the blood that contributed to the worse outcome of cerebral I/R injury with T2DM.

Targeted delivery of extracellular matrix protected against neurologic defects after focal ischemia reperfusion in rats.

Ischemic stroke is one of the leading causes of morbidity and mortality worldwide and characterized by defective angiogenesis. The functional sequences (RGDs, GRGDSPASSPISC) derived from fibronectin have been confirmed to augment angiogenesis in vivo and in vitro. However, delivery of peptides into the brain parenchyma has been hampered by the presence of the blood-brain barrier (BBB). We fused RGDs with penetratin (Antp) derived from Drosophila antennapedia homeodomain protein to improve the penetration of peptides through BBB into ischemic hemisphere. We found Antp-RGDs successfully not only penetrate the SH-SY5Y cells but also penetrated through BBB into ischemic hemisphere by intraperitoneal injection. In addition, application of Antp-RGDs to the focal cerebral ischemic reperfusion injury in rats resulted in the reduction of cerebral ischemic volume and the improvement of neurologic score according to the 21-point score. We further demonstrated that activation of phosphorylation-extracellular-signal related kinase 1/2 (p-ERK 1/2) and upregulation of gene VEGF resulted from post-treatment with Antp-RGDs 2 hours after reperfusion onset might at least partly contribute to the benefic changes after focal cerebral ischemic reperfusion injury in rats. Our data suggested that Antp-RGDs may serve as an attractive therapeutic intervention for treating ischemic stroke.