PgDDS Changes the Plant Growth of Transgenic Aralia elata and Improves the Production of Re and Rg3 in Its Leaves.

Aralia elata (Miq.) Seem is a medicinal plant that shares a common pathway for the biosynthesis of triterpenoid saponins with Panax ginseng. Here, we transferred the dammarenediol-II synthase gene from P. ginseng (PgDDS; GenBank: AB122080.1) to A. elata. The growth of 2-year-old transgenic plants (L27; 9.63 cm) was significantly decreased compared with wild-type plants (WT; 74.97 cm), and the leaflet shapes and sizes of the transgenic plants differed from those of the WT plants. Based on a terpene metabolome analysis of leaf extracts from WT, L13, and L27 plants, a new structural skeleton for ursane-type triterpenoid saponins was identified. Six upregulated differentially accumulated metabolites (DAMs) were detected, and the average levels of Rg3 and Re in the leaves of the L27 plants were 42.64 and 386.81 µg/g, respectively, increased significantly compared with the WT plants (15.48 and 316.96 µg/g, respectively). Thus, the expression of PgDDS in A. elata improved its medicinal value.

Beyond Growth Hormone: Association of Short Stature Types and Growth Hormones With Scoliosis.

STUDY DESIGN: Cross-sectional and retrospective cohort study. OBJECTIVE: We investigated the effect of 3 types of short stature [partial growth hormone deficiency (GHD), GHD, and idiopathic short stature (ISS)] and recombinant human growth hormone (rhGH) therapy on scoliosis. SUMMARY OF BACKGROUND DATA: In short stature, rhGH is widely used and the concentration of growth hormone varies among types. The epidemiologic characteristics of scoliosis and the role of rhGH in scoliosis remain unclear. PATIENTS AND METHODS: A cross-sectional study was conducted among 3896 patients with short stature (partial GHD, GHD, and ISS), and a 1:1 age and sex-matched control group with preexisting whole-spine radiographs. The cohort study included 2605 subjects who underwent radiography more than twice to assess scoliosis development, progression, and the need for bracing and surgery. Adjusted logistic regression was used to assess differences in the prevalence of scoliosis among patients with partial GHD, GHD, ISS, and controls. The Kaplan-Meier method was used to analyze the time course of scoliosis development and progression. Cox regression was applied to assess the independent factors related to scoliosis development and progression. Mendelian randomization analyses were also performed. RESULTS: Compared with controls, patients with short stature had a higher incidence of scoliosis (34.47% in partial GHD, 31.85% in GHD, 32.94% in ISS vs . 8.83% in control, P < 0.001), a higher risk of scoliosis development [hazard ratio (HR) = 1.964 in partial GHD, P < 0.001; HR = 1.881 in GHD, P = 0.001; HR = 1.706 in ISS, P = 0.001), but not a higher risk of progression, brace, or surgery. Among the 3 types of short stature, there were no differences in the incidence, development, and progression of scoliosis or the need for bracing or surgery. RhGH treatment increased the risk of scoliosis development in each short-stature group (HR = 2.673 in partial GHD, P < 0.001; HR = 1.924 in GHD, P = 0.049; HR = 1.564 in ISS, P = 0.004). Vitamin D supplementation was protective against scoliosis development (HR = 0.456 in partial GHD, P = 0.003; HR = 0.42 in GHD, P = 0.013; HR = 0.838 in ISS, P = 0.257). CONCLUSIONS: More attention should be paid to the spinal curve in patients with partial GHD, GHD, or ISS. For short stature treated with rhGH, the risk of scoliosis development was increased. Vitamin D supplementation may be beneficial for prevention. LEVEL OF EVIDENCE: Level III.

Structural and functional changes in the default mode network in drug-resistant epilepsy.

PURPOSE: To investigate brain network properties and connectivity abnormalities of the default mode network (DMN) in drug-resistant epilepsy (DRE). The study was based on probabilistic fiber tracking and functional connectivity (FC) analysis, to explore the structural and functional connectivity patterns change between frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). METHODS: A total of 33 DRE patients (18 TLE and 15 FLE) and 30 healthy controls (HCs) were recruited. The volume fraction of the septal brain region of the DMN in DRE was calculated using FreeSurfer. The FC analysis was performed using Data Processing and Analysis for Brain Imaging in MATLAB. The structural connections between brain regions of the DMN were calculated based on probabilistic fiber tracking. RESULTS: The left precuneus (PCUN) volumes in epilepsy groups were lower than that in HCs. Compared with FLE, TLE showed reduced FC between the left hippocampus (HIP) and PCUN/medial frontal gyrus, and between the right inferior parietal lobule (IPL) and right superior temporal gyrus. Compared with HCs, FLE showed increased FCs between the right IPL and occipital lobe, and between the left superior frontal gyrus (SFG) and bilateral superior temporal gyrus. In terms of structural connectivity, TLE exhibited increased connectivity strength between the left SFG and left PCUN, and showed reduced connection strength between the left HIP and left posterior cingulate gyrus/left PCUN, when compared with the FLE. CONCLUSIONS: TLE and FLE patients showed structural and functional changes in the DMN. Compared with FLE patients, the TLE patients showed reduced structural and functional connection strengths between the left HIP and PCUN. These alterations in connection strengths holds promise for the identification of TLE and FLE.

Efficacy and safety of perampanel monotherapy in Chinese patients with focal-onset seizures: A single-center, prospective, real-world observational study.

OBJECTIVE: Efficacy and safety of perampanel monotherapy for treating focal-onset seizures (FOS) has been barely studied in China. This observational study aimed to evaluate the efficacy and safety of perampanel monotherapy in treating Chinese patients with FOS. METHODS: This single-center, prospective, real-world observational study enrolled patients aged ≥4 years with FOS who visited the Epilepsy Out-Patient Clinic of Nanjing Brain Hospital affiliated to Nanjing Medical University from January 2020 to December 2021. All patients were treated with perampanel monotherapy. Seizure-freedom rates after 6 and 12 months of treatment were calculated. Adverse events (AEs) were recorded. RESULTS: Seventy patients with FOS were enrolled. The mean maintenance perampanel dose was 4.64 ± 1.55 mg/day. The 6- and 12-month retention rates of perampanel monotherapy were 78.6% (55/70) and 70.0% (49/70), respectively. The 6- and 12-month seizure-freedom rates were 69.84% (44/63) and 65.08% (41/63), respectively. Patients with focal to bilateral tonic-clonic seizures had significantly higher 6-month and numerically higher 12-month seizure freedom rates than patients with focal impaired awareness seizures (P = 0.046 and P = 0.204, respectively). Twenty-six (37.1%) patients experienced treatment-emergent AEs, and the most common AE was dizziness. Four (5.7%) patients withdrew from the study due to AEs. No new safety concern was observed. SIGNIFICANCE: This is the first prospective study on the efficacy and safety of perampanel monotherapy in treating Chinese patients with FOS, and perampanel monotherapy was effective and safe in treating Chinese patients aged ≥4 years with FOS up to 12 months. More multicenter, real-world studies with large sample sizes and longer follow-ups are needed to further evaluate the long-term efficacy and safety of perampanel monotherapy.

Comparation of differences in the performance of corporate social responsibility between Chinese and American pharmaceutical enterprises-based on corporate social responsibility report.

Objective: We compared Chinese and American pharmaceutical companies' corporate social responsibility (CSR) reports to determine their differences and to analyze the possible reasons for them. Methods: We took as a model the top 500 pharmaceutical companies from Torreya's (a global investment bank) list of the 1,000 most valuable pharmaceutical companies in the world. We then collected the 2020 corporate social responsibility reports of 97 Chinese and 94 American pharmaceutical companies. These reports were analyzed using software such as ROST Content Mining 6.0 and Gephi 0.92. Results: We formed a high-frequency word list, a semantic network diagram, and a high-frequency word centrality scale for the Chinese and American pharmaceutical corporate social responsibility reports. The Chinese pharmaceutical companies' corporate social responsibility reports formed a layout of "double centers and double themes," and the text paid more attention to the disclosure of environmental protection information. The American pharmaceutical companies formed a report presentation form of "three centers and two themes," focusing on corporate social responsibility information disclosures from the perspective of humanistic care. Discussion: The differences in between Chinese and American pharmaceutical companies' corporate social responsibility reports may be due to different corporate development strategies, regulatory requirements, social demands, and the concept of "corporate citizenship." This study makes recommendations for Chinese pharmaceutical companies to better fulfill their CSR at three levels: policy-making, company management, and society.

Expression of PnSS Promotes Squalene and Oleanolic Acid (OA) Accumulation in Aralia elata via Methyl Jasmonate (MeJA) Induction.

Aralia elata is an important herb due to the abundance of pentacyclic triterpenoid saponins whose important precursors are squalene and OA. Here, we found that MeJA treatment promoted both precursors accumulation, especially the latter, in transgenic A. elata, overexpressing a squalene synthase gene from Panax notoginseng(PnSS). In this study, Rhizobium-mediated transformation was used to express the PnSS gene. Gene expression analysis and high-performance liquid chromatography (HPLC) were used to identify the effect of MeJA on squalene and OA accumulation. The PnSS gene was isolated and expressed in A. elata. Transgenic lines showed a very high expression of the PnSS gene and farnesyl diphosphate synthase gene (AeFPS) and a slightly higher squalene content than the wild-type, but endogenous squalene synthase (AeSS), squalene epoxidase (AeSE), and ß-amyrin synthase (Aeß-AS) gene were decreased as well as OA content. Following one day of MeJA treatment, the expression levels of PeSS, AeSS, and AeSE genes increased significantly. On day 3, the maximum content of both products reached 17.34 and 0.70 mg·g-1, which increased 1.39- and 4.90-fold than in the same lines without treatment. Transgenic lines expressing PnSS gene had a limited capability to promote squalene and OA accumulation. MeJA strongly activated their biosynthesis pathways, leading to enhance yield.

Neurovascular coupling changes in patients with magnetic resonance imaging negative focal epilepsy.

Brain neuron activity is closely related to cerebral blood flow (CBF) changes. Alterations in the regional homogeneity (ReHo) and CBF occur in patients with magnetic resonance imaging negative focal epilepsy (FEP-MRI-). However, the coupling alterations of ReHo and CBF in FEP-MRI- remain unclear. The study aims to explore neurovascular coupling alterations and their clinical implication in FEP-MRI-. We collected resting-state magnetic resonance imaging (MRI) data from 31 healthy controls (HCs) and 48 patients with FEP-MRI-,including three-dimensional (3D) T1-weighted imaging, 3D arterial spin labeling (ASL) imaging,and resting-state functional MRI (rs-fMRI). The CBF and ReHo values were calculated from the ASL and rs-fMRI data, respectively. The CBF/ReHo ratio per voxel and whole-brain CBF-ReHo coupling were compared between the two groups. Correlation analysis involved the CBF/ReHo ratio and clinical indicators in FEP-MRI-. Patients with FEP-MRI- showed significantly increased cross-subject CBF-ReHo and global cross-voxel CBF-ReHo coupling. The CBF/ReHo ratio was higher in the bilateral orbitofrontal gyrus, right parietal lobe, and right middle frontal gyrus of patients with FEP-MRI-. Nevertheless, this ratio was lower in the bilateral supplementary motor areas, the left middle and posterior cingulate gyrus, and the right central sulcus cover. The CBF/ReHo ratio was markedly correlated with cognitive function, memory, intelligence, and epilepsy duration in the above abnormal brain regions. CBF/ReHo ratio may be useful as an indicator of neuropathological mechanisms. These results support the hypothesis that CBF/ReHo ratio relates to the neuropathological mechanisms of FEP-MRI-. Furthermore, it offers new perspectives for studying the mechanisms of MRI-negative epilepsy.

Immediate Effects of Vagal Nerve Stimulation in Drug-Resistant Epilepsy Revealed by Magnetoencephalographic Recordings.

Objective: Vagus nerve stimulation (VNS) has been a neuromodulatory option for treating drug-resistant epilepsy (DRE), but its mechanism remains unclear. To obtain insight into the mechanism by which VNS reduces epileptic seizures, the immediate effects of VNS in brain networks of DRE patients were investigated when the patients' vagal nerve stimulators were turned on. Methods: The brain network properties of 14 DRE patients with a vagal nerve stimulator and 14 healthy controls were evaluated using magnetoencephalography recordings for 6 main frequency bands. Results: Compared with healthy controls, DRE patients exhibited significant increases in functional connectivity in the theta, alpha, beta, and gamma bands and significant reductions in the small-world measure in the theta and beta bands. During periods when patients' vagal nerve stimulators were turned on, DRE patients showed significant reductions in functional connectivity in the theta and alpha bands and a significant increase in the small-world measure in the theta band when compared with periods when patients' vagal nerve stimulators were turned off. Conclusions: Our results indicate that the brain networks of DRE patients were pathologically hypersynchronous and instantaneous VNS can decrease the synchronization of brain networks of epileptic patients, which might play a key role in the mechanism by which VNS reduces epileptic seizures. In the theta band, instantaneous VNS can increase the network efficiency of DRE patients, and the increment in network efficiency may be helpful for improving brain cognitive function in epileptic patients. Impact statement For the first time, we investigated the immediate effects of vagus nerve stimulation (VNS) in the brain networks of drug-resistant epilepsy patients using magnetoencephalography. Our results show that instantaneous VNS can decrease the hypersynchronization of epileptic networks and increase the network efficiency of epileptic patients. Our results are helpful in understanding the mechanism of action by which VNS reduces epileptic seizures and improves the cognitive function in epileptic patients and the brain network reorganization caused by long-term VNS.

Activation of brain lactate receptor GPR81 aggravates exercise-induced central fatigue.

Exercise-induced fatigue is a complex physiological phenomenon and is greatly influenced by central mechanisms in brain. As one of the most abundant circulating carbon metabolites, l-lactate in brain has been considered to be an important supplementary fuel during exercise; however, whether it plays a signaling role in fatigue remains largely obscure. In this study, our results initially revealed that brain l-lactate levels were increased after an exhaustive swimming session in several brain regions including motor cortex, hippocampus, and cerebellum. Then, we examined the specific role of brain lactate receptor, also known as hydroxycarboxylic acid receptor 1 (GPR81), in exercise-induced fatigue. We found that intracerebroventricular injection of either d-lactate (an enantiomer that could mediate activation of GPR81 as l-lactate) or a potent GPR81 agonist 3-chloro-5-hydroxybenzoic acid (CHBA), significantly decreased the swimming time to fatigue. After being subjected to the same weight-loaded swimming for 30 min, no obvious changes of blood lactate levels, gastrocnemius pAMPK/AMPK ratio, and glycogen contents were observed between intracerebroventricular CHBA-injected mice and vehicle-treated ones, which suggested a comparable degree of peripheral fatigue. Meanwhile, there were higher extracellular γ-aminobutyric acid (GABA) levels and lower extracellular glutamate levels and glutamate/GABA ratio in motor cortex of the intracerebroventricular CHBA-injected mice than that of vehicle-treated ones, indicating a greater extent of central fatigue in CHBA-injected mice than that in vehicle animals. Collectively, our results suggested that an increased level of brain l-lactate acts as a signaling molecule via activating GPR81, which in turn exacerbates central fatigue during exercise.

Stable functional compensation within hippocampal-subregion networks in patients with temporal glioma before and after surgery.

Objective: To identify whether tumor invasion of the temporal lobe induces functional compensation of the hippocampal-subregion (HIPsub) network connectivity before surgery, and to further validate the stability of this functional compensation within the HIPsub network in patients with temporal glioma tumor (TTumor) after surgical resection of the tumor. Methods: In the first cohort, analysis of HIPsub functional connectivity (FC) was conducted to identify the functional compensation of the altered HIPsub connectivity pattern in TTumor through a pattern classification approach. Then, the second cohort investigated whether functional compensation in TTumor patients changed after surgical resection of the tumor. Results: In the first cohort, this study identified altered HIPsub network connectivity patterns and its functional compensation regions (i.e., left parahippocampal gyrus and bilateral cerebellum anterior lobe) in TTumor patients. Second, the altered HIPsub network connectivity patterns had the power to discriminate TTumor patients from healthy controls (CN) on an individual subject basis, with an AUC of 97.0%, sensitivity of 93.5%, and specificity of 90.3%. Finally, in the second cohort, we found that functional connectivities of functional compensation regions within the HIPsub network in TTumor patients did not change between before and after surgery. Conclusion: This study provides novel evidence regarding functional compensation within the HIPsub network in TTumor patients. It has been suggested that the fine hippocampal subregion was more sensitive, which reveals functional compensation induced by tumor invasion of the temporal lobe. Furthermore, this study verified the stability and persistence of this functional compensation in TTumor patients after surgical resection of the tumor.

A High-Quality Reference Genome Sequence and Genetic Transformation System of Aralia elata.

Aralia elata is a perennial woody plant of the genus Aralia in the family Araliaceae. It is rich in saponins and therefore has a wide range of pharmacological effects. Here, we report a high-quality reference genome of A. elata, with a genome size of 1.21 Gb and a contig N50 of 51.34 Mb, produced by PacBio HiFi sequencing technology. This is the first genome assembly for the genus Aralia. Through genome evolutionary analysis, we explored the phylogeny and whole genome duplication (WGD) events in the A. elata genome. The results indicated that a recent WGD event occurred in the A. elata genome. Estimation of the divergence times indicated that the WGD may be shared by Araliaceae. By analyzing the genome sequence of A. elata and combining the transcriptome data from three tissues, we discovered important genes related to triterpene saponins biosynthesis. Furthermore, based on the embryonic callus induction system of A. elata established in our laboratory, we set up the genetic transformation system of this plant. The genomic resources and genetic transformation system obtained in this study provide insights into A. elata and lays the foundation for further exploration of the A. elata regulatory mechanism.

Decreased Adiponectin Levels Are a Risk Factor for Cognitive Decline in Spinal Cord Injury.

OBJECTIVE: Spinal cord injury (SCI) has become popular in recent years, and cognitive decline is a common complication. Adiponectin is a common protein hormone involved in the course of many diseases, but its relationship with SCI has not yet been elucidated. The purpose of our prospective study is to explore whether adiponectin can be used as a biomarker of cognitive decline in SCI. METHODS: A total of 64 healthy volunteers and 92 patients with acute SCI were recruited by us. Serum adiponectin levels, demographic data (age and gender), lifestyle (smoking and drinking), medical history (diabetes and hypertension), and clinical baseline data (low-density lipoprotein, high-density lipoprotein, and fasting blood glucose) were recorded. Three months after enrollment, we used the Montreal Cognitive Assessment (MoCA) to evaluate cognitive function. Based on a quarter of the serum adiponectin levels, SCI patients were divided into 4 groups, and the differences in their MoCA scores were compared. In addition, we used multivariate linear regression to predict the risk factors of the MoCA score. RESULTS: The serum adiponectin level (6.1 ± 1.1 µg/ml) of SCI patients was significantly lower than that of the healthy control group (6.7 ± 0.9 µg/ml), and there was a significant difference between the two (p < 0.001). The group with higher serum adiponectin levels after 3 months of spinal cord injury had higher MoCA scores. Multivariate regression analysis showed that serum adiponectin level is a protective factor for cognitive function after SCI (ß = 0.210, p = 0.043). CONCLUSIONS: Serum adiponectin levels can be used as an independent predictor of cognitive function in patients with acute SCI.

Evaluation of Brain Network Properties in Patients with MRI-Negative Temporal Lobe Epilepsy: An MEG Study.

Abnormal functional brain networks of temporal lobe epilepsy (TLE) patients with structural abnormalities may partially reflect structural lesions rather than either TLE per se or functional compensatory processes. In this study, we sought to investigate the brain-network properties of intractable TLE patients apart from the effects of structural abnormalities. The brain network properties of 20 left and 23 right MRI-negative TLE patients and 22 healthy controls were evaluated using magnetoencephalographic recordings in six main frequency bands. A slowing of oscillatory brain activity was observed for the left or right TLE group vs. healthy controls. The TLE groups presented significantly increased functional connectivity in the delta, theta, lower alpha and beta bands, and significantly greater values in the normalized clustering coefficient and path length, and significantly smaller values in the weighted small-world measure in the theta band when compared to healthy controls. Alterations in global and regional band powers can be attributed to spectral slowing in TLE patients. The brain networks of TLE patients displayed abnormally high synchronization in multi-frequency bands and shifted toward a more regular architecture with worse network efficiency in the theta band. Without the contamination of structural lesions, these significant findings can be helpful for better understanding of the pathophysiological mechanism of TLE. The theta band can be considered as a preferred frequency band for investigating the brain-network dysfunction of MRI-negative intractable TLE patients.

Defining the Criteria for Reflex Testing for BRAF Mutations in Cutaneous Melanoma Patients.

Targeted therapy has been developed through an in-depth understanding of molecular pathways involved in the pathogenesis of melanoma. Approximately ~50% of patients with melanoma have tumors that harbor a mutation of the BRAF oncogene. Certain clinical features have been identified in BRAF-mutated melanomas (primary lesions located on the trunk, diagnosed in patients <50, visibly pigmented tumors and, at times, with ulceration or specific dermatoscopic features). While BRAF mutation testing is recommended for stage III-IV melanoma, guidelines differ in recommending mutation testing in stage II melanoma patients. To fully benefit from these treatment options and avoid delays in therapy initiation, advanced melanoma patients harboring a BRAF mutation must be identified accurately and quickly. To achieve this, clear definition and implementation of BRAF reflex testing criteria/methods in melanoma should be established so that patients with advanced melanoma can arrive to their first medical oncology appointment with a known biomarker status. Reflex testing has proven effective for a variety of cancers in selecting therapies and driving other medical decisions. We overview the pathophysiology, clinical presentation of BRAF-mutated melanoma, current guidelines, and present recommendations on BRAF mutation testing. We propose that reflex BRAF testing should be performed for every melanoma patient with stages ≥IIB.

Changes in resting-state cerebral blood flow and its connectivity in patients with focal to bilateral tonic-clonic seizures.

Arterial spin labeling (ASL) is an important tool for understanding cerebral perfusion in epilepsy patients. The aim of this study was to explore patterns of change in cerebral blood flow (CBF) and CBF connectivity in patients with focal to bilateral tonic-clonic seizures (FBTCS). High-resolution three-dimensional (3-D) T1-weighted and 3-D pseudo-continuous ASL magnetic resonance imaging (MRI) was collected from 32 patients with FBTCS and 16 healthy volunteers using a 3.0 T MRI scanner. Cerebral blood flow and its connectivity were compared between the FBTCS and control group. Correlation analysis was used to explore relationships of CBF and its connectivity changes with clinical parameters. Cerebral blood flow data of spatial standardization and normalization were used to improve statistical power. Patients with FBTCS exhibited increased CBF in the bilateral thalamus, caudate nucleus, olfactory cortex, and gyrus rectus, but decreased CBF in the bilateral supplementary motor areas (SMA) and middle cingulate cortex (MCC). Patients with FBTCS showed significant positive correlation between CBF and gray matter volume (GMV) in bilateral SMA and MCC. No significant correlations between CBF and clinical parameters were found among FBTCS patients. The anterior cingulate cortex (ACC) showed positive CBF connectivity with the bilateral SMA and MCC, and these CBF connectivity measures differed significantly between groups (cluster-level, FWE-corrected, P < 0.001). These findings suggest that patients with FBTCS have changes in cerebral CBF and CBF connectivity, which may relate to the underlying neuropathology of FBTCS.

Altered gray matter volume in MRI-negative focal to bilateral tonic-clonic seizures.

To investigate cortical changes in MRI-negative patients with focal to bilateral tonic-clonic seizures (FBTCS). High-resolution three-dimensional T1-weighted MRI were collected with a GE 3.0-T MRI scanner from 26 patients with FBTCS and 21 healthy volunteers at Nanjing Brain Hospital. Voxel-based morphometry was performed on T1-weighted MRI of all subjects. A two-sample t test was performed to compare the GMV of two groups. Age and gender were taken as covariables, so that brain regions with significant differences, as compared by two-sample t test, between the two group were obtained. These regions were extracted as the regions of interest (ROIs) used for correlation analysis between ROIs and clinical variables. There is no significant difference in GMF between two groups. In FBTCS, regions with decreased GMV are bilateral thalamus, bilateral orbitofrontal cortex, left medical cingulate gyrus, and right supplementary motor area. GMV is increased within the bilateral para-hippocampal regions (voxel-wise FDR-corrected, P < 0.05). The GMVs are significantly negatively correlated with disease duration in the left thalamus and the left para-hippocampal region (P < 0.05). Seizures may lead to the loss of neurons and the decrease of GMV in FBTCS. The increase of GMV in some regions might be due to inflammatory responses in the early stages of epileptic seizures.

Efficacy and safety of intra-articular injection of mesenchymal stem cells in the treatment of knee osteoarthritis: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the effects and safety of intra-articular injection of mesenchymal stem cells on patients with knee osteoarthritis by a systematic review and meta-analysis. METHODS: PubMed, EMBASE, and Cochrane Library were retrieved. An assessment of the risk of bias was done through the Cochrane Collaborative Bias Risk Tool, publication bias was assessed by plotting funnel plots and Egger tests. Pain and functional improvements in patients with knee osteoarthritis were determined by changes in VAS scores and WOMAC scores at baseline and follow-up endpoints. For the evaluation of MRI, the WORMS score and changes in cartilage volume were used. In addition, the number of adverse events in the intervention group and the control group were counted to explore the safety. RESULTS: A total of 10 randomized controlled trials involving 335 patients were included. In the pooled analysis, compared with the control groups, the VAS scores of MSC groups decreased significantly (MD,-19.24; 95% CI: -26.31 to -12.18, P < .00001. All of the WOMAC scores also improved significantly: the total scores (SMD, - 0.66; 95% CI: - 1.09 to -0.23, P = .003), pain scores (SMD, - 0.46; 95% CI: - 0.75 to -0.17, P = .002), stiffness scores (SMD, -0.32; 95% CI: -0.64 to 0.00 P = 0.05), and functional scores (SMD, -0.36; 95% CI: -0.69 to -0.04, P = .03). Two studies with non-double-blind designs were the main source of heterogeneity. In terms of cartilage repair, there was no significant difference in the WORMS score, but there was a significant increase in cartilage volume in the MSC group (SMD, 0.69; 95% CI: 0.25 to 1.13, P = .002). The proportion of patients with adverse events in the MSCs treatment group was significantly higher than that in the control group (OR, 3.20; 95% CI: 1.50 to 6.83, P = .003). CONCLUSIONS: Intra-articular injection of mesenchymal stem cells is effective and safety to relieve pain and improve motor function of patients with knee osteoarthritis in a short term which is different to conclusions of previous study.

The effect of curcuminoids for treating knee osteoarthritis: A protocol for systematic review and meta analysis.

BACKGROUND: Knee osteoarthritis (KOA) is 1 of the commonest cause of disability with joint pain in adults and a burden on healthcare resources. The limitations of current KOA treatment necessitate further researches to discover the more efficacious and safety treatments. There are increasing clinical studies investigating the potential protective effects of Curcuminoids in the alleviation of symptoms in patients suffering from KOA. However, the convincing evidence indicating the efficacy of curcuminoids for patients suffering from KOA remains unclear. METHODS: Several databases including PubMed, Web of Science, Cochrane Library, Embase, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, and Wanfang Database will be searched. And the language was not limited. We will include all Randomized controlled trials that use curcuminoids to treat patients with KOA, regardless of blinding. If the pre-crossover data can be analyzed to avoid carryover effects, the crossover randomized trials also are included. Meanwhile, We will exclude non-randomized controlled trials, qualitative studies, uncontrolled clinical trials and laboratory studies. The primary end point include Western Ontario and McMaster Universities Osteoarthritis Index, visual analog scale scores and Lequesne's pain functional index. The secondary end points are total effective rate and adverse effects. The Review Manager Version 5.3 will be used to perform the data synthesis and subgroup analysis. DISCUSSION: There are evidences that supports the potential protective effects of Curcuminoids in the alleviation of symptoms in patients suffering from KOA. This systematic review and meta-analysis would provide convincing evidence indicating that curcuminoids relieve the symptoms of patients suffering from KOA. REGISTRATION: Open Science Framework (OSF) registries (https://osf.io/fz29b) with the registration DOI: 10.17605/OSF.IO/FZ29B.

Correction to: Diffuse leptomeningeal glioneuronal tumor in a Chinese adult: a novel case report and review of literature.

The article "Diffuse leptomeningeal glioneuronal tumor in a Chinese adult: a novel case report and review of literature", written by "Honghao Xu, Fangqing Chen, Haitao Zhu, Lei Luo, and Rui Zhang", was originally published electronically on the publisher's internet portal (currently SpringerLink) on 24th December 2019 with open access.

LncRNA CASC2 inhibits astrocytic activation and adenosine metabolism by regulating PTEN in pentylenetetrazol-induced epilepsy model.

Growing evidence has indicated that long noncoding RNAs (lncRNAs) are closely implicated in the progress of epilepsy. However, the expression profile and potential function of long noncoding RNAs cancer susceptibility candidate 2 (lncRNA CASC2) in epilepsy are poorly studied. The aim of this study was to testify the influence of lncRNA CASC2 on epilepsy in rat and cell models of epileptic seizure. We adopted qRT-PCR on the hippocampus of rats following pentylenetetrazol (PTZ)-stimulated epilepsy. To further examine the correlation between lncRNA CASC2 and Phosphatase and tensin homolog (PTEN), we detected the effects of lncRNA CASC2 on PTEN expression. We found that lncRNA CASC2 and PTEN expression were positively correlated in PTZ-induced epileptic rat. Overexpression of lncRNA CASC2 prolonged the latency and reduced the frequency of epileptic seizure, suppressed the activation of astrocytes and the release of adenosine in epileptic rat, whereas downregulation of lncRNA CASC2 exhibited the opposite effects. Meanwhile, lncRNA CASC2 decreased the adenosine metabolism related proteins expression of p38, Equilibrative nucleoside transporter 1 (ENT1) and Adenosine Kinase (ADK). In PTZ-treated astrocytes, PTEN was found to be a direct target of lncRNA CASC2. Additionally, downregulation of PTEN attenuated the protective effect of lncRNA CASC2 overexpression in epileptic seizure. Our findings manifested the key role of lncRNA CASC2 in the occurrence of epilepsy by targeting PTEN, which provided a novel target for epilepsy therapy.