Melatonin enhances therapeutic outcomes of adipose tissue-derived mesenchymal stem cell therapy in rat osteoarthritis by reducing TNF-α and IL-1ß-induced injuries.

Although adipose tissue-derived mesenchymal stem cell (ADSC) transplantation has been effectively used to treat osteoarthritis (OA), the low cell survival rate induced by the inflammatory and oxidative stress, severely affects the therapeutic efficiency of ADSC transplantation in OA. This study was designed to evaluate whether melatonin pretreatment could improve ADSC survival and its therapeutic efficacy in OA. The papain-induced OA rats were pretreated with melatonin via intra-articular injection and then intra-articular injected with indocyanine green (ICG)-labeled ADSCs (3 × 106/rat). Afterward, ADSC retention was evaluated by NIR-II fluorescence imaging. The tibia and synovial fluid were collected for histopathological examination and ELISA assay, respectively. To confirm the anti-inflammatory effect of melatonin, a TNF-α and IL-1ß-induced cell model was used to evaluate the protective effects of melatonin on ADSC viability, cell apoptosis, and migration. Our results showed that melatonin pretreatment enhanced ADSC survival and improved the therapeutic effects of ADSC transplantation on cartilage repair, and anti-inflammation by reducing TNF-α, IL-6, IL-1ß, and IL-12 in vivo. In particular, we also found that melatonin promoted ADSC viability and migration, and reduced cell apoptosis in vitro. In conclusion, this study supports that melatonin pretreatment can effectively improve ADSC survival and therapeutic efficiency in OA by reducing inflammatory injuries, which provides a novel strategy for enhancing ADSC therapy.

Expert Consensus on Ion Channel Drugs for Chronic Pain Treatment in China.

Ion channel drugs have been increasing used for chronic pain management with progress in the development of selective calcium channel modulators. Although ion channel drugs have been proven safe and effective in clinical practice, uncertainty remains regarding its use to treat chronic pain. To standardize the clinical practice of ion channel drug for the treatment of chronic pain, the National Health Commission Capacity Building and Continuing Education Center for Pain Diagnosis and Treatment Special Ability Training Project established an expert group to form an expert consensus on the use of ion channel drugs for the treatment of chronic pain after repeated discussions on existing medical evidence combined with the well clinical experience of experts. The consensus provided information on the mechanism of action of ion channel drugs and their recommendations, caution use, contraindications, and precautions for their use in special populations to support doctors in their clinical decision-making.

A causal relationship between gut microbiota and subcortical brain structures contributes to the microbiota-gut-brain axis: a Mendelian randomization study.

A correlation between gut microbiota and brain structure, referring to as a component of the gut-brain axis, has been observed in observational studies. However, the causality of this relationship and its specific bacterial taxa remains uncertain. To reveal the causal effects of gut microbiota on subcortical brain volume, we applied Mendelian randomization (MR) studies in this study. Genome-wide association study data were obtained from the MiBioGen Consortium (n = 18,340) and the Enhancing Neuro Imaging Genetics through Meta-Analysis Consortium (n = 13,170). The primary estimate was obtained utilizing the inverse-variance weighted, while heterogeneity and pleiotropy were assessed using the Cochrane Q statistic, MR Pleiotropy RESidual Sum and Outlier, and MR-Egger intercept. Our findings provide strong evidence that a higher abundance of the genus Parasutterella is causally correlated with a decrease in intracranial volume (ß = -30,921.33, 95% CI -46,671.78 to -15,170.88, P = 1.19 × 10-4), and the genus FamilyXIIIUCG001 is associated with a decrease in thalamus volume (ß = -141.96, 95% CI: -214.81 to -69.12, P = 1.0× 10-4). This MR study offers novel perspectives on the intricate interplay between the gut microbiota and subcortical brain volume, thereby lending some support to the existence of the microbiota-gut-brain axis.

Lack of causal association between epilepsy and dementia: A Mendelian randomization analysis.

OBJECTIVE: Epidemiological studies have reported an association between epilepsy and dementia. However, the causal relationship between epilepsy and the risk of dementia is not clear. We aimed to inspect the causal effect of epilepsy on memory loss and dementia. METHODS: We analyzed summary data of epilepsy, memory loss, and dementia from the genome-wide association study (GWAS) using the two-sample Mendelian randomization (MR) method. We used the estimated odds ratio of memory loss and dementia associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures: all epilepsy, focal epilepsy (including focal epilepsy with hippocampal sclerosis, lesion-negative focal epilepsy, and focal epilepsy with other lesions), and genetic generalized epilepsy (including childhood absence epilepsy, generalized tonic-clonic seizures alone, Juvenile absence epilepsy, and Juvenile myoclonic epilepsy). RESULTS: According to the result of MR using the inverse variance weighted method (IVW), we found that genetically predicted epilepsy did not causally increase the risk of memory loss and dementia (p > 0.05). Results of the MR-Egger and weighted median method were consistent with the IVW method. CONCLUSIONS: No evidence has been found to support the notion that epilepsy can result in memory loss and dementia. The associations observed in epidemiological studies could be attributed, in part, to confounding or nongenetic determinants.

The causal relationship between circulating biomarkersand the risk of bipolar disorder: A two-sample Mendelian randomization study.

OBJECTIVE: To identify susceptible biomarkers for the development of bipolar disorder (BD), we conducted a Mendelian Randomization (MR) design to screen circulating proteins for the potential risk of bipolar disorder systematically. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to estimate the causality of 4782 human circulating proteins on the risk of bipolar disorder. 376 circulating biomarkers were selected in MR estimation (4406 circulating proteins with less than 3 SNPs were excluded) with 5368 European descents. GWAS meta-analysis of the potential role of all-cause bipolar disorder arose from the Psychiatric Genomics Consortium (41,917 cases, 371,549 controls). RESULTS: After IVW and sensitivity analysis, 4 circulating proteins having causal effects on bipolar disorder were identified. ISG15, as a key player in the innate immune response, decreased the risk of bipolar disorder causally (OR = 0.92, 95% CI = 0.89-0.94, P = 1.46e-09). Furthermore, MLN decreased the risk of bipolar disorder causally (OR = 0.94, 95% CI = 0.91-0.97, P = 1.04e-04). In addition, SFTPC (OR = 0.91, 95% CI = 0.86-0.96, P = 4.47e-04) and VCY (OR = 0.86, 95% CI = 0.77-0.96, P = 8.55e-03) presented a suggestive association with bipolar disorder. CONCLUSIONS: Our findings indicated that ISG15 and MLN showed evidence of causality in bipolar disorder and provided a promising target for the diagnosis and treatment of diseases.

Global, regional, and national burden and attributable risk factors of neurological disorders: The Global Burden of Disease study 1990-2019.

Background: Neurological disorders are a major and increasing global health challenge, which accounts for a substantial portion of the disease burden worldwide. The aim of this systematic analysis is to present the most comprehensive and up-to-date estimates of disease burden, epidemiological trends, and attributable risk factors of neurological disorders at global, regional, and national levels. Methods: We extracted data of 18 neurological disorders from the Global Burden of Disease 2019 study database. The burden of neurological disorders was measured using the incidence, prevalence, mortality, and disability-adjusted life years (DALYs), and further described according to age, sex, year, geographical location and socio-demographic Index (SDI). All estimates were presented with corresponding 95% uncertainty intervals (UIs). Findings: Globally, in 2019, there were nearly 10 million deaths and 349 million DALYs due to neurological disorders. Among the 18 neurological disorders, stroke was the biggest contributor to DALYs (143232.18 [95%UI 133095.81-153241.82] in thousands) and deaths (6552.72 [95%UI 5995.20-7015.14] in thousands), followed by neonatal encephalopathy due to birth asphyxia and trauma. From 1990 to 2019, the DALYs of neurological diseases belonging to the communicable, maternal, neonatal and nutritional categories showed a sharp decrease, while Alzheimer's disease and other dementias and Parkinson's disease showed a large increase. Neurological disorders exhibited different profiles in different regions and age groups. A significant correlation between the SDI and the age-standardized DALY rates was also found except for Alzheimer's disease and other dementias. In addition, risk factors such as high systolic blood pressure, low birth weight and short gestation period, and metabolic risk contribute significantly to neurological disorders. Interpretation: The overall burden of neurological disorders has increased from 1990 to 2019, especially for non-communicable neurological disorders. The substantial variations of burden across regions emphasize the need for region-specific interventional strategies and allocation of resources based on priorities.

Altered hippocampal functional connectivity after the rupture of anterior communicating artery aneurysm.

Background and purpose: Aneurysmal subarachnoid hemorrhage (SAH) predisposes hippocampal injury, a major cause of follow-up cognitive impairment. Our previous study has revealed an abnormal resting-state brain network in patients after the rupture of anterior communicating artery (ACoA) aneurysm. However, the functional connectivity (FC) characteristics of the hippocampus and its relationship with cognitive performance in these patients remain unknown. Methods: This study ultimately included 26 patients and 19 age- and sex-matched controls who completed quality control for resting-state functional magnetic resonance imaging (fMRI). The mean time series for each side of the hippocampus was extracted from individuals and then a seed-to-voxel analysis was performed. We compared the difference in FC strength between the two groups and subsequently analyzed the correlations between abnormal FC and their cognitive performance. Results: The results of bilateral hippocampus-based FC analysis were largely consistent. Compared with the healthy controls, patients after the rupture of ACoA aneurysm exhibited significantly decreased FC between the hippocampus and other brain structures within the Papez circuit, including bilateral anterior and middle cingulate cortex (MCC), bilateral medial superior frontal gyrus, and left inferior temporal gyrus (ITG). Instead, increased FC between the hippocampus and bilateral insula was observed. Correlation analyses showed that more subjective memory complaints or lower total cognitive scores were associated with decreased connectivity in the hippocampus and several brain regions such as left anterior cingulate cortex (ACC) and frontotemporal cortex. Conclusion: These results extend our previous findings and suggest that patients with ruptured ACoA aneurysm exist hypoconnectivity between the hippocampus and multiple brain regions within the Papez circuit. Deactivation of the Papez circuit may be a crucial neural mechanism related to cognitive deficits in patients after the rupture of ACoA aneurysm.

Research on the relationship between marital commitment, sacrifice behavior and marital quality of military couples.

Based on the actor-partner interdependence model, this paper studied the relationship between marital commitment, sacrifice behavior and marital quality of military couples. A convenience sample of 171 Chinese military couples from Guangdong, Jiangsu and Sichuan province was used. All participants completed the self-report questionnaires independently including the Dimension of Commitment Inventory (DCI), the Couples Sacrifice Behavior Scale (CSBS) and the Evaluation and Nurturing Relationship Issues, Communication and Happiness (ENRICH). Results showed that the scores of marital commitment and marital quality of male soldiers were significantly higher than that of their spouses. Compared to their spouses, male soldiers reported higher frequency of sacrifice behaviors and perceiving sacrifice behaviors of spouses. Furthermore, the marital commitment of military couples had significant influence on their own marital quality and frequency of perceiving each other's sacrifice behavior Military couples' perception of the frequency of each other's sacrifice behavior partially mediated the effect of marital commitment on their marital quality. Male soldiers' perception of spouse's sacrifice behavior frequency significantly predicted the marital quality of their spouses.

Single-cell RNA sequencing reveals intra-tumoral heterogeneity of glioblastoma and a pro-tumor subset of tumor-associated macrophages characterized by EZH2 overexpression.

BACKGROUND: Glioblastoma (GBM) is a highly heterogeneous disease with poor clinical outcome. AIM: To comprehensively dissect molecular landscape of GBM and heterogeneous distribution and potential role of Enhancer of zeste homolog 2 (EZH2) in tumor microenvironment (TME). METHODS: Single-cell RNA sequencing (scRNA-seq) analysis was performed in GBM samples from 8 patients. Deconvolution analysis, immunofluorescence (IF) microscopy, reverse-transcription quantitative polymerase chain reaction (RT-qPCR), colony formation experiments, and Cell Counting Kit-8 (CCK-8) assays were performed to confirmed the potential role of EZH2 in TME cells. RESULTS: Malignant cells exhibited remarkable heterogeneity in abnormal metabolic patterns. A mesenchymal-2-like (MES2-like) GBM subcluster with glial-immune dual feature was firstly discovered, which were associated with highly activated hallmark pathways, immune evasion associated transcription factor (IRF8), and poor survival. The oncogene, EZH2, was heterogeneously expressed in malignant cells and immune cells consistent with proliferative genes, cell-cycle transcription factors, and similar activated hallmark pathways. In a tumor-associated macrophages (TAMs) subset (macrophage.3), EZH2 was highly expressed with similar changes of transcriptomic dynamics with cell-cycle genes and macrophages M2-phetotype genes. In addition, the subset tightly interacted with malignant cells. Deconvolution analysis showed increased abundance of the subset in GBM compared to low-grade glioma (LGG) and significant association with worse prognosis. Functional verification experiments confirmed the pro-tumor role of TAMs with EZH2 overexpression in GBM. CONCLUSIONS: Our study illustrated a MES2-like GBM subcluster characterized by glial-immune dual feature and highlighted the pro-tumor role of a TAMs subset characterized by EZH2 overexpression.

Serum Lactate Dehydrogenase to Phosphate Ratio as an Independent Predictor for Adverse Outcome of Microsurgical Clipping for Ruptured Intracranial Aneurysm: A Propensity-Score Matching Analysis.

Objective: In this study, we assessed the correlation between the lactate dehydrogenase (LDH) to phosphate ratio and the prognosis of microsurgical clippings for ruptured intracranial aneurysm (rIA) to test the hypothesis that the serum LDH to phosphate ratio could be a predictor of the outcome of microsurgical clipping for rIA. Methods: Records of rIA patients between 2012 and 2018 were retrospectively collected. Age, sex, Hunt-Hess grade, Fisher grade, medical history, aneurysm location, hydrocephalus, laboratory data including serum LDH, phosphate, and LDH to phosphate ratio, related complications, and the outcomes in 3 months were recorded. Results: A total of 1608 rIA patients in our institution were collected, and 856 patients treated by microsurgical clipping were enrolled. On admission, a significantly higher LDH-phosphate ratio was observed in patients with poor outcomes at 3 months (median ± SD, 200.175 ± 107.290 for mRS 0−2 vs. 323.826 ± 219.075 for mRS score 3−6; p = 0.000). An LDH to phosphate ratio of 226.25 in the receiver operating characteristic (ROC) curve was the optimal cutoff value to discriminate between good and poor outcomes at 3 months. The LDH to phosphate ratio ≥ 226.25 on admission was independently correlated with poor outcomes in rIA patients. In addition, Hunt and Hess grade, Fisher grade, pneumonia, and DIND were also independently correlated with poor outcomes. After removing the bias in essential clinical variables between patients with LDH to phosphate, ratio ≥ 226.25 versus <226.25 by PSM, the number of patients with poor outcomes at 3 months increased in patients with an LDH to phosphate ratio of ≥226.25 (p = 0.005). Conclusions: The LDH to phosphate ratio was a potential biomarker and could predict the unfavorable outcome of microsurgical clipping for rIA in 3 months, related to neuronal damage, cerebral hypoxia, and early brain injury after aneurysm ruptures.

Machine Learning-Based Ultrasomics for Predicting Subacromial Impingement Syndrome Stages.

OBJECTIVES: To determine the performance of machine learning (ML)-based ultrasomic analysis of subacromial impingement syndrome (SIS) stage evaluation. METHODS: In this retrospective study, 324 patients with SIS were included. The SIS stage was evaluated with a Neer test. Regions of the musculi supraspinatus were manually segmented by an experienced radiologist. Then, 5936 ultrasomic features were extracted from the Ultrasomics Platform software. The Wilcoxon test was used to identify differentially expressed radiomic features. Then, these differentially expressed features were submitted to the least absolute shrinkage and selection operator (LASSO) for model construction. The area under the curve (AUC) of the receiver operating characteristic was used to evaluate the performance of the ultrasonic model for SIS stage evaluation. RESULTS: Finally, a total of 223 early-stage and 101 advanced-stage SIS patients were randomly divided into a training cohort (n = 227) and a validation cohort (n = 97). After feature-dimensionality reduction, a total of 28 radiomic features were submitted to LASSO analysis. Finally, 10 radiomic features were finally included for radiomics model construction. The AUC results showed that the ultrasomics model had moderate performance for SIS stage evaluation in both the training cohort (AUC = 0.839) and the validation cohort (AUC = 0.789). CONCLUSIONS: ML-derived ultrasomics can discriminate the SIS stage in patients with SIS. This noninvasive and low-cost approach may be helpful in the preliminary screening of shoulder pain.

Acetylation Profiles in the Metabolic Process of Glioma-Associated Seizures.

Objective: We test the hypothesis that lysine acetylation is involved in the metabolic process of glioma-associated seizures (GAS). Methods: We used label-free mass spectrometry-based quantitative proteomics to quantify dynamic changes of protein acetylation between gliomas with seizure (CA1 group) and gliomas without seizure (CA2 group). Furthermore, differences of acetyltransferase and deacetylase expression between CA1 and CA2 groups were performed by a quantitative proteomic study. We further classified acetylated proteins into groups according to cell component, molecular function, and biological process. In addition, metabolic pathways and protein interaction networks were analyzed. Regulated acetyltransferases and acetylated profiles were validated by PRM and Western blot. Results: We detected 169 downregulated lysine acetylation sites of 134 proteins and 39 upregulated lysine acetylation sites of 35 proteins in glioma with seizures based on acetylome. We detected 407 regulated proteins by proteomics, from which ACAT2 and ACAA2 were the differentially regulated enzymes in the acetylation of GAS. According to the KEGG analysis, the upregulated acetylated proteins within the PPIs were mapped to pathways involved in the TCA cycle, oxidative phosphorylation, biosynthesis of amino acids, and carbon metabolism. The downregulated acetylated proteins within the PPIs were mapped to pathways involved in fatty acid metabolism, oxidative phosphorylation, TCA cycle, and necroptosis. Regulated ACAT2 expression and acetylated profiles were validated by PRM and Western blot. Conclusions: The data support the hypothesis that regulated protein acetylation is involved in the metabolic process of GAS, which may be induced by acetyl-CoA acetyltransferases.

Higher Serum Levels of Lactate Dehydrogenase Before Microsurgery Predict Poor Outcome of Aneurysmal Subarachnoid Hemorrhage.

Introduction: We explored whether higher preoperative serum levels of lactate dehydrogenase (LDH) predicted outcome 3 months after surgery in patients with aneurysmal subarachnoid hemorrhage (aSAH) treated using microsurgical clipping in our institution. Methods: Patients with aSAH treated at our institution between 2010 and 2018 were enrolled. The following parameters were recorded: age, sex, smoking and drinking history, medical history, Hunt-Hess and Fisher grades, aneurysm location, aneurysm size, surgical treatment, delayed cerebral ischemia (DCI), intracranial infection, hydrocephalus, pneumonia, and preoperative serum LDH levels within 24 h of aSAH. We investigated whether preoperative serum LDH levels were associated with Hunt-Hess grade, Fisher grade, and functional neurological outcome. Results: In total, 2,054 patients with aSAH were enrolled, 874 of whom were treated using microsurgical clipping. The average serum LDH level (U/L) was significantly lower in the good outcome group (180.096 ± 50.237) than in the poor outcome group (227.554 ± 83.002; p < 0.001). After propensity score matching, the average serum LDH level (U/L) was still lower in the good outcome group (205.356 ± 76.785) than in the poor outcome group (227.119 ± 86.469; p = 0.029). The area under the receiver operating characteristic (ROC) curve was 0.702 (95% confidence interval [CI]: 0.650-0.754; p < 0.001). Based on the ROC curve, the optimal cutoff value for serum LDH levels as a predictor of poor 3-month outcome (modified Rankin Scale score > 2) was 201.5 U/L. The results revealed that Hunt-Hess grade, Fisher grade, DCI, pneumonia, and serum LDH (>201.5 U/L) were significantly associated with poor outcome. After propensity score matching, serum LDH levels > 201.5 U/L were still considered an independent risk factor for poor outcome (odds ratio: 2.426, 95% CI = 1.378-4.271, p = 0.002). Serum LDH levels were associated with Hunt-Hess and Fisher grades and were correlated with functional neurological outcomes (p < 0.001). Conclusions: Our findings showed that higher preoperative serum levels of LDH correlated with Hunt-Hess grade, Fisher grade, and neurological functional outcome, and predicted the outcome of aSAH treated by microsurgical clipping at 3 months, which was involved in the related mechanisms of early brain injury and showed its potential clinical significance in patients with aSAH.

Increased infiltration of CD8 T cells in recurrent glioblastoma patients is a useful biomarker for assessing the response to combined bevacizumab and lomustine therapy.

PURPOSE: Treatment options for recurrent glioblastoma (rGBM) remain scarce, which may be due to the limited understanding of its molecular characteristics. METHODS: Based on gene expression profiling, the infiltration scores of 26 immune cell types were calculated using gene set variation analysis. The differences between rGBM and other cancer subtypes were estimated to characterize the specific immune characteristics of rGBM, and the prognostic value of immune cells in rGBM was estimated using univariate and multivariate Cox analysis. Subgroup analyses and Kaplan-Meier analyses were performed to identify whether CD8 T-cell infiltration could be useful in selecting treatment options for rGBM patients. RESULTS: We found that rGBM patients were associated with enrichment of activated CD8 T cells, and high CD8 T-cell infiltration was associated with superior overall survival. Patients exhibiting high CD8 T-cell infiltration who received treatment with bevacizumab and lomustine combination therapy experienced a significant benefit in overall survival and progression-free survival, whereas patients with low CD8 T-cell infiltration did not experience such a benefit. CD8 T cells remained an independent prognostic factor in multivariate analyses (cohort 1: hazard ratio [HR] = 0.546, 95% confidence interval [CI]: 0.316-0.945, P = 0.031; cohort 3: HR = 0.615, 95% CI: 0.387-0.978, P = 0.040) after adjusting for clinicopathological and molecular factors. CONCLUSIONS: Activated CD8 T-cells is a promising biomarker for predicting overall survival in rGBM patients and could be used for assisting treatment selection.

Warburg effect-promoted exosomal circ_0072083 releasing up-regulates NANGO expression through multiple pathways and enhances temozolomide resistance in glioma.

BACKGROUND: Temozolomide (TMZ) resistance limits its application in glioma. Exosome can carry circular RNAs (circRNAs) to regulate drug resistance via sponging microRNAs (miRNAs). miRNAs can control mRNA expression by regulate the interaction with 3'UTR and methylation. Nanog homeobox (NANOG) is an important biomarker for TMZ resistance. Hitherto, it is unknown about the role of exosomal hsa_circ_0072083 (circ_0072083) in TMZ resistance in glioma, and whether it is associated with NANOG via regulating miRNA sponge and methylation. METHODS: TMZ-resistant (n = 36) and sensitive (n = 33) patients were recruited. The sensitive cells and constructed resistant cells were cultured and exposed to TMZ. circ_0072083, miR-1252-5p, AlkB homolog H5 (ALKBH5) and NANOG levels were examined via quantitative reverse transcription polymerase chain reaction and western blot. The half maximal inhibitory concentration (IC50) of TMZ, cell proliferation, apoptosis, migration and invasion were analyzed via Cell Counting Kit-8, colony formation, flow cytometry, wound healing and transwell assays. The in vivo function was assessed using xenograft model. The N6-methyladenosine (m6A) level was analyzed via methylated RNA immunoprecipitation (MeRIP). Target relationship was investigated via dual-luciferase reporter assay and RNA immunoprecipitation. Warburg effect was investigated via lactate production, glucose uptake and key enzymes expression. Exosome was isolated and confirmed via transmission electron microscopy and specific protein expression. RESULTS: circ_0072083 expression was increased in TMZ-resistant glioma tissues and cells. circ_0072083 knockdown restrained the resistance of resistant cells via decreasing IC50 of TMZ, proliferation, migration, invasion and xenograft tumor growth and increasing apoptosis. circ_0072083 silence reduced NANOG expression via blocking ALKBH5-mediated demethylation. circ_0072083 could regulate NANOG and ALKBH5 via targeting miR-1252-5p to control TMZ resistance. Warburg effect promoted the release of exosomal circ_0072083 in resistant cells. Exosomal circ_0072083 from resistant cells increased the resistance of sensitive cells to TMZ in vitro and xenograft model. Exosomal circ_0072083 level was enhanced in resistant patients, and it had a diagnostic value and indicated a lower overall survival in glioma. CONCLUSION: Exosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.

CSF-CN contributes to cancer-induced bone pain via the MKP-1-mediated MAPK pathway.

Pain is a major complication of cancer and significantly affects the quality of life. Cerebrospinal fluid-contacting nucleus (CSF-CN) has been reported to be involved in the development of neuropathic pain and inflammatory pain. However, whether CSF-CN contributes to cancer-induced bone pain (CIBP) remains unknown. In this study, we aimed to illustrate the role of CSF-CN in the pathogenesis of CIBP and identify its potential mechanism via the MKP-1-mediated MAPK pathway. The Walker 256 cancer cells were injected into the tibia cavity of female Sprague-Dawley rats to induce CIBP models. Intracerebroventricular injection of cholera toxin subunit B- saporin (CB-SAP) was performed to "knockout" the CSF-CN. Morphine and LV-MKP-1 were applied. Mechanical and thermal hyperalgesia behaviors, double immunofluorescence staining and Western blot were conducted after CIBP induction. The results revealed that CIBP significantly reduced the mechanical withdrawal threshold and the thermal threshold. Double immunofluorescence staining revealed that c-Fos-positive neurons in CSF-CN were significantly higher in the CIBP group than that in the sham group. Targeted ablation of CSF-CN dramatically aggravated pain sensitivity. Moreover, MKP-1 was down-regulated in the CSF-CN after CIBP induction. Pharmacological intervention with morphine significantly ameliorated the mechanical and thermal hyperalgesia through reversing the down-expression of MKP-1 in the CSF-CN on day 14 after CIBP induction. Mechanically, overexpression of MKP-1 by LV-MKP-1 injection significantly relieved CIBP via inhibiting the expression of phosphorylated p38, which subsequently decreased the protein levels of Bax, cleaved caspase-3 and Iba-1, and reduced the mRNA levels of IL-1ß, TNF-α and IL-6 in CSF-CN. In conclusion, CSF-CN contributed to CIBP via regulating the MKP-1-mediated p38-MAPK pathway. Future therapy targeting the expression of MKP-1 in the CSF-CN may be a promising new choice.

Endoscopically controlled surgery with open hemilaminectomy for the treatment of intradural extramedullary tumors: an operative technique and short-term outcomes of 20 consecutive cases.

BACKGROUND: To present a surgical technique for the treatment of intradural extramedullary (IDEM) tumors by using endoscopically controlled surgery with open hemilaminectomy technique. METHODS: In this study, 20 patients with 22 IDEM tumors were enrolled. An endoscopically controlled surgery with open hemilaminectomy was employed to remove the tumors. Data related to clinical symptoms and medical images before and after surgery were collected for perioperative evaluation and follow-up analysis. RESULTS: All the tumors in 20 patients were well removed. The clinical symptoms were significantly reduced in all the patients as well. The short-term follow-up data showed that there was no tumor recurrence or spinal deformity. CONCLUSION: The endoscopically controlled surgery with open hemilaminectomy technique provided favorable exposure and satisfactory resection to the IDEM tumors. It may be an effective surgical method for treating IDEM tumors. Larger samples and longer follow-up data are needed to verify its long-term effectiveness.

Lower Body Temperature Independently Predicts Delayed Cerebral Infarction in the Elderly With Ruptured Intracranial Aneurysm.

Purpose: To assess the correlation between admission body temperature and delayed cerebral infarction in elderly patients with ruptured intracranial aneurysm (IA). Methods: Patients with ruptured IA diagnosed between 2012 and 2020 were retrospectively analyzed. Patients were divided into a non-infarction and an infarction group based on the presence of cerebral infarction after treatment. The demographic and clinical information of the patients was gathered. Outcomes at the 3-month follow-up were assessed using the modified Rankin Scale. Correlation between admission body temperature and cerebral infarction was assessed using Spearman's rank correlation coefficient. A receiver operating characteristic (ROC) curve was used to assess the specificity and sensitivity of admission body temperature to predict cerebral infarction. Results: A total of 426 patients (142 men and 284 women) with ruptured IA were enrolled. Elderly patients with cerebral infarction (12.4%) had a lower body temperature at admission (p < 0.001), higher prevalence of hypertension and diabetes (p = 0.051 and p = 0.092, respectively), and higher rate of poor outcomes (p < 0.001). Admission body temperature was independently associated with cerebral infarction (odds ratio [OR] = 5.469, p < 0.001); however, hypertension (OR = 0.542, p = 0.056), diabetes (OR = 0.750, p = 0.465), and aneurysm size (OR = 0.959, p = 0.060) showed no association. An inverse correlation between admission body temperature and the incidence of cerebral infarction was observed (Spearman's r =-0.195, p < 0.001). An admission body temperature of 36.6°C was able to distinguish infarction and non-infarction patients. The area under the ROC curve was 0.669 (specificity, 64.15%; sensitivity, 81.50%; p < 0.001). Conclusions: Lower body temperature at admission (≤36.6°C) is an independent predictor of delayed cerebral infarction in elderly patients who have undergone treatment for ruptured IA. Therefore, it could be a risk factor for adverse outcomes of IA.

A Novel Scoring System Based on Preoperative Routine Blood Test in Predicting Prognosis of Atypical Meningioma.

PURPOSE: The aim of this study was to explore the correlation and clinical significance of preoperative fibrinogen and neutrophil-lymphocyte ratio (F-NLR) scoring system with 3-year progression-free survival (PFS) of patients with atypical meningioma. MATERIALS AND METHODS: Clinical, pathological, radiological, and laboratory variables were collected to analyze their correlation with 3-year PFS in the training set with 163 patients. Patients were classified by different F-NLR scores (0, 1, or 2). External validation for the predictive value of F-NLR scoring system was performed in the validation set with 105 patients. RESULTS: Overall, 37.3% (100 of 268) of the enrolled patients were male. The scoring system showed good performance in predicting 3-year PFS (AUC = 0.872, 95%CI = 0.811-0.919, sensitivity = 66.1%, specificity = 93.3%, and Youden index = 0.594). DeLong's test indicated that the AUC of F-NLR scoring system was significantly greater than that of fibrinogen level and NLR (Z = 2.929, P = 0.003; Z = 3.376, P < 0.001). Multivariate Cox analysis revealed that tumor size (HR = 1.39, 95%CI = 1.10-1.76, P = 0.007), tumor location (HR = 3.11, 95%CI = 1.60-6.95, P = 0.001), and F-NLR score (score of 1: HR = 12.78, 95%CI = 3.78-43.08, P < 0.001; score of 2: HR = 44.58, 95%CI = 13.02-152.65, P < 0.001) remained significantly associated with 3-year PFS. The good predictive performance of F-NLR scoring system was also demonstrated in the validation set (AUC = 0.824, 95%CI = 0.738-0.891, sensitivity = 62.5%, specificity = 87.9%, and Youden index = 0.504). CONCLUSION: Our study confirmed the correlation and clinical significance of preoperative F-NLR scoring system with 3-year PFS of patients with atypical meningioma. A prospective and large-scale study is required to validate our findings.

Can admission lipoprotein-associated phospholipase A2 predict the symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage?

BACKGROUND: Inflammation has been believed to be related to the development of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (aSAH). A potential biomarker for vascular inflammation that is well recognized is the lipoprotein-associated phospholipase A2 (Lp-PLA2). However, whether Lp-PLA2 can predict the occurrence of symptomatic cerebral vasospasm (SCV) in aSAH patients is still unknown. Thus, this study aimed to assess the value of Lp-PLA2 for predicting SCV in patients with aSAH. METHODS: Between March 2017 and April 2018, we evaluated 128 consecutive aSAH patients who were admitted in the First Affiliated Hospital of Fujian Medical University. Their Lp-PLA2 level was obtained within 24 h of the initial bleeding. Factors might be related to SCV were analyzed. RESULTS: Compared to patients without SCV, those with SCV (9.4%, 12/128) had significantly higher Lp-PLA2 level. Multivariate logistic analysis revealed that worse modified Fisher grade (OR = 10.08, 95% CI = 2.04-49.86, P = 0.005) and higher Lp-PLA2 level (OR = 6.66, 95% CI = 1.33-3.30, P = 0.021) were significantly associated with SCV, even after adjustment for confounders. Based on the best threshold, Lp-PLA2 had a sensitivity of 83.3% and a specificity of 51.7% for predicting SCV, as shown by the receiver operating characteristic curve analysis. In the poor World Federation of Neurosurgical Societies grade patient sub-group, patients with Lp-PLA2 > 200 µg/L had significantly higher SCV rate than that of patients having Lp-PLA2 ≤ 200 µg/L. CONCLUSION: The admission Lp-PLA2 level might be a helpful predictor for SCV in aSAH.