The regulation of NFKB1 on CD200R1 expression and their potential roles in Parkinson's disease.

BACKGROUND: Overactivated microglia are a key contributor to Parkinson's disease (PD) by inducing neuroinflammation. CD200R1, a membrane glycoprotein mainly found on microglia, is crucial for maintaining quiescence with its dysregulation linked to microglia's abnormal activation. We and other groups have reported a decline in CD200R1 levels in several neurological disorders including PD. However, the mechanism regulating CD200R1 expression and the specific reasons for its reduction in PD remain largely unexplored. Given the pivotal role of transcription factors in gene expression, this study aimed to elucidate the transcriptional regulation of CD200R1 and its implications in PD. METHODS: The CD200R1 promoter core region was identified via luciferase assays. Potential transcription factors were predicted using the UCSC ChIP-seq database and JASPAR. NFKB1 binding to the CD200R1 core promoter was substantiated through electrophoretic mobility shift and chromatin immunoprecipitation assays. Knocking-down or overexpressing NFKB1 validated its regulatory effect on CD200R1. Correlation between decreased CD200R1 and deficient NFKB1 was studied using Genotype-Tissue Expression database. The clinical samples of the peripheral blood mononuclear cells were acquired from 44 PD patients (mean age 64.13 ± 9.78, 43.2% male, median Hoehn-Yahr stage 1.77) and 45 controls (mean age 64.70 ± 9.41, 52.1% male). NFKB1 knockout mice were utilized to study the impact of NFKB1 on CD200R1 expression and to assess their roles in PD pathophysiology. RESULTS: The study identified the CD200R1 core promoter region, located 482 to 146 bp upstream of its translation initiation site, was directly regulated by NFKB1. Significant correlation between NFKB1 and CD200R1 expression was observed in human PMBCs. Both NFKB1 and CD200R1 were significantly decreased in PD patient samples. Furthermore, NFKB1-/- mice exhibited exacerbated microglia activation and dopaminergic neuron loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. CONCLUSION: Our study identified that NFKB1 served as a direct regulator of CD200R1. Reduced NFKB1 played a critical role in CD200R1 dysregulation and subsequent microglia overactivation in PD. These findings provide evidence that targeting the NFKB1-CD200R1 axis would be a novel therapeutic strategy for PD.

Superior cerebellar peduncle deep brain stimulation for cerebral palsy.

OBJECTIVE: Patients with coexisting spastic cerebral palsy (CP) and dystonia have limited treatment options. In this study, the authors aimed to evaluate the efficacy of deep brain stimulation (DBS) targeting the superior cerebellar peduncles (SCPs) in adults with CP. METHODS: Five patients with CP and medically refractory dystonia and spasticity underwent SCP DBS. Assessments included the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), modified Ashworth scale (mAS), and tests of cognition, mental status, and quality of life preoperatively and at 3, 6, and 12 months postoperatively (in both DBS ON and OFF states, double blinded). Active contacts and fiber bundles were examined. RESULTS: Four patients completed follow-up. The BFMDRS motor score decreased from 74 to 52 at 12 months postoperatively (30%, p = 0.008). The mean mAS score indicated significant spasticity reduction (from 2.9 ± 0.9 to 1.9 ± 0.6 after 12 months, p = 0.0454). Quality of life improved (p < 0.01), while cognition remained unaffected. Active contacts were found within the dentato-rubro-thalamic tract, with variable efficiency in decussating and nondecussating portions. CONCLUSIONS: In this pilot trial, SCP DBS showed promise as a well-tolerated treatment for CP, improving dystonic symptoms, spasticity, quality of life, and functional capacities. However, caution is needed when interpreting the results given the small sample size and heterogeneous motor outcomes.

Globus pallidus internus versus subthalamic nucleus deep brain stimulation for isolated dystonia: A 3-year follow-up.

BACKGROUND AND PURPOSE: Bilateral deep brain stimulation (DBS) surgery targeting the globus pallidus internus (GPi) or the subthalamic nucleus (STN) is widely used in medication-refractory dystonia. However, evidence regarding target selection considering various symptoms remains limited. This study aimed to compare the effectiveness of these two targets in patients with isolated dystonia. METHODS: This retrospective study evaluated 71 consecutive patients (GPi-DBS group, n = 32; STN-DBS group, n = 39) with isolated dystonia. Burke-Fahn-Marsden Dystonia Rating Scale scores and quality of life were evaluated preoperatively and at 1, 6, 12, and 36 months postoperatively. Cognition and mental status were assessed preoperatively and at 36 months postoperatively. RESULTS: Targeting the STN (STN-DBS) yielded effects within 1 month (65% vs. 44%; p = 0.0076) and was superior at 1 year (70% vs. 51%; p = 0.0112) and 3 years (74% vs. 59%; p = 0.0138). For individual symptoms, STN-DBS was preferable for eye involvement (81% vs. 56%; p = 0.0255), whereas targeting the GPi (GPi-DBS) was better for axis symptoms, especially for the trunk (82% vs. 94%; p = 0.015). STN-DBS was also favorable for generalized dystonia at 36-month follow-up (p = 0.04) and required less electrical energy (p < 0.0001). Disability, quality of life, and depression and anxiety measures were also improved. Neither target influenced cognition. CONCLUSIONS: We demonstrated that the GPi and STN are safe and effective targets for isolated dystonia. The STN has the benefits of fast action and low battery consumption, and is superior for ocular dystonia and generalized dystonia, while the GPi is better for trunk involvement. These findings may offer guidance for future DBS target selection for different types of dystonia.

Rescue procedure for isolated dystonia after the secondary failure of globus pallidus internus deep brain stimulation.

Introduction: Globus pallidus internus (GPi) deep brain stimulation (DBS) is widely used in patients with dystonia. However, 10-20% of patients receive insufficient benefits. The objectives of this study are to evaluate the effectiveness of bilateral subthalamic nucleus (STN) DBS along with unilateral posteroventral pallidotomy (PVP) in patients with dystonia who experienced unsatisfactory GPi-DBS and to address the reported rescue procedures after suboptimal DBS or lesion surgery in dystonia patients. Methods: Six patients with isolated dystonia who had previously undergone bilateral GPi-DBS with suboptimal improvement were included. Standardized assessments of dystonia using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and quality of life using SF-36 were evaluated before surgery and 1, 6 months, and last follow-up (LFU) after surgery. STN bilateral OFF (bi-OFF), unilateral ON (uni-ON), and bilateral ON (bi-ON) states were recorded at LFU. Specific items were used to find publications published before 10 April 2022 regarding rescue procedures after suboptimal DBS or lesion surgery in patients with dystonia for reference. Eleven original studies including case reports/series were identified for discussion. Results: Substantial clinical benefits were achieved in all six patients. Significant amelioration was achieved during the 1-month (6.5 ± 7.45; p = 0.0049), 6-month (5.67 ± 6.3; p = 0.0056) follow-ups, and at LFU (4.67 ± 4.72; p = 0.0094) when compared with the baseline (LFU of GPi DBS with on status) (17.33 ± 11.79) assessed by BFMDRS. The percentage of improvement reached 70.6, 74.67, and 77.05%, respectively. At LFU, significant differences were found between the stimulation bi-OFF and uni-ON (11.08 ± 8.38 vs. 9 ± 8.52, p = 0.0191), and between the stimulation bi-OFF and bi-ON (11.08 ± 8.38 vs. 4.67 ± 4.72, p = 0.0164). Trends depicting a better improvement in stimulation bi-ON compared with uni-ON (4.67 ± 4.72 vs. 9 ± 8.52, p = 0.0538) were observed. Conclusion: Our results suggest that bilateral STN-DBS plus unilateral PVP may be an effective rescue procedure for patients with isolated dystonia who experienced suboptimal movement improvement following GPi-DBS. However, given the heterogeneity of patients and the small sample size, these findings should be interpreted with caution.

Somatic mutations in genes associated with mismatch repair predict survival in patients with metastatic cancer receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have emerged as one of the most promising therapeutic options for patients with advanced cancer. The aim of the present study was to investigate the prognostic value of somatic mutations in mismatch repair (MMR) genes in metastatic cancers after ICI treatment, as well as their association with tumor mutational burden (TMB). Information regarding gene mutations in mismatch repair and the survival time of patients with advanced cancer following ICI treatment was collected from the cBioPortal database. The prognostic value of somatic mutations in MMR genes and the association between the mutation status and TMB score were analyzed among multiple types of cancer. Somatic mutation frequency in the MMR genes was identified to be 7% among all patients, which varied across different types of cancer. Somatic mutations in the MMR genes were associated with improved overall survival time in all tested patients (P=0.004). Following stratification by type of ICI treatment, a significant association was observed between somatic mutations in the MMR genes and overall survival time in patients treated with cytotoxic T-lymphocyte-associated protein 4 inhibitors (P=0.01). In addition, marked but non-significant association between somatic mutations in the MMR genes and overall survival time was revealed in patients administered with programmed death-1/programmed death-ligand-1 inhibitors (P=0.09). Multivariate Cox proportional hazards regression analysis demonstrated that somatic mutations in MMR genes were significantly associated with overall survival time (hazard ratio, 0.683; 95% confidence interval, 0.497-0.938; P=0.01). Patients with somatic mutations in the MMR genes demonstrated higher TMB compared with those not harboring mutations (P<0.01). The results of the present study suggested that somatic mutations in the MMR genes may be used as a prognostic marker of a positive outcome in patients with metastatic cancer receiving ICI treatment, since somatic mutations in the MMR genes may be one of the main factors affecting the tumor mutation load.

A comparison between drug-eluting bead-transarterial chemoembolization and conventional transarterial chemoembolization in patients with hepatocellular carcinoma: A meta-analysis of six randomized controlled trials.

OBJECTIVE: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate hepatocellular carcinoma. Drug-eluting beads (DEB)-TACE is a promising approach expected to improve the efficiency and safety of conventional (c) TACE. However, controversy remains whether DEB-TACE performs better than cTACE. This meta-analysis aimed to compare cTACE and DEB-TACE in terms of overall survival (OS), adverse events, and response rate. Literature search was performed in PubMed, Cochrane, Embase, and Web of Science. Complete response (CR), partial response (PR), disease control (DC), stable disease (SD), OS, and major complications were compared between these two modalities. The pooled relative risk and 95% confidence interval were calculated for assessment. Six randomized controlled trials were included for further analysis after a comprehensive search. No significant difference was found in overall response at 3, 6, 9, and 12 months, CR, PR, DC (SD), OS and complications between cTACE and DEB-TACE. CONCLUSION: DEB-TACE had similar therapeutic effects to those of cTACE. Furthermore, major complications in both therapies were similar. The superiority of DEB-TACE over cTACE remains unclear, and further research with high-quality evidence is needed.

Isoniazid causes heart looping disorder in zebrafish embryos by the induction of oxidative stress.

BACKGROUND: The cardiotoxicity of isoniazid on zebrafish embryos and its underlying mechanism is unclear. METHODS: Here, we exposed zebrafish embryos at 4 h post-fertilization to different levels of isoniazid and recorded the morphology and number of malformed and dead embryos under the microscope. RESULTS: The high concentration of isoniazid group showed more malformed and dead embryos than the low concentration of isoniazid group and control group. The morphology of the heart and its alteration were visualized using transgenic zebrafish (cmlc2: GFP) and confirmed by in situ hybridization. The negative effects of isoniazid on the developing heart were characterized by lower heart rate and more heart looping disorders. Mechanistically, PCR showed decreased expression of heart-specific transcription factors when exposed to isoniazid. Oxidative stress was induced by isoniazid in cardiomyocytes, mediated by decreased activities of catalase and superoxide dismutase, which were rescued by scavengers of reactive oxygen species. CONCLUSION: In conclusion, this study demonstrated that isoniazid led to heart looping disturbance by the downregulation of cardiac-specific transcription factors and induction of cardiomyocyte apoptosis.

MiR-124 attenuates doxorubicin-induced cardiac injury via inhibiting p66Shc-mediated oxidative stress.

Previous studies showed that miR-124 had a protective role by reducing oxidant stress and preventing cell apoptosis and autophagy. However, its role in doxorubicin-induced cardiomyopathy was less known. In our study, we confirmed increased ROS and decreased expression of miR-124 in doxorubicin-treated heart tissues and primary cardiomyocytes. The oxidative stress and cell apoptosis were alleviated by overexpressing miR-124, characterized by decreased activity of MDA and increased activity of SOD. While inhibiting miR-124 generated opposed effects. Mechanistically, our bioinformatic prediction and luciferase assay confirmed that miR-124 inhibited the expression of p66Shc, a proapoptotic signaling pathway. Our results suggested that miR-124 was hopeful to become a therapeutic target in doxorubicin-related cardiomyopathy.

Cognitive Gains of Aerobic Exercise in Patients With Ischemic Cerebrovascular Disorder: A Systematic Review and Meta-Analysis.

Background: Cognitive impairment has become an important problem in ischemic cerebrovascular disorder survivors as disease related deaths have been significantly reduced. Aerobic exercise, the most prevalent mode of physical activity, positively contributes to cognition in both healthy population and people with cognitive impairment. However, studies on its associations with cognitive gains in patients with ischemic cerebrovascular disease showed mixed findings. Objective: To explore the cognitive effects of aerobic exercise on ischemic cerebrovascular disorder survivors and investigate the possible moderators on exercise benefits. Method: Randomized controlled trials investigating the effects of sole aerobic exercise on cognitive function in population with ischemic intracranial vascular disorder compared to any control group who did not receive the intervention were enrolled in this systematic review and meta-analysis. Four online database (Pubmed, Cochrane Library, Embase, and Web of Science) were searched. Results: The initial search returned 1,522 citations and ultimately 11 studies were included in the systematic review. Analysis of seven studies showed the beneficial but not statistically significant impact of aerobic exercise on global cognitive function (0.13; 95% Cl -0.09 to 0.35; p = 0.25). Participants already with cognitive impairment benefited more from this intervention (0.31; 95% Cl 0.07-0.55; p = 0.01) and moderate intensity might be the optimal choice (0.34; 95% Cl -0.01 to 0.69; p = 0.06). The program duration and initiation time after stroke occurrence did not predict better cognitive outcome. Aerobic exercise was not associated with improvement of processing speed and executive function, the two subdomains of cognitive function. Conclusions: Aerobic exercise may contribute to cognitive gains in survivors of ischemic cerebrovascular disorder, especially for population already with cognitive decline. Our findings suggest that the adoption of moderate intensity aerobic exercise might improve cognition in such population.

Neutrophil to lymphocyte ratio (NLR) as a prognostic marker for in-hospital mortality of patients with sepsis: A secondary analysis based on a single-center, retrospective, cohort study.

Neutrophil-to-lymphocyte ratio (NLR) has been reported to serve as a prognostic marker in inflammatory diseases. The purpose of this study was to evaluate the association of NLR at admission with in-hospital mortality in patients with sepsis presenting to emergency department.This was a secondary analysis based on a single-center, retrospective, cohort study. Patients with sepsis admitted to an academic emergency department between January 2010 and January 2015 were enrolled. NLR of patients was analyzed from the hospital's electronic health record (EHR) system. A total of 174 adult patients, of which 80 (46.0%) died in hospital. The primary outcome was in-hospital mortality. Secondary outcome was 28-day mortality.Contrary to previous studies, a larger NLR was found to have less odds of in-hospital mortality, as well as the presence of bacteremia. Patients who has severe/shock or had a history of chronic heart failure (CHF) had larger odds of death during hospital. Multivariate logistic regression analysis indicated that low NLR was an independent predictor of in-hospital mortality (OR = -0.98; 95% CI -0.96 to -0.99; P = .022). However, no correlation was found between the NLR and 28-day hospital mortality in patients with sepsis (P = .988). As a predictor of in-hospital survival, the area under curve (AUC) of the NLR was 0.622 (95%CI 0.54-0.71; P = .006) and the cut-off value was 9.11 with 0.551 sensitivity and 0.707 specificity.NLR at admission was an independent predictor of in-hospital mortality of sepsis patients.

A comparison between radiofrequency ablation combined with transarterial chemoembolization and surgical resection in hepatic carcinoma: A meta-analysis.

OBJECTIVE: This study determined whether the effect of combination therapy for hepatic carcinoma (HCC) is comparable to surgical resection (SR). According to the guidelines of the American Association for the Study of Liver Disease, radiofrequency ablation (RFA) and SR are recommended for early HCC. However, patients treated with RFA had worse long-term survival than those who received SR. Many studies utilizing the combination therapy with RFA and transarterial chemoembolization (TACE) have reported better prognosis as compared to RFA alone. MATERIALS AND METHODS: A comprehensive search in databases was conducted. Six retrospective studies and one cohort were enrolled in this meta-analysis. The overall survival (OS), disease-free survival (DFS), and major complications were compared between RFA plus TACE and SR. The pooled hazard ratio and 95% confidence interval (CI) were calculated and analyzed. RESULTS: After comparison, no significant difference in the OS and DFS at 1 and 3 years between the combination therapy and SR was observed (OS1: pooled relative risk [RR]: 0.82, 95% CI [0.56, 1.21]; OS3: pooled RR: 1.07, 95% CI [0.82, 1.39]; DFS1: pooled RR: 0.92, 95% CI [0.58, 1.45]; DFS3: pooled RR: 1.18, 95% CI [1.00, 1.40]). SR had better clinical outcomes than combination therapy with respect to long-term survival and disease progression (OS5: pooled RR: 1.12, 95% CI [1.03, 1.23]; DFS5: pooled RR: 1.15, 95% CI [1.03, 1.28]). Major complications were reduced with combination therapy (pooled RR: 0.46, 95% CI [0.25, 0.85]). CONCLUSION: SR should remain as the first-line therapy for early HCC.