Pathophysiology and Clinical Management of Autoimmune Encephalitis-Associated Seizures.

Seizures are a very common manifestation of autoimmune encephalitis (AE), ranging from 33% to 100% depending on the antigen, most often accompanied by other clinical features such as behavioral changes, movement disorders, memory deficits, autoimmune disturbances, and altered levels of consciousness. Unusual seizure frequency, resistance to antiepileptic treatment, and often, definitive response to immunotherapy emphasize the importance for neurologists to consider the probable etiology of immune disorders. Studies on pathogenic mechanisms of autoantibodies have improved the understanding of different pathophysiologies and clinical characteristics of different AE groups. In encephalitis with antibodies to neuronal extracellular antigens, autoantibodies play a direct role in disease pathogenesis. They have access to target antigens and can potentially alter the structure and function of antigens but induce relatively little neuronal death. Prompt immunotherapy is usually very effective, and long-term antiepileptic treatment may not be needed. In contrast, in encephalitis with antibodies against intracellular antigens, autoantibodies may not be directly pathogenic but serve as tumor markers. These autoantibodies cannot reach intracellular target antigens and are considered to result from a T-cell-mediated immune response against antigens released by apoptotic tumor cells, which contain nerve tissue or express neuronal proteins. Neuronal loss is frequently described and predominantly induced through cytotoxic T-cell mechanisms. They often exhibit an inadequate response to immunotherapy and require early tumor treatment. Long-term antiepileptic treatment is usually needed. In conclusion, each neural autoantibody can specifically precipitate seizures. Early proper management of these cases may help prevent neurological deterioration and manage the occurrence of seizures. Consequently, confirmation of the presence of neuronal autoantibodies is strongly recommended even in patients with confirmed AE, as they are not only essential in achieving a good outcome but also may provide evidence for underlying neoplasia.

Deep Brain Stimulation in Treatment-Resistant Depression: A Systematic Review and Meta-Analysis on Efficacy and Safety.

Objective: Deep brain stimulation (DBS) has shown promising outcomes as new therapeutic opportunities for patients with treatment-resistant depression (TRD) who do not respond adequately to several consecutive treatments. This study aims to systematically review and conduct a meta-analysis on the efficacy and safety of DBS for TRD. Method: The literature was comprehensively reviewed using Medline, Google scholar, Cochrane library, Embase, and World Health Organization International Clinical Trials Registry Platform until January 2019. The studied outcomes included response, remission, recurrence, and adverse events (AEs) rates, and were reported as the rate ratio (RR) or pooled estimate with a 95% confidence interval (95% CI). Heterogeneity was measured by an I-square test and a sensitive analysis. Results: A total of 17 studies involving 7 DBS targets were included. For efficacy, DBS treatment was statistically beneficial for TRD, and the response, remission, and recurrence rates were 56% (ranging from 43 to 69%), 35% (ranging from 27 to 44%), and 14% (ranging from 4 to 25%), respectively. However, only two randomized-controlled trials (RCTs) considered the invalidity of DBS (RR = 1.45, 95% CI = 0.50-4.21). For safety, the AEs rate was 67% (ranging from 54 to 80%). The AEs were common and moderate, but the problems related to suicide and suicidal ideation should not be underestimated. Conclusion: These findings suggest that DBS for TRD is considered promising, which should be confirmed by well-designed and large sample studies. Future basic research and comprehensive clinical trials are needed to reach better understanding on the mechanisms of action and optimal targeted structure.

A systematic review and meta-analysis of the effects of early mobilization therapy in patients after cardiac surgery.

BACKGROUND: Prolonged hospitalization and immobility of critical care patients elevate the risk of long-term physical and cognitive impairments. However, the therapeutic effects of early mobilization have been difficult to interpret due to variations in study populations, interventions, and outcome measures. We conducted a meta-analysis to assess the effects of early mobilization therapy on cardiac surgery patients in the intensive care unit (ICU). METHODS: PubMed, Excerpta Medica database (EMBASE), Cumulative Index of Nursing and Allied Health Literature (CINAHL), Physiotherapy Evidence Database (PEDro), and the Cochrane Library were comprehensively searched from their inception to September 2018. Randomized controlled trials were included if patients were adults (≥18 years) admitted to any ICU for cardiac surgery due to cardiovascular disease and who were treated with experimental physiotherapy initiated in the ICU (pre, post, or peri-operative). Data were extracted by 2 reviewers independently using a pre-constructed data extraction form. Length of ICU and hospital stay was evaluated as the primary outcomes. Physical function and adverse events were assessed as the secondary outcomes. Review Manager 5.3 (RevMan 5.3) was used for statistical analysis. For all dichotomous variables, relative risks or odds ratios with 95% confidence intervals (CI) were presented. For all continuous variables, mean differences (MDs) or standard MDs with 95% CIs were calculated. RESULTS: The 5 studies with a total of 652 patients were included in the data synthesis final meta-analysis. While a slight favorable effect was detected in 3 out of the 5 studies, the overall effects were not significant, even after adjusting for heterogeneity. CONCLUSIONS: This population-specific evaluation of the efficacy of early mobilization to reduce hospitalization duration suggests that intervention may not universally justify the labor barriers and resource costs in patients undergoing non-emergency cardiac surgery. PROSPERO RESEARCH REGISTRATION IDENTIFYING NUMBER: CRD42019135338.

A systematic review and meta-analysis of the effects of early mobilization therapy in patients after cardiac surgery: A protocol for systematic review.

BACKGROUND: Prolonged hospitalization and immobility of critical care patients elevates the risk of long-term physical and cognitive impairments. However, the therapeutic effects of early mobilization have been difficult to interpret due to variations in study populations, interventions, and outcome measures. This systematic review and meta-analysis aims to assess the effects of early mobilization therapy for non-emergency cardiac surgery patients in the intensive care unit (ICU). METHODS: The following databases will be used to search for relevant keywords: PubMed, Embase, CINAHL, PEDro, and the Cochrane Library from inception to September 2018 by 2 researchers independently. Randomized controlled trials (RCTs), will be included if patients are adults (≥18 years) admitted to any ICU for cardiac surgery due to cardiovascular disease and who are treated with experimental physiotherapy initiated in the ICU (pre, post, or perioperative). The Review Manager 5.3 will be used for meta-analysis and the evidence level will be assessed by using the method for Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Continuous outcomes will be presented as the weighted mean difference (WMD) or standardized mean difference (SMD) with 95% confidence interval (CI), while dichotomous data will be expressed as relative risk (RR) with 95% CI. If the included studies have existing heterogeneity (P < 0.1), a random-effects model will be used. Otherwise, we will calculate using a fixed effects model. RESULTS: This review will evaluate the effects of early mobilization on length of ICU and hospital stay, physical function and adverse events in patients with cardiac surgery patients in the ICU. CONCLUSION: This systematic review will comprehensively provide conclusive evidence of the therapeutic effect of early mobilization on cardiac surgery patients in the ICU.PROSPERO Research registration identifying number: CRD42019135338.

CCCTC-binding factor inhibits breast cancer cell proliferation and metastasis via inactivation of the nuclear factor-kappaB pathway.

CCCTC-binding factor (CTCF) is an important epigenetic regulator implicated in multiple cellular processes, including growth, proliferation, differentiation, and apoptosis. Although CTCF deletion or mutation has been associated with human breast cancer, the role of CTCF in breast cancer is questionable. We investigated the biological functions of CTCF in breast cancer and the underlying mechanism. The results showed that CTCF expression in human breast cancer cells and tissues was significantly lower than that in normal breast cells and tissues. In addition, CTCF expression correlated significantly with cancer stage (P = 0.043) and pathological differentiation (P = 0.029). Furthermore, CTCF overexpression resulted in the inhibition of proliferation, migration, and invasion, while CTCF knockdown induced these processes in breast cancer cells. Transcriptome analysis and further experimental confirmation in MDA-MD-231 cells revealed that forced overexpression of CTCF might attenuate the DNA-binding ability of nuclear factor-kappaB (NF-κB) p65 subunit and inhibit activation of NF-κB and its target pro-oncogenes (tumor necrosis factor alpha-induced protein 3 [TNFAIP3]) and genes for growth-related proteins (early growth response protein 1 [EGR1] and growth arrest and DNA-damage-inducible alpha [GADD45a]). The present study provides a new insight into the tumor suppressor roles of CTCF in breast cancer development and suggests that the CTCF/NF-κB pathway is a potential target for breast cancer therapy.

Glioma localization and excision using direct electrical stimulation for language mapping during awake surgery.

The aim of this study was to investigate the method and significance of the application of direct electrical stimulation (DES) to the brain mapping of language functions during glioma surgery. A retrospective analysis of clinical data was performed for 91 cases of brain functional area glioma surgery under DES from January 2003 until January 2012. Following cortical electrical stimulation, 88 patients exhibited seizures involving facial or hand movements and 91 cases experienced language disorders such as counting interruption, naming errors or anomia. The most commonly observed areas of counting interruption were distributed on the posterior part of the left anterior central gyrus (47.7%), the operculum of the left inferior frontal gyrus (24.4%) and the triangular part of the left inferior frontal gyrus (12.8%). Postoperative magnetic resonance imaging demonstrated that overall excision was achieved in 53 cases and sub-overall excision was performed in 31 cases. A total of 42 cases (46.2%) exhibited no postoperative neurological dysfunction, 39 cases (42.9%) exhibited brief language dysfunction, 27 cases (29.7%) experienced brief limb movement disorder, and one case appeared to have permanent neurological dysfunction. DES was indicated to be a reliable and noninvasive method for the intraoperative positioning of language areas, and was able to resect gliomas in the language area with maximal safety.

Activation of STAT3 stimulates AHSP expression in K562 cells.

Studies on the chaperone protein α-hemoglobin stabilizing protein (AHSP) reveal that abundant AHSP in erythroid cells enhance the cells' tolerance to oxidative stress imposed by excess α-hemoglobin in pathological conditions. However, the potential intracellular modulation of AHSP expression itself in response to oxidative stress is still unknown. The present study examined the effect and molecular mechanism of STAT3, an oxidative regulator, on the expression of AHSP. AHSP expression increased in K562 cells upon cytokine IL-6-induced STAT3 activation and decreased in STAT3 knock-down K562 cells. Regulation of AHSP in oxidative circumstance was then examined in α-globin-overloaded K562 cells, and real-time PCR showed strengthened expression of both AHSP and STAT3. ChIP analysis showed binding of STAT3 to AHSP promoter and binding was significantly augmented with IL6 stimulation and upon α-globin overexpression. Dual luciferase reporter assays of the wildtype and mutated SB3 element, an IL-6RE site, in the AHSP promoter in K562 cells highlighted the direct regulatory effect of STAT3 on AHSP gene. Finally, direct binding of STAT3 to SB3 site of AHSP promoter was confirmed with EMSA assays. Our work reveals an adaptive AHSP regulation mediated by the redox-sensitive STAT3 signaling pathway, and provides clues to the therapeutic strategy for AHSP enhancement.

PML4 facilitates erythroid differentiation by enhancing the transcriptional activity of GATA-1.

Promyelocytic leukemia protein (PML) has been implicated as a participant in multiple cellular processes including senescence, apoptosis, proliferation, and differentiation. Studies of PML function in hematopoietic differentiation previously focused principally on its myeloid activities and also indicated that PML is involved in erythroid colony formation. However, the exact role that PML plays in erythropoiesis is essentially unknown. In this report, we found that PML4, a specific PML isoform expressed in erythroid cells, promotes endogenous erythroid genes expression in K562 and primary human erythroid cells. We show that the PML4 effect is GATA binding protein 1 (GATA-1) dependent using GATA-1 knockout/rescued G1E/G1E-ER4 cells. PML4, but not other detected PML isoforms, directly interacts with GATA-1 and can recruit it into PML nuclear bodies. Furthermore, PML4 facilitates GATA-1 trans-activation activity in an interaction-dependent manner. Finally, we present evidence that PML4 enhances GATA-1 occupancy within the globin gene cluster and stimulates cooperation between GATA-1 and its coactivator p300. These results demonstrate that PML4 is an important regulator of GATA-1 and participates in erythroid differention by enhancing GATA-1 trans-activation activity.