The pathogenesis of several neurodegenerative diseases often involves the microglial activation and associated inflammatory processes. Activated microglia release pro-inflammatory factors that may be neurotoxic. 6-Mercaptopurine (6-MP) is a well-established immunosuppressive drug. Common understanding of their immunosuppressive properties is largely limited to peripheral immune cells. However, the effect of 6-MP in the central nervous system, especially in microglia in the context of neuroinflammation is, as yet, unclear. Tumor necrosis factor-α (TNF-α) is a key cytokine of the immune system that initiates and promotes neuroinflammation. The present study aimed to investigate the effect of 6-MP on TNF-α production by microglia to discern the molecular mechanisms of this modulation. Lipopolysaccharide (LPS) was used to induce an inflammatory response in cultured primary microglia or murine BV-2 microglial cells. Released TNF-α was measured by enzyme-linked immunosorbent assay (ELISA). Gene expression was determined by real-time reverse transcription polymerase chain reaction (RT-PCR). Signaling molecules were analyzed by western blotting, and activation of NF-κB was measured by ELISA-based DNA binding analysis and luciferase reporter assay. Chromatin immunoprecipitation (ChIP) analysis was performed to examine NF-κB p65 and coactivator p300 enrichments and histone modifications at the endogenous TNF-α promoter. Treatment of LPS-activated microglia with 6-MP significantly attenuated TNF-α production. In 6-MP pretreated microglia, LPS-induced MAPK signaling, IκB-α degradation, NF-κB p65 nuclear translocation, and in vitro p65 DNA binding activity were not impaired. However, 6-MP suppressed transactivation activity of NF-κB and TNF-α promoter by inhibiting phosphorylation and acetylation of p65 on Ser276 and Lys310, respectively. ChIP analyses revealed that 6-MP dampened LPS-induced histone H3 acetylation of chromatin surrounding the TNF-α promoter, ultimately leading to a decrease in p65/coactivator-mediated transcription of TNF-α gene. Furthermore, 6-MP enhanced orphan nuclear receptor Nur77 expression. Using RNA interference approach, we further demonstrated that Nur77 upregulation contribute to 6-MP-mediated inhibitory effect on TNF-α production. Additionally, 6-MP also impeded TNF-α mRNA translation through prevention of LPS-activated PI3K/Akt/mTOR signaling cascades. These results suggest that 6-MP might have a therapeutic potential in neuroinflammation-related neurodegenerative disorders through downregulation of microglia-mediated inflammatory processes.

The adverse effects of the COVID-19 vaccine have been discovered as the rapid application of the vaccines continues. Neurological complications such as transverse myelitis raise concerns as cases were observed in clinical trials. Transverse myelitis is a rare immune-mediated disease with spinal cord neural injury, resulting in neurological deficits in the motor, sensory, and autonomic system. Vaccine-related transverse myelitis is even rarer. We present a case of acute transverse myelitis after vaccination against COVID-19 with the ChAdOx1 nCOV-19 vaccine (AZD1222), which was the first case reported in Taiwan. Although it rarely occurs, post-vaccination neurological complications should not be ignored. As the pandemic of SARS-CoV-2 continues to spread and concern about vaccination efficacy and safety rises, heterologous vaccination were implemented in health public policy in several countries. A literature review of several clinical trials shows promising effects of mix-and-match vaccination. Further study on different combinations of vaccines can be expected.

In pre-hospital settings, efficient cardiopulmonary resuscitation (CPR) is challenging; therefore, the application of mechanical CPR devices continues to increase. However, the evidence of the benefits of using mechanical CPR devices in pre-hospital settings for adult out-of-hospital cardiac arrest (OHCA) is controversial. This meta-analysis compared the effects of mechanical and manual CPR applied in the pre-hospital stage on clinical outcomes after OHCA. Cochrane Library, PubMed, Embase, and ClinicalTrials.gov were searched from inception until October 2021. Studies comparing mechanical and manual CPR applied in the pre-hospital stage for survival outcomes of adult OHCA were eligible. Data abstraction, quality assessment, meta-analysis, trial sequential analysis (TSA), and grading of recommendations, assessment, development, and evaluation were conducted. Seven randomized controlled and 15 observational studies were included. Compared to manual CPR, pre-hospital use of mechanical CPR showed a positive effect in achieving return of spontaneous circulation (ROSC) and survival to admission. No difference was found in survival to discharge and discharge with favorable neurological status, with inconclusive results in TSA. In conclusion, pre-hospital use of mechanical CPR devices may benefit adult OHCA in achieving ROSC and survival to admission. With low certainty of evidence, more well-designed large-scale randomized controlled trials are needed to validate these findings.

Purpose: Distinguishing ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) is crucial in acute myocardial infarction (AMI) research due to their distinct characteristics. However, the accuracy of International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes for STEMI and NSTEMI in Taiwan’s National Health Insurance (NHI) database remains unvalidated. Therefore, we developed and validated case definition algorithms for STEMI and NSTEMI using ICD-10-CM and NHI billing codes. Patients and Methods: We obtained claims data and medical records of inpatient visits from 2016 to 2021 from the hospital’s research-based database. Potential STEMI and NSTEMI cases were identified using diagnostic codes, keywords, and procedure codes associated with AMI. Chart reviews were then conducted to confirm the cases. The performance of the developed algorithms for STEMI and NSTEMI was assessed and subsequently externally validated. Results: The algorithm that defined STEMI as any STEMI ICD code in the first three diagnosis fields had the highest performance, with a sensitivity of 93.6% (95% confidence interval [CI], 91.7– 95.2%), a positive predictive value (PPV) of 89.4% (95% CI, 87.1– 91.4%), and a kappa of 0.914 (95% CI, 0.900– 0.928). The algorithm that used the NSTEMI ICD code listed in any diagnosis field performed best in identifying NSTEMI, with a sensitivity of 82.6% (95% CI, 80.7– 84.4%), a PPV of 96.5% (95% CI, 95.4– 97.4), and a kappa of 0.889 (95% CI, 0.878– 0.901). The algorithm that included either STEMI or NSTEMI ICD codes listed in any diagnosis field showed excellent performance in defining AMI, with a sensitivity of 89.4% (95% CI, 88.2– 90.6%), a PPV of 95.6% (95% CI, 94.7– 96.4%), and a kappa of 0.923 (95% CI, 0.915– 0.931). External validation confirmed these algorithms’ efficacy. Conclusion: Our results provide valuable reference algorithms for identifying STEMI and NSTEMI cases in Taiwan’s NHI database.

Purpose: Taiwan’s national health insurance (NHI) database is a valuable resource for large-scale epidemiological and long-term survival research for out-of-hospital cardiac arrest (OHCA). We developed and validated case definition algorithms for OHCA based on the International Classification of Diseases (ICD) diagnostic codes and billing codes for NHI reimbursement. Patients and Methods: Claims data and medical records of all emergency department visits from 2010 to 2020 were retrieved from the hospital’s research-based database. Death-related diagnostic codes and keywords were used to identify potential OHCA cases, which were ascertained by chart reviews. We tested the performance of the developed OHCA algorithms and validated them on an external dataset. Results: The algorithm defining OHCA as any cardiac arrest (CA)-related ICD code in the first three diagnosis fields performed the best with a sensitivity of 89.5% (95% confidence interval [CI], 88.2– 90.7%), a positive predictive value (PPV) of 90.6% (95% CI, 89.4– 91.8%), and a kappa value of 0.900 (95% CI, 0.891– 0.909). The second-best algorithm consists of any CA-related ICD code in any diagnosis field with a billing code for triage acuity level 1, achieving a sensitivity of 85.6% (95% CI, 84.1– 87.0%), a PPV of 93.6% (95% CI, 92.5– 94.5), and a kappa value of 0.894 (95% CI, 0.884– 0.903). Both algorithms performed well in external validation. In subgroup analyses, the former algorithm performed the best in adult patients, outpatient claims, and during the ICD-9 era. The latter algorithm performed the best in the inpatient claims and during the ICD-10 era. The best algorithm for identifying pediatric OHCAs was any CA-related ICD code in the first three diagnosis fields with a billing code for triage acuity level 1. Conclusion: Our results may serve as a reference for future OHCA studies using the Taiwan NHI database.

Translationally controlled tumor-associated protein (TCTP) has been implicated in cell growth, proliferation, and apoptosis through interacting proteins. Although TCTP is expressed abundantly in the mouse brain, little is known regarding its role in the neurogenesis of the nervous system. We used Nestin-cre-driven gene-mutated mice to investigate the function of TCTP in the nervous system. The mice carrying disrupted TCTP in neuronal and glial progenitor cells died at the perinatal stage. The Nestin^Cre/+; TCTP^f/f pups displayed reduced body size at postnatal day 0.5 (P0.5) and a lack of milk in the stomach compared with littermate controls. In addition to decreased cell proliferation, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) and caspase assay revealed that apoptosis was increased in newly committed TCTP-disrupted cells as they migrated away from the ventricular zone. The mechanism may be that the phenotype from specific deletion of TCTP in neural progenitor cells is correlated with the decreased expression of cyclins D2, E2, Mcl-1, Bcl-xL, hax-1, and Octamer-binding transcription factor 4 (Oct4) in conditional knockout mice. Our results demonstrate that TCTP is a critical protein for cell survival during early neuronal and glial differentiation. Thus, enhanced neuronal loss and functional defect in Tuj1 and doublecortin-positive neurons mediated through increased apoptosis and decreased proliferation during central nervous system (CNS) development may contribute to the perinatal death of TCTP mutant mice.