The advances of E2A-PBX1 fusion in B-cell acute lymphoblastic Leukaemia.

The E2A-PBX1 gene fusion is a common translocation in B-cell acute lymphoblastic leukaemia. Patients harbouring the E2A-PBX1 fusion gene typically exhibit an intermediate prognosis. Furthermore, minimal residual disease has unsatisfactory prognostic value in E2A-PBX1 B-cell acute lymphoblastic leukaemia. However, the mechanism of E2A-PBX1 in the occurrence and progression of B-cell acute lymphoblastic leukaemia is not well understood. Here, we mainly review the roles of E2A and PBX1 in the differentiation and development of B lymphocytes, the mechanism of E2A-PBX1 gene fusion in B-cell acute lymphoblastic leukaemia, and the potential therapeutic approaches.

Phase III clinical trial comparing the efficacy and safety of adamgammadex with sugammadex for reversal of rocuronium-induced neuromuscular block.

BACKGROUND: Preliminary clinical trials of adamgammadex, a new cyclodextrin-based selective reversal agent, have demonstrated its efficacy in reversing neuromuscular block by rocuronium. METHODS: This multicentre, randomised, double-blind, positive-controlled, non-inferiority phase III clinical trial compared the efficacy and safety of adamgammadex and sugammadex. We randomised 310 subjects to receive adamgammadex (4 mg kg-1) or sugammadex (2 mg kg-1) at reappearance of the second twitch of the train-of-four (TOF), and standard safety data were collected. RESULTS: For the primary outcome, the proportion of patients with TOF ratio ≥0.9 within 5 min was 98.7% in the adamgammadex group vs 100% in the sugammadex group, with a point estimate and 95% confidence interval (CI) of 1.3% (-4.6%, +1.3%); the lower limit was greater than the non-inferiority margin of -10%. For the key secondary outcome, the median (inter quartile range) time from the start of administration of adamgammadex or sugammadex to recovery of TOF ratio to 0.9 was 2.25 (1.75, 2.75) min and 1.75 (1.50, 2.00) min, respectively. The difference was 0.50 (95% CI: 0.25, 0.50); the upper limit was lower than the non-inferiority margin of 5 min. In addition, there were no inferior results observed in secondary outcomes. Adamgammadex had a lower incidence of adverse drug reactions compared with sugammadex (anaphylactic reaction, recurarisation, decreased heart rate, and laryngospasm; P=0.047). CONCLUSIONS: Adamgammadex was non-inferior to sugammadex with a possible lower incidence of adverse drug reactions compared with sugammadex. Adamgammadex may have a potential advantage in terms of its overall risk-benefit profile. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000039525. Registered October 30, 2020. https://www.chictr.org.cn/showproj.html?proj=56825.

Treatment of three pediatric AML co-expressing NUP98-NSD1, FLT3-ITD, and WT1.

During the treatment of 89 pediatric patients with Acute Myeloid Leukemia (AML) at the Hematology Department of Kunming Medical University's Children's Hospital from 2020 to 2023, three patients were identified to co-express the NUP98-NSD1, FLT3-ITD, and WT1 gene mutations. The bone marrow of these three patients was screened for high-risk genetic mutations using NGS and qPCR at the time of diagnosis. The treatment was administered following the China Children's Leukemia Group (CCLG)-AML-2019 protocol. All three patients exhibited a fusion of the NUP98 exon 12 with the NSD1 exon 6 and co-expressed the FLT3-ITD and WT1 mutations; two of the patients displayed normal karyotypes, while one presented chromosomal abnormalities. During the induction phase of the CCLG-AML-2019 treatment protocol, the DAH (Daunorubicin, Cytarabine, and Homoharringtonine) and IAH (Idarubicin, Cytarabine, and Homoharringtonine) regimens, in conjunction with targeted drug therapy, did not achieve remission. Subsequently, the patients were shifted to the relapsed/refractory chemotherapy regimen C + HAG (Cladribine, Homoharringtonine, Cytarabine, and G-CSF) for two cycles, which also failed to induce remission. One patient underwent Haploidentical Hematopoietic Stem Cell Transplantation (Haplo-HSCT) and achieved complete molecular remission during a 12-month follow-up period. Regrettably, the other two patients, who did not receive transplantation, passed away. The therapeutic conclusion is that pediatric AML patients with the aforementioned co-expression do not respond to chemotherapy. Non-remission transplantation, supplemented with tailor-made pre- and post-transplant strategies, may enhance treatment outcomes.

Screening potential antileukemia agents from duckweed: Integration of chemical profiling, network pharmacology, and experimental validation.

INTRODUCTION: The identification of active dietary flavonoids in food is promising for novel drug discovery. The active ingredients of duckweed (a widely recognized food and herb with abundant flavonoids) that are associated with acute myeloid leukemia (AML) have yet to be identified, and their underlying mechanisms have not been elucidated. OBJECTIVES: The objective of this study was to identify novel constituents exhibiting antileukemia activity in duckweed through the integration of chemical profiling, network pharmacology, and experimental validation. METHODS: First, high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to characterize the primary constituents of duckweed. Subsequently, AML cell-xenograft tumor models were used to validate the anticancer effect of duckweed extract. Furthermore, network pharmacology analysis was conducted to predict the potential active compounds and drug targets against AML. Lastly, based on these findings, two monomers (apiin and luteoloside) were selected for experimental validation. RESULTS: A total of 17 compounds, all of which are apigenin and luteolin derivatives, were identified in duckweed. The duckweed extract significantly inhibited AML cell growth in vivo. Furthermore, a total of 88 targets for duckweed against AML were predicted, with key targets including PTGS2, MYC, MDM2, VEGFA, CTNNB1, CASP3, EGFR, TP53, HSP90AA1, CCND1, MMP9, TNF, and MAPK1. GO and KEGG pathway enrichment analyses indicated that these targets were primarily involved in the apoptotic signaling pathway. Lastly, both apiin and luteoloside effectively induced apoptosis through CASP3 activation, and this effect could be partially reversed by a caspase inhibitor (Z-VAD). CONCLUSION: Duckweed extract has an antileukemic effect, and apiin derived from duckweed shows potential as a treatment for AML.

Activation of A1 reactive astrocytes in the medullary dorsal horn of rats participates in the chronification of trigeminal neuralgia. / å¤§é¼ å»¶é«“èƒŒè§’A1åž‹ååº”æ€§æ˜Ÿå½¢èƒ¶è´¨ç»†èƒžæ¿€æ´»å‚ä¸Žä¸‰å‰ç¥žç»ç—›æ ¢æ€§åŒ–.

OBJECTIVES: The activation of astrocytes is an important process in the formation of chronic pain. This study aims to observe the activation of A1 reactive astrocytes in the medullary dorsal horn in the rat model of trigeminal neuralgia, and to explore the mechanism of central sensitization caused by A1 reactive astrocyte. METHODS: The adult male rats were randomly divided into a sham group and a chronic constriction injury of infraorbital nerve (ION-CCI) group. The facial mechanical pain threshold and thermal withdrawal latency were measured before the operation and on the 1st, 3rd, 7th, 10th, and 14th day after the operation. After pain behavior observation, the expression of glial fibrillary acidic protein (GFAP) in the medullary dorsal horn was observed by immunohistochemistry and immunofluorescence colocalization of GFAP, complement 3 (C3)/S100A10, and 4', 6-diamidino-2-phenylindole (DAPI) was analyzed. Primary astrocytes were cultured and randomly divided into a naive group and a DHK group. The DHK group was treated with 1 mmol/L of astrocyte activation inhibitor dihydrokainic acid (DHK). Fura-2/AM was used to stain the astrocytes and the calcium wave of the 2 groups under the stimulation of high potassium was recorded and compared. The expression of C3 was detected by Western blotting. RESULTS: The facial mechanical pain threshold and thermal withdrawal latency of the ION-CCI group were significantly lower than those of the sham group (both P<0.05). There were a large number of GFAP positive astrocytes in the medullary dorsal horn of the ION-CCI group. The fluorescence intensity of GFAP in the ION-CCI group was higher than that in the sham group (P<0.05). GFAP and C3/S100A10 were co-expressed in astrocytes. Compared with the sham group, the fluorescence intensity of C3 and the protein expression of C3 in the ION-CCI group were increased (both P<0.05). The expression of C3 in ION-CCI group was significantly increased (P<0.05). Compared with the naive group, the C3 protein expression was significantly decreased in the DHK group (P<0.05). The intensity of calcium fluorescence was increased after high potassium stimulation in both groups. Furthermore, the peak and increase amplitude of calcium fluorescence in the naive group were much higher than those in the DHK group (both P<0.05). CONCLUSIONS: A1 reactive astrocytes in the medullary dorsal horn of trigeminal neuralgia model rats are increased significantly, which may participate in central sensitization of trigeminal neuralgia by impacting astrocyte calcium wave.

[Expression of miR-142 and its relationship with Th17/Treg imbalance in children with autoimmune thyroid disease]. / miR-142åœ¨å„¿ç«¥è‡ªèº«å ç–«æ€§ç”²çŠ¶è ºç–¾ç— ä¸­è¡¨è¾¾åŠä¸ŽTh17/Tregå¤±è¡¡å ³ç³»çš„ç ”ç©¶.

OBJECTIVES: To investigate the expression of microRNA-142 (miR-142) in children with autoimmune thyroid disease (AITD) and its relationship with the imbalance of helper T cell 17 (Th17) and regulatory T cell (Treg). METHODS: A total of 89 children hospitalized for AITD from January 2019 to December 2022 were prospectively selected as the study subjects, including 48 children with Graves' disease (GD group) and 41 children with Hashimoto's thyroiditis (HT group). Additionally, 55 healthy children undergoing physical examinations during the same period were selected as the control group. The differences in serum miR-142, antithyroglobulin antibody (TGAb), antithyroperoxidase antibody (TPOAb), Th17/Treg, and interleukin-17 (IL-17) expression were compared among the groups. RESULTS: The expression of miR-142, TPOAb, TGAb, Th17, Th17/Treg, and IL-17 in the GD group and HT group was higher than that in the control group, while Treg was lower than that in the control group (P<0.05). Pearson correlation analysis revealed that in the GD group, miR-142 was positively correlated with TPOAb, TGAb, Th17, Th17/Treg, and IL-17 (r=0.711, 0.728, 0.785, 0.716, 0.709, respectively; P<0.001) and negatively correlated with Treg (r=-0.725, P<0.001); in the HT group, miR-142 was positively correlated with TPOAb and TGAb (r=0.752, 0.717, respectively; P<0.001). CONCLUSIONS: miR-142 is highly expressed in children with AITD, and its expression may be related to the Th17/Treg imbalance in children with GD.

Construction and validation of a nomogram for HBV-related hepatocellular carcinoma: A large, multicenter study.

INTRODUCTION AND OBJECTIVES: We initiated this multicenter study to integrate important risk factors to create a nomogram for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) for clinician decision-making. PATIENTS AND METHODS: Between April 2011 and March 2022, 2281 HCC patients with an HBV-related diagnosis were included. All patients were randomly divided into two groups in a ratio of 7:3 (training cohort, n = 1597; validation cohort, n = 684). The nomogram was built in the training cohort via Cox regression model and validated in the validation cohort. RESULTS: Multivariate Cox analyses revealed that the portal vein tumor thrombus, Child-Pugh class, tumor diameter, alanine aminotransferase level, tumor number, extrahepatic metastases, and therapy were independent predictive variables impacting overall survival. We constructed a new nomogram to predict 1-, 2-, and 3-year survival rates based on these factors. The nomogram-related receiver operating characteristics (ROC) curves indicated that the area under the curve (AUC) values were 0.809, 0.806, and 0.764 in predicting 1-, 2-, and 3-year survival rates, respectively. Furthermore, the calibration curves revealed good agreement between real measurements and nomogram predictions. The decision curve analyses (DCA) curves demonstrated excellent therapeutic application potential. In addition, stratified by risk scores, low-risk groups had longer median OS than medium-high-risk groups (p < 0.001). CONCLUSIONS: The nomogram we constructed showed good performance in predicting the 1-year survival rate for HBV- related HCC.

The L-shaped association of mid-upper arm circumference with all-cause and cause-specific mortality in US adults: a population-based prospective cohort study.

BACKGROUND: The arm circumference is a feasible and reliable indicator in evaluating the nutritional status of children. However, its application in general adults has yet to be thoroughly investigated. OBJECTIVE: This study aimed to evaluate the association between mid-upper arm circumferences (MUACs) and mortality in general adults. METHODS: The nationally representative cohort from the National Health and Nutrition Examination Survey (1999-2018) was analyzed with mortality information obtained through linkage to the National Death Index. The baseline MUACs were collected as exposure. Survey-weighted Cox proportional hazard regressions were performed to estimate the hazard ratios (HRs) and 95% confidential intervals (CIs) of mortality risk for individuals with different MUACs. Restricted cubic spline analyses were performed to examine the nonlinear association of MUAC with all-cause and cause-specific mortality. RESULTS: A total of 52,159 participants were included in this study. During a median follow-up time of 117 months, 7157 deaths were documented, with leading causes of cardiovascular disease (CVD), cancer, and respiratory disease. Individuals in the first quartile (Q1) of MUAC tended to have higher all-cause mortality risk than the rest after full adjustment. Similarly, CVD mortality risk in Q1 was higher than that in the second quartile (Q2) and the third quartile (Q3); respiratory mortality risk in Q1 was higher than in Q2. MUAC was non-linearly associated with all-cause mortality and CVD mortality. Individuals in Q1 MUAC (≤ 29.3) tended to have higher all-cause mortality risk, with HRs (95% CIs) estimated to be 0.76 (0.67-0.87) for Q2 (29.4, 32.5), 0.69 (0.59-0.81) for Q3 (32.6, 36.0), and 0.59 (0.46-0.75) for Q4 (≥ 36.1) after adjustment of demographic, lifestyle, and comorbidity covariates. Similarly, compared with Q1, HRs (95% CIs) for CVD mortality were estimated to be 0.73 (0.58-0.93) for Q2 and 0.57 (0.43-0.47) for Q3; HRs (95% CIs) for respiratory mortality was estimated to be 0.57 (95% CI, 0.37-0.87) for Q2 with other differences not significant. CONCLUSION: The MUAC was inversely associated with long-term mortality in general adults in the United States and may serve as a valuable measurement in adult health evaluations.

Exploring the pharmacological mechanisms of Shuanghuanglian against T-cell acute lymphoblastic leukaemia through network pharmacology combined with molecular docking and experimental validation.

CONTEXT: Due to the poor prognosis of T-cell acute lymphoblastic leukaemia (T-ALL), there is an urgent need to identify safer and more cost-effective drugs. OBJECTIVE: This study evaluated the antitumour activity of Shuanghuanglian (SHL) on T-ALL cells and elucidated the mechanism. MATERIALS AND METHODS: Jurkat and Molt4 cells were treated with SHL (0.1, 0.2 and 0.4 mg/mL) for 24 and 48 h. The controls were treated with RPMI 1640 containing 10% foetal bovine serum. Cell viability was evaluated through Cell Counting Kit-8 assay. Patterns of death and signalling pathway alterations caused by SHL were identified by network pharmacology combined with GO enrichment analysis and then were verified by Hoechst 33342 staining, Annexin V-FITC/PI staining and Western blotting. Interactions of the active ingredients with targets were analysed by molecular docking. RESULTS: The IC50 values of SHL in Jurkat and Molt4 cells were 0.30 ± 0.10 and 0.48 ± 0.07 mg/mL, respectively, at 24 h and 0.27 ± 0.05 and 0.30 ± 0.03 mg/mL at 48 h. In T-ALL, 117 target genes of SHL were mainly enriched in the apoptosis and NOTCH signalling pathways. SHL induced apoptosis was confirmed by Hoechst 33342 staining and flow cytometry. The protein levels of cleaved caspase-7 and cleaved PARP were significantly increased but those of cleaved NOTCH1 and MYC were reduced. The active ingredients of SHL can interact with γ-secretase.Discussion and conclusions: SHL induces apoptosis in T-ALL cells via the NOTCH1-MYC pathway and may be a potential drug for the treatment of T-ALL.

Novel bioactive hybrid Celecoxib-HDAC Inhibitor, induces apoptosis in human acute lymphoblastic leukemia cells.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Here, we exploited the synergy between histone deacetylase inhibitors (HDACi) and cyclooxygenase 2 (COX-2) inhibitors by generating and testing a series of hybrid Celecoxib-HDAC inhibitors (selenium-containing analogues of Celecoxib) on ALL cells, of which compound 11 exhibited significant inducement to kill NALM6 cells with an average IC50 of 9.95 ± 0.44 µM compared with control Celecoxib at 28.58 ± 1.44 µM and inhibited NALM6 cells growth via the inhibition of the cell cycle in G2 phase. Furthermore, compound 11 induced apoptosis by activating PARP cleavage. Taken together, compound 11 possessed the potential to be developed further as a chemotherapeutic agent for ALL.

The burden of aortic aneurysm in China from 1990 to 2019: findings from the Global Burden of Disease Study 2019.

BACKGROUND: Aortic aneurysm (AA) is a global public health concern. However, little is known about the disease burden of AA in China. METHODS: Following the general analytic strategy used in the Global Burden of Disease Study (GBD) 2019, we analyzed the mortality and years of life lost (YLLs) due to AA, stratified by sex, age, and province-level region in China from 1990 to 2019. The temporal trend of AA burden in China was analyzed and the main attributable risk factors for AA in China were also explored. RESULTS: In China, the total AA deaths were 17,038 (95% UI: 14,392-19,980) in 2019, an increase of 136.1% compared with that in 1990, with an age-standardized death rate (ASDR) of 0.93 (95% UI: 0.79-1.08) per 100,000 person-years in 2019, a decrease of 6.8%. Meanwhile AA caused 378,578 (95% UI: 315,980-450,479) YLLs in 2019, an increase of 102.6% compared with that in 1990, with a crude YLL rate of 26.6 (95% UI: 22.2-31.7) per 100,000 person-years, an increase of 68.6%. The AA mortality and YLLs were higher in males than in females. AA caused most YLLs in the 65- to 75-year-old age group. The AA mortality and YLLs varied significantly among provinces in China, and the change in ASDR showed a negative correlation with the sociodemographic index of different provinces, namely, more decline of ASDR in developed provinces. High systolic blood pressure was shown to be the most significant attributable risk factor for AA burden in both males and females, and smoking was another major attributable risk factor, especially in males. CONCLUSIONS: The disease burden of AA increased significantly from 1990 to 2019 in China, with higher mortality and YLLs in males, senior populations, and among residents of most western provinces in China. High systolic blood pressure and smoking were two major attributable risk factors for AA mortality in China.

Calcicoptosis Induced by Purple Sweet Potato Anthocyanins through the Nonosmotic Regulation of the NFAT5/S100A4-S100A9 Pathway in Acute Lymphoblastic Leukemia.

Purple sweet potato is considered an abundant, inexpensive, and ideal source of anthocyanins. Purple sweet potato anthocyanins (PSPAs) have been shown to possess high antimutagenicity and antitumor effects due to the abundance of acylated anthocyanins. However, the effect and underlying mechanism of PSPA effects in acute lymphoblastic leukemia (ALL), especially T-cell acute lymphoblastic leukemia (T-ALL), remain unclear. In this study, the antileukemic effects of PSPAs and the underlying molecular mechanisms were evaluated by in vitro and in silico assays. PSPAs extracted from ten cultivars were analyzed and quantified. Anthocyanins from Nanzi 018, which showed the best antileukemic effect, were selected to analyze the underlying mechanism. First, the PSPAs potently reduced cell viability and induced apoptosis. Additionally, the PSPAs sharply increased intracellular Ca2+ levels, which resulted in calcium overload in T-ALL cells. Furthermore, on the basis of bioinformatics analyses, we focused on an osmotically regulated transcription factor, NFAT5. Molecular docking preliminarily indicated that PSPA molecules bound and interacted with the NFAT5 protein. Western blot analyses confirmed that PSPAs elicited calcium overload by nonosmotic regulation of NFAT5/S100A4-S100A9 pathway activation. Moreover, pretreatment with a NFAT5 inducer confirmed that PSPAs targeted NFAT5 and affected p38/NF-κB/Bcl-2/Caspase-3 axis activation. This study demonstrates that PSPAs exert their antileukemic effects through calcicoptosis induction by targeting NFAT5.

Effects of intrathecal injection of ropivacaine on spinal cord in rats based on genomics. / åŸºäºŽåŸºå› ç»„å­¦æŽ¢è®¨éž˜å† æ³¨å°„ç½—å“Œå¡å› å¯¹å¤§é¼ è„Šé«“çš„å½±å“.

OBJECTIVES: There are clinical reports of nerve injury caused by ropivacaine. The mechanism for nerve injury induced by ropivacaine has not been fully clarified. This study aims to investigate the changes of pain threshold and L3 spinal cord genomics at 6 h and 24 h after intrathecal injection of 0.5% and 1.0% ropivacaine, and to explore the underlying mechanisms for nerve injury caused by ropivacaine. METHODS: A total of 30 male Sprague Dawley rats weighing 220-260 g were successfully implanted with microspinal catheter. The rats were randomly divided into 5 groups (each n=6): a control group (given saline), a ropivacaine group 1 and a ropivacaine group 2 (both given 1% ropivacaine), a ropivacaine group 3 and a ropivacaine group 4 (both given 0.5% ropivacaine). The rats received continuous intrathecal injection of corresponding drugs at 8.3 µL/h for 24 h via an implanted intrathecal catheter followed by 24 h-pause of injection for the ropivacaine group 2, the ropivacaine group 4 and the control group, 6 h-pause of injection for the ropivacaine group 1 and the ropivacaine group 3. For each group, the observation of behavioral change and the paw withdrawal mechanical threshold (PWMT) was conducted immediately after the injection and again after the pause of injection. After the PWMT observation, the rats were dissected to acquire L3 spinal cords. Illumina sequencing was applied to construct gene libraries. Then the statistical methods were used to find out differentially expressed genes between the groups. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway analysis were conducted for those genes. Real-time RT-PCR was used to determine different expressions of some of those genes. RESULTS: Compared with control group, the PWMT got higher in the ropivacaine group 1-4 and was positively correlated with concentration, negatively correlated with discontinuation duration. Compared with control group, the ropivacaine group 1 had 488 differentially expressed genes, of which 456 were up-regulated and 32 were down-regulated; the ropivacaine group 2 had 1 194 differentially expressed genes, of which 1 092 were up-regulated and 102 were down-regulated; the ropivacaine group 3 had 518 differentially expressed genes, of which 384 were up-regulated and 134 were down-regulated; and the ropivacaine group 4 had 68 differentially expressed genes, of which 46 were up-regulated and 22 were down-regulated. GO enrichment analysis and KEGG signaling pathway analysis showed that most of these differentially expressed genes were related to signaling pathways of inflammatory response. CONCLUSIONS: After intrathecal injection of 0.5% ropivacaine and 1.0% ropivacaine for 24 h, the differentially expressed genes in L3 spinal cord of rats are mainly related to signaling pathways of inflammatory response.

PR11-364P22.2/ATF3 protein interaction mediates IL-1ß-induced catabolic effects in cartilage tissue and chondrocytes.

Osteoarthritis (OA) is a degenerative joint disease which lacks effective medical treatment due to ill-defined molecular mechanisms underlying the pathology. Inflammation is a key factor that induces and aggravates OA. Therefore, the current study aims to explore roles of the dysregulated long non-coding RNAs in the pro-inflammatory cytokine IL-1ß-mediated catabolic effects in cartilage tissue and chondrocytes. We identified RP11-364P22.2 as dysregulated in OA patient-derived cartilage tissues and highly responsive to IL-1ß stimulus. RNA pull-down coupled with mass spectrometry demonstrated that RP11-364P22.2 physically binds to activating transcription factor 3 (ATF3) and thus increases the protein stability and facilitates its nuclear translocation. Loss- and gain-of-function assays indicated that the interaction between RP11-364P22.2 and ATF3 is indispensable for the detrimental effects of IL-1ß including growth inhibition, apoptosis induction as well as degradation of the key chondrocyte structural proteins of type II collage and Aggrecan and synthesis of the extracellular matrix-degrading enzyme MMP13 in chondrocytes. In vivo, depletion of the RP11-364P22.2 effector ATF3 drastically prevented OA development in the rats with surgical destabilization of the medial meniscus (DMM). These results highlight the important roles of lncRNAs in the pathogenesis of OA and indicate the RP11-364P22.2/ATF3 regulatory axis as a potential therapeutic target of inflammation-induced OA.

Histone Deacetylase 2-Mediated Epigenetic Regulation is Involved in the Early Isoflurane Exposure-Related Increase in Susceptibility to Anxiety-Like Behaviour Evoked by Chronic Variable Stress in Mice.

Increasing studies report that prolonged or multiple anaesthetic exposures early in life are associated with detrimental effects on brain function. Although studies have evaluated the detrimental effects on neurocognitive function, few have focused on long-term neuropsychiatric effects. In the present study, C57BL/6 mice received either three neonatal isoflurane exposures or control exposure. Starting on postnatal day 45, the mice were either exposed or not to a chronic variable stress (CVS) paradigm, and CVS-related neuropsychiatric performance was evaluated using a series of behavioural tests. The expression levels of histone 3 lysine 9 acetylation (acetyl-H3K9), brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein-binding protein, and histone deacetylases 1-4 in the amygdala were measured by immunoblotting or immunohistochemistry analysis. In mice with neonatal isoflurane exposure, the effects of sodium butyrate (NaB), a commonly used HDAC inhibitor, were examined on CVS-related behavioural and molecular alterations. The results showed that repeated neonatal isoflurane exposure did not affect innate depression-like and anxiety-like behaviours under non-stress conditions but facilitated the CVS-induced anxiety-like behavioural phenotype. Increased HDAC2 expression in the amygdala was associated with an increase in the CVS-induced repression of acetyl-H3K9 and BDNF expression and an enhanced CVS-evoked anxiety-like behavioural phenotype in mice neonatal isoflurane exposure. NaB significantly decreased the CVS-induced anxiety level by elevating acetyl-H3K9 and BDNF expression. These results suggested that early anaesthesia exposure facilitated chronic stress-induced neuropsychiatric outcomes, and the HDAC2-related epigenetic dysregulation of BDNF gene expression is involved in the underlying mechanism.

Association between the variability of cerebral oxygen saturation during cardiopulmonary bypass and delayed postoperative neurocognitive recovery in cardiac valve surgical patients: A pilot study.

AIMS OF THE STUDY: The association between regional cerebral oxygen saturation (rSO2) and postoperative cognitive decline is controversial. In this study, we investigated the association between the real variability of regional cerebral oxygen saturation during cardiopulmonary bypass (CPB) and postoperative delayed neurocognitive recovery in patients undergoing heart valve surgery. METHODS USED TO CONDUCT THE STUDY: A total of 71 patients who underwent cardiac valve surgery were enrolled in this study. Patients were assessed for cognitive function using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment Scale (MOCA) on the day before surgery and the 7th day after surgery. The real variability of regional cerebral oxygen saturation (rSO2), real variability of the brain bispectral index of EEG (BIS), real variability of mean arterial pressure (MAP) and body temperature were monitored during CPB. Patients were divided into two groups according to neural cognitive function scores to explore the relationship between postoperative delayed neurocognitive recovery and the real variability of cerebral oxygen saturation, BIS, MAP, and body temperature during CPB. RESULTS OF THE STUDY: Twenty-seven patients were diagnosed with postoperative delayed neurocognitive recovery. The occurrence of postoperative delayed neurocognitive recovery after surgery was closely related to the large variability of rSO2 during the rewarming phase of CPB (P < .05). Logistic analysis showed that preoperative arrhythmia, a lower level of serum albumin after surgery and greater rSO2 variability during the rewarming phase were risk factors for postoperative delayed neurocognitive recovery (P < .05). In this study, there was no correlation between postoperative delayed neurocognitive recovery and BIS, MAP or body temperature variability (P > .05). CONCLUSIONS DRAWN FROM THE STUDY AND CLINICAL IMPLICATIONS: The real variability of rSO2 during the CPB rewarming phase was related to postoperative delayed neurocognitive recovery in patients who underwent cardiac surgery.

Annexin A3 as a Marker Protein for Microglia in the Central Nervous System of Rats.

The parenchymal microglia possess different morphological characteristics in cerebral physiological and pathological conditions; thus, visualizing these cells is useful as a means of further investigating parenchymal microglial function. Annexin A3 (ANXA3) is expressed in microglia, but it is unknown whether it can be used as a marker protein for microglia and its physiological function. Here, we compared the distribution and morphology of parenchymal microglia labeled by ANXA3, cluster of differentiation 11b (CD11b), and ionized calcium-binding adaptor molecule 1 (Iba1) and measured the expression of ANXA3 in nonparenchymal macrophages (meningeal and perivascular macrophages). We also investigated the spatiotemporal expression of ANXA3, CD11b, and Iba1 in vivo and in vitro and the cellular function of ANXA3 in microglia. We demonstrated that ANXA3-positive cells were abundant and evenly distributed throughout the whole brain tissue and spinal cord of adult rats. The morphology and distribution of ANXA3-labeled microglia were quite similar to those labeled by the microglial-specific markers CD11b and Iba1 in the central nervous system (CNS). ANXA3 was expressed in the cytoplasm of microglia, and its expression was significantly increased in activated microglia. ANXA3 was almost undetectable in the nonparenchymal macrophages. Meanwhile, the protein and mRNA expression levels of ANXA3 in different regions of the CNS were different from those of CD11b and Iba1. Moreover, knockdown of ANXA3 inhibited the proliferation and migration of microglia, while overexpression of ANXA3 enhanced these activities. This study confirms that ANXA3 may be a novel marker for parenchymal microglia in the CNS of adult rats and enriches our understanding of ANXA3 from expression patterns to physiological function.

Targeting aurora kinase B alleviates spinal microgliosis and neuropathic pain in a rat model of peripheral nerve injury.

Peripheral nerve injury elicits spinal microgliosis, contributing to neuropathic pain. The aurora kinases A (AURKA), B (AURKB), and C (AURKC) are potential therapeutic targets in proliferating cells. However, their role has not been clarified in microglia. The aim of this study was to examine the regulation of aurora kinases and their roles and druggability in spinal microgliosis and neuropathic pain. Sprague-Dawley rats received chronic constriction injury (CCI). Gene expression of aurora kinases A-C was evaluated by quantitative RT-PCR and western blot, respectively, in spinal cords at 1, 3, 7, and 14 days after CCI. AURKB gene and protein expression was up-regulated concomitantly with the development of spinal microgliosis and neuropathic pain. Using lentiviral over-expression and adeno-associated viral knockdown approaches, the function of AURKB was further investigated by western blot, immunohistochemistry, RNA sequencing, and pain behavior tests. We found that AURKB over-expression in naive rats caused spinal microgliosis and pain hypersensitivity, whereas AURKB knockdown reduced microgliosis and alleviated CCI-induced neuropathic pain. Accordingly, RNA sequencing data revealed down-regulation of genes critically involved in signaling pathways associated with spinal microgliosis and neuropathic pain after AURKB knockdown in CCI rats. To examine its therapeutic potential for treatment of neuropathic pain, animals were treated intrathecally with the pharmacological AURKB inhibitor AZD1152-HQPA resulting in the alleviation of CCI-induced pain. Taken together, our findings indicated that AURKB plays a critical role in spinal microgliosis and neuropathic pain. Targeting AURKB may be an efficient method for treatment of neuropathic pain subsequent to peripheral nerve injury.

Intubation and Ventilation amid the COVID-19 Outbreak: Wuhan's Experience.

The COVID-19 outbreak has led to 80,409 diagnosed cases and 3,012 deaths in mainland China based on the data released on March 4, 2020. Approximately 3.2% of patients with COVID-19 required intubation and invasive ventilation at some point in the disease course. Providing best practices regarding intubation and ventilation for an overwhelming number of patients with COVID-19 amid an enhanced risk of cross-infection is a daunting undertaking. The authors presented the experience of caring for the critically ill patients with COVID-19 in Wuhan. It is extremely important to follow strict self-protection precautions. Timely, but not premature, intubation is crucial to counter a progressively enlarging oxygen debt despite high-flow oxygen therapy and bilevel positive airway pressure ventilation. Thorough preparation, satisfactory preoxygenation, modified rapid sequence induction, and rapid intubation using a video laryngoscope are widely used intubation strategies in Wuhan. Lung-protective ventilation, prone position ventilation, and adequate sedation and analgesia are essential components of ventilation management.

Effects of a Preoperative Carbohydrate-Rich Drink Before Ambulatory Surgery: A Randomized Controlled, Double-Blinded Study.

BACKGROUND The guidelines recommend oral carbohydrates up to 2 hr before elective surgery. The objective of this study was to explore the safety and feasibility of preoperative carbohydrate drink in patients undergoing ambulatory surgery. MATERIAL AND METHODS Patients undergoing ambulatory surgery under general anesthesia were enrolled. They were fasted from midnight and randomly assigned to a study group (200 mL of a carbohydrate beverage) or the control group (pure water) and received the assigned drink 2 hr before surgery. Bedside ultrasonography was performed to monitor gastric emptying at T0 (before liquid intake), T1 (5 min after intake), T2 (1 hr after intake), and T3 (2 hr after intake). Subjective feelings of thirst, hunger, anxiety, and fatigue were assessed 1 hr after liquid intake using the visual analogue scale (VAS). RESULTS In both groups, gastric antrum cross-sectional area, gastric content volume, and weight-corrected gastric content volume increased at T1 and returned to baseline at T3. These parameters were significantly higher in the study group at T2 (6.28±1.38 vs. 4.98±0.78, 67.22±29.49 vs. 49.04±15.4, 1.10±0.51 vs. 0.85±0.37, P<0.05). Thirst and hunger VAS scores were reduced in both groups. The study group suffered significantly less hunger (28.44±10.41 vs. 36.03±14.42, P<0.05). Blood electrolytes (sodium, potassium, calcium) and glucose concentration levels were similar in both groups at T2. No gastric regurgitation or pulmonary aspiration was recorded. CONCLUSIONS Administration of 200 mL of oral carbohydrate beverage 2 hr before ambulatory surgery is safe, effective, and can be used for preoperative management of fasting patients.