Lidocaine induces neurotoxicity in spinal cord neurons in Goto-Kakizaki rats via AMPK-mediated mitophagy.

OBJECTIVE: Lidocaine has been reported to induce neurotoxicity, which is further enhanced by high glucose levels. This study is aimed to explore the underlying mechanisms of lidocaine neurotoxicity in spinal cord neurons of diabetes. METHODS: Take thirty specific pathogen-free (SPF) healthy Sprague-Dawley (SD) rats and thirty Goto-Kakizaki (GK) rats, aged 12 weeks, weighing 180-200 g. The spinal cord neurons of rats were isolated and cultured in vitro. Cell Counting Kit-8 was used to detect cell proliferation to determine the appropriate concentration and duration of lidocaine. Mitochondrial function was assessed using ATP content, cellular oxygen consumption rate, mitochondrial membrane potential, ROS production, and mitochondrial ultrastructure. Western blot was applied to detect the expression of autophagy- and mitophagy-related molecules PINK1, p-AMPK, LC-3II/LC3-I ratio and mTORC1. Immunofluorescent staining was used to detect the expression of PINK1 and LC3. RESULTS: Lidocaine decreased cell viability of spinal cord neurons in concentration- and time-dependent manners. And lidocaine treatment aggravated mitochondrial dysfunction in GK rats. Furthermore, mitophagy was activated in diabetes, and lidocaine exposure up-regulated mitophagy. AMPK activator MK8722 aggravated mitochondrial damage, increased the expression of PINK1, p-AMPK, LC-3II/LC3-I ratio, and decreased the expression of mTORC1, while AMPK inhibitor Compound C and autophagy inhibitor Bafilomycin A1 reduced mitochondrial damage and decreased the expression of PINK1, p-AMPK, LC-3II/LC3-I ratio, and increased the expression of mTORC1. CONCLUSIONS: Lidocaine induced neurotoxicity of spinal cord neurons in GK rats via AMPK-mediated mitophagy.

Ropivacaine suppresses the progression of renal cell carcinoma through regulating the lncRNA RMRP/EZH2/CCDC65 axis.

BACKGROUND: Renal cell carcinoma (RCC) is a common malignancy. Local anesthetics were displayed powerful effects against various cancers. This study aims to probe the functions and molecular mechanism of ropivacaine in RCC. METHODS: Different concentrations of ropivacaine were performed to administrate RCC cells including 786-O and Caki-1 cells. Cell viability and cell apoptosis were examined using CCK-8 and flow cytometry, respectively. Cell migration and invasion were determined by transwell assay. RMRP and CCDC65 expression was firstly predicted using TCGA dataset and further validated in RCC cells using qRT-PCR and western blot. The interactions among RMRP, EZH2 and CCDC65 were verified by RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays. RESULTS: Ropivacaine effectively suppressed RCC cell viability, migration and invasion and enhanced cell apoptosis rate. Aberrantly elevated RMRP expression in RCC tissues was predicted by TCGA database. Interestingly, overexpressed RMRP observed in RCC cells could be also blocked upon the administration of ropivacaine. Likewise, RMRP knockdown further strengthened ropivacaine-mediated tumor suppressive effects on RCC cells. In terms of mechanism, RMRP directly interacted with EZH2, thereby modulating the histone methylation of CCDC65 to silence its expression. Moreover, ropivacaine inhibited tumor growth in mice bearing RCC tumor through regulating RMRP/EZH2/CCDC65 axis. CONCLUSION: In sum up, our work revealed that ropivacaine suppressed capacities of RCC cell viability, migration and invasion through modulating the RMRP/EZH2/CCDC65 axis, which laid the experimental foundation of ropivacaine for clinical application in the future.

Influence by varying organic matter content and forms in suspended particulate matter: impacts on the adsorption of tetracycline and norfloxacin.

Antibiotics are commonly detected in natural waters. The organic matter (OM) in suspended particulate matter (SPM) has a critical impact on the adsorption of antibiotics in water. We investigated the contribution of OM content and form to the adsorption of tetracycline (TC) and norfloxacin (NOR) in the SPM of Taihu Lake. To change the content and form of OM in SPM, the samples were subjected to pyrolysis at 505 ˚C and oxidization with H2O2, respectively. Combustion almost completely removed OM, while oxidation removed most of the OM and transformed the remaining OM. Regardless of whether the OM changed or not, the adsorption of NOR and TC by SPM was more in line with the pseudo-second-order kinetic model instead of pseudo-first-order. The fitting of the intraparticle diffusion model showed that the removal of OM had a certain degree of change in the adsorption process. The isothermal adsorption of TC in all samples was more in line with the Temkin model. The isothermal adsorption of NOR in the oxidized sample conformed to the Temkin model, while it conformed to the Langmuir model in the original sample and the sample removed OM via combustion. The adsorption capacity of SPM with almost complete removal of OM significantly decreased, while conversely, the adsorption capacity of SPM after oxidation increased. This indicates that both the content and form of OM affect the adsorption of antibiotics by SPM, and the form of OM has a greater impact. The contribution of OM to NOR adsorption was greater than that of TC. In conclusion, the results verify the importance of OM in adsorbing antibiotics onto SPM, which may provide basic data for antibiotic migration in surface water.

Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors.

Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.

Construction of a risk prediction model for non-variceal upper gastrointestinal bleeding and rebleeding based on multi-dimensional indicators and its application research.

OBJECTIVE: To construct a predictive model for the risk of rebleeding in non-variceal upper gastrointestinal bleeding (NVUGIB) based on multidimensional indicators to provide an assessment tool for early screening of rebleeding in NVUGIB. METHODS: Retrospective analysis of the 3-month follow-up data of 85 patients with NVUGIB diagnosed at the Fifth Hospital of Wuhan from January 2019 to December 2021 who were discharged from the hospital after medical treatment. Patients were divided into a rebleeding group (n=45) and a non-rebleeding group (n=95) based on whether they rebleed during follow-up. The demographic characteristics, clinical characteristics and biochemical indicators of the two groups were compared. A multivariate logistic regression was used to analyze the influencing factors of NVUGIB rebleeding. A nomograph model was built using the screening results. The area under the working characteristic curve of the subject (AUC) was used to analyze the model differentiation, evaluate the model specificity and sensitivity, and verify the prediction performance of the model with the validation set. RESULTS: There were significant differences in age, hematemesis, red blood cell count (RBC), platelet (PLT), albumin (Alb), prothrombin time (PT), TT, fibrinogen (Fib), plasma D-dimer (D-D), and blood lactate (LAC) levels between the two groups (all P<0.05). Logistic regression analysis shows that, age ≥75, hematemesis more than 5 times, PLT≤100*109/L, D-D>0.5 mg/L were associated with greater risk of rebleeding. The nomogram model was constructed based on the above four indicators. The AUC of the training set (n=98) for predicting the risk of NVUGIB rebleeding was 0.887 (95% CI: 0.812-0.962), the specificity was 0.882, and the sensitivity was 0.833. The AUC of the validation set (n=42) was 0.881 (95% CI: 0.777-0.986), the specificity was 0.815, and the sensitivity was 0.867. After 500 times of sampling by bootstrap method, the mean absolute error of the calibration curve of the validation set model was 0.031, indicating that the calibration curve and the ideal curve fit well, and the predicted value of the model was in good agreement with the actual value. CONCLUSION: Age ≥75, hematemesis >5 times, lower PLT, and higher D-D levels rise the risk of rebleeding in NVUGIB patients and have some reference value in clinical diagnosis and disease assessment.

Diagnostic significance of microRNAs in sepsis.

BACKGROUND: Sepsis is a life-threatening condition that induce tens of million death each year, yet early diagnosis remains a formidable challenge. Many studies have focused on the diagnostic accuracy of microRNAs (miRNAs) for sepsis in recent years, particularly miR-155-5p, miR-21, miR-223-3p, miR-146a, and miR-125a. Thus, we conducted this meta-analysis to explore if miRNAs may be used as a biomarker for sepsis detection. METHODS: We searched PubMed, the Cochrane Central Register of Controlled Trials, EMBASE, and China National Knowledge Infrastructure through May 12, 2022. This meta-analysis was conducted using Meta-disc 1.4 and STATA 15.1 in a fixed/random-effect model. RESULTS: The analysis included a total of 50 relevant studies. The overall performance of total miRNAs detection was: pooled sensitivity, 0.76 (95% confidence interval [CI], 0.75 to 0.77); pooled specificity, 0.77 (95%CI, 0.75 to 0.78); and area under the summary receiver operating characteristic curves value (SROC), 0.86. The subgroup analysis suggested that detection in miR-155-5p group had the highest area under the curve (AUC) of SROC among all miRNAs: pooled sensitivity, 0.71 (95%CI, 0.67 to 0.75); pooled specificity, 0.82 (95%CI, 0.76 to 0.86); and SROC, 0.85. MiR-21, miR-223-3p, miR-146a, and miR-125a had SROC values of 0.67, 0.78, 0.69, and 0.74, respectively. The specimen type was found to be a source of heterogeneity in the meta-regression study. The SROC of serum was higher than that of plasma (0.87 and 0.83, respectively). CONCLUSIONS: Our meta-analysis revealed that miRNAs, specifically miR-155-5p, could be useful biomarkers for detecting sepsis. A clinical serum specimen is also indicated for diagnostic purposes.

Metal-free photosensitized intermolecular carboimination of alkenes: a green and direct access to both ß-amino acids and ß-amino ketones.

ß-Amino carbonyl substructures are privileged motifs in natural products and active pharmaceutical compounds. Here, we report a photoinduced metal-free and highly regioselective intermolecular carboimination method via the simultaneous introduction of amino and carbonyl groups into the CC double bond in one step, providing straightforward, green and general access to both ß-amino acid and ß-amino ketone motifs from readily available alkene feedstocks. The mild reaction conditions, excellent functional group tolerance and product diversity should make this a broadly applicable carboimination approach of very broad interest to organic and medicinal chemists.

Effects of florfenicol on methane accumulation and changes in the structure of the prokaryotic community in a water-sediment system.

Florfenicol has been widely used in the veterinary and aquaculture to control bacterial diseases because of its high efficacy, quick effect, and low cost. The water-sediment system has become an important sink for florfenicol, and the anaerobic environment of lake sediments is favorable for methane (CH4) production. Although antibiotics may impact methanogenesis under anaerobic conditions, the influence of florfenicol on CH4 accumulation in anaerobic water-sediment system remains uncertain. This study evaluated how florfenicol affects CH4 accumulation and the structure of the prokaryotic community in a water-sediment system. Anaerobic systems with different florfenicol concentrations (0, 0.2, 1, 5 and 10 mg/L) were incubated and CH4 accumulation, pH, total organic carbon content, degradation ratio of florfenicol, and structure of the prokaryotic community were monitored. It was found that CH4 accumulation raised in low florfenicol (0.2 and 1 mg/L) systems during the growth period, while CH4 accumulation declined in high florfenicol (5 and 10 mg/L) systems. In the first 13 d, 83.67-99.30 % of florfenicol degraded in different treatments. The addition of florfenicol also influenced the structure of the prokaryotic community of the sediments. Proteobacteria and Chloroflexi were dominant at the phylum level. The dominant taxa at the order level gradually changed from Methanomicrobiales to Methanobacteriales, and finally to Methanosarcinales, indicating the dynamic transformation of methanogens in the reactor. This study reveals the effects of florfenicol on CH4 production under anaerobic conditions and provides a theoretical basis for further research on the underlying mechanisms. The findings also provide some basic data on the impact of new pollutants on the global carbon cycle and greenhouse gas emission.

Mechanotransduction Regulates the Interplays Between Alveolar Epithelial and Vascular Endothelial Cells in Lung.

Mechanical stress plays a critical role among development, functional maturation, and pathogenesis of pulmonary tissues, especially for the alveolar epithelial cells and vascular endothelial cells located in the microenvironment established with vascular network and bronchial-alveolar network. Alveolar epithelial cells are mainly loaded by cyclic strain and air pressure tension. While vascular endothelial cells are exposed to shear stress and cyclic strain. Currently, the emerging evidences demonstrated that non-physiological mechanical forces would lead to several pulmonary diseases, including pulmonary hypertension, fibrosis, and ventilation induced lung injury. Furthermore, a series of intracellular signaling had been identified to be involved in mechanotransduction and participated in regulating the physiological homeostasis and pathophysiological process. Besides, the communications between alveolar epithelium and vascular endothelium under non-physiological stress contribute to the remodeling of the pulmonary micro-environment in collaboration, including hypoxia induced injuries, endothelial permeability impairment, extracellular matrix stiffness elevation, metabolic alternation, and inflammation activation. In this review, we aim to summarize the current understandings of mechanotransduction on the relation between mechanical forces acting on the lung and biological response in mechanical overloading related diseases. We also would like to emphasize the interplays between alveolar epithelium and vascular endothelium, providing new insights into pulmonary diseases pathogenesis, and potential targets for therapy.

Value of D-dimer in predicting various clinical outcomes following community-acquired pneumonia: A network meta-analysis.

BACKGROUND: Whether high D-dimer level before treatment has any impact on poor outcomes in patients with community-associated pneumonia (CAP) remains unclear. Therefore, we conducted the first meta-analysis focusing specifically on prognostic value of high D-dimer level before treatment in CAP patients. METHODS: Pubmed, Embase, the Cochrane Central Register of Controlled Trials and World Health Organization clinical trials registry center were searched up to the end of March 2021. Randomized clinical trials (RCT) and observational studies were included to demonstrate the association between the level of D-dimer and clinical outcomes. Data were extracted using an adaptation of the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS-PF). When feasible, meta-analysis using random-effects models was performed. Risk of bias and level of evidence were assessed with the Quality in Prognosis Studies tool and an adaptation of Grading of Recommendations Assessment, Development, and Evaluation. Data were analyzed using STATA 14.0 to complete meta and network analysis. MAIN OUTCOMES AND MEASURES: Besides d-dimer levels in CAP patients with poor outcomes, we also analyzed proportion of patients with or without poor outcomes correctly classified by the d-dimer levels as being at high or low risk. The poor outcome includes severe CAP, death, pulmonary embolism (PE) and invasive mechanical ventilators. RESULTS: 32 studies with a total of 9,593 patients were eventually included. Pooled effect size (ES) suggested that d-dimer level was significantly higher in severe CAP patients than non-severe CAP patients with great heterogeneity (SMD = 1.21 95%CI 0.87-1.56, I2 = 86.8% p = 0.000). D-dimer level was significantly elevated in non-survivors compared to survivors with CAP (SMD = 1.22 95%CI 0.67-1.77, I2 = 85.1% p = 0.000). Prognostic value of d-dimer for pulmonary embolism (PE) was proved by hierarchical summary receiver operating characteristic curve (HSROC) with good summary sensitivity (0.74, 95%CI, 0.50-0.89) and summary specificity (0.82, 95%CI, 0.41-0.97). Network meta-analysis suggested that there was a significant elevation of d-dimer levels in CAP patients with poor outcome than general CAP patients but d-dimer levels weren't significantly different among poor outcomes. CONCLUSION: The prognostic ability of d-dimer among patients with CAP appeared to be good at correctly identifying high-risk populations of poor outcomes, suggesting potential for clinical utility in patients with CAP.

Association Between the Circulating Level of 25-Hydroxyvitamin D and Clinical Results After Cardiac Surgery: A Meta-Analysis and Systematic Review.

Background: Vitamin D (VitD) is an important pleiotropic hormone for organ systems. Studies have focused on the level of VitD, especially that of 25-hydroxyvitamin D (25-(OH)-VitD), in patients after cardiac surgery and the relationship between VitD deficiency and adverse outcomes, but the results have been inconsistent. We carried out a meta-analysis to evaluate differences in the 25-(OH)-VitD level before and after cardiac surgery, and evaluated the predictive value of 25-(OH)-VitD level in the clinical outcomes of patients undergoing cardiac surgery. Methods: Studies related to VitD level and cardiac surgery were searched from PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases from inception to October 2020. We applied the Newcastle-Ottawa Scale to assess the risk of a bias in individual studies. We examined the heterogeneity and publication bias and performed subgroup analyses and sensitivity analyses. Results: Fifteen studies were included in our analysis. The 25-(OH)-VitD level was significantly lower immediately after surgery [stand mean difference (SMD), 0.69; 95%CI (0.1, 1.28), P = 0.023] and 24-h after surgery [0.84; (0.47, 1.21), 0.000] compared with that before surgery. A higher prevalence of 25-(OH)-VitD deficiency was recorded 24 h after surgery [RR, 0.59; 95%CI (0.47, 0.73), P = 0.00]. Pooled results demonstrated a significant relationship between the preoperative 25-(OH)-VitD level and vasoactive-inotropic score (VIS) [SMD, -3.71; 95%CI (-6.32, -1.10); P = 0.005], and patients with 25-(OH)-VitD deficiency revealed a comparatively poor prognosis and severe condition after cardiac surgery [-0.80; (-1.41, -0.19), 0.01]. However, 25-(OH)-VitD deficiency was not associated with the duration of stay in the intensive care unit. Conclusions: Cardiac surgery would leads to deficiency of 25-(OH)-VitD. And the preoperative and postoperative levels of 25-(OH)-VitD are associated with adverse events, which is eligible to work as an indicator to demonstrate clinical outcomes.

Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs.

Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.

Protective efficient comparisons among all kinds of respirators and masks for health-care workers against respiratory viruses: A PRISMA-compliant network meta-analysis.

BACKGROUND: There is no definite conclusion about comparison of better effectiveness between N95 respirators and medical masks in preventing health-care workers (HCWs) from respiratory infectious diseases, so that conflicting results and recommendations regarding the protective effects may cause difficulties for selection and compliance of respiratory personal protective equipment use for HCWs, especially facing with pandemics of corona virus disease 2019. METHODS: We systematically searched MEDLINE, Embase, PubMed, China National Knowledge Infrastructure, Wanfang, medRxiv, and Google Scholar from initiation to November 10, 2020 for randomized controlled trials, case-control studies, cohort studies, and cross-sectional studies that reported protective effects of masks or respirators for HCWs against respiratory infectious diseases. We gathered data and pooled differences in protective effects according to different types of masks, pathogens, occupations, concurrent measures, and clinical settings. The study protocol is registered with PROSPERO (registration number: 42020173279). RESULTS: We identified 4165 articles, reviewed the full text of 66 articles selected by abstracts. Six randomized clinical trials and 26 observational studies were included finally. By 2 separate conventional meta-analyses of randomized clinical trials of common respiratory viruses and observational studies of pandemic H1N1, pooled effects show no significant difference between N95 respirators and medical masks against common respiratory viruses for laboratory-confirmed respiratory virus infection (risk ratio 0.99, 95% confidence interval [CI] 0.86-1.13, I2 = 0.0%), clinical respiratory illness (risk ratio 0.89, 95% CI 0.45-1.09, I2 = 83.7%, P = .002), influenza-like illness (risk ratio 0.75, 95% CI 0.54-1.05, I2 = 0.0%), and pandemic H1N1 for laboratory-confirmed respiratory virus infection (odds ratio 0.92, 95% CI 0.49-1.70, I2 = 0.0%, P = .967). But by network meta-analysis, N95 respirators has a significantly stronger protection for HCWs from betacoronaviruses of severe acute respiratory syndrome, middle east respiratory syndrome, and corona virus disease 2019 (odds ratio 0.43, 95% CI 0.20-0.94). CONCLUSIONS: Our results provide moderate and very-low quality evidence of no significant difference between N95 respirators and medical masks for common respiratory viruses and pandemic H1N1, respectively. And we found low quality evidence that N95 respirators had a stronger protective effectiveness for HCWs against betacoronaviruses causative diseases compared to medical masks. The evidence of comparison between N95 respirators and medical masks for corona virus disease 2019 is open to question and needs further study.

Is there an association between intravenous immunoglobulin resistance and coronary artery lesion in Kawasaki disease?-Current evidence based on a meta-analysis.

BACKGROUND: Coronary artery lesion (CAL) caused by Kawasaki disease (KD) is a leading cause of acquired heart disease in children. Initial treatment of intravenous immunoglobulin (IVIG) can reduce the incidence of CAL. Although most of the current studies have shown a certain correlation between CAL and IVIG resistance, the conclusions are not completely consistent. Thus, we performed this meta-analysis to evaluate the association between IVIG resistance and CAL in KD. METHODS: PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure through April 21, 2020 were searched to detect relevant studies. Data analysis was performed with STATA 15.1. RESULTS: A total of 53 relevant studies were eligible to this analysis, including 30312 KD patients, of which 4750 were IVIG resistance and 25562 were responders. There was a significant difference found between IVIG resistance and IVIG response groups in the incidence of CAL (P < 0.001, odds ratio (OR), 3.89; 95% confidence interval (CI) (3.18, 4.75)). The heterogeneity test results showed that the I2 value was 74.8%. The meta-regression analysis showed that the study regions might be the sources of heterogeneity. The subgroup analysis suggested that the incidence of CAL in the IVIG resistance group was still higher than that in the IVIG response group under different regions, IVIG resistance diagnostic criteria, CAL diagnostic criteria, and study types. Meanwhile, the sensitivity analysis did not find any significant impact from every single study. CONCLUSIONS: This is the first meta-analysis to reveal the incidence of CAL was associated with IVIG resistance in KD patients. Further well-designed studies with uniform criteria are needed to evaluate the incidence of CAL in IVIG resistant patients.

Synthesis, biological evaluation, and structure-activity relationships of new tubulin polymerization inhibitors based on 5-amino-1,2,4-triazole scaffold.

Based on our previous research, thirty new 5-amino-1H-1,2,4-triazoles possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities. Among them, compounds IIa, IIIh, and IIIm demonstrated significant antiproliferative activities against a panel of tumor cell lines, and the promising compound IIIm dose-dependently caused G2/M phase arrest in HeLa cells. Furthermore, analogue IIa exhibited the most potent tubulinpolymerization inhibitory activity with an IC50 value of 9.4 µM, and molecular modeling studies revealed that IIa formed stable interactions in the colchicine-binding site of tubulin, suggesting that 5-amino-1H-1,2,4-triazole scaffold has potential for further investigation to develop novel tubulin polymerization inhibitors with anticancer activity.

Diagnostic significance of circulating miRNAs in Kawasaki disease in China: Current evidence based on a meta-analysis.

BACKGROUND: There is no golden standard for the diagnosis of Kawasaki disease (KD), the most common cause of acquired heart disease in children in many countries. In recent years, many studies have focused on the relationship between microRNAs (miRNAs) and KD. Thus, we perform this meta-analysis to understand the role of circulating miRNAs as a biomarker to detect KD. METHODS: We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure through March 10, 2019. Meta-disc 1.4 and STATA 15.1 (Stata Corporation, College Station, TX) were used to conduct the meta-analysis. RESULTS: Six eligible articles were included in this meta-analysis. The overall performance of total mixed miRNAs detection was: pooled sensitivity, 0.7 (95% confidence interval, 0.66-0.74); pooled specificity, 0.87 (95% confidence interval, 0.83-0.90); and area under the summary receiver operating characteristic curves value (SROC), 0.8302. The meta-regression analysis indicated that the specimen types, the composition of the control group, and types of the reference miRNA were not responsible for the existing heterogeneities. The subgroup analysis showed that SROC of the plasma group (0.8890) was more significant than the serum group (0.7204), and SROC of the non-healthy control group (0.9622) was more significant than the healthy control group (0.8096). CONCLUSIONS: : This is the first meta-analysis show that miRNAs may be used as novel biomarkers for detecting KD, especially for distinguishing KD from other febrile diseases. More studies are needed in the future to clarify the association between KD and miRNAs. PROSPERO REGISTRATION NUMBER: CRD42019129976.

Attenuation of Cardiomyocyte Hypertrophy via Depletion Myh7 using CASAAV.

Myh7 is a classic biomarker for cardiac remodeling and a potential target to attenuate cardiomyocyte (CM) hypertrophy. This study aimed to identify the dominant function of Myh7 after birth and determine whether its removal would affect CM maturation or contribute to reversal of pathological hypertrophy phenotypes. The CASAAV (CRISPR/Cas9-AAV9-based somatic mutagenesis) technique was used to deplete Myh6 and Myh7, and an AAV dosage of 5 × 109 vg/g was used to generate a mosaic CM depletion model to explore the function of Myh7 in adulthood. CM hypertrophy was induced by transverse aortic constriction (TAC) in Rosa26Cas9-P2A-GFP mice at postnatal day 28 (PND28). Heart function was measured by echocardiography. Isolated CMs and in situ imaging were used to analyze the structure and morphology of CM. We discovered that CASAAV successfully silenced Myh6 and Myh7 in CMs, and early depletion of Myh7 led to mild adulthood lethality. However, the Myh7 PND28-knockout mice had normal heart phenotype and function, with normal cellular size and normal organization of sarcomeres and T-tubules. The TAC mice also received AAV-Myh7-Cre to produce Myh7-knockout CMs, which were also of normal size, and echocardiography demonstrated a reversal of cardiac hypertrophy. In conclusion, Myh7 has a role during the maturation period but rarely functions in adulthood. Thus, the therapeutic time should exceed the period of maturation. These results confirm Myh7 as a potential therapeutic target and indicate that its inhibition could help reverse CM hypertrophy.

Preventing oxaliplatin-induced neuropathic pain: Using berberine to inhibit the activation of NF-κB and release of pro-inflammatory cytokines in dorsal root ganglions in rats.

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a serious, undesirable effect of cancer treatment which is particularly difficult to prevent. Berberine and its derivatives have been reported to display robust antioxidant and analgesic effects in rat models of diabetic neuropathic pain and peripheral nerve injury. However, the analgesic role of berberine on oxaliplatin-induced CIPNP remains unknown. The present study aimed to explore the analgesic effect of berberine on CIPNP. Sprague Dawley rats were used to create the CIPNP animal model by oxaliplatin administration. Behavioral tests were performed by von Frey test, acetone drop test, hot plate test, and motor coordination. The protein expression levels of NF-κB p65 and phosphorylated p65 in dorsal root ganglions (DGRs) were detected by western blot analysis. Finally, TNF-α and IL-6 levels in DRGs were measured using specific ELISA kits. The results from the behavioral analysis demonstrated that a single injection of berberine ameliorated the mechanical and cold allodynia and thermal hyperalgesia in the model rats in a dose-dependent manner. Cumulative administration of berberine prevented the mechanical and cold allodynia and thermal hyperalgesia in the development of CIPNP induced by oxaliplatin. This prophylactic effect of berberine was associated with reduced phosphorylation of p65 and with decreased levels of pro-inflammatory cytokines IL-6 and TNF-α. The present study indicated that berberine may have a role in preventing the development of CIPNP and may serve as a therapeutic compound for the treatment of CIPNP.

Thrombocytopenia associated with transcatheter closure of giant patent ductus arteriosus.

INTRODUCTION: Thrombocytopenia occasionally occurs following the closure of some giant patent ductus arteriosus cases. Unfortunately, there is no associated research describing the associated risk factors for thrombocytopenia post-procedure. METHODS: We reviewed all patients who received occluders with sizes ≥10/12 mm between January 2013 and June 2019. All the data and information on the characteristics of the patients and their follow-up were recorded. Univariate analysis, receiver operating characteristic curves, and linear regression were used to analyse the risk factors for thrombocytopenia and the predictors of hospitalisation stay. RESULTS: Finally, 32 patients (17.5%) suffered from thrombocytopenia. Univariate analysis revealed the ratio between occluder disc size (mm) and body weight (kg) (1.71 ± 0.51 versus 1.35 ± 0.53) as an independent predictive factor for thrombocytopenia, and the area under the curve of the ratio of occluder size and body weight for predicting thrombocytopenia post-closure was 0.691 (95% confidence interval: 0.589-0.792, p = 0.001). The best cut-off value for the ratio of occluder size and weight was 1.5895, with a sensitivity and specificity of 68.8 and 66.9%, respectively. Each unit of the ratio of occluder size and body weight predicted an average hospitalisation stay of 2.856 days (95% confidence interval: 1.380-4.332). Treatment with medication did not reduce the hospitalisation stay or benefit platelet restoration. CONCLUSION: Once the ratio of occluder size and body weight is greater than 1.6, thrombocytopenia always exists. Every unit of the ratio of occluder size and body weight represents an additional 3 days of hospitalisation. Treatment does not reduce the duration of hospitalisation.