Neonatal IL-4 Over-Exposure is Accompanied by Macrophage Accumulation in Dura Mater After Instant Anti-inflammatory Cytokine Response in CSF.

Multiple studies have shown that clinical events resulting into neonatal IL-4 over-exposure, such as asthma in early life and food allergy, were associated with brain damage and that the neuroinflammation induced by them might lead to cognitive impairments, anxiety-/depressive-like behaviors. IL-4 is the most major elevated cytokine in periphery when these clinical events occur and peripheral IL-4 level positively correlates with the severity of those events. Our previous studies have verified that neonatal IL-4 over-exposure induced a delayed neuroinflammatory damage in rodents, which might have adverse implications for brain development and cognition. Neuroinflammation in brain parenchyma is often accompanied by changes in CSF cytokines levels. However, whether the cytokines levels in CSF change after neonatal IL-4 over-exposure is unknown. Here, we found a delayed pro-inflammatory cytokines response (higher IL-6, IL-1ß and, TNF levels) in both hippocampus and CSF after an instant anti-inflammatory cytokine response in IL-4 over-exposed rats. Moreover, the pro-inflammatory cytokines response appeared earlier in CSF than in hippocampus. The level of each of the pro-inflammatory cytokines in CSF positively correlated with that in hippocampus at the age of postnatal day 42. More microglia numbers/activation and higher M-CSF level in the hippocampus in IL-4 over-exposed rats were also observed. Furthermore, there were more macrophages with inflammatory activation in dural mater of IL-4 over-exposed rats. In sum, neonatal IL-4 over-exposure in rats induces delayed inflammation in CSF, suggesting CSF examination may serve as a potential method in predicting delayed neuroinflammation in brain following neonatal IL-4 over-exposure.

Oral exposure to an acceptable daily intake dose of aspartame induced a delayed proinflammatory cytokine response in the cerebrospinal fluid of rats.

This study aimed to investigate the effect of exposure to aspartame (ASP) at safe levels on proinflammatory cytokines in the cerebrospinal fluid (CSF) of rats. Sprague Dawley rats were sacrificed after 1, 2, 4 or 8 week(s) of continuous exposure to ASP (40 mg/kg body weight). Serum, CSF and brain tissue samples were prepared, and the levels of the IL-1ß, IL-6 and TNF-α were analyzed by ELISA. In serum, the levels of all three cytokines showed a two-phase alteration, a decrease followed by an increase in the ASP group. In the brain, their levels increased from the second or fourth week compared with the control group. In CSF, the levels of these cytokines showed a similar change to that in brain tissue, but the increase appeared at a later time point. For each cytokine, there was a significant positive correlation between its levels in serum, brain tissue and CSF. This is the first discovery that ASP exposure increased the levels of proinflammatory cytokines in CSF in rats, which emerged later than in blood and brain tissue. This study suggests the necessity of conducting related clinical studies to evaluate potential neuroinflammatory effects induced by chronic ASP exposure through CSF analysis.

MicroRNA-31 induced by Fusobacterium nucleatum infection promotes colorectal cancer tumorigenesis.

Persistent Fusobacterium nucleatum infection is associated with the development of human colorectal cancer (CRC) and promotes tumorigenicity, but the underlying mechanisms remain unclear. Here, we reported that F. nucleatum promoted the tumorigenicity of CRC, which was associated with F. nucleatum-induced microRNA-31 (miR-31) expression in CRC tissues and cells. F. nucleatum infection inhibited autophagic flux by miR-31 through inhibiting syntaxin-12 (STX12) and was associated with the increased intracellular survival of F. nucleatum. Overexpression of miR-31 in CRC cells promoted their tumorigenicity by targeting eukaryotic initiation factor 4F-binding protein 1/2 (eIF4EBP1/2), whereas miR-31 knockout mice were resistant to the formation of colorectal tumors. In conclusion, F. nucleatum, miR-31, and STX12 form a closed loop in the autophagy pathway, and continuous F. nucleatum-induced miR-31 expression promotes the tumorigenicity of CRC cells by targeting eIF4EBP1/2. These findings reveal miR-31 as a potential diagnostic biomarker and therapeutic target in CRC patients with F. nucleatum infection.

A Model of Long-Term Ventricular Fibrillation in Isolated Rat Hearts.

Ventricular fibrillation (VF) is a fatal arrhythmia with a high incidence in cardiac patients, but VF arrest under perfusion is a neglected method of intraoperative arrest in the field of cardiac surgery. With recent advances in cardiac surgery, the demand for prolonged VF studies under perfusion has increased. However, the field lacks simple, reliable, and reproducible animal models of chronic ventricular fibrillation. This protocol induces long-term VF through alternating current (AC) electrical stimulation of the epicardium. Different conditions were used to induce VF, including continuous stimulation with a low or high voltage to induce long-term VF and stimulation for 5 min with a low or high voltage to induce spontaneous long-term VF. The success rates of the different conditions, as well as the rates of myocardial injury and recovery of cardiac function, were compared. The results showed that continuous low-voltage stimulation induced long-term VF and that 5 min of low-voltage stimulation induced spontaneous long-term VF with mild myocardial injury and a high rate of recovery of cardiac function. However, the low-voltage, continuously stimulated long-term VF model had a higher success rate. High-voltage stimulation provided a higher rate of VF induction but showed a low defibrillation success rate, poor recovery of cardiac function, and severe myocardial injury. On the basis of these results, continuous low-voltage epicardial AC stimulation is recommended for its high success rate, stability, reliability, reproducibility, low impact on cardiac function, and mild myocardial injury.

Activated partial thromboplastin time as a potential biomarker for the diagnosis of tuberculous pleural effusion.

BACKGROUND: The aim of this study was to explore the difference in activated partial thromboplastin time (APTT) levels in patients with tuberculous and non-tuberculous pleural effusion (TPE and non-TPE) and its possible mechanism to provide a new direction for the diagnosis of pleural effusion (PE). METHODS: A total of 61 patients diagnosed with tuberculous pleurisy with pleural effusion at Shunde Hospital of Southern Medical University from July 2013 to September 2020 were selected as the observation group (tuberculosis group). Another 89 patients (45 with malignant pleural effusion (MPE) and 44 with parapneumonic pleural effusion (PPE) composed the control group. The adenosine deaminase (ADA) level in pleural fluid and plasma APTT level were measured in the two groups. RESULTS: The levels of APTT and ADA in the TPE group were significantly higher than the control group, and were 40.03 (37.00, 42.60) (s) and 55.00 (47.00, 69.25) (U/L) for TPE, 29.50 (25.45, 34.20) (s) and 11.90 (9.15, 19.05) (U/L) for malignant pleural effusion (MPE) and 31.35 (27.43, 35.76) (s) and 15.15 (7.40, 35.00) (U/L) for parapneumonic pleural effusion (PPE), respectively. CONCLUSIONS: The level of plasma APTT has certain significance in differentiating tuberculous pleural effusion from nontuberculous pleural effusion.

Fusobacterium nucleatum induces excess methyltransferase-like 3-mediated microRNA-4717-3p maturation to promote colorectal cancer cell proliferation.

Fusobacterium nucleatum infection plays vital roles in colorectal cancer (CRC) progression. Overexpression of microRNA-4717-3p (miR-4717) was reported to be upregulated in F. nucleatum positive CRC tissues, however, the underlying mechanism is unknown. In this study, we found that miR-4717 promoted CRC cell proliferation in vitro and growth of CRC in vivo following F. nucleatum infection. MicroRNA-4717 suppressed the expression of mitogen-activated protein kinase kinase 4 (MAP2K4), a tumor suppressor, by directly targeting its 3'-UTR. Furthermore, we confirmed that methyltransferase-like 3 (METTL3)-dependent m6 A methylation could methylate primary (pri)-miR-4717, which further promoted the maturation of pri-miR-4717, and METTL3 positively regulated CRC cell proliferation through miR-4717/MAP2K4 pathways. In conclusion, F. nucleatum-induced miR-4717 excessive maturation through METTL3-dependent m6 A modification promotes CRC cell proliferation, which provides a potential therapeutic target and diagnostic biomarker for CRC.

Long non-coding RNA EVADR induced by Fusobacterium nucleatum infection promotes colorectal cancer metastasis.

Both Fusobacterium nucleatum (F. nucleatum) and long non-coding RNA (lncRNA) EVADR are associated with colorectal cancer (CRC), but their relationship with CRC metastasis and the mechanisms by which EVADR promotes CRC metastasis are poorly understood. Here, we report that F. nucleatum promotes colorectal cancer cell metastasis to the liver and lung and that it can be detected in CRC-metastasis colonization in mouse models. Furthermore, F. nucleatum upregulates the expression of EVADR, which can increase the metastatic ability of CRC cells in vivo and in vitro. Mechanistically, elevated EVADR serves as a modular scaffold for the Y-box binding protein 1 (YBX1) to directly enhance the translation of epithelial-mesenchymal transition (EMT)-related factors, such as Snail, Slug, and Zeb1. These findings suggest that EVADR induced by F. nucleatum promotes colorectal cancer metastasis through YBX1-dependent translation. The EVADR-YBX1 axis may be useful for the prevention and treatment of patients with F. nucleatum-associated CRC metastasis.

Development of machine learning models for mortality risk prediction after cardiac surgery.

Background: We developed machine learning models that combine preoperative and intraoperative risk factors to predict mortality after cardiac surgery. Methods: Machine learning involving random forest, neural network, support vector machine, and gradient boosting machine was developed and compared with the risk scores of EuroSCORE I and II, Society of Thoracic Surgeons (STS), as well as a logistic regression model. Clinical data were collected from patients undergoing adult cardiac surgery at the First Medical Centre of Chinese PLA General Hospital between December 2008 and December 2017. The primary outcome was post-operative mortality. Model performance was estimated using several metrics, including sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC). The visualization algorithm was implemented using Shapley's additive explanations. Results: A total of 5,443 patients were enrolled during the study period. The mean EuroSCORE II score was 3.7%, and the actual in-hospital mortality rate was 2.7%. For predicting operative mortality after cardiac surgery, the AUC scores were 0.87, 0.79, 0.81, and 0.82 for random forest, neural network, support vector machine, and gradient boosting machine, compared with 0.70, 0.73, 0.71, and 0.74 for EuroSCORE I and II, STS, and logistic regression model. Shapley's additive explanations analysis of random forest yielded the top-20 predictors and individual-level explanations for each prediction. Conclusions: Machine learning models based on available clinical data may be superior to clinical scoring tools in predicting postoperative mortality in patients following cardiac surgery. Explanatory models show the potential to provide personalized risk profiles for individuals by accounting for the contribution of influencing factors. Additional prospective multicenter studies are warranted to confirm the clinical benefit of these machine learning-driven models.

Prognostic nutritional index and systemic immune-inflammation index are prognostic biomarkers for non-small-cell lung cancer brain metastases.

Aim: This research aimed to elucidate the prognosis values of prognostic nutritional index (PNI) and systemic immune-inflammation index (SII) and clinical characteristics in NSCLC patients with brain metastases (BM) underwent radiotherapy. Materials & methods: Cut-off points of hematological indicators were determined by receiver operating characteristic curve. Overall survival was evaluated by Kaplan-Meier method and Cox proportional hazards model. Results: We retrospectively analyzed 214 patients from January 2009 to December 2018. The result demonstrated the independent prognostic values of PNI (hazard ratio: 0.600; p = 0.004) and SII (hazard ratio: 1.486; p = 0.019). The remaining clinicopathologic factors, including brain radiotherapy modality, smoking history, numbers of brain metastases, intracranial symptoms and Radiation Therapy Oncology Group - recursive partitioning analysis, were independently related to survival (p < 0.05). Conclusion: PNI and SII could be critical prognostic indicators for NSCLC patients with BM.

Life Cycle Greenhouse Gas Emissions for Last-Mile Parcel Delivery by Automated Vehicles and Robots.

Increased E-commerce and demand for contactless delivery during the COVID-19 pandemic have fueled interest in robotic package delivery. We evaluate life cycle greenhouse gas (GHG) emissions for automated suburban ground delivery systems consisting of a vehicle (last-mile) and a robot (final-50-feet). Small and large cargo vans (125 and 350 cubic feet; V125 and V350) with an internal combustion engine (ICEV) and battery electric (BEV) powertrains were assessed for three delivery scenarios: (i) conventional, human-driven vehicle with human delivery; (ii) partially automated, human-driven vehicle with robot delivery; and (iii) fully automated, connected automated vehicle (CAV) with robot delivery. The robot's contribution to life cycle GHG emissions is small (2-6%). Compared to the conventional scenario, full automation results in similar GHG emissions for the V350-ICEV but 10% higher for the V125-BEV. Conventional delivery with a V125-BEV provides the lowest GHG emissions, 167 g CO2e/package, while partially automated delivery with a V350-ICEV generates the most at 486 g CO2e/package. Fuel economy and delivery density are key parameters, and electrification of the vehicle and carbon intensity of the electricity have a large impact. CAV power requirements and efficiency benefits largely offset each other, and automation has a moderate impact on life cycle GHG emissions.

Thoracoscopic-Assisted Repair of Perivalvular Leakage of Prosthetic Mitral Valve.

Perivalvular leakage (PVL) after valve replacement is an awkward complication, and is liable to recur if re-replacement of a prosthetic valve is attempted. A 58-year-old male patient received initial mitral valve replacement 17 years earlier and recently developed PVL in mitral position. In this case we attempted an alternative way to repair mitral PVL through a mini-thoracotomy with thoracoscopic assistance without valve re-replacement surgery. The patient recovered uneventfully and was discharged on the day 7 after operation. Echocardiography revealed no regurgitation or new PVL developing during the 3 months follow-up.

Building a circular RNA centered gene regulation network associated with cervical squamous cell carcinoma.

Aim: The roles of circular RNA (circRNA) in tumor development are not fully understood. This study aims to explore the possible role of circRNAs as drug targets for the treatment of cervical squamous cell carcinoma (CSCC). Materials & methods: Through the bioinformatics approach to integrating multiple types of gene expression profiles, a circRNA-centered gene regulatory network was generated to explore the role of circRNAs in CSCC. Results: The expression levels of hsa_circ_0043280 and hsa_circ_0027821 were significantly different in tissues and might function as competing endogenous RNAs and play vital roles in CSCC development. Conclusion: We constructed a regulatory network consisting of two circRNAs, two miRNAs, 22 mRNAs and 19 drugs/chemicals and provided new insight into the prognosis and therapy of CSCC.

An improved quantitative real-time polymerase chain reaction technology for Helicobacter pylori detection in stomach tissue and its application value in clinical precision testing.

BACKGROUND: Helicobacter pylori (H. pylori) infection is a serious human health threat. The empiric H. pylori treatment paradigm guided by traditional testing technologies has led to antibiotic resistance. Here, we improved the qPCR method to provide technical support for precision H. pylori diagnosis and treatment. METHODS: Two pairs of primers and probes targeting the glmM gene were designed to detect H. pylori, and a multiplex qPCR method was established for virulence factor detection. Then, a rapid urease test (RUT), culturing and qPCR were performed on 141 specimens collected from Xinqiao Hospital of China in 2017 to evaluate the qPCR detection capability. Finally, the H. pylori infectious amount and virulence genes were detected by qPCR. RESULTS: 1. The improved qPCR method which used two pairs of primers had a higher detection rate (100%) and better accuracy (p = 0.000), compared with the qPCR using a pair of primers. It also had better consistency with the bacterial culture than with RUT (Kappa =0.440, p < 0.001). 2. The H. pylori infectious amount was significantly positively associated with gastritis in corpus (p = 0.003) and gastric erosion (p = 0.043). The H. pylori infectious amount in gastric precancerous patients was significantly lower than that in H. pylori-positive patients (p < 0.05), and the infectious H. pylori-vacA s1+ amount was significantly greater than that of H. pylori-vacA s1- (p < 0.05). 3. The vacA s1 frequency was significantly higher than that of vacA m1/cagA+/babA2+ in chronic superficial gastritis (p = 0.000), peptic ulcer (p = 0.037) and gastric erosion (p = 0.009). The H. pylori-vacA+/cagA+/babA2+ frequency showed a significant positive correlation (p < 0.05). CONCLUSIONS: The H. pylori infectious amount and presence of H. pylori virulence factors showed complex correlations with gastric disease occurrence and development. The improved qPCR with good detection performance can be used for quantitative H. pylori detection and testing for the virulence genes vacA s1, vacA m1, cagA and babA2 simultaneously. These findings will provide valuable information for disease diagnosis and treatment.

Effects of Resveratrol on the Mechanisms of Antioxidants and Estrogen in Alzheimer's Disease.

OBJECTIVE: To observe the effects of resveratrol (Res) on the antioxidative function and estrogen level in an Alzheimer's disease (AD) mouse model. METHODS: First, we examined the effects of Res on an AD mice model. SAMP8 mice were selected as the model, and normal-aging SAMR1 mice were used as the control group. The model mice were randomly divided into three groups: a model group, high-dose Res group (40mg/kg, intraperitoneal (ip)), and low-dose Res group (20mg/kg, ip). After receiving medication for 15 days, the mice were subjected to the water maze test to assess their spatial discrimination. The spectrophotometric method was used to detect the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) as well as the malondialdehyde (MDA) content. Quantitative PCR (q-PCR) was used to detect SOD, GSH-Px, CAT, and heme oxygenase-1 (HO-1) mRNA level changes. Western blot analysis detected HO-1 and Nrf2 protein expression. Second, we researched the effect of Res on the estrogen level in the SAMP8 model mice. The model mice were randomly divided into four groups: a model group, estrogen replacement group (0.28 mg/kg, intramuscular (im), estradiol benzoate), high-dose Res group (5 mg/kg, im), and low-dose Res group (2.5 mg/kg, im). The mice were injected, once every three days, for 5 weeks. Q-PCR was used to detect brain tissue mRNA expression changes. Western blot analysis detected ERα, ERß, and ChAT protein expression. An enzyme-linked immunosorbent assay (ELISA) kit was used to detect the expression of E2 and amyloid ß protein (Aß) in brain tissue. RESULTS: Compared with the control treatment, Res could improve the spatial abilities of the mice to a certain extent and also increase the expression of SOD, GSH-Px, CAT, and HO-1 at the mRNA level (P<0.05). In addition, enhanced SOD, GSH-Px, and CAT activities and HO-1 protein levels and decreased MDA content (P<0.05) were detected in the brain tissue of the Res-treated mice. The cytoplasmic Nrf2 content in the Res-treated mice was also decreased while the nuclear Nrf2 content and the nuclear translation rate of Nrf2 were increased (P<0.05). Res could decrease the expression of ERß in the brain tissue at the mRNA and protein levels and the expression of Aß in the brain tissue at the protein level. Res could also increase the mRNA and protein expression of ERα and ChAT and the protein expression of estradiol in the brain tissue. CONCLUSION: Res can increase the antioxidant capacity of AD models through the Nrf2/HO-1 signaling pathway. In addition, Res can enhance estrogen levels in an AD model. These findings provide a new idea for the treatment of AD.

Peri-operative application of intra-aortic balloon pumping reduced in-hospital mortality of patients with coronary artery disease and left ventricular dysfunction.

BACKGROUND: There are few reports of peri-operative application of intra-aortic balloon pumping (IABP) in patients with coronary artery disease (CAD) and different grades of left ventricular dysfunction. This study aimed to analyze the early outcomes of peri-operative application of IABP in coronary artery bypass grafting (CABG) among patients with CAD and left ventricular dysfunction, and to provide a clinical basis for the peri-operative use of IABP. METHODS: A retrospective analysis of 612 patients who received CABG in the General Hospital of People's Liberation Army between May 1995 and June 2014. Patients were assigned to an IABP or non-IABP group according to their treatments. Logistic regression analysis was performed to investigate the influence of peri-operative IABP implantation on in-hospital mortality. Further subgroup analysis was performed on patients with severe (ejection fraction [EF] ≤ 35%) and mild (EF = 36%-50%) left ventricular dysfunction. RESULTS: Out of 612 included subjects, 78 belonged to the IABP group (12.7%) and 534 to the non-IABP group. Pre-operative left ventricular EF (LVEF) and EuroSCOREII predicted mortality was higher in the IABP group compared with the non-IABP group (P < 0.001 in both cases), yet the two did not differ significantly in terms of post-operative in-hospital mortality (P = 0.833). Regression analysis showed that IABP implantation, recent myocardial infarction, critical status, non-elective operation, and post-operative ventricular fibrillation were risk factors affecting in-hospital mortality (P < 0.01 in all cases). Peri-operative IABP implantation was a protective factor against in-hospital mortality (P = 0.0010). In both the severe and mild left ventricular dysfunction subgroups, peri-operative IABP implantation also exerted a protective role against mortality (P = 0.0303 and P = 0.0101, respectively). CONCLUSIONS: Peri-operative IABP implantation could reduce the in-hospital mortality and improve the surgical outcomes of patients with CAD with both severe and mild left ventricular dysfunction.

Interleukin-33 Predicts Poor Prognosis and Promotes Renal Cell Carcinoma Cell Growth Through its Receptor ST2 and the JNK Signaling Pathway.

BACKGROUND/AIMS: Renal cell carcinoma (RCC) is currently the ninth most common cancer in men. Interleukin (IL)-33 expression has previously been associated with a number of cancers; however, its biological role in RCC is poorly understood. In this study, we sought to elucidate the role of IL-33 in RCC. METHODS: Serum IL-33 levels were measured by ELISA. IL-33 expression in clinical RCC samples was examined by immunocytochemistry. The proliferation and apoptosis rate of RCC were determined by CCK8 and flow cytometry. Mcl1 and Bcl-2 expression were measured by quantitative real-time PCR and western blotting. JNK expression were measured by western blotting and flow cytometry. The in vivo role of IL-33 in RCC tumorigenesis was examined by animal models. RESULTS: We found that increased expression of IL-33 in RCC was associated with tumor-lymph node-metastasis (TNM) stage and inversely correlated with prognosis. IL-33 enhances RCC cell growth in vivo and stimulates RCC cell proliferation and prevents chemotherapy-induced tumor apoptosis in vitro. Furthermore, we demonstrated that IL-33 promotes RCC cell proliferation and chemotherapy resistance via its receptor ST2 and the JNK signaling activation in tumor cells. CONCLUSION: Our findings suggest that targeting IL-33/ST2 and JNK signaling may have potential value in the treatment of RCC.