[An MRI multi-sequence feature imputation and fusion mutual-aid model based on sequence deletion for differentiation of high-grade from low-grade glioma].

OBJECTIVE: To evaluate the performance of magnetic resonance imaging (MRI) multi-sequence feature imputation and fusion mutual model based on sequence deletion in differentiating high-grade glioma (HGG) from low-grade glioma (LGG). METHODS: We retrospectively collected multi-sequence MR images from 305 glioma patients, including 189 HGG patients and 116 LGG patients. The region of interest (ROI) of T1-weighted images (T1WI), T2-weighted images (T2WI), T2 fluid attenuated inversion recovery (T2_FLAIR) and post-contrast enhancement T1WI (CE_T1WI) were delineated to extract the radiomics features. A mutual-aid model of MRI multi-sequence feature imputation and fusion based on sequence deletion was used for imputation and fusion of the feature matrix with missing data. The discriminative ability of the model was evaluated using 5-fold cross-validation method and by assessing the accuracy, balanced accuracy, area under the ROC curve (AUC), specificity, and sensitivity. The proposed model was quantitatively compared with other non-holonomic multimodal classification models for discriminating HGG and LGG. Class separability experiments were performed on the latent features learned by the proposed feature imputation and fusion methods to observe the classification effect of the samples in twodimensional plane. Convergence experiments were used to verify the feasibility of the model. RESULTS: For differentiation of HGG from LGG with a missing rate of 10%, the proposed model achieved accuracy, balanced accuracy, AUC, specificity, and sensitivity of 0.777, 0.768, 0.826, 0.754 and 0.780, respectively. The fused latent features showed excellent performance in the class separability experiment, and the algorithm could be iterated to convergence with superior classification performance over other methods at the missing rates of 30% and 50%. CONCLUSION: The proposed model has excellent performance in classification task of HGG and LGG and outperforms other non-holonomic multimodal classification models, demonstrating its potential for efficient processing of non-holonomic multimodal data.

[Prediction of microvascular invasion in hepatocellular carcinoma based on multi-phase dynamic enhanced CT radiomics feature and multi-classifier hierarchical fusion model].

OBJECTIVE: To predict microvascular invasion (MVI) in hepatocellular carcinoma (HCC) using a model based on multiphase dynamic-enhanced CT (DCE-CT) radiomics feature and hierarchical fusion of multiple classifiers. METHODS: We retrospectively collected preoperative DCE-CT images from 111 patients with pathologically confirmed HCC in Guangzhou First People's Hospital between January, 2016 and April, 2020. The volume of interest was outlined in the early arterial phase, late arterial phase, portal venous phase and equilibrium phase, and radiomics features of these 4 phases were extracted. Seven classifiers based on different algorithms were trained using the filtered feature subsets to obtain multiple base classifiers under each phase. According to the hierarchical fusion strategy, a multi-criteria decision-making-based weight assignment algorithm was used for fusing each base classifier under the same phase with the model after extracting the phase information to obtain the prediction model. The proposed model was evaluated using a 5-fold cross-validation and assessed for area under the ROC curve (AUC), accuracy, sensitivity, and specificity. The prediction model was also compared with the fusion models using a single phase or multiple phases, models based on a single phase with a single classifier, models with different base classifier diversities, and 8 classifier models based on other ensemble methods. RESULTS: The experimental results showed that the performance of the proposed model for predicting HCCMVI was optimal after incorporating the 4 phases and 7 classifiers, with AUC, accuracy, sensitivity, and specificity of 0.828, 0.766, 0.877, and 0.648, respectively. Comparative experiments showed that this prediction model outperformed the models based on a single phase with a single classifier and other ensemble models. CONCLUSION: The proposed prediction model is effective for predicting MVI in HCC with superior performance to other models.

[A multi-modal feature fusion classification model based on distance matching and discriminative representation learning for differentiation of high-grade glioma from solitary brain metastasis].

OBJECTIVE: To explore the performance of a new multimodal feature fusion classification model based on distance matching and discriminative representation learning for differentiating high-grade glioma (HGG) from solitary brain metastasis (SBM). METHODS: We collected multi-parametric magnetic resonance imaging (MRI) data from 61 patients with HGG and 60 with SBM, and delineated regions of interest (ROI) on T1WI, T2WI, T2-weighted fluid attenuated inversion recovery (T2_FLAIR) and post-contrast enhancement T1WI (CE_T1WI) images. The radiomics features were extracted from each sequence using Pyradiomics and fused using a multimodal feature fusion classification model based on distance matching and discriminative representation learning to obtain a classification model. The discriminative performance of the classification model for differentiating HGG from SBM was evaluated using five-fold cross-validation with metrics of specificity, sensitivity, accuracy, and the area under the ROC curve (AUC) and quantitatively compared with other feature fusion models. Visual experiments were conducted to examine the fused features obtained by the proposed model to validate its feasibility and effectiveness. RESULTS: The five-fold cross-validation results showed that the proposed multimodal feature fusion classification model had a specificity of 0.871, a sensitivity of 0.817, an accuracy of 0.843, and an AUC of 0.930 for distinguishing HGG from SBM. This feature fusion method exhibited excellent discriminative performance in the visual experiments. CONCLUSION: The proposed multimodal feature fusion classification model has an excellent ability for differentiating HGG from SBM with significant advantages over other feature fusion classification models in discrimination and classification tasks between HGG and SBM.

[Risk factors of hyperlactatemia during pulmonary endarterectomy under deep hypothermic circulatory arrest and its influence on prognosis].

Objective: To investigate the incidence, risk factors, and outcomes of hyperlactatemia after pulmonary endarterectomy (PEA) under deep hypothermic circulatory arrest (DHCA). Methods: From December 2016 to January 2022, patients receiving PEA in China-Japan Friendship Hospital were enrolled in the study. Arterial blood samples were analyzed intraoperatively. Multivariate logistic regression analysis was performed to identify the predictors of intraoperative lactate elevation as well as major factors influencing the clinical outcome of the surgery. Results: A total of 110 patients (69 males and 41 females) were enrolled, aged (50.6±12.8) years. Receiver operating characteristic curve yielded an optimal cut-off lactate level of 7 mmol/L for predicting major postoperative complications (re-operation, re-intubation, postoperative renal failure requiring renal replacement therapy, wound infection, stroke, atrial fibrillation, and perioperative extracorporeal membrane oxygenation usage within 48 hours after surgery). Thirty-nine patients (35.5%) had an intraoperative peak arterial lactate level of≥7 mmol/L. According to intraoperative peak arterial lactate level, the patients were divided into two groups (<7 mmol/L and≥7 mmol/L). There were no statistically significant differences in age, sex and body mass index between the two groups (all P>0.05). Intraoperative peak lactate level was associated with prolonged mechanical ventilation time (r=0.262, P=0.008) and intensive care unit length of stay (r=0.304, P=0.002). Multivariate logistic regression analysis identified three key variables associated with lactate level≥7 mmol/L: DHCA duration (OR=1.186, 95%CI: 1.027-1.370, P=0.020), nadir hematocrit (HCT) (OR=0.580, 95%CI: 0.341-0.988, P=0.045) and preoperative pulmonary vascular resistance (PVR) (OR=1.096, 95%CI: 1.020-1.177, P=0.012). Patients with lactate≥7 mmol/L carried a higher rate of major complications (P=0.001). For patients with lactate≥7 mmol/L, 41.0% (16 out of 39 cases) had major complications, while for patients with lactate<7 mmol/L, only 14.1% (10 out of 71) had major complications. There was no statistically significant difference in mortality (8.5% vs 10.3%, P=0.753) between patients with different lactate levels. Moreover, intraoperative peak lactate level was a predictor of postoperative combined morbidity (OR=1.625, 95%CI: 1.176-2.245, P=0.003). Conclusion: High intraoperative lactate levels are associated with higher preoperative PVR, lower nadir HCT, and longer DHCA duration. Intraoperative lactate levels are independently associated with increased combined morbidity.

[A discrimination model for differentiation of renal cell carcinoma from renal angiomyolipoma without visible fat: based on hierarchical fusion framework of multi-classifier].

OBJECTIVE: To investigate the capabilities of classification models based on hierarchical fusion framework of multi-classifier using a random projection strategy for differentiation of renal cell carcinoma (RCC) from small renal angiomyolipoma (< 4 cm) without visible fat (AMLwvf). METHODS: We retrospectively collected the clinical data from 163 patients with pathologically proven small renal mass, including 118 with RCC and 45 with AMLwvf.Target region of interest (ROI) delineation was performed on an unenhanced phase (UP) CT image slice displaying the largest lesion area.The radiomics features were used to establish a hierarchical fusion method.On the projection-based level, the homogeneous classifiers were fused, and the fusion results were further fused at the classifier-based level to construct a multi-classifier fusion system based on random projection for differentiation of AMLwvf and RCC.The discriminative capability of this model was quantitatively evaluated using 5-fold cross validation and 4 evaluation indexes[specificity, sensitivity, accuracy and area under ROC curve (AUC)].We quantitatively compared this multi-classifier fusion framework against different classification models using a single classifier and several multi-classifier ensemble models. RESULTS: When the projection number was set at 10, the proposed hierarchical fusion differentiation framework achieved the best results on all the evaluation measurements.At the optimal projection number of 10, the specificity, sensitivity, average accuracy and AUC of the multi-classifier ensemble classification system for differentiation between AMLwvf and RCC were 0.853, 0.693, 0.809 and 0.870, respectively. CONCLUSION: The proposed model constructed based on a multi-classifier fusion system using random projection shows better performance to differentiate RCC from AMLwvf than the AMLwvf and RCC discrimination models based on a single classification algorithm and the currently available benchmark ensemble methods.

[The incidence of myopia and myopic progression from 2019 to 2020 in school-age children in Zhuozhou].

Objective: To analyze the changes in refractive status and prevalence of myopia in 6-to 14-year-old children at 2 time points in Zhuozhou, Hebei Province. Methods: In the current cohort study, the visual acuity and refractive status of primary and secondary school students aged 6 to 14 years were examined from June to August 2019 and reexamined from June to August 2020. A total of 30 412 subjects with examination data were enrolled, including 15 861 males (52.2%) and 14 551 females (47.8%), with an average age of (10.0±2.7) years. The participants underwent autorefraction without cycloplegia and a naked eye visual acuity test with a standard logarithmic visual acuity chart. Myopia was screened by the standard of equivalent spherical refraction less than -0.75 diopter (D). The categorical data were analyzed by the Chi-square or Fisher's exact test. Clopper-Pearson was used to estimate the 95% confidence intervals for the incidence of myopia. Results: After the 1-year interval, the change of equivalent spherical refraction was(-0.67±1.11) D and(-0.76±1.11) D, respectively, in male and female participants, and their visual acuity decreased by 0.11±0.19 and 0.12±0.21, respectively. There were significant inter-group differences in the annual change of spherical power in different age groups (χ²=276.23, P<0.001). The naked eye visual acuity reduction was greatest in the 10-year-old students. The incidence of myopia was 42.2% (95% confidence intervals of 41.47% to 42.93%) during the 1-year follow-up period. The incidence of myopia was highest at the age of 14 (52.0% in males and 54.2% in females) and lowest at the age of 6 (31.0% in males and 33.1% in females). Conclusions: The 1-year follow-up revealed an obvious myopic shift in the refractive status of school students in Zhuozhou, with their naked eye visual acuity decreased. The incidence of myopia was higher in females than that in males.

MiR-512-3p regulates malignant tumor behavior and multi-drug resistance in breast cancer cells via targeting Livin.

Breast cancer (BCa) is one of the most lethal malignancies of female reproductive organs. Increasing evidence has revealed that miRNAs participate in both tumorigenesis and multi-drug resistance. MiR-512-3p, a small non-coding RNA (miRNA), was previously found to be upregulated in breast cancer cells. In this study, we first verified that miR-512-3p expression forced a significant reorganization of the tumor architecture, affecting important cellular processes involved in cell-cell contact, cell adhesion and cell motility. Accordingly, induction of miR-512-3p expression significantly enhanced chemosensitivity and decreased metastatic potential in BCa cells. Our study demonstrated that miR-512-3p directly targets the 3'UTR of Livin, thereby decreasing its expression in MCF-7 cells. MiR-512-3p overexpression significantly inhibited breast cancer cell growth and metastasis. Both miR-512-3p overexpression and Livin knockdown significantly increased the chemosensitivity of cancer cells. Epirubicin (EPB), gemcitabine (GCB) and docetaxel (TXT) had antitumor effects in vitro against human breast cancer cell lines, and miR-512-3p overexpression increased tumor sensitivity to these drugs. In addition, miR-512-3p overexpression significantly inhibited tumor growth in vivo. Collectively, our data suggest that miR-512-3p is a significant regulator of tumorigenesis and drug resistance in breast cancer and provides evidence that miR-512-3p may represent a promising target for breast cancer therapy.

[Correlation between the changes of innate lymphoid cells in peripheral blood of systemic lupus erythematosus and its clinical significance].

Objective: To explore the function and role of innate lymphoid cells in the pathogenesis of systemic lupus erythematosus (SLE) at different disease activity levels. Methods: From Nov 2017 to May 2018, 40 patients with SLE and 15 age-matched healthy non-immune-related diseases controls were enrolled from Anhui provincial hospital. According to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2K, the patients were divided into active group (n=20) and remission group (n=20). The frequency of ILCs, B cells, CD4+T and CD8+T cells from peripheral blood mononuclear cells (PBMCs) was detected by flow cytometry. The subsets of ILCs in each group were compared with the subsets of B cells and T cell respectively. The levels of IL-4, IL-33 and IFN-γ in each group were tested by ELISA. Result: Compared with the control group, ILC1 percentage was significantly increased in SLE active group [(22.33%±2.52%) vs (14.56%±1.28%), P=0.018 1]; ILC2 percentage was decreased significantly in both remission group [(19.67%±1.83%) vs (42.48%±3.46%), P<0.000 1] and active group [(8.67%±0.83%) vs (19.67%±1.83%), P<0.000 1]; ILC3 percentage was decreased significantly in active group [(5.72%±1.08%) vs (14.35%±2.40%), P=0.001 3]. SLEDAI score was negatively correlated with the percentage of ILC2 (P=0.023 9) in all patients. The percentage of ILCs in the remission group (P=0.046 2) and activity group (P=0.003 7) were both increased significantly. Moreover, the percentage of ILC2 in active group was negatively correlated with CD4+T cells (P=0.030 8), and the serum IgG was negatively correlated with ILC2% in all patients (P=0.013 8). Compared with control group or remission group, the levels of IFN-γ (F=10.91, P=0.000 1) and IL-4 (F=6.046, P=0.004 7) in active group were remarkable higher. However, IL-33 was significantly reduced in active group (F=6.645, P=0.002 7). The percentage of ILC2 (r=0.154 3, P=0.028 8) and ILC3 (r=0.313 6, P=0.001 1) in all patients with SLE were positively correlated with the level of IL-4. Conclusion: The percentage of ILCs is related to disease activity, and ILCs play a "double-edged" role in the pathogenesis of SLE. Its function and mechanism are worth further exploration.

The difference in medical costs between carbapenem-resistant Acinetobacter baumannii and non-resistant groups: a case study from a hospital in Zhejiang province, China.

This retrospective study aims to compare differences in the medical costs between inpatients infected/colonised with carbapenem-resistant (CRAB) and carbapenem-susceptible (CSAB) Acinetobacter baumannii in a hospital in Zhejiang province, China. Because the patient population was large, we randomly selected 60% of all inpatients with clinical specimens between 2013 and 2015. We classified the A. baumannii cases as CRAB or CSAB based on antibiotic susceptibility testing. Univariate and multivariate analyses were used to identify factors associated with the total medical cost (TMC). Those included in the study totalled 2980 inpatients, 71.3% of whom had CRAB infection/colonisation. Differences in the TMC between the CRAB and CSAB groups were lower by multivariate analyses than the differences obtained by univariate analyses. Carbapenem resistance was significantly associated with an approximately 1.5-fold increase in the TMC after accounting for confounding factors. Our study highlights the heavy financial burden imposed by A. baumannii and carbapenem resistance on the Chinese healthcare system.

[Investigation on contamination of Giardia and Cryptosporidium in drinking water in Jiangsu Province].

Objective To know the contamination status of Giardia lamblia and Cryptosporidium in drinking water of Jiangsu Province, so as to provide the evidence for producing hygiene and safety drinking water. Methods A total of 28 water plants of 13 cities in Jiangsu Province were selected, and the source water (10 L), chlorinated water (100 L) and tap water (100 L) were collected separately in each site. The water samples were then treated by filtration, washing, centrifuging concentration, immune magnetic separation, and immunofluorescent assay, to detect the numbers of Giardia cysts and Cryptosporidium oocysts. Results Totally 84 samples from 13 cities were collected, including 28 source water, 28 chlorinated water and 28 tap water samples. Among the chlorinated water and tap water samples, no Giardia cysts and Cryptosporidium oocysts were found. However, Giardia cysts were detected in 3 (10.71%, 3/28) source water samples (Yancheng, Lianyungang, Changzhou cities), with the density of 1 cyst/10 L of all. Cryptosporidium oocysts were also detected in 3 (10.71%, 3/28) source water samples (Nanjing, Zhenjiang, Yangzhou cities), with the density of 1 oocyst/10 L of all. Conclusions The source water in partial areas of Jiangsu Province has been contaminated by Giardia and Cryptosporidium. To ensure the safety of drinking, the regulation of source water and surveillance of drinking water should be strengthened.

[Diagnostic knowledge and skills of parasitic diseases based on competition of professional personnel in Jiangsu Province, China].

Objective To understand the integrated ability of parasitic disease prevention and control of professional personnel of Jiangsu Province through the contest. Methods Totally 56 players from the whole province were selected, and all the players participated in the contest. The theory knowledge and skill scores were collected and the statistical analyses were conducted. Results The average theoretical score of the participants was 88.86±15.56 and the passing rate was 91.1%. The average skill operating score was 69.16±16.01 and the passing rate was 67.9%. The average Plasmodium microscopy score was 16.54±8.09 and the passing rate was 50%. The average helminth egg microscopy score was 34.27±10.66 and the passing rate was 67.9%. There were statistical differences among the age groups and different levels of schistosomiasis endemic situation (F = 5.10, 6.39, both P < 0.01). The theoretical knowledge including schistosomiasis, malaria, hydatid disease and others and the score rates were 91.07%, 90.94%, 85.83% and 90.93%, respectively. The hydatid disease score rate was lower (χ2 = 19.17, P < 0.01). The radar chart displayed that the score rates of tabletting and microscopy test in Kato-Katz film production, malaria blood film production and microscopy test were all low. Conclusion In Jiangsu Province, the participants have higher score in the theory test. However, they have lower skill test score, especially in the parasite species identification. The operational skills still need to be strengthened for center for disease control (CDC) participants.

[Predictive value of proteinuria for in-hospital severe adverse events and prognosis of the patients with heart failure].

OBJECTIVE: To investigate the effect of proteinuria on in-hospital severe adverse events and prognosis of the patients with heart failure(HF). METHODS: Clinical data of 520 patients with severe HF( NYHA 3-4 grades) in our department were analyzed retrospectively. Proteinuria was diagnosed on admission using the spot dipstick urinalysis. Clinical characteristics were compared between the patients with and without proteinuria. Univariate and multivariate Logistic regression analysis were used to evaluate the correlations of proteinuria with in-hospital adverse events and prognosis. RESULTS: On admission, proteinuria was found in 57.7% (300/520) of the enrolled patients with severe HF. The age, proportions of the HF patients coexistent with hypertention, diabetes mellitus and aneamia, and receiving vasoactive drugs, levels of NT-proBNP, creatinine, C-reactive protein and fasting blood glucose, were significantly higher, while the levels of eGFR, hemoglobin and hematocrit significantly lower in the proteinuria group than those in the non- proteinuria group. The multivariate analysis revealed that proteinuria was an independent risk factor for mechanical ventilation (MV) (OR=2.916, 95% CI: 1.712-4.968, P<0.001), cardiopulmonary resuscitation (CPR) (OR=1.956, 95% CI: 0.997-3.843, P=0.049) and in-hospital mortality (OR=2.490, 95% CI: 1.188-5.218, P=0.016). CONCLUSIONS: The severe HF patients with proteinuria often present with severe critical conditions. Proteinuria should be a potential marker for in-hospital adverse events and prognosis of severe hospitalized HF patients.

Evaluation of deformable image registration for contour propagation between CT and cone-beam CT images in adaptive head and neck radiotherapy.

Deformable image registration (DIR) is a critical technic in adaptive radiotherapy (ART) to propagate contours between planning computerized tomography (CT) images and treatment CT/Cone-beam CT (CBCT) image to account for organ deformation for treatment re-planning. To validate the ability and accuracy of DIR algorithms in organ at risk (OAR) contours mapping, seven intensity-based DIR strategies are tested on the planning CT and weekly CBCT images from six Head & Neck cancer patients who underwent a 6 ∼ 7 weeks intensity-modulated radiation therapy (IMRT). Three similarity metrics, i.e. the Dice similarity coefficient (DSC), the percentage error (PE) and the Hausdorff distance (HD), are employed to measure the agreement between the propagated contours and the physician delineated ground truths. It is found that the performance of all the evaluated DIR algorithms declines as the treatment proceeds. No statistically significant performance difference is observed between different DIR algorithms (p> 0.05), except for the double force demons (DFD) which yields the worst result in terms of DSC and PE. For the metric HD, all the DIR algorithms behaved unsatisfactorily with no statistically significant performance difference (p= 0.273). These findings suggested that special care should be taken when utilizing the intensity-based DIR algorithms involved in this study to deform OAR contours between CT and CBCT, especially for those organs with low contrast.

Construction of an anthropopathic abdominal phantom for accuracy validation of deformable image registration.

The purpose of this study is to design and fabricate an anthropopathic abdominal phantom for accuracy evaluation of deformable image registration (DIR) algorithms in adaptive radiation therapy. The constructed deformable organs, including the liver, kidney, spleen and stomach, are made of mixture of polyvinyl chloride (PVC) and softener dioctyl terephthalate, while the rigid structures, i.e. vertebrae, are made of white cement. Relation between the PVC-softener blending ratio and organ CT number is studied, and three-dimensional printing technic is employed to create highly anthropopathic organs in terms of organ shape and density. Detailed steps for phantom construction, landmark point placement and choice of phantom ingredients and construction recipe are introduced. Preliminary results of the mechanical properties of the fabricated organs are also presented. The experimental results indicate that the constructed phantom has satisfactory elastic characteristics and close CT number with corporal organs, and can potentially be applied to simulate real abdominal organ deformation in geometric accuracy validation of DIR algorithms.

The effect of mesenchymal stem cells on the p53 methylation in irradiation-induced thymoma in C57BL/6 mice.

CONTEXT: Our previous studies showed that mesenchymal stem cells (MSCs) preferentially migrated to irradiation-damaged thymus tissue to maintain the thymus integrity and simultaneously decrease the incidence of thymoma from 57 to 37.5%. OBJECTIVE: This study was designed to investigate the mechanisms by which MSCs decrease the irradiation-induced thymoma formation. MATERIALS AND METHODS: Thymus genome DNA was extracted, treated with sulfite, and amplified by polymerase chain reaction (PCR) using bisulfite sequencing PCR (BSP) as primers. The PCR productions were sequenced after recovery from 1.5% agarose gel electrophoresis. These sequences were analyzed using ClustalW2-Multiple Sequence Alignment. p53 expression in thymus or thymoma was measured using immunohistochemistry. RESULTS: Study showed the p53 methylation in irradiation alone group took place at loci +143 and -1190, which are beyond known binding motif of transcription factors. However, Matlnspector Professional Database revealed that locus -1190 is located in binding region of E2A transcription factor. In the non tumor thymus tissues from MSCs-treated irradiated mice, p53 promoter methylation existed at four loci. Three loci of them located at either negative regulation regions or their vicinity. The methylation affects the interaction between transcription factors and p53 promoter to increase the expression of p53. Indeed, an increased p53 expression was detected by immunohistochemistry in thymus tissues from MSCs-treated irradiated mice as compared to irradiated alone mice. CONCLUSION: MSCs decrease the incidence of irradiation-induced thymoma, which may be mediated by improving thymus microenvironment and changing the methylation of p53 promoter, and subsequently maintaining genome's stability.

A novel HLA-A allele, HLA-A*02:544.

The novel allele HLA-A*02:544 has two nucleotide changes from its most closely related allele, HLA-A*02:148. Firstly at nucleotide 255 where C → T (codon 60 GAC → GAT), resulting in a non-coding change as GAC and GAT both code for the same amino acid aspartic acid. Secondly at nucleotide 368 where T → G (codon 98 TTT → TGT) resulting in a coding change, 98 phenylalanine is changed to cysteine.

Induction of COX-2-PGE2 synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia.

Neuroinflammation is a striking hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS. However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood. In this study, we show that depletion of TDP-43 in microglia, but not in astrocytes, strikingly upregulates cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production through the activation of MAPK/ERK signaling and initiates neurotoxicity. Moreover, we find that administration of celecoxib, a specific COX-2 inhibitor, greatly diminishes the neurotoxicity triggered by TDP-43-depleted microglia. Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS.

Rotenone impairs autophagic flux and lysosomal functions in Parkinson's disease.

BACKGROUND: Rotenone is an environmental neurotoxin that induces accumulation of α-synuclein and degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc), but the molecular mechanisms are not fully understood. We investigated whether rotenone induced impairment of autophagic flux and lysosomal functions. METHODS: Autophagy flux, accumulation of α-synuclein, lysosomal membrane integrity and neurodegeneration were assessed in the rotenone-treated rat model and PC12 cells, and the effects of the autophagy inducer trehalose on rotenone's cytotoxicity were also studied. RESULTS: Rotenone administration significantly reduced motor activity and caused a loss of tyrosine hydroxylase in SNpc of Lewis rats. The degeneration of nigral dopaminergic neurons was accompanied by the deposition of α-synuclein aggregates, autophagosomes and redistribution of cathepsin D from lysosomes to the cytosol. In cultured PC12 cells, rotenone also induced increases in protein levels of α-synuclein, microtubule-associated protein 1 light chain 3-II, Beclin 1, and p62. Rotenone increased lysosomal membrane permeability as evidenced by leakage of N-acetyl-beta-d-glucosaminidase and cathepsin D, the effects were blocked by reactive oxygen species scavenger tiron. Autophagy inducer trehalose enhanced the nuclear translocation of transcription factor EB, accelerated the clearance of autophagosomes and α-synuclein and attenuated rotenone-induced cell death of PC12 cells. Meanwhile, administration of trehalose to rats in drinking water (2%) decreased rotenone-induced dopaminergic neurons loss in SNpc. CONCLUSIONS: These studies indicate that the lysosomal dysfunction contributes to rotenone's neurotoxicity and restoration of lysosomal function could be a new therapeutic strategy for Parkinson's disease.

Ferulic acid enhances the chemical and biological properties of astragali radix: a stimulator for danggui buxue tang, an ancient Chinese herbal decoction.

Danggui buxue tang, an ancient formula composed of astragali radix and Angelicae sinensis radix, has been used for treating menopausal irregularity in women for more than 800 years in China. In danggui buxue tang, the complete functions of astragali radix require the assistance of Angelicae sinensis radix, and both herbs have to work harmoniously in order to achieve the maximal therapeutic purposes. In order to analyze the relationship of the two herbs, the role of ferulic acid, a major chemical within Angelicae sinensis radix, in chemical and biological properties of astragali radix was determined. Using ferulic acid in the extraction of astragali radix, the amounts of astragaloside IV, calycosin, and formononetin were increased in the final extract; however, the astragali radix polysaccharide showed a minor increase. The chemical-enriched astragali radix extract showed robust induction in osteogenic and estrogenic activities in cultured osteosarcoma MG-63 and breast MCF-7 cells. However, ferulic acid itself did not show such biological responses. The current results strongly suggest that Angelicae sinensis radix-derived ferulic acid is a positive regulator for danggui buxue tang, which enhanced the solubilities of active ingredients derived from astragali radix, and which therefore increased the biological efficacies of danggui buxue tang.

Effect of You Gui Wan on mouse sperm fertilising ability in vivo and in vitro.

This study is to explore whether YGW has an impact on sperm fertilising ability in mice. Twenty male mice were randomly divided into two groups. In vivo experiments, one group of animals were orally administrated with YGW decoction and another group administered with saline for 14 days. Afterwards, the animals were mated with their female partners. Percentages of retrieved zygotes were then compared. In vitro experiments, in vitro fertilisation (IVF) assay, sperm acrosome reaction and acrosin activity were used to compare sperm fertilising ability between the two groups. The YGW-treated group had a significantly higher percentage of zygotes than the saline controls (P = 0.005). The IVF rates induced by spermatozoa from the herb-treated mice were also significantly higher than those from the control animals (P = 0.015). The sperm acrosin activity of the herb-treated group was significantly higher than that of the saline-treated group (P = 0.048), although there was no significant difference in testicular weight, sperm count and sperm motility. These data suggest that YGW decoction has a significant effect on normal sperm fertilising ability both in vivo and in vitro, which may be due to, at least in part, increments in the sperm acrosin activity.