Predictive Role of Executive Function in the Efficacy of Intermittent Theta Burst Transcranial Magnetic Stimulation Modalities for Treating Methamphetamine Use Disorder-A Randomized Clinical Trial.

Background: Repetitive transcranial magnetic stimulation (rTMS) has therapeutic effects on craving in methamphetamine (METH) use disorder (MUD). The chronic abuse of METH causes impairments in executive function, and improving executive function reduces relapse and improves treatment outcomes for drug use disorder. The purpose of this study was to determine whether executive function helped predict patients' responses to rTMS treatment. Methods: This study employed intermittent theta burst stimulation (iTBS) rTMS modalities and observed their therapeutic effects on executive function and craving in MUD patients. MUD patients from an isolated Drug Rehabilitation Institute in China were chosen and randomly allocated to the iTBS group and sham-stimulation group. All participants underwent the Behavior Rating Inventory of Executive Function - Adult Version Scale (BRIEF-A) and Visual Analog Scales (VAS) measurements. Sixty-five healthy adults matched to the general condition of MUD patients were also recruited as healthy controls. Findings: Patients with MUD had significantly worse executive function. iTBS groups had better treatment effects on the MUD group than the sham-stimulation group. Further Spearman rank correlation and stepwise multivariate regression analysis revealed that reduction rates of the total score of the BRIEF-A and subscale scores of the inhibition factor and working memory factor in the iTBS group positively correlated with improvements in craving. ROC curve analysis showed that working memory (AUC = 87.4%; 95% CI = 0.220, 0.631) and GEC (AUC = 0.761%; 95% CI = 0.209, 0.659) had predictive power to iTBS therapeutic efficacy. The cutoff values are 13.393 and 59.804, respectively. Conclusions: The iTBS rTMS had a better therapeutic effect on the executive function of patients with MUD, and the improved executive function had the potential to become a predictor for the efficacy of iTBS modality for MUD treatment. Clinical Trial Registration: ClinicalTrials.gov, identifier: ChiCTR2100046954.

Propofol affects mouse embryonic fibroblast survival and proliferation in vitro via ATG5- and calcium-dependent regulation of autophagy.

Propofol is a commonly used intravenous anesthetic agent, which has been found to affect cell survival and proliferation especially in early life. Our previous studies show that propofol-induced neurodegeneration and neurogenesis are closely associated with cell autophagy. In the present study we explored the roles of autophagy-related gene 5 (ATG5) in propofol-induced autophagy in mouse embryonic fibroblasts (MEF) in vitro. We showed that ATG5 was functionally related to propofol-induced cell survival and damage: propofol significantly enhanced cell survival and proliferation at a clinically relevant dose (10 µM), but caused cell death at an extremely high concentration (200 µM) in ATG5-/- MEF, but not in WT cells. The dual effects found in ATG5-/- MEF could be blocked by intracellular Ca2+ channel antagonists. We also found that propofol evoked a moderate (promote cell growth) and extremely high (cause apoptosis) cytosolic Ca2+ elevation at the concentrations of 10 µM and 200 µM, respectively, only in ATG5-/- MEF. In addition, ATG5-/- MEF themselves released more Ca2+ in cytosolic space and endoplasmic reticulum compared with WT cells, suggesting that autophagy deficiency made intracellular calcium signaling more vulnerable to external stimuli (propofol). Altogether, our results reveal that ATG5 plays a crucial role in propofol regulation of cell survival and proliferation by affecting intracellular Ca2+ homeostasis.

[Construction of specific artificial antigen-presenting cells for in vitro activation of CD19 chimeric antigen receptor T cells].

OBJECTIVE: To construct CD19-specific artificial antigen-presenting cells (aAPCs) for in vitro activation and expansion of CD19 chimeric antigen receptor (CAR)-modified T cells (CD19-CAR-T) and investigate their cytotoxic effect. METHODS: CD19-specific aAPCs (NIH3T3-CD19/86, NIH3T3-CD19/86/137L) expressing costimulatory molecules CD86 and/or CD137L were prepared on the basis of NIH3T3 backbone cells by lentivirus-mediated gene transfer. Irradiated CD19-specific aAPCs were co-cultured with CD19-CAR-T cells to activate and amplify CD19-CAR-T cells. The growth curve of CD19-CAR-T cells was determined by trypan blue exclusion assay, and CD19CAR expression and phenotype on CD19-CAR-T cells were detected by flow cytometry. The in vitro cytotoxicity of CD19-CAR-T cells against the target cells was evaluated by bioluminescence-based cytotoxicity assay. RESULTS: Flow cytometry showed that NIH3T3-CD19/86 and NIH3T3-CD19/86/137L expressed high levels of CD19, CD86 and/or CD137L. Both NIH3T3-CD19/86 and NIH3T3-CD19/86/137L cells could amplify CD19-CAR-T cells efficiently, but NIH3T3-CD19/86/137L cells had better amplification effect. After 14 days of co-culture with NIH3T3-CD19/86/137L cells, the number of CD19-CAR-T cells was significantly greater than that of NIH3T3-CD19/86 cells (P<0.05), and the proportion of CD19-CAR-T cells in the total T cells increased significantly (P<0.05). CD19-CAR-T cells amplified by CD19-specific aAPCs produced target-specific cytotoxicity and were able to specifically kill CD19-positive target cells. About 20% central memory T cells were present in the final products expanded by NIH3T3-CD19/86/137L. CONCLUSION: We successfully prepared CD19-specific aAPCs that can specifically amplify functional CD19-CART cells in vitro, which facilitates the acquisition of clinical-scale high-quality CD19-CART cells.

High expression of CD39/ENTPD1 in malignant epithelial cells of human rectal adenocarcinoma.

The ectonucleotidase CD39 is pivotal in the conversion of immunostimulatory adenosine triphosphate (ATP) into immunosuppressive adenosine which potently inhibits host immune responses against cancer. This study investigated the expression level and prognostic significance of CD39 in human rectal adenocarcinoma. Our data demonstrated that CD39 staining strongly marked malignant epithelial cells where the protein and messenger RNA (mRNA) expression levels of CD39 were significantly increased compared with paracancerous controls. In addition to primary tumors, CD39 was also abundantly expressed in liver metastases and tumor-draining lymph nodes from metastatic rectal adenocarcinoma. Although patients with higher CD39 density in tumor cells were more likely to have favorable characteristics (early TNM and N stages) and overall survival, the singular parameter cannot be used as an independent factor for predicting patients' prognosis. Intriguingly, combined analysis of CD39 and CD73 expression was more efficient to foretell patient's outcome where patients with increased CD73 but decreased CD39 levels displayed a worst prognosis. Taken together, the current study revealed that malignant epithelial cells of human rectal adenocarcinoma strongly express CD39 that may play a potential role in the tumor invasion and metastasis. Although high expression of CD39 in tumor cells is correlated with favorable clinical outcome, the combination of CD39 and CD73 expression may have a better prognostic value.

Laryngoscope and a new tracheal tube assist lightwand intubation in difficult airways due to unstable cervical spine.

PURPOSE: The WEI Jet Endotracheal Tube (WEI JET) is a new tracheal tube that facilitates both oxygenation and ventilation during the process of intubation and assists tracheal intubation in patients with difficult airway. We evaluated the effectiveness and usefulness of the WEI JET in combination with lightwand under direct laryngoscopy in difficult tracheal intubation due to unstable cervical spine. METHODS: Ninety patients with unstable cervical spine disorders (ASA I-III) with general anaesthesia were included and randomly assigned to three groups, based on the device used for intubation: lightwand only, lightwand under direct laryngoscopy, lightwand with WEI JET under direct laryngoscopy. RESULTS: No statistically significant differences were detected among three groups with respect to demographic characteristics and C/L grade. There were statistically significant differences between three groups for overall intubation success rate (p = 0.015) and first attempt success rate (p = 0.000). The intubation time was significantly longer in the WEI group (110.8±18.3 s) than in the LW group (63.3±27.5 s, p = 0.000) and DL group (66.7±29.4 s, p = 0.000), but the lowest SpO2 in WEI group was significantly higher than other two groups (p<0.01). The WEI JET significantly reduced successful tracheal intubation attempts compared to the LW group (p = 0.043). The severity of sore throat was similar in three groups (p = 0.185). CONCLUSIONS: The combined use of WEI JET under direct laryngoscopy helps to assist tracheal intubation and improves oxygenation during intubation in patients with difficult airway secondary to unstable spine disorders. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-14005141.

[A New HAC Unsupervised Classifier Based on Spectral Harmonic Analysis].

Hyperspectral images classification is one of the important methods to identify image information, which has great significance for feature identification, dynamic monitoring and thematic information extraction, etc. Unsupervised classification without prior knowledge is widely used in hyperspectral image classification. This article proposes a new hyperspectral images unsupervised classification algorithm based on harmonic analysis(HA), which is called the harmonic analysis classifer (HAC). First, the HAC algorithm counts the first harmonic component and draws the histogram, so it can determine the initial feature categories and the pixel of cluster centers according to the number and location of the peak. Then, the algorithm is to map the waveform information of pixels to be classified spectrum into the feature space made up of harmonic decomposition times, amplitude and phase, and the similar features can be gotten together in the feature space, these pixels will be classified according to the principle of minimum distance. Finally, the algorithm computes the Euclidean distance of these pixels between cluster center, and merges the initial classification by setting the distance threshold. so the HAC can achieve the purpose of hyperspectral images classification. The paper collects spectral curves of two feature categories, and obtains harmonic decomposition times, amplitude and phase after harmonic analysis, the distribution of HA components in the feature space verified the correctness of the HAC. While the HAC algorithm is applied to EO-1 satellite Hyperion hyperspectral image and obtains the results of classification. Comparing with the hyperspectral image classifying results of K-MEANS, ISODATA and HAC classifiers, the HAC, as a unsupervised classification method, is confirmed to have better application on hyperspectral image classification.

Neuropeptide Y induces secretion of high-mobility group box 1 protein in mouse macrophage via PKC/ERK dependent pathway.

Despite increasing evidence highlighting the role of NPY in the modulation of inflammatory reaction, surprisingly little is known about the direct effects of NPY on the release of proinflammatory mediators. In the present work, we have evaluated the effects of NPY on the release of TNF-α, IL-1ß, IL-6 and HMGB1 mediators in peritoneal macrophages. Our results demonstrate for the first time that NPY can directly induce active HMGB1 release and cytoplasmic translocation, while the production of TNF-α, IL-1ß and IL-6 is not affected. PKC and ERK pathway inhibitors can abolish the promotive effect of NPY on HMGB1 secretion. Thus, our results indicate that NPY might impact on the innate immune system by directly potentiating the HMGB1 release from the macrophage.

Application of metabolomics in traditional chinese medicine differentiation of deficiency and excess syndromes in patients with diabetes mellitus.

Metabolic profiling is widely used as a probe in diagnosing diseases. In this study, the metabolic profiling of urinary carbohydrates was investigated using gas chromatography/mass spectrometry (GC/MS) and multivariate statistical analysis. The kernel-based orthogonal projections to latent structures (K-OPLS) model were established and validated to distinguish between subjects with and without diabetes mellitus (DM). The model was combined with subwindow permutation analysis (SPA) in order to extract novel biomarker information. Furthermore, the K-OPLS model visually represented the alterations in urinary carbohydrate profiles of excess and deficiency syndromes in patients with diabetes. The combination of GC/MS and K-OPLS/SPA analysis allowed the urinary carbohydrate metabolic characterization of DM patients with different traditional Chinese medicine (TCM) syndromes, including biomarkers different from non-DM patients. The method presented in this study might be a complement or an alternative to TCM syndrome research.

[Distribution pattern of traditional Chinese medicine syndromes in 793 patients with fatty liver disease].

OBJECTIVE: To study the distribution pattern of traditional Chinese medicine (TCM) syndromes in fatty liver disease. METHODS: A multicenter and large sample survey was carried out by adopting the model of "combining disease with syndrome". A TCM syndrome information database was established by EPidata 3.1 software. The distribution pattern of TCM syndromes in fatty liver was studied by factor analysis and cluster analysis methods with SPSS 13.0 software. RESULTS: The basic syndromes of fatty liver included insufficiency of liver and kidney, flaring fire due to yin deficiency, liver-qi stagnation and spleen deficiency, spleen deficiency, spleen deficiency and dampness stagnation, mild syndrome of internal accumulation of damp-heat, blood stasis, severe syndrome of internal accumulation of damp-heat, and internal stagnation of phlegm-dampness. Single syndrome and combination of two to four basic syndromes were common in fatty liver disease. The syndrome of spleen deficiency and dampness stagnation was the most frequent one when its pathogenesis was simple, while the syndrome of insufficiency of liver and kidney was most frequent one when the pathogenesis was complicated. A total of 108 patients (13.6%) had no obvious symptoms, 46 patients (5.8%) were classified into the pattern of non-categorization, and the other patients were classified into five syndromes including phlegm accumulating with stagnation due to spleen deficiency (11.5%, 91/793), yin deficiency of liver and kidney (18.5%, 147/793), retention of phlegmatic dampness due to spleen deficiency (32.0%, 254/793), internal accumulation of damp-heat due to spleen deficiency (10.2%, 81/793), and damp obstruction due to liver-qi stagnation and spleen deficiency (8.3%, 66/793). CONCLUSION: Multi-element analysis reveals the distribution pattern of TCM syndromes in fatty liver disease, which is worthy of further study. The basic pathogenesis is spleen deficiency, and has a close correlation with the liver and kidney. The main pathogenesis factors are phlegm, dampness, blood stasis, heat and liver-qi stagnation. Yin deficiency of liver and kidney is a typical syndrome in fatty liver disease.

Effectiveness of Danning Tablet in patients with non-alcoholic fatty liver of damp-heat syndrome type: a multicenter randomized controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of Danning Tablet (DNT) in patients with non-alcoholic fatty liver disease (NAFLD) of damp-heat syndrome type. METHODS: A multicenter, randomized, double-blinded and positive drug parallel controlled trial was performed. One hundred and thirty-five patients were enrolled into the study and divided into two groups: DNT-treated group (n=102) and ursodeoxycholic acid (UDCA)-treated group (n=33). Body mass index (BMI), principal symptoms, liver function, blood lipids, iconographic, and compositional parameters were measured before and after treatment, respectively. RESULTS: In the two groups, BMI, distress in hepatic region, fatigue, anorexia, liver function, blood lipids and iconographic parameters were significantly improved, and the improvements of BMI, distress in hepatic region were better in DNT-treated group than in UDCA-treated group. The histological study also showed that DNT had positive effect in treatment of NAFLD. CONCLUSION: DNT is an effective drug to treat patients with NAFLD of damp-heat syndrome type and is more effective than UDCA.

[Study of standardization of syndrome diagnosis: an analysis of current status].

It is one of the key problems for the development of Chinese medicine to standardize the diagnosis of syndromes. The authors mainly discuss the ideas and methods of the study of standardization of syndrome diagnosis by retrospective analysis, also put forward the following suggestions: (1) the main ideas of this study should be based on the comparison of the diseases and their relevant syndromes and the predictive diagnosis of syndromes by the effects of herbal prescription treatment; (2) they are important ways to carry out multicenter, large sample and perspective clinical trials on the basis of the investigation and study of literature, consultation of experts and retrospective case review, and following the principles of clinical epidemiology, and to use the methods of evidence-based medicine to do systemic evaluation on the criteria of syndrome diagnosis; (3) they are important sectors of the study of standardization of syndrome diagnosis to enhance the objective studies on the four diagnostic methods of traditional Chinese medicine, and to do the functional studies under the conduction of systems biology; (4) Both data excavation technology and computer intelligence are the important technique supporting this study.

Abnormal Fas/FasL and caspase-3-mediated apoptotic signaling pathways of T lymphocyte subset in patients with systemic lupus erythematosus.

OBJECTIVES: To explore the relationships between Fas-FasL-mediated signaling pathway and apoptosis disturbance of T lymphocyte subset in patients with SLE. METHODS: Flow cytometry was used to determine the percentage of apoptotic lymphocytes and necrotic lymphocytes by AnnexinV-FITC/PI double staining. Cell surface expression rates of Fas, FasL, and intracellular expression rates of activated caspase-3 were evaluated by two-color flow cytometry analysis in peripheral T lymphocyte subsets of SLE patients with inactive disease (n=22) and with active disease (n=17). The serum concentration of anti-nucleosome antibodies in SLE patients were assayed by ELISA immunoassay methods. Health volunteers (n=13) served as controls. RESULTS: The percentage of early apoptotic cells was enhanced in patients with active disease (P=0.001, vs. control) and in patients with inactive disease (P=0.004, vs. control). Compared with health control, the percentage of necrotic cells was significant higher in patients with active disease (P=0.001). The percentages of CD4(+)T cells expressing Fas (P=0.023, vs. control) and FasL (P=0.001, vs. control) were increased in patients with active disease. But there were no obvious differences of expression rates of Fas and FasL on T cell subset between two disease groups (P>0.05). In patients with active disease the percentage of CD4(+)T cells or CD8(+)T cells expressing intracellular activated caspase-3 significantly increased compared to inactive disease patients (P=0.018, P=0.027, respectively) and health controls (P=0.001, P=0.001, respectively). The serum concentration of anti-nucleosome antibodies was strikingly higher in patients with active disease (P=0.002, vs. patients with inactive disease; P=0.001, vs. control, respectively), however, the serum concentration of anti-nucleosome antibodies was not obviously different between patients with inactive disease and health control group (P=0.473). The percentage of apoptotic cells correlated with the serum concentration of anti-nucleosome antibodies in SLE patients (r(s)=0.350, P=0.031). CONCLUSIONS: Apoptosis of T lymphocyte subset in SLE patients increases. CD4(+)T cells are a state of active apoptosis. Fas/FasL-mediated apoptotic pathways are especially important for CD4(+)T cells undergoing apoptosis in SLE patients with active disease. Increased Fas expression results in a higher susceptibility to Fas-mediated apoptosis, which contributes to the increased levels of intracellular activated caspase-3 and accelerates apoptosis of T lymphocytes. The degree of lymphocytic apoptosis disturbance correlates with the level of anti-nucleosome antibodies in the circulation. Acceleration of lymphocytic apoptosis plays important roles in immune pathologic injury and immune regulation dysfunction.

[Protective effects of yanggan lidan granules on carbon tetrachloride-induced liver damage in mice].

OBJECTIVE: To observe the protective effects of Yanggan Lidan Granules (YGLDG) on carbon tetrachloride (CCl(4))-induced liver damage in mice and to find out its mechanism. METHODS: A model of chronic liver damage was established in mice by intraperitoneal injection of CCl(4). After three weeks, those model mice were treated with low-, medium-, high-dose YGLDG, Danning Tablets and bifendate respectively for four weeks. Then the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as the contents of superoxide dismutase (SOD) and malondialdehyde (MDA) in liver tissues were detected. RESULTS: YGLDG could significantly reduce the levels of serum ALT and AST in model mice, and the content of MDA was obviously decreased while the content of SOD was increased in liver tissue. CONCLUSION: The therapeutic effect of YGLDG on mice with CCl(4)-induced liver damage is to relieve the seriousness of liver damage, and its mechanism may relate to reducing peroxidation activity in liver tissue.

[General methods for clinical effect assessment of traditional Chinese medicine].

Along with the changes of disease spectrum, medical models and health concept, people pay more and more attention to the diagnostic and therapeutic approaches of traditional Chinese medicine (TCM). With the effect assessment being changed from disease-based model to patient-based model, how to scientifically and objectively explain the validity of TCM has become the premise for further development of TCM and dissemination of it throughout the world. In this article, the authors analyzed the status quo and problems of the effect assessment of TCM, and proposed some general methods for clinical effect assessment of TCM, including formulating criteria for syndrome differentiation under the guidance of TCM theories, paying attention to quality of life, proper selection of indexes for outcome assessment, application of modern clinical study methods, such as the methods of evidence-based medicine and clinical epidemiology, designing randomized controlled trials, multi-subject co-operation, strict supervision of the quality of researches, and establishment of organizations for professional training.