Effects of Cerebellar Transcranial Direct Current Stimulation in Patients with Stroke: a Systematic Review.

BACKGROUND: The cerebellum is involved in regulating motor, affective, and cognitive processes. It is a promising target for transcranial direct current stimulation (tDCS) intervention in stroke. OBJECTIVES: To review the current evidence for cerebellar tDCS (ctDCS) in stroke, its problems, and its future directions. METHODS: We searched the Web of Science, MEDLINE, CINAHL, EMBASE, Cochrane Library, and PubMed databases. Eligible studies were identified after a systematic literature review of the effects of ctDCS in stroke patients. The changes in assessment scale scores and objective indicators after stimulation were reviewed. RESULTS: Eleven studies were included in the systematic review, comprising 169 stroke patients. Current evidence suggests that anode tDCS on the right cerebellar hemisphere does not appear to enhance language processing in stroke patients. Compared with the sham group, stroke patients showed a significant improvement in the verb generation task after cathodal ctDCS stimulation. However, with regard to naming, two studies came to the opposite conclusion. The contralesional anodal ctDCS is expected to improve standing balance but not motor learning in stroke patients. The bipolar bilateral ctDCS protocol to target dentate nuclei (PO10h and PO9h) had a positive effect on standing balance, goal-directed weight shifting, and postural control in stroke patients. CONCLUSIONS: ctDCS appears to improve poststroke language and motor dysfunction (particularly gait). However, the evidence for these results was insufficient, and the quality of the relevant studies was low. ctDCS stimulation parameters and individual factors of participants may affect the therapeutic effect of ctDCS. Researchers need to take a more regulated approach in the future to conduct studies with large sample sizes. Overall, ctDCS remains a promising stroke intervention technique that could be used in the future.

Drug exposure and susceptibility of second-line drugs correlate with treatment response in patients with multidrug-resistant tuberculosis: a multicentre prospective cohort study in China.

BACKGROUND: Understanding the impact of drug exposure and susceptibility on treatment response of multidrug-resistant tuberculosis (MDR-TB) will help to optimise treatment. This study aimed to investigate the association between drug exposure, susceptibility and response to MDR-TB treatment. METHODS: Drug exposure and susceptibility for second-line drugs were measured for patients with MDR-TB. Multivariate analysis was applied to investigate the impact of drug exposure and susceptibility on sputum culture conversion and treatment outcome. Probability of target attainment was evaluated. Random Forest and CART (Classification and Regression Tree) analysis was used to identify key predictors and their clinical targets among patients on World Health Organization-recommended regimens. RESULTS: Drug exposure and corresponding susceptibility were available for 197 patients with MDR-TB. The probability of target attainment was highly variable, ranging from 0% for ethambutol to 97% for linezolid, while patients with fluoroquinolones above targets had a higher probability of 2-month culture conversion (56.3% versus 28.6%; adjusted OR 2.91, 95% CI 1.42-5.94) and favourable outcome (88.8% versus 68.8%; adjusted OR 2.89, 95% CI 1.16-7.17). Higher exposure values of fluoroquinolones, linezolid and pyrazinamide were associated with earlier sputum culture conversion. CART analysis selected moxifloxacin area under the drug concentration-time curve/minimum inhibitory concentration (AUC0-24h/MIC) of 231 and linezolid AUC0-24h/MIC of 287 as best predictors for 6-month culture conversion in patients receiving identical Group A-based regimens. These associations were confirmed in multivariate analysis. CONCLUSIONS: Our findings indicate that target attainment of TB drugs is associated with response to treatment. The CART-derived thresholds may serve as targets for early dose adjustment in a future randomised controlled study to improve MDR-TB treatment outcome.

Development of a new rapid, economical and eco-friendly HPLC method for in vitro and in vivo determination of zolmitriptan.

Multiple high-performance liquid chromatographic (HPLC) approaches have been briefly defined for the assessment of zolmitriptan (ZMT). These methods are either cumbersome or require a plentiful volume of organic solvents, thus offering extortionate procedures. The objective of this study was to establish and validate a new rapid, eco- friendly and cost-effective HPLC method for the analysis of ZMT. The calibration curve for ZMT was established using simulated salivary fluid (SSF) and rat plasma for in-vitro and in-vivo analysis, respectively. Chromatogram separation was performed using a CST column (250mm × 4.6mm, 5µm) as a stationary phase and maintained at a temperature of 40°C. The methods were authenticated for linearity, system suitability, accuracy, precision, reproducibility, limit of detection (LOD) and limit of quantification (LOQ). The results of the validation variables and stability studies indicated that the methods were established in accordance with the guidelines of ICH and the USFDA. The established technique was time-saving, precise, eco- friendly and economical compared with the reported technique. In addition, the developed method was sufficiently repeatable for in vitro and in vivo analysis of ZMT.

[Preparation and quality evaluation of orodispersible film containing ginkgolide B novel nanosuspension lyophilized powder].

To prepare a new dosage form that can improve the drug loading of the film--ginkgolide B nanosuspension lyophilized powder orodispersible film(GB-NS-LP-ODF) and to evaluate its quality. Firstly, ginkgolide B nanosuspension(GB-NS) was prepared by media milling method, and then ginkgolide B nanosuspension lyophilized powder(GB-NS-LP) was prepared with freeze-drying method. The mannitol was used as lyoprotectant and its dosage was also investigated. GB-NS-LP-ODF was prepared by solvent casting method and its formulation was screened by single factor test method and optimized by orthogonal test. The appearance, mechanical properties, content uniformity and in vitro dissolution of the optimized GB-NS-LP-ODF were investigated. The particle size of prepared GB-NS was about 201 nm, and the optimal dosage of mannitol was 8%. According to the optimal formula, the GB-NS-LP-ODF was prepared with GB-NS-LP 35.6%, PVA 0588 49.4%, PEG 400 10.7% and CMS-Na 4.3%, and completely disintegrated in about 30 s, and the particle size of reconstituted GB nanoparticles from ODF was about 210 nm. The film with smooth appearance and good mechanical properties was stable within 30 days and the content uniformity(A+2.2 S<15) conformed to the regulations. Scanning electron microscope(SEM) showed that GB-NS-LP-ODFs were evenly distributed and the particle size was about 200 nm. X-rays diffraction(XRD) showed that its crystallinity was significantly lower than that of GB raw drug and GB-ODF. The results of in vitro release test showed that the drug film was completely dissoluted within 10 minutes. These results indicated that nanosuspension lyophilized powder was prepared by freeze drying of nanosuspensions, and then loaded into the orodispersible film to effectively increase the drug loading of the ODF and have broad application prospects.

Longitudinal profiling of gut microbiome among tuberculosis patients under anti-tuberculosis treatment in China: protocol of a prospective cohort study.

BACKGROUND: Anti-tuberculosis therapy requires at least six-month treatment with continuous administration of combined antibiotics, including isoniazid, rifampicin, pyrazinamide, and ethambutol. The long-term exposure to antibiotics could cause consequent changes in gut microbiota, which may alter the gastrointestinal function and drug absorption in patients, thereby affect the outcome of treatment. The study aims to characterize the longitudinal changes of gut microbiota among tuberculosis (TB) patients under standardized first-line treatment and provide an understanding of the association between alterations in gut microbiota composition and unfavorable clinical outcomes. METHODS: The study is a multicenter, observational prospective cohort study. Three study sites are purposively selected in the western (Sichuan Province) and eastern (Jiangsu Province and Shanghai) parts of China. Three-hundred patients with bacteriologically confirmed pulmonary TB are enrolled. All eligible patients should be investigated using structured questionnaires before treatment initiation; and be followed up during the treatment at Day-14, Month-2, Month-5, the end of treatment and the sixth month after ending therapy. Stool samples are to be collected at each visit, consisting of six stool samples from each patient. Additionally, 60 healthy volunteers from Sichuan province and Shanghai city will be recruited as healthy controls to form the baseline of patient gut microbiota in the Chinese population. The dynamic changes of gut microbiota in terms of alpha diversity, beta diversity, taxonomic composition are to be illustrated individually from the time at diagnosis until the sixth month after therapy is completed. Furthermore, the diversity and component of gut microbiota will be compared between the groups with and without unfavorable treatment outcome in terms of adverse effect and treatment failure. DISCUSSION: Studies on the clinical manifestations, adverse reactions, and gut microbiota alterations will provide scientifically-sound evidence on the impact of gut microbiota alterations on TB treatment outcomes. The study is not only useful for guiding personalized TB treatment but also sheds light on the effects of continuous antibiotics administration on gut microbiota. TRIAL REGISTRATION: Chinese Clinical Trial Registry, trial ID: ChiCTR1900023369, May 24, 2019. Retrospectively registered.

Acquired drug resistance during the turnaround time for drug susceptibility testing impacts outcome of tuberculosis.

BACKGROUND: The impacts of acquired resistance to first-line drugs other than rifampicin during turnaround time (TAT) for drug susceptibility testing (DST) on tuberculosis (TB) treatment are unclear. METHOD: We performed a prospective cohort study to test acquired resistance to isoniazid, ethambutol and pyrazinamide during TAT for DST as risk factors for prolonged time to sputum culture conversion (SCC) and treatment failure in China. Participants included had a baseline DST result for a Mycobacterium tuberculosis (Mtb) isolate collected at TB diagnosis and a follow-up DST result for a Mtb isolate collected upon baseline DST results availability. Acquired drug resistance was identified by comparing baseline and follow-up DST results. RESULTS: This study included 65 patients with acquired resistance Mtb isolates and 130 patients with consistent drug susceptibility profiles. Cox proportional hazard regression analysis demonstrated acquired isoniazid resistance (aHR 0.50, 95%CI: 0.29-0.85) and acquired pyrazinamide resistance (aHR 0.54, 95%CI: 0.36-0.81) were associated with prolonged time to SCC. Moreover, acquired isoniazid resistance (aOR 7.64, 95%CI: 2.39-16.08) and acquired pyrazinamide resistance (aOR 5.71, 95%CI: 2.31-14.12) were independently associated with treatment failure. CONCLUSION: Acquired resistance to isoniazid and/or pyrazinamide during TAT for DST was associated with prolonged time to SCC as well as treatment failure.

Influence Mechanism of Energy Efficiency Label on Consumers' Purchasing Behavior of Energy-Saving Household Appliances.

Mandatory energy efficiency label is an effective way to change consumers' consumption habits and guide them to buy energy-saving appliances. However, few studies concerned about the impact of energy efficiency label on consumers' purchasing behavior. Based on the theory of planned behavior (TPB), social cognitive theory and signaling theory, this paper constructs a theoretical model of the effect of the energy label on consumers' purchasing behavior of energy-saving household appliances. The survey data of 396 household appliance consumers in Mianyang City, China, are collected by the interception method, and the theoretical model is tested by structural equation modeling (SEM). Empirical results of this study indicate that consumers' cognition and perceived value of energy efficiency label significantly affect label trust. Perceived value has a significant impact on consumers' purchasing behavior of energy-saving appliances, while label cognition and label trust indirectly influence consumers' purchasing behavior through the intermediary variable of purchase intention. External environmental factors such as publicity and education as well as subjective norms affect consumers' actual purchasing behavior through the intermediary effect of purchase intention. This study provides important insights into the policy intervention measures to promote consumers' purchasing behavior of energy-saving appliances.

Alterations of gut microbiota in patients with active pulmonary tuberculosis in China: a pilot study.

BACKGROUND: The aim of this study was to identify the differences in diversity, composition, and function of the gut microbiota between tuberculosis (TB) patients and healthy controls (HCs). METHODS: A cross-sectional study was conducted in three cities of China. Stool samples from 94 treatment-naive TB patients and 62 HCs were analyzed by 16S rRNA gene sequencing. TB patients were further divided into antibiotic-free and antibiotic-exposure according to their use of non-specific antibiotics before the TB diagnosis. RESULTS: Compared with HCs, antibiotic-free TB patients presented a different gut microbial community (P < 0.005) and decreased Shannon diversity (P < 0.005). Among TB patients, the relative abundances of short-chain fatty acid (SCFA)-producing genera such as Lachnospiraceae ND3007 group (log2(FC) = -2.74) were lower, while several conditional pathogen-related genera such as Enterococcus (log2(FC) = 12.05) and Rothia (log2(FC) = 6.322) were at higher levels. In addition, 41% of patients received antibiotics before TB diagnosis. Antibiotic exposure was correlated with an additional reduction in α diversity and depletion of SCFA-producing bacteria. Microbial functional analysis revealed that the biosynthesis capacity of amino acids and fatty acids was lower among TB patients compared to HCs. CONCLUSIONS: Significant alterations in gut microbiota composition and metabolic pathways of TB patients were observed. Antibiotic exposure could alter the gut microbiota of TB patients, which should be considered in anti-TB treatment.

Emergence of additional drug resistance during treatment of multidrug-resistant tuberculosis in China: a prospective cohort study.

OBJECTIVES: Little is known about how additional second-line drug resistance emerges during multidrug-resistant tuberculosis (MDR-TB) treatment. The present study aimed to investigate the influence of microevolution, exogenous reinfection and mixed infection on second-line drug resistance during the recommended 2-year MDR-TB treatment. METHODS: Individuals with MDR-TB were enrolled between 2013 and 2016 in a multicentre prospective observational cohort study and were followed up for 2 years until treatment completion. Whole-genome sequencing (WGS) was applied for serial Mycobacterium tuberculosis isolates from study participants throughout the treatment, to study the role of microevolution, exogenous reinfection and mixed infection in the development of second-line drug resistance. RESULTS: Of the 286 enrolled patients with MDR-TB, 63 (22.0%) M. tuberculosis isolates developed additional drug resistance during the MDR-TB treatment, including 5 that fulfilled the criteria of extensively drug-resistant TB. By comparing WGS data of serial isolates retrieved from the patients throughout treatment, 41 (65.1%) of the cases of additional second-line drug resistance were the result of exogenous reinfection, 18 (28.6%) were caused by acquired drug resistance, i.e. microevolution, while the remaining 4 (6.3%) were caused by mixed infections with drug-resistant and drug-susceptible strains. In multivariate analysis, previous TB treatment (adjusted hazard ratio (aHR) 2.51, 95% CI 1.51-4.18), extensive disease on chest X-ray (aHR 3.39, 95% CI 2.03-5.66) and type 2 diabetes mellitus (aHR 4.00, 95% CI 2.22-7.21) were independent risk factors associated with the development of additional second-line drug resistance. CONCLUSIONS: A large proportion of additional second-line drug resistance emerging during MDR-TB treatment was attributed to exogenous reinfection, indicating the urgency of infection control in health facilities as well as the need for repeated drug susceptibility testing throughout MDR-TB treatment.

Mechanisms underlying internal heat-type acupuncture in the treatment of steroid-induced osteonecrosis of the femoral head in rabbits / 中国组织工程研究

BACKGROUND:Internal heat-type acupuncture therapy is a new treatment technique that combines acupuncture therapy with hyperthermia.It has good clinical effects on steroid-induced osteonecrosis of the femoral head,but the mechanism of action is still not fully clear. OBJECTIVE:To explore the possible mechanism of internal heat-type acupuncture therapy in treating steroid-induced osteonecrosis of the femoral head in rabbits. METHODS:Thirty-two New Zealand rabbits were randomly divided into blank group,model group,internal heat-type acupuncture group and shock wave group using a random number table method,with 8 rabbits in each group.The model group,internal heat-type acupuncture group and shock wave group were modeled using methylprednisolone sodium succinate combined with Escherichia coli endotoxin.The internal heat-type acupuncture group received an internal heat-type acupuncture intervention on the buttocks of rabbits,once a week,for 20 minutes each time.The shock wave group received shock wave intervention on the buttocks of rabbits,once a week,with 2 000 beats per session.The blank group and model group were not given any treatment.After 4 weeks of intervention,blood samples and bilateral femoral head samples were collected from experimental rabbits.The levels of tumor necrosis factor-α and interleukin-6 in serum were detected by ELISA;the histomorphology of the femoral head was observed using hematoxylin-eosin staining and the rate of empty lacunae was calculated;the protein expressions of matrix metalloproteinase 2,matrix metalloproteinase 9,matrix metalloproteinase tissue inhibitor 1,and matrix metalloproteinase tissue inhibitor 2 were detected by immunohistochemistry and western blot. RESULTS AND CONCLUSION:Compared with the blank group,the model rabbits showed reduced food intake,mental fatigue,and decreased activity;compared with the model group,the above performance of the experimental rabbits was significantly improved after internal heat-type acupuncture and shock wave treatment.Compared with the blank group,the histomorphology of the femoral head in the model group deteriorated significantly and the rate of empty bone lacuna increased(P<0.001),while the histomorphology of the femoral head in the internal heat-type acupuncture group and shock wave group was significantly improved compared with the model group,and the rate of empty bone lacuna was reduced(P<0.001).The serum levels of tumor necrosis factor-α and interleukin-6 in the model group were significantly higher than those in the blank group(P<0.05),while the serum levels of tumor necrosis factor-α and interleukin-6 in the internal heat-type acupuncture group and the shock wave group were significantly lower than those in the model group(P<0.05).Compared with the blank group,the expression levels of matrix metalloproteinase 2 and matrix metalloproteinase 9 in the femoral head of the model group were significantly increased,while the expression levels of matrix metalloproteinase tissue inhibitor 1 and matrix metalloproteinase tissue inhibitor 2 were significantly decreased(P<0.001);compared with the model group,the protein expression levels of matrix metalloproteinase 2 and matrix metalloproteinase 9 were significantly decreased,while the protein expression levels of matrix metalloproteinase tissue inhibitor 1 and matrix metalloproteinase tissue inhibitor 2 were significantly increased in the internal heat-type acupuncture group and the shock wave group(P<0.001).Overall,these findings indicate that internal heat-type acupuncture may promote the repair of the necrotic femoral head by regulating the levels of matrix metalloproteinases/matrix metalloproteinase tissue inhibitors and serum inflammatory factors,thus treating early steroid-induced osteonecrosis of the femoral head.

Reynoutria Japonica from Traditional Chinese Medicine: A Source of Competitive Adenosine Deaminase Inhibitors for Anticancer.

BACKGROUND: Adenosine deaminase (ADA) is an important enzyme in purine metabolism and is known as a potential therapeutic target for the treatment of lymphoproliferative disorders and cancer. Traditional Chinese Herbal Medicine (TCHM) is widely used alone or in combination with chemotherapy to treat cancer, due to its ability to deliver a broad variety of bioactive secondary metabolites as promising sources of novel organic natural agents. OBJECTIVE: In the present study, 29 varieties of medicinal plants were screened for the presence of ADA inhibitors. RESULTS: Extracts from Reynoutria japonica, Glycyrrhiza uralensis, Lithospermum erythrorhizon, Magnolia officinalis, Gardenia jasminoides, Stephania tetrandra, Commiphora myrrha, Raphanus sativus and Corydalis yanhusuo demonstrated strong ADA inhibition with rates greater than 50%. However, Reynoutria japonica possessed the highest ADA inhibitory activity at 95.26% and so was used in our study for isolating the ADA inhibitor to be further studied. Eight compounds were obtained and their structures were identified. The compound H1 had strong ADA inhibitory activity and was deduced to be emodin by 1H and 13C-NMR spectroscopic analysis with an IC50 of 0.629 mM. The molecular docking data showed that emodin could bind tightly to the active site of ADA. Our results demonstrated that emodin displayed a new biological activity which is ADA inhibitory activity with high cytotoxic activity against K562 leukemia cells. The bioactivity of cordycepin was significantly increased when used in combination with emodin. CONCLUSION: Emodin may represent a good candidate anti-cancer therapy and adenosine protective agent.

High-risk screening and detection of multidrug-resistant tuberculosis in two prefectures of China: a drug susceptibility surveillance-based secondary data analysis.

BACKGROUND: In China, less than one-fifth of multidrug-resistant tuberculosis (MDR-TB) cases are detected. MDR-TB screening is conducted amongst the following five high-risk groups of TB patients: chronic cases, close contacts of MDR-TB patients, patients with treatment failure, relapsed and returned patients, and smear-positive patients at the end of the third month of initial treatment. OBJECTIVE: To estimate the possibility of detecting MDR-TB cases if only the high-risk screening strategy is applied in China. METHODS: A secondary analysis was applied to the surveillance-based longitudinal data of all sputum smear-positive TB patients in Prefecture E and Prefecture W of China from 2013 to 2015. The population attributable risk (PAR) was estimated using odds ratios for five risk factors/predictors and exposure proportions amongst all MDR-TB cases. RESULTS: A total of 3513 TB patients (2807 from Prefecture E and 706 from Prefecture W) were included. Males accounted for 77.91% (2737/3513) of the patients. The average age was 52.5 ± 20.0 years old. Overall, 40.34% (71/176) of MDR-TB patients were from the five high-risk groups during the three-year study period. The detected proportion of MDR-TB cases using the high-risk screening strategy was significantly higher in Prefecture E than in Prefecture W. The PAR% for all five risk factors/predictors was 43.4% (95% CI: 24.6-61.7%), 49.9% (95% CI: 31.3-67.0%), and 30.3% (95% CI: 12.9-50.1%) in Prefecture E and 36.6% (95% CI: 10.4-64.5%), 13.3% (95% CI: -1.7-39.7%), and -82.5% (95% CI: -117.5--11.2%) in Prefecture W in 2013, 2014, and 2015, respectively. The PAR% for the five specific risk factors/predictors ranged from 0.4% (95% CI: -0.2-4.8%) to 21.0% (95% CI: 13.1-30.0%) in these two prefectures. CONCLUSION: In general, a high-risk screening strategy would miss more than half of the MDR-TB patients because they do not belong to the five high-risk groups.

Multi-center evaluation of GenoType MTBDRsl line probe assay for rapid detection of pre-XDR and XDR Mycobacterium tuberculosis in China.

OBJECTIVES: The implementation of rapid and reliable drug susceptibilities diagnosis is fundamental for effective treatment of multidrug-resistant tuberculosis(MDR-TB). The present study aimed to assess the diagnostic performance of the 2nd-version GenoType MTBDRsl kit as well as the impact of its implementation on the turnaround time in a multi-center Chinese study. METHODS: Totally 353 MDR-TB patient specimens were consecutively tested. The 2nd-version GenoType MTBDRsl assay, drug susceptibility testing with the MGIT 960 system, and sequencing were performed and compared. RESULTS: MTBDRsl testing identified the major genotypes associated with fluoroquinolones resistance, predominated by gyrA MUT3B (Asp94Asn and Asp94Tyr, 26.5%) and MUT3C (Asp94Gly, 19.5%). The genotypes associated with resistance to 2nd-line injectable drugs(SLIDs) were rrsMUT1(A1401G, 64.9%) and absence of WT1(C1402T, 10.5%). The sensitivities for detection of resistance to fluoroquinolones, SLIDs, and their combination (extensively drug resistance, XDR) were 80.5%, 80.7% and 73.5% and specificities were 100.0%, 99.3% and 99.1%, respectively. Implementation of this test significantly reduced the turnaround time between sample collection and result reporting from 45 to 3 days, a reduction by 93.3% (p, 0.001). CONCLUSION: With a favorable diagnostic performance and short turnaround time, the 2nd-version GenoType MTBDRsl assay proves its value for early diagnosis of resistance to 2nd-line drugs as well as of XDR-TB in China.

Myosin Heavy Chain 7 Gene-derived miRNA-208b-3p Enhances the Fibrosis-related Gene Expression in Cardiac Fibroblasts / 中山大学学报(医学科学版)

ObjectiveTo investigate the effect of myosin heavy chain 7 gene-derived miRNA-208b-3p on the fibrotic phenotype of cardiac fibroblasts. MethodsmiRNA chip array was performed to detect the dysregulated miRNAs in the myocardium of diabetic db/db mice and db/m control mice. Neonatal mouse ventricular cardiomyocytes （NMVCs） and cardiac fibroblasts （CFs） were isolated from C57BL/6 mice and cultured. Real-time quantitative PCR （RT-qPCR） was conducted to determine the expression of miR-208b-3p in mouse CFs and NMVCs subjected to angiotensinⅡ（AngⅡ） and high glucose plus glucose oxidase （G/Go） treatment， respectively. Cell counting kit 8（CCk8） assay， flow cytometry and determination of fibrosis-related protein， including COL1A1， COL3A1and α-SMA， were performed in mCFs transfected with miR-208b-3p. Dual luciferase reporter assay was performed to confirm the interaction between miR-208b-3p and the 3'-UTR of metal response element binding transcription factor 2 （Mtf2） and progesterone receptor membrane component 1（Pgrmc1）， respectively. The expressions of Mtf2 and Pgrmc1 at the mRNA and protein levels in mCFs after miR-208b-3p mimic transfection were determined using RT-qPCR and Western blot assay， respectively. The small interfering RNA （siRNA） was used to inhibit Mtf2 and Pgrmc1 expression in mCFs， and the effects of Mtf2 siRNA， Pgrmc1 siRNA and miR-208b-3p on fibrosis-related protein expression in mCFs were investigated. ResultsResults of miRNA chip array and RT-qPCR assay showed that miR-208b-3p was up-regulated in the myocardium of the diabetic db/db mice. miR-208b precursor and the host gene of Myh7 were consistently increased in db/db mice. miR-208b-3p and Myh7 mRNA were expressed in mCFs and NMVCs， but the levels of miR-208b-3p and Myh7 mRNA in NMVCs were much higher than those in mCFs. miR-208b-3p was up-regulated in mCFs and NMVCs subjected to Ang Ⅱ and G/Go treatment， respectively. miR-208b-3p could significantly enhance fibrosis-related protein， including COL1A1， COL3A1 and α-SMA， in mCFs， without affecting the proliferation activity and cell cycle distribution of mCFs. Dual luciferase reporter assay revealed the interactions of miR-208b-3p with the 3'-UTR of Mtf2 and Pgrmc1. The results of RT-qPCR and Western blotting confirmed that miR-208b-3p inhibited Mtf2 and Pgrmc1 expression at the post- transcriptional level. Transfection with miR-208b-3p mimic， Mtf2 siRNA and Pgrmc1 siRNA could consistently enhance the fibrosis-related protein expression in the cardiac fibroblasts. ConclusionsmiR-208b-3p enhances fibrosis-related gene expression by targeting Mtf2 and Pgrmc1in mCFs.

pncA mutations are associated with slower sputum conversion during standard treatment of multidrug-resistant tuberculosis.

Despite the strong association between drug resistance and genetic mutations, the value of molecular diagnosis of drug resistance to guide the treatment of multidrug-resistant tuberculosis (MDR-TB) remains unclear. This is particularly relevant in resource-limited areas where it is difficult to perform drug susceptibility testing (DST). Here we investigated the association between drug susceptibility phenotypes and genotypes and treatment outcomes in patients with MDR-TB. This study enrolled 74 consecutive patients with confirmed MDR-TB between 2010 and 2011, and outcomes were followed-up over the 24-month treatment course. All of the isolates were tested for phenotypic susceptibility to second-line drugs using the Mycobacteria Growth Indicator Tube (MGIT)-based system, and genotypic mutations were assessed by DNA sequencing. Among the 74 MDR-TB isolates, 29 (39.2%) were resistant to fluoroquinolones and/or second-line injectable drugs, of which 21 (72.4%) harboured a mutation in drug resistance-related genes (gyrA, rrs or eis). In addition, 32 individuals (43.2%) also had pyrazinamide (PZA)-resistant isolates, with 28 (87.5%) containing the pncA mutation. By backward selection in the multivariate logistic regression and Cox proportional hazard models, PZA resistance and its related pncA gene mutation demonstrated a correlation with a lower likelihood of culture conversion at 8 weeks and treatment success. Meanwhile, the fluoroquinolone resistance-related gyrA gene mutation was negatively correlated with treatment success. DST for PZA and fluoroquinolones together with genetic information appears to provide a clinically useful indicator of the treatment outcome of MDR-TB in China.

A physical restraint device to facilitate rehabilitation in critically ill patients / 中华危重病急救医学

Physical restraints are widely used in hospitalized and critically ill patients, especially in intensive care unit (ICU), to prevent adverse events such as the accidental removal of various monitoring leads, therapeutic tubes, and self-injury or injury to others due to delirium and irritation. The existing restraint measures directly bind the upper limbs of the patients to the hospital bed, which often brings psychological harm to the patients and leads to disuse muscular atrophy. Early rehabilitation therapy can help improve the prognosis of patients, but it is difficult to be widely used in ICU due to being heavily dependent on nursing and rehabilitation physicians. A novel restraint device to facilitate rehabilitation training for critically ill patients was designed by the medical staff from the department of critical care medicine of Beijing Tiantan Hospital, Capital Medical University and obtained the National Utility Model Patent of China (ZL 2020 2 2492749.6). The device is mainly composed of a cross beam and a locking device whose two ends are connected by a rocker arm, an upper limb stopper and an upper body stopper. The upper limb and body restraint provide restrictions on the movement of the head, the upper limb, and the upper body. The angle limiter prevents the patient from pulling out the treatment tube by himself, and at the same time retains the ability to grasp the crossbar and rotate it, and the sliding block further increases the activity space, to meet the exercise of the patient's upper limb muscle strength. Carrying out physical rehabilitation training as early as possible during ICU treatment can relieve the patient's resistance to passive restraint, reduce the incidence of disuse muscle atrophy, eliminate the potential hidden dangers of medical disputes, and ultimately improve the prognosis of patients.

Efficacy comparison among high risk factors questionnaire and Asia-Pacific colorectal screening score and their combinations with fecal immunochemical test in screening advanced colorectal tumor / 中华胃肠外科杂志

Objective: To investigate the effects of high risk factors questionnaire (HRFQ), Asia-Pacific colorectal screening (APCS) score and their combinations with fecal immunochemical test (FIT) in screening advanced colorectal neoplasia, in order to provide an evidence for further optimization of cancer screening program. Methods: A retrospective cohort study method was used to summarize and analyze the results of colorectal tumor screening in Jiashan County, Zhejiang Province from March 2017 to July 2018. Those with severe diseases that were not suitable for colonoscopy and those with mental and behavioral abnormalities who can not cooperate with the screening were excluded. Those who met any one or more of the followings in the HRFQ questionnaire were classified as high-risk people of HRFQ: (1) first-degree relatives with a history of colorectal cancer; (2) subjects with a history of cancer or any other malignant tumor; (3) subjects with a history of intestinal polyps; (4) those with two or more of the followings: chronic constipation (constipation lasted for more than 2 months per year in the past two years), chronic diarrhea (diarrhea lasted for more than 3 months in the past two years, and the duration of each episode was more than one week), mucus and bloody stools, history of adverse life events (occurring within the past 20 years and causing greater trauma or distress to the subject after the event), history of chronic appendicitis or appendectomy, history of chronic biliary disease or cholecystectomy. In this study, those who were assessed as high risk by HRFQ were recorded as "HRFQ (+)", and those who were not at high risk were recorded as "HRFQ (-)". The APCS questionnaire provided risk scores based on 4 risk factors including age, gender, family history and smoking: (1) age: 2 points for 50-69 years old, 3 points for 70 years old and above; (2) gender: 1 point for male, 0 point for women; (3) family history: 2 points for first-degree relatives suffering from colorectal cancer; (4) smoking: 1 point for current or past smoking, 0 point for non-smokers. The population was divided into low-risk (0-1 point), intermediate-risk (2-3 points), and high-risk (4-7 points). Those who were assessed as high risk by APCS were recorded as "APCS (+)", and those with intermediate and low risk were recorded as "APCS (-)". The hemoglobin threshold for a positive FIT was set to 100 μg/L. Those who were assessed as high risk by APCS with positive FIT were recorded as "APCS+FIT (+)". Those who were assessed as high risk by APCS with negative FIT, those who were assessed by APCS as low-middle risk with positive FIT, and those who were assessed by APCS as low-middle with negative FIT were all recorded as "APCS+FIT(-)". Observation indicators in this study were as follows: (1) the screening compliance rate of the cohort and the detection of advanced colorectal tumors; (2) positive predictive value, negative predictive value, sensitivity and specificity of HRFQ and APCS and their combination with FIT for screening advanced colorectal tumors; (3) comparison of the detection rate between HRFQ and APCS questionnaire for different colorectal lesions. Using SPSS 21.0 software, the receiver operating characteristic (ROC) curve was drawn to evaluate the clinical value of HRFQ and APCS combined with FIT in screening advanced colorectal tumors. Results: From 2017 to 2018 in Jiashan County, a total of 53 268 target subjects were screened, and 42 093 people actually completed the questionnaire, with a compliance rate of 79.02%. A total of 8145 cases underwent colonoscopy. A total of 3607 cases among HRFQ positive population (5320 cases) underwent colonoscopy, and the colonoscopy compliance rate was 67. 80%; 8 cases were diagnosed with colorectal cancer and 88 cases were advanced colorectal adenoma. A total of 2977 cases among APCS positive population (11 942 cases) underwent colonoscopy, and the colonoscopy compliance rate was 24.93%; 17 cases were diagnosed with colorectal cancer and 148 cases were advanced colorectal adenoma. The positive rate of HRFQ screening was lower than that of APCS [12.6% (5320/42 093) vs. 28.4% (11 942/42 093), χ2=3195. 547, P<0.001]. In the FIT positive population (6223 cases), a total of 4894 cases underwent colonoscopy, and the colonoscopy compliance rate was 78.64%; 34 cases were diagnosed with colorectal cancer and 224 cases were advanced adenoma. The positive predictive values of HRFQ and APCS and their combination with FIT for screening advanced colorectal tumors were 2.67%, 5.54%, 5.44%, and 8.56%; negative predictive values were 94.89%, 96.85%, 96.11% and 96.99%; sensitivity was 29.27%, 50.30%, 12.20 % and 39.02%; specificity was 55.09%, 64.03%, 91.11% and 82.51%, respectively. The ROC curves constructed by HRFQ, APCS, FIT, HRFQ+FIT and APCS+FIT indicated that APCS+FIT presented the highest efficacy in screening advanced colorectal tumors (AUC: 0.608, 95%CI: 0.574-0.642). The comparison of the detection rates of different colorectal lesions between HRFQ and APCS questionnaires showed that there were no significant differences in detection rate of inflammatory polyps and hyperplastic polyps between the two questionnaires (both P>0.05). However, as compared to HRFQ questionnaire, APCS questionnaire had higher detection rates in non-advanced adenomas [26.10% (777/2977) vs. 19.43% (701/3607), χ2=51.228, P<0.001], advanced adenoma [4.97% (148/2977) vs. 2.44% (88/3607), χ2=30.249, P<0.001] and colorectal cancer [0.57% (17 /2977) vs. 0.22% (8/3607), χ2=5.259, P=0.022]. Conclusions: APCS has a higher detection rate of advanced colorectal tumors than HRFQ. APCS combined with FIT can further improve the effectiveness of advanced colorectal tumor screening.

Professor LU Fan's clinical experience in shallow needling technique of acupuncture / 中国针灸

Professor LU Fan adheres to the principle in clinical practice, "the needling principle concentrated on regulating qi ". She takes the advantages of shallow needling technique of acupuncture in treatment of various diseases, e.g. exogenous disease, initial onset of disorder, chronic bi disorder, intractable diseases, disorder of yang nature, disorder of heat nature, thin body, pediatric diseases, disorders on the unilateral side of the body and acute diseases. Besides in compliance with classics, she has broadened the application scope of shallow needling technique of acupuncture and improved the clinical therapeutic effect.

Changes in sensitivity of bilateral medial vestibular nuclear neurons responding to input stimuli during vestibular compensation and the underlying ionic mechanism / 生理学报

Vestibular compensation is an important model for developing the prevention and intervention strategies of vestibular disorders, and investigating the plasticity of the adult central nervous system induced by peripheral injury. Medial vestibular nucleus (MVN) in brainstem is critical center for vestibular compensation. Its neuronal excitability and sensitivity have been implicated in normal function of vestibular system. Previous studies mainly focused on the changes in neuronal excitability of the MVN in lesional side of the rat model of vestibular compensation following the unilateral labyrinthectomy (UL). However, the plasticity of sensitivity of bilateral MVN neurons dynamically responding to input stimuli is still largely unknown. In the present study, by using qPCR, whole-cell patch clamp recording in acute brain slices and behavioral techniques, we observed that 6 h after UL, rats showed a significant deficit in spontaneous locomotion, and a decrease in excitability of type B neurons in the ipsilesional rather than contralesional MVN. By contrast, type B neurons in the contralesional rather than ipsilesional MVN exhibited an increase in response sensitivity to the ramp and step input current stimuli. One week after UL, both the neuronal excitability of the ipsilesional MVN and the neuronal sensitivity of the contralesional MVN recovered to the baseline, accompanied by a compensation of spontaneous locomotion. In addition, the data showed that the small conductance Ca2+-activated K+ (SK) channel involved in the regulation of type B MVN neuronal sensitivity, showed a selective decrease in expression in the contralesional MVN 6 h after UL, and returned to normal level 1 week later. Pharmacological blockage of SK channel in contralateral MVN to inhibit the UL-induced functional plasticity of SK channel significantly delayed the compensation of vestibular motor dysfunction. These results suggest that the changes in plasticity of the ipsilesional MVN neuronal excitability, together with changes in the contralesional MVN neuronal sensitivity, may both contribute to the development of vestibular symptoms as well as vestibular compensation, and SK channel may be an essential ionic mechanism responsible for the dynamic changes of MVN neuronal sensitivity during vestibular compensation.

Safety and efficacy of left atrial appendage closure combined with patent foramen ovale closure for atrial fibrillation patients with patent foramen ovale / 中华心血管病杂志

Objective: To analyze the safety and efficacy of combined left atrial appendage (LAA) and patent foramen ovale (PFO) closure in adult atrial fibrillation (AF) patients complicating with PFO. Methods: This study is a retrospective and cross-sectional study. Seven patients with AF complicated with PFO diagnosed by transesophageal echocardiography (TEE) in Zhoupu Hospital Affiliated to Shanghai University of Medicine & Health Sciences from June 2017 to October 2020 were selected. Basic data such as age, gender and medical history were collected. The atrial septal defect or PFO occluder and LAA occluder were selected according to the size of PFO, the ostia width and depth of LAA. Four patients underwent left atrial appendage closure(LAAC) and PFO closure at the same time. PFO closure was performed during a one-stop procedure of cryoablation combined with LAAC in 2 patients. One patient underwent PFO closure at 10 weeks after one-stop procedure because of recurrent transient ischemic attack (TIA). All patients continued to take oral anticoagulants. TEE was repeated 8-12 weeks after intervention. In case of device related thrombus(DRT), TEE shall be rechecked 6 months after adjusting anticoagulant and antiplatelet drug treatment. Patients were follow-up at 1, 3, 6, 12, 24 months by telephone call, and the occurrence of cardio-cerebrovascular events was recorded. Results: Among the 7 patients with AF, 2 were male, aged (68.0±9.4) years, and 3 had a history of recurrent cerebral infarction and TIA. Average PFO diameter was (3.5±0.8)mm. Three patients were implanted with Watchman LAA occluder (30, 30, 33 mm) and atrial septal defect occluder (8, 9, 16 mm). 2 patients were implanted with LAmbre LAA occluder (34/38, 18/32 mm) and PFO occluder (PF1825, PF2525). 2 patients were implanted with LACbes LAA occluder (24, 28 mm) and PFO occluder (PF2525, PF1825) respectively. The patients were followed up for 12 (11, 24) months after operation. TEE reexamination showed that the position of LAA occluder and atrial septal defect occluder or PFO occluder was normal in all patients. DRT was detected in 1 patient, and anticoagulant therapy was adjusted in this patient. 6 months later, TEE showed that DRT disappeared. No cardiovascular and cerebrovascular events occurred in all patients with AF during follow-up. Conclusions: In AF patients complicated with PFO, LAAC combined with PFO closure may have good safety and effectiveness.