OBJECTIVES: To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients. METHODS: A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed. RESULTS: An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048). CONCLUSIONS Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT04251871 at www.clinicaltrials.gov ).
Administration, Inhalation ; Adult ; China ; Coronavirus Infections ; diagnosis ; drug therapy ; mortality ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Follow-Up Studies ; Humans ; Integrative Medicine ; Interferon-alpha ; administration & dosage ; Lopinavir ; administration & dosage ; Male ; Middle Aged ; Pandemics ; Pneumonia, Viral ; diagnosis ; drug therapy ; mortality ; Risk Assessment ; Severe Acute Respiratory Syndrome ; diagnosis ; drug therapy ; mortality ; Severity of Illness Index ; Survival Rate

The coronavirus disease 2019(COVID-19) is raging in China and more than 20 other countries and regions since the middle of December 2019. Currently, there is no specific drug or vaccine besides symptomatic supportive therapy. Taking full advantage of the clinical experience of traditional Chinese medicine(TCM) in preventing and controlling major epidemics such as SARS, it is an important mission for TCM to propose effective formula with immediate response and solid evidence by using modern biomedical knowledge and techniques(molecular docking assisted TCM formulation for short). In view of the high homology between the gene sequences of the novel coronavirus and SARS virus, and the similarities between the two in terms of pathogenic mechanism and clinical manifestations, our team established a rapid screening and optimization model for the prevention and treatment of the novel coronavirus based on clinical experience and molecular docking technology. Firstly, the clinical team and the research team pre-developed and screened TCM formula by using "back-to-back" manner. Then, the formula was optimized and determined by comparing and analyzing the results of the two groups. The results showed that the research team screened out 46 active ingredients from candidate TCMs that could act on the novel coronavirus S-protein-binding site of human ACE2 protein, which were mainly attributed to 7 herbs such as Lonicerae Japonicae Flos and Mori Folium. The result was largely consistent with the formula raised by the clinical group, verifying and supporting its rationality. This provides evidence for the scientific and potential efficacy of the TCM prescription from the perspective of treatment target analysis, and also suggests that the TCM prescription has the potential to directly inhibit viral infection in addition to improving clinical symptoms or syndromes. Based on this, our team optimized and formed a new anti-coronavirus TCM prescription "Keguan Yihao", immediately providing the TCM prescription with certain clinical experience and objective evidence support for the prevention and treatment of new emergent infectious diseases in our hospital. The TCM prescription was combined with modern medicine symptomatic supportive treatment for clinical treatment, preliminary results showed better effect than symptomatic supportive therapy alone. This research has innovated the method mode in clinical practice and basic research integration of traditional Chinese medicine for the prevention and control of new emerging infectious diseases. It is of great significance to further improve the rapid response mechanism of TCM in face of major epidemics, and further improve the capability level of TCM to prevent and treat new emerging infectious diseases.
Angiotensin-Converting Enzyme 2 ; Angiotensin-Converting Enzyme Inhibitors/pharmacology* ; Betacoronavirus ; COVID-19 ; China ; Coronavirus Infections/drug therapy* ; Drugs, Chinese Herbal/pharmacology* ; Humans ; Medicine, Chinese Traditional ; Molecular Docking Simulation ; Pandemics ; Peptidyl-Dipeptidase A/chemistry* ; Pneumonia, Viral/drug therapy* ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/chemistry* ; COVID-19 Drug Treatment

Background:Transcranial alternating current stimulation (tACS) offers a new approach for adult patients with major depressive disorder (MDD).The study is to evaluate the efficacy and safety of tACS treating MDD.Methods:This is an 8-week,double-blind,randomized,placebo-controlled study.Ninety-two drug-naive patients with MDD aged 18 to 65 years will receive 20 daily 40-min,77.5-Hz,15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas on weekdays for 4 consecutive weeks (week 4),following a 4-week observation period (week 8).The primary outcome is the remission rate defined as the 17-item Hamilton depression rating scale (HDRS-17) score ≤7 at week 8.Secondary outcomes are the rates of response at weeks 4 and 8 and rate of remission at week 4 based on HDRS-17,the proportion of participants having improvement in the clinical global impression-improvement,the change in HDRS-17 score (range,0-52,with higher scores indicating more depression) over the study,and variations of brain imaging and neurocognition from baseline to week 4.Safety will be assessed by vital signs at weeks 4 and 8,and adverse events will be collected during the entire study.Discussion:The tACS applied in this trial may have treatment effects on MDD with minimal side effects.

·Rodents have been used widely in the research of eye diseases to study visual function in animal models. Two methods of visual acuity testing in animals have been internationally recognized:the electrophysiological visual acuity test and the behavioral visual acuity test. Both of these methods have their advantages and limitations. The electrophysiology test (visual evoked potential) is invasive, and animals need recovery time after being implanted with electrodes. Also,the electrophysiological visual acuity test only reflects the electrical activity of a single cell or nuclei, it does not reflect the overall visual function of the animal. The widely used behavioral visual acuity test is able to compensate for these limitations. This paper gives a brief overview of the methods of the behavioral visual acuity test for rodents (rats, mice, guinea pigs,etc.).

Objective To understand the variation of thyroid hormones in each trimesters of pregnancy in women.Methods A total of 1 839 pregnant women in different trimesters were enrolled and thyroid hormones including FT3,FT4,TT3, TT4,TSH,TGAb and TPOAb were measured.The reference range of hormone in each trimester was calculated.Results There were statistically differences in all thyroid hormones among all trimesters of pregnancy women (P<0.05 )except for TT4 between the early and middle trimesters (P>0.05 ).The median of FT3 and FT4 were gradually reduced as the pregnant trimester grew up while the median of TSH had the adverse tendency.The median of TT3 was highest during the middle trimester (1.47 nmol/L).TT4 median was lowest during the late trimester (80.67 nmol/L).The TSH level of pregnant women over 30 years old was significantly lower than that of below 30 age group during all trimesters(P<0.05 ). There were significant differences in FT4,TT3 and TT4 level among early and middle trimesters among different ages groups(P<0.05 ).The positive rates of TGAb and TPOAb during late trimester (4.74% and 1.63%)were significantly lower than those of early trimester (1 4.40% and 5.56%)and middle trimester (1 4.40% and 5.56%)(P<0.05 ). Conclusion Significant differences of thyroid hormones are found not only in different stages of pregnancy,but also in different ages.Therefore,establishing trimester-specific reference data of thyroid hormones during different pregnency may be important for clinical practice.

This study was purposed to investigate the difference of nucleated cell (NC) count, CD34(+) cell ratio and expansion multiple, cell cycle and colony formation capability in in vitro expanded human umbilical cord blood CD34(+) cells from HOXB4-transfecting directly and HOXB4-transfected human umbilical cord mesenchymal stem cells (HUCMSC) by means of prepared feeder layers of HUCMSC. The HUCMSC were divided into 2 groups:first group, in which HOXB4 gene was transfected into HUCMSC by using lentiviral vecfor, and feeder layers were set up; and second group in which feeder layers for HUCMSC of non-transfected HOXB4 gene were set up. The CD34(+) cells were separated from HUCB by magmatic activated cell sorting(MACS). After culture in medium with cytokines for 2 days, CD34(+) cells were divided into 5 groups, including control group and experimental group. The control groups included CD34(+) cells as group A (blank control group) and GFP-CD34(+) cells as group B (negative control group) and experimental groups included HOXB4-CD34(+) cells as group C, HUCMSC+CD34(+) cells as group D, HOXB4-HUCMSC+ CD34(+) cells as group E and cells in all groups were cultured in vitro. The number of nucleated cells were counted at day 6, 10, 14 of culture and CD34 immunophenotypes, cell cycle and colony forming capability were measured at day 10 of culture in different conditions. The results indicated that HOXB4 gene could be transfected into HUCMSC by lentiviral vector and feeder layers were set up successfully. After culture for 14 days, the nucleated cells in 5 groups could be amplified effectively, and the expansion levels in 5 groups were in order HOXB4-HUCMSC+CD34(+) cell group> HOXB4-CD34(+) cell group>HUCMSC+CD34(+) cell group> control groups (P < 0.05). At day 10 of in vitro expansion the CD34(+) cell percentage decreased significantly in all groups, while the number of CD34(+) cell increased in experiment groups, which were in order HOXB4-CD34(+) cells group> HOXB4-HUCMSC+CD34(+) cell group>HUCMSC+CD34(+) cell group>control groups (P < 0.05). The cell cycle detection showed that the percentage of cells in S+G2/M phase in experiment groups were higher than that in control groups (P < 0.05), and percentage of cells in HOXB4-HUCMSC+CD34(+) cells group was higher (41.57%) than that in HOXB4-CD34(+) cells group(37.87%) and HUCMSC+CD34(+) cell group (28.65%) (P < 0.05). There was no statistical difference in the CFU number between HOXB4-HUCMSC+CD34(+) cell group and HOXB4-CD34(+) cell group, which were both higher than that in HUCMSC+CD34(+) cell group and control groups (P < 0.05).It is concluded that the CD34(+) cells cultured on HOXB4-HUCMSC feeder layers can be amplified significantly and kept the characteristics of stem cells, The feeder lager of HOXB4-HUCMSC is relative safe for amplification of CD34(+) cells in vitro, it possesses the potential useful value.
Antigens, CD34 ; immunology ; Cell Separation ; Cells, Cultured ; Fetal Blood ; cytology ; Homeodomain Proteins ; genetics ; Humans ; Mesenchymal Stromal Cells ; cytology ; immunology ; Transcription Factors ; genetics ; Transfection ; Umbilical Cord ; cytology ; immunology

BACKGROUNDAntibodies against type 3 muscarinic acetylcholine receptor (M3R) are involved in the pathogenesis of Sjögren's syndrome (SS), but the clinical value of them in SS patients has been controversial. The aims of this study were to: (1) establish an improved enzyme-linked immunosorbent assay (ELISA) to detect IgA antibodies against M3R; (2) evaluate the value of IgA antibodies against the second extracellular loop of M3R205-220 (c2M3RP) in diagnosis of SS.

METHODSTo increase the ELISA sensitivity, c2M3RP was coupled to bovine serum albumin (BSA) by the glutaraldehyde method and a 96-well microplate was treated by ultraviolet rays before coated. Concentrations of anti-c2M3RP, anti-SSA, and anti-SSB were measured in the sera of 240 individuals: 91 patients with primary SS and 149 controls (16 secondary SS, 27 systemic lupus erythematosus, 40 rheumatoid arthritis and 66 healthy controls). Diagnostic properties of anti-c2M3RP were determined by receiver-operating characteristic curve analysis.

RESULTSThe prevalence of serum IgA anti-c2M3RP antibodies in patients with pSS (46%, 42/91) was significantly higher than that in patients with systemic lupus erythematosus (19%, 5/27), in rheumatoid arthritis (15%, 6/40) and in healthy controls (5%, 3/66). However, there was no significant difference between the two SS groups (P = 0.727). The diagnostic performance of IgA anti-M3RP antibodies was similar to anti-SSA assay, but had 22% higher sensitivity than anti-SSB. By analyzing of IgA anti-c2M3RP antibodies, combination of anti-SSA and anti-SSB resulted in increased sensitivity, whereas their specificity was not significantly changed.

CONCLUSIONSThe improved anti-c2M3RP ELISA is a novel, sensitive, and specific serological test for the diagnosis of SS. The combined application of anti-c2M3RP, anti-SSA and anti-SSB tests can improve the laboratory diagnosis of SS. The IgA anti-c2M3RP antibodies may serve as a novel diagnostic marker for SS.

Adult ; Aged ; Aged, 80 and over ; Animals ; Autoantibodies ; immunology ; Biomarkers ; blood ; Cattle ; Enzyme-Linked Immunosorbent Assay ; methods ; Female ; Humans ; Immunoglobulin A ; blood ; Male ; Middle Aged ; Receptors, Muscarinic ; immunology ; Sjogren's Syndrome ; blood ; Young Adult

Antitubercular Agents ; adverse effects ; Chemical and Drug Induced Liver Injury ; prevention & control ; Chemoprevention ; China ; Clinical Trials as Topic ; Humans ; Protective Agents ; therapeutic use ; Tuberculosis ; drug therapy

OBJECTIVETo investigate the relationship between the hormesis of proliferation and oxidative stress induced by sodium arsenite (Na(2)AsO(2)) in human embryo lung fibroblasts (HELF).

METHODSHELF were treated with Na(2)AsO(2) of 0.0, 0.1, 0.5, 1.0, 5.0 and 10.0 micromol/L for 4 hours or 24 hours, respectively. The cell proliferation, the reactive oxygen species (ROS) level, the malondialdehyde (MDA) content and the activity of glutathione peroxide (GSH-Px) and the superoxide dismutase (SOD) in HELF were detected respectively.

RESULTSThe HELF proliferation induced by 0.1 and 0.5 micromol/L Na(2)AsO(2) was significantly higher than that in the control group (P < 0.01). The HELF proliferation induced by 5.0 and 10.0 micromol/L Na(2)AsO(2) was significantly lower than that in the control group (P < 0.01) with the dose-effect relation of an inverted U curve. The ROS level induced by Na(2)AsO(2) of between 0.5 and 10.0 micromol/L was significantly increased (P < 0.05, P < 0.01). The positive correlation was found between the ROS level and the exposure dose of Na(2)AsO(2) (r = 0.934, P < 0.01). The 5.0 and 10.0 micromol/L Na(2)AsO(2) induced the significant increase of the MDA contents (P < 0.01) and the significant decrease of the GSH-Px activity compared to those in the control group (P < 0.01). The SOD activity in 0.5 micromol/L Na(2)AsO(2) group was significantly higher than that in the control group (P < 0.01) while the SOD activity induced by 5.0 and 10.0 micromol/L Na(2)AsO(2) was significantly decreased (P < 0.01) if compared with the control group with the dose-effect relation of an inverted U curve.

CONCLUSIONThe sodium arsenite can induce the hormesis of proliferation in HELF with the dose-effect relation of an inverted U curve. The mechanisms probably relates to different levels of oxidative stress induced by sodium arsenite of different concentrations.

Arsenites ; toxicity ; Cell Proliferation ; drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Fibroblasts ; cytology ; drug effects ; metabolism ; Glutathione Peroxidase ; metabolism ; Humans ; Lung ; cytology ; embryology ; Malondialdehyde ; metabolism ; Oxidative Stress ; drug effects ; Reactive Oxygen Species ; metabolism ; Sodium Compounds ; toxicity ; Superoxide Dismutase ; metabolism

OBJECTIVETo study the prevalence rates of birth defects in high and low risk areas in China.

METHODSA population-based surveillance system on birth defects was used to obtain the prevalence rates of 24 kinds of major external birth defects from > or = 20 weeks of gestation to 7 days of life in selected areas in Shanxi and Jiangsu provinces.

RESULTSThe birth prevalence of birth defects (232.4 per 10,000 births) and neural tube defects (NTDs) (138.7 per 10,000 births) in four counties of Shanxi province were significantly higher than that in Taiyuan city (75.3 and 28.2 per 10,000 births, respectively). There was no significant difference for all selected birth defects between Wuxi city and Xishan counties in low risk areas. There was a 6.1-fold of higher prevalence for NTDs in Taiyuan city compared with that in Wuxi areas (4.6 per 10,000 births). In four counties of Shanxi province, the prevalence rates of anencephaly, spina bifida, hydrocephaly, cleft palate alone and polydactyly were significantly higher than in Wuxi areas. The NTDs prevalence rate in four counties of Shanxi was 30.2 times higher than in Wuxi areas. When compared with previous surveillance data, the NTDs prevalence rate did not present obvious declining trend in high risk areas. The birth prevalence rate had a 31.8% decrease when births were calculated after 28 gestational weeks and compared with those from 20 gestational weeks.

CONCLUSIONNTDs remained to be the most common birth defect seen in Shanxi province. The birth prevalence rate of NTDs in some areas of Shanxi province was among the highest that ever reported in the world in comparison with data from other countries and regions. The current prevalence rate in high risk areas in Shanxi province did not clearly show a declining trend. Programs on surveillance and prenatal diagnosis were proved to have made big impact on the rates of major external birth defects.

China ; epidemiology ; Congenital Abnormalities ; epidemiology ; Female ; Humans ; Male ; Neural Tube Defects ; epidemiology ; Prevalence ; Surveys and Questionnaires