Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

BACKGROUND:At present,the surgical treatment of atlantoaxial dislocation mainly adopts the posterior atlantoaxial screw-rod internal fixation system for lifting and reduction.During the operation,the curvature of the connecting rod is often increased to increase the drop between the atlantoaxial vertebrae to improve the reduction effect,but it increases the difficulty and risk of surgery.The axis pivot screw directly increases the reduction drop between the atlantoaxial vertebrae,but the extent to which it increases the reduction capacity is unclear.OBJECTIVE:To test the reduction ability of axis pivot screw and compare it with ordinary screw.METHODS:Six fresh human craniocervical specimens were used in study.The joint capsules of two lateral mass joints and atlanto-odontoid joint and transverse ligament were removed to make an atlantoaxial instability model.Three kinds of internal fixation were performed successively on both sides of the axis of each specimen:uniaxial axis pivot screws(group A),multi-axial axis pivot screws(group B)and ordinary screws(group C).Flexible ultra-thin film pressure sensors were placed in the anterior atlanto-odontoid space.Two connecting rods with the same curvature were placed to simulate the lifting and reduction,and the pressure of the anterior atlanto-odontoid space was obtained.Comparative analysis was conducted among the three groups.RESULTS AND CONCLUSION:(1)The anterior atlanto-odontoid space pressure of groups A-C was(97.59±8.58),(60.43±5.09),and(22.74±0.81)N,respectively.There were significant differences among the three groups(F=251.603,P=0.000).The pairwise comparison among the three groups showed significant differences(P=0.000).(2)The axis pivot screw applied to the posterior atlantoaxial screw-rod internal fixation system can improve the reduction capacity compared with the common cervical posterior screw,and the uniaxial axis pivot screw has more reduction capacity than the multi-axis uniaxial axis pivot screw to improve the posterior atlantoaxial screw-rod internal fixation system.

BACKGROUND:At present,the surgical treatment of atlantoaxial dislocation mainly adopts the posterior atlantoaxial screw-rod internal fixation system for lifting and reduction.During the operation,the curvature of the connecting rod is often increased to increase the drop between the atlantoaxial vertebrae to improve the reduction effect,but it increases the difficulty and risk of surgery.The axis pivot screw directly increases the reduction drop between the atlantoaxial vertebrae,but the extent to which it increases the reduction capacity is unclear.OBJECTIVE:To test the reduction ability of axis pivot screw and compare it with ordinary screw.METHODS:Six fresh human craniocervical specimens were used in study.The joint capsules of two lateral mass joints and atlanto-odontoid joint and transverse ligament were removed to make an atlantoaxial instability model.Three kinds of internal fixation were performed successively on both sides of the axis of each specimen:uniaxial axis pivot screws(group A),multi-axial axis pivot screws(group B)and ordinary screws(group C).Flexible ultra-thin film pressure sensors were placed in the anterior atlanto-odontoid space.Two connecting rods with the same curvature were placed to simulate the lifting and reduction,and the pressure of the anterior atlanto-odontoid space was obtained.Comparative analysis was conducted among the three groups.RESULTS AND CONCLUSION:(1)The anterior atlanto-odontoid space pressure of groups A-C was(97.59±8.58),(60.43±5.09),and(22.74±0.81)N,respectively.There were significant differences among the three groups(F=251.603,P=0.000).The pairwise comparison among the three groups showed significant differences(P=0.000).(2)The axis pivot screw applied to the posterior atlantoaxial screw-rod internal fixation system can improve the reduction capacity compared with the common cervical posterior screw,and the uniaxial axis pivot screw has more reduction capacity than the multi-axis uniaxial axis pivot screw to improve the posterior atlantoaxial screw-rod internal fixation system.

Objective To retrospectively analyze the diagnostic value of thrombin-antithrombin complex(TAT),thrombomodulin(TM),and tissue plasminogen activator-inhibitor complex(t-PAIC)in severe cases of corona virus disease 2019(COVID-19).Methods A cohort of 79 patients clinically diagnosed with COVID-19 was retrospectively assembled and categorized into two groups based on disease severity:non-severe(n=51)and severe(n=28).In this study the differences of coagulation function and inflamma-tory marker levels between the two groups were compared.The correlations of TAT,TM and t-PAIC with other biomarkers were investi-gated.The diagnostic values of all the markers for severe COVID-19 were assessed.Results The patients of severe COVID-19 exhibi-ted significantly higher levels of TAT,TM,and t-PAIC compared to those of non-severe group(P＜0.001).The levels of TAT,TM and t-PAIC showed notable positive correlation with other biomarkers.TAT demonstrated the strongest positive correlation with the level of D-dimer(r=0.786,P＜0.001).Binary logistic regression analysis identified TAT(OR=1.346,P＜0.05)and t-PAIC(OR=1.128,P＜0.05)were independent risk factors in term of severe COVID-19.The combined ROC curve for TAT,TM and t-PAIC revealed high diagnostic efficacy in severe cases with the area under the curve(AUCROC)were 0.918,and the sensitivity and specificity were of 75％and 94.1％,respectively.Conclusion The results of combined measurement of TAT,TM and t-PAIC effectively demonstrates its diagnostic value in identifying severity and stratification of COVID-19 cases and may have important clinical significance for assessment of the severity and prediction of the prognosis.

OBJECTIVE To evaluate the short-term efficacy of single-session microwave ablation for benign thyroid nodule.METHODS Patients with benign thyroid nodules treated by microwave ablation between June 2019 and December 2022 at the Department of Otolaryngology Head and Neck Surgery,the First Affiliated Hospital of Xi'an Jiaotong University,were included for analysis.Thyroid function was tested 1 month after treatment,and ultrasound and thyroid function were performed 3 months,6 months and 1 year after treatment.Volume reduction rates(VRR)of nodules were calculated.Data of the last follow-up within 1 year were included for analysis.Variables including gender,age,whether Hashimoto's thyroiditis was present,longitudinal diameter of nodules,solid volume of nodules were included for univariate and multivariate analysis.RESULTS A total of 151 patients with 163 nodules were included.The perioperative complication rate was 1.99%(3/151).The VRR at half year after treatment was(79.58±17.70)%,and the success rate at half year after treatment was 93.43%(128/137).The VRR of at 1year after treatment was(81.24±24.29)%.The 1-year treatment success rate was 92.77%(77/83).Univariate and multivariate analysis showed that nodular solid volume and age were independent factors affecting VRR after ablation.Regression coefficient of age and solid volume was 0.34(P<0.05)and-0.47(P<0.05),respectively.For every 1 cm3 increase in solid volume,1-year VRR(%)decreased by 0.47.Regression equation:1-year VRR=68.92+0.34×age-0.47×solid volume.Serum FT4 gradually decreased and the thyroid stimulating hormone(TSH)gradually increased within 6 months after ablation,and the differences were statistically significant(P<0.05).After 6 months,serum FT4 gradually recovered to the normal level and TSH gradually recovered.However,TSH still did not reach the preoperative level one year after ablation.FT3 decreased gradually after treatment,but there was no significant difference between the values at each time point(P=0.40).After the ablation of thyroid nodule,the mean value of thyroid function index fluctuated,but all of them were within the normal reference range.CONCLUSION Microwave ablation is a safe and effective treatment method for benign thyroid nodules,with an overall success rate of over 90%.Solid nodule volume and age are independent factors affecting the microwave ablation effect of benign thyroid nodules.

To investigate the effects of maternal exposure to 13 chemicals mixture (CM) during pregnancy on pregnancy outcome and health status of maternal/offspring mice. C57BL/6 pregnant mice were given drinking water containing carbaryl dimethoate glyphosate methomyl methyl parathion triadimefon aspartame sodium benzoate calcium disodium ethylene diamine tetra-acetate ethylparaben butylparaben bisphenol A and acacia gum The effects of CM exposure on pregnancy outcome, health status of dams/offspring, levels of circulating inflammatory cytokines in dams/offspring and emotional related behaviors of offspring were evaluated. CM exposure during pregnancy had no significant effect on pregnancy outcome, liver function, body weight of the dams in late pregnancy and uterine/ovarian weight after delivery, however, it led to an increase in maternal serum IFN-γ level （<0.05）. CM exposure during pregnancy had no significant effect on the liver function of offspring, but increased the serum IFN-γ, prefrontal cortex IFN-γ, and TNF-α and hippocampus IFN-γ levels in the offspring（all <0.01）. In addition, the offspring of CM group showed significant abnormal emotion-related (autism-like) behaviors in adulthood, especially in male offspring. Low dose CM exposure during pregnancy may induce inflammation status in dams/offspring, and lead to autism-like behaviors in offspring, indicating the potential effects of low dose CM exposure on human maternal and infant health.
Adult ; Animals ; Autistic Disorder/chemically induced* ; Female ; Humans ; Male ; Maternal Exposure/adverse effects* ; Mice ; Mice, Inbred C57BL ; Phenotype ; Pregnancy ; Prenatal Exposure Delayed Effects/chemically induced*

ObjectiveTo investigate the risk factors for failure in emergency endoscopic injection sclerotherapy (EIS) combined with sequential histoacryl injection (HI) for esophagogastric variceal bleeding (EGVB) with portal vein embolus (PVE). MethodsA total of 109 EGVB patients with PVE who underwent emergency gastroscopy in Beijing Shijitan Hospital, Capital Medical University, and The Fifth Medical Center of Chinese PLA General Hospital from January 2018 to December 2019 were enrolled, and according to the outcome of hemostatic treatment under emergency gastroscopy, the patients were divided into hemostatic failure group with 28 patients and hemostatic success group with 81 patients. The two groups were compared in terms of general information, varices and bleeding manifestations under gastroscopy, blood biochemical parameters, Child-Pugh class, and Model for End-Stage Liver Disease (MELD) score, and the risk factors for hemostatic failure were analyzed. The t-test or the Mann-Whitney U test was used for comparison of continuous data between groups, and the chi-square test was used for comparison of categorical data between groups; a logistic regression analysis was used for multivariate analysis. ResultsCompared with the hemostatic success group, the hemostatic failure group had significantly higher peripheral white blood cell count (WBC), total bilirubin (TBil), Child-Pugh class, and MELD score (Z=3.794, Z=4.751, χ2=40.104, Z=6.412, all P＜0001) and significantly lower prothrombin time activity (PTA), albumin (Alb), and cholinesterase (CHE) (t=9.653, Z=3.093, Z=4.092, P＜0.001, P=0.002, and P＜0.001). WBC (odds ratio ［OR］=28.543, 95% confidence interval ［CI］: 1.285-634.113, P＜0.05), PTA(OR=0.194, 95%CI: 0.045-0.835, P＜0.05), TBil (OR=2.197, 95%CI: 1.004-4.810, P＜0.05), Alb (OR=0448, 95%CI: 0.209-0.961, P＜0.05), and Child-Pugh class (OR=5.164, 95%CI: 1.307-20.406, P＜0.05) were independent risk factors for hemostatic failure. ConclusionWBC, PTA, TBil, Alb, and Child-Pugh class are independent risk factors for failure in emergency EIS combined with sequential HI in the treatment of EGVB with PVE, and adequate preoperative evaluation and correction may help to improve the success rate of hemostasis.

Objective:To analyze the prognostic factors of Krukenberg tumors derived from the gastric cancer and colorectal cancer, so as to guide comprehensive treatment; looking for objective and sensitive indicators of ovarian metastasis during the follow-up after the surgery for gastric and colorectal cancer, which provides a basis for early diagnosis.Methods:Retrospectively analyzed the clinical data of 75 patients diagnosed with Krukenberg tumor admitted to Beijing Friendship Hospital, Capital Medical University from June 2007 to February 2020. Log-rank method and COX regression analysis were used to find independent prognostic factors. Wilcoxon rank sum test was used to compare the dynamic changes of ovarian imaging and tumor markers and to find the more sensitive indicators in the follow-up of patients with metachronous metastasis.Results:In the 75 cases, the univariate analysis suggested that CA19-9≥123.5 U/mL ( P=0.001), CA12-5≥37.9 U/mL ( P=0.018), Krukenberg tumor of stomach origin ( P=0.037), extra-ovary metastasis ( P=0.014), and without cytoreductive surgery (CRS) ( P<0.001)were poor prognostic factors. Among them, cytoreductive surgery could significantly improve the prognosis, even if with visible residual lesions, the overall survival was still significantly longer than those who have not undergone cytoreductive surgery ( P=0.004). Multivariate analysis results showed that CA19-9 and cytoreductive surgery ( P=0.001) were independent prognostic factors for patients with Krukenberg tumor; during the postoperative follow-up, ultrasound and CT imaging changes were more sensitive to ovarian metastasis ( P=0.006). Conclusions:CRS can prolong significantly the overall survival (OS) of patients with krukenberg tumor. Patients with simultaneous metastases should not give up the opportunity for surgery, and patients with metachronous metastases should also receive ovary resection procedure, even if with visible residual lesions, the patients can still benefit from the procedure. In the follow-up for gastric and colorectal cancer, attention should be paid to the ovarian ultrasound and CT imaging changes to facilitate early detection of ovarian metastases.

This paper elaborates the specific implementation process of the "research-based learning" teaching reform of genetic experiment in medical undergraduate education, including the change of teaching philosophy among teachers, the integration and expansion of experimental contents, the innovation of classroom-teaching model, the compilation of proper textbook, the update of assessment methods and the establishment of evaluation mechanism for teaching and so on. Preliminary research shows that RBL teaching reform can stimulate medical students' interest and potential in learning, and improve their practical and scientific research innovation ability.

Objective:To investigate the clinical significances of CD4/CD8 ratio and neutrophil-to-lymphocyte ratio (NLR) in patients with multiple myeloma (MM).Methods:The clinical data of 124 MM patients in the Third Affiliated Hospital of Soochow University from December 2002 to April 2017 were retrospectively analyzed, and 31 healthy people were chosen as the controls. Peripheral blood T lymphocyte subsets were detected by using flow cytometry, and the correlations between CD4/CD8 ration and related clinical indicators were also investigated. All MM patients were divided into the high NLR group and the low NLR group according to the media of NLR, and the correlation of them with related clinical indicators, chromosome karyotype, overall survival (OS) and progression-free survival (PFS) was also compared.Results:Compared with the healthy control group, the proportion of CD4 + T cells [(35.28±6.58)% vs. (31.85±6.76)%, t = -2.067, P = 0.043], absolute value of NK cells [0.22×10 9/L (0.13×10 9/L-0.59×10 9/L) vs. 0.17×10 9/L (0.00×10 9/L-0.42×10 9/L), Z = -2.614, P = 0.009] and CD4/CD8 ratio [0.97 (0.50-2.69) vs. 0.81 (0.30-1.28), Z = -2.253, P = 0.024] was decreased, respectively. The proportion of CD8 + cells was increased [(36.93±7.38)% vs. (40.50±6.50)%, t = 2.074, P = 0.042] in MM group. The hemoglobin level of CD4/CD8 ratio ≥0.94 group was higher than that of CD4/CD8 ratio <0.94 [(98.89±21.35) g/L vs.(80.60±23.23) g/L, t = -2.066, P = 0.047]. Compared with the healthy control group, NLR was increased in MM group [1.54 (1.10-3.23) vs. 1.95 (0.29-12.70), Z = -2.384, P = 0.017]. Compared with the low NLR group (<1.95), serum β 2-microglobulin [4.56 mg/L (1.63-12.60 mg/L) vs. 6.17 mg/L (1.58-67.50 mg/L), Z = -2.586, P = 0.010] and serum creatinine [84.5 μmol/L (43.0-376.5 μmol/L) vs. 113.0 μmol/L (46.5-754.0 μmol/L), Z = -3.866, P < 0.001] was increased in the high NLR group for MM patients. The proportion of the male patients, β 2-microglobulin > 5.5 mg/L, serum creatinine > 177 μmol/L, stage Ⅲ of international staging system (ISS) in the high NLR group was higher than that in the low NLR group (all P < 0.05), and there was no statistically significant difference in the composition of chromosome karyotype (all P > 0.05). The median OS time in the low NLR group was longer than that in the high NLR group [30 months (20-40 months) vs. 17 months (7-27 months), χ 2 = 4.519, P = 0.034], and there was no statistically significant difference in the PFS of both groups ( P > 0.05). Multivariate Cox analysis demonstrated that the age, corrected serum calcium, serum creatinine, lactic dehydrogenase were the independent influencing factors of OS in MM (all P < 0.05), while NLR wasn′t an independent influencing factor of OS in MM ( P = 0.513). Conclusions:CD4/CD8 ratio is decreased and immune dysfunction occurs in MM patients. MM patients with high NLR have a shorter OS time.