Objective:To explore the mechanism of exacerbating chronic graft versus host disease (GVHD) in mice with inflammatory status and enhancing immune injury in mice with PD-1.Method:Bone marrow and spleen cells of DBA/2 mice were injected into BALB/C mice pretreated with chemotherapy regimen (Flu+Bu) for constructing a chronic GVHD model. The animals were assigned into two groups of zymosan (100M SPL+10M BM+Zymosan) and control (100M SPL+10M BM+ PBS). After transplantation, two groups of mice were observed for weight changes, survival status and chronic GVHD manifestations. Target organ tissues were harvested for pathological scoring. Flow cytometry was employed for detecting cell subpopulations and surface co-stimulatory molecules in target organs. PD-1 monoclonal antibody was injected into inflammatory murine model. Mice were observed and target organ cells were harvested for subsets and co-stimulatory factors.Result:In in vivo experiments, zymosan group showed more significant changes of chronic GVHD with higher mortality rate, faster weight loss and more severe symptoms of GVHD. At Week 2 post-transplantation, hematoxylin-eosin stain of target organ tissue was performed for pathology examination. Zymosan group showed more lymphocyte infiltration, more severe inflammation and more significant tissue injury with higher GVHD pathological score. The proportion of M2 in liver/lung of zymosan group was significantly lower than that of control group ( P<0.05) and no significant difference existed in the proportion of M1. In in vivo experiments, M1 ratio of splenic cell spiked markedly in zymosan group as compared to control group while M2 ratio declined greatly. The secretions of IL-4 and IL-10 dropped significantly while co-stimulatory molecules CD80 and CD86 rose obviously. Conclusion:The worsening graft-versus-host disease in inflammatory mice with anti-PD1 treatment is associated with a decline of Treg proportion.

Objective:To construct the evaluation index system of lumbar puncture teaching for medical students, aiming to create a scientific assessment and evaluation method covering theoretical knowledge, skill practice, and professional accomplishment, so as to comprehensively evaluate the teaching effect of lumbar puncture for medical students, and improve the practical ability of clinical skills of medical students more effectively.Methods:The evaluation index scheme of lumbar puncture teaching for medical students was initially formulated through literature review and group discussion, and 20 experts related to clinical front-line work and medicine were invited to revise the scheme by applying Delphi expert consultation and applying analytic hierarchy process to quantify the entries and establish the final index weights at all levels.Results:The valid recovery rate of both rounds of expert consultation questionnaires in this study was 100%. The second round of expert consultation was conducted without changing experts, with an authority factor of 0.88. Kendall's coefficient of harmony was 0.136 and 0.184, respectively. After two rounds of expert consultation, the evaluation index system of lumbar puncture teaching for medical students, including 3 primary indicators (theoretical knowledge, comprehensive clinical ability and professionalism), 7 secondary indicators and 22 tertiary indicators, was initially constructed.Conclusion:The evaluation index system of lumbar puncture teaching for medical students constructed in this study is scientific and credible, which can provide quantitative basis for the training and assessment of medical students, and is of great theoretical and practical significance.

RNA therapeutics inhibit the expression of specific proteins/RNAs by targeting complementary sequences of corresponding genes or encode proteins for the synthesis desired genes to treat genetic diseases. RNA-based therapeutics are categorized as oligonucleotide drugs (antisense oligonucleotides, small interfering RNA, RNA aptamers), and mRNA drugs. The antisense oligonucleotides and small interfering RNA for treatment of genetic diseases have been approved by the FDA in the United States, while RNA aptamers and mRNA drugs are still in clinical trials. Chemical modifications can be applied to RNA drugs, such as pseudouridine modification of mRNA, to reduce immunogenicity and improve the efficacy. The secure and effective delivery systems such as lipid-based nanoparticles, extracellular vesicles, and virus-like particles are under development to address stability, specificity, and safety issues of RNA drugs. This article provides an overview of the specific molecular mechanisms of eleven RNA drugs currently used for treating genetic diseases, and discusses the research progress of chemical modifications and delivery systems of RNA drugs.
Aptamers, Nucleotide ; RNA, Small Interfering/therapeutic use* ; RNA, Messenger ; Oligonucleotides, Antisense/therapeutic use*

RNA therapeutics inhibit the expression of specific proteins/RNAs by targeting complementary sequences of corresponding genes, or synthesize proteins encoded by the desired genes to treat genetic diseases. RNA-based therapeutics are categorized as oligonucleotide drugs (antisense oligonucleotides, small interfering RNA, RNA aptamers), and mRNA drugs. The antisense oligonucleotides and small interfering RNA for treatment of genetic diseases have been approved by the FDA in the United State, while RNA aptamers and mRNA drugs are still in clinical trials. Chemical modifications are applied to RNA drugs, such as pseudouridine modification of mRNA, to reduce immunogenicity and improve the efficacy. The secure and effective delivery systems like lipid-based nanoparticles, extracellular vesicles, and virus-like particles are under development to address stability, specificity, and safety issues of RNA drugs. This article provides an overview of the specific molecular mechanisms of 11 RNA drugs currently used for treating genetic diseases, and discusses the research progress of chemical modifications and delivery systems of RNA drugs.

OBJECTIVE: To explore the genetic etiology of Vici syndrome in a Chinese family. METHODS: Whole exome sequencing (WES) technology was used to detect gene variants in a fetus of abnormal ultrasonic structure without abnormalities in routine chromosome karyotype analysis and SNP-array. Sanger sequencing and bioinformatics prediction were performed for the suspected variants of the fetus and parents. RESULTS: The fetus and the elder sister have carried c. 2427delC (p.T809fs) and c.1886A>T (p.E629V) compound heterozygous variants of the EPG5 gene, which were respectively inherited from their mother and father. Neither variant was reported previously. According to ACMG guidelines, the c.2427delC variant was predicted as pathogenic, while the c.1886A>T variant was of uncertain significance. PolyPhen-2 and PROVEAN software indicated that c.1886A>T variant was probably damaging. CONCLUSION The c.2427delC and c.1886A>T variants of the EPG5 gene probably underlie the pathogenesis of the Vici syndrome in this family. Above finding has enriched the variational spectrum of EPG5 gene and provided a basis for genetic counseling and prenatal diagnosis for the family.
Aged ; Agenesis of Corpus Callosum ; Autophagy-Related Proteins ; Cataract ; Female ; Humans ; Mutation ; Pregnancy ; Vesicular Transport Proteins/genetics* ; Whole Exome Sequencing

Objective: To construct nomogram to predict the risk of bone metastasis in patients with non-small cell lung cancer(NSCLC). Methods: The clinical data of NSCLC patients diagnosed in the hospital were retrospectively analyzed, including the occurrence of bone metastasis, age, gender, pathological type, smoking status, PS score, TN stage, metastasis of other sites before bone metastasis, carcinoembryonic antigen(CEA) level, alpha fetoprotein(AFP) level, serum calcium(Ca2+), serum phosphorus(P), alkaline phosphatase(ALP) level, which were determined by univariate and multivariate logistic regression analysis. Receiver operating characteristic curve(ROC) and decision curve analysis were used, DCA was used to verify the accuracy and clinical benefit of the model, and nomogram was used to visualize the model. Results: Area under the ROC curve(AUC) showed that in the modeling group(n=138) and the validation group(n=92), the AUC value predicted by combined indicators(age, gender, pathological type, CEA, ALP)(modeling group=0.792, validation group=0.629) was higher than that predicted by single indicator. Conclusion The prediction model constructed in this study has good effect and can provide reference for clinical screening of high-risk patients with bone metastasis of NSCLC.

Objective:To explore the effects of secondary pulmonary hypertension(SPH)on postoperative outcomes of lung transplant recipients.Methods:The hospitalization data of 309 patients undergoing lung transplant were retrospectively analyzed. They were divided into normal(mPAP <25 mmHg, 56 cases), low-pressure(mPAP: 25 mmHg≤mPAP<40 mmHg, 155 cases)and high pressure(mPAP ≥40 mmHg, 98 cases)groups.Three groups were compared with regards to general profiles, intraoperative status, postoperative outcomes and survival rates. The postoperative patient survival was plotted by Kaplan-Meier curve and log-rank test performed. Multivariate Cox regression analysis was performed to explore the influencing factors of postoperative survival.Results:The distribution of chronic lung disease(CLD)was statistically different among 3 groups( χ2=30.837, P=0.001). Patients with different levels of pulmonary artery pressure had different decisions supported intraoperatively by extracorporeal membrane oxygenation(ECMO)( χ2=28.205, P<0.001). The 2-year survival rates of normal, low-pressure and high-pressure groups were 58.9 %, 63.9 % and 69.4 % respectively and there were no statistically significant differences( P=0.513). Multivariate Cox regression analysis indicated that preoperative cardiac function was an independent risk factor for postoperative survival. The postoperative risk of mortality was 1.796 (95 %CI: 1.078~2.991)folds higher in patients with cardiac function grade Ⅲ/Ⅳ than those with grade Ⅰ/Ⅱ( P=0.025). Conclusions:Preoperative classification of cardiac function should be emphasized in SPH patients. And surgery during early decompensated stage of cardiac function may confer a better survival.

Objective:To investigate the clinical efficacy of superficial temporal artery-anterior temporal artery bypass combined with encephalo-duro-arterio-synangiosis in the treatment of Moyamoya disease.Methods:A total of 42 patients with moyamoya disease, admitted to our hospital from January 2016 to January 2019, were selected and divided into observation group and control group according to surgical management. The patients in the observation group were treated with superficial temporal artery-anterior temporal artery bypass combined with encephalo-duro-arterio-synangiosis, and the patients in the control group were treated with superficial temporal artery-angular gyrus artery bypass combined with encephalo-duro-arterio-synangiosis. The clinical data of these patients were analyzed retrospectively, and the differences of efficacy and safety between the two groups were compared.Results:There was no significant difference in operation time between the two groups ([189.16±21.23] min vs. [179.46±16.95] min, P>0.05). One d after the operation, the patients in both groups were re-examined with CT angiography, and the anastomotic vessels were unobligated. Two patients in the observation group had cerebral infarction in the operative region and one patient in the control group had cerebral infarction in the operative region; no significant difference was noted in the incidence of postoperative complications between the two groups ( P>0.05). The modified Rankin scale (mRS) scores in both groups one month after surgery were significantly decreased as compared with those one d before surgery ( P<0.05); one month after surgery, the mRS scores in observation group (0.13±0.346) were significantly lower than those in the control group (0.42±0.515, P<0.05). Conclusion:The superficial temporal artery-anterior temporal artery bypass combined with encephalo-duro-arterio-synangiosis has definite clinical efficacy in the treatment of moyamoya disease.

Objective To analyze the effect of stroke duration on the cognitive function in the elderly population in Beijing.Methods Based on the Research Project of Beijing Chronic Disease Combined with Common Elderly Syndrome Community Management Practices,a cross-sectional study was used.From July 2013 to December 2014,the old population in 4 districts and a county (Xicheng District,Fangshan District,Tongzhou District and Yanqing County) in Beijing were sampled with the multi-stage,randomized and stratified sampling.A total of 3 024 subjects were enrolled in the study.The data were obtained from the questionnaires and clinical examinations.Mini-Mental State Examination (MMSE) was used as the evaluation index of cognitive function.The subjects were divided into either a normal cognitive function group (MMSE>26,n=1 878) or a cognitive impairment group (MMSE≤26,n=1 146) according to the MMSE scores.A multiple logistic regression model was used to analyze the effects of hemorrhagic stroke,ischemic stroke,and asymptomatic stroke,as well as disease duration on cognitive function.Results After adjusting for the confounding factors,such as sex,age,educational level,marriage,smoking,and alcohol consumption,the risks of occurring cognitive impairment in patients with hemorrhagic stroke in stroke duration for 1-3,4-10 and >10 years were OR 3.019 (95％CI 0.974-9.361,P=0.056),8.652 (95％CI 2.924-25.601,P<0.01) and 1.104 (95％CI 0.311-3.920,P=0.879) times of those without occurring stroke population;the risks of occurring cognitive impairment in patients with ischemic stroke in stroke duration for 1-3,4-10 and >10 years were 1.000 (95％CI 0.636-1.571,P=1.000),1.874 (95％CI 1.231-2.853,P=0.003),2.439 (95％CI 1.386-4.291,P=0.002) times of those without occurring stroke population.Stroke duration for 4-10 years in patients with hemorrhagic stroke and stroke duration for 4-10 and >10 years in patients with ischemic stroke were all the risk factors for occurring cognitive dysfunction.Conclusion For patients with stroke,stroke duration or long-term effects has a certain impact on cognitive function.

Objective To study the relationship between advanced liver fibrosis and peripheral neuropathy in patients with type 2 diabetes mellitus (DPN). Methods A total of 173 patients (89 men and 84 women) with type 2 diabetes who hos?pitalized in Tianjin Third Central Hospital within nearly three years (2013.02-2015.02) were divided into three groups ac?cording to non-alcoholic fatty liver disease (NAFLD) fibrosis score:group A (NFS≤-1.455), group B (-1.455