BACKGROUND: Stroke-prone spontaneously hypertensive rat(SHRsp) is an animal model of hypertensive stroke commonly used. The species is hard to be maintained due to hypertension and easily affected by environmental factors, therefore the characteristics of stroke are always aberrated.OBJECTIVE: To observe the abilities of reproduction and maintaining the characteristics of hypertensive stroke in SHPsp.DESIGN: Observational controlled study based on rats.SETTING: Cardiovascular Disease Institute and Fuwai Hospital of Chinese Academy of Medical Sciences.MATERIALS: The experiment was conducted Cardiovascular Disease Institute and Fuwai Hospital of Chinese Academy of Medical Sciences during September 1999 to December 2001. Totally 93 pairs(186) strain SHRsp, 48stroke-prone spontaneously hypertensive rats of 8 weeks age as well as 98pairs(196) rats of normal blood pressure [Wistar Kyoto rat (WKY) ] were selected.METHODS: Brother sister mating method was used. And the conception rate, number of litter size(only calculating the litter size of mother rat not eating neonatal rats), rate of eating neonatal rats by mother rats were recorded and compared with those of WKY. The systolic pressure and heart rate of strain rat were measured when they were 12, 16 and 20 weeks old. In addition, 488-week SHRsp were loaded 10 g/L salty water to accelerate the occurrence of stroke and hypertension and executed when they naturally dead or 12 weeks after salty water load. The brain tissue was processed by H-E staining and observed under microscope to detect the incidence of stroke.MAIN OUTCOME MEASURES: Conception rate of female rats within 2years; litter rate of pregnant rats; eating, rate of eating neonatal rats by mother rats; systolic pressure of strain rat; heart rate; detection rate of stroke.RESULTS: Totally 93 pairs(186) strain rats of SHRsp, 98 pairs(196) WKY and 48 SHRsp of 8 weeks old entered the final analysis. In the first year there were 2 generations delivered, the average conception rate( 100% ) and average litter number (10.3 rats) of SHRsp were higher than those of WKY of the same term(90%, P ＜ 0. 001; 6. 5 rats, P ＜ 0. 001) . In the second year, there were 2 generations of which the conception rate and average litter number(89%, 8.2 rats) of SHRsp were higher than those of WKY(59%, P ＜ 0. 001; 4. 3 rats, P ＜ 0. 001). There were 87 SHRsp female rats and 67normal blood pressure rats pregnant within 2 years, the rate of eating neonatal rats within 4 weeks postnatal was 6% (5/87) which was lower than that of WKY(18%, 12/67), P ＞ 0.05. The systolic pressure of 12weeks old male rats and female rats was 191.6-223.8 mm Hg and 174. 2-196. 3 mm Hg respectively, while that of 16-week old and 20-week male rats were 219.0 -224. 9 mm Hg and 232.0 -242.6 mm Hg respectively. The blood pressure of SHRsp increased with the advancing of age. The heart rate of 12-week old male and female rats was 388-428 times per minute and 373-417times/minute respectively while that of 16-week and 20-week male rats were 392 -410 times per minute and 404-425 times per minute respectively. The pathological detection rate of 48 SHRsp was 81% (39/48).CONCLUSION: The reproduction ability of SHRsp is similar to normal rats. The blood pressure, heart rate and pathological examination of brain tissue of them all maintain the characteristics of hypertension and stroke so that they can be used as qualified experimental model.

Objective · To explore the correlation between variants located in 3' untranslated regions (3'UTR) of NOTCH1 and JAG1 genes and conotruncal heart defects (CTD). Methods · Six hundred CTD children without 22q11 deletion and three hundred healthy children were enrolled in this hospital-based case-control study. Variants located in the 3'UTR regions of NOTCH1 and JAG1 genes were detected by high-throughput sequencing. The accuracy of the variants were verified by PCR and Sanger sequencing. Online software PicTar, TargetScan and microRNA.org were used to make functional predictions. Results · One mutation and three SNPs were found in the 3'UTR of NOTCH1. Three mutations and six SNPs were found in the 3'UTR of JAG1. The genotypic distributions of two SNPs (rs3840074 and rs8708) located in JAG13'UTR between CTD group and the controls were statistically significant (both P<0.05). Results of prediction showed that all the four mutations and two meaningful SNPs could bind to microRNA. Conclusion · The variants located in 3'UTR regions of NOTCH1 and JAG1 genes may be related to the occurrence of CTD.

Objective To explore the pathophysiologic mechanism of the development of a small-for-size syndrome(SPSS) and the role of splenectomy in the prevention and treatment of SFSS.Methods The rat models of sham-operation and 80% partial hepatectomy were established.Totally 144 rats were randomly divided into 3 groups:1)splenectomy group:splenectomy was performed following 80% partial hepatectomy;2)control group:80% partial hepatectomy was performed;3)sham group:no hepatectomy was performed.After the operation,we examined the portal venous pressures(PVP),tumor necrosis factor(TNF-α) and proliferating cell nuclear antigen(PCNA) expression,the activity of myeloperoxidase(MPO),liver function and explored the prevalence of SFSS.Results Compared with the sham group,the PVP of the rats in the control group obviously elevated after hepatectomy,and the expression level of TNF-a and the activity of MPO in the liver significantly increased(P<0.05).Compared with the control group,the PVP,the expression of TNF-a in the livers and the activity of MPO at the corresponding time points after hepatectomy in the splenectomy group significantly decreased,while the expression of PCNA in-creased(P<0.05).Administration of splenectomy resulted in a statistically significant decrease in aspartate transaminase(AST),alanine transaminase(ALT),lactate dehydrogenase(LDH),total bilirubin.and the incidence of SFSS(P<0.05).Conclusion Splenectomy could alleviate liver injury,promote liver regeneration in small-for-size liver rats by reducing portal vein perfusion and pressure and the subsequent expression of proinflammatory mediators.

Objective To explore the role of splenectomy in the prevention and treatment of small-for-size liver in rat models, as well as its pathophysiologic mechanism in the development of a small-for-size syndrome (SFSS). Methods The models of sham-operation and 80 % partial hepatectomy (PH) were used in rats. In the experiment group splenectomy was performed following 80% PH. The concentrations of serum tumor necrosis factor (TNF-α), the content of NF-cB p65 in liver nuclear extracts, the expression of TNF-α, intercellular adhesion molecular (ICAM-1), and proliferating cell nuclear antigen (PCNA) transcripts, the activities of serum aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), total bilirubin (TB), albumin (Alb) cholinesterase (CHE), and liver myeloperoxidase (MPO) were analyzed. Portal venous pressures (PVP),incidence of SFSS,and one-wk survival rate were measured. Results In the control rats,The PVP was obviously elevated immediately after PH. The level of NF-κB p65 was obviously increased at the first h and peaked at about 3rd h postoperatively. The transcription of TNF-α and ICAM-1 and the release of serum TNF-α were significantly increased 3 h after PH. Capillary endothelial cells of the livers strongly expressed ICAM-1 24 h after PH. Splenectomy significantly reduced the PVP and the content of NF-κB p65 in the livers in concurrence with the expression of TNF-α and ICAM-1 gene as well as the activity of MPO at the corresponding time points after PH (P＜0. 05), while increased the expression of PCNA gene (P＜0. 05). Administration of splenectomy resulted in a statistically significant decrease in AST, ALT, LDH, TB, the incidence of SFSS and increase in one-wk survival rate (P ＜ 0.05 ). Conclusion Splenectomy alleviates liver injury and promotes liver regeneration in small-for-size liver rats by reducing portal vein perfusion and pressure,and suppressing NFκB activation and subsequent expression of proinflammatory mediators.

Objective To investigate the correlation between ACE gene polymorphisms and stroke of Han nationality people in Fangshan district of Beijing. Methods The Insertion/Deletion(ID) polymorphisms of ACE gene were detected in 63 patients with cerebral hemorrhage,and 713 patients with cerebral infarction and 235 health control by polymerase chain reaction(PCR). We observed the frequencies of genotype of deletion homozygote(DD),insertion homozygote(II) and insertion/deletion heterozygote (ID) and the alleles of D and I. Also we analyzed the association among I/D polymorphisms of ACE gene with serum glucose(GLU),triglyceride(TG),cholesterol(TC) levels. Results There was no significant difference in the frequencies of both genotypes of DD,ID,II and alleles of D and I in three groups. The serum GLU levels in patients carrying ID,II genotype were higher than those in healthy control(P

Objective:To screen T-cell exhaustion-related signature genes as the prognostic marker for osteosarcoma and establish a prognostic model for osteosarcoma patients based on weighted gene co-expression network analysis(WGCNA)and Least absolute shrinkage and selection operator(LASSO)-COX regression analysis. Methods:GSE21257 dataset was downloaded from Gene Expression Omnibus(GEO)database for the establishment of the prognostic model for osteosarcoma.4 T-cell exhaustion-related gene sets were downloaded from The Molecular Signatures Database(MisgDB)and their enrichment scores in GSE21257 samples were calculated by single sample gene set enrichment analysis(ssGSEA).WGCNA was carried out to screen the gene module that is highly associated with T-cell exhaustion based on ssGSEA results followed by GO(Gene Ontology)and KEGG(Kyoto Encyclopedia of Genes and Genomes)analysis of the biological processes and signaling transduction pathways that those genes are involved in.The signature genes that are highly associated with the prognosis of osteosarcoma patients were obtained through LASSO-COX regression and a prognostic model was established based on these signature genes.Osteosarcoma-related expression profile data from the GSE21257 and TAEGET datasets on XENA were downloaded from the Gene Expression Omnibus.Clinical information for the training and validation sets was obtained.T-cell exhaustion-related genes were screened using a weighted correlation network analysis.Realtime fluorescence quantitative PCR,COX regression analysis,external dataset and nomogram were used to evaluate the reliability and accuracy of the prognostic model.A immunotherapy-related dataset was used to assess the efficacy of this prognostic model for the prediction of patients'responses to immunotherapy. Results:Analysis results based on the ssGSEA scores showed that T-cell exhaustion-related genes were related to the metastasis and age of osteosarcoma patients.Many T-cell exhaustion-related genes were found to be differentially expressed in metastatic and non-metastatic osteosarcoma patients.1 256 T-cell exhaustion-related genes were identified through WGCNA and these candidate markers were mainly distributed in structures like secretory granule membranes and endocytic vesicles and were involved in T-cell activation.COX regression analysis screened 68 significant prognostic markers out of the 1 256 genes,and 12 signature genes were further confirmed with LASSO-COX regression analysis.A prognostic model was established based on the 12 signature genes.Results of real-time fluorescence quantitative PCR showed a similar trend in the expression of most of the signature genes in different osteosarcoma cell lines.COX regression analysis of the internal and external datasets verified that the risk score calculated with the prognostic model was an independent prognostic factor for osteosarcoma patients,and high-risk score was associated with poor prognosis of the patients.Receiver operating characteristic(ROC)curves demonstrated excellent prognostic efficacy of the model.Nomogram analysis verified the prognostic model is highly accurate and reliable in predicting the prognosis of osteosarcoma patients.Analysis using the immunotherapy-related dataset indicated that this prognostic model could also be used to predict patients'responses to immunotherapy. Conclusion:The 12 signature gene(CD300LB,TRO,SNX3,VENTX,PPM1M,DOT1L,CDC37,NAT9,TRMT1,PPP1R3C,CHTF18 and NSUN5)-based prognostic model can effectively predict the prognosis and responses to immune check-point inhibitors for osteosarcoma patients,which may provide evidence for the prediction of prognosis as well as the selection of immunotherapy plans in clinical practice.

Objective:To summarize and analyze the clinical data of Chinese patients with colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy, and clarify the phenotypic and genetic characteristics of Chinese patients.Methods:Medical history of patients with CSF1R-related leukoencephalopathy diagnosed from April 1, 2018 to January 31, 2021 in the department of neurology of 22 hospitals in China was collected, and scores of Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment Scale (MoCA), magnetic resonance severity scale were evaluated. Group comparison was performed between male and female patients.Results:A total of 62 patients were included, and the male-female ratio was 1∶1.95. The age of onset was (40.35±8.42) years. Cognitive impairment (82.3%, 51/62) and motor symptoms (77.4%,48/62) were the most common symptoms. The MMSE and MoCA scores were 18.79±7.16 and 13.96±7.23, respectively, and the scores of two scales in male patients (22.06±5.31 and 18.08±5.60) were significantly higher than those in females (15.53±7.41 , t=2.954, P=0.006; 10.15±6.26, t=3.328 , P=0.003). The most common radiographic feature was bilateral asymmetric white matter changes (100.0%), and the magnetic resonance imaging severity scale score was 27.42±11.40, while the white matter lesion score of females (22.94±8.39) was significantly higher than that of males (17.62±8.74 , t=-2.221, P<0.05). A total of 36 CSF1R gene mutations were found in this study, among which c.2381T>C/p.I794T was the hotspot mutation that carried by 17.9% (10/56) of the probands. Conclusions:The core phenotypic characteristics of CSF1R-related leukoencephalopathy in China are progressive motor and cognitive impairment, with bilateral asymmetrical white matter changes. In addition, there exist gender differences clinically, with severer cognitive impairment and imaging changes in female patients. Thirty-six CSF1R gene mutations were found in this study, and c.2381T>C/p. I794T was the hotspot mutation.

OBJECTIVE To study the effects of bergapten in the treatment of liver fibrosis and its mechanism based on serum metabolomics. METHODS Forty mice were divided into normal control group （0.5% carboxymethyl cellulose sodium solution）， model group （0.5% carboxymethyl cellulose sodium solution）， and BP low-dose and high-dose groups （50， 100 mg/kg）， with 10 mice in each group. Except for the normal control group， the other three groups were all treated with carbon tetrachloride to induce liver fibrosis model； they were given relevant medicine/solution intragastrically， once a day， for consecutive 8 weeks. After the last medication， the levels of alanine aminotransferase （ALT） and aspartate aminotransferase （AST） in serum were detected， and liver pathological changes were observed； the expressions of α-smooth muscle actin （α-SMA） and Collagen Ⅰ were detected in liver tissue； the serum of the mice was collected for metabolomics analysis. RESULTS Compared with the model group， serum levels of ALT and AST and protein expressions of α-SMA and Collagen Ⅰ in liver tissue were decreased significantly in BP high-dose and low-dose groups （P＜0.05）， while liver fibrosis was improved significantly. Meanwhile， metabolomics analyses showed that there were a total of 175 serum differential metabolites in the BP high-dose group and model group， of which 18 substances were upregulated and 157 substances were downregulated； the main metabolic pathways involved in bergapten intervention were pyrimidine metabolism， butanoate metabolism， fatty acid synthesis， tyrosine metabolism， β-alanine metabolism， nicotinic acid and nicotinamide metabolism， glutathione metabolism， etc. CONCLUSIONS BP is effective in the treatment of liver fibrosis by regulating pyrimidine metabolism， butanoate metabolism， glutathione metabolism and so on in rats with liver fibrosis.