Objective To establish a new method for inducing the primordial germ cells to differentiate into hepatocyte-like in vitro.Methods The primordial germ cells(PGCs) from the gonadal ridges of the mouse embryos of 13 days postcoitum from Kunming pregnant mice were cultured in vitro.Then embryonic hepatocytes enclosed in microcapsule and liver tissue extract of newborn mice were added into medium to co-culture with PGCs for committed differentiation.Albumin(ALB) and ?-1-antitrypsin(AAT) were assayed by immunocytochemistry.Results The morphology of cells differentiated from PGCs likes star or ovum,the ALB and AAT immune positive expression were detected in those differentiated cells.The ratio of positive cells was above 70% in 2 weeks.Conclusion Microenvironment of embryonic hepatocyte microcapsules and liver tissue extract could effectively induce PGCs to differentiate into hepatocytes.

BACKGROUND: Chemotherapy has been the very important adjunctive treatment for the patients with large intestine cancer. However, obvious individual difference exists in the sensitivity of the patients to the chemotherapeutic drugs, and the difference is related with the age and sex of the patients or not?OBJECTIVE: To make an exploratory discussion of that whether the difference of the sensitivity of chemotherapeutic drugs exists in different ages and different sexes of the patients with epidemiological investigation of the tumor cell survival rate.DESIGN: Controlled experimental study based on pathological samples.SETTING: General surgery department of an affiliated hospital of a medical college.PARTICIPANTS: Tumor cell samples of 169 cases of colorectal cancer tissue obtained from patients with colorectal cancer at the Department of General Surgery of the affiliated hospital of North Sichuan Medical College during the period from January 2001 to January 2003 were involved as subjects. The patients, 97 males and 72 females, were made a definite diagnosis of the large intestine cancer by operation and pathological examination and have not been treated with chemotherapy before operation.METHODS: The sensitivity of chemotherapy drugs were measured on the survival tumor specimens of 169 patients with colorectal carcinoma with Methyl thiazolyl tetrazolium(MTT) test method in vitro. The differences of different ages and different sexes were analyzed in patients.MAIN OUTCOME MEASURES: The absorbance values of tumor cell 72hours after treatment with chemotherapeutic drugs.RESULTS: There was no obvious significance of the tumor' s sensitivity to chemotherapeutic agents in different ages and sexes in patients with colorectal cancer( P ＞ 0.05).ONCLUSION: The individual difference of sensitivity for chemotherapeutic agents in patients with colorectal cancer is not related with the age and gender, needless to consider age and gender in selecting chemotherapeutic agents for different individuls.

Contracture and spasticity of ankle joints were major sources of disability in neurological impairment including stroke and cerebral palsy, etc. The manual stretching used in physical therapy might be laborious and time-consuming to the therapists and the outcome was dependent on the experience and the subjectiveend feelingof the therapists. A device was developed that could safely stretch the an-kle joint to its extreme positions with quantitative control of the resistance torque and stretching velocity. Furthermore, it could satisfy a strong need for quantitative and objective measures of the impairment and rehabilitation outcome. This was just the meaning intelligent stretching referred to. This article described the origin of the concept of intelligent stretching and its definition, operational principle, and su-periority and weakness, as well as its application in ankle joint spasticity and contracture in patients with stroke and cerebral palsy.

Objective: To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from different donors as first-line treatment for children and adolescents with severe aplastic anemia (SAA) . Methods: The clinical data of 79 children and adolescents with SAA diagnosed from January 2013 to December 2016 in Henan Province were retrospectively analyzed. There were 50 males and 29 females, with a median age of 14(4-18) years. 40 cases received matched sibling transplantation (MSD-HSCT), 17 with unrelated donor transplantation (UD-HSCT), and 22 with haploidentical transplantation (haplo-HSCT). Results: The comparison of MSD-HSCT, UD-HSCT, haplo-HSCT groups was conducted and the median times of neutrophils engraftment were statistically significant [12(9-25) d, 14(10-22) d, 16(11-26) d, respectively (χ²=13.302, P=0.001)], but no difference in+30 d engraftment rate [97.3%(36/37), 100%(15/15), 100%(20/20), χ²=0.959, P=0.619]. The median times of PLT engraftment were not statistically significant [14(6-34)d, 16(7-32)d, 19(10-34)d, respectively, χ²=5.892, P=0.053], and the +30 d engraftment rate had no difference [97.3%(36/37), 100%(15/15), 100%(20/20), χ²=0.959, P=0.619]. The post-transplant infection rate showed no statistically significance [35.0% (14/40), 29.4% (5/17), 45.5% (10/22), χ²=1.158, P=0.560], as well as the incidences of aGVHD, grade III/IV aGVHD and cGVHD(χ²=0.230, P=0.891; χ²=2.628, P=0.269; χ²=3.187, P=0.203). The two-years OS rate was not statistically significant respectively [(77.1±6.7)%, (70.6±11.1)%, (77.3±8.9)%, χ²=0.330, P=0.845]. Severe post-transplant infection (RR=4.617, P=0.009), grade Ⅲ/Ⅳ aGVHD (RR=2.707, P=0.048) were independent risk factors for OS. Conclusion The overall efficacy of MSD-HSCT, UD-HSCT and haplo-HSCT as first-line therapy for children and adolescents with SAA/VSAA is comparable.

Objective·To develop physiologically based pharmacokinetic(PBPK)models specifically designed for the Chinese population by utilizing the combination of clozapine and fluvoxamine as a case,and predict the drug-drug interaction(DDI)associated with the combination medication of clozapine,ultimately optimizing the dosage of clozapine.Methods·By obtaining the physicochemical parameters,absorption,distribution,metabolism,excretion(ADME)-related parameters,and physiologically relevant parameters of the Chinese population through literature and pharmacology-related databases,PBPK models for the clozapine and fluvoxamine were constructed by using PK-Sim? software.The models' accuracy was evaluated by comparing predicted values of the area under the curve(AUC)and peak concentration(Cmax)to observed data,using the mean percentage error(MPE)and mean absolute percentage error(MAPE)as evaluation indicators.The models were validated against real-world plasma drug concentration data.Additionally,combining the inhibitory effect of fluvoxamine on clozapine,models for the combination therapy of clozapine and fluvoxamine were developed to predict the pharmacokinetic changes of clozapine.The presence of clinically significant DDI was determined by using the 90%confidence interval of the AUC ratio(AUCR)or Cmax ratio(CmaxR)as evaluation metrics,with a non-effect boundary set at 80%?125%.The pharmacokinetic changes of clozapine upon co-administration with fluvoxamine based on PBPK models were quantified,and a dosage optimization for clozapine was developed.Results·The constructed model of clozapine and fluvoxamine was considered accurate if the absolute value of the MPE was≤10%and the MAPE was<25%during validation,indicating that the predicted concentration-time curves were accurate.The PBPK model for the co-administration of clozapine and fluvoxamine was able to accurately predict pharmacokinetic parameters if the ratio of predicted AUC to observed AUC was within 1.25.The prediction of PBPK model for the co-administration showed that the 90%confidence intervals for AUCR and CmaxR of the combination therapy of clozapine and fluvoxamine were not entirely within the ineffective effect boundary,indicating a clinically significant DDI when these two drugs were used concomitantly.Moreover,the dose optimization according to the PBPK models indicated that when subjects were co-administered with clozapine and fluvoxamine,reducing the dose of clozapine to 50%of the original dose could maintain the exposure levels of clozapine consistent with monotherapy.Conclusion·The established PBPK model can effectively simulate the impact of combination therapy on pharmacokinetic changes of clozapine,providing valuable insights for predicting potential DDI and optimizing dosage regimens.If clozapine needs to be co-administered with fluvoxamine during the treatment,clinicians should remain vigilant for clinically significant DDI and contemplate optimizing the dosage of clozapine accordingly.

Objective To compare the safety and effectiveness of intravenous thrombolysis treatment in large artery atherosclerosis (LAA) and cardioembolic (CE) strokes in patients with acute anterior circulation ischemic stroke.Methods Two hundred and thirty-eight patients with acute anterior circulation ischemic stroke, admitted to and treated with intravenous thrombolysis in our hospital from January 2017 to June 2018 were chosen in our study. These patients were divided into either a LAA group (n=158) or a CE group (n=80) according to etiological subtypes. The differences in baseline data and outcomes 90 d after the onset between the two groups were compared. Baseline data of patients in the good outcome group and the poor outcome group were compared and independent risk factors for poor outcome were determined by multivariate Logistic regression analysis.Results As compared with the patients from the LAA group, patients from the CE group had older age and higher proportion of patients combined with atrial fibrillation, with significant differences (P<0.05); there were no statistically significant differences in the good outcome rate, mortality rate and incidence of symptomatic intracranial hemorrhage between the two groups (P>0.05). Among the 238 patients, 112 were into the good outcome group and 126 were into the poor outcome group; as compared with patients from the poor outcome group, patients from the good outcome group had younger age, and lower National Institute of Health Stroke Scale (NIHSS) scores and lower levels of fasting blood glucose before and after thrombolysis, with statistically significant differences (P<0.05); multivariate Logistic regression analysis showed that older age (odds ratio [OR]=1.040, 95％ confidence interval [CI]: 1.010-1.071,P=0.008) and higher NIHSS scores 24 h after thrombolysis (OR=1.259, 95％CI: 1.175-1.350,P=0.000) were independently associated with poor outcome.Conclusion The outcomes of intravenous thrombolysis in patients with acute anterior ischemic stroke are only associated with age and severity of stroke, and not associated with TOAST etiological subtypes; intravenous thrombolysis for cardiogenic stroke is safe and effective.

Objective:To investigate the diagnostic accuracy of serological indicators and evaluate the diagnostic value of a new established combined serological model on identifying the minimal hepatic encephalopathy (MHE) in patients with compensated cirrhosis.Methods:This prospective multicenter study enrolled 263 compensated cirrhotic patients from 23 hospitals in 15 provinces, autonomous regions and municipalities of China between October 2021 and August 2022. Clinical data and laboratory test results were collected, and the model for end-stage liver disease (MELD) score was calculated. Ammonia level was corrected to the upper limit of normal (AMM-ULN) by the baseline blood ammonia measurements/upper limit of the normal reference value. MHE was diagnosed by combined abnormal number connection test-A and abnormal digit symbol test as suggested by Guidelines on the management of hepatic encephalopathy in cirrhosis. The patients were randomly divided (7∶3) into training set ( n=185) and validation set ( n=78) based on caret package of R language. Logistic regression was used to establish a combined model of MHE diagnosis. The diagnostic performance was evaluated by the area under the curve (AUC) of receiver operating characteristic curve, Hosmer-Lemeshow test and calibration curve. The internal verification was carried out by the Bootstrap method ( n=200). AUC comparisons were achieved using the Delong test. Results:In the training set, prevalence of MHE was 37.8% (70/185). There were statistically significant differences in AMM-ULN, albumin, platelet, alkaline phosphatase, international normalized ratio, MELD score and education between non-MHE group and MHE group (all P<0.05). Multivariate Logistic regression analysis showed that AMM-ULN [odds ratio ( OR)=1.78, 95% confidence interval ( CI) 1.05-3.14, P=0.038] and MELD score ( OR=1.11, 95% CI 1.04-1.20, P=0.002) were independent risk factors for MHE, and the AUC for predicting MHE were 0.663, 0.625, respectively. Compared with the use of blood AMM-ULN and MELD score alone, the AUC of the combined model of AMM-ULN, MELD score and education exhibited better predictive performance in determining the presence of MHE was 0.755, the specificity and sensitivity was 85.2% and 55.7%, respectively. Hosmer-Lemeshow test and calibration curve showed that the model had good calibration ( P=0.733). The AUC for internal validation of the combined model for diagnosing MHE was 0.752. In the validation set, the AUC of the combined model for diagnosing MHE was 0.794, and Hosmer-Lemeshow test showed good calibration ( P=0.841). Conclusion:Use of the combined model including AMM-ULN, MELD score and education could improve the predictive efficiency of MHE among patients with compensated cirrhosis.