OBJECTIVE To establish population pharmacokinetic model of levetiracetam （Lev） for Chinese patients with post- stroke epilepsy （PSE）， and provide reference for formulating individualized dosing regimens for Lev therapy in this specific population. METHODS Blood concentration data and clinical diagnosis and treatment information of PSE patients meeting the inclusion criteria were retrospectively collected and divided into model group and validation group at an 8∶2 ratio using a random number method. Based on the model group data， a population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Internal evaluation was performed through goodness-of-fit tests and bootstrap analysis， while external validation was conducted using the validation group data. RESULTS A total of 75 blood concentration measurements from 70 PSE patients were collected， with 60 measurements from 55 patients used for model development and 15 measurements from 15 patients reserved for external validation. The final model estimated a population typical value of clearance at 2.98 L/h. Estimated glomerular filtration rate， daily dose， and homocysteine level significantly influenced clearance of Lev （P＜0.01）. The model demonstrated satisfactory predictive performance， as evidenced by goodness-of-fit tests， bootstrap analysis， and external validation results. CONCLUSIONS Daily dose， estimated glomerular filtration rate， and homocysteine level are identified as significant covariates influencing Lev clearance in Chinese PSE patients. When making clinical decisions， comprehensive consideration should be given to the patient’s treatment response， physiological and pathological conditions， and the occurrence of adverse reactions， etc. The dosage of Lev should be adjusted based on the results of population pharmacokinetic model.

OBJECTIVES: The mechanism of the odontogenic differentiation of apical papillary cells (APCs) stimulated by bioactive glass 45S5 is still unclear. This study aims to investigate the effect of autophagy on the odontogenic differentiation of APCs stimulated by bioactive glass 45S5. METHODS: APCs were isolated and cultured in vitro, and the cell origin was identified by flow cytometry. The culture medium was prepared with 1 mg/mL 45S5, and its pH and ion concentration were determined. The experiments were divided into control, 45S5, and 3-methyladenine (3-MA) 45S5 groups. In the 45S5 group, APCs were induced to culture with 1 mg/mL 45S5. In the 3-MA 45S5 group, the autophagy inhibitor 3-MA was added to 1 mg/mL 45S5. Protein immunoblotting assay (Western blot) was used to detect the expression of autophagy-associated proteins of microtubule-associated protein 1 light-chain 3β (LC3B) and P62 after 24 h of induction culture in each group. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of bone sialoprotein (BSP), Runt-related transcription factor 2 (Runx2), dentin sialophosphoprotein (DSPP), and dentin matrix protein-1 (DMP-1) after 7 d of induction culture. Cellular alkaline phosphatase (ALP) staining analyzed cellular ALP activity at 7 d of induction, and alizarin red staining evaluated the formation of mineralized nodules at 21 d of induction. RESULTS: The pH of the 45S5 extract culture medium was 8.65±0.01, which was not significantly different from that of the control group (P>0.05). The silicon ion concentration of the 45S5 induction culture medium was (1.56±0.07) mmol/L, which was higher than that of the control group (0.08±0.01) mmol/L (P<0.05). The calcium ion concentration of the 45S5 induction culture was (1.57±0.15) mmol/L, which was not significantly different from that of the control group (P>0.05). Western blot results showed that LC3B-Ⅱ/Ⅰ ratio increased and P62 expression decreased in the 45S5 group compared with those in the control group (P<0.05). By contrast, the ratio decreased and the expression increased in the 3-MA 45S5 group compared with those in the 45S5 group (P<0.05). RT-qPCR results showed that the expression of BSP, Runx2, DMP-1, and DSPP enhanced in the 45S5 group compared with that in the control group (P<0.05), but the expression decreased in the 3-MA 45S5 group compared with that in the 45S5 group (P<0.05). Semi-quantitative analysis of ALP staining and alizarin red staining showed that the ALP activity was enhanced, and the formation mineralized nodule increased in the 45S5 group compared with those in the control group. The ALP activity weakened, and the formation mineralized nodules were reduced in the 3-MA 45S5 group compared with that those in the 45S5 group. CONCLUSIONS Cell autophagy participates in the odontogenic differentiation of APCs induced by 1 mg/mL 45S5 in vitro.
Autophagy/drug effects* ; Cell Differentiation/drug effects* ; Odontogenesis/drug effects* ; Dental Papilla/cytology* ; Humans ; Microtubule-Associated Proteins/metabolism* ; Glass/chemistry* ; Cells, Cultured ; Core Binding Factor Alpha 1 Subunit/metabolism* ; Extracellular Matrix Proteins/metabolism* ; Ceramics/pharmacology* ; Adenine/pharmacology* ; Sialoglycoproteins/metabolism* ; Phosphoproteins/metabolism* ; Integrin-Binding Sialoprotein/metabolism* ; Alkaline Phosphatase/metabolism* ; RNA-Binding Proteins

Objective:To study the role of special microbial communities in the development of periodontitis in type 2 diabetes melli-tus(T2DM)patients.Methods:40 subjects aged 20-70 years were included and divided into 3 groups:moderate to severe periodon-titis with T2DM(SP.T2DM,n=15),moderate to severe periodontitis group(SP,n=15)and normal healthy group(N,n=10).The basic information,periodontal clinical indicators and blood sugar of the subjects were recorded.Subgingival plaque samples were col-lected,DNA samples of the plaque were extracted,and sequenced by Illumina NovaSeq6000 platform.The microbial diversity,eco-logical characteristics and functions of the plaque were analyzed by Uparse,SPSS and other softwares.Results:481 species in 22 phyla,30 classes,73 orders,129 families and 265 genera were obtained from the samples.Beta polymorphism analysis showed that the species composition of CP.T2DM group and CP group was similar.Alpha polymorphism analysis showed that the species richness and evenness in CP.T2DM group and CP group were higher than those in N group(P＜0.01).Venn diagram analysis showed that the species richness of the plaque in CP.T2DM group was the highest,followed by CP group and the lowest in N group.At the genus lev-el,Klebsiella and Bifidobacterium in CP.T2DM group were larger than those in CP group and N group(P＜0.05),and between group CP and N,P＞0.05.At the species level,the Capnocytophaga leadbetteri in CP.T2DM group was higher than that in CP group and N group(P＜0.05),between group CP and N,P＞0.05;There were some differences in the microbial community structure of subgingival plaque among the 3 groups.The species richness of subgingival flora in patients with CP and T2DM was higher than that in patients with CP and healthy people.Conclusion:The increase of Klebsiella,Bifidobacterium and Capnocytophaga leadbetter in subgingival flora of patients with moderate and severe periodontitis may be related to the development of T2DM.

Objective: To systematically evaluate the influencing factors for medication compliance in patients with comorbidities of chronic diseases, so as to provide the evidence for improving medication compliance. Methods: Literature on influencing factors for medication compliance in patients with comorbidities of chronic diseases were retrived from CNKI, Wanfang Data, VIP, SinoMed, PubMed, Web of Science, Cochrane Library and Embase from inception to January 20, 2024. After independent literature screening, data extraction, and quality assessment by two researchers, a meta-analysis was performed using RevMan 5.4 and Stata 16.0 softwares. Literature were excluded one by one for sensitivity analysis. Publication bias was assessed using Egger's test. Results: Initially, 7 365 relevant articles were retrieved, and 35 of them were finally included, with a total sample size of about 150 000 individuals. There were 30 cross-sectional studies and 5 cohort studies; and 11 high-quality studies and 24 medium-quality studies. The meta-analysis showed that the demographic factors of lower level of education (OR=2.148, 95%CI: 1.711-2.696), lower economic income (OR=1.897, 95%CI: 1.589-2.264), male (OR=0.877, 95%CI: 0.782-0.985), living alone (OR=2.833, 95%CI: 1.756-4.569) and unmarried (OR=2.784, 95%CI: 1.251-6.196); the medication treatment factors of polypharmacy (OR=1.794, 95%CI: 1.190-2.706), potentially inappropriate medication (OR=2.988, 95%CI: 1.527-5.847), low frequency of daily medication (OR=0.533, 95%CI: 0.376-0.754) and adverse drug reactions (OR=3.319, 95%CI: 1.967-5.602); the disease factors of long course of disease (OR=2.118, 95%CI: 1.643-2.730), more comorbidities (OR=1.667, 95%CI: 1.143-2.431) and cognitive impairment (OR=2.007, 95%CI: 1.401-2.874); and the psychosocial factors of poor belief in taking medication (OR=1.251, 95%CI: 1.011-1.547), poor self-rated health (OR=1.990, 95%CI: 1.571-2.522) and being guided by healthcare professionals (OR=0.151, 95%CI: 0.062-0.368) were the influencing factors for medication compliance in patients with chronic comorbidities. Conclusion The medication compliance in patients with comorbidities of chronic diseases is associated with demographic factors, pharmacological factors, disease factors and psychosocial factors, mainly including living alone, adverse drug reactions, course of disease, number of comorbidities and medication beliefs.

Objective To establish the argatroban drug use evaluation(DUE)criteria and provide reference for the rational use of argatroban in clinical practice.Methods Based on the domestic and foreign drug instructions of argatroban,referring to relevant guidelines and literature,the DUE standard rules were established by expert consultation.Using the established standard rules,the medical records of argatroban in the Fuzhou First Hospital Affiliated with Fujian Medical University from August 2020 to August 2022 were evaluated for the rationality of medication.Results A total of 368 medical records were included,the rational rate of drug use was 48.64％,and the irrational drug use was mainly without indications(46.19％)and inappropriate combination of drugs(4.35％).Conclusion The rational rate of argatroban clinical use in the hospital is not high,and the problems mainly include off-indication drug use and unreasonable combination drug use.Through the establishment and clinical application of DUE standard rules,the clinical use of argatroban can be further standardized and the ability of rational drug use can be improved.

Objective To study the effect of changes in estradiol(E2)levels on the reproductive outcomes of pa-tients with polycystic ovary syndrome(PCOS)undergoing controlled ovarian stimulation(COS)with gonadotropin-releasing hormone antagonist(GnRH-ant)protocol.Methods A retrospective study was conducted involving 338 patients with polycystic ovary syndrome(PCOS)infertility who underwent GnRH-ant protocol for controlled ovarian hyperstimulation followed by in vitro fertilization(IVF)or intracytoplasmic sperm injection(ICSI),and subse-quently underwent their first frozen-thawed embryo transfer(FET).The clinical data of these patients were ana-lyzed.Patients were grouped based on the changes in serum E2 levels on the first and fourth day of GnRH-ant ad-ministration(blood samples collected before GnRH-ant injection):the E2 elevation group(Group A,E2 value in-creased more than 30％,165 cases),the E2 stable group(Group B,E2 rate of change was within-30％～30％,162 cases),and the E2 decline group(E2 value declined more than 30％,11 cases,not included in statistical a-nalysis due to small sample size).The differences in demographic characteristics,ovulation induction outcomes,embryo outcomes and clinical pregnancy-related indicators were analyzed between Groups A and B.Results There were no statistically significant differences in basic information such as age,duration of infertility,body mass index(BMI),basal endocrine levels,and anti-Müllerian hormone(AMH)levels between groups A and B.Regarding embryo characteristics,there were no statistically significant differences in fertilization method and number of trans-ferred embryos between groups A and B.However,group A had a higher total number of retrieved oocytes,normal fertilization rate,number of high-quality embryos,and rate of high-quality embryos compared to group B,with sta-tistically significant differences(P＜0.05).In terms of clinical pregnancy outcomes,there were no statistically significant differences in the incidence of severe ovarian hyperstimulation syndrome(OHSS)between groups A and B.However,group A had higher rates of clinical pregnancy,implantation,and live birth compared to group B,with statistically significant differences.Group A also had a lower rate of early miscarriage compared to group B,with statistically significant differences.Conclusion Choosing the GnRH-ant protocol for IVF/ICSI-FET in PCOS patients,if the blood E2 level increases by more than 30％after 4 days of adding the antagonist(blood sample col-lected before administering GnRH-ant),the clinical pregnancy outcome will be better.

Objective To investigate the effects of Danshen Tongluo Jiedu Decoction medicated serum for regulating miR-126 on autophagy in hypoxia/reoxygenation myocardial microvascular endothelial cells(CMECs)of rats.Methods Hypoxia/reoxygenation injury cell model was constructed by culturing CMECs in vitro.The cells were divided into blank group,model group,TCM group,silencing group,empty vector group,and silencing+TCM group by lentivirus transfection with miR-126 inhibitor.Lactate dehydrogenase(LDH)content in the supernatant of CMECs was detected using a reagent kit,and cell apoptosis rate was detected using flow cytometry,the miR-126 mRNA expression was detected using RT-PCR,the expressions of autophagy-related proteins Atg5,Beclin1 and p62 proteins were detected by Western blot.Results Compared with the blank group,the LDH content in the supernatant of the model group cells significantly increased,the apoptosis rate significantly increased,the miR-126 mRNA expression significantly decreased,the Atg5 and Beclin1 protein expressions significantly increased,and the p62 protein expression significantly decreased,with statistical significance(P<0.01).Compared with the model group,the TCM group and the silencing+TCM group showed a significant decrease in LDH content in the cell supernatant,a significant decrease in cell apoptosis rate,a significant increase in miR-126 mRNA expression,a significant decrease in Atg5 and Beclin1 protein expressions,and a significant increase in p62 protein expression in the TCM group,with statistical significance(P<0.05,P<0.01);the LDH content in the supernatant,apoptosis rate,Atg5 and Beclin1 protein expressions of the silence group cells significantly increased,while miR-126 mRNA expression significantly decreased(P<0.01).Compared with the TCM group,the LDH content in the cell supernatant and apoptosis rate of the silence group and the silencing+TCM group significantly increased(P<0.05,P<0.01),while the miR-126 mRNA expression significantly decreased(P<0.01);the expressions of Atg5 and Beclin1 proteins in the silence group significantly increased(P<0.01),and the expression of p62 protein significantly decreased(P<0.01).Compared with the silence group,the LDH content in the cell supernatant,apoptosis rate,and Atg5 and Beclin1 protein expression of the empty vector group group and the silencing+TCM group were significantly decreased(P<0.01),the miR-126 mRNA and p62 protein expression significantly increased(P<0.05,P<0.01).Conclusion Danshen Tongluo Jiedu Decoction medicated serum can inhibit autophagy and apoptosis of CMECs caused by hypoxia/reoxygenation injury,thereby protecting CMECs.Its mechanism may be related to promoting miR-126 expression.

Objective To improve the efficiency of induced differentiation of primitive neural epithelial cells derived from human induced pluripotent stem cells(hiPSCs-NECs)into functional midbrain dopaminergic progenitor cells(DAPs).Methods HiPSCs were cultured in mTeSRTM medium containing DMH1(10 μmol/L),SB431542(10 μmol/L),SHH(200 ng/mL),FGF8(100 ng/mL),purmorphamine(2 μmol/L),CHIR99021(3 μmol/L),and N2(1%)for 12 days to induce their differentiation into primitive neuroepithelial cells(NECs).The hiPSCs-NECs were digested with collagenase IV and then cultured in neurobasal medium supplemented with 1%N2,2%B27-A,BDNF(10 ng/mL),GDNF(10 ng/mL),AA,TGF-β,cAMP,and 1%GlutaMax in the presence of different concentrations of Rho kinase inhibitor Y27632,and the culture medium was changed the next day to remove Y27632.Continuous induction was performed until day 28 to obtain DAPs.Results Human iPSCs expressed the pluripotency markers OCT4,SOX2,Nanog,and SSEA1 and were positive for alkaline phosphatase staining.The hiPSCs-NECs were obtained on day 13 in the form of neural rosettes expressing neuroepithelial markers SOX2,nestin,and PAX6.In digested hiPSCs-NECs,the addition of 5 μmol/L Y27632 significantly promoted survival of the adherent cells,increased cell viability and the proportion of S-phase cells(P<0.01),and reduced the rate of apoptotic cells(P<0.05).On day 28 of induction,the obtained cells highly expressed the specific markers of DAPS(TH,FOXA2,NURR1,and Tuj1).Conclusion Treatment with Y27632(5 μmol/L)for 24 h significantly promotes the survival of human iPSCs-NECs during their differentiation into DPAs without affecting the cell differentiation,which indirectly enhances the efficiency of cell differentiation.

Thyroid carcinoma is closely related to environmental factors. Gene mutations and molecular biological changes of gland tissue caused by environmental changes are important factors inducing thyroid carcinoma. Although the molecular mechanism of thyroid carcinoma has not been fully elucidated,increasingly specific genetic changes and molecular markers for thyroid carcinoma have been discovered with the development of molecular biology techniques. This article reviews the recent progresses on the etiology,specific molecular markers,diagnosis and targeted therapies of thyroid carcinoma,so as to provide theoretical support for the clinical diagnosis and treatment of thyroid carcinoma.

Immunotherapy has made breakthrough in the field of tumor treatment. How to accurately predict the response of tumor patients to immunotherapy in the early stage is currently a clinical challenge. Nuclear medicine molecular imaging provides a new technological means for early accurate diagnosis, treatment monitoring, early warning of recurrence and metastasis, and guidance for personalized treatment of diseases. Therefore, it plays an irreplaceable role in precise diagnosis and treatment of tumors and patient stratification. This article reviews the progress of molecular imaging research on immune cells and related targets within the tumor microenvironment.