In this article, the projects in drug metabolism and pharmacokinetics funded by NSFC during "10th Five Year Plan" (2001~2005) in China were reviewed. The major research fields of these projects in drug metabolism and pharmacokinetics funded by NSFC during the financial years were overviewed and analyzed. Finally, current problems in these research fields in China were also briefly analyzed.

Identification and validation of a new target is one of the most important steps for new antituberculosis (TB) drug discovery. Researches have shown that Mycobacterium tuberculosis (Mtb) encodes 20 CYP450 enzymes which play important roles in the synthesis and metabolism of lipid, cholesterol utilization, and the electron transport of respiratory chain in Mtb. With the critical roles within the organism as well as the protein structures of six Mtb CYP450 enzymes being clarified, some of them have been highlighted as potential anti-tuberculosis targets. In this paper, the phylogenetic analysis, the structural features, and the enzymatic functions of Mtb CYPs, as well as the mechanism of interactions with selective inhibitors such as azole antifungal agents for the CYPs have been reviewed and summarized. The druggability of the CYPs has also been analyzed for their further utility as targets in high throughput screening and rational design of more selective inhibitors.

Objective To investigate the phenotypic and genetic characteristics of the lysostaphin‐resistant Staphylococcus aureus variants induced by recombinant lysostaphin in vitro .Methods Three clinical isolates of S . aureus ,including two resistant to methicillin (MRSA ) and one susceptible to methicillin (MSSA ) were induced by treatment with sub‐MIC of recombinant lysostaphin via one‐step selection in vitro .Susceptibility of the variants to antibiotics were determined and compared with their parental strains .The full length of femABX genes was amplified by polymerase chain reaction and sequenced to identify the potential mutation sites in these genes .The growth‐curve in liquid medium and virulence in a mouse systemic infection model of both parental and variant strains were observed . Results The frequency of lysostaphin resistance in S . aureus was between 10-4 to 10-8 following induction by lysostaphin . Resistance to lysostaphin was associated with a significant decrease in growth rate in vitro and virulence in vivo ,as well as increased susceptibility toβ‐lactams evidenced by the M IC of β‐lactams against the variants as low as 1/4 000 to 1/2 of the M IC against their parental strains . Sequencing of f emA BX genes showed mutation in femA gene in both variants ,which resulted in a premature termination codon .Conclusions Resistance of S . aureus to lysostaphin may develop following induction by recombinant lysostaphin in vitro . The lysostaphin‐resistant S . aureus variants are characteristic of lower growth rate , decreased virulence ,and higher susceptibility to β‐lactams .

Objective To explore the significance of serum β-nerve growth factor(β-NGF)and tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)testing in clinical diagnosis and prognosis assessment in patients with pulmonary heart disease(PHD)complicated with pulmonary artery hypertension(PAH).Methods A 1:1 case-control study was conducted in Daxing District People's Hospital of Beijing from January 2019 to June 2022,in which 86 patients with PHD complicated with PAH and 86 patients with isolated PHD were selected as case group and control group.Retrospective analysis was conducted.The case group was divided into mild PAH group(n=39),moderate PAH group(n=25)and severe PAH group(n=22)according to pulmonary artery systolic pressure(PASP).Meanwhile,the case group was divided into good prognosis group(n=75)and poor prognosis group(n=11)based on the outcomes after one year of discharge.Demographic data and laboratory examination indicators of study subjects were collected,and serum β-NGF and TRAIL levels were measured using enzyme-linked immunosorbent assay(ELISA).Pearson product-moment correlation analysis was used to assess the relationship among β-NGF,TRAIL and PASP.Logistic regression analysis was performed to identify factors influencing PAH in patients with PHD.ROC curve was used to evaluate the diagnostic value of β-NGF and TRAIL for PAH.Cox proportional hazards regression analysis was carried out to assess the relationship among β-NGF,TRAIL and poor prognosis in patients with PHD complicated with PAH,and ROC curve was used to evaluate its predictive value for poor prognosis.Result Compared with control group,the duration of PHD in case group was longer(8.63±1.27 years vs 5.49±1.15 years),and serum β-NGF level(26.97±8.25 ng/ml vs 22.14±7.32 ng/ml)and TRAIL level(2.83±0.76 ng/ml vs 1.71±0.68 ng/ml)were increased,with significant differences(t=17.006,4.064,10.183,all P＜0.05).Serum β-NGF and TRAIL had certain diagnostic values for PAH in PHD patients,with AUC of 0.842 and 0.838,respectively.And the combined diagnostic AUC was 0.920,which was higher than that of single indicators(Z=3.416,3.508,all P＜0.05).Serum β-NGF(23.26±5.13 ng/ml,27.83±5.57 ng/ml,32.57±6.02 ng/ml)and TRAIL(2.24±0.65 ng/ml,2.89±0.71 ng/ml,3.81±0.90 ng/ml)levels among patients with mild PAH,moderate PAH,severe PAH were sequentially elevated,and the differences were significant(F=20.624,31.972,all P＜0.05).Serum β-NGF and TRAIL were positively associated with PASP(r=0.673,0.659,P＜0.05).Serum β-NGF(36.34±8.05 ng/ml)and TRAIL(3.49±1.01 ng/ml)levels in poor prognosis group were higher compared to good prognosis group(25.59±7.28 ng/ml,2.73±0.89 ng/ml),and the differences were significant(t=4.516,2.604,all P＜0.05).Logistic regression analysis showed that,the PHD duration[OR(95％CI):1.784(1.135～2.806)],β-NGF[OR(95％CI):1.976(1.108～3.523)]and TRAIL[OR(95％CI):1.866(1.123～3.101)]were independent risk factors for occurrence of PAH in patients with PHD(all P＜0.05).Multivariate COX proportional risk regression results showed that PHD duration[OR(95％CI):1.167(1.082～1.364)],β-NGF[OR(95％CI):1.322(1.134～1.649)],TRA-IL[OR(95％CI):1.259(1.087～1.590)]were independent risk factors for poor prognosis in patients with PHD complicated with PAH(all P＜0.05).Serum β-NGF and TRAIL could predict the poor prognosis in patients with PHD complicated with PAH,with AUC of 0.863 and 0.881,respectively.The combined diagnostic AUC was 0.907,which was higher than that of single indicators(Z=2.905,3.128,all P＜0.05).Conclusion Elevated serum β-NGF and TRAIL were independent risk factors for PAH and were associated with severity of PAH.Early combined detection of β-NGF and TRAIL can improve the diagnostic value for PAH and predict poor prognosis of patients.

Objective: To report the operation methods and clinical effects of repairing finger tip defect with the free tibial dorsal nerve flap of the second toe. Methods: 13 patients with finger tip defects were repaired by the tibial dorsal nerve flap of the second toe. The area of finger tip defect was 2.5 cm×1.5 cm-1.3 cm×1.0 cm, and the area of cutting flap was 2.7 cm×1.7 cm-1.5 cm×1.1 cm. All donor site defects on the second toe were covered with full-thickness skin graft. Results: There were 13 cases in this group, and all the flaps and skin grafts were survived. Postoperative follow-up ranged from 6 to 18 months, with an average of 13 months. The appearance of the fingers was satisfied and the sensory recovery was good. Two-point discrimination of the flaps returned to 7-13 mm, with an average of 9 mm. According to the total active move(TAM)scale, results were excellent in 11 fingers, good in 1 finger, and fair in 1 finger. The donor site skin graft was well healed, the second toe pulp was full, and the two-point discrimination of the toe pulps were 6-10 mm, with an average of 8 mm. Conclusions Compared to the traditional method of repairing finger tip defect with the tibial inherent nerve flap of the second toe, our new method can reduce the damage to the donor site, and we can repair finger tip defect as well as the traditional one at the same time. So it was a better operative method to repair finger tip defect with the tibial dorsal nerve flap of the second toe.

Objective To observe the clinical characteristics of non-viral liver diseases which were examined by ultrasound guided liver biopsy in order to explore the significance of liver biopsy.Methods From January 2006 to December 2015,patients with non-viral liver diseases who received liver biopsy were retrospectively enrolled.Etiology,pathological diagnosis and clinical diagnosis of the patients were analyzed;the differences in disease types between male and female,among different age (less than 60 years and over 60 years)were compared;and the consistency of two pathologists in the pathological diagnosis was analyzed.Chi-square test was performed for statistical analysis.Results Among 182 patients,there were 73 (40.1％) males and 109 (59.9％) females.The most common etiology were autoimmune liver disease (68 cases,37.4％),non-alcoholic fatty liver disease (NAFLD) (40 cases,22.0％) and drug-induced liver injury (DILI) (29 cases,15.9％).The differences in etiology between male and female,between age less than 60 years and over 60 years were statistically significant (X2 =7.31 and 5.87,both P ＜ 0.05).The consistency of two pathologists in the diagnosis of NAFLD,alcoholic liver disease,hereditary metabolic disease and neoplastic disease was good (Kappa=0.85,0.88,0.75 and 1.00).The consistency rates of two pathologists in the diagnosis of autoimmune disease,NAFLD and DILI were 52.9％ (36/68),75.0％ (30/40) and 48.3％ (14/29),respectively.The consistency rate was highest in NAFLD,and the difference was statistically significant (X2 =7.68,P=0.023).However,there was no significant difference in consistency rates of two pathologists in the diagnosis of autoimmune liver disease and DILI (X2 =0.12,P=0.859).The consistency rates between pathological diagnosis and clinical diagnosis in autoimmune liver disease,NAFLD and DILI were 60.3％ (41/68),85.0％ (34/40) and 55.2％ (16/29),respectively,and the difference was statistically significant (X2 =8.98,P=0.011).The consistency rate in NAFLD was highest.However,there was no significant difference in consistency rates between pathological diagnosis and clinical diagnosis in autoimmune liver disease and DILI (X2 =0.22,P=0.639).Conclusions The liver biopsy may guide the clinical diagnosis of NAFLD.However,to improve the diagnostic rates of autoimmune liver disease and DILI,biopsy results,history and laboratory results should be combined.

Objective:To systematically evaluate the effect of cognitive behavioral therapy (CBT) in elderly patients with depression.Methods:The randomized controlled trials on the effect of CBT in elderly patients with depression, published until December 15, 2022, were searched in PubMed, CINHAL, Cochrane Library, China Biology Medicine, China National Knowledge Infrastructure, WanFang Data, and VIP. Two researchers independently screened the literature, extracted data, and used the revised Cochrane risk of bias tool for randomized trials (ROB 2.0) to evaluate the quality of the included studies. Statistical analysis was conducted using Stata 16.0, and the quality of evidence was rated using Appraisal of Guidelines for Research and Evaluation (GRADE) predictor software.Results:A total of 11 randomized controlled trials were included, with a total of 833 elderly patients with depression. Randomized effect models were used to analyze outcome indicators such as depression, anxiety, and quality of life by combining effect quantities. Meta-analysis and GRADE evidence quality showed that compared to the control group, medium quality evidence showed that CBT could relieve depression in elderly depression patients with a statistical difference [ SMD=-1.58, 95% CI (-2.16, -0.99), P<0.05]. Low quality evidence suggested that CBT could alleviate anxiety in elderly depression patients also with a statistical difference [ SMD=-2.25, 95% CI (-4.04, -0.47), P<0.05]. Very low quality evidence indicated that CBT did not significantly improve the quality of life in elderly depression patients compared to conventional or pharmacological treatment [ SMD=-0.09, 95% CI (-2.07, 1.88), P>0.05] . Conclusions:Existing evidence suggests that CBT can alleviate depression and anxiety in elderly depression patients, but its improvement in quality of life is not yet significant. Treatment feedback and forms of CBT may become a research focus in recent years on intervention for elderly depression patients.

The objective of this study was to investigate the genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii clinical isolates from Beijing, China. 173 A. baumannii clinical isolates from hospitals in Beijing from 2006 to 2009 were first subjected to high level aminoglycoside resistance (HLAR, MIC to gentamicin and amikacin>512 µg/mL) phenotype selection by broth microdilution method. The strains were then subjected to genetic basis analysis by PCR detection of the aminoglycoside modifying enzyme genes (aac(3)-I, aac(3)-IIc, aac(6')-Ib, aac(6')-II, aph(4)-Ia, aph(3')-I, aph(3')-IIb, aph(3')-IIIa, aph(3')-VIa, aph(2″)-Ib, aph(2″)-Ic, aph(2″)-Id, ant(2″)-Ia, ant(3″)-I and ant(4')-Ia) and the 16S rRNA methylase genes (armA, rmtB and rmtC). Correlation analysis between the presence of aminoglycoside resistance gene and HLAR phenotype were performed by SPSS. Totally 102 (58.96%) HLAR isolates were selected. The HLAR rates for year 2006, 2007, 2008 and 2009 were 52.63%, 65.22%, 51.11% and 70.83%, respectively. Five modifying enzyme genes (aac(3)-I, detection rate of 65.69%; aac(6')-Ib, detection rate of 45.10%; aph(3')-I, detection rate of 47.06%; aph(3')-IIb, detection rate of 0.98%; ant(3″)-I, detection rate of 95.10%) and one methylase gene (armA, detection rate of 98.04%) were detected in the 102 A. baumannii with aac(3)-I+aac(6')-Ib+ant(3″)-I+armA (detection rate of 25.49%), aac(3)-I+aph(3')-I+ant(3″)-I+armA (detection rate of 21.57%) and ant(3″)-I+armA (detection rate of 12.75%) being the most prevalent gene profiles. The values of chi-square tests showed correlation of armA, ant(3″)-I, aac(3)-I, aph(3')-I and aac(6')-Ib with HLAR. armA had significant correlation (contingency coefficient 0.685) and good contingency with HLAR (kappa 0.940). The high rates of HLAR may cause a serious problem for combination therapy of aminoglycoside with β-lactams against A. baumannii infections. As armA was reported to be able to cause high level aminoglycoside resistance to most of the clinical important aminoglycosides (gentamicin, amikacin, tobramycin, etc), the function of aminoglycoside modifying enzyme gene(s) in A. baumannii carrying armA deserves further investigation.

(E)-Methyl-4-aryl-4-oxabut-2-enoate (YH-8) is a novel PKnB protein kinase inhibitor with good anti-tuberculosis activity. To evaluate its pharmacokinetics in rats, a sensitive and selective high performance liquid chromatography-tandem mass spectrometric (LC--MS/MS) method has been developed and validated for the quantification of YH-8 in rat plasma for the first time. Samples were pre-treated using a liquid--liquid extraction with ethyl acetate and the chromatographic separation was performed on a C18 column by gradient elution with methanol--water as the mobile phase. YH-8 was detected using a tandem mass spectrometer in positive selected reaction monitoring (SRM) mode. Method validation revealed good linearity over the range of 1-500 ng/mL for YH-8 with a lower limit of quantification (LLOQ) of 1 ng/mL. Intra- and inter-day precision of YH-8 assay in rat plasma samples were 2.0%-6.8%, with accuracy of the method being 100.69%-106.18%. Stability test showed that when spiked into rat plasma, YH-8 was stable for 12 h at room temperature, for up to 15 days at -70 °C, and after three freeze-thaw cycles. Extracted samples were found to be stable over 12 h in an auto-sampler. The method was successfully applied to the pharmacokinetic study of YH-8 in rats after oral administration at 100 mg/kg and 200 mg/kg.

Objective The number of confirmed and suspected cases of the COVID-19 in Hubei province is still increasing. However, the estimations of the basic reproduction number of COVID-19 varied greatly across studies. The objectives of this study are 1) to estimate the basic reproduction number ( R 0 ) of COVID-19 reflecting the infectiousness of the virus and 2) to assess the effectiveness of a range of controlling intervention. Method The reported number of daily confirmed cases from January 17 to February 8, 2020 in Hubei province were collected and used for model fit. Four methods, the exponential growth (EG), maximum likelihood estimation (ML), sequential Bayesian method (SB) and time dependent reproduction numbers (TD), were applied to estimate the R 0 . Result Among the four methods, the EG method fitted the data best. The estimated R 0 was 3.49 (95% CI : 3.42-3.58) by using EG method. The R 0 was estimated to be 2.95 (95% CI : 2.86-3.03) after taking control measures. Conclusion In the early stage of the epidemic, it is appropriate to estimate R 0 using the EG method. Meanwhile, timely and effective control measures were warranted to further reduce the spread of COVID-19.