Great changes in drug metabolizing enzyme (DME) expression occur in the fetus and child during development. Individual hepatic DME ontogeny can be categorized into one of three groups based on developmental trajectories.Some enzymes such as CYP3A7,are expressed at highest level in the fetus dur-ing the first trimester and either remain elevated or slightly de-crease during gestation,but are silenced or reduced to relatively low levels within one to two years after birth.SULT1 A1 is an ex-ample of the second group of DME.These enzymes are ex-pressed at relatively constant levels throughout gestation and into adulthood.CYP3A4 belongs to the third DME group .These en-zymes are expressed at negligible or low levels in the fetus.Sig-nificant increases in enzyme levels are exhibited within the first one to two years after birth.The epigenetic regulation refers to genomic modifications that do not involve changes in DNA se-quence and include DNA methylation,histone modifications, and non-coding RNAs.The epigenetic regulation mechanisms are responsible for the developmental expression of DME genes dur-ing liver maturation.This review will provide a summary of DME developmental expression profiles and reveal epigenetic mecha-nisms underlying variable drug metabolism and drug response. Thus,knowledge regarding DME ontogeny has permitted im-proved capability to predict drug disposition in pediatric pa-tients,which is crucial for improving drug dosing leading to opti-mal safety and efficacy in children.

Objective To evaluate the changes in the expression of NRF-1 in the spinal cord during remifentail-induced hyperalgesia in a rat model of incisional pain.Methods Forty-eight Sprague-Dawley rats,weighing 180-220 g,were randomly divided into 4 groups (n =12 each) using a random number table:control group (C); incisional pain group (group Ⅰ); remifentanil group (group R); incisional pain + remifentanil group (group Ⅰ + R).All the rats were anesthetized with sevoflurane.A 1-cm longitudinal incision was made through skin,fascia and muscle of the plantar aspect of the right hindpaw in I and I + R groups.In C and I groups,normal saline was subcutaneously infused for 30 min.In group I + R,remifentanil (0.04 mg/kg,0.4ml) was subcutaneously infused for 30 min starting from the onset of skin incision.Paw withdrawal threshold to mechanical stimulation (PWMT) was measured at 24 h before operation and at 2,6,12,24 and 48 h after operation.After measurement of PWMT at 48 h,the rats were sacrificed and L4,5 segments of the spinal cord were removed rapidly to detect the expression of nuclear respiratory factor 1 (NRF-1) by immunofluorescence and Western blot.Results Compared with group C,PWMT was significantly decreased at each time point after operation,and the expression of NRF-1 in the spinal cord was up-regulated in I and I + R groups (P ＜ 0.05).Compared with group I,PWMT was significantly decreased at each time point after operation,and the expression of NRF-1 in the spinal cord was up-regulated in group I + R (P ＜ 0.05).Conclusion Up-regulation of NRF-1 expression in the spinal cord may be involved in the development of remifentail-induced hyperalgesia in a rat model of incisional pain.

Objective To evaluate the correlation between CYP3A4 enzyme and analgesia with fentanyl after gynecological operation. Methods One hundred and fifty-nine ASA Ⅰ or Ⅱ patients, aged 30-50 yr, scheduled for elective myomectomy or abdominal total hysterectomy, were enrolled in this study. Anesthesia was induced with midazolam, remifentanil, propofol and succinylcholine and maintained with iv infusion of propofol and remifentanil and intermitent iv injection of atracurium. Venous blood samples were obtained for determination of the plasma 1'-hydroxymidazolam and midazolam concentrations at 1 h after iv injection of midazolam. The ratio of the 1'-hydroxymidazolam concentration to the midazolam concentration was used to reflect the effect of CYP3A4 enzyme. Pain was assessed with visual analog scale (VAS) after consciousness was regained. When VAS score ＞ 4,the patients were given fentanyl 10 μg every 5 min until VAS score ≤ 4 and then PCIA with fentanyl was performed. VAS score was maintained ≤4. The times of successful delivery within 24 h after operation and during the period of 24-28 h after operation and fentanyl consumption within 48 h after operation were recorded. Pearson correlation was used to analyze the data. Results There was no correlation between the effect of CYP3 A4 enzyme and the times of successful delivery or fentanyl consumption, and the correlation coefficients were 0.16, 0.13 and 0.11 respectively ( P ＞ 0.05). Conclusion CYP3A4 enzyme is not the major enzyme metabolizing fentanyl.

Objective To evaluate the effects of gender on the pharmacokinetics of propofol in patients.Methods Twenty ASA physical status Ⅰ or Ⅱ patients of both sexes (10 male,10 female),aged 42-59 yr,weighing 46-76 kg,scheduled for elective surgery for gastrointestinal cancer,were randomly divided into 2 gender groups (n =10 each):male group and female group.Combined intravenous-inhalational anesthesia was performed during surgery.Anesthesia was induced with iv injection of 2％ propofol 2 mg/kg,remifentanil 1.5 μg/kg,and suxamethonium chloride 1.5 mg/kg.The patients were tracheally intubated and mechanically ventilated.Anesthesia was maintained with inhalation of the mixture of 1％-2 ％ isoflurane and nitrous oxide (N2 O ∶ O2 =1 ∶ 1.),iv infusion of remifentanil 0.2-0.3 μg/kg and intermittent iv boluses of atracurium.Blood samples were taken from the central vein before propofol administration,and at 1,2,3,4,6,10,15,30,45,60,90,120,180,240,360 and 720 min after propofol administration for determination of the plasma concentration of propofol by high-performance liquid chromatography.The blood concentration-time curve of propofol was drawn and the pharmacokinetic parameters were calculated.Results The blood concentrations of propofol were significantly lower at each time points within 10 rmin after administration of the single bolus of propofol in female group than in male group (P ＜0.05).The blood concentration-time curves of propofol were fitted to a three-compartment open model in the 2 groups.The central volume of distribution and clearance rate were significantly larger in female patients than in male patients (P ＜ 0.05).Conclusion After iv injection of propofol,the blood concentration of propofol is lower,and the central volume of distribution and clearance rate are larger in female than in male,suggesting that gender has significant effect on pharmacokinetics of propofol.

Objective To explore the effect of uric acid (UA) on the rat glomerular mesangial cells (GMCs) and its possible mechanism in vitro. Methods Cultured rat GMCs were treated with various concentrations of UA (50 μmol/L, 100 μmol/L, 300 μmol/L) in the presence or absence of U0126, apocynin, rotenone. The incorporation of 3H-thymidine (3H-TdR) and cell counting were used to measure GMCs proliferation. GMCs cell-cycle was analyzed by flow cytometry. CyclinD1 and cyclin A2 expression were determined by real-time PCR and Western blotting analysis. ERK1/2 phosphorylation was detected by Western blotting. Reactive oxygen species (ROS) was measured by 2, 7-dichlorofluorescein diacetate (DCFDA) fluorescence. Results (1) Uric acid increased GMCs proliferation in dose-dependent manner compared with the control groups, as assessed by 3H-TdR incorporation and cell counting. GMCs proliferation induced by 300 μmol/L uric acid was increased by more than 1.5-fold assessed by both of the methods. (2) Uric acid decreased cell number in G1/G0 phase and increased cell number in S phase in dosedependent manner, as assessed by flow cytometry. (3) Uric acid iuduced cyclin D1 and cyclin A2 expression in dose-dependent manner. (4)Uric acid increased pospho-ERK1/2 in dose-dependent manner and ERK1/2 specific inhibitor U0126 could suppress uric acid-induced cell proliferation.The inhibition percentage of U0126 was 22% and 31% assassed by cell counting and 3H-TdR incorporation, respectively. (5) Uric acid increased ROS production in dose-dependent manner.NADPH oxidase inhibitor apocynin could also significantly inhibit uric acid-induced ROS production, ERK phosphorylation and cell proliferation. In contrast, rotenone had no effect on them.Conclusion Uric acid can stimulate rat GMCs proliferation, partially by the activation of ERK pathway via NADPH oxidase-derived ROS generation.

Objective To establish in vitro metabolism of fentanyl by human liver microsomes in Chinese population.Methods Thirty patients undergoing elective operation on liver were enrolled in the study.Normal liver specimens were obtained during removal of liver and gall for preparation of liver microsomes (by calcium precipitation) which were used for establishment of the liver microsomal incubation system for fentanyl.Fentanyl served as the metabolic substrate in the incubation reaction.The concentration of fentanyl in the incubation medium was detected at 0,5,10,15,20 and 30 min of incubation using HPLC-UV.Sufentanil served as the interior label element.The n-hexane-ethanol absolute was used to extract the sample.The chromatographic column used in this method was Grace C18 (4.6 mm × 250.0 mm,5 μm).The mobile phase was methyl cyanide-KH2PO4 buffer solution with the flow rate of 1.0 ml/min,detection wavelength of 205 nm and sample size of 20 μl.Linear regression analysis was performed by using the least-squares method.The specimens of the blank incubation system with the final concentration of fentanyl 0.6,2.4 and 10.0 μg/ml were obtained to determine the recovery,precision and stability.The metabolic rate of fentanyl in human hepatic microsomes was calculated.Results Fentanyl and the interior label element sufentanil were separated completely,and the retention time were 5.730 and 9.336 min,respectively.Endogenous matrix of microsomes did not interfere with the analysis.Regression equation was C =0.945 8A-0.140 4,R2 =0.999 2.C was the concentration of fentanyl,and A was the peak area ratio of fentanyl versus sufentanil.The recovery of incubation system with low,medium and high concentrations of fentanyl was 85％-115％,and relative standard deviation (RSD) was less than 10％.The RSD of intra-and inter-day precision and stability was less than 10％.The method was proved to meet the requirements of biological sample analysis.The metabolic rate of fentanyl was (1.6 + 0.8) nmol/min per milligram protein in human hepatic microsomes of 30 cases.Conclusion The in vitro metabolism of fentanyl by human liver microsomes is convenient,and the detectability is high,so it can be used for the research on the in vitro metabolism of fentanyl in Chinese population.

Objective To develop the knowledge-attitude-practice scale for evaluating intra-abdominal pressure measurement in ICU nurses and assess its reliability and validity preliminary. Methods Applied the methods of literature review and Delphi expert consultation to form the knowledge-attitude-practice scale for evaluating intra-abdominal pressure measurement in ICU nurses on the basis of the knowledge-attitude-practice framework. A total of 165 nurses from ICU department were finally involved. Items analysis, exploratory factor analysis, content validity, internal consistency test and split-half reliability were used to evaluate the scale. Results Factor analysis revealed five factors (23 items), accounting for 52.5%of the total variance. The Cronbach αcoefficient was 0.869 for the total scale and 0.612, 0.749 and 0.848 for the subscales of knowledge, attitude and practice. The split-half coefficient was 0.784. Conclusions The knowledge-attitude-practice scale has good reliability and validity, and can be used to assess the intra-abdominal pressure measurement in ICU nurses.

Objective To investigate the subtype distribution and changing trend of human immunodeficiency virus (HIV)-1 strains among men who have sex with men (MSM) during 2005-2011 in Beijing.Methods Five serial cross-sectional surveys of MSM were conducted in the year of 2005-2006,2007,2008,2009,and 2010-2011 in Chaoyang district of Beijing.Whole blood samples were collected and then RNA was extracted.HIV-1 gag gene was characterized by reverse transcriptase and nested polymerase chain reaction (RT-PCR) amplification,DNA sequencing,and phylogenetic analysis of viral sequences to determine the HIV-1 subtypes.Results Phylogenetic analysis of the sequences revealed that the predominant subtypes of HIV-1 gag gene included subtype B,CRF01_AE and CRF07_BC.And CRF15_01B was detected from the year of 2008.In addition,significant changes of the distributions of subtypes and CRFs occurred from 2005 to 2011 in HIV+ MSM.Subtype B showed a significant decreased trend,while the proportions of CRF01 _AE and CRF07_BC significantly increased in the 7-year period,particularly that of CRF01_AE.Conclusions The substantial changes are observed in the diversity of HIV-1 strains circulating among MSM in Beijing during a 7-year period.

Objective To investigate the effects of CYP3A5~* 3 genetic polymorphism on analgesia with fentanyl. Methods One hundred and eighty ASA Ⅰ or Ⅱ patients, aged 20-50 yr, Hart nationality, Henan province, scheduled for elective abdominal total hysterectomy or myomectomy under general anesthesia, were enrolled in this study. The polymorphic sites of the CYP3A5~* 3 allele were analyzed by polymerase chain reaction-restriction fragment length polymorphism. The patients were assigned to one of 3 groups according to their genotypes: wild homozygote group, mutation heterozygote group and mutation homozygote group. Midazolam, remifentanyl, propofol and succinylcholine were used for induction of anesthesia. The patients were mechanically ventilated after tracheal intubation. Remifentanyl, propofol and atracurium were given iv for maintenance of anesthesia. The pain was assessed with visual analog scale (VAS) after consciousness was regained. When VAS score > 3, the patients were given fentanyl 20 μg every 5 min until VAS score was decreased to ≤3 and then patient-controlled intravenous analgesia (PCIA) with fentanyl was started. The background infusion rate of fentanyl 1.0 mg and droperidol 5 mg (in 100 ml normal saline) was 0.5 ml/h. The PCIA pump was programmed to give a 2 ml bolus of fentanyl solution with a 5 min lockout interval, 7 time successful delivery per hour and maximum dosage 145 μg/h, and VAS score was maintained less than 3. The amount of fentanyl used within 24 h after surgery was recorded. Results No significant difference was detected in the fentanyl consumption in the 24 h during PCIA among the 3 groups (P> 0.05). Conclusion The genetic polymorphism CYP3 A5~* 3 is not the factor contributing to the individual variation in the patient's response to analgesia with fentanyl.

Objective To investigate the effect of PXR* 1B polymorphism on postoperative analgesia with fentanyl in the patients undergoing gynecological operation.Methods A total of 102 female patients from Henan province, of Han nationality, aged 20-50 yr, of American Society of Anesthesiologists physical status Ⅰ or Ⅱ , with body mass index of 14.8-30.0 kg/m2, scheduled for elective abdominal total hysterectomy or myomectomy under general anesthesia, were enrolled in this study.PXR genetic polymorphic sites were analyzed by polymerase chain reaction (PCR)-direct DNA sequencing.PXR* 1B haplotype was analyzed by the PHASE V.2.1 software.The patients were assigned into 3 groups according to their genotypes: PXR* 1B haplotype group (group PXR* 1B), non-PXR* 1B haplotype group (group n-PXR* 1B) and PXR* 1B/PXR * 1B group (group PXR* 1B/PXR* 1B).Postoperative pain was assessed with visual analogue scale (VAS) score.When VAS ＞ 3, fentanyl 20 μg was injected intermittently until VAS ≤ 3, and then a pump was connected to perform patient-controlled intravenous analgesia (PCIA) with fentanyl.PCIA solution contained fentanyl 1.0 mg and droperidol 5 mg in 100 ml of normal saline.The PCA pump was set up with a 2 ml bolus dose, a 5 min lockout interval and background infusion at a rate of 0.5 ml/h.The number of successfully delivered doses was set at 7 times, and the maximal amount of fentanyl was 145 μg.If exceeding the maximal dose, the VAS score was still more than 3, nonsteroidal anti-inflammatory drugs were given as rescue medication.VAS score immediately after the end of operation, and the consumption of fentanyl within 24 h after operation were recorded.Midazolam 0.1 mg/kg was injected intravenously during induction of general anesthesia, and 1 h later venous blood samples were collected for determination of plasma 1'-hydroxymidazolam and midazolam concentrations.The ratio of 1'-hydroxymidazolam concentration to midazolam concentration was calculated to reflect the activity of CYP3A4.Results No patients required rescue anesthetics in the three groups.There were 27 cases in group PXR * 1B, 53 cases in group n-PXR* 1B, and 22 cases in group PXR* 1B/PXR* 1B.PXR* 1B allele frequency was 37.2％.There was no significant difference in VAS score immediately after the end of operation, consumption of fentanyl within 24 h after operation, and activity of CYP3A4 between the three groups (P＞0.05).Conclusion PXR* 1B polymorphism has no effect on postoperative analgesia with fentanyl in the patients undergoing gynecological operation, and is not one of the genetic factors producing individual variation in postoperative analgesia.