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Objective: To anlysis the efficacy and safety of cut-umbilical cord milking (C-UCM) compared with immediate cord clamping in preventing anemia and iron deficiency among term cesarean-delivered newborns. Methods: A total of 485 pregnant women planning to deliver by cesarean section were recruited in this randomized controlled trial in Hunan Maternal and Child Health Hospital and Liuyang Maternal and Child Health Care Hospital from July 2016 to April 2019. A block randomization was conducted to evenly allocate them to the controlled group and the C-UCM group. In the controlled group, the cord was clamped within 30 seconds as routine. In the C-UCM group, the cord was first clamped at 25 cm from the newborn's navel, and then the blood in the cord was gently squeezed into the newborn's body until the cord became white and shriveled. The cord was clamped twice at 2-3 cm from the newborn's navel subsequently. Neonatal jaundice, hyperbilirubinemia and polycythemia were monitored before discharge. After the newborns discharged, their hemoglobin, red blood cell count, hematocrit (at the age of 1, 6 and 12 months) and serum ferritin (at the age of 6 and 12 months) were followed up; body length and weight were measured; and information about their feeding and iron supplementation were collected (at the age of 1, 6, 12 and 18 months). The two groups were compared by t test, Mann-Whitney U test, χ² test, or Fisher exact probability method. The hospital was set as a random item, and the mixed effects regression model was used to evaluate the effect of C-UCM on relevant indicators of cesarean-delivered newborns. Results: There were 244 women in the C-UCM group with an average age of (31.9±4.4) years, and 241 in the control group with an average age of (31.8±4.2) years ( P >0.05). There was no statistically significant difference between the C-UCM group and the control group at 1, 6 and 12 months of age in hemoglobin [(123.6±14.5) vs (122.2±14.5) g/L, (115.3±9.4) vs (114.1±8.5) g/L, (115.6±9.6) vs (116.1±12.6) g/L] or anemia incidence rate [15.2% (17/112) vs 18.4% (19/103), 22.7% (34/150) vs 26.8% (44/164), 22.3% (25/112) vs 19.5% (22/113)] (all P >0.05). There was no statistically significant difference between the two groups at 6 and 12 months of age in serum ferritin [ M ( Q 1 , Q 3 ), 39.9 (24.9, 61.8) vs 43.6 (25.2, 100.9) μg/L, 40.3 (25.4, 259.2) vs 40.3 (26.4, 167.6) μg/L)] or iron deficiency incidence rate [6.1% (5/82) vs 4.2% (3/72), 6.7% (5/75) vs 3.8% (3/80)] (all P >0.05). There were also no significant difference between the two groups in other indicators, such as the Z-score of weight-for-length, the incidence of neonatal jaundice, and the incidence of neonatal hyperbilirubinemia (all P >0.05). After adjusting for the relevant covariates, there were still no significant effects of C-UCM on these outcomes above. Conclusions: Compared to immediate cord clamping, the intervention of gently squeezing 25 cm of the cord does not significantly reduce the risk of anemia or iron deficiency in term cesarean-delivered newborns, nor does it have a significant impact on infant growth and development. Yet this intervention does not increase the risk of jaundice or hyperbilirubinemia in newborns as well.

Gut microbiota (GM) dysbiosis has been increasingly associated with Alzheimer's disease (AD). However, the association between APOE4, the most common genetic risk factor for sporadic AD, and GM in AD remains unclear. In this study, we conducted a comparative analysis of the GM of participants from China and the USA, with and without APOE4 genes and with or without AD (67 AD cases, 67 control cases). Our results revealed that the GM alpha diversity was not different between groups (AD&#95;APOE4, Control&#95;APOE4, AD&#95;non-APOE4, and Control&#95;non-APOE4) (419.031 ± 143.631 vs 391.091 ± 126.081, 351.086 ± 169.174 and 386.089 ± 177.200, respectively. P > 0.05). Interestingly, individuals in the AD&#95;APOE4 group had different bacterial compositions and bacterial biomarkers. The Kruskal-Wallis rank sum test indicated that the abundances of many bacterial species in the AD&#95;APOE4 patients differed from those in control individuals, including decreases in unclassified&#95;g&#95;&#95;Escherichia-Shigella (1.763 ± 6.73, 4.429 ± 11.13, 8.245 ± 16.55, and 5.69 ± 13.91 in four groups, respectively; P < 0.05), and unclassified&#95;g&#95;Clostridium&#95;sensu&#95;stricto&#95;1 (0.1519 ± 0.348, 2.502 ± 5.913, 0.5146 ± 0.9487, 1.063 ± 3.428 in four groups, respectively; P < 0.05), and increases in gut&#95;metagenome&#95;g&#95;Faecalibacterium (2.885 ± 4.47, 2.174 ± 3.957, 0.5765 ± 1.784, 1.582 ± 2.92 in four groups, respectively. P < 0.01) and unclassified&#95;g&#95;Bacteroides (3.875 ± 3.738, 2.47 ± 2.748, 2.046 ± 3.674, 3.206 ± 3.446 in four groups, respectively; P < 0.05). In the KEGG pathway level 2 analysis, we identified three significant differences in relative abundances of predicted functions between AD&#95;APOE4 and AD&#95;non-APOE4&#95;carrier groups: neurodegenerative diseases (0.0007 ± 0.0005 vs 0.0009 ± 0.0004; P < 0.01), metabolism (0.0240 ± 0.0003 vs 0.0250 ± 0.0003; P < 0.05), and biosynthesis of other secondary metabolites (0.0094 ± 0.0002 vs 0.0090 ± 0.0002; P < 0.05). Receiver operating characteristic curves further demonstrated an area under the curve (AUC) of 0.74 for the discrimination of AD&#95;APOE4&#95;carrier and AD&#95;non-APOE4&#95;carrier individuals.

Objective: To investigate the prevalence of albuminuria in Chinese residents aged >35 years and its potential association with cardiovascular disease (CVD). Methods: A total of 34 647 Chinese subjects aged ≥35 years were selected by stratified multi-stage random sampling from 2012 to 2015. Data were collected through questionnaires, physical examinations, and laboratory tests. Albuminuria was categorized into 3 types according to urinary albumin-to- creatinine ratio: normal (<30 mg/g), microalbuminuria (MAU, 30-300 mg/g), and macroalbuminuria (≥300 mg/g). Measurement data were expressed as x¯±s, and t -tests were used for comparisons between indicators. Qualitative data were expressed as rate or constituent ratio, and the χ 2 test or Kruskal-Wallis test was used to examine differences. Logistic regression was used for multivariate analyses. SAS 9.4 software was used for statistical analyses, and P <0.05 was considered statistically significant. Results: The prevalence of abnormal albuminuria was 19.1%; the prevalence was 17.2% for MAU and lower in males (13.8%) than females (20.1%, P <0.01). The risk of CVD was higher among subjects with MAU ( OR =1.23, 95% CI 1.12-1.35) and macroalbuminuria ( OR =1.86, 95% CI 1.50-2.32). When MAU was complicated by hypertension and diabetes mellitus, the CVD risk was 1.76 times higher. Conclusions: The prevalence of MAU is high among Chinese subjects aged 35 years and over. Those with MAU have higher CVD risk, especially those with hypertension and diabetes mellitus.

Objective: To estimate the prevalence, awareness, treatment and control rate of hypertension among young and middle-aged population in China. Methods: The analysis was based on the results of 2012-2015 China Hypertension Survey, which was a cross-sectional stratified multistage random sampling survey. A total of 229 593 subjects were included in the final analysis. The data including sex, age, living in urban and rural areas, prevalence of hypertension, history of stroke, family history of coronary heart disease and drinking, physical examination, heart rate were collected. Hypertension was defined as mean systolic blood pressure (SBP) ≥140 mmHg (1 mmHg=0.133 kPa), and (or) diastolic blood pressure (DBP) ≥90 mmHg, and (or) self-report a history of hypertension, and (or) use of antihypertensive medicine within 2 weeks before survey. Prehypertension was defined as SBP between 120-139 mmHg, and (or) DBP between 80-89 mmHg. Control of hypertension was considered for hypertensive individuals with SBP<140 mmHg and DBP<90 mmHg. The prevalence of prehypertension, hypertension, awareness, treatment, control rate were calculated, and the control rate among those with antihypertensive medication was also calculated. Results: The prevalence of prehypertension and hypertension was 43.8% (95% CI : 42.3%-45.4%), and 22.1% (95% CI : 20.8%-23.3%), respectively. The prevalence of prehypertension and hypertension was significantly higher among male than female across different age groups. The awareness, treatment, control rate of hypertension and control rate among treated hypertensive participants were 43.8%, 33.2%, 16.7%, and 40.2%, respectively. The prevalence was higher, and the control rate was lower among individuals with higher heart rate. Conclusion: The prevalence of prehypertension and hypertension among young and middle-aged population is high, the awareness, treatment and control rate need to be further improved in this population. The prevention and treatment of hypertension should be strengthened in the future to improve the control rate of hypertension in China.

Objective: This study aimed to evaluate the effect of resistance exercise on peripheral inflammatory biomarkers in healthy adults., Materials and Methods: Four databases, including PubMed, Web of Science, Cochrane Library, and SPORTDiscus, were searched from inception until April 1st, 2022. A meta-analysis was conducted using a random-effects model, followed by sensitivity analysis, subgroup analysis, meta-regression analysis, and publication bias analysis., Results: 15 randomized controlled trials were included in the meta-analysis. The pooled results showed that resistance exercise significantly decreased TNF-α levels (SMD = -0.81, 95% CI: -1.42 to -0.20, p = 0.009) but did not affect IL-6 and CRP levels. Individuals with BMI 18.5-24.9 exhibited significantly decreased IL-6 levels, while moderate strength resistance exercise could significantly decrease TNF-α levels. Finally, age might be a confounding factor influencing the effect of resistance exercise on IL-6., Conclusions: Resistance exercise could reduce TNF-α levels in healthy adults, and resistance exercise with moderate intensity could reduce TNF-α levels more effectively.

Objective: To investigate the prevalence, awareness, treatment and control status of dyslipidemia among females aged ≥35 years old across China. Methods: Participants were selected by stratified multistage random sampling method in the "Twelfth Five-Year Plan" National Science and Technology Support Project "Survey on the Prevalence of Important Cardiovascular Diseases and Key Technology Research in China" project. This study is a retrospective, cross-sectional study. A total of 17 418 females aged 35 years and over were included in the current study. The basic information such as age, medical history and menopause was collected by questionnaire. The blood lipid parameters were derived from clinical laboratory examinations. The prevalence of dyslipidemia and the rate of awareness, treatment, and control of dyslipidemia were analyzed in females aged 35 years and over. Results: The age of participants was (56.2±13.0) years old, and the prevalence of dyslipidemia was 33.1% (5 765/17 418). The prevalence rates of high total cholesterol, hypertriglyceridemia, low HDL-C and high LDL-C were 9.7% (1 695/17 418), 11.1% (1 925/17 418), 10.9% (1 889/17 418) and 7.3% (1 262/17 418), respectively. The prevalence of dyslipidemia increased with age and the prevalence of dyslipidemia in women who were not married, Han, menarche age>16 years, obesity, central obesity, alcohol consumption, diabetes, hypertension and family history of cardiovascular disease were higher than those without such characteristics ( P <0.05). There were 10 432 (59.9%) menopausal females in this cohort and prevalence of dyslipidemia of these participants was 38.8% (4 048/10 432), which was higher than that of non-postmenopausal females (24.6%, 1 717/6 986) ( P <0.05). The awareness rates, treatment rates and control rates of dyslipidemia were 33.9% (1 953/5 765), 15.1% (870/5 765) and 2.5% (143/5 765) respectively among females aged 35 years and over in China. Conclusion: The prevalence of dyslipidemia in Chinese females aged 35 years and over is high, and its awareness, treatment, and control rates need to be optimized.

Objective: To investigate pathogenic genes related to the phenotype of fetus with severely short limbs in the first and second trimester by whole exome sequencing (WES). Methods: Thirteen fetuses with severely short limbs detected by ultrasonography in the first and second trimester admitted in Chinese PLA General Hospital from September 2016 to June 2018 were collected. All cases were performed induced abortion, 6 of which were carried out karyotype analysis of amniotic fluid at the same time. WES and copy number variations (CNV) were performed on specimens from fetal tissues after labor induction. The suspected pathogenic mutations were validated by Sanger sequencing reactions. Results: No abnormal karyotypes or pathological CNV were found. In 10 fetuses, pathogenic or possibly pathogenic mutations were detected in the following genes: COL2A1, FGFR3, COL1A1, COL1A2, DYNC2LI1 and TRIP11, all of which were essential to skeletal development. The diagnostic yield of WES in the fetuses with severe short limbs was 10/13. Conclusions: In the first and second trimester, most of the fetuses with extremely short limbs suffer from monogenic diseases. WES is likely to be a valuable diagnostic testing option for the fetuses with severe short limbs.

Wnt signaling regulates a broad variety of processes in both embryonic development and various diseases. Recent studies indicated that some genetic variants in Wnt signaling pathway may serve as predictors of diseases. Low-density lipoprotein receptor protein 6 (LRP6) is a Wnt co-receptor with essential functions in the Wnt/β-catenin pathway, and mutations in LRP6 gene are linked to many complex human diseases, including metabolic syndrome, cancer, Alzheimer's disease and osteoporosis. Therefore, we focus on the role of LRP6 genetic polymorphisms and Wnt signaling in complex diseases, and the mechanisms from mouse models and cell lines. It is also highly anticipated that LRP6 variants will be applied clinically in the future. The brief review provided here could be a useful resource for future research and may contribute to a more accurate diagnosis in complex diseases.

Objective: To analyze the efficiency and safety of navigation guided extraction of impacted supernumerary tooth. Methods: Twenty-five cases of navigation guided supernumerary tooth extraction and 25 cases of non-navigation guided supernumerary tooth extraction (control group) were included in the study. Each group had 3 cases with one impacted supernumerary tooth and 22 cases with two impacted teeth. Results: Preoperative navigation system designing time was (45.0±8.0) min in average. Navigation system installation time was (15.0±2.8) min. The average operation time was (0.64±0.08) hour in navigation group and (0.91±0.09) hour in control group. Conclusions: Navigation guided extraction of impacted supernumerary tooth takes less time for operation but more time for the preoperative navigation system design.

What Is Known and Objective: Warfarin is a widely used anticoagulant with a narrow therapeutic index. Polymorphisms in the VKORC1, CYP2C9 and CYP4F2 genes have been verified to correlate with warfarin stable dosage (WSD). Whether any other genes or variants affect the dosage is unknown. The aim of our study was to investigate the relationship between GGCX, miR-133 variants and the WSD in Han Chinese patients with mechanical heart valve replacement (MHVR)., Methods: A total of 231 patients were enrolled in the study. Blood samples were collected for genotyping. The average WSD among subjects with different GGCX or miR-133 genotypes was compared. Regression analyses were performed to test for any association of genetic polymorphisms with WSD., Results and Discussion: The warfarin dosage in patients with the GGCX rs699664 TT and rs12714145 TT genotypes was 3.77±0.93 (95% CI: 3.35-4.19) mg/d and 3.70±1.00 (95% CI: 3.32-4.09) mg/d, respectively. The GGCX rs699664 and rs12714145 genotypes were significantly associated with WSD (P<.05). But they were ruled out in the multivariate regression analysis. There were no significant differences in the average warfarin stable dosage between subjects with MIR133B rs142410335 wild-type and variant genotypes (P>.05)., What Is New and Conclusion: The genotypes of GGCX rs699644 and rs12714145 were significantly associated with WSD (P<.05), but their contributions were not significant after accounting for other factors. MIR133B rs142410335 makes no significant contributions to warfarin stable dosage in Han Chinese patients with MHVR neither in univariate regression nor in multivariate regression analyses., (© 2017 John Wiley & Sons Ltd.)

Nano nickel oxide (NiO), widely used in industry, has recently been discovered to have pulmonary toxicity. However, no subchronic exposure studies about nano NiO-induced pulmonary fibrosis have been reported. The objective of this study was to investigate pulmonary fibrosis induced by nano NiO and its potential mechanism in rats. Male Wistar rats ( n = 40, 200-240 g) were randomized into control group, nano NiO groups (0.015, 0.06, and 0.24 mg/kg), and micro NiO group (0.024 mg/kg). All rats were killed to collect lung tissue after intratracheal instillation of NiO particles twice a week for 6 weeks. To identify pulmonary fibrosis, Masson trichrome staining, hydroxyproline content, and collagen protein expression were performed. The results showed widespread lung fibrotic injury in histological examination and increased content of hydroxyproline, collagen types I and III in rat lung tissue exposed to nano NiO. To explore the potential pulmonary fibrosis mechanism, transforming growth factor beta 1 (TGF- β1) content was measured by enzyme-linked immunosorbent assay, and the messenger RNA expression of key indicators was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The TGF- β1 content was increased in nano NiO exposure groups, as well as the upregulated gene expression of TGF- β1, Smad2, Smad4, matrix metalloproteinase, and tissue inhibitor of metalloproteinase. The findings indicated that nano NiO could induce pulmonary fibrosis, which may be related to TGF- β1 activation.

Objective: To analyze the clinical features and to explore the etiology of short fetal femur during the third trimester. Methods: From January 2010 to June 2016, 21 singleton pregnancies with short fetal femur detected by ultrasonography during the third trimester were referred to the Chinese PLA General Hospital. Clinical data were collected, karyotype or single nucleotide polymorphism microarray was carried out to detect chromosomal abnormalities, and FGFR3 c.1138G>A mutation detection was carried out to detect achondroplasia (ACH) via invasive procedure, respectively. The deviation of femur length from the mean value of the gestational age in ultrasonography was expressed as the Z -score. The difference between ACH and isolated short femur (ISF, in the absence of associated structure abnormality or genetic abnormality) was then explored. Results: In the 21 fetuses, 11 had abnormal genetic test results(52%, 11/21), including 9 cases of ACH, 1 case of Ellis-van Creveld Syndrome and 1 case of Pallister-Killian syndrome. In the 10 ISF fetuses (48%, 10/21), 3 cases were fetal growth restriction, 1 was normal small for gestational age infant and 6 cases were unexplained. The median Z -scores for 9 cases of ACH and 10 cases of ISF in the third trimester were -5.04, -3.20, respectively. The short femur in ACH was more severe than in ISF ( P= 0.005) in the third trimester. Conclusions: The etiology of short fetal femur is complicated, including skeletal dysplasia, chromosomal abnormality, fetal growth restriction, as well as normal variants during fetal development. Genetic test should be considered during the antenatal consultation.

The adverse reactions of warfarin that were found mainly occurred in the first month. This study was carried out to observe the effect of gene polymorphisms on the warfarin therapy at the initial stage. Four-hundred and sixty Chinese patients began warfarin treatment with daily 2.5 mg after heart valve replacement operations were enrolled. The daily international normalized ratio (INR) for anticoagulation were recorded till the seventh day. Blood samples were collected and used to detect genotypes for VKORC1 rs7294, CYP2C9 rs1057910, CYP4F2 rs2108622 and ORM1 rs17650. INR and their changes were compared among genotypes. INR was partially correlated with the VKORC1 rs7294, CYP2C9 rs1057910, CYP4F2 rs2108622 and ORM1 rs17650 polymorphisms from the third, fourth and sixth day on, respectively. VKORC1 rs7294 and CYP4F2 rs2108622 carriers responded lower than the wild genotype, whereas CYP2C9 rs1057910 and ORM1 rs17650 carriers responded higher, respectively. Fifty percent of AA/*1*3/CC/*S*S patients and 16% of AA/*1*1/CC/*S*S patients were over anticoagulation treated with INR >4.0 at the third day. Ninety percent of VKORC1 rs7294 carrier patients have INR <1.63, a mark of the 25% of lower responders of the wild genotype. Our study provided another kind of evidence that VKORC1 rs7294, CYP2C9 rs1057910, CYP4F2 rs2108622 and ORM1 rs17650 affected the action of warfarin in different styles. Patients with AA/*1*1/CC/*S*S, AA/*1*3/CC/*S*S should use a less initial dosage to avoid over anticoagulation, and patients with VKORC1 rs7294 should use larger initial dose to proof an effective therapy.

Aim: Several factors have been implicated in the pathogenesis of colorectal cancer (CRC) associated with ulcerative colitis (UC). We investigated markers of cancer cell pluripotency, including CD44 and CD166, microRNA-21 (miR-21) and microRNA-215 (miR-215), and APC, K-ras and DCC mutations in biopsy specimens from patients with UC to evaluate any correlations with clinical risk factors., Method: We observed 18 patients with UC and collected two biopsy specimens from each patient at diagnosis and at a follow-up end-point. We examined the expression of CD44, CD166, miR-21 and miR-215, and APC, K-ras and DCC mutations. We compared these markers at the two time points and assessed their associations with clinical characteristics, including the duration of colitis, histological alterations and the age of the patient at the onset of UC., Results: Most (16/18) patients had alleviation of mucosal inflammation or remained stable during follow-up; one patient developed dysplasia and one had severe aggravation of the lesion during follow-up. Enhanced expression of CD44, CD166 and miR-21 with miR-215 was found in the specimens obtained at follow-up, despite alleviation of mucosal lesions. Coherence of cancer stem cell markers and miRNAs was seen in patients who had significant worsening of inflammation, dysplasia and a long duration of colitis. APC mutation occurred in only one patient; this patient had the longest duration of UC (23 years)., Conclusion: Enhanced markers of CRC in follow-up colonic mucosal samples support the conclusion that the duration of UC plays the most important role in UC-related carcinogenesis., (Colorectal Disease © 2016 The Association of Coloproctology of Great Britain and Ireland.)

What Is Known and Objective: Identification of biomarkers that could predict high-dose cytarabine (Ara-C) efficacy and toxicity is a key issue in individualized therapy. The aim of our study was to evaluate the influence of cytidine deaminase (CDA) single nucleotide polymorphisms (SNPs) -451G>A (rs532545), 435C>T (rs1048977) and -33delC (rs3215400) on treatment outcome in patients with relapsed acute myeloid leukaemia (AML) after high-dose Ara-C chemotherapy., Methods: In total, 173 patients with relapsed AML, treated with high-dose Ara-C chemotherapy, were genotyped for three polymorphisms in CDA gene using the allele-specific matrix-assisted laser desorption/ionization time-of-flight mass spectrometry assays. Binary logistic regression was used to evaluate the influence of selected polymorphisms on tumour response and occurrence of treatment-related toxicity., Results and Discussion: The CC genotype at -33delC, a promoter polymorphism, increased the odds of overall response rate (odds ratio [OR] = 5·125; 95% confidence intervals (CI) = 2·446-10·74; P = 0·0008) and grade ≥3 infection toxicity incidence rate (OR = 3·572; 95% CI = 1·68-7·594; P = 0·003). In multivariable analysis, this polymorphism was a potential independent prognostic marker for the risk of overall response (P = 0·011), but not grade ≥3 infection toxicity incidence rate (P = 0·49). Two other polymorphisms, -451G>A and 435C>T, did not influence treatment outcome, including overall response rate, infection toxicity and nausea/vomiting, in patients with relapsed AML (P > 0·05)., What Is New and Conclusion: The findings suggest that CDA -33delC variant might be a potential marker for predicting treatment outcome in Chinese patients with relapsed AML given high-dose cytarabine chemotherapy., (© 2015 John Wiley & Sons Ltd.)

The objective of this study was to assess the associations of presenilin 1 (PS1) 1/2, angiotensin I-converting enzyme (ACE) insertion/deletion (I/D), and low-density lipoprotein receptor-related protein (LRP) C/T polymorphisms with the risk of Alzheimer's disease (AD) in the Chinese population. PS1 1/2, ACE I/D, and LRP C/T, which are commonly investigated polymorphisms, were evaluated to obtain summary estimates regarding their associations with AD. In total, the data from 24 studies (2611 patients with AD and 2822 control subjects from 23 provinces and special districts in China) that were obtained from the Chinese Biomedicine Database, China National Knowledge Infrastructure, PubMed, and Medline were included. Different models (i.e., dominant, recessive, etc.) of these polymorphisms were analyzed using the Cochrane Review Manager. Statistically significant associations among patients with AD for the 1/1 genotype of the PS1 1/2 polymorphism [odds ratio (OR) = 1.77, 95% confidence interval (CI) = 1.03-3.04; P = 0.04] and the I/I genotype of the ACE I/D polymorphism (OR = 2.44, 95%CI = 1.78-3.35; P < 0.01) were identified. Statistically significant associations were also found for the PS1 1/2 polymorphism in both the dominant and recessive genetic models, whereas no association was found for the LRP C/T polymorphism. All studies exhibited heterogeneity (P < 0.05). This meta-analysis suggests that the 1/1 genotype of the PS1 1/2 polymorphism and the I/I genotype of the ACE I/D polymorphism are significantly associated with an increased risk of AD in the Chinese population.

What Is Known and Objective: Variation in the expression of drug-response-related genes contributes significantly to interindividual differences in drug response. DNA methylation is one of the most common epigenetic modifications that control gene expression. DNA methylation may occur in genes encoding drug metabolizing enzymes (DMEs), drug transporters and drug targets, and can thereby alter the pharmacokinetics and pharmacodynamics of drugs. In this review, we discuss recent advances in pharmacoepigenetics with a focus on DNA methylation., Methods: The literature search focusing on DNA methylation of drug-response-related genes and DNA methylation-related SNPs in pharmacogenomics was carried out using the PUBMED database and a combination of keywords including DNA methylation, drug response, DMEs, drug transporters, drug target and SNPs., Results and Discussion: An extensive range of research has contributed to our understanding of how DNA methylation of drug-response-related genes alters their function. This is particularly well studied in cancer chemotherapy and drug resistance. The impact of polymorphisms of miRNAs in these processes requires further study., What Is New and Conclusion: DNA methylation-related genetic variation is an increasingly recognized mechanism for altered drug-response and disease susceptibility. These new discoveries require assimilation into the practice of personalized medicine., (© 2014 John Wiley & Sons Ltd.)

Objectives: The aim of this study was to investigate the effect of quercetin on P-glycoprotein (P-gp) transport ability in vivo., Subjects/methods: Genotype data were available from a total of 165 health volunteers. An open, randomized, two-period crossover clinical trial was performed in eighteen subjects with different MDR1 3435 C/T genotypes. All subjects took 500 mg quercetin or placebo daily from 1st to 13th day or from 43 st to 55th day, and 100 mg talinolol was given at the 14th or 56th day. The washout period is 28 days., Results: In this study, we found the values of area under the curve (AUC)0-48 h, AUC0-∞ and Cmax of talinolol in all subjects significantly decreased (6496.6 ± 2389.9 vs 7809.5 ± 2386.8 ng.h/ml, P=0.04), (8414.7 ± 344.8 vs 10478.2 ± 4195.4 ng.h/ml, P=0.03), (412.9 ± 132.6 vs 543.3 ± 97.9 ng.h/ml, P=0.01) after administration of quercetin, respectively. There were no significant differences in tmax and t1/2 of talinolol. The results also showed AUC0-48 h (5598.6 ± 2202.1 vs 8229.4 ± 1491.7 ng.h/ml, P=0.02) and AUC0-∞ (7110.0 ± 3437.0 vs 12681.2 ± 4828.2 ng.h/ml, P=0.01) of talinolol to be significantly decreased in MDR1 3435 TT individuals administered of quercetin. The Cmax of talinolol in MDR1 3435 TT (382.4 ± 149.1 vs 584.9 ± 115.2 ng/ml, P=0.04) and MDR1 3435 CT (383.5 ± 104.9 vs 554.6 ± 80.6 ng/ml, P=0.01) individuals significantly decreased after the administration of quercetin., Conclusions: Quercetin significantly induced the activity of P-gp and this induced effect was more obvious in MDR1 3435 TT individuals.

Background: Pharmacogenetics-based algorithms would be especially desirable for patients undergoing heart valve replacement (HVR), who are particularly sensitive to warfarin during the initial treatment phase following surgery. We aimed to derive a warfarin dosing algorithm from data of Chinese patients undergoing HVR, and to compare it with previously published dosing algorithms as applied to our HVR patients., Methods: 641 Chinese HVR patients on stable maintenance dose of warfarin were enrolled from a single clinic site. Data of 321 patients were used to derive a warfarin dosing algorithm using stepwise multiple linear regression analysis. Previously published algorithms were selected from Pubmed database for comparison. The performance of all the algorithms was characterized according to mean absolute error (MAE) and percentage of predicted doses falling within +/- 20% of clinically observed doses (percentage of ideal prediction) in the other 320 patients., Results: The newly developed algorithm included eight factors: VKORC1-1639G > A, CYP2C9*3, BSA, age, number of increasing INR drugs, smoking habit, preoperative stroke history and hypertension. Our algorithm accounted for 56.4% of variations in the inter-patient warfarin stable doses. All the algorithms showed better performance in a medium-dose (1.88-4.38 mg/day) and high-dose (> or = 4.38 mg/day) groupings than in a low-dose (< or = 1.88 mg/day) grouping. Compared with the 14 previously published algorithms, our algorithm had the lowest MAE (-0.07 mg/day) and the highest percentage of ideal prediction (62.8%) in the total validation cohort., Conclusions: Our warfarin dosing algorithm is potentially useful for patients whose population profiles are similar to those of our patients.

Aims: Sodium ferulate (SF) is widely prescribed in clinic for the treatments of cardiovascular and cerebrovascular diseases. In our study, we investigated the effect of SF on the pharmacokinetics of bupropion and its active metabolite 4-hydroxybupropion in healthy Chinese men., Methods: In a two-phase, randomized, crossover study with a 2-week wash-out period between phases, nineteen healthy male volunteers were given with or without pretreatment with SF 150 mg three times daily for fourteen days, and a single dose of bupropion 150 mg was administered. Pharmacokinetics profiles for bupropion and 4-hydroxybupropion were determined., Results: After SF treatment relative to bupropion alone, the geometric mean ratios and 90% confidence interval of 4-hydroxybupropion were 1.25 (1.17, 1.34) for AUC  0-infinity, 1.10 (1.05, 1.15) for Cmax, and 1.14 (1.09, 1.20) for t1/2 respectively. The corresponding values for bupropion were 0.907 (0.811, 1.014), 0.974 (0.910, 1.045) and 1.13 (1.06, 1.21) respectively. The corresponding values for AUC  0-infinity ratio of 4-hydroxybupropion over bupropion were 1.28 (0.811, 1.014).CONCLUSIONS, Bupropion hydroxylation was slightly induced by the 14 days of SF pre-treatment. Whether co-administration with SF require a dosage adjustment of bupropion needs further exploration.

To determine the effect of genistein on cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) function using the probe substrates midazolam and talinolol, respectively. Eighteen healthy adult male participants were enrolled in a two-phase randomized crossover design. In each phase, the participants received placebo or genistein for 14 days. On the 15th day, midazolam and talinolol were administered and blood samples were obtained. Midazolam and talinolol pharmacokinetic parameter values were calculated and compared before and after genistein administration. Co-administration of genistein decreased the area under the concentration-time curve from 0 to 36 h (AUC 0-36) (143.65 ± 55.40 ng h/mL versus 126.10 ± 40.14 ng h/mL, p < 0.05), and the area under the concentration-time curve from zero to infinity (AUC 0-∞) (209.18 ± 56.61 ng h/mL versus 180.59 ± 43.03 ng h/mL, p < 0.05), and also maximum concentration (Cmax) of midazolam (48.86 ± 20.21 ng/mL versus 36.25 ± 14.35 ng/mL p < 0.05). Similarly, AUC 0-36 (2490.282 ± 668.79 ng h/mL versus 2114.46 ± 861.11 ng h/mL, p < 0.05), AUC 0-∞ (2980.45 ± 921.09 ng h/mL versus 2626.92 ± 1003.78 ng h/mL, p < 0.05) and Cmax of talinolol (326.58 ± 197.67 ng/mL versus 293.42 ± 127.19 ng/mL, p < 0.05) were reduced by genistein co-administration. The oral clearance of midazolam (1.68 ± 0.85 h-1 versus 3.98 ± 0.59 h-1, p < 0.05) and talinolol (3.34 ± 1.24 h-1 versus 3.79 ± 1.55 h-1, p<0.05) were increased by genistien significantly. Administration of genistein can result in a modest induction of CYP3A and possibly P-gp activity in healthy volunteers.

The objective of this study was to investigate the interaction between glycyrrhizin and omeprazole and observe the effects of glycyrrhizin on CYP2C19 and CYP3A4 activities in healthy Chinese male volunteers with different CYP2C19 genotypes. Eighteen healthy subjects (six CYP2C19*1/*1, five CYP2C19*1/*2, one CYP2C19*1/*3, five CYP2C19*2/*2 and one CYP2C19*2/*3) were enrolled in a two-phase randomized crossover trial. In each phase, all subjects received placebo or glycyrrhizin salt tablet 150 mg twice daily for 14 consecutive days. The pharmacokinetics of omeprazole (20 mg orally on day 15) was determined for up to 12 h following administration by high-performance liquid chromatography. After 14-day treatment of glycyrrhizin, plasma omeprazole significantly decreased, and those of omeprazole sulfone significantly increased. However, plasma concenetrations of 5-hydroxyomeprazole did not significantly change. The ratio of AUC(0-infinity) of omeprazole to omeprazole sulfone decreased by 43.93% + or - 13.56% (p = 0.009) in CYP2C19*1/*1, 44.85% + or - 14.84% (p = 0.002) in CYP2C19*1/*2 or *3 and 36.16% + or - 7.52% (p < 0.001) in CYP2C19*2/*2 or *3 while those of omeprazole to 5-hydroxyomeprazole did not change significantly in all three genotypes. No significant differences in glycyrrhizin response were found among CYP2C19 genotypes. Glycyrrhizin induces CYP3A4-catalyzed sulfoxidation of omeprazole and leads to decreased omeprazole plasma concentrations, but has no significant impact on CYP2C19-dependent hydroxylation of omeprazole.

The objective of this study was to investigate the effects of continuous St. John's wort administration on single-dose pharmacokinetics of bupropion, a substrate of cytochrome P450 (CYP) 2B6, in healthy Chinese volunteers. Eighteen unrelated healthy male subjects participated in this study. The single-dose pharmacokinetics of bupropion and hydroxybupropion were determined before (control) and after a long-term period of St. John's wort intake (325 mg, three times a day for 14 days). Plasma concentrations of bupropion and hydroxybupropion were determined before and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60 and 72 h after dosing. St. John's wort treatment decreased the area under the concentration versus time curve extrapolated to infinity of bupropion in healthy volunteers from 1.4 microg.h ml(-1) (95% confidence interval [CI] = 1.2-1.6 microg.h ml(-1)) after bupropion alone to 1.2 microg.h ml(-1) (95% CI = 1.1-1.3 microg.h ml(-1)) during St. John's wort treatment. St. John's wort treatment increased the oral clearance of bupropion from 108.3 l h(-1) (95% CI = 95.4-123.0 l h(-1)) to 130.0 l h(-1) (95% CI = 118.4-142.7 l h(-1)). No change in the time to peak concentration (t(max)) and the blood elimination half-life (t(1/2)) of bupropion was observed between the control and St. John's wort-treated phases. However, the half-life of hydroxybupropion between two phases had a significant difference by a Student's t test after logarithmic transformation. St. John's wort treatment decreased the half-life of hydroxybupropion from 26.7 h (95% CI = 23.8-29.9 h) to 24.4 h (95% CI = 21.9-27.3 h). St. John's wort decreased, to a statistically significant extent, the plasma concentrations of bupropion, probably mainly by increasing the clearance of bupropion.

This study showed that the polymorphisms KCNJ11 Lys23Glu and TCF7L2 rs290487(C/T) are associated with a heightened risk of developing type 2 diabetes mellitus (T2DM). We also explored the effects of these polymorphisms on the efficacy of repaglinide therapy in Chinese patients with T2DM. A total of 259 patients with T2DM and 188 healthy controls were genotyped. Forty patients with various genotypes were randomly selected to undergo an 8-week repaglinide treatment regimen. Patients with the G allele of the KCNJ11 Lys23Glu polymorphism showed higher levels of fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) (P < 0.05). After repaglinide treatment, patients with the GA or AA genotype showed higher levels of FPG, PPG, and glycated hemoglobin (HbA(1c)) compared with patients with the GG genotype (P < 0.05). Patients with the C allele of TCF7L2 rs290487(C/T) had higher total cholesterol levels and lower body mass index (BMI) (P < 0.05). In patients with the TT genotype, the drug showed better efficacy with respect to levels of fasting insulin, triglycerides, and low-density lipoprotein cholesterol (LDL-c) than in patients with the CC or CT genotype (P < 0.05). The KCNJ11 and TCF7L2 polymorphisms were associated with repaglinide efficacy.

To evaluate the effect of bifendate on the pharmacokinetics of talinolol, 16 unrelated male healthy subjects were selected for this study. After repeated oral administration of placebo or bifendate (three times daily for 14 days), the plasma concentration of talinolol was measured by high-performance liquid chromatography-electrospray mass spectrometry. This study was carried out in a randomized, single-blinded, placebo-controlled, crossover manner. After the treatment of bifendate, the area under the curve (AUC(0-infinity)) was decreased significantly by 11.2% (90% confidence interval (CI), 7.3-12.4%; p = 0.001), and the Cmax value of talinolol was decreased by approximately 9.7% (90% CI, 5.5-11.4%; p = 0.001). The oral clearance of talinolol was increased significantly by 13.1% (90% CI, 8.0-14.4%; p = 0.001). The results suggest that the treatment of bifendate can decrease the plasma concentration of talinolol in healthy subjects.

The aim of the study was to determine the pharmacokinetics of losartan in relation to the CYP2C9*13 allele. A single oral dose of 50 mg losartan was administrated to each of the 16 healthy male volunteers with a different genotype (CYP2C9*1/*1, n = 6; CYP2C9*1/*13, n = 4; and CYP2C9*1/*3, n = 6). Blood samples were collected from pre-dose up to 24 h after the drug administration. Plasma losartan and E3174 (an active metabolite of losartan) were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). All the subjects finished the study without adverse drug effects. In the present study, the frequencies of CYP2C9*13 and *13 alleles were 0.6% and 2.6% in Chinese healthy volunteers, respectively, and both alleles were in Hardy-Weinberg equilibrium. Compared with the subjects in the CYP2C9*1/*1 group, individuals carrying the CYP2C9*1/*13 genotype showed significantly a longer t(1/2) of losartan and E3174 and markedly increased the area under the curve (AUC) of losartan. Meanwhile, the CYP2C9*1/*3 genotype group had significant differences in t(1/2) and Cmax of E3174 compared with the CYP2C9*1/*1 group. The ratio of AUC(E3174)/AUC(losartan) after losartan administration in the CYP2C9*1/*13 and CYP2C9*1/*3 groups was also statistically different from that in the CYP2C9*1/*1 group. The data indicate that the presence of the CYP2C9*13 allele results in poor metabolism of losartan after a single oral dose.

1. The objective of this study was to investigate the effect of concomitantly administered silymarin on the pharmacokinetics of talinolol, a typical substrate for P-glycoprotein (P-gp), in healthy Chinese volunteers and its association with a multidrug resistance 1 (MDR1) C3435T genetic polymorphism. 2. Eighteen healthy adult men (six MDR1 3435CC homozygotes, six MDR1 3435CT heterozygotes and six MDR1 3435TT homozygotes) were recruited in a two-phase, randomized, single-blind, crossover design. The pharmacokinetics of talinolol were measured after co-administration of placebo or 140 mg silymarin capsules three times daily for 14 days. Concentrations of talinolol in plasma were measured for up to 36 h after drug administration by liquid chromatography-mass spectrometry (HPLC-MS). 3. The peak plasma concentration (C(max)) of talinolol was significantly higher after silymarin administration as compared with placebo (p = 0.007). The area under the plasma concentration-time curve from zero to 36 h (AUC(0-36)) and AUC(0-infinity) of talinolol was increased by 36.2% +/- 33.2% and 36.5% +/- 37.9%, respectively, by silymarin co-administration. The oral clearance (CL/F) of talinolol was decreased by 23.1% +/- 16.6% (p < 0.001) during the silymarin-treated phase. No change in the time to peak concentration (t(max)) and the blood elimination half-life (t(1/2)) of talinolol was observed between the placebo- and silymarin-treated phases. 4. Co-administration of silymarin significantly increased the plasma concentration of talinolol in healthy volunteers.

Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA, a famous Chinese medicine which has been used in the treatment of cardiovascular disorders for many years. Using caffeine as a probe drug, this project was designed to investigate the effect of STS on the activity of CYP1A2 in humans. Sixteen unrelated healthy volunteers were recruited for this two-phase, randomized and crossover study. The volunteers received either placebo or 60 mg day(-1) of STS injections through vein for 13 days. Pharmacokinetics of caffeine and the metabolite paraxanthine was determined by high-performance liquid chromatography. CYP1A2 activity was monitored by the ratio of paraxanthine to caffeine at 6 h in plasma. Enzyme activity analysis showed that STS significantly increased the activity of CYP1A2 by 41.1% [90% confidence interval (CI), 17.4-64.8%] (p = 0.036). The area under the curve [AUC((0-24h))] of caffeine significantly decreased by 13.3% [90% CI = 7.0-19.6%] (p = 0.005) with 13 days of treatment of STS. AUC((0-24h)) of paraxanthine significantly increased by 17.4% [90% CI = 4.3-30.5%] (p = 0.035). No significant difference was found for other parameters of caffeine and paraxanthine between two phases. STS has significantly induced the activity of CYP1A2 in vivo. Simultaneously, AUC((0-24h)) of caffeine and paraxanthine were significantly affected by STS. The findings have provided some useful information for safe and effective usage of STS in clinic.

This study explores the impact of clopidogrel on the pharmacokinetics of omeprazole related to CYP2C19 genetic polymorphisms. Twelve healthy volunteers (6 CYP2C19*1/*1, 5 CYP2C19*2/*2, and 1 CYP2C19*2/*3) are enrolled in a 2-phase randomized crossover trial. In each phase, the volunteers are administered a single oral dose of omeprazole 40 mg after pretreatment of either placebo or clopidogrel (300 mg on the first day and then 75 mg once daily for 3 consecutive days). Plasma concentrations of omeprazole and its metabolites are quantified by high-performance liquid chromatography with UV detection. After clopidogrel treatment, the AUC(0-infinity) of omeprazole increases by 30.02% +/- 18.03% (P = .004) and that of 5-hydroxyomeprazole decreases by 24.30% +/- 11.66% (P = .032) in CYP2C19*1/*1. The AUC(0-infinity) ratios of omeprazole to 5-hydroxyomeprazole increase by 74.98% +/- 35.48% (P = .001) and those of omeprazole to omeprazole sulfone do not change significantly (P = .832) in CYP2C19*1/*1. No significant alteration is observed in CYP2C19*2/*2 or *3. Clopidogrel inhibits CYP2C19-dependent hydroxylation of omeprazole in CYP2C19*1/*1 and has no impact on CYP3A4-catalyzed sulfoxidation of omeprazole.

The authors investigated the effect of herbal medicine Schisandra chinensis extract (SchE) and Ginkgo biloba extract (GBE) on the oral pharmacokinetics of P-glycoprotein substrate talinolol in humans. Twelve healthy male volunteers took a single 100-mg oral dose of talinolol either alone or after pretreatment with 300 mg SchE twice daily or with 120 mg GBE three times daily for 14 days. On day 14, a single 100-mg oral dose of talinolol was administered. Plasma concentrations of talinolol from zero to 24 h were measured by high-performance liquid chromatography. SchE increased the area under the curve (AUC)(0-24) of talinolol by 47% (90% confidence interval (CI), 18-84%; p = 0.010), and GBE by 21% (90% CI = 11-32%; p = 0.002). The C(max) of talinolol increased by 51% (90% CI = 21-89%; p = 0.007) with SchE treatment and by 33% (90% CI = 18-51%; p = 0.002) with GBE treatment, respectively. The t(1/2) of talinolol increased by 7% (90% CI = -4% to 19%; p = 0.320) with SchE treatment and by 11% (90% CI = -12% to 38%; p = 0.436) with GBE treatment, respectively. The results suggest that both SchE and GBE significantly inhibited P-glycoprotein in humans. Patients receiving either SchE or GBE may require dose adjustments when treated with drugs primarily transported by P-glycoprotein.

The aim of this study was to explore potential herb-drug interaction between baicalin and rosuvastatin, a typical substrate for organic anion-transporting polypeptide 1B1 (OATP1B1) related to different OATP1B1 haplotype groups. Eighteen unrelated healthy volunteers who were CYP2C9*1/*1 with different OATP1B1 haplotypes (six OATP1B1*1b/*1b, six OATP1B1*1b/*15, and six OATP1B1*15/*15) were selected to participate in this study. Rosuvastatin (20 mg orally) pharmacokinetics after coadministration of placebo and 50-mg baicalin tablets (three times daily orally for 14 days) were measured for up to 72 h by liquid chromatography-mass spectrometry in a two-phase randomized crossover study. After baicalin treatment, the area under the plasma concentration-time curve (AUC)(0-72) and AUC(0-infinity) of rosuvastatin decreased by 47.0+/-11.0% (P=0.001) and 41.9+/-7.19% (P=0.001) in OATP1B1*1b/*1b, 21.0+/-20.6% (P=0.035) and 23.9+/-8.66% (P=0.004) in OATP1B1*1b/*15, and 9.20+/-11.6% (P=0.077) and 1.76+/-4.89% (P=0.36) in OATP1B1*15/*15, respectively. Moreover, decreases of both AUC(0-72) and AUC(0-infinity) of rosuvastatin among different haplotype groups were significantly different (P=0.002 and <0.001). Baicalin reduces plasma concentrations of rosuvastatin in an OATP1B1 haplotype-dependent manner.

Due to their high stability in general acidic solutions, SiO(2) nanoparticles were selected as the second catalyst for ethanol oxidation in sulfuric acid aqueous solution. Pt-SiO(2) nanocatalysts were prepared in this paper. The micrography and elemental composition of Pt-SiO(2) nanoparticles were characterized by scanning electron microscopy and energy dispersive X-ray spectroscopy, respectively. The electrocatalytic properties of Pt-SiO(2) nanocatalysts for ethanol oxidation were investigated by cyclic voltammetry. Under the same Pt loading mass and experimental conditions for ethanol oxidation, Pt-SiO(2) nanocatalysts show higher activity than PtRu/C (E-Tek), Pt/C (E-Tek), and Pt catalysts. Additionally, Pt-SiO(2) nanocatalysts possess good anti-poisoning ability. The results indicate that Pt-SiO(2) nanocatalysts may have good potential applications in direct ethanol fuel cells.

The aim of this study is to evaluate the association of the CYP3A4*18B genotype with the cyclosporine metabolism in healthy subjects. We employed PCR-RFLP assays for analysis of the CYP3A4*18B genotype. Each of 26 subjects, comprising 12 CYP3A4*1/*1, 12 CYP3A4*1/*18B and 2 CYP3A4*18B/*18B, was given a single oral dose of cyclosporine (4 mgkg(-1)). The plasma concentrations of cyclosporine were measured for up to 24 h post dose by high-performance liquid chromatography-electrospray mass spectrometry. We found that the mean Cmax (95% confidence intervals) of cyclosporine were 2237 (2905, 1859) (*1/*1), 2247 (2916, 1869) (*1/*18B), and 905 (1192, 506) ng ml(-1) (*18B/*18B)(p = 0.037) and the mean AUCO-4 were 5026 (6181, 4372) (*1/*1), 4434 (5481, 3841) (*1/*18B) and 2561 (3155, 1736) ng ml(-1) h (*18B/*18B) (p=0.021). The CL in the *18B/*18B group was significantly higher than in the *1/*1 group. However, Tmax exhibited no difference among the three genotypes. *18B/*18B group showed 50% reduction in concentration at 2 h post dose compared with *1/*18B (p = 0.062) or *1/*1 (p = 0.047), but no statistical significance was detected between*1/*1 and *1/*18B groups (p > 0.05). The data suggest that the CYP3A4*18B genotype affects cyclosporine pharmacokinetics probably resulting from a higher enzymatic activity of this mutation in healthy subjects.

Existing data has shown that SP-A-like protein or mRNA is widely distributed in lamellar bodies such as tissues and mucosal surfaces. Using immunohistochemistry method with a polyclonal antibody against human SP-A, in this study we investigated distribution of immunoreactive pulmonary surfactant protein A (IR-SP-A) in a number of rat tissues. The SP-A-like immunoreactivity was found in alveolar, parenchyma, pleura of lung; myelin sheath of brain; epithelia of Bowman's capsule, glomerulus and renal tubules of kidney; epithelia of colon, stomach, duct of salivary gland, pharynx; and blood vessel wall and connective tissue of extracellular matrix. The positive signal was blocked by pre-absorbed SP-A antigen from recombinant or bronchoalveolar lavage (BAL). SP-A has long been considered as an important frontier host defense molecule which participates in immune and inflammatory regulation of lung. With every inhalation, small particles, viruses, bacteria, and antigens from environment are continuously deposited onto the vast pulmonary epithelial surface. While a proper host defense is required to protect the lung, an over-exuberant response can disrupt the appropriate balance between pro- and anti-inflammatory. Traditional Chinese medicine believes that body is an open system relevant to the external environment. The physical, chemical and biological environmental factors constantly affect the open system, and the body properly reacts to maintain homeostasis of body machinery. The Chinese traditional medicine scholars have thus hypothesized that 'Qi' (meaning air) is the communication way between the body and external environment. What is 'Qi'? The results from our study suggest that IR-SP-A is a candidate of 'Qi'. It is compatible with the sites, theoretically containing collagenous and lectin domain molecules, also compatible with the primary injury sites of some autoimmune diseases. SP-A may be as one of 'Qi' molecules mentioned in traditional Chinese medicine that trigger some of autoimmune diseases.

Introduction: Histamine plays a crucial role in the regulation of gastric acid secretion, which is involved in the pathogenesis of peptic ulcer. Histamine N-methyltransferase (HNMT) is the major metabolizing enzyme for histamine inactivation in human stomach., Objective: This study aims to determine whether there exists a relationship between HNMT gene polymorphisms and the risk for gastric ulcer (GU)., Methods: 118 GU patients and 154 ethnically matched control subjects were enrolled and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays were developed to genotype all these subjects for the T-1637C, C-411T, C314T and A1097T point mutations in HNMT gene. Haplotypes were reconstructed from the genotype data., Results: Frequencies of the variant alleles in cases and controls were 0.398 vs 0.396 for T-1637C, 0.144 vs 0.110 for C-411T, 0.034 vs 0.042 for C314T, and 0.242 vs 0.273 for A1097T, respectively, with no significant difference for any locus between the two groups (all P > 0.05). Also the frequencies of genotypes, haplotypes and haplotype pairs based on these polymorphisms did not differ significantly between cases and controls., Conclusion: This study provided no evidence for the involvement of HNMT polymorphisms in the susceptibility to GU.

This study examined the disposition kinetics and bioavailability of florfenicol after intravenous (i.v.), intramuscular (i.m.) and oral administration to rabbits at a dose of 30 mg/kg BW. Serial blood samples were collected through an indwelling catheter intermittently for 24 h for various routes. Plasma antibacterial concentrations were determined using a microbiological assay method with Bacillus subtilis ATCC 6633 as a reference organism. Plasma concentration-time data generated in the present study were analysed by non-compartmental methods based on statistical moment theory. Following i.v. administration, the overall elimination half-life (t1/2beta) was 1.54 h, mean residence time (MRT) was 1.69 h, mean volume of distribution at steady-state (Vdss) was 0.57 L/kg, and total body clearance (Cltot) was 0.34 L/kg/h. After i.m. and oral dosing, the terminal part of the curve should correspond to the absorption phase, instead of to the elimination phase, with terminal half-lives of 3.01 and 2.57 h, respectively. The mean absorption time (MAT) was 2.65 h for i.m. and 2.01 h for oral administration. Elimination rate constants differed with i.v., i.m. and oral administrations, suggesting a flip-flop situation. The observed mean peak plasma concentrations (Cmax obs) were 21.65 and 15.14 microg/ml achieved at a post-injection time (Tmax obs) of 0.5 h following i.m. and oral dosing, respectively. The absolute systemic availabilities were 88.25% and 50.79%, respectively, and the extent of plasma protein binding percent was 11.65%.

The pharmacokinetics of doxycycline hydrochloride (DoxHcl) at a dose of 5 mg kg-1 BW was studied after an intravenous (i.v.) bolus and intramuscular (i.m.) injections in non lactating goats. A microbiological assay employing Bacillus subtilis as the test organism was used to measure its concentrations in serum and urine. Following a single i.v. injection, the serum concentration-time curves of doxycycline hydrochloride were best represented by a two-compartment open model. The drug was rapidly distributed and slowly eliminated with half-lives of distribution (t1/2 alpha) and elimination (t1/2 beta) of 0.52 and 4.62 h, respectively. After i.m. injection of the same dose, the peak serum concentration C(max) was 1.60 microg ml-1 attained at 0.86 h (Tmax). Following i.v. and i.m. injections, the concentrations of doxycycline in urine were much higher than that in serum. Urinary drug concentrations decreased gradually till reaching its lowest detectable level 12 and 24h post-injections, respectively. The extent of serum protein binding percent was 32.8% and the systemic bioavailability was 99.40% after i.m. injection of 5 mg kg-1 BW

Background: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) that accumulates in renal insufficiency and may be a uremic toxin. To determine whether ADMA inhibits bone metabolism, we investigated the in vitro effect of ADMA on osteoblastic differentiation in mouse bone marrow-derived mesenchymal stem cells (BMSCs)., Methods: The effect of ADMA on nitric oxide (NO) production was determined by measuring the stable end product of NO, nitrite, in the culture medium using commercial NO kit. The temporal sequence of osteoblastic differentiation in BMSCs was assessed in the presence and absence of ADMA by measuring alkaline phosphatase (ALP) activity, mineralization, and osteoblast gene expression at 0, 4, 8, 12 days of culture., Results: ADMA (5, 50, 500 micromol. L-1) resulted in a dose-dependent decrease in nitrite formation in conditioned media of BMCS cultures, consistent with inhibition of NOS. ADMA treatment was associated with reduced ALP activity, calcium deposition and osteoblast-related gene expression in BMSCs cultures. Concurrent treatment with l-arginine (3600 micromol. L-1) reversed the ADMA (500 micromol. L-1)-mediated decrease in NO production, restored the differentiation potential of BMSCs, and significantly attenuated the down-regulation of Cbfa1 and osteocalcin gene expression by ADMA., Conclusions: ADMA inhibition of the NO-NOS pathway in BMSCs impairs osteoblastic differentiation of mouse BMSC cultures. These studies further support a role of NO in the local regulation of bone metabolism and the possibility that ADMA may act as uremic toxin on bone through its effect to inhibit NO actions in osteoblasts.

Objectives: Our goal was to establish and validate a modified cocktail approach including probe drugs caffeine, chlorzoxazone, mephenytoin, metoprolol, and midazolam for simultaneous phenotyping of CYP1A2, CYP2E1, CYP2C19, CYP2D6, and CYP3A., Methods: The study was conducted in 14 healthy, nonsmoking male volunteers with a cocktail of 5 drugs consisting of 100 mg caffeine, 200 mg chlorzoxazone, 100 mg mephenytoin, 100 mg metoprolol, and 7.5 mg midazolam in a randomized manner with a 7 x 7 Latin square design. Plasma was obtained at 1, 4, and 6 hours, and urine was collected from 0 to 8 hours after oral drug administration., Results: The phenotypic indexes determined for caffeine, chlorzoxazone, mephenytoin, metoprolol, and midazolam were not significantly different when the drugs were given in different combinations. There were no metabolic interactions or analytic interference of these probe drugs., Conclusions: This cocktail approach can simultaneously provide independent in vivo phenotypic measures for the cytochrome P450 (CYP) enzymes CYP1A2, CYP2E1, CYP2C19, CYP2D6, and CYP3A.

Background: The association between decreased drug clearance and decreased activity of cytochrome P4502C19 (CYP2C19), the inherited nature of the deficiency, and its frequency and clinical importance were evaluated extensively in the past over one decade. There is an interethnic difference in the frequency of poor metabolizers and mutant alleles of CYP2C19 among Chinese nationalities. Different frequency of mutations that code for CYP2C19 results in interethnic differences in distribution of the polymorphic trait for this enzyme. CYP2C19 genotype is a major determined factor for metabolisms of S-mephenytoin (S-MP), diazepam, and omeprazole (OP). The formations of their metabolites, 4'-hydroxymephenytoin (4'-OH-MP), demethyldiazepam, and 5-hydroxyomeprazole (5-OH-OP) are CYP2C19 genotype dependent. The inducibility of CYP2C19 activity is also related to CYP2C19 genotype., Conclusions: The availability of phenotyping and genotyping methods should help identify the adverse reaction and toxicity of drugs that metabolized by CYP2C19 and determine the doses of these drugs according to individual CYP2C19 genotype.

Aims: The study was designed to investigate whether genetically determined CYP2C19 activity affects the metabolism of fluoxetine in healthy subjects., Methods: A single oral dose of fluoxetine (40 mg) was administrated successively to 14 healthy young men with high (extensive metabolizers, n=8) and low (poor metabolizers, n = 6) CYP2C19 activity. Blood samples were collected for 5-7 half-lives and fluoxetine, and norfluoxetine were determined by reversed-phase high performance liquid chromatography., Results: Poor metabolizers (PMs) showed a mean 46% increase in fluoxetine peak plasma concentrations (Cmax, P < 0.001), 128% increase in area under the concentration vs time curve (AUC(0, infinity), P < 0.001), 113% increase in terminal elimination half-life (t(1/2)) (P < 0.001), and 55% decrease in CLo (P < 0.001) compared with extensive metabolizers (EMs). Mean +/- (s.d) norfluoxetine AUC(0, 192 h) was significantly lower in PMs than that in EMs (1343 +/- 277 vs 2935 +/- 311, P < 0.001). Mean fluoxetine Cmax and AUC(0, infinity) in wild-type homozygotes (CYP2C19*1/CYP2C19*1) were significantly lower than that in PMs (22.4 +/- 3.9 vs 36.7 +/- 8.9, P < 0.001; 732 +/- 42 vs 2152 +/- 492, P < 0.001, respectively). Mean oral clearance in individuals with the wild type homozygous genotype was significantly higher than that in heterozygotes and that in PMs (54.7 +/- 3.4 vs 36.0 +/- 8.7, P < 0.01; 54.7 +/- 3.4 vs 20.6 +/- 6.2, P < 0.001, respectively). Mean norfluoxetine AUC(0, 192 h) in PMs was significantly lower than that in wild type homozygotes (1343 +/- 277 vs 3163 +/- 121, P < 0.05) and that in heterozygotes (1343 +/- 277 vs 2706 +/- 273, P < 0.001), respectively., Conclusions: The results indicated that CYP2C19 appears to play a major role in the metabolism of fluoxetine, and in particular its N-demethylation among Chinese healthy subjects.

Either G-2964 or A734 in the human CYP1A2 gene was confirmed to be associated with high inducible enzyme activity in smokers, but not in nonsmokers. In this study, for the first time, we observed an association between phenotypes and genotypes of CYP1A2 with respect to the two genetic polymorphisms in 163 healthy Chinese volunteers living in Qidong. The ratio of plasma 17X/137X at 6 h after oral administration of 300 mg caffeine was employed in CYP1A2 phenotyping analysis, while genotyping analysis was carried out by polymerase chain reaction-restriction fragment length polymorphism. The allele frequencies of A at -2964 and A at 734 in 139 non-smoking subjects were 0.25 and 0.67, respectively. The A/A-2964C/C734, G/A-2964C/C734 or A/A-2964C/A734 genotype that was thought to have lower inducibility/activity of CYP1A2 than the other genotypes did not exist in the tested Chinese subjects. The ratio of 17X/137X was 0.46 +/- 0.26 in G/G-2964A/A734 genotypes (n = 22) and 0.36 +/- 0.19 in non-G/G-2964A/A734 (n = 117). In addition, there was significant difference between them (P = 0.036). A similar result was also achieved in 24 smokers. Since Qidong is a special region with particularly high incidence of hepatocellular carcinoma in China, the association of phenotypes with genotypes of CYP1A2 in the Qidong population might result from some inducible environmental factors such as those of cigarettes in smokers.

Aim: To find out a single plasma sampling to estimate oral clearance of midazolam (MDZ) and CYP3A activity, and explore the pharmacokinetics of midazolam hydroxylation in Chinese subjects., Methods: The pharmacokinetics of midazolam was assessed in ten healthy male individuals after an oral dose of 7.5 mg midazolam., Results: A significant correlation (r = 0.7, P < 0.05, n = 10) was found between plasma MDZ clearance and the plasma ratio of 1'-hydroxymidazolam to midazolam, which was assessed at 1 h after MDZ intake in the volunteers. Pharmacokinetics parameters of midazolam were as follows: Cmax (191 +/- 17) nmol/L, tmax (1.01 +/- 0.14) h, t(1/2) (3.2 +/- 0.4) h, AUC(0-infinity) (681 +/- 43) nmol.h.L-1), Cl(oral) (0.54 +/- 0.04) L.h-1.kg-1, Ke (0.2415 +/- 0.0021) h-1, Kalpha (0.82 +/- 0.18) h-1., Conclusion: Single plasma sampling of 1 h after 7.5 mg oral MDZ intake can be used to predict the oral clearance of midazolam.

Objective: Our objective was to evaluate the relationship between the disposition of sertraline and the presence of the CYP2C19 gene and to define the contribution of cytochrome P450 2C19 (CYP2C19) to sertraline N-demethylation., Methods: A single oral 100-mg dose of sertraline was administered to 6 subjects who were extensive metabolizers and 6 subjects who were poor metabolizers recruited from 77 healthy Chinese volunteers whose genotypes were predetermined by polymerase chain reaction-based amplification, followed by restriction fragment length polymorphism analysis. Phenotypes were determined by use of the omeprazole metabolic rate. The plasma concentrations of sertraline and desmethylsertraline were determined by gas chromatography with electron-capture detection., Results: Six poor metabolizers with m1 mutation had area under the plasma concentration versus time curve (AUC(0-infinity)) values (983.6 +/- 199.3 microg x h/L versus 697.6 +/- 133.0 microg x h/L; P <.05) and terminal elimination half-life values of sertraline (35.5 +/- 5.6 hours versus 23.5 +/- 4.4 hours; P <.01) that were significantly higher than the values in 6 extensive metabolizers who were either homozygous or heterozygous for CYP2C19*1. The oral clearance of sertraline in poor metabolizers (105.3 +/- 19.4 L/h) was significantly lower than that of extensive metabolizers (148.4 +/- 28.6 L/h). The area under the concentration-time curve from 0 to 144 hours and the maximum plasma concentration of desmethylsertraline in poor metabolizers were significantly lower than the values of extensive metabolizers (627.6 +/- 203.8 microg x h/L versus 972.1 +/- 270.3 microg x h/L; P <.05; and 23.6 +/- 6.5 nmol/L versus 32.4 +/- 8.2 nmol/L; P <.01; respectively)., Conclusions: The polymorphic CYP2C19 appears to be a major enzyme involved in the N-demethylation of sertraline, and both extensive and poor metabolizers had marked differences in the disposition of sertraline.

Objective: This study was designed to examine whether transcranial electrical motor evoked potential (MEP) monitoring is safe, feasible, and valuable for brain tumor surgery., Methods: Fifty consecutive patients undergoing brain tumor resection were studied, using nitrous oxide/propofol anesthesia. MEPs were continuously recorded throughout surgery, using a Sentinel 4 evoked potential system (Axon Systems, Inc., Hauppauge, NY). The MEPs were elicited by transcranial electrical stimulation (train of 5; stimulation rate, 0.5-2 Hz; square wave pulse with a time constant of 0.5 ms; stimulation intensity, 40-160 mA) through spiral electrodes placed over the primary motor cortex and were recorded by needle electrodes inserted into the contralateral orbicularis oris, biceps, abductor pollicis brevis, and anterior tibialis muscles. When MEP amplitudes decreased by more than 50%, MEP stimulation was repeated, with increased stimulation intensity, and MEP changes were reported to the surgeon. The motor function of each patient was examined before and after surgery, using a reproducible scale. The relationship between MEP amplitude decreases and worsening motor status was analyzed using linear regression., Results: Preoperative neurological examinations revealed mild to moderate motor deficits (2/5 to 4/5) for 38% of patients (19 of 50 patients). Most of the patients (96%) exhibited recordable baseline MEPs. Persistent MEP decreases of more than 50% were noted for eight patients (16%) (11 muscles). The MEPs were completely abolished in two patients (three muscles). The degree of postoperative worsening of motor status was correlated with the degree of intraoperative MEP amplitude reduction (r = -0.864; P < 0.001)., Conclusion: Persistent intraoperative MEP reductions of more than 50% were associated with postoperative motor deficits. The degree of MEP amplitude reduction was correlated with postoperative worsening of motor status. Transcranial electrical MEP monitoring is feasible, safe, and valuable for brain tumor surgery.

There are marked interethnic differences in beta 1-adrenoceptor-mediated responsiveness, with sensitivity decreased in African-Americans and increased in Chinese compared with Caucasians. Therefore, the frequency of a common naturally occurring polymorphism of the human beta 1-adrenoceptor gene (Arg389Gly), which has functional importance in vitro, was determined in 194 African-Americans, 316 Caucasian-Americans, 221 Hispanic-Americans and 142 Chinese. African-Americans were found to have a significantly lower frequency of the Arg389 allele than the other three ethnic groups (all P < 0.01). In the populations studied, the order of the distribution of the Arg389 allele was: Chinese (74%) > Caucasians (72%) > Hispanics (67%) > African-Americans (58%). To determine the functional significance of the Arg389Gly beta 1-adrenoceptor polymorphism, in-vivo heart rate responses to exercise were compared in healthy subjects homozygous for the Arg (n = 9) and Gly (n = 8) alleles. Heart rate response to exercise was not affected by genotype (P = 0.4). Although ethnic differences in the frequency of the beta 1-adrenoceptor Arg389Gly polymorphism exist, the polymorphism does not appear to have functional significance in healthy subjects and therefore may not contribute to ethnic differences in response to drugs acting through the beta 1-adrenoceptor.

Aim: To constitute a method to determine the estradiol metabolites in human liver microsome in low concentration of estradiol., Methods: Use high performance liquid chromatography after solvent extraction, evaporation, and reconstitution to separate the metabolites and use a electrochemistry detector to detect the metabolites., Results: With a mobile phase of acetic acid buffer-acetonitrile (50:50, v/v, pH 4.5) at flow rate of 1.0 mL/min and a potential of +0.7 V vs Ag/AgCl, all six composition were well separated and satisfactorily detected. There are E3, 16alpha-OHE1, 2-OHE2, E1, and two unidentified composition. The minimum detectable amount is about 100 p g on column. This method is sensitive enough to detect E1 in a substrate concentration of 1 micromol/L., Conclusion: The method can be used to study the metabolism mechanism of estradiol in liver microsome.