OBJECTIVE:To establish the method for the determination of mildronate in human plasma and urine,and to study the pharmacokinetic characteristics in healthy volunteers. METHODS:After precipitating plasma and urine sample,LC-MS/MS method was adopted. Dikma Diamonsil C18 column was used with mobile phase consisted of methanol-water(containing 0.2% for-mic acid,0.3% ammonium acetate)(31∶69,V/V)at the flow rate of 0.6 ml/min. ESI was adopted in MRM mode,by using nega-tive ion. The ion for quantitative analysis were m/z 147.10→58.20 (mildronate) and m/z 152.00→110.10 (internal standard,acet-aminophen). The pharmacokinetic parameters of mildronate with single administration and multiple administration were calculated by using DAS 2.1 software and compared. RESULTS:The linear range of mildronate in plasma were 0.02-20 ng/ml(r=0.999 3) and in urine were 0.05-40 ng/ml(r=0.998 2). The lowest limits of quantitation were 0.02 and 0.05 ng/ml. Precision and recovery met the requirements of biological specimen determination,and endogenous impurities hadn’t effect on the determination. The main pharmacokinetics parameters of low-dose,medium-dose and low-dose(250,500,750 mg)of mildronate in plasma with single ad-ministration were as follows:t1/2 were(3.39±0.81),(5.52±0.57)and(5.32±0.96)h;tmax were(0.80±0.45),(1.38±0.43)and (1.10±0.36)h;cmax were(4.17±1.46),(8.08±1.04)and(15.04±1.86)ng/ml;AUC0-36 h were(24.55±5.81),(45.50±7.07)and (85.60 ± 13.09)ng·h/ml. In the dose range,cmax,AUC0-36 h h had a linear relationship with dose (R2 were 0.974 5 and 0.968 3). The main pharmacokinetic parameters of low-dose of mildronate with multiple administration after keeping stable were as follows:cmin was(0.28 ± 0.10)ng/ml;AUCs was(38.78 ± 4.18)ng·h/ml;cs was(1.62 ± 0.17)ng/ml;DF was(3.81 ± 1.14);t1/2 was(6.17 ± 1.46)h;tmax was(1.20 ± 0.33)h;cmax was(6.46 ± 1.96)ng/ml;AUC0-36 h was(40.33 ± 4.65)ng·h/ml;accumulation factor of cmax and AUC were(1.73±0.90)and(1.64±0.40). Compared with single administration,t1/2,cmax and AUC of mildronate with multiple admin-istration after keeping stable all changed,and tmax had no signifi-cant difference. After single administration,26 h accumulative excretion rate of those groups were (0.004 009 ± 0.001 1)%, (0.004 026±0.001 01)% and(0.003 858±0.000 68)% respec-tively. CONCLUSIONS:Established method is sensitive,accurate and specific,and suitable for the determination of mildronate concentration in human plasma and urine and pharmacokinetics study. Mildronate capsule shows certain accumulation effect in healthy volunteers,and linear pharmacokinetic characteristics.

To explore the effect of magnitude and duration on the performance of Cumulative Sum (CUSUM),with simulation method used on the subject after the insertion of 11 outbreak events into baseline data with Poisson distribution.Sensitivity fluctuated from 9.1％ to 100.0％ with specificities higher than 98.6％.Sensitivity was significantly correlated with magnitude,and increased along with the increase of magnitude.However,no significant correlation was observed between sensitivity and duration.A magnitude which was at least 2.6 times higher than that of the mean daily baseline could result in the sensitivity of 100.0％.Time-lag would be improved along with the increase of magnitude.Time between onset and detection of an outbreak was no longer than one day when magnitude was more than 1.8 of the mean daily baseline.In summary,the performance of CUSUM was influenced by magnitude,but not by duration.CUSUM had the advantage of good time-lag and high sensitivity when the outbreak magnitude was more than 2.4 time over the baseline data.

OBJECTIVETo investigate the relationship between simple exposure to chrysotile and lung cancer.

METHODSThe nested case-control study method was used. All of lung cancer cases collected from a male fixed prospective cohort with follow-up of 30 years served as cases and a 1:4 matched proportion was used to select non-cancer case as controls. Controls matched for sex age (+/-5 years old), work time (+/-5 years) and smoking were collected in the same cohort.

RESULTSForty cases died of lung cancer in the study cohort, and the incidence was higher than the average incidence (SMR =1.77). The top four work types of death density were raw material (741.5), combing and spinning (424.3), weaving (365.0), and repairing (285.5), which was consistent with exposed level. According to the exposed level of chrysotile, the research objects were divided into the high level group and the low level group. The result demonstrated that lung cancer incidence of the high exposed level group of chrysotile was higher (OR = 3.7 95% CI 2.30 approximately 8.16), compared with the low exposed level group.

CONCLUSIONSimple exposure to chrysotile can increase the risk of lung cancer for workers who are exposed to chrysotile.

Aged ; Aged, 80 and over ; Asbestos, Serpentine ; adverse effects ; Case-Control Studies ; Humans ; Lung Neoplasms ; epidemiology ; etiology ; Male ; Middle Aged ; Occupational Exposure ; adverse effects

OBJECTIVETo clarify the dose-response relationship between asbestos dust exposure and lung cancer incidence in chrysotile asbestos miners by fixed cohort study and to investigate the incidence rates of lung cancer in exposure to different concentrations of asbestos dust.

METHODSA retrospective cohort study was conducted in 1932 asbestos miners who registered from January 1, 1981 to December 31, 1988, had worked for at least 1 year, and had no obvious cardiopulmonary diseases; the cohort study began in July 2009 and covered a time span of 29 years (1981 - 2009). The personal information, occupational history, disease history, and health data of these miners were recorded, and the monitoring data on dust concentrations in the mine over the years were collected. The dose-response relationship between asbestos dust concentration and lung cancer incidence was established by the method of life table; a regression equation was fitted to predict the excess incidence rates of lung cancer under the conditions of different working years and dust concentrations.

RESULTSA significant dose-response relationship was observed between cumulative exposure (Ce) and cumulative probability (Px) of lung cancer incidence, and the smokers hada higher Px than nonsmokers. When Ce was less than 2000 mg/m(3)·each year, Px reached 6.58/10000; when Ce was not less than 2000 mg/m(3)·and less than 3000 mg/m(3)·each year, Px reached 91.72/10000; when Ce was more than 5000 mg/m(3)·each year, Px was as high as 141.02/10000. The three models were fitted to obtain the optimal regression equation: Px = -0.0004Ce(2) + 0.0052Ce - 0.0011 (r(2) = 0.9387). In the workshop of asbestos mine in this study, the average dust concentration was 85 times higher than the limit in 2009, so the excess incidence rate of lung cancer was 112.598/10000 if the miners worked under this condition for 40 years, according to the equation.

CONCLUSIONThere is a significant dose-response relationship between cumulative asbestos exposure and lung cancer incidence in chrysotile asbestos miners. The risk for lung cancer rises as asbestos exposure increases.

Asbestos, Serpentine ; toxicity ; Dust ; Female ; Humans ; Lung Neoplasms ; etiology ; Male ; Mining ; Occupational Exposure ; Retrospective Studies

Objective To reveal the characteristics and stability of the system through the analyzing the surveillance data of respiratory-feverous syndrome via the syndromic surveillance system which was established during the Shanghai World Expo in Pudong New District and provide references for the development and operation optimization on this Mass Gatherings Surveillance Systems.Methods Data used was from the surveillance data of respiratory-feverous syndrome collected from Pudong New District Syndromic Surveillance System,through May 1 to October 31,2010.On the basis of description of data characteristics,correlation analyses were conducted,when compared to the surveillance data of respiratory-feverous syndrome and Pudong influenza-like illness (ILI) used as reference.Comparison of variances on the surveillance data and the report lag time of the earlier and later surveillance periods were also carried out to evaluate the quality and stability of data.Results Reports on the respiratory-feverous syndrome showed a peak in late September with day-of-week effects and holiday effects.Correlation between respiratory-feverous syndrome and ILI was the strongest in the same day (r=0.596,P＜0.05).In the earlier surveillance period from 2010-05-01 to 2010-07-31,the correlation between respiratory-feverous syndrome and ILI was not obvious (r=-0.058,P＞0.05) ; however,the two-time series showed consistent trend with the correlation coefficient as 0.798 (P＜0.05),in the later period from 2010-08-01 to 2010-10-31.In addition,variability of the surveillance data on respiratory-feverous syndrome was less in the later period than in the earlier one,with quality of the report on relatcd data better in the later period.Analyses on the correlations of reference sequence,variability and quality of report indicated that the stability of the later surveillance period was better than the earlier one.Conclusion Only with the operation of syndromic surveillance system for a certain period of time,could data in the system maintain stability.Surveillance data showed both day-of-week effects and holiday effects,suggesting that there was a need to choose early warning models with short baseline data.

OBJECTIVETo study the molecular mechanisms of nm23-H1 for regulating PKC signal pathway before and after transfection with nm23-H1 gene.

METHODSUsing Western-blot, Boyden-chamber, MTT and laser scanning confocal microscopy (LSCM) techniques to detect the distribution of PKC in cytosol and plasma membrane, changes of invasion and proliferation activity, PKC translocation status and changes of intracellular Ca(2+) concentration among different human pulmonary carcinoma cells with transfected or untransfected nm23-H1 gene, and changes of the three cell lines after treatment with Calphostin C, a PKC inhibitor.

RESULTS(1) The expression of PKCalpha, PKCbeta II on L9981 and L9981-pLXSN cell membrane, which was in activated status, was remarkably higher than those in L9981-nm23-H1 cell line (P < 0.001). The expression of PKCalpha, PKCbeta II in cytosol in L9981 and L9981-pLXSN cell lines, which was in inactivated status, was lower than those in L9981-nm23-H1 cell line (P < 0.001). It means that the PKC signal pathway was activated in L9981 and L9981-pLXSN cell lines. (2) PKCalpha and PKCbeta II mainly located in nuclei and perinuclear area in L9981 and L9981-pLXSN cells, which were in active status, and the Ca(2+) concentration in these cells was obviously higher than that in L9981-nm23-H1 cell line (P < 0.01). In L9981-nm23-H1 cell line, which was transfected with nm23-H1 gene, PKCalpha and PKCbeta II mainly located in soluble cytosolic section, in an inactive status. (3) The invasion and proliferation ability of L9981 and L9981-pLXSN lung cancer cells was higher than that of L9981-nm23-H1 cell line (P < 0.001). There was no statistically significant difference between L9981 and L9981-pLXSN cell lines (P > 0.05). (4) After treated with PKC inhibitor Calphstin C, the expression of PKC and PKCbeta II in membrane in L9981 and L9981-pLXSN cell lines was down-regulated (P < 0.001), PKCalpha and PKCbeta II were mainly located in cytosolic area, mainly in an inactive status, and the Ca(2+) concentration was found to be decreased in all the three cell lines. The invasion and proliferation ability of the three lung cancer cell lines were obviously decreasing (P < 0.001). However, the invasion and proliferation ability of L9981-nm23-H1 lung cancer cell line was still lower than that of L9981 and L9981-pLXSN lung cancer cell lines (P < 0.001). There was also no significant difference between L9981 and L9981-pLXSN cell lines (P > 0.05).

CONCLUSIONThe results of this study suggest that nm23-H1 gene might inhibit the invasion and metastasis of lung cancer cells by down-regulating PKC signaling pathway. The Ca(2+) in cells might be involved in this process.

Calcium ; metabolism ; Cell Line, Tumor ; Cell Membrane ; metabolism ; Cell Proliferation ; drug effects ; Cytosol ; metabolism ; Down-Regulation ; Humans ; Lung Neoplasms ; enzymology ; metabolism ; pathology ; NM23 Nucleoside Diphosphate Kinases ; genetics ; Naphthalenes ; pharmacology ; Neoplasm Invasiveness ; Protein Kinase C ; antagonists & inhibitors ; metabolism ; Protein Kinase C beta ; Protein Kinase C-alpha ; metabolism ; Signal Transduction ; Transfection

OBJECTIVESTo evaluate the efficacy and safety of famciclovir on the decreasing levels of serum HBV-DNA and ALT and HBeAg/antiHBe seroconversion in chronic hepatitis B patients irresponsive to 3 months treatment with alpha interferon.

METHODSTwo hundred and nineteen patients with chronic HBV infection, defined as positive HBsAg, HBeAg and HBV DNA, were enrolled and randomly half-and- half put into famciclovir and placebo groups. The two groups received either famciclovir 500 mg tid or a placebo treatment for 24 weeks, and then were followed-up for another 24 weeks with no treatment.

RESULTSAt the end of 24 weeks, the log value of HBV DNA dropped from 6.54+/-1.26 to 5.70+/-2.03 in the famciclovirt group and were elevated from 6.30+/-1.32 to 6.51+/-1.65 in the placebo group (P < 0.01). The rate of cases with persistence HBV DNA dropped 2 log of quantity in the famciclovir group and was 28.28% (28/99); it was 9.47% (9/95) in the placebo group (P < 0.01). Those with persistence negative HBV DNA was 28.28% (28/99) in the flamciclovir treated group and 14.74% (14/95) in the placebo group (P < 0.05). Those persistently being HBeAg negative were 7.69% (7/91) in the famciclovir treated group and 3.33% (3/90) in the placebo group (P > 0.05). The HBeAg/antiHBe seroconversion was 4.40% (4/91) in the famciclovir group and 2.22% (2/90) in the placebo group (P > 0.05). The percentage of cases with normal of ALT level was 15.15% in the famciclovir group and 6.35% in the placebo group (P < 0.05).

CONCLUSIONFamciclovir is effective in inhibiting HBV DNA replication and in decreasing serum ALT levels. The rate of HBeAg/antiHBe seroconversion in the famciclovir treated group was similar to that of the placebo group. Famciclovir was well tolerated without severe adverse effects during our treatment.

2-Aminopurine ; adverse effects ; analogs & derivatives ; therapeutic use ; Adolescent ; Adult ; Antiviral Agents ; adverse effects ; therapeutic use ; Double-Blind Method ; Female ; Follow-Up Studies ; Hepatitis B virus ; physiology ; Hepatitis B, Chronic ; drug therapy ; virology ; Humans ; Interferon-alpha ; therapeutic use ; Male ; Middle Aged ; Treatment Outcome ; Virus Replication ; drug effects

Objective: To explore the change of hearing threshold of workers exposed to noise, establish an individual-based hearing loss early warning model, accurately and differentiated the health of workers exposed to noise. Methods: In September 2019, all physical examination data of 561 workers exposed to noise from an enterprise were collected since their employment. Three indicators of average hearing threshold of the better ear, namely, at high frequency, 4000 Hz and speech frequency, were constructed. The generalized estimating equation (GEE) was used to adjust gender and age and establish the warning model of each indicator. Finally, sensitive indicators and warning models were screened according to AUC and Yoden index. Results: Among the 561 workers exposed to noise, 26 (4.6%) workers had hearing loss. The sensitivity indicators were the average hearing threshold at speech frequency ≥20 dB, high frequency ≥30 dB and 4000 Hz ≥25 dB. The AUC of each index was 0.602, 0.794 and 0.804, and the Youden indexes were 0.204, 0.588 and 0.608, respectively. In GEE of hearing loss warning models, high-frequency hearing threshold ≥20 dB and 4000 Hz hearing threshold ≥25 dB were the optimal models, with AUC of 0.862. Conclusion: Combined with the changes of individual hearing threshold over the years, can accurately assess the risk of individual hearing loss of workers exposed to noise.
Humans ; Hearing Loss, Noise-Induced/diagnosis* ; Noise, Occupational/adverse effects* ; Audiometry ; Deafness ; Employment ; Occupational Exposure/adverse effects* ; Occupational Diseases/diagnosis*