The purpose of this study is to investigate the effects of multiple-trough sampling design and nonlinear mixed effect modeling (NONMEM) algorithm on the estimation of population and individual pharmacokinetic parameters. Oxcarbazepine and tacrolimus were used as one-compartment and two-compartment model drugs, respectively. Seven sampling designs were investigated using various number of trough concentrations per individual ranging from 1-4. Monte Carlo simulations were performed to produce state-steady trough concentrations. One-compartment model was used to fit simulated data from oxcarbazepine and tacrolimus. The accuracy and precision of the estimated parameters were evaluated using the median prediction error (PE), the median absolute PE and boxplot. The results indicated that trough concentrations could yield reliable estimates of apparent clearance (CL/F). For oxcarbazepine, as the number of trough concentrations per subject increased, the accuracy and precision of CL/F, between-subject variability (BSV) of CL/F and residual variability (RUV) tended to be improved. For tacrolimus, however, although no improvement were observed in the accuracy of CL/F and BSV of CL/F, the PE distribution ranges were significantly narrowed and the RUV estimates were less bias and imprecise. In terms of algorithm, Monte Carlo importance sampling (IMP) and IMP assisted by mode a posteriori estimation (IMPMAP) were consistently better than other methods. Additionally, the sampling design had no significant effects on the individual parameter estimates, which were only depended on the interaction between BSV and RUV in various algorithms. Decreased in BSV and RUV levels can improve the accuracy and precision of the estimation for both population and individual pharmacokinetic parameter estimates.
Algorithms ; Bayes Theorem ; Carbamazepine ; analogs & derivatives ; pharmacokinetics ; Humans ; Immunosuppressive Agents ; pharmacokinetics ; Models, Biological ; Monte Carlo Method ; Nonlinear Dynamics ; Regression Analysis ; Tacrolimus ; pharmacokinetics

For medical service provision for the Olympic Games, a special medical service mechanism for important international sport events eventually took shape, based on task analysis and medical services provided in test games for two years including 2006 and 2007 Qingdao Sailing Regatta. This mechanism features the following: First, "7-Special" sport event medical practice - Medical zones, medical teams, service flows, service signs, medical papers, and drug management, all exclusively earmarked for the event; Second, medical services up to international standard; Third, special flows for medical rescue; Fourth, Special system for information reporting. Thanks to this special mechanism, the hospital provided its medical assurance for the Olympic Games successfully, and upgraded its routine medical services as a result.

Azacitidine ; analogs & derivatives ; therapeutic use ; Clinical Trials, Phase III as Topic ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; Multicenter Studies as Topic

Objective To investigate the plasma vitamin D3 level and its association with B cell subsets of patients with primary Sj(o)gren's syndrome (pSS).The role of vitamin D3 levels in the pathogenesis of pSS was explored.Methods The expression of plasma vitamin D3 levels of 55 patients with pSS and 32 controls were analyzed by ELISA.Frequencies of peripheral blood CD19+CD27-na(i)ve B cells,CD19+CD27+ memory B cells and CD19+CD27high plasma cells were analyzed by flow cytometry in 34 pSS patients without therapy and 22 controls.The relationship between the vitamin D3 levels and B cell subsets,SSDAI,tear flow rate,saliva flow rate,rheumatoid factor,immunoglobulin was analyzed in pSS patients.Non-parametric test,t test,one-way ANOVA,x2test,Pearman's and Spearman's correlation analysis were used for statistical analysis.Results ① There was significant difference in the levels of plasma 1,25 (OH)2D3 between the pSS patients group and normal control group,1,25 (OH)2D3 was significantly lower in pSS patients than that in the normal control group [24.17(22.20,28.41) pg/ml and 41.25(23.38,62.18) pg/ml,P＜0.05],and that was also obviously lower in the active group [22.64(20.74,24.90) pg/ml] than that in the normal control group (P＜0.05),and that was also obviously lower in the active disease group than that in the inactive disease group [25.39 (23.16,33.09) pg/ml,P＜0.05],but there was no difference between the inactive group and the normal control group (P＞0.05).② The percentage of peripheral blood of CD19+CD27high plasma cells and CD19+CD27+ memory B cells in CD19+ cells was reduced in patients in the pSS group compared with the control group [(0.89±0.30)％ and (1.72±0.43)％,(24±8)％ and (34±5)％; P＜0.05],and that was also significantly lower in the active group [(1.03±0.59) ％ ; (26± 10)％] and inactive group [(1.00±0.16)％,(26± 3)％] than that in the normal controls (P＜0.05).However,there was no difference between the active group and the inactive group (P＞0.05),but the frequency of peripheral blood of CD19+ CD27-naive B cells in CD19+ B cells was increased in patients with pSS compared with normal control group [(75.4±7.5)％ and (63.9±5.2)％,P＜0.05],and that was also significantly higher in the active group [(73.4±9.7)％] and inactive group [(73.3±2.9)％] than that in the normal control (P＜0.05),there was no difference between the active group and the inactive group.③ Significant negative correlation was observed between 1,25 (OH)2D3 and the percentage of peripheral blood CD19+CD27+ memory B cells in CD19+ cells as well as immunoglobulin G(r=-0.627,P=0.039; r=-0.657,P＜0.01) level.Conclusions These results demonstrate that abnormality of vitamin D levels may play an important role in the pathogenesis of pSS.

Objective To investigate the effect of implanted cortical electrical stimulation (CES) on the expression of Nissl bodies and growth-associated protein 43 (GAP-43) in the brain after ischemic injury,and its mechanism.Methods Models of middle cerebral artery occlusion (MCAO) were established in 23 male Sprague-Dawley rats.They were randomly divided into a CES group (CES,n=13) and a no stimulation group (NS,n=10) and electrical stimulators were implanted in both groups.CES was applied for 14 d in the CES group but not in the NS group.The expression of Nissl bodies and GAP-43 around the infarct were quantified using version 6.0 of the ImagePro Plus system.Results In the CES group the Nissl bodies had a deep color,and their percentage of area was higher than that in the NS group.The GAP-43 positive expression area also had a relatively deep color,and the average percentage of positive expression area was also higher than that in the NS group.Conclusions CES can enhance the expression of Nissl bodies and GAP-43 after cerebral infarction.This suggests that CES can promote axon growth and the formation of new neural circuits.

Objective To explore the probable function of peptidyl arginine deiminase 4 (PAD4) in rheumatoid arthritis(RA).Methods Real-time quantitative polymerase chain reaction (PCR) was used to determine the expression of PAD4 mRNA in peripheral blood mononucleated cells (PBMCs) from 60 RA patients and 40 healthy individuals.Asymmetric di-methylation of histone H3R17,symmetric di-methylation and mono-methylation of H4R3 were semi-quantified by Western blotting in 12 patients with osteoarthritis (OA),26 patients with RA and 10 healthy controls.Results PAD4 mRNA in RA was significantly higher than that in healthy controls [34.6 (16.7,70.8) vs 20.6 (11.1,51.8),P ＜ 0.05].The level of histone H3R17 asymmetric di-methylation in RA was significantly higher than that of OA or control groups(71.34 ±25.65 vs 37.18 ± 18.62 vs 50.67 ± 13.99,P ＜0.01),which was positively related to Tender joint count and Swollen joint count in 28 joints (r =0.418,P =0.034 ; r =0.402,P =0.042).The level of histone H4R3 symmetric di-methylation was similar in RA,OA and control groups (75.02 ± 20.35 vs 57.92 ± 22.77 vs 68.37 ± 17.57,P ＞ 0.05).The level of histone H4R3 mono-methylation in RA patients was significantly lower than that of OA patients and healthy individuals (11.24 ±7.81 vs 32.77 ±30.77 vs 51.20 ±47.14,P ＜ 0.05).The level of histone H4R3 mono-methylation in RA patients was negatively correlated to PAD4 (r =-0.643,P ＜ 0.01).The level of histone H3R17 asymmetric di-methylation and H4R3 symmetric di-methylation was not associated with PAD4 level in RA group (r =-0.185,P =0.377; r =0.198,P =0.344).Conclusions The level of histone H3R17 asymmetric di-methylation is significantly higher and the level of histone H4R3 mono-methylation is significantly lower in RA patients comparing with OA and control groups.Abnormality of histone methylation may be one of the mechanisms for the development of RA.PAD4 probably plays an important role in rheumatoid arthritis by influencing histone methylation.

AIM: To study in vivo the effect of androgen on mice tear film stability and Mucins expressions in corneal epithelial cells in BALB/ c mice after orchectomy.
METHODS: With orchiectomy operation, we set up mice model. And serum androgen concentration of mice was detected by radioimmunoassay. Break - up time ( BUT ) of tear film was tested in the different experimental points. Mice corneal epithelia were peeled and MUC1 and MUC4 mRNA and protein levels were measured by RT-PCR and Western blot.
RESULTS: The serum androgen concentration reduced to 0ng/ μ L at 1wk after orchiectomy. The BUT values were 68. 33±12. 86s, 62. 47±3. 75s, 58. 67± 10. 03s, 47. 17±7. 64s, 39. 51±3. 39s, 32. 67±3. 88s and 31. 00±2. 36s in the normal control group, sham group and in orchectomy group at 1, 2, 4, 6 and 8wk, respectively, and the BUTs were significantly shorter in the orchectomy at 2, 4, 6 and 8wk groups than those in the normal control group (all at P< 0. 05). MUC1 and MUC4 mRNA and proteins levels decreased with androgen level lowering (P<0. 05). Mucin1 level was the lowest at 2wk after orchiectomy, and the lowest Mucin4 level was found at 1wk after orchiectomy.
CONCLUSION: In vivo, androgen regulates Mucins expressions in mice corneal epithelial cells, makes BUT shorter,and influence the stability of tear film.

Objective To discuss the value of magnetic resonance (MR) diffusion tensor imaging (DTI) technology in the diagnosis of the apparent diffusion coefficient (ADC) and the fraction anisotropy (FA) of neonates with hypoxic-ischemic encephalopathy (HIE) in the subacute stage.Methods Ten cases of normal full-term neonates and 34 term neonates diagnosed with HIE in the subacute stage were investigated with conventional MR and DTI.Of the 34 cases, 15 cases were mild HIE, 12 cases were moderate HIE,7 cases were severe HIE.ADC/FA values in different parts of the brain were analyzed.And the receiver operating characteristic (ROC) curve was used,the sensitivity and specificity of the FA in specific parts were also analyzed.Results (1) On convention MRI : according to the MRl scoring system,score of mild group was(2.6 ±-1.7) points, moderate group was (3.0 ± 1.5) points, severe group was (5.8 ± 1.3) points.There was significant difference between mild group and severe group, moderate and severe group (P ＜ 0.05).(2) The ADC and FA values in each group on DTI : ADC values in all of the regions of interest (ROIs) had no statistic difference between the HIE group and the controls(all P ＞ 0.05).FA values in posterior limb of internal capsule (PLIC) ,splenium had statistic difference between the HIE group and the controls.FA values in mild group were (0.317-0.018,0.339 ±0.025) ,moderate group (0.295 ±0.025,0.324 ±0.026) and severe group (0.252 ±0.039,0.253-0.036) and control group (0.455 ± 0.047,0.372 ± 0.032).(3) ROC analysis of the neonates diagnosed with HIE:the area under the ROC curve of FA values in PLIC, Splenium had statistic difference between mild group and moderate group (P ＜ 0.05).The area under the ROC curve in each group was 0.744 (P =0.032) ,0.658 (P =0.164).ROC curve was used to evaluate the diagnostic accuracy of FA values in PLIC between HIE group and control group,when FA value was lower than 0.337,0.803 was the largest area under the ROC curve, and there was significant difference between them(P ＜ 0.01).Conclusions FA values can reflect the brain white matter WM injury of HIE neonates quantitatively,and its diagnostic veracity is better than ADC value and conventional MR during the subacute phase of HIE.The diagnostic veracity of FA values in PLIC is higher than other parts.When the FA value is lower than 0.337, there is good sensitivity and specificity in diagnosis of HIE, so DTI technology can provide accurate and objective basis for clinical treatment with good sensitivity and specificity about the diagnosis of HIE in early stage.

Objective To investigate the clinicopathology and immunophenotype of primary non- Hodgkin lymphoma(NHL)of the female genital system,and to analyze the prognosis of such tumors. Methods Clinicopathologic features of 43 cases of primary NHL of the female genital system were studied retrospectively,with the histological classification based on the Classification of Haematopoietic and Lymphoid Tumors(WHO,2001).Immunochemistry technique,in-situ-hybridization and polymerase chain reaction methods were used to detect the immunophenotype,epstein barrvirus(EB)virus infection status and immunoglobulin heavy chain gene rearrangement,respectively.Results(1)Primary lesions:there were 24 cases of lymphoma originating in the ovary,3 cases in the endometrium,10 cases in the cervix,2 cases in the vagina and 4 cases in the vulva.(2)Staging:12 cases(28%)were in stage Ⅰ,9 cases (21%)in stage Ⅱ,and 22 cases(51%)in stage Ⅲ.(3)Histological classification:37 cases(86%)were diffuse large B cell lymphoma(DLBCL),3 cases were Burkitt lymphoma and the remaining 3 cases were unspecified peripheral T-cell lymphoma according to biopsy,immunophenotype analysis,in-situ- hybridization technique and IgH gene rearrangement detection.(4)Prognosis analysis:increase in the level of lactic acid dehydrogenase,stage Ⅲ,DLBCL and single operation suggest poor prognosis.Conclusions Establishment of the diagnosis of primary NHL of the female genital system is based on biopsy, immunophenotype analysis,in-situ-hybridization technique and IgH gene rearrangement detection,which play important roles in diagnosis and differential diagnosis of the tumor.Combined therapy is the first choice of therapeutic regimens.

Objective To investigate whether miR-122 is a target of oxymatrine against HBV. Methods HepG2.2.15 cells were incubated with culture medium containing different concentrations of oxymatrine. The cyto-toxicity of oxymatrine was determined by cck-8 assay. The surface antigen of HBV (HBsAg),antigenof HBV (HBeAg)and HBV DNA in supernatant and intracellular miR-122 were determined in HepG2.2.15 cells after incu-bation with culture medium containing oxymatrine for 72 h. Results The survival percentage of HepG2.2.15 cells under different concentrations of oxymatrine was higher than 95% when the concentration of oxymatrine was lower than 4 mg/mL. After treatment with oxymatrine for 72 h,the secretion of HBsAg and HBeAg,the level of HBV DNA in the supernatant were reduced. The intracellular miR-122 in oxymatrine experience group was 3.5 times higher than that in the negative control group. Conclusions Oxymatrine might be used to inhibit viral replication and antigen expression by enhancing the expression of miR-122 in HepG2.2.15 cells.