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

Objective To study the expression of multidrug resistance associated protein 1 (MRP1) and MRP2 in the peripheral blood mononuclear cells of children with intractable epilepsy (IE).Methods During Nov.2010 to Oct.2013,50 children with I E were collected as the experimental group,simultaneously 50 children with epilepsy controlled by the anti-epileptic drugs (AEDs) and 50 healthy children without epilepsy were collected as the control group from the outpatient or inpatient of Xuzhou Children's Hospital.The expressions of MRP1 and MRP2 in the peripheral blood mononuclear cells of children were detected by reverse transcriptase polymerase chain reaction and Western blot.Results 1.The mean relative expression of MRP1 and MRP2 mRNA in the peripheral blood mononuclear cells of children with IE (0.795 ± 0.042,0.804 ± 0.023) were higher than those in epilepsy controlled by AEDs (0.682 ± 0.030,0.675 ± 0.021) and healthy children without epilepsy (0.665 ± 0.031,0.654 ± 0.029) (all P ＜0.001).2.The mean relative expression of MRP1 and MRP2 protein in the peripheral blood mononuclear cells of children with IE (2.027 ±0.034,1.902 ±0.021) were higher than those in epilepsy controlled by AEDs(1.131 ±0.042,1.086 ± 0.027) and healthy children without epilepsy (1.093 ± 0.023,1.045 ± 0.018) (all P ＜ 0.001).3.There was no difference in the expression of MRP1,MRP2 mRNA and proteins between the children with epilepsy controlled by AEDs and healthy children without epilepsy (all P ＞ 0.05).Conclusions MRP1 and MRP2 over-expression in the peripheral blood mononuclear cells of children with IE may be associated with drug-resistance mechanism for medically intractable epilepsy.

Recent studies suggest that glial cells play an impor-tant role in nervous system. Like astrocytes in the central nervous system,satellite glial cells( SGCs) also participate in the physio-logical and pathological processes of the peripheral nervous sys-tem. SGCs affect neuronal functions through neuro-glial interac-tions. In this review,we summarize the current understanding of how SGCs affect the function of neurons.

AIM:By analyzing optical coherence tomography angiography (OCTA) characteristics of central serous chorioretinopathy (CSC) and comparing the differences of CSC between OCTA and indocyanine green angiography(ICGA), to explore if OCTA can substitute ICGA for diagnosis of CSC patients, and guide the treatment of photodynamic therapy (PDT).METHODS: We reviewed 30 eyes of 30 patients with CSC, who were diagnosed by fluorescein angiography (FFA) and ICGA at Beijing Tongren Eye Center from November 2015 to March 2016.All patients underwent best-corrected visual acuity (BCVA) measurement, intraocular pressure, slit-lamp examination, indirect ophthalmoscope, color fundus photography, FFA, ICGA and OCTA.FFA and ICGA were captured by Spectralis HRA + OCT (Spectralis HRA + OCT;Heidelberg Engineering, Heidelberg, Germany).OCTA was performed by RTVue XR Avanti device (OptovueInc, Fremont, CA) with 6mm×6mm Angio Retina mode.The software (version 2017.100.0.1;OptovueInc) automatically segmented the tissue into four layers, the characteristics of choriocapillaris layer were analyzed.At the same time, the differences between OCTA and ICGA images were compared among CSC patients.The maximum diameters and areas of both choroidal hyperperfusion in ICGA and high flow signal in OCTA were measured.Then, the paired t test was used to analyze the differences between the maximum diameter and area of OCTA and ICGA measurement.RESULTS: Among 30 cases, high blood flow signals of OCTA were clearly visible in 27 cases, namely the coarse grain region;the inner low flow signals surrounded by high blood flow signals were seen in 21 cases;the outer low flow signals surrounding high blood flow signals were seen in 7 cases.High blood flow signals of OCTA were corresponded with the choroidal hyperperfusion of ICGA images;among these 30 cases, there were low reflection shadows in choroidal hyperperfusion with ICGA for 22 cases, for 21 cases out of these 22 cases, low flow signals inside of high flow signals of OCTA could be seen;9 out of 30 cases, there were low reflection halo outside of choroidal hyperperfusion of ICGA, and 7 out of these 9 cases, low flow signals outside of high flow signals of OCTA could be seen;still for those 30 cases, leakage point in late ICGA could be seen with 14 cases, however, special flow signals in OCTA could not be seen for them.For ICGA, the maximum diameter of choroidal hyperperfusion was 1.589±0.295mm, whose area was 0.705±0.131mm2;while for OCTA, the maximum diameter of high flow signal was 1.576±0.293mm, whose area was 0.745±0.138mm2.By using paired t test, there was no statistical difference between the maximum diameter of choroidal hyperperfusion in ICGA and the maximum diameter of high flow signal in OCTA, nor difference between the area of ICGA and OCTA.CONCLUSION: The high flow signals can be clearly visible in OCTA, which are corresponded with choroidal hyperperfusion in ICGA.OCTA can substitute ICGA for diagnosis of CSC patients, and guide the treatment of PDT.

Background The current epidemiology study had shown the prevalence of age and sex adjusted dry eye was higher in patients with diabetes than population without diabetes.Further researches demonstrated that the tear film disturbance is common after the phacoemulsification or photocoagulation in the eyes of diabetic patients.Objective The aim of this study was to characterize the clinical features of tear film instability in diabetes patients.Methods One hundred and sixty-two patients with tear-film abnormality referred to Tongren Eye Center from January 1,2010 to September 1,2010 underwent questionnaire about diabetes and other diseases,BUT,Schirmer test.Tear film instability was diagnosed as abnormality of either Schirmer test or BUT and showed as M ( Q25,Q75 ).The right eyes of 162 dry eye patients meeting with the including criteria were enrolled.The patients were assigned to two groups according to with ( 80 patients) or without ( 82 patients) diabetes mellitum.DEQ questionnaire were scored.The percentage of cases with meibomain gland abnormal score ＞ 1 was calculated.Mann-Whitney U analysis and Chisquare analysis were used to compare the difference between the two groups.Results The Schirmer test in diabetic group was 8 ( qualities:5,9 )mm and was longer than 6 ( qualities:5,7 ) mm in non-diabetic patients ( U =2452,P =0.00).The result of BUT test was 3 ( qualities:2,4 ) seconds in diabetic patients and was shorter than 4 (qualities:3,5) seconds in non-diabetic patients( U=2104,P＜0.01 ).The DEQ score of diabetic patients was 15 ( qualities:1 0,19,which was less than21 ( qualities:19,23.25 ) in non-diabetic patients.51.2 ％ ( 41/80 ) diabetic participants and 32.9％ (27/82) nondiabetic participants appeared meibography ( grade larger than 1 ) (x2 =16.07,P=0.00).The percentages of dry eyes were 51.2％ (41/80) and 93.9％ (77/82) respectively in diabetes and nondiabetes groups(x2 =37.24,P＜0.01 ).No significant correlation was found between the diabetes course and DEQ score or meibography( r =0.16,P =0.16 ; r =0.10,P =0.36 ).Conclusions Diabetes patients with tear film instability have longer Schirmer test results,shorter BUT,more severe meibomain glands damage and lower DEQ scores.The dry eye symptom is lack in the diabetic patients though appearing the tear film and meibomain glands damage.Therefore,more attention should be given to ocular surface health in diabetes patients.

Adult ; Foot Diseases ; diagnostic imaging ; Humans ; Male ; Melorheostosis ; diagnostic imaging ; Radiography ; X-Rays

Objective:To study the association of air pollution with health service demand of the elderly and middle-age patients with cardiovascular and cerebrovascular diseases,and to provide a scientific ba-sis for development of environmental protection policy and health service policy of the Chinese govern-ment.Methods:This study included survey data on self-evaluated health,outpatient service demand and inpatient service demand of the patients with hypertension,heart disease and stroke in 62 cities of 1 7 provinces from China Health and Retirement Longitudinal Study(CHARLS)in 201 1 and 201 3,and com-bined it with the data on the annual concentrations of inhalable particulate matter(PM1 0 ),sulfur dioxide (SO2 )and nitrogen dioxide(NO2 )of those provinces and cities.Conditional Logistic regression was car-ried out to assess the possible effects of air pollutants on self-evaluated health and health service utiliza-tion.Results:The results showed that turning points existed in the effects of concentrations of NO2 and SO2 on the health service demand of the patients with hypertension,heart disease and stroke.The inpa-tient service demand of the hypertension patients increased with NO2 concentration when it was lower than 35.1 μg/m3 and decreased with NO2 concentration for higher value.Self-evaluated health of the patients with heart disease and stroke decreased with SO2 concentration when it was lower than 63.8 μg/m3 and increased with SO2 concentration for higher value.In addition,no evidence was found for the association between PM1 0 and health service demand.Conclusion:Air pollution may have effects on health service demand of the patients with hypertension,cardiovascular and cerebrovascular diseases,and different air pollutants at high or low concentration may have different health effects.

Objective To study the expressions of HSP70 and AQP4 in the H.Pylori-associated gastritis mice of Pi-Wei hygropyrexia syndrome;To investigate the mechanism of Mieyou Soup. Methods The mice were randomly divided into high concentration of Mieyou Soup group, low concentration of Mieyou Soup group, gastric triad group, model group and control group. BALB/c mice of H.Pylori-associated gastritis mice of Pi-Wei hygropyrexia syndrome model was established by composite factor. After modeling, the mice were administered for of continuous 14 days. The drug dosage of high concentration of Mieyou Soup group, low concentrations of Mieyou Soup group, and gastric triad group were 12.4, 6.2 g/kg, and 0.279 8 mg/kg, respectively. Western Blot was used to detect the expression of HSP70 protein, and immunohistochemistry was employed to detect the expression of AQP4 protein. Results Compared with control group, the expression of HSP70 and AQP4 in model group significantly increased (P<0.05);compared with the model group, the HSP70 in high concentration of Mieyou Soup group, low concentrations of Mieyou Soup group, gastric triad group increased, the AQP4 in high concentration of Mieyou Soup group, low concentrations of Mieyou Soup group, gastric triad group decreased, with statistical significance (P<0.01). Conclusion Mieyou Soup may play a role in treatment of H.Pylori-associated gastritis mice of Pi-Wei hygropyrexia syndrome by raising the expression of HSP70, and reducing the expression of AQP4 protein expression.

Objective To investigate the mechanisms of Mieyou Decoction in the treatment of Hp-associated gastritis of spleen-stomach damp-heat syndrome. Methods Seventy BALB/c mice were randomly divided into control group, model group, high concentration of Mieyou Decoction group, low concentrations of Mieyou Decoction group, and gastric triad group, with 14 rats in each group. BALB/c mice of Hp-associated gastritis of spleen-stomach damp-heat syndrome models were established by composite factor. After the success of modeling and continuous 14-day administration, the expressions of TLR2, TLR4 protein, TLR2 mRNA, and TLR4 mRNA were detected by immunohistochemistry and qPCR. ELISA was used to detect the expressions of IL-6 and IL-8 in the serum. Results Compared with control group, the expressions of TLR2, TLR4 protein, mRNA, IL-6, and IL-8 in model group significantly increased (P<0.01);the expressions of TLR2, TLR4 protein, mRNA, IL-6, and IL-8 in high concentration of Mieyou Decoction group, low concentrations of Mieyou Decoction group, gastric triad group were lower than model group, with statistical significance (P<0.01);the expressions of TLR2, TLR4 protein, mRNA, IL-6, and IL-8 in high concentration of Mieyou Decoction group were higher than gastric triad group, but the differences were not statistically significant (P>0.05). Conclusion Mieyou Decoction may play a role in the treatment of Hp-associated gastritis of spleen-stomach damp-heat syndrome through intervention in the expressions of TLR2 and TLR4.

OBJECTIVETo study the genotoxicity of carbon disulfide by detecting DNA damage in mice sperm with single-cell gel electrophoresis assay (SCGE).

METHODSSCGE was used to detect sperm DNA damage. The index of DNA damage, tail length and tail moment were used to evaluate the extent of DNA damage.

RESULTSIn three dosage groups, the rate of DNA damage (67.14%, 84.29% and 91.00%, respectively), index of DNA damage intensity (507, 656 and 745, respectively), tail length (5.87, 8.81 and 13.49 microm, respectively) and tail moment (1.30, 1.63, 2.66 microm, respectively) were significantly increased, while the percentage of head of the comet was significantly decreased (84.55%, 73.84% and 55.71%, respectively). A significant changes were clearly observed in all dosage groups compared to those of the control group (P<0.05).

CONCLUSIONSCGE which is a quick and sensitive method to detect DNA damage induced by CS2 may be used to monitor carcinogen and mutagen.

Animals ; Carbon Disulfide ; toxicity ; Comet Assay ; DNA Damage ; Male ; Mice ; Spermatozoa ; chemistry ; drug effects