OBJECTIVE To investigate the effects of multiple doses of Shugan jieyu capsules on the pharmacokinetics of voriconazole， rivaroxaban and apixaban in rats. METHODS Male SD rats were randomly divided into voriconazole group （30 mg/kg）， rivaroxaban group （2 mg/kg）， apixaban group （0.5 mg/kg）， Shugan jieyu capsules+voriconazole group （145 mg/kg+30 mg/kg）， Shugan jieyu capsules+rivaroxaban group （145 mg/kg+2 mg/kg）， Shugan jieyu capsules+apixaban group （145 mg/kg+0.5 mg/kg）， with 6 rats in each group. After the rats in each group were consecutively administered solvent （0.5% sodium carboxymethyl cellulose solution） or Shugan jieyu capsules by intragastric gavage for 8 days， they were respectively given voriconazole， rivaroxaban and apixaban solution by intragastric gavage on the 8th day. Blood samples were then collected at different time points （in voriconazole group， rivaroxaban group and corresponding drug combination groups， blood was collected before administration and at 0.17， 0.34， 0.5， 0.75， 1， 1.5， 2， 3， 4， 5， 6， 8， 10 and 12 hours post-administration； in apixaban group and corresponding drug combination group， blood was collected before administration and at 0.08， 0.17， 0.25， 0.34， 0.5， 0.75， 1， 3， 5， 7， 10 and 12 hours post-administration）. Ultra-high performance liquid chromatography-tandem mass spectrometry method was employed to determine the mass concentrations of voriconazole， rivaroxaban and apixaban in rat plasma. The main pharmacokinetic parameters of these drugs were calculated using a non-compartmental model， and the comparisons were made between groups. RESULTS Compared with single drug group， after multiple administrations of Shugan jieyu capsules， AUC0－t， AUC0－∞ and cmax of voriconazole were significantly decreased， while CLz/F was significantly increased， and tmax was also significantly prolonged （P＜0.05）. For rivaroxaban and apixaban， their tmax values were both significantly prolonged （P＜0.05）. However， there were no statistically significant differences in the other pharmacokinetic parameters between the two groups （P＞0.05）. CONCLUSIONS The combination of Shugan jieyu capsules can decrease the exposure， increase the clearance， and delay the peak concentration of oral voriconazole. However， it does not affect the exposure levels of rivaroxaban and apixaban， but it does delay the time to reach peak concentration for both drugs.

Objective To investigate the effects of acute sleep deprivation on the behavior and synaptic protein expression of rats.Methods Seventy healthy male Wistar rats were randomly divided into seven groups,a Control group and sleep deprivation groups(24,48,72,96,120 and 144 hours).The sleep deprivation rat model was established by the modified multiplatform water environment sleep deprivation method.Spatial learning and memory were assessed by the Morris water maze.Anxiety was assessed by the open field test.The morphology and quantity of hippocampal neurons were observed by Nissl staining.Western blot and Real-time PCR were used to determine the expression of synaptophysin(SYN),post-synaptic density protein-95(PSD-95),and brain-derived neurotrophic factor(BDNF)in rats.Results Compared with the Control group,the numbers of standing and modification were significantly increased by prolongation of the sleep deprivation time(P＜0.05).The escape latency and path length were significantly increased in 120 and 144 h groups(P＜0.05),whereas the number of platform crossings and the percentage of the target quadrant time were significantly decreased(P＜0.01)and negatively correlated to the sleep deprivation time.The expression levels of BDNF,SYN,and PSD-95 were significantly decreased with the prolongation of sleep deprivation time(P＜0.01).Conclusions With the increase in sleep deprivation time,cognitive dysfunction and anxiety gradually deteriorated,which may be related to decreases in the expression of synaptic biomarkers.

FRMD6, a member of the 4.1 ezrin-radixin-moesin domain-containing protein family, has been reported to inhibit tumor progression in multiple cancers. Here, we demonstrate the involvement of FRMD6 in lung cancer progression. We find that FRMD6 is overexpressed in lung cancer tissues relative to in normal lung tissues. In addition, the enhanced expression of FRMD6 is associated with poor outcomes in patients with lung squamous cell carcinoma (n = 75, P = 0.0054) and lung adenocarcinoma (n = 94, P = 0.0330). Cell migration and proliferation in vitro and tumor formation in vivo are promoted by FRMD6 but are suppressed by the depletion of FRMD6. Mechanistically, FRMD6 interacts and colocalizes with mTOR and S6K, which are the key molecules of the mTOR signaling pathway. FRMD6 markedly enhances the interaction between mTOR and S6K, subsequently increasing the levels of endogenous pS6K and downstream pS6 in lung cancer cells. Furthermore, knocking out FRMD6 inhibits the activation of the mTOR signaling pathway in Frmd6^-/- gene KO MEFs and mice. Altogether, our results show that FRMD6 contributes to lung cancer progression by activating the mTOR signaling pathway.

OBJECTIVE：To provid e reference for hospital decision-maker to select and use repaglinide and naglinide reasonably. METHODS ：Through reviewing literautre ，guideline and instruction ，full score system was estalished for comunni- cation between pharmacists and physicians ；from the aspects of clinical necessity ，effectiveness，safety，economy，medical insu- rance attribute ，essential medicine attribute ，original research attribute ，drug packaging attribute ，drug market and enterprise attributes，the Mini health technology assessment （Mini HTA ）was carried out for repaglinide and nateglinide ，and scored on the basis of weight value. RESULTS ：Repaglinide and naglinide ’s final score were 77 and 74，respectively. For type 2 diabetes，both of them could reduce postprandial blood glucose ，and had less side effect and good safety. They were both included in the medical insurance list. Both of them were original varieties ，easy to store and had a long period of validity. Although they were expensive in the treatment of type 2 diabetes，their manufacturers had a good reputation and were widely used in the world ，which was a good choice for patients with type 2 diabetes. But they were different to certain extent ；repaglinide could be used in patients with poor renal function [eGFR ＜30 mL/min] without dose adjustment ；nateglinide should be adjusted according to eGFR for renal excretion. Repaglinide was essential medicine but nateglinide wasn ’t；repaglinide didn ’t need shading storage but nateglinide did. In addition ， a variety of liver drug enzyme inducers or inhibitors may interact with the two drugs ，and special groups should be used with. CONCLUSIONS ：Mini HTA provide reference for the selection and rational use of repaglinide and nateglinide ；patients with type 2 diabetes can select suitable drug according to their own conditions and needs. When combined with other drugs ，blood glucose should be closely monitored to prevent the occurrence of hypoglycemia.

Objective To observe the clinical effect of the method of Shugan-Yiqi-Yangyin treatment for the steroid-resistant nephrotic syndrome (SRNS). Methods A total of 80 patients with SRNS were divided into 2 groups by random number table method, 40 in each group. The control group received glucocorticoids combined with Tripterygium Glycosides;and the treatment group received Shugan-Yiqi-Yangyin on the basis of the control group, 3 month as a course. The 24 h urine protein quantitative (propagated), plasma albumin, blood lipid (total cholesterol, triglycerides), hemorrheology, blood urea nitrogen (BUN), creatinine (Cr), urinary inhibition C (Cys C) were detected before and after the treatment of two groups, and the clinical effect was compared. Results The total effective rate of the treatment group was 92.50% (37/40) and 82.50% (33/40) in the control group, and the difference was statistically significant (Z=-1.966, P<0.05). After the treatment, the 24 hPRO (1.03 ± 0.64 mg vs.2.81 ± 1.43 mg,t=3.025),Cys C(0.35 ± 0.41 mg/L vs.0.76 ± 0.51 mg/L, t=3.058) of the treatment group was significantly lower than those of the control group(P<0.05).The Alb(34.88 ± 2.17 mg vs. 31.69 ± 2.05 mg, t=2.986) of the treatment group was significantly higher than this of the control group (P<0.05), After treatment,the whole blood high shear viscosity(7.84 ± 1.42 mPa?s vs.8.94 ± 1.38 mPa?s,t=3.160),the whole blood low shear viscosity(4.55 ± 0.37 mPa?s vs.5.02 ± 0.44 mPa?s,t=3.825),plasma viscosity(1.33 ± 0.10 mPa?s vs.1.95 ± 0.26 mPa?s,t=2.981),hematocrit(0.28 ± 0.03 vs.0.34 ± 0.03,t=2.993),fibrinogen(3.96 ± 0.57 g/L vs.4.52 ± 0.47 g/L,t=4.863)of the treatment group were significantly lower than those of the control group(P<0.05).The TC(5.04 ± 1.72 mmol/L vs.6.99 ± 1.06 mmol/L,t=3.67),TG(1.4 ± 0.64 mmol/L vs.2.02 ± 0.31 mmol/L, t=3.040) of the treatment group were significantly lower than those of the control group (P<0.05). Conclusions The Shugan-Yiqi-Yangyin treatment for SRNS can obviously improve the symptoms,reduce the side effects of hormone of antagonism. The possible mechanisms are to restore kidney function, improve blood viscosity and lower blood lipid levels.

OBJECTIVE:To investigate the compatible stability of Xiao'aiping injection combined with 3 kinds of common in-jections. METHODS:Referring to package inserts,Xiao'aiping injection 40 mL was compatible with 5% Glucose injection,10%Glucose injection or 0.9% Sodium chloride injection 160 mL,respectively. At room temperature(about 25 ℃)and high tempera-ture(40 ℃),the appearance of mixtures were observed at 0,1,2,4,8,12,24,48 h;pH value and the number of insoluble particles were detected. The contents of tenacissoside A and tenacissoside Ⅰ in mixtures were determined by HPLC. RESULTS:Un-der above condition,the mixtures were brownish yellow liquid within 48 h after Xiao'aiping injection was compatible with 5%Glucose injection or 10% Glucose injection;24 h after mixed with 0.9% Sodium chloride injection,the mixture changed from brownish yellow to reddish brown,but no precipitation was found. The pH value of mixtures had no significant change(RSD<1%,n=8). The number of particles ≥25 μm was in line with the requirements of Chinese Pharmacopeia(2015 edition). For-ty-eight hours after mixing,the number of particles ≥10 μm in the mixtures exceeded the pharmacopoeia limits. Within 48 h after mixing,the relative contents of tenacissoside A and tenacissoside I in mixtures had no significant change(RSD<2%,n=8). CON-CLUSIONS:The mixture should be used up within 24 h after Xiao'aiping injection combined with 5% Glucose injection,10%Glucose injection or 0.9% Sodium chloride injection.

Objective To investigate the accumulation of mutations and single nucleotide polymorphisms ( SNPs) in the displacement loop ( D-loop ) of mitochondrial DNA ( mtDNA ) might be associated with cancer risk and disease outcome.Methods We obtained cancerous and noncancerous liver tissues from 49 HBV-related HCC patients at the Fourth Hospital of Hebei Medical University.mtDNA of the liver tissues was extracted with Mitochondrial DNA Extraction Kit.Mutation and polymorphism were confirmed by repeated analysis.We assessed the prediction power of D-loop SNPs in hepatocellular carcinoma ( HCC) patients.Results No mutation in these HCC patients had prediction power for post-operational survival, whereas one SNP site ( nucleotide 150 C/T ) was identified by the log-rank test for statistically significant prediction of HCC survival.In an overall multivariate analysis, allele 150 was identified as an independent predictor of HCC outcome.The length of survival of patients with allele 150C was significantly shorter than that of patients with allele 150T (relative risk, 0.246;95% CI, 0.070–0.861; P=0.028).Conclusions The analysis of genetic polymorphisms in the mitochondrial D-loop helps to identify patient subgroups at high risk of a poor disease outcome.

Objective To summarize the relationship between metabolic syndrome (MS),its components and T1 stage with high grade urothelial carcinoma (HGUC) of the Bladder.Methods The clinical data of 200 patients with T1 high grade bladder cancer who were admitted to our hospital from January 2010 to June 2014 were retrospectively analyzed,including 155 males and 45 females.Ages were 24 to 86 years old,average 66 years old.Based on the history or blood glucose levels,patients were divided into diabetic group (n =41) (20.5％) and non diabetes group 159 cases (79.5％);According to the body mass index (BMI) were divided into obese group (≥25 kg / m2) of 98 cases (49.0％) and non obese group (＜ 25 kg / m2) of 102 cases (51.0％).According to the blood pressure level,71 cases (35.5％) were divided into hypertension group and 129 cases of non hypertension group (64.5％).MS and its components and the relationship between the recurrence and progress of bladder cancer were analyzed.The Kaplan Meier method was used to assess MS and its components division of tumor progression free survival (progress-free survival,PFS) and recurrence free survival (recurrence-free survival,RFS) influence.Cox regression model of multi factor analysis were used to evaluate the PFS and RFs of MS and its components with bladder cancer.Results Of the 200 cases,16 cases (8.0％) were MS.Tumor recurrence occurred in 121 cases (60.5％),and 84 patients (42.0％) were in progress.Diabetes and non diabetes groups the average RFs were 21.7 and 29.3 months respectively,and the difference was statistically significant (x2 =10.115,P =0.001);The median PFS were 32.8 and 39.8 months respectively,the difference has statistical significance (x2 =14.760,P ＜0.001).Obese group and non obese group average RFs were 34.7 and 42.0 months respectively,and the difference were statistically significant (x2 =16.077,P ＜ 0.001);The median PFS were 22.8 and 32.6 months respectively,the difference was statistically significant (x2 =16.174,P＜0.001).The average RFS of MS group and non MS group were 21.5 and 28.4 months respectively,the difference was statistically significant (x2 =5.429,P =0.02);the average PFS was 35.1 and 38.7 months respectively,and the difference was statistically significant (x2 =3.854,P ＜ 0.05).Cox multivariate survival analysis showed that diabetes and obesity can increase the risk of recurrence and progression of T1 advanced stage bladder cancer (HR =1.792,P =0.013,HR =2.498,P ＜ 0.001;HR =0.559,P ＜ 0.001;HR =0.492,P ＜ 0.001).Conclusions Diabetes mellitus and obesity are high risk factors for the recurrence and progression of T1 advanced stage bladder cancer,but MS is not related to the prognosis of T1 patients with advanced bladder cancer.

Objective To investigate the clinicopathological features, treatment modalities, and prognostic factors for survival in patients with urinary tract small cell carcinoma (UT-SCC).Methods A total of 25 patients treated from June 2000 to December 2014 were included in the retrospective study.The data included age, gender, primary tumors origins, stage, treatment modalities, progression-free survival (PFS), overall survival (OS), pathology and immunohistochemistry.Of these cases, 22 were male, and the other was female, whose age was 45-79 years (mean age 67).20 cases small cell carcinoma of bladder patients and 2 small cell carcinoma of prostate cancer patients were included.The number of small cell carcinoma in pelvis,ureter and retroperitoneal was 1 respectively.The patients with small cell carcinoma of the urinary tract were classified as disease and extensive disease.17 bladder small cell carcinomas were limited disease and 3 cases were extensive disease;Prostate small cell carcinomas were both extensive disease;The small cell carcinomas in pelvis, ureter were limited disease;The small cell carcinoma in retroperitoneal was extensive disease.10 bladder small cell carcinomas which were limited disease received radical cystectomy.6 of 10 patients received etoposide and cisplatnum (EC).4 of 10 patients received gemcitabine and cisplatnum (GC).7 bladder small cell carcinomas patients who with limited disease refused to receive radical cystectomy in which 2 patients received TURBT and 5 patients received TURBT followed chemotherapy.Both prostate small cell carcinomas received chemoradiotherapy.2 small cell carcinomas in upper urinary tract (pelvis and ureter) received radical nephroureterectomy with bladder cuff resection.The patient of retroperitoneal small cell carcinoma received percutaneous nephrostomy after biopsy.The progression-free survival (PFS) and overall survival (OS) of these patients are analyzed;the influence of TURBT with adjuvant chemotherapy and clinicopathologic characteristics were analyzed in median PFS and OS.PFS and OS were compared between groups as a function of time, using a Kaplan-Meier survival curve analysis and the log-rank significance test.All statistical tests were two-sided, and P values ＜ 0.05 were considered statistically significant.Results 25 patients with a pathologic confirmation of UT-SCC,either by biopsy or surgery,were finally included.These patients were classified as pure UT-SCC (14) and Mixed UT-SCC (11).Mixed UT-SCC was defined as tumors containing both SCC and non-SCC components,regardless of the proportion of the latter.13 cases were strongly positive and 3 cases were weakly positive in neuron specific enolase (NSE) level.8 cases were strongly positive and 2 cases were weakly positive in CgA level.Patients with limited disease experienced a significant longer PFS and OS compared with extensive disease subjects (PFS 13.2 vs.7.8 x2=13.53 P＜0.01;OS27.2 vs.12.7x2=19.88 P＜0.01).Patients with bladder SCC showed a significantly higher median PFS and OS compared with patients with SCC of other parts of urinary tract (PFS 12.8 vs.8.2 x2 =12.00, P =0.001;OS 26.3 vs.13.2 x2 =14.45,P ＜0.01) .The two different chemotherapy regimens (GC and EC) have no influence on survival (PFS: 16.3 vs.12.5,x2 =3.34, P =0.07;OS 29.5 vs.22.8, x2 =1.66, P =0.198).TURBT followed by adjuvant therapy have no influence on survival (PFS 14.5 vs.12.0 t =1.30 P =0.251;OS 24.5 vs.28.4 t =0.50,P =0.636).Conclusions The primary tumors origins and stage may have influence on survival in patients with UT-SCC.Patients with bladder small cell carcinoma and limited disease experienced a longer survival.

Objective To analyze the diagnosis,treatment and prognosis of small cell carcinoma of bladder (SCCB) in order to improve the understanding of it.Methods The pathological and clinical data of 5 cases of SCCB were retrospectively analyzed.All patients were male,aged 50 to 78 years (mean age,64 years).Clinical manifestations of 4 cases were gross hematuria,the other case was found by health examination.Ultrasonography results of 3 cases were medium echo tumors,the other 2 cases were hypoecho tumors.The diameter of the tumor was 2.1 to 4.0 cm (mean,3.0 cm).There were 3 patients accepted CT scan.One of them was found of hydronephrosis and multiple pelvic lymph nodes.All patients accepted diagnostic TURBT.Three of them accepted postoperative chemotherapy (1 cycle) without other surgery.Two patients accepted radical cystectomy with postoperative chemotherapy (3 cycles) after bladder tumor biopsy.Results Pathological findings showed that tumor cells were small,round and sheet in arrangement.These hyperchromatic nuclei showed limited cytoplasm with lack of nesting character.Neuron specific enolase,chromogranin A and synaptophysin were positive in immunohistochemistry.The final diagnosis was SCCB'.Two of the three patients who accepted TURBT with postoperative chemotherapy died 7 and 8 months postoperatively,the other one was alive for 32 months.Another two patients who accepted radical cystectomy with postoperative chemotherapy were alive for 16 and 26 months.Conclusions SCCB is a rare tumor which has high malignancy and poor prognosis.Radical cystectomy in combination with postoperative chemotherapy is the main treatment.Retained bladder surgery with chemotherapy is an alternative choice.