Central nervous system（CNS） disorders are characterized by complex pathological mechanisms and the presence of the blood-brain barrier（BBB）， which significantly limits the effectiveness of drug therapy. Traditional drug delivery modes include oral administration， intravenous injection and transdermal delivery， which have certain advantages， but it is difficult for the drugs to effectively cross the BBB. Therefore， it is crucial to find drug delivery modes that can efficiently traverse the BBB. Nasal drug delivery， as a non-invasive method， can realize the targeted delivery of drugs to the CNS via three pathways， including olfactory neurons， trigeminal neurons and blood circulation， and shows a broad application prospect in the treatment of CNS diseases. Numerous studies have further confirmed that nasal drug delivery combined with novel drug delivery systems such as lipid nanocarriers， nanoparticles， nanoemulsions and composite in situ gels can effectively load the active components of traditional Chinese medicine（TCM）， and significantly increase drug concentration in the brain， which provides new strategies for the treatment of CNS diseases. In this paper， the current status of drug delivery for CNS diseases was systematically sorted out， the characteristics of nasal drug delivery were discussed in depth， and the research progress of passive targeting， active targeting， and "guiding the meridian" drug delivery strategies for the nasal-to-brain transport of TCM active components was summarized and analyzed， which was aimed to provide references and insights for the development of drugs for CNS diseases and the application of TCM in nasal-to-brain delivery.

Central nervous system（CNS） disorders are characterized by complex pathological mechanisms and the presence of the blood-brain barrier（BBB）， which significantly limits the effectiveness of drug therapy. Traditional drug delivery modes include oral administration， intravenous injection and transdermal delivery， which have certain advantages， but it is difficult for the drugs to effectively cross the BBB. Therefore， it is crucial to find drug delivery modes that can efficiently traverse the BBB. Nasal drug delivery， as a non-invasive method， can realize the targeted delivery of drugs to the CNS via three pathways， including olfactory neurons， trigeminal neurons and blood circulation， and shows a broad application prospect in the treatment of CNS diseases. Numerous studies have further confirmed that nasal drug delivery combined with novel drug delivery systems such as lipid nanocarriers， nanoparticles， nanoemulsions and composite in situ gels can effectively load the active components of traditional Chinese medicine（TCM）， and significantly increase drug concentration in the brain， which provides new strategies for the treatment of CNS diseases. In this paper， the current status of drug delivery for CNS diseases was systematically sorted out， the characteristics of nasal drug delivery were discussed in depth， and the research progress of passive targeting， active targeting， and "guiding the meridian" drug delivery strategies for the nasal-to-brain transport of TCM active components was summarized and analyzed， which was aimed to provide references and insights for the development of drugs for CNS diseases and the application of TCM in nasal-to-brain delivery.

ObjectiveTo understand the current status of Cronobacter sakazakii (Cronobacter spp.) infection and its molecular epidemiological characteristics among patients with diarrhea, so as to provide evidence for the prevention and control of diarrhea disease caused by infection with Cronobacter spp. in Changping District, Beijing. Methods760 stool samples were collected from the diarrhea patients in a sentinel hospital in 2019, for the detection of Cronobacter spp., Salmonella, diarrheogenic Escherichia coli (DEC), and Vibrio Parahaemolyticus. Meanwhile, drug sensitivity experiment and pulsed-field gel electrophoresis (PFGE) typing analysis were conducted on the Cronobacter spp. strains isolated. ResultsA total of 20 Cronobacter spp. strains (2.63%) were isolated, with a lower detection rate than that of Salmonella and Vibrio Parahaemolyticus (χ²=9.052, P=0.011). However, there were no statistically significant differences between the detection rates in Cronobacter spp. and DEC (χ²=1.076, P=0.300). Seasonal characterization analysis showed that Cronobacter spp. could be detected in spring (1.00%), summer (4.17%), autumn (3.00%) and winter (1.67%), and the differences were statistically significant (χ²=662.700, P<0.001). The PFGE analysis showed that 20 PFGE banding patterns were found in 20 Cronobacter spp. strains, with a similarity coefficient ranging from 56.30% to 90.09% and a diverse PFGE banding pattern. The drug sensitivity experiment results showed that 18 (90.00%) strains were resistant to cefazolin, and2 (10.00%) strains were intermediate. While, as for cefoxitin, 2 (10.00%) strains were resistant to it, and 5 (25.00%) strains were intermediate. All the 20 strains were 100.00% sensitive to the other 11 antibiotics. ConclusionIn the study, Cronobacter spp. is detected in all seasons through the year, with a high resistance rate to cefazolin, no multi-drug resistant bacteria appeared, and diverse PFGE banding patterns.

Objective To investigate the changes and clinical significance of serum C1q tumor necrosis factor-related protein 12(CTRP12),adiponectin(APN),and resistin(RETN)in patients with type 2 diabetes mellitus(T2DM)combined with different grades of hypertension.Methods A total of 156 patients with T2DM were selected and divided into the following groups:isolated T2DM group(T2DM,n=38),T2DM combined with hypertension grade 1(DH1,n=39)group,T2DM combined with hypertension grade 2(DH2,n=39)group,and T2DM combined with hypertension grade 3(DH3,n=40)group.Additionally,healthy individuals who underwent physical examinations at our hospital were selected as the normal control(NC,n=40)group.Serum levels of CTRP12,APN,and RETN were measured using ELISA.Pearson correlation analysis was used to evaluate the relationship between serum CTRP12,APN,RETN,and other indicators.Multiple linear regression analysis was performed to determine the influencing factors for the three indicators.Results In NC,T2DM,DH1,DH2 and DH3 groups,DBP increased in turn(P<0.05),while CTRP12 decreased in turn(P<0.05).SBP in T2DM,DH1,DH2 and DH3 groups increased in turn(P<0.05).In DH1,DH2 and DH3 groups,RENT increased in turn(P<0.05),while APN decreased in turn(P<0.05).Pearson correlation analysis showed that serum CTRP12 was negatively correlated with WHR,BMI,HOMA-IR,FPG,HbA1c,FIns,TC,LDL-C,SBP,and DBP(P<0.05).Serum APN was negatively correlated with BMI,FPG,HbA1c,FIns,TC,SBP,and DBP(P<0.05),and positively correlated with HDL-C(P<0.05).Serum RETN was positively correlated with WHR,HOMA-IR,FPG,HbA1c,FIns,SBP,and DBP(P<0.05).Multiple linear regression analysis indicated that SBP was an influencing factor for CTRP12 and RETN,while SBP and HbA1c were influencing factors for RETN.Conclusions In patients with T2DM combined with hypertension,serum CTRP12 and APN levels decrease,while RETN levels increase,with significant changes observed as HP grades increase,suggesting that these three factors may collectively influence the occurrence and development of T2DM combined with HP.

Objective To investigate the changes and clinical significance of serum C1q tumor necrosis factor-related protein 12(CTRP12),adiponectin(APN),and resistin(RETN)in patients with type 2 diabetes mellitus(T2DM)combined with different grades of hypertension.Methods A total of 156 patients with T2DM were selected and divided into the following groups:isolated T2DM group(T2DM,n=38),T2DM combined with hypertension grade 1(DH1,n=39)group,T2DM combined with hypertension grade 2(DH2,n=39)group,and T2DM combined with hypertension grade 3(DH3,n=40)group.Additionally,healthy individuals who underwent physical examinations at our hospital were selected as the normal control(NC,n=40)group.Serum levels of CTRP12,APN,and RETN were measured using ELISA.Pearson correlation analysis was used to evaluate the relationship between serum CTRP12,APN,RETN,and other indicators.Multiple linear regression analysis was performed to determine the influencing factors for the three indicators.Results In NC,T2DM,DH1,DH2 and DH3 groups,DBP increased in turn(P<0.05),while CTRP12 decreased in turn(P<0.05).SBP in T2DM,DH1,DH2 and DH3 groups increased in turn(P<0.05).In DH1,DH2 and DH3 groups,RENT increased in turn(P<0.05),while APN decreased in turn(P<0.05).Pearson correlation analysis showed that serum CTRP12 was negatively correlated with WHR,BMI,HOMA-IR,FPG,HbA1c,FIns,TC,LDL-C,SBP,and DBP(P<0.05).Serum APN was negatively correlated with BMI,FPG,HbA1c,FIns,TC,SBP,and DBP(P<0.05),and positively correlated with HDL-C(P<0.05).Serum RETN was positively correlated with WHR,HOMA-IR,FPG,HbA1c,FIns,SBP,and DBP(P<0.05).Multiple linear regression analysis indicated that SBP was an influencing factor for CTRP12 and RETN,while SBP and HbA1c were influencing factors for RETN.Conclusions In patients with T2DM combined with hypertension,serum CTRP12 and APN levels decrease,while RETN levels increase,with significant changes observed as HP grades increase,suggesting that these three factors may collectively influence the occurrence and development of T2DM combined with HP.

Objective:To investigate the application value of different metal stents place-ment position in endoscopic drainage of malignant hilar bile duct obstruction.Methods:The retro-spective cohort study was conducted. The clinicopathological data of 300 patients with malignant hilar bile duct obstruction who were admitted to 3 medical centers, including 216 patients in the Third Affiliated Hospital of Naval Medical University, 48 patients in the Xijing Hospital of Air Force Medical University, 36 patients in the First People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, from January 2012 to January 2019 were collected. There were 164 males and 136 females, aged (67±12)years. All patients were determined to be unresectable by multidisciplinary consultation and underwent endoscopic retrograde cholangiopancreatography. Observation indicators: (1) clinicopathological features of patients; (2) follow-up; (3) analysis of influencing factors for patency time of metal biliary stents and overall survival time of patients. Follow-up was conducted using outpatient examination and telephone interview to detect patency of metal biliary stents and survival of patients up to July 2019 or death of patients. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M( Q1, Q3), and comparison between groups was conducted using the Mann-Whitney U test. Count data were expressed as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test or Fisher exact probability. Comparison of ordinal data was conducted using the rank sum test. Kaplan-Meier method was used to calculate survival rates and draw survival curves, and Log-Rank test was used to conduct survival analysis. COX regression model was used for univariate and multivariate analyses. Factors with P<0.1 in univariate analysis were included in multivariate analysis. Results:(1) Clinicopathological features of patients. Of the 300 patients, 163 cases underwent endoscopic drainage with at least one metal biliary stent' distal portion crossing the duodenal main papilla (hereinafter referred to as crossing papilla), and 137 cases underwent endoscopic drainage with no metal biliary stent' distal portion crossing the duodenal main papilla (hereinafter referred to as no crossing papilla). Age, disease type (hilar cholangiocarcinoma, hepatocellular carcinoma, intrahepatic cholangio-carcinoma, gallbladder carcinoma, metastatic cholangiocarcinoma), metal biliary stents type (unilateral metal biliary stent, bilateral metal biliary stents) of patients with crossing papilla were (68±13)years, 95, 8, 11, 31, 18, 63, 100, respectively. The above indicators of patients with no crossing papilla were (64±12)years, 63, 22, 20, 23, 9, 126, 11, respectively. There were significant differences in the above indicators between patients with crossing papilla and patients with no crossing papilla ( t=2.70, χ2=17.69, 90.79, P<0.05). (2) Follow-up. All the 300 patients were followed up for 5.4(3.1,9.3)months. The patency time of metal biliary stents was 9.0(8.2,9.8)months and 6.4(4.8,8.0)months of patients with crossing papilla and patients with no crossing papilla, showing a significant difference between them ( χ2=8.23, P<0.05). The overall survival time was 5.5(4.2,6.8)months and 5.5(4.3,6.8)months of patients with crossing papilla and patients with no crossing papilla, showing no significant difference between them ( χ2=0.28, P>0.05). (3) Analysis of influencing factors for patency time of metal biliary stents and overall survival time of patients. Results of univariate analysis showed that type of metal biliary stents and the placement position of metal biliary stents were related factors affecting the patency time of metal biliary stents [ hazard ratio( HR)=0.44, 0.60, 95% confidence intervals as 0.30?0.64, 0.42?0.85, P<0.05]. Results of multi-variate analysis showed that bilateral metal biliary stents was an independent protective factor for the patency time of metal biliary stents ( HR=0.46, 95% confidence interval as 0.29?0.72, P<0.05). Results of univariate analysis showed that disease type (intrahepatic cholangiocarcinoma versus hilar cholangiocarcinoma), preoperative serum total bilirubin, type of metal biliary stents, anti-tumor therapy were related factors affecting the overall survival time of patients ( HR=1.05, 1.43, 0.72, 0.61, 95% confidence intervals as 0.70?1.57, 1.12?1.83, 0.55?0.92, 0.47?0.81, P<0.05). Results of multi-variate analysis showed that age >60 years, disease type as hepatocellular carcinoma, preoperative serum total bilirubin >200 μmol/L were independent risk factors for the overall survival time of patients ( HR=1.35, 1.98, 1.46, 95% confidence intervals as 1.02?1.79, 1.40?2.80, 1.13?1.89, P<0.05), and bilateral metal biliary stents, anti-tumor therapy were independent protective factors for the overall survival time of patients ( HR=0.68, 0.60, 95% confidence intervals as 0.53?0.89, 0.45?0.80, P<0.05). Conclusions:Endoscopic drainage with or without metal biliary stents' distal portion crossing the duodenal main papilla is safe and feasible for patients with malignant hilar bile duct obstruction. Bilateral metal biliary stents is an independent protective factor for the patency time of metal biliary stents. Age >60 years, disease type as hepatocellular carcinoma, preoperative serum total bilirubin >200 μmol/L are independent risk factors for the overall survival time of patients, and bilateral metal biliary stents, anti-tumor therapy are independent protective factors for the overall survival time of patients.

Objective:To investigate the change of fibroblast growth factor 19 (FGF19) in patients with metabolic syndrome (MS) and its diagnostic significance.Methods:According to the number of abnormal metabolic indexes, 175 outpatients and inpatients with MS were divided into Group Ⅲ, Group Ⅳ and Group Ⅴ, with 68 cases, 57 cases and 50 cases, respectively. 40 healthy people were served as normal control group (NC group). Serum FGF19 concentration was measured by enzyme-linked immunosorbent assay (ELISA). The height, weight, waist circumference, blood pressure, blood lipid, fasting and 2-hour postprandial blood glucose, fasting insulin and serum C-reactive protein were measured. Multiple stepwise regression was used to analyze the related influencing factors of FGF19, and the threshold value of FGF19 in the diagnosis of MS was determined by drawing receiver operating characteristic (ROC) curve.Results:The levels of serum FGF19 in NC, Ⅲ, Ⅳ and Ⅴ groups decreased gradually, and the differences were statistically significant ( P<0.05). Multiple stepwise regression analysis showed that BMI, serum total cholesterol, glycosylated hemoglobin and waist circumference were independent influencing factors of FGF19 ( P<0.05). ROC curve analysis showed that the ROC area of FGF19 was 0.849, the threshold was 115.4 pg/ml, with sensitivity 0.875 and specificity 0.667. Conclusions:With the increase of metabolic abnormalities in MS, the level of FGF19 decreased, which was related to obesity and glucose and lipid metabolism disorder. It may be an index to predict and diagnose MS.

OBJECTIVE:To observe therapeutic efficacy and safety of paroxetine combined with flupentixol melitracen in the treatment of post-stroke major depressive disorder(PSMDD). METHODS:120 PSMDD patients were randomly divided into group A(40 cases),group B(40 cases)and group C(40 cases). All patients received routine stroke treatment;group A was additionally given Paroxetine hydrochloride enteric-coated sustained-release tablet 25 mg orally,once a day;group B was additionally given Flu-pentixol melitracen tablet 20 mg orally twice a day;group C was additionally given Paroxetine hydrochloride enteric-coated sus-tained-release tablet (same usage and dosage as group A)+flupentixol melitracen (same usage and dosage as group B). Three groups were treated for 28 d. Clinical efficacies of 3 groups were observed as well as NIHSS,ADL,HADM,SS-QOL score,hos-pitalization stay and the occurrence of ADR. RESULTS:Total response rate of group C was significantly higher than those of group A and B;hospitalization day was significantly less than those of group A and B,with statistical significance(P<0.05);there was no statistical significance between group A and B(P>0.05). There was no statistical significance in the incidence of ADR among 3 groups (P>0.05). Before treatment,there was no statistical significance in NIHSS,ADL,HADM,SS-QOL score among 3 groups(P>0.05). After 10,28 d of treatment,NIHSS,HADM,SS-QOL score of 3 groups were significantly lower than before, above indexes were decreased gradually as time,and the group C were lower than the group A and B;ADL score of 3 groups were significantly higher than before,this index was increased gradually as time,and the group C were lower than the group A and B with statistical significance (P<0.05);there was no statistical significance between group A and B (P>0.05). CONCLUSIONS:Based on routine treatment,paroxetine combined with flupentixol melitracen in the treatment of PSMDD can relieve neurologic function injury,improve depression condition and the quality of life without increasing the occurrence of ADR.

Objective To optimize the prescription of GA and GB hydrophilic gel matrix tablets; To study the in vitro release mechanism. Methods On the basis of the results of the mono-factor investigation, mixture uniform design was used to optimize the handicraft molding prescription of GA and GB hydrophilic gel matrix tablets. The release mechanism was investigated by the vitro of the GA and GB hydrophilic gelmatrix tablets to accumulate releasing rate to conduct linear fitting. Results The optimized prescription of GA and GB hydrophilic gel matrix tablets was: powder: HPMC: lactose=23:24:53. Conclusion Mixture uniform design can be used to optimize the prescriptions of GA and GB hydrophilic gel matrix tablets, and the results are accurate. The hydrophilic gelmatrix tablets release medicine by non-Fick mechanism, and the medicine release is in accordance with zero-order.