Dopamine D₃ receptor (D₃R) is implicated in multiple psychotic symptoms. Increasing the D₃R selectivity over dopamine D₂ receptor (D₂R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D₃R selective ligands. Through a structure-based virtual screen, ZLG-25 (D₃R K_i = 685 nmol/L; D₂R K_i > 10,000 nmol/L) was identified as a novel D₃R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D₃R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD₃R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

Patients who initiated peritoneal dialysis (PD) in Sichuan Provincial People's Hospital from January 1, 2001 to December 31, 2013 were enrolled in the single center and retrospective study. Clinical and laboratory data were collected to analyze the long-term survival rates, technique survival rates and associated influencing factors. Patients were followed up until December 31, 2021 or endpoints occurred (death or stopping PD treatment). Kaplan-Meier survival curves were used to estimate survival rates and technique survival rates. Cox proportional hazards regression model was used to analyze the risk factors of death and technique failure in PD patients. A total of 373 patients were enrolled in the study, with age of (52.1±15.8) years old and 199 (53.4%) males. During the follow-up, 154 (41.3%) patients died, 72 (19.3%) patients transferred to hemodialysis, and 40 (10.7%) patients received kidney transplant. Kaplan-Meier survival curves revealed that overall survival rates of PD patients at 1, 3, 5, 7, and 10 years were 92.2%, 76.6%, 66.0%, 52.4% and 38.6%, respectively. Technique survival rates were 93.5%, 84.8%, 74.2%, 62.8% and 44.5% at 1, 3, 5, 7, and 10 years, respectively. Multivariate Cox regression model results showed that age ( HR=1.055, 95% CI 1.039-1.073, P<0.001), transfer from hemodialysis ( HR=2.212, 95% CI 1.514-3.231, P<0.001), episodes of peritonitis ( HR=2.141, 95% CI 1.194-3.837, P=0.011), Charlson comorbidity index ( HR=1.525, 95% CI 1.305-1.783, P<0.001), and baseline albumin ( HR=0.951, 95% CI 0.925-0.978, P<0.001) were independent influencing factors of survival in PD patients. Episodes of peritonitis ( HR=2.327, 95% CI 1.274-4.250, P=0.006) and Charlson comorbidity index ( HR=1.244, 95% CI 1.035-1.496, P=0.020) were independent influencing factors of technique survival in PD patients. PD patients have good early survival rates and technical survival rates, but long-term outcomes need to be further improved. Peritonitis is a major risk factor for low long-term survival rates and technical survival rates in PD patients.

ObjectiveTo explore the therapeutic effect and mechanism of Yiqi Huoxue Tongbian prescription on slow transit constipation （STC） in rats. MethodThe rat model of STC was established by gavage of loperamide hydrochloride. Rats were assigned into control， model， mosapride， low-， medium-， and high-dose （3.51， 7.02， and 14.04 g·kg^-1， respectively） Yiqi Huoxue Tongbian prescription groups. The changes of general signs， fecal moisture content， and intestinal propulsion rate were measured after model establishment and drug administration. The colonic mucosal changes were observed by hematoxylin eosin staining. Enzyme-linked immunosorbent assay was employed to determine the content of substance P （SP） and vasoactive intestinal peptide （VIP） in the colon of rats in each group. The gray values of aquaporin （AQP） 3， AQP4， AQP8， and c-Kit in rat colon tissue were measured by immunohistochemistry and Western blot， and the changes of intestinal flora were detected by 16S rRNA high-throughput sequencing. ResultCompared with the model group， 10 days of treatment with Yiqi Huoxue Tongbian prescription increased the fecal moisture content and intestinal propulsion rate （P<0.01）. The medium- and high-dose Yiqi Huoxue Tongbian prescription groups and the mosapride group showed no obvious mucosal inflammation and neat arrangement of goblet cells with a large number in the colon tissue. Moreover， the three groups showed increased SP content （P<0.01） and decreased VIP content （P<0.01） in the serum. The medium- and high-dose Yiqi Huoxue Tongbian prescription groups showed down-regulated protein levels of AQP3， AQP4， and AQP8 （P<0.01） and up-regulated protein level of c-Kit （P<0.01）. The drug administration groups presented slightly increased observed species， Chao1， ACE， and Shannon， Simpson， and PD whole tree. The principal component analysis showed that the control group had a short distance with the high- and medium-dose Yiqi Huoxue Tongbian prescription groups， indicating that high- and medium-dose Yiqi Huoxue Tongbian prescription can recover the intestinal flora to that in the control group. ConclusionYiqi Huoxue Tongbian prescription can alleviate the defecation status of rats with slow transit constipation by down-regulating the expression of AQP3， AQP4， and AQP8 to reduce the absorption of water in the intestine， up-regulating the expression of c-Kit to increase the number and distribution of Cajal interstitial cells， and regulating the balance of flora in the colon tissue.

Anoctamin 1 (ANO1) is a kind of calcium-activated chloride channel involved in nerve depolarization. ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration. In this study, several thiophenecarboxylic acid and benzoic acid derivatives were identified as novel ANO1 inhibitors through the shape-based virtual screening, among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed, synthesized and compound

Objective To investigate the relationship between the expression of Wnt induced secreted protein-1 (WISP-1) and the fibrosis of renal biopsy tissue in IgA nephropathy (IgAN) patients.Methods Fifty-three patients firstly diagnosed as IgA nephropathy by renal biopsy were included and classified according to Oxford and Lee's classification.Sixteen patients with MCD entered the fibrosis negative control group,and fourteen healthy adults entered the normal control group.The expression of WISP-1 in renal tissues and serum of all subjects were detected by immunohistochemistry and ELISA respectively.Results Immunohistochemistry results showed that WISP-1 was not expressed in MCD patients and normal human kidney tissues,which was abundantly deposited in renal tissue of patients with focal proliferative IgAN with renal interstitial fibrosis.The serum level of WISP-1 in IgAN patients was significantly higher than that in normal subjects (P=0.015) and MCD patients (P=0.030).In the subgroup analysis of IgAN renal fibrosis,the serum concentration of WISP-1 of fibrosis grade between 0-10％ (F1 group) and fibrosis ＞ 25％ (F3 group) were significantly higher than that in the normal group and the MCD group (all P ＜ 0.05).There was no significant difference between F2 group (10％ ＜ fibrosis≤25％) and normal group or MCD group (P ＞ 0.05).Conclusions The expression of WISP-1 in serum and renal tissue of renal interstitial fibrosis IgAN patients is higher than that of normal and MCD patients without renal fibrosis,and the IgAN patients' serum level of WISP-1 is significantly increased in fibrosis lower score group.The expressions of WISP-1 in serum and renal tissue are related to the occurrence of IgAN renal interstitial fibrosis,in which WISP-1 may play an important role as an early precursor factor in the pathogenesis of IgAN renal interstitial fibrosis.

Objective To observe the effect of recombinant adenovirus-mediated the fms-like tyrosine kinast-1 (FLT-1) gene promoter carrying protein C (PC) gene (Ad-FLT-1/PC) on apoptosis and oxidative stress in rat with diabetic nephropathy atherosclerosis. Methods High sugar, high fat diet and streptozotocin by intraperitoneal injection were used to establish diabetic nephropathy atherosclerosis rat model. The rats were randomly divided into Ad-FLT-1/PC group (n=23), Ad-GFP group (n=23) and normal saline group (n=22) and injected with 300 ul Ad-FLT-1/PC, Ad-GFP and normal saline by caudal vein. Another healthy rats (n=23) were control group. At day 1, 3, 7 and 14 after transfection, rats of each group were randomly executed to observe vascular apoptosis and assay the level of SOD and MDA in plasma by the kit method of WST and TBA. Results Vascular cell apoptosis was observed in Ad-FLT-1/PC group, Ad-GFP group and NS group, the apoptosis index showed no statistical difference between three groups at each time point (P>0.05). At day 14 after transfection, Ad-FLT-1/PC group rats had higher concentration of the plasma SOD and lower MDA than Ad - GFP group and NS group. The difference were statistically significant (all P<0.05). Conclusions The recombinant adenovirus Ad-FLT-1/PC can effectively regulate oxidative stress but not apoptosis.

BACKGROUND:Bony and structural feature often cause pulout strength decrease of pedicle screw, which induces loosening and pulout, and finaly results in fixation failure. Thus, it is very important to elevate the stability of pedicle screw.
OBJECTIVE:To detect the biomechanical stability of bone cement injectable canulated pedicle screw, and to provide reference for bone cement dosage.
METHODS: We selected T11-L4 samples of seven fresh adult corpses, containing 40 vertebral bodies. They were randomly divided into bone cement injectable canulated pedicle screw group and DTPSTM pedicle screw group (n=20). After screw implantation, 1, 2, 3 and 5 mL bone cement was injected. The diffuse distribution of bone cement was observed by imaging. The maximum axial pulout strength was measured.
RESULTS AND CONCLUSION:When the dose of bone cement was 1-3 mL, the average maximum axial pulout strength was significantly greater in the bone cement injectable canulated pedicle screw group than in the DTPSTM pedicle screw group (P < 0.05). When the bone cement dosage was 5 mL, no significant difference in the maximum axial pulout strength was detected between the two groups (P > 0.05). The regression equation was Y=25.269X+133.681 (R2=0.837) in the bone cement injectable canulated pedicle screw, and Y=32.039X+99.251 (R2=0.936) in the DTPSTM pedicle screw group. When the dosage of bone cement was 1-5 mL, the maximum axial pulout strength was highly positively correlated with bone cement dosage (|R| > 0.8). These results suggested that bone cement augmentation pedicle screw could apparently elevate the stability of the screw. The maximum axial pulout strength of the pedicle screw was positively correlated with bone cement dosage. After reaching the satisfactory fixation effects, the bone cement injectable canulated pedicle screw can reduce bone cement dosage, diminish the risk of bone cement leakage, and have more advantages than DTPSTM pedicle screw.

Objective To analyze the relationship between the level of 25 (OH )D and mortality in maintenance hemodialysis (M HD) patients .Methods This study was a prospective cohort study .We enrolled 156 M HD patients of Sichuan people′s hospital dialysis center in July of 2010 .The patients were divided into three groups according to the level of 25(OH)D .The three groups were normal(25(OH)D>30 ng/mL) ,insufficient(15 ng/mL<25(OH)D≤30 ng/mL) and deficient(25(OH)D≤15 ng/mL) re‐spectively .All the patients were follow‐up 40 months ;the end point was all‐cause and cardiovascular death .Results After follow‐up 40 months ,there were 26 deaths (16 .7% ) and 13 cardiovascular deaths among the 156 cases .There were 15 deaths (30 .6% ) in in‐sufficient group ,among which there were nine cardiovascular deaths ;there were eight deaths (11 .6% ) in deficient group ,among which there were three cardiovascular deaths ;there were three deaths (7 .9% ) in normal group ,among which there was one cardio‐vascular death .There was statistically significance either between all‐cause and cardiovascular mortality of deficient and normal group or between deficient and insufficient group (P<0 .05) .The Kaplan‐Meier curve analysis showed 25(OH)D≤15 ng/mL was the independent risk factor of the all‐cause and cardiovascular mortality(P<0 .05) .Cox regression showed 25(OH)D≤15 ng/mL was the independent risk factor of the all‐cause mortality in crude analysis (RR=4 .43 ,95% CI:1 .28-15 .32 ,P<0 .05) and adjus‐ted analysis (RR=4 .92 ,95% CI 1 .23-19 .66 ,P<0 .05) .Cox regression showed 25(OH)D≤15 ng/mL was the risk factor of the cardiovascular mortality in crude analysis(RR=8 .12 ,95% CI:1 .04 -64 .15 ,P=0 .047) .Conclusion 25(OH)D≤15 ng/mL was the risk factor and predictor of the all‐cause and cardiovascular mortality in M HD patients .

Objective To evaluate the performance of different GFR equations in estimating renal function of people undertake health examination.Methods A total of 8 476 occupational physical examination population were selected.Serum creatinine,urea nitrogen,serum cystatin and urine routine of all cases were collected to be used to calculate eGFR through different GFR equations of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)equation.,the equation based on cystatin C(Cys-EPI),the combined creatinine-cystatin C equation(CC-EPI),simplified MDRD equtation (a-MDRD),modified eGFR equation for Chinese pa-tients (c-MDRD).Results There was a significant correlation among physical examination population using different GFR equa-tions calculated results(P <0.01).But comparisons the means of eGFR calculated by different equations are statistical significant (P <0.01).Comparing with CKD-EPI,the eGFR calculated by c-MDRD is higher(P =8.7×10-263 ).The ratios of population,eG-FR<60 mL·min-1 ·1.73(m2 )-1 by different equations,have significant difference (P <0.01).And the ratio difference is more concentrated in the range Of 45-59 mL·min-1 ·1.73(m2 )-1 .Devide the populations into two groups,which are chronic kidney disease (CKD)and Non-CKD according to the standard of eGFR and Urine protein by CKD-EPI.Among CKD,the eGFR calculated by Cys-EPI,CC-EPI,c-MDRD are higher;but among non-CKD group,eGFR calculated by Cys-EPI,a-MDR are lower,the eGFR of c-MDRD is significantly higher,while the result of CC-EPI is most close to the CKD-EPI.Conclusion There were significant corre-lations between the different equations to calculate GFR among physical examination population.

To explore novel non-opioid analgesic agents, 16 compounds were synthesized and their structures were confirmed by 1H NMR and HR-MS. YX0611-1 was treated as the leading compound. The results of mice writhing model and hot plate model showed that compounds 2, 7, 8, 9, 11 and 15 had obvious analgesic activities in vivo. The test of affinity to mu, delta, kappa receptor displayed that active compounds didn't act on opioid receptor. The results of preliminary toxicity and pharmacokinetic tests showed that compound 7 had better safety and pharmacokinetic properties than that of YX0611-1, and it deserved further development.