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.

Objective To assess the value of SPECT/CT lung perfusion imaging (SPECT/CT-LPI) in evaluation of the regional lung function and the correlation between lung perfusion defects (LPD) and the clinical findings in NSCLC patients.Methods A total of 48 NSCLC patients (43 males,5 females;average age 61.06 years) who underwent pulmonary function tests (PFT),CT and 99Tcm-MAA SPECT/CT-LPI from December 2006 to March 2013,were retrospectively studied.LPD were divided into four grades:grade 0 (no lung perfusion defect was identified),grade 1 (the area of lung perfusion defect (LPDA) was similar to the size of local tumor),grade 2 (the LPDA was larger than local tumor and extends to 1 pulmonary lobe),grade 3 (the LPDA exceeded 1 pulmonary lobe).x2 test,one-way analysis of variance and Logistic regression analysis were used to analyze the correlation of the lung perfusion function and clinical findings.Results LPD were found in 44 patients (91.67％,44/48),including 18 with grade 1,15 with grade 2,11 with grade 3.The abnormal results of PFT were found in 16 patients (33.33％,16/ 48).The abnormal findings by SPECT/CT-LPI were more than that by PFT (x2=34.844,P＜0.01).The rates of LPD with grade ≥ 2 were significant different between patients with central lung cancer and those with peripheral lung cancer (x2 =8.392,P＜0.01),and between hilar lymph nodes positive group and negative group (x2=10.801,P＜0.01).The degree of LPD was related to tumor location (1 was assigned for central lung cancer,2 was assigned for peripheral lung cancer),tumor size (1 was assigned for maximum diameter ≤3.0 cm,2 was assigned for ＞3.0 cm and ≤5.0 cm,3 was assigned for ＞5.0 cm) and hilar lymph node (1 was assigned for with metastasis,0 was assigned for no metastasis) (Wald=8.176,5.352,10.100,all P＜0.05).Conclusions Compared with PFT,SPECT/CT-LPI has a more significant value in assessment of the regional lung function in NSCLC patients.Tumor location,tumor size and metastasis of hilar lymph nodes may be helpful for LPD grading.SPECT-LPI may be beneficial for patients with central lung cancer,large tumor and hilar lymph nodes metastasis.

Purpose To investigate the expression of Par3, Par6 and aPKC in gastric carcinoma and their significance. Method Ex-pression of Par3, Par6 and aPKC, by using immunohistochemistry, was detected in different sites of gastric carcinoma ( including the gastric carcinoma in gastric mucosa, the central area and the invasive front of gastric carcinoma) and the lymph node metastasis, using normal gastric mucosa as controls. Results Expression of Par3, Par6 and aPKC in different sites of gastric carcinoma was lower than in that of normal gastric mucosa (P<0. 01). Expression of Par3, Par6 and aPKC was obviously lower in gastric carcinoma with gastric phenotype than in that with intestinal phenotype and mixed phenotype of gastric carcinoma (P<0. 05, P<0. 01, P<0. 01);the rate of down-regulation of Par6 and aPKC in gastric carcinoma with invasion to ectoptygma and out of ectoptygma was obviously higher than that in gastric carcinoma which located at mucosa and under mucosa (P both<0. 01), and the rate of down-regulation of Par6 in gas-tric carcinoma with lymph node metastasis was obviously lower than that with no lymph node metastasis ( P>0. 05 ) . Conclusions The down-regulation expression of Par3, Par6 and aPKC may promote the carcinogenesis and progression of gastric carcinoma.

Objective To compare 18 F-FDG PET/CT and electronic endoscopy for measuring the length of esophageal squamous cell carcinoma (ESCC) and to evaluate the optimal SUV threshold for contour determination of the size of the lesion.Methods Twenty-four patients (19 males and 5 females,median age:59 years) with histologically confirmed ESCC were enrolled.Three patients had stage Ⅱ,14 had stage Ⅲ and 7 had stage Ⅳ diseases.PET studies were performed before treatment.The length of ESCC was measured on FDG PET imaging using different SUV thresholds of 2.0 (L2.0),2.5 (L2.5),3.0 (L3.0),3.5 (L3.5),and 35％(L35),40％(L40),45％(L45),50％(L50),55％(L55) of SUVmax.The length of ESCC on PET imaging was compared with the length of gross tumor in vivo measured by electronic endoscopy (Lst) to determine the optimal threshold of SUV using paired t test.Pearson correlation analysis was used to assess the correlation.Results The SUVmax of primary tumor was 14.51±5.72 and the Lst was (5.27± 2.45) cm.The length was in a descending order of L2.0,L2.5,Lst,L3.0,L3.5,L35,L40,L45,L50 and L55 when using different criteria.There were significant differences between the Lst and the lengths measured on PET except those by L2.5 and L3.0((5.65±2.69) cm,(5.11±2.51) cm; t=-1.74 and 0.76,both P＞0.05).The lengths measured on PET by all criteria were significandy correlated with the Lst,respectively,with the better r values by L3.5(0.935),L2.5(0.920) and L3.0(0.919) (all P＜0.01).When SUVm~＜15,there were no significant differences between the Lst ((4.82±2.14) cm) and L2.5((4.95±2.76) cm),L3.0((4.45±2.50) cm) and L35((4.42±1.85) cm),respectively (t=-0.439,1.299,2.011,all P＞0.05).The best correlation (r=0.953,P＜0.05) was between Lst and Lz5.When SUVmax ≥ 15,there was no significant difference between Lst ((5.67±2.64) cm) and L3.0((6.11±2.61) cm; t=-0.897,P＞0.05; r=0.791,P＜ 0.05).Conclusions For better correlation of ESCC lesion size,it is suggested that the optimal threshold of SUV for contouring is 2.5 for tumor SUVmax＜15,and 3.0 for tumor SUVmax ≥ 15.A larger sampling size is needed for further confirmation or modification.

Objective To evaluate the treatment efficacy and treatment-related toxicity of late course accelerated hyperfractionated radiotherapy (LCAHRT) combined with cisplatin-based chemotherapy (CHT) for locally advanced esophageal squamous cell carcinoma (ESCC).Methods A total of 46 patients with histologically confirmed ESCC,11 in the stage Ⅱa,3 in the stage Ⅱb,and 32 in the stage Ⅲ,underwent conventional fractioned radiation of 40 Gy in 20 fractions on the primary and metastatic lymph nodes,and high-risk lymph node drainage regions,and then the primary and metastatic lymph nodes were irradiated as boost with an additional dose of 19.6 Gy in 14 fractions (1.4 Gy twice a day),and the total prescribed dose was 59.6 Gy in 34 fractions.Two cycles of CHT were administered concurrently during the radiotherapy.The 1-,3-,and 5-year overall survival (OS) rates and local control rates (LCRs) were evaluated by Kaplan-Meier method,and treatment-related toxicity was analyzed based on the RTOG and CTCAE criteria 3.0.Results All patients received the whole course of treatment.The median followup time was 34.4 months (6-67 months).The overall response rate was 91.3％ (42/46).The median OS was 38.5 months (95％ CI 29.6-47.4 months).The 1-,3-,and 5-year OS rates and LCRs were 78.6％,49.4％,and 39.9％,and 84.3％,68.2％,and 61.4％ respectively.The incidence of ≥ G3 radiationinduced esophagitis was 23.9％.Three kinds of serious (≥G3) hematologic toxicities were recorded,including leucopenia (26.1％),thrombocytopenia (13.0％),and anemia (10.9％).Esophagotracheal fistula was recorded in 2 patients (4.3％).Conclusion LCAHRT plus CTH can be favorable for the patients with locally advanced ESCC,however,the treatment-related toxicities may be serious.

Objective To assess the efficacy and the adverse effects of improved late course accelerated hyperfractionated radiotherapy (LCAHRT) combined with cisplatin-based chemotherapy for locally advanced esophageal squamous cell carcinoma (ESCC).Methods 68 Patients with pathologically confirmed ESCC were enrolled.Conventional fractionation was implemented to 40 Gy/20 fractions,followed by LCAHRT delivered 2 fractions of 1.4 Gy with an interval of 6-8 hours per day to 14 fractions,thus the total dose was 59.6 Gy.Two cycles of cisplatin-based chemotherapy were administered concurrently,followed by two more cycles.The short-term efficacy of treatment,overall survival for 1-,3-,5-year,and treatment-related toxicity were evaluated.Results All patients successfully completed LCAHRT and the overall response rate was 91.6％ (62/68).The overall survival rate of 1-,3-,and 5-year was 75.5％,46.5％,22.7％,respectively.The incidence of radiation esophagitis (grade 3 or greater) was 26.4％,and no patients developed grade 3 or worse radiation pneumonitis.The radiation-induced skin injury were most of grade 0 or 1.Grade 3 of leucopenia and neutropenia were observed in 29.4％ and 7.4％ of patients,respectively,and grade 4 were both in 2.9％.During long-term follow-up,no esophageal stenosis and severe pulmonary fibrosis was developed except for two cases(2.9％)of esophageal mediastinal fistula.Conclusion Late course accelerated hyperfractionated radiotherapy combined with chemotherapy yields promising long-term survival,with lower treatment-related toxicity for patients of locally advanced esophageal squamous cell carcinoma.

Objective To explore the utilization and effectiveness of ultrasound screening for neural tube defects (NTDs),so that to provide scientific evidences for the secondary prevention of NTDs.MethodsFour hundred and fifty-nine women who delivered or gestated NTDs babies or fetuses were randomly selected from Shandong Province and Shanxi Province,and the related information was collected with structured questionnaire by trained interviewers.Results Of the 459 cases,the ultrasonography utilization rate was 98.7%,and 6 cases (1.3%) never took examinations by ultrasonography during the whole pregnancy period.The total diagnosis rate of ultrasound screening for NTDs was 85.9%,and those of anencephalus,spina bifida and encephalocele were 96.4%,79.6% and 73.8% respectively (P<0.05).The average diagnosis week of NTDs was 24.0 and those of anencephalus,spina bifida and encephalocele were 21.2,27.1 and 24.7 respectively (P<0.05).The detection rates of NTDs before 16 weeks,16-20 weeks,20-24 weeks,24-28 weeks and after 28 weeks were 14.1%,49.4%,46.3%,49.2% and 52.1% respectively (P<0.05).The detection rates of NTDs in hospitals,maternal and child care service centers and family planning centers were 46.4%,52.0% and 28.1% respectively (P<0.05).The detection rate of NTDs by two-dimensional ultrasound equipment was 41.3% and 83.3% by three-dimensional ultrasound equipment (P>0.05).Conclusions The detection rates of NTDs and the subtypes by ultrasonography are low at different pregnant periods and in different medical institutions.It is important to increase the utilization rate of ultrasound screening by pregnant women and improve the NTDs diagnostic level of primary health care institutions,so that to improve the efficacy of secondary prevention strategy for NTDs in China.

Objective To respectively analyze the results and complications of hip arthroplasty for failed intertrochanteric hip fractures treating with internal fixation.Methods From July 2004 to June 2006,32 patients(24 males and 8 females)were treated with hip arthroplasty after the failed internal fixation of intertrochanteric fractures.The mean age was 71 years(range,57-81 years)at the time of the hip arthroplasty.The average interval from fracture to arthroplasty was 40 months(range,5-70 months).Fifteen patients had been treated with sliding hip screw,10 with intramedullary nail,5 with plate and screws,2 with multiple screws.The failure modes were nonunion in 8 patients,implant cut out from the femoral head in 9,avascular necrosis of the femoral head in 7,and traumatic arthritis in 8 patients.Cemented stems were used in 12 hips,and uncemented stems in 20 hips.Standard prostheses were used in 25,long-stem prostheses in 7.Results Twenty-eight patients were followed up for a minimum of 4 years after the hip arthroplasty,with the mean period of 5 years(range,4-6 yeas).For these 28 patients,the average preoperative Harris Hip Score was 37(range,32-45),and 88(range,84-95)at the latest follow-up.The average acetabular inclination was 44°(range,42°-48°).No loosing was found in cotyloid components.Nine of 10 cemented femoral components had cementation rated as grade C,and 1 as grade A.Three had heterotopic bone six months postoperatively,and 2 were Brooker type Ⅱ,one was type Ⅲ.Conclusion Hip arthroplasty is an effective salvage procedure after the failed treatment of an intertrochanteric fracture in an older patient.

Objective To analyze the clinical and dosimetric risk factors for acute radiation esophagitis (ARE) in non-small cell lung cancer (NSCLC) patients treated with three-dimensional conformal radiotherapy (3D-CRT),and to find significant risk factors for clinical therapy.Methods A total of 102 NSCLC patients treated with 3D-CRT were retrospectively analyzed.ARE was scored according to the Radiation Therapy Oncology Group (RTOG) criteria with grade 2 or worse.Patients were divided into non-concurrent chemoradiotherapy group and concurrent chemoradiotherapy group.The clinical and dosimetric factors associated with grade 2 or worse ARE were analyzed using univariate logistic regression,multivariate logistic analysis and receiver operating characteristic ( ROC ) curve.Results There were no grade 4 or5 ARE observed in the 102 patients.Nineteen developed grade 2,15 developed grade 3.In nonconcurrent chemoradiotherapy group,multivariate analysis showed that V55 was the only risk factor of grade 2/3 ARE.For ROC curve analysis,the cut-off point of V55 was 16.0 while the area under ROC curve was 0.870 ( 95 ％ CI:0.782 - 0.957,P ＜ 0.05 ).In concurrent chemoradiotherapy group,multivariate analysis showed that V35 and chemotherapy regimens during radiotherapy were risk factors of grade 2/3 ARE.The cut-off point of V35 was 23.75 while the area under ROC curve was 0.782 (95％ CI:0.636 -0.927,P ＜0.05).Vinorelbine and cisplatin regimen showed low incidence of ARE contrast with gemcitabine/docetaxel and cisplatin regimens (33.3％ and 66.7％ ).Conclusions V55 is the only statistically significant risk factor associated with grade 2 or worse ARE for patients who don't accepted concurrent chemotherapy.V35 and chemotherapy regimens during radiotherapy are statistically significant risk factors associated with grade 2 or worse ARE for patients who accept concurrent chemotherapy.Vinorelbine and cisplatin regimen during radiotherapy shows low incidence of ARE.

Objective To explore the relationship between the typing of lower eyelid bag and surgical procedures and their clinical efficacy. Methods The eyelid bag was divided into three types and seven subtypes according to the clinical manifestation in 216 cases. Congenital structural abnoma-lities caused type Ⅰ of lower eyelid bag, long-term ophthalmokopia caused type Ⅱ of lower eyelid bag. Anaplasia of tissue and bone caused type Ⅲ of lower eyelid bag. Seven surgical methods were per-formed for lower eyelid blepharoplasty by various type. Results 159 of 216 cases were followed-up for 3 - 12 months, and most of the patients had excellent clinical results. Conclusion This simple typing is valuable for adopting surgical methods.