Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

ABSTRACT:OBJECTIVE To observe the clinical effect and safety of treatment of Gushibao pill on severe kidney circulation deficiency and blood stasis type knee osteoarthritis.METHODS 70 patients with severe knee osteoarthritis were selected for this study,and were divided into the treatment group(38 cases)and the control group(32 cases).Patients of two groups were given health education and basic knee stick therapy treatment.On the basis of basic treatment,patients in the control group were given glucosamine hydrochloride capsules orally and treatment group were give Gubaoshi pill.WOMAC Osteoarthritis In-dex Scale and ISOA knee osteoarthritis severity index scale were used to evaluate the outcomes of two groups.Chinese medi-cine symptom score were used to evaluate the clinical symptoms.ESR,calcitonin(CT)and bone alkaline phosphatase(BALP) were detected before and after treatment.RESULTS Erythrocyte sedimentation rate in the control group significantly de-creased after a course of treatment(P <0.05),and bone alkaline phosphatase and calcitonin showed no significant change(P >0.05).Erythrocyte sedimentation rate decreased significantly in treatment group after treatment(P <0.05),and bone alkaline phosphatase and calcitonin showed no significant change(P >0.05).Scored of symptoms and signs significantly decreased in two groups,and the decreased extent of treatment group was significantly greater than that of the control group(P <0.05). Pain score,WOMAC score and ISOA scores were significantly lower in two groups of patients compared with the condition be-fore treatment(P <0.05).After treatment,pain score,WOMAC score and ISOA scores of treatment group were lower than those of the control group(P <0.05).The total effective rate of treatment group was 97.37%,and was significantly higher than the control group(80.00%).The difference was statistically significant(P <0.05).Two patients had no obvious adverse reactions during treatment.CONCLUSION Gushibao pill can decrease the level of erythrocyte sedimentation rate in patients with severe kidney circulation deficiency and blood stasis knee osteoarthritis.It is effective and safe.

BACKGROUNDThe role of gastro-protecting agents on symptomatic chronic gastritis is unclear. This multicenter, open, randomized trial was designed to compare the comprehensive effects of gefarnate with sucralfate on erosive gastritis with dyspeptic symptoms.

METHODSTotally 253 dyspepsia patients confirmed with erosive gastritis were enrolled from six centers in China. They randomly received either daily 300 mg gefarnate or 3 g sucralfate for six weeks. The primary endpoint was the effective rate of both treatments on endoscopic erosion at week six.

RESULTSGefarnate showed an effective rate of 72% and 67% on endoscopic score and dyspeptic symptom release, which is statistically higher than sucralfate (40.1% and 39.3%, P < 0.001, intension-to-treat). For histological improvement, gefarnate showed both effective in decreasing mucosal chronic inflammation (57.7% vs. 24.8%, P < 0.001, intension-to-treat) and active inflammation (36.4% vs. 23.1%, P < 0.05, intension-to-treat) than the control. A significant increase of prostaglandins and decrease of myeloperoxidase in mucosa were observed in gefarnate group. Severity of erosion is non-relevant to symptoms but Helicobacter pylori (H. pylori) status does affect the outcome of therapy.

CONCLUSIONSGefarnate demonstrates an effective outcome on the mucosal inflammation in patients with chronic erosive gastritis. Endoscopic and inflammation score should be the major indexes used in gastritis-related trials.

Adolescent ; Adult ; Aged ; Anti-Ulcer Agents ; therapeutic use ; Dyspepsia ; drug therapy ; Female ; Gastritis ; drug therapy ; Gefarnate ; therapeutic use ; Humans ; Male ; Middle Aged ; Sucralfate ; therapeutic use ; Treatment Outcome ; Young Adult

Adolescent ; Adult ; Aged ; Child ; Child, Preschool ; China ; epidemiology ; Cross-Sectional Studies ; Hepatitis B ; epidemiology ; Humans ; Incidence ; Infant ; Infant, Newborn ; Middle Aged ; Young Adult

The purpose of this study was to explore the expression characteristics of SDF-1 receptor, CXCR4, in mesenchymal stem cells (MSC) of different passages derived from human umbilical cord (hucMSC). The hucMSC were isolated from Wharton's jelly tissue of human umbilical cord by tissue culture. The expressions of specific marker in hucMSC were detected by flow cytometry. The adipogenic and osteogenic induction of hucMSC were detected by alizarin bordeaux and Oil red O staining. The expressions of CXCR4 protein in hucMSC of 2nd-5th passages were detected by flow cytometry, and cxcr4 mRNA levels in hucMSC of 2nd-5th passages were evaluated by real-time quantitative PCR. The results showed that the expression of CD44, CD13, CD71 were positive while CD38, CD117, HLA-DR were negative. After induced by osteogenic and adipogenic inductors, the lipid droplets and calcium nodals appeared in hucMSC, hucMSC stained with oil red O and alizarin red were shown to be positive. The cxcr4 was found in hucMSC of 2nd-5th passages, and their expressions were (89.82 ± 0.62)%, (86.87 ± 1.32)%, (80.50 ± 4.46)%, (70.10 ± 0.68)% respectively. The cxcr4 mRNA was found in hucMSC of 2nd-5th passages, and expression of cxcr4 of 3rd-5th passages were 0.5585 ± 00875, 0.6205 ± 0.1377, 0.4634 ± 0.0447 times of expression of 2nd passage respectively. It is concluded that the cxcr4 mRNA expresses in hucMSC of 2nd-5th passages, and declines when the number of passages increases. Compared with 2nd passage, cxcr4 mRNA levels in hucMSC of 3rd-5th passages decline, but the expression level of cxcr4 mRNA between hucMSC of 3rd-5th passages is stable.
Cell Differentiation ; Cells, Cultured ; Flow Cytometry ; Humans ; Mesenchymal Stromal Cells ; cytology ; metabolism ; Receptors, CXCR4 ; metabolism ; Umbilical Cord ; cytology ; metabolism

OBJECTIVE: To summarize the clinical application of bioprosthetic valve replacement. METHODS: Fifty two patients, aged 13-73(52.4+/-14.0) years, underwent cardiac valve replacement with biovalves from June 2002 to June 2006 in our hospital. Fifty three tissue valve replacements combined with 8 mechanical valve replacements were performed. Other procedures were also carried out if appropriate, including bidirectional Glenn shunt in 1 patient with double outlet of right ventricle and pulmonary artery stenosis; interruption of accessory pathway in 1 patient with Wolff-Parkinson-White syndrome; coronary artery bypass graft in 5 with severe coronary artery disease; and atrial or ventricular repair in 4 with congenital septum defects. RESULTS: One patient died in hospital due to multiple organ failure. The hospital mortality rate was 1.9%. The mean follow-up was 25 months. Two patients lost follow-up and the follow-up rate was 96%. Forty one patients returned to NYHA class I, 9 to class II, and 1 to class III. Echocardiography showed the implanted bioprosthesis functioned well without stenosis or regurgitation. There was no structural deterioration with freedom from thromboembolism and anticoagulant hemorrhage in all patients. CONCLUSION The efficacy of biovalves in heart valve replacement is satisfactory.
Adolescent ; Adult ; Aged ; Bioprosthesis ; Female ; Follow-Up Studies ; Heart Valve Prosthesis ; Heart Valve Prosthesis Implantation ; methods ; Humans ; Male ; Middle Aged ; Mitral Valve ; surgery ; Retrospective Studies ; Tricuspid Valve ; surgery

OBJECTIVE: To evaluate the therapeutic effect of remaining integrated mediastinal pleura upon the aortic arch and performing the anastomosis at the left cervix in radical operation for esophageal carcinoma. METHODS: Ninety-eight patients with esophageal carcinoma were treated with the operation mentioned above. Among them, 56 patients had cancer in the middle, 12 in the upper-middle, 24 in the lower-middle segments, and 6 had double-primary tumors, with carcinoma length of (5.2+/- 2.4) cm. The TNM stages were 6 of Stage I and 92 of Stages II-III. All cases were squamous cell carcinomas. RESULTS: All patients had satisfactory operation processes, without perioperative death, chylothorax, dyspnea, gastric retention, incision infection, and severe gastro-esophageal reflux. The life quality of the patients was improved. CONCLUSION The radical operation with remaining integrated mediastimal pleura upon the aortic arch and anastomosis at the cervix for treating esophageal carcinomas is of minimal invasion with fewer complications, and may be used in clinical practice.
Aged ; Anastomosis, Surgical ; methods ; Aorta, Thoracic ; surgery ; Carcinoma, Squamous Cell ; surgery ; Esophageal Neoplasms ; surgery ; Female ; Humans ; Male ; Middle Aged ; Pleura ; surgery ; Thoracic Surgical Procedures ; methods

Down Syndrome ; complications ; Humans ; Infant, Newborn ; Male ; Pleural Effusion ; complications ; congenital

OBJECTIVETo study the etiology and preventive measures of the long-term postoperative complication after esophageal replacement with colon for esophageal benign disease.

METHODSTo review the clinical data of 577 patients with esophageal replacement with colon our department, including 123 cases of esophageal benign disease. Of all, there were 25 cases-time for 11 cases following with severe complication: redundancy and dilated colon 12 cases-time, severe stricture of stoma 4, macrocyst esophagus 2, colon-stomach stoma expansion 4, mechanical obstruction of colon 3. The etiology included iatrogenic and functionality. The therapy included stricture form or resection, redundancy segment resection, obstructed segment solution and stoma resection and form.

RESULTSEight cases underwent once operation, 2 case twice, 1 case three times. After operation, 9 cases took food normally, 2 improved symptoms obviously.

CONCLUSIONSThe iatrogenic and functionality factor contributed to severe complication after esophageal replacement with colon for esophageal benign disease. The preventive measure is followed during operation: cervical esophageal-colon anastomosis exceed 2.5 centimeter, abdominal colon-stomach anastomosis reflux, channel width of colon passage, intestinal canal lay up straight. Re-operation is best choice to for local stricture, colon expansion, redundancy and dilated colon.

Adult ; Colon ; surgery ; Esophageal Diseases ; surgery ; Esophagoplasty ; adverse effects ; methods ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Postoperative Complications ; etiology ; prevention & control ; surgery ; Reoperation ; Retrospective Studies

OBJECTIVE: To observe the structural and hemodynamic changes after the reconstruction of right ventricular outflow tract (RVOT) with valved bovine jugular vein conduit (BJVC) in the canine model by color Doppler echocardiography (UCG). METHODS: BJVC was used in the reconstruction of RVOT of 32 canines. UCG was used to observe the structure of the right ventricle and RVOT. The structure and hemodynamics were observed, and the diameter, width, blood velocity and pressure gradient (PG) were measured between the right ventricle and the conduits. RESULTS: In the first stage, UCG showed that PG between the right ventricle and BJVC was high in 5 canines, and a few anastomosis in BJVCs with main pulmonary artery was small. Blood velocity quickened and PG increased, and color Doppler showed that the bloodstream was very bright. In the second stage, 7 canines survived for 1 year after the implantation. One year after the operation, UCG showed that the valve closed well, no graft kinking or obvious regurgitation of the valve was observed. The PG of the valve was low. The BJVCs were unobstructed and there was no thrombus.All the valves of BJVC opened well except one. In the third stage, 20 canines survived for 1 year after the implantation. UCG showed that the valve motion was good, no graft kinking or obvious regurgitation of the valve was observed. No neoplasm was observed. CONCLUSION UCG is one of the most useful measurements in the structural and hemodynamic study of RVOT reconstruction by BJVC in the canine model. The good evaluation of UCG implies that it is important for the study and clinical practice.
Animals ; Blood Vessel Prosthesis ; Cattle ; Dogs ; Echocardiography, Doppler, Color ; Female ; Heart Ventricles ; diagnostic imaging ; surgery ; Hemodynamics ; Jugular Veins ; diagnostic imaging ; transplantation ; Male ; Pulmonary Artery ; diagnostic imaging ; surgery