Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound 8e, a selective reversible BuChE inhibitor (eqBuChE IC₅₀ = 0.049 μmol/L, huBuChE IC₅₀ = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound 8e demonstrated favorable blood-brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, 8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, 8e significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor (VLDLR), offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway. Thus, compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD, with significant implications for further exploration into its mechanisms of action and therapeutic applications.

Objective:To establish an animal model of trans-sutural distraction osteogenesis in SD rats.Methods:A self-designed V-shaped distraction device(distractor)was fabricated with the traction force(N)of 0,1.3,2.2,3.0,4.3 and 5.0 corresponding to the distraction length(mm)of 5,4,3,2,1 and 0 respectively,meeting the trans-sutural distraction osteogenesis requirements in skull of 5-week-old SD rats.The distractor was plased into the sagittal suture of 12 SD rats.Continuous sampling was conducted 1,3,5 and 7 days respectively(n=3)after operation.The tissue changes in the trans-sutural distraction area were observed by HE and Masson's trichrome staining.Inflammation levels were determined using Arg-1 immunofluorescence staining.The early angiogenesis was clarified through co-staining with CD31 and EMCN.Results:A stable trans-sutural distraction osteogenesis model was estab-lished,5 mm distraction osteogenesis width was observed completely within 7 days of distraction.Significant new bone formation was observed at 7 days after operation.Arg-1 expression increased and was concentrated at the bone margins,overlapping with the areas of new bone formation.EMCN expression gradually decreased,and by day 7 CD31 was predominant,indicating the basic maturation of blood vessels.Conclusion:This study successfully constructed a stable and effective trans-sutural distraction osteogenesis animal model,and provides an experimental basis for the investigation of its early continuous histological changes.

Cardiomyopathy, Dilated/metabolism* ; Humans ; Microfilament Proteins/metabolism* ; Models, Cardiovascular ; Mutation ; Myocytes, Cardiac ; Pluripotent Stem Cells/metabolism* ; Transcription Factors/metabolism* ; Troponin T/metabolism*

Objective:To explore the effect of post-pyloric feeding by spiral nasoenteric tubes on the prognosis of critically ill patients with acute gastrointestinal injury (AGI) grade Ⅱ.Methods:A retrospective study was performed to analyze the clinical data of critically ill adult patients with AGI grade Ⅱ, who were enrolled in three randomized controlled trials conducted by Guangdong Provincial People's Hospital for post-pyloric tube placement between April 2012 and May 2019. Data including demographic characteristics, serological indicators of nutrition, the tube tip position confirmed by abdominal X-ray 24 h after tube insertion, and intensive care unit (ICU), 28-day and hospital mortality were collected. Patients were divided into the post-pyloric feeding group and gastric feeding group according to the tube tip position. Propensity score matching method was used to perform 1:1 matching, and the differences of each index between the two groups were compared after matching. Then the influencing factors of P<0.1 were included in multivariate logistic regression analysis to investigate the potential ICU mortality risk factors of critically ill patients with AGI gradeⅡ. Factors with 0.1 level of significance from the univariate analysis were considered in the multivariate analysis. Results:There were 90 patients in post-pyloric feeding group and 90 patients in the gastric feeding group. Demographics and clinical characteristics of study population were well balanced between the two groups after matching. ICU, 28-day and hospital mortality in the post-pyloric feeding group were significantly lower than those in the gastric feeding group (4.4% vs 15.6%, 14.4% vs 27.8%, 6.7% vs 17.8%, all P < 0.05). Multivariate logistic regression analysis indicated that post-pyloric feeding was an independent protective factor [odds ratio ( OR)=0.295, 95% confidence internal (95% CI): 0.091-0.959, P=0.042] and APACHEⅡ score was an independent risk factor ( OR=1.111, 95% CI: 1.025-1.203, P=0.010) for ICU mortality of critically ill patients with AGI gradeⅡ. Conclusions:Post-pyloric feeding for critically ill patients with AGI grade Ⅱ could decrease ICU mortality and is an independent protective factor against mortality.

OBJECTIVE: To optimize the method for embedding multiple undecalcified mouse tibias in plastic blocks, improve the efficiency and stability of plastic embedding and reduce the detachment rate of plastic slides. METHODS: Thirty undecalcified tibias from 15 B6 mice were used for plastic embedding after calcein labeling, fixation, dehydration and infiltration. The tibias were embedded in cylindrical plastic blocks with a diameter of 4 mm. For each bone, the 1/4 proximal tibia was cut off, and the remaining 3/4 was used for re-embedding. Five bones were embedded in a single block with each bone standing closely on the surface of a flat plate. The samples were randomized into control and experimental groups in all the processes of embedding, sectioning and staining. In the 3 groups with modified embedment, flowing CO was added into the embedding solution, embedding solution was applied to the section surface, and the slides were heated at 95 ℃ for 15 min. The polymerization time, slide detachment rate, bone formation and osteoblast parameters were analyzed. RESULTS: We prepared 6 plastic blocks, each containing 5 tibias, whose cross sections were on the same plane. The blocks were completely polymerized and suitable for sectioning. Flowing CO into the embedding solution reduced the polymerization time and increased the rate of complete polymerization. Application of the embedding solution on the section surface significantly reduced the detachment rate of the sections ( < 0.05) without affecting bone formation analysis ( > 0.05). Heating the slides significantly lowered the detachment rate of the sections ( < 0.05) without affecting osteoblast analysis ( > 0.05). CONCLUSIONS The optimized method allows effective embedding of multiple undecalcified mice tibias in the same block and can be an ideal method for histological analysis of undecalcified bones.
Animals ; Mice ; Plastics ; Staining and Labeling ; Tibia ; Tissue Embedding ; methods

Objective To explore the application value of iASSIST portable navigation in total knee arthroplasty.Methods Seventy-four patients with knee osteoarthritis from April 2016 to April 2017 were retrospectively recruited.Thirty-seven patients (37 knees) underwent TKA with iASSIST navigation,while 37 patients (37 knees) underwent conventional TKA.Five parameters were measured on the weight-bearing radiographs at six months after TKA,including mechanical axis (MA),mechanical lateral distal femoral angle (mLDFA),mechanical medial proximal tibial angle (mMPTA),sagittal femoral component angle (sFCA) and sagittal tibial component angle (sTCA).Duration of operation,blood loss volume,postoperative hospital day,Western Ontario and McMaster Universities (WOMAC) osteoarthritis index,Knee Society Score (KSS) clinical score and functional score at 6 weeks,12 weeks and 24 weeks after surgery were also recorded.Results The accuracy of MA (180.85°±0.88° versus 182.23°±1.09° in the conventional group,P＜0.05),mLDFA (90.52° ±0.78° versus 91.09° ±0.96° in the conventional group,P＜0.05),and mMPTA (90.34°± 1.25° versus 91.13°± 1.46° in the conventional group,P＜0.05) was improved significantly in navigation group.The WOMAC osteoarthritis index at 6 weeks postoperatively in the navigation group and in the conventional group were 58.54±1.45 and 56.54± 1.77 respectively.The KSS clinical score in the navigation group and in the conventional group were 53.14± 1.13 and 49.35± 1.11 respectively.The KSS functional score in two groups were 61.24± 1.30 and 59.81 ± 1.29 respectively (P＜0.05).The WOMAC osteoarthritis index at 12 weeks postoperatively in the navigation group and in the conventional group were 43.54± 1.19 and 41.92± 1.42 respectively.At 12 weeks,the KSS clinical score in two groups were 67.11 ± 1.51 and 62.08± 1.46 respectively.The KSS functional score in two groups were 68.14±1.11 and 66.38±1.26 respectively (P＜0.05).The blood loss volume in the navigation group and in the conventional group were 113.11±57.29 ml and 147.57±68.77 ml respectively (P＜0.05).There were no significant difference in the duration of operation,postoperative hospital day,WOMAC osteoarthritis index,knee clinical score and functional score at 24 weeks postoperatively between two groups (P＞0.05).Conclusion More accurate restoration in mechanical axis and optimal implantation can be achieved with the help of iASSIST navigation.This navigation system can also achieve better knee function in the early stage after TKA.

Objective To assess the effect of ascorbic acid/ferric chloride (AA/FeCl3) in attenuating cartilage damage in rats with osteoarthritis. Methods Thirty adult male Wistar rats with surgically induced osteoarthritis were randomized into 2 groups for treatment with intra-articular injection of saline (control group) or AA/FeCl3 mixture (AA group) once a week starting from the third week after the operation. At 6, 9, and 12 weeks after the operation, 5 rats from each group were sacrificed for observing subchondral bone changes on X-ray films and evaluation of cartilage degeneration in the right knee joints using safranin-O/Fast green staining and a modified OARSI scoring system. The degradation of the cartilage matrix was observed by immunohistochemical staining for type II collagen. Results X-ray examination in saline control group revealed the presence of osteophytes and narrowing of the joint space at 9 weeks, and the joint line disappeared at 12 weeks after the surgery; only slight irregularity of the articular surface was observed in the AA group at 9 and 12 weeks. OARSI scores were significantly lower in AA group than in the control group at 9 weeks (18.67 ± 0.67 vs 12.17 ± 2.75;P<0.05) and 12 weeks (20.11 ± 1.84 vs 13.77 ± 0.40;P<0.05) but not at 6 weeks after the surgery. The content of type 2 collagen in AA group was significantly higher than that in the control group at 6 weeks (0.36 ± 0.039 vs 0.49 ± 0.029;P<0.05) and 9 weeks after the surgery (0.25 ± 0.041 vs 0.38 ± 0.040;P<0.05). Conclusions Early intra-articular injection of AA/FeCl3 can effectively delay the progression of post-traumatic osteoarthritis in rats.

Objective To summarize our experience with tubular gastric elongation surgery for management of insufficient gastric length for high esophageal-gastric anastomosis following esophageal carcinoma resection. Methods From September, 2015 to October 2016, 5 patients with esophageal cancer were treated in our department, including two with cervical esophageal cancer and 3 with thoracic esophageal cancer. The patients with cervical esophageal cancer underwent pharyngeal resection, total laryngectomy, esophageal varus extubation and gastric oropharyngeal anastomosis, and the patients with thoracic esophageal cancer underwent esophageal cancer resection with incisions on the left neck, the right chest and the median abdomen. During the surgery, the length of the stomach was found insufficient to allow routine oropharyngeal anastomosis, and tubular gastric elongation was conducted to extend the tubular stomach to enable successful completion of the surgery. Results All the patients recovered smoothly after the surgery and were discharged after 2-3 weeks. Conclusion Tubular gastric elongation surgery can be a good choice for high esophageal-gastric anastomosis after resection of esophageal cancer in cases of insufficient tubular stomach length or high tension at the anastomosis.

Objective To assess the effect of ascorbic acid/ferric chloride (AA/FeCl3) in attenuating cartilage damage in rats with osteoarthritis. Methods Thirty adult male Wistar rats with surgically induced osteoarthritis were randomized into 2 groups for treatment with intra-articular injection of saline (control group) or AA/FeCl3 mixture (AA group) once a week starting from the third week after the operation. At 6, 9, and 12 weeks after the operation, 5 rats from each group were sacrificed for observing subchondral bone changes on X-ray films and evaluation of cartilage degeneration in the right knee joints using safranin-O/Fast green staining and a modified OARSI scoring system. The degradation of the cartilage matrix was observed by immunohistochemical staining for type II collagen. Results X-ray examination in saline control group revealed the presence of osteophytes and narrowing of the joint space at 9 weeks, and the joint line disappeared at 12 weeks after the surgery; only slight irregularity of the articular surface was observed in the AA group at 9 and 12 weeks. OARSI scores were significantly lower in AA group than in the control group at 9 weeks (18.67 ± 0.67 vs 12.17 ± 2.75;P<0.05) and 12 weeks (20.11 ± 1.84 vs 13.77 ± 0.40;P<0.05) but not at 6 weeks after the surgery. The content of type 2 collagen in AA group was significantly higher than that in the control group at 6 weeks (0.36 ± 0.039 vs 0.49 ± 0.029;P<0.05) and 9 weeks after the surgery (0.25 ± 0.041 vs 0.38 ± 0.040;P<0.05). Conclusions Early intra-articular injection of AA/FeCl3 can effectively delay the progression of post-traumatic osteoarthritis in rats.