OBJECTIVE To investigate the effect of bs-5-YHEDA iron chelating peptide combined with semaglutide on the cognitive ability and pathological characteristics of D-Gal-induced Alzheimer's disease(AD) model mice. METHODS Forty mice were randomly divided into 5 groups, namely the healthy control group, PBS group, bs-5-YHEDA iron chelating peptide group, combined treatment group and positive control group, with 8 mice in each group, half of each sex. Except for the healthy control group, D-galactose was injected to induce the AD mice model for 6 weeks. For 3 consecutive weeks starting from the 4th week, the bs-5-YHEDA iron chelating peptide group was injected with bs-5-YHEDA(1 mg·mL–1) once every other day at 200 µL in the tail vein; the bs-5-YHEDA iron chelating peptide(1 mg·mL–1) and semaglutide(25 nmol·kg–1·d–1) were given alternately once a day in the combination treatment group; the positive control group was given memantine(3.3 mg·kg–1·d–1) by gavage every other day. The healthy control group and PBS group were injected with the equal dose of PBS. At the end of treatment, the learning memory ability of mice was detected by the Morris water maze method, whole brain and whole blood were dissected, and pathological changes in hippocampal region were observed by HE staining, and Aβ expression and Tau protein phosphorylation levels were detected by immunohistochemistry, enzyme-linked immunosorbent assay and immunoblotting. RESULTS In the Morris water maze spatial exploration experiment, the differences in the number of times the mice traversed the platform, the ratio of swimming distance to the target quadrant, and the time ratio were statistically significant in each group(P<0.05); compared with the PBS group, the ratio of swimming distance to the target quadrant increased in the combined treatment group, and the differences were statistically significant(P<0.05). The results of HE staining showed that compared with the healthy control mice, the hippocampal area in the PBS group showed reduced levels of pyramidal cells, disorganized arrangement, cell edema, and deep staining of nuclei consolidation. Cellular disorganization, deep staining of nuclei and apoptosis in the hippocampus were significantly improved in each treatment group after drug treatment. Immunohistochemistry and Western blotting results showed that the Aβ expression levels and Tau protein phosphorylation levels were significantly higher in the PBS-administered mice compared with the healthy control mice, and the Aβ expression levels and Tau protein phosphorylation levels were reduced in each group after drug treatment, with statistically significant differences(P<0.01 or P<0.001 ). CONCLUSION The combination of bs-5-YHEDA iron chelating peptide and semaglutide can effectively improve the learning and memory ability and pathological characteristics of AD mice, but from the results of immunohistochemistry and immunoblotting experiments, the improvement of pathological characteristics of AD mice in the combination treatment group is not obvious compared with the single bs-5-YHEDA iron chelating peptide group, suggesting that there may be a threshold effect of our designed dual-target combination treatment on the cognitive improvement of AD mice, and the optimization and validation of the effect of multi-target combination treatment need further study.

Global Burden of Disease ; Risk Factors ; Quality-Adjusted Life Years

A new class of potent liver injury protective compounds, phychetins A-D ( 1- 4) featuring an unique 6/6/5/6/5 pentacyclic framework, were isolated and structurally characterized from a Chinese medicinal plant Phyllanthus franchetianus. Compounds 2- 4 are three pairs of enantiomers that were initially obtained in a racemic manner, and were further separated by chiral HPLC preparation. Compounds 1- 4 were proposed to be originated biosynthetically from a coexisting lignan via an intramolecular Friedel-Crafts reaction as the key step. A bioinspired total synthesis strategy was thus designated, and allowed the effective syntheses of compounds 2- 4 in high yields. Some of compounds exhibited significant anti-inflammatory activities in vitro via suppressing the production of pro-inflammatory cytokine IL-1β. Notably, compound 4, the most active enantiomeric pair in vitro, displayed prominent potent protecting activity against liver injury at a low dose of 3 mg/kg in mice, which could serve as a promising lead for the development of acute liver injury therapeutic agent.

The extraordinary advantages associated with mRNA vaccines, including their high efficiency, relatively low severity of side effects, and ease of manufacture, have enabled them to be a promising immunotherapy approach against various infectious diseases and cancers. Nevertheless, most mRNA delivery carriers have many disadvantages, such as high toxicity, poor biocompatibility, and low efficiency in vivo, which have hindered the widespread use of mRNA vaccines. To further characterize and solve these problems and develop a new type of safe and efficient mRNA delivery carrier, a negatively charged SA@DOTAP-mRNA nanovaccine was prepared in this study by coating DOTAP-mRNA with the natural anionic polymer sodium alginate (SA). Intriguingly, the transfection efficiency of SA@DOTAP-mRNA was significantly higher than that of DOTAP-mRNA, which was not due to the increase in cellular uptake but was associated with changes in the endocytosis pathway and the strong lysosome escape ability of SA@DOTAP-mRNA. In addition, we found that SA significantly increased the expression of LUC-mRNA in mice and achieved certain spleen targeting. Finally, we confirmed that SA@DOTAP-mRNA had a stronger antigen-presenting ability in E. G7-OVA tumor-bearing mice, dramatically inducing the proliferation of OVA-specific CLTs and ameliorating the antitumor effect. Therefore, we firmly believe that the coating strategy applied to cationic liposome/mRNA complexes is of potential research value in the field of mRNA delivery and has promising clinical application prospects.

Objective:To explore the treatments and outcomes of heart and kidney transplantation(HKTx)and summarize its management experiences.Methods:From October 2016 to October 2020, clinical data, treatment strategies and prognosis of 11 patients received HKTx were analyzed retrospectively.In 11HKTx cases, the ratio of male-to-female was 10∶1, the age(50.6±12.9)years and the preoperative body mass index(26.72±3.29)kg/m 2.The preoperative cardiac function was class Ⅳ and the preoperative left ventricular ejection fraction(29.40±4.48)%.All patients were in uremic state pre-operation and underwent regular dialysis.The mean duration of dialysis was 2.5(0.5-7.0)years, preoperative creatinine 753.5(434-1144)μmol/L and preoperative predictive glomerular filtration rate 5.59(3.93-17.23)ml/(min preop 2). Non-staged transplant was performed and donor heart and kidney were from the same donor.The median time of cold cardiac ischemia 2.75(2.5, 4.0)hours, the median time of cold renal ischemia 9(8.5, 15.0)hours and the median time from the end of heart transplantation to the beginning of kidney transplantation 2(1.0, 3.5)hours.The immunosuppressive regimen was a combination of tacrolimus, mycophenolate mofetil and methylprednisolone. Results:Normal cardiac function and renal function normalized in 9 cases.At Month 6 post-operation, the postoperative left ventricular ejection fraction was(57.55±2.51)%, creatinine 107.7(85-132)μmol/L and urine volume in 24h 1988(1800-2200)ml.The long-term survival time was 6-62 months.No such complications as infection or rejection occurred in 9 patients.The cardiac function was class Ⅰ at Month 6 post-operation.One patient died from pulmonary mucor infection at Month 4 post-operation.Another death was due to gastrointestinal fungal infection at Month 1 after HKTx.Conclusions:HKTx is an effective treatment for end-stage heart disease with renal failure.

Objective:After the propensity score matching method was used to balance the covariates between groups, the effects of pancreaticoduodenectomy (PD) and total pancreatectomy (TP) on the survival of patients with pancreatic head cancer and related prognostic factors were compared.Methods:The National Cancer Institute Surveillance, Epidemiology and Results (SEER) database were searched and 3 676 patients with pancreatic head cancer from 2010 to 2016 were selected, of whom 3 559 patients underwent PD (PD group) and 117 patients underwent TP (TP group) . Using propensity score matching to balance confounding factors, 117 pairs of cases from PD group and TP group were matched successfully. The Kaplan-Meier curve was used to observe the overall survival rate and cancer-specific survival rate of patients before and after matching. Log-rank test and Cox proportional hazard model were used to analyze and evaluate the impact of different clinicopathological characteristics on the prognosis of patients with pancreatic head cancer.Results:Before matching, the 1, 3, and 5-year cancer-specific survival rates of 3 559 patients in the PD group were 72.8%, 35.1% and 24.9%, and the median survival time was 23.89 months; the 1, 3, and 5-year cancer-specific survival rates of 117 patients in the TP group were 67.9%, 29.4% and 26.1%, and the median survival time was 21.51 months, and all the differences were not statistically significant (all P>0.05). After matching, the 1, 3, and 5-year cancer-specific survival rates of 117 patients in the PD group were 77.8%, 44.5% and 31.8%, and the median survival time was 31.50 months, which was significantly better than that of the TP group, and the differences were statistically significant (all P values <0.05). Cox regression analysis showed that surgical methods, tumor differentiation degree, N staging and pathological types were independent risk factors for overall survival and cancer-specific survival. Conclusions:Surgical methods, tumor differentiation degree, N stage and pathological type were independent risk factors affecting the overall survival rate and cancer-related survival rate. The survival benefit of PD was significantly better than that of TP, and the clinical choice of TP treatment for patients with pancreatic head cancer should be cautious.

Objective: To understand the real experience of the head nurses in the management process of standardized training nurses and to provide a reference for perfecting the standardized training project and improving the training quality. Methods: Semi-structured interviews were conducted among eleven head nurses and data were analyzed by Colaizzi method. Results: Three themes were extracted as follows: positive management methods; difficulties and challenges; need of support from superior nursing managers. Conclusion Understanding the experiences and feelings of head nurses in the management process of standardized training nurses can help sum up experience and find out the defect,then pay attention to seek effective solution and enhance training result.

Objective To explore the feasibility of the deep convolutional neural network (DCNN) judging the indications and prognosis of the total knee arthroplasty based on the trained DCNN computer learning system.Methods C1FAR-10 DCNN model based on TensorFlow (an open source system,Google,USA) optimized by Alex Krizhevsky were constructed.There were 400 cases with knee osteoarthritis from different databases used for analysis.Three hundred patients underwent total knee arthroplasty,while 100 did not.X-ray of 200 preoperative cases from the 400 cases and their enlarged image (50 times) were applied for training DCNN,while the enlarged images from other 200 cases were used to test the DCNN.The correlation and the regression between judgment of the DCNN and clinical truth were analyzed.The clinical truths were rechecked three times and were confirmed by treatment results.Pearson correlation and linear regression analysis were used.The relation test of the software was only used as a reference.Results There was no significant difference between the baseline of cases for learning and test.After learning 200 cases,the DCNN judged the 10 000 cases enlarged from remaining 200 cases.The correlation between the DCNN judgment and the clinical truth was not significant (r=0.000,F=0.001,P=0.970).False positive was observed in 1 681 cases,false negative in 3 296.After enlarged to 10 000 images,the correlation between the two judgments was significant (F=11 228.735,P=0.000,r=0.727 and R2=0.529).The software detection precision was 0.860.Conclusion DCNN can be applied in judging the indications of the total knee arthroplasty.Large sample size can improve the accuracy of the judgment significantly.

Objective To explore the effects of early intervention with heparin on function of coagulopathy, liver and kidney as well as the prognosis in rats with exertional heatstroke (EHS) under the ambient air of high temperature and low humidity. Methods 108 healthy SPF male Sprague-Dawley (SD) rats were randomly divided into normal temperature control group, EHS + normal saline (NS) group and EHS + heparin group. Of which 54 rats were collected for survival analysis (18 rats in each group), the weight change and 8-hour survival rate were observed,and Kaplan-Meier survival curves were drawn. Other 54 rats were collected for intervention experiment, the rats in each group were subdivided into 0, 1, 2 hours subgroups according to the time points of intervention with heparin after model reproduction, with 6 rats in each subgroup. The rats were placed in an artificial experiment cabin with northwest special environment, and the temperature and the relative humidity were (25.0±1.0) ℃ and (35±5)%, respectively, in normal temperature control group, and the rats were not treated in the cabin. The rats in EHS + NS group and EHS + heparin group kept running in the cabin which temperature and relative humidity were set at (43.0±0.5)℃ and (35±5)% until the anus temperature of rats reached 43.0 ℃, and then the rats were placed in room temperature. The rats were injected with 1 mL/kg NS or 250 U/kg heparin sodium injection through their caudal veins at 0, 1, and 2 hours, respectively, and then the blood was collected after 1.5 hours to determine the biochemical parameters including coagulation, liver and kidney as well as platelet count (PLT). Results ① The weight loss of EHS + NS group and EHS + heparin group was more significant than that of normal temperature control group (g: 8.28±1.41, 8.39±1.38 vs. 2.06±1.06, both P < 0.05), but there was no significant difference between EHS + NS group and EHS + heparin group. ② As the time went on after modeling, serum creatinine (SCr), blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), activated partial thromboplastin time (APTT), and D-dimer of EHS rats showed a tendency of increasing, but fibrinogen (FBG), antithrombin Ⅲ (ATⅢ) and PLT were decreased gradually, which were obviously abnormal as compared with those at corresponding time point of the normal temperature control group. Heparin intervention 0 hour after modeling could improve the function of liver and kidney, FBG, D-dimer, ATⅢ and PLT, but APTT was prolonged further. The SCr, BUN, ALT, AST and CK in EHS 2 hours + heparin group were still better than EHS + NS group [SCr (μmol/L): 93.33±7.69 vs. 110.50±13.56, BUN (mmol/L): 20.55±1.35 vs. 24.88±2.41, ALT (U/L): 322.17±36.36 vs. 492.33±64.19, AST (U/L): 1 252.33±240.86 vs. 2 725.67±461.17, CK (U/L):1 4628.67±2 784.68 vs. 2 6843.00±2 637.16, all P < 0.01], APTT was significantly prolonged (s: 51.83±6.11 vs. 33.83±4.31, P < 0.01), and ATⅢ and PLT were significantly increased [ATⅢ: (78.03±9.15)% vs. (64.28±12.55)%, PLT (×109/L): 457.67±32.33 vs. 415.83±26.45, both P < 0.05], however, there was no obvious influence on FBG or D-dimer. ③ The rats in normal temperature control group were all survived within 8 hours, and all dead in EHS + NS group. The survival rate of rats given heparin intervention at 0, 1, 2 hours after successfully modeling was 50.0%, 33.3% and 0%, respectively. Kaplan-Meier survival curve analysis showed that 8-hour cumulative survival rate in EHS 0 hour, 1 hour + heparin groups was higher than that in EHS 0 hour, 1 hour + NS groups (χ12 = 7.930, P1= 0.005; χ22 = 4.408, P2= 0.036), however, there was no significant difference between EHS 2 hours + heparin group and EHS 2 hours + NS group (χ2= 2.660, P = 0.103). Conclusion Early heparin intervention can improve the coagulation function and organ function of EHS rats, while improving the survival rate of rats, indicating the earlier intervention of heparin, the better prognosis of rats is.

Objective To summarize the outcomes and clinical experience of combined heart and kidney transplantation.Methods The clinical data of one case of combined heart and kidney transplantation were retrospectively analyzed.The kidney transplant was completed immediately after the heart transplant.The immunosuppressive therapy strategies included tacrolimus,corticosteroids and mycophenolate mofetil.Results For heart transplantation,heart cold ischemia time was 200 min,aorta blocking time was 136 min,and extracorporeal circulation time was 201 min.The kidney was transplanted to the right iliac fossa after heart transplantation.The endotracheal tube was removed 15 h after surgery.The patient was transferred to the general ward on the 8th day after surgery.The patient was discharged from the hospital at 27th day after surgery,the renal function was normal and no activity was restricted.Conclusion Reasonable perioperative management and selection of surgical methods are the keys to the success of combined heart and kidney transplantation.