Structural repurposing of SGLT2 inhibitor empagliflozin for strengthening anti-heart failure activity with lower glycosuria

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reapproved for heart failure (HF) therapy in patients with and without diabetes. However, the initial glucose-lowering indication of SGLT2i has impeded their uses in cardiovascular clinical practice. A challenge of SGLT2i then becomes how to separate their anti-HF activity from glucose-lowering side-effect. To address this issue, we conducted structural repurposing of EMPA, a representative SGLT2 inhibitor, to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2. Compared to EMPA, the optimal derivative JX01, which was produced by methylation of C2-OH of the glucose ring, exhibited weaker SGLT2-inhibitory activity (IC50 > 100 nmol/L), and lower glycosuria and glucose-lowering side-effect, better NHE1-inhibitory activity and cardioprotective effect in HF mice. Furthermore, JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity, and good pharmacokinetic properties in both mouse and rat species. Collectively, the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs, and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.

Repurposing antimycotic ciclopirox olamine as a promising anti-ischemic stroke agent

Ischemic stroke is a severe disorder resulting from acute cerebral thrombosis. Here we demonstrated that post-ischemic treatment with ciclopirox olamine (CPX), a potent antifungal clinical drug, alleviated brain infarction, neurological deficits and brain edema in a classic rat model of ischemic stroke. Single dose post-ischemic administration of CPX provided a long-lasting neuroprotective effect, which can be further enhanced by multiple doses administration of CPX. CPX also effectively reversed ischemia-induced neuronal loss, glial activation as well as blood-brain barrier (BBB) damage. Employing quantitative phosphoproteomic analysis, 130 phosphosites in 122 proteins were identified to be significantly regulated by CPX treatment in oxygen glucose deprivation (OGD)-exposed SH-SY5Y cells, which revealed that phosphokinases and cell cycle-related phosphoproteins were largely influenced. Subsequently, we demonstrated that CPX markedly enhanced the AKT (protein kinase B, PKB/AKT) and GSK3 (glycogen synthase kinase 3) phosphorylation in OGD-exposed SH-SY5Y cells, and regulated the cell cycle progression and nitric oxide (NO) release in lipopolysaccharide (LPS)-induced BV-2 cells, which may contribute to its ameliorative effects against ischemia-associated neuronal death and microglial inflammation. Our study suggests that CPX could be a promising compound to reduce multiple ischemic injuries; however, further studies will be needed to clarify the molecular mechanisms involved.

Preliminary study on the a novel individualized 3D printing artificial vertebral body in spine reconstruction / 中华骨科杂志

Objective:To explore the advantages of the novel individualized 3D printing artificial vertebral body in spine reconstruction and to evaluate its clinical effect.Methods:From January 2017 to December 2018, the 15 patients who underwent total vertebrectomy and spine reconstruction with individualized 3D printing artificial vertebral body were analyzed retrospectively. There were 8 males and 7 females, with the mean age 39.5 years (range: 20-57), including 12 primary tumors and 3 metastatic tumors. According to tumor location and surrounding soft tissue invasion range, simple posterior or combined anterior and posterior approach were used for total vertebral resection, and the defection was reconstructed by 3D printing artificial vertebral body. The operation time, intraoperative bleeding volume, postoperative stability of artificial vertebral body and bone ingrowth of adjacent vertebral body, preoperative and postoperative neurological changes, preoperative and postoperative VAS score, local control and survival of patients were analyzed.Results:The mean operation time was 412.0 min (range: 135-740 min), and the mean blood loss was 4 140.0ml (range: 100-14 000 ml). The mean follow-up time was 23.2 months (range: 12-35 months), and no one loss to follow-up. One case had pleural rupture, one case had cerebrospinal fluid leakage and one case had L5 nerve root palsy. All patients recovered after active symptomatic treatment. Compare with the preoperative VAS score (4.7±1.1), the differences of VAS score at 7 d postoperative and last follow-up (1.6±0.6 and 1.0±0.5) were significantly reduced ( P<0.001). Three patients with Frankel grade C gradually recovered to grade D, and no change were found in grade D and Grade E patients, there was no significant improved at last follow-up. Preliminary bone growth was found between the artificial vertebral body and the adjacent vertebral body 3 months after operation. The bone growth was more obvious at 12 months post-operation, and the artificial vertebral body fused with the adjacent vertebral bodies to form bone integration. At 24 months post-operation, the integration of the artificial vertebral body was more accurate. During the follow-up period, there was no loosening or displacement of the artificial vertebral body and no failure of internal fixation. A case of hemangioendothelioma and a case of epithelioid angiosarcoma died at 33 months and 35 months postoperatively. One patient with chondrosarcoma had local recurrence at16 months post-operation. After treated with arotinib, the tumor did not progress. The other 12 patients had no tumor recurrence or distant metastasis. Conclusion:After spinal tumor resection, individualized 3D printing artificial vertebral body can be used to accurate restoration of spinal continuity, and provide nice interface matching and bone growth between artificial vertebral body and the adjacent vertebral endplates. Moreover, the immediate and long-term stability of the artificial vertebral body can meet the needs of spinal reconstruction.

Establishing A Modified Isolated Perfused Rat Liver Model for Applied in Study of Cold Storage of Liver Grafts / 胃肠病学

Background:Cold storage and ischemia-reperfusion injury of liver grafts are critical for the prognosis of patients undergoing liver transplantation. Establishing a stable cold storage and reperfusion animal model is a fundamental measure for related studies. Aims:To establish a modified isolated perfused rat liver model for comprehensive assessment of liver grafts in studies on preservation of liver grafts before transplantation. Methods:Twelve Sprague-Dawley rats were randomly allocated into two groups. Livers of rats in control group were retrieved and perfused immediately for 90 minutes without preservation. In experimental group,liver grafts underwent a 30-minute warm ischemia followed by 24-hour cold storage before ex vivo perfusion. The perfusate was collected dynamically for monitoring the levels of transaminases,electrolytes and pH value;the portal vein pressure of liver grafts was measured by pressure sensor,and the hepatic hydrogen peroxide (HPO)level was assessed by microprobe for free radicals. The bile production was recorded after the ex vivo perfusion;meanwhile,the levels of malondialdehyde (MDA)and superoxide dismutase (Cu/ Zn SOD),the histopathological changes and apoptosis of hepatocytes of liver grafts were examined. Results:Compared with the control group,the levels of AST and ALT,the portal vein pressure and the HPO level of liver grafts in experimental group were obviously increased throughout the perfusion. Furthermore,the bile production and level of Cu/ Zn SOD of liver grafts in experimental group were significantly decreased. The histopathological injury and hepatocytes apoptosis of liver grafts were milder in control group. Conclusions:The liver function and antioxidant effect were reduced in warm ischemic and cold preserved liver grafts. The modified isolated perfused rat liver model established in this study is useful for monitoring and evaluation of the cold storage and reperfusion injury in liver grafts.

Discussion on Medical Safety Management and its Function to Construct Harmonious Doctor-patient Relationship / 中国医学伦理学

From the perspective of medical safety management, this paper states that it should foster the con-cept of medical safety, establish the goals of safety management, improve the safety management organization, and implement safety management and control measures. Furthermore, it analyzes several factors of doctors that influ-ence the doctor-patient relationship, which include hospital′s development direction and operation mode, the con-tradiction between the patient′s expectation and the limitation of medical technology, and the uncontrollable factors of medical development. Finally, it puts forward that the implementation of safety management is beneficial to en-hance the basic medical quality, decrease the medical errors, and improve the medical service level.

Explorations in disciplines development at a research hospital / 中华医院管理杂志

Aiming at building research disciplines,Xijing hospital has initially achieved a strategic transformation into a hospital with research disciplines,with such measures as scientific layout of disciplines,making of advantageous disciplines with overseas benchmarks,encouragement of potential disciplines with advantageous disciplines,promotion of medical innovation with innovative ideas,and upgrading clinical service quality with technical innovation.

Expression and adjuvant effects of the fusion peptide TBP5 / 生物工程学报

Thymopentin (TP5) and bursopentin (BP5) are both immunopotentiators. To explore whether the TP5-BP5 fusion peptide (TBP5) has adjuvant activity or not, we cloned the TBP5 gene and confirmed that the TBP5 gene in a recombinant prokaryotic expression plasmid was successfully expressed in Escherichia coli BL21. TBP5 significantly promoted the proliferation of thymic and splenic lymphocytes of mice. The potential adjuvant activity of the TBP5 was examined in mice by coinjecting TBP5 and H9N2 avian influenza virus (AIV) inactivated vaccine. HI antibody titers, HA antibodies and cytokines levels (IL-4 and IFN-γ) were determined. We found that TBP5 markedly elevated serum HI titers and HA antibody levels, induced the secretion of both IL-4 and IFN-γ cytokines. Furthermore, virus challenge experiments confirmed that TBP5 contributed to inhibition replication of the virus [H9N2 AIV (A/chicken/Jiangsu/NJ07/05)] from mouse lungs. Altogether, these findings suggest that TBP5 may be an effective adjuvant for avian vaccine and that this study provides a reference for further research on new vaccine adjuvants.

Direct intercellular communications dominate the interaction between adipose-derived MSCs and myofibroblasts against cardiac fibrosis

The onset of cardiac fibrosis post myocardial infarction greatly impairs the function of heart. Recent advances of cell transplantation showed great benefits to restore myocardial function, among which the mesenchymal stem cells (MSCs) has gained much attention. However, the underlying cellular mechanisms of MSC therapy are still not fully understood. Although paracrine effects of MSCs on residual cardiomyocytes have been discussed, the amelioration of fibrosis was rarely studied as the hostile environment cannot support the survival of most cell populations and impairs the diffusion of soluble factors. Here in order to decipher the potential mechanism of MSC therapy for cardiac fibrosis, we investigated the interplay between MSCs and cardiac myofibroblasts (mFBs) using interactive co-culture method, with comparison to paracrine approaches, namely treatment by MSC conditioned medium and gap co-culture method. Various fibrotic features of mFBs were analyzed and the most prominent anti-fibrosis effects were always obtained using direct co-culture that allowed cell-to-cell contacts. Hepatocyte growth factor (HGF), a well-known anti-fibrosis factor, was demonstrated to be a major contributor for MSCs' anti-fibrosis function. Moreover, physical contacts and tube-like structures between MSCs and mFBs were observed by live cell imaging and TEM which demonstrate the direct cellular interactions.

Enhancement characterization of breast masses of contrast-enhanced ultrasound: comparison with MRI / 中华超声影像学杂志

Objective To assess the enhancement characteristic of breast lesions of contrast-enhanced ultrasound (CEUS) in comparison with contrast-enhanced magnetic resonance imaging (MRI).Methods Between August 2011 and March 2013,72 women with 72 lesions were enrolled.All patients underwent ultrasound,CEUS and MRI.The histopathologic results obtained from ultrasound-guided core biopsy or operation excisions were used as the reference standard.CEUS section evaluations were made similar with MRI regarding the size and shape of lesions.Different contrast enhancement patterns including homogeneous/heterogeneous,the tumor areas,the perfusion defect areas,and modality of time-intensity curve were evaluated.Pearson's correlation coefficient,Student's t-tests,and the concordance test were used for evaluation.Results Of the 72 lesions,pathologic examination revealed 56 (77.8％) malignant lesions and 16 (22.2％) benign lesions.The tumor areas measured by CEUS and MRI agreed well,with a correlation of r =0.894,P =0.000.The difference between the two measurements was not significant according to a paired t test (P =0.886).The concordance tests gave a value of the coefficient Kappa =-0.153 (P =0.061),indicating a low concordance between the results obtained with CEUS and those obtained with MRI regarding the enhanced uniformity.There were statistically significant differences in the perfusion defect areas as measured by CEUS and MRI (P =0.01).The CEUS estimates [(0.837 ± 0.827)cm2] were consistently higher than the MRI estimates [(0.576 ± 0.524)cm2].The time-intensity curve patterns between the two groups showed no correlation.Conclusions The enhancement patterns evaluated by CEUS and MRI partly agreed well.There was no direct association between the two methods regarding the enhancement patterns because of the different contrast agent.

Correlation between ultrasonic appearance and pathology of phyllodes tumors of the breast / 中国肿瘤临床

Objective:This study aims to evaluate the sonographic features of phyllodes tumors of the breast (PTBs) and the cor-relation between sonographic and pathologic findings to improve the understanding of the disease. Methods:Sonographic findings of 85 PTBs from 83 patients were reviewed. The sonographic findings included the results of two-dimensional ultrasound and color Dop-pler flow imaging, elastographic features, and pathologic data. Results:Of the 85 lesions, 33 were the benign tumors, 28 were border-line, and 24 were malignant according to the pathologic diagnosis. Tumor morphology revealed that most masses were lobulated, with a clear-cut boundary, smooth verge, and inhomogeneous internal echo. Clear boundary was more common in the benign phyllodes tumors (χ2=12.721, P=0.002), and a cystic echo-free area was more commonly observed in these malignant tumors (χ2=9.677, P=0.046). LevelⅡandⅢsignals of the blood flow were observed in 75.3%of PTB cases. Of all lesions, only 26 were subjected to elasticity imaging, and the elastographic scores ranged from 2 to 3 in 88.5%of the cases (23/26). Conclusion:Conventional ultrasound and elastographic findings on PTBs exhibited definite characteristics. The border and cystic areas in the tumors can be used to differentiate between be-nign and malignant PTBs.

The resection of internal hemi-pelvic tumor using computer navigation and the reconstruction assisted by finite element analysis / 中华骨科杂志

Objective To analyze the security and effectiveness of the accurate resection and reconstruction of pelvic tumor with computer navigation and to evaluate the feasibility of pelvic ring structure and mechanics reconstruction using finite element analysis.Methors From December 2008 to June 2010,tumor resections assisted by computer navigation technology and pelvic reconstructions with assembly prosthesis designed by finite element analysis were performed in 12 patients with internal hemi-pelvic malignant tumors.There were 8 male and 4 female patients,with the average age of 39.7 years(range,25-53).The malignant tumors involved chondrosarcoma(4 cases),osteosarcoma(2),Ewing sarcoma(2),malignant fibrohistiocytoma(1),and metastatic tumor(3,in which including renal cell carcinoma 1 case,thyroid carcinoma 1,and breast carcinoma 1).According to Enneking staging classification,there were 1 case in Ⅰ A,2 cases in ⅠB,2 cases in Ⅱ A.and 4 cases in Ⅱ B.The local recurrence of tumor and functional results were followed up postoperatively.Results There were no nerves,vessels and pelvic organs injuries intra-operatively.The postoperative X-rays showed that the excised regions were proper to the preoperative schedule and en bloc resections were performed in all patients.All assembly prostheses were in satisfactory position.and the screw fixation was accordance with the finite element biomechanical analysis.All the cases were followed up for average 18.2 months (range,8-26).There were 1 case with local recurrence and pulmonary metastasis,1 case with deep infection,and 1 case with deep vein thrombosis.No prosthesis dislocation,loosening,breaking,and limb length discrepancy occurred in all patients.The average MSTS93 functional score was 70%in all patients at 6 months,and 68 % in 6 patients at 20 months follow.up.Conclusion The resection and reconstruction of pelvic tumor assisted by computer navigation is a safe and effective procedure.The finite element analysis can provide accurate biomechanical guidance to the reconstruction of pelvic ring.

Breast MRI in detecting primary malignancy of patients presenting with axillary metastases and negative X-ray mammography / 中华放射学杂志

Objective To evaluate the role of breast MRI in detecting the primary malignancy in patients presenting solely with axillary lymph node metastases. Methods Thirty-three patients with axillary lynph node metastases but negative findings on either physical examination or mammography underwent breast MRI to identify occult breast carcinoma. MRI of the breast was assessed according to BI-RADS criteria. The pathologic diagnosis was made according to the standard criteria by the WHO Classification of Tumor. Results Among 33 patients presenting solely with axillary metastases, 30 patients underwent modified radical mastectomy. Primary breast carcinoma was proven in 17 patients. MRI detected lesions in 16 patients, including 10 masses and 6 non-mass lesions. Size of the masses ranged from 0. 5 to 2. 6 cm (mean 1.5 cm). Six lesions were smaller than 1.5 cm in size. Non-mass lesions showed ductal enhancement in 4 cases and segmental enhancement in 2 cases. One patient with tumor detected by histopathology showed no abnormal enhancement on MRI. No tumor was found at mastectomy in the other 13 womeu, and negative MR findings were revealed in 9. Four cases with suspicious enhancement on MRI had no corresponding primary foci on pathology. Three patients didn't undergo surgical procedure. The sensitivity, specificity, and accuracy of MRI in the diagnosis of the primary malignancy were 94. 1%,69. 2%, and 83.3%, respectively. Conclusions Small size of mass and ductal or segmental enhancement of non-mass lesion were common MR features of occult malignancy. MRI showed high sensitivity and accuracy in diagnosing occult breast carcinoma. Breast MRI should be taken in search of occult malignancy in patients with axillary metastases.

Low modulus titanium alloy plating for femoral shaft fractures: A finite element analysis / 中华创伤骨科杂志

Objective To investigate the effects of internal plating with high and low moduli of elasticity on the stress and its distribution on the femoral shaft fracture. Methods A femur from a normal Chinese adult male was scanned by 64-detector row helical CT at 0. 5 mm interval. The CT images were used to establish a finite element model of the femur by software. The mid-femoral fracture was simulated in the model and fixated by eight-hole plates of Ti-6Al-4V (high modulus group, E = 110 GPa) and of Ti2448 (low modulus group, E = 30 GPa). When the femur was in axial compression, flexion and torsion loads, the stress and its distribution on the bone fracture site were analyzed to compare the biomechanics of the plates with high and low moduli. Results Under axial compression load, the contact stress between fracture ends in the low modulus group was larger than that in the high modulus group, while the max stress at the hole (11.47MPa) was smaller than that in the high modulus group (13.89 MPa) . Under four-point bending load, the contact stress in the low modulus group was still larger, while the bending movement was smaller. Under the torsion load, stress on the femur was well-distributed in both groups, but the max stress at the hole in the low modulus group (11.47 MPa) was smaller than that in the high modulus group (31.24 MPa). Conclusions Under internal fixation by plates of low modulus, the stress stimulus at the fracture site may be increased,while the stress concentrated at the hole may be decreased. The stress shielding of the low modulus plate may also be modified.

Effect of passive smoking on the behavior and emotion of rats with acute sleep deprivation / 中国组织工程研究

BACKGROUND:Sleep deprivation, resulting in a series of physiological and psychological reactions, is a common phenomenon in our modem society. Recently, many physical and medical therapies are on their way to eliminate the negative influence the sleep deprivation exerted on our human beings, and a large number of cigarette smokers believe that cigarette smoke can obviously improve their abnormal behavioral performance and negative emotional fluctuation caused by sleep deprivation in short terms.However, there are few researches but many disputes when it comes to effect of passive smoking on the behavior and emotion of rats on the occasion of acute sleep deprivation.OBJECTIVE: To investigate the effect of passive smoking (PS) on the behavior and emotion of rats with acute sleep deprivation (SD).DESIGN: Completed randomized and controlled study.SETTING: Basic Medicine Experiment Center, School of Basic Medicine;Department of Radiation Medicine, School of Preventive Medicine, Fourth Military Medical University of Chinese PLA.MATERIALS: The experiment was carried out at Experiment Center of Basic Medicine, Fourth Military Medical University of Chinese PLA from April to June 2004. Totally 49 healthy adult male Sprague-Dawley rats,being 3 months old, weighting (180±15) g, were randomly divided into 5groups: sleep deprivation + 24-hour passive smoking group (n=8), 24-hour sleep deprivation group (n=8), sleep deprivation + 54-hour passive smoking group (n=8), 54-hour sleep deprivation group (n=8), and blank control group (n=7).METHODS: ① Rats in sleep deprivation + 24-hour passive smoking group, 24-hour sleep deprivation group, sleep deprivation + 54-hour passive smoking group and 54-hour sleep deprivation group were performed with sleep deprivation with flower pot method for 24 and 54 hours, and rats in sleep deprivation + 24-hour passive smoking group and sleep deprivation + 54-hour passive smoking group were treated with passive smoking at the same time at a frequency of 12 times/day, 120 minute/time, 3cigarettes were lighted at the same time and kept into ashes. ② Broad field test was conducted to determine the behavioral and emotional changes of the rats. We trailed their activities by video recorder for 5 minutes each time. Then we presented the image information to computer process and finally got the total distance and the average distance from the center of the broad field for each rat during the 5-minite test. Meanwhile, we also observed the emotional variety and excitability of the rats. The nearer the average distance from center was, the more the emotional behavior and the greater excitability were; and the longer the total distance was, the greater the excitability was. ③ All the data were expressed with Mean ± SD, the method of non-parametric rank sum test was adopte d for comparing among groups, P ＜ 0.05 was regarded as statistical significance.MAIN OUTCOME MEASURES: Comparisons between DC and TD of rats in each group, and changes of behavior and emotion of rats in each group.RESULTS: Data of all the 49 rats was entered the final data analysis without any loss. ① Observation of emotional stage: Compared with sleep deprivation + 54-hour passive smoking group, rats in sleep deprivation+24-hour passive smoking group appeared more quiet and indifferent, and presented lower excitability, less sensitivity to outside stimulus and less aggressive behaviors towards other rats, and the same as 24-hour sleep deprivation group, compared with 54-hour sleep deprivation group. ② Results from the open field test: DC of 24-hour sleep deprivation group was significantly smaller than that of blank control group and sleep deprivation + 24-hour passive smoking group [(53.93±1.83, 58.21±4.45, 58.11±1.62) cm, (P＜ 0.01-0.05)]. DC of 54-hour sleep deprivation group was significantly bigger than that of 24-hour sleep deprivation group [(61.53±3.02, 58.11±1.62) cm, (P＜ 0.01)]; TD of 24-hour sleep deprivation group was significantly bigger than that of sleep deprivation + 24-hour passive smoking group [(3310.45±1 445.97, 1 818.20±733.25, 2 338.15±694.70) cm, (P ＜ 0.01-0.05)], and that of 54-hour sleep deprivation group was bigger than that of sleep deprivation + 54-hour passive smoking group andsmaller than that of 24-hour sleep deprivation group [(2 410.70t548.64, 1 473.50±945.89, 3 310.45±1 445.97) cm, (P＜0.05)].CONCLUSION: With the prolongation of sleep deprivation time, behavior and emotional reaction of rats are shown from exciting to inhibiting, however, passive smoking can inhibit behavior and emotional state of rats during the whole sleep deprivation.

Design of Medical Insurance Management System in No.1 Military Medical Project / 医疗卫生装备

Objective To design a suit of medical insurance management system that is in accordance with local medical insurance requirements and hospital management of medical insurance needs.Methods Combining the analysis of the needs of local medical insurance and hospital medical insurance management with the actual flow control of the medical insurance patient in hospital,on the basis of No.1 Military Medical Project,the MMS was designed by using Visual Basic 2005 tool,VB.NET and C/S mode.Results By the successful development,the managers of hospital can be carried out integrated management and dynamic tracing to hospitalized patients with medical insurance and the whole microcomputer operation of medical insurance management can become true.Conclusion The modular design,scalability and simple operation can improve medical insurance efficiency,management capacity and practical value.