Objective:To examine the prevention effecacy and safety of preprotein convertase subtilisin-kexin 9 (PCSK9) inhibitors in stroke in patients with atherosclerotic cardiovascular disease (ASCVD) at primary and secondary prevention.Methods:PubMed, Embase, Web of Science, Cochrane Library, and Wanfang and CNKI databases were searched for randomized controlled trials comparing evolocumab, alirocumab, tafolecimab or inclisiran (experimental group) with placebo or conventional therapy (control group) in hyperlipidemia and ASCVD from inception to March 2024. Valid data were extracted after screening and applying Cochrane Literature quality assessment tool to assess the literature quality. Efficacy outcome (incidences of stroke and ischemic stroke) and safety outcome (cardiovascular mortality, and incidences of aminotransferase increased by more than 3 times, creatine kinase increased by more than 3 times, allergic reaction and hemorrhagic stroke) were recorded. Meta analysis of the extracted data was conducted using Stata software to calculate the risk difference ( RD). Results:Twenty articles (21 randomized controlled trials) were included with 62 799 patients. For primary prevention, no significant difference was found between PCSK9 inhibitors and control groups in stroke incidence ( RD=0.000, 95% CI: -0.002-0.003, P=0.905) or ischemic stroke incidence ( RD=0.001, 95% CI: -0.005-0.006, P=0.824); incidence of creatine kinase increased by more than 3 times in the PCSK9 inhibitors group was significantly decreased compared with that in the control group ( RD=-0.005, 95% CI: -0.010-0.000, P=0.039). For secondary prevention, PCSK9 inhibitors group had significantly reduced stroke incidence ( RD=-0.004, 95% CI: -0.006--0.002, P<0.001) and ischemic stroke incidence ( RD=-0.003, 95% CI: -0.005--0.002, P<0.001) compared with control group; no significant differences in cardiovascular mortality, or incidences of aminotransferase increased by more than 3 times, creatine kinase increased by more than 3 times, allergic reaction and hemorrhagic stroke were noted between the PCSK9 inhibitors group and control group ( P>0.05). Conclusion:PCSK9 inhibitors in primary prevention have no significant effect on stroke or ischemic stroke incidences, but can decrease the incidence of creatine kinase increased by more than 3 times; PCSK9 inhibitors in secondary prevention can reduce stroke and ischemic stroke incidences without increasing complications and thus enjoying certain safety.

Objective:To evaluate the preventive role and safety of evolocumab and alirocumab in ischemic stroke in hyperlipidemia and atherosclerotic high-risk cardiovascular patients.Methods:PubMed, Embase, Web of Science, Cochrane Library, Wanfang, and CNKI databases were searched for randomized controlled trials (RCTs) comparing evolocumab or alirocumab (experimental group) with placebo or usual care (control group) in hyperlipidemia and atherosclerotic high-risk cardiovascular patients from database inception to March 2023. References were screened and data were extracted according to the preset inclusion and exclusion criteria; incidence of ischemic stroke was as the efficacy index, and incidences of cardiovascular death, cognitive impairment, aminotransferase increased for more than 3 times and creatine kinase increased for more than 3 times were as the safety index. Cochrane Reviewer Handbook 2.0 was used to evaluate the RCTs literature quality. Meta analysis was performed using Stata software.Results:A total of 11 articles were included, including 12 studies with a total of 53 666 patients. Compared with the control group, the incidence of ischemic stroke in the experimental group was significantly decreased (risk difference [ RD]=-0.004, 95% CI: -0.005--0.002, P<0.001); there were no significant differences in the incidence of cardiovascular death, cognitive impairment, aminotransferase increased for more than 3 times and creatine kinase increased for more than 3 times between the 2 groups ( RD=-0.001, 95% CI: -0.004-0.001, P=0.401; RD=0.000, 95% CI: -0.003-0.002, P=0.638; RD=-0.001, 95% CI: -0.004-0.002, P=0.443; RD=-0.001, 95% CI: -0.003-0.000, P=0.137). Subgroup analysis was performed according to drugs: compared with the control group, the incidence of ischemic stroke was significantly reduced in the evolocumab group and alirocumab group ( RD=-0.004, 95% CI: -0.007--0.001, P=0.006; RD= -0.003, 95% CI: -0.006-0.000, P=0.024); there were no significant differences in incidences of cardiovascular death ( RD=0.001, 95% CI: -0.002-0.004, P=0.619; RD=-0.003, 95% CI: -0.007-0.001, P=0.100), cognitive impairment ( RD=0.001, 95% CI:-0.002-0.004, P=0.463; RD=-0.002, 95% CI: -0.005-0.001, P=0.145), aminotransferase increased for more than 3 times ( RD=0.000, 95% CI: -0.003-0.003, P=0.888; RD=-0.002, 95% CI: -0.007-0.003, P=0.392) or creatine kinase increased for more than 3 times ( RD=0.000, 95% CI: -0.002-0.002, P=0.668; RD=-0.002, 95% CI: -0.005-0.000, P=0.106) between the evolocumab group and alirocumab group. Subgroup analysis was performed according to the medication duration: compared with the control group, no significant differences in incidences of cardiovascular death ( RD=0.000, 95% CI:-0.022-0.022, P=1.000; RD=-0.003, 95% CI: -0.009-0.002, P=0.193; RD=-0.001, 95% CI:-0.004-0.002, P=0.521), cognitive impairment ( RD=-0.003, 95% CI: -0.014-0.008, P=0.569; RD=-0.001, 95% CI: -0.006-0.004, P=0.696; RD=0.000, 95% CI: -0.003-0.002, P=0.735), aminotransferase increased for more than 3 times ( RD=-0.002, 95% CI: -0.016-0.012, P=0.749; RD=-0.002, 95% CI: -0.013-0.010, P=0.773; RD=-0.001, 95% CI: -0.004-0.002, P=0.489) or creatine kinase increased for more than three times ( RD=-0.015, 95% CI: -0.032-0.003, P=0.099; RD= -0.011, 95% CI: -0.025-0.002, P=0.104; RD=0.000, 95% CI: -0.002-0.001, P=0.722) were noted among medication duration<1 year group, medication duration of 1-2 years group and medication duration>2 years group. Conclusion:Both evolocumab and alirocumab can reduce the incidence of ischemic stroke in hyperlipidemia and atherosclerotic high-risk cardiovascular patients, with good safety.

Objective:To explore the effects of varicella-zoster virus (VZV) on the glycosylation characteristics of cellular prion protein (PrP C) in human Schwann cells (hSC) and the regulation of methylcobalamin (MeB 12). Methods:The hSC were inoculated with VZV at 1.0 multiplicity of infection for 48 hours, then 250 μg/ml of MeB 12 were added and cultured for 48 hours. PrP C from the supernatant and sediment were coated with anti-PrPC antibody (3F4) respectively and subjected to screening for glycans by sandwich lectin-ELISA. Meanwhile, the superoxide dismutase (SOD) and malondialdehyde (MDA) from the supernatant were detected by diagnostic reagent kit. Results:The ratio of PrP C glycans in the supernatant to sediment of VZV-infected cells was found to be significantly different compared with those in the VZV-non-infected cells. The overall glycans ratios of the supernatant to the sediment was 1∶2.6 in the uninfected cells, while the ratio was 1∶1.5 in the VZV-infected cells (F=24.18, P<0.001, LSD-t=8.27, P<0.001), suggesting that stability of PrP C decreased after VZV infection, and correspondingly the activity of SOD (4.43±2.05 U/mg) was significantly reduced in the VZV-infected hSCs compared with those(14.23±1.27 U/mg) in the uninfected cells (F=18.19, P=0.001, LSD-t=6.54, P<0.001), the level of MDA (11.17±1.89 nmol/mg) was significantly elevated in the VZV-infected hSCs compared with those (3.73±0.35nmol/mg) in the uninfected cells (F=30.70, P<0.001, LSD-t=8.25, P<0.001). When the VZV-infected cells were added with 250 μg/ml MeB 12, glycans in the sediment of infected cells significantly increased compared with those in the VZV-infected cells without MeB 12, the overall glycans ratio of the supernatant to the sediment was 1∶2.4, suggesting that MeB 12 improved the stability of PrP C. Moreover, SOD activity (11.07±2.07 U/mg) was significantly increased (LSD-t=4.42, P=0.002), MDA level (5.23±0.96 nmol/mg) was significantly decreased (LSD-t=6.58, p<0.001) in the VZV-infected cells added with MeB 12 compared with those in the VZV-infected cells without MeB 12. Conclusions:The glycosylation characteristics of PrP C in hSC could be changed by VZV, while MeB 12 could regulate the glycosylation characteristics to improve the stability of PrP C, thereby increase the antioxidant capacity of hSC.

Objective:To investigate the long-term outcome and prognostic indicators of diffuse pro-liferative lupus nephritis (DPLN).Methods:The primary endpoint of long-term follow-up and factors pos- sibly influencing the outcome were analyzed retrospectively in DPLN patients admitted to the First Affiliated Hospital of Wenzhou Medical University between Jan 1, 2000 and Dec 31, 2014. Patients were classified into three groups according to the evaluated glomerular filtration rate(eGFR) on the first day of admission: eGFR≥60 ml·min -1·1.73 m -2 (regular illness group); 15 ml·min -1·1.73 m -2≤eGFR<60 ml·min -1·1.73 m -2 (serious illness group); eGFR<15 ml·min -1·1.73 m -2 or dialysis (critical illness group). Clinical, histological, and outcome differences among the three groups were evaluated and compared using one-way analysis of variance (ANOVA) , χ2 test, Kaplan-Meier survival curve and Cox reggression analysis. Results:167 DPLN patients were studied [155 women; mean age (30±10) years; mean follow-up of (61±45) months]. Renal and patient survival of all patients was 86% at 5 years and 79% at 10 years. Kaplan-Meier analysis showed the renal and patient survival rate at 10 years in the regular illness group, serious illness group and critical illness group was 91%, 70% and 8%, respectively ( χ2=121.93, P<0.01, overall); regular illness group vs serious illness group ( χ2=4.05, P<0.05); regular illness group vs critical illness group ( χ2=97.05, P<0.01); serious illness group vs critical illness group ( χ2=52.28, P<0.01). Multivariable Cox regression analysis found that haematoglobin (Hb)<80 g/L [ HR=2.7, 95% CI(1.2, 6.3), P=0.019], eGFR<60 ml·min -1·1.73 m -2 [ HR=4.1, 95% CI(2.0, 8.2), P<0.01] and large crescents ≥30%[ HR=1.8, 95% CI (1.1, 2.9), P=0.021], were risk factors for the long-term outcome. Conclusion:DPLN patients with normal or slightly decreased renal function have a better long-term prognosis. Moderate to severe impairment of renal function, anemia and large crescents are associated with poor outcome.

Objective:To explore the relationship between serum matrix metalloproteinase-8 (MMP-8), myeloperoxidase (MPO), human cytomegalovirus (HCMV) infection and the type of carotid atherosclerosis in patients with ischemic cerebrovascular disease (ICVD).Methods:From February 2017 to May 2019, 90 patients with ischemic cerebrovascular disease diagnosed by Peking University Medical Rehabilitation Hospital were selected as study group and 90 healthy adult persons who underwent health checkup as control group, and the study group was divided into non-stable plaque type group (30 cases) and stable plaque type group (30 cases) according to the ultrasonic imaging data and referring to the type of carotid plaque of the patients. The patients whose plaque property were between the two groups were were enrolled as the middle type group (30 cases). The relationship between human cytomegalovirus PP65 antigen (HCMV-PP65) in the serum, MMP-8, MPO and peripheral blood white blood cells and carotid atherosclerotic plaque in patients with ischemic cerebrovascular disease was analyzed.Results:The serum MMP-8, MPO level and HCMV-PP65 positive rate in the 3 study groups were significantly higher than that of the control group ( P<0.05), and the serum MMP-8 in different plaque types groups was significantly higher in the study group and the control group than in the control group. The higher the level of MPO and the positive rate of HCMV-PP65, the higher the serum MMP-8 and MPO level in the middle plaque type group, and the positive rate of HCMV-PP65 in the middle plaque type group was higher than that of the stable plaque group and the unstable plaque group ( P<0.05). Conclusions:The serum MMP-8, the MPO level and the HCMV infection are related to the unstable type of the carotid atherosclerosis plaque in the patients with the ischemic cerebrovascular disease, and the recognition of the carotid atherosclerosis is improved; it is an important link to control the severity of patients with ischemic cerebrovascular disease and to take timely and effective prevention and treatment measures.

Objective? To explore the application effect of remote management mode for essential hypertensive patients in the army. Methods? By purposive sampling, a total of 70 male army cadres who had been diagnosed as essential hypertension admitted or during health check in the Sixth Medical Center of PLA General Hospital since 2017 were selected as the research objects. The remote management mode was adopted for them in the intervention. Re-examination was conducted for them one year after implementing the remote mode of management. The patients' blood pressure, lifestyle modification status, and related knowledge acquisition about hypertension were compared before and after the management. Results? The systolic and diastolic blood pressures of patients after intervention were lower than those before intervention, and the differences were statistically significant (P＜ 0.01). After intervention, patients' compliance with medication, salt control behavior, alcohol restriction and exercise were better than those before intervention, and the differences were statistically significant (P＜0.01). The score of hypertension related knowledge after intervention was higher than that before intervention,and the difference was statistically significant (P＜0.01). Conclusions? The remote management mode on blood pressure can achieve good effects in the blood pressure management of the patients with hypertension in the army.

OBJECTIVETo determine whether hyperglycemia activates NFAT2 in cultured podocytes to cause podocyte apoptosis and explore the role of NFAT2 in high glucose-induced podocyte apoptosis.

METHODSImmortalized mouse podocytes were cultured in the presence of normal (5.3 mmol/L) or high glucose (10, 20, 30, and 40 mmol/L) or pretreated with 11R-vivit (100 nmol/L) or cyclosporine A (500 nmol/L) before exposure to 20 mmol/L glucose for different durations (0.5-48 h). The activation of NFAT2 in the podocytes was detected using Western blotting and immunofluorescence assay. The role of NFAT2 in hyperglycemia-induced podocyte apoptosis was explored by observing the inhibition of NFAT2 activation by 11R-vivit using flow cytometry. Intracellular Ca was monitored in high glucose-treated podocytes using Fluo-3/AM. The mRNA and protein expressions of the apoptosis gene Bax were detected using real time-qPCR and Western blotting.

RESULTSExposure to high glucose in the medium time- and dose-dependently activated NFAT2 in cultured podocytes. Pretreatment with cyclosporine A or 11R- VIVIT completely blocked nuclear accumulation of NFAT2. Treatment with 11R- vivit also inhibited high glucoseinduced apoptosis in cultured podocytes. Exposure to high glucose obviously increased [Ca]I in the podocytes to cause activation of calcineurin and the subsequent increment of nuclear accumulation of NFAT2 and Bax expression.

CONCLUSIONSHigh glucose-induced apoptosis in podocytes is mediated by calcineurin/NFAT2/Bax signaling pathway, which may serve as a potential target for therapeutic intervention.

PURPOSE: Adenoid cystic carcinoma (ACC) of the trachea and bronchus is a rare tumor. Although MYB-NFIB oncogene fusion and Notch1 mutation have been identified in ACC, little is known about the expression and clinical significance of Notch1 and its target gene fatty acid binding protein 7 (FABP7) in tracheobronchial ACC. MATERIALS AND METHODS: Primary tracheobronchial ACC that were resected between 1998 and 2014 were identified through the pathology and oncology database from five thoracic oncology centers in China. A tissue array was constructed from the patients’ samples and the expressions of Notch1 and FABP7 were evaluated by immunohistochemistry. The association between the expression of both markers and survival was determined. RESULTS: Overexpression of Notch1 and FABP7, detected in 37.8% and 38.3% of 368 patients with tracheobronchial ACC, respectively, was an independent prognostic indicator for recurrencefree survival (RFS) by multivariable Cox proportional hazard model (p=0.032 and p=0.048, respectively). Overexpression of Notch1, but not of FABP7, predicted overall survival (OS) (p=0.018). When categorized into four groups according to coexpression of Notch1 and FABP7, patients with overexpression of both Notch1 and FABP7 belonged to the group with the shortest RFS and OS (p=0.01 and p=0.048, respectively). CONCLUSION: Expression of Notch1 and FABP7, and coexpression of Notch1 and FABP7, is strongly associated with poor survival in resected tracheobronchial ACC. These data are consistent with the hypothesis that poor differentiation of tracheobronchial ACC correlates with the activation of Notch signaling.
Adenoids* ; Bronchi ; Carcinoma, Adenoid Cystic* ; Carrier Proteins* ; China ; Humans ; Immunohistochemistry ; Oncogene Fusion ; Pathology ; Prognosis ; Proportional Hazards Models ; Retrospective Studies* ; Trachea

Objective To investigate the influence of the nursing intervention on the ankle-brachial pulse wave velocity (PWV) and the ankle-brachial index (ABI) in patients with newly diagnosed type 2 diabetes mellitus. Methods Eighty patients with newly-diagnosed type 2 diabetes mellitus were selected and were completely randomly divided into the intervention group (40 patients) and the control group (40 patients). In the intervention group, the closed integrated nursing management mode was applied. Group health records were established and the nursing management group mode of chronic diseases was applied. The chronic disease management team was organized with specialist physicians, chronic disease specialist nurses and general practice nurses who were specialized trained and got related qualification. The whole team diagnosed patients in hospital and out of hospital, gave mental intervention and daily life guidance to patients (diet, sports and so on). Outside of hospital, the telephone follow-up was made every week; the regular family visit was made and the guidance was given to patients every month; the related presupposed indicators were tested every three months. All the patients who were enrolled in the chronic disease management team were given the pre-job training to fully understand their responsibilities, obligations, work contents, etc. in the team. They also signed the team's responsibility statement. In the control group the traditional diabetes nursing management mode was used. After two years intervention, the early detection atherosclerosis blood indexes (PWV and ABI) of patients in the two groups were compared. Results Before the intervention, there was no significant difference in the PWV or the ABI between the two groups (P> 0.05). After the intervention, the PWV in the intervention group was (1 552±462)cw/s, which was significantly different compared with that in the control group(1 613±417)cw/s (t=2.031, P=0.047). Moreover, in the intervention group, the PWV before the intervention was significantly different compared to the PWV after the intervention(t=2.533,P=0.008). After the intervention, the ABI was improved, but the ABI in the intervention group was not significantly different compared with that in the control group. In the intervention group, the ABI before the intervention was not significantly different from that after the intervention(P>0.05). Conclusions The closed nursing management mode can improve the PWV value in patients with newly diagnosed type 2 diabetes mellitus and delay the development of atherosclerosis.

OBJECTIVETo observe the effect of amiloride on the proteinuria of the 5/6 nephrectomy rats.

METHODSTo establish the 5/6 nephrectomy rats model and divide the experiment into 3 groups, sham operated group(Sham), 5/6 nephrectomy model group(NTX) and 5/6 nephrectomy with amiloride-treated group (NTX+amiloride, n=15). The concentration of protein and mRNA of uPAR and the change of podocytes motility were detected by coomassiebluestaining, immunofluorence method and real-time PCR.

RESULTSAt second week, compared with Control group, the 24 h urine protein of NTX group was significantly increased (47.50 ± 28.05 mg vs 14.28 ± 3.8 mg, P = 0.023). There was no statistical significance in 24-hour urine protein between NTX+amiloride group and NTX group (51.56 ± 21.03 mg vs 47.50 ± 28.05 mg, P = 0.748). The same situation was also observed at the time point of 12 week, comparing with NTX group, 24-hour urine protein decreased in Sham group (188.31 ± 29.82 mg vs 21.32 ± 8.59 mg, P = 0.000) and NTX+amiloride group (188.31 ± 29.82 mg vs 121.37 ± 31.14 mg, P=0.000), with statistical significance when comparing with Sham group, the expression of uPAR mRNA in NTX group was significantly increased (9.74 ± 1.44 vs 1.01 ± 0.13, P = 0.000). In contrast, the expression of uPAR mRNA in NTX rats treated with amiloride was significantly lower than in NTX group (9.74 ± 1.44 vs 5.01 ± 1.36, P = 0.000).

CONCLUSIONAmiloride can reduce the proteinuria of the 5/6 nephrectomy rats model of transient proteinuria by inhibiting the induction of uPAR expression.

Amiloride ; pharmacology ; Animals ; Cell Movement ; Disease Models, Animal ; Nephrectomy ; Podocytes ; drug effects ; metabolism ; Proteinuria ; drug therapy ; Rats ; Real-Time Polymerase Chain Reaction ; Receptors, Urokinase Plasminogen Activator ; metabolism