BACKGROUND: Based on the China-VHD database, this study sought to develop and validate a Valvular Heart Disease- specific Age-adjusted Comorbidity Index (VHD-ACI) for predicting mortality risk in patients with VHD. METHODS & RESULTS: The China-VHD study was a nationwide, multi-centre multi-centre cohort study enrolling 13,917 patients with moderate or severe VHD across 46 medical centres in China between April-June 2018. After excluding cases with missing key variables, 11,459 patients were retained for final analysis. The primary endpoint was 2-year all-cause mortality, with 941 deaths (10.0%) observed during follow-up. The VHD-ACI was derived after identifying 13 independent mortality predictors: cardiomyopathy, myocardial infarction, chronic obstructive pulmonary disease, pulmonary artery hypertension, low body weight, anaemia, hypoalbuminaemia, renal insufficiency, moderate/severe hepatic dysfunction, heart failure, cancer, NYHA functional class and age. The index exhibited good discrimination (AUC, 0.79) and calibration (Brier score, 0.062) in the total cohort, outperforming both EuroSCORE II and ACCI (P < 0.001 for comparison). Internal validation through 100 bootstrap iterations yielded a C statistic of 0.694 (95% CI: 0.665-0.723) for 2-year mortality prediction. VHD-ACI scores, as a continuous variable (VHD-ACI score: adjusted HR (95% CI): 1.263 (1.245-1.282), P < 0.001) or categorized using thresholds determined by the Yoden index (VHD-ACI ≥ 9 vs. < 9, adjusted HR (95% CI): 6.216 (5.378-7.184), P < 0.001), were independently associated with mortality. The prognostic performance remained consistent across all VHD subtypes (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation, tricuspid valve disease, mixed aortic/mitral valve disease and multiple VHD), and clinical subgroups stratified by therapeutic strategy, LVEF status (preserved vs. reduced), disease severity and etiology. CONCLUSION The VHD-ACI is a simple 13-comorbidity algorithm for the prediction of mortality in VHD patients and providing a simple and rapid tool for risk stratification.

This paper explores the impacts of accelerated rehabilitation protocols following anterior cruciate ligament reconstruction(ACLR)on bone tunnel enlargement(BTE).While accelerated rehabilitation can shorten the recovery time and improve the knee function,it may increase the risk of BTE.In the early rehabilitation phase after ACLR,excessive early weight-bearing and rapid progression of knee flexion angles should be avoided,along with the proper use of braces.Continuous passive motion is not recommended in the early phase post-ACLR to prevent potential effects on BTE.Further research is needed to investigate the mechanisms of BTE and develop more effective rehabilitation strategies.This will help to select appropriate rehabilitation protocols for patients and balance functional recovery with the risk of BTE,thereby reducing the revision rate and improving postoperative outcomes.
Humans ; Anterior Cruciate Ligament Reconstruction/rehabilitation*

Purpose To investigate the corr-elation between Rap1 GAP expression in colon cancer tissues and clinicopatho-logical features and prognosis.Methods Immunohistochemistry was used to detect Rap1 GAP protein expression in 125 cases of colon cancer,and its correlation with clinicopathological features and prognosis was analyzed.Rap1 GAP protein expression in co-lon cancer LOVO,HCT116,SW480 cells and normal colon epi-thelial HCoEPiC cells was detected by Western blot.The expres-sion of Rap1 GAP was down-regulated and up-regulated in LO-VO,HCT116 and SW480 cells by lentivirus transfection,and di-vided into no-load group(sh-NON,LV-NON),sh-Rap1 GAP group(low expression Rap1 GAP)and LV-Rap1 GAP group(overexpression Rap1 GAP)according to different treatments.The transfection efficiency was verified by Western blotting.MTT assay and Transwell assay were used to detect cell proliferation,invasion and migration in each group.Results In 125 colon cancer samples,83 cases(66.4％)had the loss of Rap1 GAP expression,which was higher than that in paracancer control(7.2％,P＜0.001).The rate of loss of Rap1 GAP expression was correlated with the degree of tumor differentiation(x2=6.152,P=0.011)and the presence of mucinous adenocarcino-ma(x2=4.908,P=0.028),but not with gender,age,tumor location,tumor stage,or lymph node metastasis(P＞0.05).Western blotting results showed that compared with HCoEPiC(0.189±0.081)cells,Rap1 GAP protein expression was in-creased in colon cancer LOVO(0.238±0.008)cells.Rap1 GAP protein expression was decreased in HCT116(0.064± 0.002)and SW480(0.152±0.026)cells(F=159.6,P＜0.05).After LOVO cells were transfected with Rap1 GAP low expression lentivirus,the expression level of Rap1 GAP in sh-Rap1 GAP-1 group(0.733±0.071)and sh-Rap1 GAP-2 group(0.559±0.136)and sh-Rap1 GAP-3 group(0.606±0.037)was significantly lower than that in LOVO group(1.880± 0.129)(F=49.57,P＜0.05).Compared with sh-NON(1.260±0.109)group,the proliferation ability of sh-Rap1 GAP-2(1.569±0.059)and sh-Rap1 GAP-3(1.548±0.087)cells was significantly increased at 72 h(F=28.36,P＜0.05).Its invasion and migration ability were significantly increased(P＜0.05).After HCT116 cells transfected with overexpression lentivirus,the expression of Rap1 GAP protein in LV-Rap1 GAP group(1.395±0.137)was relatively higher than that in LV-NON group(0.485±0.097)(P＜0.05).The results of MTT assay showed that compared with LV-NON(0.652±0.047)group,the proliferation ability of cells in LV-Rap1 GAP(1.212 ±0.038)group was decreased,and the invasion and migration ability were significantly decreased(P＜0.05).The transfection results,proliferation,invasion and migration of SW480 cells were consistent with those of HCT116 cells.Conclusion The loss rate of Rap1 GAP expression is related to the differentiation degree of colon cancer and whether it is accompanied by mucin-ous adenocarcinoma.The up-regulation of Rap1 GAP expression can inhibit the proliferation,invasion and migration of colon cancer cells,providing a theoretical basis for exploring the occur-rence and development of colon cancer.

Peroxisome proliferator-activated receptor gamma(PPAR-γ)is a member of the ligand-activated nuclear tran-scription factor superfamily.Activated PPAR-γ is involved in the regulation of many central nervous system(CNS)events,and is involved in cholesterol metabolism by inducing or inhibi-ting a series of gene pathways,thereby inhibiting the deposition of β-amyloid protein(Aβ).It plays an important neuroprotec-tive role in Alzheimer's disease(AD),improves memory and cognition in AD,and is a potential target for AD.Drug develop-ment aimed at restoring cholesterol homeostasis may be a poten-tial strategy to counteract AD.By analyzing the distribution and structure of PPAR-γ,focusing on the biological correlation be-tween PPAR-γ-mediated cholesterol metabolism and AD,this paper describes the mechanism regulation of PPAR-γ on key proteins,genes and their corresponding molecules,providing a new reference for the treatment of AD.

Objective:To analyze the application value of color Doppler ultrasound,microribonucleic acid-19a(miR-19a)and miR-210 in carotid artery stenosis.Methods:A total of 102 patients with carotid artery stenosis who were diagnosed and treated in Cangzhou People's Hospital from October 2020 to October 2022 were selected as the research group,and 102 health persons who underwent color Doppler ultrasound of physical examination in hospital at the same period were selected as the health control group.Both two groups underwent color Doppler ultrasound examination and digital subtraction angiography(DSA)within one week after admitted to hospital.The miR-19a and miR-210 between the two groups were compared,and the miR-19a and miR-210 of patients with different stenosis degrees of research group also were compared.And then,the diagnostic values of color Doppler,miR-19a,miR-210 and the combination of them were analyzed in diagnosing carotid artery stenosis.Results:The results of color Doppler ultrasound in detecting common carotid artery 102 patients of research group indicated that 15 cases were normal,and 15 cases occurred mild stenosis,and 21 cases occurred moderate stenosis,and 21 cases occurred severe stenosis and 33 cases occurred complete occlusion.The miR-19a of the research group was significantly higher than that of the health control group,and the miR-210 of the research group was significantly lower than that of the health control group(t=10.755,-5.903,P<0.05).The miR-19a results of the research group indicated that the miR-19a of mild stenosisthat of moderate stenosis>severe stenosis>complete occlusion,and the differences were statistical significant(F=160.399,147.462,P<0.05),respectively.The receiver operating characteristic(ROC)curve analysis showed that the area under curve(AUC)values of color Doppler ultrasound,miR-19a,miR-210 and combined diagnosis of them for carotid artery stenosis were respectively 0.892,0.842,0.729 and 0.978,and the sensitivity and specificity of the combined diagnosis were respectively 97.1%and 95.1%.Conclusion:The combined diagnosis of color Doppler ultrasound,miR-19a and miR-210 has higher diagnostic value for carotid artery stenosis.

This study aims to investigate the effects of Bushen Huoxue Decoction regulating adipose-derived stem cells(ADSCs)-exosomes(Exos) on the apoptosis of intervertebral disc nucleus pulposus cells(NPCs) and extracellular signal-regulated kinase(ERK) signaling pathway. Tert-butyl hydrogen peroxide(TBHP)-induced NPCs were divided into control, model, drug-containing serum, blank Exos, normal serum Exos, and drug-containing serum Exos groups. Cell viability and proliferation were examined by the CCK-8 assay and EdU staining, respectively. The cell cycle and apoptosis were evaluated by flow cytometry. Enzyme-linked immunosorbent assay was employed to measure the levels of interleukin(IL)-1β, tumor necrosis factor(TNF)-α, and IL-6. The mRNA levels of aggrecan, collagen type Ⅱ alpha 1 chain(COL2A1), and ERK were determined by qRT-PCR, and the protein levels of aggrecan, COL2A1, and p-ERK were determined by Western blot. The results showed that compared with the model group, the treatments with drug-containing serum, blank Exos, and normal serum Exos enhanced the viability and proliferation of NPCs, decreased the proportion of cells in the G_0/G_1 phase, increased the proportion of cells in the S phase, reduced apoptosis, lowered the levels of IL-1β, TNF-α, and IL-6, up-regulated the mRNA and protein levels of aggrecan and COL2A1, and down-regulated the mRNA level of ERK and the protein level of p-ERK. Compared with the drug-containing serum, blank Exos, and normal serum Exos groups, the treatment with drug-containing serum Exos enhanced the viability and proliferation of NPCs, decreased the proportion of cells in the G_0/G_1 phase, increased the cells in the S phase, reduced apoptosis, lowered the levels of IL-1β, TNF-α, and IL-6, up-regulated the mRNA and protein levels of aggrecan and COL2A1, and down-regulated the mRNA level of ERK and the protein level of p-ERK. The results confirmed that the Exos secreted by ADSCs after treatment with Bushen Huoxue Decoction-containing serum promoted the proliferation of degenerated NPCs, inhibited apoptosis and the expression of inflammatory mediators, and promoted the production of proteoglycans and collagen, thus delaying the progression of intervertebral disc degeneration, the mechanism of which was related to the regulation of the ERK signaling pathway.
Intervertebral Disc Degeneration/drug therapy* ; Apoptosis/drug effects* ; Nucleus Pulposus/cytology* ; Drugs, Chinese Herbal/pharmacology* ; Animals ; Rats ; MAP Kinase Signaling System/drug effects* ; Rats, Sprague-Dawley ; Collagen Type II/metabolism* ; Humans ; Cell Proliferation/drug effects* ; Stem Cells/metabolism* ; Aggrecans/metabolism* ; Cell Survival/drug effects* ; Male ; Cells, Cultured ; Tumor Necrosis Factor-alpha/metabolism*

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.

Humans ; Comorbidity ; Diabetes Mellitus/genetics* ; East Asian People ; Hypertension/genetics* ; Hypertriglyceridemia/genetics* ; Obesity/genetics* ; Receptors, Calcitriol/genetics*

Background: and Purpose Intravenous tenecteplase (TNK) efficacy has not been well demonstrated in acute ischemic stroke (AIS) beyond 4.5 hours after onset. This study aimed to determine the effect of intravenous TNK for AIS within 4.5 to 24 hours of onset. Methods: In this pilot trial, eligible AIS patients with diffusion-weighted imaging (DWI)-fluid attenuated inversion recovery (FLAIR) mismatch were randomly allocated to intravenous TNK (0.25 mg/kg) or standard care within 4.5–24 hours of onset. The primary endpoint was excellent functional outcome at 90 days (modified Rankin Scale [mRS] score of 0–1). The primary safety endpoint was symptomatic intracranial hemorrhage (sICH). Results: Of the randomly assigned 80 patients, the primary endpoint occurred in 52.5% (21/40) of TNK group and 50.0% (20/40) of control group, with no significant difference (unadjusted odds ratio, 1.11; 95% confidence interval 0.46–2.66; P=0.82). More early neurological improvement occurred in TNK group than in control group (11 vs. 3, P=0.03), but no significant differences were found in other secondary endpoints, such as mRS 0–2 at 90 days, shift analysis of mRS at 90 days, and change in National Institutes of Health Stroke Scale score at 24 hours and 7 days. There were no cases of sICH in this trial; however, asymptomatic intracranial hemorrhage occurred in 3 of the 40 patients (7.5%) in the TNK group. Conclusion This phase 2, randomized, multicenter study suggests that intravenous TNK within 4.5–24 hours of onset may be safe and feasible in AIS patients with a DWI-FLAIR mismatch.

OBJECTIVES: To observe the effects on the glucose-lipid metabolism and the expression of zinc-α2-glycoprotein (ZAG) and glucose transporter 4 (GLUT4) in the femoral quadriceps and adipose tissue after electroacupuncture (EA) at "Pishu" (BL 20), "Weiwanxiashu" (EX-B 3), "Zusanli" (ST 36) and "Sanyinjiao" (SP 6) in the rats with diabetes mellitus type 2 (T2DM), so as to explore the effect mechanism of EA in treatment of T2DM. METHODS: Twelve ZDF male rats were fed with high-sugar and high-fat fodder, Purina #5008 for 4 weeks to induce T2DM model. After successfully modeled, the rats were randomly divided into a model group and an EA group, with 6 rats in each one. Additionally, 6 ZL male rats of the same months age were collected as the blank group. The rats in the EA group were treated with EA at bilateral "Pishu" (BL 20), "Weiwanxiashu" (EX-B 3), "Zusanli" (ST 36) and "Sanyinjiao" (SP 6), with continuous wave, 15 Hz in frequency, and 2 mA in intensity. The electric stimulation lasted 20 min each time. EA was delivered once daily, 6 times a week for 4 weeks. Separately, the levels of fasting blood glucose (FBG) was measured before modeling, before and after intervention, and the body mass of each rat was weighted before and after intervention. After intervention, the levels of the total cholesterol (TC), triacylglycerol (TG) and free fatty acid (FFA) in serum were detected using enzyme colorimetric method; and the levels of the serum insulin (INS) and ZAG were detected by ELISA. Besides, the insulin sensitivity index (HOMA-ISI) was calculated. With Western blot technique adopted, the protein expressions of ZAG and GLUT4 in the femoral quadriceps and adipose tissue were determined. RESULTS: After intervention, compared with the blank group, the levels of FBG and body mass, and the levels of serum TC, TG, FFA and INS increased (P<0.01), while HOMA-ISI decreased (P<0.01); the level of ZAG in the serum and the protein expressions of ZAG and GLUT4 in the femoral quadriceps and adipose tissue dropped (P<0.01) in the model group. In the EA group, compared with the model group, the levels of FBG and body mass, and the levels of serum TC, TG, FFA and INS were reduced (P<0.01), and HOMA-ISI increased (P<0.01); the level of ZAG in the serum and the protein expressions of ZAG and GLUT4 in the femoral quadriceps and adipose tissue increased (P<0.01, P<0.05). CONCLUSIONS Electroacupuncture can effectively regulate glucose-lipid metabolism, improve insulin resistance and sensitivity in the rats with T2DM, which is associated with the modulation of ZAG and GLUT4 expression in the skeletal muscle and adipose tissue.
Rats ; Male ; Animals ; Glucose/metabolism* ; Electroacupuncture ; Rats, Sprague-Dawley ; Diabetes Mellitus, Type 2/therapy* ; Lipid Metabolism ; Triglycerides ; Adipose Tissue/metabolism* ; Acupuncture Points