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ObjectiveTo develop and validate a nomogram for predicting the risk of peripheral artery disease (PAD) in patients with type 2 diabetes mellitus (T2DM) and assess its clinical application value.MethodsClinical data were retrospectively collected from 474 patients with T2DM at the Air Force Medical Center between January 2019 and April 2022. The patients were divided into training and validation sets using the random number table method in a ratio of 7:3. Multivariate logistic regression analysis was performed to identify the independent risk factors for PAD in patients with T2DM. A nomogram prediction model was developed based on the independent risk factors. The predictive efficacy of the prediction model was evaluated using the consistency index (C-index), area under the curve (AUC), receiver operating characteristic (ROC) curve, Hosmer-Lemeshow (HL) test, and calibration curve analysis. Additionally, decision curve analysis (DCA) was performed to evaluate the prediction model’s performance during clinical application.ResultsAge, disease duration, blood urea nitrogen (BUN), and hemoglobin (P<0.05) were observed as independent risk factors for PAD in patients with T2DM. The C-index and the AUC were 0.765 (95% CI: 0.711-0.819) and 0.716 (95% CI: 0.619-0.813) for the training and validation sets, respectively, indicating that the model had good discriminatory power. The calibration curves showed good agreement between the predicted and actual probabilities for both the training and validation sets. In addition, the P-values of the HL test for the training and validation sets were 0.205 and 0.414, respectively, indicating that the model was well-calibrated. Finally, the DCA curve indicated that the model had good clinical utility.ConclusionA simple nomogram based on three independent factors–duration of diabetes, BUN, and hemoglobin levels–may help clinicians predict the risk of developing PAD in patients with T2DM.

Apoptosis of THP-1 macrophage-derived foam cells induced by 5-aminolevulinic acid-mediated sonodynamic therapy is mitochondria-caspase pathway predominant despite the participation of endoplasmic reticulum stress Wang Huan, Ye Tian The first affiliated hospital of Harbin Medical University Objectives: In advanced atherosclerosis, chronic endoplasmic reticulum (ER) stress induces foam cells apoptosis and generates inflammatory reactions. Sonodynamic therapy (SDT) is a non-thermal synergistic method for cancer treatment utilizing low-intensity ultrasound and sonosensitizers. 5-Aminolaevulinic acid (ALA) is the biological precursor of sonosensitizer PpIX in the heme biosynthesis pathway in mitochondria. In this study, we investigated the sub-cellular location of ALA-PpIX in THP-1 macrophage-derived foam cells (FC) and the activation of mitochondria pathway and ER stress induced by ALA-SDT. Methods: FC were incubated with 1 mM ALA. Fluorescence spectrometer was used to detect the location and metabolism of ALA-PpIX in mitochondria and endoplasmic reticulum (ER) of FC. Annexin V-PI staining was used to optimize ALA-SDT treatment parameters by detecting the apoptotic and necrotic rates of FC induced by ALA-SDT with different ALA incubation time and ultrasonic irradiation intensities. Intracellular reactive oxygen species (ROS) level after ALA-SDT was detected by staining with CellROX Ò Green Reagent. Mitochondrial membrane potential after ALA-SDT was detected by staining with JC-1. Pretreated with ROS inhibitor N-acetylcysteine (NAC), pan-caspase inhibitor Z-VAD-FMK and ER stress inhibitor 4-phenylbutyrate (4-PBA), expressions of mitochondria apoptosis associated proteins cytochromc c, cleaved caspase3, cleaved caspase9, Bcl-2, BAX and ER stress associated protein C/EBP-homologous protein (CHOP) in FC after ALA-SDT were detected by Western blotting. Results: Accumulation of ALA-PpIX in mitochondria and ER reached peak at 6-hour, and the fluorescence intensity in mitochondria was triple of that in ER. The highest percentage of apoptotic cells (63.6%AE9.8%) and the maximum apoptosis/necrosis ratio (21.7AE6.3) was observed at 5-hour after ALA-SDT with 6-hour incubation of ALA and 0.4 W/cm 2 ultrasound intensity. After ALA-SDT, intracellular ROS level increased and the mitochondrial membrane potential collapsed. The translocations of cytochrome c from mitochondria into cytosol and Bax from cytosol into mitochondria, cleaved caspase 9, cleaved caspase 3, downregulation of Bcl-2, as well as upregulation of CHOP were detected at 5-hour after ALA-SDT, which could be suppressed by NAC. Activation of mitochondria apoptosis pathway could not be inhibited by 4-PBA. Apoptosis induced by ALA-SDT could be inhibited by Z-VAD-FMK. 4-PBA reduced FC apoposis by one third. Conclusions: Mitochondria-caspase pathway is predominant in the apoptosis of FC induced by ALA-SDT though ER stress participates in.

Objectives Cytochrome P450 (CYP), ATP-binding cassette transporters (ABCB1), and paraoxonase-1 (PON1) play crucial roles in clopidogel absorption and bioactivation. Genotypes in these genes have been associated with the variability of responsiveness to clopidogrel, however their contribution to clopidogrel antiplatelet efficacy in clinical practice is controversy. This study aimed to evaluate the contribution of the genotypes in CYP2C19, ABCB1 and PON1 to clopidogrel antiplatelet efficacy in a cohort of Chinese patients with acute coronary syndrome. Methods A total of 1,329 Chinese-Han patients treated with clopidogrel for acute coronary syndrome (ACS) were consecutively recruited from the Department of Geriatric Cardiology, General Hospital of Chinese People’s Liberation Army, from September 2008 to September 2012. We assessed the relations of CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), CYP2C19*17 (rs12248560), PON1Q129R (rs662) and ABCB1C3435T (rs1045642) to the platelet aggregation after 5 days maintenance dose of clopidogrel administration, the risk for high on-treatment platelet reactivity (HPR), as well as the risk for clinical ischaemic events. The cutoff of HPR was defined as 20 μmol/L adenosine diphosphate (ADP)-induced platelet aggregation >50%. The primary ischaemic endpoints were a composite of cardiovascular death, myocardial infarction, stent thrombosis, urgent revascularisation, and fatal or nonfatal stroke. The follow-up interval for each case was 12 months. Results Both CYP2C19*2 and *3 alleles were significantly associated with higher platelet aggregation after 5 days maintenance dose of clopidogrel administration (P < 0.001 and P = 0.042, respectively). The platelet aggregation in carriers of at least one CYP2C19 loss-of-function allele (CYP2C19*2 or *3) was obviously higher than that in non-carriers (P < 0.001). The carriers of at least one CYP2C19 loss-of-function allele could also predict significantly greater risk of HPR compared with non-carriers (adjusted HR: 1.79, 95% CI: 1.33-2.4, P = 0.003). Patients with the CYP2C19*2 allele had a higher risk of HPR than those with the CYP2C19 wild-type genotype (adjusted HR: 1.56; 95% CI, 1.04-2.33, P = 0.03). However, the carriage of CYP2C19*3 alone could not predict the risk of HPR significantly. During follow-up, carriers of CYP2C19 loss-of-function alleles did not have an increased rate of primary or secondary ischaemic endpoints. No significant relation of CYP2C19*17, PON1Q129R and ABCB1C3435T to the platelet aggregation or ischaemic events could be found. Conclusions In clopidogrel treated Chinese patients with ACS, carriers of at least one CYP2C19 loss-of-function allele could predict greater risk of HPR, with the impact mainly attributing to CYP2C19*2. However, no relationship was seen between CYP2C19 genotypes and ischaemic outcomes. Neither ABCB1 nor PON1 genotype could influence the antiplatelet efficacy of clopidogrel.