Development and Validation of a Novel Model for Predicting Coronary Heart Disease in Snoring Hypertensive Patients with Hyperhomocysteinemia.

Hypertensive patients with snoring and elevated plasma homocysteine levels are common. When these factors are combined, the risk of coronary heart disease (CHD) is high. Herein, we developed and validated an easy-to-use nomogram to predict high-risk CHD in snoring hypertensive patients with elevated plasma homocysteine.Snoring patients (n = 1,962) with hyperhomocysteinemia and hypertension were divided into training (n = 1,373, 70%) and validation (n = 589, 30%) sets. We extracted CHD predictors using multivariate Cox regression analysis, then constructed a nomogram model. Internal validation using 1,000 bootstrap resampling was performed to assess the consistency and discrimination of the predictive model using the area under the receiver operating characteristic curve (AUC) and calibration plots.We constructed a nomogram model with the extracted predictors, including age, waist-height ratio, smoking, and low-density lipoprotein cholesterol levels. The AUCs of the training and validation cohorts at 80 months were 0.735 (95% CI: 0.678-0.792) and 0.646 (95% CI: 0.547-0.746), respectively. The consistency between the observed CHD survival and the probability of CHD survival in the training and validation sets was acceptable based on the calibration plots. A total of more than 151 points in the nomogram can be used in the identification of high-risk patients for CHD among snoring hypertensive patients with elevated plasma homocysteine.We developed a CHD risk prediction model for snoring hypertension patients with hyperhomocysteinemia. Our findings provide a useful clinical tool for the rapid identification of high-risk CHD at an early stage.

Development and Validation of a Coronary Heart Disease Risk Prediction Model in Snorers with Hypertension: A Retrospective Observed Study.

Purpose: To develop and validate a risk prediction model for coronary heart disease (CHD) in snorers with hypertension, including traditional and new risk factors. Patients and Methods: Twenty factors were evaluated in the records of 2810 snorers with hypertension. Training (70%) and validation (30%) sets were created by random allocation of data, and a new nomogram model was developed. The model's discrimination and calibration were measured by calculating the area under the receiver operating curve (AUC) and creating calibration charts. The performance of the nomogram model was compared with that of the Prediction for ASCVD Risk in China (China-PAR) and Framingham models by decision curve analysis. An optimal cutoff point for the risk score in the training set was computed to stratify patients. Results: In the nomogram model, the AUCs for predicting CHD at 5, 7 and 9 years in the training set were 0.706 (95% confidence interval [CI] 0.649-0.763), 0.703 (95% CI 0.655-0.751) and 0.669 (95% CI 0.593-0.744), respectively. The respective AUCs were 0.682 (95% CI 0.607-0.758), 0.689 (95% CI 0.618-0.760) and 0.664 (95% CI 0.539-0.789) in the validation set. The calibration chart showed that the predicted events from the nomogram score were close to the observed events. Decision curve analysis indicated that the nomogram score was slightly better than the Prediction for ASCVD Risk in China (China-PAR) and Framingham models for predicting the risk of CHD in snorers with hypertension. A cutoff point was identified for being CHD-free (a nomogram score of ≤121), which could be helpful for the early identification of individuals at high-risk of CHD. Conclusion: The nomogram score predicts the risk probability of CHD in snorers with hypertension at 5, 7 and 9 years, and shows good capability in terms of discrimination and calibration. It may be a useful tool for identifying individuals at high risk of CHD.

The non-linear relationship between triglyceride-glucose index and risk of chronic kidney disease in hypertensive patients with abnormal glucose metabolism: A cohort study.

Background: Triglyceride-glucose (TyG) index has been reported to be associated with cardiovascular disease (CVD). However, few studies have focused on TyG index and the risk of chronic kidney disease (CKD). Thus, this study aims to explore the relationship between TyG index and CKD. Methods: A total of 2,033 participants with hypertension between January 2012 and May 2019 were included in the longitudinal observational study. All patients are grouped according to the TyG index quartile. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m2 and/or positive proteinuria. Multivariate Cox proportional hazards models were used to investigate the relationship between TyG index and CKD. Results: During a median follow-up of 31 months, 302 participants developed CKD, with a mean age of 55.5 years and median TyG of 8.94. Compared with those in the lowest quartile of TyG index, participants in the highest quartile of TyG index exhibited 1.63-fold higher hazard ratio (95% CI: 1.14-2.33, P = 0.007) for presence of CKD. And restricted cubic spline analysis showed the relationship between TyG index and CKD is non-linear (P non-linearity = 0.021). The hazard ratio for CKD first fell and after rising until around 8.94 of TyG index and started to increase rapidly afterward (P for TyG < 0.001). Conclusion: Higher TyG index is associated with the increased risk for CKD. Early intervention of metabolic factors may prevent the occurrence of CKD, thereby reducing the incidence of CVD and premature death.

Diagnosis and treatment of acquired factor VIII deficiency: a case report and literature review.

Acquired haemophilia A (AHA) is a rare haemorrhagic disease characterized by spontaneous extensive subcutaneous haemorrhage and soft tissue haematoma. The activated partial thromboplastin time is significantly prolonged and cannot be corrected by normal plasma. Approximately 50% of AHA patients lack a specific aetiology, so this can easily result in a misdiagnosis. This current case report describes a 27-year-old male that presented with gingival bleeding, haematuria and haematochezia with no obvious cause. At first, it was thought that he might have experienced anticoagulant rodenticide poisoning, but the subsequent anticoagulant rodenticide test was negative. At the same time, the patient was screened for mutations associated with bleeding and coagulation diseases. Two mutations were identified: a p.Y471H mutation the plasminogen activator, tissue type (PLAT) gene; and a p.Y244Y mutation the serpin family E member 1 (SERPINE1) gene. It should be noted that patient had no previous history of thrombosis or haemorrhagic disease, which confused the diagnosis. A professional haemophilia research centre provided clarification of the diagnosis when anti-factor VIII antibodies were detected. The patient was treated with 30 mg/day prednisone orally. Multiple follow-up examinations showed continuous complete remission. No factor VIII antibodies were detected in his blood and coagulation factor VIII increased significantly.

Development and Validation of a Prognostic Model to Predict High-Risk Patients for Coronary Heart Disease in Snorers With Uncontrolled Hypertension.

Purpose: Snoring or obstructive sleep apnea, with or without uncontrolled hypertension, is common and significantly increases the risk of coronary heart disease (CHD). The aim of this study was to develop and validate a prognostic model to predict and identify high-risk patients for CHD among snorers with uncontrolled hypertension. Methods: Records from 1,822 snorers with uncontrolled hypertension were randomly divided into a training set (n = 1,275, 70%) and validation set (n = 547, 30%). Predictors for CHD were extracted to construct a nomogram model based on multivariate Cox regression analysis. We performed a single-split verification and 1,000 bootstraps resampling internal validation to assess the discrimination and consistency of the prediction model using area under the receiver operating characteristic curve (AUC) and calibration plots. Based on the linear predictors, a risk classifier for CHD could be set. Results: Age, waist circumference (WC), and high- and low-density lipoprotein cholesterol (HDL-C and LDL-C) were extracted as the predictors to generate this nomogram model. The C-index was 0.720 (95% confidence interval 0.663-0.777) in the derivation cohort and 0.703 (0.630-0.776) in the validation cohort. The AUC was 0.757 (0.626-0.887), 0.739 (0.647-0.831), and 0.732 (0.665-0.799) in the training set and 0.689 (0.542-0.837), 0.701 (0.606-0.796), and 0.712 (0.615-0.808) in the validation set at 3, 5, and 8 years, respectively. The calibration plots showed acceptable consistency between the probability of CHD-free survival and the observed CHD-free survival in the training and validation sets. A total of more than 134 points in the nomogram can be used in the identification of high-risk patients for CHD among snorers with uncontrolled hypertension. Conclusion: We developed a CHD risk prediction model in snorers with uncontrolled hypertension, which includes age, WC, HDL-C, and LDL-C, and can help clinicians with early and quick identification of patients with a high risk for CHD.

Proteomics analysis reveals the correlation of programmed ROS-autophagy loop and dysregulated G1/S checkpoint with imatinib resistance in chronic myeloid leukemia cells.

Although tyrosine kinase inhibitors (TKIs), including imatinib, have greatly improved clinical treatment of patients with chronic myeloid leukemia (CML), drug resistance remains a major obstacle. Studies on the mechanisms underlying imatinib resistance and other alternative drugs are urgently needed. Liquid chromatography tandem mass spectrometry was applied to investigate the differences in proteomics and phosphoproteomics between K562 and K562/G (imatinib resistant K562). Multiple bioinformatics analyses were performed to unveil the differential signal pathways. CCK-8 was used to detect cell proliferation. Flow cytometry was performed to analyze reactive oxygen species (ROS), cell cycle, and cell apoptosis. Western blotting and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) were used to observe the changes of ROS and autophagy associated with imatinib resistance in CML. Our results indicated that ROS-autophagy formed one negative feedback loop and was associated with imatinib resistance. Additionally, the limited-rate enzymes of serine synthesis pathway were escalated in K562/G, which could contribute to the increased cyclin-dependent kinases and cell proliferation index. According to phosphoproteomics data, K562/G cells exhibited abnormal phosphorylation of splicing signals. These results revealed that it could be one useful strategy to correct metabolism shift and oxidative stress, or moderately regulate autophagy. Future research should focus on the discovery of potential targets in ROS-autophagy loop.

Higher aldosterone is associated with increased renal impairment risk in patients with hypertension and abnormal glucose metabolism: a longitudinal study.

OBJECTIVE: The aim of this study was to evaluate the association between plasma aldosterone concentration (PAC) and renal impairment in patients with both hypertension and abnormal glucose metabolism (AGM). METHODS: The longitudinal observational study included 2033 hypertensive individuals with AGM who did not have chronic kidney disease (CKD) at baseline. CKD was defined as estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m2 and/or positive proteinuria. Directed acyclic graphs and LASSO regression analyses were applied to identify adjusted sets. Cox proportional hazard models and linear regression were used to evaluate the association of PAC with CKD and its components including decreased renal function (DRF) and proteinuria. Mediation analysis was used to examine the role of blood pressure (BP) in the association between the two. RESULTS: During total follow-up of 5951 person-years with a median follow-up of 31 months, 291 participants developed CKD. The incidence of CKD was increased with the elevation in tertile PAC. Multivariable Cox model showed that PAC was positively associated with increased CKD risk (hazard ratio = 1.76 for natural log-transformed PAC, P < 0.001), and with increased risk of DRF and proteinuria. SBP mediated 7.5-17.9% of the association between PAC and renal impairment. Overall results remained consistent and significant in sensitivity analysis by excluding those with suspicious primary aldosteronism, too short follow-up time and mineralocorticoid receptor antagonists use. CONCLUSION: Higher PAC was associated with increased CKD risk in patients with hypertension and AGM, even in the absence of suspicious primary aldosteronism. The results indicate PAC may serve as a potential therapeutic target in this population.

Association between Plasma Homocysteine Concentrations and the First Ischemic Stroke in Hypertensive Patients with Obstructive Sleep Apnea: A 7-Year Retrospective Cohort Study from China.

PURPOSE: This study was aimed at investigating the association between baseline plasma homocysteine (Hcy) concentrations and the risk of the first ischemic stroke (IS) and at investigating any possible influential modifying factors in hypertensive patients with obstructive sleep apnea (OSA). METHODS: Cox proportional hazards regression was employed to investigate the relationship between plasma Hcy concentration and the first IS. A generalized additive model was applied to determine the nonlinear relationship. In addition, we conducted subgroup analysis. RESULTS: A total of 2350 hypertensive patients with OSA without a history of IS were enrolled in this study. At a median follow-up of 7.15 years, we identified 93 cases of the first IS. After adjusting for potential confounding, the findings revealed that plasma Hcy concentration was strongly and positively associated with the occurrence of the first IS (per SD increment; HR = 1.37, 95% CI: 1.30-1.44). A nonlinear relationship was found between plasma Hcy concentration and the risk of developing the first IS with inflection points for plasma Hcy of 5 µmol/L. In stratified analysis, a greater positive correlation was found between baseline plasma Hcy concentrations and new-onset IS in patients with DBP ≥ 90 mmHg (per SD increment; HR = 1.48, 95% CI: 1.33-1.65 vs. <90 mmHg: HR = 1.20, 95% CI: 1.02-1.42; P-interaction = 0.04) and BMI ≥ 24 and <28 kg/m2 (per SD increment; HR = 1.46, 95% CI: 1.26-1.70 vs. <24 kg/m2: HR = 1.13, 95% CI: 0.95-1.33 vs. ≥28 kg/m2: HR = 1.46, 95% CI: 1.25-1.70; P-interaction = 0.03). CONCLUSION: Elevated plasma Hcy concentrations are independently associated with the risk of the first IS in hypertensive patients with OSA. Plasma Hcy concentrations ≥ 5 µmol/L surely increased the risk of the first IS in hypertensive patients with OSA.

Direct-on-Target Microdroplet Growth Assay Applications for Clinical Antimicrobial Susceptibility Testing.

Direct-on-target microdroplet growth assay is a new technique for analysing bacterial sensitivity and mechanisms of resistance. It is based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and allows for easy and rapid testing. Here, we describe the development and procedure of the direct-on-target microdroplet growth assay and summarise the latest clinical applications.

Effects of tacrolimus on the TGF­ß1/SMAD signaling pathway in paraquat­exposed rat alveolar type II epithelial cells.

Paraquat is a highly toxic pesticide, which often causes pulmonary interstitial fibrosis after poisoning, and there is no specific antidote. At present, limited studies have reported that tacrolimus, as an immunosuppressant, can inhibit pulmonary fibrosis, but the specific mechanism remains unknown. The aim of the present study was to demonstrate the effect of tacrolimus on the TGF­ß1 pathway associated with pulmonary fibrosis in paraquat exposed alveolar type II epithelial cells, and to identify the antipulmonary fibrosis mechanism of tacrolimus The rat alveolar epithelial type II RLE­6TN cell line was exposed to paraquat and treated with or without tacrolimus for 24 h, or with a TGF­ß1 receptor type I/II inhibitor (LY2109761) for 1, 4, 8 or 16 h. MTT assays were used to detect the viability of rat alveolar type II epithelial cells under these different treatment conditions, while the concentrations of TGF­ß1, SMAD3, SMAD7 and connective tissue growth factor (CTGF) in the cell culture supernatant were determined using ELISAs. Additionally, reverse transcription­quantitative PCR and immunofluorescence were used to analyze the mRNA and protein expression levels of TGF­ß1, SMAD3, CTGF and SMAD7. The results demonstrated that the inhibition of the proliferation of RLE­6TN cells exposed to 200 nmol/l paraquat was 26.05±2.99%. The inhibition rate of 10 ng/ml tacrolimus on paraquat­exposed alveolar type II epithelial cells was 18.40±3.49%. The inhibition rate caused by 5 µmol/l LY2109761 was 26.56±4.49%. The expression levels of TGF­ß1, SMAD3 and CTGF, as well as their concentrations in the culture supernatant, were significantly downregulated in the tacrolimus group compared with the paraquat group. However, both the concentration and expression levels of SMAD7 were significantly upregulated in the tacrolimus group compared with the paraquat group. In conclusion, tacrolimus can reduce the levels of TGF­ß1, SMAD3 and CTGF, increase the level of SMAD7 in TGF­ß1 signaling pathway and protect the development of pulmonary fibrosis in paraquat exposed alveolar epithelial cells.

Insulin-like growth factor-binding proteins play a significant role in the molecular response to imatinib in chronic myeloid leukemia patients.

Imatinib (IM) is successfully used in the majority of patients with chronic myeloid leukemia (CML), but some patients develop resistance to drug treatment. Insufficient apoptosis results in uncontrolled cell proliferation, which is closely associated with the occurrence of drug resistance. Therefore, it is crucial to identify new biomarkers related to drug resistance. This aim of the present study was to investigate the profile of apoptosis-related proteins in K562 and K562/G (IM-resistant K562 cells) cells, in order to identify new biomarkers. A human apoptosis antibody array was used to screen 46 proteins in the two cells lines, among which 20 proteins were found to be differentially expressed between K562 and K562/G cells. The major proteins included secreted caspase-8, insulin-like growth factor-binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, caspase-3 and p27. IGFBP-1 IGFBP-2 and IGFBP-3 were selected for the follow-up study. Subsequently, reverse transcription-quantitative PCR analysis and western blotting were used to detect the expression levels of the IGFBPs. The results revealed that the expression levels of IGFBP-2 and IGFBP-3 in K562/G cells were significantly decreased compared with those in K562 cells, whereas the IGFBP-1 level was higher. Moreover, no significant correlation was observed between IGFBP-1 or IGFBP-2 and the level of the BCR-ABL fusion protein, whereas decreasing IGFBP-3 levels were associated with increasing BCR-ABL levels. These results suggested that IGFBP-1, IGFBP-2 and IGFBP-3 could be useful novel biomarkers for IM resistance in CML.

MicroRNA-221 sensitizes chronic myeloid leukemia cells to imatinib by targeting STAT5.

MicroRNAs (miRNAs) are involved in various processes from the development to drug resistance of tumors, including chronic myeloid leukemia (CML). In this study, we examined the STAT5-related miRNA-expression profile in CML cell lines (K562 and imatinib-resistant K562/G) by quantitative real-time reverse-transcriptase polymerase chain reactions. MiR-221 expression was markedly decreased in K562/G cells and peripheral blood mononuclear cells from patients with treatment failure, when compared to imatinib-sensitive CML cells and patients with optimal responses respectively. We also observed the expression of STAT5 inversely correlated with miR-221 expression in K562 and KBM5 cells. Additionally, STAT5 was validated as a direct target of miR-221 in dual-luciferase reporter vector assays. MiR-221 restoration and STAT5 knockdown in K562/G cells increased the sensitivity of CML cells to imatinib by reducing the Bcl2: Bax ratio. Collectively, our data suggested that miR-221-STAT5 axis played crucial roles in controlling the sensitivity of CML cells to imatinib.