H-type Hypertension Status and Influencing Factors of the Elderly People Over 80 Years Old Based on Random Forest Model.

Hypertension is a common chronic disease in elderly people over 80 years old. Clinically, H-type hypertension occurs when hypertension coexists with hyperhomocysteinemia level of ≥ 10 umol/L. Effective identification of risk factors for H-type hypertension in the elderly can greatly improve patient prognosis.Consecutively, 494 patients with hypertension admitted to the Fourth Affiliated Hospital of Harbin Medical University from January 2019 to December 2021 were selected as the study population. They were divided into H-type hypertension (n = 197) and non-H-type hypertension groups (n = 297). Patient data were collected, including basic information, history, and clinical data. The random forest model and LASSO analysis were used to screen the influencing factors for H-type hypertension. Multiple stepwise regression analysis was used to analyze the selected variables.A total of 197 elderly people over 80 years old suffered from H-type hypertension, with an incidence rate of 39.88%. The random forest model and LASSO analysis results showed that the top 8 independent variables in importance ranking were ejection fraction (EF), fibrinogen, glycated hemoglobin (HbA1c), B-type natriuretic peptide, creatinine, fasting blood glucose, uric acid, and serum triiodothyronine levels. The results of multivariate analysis showed that EF was the protective factor, while fibrinogen, HbA1c, and creatinine were the risk factors for H-type hypertension in elderly people over 80 years old (P < 0.05).Healthcare professionals can indirectly assess the prevalence of H-type hypertension by focusing on EF, fibrinogen, creatinine, and HbA1c in elderly hypertensive patients. This provided proactive intervention and medical services to improve prognosis outcomes.

MultiscaleDTA: A multiscale-based method with a self-attention mechanism for drug-target binding affinity prediction.

The task of predicting drug-target affinity (DTA) plays an increasingly important role in the early stage of in silico drug discovery and development. Currently, a variety of machine learning-based methods have been presented for DTA prediction and achieved outstanding performance, which is beneficial for speeding up the development of new drugs. However, most convolutional neural networks (CNNs) based methods ignore the significance of information from CNN layers with different scales for DTA prediction. In addition, each feature provides different contributions to the final task. Therefore, in this study, we propose a novel end-to-end deep learning-based framework, MultiscaleDTA, to predict drug-target binding affinity. MultiscaleDTA incorporates multi-scale CNNs and a self-attention mechanism to capture multi-scale and comprehensive features for characterizing the intrinsic properties of drugs and targets. Extensive experimental results on both regression and binary classification tasks demonstrate that MultiscaleDTA achieves competitive performance compared to state-of-the-art methods.

Translation and validation of the simplified Chinese new Knee Society Scoring System.

BACKGROUND: The NKSS has recently been translated into Dutch version. The reliability and validity were also assessed. However, there is no Simplified Chinese version of New Society Knee Scoring System (SC-NKSS) for Chinese population. METHODS: The SC-NKSS was translated from the original English version following international guidelines. All patients undergoing total knee arthroplasty (TKA) between September 2012 and September 2013 were invited to participate in this study. Finally, a total of 105 did so. Patients (preoperative and postoperative) completed the Chinese version of NKSS, Oxford Knee Score (OKS), the Medical Outcomes General Health Survey (SF-36) and Visual analog scale (VAS). Psychometric testing of reliability, construct validity, content validity were conducted. RESULTS: All the 105 participants completed the questionnaires and no floor or ceiling effects were checked. Internal consistency was excellent with Cronbach's alpha coefficient ranging from 0.71 to 0.85. Test-retest reliability was satisfactory with an intraclass correlation coefficient of 0.92 (95%confidence interval, 0.86-0.95). Construct validity was demonstrated to correlate well with the Chinese version of OKS (r = -0.78; p < 0.01), VAS (r = -0.70; p < 0.01), Physical Function (PF) (r = 0.74; p < 0.01), Body Pain (BP) (r = 0.63; p < 0.01) and General Health (GH) (r = 0.51; p < 0.01) of SF-36 domains. CONCLUSION: The SC-NKSS was well accepted and demonstrated acceptable psychometric properties in mainland China.

Early failure of the Durom prosthesis in metal-on-metal hip resurfacing in Chinese patients.

Hip resurfacing (HR) is being used increasingly as an alterative to total hip arthroplasty in osteonecrosis (ON) and ankylosing spondylitis (AS) of the hip. We performed 141 consecutive HR arthroplasties in 111 patients comprising 3 etiology groups: ON, AS, and osteoarthritis (OA). After retrospective study of retrieved components, we hypothesized that the main reason for revision was femoral loosening in the ON group (4 of 46 hips; 8.7%) and femoral-neck fracture in the AS group (3 of 58 hips; 5.2%). Necrotic areas were seen on femoral heads retrieved from patients with femoral loosening, whereas femoral heads were fixed tightly to components in patients with femoral-neck fractures. Etiology may be an important risk factor for postoperative complications.

Appraising the Associations Between Systemic Iron Status and Epigenetic Clocks: A Genetic Correlation and Bidirectional Mendelian Randomization Study.

BACKGROUND: Genetic correlations (Rg) and bidirectional causal effects between systemic iron status and epigenetic clocks have not been fully investigated, although observational studies have suggested systemic iron status is associated with human aging. OBJECTIVES: We explored the genetic correlations and bidirectional causal effects between systemic iron status and epigenetic clocks. METHODS: Leveraging large-scale genome-wide association study summary-level statistics for 4 systemic iron status biomarkers (ferritin, serum iron, transferrin, and transferrin saturation) (N = 48,972) and 4 measures for epigenetic age (GrimAge, PhenoAge, intrinsic epigenetic age acceleration (IEAA), and HannumAge) (N = 34,710), genetic correlations, and bidirectional causal effects were estimated between them mainly by applying linkage disequilibrium score (LDSC) regression, Mendelian randomization (MR), and MR based on Bayesian model averaging. The main analyses were conducted employing multiplicative random-effects inverse-variance weighted MR. MR-Egger, weighted median, weighted mode, and MR-PRESSO were performed as sensitivity analyses to support the robustness of causal effects. RESULTS: The LDSC results illustrated Rg between serum iron and PhenoAge (Rg = 0.1971, P = 0.048) and between transferrin saturation and PhenoAge (Rg = 0.196, P = 0.0469). We found that increased ferritin and transferrin saturation significantly increased all 4 measures of epigenetic age acceleration (all P < 0.0125, ß > 0). Each standard deviation genetically increases in serum iron only significantly associated with increased IEAA (ß: 0.36; 95% CI: 0.16, 0.57; P = 6.01 × 10-4) and increased HannumAge acceleration (ß: 0.32; 95% CI: 0.11, 0.52; P = 2.69 × 10-3). Evidence showed a suggestively significant causal effect of transferrin on epigenetic age acceleration (all 0.0125

Inhibition of CXCR4 inhibits the proliferation and osteogenic potential of fibroblasts from ankylosing spondylitis via the Wnt/ß­catenin pathway.

Ankylosing spondylitis (AS) is an autoimmune condition characterized by chronic inflammation and abnormal ossification as the primary features of the disease. The aim of the present study was to investigate the role of C­X­C chemokine receptor type 4 (CXCR4) in ossification from patients with AS. CXCR4 expression was assessed by western blot analysis and immunohistochemistry analysis of tissues obtained from patients with AS and controls. Fibroblasts were isolated, cultured and incubated with AMD 3100 and stromal cell­derived factor­1 to inhibit and promote CXCR4 levels, respectively. CXCR4 was upregulated in hip synovial tissues from patients with AS compared with that observed in controls. AS fibroblasts exhibited increased proliferation and growth rates. Inhibition of CXCR4 increased the phosphorylation of ß­catenin and downregulated the expression of ß­catenin, v­myc avian myelocytomatosis viral oncogene homolog, cyclin D1 and osteocalcin. Alizarin red staining demonstrated a decrease in biomineralization activity following the inhibition of CXCR4. These data support the hypothesis that inhibiting CXCR4 in patients with AS may suppress the ossification of fibroblasts.

Astaxanthin mitigates cobalt cytotoxicity in the MG-63 cells by modulating the oxidative stress.

BACKGROUND: With the re-popularity of metal-on-metal (MoM) bearing in recent years, the cobalt toxicity has been a cause for concern in the total hip replacement surgery by both physicians and patients. METHODS: MG-63 cell line was cultured in vitro and incubated with cobalt (II) chloride (CoCl2) and/or with astaxanthin (ASX) for 24 h. MTT assay was conducted to evaluate the cell viability after cobalt exposure and ASX treatment. Fluorescence-activated cell sorting (FACS) analysis was performed to examine the reactive oxygen species (ROS) level. Quantitative real-time polymerase chain reaction (PCR) was adopted to determine the mRNA levels of related targets. And western blot analysis was used to examine the protein expressions. One-way ANOVA with posttest Newman-Keuls multiple comparisons was adopted to analysis all the obtained data. RESULTS: In the current study, ASX exhibited significant protective effect against the Co(II)-induced cytotoxicity in MG-63 cell line. We also found that ASX protected the cells against Co-induced apoptosis by regulating the expression of Bcl-2 family proteins. Besides, heme oxygenase 1 (HO-1) could be activated by Co exposure; ASX treatment significantly inhibited HO-1 activation, suppressing the oxidative stress induced by Co exposure. Moreover, c-Jun N-terminal Kinase (JNK) phosphorylation was shown to participate in the signaling pathway of the protective effect of ASX. However, knockdown of JNK expression by siRNA transfection or JNK inhibitor SP600125 treatment did not affect the protective effect of ASX against cobalt cytotoxicity in MG-63 cells. CONCLUSIONS: ASX mitigated cobalt cytotoxicity in the MG-63 cells by modulating the oxidative stress. And ASX could be a promising therapy against cobalt toxicity in the hip articulation surgery.

Role of HLA-B27 in the pathogenesis of ankylosing spondylitis (Review).

The study of ankylosing spondylitis (AS) has made significant progress over the last decade. Genome-wide association studies have identified and further substantiated the role of susceptibility genes outside the major histocompatibility complex locus. However, human leukocyte antigen (HLA)­B27 has been suggested to be important in the pathogenesis of AS, contributing to ~20.1% of AS heritability. The current review will present the classical and non­classical forms of HLA-B27, as well as their pathogenic roles, and further discuss the hypotheses regarding the potential pathogenesis of AS. In addition, the association between the pathogenic role of HLA­B27 and inflammatory indexes, including the interleukin-23/­17 axis will be investigated to provide novel insights into the pathogenesis of AS. The aim of the present review is to provide an update of the current research into the pathogenesis of AS, and provide a comprehensive description of the pathogenic role of HLA-B27 in AS.

Cross-cultural adaptation and validation of the Chinese version of the Health Assessment Questionnaire for the Spondyloarthropathies (HAQ-S).

The Health Assessment Questionnaire for Spondyloarthropathies (HAQ-S) is a commonly used questionnaire to evaluate function and health status of patients with ankylosing spondylitis (AS). The objective of this study was to cross-culturally adapt the HAQ-S into Chinese and then to evaluate its reliability and validity. The Chinese version of the HAQ-S was obtained with a five-step procedure of translation and cross-cultural adaptation. All invited patients met the New York criteria for AS, and a total of 103 patients finally participated in this study. Intraclass correlation coefficient (ICC) was used to evaluate the test-retest and inter-rater reliability of the HAQ-S. Internal consistency of the questionnaire was evaluated by Cronbach's alpha coefficient. Spearman's correlation coefficient was calculated to assess the construct validity between the HAQ-S and Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), Bath AS Metrology Index (BASMI), and the laboratory parameters (erythrocyte sedimentation rate, ESR; C-reactive protein, CRP). Test-retest and inter-rater reliability were excellent with intraclass correlation coefficients of 0.987 (p < 0.05) and 0.982 (p < 0.05), respectively. The overall internal consistency of the HAQ-S was found satisfactory (Cronbach's alpha = 0.914). The Chinese version of the HAQ-S correlated good with the BASFI (r = 0.749, p < 0.01), and moderate with the BASDAI (r = 0.581, p < 0.01) and the BASMI (r = 0.425, p < 0.01). But, the adapted questionnaire correlated poorly with ESR (r = 0.298, p < 0.01) or CRP (r = 0.283, p < 0.01). The Chinese version of the HAQ-S is reliable and valid for the evaluation of Chinese-speaking patients with AS.

Annexin A2, up-regulated by IL-6, promotes the ossification of ligament fibroblasts from ankylosing spondylitis patients.

BACKGROUND: Annexin A2, a calcium-dependent phospholipid binding protein, is involved in osteogenesis. The objective of the present study was to explore the expression of Annexin A2 in spinal ligament tissues (LT) of ankylosing spondylitis (AS) patients and determine its pathological functions. METHODS: mRNA and protein expression of Annexin A2 was detected by real-time PCR and Western blotting, respectively. Interleukin-6 (IL-6) concentration in serum was assessed by enzyme linked immunosorbent assay. Alkaline phosphatase (ALP) activity was measured with ALP activity kit on a microplate reader. RESULTS: mRNA and protein expression of Annexin A2 in LT, and IL-6 concentration in serum were significantly increased in AS patients. Moreover, exogenous IL-6 treatment significantly up-regulated Annexin A2 expression and ALP activity. Silencing of Annexin A2 expression significantly ameliorated IL-6-induced ossification of fibroblasts from AS patients, as indicated by ALP activity, expression of proteins associated with osteogenic differentiation, including bone morphogenetic protein-2, osteocalcin and osterix, and the ratio of osteoprotegerin to receptor activator of NF-κB ligand. Further MEK inhibitor experiments suggested that Annexin A2 may exert its function through extracellular signal-related kinase pathway. CONCLUSIONS: Annexin A2, up-regulated by IL-6, may promote ligament ossification of AS patients.

Tanshinone IIA blocks dexamethasone-induced apoptosis in osteoblasts through inhibiting Nox4-derived ROS production.

Apoptosis of osteoblasts caused by glucocorticoids has been identified as an important contributor to the development of osteoporosis. Tanshinone IIA (Tan), an active ingredient extracted from the rhizome of the Salvia miltiorrhiza Bunge (Danshen), has been reported to cast positive effects on osteoporosis. However, the precise mechanisms accounting this action remain elusive. In this study, by using osteoblastic MC3T3-E1 cells as a model, we confirmed the protective effects of Tan against dexamethasone (Dex)-induced cell apoptosis and further clarified its molecular mechanism of action. Our results showed that treatment with Dex caused cell injury, increased cytosol cytochrome c level and Nox expression, induced apoptosis in caspase-9-dependent manner, and enhanced reactive oxygen species (ROS) production. Tan attenuated these deleterious consequence triggered by Dex. Moreover, Dex-induced ROS production and cell injury were inhibited by antioxidant, NADPH oxidases inhibitors, Nox4 inhibitor, and Nox4 small interfering RNA (siRNA). Overexpression of Nox4 almost abolished the inhibitory effect of Tan on Dex-induced cell injury and apoptosis. The results also demonstrated significant involvement of Nox4 in the Dex-induced apoptosis. Nox4-derived ROS led to apoptosis through activation of intrinsic mitochondrial pathway. Additionally, we evidenced that Tan reversed Dex-induced apoptosis via inactivation of Nox4. The present findings suggest that inhibition of Nox4 may be a novel therapeutic approach of Tan to prevent against glucocorticoids-induced osteoblasts apoptosis and osteoporosis.

Up-regulation of fatty acid oxidation in the ligament as a contributing factor of ankylosing spondylitis: A comparative proteomic study.

OBJECTIVES: The present study first utilized a standardized shotgun proteomic analysis method to determine differences in protein expression of fibroblasts in the ligament between AS patients and healthy controls. METHODS: Proteins extracted from primarily cultured FLLs from 35 AS patients and 10 normal subjects were analyzed by automated 2D-Nano-LC-ESI-MS/MS. Differentially expressed proteins were screened by 2-sample t-test and fold change. Bioinformatics analysis of differentially expressed proteins was based on the IPA. Fatty acid ß-oxidation-related proteins and INSR pathway-related proteins in the ligament were confirmed by real-time PCR and Western blot. RESULTS: A total of 556 differential proteins were screened in AS. Of them, 322 proteins were up-regulated and the remaining 234 proteins were down-regulated. GO and pathway analyses showed that six fatty acid ß-oxidation-related proteins (HADHB, ECHS1, ACSL4, ACADM, ACSL1 and HADH) were up-regulated in FLL cells, which was consistent with the results obtained from real-time PCR, Western blot and MS, while INSR pathway-related proteins (INSR, IRS1, PI3K and PKC) was low in the ligament of AS as compared with that in healthy controls. CONCLUSION: The lower body fat level in AS maybe due to up-regulation of fatty acid ß-oxidation-related enzymes regulated by INSR/PI3K/PKC pathway. BIOLOGICAL SIGNIFICANCE: Ankylosing spondylitis (AS), a common spondyloarthropathy, is an inflammatory rheumatic disease with a predilection for the axial skeleton. Clinical hallmarks of AS include sacroiliitis, uveitis, enthesitis and persistent spinal inflammation. The pathogenic mechanism of disease causation and perpetuation remains poorly understood. In this study, we primarily cultured fibroblast cells from ligament biopsies, knowing that fibroblast cells are dominant cells in the diseased ligament. One of the characteristic pathologic changes in AS is inflammation of the attachment points, including the muscle, ligament and bone or joint capsule. Inflammation of the tendon attachment point is usually non-bacterial and can lead to pain and swelling of the tendon ligament. To obtain more information, we used Shotgun proteomic analysis based on multidimensional liquid chromatography tandem mass spectrometry (LC-MS/MS). we firstly mixed the lysates of FLL cells derived from the ligaments of 35 AS patients and 10 normal subjects, identified proteins by automated 2D-Nano-LC-ESI-MS/MS method, GO and pathway analyses showed that six fatty acid ß-oxidation-related proteins (HADHB, ECHS1, ACSL4, ACADM, ACSL1 and HADH) were up-regulated in the ligament, which was consistent with the results obtained from real-time PCR, Western blot and MS, while INSR pathway-related proteins (INSR, IRS1, PI3K and PKC) was low in the ligament of AS as compared with that in healthy controls. We also find that AS subjects had significantly lower body mass index (BMI) and BMI Z-scores compared with that in healthy controls. The results remind us that up-regulation of fatty acid ß-oxidation-related proteins lower the body fat content, which is a new discovery contributing to the progression of AS. This is the first report on fatty acid oxidation in AS. It was found that the body fat level was low in AS due to high fatty acid oxidation, suggesting that insulin signaling may play an important role in the metabolic switch from predominant to fatty acid metabolism that characterizes the ligament of AS. One mechanism for this transition is increased expression of genes that regulate the rate of fatty acid oxidation. This effect may be mediated by PI3K, a downstream mediator of many receptor tyrosine kinases, including the INSR. This is a newly discovered factor contributing to the progression of AS.

Association of ankylosing spondylitis with HLA-B27 and ERAP1: pathogenic role of antigenic peptide.

Ankylosing spondylitis (AS) is a form of seronegative inflammatory arthritis whose strong genetic association with the human leucocyte antigen (HLA)-B27 has been known for almost 4 decades. However, its mechanism remains poorly understood. Recently, with the development of genetics, further more genes have been robustly associated with the disease. Genome-wide association studies identified the association between AS and ERAP1 (endoplasmic reticulum associated aminopeptidase 1). And ERAP1 has shown the potential in trimming antigenic peptides to optimal length for binding to HLA-B27 in the ER (endoplasmic reticulum). However, the length of the peptides are strictly restricted in the process of peptide transporting, processing and presentation. A hypothesis is proposed that the abnormal mechanism of AS may related to the trimming of N-terminal sequences from antigenic precursors in the ER and the length of the antigenic peptides that are presented to the T-cell receptors.