Risk factors of aortic regurgitation progression in Chinese patients with Takayasu's arteritis: a prospective cohort study.

Objective: To elucidate the 3-year follow-up outcomes and risk factors associated with aortic regurgitation progression in Takayasu's arteritis (TAK). Methods: This study was a prospective cohort study conducted among 77 patients with TAK at Zhongshan Hospital, Fudan University, China. All the participants were followed up and assessed with echocardiography for 3 years, and the baseline characteristics and dynamic changes in the aortic valve were recorded and investigated. A multivariable Cox model was used to explore the risk factors for aortic regurgitation progression. Results: The median onset age was 36.9 (26.0-44.4) years, and 57 patients (74.0%) were females. Fifty patients (64.9%) complained of aortic regurgitation, which was the most common valvular lesion at baseline. During the 3-year follow-up period, the progression of aortic regurgitation was observed in 29 (37.7%) patients with TAK. The progression group had higher baseline erythrocyte sedimentation rate (ESR; p = 0.013) and interleukin (IL)-6 (p = 0.029) levels and lower early treatment remission rates (p = 0.024). According to the Cox model, the elevated baseline IL-6 level [>13 pg/ml, hazard ratio (HR) = 2.4, 95% confidence interval (CI) = 1.0-5.8, p = 0.042] and absence of early treatment remission (HR = 3.3, 95% CI = 1.3-8.2, p = 0.010) were the independent risk factors for aortic regurgitation deterioration. Conclusion: About one-third of patients with TAK experienced aortic regurgitation progression within 3 years from first admission. Elevated IL-6 levels at baseline and absence of early treatment remission were the two important risk factors for subsequent aortic regurgitation progression.

A comprehensive profile of chemokines in the peripheral blood and vascular tissue of patients with Takayasu arteritis.

BACKGROUND: Takayasu arteritis (TAK) is a chronic granulomatous large vessel vasculitis with multiple immune cells involved. Chemokines play critical roles in recruitment and activation of immune cells. This study aimed to investigate chemokine profile in the peripheral blood and vascular tissue of patients with TAK. METHODS: A total of 58 patients with TAK and 53 healthy controls were enrolled. Chemokine array assay was performed in five patients with TAK and three controls. Chemokines with higher levels were preliminarily validated in 20 patients and controls. The validated chemokines were further confirmed in another group of samples with 25 patients and 25 controls. Their expression and distribution were also examined in vascular tissue from 8 patients and 5 controls. Correlations between these chemokines and peripheral immune cells, cytokines, and disease activity parameters were analyzed. Their serum changes were also investigated in these 45 patients after glucocorticoids and immunosuppressive treatment. RESULTS: Patients and controls were age and sex-matched. Twelve higher chemokines and 4 lower chemokines were found based on the chemokine array. After validation, increase of 5 chemokines were confirmed in patients with TAK, including CCL22, RANTES, CXCL16, CXCL11, and IL-16. Their expressions were also increased in vascular tissue of patients with TAK. In addition, levels of RANTES and IL-16 were positively correlated with peripheral CD3+CD4+ T cell numbers. Close localization of CCL22, CXCL11, or IL-16 with inflammatory cells was also observed in TAK vascular tissue. No correlations were found between these chemokines and cytokines (IL-6, IL-17, IFN-γ) or inflammatory parameters (ESR, CRP). No differences were observed regarding with these chemokines between active and inactive patients. After treatment, increase of CCL22 and decrease of RANTES and CXCL16 were found, while no changes were showed in levels of CXCL11 and IL-16. CONCLUSIONS: CCL22, RANTES, CXCL16, CXCL11, and IL-16 were identified as the major chemokines involved in the recruitment of immune cells in the vascular tissue of patients with TAK. Additionally, the persistently high levels of CCL22, CXCL11, and IL-16 observed after treatment indicate their role in vascular chronic inflammation or fibrosis and demonstrate the need for developing more efficacious treatment options.

FABP3 overexpression promotes vascular fibrosis in Takayasu's arteritis by enhancing fatty acid oxidation in aorta adventitial fibroblasts.

OBJECTIVE: To identify the role of fatty acid binding protein 3 (FABP3) in vascular fibrosis in Takayasu's arteritis (TAK) and to explore the underlying molecular mechanism. METHODS: The expression of FABP3 and extracellular matrix proteins (ECMs) were detected in aorta tissues from TAK patients (n = 12) and healthy controls (n = 8) by immunohistochemistry. The concentration of serum proteins was determined by ELISA. CCK8 and Ki67 staining were used to measure aorta adventitial fibroblast (AAF) proliferation. Widely targeted lipidomic profiling was used to screen for associated metabolic pathways. Changes in ECMs and fatty acid oxidation (FAO)-related enzymes were determined by RT-qPCR and Western blot. The interactions between FABP3 and these enzymes were explored with a co-immunoprecipitation (Co-IP) assay. RESULTS: The expression of FABP3 was increased in the thickened adventitia of TAK patients and was positively correlated with the serum expression of ECMs. FABP3 knockdown inhibited AAF proliferation and ECM production, whereas FABP3 overexpression enhanced these processes. Further analysis revealed that FABP3 upregulation promoted carnitine palmitoyltransferase 1A and carnitine/acylcarnitine carrier protein (CACT) expression, two key enzymes in FAO, as well as adenosine triphosphate (ATP) levels. FABP3 and CACT were co-localized in the adventitia and bound to each other in AAFs. Etomoxir reversed the enhanced FAO, ATP production, AAF proliferation and ECM production mediated by FABP3 upregulation. Treatment with 60 g/day curcumin granules for 3 months reduced the level of serum FABP3. Curcumin also inhibited vascular fibrosis by reducing FABP3-enhanced FAO in AAFs. CONCLUSION: Elevated FABP3 expression accelerated vascular fibrosis in TAK, which was likely mediated by promoting FAO in AAFs.

Curcumin alleviates inflammation in Takayasu's arteritis by blocking CCL2 overexpression in adventitial fibroblasts.

OBJECTIVES: Takayasu's arteritis (TAK) is a chronic inflammatory disease with several challenges in treatment. Curcumin is known for its anti-inflammatory effects, whereas its effect in the treatment of TAK remains unclear. In this study, we aimed to investigate the effect of curcumin in the treatment of TAK and its underlying mechanisms. METHODS: 16 TAK patients were treated with curcumin granules at a dose of 15 g/day for three months. Kerr score was explored to assess disease activity. Serum levels of inflammatory factors were measured by ELISA. Immunohistochemical and immunofluorescence staining were used to detect the expression of CCL2 (also known as MCP-1) in aortic adventitia. RT-qPCR, ELISA and western blot were used to determine the regulatory effect of curcumin on CCL2 expression in aortic adventitia fibroblasts (AAFs) and its mechanism. RESULTS: Curcumin treatment significantly lowered Kerr score and the levels of serum CCL2 in TAK patients. The expression of CCL2 in TAK aortic adventitia was increased and colocalised with CD68. Serum levels of CCL2 was increased in subjects with Kerr score ≥2. After curcumin treatment, the changes in CCL2 were positively associated with the changes in IL-6. In further analysis, it showed that CCL2 was co-localised with CD90 and α-SMA, markers of adventitia fibroblasts. In vitro, HSP65, an agonist of TLR4, could induce CCL2 expression in AAFs via phosphorylating and activating the JAK2/AKT/STAT3 pathway. Nevertheless, curcumin could reverse the HSP65-induced CCL2 upregulation through restraining JAK2/AKT/STAT3 pathway. The inhibitory effect of curcumin on the JAK2/AKT/STAT3 pathway was even more obvious than that of methotrexate and tofacitinib. CONCLUSIONS: Curcumin alleviated inflammation in TAK by downregulating CCL2 overexpression in AAFs through inhibiting the JAK2/AKT/STAT3 signalling pathway.

Efficacy of high-dose ambroxol for paraquat poisoning: A meta-analysis of randomized controlled trials.

BACKGROUND: Paraquat (PQ) poisoning is characterized by rapidly progressive acute poisoning with high mortality and no specific antidote. Although some clinical studies have been conducted to investigate the benefits of high-dose ambroxol as an adjuvant treatment for PQ poisoning, the efficacy is controversial. MATERIALS AND METHODS: After searching for relevant articles in English and Chinese databases from 1978 to 2019 according to the keywords (paraquat poisoning/methy viologen/gramoxone, and ambroxol/mucosolvan/Bromhexine), we found seven articles that met our inclusion and exclusion criteria. A meta-analysis was performed using fixed-effects model and random-effects model according to the I 2 value in Stata software (version 15.0). Four outcome indicators (hospital mortality, partial pressure of oxygen (PaO2), oxygenation index (PaO2/FiO2), and survival time of the deceased patients) were of interest to us. RESULTS: The meta-analysis showed that adjuvant treatment with high doses of ambroxol increased PaO2 (weighted mean difference [WMD] = 13.73 [mmHg], 95% confidence interval [CI]: 8.68-18.79, Z = 11.80, P < 0.001), PaO2/FiO2 (WMD = 38.81 [mmHg], 95% CI: 29.85-47.76, Z = 8.49, P = 0.000), and survival time of the deceased patients (WMD = 2.58 [d], 95% CI: 0.97-4.18, Z = 3.15, P = 0.002) compared with usual treatment. Treatment with high doses of ambroxol also appeared to reduce the hospital mortality (relative risk = 0.69, 95% CI: 0.55-0.86, Z = 3.25, P = 0.001). CONCLUSION: This study found that high-dose ambroxol is an effective therapy for PQ poisoning and may reduce the in-hospital mortality.

Serum leptin, a potential predictor of long-term angiographic progression in Takayasu's arteritis.

AIM: In patients with Takayasu's arteritis (TA), current biomarkers that properly reflect the progression of the vascular structure remain absent. We aimed to determine the serum leptin level to investigate its relationship with imaging changes and assess its value as a predictor for long-term radiological progression. METHOD: This study included 34 untreated TA patients and 40 age-matched healthy controls. At baseline and during the 5-year follow-up, we assessed disease activity using Kerr's criteria and Indian Takayasu Clinical Activity Score (ITAS2010) and monitored laboratory biomarkers as well as imaging findings. Serum leptin levels were measured by enzyme-linked immunosorbent assay. RESULTS: The baseline serum leptin levels were significantly higher in TA patients than in healthy controls. Leptin was significantly positively correlated with triglyceride and high-density lipoprotein cholesterol levels and negatively correlated with fibrinogen and C-reactive protein levels. Patients were subdivided into three groups based on their baseline leptin level. During a 5-year follow-up, patients in the high and medium leptin groups showed more radiological progression compared to those in the low leptin group. Cox proportional hazard regression analysis showed that a high serum leptin level was a positive predictor of radiological progression. CONCLUSION: Leptin is a potential biomarker for assessing TA structural progression. Untreated patients with elevated serum leptin levels are at a higher risk of progression in the aorta. Thus, the leptin level can be a predictor of long-term radiological progression.

Stereotactic Aspiration of Necrotic Brain Tissue for Treating Malignant Middle Cerebral Artery Infarction: A Report of 13 Consecutive Cases.

BACKGROUND: This study aimed to evaluate the efficacy and safety of stereotactic aspiration of necrotic brain tissue for treating malignant middle cerebral artery infarction (MMI) in patients older than 60 years of age. CASE DESCRIPTION: A total of 13 consecutive patients with MMI (mean age, 67 ± 6.62 years) were enrolled in the study. These patients were treated with stereotactic aspiration of necrotic brain tissue within 72 hours from stroke onset between January 2016 and June 2017. The surgical results and clinical outcomes were evaluated in response to stereotactic aspiration of necrotic brain tissue. The mean preoperative infarction volume in the patients was found to be 153.46 ± 9.39 mL according to the latest computed tomography scan. The 30-day mortality was 2 out of 13 patients (15.4%). Patients were followed-up for 6 months to evaluate the efficacy of stereotactic aspiration of necrotic brain tissue using the modified Rankin Scale (mRS). Among the 11 surviving surgical patients, 6 (54.5%) had an mRS score of 3 (defined as moderate disability), 4 (36.4%) had an mRS score of 4 (defined as moderate to severe disability), and 1 (9.1%) had an mRS score of 5 (defined as severe disability). The probability of 6-month unfavorable outcome, defined as an mRS score of 5 or 6 (death), was 3 out of 13 (23.1%). CONCLUSIONS: Our results suggest the stereotactic aspiration of necrotic brain tissue is an effective and safe method in patients with MMI who are over 60 years of age.