Glutamate grabbers, such as glutamate oxaloacetate transaminase (GOT), have been proposed to prevent excitotoxicity secondary to high glutamate levels in stroke patients. However, the efficacy of blood glutamate grabbing by GOT could be dependent on the extent and severity of the disruption of the blood-brain barrier (BBB). Our purpose was to analyze the relationship between GOT and glutamate concentration with the patient\'s functional status differentially according to BBB serum markers (soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and leukoaraiosis based on neuroimaging). This retrospective observational study includes 906 ischemic stroke patients. We studied the presence of leukoaraiosis and the serum levels of glutamate, GOT, and sTWEAK in blood samples. Functional outcome was assessed using the modified Rankin Scale (mRS) at 3 months. A significant negative correlation between GOT and glutamate levels at admission was shown in those patients with sTWEAK levels > 2900 pg/mL (Pearson\'s correlation coefficient: -0.249; p < 0.0001). This correlation was also observed in patients with and without leukoaraiosis (Pearson\'s correlation coefficients: -0.299; p < 0.001 vs. -0.116; p = 0.024). The logistic regression model confirmed the association of higher levels of GOT with lower odds of poor outcome at 3 months when sTWEAK levels were >2900 pg/mL (OR: 0.41; CI 95%: 0.28-0.68; p < 0.0001) or with leukoaraiosis (OR: 0.75; CI 95%: 0.69-0.82; p < 0.0001). GOT levels are associated with glutamate levels and functional outcomes at 3 months, but only in those patients with leukoaraiosis and elevated sTWEAK levels. Consequently, therapies targeting glutamate grabbing might be more effective in patients with BBB dysfunction.

BACKGROUND: Successful recanalization does not lead to complete tissue reperfusion in a considerable percentage of ischemic stroke patients. This study aimed to identify biomarkers associated with futile recanalization. Leukoaraiosis predicts poor outcomes of this phenomenon. Soluble tumour necrosis factor-like weak inducer of apoptosis (sTWEAK), which is associated with leukoaraiosis degrees, could be a potential biomarker.
METHODS: This study includes two cohorts of ischemic stroke patients in a multicentre retrospective observational study. Effective reperfusion, defined as a reduction of ≥8 points in the National Institutes of Health Stroke Scale (NIHSS) within the first 24 h, was used as a clinical marker of effective reperfusion.
RESULTS: In the first cohort study, female sex, age, and high NIHSS at admission (44.7% vs. 81.1%, 71.3 ± 13.7 vs. 81.1 ± 6.7; 16 [13, 21] vs. 23 [17, 28] respectively; p < .0001) were confirmed as predictors of futile recanalization. ROC curve analysis showed that leukocyte levels (sensitivity of 99%, specificity of 55%) and sTWEAK level (sensitivity of 92%, specificity of 88%) can discriminate between poor and good outcomes. Both biomarkers simultaneously are higher associated with outcome after effective reperfusion (OR: 2.17; CI 95% 1.63-4.19; p < .0001) than individually (leukocytes OR: 1.38; CI 95% 1.00-1.64, p = .042; sTWEAK OR: 1.00; C I95% 1.00-1.01, p = .019). These results were validated using a second cohort, where leukocytes and sTWEAK showed a sensitivity of 100% and specificity of 66.7% and 75% respectively.
CONCLUSIONS: Leukocyte and sTWEAK could be biomarkers of reperfusion failure and subsequent poor outcomes. Further studies will be necessary to explore its role in reperfusion processes.

BACKGROUND: An increased midnight cortisol (MC) has been described in end-stage kidney disease (ESKD) and type 1 diabetes (T1D). Lower circulating levels of the cytokine soluble tumor necrosis factor (TNF)-like weak inducer of apoptosis (sTWEAK) have been found in T1D and ESKD and associated with cardiovascular (CV) events in the latter. We aimed to study MC and sTWEAK in simultaneous pancreas-kidney transplant (SPKT) recipients, and the association of these markers with CV risk factors and transplant outcomes.
METHODS: This was a retrospective cohort study including subjects with T1D who received a first SPKT between 2008 and 2020. MC and sTWEAK at baseline were correlated with CV risk factors and evolution 1 year after SPKT.
RESULTS: We included 29 subjects (58.6% women, mean age 43.5 ± 7.5 years, diabetes duration 31.9 ± 9.4 years). Systolic blood pressure (SBP) increased directly with MC quartiles, despite similar hypertension prevalence (p < 0.05). At 1 year, antihypertensive treatment was deintensified in those in lower MC quartiles (p < 0.05). Diabetic neuropathy prevalence decreased progressively in higher cortisol quartiles (p for trend = 0.005). Low MC was associated with delayed kidney graft function (p for trend = 0.044), and high sTWEAK with kidney graft rejection (p for trend = 0.018). In multivariate analyses, MC (standardized-β 0.505, p = 0.004) and age (standardized-β - 0.460, p = 0.040) were independently correlated with SBP, and MC was independently associated with the presence of diabetic neuropathy (OR 0.633, 95% CI 0.425-0.944, p = 0.025), adjusted for confounders.
CONCLUSIONS: In this exploratory study, lower MC was associated with a lower baseline SBP, an improvement of antihypertensive treatment 1 year after transplant, and a higher diabetic neuropathy prevalence in SPKT recipients.

UNASSIGNED: To investigate the pathogenic characteristics of pulmonary infection in hospitalized patients with chronic heart failure as well as the diagnostic value of soluble myeloid cell expression triggering receptor-1 (sTREM-1), soluble CD163 (sCD163) and soluble tumor necrosis factor-like weak inducing factor (sTWEAK).
UNASSIGNED: A total of 72 patients with pulmonary infection who were hospitalized with chronic heart failure from December 2017 to December 2019 in the Department of Cardiology of Hebei Baoding Huaying Hospital of Traditional Chinese Medicine, China, were selected as the infection group, seventy-two patients without pulmonary infection who were hospitalized with chronic heart failure were selected as the non-infection group, and 50 healthy subjects who underwent physical examination in the hospital during the same period were selected as the control group. The distribution characteristics of pathogens in the infection group were statistically analyzed. The levels of sTREM-1, S CD163 and STweak in serum of patients with different infection severity and different cardiac function grades were compared among the three groups. Receiver operating characteristic curve (ROC) was utilized to evaluate the predictive value of the three indicators for the adverse prognosis of patients in hospital.
UNASSIGNED: A total of 76 strains of pathogens were cultured from two hospitalized patients with pulmonary infection of chronic heart failure, among which 43 strains (56.58%) were gram-negative bacteria, 29 strains (38.15%) were gram-positive bacteria, and four strains (5.26%) were fungi. The levels of sTREM-1 and sCD163 in the control group, non-infection group and infection group were gradually increased (p<0.05), while there was no difference in sTWEAK between the infection group and the non-infection group (p>0.05). In the infection group, the expression levels of sTREM-1 and sCD163 increased with the severity of infection, with statistically significant differences (p<0.05), while there was no statistically significant difference in the expression level of sTWEAK among different infection severity (p>0.05). The higher the cardiac function grade of patients in the infection group, the higher the levels of sTREM-1 and sCD163, and the lower the level of sTWEAK, with a statistical significance (p<0.05). ROC analysis results showed that the serum sTREM-1, sCD163, and sTWEAK levels for the poor prognosis of patients with CHF combined with lung infection had areas under the curve of 0.864, 0.870, and 0.822, respectively, and the 95% CI values were 0.787-0.941, 0.795-0.945 and 0.733-0.910, respectively, all p<0.001.
UNASSIGNED: Pulmonary infection in hospitalized patients with chronic heart failure is mainly caused by gram-negative bacteria. Detection of sTREM-1, sCD163, and sTWEAK levels is of certain value in judging the condition and prognosis, which is worthy of clinical promotion.

BACKGROUND: Cytokines soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and interleukin 6 (IL-6) are involved in immune response, proliferation, apoptosis, and cardiovascular pathologies. We have previously confirmed that changes of their platelet or plasma contents are associated with pulmonary arterial hypertension (PAH). The positron emission tomography/magnetic resonance imaging (PET/MRI) hybrid imaging provides detailed insight into right ventricle (RV) hemodynamic and metabolic function.
OBJECTIVE: To evaluate the relationship between RV parameters obtained using PET/MRI and concentrations of plasma and platelet sTWEAK and IL-6 in stable PAH patients.
METHODS: Eighteen stable PAH patients (48.44 ±16.7 years) had simultaneous PET/MRI scans with 18F-fluorodeoxyglucose (18F-FDG) performed. Its uptake was presented as a standardized uptake value (SUV) for RV and left ventricle (LV). Cytokines concentrations were measured in platelet-poor plasma and platelet lysate. Follow-up time of this study was 58 months; the combined endpoint (CEP) was defined as death or clinical deterioration.
RESULTS: We observed significant correlations between platelet sTWEAK levels, plasma IL-6 and PET parameter SUVRV/LV (r = -0.57, p = 0.011; r = 0.50, p = 0.032, respectively). In logistic regression, platelet sTWEAK and IL-6 were both prognostic factors for unfavorable ratio of SUVRV/LV higher than 1 (hazard ratio (HR) = 0.44, 95% confidence interval (95% CI): [0.23; 0.84], p = 0.017; and HR = 3.62, 95% CI: [1.21; 10.17], p = 0.011, respectively). Furthermore, their concentrations were related with prognostically important higher late gadolinium enhancement mass index (LGEMI) and RV global longitudinal strain/systolic pulmonary artery pressure (RV GLS/sPAP) values. Patients who had CEP in follow-up (n = 13) had significantly lower platelet sTWEAK content and higher plasma IL-6 at baseline than stable patients. Lower platelet sTWEAK was related to a worse prognosis in log-rank test (p = 0.006). Platelet sTWEAK and plasma IL-6 together with RV GLS/sPAP, RV ejection fraction (RVEF), mean pulmonary arterial pressure (mPAP), and SUVRV/LV were significantly associated with time to CEP in univariate Cox analysis.
CONCLUSIONS: The sTWEAK and IL-6 concentrations in PAH patients are linked with metabolic and functional changes of RV visualized in PET/MRI, and both sTWEAK and IL-6 predict clinical deterioration.

BACKGROUND: To date, no study has investigated the effects of probiotic yogurt as a functional food in patients with chronic heart failure (CHF). Therefore, the aim of this study was to compare the impact of probiotic yogurt versus ordinary yogurt on inflammatory, endothelial, lipid and renal indices in CHF patients. In this randomized, triple-blind clinical trial, 90 patients with CHF were randomly allocated into two groups to take either probiotic or ordinary yogurt for 10 weeks. Serum levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK), soluble cluster of differentiation 163 (sCD163), asymmetric dimethylarginine (ADMA), and lecithin cholesterol acyltransferase (LCAT) were measured by using ELISA kits, and blood urea nitrogen (BUN) was measured by calorimetry method at baseline and at the end of trial. The P-value <0.05 was defined as statistically significant.
RESULTS: Seventy-eight patients completed the study. At the end of the intervention, the levels of sTWEAK in both groups increased significantly, and this increase was greater in the probiotic yogurt group [691.84 (335.60, 866.95)] compared to control group [581.96 (444.99, 929.40)], and the difference between the groups was statistically significant after adjusting for confounders (P-value: 0.257, adjusted P-value: 0.038). However, no significant differences were found between the groups in the cases of other study indices.
CONCLUSIONS: Probiotic yogurt may be useful for improving the inflammatory status in patients with CHF through increasing sTWEAK levels, however, further studies are needed in this area. © 2022 Society of Chemical Industry.

UNASSIGNED: This study aimed to explore the association between smoking habit and the serum levels of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK), in relation with the functional outcome of patients with acute ischemic stroke undergoing reperfusion treatment.
UNASSIGNED: Observational and retrospective study of a series of patients with acute ischemic stroke subjected to reperfusion treatments. Clinical, analytical, and neuroimaging parameters were analyzed. The main endpoint was the functional outcome at 3 months, measured by the modified Ranking Scale (mRS). Logistic regression models were used to analyze the association between smoking and sTWEAK levels with functional outcome and leukoaraiosis.
UNASSIGNED: The results showed that smoking habit was associated with a good functional outcome at 3 months in patients with stroke (OR: 3.52; 95% CI: 1.03-11.9; p = 0.044). However, this independent association was lost after adjusting by sTWEAK levels (OR 1.73; 95% CI: 0.86-13.28; p = 0.116). sTWEAK levels were significantly lower in smoker patients [4015.5 (973.66-7921.83) pg/ml vs. 5,628 (2,848-10,202) pg/ml, p < 0.0001], while sTWEAK levels were significantly higher in patients with poor functional outcomes at 3 months [10,284 (7,388-13.247) pg/ml vs. 3,405 (2,329-6,629) pg/ml, p < 0.0001].
UNASSIGNED: The decrease in sTWEAK levels was associated with a good functional outcome in smoker patients with stroke undergoing reperfusion therapy.

UNASSIGNED: The etiology of rheumatoid arthritis (RA) remains poorly understood. Early and accurate diagnosis still difficult to achieve. Inflammatory related molecules released into the circulation such cytokines and exosome-derived microRNAs (exomiRNAs) could be good candidates for early diagnosis of autoimmune diseases. We sought to discover a serum biomarker panel for the early detection of RA based on exomiRNAs and inflammatory markers.
UNASSIGNED: A 179 miRNAs-microarray panel was analyzed in a pilot study (4 early RA and 4 controls). Validation of deregulated exomiRNAs was performed in a larger cohort (24 patients with early RA and 24 controls). miRNet software was used to predict exomiRNA gene-targets interactions. Potentially altered pathways were analyzed by Reactome pathway database search. STRING database was used to predict protein-protein interaction networks. Enzyme-linked immunosorbent assay was used to measure serum levels of sTWEAK and sCD163. Signature biomarker candidates were statistical analyzed.
UNASSIGNED: We detected 11 differentially expressed exomiRNAs in early RA pilot study. Validation analysis revealed that 6/11 exomiRNAs showed strong agreement with the pilot microarray data (exomiR-144-3p, -25-3p, -15a-5p, -451a, -107 and -185-5p). sTWEAK and sCD163 biomarkers were significantly elevated in the serum of patients with early RA. Receiver operating characteristic (ROC) analysis showed that the best panel to diagnose early RA contained exomiR-451a, exomiR-25-3p and sTWEAK, and could correctly classify 95.6% of patients, with an area under the ROC curve of 0.983 and with 100% specificity and 85.7% sensitivity. The YWHAB gene was identified as a common target of the putative miRNA-regulated pathways.
UNASSIGNED: A novel serum biomarker panel composed of exomiR-451a, exomiR-25-3p and serum levels of sTWEAK may have use in the early clinical diagnosis of RA. A new predicted exomiRNA-target gene YHWAB has been identified and may have a relevant role in the development of RA.

The present study sought to evaluate the effect of resveratrol supplementation on mRNA expression levels of peroxisome proliferator-activated receptor alpha (PPARα), p53, p21, p16, and serum levels of cluster of differentiation 163 (CD163) to TNF-like weak inducer of apoptosis (TWEAK) ratio in patients with type 2 diabetes. In this double-blind randomized controlled trial, 71 patients were randomly assigned to receive either 1,000 mg of trans-resveratrol or placebo (methyl cellulose) for 8 weeks. Expression levels of genes of interest, and serum levels of sCD163 and sTWEAK were assessed at baseline and at the end of the study. Resveratrol supplementation significantly increased mRNA expression levels of p53 and p21 genes, compared with the placebo group (fold change of p53 = 1.29, p = .04; fold change of p21 = 1.46, p = .006). However, no significant effect on expression levels of PPARα and p16 genes was observed after supplementation. In addition, resveratrol significantly reduced serum levels of sCD163/sTWEAK ratio compared with the placebo group (p = .003). Resveratrol supplementation resulted in significant changes in p53 and p21 genes expression, while serum levels of sCD163/sTWEAK ratio also improved in the resveratrol group, without any significant change in adjusted sCD163 levels. More research is needed to confirm the beneficial effects of resveratrol for patients with diabetes.

The TNF-superfamily member sTWEAK and its scavenger receptor sCD163 are potentially involved in pathophysiological processes of atherosclerosis. In patients with peripheral arterial disease, previous research has shown that sTWEAK and the sCD163/sTWEAK ratio were independently associated with long term all-cause and cardiovascular survival. Since previous investigations emphasized on symptomatic peripheral arterial disease including critical limb ischemia, this study evaluates sTWEAK and sCD163 in a cohort of stable peripheral arterial disease including asymptomatic (Fontaine stage I) and intermittent claudication (Fontaine stage II) patients.
sTWEAK concentrations of 354 patients were measured using a commercially available ELISA kit. sCD163 was quantified using a multiplex bead assay. Cox proportional hazards regression was used to assess outcome after a seven-year follow-up. Hazard ratios are given as interquartile range.
Patients with intermittent claudication exhibited increased sCD163 levels in comparison to asymptomatic patients (p = 0.002). However, sTWEAK was not related to peripheral arterial disease severity (p = 0.740). A multivariable Cox-proportional hazard models including sTWEAK and cardiovascular risk factors (age, HbA1c, CRP, LDL-C, BMI, eGFR) revealed an inverse association with all-cause mortality (HR 0.775 (95% CI 0.623-0.965) and cardiovascular mortality (HR 0.710 (95% CI 0.534-0.944)). Further multivariable models including sCD163 or the sCD163/sTWEAK ratio and cardiovascular risk factors showed no association with mortality.
This study highlights the use of sCD163 as a novel biomarker for PAD severity and supports sTWEAK as an independent predictor of all-cause and cardiovascular mortality even in stable peripheral arterial disease.