Epicardial adipose tissue thickness and growth differentiation factor 15 in axial spondyloarthritis

Objectives:Toinvestigategrowthdifferentiationfactor-15 (GDF-15) levels and the thickness of epicardial adipose tissue (EAT) in patients with axial spondyloarthritis (axSpA) and to evaluate their relationship with functional status, disease activity, disease duration, and the type of medical treatment received by the patients. Methods: This cross-sectional study was carried out at Kırşehir Ahievran University School of Medicine between February and June 2020. Twenty-nine healthy controls and 44 patients with axSpA were included in the study. Gender, age, erythrocyte sedimentation rate, GDF-15, body mass index, complete blood count, ejection fraction, the EAT thickness, and C-reactive protein of all participants were recorded. Ankylosing Spondylitis Quality of Life Index, Bath Ankylosing Spondylitis Functional Index, the disease duration, Bath Ankylosing Spondylitis Metrology Index, and Bath Ankylosing Spondylitis Disease Activity Index scores of patients with axSpA were noted. Results: Epicardial adipose tissue thickness values (0.35±0.09 cm) in the AxSpA group were higher compared to the control group (0.26±0.06 cm) (p<0.01). Growth differentiation factor-15 levels of the control group and axSpA group were similar. The treatment received by the patients did not have a significant relationship with EAT thickness and GDF-15. Bath Ankylosing Spondylitis Functional Index scores, disease duration, and age were significantly positively correlated with GDF-15 levels. Conclusion: In this study, EAT thickness values were found to be significantly higher in the axSpA group. In addition, GDF-15 was positively correlated with age, Bath Ankylosing Spondylitis Functional Index score, and disease duration. © 2022 Saudi Arabian Armed Forces Hospital. All rights reserved

The prognostic impact of comorbidity, nutritional and performance status on patients with diffuse large B cell lymphoma

Background: The aim of the study was to investigate the impact of nutritional status, comorbidity, and performance status on patients with diffuse large B-cell lymphoma (DLBCL). Methods: A retrospective study was conducted on 112 DLBCL patients who were diagnosed at our center between 2009 and 2018. Demographic and disease characteristics and laboratory test results were recorded. Assessments were made using the age-adjusted Charlson comorbidity index (CCI-A) for comorbidity, albumin level for nutritional status, and Eastern Cooperative Oncology Group (ECOG) score for performance status. Results: The mean age of the patients was found to be 62.63 ± 15.16 years. The ECOG score of 65 patients (69.1%) was in the range of 0-1. The mean follow-up time of the patients was determined to be 25.24 ± 25.11 months, and at the end of the follow-up period, 64 patients (57.1%) were survivors. The progression-free survival (PFS), overall survival (OS), and 5-year OS rates of those with CCI-A > 4 were found to be significantly lower than those with CCI-A score ≤4 (P < 0.05). As a result of the Cox-Regression (Backward: LR method) analysis, ECOG and albumin levels were found to be independent risk factors for both OS and PFS (P < 0.05). Conclusion: This study demonstrated that CCI-A, ECOG, and nutritional status are independent prognostic markers for DLBCL patients. Initial evaluation of these patients should include all these parameters, which are easily available at the time of diagnosis

Pharmacologically diverse antidepressants facilitate TRKB receptor activation by disrupting its interaction with the endocytic adaptor complex AP-2

Several antidepressant drugs activate tropomyosin-related kinase B (TRKB) receptor, but it remains unclear whether these compounds employ a common mechanism for TRKB activation. Here, using MS, we found that a single intraperitoneal injection of fluoxetine disrupts the interaction of several proteins with TRKB in the hippocampus of mice. These proteins included members of adaptor protein complex-2 (AP-2) involved in vesicular endocytosis. The interaction of TRKB with the cargo-docking ? subunit of the AP-2 complex (AP2M) was confirmed to be disrupted by both acute and repeated fluoxetine treatments. Of note, fluoxetine disrupted the coupling between full-length TRKB and AP2M, but not the interaction between AP2M and the TRKB C-terminal region, indicating that the fluoxetine-binding site in TRKB lies outside the TRKB:AP2M interface. ELISA experiments revealed that in addition to fluoxetine, other chemically diverse antidepressants, such as imipramine, rolipram, phenelzine, ketamine, and its metabolite 2R,6R-hydroxynorketamine, also decreased the interaction between TRKB and AP2M in vitro. Silencing the expression of AP2M in a TRKB-expressing mouse fibroblast cell line (MG87.TRKB) increased cell-surface expression of TRKB and facilitated its activation by brain-derived neurotrophic factor (BDNF), observed as levels of phosphorylated TRKB. Moreover, animals haploinsufficient for the Ap2m1 gene displayed increased levels of active TRKB, along with enhanced cell-surface expression of the receptor in cultured hippocampal neurons. Taken together, our results suggest that disruption of the TRKB:AP2M interaction is a common mechanism underlying TRKB activation by several chemically diverse antidepressants.Peer reviewe

Fibroblast Growth Factor 21 Response in a Preclinical Alcohol Model of Acute-on-Chronic Liver Injury

Background and Aims: Fibroblast growth factor (FGF) 21 has recently been shown to play a potential role in bile acid metabolism. We aimed to investigate the FGF21 response in an ethanol-induced acute-on-chronic liver injury (ACLI) model in Abcb4−/− mice with deficiency of the hepatobiliary phospholipid transporter. Methods: Total RNA was extracted from wild-type (WT, C57BL/6J) and Abcb4−/ − (KO) mice, which were either fed a control diet (WT-Cont and KO-Cont groups; n = 28/group) or ethanol diet, followed by an acute ethanol binge (WT-EtOH and KOEtOH groups; n = 28/group). A total of 58 human subjects were recruited into the study, including patients with alcohol-associated liver disease (AALD; n = 31) and healthy controls (n = 27). The hepatic and ileal expressions of genes involved in bile acid metabolism, plasma FGF levels, and bile acid and its precursors 7α- and 27-hydroxycholesterol (7α- and 27-OHC) concentrations were determined. Primary mouse hepatocytes were isolated for cell culture experiments. Results: Alcohol feeding significantly induced plasma FGF21 and decreased hepatic Cyp7a1 levels. Hepatic expression levels of Fibroblast growth factor receptor 1 (Fgfr1), Fgfr4, Farnesoid X-activated receptor (Fxr), and Small heterodimer partner (Shp) and plasma FGF15/FGF19 levels did not differ with alcohol challenge. Exogenous FGF21 treatment suppressed Cyp7a1 in a dose-dependent manner in vitro. AALD patients showed markedly higher FGF21 and lower 7α-OHC plasma levels while FGF19 did not differ. Conclusions: The simultaneous upregulation of FGF21 and downregulation of Cyp7a1 expressions upon chronic plus binge alcohol feeding together with the invariant plasma FGF15 and hepatic Shp and Fxr levels suggest the presence of a direct regulatory mechanism of FGF21 on bile acid homeostasis through inhibition of CYP7A1 by an FGF15-independent pathway in this ACLI model. Lay Summary: Alcohol challenge results in the upregulation of FGF21 and repression of Cyp7a1 expressions while circulating FGF15 and hepatic Shp and Fxr levels remain constant both in healthy and pre-injured livers, suggesting the presence of an alternative FGF15-independent regulatory mechanism of FGF21 on bile acid homeostasis through the inhibition of Cyp7a1

Turkish Accession and Defining the Boundaries of Nationalism and Supranationalism: Discourses in the European Commission

The European Union in general and the European Commission in particular are characterised by supranational governance. The enlargement policy gives the Commission the opportunity to export and promote supranational norms and define the boundaries of Europe as a supranational polity through the conditionality of membership and intensive contact with the candidate countries. This article analyses the discourses of the Commission on Turkey and gives us insights into how well Turkey fits the supranational model in the eyes of Commission officials. It demonstrates how the boundaries of supranationalism are set and even challenged by the prospects of Turkey’s accession

Towards a definitive symptom structure of obsessive-compulsive disorder: A factor and network analysis of 87 distinct symptoms in 1366 individuals

Background The symptoms of obsessive-compulsive disorder (OCD) are highly heterogeneous and it is unclear what is the optimal way to conceptualize this heterogeneity. This study aimed to establish a comprehensive symptom structure model of OCD across the lifespan using factor and network analytic techniques. Methods A large multinational cohort of well-characterized children, adolescents, and adults diagnosed with OCD (N = 1366) participated in the study. All completed the Dimensional Yale-Brown Obsessive-Compulsive Scale, which contains an expanded checklist of 87 distinct OCD symptoms. Exploratory and confirmatory factor analysis were used to outline empirically supported symptom dimensions, and interconnections among the resulting dimensions were established using network analysis. Associations between dimensions and sociodemographic and clinical variables were explored using structural equation modeling (SEM). Results Thirteen first-order symptom dimensions emerged that could be parsimoniously reduced to eight broad dimensions, which were valid across the lifespan: Disturbing Thoughts, Incompleteness, Contamination, Hoarding, Transformation, Body Focus, Superstition, and Loss/Separation. A general OCD factor could be included in the final factor model without a significant decline in model fit according to most fit indices. Network analysis showed that Incompleteness and Disturbing Thoughts were most central (i.e. had most unique interconnections with other dimensions). SEM showed that the eight broad dimensions were differentially related to sociodemographic and clinical variables. Conclusions Future research will need to establish if this expanded hierarchical and multidimensional model can help improve our understanding of the etiology, neurobiology and treatment of OCD. © 2021 The Author(s). Published by Cambridge University Press

Structural basis for potency differences between GDF8 and GDF11.

BACKGROUND: Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties. RESULTS: Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8. CONCLUSIONS: These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined