Sedentary behaviour is associated with increased long-term cardiovascular risk in patients with rheumatoid arthritis independently of moderate-to-vigorous physical activity

Background Rheumatoid Arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD). The physical dysfunction symptomatic of RA means people living with this disease spend large periods of the day sedentary, which may further elevate their risk of CVD. The primary aim of this study was to investigate relationships between objectively assessed sedentary behaviour patterns and light physical activity (LPA) with 10-year risk of CVD. Secondary aims were to explore the role of sedentary behaviour patterns and LPA for individual CVD risk factors and functional disability in RA. The extent to which associations were independent of moderate-to-vigorous physical activity (MVPA) engagement was also examined. Methods Baseline data from a subsample of participants recruited to the Physical Activity in Rheumatoid Arthritis (PARA) study were used to answer current research questions. Sixty-one patients with RA (mean age (± SD) = 54.92 ± 12.39 years) provided a fasted blood sample and underwent physical assessments to evaluate factors associated with their cardiovascular health. Sedentary behaviour patterns (sedentary time, sedentary bouts, sedentary breaks), LPA and MVPA were measured via 7-days of accelerometry. Ten-year CVD risk was computed (Q-risk-score2), and functional disability determined via questionnaire. Results Regressions revealed significant positive associations between sedentary time and the number of sedentary bouts per day ≥20 min with 10-year CVD risk, with the reverse true for LPA participation. Associations were independent of MVPA engagement. Conclusions Promoting LPA participation and restricting sedentary bouts to <20 min may attenuate long-term CVD risk in RA, independent of MVPA engagement

CCL25/CCR9 Interactions Regulate Large Intestinal Inflammation in a Murine Model of Acute Colitis

CCL25/CCR9 is a non-promiscuous chemokine/receptor pair and a key regulator of leukocyte migration to the small intestine. We investigated here whether CCL25/CCR9 interactions also play a role in the regulation of inflammatory responses in the large intestine.Acute inflammation and recovery in wild-type (WT) and CCR9(-/-) mice was studied in a model of dextran sulfate sodium (DSS)-induced colitis. Distribution studies and phenotypic characterization of dendritic cell subsets and macrophage were performed by flow cytometry. Inflammatory bowel disease (IBD) scores were assessed and expression of inflammatory cytokines was studied at the mRNA and the protein level.CCL25 and CCR9 are both expressed in the large intestine and are upregulated during DSS colitis. CCR9(-/-) mice are more susceptible to DSS colitis than WT littermate controls as shown by higher mortality, increased IBD score and delayed recovery. During recovery, the CCR9(-/-) colonic mucosa is characterized by the accumulation of activated macrophages and elevated levels of Th1/Th17 inflammatory cytokines. Activated plasmacytoid dendritic cells (DCs) accumulate in mesenteric lymph nodes (MLNs) of CCR9(-/-) animals, altering the local ratio of DC subsets. Upon re-stimulation, T cells isolated from these MLNs secrete significantly higher levels of TNFα, IFNγ, IL2, IL-6 and IL-17A while down modulating IL-10 production.Our results demonstrate that CCL25/CCR9 interactions regulate inflammatory immune responses in the large intestinal mucosa by balancing different subsets of dendritic cells. These findings have important implications for the use of CCR9-inhibitors in therapy of human IBD as they indicate a potential risk for patients with large intestinal inflammation

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field