Attenuation of monocyte chemotaxis--a novel anti-inflammatory mechanism of action for the cardio-protective hormone B-type natriuretic peptide

B-type natriuretic peptide (BNP) is a prognostic and diagnostic marker for heart failure (HF). An anti-inflammatory, cardio-protective role for BNP was proposed. In cardiovascular diseases including pressure overload-induced HF, perivascular inflammation and cardiac fibrosis are, in part, mediated by monocyte chemoattractant protein (MCP)1-driven monocyte migration. We aimed to determine the role of BNP in monocyte motility to MCP1. A functional BNP receptor, natriuretic peptide receptor-A (NPRA) was identified in human monocytes. BNP treatment inhibited MCP1-induced THP1 (monocytic leukemia cells) and primary monocyte chemotaxis (70 and 50 %, respectively). BNP did not interfere with MCP1 receptor expression or with calcium. BNP inhibited activation of the cytoskeletal protein RhoA in MCP1-stimulated THP1 (70 %). Finally, BNP failed to inhibit MCP1-directed motility of monocytes from patients with hypertension (n = 10) and HF (n = 6) suggesting attenuation of this anti-inflammatory mechanism in chronic heart disease. We provide novel evidence for a direct role of BNP/NPRA in opposing human monocyte migration and support a role for BNP as a cardio-protective hormone up-regulated as part of an adaptive compensatory response to combat excess inflammation.

Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5)

Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) focuses on the integrated care of chronic diseases. Area 5 (Care Pathways) was initiated using chronic respiratory diseases as a model. The chronic respiratory disease action plan includes (1) AIRWAYS integrated care pathways (ICPs), (2) the joint initiative between the Reference site MACVIA-LR (Contre les MAladies Chroniques pour un VIeillissement Actif) and ARIA (Allergic Rhinitis and its Impact on Asthma), (3) Commitments for Action to the European Innovation Partnership on Active and Healthy Ageing and the AIRWAYS ICPs network. It is deployed in collaboration with the World Health Organization Global Alliance against Chronic Respiratory Diseases (GARD). The European Innovation Partnership on Active and Healthy Ageing has proposed a 5-step framework for developing an individual scaling up strategy: (1) what to scale up: (1-a) databases of good practices, (1-b) assessment of viability of the scaling up of good practices, (1-c) classification of good practices for local replication and (2) how to scale up: (2-a) facilitating partnerships for scaling up, (2-b) implementation of key success factors and lessons learnt, including emerging technologies for individualised and predictive medicine. This strategy has already been applied to the chronic respiratory disease action plan of the European Innovation Partnership on Active and Healthy Ageing.

Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo

Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala(8)-substituted analogues of GLP-1, (Abu(8))GLP-1 and (Val(8) GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu(8))GLP-1 and (Val(8))GLP-1 exhibited moderate affinities (IC50: 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC50: 0.37 nM). (Abu(8))GLP-1 and (Val(8))GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1.5- and 3.5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val(8))GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu(8))GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val(8))GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala(8) in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val(8))GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.

Comparisons, mental models, and the action effect in judgments of regret

People tend to attribute more regret to a character who has decided to take action and experienced a negative outcome than to one who has decided not to act and experienced a negative outcome. For some decisions, however, this finding is not observed in a between-participants design and thus appears to rely on comparisons between people's representations of action and their representations of inaction. In this article, we outline a mental models account that explains findings from studies that have used within- and between-participants designs, and we suggest that, for decisions with uncertain counterfactual outcomes, information about the consequences of a decision to act causes people to flesh out their representation of the counterfactual states of affairs for inaction. In three experiments, we confirm our predictions about participants' fleshing out of representations, demonstrating that an action effect occurs only when information about the consequences of action is available to participants as they rate the nonactor and when this information about action is informative with respect to judgments about inaction. It is important to note that the action effect always occurs when the decision scenario specifies certain counterfactual outcomes. These results suggest that people sometimes base their attributions of regret on comparisons among different sets of mental models.

Auditory cueing in Parkinson's patients with freezing of gait. What matters most: action-relevance or cue-continuity?

Gait disturbances are a common feature of Parkinson’s disease, one of the most severe being freezing of gait. Sensory cueing is a common method used to facilitate stepping in people with Parkinson’s. Recent work has shown that, compared to walking to a metronome, Parkinson’s patients without freezing of gait (nFOG) showed reduced gait variability when imitating recorded sounds of footsteps made on gravel. However, it is not known if these benefits are realised through the continuity of the acoustic information or the action-relevance. Furthermore, no study has examined if these benefits extend to PD with freezing of gait. We prepared four different auditory cues (varying in action-relevance and acoustic continuity) and asked 19 Parkinson’s patients (10 nFOG, 9 with freezing of gait (FOG)) to step in place to each cue. Results showed a superiority of action-relevant cues (regardless of cue-continuity) for inducing reductions in Step coefficient of variation (CV). Acoustic continuity was associated with a significant reduction in Swing CV. Neither cue-continuity nor action-relevance was independently sufficient to increase the time spent stepping before freezing. However, combining both attributes in the same cue did yield significant improvements. This study demonstrates the potential of using action-sounds as sensory cues for Parkinson’s patients with freezing of gait. We suggest that the improvements shown might be considered audio-motor ‘priming’ (i.e., listening to the sounds of footsteps will engage sensorimotor circuitry relevant to the production of that same action, thus effectively bypassing the defective basal ganglia).