Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1)

Large clonal expansions of peripheral CD8+ T cells carrying receptors for single epitopes of CMV and EBV are common in the elderly and may be associated with an immune risk phenotype predicting mortality. Here we show that the frequency of CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1), a marker of cells unable to undergo further clonal expansion, was markedly elevated in CD8+ T cells from old donors. Moreover, tetramer staining revealed that the elevated frequency of CMV-specific CD8+ T cells in the elderly was due to an accumulation of cells bearing this dominant negative receptor. The fraction of CMV-specific T cells able to secrete interferon-gamma after specific antigenic stimulation was significantly lower in the elderly than in the young, although the total number of functional cells was comparable. Therefore, the majority of the clonally expanded virus-specific CD8+ cells in the elderly was dysfunctional. Thus, T cell responses are altered in the aged by an accumulation of replicatively senescent dysfunctional T cells carrying receptors for persistent herpes viruses. The presence of clonal expansions of such virus-specific cells may shrink the available repertoire for other antigens and contribute to the increased incidence of infectious disease in the elderly.     

Development of a Brief Cognitive and Behavioral Intervention for the Management of Episodic Breathlessness—A Delphi Survey With International Experts

ContextEpisodic breathlessness is characterized by a severe worsening of breathlessness intensity that goes beyond usual fluctuations. Episodes are usually short; therefore, nonpharmacological strategies (cognitive and behavioral) seem most promising to be beneficial. Which strategies—delivered separately or in combination—might be most effective and feasible remains unclear.ObjectivesThe Delphi survey selects and determines different nonpharmacological strategies for coping with episodic breathlessness to develop a brief cognitive and behavioral intervention for the management of episodic breathlessness.MethodsUsing an online Delphi survey comprising three rounds, international, multidisciplinary experts in breathlessness summarized and determined cognitive and behavioral strategies. The a priori target agreement for close-ended questions was 70%.ResultsExperts (n = 41/87; n = 45/85; n = 36/85) agreed on 15 of the 31 cognitive and behavioral strategies. Based on the panellists' opinion, the final version of the cognitive and behavioral intervention comprised the following characteristics: individually tailored intervention, a high proportion of communication, short duration, the involvement of carers, and use of the Breathing, Thinking, Functioning Model of Spathis et al. Consensus upon the delivery of the subsequent strategies within the intervention was reached: handheld fan, forward lean, diaphragmatic breathing, distraction, pursed lips breathing, long breaths out, and relaxation training.ConclusionUsing the consented nonpharmacological strategies, a brief cognitive and behavioral intervention was developed that balances between individualization and standardization of the intervention.     

Caspase-6 activity predicts lower episodic memory ability in aged individuals

Caspase-6 (Casp6), a cysteinyl protease that induces axonal degeneration, is activated early in Alzheimer Disease (AD) brains. To determine whether Casp6 activation is responsible for early cognitive impairment, we investigated the abundance of Casp6 activity, paired helical filament–1 (PHF-1) phosphorylated Tau and amyloid beta peptide (Aβ) pathology by immunohistochemistry in the hippocampal formation of aged non–cognitively impaired (NCI) individuals. Casp6 activity was restricted to the entorhinal cortex (ERC) and CA1 regions of the hippocampus. Pathology scores were then correlated with cognitive scores obtained within 1 year of death. Regression analyses revealed that ERC and CA1 Casp6 activity were the main contributor to lower episodic memory performance, whereas ERC PHF-1 pathology predicted lower semantic and working memory performance. Aβ did not correlate with any of the cognitive tests. Because Casp6 activity and PHF-1 pathology are intimately associated with AD pathology and memory decline is an early event in AD, we conclude that Casp6 activity and PHF-1 immunoreactivity in ERC identifies aged individuals at risk for developing AD.     

Microparticles as mediators of cellular cross-talk in inflammatory disease

Microparticles are a heterogeneous population of membrane-coated vesicles which can be released from virtually all cell types during activation or apoptosis. Release occurs from the cell surface in an exogenous budding process involving local rearrangement of the cytoskeleton. Given their origin, these particles can be identified by staining for cell surface markers and annexin V. As shown in in vitro studies, microparticles may represent a novel subcellular element for intercellular communication in inflammation. Thus, microparticles can transfer chemokine receptors and arachidonic acid between cells, activate complement, promote leukocyte rolling and stimulate the release of pro-inflammatory mediators. Under certain conditions, however, microparticles may also exert anti-inflammatory properties by inducing immune cell apoptosis and the production of anti-inflammatory mediators. Microparticles may play an important role in the pathogenesis of rheumatologic diseases as evidenced by their elevation in diseases such as systemic sclerosis (SSc), systemic vasculitis and antiphospholipid antibody syndrome and correlation with clinical events. A role in inflammatory arthritis is suggested by the finding that leukocyte-derived microparticles induce the production of matrix metalloproteinases and cytokines by synovial fibroblasts. Together, these findings point to novel signaling pathways of cellular cross-talk that may operate along the spectrum of soluble cytokines and mediators of direct cell–cell contact.     

An Analysis of the Impact of Brain-Computer Interfaces on Autonomy

Research conducted on Brain-Computer Interfaces (BCIs) has grown considerably during the last decades. With the help of BCIs, users can (re)gain a wide range of functions. Our aim in this paper is to analyze the impact of BCIs on autonomy. To this end, we introduce three abilities that most accounts of autonomy take to be essential: (1) the ability to use information and knowledge to produce reasons; (2) the ability to ensure that intended actions are effectively realized (control); and (3) the ability to enact intentions within concrete relationships and contexts. We then consider the impact of BCI technology on each of these abilities. Although on first glance, BCIs solely enhance self-determination because they restore or improve abilities, we will show that there are other positive, but also negative impacts on user autonomy, which require further philosophical and ethical discussions.

     

Metacognitive beliefs in obsessive-compulsive patients: A comparison with healthy and schizophrenia participants

Introduction. Distorted metacognitive beliefs are increasingly considered in theoretical models of obsessive-compulsive disorder (OCD). However, so far no consensus has emerged regarding the specific metacognitive profile of OCD.

Methods. Participants with OCD (n=55), schizophrenia (n=39), and nonclinical controls (n=49) were assessed with the Metacognitions Questionnaire (MCQ-30).

Results. Except for positive beliefs about worry, both patient samples exceeded nonclinical controls on all MCQ subscales. The MCQ “need to control thoughts” and “negative beliefs about uncontrollability and danger” subscales showed strong correlations with obsessions, and scores in the former scale were elevated in hallucinators. In contrast to several prior studies, “cognitive confidence” was related neither to core OCD nor to schizophrenia symptomatology.

Conclusions. Notwithstanding large pathogenetic differences between OCD and schizophrenia, findings suggest that obsessions and hallucinations may share a common metacognitive pathway. Need to control thoughts and dysfunctional beliefs about the malleability of worries may represent critical prerequisites for the two phenomena to emerge.