Lessons from Mycobacterium avium complex-associated pneumonitis: a case report

ABSTRACT: INTRODUCTION: Mycobacterium avium complex (MAC) is an increasingly recognized cause of pulmonary disease in immunocompetent individuals. An acute form of MAC lung disease, MAC-associated pneumonitis, has generally been associated with the use of hot tubs. There is controversy in the literature about whether MAC-associated pneumonitis is a classic hypersensitivity pneumonitis or is a direct manifestation of mycobacterial infection. CASE PRESENTATION: We report the second case in the literature of MAC-associated pneumonitis not related to the use of hot tubs. The source of MAC in a 52-year-old immunocompetent patient was an intrapulmonary cyst containing numerous acid-fast bacilli. The patient developed disseminated miliary nodules throughout both lung fields. Histological examination of resected lung tissue revealed well-formed, acid-fast negative granulomas composed predominantly of CD4+ T-cells and CD68+ histiocytes. The granulomas were strongly positive for tumor necrosis factor-alpha, a pro-inflammatory cytokine. CONCLUSION: The attempt to classify MAC-associated pneumonitis as either a classic hypersensitivity pneumonitis or a direct manifestation of mycobacterial infection is not particularly useful. Our case demonstrates that MAC-associated pneumonitis is characterized by a vigorous T-helper 1-like, pro-inflammatory, immune response to pulmonary mycobacterial infection. The immunopathology provides a rationale for clinical studies of anti-MAC therapy with the addition of anti-inflammatory agents (for example, corticosteroids) to hasten the resolution of infection and symptoms

The Sleeping Brain's Influence on Verbal Memory: Boosting Resistance to Interference

Memories evolve. After learning something new, the brain initiates a complex set of post-learning processing that facilitates recall (i.e., consolidation). Evidence points to sleep as one of the determinants of that change. But whenever a behavioral study of episodic memory shows a benefit of sleep, critics assert that sleep only leads to a temporary shelter from the damaging effects of interference that would otherwise accrue during wakefulness. To evaluate the potentially active role of sleep for verbal memory, we compared memory recall after sleep, with and without interference before testing. We demonstrated that recall performance for verbal memory was greater after sleep than after wakefulness. And when using interference testing, that difference was even more pronounced. By introducing interference after sleep, this study confirms an experimental paradigm that demonstrates the active role of sleep in consolidating memory, and unmasks the large magnitude of that benefit

Protocol for a randomised controlled trial of risk screening and early intervention comparing child- and family-focused cognitive-behavioural therapy for PTSD in children following accidental injury

Background: Accidental injury represents the most common type of traumatic event to which a child or adolescent may be exposed, with a significant number of these children going on to experience posttraumatic stress disorder (PTSD). However, very little research has examined potential interventions for the treatment of PTSD in these children. The present trial aims to evaluate and compare child- and family-focused versions of a cognitive-behavioural early intervention for PTSD following accidental injury.Methods/Design: The principal clinical question under investigation is the efficacy of an early, trauma-focused cognitive-behavioural intervention for the treatment of PTSD in children following accidental injury. Specifically, we compare the efficacy of two active treatments (child-focused and family-focused CBT) and a waitlist control (no therapy) to determine which is associated with greater reductions in psychological and health-related outcome measures over time. The primary outcome will be a reduction in trauma symptoms on a diagnostic interview in the active treatments compared to the waitlist control and greater reductions in the family-compared to the child-focused condition. In doing so, this project will also trial a method of stepped screening and assessment to determine those children requiring early intervention for PTSD following accidental injury.Discussion: The present trial will be one of the first controlled trials to examine a trauma-focused CBT, early intervention for children experiencing PTSD following accidental injury (as opposed to other types of traumatic events) and the first within a stepped care approach. In addition, it will provide the first evidence comparing the efficacy of child and family-focused interventions for this target group. Given the significant number of children and adolescents exposed to accidental injury, the successful implementation of this protocol has considerable implications. If efficacious, this early intervention will assist in reducing symptoms of traumatic stress as well as preventing chronic disorder and disability in children experiencing acute PTSD following accidental injury

Deconstructing Insight: EEG Correlates of Insightful Problem Solving

Background: Cognitive insight phenomenon lies at the core of numerous discoveries. Behavioral research indicates four salient features of insightful problem solving: (i) mental impasse, followed by (ii) restructuring of the problem representation, which leads to (iii) a deeper understanding of the problem, and finally culminates in (iv) an “Aha!” feeling of suddenness and obviousness of the solution. However, until now no efforts have been made to investigate the neural mechanisms of these constituent features of insight in a unified framework. Methodology/Principal Findings: In an electroencephalographic study using verbal remote associate problems, we identified neural correlates of these four features of insightful problem solving. Hints were provided for unsolved problems or after mental impasse. Subjective ratings of the restructuring process and the feeling of suddenness were obtained on trial-by-trial basis. A negative correlation was found between these two ratings indicating that sudden insightful solutions, where restructuring is a key feature, involve automatic, subconscious recombination of information. Electroencephalogram signals were analyzed in the space×time×frequency domain with a nonparametric cluster randomization test. First, we found strong gamma band responses at parieto-occipital regions which we interpreted as (i) an adjustment of selective attention (leading to a mental impasse or to a correct solution depending on the gamma band power level) and (ii) encoding and retrieval processes for the emergence of spontaneous new solutions. Secondly, we observed an increased upper alpha band response in right temporal regions (suggesting active suppression of weakly activated solution relevant information) for initially unsuccessful trials that after hint presentation led to a correct solution. Finally, for trials with high restructuring, decreased alpha power (suggesting greater cortical excitation) was observed in right prefrontal area. Conclusions/Significance: Our results provide a first account of cognitive insight by dissociating its constituent components and potential neural correlates

The Causal Cascade to Multiple Sclerosis: A Model for MS Pathogenesis

BACKGROUND: MS pathogenesis seems to involve both genetic susceptibility and environmental risk factors. Three sequential factors are implicated in the environmental risk. The first acts near birth, the second acts during childhood, and the third acts long thereafter. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem well suited to the first two environmental events. METHODOLOGY/PRINCIPAL FINDINGS: A mathematical Model for MS pathogenesis is developed, incorporating these environmental and genetic factors into a causal scheme that can explain some of the recent changes in MS-epidemiology (e.g., increasing disease prevalence, a changing sex-ratio, and regional variations in monozygotic twin concordance rates). CONCLUSIONS/SIGNIFICANCE: This Model suggests that genetic susceptibility is overwhelmingly the most important determinant of MS pathogenesis. Indeed, over 99% of individuals seem genetically incapable of developing MS, regardless of what environmental exposures they experience. Nevertheless, the contribution of specific genes to MS-susceptibility seems only modest. Thus, despite HLA DRB1*1501 being the most consistently identified genetic marker of MS-susceptibility (being present in over 50% of northern MS patient populations), only about 1% of individuals with this allele are even genetically susceptible to getting MS. Moreover, because genetic susceptibility seems so similar throughout North America and Europe, environmental differences principally determine the regional variations in disease characteristics. Additionally, despite 75% of MS-patients being women, men are 60% more likely to be genetically-susceptible than women. Also, men develop MS at lower levels of environmental exposure than women. Nevertheless, women are more responsive to the recent changes in environmental-exposure (whatever these have been). This explains both the changing sex-ratio and the increasing disease prevalence (which has increased by a minimum of 32% in Canada over the past 35 years). As noted, environmental risk seems to result from three sequential components of environmental exposure. The potential importance of this Model for MS pathogenesis is that, if correct, a therapeutic strategy, designed to interrupt one or more of these sequential factors, has the potential to markedly reduce or eliminate disease prevalence in the future

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

Spike-Based Bayesian-Hebbian Learning of Temporal Sequences

Many cognitive and motor functions are enabled by the temporal representation and processing of stimuli, but it remains an open issue how neocortical microcircuits can reliably encode and replay such sequences of information. To better understand this, a modular attractor memory network is proposed in which meta-stable sequential attractor transitions are learned through changes to synaptic weights and intrinsic excitabilities via the spike-based Bayesian Confidence Propagation Neural Network (BCPNN) learning rule. We find that the formation of distributed memories, embodied by increased periods of firing in pools of excitatory neurons, together with asymmetrical associations between these distinct network states, can be acquired through plasticity. The model's feasibility is demonstrated using simulations of adaptive exponential integrate-and-fire model neurons (AdEx). We show that the learning and speed of sequence replay depends on a confluence of biophysically relevant parameters including stimulus duration, level of background noise, ratio of synaptic currents, and strengths of short-term depression and adaptation. Moreover, sequence elements are shown to flexibly participate multiple times in the sequence, suggesting that spiking attractor networks of this type can support an efficient combinatorial code. The model provides a principled approach towards understanding how multiple interacting plasticity mechanisms can coordinate hetero-associative learning in unison