Integrating Region- and Network-level Contributions to Episodic Recollection Using Multilevel Structural Equation Modeling.

The brain is composed of networks of interacting brain regions that support higher-order cognition. Among these, a core network of regions has been associated with recollection and other forms of episodic construction. Past research has focused largely on the roles of individual brain regions in recollection or on their mutual engagement as part of an integrated network. However, the relationship between these region- and network-level contributions remains poorly understood. Here, we applied multilevel structural equation modeling to examine the functional organization of the posterior medial (PM) network and its relationship to episodic memory outcomes. We evaluated two aspects of functional heterogeneity in the PM network: first, the organization of individual regions into subnetworks, and second, the presence of regionally specific contributions while accounting for network-level effects. Our results suggest that the PM network is composed of ventral and dorsal subnetworks, with the ventral subnetwork making a unique contribution to recollection, especially to recollection of spatial information, and that memory-related activity in individual regions is well accounted for by these network-level effects. These findings highlight the importance of considering the functions of individual brain regions within the context of their affiliated networks.

Patterns of episodic content and specificity predicting subjective memory vividness.

The ability to remember and internally represent events is often accompanied by a subjective sense of "vividness". Vividness measures are frequently used to evaluate the experience of remembering and imagining events, yet little research has considered the objective attributes of event memories that underlie this subjective judgment, and individual differences in this mapping. Here, we tested how the content and specificity of event memories support subjectively vivid recollection. Over three experiments, participants encoded events containing a theme word and three distinct elements - a person, a place, and an object. In a memory test, memory for event elements was assessed at two levels of specificity - semantic gist (names) and perceptual details (lure discrimination). We found a strong correspondence between memory vividness and memory for gist information that did not vary by which elements were contained in memory. There was a smaller, additive benefit of remembering specific perceptual details on vividness, which, in one study, was driven by memory for place details. Moreover, we found individual differences in the relationship between memory vividness and objective memory attributes primarily along the specificity dimension, such that one cluster of participants used perceptual detail to inform memory vividness whereas another cluster was more driven by gist information. Therefore, while gist memory appears to drive vividness on average, there were idiosyncrasies in this pattern across participants. When assessing subjective ratings of memory and imagination, research should consider how these ratings map onto objective memory attributes in the context of their study design and population.

Progression from Feature-Specific Brain Activity to Hippocampal Binding during Episodic Encoding.

The hallmark of episodic memory is recollecting multiple perceptual details tied to a specific spatial-temporal context. To remember an event, it is therefore necessary to integrate such details into a coherent representation during initial encoding. Here we tested how the brain encodes and binds multiple, distinct kinds of features in parallel, and how this process evolves over time during the event itself. We analyzed data from 27 human subjects (16 females, 11 males) who learned a series of objects uniquely associated with a color, a panoramic scene location, and an emotional sound while fMRI data were collected. By modeling how brain activity relates to memory for upcoming or just-viewed information, we were able to test how the neural signatures of individual features as well as the integrated event changed over the course of encoding. We observed a striking dissociation between early and late encoding processes: left inferior frontal and visuo-perceptual signals at the onset of an event tracked the amount of detail subsequently recalled and were dissociable based on distinct remembered features. In contrast, memory-related brain activity shifted to the left hippocampus toward the end of an event, which was particularly sensitive to binding item color and sound associations with spatial information. These results provide evidence of early, simultaneous feature-specific neural responses during episodic encoding that predict later remembering and suggest that the hippocampus integrates these features into a coherent experience at an event transition.SIGNIFICANCE STATEMENT Understanding and remembering complex experiences are crucial for many socio-cognitive abilities, including being able to navigate our environment, predict the future, and share experiences with others. Probing the neural mechanisms by which features become bound into meaningful episodes is a vital part of understanding how we view and reconstruct the rich detail of our environment. By testing memory for multimodal events, our findings show a functional dissociation between early encoding processes that engage lateral frontal and sensory regions to successfully encode event features, and later encoding processes that recruit hippocampus to bind these features together. These results highlight the importance of considering the temporal dynamics of encoding processes supporting multimodal event representations.

Mapping the organization and dynamics of the posterior medial network during movie watching.

Brain regions within a posterior medial network (PMN) are characterized by sensitivity to episodic tasks, and they also demonstrate strong functional connectivity as part of the default network. Despite its cohesive structure, delineating the intranetwork organization and functional diversity of the PMN is crucial for understanding its contributions to multidimensional event cognition. Here, we probed functional connectivity of the PMN during movie watching to identify its pattern of connections and subnetwork functions in a split-sample replication of 136 participants. Consistent with prior findings of default network fractionation, we identified distinct PMN subsystems: a Ventral PM subsystem (retrosplenial cortex, parahippocampal cortex, posterior angular gyrus) and a Dorsal PM subsystem (medial prefrontal cortex, hippocampus, precuneus, posterior cingulate cortex, anterior angular gyrus). Ventral and Dorsal PM subsystems were differentiated by functional connectivity with parahippocampal cortex and precuneus and integrated by retrosplenial cortex and posterior cingulate cortex, respectively. Finally, the distinction between PMN subsystems is functionally relevant: whereas both Dorsal and Ventral PM connectivity tracked the movie content, only Ventral PM connections increased in strength at event transitions and appeared sensitive to episodic memory. Overall, these findings reveal PMN functional pathways and the distinct functional roles of intranetwork subsystems during event cognition.

A database of news videos for investigating the dynamics of emotion and memory.

Emotional experiences are known to be both perceived and remembered differently from nonemotional experiences, often leading to heightened encoding of salient visual details and subjectively vivid recollection. The vast majority of previous studies have used static images to investigate how emotional event content modulates cognition, yet natural events unfold over time. Therefore, little is known about how emotion dynamically modulates continuous experience. Here we report a norming study wherein we developed a new stimulus set of 126 emotionally negative, positive, and neutral videos depicting real-life news events. Participants continuously rated the valence of each video during its presentation and judged the overall emotional intensity and valence at the end of each video. In a subsequent memory test, participants reported how vividly they could recall the video details and estimated each video's duration. We report data on the affective qualities and subjective memorability of each video. The results replicate the well-established effect that emotional experiences are remembered more vividly than nonemotional experiences. Importantly, this novel stimulus set will facilitate research into the temporal dynamics of emotional processing and memory.

Memories Fade: The Relationship Between Memory Vividness and Remembered Visual Salience.

Past events, particularly emotional experiences, are often vividly recollected. However, it remains unclear how qualitative information, such as low-level visual salience, is reconstructed and how the precision and bias of this information relate to subjective memory vividness. Here, we tested whether remembered visual salience contributes to vivid recollection. In three experiments, participants studied emotionally negative and neutral images that varied in luminance and color saturation, and they reconstructed the visual salience of each image in a subsequent test. Results revealed, unexpectedly, that memories were recollected as less visually salient than they were encoded, demonstrating a novel memory-fading effect, whereas negative emotion increased subjective memory vividness and the precision with which visual features were encoded. Finally, memory vividness tracked both the precision and remembered salience (bias) of visual information. These findings provide evidence that low-level visual information fades in memory and contributes to the experience of vivid recollection.

Reduced Hippocampal Functional Connectivity During Episodic Memory Retrieval in Autism.

Increasing recent research has sought to understand the recollection impairments experienced by individuals with autism spectrum disorder (ASD). Here, we tested whether these memory deficits reflect a reduction in the probability of retrieval success or in the precision of memory representations. We also used functional magnetic resonance imaging (fMRI) to study the neural mechanisms underlying memory encoding and retrieval in ASD, focusing particularly on the functional connectivity of core episodic memory networks. Adults with ASD and typical control participants completed a memory task that involved studying visual displays and subsequently using a continuous dial to recreate their appearance. The ASD group exhibited reduced retrieval success, but there was no evidence of a difference in retrieval precision. fMRI data revealed similar patterns of brain activity and functional connectivity during memory encoding in the 2 groups, though encoding-related lateral frontal activity predicted subsequent retrieval success only in the control group. During memory retrieval, the ASD group exhibited attenuated lateral frontal activity and substantially reduced hippocampal connectivity, particularly between hippocampus and regions of the fronto-parietal control network. These findings demonstrate notable differences in brain function during episodic memory retrieval in ASD and highlight the importance of functional connectivity to understanding recollection-related retrieval deficits in this population.

Non-antibiotic antimicrobial interventions and antimicrobial stewardship in wound care.

Control of wound infection today relies largely on antibiotics, but the continual emergence of antibiotic-resistant microorganisms threatens a return to the pre-antibiotic era when physicians used antiseptics to prevent and manage infection. Some of those antiseptics are still used today, and others have become available. A diverse variety of non-antibiotic antimicrobial interventions are found on modern formularies. Unlike the mode of action of antibiotics, which affect specific cellular target sites of pathogens, many non-antibiotic antimicrobials affect multiple cellular target sites in a non-specific way. Although this reduces the likelihood of selecting for resistant strains of microorganisms, some have emerged and cross-resistance between antibiotics and antiseptics has been detected. With the prospect of a post-antibiotic era looming, ways to maintain and extend our antimicrobial armamentarium must be found. In this narrative review, current and emerging non-antibiotic antimicrobial strategies will be considered and the need for antimicrobial stewardship in wound care will be explained.

Presenting a food in multiple smaller units increases expected satiety.

Presentation of the same amount of a food in multiple smaller units ('segmentation') has been shown to reduce food intake and increase estimates of the amount of food consumed. However, this effect has been demonstrated for ad libitum food intake only. In the majority of cases, meals are not consumed ad libitum, but are pre-selected and consumed in their entirety, Expected satiety (ES; the anticipated capacity of a portion of food to relieve hunger between meals) is an excellent predictor of portion size selection. This study tested the hypothesis that segmentation increases ES. It was also hypothesised that perceived volume (PV) may account for the relationship between segmentation and ES. Sixty-eight participants made computer-based ES and PV judgments for equicaloric portions of three test foods (salted peanuts, spaghetti Bolognese, and chicken tikka masala), which were presented in either a single unit or as multiple smaller units (three or six units). Results revealed a consistent effect of segmentation on ES - foods presented in multiple smaller units were expected to deliver significantly greater satiety than when presented in a single unit (p < 0.005). Furthermore, results indicated that the effect of segmentation on ES was attributable to an increase in PV. ES plays an important role in determining the portion sizes that people select. Therefore, awareness of the effect of segmentation on ES may help to inform the design of foods that confer benefits for healthy weight maintenance.

Manuka honey reduces the motility of Pseudomonas aeruginosa by suppression of flagella-associated genes.

OBJECTIVES: Manuka honey is a broad-spectrum antimicrobial agent that seems to affect different bacteria in many different ways. It has been shown to be bactericidal against Pseudomonas aeruginosa by destabilizing the cell wall, but we aimed to investigate whether there were further intracellular target sites. METHODS: In this study inhibitory effects of manuka honey on P. aeruginosa were investigated using hydrophobicity assays, two-dimensional electrophoresis, quantitative RT-PCR, transmission electron microscopy and motility assays. RESULTS: Exposure of P. aeruginosa to manuka honey reduced both swarming and swimming motility. Moreover, this was a consequence of de-flagellation of the bacterial cell, which was correlated with decreased expression of the major structural flagellin protein, FliC, and concurrent suppression of flagellin-associated genes, including fliA, fliC, flhF, fleN, fleQ and fleR. The differential expression of the flagellar regulon in the presence of manuka honey was mapped schematically. Flagella are integral to bacterial adhesion, the initiation of infection and biofilm formation, and swarming has been associated with increased virulence. CONCLUSIONS: By limiting motility in vitro, we infer that manuka honey impacts on the virulence of P. aeruginosa. This deduction must now be tested in vivo.

A demonstration of the susceptibility of clinical isolates obtained from cystic fibrosis patients to manuka honey.

Pseudomonas and Burkholderia pose a significant health threat to people with chronic respiratory conditions; the resistance inherent in these bacteria indicates that new antimicrobial strategies are required. Susceptibility of 56 strains of P. aeruginosa and 55 strains of Burkholderia to manuka honey, tobramycin and colistin using microbroth dilution and E strip was determined. MICs of antibiotics with honey were determined to search for synergistic combinations against two representative strains of each genus. All strains exhibited susceptibility to honey ≤10 % (w/v); mean susceptibility of Burkholderia (4.6 % w/v) was lower than P. aeruginosa (7.3 % w/v). Synergistic or additive combinations were found with all four strains tested. Combinations of manuka honey with antibiotics can be used to lower the MIC need to successfully inhibit both P. aeruginosa and B. cepacia. The use of honey as a combination agent may be possible for the management of P. aeruginosa and B. cepacia.

Proteomic and genomic analysis of methicillin-resistant Staphylococcus aureus (MRSA) exposed to manuka honey in vitro demonstrated down-regulation of virulence markers.

OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen. Its resistance to multiple antibiotics and its prevalence in healthcare establishments make it a serious threat to human health that requires novel interventions. Manuka honey is a broad-spectrum antimicrobial agent that is gaining acceptance in the topical treatment of wounds. Because its mode of action is only partially understood, proteomic and genomic analysis was used to investigate the effects of manuka honey on MRSA at a molecular level. METHODS: Two-dimensional gel electrophoresis with dual-channel imaging was combined with matrix-assisted laser desorption ionization-time of flight mass spectrometry to determine the identities of differentially expressed proteins. The expression of the corresponding genes was investigated by quantitative PCR. Microarray analysis provided an overview of alterations in gene expression across the MRSA genome. RESULTS: Genes with increased expression following exposure to manuka honey were associated with glycolysis, transport and biosynthesis of amino acids, proteins and purines. Those with decreased expression were involved in the tricarboxylic acid cycle, cell division, quorum sensing and virulence. The greatest reductions were seen in genes conferring virulence (sec3, fnb, hlgA, lip and hla) and coincided with a down-regulation of global regulators, such as agr, sae and sarV. A model to illustrate these multiple effects was constructed and implicated glucose, which is one of the major sugars contained in honey. CONCLUSIONS: A decreased expression of virulence genes in MRSA will impact on its pathogenicity and needs to be investigated in vivo.

Antimicrobials and Non-Healing Wounds. Evidence, controversies and suggestions-key messages.

This article constitutes an extraction of key messages originally presented in the Document: Antimicrobials and Non-Healing Wounds. Evidence, controversies and suggestions written by the European Wound Management Association (EWMA), and originally published by the Journal of Wound Care in 2013. All sections are shortened and some not included. For further details please refer to in the original document which can be downloaded via www.ewma.org .

A novel approach to sterile pharmaceutical freeze-drying.

A novel approach has been developed that enables sterile pharmaceutical products to be freeze-dried in the open laboratory without specialist facilities. The product is filled into vials, semi-stoppered and sealed inside one, followed by a second, sterilization pouch under class 100 conditions. The product is then freeze-dried in the laboratory where the vials are shelf-stoppered before being returned to class 100, unwrapped and crimped. The sterilization pouches increased the resistance to water vapor movement during sublimation, thereby increasing the sublimation time and product temperature. Ovine immunoglobulins were double wrapped and lyophilized (as above) adjusting the primary drying time and shelf temperature for increased product temperature and, therefore, prevention of collapse. Ovine immunoglobulin G formulations freeze-dried to ≤ 1.1% residual moisture with no effect on protein aggregation or biological activity. The process was simulated with tryptone soya broth and no growth of contaminating microbial cells was observed after incubation at 35 °C for 2 weeks. Although increasing lyophilization time, this approach offers significant plant and validation cost savings when sterile freeze-drying small numbers of vials thereby making the manufacture of treatments for neglected and orphan diseases more viable economically.

Inhibition of biofilms by glucose oxidase, lactoperoxidase and guaiacol: the active antibacterial component in an enzyme alginogel.

The association of biofilms with wound chronicity has prompted a search for antimicrobial interventions that are effective against biofilms. A patented preparation of glucose oxidase, lactoperoxidase and guaiacol (GLG), which is the antibacterial component of Flaminal, has been shown to inhibit a wide range of bacteria, but it has not yet been tested on biofilms. This study aims to determine the effect of GLG on biofilms of Staphylococcus aureus, methicillin-resistant S. aureus and Pseudomonas aeruginosa. Static biofilms were grown in microtitre plates and on coverslips and treated with a range of concentrations of GLG. Effects were monitored by estimating biofilm biomass by staining with crystal violet, biofilm activity by staining with either resazurin or fluorescein diacetate and biofilm viability by staining with LIVE/DEAD BacLight Bacterial Viability Kit. GLG was able to prevent the formation of biofilms at concentration ≤0.5% (w/v) and higher concentrations were required to inhibit established biofilms. GLG did not disrupt biofilm biomass. Staphylococci were more susceptible to GLG than P. aeruginosa. These in vitro findings must be verified by in vivo studies.

Surgical site infections: epidemiology and microbiological aspects in trauma and orthopaedic surgery.

Causative agents of wound infections and the routes by which they access surgical incision sites have been recognised for more than a century. Despite knowledge of the factors that influence the risks of surgical site infections (SSIs) and the means to prevent and/or control them, surgical patients still get infections. Traditional systems of classifying and diagnosing SSIs and the diversity of microbial flora reported in contemporary SSIs will be described. Strategies available to prevent and control SSIs will be critically reviewed and the need to develop alternative approaches will be discussed.

Manuka honey inhibits the development of Streptococcus pyogenes biofilms and causes reduced expression of two fibronectin binding proteins.

Streptococcus pyogenes (group A Streptococcus; GAS) is always of clinical significance in wounds where it can initiate infection, destroy skin grafts and persist as a biofilm. Manuka honey has broad spectrum antimicrobial activity and its use in the clinical setting is beginning to gain acceptance with the continuing emergence of antibiotic resistance and the inadequacy of established systemic therapies; novel inhibitors may affect clinical practice. In this study, the effect of manuka honey on S. pyogenes (M28) was investigated in vitro with planktonic and biofilm cultures using MIC, MBC, microscopy and aggregation efficiency. Bactericidal effects were found in both planktonic cultures and biofilms, although higher concentrations of manuka honey were needed to inhibit biofilms. Abrogation of adherence and intercellular aggregation was observed. Manuka honey permeated 24 h established biofilms of S. pyogenes, resulting in significant cell death and dissociation of cells from the biofilm. Sublethal concentrations of manuka honey effectively prevented the binding of S. pyogenes to the human tissue protein fibronectin, but did not inhibit binding to fibrinogen. The observed inhibition of fibronectin binding was confirmed by a reduction in the expression of genes encoding two major fibronectin-binding streptococcal surface proteins, Sof and SfbI. These findings indicate that manuka honey has potential in the topical treatment of wounds containing S. pyogenes.

Manuka honey is bactericidal against Pseudomonas aeruginosa and results in differential expression of oprF and algD.

The presence of Pseudomonas aeruginosa in cutaneous wounds is of clinical significance and can lead to persistent infections. Manuka honey has gained ground in clinical settings due to its effective therapeutic action and broad spectrum of antibacterial activity. In this study, the effect of manuka honey on P. aeruginosa was investigated using MIC, MBC, growth kinetics, confocal microscopy, atomic force microscopy and real-time PCR. A bactericidal mode of action for manuka honey against P. aeruginosa was deduced (12 %, w/v, MIC; 16 %, w/v, MBC) and confirmed by confocal and atomic force microscopy, which showed extensive cell lysis after 60 min exposure to inhibitory concentrations of manuka honey. The inability of honey-treated cells to form microcolonies was demonstrated and investigated using Q-PCR for three key microcolony-forming genes: algD, lasR and oprF. The expression of algD increased 16-fold whereas oprF expression decreased 10-fold following honey treatment; lasR expression remained unaltered. These findings confirm that manuka honey is effective at inducing cell lysis and identify two targets, at the genetic level, that might be involved in this process.

Synergy between oxacillin and manuka honey sensitizes methicillin-resistant Staphylococcus aureus to oxacillin.

OBJECTIVES: Honey is an ancient wound remedy that has recently been introduced into modern clinical practice in developed countries. Manuka honey inhibits growth of methicillin-resistant Staphylococcus aureus (MRSA) by preventing cell division. In Gram-negative bacteria a synergistic interaction between honey and antibiotics has been suggested. We aimed to determine the effect of manuka honey on oxacillin resistance in MRSA. METHODS: Inhibition of MRSA by manuka honey and oxacillin separately and in combination was tested by disc diffusion, Etest strips, serial broth dilution, chequerboards and growth curves. RESULTS: Manuka honey and oxacillin interacted synergistically to inhibit MRSA. Manuka honey reversed oxacillin resistance in MRSA, and down-regulation of mecR1 was found in cells treated with manuka honey. CONCLUSIONS: Microarray analysis showed that exposure of MRSA to inhibitory concentrations of manuka honey resulted in down-regulation of mecR1. Here we demonstrated that subinhibitory concentrations of honey in combination with oxacillin restored oxacillin susceptibility to MRSA. Other honey and antibiotic combinations must now be evaluated.