Empirical and methodological investigations into novelty and familiarity as separate processes that support recognition memory in rats and humans

There is a prevalent assumption in the recognition memory literature that the terms “novelty” and “familiarity” are words ascribed to differing extremities of a single memory strength continuum. The aim of the current thesis was to integrate experimental methodologies across human and rodents to further investigate novelty processing at both a cognitive and neural level, and assess whether it is dissociable from familiarity processing. This dissociation was questioned at a cognitive level in human participants in Experiments 1 to 3 and at a neural level in rats in Experiment 4 and 5. Participants were found to differentially assess novelty and familiarity when making confidence judgements about the mnemonic status of an item (Experiment 1). Additionally, novelty and familiarity processing for questioned items were found to be dissimilarly affected by the presence of a concurrent item of varying mnemonic statuses (Experiment 2 and 3). The presence of a concurrent familiar item did not impact novelty processing in the perirhinal cortex (Experiment 4 and 5), yet disrupted the neural networks established to be differentially engaged by novelty and familiarity (Experiment 5). These findings challenge the assumption that the terms “novelty” and “familiarity” relate to a single recognition memory process. Finally, to allow integration of the findings from the human and rodent experiments, the relationship between measures or recognition memory obtained from spontaneous object recognition (SOR) task in rats and recognition memory measures estimated from signal-detection based models of recognition memory in humans was investigated (Experiment 6 and 7). This revealed that novelty preference in the SOR was positively correlated to measures of recognition memory sensitivity, but not bias. Thus, this thesis argues for the future inclusion of a novelty as a dissociable process from familiarity in our understanding of recognition memory, and for the integrations of experimental methodologies used to test recognition memory across species

Adjunctive quetiapine for serotonin reuptake inhibitor-resistant obsessive-compulsive disorder: A meta-analysis of randomised controlled treatment trials

Small studies have shown positive effects from adding a variety of antipsychotic agents in patients with obsessive–compulsive disorder who are unresponsive to treatment with serotonin reuptake inhibitors. The evidence, however, is contradictory. This paper reports a meta-analysis of existing double-blind randomized placebo-controlled studies looking at the addition of the second-generation antipsychotic quetiapine in such cases. Three studies fulfilled the inclusion criteria. Altogether 102 individuals were subjected to analysis using Review Manager (4.2.7). The results showed evidence of efficacy for adjunctive quetiapine (< 400 mg/day) on the primary efficacy criterion, measured as changes from baseline in total Yale–Brown Obsessive Compulsive Scale scores (P = 0.008), the clinical significance of which was limited by between-study heterogeneity. The mechanism underlying the effect may involve serotonin and/or dopamine neurotransmission

In vitro IFN-α release from IFN-α- and pegylated IFN-α-loaded poly(lactic-co-glycolic acid) and pegylated poly(lactic-co-glycolic acid) nanoparticles

Aim: Interferon alpha (IFN-α) controlled release of nanoparticles was investigated under in vitro conditions. Materials &amp; methods: IFN-α and pegylated IFN-α (PEG-IFN-α) were encapsulated by poly(lactic-co-glycolic acid) (PLGA) and pegylated PLGA (PEG-PLGA) copolymers using double emulsion solvent evaporation method. Results: The size of resulting four nanoparticles (IFN-α in poly(lactic-co-glycolic acids), IFN-α in poly(lactic-co-glycolic acid)-polyethylene glycol, PEG-IFN-α in poly(lactic-co-glycolic acids) and PEG-IFN-α in poly(lactic-co-glycolic acid)-polyethylene glycol) was below 130 nm diameter. IFN-α encapsulation efficiency of the nanoparticles was between 78 and 91%. Conclusion: The in vitro drug release studies conducted in phosphate-buffered saline and human plasma highlighted the role of incubation medium on the IFN release from the nanoparticles. The PEG-IFN-α in poly(lactic-co-glycolic acid)-polyethylene glycol was the most promising nanoparticle among the four formulations because of its remarkably constant release in both phosphate-buffered saline and plasma. </jats:p

Perirhinal cortex and the recognition of relative familiarity

Spontaneous object recognition (SOR) is a widely used task of recognition memory in rodents which relies on their propensity to explore novel (or relatively novel) objects. Network models typically define perirhinal cortex as a region required for recognition of previously seen objects largely based on findings that lesions or inactivations of this area produce SOR deficits. However, relatively little is understood about the relationship between the activity of cells in the perirhinal cortex that signal novelty and familiarity and the behavioural responses of animals in the SOR task. Previous studies have used objects that are either highly familiar or absolutely novel, but everyday memory is for objects that sit on a spectrum of familiarity which includes objects that have been seen only a few times, or objects that are similar to objects which have been previously experienced. We present two studies that explore cellular activity (through c-fos imaging) within perirhinal cortex of rats performing SOR where the familiarity of objects has been manipulated. Despite robust recognition memory performance, we show no significant changes in perirhinal activity related to the level of familiarity of the objects. Reasons for this lack of familiarity-related modulation in perirhinal cortex activity are discussed. The current findings support emerging evidence that perirhinal responses to novelty are complex and that task demands are critical to the involvement of perirhinal cortex in the control of object recognition memory

fMRI evidence supporting the role of memory conflict in the déjà vu experience

This research was funded by an anonymous donation to the School of Psychology and Neuroscience at the University of St Andrews.Attempts to generate déjà vu experimentally have largely focused on engineering partial familiarity for stimuli, relying on an ensuing, but unprompted evaluation of conflict to generate the experience. Without verification that experimentally-generated familiarity is accompanied by the awareness of stimulus novelty, these experimental procedures potentially provide an incomplete déjà vu analogue. We used a modified version of the Deese-Roediger-McDermott (DRM) false memory procedure to generate both familiarity and novelty within a déjà vu analogue—we coupled experimentally-generated familiarity with cues indicating that the familiarity was erroneous, using this additional source of mnemonic information to generate cognitive conflict in our participants. We collected fMRI and behavioural data from 21 participants, 16 of whom reported déjà vu. Using univariate contrasts we identified brain regions associated with mnemonic conflict, including the anterior cingulate cortex, medial prefrontal cortex and parietal cortex. This is the first experiment to image an analogue of the déjà vu experience in healthy volunteers. The increased likelihood of déjà vu reports to DRM critical lures correctly identified as “new”, and the activation of neural substrates supporting the experience of cognitive conflict during déjà vu, suggest that the resolution of memory conflict may play an integral role in déjà vu.PostprintPeer reviewe

Novel transcriptional signatures for sputum-independent diagnostics of tuberculosis in children

Pediatric tuberculosis (TB) is challenging to diagnose, confirmed by growth of Mycobacterium tuberculosis at best in 40% of cases. The WHO has assigned high priority to the development of non-sputum diagnostic tools. We therefore sought to identify transcriptional signatures in whole blood of Indian children, capable of discriminating intra-thoracic TB disease from other symptomatic illnesses. We investigated the expression of 198 genes in a training set, comprising 47 TB cases (19 definite/28 probable) and 36 asymptomatic household controls, and identified a 7- and a 10-transcript signature, both including NOD2, GBP5, IFITM1/3, KIF1B and TNIP1. The discriminatory abilities of the signatures were evaluated in a test set comprising 24 TB cases (17 definite/7 probable) and 26 symptomatic non-TB cases. In separating TB-cases from symptomatic non-TB cases, both signatures provided an AUC of 0.94 (95%CI, 0.88–1.00), a sensitivity of 91.7% (95%CI, 71.5–98.5) regardless of culture status, and 100% sensitivity for definite TB. The 7-transcript signature provided a specificity of 80.8% (95%CI, 60.0–92.7), and the 10-transcript signature a specificity of 88.5% (95%CI, 68.7–96.9%). Although warranting exploration and validation in other populations, our findings are promising and potentially relevant for future non-sputum based POC diagnostic tools for pediatric TB.publishedVersio

Impact of COVID-19 lockdown on the incidence and mortality of acute exacerbations of chronic obstructive pulmonary disease: national interrupted time series analyses for Scotland and Wales

The COVID-19 pandemic and ensuing national lockdowns have dramatically changed the healthcare landscape. The pandemic’s impact on people with chronic obstructive pulmonary disease (COPD) remains poorly understood. We hypothesised that the UK-wide lockdown restrictions were associated with reductions in severe COPD exacerbations. We provide the first national level analyses of the impact of the COVID-19 pandemic and first lockdown on severe COPD exacerbations resulting in emergency hospital admissions and/or leading to death as well as those recorded in primary care or emergency departments

Combining host-derived biomarkers with patient characteristics improves signature performance in predicting tuberculosis treatment outcomes

CITATION: Sivakumaran, Dhanasekaran et al. 2020. Combining host-derived biomarkers with patient characteristics improves signature performance in predicting tuberculosis treatment outcomes. Communications Biology, 3(1):359, doi:10.1038/s42003-020-1087-x.The original publication is available at: https://pubmed.ncbi.nlm.nih.gov/Tuberculosis (TB) is a global health concern. Treatment is prolonged, and patients on anti-TB therapy (ATT) often experience treatment failure for various reasons. There is an urgent need to identify signatures for early detection of failure and initiation of a treatment switch.We investigated how gene biomarkers and/or basic patient characteristics could be used to define signatures for treatment outcomes in Indian adult pulmonary-TB patients treated with standard ATT. Using blood samples at baseline, a 12-gene signature combined with information on gender, previously-diagnosed TB, severe thinness, smoking and alcohol consumption was highly predictive of treatment failure at 6 months. Likewise a 4-protein biomarker signature combined with the same patient characteristics was almost as highly predictive of treatment failure. Combining biomarkers and basic patient characteristics may be useful for predicting and hence identification of treatment failure at an early stage of TB therapy.Publlisher's versio

Human Gastrointestinal Juices Intended for Use in In Vitro Digestion Models

The aim of this study was to characterise the individual human gastric and duodenal juices to be used in in vitro model digestion and to examine the storage stability of the enzymes. Gastroduodenal juices were aspirated, and individual variations in enzymatic activities as well as total volumes, pH, bile acids, protein and bilirubin concentrations were recorded. Individual pepsin activity in the gastric juice varied by a factor of 10, while individual total proteolytic activity in the duodenal juice varied by a factor of 5. The duodenal amylase activity varied from 0 to 52.6 U/ml, and the bile acid concentration varied from 0.9 to 4.5 mM. Pooled gastric and duodenal juices from 18 volunteers were characterised according to pepsin activity (26.7 U/ml), total proteolytic activity (14.8 U/ml), lipase activity (951.0 U/ml), amylase activity (26.8 U/ml) and bile acids (4.5 mM). Stability of the main enzymes in two frozen batches of either gastric or duodenal juice was studied for 6 months. Pepsin activity decreased rapidly and adjusting the pH of gastric juice to 4 did not protect the pepsin from degradation. Lipase activity remained stable for 4 months, however decreased rapidly thereafter even after the addition of protease inhibitors. Glycerol only marginally stabilised the survival of the enzymatic activities. These results of compositional variations in the individual gastrointestinal juices and the effect of storage conditions on enzyme activities are useful for the design of in vitro models enabling human digestive juices to simulate physiological digestion