Tau Aggregation Correlates with Amyloid Deposition in Both Mild Cognitive Impairment and Alzheimer’s Disease Subjects

Background:Amyloid plaque and tau-containing neurofibrillary tangles are important features of Alzheimer’s disease (AD). However, the relationship between these processes is still debated. Objective:We aimed to investigate local and distant relationships between tau and amyloid deposition in the cortex in mild cognitive impairment (MCI) and AD using PET imaging. Methods:Seventy-nine subjects (51 controls, 13 amyloid-positive MCI subjects, and 15 amyloid positive AD subjects) underwent MRI and 18F-flutemetamol PET. All MCI/AD subjects and 8 healthy controls as well as 33 healthy control subjects from the ADNI dataset also had 18F-AV1451 PET. Regional and distant correlations were examined after sampling target-to-cerebellar ratio images. Biological parametric mapping was used to evaluate voxel level correlations locally. Results:We found multiple clusters of voxels with highly significant positive correlations throughout the association cortex in both MCI and AD subjects. Conclusion:The multiple clusters of positive correlations indicate that tau and amyloid may interact locally and be involved in disease progression. Our findings suggest that targeting both pathologies may be required

Delirium, frailty and mortality:interactions in a prospective study of hospitalized older people

AbstractBackgroundIt is unknown if the association between delirium and mortality is consistent for individuals across the whole range of health states. A bimodal relationship has been proposed, where delirium is particularly adverse for those with underlying frailty, but may have a smaller effect (perhaps even protective) if it is an early indicator of acute illness in fitter people. We investigated the impact of delirium on mortality in a cohort simultaneously evaluated for frailty.MethodsWe undertook an exploratory analysis of a cohort of consecutive acute medical admissions aged ≥70. Delirium on admission was ascertained by psychiatrists. A Frailty Index (FI) was derived according to a standard approach. Deaths were notified from linked national mortality statistics. Cox regression was used to estimate associations between delirium, frailty and their interactions on mortality.ResultsThe sample consisted of 710 individuals. Both delirium and frailty were independently associated with increased mortality rates (delirium: HR 2.4, 95%CI 1.8-3.3, p&lt;0.01; frailty (per SD): HR 3.5, 95%CI 1.2-9.9, p=0.02). Estimating the effect of delirium in tertiles of FI, mortality was greatest in the lowest tertile: tertile 1 HR 3.4 (95%CI 2.1-5.6); tertile 2 HR 2.7 (95%CI 1.5-4.6); tertile 3 HR 1.9 (95% CI 1.2-3.0).ConclusionWhile delirium and frailty contribute to mortality, the overall impact of delirium on admission appears to be greater at lower levels of frailty. In contrast to the hypothesis that there is a bimodal distribution for mortality, delirium appears to be particularly adverse when precipitated in fitter individuals.</jats:sec

Not All Strokes Are Strokes - An Example of Diagnostic Confirmation Bias

A 72-year-old woman presented with a complex partial seizure and right hemiparesis, after a four-week history of cognitive decline, apraxia and speech disturbance. She previously had chronic lymphocytic leukaemia (CLL) and had finished chemotherapy one year prior to presentation. She was receiving monthly intravenous immunoglobulins for bronchiectasis. Brain imaging showed hypodensity in the left temporo-parietal regions. Cerebrospinal fluid was positive for the JC virus, leading to a diagnosis of progressive multifocal leucoencephalopathy (PML). She remains alive, eight months following initial presentation. The case was valuable for reflective practice in avoiding diagnostic (confirmation) bias because the treating team pursued an incorrect diagnosis of stroke and secondary seizure after radiology findings appeared consistent with this. Additionally, PML has not previously been reported in individuals with CLL receiving immunoglobulin therapy, and may explain the relatively benign course in this individual patient. This offers a potential research question for disease modifying treatments in PML

Teaching geriatric medicine through gamification: a tool for enhancing postgraduate education in geriatric medicine

Background Polypharmacy is becoming increasingly common and all doctors must be prepared to manage it competently. Aims The aim of this project is to evaluate the feasibility and use of a novel gamification-based teaching intervention on polypharmacy among doctors undergoing advanced geriatric training. Among others, one of the learning goals for the students was to be able to describe the adherence to medication. Methods Electronic questionnaire sent to students of the third session “evidence-based medicine in geriatrics” of advanced postgraduate course in geriatrics of the European Academy for Medicine of Ageing. Results Most students reported issues with forgetting doses and remembering sufficiently to establish a medication routine due to busy schedules as well as social influences around medication taking. Reflecting on the challenges of the game, most students reported that their own prescribing practice was likely to change. Discussion and conclusion The current model of learning appears to be a feasible approach for postgraduate medical education or in other areas of healthcare such as nursing or physiotherapy. Learning through action and reflection promotes deeper thinking and can lead to behavioral change, in this case thus enhancing the attitudes and understanding regarding pharmacological issues associated with ageing. Recommendations for future research in medical education about medication adherence are outlined.publishedVersio

Novel insights in antimicrobial and immunomodulatory mechanisms of action of PepBiotics CR-163 and CR-172

Objectives: Our group recently developed a new group of antimicrobial peptides termed PepBiotics, of which peptides CR-163 and CR-172 showed optimized antibacterial activity against Pseudomonas aeruginosa and Staphylococcus aureus without inducing antimicrobial resistance. In this study, the antibacterial mechanism of action and the immunomodulatory activity of these two PepBiotics was explored. Methods: RAW264.7 cells were used to determine the ability of PepBiotics to neutralize Lipopolysaccharide (LPS)-and Lipoteichoic acid (LTA)-induced activation of macrophages. Isothermal titration calorimetry and competition assays with dansyl-labeled polymyxin B determined binding characteristics to LPS and LTA. Combined bacterial killing with subsequent macrophage activation assays was performed to determine so-called ‘silent killing’. Finally, flow cytometry of peptide-treated genetically engineered Escherichia coli expressing Green Fluorescent Protein (GFP) and mCherry in the cytoplasm and periplasm, respectively, further established the antimicrobial mechanism of PepBiotics. Results: Both CR-163 and CR-172 were shown to have broad-spectrum activity against ESKAPE pathogens and E. coli using a membranolytic mechanism of action. PepBiotics could exothermically bind LPS/LTA and were able to replace polymyxin B. Finally, it was demonstrated that bacteria killed by PepBiotics were less prone to stimulate immune cells, contrary to gentamicin and heat-killed bacteria that still elicited a strong immune response. Conclusions: These studies highlight the multifunctional nature of the two peptide antibiotics as both broad-spectrum antimicrobial and immunomodulator. Their ability to kill bacteria and reduce unwanted subsequent immune activation is a major advantage and highlights their potential for future therapeutic use

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal alpha-toxin

The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor kappa B signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor alpha-toxin. Naturally elicited antibodies against alpha-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to alpha-toxin in nonleukocytic cells.Peer reviewe

The FunGenES Database: A Genomics Resource for Mouse Embryonic Stem Cell Differentiation

Embryonic stem (ES) cells have high self-renewal capacity and the potential to differentiate into a large variety of cell types. To investigate gene networks operating in pluripotent ES cells and their derivatives, the “Functional Genomics in Embryonic Stem Cells” consortium (FunGenES) has analyzed the transcriptome of mouse ES cells in eleven diverse settings representing sixty-seven experimental conditions. To better illustrate gene expression profiles in mouse ES cells, we have organized the results in an interactive database with a number of features and tools. Specifically, we have generated clusters of transcripts that behave the same way under the entire spectrum of the sixty-seven experimental conditions; we have assembled genes in groups according to their time of expression during successive days of ES cell differentiation; we have included expression profiles of specific gene classes such as transcription regulatory factors and Expressed Sequence Tags; transcripts have been arranged in “Expression Waves” and juxtaposed to genes with opposite or complementary expression patterns; we have designed search engines to display the expression profile of any transcript during ES cell differentiation; gene expression data have been organized in animated graphs of KEGG signaling and metabolic pathways; and finally, we have incorporated advanced functional annotations for individual genes or gene clusters of interest and links to microarray and genomic resources. The FunGenES database provides a comprehensive resource for studies into the biology of ES cells

Radical Immersions: Navigating between virtual/physical environments and information bubbles - DRHA 2019 Conference Proceedings

This publication consists of the peer-reviewed papers and posters presented at the DRHA 2019 Conference "Radical Immersions: navigating between virtual / physical environments and information bubbles". The conference was held at Watermans Arts Centre, London (8-10 September 2019). For further information: http://www.2019.drha.uk

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe