Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

/pdf/neuroinflammation-in-alzheimer-s-disease-36czdowiut.pdf

Neuroinflammation in Alzheimer's disease

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. The full document can be downloaded for free on the website of this journal: http://www.rhinologyjournal.com.

/pdf/european-position-paper-on-rhinosinusitis-and-nasal-polyps-mj734vsl7p.pdf

European Position Paper on Rhinosinusitis and Nasal Polyps 2020

Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs.

/pdf/origins-and-functional-impact-of-copy-number-variation-in-2bsbvet2tw.pdf

Origins and functional impact of copy number variation in the human genome

Neutrophils are innate immune phagocytes that have a central role in immune defence. Our understanding of the role of neutrophils in pathogen clearance, immune regulation and disease pathology has advanced dramatically in recent years. Web-like chromatin structures known as neutrophil extracellular traps (NETs) have been at the forefront of this renewed interest in neutrophil biology. The identification of molecules that modulate the release of NETs has helped to refine our view of the role of NETs in immune protection, inflammatory and autoimmune diseases and cancer. Here, I discuss the key findings and concepts that have thus far shaped the field of NET biology.

Neutrophil extracellular traps in immunity and disease

Asthma is a common disease that affects 300 million people worldwide. Given the large number of eosinophils in the airways of people with mild asthma, and verified by data from murine models, asthma was long considered the hallmark T helper type 2 (T(H)2) disease of the airways. It is now known that some asthmatic inflammation is neutrophilic, controlled by the T(H)17 subset of helper T cells, and that some eosinophilic inflammation is controlled by type 2 innate lymphoid cells (ILC2 cells) acting together with basophils. Here we discuss results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans and describe the extraordinary heterogeneity of asthma.

The immunology of asthma

Pulmonary Innate Lymphoid Cell Responses During Rhinovirus-Induced Asthma Exacerbations

P. Papinius Statius: Thebaid and Achilleid Volume I

The following information was missing from the funding section: This work was funded in part by the MoRIAE European Research Council FP7 Advanced Investigator award to SLJ, Grant number 233015.

Correction: The Role of IL-15 Deficiency in the Pathogenesis of Virus-Induced Asthma Exacerbations

Whole Lung Transcriptome Analysis Of A Model Of Schistosomiasis-Associated Pulmonary Hypertension

), and its activity was usually deter-mined by a radioactive assay in which product from aradioactive substrate was identiWed by chromatographyand measured by a scintillation counter [1–4]. However,this assay has major concerns about safety, complicatedhandling, and availability of radioactive substrates. Mioet al. [5] mentioned another strategy in which a couplingenzyme, pyrophosphatase, is included in the anabolicreaction to convert the pyrophosphate into inorganicphosphate that can be readily quantiWed by a malachitegreen colorimetric assay. Nevertheless, the precautionsof this assay have never been discussed, and ignorance ofproper controls was found to result in signiWcant arti-facts. The current report describes the basic principle,reaction condition, and critical sources of error of thiscolorimetric assay to allow accurate and reliable mea-surement of UAP activity.The principle of the malachite green colorimetricassay is based on the reaction between phosphate andmolybdate to form a phosphomolybdate complex thatbinds to the dye and induces the color changes [6]. It iswell known that on the addition of acid, molybde-num(VI) salts form numerous polymolybdate(VI) struc-tures. When phosphate is present, heteropolyanions areformed; that is, the phosphate group is surrounded by acage of MoO

Michael R. Edwards

Papers

Pulmonary Innate Lymphoid Cell Responses During Rhinovirus-Induced Asthma Exacerbations

P. Papinius Statius: Thebaid and Achilleid Volume I

Correction: The Role of IL-15 Deficiency in the Pathogenesis of Virus-Induced Asthma Exacerbations

Whole Lung Transcriptome Analysis Of A Model Of Schistosomiasis-Associated Pulmonary Hypertension

Notes & Tips Critical sources of error in colorimetric assay for UDP-N-acetylglucosamine pyrophosphorylase