Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease.

The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus rich in mucin glycoproteins. Abnormal mucus accumulation is a cardinal feature of chronic respiratory diseases but the relationship between mucus and pathogens during exacerbations is poorly understood. We identified elevations in airway MUC5AC and MUC5B concentrations during spontaneous and experimentally-induced chronic obstructive pulmonary disease (COPD) exacerbations. MUC5AC was more sensitive to changes in expression during exacerbation and was therefore more predictably associated with virus load, inflammation, symptom severity, decrements in lung function, and secondary bacterial infections. MUC5AC was functionally related to inflammation as Muc5ac-deficient (Muc5ac-/-) mice had attenuated rhinovirus (RV)-induced airway inflammation and exogenous MUC5AC glycoprotein administration augmented inflammatory responses and increased release of extracellular adenosine triphosphate (ATP) in mice and human airway epithelial cell cultures. Hydrolysis of ATP suppressed MUC5AC augmentation of rhinovirus-induced inflammation in mice. Therapeutic suppression of mucin production using an epidermal growth factor receptor (EGFR) antagonist ameliorated immunopathology in a mouse COPD exacerbation model. The coordinated virus induction of MUC5AC and MUC5B suggests that non-Th2 mechanisms trigger mucin hypersecretion during exacerbations. Our data identifies a pro-inflammatory role for MUC5AC during viral infection and suggest that MUC5AC inhibition may ameliorate COPD exacerbations

The Role of Interleukin-1 and Interleukin-18 in Pro-Inflammatory and Anti-Viral Responses to Rhinovirus in Primary Bronchial Epithelial Cells

Human Rhinovirus (HRV) is associated with acute exacerbations of chronic respiratory disease. In healthy individuals, innate viral recognition pathways trigger release of molecules with direct anti-viral activities and pro-inflammatory mediators which recruit immune cells to support viral clearance. Interleukin-1alpha (IL-1α), interleukin-1beta (IL-1β) and interleukin-18 (IL-18) have critical roles in the establishment of neutrophilic inflammation, which is commonly seen in airways viral infection and thought to be detrimental in respiratory disease. We therefore investigated the roles of these molecules in HRV infection of primary human epithelial cells. We found that all three cytokines were released from infected epithelia. Release of these cytokines was not dependent on cell death, and only IL-1β and IL-18 release was dependent on caspase-1 catalytic activity. Blockade of IL-1 but not IL-18 signaling inhibited up-regulation of pro-inflammatory mediators and neutrophil chemoattractants but had no effect on virus induced production of interferons and interferon-inducible genes, measured at both mRNA and protein level. Similar level of virus mRNA was detected with and without IL-1RI blockade. Hence IL-1 signaling, potentially involving both IL-1β and IL-1α, downstream of viral recognition plays a key role in induction of pro-inflammatory signals and potentially in recruitment and activation of immune cells in response to viral infection instigated by the epithelial cells, whilst not participating in direct anti-viral responses

Cross-Serotype Immunity Induced by Immunization with a Conserved Rhinovirus Capsid Protein

Human rhinovirus (RV) infections are the principle cause of common colds and precipitate asthma and COPD exacerbations. There is currently no RV vaccine, largely due to the existence of ∼150 strains. We aimed to define highly conserved areas of the RV proteome and test their usefulness as candidate antigens for a broadly cross-reactive vaccine, using a mouse infection model. Regions of the VP0 (VP4+VP2) capsid protein were identified as having high homology across RVs. Immunization with a recombinant VP0 combined with a Th1 promoting adjuvant induced systemic, antigen specific, cross-serotype, cellular and humoral immune responses. Similar cross-reactive responses were observed in the lungs of immunized mice after infection with heterologous RV strains. Immunization enhanced the generation of heterosubtypic neutralizing antibodies and lung memory T cells, and caused more rapid virus clearance. Conserved domains of the RV capsid therefore induce cross-reactive immune responses and represent candidates for a subunit RV vaccine

The mechanisms of boronate ester formation and fluorescent turn-on in ortho-aminomethylphenylboronic acids

ortho-Aminomethylphenylboronic acids are used in receptors for carbohydrates and various other compounds containing vicinal diols. The presence of the o-aminomethyl group enhances the affinity towards diols at neutral pH, and the manner in which this group plays this role has been a topic of debate. Further, the aminomethyl group is believed to be involved in the turn-on of the emission properties of appended fluorophores upon diol binding. In this treatise, a uniform picture emerges for the role of this group: it primarily acts as an electron-withdrawing group that lowers the pK(a) of the neighbouring boronic acid thereby facilitating diol binding at neutral pH. The amine appears to play no role in the modulation of the fluorescence of appended fluorophores in the protic-solvent-inserted form of the boronic acid/boronate ester. Instead, fluorescence turn-on can be consistently tied to vibrational-coupled excited-state relaxation (a loose-bolt effect). Overall, this Review unifies and discusses the existing data as of 2019 whilst also highlighting why o-aminomethyl groups are so widely used, and the role they play in carbohydrate sensing using phenylboronic acids

Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis.

Objectives Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database. Methods Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12\ub13 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression. Results Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model. Conclusions The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trial

Selkeäkielisen potilasohjeen kehittäminen varfariinihoitoa saavalle potilaalle

Tässä opinnäytetyössä on tarkoituksena selvittää selkeän kielen tarvetta eteisvärinäpotilaan kirjallisessa ohjauksessa sekä tuottaa juurruttamisen menetelmällä varfariinihoitoa saavan potilaan selkeäkielinen hoito-opas. Opinnäytetyö on tehty yhteistyössä perusturvakuntayhtymä Karviaisen terveyskeskuksien henkilökunnan kanssa. Opinnäytetyö on osa Laurea-ammattikorkeakoulun Pumppu-osahanketta. Pumppu-hanke on ylimaakunnallinen vuosina 2011–2014 toteutettava teemahanke, jota rahoittavat Päijät-Hämeen liitto ja Etelä-Suomen maakuntien EU-yksikkö. Laurea-ammattikorkeakoulun Pumppu-osahankkeessa etsitään keinoja asiakkaan terveyden ja hyvinvoinnin edistämiseen sekä hoitamiseen erilaisilla hyvinvointipoluilla. Aineiston tiedonkeruu tehtiin teemahaastattelulla sekä sähköisellä kyselylomakkeella. Vastaukset analysoitiin sisällönanalyysin avulla. Kehittämistoiminnan lopputuotoksena laadittiin selkeäkielinen Marevan®-hoidon miniopas. Marevan®-hoidon miniopas sisältää selkeäkielistä tietoa Marevan®-lääkityksestä, veren hyytymiskyvyn seurannan merkityksestä, lääkkeen annostelusta sekä ruokavalion, alkoholin että muiden lääkkeiden ja luontaistuotteiden vaikutuksista Marevan®-lääkityksessä. Oppaassa on myös kerrottu Marevan®-lääkityksen erityistilanteista, kuten lääkitykseen liittyvistä vaaratekijöistä. Marevan®-hoidon miniopas on otettu työyhteisössä käyttöön toukokuussa 2013. Työyhteisö kerää asiakkailta palautetta minioppaasta puolistrukturoidulla arviointilomakkeella. Palautteiden pohjalta he tulevat jatkossa arvioimaan oppaan käytön ja kehittämisen tarvetta.The development of a clear language patient guide for a patient with warfarin therapy In this thesis the purpose is to find out the need for a clear language written guidance for a patient with atrial fibrillation and produce a clear language patient´s Guide for a patient with warfarin therapy by using dissemination method. The thesis is made in cooperation with the staff of health centers in Karviainen Health District. The thesis is a part of Pumppu subproject in Laurea University for Applied Sciences. The Pumppu project is an interregional theme of the project which to be carried out in 2011- 2014, and is financed by Päijät-Häme Region Association and the EU unit of southern provinces of Finland. A subproject Pumppu in Laurea University for Applied Sciences is searching for ways to promote and care for a customer`s health and welfare by different welfare paths. The material for this thesis was gathered by using a theme interview and an electronic questionnaire. The answers were analyzed by using content analysis. As the final result of development, a clear language mini guide of Marevan® therapy was drawn up. A Marevan® therapy mini guide includes clear language information about Marevan® therapy, the importance of blood clotting ability monitoring, drug delivery and the effects of diet, alcohol, other medicines and natural remedies for medicine in Marevan® therapy. The guide tells also about the specific situations in Marevan® therapy, such as the risk factors of Marevan® therapy. Marevan® therapy mini guide has been introduced at workplace in May 2013. The workplace collects the feedback of the mini guide from the patients with a semi- structured form. On the basis of feedback they will estimate the need of use and development of the guide in the future