The temporal relationship between the neural and vascular actions of kallidin within the nose

The time course of effect of the B2-receptor agonist kallidin (K) on induced changes of nasal airflow, rhinorrhoea, nasal pain, sneezing and nasal microvascular leakage has been examined and compared with its B2 metabolite agonist bradykinin (B) and the B1-agonist [des-arg9]-bradykinin (D). When administered as a single dose K and B induced an immediate sensation of pain, rhinorrhoea, elevations in lavage albumin and protein levels and a sustained increase in nasal airways resistance (NAR) for 5–40 min post-challenge. [des-arg9]-Bradykinin and vehicle placebo (V) were without effect on any of these indices. These studies identify the action of K and B within the nose and differentiate the neural and vascular effects of these kinins in addition to suggesting the potential that nasal blockage and nasal microvascular leakage represent alterations in differing vascular compartments. These findings have implications for the understanding and therapeutic manipulation of rhinitis

Determinants of voluntary audit and voluntary full accounts in micro- and non-micro small companies in the UK

This is an Author's Accepted Manuscript of an article published in Accounting and Business Research, 42(4), 441 - 468, 2012, copyright Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/00014788.2012.667969.This study investigates the link between the auditing and filing choices made by a sample of 592 small private companies, which includes 419 micro-companies. It examines decisions made in connection with the 2006 accounts following UK's adoption of the maximum EU size thresholds in 2004, and the impact of the proposed Directive on the annual accounts of micro-companies. The research extends the model of cost, management and agency factors associated with voluntary audit, and develops a complementary model for voluntary full accounts. The results show the benefits of placing full audited accounts on public record that outweigh the costs for a significant proportion of companies. In non-micro small companies, voluntary audit is determined by cost and agency factors, whereas in micro-companies it is driven by cost, management and agency factors. In both groups, the predictors of voluntary full accounts include management and agency factors, and choosing voluntary audit is one of the key factors. The study provides models that can be tested in other jurisdictions to provide evidence of the needs of micro-companies, and the discussion of the methodological challenges for small company researchers in the UK makes further contribution to the literature

Chronic Respiratory Aeroallergen Exposure in Mice Induces Epithelial-Mesenchymal Transition in the Large Airways

Chronic allergic asthma is characterized by Th2-polarized inflammation and leads to airway remodeling and fibrosis but the mechanisms involved are not clear. To determine whether epithelial-mesenchymal transition contributes to airway remodeling in asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM) extract for up to 15 consecutive weeks. We report that respiratory exposure to HDM led to significant airway inflammation and thickening of the smooth muscle layer in the wall of the large airways. Transforming growth factor beta-1 (TGF-β1) levels increased in mouse airways while epithelial cells lost expression of E-cadherin and occludin and gained expression of the mesenchymal proteins vimentin, alpha-smooth muscle actin (α-SMA) and pro-collagen I. We also observed increased expression and nuclear translocation of Snail1, a transcriptional repressor of E-cadherin and a potent inducer of EMT, in the airway epithelial cells of HDM-exposed mice. Furthermore, fate-mapping studies revealed migration of airway epithelial cells into the sub-epithelial regions of the airway wall. These results show the contribution of EMT to airway remodeling in chronic asthma-like inflammation and suggest that Th2-polarized airway inflammation can trigger invasion of epithelial cells into the subepithelial regions of the airway wall where they contribute to fibrosis, demonstrating a previously unknown plasticity of the airway epithelium in allergic airway disease

Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life

Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene A Disintegrin and Metalloprotease (ADAM)33, acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble (s)ADAM33 is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed in Adam33 null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances post-natal airway eosinophilia and bronchial hyperresponsiveness following sub-threshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma

Smoking in asthma is associated with elevated levels of corticosteroid resistant sputum cytokines—an exploratory study

<p>Background: Current cigarette smoking is associated with reduced acute responses to corticosteroids and worse clinical outcomes in stable chronic asthma. The mechanism by which current smoking promotes this altered behavior is currently unclear. Whilst cytokines can induce corticosteroid insensitivity in-vitro, how current and former smoking affects airway cytokine concentrations and their responses to oral corticosteroids in stable chronic asthma is unclear.</p> <p>Objectives: To examine blood and sputum cytokine concentrations in never, ex and current smokers with asthma before and after oral corticosteroids.</p> <p>Methods: Exploratory study utilizing two weeks of oral dexamethasone (equivalent to 40 mg/day prednisolone) in 22 current, 21 never and 10 ex-smokers with asthma. Induced sputum supernatant and plasma was obtained before and after oral dexamethasone. 25 cytokines were measured by multiplex microbead system (Invitrogen, UK) on a Luminex platform.</p> <p>Results: Smokers with asthma had elevated sputum cytokine interleukin (IL) -6, -7, and -12 concentrations compared to never smokers with asthma. Few sputum cytokine concentrations changed in response to dexamethasone IL-17 and IFNα increased in smokers, CCL4 increased in never smokers and CCL5 and CXCL10 reduced in ex-smokers with asthma. Ex-smokers with asthma appeared to have evidence of an ongoing corticosteroid resistant elevation of cytokines despite smoking cessation. Several plasma cytokines were lower in smokers wi</p> <p>Conclusion: Cigarette smoking in asthma is associated with a corticosteroid insensitive increase in multiple airway cytokines. Distinct airway cytokine profiles are present in current smokers and never smokers with asthma and could provide an explanatory mechanism for the altered clinical behavior observed in smokers with asthma.</p&gt

A deimmunised form of the ribotoxin, α-sarcin, lacking CD4+ T cell epitopes and its use as an immunotoxin warhead

Fungal ribotoxins that block protein synthesis can be useful warheads in the context of a targeted immunotoxin. α-Sarcin is a small (17 kDa) fungal ribonuclease produced by Aspergillus giganteus that functions by catalytically cleaving a single phosphodiester bond in the sarcin–ricin loop of the large ribosomal subunit, thus making the ribosome unrecognisable to elongation factors and leading to inhibition of protein synthesis. Peptide mapping using an ex vivo human T cell assay determined that α-sarcin contained two T cell epitopes; one in the N-terminal 20 amino acids and the other in the C-terminal 20 amino acids. Various mutations were tested individually within each epitope and then in combination to isolate deimmunised α-sarcin variants that had the desired properties of silencing T cell epitopes and retention of the ability to inhibit protein synthesis (equivalent to wild-type, WT α-sarcin). A deimmunised variant (D9T/Q142T) demonstrated a complete lack of T cell activation in in vitro whole protein human T cell assays using peripheral blood mononuclear cells from donors with diverse HLA allotypes. Generation of an immunotoxin by fusion of the D9T/Q142T variant to a single-chain Fv targeting Her2 demonstrated potent cell killing equivalent to a fusion protein comprising the WT α-sarcin. These results represent the first fungal ribotoxin to be deimmunised with the potential to construct a new generation of deimmunised immunotoxin therapeutics

The respiratory research agenda in primary care in Portugal: a Delphi study

Background: A research agenda can help to stimulate and guide research. The International Primary Care Respiratory Group (IPCRG) published a Research Needs Statement (RNS) in 2010 in which 145 research questions were identified. In 2012, priorities for respiratory research were established, based on these questions. To date, there has been no statement on primary care respiratory research needs in Portugal. The aim of the study was to develop a national consensus on research priorities in respiratory diseases in primary care in Portugal and to assess the applicability of the priorities for respiratory research set by the IPCRG. Method: We conducted a Delphi study by electronic mail with a panel of experts on respiratory disease from primary and secondary care in Portugal. In the first round, the research needs in respiratory disease in Portugal were identified. In the second round, 196 research questions in six disease areas, derived from the first round and from the IPCRG Respiratory needs statement, were prioritised on a five-point Likert-type scale. In the third round, the questions were prioritized again with feed-back provided on the median scores for each item in the second round. Consensus was considered to have been reached when 80 % of the participants gave a score of 4 or 5 out of five on a given item. Results: The 40 experts identified 121 respiratory research questions in Round 1 and expressed their views on 196 questions in Rounds 2 and 3. Twelve research questions (6 %) reached consensus. There were five questions in the asthma domain on early diagnosis, pulmonary function tests, the use of inhalers, and adherence to treatment. There were four questions in the chronic obstructive pulmonary disease domain on vaccinations, on routine monitoring and evaluation of treatment, on diagnosis, and on adherence to treatments. There was one question in the smoking domain on the effects of brief counselling. There were two questions on respiratory tract infections on the treatment of children and on the prescription of antibiotics. An additional 23 research questions (12 %) achieved consensus between 75 and 79 %. Conclusion: The results reflect the Portuguese reality in response the international agenda for research on respiratory diseases published by the IPCRG. They can support the development of future respiratory disease research in Portugal.Financial support for this work was provided by FEDER funds through the Operational Programme Competitiveness Factors - COMPETE and National Funds through FCT - Foundation for Science and Technology under the project POCI-01-0145-FEDER-007038; and by the project NORTE-01-0145-FEDER-000013, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). PMT is partially supported by a grant from the International Primary Care Respiratory Group

Trade unions and precariat in Europe : representative claims

Trade unions have been charged with neglecting labour market ‘outsiders’, while alternative actors have emerged to represent these. In response, unions have stepped up their claim to be representative of all workers, without distinction. We review the theoretical and policy debates on this issue, and argue that representation as such has been under-theorized. We draw on Saward’s concept of ‘representative claims’ to analyse the different grounds for competing assertions of representativeness. We identify four main forms of claims, and illustrate these with empirical examples. We conclude that these different claims are mutually reinforcing in stimulating attention to the outsiders, and in their interaction with institutional settings, they have a performative effect in defining new social actors

Progress in the discovery of selective, high affinity A2B adenosine receptor antagonists as clinical candidates

The selective, high affinity A2B adenosine receptor (AdoR) antagonists that were synthesized by several research groups should aid in determining the role of the A2B AdoR in inflammatory diseases like asthma or rheumatoid arthritis (RA) and angiogenic diseases like diabetic retinopathy or cancer. CV Therapeutics scientists discovered the selective, high affinity A2B AdoR antagonist 10, a 8-(4-pyrazolyl)-xanthine derivative [CVT-6883, Ki(hA2B) = 22 nM; Ki(hA1) = 1,940 nM; Ki(hA2A) = 3,280; and Ki(hA3) = 1,070 nM] that has favorable pharmacokinetic (PK) properties (t1/2 = 4 h and F > 35% rat). Compound 10 demonstrated functional antagonism at the A2B AdoR (KB = 6 nM) and efficacy in a mouse model of asthma. In two phase 1 clinical trials, CVT-6883 was found to be safe, well tolerated, and suitable for once daily dosing. A second compound 20, 8-(5-pyrazolyl)-xanthine, has been nominated for development from Baraldi’s group in conjunction with King Pharmaceuticals that has favorable A2B AdoR affinity and selectivity [Ki(hA2B) = 5.5 nM; Ki(hA1) > 1,000 nM; Ki(hA2A) > 1,000; and Ki(hA3) > 1,000 nM], and it has been demonstrated to be a functional antagonist. A third compound 32, a 2-aminopyrimidine, from the Almirall group has high A2B AdoR affinity and selectivity [Ki(hA2B) = 17 nM; Ki(hA1) > 1,000 nM; Ki(hA2A) > 2,500; and Ki(hA3) > 1,000 nM], and 32 has been moved into preclinical safety testing. Since three highly selective, high affinity A2B AdoR antagonists have been nominated for development with 10 (CVT-6883) being the furthest along in the development process, the role of the A2B AdoR in various disease states will soon be established

Looking ahead at the potential benefits of biotechnology-derived allergen therapeutics

While biotechnology-derived allergen therapeutics show promise in improving the safety of immunotherapy, they may prove to have additional benefits in comparison to conventional allergenic extracts that deserve commentary. These issues range from product stability and compatibility to medical practice issues, which will be the focus of this article