Smoking cessation and bronchial epithelial remodelling in COPD: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Chronic Obstructive Pulmonary Disease (COPD) is associated with bronchial epithelial changes, including squamous cell metaplasia and goblet cell hyperplasia. These features are partially attributed to activation of the epidermal growth factor receptor (EGFR). Whereas smoking cessation reduces respiratory symptoms and lung function decline in COPD, inflammation persists. We determined epithelial proliferation and composition in bronchial biopsies from current and ex-smokers with COPD, and its relation to duration of smoking cessation.</p> <p>Methods</p> <p>114 COPD patients were studied cross-sectionally: 99 males/15 females, age 62 ± 8 years, median 42 pack-years, no corticosteroids, current (n = 72) or ex-smokers (n = 42, median cessation duration 3.5 years), postbronchodilator FEV₁63 ± 9% predicted. Squamous cell metaplasia (%), goblet cell (PAS/Alcian Blue⁺) area (%), proliferating (Ki-67⁺) cell numbers (/mm basement membrane), and EGFR expression (%) were measured in intact epithelium of bronchial biopsies.</p> <p>Results</p> <p>Ex-smokers with COPD had significantly less epithelial squamous cell metaplasia, proliferating cell numbers, and a trend towards reduced goblet cell area than current smokers with COPD (p = 0.025, p = 0.001, p = 0.081, respectively), but no significant difference in EGFR expression. Epithelial features were not different between short-term quitters (<3.5 years) and current smokers. Long-term quitters (≥3.5 years) had less goblet cell area than both current smokers and short-term quitters (medians: 7.9% vs. 14.4%, p = 0.005; 7.9% vs. 13.5%, p = 0.008; respectively), and less proliferating cell numbers than current smokers (2.8% vs. 18.6%, p < 0.001).</p> <p>Conclusion</p> <p>Ex-smokers with COPD had less bronchial epithelial remodelling than current smokers, which was only observed after long-term smoking cessation (>3.5 years).</p> <p>Trial registration</p> <p>NCT00158847</p

Multidrug resistance-associated protein-1 (MRP1) genetic variants, MRP1 protein levels and severity of COPD

<p>Abstract</p> <p>Background</p> <p>Multidrug resistance-associated protein-1 (MRP1) protects against oxidative stress and toxic compounds generated by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease (COPD). We have previously shown that single nucleotide polymorphisms (SNPs) in <it>MRP1 </it>significantly associate with level of FEV₁in two independent population based cohorts. The aim of our study was to assess the associations of <it>MRP1 </it>SNPs with FEV₁level, MRP1 protein levels and inflammatory markers in bronchial biopsies and sputum of COPD patients.</p> <p>Methods</p> <p>Five SNPs (rs212093, rs4148382, rs504348, rs4781699, rs35621) in <it>MRP1 </it>were genotyped in 110 COPD patients. The effects of <it>MRP1 </it>SNPs were analyzed using linear regression models.</p> <p>Results</p> <p>One SNP, rs212093 was significantly associated with a higher FEV₁level and less airway wall inflammation. Another SNP, rs4148382 was significantly associated with a lower FEV₁level, higher number of inflammatory cells in induced sputum and with a higher MRP1 protein level in bronchial biopsies.</p> <p>Conclusions</p> <p>This is the first study linking <it>MRP1 </it>SNPs with lung function and inflammatory markers in COPD patients, suggesting a role of <it>MRP1 </it>SNPs in the severity of COPD in addition to their association with MRP1 protein level in bronchial biopsies.</p

Tuberculosis prevalence surveys: rationale and cost

This article is the first of the educational series 'Assessing tuberculosis (TB) prevalence through population-based surveys'. The series will give overall guidance in conducting cross-sectional surveys of pulmonary TB (PTB) disease. TB prevalence surveys are most valuable in areas where notification data obtained through routine surveillance are of unproven accuracy or incomplete, and in areas with an estimated prevalence of bacteriologically confirmed TB of more than 100 per 100,000 population. To embark on a TB prevalence survey requires commitment from the national TB programme, compliance in the study population, plus availability of trained staff and financial resources. The primary objective of TB prevalence surveys is to determine the prevalence of PTB in the general population aged >or=15 years. Limitations of TB prevalence surveys are their inability to assess regional or geographic differences in prevalence of TB, estimate the burden of childhood TB or estimate the prevalence of extra-pulmonary TB. The cost of a prevalence survey is typically US$4-15 per person surveyed, and up to US$ 25 per person with radiographic screening. A survey of 50,000 people, of limited precision, would typically cost US$ 200,000-1,250,00

A potential for molecular simulation of compounds with linear moieties

The harmonic angle bending potential is used in many force fields for (bio)molecular simulation. The force associated with this potential is discontinuous at angles close to 180 degrees, which can lead to numeric instabilities. Angle bending of linear groups, such as alkynes or nitriles, or linear molecules, such as carbon dioxide, can be treated by a simple harmonic potential if we describe the fluctuations as a deviation from a reference position of the central atom, the position of which is determined by the flanking atoms. The force constant for the linear angle potential can be derived analytically from the corresponding force constant in the traditional potential. The new potential is tested on the properties of alkynes, nitriles, and carbon dioxide. We find that the angles of the linear groups remain about 2 degrees closer to 180 degrees using the new potential. The bond and angle force constants for carbon dioxide were tuned to reproduce the experimentally determined frequencies. An interesting finding was that simulations of liquid carbon dioxide under pressure with the new flexible model were stable only when explicitly modeling the long-range Lennard-Jones (LJ) interactions due to the very long-range nature of the LJ interactions (&gt;1.7 nm). In the other tested liquids, we find that a Lennard-Jones cutoff of 1.1 nm yields similar results as the particle mesh Ewald algorithm for LJ interactions. Algorithmic factors influencing the stability of liquid simulations are discussed as well. Finally, we demonstrate that the linear angle potential can be used in free energy perturbation calculations. (c) 2020 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)

Small percentage of anaphylactic reactions treated with epinephrine during food challenges in Dutch children

Background: Severe allergic reactions, including anaphylaxis, occur during oral food challenges (OFCs) and the first-line treatment of anaphylaxis is epinephrine. Objective: To evaluate the percentage of anaphylactic reactions treated with epinephrine during OFCs and to identify associated factors for the administration of epinephrine. Methods: Children who underwent an OFC with peanut, hazelnut, cow's milk, hen's egg, or cashew nut from 2005 through 2015 in the Netherlands were evaluated. Children with reactions meeting the criteria for anaphylaxis according to the European Academy of Allergy and Clinical Immunology guidelines for food allergy and anaphylaxis were included. Children with an anaphylactic reaction treated with vs without epinephrine were compared. Possible factors associated with the administration of epinephrine, such as age, sex, symptoms consistent with asthma, history of an allergic reaction to the tested allergen, and symptom types during the anaphylactic reaction, were evaluated using logistic regression analysis. Results: Eighty-three children in clinical and research settings (43% boys; median age, 7 years; range, 1-17) who met the criteria for anaphylaxis were included in this study. Thirty-two of 83 children (39%) with anaphylaxis were treated with epinephrine. Respiratory symptoms during the OFC were treated significantly more often with epinephrine than gastrointestinal symptoms (P = .01). Conclusion: Only 39% of children with anaphylaxis, according to the guideline criteria, were treated with epinephrine during the OFC and most of these children had respiratory symptoms. There is need for an easy-to-use international guideline for the treatment of allergic symptoms during OFCs