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Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations.

Previous studies investigating a genetic basis for idiopathic pulmonary fibrosis (IPF) have focused on resequencing single genes in IPF kindreds or cohorts to determine the genetic contributions to IPF. None has investigated interactions among the candidate genes.

OBJECTIVE: To compare the frequencies and interactions of mutations in six IPF-associated genes in a cohort of 132 individuals with IPF with those of a disease-control cohort of 192 individuals with chronic obstructive pulmonary disease (COPD) and the population represented in the Exome Variant Server.

METHODS: We resequenced the genes encoding surfactant proteins A2 (SFTPA2), and C (SFTPC), the ATP binding cassette member A3 (ABCA3), telomerase (TERT), thyroid transcription factor (NKX2-1) and mucin 5B (MUC5B) and compared the collapsed frequencies of rare (minor allele frequency <1%), computationally predicted deleterious variants in each cohort. We also genotyped a common MUC5B promoter variant that is over-represented in individuals with IPF.

RESULTS: We found 15 mutations in 14 individuals (11%) in the IPF cohort: (SFTPA2 (n=1), SFTPC (n=5), ABCA3 (n=4) and TERT (n=5)). No individual with IPF had two different mutations, but one individual with IPF was homozygous for p.E292V, the most common ABCA3 disease-causing variant. We did not detect an interaction between any of the mutations and the MUC5B promoter variant.

CONCLUSIONS: Rare mutations in SFTPA2, SFTPC and TERT are collectively over-represented in individuals with IPF. Genetic analysis and counselling should be considered as part of the IPF evaluation.

The Role of Pulmonology in the National Health Sytem Chronicity Strategy.

Longer life expectancy and the progressive aging of the population is changing the epidemiological pattern of healthcare, with a reduction in the incidence of acute diseases and a marked increase in chronic diseases.

This change brings important social, healthcare and economic consequences that call for a reorganization of patient care. In this respect, the Spanish National Health System has developed a Chronicity strategy that proposes a substantial change in focus from traditional rescue medicine to patient- and environment-centered care, with a planned, proactive, participative and multidisciplinary approach. Some of the more common chronic diseases are respiratory. In COPD, this integrated approach has been effective in reducing exacerbations, improving quality of life, and even reducing costs. However, the wide variety of management strategies, not only in COPD but also in asthma and other respiratory diseases, makes it difficult to draw definitive conclusions.

Pulmonologists can and must participate in the new chronicity models and contribute their knowledge, experience, innovation, research, and special expertise to the development of these new paradigms.

The Early History of the Eosinophil.

The Early History of the Eosinophil.

Clin Exp Allergy. 2014 Dec 27;

Authors: Barry Kay A

Abstract
In 1879 Paul Ehrlich published his technique for staining blood films and his method for differential blood cell counting using coal tar dyes and mentions the eosinophil for the first time. Eosin is a bright red synthetic dye produced by the action of bromine on fluorescein and stains basic proteins due to its acidic nature. It was discovered in 1874 by Heinrich Caro, Director of the German chemical company Badische Anilin- und Soda-Fabrik. Ehrlich introduced the term "eosinophil" to describe cells with granules (which he called alpha-granules) having an affinity for eosin and other acid dyes. He also observed black-staining, indulinophilic, beta-granules in bone marrow-derived eosinophils which were probably immature crystalloid granules in eosinophil myelocytes. Ehrlich described the features of the alpha-granule and the cell's distribution in various species and tissues. He speculated correctly that the alpha-granule contents were secretory products and described several causes of eosinophilia including asthma, various skin diseases, helminths and reactions to medications. However, the cell was almost certainly observed by others before Ehrlich.. In 1846 Thomas Wharton Jones (1808-1891) described "granule blood-cells" in the lamprey, frog, fowl, horse, elephant and man. He "borrowed" the term granule cell from Julius Vogel (1814-1880) who had observed similar cells in inflammatory exudates. Vogel in turn was aware of the work of the Gottlieb (Théophile) Gluge (1812-1898) who used the term "compound inflammatory globules" to describe cells in pus and serum. Almost 20 years before Ehrlich developed his staining methods, Max Johann Sigismund Schultze (1825 -1874) performed functional experiments on coarse granular cells using a warm stage microscopic technique and showed they had amoeboid movement and phagocytic abilities. Although these early investigators recognised distinct granular cells Ehrlich's use of stains was a landmark contribution which heralded modern studies on eosinophils and other blood leucocytes. This article is protected by copyright. All rights reserved.

PMID: 25544991 [PubMed - as supplied by publisher]

The concept of control of COPD in clinical practice.

The concept of control of COPD in clinical practice.

Int J Chron Obstruct Pulmon Dis. 2014;9:1397-405

Authors: Soler-Cataluña JJ, Alcázar-Navarrete B, Miravitlles M

Abstract
Treatment of chronic obstructive pulmonary disease (COPD) requires a personalized approach according to the clinical characteristics of the patients, the level of severity, and the response to the different therapies. Furthermore, patients with the same level of severity measured by the degree of airflow obstruction or even with multidimensional indices may have very different symptoms and limitations for daily activities. The concept of control has been extensively developed in asthma but has not been defined in COPD. Here, we propose a definition of COPD control based on the concepts of impact and stability. Impact is a cross-sectional concept that can be measured by questionnaires such as the COPD Assessment Test or the Clinical COPD Questionnaire. Alternatively, impact can be assessed by the degree of dyspnea, the use of rescue medication, the level of physical activity, and sputum color. Stability is a longitudinal concept that requires the absence of exacerbations and deterioration in the aforementioned variables or in the COPD Assessment Test or Clinical COPD Questionnaire scores. Control is defined by low impact (adjusted for severity) and stability. The concept of control in COPD can be useful in the decision making regarding an increase or decrease in medication in the stable state.

PMID: 25548521 [PubMed - in process]

Virus-Induced Modulation of Lower Airway Diseases: Pathogenesis and Pharmacologic Approaches to Treatment.

Virus-Induced Modulation of Lower Airway Diseases: Pathogenesis and Pharmacologic Approaches to Treatment.

Pharmacol Ther. 2014 Dec 27;

Authors: Leigh R, Proud D

Abstract
Uncomplicated upper respiratory viral infections are the most common cause of days lost from work and school and exert a major economic burden. In susceptible individuals, however, common respiratory viruses, particularly human rhinoviruses, also can have a major impact on diseases that involve the lower airways, including asthma, chronic obstructive pulmonary diseases (COPD) and cystic fibrosis (CF). Respiratory virus-induced wheezing illnesses in early life are a significant risk factor for the subsequent development of asthma, and virus infections may also play a role in the development and progression of airway remodeling in asthma. It is clear that upper respiratory tract virus infections can spread to the lower airway and trigger acute attacks of asthma, COPD or CF. These exacerbations can be life-threatening, and exert an enormous burden on health care systems. In recent years we have gained new insights into the mechanisms by which respiratory viruses may induce acute exacerbations of lower airway diseases, as well as into host defense pathways that may regulate the outcomes to viral infections. In the current article we review the role of viruses in lower airway diseases, including our current understanding on pathways by which they may cause remodeling and trigger acute exacerbations. We also review the efficacy of current and emerging therapies used to treat these lower airway diseases on the outcomes due to viral infection, and discuss alternative therapeutic approaches for the management of virus-induced airway inflammation.

PMID: 25550230 [PubMed - as supplied by publisher]

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