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The K(+) Channel KCa3.1 as a Novel Target for Idiopathic Pulmonary Fibrosis.

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The K(+) Channel KCa3.1 as a Novel Target for Idiopathic Pulmonary Fibrosis.

PLoS One. 2013;8(12):e85244

Authors: Roach KM, Duffy SM, Coward W, Feghali-Bostwick C, Wulff H, Bradding P

Abstract
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a common, progressive and invariably lethal interstitial lung disease with no effective therapy. We hypothesised that KCa3.1 K(+) channel-dependent cell processes contribute to IPF pathophysiology.
METHODS: KCa3.1 expression in primary human lung myofibroblasts was examined using RT-PCR, western blot, immunofluorescence and patch-clamp electrophysiology. The role of KCa3.1 channels in myofibroblast proliferation, wound healing, collagen secretion and contraction was examined using two specific and distinct KCa3.1 blockers (TRAM-34 and ICA-17043 [Senicapoc]).
RESULTS: Both healthy non fibrotic control and IPF-derived human lung myofibroblasts expressed KCa3.1 channel mRNA and protein. KCa3.1 ion currents were elicited more frequently and were larger in IPF-derived myofibroblasts compared to controls. KCa3.1 currents were increased in myofibroblasts by TGFβ1 and basic FGF. KCa3.1 was expressed strongly in IPF tissue. KCa3.1 pharmacological blockade attenuated human myofibroblast proliferation, wound healing, collagen secretion and contractility in vitro, and this was associated with inhibition of TGFβ1-dependent increases in intracellular free Ca(2+).
CONCLUSIONS: KCa3.1 activity promotes pro-fibrotic human lung myofibroblast function. Blocking KCa3.1 may offer a novel approach to treating IPF with the potential for rapid translation to the clinic.

PMID: 24392001 [PubMed - as supplied by publisher]

AARC clinical practice guideline: effectiveness of nonpharmacologic airway clearance therapies in hospitalized patients.

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AARC clinical practice guideline: effectiveness of nonpharmacologic airway clearance therapies in hospitalized patients.

Respir Care. 2013 Dec;58(12):2187-93

Authors: Strickland SL, Rubin BK, Drescher GS, Haas CF, O'Malley CA, Volsko TA, Branson RD, Hess DR

Abstract
Airway clearance therapy (ACT) is used in a variety of settings for a variety of ailments. These guidelines were developed from a systematic review with the purpose of determining whether the use of nonpharmacologic ACT improves oxygenation, reduces length of time on the ventilator, reduces stay in the ICU, resolves atelectasis/consolidation, and/or improves respiratory mechanics, versus usual care in 3 populations. For hospitalized, adult and pediatric patients without cystic fibrosis, 1) chest physiotherapy (CPT) is not recommended for the routine treatment of uncomplicated pneumonia; 2) ACT is not recommended for routine use in patients with COPD; 3) ACT may be considered in patients with COPD with symptomatic secretion retention, guided by patient preference, toleration, and effectiveness of therapy; 4) ACT is not recommended if the patient is able to mobilize secretions with cough, but instruction in effective cough technique may be useful. For adult and pediatric patients with neuromuscular disease, respiratory muscle weakness, or impaired cough, 1) cough assist techniques should be used in patients with neuromuscular disease, particularly when peak cough flow is < 270 L/min; CPT, positive expiratory pressure, intrapulmonary percussive ventilation, and high-frequency chest wall compression cannot be recommended, due to insufficient evidence. For postoperative adult and pediatric patients, 1) incentive spirometry is not recommended for routine, prophylactic use in postoperative patients, 2) early mobility and ambulation is recommended to reduce postoperative complications and promote airway clearance, 3) ACT is not recommended for routine postoperative care. The lack of available high-level evidence related to ACT should prompt the design and completion of properly designed studies to determine the appropriate role for these therapies.

PMID: 24222709 [PubMed - in process]

Principles of judicious antibiotic prescribing for upper respiratory tract infections in pediatrics.

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Most upper respiratory tract infections are caused by viruses and require no antibiotics. This clinical report focuses on antibiotic prescribing strategies for bacterial upper respiratory tract infections, including acute otitis media, acute bacterial sinusitis, and streptococcal pharyngitis. The principles for judicious antibiotic prescribing that are outlined focus on applying stringent diagnostic criteria, weighing the benefits and harms of antibiotic therapy, and understanding situations when antibiotics may not be indicated.
The principles can be used to amplify messages from recent clinical guidelines for local guideline development and for patient communication; they are broadly applicable to antibiotic prescribing in general.

The debated problem of community-acquired pneumonia diagnosis: many guidelines, any guideline?

The term community-acquired pneumonia (CAP) refers to a common lower respiratory infection diagnosed by a combination of some or all of the following: clinical signs and symptoms, an infiltrate seen on chest radiography, and abnormal laboratory values. It occurs outside of the hospital, or within 48 hours after hospital admission in a patient who has not been recently hospitalised and is not living in a long-term care facility. Pneumonia acquired in hospitCAPal or while living in an inpatient setting is referred to as “nosocomial pneumonia”. The clinical symptoms and signs of CAP include cough (with or without sputum production), fever, chills, tachypnoea, tachycardia, pleuritic chest pain, dyspnoea, altered mental status, dehydration, and hemoptysis; clinical findings will include a temperature greater than 37.8°C, heart rate over 100/min, respiratory rate greater than 25/min, oxygen saturations in room air < 90%, rhonchi or focal rales on auscultation of the lungs, decreased breath sounds, and bronchophony.

CAP is a major health problem worldwide and is associated with considerable morbidity, mortality and health care costs. However, although data are available from many prospective studies and national databases, it is difficult to determine the real clinical and economic impact of CAP for a number of reasons, the most common being that diagnostic certainty is usually only obtained in the hospital setting where (unlike the primary care setting) all diagnostic tools are readily available. ...

Review of IPF diagnosis and management recommendations in Europe.

Increased knowledge of Idiopathic Pulmonary Fibrosis (IPF) led to the development of evidence-based diagnosis and treatment guidelines.

A 2011 update of the American Thoracic Society and the European Respiratory Society, together with the Japanese Respiratory Society ( JRS) and Latin AmericanThoracic Association (ALAT) provided new guidance on the diagnosis and treatment of IPF. Although the 2011 statement was a major advance, the application of guideline recommendations has identified limitations.

The guidelines focus primarily on 'definite' IPF, most often diagnosed from typical High-Resolution Computed Tomography (HRCT) appearances.The definition of 'probable' and 'possible' IPF is an advance, but there is a lack ofmanagement guidance for these highly prevalent clinical scenarios.The integration ofHRCT and histological data in assigning of diagnostic likelihood is also important, but does not always meet the needs of some patients in whom a multidisciplinary diagnosis of definite IPF should be made.Moreover, the committee did not find sufficient evidence to support the use of any specific pharmacological therapy for patients with IPF.These issues highlight the need for updating available clinical guidelines.

Since 2012, several national European recommendations documents and guidelines have been updated.These generally follow the 2011 guidelines, but reflect more recently available clinical study data. Following the publication of the CAPACITY trials showing positive effects of pirfenidone in IPF and its approval in the European Union,many of these updated guideline documents recommend that patients with mild-to-moderate IPF should be offered this therapy.

This review analyses the recently developed European country updates, comparing and contrasting recommendations on the diagnosis and treatment of IPF.

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