A novel nonhuman primate model of cigarette smoke-induced airway disease.

Small animal models of chronic obstructive pulmonary disease (COPD) have several limitations for identifying new therapeutic targets and biomarkers for human COPD. These include a pulmonary anatomy that differs from humans, the limited airway pathologies and lymphoid aggregates that develop in smoke-exposed mice, and the challenges associated with serial biological sampling. Thus, we assessed the utility of cigarette smoke (CS)-exposed cynomolgus macaque as a nonhuman primate (NHP) large animal model of COPD. Twenty-eight NHPs were exposed to air or CS 5 days per week for up to 12 weeks. Bronchoalveolar lavage and pulmonary function tests were performed at intervals. After 12 weeks, we measured airway pathologies, pulmonary inflammation, and airspace enlargement. CS-exposed NHPs developed robust mucus metaplasia, submucosal gland hypertrophy and hyperplasia, airway inflammation, peribronchial fibrosis, and increases in bronchial lymphoid aggregates. Although CS-exposed NHPs did not develop emphysema over the study time, they exhibited pathologies that precede emphysema development, including increases in the following: i) matrix metalloproteinase-9 and proinflammatory mediator levels in bronchoalveolar lavage fluid, ii) lung parenchymal leukocyte counts and lymphoid aggregates, iii) lung oxidative stress levels, and iv) alveolar septal cell apoptosis. CS-exposed NHPs can be used as a model of airway disease occurring in COPD patients. Unlike rodents, NHPs can safely undergo longitudinal sampling, which could be useful for assessing novel biomarkers or therapeutics for COPD.

Protective role for club cell secretory protein-16 (CC16) in the development of COPD.

Club cell secretory protein-16 (CC16) is the major secreted product of airway club cells, but its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) is unclear. We measured CC16 airway expression in humans with and without COPD and CC16 function in a cigarette smoke (CS)-induced COPD murine model. Airway CC16 expression was measured in COPD patients, smokers without COPD and non-smokers. We exposed wildtype (WT) and CC16(-/-)mice to CS or air for up to 6 months, and measured airway CC16 expression, pulmonary inflammation, alveolar septal cell apoptosis, airspace enlargement, airway mucin 5AC (MUC5AC) expression, small airway remodelling and pulmonary function. Smokers and COPD patients had reduced airway CC16 immunostaining that decreased with increasing COPD severity. Exposing mice to CS reduced airway CC16 expression. CC16(-/-) mice had greater CS-induced emphysema, airway remodelling, pulmonary inflammation, alveolar cell apoptosis, airway MUC5AC expression, and more compliant lungs than WT mice. These changes were associated with increased nuclear factor-κB (NF-κB) activation in CC16(-/-) lungs. CS-induced acute pulmonary changes were reversed by adenoviral-mediated over-expression of CC16. CC16 protects lungs from CS-induced injury by reducing lung NF-κB activation. CS-induced airway CC16 deficiency increases CS-induced pulmonary inflammation and injury and likely contributes to the pathogenesis of COPD.

Muscle weakness predicts pharyngeal dysfunction and symptomatic aspiration in long-term ventilated patients.

BACKGROUND: Prolonged mechanical ventilation is associated with muscle weakness, pharyngeal dysfunction, and symptomatic aspiration. The authors hypothesized that muscle strength measurements can be used to predict pharyngeal dysfunction (endoscopic evaluation-primary hypothesis), as well as symptomatic aspiration occurring during a 3-month follow-up period. METHODS: Thirty long-term ventilated patients admitted in two intensive care units at Massachusetts General Hospital were included. The authors conducted a fiberoptic endoscopic evaluation of swallowing and measured muscle strength using medical research council score within 24 h of each fiberoptic endoscopic evaluation of swallowing. A medical research council score less than 48 was considered clinically meaningful muscle weakness. A retrospective chart review was conducted to identify symptomatic aspiration events. RESULTS: Muscle weakness predicted pharyngeal dysfunction, defined as either valleculae and pyriform sinus residue scale of more than 1, or penetration aspiration scale of more than 1. Area under the curve of the receiver-operating curves for muscle strength (medical research council score) to predict pharyngeal, valleculae, and pyriform sinus residue scale of more than 1, penetration aspiration scale of more than 1, and symptomatic aspiration were 0.77 (95% CI, 0.63-0.97; P = 0.012), 0.79 (95% CI, 0.56-1; P = 0.02), and 0.74 (95% CI, 0.56-0.93; P = 0.02), respectively. Seventy percent of patients with muscle weakness showed symptomatic aspiration events. Muscle weakness was associated with an almost 10-fold increase in the symptomatic aspiration risk (odds ratio = 9.8; 95% CI, 1.6-60; P = 0.009). CONCLUSION: In critically ill patients, muscle weakness is an independent predictor of pharyngeal dysfunction and symptomatic aspiration. Manual muscle strength testing may help identify patients at risk of symptomatic aspiration.

Caring for patients with advanced COPD: beyond the inhalers .

COPD affects millions of people worldwide. Patients with advanced COPD have a high symptom burden. Breathlessness, cough and fatigue are frequent daily symptoms. Guidelines often focus on pharmacological treatment, especially inhaler therapy, but other approaches in combination with medications offer symptomatic benefit. In this review, we take a multidisciplinary approach with contributions from pulmonary physicians, cardiothoracic surgeons and a physiotherapist. The following areas are addressed: oxygen therapy and noninvasive ventilation (NIV), dyspnoea management, surgical and bronchoscopic options, lung transplantation and palliative care. Oxygen therapy prescribed within guidelines improves mortality in patients with COPD. NIV guidelines offer only low-certainty instruction on the use of this therapy on the basis of the limited available evidence. Dyspnoea management can take place through pulmonary rehabilitation. Specific criteria aid decisions on referral for lung volume reduction treatments through surgical or bronchoscopic approaches. Lung transplantation requires precise disease severity assessment to determine which patients have the most urgent need for lung transplantation and are likely to have the longest survival. The palliative approach runs in parallel with these other treatments, focusing on symptoms and aiming to improve the quality of life of patients and their families facing the problems associated with life-threatening illness. In combination with appropriate medication and an individual approach to symptom management, patients' experiences can be optimised. Educational aims: To understand the multidisciplinary approach to management of patients with advanced COPD.To recognise the parallel approaches to oxygen, NIV and dyspnoea management with consideration of more interventional options with lung volume reduction therapy or lung transplantation.To understand the high level of symptomatology present in advanced COPD and the relevance of palliative care alongside optimal medical management.

Pulmonary zygomycosis in a non-neutropenic patient with myelodysplastic syndrome on lenalidomide.

Pulmonary zygomycosis is an uncommon infection that occurs mostly in immunocompromised patients. We report the case of a 75-year-old man with myelodysplastic syndrome, treated with lenalidomide for 3 months, who developed respiratory failure and a rapidly progressive left upper lobe consolidation. An extensive workup was unrevealing of the etiology, and the patient expired. A full autopsy was declined, but an in situ post-mortem transbronchial lung biopsy revealed pulmonary zygomycosis. This unique case illustrates the potential risks of lenalidomide therapy in patients with myelodysplastic syndrome and the difficulties in diagnosing pulmonary zygomycosis. To our knowledge this is the first report of a diagnostic in situ post-mortem transbronchial lung biopsy.

Secretory leucoprotease inhibitor binds to NF-kappaB binding sites in monocytes and inhibits p65 binding.

Secretory leucoprotease inhibitor (SLPI) is a nonglycosylated protein produced by epithelial cells. In addition to its antiprotease activity, SLPI has been shown to exhibit antiinflammatory properties, including down-regulation of tumor necrosis factor alpha expression by lipopolysaccharide (LPS) in macrophages and inhibition of nuclear factor (NF)-kappaB activation in a rat model of acute lung injury. We have previously shown that SLPI can inhibit LPS-induced NF-kappaB activation in monocytic cells by inhibiting degradation of IkappaBalpha without affecting the LPS-induced phosphorylation and ubiquitination of IkappaBalpha. Here, we present evidence to show that upon incubation with peripheral blood monocytes (PBMs) and the U937 monocytic cell line, SLPI enters the cells, becoming rapidly localized to the cytoplasm and nucleus, and affects NF-kappaB activation by binding directly to NF-kappaB binding sites in a site-specific manner. SLPI can also prevent p65 interaction with the NF-kappaB consensus region at concentrations commensurate with the physiological nuclear levels of SLPI and p65. We also demonstrate the presence of SLPI in nuclear fractions of PBMs and alveolar macrophages from individuals with cystic fibrosis and community-acquired pneumonia. Therefore, SLPI inhibition of NF-kappaB activation is mediated, in part, by competitive binding to the NF-kappaB consensus-binding site.

Selenoprotein S/SEPS1 modifies endoplasmic reticulum stress in Z variant alpha1-antitrypsin deficiency.

Z alpha(1)-antitrypsin (ZAAT) deficiency is a disease associated with emphysematous lung disease and also with liver disease. The liver disease of AAT deficiency is associated with endoplasmic reticulum (ER) stress. SEPS1 is a selenoprotein that, through a chaperone activity, decreases ER stress. To determine the effect of SEPS1 on ER stress in ZAAT deficiency, we measured activity of the grp78 promoter and levels of active ATF6 as markers of the unfolded protein response in HepG2 cells transfected with the mutant form of AAT, a ZAAT transgene. We evaluated levels of NFkappaB activity as a marker of the ER overload response. To determine the effect of selenium supplementation on the function of SEPS1, we investigated glutathione peroxidase activity, grp78 promoter activity, and NFkappaB activity in the presence or absence of selenium. SEPS1 reduced levels of active ATF6. Overexpression of SEPS1 also inhibited grp78 promoter and NFkappaB activity, and this effect was enhanced in the presence of selenium supplementation. This finding demonstrates a role for SEPS1 in ZAAT deficiency and suggests a possible therapeutic potential for selenium supplementation.

Chemotherapy-associated recurrent pneumothoraces in lymphangioleiomyomatosis.

Lymphangioleiomyomatosis is a rare cause of pneumothorax in women. We present the case of a 48-year-old woman with lymphangioleiomyomatosis, who had never had a pneumothorax prior to commencing chemotherapy for breast cancer. During chemotherapy she developed 3 pneumothoraces and 2 episodes of pneumomediastinum. We suggest that the pneumothoraces were caused by the chemotherapy. To our knowledge, this is the first reported case of chemotherapy triggering pneumothoraces in a woman with lymphangioleiomyomatosis.

Interventions to standardise hospital care at presentation, admission or discharge or to reduce unnecessary admissions or readmissions for patients with acute exacerbation of chronic obstructive pulmonary disease: a scoping review.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease that may be punctuated by episodes of worsening symptoms, called exacerbations. Acute exacerbations of COPD (AECOPD) are detrimental to clinical outcomes, reduce patient quality of life and often result in hospitalisation and cost for the health system. Improved diagnosis and management of COPD may reduce the incidence of hospitalisation and death among this population. This scoping review aims to identify improvement interventions designed to standardise the hospital care of patients with AECOPD at presentation, admission and discharge, and/or aim to reduce unnecessary admissions/readmissions. METHODS: The review followed a published protocol based on methodology set out by Arksey and O'Malley and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Electronic database searches for peer-reviewed primary evidence were conducted in Web of Science, EMBASE (Elsevier) and PubMed. Abstract, full-text screening and data extraction were completed independently by a panel of expert reviewers. Data on type of intervention, implementation supports and clinical outcomes were extracted. Findings were grouped by theme and are presented descriptively. RESULTS: 21 articles met the inclusion criteria. Eight implemented a clinical intervention bundle at admission and/or discharge; six used a multidisciplinary care pathway; five used coordinated case management and two ran a health coaching intervention with patients. CONCLUSION: The findings indicate that when executed reliably, improvement initiatives are associated with positive outcomes, such as reduction in length of stay, readmissions or use of health resources. Most of the studies reported an improvement in staff compliance with the initiatives and in the patient's understanding of their disease. Implementation supports varied and included quality improvement methodology, multidisciplinary team engagement, staff education and development of written or in-person delivery of patient information. Consideration of the implementation strategy and methods of support will be necessary to enhance the likelihood of success in any future intervention.

Community-acquired pneumonia in older patients: does age influence systemic cytokine levels in community-acquired pneumonia?

BACKGROUND AND OBJECTIVE: Community-acquired pneumonia (CAP) is a major cause of death in the elderly. The age-related increase in comorbid illnesses plays a part but the effect of aging on the immune response may be equally important. We aimed to evaluate patients with CAP for evidence of a muted response to infection in elderly patients admitted to hospital compared with a younger patient group. METHODS: Patients with CAP admitted through the Emergency Department were recruited for this prospective observational study. Clinical data were collected at presentation. Severity of pneumonia was assessed using the British Thoracic Society confusion, urea nitrogen, respiratory rate, blood pressure (CURB) score, the Pneumonia Severity Index (PSI) and the systemic inflammatory response syndrome (SIRS) definition. IL-6 and IL-10 levels were measured within 24 h of admission. RESULTS: Eighty patients were included in the study, of whom 38 (48%) were female. The median age was 74 years (range 18-95). Patients greater than 65 years of age had a lower incidence of chest pain and a higher incidence of altered mental status on presentation. CURB score and PSI were higher in the older patients. SIRS showed similar frequencies in both groups. IL-6 and IL-10 levels were similar in young (< 65 years), older (> 65 years) and very elderly (> 80 years) patients. This finding was not altered by severity of pneumonia. CONCLUSIONS: Age does not diminish the severity of illness scores in patients with CAP. There was no blunting of the systemic cytokine response with advanced age in this study.

Transcriptional control of central carbon metabolic flux in Bifidobacteria by two functionally similar, yet distinct LacI-type regulators.

Bifidobacteria resident in the gastrointestinal tract (GIT) are subject to constantly changing environmental conditions, which require rapid adjustments in gene expression. Here, we show that two predicted LacI-type transcription factors (TFs), designated AraQ and MalR1, are involved in regulating the central, carbohydrate-associated metabolic pathway (the so-called phosphoketolase pathway or bifid shunt) of the gut commensal Bifidobacterium breve UCC2003. These TFs appear to not only control transcription of genes involved in the bifid shunt and each other, but also seem to commonly and directly affect transcription of other TF-encoding genes, as well as genes related to uptake and metabolism of various carbohydrates. This complex and interactive network of AraQ/MalR1-mediated gene regulation provides previously unknown insights into the governance of carbon metabolism in bifidobacteria.

When an MI is not an MI: a case of varicella zoster myocarditis.

A sixteen-year-old male presented with symptoms and investigations suggestive of acute myocardial infarction. The patient had suffered from a varicella zoster infection 5 days prior to presentation. Varicella myocarditis was suspected and diagnosed following treatment and positive varicella serology. This case highlights a rare but serious cardiac presentation of a common condition.

Adult-onset nemaline myopathy presenting as respiratory failure.

Nemaline myopathy is a rare congenital myopathy that generally presents in childhood. We report a case of a 44-year-old man who presented with severe hypoxic hypercapnic respiratory failure as the initial manifestation of nemaline myopathy. After starting noninvasive ventilation, his pulmonary function test results improved substantially, and over the 4 years since diagnosis his respiratory function remained stable. There are few reported cases of respiratory failure in patients with adult-onset nemaline myopathy, and the insidious onset in this case is even more unusual. This case highlights the varied presenting features of adult-onset nemaline myopathy and that noninvasive ventilation improves respiratory function.

Air Travel for Subjects Receiving Long-Term Oxygen Therapy.

BACKGROUND: Ambulatory oxygen (O2) is the recommended treatment for hypoxemia at rest or induced by exercise. Commercial aircraft often fly at altitudes of 30,000 feet; their cabins are pressurized to altitudes of 6,000-8,000 feet, with an equivalent FIO2 of 0.15. O2 supplementation, for those receiving baseline ambulatory O2, is paramount. METHODS: We gathered information on subjects' experience traveling with supplementary oxygen and reasons individuals receiving O2 do not travel. Subjects were identified using a home oxygen database. Data were gathered by postal questionnaire. The objective of this study was to gather information relevant to subjects' experience organizing travel with supplementary oxygen and their experience of traveling itself. RESULTS: Between 2013 and 2015, 512 patients were entered into the database: 277 were excluded (269 had died, 8 had incomplete records). We sent 235 questionnaires, and 50 responses were received (21% response rate). Of these, 11 (22%) were returned as the patient had died, 20 (40%) had not traveled by air, 11 (22%) had flown with O2, 4 (8%) no longer used O2, and 4 (8%) forms were incomplete. Of those who traveled with O2, 54% found it complicated to organize their trip, 72% found it complicated to access information, and 81% would fly again. Regarding those who had never flown with O2, 35% were unaware that O2 was available on commercial aircraft, 30% had no wish to travel, and 30% had worries regarding their health. CONCLUSIONS: Air travel is challenging; however, those who did travel reported a mainly positive experience. Increasing available information on options for travel should help individuals.

Coeliac crisis presenting with cytomegalovirus hepatitis.

We present the case of a 23-year-old woman who presented with cytomegalovirus infection complicated by pancytopaenia, haemolysis and disseminated intravascular coagulopathy on a background diagnosis of coeliac crisis as the first presentation of coeliac disease. This is the first reported case of coeliac crisis presenting as cytomegalovirus infection.

Glycoside hydrolase family 13 α-glucosidases encoded by Bifidobacterium breve UCC2003; A comparative analysis of function, structure and phylogeny.

Bifidobacterium breve is a noted inhabitant and one of the first colonizers of the human gastro intestinal tract (GIT). The ability of this bacterium to persist in the GIT is reflected by the abundance of carbohydrate-active enzymes that are encoded by its genome. One such family of enzymes is represented by the α-glucosidases, of which three, Agl1, Agl2 and MelD, have previously been identified and characterized in the prototype B. breve strain UCC2003. In this report, we describe an additional B. breve UCC2003-encoded α-glucosidase, along with a B. breve UCC2003-encoded α-glucosidase-like protein, designated here as Agl3 and Agl4, respectively, which together with the three previously described enzymes belong to glycoside hydrolase (GH) family 13. Agl3 was shown to exhibit hydrolytic specificity towards the α-(1→6) linkage present in palatinose; the α-(1→3) linkage present in turanose; the α-(1→4) linkages found in maltotriose and maltose; and to a lesser degree, the α-(1→2) linkage found in sucrose and kojibiose; and the α-(1→5) linkage found in leucrose. Surprisingly, based on the substrates analyzed, Agl4 did not exhibit biologically relevant α-glucosidic activity. With the presence of four functionally active GH13 α-glucosidases, B. breve UCC2003 is capable of hydrolyzing all α-glucosidic linkages that can be expected in glycan substrates in the lower GIT. This abundance of α-glucosidases provides B. breve UCC2003 with an adaptive ability and metabolic versatility befitting the transient nature of growth substrates in the GIT.

Are respiratory specialist registrars trained to teach?

Respiratory SpRs are interested in medical education but rarely observed when teaching and receive little feedback http://ow.ly/Our0m.

Defining exacerbations in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease is a very common disease often punctuated by intermittent episodes of exacerbation. These exacerbations affect the natural history of the disease, accelerating a decline in lung function. They affect the individual in many ways and affect the health service caring for these patients. The definition of exacerbation varies and lacks clarity. The definitions used most are either symptom based, for example, breathlessness, sputum production and sputum purulence, or event driven, for example, an event causing a patient to seek healthcare input or change to medications. In this article, we discuss the importance of exacerbations, the clinical definitions, clinical trial definitions, physiological and biomarker evidence of exacerbations and the challenges associated with each of these. Application of a practical definition would aid in our clinical management of patients with chronic obstructive pulmonary disease and facilitate developments in future therapeutic advances through clinical trials.

Umeclidinium bromide and vilanterol in combination for the treatment of chronic obstructive pulmonary disease.

Drugs from the two major classes of bronchodilator; umeclidinium, a long-acting muscarinic antagonist (LAMA), and vilanterol, a long-acting ß2 agonist (LABA), have been combined in a single inhaler device for once-daily use in chronic obstructive pulmonary disease (COPD). These drugs have been proven safe and well tolerated in patients with COPD and show an enhanced improvement in FEV1 when compared to either drug in isolation and when compared with an established LAMA drug. In this article, we discuss the data supporting this combination inhaler and also review alternative combined LAMA/LABA options. We discuss where these agents are likely to find a place in the current therapy of COPD and where the future is likely to lead with these and other therapies.