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Hans Lennart Persson,1,2,&ast; Apostolos Sioutas,1,2,&ast; Magnus Kentson,1,3 Petra Jacobson,1,2 Peter Lundberg,1,4,5 Olof Dahlqvist Leinhard,1,5,6 Mikael Fredrik Forsgren1,5,6 1Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden; 2Department of Respiratory Medicine in Linköping, Linköping University, Linköping, Sweden; 3Department of Pulmonology, Ryhov County Hospital, Jönköping, Sweden; 4Department of Radiation Physics in Linköping, Linköping University, Linköping, Sweden; 5Centre for Medical Image Science and Visualization, Linköping University, Linköping, Sweden; 6AMRA Medical AB, Linköping, Sweden&ast;These authors contributed equally to this workCorrespondence: Hans Lennart Persson; Apostolos Sioutas, Department of Respiratory Medicine in Linköping, Linköping University, Linköping, SE-581 85, Sweden, Tel +46 0 13 1033621, Email lennart.persson@liu.se; apostolos.sioutas@regionostergotland.seBackground: Common features among patients with more advanced chronic obstructive pulmonary disease (COPD) are systemic inflammation and a loss of both muscle mass and normal muscle composition. In the present study, we investigated COPD subjects to better understand how thigh muscle fat infiltration (MFI) and energy metabolism relate to each other and to clinical features of COPD with emphasis on systemic inflammation.Methods: Thirty-two Caucasians with stable COPD were investigated using questionnaires, lung function tests, blood analysis and magnetic resonance imaging (MRI) for analysis of body- and thigh muscle composition. Bioenergetics in the resting thigh muscle, expressed as the PCr/Pi ratio, were analysed using 31phosphorus magnetic resonance spectroscopy (31P-MRS).Results: Based on the combination of the MFI adjusted for sex (MFIa) and the thigh fat-tissue free muscle volume, expressed as the deviation from the expected muscle volume of a matched virtual control group (FFMVvcg), all COPD subjects displayed abnormally composed thigh muscles. Clinical features of increased COPD severity, including a decrease of blood oxygenation (r = − 0.44, p < 0.05) and FEV1/FVC ratio, reflecting airway obstruction (r = − 0.53, p < 0.01) and an increase of COPD symptoms (r = 0.37, p < 0.05) and breathing frequency at rest (r = 0.41, p < 0.05), were all associated with a raise of the PCr/Pi ratio in the thigh muscle. Increased MFIa of the thigh muscle correlated positively with markers of systemic inflammation (white blood cell count, r = 0.41, p < 0.05; fibrinogen, r = 0.44, p < 0.05), and negatively with weekly physical activity (r = − 0.40, p < 0.05) and the PCr/Pi ratio in the resting thigh muscle (r = − 0.41, p < 0.05).Conclusion: The present study implies a link between systemic inflammation, excessive MFI and a loss of bioenergetics in subjects with stable COPD.Keywords: adiposity, body composition, muscle fat infiltration, magnetic resonance imaging, 31P-MRS, biomarkers

Magnus Kentson,1,2 Per Leanderson,3 Petra Jacobson,4,5 Hans Lennart Persson4,5 1Division of Medicine, Ryhov Hospital, Jönköping, Sweden; 2Department of Medical and Health Sciences (IMH), Linköping University, Linköping, Sweden; 3Department of Occupational and Environmental Medicine, Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden; 4Department of Respiratory Medicine, 5Department of Medical and Health Sciences (IMH), Linköping University, Linköping, Sweden Background: The prevalence of individuals deficient in vitamin D (defined as a serum level of the stable metabolite 25(OH)D

Apostolos Sioutas,1 Linda K Vainikka,2 Magnus Kentson,3 Sören Dam-Larsen,4 Urban Wennerström,5 Petra Jacobson,1 Hans Lennart Persson1 1Division of Respiratory Medicine, Department of Medical and Health Sciences, 2Division of Experimental Pathology, Department of Clinical and Experimental Medicine, Linköping University, Linköping,3Division of Medicine, Ryhov Hospital, Jönköping, 4Division of Medicine, Hospital of Eksjö, Eksjö, 5Division of Medicine, Hospital of Västervik, Västervik, Sweden Purpose: Transforming growth factor (TGF)-β1 triggers epithelial–mesenchymal transition (EMT) through autophagy, which is partly driven by reactive oxygen species (ROS). The aim of this study was to determine whether leaking lysosomes and enhanced degradation of H-ferritin could be involved in EMT and whether it could be possible to prevent EMT by iron chelation targeting of the lysosome. Materials and methods: EMT, H-ferritin, and autophagy were evaluated in TGF-β1-stimulated A549 human lung epithelial cells cultured in vitro using Western blotting, with the additional morphological assessment of EMT. By using immunofluorescence and flow cytometry, lysosomes and ROS were assessed by acridine orange and 6-carboxy-2’,7’-dichlorodihydrofluorescein acetate assays, respectively. Results: TGF-β1-stimulated cells demonstrated a loss of H-ferritin, which was prevented by the antioxidant N-acetyl-L-cysteine (NAC) and inhibitors of lysosomal degradation. TGF-β1 stimulation generated ROS and autophagosome formation and led to EMT, which was further promoted by the additional ROS-generating cytokine, tumor necrosis factor-α. Lysosomes of TGF-β1-stimulated cells were sensitized to oxidants but also completely protected by lysosomal loading with dextran-bound deferoxamine (DFO). Autophagy and EMT were prevented by NAC, DFO, and inhibitors of autophagy and lysosomal degradation. Conclusion: The findings of this study support the role of enhanced autophagic degradation of H-ferritin as a mechanism for increasing the vulnerability of lysosomes to iron-driven oxidant injury that triggers further autophagy during EMT. This study proposes that lysosomal leakage is a novel pathway of TGF-β1-induced EMT that may be prevented by iron-chelating drugs that target the lysosome. Keywords: A549 cells, pulmonary disease, transforming growth factor, pulmonary fibrosis, tumor necrosis factor, COPD

Kristina Tödt,1,2 Elisabeth Skargren,3 Magnus Kentson,4 Kersti Theander,5,6 Per Jakobsson,2 Mitra Unosson1 1Department of Social and Welfare Studies, Faculty of Health Sciences, Linköping University, Norrköping, Sweden; 2Department of Pulmonary Medicine, University Hospital, 3Department of Medicine and Health, Faculty of Health Sciences, Linköping University, Linköping, Sweden; 4Department of Pulmonary Medicine, Ryhov Hospital, Jönköping, Sweden; 5Department of Nursing, Faculty of Social and Life Sciences, Karlstad University, Karlstad, Sweden; 6Primary Care Research Unit, County Council of Värmland, Sweden Introduction: Several differences have been reported in the clinical characteristics of chronic obstructive pulmonary disease (COPD) between men and women. Differences have been found in the association between respiratory symptoms and lung function, and in the factors associated with dyspnea. This raises the question of whether there are differences between the sexes in the relationship between fatigue, the second most prevalent symptom, and the variables of physical capacity and disease severity. Objectives: To examine the experience of fatigue and its relationship to physical capacity and disease severity in men and women with COPD. Methods: In a cross-sectional study 121 patients with COPD (54 men and 67 women), the experience of fatigue (frequency, duration, and severity) and physical capacity (lung function, 6-minute walk distance [6MWD], grip strength, and timed-stand test) were assessed. Disease severity was graded according to the Body mass index, airway Obstruction, Dyspnoea and Exercise capacity (BODE) index. Two multiple logistic regression models were tested, both of which were performed separately in men and women, to examine the association between the experience of fatigue and variables of physical capacity and the BODE index. Results: Eighty-nine (73.6%) patients experienced fatigue, with similar proportions in men and women. The men with fatigue had worse physical capacity and more severe disease than did the men without fatigue: for men with and without fatigue, respectively, the percent of predicted forced expiratory volume in 1 second (FEV1) (mean [standard deviation]) was 47 (14) vs 64 (17); the 6MWD (mean [standard deviation]) was 398 (138) vs 539 (105) m; and the BODE index (median [quartile 1-3]) was 3 (2–5) vs 1 (0–1) (P

Aims: Erlotinib is a tyrosine kinase inhibitor used in the treatment of non-small cell lung cancer highly metabolized by the cytochrome P450 (CYP) 3A. Hence, CYP3A4 activity might be a useful predictor of erlotinib pharmacokinetics in personalized medicine. The effect of erlotinib on CYP3A activity was therefore studied in non-small cell lung cancer patients., Methods: The study included 32 patients scheduled for erlotinib monotherapy. CYP3A activity was assessed using quinine as a probe before and during erlotinib treatment. Plasma from blood samples drawn 16 hours post quinine administration were analysed using HPLC with fluorescence detection to determine the quinine/3-OH-quinine ratio., Results: Matched samples, available from 13 patients, showed an induction of CYP3A activity (P = 0.003, Wilcoxon's signed rank test) after 2 months of treatment. The quinine/3-OH-quinine ratio decreased from 20.2 (± 13.4) at baseline to 11.0 (± 4.34). Single-point samples, available from 19 patients, supported the decrease in ratio (P = 0.007, Mann-Whitney U-test). Generally, females had a higher CYP3A activity both at baseline and after two months of treatment. Statistical analysis by gender also showed significant increase in CYP3A activity (males, n = 10, P = 0.001, and females, n = 22, P = 0.001)., Conclusions: An induction of CYP3A activity was observed after 2 months of erlotinib treatment which was also seen when subdividing based on gender. It could be important to take this into consideration for patients co-administering other CYP3A-metabolizing drugs during erlotinib treatment and also makes it difficult to use baseline CYP3A activity to predict erlotinib pharmacokinetics., (© 2019 The British Pharmacological Society.)

Background: The aim of this study was to determine the influence of selected physiological, psychological and situational factors on experience of fatigue, and functional limitations due to fatigue in patients with stable chronic obstructive pulmonary disease (COPD)., Methods: In total 101 patients with COPD and 34 control patients were assessed for experience of fatigue, functional limitation due to fatigue (Fatigue Impact Scale), physiological [lung function, 6-minute walk distance (6MWD), body mass index (BMI), dyspnoea, interleukin (IL)-6, IL-8, high sensitivity C-reactive protein (hs-CRP), surfactant protein D], psychological (anxiety, depression, insomnia), situational variables (age, sex, smoking, living alone, education), and quality of life., Results: Fatigue was more common in patients with COPD than in control patients (72% versus 56%, p < 0.001). Patients with COPD and fatigue had lower lung function, shorter 6MWD, more dyspnoea, anxiety and depressive symptoms, and worse health status compared with patients without fatigue (all p < 0.01). No differences were found for markers of systemic inflammation. In logistic regression, experience of fatigue was associated with depression [odds ratio (OR) 1.69, 95% confidence interval (CI) 1.28-2.25) and insomnia (OR 1.75, 95% CI 1.19-2.54). In linear regression models, depression, surfactant protein D and dyspnoea explained 35% (R(2)) of the variation in physical impact of fatigue. Current smoking and depression explained 33% (R(2)) of the cognitive impact of fatigue. Depression and surfactant protein D explained 48% (R(2)) of the psychosocial impact of fatigue., Conclusions: Experiences of fatigue and functional limitation due to fatigue seem to be related mainly to psychological but also to physiological influencing factors, with depressive symptoms, insomnia problems and dyspnoea as the most prominent factors. Systemic inflammation was not associated with perception of fatigue but surfactant protein D was connected to some dimensions of the impact of fatigue., (© The Author(s), 2016.)

Introduction: Several differences have been reported in the clinical characteristics of chronic obstructive pulmonary disease (COPD) between men and women. Differences have been found in the association between respiratory symptoms and lung function, and in the factors associated with dyspnea. This raises the question of whether there are differences between the sexes in the relationship between fatigue, the second most prevalent symptom, and the variables of physical capacity and disease severity., Objectives: To examine the experience of fatigue and its relationship to physical capacity and disease severity in men and women with COPD., Methods: In a cross-sectional study 121 patients with COPD (54 men and 67 women), the experience of fatigue (frequency, duration, and severity) and physical capacity (lung function, 6-minute walk distance [6MWD], grip strength, and timed-stand test) were assessed. Disease severity was graded according to the Body mass index, airway Obstruction, Dyspnoea and Exercise capacity (BODE) index. Two multiple logistic regression models were tested, both of which were performed separately in men and women, to examine the association between the experience of fatigue and variables of physical capacity and the BODE index., Results: Eighty-nine (73.6%) patients experienced fatigue, with similar proportions in men and women. The men with fatigue had worse physical capacity and more severe disease than did the men without fatigue: for men with and without fatigue, respectively, the percent of predicted forced expiratory volume in 1 second (FEV1) (mean [standard deviation]) was 47 (14) vs 64 (17); the 6MWD (mean [standard deviation]) was 398 (138) vs 539 (105) m; and the BODE index (median [quartile 1-3]) was 3 (2-5) vs 1 (0-1) (P<0.01). In women, only higher leg fatigue post-6MWD was seen among those experiencing fatigue compared with women without fatigue: for women with and without fatigue, respectively, leg fatigue (median [quartile 1-3]) was 4 (3-5) vs 2 (0-3) (P<0.001). The regression models showed that the 6MWD and the BODE index were associated with fatigue in both men and women, but in women, leg fatigue remained an independent associate in both models., Conclusion: Exercise capacity and disease severity were associated with fatigue in both men and women. In women, leg fatigue was strongly associated with fatigue, which warrants further investigation.

Background: Reduced ventilation in lung regions affected by chronic obstructive pulmonary disease (COPD), reflected as inhomogeneities in the single-photon emission computed tomography (SPECT) lung image, is correlated to disease advancement. An analysis method for measuring these inhomogeneities is proposed in this work. The first aim was to develop a quantitative analysis method that could discriminate between Monte Carlo simulated normal and COPD lung SPECT images. A second aim was to evaluate the ability of the present method to discriminate between human subjects with advanced COPD and healthy volunteers., Methods: In the simulated COPD study, different activity distributions in the lungs were created to mimic the healthy lung (normal) and different levels of COPD. Gamma camera projections were Monte Carlo simulated, representing clinically acquired projections of a patient who had inhaled 125 MBq 99mTc-Technegas followed by a 10-min SPECT examination. Reconstructions were made with iterative ordered subset expectation maximisation. The coefficient of variance (CV) was calculated for small overlapping volumes covering the 3D reconstructed activity distribution. A CV threshold value (CVT) was calculated as the modal value of the CV distribution of the simulated normal. The area under the distribution curve (AUC), for CV values greater than CVT, AUC(CVT), was then calculated. Moreover, five patients with advanced emphysema and five healthy volunteers inhaled approximately 75 MBq 99mTc-Technegas immediately before the 20-min SPECT acquisition. In the human study, CVT was based on the mean CV distribution of the five healthy volunteers., Results: A significant difference (p < 0.001) was found between the Monte-Carlo simulated normal and COPD lung SPECT examinations. The present method identified a total reduction of ventilation of approximately 5%, not visible to the human eye in the reconstructed image. In humans the same method clearly discriminated between the five healthy volunteers and five patients with advanced COPD (p < 0.05)., Conclusions: While our results are promising, the potential of the AUC(CVT) method to detect less advanced COPD in patients needs further clinical studies.

Objective: A health economic evaluation of two alternative treatment settings, inpatient care and outpatient care, for acute deep venous thrombosis., Design: A randomised multicentre trial in a defined population in regular clinical practice., Setting: Hospitals and related health care centres in the Jönköping county council in Sweden., Interventions: Patients were randomised to either an inpatient strategy (n = 66) or an outpatient strategy (n = 65) using low-molecular-weight heparin, dalteparin, administered subcutaneously once daily and adjusted for body weight., Subjects: Of 224 eligible patients, 131 entered the trial and 124 completed the economic part of the study., Main Outcome Measures: Direct medical and direct non-medical costs during a 3-month period., Results: Total direct costs were higher for those in the inpatient strategy group, i.e. Swedish Crowns (SEK) 16400 per patient (Euro 1899) compared to SEK 12100 per patient (Euro 1405) in the outpatient strategy group (p < 0.001). More patients in the outpatient group received assistance when they returned home. Few patients in either group reported sick leave. There was no difference in total number of days between the two groups., Conclusions: Total direct costs were significantly lower for the outpatient treatment strategy for deep venous thrombosis compared to the inpatient treatment strategy. No significant difference in health impact could be detected. Deep venous thrombosis can to a greater extent than previously be treated in primary care, safely, at a lower cost, and in accordance with patient preferences.