Publications by authors named "Roberto A Rabinovich"

41 Publications

Physical activity and fat-free mass during growth and in later life.

Am J Clin Nutr 2021 Sep 3. Epub 2021 Sep 3.

Unité Mixte de Recherche en Nutrition et Alimentation, CNESTEN-Université Ibn Tofail URAC39, Regional Designated Center of Nutrition Associated with African Regional Agreement for Research/International Atomic Energy Agency, Rabat, Morocco.

Background: Physical activity may be a way to increase and maintain fat-free mass (FFM) in later life, similar to the prevention of fractures by increasing peak bone mass.

Objectives: A study is presented of the association between FFM and physical activity in relation to age.

Methods: In a cross-sectional study, FFM was analyzed in relation to physical activity in a large participant group as compiled in the International Atomic Energy Agency Doubly Labeled Water database. The database included 2000 participants, age 3-96 y, with measurements of total energy expenditure (TEE) and resting energy expenditure (REE) to allow calculation of physical activity level (PAL = TEE/REE), and calculation of FFM from isotope dilution.

Results: PAL was a main determinant of body composition at all ages. Models with age, fat mass (FM), and PAL explained 76% and 85% of the variation in FFM in females and males < 18 y old, and 32% and 47% of the variation in FFM in females and males ≥ 18 y old, respectively. In participants < 18 y old, mean FM-adjusted FFM was 1.7 kg (95% CI: 0.1, 3.2 kg) and 3.4 kg (95% CI: 1.0, 5.6 kg) higher in a very active participant with PAL = 2.0 than in a sedentary participant with PAL = 1.5, for females and males, respectively. At age 18 y, height and FM-adjusted FFM was 3.6 kg (95% CI: 2.8, 4.4 kg) and 4.4 kg (95% CI: 3.2, 5.7 kg) higher, and at age 80 y 0.7 kg (95% CI: -0.2, 1.7 kg) and 1.0 kg (95% CI: -0.1, 2.1 kg) higher, in a participant with PAL = 2.0 than in a participant with PAL = 1.5, for females and males, respectively.

Conclusions: If these associations are causal, they suggest physical activity is a major determinant of body composition as reflected in peak FFM, and that a physically active lifestyle can only partly protect against loss of FFM in aging adults.
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http://dx.doi.org/10.1093/ajcn/nqab260DOI Listing
September 2021

Energy compensation and adiposity in humans.

Curr Biol 2021 Aug 26. Epub 2021 Aug 26.

Unité Mixte de Recherche en Nutrition et Alimentation, CNESTEN, Université Ibn Tofail URAC39, Regional Designated Center of Nutrition Associated with AFRA/IAEA, Kénitra, Morocco.

Understanding the impacts of activity on energy balance is crucial. Increasing levels of activity may bring diminishing returns in energy expenditure because of compensatory responses in non-activity energy expenditures. This suggestion has profound implications for both the evolution of metabolism and human health. It implies that a long-term increase in activity does not directly translate into an increase in total energy expenditure (TEE) because other components of TEE may decrease in response-energy compensation. We used the largest dataset compiled on adult TEE and basal energy expenditure (BEE) (n = 1,754) of people living normal lives to find that energy compensation by a typical human averages 28% due to reduced BEE; this suggests that only 72% of the extra calories we burn from additional activity translates into extra calories burned that day. Moreover, the degree of energy compensation varied considerably between people of different body compositions. This association between compensation and adiposity could be due to among-individual differences in compensation: people who compensate more may be more likely to accumulate body fat. Alternatively, the process might occur within individuals: as we get fatter, our body might compensate more strongly for the calories burned during activity, making losing fat progressively more difficult. Determining the causality of the relationship between energy compensation and adiposity will be key to improving public health strategies regarding obesity.
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http://dx.doi.org/10.1016/j.cub.2021.08.016DOI Listing
August 2021

Daily energy expenditure through the human life course.

Science 2021 08;373(6556):808-812

Unité Mixte de Recherche en Nutrition et Alimentation, CNESTEN-Université Ibn Tofail URAC39, Regional Designated Center of Nutrition Associated with AFRA/IAEA, Rabat, Morocco.

Total daily energy expenditure ("total expenditure") reflects daily energy needs and is a critical variable in human health and physiology, but its trajectory over the life course is poorly studied. We analyzed a large, diverse database of total expenditure measured by the doubly labeled water method for males and females aged 8 days to 95 years. Total expenditure increased with fat-free mass in a power-law manner, with four distinct life stages. Fat-free mass-adjusted expenditure accelerates rapidly in neonates to ~50% above adult values at ~1 year; declines slowly to adult levels by ~20 years; remains stable in adulthood (20 to 60 years), even during pregnancy; then declines in older adults. These changes shed light on human development and aging and should help shape nutrition and health strategies across the life span.
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http://dx.doi.org/10.1126/science.abe5017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370708PMC
August 2021

A standard calculation methodology for human doubly labeled water studies.

Cell Rep Med 2021 Feb 16;2(2):100203. Epub 2021 Feb 16.

Maastricht University, Maastricht, the Netherlands.

The doubly labeled water (DLW) method measures total energy expenditure (TEE) in free-living subjects. Several equations are used to convert isotopic data into TEE. Using the International Atomic Energy Agency (IAEA) DLW database (5,756 measurements of adults and children), we show considerable variability is introduced by different equations. The estimated rCO is sensitive to the dilution space ratio (DSR) of the two isotopes. Based on performance in validation studies, we propose a new equation based on a new estimate of the mean DSR. The DSR is lower at low body masses (<10 kg). Using data for 1,021 babies and infants, we show that the DSR varies non-linearly with body mass between 0 and 10 kg. Using this relationship to predict DSR from weight provides an equation for rCO over this size range that agrees well with indirect calorimetry (average difference 0.64%; SD = 12.2%). We propose adoption of these equations in future studies.
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http://dx.doi.org/10.1016/j.xcrm.2021.100203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897799PMC
February 2021

Validity and responsiveness of the Daily- and Clinical visit-PROactive Physical Activity in COPD (D-PPAC and C-PPAC) instruments.

Thorax 2021 03 21;76(3):228-238. Epub 2021 Jan 21.

Department of Respiratory Diseases, University Hospital Leuven, Leuven, Belgium.

Background: The Daily-PROactive and Clinical visit-PROactive Physical Activity (D-PPAC and C-PPAC) instruments in chronic obstructive pulmonary disease (COPD) combines questionnaire with activity monitor data to measure patients' experience of physical activity. Their amount, difficulty and total scores range from 0 (worst) to 100 (best) but require further psychometric evaluation.

Objective: To test reliability, validity and responsiveness, and to define minimal important difference (MID), of the D-PPAC and C-PPAC instruments, in a large population of patients with stable COPD from diverse severities, settings and countries.

Methods: We used data from seven randomised controlled trials to evaluate D-PPAC and C-PPAC internal consistency and construct validity by sex, age groups, COPD severity, country and language as well as responsiveness to interventions, ability to detect change and MID.

Results: We included 1324 patients (mean (SD) age 66 (8) years, forced expiratory volume in 1 s 55 (17)% predicted). Scores covered almost the full range from 0 to 100, showed strong internal consistency after stratification and correlated as a priori hypothesised with dyspnoea, health-related quality of life and exercise capacity. Difficulty scores improved after pharmacological treatment and pulmonary rehabilitation, while amount scores improved after behavioural physical activity interventions. All scores were responsive to changes in self-reported physical activity experience (both worsening and improvement) and to the occurrence of COPD exacerbations during follow-up. The MID was estimated to 6 for amount and difficulty scores and 4 for total score.

Conclusions: The D-PPAC and C-PPAC instruments are reliable and valid across diverse COPD populations and responsive to pharmacological and non-pharmacological interventions and changes in clinically relevant variables.
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http://dx.doi.org/10.1136/thoraxjnl-2020-214554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892393PMC
March 2021

Patterns of Physical Activity Progression in Patients With COPD.

Arch Bronconeumol (Engl Ed) 2021 Mar 8;57(3):214-223. Epub 2020 Oct 8.

ISGlobal, Barcelona, Spain; Pompeu Fabra University (UPF), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. Electronic address:

Introduction: Although mean physical activity in COPD patients declines by 400-500steps/day annually, it is unknown whether the natural progression is the same for all patients. We aimed to identify distinct physical activity progression patterns using a hypothesis-free approach and to assess their determinants.

Methods: We pooled data from two cohorts (usual care arm of Urban Training [NCT01897298] and PROactive initial validation [NCT01388218] studies) measuring physical activity at baseline and 12 months (Dynaport MoveMonitor). We identified clusters (patterns) of physical activity progression (based on levels and changes of steps/day) using k-means, and compared baseline sociodemographic, interpersonal, environmental, clinical and psychological characteristics across patterns.

Results: In 291 COPD patients (mean±SD 68±8 years, 81% male, FEV 59±19%) we identified three distinct physical activity progression patterns: Inactive (n=173 [59%], baseline: 4621±1757 steps/day, 12-month change (Δ): -487±1201 steps/day), ActiveImprovers (n=49 [17%], baseline: 7727±3275 steps/day, Δ:+3378±2203 steps/day) and ActiveDecliners (n=69 [24%], baseline: 11 267±3009 steps/day, Δ: -2217±2085 steps/day). After adjustment in a mixed multinomial logistic regression model using Active Decliners as reference pattern, a lower 6-min walking distance (RRR [95% CI] 0.94 [0.90-0.98] per 10m, P=.001) and a higher mMRC dyspnea score (1.71 [1.12-2.60] per 1 point, P=.012) were independently related with being Inactive. No baseline variable was independently associated with being an Active Improver.

Conclusions: The natural progression in physical activity over time in COPD patients is heterogeneous. While Inactive patients relate to worse scores for clinical COPD characteristics, Active Improvers and Decliners cannot be predicted at baseline.
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http://dx.doi.org/10.1016/j.arbres.2020.08.001DOI Listing
March 2021

ERS statement on standardisation of cardiopulmonary exercise testing in chronic lung diseases.

Eur Respir Rev 2019 Dec 18;28(154). Epub 2019 Dec 18.

Paediatric Dept, University Hospital Würzburg, Würzburg, Germany

The objective of this document was to standardise published cardiopulmonary exercise testing (CPET) protocols for improved interpretation in clinical settings and multicentre research projects. This document: 1) summarises the protocols and procedures used in published studies focusing on incremental CPET in chronic lung conditions; 2) presents standard incremental protocols for CPET on a stationary cycle ergometer and a treadmill; and 3) provides patients' perspectives on CPET obtained through an online survey supported by the European Lung Foundation. We systematically reviewed published studies obtained from EMBASE, Medline, Scopus, Web of Science and the Cochrane Library from inception to January 2017. Of 7914 identified studies, 595 studies with 26 523 subjects were included. The literature supports a test protocol with a resting phase lasting at least 3 min, a 3-min unloaded phase, and an 8- to 12-min incremental phase with work rate increased linearly at least every minute, followed by a recovery phase of at least 2-3 min. Patients responding to the survey (n=295) perceived CPET as highly beneficial for their diagnostic assessment and informed the Task Force consensus. Future research should focus on the individualised estimation of optimal work rate increments across different lung diseases, and the collection of robust normative data.
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http://dx.doi.org/10.1183/16000617.0101-2018DOI Listing
December 2019

Progression of physical inactivity in COPD patients: the effect of time and climate conditions - a multicenter prospective cohort study.

Int J Chron Obstruct Pulmon Dis 2019 3;14:1979-1992. Epub 2019 Sep 3.

National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, UK.

Purpose: Longitudinal data on the effect of time and environmental conditions on physical activity (PA) among COPD patients are currently scarce, but this is an important factor in the design of trials to test interventions that might impact on it. Thus, we aimed to assess the effect of time and climate conditions (temperature, day length and rainfall) on progression of PA in a cohort of COPD patients.

Patients And Methods: This is a prospective, multicenter, cohort study undertaken as part of the EU/IMI PROactive project, in which we assessed 236 COPD patients simultaneously wearing two activity monitors (Dynaport MiniMod and Actigraph GT3X). A multivariable generalized linear model analysis was conducted to describe the effect of the explanatory variables on PA measures, over three time points (baseline, 6 and 12 months).

Results: At 12 months (n=157; FEV% predicted=57.7±21.9) there was a significant reduction in all PA measures (Actigraph step count (4284±3533 vs 3533±293)), Actigraph moderate- to vigorous-intensity PA ratio (8.8 (18.8) vs 6.1 (15.7)), Actigraph vector magnitude units (374,902.4 (265,269) vs 336,240 (214,432)), MiniMod walking time (59.1 (34.9) vs 56.9 (38.7) mins) and MiniMod PA intensity (0.183 (0) vs 0.181 (0)). Time had a significant, negative effect on most PA measures in multivariable analysis, after correcting for climate factors, study center, age, FEV% predicted, 6MWD and other disease severity measures. Rainfall was the only climate factor with a negative effect on most PA parameters.

Conclusion: COPD patients demonstrate a significant decrease in PA over 1 year follow-up, which is further affected by hours of rainfall, but not by other climate considerations.
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http://dx.doi.org/10.2147/COPD.S208826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732558PMC
March 2020

ERS statement on respiratory muscle testing at rest and during exercise.

Eur Respir J 2019 06 13;53(6). Epub 2019 Jun 13.

Hypoxia Physiopathology laboratory (HP2), INSERM U1042, Grenoble Alpes University, Grenoble, France.

Assessing respiratory mechanics and muscle function is critical for both clinical practice and research purposes. Several methodological developments over the past two decades have enhanced our understanding of respiratory muscle function and responses to interventions across the spectrum of health and disease. They are especially useful in diagnosing, phenotyping and assessing treatment efficacy in patients with respiratory symptoms and neuromuscular diseases. Considerable research has been undertaken over the past 17 years, since the publication of the previous American Thoracic Society (ATS)/European Respiratory Society (ERS) statement on respiratory muscle testing in 2002. Key advances have been made in the field of mechanics of breathing, respiratory muscle neurophysiology (electromyography, electroencephalography and transcranial magnetic stimulation) and on respiratory muscle imaging (ultrasound, optoelectronic plethysmography and structured light plethysmography). Accordingly, this ERS task force reviewed the field of respiratory muscle testing in health and disease, with particular reference to data obtained since the previous ATS/ERS statement. It summarises the most recent scientific and methodological developments regarding respiratory mechanics and respiratory muscle assessment by addressing the validity, precision, reproducibility, prognostic value and responsiveness to interventions of various methods. A particular emphasis is placed on assessment during exercise, which is a useful condition to stress the respiratory system.
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http://dx.doi.org/10.1183/13993003.01214-2018DOI Listing
June 2019

Smartphone-Based Physical Activity Telecoaching in Chronic Obstructive Pulmonary Disease: Mixed-Methods Study on Patient Experiences and Lessons for Implementation.

JMIR Mhealth Uhealth 2018 Dec 21;6(12):e200. Epub 2018 Dec 21.

Department of Rehabilitation Sciences, KU Leuven, Leuven, Belgium.

Background: Telecoaching approaches can enhance physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD). However, their effectiveness is likely to be influenced by intervention-specific characteristics.

Objective: This study aimed to assess the acceptability, actual usage, and feasibility of a complex PA telecoaching intervention from both patient and coach perspectives and link these to the effectiveness of the intervention.

Methods: We conducted a mixed-methods study based on the completers of the intervention group (N=159) included in an (effective) 12-week PA telecoaching intervention. This semiautomated telecoaching intervention consisted of a step counter and a smartphone app. Data from a project-tailored questionnaire (quantitative data) were combined with data from patient interviews and a coach focus group (qualitative data) to investigate patient and coach acceptability, actual usage, and feasibility of the intervention. The degree of actual usage of the smartphone and step counter was also derived from app data. Both actual usage and perception of feasibility were linked to objectively measured change in PA.

Results: The intervention was well accepted and perceived as feasible by all coaches present in the focus group as well by patients, with 89.3% (142/159) of patients indicating that they enjoyed taking part. Only a minority of patients (8.2%; 13/159) reported that they found it difficult to use the smartphone. Actual usage of the step counter was excellent, with patients wearing it for a median (25th-75th percentiles) of 6.3 (5.8-6.8) days per week, which did not change over time (P=.98). The smartphone interface was used less frequently and actual usage of all daily tasks decreased significantly over time (P<.001). Patients needing more contact time had a smaller increase in PA, with mean (SD) of +193 (SD 2375) steps per day, +907 (SD 2306) steps per day, and +1489 (SD 2310) steps per day in high, medium, and low contact time groups, respectively; P for-trend=.01. The overall actual usage of the different components of the intervention was not associated with change in step count in the total group (P=.63).

Conclusions: The 12-week semiautomated PA telecoaching intervention was well accepted and feasible for patients with COPD and their coaches. The actual usage of the step counter was excellent, whereas actual usage of the smartphone tasks was lower and decreased over time. Patients who required more contact experienced less PA benefits.

Trial Registration: ClinicalTrials.gov NCT02158065; http://clinicaltrials.gov/ct2/show/NCT02158065 (Archived by WebCite at http://www.webcitation.org/73bsaudy9).
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http://dx.doi.org/10.2196/mhealth.9774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320438PMC
December 2018

Validation of the Incremental Shuttle Walk Test as a Clinical End Point in Bronchiectasis.

Chest 2018 12 6;154(6):1321-1329. Epub 2018 Oct 6.

MRC Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom; Department of Respiratory Medicine, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.

Background: A validated clinical end point is needed to assess response to therapies in bronchiectasis.

Objectives: The goal of this study was to assess the reliability, validity, and responsiveness of the incremental shuttle walk test (ISWT) as a clinical end point in bronchiectasis.

Methods: In clinically stable patients (n = 30), the ISWT was performed twice, 6 months apart. Correlation between the St. George's Respiratory Questionnaire (SGRQ) and the ISWT (n = 94) was performed. The 1-year gentamicin study was reanalyzed to assess the area under the curve (percent change of ISWT with a ≥ 4 unit improvement in total SGRQ). ISWT was performed prior to and following 14 days of antibiotics for an exacerbation (94 oral courses and 30 IV courses, n = 124) and reanalysis of the 1-year gentamicin study (n = 57).

Results: The ISWT did not significantly change over 6 months while clinically stable. The ISWT correlated inversely with the SGRQ (rs = -0.60; P < .0001), Bronchiectasis Severity Index score (rs = -0.44; P < .0001), and sedentary time (rs = -0.48; P = .0007) but correlated with physical activity (rs = 0.42; P = .004). The area under the curve for percent change in ISWT with ≥ 4 unit improvement in SGRQ was 0.79 (95% CI, 0.66-0.91; P = .001). A threshold of 5% improvement in the ISWT had a 92% sensitivity but 50% specificity, and from the responsiveness studies would capture 73% of all patients.

Conclusions: This study confirmed the ISWT to be reliable, valid, and responsive to change in patients with bronchiectasis. The authors propose that a minimum clinically important difference of 5% improvement in the ISWT would be a useful objective end point to assess therapies in bronchiectasis.
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http://dx.doi.org/10.1016/j.chest.2018.09.019DOI Listing
December 2018

Role of accelerated aging in limb muscle wasting of patients with COPD.

Int J Chron Obstruct Pulmon Dis 2018 25;13:1987-1998. Epub 2018 Jun 25.

ELEGI Colt Laboratory, MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK,

Purpose: Skeletal muscle wasting is an independent predictor of health-related quality of life and survival in patients with COPD, but the complexity of molecular mechanisms associated with this process has not been fully elucidated. We aimed to determine whether an impaired ability to repair DNA damage contributes to muscle wasting and the accelerated aging phenotype in patients with COPD.

Patients And Methods: The levels of phosphorylated H2AX (γH2AX), a molecule that promotes DNA repair, were assessed in vastus lateralis biopsies from 10 COPD patients with low fat-free mass index (FFMI; COPD), 10 with preserved FFMI and 10 age- and gender-matched healthy controls. A panel of selected markers for cellular aging processes (CDKN2A/p16, SIRT1, SIRT6, and telomere length) were also assessed. Markers of oxidative stress and cell damage and a panel of pro-inflammatory and anti-inflammatory cytokines were evaluated. Markers of muscle regeneration and apoptosis were also measured.

Results: We observed a decrease in γH2AX expression in COPD, which occurred in association with a tendency to increase in CDKN2A/p16, and a significant decrease in SIRT1 and SIRT6 protein levels. Cellular damage and muscle inflammatory markers were also increased in COPD.

Conclusion: These data are in keeping with an accelerated aging phenotype as a result of impaired DNA repair and dysregulation of cellular homeostasis in the muscle of COPD. These data indicate cellular degeneration via stress-induced premature senescence and associated inflammatory responses abetted by the senescence-associated secretory phenotype and reflect an increased expression of markers of oxidative stress and inflammation.
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http://dx.doi.org/10.2147/COPD.S155952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022820PMC
January 2019

Can muscle protein metabolism be specifically targeted by nutritional support and exercise training in chronic obstructive pulmonary disease?

J Thorac Dis 2018 May;10(Suppl 12):S1377-S1389

ELEGI Colt Laboratory, MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Scotland, UK.

Chronic obstructive pulmonary disease (COPD) associates with several extra-pulmonary effects. Muscle dysfunction and wasting is one of the most prominent extra-pulmonary effects and contributes to exercise limitation and health related quality of life (HRQoL), morbidity as well as mortality. The loss of muscle mass is characterised by an impaired balance between protein synthesis (anabolism) and protein breakdown (catabolism) which relates to nutritional disturbances, muscle disuse and the presence of a systemic inflammation, among other factors. Current approaches to reverse skeletal muscle dysfunction and wasting attain only modest improvements. The development of new therapeutic strategies aiming at improving skeletal muscle dysfunction and wasting are needed. This requires a better understanding of the underlying molecular pathways responsible for these abnormalities. In this review we update recent research on protein metabolism, nutritional depletion as well as physical (in)activity in relation to muscle wasting and dysfunction in patients with COPD. We also discuss the role of nutritional supplementation and exercise training as strategies to re-establish the disrupted balance of protein metabolism in the muscle of patients with COPD. Future areas of research and clinical practice directions are also addressed.
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http://dx.doi.org/10.21037/jtd.2018.05.81DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989103PMC
May 2018

Physical Activity in COPD. Significance, Prognosis, Measurement and Therapeutic Interventions.

Arch Bronconeumol (Engl Ed) 2018 Sep 2;54(9):449-450. Epub 2018 Mar 2.

The Queen's Medical Research Institute and Respiratory Medicine Department, Royal Infirmmary of Edinburgh, Edinburgh, Reino Unido. Electronic address:

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http://dx.doi.org/10.1016/j.arbres.2018.01.011DOI Listing
September 2018

An Improved Dynamic Model for the Respiratory Response to Exercise.

Front Physiol 2018 7;9:69. Epub 2018 Feb 7.

ELEGI and COLT Laboratories, Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.

Respiratory system modeling has been extensively studied in steady-state conditions to simulate sleep disorders, to predict its behavior under ventilatory diseases or stimuli and to simulate its interaction with mechanical ventilation. Nevertheless, the studies focused on the instantaneous response are limited, which restricts its application in clinical practice. The aim of this study is double: firstly, to analyze both dynamic and static responses of two known respiratory models under exercise stimuli by using an incremental exercise stimulus sequence (to analyze the model responses when step inputs are applied) and experimental data (to assess prediction capability of each model). Secondly, to propose changes in the models' structures to improve their transient and stationary responses. The versatility of the resulting model vs. the other two is shown according to the ability to simulate ventilatory stimuli, like exercise, with a proper regulation of the arterial blood gases, suitable constant times and a better adjustment to experimental data. The proposed model adjusts the breathing pattern every respiratory cycle using an optimization criterion based on minimization of work of breathing through regulation of respiratory frequency.
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http://dx.doi.org/10.3389/fphys.2018.00069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808356PMC
February 2018

Translation to Spanish and Validation of the Specific Saint George's Questionnaire for Idiopathic Pulmonary Fibrosis.

Arch Bronconeumol (Engl Ed) 2018 Feb 2;54(2):68-73. Epub 2017 Nov 2.

Consultorio multidisciplinario especializado en enfermedades pulmonares intersticiales difusas, Hospital de Rehabilitación Respiratoria María Ferrer, Buenos Aires, Argentina.

Introduction: Interstitial lung disease (ILD) is associated with low exercise tolerance, dyspnea, and decreased health-related quality of life (HRQL). Idiopathic pulmonary fibrosis (IPF) is one of the most prevalent in the group. A specific version of the Saint George's questionnaire (SGRQ-I) has been developed to quantify the HRQL of IPF patients. However, this tool is not currently validated in the Spanish language. The objective was to translate into Spanish and validate the specific Saint George's Respiratory Questionnaire for idiopathic pulmonary fibrosis (SGRQ-I).

Methods: The repeatability, internal consistency and construct validity of the SGRQ-I in Spanish were analyzed after a backtranslation process.

Results: In total, 23 outpatients with IPF completed the translated SGRQ-I twice, 7 days apart. Repeatability was studied, revealing good concordance in test-retest with an ICC (interclass correlation coefficient) of 0.96 (P<.001). Internal consistency was good for different questionnaire items (Cronbach's alpha of 0.9 including and 0.81 excluding the total value) (P<.001). The total score of the questionnaire showed good correlation with forced vital capacity FVC% (r=-0.44; P=.033), diffusing capacity of the lungs for carbon monoxide (DL%) (r=-0.55; P=.011), partial pressure of oxygen in arterial blood PaO (r=-0.44; P=.036), Medical Research Council Dyspnea scale (r=-0.65; P<.001), and number of steps taken in 24hours (r=-0.47; P=.024).

Conclusions: The Spanish version of SGRQ-Ideveloped by our group shows good internal consistency, reproducibility and validity, so it can be used for the evaluation of quality of life (QOL) in IPF patients.
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http://dx.doi.org/10.1016/j.arbres.2017.09.004DOI Listing
February 2018

Effectiveness of Smartphone Devices in Promoting Physical Activity and Exercise in Patients with Chronic Obstructive Pulmonary Disease: A Systematic Review.

COPD 2017 Oct 24;14(5):543-551. Epub 2017 Aug 24.

d ELEGI Colt Laboratory, Centre for Inflammation Research, The Queen's Medical Research Institute , University of Edinburgh , Scotland , UK.

The objectives of this systematic review were to analyse existing evidence on the efficacy of smartphone devices in promoting physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD) and to identify the validity and precision of their measurements. A systematic review was undertaken across nine electronic databases: WOS Core Collection, PubMed, CINAHL, AMED, Academic Search Complete, Cochrane Central Register of Controlled Trials, SciELO, LILACS and ScienceDirect. Randomized and non-randomized controlled clinical trials were identified. To obtain additional eligible articles, the reference lists of the selected studies were also checked. Eligibility criteria and risk of bias were assessed by two independent authors. A total of eight articles met eligibility criteria. The studies were focused on promoting PA (n  =  5) and the precision of device measurements (n = 3). The effectiveness of smartphones in increasing PA level (steps/day) at short and long term is very limited. Mobile-based exercise programs reported improvements in exercise capacity (i.e. incremental Shuttle-Walk-Test) at short and long term (18.3% and 21%, respectively). The precision of device measurements was good-to-excellent (r = 0.69-0.99); however, these data should be interpreted with caution due to methodological limitations of studies. The effectiveness of smartphone devices in promoting PA levels in patients with COPD is scarce. Further high-quality studies are needed to evaluate the effectiveness of smartphone devices in promoting PA levels. Registration number: CRD42016050048.
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http://dx.doi.org/10.1080/15412555.2017.1358257DOI Listing
October 2017

Physical activity in patients with COPD: the impact of comorbidities.

Expert Rev Respir Med 2017 09 20;11(9):685-698. Epub 2017 Jul 20.

a ELEGI and COLT Laboratories , Queen's Medical Research Institute, The University of Edinburgh , Edinburgh , UK.

Introduction: Comorbidities are common in patients with chronic obstructive pulmonary disease (COPD) and it plays an important role on physical activity (PA) in this population. Since low PA levels have been described as a key factor to predict morbi-mortality in COPD, it seems crucial to review the current literature available on this topic. Areas covered: This review covers the most common comorbidities found in COPD, their prevalence and prognostic implications. We explore the differences in PA between COPD patients with and without comorbidities, as well as the impact of the number or type of comorbidities on activity levels of this population. The effect of different comorbidities on activities of daily living in patients with COPD is also reviewed. Finally, we discuss options for the treatment of inactivity in COPD patients considering their comorbidities and limitations. Expert commentary: Comorbidities are highly prevalent in patients with COPD and further deteriorate PA levels in this population. Despite the wide range of interventions available in COPD, the evidence in the field seems to point at PA coaching with feedback on individual goals and longer lasting PR programmes with more than 12 weeks of duration when attempting to raise the activity levels of this population.
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http://dx.doi.org/10.1080/17476348.2017.1354699DOI Listing
September 2017

2D-DIGE proteomic analysis of vastus lateralis from COPD patients with low and normal fat free mass index and healthy controls.

Respir Res 2017 05 3;18(1):81. Epub 2017 May 3.

ELEGI Colt Laboratory, Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK.

Background: Chronic obstructive pulmonary disease (COPD) is associated with several extra-pulmonary effects of which skeletal muscle wasting is one of the most common and contributes to reduced quality of life, increased morbidity and mortality. The molecular mechanisms leading to muscle wasting are not fully understood. Proteomic analysis of human skeletal muscle is a useful approach for gaining insight into the molecular basis for normal and pathophysiological conditions.

Methods: To identify proteins involved in the process of muscle wasting in COPD, we searched differentially expressed proteins in the vastus lateralis of COPD patients with low fat free mass index (FFMI), as a surrogate of muscle mass (COPD n = 10) (FEV 33 ± 4.3% predicted, FFMI 15 ± 0.2 Kg.m), in comparison to patients with COPD and normal FFMI (COPD n = 8) and a group of age, smoking history, and sex matched healthy controls (C, n = 9) using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) technology, combined with mass spectrometry (MS). The effect of silencing DOT1L protein expression on markers of cell arrest was analyzed in skeletal muscle satellite cells (HSkMSCs) in vitro and assessed by qPCR and Western blotting.

Results: A subset of 7 proteins was differentially expressed in COPD compared to both COPD and C. We found an increased expression of proteins associated with muscle homeostasis and protection against oxidative stress, and a decreased expression of structural muscle proteins and proteins involved in myofibrillogenesis, cell proliferation, cell cycle arrest and energy production. Among these was a decreased expression of the histone methyltransferase DOT1L. In addition, silencing of the DOT1L gene in human skeletal muscle satellite cells in vitro was significantly related to up regulation of p21 /CDKN1A, a marker of cell arrest and ageing.

Conclusions: 2D-DIGE coupled with MS identified differences in the expression of several proteins in the wasted vastus lateralis that are relevant to the disease process. Down regulation of DOT1L in the vastus lateralis of COPD patients may mediate the muscle wasting process through up regulation of markers of cell arrest and senescence.
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http://dx.doi.org/10.1186/s12931-017-0525-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415759PMC
May 2017

Home monitoring of breathing rate in people with chronic obstructive pulmonary disease: observational study of feasibility, acceptability, and change after exacerbation.

Int J Chron Obstruct Pulmon Dis 2017 20;12:1221-1231. Epub 2017 Apr 20.

Edinburgh Lung and the Environment Group Initiative (ELEGI) Colt Laboratory, Centre for Inflammation Research.

Telehealth programs to promote early identification and timely self-management of acute exacerbations of chronic obstructive pulmonary diseases (AECOPDs) have yielded disappointing results, in part, because parameters monitored (symptoms, pulse oximetry, and spirometry) are weak predictors of exacerbations.

Purpose: Breathing rate (BR) rises during AECOPD and may be a promising predictor. Devices suitable for home use to measure BR have recently become available, but their accuracy, acceptability, and ability to detect changes in people with COPD is not known.

Patients And Methods: We compared five BR monitors, which used different monitoring technologies, with a gold standard (Oxycon Mobile; CareFusion, a subsidiary of Becton Dickinson, San Diego, CA, USA). The monitors were validated in 21 stable COPD patients during a 57-min "activities of daily living protocol" in a laboratory setting. The two best performing monitors were then tested in a 14-day trial in a home setting in 23 stable COPD patients to determine patient acceptability and reliability of signal. Acceptability was explored in qualitative interviews. The better performing monitor was then given to 18 patients recruited during an AECOPD who wore the monitor to observe BR during the recovery phase of an AECOPD.

Results: While two monitors demonstrated acceptable accuracy compared with the gold standard, some participants found them intrusive particularly when ill with an exacerbation, limiting their potential utility in acute situations. A reduction in resting BR during the recovery from an AECOPD was observed in some, but not in all participants and there was considerable day-to-day individual variation.

Conclusion: Resting BR shows some promise in identifying exacerbations; however, further prospective study to assess this is required.
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http://dx.doi.org/10.2147/COPD.S120706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404493PMC
March 2018

Age-dependent elastin degradation is enhanced in chronic obstructive pulmonary disease.

Eur Respir J 2016 10 1;48(4):1215-1218. Epub 2016 Sep 1.

MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, UK.

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http://dx.doi.org/10.1183/13993003.01125-2016DOI Listing
October 2016

Depression symptoms reduce physical activity in COPD patients: a prospective multicenter study.

Int J Chron Obstruct Pulmon Dis 2016 10;11:1287-95. Epub 2016 Jun 10.

ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; CIBEREpidemiología y Salud Pública (CIBERESP), Barcelona, Spain.

Background: The role of anxiety and depression in the physical activity (PA) of patients with COPD is controversial. We prospectively assessed the effect of symptoms of anxiety and depression on PA in COPD patients.

Methods: We evaluated anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), PA (Dynaport(®) accelerometer), and other relevant characteristics in 220 COPD patients from five European countries at baseline and at 6 and 12 months of follow-up. HADS score was categorized as: no symptoms (score 0-7), suggested (8-10), and probable (>11) anxiety or depression. We estimated the association between anxiety and depression at t (baseline and 6 months) and PA at t+1 (6 and 12 months) using regression models with a repeated measures approach.

Results: Patients had a mean (standard deviation) age of 67 (8) years, forced expiratory volume in 1 second 57 (20)% predicted. At baseline, the prevalence of probable anxiety and depression was 10% and 5%, respectively. In multivariable models adjusted by confounders and previous PA, patients performed 81 fewer steps/day (95% confidence interval, -149 to -12, P=0.02) per extra point in HADS-depression score. HADS-anxiety symptoms were not associated with PA.

Conclusion: In COPD patients, symptoms of depression are prospectively associated with a measurable reduction in PA 6 months later.
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http://dx.doi.org/10.2147/COPD.S101459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910613PMC
August 2017

Interventions to modify physical activity in patients with COPD: a systematic review.

Eur Respir J 2016 07 21;48(1):69-81. Epub 2016 Apr 21.

ELEGI and COLT Laboratories, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK

The broad range of interventions to increase physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD) has not been systematically assessed. We aimed to perform a systematic review of the interventional studies that have assessed PA as an outcome in patients with COPD.A systematic search in five different databases (Medline, Embase, PsycINFO, CINAHL and Web of Science) was performed in March 2015. Two independent reviewers analysed the studies against the inclusion criteria (COPD defined by spirometry; prospective, randomised/nonrandomised studies, cohort and experimental studies with interventions using PA as an outcome), extracted the data and assessed the quality of evidence.60 studies were included. Seven intervention groups were identified. PA counselling increased PA levels in COPD, especially when combined with coaching. 13 studies showed positive effects of pulmonary rehabilitation (PR) on PA, while seven studies showed no changes. All three PR programmes >12 weeks in duration increased PA. Overall, the quality of evidence was graded as very low.Interventions focusing specifically on increasing PA, and longer PR programmes, may have greater impacts on PA in COPD. Well-designed clinical trials with objective assessment of PA in COPD patients are needed.
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http://dx.doi.org/10.1183/13993003.01744-2015DOI Listing
July 2016

Circulating desmosine levels do not predict emphysema progression but are associated with cardiovascular risk and mortality in COPD.

Eur Respir J 2016 05 23;47(5):1365-73. Epub 2016 Mar 23.

Medical Research Institute, School of Medicine, University of Dundee, Dundee, UK.

Elastin degradation is a key feature of emphysema and may have a role in the pathogenesis of atherosclerosis associated with chronic obstructive pulmonary disease (COPD). Circulating desmosine is a specific biomarker of elastin degradation. We investigated the association between plasma desmosine (pDES) and emphysema severity/progression, coronary artery calcium score (CACS) and mortality.pDES was measured in 1177 COPD patients and 110 healthy control subjects from two independent cohorts. Emphysema was assessed on chest computed tomography scans. Aortic arterial stiffness was measured as the aortic-femoral pulse wave velocity.pDES was elevated in patients with cardiovascular disease (p<0.005) and correlated with age (rho=0.39, p<0.0005), CACS (rho=0.19, p<0.0005) modified Medical Research Council dyspnoea score (rho=0.15, p<0.0005), 6-min walking distance (rho=-0.17, p<0.0005) and body mass index, airflow obstruction, dyspnoea, exercise capacity index (rho=0.10, p<0.01), but not with emphysema, emphysema progression or forced expiratory volume in 1 s decline. pDES predicted all-cause mortality independently of several confounding factors (p<0.005). In an independent cohort of 186 patients with COPD and 110 control subjects, pDES levels were higher in COPD patients with cardiovascular disease and correlated with arterial stiffness (p<0.05).In COPD, excess elastin degradation relates to cardiovascular comorbidities, atherosclerosis, arterial stiffness, systemic inflammation and mortality, but not to emphysema or emphysema progression. pDES is a good biomarker of cardiovascular risk and mortality in COPD.
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http://dx.doi.org/10.1183/13993003.01824-2015DOI Listing
May 2016

Physical Activity Characteristics across GOLD Quadrants Depend on the Questionnaire Used.

PLoS One 2016 14;11(3):e0151255. Epub 2016 Mar 14.

NIHR Respiratory Biomedical Research Unit of the Royal Brompton and Harefield NHS foundation Trust and Imperial College London, London, United Kingdom.

Background: The GOLD multidimensional classification of COPD severity combines the exacerbation risk with the symptom experience, for which 3 different questionnaires are permitted. This study investigated differences in physical activity (PA) in the different GOLD quadrants and patient's distribution in relation to the questionnaire used.

Methods: 136 COPD patients (58±21% FEV1 predicted, 34F/102M) completed COPD assessment test (CAT), clinical COPD questionnaire (CCQ) and modified Medical Research Council (mMRC) questionnaire. Exacerbation history, spirometry and 6MWD were collected. PA was objectively measured for 2 periods of 1 week, 6 months apart, in 5 European centres; to minimise seasonal and clinical variation the average of these two periods was used for analysis.

Results: GOLD quadrants C+D had reduced PA compared with A+B (3824 [2976] vs. 5508 [4671] steps.d-1, p<0.0001). The choice of questionnaire yielded different patient distributions (agreement mMRC-CAT κ = 0.57; CCQ-mMRC κ = 0.71; CCQ-CAT κ = 0.72) with different clinical characteristics. PA was notably lower in patients with an mMRC score ≥2 (3430 [2537] vs. 5443 [3776] steps.d-1, p <0.001) in both the low and high risk quadrants.

Conclusions: Using different questionnaires changes the patient distribution and results in different clinical characteristics. Therefore, standardization of the questionnaire used for classification is critical to allow comparison of different studies using this as an entry criterion.

Clinical Trial Registration: ClinicalTrials.gov NCT01388218.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151255PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790973PMC
August 2016

Can health status questionnaires be used as a measure of physical activity in COPD patients?

Eur Respir J 2016 05 25;47(5):1565-8. Epub 2016 Feb 25.

KU Leuven-University of Leuven, Department of Rehabilitation Sciences, Leuven, Belgium University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium

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http://dx.doi.org/10.1183/13993003.01815-2015DOI Listing
May 2016

Should we treat chronic obstructive pulmonary disease as a cardiovascular disease?

Expert Rev Respir Med 2015 Aug 18;9(4):459-72. Epub 2015 Jul 18.

Edinburgh Lung and the Environment Group Initiative (ELEGI), Centre for Inflammation Research, Queens Medical Research Institute, Edinburgh, UK.

Chronic obstructive pulmonary disease (COPD) is characterized by largely irreversible airflow limitation and is associated with several extrapulmonary manifestations and co-morbidities. Cardiovascular diseases are among the most frequent co-morbid conditions affecting patients with COPD and have important prognostic implications for hospitalization and mortality. In turn, COPD shares common risk factors with several cardiovascular diseases (i.e., smoking habit), while several features of COPD can predispose to cardiovascular disease (i.e., gas exchange abnormalities, polycythemia, systemic inflammation and sedentary lifestyle). Cardiovascular co-morbidities in patients with COPD are under-recognized and undertreated and should be actively sought and treated according to usual guidelines. This review will discuss the increased prevalence and prognostic implications of cardiovascular co-morbidities in patients with COPD. The effect of COPD on the outcomes in cardiovascular disease will also be highlighted and the pathogenic mechanisms that underlie cardiovascular co-morbidities in patients with COPD will also be reviewed. Finally, options for the management of cardiovascular co-morbidities in patients with COPD will be discussed.
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http://dx.doi.org/10.1586/17476348.2015.1070099DOI Listing
August 2015

The PROactive instruments to measure physical activity in patients with chronic obstructive pulmonary disease.

Eur Respir J 2015 Oct 28;46(4):988-1000. Epub 2015 May 28.

Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Universitat Pompeu Fabra (UPF), Barcelona, Spain

No current patient-centred instrument captures all dimensions of physical activity in chronic obstructive pulmonary disease (COPD). Our objective was item reduction and initial validation of two instruments to measure physical activity in COPD.Physical activity was assessed in a 6-week, randomised, two-way cross-over, multicentre study using PROactive draft questionnaires (daily and clinical visit versions) and two activity monitors. Item reduction followed an iterative process including classical and Rasch model analyses, and input from patients and clinical experts.236 COPD patients from five European centres were included. Results indicated the concept of physical activity in COPD had two domains, labelled "amount" and "difficulty". After item reduction, the daily PROactive instrument comprised nine items and the clinical visit contained 14. Both demonstrated good model fit (person separation index >0.7). Confirmatory factor analysis supported the bidimensional structure. Both instruments had good internal consistency (Cronbach's α>0.8), test-retest reliability (intraclass correlation coefficient ≥0.9) and exhibited moderate-to-high correlations (r>0.6) with related constructs and very low correlations (r<0.3) with unrelated constructs, providing evidence for construct validity.Daily and clinical visit "PROactive physical activity in COPD" instruments are hybrid tools combining a short patient-reported outcome questionnaire and two activity monitor variables which provide simple, valid and reliable measures of physical activity in COPD patients.
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http://dx.doi.org/10.1183/09031936.00183014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589432PMC
October 2015

Genome-wide mRNA expression profiling in vastus lateralis of COPD patients with low and normal fat free mass index and healthy controls.

Respir Res 2015 Jan 8;16. Epub 2015 Jan 8.

ELEGI Colt Laboratory, Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, Scotland, EH16 4TJ, UK.

Background: Chronic Obstructive Pulmonary Disease (COPD) has significant systemic effects beyond the lungs amongst which muscle wasting is a prominent contributor to exercise limitation and an independent predictor of morbidity and mortality. The molecular mechanisms leading to skeletal muscle dysfunction/wasting are not fully understood and are likely to be multi-factorial. The need to develop therapeutic strategies aimed at improving skeletal muscle dysfunction/wasting requires a better understanding of the molecular mechanisms responsible for these abnormalities. Microarrays are powerful tools that allow the investigation of the expression of thousands of genes, virtually the whole genome, simultaneously. We aim at identifying genes and molecular pathways involved in skeletal muscle wasting in COPD.

Methods: We assessed and compared the vastus lateralis transcriptome of COPD patients with low fat free mass index (FFMI) as a surrogate of muscle mass (COPDL) (FEV1 30 ± 3.6%pred, FFMI 15 ± 0.2 Kg.m(-2)) with patients with COPD and normal FFMI (COPDN) (FEV1 44 ± 5.8%pred, FFMI 19 ± 0.5 Kg.m(-2)) and a group of age and sex matched healthy controls (C) (FEV1 95 ± 3.9%pred, FFMI 20 ± 0.8 Kg.m(-2)) using Agilent Human Whole Genome 4x44K microarrays. The altered expression of several of these genes was confirmed by real time TaqMan PCR. Protein levels of P21 were assessed by immunoblotting.

Results: A subset of 42 genes was differentially expressed in COPDL in comparison to both COPDN and C (PFP < 0.05; -1.5 ≥ FC ≥ 1.5). The altered expression of several of these genes was confirmed by real time TaqMan PCR and correlated with different functional and structural muscle parameters. Five of these genes (CDKN1A, GADD45A, PMP22, BEX2, CGREF1, CYR61), were associated with cell cycle arrest and growth regulation and had been previously identified in studies relating muscle wasting and ageing. Protein levels of CDKN1A, a recognized marker of premature ageing/cell cycle arrest, were also found to be increased in COPDL.

Conclusions: This study provides evidence of differentially expressed genes in peripheral muscle in COPD patients corresponding to relevant biological processes associated with skeletal muscle wasting and provides potential targets for future therapeutic interventions to prevent loss of muscle function and mass in COPD.
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http://dx.doi.org/10.1186/s12931-014-0139-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333166PMC
January 2015
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