Correction: Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness.

[This corrects the article DOI: 10.1371/journal.pone.0287412.].

Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness.

Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial dysfunction is an important contributor to GWI, based on the similarity of some GWI symptoms to those occurring in some mitochondrial diseases; the plausibility that certain pollutants to which GW veterans were exposed affect mitochondria; mitochondrial effects observed in studies in laboratory models of GWI; and previous evidence of mitochondrial outcomes in studies in GW veterans. A primary role of mitochondria is generation of energy via oxidative phosphorylation. However, direct assessment of mitochondrial respiration, reflecting oxidative phosphorylation, has not been carried out in veterans with GWI. In this case-control observational study, we tested multiple measures of mitochondrial function and integrity in a cohort of 114 GW veterans, 80 with and 34 without GWI as assessed by the Kansas definition. In circulating white blood cells, we analyzed multiple measures of mitochondrial respiration and extracellular acidification, a proxy for non-aerobic energy generation; mitochondrial DNA (mtDNA) copy number; mtDNA damage; and nuclear DNA damage. We also collected detailed survey data on demographics; deployment; self-reported exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents; and current biometrics, health and activity levels. We observed a 9% increase in mtDNA content in blood in veterans with GWI, but did not detect differences in DNA damage. Basal and ATP-linked oxygen consumption were respectively 42% and 47% higher in veterans without GWI, after adjustment for mtDNA amount. We did not find evidence for a compensatory increase in anaerobic energy generation: extracellular acidification was also lower in GWI (12% lower at baseline). A subset of 27 and 26 veterans returned for second and third visits, allowing us to measure stability of mitochondrial parameters over time. mtDNA CN, mtDNA damage, ATP-linked OCR, and spare respiratory capacity were moderately replicable over time, with intraclass correlation coefficients of 0.43, 0.44, 0.50, and 0.57, respectively. Other measures showed higher visit-to-visit variability. Many measurements showed lower replicability over time among veterans with GWI compared to veterans without GWI. Finally, we found a strong association between recalled exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents and GWI (p < 0.01, p < 0.01, and p < 0.0001, respectively). Our results demonstrate decreased mitochondrial respiratory function as well as decreased glycolytic activity, both of which are consistent with decreased energy availability, in peripheral blood mononuclear cells in veterans with GWI.

Deployed Veterans exhibit distinct respiratory patterns and greater dyspnea during maximal cardiopulmonary exercise: A case-control study.

BACKGROUND: Exertional dyspnea and exercise intolerance are frequently endorsed in Veterans of post 9/11 conflicts in Southwest Asia (SWA). Studying the dynamic behavior of ventilation during exercise may provide mechanistic insight into these symptoms. Using maximal cardiopulmonary exercise testing (CPET) to experimentally induce exertional symptoms, we aimed to identify potential physiological differences between deployed Veterans and non-deployed controls. MATERIALS AND METHODS: Deployed (n = 31) and non-deployed (n = 17) participants performed a maximal effort CPET via the Bruce treadmill protocol. Indirect calorimetry and perceptual rating scales were used to measure rate of oxygen consumption ([Formula: see text]), rate of carbon dioxide production ([Formula: see text]), respiratory frequency (f R), tidal volume (VT), minute ventilation ([Formula: see text]), heart rate (HR), perceived exertion (RPE; 6-20 scale), and dyspnea (Borg Breathlessness Scale; 0-10 scale). A repeated measures analysis of variance (RM-ANOVA) model (2 groups: deployed vs non-deployed X 6 timepoints: 0%, 20%, 40%, 60%, 80%, and 100% [Formula: see text]) was conducted for participants meeting valid effort criteria (deployed = 25; non-deployed = 11). RESULTS: Significant group (η2partial = 0.26) and interaction (η2partial = 0.10) effects were observed such that deployed Veterans exhibited reduced f R and a greater change over time relative to non-deployed controls. There was also a significant group effect for dyspnea ratings (η2partial = 0.18) showing higher values in deployed participants. Exploratory correlational analyses revealed significant associations between dyspnea ratings and fR at 80% (R2 = 0.34) and 100% (R2 = 0.17) of [Formula: see text], but only in deployed Veterans. CONCLUSION: Relative to non-deployed controls, Veterans deployed to SWA exhibited reduced fR and greater dyspnea during maximal exercise. Further, associations between these parameters occurred only in deployed Veterans. These findings support an association between SWA deployment and affected respiratory health, and also highlight the utility of CPET in the clinical evaluation of deployment-related dyspnea in Veterans.

Hemorheological responses to an acute bout of maximal exercise in Veterans with Gulf War Illness.

BACKGROUND: Altered red blood cell (RBC) deformability has been reported in Veterans with Gulf War Illness (GWI) who endorse exercise-induced symptom exacerbation and fatigue. However, it is unknown whether altered RBC deformability is worsened secondary to exercise. OBJECTIVE: To evaluate RBC deformability in response to maximal exercise in individuals with and without GWI. METHODS: Seventeen Veterans with GWI and 11 controls performed maximal exercise and provided blood samples (pre-, immediately post- and 60-min post-exercise). We calculated RBC deformation at infinite stress (EIMAX), shear stress for half-deformation (SS1/2) and their ratio (SS1/2/EIMAX) via repeated measures ANOVA with group and time as factors. RESULTS: A moderate interaction effect (p = 0.08, η2p = 0.10), large main effect for group (p = 0.02, η2p = 0.19) and moderate main effect for time (p = 0.20, η2p = 0.06) were observed for EIMAX, but only the main effect for group reached statistical significance. Changes in SS1/2 and SS1/2/EIMAX over time were similar between cases and controls as were main effects. CONCLUSIONS: Veterans with GWI had more deformable RBCs in comparison to controls that was unaffected by maximal exercise. Future studies to confirm our findings and identify associated mechanisms are warranted.

Exercise-Induced Bronchoconstriction in Iraq and Afghanistan Veterans With Deployment-Related Exposures.

INTRODUCTION: Acute exposure to high-levels of ambient fine particulate matter while exercising results in airway narrowing, but the long-term effects of repeated exposure on exercise-induced bronchoconstriction (EIB) are not well known. The goal of this preliminary study is to determine the rate of EIB among a sample of non-treatment seeking veterans deployed to Iraq and Afghanistan. MATERIALS AND METHODS: Twenty-four veterans (median [interquartile range]: 35.0 [27.3, 45] years) without history of asthma volunteered for this study. Spirometry was assessed before and after a standardized exercise challenge. A positive EIB response was defined as an exercise-induced fall in forced expiatory volume in 1 second ≥10%. Secondary criteria (peak flow ≥10% or mid-expiratory flow ≥15%) were also considered as an estimate of probable EIB. RESULTS: A positive EIB response was observed in 16.7% and probable EIB response was observed in 41.7% of our sample. Median deployment length to Iraq or Afghanistan was 13.0 [10.3, 17.5] months and the median time since deployment was 4.2 [2.7, 7.7] years. At the time of testing, veterans reported persistent cough (58.3%), wheeze (37.5%), and shortness of breath (37.5%). During deployment, veterans reported exposure to dust and sand (70.8%), smoke from burn pits (66.7%), vehicle exhaust (83.3%), and regional air pollution (26.0%) on most days or daily. CONCLUSIONS: Approximately 17% of our sample of non-treatment seeking deployed Iraq and Afghanistan veterans demonstrated EIB, similar to the general population prevalence. However, persistent respiratory symptoms and alternative indices of probable EIB supports continued monitoring of this population.

Veterans with Gulf War Illness exhibit distinct respiratory patterns during maximal cardiopulmonary exercise.

INTRODUCTION: The components of minute ventilation, respiratory frequency and tidal volume, appear differentially regulated and thereby afford unique insight into the ventilatory response to exercise. However, respiratory frequency and tidal volume are infrequently reported, and have not previously been considered among military veterans with Gulf War Illness. Our purpose was to evaluate respiratory frequency and tidal volume in response to a maximal cardiopulmonary exercise test in individuals with and without Gulf War Illness. MATERIALS AND METHODS: 20 cases with Gulf War Illness and 14 controls participated in this study and performed maximal cardiopulmonary exercise test on a cycle ergometer. Ventilatory variables (minute ventilation, respiratory frequency and tidal volume) were obtained and normalized to peak exercise capacity. Using mixed-design analysis of variance models, with group and time as factors, we analyzed exercise ventilatory patterns for the entire sample and for 11 subjects from each group matched for race, age, sex, and height. RESULTS: Despite similar minute ventilation (p = 0.57, η2p = 0.01), tidal volume was greater (p = 0.02, η2p = 0.16) and respiratory frequency was lower (p = 0.004, η2p = 0.24) in Veterans with Gulf War Illness than controls. The findings for respiratory frequency remained significant in the matched subgroup (p = 0.004, η2p = 0.35). CONCLUSION: In our sample, veterans with Gulf War Illness adopt a unique exercise ventilatory pattern characterized by reduced respiratory frequency, despite similar ventilation relative to controls. Although the mechanism(s) by which this pattern is achieved remains unresolved, our findings suggest that the components of ventilation should be considered when evaluating clinical conditions with unexplained exertional symptoms.