Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Dynamic cerebral autoregulation is impaired in Veterans with Gulf War Illness: A case-control study.

Neurological dysfunction has been reported in Gulf War Illness (GWI), including abnormal cerebral blood flow (CBF) responses to physostigmine challenge. However, it is unclear whether the CBF response to normal physiological challenges and regulation is similarly dysfunctional. The goal of the present study was to evaluate the CBF velocity response to orthostatic stress (i.e., sit-to-stand maneuver) and increased fractional concentration of carbon dioxide. 23 cases of GWI (GWI+) and 9 controls (GWI) volunteered for this study. Primary variables of interest included an index of dynamic autoregulation and cerebrovascular reactivity. Dynamic autoregulation was significantly lower in GWI+ than GWI- both for autoregulatory index (2.99±1.5 vs 4.50±1.5, p = 0.017). In addition, we observed greater decreases in CBF velocity both at the nadir after standing (-18.5±6.0 vs -9.8±4.9%, p = 0.001) and during steady state standing (-5.7±7.1 vs -1.8±3.2%, p = 0.042). In contrast, cerebrovascular reactivity was not different between groups. In our sample of Veterans with GWI, dynamic autoregulation was impaired and consistent with greater cerebral hypoperfusion when standing. This reduced CBF may contribute to cognitive difficulties in these Veterans when upright

Acute effects of brewed cocoa consumption on attention, motivation to perform cognitive work and feelings of anxiety, energy and fatigue: a randomized, placebo-controlled crossover experiment

BACKGROUND: Acute effects of caffeinated and non-caffeinated cocoa on mood, motivation, and cognitive function are not well characterized. The current study examined the acute influence of brewed cocoa, alone and with supplemental caffeine, on attention, motivation to perform cognitive tasks and energy and fatigue mood states. METHODS: A randomized, double-blinded, within-subjects crossover trial was conducted with four 473-milliliter brewed beverage treatments: cocoa, caffeinated cocoa (70 milligrams caffeine total), placebo (flavored and colored brewed water) and positive control (placebo plus 66 milligrams caffeine, “caffeine alone”). Participants (n = 24) were low consumers of polyphenols without elevated feelings of energy. Before and three times after beverage consumption, a 26-minute battery was used to assess motivation to perform cognitive tasks, mood and attention (serial subtractions of 3 and 7, the continuous performance task, and the Bakan dual task) with a 10-minute break between each post-consumption battery. The procedure was repeated with each beverage for each participant at least 48 h apart and ±30 min the same time of day. Data were evaluated using Treatment X Time analysis of covariance controlling for hours of prior night’s sleep. RESULTS: Compared to placebo, cocoa reduced overall false alarm errors progressively across time with 0.92, 1.44 and 2.35 fewer false alarms on average 22–48, 60–86 and 98–124 min post-consumption (η 2 = 0.08, p = 0.019). Caffeinated cocoa: (i) attenuated the anxiety-provoking effects of cognitive testing found after drinking caffeine alone (η 2 = 0.064, p = 0.038), and (ii) increased accuracy (η 2 = 0.085, p = 0.01) and reduced omission errors (η 2 = 0.077, p = 0.016) on the Bakan primary task compared to cocoa alone. CONCLUSIONS: Brewed cocoa can acutely reduce errors associated with attention in the absence of changes in either perceived motivation to perform cognitive tasks or feelings of energy and fatigue. Supplemental caffeine in brewed cocoa can enhance aspects of attention while brewed cocoa can attenuate the anxiety-provoking effects found from drinking caffeine alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01651793. Registered July 25, 2012

Acute effects of brewed cocoa consumption on attention, motivation to perform cognitive work and feelings of anxiety, energy and fatigue: a randomized, placebo-controlled crossover experiment

BACKGROUND: Acute effects of caffeinated and non-caffeinated cocoa on mood, motivation, and cognitive function are not well characterized. The current study examined the acute influence of brewed cocoa, alone and with supplemental caffeine, on attention, motivation to perform cognitive tasks and energy and fatigue mood states. METHODS: A randomized, double-blinded, within-subjects crossover trial was conducted with four 473-milliliter brewed beverage treatments: cocoa, caffeinated cocoa (70 milligrams caffeine total), placebo (flavored and colored brewed water) and positive control (placebo plus 66 milligrams caffeine, “caffeine alone”). Participants (n = 24) were low consumers of polyphenols without elevated feelings of energy. Before and three times after beverage consumption, a 26-minute battery was used to assess motivation to perform cognitive tasks, mood and attention (serial subtractions of 3 and 7, the continuous performance task, and the Bakan dual task) with a 10-minute break between each post-consumption battery. The procedure was repeated with each beverage for each participant at least 48 h apart and ±30 min the same time of day. Data were evaluated using Treatment X Time analysis of covariance controlling for hours of prior night’s sleep. RESULTS: Compared to placebo, cocoa reduced overall false alarm errors progressively across time with 0.92, 1.44 and 2.35 fewer false alarms on average 22–48, 60–86 and 98–124 min post-consumption (η 2 = 0.08, p = 0.019). Caffeinated cocoa: (i) attenuated the anxiety-provoking effects of cognitive testing found after drinking caffeine alone (η 2 = 0.064, p = 0.038), and (ii) increased accuracy (η 2 = 0.085, p = 0.01) and reduced omission errors (η 2 = 0.077, p = 0.016) on the Bakan primary task compared to cocoa alone. CONCLUSIONS: Brewed cocoa can acutely reduce errors associated with attention in the absence of changes in either perceived motivation to perform cognitive tasks or feelings of energy and fatigue. Supplemental caffeine in brewed cocoa can enhance aspects of attention while brewed cocoa can attenuate the anxiety-provoking effects found from drinking caffeine alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01651793. Registered July 25, 2012

Reconceptualizing the measurement of expectations to better understand placebo and nocebo effects in psychological responses to exercise

The understanding of placebo and nocebo effects in psychological responses to exercise may be improved by measuring expectations. Despite availability of several validated expectation measures, we argue for using scales that take both positive and negative expectations for exercise-induced changes into account. A cross-sectional survey was used to collect information on positive and negative expectations pertaining to how exercise would affect 14 different outcomes related to psychological health (n = 966). Outcomes for which a majority of the sample (>50%) reported positive expectations for exercise-induced changes included: psychological well-being (75.3%), depression (74.3%), relaxation (74.2%), sleep quality (73.3%), stress (72.2%), anxiety (69.8%), energy (67.1%), and attention (60.2%). Outcomes for which a majority of the sample (>50%) reported a negative expectation for exercise-induced changes were muscle pain (66.3%), fatigue (57.3%), and joint pain (50.7%). Across all 14 outcomes, the percentage of participants with negative expectations for exercise-induced changes ranged from 5.9 to 66.3%. Elucidating the potential presence of placebo and nocebo effects through measurement of expectations may improve the understanding of variability in the direction and magnitude of exercise-related effects on psychological health. Although there were only 3 outcomes for which the majority of participants reported negative expectations, we found that negative expectations were present to some degree for all 14 outcomes. Thus, for researchers who wish to characterize expectations in studies of psychological responses to exercise, we recommend using measures that give equal consideration to positive and negative expectations

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

BackgroundExertional 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 methodsDeployed (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).ResultsSignificant 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.ConclusionRelative 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

Exercise-induced changes in gene expression do not mediate post exertional malaise in Gulf War illness

Background: Post-exertional malaise (PEM) is considered a characteristic feature of chronic multi-symptom illnesses (CMI) like Gulf War illness (GWI); however, its pathophysiology remains understudied. Previous investigations in other CMI populations (i.e., Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) have reported associations between PEM and expression of genes coding for adrenergic, metabolic, and immune function. Objectives: To investigate whether PEM is meditated by gene expression in Veterans with GWI. Methods: Veterans with GWI (n = 37) and healthy control Gulf War Veterans (n = 25) provided blood samples before and after 30-min of cycling at 70% of age-predicted heart rate reserve. Relative quantification of gene expression, symptom measurements, and select cardiopulmonary parameters were compared between groups at pre-, 30 minpost-, and 24 hpost-exercise using a doubly multivariate repeated measures analysis of variance (RM-MANOVA). Mediation analyses were used to test indirect effects of changes in gene expression on symptom responses (i.e., PEM) to the standardized exercise challenge. Results: Veterans with GWI experienced large symptom exacerbations following exercise compared to controls (Cohen's d: 1.65; p < 0.05). Expression of β-actin (ACTB), catechol-O-methyltransferase (COMT), and toll-like receptor 4 (TLR4) decreased in Veterans with GWI at 30 min (p < 0.05) and 24 h post-exercise (p < 0.05). Changes in gene expression did not mediate post-exercise symptom exacerbation in GWI (Indirect Effect Slope Coefficient: 0.06 – 0.02; 95% CI: 0.19, 0.12). Conclusion: An acute bout of moderate intensity cycling reduced the expression of select structural, adrenergic, and immune genes in Veterans with GWI, but the pathophysiological relevance to PEM is unclear

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

A Common Language for Gulf War Illness (GWI) Research Studies: GWI Common Data Elements

AIMS: The Gulf War Illness programs (GWI) of the United States Department of Veteran Affairs and the Department of Defense Congressionally Directed Medical Research Program collaborated with experts to develop Common Data Elements (CDEs) to standardize and systematically collect, analyze, and share data across the (GWI) research community. MAIN METHODS: A collective working group of GWI advocates, Veterans, clinicians, and researchers convened to provide consensus on instruments, case report forms, and guidelines for GWI research. A similar initiative, supported by the National Institute of Neurologic Disorders and Stroke (NINDS) was completed for a comparative illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and provided the foundation for this undertaking. The GWI working group divided into two sub-groups (symptoms and systems assessment). Both groups reviewed the applicability of instruments and forms recommended by the NINDS ME/CFS CDE to GWI research within specific domains and selected assessments of deployment exposures. The GWI CDE recommendations were finalized in March 2018 after soliciting public comments. KEY FINDINGS: GWI CDE recommendations are organized in 12 domains that include instruments, case report forms, and guidelines. Recommendations were categorized as core (essential), supplemental-highly recommended (essential for specified conditions, study types, or designs), supplemental (commonly collected, but not required), and exploratory (reasonable to use, but require further validation). Recommendations will continually be updated as GWI research progresses. SIGNIFICANCE: The GWI CDEs reflect the consensus recommendations of GWI research community stakeholders and will allow studies to standardize data collection, enhance data quality, and facilitate data sharing