Cerebrovascular reactivity and cerebral autoregulation are two major mechanisms that regulate cerebral blood flow. Both mechanisms are typically assessed in either supine or seated postures, but the ...effects of body position and sex differences remain unclear. This study examined the effects of body posture (supine vs. seated vs. standing) on cerebrovascular reactivity during hyper and hypocapnia and on cerebral autoregulation during spontaneous and slow-paced breathing in healthy men and women using transcranial Doppler ultrasonography of the middle cerebral artery. Results indicated significantly improved cerebrovascular reactivity in the supine compared with seated and standing postures (supine = 3.45±0.67, seated = 2.72±0.53, standing = 2.91±0.62%/mmHg, P<0.0167). Similarly, cerebral autoregulatory measures showed significant improvement in the supine posture during slow-paced breathing. Transfer function measures of gain significantly decreased and phase significantly increased in the supine posture compared with seated and standing postures (gain: supine = 1.98±0.56, seated = 2.37±0.53, standing = 2.36±0.71%/mmHg; phase: supine = 59.3±21.7, seated = 39.8±12.5, standing = 36.5±9.7°; all P<0.0167). In contrast, body posture had no effect on cerebral autoregulatory measures during spontaneous breathing. Men and women had similar cerebrovascular reactivity and similar cerebral autoregulation during both spontaneous and slow-paced breathing. These data highlight the importance of making comparisons within the same body position to ensure there is not a confounding effect of posture.
Gulf War Illness (GWI) is a chronic multi-symptom illness not currently diagnosed by standard medical or laboratory test that affects 30% of veterans who served during the 1990-1991 Gulf War. The ...clinical presentation of GWI is comparable to that of patients with certain mitochondrial disorders-i.e., clinically heterogeneous multisystem symptoms. Therefore, we hypothesized that mitochondrial dysfunction may contribute to both the symptoms of GWI as well as its persistence over time. We recruited 21 cases of GWI (CDC and Kansas criteria) and 7 controls to participate in this study. Peripheral blood samples were obtained in all participants and a quantitative polymerase chain reaction (QPCR) based assay was performed to quantify mitochondrial and nuclear DNA lesion frequency and mitochondrial DNA (mtDNA) copy number (mtDNAcn) from peripheral blood mononuclear cells. Samples were also used to analyze nuclear DNA lesion frequency and enzyme activity for mitochondrial complexes I and IV. Both mtDNA lesion frequency (p = 0.015, d = 1.13) and mtDNAcn (p = 0.001; d = 1.69) were elevated in veterans with GWI relative to controls. Nuclear DNA lesion frequency was also elevated in veterans with GWI (p = 0.344; d = 1.41), but did not reach statistical significance. Complex I and IV activity (p > 0.05) were similar between groups and greater mtDNA lesion frequency was associated with reduced complex I (r2 = -0.35, p = 0.007) and IV (r2 = -0.28, p < 0.01) enzyme activity. In conclusion, veterans with GWI exhibit greater mtDNA damage which is consistent with mitochondrial dysfunction.
Abstract Limb movements involving contraction times of 50–200 ms occur in many everyday activities, such as gait, which is faster than the time required to generate maximal force. Therefore, the ...ability to rapidly produce force may be even more important for the performance of functional activities. In this study rate of force development (RFD) and impulse of the knee extensors were examined in 12 ambulatory children with cerebral palsy (CP) (age: 11.9 ± 2.9 years) and 11 with typical development (TD) (Age: 11.3 ± 3.0 years). The relationship with muscle architecture and functional mobility was also determined. RFD and impulse were calculated during a maximal isometric knee extension contraction. Rectus femoris (RF) cross-sectional area and RF and vastus lateralis (VL) muscle thickness (MT), fascicle length (FL), and fascicle angle (FA) were measured using ultrasound imaging. Gait temporal–spatial parameters, Pediatric Outcomes Data Collection Instrument (PODCI), and Activities Scale for Kids performance version (ASKp) were collected. Although VL MT was the primary determinant of RFD and impulse in CP, FA and FL were also significant predictors in the TD group. RFD and impulse were significantly lower in CP compared to TD (70% decrease) in addition to maximal strength (50% decrease). RFD and impulse were predictive of measures of functional mobility, including gait, transfers, and sports and higher level activities but not temporal–spatial gait measures. Results suggest that the ability to rapidly generate torque may be of greater importance than maximal strength during certain tasks, such as transfers and sports and higher level activities.
Cardiopulmonary exercise testing has demonstrated clinical utility in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, to what extent exercise responses are independent of, or ...confounded by, aerobic fitness remains unclear.
To characterize and compare exercise responses in ME/CFS and controls with and without matching for aerobic fitness.
As part of the Multi-site Clinical Assessment of ME/CFS (MCAM) study, 403 participants (n = 214 ME/CFS; n = 189 controls), across six ME/CFS clinics, completed ramped cycle ergometry to volitional exhaustion. Metabolic, heart rate (HR), and ratings of perceived exertion (RPE) were measured. Ventilatory equivalent (Formula: see text, Formula: see text), metrics of ventilatory efficiency, and chronotropic incompetence (CI) were calculated. Exercise variables were compared using Hedges' g effect size with 95% confidence intervals. Differences in cardiopulmonary and perceptual features during exercise were analyzed using linear mixed effects models with repeated measures for relative exercise intensity (20-100% peak Formula: see text). Subgroup analyses were conducted for 198 participants (99 ME/CFS; 99 controls) matched for age (±5 years) and peak Formula: see text (~1 ml/kg/min-1).
Ninety percent of tests (n = 194 ME/CFS, n = 169 controls) met standard criteria for peak effort. ME/CFS responses during exercise (20-100% peak Formula: see text) were significantly lower for ventilation, breathing frequency, HR, measures of efficiency, and CI and significantly higher for Formula: see text, Formula: see text and RPE (p<0.05adjusted). For the fitness-matched subgroup, differences remained for breathing frequency, Formula: see text, Formula: see text, and RPE (p<0.05adjusted), and higher tidal volumes were identified for ME/CFS (p<0.05adjusted). Exercise responses at the gas exchange threshold, peak, and for measures of ventilatory efficiency (e.g., Formula: see text) were generally reflective of those seen throughout exercise (i.e., 20-100%).
Compared to fitness-matched controls, cardiopulmonary responses to exercise in ME/CFS are characterized by inefficient exercise ventilation and augmented perception of effort. These data highlight the importance of distinguishing confounding fitness effects to identify responses that may be more specifically associated with ME/CFS.
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.
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.
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).
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.
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.
Abstract
Alternative methods have been proposed to report spirometry indices from test sessions (forced expiratory volume 1 s, FEV
1
; forced vital capacity, FVC). However, most use the American and ...European Societies’ standard (ATS/ERS) which stops sessions once a repeatability threshold is met which may not accurately represent intra-session variability. Our goal was to repeat trials beyond the repeatability threshold and evaluate alternative reporting methods. 130 adults performed spirometry across two visits. Spirometry indices were reported using the ATS/ERS standard and four alternatives. 78 participants (60%) had valid data for all methods and visits. Intra-session coefficients of variation were low (FEV
1
: 3.1–3.7%; FVC: 2.3–2.8%). Our four alternative methods yielded FEV
1
and FVC values ≤ 0.08 L different from ATS/ERS standard, which is not clinically meaningful. Intraclass correlation coefficients were ≥ 0.97 indicating consistency across repeated measures. The smallest real differences ranged from FEV
1
: 0.20–0.27 L and FVC: 0.18–0.24 L indicating consistency and low measurement error. Overall, all methods for reporting FEV
1
and FVC demonstrated similar measurement error, precision, and stability within- and between-visits. These results suggest that once ATS/ERS repeatability is achieved, which approach is used for reporting spirometric variables may be of low clinical significance in a healthy population.
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.
Abstract
Forced oscillation technique (FOT) provides unique information on respiratory system mechanical properties complementing pulmonary function testing. However, a lack of evidence guiding ...acquisition/reporting of parameters has slowed clinical FOT adoption. Current European Respiratory Society (ERS) standards recommend 3–5 trials per session comprising three trials with a coefficient of variation (CoV) ≤ 10% for low-frequency resistance. We present an analysis of different combinations of trial selection methods and session validity thresholding variables (low- and mid-frequency resistance and reactance R5, R19, X5, low-frequency reactance area AX and tidal volume) comparing proportion of subjects achieving valid data across two test sessions (7 ± 3 days apart) and within and between session measurement variabilities. 126 (98%) subjects achieved valid data across both sessions (2666 trials). With R5 or R19 as criteria and selection of any three trials from ≥ 4 attempts, ≥ 75% of subjects achieved validity. Furthermore, with R5 or R19 criteria and selection of any trials from ≥ 5 attempts, CoVs for resistance outcomes were reduced within session while variabilities of FOT outcomes between sessions remained consistent. Within session differences in measurement variabilities were not clinically meaningful. Our analyses support current ERS reporting recommendations for healthy adults. Future work should apply this analytic approach to patient populations.
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