Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome.

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.

The Effects of Interrupting Sitting Time on Affect and State Anxiety in Children of Healthy Weight and Overweight: A Randomized Crossover Trial.

PURPOSE: Sedentary time relates to higher anxiety and more negative affect in children. This study assessed whether interrupting sitting over 3 hours is sufficient to influence state anxiety, positive affect, or negative affect, and tested weight status as a moderator. METHODS: Analyses were the second (preplanned) purpose of a larger study. Children (N = 61; age: mean [SD] = 9.5 [1.3]; 43% healthy weight) completed 2 experimental conditions: continuous sitting for 3 hours and sitting for 3 hours interrupted with walking for 3 minutes in every 30 minutes. State anxiety, positive affect, and negative affect were reported at pretest and posttest. Multilevel models for repeated measures assessed whether experimental condition predicted posttest scores. RESULTS: Experimental condition was unrelated to posttest state anxiety or positive affect. Weight status moderated how experimental condition influenced posttest negative affect (P = .003). Negative affect was lower in the children of healthy weight after interrupted sitting (vs continuous sitting; ß = -0.8; 95% confidence interval, -1.5 to 0.0, P = .05), but it was higher in the children with overweight/obesity after interrupted sitting (vs continuous sitting; ß = 0.6; 95% confidence interval, 0.0 to 1.2, P = .06). CONCLUSIONS: Interrupting sitting acutely reduced negative affect in children of healthy weight, but not in children with overweight. Further research is needed to better understand the potential emotional benefits of sitting interruptions in youth.

Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies.

OBJECTIVE: To investigate the efficacy of N-acetylcysteine (NAC) for decreasing elevated oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (RYR1-RM). METHODS: In this 6-month natural history assessment (n = 37) followed by a randomized, double-blinded, placebo-controlled trial, 33 eligible participants were block-randomized (1:1) to receive NAC (n = 16) or placebo (n = 17), orally for 6 months (adult dose 2,700 mg/d; pediatric dose 30 mg/kg/d). The primary endpoint was urine 15-F2t isoprostane concentration and the clinically meaningful co-primary endpoint was 6-minute walk test (6MWT) distance. RESULTS: When compared to the general population, participants had elevated baseline 15-F2t isoprostane concentrations and most had a decreased 6MWT distance (mean ± SD 3.2 ± 1.5 vs 1.1 ± 1.7 ng/mg creatinine and 468 ± 134 vs 600 ± 58 m, respectively, both p < 0.001). 15-F2t isoprostane concentration and 6MWT distance did not change over the 6-month natural history assessment (p = 0.98 and p = 0.61, respectively). NAC treatment did not improve 15-F2t isoprostane concentration (least squares means difference 0.1 [95% confidence interval [CI] -1.4 to 1.6] ng/mg creatinine, p = 0.88) or 6MWT distance (least squares means difference 24 [95% CI -5.5 to 53.4] m, p = 0.11). NAC was safe and well-tolerated at the doses administered in this study. CONCLUSION: In ambulatory RYR1-RM-affected individuals, we observed stable disease course, and corroborated preclinical reports of elevated oxidative stress and decreased physical endurance. NAC treatment did not decrease elevated oxidative stress, as measured by 15-F2t isoprostane. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for people with RYR1-RM, treatment with oral NAC does not decrease oxidative stress as measured by 15-F2t isoprostane. CLINICALTRIALSGOV IDENTIFIER: NCT02362425.

Insulin Sensitivity, Depression/Anxiety, and Physical Fitness in At-Risk Adolescents.

Poor physical fitness contributes to the early progression of cardiometabolic disease, yet the physiological and psychological factors underpinning poor fitness in at-risk adolescents are not well understood. In this study, we sought to determine the relationship of physical fitness with two developmental phenomena of adolescence, insulin resistance and depression/anxiety symptoms among at-risk youth. We conducted secondary data analyses of 241 overweight or obese adolescents (12-17 years), drawn from two study cohorts. Insulin sensitivity index was derived from oral glucose tolerance tests. Adolescents self-reported depressive symptoms and anxiety symptoms on validated surveys. A walk/run test was administered to determine perceived exertion and physical fitness (distance traveled). Insulin sensitivity was positively associated with walk/run distance ( b =0.16, P< 0.01), even after accounting for all covariates. Anxiety symptoms were inversely related to perceived exertion ( b =-0.11, P< 0.05), adjusting for covariates. These findings suggest that insulin resistance and anxiety symptoms are associated with different dimensions of physical fitness in overweight or obese adolescents and could both potentially contribute to declining fitness and worsening metabolic outcomes in at-risk youth.

Reliability and Validity of Self-Report Questionnaires as Indicators of Fatigue in RYR1-Related Disorders.

BACKGROUND: RYR1-related disorders (RYR1-RD), are a spectrum of genetic neuromuscular disorders. Affected individuals frequently experience fatigue yet appropriate tools to assess RYR1-RD-associated fatigue remain underdeveloped. OBJECTIVE: This study assessed the reliability and validity of two self-report questionnaires, the multidimensional fatigue inventory (MFI-20) and adult/pediatric functional assessment of chronic illness-fatigue (FACIT-F/Peds-FACIT-F) as potential fatigue measures in RYR1-RD affected individuals. METHODS: Participants (n = 37) were enrolled in an RYR1-RD combined natural history study and clinical trial. At baseline, participants completed fatigue questionnaires, six-minute walk test (6MWT), cardiopulmonary exercise test (CPET) and saliva collection for fatigue biomarker index (FBI) quantification. RESULTS: All questionnaires exhibited good test-retest reliability (n = 18, ICC > 0.80). MFI-20 (n = 37), and FACIT-F (n = 28) also showed good internal consistency (Cronbach's α> 0.80). All MFI-20 subscales, except mental fatigue, and FACIT-F demonstrated evidence of criterion validity when correlated against percent predicted 6MWT distance (MFI-20 n = 37; r = -0.34 to -0.47, all p < 0.05, mental fatigue, r = -0.16, p = 0.35; FACIT-F n = 28, r = 0.41, p = 0.03). This was not the case for percent predicted VO2 peak (all p > 0.05). FBI correlated with MFI-20 general fatigue dimension only (r = -0.35, p = 0.03). Comparison of standardized questionnaire scores revealed that RYR1-RD affected individuals experience significantly greater fatigue than the general population. CONCLUSIONS: MFI-20 and FACIT-F are valid and reliable tools for assessing RYR1-RD-associated fatigue, a symptom centrally implicated in this rare disorder.

Oxygen uptake on-kinetics before and after aerobic exercise training in individuals with traumatic brain injury.

Objective: The high prevalence of fatigue among persons with traumatic brain injury (TBI) may be related to poor cardiorespiratory fitness observed in this population. Oxygen uptake on-kinetics is a method of assessing cardiorespiratory fitness and may be used to examine performance fatigability (decline in performance during a given activity) in persons with TBI.Purpose: To examine the effect of aerobic exercise training on oxygen uptake on-kinetics during treadmill walking in individuals with TBI.Methods: Seven ambulatory adults with chronic non-penetrating TBI performed short moderate-intensity (3-6 metabolic equivalents) walking bouts on a treadmill, prior to and following an aerobic exercise training program (clinicaltrials.gov: NCT01294332). The 12-week training program consisted of vigorous-intensity exercise on a treadmill for 30 min, 3 times a week. Breath-by-breath pulmonary gas exchange was measured throughout the bouts, and oxygen uptake on-kinetics described the time taken to achieve a steady-state response.Results: Faster oxygen uptake on-kinetics was observed after exercise training, for both the absolute and relative intensity as pre-training.Conclusions: Faster oxygen uptake on-kinetics following aerobic exercise training suggests an attenuated decline in physical performance during a standardized walking bout and improved performance fatigability in these individuals with TBI.Implications for rehabilitationSevere fatigue is a common complaint among persons with traumatic brain injury (TBI).Oxygen uptake on-kinetics may be used as an objective physiological measure of performance fatigability in persons with TBI.Faster oxygen uptake on-kinetics following aerobic exercise training suggests improved performance fatigability in these individuals with TBI.Aerobic exercise training appeared beneficial for reducing performance fatigability and may be considered as part of the rehabilitative strategy for those living with TBI.

Effects of Interrupting Sedentary Behavior With Short Bouts of Moderate Physical Activity on Glucose Tolerance in Children With Overweight and Obesity: A Randomized Crossover Trial.

OBJECTIVE: Sedentary children have greater risk of developing abnormalities in glucose homeostasis. We investigated whether interrupting sedentary behavior (sitting) with very short periods of walking would improve glucose metabolism without affecting dietary intake in children with overweight or obesity. We hypothesized that interrupting sitting with short bouts of moderate-intensity walking would decrease insulin area under the curve (AUC) during an oral glucose tolerance test (OGTT) compared with uninterrupted sitting. RESEARCH DESIGN AND METHODS: Overweight/obese (BMI ≥85th percentile) children 7-11 years of age underwent two experimental conditions in random order: prolonged sitting (3 h of continuous sitting) and interrupted sitting (3 min of moderate-intensity walking at 80% of ventilatory threshold every 30 min for 3 h). Insulin, C-peptide, and glucose were measured every 30 min for 3 h during an OGTT. Each session was followed by a buffet meal. Primary outcomes were differences in OGTT hormones and substrates and in buffet meal intake by condition. RESULTS: Among 35 children with complete data, mixed-model results identified lower insulin and C-peptide in the interrupted condition (P = 0.007 and P = 0.029, respectively); the intervention reduced insulin AUC by 21% (P < 0.001) and C-peptide AUC 18% (P = 0.001) and improved estimated insulin sensitivity (P = 0.013). Neither buffet total energy intake (1,262 ± 480 vs. 1,260 ± 475 kcal; P = 0.89) nor macronutrient composition of the meal (P values >0.38) differed between conditions significantly. CONCLUSIONS: Interrupting sitting with brief moderate-intensity walking improved glucose metabolism without significantly increasing energy intake in children with overweight or obesity. Interrupting sedentary behavior may be a promising intervention strategy for reducing metabolic risk in such children.

The Subclinical Cardiomyopathy of Friedreich's Ataxia in a Pediatric Population.

BACKGROUND: Identification of a subclinical cardiomyopathy in pediatric patients with Friedreich's ataxia (FA) has not been well-described. METHODS: We performed echocardiography (Echo), cardiac magnetic resonance imaging (cMRI), and neurologic assessment in a cross-sectional analysis of 48 genetically confirmed FA subjects aged 9-17 years with moderate neurologic impairment but without a cardiovascular history. Echo- and cMRI-determined left ventricular mass were indexed (LVMI) to height in grams/m2.7. LV remodeling was categorized as concentric remodeling (CR), concentric hypertrophy (CH), or eccentric hypertrophy based upon Echo- determined relative LV wall thickness. RESULTS: Echo LVMI exceeded age-based normal values in 85% of subjects, and cMRI-determined LVMI correlated with depression of both diastolic and systolic tissue Doppler velocity (E': r = -0.65, P < .001, S': r = -0.46, P < .001) as well as increased early diastolic Doppler flow velocity/tissue velocity ratio (r= 0.55, P < .001), a marker of elevated LV filling pressure. Similar associations were found with echo-determined LV mass. Evidence of depressed LV relaxation and increased LV stiffness were observed in 88% and 71%, of subjects, respectively, despite a normal LV ejection fraction in almost all cases (mean = 60% + 7%). CR and CH were present in 40% and 44% of the study group, respectively, although significant depressions of E' and S' were observed only in subjects with CH (P < .005). CONCLUSIONS: A subclinical hypertrophic cardiomyopathy is common in pediatric FA patients and CH is associated with both diastolic and systolic dysfunction.

A randomized controlled trial of exercise in spinal and bulbar muscular atrophy.

OBJECTIVE: To determine the safety and efficacy of a home-based functional exercise program in spinal and bulbar muscular atrophy (SBMA). METHODS: Subjects were randomly assigned to participate in 12 weeks of either functional exercises (intervention) or a stretching program (control) at the National Institutes of Health in Bethesda, MD. A total of 54 subjects enrolled, and 50 completed the study with 24 in the functional exercise group and 26 in the stretching control group. The primary outcome measure was the Adult Myopathy Assessment Tool (AMAT) total score, and secondary measures included total activity by accelerometry, muscle strength, balance, timed up and go, sit-to-stand test, health-related quality of life, creatine kinase, and insulin-like growth factor-1. RESULTS: Functional exercise was well tolerated but did not lead to significant group differences in the primary outcome measure or any of the secondary measures. The functional exercise did not produce significantly more adverse events than stretching, and was not perceived to be difficult. To determine whether a subset of the subjects may have benefited, we divided them into high and low functioning based on baseline AMAT scores and performed a post hoc subgroup analysis. Low-functioning individuals receiving the intervention increased AMAT functional subscale scores compared to the control group. INTERPRETATION: Although these trial results indicate that functional exercise had no significant effect on total AMAT scores or on mobility, strength, balance, and quality of life, post hoc findings indicate that low-functioning men with SBMA may respond better to functional exercises, and this warrants further investigation with appropriate exercise intensity.

Effects of Interrupting Children's Sedentary Behaviors With Activity on Metabolic Function: A Randomized Trial.

CONTEXT: Limited data suggest that interrupting sedentary behaviors with activity improves metabolic parameters in adults. OBJECTIVE: We tested whether interrupting sitting with short, moderate-intensity walking bouts improved glucose tolerance in children. DESIGN: Participants underwent two experimental conditions in random order on different days: continuous sitting for 3 hours or sitting interrupted by walking (3 min of moderate-intensity walking every 30 min). Insulin, C-peptide, glucose, and free fatty acids were measured every 30 minutes for 3 hours during an oral glucose tolerance test. Area under the curve (AUC) was calculated from hormone and substrate measurements. Children were given a buffet meal after each condition. SETTING: The study was conducted at the National Institutes of Health Hatfield Clinical Research Center. PARTICIPANTS: Twenty-eight normal-weight 7-11 year olds participated. MAIN OUTCOMES: Patterns of substrate/hormone secretion and AUC, as well as energy intake, were examined by experimental condition. RESULTS: Interrupting sitting resulted in a 32% lower insulin AUC (P < .001), 17% lower C-peptide AUC (P < .001), and 7% lower glucose AUC (P = .018) vs continuous sitting. Mixed model results indicated that insulin (P = .036) and free fatty acid concentrations (P = .009) were significantly lower in the interrupted vs the continuous sitting condition. Lunchtime buffet meal energy intake did not significantly differ between the conditions (975 ± 387 vs 963 ± 309 kcal; P = .85). CONCLUSIONS: Interrupting sedentary time with brief moderate-intensity walking improved short-term metabolic function in non-overweight children without increasing subsequent energy intake. These findings suggest that interrupting sedentary behavior may be a promising prevention strategy for reducing cardiometabolic risk in children.

Changes in fatigability following intense aerobic exercise training in patients with interstitial lung disease.

OBJECTIVE: To determine if, in patients with interstitial lung disease (ILD), fatigue might be lessened after vigorous aerobic exercise. METHODS: 13 physically inactive patients (5 men and 8 women; age 57.2 ± 9.1 years, BMI 28.2 ± 4.6 kgm(-2)) with ILD of heterogeneous etiology and able to walk on a motor driven treadmill without physical limitation were enrolled. Subjects underwent cardiopulmonary exercise (CPET) and 6-min walk (6MWT) tests and completed Fatigue Severity Scale and Human Activity Profile questionnaires before and after an aerobic exercise-training regimen. The training regimen required participation in at least 24 of 30 prescribed aerobic exercise training sessions at a target heart rate of 70-80% of the heart rate reserve, 30 min per session, 3 times per week for 10 weeks. RESULTS: After training, a 55% (p < 0.001) increase in time to anaerobic threshold on the CPET, and an 11% (p = 0.045) reduction in performance fatigability index (PFI), calculated from the performance on the 6MWT were observed. Distance walked on the 6MWT (6MWD) increased by 49.7 ± 46.9 m (p = 0.002). Significant improvements in scores on the Fatigue Severity Scale (p = 0.046) and Human Activity Profile (AAS p = 0.024; MAS p = 0.029) were also observed. No adverse events related to the training regimen were noted. CONCLUSION: After training, the decrease in fatigability appeared to result in increased 6MWD and was associated with physical activity. Since significant declines in 6MWD may be a marker for impending mortality in ILD, a better understanding of the etiological state of fatigue in patients with ILD and its reversal might provide fundamental insight into disease progression and even survival. [ClinicalTrials.gov identifier NCT00678821].

Cardiorespiratory function before and after aerobic exercise training in patients with interstitial lung disease.

PURPOSE: To characterize the cardiorespiratory response to exercise before and after aerobic exercise training in patients with interstitial lung disease. METHODS: We performed a clinical study, examining 13 patients (New York Heart Association/World Health Organization Functional class II or III) before and after 10 weeks of supervised treadmill exercise walking, at 70% to 80% of heart rate reserve, 30 to 45 minutes per session, 3 times a week. Outcome variables included measures of cardiorespiratory function during a treadmill cardiopulmonary exercise test, with additional near infrared spectroscopy measurements of peripheral oxygen extraction and bioimpedance cardiography measurements of cardiac output. Six-minute walk test distance was also measured. RESULTS: All subjects participated in at least 24 of their 30 scheduled exercise sessions with no significant adverse events. After training, the mean 6-minute walk test distance increased by 52 ± 48 m (P = .001), peak treadmill cardiopulmonary exercise test time increased by 163 ± 130 s (P = .001), and time to achieve gas exchange threshold increased by 145 ± 37 s (P < .001). Despite a negligible increase in peak (Equation is included in full-text article.)o2 with no changes to cardiac output, the overall work rate/(Equation is included in full-text article.)o2 relationship was enhanced after training. Muscle O2 extraction increased by 16% (P = .049) after training. CONCLUSIONS: Clinically significant improvements in cardiorespiratory function were observed after aerobic exercise training in this group of subjects with interstitial lung disease. These improvements appear to have been mediated by increases in the peripheral extraction of O2 rather than changes in O2 delivery.

Benefits of intensive treadmill exercise training on cardiorespiratory function and quality of life in patients with pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) restricts the ability to engage in physical activity and decreases longevity. We examined the impact of aerobic exercise training on function and quality of life in patients with World Health Organization group 1 PH. METHODS: Patients were randomized to a 10-week education only (EDU) or education/exercise combined (EXE) group. The exercise program consisted of 24-30 sessions of treadmill walking for 30-45 min per session at 70% to 80% of heart rate reserve. Outcome variables included changes in 6-min walk test (6MWT) distance, time to exercise intolerance, peak work rate (WR) from a cardiopulmonary treadmill test, and quality-of-life measures, including the Short Form Health Survey, version 2 (SF-36v2) and Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR). RESULTS: Data are presented as mean SD. Twenty-three women (age, 54 11 years; BMI, 31 7 kg/m 2 ) were randomized to the EDU (n 5 13) or EXE (n 5 10) groups. Following 10 weeks of intervention, patients in the EXE group demonstrated an improvement in 6MWT distance (56 45 m; P 5 .002), increased time to exercise intolerance (1.9 1.3 min; P 5 .001), and peak WR (26 23 W; P 5 .004). Additionally, the EXE group scored significantly ( P , .050) better on six of the eight scales on SF-36v2, and fi ve of the six scales on CAMPHOR. In contrast, no significant improvement was observed for any of the outcome measures following EDU. No adverse events were noted in either group. CONCLUSION: Ten weeks of brisk treadmill walking improved 6MWT distance, cardiorespiratory function, and patient-reported quality of life in female patients with group 1 PH.

Depressive symptoms and cardiorespiratory fitness in obese adolescents.

PURPOSE: Depressive symptoms in adolescents have been associated with reduced physical activity. However, existing studies have relied on questionnaire measures of physical activity, which may not necessarily reflect actual energy expenditures. We sought to evaluate the relationship between depressive symptoms and objectively measured cardiorespiratory fitness among severely obese adolescents. METHODS: One hundred thirty-four obese (body mass index [kg/m(2)]: ≥95th percentile) adolescent girls and boys (ages: 12-17 years) reported their depressive symptoms on the Children's Depression Inventory. Adolescents also participated in a maximal cycle ergometry exercise test to measure cardiorespiratory fitness. Body composition was assessed with dual-energy X-ray absorptiometry scanning. RESULTS: Among the 103 adolescents who reached maximal exertion, those with elevated depressive symptoms (16%) displayed poorer cardiorespiratory fitness than those without elevated depressive symptoms (maximal oxygen uptake: 1,873.2 ± 63.6 vs. 2,012.9 ± 28.6 mL/min, p < .05). Symptoms of anhedonia also were related to lower fitness levels (p < .05). These effects were observed after accounting for age, sex, race, and lean mass. CONCLUSIONS: Among obese adolescents, elevated depressive symptoms are associated with poorer objectively measured cardiorespiratory fitness. Future experimental tests should investigate whether cardiorespiratory fitness acts as a mediator of adolescent depressive symptoms' effect on obesity or obesity-related health comorbidities.

Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus levothyroxine.

CONTEXT: Levothyroxine (L-T(4)) therapy is based on the assumption that the conversion of T(4) into T(3) provides adequate amounts of active hormone at target tissues. However, in rodents, L-T(4) alone does not restore a euthyroid state in all tissues. Previous combination L-T(4)/liothyronine (L-T(3)) therapy trials focused on quality-of-life endpoints, and limited information is available on the effects on other measures of thyroid hormone action. OBJECTIVE: Our objective was to evaluate the efficacy of thyroid hormone replacement with L-T(4) or L-T(3) at doses producing equivalent normalization of TSH. PARTICIPANTS, DESIGN, AND SETTING: Fourteen hypothyroid patients participated in this randomized, double-blind, crossover intervention at the National Institutes of Health Clinical Center. INTERVENTIONS: L-T(3) or L-T(4) were administered thrice daily to achieve a target TSH from 0.5-1.5 mU/liter. Volunteers were studied as inpatients after 6 wk on a stable dose and at the target TSH. MAIN OUTCOME MEASURES: Serum thyroid hormones, lipid parameters, and indices of glucose metabolism were evaluated. RESULTS: No difference was observed in TSH between L-T(3) and L-T(4) treatments. L-T(3) resulted in significant weight loss [L-T(4), 70.6 ± 12.5, vs. L-T(3), 68.5 ± 11.9 kg (P = 0.009)] and in a 10.9 ± 10.0% decrease in total cholesterol (P = 0.002), 13.3 ± 12.1% decrease in low-density lipoprotein-cholesterol (P = 0.002), and an 18.3 ± 28.6% decrease in apolipoprotein B (P = 0.018). No significant differences were observed in high-density lipoprotein-cholesterol, heart rate, blood pressure, exercise tolerance, or insulin sensitivity. CONCLUSIONS: The substitution of L-T(3) for L-T(4) at equivalent doses (relative to the pituitary) reduced body weight and resulted in greater thyroid hormone action on the lipid metabolism, without detected differences in cardiovascular function or insulin sensitivity.

Exercise capacity and idebenone intervention in children and adolescents with Friedreich ataxia.

OBJECTIVE: To determine the exercise capacity of children and adolescents with Friedreich's Ataxia (FA) and to evaluate the effects of 6 months of idebenone treatment on exercise capacity. DESIGN: Exploratory endpoint in a randomized double-blind, placebo-controlled, phase II clinical trial designed to investigate the effects of idebenone on a biomarker of oxidative stress. SETTING: Exercise physiology laboratory in a single clinical research center. PARTICIPANTS: Ambulatory subjects (N=48; age range, 9-17 y) with genetically confirmed FA. INTERVENTION: Idebenone administered orally 3 times a day for a total daily dose of approximately 5, 15, and 45 mg/kg or matching placebo for 6 months. MAIN OUTCOME MEASURES: Peak oxygen consumption per unit time (peak VO(2)) and peak work rate (WR) were measured during incremental exercise testing at baseline and after treatment. Echocardiography and neurologic assessments were also completed before and after treatment. RESULTS: Baseline mean peak VO(2) +/- SD was 746+/-246 mL/min (16.2+/-5.8 mL/kg/min), and WR was 40+/-23 W for all subjects. Peak VO(2) and WR were correlated with short guanine-adenine-adenine allele length and neurologic function. Relative left ventricular wall thickness was increased but left ventricular ejection fraction was normal in most subjects; there was no relationship between any exercise and echocardiographic measures. There were no significant changes in mean peak VO(2) or WR after idebenone treatment at any dose level relative to placebo. CONCLUSIONS: Exercise capacity in children and adolescents with FA was significantly impaired. The basis for the impairment appears to be multifactorial and correlated to the degree of neurologic impairment. Although idebenone has previously been shown potentially to improve features of FA, idebenone treatment did not increase exercise capacity relative to placebo.

Exploratory analysis of the relationships between aerobic capacity and self-reported fatigue in patients with rheumatoid arthritis, polymyositis, and chronic fatigue syndrome.

OBJECTIVE: To determine if self-reported levels of physical activity and fatigue are related to peak oxygen uptake (VO(2peak)) and whether these relationships differ among the patient groups (rheumatoid arthritis [RA], polymyositis [PM], and chronic fatigue syndrome [CFS]). DESIGN: Correlational investigation. SETTING: Two ambulatory research clinics at the National Institutes of Health, Clinical Center, Bethesda, MD. PARTICIPANTS: There were 9 patients with PM, 10 with RA, and 10 with CFS. All patients met case criteria for their respective diagnoses. METHODS/MAIN OUTCOME MEASUREMENTS: VO(2peak) during bicycle ergometry and self-reported fatigability, fatigue, and physical activity. VO(2peak) was used as the criterion measurement of physiological fatigue with which the self-reported variables were compared. RESULTS: The Pearson r revealed that self-reported physical activity correlated with VO(2peak) (r = 61, P = .01). However, fatigability and fatigue did not correlate with VO(2peak). Linear regression analysis was performed to assess the effects of diagnosis group, self-reported activity level or fatigue, and their interaction. A trend in the data showed a distinctive relationship between fatigue/fatigability within the 3 groups. In addition, when controlling for group status, self-reported activity predicted aerobic capacity as measured by VO(2peak). CONCLUSIONS: This study confirms that patients with chronic, but stable RA, PM, or CFS are fatigued and have significantly decreased aerobic capacity. Self-reports of physical activity predicted VO(2peak), and may be used as an indicator of activity-based aerobic capacity. Self-reports of fatigue, however, did not correlate with VO(2peak) and hence are assessing something other than an index of aerobic capacity, and provide additional information about patients' perceptions, which will require further investigation.

Recruitment to a physical activity intervention study in women at increased risk of breast cancer.

BACKGROUND: Physical activity is being studied as a breast cancer prevention strategy. Women at risk of breast cancer report interest in lifestyle modification, but recruitment to randomized physical activity intervention studies is challenging. METHODS: We conducted an analysis of recruitment techniques used for a prospective, randomized pilot study of physical activity in women at risk of breast cancer. We evaluated differences in proportion of eligible patients, enrolled patients, and successful patients identified by each individual recruitment method. The Fisher-Freeman-Halton test (an extension of Fisher's exact test from 2 x 2 tables to general row by column tables) was used to compare the success of different recruitment strategies. RESULTS: We received 352 inquiries from women interested in participating, of whom 171 (54%) were eligible. Ninety-nine women completed a baseline activity evaluation, and 58 (34% of eligible; 16% of total inquiries) were randomized. Recruitment methods fell into three broad categories: media techniques, direct contact with potential participants, and contacts with health care providers. Recruitment strategies differed significantly in their ability to identify eligible women (p = 0.01), and women who subsequently enrolled in the study (p = 0.02). CONCLUSION: Recruitment techniques had varying success. Our data illustrate the challenges in recruiting to behavior modification studies, and provide useful information for tailoring future recruitment efforts for lifestyle intervention trials. TRIAL REGISTRATION NO(S): CDR0000393790, NCI-04-C-0276, NCI-NAVY-B05-001.

Oxygen-uptake efficiency slope as a determinant of fitness in overweight adolescents.

PURPOSE: Peak oxygen uptake (VO2peak) is frequently difficult to assess in overweight individuals; therefore, submaximal measures that predict VO2peak are proposed as substitutes. Oxygen uptake efficiency slope (OUES) has been suggested as a submaximal measurement of cardiorespiratory fitness that is independent of exercise intensity. There are few data examining its value as a predictor of V O2peak in severely overweight adolescents. METHODS: One hundred seven severely overweight (BMI Z 2.50 +/- 0.34) and 43 nonoverweight (BMI Z 0.13 +/- 0.84) adolescents, performed a maximal cycle ergometer test with respiratory gas-exchange measurements. OUES was calculated through three exercise intensities: lactate inflection point (OUES LI), 150% of lactate inflection point (OUES 150), and VO2peak (OUES PEAK). RESULTS: When adjusted for lean body mass, VO2peak and OUES at all exercise intensities were lower in overweight subjects (VO2peak: 35.3 +/- 6.4 vs 46.8 +/- 7.9 mL.kg(-1) LBM.min(-1), P < 0.001; OUES LI: 37.9 +/- 10.0 vs 43.7 +/- 9.2 mL.kg(-1) LBM.min(-1).logL(-1) P < 0.001; OUES 150: 41.6 +/- 9.0 vs 49.8 +/- 11.1 mL.kg(-1) LBM.min(-1).logL(-1) P < 0.001; and OUES PEAK: 45.1 +/- 8.7 vs 52.8 +/- 9.6 mL.kg(-1) LBM.min(-1).logL(-1) P < 0.001). There was a significant increase in OUES with increasing exercise intensity in both groups (P < 0.001). OUES at all exercise intensities was a significant predictor of VO2peak for both groups (r2 = 0.35-0.83, P < 0.0001). However, limits of agreement for predicted VO2peak relative to actual VO2peak were wide (+/- 478 to +/- 670 mL.min(-1)). CONCLUSIONS: OUES differs significantly in overweight and nonoverweight adolescents. The wide interindividual variation and the exercise intensity dependence of OUES preclude its use in clinical practice as a predictor of VO2peak.

Patients with classic congenital adrenal hyperplasia have decreased epinephrine reserve and defective glycemic control during prolonged moderate-intensity exercise.

CONTEXT: Patients with classic congenital adrenal hyperplasia (CAH) have adrenomedullary dysplasia and hypofunction, and their lack of adrenomedullary reserve has been associated with a defective glucose response to brief high-intensity exercise. OBJECTIVE: Our objective was to assess hormonal, metabolic, and cardiovascular response to prolonged moderate-intensity exercise comparable to brisk walking in adolescents with classic CAH. SUBJECTS AND METHODS: We compared six adolescents with classic CAH (16-20 yr old) with seven age-, sex-, and body mass index group-matched controls (16-23 yr old) using a 90-min standardized ergometer test. Metabolic, hormonal, and cardiovascular parameters were studied during exercise and recovery. RESULTS: Glucose did not change throughout exercise and recovery for controls, whereas CAH patients showed a steady decline in glucose during exercise with an increase in glucose in the postexercise period. Glucose levels were significantly lower in CAH patients at 60 (P = 0.04), 75 (P = 0.01), and 90 (P = 0.03) min of exercise and 15 (P = 0.02) min post exercise, whereas glucose levels were comparable between the two groups early in exercise and at 30 min (P = 0.19) post exercise. As compared with controls, CAH patients had significantly lower epinephrine (P = 0.002) and cortisol (P < or = 0.001) levels throughout the study and similar norepinephrine, glucagon, and GH levels. Patients with CAH and controls had comparable cardiovascular parameters and perceived level of exertion. Despite having lower glucose levels, insulin levels were slightly higher in CAH patients during the testing period (P = 0.17), suggesting insulin insensitivity. CONCLUSION: CAH patients have defective glycemic control and altered metabolic and hormonal responses during prolonged moderate-intensity exercise comparable to brisk walking.