Webb A. Smith

Physiologic Frailty As a Sign of Accelerated Aging Among Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study

PURPOSE Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the prevalence of frailty and examined associations with morbidity and mortality. METHODS Participants included 1,922 CCS at least 10 years from original cancer diagnosis (men, 50.3%; mean age, 33.6 ± 8.1 years) and a comparison population of 341 participants without cancer histories. Prefrailty and frailty were defined as two and ≥ three of the following conditions: low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Morbidity was defined as grade 3 to 4 chronic conditions (Common Terminology Criteria for Adverse Events version 4.0). Fishers exact tests were used to compare, by frailty status, percentages of those with morbidity. In a subset of 162 CCS who returned for a second visit, Poisson regression was used to evaluate associations between frailty and new onset morbidity. Cox proportional hazards regression was used to evaluate associations between frailty and death. RESULTS The prevalence of prefrailty and frailty were 31.5% and 13.1% among women and 12.9% and 2.7% among men, respectively, with prevalence increasing with age. Frail CCS were more likely than nonfrail survivors to have a chronic condition (82.1% v 73.8%). In models adjusted for existing chronic conditions, baseline frailty was associated with risk of death (hazard ratio, 2.6; 95% CI, 1.2 to 6.2) and chronic condition onset (relative risk, 2.2; 95% CI, 1.2 to 4.2). CONCLUSION The prevalence of frailty among young adult CCS is similar to that among adults 65 years old and older, suggesting accelerated aging.

Lifestyle and metabolic syndrome in adult survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study.

Childhood cancer survivors (CCS) are at an increased risk of developing metabolic syndrome (MetSyn), which may be reduced with lifestyle modifications. The purpose of this investigation was to characterize lifestyle habits and associations with MetSyn among CCS.

Prior exercise and antioxidant supplementation: effect on oxidative stress and muscle injury

BackgroundBoth acute bouts of prior exercise (preconditioning) and antioxidant nutrients have been used in an attempt to attenuate muscle injury or oxidative stress in response to resistance exercise. However, most studies have focused on untrained participants rather than on athletes. The purpose of this work was to determine the independent and combined effects of antioxidant supplementation (vitamin C + mixed tocopherols/tocotrienols) and prior eccentric exercise in attenuating markers of skeletal muscle injury and oxidative stress in resistance trained men.MethodsThirty-six men were randomly assigned to: no prior exercise + placebo; no prior exercise + antioxidant; prior exercise + placebo; prior exercise + antioxidant. Markers of muscle/cell injury (muscle performance, muscle soreness, C-reactive protein, and creatine kinase activity), as well as oxidative stress (blood protein carbonyls and peroxides), were measured before and through 48 hours of exercise recovery.ResultsNo group by time interactions were noted for any variable (P > 0.05). Time main effects were noted for creatine kinase activity, muscle soreness, maximal isometric force and peak velocity (P < 0.0001). Protein carbonyls and peroxides were relatively unaffected by exercise.ConclusionThere appears to be no independent or combined effect of a prior bout of eccentric exercise or antioxidant supplementation as used here on markers of muscle injury in resistance trained men. Moreover, eccentric exercise as used in the present study results in minimal blood oxidative stress in resistance trained men. Hence, antioxidant supplementation for the purpose of minimizing blood oxidative stress in relation to eccentric exercise appears unnecessary in this population.

Chemotherapy-related neuropathic symptoms and functional impairment in adult survivors of extracranial solid tumors of childhood: results from the St. Jude Lifetime Cohort Study.

OBJECTIVES To ascertain prevalence of peripheral sensory and motor neuropathy, and to evaluate impairments in relation to function. DESIGN St. Jude Lifetime Cohort Study, a clinical follow-up study designed to evaluate adverse late effects in adult survivors of childhood cancer. SETTING A childrens research hospital. PARTICIPANTS Eligibility required treatment for an extracranial solid malignancy between 1962 and 2002, age ≥ 18 years, ≥ 10 years postdiagnosis, and no history of cranial radiation. Survivors (N=531) were included in the evaluation with a median age of 32 years and a median time from diagnosis of 25 years. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Primary exposure measures were cumulative doses of vinca-alkaloid and platinum-based chemotherapies. Survivors with scores ≥ 1 on the sensory subscale of the Modified Total Neuropathy Score were classified with prevalent sensory impairment. Those with sex-specific z scores of ≤-1.3 for dorsiflexion strength were classified with prevalent motor impairment. Participants completed the 6-minute walk test (endurance), the Timed Up & Go test (mobility), and the Sensory Organization Test (balance). RESULTS The prevalence of sensory and motor impairment was 20% and 17.5%, respectively. Vinca-alkaloid exposure was associated with an increased risk of motor impairment (adjusted odds ratio [OR]=1.66; 95% confidence interval [CI], 1.04-2.64) without evidence for a dose response. Platinum exposure was associated with increased risk of sensory impairment (adjusted OR=1.62; 95% CI, .97-2.72) without evidence of a dose response. Sensory impairment was associated with poor endurance (OR=1.99; 95% CI, .99-4.0) and mobility (OR=1.65; 95% CI, .96-2.83). CONCLUSIONS Vincristine and cisplatin exposure may increase risk for long-term motor and sensory impairment, respectively. Survivors with sensory impairment are at increased risk for functional performance limitations.

Oxidative stress in response to aerobic and anaerobic power testing: influence of exercise training and carnitine supplementation.

The purpose of this study is to compare the oxidative stress response to aerobic and anaerobic power testing, and to determine the impact of exercise training with or without glycine propionyl-L-carnitine (GPLC) in attenuating the oxidative stress response. Thirty-two subjects were assigned (double blind) to placebo, GPLC-1 (1g PLC/d), GPLC-3 (3g PLC/d) for 8 weeks, plus aerobic exercise. Aerobic (graded exercise test: GXT) and anaerobic (Wingate cycle) power tests were performed before and following the intervention. Blood was taken before and immediately following exercise tests and analyzed for malondialdehyde (MDA), hydrogen peroxide (H2O2), and xanthine oxidase activity (XO). No interaction effects were noted. MDA was minimally effected by exercise but lower at rest for both GPLC groups following the intervention (p = 0.044). A time main effect was noted for H2O2 (p = 0.05) and XO (p = 0.003), with values increasing from pre- to postexercise. Both aerobic and anaerobic power testing increase oxidative stress to a similar extent. Exercise training plus GPLC can decrease resting MDA, but it has little impact on exercise-induced oxidative stress biomarkers.

Repeated bout effect is absent in resistance trained men: An electromyographic analysis

A prior bout of exercise is well known to confer protection from subsequent eccentric bouts (i.e. repeated bout effect; RBE), which may be fostered through neural adaptations, specifically a shift in the frequency content of the surface electromyogram (EMG). It is currently not clear whether chronically resistance trained men are capable of a RBE driven by neural adaptations. Eleven resistance trained men (23.5+/-3.4 yrs) performed 100 eccentric actions of the barbell bench press exercise, followed by an equivalent bout 14 days later. Indirect markers of muscle damage (i.e. force production, soreness) along with surface EMG were measured before and through 48 h of recovery. Median frequency and maximal isometric force demonstrated time main effects (p>0.05), but no RBE. A prior bout of eccentric exercise does not confer a RBE for indirect markers of muscle injury or elicit changes in the frequency content of the EMG signal in resistance trained men.

Postprandial oxidative stress is exacerbated in cigarette smokers

Both cigarette smoking and high fat meals induce oxidative stress, which is associated with the pathogenesis of numerous diseases. We compared blood antioxidant status, oxidative stress biomarkers and TAG in twenty smokers and twenty non-smokers, matched for age and physical activity, in response to a high fat test meal standardized to body mass. Blood samples were collected before feeding (resting and fasted) and at 1, 2, 4 and 6 h post feeding and analysed for antioxidant capacity (trolox equivalent antioxidant capacity; TEAC), xanthine oxidase activity (XO), hydrogen peroxide (H2O2), malondialdehyde (MDA) and TAG. Smoking status (P < 0.001) and time (P < or = 0.01) effects were noted for all variables, with smokers demonstrating higher values compared with non-smokers for all variables except for TEAC, for which values were lower for smokers. XO, H2O2, MDA and TAG increased following feeding with a peak response at the 4 h post feeding time point, with the opposite response occurring for TEAC. Although no interaction effects were noted (P>0.05), contrasts revealed greater values in smokers compared with non-smokers for XO, H2O2, MDA and TAG, and lower values for TEAC at times from 1-6 h post feeding (P < or = 0.05). Our findings indicate that young cigarette smokers experience an exaggerated oxidative stress response to feeding, as well as hypertriacylglycerolaemia, as compared with non-smokers. These data provide insight into another possible mechanism associating cigarette smoking with ill health and disease.

Physical Work-Induced Oxidative Stress is Exacerbated in Young Cigarette Smokers

Both cigarette smoking and strenuous physical work are associated with increased oxidative stress, which is implicated in the pathogenesis of cardiovascular disease. No study to date has measured oxidative stress in response to graded exercise in cigarette smokers. We compared oxidative stress biomarkers before and after strenuous exercise (Bruce treadmill protocol) in 14 cigarette smokers and 15 nonsmokers of similar age (24+/-6 years) and fitness status. Plasma protein carbonyls (PC), malondialdehyde (MDA), and 8-hydroxydeoxyguanosine (8-OHdG) were measured pre- and postexercise. Smoking status (p<.01) and time (p<.01) effects were noted for PC with values higher for smokers than nonsmokers and increasing from pre- to postexercise (52% vs. 25%, respectively). The smoking statusxtime interaction for PC approached statistical significance (p=.07). The change in PC from pre- to postexercise was positively correlated with the number of cigarettes smoked per day (r=.5782, p=.03). A smoking statusxtime interaction was noted for MDA (p<.01), with values increasing 37% from pre- (0.6140+/-0.0708 micromol/L) to postexercise (0.8440+/-0.0687 micromol/L) for smokers and remaining relatively unchanged for nonsmokers (from 0.7664+/-0.0901 to 0.7419+/-0.0776 micromol/L). 8-OHdG was unaffected by smoking status (p=.43) or exercise (p=.40). These findings indicate that young cigarette smokers experience an exaggerated oxidative stress response to strenuous physical work, compared with nonsmokers of similar age. These results highlight yet another detrimental impact of cigarette smoking on human health. Future investigations should focus on older, more established smokers.

Glycine propionyl-L-carnitine modulates lipid peroxidation and nitric oxide in human subjects.

OBJECTIVE To determine the efficacy of glycine propionyl-L-carnitine (GPLC) to decrease lipid peroxidation, elevate nitric oxide, and improve blood lipid profiles in human subjects. METHODS Thirty untrained, normolipidemic subjects performed eight weeks of supervised aerobic exercise while supplementing GPLC at one of two doses (1 or 3 grams daily of PLC + glycine) or placebo, following random assignment in a double-blind manner. Fasting blood samples were analyzed at rest for malondialdehyde, nitric oxide, and lipids before and after the intervention. RESULTS Malondialdehyde was decreased (p<0.05) from pre- to post-intervention with 1 g GPLC (1.08+/-0.24 vs. 0.69+/-0.25 micromol.L (-1)) and 3 g GPLC (0.94+/-0.18 vs. 0.66+/-0.17 micromol.L (-1)), but did not change statistically (p>0.05) with placebo (1.12+/-0.21 vs. 1.03+/-0.23 micromol.L (-1)). Nitric oxide was increased (p<0.05) from pre- to post-intervention with 3 g GPLC (21.34+/-2.27 vs. 29.46+/-3.61 micromol.L (-1)), but did not change statistically (p>0.05) with 1 g GPLC (23.22+/-4.13 vs. 26.24+/-4.32 micromol.L (-1)) or placebo (24.31+/-3.90 vs. 26.14+/-4.11 micromol.L (-1)). No main effects or interaction effects were noted for blood lipids (p>0.05). CONCLUSION GPLC supplementation combined with eight weeks of aerobic exercise decreases lipid peroxidation and elevates nitric oxide, but does not further improve blood lipid profiles in normolipidemic subjects.

Feasibility and Initial Effectiveness of Home Exercise During Maintenance Therapy for Childhood Acute Lymphoblastic Leukemia

Purpose: Children with acute lymphoblastic leukemia (ALL) are at increased risk of obesity and deconditioning from cancer therapy. This pilot study assessed feasibility/initial efficacy of an exercise intervention for patients with ALL undergoing maintenance therapy. Methods: Participants were aged 5 to 10 years, receiving maintenance therapy, in first remission. A 6-month home-based intervention, with written and video instruction, was supervised with weekly calls from an exercise coach. Pre- and poststudy testing addressed strength, flexibility, fitness, and motor function. Results: Seventeen patients enrolled (participation 63%). Twelve (71%) finished the intervention, completing 81.7 ± 7.2% of prescribed sessions. Improvements of 5% or more occurred in 67% for knee and 75% for grip strength, 58% for hamstring/low-back and 83% for ankle flexibility, 75% for the 6-Minute Walk Test, and 33% for performance on the Bruininks-Oseretsky Test of Motor Proficiency Version 2. Conclusions: This pilot study demonstrated that exercise intervention during ALL therapy is feasible and has promise for efficacy.