Daniela A. Rubin

Inflammatory cytokines and metabolic risk factors during growth and maturation: influence of physical activity.

Cytokines influence tissue and cell physiology in positive and negative ways. Our aim in this chapter is to briefly present on select cytokines and their relationship to disease, metabolic risk factors, and physical activity in youth. We discuss the association of adiponectin, interleukin-6 (IL-6), resistin, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) with metabolic risk factors in youth, and whether circulating concentrations of these cytokines are different based on being physically active or engaging in exercise training. Results from several studies show that adiponectin concentrations are reduced with increased adiposity, while others show that TNF-α, IL-6, resistin and CRP concentrations may be elevated with increased adiposity. Results from studies link decreased adiponectin with increased insulin resistance, while some evidence links increased TNF-α and resistin with increased insulin resistance. Several studies relate higher blood pressures to decreased adiponectin, increased TNF-α, and CRP concentrations. The only lipids associated with the cytokines appear to be triglycerides and HDL cholesterol. Higher levels of habitual physical activity are associated with higher adiponectin and perhaps decreased TNF-α and resistin concentrations. Exercise training also appears to positively influence the concentrations of these cytokines. In conclusion, the role of these cytokines is still somewhat unclear as is their associations with metabolic risk factors. However, the available evidence indicates that chronic inflammatory states such as obesity in childhood are associated with a pro-inflammatory profile and the presence of increased risk factors for disease while physical activity or exercise training elicit a protective role relative to this profile.

Testosterone responses to intensive interval versus steady-state endurance exercise

Free testosterone (FT) hormonal responses were compared between high-intensity interval exercise (IE) and steady-state endurance exercise (SSE) in endurance trained males (no.=15). IE session was repeated periods of 90-sec treadmill running at 100–110% maximal oxygen uptake (VO2max) and 90-sec active recovery at 40% VO2max for 42–47 min. The SSE session consisted of a continuous 45-min run at 60–65% VO2max. Total work output was equal for each exercise session. A 45-min supine rest control session (CON) was also performed. All three sessions were on separate days. Pre-session (PRE), immediate post-session (POST), and 12-h post-session (12POST) blood samples were collected and used to determine FT, SHBG, LH, 3-α-androstanediol glucuronide (3-α Diol G) and cortisol. Analysis of variance compared IE and SSE biomarker responses to the reference CON session. IE and SSE each caused an increase (p<0.01) in FT, but IE more so than SSE (p<0.05). The 5α-reduc-tase marker 3-α Diol G response at 12POST IE was elevated while FT was reduced (p<0.05); no such change occurred following SSE. These findings suggest IE might produce a more pronounced turnover of FT by androgen sensitive tissue than the SSE form of exercise.

Do surrogate markers for adiposity relate to cytokines in adolescents

Purpose To determine the associations between field-collected surrogates of adiposity and concentrations of resistin, tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and adiponectin in youth. Methods Cross-sectional data from 60 normal weight and 60 overweight adolescents, ages 10-14 years, were retrospectively examined. Body mass index (BMI) percentile, sum of subscapular and triceps skinfolds (SSF), and waist circumference (WC) were used to classify weight status (BMI) or adiposity (SSF and WC). Percentiles for each surrogate were used for comparison groups. Fasting TNF-α, IL-6, resistin, and adiponectin concentrations were measured in plasma. Results Multiple regression models, controlling for sex and ethnicity, indicated that TNF-α was associated with BMI percentile (R 2 = 0.107, P < 0.05) and SSF (R 2 = 0.085, P < 0.05), whereas resistin was associated with SSF (R 2 = 0.118, P < 0.05). Adiponectin was associated with all 3 adiposity markers: BMI percentile (R 2 = 0.298, P < 0.05), SSF (R 2 = 0.297, P < 0.05), and waist (R 2 = 0.278, P < 0.05). Analyses of variance indicated higher TNF-α and lower adiponectin concentrations in youth with a BMI higher than the 95th percentile (P = 0.014; P < 0.001) or SSF higher than the 95th percentile (P = 0.025; P < 0.001). Youth with WC higher than the 90th percentile had higher resistin (P = 0.029), higher IL-6 (P = 0.028), and lower adiponectin (P < 0.001) concentrations. Conclusions Of the 3 surrogates examined, differences in cytokine concentrations were mostly observed in youth who had WC percentiles higher than the 90th percentiles versus WC lower than the 75th percentiles. Alternatively, from the multiple-regression models SSF, an estimate of subcutaneous adiposity was the surrogate most consistently related to all cytokines, although the degrees of associations were low. The results suggest that although some surrogates were more strongly associated to certain cytokines, WC and SSF seemed more closely associated with cytokines than a BMI percentile indicating obesity.

Thyroid hormonal responses to intensive interval versus steady-state endurance exercise sessions.

OBJECTIVETo compare the thyroid hormonal responses to high-intensity interval exercise (IE) and steady-state endurance exercise (SEE) in highly trained males (n=15).DESIGNThe IE session consisted of repeated periods of 90-seconds treadmill running at 100–110% VO2max and 90-seconds active recovery at 40% VO2max for 42–47 minutes. The SEE session was a 45-minute run at 60–65% VO2max. Total work output was equal for each session. A 45-minute supine rest control session (CON) was also performed. Pre-session (PRE), immediate post-session (POST), and 12-hours post-session (12POST) blood samples were collected and used to determine free (f) T4, fT3, reverse (r) T3, and cortisol levels. RESULTSAll PRE hormone levels were within clinical norms and did not differ significantly between sessions. All POST IE and SEE hormone levels were significantly elevated compared to POST CON (p<0.001). At 12POST, no significant differences between CON and SEE hormonal levels were observed; however, fT3 was significantly reduced and rT3 was significantly elevated in 12POST IE compared to 12POST SEE and CON (p=0.022). For IE, at 12POST a negative correlation (rs = -0.70, p<0.004) was found between fT3 and rT3. Also, for IE, a positive correlation (rs = 0.74, p<0.002) between cortisol POST and rT3 12POST was noted, and a negative correlation (rs = -0.72, p<0.003) between cortisol POST and fT3 12POST.CONCLUSIONIE results in a suppressed peripheral conversion of T4 to T3 implying that a longer recovery period is necessary for hormonal levels to return to normal following IE compared to SEE. These findings are useful in the implementation of training regimens relative to recovery needs and prevention of over-reaching -overtraining.

Patterns of habitual physical activity in youth with and without Prader-Willi Syndrome.

Children classified as overweight or obese and those with disabilities are at a greater risk of not meeting the minimum recommendation of 60 min a day of moderate to vigorous physical activity (PA). Youth with Prader-Willi Syndrome (PWS) appear to participate in less PA compared to nonsyndromal children, likely due to syndrome-related factors. However, description of PA patterns in youth with PWS is lacking. The purpose of this study was to characterize PA in youth with PWS and to compare it to PA in children with nonsyndromal obesity. Twenty-four youth with PWS (ages 8-16 years) and 40 obese children without PWS (OB) (ages 8-11 years) wore accelerometers for eight consecutive days. Data were screened for compliance and classified into PA intensities: sedentary behavior (SED), light (LPA), moderate (MPA), vigorous (VPA) and moderate plus vigorous (MVPA). Youth with PWS spent 19.4% less time in weekly LPA (p=0.007) and 29.8% less time in weekly VPA compared to OB controls (p=0.036). All other intensities were similar between groups. In addition, PWS participated in less LPA and VPA during the weekends compared to OB, and less LPA on weekdays when compared to OB. There was also a trend towards PWS participating in less MVPA during the weekends and less VPA during the weekends than OB controls. There was a trend towards PWS participating in less VPA on weekends compared to weekdays, while OB participated similarly in VPA on weekdays and weekend days. On average, neither PWS nor OB children met minimum MVPA recommendations. The results suggest there is a need to design exercise programs for PWS youth that focus on integrating vigorous intensity activities, especially during the weekends when structured PA may not be available.

Prader-Willi syndrome, excessive daytime sleepiness, and narcoleptic symptoms: a case report

IntroductionSleep abnormalities, including narcolepsy and cataplexy, are a common feature of Prader-Willi syndrome. Long-term treatment with the central nervous system stimulant modafinil has not been reported. In this case report we present a longitudinal perspective of sleep abnormalities in a nine-year-old Caucasian girl with Prader-Willi syndrome from age two to age nine, and detail the response to treatment with the central nervous system stimulant modafinil.Case presentationOur patient presented at two years of age with hypersomnia and narcoleptic episodes with cataplectic features. Initial polysomnograph testing revealed adequate sleep efficiency, but increased sleep fragmentation especially during rapid eye movement sleep. The narcoleptic episodes continued and a repeat polysomnograph at age five years confirmed features consistent with narcolepsy. Further sleep studies at six years, including a multiple sleep latency test, demonstrated signs of excessive daytime sleepiness. Treatment with modafinil was initiated at age seven years six months due to persistent hypersomnia and narcoleptic symptoms. Two polysomnograph studies were performed following treatment with modafinil, at age eight years six months and nine years three months. These studies showed excellent sleep efficiency and improvement of rapid eye movement sleep parameters, supporting the beneficial effects of long-term modafinil therapy.ConclusionsLong-term modafinil therapy may ameliorate the sleep disturbances of Prader-Willi syndrome and should be the focus of future clinical trials.

Rationale and design of active play @ home: a parent-led physical activity program for children with and without disability.

BackgroundCompared to other children, those with disability have additional challenges to being physically active. Prader-Willi Syndrome is a genetic form of childhood obesity that is characterized by hypotonia, growth hormone deficiency, behavioral, and cognitive disability. In children, the low prevalence of this syndrome (1 in 10,000 to 15,000 live births) makes group-based physical activity interventions difficult. In contrast, the home environment presents a natural venue to establish a physical activity routine for this population. This manuscript describes the design of a parent-led physical activity intervention incorporating playground and interactive console-based games to increase physical activity participation in youth with and without Prader-Willi Syndrome.Methods/DesignThe study participants will be 115 youth ages 8-15 y (45 with the syndrome and 70 without the syndrome but categorized as obese). The study will use a parallel design with the control group receiving the intervention after serving as control. Participants will be expected to complete a physical activity curriculum 4 days a week for 6 months including playground games 2 days a week and interactive console games 2 days a week. Parents will be trained at baseline and then provided with a curriculum and equipment to guide their implementation of the program. Tips related to scheduling and coping with barriers to daily program implementation will be provided. Throughout, parents will be contacted by phone once a week (weeks 1-4) and then every other week to receive support in between visits. Measurements of children and parents will be obtained at baseline, 12 weeks, and at the end (week 24) of the intervention. Children main outcomes include physical activity (accelerometry), body composition (dual x-ray absorptiometry), motor proficiency (Bruininks-Oseretsky Test of Motor Proficiency), quality of life and physical activity self-efficacy (questionnaires). Intervention compliance will be monitored using mail-in daily self-report checklists.DiscussionThis parent-guided physical activity intervention aims to increase physical activity by using a curriculum that builds physical activity related self-confidence through the development and/or enhancement of motor skill competency. Ultimately, helping children develop these skills as well as joy in being physically active will translate into sustained behavior change.Trial registrationCurrent Controlled Trial: NCT02058342

Hormonal and Metabolic Responses to Endurance Exercise in Children With Prader–Willi Syndrome and Non-Syndromic Obesity

OBJECTIVE Excess adiposity affects endocrine and metabolic function at rest and during exercise. This study evaluated the endocrine and metabolic responses to exercise in syndromic (Prader-Willi syndrome) and non-syndromic pediatric obesity. MATERIALS/METHODS Eleven PWS (10.9±1.6 y, 45.4±9.5% body fat), 12 lean (9.4±1.2 y, 17.5±4.6% body fat), and 12 obese (9.2±1.2 y, 39.9±6.8% body fat) children completed ten two-minute cycling exercise bouts, separated by one-minute rest. Blood samples were obtained at rest pre-exercise (PRE), immediately post-exercise (IP), and 15, 30 and 60 minutes into recovery. Samples were analyzed for hormones and metabolites. RESULTS Growth hormone increased in response to exercise in lean and obese but not PWS (IP>PRE; IP: lean>obese). Epinephrine increased with exercise in lean (IP>PRE), while norepinephrine increased in lean and obese (IP>PRE) but not PWS; no differences were observed between lean and obese groups at IP. No other significant hormonal group interactions existed. Glucose, lactate, free fatty acid, glycerol and ketone responses were similar among groups. CONCLUSION PWS children exhibited altered stress hormone responses to exercise. However, glucose-regulating hormones and metabolic responses to exercise appeared normal.

The use of magnetic resonance imaging to characterize abnormal body composition phenotypes in youth with Prader–Willi syndrome

INTRODUCTION Magnetic resonance imaging (MRI) provides detailed assessment of body composition compartments. No studies have employed state-of-the-art MRI methods to accurately examine abdominal adipose tissue (AT) and skeletal muscle in youth with Prader-Willi syndrome (PWS). Therefore, this study aimed to describe AT distribution and skeletal muscle in the abdominal region of youth with PWS using MRI. METHODS Anthropometric measures and whole-abdominal T1-weighted MRI were performed in sixteen (5 males and 11 females) youth diagnosed with PWS, and seventeen (10 males and 7 females) youth who did not have PWS (controls). Volume of subcutaneous, visceral, intermuscular, and total AT, and skeletal muscle in the abdominal region were quantified using a semiautomatic procedure. Results were summarized using median and interquartile range (IQR, 25th-75th), and ANCOVA test was used (with age and sex as covariates) to examine differences in body composition compartments between PWS and control group. RESULTS PWS group had similar age (10.5, 6.6-13.9 vs. 12.8, 10.0-14.4years; P=0.14) and BMI z-score (0.5, 0.2-1.3 vs. 0.2, -0.3 to 1.0; P=0.33) when compared with controls. Significant differences were observed in absolute volumes of total AT (PWS: 4.1, 2.0-6.6L; control: 2.9, 2.0-4.5L; P=0.01), subcutaneous AT (PWS: 2.8, 1.4-4.8L; control: 1.8, 1.1-3.2L; P=0.01), and intermuscular AT (PWS: 0.3, 0.1-0.4L; control: 0.3, 0.2-0.3L; P<0.005). Visceral AT/subcutaneous AT was lower in PWS (0.4, 0.3-0.5) compared to controls (0.5, 0.4-0.6), P=0.01. In addition, skeletal muscle volume was lower in PWS (1.5, 1.0-2.6L) compared to controls (3.1, 1.6-3.9L), P=0.03. Ratios of abdominal AT compartments to skeletal muscle were all higher in PWS compared to controls (all P<0.005). CONCLUSIONS PWS youth have greater abdominal adiposity, particularly subcutaneous AT and intermuscular AT, and lower volume of skeletal muscle compared to controls. The decreased ratio of visceral AT/subcutaneous AT in youth with PWS suggests an improved metabolic profile for the level of adiposity present; however, elevated ratios of AT to skeletal muscle suggest a sarcopenic obesity-like phenotype, which could lead to worse health outcomes.

A Characterization of Movement Skills in Obese Children With and Without Prader-Willi Syndrome

Purpose: The aim of this study was twofold: (a) to measure and compare motor proficiency in obese children with Prader-Willi syndrome (OB-PWS) to that in obese children without PWS (OB), and (b) to compare motor proficiency in OB-PWS and OB to normative data. Method: Motor proficiency was measured using the Bruininks-Oseretsky Test of Motor Proficiency-Second Edition-Complete Form, a norm-referenced assessment of motor function. Participants were 18 OB-PWS and 44 OB (8 to 11 years of age). The scores on the 8 subtests and the total motor composite were used to compare OB-PWS and OB. Furthermore, the scores on the 4 motor-area composites were used to compare OB-PWS and OB against normative data. Results: OB-PWS scored significantly lower than OB across all 8 subtests. OB-PWS also had significantly lower motor proficiency scores on all motor-area composites when compared with the normative sample. OB-PWS most frequently (67%–83%) scored well below average on the gross motor subtests. Although not as high as on the gross motor subtests, this finding also held true for the fine motor subtests with 39% to 45% of OB-PWS scoring well below average. Conclusion: Motor proficiency is very poor in OB-PWS, in particular for gross motor skills. Physical, neurological, and developmental characteristics inherent to the syndrome may explain this low performance.