Michael L. Pennell

Energy costs of physical activities in children and adolescents

PURPOSE The primary aim was to determine the energy expenditure (EE: kcal.kg(-1).h(-1)) in terms of caloric cost and metabolic equivalents of activities commonly performed by children and adolescents. Secondary aims were to determine at what age and pubertal developmental stage values approach those of adults. METHODS In this descriptive study, 295 volunteer youth 8-18 yr of age completed 18 common physical activities (including rest) while EE was measured continuously with a portable metabolic system. Three sets of activities were assigned in random order for each subject. Activities ranged from television viewing and video game play to running and rope skipping. Pubertal development was estimated from a self-report questionnaire. RESULTS At rest, VO(2) and EE were highest in the youngest children and decreased with advancing age and higher pubertal stage in both genders. The age-adjusted and puberty-adjusted energy expenditure values were generally lower than the compendium MET values for sedentary and moderate activities but were more varied for high-intensity activities. However, the ratio of activity EE to REE was comparable in children and adults. CONCLUSIONS Energy expenditure per kilogram of body mass at rest or during exercise is greater in children than adults and varies with pubertal status, thus using the definition of a MET in the compendium of physical activities without adjustment is inadequate for energy estimation in children, until a child reaches Tanner Stage 5. However, the ratio of activity EE to resting EE in children appears to be similar or slightly less than in the compendium, suggesting that the compendium MET increments used with our adjusted EE values more closely approximate the true EE of activities in children than present adult norms.

Standardizing the power of the Hosmer–Lemeshow goodness of fit test in large data sets

The Hosmer-Lemeshow test is a commonly used procedure for assessing goodness of fit in logistic regression. It has, for example, been widely used for evaluation of risk-scoring models. As with any statistical test, the power increases with sample size; this can be undesirable for goodness of fit tests because in very large data sets, small departures from the proposed model will be considered significant. By considering the dependence of power on the number of groups used in the Hosmer-Lemeshow test, we show how the power may be standardized across different sample sizes in a wide range of models. We provide and confirm mathematical derivations through simulation and analysis of data on 31,713 children from the Collaborative Perinatal Project. We make recommendations on how to choose the number of groups in the Hosmer-Lemeshow test based on sample size and provide example applications of the recommendations.

The Ohio Patient Navigation Research Program: Does the American Cancer Society Patient Navigation Model Improve Time to Resolution in Patients with Abnormal Screening Tests?

Background: Patient navigation (PN) has been suggested as a way to reduce cancer health disparities; however, many models of PN exist and most have not been carefully evaluated. The goal of this study was to test the Ohio American Cancer Society model of PN as it relates to reducing time to diagnostic resolution among persons with abnormal breast, cervical, or colorectal cancer screening tests or symptoms. Methods: A total of 862 patients from 18 clinics participated in this group-randomized trial. Chart review documented the date of the abnormality and the date of resolution. The primary analysis used shared frailty models to test for the effect of PN on time to resolution. Crude HR were reported as there was no evidence of confounding. Results: HRs became significant at 6 months; conditional on the random clinic effect, the resolution rate at 15 months was 65% higher in the PN arm (P = 0.012 for difference in resolution rate across arms; P = 0.009 for an increase in the HR over time). Conclusions: Participants with abnormal cancer screening tests or symptoms resolved faster if assigned to PN compared with those not assigned to PN. The effect of PN became apparent beginning six months after detection of the abnormality. Impact: PN may help address health disparities by reducing time to resolution after an abnormal cancer screening test. Cancer Epidemiol Biomarkers Prev; 21(10); 1620–8. ©2012 AACR.

Oncostatin M promotes STAT3 activation, VEGF production, and invasion in osteosarcoma cell lines

BackgroundWe have previously demonstrated that both canine and human OSA cell lines, as well as 8 fresh canine OSA tumor samples, exhibit constitutive phosphorylation of STAT3, and that this correlates with enhanced expression of matrix metalloproteinase-2 (MMP2). While multiple signal transduction pathways can result in phosphorylation of STAT3, stimulation of the cytokine receptor gp130 through either IL-6 or Oncostatin M (OSM) is the most common mechanism through which STAT3 is activated. The purpose of this study was to evaluate the role of IL-6 and OSM stimulation on both canine and human OSA cell lines to begin to determine the role of these cytokines in the biology of OSA.MethodsRT-PCR and Western blotting were used to interrogate the consequences of OSM and IL-6 stimulation of OSA cell lines. OSA cells were stimulated with OSM and/or hepatocyte growth factor (HGF) and the effects on MMP2 activity (gel zymography), proliferation (CyQUANT), invasion (Matrigel transwell assay), and VEGF production (Western blotting, ELISA) were assessed. The small molecule STAT3 inhibitor LLL3 was used to investigate the impact of STAT3 inhibition following OSM stimulation of OSA cells.ResultsOur data demonstrate that the OSM receptor (OSMR), but not IL-6 or its receptor, is expressed by all human and canine OSA cell lines and canine OSA tumor samples; additionally, OSM expression was noted in all tumor samples. Treatment of OSA cell lines with OSM induced phosphorylation of STAT3, Src, and JAK2. OSM stimulation also resulted in a dose dependent increase in MMP2 activity and VEGF expression that was markedly reduced following treatment with the small molecule STAT3 inhibitor LLL3. Lastly, OSM stimulation of OSA cell lines enhanced invasion through Matrigel, particularly in the presence of rhHGF. In contrast, both OSM and HGF stimulation of OSA cell lines did not alter their proliferative capacity.ConclusionsThese data indicate OSM stimulation of human and canine OSA cells induces STAT3 activation, thereby enhancing the expression/activation of MMP2 and VEGF, ultimately promoting invasive behavior and tumor angiogenesis. As such, OSM and its receptor may represent a novel target for therapeutic intervention in OSA.

Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT-335 in spontaneous canine cancer: Results of a phase i study

Background The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability. Methods and Findings Canine tumor cell lines derived from non-Hodgkin lymphoma (NHL), mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2–42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed), mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday) although biologic activity was observed at 1 mg/kg. Clinical benefit (CB) including partial response to therapy (PR, n = 2) and stable disease (SD, n = 7) was observed in 9/14 dogs with NHL with a median time to progression (TTP) for responders of 66 days (range 35–256 days). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35–354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities. Conclusions This study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer.

Impaired myocardial perfusion reserve and fibrosis in Friedreich ataxia: a mitochondrial cardiomyopathy with metabolic syndrome

AIMS Cardiomyopathy produces significant mortality in patients with Friedreich ataxia (FA), a genetic disorder that produces intra-mitochondrial iron accumulation. We sought to test the hypothesis that abnormal myocardial perfusion reserve and fibrosis represent early manifestations of cardiomyopathy. METHODS AND RESULTS Twenty-six patients with genetically proven FA ages 36 ± 12 years without cardiomyopathy and eight controls underwent cardiac magnetic resonance with adenosine. Precontrast imaging for myocardial iron estimation was performed. Myocardial perfusion reserve index (MPRI) was quantified using the normalized upslope of myocardial enhancement during vasodilator stress vs. rest. Left ventricular (LV) mass and volumes were computed from short-axis cine images. Serologies included lipids, and platelets were isolated for iron quantification using inductively coupled plasma mass spectrometry. Left ventricular ejection fraction and mass averaged 64.1 ± 8.3% and 62.7 ± 16.7 g/m², respectively, indicating preserved systolic function and absence of significant hypertrophy. Myocardial perfusion reserve index quantification revealed significantly lower endocardial-to-epicardial perfusion reserve in patients vs. controls (0.80 ± 0.18 vs. 1.22 ± 0.36, P = 0.01). Lower MPRI was predicted by increased number of metabolic syndrome (met-S) features (P < 0.01). Worse concentric remodelling occurred with increased GAA repeat length (r = 0.64, P < 0.001). Peripheral platelet iron measurement showed no distinction between patients and controls (5.4 ± 8.5 × 10⁻⁷ vs. 5.5 ± 2.9 × 10⁻⁷ ng/platelet, P = 0.88), nor did myocardial T2* measures. CONCLUSIONS Patients with FA have abnormal myocardial perfusion reserve that parallels met-S severity. Impaired perfusion reserve and fibrosis occur in the absence of significant hypertrophy and prior to clinical heart failure, providing potential therapeutic targets for stage B cardiomyopathy in FA and related myocardial diseases.

Maternal Docosahexaenoic Acid Supplementation Decreases Lung Inflammation in Hyperoxia-Exposed Newborn Mice

DHA is a long-chain fatty acid that has potent antiinflammatory properties. Whereas maternal DHA dietary supplementation has been shown to improve cognitive development in infants fed DHA-supplemented milk, the antiinflammatory effects of maternal DHA supplementation on the developing fetus and neonate have not been extensively explored. Pregnant C3H/HeN dams were fed purified control or DHA-supplemented diets (~0.25% of total fat) at embryonic d 16 and consumed these diets throughout the study. At birth, the nursing mouse pups were placed in room air (RA; 21% O(2)) or >95% O(2) (hyperoxia) for up to 7 d. These studies tested the hypothesis that maternal DHA supplementation would decrease inflammation and improve alveolarization in the lungs of newborn mouse pups exposed to hyperoxia. Survival, inflammatory responses, and lung growth were compared among control diet/RA, DHA/RA, control/O(2), and DHA/O(2) pups. There were fewer neutrophils and macrophages in lung tissues from pups nursed by DHA-supplemented dams than in those nursed by dams fed the control diet at 7 d of hyperoxia exposure (P < 0.015). Although differences due to hyperoxia exposure were observed, maternal diet did not affect keratinocyte-derived chemokine, macrophage inflammatory protein-2, IL-1β, or TNFα mRNA levels in pup tissues. Hyperoxia also induced NF-κB activity, but maternal diet did not affect NF-κB or PPARγ activities. In mice, DHA supplementation decreases leukocyte infiltration in the offspring exposed to hyperoxia, suggesting a potential role for DHA supplementation as a therapy to reduce inflammation in preterm infants.

Myocardial T2 Mapping With Respiratory Navigator and Automatic Nonrigid Motion Correction

Quantitative T2 mapping was recently shown to be superior to T2‐weighted imaging in detecting T2 changes across myocardium. Pixel‐wise T2 mapping is sensitive to misregistration between the images used to generate the parameter map. In this study, utility of two motion‐compensation strategies—(i) navigator gating with prospective slice correction and (ii) nonrigid registration—was investigated for myocardial T2 mapping in short axis and horizontal long axis views. Navigator gating provides respiratory motion compensation, whereas registration corrects for residual cardiac and respiratory motion between images; thus, the two strategies provided complementary functions. When these were combined, respiratory‐motion‐induced T2 variability, as measured by both standard deviation and interquartile range, was comparable to that in breath‐hold T2 maps. In normal subjects, this combined motion‐compensation strategy increased the percentage of myocardium with T2 measured to be within normal range from 60.1% to 92.2% in short axis and 62.3% to 92.7% in horizontal long axis. The new motion‐compensated T2 mapping technique, which combines navigator gating, prospective slice correction, and nonrigid registration to provide through‐plane and in‐plane motion correction, enables a method for fully automatic and robust free‐breathing T2 mapping. Magn Reson Med, 2012.

Real-time cine and myocardial perfusion with treadmill exercise stress cardiovascular magnetic resonance in patients referred for stress SPECT

BackgroundTo date, stress cardiovascular magnetic resonance (CMR) has relied on pharmacologic agents, and therefore lacked the physiologic information available only with exercise stress.Methods43 patients age 25 to 81 years underwent a treadmill stress test incorporating both Tc99m SPECT and CMR. After rest Tc99m SPECT imaging, patients underwent resting cine CMR. Patients then underwent in-room exercise stress using a partially modified treadmill. 12-lead ECG monitoring was performed throughout. At peak stress, Tc99m was injected and patients rapidly returned to their prior position in the magnet for post-exercise cine and perfusion imaging. The patient table was pulled out of the magnet for recovery monitoring. The patient was sent back into the magnet for recovery cine and resting perfusion followed by delayed post-gadolinium imaging. Post-CMR, patients went to the adjacent SPECT lab to complete stress nuclear imaging. Each modalitys images were reviewed blinded to the others results.ResultsPatients completed on average 9.3 ± 2.4 min of the Bruce protocol. Stress cine CMR was completed in 68 ± 14 sec following termination of exercise, and stress perfusion CMR was completed in 88 ± 8 sec. Agreement between SPECT and CMR was moderate (κ = 0.58). Accuracy in eight patients who underwent coronary angiography was 7/8 for CMR and 5/8 for SPECT (p = 0.625). Follow-up at 6 months indicated freedom from cardiovascular events in 29/29 CMR-negative and 33/34 SPECT-negative patients.ConclusionsExercise stress CMR including wall motion and perfusion is feasible in patients with suspected ischemic heart disease. Larger clinical trials are warranted based on the promising results of this pilot study to allow comparative effectiveness studies of this stress imaging system vs. other stress imaging modalities.

Clean Indoor Air Ordinance Coverage in the Appalachian Region of the United States

OBJECTIVES We sought to quantitatively examine the pattern of, and socioeconomic factors associated with, adoption of clean indoor air ordinances in Appalachia. METHODS We collected and reviewed clean indoor air ordinances in Appalachian communities in 6 states and rated the ordinances for completeness of coverage in workplaces, restaurants, and bars. Additionally, we computed a strength score to measure coverage in 7 locations. We fit mixed-effects models to determine whether the presence of a comprehensive ordinance and the ordinance strength were related to community socioeconomic disadvantage. RESULTS Of the 332 communities included in the analysis, fewer than 20% had adopted a comprehensive workplace, restaurant, or bar ordinance. Most ordinances were weak, achieving on average only 43% of the total possible points. Communities with a higher unemployment rate were less likely and those with a higher education level were more likely to have a strong ordinance. CONCLUSIONS The majority of residents in these communities are not protected from secondhand smoke. Efforts to pass strong statewide clean indoor air laws should take priority over local initiatives in these states.