No evidence for metabolic adaptation during exercise-related energy compensation.

The constrained energy model posits that the increased total daily energy expenditure (TDEE) in response to exercise is often less than the energy cost of the exercise prescribed. The mechanisms behind this phenomenon, coined "exercise-related energy compensation" (ExEC), are poorly understood, and it is unknown if ExEC is coupled with metabolic adaptation. Using a randomized controlled 24-week exercise intervention, individuals who demonstrated ExEC were identified. Changes to all components of TDEE and metabolic adaptation were assessed using doubly labeled water over 14 days and room calorimetry over 24-h 48% of individuals exhibited ExEC (-308 ± 158 kcals/day). There were no statistically significant differences in sex, age, or BMI between ExEC and non-ExEC. ExEC was associated with baseline TDEE (r = -0.50, p = 0.006). There were no statistically significant differences in metabolic adaptations for 24 h, sleep, or resting expenditures. These findings reveal that ExEC occurs independent of metabolic adaptation in sedentary components of EE.

Patterns of Early Coronary Artery Changes in Pediatric Heart Transplant Recipients Detected Using Optical Coherence Tomography.

BACKGROUND: Cardiac allograft vasculopathy, the leading cause of graft failure in pediatric heart transplant recipients, is characterized by diffuse and concentric coronary intimal thickening. Early treatment yields better outcomes. While coronary angiography is the standard for cardiac allograft vasculopathy screening and diagnosis, it only identifies luminal narrowing, which occurs in more severe disease. Coronary optical coherence tomography (OCT) is a high-definition intravascular imaging modality that may offer earlier diagnosis. We used OCT to investigate coronary intimal thickening in pediatric transplant recipients and examined its (1) location (ie, vessel type and location) and (2) nature (ie, characteristics of cross-sectional and longitudinal thickening). METHODS: Sites collected coronary angiography and OCT data from participants (N=258 vessel segments from 73 individuals; median age: 11.5 years [8.4-15.3]; 55% male). Images were collected from the left anterior descending, left circumflex, and right coronary arteries, and location (ie, proximal, middle, and distal) were classified using coronary angiography. RESULTS: OCT identified 32 vessel segments meeting criteria for significant thickening, 88% of which were angiographically silent. Longitudinal thickening was segmental rather than global in 88%, and cross-sectional thickening was 48% eccentric and 52% concentric. Intimal thickening prevalence and severity measures did not consistently differ between coronary artery type (P=1.000) or location (P=0.248) but increased with time since transplant and age at transplant and OCT procedure. CONCLUSIONS: In pediatric transplant recipients, we observed a surprisingly high prevalence of segmental and eccentric intimal thickening. Insights from intravascular imaging suggest these patterns of coronary vascular changes may precede overt cardiac allograft vasculopathy. Identifying early changes may offer opportunity for enhanced surveillance and earlier intervention.

Physiological Responses to Exercise in Pediatric Heart Transplant Recipients.

INTRODUCTION: Pediatric heart transplant (HTx) recipients have reduced exercise capacity typically two-thirds of predicted values, the mechanisms of which are not fully understood. We sought to assess the cardiorespiratory responses to progressive exercise in HTx relative to controls matched for age, sex, body size, and work rate. METHODS: Fourteen HTx recipients and matched controls underwent exercise stress echocardiography on a semisupine cycle ergometer. Hemodynamics, left ventricular (LV) dimensions, and volumes were obtained and indexed to body surface area. Oxygen consumption (V˙O2) was measured, and arteriovenous oxygen difference was estimated using the Fick Principle. RESULTS: At rest, LV mass index (P = 0.03) and volumes (P < 0.001) were significantly smaller in HTx, whereas wall thickness (P < 0.01) and LV mass-to-volume ratio (P = 0.01) were greater. Differences in LV dimensions and stroke volume persisted throughout exercise, but the pattern of response was similar between groups as HR increased. As exercise progressed, heart rate and cardiac index increased to a lesser extent in HTx. Despite this, V˙O2 was similar (P = 0.82) at equivalent work rates as HTx had a greater change in arteriovenous oxygen difference (P < 0.01). CONCLUSIONS: When matched for work rate, HTx had similar metabolic responses to controls despite having smaller LV chambers and an attenuated increase in hemodynamic responses. These findings suggest that HTx may increase peripheral O2 extraction as a compensatory mechanism in response to reduced cardiovascular function.

Optical Coherence Tomography for the Early Detection of Coronary Vascular Changes in Children and Adolescents After Cardiac Transplantation: Findings From the International Pediatric OCT Registry.

OBJECTIVES: This study sought to describe the initial findings from the International Pediatric Optical Coherence Tomography (OCT) registry in pediatric heart transplant recipients. BACKGROUND: Cardiac allograft vasculopathy (CAV) is a common cause of late graft failure and mortality in pediatric heart transplant recipients. Early diagnosis may improve outcomes. OCT is a high-resolution intravascular imaging technique that has the potential to identify CAV earlier than angiography. METHODS: OCT and angiography of the coronary arteries were performed in pediatric heart transplant recipients at participating centers. Demographics, clinical data, medications, episodes of rejection, and angiographically confirmed CAV were collected for each case. OCT and angiography images were analyzed in a central core imaging laboratory. Intimal thickness and intima/media cross sectional area (I/M CSA) ratios were calculated for each case. Intimal thickness ≥0.25 mm was defined as abnormal and ≥0.4 mm as severe intima thickening. I/M CSA ratio of ≥1 was defined as abnormal. OCT findings were compared to angiographic findings for each case. RESULTS: Across 3 centers, 110 cases were analyzed from 76 patients. Intimal thickening was present in 26 of 110 cases. Eleven of these cases had severe intima thickening (≥0.4 mm) and notably, angiography results were normal in 8 cases. All 5 cases with a median I/M CSA ratio of ≥2 had normal angiography. The maximal intima thickness was ≥0.25 mm in 24% and ≥0.4 mm in 10% of cases. Median I/M CSA ratio was ≥1 for 80% of cases. I/M CSA ratio was significantly higher in cases with concurrent CAV (p = 0.03). Maximal intima thickness was significantly greater in cases with current or previous rejection (p = 0.01). I/M CSA ratio was significantly lower in patients treated with statins (p = 0.01). OCT findings alone prompted a change to medical management in 17% of cases. CONCLUSIONS: OCT provides important insights into coronary vascular changes not detected by angiography in pediatric transplant recipients. The use of OCT for pediatric heart transplant recipients should be further investigated, given its potential to impact the management of CAV.

Intimal thickening at coronary bifurcations in pediatric heart transplant recipients.

Heart transplant recipients are at increased risk for atherosclerosis and cardiac allograft vasculopathy, both initially presenting as intimal thickening. We aimed to determine the presence, extent, and anatomical characteristics of intimal thickness at coronary bifurcations in children using OCT. We measured the intimal thickness of coronary arteries in pediatric transplant recipients using OCT during routine cardiac catheterization. Intimal thickening was defined as (i) a percent change in contralateral intimal thickness greater than 50% when comparing the thickness at the bifurcation to the baseline thickness, and (ii) greater than 0.1 mm. We evaluated 153 unique coronary bifurcations in 31 children (58% boys, median 12.7 years). Intimal thickening was almost exclusively observed in the left coronary system (22 of 67 bifurcations) and rare in the right coronary system (2 of 86 bifurcations; P < .001). There was a positive association between the relative size of the side branch and contralateral intimal thickening at coronary bifurcations (P = .009). Intimal thickening at coronary bifurcations is already present in the left coronary system in many pediatric transplant recipients. The correlation between intimal thickening and side branch size suggests that low shear stress and oscillating shear stress may have an important role in the development of intimal thickening at coronary bifurcations.

A Systematic Review of Infective Endocarditis in Patients With Bovine Jugular Vein Valves Compared With Other Valve Types.

OBJECTIVES: The aim of this study was to systematically evaluate the incidence of infective endocarditis (IE) in right ventricle-to-pulmonary artery conduits and valves, comparing bovine jugular vein (BJV) valves with all others. BACKGROUND: Recent evidence suggests that the incidence of IE is higher in patients with congenital heart disease who have undergone implantation of BJV valves in the pulmonary position compared with other valves. METHODS: Systematic searches of published research were conducted using electronic databases (MEDLINE, Embase, and CINAHL) and citations cross-referenced current to April 2016. Included studies met the following criteria: patients had undergone right ventricle-to-pulmonary artery conduit or percutaneous pulmonary valve implantation, and investigators reported on the type of conduit or valve implanted, method of intervention (surgery or catheter based), IE incidence, and follow-up time. RESULTS: Fifty studies (Levels of Evidence: 2 to 4) were identified involving 7,063 patients. The median cumulative incidence of IE was higher for BJV compared with other valves (5.4% vs. 1.2%; p < 0.0001) during a median follow-up period of 24.0 and 35.5 months, respectively (p = 0.03). For patients with BJV valves, the incidence of IE was not different between surgical and catheter-based valve implantation (p = 0.83). CONCLUSIONS: There was a higher incidence of endocarditis with BJV valves than other types of right ventricle-to-pulmonary artery conduits. There was no difference in the incidence of endocarditis between catheter-based bovine valves and surgically implanted bovine valves, suggesting that the substrate for future infection is related to the tissue rather than the method of implantation.

Extended calorie restriction suppresses overall and specific food cravings: a systematic review and a meta-analysis.

BACKGROUND: Multiple studies have concluded that calorie restriction for at least 12 weeks is associated with reduced food cravings, while others have shown that calorie restriction may increase food cravings. We addressed this ambiguity in a systematic review and meta-analysis. METHODS: We searched for studies conducted on subjects with obesity, implemented calorie restriction for at least 12 weeks and measured food cravings pre-intervention and post-intervention. Our final eight studies mostly used the Food Craving Inventory. Other comparable methods were converted to a similar scale. We used the duration ≥12 weeks, but closest to 16 weeks for studies with multiple follow-ups and performed DerSimonian-Laird random-effects meta-analyses using the 'metafor' package in r software. RESULTS: Despite heterogeneity across studies, we observed reductions in pooled effects for overall food cravings (-0.246 [-0.490, -0.001]) as well as cravings for sweet (-0.410 [-0.626, -0.194]), high-fat (-0.190 [-0.343, -0.037]), starchy (-0.288 [-0.517, -0.058]) and fast food (-0.340 [-0.633, -0.048]) in the meta-analysis. Baseline body weight, type of intervention, duration, sample size and percentage of female subjects explained the heterogeneity. CONCLUSIONS: Calorie restriction is associated with reduced food cravings supporting a de-conditioning model of craving reductions. Our findings should ease the minds of clinicians concerned about increased cravings in patients undergoing calorie restriction interventions.

Outcomes of Radiofrequency Perforation for Pulmonary Atresia and Intact Ventricular Septum: A Single-Centre Experience.

Percutaneous radiofrequency perforation (RFP) of the pulmonary valve is used as a primary therapy in neonates with pulmonary atresia and intact ventricular septum (PAIVS). We sought to determine the safety and efficacy of RFP for PAIVS in a single center and assess the pre-intervention anatomical parameters associated with a biventricular outcome. We retrospectively reviewed all cases of PAIVS treated with RFP at a single center from 1999 through 2012. We collected baseline imaging data, technical aspects of the procedure, adverse events and outcomes. RFP was attempted in 18 patients with 17 successful procedures. There was no mortality; one patient had an acute complication requiring surgical intervention. All were alive at the most recent follow-up (median 4.9 years; IQR = 2.0-6.8 years), 12/17 (71%) had a biventricular circulation, 2/17 (12%) had a 1½ ventricle repair, 2/17 (12%) had a univentricular repair and 1/17 was lost to follow-up. A biventricular outcome in patients with PAIVS was associated with the pre-intervention tricuspid valve/mitral valve (TV/MV) ratio and tricuspid valve (TV) z-score. The median TV/MV ratio for patients who underwent a biventricular repair and a non-biventricular repair was 0.82 (IQR = 0.71-0.90) and 0.59 (IQR = 0.39-0.76), P = 0.036, respectively. The median TV z-scores were -3.2 [(-4.9 to -2.6), and -6.8 (-9.7 to -4.8] P = 0.036 for the biventricular and non-biventricular groups, respectively. RFP is a safe primary therapy for PAIVS. With appropriate patient selection, RFP will often result in a biventricular circulation. Both the TV/MV and TV z-score were found to be a predictor of a biventricular outcome in our cohort.

Combined zoledronic acid and meloxicam reduced bone loss and tumour growth in an orthotopic mouse model of bone-invasive oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is common in cats and humans and invades oral bone. We hypothesized that the cyclooxygenase (COX)-2 inhibitor, meloxicam, with the bisphosphonate, zoledronic acid (ZOL), would inhibit tumour growth, osteolysis and invasion in feline OSCC xenografts in mice. Human and feline OSCC cell lines expressed COX-1 and COX-2 and the SCCF2 cells had increased COX-2 mRNA expression with bone conditioned medium. Luciferase-expressing feline SCCF2Luc cells were injected beneath the perimaxillary gingiva and mice were treated with 0.1 mg kg(-1) ZOL twice weekly, 0.3 mg kg(-1) meloxicam daily, combined ZOL and meloxicam, or vehicle. ZOL inhibited osteoclastic bone resorption at the tumour-bone interface. Meloxicam was more effective than ZOL at reducing xenograft growth but did not affect osteoclastic bone resorption. Although a synergistic effect of combined ZOL and meloxicam was not observed, combination therapy was well-tolerated and may be useful in the clinical management of bone-invasive feline OSCC.

Feasibility of optical coherence tomography in children with Kawasaki disease and pediatric heart transplant recipients.

BACKGROUND: Optical coherence tomography (OCT) is a high-resolution intravascular imaging technique used in adults. We tested the hypothesis that OCT could identify coronary abnormalities not seen by angiography in children with a history of Kawasaki disease (KD) and pediatric heart transplant (TX) recipients. METHODS AND RESULTS: Patients with KD and TX recipients were evaluated between December 2012 and October 2013 with angiography and OCT (Ilumien System, LightLabs, St Jude Medical, Westford, MA). Modifications were made to the adult OCT protocol to adapt this technique for children. Serial cross-sectional area measurements of the lumen, intima, and media were made. Entire imaging data were analyzed for the presence of qualitative changes. Seventeen children were evaluated (5 patients with KD; 12 TX recipients). In patients with KD, angiography was normal. However, OCT imaging revealed that significant vessel wall abnormalities were present in all children including intimal thickening (intima/lumen cross-sectional area ratio>0.4), loss of the normal layered structure of the vessel wall, white thrombus, calcification, and neovascularization. There was extensive destruction of the internal elastic lamina. In TX recipients, angiography was normal; however, intimal thickening (intima/media cross-sectional area ratio>1) was seen in 9 of 12 patients. The median intima/media cross-sectional area ratio was 1.18. CONCLUSIONS: In this initial experience with OCT in children, we have identified significant coronary abnormalities with OCT that are angiographically silent in children with a history of coronary aneurysms because of KD and in pediatric TX recipients.

Tumor microenvironment regulates metastasis and metastasis genes of mouse MMTV-PymT mammary cancer cells in vivo.

Metastasis is the primary cause of death in breast cancer patients, yet there are challenges to modeling this process in vivo. The goal of this study was to analyze the effects of injection site on tumor growth and metastasis and gene expression of breast cancer cells in vivo using the MMTV-PymT breast cancer model (Met-1 cells). Met-1 cells were injected into 5 sites (subcutaneous, mammary fat pad, tail vein, intracardiac, and intratibial), and tumors and metastases were monitored using bioluminescent imaging and confirmed with gross necropsy and histopathology. Met-1 tumors were analyzed based on morphology and changes in gene expression in each tissue microenvironment. There were 6 permissible sites of Met-1 tumor growth (mammary gland, subcutis, lung, adrenal gland, ovary, bone). Met-1 cells grew faster in the subcutis compared to mammary fat pad tumors (highest Ki-67 index). Morphologic differences were evident in each tumor microenvironment. Finally, 7 genes were differentially expressed in the Met-1 tumors in the 6 sites of growth or metastasis. This investigation demonstrates that breast cancer progression and metastasis are regulated by not only the tumor cells but also the experimental model and unique molecular signals from the tumor microenvironment.

Measuring food intake with digital photography.

The digital photography of foods method accurately estimates the food intake of adults and children in cafeterias. When using this method, images of food selection and leftovers are quickly captured in the cafeteria. These images are later compared with images of 'standard' portions of food using computer software. The amount of food selected and discarded is estimated based upon this comparison, and the application automatically calculates energy and nutrient intake. In the present review, we describe this method, as well as a related method called the Remote Food Photography Method (RFPM), which relies on smartphones to estimate food intake in near real-time in free-living conditions. When using the RFPM, participants capture images of food selection and leftovers using a smartphone and these images are wirelessly transmitted in near real-time to a server for analysis. Because data are transferred and analysed in near real-time, the RFPM provides a platform for participants to quickly receive feedback about their food intake behaviour and to receive dietary recommendations for achieving weight loss and health promotion goals. The reliability and validity of measuring food intake with the RFPM in adults and children is also reviewed. In sum, the body of research reviewed demonstrates that digital imaging accurately estimates food intake in many environments and it has many advantages over other methods, including reduced participant burden, elimination of the need for participants to estimate portion size, and the incorporation of computer automation to improve the accuracy, efficiency and cost-effectiveness of the method.

Can a weight loss of one pound a week be achieved with a 3500-kcal deficit? Commentary on a commonly accepted rule.

Despite theoretical evidence that the model commonly referred to as the 3500-kcal rule grossly overestimates actual weight loss, widespread application of the 3500-kcal formula continues to appear in textbooks, on respected government- and health-related websites, and scientific research publications. Here we demonstrate the risk of applying the 3500-kcal rule even as a convenient estimate by comparing predicted against actual weight loss in seven weight loss experiments conducted in confinement under total supervision or objectively measured energy intake. We offer three newly developed, downloadable applications housed in Microsoft Excel and Java, which simulates a rigorously validated, dynamic model of weight change. The first two tools available at http://www.pbrc.edu/sswcp, provide a convenient alternative method for providing patients with projected weight loss/gain estimates in response to changes in dietary intake. The second tool, which can be downloaded from the URL http://www.pbrc.edu/mswcp, projects estimated weight loss simultaneously for multiple subjects. This tool was developed to inform weight change experimental design and analysis. While complex dynamic models may not be directly tractable, the newly developed tools offer the opportunity to deliver dynamic model predictions as a convenient and significantly more accurate alternative to the 3500-kcal rule.

Activity related energy expenditure, appetite and energy intake: potential implications for weight management.

The aim was to investigate relationships between activity related energy expenditure (AREE), appetite ratings and energy intake (EI) in a sample of 40 male (26.4years; BMI 23.5kg/m(2)) and 42 female (26.9years; BMI 22.4kg/m(2)) participants. AREE was expressed as the residual value of the regression between total daily EE (by doubly labeled water) and resting EE (by indirect calorimetry). EI was measured using an ad libitum buffet meal and visual analogue scales measured subjective appetite ratings before and after the meal. AREE was divided into low, middle and high sex-specific tertiles. General linear models were used to investigate differences in appetite ratings and EI across AREE tertiles. Before the meal, males in the high AREE tertile had significantly lower desire to eat and lower prospective food consumption and higher feelings of fullness compared to those in the low tertile. Males in the middle tertile had significantly higher satiety quotients after the meal and lower EI compared to the other tertiles. No significant differences across tertiles were found in females. Sex differences in relationships between AREE, appetite ratings and EI may lead to differing patterns of EI and subsequent weight maintenance.

Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE Phase 2) screening and recruitment: methods and results.

The Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE) study is a systematic investigation of sustained 25% calorie restriction (CR) in non-obese humans. CALERIE is a multicenter (3 clinical sites, one coordinating center), parallel group, randomized controlled trial. Participants were recruited, screened, and randomized to the CR or control group with a 2:1 allocation. Inclusion criteria included ages 21-50 years for men and 21-47 years for women, and a body mass index (BMI) of 22.0 ≤ BMI < 28.0 kg/m(2). Exclusion criteria included abnormal laboratory markers, significant medical conditions, psychiatric/behavioral problems, and an inability to adhere to the rigors of the evaluation/intervention schedule. A multi-stage screening process (telephone screen and 3 in-clinic visits) was applied to identify eligible participants. Recruitment was effective and enrollment targets were met on time. 10,856 individuals contacted the clinical sites, of whom 9787 (90%) failed one or more eligibility criteria. Of the 1069 volunteers who started the in-clinic screening, 831 (78%) were either ineligible or dropped. 238 volunteers were enrolled (i.e., initiated the baseline evaluations), 220 were randomized, and 218 started the assigned intervention (2% from the first screening step). This study offered lessons for future multi-center trials engaging non-disease populations. Recruitment strategies must be tailored to specific sites. A multi-disciplinary screening process should be applied to address medical, physical, and psychological/behavioral suitability of participants. Finally, a multi-step screening process with simple criteria first, followed by more elaborate procedures has the potential to reduce the use of study resources.

Why do individuals not lose more weight from an exercise intervention at a defined dose? An energy balance analysis.

Weight loss resulting from an exercise intervention tends to be lower than predicted. Modest weight loss can arise from an increase in energy intake, physiological reductions in resting energy expenditure, an increase in lean tissue or a decrease in non-exercise activity. Lower than expected, weight loss could also arise from weak and invalidated assumptions within predictive models. To investigate these causes, we systematically reviewed studies that monitored compliance to exercise prescriptions and measured exercise-induced change in body composition. Changed body energy stores were calculated to determine the deficit between total daily energy intake and energy expenditures. This information combined with available measurements was used to critically evaluate explanations for low exercise-induced weight loss. We conclude that the small magnitude of weight loss observed from the majority of evaluated exercise interventions is primarily due to low doses of prescribed exercise energy expenditures compounded by a concomitant increase in caloric intake.

Reliability of a common solution-based taste perception test: implications for validity and a briefer test.

The aim of this study was to assess test-retest reliability of a common method for quantifying taste perception and its association with gustatory responses and individual risk for obesity and related health conditions. Forty-six healthy adults rated 20 mixtures comprised of 5 dairy beverages varied in fat content and mixed with sugar concentrations of 0%, 5%, 10%, and 20%, following existing procedures. Individuals rated the sweetness, creaminess, and pleasantness of each mixture during two taste testing sessions occurring 7±2 days apart. Test-retest correlations were of the expected magnitudes (r≥.50) only for the pleasantness ratings of mixtures with higher sugar concentrations. Correlations for sweetness and creaminess taste perception ratings were low, indicating that such ratings may not be reliable over approximately one week, and challenging the validity of such ratings for measuring trait taste perception. A shortened version of the test may be warranted.

Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320.

PTEN (Phosphatase and tensin homolog deleted on chromosome 10) expression in stromal fibroblasts suppresses epithelial mammary tumours, but the underlying molecular mechanisms remain unknown. Using proteomic and expression profiling, we show that Pten loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets, ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2) are critical events in Pten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumour angiogenesis and tumour-cell invasion. Expression of the Pten-miR-320-Ets2-regulated secretome distinguished human normal breast stroma from tumour stroma and robustly correlated with recurrence in breast cancer patients. This work reveals miR-320 as a critical component of the Pten tumour-suppressor axis that acts in stromal fibroblasts to reprogramme the tumour microenvironment and curtail tumour progression.