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Key pointsKetone bodies are proposed to represent an alternative fuel source driving energy production, particularly during exercise. Biologically, the extent to which mitochondria utilize ketone bodies compared to other substrates remains unknown. We demonstratein vitrothat maximal mitochondrial respiration supported by ketone bodies is low when compared to carbohydrate-derived substrates in the left ventricle and red gastrocnemius muscle from rodents, and in human skeletal muscle. When considering intramuscular concentrations of ketone bodies and the presence of other carbohydrate and lipid substrates, biological rates of mitochondrial respiration supported by ketone bodies are predicted to be minimal. At the mitochondrial level, it is therefore unlikely that ketone bodies are an important source for energy production in cardiac and skeletal muscle, particularly when other substrates are readily available. Ketone bodies (KB) have recently gained popularity as an alternative fuel source to support mitochondrial oxidative phosphorylation and enhance exercise performance. However, given the low activity of ketolytic enzymes and potential inhibition from carbohydrate oxidation, it remains unknown if KBs can contribute to energy production. We therefore determined the ability of KBs (sodiumdl-beta-hydroxybutyrate, beta-HB; lithium acetoacetate, AcAc) to stimulatein vitromitochondrial respiration in the left ventricle (LV) and red gastrocnemius (RG) of rats, and in human vastus lateralis. Compared to pyruvate, the ability of KBs to maximally drive respiration was low in isolated mitochondria and permeabilized fibres (PmFb) from the LV (similar to 30-35% of pyruvate), RG (similar to 10-30%), and human vastus lateralis (similar to 2-10%). In PmFb, the concentration of KBs required to half-maximally drive respiration (LV: 889 mu m beta-HB, 801 mu mAcAc; RG: 782 mu m beta-HB, 267 mu mAcAc) were greater than KB content representative of the muscle microenvironment (similar to 100 mu m). This would predict low rates (similar to 1-4% of pyruvate) of biological KB-supported respiration in the LV (8-14 pmol s(-1) mg(-1)) and RG (3-6 pmol s(-1) mg(-1)) at rest and following exercise. Moreover, KBs did not increase respiration in the presence of saturating pyruvate, submaximal pyruvate (100 mu m) reduced the ability of physiological beta-HB to drive respiration, and addition of other intracellular substrates (succinate + palmitoylcarnitine) decreased maximal KB-supported respiration. As a result, product inhibition is likely to limit KB oxidation. Altogether, the ability of KBs to drive mitochondrial respiration is minimal and they are likely to be outcompeted by other substrates, compromising their use as an important energy source.

Thank you for the opportunity to respond to the letter submitted by Gayda and colleagues in response to our recent review published in The Journal of Physiology (Gibala et al. 2012). With regards to their first comment regarding our new ‘practical’ high-intensity interval exercise (HIIE) protocol, we disagree with the assertion that ‘exercise intensity at 60% of peak power cannot be considered high intensity.’ In our efforts to develop a low-volume HIIE protocol that can be applied across different cohorts including clinical populations, we devised a model comprising 10 × 60 s work bouts at an intensity eliciting ∼85–90% of maximal heart rate (HRmax; averaged over the 10 intervals), interspersed by 60 s of recovery. We have found that the percentage of peak power output (PPO; determined using a standard ramp test to volitional fatigue which does not always elicit peak O2 uptake) that approximates the desired target heart rate (i.e. the % of HRmax) varies considerably between subjects and is exercise-mode specific. For example, in the study by Hood et al. (2011) which was conducted on sedentary healthy adults, a workload equivalent to 60% of PPO during upright cycling was sufficient to elicit a training intensity of ∼90% HRmax. However, in our recent study conducted on patients with type 2 diabetes, the intensity required to elicit ∼90% HRmax was ∼95% of PPO determined during recumbent cycling (Little et al. 2011). We agree with the assertion by Gayda and colleagues that ‘acute physiological responses during different HIIE protocols as well as patient's safety, tolerance and comfort should be tested before their implementation into training programs’. Ongoing protocol optimization work in our laboratory reveal that when interval exercise was prescribed as 80% of PPO in coronary artery disease (CAD) patients – most of whom were taking beta-blocker medication – the 10 × 60 s protocol resulted in peak heart rates during the exercise that averaged ∼85% of age-predicted HRmax. Further, the 10 × 60 s protocol was best tolerated and rated as most preferred by CAD patients in comparison with a modified Wingate protocol (repeated 30 s efforts at 100% PPO with 4 min unloaded cycling for recovery), the standard aerobic interval training protocol used by Wisloff and colleagues (2007), or a moderate-intensity continuous exercise (MICE) protocol. It is likely that high-intensity interval training (HIT) does not conform to a ‘one size fits all’ approach and the interval training stimulus needs to be tailored to individuals depending on their initial level of fitness, exercise tolerance, use of prescription medications and other factors. We also concur with the other main comment by Gayda and colleagues that ‘the superiority of this HIIE protocol [our 10 × 60 s ‘hard’/60 s ‘easy’ model]… needs to be demonstrated.’ Indeed, our review concluded ‘One aspect that is unclear from the present literature is the precise intensity and minimal volume of training that is needed to potentiate the effect of the stimulus-adaptation on outcomes such as mitochondrial biogenesis and relevant health markers. To answer such questions, a complex series of studies needs to be undertaken that systematically ‘titrate’ levels of the ‘training impulse’ and determine subsequent cellular, performance and clinical responses after divergent training interventions.’ Specifically with respect to the use of HIIE in patients with cardiovascular risk or cardiovascular disease, the letter by Gayda and colleagues highlights four references from their laboratory that were not cited in our review. Given the relatively broad scope of our review and the fact that Journal guidelines restricted the number of references to 50, it was obviously not possible to cite all relevant work. Moreover, two of the citations listed by Gayda et al. were acute exercise studies (whereas the focus of our review was training adaptations) and the other two citations were a journal abstract and a recent paper published in February 2012 (neither of which we had access to at the time of submission of our original manuscript). We are also aware of the pioneering research conducted by Meyer and colleagues (e.g. Meyer et al. 1998) and have acknowledged this work in a previous commentary (MacDonald & Currie, 2009). We apologize to all authors whose work on interval training we could not cite due to the broad focus of our review and referencing limitations imposed by The Journal.

BACKGROUND: There are two approaches to the differential examination of school motivation. The first is to examine motivation towards specific school subjects (between school subject differentiation). The second is to examine school motivation as a multidimensional concept that varies in terms of not only intensity but also quality (within school subject differentiation). These two differential approaches have led to important discoveries and provided a better understanding of student motivational dynamics. However, little research has combined these two approaches. AIMS: This study examines young elementary students' motivations across school subjects (writing, reading, and maths) from the stance of self-determination theory. First, we tested whether children self-report different levels of intrinsic, identified, and controlled motivation towards specific school subjects. Second, we verified whether children self-report differentiated types of motivation across school subjects. SAMPLE: Participants were 425 French-Canadian children (225 girls, 200 boys) from three elementary schools. Children were in Grades 1 (N=121), 2 (N=126), and 3 (N=178). RESULTS: Results show that, for a given school subject, young elementary students self-report different levels of intrinsic, identified, and controlled motivation. Results also indicate that children self-report different levels of motivation types across school subjects. Our findings also show that most differentiation effects increase across grades. Some gender effects were also observed. CONCLUSION: These results highlight the importance of distinguishing among types of school motivation towards specific school subjects in the early elementary years.

The purpose of this study was to identify factors that are associated with experiencing genetic discrimination (GD) among individuals at risk for Huntington disease (HD). Multivariable logistic regression analysis was used to examine factors associated with experiencing GD in data from a cross-sectional, self-report survey of 293 individuals at risk for HD. The study sample comprised 167 genetically tested respondents, and 66 who were not tested (80% response rate). Overall, individuals who learn they are at risk for HD at a younger age (OR = 3.1; 95% CI: 1.5–6.2; P = 0.002), are mutation-positive (OR = 2.8; 95% CI: 1.4–6.0; P = 0.006), or are highly educated (OR = 2.7; 95% CI: 1.4–5.1; P = 0.002) are more likely to experience GD, particularly in insurance, family, and social settings. Further, younger age was associated with discrimination in insurance (OR = 0.97; 95% CI: 0.94–1.00; P = 0.038). This study provides evidence that some people who are at risk for HD were more likely to experience GD than others. Individuals who learned they are at risk for HD at a younger age and those who are mutation-positive were more likely to experience GD, particularly in insurance, family, and social settings. Younger individuals were more likely to experience discrimination in the insurance setting. Overall, highly educated individuals were also more likely to report discrimination. These results provide direction for clinical and family discussions, counseling practice, and policy aimed at mitigating experiences of GD. © 2010 Wiley-Liss, Inc.

Background:\ud \ud To better understand a potential association of elevated C-reactive protein (CRP) level with progression of chronic kidney disease (CKD), we examined the relationship of CRP level with the development of end-stage renal disease (ESRD) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).\ud \ud Study Design\ud \ud Post hoc analysis of a randomized controlled trial.\ud \ud Setting & Participants:\ud \ud 4,038 patients with type 2 diabetes, CKD, and anemia in TREAT.\ud \ud Predictor:\ud \ud Baseline serum CRP concentrations.\ud \ud Outcomes:\ud \ud The primary outcome was development of ESRD; secondary outcomes included doubling of serum creatinine level, a composite of ESRD/serum creatinine doubling, and a composite of death or ESRD.\ud \ud Measurements:\ud \ud We fit unadjusted and adjusted Cox regression models to test the association of baseline CRP level with time to the development of the outcomes of interest.\ud \ud Results:\ud \ud Mean age of participants was 67 years, 43% were men, and 64% were white. Approximately half (48%) the patients had CRP levels > 3.0 mg/L; 668 patients developed ESRD, and 1,270 developed the composite outcome of death or ESRD. Compared with patients with baseline CRP levels ≤ 3.0 mg/L, those with moderately/markedly elevated CRP levels (≥6.9 mg/L; 24% of patients) had a higher adjusted risk for ESRD (HR, 1.32; 95% CI, 1.07-1.63) and the composite outcome of death or ESRD (HR, 1.41; 95% CI, 1.21-1.64). Although nonsignificant, similar trends were noted in competing-risk models.\ud \ud Limitations:\ud \ud Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia.\ud \ud Conclusions:\ud \ud Elevated baseline CRP levels are common in type 2 diabetic patients with anemia and CKD and are associated with the future development of ESRD and the composite of death or ESRD.

s directions. Our findings confirm that non-renewable energy sources have a positive association with economic growth and CO2 emissions. However, human development, technology, and renewable energy boost economic development and reduce environmental pollution in Pakistan. The co-integration results confirmed the long run connectivity among all variables. The causality outcomes support the bidirectional causality between renewable and non-renewable energy consumption, economic growth, and CO2 emissions, both in the short and long run. These outcomes suggest that Pakistan should focus on energy shifts and gradually increase the share of renewables in its energy mix under the China Pakistan Economic Corridor (CPEC). Additionally, the government should increase human and technological development to enhance economic and environmental sustainability. Energy acts as a catalyst to boost the human development index (HDI) in a country. However, the overuse of energy leads to environmental deterioration, which is a byproduct of economic development. Due to the utilization of non-renewable energy sources for a long time, worldwide environmental conditions have become alarming. This study investigates the relationship between renewable and non-renewable energy consumption, economic growth, environmental sustainability, and the human development index (HDI) in Pakistan. The investigation incorporates population growth and technology variables to form a multivariate framework. We use a fully modified ordinary least squares (FMOLS) approach to time-series data from 1990&ndash Hansen test with a causality test under the VECM to confirm this association&rsquo 2017. To check the robustness of estimations, we apply the Gregory&ndash

SummaryThe AMP-activated protein kinase (AMPK) activates autophagy, but its role in aging and fasting-induced muscle function has not been defined. Here we report that fasting mice lacking skeletal muscle AMPK (AMPK-MKO) results in hypoglycemia and hyperketosis. This is not due to defective fatty acid oxidation, but instead is related to a block in muscle proteolysis that leads to reduced circulating levels of alanine, an essential amino acid required for gluconeogenesis. Markers of muscle autophagy including phosphorylation of Ulk1 Ser555 and Ser757 and aggregation of RFP-LC3 puncta are impaired. Consistent with impaired autophagy, aged AMPK-MKO mice possess a significant myopathy characterized by reduced muscle function, mitochondrial disease, and accumulation of the autophagy/mitophagy proteins p62 and Parkin. These findings establish an essential requirement for skeletal muscle AMPK-mediated autophagy in preserving blood glucose levels during prolonged fasting as well as maintaining muscle integrity and mitochondrial function during aging.

Adolescent depressive symptoms are risk factors for lower education and unemployment in early adulthood. This study examines how the course of symptoms from ages 16–25 influences early adult education and employment in Canada and the USA. Using data from the National Longitudinal Survey of Children and Youth (n = 2348) and the National Longitudinal Survey of Youth 79 Child/Young Adult (n = 3961), four trajectories (low-stable and NEET, i.e., not in employment, education, or training). In both countries, increasing, decreasing, and mid-peak trajectories were associated with higher odds of working with low educational credentials, and/or NEET relative to low-stable trajectories. In Canada, however, all trajectories had a higher predicted probability of either being in school or working with a post-secondary degree than the other outcomes in the USA, all trajectory groups were most likely to be working with a high school degree. Higher depressive symptom levels at various points between adolescent and adulthood are associated with working with low education and NEET in Canada and the USA, but Canadians are more likely to have better education and employment outcomes. and increasing then decreasing, i.e., mid-peak) were linked to five outcomes (working with a post-secondary degree a high school degree increasing decreasing in school no degree

The final meeting of the EXPOsOMICS project "Final Policy Workshop and Stakeholder Consultation" took place 28-29 March 2017 to present the main results of the project and discuss their implications both for future research and for regulatory and policy activities. This paper summarizes presentations and discussions at the meeting related with the main results and advances in exposome research achieved through the EXPOsOMICS project; on other parallel research initiatives on the study of the exposome in Europe and in the United States and their complementarity to EXPOsOMICS; lessons learned from these early studies on the exposome and how they may shape the future of research on environmental exposure assessment; and finally the broader implications of exposome research for risk assessment and policy development on environmental exposures. The main results of EXPOsOMICS in relation to studies of the external exposome and internal exposome in relation to both air pollution and water contaminants were presented as well as new technologies for environmental health research (adductomics) and advances in statistical methods. Although exposome research strengthens the scientific basis for policy development, there is a need in terms of showing added value for public health to: improve communication of research results to non-scientific audiences; target research to the broader landscape of societal challenges; and draw applicable conclusions. Priorities for future work include the development and standardization of methodologies and technologies for assessing the external and internal exposome, improved data sharing and integration, and the demonstration of the added value of exposome science over conventional approaches in answering priority policy questions.

In April 2014, the International Olympic Committee (IOC) published a Consensus Statement in this journal entitled “Beyond the Female Athlete Triad: Relative Energy Deficiency in Sport (RED-S)”.1 In reference to that Consensus Statement, Professor Mary Jane De Souza and colleagues published an editorial (July 2014).2 The editorial below expands on the original Consensus Statement and comments on the 2014 Editorial by Professor Mary Jane De Souza and colleagues. Albert Einstein said: “The important thing is to never stop questioning.” A group of 11 IOC authors have called attention, as others in the past,3 ,4 to a problem that is wider and more complex than originally identified when the term ‘Female Athlete Triad’ (Triad or FAT) was first coined in 1992. Just as knowledge evolves, so too should ideas and constructs on how to address it. Given the evolution of science since 1992, and to more accurately describe the clinical syndrome originally known as the Female Athlete Triad, the IOC introduced a more comprehensive, broader term: Relative Energy Deficiency in Sport. The syndrome of RED-S refers to impaired physiological functioning caused by relative energy deficiency, and includes but is not limited to impairments of metabolic rate, menstrual function, bone health, immunity, protein synthesis, and cardiovascular health. Our April 2014 Consensus statement identifies the aetiological factor underpinning the syndrome as: an energy deficiency relative to the balance between dietary energy intake and the energy expenditure required to support homeostasis, health and the activities of daily living, growth and sporting activities. We reaffirm the principle that the IOC Consensus Statement highlights about energy deficiency/low energy availability among exercising people. De Souza and colleagues’ editorial criticises the use of the word ‘balance,’ suggesting that the IOC authors have confused the terms energy availability and energy balance. We used the term …