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Seventy six senior academics from 11 countries invite The BMJ ’s editors to reconsider their policy of rejecting qualitative research on the grounds of low priority. They challenge the journal to develop a proactive, scholarly, and pluralist approach to research that aligns with its stated mission

Key points Ketone 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.

International audience; Fiber tractography (FT) using diffusion magnetic resonance imaging (dMRI) is widely used for investigating microstructural properties of white matter (WM) fiber-bundles and for mapping structural connections of the human brain. While studying the architectural configuration of the brain's circuitry with FT is not without controversy, recent progress in acquisition, processing, modeling, analysis, and visualization of dMRI data pushes forward the reliability in reconstructing WM pathways. Despite being aware of the well-known pitfalls in analyzing dMRI data and several other limitations of FT discussed in recent literature, we present the superoanterior fasciculus (SAF), a novel bilateral fiber tract in the frontal region of the human brain that-to the best of our knowledge-has not been documented. The SAF has a similar shape to the anterior part of the cingulum bundle, but it is located more frontally. To minimize the possibility that these FT findings are based on acquisition or processing artifacts, different dMRI data sets and processing pipelines have been used to describe the SAF. Furthermore, we evaluated the configuration of the SAF with complementary methods, such as polarized light imaging (PLI) and human brain dissections. The FT results of the SAF demonstrate a long pathway, consistent across individuals, while the human dissections indicate fiber pathways connecting the postero-dorsal with the antero-dorsal cortices of the frontal lobe.

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.

Although the role of IQ in developmental dyslexia remains ambiguous, the dominant clinical and research approaches rely on a definition of dyslexia that requires reading skill to be significantly below the level expected given an individual’s IQ. In the study reported here, we used functional MRI (fMRI) to examine whether differences in brain activation during phonological processing that are characteristic of dyslexia were similar or dissimilar in children with poor reading ability who had high IQ scores (discrepant readers) and in children with poor reading ability who had low IQ scores (nondiscrepant readers). In two independent samples including a total of 131 children, using univariate and multivariate pattern analyses, we found that discrepant and nondiscrepant poor readers exhibited similar patterns of reduced activation in brain areas such as left parietotemporal and occipitotemporal regions. These results converge with behavioral evidence indicating that, regardless of IQ, poor readers have similar kinds of reading difficulties in relation to phonological processing.

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.

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.

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.

International audience; BACKGROUND: Measurement of the global burden of disease with disability-adjusted life-years (DALYs) requires disability weights that quantify health losses for all non-fatal consequences of disease and injury. There has been extensive debate about a range of conceptual and methodological issues concerning the definition and measurement of these weights. Our primary objective was a comprehensive re-estimation of disability weights for the Global Burden of Disease Study 2010 through a large-scale empirical investigation in which judgments about health losses associated with many causes of disease and injury were elicited from the general public in diverse communities through a new, standardised approach. METHODS: We surveyed respondents in two ways: household surveys of adults aged 18 years or older (face-to-face interviews in Bangladesh, Indonesia, Peru, and Tanzania; telephone interviews in the USA) between Oct 28, 2009, and June 23, 2010; and an open-access web-based survey between July 26, 2010, and May 16, 2011. The surveys used paired comparison questions, in which respondents considered two hypothetical individuals with different, randomly selected health states and indicated which person they regarded as healthier. The web survey added questions about population health equivalence, which compared the overall health benefits of different life-saving or disease-prevention programmes. We analysed paired comparison responses with probit regression analysis on all 220 unique states in the study. We used results from the population health equivalence responses to anchor the results from the paired comparisons on the disability weight scale from 0 (implying no loss of health) to 1 (implying a health loss equivalent to death). Additionally, we compared new disability weights with those used in WHO's most recent update of the Global Burden of Disease Study for 2004. FINDINGS: 13,902 individuals participated in household surveys and 16,328 in the web survey. Analysis of paired comparison responses indicated a high degree of consistency across surveys: correlations between individual survey results and results from analysis of the pooled dataset were 0*9 or higher in all surveys except in Bangladesh (r=0*75). Most of the 220 disability weights were located on the mild end of the severity scale, with 58 (26%) having weights below 0*05. Five (11%) states had weights below 0*01, such as mild anaemia, mild hearing or vision loss, and secondary infertility. The health states with the highest disability weights were acute schizophrenia (0*76) and severe multiple sclerosis (0*71). We identified a broad pattern of agreement between the old and new weights (r=0*70), particularly in the moderate-to-severe range. However, in the mild range below 0*2, many states had significantly lower weights in our study than previously. INTERPRETATION: This study represents the most extensive empirical effort as yet to measure disability weights. By contrast with the popular hypothesis that disability assessments vary widely across samples with different cultural environments, we have reported strong evidence of highly consistent results. FUNDING: Bill & Melinda Gates Foundation.