Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing.

Prolonged unaccustomed exercise involving muscle lengthening (eccentric) actions can result in ultrastructural muscle disruption, impaired excitation-contraction coupling, inflammation and muscle protein degradation. This process is associated with delayed onset muscle soreness and is referred to as exercise-induced muscle damage. Although a certain amount of muscle damage may be necessary for adaptation to occur, excessive damage or inadequate recovery from exercise-induced muscle damage can increase injury risk, particularly in older individuals, who experience more damage and require longer to recover from muscle damaging exercise than younger adults. Furthermore, it is apparent that inter-individual variation exists in the response to exercise-induced muscle damage, and there is evidence that genetic variability may play a key role. Although this area of research is in its infancy, certain gene variations, or polymorphisms have been associated with exercise-induced muscle damage (i.e. individuals with certain genotypes experience greater muscle damage, and require longer recovery, following strenuous exercise). These polymorphisms include ACTN3 (R577X, rs1815739), TNF (-308 G>A, rs1800629), IL6 (-174 G>C, rs1800795), and IGF2 (ApaI, 17200 G>A, rs680). Knowing how someone is likely to respond to a particular type of exercise could help coaches/practitioners individualise the exercise training of their athletes/patients, thus maximising recovery and adaptation, while reducing overload-associated injury risk. The purpose of this review is to provide a critical analysis of the literature concerning gene polymorphisms associated with exercise-induced muscle damage, both in young and older individuals, and to highlight the potential mechanisms underpinning these associations, thus providing a better understanding of exercise-induced muscle damage

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

How do postgraduate GP trainees regulate their learning and what helps and hinders them? A qualitative study

Contains fulltext : 108146.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Self-regulation is essential for professional development. It involves monitoring of performance, identifying domains for improvement, undertaking learning activities, applying newly learned knowledge and skills and self-assessing performance. Since self-assessment alone is ineffective in identifying weaknesses, learners should seek external feedback too. Externally regulated educational interventions, like reflection, learning portfolios, assessments and progress meetings, are increasingly used to scaffold self-regulation.The aim of this study is to explore how postgraduate trainees regulate their learning in the workplace, how external regulation promotes self-regulation and which elements facilitate or impede self-regulation and learning. METHODS: In a qualitative study with a phenomenologic approach we interviewed first- and third-year GP trainees from two universities in the Netherlands. Twenty-one verbatim transcripts were coded. Through iterative discussion the researchers agreed on the interpretation of the data and saturation was reached. RESULTS: Trainees used a short and a long self-regulation loop. The short loop took one week at most and was focused on problems that were easy to resolve and needed minor learning activities. The long loop was focused on complex or recurring problems needing multiple and planned longitudinal learning activities. External assessments and formal training affected the long but not the short loop. The supervisor had a facilitating role in both loops. Self-confidence was used to gauge competence.Elements influencing self-regulation were classified into three dimensions: personal (strong motivation to become a good doctor), interpersonal (stimulation from others) and contextual (organizational and educational features). CONCLUSIONS: Trainees did purposefully self-regulate their learning. Learning in the short loop may not be visible to others. Trainees should be encouraged to actively seek and use external feedback in both loops. An important question for further research is which educational interventions might be used to scaffold learning in the short loop. Investing in supervisor quality remains important, since they are close to trainee learning in both loops

Convergence of mitochondrial and chloroplastic ANAC017/PAP-dependent retrograde signalling pathways and suppression of programmed cell death

The energy-converting organelles mitochondria and chloroplasts are tightly embedded in cellular metabolism and stress response. To appropriately control organelle function, extensive regulatory mechanisms are at play that involve two-way exchange between the nucleus and mitochondria/chloroplasts. In recent years, our understanding of how mitochondria and chloroplasts provide â € retrograde' feedback to the nucleus, resulting in targeted transcriptional changes, has greatly increased. Nevertheless, mitochondrial and chloroplast retrograde signalling have largely been studied independently, and only few points of interaction have been found or proposed. Through reassessment of recent publications, this perspective proposes that two of the most well-studied retrograde signalling pathways in plants, those mediated by ANAC017 and those mediated by phosphoadenosine phosphate (PAP), are most likely convergent and can direct overlapping genes. Furthermore, at least part of this common retrograde response appears targeted towards suppression of programmed cell death (PCD) triggered by organellar defects. The identified target genes are discussed in light of their roles in PCD suppression and amplifying the signalling cascade via positive-feedback loops. Finally, a mechanism is proposed that may explain why the convergence of PAP/ANAC017-dependent signalling appears capable of suppressing some types of PCD lesions, but not others, based on the subcellular location of the initial PCD-inducing dysfunction