An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Contrasted mediolateral postural control mechanisms in varied foot positions.

International audienc

Advantages and disadvantages of stiffness instructions when studying postural control

To understand the maintenance of upright stance, researchers try to discover the fundamental mechanisms and attentional resources devoted to postural control and eventually to the performance of other tasks (e.g., counting in the head). During their studies, some researchers require participants to stand as steady as possible and other simply ask participants to stand naturally. Surprisingly, a clear and direct explanation of the usefulness of the steadiness requirement seems to be lacking, both in experimental and methodological discussions. Hence, the objective of the present note was to provide advantages and disadvantages of this steadiness requirement in studies of postural control. The advantages may be to study fundamental postural control, to eliminate useless postural variability, to control spurious body motions and to control the participants' thoughts. As disadvantages, this steadiness requirement only leads to study postural control in unnatural upright stance, it changes the focus of attention (internal vs. external) and the nature of postural control (unconscious vs. conscious), it increases the difficulty of a supposedly easy control task and it eliminates or reduces the opportunity to record exploratory behaviors. When looking carefully at the four advantages of the steadiness requirement, one can believe that they are, in fact, more disadvantageous than advantageous. Overall therefore, this requirement seems illegitimate and it is proposed that researchers should not use it in the study of postural control. They may use this requirement only if they search to know the limit until which participants can consciously reduce their postural sway

Broad stance conditions change postural control and postural sway.

Intuitively, a broad stance (i.e., standing with the feet farther apart than usual) should significantly improve postural stability. However, this intuition was not confirmed in quiet stance. Hence, a motion analysis system (markers attached to the trunk and head) and a force platform were used to investigate 13 healthy, young adults who performed 8 trials in standard and broad stances. In broad stance, the medialateral center of pressure (COP) sway mean power frequency was expected to be greater, whereas the variability (standard deviation) of COP, head, and trunk sway and the mean velocity of head and trunk sway was expected to be significantly lower. Accordingly, adoption of a broad stance significantly increased the medialateral mean power frequency of COP sway; decreased the standard deviation of medialateral COP, trunk, and head sway; and decreased the medialateral mean velocity of head sway. A broad stance was also associated with lower variability for head and COP sways in the anteroposterior axis. Unexpectedly, an effect of trial repetition was found for the variability of medialateral trunk sway. This was probably due to the break halfway through the study. In practical terms, broad stance conditions can improve postural control in the medialateral and anteroposterior axes

Contrôle postural de patients parkinsoniens lors d’observations libres de larges images

Introduction Les patients parkinsoniens ont un contrôle postural moins efficace que les personnes témoins surtout face à des perturbations extérieures. Nous avons vérifié s’il en était de même lors d’observations libres de larges images. Nous supposions qu’ils tourneraient moins leur corps que les témoins pour maintenir un contrôle postural efficace. Matériel et méthodes Vingt-trois patients (77,79 ± 16,56 ans ; stade Hoehn et Yahr : 2,04 ± 0,36 ; sous médication) et vingt témoins ont réalisé trois tâches visuelles : regarder une cible fixe (contrôle) et explorer des images, soit sans but (observation), soit pour y localiser 5 cibles (recherche). Une plateforme de force, un système d’analyse du mouvement, un oculomètre mobile et un écran panoramique ont été utilisés. Résultats Les patients ont trouvé moins de cibles en recherche que les témoins. Avec leurs yeux, ils exploraient les images significativement plus loin que les témoins, ils réalisaient plus de fixations et de plus longues fixations que les témoins. Ils tournaient leur corps de la même façon que les témoins en recherche et significativement plus leur dos et cou en tâche d’observation. Pourtant, les patients n’oscillaient jamais plus que les témoins. Discussion–conclusion Comme attendu, les patients ont utilisé plus leurs yeux que les témoins pour explorer les images. De façon inattendue, les patients tournaient globalement plus leur corps que les témoins, surtout en tâche d’observation. De façon surprenante, les patients n’étaient pas déstabilisés par leur exploration visuelle. Leur performance visuelle devait donc être diminuée à cause d’une stratégie de fixation inadaptée

Peripheral neuropathy may not be the only fundamental reason explaining increased sway in diabetic individuals.

Individuals with diabetic neuropathy sway more than control individuals while standing. This review specifically evaluated whether peripheral sensory neuropathy can be the only fundamental reason accounting for significant increased sway within this population. Twenty-six experimental articles were selected using MEDLINE and reference lists of relevant articles. The articles chosen investigated kinematic data of postural behaviour in controls and individuals with diabetic neuropathy during stance. Results of literature were compared with four expectations related to the peripheral sensory neuropathy fundamental hypothesis. Consistent with the peripheral sensory neuropathy hypothesis, the literature showed that individuals with diabetic neuropathy sway more than controls in quiet stance and even more so if their visual or vestibular systems were perturbed. Inconsistent with the hypothesis, individuals with diabetic neuropathy are more destabilised than controls in conditions altering sensation of the feet and legs (standing on a sway-referenced surface). The review showed that the peripheral sensory neuropathy hypothesis may not be the only fundamental cause accounting for significant increased postural sway in individuals with diabetic neuropathy. Visual impairments and changes in postural coordination may explain the divergence between expectations and results. In order to develop interventions aimed at improving postural control in individuals with diabetic neuropathy, scientific exploration of these new expectations should be detailed. Also at the practical level, the review discussed which additional sensory information - at the level of the hands and feet - may be more beneficial in individuals with diabetic neuropathy to reduce their postural sway

Large lateral head movements and postural control.

International audienceRiccio and Stoffregen (1988) have suggested that task performance is the predominant constraint of change in postural control. To test this hypothesis, 12 healthy, young adults performed large lateral gaze shifts (left/right gaze shifts with a visual angle of 150° and at a frequency of 0.5 Hz or 1 Hz) and a control condition (looking at a stationary dot). Performance in the visual task was expected to be good under all conditions. In accordance with Riccio and Stoffregen's hypothesis, the center of pressure sway variability (range or standard deviation) was expected to be similar in the three visual tasks when a destabilizing, narrow stance was adopted. Indeed, body sway had to be restrained in narrow stance to adequately perform the task. In standard and wide stance conditions, the center of pressure sway variability was expected to be larger when gaze shifts were performed. Indeed, in these more stable stance conditions, the task could be performed successfully in minimizing energy expenditure, that is, in letting body sway increase naturally. The results were consistent with these expectations. On a practical level, intentional, large gaze shifts may not cause postural instability per se, even though postural sway may increase significantly

Large lateral head movements and postural control.

International audienceRiccio and Stoffregen (1988) have suggested that task performance is the predominant constraint of change in postural control. To test this hypothesis, 12 healthy, young adults performed large lateral gaze shifts (left/right gaze shifts with a visual angle of 150° and at a frequency of 0.5 Hz or 1 Hz) and a control condition (looking at a stationary dot). Performance in the visual task was expected to be good under all conditions. In accordance with Riccio and Stoffregen's hypothesis, the center of pressure sway variability (range or standard deviation) was expected to be similar in the three visual tasks when a destabilizing, narrow stance was adopted. Indeed, body sway had to be restrained in narrow stance to adequately perform the task. In standard and wide stance conditions, the center of pressure sway variability was expected to be larger when gaze shifts were performed. Indeed, in these more stable stance conditions, the task could be performed successfully in minimizing energy expenditure, that is, in letting body sway increase naturally. The results were consistent with these expectations. On a practical level, intentional, large gaze shifts may not cause postural instability per se, even though postural sway may increase significantly

The Stationary-Gaze Task Should Not Be Systematically Used as the Control Task in Studies of Postural Control

In studies of postural control, a control task is often used to understand significant effects obtained with experimental manipulations. This task should be the easiest task and (therefore) engage the lowest behavioral variability and cognitive workload. Since 1983, the stationary-gaze task is considered as the most relevant control task. Instead, the authors expected that free looking at small targets (white paper or images; visual angle: 12°) could be an easier task. To verify this assumption, 16 young individuals performed stationary-gaze, white-panel, and free-viewing 12° tasks in steady and relaxed stances. The stationary-gaze task led to significantly higher cognitive workload (mean score in the National Aeronotics and Space Administration Task Load Index questionnaire), higher interindividual body (head, neck, and lower back) linear variability, and higher interindividual body angular variability-not systematically yet-than both other tasks. There was more cognitive workload in steady than relaxed stances. The authors also tested if a free-viewing 24° task could lead to greater angular displacement, and hence greater body sway, than could the other tasks in relaxed stance. Unexpectedly, the participants mostly moved their eyes and not their body in this task. In the discussion, the authors explain why the stationary-gaze task may not be an ideal control task and how to choose this neutral task

Proximal postural control mechanisms may be exaggeratedly adopted by individuals with peripheral deficiencies: a review.

In quiet stance, it is understood that healthy individuals control their posture primarily by a peripheral mechanism for anteroposterior sway and by a proximal mechanism for medialateral sway. The authors proposed the hypothesis that patients suffering from disease-related deficiencies, at their feet and legs, may exaggeratedly adopt proximal control mechanisms at their hip in the anteroposterior and medialateral axes. They critically reviewed the literature to test the proximal control hypothesis against published findings. The selected articles analyzed postural control mechanisms in individuals with diabetic peripheral neuropathy and in healthy controls. The data selected were kinematic and electromyographic. In the anteroposterior axis, 4 authors had previously tested the proposed hypothesis, but the findings are contrasted. In the medialateral axis, one study failed to validate the tested hypothesis. Overall, the published studies did not conform with the proximal control hypothesis. However, these studies did not specifically or deeply test such a hypothesis. The lack of results is critical because individuals suffering from peripheral disease-related deficiencies may be unstable, in part, because of a change in postural control mechanisms. For improvement of their stability and appropriate interventions, scientific explorations of the proximal control hypothesis should be investigated. Two proposals are made to move forward