Stochasticity in the miR-9/Hes1 oscillatory network can account for clonal heterogeneity in the timing of differentiation.

Recent studies suggest that cells make stochastic choices with respect to differentiation or division. However, the molecular mechanism underlying such stochasticity is unknown. We previously proposed that the timing of vertebrate neuronal differentiation is regulated by molecular oscillations of a transcriptional repressor, HES1, tuned by a post-transcriptional repressor, miR-9. Here, we computationally model the effects of intrinsic noise on the Hes1/miR-9 oscillator as a consequence of low molecular numbers of interacting species, determined experimentally. We report that increased stochasticity spreads the timing of differentiation in a population, such that initially equivalent cells differentiate over a period of time. Surprisingly, inherent stochasticity also increases the robustness of the progenitor state and lessens the impact of unequal, random distribution of molecules at cell division on the temporal spread of differentiation at the population level. This advantageous use of biological noise contrasts with the view that noise needs to be counteracted

Clinical examination of the foot and the ankle. Data collection and interpretation of the pathogenic causal sequence of disorders

SummaryThe clinical examination remains the irreplaceable stage in assessing foot and the ankle disorders. It comprises a complete inventory of the patient's complaints and the data obtained from the physical examination. Afterwards, it should concentrate on establishing consistency between symptoms that can be disparate, to link them in a logical pathogenic causal pattern to be used in developing a treatment programme. These correlations are the most often obvious and only require confirmation with standard X-rays. In the absence of consistency, and if a diagnosis is difficult to establish, recourse to more sophisticated investigations (CT scan, MRI or an intra-articular local anaesthetic test) becomes worthwhile. To achieve maximum value, the physical examination must be based on prerequisite knowledge of functional anatomy, admittedly basic but covering all the bone and joint, ligament, muscle, skin and neurovascular components. All these structures being closely interrelated. This organization allows for remarkable protection mechanisms and the capacity to endure considerable cyclic stress. This interdependence can also command chains of injury difficult to unravel. The examination must thus be methodical and comprehensive: history taking (ranking of symptoms, evaluation of the patient's psychological profile); physical examination, standing, on a podoscope, gait analysis, lying down (trophic disorders, joint range of motion, muscle testing); standard X-rays, always weight bearing. This discursive organization, essential in everyday practice, avoids the sequence “symptom → MRI → surgical indication” which is a professional and intellectual deviance; it enables the development, in terms of advantages against risks, or an appropriate treatment plan in the best conditions