Antisense oligonucleotide eluforsen improves CFTR function in F508del cystic fibrosis

BackgroundCystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. In this study we assessed the effect of antisense oligonucleotide eluforsen on CFTR biological activity measured by Nasal Potential Difference (NPD) in patients with the most common mutation, F508del-CFTR.MethodsThis multi-centre, exploratory, open-label study recruited adults with CF homozygous or compound heterozygous for the F508del-CFTR mutation. Subjects received intranasal eluforsen three times weekly for 4 weeks. The primary endpoint was the within-subject change from baseline in total chloride transport (Cl-free+iso), as assessed by NPD. Secondary endpoints included within-subject change from baseline in sodium transport.ResultsIn the homozygous cohort (n = 7; per-protocol population), mean change (90% confidence interval) in Cl-free+iso was ?3.0 mV (?6.6; 0.6) at day 15, ?4.1 mV (?7.8; ?0.4, p = .04) at day 26 (end of treatment) and ? 3.7 mV (?8.0; 0.6) at day 47. This was supported by improved sodium transport as assessed by an increase in average basal potential difference at day 26 of +9.4 mV (1.1; 17.7, p = .04). The compound heterozygous cohort (n = 7) did not show improved chloride or sodium transport NPD values. Eluforsen was well tolerated with a favourable safety profile.ConclusionsIn F508del-CFTR homozygous subjects, repeated intranasal administration of eluforsen improved CFTR activity as measured by NPD, an encouraging indicator of biological activity.     

Determination of 241Am in sediments by isotope dilution high resolution inductively coupled plasma mass spectrometry (ID HR ICP-MS).

Trace levels (pg kg(-1)) of 241Am in sediments were determined by isotope dilution high resolution inductively coupled plasma mass spectrometry (ID HR ICP-MS) using a microconcentric nebulizer. 241Am was isolated from major elements like Ca and Fe by different selective precipitations. In further steps. Am was first separated from other transuranic elements and purified by anion exchange and extraction chromatography prior to the mass spectrometric measurements. The ID HR ICP-MS results are compared with isotope dilution alpha spectrometry.     

Does body stability depend on postural chain mobility or stability area?

The purpose of this study was to examine whether postural stability depends only on the support base perimeter, that is the stability area, when body balance is perturbed by respiration. To this end, seven normal subjects were asked to breathe quietly, breathe deeply and to hold their breath (apnoea). They were asked to maintain a standing posture (Sta), and two sitting postures differing by the ischio femoral contact with the seat (Sit100 and Sit30). In other words, these three postures differed not only by the stability area, but also by pelvis mobility. The thoracic perimeter, displacement of the centre of pressure (CP) and iliac crest acceleration (Ah), taken as an index of pelvis mobility, of seven normal subjects were recorded. The results showed that the sway path (SP) was longer in seated subjects than in standing ones, and in Sit100 than in Sit30. The distance between the CP extreme positions (Delta Xp) varied in the opposite direction to SP. Iliac crests and thoracic displacements were shown to be in phase in Sit condition, and did not display any particular pattern in Sta. It was concluded that postural steadiness depends on the postural chain mobility in addition to stability area. As pelvis and lumbar column mobility are related, it is proposed that both contribute to postural chain mobility, owing to respiratory perturbation being compensated.     

Compensatory reactions in forward fall: are they initiated by stretch receptors?

Electromyographic activities from soleus and tibialis anterior muscles of 12 healthy subjects and 3 patients with vestibular syndrome, together with onset of movement of the head and leg were recorded during balance recovery. The disequilibrium was induced from initial forward inclination of the body. Soleus of the oscillatory foot showed brisk activity starting 59 msec (mean latency) after the perturbation and lasting 100-120 msec. Soleus of the stance foot showed similar activity, except that its duration was longer. The antagonist muscle activities started 5-20 msec later and showed similar time courses but of smaller amplitude. Ischaemia of the leg did not modify the latency. The onset of head movement was 10-20 msec after the perturbation, and those of leg were 70-90 msec. The results suggest that the early motor responses of the balance recovery were neither triggered by discharges from soleus group I and group II afferents, nor from vestibular cues, but could possibly originate in receptors located at the abdominal or lumbar level.     

Motor unit activity and preprogramming of movement in man.

The activity of single motor units (MUs) is studied during voluntary dynamic movements in man. It is shown that as soon as a MU is set into activity, i.e., at the beginning of the myoelectric burst which precedes the start of the limb movement, there exists a consistent relationship between the peak velocity (for a given inertia) had the interval between the first two consecutive discharges of this MU. Thus, it is likely that when the amplitude of the movement is voluntarily limited, the peak velocity of the movement is preprogrammed.     

Does postural chain muscular stiffness reduce postural steadiness in a sitting posture?

This study investigated the effect of postural chain muscular stiffening on postural steadiness when it is rhythmically perturbed by respiration. It consisted of an analysis of centre of pressure (CP) displacements when constant sub-maximum pushing efforts were performed in a sitting posture. Muscular stiffness, assessed by surface electromyography (iEMG), was imposed at two controlled levels, using two intensities of pushing effort (20% and 40% of the maximum voluntary contraction: 20MVC and 40MVC). Lumbo-pelvic mobility was varied using two different support areas at the seat contact (100% and 30% of the ischio-femoral length: 100BP and 30BP). Respiratory disturbance to posture was varied using two respiratory rate conditions (quiet breathing (QB), which is the spontaneous rate, and fast breathing (FB) at a rate imposed by a metronome). The results demonstrated that an increased push effort was associated to a higher iEMG level, and induced greater mean deviation (X (p)) and sway path (SP) of antero-posterior CP displacements. It was concluded that postural muscle stiffness reduces postural steadiness. It was suggested that it could be related to a weaker compensation of respiratory disturbance to body posture.     

Does postural chain mobility influence muscular control in sitting ramp pushes?

This study was conducted under the hypothesis that voluntary movement involves a perturbation of body balance and that a counter-perturbation has to be developed to limit the perturbation effects, which is a condition necessary to perform the movement efficiently. The stabilising action is produced in body segments that constitute the postural chain, and the voluntary movement by the segments said to constitute the focal chain. In order to deepen the understanding of how the postural chain contributes to the motor act, isometric transient efforts were considered. Seven adults in a sitting posture were instructed to exert bilateral horizontal pushes on a dynamometric bar, as rapidly as possible, up to their maximal force (Fx). Two sitting conditions were considered: full ischio-femoral contact (100 BP) and one-third ischio-femoral contact (30 BP), the latter being known to yield greater pelvis and spine mobility, that is greater postural mobility. Each session consisted of ten maximal pushes for each sitting condition. In order to explore the influence of postural mobility on muscular control and push force, surface EMGs of 14 postural and focal muscles were recorded. In addition, reaction forces (Rx) and displacement (Xp) of the centre of pressure (along the anteroposterior axis) were measured, as well as iliac crest acceleration ( and , along the anteroposterior and vertical axes, respectively). The results showed that push force varied abruptly during the task ramp effort. When the ischio-femoral contact was limited, push force was enhanced, as well as the rate of push force rise (Fx/t, t being the force rise duration), suggesting a greater perturbation to balance. Also, there were significant increases in the Rx reaction forces, indicating body segment acceleration: dynamic phenomena occurred in the articulated body chain in response to increases in Fx. In addition, even though muscular contraction was isometric, postural EMGs, as well as focal EMGs, were phasic, a feature which characterises transient force exertion. The Rx reaction forces were associated with backward displacement of the centre of pressure, Xp. The centre of pressure displacement was interpreted as a backward pelvis rotation, an interpretation which was confirmed by backward and upward iliac crest accelerations. When ischio-femoral contact was reduced, the backward pelvis rotation was significantly increased, resulting from an increased pelvis and spine mobility. Distinct focal and postural EMG sequences were found to be associated with the effort. Two different sets of muscles were observed when considering recruitment order, the focal and the postural muscles. The ankle muscles were activated before the pelvis, the back and the scapular girdle, with the upper limb muscles activated only after the onset of the primum movens of push action (serratus anterior): the activation process followed a distal to proximal progression order. Moreover, the postural EMG sequence was anticipatory, that is there were anticipatory postural adjustments (APAs). Modifying the ischio-femoral contact did not induce a change in either the postural muscle set or in the recruitment order. There were significant increases in the level of activation (integrated EMG) of the postural muscles when ischio-femoral contact was reduced. They did not result from an increase in EMG duration but only from a modulation of EMG amplitude, suggesting that postural control for different ischio-femoral contacts involves adapting the motor program according to the postural requirements, rather than changing the postural strategy. Moreover, as APA amplitude was increased when ischio-femoral contact was reduced, it could be assumed that the postural chain is programmed in relation to postural chain mobility. In addition, the increase in postural EMGs was interpreted as an increased counter-perturbation opposed to an increased push force. It is concluded that greater mobility of the postural chain favours a greater dynamic counter-perturbation, which, in turn, allows the development of a greater push force; the ability to develop such a counter-perturbation (termed PKC: posturo-kinetic capacity) is enhanced when postural chain mobility is greater. Postural chain mobility appears to be a task parameter, and postural control appears to involve adapting the motor program according to the postural requirements, rather than changing the postural strategy.     

Are there anticipatory segmental adjustments associated with lower limb flexions when balance is poor in humans?

For a leg raising task performed in a sagittal plane, it has been shown that body balance instability can suppress anticipatory postural adjustments (APAs). The aim of this study was to determine whether the global (centre of mass) postural adjustments were replaced by local (segmental) ones, which were compensating each other and resulting in a lack of global APAs. Six healthy subjects must perform a lower limb flexion from two initial postures, corresponding to a bipedal (Fbu) and an unipedal (Fuu) stance. Kinematics of postural adjustments were recorded with accelerometers. The results showed that in Fbu the kinematics have large durations of APAs, contrary to Fuu where there are none. They showed also that during the voluntary movement the magnitudes of the segmental postural accelerations were equal or superior in Fuu than in Fbu on the anteroposterior and lateral axes, where balance is poor. Also while, on the contrary, the magnitudes are reversed on the vertical axis. These results suggest that firstly: (1) the absence of APAs can correspond to a strategic response for weak postural base configuration and secondly; (2) the local postural accelerations, depending to the axes, are linked to two different functions: to maintaining the balance and to performing the focal movement.     

Anticipatory EMG patterns associated with preferred and non-preferred arm pointing movements

Rapid arm movements generate balance perturbations, which are anticipated and counteracted by postural adjustments. The effect of lateral preference on the control of the postural preparation to maximal velocity upperlimb pointing movements was investigated in right-handers. The muscular activities characterizing the postural adjustments were compared for preferred and non-preferred upper-limb movements. Movements were performed in two sitting conditions differing by their stability ("full on seat" and "edge of seat"). The electromyographic activity of the arm-movement prime mover and of several trunk and hip muscles involved in postural control was recorded with surface electrodes. Results indicate the presence of a reproducible pattern of anticipatory postural adjustments (APAs) involving trunk and hip muscles preceding the activation of the prime mover. In the "full on seat" condition, APAs started earlier and movement velocity was higher for preferred than for non-preferred arm movements. In the "edge of seat" condition, maximal velocity of movement did not differ significantly between both sides, but a higher excitation level of postural muscles was required to achieve this similar performance when the non-preferred upper limb was used. These findings are consistent with the hypothesis that handedness involves differences in the postural control associated with upperlimb movements, in other words that lateral preference is associated with a postural laterality.