The effect of ionic strength on the kinetics of rigor development in skinned fast-twitch skeletal muscle fibres.

Recent atomic 3-D reconstructions of the acto-myosin interface suggest that electrostatic interactions are important in the initial phase of cross-bridge formation. Earlier biochemical studies had also given strong evidence for the ionic strength dependence of this step in the cross-bridge cycle. We have probed these interactions by altering the ionic strength (Gamma/2) of the medium mainly with K+, imidazole+ and EGTA2- to vary charge shielding. We examined the effect of ionic strength on the kinetics of rigor development at low Ca2+ (experimental temperature 18-22 degrees C) in chemically skinned single fast-twitch fibres of mouse extensor digitorum longus (EDL) muscle. On average the delay before rigor onset was 10 times longer, the maximum rate of rigor tension development was 10 times slower, the steady-state rigor tension was 3 times lower and the in-phase stiffness was 2 times lower at high (230 mM) compared to low (60 mM) ionic strength. These results were modelled by calculating ATP depletion in the fibre due to diffusional loss of ATP and acto-myosin Mg.ATPase activity. The difference in delay before rigor onset at low and high ionic strength could be explained in our model by assuming a 15 times higher Mg.ATPase activity and a threefold increase in Km in relaxing conditions at low ionic strength. Activation by Ca2+ induced at different time points before and during onset of rigor confirmed the calculated time course of ATP depletion. We have also investigated ionic strength effects on rigor development with the activated troponin/tropomyosin complex. ATP withdrawal at maximum activation by Ca2+ induced force transients which led into a "high rigor" state. The peak forces of these force transients were very similar at low and high ionic strength. The subsequent decrease in tension was only 10% slower and steady-state "high rigor" tension was reduced by only 27% at high compared to low ionic strength. Addition of 10 mM phosphate to lower cross-bridge attachment strongly suppressed the transient increases in force at high ionic strength and reduced the steady-state rigor tension by 17%. A qualitatively similar but smaller effect of phosphate was observed at low ionic strength where steady-state rigor force was reduced by 10%. The data presented in this study show a very strong effect of ionic strength on rigor development in relaxed fibres whereas the ionic strength dependence of rigor development after thin filament activation was much less. The data confirm the importance of electrostatic interactions in cross-bridge attachment and cross-bridge-attachment-induced activation of thin filaments.

Evidence for independent feedback control of horizontal and vertical saccades from Niemann-Pick type C disease.

We measured the eye movements of three sisters with Niemann-Pick type C disease who had a selective defect of vertical saccades, which were slow and hypometric. Horizontal saccades, and horizontal and vertical pursuit and vestibular eye movements were similar to control subjects. The initial movement of oblique saccades was mainly horizontal and most of the vertical component occurred after the horizontal component ended; this resulted in strongly curved trajectories. After completion of the horizontal component of an oblique saccade, the eyes oscillated horizontally at 10-20 Hz until the vertical component ended. These findings are best explained by models that incorporate separate feedback loops for horizontal and vertical burst neurons, and in which the disease selectively affects vertical burst neurons.

Quantitative measurements of eye movements in a patient with Tullio phenomenon.

The Tullio phenomenon consists of vestibular symptoms on exposure to high-intensity acoustic stimuli, reflecting pathological stimulation of semicircular canals or otoliths. We report a patient with posttraumatic Tullio phenomenon to illustrate how precise measurement of eye movements during auditory stimulation, using the magnetic search coil technique, may characterize movements that are not clinically apparent or easily measured by other means. Such measurements in patients with surgically verified lesions may further elucidate the mechanisms responsible for this phenomenon.

A pilot study of gabapentin as treatment for acquired nystagmus.

The effects of the anticonvulsant gabapentin were measured on vision and eve movements in three patients with acquired pendular nystagmus. In two patients, the nystagmus was associated with multiple sclerosis and, in the other, it followed brainstem stroke. A single oral 600 mg dose of gabapentin produced improvement of vision due to changes in ocular oscillations in all three patients. The effect was sustained after five weeks of treatment in two patients who elected to continue taking gabapentin 900-1500 mg/day. The results of this pilot study suggest that a controlled trial of gabapentin should be conducted to evaluate its role in the treatment of acquired forms of nystagmus.