No abstract

To identify the mechanisms responsible for the fluctuations in force that occur during voluntary contractions, experimental measurements were compared with simulated forces in the time and frequency domains at contraction intensities that ranged from 2 to 98% of the maximum voluntary contraction (MVC). The abduction force exerted by the index finger due to an isometric contraction of the first dorsal interosseus muscle was measured in 10 young adults. Force was simulated with computer models of motor-unit recruitment and rate coding for a population of 120 motor units. The models varied recruitment and rate-coding properties of the motor units and the activation pattern of the motor-unit population. The main finding was that the experimental observations of a minimum in the coefficient of variation (CV) for force (1.7%) at approximately 30% MVC and a plateau at higher forces could not be replicated by any of the models. The model that increased the level of short-term synchrony with excitatory drive provided the closest fit to the experimentally observed relation between the CV for force and the mean force. In addition, the results for the synchronization model extended previous modeling efforts to show that the effect of synchronization is independent from that of discharge-rate variability. Most of the power in the force power spectra for the models was contained in the frequency bins below 5 Hz. Only a model that included a low-frequency oscillation in excitation, however, could approximate the experimental finding of peak power at a frequency below 2 Hz: 38% of total power at 0.99 Hz and 43% at 1.37 Hz, respectively. In contrast to the experimental power spectra, all model spectra included a second peak at a higher frequency. The secondary peak was less prominent in the synchronization model because of greater variability in discharge rate. These results indicate that the variation in force fluctuations across the entire operating range of the muscle cannot be explained by a single mechanism that influences the output of the motor-unit population.

Niemann-Pick type C1 (NPC1) disease arises from a mutation inactivating NPC1 protein that normally moves unesterified cholesterol from the late endosomal/lysosomal complex of cells to the cytosolic compartment for processing. As a result, cholesterol accumulates in every tissue of the body causing liver, lung, and CNS disease. Treatment of the murine model of this disease, the npc1 Ϫ/Ϫ mouse, s.c. with ␤-cyclodextrin (4000 mg/kg) one time each week normalized cellular cholesterol metabolism in the liver and most other organs. At the same time, the hepatic dysfunction seen in the untreated npc1 Ϫ/Ϫ mouse was prevented. The severity of cerebellar neurodegeneration also was ameliorated, although not entirely prevented, and the median lifespan of the animals was doubled. However, in contrast to these other organs, lung showed progressive macrophage infiltration with development of lipoid pneumonitis. These studies demonstrated that weekly cyclodextrin administration overcomes the lysosomal transport defect associated with the NPC1 mutation, nearly normalizes hepatic and whole animal cholesterol pools, and prevents the development of liver disease. Furthermore, this treatment slows cerebellar neurodegeneration but has little or no effect on the development of progressive pulmonary disease. (Pediatr Res 68: 309-315, 2010)

Rats on a chronic intermittent ethanol (CIE) regimen showed a persistent reduction in seizure threshold to the convulsant drug pentylenetetrazol (PTZ). CIE rats were given ethanol by intubation on an alternate day schedule and tested at selected intervals for seizure threshold with PTZ. A significant reduction in seizure threshold, a sign of withdrawal, was observed 20 hr after the first dose. The severity of withdrawal intensified on repetition of the ethanol administration and depression-hyperexcitability cycle, with the seizure threshold reaching a maximum decrease after 12 doses and remaining reduced up to 60 doses. The reduction in seizure threshold persisted for at least 40 days of no alcohol following the 60th dose. The long-lasting decrease in seizure threshold following CIE treatment resembled the "kindling" phenomenon produced by chronic administration of PTZ (25 mg/kg, 3 times/week). The CIE rats developed, in addition, a tolerance to the anticonvulsant action of ethanol, which occurred well after the decrease in PTZ seizure threshold, and a tolerance to the hypothermic effect of ethanol, which developed rapidly. PTZ kindled rats that had never been exposed to ethanol also exhibited tolerance to the hypothermic effect of ethanol. We propose that kindling contributes to the mechanism of the development of dependence on central nervous system depressants like benzodiazepines, barbiturates, and alcohol, drugs that act on the gamma-aminobutyric acid-A receptor chloride ion channel complex. Repeated episodes of depression and withdrawal hyperexcitability are postulated to produce kindling during the repeated withdrawal episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of the study was to quantify the effect of motor-unit synchronization on the spike-triggered average forces of a population of motor units. Muscle force was simulated by defining mechanical and activation characteristics of the motor units, specifying motor neuron discharge times, and imposing various levels of motor-unit synchronization. The model comprised 120 motor units. Simulations were performed for motor units 5-120 to compare the spike-triggered average responses in the presence and absence of motor-unit synchronization with the motor-unit twitch characteristics defined in the model. To synchronize motor-unit activity, selected motor-unit discharge times were adjusted; this kept the number of action potentials constant across the three levels of synchrony for each motor unit. Because there was some overlap of motor-unit twitches even at minimal discharge rates, the simulations indicated that spike-triggered averaging underestimates the twitch force of all motor units and the contraction time of motor units with contraction times longer than 49 ms. Although motor-unit synchronization increased the estimated twitch force and decreased the estimated contraction time of all motor units, spike-triggered average force changed systematically with the level of synchrony in motor units 59-120 (upper 90% of the range of twitch forces). However, the reduction in contraction time was similar for moderate and high synchrony. In conclusion, spike-triggered averaging appears to provide a biased estimate of the distribution of twitch properties for a population of motor units because twitch fusion causes an underestimation of twitch force for slow units and motor-unit synchronization causes an overestimation of force for fast motor units.