Mechanisms of fatigue in normal intercostal muscle and muscle from patients with myasthenia gravis.

Fatigue mechanisms in normal intercostal muscle and muscle from patients with myasthenia gravis (MG) were evaluated by monitoring the compound muscle action potential (CMAP) and tetanic tension responses to repetitive nerve or muscle stimulation in vitro. When fatigue was induced by nerve stimulation at 30 Hz for 0.5 s every 2.5 s, about half of the original tension decreased after 30 min in normal muscle and 5 min in MG muscle. Analysis of the changes in area of CMAPs and tension indicated that impairment of neuromuscular transmission, muscle membrane excitation, and excitation-contraction (E-C) coupling and contractility accounted for 40%, 29%, and 31% of fatigue in normal muscle, and 83%, 0%, and 17% of fatigue in MG muscle. When fatigue was induced by muscle stimulation at 30 Hz, tension declined by a quarter after 30 min in normal muscle, but by a half after 17 min in MG muscle. Impairment of muscle membrane excitation and E-C coupling and contractility accounted for 58% and 42% of fatigue in normal muscle, and 22% and 78% of fatigue in MG muscle. Thus, fatigue of normal muscle is caused by impairment of at least four processes, and enhanced fatigue of MG muscle is caused by greater impairment of neuromuscular transmission, E-C coupling, and contractility.

Effect of cocaine on responses of mouse phrenic nerve-diaphragm preparation.

Effects of 5 to 40 microM cocaine on the compound action potential (AP) and tension responses of the mouse phrenic nerve-diaphragm preparation were monitored following nerve and muscle stimulation at 37 degrees C. Cocaine caused concentration dependent reduction in amplitude of the nerve AP, muscle AP, and tension response to a single nerve stimulus, and greater reduction in amplitude of these responses to repetitive nerve stimuli at 100 Hz for 0.5 sec. Cocaine caused similar reduction in the muscle AP and tension responses to direct muscle stimulation in the presence or absence of curare, and markedly reduced the overshoot, total potential, and maximum rate of rise and fall of intracellularly recorded muscle AP, without affecting the resting potential, or the contracture responses evoked by caffeine. These results indicate that cocaine reduces skeletal muscle function by reducing the excitability of muscle and nerve membranes, without significantly affecting neuromuscular transmission, excitation-contraction coupling or contractility.

Peripheral mechanisms of fatigue in muscles of normal and dystrophic mice.

We evaluated the contribution of different processes to fatigue of normal and dystrophic mouse muscles using an in vitro electromyography chamber. Fatigue was induced by repetitive nerve stimulation at 30 Hz for 0.5 s, every 2.5 s until tension decreased by about 50%. We monitored the compound nerve action potential (AP), compound muscle AP, and isometric tension responses to nerve stimulation, and compound muscle AP and tension responses to direct muscle stimulation. In normal mice, about 50% reduction in nerve-evoked tension occurred by 2.4 min in extensor digitorum longus (EDL), 4.8 min in diaphragm, and 9 min in soleus. Analysis of the responses revealed that the fatigue was caused by failure of more than one process in all muscles, and failure of nerve conduction did not contribute to fatigue in any muscle. Failure of neuromuscular transmission, muscle membrane excitation, and excitation-contraction (E-C) coupling and contractility accounted for 55, 45, and 0%, respectively, of the fatigue in EDL, for 21, 74, and 5% of the fatigue in diaphragm, and for 2, 54, and 44% of the fatigue in soleus. In dystrophic mice, while about 50% reduction in nerve-evoked tension occurred by 8.1 min in EDL and 5.6 min in diaphragm, only 29% reduction in tension occurred by 80 min in soleus. Failure of neuromuscular transmission, muscle membrane excitation, E-C coupling and contractility accounted for 22, 63 and 15% of the fatigue in EDL, for 21, 79, and 0% of the fatigue in diaphragm, and for 15, 59, and 26% of the fatigue in soleus. The proportion of slow-twitch oxidative fibers was more than normal in dystrophic EDL, but the same as normal in dystrophic diaphragm and soleus. The slower onset of fatigue was attributable to lesser failure of neuromuscular transmission in dystrophic EDL, and to lesser failure of E-C coupling and contractility in dystrophic soleus.

Comparisons of Isozyme Phenotypes in Five Meloidogyne spp. with Isoelectric Focusing.

Meloidogyne incognita race 1, M. javanica, M. arenaria race 1, M. hapla, and an undescribed Meloidogyne sp. were analyzed by comparing isozyme phenotypes of esterase, malate dehydrogenase, phosphoglucomutase, isocitrate dehydrogenase, and alpha-glycerophosphate dehydrogenase. Isozyme phenotypes were obtained from single mature females by isoelectric focusing electrophoresis. Of these five isozymes, only esterase and phosphoglucomutase could be used to separate all five Meloidogyne spp.; however, the single esterase electromorphs were similar for M. incognita and M. hapla. Yet when both nematodes were run on the same gel, differences in their esterase phenotypes were detectable. Isozyme phenotypes from the other three isozymes revealed a great deal of similarity among M. incognita, M. javanica, M. arenaria, and the undescribed Meloidogyne sp.

Responses of intercostal muscle biopsies from normal subjects and patients with myasthenia gravis.

In order to evaluate the mechanisms of weakness in muscles of patients with myasthenia gravis (MG), intercostal muscle biopsies were obtained from 9 normal subjects and 6 MG patients, and the compound muscle action potential (AP) and tension responses to nerve and muscle stimulation, and contracture responses on exposure to caffeine, were monitored in vitro. In normal muscle, on stimulation of the nerve or muscle at 30 to 100 Hz, the AP responses showed decrement in amplitude, one-third of which was attributable to failure of neuromuscular transmission and two-thirds to failure of muscle membrane excitation. On stimulation at 1 to 5 Hz, the AP responses showed very little decrement, while the contractile responses showed significant fade in tension, due to failure of E-C coupling or contractility. In muscle from patients with generalized MG, stimulation of the nerve at all frequencies (1 to 100 Hz) caused much greater decrement in APs and fade in tension responses than in normal muscle, due mainly to failure of neuromuscular transmission. However, at 100 Hz, 40% of the decrement in APs was due to failure of muscle membrane excitation, and at 1 to 5 Hz, 40% of the fade in tension was due to failure of E-C coupling or contractility, as in normal muscle. On direct stimulation the contraction and half-relaxation times were slower and the tetanic tension was smaller than in normal muscle, especially in the MG patient with thymoma. Caffeine-induced contractures were smaller in MG muscle than in normal muscle. These results indicate that while the weakness of MG muscle is due mainly to failure of neuromuscular transmission, it is also partly due to reduced E-C coupling or contractility.

Effect of Cleistanthus collinus leaf extract on neuromuscular function of the isolated mouse phrenic nerve-diaphragm.

Cleistanthus collinus is a toxic plant whose leaves have been used for homicidal or suicidal purposes. Since the toxic effects include muscle cramps and weakness, the effect of the leaf extract on the electrical and mechanical responses to nerve and muscle stimulation was studied in the isolated phrenic nerve-diaphragm preparation of the mouse. Following a 1 hr exposure to 0.015% leaf extract, the response of the compound nerve action potential to supramaximal nerve stimulation was reduced by 38%. The compound muscle action potential was reduced by 97%, and isometric tension by 99%. In response to direct muscle stimulation the compound muscle action potential and isometric tension were reduced by 38%. There was only an 11% reduction in resting membrane potential, but a 51% reduction in the amplitude of miniature endplate potentials. Endplate potentials could be evoked by nerve stimulation without prior treatment of the muscle with curare or a high concentration of magnesium. These studies indicate that the leaf extract markedly inhibits muscle contraction by reducing excitability of the nerve and muscle membranes, and by blocking neuromuscular transmission, without affecting excitation-contraction coupling or contractility of the muscle fibers.

Effect of fiber types, fascicle size and halothane on caffeine contractures in rat muscles.

Caffeine contractures were recorded from thin bundles and whole extensor digitorum longus (EDL) and soleus muscles of rat, and correlated with preparation size and fiber types. Thin bundles were more sensitive to caffeine and halothane than whole muscles, and bundles of 100% type I fibers were more sensitive than bundles of 100% type II fibers. Magnitude of contracture had significant correlation with maximal tetanic tension, total number of fibers, thickness of the preparation, and proportion of type I fibers. These results suggest that fascicle size and fiber types significantly affect results of in vitro contracture test for susceptibility to malignant hyperthermia.

On the possible mode of action of neurohormones on cholinesterase activity in the ventral nerve cord of scorpion, Heterometrus fulvipes.

It is shown that Km of ChE is not affected by the neurohormones but Vmax is increased and decreased in presence of acceleratory and inhibitory neurohormones respectively. Hence it is suggested that the neurohormones might modulate the enzyme activity be altering the maximal velocities (Vmax) rather than affecting the enzyme affinity (Km) towards the substrate.

A trial of long-acting sulphonamide R.O. 4-4393 (fanasil) in treatment of cases of lepromatous leprosy with repeated E.N.L.

A trial of long-acting Sulphonamide RO.4-4393 (Fanasil) in the treatment of Lepromatous Leprosy patients with repeated E.N.L. is reported in this paper. There were 9 patients treated with Fanasil in this trial for a period of 2 years. The results of the trial have shown that the treatment with Fanasil helps to prevent the occurrence of E.N.L. under treatment with D.D.S. In addition, even after the completion of treatment with Fanasil, these patients seem to be stabilised and are able to tolerate D.D.S. But, the clinical and Bacteriological progress under Fanasil therapy is not satisfactory.