Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because of the association of D-penicillamine (DP) therapy with myasthenia gravis, we have studied long-term DP treatment in five inbred strains of mice with doses comparable to those used in patients with rheumatoid arthritis. No clinical weakness or anti-acetylcholine receptor (AChR) antibody developed with up to 6 months of treatment, but augmented responses did occur to challenge with purified AChR in adjuvant. Anti-AChR antibody titers in C57BL/6 and C3H/He mice were significantly higher after challenge with AChR in DP-treated than in control mice. Augmented anti-AChR titers were not seen in strain A mice, but after 6 months of DP treatment increased susceptibility developed to the induction of experimental autoimmune myasthenia gravis. Nine weeks after challenge with purified AChR, 10 of 11 mice developed clinical weakness, leading to death in 6. Results of edrophonium testing were positive in 5 of 6 mice, and electrophysiological abnormalities were demonstrated in 3 of the surviving mice. Long-term DP treatment is associated with augmented anti-AChR antibody responses in C3H/He and C57BL/6 mice, and increased susceptibility to experimental autoimmune myasthenia gravis in strain A mice.
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PMID:Augmented anti-acetylcholine receptor response following long-term penicillamine administration. 643

Of seven rat monoclonal antibodies directed against nicotinic acetylcholine receptor, the three whose binding was blocked by alpha-bungarotoxin produced acute paralysis in chicken hatchlings, whereas the four others had no effect. In the affected animals, weakness and decremental electromyographic responses appeared within 1 hr after intravenous injection and both abnormalities improved after anticholinesterase administration. No histological changes were seen in the muscle of injected animals. These data suggest that antibodies binding in relationship to the cholinergic binding site, and presumably producing pharmacologic blockade of acetylcholine receptor, may play an important role in the pathogenesis of the defective neuromuscular transmission in myasthenia gravis.
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PMID:Anti-acetylcholine receptor antibodies directed against the alpha-bungarotoxin binding site induce a unique form of experimental myasthenia. 657 98

To investigate pathogenic mechanisms in experimental autoimmune myasthenia gravis (EAMG) and myasthenia gravis (MG), we studied the acute and chronic effects in rats of injection of rat monoclonal antibodies ( MCABs ) directed against the acetylcholine receptor (AChR). Animals were severely weak 12 h after a single injection, at which time macrophages were found invading endplate regions of muscle and cholinesterase-stained regions were separted from the underlying muscle fibers. Ultrastructural studies showed findings identical to the acute phase of EAMG: degenerating postsynaptic membranes and invasion and phagocytosis of endplate regions by macrophages. Animals receiving sublethal doses of MCAB recovered clinically by 4-5 days after injection. Recovery was accompanied by a progressive decrease in the number of macrophages associated with endplates and reapposition to the myofibers of the cholinesterase-stained regions. Animals injected once, or repeatedly over several months, remained clinically and electromyographically normal after recovery from the initial episode of weakness, but their endplate ultrastructure was highly simplified with blunted or absent synaptic folds and shallow or absent secondary synaptic clefts. These studies demonstrate that anti-AChR MCABs can induce the changes of both acute and chronic EAMG. There is good correlation between the inflammatory changes and the acute clinical disease but poor correlation between morphological and clinical parameters in the chronic syndrome. The latter observation suggests that severe ultrastructural changes, similar to those seen in chronic EAMG and MG, cannot account, at least in rats, for the clinical and electrophysiologic abnormalities of MG.
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PMID:Induction of the morphologic changes of both acute and chronic experimental myasthenia by monoclonal antibody directed against acetylcholine receptor. 661 Feb 75

Sixty patients with myasthenia gravis were examined prospectively by measuring serial titers of antibodies against human acetylcholine receptor, and these were correlated with a quantitative clinical score. Serial titers of antibodies detected by the standard immunoprecipitation assay (binding antibodies) correlated with the clinical score in most patients. Antibodies blocking the binding of alpha-bungarotoxin to receptors (blocking antibodies) were detected in 29 patients. Serial blocking antibody titers correlated with changes in muscle weakness less often than binding antibody titers. Titers of both classes of antibodies often followed a divergent course, suggesting that the autoimmune B-cell clones that formed these classes of antibodies may have been activated asynchronously.
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PMID:Myasthenia gravis: long-term correlation of binding and bungarotoxin blocking antibodies against acetylcholine receptors with changes in disease severity. 668 26

Mice immunized with acetylcholine receptor (AChR) purified from Torpedo californica form anti-AChR antibodies and often develop muscular weakness and flaccid paralysis closely resembling the human disease myasthenia gravis. This condition, termed experimental myasthenia gravis (EMG), is strain dependent in that the frequency of paralysis is much greater in some strains than in others. Differences in the frequency of EMG might result from differences in the immune system or the neuromuscular junction. In these studies, we have identified two loci, the major histocompatibility complex (H-2) region on chromosome 17 and the region that contains the structural genes for the constant region of immunoglobulin heavy chains (IgCH region) on chromosome 12, which significantly effect the probability with which a mouse immunized with T. californica AChR can be expected to become paralyzed. One genotype (H-2b, Ig-1b) correlated with high susceptibility to EMG in four strains with three dissimilar backgrounds. These studies demonstrate that susceptibility to EMG is a heritable trait determined by at least two distinct loci that are linked to regions of the mouse genome that regulate immune responsiveness.
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PMID:Linkage between the frequency of muscular weakness and loci that regulate immune responsiveness in murine experimental myasthenia gravis. 677 45

In 13 Smooth Fox Terriers with a congenital form of myasthenia gravis, clinical signs included intermittent, progressive muscle weakness that became more pronounced with exercise; muscle wasting; megaesophagus; and aspiration pneumonia. Neurologic abnormalities were apparent only during periods of weakness and included inability to retract the fore- and hindlimbs from painful stimuli. A decrement of the compound muscle action potential was evident during repetitive supramaximal nerve stimulation. Intravenous injection of a short-acting cholinesterase inhibitor evoked immediate improvement of clinical and electromyographic signs. Intracellular microelectrode studies of a biopsied external intercostal muscle revealed reduced amplitude of miniature end-plate potentials, as occurs in acquired myasthenia gravis. However, in contrast to acquired myasthenia gravis, antibodies directed against acetylcholine receptors were not demonstrable in serum and were not bound to acetylcholine receptors in muscle. Despite lack of complexing with immunoglobulin, the amount of acetylcholine receptor protein in biopsied external intercostal muscles from 9 affected pups was less than 25% of the amount in 5 unaffected littermates. The latter finding accounted for the reduction in amplitude of miniature end-plate potential and the failure of neuromuscular transmission. Treatment with a long-acting cholinesterase inhibitor in 6 cases resulted in temporary improvement in muscle strength.
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PMID:Congenital myasthenia gravis in 13 smooth fox terriers. 684 Dec 51

Monoclonal cell lines synthesizing antibodies against partially purified acetylcholine receptor from human muscle (H.AChR) were produced. Eleven clones secreted antibodies against H.AChR. Four were obtained in ascitic form. Two of them have been exhaustively studied. Specificity and affinity for H.AChR were demonstrated. Cross-reactivity with mouse AChR was shown but not with torpedo or porcine AChR at the same concentration. Purified IgG injected intravenously provoked an obvious muscular weakness. Inhibition experiments on myasthenia gravis sera binding have demonstrated that monoclonal antibody specificity is directed against an antigenic determinant shared by human and mouse AChR.
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PMID:Monoclonal antibodies against the human acetylcholine receptor. 686 Mar 25

Myasthenia gravis is a disorder of autoimmunity in which neuromuscular transmission is impaired by autoantibodies to the acetylcholine receptor (AChR). There is evidence for more than one form of the disorder with differing genetic susceptibilities. The aetiology is unknown, but thymic involvement is suggested by abnormal histology and by the beneficial response of the disorder to thymectomy in more than two-thirds of patients. Thymectomy is indicated in most patients unless the symptoms are minimal or are confined to the extraocular muscles alone, or the patient is elderly. Thymectomy alone results in remission in about one-third of patients, but, in addition, most patients require symptomatic anticholinesterase drugs to prolong the action of acetylcholine at the muscle end-plate. Over-dosage of these drugs can also cause weakness. Immunosuppression with corticosteroids or azathioprine may also improve myasthenia; at present, these drugs are used mainly in patients who do not respond to thymectomy or in those patients considered unsuitable for operation. Plasma exchange can cause a rapid, though temporary, involvement in myasthenia, but it probably has no long term place in its treatment. Future therapy will probably involve specific immunotherapy, such as anti-idiotype antibodies.
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PMID:Myasthenia gravis. Pathogenesis and current concepts in management. 688 41

Myasthenia gravis is a neuromuscular disease that presents clinically as fluctuating weakness of one or more skeletal muscle groups. Weakness becomes more severe with exercise and improves with rest. The disease is caused by an autoimmune reaction at or near the post-synaptic nicotinic acetylcholine receptor. The results of this immune reaction are the lytic destruction of the post-synaptic membrane and a reduction in the number of acetylcholine receptors. Myasthenia gravis can be diagnosed by repetitive exercise of the involved muscles, administration of edrophonium (Tensilon), electrophysiologic testing, or demonstration of anti-acetylcholine receptor antibodies. When the myasthenic weakness is mild or limited to the extraocular muscles, it may be treated with acetylcholinesterase inhibitors. When the weakness is more severe and/or more generalized, immunotherapy is most often indicated. Prednisone or prednisone plus thymectomy is the most frequently used form of immunotherapy. Azathioprine, 6-mercaptopurine, plasmapheresis, or gamma globulin injections are other immunotherapeutic options that may be useful in selected patients. A large number of drugs may precipitate or exacerbate myasthenic weakness.
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PMID:Myasthenia gravis: signs, symptoms, diagnosis, immunology, and current therapy. 692 2

Myasthenia gravis is characterized by muscle weakness, which is alleviated by rest and by anticholinesterase drugs. There are two forms of the disease in the dog, acquired and congenital. The acquired form occurs either in young adults, or in older animals that have developed mediastinal tumors. Clinically, there is weakness of the muscles of the limbs, neck, and head, together with dilatation of the esophagus. In some cases, circulating antibody to acetylcholine receptor is present and the amount of receptor in the end-plates is decreased. It is thought to be an autoimmune disease. The congenital form of canine myasthenia gravis occurs most frequently in Jack Russell terriers from six to eight weeks of age. The clinical manifestations are similar to those accompanying acquired myasthenia, although dilatation of the esophagus is not a feature. Raised antibody levels to acetylcholine receptor have not been noted, although the amount of receptor in the end-plates is decreased. Thus, the congenital form does not appear to be an autoimmune disease and the pathophysiology has yet to be established. Both forms of canine myasthenia gravis provide useful models analogous to the disease in man.
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PMID:Myasthenia gravis. 699 86


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