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Biomedical subjects

A Pestronk

Publications and source records attributed to A Pestronk.

142 records · Page 8Linked to original sources
PubMed1980

Mechanisms of acetylcholine receptor loss in myasthenia gravis.

The fundamental abnormality affecting the neuromuscular junctions of myasthenic patients is a reduction of available AChRs, due to an autoimmune attack directed against the receptors. Antibodies to AChR are present in most patients, and there is evidence that they have a predominant pathogenic role in the disease, aided by complement. The mechanism of antibody action involves acceleration of the rate of degradation of AChRs, attributable to cross-linking of the receptors. In addition, antibodies may block AChRs, and may participate in producing destructive changes, perhaps in conjunction with complement. The possibility that cell-mediated mechanisms may play a role in the autoimmune responses of some myasthenic patients remains to be explored. Although the target of the autoimmune attack in myasthenic patients is probably always the acetylcholine receptors, it is not yet clear which of these immune mechanisms are most important. It is likely that the relative role of each mechanism varies from patient to patient. One of the goals of future research will be to identify the relative importance of each of these mechanisms in the individual patient, and to tailor specific immunotherapeutic measures to the abnormalities found.

Acetylcholine↗
PubMed1978

Motor nerve sprouting and acetylcholine receptors.

Sprouting of motor nerve terminals was evoked by functional denervation of skeletal muscles brought about by presynaptic blockade or disuse. The amount of sprouting, determined by morphometric measurement, was correlated with the level of extrajunctional acetylcholine receptors. Sprouting was inhibited by blockade of acetylcholine receptors with alpha-bungarotoxin. Extrajunctional acetylcholine receptors may play an important role in eliciting motor nerve terminal sprouting.

Acetylcholine↗
PubMed1977

Myasthenia gravis. Study of humoral immune mechanisms by passive transfer to mice.

To study the role of humoral factors in the pathogenesis of myasthenia gravis, we employed passive transfer of human serum fractions to mice. Immunoglobulins from 16 patients with myasthenia gravis were injected into mice daily for one to 14 days. Typical myasthenic features of reduction in amplitude of miniature end-plate potentials (mean change more than 50 per cent, P less than 0.005) or reduction in acetylcholine receptors at neuromuscular junctions (mean change more than 50 per cent, P less than 0.005) (or both) were produced by immunoglobulin from 15 of the 16 patients. Some mice showed weakness or decremental responses to repetitive nerve stimulation as well. The active fraction was identified as IgG by three different purification methods. Its effect was enhanced by the third component (C3) of the complement system, but the fifth component (C5) had no effect. These data suggest that the pathogenesis of myasthenia gravis often involves and antibody-mediated autoimmune attack on the acetylcholine receptors of the neuromuscular junction.

Acetylcholine↗
PubMed1976

[A transferable "myasthenogenic" factor in the serum of patients with myasthenia gravis (author's transl)].

Recent evidence indicates that patients with myasthenia gravis (MG) have a reduced number of acetylcholine receptors (Ach-R) at the neuromuscular junction. It has been shown that this abnormality by itself, when produced experimentally, may induce all electrophysiological signs of MG. Furthermore, autoantibodies against human Ach-R have been detected in the serum of patients with MG. It has been proposed that serum autoantibodies may produce the symptomatology of the disease. The purpose of this study was to evaluate whether prolonged exposure to a MG serum fraction in vivo might serve to bring about the myasthenic disorder. A 33% ammonium sulfate precipitated fraction of serum from 9 patients with MG was injected daily into BDF1 mice for up to 14 days. The amount of IgG in this fraction equaled 10-15 mg per single injection. The mice showed reduced amplitudes of the miniature endplate potentials in the diaphragm (mean reduction by 65%), and a reduced number of Ach-R available for 125I-alpha-bungarotoxin binding (mean reduction by 38% in the extensor digitorum m. and 54% in the soleus m.). In some of the mice a decremental response on repetitive nerve stimulation and clinical signs of muscle weakness could also be demonstrated. None of the animals injected with the immunoglobulin fraction from control sera developed these abnormalities. The results indicate that the immunoglobulin fraction of MG serum contains a transferable "myasthenogenic" factor, presumably an antibody, which is able to bring about many of the characteristic features of MG. These findings provide support for the concept of MG as an autoimmune disease.

Adolescent↗
PubMed1975

Myasthenia gravis: passive transfer from man to mouse.

Daily injections into mice of an ammonium sulfate-precipitated immunoglobulin fraction of serum from patients with myasthenia gravis were carried out for up to 14 days. The mice showed reduced amplitudes of miniature endplate potentials and reduced numbers of acetylcholine receptors at the neuromuscular junctions. Some mice showed typical decremental responses on repetitive nerve stimulation, with reversal by neostigmine. This represents the first evidence of a circulating factor in the serum of patients with myasthenia gravis which on passive transfer reproduces features of the disease in experimental animals.

Acetylcholine↗
PubMedDate not supplied

A new stain for quantitative measurement of sprouting at neuromuscular junctions.

A new combined stain for the simultaneous demonstration of motor nerve terminals and cholinesterase at neuromuscular junctions is described. It employs bromoindoxyl acetate dye-staining for cholinesterase and silver-gold impregnation for nerve terminals. The clarity and reliability of the stain permit quantitative measurements of neuromuscular junctions in order to evaluate nerve terminal sprouting as well as other pathological changes. The method is rapid, reproducible, and simple, and it is well suited for the processing of large numbers of frozen sections.

Botulinum Toxins↗
PubMedDate not supplied

Critical reexamination of the thymus immunization model of myasthenia gravis.

Previous studies have described an experimental model of myasthenia gravis (MG) produced by immunizing animals with thymus extracts. In view of the hypothesis that the autoimmune process in MG may be initiated within the thymus itself, we have reexamined this model using presently available methods to evaluate its resemblance to MG. We immunized Lewis rats with extracts of rat thymus in Freund's adjuvant, as originally described by G. Goldstein. Five procedures were used to test for myasthenic characteristics: (1) repetitive nerve stimulation; (2) recording of miniature endplate potentials; (3) assays of anti-ACh receptor antibodies in serum; (4) determination of ACh receptors at neuromuscular junctions by [125I] alpha-bungarotoxin binding; and (5) evaluation of the histology of the thymus gland. Our results showed that the thymus-immunized animals did not demonstrate abnormalities in any of these parameters. We conclude that immunization of rats with thymus extracts, as described, failed to produce a myasthenia-like condition.

Animals↗
PubMedDate not supplied

Polymyositis: reduction of acetylcholine receptors in skeletal muscle.

In polymyositis (PM), neither the precise target nor the mechanism of the attack against skeletal muscle have yet been defined. In this study, we report evidence of a pathologic process involving a membrane component of muscle, acetylcholine receptors (AChRs). Our results show that PM patients have significantly reduced AChRs at neuromuscular junctions, averaging 55% below control values (P less than 0.01). Incubation of cultured mammalian muscle cells with sera from PM patients significantly reduced (P less than 0.005) the number of surface AChRs and increased their rate of degradation in 7/8 cases (P less than 0.005). Similar effects were produced by purified IgG from PM patients. These results demonstrate the presence in PM patients of circulating IgG with functional effects on a component of the surface membrane of skeletal muscle. They suggest that PM and myasthenia gravis may have important features in common.

Autoantibodies↗
PubMedDate not supplied

Measurement of junctional acetylcholine receptors in myasthenia gravis: clinical correlates.

We measured the number of acetylcholine receptors (AChRs) at neuromuscular junctions (NMJs) in motor point biopsies from 76 patients with myasthenia gravis (MG) and 49 control subjects, using an alpha-bungarotoxin binding technique. The mean number of AChRs/NMJ was significantly lower (P less than 0.001) in muscles of MG patients (deltoid 0.7 +/- 0.1 X 10(7) than in controls (2.1 X 0.2 X 10(7). None of the control muscles had fewer than 0.9 X 10(7) AChRs/NMJ, and 75% of MG muscles were below that level. Conversely, 88% of controls had 1.5 X 10(7) or more AChRs/NMJ, whereas only one of the MG muscles (2.5%) was at or above that level. The reduction of AChRs correlated approximately with the clinical severity of weakness (P less than 0.02). Patients with focal weakness had reduced numbers of AChRs/NMJ in clinically strong muscles. The only other condition in which junctional AChRs were reduced was polymyositis. These findings in a large sample of patients confirm the reduction of junctional AChRs in MG, the relationship of available junctional AChRs to clinical manifestations, and the systemic nature of the disorder even in cases with focal weakness. Measurement of AChRs can be useful diagnostically in situations where other tests are inconclusive.

Adult↗
PubMedDate not supplied

An epidemic of urinary retention caused by dimethylaminopropionitrile.

An epidemic of urinary retention among workers in a polyurethane manufacturing plant was discovered in the spring of 1978. The most severely affected workers had neurogenic bladders confirmed by cystometrograms and mild sensory peripheral neuropathy. A survey of the plant disclosed increased incidence of urinary retention, muscle weakness, paresthesia, insomnia, and sexual dysfunction in exposed workers. A catalyst containing dimethylaminopropionitrile was identified as the probable causative agent, and after its removal no new cases occurred.

Air Pollutants↗