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Biomedical subjects

S H Appel

Publications and source records attributed to S H Appel.

At least 181 records · Page 10Linked to original sources
PubMed1979

The role of acetylcholine receptor antibodies in myasthenia gravis.

Myasthenia gravis is an autoimmune disease of man characterized by remitting and relapsing muscle fatigability. Although the etiology and pathogenesis are incompletely understood, the presence of circulating antibodies directed against the nicotinic acetylcholine (ACh) receptor in 80--90% of patients with myasthenia gravis and the identification of immune complexes at their neuromuscular junction have helped explain the altered neuromuscular transmission. The ACh receptor antibodies do not block access of ACh to the receptor, but do decrease the number of receptors by accelerating their degradation both in rat myotube cultures and in vivo models. In vitro these antibodies play a major role in myasthenia gravis. However, correlations of antibody titers with the clinical state following thymectomy or in neonatal myasthenia suggest that host factors may be equally important in determining whether the ACh receptor antibodies will result in clinical myasthenia.

Acetylcholine↗
PubMed1978

Myotonic muscular dystrophy: altered calcium transport in erythrocytes.

Erythrocytes from patients with myotonic muscular dystrophy accumulate calcium at a significantly higher rate than normals do. This increased rate of net accumulation appears related to an enhanced permeability of the membrane to calcium, rather than to an impairment in its active outward transport.

Biological Transport↗
PubMed1978

Acetylcholine receptor in myasthenia gravis: increased affinity for alpha-bungarotoxin.

Studies of the binding of 125 I-labeled alpha-bungarotoxin to myasthenic motor end-plates have been interpreted as showing a decrease in the number of acetylcholine (ACh) receptors at these end-plates. Equilibrium binding studies of 125 I-tagged alpha-bungarotoxin rather than to a decreased number of receoptors. Our results show increased rather than decreased affinity of myasthenic receptors for alpha-bungarotoxin and also suggest that the number of ACh receptors is indeed reduced. The presence of a change in binding affinity, in addition to the reduced number of ACh receptors, suggests the presence of membrane changes that may contribute to the pathogenesis of myasthenia gravis.

Acetylcholine↗
PubMed1978

The muscular dystrophies. Clinical update on two major types.

The muscular dystrophies are inherited diseases involving skeletal muscle and, to a variable extent, many other organs of the body. Each presents a distinctive clinical syndrome, and each presumably reflects a distinctive inborn error of metabolism. The precise metabolic defect is not known for any of these disorders. However, recent studies suggest that abnormalities in cellular membranes may help explain clinical deficits in two of the most important disorders, Duchenne's muscular dystrophy and myotonic muscular dystrophy.

Adolescent↗
PubMed1977

Isolation and characterization of the surface membranes of fast and slow mammalian skeletal muscle.

Fast (extensor digitorum longus) and slow (soleus) rat skeletal muscles served as the source for isolation and biochemical comparison of two distinct surface membrane fractions with properties of the sarcolemma and transverse tubular system. Enriched sarcolemmal membrane from soleus demonstrated a lighter density after sucrose density centrifugation. Sialic acid content was 1.5-fold higher in soleus (62 nmol/mg) than extensor (40 nmol/mg). The specific activity of (Na+ + K+ + Mg2+)-ATPase was similar (1.40 and 1.65 micronmol Pi/mg per 5 min) with the soleus enzyme displaying a (1) greater resistance to inhibition by ouabain, and (2) broader ionic ratio (Na+/K+) requirement than extensor enzyme. The polypeptide and phospholipid composition showed no major differences between the two muscle types. The second surface membrane fraction, tentatively identified as transverse tubule, differed in membrane composition. The major polypeptide of extensor was of 95 000 molecular weight whereas for soleus a Mr=28 000 species was dominant. Total phospholipid content of soleus was 1.5-fold greater than extensor due mostly to increased levels of phosphatidylcholine and phosphatidylethanolamine. Endogenous membrane protein kinase for the 28 000 molecular weight polypeptide was found exclusively in this membrane. The reaction conditions were identical for extensor and soleus since both required divalent cations (Ca2+ and Mg2+) and neither was affected by cyclic AMP. Soleus showed a 2-fold higher capacity for phosphate incorporation than extensor. These studies show that surface membrane fractions derived from fast and slow muscles differ in terms of functional and compositional properties. These differences are specific not only for the surface membrane but for the muscle type and may relate to the known physiological differences observed between fast and slow mammalian muscle.

Adenosine Triphosphatases↗
PubMed1977

Is there acetylcholine receptor in human thymus?

Recent studies have suggested that thymus tissue of the calf may bear nicotinic acetylcholine receptors. The presence of similar receptors in thymus tissue of man could thereby serve as a source of antigen for the production of antibody to the acetylcholine receptor in patients with myasthenia gravis. In the present experiments, human thymus tissue was examined for the presence of acetylcholine receptor. Both [125I] alpha-bungarotoxin binding and antiserum to the human acetylcholine receptor were used in tests for acetylcholine receptor in thymus glands from normal individuals and from patients with myasthenia gravis. Neither normal nor myasthenic thymus tissue were found to possess the [125I] alpha-bungarotoxin binding or the antigenic properties of the acetylcholine receptor.

Antibodies↗
PubMed1977

Accelerated degradation of acetylcholine receptor from cultured rat myotubes with myasthenia gravis sera and globulins.

Altered geometry of the neuromuscular junction and a decreased number of acetylcholine receptors appear responsible for the defect of neuromuscular transmission in myasthenia gravis. We have used cultured rat myotubes as a model to study in vitro the potential role of myasthenic globulins in the pathological process. Acetylcholine receptor content was assayed by the extent of 125I-labeled alpha-bungarotoxin binding, and acetylcholine receptor function was assayed by the sensitivity to acetylcholine iontophoresis. The half-life of the acetylcholine receptor was 18.5 hr in the presence or absence of control sera. Myasthenic sera and globulins produced a gradual reduction in acetylcholine receptors, as assessed by biochemical and electrophysiological techniques. The half-life in the presence of myasthenic sera was 6 hr. The accelerated turnover was unaffected by puromycin but was slowed by lowered temperature (18-20 degrees), interference with energy metabolism (2,4-dinitrophenol), and interference with cytoskeletal structures (colchicine and cytochalasin B). We found no electrophysiological evidence to suggest globulin blockade of acetylcholine access to the acetylcholine receptor. Our observations suggest that circulating globulins in myasthenia gravis may contribute to the functional defects of neuromuscular transmission by accelerating the rate of internationalization and degradation of surface membrane acetylcholine receptors.

Acetylcholine↗
PubMed1976

Cholinergic sites in skeletal muscle. I. Denervation effects.

Cholinergic interactions in systems derived from rat skeletal mixed muscle are detailed. The isotherms of the binding of [125I]diiodo-alpha-bungarotoxin over the range of 10(-10)-10(-5) M toxin have been separated into a "nonspecific" component exclusive to the toxin and a "specific" component that binds both the toxin and d-tubocurarine. The "specific" component appears to reflect two independent sets of binding sites. One of the sets has an affinity constant on the order of 10(9) M-1. Following denervation, the number of sites in this high-affinity set begins to increase after 3 days, reaches a peak (28-fold higher than normal) on the 8th day, and begins to decline. Similar results are obtained when sensitivity of this set to an antibody derived from patients with myasthenia gravis is examined. This sensitivity is reflected by the inhibition of the alpha-bungarotoxin binding by the myasthenic IgG fraction. Following denervation, sensitivity first appears on day 3 progresses coincidentally with the increase in new sites in the set. The charcteristics of this set suggest that it represents the acetylcholine receptor and that the new sites appearing during the course of denervation are extrajunctional receptor sites. The interaction with the myasthenic IgG indicates an antigenic difference between junctional and extrajunctional receptors. The second set of specific binding sites has an affinity constant on the order of 10(5) M-1. The number of sites in this set increases only fivefold as a result of denervation. The increase also begins between days 2 and 3. The definition of this low affinity set of sites is not presently clear.

Animals↗