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Biomedical subjects

A Pestronk

Publications and source records attributed to A Pestronk.

At least 109 records · Page 6Linked to original sources
PubMed1989

Reorganization of intrinsic components in the distal motor axon during outgrowth.

We have studied the changes in the distribution of three intrinsic axonal components during the growth and maturation of sprouts in vivo. Neurofilaments, tubulin and synaptophysin, a synaptic vesicle protein, were visualized in motor axons and their sprouts using immunocytochemical staining of frozen longitudinal sections of muscle. We examined changes in these elements in sprouts regenerating after axonal crush injury and in those evoked from intact axons by denervation changes in muscle. Our results show that intrinsic axonal components move into newly formed motor axon sprouts in different temporal patterns. Based on the patterns of reorganization of staining of intrinsic axonal components, two types of outgrowth can be distinguished. One type, synaptic elaboration, is manifest by short, broad axonal processes that produce enlargement of the synaptic zone (synaptophysin staining) with little change in the distribution of intrinsic cytoskeletal elements. A second type of outgrowth, axonal elongation, occurs during axonal regeneration and ultraterminal sprouting and is longitudinal in form. In these sprouts there is a sequential appearance of neurofilament and then, several days later, tubulin immunostaining. Synaptophysin only accumulates in these sprouts after two weeks at points of synaptic contact with a muscle fibre.

Animals↗
PubMed1989

Neural regulation of mRNA for the alpha-subunit of acetylcholine receptors: role of neuromuscular transmission.

Levels of mRNA for acetylcholine receptor (AChR) subunits are relatively low in innervated skeletal muscles. Following denervation they rise rapidly, leading to increased AChR synthesis. The mechanism by which motor nerves normally regulate these mRNA levels is not yet known. In order to determine the possible role of synaptic transmission in this process, we have compared the effect of blockade of cholinergic ACh transmission with that of surgical denervation. Blockade of quantal ACh transmission was produced by injection of type A botulinum toxin into the soleus muscles of rats. We measured mRNA for the alpha-subunit of the AChR (alpha-AChR mRNA) in RNA extracts of botulinum-treated, denervated, and normal control muscles by hybridization with a highly specific cDNA probe. Our findings show that treatment with botulinum toxin resulted in an increase in alpha-AChR mRNA which was similar to the effect of surgical denervation, although slower in its time course. Since botulinum toxin specifically inhibits quantal ACh release, these results support the concept that cholinergic synaptic transmission plays a key role in mediating the neural control of the alpha-AChR message. The difference between the effects of denervation and botulinum-treatment may be explained by the fact that botulinum toxin does not block the spontaneous non-quantal component of ACh transmission, which has previously been shown to have a partial influence in regulating certain properties of muscles. The present results suggest that synaptic transmission has an important influence in regulating gene expression in the target cell.

Animals↗
PubMed1989

Anti-GM1 ganglioside antibodies with differing fine specificities in patients with multifocal motor neuropathy.

Antibodies to gangliosides were detected in sera from three of 19 patients with chronic inflammatory polyneuropathy (CIP) by a thin-layer chromatogram overlay technique. All three of the patients fell into a clinical subset of the group that had multifocal motor neuropathy, and in all three patients the antibodies reacted with GM1 ganglioside. However, the fine specificities of the antibodies differed as demonstrated by cross-reactivity with different gangliosides in each of the three patients. The antibodies in patient 1 reacted with GM1, GD1b, and asialo-GM1 suggesting that the terminal Gal(beta 1-3)GalNAc moiety that is common to these three glycolipids is an important part of the epitope(s). This was confirmed by showing reactivity of the antibodies with Gal(beta 1-3)GalNAc conjugated to bovine serum albumin. Patient 2 had antibodies that did not react with GD1b, but cross-reacted with GM2 ganglioside suggesting that the epitope(s) involved the inner portion of the oligosaccharide moiety that is shared between GM1 and GM2. Patient 3 had antibodies that reacted with GM1 and asialo-GM1, but they did not cross-react with either GD1b or GM2. These results provide further evidence for a relationship between motor nerve syndromes and anti-GM1 antibodies and also suggest that GM1 could be a principal target antigen since other reactive gangliosides differed among the patients. However, the possible pathogenic effects of anti-GM1 antibodies on motor nerves remain to be established.

Antibodies↗
PubMed1989

The effect of thalidomide on experimental autoimmune myasthenia gravis.

Thalidomide is reported to have immunosuppressive and anti-inflammatory effects which have led to its use in the treatment of a number of immune-mediated disorders including leprosy, prurigo, discoid lupus, and Behcet's disease. In addition, thalidomide has recently been used to prevent immunological rejection phenomena following skin and bone-marrow grafts. The immune responses in these conditions are thought to be cell-mediated. However, little is known about the effectiveness of thalidomide in suppressing antibody-mediated immune responses. In the present study, we have examined the effect of thalidomide in a model antibody-mediated autoimmune disorder--experimental autoimmune myasthenia gravis (EAMG). To induce EAMG, Lewis rats were immunized with acetylcholine receptor (AChR) purified from the electric organ of Torpedo californicus. Groups of rats were treated daily, either with thalidomide in excess of doses reported to prevent graft-versus-host (GVH) disease in bone-marrow-transplanted rats, or with control treatments. Our results show that thalidomide failed to inhibit AChR antibody production despite good absorption and high blood levels of the drug. This suggests that thalidomide is not likely to be generally useful in the treatment of antibody-mediated autoimmune conditions. However the selective effect of thalidomide in suppressing certain presumably cellular immune responses, while sparing antibody production, is inherently interesting, and merits further study.

Animals↗
PubMed1989

Nifedipine in the prophylaxis of classic migraine: a crossover, double-masked, placebo-controlled study of headache frequency and side effects.

Twenty-four patients with classic migraine attacks were treated with either nifedipine or placebo for up to 12 weeks. No significant differences were observed between the nifedipine (2.1 +/- 0.2) and placebo (2.3 +/- 0.2) treatment groups in the monthly frequency of headaches. However, the incidence of side effects was significantly greater (p less than 0.001) in the nifedipine (54% of patients) than in the placebo (8% of patients) treatment groups.

Clinical Trials as Topic↗
PubMed1989

Differential effects of prednisone and cyclophosphamide on autoantibodies in human neuromuscular disorders.

We compared the effects of treatment of patients with prednisone or cyclophosphamide on a series of different types of autoantibodies. Levels of antiacetylcholine receptor (anti-AChR) antibodies and of antibodies to GM1 and GD1a gangliosides were measured in patients with a variety of neuromuscular disorders before and after treatment. Most patients had several autoantibodies present. We showed that prednisone treatment resulted in a reduction in titers of anti-AChR but not antiganglioside antibodies. Cyclophosphamide treatment produced a reduction of antiganglioside antibody titers. An intravenous and oral regimen was more effective than a single intravenous course of cyclophosphamide. We conclude that an immunosuppressive medication such as prednisone may reduce levels of some autoantibodies while producing no change in others, even in an individual patient. In addition, cyclophosphamide can suppress autoantibodies that prednisone does not. These differences in immunopharmacologic responses suggest that there are several distinct mechanisms of autoantibody production in humans. The utility of immunosuppressive medications in specific disease processes may be related in part to the mechanism of production of pathogenic antibodies.

Autoantibodies↗
PubMed1989

Neurotransmission regulates stability of acetylcholine receptors at the neuromuscular junction.

The majority of acetylcholine receptors (AChRs) at normally innervated neuromuscular junctions are stable, with a half-life averaging about 12 d in most rodent muscles. Following denervation, the AChRs turn over much more rapidly after a lag period. The mechanism by which motor nerves normally maintain stabilization of junctional AChRs is not yet known. In order to determine whether synaptic transmission plays a role in this process, we have compared the effects of pre-and postsynaptic chloinergic blockade with those of surgical denervation. 125l-alpha-bungarotoxin was used to label junctional AChRs and follow their loss over time. Presynaptic blockade of quantal ACh transmission was produced in the soleus (SOL) and flexor digitorum brevis muscles of mice by repeated injections of type A botulinum toxin. Postsynaptic blockade of quantal and nonquantal ACh transmission was produced by continuous infusion of alpha-bungarotoxin in the SOL. Our findings show that treatment with botulinum toxin resulted in an accelerated loss of junctional AChRs that was similar to the effects of surgical denervation, though briefly delayed in its onset. Treatment with alpha-bungarotoxin produced an effect that was quantitatively equivalent to the accelerated loss of junctional AChRs following surgical denervation, with an identical time course. These results support the concept that cholinergic transmission is a mediator of the neural control of stability of junctional AChRs. The possibility that receptor stabilization may represent a mechanism of long-term postsynaptic "memory" dependent on neural transmission is discussed.

Animals↗
PubMed1988

Motor nerve outgrowth: reduced capacity for sprouting in the terminals of longer axons.

The ability of axons to grow or sprout can vary considerably. In this study we have examined the relation between axon length and the abundance of outgrowth from motor nerve terminals in vivo. Outgrowth from nerve terminals was evoked using botulinum toxin. Terminal axons, sprouts and neuromuscular junctions were visualized using a cholinesterase-silver stain. The amount of axonal outgrowth was compared in several proximal (e.g. rhomboid and paraspinous), intermediate, and distal (e.g. soleus and foot) muscles. Our results show that sprouting is generally more abundant in proximal than in distal muscles. There is a significant inverse correlation between nerve length and the abundance of sprouting from terminal axons. Thus, terminals of short axons appear to have more ability or potential to sprout than those of long axons.

Animals↗
PubMed1988

Rapid synthesis of acetylcholine receptors at neuromuscular junctions.

The rate of acetylcholine receptor (AChR) degradation in mature, innervated mammalian neuromuscular junctions has recently been shown to be biphasic; up to 20% are rapidly turned over (RTOs; half life less than 1 day) whereas the remainder are lost more slowly ('stable' AChRs; half life 10-12 days). In order to maintain normal junctional receptor density, synthesis and insertion of AChRs should presumably be sufficiently rapid to replace both the RTOs and the stable receptors. We have tested this prediction by blocking pre-existing AChRs in the mouse sternomastoid muscle with alpha-bungarotoxin (alpha-BuTx), and monitoring the subsequent appearance of 'new' junctional AChRs at intervals of 3 h to 20 days by labeling them with 125I-alpha-BuTx. The results show that new receptors were initially inserted rapidly (16% at 24 h and 28% at 48 h). The rate of increase of 'new' 125I-alpha-BuTx binding sites gradually slowed down during the remainder of the time period studied. Control observations excluded possible artifacts of the experimental procedure including incomplete blockade of AChRs, dissociation of toxin-receptor complexes, or experimentally induced alteration of receptor synthesis. The present demonstration of rapid synthesis and incorporation of AChRs at innervated neuromuscular junctions provides support for the concept of a subpopulation of rapidly turned over AChRs. The RTOs may serve as precursors for the larger population of stable receptors and have an important role in the metabolism of the neuromuscular synapse.

Animals↗
PubMed1988

The first neurology book. De Cerebri Morbis...(1549) by Jason Pratensis.

In 1549, Jason Pratensis published De Cerebri Morbis...(DCM), the first separate book on the general subject of neurologic disease. The publication of DCM reflected two trends in 16th century medicine: (1) interest in the anatomy and function of specific organs, and (2) retranslation of the works of Galen, who emphasized the primacy of the brain in behavioral and motor functions. Brain diseases in DCM were classified in terms of symptom complexes. Some of the 33 chapters discuss tremor, tetanus, vertigo, epilepsy, and hemicrania. Concepts of diseases, and their pathogenesis and treatment, reflected the writings of Greek, Roman, and Arabic authors, as well as newer concepts of astrology and pharmacy that were prevalent during the Renaissance. There were few new bedside or clinical observations in DCM. However, DCM is an important text, crystallizing several 16th century trends to provide the first compendium of brain disorders.

Books↗
PubMed1988

A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside.

We report 2 patients with a treatable, immune-mediated motor polyneuropathy associated with antibodies to defined neural antigens. In these patients asymmetrical weakness developed in one arm and progressed over 2 to 3 years to involve the other arm, legs, and trunk. Both patients were initially diagnosed as having lower motor neuron forms of amyotrophic lateral sclerosis. However, repeated electrophysiological testing eventually showed multifocal conduction blocks in motor but not sensory fibers compatible with patchy selective demyelination. Serum testing by thin-layer chromatography and enzyme-linked immunosorbent assay revealed that both patients had high titers of antibody directed against GM1 and other gangliosides. Initial therapeutic trials of prednisone (100 mg daily for 4 to 6 months) and plasmapheresis were unsuccessful. Treatment with cyclophosphamide, however, was followed by marked improvement in strength in both patients.

Adult↗
PubMed1988

Regional heterogeneity in the distal motor axon: three zones with distinctive intrinsic components.

In this study we examined the distribution of cytoskeletal and other intrinsic axonal elements in motor nerve terminals in vivo. Components of axons were visualized with immunocytochemical staining of frozen longitudinal sections of muscle. Using these methods we compared the distribution of neurofilaments, tubulin, MAP2, actin and synaptic elements in distal regions of axons at and near neuromuscular junctions in rat muscles. Our results show that three discrete regions can be defined based on the anatomy and intrinsic components of distal axons. The preterminal axon, extending from its exit from the intramuscular nerve toward the neuromuscular junction, has a cytoskeletal composition similar to the more proximal axon with abundant staining of neurofilaments, tubulin, MAP2 and actin. The terminal arborization, a branched region of the axon extending through the endplate region, contains neurofilaments but little tubulin, actin, MAP2 or synaptic elements. Finally, the synaptic zone, demonstrated with antibodies to the synaptic vesicle protein synaptophysin, contains few cytoskeletal elements. We conclude that there is considerable regional heterogeneity in the composition of distal motor axons. The distribution of neurofilaments, other cytoskeletal elements and synaptic vesicle proteins varies among different discrete zones of terminal motor axons.

Animals↗
PubMed1988

Effect of ketoleucine treatment on atrophy of skeletal muscle.

There is a net loss of skeletal muscle protein in muscle-wasting disorders including the muscular dystrophies and denervation atrophy. Regardless of the nature of the underlying defect, a treatment that could reduce the rate of muscle protein degradation may be of therapeutic value in these conditions. Ketoleucine (alpha-ketoisocaproic acid) has been reported to reduce the rate of protein degradation in skeletal muscle. To evaluate ketoleucine's therapeutic potential, we studied its effect on the muscle protein loss that follows denervation in rats. Maximum tolerated doses of ketoleucine were administered twice daily to rats after surgical denervation of one leg. Wet weights and noncollagen proteins of the soleus and extensor digitorum longus muscles were measured. The ketoleucine-treated animals failed to show significant decrease in muscle wasting, compared with nontreated denervated controls. Further, urinary 3-methylhistidine excretion, a putative measure of muscle breakdown, was not reduced in ketoleucine-treated animals. Our findings do not support the suggested therapeutic role for ketoleucine in muscle-wasting disease.

Animals↗
PubMed1988

Serum antibodies to GM1 ganglioside in amyotrophic lateral sclerosis.

We report the presence of serum antibodies directed against GM1 ganglioside, a defined neural antigen, in many patients with amyotrophic lateral sclerosis (ALS). We examined serum from a series of patients with well-documented clinical diagnoses. Serum antibodies to GM1 ganglioside were measured using ELISA assays. Our results showed that polyclonal IgM anti-GM1 antibodies were present at dilutions of 1:25 to 1:2,000 in 42 of 74 (57%) patients with ALS. The anti-GM1 antibodies were especially frequent in patients with prominent lower motor neuron signs (41/59; 69%). Few normal controls (2/23) and motor-sensory neuropathy patients (3/27) had similar antibodies. Anti-GM1 antibodies did occur in patients with nonneural autoimmune disorders. However, the anti-GM1 antibodies in these patients tended to differ from those in ALS based on an analysis of their light chain types. Further examination of the role and spectrum of serum antiganglioside antibody activity in motor neuron syndromes is warranted.

Adult↗
PubMed1987

Mechanism of action of lithium on acetylcholine receptor metabolism in skeletal muscle.

Changes in the levels of cations within skeletal muscle are thought to mediate the neural regulation of turnover of extrajunctional acetylcholine receptors (AChRs). We have used lithium as a probe of these cation influences because of its resemblance to calcium and other ions. In the present experiments we studied the mechanism of action of lithium on AChR metabolism in cultured mammalian skeletal muscle. We measured the effects of lithium on AChR turnover (using [125I]alpha-bungarotoxin binding), and evaluated the resemblance of lithium and calcium in producing their effects on AChR metabolism. Our results provide insight into the mechanisms of action of lithium and the cellular processes controlling AChR metabolism in muscle. Lithium reduces the number of AChRs in skeletal muscle in vitro to a degree similar to that which we previously reported in vivo. Lithium appears to enter cells via both sodium and calcium channels. It then produces its effect on levels of AChRs primarily by selectively reducing AChR synthesis and insertion into the surface membrane. Lithium induces this change in AChR metabolism in a manner resembling neural and calcium-mediated effects on AChRs. Phosphoinositide pathways may be involved in the lithium-induced effects. Further analysis of the effects of lithium on AChR turnover should provide new information about the mechanisms underlying the cellular control of receptor metabolism.

Animals↗
PubMed1987

Mechanisms of postsynaptic plasticity: remodeling of the junctional acetylcholine receptor cluster induced by motor nerve terminal outgrowth.

Motor nerve terminal outgrowth (NTO) at neuromuscular junctions (NMJs) occurs rapidly in response to denervation changes in muscle. We have previously found that NTO can produce an elongation of the synaptic area of the NMJ as defined by cholinesterase-silver staining. In the present study, we examined the effects of NTO on a postsynaptic muscle membrane component, the usually stable cluster of acetylcholine receptors (AChRs) at the NMJ. NTO was evoked in rat soleus muscles using botulinum toxin. AChRs were demonstrated using immunocytochemistry or autoradiography of alpha-bungarotoxin binding. Our results show that NTO induces rapid elongation of the cluster of AChRs at the NMJ within 7 d of treatment with botulinum toxin. The growth in the size of the AChR clusters was accompanied by an increase in the number of AChRs/NMJ. No elongation of AChR clusters was seen following surgical denervation, suggesting that cluster growth is related to NTO and not to denervation changes in muscle per se. Growth of NMJ-AChR clusters appeared to result primarily from 2 processes: insertion of new AChRs into the NMJ membrane and, surprisingly, redistribution of preexisting NMJ-AChRs. These results show that NTO can cause rapid changes in the normally stable cluster of AChRs at the NMJ. Motor nerve terminals provide a strong and anatomically precise control of AChRs at the NMJ.

Animals↗