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Biomedical subjects

A Pestronk

Publications and source records attributed to A Pestronk.

At least 127 records · Page 7Linked to original sources
PubMed1986

Subacute sensory neuronopathy secondary to dorsal root ganglionitis in primary Sjögren's syndrome.

Sensory neuropathies, particularly trigeminal neuropathy, have been recognized as neurological complications of Sjögren's syndrome, but the pathogenesis has not been established. We describe a woman with primary Sjögren's syndrome who developed a progressive debilitating subacute sensory neuronopathy. Results of electrophysiological studies were consistent with involvement of the trigeminal and dorsal root ganglia. A thoracic dorsal root ganglion biopsy showed lymphocytic infiltration and degeneration of ganglion cells. We believe that this is the first description of biopsy-documented dorsal root ganglionitis in a subacute sensory neuronopathy associated with Sjögren's syndrome and that the finding suggests an immunopathogenic basis.

Female↗
PubMed1986

The pathophysiology of penicillamine-induced myasthenia gravis.

The temporal course and pathophysiology of penicillamine-induced myasthenia gravis were studied in detail in a typical case. Our results suggest that this disorder and idiopathic autoimmune myasthenia gravis share the same essential pathophysiological features, including the presence of anti-acetylcholine receptor (AChR) antibody, serum-induced blockade of AChRs, antibody-mediated accelerated degradation of AChRs, and a resultant quantitative reduction in available junctional AChRs. An initial severe reduction in junctional AChRs was reversed and the patient recovered, both within 8 months of stopping penicillamine. Our data suggest that penicillamine probably produced myasthenia gravis by initiating a new autoimmune response rather than by enhancing ongoing autoimmunity.

Animals↗
PubMed1985

Treatment of experimental myasthenia gravis with cyclosporin A.

Cyclosporin A (CsA) is an immunosuppressive agent that has recently been used to prevent rejection of transplanted tissues. The effects of CsA treatment of rats with experimental autoimmune myasthenia gravis (EAMG), an antibody-mediated autoimmune disorder of acetylcholine receptors (AChRs) at neuromuscular junctions, have been studied. CsA treatment at the time of primary immunization suppressed the antibody responses to AChR virtually completely. Following 12 weeks of CsA, the AChR-immunized rats responded like naive controls to a further challenge of AChR. Treatment of ongoing EAMG resulted in a reduction of AChR antibody by more than 50%. The secondary response to a challenge of AChR was prevented by CsA treatment, but a very large challenge dose in adjuvant partially overwhelmed the effect of CsA. CsA treatment also prevented the loss of AChRs at neuromuscular junctions, as compared with untreated EAMG controls (P less than 0.02). The efficacy of CsA in suppressing ongoing and secondary hetero- and autoimmune responses against AChR in EAMG encourages its ultimate application in autoimmune diseases of man, such as MG. Its usefulness will depend on the ability to determine effective doses of CsA that are well tolerated.

Animals↗
PubMed1985

Effects of dimethyl sulfoxide on humoral immune responses to acetylcholine receptors in the rat.

The effects of dimethyl sulfoxide (DMSO) on the humoral immune responses to acetylcholine receptors (AChR) were studied in rats with experimental autoimmune myasthenia gravis. DMSO was administered during primary, ongoing, and secondary phases of the immune response to AChR. Anti-AChR antibody titers were measured to determine the effect of the treatment. DMSO had pronounced effects on the humoral immune response, which differed depending on the stage of the response and the strength of antigenic stimulation. When given during an ongoing immune response, DMSO suppressed anti-AChR antibody levels by an average of 53-76%. This effect was similar whether DMSO was given by oral, rectal, or intraperitoneal routes. DMSO treatment also suppressed the anti-AChR antibody response to a weak primary antigenic stimulus to a similar extent. In contrast, when administered during a secondary or a strong primary immunization, DMSO enhanced the anti-AChR antibody response 1.7- to 2.8-fold. These results show that DMSO may either enhance or suppress humoral immune responses. Further studies will be required to analyze the cellular mechanisms underlying the actions of DMSO.

Animals↗
PubMed1985

Motor nerve terminal outgrowth and acetylcholine receptors: inhibition of terminal outgrowth by alpha-bungarotoxin and anti-acetylcholine receptor antibody.

Motor nerves undergo extensive terminal outgrowth when the muscles they supply are "functionally denervated." In this study, we have investigated the role of the acetylcholine receptors (AChRs), newly appearing in such muscles, in promoting nerve terminal outgrowth. The amount of outgrowth was determined by morphometric measurement of nerve terminal branching, endplate length, and ultraterminal sprouts, in cholinesterase-silver-stained neuromuscular junctions. Presynaptic neuromuscular blockade with botulinum toxin induced pronounced nerve terminal outgrowth in both the rat and mouse soleus muscles, although ultraterminal sprouts did not occur in the rat soleus. By contrast, postsynaptic neuromuscular blockade with alpha-bungarotoxin (alpha-BuTx) induced little or no terminal outgrowth, although it caused "functional denervation." Moreover, alpha-BuTx and anti-AChR antibody inhibited the terminal outgrowth otherwise induced by botulinum toxin. Other types of motor nerve growth, such as nerve regeneration, were unaffected by these agents. Our results are consistent with the concept that extrajunctional AChRs in skeletal muscle play an important role in the control of motor nerve terminal outgrowth at neuromuscular junctions.

Animals↗
PubMed1985

Intracellular acetylcholine receptors in skeletal muscles of the adult rat.

We have examined the localization and numbers of acetylcholine receptors (AChRs) within adult mammalian skeletal muscle using 125I-alpha-bungarotoxin (125I-alpha-BuTx). Intracellular AChRs were exposed to 125I-alpha-BuTx by permeabilizing the muscle membrane with the detergent saponin. Our results show that, in muscles of young adult rats, internal AChRs occur in a number and pattern of distribution similar to that for surface membrane AChRs. Internal AChRs are found only in perijunctional regions of normally innervated muscles, but they appear all along the length of muscle fibers after denervation. A minority of internal AChRs may be newly synthesized AChRs en route to insertion in the surface membrane; however, most internal AChRs appear to be antigentically different from and to behave independently of surface membrane AChRs. With increasing age, internal AChRs decline in number, while surface AChRs remain relatively constant. In older animals, internal AChRs may reappear in muscles that have undergone degeneration and regeneration. We conclude that a significant proportion of AChRs in skeletal muscle may be intracellular. Internal AChRs are a useful marker for young muscle cells. Their distribution may provide information about the intracellular pathways of AChR metabolism.

Animals↗
PubMed1984

Susceptibility of skeletal muscle to Coxsackie A2 virus infection: effects of botulinum toxin and denervation.

Coxsackie A viruses can infect denervated but not innervated mature skeletal muscles. The role of synaptic transmission in preventing susceptibility to Coxsackievirus infection was studied by surgically denervating leg muscles of mice or injecting the muscles with botulinum toxin to block quantal release of acetylcholine. Control muscles were injected with heat-inactivated toxin. Subsequent injection of Coxsackie A2 virus resulted in extensive virus replication and tissue destruction in the denervated and botulinum toxin-treated muscles, while the control muscles showed only minimal changes. This suggests that the susceptibility of skeletal muscle to Coxsackievirus infection is regulated by synaptic transmission.

Animals↗
PubMed1983

Goggle migraine.

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Adult↗
PubMed1983

Combined short-term immunotherapy for experimental autoimmune myasthenia gravis.

A therapeutic strategy was designed to eliminate the humoral immune response to acetylcholine receptor (AChR) in ongoing experimental autoimmune myasthenia gravis (EAMG). Rats with EAMG were treated with a protocol consisting of three components: (1) A single high dose of cyclophosphamide (200 mg/kg) was used to produce a rapid and sustained fall in the anti-AChR antibody levels by preferential destruction of antibody-producing B-lymphocytes. "Memory" lymphocytes were not eliminated by cyclophosphamide. (2) Irradiation (600 rads) was used to eliminate the "memory" cells. It eliminated the anamnestic response to a challenge with the antigen AChR. (3) Bone marrow transplantation was used to repopulate the hematopoietic system after the otherwise lethal dose of cyclophosphamide. We used bone marrow from syngeneic rats with active EAMG to simulate an autologous transplant. Rats with EAMG treated with this combined protocol showed a prompt and sustained fall in the anti-AChR antibody levels and had no anamnestic response to a challenge with AChR. Thus, an affected animal's own marrow could be stored and used later for repopulation after cyclophosphamide-irradiation treatment. This treatment eliminates the animal's ongoing immune responses and reconstitutes the immune system in its original state. The success of this approach suggests that, if their safety could be established, similar "curative" strategies might be developed for the treatment of patients with severe antibody-mediated autoimmune disorders, such as myasthenia gravis.

Animals↗
PubMed1982

Treatment of ongoing experimental myasthenia gravis with short term high dose cyclophosphamide.

We have treated animals with an ongoing autoimmune disease, experimental autoimmune myasthenia gravis (EAMG), using a strategy designed to eliminate the antibody-producing cells. During well-established EAMG, a single high dose of cyclophosphamide was given because of its known effectiveness against B-lymphocytes. To counteract the lethal effects of the drug, the rats were "rescued" by bone marrow cell transplantation. This treatment produced a rapid and sustained fall of antibody titers against both the immunizing antigen (Torpedo acetylcholine receptor) and the autoantigen (rat acetylcholine receptor). Immunologic memory, as measured by an anamnestic response to the antigen, was partially suppressed. Cyclophosphamide treatment produced improvement in the neuromuscular defect: treated animals had, on the average, twice as many acetylcholine receptors at neuromuscular junctions compared with untreated EAMG animals. This treatment method of short-term high doses of an immunosuppressive drug, such as cyclophosphamide, may eventually prove useful for human myasthenia gravis and other autoimmune diseases.

Animals↗
PubMed1982

Membrane myopathy: morphological similarities to Duchenne muscular dystrophy.

Focal lesions in the plasma membrane overlying wedge-shaped defects in muscle fibers ("delta lesions") are an early pathological change in Duchenne muscular dystrophy (DMD). Abnormalities in the plasma membrane have been suggested as a cause of these lesions and of the degeneration of muscle fibers in DMD. We investigated the role of plasma membrane defects in the production of delta lesions by examining the effects of a series of membrane-active agents--lysolecithin, deoxycholate, Triton X-100, and melittin--on the muscles of rats in vivo. Within minutes after treatment with these agents, the muscle fibers developed typical delta lesions. Identical morphological changes were produced by the calcium ionophore A23187, suggesting that calcium entry may play an important role in this process. We conclude that damage to the plasma membrane or calcium entry can reproduce characteristic features of the muscle pathology seen in DMD. This model should prove useful in elucidating the mechanisms of muscle fiber damage and degeneration in DMD.

Animals↗
PubMed1980

Dimethyl sulphoxide reduces anti-receptor antibody titres in experimental myasthenia gravis.

The basic abnormality in myasthenia gravis (MG) is a reduction of acetylcholine receptors (AChRs) at neuromuscular junctions, due to an autoimmune attack directed against the receptors. Several lines of evidence support the idea that humoral immune mechanisms play an important part in this process: anti-AChR antibodies are present in the sera of more than 80% of myasthenic patients; the pathogenicity of the antibodies has been demonstrated by passive transfer of IgG from myasthenic patients to mice which reproduces the typical features of MG in the recipient animals; finally, procedures that reduce levels of anti-AChR antibody, such as plasmapheresis, produce improvement in the clinical symptoms of MG. Present treatments of MG depend largely on the prolonged use of immunosuppressive drugs, which have significant drawbacks, for they usually produce only a slow fall in antibody titres, and have toxic side effects. An agent that could produce a rapid and sustained fall of autoantibody titre might have wide application in the treatment of MG and other autoimmune diseases. In the course of testing immunosuppressive drugs for their effect in treating experimental autoimmune MG (EAMG), we discovered that the vehicle used to dissolve some of these agents, dimethyl sulphoxide (DMSO), itself produced a rapid and sustained fall of anti-AChR antibody titre. We now report similar results for a controlled trial of DMSO treatment in rats with EAMG.

Animals↗
PubMed1980

Lithium reduces the number of acetylcholine receptors in skeletal muscle.

Extended treatment of rats with lithium inhibits the increase in the number of extrajunctional acetylcholine receptors that occurs in their denervated skeletal muscle. In normal muscle, lithium reduces the number of acetylcholine receptors at neuromuscular junctions. These changes appear to be a relatively specific effect of lithium on the turnover of receptors. Skeletal muscle provides an accessible system for analyzing the role of lithium (and other cations) in the regulation of cell surface receptors. This regulation may play a role in the mechanism by which lithium prevents recurrent manic-depressive episodes.

Acetylcholine↗