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Biomedical subjects

A S Penn

Publications and source records attributed to A S Penn.

At least 19 recordsLinked to original sources
PubMed1998

TCR-Vbeta usage in the thymus and blood of myasthenia gravis patients.

In myasthenia gravis (MG) the muscle acetylcholine receptor (AChR) is the target of an autoimmune response. The anti-AChR response may originate in the thymus, which is abnormal in most MG patients and contains anti-AChR T and B cells. Microbial superantigens (sAg) may trigger autoimmune responses and in this study we sought clues as to whether sAg play a role in the pathogenesis of MG. We investigated the frequency of use of the different TCR Vbeta families by the thymus and blood T cells in MG patients and in control subjects, using a multi-primer PCR assay. Identical TCR-Vbeta usage was found in the thymi of MG patients and controls, except Vbeta2, which showed a small increase in MG patients' thymi. Blood T cells of MG patients used Vbeta4, Vbeta6, Vbeta15, Vbeta16 and Vbeta24 significantly more than those of the controls. Vbeta4 and Vbeta6 are the gene families most frequently used by anti-AChR CD4(+) cells in MG patients. Blood T cells from MG patients used Vbeta12, Vbeta14, Vbeta17 and Vbeta18 significantly less than controls. MG patients used Vbeta4 and Vbeta6 significantly more in the blood than in the thymus, while the opposite occurred for Vbeta7, Vbeta12 and Vbeta14. Controls used Vbeta17 more and Vbeta24 less in the blood than in the thymus. The preferential expansion of Vbeta4 and Vbeta6 in MG patients might reflect the immunodominance of certain AChR epitopes, or the action of a sAg outside the thymus. The minimal differences in the TCR-Vbeta usage in the blood and thymus of control subjects might be due to expansion of T cell clones specific for common antigens. Identical Vbeta usage in the thymi of MG patients and controls does not support an important role of the thymus as the location of anti-AChR sensitization when MG is clinically evident. The differences observed in the Vbeta usage in blood and thymi of MG patients are likely to be due to preferential Vbeta usage by the anti-AChR T cells in the blood.

Adolescent↗
PubMed1996

Inflammation.

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Humans↗
PubMed1994

Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features.

Andersen's syndrome is a clinically distinct form of potassium-sensitive periodic paralysis associated with cardiac dysrhythmias. The subtle nature of the cardiac and dysmorphic features may delay the recognition of this syndrome and its potentially lethal cardiac dysrhythmias. The genetic defect in Andersen's syndrome is not genetically linked to other forms of potassium-sensitive periodic paralysis and is probably distinct from the long QT syndrome locus.

Abnormalities, Multiple↗
PubMed1988

Seronegative myasthenia gravis.

Of 221 patients with myasthenia gravis, 18.5% had no detectable antibodies to acetylcholine receptor. Seven of 14 patients (50%) with only ocular symptoms for more than 2 years were seronegative, and 25 of 145 (17%) patients with generalized myasthenia were seronegative. The clinical characteristics of seronegative patients did not differ from patients with high antibody titers. No seronegative patient had a thymoma, but that difference did not reach statistical significance. Lack of serum antibodies did not preclude favorable response to thymectomy or plasmapheresis.

Adult↗
PubMed1988

"Maximal" thymectomy for myasthenia gravis. Results.

Thymectomy has been shown to be effective in the treatment of myasthenia gravis. The logical goal of operation has been complete removal of the thymus, but there has been controversy about the surgical technique and its relation to results. Surgical-anatomic studies have shown gross and microscopic thymus widely distributed in the neck and mediastinum. We believe that an en bloc transcervical-transsternal "maximal" thymectomy is required to remove all thymic tissue predictably. Ninety-five patients with generalized myasthenia gravis underwent "maximal" thymectomy consecutively between 1977 and 1985 and were evaluated 6 months to 89 months after operation. In Group A (N = 72), myasthenia gravis without thymoma, the uncorrected data revealed that 96% (69) had benefited from operation: 79% (57) had no symptoms; 46% (33) were in remission; 33% (24) were symptom free when receiving minimal doses of pyridostigmine; and none were worse. Life table analysis yielded a remission rate of 81% at 89 months. In group B (N = 8), myasthenia gravis without thymoma for which patients underwent reexploration for incapacitating weakness after earlier transcervical or transsternal operations, residual thymus was found in all. One patient was in remission, two were symptom free when receiving medication, one was unchanged, and none were worse. In group C (N 15), myasthenia gravis and thymoma, two patients were in remission and nine were symptom free when receiving medication. Two patients in this group died 2 and 4 years postoperatively in crisis. Response to thymectomy in group A was greater in patients with mild myasthenia gravis and may have been better in patients who had symptoms for less than 60 months preoperatively, but the response did not depend on age, sex, presence or absence of thymic hyperplasia or involution, or titers of acetylcholine receptor antibodies. The response to thymectomy in group B was striking but slower than in group A, perhaps because symptoms were more severe and of longer duration. The response in group C was also less good than in group A and proportionately fewer benefited. These results support the recommendation for thymectomy in the treatment of patients with generalized myasthenia gravis and indicate the desirability of a maximal procedure. For persistent or recurrent severe symptoms after previous transcervical or submaximal transsternal resections, reoperation by this technique is also recommended.

Actuarial Analysis↗
PubMed1986

Antimuscle and antiacetylcholine receptor antibodies in myasthenia gravis.

The sera of 134 patients were examined for antimuscle antibodies by immunofluorescence (IF). These derived from 77 myasthenics, 30 myasthenics with thymoma, 6 patients with thymoma and no clinical evidence of myasthenia, and 21 patients with other autoimmune or neuromuscular diseases. Three separate patterns of antimuscle antibodies could be identified in the myasthenic sera by examination of the relaxed glycerinated myofibrils by both IF and phase-contrast optics: A-band (9 with thymoma, 1 without), I-band (11 with thymoma, 17 without), and a mixed A plus I pattern (5 with thymoma, 3 without). Seventy-seven myasthenic serum samples (24 with thymoma, 53 without) were available for evaluation of antibodies to acetylcholine receptor (anti-AChR) by radioimmunoassay. Ninety-one percent reacted with crude human receptor extract and 80% with receptor extracted from denervated rat muscle. There was no correlation between the titers of anti-AChR and the presence or staining patterns of antimuscle antibodies, but patients without anti-AChR did not have antimuscle antibodies. Myasthenics with thymoma had the highest prevalence of anti-AChR (23/24) and of antimuscle antibodies (25/30), and 15 of the 20 positives stained A-bands alone or with I-band, as compared to 4 of 21 positive reactions in those without tumor. Immunoabsorption, which removed or significantly reduced anti-AChR, did not alter antimuscle reactivity. The discrepancies between anti-AChR levels and the presence and types of antimuscle antibodies suggest that these are independent autoantibodies. Current theories of immunopathogenesis implicate altered thymic antigens or a major breakdown in immune regulation, either of which could explain their production.

Animals↗
PubMed1985

Potentially fatal cardiac dysrhythmia and hyperkalemic periodic paralysis.

An 11-year-old boy was evaluated for mild periodic muscular weakness exacerbated on separate occasions by disopyramide phosphate and procainamide. He and his mother both had bidirectional ventricular tachydysrhythmia (BVT), short stature, microcephaly, and clinodactyly. The mother, but not the child, had lingual myotonia. The two antiarrhythmic drugs worsened the muscular weakness without benefiting the cardiac dysrhythmia. Potassium loading produced skeletal muscle weakness and transient conversion of the BVT to normal sinus rhythm. Hypokalemia aggravated the BVT without causing weakness. Acetazolamide had no effect. The patient suffered a nonfatal cardiac arrest after several days of increased carbohydrate intake. Imipramine controlled the dysrhythmia without inducing weakness. Periodic paralysis should be considered as the diagnosis in children with BVT, a potentially fatal condition.

Arrhythmias, Cardiac↗
PubMed1984

Alpha-bungarotoxin binding to the myotome and choline acetyltransferase activity in the rabbit embryo.

We have previously found incomplete sarcomeres and acetylcholinesterase activity in the myoblasts of the myotome of the rabbit at day 13 of gestation. We now report that an acetylcholine (ACh)-synthesizing enzyme and the nicotinic receptor are present at this stage as well. A study of the myotome using [125I]alpha-bungarotoxin shows that the mononucleated myoblasts have alpha-bungarotoxin binding sites before they migrate away to form multinucleated myotubes. Choline acetylcholinesterase activity and/or a different ACh-synthesizing enzyme are found at early stages of development, even before the spinal nerve has formed. An ACh-synthesizing enzyme is present in the notochord, a neural tube-dorsal root ganglion preparation, as well as in rows of myotomes separated from the latter preparation. Assays of isolated myotomes with very little adherent mesenchyme indicate that the enzyme is located either within the myotome or in its immediate vicinity. Cholinergic components, therefore, are associated with the mononucleated myoblasts of the myotome before they fuse to form myotubes and before they receive their permanent innervation.

Animals↗
PubMed1984

Augmented anti-acetylcholine receptor response following long-term penicillamine administration.

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.

Animals↗
PubMed1984

Myasthenia gravis: determinants for independent ventilation after transsternal thymectomy.

We evaluated the respiratory function of 32 patients with myasthenia gravis who had transsternal thymectomy. Preoperative clinical, pulmonary function, and respiratory muscle pressure data were submitted to stepwise logistic regression analysis to identify preoperative factors that correlated with duration of supported ventilation after surgery. Ten patients (31%) had postoperative supported ventilation for more than 3 days. The duration of ventilatory support correlated most closely with maximal static expiratory pressure (r = 0.714, p less than 0.001). Expiratory weakness, by reducing cough efficacy, seems to be the main determinant that predicts need for longer postoperative supported ventilation.

Adolescent↗
PubMed1983

Prognosis of ocular myasthenia.

A retrospective study of 108 patients with myasthenia gravis who had solely ocular symptoms and signs at onset was carried out to identify factors influencing prognosis. Increasing duration of pure ocular myasthenia was associated with a decreasing risk of late generalized symptoms; only 9 (15%) of the observed generalizations occurred after more than 2 years of solely ocular symptoms. Increasing age at onset was associated with greater risk of respiratory crisis or death caused by myasthenia, whereas patients younger at onset had a greater chance of a benign outcome. Neither systemic curare tests nor responses to repetitive nerve stimulation had prognostic value.

Adolescent↗
PubMed1982

Anti-idiotypic route to anti-acetylcholine receptor antibodies and experimental myasthenia gravis.

trans-3,3'-Bis[alpha-(trimethylammonio)methyl]azobenzene bromide (BisQ) is a potent agonist of the acetylcholine receptor (AcChoR) of Electrophorus electricus. BisQ is highly constrained, suggesting that its structure is complementary to the combining site of the AcChoR when the latter is in its activated state. Antibodies produced in rabbits to a conjugate of bovine serum albumin and a derivative of BisQ mimicked the binding characteristics of the AcChoR with respect to the order of binding of a variety of agonists and to the preferred recognition of decamethonium ion (an agonist) over hexamethonium ion (an antagonist). Immunization of three rabbits with purified anti-BisQ yielded antisera having binding characteristics of anti-AcChoR in that, by complement fixation and enzyme immunoassay, crossreactions with receptor preparations from rat, Torpedo, and eel could be demonstrated in sera of all three rabbits immunized. Two of the three rabbits showed signs of muscle weakness similar to that seen after immunization with the AcChoR. One of the rabbits was injected intramuscularly with neostigmine and showed temporary improvement. Another showed post-tetanic exhaustion of hind-limb muscles after stimulation of the sciatic nerve at 50 Hz. Antibodies reactive with the AcChoR, therefore, were elicited by immunization with an antibody to a potent ligand of the AcChoR without the necessity of isolating the receptor itself. A similar mechanism may play a part in the etiology of at least some autoimmune diseases in which antibodies to various other receptors are involved.

Animals↗