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Biomedical subjects

A G Engel

Publications and source records attributed to A G Engel.

At least 199 records · Page 11Linked to original sources
PubMed1978

Intracellular calcium accumulation in Duchenne dystrophy and other myopathies: a study of 567,000 muscle fibers in 114 biopsies.

Ultrastructural studies have shown plasmalemmal defects in a proportion of non-necrotic muscle fibers in Duchenne dystrophy, suggesting that intracellular calcium overloading may be an important mechanism of muscle fiber degeneration. To investigate this assumption, we studied the localization of calcium with the von Kóssa method, with alizarin red, and with glyoxalbis-(o-hydroxyanil) in serial, fresh-frozen sections of 114 biopsy specimens. The biopsy material included Duchenne dystrophy (24 cases), other dystrophies (27 cases), inflammatory myopathies (47 cases), and normal controls (11 cases). Counted in each specimen were every muscle fiber, the so-called large-dark fibers, and all calcium-positive fibers. Separate counts were made of the large-dark, necrotic, and other types of calcium-positive fibers. In Duchenne dystrophy, non-nectotic calcium-positive fibers occurred with a mean frequency of 4.83 percent. For all other groups, the corresponding value was 0.57 percent, with a range of 0.21 percent (normals) to 1.76 percent (scleroderma), p less than 0.001. Large-dark fibers were 12 times more common in Duchenne dystrophy than in all other cases. Forty-three percent of the fibers were calcium-positive in Duchenne dystrophy, whereas calcium-positive large-dark fibers were extremely rare in the other cases.

Biopsy↗
PubMed1978

Structure-function correlations in myasthenia gravis and a new myasthenic syndrome.

The physiologic hallmark of MG is the small amplitude of the mepp. This can be correlated with a deficiency of postsynaptic AChR. The AChR deficiency is caused by antiAChR antibodies. Antibody dependent, complement mediated lysis of the postsynaptic membrane contributes significantly to the AChR deficiency. The abundance of immune complexes localized at the end-plate correlates with the amount of AChR remaining at the end-plate and with the mepp amplitude. The physiologic hallmarks of the new myasthenic syndrome are a small quantum content of the end-plate potential due to a decreased store of immediately releasable quanta, repetitive response of the muscle to a single nerve stimulus and refractoriness to anticholinesterase drugs. The findings are explained by a marked decrease of the size of the nerve terminal and by the total absence of AChE from the end-plate.

Adolescent↗
PubMed1977

A new myasthenic syndrome with end-plate acetylcholinesterase deficiency, small nerve terminals, and reduced acetylcholine release.

A new myasthenic syndrome is described in a patient whose symptoms began soon after birth and included generalized weakness increased by exertion, easy fatigability, hyporeflexia, and refractoriness to anticholinesterase drugs. Electromyography showed a decremental response at all frequencies of stimulation and a repetitive response to single nerve stimulation. Miniature end-plate potentials (mepps) were of normal amplitude but of decreased frequency. The mepp duration and half-decay time were prolonged, and prostigmine was without any addtitional effect. The quantum content of the end-plate potential was decreased due to a reduced store of quanta immediately available for release, but the probability of release was normal. Quantitative electron microscopy demonstrated a 3-fold to 4-fold decrease of nerve terminal size and reduced postsynaptic membrane density. The postsynaptic folds showed focal degeneration, and many were distended by labyrinthine membranous networks that communicated with the synaptic space. Degenerating nuclei were found in the junctional sarcoplasm. The ultrastructural localization of the acetylcholine receptor protein was normal. Acetylcholinesterase (AChE) was absent from the motor end-plates by histochemical and electron cytochemical criteria. Biochemical studies indicated total absence of the end-plate-specific 16 S species of AChE and marked decrease in total muscle AChE. A congenital defect in the molecular assembly of AChE or in its attachment to the postsynaptic membrane might represent the basic abnormality and condition the morphological and physiological alterations.

Acetylcholine↗
PubMed1977

Carnitine deficiency: clinical, morphological, and biochemical observations in a fatal case.

A fatal case of carnitine deficiency is described. The patient had intermittent metabolic acidosis, fluctuating hepatomegaly, and progressive muscle weakness since 22 months of age. One of two liver biopsies revealed lipid accumulation in the hepatocytes, and a muscle biopsy at age 5 years showed a lipid storage myopathy. Type 1 fibres were the most severely affected. Satellite and vascular endothelial cells also contained abnormal lipid deposits. Quantitative electron microscopy demonstrated an approximately 50-fold increase in lipid material, and a twofold increase in mitochondria in myofibres. The muscle carnitine level was less than one-seventh of the lowest value encountered in 74 biopsies from non-weak or neuromuscular disease controls. The basic abnormality in this patient is assumed to be a defect in carnitine biosynthesis.

Acidosis↗
PubMed1977

Ultrastructural localization of the acetylcholine receptor in myasthenia gravis and in its experimental autoimmune model.

Peroxidase-conjugated alpha-bungarotoxin (P-BGT) was used for the ultrastructural localization of the acetylcholine receptor in end-plates in external intercostal muscles of four patients with myasthenia gravis, in forelimb digit extensor muscles of rats with advanced chronic experimental autoimmune myasthenia gravis, and in suitable human and rat controls. In control end-plates, the previously reported localization of acetylcholine receptor on the terminal expansions of the postsynaptic folds and, in traces, on the presynaptic membrane was confirmed. By contrast, in myasthenia gravis some postsynaptic regions bound no P-BGT; in other regions, the folds displayed only faint traces of the reaction product, or only some segments of the postsynaptic membrane showed the reaction product; finally, in some regions there was no apparent decrease in reaction product. In general, those postsynaptic regions showing the greatest decrease in P-BGT binding were also the simplest or showed the most degenerative changes, and the presynaptic staining was decreased in proportion to the decrease in the adjacent postsynaptic P-BGT binding. In the experimental animals, the abnormalities in the amount and distribution of the acetylcholine receptor were essentially like those in the more severely affected patients. Morphometric estimates of the postsynaptic acetylcholine receptor surface correlated well with the patients' clinical status and linearly with the miniature end-plate potential amplitude.

Action Potentials↗
PubMed1977

Failure of inactivation of Duchenne dystrophy X-chromosome in one of female identical twins.

Duchenne muscular dystrophy manifested in one of girl twins. The twins were monozygous on the basis of red cell and HL antigens and skin graft compatibility. Karyotyping, including banding techniques, showed a normal number of chromosomes and a normal configuration of the X-chromosome in both twins. The twins were identical in appearance until symptoms of Duchenne dystrophy developed in one at age 4 years. The maternal uncle had classic Duchenne dystrophy; the mother and the nonmanifesting twin showed evidence of being heterozygous for Duchenne dystrophy. The phenotypic difference in monozygous twins is readily explained by lyonization of the X-chromosome after twinning has occurred. The findings substantiate the existence of Duchenne dystrophy manifesting in females with normal karyotypes.

Child↗
PubMed1977

Duchenne dystrophy: ultrastructural localization of the acetylcholine receptor and intracellular microelectrode studies of neuromuscular transmission.

Despite focal degeneration and simplification of the postsynaptic region in Duchenne dystrophy, the postsynaptic acetylcholine receptor (AChR) is preserved. This is in contrast to myasthenia gravis where similar postsynaptic alterations are invariably associated with a marked decrease in AChR. There is no extrajunctional spread of AChR in Duchenne dystrophy. The amplitude and frequency of miniature end-plate potentials and the number of transmitter quanta released by nerve impulse are normal but the resting membrane potential is lower than normal. The findings indicate that the release and the postsynaptic responsiveness to acetylcholine are intact in Duchenne dystrophy.

Acetylcholine↗
PubMed1977

Immune complexes (IgG and C3) at the motor end-plate in myasthenia gravis: ultrastructural and light microscopic localization and electrophysiologic correlations.

Although there is strong evidence that myasthenia gravis (MG) is caused by an autoimmune reaction to the nicotinic postsynaptic acetylcholine receptor (AChR) protein, immune complexes have never been directly demonstrated at the end-plate by immunocyto-chemistry or immunoelectron microscopy. Staphylococcal protein A (which binds to the Fc region of human IgG subclasses 1, 2, and 4) and rabbit anti-human C3 conjugated with peroxidase were used for the ultrastructural (5 patients) and light microscopic (12 patients) localization of IgG and C3, respectively, at MG end-plates. Both IgG and C3 were localized on segments of the postsynaptic membrance and fragments of degenerating junctional folds in the synaptic space. In nonmyasthenic control patients no immune complexes were evident at the end-plate. As judged by morphometric analysis of electron micrographs, the immune complexes were more abundant in the less severely affected MG patients than in the more severely affected ones. A linear correlation was demonstrated between the length of the postsynaptic membrance binding immune complexes and the amplitude of the miniature end-plate potential. The less intense reaction for immune complexes in the more severely affected MG patients can be attributed to the smaller quantity of AChR remaining at their end-plates. The findings provide unambiguous evidence for a destructive auto-immune reaction involving the postsynaptic membrance in MG. Immunopharmacologic blockade of AChR and IgG-induced modulation of AChR may also contribute to the AChR deficiency at the MG end-plates.

Adult↗
PubMed1977

Survival in polymyositis: corticosteroids and risk factors.

Thirty-one polymyositis patients treated with low-dose corticosteroid were age and sex matched with 31 polymyositis patients treated with high-dose corticosteroid. Although disease severity at onset of the study was similar in the groups, no statistically significant difference in survival was found. The death rate in each group was greater than normal. The presence of dysphagia or severe muscle weakness lessened the chances of survival. Controlled trials with other drugs should be carried out.

Adrenal Cortex Hormones↗
PubMed1976

Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine recepotr antibodies.

Passive transfer of experimental autoimmune myasthenia gravis (EAMG) was achieved using the gamma globulin fraction and purified IgG from sera of rats immunized with Electrophus electricus (eel) acetylcholine receptor (AChR). This demonstrates the critical role of anti-AChR antibodies in impairing neuromuscular transmission in EAMG. Passive transfer of anti-AChR antibodies from rats with chronic EAMG induced signs of the acute phase of EAMG in normal recipient rats, including invasion of the motor end-plate region by mononuclear inflammatory cells. Clinical, eletrophysiological, histological, and biochemical signs of acute EAMG were observed by 24 h after antibody transfer. Recipient rats developed profound weakness and fatigability, and the posture characteristic of EAMG. Striking weight loss was attributable to dehydration. Recipient rats showed large decreases in amplitude of muscle responses to motor nerve stimulation, and repetitive nerve stimulation induced characteristic decrementing responses. End-plate potentials were not detectable in many muscle fibers, and the amplitudes of miniature end-plate potentials were reduced in the others. Passively transferred EAMG more severely affected the forearm muscles than diaphragm muscles, though neuromuscular transmission was impaired and curare sensitivity was increased in both muscles. Some AChR extracted from the muscles of rats with passively transferred EAMG was found to be complexed with antibody, and the total yield of AChR per rat was decreased. The quantitative decrease in AChR approximately paralleled in time the course of clinical and electrophysiological signs. The amount of AChR increased to normal levels and beyond at the time neuromuscular transmission was improving. The excess of AChR extractable from muscle as the serum antibody level decreased probably represented extrajunctional receptors formed in response to functional denervation caused by phagocytosis of the postsynaptic membrane by macrophages. The amount of antibody required to passively transfer EAMG was less than required to bind all AChR molecules in a rat's musculature. The effectiveness of samll amounts of antibody was probably amplified by the activation of complement and by the destruction of large areas of postsynaptic membrane by phagocytic cells. A self-sustaining autoimmune response to AChR was not provoked in animals with passively transferred EAMG.

Animals↗
PubMed1976

Fatal systemic carnitine deficiency with lipid storage in skeletal muscle, heart, liver and kidney.

A fatal case of systemic carnitine deficiency is reported. The patient suffered from slowly progressive muscle weakness since early childhood. After the age of 17 years her weakness progressed more rapidly until her death at the age of 20. A pregnancy during the last year of the patient's life was followed by rapid deterioration in her condition. An episode of renal insufficiency occurred at the age of 17 years and hepatomegaly, increased BSP dye retention and intermittent ketoacidosis were present during the last month of her life. Biopsy and autopsy specimens of muscle showed a lipid storage myopathy. Type 1 fibers were selectively severely affected, and many Type 1 fibers were atrophic. Abundant large mitochondria, some also containing abnormal inclusions, were also present in the muscle fibers. At autopsy there was marked accumulation of sudanophilic lipid deposits in all hepatocytes, in the renal tubular epithelial cells, and a patchy increase of lipid material was found in the myocardial fibers. There was marked carnitine deficiency in the patient's liver as well as muscel, while the carnitine palmityltransferase activities in these tissues were abnormally high. The basic metabolic abnormality is assumed to be a defect in carnitine biosynthesis.

Adult↗
PubMed1976

Experimental acetylcholine blockade of the neuromuscular junction. Effects on end plate and muscle fiber ultrastructure.

To investigate the effect of acetylcholine on the formation and maintenance of the end plate, presynaptic (hemicholinium-3 and botulinum toxin) and postsynaptic (curare and alpha-bungarotoxin) blocking agents were injected into the amniotic sac or chorioallantoic circulation of chick embryos during different stages of their development (days 3 to 11, 3 to 18, and 12 to 18). Tntercostal or anterior and posterior latissimus dorsi muscles were examined by electron microscopy. Regardless of the duration of treatment, the type of agent, or the type of muscle, nerve ingrowth into muscle and end-plate formation were not arrested and the ultrastructure of nerve terminals and postsynaptic regions was normal. By contrast, muscle fiber ultrastructure was affected by acetylcholine blockade if continued beyond day 11. By day 11 both treated and control muscles were composed primarily of myotubes. Muscles treated beyond day 11 showed impaired fiber differentiation and persistence of many myotubes. In addition, many fiber regions contained unassembled fine filaments intermingled with other organelles. In hemicholinium-3 treated muscles ther were also mitochondrial abnormalities and an increased number of lipid droplets. The findings suggest that the altered structure of the neuromusclar junction in myasthenia gravis is not due to the lack of a trophic effect of acetylcholine. The impaired fiber maturation in the chick embryos may be related to the lack of acetylcholine mediated fiber activity.

Acetylcholine↗
PubMed1976

The motor end plate in myasthenia gravis and in experimental autoimmune myasthenia gravis. A quantitative ultrastructural study.

Neuromuscular junction ultrastructure in rat forelimb digit extensor muscle was sequentially and quantitatively investigated in experimental autoimmune myasthenia gravis (EAMG). Experimental animals received a single dose of highly purified eel-electroplax acetylcholine receptor protein plus complete Freund's adjuvant and B. pertussis organisms. During the first 7 days (latent period) after immunization the experimental end plates remained normal. Between day 7 and 11 (acute phase) mononuclear cells infiltrated those regions of muscle where the end plates were located and the was sudden degeneration of the postsynaptic regions with splitting away of the abnormal junctional folds from the underlying muscle fibers. Macrophages entered the gaps arising between the muscle fibers and the separating postsynaptic folds and removed the degenerating folds by phagocytosis. The nerve terminals were displaced from their usual location but maintained their structural integrity. After day 11 (chronic phase) the inflammatory reaction subsided and the nerve terminals returned to the highly simplified postsynaptic regions. Subsequently the postsynaptic folds were reconstituted and again they degenerated. The degeneration involved especially the tips of the folds where acetylcholine receptor sites are concentrated. Immature junctions with poorly differentiated postsynaptic regions and nerve sprouts near end plates were also observed. In two animals that relapsed on day 27 and 33, respectively, degeneration of the postsynaptic folds was more intense than in the remaining animals that had not relapsed during the chronic phase. Morphometric analysis of the end plates demonstrated significant decreases in the postsynaptic membrane length, in the postsynaptic membrane density and in the postsynaptic to presynaptic membrane length ratio in chronic EAMG. In addition, the concentration of synaptic vesicles in the nerve terminals was increased in acute and chronic EAMG while the nerve terminal area was decreased in acute EAMG. The alterations in the nerve terminal may be secondary to the postsynaptic changes. The postsynaptic region is the primary target of the autoimmune reaction in EAMG and the ultrastructural and morphometric abnormalities of the end plate in the chronic phase of the syndrome closely resemble those which have been observed in human myasthenia gravis.

Animals↗
PubMed1975

Studies on in vitro polymerization of tubulin from renal medullary extracts.

Previous in vivo studies showed that microtubules are involved in the cellular action of vasopressin. In order to analyze the role of renal medullary microtubules, a system was developed which would allow the study of the assembly of tubulin in renal medulla extracts into microtubules in vitro. The assembly of tubulin into microtubules occurred in renal medullary cytosol (100 000 times g supernatant) under specific conditions which include pre-concentration of cytosol by ultrafiltration, the presence of ethylene glycol bis(2-aminoethyl)ether tetraacetic acid (EGTA) and 4 M glycerol, and warming at 37 degrees C. Formation of microtubules, which sedimented at 100 000 times g, was proved by (a) an increase in the apparent [3H]colchicine-binding activity of depolymerized pellets, (b) appearance of typical microtubules as shown by electron microscopy, and (c) by the increase in the quantity of microtubular protein analyzed by polyacrylamide gel electrophoresis. Vinblastine at a concentrationof 10(-6) M completely blocked formation of microtubules. A slight increase of ionized calcium in the polymerization mixture also prevented microtubule assembly; this inhibitory effect of ionized calcium was present at concentrations as low as 10(-4) M. Blockade of microtubule assembly by the increase in concentration of ionized calcium or by vinblastine may be the basis of known inhibitory effect of these two agents upon the hydroosmotic effect of vasopressin in vivo.

Animals↗
PubMed1975

Effects of microembolization on the skeletal muscle blood flow. A critique of the microvascular occlusion model of Duchenne dystrophy.

Muscle blood flow (MBF) during exercise was determined in both anterior tibial muscles of 12 rabbits by the local 133-Xe method before and after embolization of 20 to 80 mum dextran particles into the right femoral artery. With a relatively low dose of particles (dry weight: 8.7 mg), MBF was significantly decreased up to 4 days after each embolization, and mild histologic abnormalities were observed in the embolized muscles. A four-fold higher dose resulted in a marked and permanent decrease of the MBF, ischemic necrosis of the distal leg muscles and toe gangrene. In the light of these findings and the previously demonstrated normal MBF in Duchenne dystrophy, the validity of the assumption that Duchenne dystrophy is caused by small vessel occlusions is questioned.

Animals↗
PubMed1975

The syndrome of systemic carnitine deficiency. Clinical, morphologic, biochemical, and pathophysiologic features.

An 11-year old boy had had recurrent episodes of hepatic and cerebral dysfunction and underdeveloped musculature. Overt weakness developed at age 10. Lipid excess, especially in type I fibers, was found in muscle. Hypertrophied smooth endoplasmic reticulum and excessive microbodies were present in liver. Marked carnitine deficiency was shown in skeletal muscle, plasma, and liver. Ketogenesis was impaired on a high fat diet, but omega oxidation of fatty acids was enhanced. There was excessive glucose uptake and essentially no oxidation of labeled long-chain fatty acids by perfused forearm muscles in vivo. Oral replacement therapy restored plasma carnitine levels to normal, but not liver or muscle carnitine levels, and was accompanied by clinical improvement.

Adenosine Triphosphatases↗
PubMed1975

Duchenne dystrophy: electron microscopic findings pointing to a basic or early abnormality in the plasma membrane of the muscle fiber.

In seven patients with Duchenne dystrophy, high-resolution phase microscopy demonstrated a population on non-necrotic fibers with one or more focal lesions. The typical lesion was wedge-shaped, with the base resting on the fiber surface. In the electron microscope, the plasma membrane overlying the lesion was either absent or disrupted, while the basement membrane was always preserved. Within the lesion, there were cytoplasmic abnormalities, and in the neighboring fiber region, the myofibrils were usually highly contracted. The structural defect in the plasma membrane suggested that this site was an ineffective cellular barrier. This was confirmed by the frequent ingress of peroxidase-containing extracellular fluid into the lesions. In two control subjects, peroxidase penetration into fibers was seen only rarely and only with other evidence of mechanical injury to the specimen. The findings point to an early and possibly basic abnormality in the plasma membrane of the muscle fiber in Duchenne's dystrophy.

Adult↗