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Biomedical subjects

A G Engel

Publications and source records attributed to A G Engel.

At least 181 records · Page 10Linked to original sources
PubMed1981

Primary systemic carnitine deficiency: I. Carnitine biosynthesis.

[Methyl-3H]epsilon-N-trimethyl-L-lysine was administered to patients with primary systemic carnitine deficiency and to controls. In both groups, labeled carnitine appeared in blood and urine within 2 hours, and the specific radioactivity of urinary carnitine peaked between 2 and 6 hours. The specific radioactivity of serum carnitine peaked at 6 hours in the controls and in one patient, but in the other patient it rose sharply in the first 2 hours, fell slightly, and then gradually increased to a maximum at 48 hours. The 48-hour excretion of [methyl-3H]-L-carnitine was 4.4 to 6.0 muCi for the controls and 24.2 and 5.6 muCi for patients A and B, respectively. Eight other radioactive metabolites were found in urines of all subjects. Each metabolite was present in comparable amounts. Primary systemic carnitine deficiency in these patients did not result from defective biosynthesis or abnormal degradation of carnitine.

Adult↗
PubMed1981

Primary systemic carnitine deficiency. II. Renal handling of carnitine.

Renal tubular reabsorption rates, reabsorptive maxima, and apparent renal plasma excretory thresholds for carnitine were determined in four children with primary systemic carnitine deficiency (SCD), in two of the mothers of these children, in one patient with muscle carnitine deficiency (MCD), and in seven controls. In SCD the observed values were well below those found in six of seven controls, but one control, a healthy 20-year-old woman with normal muscle carnitine level, also exhibited a renal carnitine leak. In the two mothers of patients with SCD and in the case of MCD some of the parameters of the renal handling of carnitine were slightly altered. Tubular secretion of short-chain acylcarnitines was noted in patients and controls at high plasma free carnitine levels. Augmented excretion of short-chain acylcarnitines occurred at lower plasma free carnitine levels in the patients with SCD than in the other subjects. Free and short-chain acyl-carnitines may compete for the same renal reabsorptive site. A renal defect cannot fully account for primary SCD but may contribute to the carnitine depletion in this disorder.

Carnitine↗
PubMed1981

Freeze-fracture electronmicroscopic analysis of plasma membranes of cultured muscle cells in Duchenne dystrophy.

Depletion of intramembranous particles has been reported in the muscle fiber plasma membrane in Duchenne dystrophy. We searched for a similar abnormality in plasma membranes of cultured muscle cells obtained from six patients with Duchenne dystrophy and six controls. A precise method for phase microscopic to freeze-fracture electronmicroscopic correlation was devised to identify the cell of origin of each replicated membrane face. For both control and patient cells, P-face particle density was higher in myotubes than in mononuclear cells. However, there were no significant differences between control and dystrophic cells when comparing P faces of myotubes, E faces of myotubes, P faces of single cells, or E faces of single cells. The frequency distribution of particle diameters was similar in P faces of control and Duchenne myotubes. Other structural features of the freeze-fractured plasma membrane also were similar.

Adolescent↗
PubMed1980

In vitro analysis of hepatic carnitine biosynthesis in human systemic carnitine deficiency.

The syndrome of systemic carnitine deficiency (progressive muscle weakness, recurrent metabolic encephalopathy, low liver and muscle and fluctuating serum carnitine levels) has been attributed to a defect of carnitine biosynthesis. We determined activities in liver of the four enzymes which convert epsilon-N-trimethyl-L-lysine to L-carnitine in three patients with systemic carnitine deficiency and in 12 control subjects. In the three patients all enzyme activities were within the nornal range except one, which was slightly below the normal range. We conclude that in systemic carnitine deficiency no enzymatic defect exists in the conversion of epsilon-N-trimethyl-L-lysine to carnitine.

Adolescent↗
PubMed1980

Significance of renal gamma-butyrobetaine hydroxylase for carnitine biosynthesis in man.

Carnitine biosynthesis was studied in man and rat. Three healthy adult men were given intravenous injections of 1 mCi of [methyl-3H]epsilon-N-trimethyl-L-lysine, a precursor of carnitine. Labeled metabolites of this compound were monitored in serum and urine at 2, 6, 12, 24, and 48 h. At least nine radioactive metabolites were detected. For each collecton period, the specific activity of urinary carnitine exceeded the average serum specific activity. In man, the amount of labeled carnitine in urine was 2 to 8 times greater than labeled gamma-butyrobetaine (the immediate precursor of carnitine). In similar experiments in rats (intravenous injection of 0.1 mCi of [methyl-3H]epsilon-N-trimethyl-L-lysine), the specific activity of carnitine in urine was always lower than the corresponding average specific activity in serum. Between 0 and 2 h after administration of labeled precursor, the animals excreted large amounts of labeled gamma-butyrobetaine but little labeled carnitine. Significant gamma-butyrobetaine, 2-oxoglutarate dioxygenase (EC 1.14.11.1) activity was found in human kidney but this activity was absent in rat kidney. The results indicate that in man and rat the kidney accumulates intravenously administered [methyl-3H]epsilon-N-trimethyl-L-lysine. This compound is metabolized predominantly to gamma-butyrobetaine in rat kidney and to carnitine in human kidney. In both species, the synthesized products are at least partially leaked (either by secretion or by passive diffusion down a concentration gradient) into the renal tubular lumen from which they are either reabsorbed into the circulation for distribution to other tissues or excreted.

Adult↗
PubMed1980

Tissue distribution of carnitine biosynthetic enzymes in man.

The distribution in human tissues of enzymes which convert epsilon-N-trimethyl-L-lysine to L-carnitine was studied. Existing methodology was modified and new procedures were developed to measure enzyme activities. Epsilon-N-Trimethyl-L-lysine was converted to gamma-butyrobetaine in three enzymatic steps (hydroxylation at carbon 3, aldol cleavage between carbons 2 and 3 to yield glycine and gamma-trimethylaminobutyraldehyde, and subsequent oxidation of the aldehyde) in all tissues studied (liver, brain, kidney, heart and skeletal muscle), but gamma-butyrobetaine was hydroxylated to form L-carnitine only in liver, kidney and brain. Gamma-Butyrobetaine hydroxylase (4-trimethylaminobutyrate, 2-oxoglutarate: oxygen oxidoreductase (3-hydroxylating), EC 1.14.11.1) activity in liver was dependent on the age of the subject. The activity rose from 12% in infants to 100% of the adult mean by age 15 years. No age dependence could be demonstrated for the other three enzymes studied.

Adolescent↗
PubMed1980

[Carnitine deficiency myopathy (author's transl)].

Carnitine is a carrier for the transport of long-chain fatty acids from the cytoplasmic to the mitochondrial space. So far 18 cases of carnitine deficiency myopathy have been recognized, generally occurring as progressive or relapsing myopathy. In contrast episodic exercise-induced myalgia and paresis was found in a 46-year-old patient with carnitine deficiency myopathy which was quickly reversible at rest. As a consequence of this observation carnitine deficiency myopathy must be added to the differential diagnosis of the McArdle syndrome (muscular phosphorylase deficiency) and other "exercise myopathies".

Biopsy↗
PubMed1980

Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis.

The terminal and lytic complement component (C9) was localized at the motor end-plate in acquired autoimmune myasthenia gravis (MG) by the immunoperoxidase method, with adequate preservation of fine structure and negligible background staining. C9 was localized on short segments of the postsynaptic membrane on degenerated fragments of the junctional folds shed into the synaptic space, and on disintegrating junctional folds. An inverse relationship was noted between the structural integrity of the junctional folds and the abundance of C9 at a given end-plate region. Destruction of junctional folds by complement may induce relocation of the nerve terminal and increased spatial separation of end-plate regions on the muscle fiber. Destruction of junctional folds by the complement membrane attack complex is a cause of the acetylcholine receptor deficiency at the MG end-plate, but antibody-dependent modulation of the receptor may also contribute to deficiency of the receptor. In certain disorders other than autoimmune MG, pathological mechanisms other than complement-mediated lysis may affect the structural integrity of the postsynaptic region.

Adolescent↗
PubMed1980

Morphologic and immunopathologic findings in myasthenia gravis and in congenital myasthenic syndromes.

Overwhelming evidence now supports Simpson's concept, originally proposed in 1960, that acquired myasthenia gravis (MG) is an autoimmune disease in which antibodies are directed against the nicotine postsynaptic acetylcholine receptor (AChR).1 An autoimmune pathogenesis of acquired MG implies that those myasthenic syndromes which occur in a congenital and familial setting may have a different, non-autoimmune basis. This paper focuses on ultrastructural, immunoelectron microscopic and cytochemical aspects of acquired autoimmune MG and some recently recognised congenital myasthenic syndromes.

Acetylcholine↗
PubMed1980

Azathioprine with prednisone for polymyositis. A controlled, clinical trial.

A controlled, prospective, double-blind, therapeutic trial of azathioprine was conducted in the initial therapy of polymyositis. Sixteen patients received 60 mg prednisone per day plus either azathioprine (2 mg/kg of body weight per day) or placebo for a period of 3 months. Creatine phosphokinase (CPK) levels fell to normal slightly sooner in the placebo group, but not significantly so. The azathioprine group did not become significantly stronger (P = 0.58) and did not manifest significantly greater improvement of histopathologic features of muscle (P = 0.80) than the placebo group. Initial CPK elevations were significantly related to the degree of muscle inflammation (P = 0.037), but this was not the case at 3 months (P greater than 0.05). Normalization of the CPK could not be equated with disease control. Type II fiber atrophy, attributed to steroid therapy, was more marked in women than in men (P less than 0.03).

Adult↗
PubMed1979

Passively transferred experimental autoimmune myasthenia gravis. Sequential and quantitative study of the motor end-plate fine structure and ultrastructural localization of immune complexes (IgG and C3), and of the acetylcholine receptor.

Experimental autoimmune myasthenia gravis (EAMG) was passively transferred with immunoglobulin from rats with chronic EAMG to normal recipients. IgG and C3 were localized on terminal expansions of junctional folds of end-plates by 6 hours. Segments of folds rich in acetylcholine receptor (AChR) and coated with IgG and C3 were shed into the synaptic space by 24 hours, resulting in AChR deficiency of the postsynaptic membrane. Many sensitized postsynaptic regions were destroyed by macrophages by day 2, but effective nerve-muscle contacts were reestablished by day 5. On day 10, end-plates were still structurally abnormal and showed AChR deficiency, but the animals were clinically recovered. On day 54, postsynaptic regions were still reduced in size, with slight reduction of postsynaptic AChR. Throughout the study, the miniature end-plate potential amplitude tended to vary directly with morphometric estimates of the abundance of the postsynaptic membrane reacting for AChR. Complement-mediated injury to the junctional folds and opsonization of the postsynaptic region can explain the morphologic changes. It is not yet known why phagocytic invasion of the end-plate occurs in acute EAMG and in passively transferred EAMG induced by chronic EAMG immuglobulin, but not in chronic EAMG and only rarely in the human disease.

Animals↗
PubMed1978

Acid maltase deficiency in adults presenting as respiratory failure.

During the past nine years 10 patients with the adult form of acid maltase deficiency have been observed at the Mayo Clinic. Three of the adults presented with respiratory failure. In all three the respiratory manifestations dominated the clinical picture and the cause of the respiratory failure (muscle weakness) and the underlying myopathy (glycogen storage disease) were initially unsuspected. Careful evaluation of the respiratory function tests, including the maximal static respiratory pressures, electromyographic examination and histochemical and biochemical studies of muscle biopsy specimens eventually led to the correct diagnosis.

Adult↗
PubMed1978

Experimental lipid storage myopathy. A quantitative ultrastructural and biochemical study.

A lipid storage myopathy was induced in rats treated with daily doses of 2.5 g/kg brominated vegetable oil. As in human lipid storage myopathies, type I fibers were selectively severely affected, the lipid deposits were surrounded by mitochondria and the mitochondrial fraction of the affected fibers was increased. The oxidation of [U-14C]palmitate, [1(-14)C]octanoate and beta-[3(-14)C]hydroxybutyrate was significantly depressed but [1(-14)C]palmitate, as well as labeled pyruvate and succinate were oxidized at normal rates. The activities of long-chain, medium-chain and short-chain carnitine acyltransferases and the muscle carnitine levels were normal. The lipid storage is attributed to impaired beta oxidation of medium-chain and short-chain fatty acyl residues. An approach to the investigation of those human lipid storage myopathies not due to defects in the carnitine system is suggested.

Animals↗