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Biomedical subjects

D C Lehotay

Publications and source records attributed to D C Lehotay.

At least 19 recordsLinked to original sources
PubMed1995

Fatty acid oxidation abnormalities in childhood-onset spinal muscular atrophy: primary or secondary defect(s)?

The purpose of this study was to further identify and quantify the fatty acid oxidation abnormalities in spinal muscular atrophy, correlate these with disease severity, and identify specific underlying defect(s). Fifteen children with spinal muscular atrophy (3 type I, 8 type II, 4 type III) were studied. Serum carnitine total/free ratios demonstrated a tendency toward an increased esterified fraction ranging 35-58% of total carnitine (normal: 25-30% of total) in younger children with types I and II. The remaining type II and III patients, older than 23 months of age at sampling, had normal esterified carnitine levels. Urinary organic acid analysis demonstrated mild to moderate medium-chain dicarboxylic aciduria in type I patients and normal, mild, or moderate increases in short-chain and medium-chain organic acids in type II patients. In the type III group, the organic acids were normal except for one patient with mild medium-chain dicarboxylic aciduria. Muscle intramitochondrial beta-oxidation was measured in 5 children (2 type I, 2 type II, and 1 type III) and a significant reduction in the activities of short-chain L-3-hydroxyacyl-CoA dehydrogenase, long-chain L-3-hydroxyacyl-CoA dehydrogenase, acetoacetyl-CoA thiolase, and 3-ketoacyl-CoA thiolase were found; however, normal crotonase activity was documented. Most strikingly, there was a marked increase (3- to 5-fold) in the activity ratios of crotonase to L-3-hydroxyacyl-CoA dehydrogenase and thiolase activities with both short- and long-chain substrates. The combined abnormalities suggest a defect in a mitochondrial multifunctional enzyme complex, distinct from the trifunctional enzyme. These abnormalities may be either primary or secondary and may respond to dietary measures to reduce the dependence on fatty acid oxidation.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1995

Organic acidurias and related abnormalities.

Organic acid analysis is a powerful technique in the diagnosis of inborn errors of metabolism. Since the development of the technique over twenty-five years ago, it has evolved into a sophisticated and powerful method and is an essential tool in the diagnosis of the organic acidurias. The chemistry and biochemistry of organic acids, as well as sample preparation, instrumentation, and many aspects of the more commonly used methods for the analysis of these compounds, are reviewed. The biochemical and clinical characteristics of each of the primary organic acidurias are described. In addition, the various noninherited causes of secondary organic acidurias that lead to the excretion of abnormal organic acids are also described, and ways of differentiating primary from secondary causes are discussed.

Acids↗
PubMed1994

Barth syndrome: clinical observations and genetic linkage studies.

Barth syndrome is an X-linked recessive condition characterized by skeletal myopathy, cardiomyopathy, proportionate short stature, and recurrent neutropenia, but with normal cognitive function. Some, but not all patients, exhibit carnitine deficiency and/or the presence of 3-methylglutaconic and ethylhydracylic acids in urine. Recently the mutation causing Barth syndrome was localised to the Xq28 region by linkage analysis. We report 6 cases of Barth syndrome from 4 families and highlight the fact that neuromuscular and cardiovascular symptoms and the severity of infections tend to improve with age, while short stature persists. Also previously unreported was myopathic facies and nasal quality to speech in our cases. The urinary organic acid abnormalities and plasma carnitine deficiency were inconsistent findings. We propose that they may be epiphenomena rather than indicators of the primary metabolic defect, and that the primary defect or defects in this disorder may lie in the mitochondrial electron transport chain.

Abnormalities, Multiple↗
PubMed1994

Feto-maternal plasma phenylalanine concentration gradient from 19 weeks gestation to term.

Plasma phenylalanine concentrations in fetal blood, obtained by cordocentesis, were compared with simultaneous peripheral venous plasma phenylalanine levels in mothers. The feto-maternal phenylalanine concentration ratio showed a gradual decrease from 19 weeks of gestation to term with an overall ratio of 1.35 +/- 0.42 (mean +/- S.D., n = 14).

Chromatography, Ion Exchange↗
PubMed1994

Plasma carnitine levels in cystic fibrosis.

Plasma carnitine concentrations were measured in 43 children and adults with cystic fibrosis (CF), and values were compared with those from normal controls. Clinically significant abnormalities of plasma carnitine concentration were not found in CF patients. The concentration of free carnitine was slightly but significantly elevated in CF patients, and the acylcarnitine concentration and acylcarnitine/free-carnitine ratio were slightly but significantly lower. Total carnitine concentrations were similar to those of controls. The CF patients did not have abnormal urinary acylcarnitines. Altered concentrations of free and esterified carnitine were not associated with nutritional status or with liver or pulmonary function.

Adolescent↗
PubMed1991

Chromatographic techniques in inborn errors of metabolism.

Chromatography has played a pivotal role in the advances made during the last 30 years in our knowledge of inborn errors of metabolism. This review discusses the application of some of these techniques to the analysis of organic acids and acylcarnitines. The separation of organic acids needed a comprehensive approach that would permit all of the many organic acids present in urine or other complex mixtures to be extracted, analysed and identified in a single run. This required analytical methods of great resolving power, wide linear range and universal detectors such as gas chromatography (GC), or GC coupled with mass spectrometry. Sample preparation was another problem that has been tackled by a variety of approaches. Organic solvents have been employed widely for the extraction of organic acids from physiological fluids. Unfortunately, recoveries of the different organic acids by this method are sometimes less than quantitative and variable depending on the compound. Other methods, such as the use of DEAE-Sephadex columns, have the advantage of resulting in close to 100% recoveries, but are more tedious. Liquid partition chromatography on short silicic acid columns has also been recommended as a useful clean-up step prior to GC, permitting both the identification and quantitation of organic acids in urine, plasma or amniotic fluid. Although many derivatization procedure have been used to prepare organic acids for gas chromatography, the most common is trimethylsilylation. Oxo acids are usually reacted with one of several commonly used reagents to form oximes. GC analysis of organic acids was initially done using packed columns with methylsilicone-based, non-polar stationary phases.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcarnitine↗
PubMed1988

Relative roles of acid and mucosal compression in ulcerogenesis in indomethacin-insulin-treated rat.

We have proposed that gastric peristaltic activity is primarily responsible for ulcerogenesis in the phenylbutazone-treated rat and that acid plays only a synergistic role. This study examines the effect of graded doses of the H2 blocker cimetidine on acid secretion and ulcerogenesis occurring during insulin-induced peristalsis in the indomethacin (Indo) -pretreated rat. The second part of the study utilizes graded gastric distension with exogenous acid to examine the role of the forceful apposition of the mucosal folds during peristalsis in lesion genesis. It is demonstrated that the inhibition of acid secretion by cimetidine reduces but does not prevent ulceration. Gastric inflation with acid obliterates mucosal folding, prevents mucosal apposition during peristalsis, and abolishes ulcerogenesis. It is concluded that mucosal compression is the primary cause of the linear lesions along the base of the mucosal folds but that acid is necessary to extend the lesions once initiated.

Animals↗
PubMed1985

Biochemical mechanisms responsible for alcohol-associated myocardiopathy.

An overview of alcohol metabolism is presented followed by a discussion of the unique pathways for the metabolism of ethanol by the heart. The evidence for cardiac metabolic injury produced as a result of ethanol metabolism is then presented. Such injury involves the mitochondria, contractile proteins, and alterations in calcium fluxes and storage.

Acetaldehyde↗
PubMed1984

Influence of clofibrate on thyroid hormone and muscle protein turnover.

Clofibrate, a hypolipidemic agent, has been shown to increase muscle protein degradation. The possible role of thyroid hormones in this phenomena was examined. Clofibrate treatment of rats for 2 weeks resulted in a significant decrease in total thyroxine and triiodothyronine levels in serum. Reverse T3 and resin uptake values remained unchanged. When exogenous thyroxine was co-administered with clofibrate, serum TSH levels were suppressed, but the increased muscle protein degradation was not reversed. Equilibrium dialysis and Scatchard analysis of the binding of 125I-thyroxine to serum proteins indicated that clofibrate competitively inhibits the binding of thyroid hormone to serum proteins by decreasing its apparent binding affinity. In the presence of lower total thyroid hormone concentrations and an elevated free thyroxine fraction, the total free hormone levels are estimated to be in the normal range in the serum of clofibrate treated rats. Clofibrate seems to act like thyroid hormone since it binds to and displaces T4 from plasma proteins. Because free thyroid hormone levels are in the normal range, the thyroid hormone-like effects of clofibrate on the cell may be additive to the T4 effects, and are probably responsible for the hypermetabolic state seen in the muscle of clofibrate-treated animals. Our data suggest that the effects of clofibrate in muscle are complex. In addition to competitively altering the binding of thyroxine to serum proteins, this substance may also exert a hitherto unrecognized thyroid-hormone-like subcellular effect resulting in increased muscle protein degradation, and in augmented ouabain-sensitive ATPase activities.

Animals↗
PubMed1983

Clofibrate does not alter cyclic nucleotide metabolism in muscle.

Clofibrate is a hypolipidemic agent that causes muscle protein breakdown in rats, and an acute muscular syndrome in man. It also inhibits adenylate cyclase in fat tissue. Muscle protein metabolism has been shown to be regulated by cyclic nucleotides. In the present experiments were measured several parameters of cyclic nucleotide metabolism to determine the role that cyclic nucleotides play in clofibrate-induced muscle protein degradation. It was found that clofibrate treatment did not alter cyclic nucleotide levels, nor did it change the activities of basal or hormone-stimulated adenylate cyclase, or cyclic nucleotide phosphodiesterase in muscle. Our results suggest that muscle protein breakdown in clofibrate-treated rats is not regulated by cyclic nucleotides.

Adenylyl Cyclases↗
PubMed1983

Inhibition of cardiac guanylate cyclase by doxorubicin and some of its analogs.

Doxorubicin, an anthracycline antibiotic and antitumor agent, has cardiotoxic side-effects that limit its therapeutic usefulness. We have demonstrated that the drug inhibits cardiac guanylate cyclase activity in vitro. The biochemical changes following anthracycline treatment are described, and the various hypotheses attempting to account for cardiotoxicity in terms of a molecular mechanism are reviewed. It is suggested that inhibition of cardiac guanylate cyclase activity may be a consequence of the increase in free radicals and oxidative damage following treatment with doxorubicin or related compounds.

Animals↗
PubMed1982

A program for training physician-investigators.

A decreasing number of physicians are selecting careers in clinical investigation. In order to aid in reversing this trend, the Physician Investigator Training Program for residents and postdoctoral fellows was developed within the Department of Medicine at the University of Pittsburgh School of Medicine. Ph. D.s with broad-based research experience serve as the core faculty. The trainees are not assigned clinical duties during the two-year period of the program. The first nine months of the curriculum consist of formal lectures and laboratory training encompassing basic laboratory techniques, cell and tissue culture, separation techniques, advanced instrumental techniques, kinetics, enzymology and receptors, membrane structure and transport, radioimmunoassay, statistical analysis, computer programming, mathematics, microbiology, animals in research, immunology, epidemiology, teaching methods, and manuscript and grant-writing. The last 15 months are devoted to a supervised laboratory research project. The program may serve as a model to train increased numbers of physician-investigators.

Curriculum↗
PubMed1982

Inhibition of cardiac guanylate cyclase by doxorubicin and some of its analogs: possible relationship to cardiotoxicity.

The anthracycline antibiotic doxorubicin induces a variety of cardiotoxic effects. We have recently demonstrated that this drug also causes a selective inhibition of rat and human cardiac guanylate cyclase activity in vitro. In the present study, we examined the effect of 30 analogs of doxorubicin on cardiac guanylate cyclase activity. Structural modifications of these anthracycline antibiotics were found to alter their effect on rat cardiac guanylate cyclase activity, N-Substitutions on the sugar moiety eliminated the inhibitory action observed with the parent compound. Long-chain hydrocarbon substitutions in place of the methylketone side chain had a similar effect. Removal or substitution of the C-4 methoxy group had little or no effect on the ability of these compounds to modify guanylate cyclase activity. Substitutions of the C-9 side chain by a hydrazone derivative resulted in compounds that stimulated the enzyme. All of the anthracenedione derivatives were inhibitory. A comparison of the inhibitory effect of some of these anthracycline derivatives on in vitro cardiac guanylate cyclase activity with their cardiotoxic potency suggests a possible relationship between these two parameters.

Animals↗
PubMed1981

Human parathyroid adenoma adenylate cyclase: stimulation by histamine that is blocked by cimetidine.

Recent evidence suggests that the histamine receptor blocking agent cimetidine can decrease parathyroid hormone release from human parathyroids. To determine the mechanism for inhibition we examined the ability of histamine 1 X 10(-5) moles/liter to stimulate adenylate cyclase in a particulate membrane preparation from 13 human parathyroid glands. Histamine significantly increased adenylate cyclase activity as compared to control; however, the degree of stimulation was variable among the individual tissue samples. Enzyme stimulation was dose dependent over the concentration range of 1 X 10(-7) to 1 X 10(-4) moles/liter. Cimetidine at 1 X 10(-4) moles/liter completely abolished the histamine mediated increase in activity, but did not block the epinephrine-induced stimulation. The identification of an adenylate cyclase system in certain human parathyroid adenomas that is stimulated by histamine and blocked by cimetidine may offer a basis for the pharmacologic alteration of parathyroid hormone secretion.

Adenoma↗