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Biomedical subjects

D Penn

Publications and source records attributed to D Penn.

At least 37 records · Page 2Linked to original sources
PubMed1992

Urinary medium-chain acylcarnitines in medium-chain acyl-CoA dehydrogenase deficiency, medium-chain triglyceride feeding and valproic acid therapy: sensitivity and specificity of the radioisotopic exchange/high performance liquid chromatography method.

To determine the sensitivity and specificity of detecting urinary medium-chain acylcarnitines for the diagnosis of MCAD deficiency, 114 urine specimens from 75 children with metabolic diseases and controls were analyzed in a blinded fashion using a radioisotopic exchange/HPLC method. All 47 patients with MCAD deficiency were correctly diagnosed using the criterion hexanoylcarnitine or octanoylcarnitine peak areas larger than those of other medium-chain acylcarnitines. The majority of them were tested during the asymptomatic state without L-carnitine loading. Four patients with other defects of fatty acid oxidation and three patients receiving valproic acid had a similar acylcarnitine excretion pattern. To further examine the specificity of the method, eight infants receiving a diet enriched with medium-chain triglycerides and 13 additional patients receiving valproic acid were studied. Most of these also tested positive for MCAD deficiency by the above criterion. Analysis by a new gas chromatographic-mass spectrometric procedure revealed that octanoylcarnitine, not valproylcarnitine, was the most abundant medium-chain carnitine ester excreted by a patient treated with valproic acid. Quantitation of urinary hexanoylcarnitine and octanoylcarnitine showed considerable overlap among patients with MCAD deficiency and those receiving valproic acid or a medium-chain triglyceride-enriched diet. MCAD deficiency can be reliably detected in urine specimens by this method without the need for prior carnitine loading. However, other defects in fatty acid oxidation must be differentiated from MCAD deficiency, and a history of medium-chain triglyceride or valproic acid administration must be considered if the diagnosis of MCAD deficiency is sought through analysis of urinary acylcarnitines.

Acyl-CoA Dehydrogenase↗
PubMed1992

Detection and quantitation of acylcarnitines in plasma and blood spots from patients with inborn errors of fatty acid oxidation.

Acylcarnitine profiling in plasma and dried blood spots by radioisotopic exchange/HPLC demonstrates that MCAD deficiency can be reliably detected in the asymptomatic state without L-carnitine therapy. The OC/AcC ratio differentiates MCAD deficiency from normal controls. A longer chain acylcarnitine (r.t. 43 min.) was detected in all 3 patients with a defect in long chain fatty acid oxidation. Detection of C4- and C5-acylcarnitine isomers in plasma helped characterize a metabolic defect affecting branched chain acyl-CoA oxidation in 3 patients. Quantitative data in 2 patients with MCAD deficiency showed that plasma concentrations of OC and AcC are dependent on both the availability of free carnitine and the severity of metabolic decompensation.

Acyl-CoA Dehydrogenase↗
PubMed1990

Carnitine and total parenteral nutrition of the neonate.

The newborn is dependent upon fat for energy production. Fatty acid oxidation requires the cofactor carnitine. The preterm infant is born with limited carnitine reserves. During total parenteral nutrition (TPN) plasma and tissue carnitine concentrations decrease indicating that rates of carnitine biosynthesis are inadequate. The ability of the premature infant to oxidize fatty acids is related to the carnitine status. Several studies suggest an improvement of fatty acid oxidation after a fat challenge if TPN is supplemented with L-carnitine. Nitrogen balance may also be improved but this needs confirmation. It remains to be established whether routine L-carnitine supplementation is needed in neonatal TPN.

Carnitine↗
PubMed1990

Carnitine ester excretion in pediatric patients receiving parenteral nutrition.

Carnitine plasma concentrations and the excretion of carnitine and individual carnitine esters were determined in 25 children and adolescents with gastrointestinal diseases receiving carnitine-free parenteral nutrition for at least 1 mo using radiochemical and radioisotopic exchange HPLC methods. Children less than 12-y-old usually had carnitine plasma concentrations less than -2 SD from the normal mean for age, whereas patients greater than 12-y-old had carnitine plasma concentrations within the normal range. Age was the only variable to correlate significantly with plasma carnitine concentrations during parenteral nutrition. Free carnitine (FC) excretion was closely correlated with plasma FC concentrations and minimal at values less than 25 mumols/L. The excretion of FC and short-chain acylcarnitines was reduced by an order of magnitude in younger compared with older patients and controls, but the excretion of "other" acylcarnitines was less affected. Some of the latter were tentatively identified using gas-liquid chromatographic and mass spectroscopic techniques as unsaturated and/or branched medium-chain carnitine esters with a carbon chain of C8-C10. The results suggest that FC and short-chain acylcarnitine are conserved by the kidney in nutritional carnitine deficiency but that there may be an obligatory renal excretion of other carnitine esters that contributes to the development of hypocarnitinemia in the younger age group.

Absorption↗
PubMed1989

Isolated colonocyte metabolism of glucose, glutamine, n-butyrate, and beta-hydroxybutyrate in malnutrition.

The colonic mucosa may be especially vulnerable during starvation and malnutrition, as luminal nutrients make the greatest contribution to its energy production. To investigate possible metabolic changes in the colonic mucosa during nutrient restriction, we studied substrate utilization by colonocytes isolated from three groups of 6-wk-old rats: control, fasted (72 h), and chronically malnourished animals. Isolated colonocytes were incubated with nonlabeled and 14C-labeled substrates (glucose, glutamine, n-butyrate, or beta-hydroxybutyrate). Substrate oxidation and net increase of intermediary metabolites were reduced in fasted and malnourished animals. The effect of fasting on substrate oxidation was greater than that of chronic malnutrition for all substrates tested except n-butyrate. The total ketone body concentrations and beta-hydroxybutyrate to acetoacetate ratios were higher in the fasted and malnourished groups than in controls. The findings suggest that the colonic mucosa responds to nutrient deprivation by a general reduction of oxidative metabolism that is associated with an altered redox state.

3-Hydroxybutyric Acid↗
PubMed1989

Quantitation of urinary carnitine esters in a patient with medium-chain acyl-coenzyme A dehydrogenase deficiency: effect of metabolic state and L-carnitine therapy.

Urinary carnitine esters were quantitated in an infant with medium-chain acylcoenzyme A dehydrogenase deficiency by means of a highly sensitive and specific radioisotopic exchange high-pressure liquid chromatography method. During fasting, the excretion of free carnitine and of acetylcarnitine, octanoylcarnitine, and hexanoylcarnitine was increased. The fractional tubular reabsorption of free carnitine was decreased, suggesting a renal leak of free carnitine. In the symptom-free, fed state, only minor amounts of free carnitine and of short-chain acylcarnitine, octanoylcarnitine, and hexanoylcarnitine were present in urine, and carnitine loss occurred in the form of "other" carnitine esters not exceeding that of control subjects. During L-carnitine therapy, the excretion of free carnitine, short-chain acylcarnitine, octanoylcarnitine, and hexanoylcarnitine, and particularly of "other" carnitine esters, was increased, suggesting a possible detoxifying effect of administered carnitine that is not confined to the elimination of octanoic and hexanoic acids. The employed method detects very low urinary concentrations of octanoylcarnitine and hexanoylcarnitine (less than 1 mumol/L) characteristic of medium-chain acyl-coenzyme A dehydrogenase deficiency and may be useful in screening for this disease, which has been associated with sudden infant death.

Acetylcarnitine↗
PubMed1989

Biochemical and morphological changes in the digestive tract of rats after prenatal and postnatal malnutrition.

Six-week-old rats subjected to prenatal and postnatal dietary restriction (maternal and weanling intake = 50% that of controls) were studied. Compared with controls, malnourished rats not only had reduced body (78 +/- 12 vs 187 +/- 21 g) and organ weights (small intestine: 4.51 +/- 0.46 vs 9.89 +/- 0.61 g; colon: 0.75 +/- 0.08 vs 1.77 +/- 0.18 g; liver: 2.75 +/- 0.34 vs 9.13 +/- 1.33 g; pancreas: 0.78 +/- 0.14 vs 1.67 +/- 0.49 g) but also decreased body weight-length ratios (6.5 +/- 0.3 vs 10.8 +/- 1.4 g/cm) and serum albumin levels. The small intestinal mucosa was hypotrophic (protein-DNA ratio: 5.02 +/- 1.43 vs 8.82 +/- 0.68, malnourished vs controls, respectively) with reduced mucosal thickness, villus height, and crypt depth. Specific activities of lactase, maltase, and sucrase were diminished (53%, 66%, 54% of control values, respectively). Colonic mucosa was hypoplastic with decreased mucosal thickness and crypt depth. Liver and pancreas were both hypotrophic and hypoplastic. The findings suggest that, in contrast to colonic mucosa, pancreas, and liver, the small intestinal mucosa maintained cell number during prolonged prenatal and postnatal malnutrition.

Animals↗
PubMed1988

Carnitine plasma concentrations in 353 metabolically healthy children.

Carnitine plasma concentrations were determined by an enzymatic radioisotopic method in 353 metabolically healthy children and in 41 adults. There was a positive correlation between total and free carnitine plasma concentrations and the age of the children. Both free and acylcarnitine concentrations were elevated on the 1st day of life, reflecting an increased rate of fatty acid oxidation. Carnitine plasma concentrations decreased after the 1st day and subsequently increased during the 1st year. From the 2nd year of life until adulthood, no further change was noted. Up to 17 years of age no differences were seen between male and female individuals. However, adult males had higher carnitine concentrations in plasma than adult females. Total carnitine concentrations were higher in 10- to 17-year-old females and lower in 10- to 17-year-old males compared with adults of the same sex, indicating a possible role for sex hormones in the regulation of carnitine plasma concentrations.

Adolescent↗
PubMed1988

The carnitine-deprived newborn rabbit: a potential model to study carnitine deficiency.

This report describes the novel development of an animal model for neonatal carnitine deficiency using the artificially fed newborn rabbit. Each litter was separated from the mother following the first colostrum feeding and divided into 2 groups, one of which was fed a purified rabbit formula that was essentially free of carnitine; the other received the same formula supplemented with L-carnitine (100 mg/l). At 9-13 d of age, rabbit pups receiving the carnitine-free formula had lower concentrations of total, free and acylcarnitine in plasma and urine, as well as lower total acid soluble carnitine concentrations in liver, muscle, heart and brown adipose tissue than those receiving the same formula supplemented with L-carnitine. Their plasma and tissue levels were also lower, but their urinary carnitine concentrations were higher than those in naturally-raised pups. The findings suggest that the described animal model may prove to be a useful tool for the investigation of certain aspects of neonatal carnitine deficiency.

Adipose Tissue, Brown↗
PubMed1987

Amniotic fluid propionylcarnitine in methylmalonic aciduria.

Amniotic fluid samples from pregnancies complicated by foetal methylmalonic aciduria and from metabolically normal pregnancies were obtained at 16-18 weeks of gestation and analysed for total, free and acylcarnitine and individual carnitine esters. The amniotic fluid concentrations of total acylcarnitine and propionylcarnitine were higher in pregnancies with higher in pregnancies with methylmalonic aciduria than in normal pregnancies. The predominant carnitine ester was propionylcarnitine in the methylmalonic aciduria group and acetylcarnitine in the normal group. These findings suggest that in methylmalonic aciduria, abnormalities of carnitine metabolism already occur early in gestation. The amount of propionylcarnitine in amniotic fluid may be useful as an additional indicator of foetal methylmalonic aciduria.

Acetylcarnitine↗
PubMed1987

Carnitine concentrations in the milk of different species and infant formulas.

Carnitine concentrations were measured in the milk of sheep, cows, goats, and horses, in human milk of term and preterm infants and in European infant formulas. There were significant species' differences in carnitine milk content. Acylcarnitine concentrations ranged from 13 to 47% of total carnitine. This may be related to differences in maternal and/or mammary gland metabolism. The concentration of long-chain acylcarnitine in milk was under 1% in all investigated species. In cow's milk, there was a decrease in acylcarnitine concentration during the first 2 months of lactation. In human milk, carnitine concentrations did not change during the 1st month postpartum, but maternal plasma carnitine concentrations increased and plasma concentrations of acylcarnitine were always lower than those in simultaneously sampled milk. Milk carnitine concentrations in mothers of premature infants were not different from those in mothers of term infants. European formulas based on cow's milk contained somewhat more carnitine than human milk. However, very low carnitine concentrations were found in soy-based or protein hydrolysate formulas. This may lead to nutritional carnitine deficiency in infants receiving these formulas without carnitine supplementation.

Animals↗
PubMed1987

The role of phosphatidylglycerol in phospholipid analysis of tracheal and gastric aspirate in premature infants.

Tracheal and gastric aspirates from premature infants simultaneously sampled shortly after birth were analyzed for their phospholipid composition using 2-dimensional thin layer chromatography. The results were related to clinical outcome. The L/S ratio was higher in infants without than in infants with hyaline membrane disease (HMD). The L/S values and the concentrations of phosphatidylglycerol (PG) were higher in tracheal compared with gastric aspirates (table I). This resulted in different L/S cutoff points with respect to lung maturity. In both aspirates, the predictive value of a "mature" (but not of an "immature") L/S ratio was improved by PG determination (table II). Only one out of 22 infants with HMD had a completely "mature" phospholipid profile in its tracheal aspirate. Two vaginally delivered premature infants without HMD had an "immature" phospholipid pattern in their gastric aspirates, but a "mature" one in their tracheal aspirates. The results indicate that phospholipid analysis of tracheal and gastric aspirates shortly after birth is useful in the biochemical diagnosis of HMD if proper cutoff points for the L/S ratio are used and the determination of PG is included. It may prove to be important in establishing criteria for a therapeutic trial of surfactant substitution.

Chromatography, Thin Layer↗
PubMed1986

[Carnitine in the treatment of methylmalonic aciduria (MMA)].

Carnitine metabolism was studied and a therapeutic trial with L-carnitine was undertaken in 3 patients with methylmalonic aciduria. Prior to carnitine therapy, the concentration of free carnitine was diminished and the contribution of acylated carnitine to total carnitine was increased in both plasma and urine. During a metabolic crisis, in a patient the intravenous administration of L-carnitine greatly increased, the urinary excretion of acylcarnitine and the plasma concentration of methylmalonic acid fell. In all 3 patients, the chronic oral administration of L-carnitine resulted in the normalisation of the plasma free carnitine concentrations and an increased urinary excretion of carnitine esters. One patient clearly showed clinical improvement under carnitine therapy. The administration of L-carnitine to patients with methylmalonic aciduria results in an increased elimination of toxic propionyl groups and thus to a regeneration of intramitochondrial CoA. In conjunction with appropriate dietary measures, this may improve the metabolic situation of these patients.

Amino Acid Metabolism, Inborn Errors↗
PubMed1986

[Carnitine deficiency].

Carnitine facilitates the transport of activated fatty acids across the mitochondrial membrane and regulates energy metabolism through regeneration of intramitochondrial coenzyme A. In carnitine deficiency it may be a limiting factor for fatty acid oxidation and ketogenesis. Primary myopathic carnitine deficiency is characterized by low carnitine concentrations usually restricted to muscle; whereas systemic carnitine deficiency shows decreased concentrations in other organs and plasma as well. The latter condition features recurrent metabolic crises similar to those seen in Reye's syndrome and nonketotic hypoglycemia. A therapy with L-carnitine should be undertaken, but does not always prove effective. Similar symptoms may be caused by defects in beta-oxidation, Krebs cycle or respiratory chain enzymes. The conditions may be associated with secondary carnitine deficiency. Patients with organic acidurias exhibit an increased excretion of carnitine esters and an insufficiency of free carnitine. Carnitine supplementation may ameliorate the metabolic disturbance. Secondary carnitine deficiency has also been described in patients receiving chronic valproic acid therapy. Hemodialysed chronic renal patients may benefit from L-carnitine therapy and show improvement of their hyperlipidemia. Nutritional carnitine deficiency can be primarily expected in premature infants receiving a carnitine free diet, since these infants have an impaired capacity for carnitine biosynthesis.

Carnitine↗
PubMed1985

Effect of nutrition on tissue carnitine concentrations in infants of different gestational ages.

To investigate the effect of nutrition on tissue carnitine concentrations in infants of different gestational ages, specimens of muscle, heart, liver and kidney obtained at autopsy from 62 infants were analyzed for total acid-soluble carnitine content. Immature infants had smaller carnitine tissue reserves than term infants. Parenterally alimented premature infants (greater than 10 days old) had lower carnitine levels in heart, liver and kidney than those dying within 24 h after birth. Infants who received oral or intravenous carnitine had larger carnitine tissue reserves than those who did not. These data suggest that both gestational age and exogenous carnitine supply affect tissue carnitine reserves.

Carnitine↗