摘要:

Long-chain acyl-CoA dehydrogenase (LCAD) deficiency is a disorder of mitochondrial fatty acid oxidation that is characterized by hypoglycemia, muscle weakness, and hepato- and cardiomegaly. To characterize variant LCAD, we first carried out preliminary experiments using pure enzyme preparations. Despite the significant sequence similarity of LCAD to medium-chain acyl-CoA dehydrogenase, the antibody raised against rat LCAD was monospecific for human and rat LCAD and did not cross-react with either human or rat medium-chain acyl-CoA dehydrogenase. Immunoblot analysis of variant LCAD in cultured fibroblasts from nine patients with LCAD deficiency revealed a single LCAD band in all nine LCAD-deficient cell lines. Each variant LCAD was comparable in molecular size and quantity to normal LCAD, suggesting that the LCAD mutation in each of these cell lines is likely to be a point mutation that produces a stable variant LCAD. The uniform nature of variant LCAD suggests that only a single, or at most a few, prevalent point mutations may be found in the majority of LCAD-deficient patients. If this is the case, it should be possible to devise a molecular diagnostic method for LCAD deficiency.

ISSN:0031-3998    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

A 9-y-old girl with ethylmalonic/adipic aciduria was hospitalized to determine the possible therapeutic efficacy of oral carnitine and glycine supplementation. To provoke a mild metabolic stress, her diet was supplemented with 440 mg/kg/d of medium-chain triglycerides. She was treated successively with carnitine (100 mg/kg/d) for 5 d, neither carnitine nor glycine for 2 d, and then glycine (250 mg/kg/d) for 6 d. Consecutive 12-h urine collections were obtained throughout the entire period. The urinary excretion of eight organic acids, four acylglycines, and four acylcarnitines, which accumulate as a result of a metabolic block of five mitochondrial acyl-CoA dehydrogenases, were quantitatively determined by capillary gas chromatography, stable isotope dilution gas chromatography/mass spectrometry, and radioisotopic exchange HPLC, respectively. The excretion of each group of metabolites was calculated as the mean percentage of total output (μmol/24 h) during the four phases of the protocol (organic acids/acylglycines/acylcarnitines = 100.0%):1) regular diet (3 d); 88.1/10.8/1.1;2) medium-chain triglyceride supplementation (4); 82.5/15.6/1.9;3) medium-chain triglycerides plus carnitine (5); 79.2/8.2/12.6; and4) medium-chain triglycerides plus glycine (6); 81.0/18.7/0.3. Comparison between total and individual excretion of acylglycines and acylcarnitines indicates that oral glycine supplementation enhanced the conjugation and excretion of fatty acyl-CoA intermediates as efficiently as carnitine. We propose that oral glycine supplementation should be considered in the treatment of other inborn errors of metabolism associated with abnormal urinary excretion of acylglycines.

ISSN:0031-3998    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Uridine-containing sugar nucleotides, uridine diphosphate (UDP) -glucose and UDPgalactose are important intermediates in galactose metabolism, and tissue UDPgalactose may be a salient factor in the etiology of the long-term clinical manifestations of patients with galactose-1-phosphate uridyltransferase deficient galactosemia. Because uridine and uridine nucleotides such as uridine triphosphate (UTP) are known inhibitors of rat hepatic transferase, we have examined the effects of these compounds on the activity of the enzyme in homogenates of rat brain and ovary which are target organs of galactose toxicity in classical galactosemia. In addition, the concerted effect of uridine and UTP together on hepatic transferase has been assessed. These investigations have been prompted by considerations that uridine administration may have a therapeutic role in the long-term treatment of classical galactosemia. Both uridine and UTP have been found to be potent inhibitors of brain and ovarian transferase activity. Brain enzyme activity is more sensitive to these compounds than is that of the ovary. They are competitive inhibitors of UDPglucose in both newborn and adult brain enzyme preparations with a kiof 0.15 to 0.20 mM. Uridine and UTP at low concentrations were found to have an additive effect on rat hepatic transferase activity, which is especially significant in that uridine administration is known to increase hepatic UTP concentration. These findings suggest judicious caution should be used in giving uridine to patients with genetically limited transferase activity because the possibility exists of inhibiting small amounts of residual enzyme in the tissues of affected subjects.

ISSN:0031-3998    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

We examined 78 fetuses on d 21 of gestation (G21) and 83 neonates on d 2 after birth (A2), which were first generation offspring of WKY rats mated with normal Wistar rats (Fl). In addition, we examined six groups of fetuses on d 19 of gestation (G19): 65 Wistar rats, 111 WKY rats, 85 F1, 100 F1 × F1, 92 F1 × Wistar, and 97 F1 × WKY progeny. In the F1 at G19, G21, and A2, there were abnormalities of the pulmonary valve, pulmonary outflow tract, architecture of muscle bundle, and pulmonary arterial branch, as well as hypoplastic ductus arteriosus and postnatal cardiac hypertrophy, similarly in males and females but at a lower incidence and to a lesser extent than in the WKY rats. Severe pulmonary valve dysplasia and ventricular septal defect with overriding of the aorta (tetralogy of Fallot), usually associated with a markedly small ductus, were not present or were very rare in the F1 and the F1 × Wistar but were present in the F1 × WKY and in the F1 × F1 less prevalently than in the WKY. The size of the ductus showed a continuous distribution in all of the six groups; there was a large skewing toward lower values in the WKY, the F1 × WKY, and the F1 × F1. These results suggest that cardiovascular anomalies of WKY rats are transmitted as autosomal recessive or incomplete autosomal dominant traits with an incomplete penetrance and variable expressivity or as polygenic traits. Chromosomal analysis of 31 WKY fetuses revealed no abberations specifically related to the development of cardiovascular malformations.

ISSN:0031-3998    

出版商:OVID    

年代:1991

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Developmental differences in myocardial performance are known to exist. It is likely that the profile of protein isoforms present on the developing thin filament contributes to these observed differences. We have prepared thin filaments from developing and mature rat hearts by using an immunoprecipitation procedure developed in our laboratory. Analysis of these isolated thin filaments by Western immunoblots and two-dimensional gel electrophoresis demonstrates troponin I and troponin T isoform switching on the developing thin filament. Troponin I isoform switching begins by embryonic d 18 and is complete before the 3rd postnatal wk. Troponin T isoform switching begins between embryonic d 18 and birth and is complete between the 2nd and 3rd postnatal wk. The degree of phosphorylation of tropomyosin in thin filaments appears to be developmentally regulated, decreasing with advancing age. Nonmuscle isoforms of tropomyosin are also detectable in thin filaments from developing and mature rat hearts. These phenomena (troponin isoform switching, the degree of phosphorylation of tropomyosin, and the presence of nonmuscle isoforms of tropomyosin on cardiac thin filaments) likely play a role in the function of immature thin filaments and in the assembly of mature thin filaments.

ISSN:0031-3998    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

The present experiments were designed to test whether selective blocking of the surfactant-associated hydrophobic polypeptide SP-B (8.7 kD) would interfere with lung function during neonatal adaptation. A MAb to porcine SP-B was produced by hybridoma cell line (8B5E); this antibody cross-reacts with rabbit SP-B. Six mg of MAb to SP-B, dissolved in 0.2 mL of saline, was instilled into the airways of near-term newborn rabbits (gestational age 29 d), before the onset of ventilation. Control animals received the same amount of nonspecific rabbit IgG in saline, or were untreated. The animals were ventilated for 120 min with a standardized tidal volume (10 mL/kg). The specific antibody caused a prominent, immediate decrease in lung-thorax compliance, associated with acute inflammatory and exudative lung lesions including hyaline membranes. IgG alone had no such effects. Our data suggest that the MAb to SP-B inhibits surfactant function in the neonatal period by blocking one of the mechanisms responsible for fast adsorption of the surfactant phospholipids to the alveolar air-liquid interface. In addition, an acute inflammatory reaction is probably triggered in the lung parenchyma by the immune reaction.

ISSN:0031-3998    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

To elucidate the effects of birth stress on immunoreactive endothelin-1 (irET-1) concentrations in fetal blood, we determined irET-1 levels in cord plasma in different modes of delivery associated with or without complications such as asphyxia. The irET-1 concentrations in both the umbilical artery and vein were significantly higher than those found in maternal venous blood at delivery, although there was no significant difference between preterm and full-term infants. When plasma irET-1 concentrations of healthy infants born by vaginal delivery and by cesarean section without labor were compared, the former had significantly (p< 0.05) higher levels than the latter (15.4 ± 4.9 pg/mL versus 11.1 ± 3.1 pg/mL). Furthermore, umbilical venous plasma obtained from vaginally delivered infants complicated by asphyxia showed significantly (p< 0.001) higher irET-1 levels (28.2 ± 9.4 pg/ mL) than those of nonasphyxiated infants (14.2 ± 4.5 pg/ mL). These data suggest that birth stress, especially asphyxia, may contribute to the increase in fetal circulating irET-1 levels.

ISSN:0031-3998    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

We have examined the effect of IGF-I on tropoelastin (TE) synthesis in cultured rat neonatal pulmonary fibroblasts, because this growth factor has been shown to stimulate TE synthesis in vascular smooth muscle cells. IGF-I stimulated TE and total protein synthesis in a dose-dependent manner even when cells were cultured in the medium supplemented with 0.5% FCS. The maximal stimulation was at IGF-I concentration 500 ng/mL and was an increase of 86 ± 14 and 35 ± 5% for TE and estimated total protein synthesis, respectively. There was a corresponding 95 ± 20% increase in the TE mRNA/β-actin mRNA ratio assessed by densitometry of the Northern blot analysis. At this low concentration of FCS, however, there was neither TE stimulation by dexamethasone alone nor in combination with IGF-I. We conclude that IGF-I stimulation of TE synthesis may occur in cells other than vascular smooth muscle cells and that there is no additive stimulation by glucocorticoids.

ISSN:0031-3998    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

To determine whether expression of the hepatic angiotensinogen (Ao) gene is modulated by1) ontogeny,2) pregnancy,3) glucocorticoids, or4) triiodothyroxine (T3), time-dated pregnant Wistar-Kyoto rats were studied at different gestational ages (15, 17, and 20 d) without the influence of hormonal treatment or were given a daily intraperitoneal injection of dexamethasone (Dex) or T3 for 5 d (chronic Dex or T3) or a single injection of Dex (acute Dex). Maternal and fetal hepatic Ao mRNA levels were detected by dot and Northern blot analysis by using a full-length rat Ao cDNA. Fetal Ao mRNA levels were lower than in their maternal counterparts and lower than in adult rats of either sex. Maternal hepatic Ao mRNA levels were markedly diminished. mRNA levels were their lowest at 15 d of gestation and increased progressively as gestation advanced, reaching a peak at 20 d of gestation. Chronic Dex treatment resulted in a 190% increase in maternal and a 370% increase in the fetal hepatic Ao mRNA levels. Acute Dex treatment resulted in a 260% increase in maternal hepatic Ao mRNA levels with no change in the fetus. Hepatic Ao mRNA levels increased to the nonpregnant level with acute and chronic Dex treatment. Chronic T3 treatment resulted in a 20% increase in maternal hepatic Ao mRNA levels, without alteration of fetal Ao gene expression. We conclude that1) the fetal and pregnant state results in a profound decrease in maternal and fetal hepatic Ao gene expression,2) Ao gene expression is regulated by glucocorticoids in the term fetal and maternal liver, and3) chronic T3 treatment results in a modest increase in maternal hepatic Ao gene expression.

ISSN:0031-3998    

出版商:OVID    

年代:1991

数据来源: OVID