摘要:

Holocarboxylase synthetase (HCS) is an essential enzyme for the biotinylation of several mammalian carboxylases. A deficiency of HCS is accountable for early onset biotin-responsive multiple carboxylase deficiency. To address the mechanism of biotin responsiveness, we analyzed the kinetic properties of the previously identified mutant. L237P, and another mutant, V550M, described in this report. The V550M mutant contains a G to A transition at position 1935, which is within the putative biotin binding site, whereas the mutation in L237P occurs outside the biotin binding site.KmandVmaxvalues for the mutant proteins were determined by overexpressing cDNAs encoding the mutants in transformed fibroblasts from an HCS-deficient patient. Enzyme activity assays were performed using apocarboxyl carrier protein as a substrate. AKmfor biotin that was larger than the value found for the wild-type cDNA was observed in fibroblasts transfected with the V550M cDNA, but not the L237P cDNA. TheVmaxfor the expressed L237P cDNA was 4.3% of that observed for the wild-type cDNA. Biotin-responsiveness in the patient with the L237P mutation was neither due to an increased affinity for biotin nor a restoration of stability of the mutant by biotin treatment. A new mechanism of biotin responsiveness in HCS deficiency is presented.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Although numerous reports have appeared showing high levels of galactitol in the urine of patients with galactose-1-phosphate uridylyltransferase deficiency, little attention has been paid to measurement of urinary galactonate. Herein we explored the use of1H and13C nuclear magnetic resonance, which required only the concentration of urine without derivatization, to detect and quantitate urinary galactonate. We report that transferase deficient infants, as well as adults on galactose restricted diets excrete significant amounts of galactonate, whereas none is detected in the urine of normal subjects. Galactose-toxic infants were found to excrete large amounts of galactonate, which decreased when the lactose-free diet was instituted. We also found that normal individuals subjected to an oral galactose load also excrete high levels of galactonate for at least 4 h after galactose ingestion. Our data provide evidence that the first reaction in the oxidative pathway of galactose metabolism described in rat liver in 1966 is activated in patients with a variety of galactose-1-phosphate uridylyltransferase gene mutations even while on a lactose-restricted diet. In both patients and normal individuals, flux through the alternate galactonate pathway appears to be related to the body galactose burden.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

We determined the concentrations of copper, the activities of ceruloplasmin and peptidylglycine α-amidating monooxygenase (PAM), and the stimulation index of PAM by thein vitroaddition of copper in plasma samples obtained from three male patients with occipital horns and a milder Menkes disease phenotype, having severe copper deficiency due to the defect in copper transport. We found a decreased plasma ceruloplasmin activity and an increased copper stimulation index of plasma PAM in these patients compared with healthy control subjects. The combination of these two determinations may provide a means for the assessment of copper nutriture in humans using blood samples obtained in a single microhematocrit tube. Further investigation is warranted to evaluate whether these noninvasive measurements can be used for the diagnosis of mild copper deficiency in humans with sufficient specificity and sensitivity.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

We used phosphorus magnetic resonance spectroscopy (31P MRS) to investigatein vivothe brain and skeletal muscle energy metabolism of 15 children with migraine with aura in interictal periods. Brain31P MRS disclosed low phosphocreatine and high inorganic phosphate contents, and high intracellular pH in all patients. Calculated [ADP] and the relative rate of mitochondrial oxidation were higher in the brain of patients than in control subjects, whereas the phosphorylation potential was lower. Brain intracellular free Mg2+concentration was reduced by 25% in patients. Abnormal skeletal muscle mitochondrial respiration was also disclosed in 7 of 15 patients as shown by the slow rate of phosphocreatine postexercise recovery. The multisystem bioenergetic failure found in patients with juvenile migraine is comparable to that found in adults with different types of migraine.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

After anoxia-induced apnea, gasping remains the last operative mechanism for survival. In developing rats, the gasping response to anoxia exhibits triphasic characteristics. Because anoxia is associated with enhanced release of glutamate, we hypothesized thatN-methyl-D-aspartate (NMDA) glutamate receptors may underlie components of the gasping response. Rat pups aged 2 d (n= 50), 5 d (n= 43), 10 d (n= 42), and 15 d (n= 45) underwent anoxic challenges with 100% N2in a whole body plethysmograph, 30 min after intraperitoneal administration of MK801[(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d-]cyclohepten-5,10-imine hydrogen maleate; dizocilpine] (3 mg/kg), a noncompetitive NMDA glutamate receptor channel antagonist, or normal saline. In control pups, after primary apnea onset, a triphasic gasping pattern was apparent at all postnatal ages and included two distinct types of gasps (I and II). In 2- and 5-d MK801-treated animals, phase 1 and type I gasps were absent, leading to marked prolongations of the gasp latency and phase 2, the latter displaying type II gasps only. In addition, phase 3 duration was also prolonged with increased type II gasp frequencies. In contrast, in some 10-d-old (40%) and in all 15-d-old MK801-treated pups, although overall gasping duration was prolonged, the triphasic gasping pattern seen in matched controls was also present. We conclude that NMDA glutamate receptors mediate particular phasic components of the gasping response during early postnatal life but not at later stages of development. We speculate that developmental changes occur in both function and expression of NMDA and other neurotransmitters within brainstem regions underlying the neural substrate for gasp generation.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

In this study we wanted to assess the relationship between mixed venous oxygen saturation (Svo2) and tissue oxygenation. For that, we compared the values of Svo2with oxygen delivery (Do2), oxygen consumption (Vo2), and markers of tissue hypoxia such as lactate and pyruvate during progressive hypoxemia. Eight 10-14-d-old piglets were anesthetized, tracheotomized, intubated, and ventilated. A fiberoptic catheter was placed in the carotid artery to monitor arterial oxygen saturation(Sao2). A thoracotomy was performed, and a fiberoptic catheter was placed in the pulmonary artery to monitor Svo2. A transit time ultrasound flow probe was positioned around the ascending aorta to measure aorta flow. Progressive graded hypoxemia was induced by decreasing fractional inspiratory oxygen concentration (Fio2) from 1.0 to 0.30, 0.21, 0.15, and 0.10. After each Fio2interval blood samples were taken for blood gases, lactate, and pyruvate. Do2and Vo2were calculated. Svo2decreased similarly to Sao2. A value of Svo2of more than 40% excluded oxygen restricted metabolism. When Do2decreased below a critical range (8.4-12.8 mL/kg·min), Svo2decreased below 15%, and lactate and the lactate/pyruvate ratio increased. We conclude1) that baseline Svo2values excluded oxygen-restricted metabolism,2) that Svo2values between 15 and 40% were not a marker for oxygen-restricted metabolism, and3) that Svo2values below 15% were associated with oxygen-restricted metabolism. Reduced Svo2values must be interpreted as a change of the factors that determine the balance between Do2and Vo2and as a warning that, with further reduction of Svo2, oxygen restricted metabolism can develop.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The effect of fetal gender on postnatal lung function and response to prenatal steroid exposure were examined retrospectively in a group of 115 preterm lambs. Fetuses received a single intramuscular injection of 0.5 mg/kg betamethasone alone or in conjunction with l-thyroxine 48 h before delivery at 128-d gestational age. Control animals received an equivalent volume of saline. After delivery, respiratory mechanics and blood gas parameters were recorded for 40 min. Deflation pressure volume curves were constructed in excised lungs. Right upper lobes from a randomly selected subgroup of control animals were examined morphometrically. Control (saline-treated) females were able to be ventilated at lower ventilatory pressures with equivalent tidal volumes and more efficient gas exchange. There were no gender differences in compliance, conductance, or excised lung volumes for saline-treated animals. More efficient gas exchange in females could not be explained by thinner alveolar septa or greater alveolar surface area. After hormone treatment, both males and females exhibited significant improvements in respiratory mechanics, gas exchange, and an increase in alveolar surfactant concentration. However, females exhibited a significantly greater improvement than males for compliance, conductance, excised lung volume, and arterial oxygen partial pressure. These data provide a comprehensive description of gender differences in postnatal lung function and response to steroid treatment in preterm animals, and support clinical findings of sexual dimorphism.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Intratracheal administration of a single dose of the perfluorocarbon FC-100 improves lung function in surfactant-deficient animals. In this study we compared the response to repeated doses of FC-100 (3 mL/kg 3% solution.n= 5) with that observed after administration of Exosurf (5 mL/kg,n= 5) to mechanically ventilated preterm lambs of 125 d of gestation. The initial dose of FC-100 rapidly increased arterial Po2, decreased arterial Pco2, and improved arterial pH. Also dynamic lung compliance markedly improved with this agent. Administration of an additional dose of FC-100 resulted in relatively similar changes, albeit of lesser magnitude than those observed with the initial dose. In contrast, Exosurf did not improve these variables even after three doses. All lambs treated with FC-100 survived the 6-h study period, whereas one of the five Exosurf-treated lambs survived (p< 0.05). Mean arterial blood pressure and heart rate decreased in those lambs that received FC-100, but not in surviving lambs that received Exosurf. Our data demonstrate that repeated intratracheal administration of the perfluorocarbon FC-100 improves lung function and survival of surfactant-deficient lambs better than the synthetic surfactant Exosurf. We speculate that tensio-active agents with properties different from surfactant, such as FC-100, might improve lung function in preterm neonates with diseases due to surfactant deficiency.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Male subfertility often remains unexplained. Severe intrauterine growth retardation has previously been linked to hypergonadotropic hypogonadism. We examined whether reduced fetal growth, as judged by low birth weight, is associated with unexplained male subfertility later in life. Birth weight and gestational age were obtained by questionnaire from male partners of couples consulting for subfertility, and were transformed into birth weight SD scores. Men with normal semen analysis (n= 128) had a median birth weight SD score of 0.0 (P25-P75range: -0.7 to 1.0), comparable to that of men with explained subfertility (n= 28), and higher (p= 0.012) than that of men with unexplained subfertility (n= 32; median -0.5 SD score; P25-P75range: -0.9 to -0.1). These results extend the link between reduced fetal growth and male subfertility to a range of birth weight that is well within normality. The pathophysiologic mechanism governing this association now remains to be unraveled.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID