摘要:

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of &bgr;-glucuronidase (1). MPS VII is a fatal, progressive degenerative disorder, and a number of patients die of hydrops fetalis. Thus an approach to treating this disease may be by transplantation or gene therapyin utero. A mouse model of MPS VII has been studied extensively but the disease in affected fetal mice has not been characterized, which is essential for evaluation of therapeutic efficacy. Fetal and newborn mice affected with MPS VII were examined for lysosomal enzyme activities and for the presence of typical storage lesions in comparison to normal and carrier littermates. No &bgr;-glucuronidase enzymatic activity was detected in any of the tissues of affected mice, indicating that transplacental transfer of &bgr;-glucuronidase from the dam did not occur. Lesions were not detected in affected fetuses of 13.5 d gestational age on light or electron microscopy. Vacuolation in cells, typical of lysosomal accumulation of substrate, was first seen in a small number of cells of the reticulo-endothelial system in 15.5 d gestational age livers and in 18.5 d gestational age brains. Storage lesions were not seen consistently in endothelial and Kupffer cells of fetal livers until 18.5 d gestational age and in brains until birth. The results suggest that treatment of affected mice performed at 13.5 d gestational age may be effective in forestalling disease manifestations.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Lysosomal storage diseases are a class of inborn errors of metabolism that lead to widespread disease in multiple tissues. The murine model of mucopolysaccharidosis type VII (MPS VII) closely parallels the human syndrome and has been extensively used to investigate the natural history and therapeutic strategies for lysosomal storage diseases in general. Here we demonstrate a previously undescribed immune defect in the MPS VII mouse. Although the normal populations of cells are present in lymph nodes of these mice, MPS VII mice show a blunted T cell proliferative response and decreased antibody production after immunization with antigens. One mechanism of this defect is ineffective processing of protein antigens, as responses to peptide antigens are normal. This phenotype is presumably caused by the lysosomal disorder, as the defect can be correctedin vivoby direct enzyme replacement therapy. These findings have implications for the use of this animal model, and may have clinical significance for other, more-common lysosomal storage diseases.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The outcome for children with deep vein thrombosis (DVT) and pulmonary embolism (PE) is unknown. An understanding of morbidity and mortality of DVT/PE is crucial to the development of rational treatment protocols. The Canadian Childhood Thrombophilia Registry has followed 405 children aged 1 mo to 18 y with DVT/PE for a mean of 2.86 y (range, 2 wk to 6 y) to assess outcome. The all-cause mortality was 65 of 405 children (16%). Mortality directly attributable to DVT/PE occurred in nine children (2.2%), all of whom had central venous line–associated thrombosis. Morbidity was substantial, with 33 children (8.1%) having recurrent thrombosis, and 50 children (12.4%) having postphlebitic syndrome. Recurrent thrombosis and postphlebitic syndrome were more common in older children, although deaths occurred equally in all age groups. The incidence of recurrent thrombosis and postphlebitic syndrome are likely underestimated because of difficulties in diagnosis, especially in younger children. The significant mortality and morbidity found in our study supports the need for international multicenter randomized clinical trials to determine optimal prophylactic and therapeutic treatment for children with DVT/PE.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The aim of the present study was to assess with ultrasound the ductus venosus flow velocity in newborn lambs with increasing pulmonary artery pressures and to evaluate whether this is a useful method to detect elevated pulmonary artery pressure. The ductus venosus flow velocity was studied with pulsed-wave Doppler echocardiography in nine newborn lambs ≤30 h old. The lambs were anesthetized, mechanically ventilated, and instrumented to measure mean airway pressure and pulmonary artery and arterial blood pressures. A vascular occluder was placed around the main pulmonary artery. With mean pressures ranging from 20 to 50 mm Hg in the pulmonary artery, the ductus venosus flow velocity was examined. In seven lambs, the mean portal pressure and central venous pressure were also measured. With a stepwise increase in the pulmonary artery pressure, the minimum ductus venosus flow velocity during atrial systole decreased to a reversed flow, and the duration of this reversed flow component increased. The systolic forward peak flow velocity signal also gradually decreased. No changes were detected in the mean central venous or in the portal pressure with increasing pulmonary artery pressure or changes in ductus venosus flow. The flow velocity in the ductus venosus, which is higher than in other precordial veins, shows a reduction and even reversal of the nadir and an increase of the duration of reversed flow during atrial systole as a response to increased pulmonary artery pressure. Thus, Doppler ultrasound of the ductus venosus flow velocity may be a useful noninvasive diagnostic supplement to detect pulmonary hypertension of the newborn.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Daily rhythmicity of renal blood flow (RBF) and urine flow (UF) was studied in fetal sheep between 121–125 d of gestation. Fetal arterial blood pressure, heart rate, UF, and right RBF were measured continuously for 24-h periods in 10 sheep. Rhythmic variations during a 24-h period were found for all variables studied. The rhythms of arterial blood pressure and heart rate were highly correlated, whereas an inverse correlation was found between arterial blood pressure with RBF and between arterial blood pressure with UF. These findings indicate that fetal RBF is not blood pressure dependent. Furthermore, fetal UF appears not to be mediated by pressure-dependent diuresis.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The aim of the present study was to examine gender-related differences in heart rate of human neonates controlled for their behavior. Previous studies could not find any difference in male and female fetuses and newborns, although this gender-dependent difference clearly exists in children and adults. The heart rate of 99 newborns (47 girls and 52 boys) was measured with simultaneous video recording of their behavior. Results proved that alert newborns showed the same difference as adults: boys had a significantly lower baseline heart rate than girls. This suggests that heart rate is gender-dependent from birth onward.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

We investigated the influence of maternal nutritional enhancement during the second half of gestation on prolactin receptor (PRLR) abundance in fetal brown adipose tissue (BAT) and liver close to term (i.e.141–144 d gestation). Ewes were provided with 100% (i.e.control;n= 8) or 150% (i.e.well-fed;n= 7) of their metabolic requirements from 80 to 144 d gestation. Crude plasma membranes were prepared from fetal BAT and hepatic tissue, and individual molecular weight isoforms for the long and short forms of the PRLR were detected by immunoblotting. Mitochondrial preparations were prepared from BAT to measure the amount of the BAT-specific mitochondrial uncoupling protein-1 and its thermogenic activity (i.e.guanosine 5′-diphosphate binding). Fetuses sampled from well-fed ewes were heavier (controls, 3927 ± 196 g; well-fed, 4783 ± 219 g;p= 0.01) but possessed less BAT per kilogram body weight (controls, 5.92 ± 0.43 g/kg; well-fed, 3.85 ± 0.19 g/kg;p= 0.001), which had a greater uncoupling protein-1 abundance (controls, 56 ± 5% of reference; well-fed, 78 ± 9% of reference;p< 0.01) and higher thermogenic activity (controls, 157 ± 41 pmol guanosine 5′-diphosphate per milligram mitochondrial protein; well-fed, 352 ± 36 pmol guanosine 5′-diphosphate per milligram mitochondrial protein;p< 0.01) than controls. Multiple isoforms of the long and short forms of the PRLR were detected in all tissues. BAT from well-fed fetuses had a higher abundance of the 15-kD isoform of the long form of the PRLR (controls, 1.6 ± 0.4 densitometric units; well-fed, 16.3 ± 2.0 densitometric units;p< 0.001). This isoform was not detected in hepatic tissue. Maternal nutrient intake had no effect on any other isoforms of the PRLR in BAT or liver. In conclusion, increasing the quantity of feed provided in late gestation acts to promote fetal weight and BAT maturation, the combination of which will enhance neonatal viability.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The use of a stable isotope-labeled [13C]bicarbonate infusion to measure energy expenditure is advantageous, as a complete collection of expired air is not required. This technique allows for facile measurements of energy expenditure in intubated neonates. The aim of the present study was to determine the accuracy of energy expenditure estimates in postsurgical neonates by using the [13C]bicarbonate method compared with the current standard, indirect calorimetry. Eight neonates who were receiving total parenteral nutrition [98 ± 21 (SD) kcal·kg−1·d−1; 3.1 ± 0.7 (SD) protein g·kg−1·d−1] were studied on postoperative d 15.5 ± 11.9. A primed continuous 3-h intravenous infusion of NaH13CO3and indirect calorimetry were performed simultaneously. Energy expenditure was calculated separately from the Weir equation and from the dilution of13CO2in the breath in combination with the individual energy equivalents of CO2from the diet. The rate of CO2appearance and energy expenditure calculated from the bicarbonate method (0.725 ± 0.021 mol·kg−1·d−1; 89.5 ± 2.5 kcal·kg−1·d−1) highly correlated (r= 0.94 and 0.98, respectively) with the CO2excretion and energy expenditure determined by indirect calorimetry (0.489 ± 0.016 mol·kg−1·d−1; 60.2 ± 2.0 kcal·kg−1·d−1) when analyzed nonproportionately to weight. Bland-Altman analysis demonstrated the 95% confidence interval to be ±8.2 kcal·kg−1·d−1. Linear regression anal- ysis revealed a highly statistically significant equationrelating the two energy expenditures: Indircal (kcal/d) = − 9.341 + [0.705 × Bicarb (dcal/d)];p< 0.001, r2= 96.4%. We conclude that energy expenditure in neonates can be accurately determined using the [13C]bicarbonate method and a regression equation. Therefore, the bicarbonate method may be useful for determining energy expenditure in neonates not readily accessible to indirect calorimetry, such as those being mechanically ventilated or on extracorporeal life support.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Uteroplacental insufficiency increases the risk of perinatal and long-term neurologic morbidity by depriving the fetus of oxidative substrate and causing intrauterine growth retardation. Skeletal muscle and liver from growth retarded fetal and juvenile rats respond to this deprivation by altering mitochondrial gene expression and function. The objective of this study was to determine whether cerebral mitochondrial mRNA is similarly altered in fetal and juvenile growth retarded rats and to correlate these alterations with mitochondrial DNA and marker protein levels. To fulfill this objective, mRNA levels of four important mitochondrial proteins were quantified using RT-PCR in growth retarded and sham-operated control fetal and juvenile rat brains; these proteins were NADH-ubiquinone oxireductase subunit 4, subunit C of the F1F0-ATPase, and the adenine nucleotide transporters 1 and 2. Mitochondrial DNA/nuclear DNA ratios and mitochondrial 60 kD marker protein levels were also quantified in growth retarded and sham-operated control fetal and juvenile rat brains using PCR and Western Blotting, respectively. Cerebral mRNA levels of all four proteins were increased in the IUGR fetuses and decreased in the IUGR juvenile animals. Cerebral mitochondrial/nuclear DNA ratios and mitochondrial marker protein levels were not significantly altered in the IUGR fetuses; however, both were significantly diminished in IUGR juvenile pups. These studies suggest that the metabolic stresses associated with uteroplacental insufficiency in the rat cause altered fetal and postnatal cerebral mitochondrial mRNA and DNA levels.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Inhaled nitric oxide (INO) therapy is currently used clinically to selectively dilate the pulmonary vasculature and to help treat persistent pulmonary hypertension and bronchopulmonary dysplasia in the neonate. However, in the presence of oxygen or superoxide, nitric oxide forms potentially harmful reactive nitrogen species. Using an experimental mice model, we examined the effects of concurrent hyperoxia and INO on protein tyrosine nitration and cysteineS-nitrosylation in pulmonary tissue. Data showed enhanced 3-nitrotyrosine staining within the airway epithelium and alveolar interstitium of mice lungs treated with hyperoxia, which did not increase significantly with INO administration. Within the alveolar interstitium, 3-nitrotyrosine staining was localized to macrophages.S-Nitrosocysteine staining in airway epithelium was significantly enhanced with INO administration regardless of oxygen content. These data suggest that the formation of proteinS-nitrosocysteine is the major protein modification during administration of INO.

ISSN:0031-3998    

出版商:OVID    

年代:2000

数据来源: OVID