摘要:

Tacrolimus (FK506) is a potent immunosuppressive drug that, when complexed to a family of immunophilin proteins known as FK binding proteins, inhibits calcineurin in T lymphocytes. Although i.v. use of FK506 in pediatric transplant recipients has been linked to development of cardiomyopathies, its mechanism of cardiotoxicity has not been examined in a neonatal animal model. In our study the effects of FK506 were investigated in cardiac myocytes isolated from newborn piglets. The peak amplitude of electrically triggered fura-2 Ca2+transients was increased in FK506-treated myocytes, but Ca2+transient duration and baseline fura-2 Ca2+ratios were not altered.45Ca2+uptake by digitonin-lysed piglet cells decreased at pCa ≤ 6.0, indicating that sarcoplasmic reticulum efflux channels were leaky. The results suggest that elevated release of sarcoplasmic reticulum Ca2+during systole contributes to cardiotoxic effects observed in children.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

An increasing series of pediatric endocrinopathies and metabolic anomalies has been recognized as related to reduced prenatal growth. We have tested whether the association of precocious pubarche (PP), dyslipidemia, and low serum IGF binding protein-1 in girls is also related to reduced prenatal growth. Fasting serum lipids, lipoproteins, and IGFBP-1 concentrations were measured in 187 girls (83 without PP and 104 with PP; mean age, 11.8 y; range, 5-18 y) with known birthweight and gestational age, the latter being transformed into birthweight SD scores. Birthweight SD scores of girls with PP were lower than those of girls without PP. Within the group of PP girls, those with dyslipidemia and low IGFBP-1 had lower (p< 0.0001) birthweight SD scores (-2.02 ± 0.23; mean ± SEM) than those with normal lipids, lipoproteins, and IGFBP-1 (-0.37 ± 0.15), whereas girls with an intermediate number of abnormalities had intermediate birthweight SD scores (-0.80 ± 0.18). In conclusion, dyslipidemia and low serum IGFBP-1 in girls with PP were found to be related to reduced prenatal growth, an observation pointing to the prenatal origin of these metabolic abnormalities.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Allopregnanolone is the best characterized among neurosteroids, and its role in the control of neuroendocrine axes has attracted increasing interest recently. However, there is no available information about circulating levels of allopregnanolone during infancy, childhood and puberty. We studied two groups of children:1) those aged between 0 and 2 y (n= 72), and2) those aged between 6 and 18 y, at different Tanner's stages (n= 82). In each of these patients, serum allopregnanolone, progesterone, cortisol, and dehydroepiandrosterone levels were evaluated after informed consent; allopregnanolone was measured by RIA after acid extraction on cartridge. There was no significant variation of serum allopregnanolone levels either in male and female children during the first 2 y of life. Furthermore, although serum dehydroepiandrosterone levels showed a significant decrease, inversely correlated with age of the children (p< 0.01), serum cortisol and progesterone levels showed a significant age-related increase during the first 2 y of life. Cortisol and allopregnanolone levels were positively correlated (p< 0.01). During puberty, we observed a progressive increase in serum allopregnanolone levels in both boys and in girls, which were higher at Tanner's stage IV-V (0.7 ± 0.01 nM; mean ± SEM) than at stages I-II (0.32 ± 0.02 nM;p< 0.01); mean levels were significantly higher at puberty than in the first 2 y of life (p< 0.01). Furthermore, during puberty, serum progesterone and dehydroepiandrosterone levels also increased progressively with age in both boys and girls. Allopregnanolone and dehydroepiandrosterone levels were positively correlated throughout puberty. The present results indicate that serum allopregnanolone levels do not change during the first 2 y of life but increase during pubertal development, suggesting that this steroid may be involved in the adaptive neuroendocrine mechanisms related to puberty.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Neuroblastoma, a neural crest-derived childhood tumor of the sympathetic nervous system, may in some cases differentiate to a benign ganglioneuroma or regress due to apoptosis. However, the majority of neuroblastomas are diagnosed as metastatic tumors with a poor prognosis despite intensive multimodal therapy. The neuropeptide somatostatin (SOM) has been shown to inhibit neuroblastoma growth and induce apoptosisin vitro. Therapeutic effects of SOM analogues are dependent on tumor expression of high-affinity receptors. In the present study, human neuroblastoma SH-SY5Y cells were grown as xenografts in nude rats.In vivoSOM receptor expression in the xenografts was identified using scintigraphy with111In-pentetreotide. Rats were randomized to treatment with the long-acting SOM analogue octreotide (10 µg s.c. every 12 h), 13-cis-retinoic acid (4 mg orally every 24 h), or vasoactive intestinal peptide (40 µg s.c. every 24 h) and compared with controls. Tumor volume was assessed every second day and tumor weight after 10-12 d. Octreotide treatment inhibited neuroblastoma growth significantly with reduced tumor volumes at 10 and 12 d compared with untreated controls (mean 3.56 and 4.24versus6.48 and 8.01 mL, respectively;p< 0.01). Also, tumor weights after 10-12 d were reduced in octreotide-treated animals (n= 8, median weight 2.90 g, range 1.67-5.57 g) compared with untreated rats (n= 14, 7.54 g, 1.65-10.82 g,p= 0.005). Serum IGF-I decreased significantly over time both in rats treated with octreotide and in untreated controls. It is concluded that treatment with the SOM analogue octreotide may significantly decrease neuroblastoma tumor growthin vivo. Further studies are warranted to establish the role of SOM analogues in the treatment of children with unfavorable neuroblastoma.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Granulocyte colony-stimulating factor (G-CSF) promotes neutrophil proliferation, differentiation, and survival. It acts by binding to specific cell-surface receptors (G-CSF-R), which are expressed on cells of granulocytic lineage, human endothelial cells, and placenta. It has been postulated that the administration of recombinant G-CSF (rG-CSF) to preterm neonates might be useful in treating infections or in reducing nosocomial infections. Whereas it is known that G-CSF and G-CSF-R are present in the developing fetal bone marrow and liver, no information is available as to the existence or distribution of nonhematopoietic G-CSF-R in other tissues of the developing human fetus. We hypothesized that G-CSF and its receptor might be expressed in various fetal tissues, as has been shown for other growth factors such as erythropoietin and fibroblast growth factor. Therefore, we studied the anatomical distribution of mRNA-encoding G-CSF and G-CSF-R, using RT-PCR andin situRT-PCR in a variety of human fetal tissues ranging from 8 to 24 weeks postconception. The cellular distributions of the corresponding proteins were determined by immunohistochemistry. Both G-CSF and G-CSF-R were present in nearly every organ and tissue examined, but in discrete cellular localizations. G-CSF-R in kidney and intestine underwent changes in anatomical distribution with fetal development. These results indicate that G-CSF and G-CSF-R have wide anatomical expression in the developing human fetus.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The effects of oxytocin on fetal and placental growth and on maternal weight gain and accumulation of body fat were studied inad libitum-fed and food-restricted (receiving 70% of the food intake of thead libitum-fed group) pregnant rats. Further, a possible role of the IGF axis in mediating oxytocin-induced changes was assessed. Pregnant rats were injected subcutaneously once a day during gestational d 1-5 with saline or oxytocin (1 mg/kg).Ad libitum-fed oxytocin-treated pregnant rats had higher circulating levels of IGF-I, larger placentas, fetuses, and newborn pups and contained less body fat at the end of pregnancy. In food-restricted dams, oxytocin-treatment had no effect on fetal and placental growth. Additionally, food restriction attenuated the normal increase in IGF binding protein-3 protease proteolysis during pregnancy. The results show that oxytocin may affect maternal adaptations to pregnancy and stimulate fetal growth. We suggest that this effect may be mediated by increased IGF-I inad libitum-fed animals, whereas food restriction may block this effect by resulting in low levels of circulating IGF-I and by attenuating the pregnancy-associated increase in IGF binding protein-3 protease activity and, thereby, further compromise IGF bioavailability.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Fibroblasts were cultured to determine the involvement of peroxisomes in cholesterol and dolichol synthesis. For this purpose, the behavior of cells from patients with Zellweger syndrome, with X-linked adrenoleukodystrophy, and from nondiseased control subjects was studied. Cells both after pretreatment with mevinolin and without pretreatment were incubated in a medium containing [3H]-mevalonate. In fibroblasts from patients with peroxisomal defects, the cholesterol content and mevalonate incorporation into cholesterol were decreased by 10-20% in comparison with control cells. Mevinolin pretreatment decreased the incorporation rate of [3H]-mevalonate into cholesterol but increased the labeling of ubiquinone and dolichol both in diseased and control cells. Squalene synthase activity was unchanged, whereas the activity of farnesyl-pyrophosphate synthase was increased in the diseased states. The results show that in patients with peroxisomal deficiency neither the amount nor the rate of synthesis of cholesterol and dolichol is reduced to any greater extent.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The regulation of adrenarche is one of the enigmas of pediatric endocrinology. Adrenarche is thought to be governed by a dual control mechanism in which an adrenal androgen secretagogue acts upon a zona reticularis primed by ACTH. We hypothesized that corticotropin-releasing hormone (CRH) may serve as adrenal androgen secretagogue. We tested the concept by infusing either saline or human (h) CRH (1 µg/kg/h in saline) over 3 h, after overnight dexamethasone pretreatment, into eight young men within a randomized, cross-over study design. Serum ACTH and dehydroepiandrosterone-sulfate were measured once hourly; DHEA, androstenedione and 17-hydroxy-progesterone were determined at baseline and after 3 h of saline/hCRH infusion. ACTH levels remained unaltered during saline infusion and average ACTH responses amounted to 13 pg/mL (3.3 pmol/L) during hCRH infusion. Neither saline nor hCRH infusion altered 17-hydroxy-progesterone levels. Serum dehydroepi-androsterone-sulfate rose swiftly within 3 h of hCRH infusion and remained unchanged after saline (mean increase 37versus1%;p< 0.01). On average, serum DHEA doubled and androstenedione tripled during hCRH infusion, although no changes were observed during saline infusion (p< 0.01). In conclusion, CRH appears to have the capacity to act as adrenal androgen secretagogue. We suggest that the enigma of adrenarche may have an elegant solution, with CRH and ACTH coupled in sequence at the hypothalamic-pituitary level, and in parallel within the zona reticularis, just as they presumably are within the fetal adrenal, which is exposed to CRH of placental origin.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID