摘要:

During the past decade there have been significant advances in our understanding of the mechanisms underlying allergic responses. Immediate hypersensitivity reactions are mediated primarily by mast cells in an IgE-dependent manner. After the local release of various mediators, proinflammatory cytokines, and chemokines, there is a cell-mediated response that is dominated by eosinophils and T lymphocytes. The majority of T cells in early allergic reactions are memory T cells secreting helper type 2 (TH2)-like cytokines,i.e.IL-4, IL-5, and IL-13, but not interferon-γ. These cytokines regulate IgE synthesis and promote eosinophil differentiation and cell survival, thus contributing to allergic inflammatory responses. Failure to control immune activation early in the course of allergic inflammation may blunt the response to glucocorticoid therapy and contribute to long-term morbidity of disease. The identification of key cells and cytokines involved in the initiation and maintenance of allergic inflammation is likely to become an important therapeutic target in the future management of this important group of diseases.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

A Japanese male neonate died at 13 d of age after presenting at 2 d of age with vomiting, dehydration, metabolic acidosis, liver dysfunction, and terminal rabdhomyolysis with myoglobinuria. Multiple urine organic acid analyses consistently revealed a markedly elevated excretion of lactic acid, 3-hydroxybutyric acid, and saturated and unsaturated C6-C16dicarboxylic acids, with predominant C12-C16species. Oxidation of [1-14C]octanoic acid in cultured skin fibroblasts was significantly reduced (0.59 nmol/h/mg of protein; controls, 1.93 ± 0.65), [1-14C]palmitic acid oxidation was 1.11 nmol/h/mg of protein (controls, 1.63 ± 0.41). A systematic study of the catalytic activities of nine enzymes of the β-oxidation cycle using the respective optimal substrate revealed a deficiency of a single enzyme not previously associated with a metabolic disorder, medium chain 3-ketoacyl-CoA thiolase (patient, 3.9 nmol/min/mg protein; controls (n= 6), 10.2 ± 2.3). Immunoprecipitation with antibodies raised against medium chain 3-ketoacyl-CoA thiolase revealed a 60% decrease compared with controls.

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

摘要:

The neurologic complications of cystathionine β-synthase deficiency are though to be secondary to accumulation of homocyst(e)ine in the CNS. Treatment of this disorder with betaine has been shown to improve the behavior of individuals, to reduce plasma total homocysteine, and to correct secondary abnormalities of serine. To test the hypothesis that homocyst(e)ine accumulates within the CNS and that this can be reduced by treatment with betaine, we measured total homocysteine and related metabolites in the plasma of 10 children with cystathionine β-synthase deficiency and cerebrospinal fluid of five children before and during betaine therapy. In plasma, betaine significantly lowered total homocysteine (but not to the normal range) and had a variable effect on methionine. In the cerebrospinal fluid, total homocysteine was raised before treatment (mean 1.2 μM) and was significantly reduced by betaine (mean 0.32 μM) but not to the normal range (<0.10 μM). Cerebrospinal fluid methionine was raised before and during treatment, but betaine did not cause a significant further increase. Cerebrospinal fluid serine was significantly reduced before treatment and rose to the normal range with betaine. Cerebrospinal fluidS-adenosylmethionine was normal before treatment and rose significantly with treatment; there were no significant changes in cerebrospinal fluid 5-methyltetrahydrofolate. The demonstration of accumulation of homocysteine within the CNS lends support to the hypothesis that this may be one cause of the neurologic complications of cystathionine β-synthase deficiency. Betaine is effective in reducing cerebrospinal fluid homocysteine, but concentrations are still significantly raised during treatment.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Primary carnitine deficiency is associated with deficient blood and tissue carnitine concentrations. The clinical syndrome is dominated by heart and skeletal muscle symptoms, and the clinical response to oral carnitine supplementation is life-saving. Carnitine uptake has been shown to be defective in cultured skin fibroblasts and leukocytes obtained from patients with this condition. We report a new case of primary carnitine deficiency and offer direct evidence consistent with an impairment of carnitine uptake in differentiating muscle culture. The patient presented with severe and progressive cardiomyopathy and moderate proximal limb weakness. Plasma and muscle carnitine levels were very low, and the maximal rate of carnitine transport in cultured fibroblasts was deficient. An asymptomatic sister with intermediate levels of carnitine in plasma showed partially deficient carnitine uptake in fibroblasts, indicating heterozygosity. The patient's condition improved dramatically with oral carnitine therapy. Further studies were performed in cultured muscle cells at different stages of maturation, which demonstrated deficient maximal rates of carnitine uptake. Our findings are consistent with the concept that primary carnitine deficiency is the result of a generalized defect involving carnitine transport across tissue membranes.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The renin-angiotensin system plays an important role in renal growth and development: exposure of the fetus or neonate to angiotensin-converting enzyme (ACE) inhibitors increases mortality and results in growth retardation and abnormal renal development. This study was designed to investigate the effects of ACE inhibition in the neonatal rat on the expression of genes known to modulate renal cellular proliferation, cell interactions, and extracellular matrix. Newborn rat pups were treated with enalapril (30 mg/kg/d) or vehicle for 14 d, and kidneys were removed for Northern analysis of mRNA for transforming growth factor-β1 (TGF-β1), prepro epidermal growth factor (EGF), clusterin, and renin. Distribution of TGF-β1, EGF, and clusterin was also determined by immunohistochemistry. Enalapril treatment resulted in 40% mortality by d 14, reduced body and kidney weight, decreased glomerular area, and caused tubular dilatation (p< 0.05versusvehicle group). Enalapril decreased renal TGF-β1 and EGF mRNA expression, and increased renal clusterin and renin expression (p< 0.05). Renal tubular immunoreactive EGF was decreased, and clusterin was increased by enalapril treatment. These results indicate that ACE inhibition in the developing kidney reduces the renal expression of critical growth factors, which may account for renal growth impairment. Clusterin expression may increase either due to blockade of tonic angiotensin-mediated inhibition, or as an adaptive response to renal ischemia.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

To study the potential role of theobgene pathway in childhood obesity, we have investigated leptin mRNA levels in s.c. adipose tissue obtained from nonobese prepubertal children (n= 20), obese nonsyndromal children (n= 6), and children with Prader-Willi syndrome (n= 6) byin situhybridization histochemistry. We have also investigated the fasting serum leptin levels in such children. Compared with nonobese children, leptin mRNA expression was higher both in children with Prader-Willi syndrome and in children with nonsyndromal obesity (p< 0.01). Furthermore, the serum leptin levels were also significantly higher in both children with Prader-Willi syndrome and nonsyndromal obesity compared with the nonobese children (p< 0.001). However, no significant differences in adipose tissue leptin mRNA or serum leptin levels were observed between children with Prader-Willi syndrome and nonsyndromal obese children. As expected both fasting serum leptin levels and leptin mRNA expression levels correlated to body mass index (rs= 0.80 and 0.73, respectively,p< 0.005). No difference in leptin expression between Prader-Willi syndrome and nonsyndromal childhood obesity could be revealed in the present study. However, differences in the hypothalamic response to leptin between the two forms of obesity cannot be excluded.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Platelet-activating factor (PAF) is a proinflammatory phospholipid mediator implicated in necrotizing enterocolitis. Regulation of PAF-acetylhydrolase (AH), the enzyme degrading PAF, is poorly understood. In this study we found that administration of a dose of PAF (1.5 μg/kg, i.v.), which does not cause gross intestinal injury, increased plasma and intestinal PAF-AH in the rat. Cycloheximide (CHX, 5 mg/kg, i.v.) reduced the activity of plasma (but not intestinal tissue) AH in control, as well as in PAF-injected rats, and aggravated systemic inflammation and tissue injury in the latter. The intestinal necrosis induced by PAF and CHX was ameliorated by posttreatment with WEB2170 (a PAF antagonist), indicating a role of endogenous PAF in mediating injury. Both WEB2170 and anti-TNF antibody reduced PAF-induced AH activity in intestinal tissue, but not in the plasma. Allopurinol largely prevented the injury induced by PAF and CHX, but had no effect on the up-regulation of AH. We conclude:1)de novoprotein synthesis is required to maintain physiologic AH level in the plasma;2) PAF up-regulates plasma and intestinal AH activity;3) CHX enhances the injurious effect of PAF;4) endogenous PAF and TNF also play a role in the up-regulation of intestinal AH; the former probably mediating the intestinal injury by PAF; and5) reactive oxygen species may mediate the injurious effect of PAF plus CHX, but do not contribute to the regulation of AH by PAF.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

It is not known how immaturity and disease influence postnatal thyroid function in infants <30 wk of gestational age. We performed serial measurements of plasma thyroxine (T4), free T4(FT4), triiodothyronine (T3), reverse T3(rT3), TSH, and T4-binding globulin (TBG) in 100 infants of <30 wk of gestation, during the first 8 postnatal weeks, to investigate the influences of disease and gestational age on the time course of thyroid hormones. One hundred infants were divided twice into two groups: 1) in a group of 25-28 and of 28-30 wk of gestation; and 2) in a sick and a healthy group, with similar gestational ages. The time course of T4, FT4, T3, TSH, and TBG, but not rT3differed significantly (p< 0.005) between the gestational age groups. T4and FT4decreased to levels below the cord blood value with a deeper FT4nadir on d 7 in the youngest group. Disease decreased T4, FT4, T3, TSH, and TBG concentrations especially during the 1st wk after birth (p< 0.005). However, the FT4nadir on d 7 was similar in sick and healthy infants. After 3 wk, T4, FT4, T3, and TBG were higher in the sick group compared with the healthy group. rT3levels were not increased in sick infants. We conclude that the extent of the FT4decrease after birth in infants of <30 wk gestation is mainly influenced by gestational age and probably reflects a transient depletion of thyroidal hormone reserves. rT3cannot be used as a marker of nonthyroidal illness in very preterm infants.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The epidermal permeability barrier, required for terrestrial life, is localized to lipid-enriched lamellar membranes in the extracellular spaces of the stratum corneum (SC). Immaturity of the SC is a significant contributor to morbidity and mortality in premature infants. Previous studies have shown that supraphysiologic concentrations of thyroid hormone accelerate epidermis/SC ontogenesis. Here we studied SC development in Hyt/Hyt mice who are genetically hypothyroid due to a mutation in the TSH receptor. In control mice on d 18 of gestation (term 19.5 d), only focal areas displayed a mature SC membrane pattern. By 19 d of gestation there was a mature multilayered SC with lamellar unit structures filling the extracellular spaces similar to that seen in mature mice. In Hyt/Hyt mice SC development was delayed at both 18 and 19 d of gestation. In both strains of mice, within the first day after birth there were no differences in epidermal or SC appearance, and the SC was fully mature. These findings indicate that thyroid hormone plays a physiologic role during normal intrauterine development of the SC. However, normal SC maturation ultimately occurs, indicating that thyroid hormone is not absolutely essential. Previous studies have shown that glucocorticoids accelerate SC development in euthyroid rats, and in the present study we demonstrate that glucocorticoids also accelerate SC ontogenesis in euthyroid mice. In contrast, in Hyt/Hyt mice glucocorticoids did not accelerate or normalize SC development, indicating that the glucocorticoid effect on SC maturation requires a euthyroid state or that glucocorticoids act via thyroid hormone. These studies demonstrate that thyroid hormone status is an important regulator of fetal SC development.

ISSN:0031-3998    

出版商:OVID    

年代:1997

数据来源: OVID