摘要:

Proton magnetic resonance spectroscopy (MRS) is an emerging technology that allows for the quantitative noninvasive assessment of regional brain biochemistry. The capacity to carry out MRS studies requires existing magnetic resonance imaging (MRI) technology platforms and the purchase of commercially available software modifications. In this review, the physical basis for MRS will be presented leading to an understanding of its potential applications and limitations within the clinical research milieu. Thus far, within pediatric neurology, proton MRS studies have been used to assist in the prediction of outcome in a variety of settings of acquired brain injuries(perinatal asphyxia, near drowning). In addition, proton MRS has been used to document disturbances in oxidative metabolism in neurometabolic disorders, assisting in defining phenotype and the response to therapeutic interventions. In epilepsy, spectroscopic studies have been useful in localizing the epileptogenic zone in intractable focal epilepsies. Future applications of proton MRS will also be highlighted. These include its use as a means of observing the transport and metabolism of various compounds in the brain, its concurrent application with other nuclear magnetic resonance techniques such as MRI and functional MRI, and finally its potential as a means of assessing the short-term effects of any CNS targeted pharmacologic interventions.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Although a strong clinical association exists between congenital heart block (CHB) and an immune response to SSA/Ro and SSB/La proteins, a causative role of these antibodies in the pathogenesis is just emerging. In a preliminary report, we have demonstrated that IgG fractions isolated from the sera of mothers whose children have CHB are arrhythmogenic in the human fetal heart. To more precisely define the arrhythmogenic effect of anti-SSA/Ro-SSB/La antibodies, we used the readily available rat heart model to record:1) ECGs from Langendorff beating hearts;2) action potentials from atrioventricular (AV) nodal preparations;3) L-type Ca currents,ICaat the whole-cell and single channel levels; and4) other currents such as the transient outward K+current,Ito, the inward rectifier K+current,IK1, and the Na+current,INa. Perfusion of hearts with purified IgG (800 µg/mL), isolated from the serum of a mother with SSA/Ro and SSB/La antibodies whose child had CHB, resulted in bradycardia associated with 2:1 AV block. Simultaneous action potentials were recorded from dissected atrial and AV nodal areas of the rat heart. Superfusion of these preparations with the same mother's IgG fraction resulted in 2:1 AV block followed by complete inhibition of AV nodal action potential. Because AV nodal electrogenesis is largely dependent onICa, the effect of these antibodies onICawas subsequently determined. Superfusion of myocytes with whole serum or purified IgG (80 µg/mL) from the same mother consistently inhibited whole cellICa, ensemble average Ba2+currents (IBa) and open state probability,po, without affecting the channel conductance. IgG had no significant effect onIto,IK1, orINa. Whole sera and IgG fractions from a healthy mother with no detectable anti-SSA/Ro or SSB/La antibodies did not inhibitICaorIBa. These results demonstrate that IgG containing anti-SSA/Ro and -SSB/La antibodies induces complete AV block in beating hearts and in multicellular preparations, thus implicating a preferential interaction of these autoantibodies with Ca channels and/or associated regulatory proteins. This is consistent with the observed inhibition of Ca channels that may be a critical factor contributing to the pathogenesis of CHB.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Immaturity of local innate defenses has been suggested as a factor involved in the pathophysiology of necrotizing enterocolitis (NEC). The mRNA of enteric human defensins 5 (HD5) and 6 (HD6), antibiotic peptides expressed in Paneth cells of the small intestine, have significantly lower levels of expression in fetal life compared with the term newborn and adult. In the current study, intracellular HD5 was demonstrated by immunohistochemistry at 24 wk of gestation, but at low levels, consistent with findings at the mRNA level. These data suggest that the low level enteric defensin expression, characteristic of normal intestinal development, may contribute to the immaturity of local defense, which predisposes the premature infant to NEC. To test if levels of defensin expression are altered in NEC, specimens from six cases of patients with NEC and five control subjects (four patients with atresia and one with meconium ileus) were analyzed to determine HD5 and HD6 mRNA levels byin situhybridization. Compared with the control group, the level of enteric defensin expression per Paneth cell assessed by image analysis was increased 3-fold in cases of NEC (p= 0.02, analysis of variance and covariance). In addition, the number of Paneth cells was increased 2-fold in the small intestinal crypts of NEC specimens compared with those of control subjects (p< 0.01, covariance analysis). In healthy tissue, peptide levels within Paneth cells paralleled mRNA levels through development. In tissue from infants with NEC, the steady state level of intracellular peptide was not increased in conjunction with the observed rise in defensin mRNA. A straightforward interpretation of this finding is that HD5 is actively secreted in this setting and the Paneth cells maintain a constant steady state level of intracellular peptide, but the possibility of translational regulation of peptide expression is also consistent with these data. The associations between NEC and enteric defensin expression reported here offer support for future studies to address the role of these endogenous host defense factors in the pathophysiology of this disease.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Superantigens (SAs) are known to induce transient anergy followed by T cell activation. Recent reports have suggested that SAs are involved in the pathogenesis of Kawasaki disease (KD). In the present study, we investigated the peripheral T cell response to SAs by measuring proliferation and IL-2 production to determine whether the T cell anergy is induced by SAs in patients with KD. T cells were obtained from 45 Japanese patients with KD in different stages of the disease and were stimulated by streptococcal pyrogenic exotoxin (SPE)-A, SPE-C, and toxic shock syndrome toxin-1 (TSST-1). T cells from patients with KD in the acute or convalescent stage up to 2 mo showed significantly lower proliferation and IL-2 production than did T cells from healthy subjects stimulated by SPE-C, but not SPE-A or TSST-1. The T cell response to SPE-C normalized within 1 y. The low T cell response to SPE-C in the acute stage correlated with a peak platelet count and the C-reactive protein-positive period. These findings suggest that the transient low T cell response to SPE-C in patients with KD may have been related to SA-induced anergy or disappearance of SPE-C-responding cells from the circulation. The present results suggested that SPE-C may be involved in the pathogenesis of KD.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We have previously shown that Curosurf®, a natural porcine surfactant, and its phospholipids effectively suppressed secretion of tumor necrosis factor (TNF-α) by resting and through lipopolysaccharide(LPS)-stimulated human monocytes. In this study the effect of Curosurf® on monocyte mRNA for TNF-α and TNF-α type II-receptor(TNF-α-RII) were analyzed to evaluate the cellular mechanisms involved in the modulation of TNF-α expression. LPS-stimulated monocytes simultaneously exposed to Curosurf® (500 µg/mL for 24 h) expressed approximately 70% less TNF-α mRNA when compared with control subjects(p< 0.05). In addition, 86% less TNF-α RII mRNA was found in monocytes exposed to Curosurf® (p< 0.001). Decreased mRNA expression was clearly associated with significantly reduced secretion of TNF-α protein (Curosurf®-exposed LPS-stimulated monocytes 3628 ± 1873 pg/mL TNF, LPS-stimulated monocytes 31 376± 2524 pg/mL TNF; mean ± SEM,p< 0.001). The activation of the transcription factor nuclear factor-κB upon LPS stimulation is not affected by Curosurf® incubation. This excludes that the decrease in mRNA and protein levels of TNF-α and TNF-α-RII is due to an inhibition of nuclear factor-κB activation by Curosurf®. We conclude that Curosurf® affects TNF-α release of LPS-stimulated monocytes at a pretranslational site by down-regulating both mRNA for TNF-α and TNF-α-RII, therefore acting as an anti-inflammatory agent within alveolar space.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We used column chromatography, affinity binding, and bioassay methods to address whether the soluble tumor necrosis factor (TNF)-α receptors present in human colostrum and milk bind to and modify TNF-α bioactivity. In gel chromatography experiments, soluble TNF-α receptor I (sTNFRI) and sTNFRII in human colostrum sequentially increased their molecular sizes from 49 kD to 71 kD and 60 kD, respectively, after addition of increasing molar excesses of recombinant TNF-α. Application of colostrum to a TNF-α affinity matrix followed by washing and elution resulted in 2925-fold enrichment of sTNFRI, consistent with sTNFRI binding to the TNF-α affinity matrix. In other samples of colostrum and milk, the content of both sTNFRI and sTNFRII decreased significantly after passage over the matrix, but the material eluted from the matrix lost the ability to rebind to the TNF-α and was not active in a WEHI-13var bioassay for TNF-α. Specimens of human colostrum and milk diluted 1:16 shifted the LD50for TNF-α 4-fold in this bioassay, and milk protection of WEHI-13var cells against TNF-α was significantly diminished after passage down the TNF-α affinity matrix (p< 0.001). Affinity purification of milk sTNFRI using polyclonal anti-sTNFRI produced fractions containing proteins of 30 kD, which could be visualized by Western blot using polyclonal anti-sTNFRI. Addition of this fraction to the WEHI-13var bioassay reversed the effects of 10 pg/mL TNF-α in the assay. These data demonstrate that sTNFRI and II from human colostrum and milk bind to TNF-α, that both colostrum and milk interfere with the bioactivity of TNF-α, and that affinity-purified sTNFRI from human milk blocks the bioactivity of TNF-α. These effects may contribute to the anti-inflammatory character of human colostrum and milk.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The effects of cocaine are well documented in the CNS; however, recent evidence suggests that cocaine may suppress the immune system. Maternal cocaine use essentially exposes the fetus to a continuous exposure of cocaine. The objective of this study was to investigate the immunomodulatory effects of cocaine and its metabolites on maternal and fetal immune systems. Subjects were recruited from an Investigational Review Board approved protocol, and biologic specimens were collected. For each subject peripheral blood mononuclear cells (PBMCs) were isolated by density gradient. Each PBMC sample was stimulated in separate wells with phytohemagglutinin and phrobol 12-myristate 13-acetate. Samples were radiolabeled and stimulation was measured. Cytokine measurements were made on the serum via ELISA assay techniques. In both the phorbol 12-myrisate 13-acetate and the phytohemagglutinin group, the PBMCs isolated from fetal cord blood in the cocaine-using group had significantly (p< 0.05) decreased responses compared with control subjects. IL 1 and IL 2 concentrations were suppressed in the cocaine-exposed fetal serum compared with controls(p< 0.005 andp< 0.05, respectively). We have shown thatin uterococaine exposure results in a nonspecific suppression of fetal T lymphocyte response. The clinical consequences of prenatal cocaine-induced immunosuppression need to be further explored.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Zidovudine (azidothymidine, AZT) is used in pregnancy to reduce mother to infant transmission of HIV. Understanding the disposition of AZT in the fetus is necessary to optimize therapeutic regimens directed toward the fetus. Recent studies in primates found similar steady-state levels of the glucuronide metabolite of AZT (AZT-glu) in the fetus to those in the mother, raising the question of whether metabolite was of fetal or maternal origin. The objective of this study was to determine whether glucuronidation occurred in the fetal compartment and to quantify the placental and fetal clearances of AZT using the two-compartment model at steady state. Steady-state concentrations were obtained after paired maternal and fetal infusions of AZT in chronically catheterized pregnant baboons. During maternal infusion, the mean (±SE) fetal to maternal ratio of AZT was <1 (0.84 ± 0.06,p< 0.02), suggesting clearance of AZT in the fetus. Mean total maternal clearance of AZT was 725 ± 49 mL/min and placental clearance was 36 ± 4 mL/min, or ∼5% of maternal clearance. Fetal clearance of AZT was estimated at ∼15% of placental clearance. This suggests fetal nonplacental clearance is minimal compared with that in the mother, but does not preclude the fetus from actively contributing to the metabolite in the fetal circulation. During infusion of AZT to the fetus, the concentration of AZT-glu in the fetus was 7.0 ± 0.8 times that in the mother. This is compelling evidence that glucuronide can be formed in the fetal compartment. Thus, fetal metabolism has an impact on the concentration of both AZT and AZT-glu in the fetal circulation.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Prematurely born, low birth weight infants are generally considered to be marginally vitamin E-deficient. Vitamin E deficiency has so far been defined as a low plasma α-tocopherol level (below 500 µg/dL) accompanied by a low tocopherol to lipid ratio or increased hydrogen peroxide hemolysis of erythrocytes. In the present study, we determined α- andγ-tocopherol in plasma, red blood cells, platelets, buccal mucosal cells, monocytes, and polymorphonuclear leukocytes of premature infants to assess vitamin E status. Fourteen healthy, premature infants with birth weight (mean ± SD) 1439 ± 364 g and gestational age 30 ± 1.7 wk were enrolled in the study. α- and γ-tocopherol were determined in cord blood and on d 0 to 1, 7, 14, 28, and 42 after birth in plasma and various cell types. Moreover, two randomly selected human milk samples were studied in each mother. Although subclinical or biochemical vitamin E deficiency was seen in healthy, premature infants in the first 6 wk of life in plasma and buccal mucosal cells, the other cells showed no such deficiency during the study. We conclude that these infants do not need routine vitamin E supplementation.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We investigated whether supplementation of regular formula (RF) with cholesterol (Ch) (RF+Ch) influenced circulating Ch levels andde novosynthesis compared with their breast-fed (BF) counterparts in 4-mo-old infants. The incorporation rate of deuterium in body water into erythrocyte membrane-free Ch over 48 h was used as an index of cholesterogenesis. Plasma total-Ch and LDL-Ch concentrations were highest(p< 0.02) in BF infants, compared with infants in the RF-fed groups. Infants in the RF+Ch groups showed an intermediate response; their plasma total-Ch and LDL-Ch concentrations were not significantly different from the BF or the RF-fed groups. Plasma total/HDL-Ch and LDL/HDL-Ch ratios were higher (p< 0.05) in BF, and higher in RF+Ch-fed infants, compared with those fed RF, whereas not different between BF and RF+Ch-fed infants. At 4 mo of age, Ch FSR was 4-fold lower(p< 0.0001) in BFversusother groups, but not significantly different between RF- and RF+Ch-fed infants. Thus, despite addition of Ch to the concentration found in breast milk, FSR remained elevated compared with that of the group fed breast milk, with an intermediate response in circulating Ch levels. It is speculated that factors other than Ch intake account for the differential Ch metabolism between formula-fed and BF infants.

ISSN:0031-3998    

出版商:OVID    

年代:1998

数据来源: OVID