Inhibition of insulin-like growth factor I receptor expression in neuroblastoma cells induces the regression of established tumors in mice.

Several lines of evidence now indicate that type 1 insulin-like growth factor receptor (IGF1R) function may be particularly important in the pathogenesis of the pediatric cancer neuroblastoma. Modulating the expression of specific genes involved in neuroblastoma tumorigenesis could provide a much needed alternative treatment strategy for poor prognosis disease. We now report construction of an antisense expression vector to the IGF1R that markedly reduces cellular IGF1R levels and inhibits the proliferation and clonogenicity of neuroblastoma cells in vitro but not that of IGF1R null cells.

Molecular cloning and characterization of the rat NHE-2 gene promoter.

To understand the molecular mechanisms underlying NHE-2 regulation in the mammalian kidney and intestine, we cloned and sequenced 5.6 kb of the 5'-flanking region of the rat NHE-2 gene. DNA sequence analysis revealed multiple putative cis-acting regulatory elements including SP1, CK, NFY-CBF, Tant, GCN4, and one progesterone and several retinoic acid response elements.

Genetic screening for X-linked hypophosphatemic mice and ontogenic characterization of the defect in the renal sodium-phosphate transporter.

X-linked hypophosphatemic (Hyp) rickets is characterized by short stature, rickets, and bone abnormalities. Biochemically, hypophosphatemia and decreased renal reabsorption of phosphate are the hallmark of the disorder. Mutation of the PEX gene has been linked to human and murine Hyp rickets.

From "magic bullet" to "specially engineered shotgun loads": the new genetics and the need for individualized pharmacotherapy.

Steady progress in the identification of human pharmacogenetic variants and new discoveries of disease susceptibility genes makes the old notion of one disease/one drug untenable. Advances in the ability to rapidly identify these variants, when coupled with appropriate drug delivery systems, should revolutionize pharmacotherapy.

Acute effects of caffeine ingestion on signal-averaged electrocardiograms.

Background: Although moderate caffeine ingestion has not been shown to be arrhythmogenic, caffeine toxicity can cause severe cardiac arrhythmias, including atrial fibrillation and ventricular tachycardia. Atrial fibrillation and ventricular tachycardia have been associated with prolongation of P-wave and QRS complex durations on signal-averaged electrocardiograms. This study investigated acute effects of caffeine ingestion on signal-averaged P-wave and QRS complexes.

The expression of epidermal growth factor and transforming growth factor-alpha mRNA in the small intestine of suckling rats: organ culture study.

Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) are associated with regulation of various gastrointestinal functions. In order to better understand their role in developing small intestine EGF, TGF-alpha and EGF-R steady-state mRNA levels and transcript stability were determined. Reverse transcription (RT) competitive-polymerase chain reaction (PCR) revealed that intestinal TGF-alpha mRNA levels were 10-fold higher in comparison with EGF mRNA.

Increased NHE2 expression in rat intestinal epithelium during ontogeny is transcriptionally mediated.

We have previously described changes in intestinal brush-border membrane vesicle (BBMV) Na+/H+ exchange activity and characterized Na+/H+ exchanger (NHE3) expression during rat ontogeny. The current studies were designed to investigate developmental changes in NHE2 expression in rat intestine. In previous studies, pH-dependent uptake of Na+ in jejunal BBMV utilizing HOE-694 inhibition demonstrated that NHE2 functional protein levels were lowest in 2-wk-old rats, higher in 3-wk-old and adult rats, and highest in 6-wk-old rats [Collins et al.

Pediatric death certification.

Objective: To determine location, manner, and physician certifier of pediatric deaths.

Design: A descriptive study of death certificate information for all child deaths (aged birth through 17 years) for the years 1995 and 1996.

Setting: Urban county of more than 780,000 population.

Cardiac teratogenicity of trichloroethylene metabolites.

Objectives: The hypothesis of this study was that metabolites of trichloroethylene (TCE), dichloroethylene (DCE) and related compounds were responsible for fetal cardiac teratogenic effects seen when TCE or DCE is consumed by pregnant rats during organogenesis. Identification of teratogenic metabolites would allow more accurate assessment of environmental contaminants and public health risks from contaminated water or possibly municipal water supplies which, when chlorinated, may produce these potentially dangerous chemicals.

Background: Human epidemiologic studies and previous teratogenic studies using chick embryos and fetal rats have shown an increased incidence of congenital cardiac lesions in animals exposed to TCE and DCE.

A review: trichloroethylene metabolites: potential cardiac teratogens.

This review is a a series of the authors' studies designed to test the hypothesis that administration of trichloroethylene (TCE), dichloroethylene (DCE), their metabolites, and related compounds are responsible for fetal cardiac teratogenesis when given to pregnant rats during organogenesis. Identification of teratogenic compounds will allow more accurate assessment of environmental contaminants and public health risks. Epidemiologic studies and previous teratogenic studies using chick embryos and fetal rats have reported an increased number of congenital cardiac defects when exposed to TCE or DCE during fetal development.

Plasma transferrin receptor levels and indices of erythropoiesis and iron status in healthy term infants.

Purpose: The goal of this study was to determine if the postnatal changes in plasma transferrin receptor (TfR) levels in healthy infants were associated with changes in erythropoiesis or iron status.

Subjects And Methods: Longitudinal blood samples were obtained monthly from healthy term infants fed iron-fortified formula for the first 7 months and analyzed for plasma TfR and indices of erythropoiesis and iron status.

Results: Plasma TfR level rose during the first 2 months of life (p < 0.

Increasing breastfeeding rates to reduce infant illness at the community level.

Objective: Although breastfeeding is associated with lower rates of a variety of infant illnesses, skeptics have suggested that much of the association is attributable to confounding, even after appropriate statistical adjustment. This article utilizes a novel design to investigate changes in infant illness at the community level after a successful breastfeeding promotion program.

Methods: In this population-based cohort study, the medical records of all infants born in one Navajo community the year before a breastfeeding promotion program (n = 977) and the year during the intervention (n = 858) were reviewed.

Ontogeny of basolateral membrane sodium-hydrogen exchange (NHE) activity and mRNA expression of NHE-1 and NHE-4 in rat kidney and jejunum.

Na+/H+ exchange (NHE) activity varies with ontogenic state in rat intestinal basolateral membrane vesicles (BLMV). The current investigation sought to determine if these observations are due to differential expression of BLM NHE isoforms, NHE-1 and NHE-4. In rat kidney, BLMV sodium uptake levels were similar in 2, 3 and 6 week rats (13.

Biosynthesis of endotubin: an apical early endosomal glycoprotein from developing rat intestinal epithelial cells.

Endosomes are the site of sorting of internalized receptors and ligands in all cell types and, in polarized cells, the apical endosomal compartment is involved in the selective transepithelial transport of immunoglobulins and growth factors. The biochemical composition of this specialized compartment remains largely unresolved. We have characterized a glycoprotein, called endotubin, that is located in the apical endosomal tubules of developing rat intestinal epithelial cells.

Intermediate-term results of Phase I Food and Drug Administration Trials of buttoned device occlusion of secundum atrial septal defects.

Objectives: This study was conducted to evaluate the intermediate-term results of the multi-institutional U.S. trial of the buttoned device for transcatheter closure of atrial septal defects (ASDs).

The physical association of multiple molecular chaperone proteins with mutant p53 is altered by geldanamycin, an hsp90-binding agent.

Wild-type p53 is a short-lived protein which turns over very rapidly via selective proteolysis in the ubiquitin-proteasome pathway. Most p53 mutations, however, encode for protein products which display markedly increased intracellular levels and are associated with positive tumor-promoting activity. The mechanism by which mutation leads to impairment of ubiquitination and proteasome-mediated degradation is unknown, but it has been noted that many transforming p53 mutants are found in stable physical association with molecular chaperones of the hsp70 class.

Human milk as a potential enteral source of erythropoietin.

In addition to its content of traditional nutrients, milk is a rich source of hormones and peptides, which survive digestion in the neonatal gastrointestinal tract secondary to lower proteolytic activity and increased protein permeability. Previous studies have shown accelerated erythropoiesis or elevated serum erythropoietin (Epo) levels in neonatal (suckling) animals after maternal phlebotomy or maternal hypoxia exposure. We sought to determine whether significant quantities of Epo are present in human milk and whether Epo remains intact under physiologic digestion conditions.

Blepharophimosis: a causally heterogeneous malformation frequently associated with developmental disabilities.

We report on 22 individuals referred for genetic evaluation because of blepharophimosis. Fourteen of these patients had the blepharophimosis syndrome: 5 familial and 9 sporadic. Mental retardation or developmental delay was seen in 8 of the 12 children in whom this could be assessed.

Functional and molecular characterization of NHE3 expression during ontogeny in rat jejunal epithelium.

Ontogenic changes occur in intestinal brush-border membrane vesicle (BBMV) Na+/H+ exchange activity. The present studies were designed to investigate ontogenic changes in Na+/H+ exchanger (NHE) isoform 3 in rat jejunum. pH-dependent Na+ uptake was assayed in four age groups of rats in the presence of 0, 50, or 800 microM HOE-694, a specific NHE inhibitor with differential sensitivities for NHE2 [inhibition constant (Ki) = 5 microM in PS120 fibroblasts] and NHE3 (Ki = 650 microM).

Does sex determination start at conception?

Recent molecular studies of mammalian sexual determination have been focused on gene expression in the gonadal ridge at the time of appearance of sexual dimorphism: the critical time defined by the 'Jost principle'. Three lines of evidence suggest that, instead, sex determination may start shortly after conception: (1) the XY preimplantation embryo usually develops more rapidly than the XX preimplantation embryo (this phenotype has been linked to the Y chromosome and will be termed 'Growth factor Y'); (2) the gene for testis determination, SRY/Sry, and the closely linked genes ZFY/Zfy and Smcy, are transcribed in the preimplantation embryo; and (3) male and female preimplantation embryos are antigenically distinguishable, indicating sex differences in gene expression. The data to support these assertions are reviewed.

Use of a cerebral angiographic catheter facilitates crossing the pulmonary valve in neonates with critical or severe pulmonary valve stenosis.

The inability to cross the pulmonary valve in neonates with severe pulmonary stenosis remains a primary reason for procedural failure. We describe the use of a standard pediatric cerebral angiographic catheter that enables crossing the pulmonary valve in these neonates with relative ease and rapidity.

Ragweed sensitization alters pulmonary vascular responses to bronchoprovocation in beagle dogs.

In ragweed (RW)-sensitized beagle dogs, we tested the hypothesis that reactivity of the pulmonary vasculature was enhanced with aerosolized histamine (Hist) and RW. Seven dogs were neonatally sensitized with repeated intraperitoneal RW injections, and 12 dogs were controls (Con). The dogs were anesthetized with intravenous chloralose, mechanically ventilated, and instrumented with femoral arterial and pulmonary artery catheters.