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Biomedical subjects

K G Nelson

Publications and source records attributed to K G Nelson.

At least 19 recordsLinked to original sources
PubMed1992

Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor.

Epidermal growth factor (EGF) reproduces many of the effects of estrogen on the murine female reproductive tract and may partially mediate estrogen-induced growth and differentiation. This study was performed to investigate the mechanism by which EGF elicits estrogen-like actions in the whole animal. EGF was administered to adult ovariectomized mice by slow release pellets implanted under the kidney capsule. The induction of uterine DNA synthesis and phosphatidylinositol lipid turnover by EGF or administration of diethylstilbestrol (5 micrograms/kg), a potent estrogen, was attenuated by the estrogen receptor antagonist ICI 164,384. Furthermore, EGF mimicked the effects of estrogen on enhanced nuclear localization of the estrogen receptor and the formation of a unique form of the estrogen receptor found exclusively in the nucleus. These results suggest that EGF may induce effects similar to those of estrogen in the mouse uterus by an interaction between the EGF signaling pathway and the classical estrogen receptor. The demonstration of cross-talk between polypeptide growth factors and steroid hormone receptors may be of importance to our understanding of the regulation of normal growth and differentiation as well as the mechanisms of transmission of extracellular mitogen signals to the nucleus.

Animals↗
PubMed1992

Lactoferrin expression in the mouse reproductive tract during the natural estrous cycle: correlation with circulating estradiol and progesterone.

Lactoferrin (LTF), an iron-binding glycoprotein present in most exocrine secretions and in the secondary granules of polymorphonuclear leucocytes (PMN), is regulated by estrogen in the mouse reproductive tract. We investigated the expression of LTF mRNA and protein during the natural estrous cycle to increase our understanding of how this uterine secretory protein is regulated under physiological conditions. There was a positive correlation between LTF mRNA expression in the genital tract and serum estradiol (E2) concentrations. When E2 peaked in proestrus, LTF mRNA and protein were expressed in the uterus; however, during metestrus, when both E2 and progesterone levels were high, LTF mRNA was expressed, while LTF protein was decreasing. LTF protein expression may be hindered by progesterone or some other local factor in the endometrial epithelium after ovulation. Immunohistochemistry demonstrated two distinct staining patterns for LTF in the vaginal and endometrial epithelium. In one staining pattern, the colorimetric reaction was noted over the cytoplasm, and in the other, the nuclear region stained more intensely. This suggests the possibility that in addition to its known role as a secretory protein, LTF may be transported to the nucleus, serving an autocrine role. Our results also indicated that LTF protein is a useful marker for tracking PMN. Nonproliferating epithelial cells in the vagina and endometrium may synthesize chemotactic and/or adhesion molecules for PMN.

Animals↗
PubMed1992

Transforming growth factor-alpha is a potential mediator of estrogen action in the mouse uterus.

To better understand the role of peptide growth factors in sex steroid hormone-mediated growth of the female reproductive tract, the effect of estrogen on the expression of transforming growth factor-alpha (TGF alpha) in mouse uterus was investigated. Our results show that estrogen induces the expression of TGF alpha mRNA in the mouse uterus in a dose- and time-dependent manner. The up-regulation of TGF alpha transcripts occurs predominantly in uterine epithelial cells. RIA and Western blot analysis demonstrate that immunoreactive TGF alpha protein is secreted at high levels into mouse uterine luminal fluid after estrogen treatment. The induction of uterine TGF alpha mRNA is specific to estrogen; nonestrogenic steroids did not induce expression. Antibody specific to TGF alpha significantly reduces estrogen-mediated uterine growth, which supports the concept that TGF alpha is a mitogen for the reproductive tract. Analysis of TGF alpha/EGF receptors by binding, affinity labeling, and phosphorylation studies indicates that functional receptors are present in the mouse uterus after estrogen exposure. Thus, our data support a physiological role for TGF alpha and its receptor pathway in the female mouse reproductive tract.

Animals↗
PubMed1992

The influence of previous low birth weight on birth weight, gestational age, and anthropometric measurements in the current pregnancy.

The effect of a previous low birth weight birth (less than 2750 g) was examined using a series of regression analyses. Effects on birth weight were partitioned into those associated with preterm delivery (128 g) and term delivery (178 g). Among term births, a mean difference of 107 g was associated with a previous birth of less than 2750 g, even after controlling for other risk factors including smoking, drug and alcohol use, maternal race, size, and hypertension. The pattern of measurements seen after a previous birth of less than 2750 g included significantly smaller head, chest, abdomen, arm, and thigh circumferences, but an insignificant impact on skinfold thicknesses and no significant effect on length measurements.

Anthropometry↗
PubMed1991

Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation.

The in vivo studies presented here demonstrate that epidermal growth factor (EGF) is an important autocrine and/or paracrine mediator of estrogen-induced growth and differentiation in mouse uterus and vagina. An antibody specific for EGF significantly inhibited estrogen-induced uterine and vaginal growth, thereby implicating EGF involvement in estrogen action. Furthermore, EGF administered via slow-release pellets in ovariectomized mice acted as a potent uterine and vaginal mitogen as well as an inducer of vaginal keratinization. Experiments with ovariectomized, adrenalectomized, hypophysectomized mice indicated that EGF mitogenesis does not require pituitary or adrenal hormones. Treatment with EGF also mimicked estrogen in the induction of uterine lactoferrin (a major estrogen-inducible secretory protein) mRNA and protein. These data suggest that EGF has estrogen-like effects in the promotion of cell growth in the reproductive tract and that EGF may serve as an important mediator of estrogen action in vivo.

Adrenalectomy↗
PubMed1991

Localization of the estrogen receptor in uterine cells by affinity labeling with [3H]tamoxifen aziridine.

The possibility that estrogen receptors may exist in uterine plasma membranes was investigated by covalent labeling of estrogen receptors in mouse uterine cells with [3H]tamoxifen aziridine (TA). Isolated epithelial and stromal cells of immature mice were incubated with [3H]TA in the presence or absence of unlabeled tamoxifen, homogenized and separated into nuclear, cytosolic and microsomal fractions by differential centrifugation. These fractions were subjected to SDS-polyacrylamide gel electrophoresis and the proteins labeled covalently with TA were visualized by autoradiography. Proteins labeled specifically with [3H]TA were observed almost exclusively in the nuclear fraction of both epithelial and stromal cells. In contrast, very little labeled protein was detected in the cytosolic or microsomal fraction. Although these data do not preclude the possibility that estrogen binding sites are present in plasma membranes of uterine cells, this cellular fraction is definitely not labeled to a significant extent by [3H]TA. Thus, if membrane estrogen binding sites exist, their structural conformations may be different from that of nuclear estrogen receptors.

Affinity Labels↗
PubMed1991

Black-white differences in newborn anthropometric measurements.

The mean birth weight of black infants is consistently less than that of white infants. In 1518 low-income multiparous women, the mean difference in singleton births was 171 g, of which 38 g was partitioned to preterm births and another 35 g reflected lower gestational ages in term births. A series of regression analyses were used to determine the effect of black race on various newborn measurements in 1205 term newborns, adjusting for other known risk factors. In this model, black race accounted for a mean decrease of 148 g in weight and 0.52 cm in length. There were also significant decreases in mean head (0.44 cm), chest (0.66 cm), and abdominal (0.56 cm) circumferences. Arm and leg lengths were not different, but black arm circumferences (0.14 cm) were significantly larger. Triceps and thigh skin fold measurements were not statistically different, but black subscapular skin fold values were significantly smaller (0.17 mm). The ponderal index in blacks was significantly less than in whites. These data suggest that in this population, intrinsic and/or extrinsic factors associated with race account for most smaller black newborn measurements and for much of the racial difference in birth weight.

Alabama↗
PubMed1990

Epidermal growth factor binding and receptor distribution in the mouse reproductive tract during development.

The ontogeny of the epidermal growth factor (EGF) receptor in the different cell types in the neonatal and immature mouse uterus and vagina was examined. Immunohistochemical examination of prenatal and neonatal reproductive tracts with a polyclonal antibody to the EGF receptor shows immunoreactive EGF receptors as early as Day 13 of gestation. Autoradiographic analysis of tissue sections at 3 to 17 days of age (the day of birth is Day 1) demonstrates that both uterine and vaginal epithelial and stromal cells are capable of binding 125I-labeled EGF. Both the 125I-labeled EGF autoradiography and immunohistochemistry in whole tissue show higher EGF receptor levels in the uterine epithelium than the uterine stroma. The presence of EGF receptors was also confirmed by affinity labeling and Scatchard analysis of isolated uterine cell types at 7 and/or 17 days of age. However, in contrast to the autoradiography and immunohistochemistry data of intact tissue, the affinity labeling and Scatchard data of isolated cells indicate that the uterine stroma contains higher levels of EGF receptor than that of the uterine epithelium. The reason for this discrepancy between the different techniques is, as yet, unknown. Regardless of the differences in the actual numbers of EGF receptors obtained, our data demonstrate that the developing mouse reproductive tract contains immunoreactive EGF receptors that are capable of binding 125I-labeled EGF.

Affinity Labels↗
PubMed1990

Mycoplasmal infections of cerebrospinal fluid in newborn infants from a community hospital population.

Mycoplasma hominis or Ureaplasma urealyticum have previously been isolated from cerebrospinal fluid (CSF) in 13 of 100 newborn infants tested from a high risk university hospital population where the mothers were of predominantly lower income and socioeconomic status and had often received little or no prenatal care. We sought to determine whether such infections occur in neonates born to women cared for mainly through private obstetric practices and who delivered in 4 suburban community hospitals. CSF cultures were done in 318 infants during an 8-month period. M. hominis was isolated from 9 and U. urealyticum from 5 CSF cultures. Four infants infected with U. urealyticum and 3 infected with M. hominis were born at term. One infant infected with U. urealyticum had a birth weight of less than 1000 g. In 5 infants clearance of the infecting organism was documented without specific treatment. Twelve infants had good perinatal outcomes regardless of treatment and 2 died. One death in a 2240-g infant infected with M. hominis was associated with Haemophilus influenzae sepsis and pneumonia. The other death occurred 3 days after birth in a 630-g infant infected with U. urealyticum who had evidence of meningitis and intraventricular hemorrhage. Results of this study suggest that mycoplasmas are common causes of neonatal CSF infections, not only in high risk populations, but also in the general population.

Alabama↗
PubMed1989

Intrauterine growth retardation: standards for diagnosis.

An intrauterine growth-retarded infant is commonly defined as one weighing less than the 10th percentile in birth weight for its gestational age. However, because there is no standard population from which to derive these percentiles, the birth weights that serve as the cutoff point in various published studies may differ by several hundred grams at any gestational age. For this reason, we examined the studies from which the currently used 10th-percentile standards are derived to determine which factors may be responsible for the variation. In addition to obvious differences in the populations and geographic areas on which they were based, studies differed in how gestational age was determined, whether the gestational age was "rounded" or given in completed weeks, which types of infants were excluded, whether the studies were hospital or population based, and whether they were controlled for sex of the infant and race and parity of the mother. These differences in study methodology may be as or more important than the population differences in defining the 10th percentile cutoffs. A single national standard for intrauterine growth retardation would allow comparison between studies of risk factors, diagnostic tests, management, and long-term follow-up status of fetuses and infants with intrauterine growth retardation.

Birth Weight↗
PubMed1989

Decreased ligand binding to the hepatic glucocorticoid and epidermal growth factor receptors after 2,3,4,7,8-pentachlorodibenzofuran and 1,2,3,4,7,8-hexachlorodibenzofuran treatment of pregnant mice.

2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) are environmental contaminants which mimic many of the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Like TCDD, these polychlorinated dibenzofurans (PCDFs) induce hepatic benzo[a]pyrene hydroxylase activity (BPH) and possess high affinity for the Ah receptor. Another similarity of these PCDFs to TCDD is their ability to induce teratogenic effects such as cleft palate and hydronephrosis in mice. Recent studies have shown that TCDD modifies the equilibrium binding kinetics of the rat liver cytosolic glucocorticoid receptor (GRc) and the hepatic plasma membrane epidermal growth factor (EGF) receptor. To gain a better understanding of the action of halogenated hydrocarbons on these cytosolic and membrane-bound receptor systems during pregnancy, we investigated the biochemical effects of PeCDF and HCDF on the binding kinetics of maternal mouse liver GRc and EGF receptors and the induction of BPH activities. Pregnant C57BL/6N mice were treated once daily on gestation Days 10 through 13 with PeCDF (0-30 micrograms/kg) or HCDF (0-300 micrograms/kg). Hepatic [3H]dexamethasone and [125I]EGF equilibrium binding studies indicated that all doses of PeCDF tested (10, 20, and 30 micrograms/kg) significantly reduced the GRc and EGF receptor maximum binding capacities but did not affect the binding affinities of these receptors when compared to corn oil-treated control pregnant mice. Similar effects were observed for doses of HCDF greater than or equal to 100 micrograms/kg. These data suggest that the dibenzofuran-mediated decreases in GRc and EGF receptor binding capacities are similar to those caused by TCDD. Although the mechanism of action is not yet clear, our results indicate that halogenated aromatic compounds in addition to TCDD have profound effects on both steroid and growth factor receptor systems.

Animals↗
PubMed1989

Preliminary results from the Collaborative Alabama and Scandinavian Study of Successive Small-for-Gestational Age Births.

The study "Successive Small-for-Gestational Age Births" (SGA study) was initiated and is sponsored by the National Institutes of Health (N.I.H.) in the U.S.A. Its purpose is to describe and characterize the different types of intra-uterine growth retardation and their consequences, to assess the associated risk factors, and to provide a basis for preventive measures. Starting in 1986, it runs concurrently in Bergen and Trondheim (Norway), Uppsala (Sweden) and Birmingham, Alabama (U.S.A.), recruiting pregnant para 1 and 2 mothers at high risk of having an SGA birth and a random (control) sample of the total pregnant population. Data collection will end in late 1989, when the last-born children have reached 13 months of age. At the present symposium, investigators from all four study centers and the N.I.H. described the study design and discussed problems of methodology. Strict standardization of parameters to determine gestational age (ultrasound, menstrual dates) is a prerequisite for comparison of results over time and between study centers. Some preliminary results were presented.

Alabama↗
PubMed1989

Characterization of 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated decreases in dexamethasone binding to rat hepatic cytosolic glucocorticoid receptor.

An investigation of the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the liver cytosolic glucocorticoid receptor (GRc) in intact and adrenalectomized (ADX) rats, using equilibrium binding analysis, sucrose gradient sedimentation, and affinity labeling experiments, clearly demonstrated that TCDD significantly reduced the binding capacity (Bmax) of the hepatic GRc but did not alter the apparent equilibrium dissociation constant (Kd). This effect was maximal after 24 hr and was still present 22 days after treatment. Western blot analysis revealed that TCDD treatment did not cause a comparable decrease in the levels of immunodetectable receptor protein, which suggests that the steroid-binding properties of the hepatic GRc are altered, rather than the absolute concentration of receptor protein. Studies of TCDD effects on the uptake of GRc by nuclei indicated that TCDD treatment did not alter the ability of the steroid-GRc complex to be taken up by nuclei; however, TCDD treatment did increase the total capacity of liver nuclei to bind steroid-GRc complexes. TCDD dose-response studies that compared the hepatic GRc steroid binding of ADX and intact rats indicated that adrenalectomy markedly enhanced the response to TCDD. Significant effects on the GRc binding in ADX animals were induced at TCDD doses that were 10,000 times lower than those required for a response in intact rats. Analysis of two other biochemical markers demonstrated that ADX rats were 10-fold more sensitive to the induction of microsomal benzo[a]pyrene hydroxylase but of similar sensitivity to reduction of epidermal growth factor receptor binding, when compared with the responses of intact animals. These data indicate that adrenal status may be important in modulating the responses of the animals to TCDD and that the alteration of the hepatic GRc pathway may have a role in some of the actions of TCDD.

Adrenalectomy↗
PubMed1987

Flow cytometric analysis of human uterine sarcomas and cell lines.

Flow cytometric techniques were used to characterize multiple human uterine sarcomas and cell lines derived from some of these tumors. Analysis of DNA content showed that 9 of the 11 uterine sarcomas investigated were composed of at least one aneuploid population as well as a distinct diploid population. These data indicate that aneuploidy, as measured by flow cytometry, is a characteristic more common to uterine sarcomas than that previously reported for uterine adenocarcinomas. Unlike the original tumors, the cell lines established from three of the sarcomas contained predominantly diploid populations with only minor aneuploid populations. Treatment of one of the sarcoma cultures with tumor promoters did not result in an increase in the aneuploid populations. Tumors which arose in nude mice upon transplantation of two of the sarcomas did not contain the same distribution of tumor subpopulations as found in the original sarcomas. Apparently, the in vitro culture and and in vivo nude mouse conditions were not appropriate for maintaining the original equilibrium between the aneuploid and diploid subpopulations but instead provided a selective environment that resulted in the preferential growth of only certain tumor populations. Dual-parameter analysis of DNA content and alkaline phosphatase levels of one of the sarcomas were useful for distinguishing the aneuploid from the diploid population coexisting in this tumor. Our data suggest that flow cytometry is a valuable tool to analyze the characteristics of the tumor populations residing in primary uterine sarcomas as well as to determine which of these tumor subpopulations survive in culture and transplantation to nude mice.

Alkaline Phosphatase↗
PubMed1987

Mass transport in dissolution kinetics. I: Convective diffusion to assess the role of fluid viscosity under forced flow conditions.

The quantitative influence of viscosity on dissolution kinetics is assessed under laminar flow conditions by utilizing a convective diffusion model for drug dissolution. Functional dependency of three types of viscosity inducing agents is established with respect to the parameters of fluid flow rate, diffusivity, and solubility. Studies of aqueous solutions of sucrose and of glycerol demonstrate that the decrease in dissolution rate of ethyl p-aminobenzoate is related to the decrease in solute diffusivity in these solutions, whereas the solubility change in the glycerol solutions has an additional independent simultaneous effect. Dissolution in hydroxypropyl cellulose solutions remains constant under fixed fluid flow conditions because of the negligible effect of the polymer upon the drug diffusivity. A change in fluid flow rate, however, alters the dissolution rate and correlates quantitatively with the rate of shear in the convective diffusion model. The interpretation of the effect of viscosity on dissolution kinetics with the convective diffusion model explains these phenomena quantitatively in terms of the fundamental mass transport processes.

Cellulose↗
PubMed1987

Mass transport in dissolution kinetics. II: Convective diffusion to assess role of viscosity under conditions of gravitational flow.

Dissolution kinetics was studied in a laminar flow cell, through which aqueous solutions of increasing viscosity flowed under the force of gravity, in order to help elucidate the mechanism of drug dissolution. The viscosity was varied by addition of either hydroxypropyl cellulose, sucrose, or glycerin. The dissolution data were evaluated quantitatively in terms of a convective diffusion model for dissolution. It was demonstrated that the decrease in dissolution rate of a test compound due to viscosity in the polymer solution occurs primarily because of a decrease in the rate of shear over the dissolving surface. In solutions of sucrose or glycerin, the decrease in dissolution rate due to viscosity results because of a decrease in the diffusivity of the solute in addition to the decreased rate of shear. Also, the model accounts for the increase in solubility in the glycerin solution. Thus, the influence of viscosity on dissolution depends on whether the viscosity-inducing agent primarily affects only the flow properties of the liquid, or whether it affects diffusivity (i.e., a "micro" viscosity effect, in addition to the flow properties).

Cellulose↗