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Biomedical subjects

J E Olson

Publications and source records attributed to J E Olson.

At least 73 records · Page 4Linked to original sources
PubMed1990

Transmodulation of epidermal growth factor binding by platelet-derived growth factor and 12-O-tetradecanoylphorbol-13-acetate is not sodium-dependent in Balb/c/3T3 cells.

The addition of platelet-derived growth factor (PDGF) to many types of cells causes a rapid decrease in high affinity binding of 125I-epidermal growth factor (EGF), a process which has been termed transmodulation. Treatment with the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) also results in the transmodulation of the EGF receptor in many cell types. PDGF can transmodulate EGF binding through a mechanism that is not dependent on protein kinase C activity. A recent report (Wattenberg, E. V., McNeil, P. L., Fujiki, H., and Rosner, M. R. (1989) J. Biol. Chem. 264, 213-219) described the requirement for a sodium ion influx in the down-modulation of the EGF receptor stimulated by a non-TPA-type tumor promoter, palytoxin, in Swiss 3T3 cells. We tested for a similar sodium requirement in Balb/c/3T3 and Swiss 3T3 cells stimulated by PDGF or TPA in Balb cells treated with TPA for prolonged periods to down-regulate protein kinase C activity. Our results clearly show that the PDGF- and TPA-stimulated transmodulation of the EGF receptor does not require external sodium nor is the process affected by amiloride. In each of these experiments, the loss of 125I-EGF binding occurred to a similar extent and at a similar rate in the presence or absence of sodium. Intracellular pH also did not appear to have a role in the response. The sodium ionophore, monensin, was previously shown to bring about the down-modulation of 125I-EGF binding in Swiss cells. However, our results indicate that monensin-induced transmodulation of the EGF receptor occurs with or without external sodium, suggesting that the loss of binding is not the result of a sodium ion influx. These findings demonstrate that an increase in intracellular sodium does not cause nor is it required for PDGF- or TPA-stimulated EGF receptor transmodulation.

Animals↗
PubMed1990

Intracellular lipid droplets in functioning transitional parathyroid oxyphil adenomas. A caveat.

Histochemical demonstration of intracellular lipid droplets on frozen section has been used to distinguish normal parathyroid tissue from that of adenoma and chief cell hyperplasia. Differentiation is based on the observation that the cells of adenoma and chief-cell hyperplasia largely lack intracellular lipid, which is present in the suppressed chief cells of normal glands in patients with adenoma. We present two functional transitional oxyphil adenomas that contained abundant intracellular lipid. Failure to recognize that transitional oxyphilic adenomas may contain focal accumulation of intracellular lipid droplets could lead to confusion in histologic interpretation.

Adenoma↗
PubMed1990

Control of astrocyte volume by intracellular and extracellular Ca2+.

Astrocytes from primary culture were exposed to conditions that affect intracellular and extracellular Ca2+ concentrations. Astrocyte cell volume was increased approximately 16% after a 30 min exposure to isoosmotic phosphate-buffered saline (PBS) containing the Ca2+ buffer EDTA. Cell volume returned to control values within 30 min of resuspension in normal PBS. Cellular calcium content was not affected by these treatments; however, the recovery of normal cell volume following EDTA exposure was inhibited by 0.1-1.0 mM quinine HCl in a dose-dependent fashion suggesting that a potassium channel controlled by the intracellular Ca2+ concentration is important in this volume response. Intracellular accumulation of an exogenous Ca2+ buffer, BAPTA, also produced cell swelling that persisted following resuspension in normal PBS. Lowering the extracellular Ca2+ concentration with EDTA enhanced the swelling of BAPTA-loaded cells. These data suggest that conditions leading to a decrease in free intracellular Ca2+ concentration may influence astrocyte volume by a mechanism similar to that described in other cell types.

Animals↗
PubMed1990

Amino acid content of rat cerebral astrocytes adapted to hyperosmotic medium in vitro.

Rat cerebral astrocytes from confluent primary cultures were grown for two weeks in medium made hyperosmotic with additional NaCl. At the time the cells were harvested (four weeks in culture), the medium osmolality of experimental cultures was approximately 600 mOsm. Amino acid, protein, and potassium contents and the cell volume were measured. Compared to cells maintained in control medium (approximately 300 mOsm), cells grown in hyperosmotic conditions had over two times the content of taurine and five times the content of glutamine. Alanine, aspartate, glutamate, glycine, and tyrosine contents also were elevated in these hyperosmotic-treated cells, while asparagine contents were unchanged relative to control cells. Cell volume and potassium content were decreased to approximately 50% of control levels by the hyperosmotic treatment while total protein content per cell was unchanged relative to cells from control cultures. Seven min after hyperosmotic-exposed cells were rapidly diluted into PBS with osmolality equal to about 330 mOsm, cell contents of alanine, asparagine, glutamine, glutamate, glycine, taurine, and tyrosine fell toward control levels. The data indicate that significant alterations in intracellular osmolytes occur in astrocytes adapted to hyperosmotic conditions. We suggest that a loss of intracellular potassium is at least partially compensated by accumulation of taurine, glutamine, and perhaps other amino acids acting as intracellular osmolytes.

Amino Acids↗
PubMed1990

Brain water content, brain blood volume, blood chemistry, and pathology in a model of cerebral edema.

STUDY OBJECTIVES: The objective was to correlate regional changes during brain water content with alterations in blood chemistry and cerebral pathology during hypo-osmotic edema. PARTICIPANTS: Sprague-Dawley male adult rats were used in these studies. DESIGN: Animals were block-randomized to receive either an intraperitoneal distilled water injection equivalent to 5% or 15% of their body weight or no injection (controls). Rats were sacrificed 15 or 60 minutes after water injection or at an equivalent time for controls. INTERVENTIONS: No interventions were performed. MEASUREMENTS AND MAIN RESULTS: Water content of cerebral cortical gray and white matter was calculated from measurements of tissue specific gravity. Blood plasma osmolality and sodium and potassium concentrations were determined at various times after water injection. An index of blood-brain barrier permeability was obtained by measuring brain red blood cell and plasma volumes. A qualitative assessment of edema was made from light and electron micrographs of the cerebral cortex. We found that water injection produced a dose-dependent decrease in plasma osmolality and sodium concentration within 15 minutes. Cortical water content was unchanged after this period. An influx of water into cerebral gray, and, less readily, into cerebral white matter occurred during the next 15 minutes. Whole blood specific gravity and brain blood content were unchanged and thus did not confound the measurement of cerebral water content. Hematocrit was increased 60 minutes after a 15% water injection. The blood-brain barrier remained intact throughout this period. Microscopy revealed astrocytic swelling with slight extracellular fluid accumulation 60 minutes after the water injection. CONCLUSIONS: Homeostatic mechanisms in the cerebral cortex can maintain constant water content for at least 15 minutes during maintained intravascular hypo-osmolality. Fluid that subsequently moves into the tissue primarily enters an intracellular compartment. This model will be useful in investigating physiological mechanisms of brain water regulation and the pathogenesis of brain edema, a common clinical entity in emergency conditions.

Animals↗
PubMed1990

The effect of tamoxifen on cervical squamous maturation in Papanicolaou stained cervical smears of post-menopausal women.

Using cervical smears obtained as part of routine gynaecological examinations, a retrospective study of the effects of the drug tamoxifen on squamous epithelial maturation of the cervix of post-menopausal women being treated for advanced breast cancer was made. The degree of squamous epithelial maturation was quantitated by using the Maturation Index and the Maturation Value. Although tamoxifen is a synthetic, non-steroidal compound classified as anti-oestrogenic, the findings indicate that this drug commonly produces a level of squamous maturation indicative of oestrogenic stimulation in Papanicolaou stained cervical smears from post-menopausal patients receiving this drug. Knowledge of the oestrogenic effect of tamoxifen in the cervix can obviate clinical concern about endometrial carcinoma.

Adenocarcinoma↗
PubMed1989

Octanoic acid inhibits astrocyte volume control: implications for cerebral edema in Reye's syndrome.

Octanoic acid has been implicated in the pathogenesis of cytotoxic cerebral edema in Reye's syndrome. Using astrocytes from primary culture, we studied the dose-dependent effects of octanoate on cellular volume regulation and metabolism. Astrocyte volume recovery following hypoosmotic swelling was stimulated by 1.0 mM octanoate and inhibited by 3.0 mM octanoate. Parallel effects were obtained at these concentrations on the activity of the Na+,K+-dependent ATPase. Cellular ATP concentrations also were reduced 36% with the higher octanoate concentration. These effects of octanoate may contribute to the severe astrocyte swelling observed in the brains of Reye's syndrome patients.

Adenosine Triphosphate↗
PubMed1989

Cerebral oxygenation and blood flow in infant and young adult rats.

In vitro cerebral oxidative metabolism undergoes dramatic increases in infant rats between 10 and 20 days of age. To determine this was also the case in vivo, comparisons were made of cerebral blood flow (CBF) and oxygenation in rats at 10, 20, and 60-90 days of age, under pentobarbital sodium anesthesia. Measurements were made of CBF, arterial and venous O2 content, cerebral PO2 distributions, and the oxidation state of cytochrome-c oxidase (cytochrome aa3). CBF, O2 delivery, and O2 consumption all increased progressively with maturation. In contrast, cerebral PO2, cytochrome aa3 oxidation state, and O2 extraction fraction were higher in 20-day-old rats than in either 10-day-old or adult rats. We attribute this difference primarily to the high density of cerebral capillaries in the 20-day-old rat. We conclude that cerebral tissue PO2 and the oxidation state of cytochrome aa3 are determined by the density of perfused capillaries in addition to the more commonly accepted factors of cerebral O2 delivery and consumption.

Animals↗
PubMed1989

Six-year results of the Eastern Cooperative Oncology Group trial of observation versus CMFP versus CMFPT in postmenopausal patients with node-positive breast cancer.

The Eastern Cooperative Oncology Group (ECOG) trial of adjuvant cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen (CMFPT) for 1 year compared with observation alone in 265 postmenopausal patients with node-positive breast cancer is reported with 74 months median follow-up. Overall relapse-free survival tended to favor CMFPT (P = .08), but no survival differences existed between any treatment group. The addition of tamoxifen to CMFP led to slightly (but not significantly) better relapse-free status in all subgroups analyzed. Subgroup analysis based on stratification variables showed significant benefit from CMFP (+/- T) only in estrogen receptor (ER)-negative patients with respect to disease-free status (P = .0003), but not survival (P = .54). Relapse-free status was actually worse for CMFP-treated patients with ER-positive tumors, but not significantly so (P = .15). By multivariate analysis other significant risk factors for relapse-free status were primary tumor size, number of nodes pathologically involved, and the number of nodes examined. ER status was prognostic only for the observation group with the benefit from chemotherapy on ER-negative patients obliterating this difference in treated patients. Survival was affected by the number of involved nodes, tumor size, presence of tumor necrosis, and patient obesity. Analysis of toxicity showed elevation of liver enzymes during the first year to be more common in the observation group compared with those patients receiving adjuvant treatment and to be associated with early recurrence. Toxicity from adjuvant treatment persisted beyond termination of therapy in 53% of patients, but was usually mild and self-limited. We conclude CMFPT offers relapse-free survival benefit in ER-negative patients, but the value of chemotherapy in ER-positive postmenopausal, node-positive patients must be questioned.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Plasma free thyroxine concentrations in patients receiving levothyroxine for thyroid suppression.

The usual recommendation is to follow total triiodothyronine (T3) concentration during levothyroxine (L-thyroxine) therapy because 65% of clinically euthyroid patients receiving L-thyroxine have normal T3 but elevated total thyroxine (T4) levels. Because free thyroxine (FT4) is the metabolically active form of T4, our study was designed to determine whether FT4 by analog radioimmunoassay method is normal or increased in euthyroid patients receiving L-thyroxine. Twenty-seven clinically euthyroid patients, 5 males and 22 females, receiving L-thyroxine for thyroid suppression, were studied in a prospective protocol. Twenty-one euthyroid patients not receiving L-thyroxine served as controls. Samples were analyzed for T4, T3, T3 (RU), TSH, and FT4 by three analog methods. Mean FT4 levels were greater than control for all three assays. The percentage of patients with FT4 in the hyperthyroid range was 63% for assay I, 41% for assay II, and 52% for assay III. When patients were grouped by dose of L-thyroxine, FT4 levels were not significantly increased. Sixty-two percent of patients receiving L-thyroxine had T4 levels in the hyperthyroid range. T3 concentrations were not significantly greater in the L-thyroxine group when compared with control. In the L-thyroxine group, thyrotropin was significantly less than in the control group. FT4 concentration by analog method is in the hyperthyroid range in as many as 63% of clinically euthyroid patients receiving L-thyroxine. The use of FT4 to assess thyroid status may cause inappropriate adjustment of L-thyroxine dose. T3 level continues to parallel closely the physician's clinical impression and best represents peripheral metabolic status.

Adenocarcinoma↗
PubMed1988

Reduction of dye coupling in glial cultures by microinjection of antibodies against the liver gap junction polypeptide.

Intracellular injection of antibodies to the 27-kDa liver gap junction polypeptide have been shown previously to uncouple pairs of cultured mammalian hepatocytes, cardiac myocytes, and ganglionic neurons (Proc. Natl. Acad. Sci. U.S.A., 82 (1985) 2412-2416). In confluent primary cultures of astrocytes, similar injections significantly reduced dye coupling for cells closer than 80 micron to the injected glial cell. Western blots identified a 27-kDa protein in extracts of the astrocyte cultures that cross-react with the gap junction-specific antibodies. These results suggest that homologous gap junction polypeptides exist in liver and glial cells.

Animals↗
PubMed1988

Intracellular acidification inhibits the proliferative response in BALB/c-3T3 cells.

One of the earliest events to occur upon the addition of serum to quiescent cells is an increase in the intracellular pH (pHin). The relationship between this pH change and proliferation is not known. In the present study, we investigate the consequences of acidifying the cytosol using the weak acid, 5', 5"-dimethyl oxazolidine 2,4-dione (DMO). At a concentration of 50 mM, DMO inhibits the serum-induced increases in pHin, DNA synthesis, and cell number. This concentration of DMO is shown not to inhibit the steady-state rate of mitochondrial respiration and not to inhibit DNA synthesis in a pH-independent fashion. The effects of DMO treatments are also shown to be reversible, indicating that this compound is not cytotoxic. These observations indicate that DMO inhibits cell proliferation by lowering intracellular pH. One important event that must occur prior to the initiation of DNA synthesis is an elevated rate of protein synthesis. The rate of protein synthesis in situ is extremely pH sensitive. Addition of 50 mM DMO to serum-stimulated cultures reduces the rate of leucine incorporation to unstimulated levels. These observations suggest that cytoplasmic acidification may inhibit proliferation through its effects on protein synthesis.

Animals↗
PubMed1987

Lead toxicity in primary cultured cerebral astrocytes and cerebellar granular neurons.

Neurons are more sensitive than astrocytes to lead toxicity in vivo. In order to understand the bases for the differences in brain cell responses to lead, the effects of lead acetate on cell morphology and on aerobic energy metabolism were studied in rat primary cultured neurons and astrocytes. By transmission electron microscopy, neuronal cell damage was seen with exposure to lead concentrations which were much lower than those required for similar changes in the astrocyte. As previously described in our studies of in vivo lead exposure, astrocytes in primary culture concentrated lead in nuclear, cytoplasmic, and lysosomal inclusions while neurons showed lead densities only in lysosomes. With acute lead exposures, inhibition of maximal respiratory capacity was greater and occurred at lower lead concentrations in neurons than in astrocytes. Similarly, respiratory rates were inhibited at lower lead concentrations in cerebral cortical slices from 8-day-old rat pups compared to those from adults. We conclude that primary cultured brain cells are appropriate in vitro systems for studying the in vivo cellular responses to lead. As in vivo, neurons are more sensitive than astrocytes to lead toxicity. In both cells, inhibition of aerobic energy metabolism appears to be closely associated with cell damage. The capacity of the astrocyte to sequester lead in nonmitochondrial intracellular sites may be critical in resistance to lead toxicity in vitro and in the mature brain.

Animals↗
PubMed1987

Brain cellular and mitochondrial respiration in media of altered pH.

This study was designed to investigate the effects of altered pH on cellular aerobic energy metabolism in the immature and adult rat cerebral cortex. Cerebral cortical slice respiration was measured polarographically in acid and alkaline media. In separate experiments, the extracellular pH was changed by altering the HCO3- concentration or the intracellular pH and extracellular pH were changed by altering the CO2. Respiratory rates and oxidative phosphorylation in adult rat cerebral mitochondria also were measured in media with an altered pH. Increased intracellular pH inhibited respiratory rates in cortical slices from immature rats more than in tissue from adults. Decreasing the pH to 6.7 produced no changes in respiration in mature cortical slices and moderate inhibition of immature tissue respiration. In cerebral mitochondria, altered pH caused inhibition of State 3 respiration, respiratory control ratios, and ADP/O ratios. These changes were greater and occurred with smaller pH changes in the alkaline compared to the acid direction. From the results of these studies, we conclude that brain cellular respiration is not affected by moderate decreases in intracellular pH. With increased pH, there is inhibition of cellular and mitochondrial respiration, which may be the mechanism for the rise in lactic acid previously observed to result from hypocarbia in vivo.

Aging↗
PubMed1986

Energy-dependent volume regulation in primary cultured cerebral astrocytes.

Cell volume regulation and energy metabolism were studied in primary cultured cerebral astrocytes during exposure to media of altered osmolarity. Cells suspended in medium containing 1/2 the normal concentration of NaCl (hypoosmotic) swell immediately to a volume 40-50% larger than cells suspended in isoosmotic medium. The cell volume in hypoosmotic medium then decreases over 30 min to a volume approximately 25% larger than cells in isoosmotic medium. In hyperosmotic medium (containing twice the normal concentration of NaCl), astrocytes shrink by 29%. Little volume change occurs following this initial shrinkage. Cells resuspended in isoosmotic medium after a 30 min incubation in hypoosmotic medium shrink immediately to a volume 10% less than the volume of cells incubated continuously in isoosmotic medium. Thus, the regulatory volume decrease (RVD) in hypoosmotic medium involves a net reduction of intracellular osmoles. The RVD is partially blocked by inhibitors of mitochondrial electron transport but is unaffected by an inhibitor of glycolysis or by an uncoupler of oxidative phosphorylation. Inhibition of RVD by these metabolic agents is correlated with decreased cellular ATP levels. Ouabain, added immediately after hypoosmotic induced swelling, completely inhibits RVD, but does not alter cell volume if added after RVD has taken place. Ouabain also inhibits cell respiration 27% more in hypoosmotic medium than in isoosmotic medium indicating that the (Na,K)-ATPase-coupled ion pump is more active in the hypoosmotic medium. These data suggest that the cell volume response of astrocytes in hypoosmotic medium involves the net movement of osmoles by a mechanism dependent on cellular energy and tightly coupled to the (Na,K)-ATPase ion pump. This process may be important in the energy-dependent osmoregulation in the brain, a critical role attributed to the astrocyte in vivo.

Adenosine Triphosphate↗