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Biomedical subjects

K L White

Publications and source records attributed to K L White.

At least 37 records · Page 2Linked to original sources
PubMed2001

Evaluation of the immunomodulatory effects of the macrolide antibiotic, clarithromycin, in female B6C3F1 mice: a 28-day oral gavage study.

The macrolide antibiotic, clarithromycin, is used extensively to treat bacterial infections associated with pneumonia, duodenal ulcers, and the advanced stages of human immunodeficiency viral (HIV) infection. In addition to its antimicrobial properties, several studies have indicated that clarithromycin also has anti-inflammatory and immunomodulatory properties. In this study, clarithromycin's immunomodulatory properties were evaluated using female B6C3F1 mice and a panel of immune assays that were designed to evaluate potential changes in innate, and acquired cellular and humoral immune responses. Female B6C3F1 mice were treated daily by gavage with clarithromycin (0, 125, 250, and 500 mg/kg) for 28 days then evaluated for immunomodulation. Minimal immunological changes were observed after 28 days of treatment. A slight increase in the number of spleen antibody-forming cells was observed at the 250 mg/kg treatment level, but not at other doses. Serum IgM levels were unaffected by the clarithromycin treatment. A significant increase in the number of splenic macrophages was also observed in mice treated with 125 mg/kg of clarithromycin, but this increase was not observed at the other treatment levels. Innate and cell-mediated immunity, as measured by natural killer cell activity, and mixed leukocyte and cytotoxic T cell response, respectively, were unchanged following treatment with clarithromycin. These results suggest that the immune system is not a target for clarithromycin at doses of 500 mg/kg or below.

Adjuvants, Immunologic↗
PubMed2001

Evaluation of the immunomodulatory effects of the disinfection by-product, sodium chlorite, in female B6C3F1 mice: a drinking water study.

Sodium chlorite is an inorganic by-product of chlorine dioxide formed during the chlorination of drinking water. Relatively little is known about the adverse health effects of exposure to sodium chlorite in drinking water. In this study, we evaluated sodium chlorite's immunomodulatory properties using female B6C3F1 mice and a panel of immune assays that were designed to evaluate potential changes in innate and acquired cellular and humoral immune responses. Female B6C3F1 mice were exposed to sodium chlorite in their drinking water (0, 0.1, 1, 5, 15, and 30 mg/L) for 28 days, and then evaluated for immunomodulation. Overall, minimal toxicological and immunological changes were observed after exposure to sodium chlorite. Increases in the percentages of blood reticulocytes, and the relative spleen weights were both observed at different sodium chlorite treatment levels; however, these increases were not dose-dependent. An increasing trend in the number of spleen antibody-forming cells was observed over the range of sodium chlorite concentrations. This increase was not, however, significant at any individual treatment level, and was not reflected by changes in serum IgM levels. A significant increase (26%) in the total number of splenic CD8+ cells was observed in mice treated with 30 mg/L of sodium chlorite, but not at the other concentrations. Splenic mixed leukocyte response and peritoneal macrophage activity were unaffected by sodium chlorite. Lastly, exposure to sodium chlorite did not affect natural killer cell activity, although a decrease in augmented natural killer cell activity (42%) was observed at the lowest sodium chlorite treatment level. These results suggest that sodium chlorite, within the range 0.1-30 mg/L, produces minimal immunotoxicity in mice.

Adjuvants, Immunologic↗
PubMed2001

Somatic cell cloning in Buffalo (Bubalus bubalis): effects of interspecies cytoplasmic recipients and activation procedures.

Successful nuclear transfer (NT) of somatic cell nuclei from various mammalian species to enucleated bovine oocytes provides a universal cytoplast for NT in endangered or extinct species. Buffalo fetal fibroblasts were isolated from a day 40 fetus and were synchronized in presumptive G(0) by serum deprivation. Buffalo and bovine oocytes from abattoir ovaries were matured in vitro and enucleated at 22 h. In the first experiment, we compared the ability of buffalo and bovine oocyte cytoplasm to support in vitro development of NT embryos produced by buffalo fetal fibroblasts as donor nuclei. There were no significant differences (p > 0.05) between the NT embryos derived from buffalo and bovine oocytes, in fusion (74% versus 71%) and cleavage (77% versus 75%) rates, respectively. No significant differences were also observed in blastocyst development (39% versus 33%) and the mean cell numbers of day 7 cloned blastocysts (88.5 +/- 25.7 versus 51.7 +/- 5.4). In the second experiment, we evaluated the effects of activation with calcium ionophore A23187 on development of NT embryos after electrical fusion. A significantly higher (p < 0.05) percentage of blastocyst development was observed in the NT embryos activated by calcium ionophore and 6-DMAP when compared with 6-DMAP alone (33% versus 17%). The results indicate that the somatic nuclei from buffalo can be reprogrammed after transfer to enucleated bovine oocytes, resulting in the production of cloned buffalo blastocysts similar to those transferred into buffalo oocytes. Calcium ionophore used in conjunction with 6-DMAP effectively induces NT embryo development.

Adenine↗
PubMed2001

Pathways involved in RGD-mediated calcium transients in mature bovine oocytes.

An arginine-glycine-aspartic acid (RGD)-containing peptide has been reported to generate calcium transients in bovine oocytes similar to those observed at fertilization. The research objective herein was to evaluate the response of bovine oocytes to an RGD peptide after injection with known antagonists of calcium releasing mechanisms in order to determine the initial calcium releasing pathway. Oocytes were injected with either heparin, an inhibitor of inositol 1,4,5-trisphosphate (IP3) induced calcium response, or procaine, which inhibits calcium release through the ryanodine receptor. Oocytes injected with heparin prior to RGD exposure did not display a calcium response. Oocytes injected with procaine prior to RGD exposure did exhibit a calcium response. Electroporation of IP3, caffeine, or exposure to RGD alone elicited a calcium response for each treatment group. Injection of heparin, procaine, vehicle medium (VM), or exposure to a non-RGD-containing peptide alone failed to elicit a calcium response. The data indicates that the RGD peptide is able to induce calcium transients in oocytes inhibited with procaine, but not those inhibited with heparin. These data suggest the pathway whereby the RGD peptide induces the first intracellular calcium transient in bovine oocytes is through IP3-mediated stores.

Animals↗
PubMed2001

Genistein modulates immune responses and increases host resistance to B16F10 tumor in adult female B6C3F1 mice.

The isoflavone genistein (4,7,4'-trihydroxyisoflavone) is a phytoestrogen found in high levels in soy products that has been associated with decreased incidences of breast and prostate cancers. The potential effects of genistein on the immune system were evaluated in adult female B6C3F1 mice. Groups of mice were exposed to vehicle or genistein by gavage for 28 d. The doses of genistein used were 2, 6 and 20 mg/kg body. Consistent with the chemopreventive effect of genistein, exposure to this compound significantly increased host resistance to B16F10 tumor as reflected by a decrease in the number of lung tumor nodules after tumor cell injection at the middle and high dose levels. Inhibition of B16F10 tumor formation was not due to a direct effect of serum genistein and/or its metabolites on the proliferation of B16F10 tumor cells. When innate and acquired immune responses were evaluated, a dose-related increase of cytotoxic T-cell activity was observed in genistein-treated mice with significant changes observed at the middle and high dose levels. Furthermore, in vitro interleukin (IL)-2-stimulated natural killer (NK) cell activity was significantly enhanced in the high genistein dose group, although the basal NK cell activity was not affected. Although no affect on the mixed lymphocyte responses and anti-CD3 antibody-mediated splenocyte proliferation was observed, exposure to genistein significantly increased basal splenocyte proliferation. Exposure to genistein did not alter the activity of the mononuclear phagocyte system and the cytotoxic/cytostatic function of thioglycollate-recruited peritoneal cells on B16F10 tumor cells. Finally, exposure to genistein did not produce biologically meaningful changes in spleen immunoglobulin (Ig)M and IgG antibody-forming cell responses. In conclusion, genistein enhanced host resistance as evaluated in the B16F10 tumor model, which may be related to the increases in the activities of cytotoxic T cells and NK cells.

Animals↗
PubMed2001

Levels of malondialdehyde-deoxyguanosine in the gastric mucosa: relationship with lipid peroxidation, ascorbic acid, and Helicobacter pylori.

Helicobacter pylori infection is associated with elevated gastric mucosal concentrations of the lipid peroxidation product malondialdehyde and reduced gastric juice vitamin C concentrations. Malondialdehyde can react with DNA bases to form the mutagenic adduct malondialdehyde-deoxyguanosine (M(1)-dG). We aimed to determine gastric mucosal levels of M(1)-dG in relation to H. pylori infection and malondialdehyde and vitamin C concentrations. Patients (n = 124) attending for endoscopy were studied. Levels of antral mucosal M(1)-dG were determined using a sensitive immunoslot-blot technique; antral mucosal malondialdehyde was determined by thiobarbituric acid extraction, and gastric juice and antral mucosal ascorbic acid and total vitamin C were determined by high-performance liquid chromatography. Sixty-four H. pylori-positive patients received eradication therapy, and endoscopy was repeated at 6 and 12 months. Levels of M(1)-dG did not differ between subjects with H. pylori gastritis (n = 85) and those with normal mucosa without H. pylori infection (n = 39; 56.6 versus 60.1 adducts/10(8) bases) and were unaffected by age or smoking habits. Malondialdehyde levels were higher (123.7 versus 82.5 pmol/g; P < 0.001), gastric juice ascorbic acid was lower (5.7 versus 15.0 micromol/ml; P < 0.001), and antral mucosal ascorbic acid was unchanged (48.0 versus 42.7 micromol/g) in H. pylori gastritis compared with normal mucosa. Multiple regression analysis revealed that M(1)-dG increased significantly with increasing levels of malondialdehyde, antral ascorbic acid, and total antral vitamin C. M(1)-dG levels were unchanged 6 months (63.3 versus 87.0 adducts/10(8) bases; P = 0.24; n = 38) and 12 months (66.7 versus 77.5 adducts/10(8) bases; P = 0.8; n = 13) after successful eradication of H. pylori. M(1)-dG thus is detectable in gastric mucosa, but is not affected directly by H. pylori.

Adult↗
PubMed2000

Carbon tetrachloride is immunosuppressive and decreases host resistance to Listeria monocytogenes and Streptococcus pneumoniae in female B6C3F1 mice.

Carbon tetrachloride (CCl(4)) is an environmental contaminant that has been detected in ambient air, seawater, surface-water and snow. The immunotoxic potential of CCl(4) was evaluated in female B6C3F1 mice. The animals were administered with CCl(4) daily for 14 days at doses of 50, 100, 500 or 1000 mg/kg body weight by gavage with corn oil as a vehicle. Exposure to CCl(4) resulted in an increase of liver weight but not the body weight and the weights of brain, spleen, lungs, thymus and kidneys. Exposure to CCl(4) produced minimal effect on differential hematological parameters; however, it produced a significant increase in serum glutamic-pyruvic transaminase (SGPT) levels in all dose groups while other serum chemistries showed sporadic increases, primarily at the dose level of 1000 mg/kg. Exposure to CCl(4) produced a decreased humoral immune response; the IgM antibody forming cell (AFC) response to sheep red blood cells (sRBC) was suppressed with the maximal decrease (45%) observed at the dose level of 1000 mg/kg. The IgM serum titer to sRBC was also reduced with a maximal decrease (54%) observed at the dose level of 500 mg/kg. Although exposure to CCl(4) had no effects on the mixed leukocyte response (MLR), cytotoxic T lymphocyte activity and natural killer (NK) cell activity, a decrease in both the absolute number and the percentage of CD4(+)CD8(-) at the dose level of 500 mg/kg was observed. The functional activity of the mononuclear phagocyte system was compromised as reflected by a decrease in the vascular clearance of (51)Cr-sRBC and a decrease in the uptake of (51)Cr-sRBC by the liver. Finally, in the two host resistance models evaluated, exposure to CCl(4) decreased host resistance to both Streptococcus pneumoniae and Listeria monocytogenes with greater susceptibility to the latter. Overall, these studies demonstrate that CCl(4) was immunosuppressive in female B6C3F1 mice.

Alanine Transaminase↗
PubMed2000

Ontogenic and nutritionally induced changes in fetal metabolism in the horse.

1. Using the Fick principle and tracer methodology, the metabolic rates of chronically catheterized fetal foals (n = 24) were measured at different gestational ages during the second half of gestation and in response to maternal fasting for 36 h in late gestation (n = 4, term approximately 335 days). 2. Absolute rates of umbilical blood flow, fetal glucose utilization and umbilical uptake of oxygen (O2) and glucose increased from mid-gestation to 300 days and then plateauxed until term. The absolute rate of umbilical lactate uptake was significant after, but not before, 280 days of gestation. Weight specific rates of umbilical uptake and fetal utilization of glucose decreased progressively throughout the second half of gestation. 3. Weight specific rates of CO2 production from glucose carbon were also inversely correlated with gestational age. Umbilical lactate uptake per kilogram of fetus was lower after 320 days than between 281 and 300 days. In contrast, no gestational trends were observed in the weight specific rates of fetal O2 uptake and urea production. Glucose production by the fetal horse was negligible, even very close to term. 4. Maternal fasting for 36 h reduced the rate of umbilical uptake and utilization of glucose production but had no effect on the rates of endogenous glucose production and umbilical uptake of oxygen and lactate by the horse fetus. 5. The observations show that fetal metabolism is highly dependent on glucose in the horse compared to the sheep in mid- and late gestation. Different species therefore adopt different strategies in meeting the nutritional demands of the growing fetus during the second half of gestation.

Animal Nutritional Physiological Phenomena↗
PubMed2000

In vivo DNA damage in gastric epithelial cells.

A number of risk factors have been linked epidemiologically with gastric cancer, but studies of DNA damage in gastric epithelial cells are limited. The comet assay is a simple technique for determining levels of DNA damage in individual cells. In this study, we have validated the comet assay for use in epithelial cells derived directly from human gastric biopsies, determined optimal conditions for biopsy digestion and investigated the effects of oxidative stress and digestion time on DNA damage. Biopsies taken at endoscopy were digested using combinations of pronase and collagenase, ethylenediaminetetra-acetic acid (EDTA) and vigorous shaking. The resultant cell suspension was assessed for cell concentration and epithelial cell and leukocyte content. A score for DNA damage, the comet %, was derived from the cell suspension, and the effect of various digestion conditions was studied. Cells were incubated with H(2)O(2) and DNA damage was assessed. Pronase and collagenase provided optimum digestion conditions, releasing 1. 12x10(5) cells per biopsy, predominantly epithelial. Of the 23 suspensions examined, all but three had leukocyte concentrations of less than 20%. The comet assay had high inter-observer (6.1%) and inter-assay (4.5%) reproducibility. Overnight storage of the biopsy at 4 degrees C had no significant effect on DNA migration. Comet % increased from a median of 46% in untreated cells to 88% in cells incubated for 45 min in H(2)O(2) (p=0.005). Serial 25-min digestions were performed on biopsies from 13 patients to release cells from successively deeper levels in the crypt. Levels of DNA migration were significantly lower with each digestion (r=-0.94, p<0.001), suggesting that DNA damage is lower in younger cells released from low in the gastric crypt. The comet assay is a reproducible measure of DNA damage in gastric epithelial cells. Damage accumulates in older, more superficial cells, and can be induced by oxidative stress.

Biopsy↗
PubMed2000

Thalidomide stimulates splenic IgM antibody response and cytotoxic T lymphocyte activity and alters leukocyte subpopulation numbers in female B6C3F1 mice.

Thalidomide has been shown to have antiinflammatory and, more recently, immunomodulating properties, which are beneficial for the treatment of an ever-increasing list of immune related diseases. Although considerable knowledge regarding thalidomide s antiinflammatory properties has been acquired, relatively little is known about its immunomodulating properties in vivo. In this paper, a panel of immune assays was used to evaluate immunomodulation in female B6C3F1 mice treated intraperitoneally for 28 days with thalidomide (30, 100, or 150 mg/kg/day). Spleen antibody forming cell response was significantly enhanced by 37% in mice treated with 150 mg/kg/day, despite an 8% decrease in the percentage of Ig+ B cells. A significant stimulatory trend was observed for the cytotoxic T cell response across thalidomide treatment groups. An evaluation of the spleen leukocyte subpopulations revealed a 23% increase in the absolute number of CD8+ T cells in the 150 mg/kg treatment group and a 9 and 11% decrease in the absolute number of NK cells in both the 100 and 150 mg/kg thalidomide treatment groups, respectively. These findings demonstrate that, in addition to modulating spleen leukocyte numbers, thalidomide also stimulates murine humoral and cellular immune responses in vivo.

Animals↗
PubMed2000

Assessment of autoimmunity-inducing potential using the brown Norway rat challenge model.

The development of autoimmune disease in humans is thought to occur as a result of the interactions of a genetic predisposition of the host and environmental factors. There is evidence that treatment with certain drugs and exposure to environmental toxicants increase the risk associated with the development and severity of autoimmune disease. When exposed to certain chemicals, Brown Norway (BN) rats develop autoimmune disease similar to human systemic lupus erythematosus (SLE) characterized by elevation of antibody levels to self and non-self antigens which can result in the formation of immune complexes and lead to a fatal glomerulonephritis. A unique characteristic of the BN rat model is that the increase in IgE is self-limiting with levels eventually returning to normal. The objective of these studies was to determine if the BN rat and the self-limiting nature of the IgE response could be used in identifying compounds capable of initiating autoimmune responses. Two compounds known to produce autoimmunity, mercuric chloride and D-penicillamine, were studied as were, trichloroethylene and silicone gel, two agents suspected of inducing autoimmune disease. The results indicated that the BN rat model may prove useful for detecting compounds with the potential to produce autoimmunity, particularly if a HgCl(2) challenge is incorporated into the evaluation.

Animals↗
PubMed2000

Differential protection by rat UDP-glucuronosyltransferase 1A7 against Benzo[a]pyrene-3,6-quinone- versus Benzo[a]pyrene-induced cytotoxic effects in human lymphoblastoid cells.

UDP-glucuronosyltransferase 1A7 (UGT1A7) is a polyaromatic hydrocarbon (PAH)-inducible UGT with activity toward various benzo[a]pyrene (B[a]P) metabolites. To investigate the influence of rat UGT1A7 on B[a]P-induced cytotoxicity, human lymphoblastoid L3 cells were transfected with pMF6 (control expression vector), p167Dtk2 (microsomal epoxide hydrolase expression vector), or p167Dtk2-1A7 (epoxide hydrolase/UGT1A7 coexpression vector), and the cell populations were compared for sensitivity to B[a]P-induced effects. B[a]P inhibited cell proliferation and decreased relative cell survival of p167Dtk2 and p167Dtk2-1A7 cells to a similar extent. Metabolism studies using [(3)H]B[a]P revealed increased formation of glucuronide conjugates of B[a]P-4,5-diol, 3-OH-, or 9-OH-B[a]P and an unidentified metabolite by p167Dtk2-1A7 cells, but the presence of unconjugated metabolites suggested that glucuronidation capacity may be limited. No differences between p167Dtk2 and p167Dtk2-1A7 L3 cells were observed in the growth inhibitory effects of 3-OH-B[a]P or B[a]P-7,8-diol, but p167Dtk2-1A7-expressing cells were found to be less sensitive to B[a]P-3,6-quinone-induced effects on cell proliferation and relative cell survival. The effect was also observed in AHH-1 lymphoblastoid cells expressing UGT1A7 without epoxide hydrolase. The UGT1A7-expressing AHH-1 cells were also less sensitive to growth inhibition by B[a]P-1,6-quinone and B[a]P-6,12-quinone. Flow cytometric analysis of vehicle and B[a]P-3, 6-quinone-exposed cell populations showed an association between UGT1A7 expression and resistance to B[a]P-3,6-quinone-induced apoptosis and loss of cell viability. These data suggest that UGT1A7 may be preferentially active toward B[a]P-quinones and that UGT1A7 may represent the PAH-inducible UGT activity previously implicated in protection against toxic redox cycling by B[a]P-3,6-quinone.

Animals↗
PubMed2000

Medical education, research, and scientific thinking in the 21st century (part one of three).

BACKGROUND: During the 20th century medical education has been preoccupied largely with discussions of the venues and methods for teaching. Little attention has been paid to what should be learned about the scientific paradigm underlying research and practice. A 17th century model has gradually produced a technically efficient but increasingly narrow, monocausal, reductionistic view of health and disease. This "belief system" fails to accommodate or explain the meaning and impact on patients' health of diverse internal and external experiences and influences. During this period new physics and systemic views of biosystems have extended the Newtonian scientific paradigm beyond its materialistic boundaries, which still determines most of the medical sciences. METHODS: A broad range of historical and contemporary scientific literature is examined in support of four central questions addressed in this three-part series: Is there a reason to examine these matters now? How is medical scientific thinking influenced by the general reorientation of science during the 20th century? Is there is a reason to examine the impact of these changes on medicine now? Will a change of paradigm affect medical practice, research, and education? RESULTS: The extraordinarily productive contemporary biomedical model should be expanded to include meaningful information about how each patient's experiences impinge on health status. CONCLUSIONS: Family physicians, together with collaborators in the biological and behavioral sciences and other health professionals, should undertake rigorous research to establish the validity of the expanded paradigm espoused. Its impact could be profound on practice, research, education, and policies.

Journal Article↗
PubMed2000

Medical education, research, and scientific thinking in the 21st century (part two of three).

BACKGROUND: During the 20th century medical education has been largely preoccupied with discussions of the venues and methods for teaching. Little attention has been paid to what should be learned about the scientific paradigm underlying research and practice. A 17th century model has gradually produced an increasingly narrow, monocausal, reductionistic view of health and disease. Much good has resulted, but this "belief system" fails to accommodate or explain the meaning and impact on patients' health of diverse internal and external experiences and influences. During this period quantum mechanics and its ever-expanding capacity to accommodate new information and enhance understanding have superseded Newtonian physics in much scientific thinking. METHODS: A broad range of historical and contemporary scientific literature is examined in support of four central questions in this three-part series: (1) Are there reasons to examine these matters now? (2) How is medical scientific thinking influenced by the general reorientation of science during the 20th century? (3) Are there reasons now to examine the impact of these changes on medicine? (4) Will a change of paradigm affect medical practice, research, and education? RESULTS: The extraordinarily productive contemporary biomedical model should be expanded beyond the physical and biological to incorporate meaningful information about how each patient's experiences impinge on health status. CONCLUSIONS: Family and other primary care physicians together with collaborators in the biological and behavioral sciences and other health professions should undertake rigorous research to establish the validity of the expanded paradigm espoused. Its impact on practice, research, education, and policies could be profound.

Journal Article↗