Search PubMed⌕ Search

Biomedical subjects

K L White

Publications and source records attributed to K L White.

At least 145 records · Page 8Linked to original sources
PubMed1988

Enhancement of in vivo and in vitro murine immune responses by the cyclophosphamide metabolite acrolein.

Cyclophosphamide (CY)-mediated immunoenhancement has been attributed to the inhibition of suppressor T-cell generation. In order to exert its effects on the immune system, metabolic activation of CY is required. The metabolite of CY responsible for its immunoenhancing properties are not known. Two reactive metabolites of CY which may inhibit suppressor T-cell generation are phosphoramide mustard and acrolein, compounds known to primarily bind to DNA and sulfhydryl groups, respectively. The objective of this study was to determine whether acrolein and/or phosphoramide mustard are capable of enhancing the immune response in a manner similar to CY. Administration of 100 mumol/kg of acrolein, i.v., to female C57BL/6 x C3H F1 mice 1 day before antigen exposure (sheep red blood cells) resulted in a 50% increase in the delayed-type hypersensitivity response (foot pad swelling). The Day 4 primary humoral immune response to sheep red blood cells was also increased by 88 and 60% after the administration of 30 and 100 mumol/kg acrolein 1 day before sensitization with sheep red blood cells. Exposure of splenocyte cultures to 3 x 10(-7) and 10(-6) M 4-hydroperoxy-CY or acrolein produced significant increases in the in vitro T-dependent antibody-forming cell response. In contrast, the antibody-forming cell response of cultures exposed to 3 x 10(-8) - 10(-4) M phosphoramide mustard did not increase above control levels. These results suggest that acrolein is responsible for the CY-induced enhancement of the immune response. Moreover, the enhancement may be produced by the binding of acrolein to sulfhydryl groups of molecules of cells required for the generation of suppressor T-cells.

Acrolein↗
PubMed1988

Evaluation of the expression of a male-specific antigen on cells of equine blastocysts.

This experiment was designed (1) to determine if H-Y antigen is expressed on the cell surface of pre-implantation equine blastocyst stage embryos, (2) if so, to identify differences in expression on inner cell mass (ICM) verses trophectoderm cells and (3) to evaluate whether the detection of this glycoprotein would aid in the identification of equine embryonic sex. A total of 33 blastocyst stage horse embryos were collected 6-7 days post-ovulation by trans-cervical flush and were immediately evaluated for the presence of H-Y antigen. Additionally, 17 embryos, collected at similar stages and cultured for 72 h, were similarly evaluated. Embryos were recovered and evaluated by use of a dissecting microscope and then washed for 5 min in phosphate buffered saline supplemented with 1 g/l glucose, 36 mg/l pyruvate, 1% antibiotic-antimycotic and 10% fetal calf serum (FCS) (PBS-2). Embryos were placed in the primary antibody medium and cultured for 60 min. The primary antibody medium consisted of monoclonal antibodies to H-Y antigen (previously determined to have male-specific activity) dilute 1/5 (v/v) with PBS-2 (without FCS, PBS-1). Following an additional wash, embryos were cultured in PBS-1 containing 1/10 (v/v) fluorescein isothiocyanate conjugated goat anti-mouse or rabbit antimouse IgM Fc specific antiserum. Embryos were evaluated at 200-400 x to identify cell specific fluorescence of either trophectoderm or ICM cells. Following evaluation, embryonic sex was independently verified with karyotypes to identify sex chromosomes. Of the 50 embryos evaluated, 29 were evaluated as non-fluorescent and 21 fluorescent. Expression of H-Y antigen was detected on both trophectoderm and ICM cell types in those embryos classified as fluorescent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

An immunotoxicological evaluation of 4,4'-thiobis-(6-t-butyl-m-cresol) in female B6C3F1 mice. 1. Body and organ weights, hematology, serum chemistries, bone marrow cellularity, and hepatic microsomal parameters.

Adult female B6C3F1 mice were gavaged with 4,4'-thiobis-(6-t-butyl-m-cresol) (TBBC) in corn oil at doses of 10, 100, or 200 mg/kg daily for 14 consecutive days. There was no overt toxicity, as manifested by grossly observable behavioral changes, decreased growth rate over the exposure period, or mortality. There were also no marked effects on serum chemistries or hematology, with the exception of a significant increase (41%) in the number of leukocytes at the highest dose. Absolute differential counts indicated that significant increases occurred in the number of lymphocytes (31%) and neutrophils (177%). Studies with bone marrow indicated a significant 30% increase in the number of cells/femur from animals treated with the highest dose of TBBC. The number of macrophage progenitors (CFU-M)/femur was significantly increased by 28%, while the number of granulocyte-monocyte progenitors (CFU-GM)/femur was nonsignificantly increased by 20% in the high dose animals. The weight of both the spleen and liver was increased in a dose-related fashion, although the histopathology of the spleen of TBBC-treated mice was not different from control. The livers of mice receiving the high dose showed mild focal hydropic degeneration, mild hepatitis, and a slight increase in the number of Kupffer cells. No other organs were affected. Liver microsomal protein and cytochrome P-450 levels were increased in a dose-related fashion. Enzyme activities of aminopyrine demethylase and aniline hydroxylase, but not arylhydrocarbon hydroxylase, were also increased in a dose-related fashion.

Animals↗
PubMed1988

An immunotoxicological evaluation of 4,4'-thiobis-(6-t-butyl-m-cresol) in female B6C3F1 mice. 2. Humoral and cell-mediated immunity, macrophage function, and host resistance.

Adult female B6C3F1 mice were gavaged with TBBC in corn oil at doses of 10, 100, or 200 mg/kg daily for 14 consecutive days. All immunological parameters were measured 24 hr after the last chemical exposure. When indicated, animals were immunized during the exposure. TBBC produced a decrease in the peak IgM (44%) and peak IgG (48%) antibody response to sheep erythrocytes (SRBCs), but had no effect on the delayed hypersensitivity response (DHR) to keyhole limpet hemocyanin (KLH). Paradoxically, TBBC caused an overall increase in the number of splenic cells, a decrease in the percentage of splenic T cells and no effect on the percentage of splenic B cells. There were no effects on the lymphoproliferative responses to optimal concentrations of concanavalin A (Con A), phytohemagglutinin (PHA), and lipopolysaccharide (LPS), but there was a significant decrease in the mixed lymphocyte response (MLR). In both the mitogen assays and the MLR there was a dose-related increase in the basal (unstimulated) DNA synthesis of the spleen cells. Innate immunity, as measured by natural killer (NK) cell activity and serum complement, was significantly increased. Effects on macrophage function were complex, as an increase or no effect was observed depending on the parameter measured. In the host resistance models, animals were infected with various pathogens 24 hr after the last chemical exposure. Exposure to TBBC caused an increased resistance to challenge with Streptococcus and B16F10 melanoma, a decreased resistance to challenge with PYB6 tumors, and no effect on the resistance to HSV-2, Listeria or Plasmodium.

Animals↗
PubMed1988

In vitro cytocidal effect of novel lytic peptides on Plasmodium falciparum and Trypanosoma cruzi.

Plasmodium falciparum and Trypanosoma cruzi were killed by two novel lytic peptides (SB-37 and Shiva-1) in vitro. Human erythrocytes infected with P. falciparum, and Vero cells infected with T. cruzi, were exposed to these peptides. The result, in both cases, was a significant decrease in the level of parasite infection. Furthermore, the peptides had a marked cytocidal effect on trypomastigote stages of T. cruzi in media, whereas host eukaryotic cells were unaffected by the treatments. In view of the worldwide prevalence of these protozoan diseases and the lack of completely suitable treatments, lytic peptides may provide new and unique chemotherapeutic agents for the treatment of these infections.

Amino Acid Sequence↗
PubMed1988

Evaluation of the presence of a specific histocompatibility protein on equine embryonic cells.

An indirect immunofluorescence assay was used to detect the presence of H-Y antigen on equine blastocysts. A total of 33 blastocyst stage horse embryos were collected 6 to 7 days post-ovulation by trans-cervical flush and were immediately evaluated for the presence of H-Y antigen. Additionally, 17 embryos, were collected and cultured for 72 h to the expanded blastocyst stage and similarly evaluated. Embryos were placed in medium containing monoclonal antibodies to H-Y antigen followed by incubation in medium containing 1/10 (v/v) fluorescein isothiocyanate conjugated goat anti-mouse IgM Fc specific antiserum. Embryos were individually evaluated at 400X to identify cell specific fluorescence. Following evaluation, embryonic sex was independently verified with karyotypes to identify sex chromosomes. Of the 50 embryos evaluated, 29 were evaluated as non-fluorescent and 21 fluorescent. Expression of H-Y antigen was determined to be uniform in those embryos classified as fluorescent. Twenty-three of 28 (82%) readable karyotypes corresponded to the predicted sex. These results indicate a specific histocompatibility antigen is expressed and maintained at the blastocyst stage of development. In addition, no segregation of this protein on specific cell types occurs in this species.

Animals↗
PubMed1987

Suppression of the vitro humoral immune response of mouse splenocytes by benzo(a)pyrene metabolites and inhibition of benzo(a)pyrene-induced immunosuppression by alpha-naphthoflavone.

Several investigators have demonstrated that the humoral immune response of mice and splenocyte cultures was suppressed with benzo(a)pyrene [B(a)P] exposure. The mechanism of the B(a)P immunosuppression, however, has not been established. Since reactive metabolites of B(a)P, rather than the parent compound, have been shown to mediate the carcinogenic effects of B(a)P, it was hypothesized that the immunosuppression produced by B(a)P may also be mediated by its reactive metabolites. The objective of this investigation was to examine the role of B(a)P metabolism in the B(a)P-induced suppression of the in vitro humoral immune response. This was addressed by first determining if various B(a)P metabolites are capable of inhibiting the generation of antibody-forming cells (AFC) of splenocyte cultures. Addition of B(a)P or B(a)P-7,8-diol (2 X 10(-5) M) to splenocyte cultures produced a similar dose-dependent suppression of the in vitro T-dependent AFC response to sheep red blood cells. In contrast, decreases in the AFC response and cell viability of cultures exposed to the 4,5-diol or 9,10-diol were only observed at 2 X 10(-5) M. Exposure of cultures to 3-hydroxy-B(a)P resulted in a significant decrease in the AFC response at 2 X 10(-6) and 2 X 10(-5) M. Slight decreases in the AFC response were observed with the addition of B(a)P-4,5-epoxide or B(a)P-6,12-dione at 2 X 10(-6) M, whereas a dramatic decrease in the AFC response, as well as a 45% decrease in cell viability, was obtained at 2 X 10(-5) M. The second objective was to examine the effects of the cytochrome P-450 inhibitor, alpha-naphthoflavone (ANF), on the B(a)P- and B(a)P-7,8-diol-induced suppression of the in vitro AFC response. Exposure of splenocyte cultures to 2 X 10(-5) M ANF did not affect the AFC response. Coincubation of splenocytes with ANF was observed to attenuate the suppressive effects of B(a)P and B(a)P-7,8-diol. This concentration of ANF was observed to inhibit the metabolism of [3H]B(a)P by splenocyte cultures to water soluble metabolites. Moreover, B(a)P metabolism by splenic microsomal preparations of untreated mice was inhibited by ANF. These findings suggest that the B(a)P-induced suppression of the in vitro AFC response is mediated by B(a)P metabolites generated by cytochrome P-450 present within splenocytes.

Animals↗
PubMed1987

Identification of a male-specific histocompatibility protein on preimplantation porcine embryos.

An indirect immunofluorescence assay was used to detect the presence of male-specific protein(s) on various stages of preimplantation porcine embryos. Embryos were collected at slaughter from the reproductive tracts of day-2.5, -4, -5, -6, and -8 (day 0 = first day of estrus) sows and gilts. Embryos were placed in medium containing an anti-male primary antibody, washed, and transferred to culture drops containing a fluorescein isothiocyanate (FITC)-labeled secondary antibody. Embryos were classified as either fluorescent (H-Y positive) or nonfluorescent (H-Y negative), transferred to coded drops, and karyotyped to examine sex chromosomes. A total of 91 eight-cell to blastocyst stage embryos were evaluated; of these, 46% were classified as fluorescent and 54% as nonfluorescent. Of readable metaphase spreads (65%) from these embryos, 81% (48 of 59, P less than 0.005) were correctly sexed by immunological detection of the male-specific antigen. Although 13% (2/15) of four-cell embryos evaluated were classified as fluorescent, the accuracy with which embryos at this stage were sexed by detection of H-Y antigen was not different from 50%. Fifty percent of eight-cell embryos were classified as H-Y positive with 78% of embryos correctly sexed. It was concluded that the eight-cell embryo is the earliest stage of development for which there is evidence for expression of H-Y antigen. Detection of the male-specific protein was difficult at the expanded blastocyst stage.

Animals↗
PubMed1987

Detection of histocompatibility-Y antigen: identification of sex of pre-implantation ovine embryos.

Indirect immunofluorescence was used to detect the presence of a male-specific protein (H-Y antigen) on pre-implantation ovine embryos. Eight-cell to blastocyst stage embryos were surgically collected from superovulated ewes, classified as fluorescent (H-Y positive) or non-fluorescent (H-Y negative) and either transferred to recipient ewes or karyotyped to confirm embryonic sex. H-Y antigen was detected on eight-cell through blastocyst stage embryos. Overall, 88% (50/57) of the embryos (eight-cell to early blastocyst stage) classified as H-Y positive or H-Y negative were male and female, respectively. Survival after transfer of embryos subjected to the H-Y antigen assay was high (63%), which supports the use of this procedure in conjunction with embryo transfer in sheep to produce pregnancies in which sex of the fetus is known.

Animals↗
PubMed1987

Expression of a male-specific factor on various stages of preimplantation bovine embryos.

Four-cell to blastocyst stage bovine embryos were collected from superovulated donors and cultured for 90 min in Ham's F-10 medium (HF-10) containing 10% (V/V) absorbed anti-histocompatibility (H)-Y antiserum. Embryos were then washed 3 times and placed in HF-10 supplemented with 10% (V/V) fluorescein isothiocynate (FITC)-conjugated goat anti-mouse gamma globulin. After an additional wash, embryos were placed in fresh drops of HF-10, individually evaluated at 200 X magnification, and classified as either fluorescent (H-Y-positive) or nonfluorescent (H-Y-negative). Embryos were then placed in drops of HF-10 containing 14% vinblastin and cultured for 4-6 h. Embryos were coded and individually karotyped, and the sex chromosomes were identified. H-Y antigen was detected as early as the eight-cell stage, but not at the four-cell stage. Seventy-nine percent of fluorescent embryos and 89% of nonfluorescent embryos were XY and XX, respectively. Another experiment was carried out in which H-Y antigen was detected on intact inner cell masses (ICM) isolated by immunosurgery from expanded blastocysts that also had been assayed for H-Y antigen. Eighty-eight and 92%, respectively, of ICM classified as fluorescent or nonfluorescent had been scored the same as intact blastocysts. It is concluded from these data that H-Y antigen can be detected on eight-cell to blastocyst stage bovine embryos. There appears to be a localization of detectable antigen in the area of the ICM at the expanded blastocyst stage. Detection of H-Y antigen is an effective, noninvasive method for identification of the sex of preimplantation bovine embryos.

Animals↗
PubMed1986

Modulation of serum complement levels following exposure to polychlorinated dibenzo-p-dioxins.

Subchronic 14-day exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppressed serum total hemolytic complement activity (CH50) in female B6C3F1 mice at doses of 0.01, 0.05, 0.1, 0.5, 1.0, and 2.0 micrograms/kg. Serum levels of complement component C3 were also suppressed at doses of 0.5, 1.0, and 2.0 micrograms/kg. Another dioxin isomer, 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HCDD), also produced dose-dependent suppression of complement activity at doses of 0.1, 1.0, and 10 micrograms/kg with decreased C3 levels at 10 micrograms/kg. Both TCDD and HCDD enhanced susceptibility to Streptococcus pneumoniae, a bacterial pathogen whose host defense is complement mediated. Recovery studies demonstrated that complement activity in TCDD (1 microgram/kg) and HCDD (10 micrograms/kg)-treated animals was suppressed until 50 days post-treatment, while low doses of HCDD (0.1 and 1.0 micrograms/kg) elevated CH50 levels. Acute exposure to TCDD (14 micrograms/kg) also suppressed complement CH50 and C3 levels. These studies demonstrate that the complement system and innate immunity represent potential target sites for polychlorinated dibenzo-p-dioxins.

Administration, Oral↗
PubMed1986

Suppression of the in vitro humoral immune response by chrysotile asbestos.

The direct addition of UICC chrysotile B asbestos to spleen cell cultures produced a dose-dependent suppression of the antibody-forming cell (AFC) response to the T-dependent antigen, sheep erythrocytes. Concentrations of 0.1, 1, 10, and 100 micrograms/ml, which had no effect on either cell number or viability, suppressed the in vitro response by 12, 43, 71, and 95%, respectively. By separating spleen cells into nonadherent and plastic-adherent populations, the effects of asbestos on each cell type were studied utilizing reconstituted cultures. Treatment of adherent cells for 1 hr with asbestos and reconstitution with untreated nonadherent cells resulted in a dose-dependent suppression of the AFC response similar to that observed when asbestos was added to whole spleen cultures. Reconstitution studies were also conducted with spleen cell populations from animals administered asbestos in vivo. In cultures reconstituted with adherent cells from asbestos-treated mice and nonadherent cells from saline-treated animals, the AFC response was significantly suppressed. The T-dependent AFC response with reconstitution of adherent cells from saline-treated mice and nonadherent cells from asbestos-exposed animals was no different from reconstituted saline controls. Both adherent alveolar and pleural cells were capable of reconstituting the T-dependent AFC response with nonadherent spleen cells and demonstrated reduced immunological capability when exposed to asbestos fibers. The results of this investigation have identified the adherent spleen cell (macrophage) as the target cell type responsible for asbestos-induced immunosuppression of the in vitro T-dependent antibody-forming cell response.

Animals↗
PubMed1986

Effects of hydroxyethylstarch (Hespan), a plasma expander, on the functional activity of the reticuloendothelial system. Comparison with human serum albumin and pyran copolymer.

The purpose of the present investigation was to determine if RES activity was altered after the infusion (bolus i.v. injection over approximately 3-5 min) of hydroxyethylstarch (HES). RES function was determined by vascular clearance of 51Chromium-labeled sheep erythrocytes and the subsequent uptake into the liver, spleen, lungs, and thymus at 1 hr, 3 hr, 6 hr, 1 day, 3 days, and 7 days post infusion. Infusion with the low doses of HES (20 and 40 ml/kg) produced changes in vascular clearance which were comparable to physiological saline. Infusion with 80 ml/kg HES produced a biphasic response with a modest suppression of vascular clearance (i.e., 151% increase in half life) and hepatic phagocytosis (50%) during the first 6 hours after injection, followed by recovery at 24 hours and a stimulation in hepatic uptake (42%) after 3 days. These effects by HES were compared to those produced by infusion with 80 ml/kg HSA, a comparable colloid and with 80 ml/kg pyran copolymer, a positive control.

Animals↗
PubMed1985

Suppression of mouse complement activity by contaminants of technical grade pentachlorophenol.

Pentachlorophenol (PCP) is an antimicrobial agent used chiefly for the preservation of wood. Subchronic oral exposure (14 days) to Technical Grade PCP significantly inhibited the functional activity of female B6C3F1 mouse complement when measured in a microtiter hemolytic assay. When evaluated one day following the final exposure the highest administered dose (100 mg/kg) significantly suppressed the Classical complement pathway, the Spontaneous C1 autoactivation pathway, the Alternate pathway and the level of complement component, C3. Reconstitution studies using C5-deficient serum also demonstrated deleterious effects on this complement component. The Classical pathway was the most sensitive to Technical Grade PCP effects. Animals treated with 100 mg/kg Technical Grade PCP had CH 50 levels 30% of vehicle controls. Animals treated for 14 days and allowed a 15 day recovery period had CH 50 values 36% of control and animals which recovered for 30 days had only 52% of the complement activity of control animals. C3 recovery studies also demonstrated continued suppression on days 15 and 30 post-final exposure. Doses of 10 and 30 mg/kg did not produce the marked effects observed with the highest dose; however, a dose-dependent trend was observed for all responses. Animals treated with 100 mg/kg of EC-7, a PCP preparation with reduced amounts of contaminating dioxins and dibenzofurans, did not demonstrate detrimental effects on the complement system.

Animals↗
PubMed1985

Immunosuppression by polycyclic aromatic hydrocarbons: a structure-activity relationship in B6C3F1 and DBA/2 mice.

The structure-activity relationship of polycyclic aromatic hydrocarbon-induced immunosuppression was investigated using the antibody-forming cell response to sheep erythrocytes. Ten polycyclic aromatic hydrocarbons were evaluated following 14 days of subchronic exposure in female B6C3F1 mice. Additionally, the immunotoxicity of benzo(a)pyrene and 3 of its congeners was evaluated following acute exposure. The immunosuppression observed following both subchronic and acute exposure was similar to the structure-activity relationship observed for the carcinogenicity of the compounds tested. Anthracene, chrysene, benzo(e)pyrene and perylene did not significantly suppress the antibody-forming cell response compared to the corn oil vehicle controls. Benz(a)anthracene, benzo(a)pyrene, dibenz(a,c)anthracene, and dibenz(a,h)anthracene suppressed the antibody-forming cell response by 55 to 91%. The greatest suppression was observed with the 3-methylcholanthrene and 7,12,-dimethylbenz(a)anthracene. Studies using mice with different susceptibility to aryl hydrocarbon hydroxylase induction demonstrated that susceptible mice (B6C3F1) were not as immunosuppressed following exposure to polycyclic aromatic hydrocarbons as were nonsusceptible mice (DBA/2).

Animals↗
PubMed1985

Interpretation and application of world-wide safety data on diltiazem.

The safety of medicinal agents being introduced into the marketplace is of growing concern to consumers, health care providers, and regulatory agencies. Although there are ever increasing efforts to improve techniques for testing drugs, and for anticipating and confirming possible adverse effects, arrangements for monitoring and detecting adverse drug reactions are far from satisfactory. Some factors which need to be understood in order to appropriately interpret data include: maturation processes; pretesting affects, measuring instruments affects; selection bias; and the affects of differential experimental mortality. A safety profile has been presented for the calcium entry blocker diltiazem hydrochloride. Efforts were made to focus attention upon the source of safety information as it relates to the quality of the report. The data presented suggests that diltiazem hydrochloride has a low incidence of adverse experiences.

Adrenergic beta-Antagonists↗