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N Harper

Publications and source records attributed to N Harper.

At least 37 records · Page 2Linked to original sources
PubMed1994

An enzyme-linked immunosorbent assay (ELISA) specific for antibodies to TNP-LPS detects alterations in serum immunoglobulins and isotype switching in C57BL/6 and DBA/2 mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds.

An enzyme-linked immunosorbent assay (ELISA) was developed to detect IgM and IgG antibodies specific for trinitrophenyl-lipopolysaccharide (TNP-LPS). Treatment of C57BL/6 and DBA/2 mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other aryl hydrocarbon (Ah) receptor agonists followed by immunization with TNP-LPS resulted in a dose-dependent decrease in serum IgM which paralleled the decrease in the splenic PFC response. The ED50 values for the IgM and splenic PFCs in C57BL/6 mice for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (pentaCB) and 3,3',4,4',5,5'-hexaCB were 2.8 and 1.6, 11 and 14, and 25 and 20 micrograms/kg, respectively; in the less Ah-responsive DBA/2 mice, the ED50 values were 8.5 and 10, 61 and 69, and 73 and 71 micrograms/kg, respectively. In addition, treatment of C57BL/6 mice with TCDD resulted in alterations of serum IgG relative to IgM and a delay of isotype switching was observed after immunization and boosting with TNP-LPS. This ELISA may prove to be a useful tool in monitoring immune function during long-term exposure of mice to TCDD and related compounds and exploring the mechanism of Ah receptor-mediated immunosuppression.

Animals↗
PubMed1994

Relative sensitivities of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced Cyp1a-1 and Cyp1a-2 gene expression and immunotoxicity in female B6C3F1 mice.

Improvements in risk assessment require better linkage of exposure to response by the determination of target tissue dose. The relative sensitivity of several responses in female B6C3F1 mice was compared on the basis of administered and target tissue dose spanning 3 orders of magnitude. Twenty-four hours after administration, [3H]TCDD was detected in the heart, spleen, kidney, uterus, thymus, lung, and liver, and the highest concentrations were noted in the liver, uterus, and lung. At doses from 5 to 25 ng/kg, hepatic [3H]TCDD levels associated with the cytosolic and nuclear subcellular fractions increased from 12 to 62% of the total liver levels and then decreased at higher doses. At the two lowest doses used in the enzyme induction study, 5 and 10 ng/kg, the levels of specifically bound nuclear Ah receptor complex liganded with [3H]TCDD were 2.3 and 2.5 fmol/mg protein. Slightly higher levels of nuclear Ah receptor complex were observed at doses between 25 and 100 ng/kg (i.e., 3.6 to 4.2 fmol/mg protein) and a steep dose-dependent increase in nuclear Ah receptor levels was noted at doses of 500, 1000, and 5000 ng/kg (8.0, 39.3, and 92.8 fmol/mg protein, respectively). The dose-dependent effects of [3H]TCDD on hepatic Cyp1a-1 and Cyp1a-2 mRNA levels, ethoxyresorufin O-deethylase (EROD) activity, and the splenic antibody plaque-forming cell (PFC) response to sheep red blood cells were also determined; the latter response was determined 9 days after administration of TCDD. Statistically significant induction of hepatic Cyp1a-1 was observed at lower doses (25 ng/kg) than any other marker, followed by induction of EROD and PFCs expressed per spleen or per 10(6) cells which was observed at 100 ng TCDD/kg and at higher doses. Cyp1a-2 was elevated significantly relative to control at doses > or = 1000 ng/kg. The ED50 value for PFCs/10(6) cells was the lowest of the variables analyzed and was not statistically significantly different from control (91 +/- 92 ng/kg). A 50% increase in Cyp1a-2 and Cyp1a-1 mRNA levels was observed at doses of 736 +/- 132 and 1630 +/- 431 ng/kg, respectively. Due to variability in response in PFCs/spleen and the submaximal induction of EROD activity, ED50 values could not be calculated for these responses. The analyses indicate that the immunosuppressive response (when normalized for the number of spleen cells) may be depressed by administered doses as low as 90 ng TCDD/kg body weight. A 50% increase in Cyp1a-1 or Cyp1a-2 was observed at higher administered doses (1630 or 736 ng/kg, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Inhibition of estrogen-induced progesterone receptor in MCF-7 human breast cancer cells by aryl hydrocarbon (Ah) receptor agonists.

17 beta-Estradiol (E2) induces progesterone receptor (PR) binding, immunoreactive protein, nuclear PR formation and PR mRNA levels in MCF-7 human breast cancer cells. Gel mobility shift analysis of nuclear extracts from E2-treated cells also exhibited a higher intensity retarded band associated with formation of a PR complex with a consensus [32P]progesterone/glucocorticoid responsive element. In contrast, 1 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alone did not alter or decrease these same responses in MCF-7 cells; however, in cells co-treated with 1 nM TCDD plus 1 nM E2, TCDD significantly inhibited all the E2-induced responses. Scatchard analysis of PR binding demonstrated that TCDD decreased the number of E2-induced PR cellular binding sites but not the binding affinity of the PR for a radiolabeled promegestrone. In parallel studies, 3-methylcholanthrene, a prototypical polynuclear aromatic hydrocarbon, also inhibited E2-induced PR binding and immunoreactive protein. For a series of halogenated aromatics including 2,3,7,8- and 1,2,7,8-tetrachlorodibenzofuran, 1,3,7,8-TCDD and 6-methyl-1,3,8-trichlorodibenzofuran, their rank order potency for inhibiting E2-induced PR binding paralleled their rank order binding to the aryl hydrocarbon (Ah) receptor. These results support a role for the Ah receptor in mediating the antiestrogenic activity of polynuclear and halogenated aromatic hydrocarbons and illustrate cross-talk between the Ah and estrogen receptor signal transduction pathways.

Blotting, Northern↗
PubMed1993

Immunosuppressive effects of highly chlorinated biphenyls and diphenyl ethers on T-cell dependent and independent antigens in mice.

The dose-dependent effects of 2,2',3,3',4,4',5,5',6-nonachlorobiphenyl (nonaCB), 2,2',3,3',4,4',5,6,6'-nonaCB, 2,2',3,3',4,5,5',6,6'-nonaCB and decaCB on the suppression of the splenic plaque-forming cell (PFC) response to the T-cell-dependent antigen, sheep red blood cells (SRBCs) and the T-cell-independent antigen, trinitrophenyl-lipopolysaccharide (TNP-LPS), were determined in genetically inbred mice. In addition, the induction of hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity was also measured. The highly chlorinated biphenyls suppressed the splenic PFC response to SRBCs in C57BL/6 and DBA/2 mice and were relatively more active in the former strain. The C57BL/6 mice are more responsive to aryl hydrocarbon (Ah) receptor agonists than DBA/2 mice and these data support a possible role for the Ah receptor in mediating this response. However, previous studies with polychlorinated biphenyls (PCBs) indicate that congeners with 3 or 4 ortho-chloro substituents are inactive as Ah receptor agonists and this was consistent with the minimal induction of hepatic microsomal EROD activity by the highly chlorinated biphenyls in both strains of mice. Thus, the results suggest that the inhibition of the splenic PFC response to SRBCs observed in this study was primarily an Ah receptor-independent response. Some of the highly chlorinated diphyenyl ethers namely decachlorodiphenyl ether and 2,2',3,3',4,4',5,6,6'-nonachlorodiphenyl ether, inhibited the antigenic response to TNP-LPS in C57 BL/6 mice. The results indicate that the suppression of the TNP-LPS-mediated immune response may be a more reliable indicator of the Ah receptor-dependent immunotoxicity of halogenated hydrocarbons.

Animals↗
PubMed1993

Immunotoxic potencies of polychlorinated biphenyl (PCB), dibenzofuran (PCDF) and dibenzo-p-dioxin (PCDD) congeners in C57BL/6 and DBA/2 mice.

The dose-dependent effects of a single acute exposure of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 1,2,3,7,9-PeCDF, 1,3,6,8-tetrachlorodibenzofuran (TCDF), 3,3',4,4',5-pentachlorobiphenyl (pentaCB), and 3,3,',4,4',5,5'-hexaCB on the suppression of the splenic plaque-forming cell (PFC) response to the T-cell-independent antigen trinitrophenyl-lipopolysaccharide were determined in C57BL/6 and DBA/2 mice. In addition, the induction of hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity was also measured in these animals. 2,3,7,8-TCDD and 2,3,4,7,8-PeCDF were the most immunotoxic congeners in both strains of mice and with the exception of the latter congener, the ED50 values for each compound were lower in the C57BL/6 than the DBA/2 mice. 2,3,7,8-TCDD induced hepatic microsomal EROD activity in both strains of mice whereas the other congeners were considerably less active or inactive as inducers. The results of this study demonstrated that for the halogenated aromatic hydrocarbons the immunotoxic response was a more sensitive indicator of exposure than the induction of CYP1A1 activity. The rank order for the immunotoxic potencies of the chlorinated aromatic compounds used in this study was 2,3,7,8-TCDD approximately 2,3,4,7,8-PeCDF > 3,3',4,4',5-pentaCB approximately 3,3',4,4',5,5'-hexaCB > 1,2,3,7,9-PeCDF > 1,3,6,8-TCDF. The order of activity for these congeners was similar for other Ah receptor-mediated responses and these results coupled with the differential responsiveness of the C57BL/6 and DBA/2 mice confirms the role of aryl hydrocarbon (Ah) receptor in mediating the suppression of this T-cell-independent response.

Animals↗
PubMed1993

Immunosuppressive and monooxygenase induction activities of highly chlorinated diphenyl ether congeners in C57BL/6 and DBA/2 mice.

The dose-response effects of 2,2',3,3',4,5,5',6,6'-2,2',3,3',4,4',5,6,6'- and 2,2',3,3',4,4',5,5',6- nonachlorodiphenyl ether (non-aCDE) and decachlorodiphenyl ether (decaCDE) on the splenic plaque-forming cell (PFC) response to sheep red blood cells (SRBCs) and the induction of hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity was determined in aryl hydrocarbon (Ah)-responsive C57BL/6 and less Ah-responsive DBA/2 mice. All the congeners exhibited immunotoxicity at doses between 2.5 and 10 mumol/kg in C57BL/6 mice whereas in DBA/2 mice doses > or = 25 mumol/kg were required to cause inhibition of the PFC response to SRBCs. The results also showed that the nonaCDE isomers and decaCDE were more active as inducers of hepatic EROD activity in C57BL/6 than DBA/2 mice; however, there was not a correlation between the induced EROD activity and the CYP1A1 and CYP1A2 mRNA levels in the C57BL/6 mice. These data suggested that the immunotoxicity of these compounds was mediated through the Ah receptor. However, the results showed that the immunotoxicity of the nonaCDE isomers and decaCDE was unexpectedly high compared to that of lower chlorinated diphenyl ethers and there were no apparent structure-activity relationships among the higher chlorinated congeners. This suggests that some of the immunosuppressive effects observed for the nonaCDE isomers and decaCDE may be Ah receptor-independent.

Animals↗
PubMed1993

Synergistic activity of polynuclear aromatic hydrocarbon mixtures as aryl hydrocarbon (Ah) receptor agonists.

The relative potencies of benzo[a]pyrene and a complex mixture of polynuclear aromatic hydrocarbons (PAHs) produced as by-products of manufactured gas plant (MGP) residues as inducers of hepatic microsomal ethoxyresorufin O-deethylase (EROD) activity were determined in the B6C3F1 mouse. The ED50 values for the induction response were 78 and 65 mg/kg for benzo[a]pyrene and the MGP-PAH mixture, respectively. Analysis of the MGP-PAH mixture indicated that benzo[a]pyrene and other compounds containing four or more rings and which are known to induce EROD activity were only present as trace components of this mixture. A comparison of the EROD induction potencies of benzo[a]pyrene and the MGP-PAH mixture showed that the mixture was approximately 706 times more potent than expected based on its benzo[a]pyrene content (0.17%). This induced P-450 activity could significantly increase the metabolism of the carcinogenic PAHs and thereby modulate the overall carcinogenicity of the mixture. The apparent synergistic activity of the MGP-PAH mixture was further investigated by comparing the activities of this mixture and benzo[a]pyrene for several other aryl hydrocarbon (Ah) receptor-mediated responses including (i) induction of hepatic CYP1A1 mRNA levels, (ii) transformation of the rat cytosolic Ah receptor to a complex which binds to a dioxin responsive element, (iii) induction of EROD activity and (iv) antiestrogenicity in MCF-7 human breast cancer cells, and (v) inhibition of the splenic plaque-forming cell (PFC) response to both T cell-dependent and independent antigens in B6C3F1 mice. For the EROD and CYP1A1 mRNA induction and cytosolic transformation activities and immunosuppressive effects, the MGP-PAH mixture was approximately 100-900 times more potent as an Ah receptor agonist than expected based on its benzo[a]pyrene content. The synergistic activity was lower (19-fold) for the antiestrogenic response in MCF-7 cells. The reason for the synergistic effects of the MGP-PAH mixture were not due to contamination of the mixture by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds and the results suggest that the enhanced potency of the mixture is due to unknown interactions between the individual PAHs present in the mixture.

Animals↗
PubMed1993

Suppression of collagen induced arthritis by oral administration of type II collagen: changes in immune and arthritic responses mediated by active peripheral suppression.

The oral administration of CII by gavage to WA/KIR rats before a conventional arthritogenic challenge with bovine CII in FIA reduced the incidence (by 23%) and delayed the onset of collagen-induced arthritis in about 50% of the animals. Selective changes in B cell and T cell responses to CII in animals treated this way are interpreted to indicate a state of tolerance or hyporesponsiveness to CII. Tolerant animals made less serum antibody, to bovine and rat CII, of the IgG2b isotype and more of the IgG1 isotype. Phenotypic and functional analysis of peripheral lymph node cells showed that those from tolerized animals expressed less MHC Class II, proliferated less and secreted less IgG2b anti-CII antibody in response to stimulation in vitro with CII when compared with cells from non-tolerant animals. However, this depression of the immune responses to CII seen in vitro was overcome when the cells were incubated with increasing amounts of CII. Tolerance could be transferred to normal animals. Spleen cells, and nylon wool-filtered splenic T cells (but not mesenteric lymph node cells) adoptively transferred hyporesponsiveness to normal recipients which were then less susceptible to collagen-induced arthritis. Transfer of serum from gavaged animals did not modify the susceptibility of normal recipients to arthritis. Spleen cells from gavaged animals suppressed proliferative and antibody responses in co-cultures in vitro with lymph node cells from animals immunized with CII in FIA. The suppressive spleen cell population contained more cells expressing MHC Class II, in both the CD8+ and CD4+ populations. These studies show that the oral administration of CII alters the subsequent immune response to the arthritogenic challenge and indicate that this oral tolerance of CII is due, not to clonal deletion or anergy, but rather to an antigen-driven active suppression mechanism that affects both T cells and B cells, most likely through the action of regulatory cytokines IL-4, IL-10 and TGF beta.

Administration, Oral↗
PubMed1993

Prevention of pristane-induced arthritis by the oral administration of type II collagen.

This is the first demonstration of a role for type II collagen in pristane-induced arthritis. Pretreatment with soluble type II collagen either lowers or raises the subsequent incidence and severity of pristane-induced arthritis. These effects are dependent upon both the dose and route of administration of the soluble type II collagen. Increasing doses of orally administered type II collagen lowered both the incidence and severity of pristane-induced arthritis. Conversely, increasing doses of intraperitoneally administered type II collagen increased both the incidence and severity of arthritis. This exacerbation of pristane-induced arthritis was accompanied by elevated B- and T-cell responses to type II collagen. These findings highlight the importance of the site at which antigen is encountered in influencing subsequent immune responses and extend the observations of the use of orally administered antigens to ameliorate experimental autoimmunity.

Administration, Oral↗
PubMed1992

Metabolism and radiosensitization of 4,5-dimethylmisonidazole, a ring-substituted analog of misonidazole.

4,5-Dimethylmisonidazole (DMM) is a ring-substituted derivative of the 2-nitroimidazole, misonidazole. 2-Nitroimidazoles are able to sensitize radioresistant hypoxic cells, and to kill them outright through bioreductive metabolism. The toxic process is believed to reflect the consequences of reductively activated drugs forming adducts with cellular (macro)molecules. Both this process and the radiosensitizing activity are thought to correlate with the electron affinity of radiosensitizing agents. In the present study, methyl groups were added to the imidazole ring of misonidazole in order to hinder adduct formation with cellular molecules after reductive-activation of the compound. It was anticipated that this would substantially decrease the hypoxic-cell toxicity of the parent drug. The presence of the two methyl groups reduced the half-wave reduction potential of DMM by about 70 mV, so we expected that its radiosensitizing ability would also decrease. In direct comparison with misonidazole, DMM, at equimolar concentrations, showed dramatically reduced binding to cellular macromolecules under bioreductive conditions, both in vivo, using a liver perfusion system, and in vitro, using tissue culture cells incubated under extreme hypoxia. However, DMM was only moderately less toxic than the parent compound, and showed greatly diminished radiation sensitization capacity. Since the decrease in toxicity was much less than expected, and the decrease in radiosensitization was much more than expected, this compound may be an important drug for continuing studies on the mechanisms of radiation sensitization, binding and cytotoxicity caused by electron affinic drugs.

Animals↗
PubMed1990

Neonatal extracorporeal membrane oxygenation in Texas.

Extracorporeal membrane oxygenation (ECMO) has been a successful treatment (80% survival) in over 3,000 neonates with severe respiratory failure (80% predicted mortality without ECMO). ECMO is prolonged extracorporeal cardiopulmonary bypass achieved by extrathoracic vascular cannulation using a modified heart-lung machine. ECMO as treatment for severe respiratory failure in neonates is currently available in Texas in San Antonio, Galveston, Lubbock, and Dallas. Of 116 Texas neonates treated with ECMO, 74% survived. Because of the distances between ECMO programs in Texas, early communication with the nearest center is highly recommended.

Extracorporeal Membrane Oxygenation↗
PubMed1988

Planned short-stay admission to a geriatric unit: one aspect of respite care.

Our unit aims to provide planned short-term in-patient care for any disabled elderly person who requests it. The patients using the service over a 12-month period are described. Most were heavily disabled and it seems unlikely that their carers could cope at home without the opportunity of a break from time to time. The service is cheap, as relatively few beds are needed and those mostly in the summer. Morbidity amongst patients (and their carers) was high but we could find no evidence to support recent suggestions that admitting such patients was harmful.

Aged↗
PubMed1988

Pulmonary clearance of vasoactive drugs: N-oxidation of SK&F 86466 in the isolated perfused rat lung.

The contribution of the lung to the systemic clearance of the alpha receptor antagonist SK&F 86466 in rats was determined using the isolated perfused rat lung. Lungs were perfused with a blood-free medium containing SK&F 86466 at initial concentrations ranging from 0.26 to 5.1 microM at a flow rate of 104 ml/min. During the perfusion the concentration of SK&F 86466 in the perfusion medium declined monoexponentially. The half-life (8.0 +/- 1.8 min), steady state volume of distribution (205 +/- 16 ml), clearance (18.3 +/- 2.4 mL/min) and extraction ratio (0.18 +/- 0.02) were independent of the initial concentration of SK&F 86466. The free fraction of SK&F 86466 in the perfusion medium, determined by equilibrium dialysis, was 0.598. The average intrinsic clearance of SK&F 86466 in the lung, calculated using the flow rate, free fraction and clearance, was 37.4 ml/min. The concentration of the N-oxide metabolite of SK&F 86466 (SK&F 102102) in the perfusion medium increased with time, and at the end of the perfusion was approximately equal to the initial concentration of SK&F 86466. The pharmacokinetics of SK&F 86488 in lungs from rats pretreated with the suicide substrate inhibitor of cytochrome P-450 1-aminobenzotriazole were identical to the kinetics in lungs from control animals. The pretreatment regimen used reduced the activity of ethoxycoumarin-O-deethylase in lung microsomes by 70% and reduced P-450 content to below the limit of detection.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1985

Trigeminal trophic syndrome.

Two cases of ulceration of the face following surgical sensory denervation are described. Both patients presented to a geriatric unit because of problems associated with mental impairment. There are relatively few reports of similar ulcers. A review of the literature suggests that mental impairment is an important aetiological factor.

Aged↗
PubMed1984

Increased glycolysis in ageing cultured human diploid fibroblasts.

With increasing population doubling in vitro, human diploid fibroblasts exhibited a highly significant increase in glucose uptake from the growth medium and a corresponding increase in lactate production. The switch to glycolysis occurred prior to the onset of changes in intracellular glucose and lactate concentrations or in the specific activity of the glycolytic regulatory enzyme, pyruvate kinase. It also preceded the morphological alterations held to be characteristic of cellular senescence.

Cell Line↗
PubMed1982

Hydration and percutaneous absorption III: Influences of stripping and scalding on hydration alteration of the permeability of hairless mouse skin to water and n-alkanols.

The influence of hydration on the permeability of stripped and scalded skins of hairless mice was investigated in vitro using water and n-alkanols as test permeants. Irrespective of pretreatment, the permeation rates of water, methanol, and ethanol were unaffected by aqueous immersion of skin sections in a diffusion cell, consistent with earlier data on unprocessed skins. The permeation rates of butanol and hexanol also were insensitive to hydration, differing from earlier studies on normal, intact skin in which both solutes' rates doubled after 10 hr of soaking. Following both pretreatments, the permeability of octanol declined over the first 5-10 hr of maceration, but remained invariant thereafter. The decline was most pronounced for the scalded skins. With untreated skin, octanol permeability initially increased and then declined before assuming a constant value. This study indicates that the barrier properties of the epidermis and dermis are not particularly sensitive to extended hydration except in the case of octanol. Scalding at 60 degrees for 60 sec rapidly hydrates the skin, altering tissue permeability to about the same extent as a 10-hr (or longer) immersion in water at 37 degrees. Octanol's unique hydration profile is explained by locating the origin of permeability decline in tissue beneath the horny exterior of the skin.

Abdomen↗
PubMed1980

Hydration and percutaneous absorption: I. Influence of hydration on alkanol permeation through hairless mouse skin.

A method to study the influence of hydration on skin permeability where the skin is immersed in saline for up to 30 hr and under circumstances where a steady state rate of permeation can be established in several minutes is indicated. These circumstances allow multiple, sequential runs over a period where the permeability coefficients of some chemicals are gradually changing. It has been found that the permeabilities of water, methanol and ethanol are little affected by such hydration. However, there is a doubling of the permeability coefficients of butanol and hexanol during the first 10 hr of immersion. More hydrophobic alkanols seem to be less sensitive to the protracted aqueous conditioning. In general the results indicate that there are complex molecular structure-permeability relationships operating in skin. More specifically, the hydration effects are insightful with respect to developing barrier models for skin as they are further indications that different parallel diffusional paths are followed by polar and semi- and nonpolar species.

Alcohols↗