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R D Stoner

Publications and source records attributed to R D Stoner.

At least 19 recordsLinked to original sources
PubMed1990

Cyclosporine A inhibition of microcystin toxins.

Cyclosporine A (CyA) given i.v. at a dose of 1.25 mg/mouse blocks a subsequent i.v. lethal dose (1.7-1.8 x LD50) of microcystin-LR for 24 hr, and is about 50% protective at 48 hr. Conversely, the fraction of mice that can be rescued by CyA (0.2 mg/mouse) after a lethal dose of microcystin-LR decreases rapidly with a pharmacodynamic half-time of only about 100 sec. The prophylactic action of CyA was tested against lethal doses of four microcystins. The acute lethality of 1.7-1.8 x LD50 dose of microcystin-LR, -RR, -LY, or -LA given 1 hr after administration of 0.2 mg of CyA is 0%, 0%, 58%, or 100%, respectively. Even a 0.6 mg/mouse dose of CyA is ineffective prophylaxis against a lethal dose of microcystin-LA. The inhibitory potency of CyA on microcystin toxicity can be completely reversed by the single L-amino acid substitution of alanine for arginine in the microcystin.

Animals↗
PubMed1989

The effects of single L-amino acid substitutions on the lethal potencies of the microcystins.

Microcystin-LR and -LA are more toxic than microcystin-LY and -RR in adult mice. They induce different degrees of thrombocytopenia and leukopenia, and the lethalities of their binary and ternary mixtures are addictive. Postnatal mice are resistant to doses of microcystin-LR that are lethal to adults but they are susceptible to higher doses. Substitution of a single L-amino acid for another in a microcystin markedly affects the dosimetric potency, but not the pathophysiology of its toxicity.

Aging↗
PubMed1989

Germinal center kinetics in lymph nodes of primed mice stimulated with complexed as opposed to free antigen.

Primed mice with low titers of circulating tetanus antitoxin (AB) were stimulated via the hind footpads with either fluid tetanus toxoid alone (AG) to create in vivo complexes in AG excess, or the same dose of toxoid complexed at equivalence with isologous antibody (AB-AG CPX), to have in vivo complexes in AB excess. All experimental animals reacted with three topically distinct consecutive waves of enhanced proliferative activity in popliteal lymph nodes, i.e., in the T-zone (peak on day 2), in the medullary area, the main site of plasmocytopoiesis (day 3), and in lymphoid follicles (day 5-6). Maximum serum AB titers following injection of AG-AB CPX were only about 25% of those found in animals boosted with AG alone. This suppressive effect was best reflected in a comparable reduction in plasmocytopoiesis, and to an lesser extent in the proliferative activity within the T-zone, and not at all in the overall magnitude of germinal center formation and/or expansion. However, the patterns of germinal center kinetics differed markedly between the two groups: a high sharp peak of development on day 5, followed by a marked drop on day 6 characterized the response in mice given AG alone, and a broad peak around day 6 that of those receiving AG-AB CPX. These differences could not adequately be accounted for by variations in centroblast/centrocyte proliferation rate vs. pycnotic indices, so that different patterns of lymphoid cell emigration from the centers may be considered. The results suggest that immune complexes, fixed on follicular dendritic cells, with different antigen-to-antibody ratios have divergent effects on the development and kinetics of germinal centers, the principal sites of memory B cell generation.

Animals↗
PubMed1989

Prophylaxis of cyanobacterial and mushroom cyclic peptide toxins.

The pathogenicity of virulent cyclic peptide toxins of the cyanobacterium, Microcystis aeruginosa, and the mushroom, Amanita phalloides, was prevented in mice by pretreatment with a variety of chemically unrelated agents including hydrocortisone, shellac, certain diazo and triazine dyes and cyclosporine. A. Despite the diverse nature of the protective agents, a feature commonly associated with protection was the ability to impair hepatic uptake of 51Cr-labeled sheep erythrocytes, a function of hepatic macrophages (Kupffer cells). In addition, several of the protective agents are known to affect other aspects of reticuloendothelial cell function. Therefore it seems likely that the hepatic macrophage is involved in the observed protection, although by what mechanism(s) is unknown. The most remarkable prophylaxis was seen with a single injection of Trypan red, which provided nonimmunologic protection against a lethal dose of a cyanobacterial toxin, cyanoginosin-LR, for periods up to 3 months.

Amanitins↗
PubMed1989

Tetanus toxoid complexed with heterologous antibody can induce germinal centre formation and B cell memory in mice without evoking a detectable anti-toxin response.

Fluid free tetanus toxoid (FTT) alone or FTT complexed in vitro at equivalence (EQ) or in antibody excess (ABEX) with anti-toxin contained in a human gammaglobulin preparation (HGG), or HGG alone, were injected into the hind leg footpads of mice. Anti-toxin titres of mouse serum were measured and compared with proliferative reactions in popliteal lymph nodes, based on combined 3H-thymidine autoradiography and planimetry, as a function of time. FTT in complex with HGG in ABEX failed to elicit a measurable anti-toxin response but caused, of all the materials tested, the most marked numerical increase of germinal centres. This finding is in accord with results of earlier studies indicating that the same heterologous antigen-antibody complexes at EQ or in ABEX can prime the animals, usually without eliciting antibody production detectable by serum titration. The model system used in the present experiments is thus well suited for a separation of the two principal arms of the dichotomous humoral immune response, i.e. by inducing germinal centre and B cell memory development but not specific antibody formation.

Animals↗
PubMed1988

Pathophysiology of cyanoginosin-LR: in vivo and in vitro studies.

Cyanoginosin-LR, one of the group of virulent cyclic heptapeptide toxins (cyanoginosins) isolated from some strains of the cyanobacterium, Microcystis aeruginosa, kills mice within 1-2 hr after iv or ip injection. Although the liver is a target organ of the toxin, the rapidity of lethality is incompatible with metabolic death from failure of hepatocellular function. However, disintegration of sinusoidal endothelium causes massive intrahepatic hemorrhage. The loss of the structural integrity of hepatic sinusoids provides a previously undescribed mechanism for embolization of disintegrating cells from the liver to the lung. No injury to either cultured bovine pulmonary artery endothelial cells or mouse peritoneal macrophages was observed following prolonged incubation with high concentrations of the toxin, and there was no increase in vascular permeability to 125I-labeled albumin detected before intrahepatic hemorrhage. However, plasma fibronectin increased transiently after toxin injection. Acute, severe thrombocytopenia, a characteristic of cyanoginosin-LR toxicity, remains unexplained since platelets did not concentrate in the lungs, liver, or spleen. There are similarities between the effects of cyanoginosin-LR and of the lipopolysaccharide endotoxins, such as elevations of plasma levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha.

Animals↗
PubMed1988

Central nervous system radiation syndrome in mice from preferential 10B(n, alpha)7Li irradiation of brain vasculature.

Ionizing radiations were directed at the heads of anesthetized mice in doses that evoked the acute central nervous system (CNS) radiation syndrome. Irradiations were done using either a predominantly thermal neutron field at a nuclear reactor after intraperitoneal injection of 10B-enriched boric acid or 250-kilovolt-peak x-rays with and without previous intraperitoneal injection of equivalent unenriched boric acid. Since 10B concentrations were approximately equal to 3-fold higher in blood than in cerebral parenchyma during the reactor irradiations, more radiation from alpha and 7Li particles was absorbed by brain endothelial cells than by brain parenchymal cells. Comparison of the LD50 dose for CNS radiation lethality from the reactor experiments with the LD50 dose from the x-ray experiments gives results compatible with morphologic evidence that endothelial cell damage is a major determinant of acute lethality from the CNS radiation syndrome. It was also observed that boric acid is a low linear energy transfer radiation-enhancement agent in vivo.

Animals↗
PubMed1987

Satisfactory primary tetanus antitoxin responses but markedly reduced germinal centre formation in first draining lymph nodes of ageing mice.

The present report deals with primary antibody responses to tetanus toxoid in 50-54-week-old ('ageing') as compared to 8-9-week-old ('young adult') mice. Antitoxin in the serum appeared 6 days earlier in the older than in the young animals, but in the latter reached 5 times higher titres on day 20. The magnitude of the proliferative response in the paracortex and the medulla of popliteal lymph nodes, as estimated by combined 3H-thymidine autoradiography and planimetry, was 3-7 times greater in the younger than in the older age group, thus approximately reflecting the difference in antibody titres on day 20. In contrast, germinal centre formation in response to the stimulus proved to be about 14 times less in ageing than in young adult mice. The findings demonstrate that, in the model system used, the age-related slopes of decline in humoral antibody responsiveness and proliferative reactivity in paracortex and medulla of first regional lymph nodes tend to be in parallel, while the ability of the immune apparatus to form germinal centres at this site deteriorates at a considerably faster pace. Results are also in line with the notion that centroblasts/centrocytes contribute little, if anything, to the ongoing antibody production elicited by the same stimulus which had triggered germinal centre formation. Finally, the observations made disprove the general validity of the suggestion that immune reactivity is maintained on the same level throughout life if tested with a novel antigen.

Aging↗
PubMed1985

Pathophysiologic effects of a toxic peptide from Microcystis aeruginosa.

Toxin-LR, a hexapeptide produced by Microcystis aeruginosa, causes marked hepatic vascular congestion, thrombocytopenia, microscopic pulmonary thrombi and death in 50-70 min when injected into mice. Although it is considered an hepatotoxin, we report that sublethal hepatocellular damage produced by CCl4 given 24 hr prior to toxin-LR administration prevents the acute deaths. However, CCl4-treated mice surviving toxin-LR acute effects often died during the subsequent three days. Pretreatment of mice with the microsomal enzyme inhibitors SKF 525A or cobaltous chloride did not alter the acute lethality of toxin-LR, but pharmacologic doses of hydrocortisone prevented both the acute and delayed deaths. X irradiation-induced thrombocytopenia or thrombocytopenia and leukopenia did not significantly affect the toxin's lethality. In vitro platelet aggregation or lysis did not occur during incubation with toxin-LR, nor was a humoral aggregating factor detected in plasma from toxin-injected mice.

Animals↗
PubMed1983

Atypical pulmonary thrombosis caused by a toxic cyanobacterial peptide.

Parenteral injection into mice of a toxic pentapeptide isolated from the cyanobacterium Microcystis aeruginosa induced thrombocytopenia, pulmonary thrombi, and hepatic congestion. The lethality of the toxin was unaffected by several anticoagulants. The acute liver damage that follows injection of the toxin has been attributed to direct action on liver cells but may be due to hypoxemia, heart failure, and shock.

Animals↗
PubMed1983

Early changes in lymphocyte traffic between distant lymph nodes following regional antigenic stimulation.

Regional labeling of mice by injection of cytidine-3H ([3H]CR) into the footpad of the left hind leg was used to evaluate lymphocyte traffic from the left regional nodes to the right popliteal lymph node (PLN) within a 24-h period, with or without concomitant primary or secondary stimulation of the right PLN with fluid tetanus toxoid. Results indicate that 1) in the case of primary antigen injection the relative contribution of lymphocytes from the left regional nodes to the small lymphocyte population present in the stimulated right PLN 24 h after labeling was slightly, but not significantly, greater than in non-stimulated controls; 2) a booster injection of antigen into the right hind leg footpad resulted in a significantly smaller relative contribution of lymphocytes from the previously primed left regional nodes to the small lymphocyte population in the right PLN, 24 h after injection of [3H]CR and secondary stimulation, as compared with controls or animals given a primary stimulation to the receiver node; and 3) in contrast to controls and mice subjected to primary stimulation only, the right PLN 24 h after booster contained a significant number of large lymphoid cells which, or whose precursors, had migrated to this site from contralateral nodes within a day, possibly also in the form of small lymphocytes. These findings are discussed in relation to the problem of lymphocyte recruitment and divergent behavior of non-committed lymphocytes as compared with memory cells in the initial phase after primary or secondary antigenic stimulation.

Animals↗
PubMed1983

Whole-body irradiation of deuterated mice by the 10B(n, alpha)7Li reaction.

Specific pathogen-free mice, 8-12 wk of age, were supplied with either acidified tap water or acidified 30 atom % 2H2O in tap water. Thirteen days later, when body water deuterium was about 20 atom %, mice were irradiated either by neutrons or by x-rays after intraperitoneal injection of boric acid. Mortality from whole-body neutron-boron radiation, unlike mortality from whole-body x-radiation, was not lowered by such deuteration. Time intervals to death of neutron-irradiated mice were compatible with the gastrointestinal syndrome. Neither species nor numbers of colonic bacteria were measurably altered by deuteration alone. Because the toxic, nonlethal range of deuterium substitution for aqueous hydrogen in mammals is approximately 1/5th to 1/3rd, these results indicate that partial deuteration of human tissues would improve neutron capture therapy of deep tumors. Neutron penetration would be enhanced and damage to normal tissues from photons would be decreased. The number of deuterium recoils due to neutron capture by hydrogen would also be decreased.

Animals↗
PubMed1983

Protection of mice from whole-body gamma radiation by deuteration of drinking water.

Drinking water made available to mice was changed from ordinary tap water to tap water containing 30 atom% D2O when the animals were 6 to 8 weeks old. Twelve days later, the deuterated mice and an approximately equal number of nondeuterated control mice were subjected to whole-body gamma radiation from a 60Co source. All mice received ordinary tap water after the irradiation. Postirradiation mortality was significantly less in deuterated than in nondeuterated animals. These results may have practical implications for radiotherapy of human malignant tumors.

Animals↗
PubMed1983

Distinct kinetic responses in vivo of cortical thymocytes of ageing mice to primary as compared to secondary peripheral antigenic stimulation.

We have studied cellular kinetic changes in the thymic cortex of ageing mice as a function of time after primary and secondary stimulation with aluminum phosphate adsorbed tetanus toxoid via the hind leg footpads. Absolute numbers of DNA synthesizing cortical thymocytes per cross-section of the thymus were computed from combined data obtained by planimetry, counts of cell density (cellularity) and assessment of the labelling index, 1 h after injection of (methyl-3H)-thymidine. The proliferative activity of these cells in the outer fourth of the thymic cortex reached a peak exceeding significantly control values by 45% 14 days after primary, but not secondary, peripheral antigenic stimulation. We conclude that the cortical thymocyte population responded in a distinct manner to the first immunization as opposed to the booster injection of the same antigen.

Aging↗
PubMed1980

Increased lymphocyte load of postcapillary venules in regional lymph nodes following stimulation with antigen -- isologous antibody complexes as compared with antigen alone.

In an attempt to study changing patterns of lymphocyte influx from blood into lymph nodes following regional antigenic stimulation, mice were injected with either fluid tetanus toxoid alone or complexed (at equivalence) with isologous antibody. The mean number of lymphocytes inside the basement membrane of cross-sectioned postcapillary venules (PCV) was evaluated as a function of time after antigen injection. 'Lymphocyte load' of PCV (LL/PCV) began to increase within less than a day after antigenic stimulation. The initial increment of LL/PCV values in both primary and secondary responses was greater when complexed rather than fluid antigen was used. Peak values were reached earlier, i.e., at the end of day 2, in presensitized as compared with unprimed animals (day 4). Maximum values of mean LL/PCV did not reflect the magnitude of subsequent antibody production under all experimental conditions. We conclude that changes in the LL/PCV belong to early lymph node reactions following regional antigenic stimulation. The pattern of this particular response may vary according to the type of immunizing agent used and the state of immunity (sensitization) of the animal as well as other factors still to be elucidated.

Animals↗