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

L-line x-ray fluorescence of cortical bone lead compared with the CaNa2EDTA test in lead-toxic children: public health implications.

Mild to moderate lead toxicity (blood lead, 25-55 micrograms/dl) is a preventable pediatric illness affecting several million preschool children ("lead-toxic children") in the United States. In-hospital lead-chelation treatment is predicated upon a positive CaNa2EDTA test, which is difficult to perform and impractical in large populations. After the development of an L-line x-ray fluorescence technique (LXRF) that measures cortical bone lead content safely, rapidly, and noninvasively, this study was initiated in lead-toxic children to compare LXRF with the CaNa2EDTA test. Moreover, LXRF provided the opportunity to quantify bone lead content. From blood lead and LXRF alone, 90% of lead-toxic children were correctly classified as being CaNa2EDTA-positive or -negative. In 76% of 59 lead-toxic children, bone lead values measured by LXRF were equal to or greater than those measured in normal and industrially exposed adults. These results indicate that LXRF may be capable of replacing the CaNa2EDTA test. When considered with the known neurotoxic effects on children of "low levels" of exposure to lead, these results also suggest that either an excessively narrow margin of safety or insufficient safety is provided by present U.S. guidelines, which classify an elevated blood lead concentration as 25 micrograms/dl or greater.

Bone and Bones↗

PubMed1989

Distribution of 10B after infusion of Na210B12H11SH into a patient with malignant astrocytoma: implications for boron neutron capture therapy.

If a sufficient concentration of the stable isotope 10B is introduced into a neoplasm, radiation therapy can be effected by short-range heavy charged particles from the disintegration of 10B by slow neutrons. Brain tumors were irradiated postoperatively by Hatanaka and co-workers in Japan using a 1 to 2 hour intraarterial infusion of 10B-enriched Na2B12H11SH (Na210B12H11SH) before exposure of the tumor-bearing area of the brain to slow neutrons from a 100 kilowatt nuclear reactor. The clinical outcome of such boron neutron capture therapy has been favorably impressive in some patients, but its efficacy in brain tumors needs improvement. In our study, a terminally ill patient with malignant astrocytoma was infused intravenously with Na210B12H11SH for 25 hours. The postmortem distribution of 10B in unfixed, frozen, tumor-bearing brain and spinal cord tissues was studied by comparing representative cryostat sections of these specimens with neutron-induced heavy charged particle radiographs of the same sections. Preferential accumulation of 10B was observed in the tumor, with relatively little accumulation of 10B in the parenchyma of the central nervous system.

Animals↗

PubMed1989

Recent developments in neutron capture therapy.

The conditions for the possible initiation of clinical trials with neutron capture therapy at a number of locations in the U.S. is reviewed. There are several new technical developments or plans at the Brookhaven Medical Research Reactor (BMRR), the Power Burst Facility (PBF) at INEL, the Massachusetts Institute of Technology Reactor (MITR) and the Georgia Institute of Technology Research Reactor (GTRR). Emphasis is on the development of epithermal beams for the treatment of deepseated tumors with neutron fluxes in between 10(9) to 10(10) n/cm2s. Therapeutic dose gains, defined as the ratio of tumour dose to maximum normal tissue dose in the treatment volume are expected to be between 2 and 4, depending on the degree of suppression of fast neutron dose. Boron concentrations considered in this case in the tumour are around 35 micrograms 10B/g and tumour/normal tissue concentrations are around 10. The compound development throughout three generations is discussed. The compound proposed nowadays, Na2B12H11SH (or BSH), employed in the treatments in Japan, will likely be replaced in the future by analogous of biomolecules being enriched in the tumour by physiological pathways. Examples are p-boronophenylalanine or boronated porphyrius. The most promising solution envisaged would be the employment of tumour cell specific brononated monoclonal antibodies. Finally the mode of therapy is discussed which will likely be based on a fractioned scheme, to achieve optimized results.

Fast Neutrons↗

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↗

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↗

PubMed1986

Extracorporeal irradiation of blood: dosimetry corrected for shortened erythrocyte lifespans.

The amount of radiation delivered to erythrocytes during extracorporeal irradiation of blood (ECIB) has been described using Poisson distribution statistics. The Poisson expression for erythrocyte radiation dose distribution was simplified by considering the slight dilution of blood with fluid that is initially in the extracorporeal tubing. An algorithm was devised that allows curtailed lifespans of irradiated erythrocytes to be taken into account in a short computer program of radiation dosimetry for ECIB. Radiation doses to erythrocytes with and without lifespan corrections are compared.

Blood Cells↗

PubMed1985

The stability of DNA in human cerebellar neurons.

Human tissues have carbon-isotope ratios (13C/12C) that reflect dietary ratios. This observation has been used to determine the extent of metabolic turnover of DNA in cells of the adult human cerebellum (90 percent of which are neuronal). If adult human neuronal DNA were metabolically stable, its 13C/12C would reflect that in the maternal diet during fetal development as nearly all neurons are formed during maturation of the fetal brain and do not undergo cell division thereafter. The 13C/12C ratios in the food chains and body tissues of Europeans differ from corresponding American ratios by about 50 parts per million on the average. Therefore, turnover was studied by comparing 13C/12C ratios in cerebellar DNA of American-born Americans, European-born Americans, and European-born Europeans. The 13C/12C ratios in cerebellar DNA from European-born Americans were closer to 13C/12C ratios in cerebellar DNA from European-born Europeans than from American-born Americans, indicating that there was little or no turnover of neuronal DNA.

Adult↗

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

Chronic airway obstruction and bronchiectasis in the rat after intratracheal bleomycin.

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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

The use of heavy water in boron neutron capture therapy of brain tumours.

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Boron↗