Subcellular and intranuclear localization of neptunium-237 (V) in rat liver.

The present investigation was aimed at establishing the distribution of 237Np within the different structures of hepatocytes. Rats were contaminated experimentally by intravenous injection of 237Np (V) and the subcellular structures of the liver were separated by ultracentrifugation. Twenty-four hours after contamination, the nuclear and cytosolic fractions bound 54 and 32%, respectively, of the total radionuclide. Purification of the nuclei followed by dissociation of the protein components in medium of increasing ionic strength showed a specific binding of neptunium to the structural proteins of the nuclear matrix.

Translocation of plutonium from rat and monkey lung after inhalation of industrial plutonium oxide and mixed uranium and plutonium oxide.

This study was designed to compare the translocation from lung of the Pu contained in the pure and mixed industrial oxides PuO2 and (U,Pu)O2. The latter had a Pu content of 20% w/w. For this purpose, young adult male rats and male and female baboons were exposed to a single inhalation of these oxides. Two baboons were exposed to the reference PuO2, i.e. 239PuO2. Rats were killed under anaesthesia 1, 15, 30, 90 and 180 days after exposure, and baboons, also under anaesthesia, 1 year thereafter. The results indicate that lung retention of Pu was independent of the oxide inhaled, but was smaller in rat (12-15% of the initial pulmonary burden, 6 months after exposure) than in baboon (56-80% of this burden, 1 year after exposure). In rat, Pu translocation kinetics were similar for the two industrial oxides, but as from day 15 after inhalation until 6 months thereafter, measurement of Pu deposits in the liver and skeleton showed that translocation of Pu from the mixed oxide was 2-3 times greater than that from the industrial Pu oxide. In baboon, the largest amounts of Pu were retained in the lung and thoracic lymph nodes for the three oxides inhaled. Pu translocation to the liver, skeleton and kidneys, and also urinary Pu excretion, were greater after inhalation of the mixed oxide than after inhalation of the industrial and reference Pu oxides. Nevertheless, the amount of mixed oxide Pu translocated to these sites and excreted in urine remained under 3% of the initial pulmonary burden.

Antiplatelet therapy in the prevention of ischaemic stroke.

Prevention of stroke is a crucial health care issue, as stroke is the third cause of death and the first cause of major disability in developed countries. The established role of platelet aggregation in TIA or minor and major ischaemic stroke has provided the rationale for many randomized trials of antiplatelet agents (aspirin, sulfinpyrazone, dipyridamole alone or in combination with aspirin, suloctidil, ticlopidine). The recent Antiplatelet Trialists' Collaboration (APT) meta-analysis (1994) based on 142 trials involving 100,000 vascular patients confirmed the data of the previous overview (1988). Aspirin, the only drug evaluated for primary prevention of ischaemic events, is not indicated for safety reasons in subjects at low risk of occlusive disease. Compared to control, antiplatelet therapy, notably aspirin which is by far the most widely used agent in trials, provides a 27% risk reduction of stroke, myocardial infarction or vascular death in patients suffering from ischaemic vascular events and a 22% risk reduction of these outcomes in patients having experienced a prior TIA/stroke. Aspirin (around 325 mg/day) and ticlopidine (500 mg/day) are currently the reference drugs for secondary prevention in cerebrovascular patients. The long term efficacy of ticlopidine, a specific antiaggregating agent, has been evaluated in two North American trials involving more than 4,000 patients. TASS showed ticlopidine to be significantly more effective in reducing the incidence of fatal or nonfatal stroke and death than aspirin in patients with TIA or minor stroke. The relative risk reductions over aspirin, the first year of greatest risk, were 41% for stroke and death and 46% for fatal or nonfatal stroke. CATS showed that ticlopidine compared with placebo induces a significant 30% relative risk reduction of stroke, myocardial infarction and vascular death over three years in patients who had suffered a recent thromboembolic stroke. The above results elicit two important issues: the optimal dose of aspirin and its tolerability compared to ticlopidine. The three controlled trials (UK-TIA, SALT, Dutch TIA) which have compared high (> or = 1 g/day) and low dose aspirin (< or = 300 mg/day) or various low doses of aspirin did not give a definite answer on the efficacy of low or very low (30 or 75 mg/day) doses of aspirin for reducing the risk of vascular outcomes in patients with stroke precursors. Even with low doses of aspirin there was still a risk of severe gastrointestinal bleeding, although minor side effects were less frequent.(ABSTRACT TRUNCATED AT 400 WORDS)

In vitro dissolution of uranium oxide by baboon alveolar macrophages.

In vitro cellular dissolution tests for insoluble forms of uranium oxide are technically difficult with conventional methodology using adherent alveolar macrophages. The limited number of cells per flask and the slow dissolution rate in a large volume of nutritive medium are obvious restricting factors. Macrophages in suspension cannot be substituted because they represent different and poorly reproducible functional subtypes with regard to activation and enzyme secretion. Preliminary results on the dissolution of uranium oxide using immobilized alveolar macrophages are promising because large numbers of highly functional macrophages can be cultured in a limited volume. Cells were obtained by bronchoalveolar lavages performed on baboons (Papio papio) and then immobilized after the phagocytosis of uranium octoxide (U3O8) particles in alginate beads linked with Ca2+. The dissolution rate expressed as percentage of initial uranium content in cells was 0.039 +/- 0.016%/day for particles with a count median geometric diameter of 3.84 microns(sigma g = 1.84). A 2-fold increase in the dissolution rate was observed when the same number of particles was immobilized without macrophages. These results, obtained in vitro, suggest that the U3O8 preparation investigated should be assigned to inhalation class Y as recommended by the International Commission on Radiological Protection. Future experiments are intended to clarify this preliminary work and to examine the dissolution characteristics of other particles such as uranium dioxide. It is recommended that the dissolution rate should be measured over an interval of 3 weeks, which is compatible with the survival time of immobilized cells in culture and may reveal transformation states occurring with aging of the particles.

Two novel agents affecting eating through an action on monoaminergic systems.

The pharmacological effects of two newly synthesized anorectic agents CM 57373 (4-amino-1-(6-bromopyrid-2-yl) piperidine hydrochloride) and CM 57493 (4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6 tetrahydrophyridine hydrochloride) have been studied. Both drugs decreased food intake dose dependently in rats deprived of food for 20 h/d. The doses that inhibited food intake by 50 percent (ID50) were 9.74 mg kg-1 p.o. for CM 57493 and 7.37 mg kg-1 p.o. for CM 57373. The general behaviour of the rats was not affected at anorectic doses and no amphetamine-like stimulation was observed. The anorectic effect of CM 57373 was selectively, but not completely, antagonized by metergoline and methysergide, two antagonists of serotoninergic receptors in the central nervous system. Neither noradrenaline antagonists (propranolol and phentolamine) nor a dopamine antagonist (penfluridol) affected the anorexia induced by CM 57373. These results indicate that the anorectic effect of CM 57373 is, at least, partially mediated by the serotoninergic system. The mechanism of action of CM 57493 is more complex, since several distinct neurotransmitter systems appear to be involved in its effect. In cross-tolerance experiments with fenfluramine, there was a reduction of the anorectic activity of CM 57493, suggesting similar mechanisms of action for these two drugs, even though pretreatment with metergoline or methysergide antagonized the anorectic effect of fenfluramine but not that of CM 57493. The anorectic effect of CM 57493 was antagonized by pretreatment with propranolol, a beta-noradrenergic antagonist, suggesting an involvement for the beta-noradrenergic system as well. Pretreatment with phentolamine or penfluridol did not modify the effect of CM 57493 on food intake. In-vitro and in-vivo biochemical studies showed that CM 57373 and CM 57493 act mainly on central serotoninergic mechanisms. CM 57373 is a serotonin releaser and a serotonin reuptake inhibitor. But, unlike fenfluramine which affects the storage pool for 5HT, it releases 5HT mainly from a functional pool. CM 57493 did not affect serotonin release and uptake but exhibited a high affinity to serotonin postsynaptic receptors.