Toxicology
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We have previously shown that intratracheal instillation of carbon nanoparticles exacerbates lung inflammation related to bacterial endotoxin (lipopolysaccharide, LPS) and subsequent systemic inflammation with coagulatory disturbance in mice [Inoue, K., Takano, H., Yanagisawa, R., Hirano, S., Sakurai, M., Shimada, A., Yoshikawa, T., 2006b. Effects of airway exposure to nanoparticles on lung inflammation induced by bacterial endotoxin in mice. Environ. ⋯ Nanoparticle inhalation did not significantly increase lung expression of proinflammatory cytokines or facilitate systemic inflammation and coagulatory disturbance. Isolated alveolar macrophages (AMs) from nanoparticle-exposed mice showed greater production of interleukin-1beta and keratinocyte chemoattractant stimulated with ex vivo LPS challenge than those from clean air-exposed mice, although the differences did not reach statistical significance. These results suggest that acute exposure to diesel nanoparticles exacerbates lung inflammation induced by LPS.
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In clinical use, a single infusion of oxaliplatin, widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs triggered or aggravated by exposure to cold. To study the pathophysiology of these symptoms, we developed and characterized an animal model that reproduces the effects of a single intraperitoneal oxaliplatin administration (3, 6 and 12 mg/kg). Significant allodynia and hyperalgesia to cold stimuli were rapidly observed from 24 h to day 5 with a maximum lowering of 76% at t+30 h versus control. ⋯ This new animal model for the first time closely mimics the effects observed in humans after a single oxaliplatin infusion, especially onset and highly intense sensory disturbances, hypersensitivity to cold with allodynia and hyperalgesia signs. This model may help to elucidate the mechanisms of this thermal hypersensitivity, especially the possible involvement of small-diameter A-fibers in cold allodynia symptoms. These selective effects may clue up the mechanistic basis for the acute oxaliplatin neuropathy leading to a better understanding of the clinical condition and to optimize its treatment.
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In scenarios of mass destruction it is likely that victims are intoxicated by organophosphates and, at the same time, physically injured. Organophosphate compounds produce excessive cholinergic overstimulation in the CNS via blocking acetylcholinesterase activity. The specifics of acute care and anaesthesia in physically traumatized and intoxicated patients are largely unknown. ⋯ In order to identify potential mechanisms involved in cholinergic reversal of anaesthesia we have investigated interactions between acetylcholine and the volatile anaesthetic sevoflurane in isolated cortical brain slices. Our results provide evidence that cholinergic stimulation counterbalances the effects of general anaesthetics by increasing neuronal excitability, and, in addition, by decreasing anaesthetic potency. These findings imply that in patients suffering from organophosphorus intoxication dose requirements for general anaesthetics are considerably increased.
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Case Reports
Lessons to be learnt from organophosphorus pesticide poisoning for the treatment of nerve agent poisoning.
The increasing threat of nerve agent use for terrorist purposes against civilian and military population calls for effective therapeutic preparedness. At present, administration of atropine and an oxime are recommended, although effectiveness of this treatment is not proved in clinical trials. Here, monitoring of intoxications with organophosphorus (OP) pesticides may be of help, as their actions are closely related to those of nerve agents and intoxication and therapy follow the same principles. ⋯ From these cases it was concluded that sufficient reactivation of nerve agent inhibited non-aged AChE should be possible, if the poison load was not too high and the effective oximes were administered early and with an appropriate duration. When RBC-AChE activity was higher than some 30%, neuromuscular transmission was relatively normal. Relatively low atropine doses (several milligrams) should be sufficient to cope with muscarinic symptoms during oxime therapy.
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Respiratory failure, through a combination of muscarinic, nicotinic, and central effects, is the primary cause of death in acute organophosphate poisoning. However, the mechanisms inducing respiratory failure remain unclear. In rats poisoned subcutaneously with paraoxon at doses near the LD(50), we studied the pattern of respiration using whole body plethysmography and the occurrence of respiratory failure using arterial blood gases. ⋯ Even at the 75% dose, paraoxon had no effects on PaO(2), PaCO(2) or HCO(3)(-); however, a significant decrease in arterial pH was observed at 30min (7.34+/-0.07 versus 7.51+/-0.01, p=0.03). Atropine completely reversed the paraoxon-induced respiratory alterations. We conclude that paraoxon, at doses equal to 50 and 75% of the LD(50), alters ventilation at rest without inducing respiratory failure during the study period.