Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis.

In the present study, the toxicity of yperite, SM, and its structural analogue mechlorethamine, HN2, was investigated in a human bronchial epithelial cell line 16HBE. Cell detachment was initiated by caspase-2 activation, down-regulation of Bcl-2 and loss of mitochondrial membrane potential. Only in detached cells, mustards induced apoptosis associated with increase in p53 expression, Bax activation, decrease in Bcl-2 expression, opening of the mitochondrial permeability transition pore, release of cytochrome c, caspase-2, -3, -8, -9 and -13 activation and DNA fragmentation. Apoptosis, occurring only in detached cells, could be recognized as anoikis and the mitochondrion, involved both in cell detachment and subsequent cell death, appears to be a crucial checkpoint. Based on our understanding of the apoptotic pathway triggered by mustards, we demonstrated that inhibition of the mitochondrial pathway by ebselen, melatonin and cyclosporine A markedly prevented mustard-induced anoikis, pointing to these drugs as interesting candidates for the treatment of mustard-induced airway epithelial lesions.

Alcohol is the main factor in excess traffic accident fatalities in France.

BACKGROUND: The aim of this study was to better evaluate the role of alcohol drinking in fatalities linked to road traffic accidents. METHODS: The data of accidents were collected by a French official agency from police records, including many variables, among which was a blood alcohol test. They were analyzed in a descriptive way and toward a logistic regression. This exhaustive database comprised all of the 500,961 accidents with casualties that involved less than three vehicles (28,506 fatal accidents) recorded in France during a 52 month period (September 1995 to December 1999). The results of the alcohol tests were known in 78.7 of the drivers. RESULTS: The blood alcohol concentration was over the legal limit (0.50 g/L in France) in 9.8% of the accidents with casualties overall. Considering only fatal accidents, the rate of positive alcohol test in drivers was approximately 31.5%. This rate varied depending on the period and the type of accident, raising up to 71.2% in single-vehicle accidents (loss of control) at night during the weekend. The percentage of positive alcohol tests also dramatically increased following the number of fatalities per accident (87.5% in single-vehicle accidents during weekend nights involving three or more killed). The logistic regression in single-vehicle accident shows that the higher odds ratios concern the positive blood alcohol test (OR = 4.19), clearly overwhelming the other precipitating factors of accidents (age of driver, meteorological conditions, time of day, and other factors). CONCLUSIONS: Drinking alcohol before driving is a well known factor of accidents. We clearly demonstrate here that it is the main factor leading to deaths linked to road traffic accidents in France. The results are strengthened, and some analyses are allowed, by the exceptional features of our database. The authors emphasize the need for prevention measures.

Evidence for a neurotoxic activity in crude venom of the stonefish (Synanceia verrucosa).

The neurotoxic effects of the Synanceia verrucosa venom were investigated in rodents. After intracranial injection in mice (50-125 ng/g), venom induced constant symptoms such as ataxia, circling, partial or complete reversible limbs paralysis, scratching, rolling, sleep-like periods and violent clonic seizure conducing in few seconds to death. EEG alterations occurring in rat brain after intracerebroventricular injection (50-100 microg) were precised. An initial phase was characterized by short repetitive tonic seizure periods together with a significant rise of the relative power in the delta band, no significant modification of the theta II rhythm (4-7 Hz), a decreasing of energy in theta I (7-12 Hz) and 15-40 Hz bands. A second phase was characterized by a marked generalized slowing with transient drastic decreasing of the amplitude and flattening of cortical EEG (comatose state) as the main elements. Propanolol did not reverse the EEG effects of the venom except a slight decrease of the slow wave amplitude. Previous intracerebroventricular administration of a K+(ATP) blocker generally decrease the delay of death. Histopathologic examination of the brain of surviving animals did not reveal any microscopic lesions. These results suggest (1) a complex mechanism of the venom in its neuropathologic expression; (2) at the doses tested, symptoms are not related to adrenergic pathways, K+(ATP) channel opener (verrucotoxin) is not implied in the neurotoxic effect, and the effect of the venom, which not affecting the theta II rhythm, seemed not to be exerted through cholinergic pathway.

The dopamine mesocorticolimbic pathway is affected by deficiency in n-3 polyunsaturated fatty acids.

BACKGROUND: Several findings in humans support the hypothesis of links between n-3 polyunsaturated fatty acid (PUFA) status and psychiatric diseases. OBJECTIVE: The involvement of PUFAs in central nervous system function can be assessed with the use of dietary manipulation in animal models. We studied the effects of chronic dietary n-3 PUFA deficiency on mesocorticolimbic dopamine neurotransmission in rats. DESIGN: Using dual-probe microdialysis, we analyzed dopamine release under amphetamine stimulation simultaneously in the frontal cortex and the nucleus accumbens. The messenger RNA (mRNA) expression of vesicular monoamine transporter(2) and dopamine D(2) receptor was studied with the use of in situ hybridization. The protein expression of the synthesis-limiting enzyme tyrosine 3-monooxygenase (tyrosine 3-hydroxylase) was studied with the use of immunocytochemistry. RESULTS: Dopamine release was significantly lower in both cerebral areas in n-3 PUFA-deficient rats than in control rats, but this effect was abolished in the frontal cortex and reversed in the nucleus accumbens by reserpine pretreatment, which depletes the dopamine vesicular storage pool. The mRNA expression of vesicular monoamine transporter(2) was lower in both cerebral areas in n-3 PUFA-deficient rats than in control rats, whereas the mRNA expression of D(2) receptor was lower in the frontal cortex and higher in the nucleus accumbens in n-3 PUFA-deficient rats than in control rats. Finally, tyrosine 3-monooxygenase immunoreactivity was higher in the ventral tegmental area in n-3 PUFA-deficient rats than in control rats. CONCLUSIONS: Our results suggest that the mesolimbic dopamine pathway is more active whereas the mesocortical pathway is less active in n-3 PUFA-deficient rats than in control rats. This provides new neurochemical evidence supporting the effects of n-3 PUFA deficiency on behavior.