Rock falls can cause delays, damage, injury, and death to highway users. In 1982, a rock fell on a vehicle in the Argillite Cut on British Columbia (B.C.) Highway 99 killing a woman and disabling her father. The father successfully sued the provincial Ministry of Transportation and Highways for damages. The Supreme Court of Canada found that the Ministry could readily foresee the risk that harm might befall users of the highway if it were not reasonably maintained and that maintenance could be found to extend to the prevention of injury from falling rock. A risk analysis methodology can assess the probability of loss of life due to rock fall. Rock fall impact-mark mapping supplemented by documented rock fall records was used to establish a rock fall frequency. The risk of rock fall on this highway in 1982 can be compared with accepted societal risks. For the Argillite Cut, the probabilities of death of a one time user and a daily commuter on the highway were 6 × 10 -8 and 3 × 10 -5 per year, respectively. The annual probability of a rock fall causing a death in the exposed population was 8 × 10 -2 in the Argillite Cut. This was higher than the level of risk now commonly accepted in some industries and large engineering projects.Résumé : Les chutes de roches peuvent causer des retards, dommages, blessures et pertes de vie aux usagers des routes. En 1982, une roche est tombée sur un véhicule dans l'Argillite Cut sur la route 99 en Colombie-Britannique, tuant une femme et invalidant son père. Le père a poursuivi avec succès pour dommages le ministère des transports et des routes de la province. La Cour suprême du Canada a trouvé que le ministère pouvait facilement prévoir que les usagers encourraient des risques si la route n'était pas raisonnablement bien entretenue, et que l'entretien devrait s'étendre à la prévention de blessures résultant de la chute d'une roche. Une méthodologie d'analyse de risques peut évaluer la probabilité de perte de vie résultant de la chute d'une roche. Une cartographie des points d'impacts de chutes de roches avec comme ajout les dossiers des chutes de roches documentées a été utilisée pour établir une fréquence des chutes de roches. Le risque de chute de roche sur cette route en 1982 peut être comparé aux risques acceptables par la société. Pour l'Argillite Cut, les probabilités de décès pour un seul passage d'un usager et pour un passage journalier d'un banlieusard sur cette route étaient de 6 × 10 -8 et 3 ×10 -5 par année. La probabilité annuelle qu'une chute de roche cause un décès dans la population exposée était de 8 × 10 -2 dans l'Argillite Cut. Ceci était plus élevé que le niveau de risque présentement accepté dans certaines industries et dans de grands projets d'ingénierie.
HL60 cells are human promyeloid cells that can be induced to differentiate by physiological stimuli (e.g. all-trans retinoic acid (ATRA), 1 alpha,25-dihydroxyvitamin D3 (D3), granulocyte colony-stimulating factor (G-CSF)) and by non-physiological agents such as dimethysulphoxide (DMSO) and protein kinase C-activating phorbol esters. The sensitivity of HL60 cells to physiological differentiating agents, but not to DMSO, is enhanced when cells are exposed to 'anti-inflammatory agents' (e.g. indomethacin) or are 'primed' (pretreated) with a small amount of ATRA: alone, neither treatment induces differentiation. We earlier suggested that indomethacin might act by inhibiting the endogenous formation of a differentiation-suppressing prostanoid (Bunce, C.M., et al. (1994) Leukemia 8, 595-604). Studies of the formation of prostanoids by HL60 cells and of the effects of prostanoids on these cells failed to identify any prostanoid that could be implicated in sensitization by indomethacin. 3 alpha-Hydroxysteroid dehydrogenase (3 alpha-HSD) is another target of such 'anti-inflammatory agents'. Steroid inhibitors of 3 alpha-HSD sensitized HL60 cells to inducers of differentiation in a manner similar to indomethacin. 3 alpha-HSD is a member of the aldoketoreductase enzyme family, which comprises many enzymes of similar size and primary sequence. A protein that was recognised by an antiserum to 3 alpha-HSD was found in HL60 cells, but the cells showed no detectable 3 alpha-HSD activity. The 3 alpha-HSD-like protein was strikingly down-regulated by 'priming' doses of ATRA. When treatment with a differentiation-sensitizing 'anti-inflammatory agent' or steroid was combined with ATRA "priming', the effects of the different treatments were not additive: the resulting increase in sensitivity equalled that achievable by either treatment alone. We conclude that interference with a single intracellular regulatory mechanism underlies the increases in sensitivity of cells to differentiating agents that are caused by anti-inflammatory agents, by certain steroids and by 'priming' with ATRA. Decreased activity of a yet-to-be-identified member of the aldoketoreductase family of dehydrogenases is likely to be a central feature of a previously unrecognised mechanism that controls the responsiveness of cells to environmental stimuli such as retinoids and D3.
Abstract:This semi historical account of the origins of the nuclear receptor field and our current understanding of the biology these receptors is aimed at both the novice and experienced nuclear receptor biologist. For the novice it will provide a background scaffold for the forthcoming chapters. For the most experienced it will serve as a timely reminder of what fun we have had and how far this vitally important field has come since the first report of a nuclear rector in the mid 1980s.
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