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Sphingosine 1-phosphate (S1P) is a bioactive lysolipid with pleiotropic functions mediated through a family of G protein-coupled receptors, S1P(1,2,3,4,5). Physiological effects of S1P receptor agonists include regulation of cardiovascular function and immunosuppression via redistribution of lymphocytes from blood to secondary lymphoid organs. The phosphorylated metabolite of the immunosuppressant agent FTY720 (2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol) and other phosphonate analogs with differential receptor selectivity were investigated. No significant species differences in compound potency or rank order of activity on receptors cloned from human, murine, and rat sources were observed. All synthetic analogs were high-affinity agonists on S1P(1), with IC(50) values for ligand binding between 0.3 and 14 nM. The correlation between S1P(1) receptor activation and the ED(50) for lymphocyte reduction was highly significant (p < 0.001) and lower for the other receptors. In contrast to S1P(1)-mediated effects on lymphocyte recirculation, three lines of evidence link S1P(3) receptor activity with acute toxicity and cardiovascular regulation: compound potency on S1P(3) correlated with toxicity and bradycardia; the shift in potency of phosphorylated-FTY720 for inducing lymphopenia versus bradycardia and hypertension was consistent with affinity for S1P(1) relative to S1P(3); and toxicity, bradycardia, and hypertension were absent in S1P(3)(-/-) mice. Blood pressure effects of agonists in anesthetized rats were complex, whereas hypertension was the predominant effect in conscious rats and mice. Immunolocalization of S1P(3) in rodent heart revealed abundant expression on myocytes and perivascular smooth muscle cells consistent with regulation of bradycardia and hypertension, whereas S1P(1) expression was restricted to the vascular endothelium.

OBJECTIVE: To assess the extent to which smokers and non-smokers in Victoria, Australia attempt to keep their homes smoke free and to determine whether the proportion of people attempting to do so has changed over time. DESIGN: Face to face surveys conducted in Victoria each year from 1989 to 1997. PARTICIPANTS: Approximately 2500 randomly selected adults each year. MAIN OUTCOME MEASURES: Proportion of respondents who discourage their visitors from smoking; proportion of smokers who always smoke outside their own homes; behaviour of smokers when they are around children. Changes in each of these measures over time. RESULTS: Reports of visitors being discouraged from smoking rose from 27% in 1989 to 53% in 1997. Smokers who reported always smoking outside the home rose from 20% in 1995 to 28% in 1997. Not smoking in the presence of children rose from 14% in 1989 to 33% in 1996. Indoor restrictions on smoking were associated with the presence of children in the household and even more strongly with the presence of non-smoking adults. People who worked in places where smoking was totally banned were more likely to ask their visitors not to smoke than those who worked where smoking was allowed. CONCLUSIONS: The results indicate a strong move towards homes and towards protecting children from smoke. Efforts to support and facilitate this social change should be further encouraged.