The Richmond Agitation-Sedation Scale: translation and reliability testing in a Swedish intensive care unit.

BACKGROUND: Awareness about adequate sedation in mechanically ventilated patients has increased in recent years. The use of a sedation scale to continually evaluate the patient's response to sedation may promote earlier extubation and may subsequently have a positive effect on the length of stay in the intensive care unit (ICU). The Richmond Agitation-Sedation Scale (RASS) provides 10 well-defined levels divided into two different segments, including criteria for levels of sedation and agitation. Previous studies of the RASS have shown it to have strong reliability and validity. The aim of this study was to translate the RASS into Swedish and to test the inter-rater reliability of the scale in a Swedish ICU. METHODS: A translation of the RASS from English into Swedish was carried out, including back-translation, critical review and pilot testing. The inter-rater reliability testing was conducted in a general ICU at a university hospital in the south of Sweden, including 15 patients mechanically ventilated and sedated. Forty in-pair assessments using the Swedish version of the RASS were performed and the inter-rater reliability was tested using weighted kappa statistics (linear weighting). RESULT: The translation of the RASS was successful and the Swedish version was found to be satisfactory and applicable in the ICU. When tested for inter-rater reliability, the weighed kappa value was 0.86. CONCLUSION: This study indicates that the Swedish version of the RASS is applicable with good inter-rater reliability, suggesting that the RASS can be useful for sedation assessment of patients mechanically ventilated in Swedish general ICUs.

Evolution of clonality and polyploidy in a weevil system.

The increased interest in asexual organisms calls for in-depth studies of asexual complexes that actively give rise to new clones. We present an extensive molecular study of the Otiorhynchus scaber (Coleoptera, Curculionidae) weevil system. Three forms have traditionally been recognized: diploid sexuals, triploid, and tetraploid parthenogens. All forms coexist in a small central area, but only the polyploid parthenogens have colonized marginal areas. Analyzing the phylogenetic relationship, based on three partial mitochondrial genes, of 95 individuals from 19 populations, we find that parthenogenesis and polyploidy have originated at least three times from different diploid lineages. We observe two major mitochondrial lineages, with over 2.5% sequence divergence between the most basal groups within them, and find that current distribution and phylogenetic relationships are weakly correlated. Quite unexpectedly, we also discover diploid clones that coexist with, and are morphologically indistinguishable from, the diploid sexual females. Our results support that these diploid clones are derived directly from the diploid sexuals. We also find that it is mainly an increase in ploidy level and not the benefits of asexual reproduction that confers to polyploid parthenogens the advantage over their diploid sexual relatives.

Synthesis and pharmacological evaluation of thiopyran analogues of the dopamine D3 receptor-selective agonist (4aR,10bR)-(+)-trans-3,4,4a,10b-tetrahydro-4-n-propyl-2H,5H [1]b enzopyrano[4,3-b]-1,4-oxazin-9-ol (PD 128907).

Benzopyranoxazine (+)-7 (PD 128907) is the most dopamine (DA) D3 receptor-selective agonist presently known. The only structural feature which distinguishes 7 from the analogous nonselective naphthoxazines is an oxygen atom in the 6-position. To extend this series of tricyclic DA agonists we used a classic bioisoster approach and synthesized thiopyran analogues of 7, which have a sulfur atom in the 6-position. We prepared trans-4-n-propyl-3,4,4a,10b-tetrahydro-2H,5H-[1]benzothiopyrano[4, 3-b]-1,4-oxazin-9-ol (9, trans-9-OH-PTBTO), its enantiomers ((+)-9 and (-)-9), the racemic cis-analogue (10), and the racemic trans-sulfoxide (11) and studied the potency and selectivity for DA receptors of these compounds. As with other rigid DA agonists, the highest affinity for DA receptors resided in one of the enantiomers, in this case the (-)-enantiomer of 9. On the basis of a single-crystal X-ray analysis of a key intermediate, the absolute configuration of (-)-9 was found to be 4aS,10bR, which is homochiral with (+)-(4aR,10bR)-7. In contrast to (+)-7 however, (-)-9 displayed no selectivity for any of the DA receptors. In addition, it has affinity for 5HT1A receptors. (+/-)-cis-4-n-Propyl-3,4,4a,10b-tetrahydro-2H,5H-[1]benzothiopyrano++ +[4,3-b]-1,4-oxazin-9-ol (10), which was expected to be inactive, displayed affinity and selectivity for the DA D3 receptor, whereas the sulfoxide 11 displayed some DA D3 selectivity, but with a lower affinity. Further pharmacological evaluation revealed that (-)-9 is a very potent full agonist at DA D2 receptors and a partial agonist at DA D3 receptors. The cis-analogue (+/-)-10 displayed the same profile, but with lower potency. These findings were confirmed in vivo: in reserpinized rats (-)-9 displayed short-acting activation of locomotor activity (DA D2 agonism) and also lower lip retraction and flat body posture, (5HT1A agonism). Compound (+/-)-10 had no effect on locomotor activity. In unilaterally 6-OH-DA lesioned rats, (-)-9 gave short-acting locomotor activation. Furthermore, in microdialysis studies in rat striatum, (-)-9 potently decreased DA release, confirming its activation of presynaptic DA D2 receptors.

5-(Sulfonyl)oxy-tryptamines and ethylamino side chain restricted derivatives. Structure-affinity relationships for h5-HT1B and h5-HT1D receptors.

A number of sulfonic acid ester derivatives of serotonin (5-hydroxytryptamine; 5-HT; 1) were prepared and their affinities are compared to that of the reference compound 5-[[(trifluoromethyl)sulfonyl]oxy]-tryptamine (8b). The structure-affinity relationship (SAFIR) is discussed in terms of in vitro binding for cloned human h5-HT1A, h5-HT1B and h5-HT1D receptors. All tryptamine derivatives exhibited the best affinities for h5-HT1D receptors but still, these were comparatively lower than that of compound 8b. 5-Tosylated tryptamine 11b (Ki = 6 nM) and the sulfamate derivatives 13b and 14b (Ki = 7 and 11 nM, respectively) were found to have the highest affinities for the h5-HT1D receptor. Other tryptamine derivatives displayed moderate binding for h5-HT1A and h5-HT1B receptors, along with Ki values ranging from 14-20 nM for the h5-HT1D sites. In addition, the syntheses of two alkylamino side chain restricted derivatives are described. 3-Amino-6-[[(trifluoromethyl)sulfonyl]oxy]-1,2,3,4-tetrahydrocarbazol e 21, as well as 4-[5-[[(trifluoromethyl)sulfonyl]oxy]-1H-indol-3-yl]piperidines 24 and 25, induced a shift in selectivity in favor of the h5-HT1B receptor. The relatively longer distance between the basic amine and a hydrogen-bond accepting oxygen in 21, 24 and 25 as compared to the non-restricted tryptamines, is likely responsible for this observation.

Indolizidine and quinolizidine derivatives of the dopamine autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP).

Eight indolizidine and quinolizidine derivatives of 3-PPP were synthesized and tested for possible dopamine (DA) autoreceptor activity. The equatorial indolizidine derivative 19e had the profile of a selective autoreceptor agonist and was half as active as 3-PPP. However, resolution of the compound revealed that the 8R enantiomer was an unselective DA agonist with a profile similar to (+)-3-PPP, while the 8S enantiomer was a weak DA antagonist without any DA agonist activity. The unsaturated quinolizidine derivative 21 also had the profile of a DA antagonist while the axial quinolizidine derivative 18a had an amphetamine-like profile in 6-OHDA-lesioned rats. All other derivatives were inactive. The observed structure-activity relationships were in agreement with existing DA receptor models, although these models are not apparently detailed enough to explain why the 8S enantiomer of 19e is inactive as a DA agonist.