Morbidity among anaesthetists

Anaesthetists may be exposed to a number of occupational hazards. These include exposure to infections, environmental pollution with volatile anaesthetic agents and psychological and stress-related illness which may predispose to drug dependence or suicide.     

Oestrogen and progesterone do not regulate the expression of retinoic acid receptors and retinoid 'X' receptors in human endometrial stromal cells in vitro

Elucidation of the gene structure for retinoic acid receptor-(RAR-) has suggested a potential role for oestrogen in regulatingthe expression of RAR-. We have previously shown that all threeRAR types are expressed in human endometrial stromal cells invitro and that RAR- expression is induced in response to retinoicacid. The aim of this study was to ask whether oestradiol andprogesterone could play a part in regulating the expressionof RARs in human endometrial stromal cells and to establishthe patterns of expression of a related group of nuclear retinoidreceptors, retinoid ‘X’ receptors (RXRs) and theirpotential for regulation by steroid hormones. The RAR expressionpatterns of endometrial stromal cells, grown in steroid-freemedium, did not change in response to the presence of steroidhormones. Furthermore, the retinoic acid-mediated inductionof RAR- was not affected by oestradiol or progesterone, andwas dependent on the continued presence of retinoic acid. Ofthe three RXR types, only RXR- was detectably expressed in stromalcells in vitro and the expression of RXR- did not change inresponse to steroid hormones or retinoic acid. These data indicatethat oestradiol and progesterone are not important in the regulationof RAR and RXR expression in human endometrial stromal cells.     

Variation in the expression of cellular retinoid binding proteins in human endometrium throughout the menstrual cycle

Human endometrium is a glandular epithelial tissue with a substantialunderlying stroma. Under the influence of ovarian steroids,endometrium undergoes a cyclical pattern of proliferation followedby secretory differentiation. Since retinoids promote the differentiationof many epithelia to secretory phenotypes they may be involvedin controlling the secretory differentiation of human endometrialepithelium. Cytosolic binding proteins for retinol (cellularretinol binding protein) and retinoic acid (cellular retinoicacid binding protein) may play an important part in regulatingthe availability of retinoic acid to its nuclear receptors andwe have therefore asked whether expression of mRNA for theseproteins varies in relation to endometrial differentiation.In a series of 54 endometrial biopsies, both endometrial epithelialand stromal cells expressed mRNA for cellular retinol bindingprotein type I at a constant level throughout the menstrualcycle. Cellular retinoic acid binding protein type II was alsoexpressed but the level of expression varied dramatically, beingelevated in the proltferative phase and depressed during thesecretory phase of the menstrual cycle in both epithelial andstromal cells. These data suggest that cytosolic binding proteinsmodulate the supply of retinoic acid to the nuclei of endometrialcells during the menstrual cycle and that retinoic acid is involvedin the cyclical control of endometrial differentiation. cellular retinoic acid binding protein/cellular retinol binding protein/endometrium     

The pharmacology of RS-15385-197, a potent and selective α2-adrenoceptor antagonist

1 RS-15385-197 ((8aR, 12aS, 13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(methylsul- phonyl)-6H-isoquino [2,1-g][1,6]-naphthyridine) was evaluated in a series of in vitro and in vivo tests as an antagonist at α₂-adrenoceptors.2 RS-15385-197 had a pK_i of 9.45 for α₂-adrenoceptors in the rat cortex (pA₂ in the guinea-pig ileum of 9.72), whereas the 8aS, 12aR, 13aR enantiomer, RS-15385-198, had a pK_i of only 6.32 (pA₂ 6.47) indicating a high degree of stereoselectivity. The racemate RS-15385-196 had a pK_i of 9.18.3 RS-15385-197 showed unprecedented α₂ vs. α₁ adrenoceptor selectivity in vitro. In the rat cortex, RS-15385-197 had a pK_i of 9.45 in displacing [³H]-yohimbine and 5.29 in displacing [³H]-prazosin (α₂/α₁ selectivity ratio in binding experiments > 14000). The compound had a pA₂ of 9.72 as a competitive antagonist of the inhibitory effects of UK-14,304 in transmurally-stimulated guinea-pig ileum and 10.0 against BHT-920-induced contractions in dog saphenous vein (DSV); this latter value was unaltered by phenoxybenzamine. An apparent pK_B of 5.9 was obtained against cirazoline-induced contractions in DSV, whilst a pA₂ of 6.05 was obtained against phenylephrine-induced contractions in the rabbit aorta (α₂/α₁ selectivity ratio in functional experiments > 4000).4 RS-15385-197 was highly selective for α₂-adrenoceptors over other receptors: the compound showed low affinity for 5-HT_1A (pK_i 6.50) and 5-HT_1D (pK_i 7.00) receptor subtypes, and even lower affinity (pK_i≤5) for other 5-HT receptor subtypes, dopamine receptors, muscarinic cholinoceptors, β-adrenoceptors and dihydropyridine binding sites. RS-15385-197 was devoid of affinity for the non-adrenoceptor imidazoline binding site, labelled by [³H]-idazoxan, which provides further evidence that these sites are not related to α₂-adrenoceptors. In the DSV, contractile responses to 5-hydroxytryptamine (5-HT) were unaffected by a concentration of 1 μM RS-15385-197.5 RS-15385-197 was non-selective for the α_2A- and α_2B-adrenoceptor subtypes in that the pK_i for the α_2A-adrenoceptor in human platelets was 9.90 and the pK_i for the α_2B-adrenoceptor in rat neonate lung was 9.70. However, RS-15385-197 showed lower affinity for the α₂-adrenoceptor subtype in hamster adipocytes (pK_i 8.38).6 In anaesthetized rats, RS-15385-197 was a potent antagonist of the mydriasis response induced by UK-14,304 or clonidine (AD₅₀ 5 and 7 μg kg^-1, i.v., respectively; 96 μg kg^-1, p.o.) and of UK-14,304-induced pressor responses in pithed rats (AD₅₀ 7 μg kg^-1, i.v.); the compound therefore is both centrally and orally active. Even at a high dose (10 mg kg^-1, i.v.), RS-15385-197 did not antagonize pressor responses to cirazoline in pithed rats, indicating that the selectivity for α₂ vs. α₁-adrenoceptors was maintained in vivo.8 RS-15385-197 is therefore a very potent, selective, competitive α₂-adrenoceptor antagonist, both in vitro and in vivo, is orally active and readily penetrates the brain. It will thus be a powerful pharmacological tool for exploring the various physiological roles of α₂-adrenoceptors.     

对发展中国家改善用药的10点建议

WHO建议改善药品管理的工作要在国家药物政策保障之下.在许多国家,执行国家药物政策的机制是实施国家基本药物计划,其要点是强调公共领域的药品选择、采购、流通与使用的合理性.不适当的处方使医疗质量降低并导致资源浪费.本文以探讨在国家药物政策范畴内鼓励更合理地使用药品的问题为重点,在已有证据的基础上,详细阐明基本药物计划内容中的合理用药问题.本文评述了在发展中国家改善用药状况的有效策略及最新知识,并为决策者与管理者提出达到改善用药目标的建议.