The distribution of (-)-propranolol in the isolated rabbit iris

It has been postulated that propranolol lowers the intraocular pressure by adrenergic neurone block. However, in the isolated iris of albino rabbits, there was only a small degree of cocaine-sensitive (i.e., neuronal) accumulation of ³H-(-)-propranolol, and none at all after pretreatment of the animals with reserpine. Moreover, after preloading of the iris with ³H-(-)-propranolol, veratridine failed to release any labelled material. Hence, any adrenergic neurone blocking action of propranolol is highly unlikely.Albino and pigmented irides were first exposed to ³H-(-)-propranolol and then washed out. The results and their compartmental analysis indicated an extensive binding of ³H-(-)-propranolol in or at pigment cells; the binding is characterized by a low dissociation constant. It is very likely that the initial binding and the subsequent slow dissociation from pigment cells explains the long duration of action of beta-adrenoceptor antagonists in human therapy.     

Rolipram forms a potent discriminative stimulus in drug discrimination experiments in rats

Long Evans rats were trained to discriminate 0.2 mg/kg IP (±)-rolipram from vehicle injection in a food-motivated two-lever operant task. Eight out of nine rats acquired the discrimination after an average of 91 sessions (min 65, max 137). The ED₅₀ of (±)-rolipram was 0.06 mg/kg IP. Generalization tests with (–)- and (+)-rolipram showed that the (–)-isomer was 8 times more active than (+)-rolipram with an ED₅₀ of 0.06 and 0.4 mg/kg IP respectively. The phosphodiesterase inhibitor RO 20-1724 partially (83%) generalized to (±)-rolipram in doses of 0.6 and 1.0 mg/kg IP. IBMX 5 mg/kg IP showed 63% generalization. Tests with imipramine and the (+)- and (–)-isomer of the noradrenaline uptake inhibitor oxaprotiline suggest that NA-uptake inhibiting drugs do not form an interoceptive cue which is (±)-rolipram-like. dbcAMP 12.5 mg/kg SC and 100 mg/kg SC dbcGMP did not generalize to the training drug. The nature of the discriminative stimulus produced by this dose of (±)-rolipram in rats remains to be elucidated. Offprint requests to: R. Ortman     

Discriminative stimulus properties of β-carbolines characterized as agonists and inverse agonists at central benzodiazepine receptors

The discriminative stimulus properties of three h/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-carboline derivatives were studied in three groups of rats trained, respectively, to discriminate diazepam (2.5 mg/kg IP), chlordiazepoxide (CDP, 5 mg/kg IP) or pentylenetetrazol (PTZ, 15 mg/kg IP) from saline in standard procedures employing two-lever operant chambers. Two h/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-carbolines, ZK 91296 and ZK 93423, substituted for the benzodiazepines in both CDP- and diazepam-trained rats. The neutral benzodiazepine antagonist Ro 15-1788 blocked the diazepam discriminative stimulus and the ability of ZK 91296 to substitute for diazepam. A third h/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-carboline, FG 7142, was not identified as benzodiazepine-like in generalization tests in either diazepam- or CDP-trained rats, but when administered together with CDP antagonized the benzodiazepine discriminative stimulus. In rats trained to discriminate PTZ from saline (a discrimination which is thought to depend on the anxiogenic properties of PTZ) the PTZ cue was antagonized by diazepam and ZK 93423, and partially antagonized by ZK 91296. The PTZ cue generalized to FG 7142 and this generalization was partially antagonized by Ro 15-1788. These results suggest that the three h/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-carbolines provide more than one kind of discriminative stimulus, consistent with the classification of ZK 93423 as an agonist at central benzodiazepine receptors, with ZK 91 296 as a partial agonist, and with FG 7142 as an inverse agonist. Pharmacologically, ZK 93 423 and ZK 91 296 may exhibit anxiolytic qualities, whereas FG 7142 produces anxiogenic effects.     

Alpha-adrenoceptors, 5-hydroxytryptamine receptors and the action of dihydroergotamine in human venous preparations obtained during saphenectomy procedures for varicose veins

Summary Changes in tension were monitored isometrically on spiral strips from human saphenous veins obtained during surgical removal of varicose veins. Concentration-response curves for noradrenaline and 5-hydroxytryptamine (5-HT) were established by cumulative administrations, curves for dihydroergotamine were constructed from the mean responses to single concentrations. The use of the antagonists prazosin, yohimbine and pizotifen provided evidence for the existence of both postjunctional h012n24/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₁- and h012n24/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">₂-adrenoceptors and for the existence of 5-HT receptors. The venoconstrictor effects of dihydroergotamine were unchanged by prazosin. Yohimbine antagonized both dihydroergotamine and 5-HT at about 60 times higher concentrations than required against noradrenaline whereas pizotifen inhibited responses to both dihydroergotamine and 5-HT at about 100 times lower concentrations than those to noradrenaline.These new results are in contrast to conclusions drawn from animal studies and do not support the suggestion that in man the venoconstrictor activity of dihydroergotamine is mediated through stimulation of h012n24/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-adrenoceptors. The present results strongly suggest that in human saphenous veins the constrictor activity of dihydroergotamine is mediated at least in part through stimulation of 5-HT receptors.     

A qualitative exploration of the mechanisms,pathways and public health outcomes of a city centre 20mph speed limit intervention: The case of Belfast,United Kingdom

Twenty miles per hour (mph) speed limits can impact the health of the public (e.g., road safety, active travel). However, a better understanding of how individuals experience 20mph limits is required, to ensure interventions are cognisant of perceptions and potential un/intended outcomes. Focus groups (n = 9, 60 participants) to explore the Belfast 20mph intervention highlighted divergent perspectives and experiences including: 12 mechanisms (e.g., limited awareness), 15 pathways (e.g., reduced driving speed→improved liveability) and 10 public health outcomes (e.g., increased cyclist safety). Future interventions should consider un/intended outcomes and implement strategies to enhance effectiveness and mitigate harms (e.g., through training, enforcement).     

选择性动脉造影在不明原因的下消化道出血诊断中的价值探讨

目的 探讨选择性动脉造影和造影时机选择在不时原因下消化道出血诊断中的价值。方法 运用Seldinger技术对32例患者进行选择性肠系膜上、下动脉及其分支造影,其中少量出血患者17例,中至大量15例。首次出血3例,2次以上反复出血29例。结果 32例中28例发现病变（87.5%）,其中肿瘤性病变（n=15）非肿瘤性病变（n=13）,少理出血未见造影剂外溢征,中至大量出血中造影剂外溢征占33％。结论 选择性动脉造影检查下消化道出血是一种安全、有效的方法,在少量出血和出血间歇期仍有很大价值;造影显示病变部位更重要于显示出血征象。     

高血压病患者血压40例昼夜模式分析

目的 探讨高血压病患者的血压昼夜模式,为临床治疗提供依据。方法 按WHO标准选40例高血压病人,用美国罗京公司产2420－2020型动态血压仪连续观察血压24h,结束后使用该机器配置的计算机回放进行分析,观察24h昼夜间平均收缩压、舒张压及标准差,观察血压负荷及血压模式。统计方法采用t检验。结果 构型组昼夜平均收缩压、舒张压、血压变异均值昼＞夜（P＜0．05）;收缩压和舒张压负荷昼＝夜,差异无显著性（P＞0．05）;非构型组平均收缩压、舒张压及血压变异昼夜差异无显著性（P＞0．05）,但收缩压与舒张压负荷夜间明显高于日间,差异有显著性（P＜0．01）。结论 血压昼夜变化受交感神经与肾素血管紧张素系统等双重作用有关。     

Characterisation of the IgE-binding immunodominant epitopes on Ara h1

Peanut allergy is one of the most severe food allergies due to its persistency and life-threatening character. Serum IgE from patients with documented peanut hypersensitivity reactions and synthetic peptides were used to screen the linear IgE-binding epitopes on the major peanut allergen, Ara h 1. Five major epitopes that bound peanut-specific serum IgE from more than 60% of patients tested were identified. Mutational analysis of the immunodominant epitope showed that single amino acid changes had dramatic effects on IgE-binding characteristics. Mapping and characterisation of the IgE-binding epitopes on Ara h1 could be used in future immunotherapeutic approaches for peanut allergy disease.     

Human myeloma light chains with increased molecular weight: high frequency among lambda chains

The discovery of a human myeloma protein comprising a kappa L-chain with an increased mol. wt of 30,000) (Bouvet et. al., 1980) prompted investigations on the incidence of such heavier L-chains among other human myeloma proteins. In 105 samples examined, 34 were found to have L-chains heavier than normal (23,000-24,000), ranging from 25,000 up to 31,000, and five of lighter mol. wt (21,000-22,000). These mol. wt abnormalities were detected by electrophoresis in sodium dodecyl sulfate 10% polyacrylamide gels (SDS-PAGE) after reduction with 2-mercaptoethanol. The mol. wt of three of the heavier kappa or lambda chains was also estimated by filtration through a Sephadex G100 column and by sedimentation equilibrium. All three methods indicated a mol. wt increase of about 15-25% as compared with the usual mol. wt. The distribution of the high mol. wt chains among all L-chains examined was found to be 11 out of 62 kappa chains (17.7%) and 23 out of 43 lambda chains (53%) (P less than 0.001). A preferential association of such L-chains with H-chains producing multiple bands in SDS-PAGE (P less than 0.01) and an association between multiple L-chain and multiple H-chain band (P less than 0.05) were also observed. In contrast, no abnormal L-chain was found in immunoglobulins from normal subjects. Spontaneous degradation of the normal H-chains sometimes yielded fragments of 30,000 mol. wt. These fragments were easily distinguishable from abnormal L-chains. The nature of extra mol. wt in heavy L-chains was investigated for the presence of carbohydrate moiety. Four large and three normal size L-chains were examined for amino-sugar and sialic acid content. A small amount (one residue per molecule) of amino-sugar was detected only in two normal and two heavy L-chains, whereas sialic acid was only found in the heaviest (27,000-30,000) L-chains (Lh) and in small percentage (one or two residues per molecule). Total sugar estimation in one Lh chain indicated a proportion not exceeding three or four residues per L-chain (mol. wt 1,000) and this is insufficient to explain the 15-25% (3,600-6,000) mol. wt increase. It is therefore possible that, at least in some heavy myeloma L-chains, an additional peptide is expressed. Whatever the nature of the increase it would be of interest to elucidate whether this is a marker of malignant process or of an intermediate step of normal Ig synthesis.