LHRH-A对孕中期大鼠抗妊娠作用的研究

本文观察了[D-Ala⁶,Pro⁹-Ethylamide¹⁰]-LHRH(LHRH-A)对孕中期大鼠的抗妊娠作用。结果显示:在孕9～11d sc 200μg/d LHRH-A,血浆孕酮水平自第二次给药后明显下降(P<0.05),给药大鼠均流产终止妊娠;LHRH-A的抗妊娠作用可被醋酸甲地孕酮所拮抗;LHRH-A对体外培养的假孕大鼠和孕d 9大鼠黄体细胞分泌孕酮有明显的直接抑制作用。     

GGA1 acts as a spatial switch altering amyloid precursor protein trafficking and processing

The beta-amyloid (Abeta) precursor protein (APP) is cleaved sequentially by beta-site of APP-cleaving enzyme (BACE) and gamma-secretase to release the Abeta peptides that accumulate in plaques in Alzheimer's disease (AD). GGA1, a member of the Golgi-localized gamma-ear-containing ARF-binding (GGA) protein family, interacts with BACE and influences its subcellular distribution. We now report that overexpression of GGA1 in cells increased the APP C-terminal fragment resulting from beta-cleavage but surprisingly reduced Abeta. GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity. GGA1 blunted only APP but not notch intracellular domain release. These results suggest that GGA1 prevented APP beta-cleavage products from becoming substrates for gamma-secretase. Direct binding of GGA1 to BACE was not required for these effects, but the integrity of the GAT (GGA1 and TOM) domain of GGA1 was. GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP-GGA1 interactions may have pathophysiological relevance in AD.     

Evaluation and audit in a paediatric disability service

Parental and professional responses to questionnaires evaluating a paediatric disability service are reported and the viability of auditing structural, process, and outcome aspects of clinical practice are discussed. Expectations of waiting time to first appointment (met for only 52% of consumers) illustrate structural issues. Process issues are reflected in consumer reactions to outreach work (for example, 94% of parents and 84% of professionals found this supportive). Outcome measures such as consumer satisfaction with the service (76% of consumers reported being 'very satisfied' and 20% 'fairly satisfied') suggest that service aims are being met. Good concurrence of service aims with consumer needs is indicated by parental reasons for referral (for example, 75% for diagnostic help, 73% for a better understanding of the disorder, 88% for practical help), referrers' reasons (for example, 55% for a second diagnostic opinion, 45% due to lack of local expertise), and reports from most other professionals involved with the case that a similar service was not provided locally.     

Withdrawal of magnesium causes vasospasm while elevated magnesium produces relaxation of tone in cerebral arteries

Excised middle cerebral and basilar arteries from dogs were incubated in Krebs-Ringer bicarbonate solution and exposed to normal, high and low concentrations of magnesium [Mg] in the medium. Sudden withdrawal of extracellular Mg²⁺ ([Mg²⁺]_o) from the medium produced contraction of arterial smooth muscle, whereas elevated concentrations of [Mg²⁺]_o decreased the basal tensions in a concentration-dependent manner.     

总粉尘浓度转换为呼吸性粉尘浓度的两种方法学研究

目的探讨流行病学研究中历史性总粉尘浓度转换成呼吸性粉尘浓度的理论方法。方法采用两种方法：一种通过体积直接计算;另一种用ＨａｔｃｈＣｈｏａｔｅ方程计算,推导出计数百分比和计量百分比的转换关系。结果得到总粉尘浓度与呼吸性粉尘浓度的理论转换系数,其中,用ＨａｔｃｈＣｈｏａｔｅ方程计算结果偏低。结论体积直接计算法更适用。     

Hydrogen peroxide induces contraction and raises [Ca2+]i in canine cerebral arterial smooth muscle: participation of cellular signaling pathways

The effects of hydrogen peroxide (H2O2) on isolated canine basilar arteries, and single smooth muscle cells isolated from these arteries, were investigated in the present study. Exposure of isolated endothelium-intact and denuded arterial rings to H2O2, at concentrations of 2.2x10(-5) M to 4.4x10(-3) M, produced concentration-dependent contractile responses. Removal of the endothelium attenuated, but did not eliminate the contractions. H2O2-induced contractions were inhibited, to different degrees, by preincubation of the vessels with low concentrations of staurosporine or bisindolylmaleimide I HCl [antagonists of protein kinase C (PKC)], G?6976 (a PKCalpha and PKCbeta1 selective antagonist), genistein (an antagonist of protein tyrosine kinase), PD-98059 (an antagonist of mitogen-activated protein kinase), wortmannin [an antagonist of phosphatidylinositol 3 (PI3)-kinases], and LY-294002 (an antagonist of PI3-kinases). These agents were also found to relax arteries precontracted by H2O2. Removal of extracellular Ca2+ or pretreatment of the vessels with 5.0 microM verapamil markedly attenuated the contractions. Complete inhibition of the contractile response was obtained after buffering intracellular Ca2+ with BAPTA-AM. A variety of specific pharmacological antagonists of several known vasoconstrictors neither inhibited nor attenuated the H2O2-induced contractions. Exposure of smooth muscle cells to H2O2 (4.4x10(-6) M to 4.4x10(-4) M) significantly raised intracellular Ca2+ ([Ca2+]i) within 20 s. This was abolished in the absence of extracellular Ca2+ or after application of 5.0 microM verapamil. Pretreatment of the cells with low concentrations of staurosporine, bisindolylmaleimide I, G?6976, genistein, PD-98059, wortmannin, and LY-294002 markedly suppressed the H2O2-mediated [Ca2+]i elevation. The present findings suggest that hydrogen peroxide, in vitro, produces endothelium-dependent and independent contractions of canine basilar arteries, which are clearly Ca2+-dependent and are not associated with release of endogenous vasoconstrictors. Several intracellular signal transduction systems, such as PKC (both Ca2+-dependent and Ca2+-independent), protein tyrosine phosphorylation, IP3, mitogen-activated protein kinase and PI3 kinase appear to play a role in the H2O2-induced contractions in cerebral arterial muscle.     

Propranolol induces contractions of canine small and large coronary arteries

Summary Using isolated canine small (right coronary branch, left coronary branch; o. d. 0.4–0.8 mm) and large (left coronary, circumflex; o. d. 1–2 mm) coronary arteries, thebeta-adrenergic antagonist dl-propranolol (5×10^–7 to 5×10^–5 m/l) was found to produce concentration-dependent contractions. Interestingly, most of these contractile events take place with concentrations of propranolol (0.1–1 g/ml) found in the blood of patients who are taking this drug for various therapeutic reasons. These propranolol-induced contractions were enhanced in Krebs-Ringer solution containing slightly elevated (weak contractile) concentrations of potassium (15 mmol/l). Experiments with specific pharmacologic antagonists indicated that propranolol-induced contractions on canine coronary arteries can not be mediated by release (or inhibition) of catecholamines, histamine, sertonin or acetycholine. Propranolol contractions could be relaxed by low concentrations of potassium ions (4 mmol/l), suggesting that thebeta receptor antagonist might inactivate coronary arterial membrane Na⁺, K⁺-ATPase. Other experiments demonstrated that propranolol can enhance coronary arterial membrane permeability to calcium ions; these observations suggest that propranolol might sensitize coronary vascular smooth muscle cells to calcium ions. Removal of calcium ions from the Krebs-Ringer solution or addition of the calcium entry blocker, verapamil, prevented completely the propranolol-induced contractions. Catecholamines (i.e., epinephrine, norepinephrine, isoproterenol), which normally induce relaxation on these isolated coronary arteries, always induced contraction after use of dl-propranolol. Overall, these experiments suggest that the so-called beta-blocker poisoning sometimes noted with propranolol in patients might be brought about by four actions of this drug acting in concert: 1. direct coronary arterial vasospasm; 2. an unmasking of normally silentalpha-adrenergic receptors, thus allowing circulating and released catecholamines to induce potent coronary constriction; 3. attenuation of membrane Na⁺, K⁺-ATPase activity; and 4. an enhancement of coronary vascular smooth muscle membrane permeability to calcium ions.

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Zusammenfassung An isolierten Präparaten verschiedener Abschnitte des Koronararteriensystems vom Hund bewirkte der -adrenerge Antagonist dl-Propranolol (5×10^–7 bis 5×10^–5 mmol/l) Kontraktionen der glatten Gefäßmuskulatur. Interessanterweise treten solche Kontraktionen häufig in einem Konzentrationsbereich von Propranolol (0,1–1 g/ml) auf, wie er bei Patienten verzeichnet wird, die diese Substanz aus therapeutischen Gründen einnehmen. Diese Propranolol-induzierte Kontraktionen wurden in Krebs-Ringer-Lösung durch leichte Steigerung der K⁺-Konzentration (15 mmol/l) verstärkt. Experimente mit spezifischen pharmakologischen Antagonisten wiesen darauf hin, daß Propranolol-induzierte Kontraktionen an den Koronararterien vom Hund nicht durch Freisetzung (oder Hemmung) von Katecholaminen, Histamin, Serotonin oder Acetylcholin vermittelt werden kann. Bei Propranolol-induzierten Kontraktionen führten geringe K⁺-Konzentrationen (4 mmol/l) zur Erschlaffung; als mögliche Ursache wird eine Inaktivierung der membranären Na⁺, K⁺-ATPase diskutiert. Andere Experimente zeigten, daß Propranolol die Membranpermeabilität bzw. die Empfindlichkeit für Ca²⁺-Ionen steigern kann. Beseitigung der Ca²⁺-Ionen aus der Krebs-Ringer-Lösung oder Applikation des Ca²⁺-Antagonisten Verapamil verhinderten die Propranolol-induzierten Kontraktionen völlig. Katecholamine (Adrenalin, Noradrenalin, Isoproterenol), die normalerweise eine Erschlaffung der isolierten Koronararterien bewirken, induzierten nach Anwendung von dl-Propranolol immer Kontraktionen. Insgesamt lassen diese Experimente vermuten, daß die sog. -Blockervergiftung, die gelegentlich bei Propranolol-behandelten Patienten verzeichnet wird, auf einem Zusammenwirken von 4 verschiedenen Mechanismen dieser Substanz beruht: 1. direkter arterieller Spasmus, 2. Demaskierung eines alpha-adrenergen Rezeptors, 3. Abschwächung der Aktivität einer membranären Na⁺, K⁺-ATPase, 4. Steigerung der Membranpermeabilität des vaskulären glatten Muskels für Ca²⁺-Ionen.

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This work was supported in part by research grants HL 18015 and DA 02339 from the U.S.P.H.S., D.H.E.W.