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.     

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。     

Halofantrine metabolism in microsomes in man: major role of CYP 3A4 and CYP 3A5.

We have clarified the contribution of the different enzymes involved in the N-debutylation of halofantrine in liver microsomes in man. The effect of ketoconazole and cytochrome P450 (CYP) 3A substrates on halofantrine metabolism has also been studied. The antimalarial drug halofantrine is metabolized into one major metabolite, N-debutylhalofantrine. In microsomes from nine livers from man, N-debutylation of halofantrine was highly variable with apparent Michaelis-Menten constant V(max) and K(m) values of 215+/-172 pmol min(-1) mg(-1) and 48+/-26 micromol L(-1), respectively, (mean+/-standard deviation). Formation of N-debutylhalofantrine was cytochrome P450 (CYP)-mediated. Studies using selective inhibitors of individual CYPs revealed the role of CYP 3As in the formation of N-debutylhalofantrine. alpha-Naphthoflavone, a CYP 3A activator, increased metabolite formation. In microsomes from 12 livers from man the rate of N-debutylation of halofantrine correlated strongly with CYP 3A4 relative levels (P = 0.002) and less strongly, but significantly, with CYP 2C8 levels (P = 0.025). To characterize CYP-mediated metabolism of halofantrine further, incubations were performed with yeast microsomes expressing specific CYP 3A4, CYP 3A5, CYP 2D6, CYP 2C8 and CYP 2C19 from man. The rate of formation of N-debutylhalofantrine was six- and twelvefold with CYP 3A4 than with CYP 3A5 and CYP 2C8, respectively. CYP 2D6 and CYP 2C19 did not mediate the N-debutylation of halofantrine, but, because in-vivo CYP 2C8 is present at lower concentrations than CYP 3A in the liver in man, the involvement of CYP 3As would be predominant. Diltiazem, erythromycin, nifedipine and cyclosporin (CYP 3A substrates) inhibited halofantrine metabolism. Similarly, ketoconazole inhibited, non-competitively, formation of N-debutylhalofantrine with an inhibition constant, K(i), of 0.05 microM. The theoretical percentage inhibition of halofantrine metabolism in-vivo by ketoconazole was estimated to be 99%. These results indicate that both CYP 3A4 and CYP 3A5 metabolize halofantrine, with major involvement of CYP 3A4. In-vivo, the other CYPs have a minor role only. Moreover, strong inhibition, and consequently increased halofantrine cardiotoxicity, might occur with the association of ketoconazole or other CYP 3A4 substrates.     

Behaviour and physiological responses during prone and supine sleep in early infancy

AIMS: To study the effect of prone and supine sleep on infant behaviour, peripheral skin temperature, and cardiorespiratory parameters to aid understanding of why prone sleeping is associated with an increased risk of sudden infant death syndrome. METHODS: Of 33 enrolled infants, 32 were studied at 2.5 and 28 at 5 months of age. A computer aided multichannel system was used for polysomnographic recordings. Behaviour was charted separately. RESULTS: Prone REM (active) sleep was associated with lower frequencies of short arousals, body movements and sighs, and a shorter duration of apnoeas than supine REM sleep at both ages. At 2.5 months there were less frequent episodes of periodic breathing during prone sleep in non-REM (quiet) and REM sleep. Heart rate and peripheral skin temperature were higher in the prone position during both sleep states at both ages. CONCLUSIONS: The observation of decreased variation in behaviour and respiratory pattern, increased heart rate, and increased peripheral skin temperature during prone compared with supine sleep may indicate that young infants are less able to maintain adequate respiratory and metabolic homoeostasis during prone sleep.     

Modulation of early stress-induced neurobiological changes: a review of behavioural and pharmacological interventions in animal models

Childhood adversity alters the predisposition to psychiatric disorders later in life. Those with psychiatric conditions and a history of early adversity exhibit a higher incidence of treatment resistance compared with individuals with no such history. Modulation of the influence early stress exerts over neurobiology may help to prevent the development of psychiatric disorders in some cases, while attenuating the extent of treatment resistance in those with established psychiatric disorders. This review aims to critically evaluate the ability of behavioural, environmental and pharmacologic interventions to modulate neurobiological changes induced by early stress in animal models. Databases were systematically searched to locate literature relevant to this review. Early adversity was defined as stress that resulted from manipulation of the mother–infant relationship. Analysis was restricted to animal models to enable characterisation of how a given intervention altered specific neurobiological changes induced by early stress. A wide variety of changes in neurobiology due to early stress are amenable to intervention. Behavioural interventions in childhood, exercise in adolescence and administration of epigenetic-modifying drugs throughout life appear to best modulate cellar and behavioural alterations induced by childhood adversity. Other pharmacotherapies, such as endocannabinoid system modulators, anti-inflammatories and antidepressants can also influence these neurobiological and behavioural changes that result from early stress, although findings are less consistent at present and require further investigation. Further work is required to examine the influence that behavioural interventions, exercise and epigenetic-modifying drugs exert over alterations that occur following childhood stress in human studies, before possible translational into clinical practice is possible.     

Augmentative and Alternative Communication (AAC) for adults with severe aphasia: where we stand and how we can go further

Purpose: To review literature specific to the use of AAC with adults who have severe aphasia. Method: The authors reviewed studies involving AAC interventions for adults with severe aphasia. Results: Published data support the use of aided and unaided AAC with adults with severe aphasia in controlled treatment contexts. Reported gains in communication typically have not generalized to everyday settings. Conclusions: The application of AAC with persons with severe aphasia must address factors potentially limiting treatment success outside of training environments.