Pharmacodynamic Modeling for Change of Locomotor Activity by Methylphenidate in Rats

Purpose. The locomotive activity changes after intravenous (i.v.) administration of methylphenidate (MPD) in rats were pharmacodynamically analyzed. Methods. MPD concentration in plasma, MPD concentration and dopamine (DA) level in striatal dialysate collected by microdialysis method, and the locomotor activity after i.v. administration of MPD (2, 5 and 10 mg/kg doses) were used for the analysis. Results. The transport of MPD from plasma to the interstitial fluid in the brain could be expressed by the linear two-compartment model. The clockwise hysteresis between the MPD concentration and the DA level in the dialysate could be explained by the pharmacodynamic model considering Michaelis-Menten type reuptake process of the extracellular DA into the terminal of the dopaminergic nerve and its competitive inhibition by the extracellular MPD. The inhibition constant (K_i) of MPD for DA reuptake was estimated to be 41.3 ± 73.8 nM (mean ± SE), which was closely consistent with the in vitro value after correction with dialysis recovery. The relationship between DA level in dialysate and locomotor activity was expressed by the Emax model considering two contrary effects, hyperkinesia and stereotypy. The bi-phasic locomotor activity-time profiles after high dose of MPD could be represented by this model. Conclusions. The developed model made it possible to explain the tolerance in DA increase and the complicated locomotive change induced by MPD, and may be useful for other DA reuptake inhibitors, such as amphetamine and methamphetamine.     

Correlation between 5-HT7 receptor affinity and protection against sound-induced seizures in DBA/2J mice

Audiogenic seizures can be induced in DBA/2J mice following intense auditory stimulation. A number of neurotransmitters, including 5-hydroxytryptamine (5-HT), are believed to be involved in mediating this effect since it has been shown previously that depletion of 5-HT or blockade of 5-HT receptors protects DBA/2J mice from these audiogenic seizures. The present study was undertaken to determine whether antagonism of the newly identified 5-HT₇ receptor may protect DBA/2J mice from audiogenic seizures by attempting to correlate in vivo potency of compounds with their affinity at the 5-HT₇ receptor. All compounds used in the correlation were shown to be antagonists at the 5-HT₇ receptor and a statistically significant correlation was observed between 5-HT₇ affinity and doses for half-maximal response (ED₅₀) for protection of DBA/2J mice from sound-induced seizures (r = 0.80; P < 0.05). No significant correlation was observed between in vivo activity and affinity at either 5-HT_1A, 5-HT_2A or 5-HT_2C receptors. It is also unlikely that interactions between the 5-ht₅ receptor will protect DBA/2J mice from audiogenic seizures since metergoline and mesulergine which are both active in this in vivo model have no affinity for the 5-ht₅ receptor. There are similarities between the pharmacology of the 5-HT₇ receptor and that of the 5-HT_1A receptor, however the correlation between the in vivo potency in DBA/2J mice and 5-HT_1A affinity was not significant. Furthermore, the 5-HT_1A receptor antagonist WAY 100135 did not protect DBA/2J mice from audiogenic seizures at doses that antagonise 5-HT_1A receptor-mediated effects in mice. These data suggest that antagonism of 5-HT₇ receptors may protect against audiogenic seizures in DBA/2J mice although a definitive conclusion must await studies with selective 5-HT₇ antagonists. Received: 20 March 1997 / Accepted: 10 August 1997     

Modulation of cytokine production from an EpiOcular corneal cell culture model in response to Staphylococcus aureus superantigen

The present study investigated the hypothesis that Staphylococcus aureus enterotoxin B (SEE) produces epithelial cell death and releases inflammatory cytokines that produce stromal infiltration during contact lens induced peripheral ulceration. Epithelial cells were incubated with different doses of SEB for various time periods. Culture supernatants were assayed for cytokines IL- lo, IL-6 and chemotactic agents IL-8 and LTB,. SEE induced the production of IL- I p and IL-8. Epithelial cells exposed for longer periods (48 h) with low concentrations of SEB produced significantly higher levels (N0.02) of IL-Ip and IL-8 (P<0.05) compared t o a 24 h exposure. SEB did not induce the production o f IL-6 and     

Implication of the systolic hump in systemic arterial pressure waves

The systolic hump in the aortic blood pressure wave is defined as the aorticresistance component proportional to the aortic blood flow superimposed on the windkessel component. An electrical analogue comprising a series resistance (aortic resistance) plus a resistance (peripheral resistance) and capacitance (aortic compliance) in parallel (i.e. windkessel component) is used for analysis. Curve fitting using the leastsquares method is performed on calculated and measured blood pressure waves from dogs under haemodynamical conditions induced by infusion of three drugs (noradrenaline, isoproterenol and acetylcholine). The curve fitting RMS (root mean square) errors are <3% for blood pressure waves and <30% for blood flow waves, with good agreement between measured and calculated blood flow waveforms. Infusion of noradrenaline and acetylcholine is found to induce a significant decrease and increase in the aortic resistance, respectively. Although only a small fraction of the blood pressure wave, the systolic hump has a marked effect on the systolic pressure waveform.     

A preliminary statistical model for identifying repeaters of parasuicide

This paper presents a statistical model constructed using logisticregression to identify those at high-risk of repeating parasuicide. Thesubjects in the study are Cork city residents who exhibited parasuicidalbehaviour between 1 January and 30 June 1995. Repetition of the behaviourwithin six months of the index episode distinguishes repeaters fromnon-repeaters. The model was designed so that it could be used bynon-clinicians and hence does not require information relating topsychiatric diagnosis or use of psychiatric services. The proportion ofsubjects correctly classified remained stable across a range of cut-pointprobabilities (mean = 86%, range: 83.9–87.5%). Using acut-point of 0.2, 96% of repeaters and 81% of non-repeaters were correctly classified. Using 0.45 led to the correct identification of81% of repeaters and 90% of non-repeaters. If these highlevels of sensitivity and specificity are maintained in validation tests onfuture cohorts in Cork city then the model could form the basis of anintervention programme designed to prevent the repetition of parasuicide.     

指示肺通气不均匀性的熵变及其同其他指标的理论比较

熵代表无序的水平，作者使用通气的熵变（ＥＣＶ）指示肺通气的不均匀性，ＥＣＶ定义为当前泡潮气量趋近于零时每摩尔被吸入气体从不均匀通气到均匀通气的熵变的极限。本文从熵的基本公式民地出ＥＣＶ的计算方程。用几个数学模型肺将ＥＣＶ同其他７个洗出指标进行了比较。８个指标中，只有ＥＣＶ仅取决于通气分布，其他７个指标不仅取决于通气分布，还同潮气量和死腔的大小有关。这影响了它们评价肺通气不均匀性的效果，ＥＣＶ的另一     

贫血患者血清红细胞生成素浓度的测定及临床意义

用小鼠胎肝细胞体外血浆凝块培养红系集落(Erythroid colong formig unit inculturc,E-CFUc)方法,以红细胞生成素(Erythropoietin,EPO)850323为标准试剂,测定正常人、贫血病人血清EPO浓度。实验用妊娠13～15d小鼠胎肝细胞。血清均经透析处理,培养液中加量最大不超过10％。EPO(850323)在培养液中浓度为2.5～100mU/ml。血清EPO(mU/ml)测定结果:28例正常人为48.O±17.7,12例再生障碍性贫血病人为946～>10000,1例巨幼细胞性贫血病人为500,1例缺铁性贫血病人为400和18例慢性肾功能衰竭病人则为94.2±87.6。结果表明:贫血病因对血清EPO浓度有影响。     

Transactional models of early education effectiveness - What is the message for policy?

There is now a substantial body of American research evidence demonstrating that early education programmes can have major long term effects right through into adult life. Cost-benefit analysis has enabled the data to be transformed into a compelling case for public financial investment. But insufficient attention has been paid to explaining how a short term preschool programme could have such enduring effects. The effects are best understood by applying a transactional model which shows how processes in the school and community transformed and amplified short term effects into long term outcomes. Adopting a transactional model modifies the messages for policy. The results of evaluations carried out in one society may not apply in another. In some school systems there may be more effective strategies than early education for improving educational prospects.     

Development of intestinal epithelial cell lines using a transgenic mouse

The epithelial cells of the colonic mucosa of the animal have proved impossible to culture using standard tissue culture techniques. Immortalization of adult colonic epithelial cells has been unsuccessful due to the lack of DNA synthesis in these cells once they are isolated from the tissue. Recently an unique transgenic mouse bearing a temperature sensitive mutant of the known immortalizing gene, SV40 large T has become available. The advantage of this mouse is that the SV40 large T gene is expressed in every cell. Active immortalizing protein is produced in each cell at the permissive temperature. We have used colonic mucosa from these mice to initiate cultures of epithelial cells from the colon of adult mice. The cells grow readily at the permissive temperature but die within 7 days at the non-permissive temperature. The methods used to develop these cultures are described.     

Ethanol regulated preference in rats

A series of experiments evaluated the determinants of preference for mixtures of ethanol plus sucrose relative to sucrose in rats. One dipper served 10% ethanol mixed with 10% sucrose, and the second dipper served 10% sucrose. Lever presses operated each dipper according to a variable-interval 5-s schedule. In three experiments the subjects were given pre-session meals of sucrose (2.5–20 ml) or sucrose (20 ml) plus chow (5 or 10 g). Pre-session meals decreased responding maintained by sucrose but not responding maintained by ethanol mixture. In two experiments body weight was varied from 85% to 125% of the initial free-feeding values. Increases in body weight, like pre-session meals, decreased responding reinforced by sucrose, but typically did not decrease responding reinforced by ethanol mixture. Throughout most of the study, ethanol consumption remained at about 1.25 ml per half hour session (3–4 g/kg per 30 min). For example, pre-session access to ethanol mixture decreased within-session ethanol consumption, but total consumption, counting both sources, remained about 1.25 ml/session. The within-session patterns of responding also differed. Responding reinforced by ethanol mix decreased as a function of ethanol consumption, whereas responding reinforced by sucrose was relatively constant throughout the session. The simplest explanation of the results is that ethanol's pharmacological consequences regulated preference.