BACKGROUND & AIMS: :As the malaria parasite, Plasmodium falciparum, grows within its host erythrocyte it induces an increase in the permeability of the erythrocyte membrane to a range of low-molecular-mass solutes, including Na+ and K+ (ref. 1). This results in a progressive increase in the concentration of Na+ in the erythrocyte cytosol. The parasite cytosol has a relatively low Na+ concentration and there is therefore a large inward Na+ gradient across the parasite plasma membrane. Here we show that the parasite exploits the Na+ electrochemical gradient to energize the uptake of inorganic phosphate (P(i)), an essential nutrient. P(i) was taken up into the intracellular parasite by a Na+-dependent transporter, with a stoichiometry of 2Na+:1P(i) and with an apparent preference for the monovalent over the divalent form of P(i). A P(i) transporter (PfPiT) belonging to the PiT family was cloned from the parasite and localized to the parasite surface. Expression of PfPiT in Xenopus oocytes resulted in Na+-dependent P(i) uptake with characteristics similar to those observed for P(i) uptake in the parasite. This study provides new insight into the significance of the malaria-parasite-induced alteration of the ionic composition of its host cell.

背景与目标： ：由于疟原虫恶性疟原虫在其宿主红细胞内生长，导致红细胞膜对一系列低分子质量溶质（包括Na和K）的渗透性增加（参考文献1）。这导致红细胞溶质中Na的浓度逐渐增加。寄生虫的细胞质具有相对较低的Na浓度，因此在整个寄生虫质膜上都有较大的内向Na梯度。在这里，我们显示该寄生虫利用Na电化学梯度来激发对无机磷酸盐（P（i））（一种基本营养素）的吸收。 P（i）被Na依赖性转运蛋白吸收到细胞内的寄生虫中，化学计量比为2Na：1P（i），显然单价优于P（i）的二价形式。从该寄生虫克隆了一个属于PiT家族的P（i）转运蛋白（PfPiT），并将其定位于该寄生虫的表面。 PfPiT在非洲爪蟾卵母细胞中的表达导致依赖Na的P（i）摄取，其特征类似于在寄生虫中观察到的P（i）摄取的特征。这项研究提供了新的见解，以疟疾寄生虫诱导其宿主细胞的离子组成的改变的意义。

BACKGROUND & AIMS: AIMS:Case reports suggest an interaction between rofecoxib and the CYP1A2 substrate tizanidine. Our objectives were to explore the extent and mechanism of this possible interaction and to determine the CYP1A2 inhibitory potency of rofecoxib. METHODS:In a randomized, double-blind, two-phase cross-over study, nine healthy subjects took 25 mg rofecoxib or placebo daily for 4 days and, on day 4, each ingested 4 mg tizanidine. Plasma concentrations and the urinary excretion of tizanidine, its metabolites (M) and rofecoxib, and pharmacodynamic variables were measured up to 24 h. On day 3, a caffeine test was performed to estimate CYP1A2 activity. RESULTS:Rofecoxib increased the area under the plasma concentration-time curve (AUC(0-infinity)) of tizanidine by 13.6-fold [95% confidence interval (CI) 8.0, 15.6; P < 0.001), peak plasma concentration (C(max)) by 6.1-fold (4.8, 7.3; P < 0.001) and elimination half-life (t(1/2)) from 1.6 to 3.0 h (P < 0.001). Consequently, rofecoxib markedly increased the blood pressure-lowering and sedative effects of tizanidine (P < 0.05). Rofecoxib increased several fold the tizanidine/M-3 and tizanidine/M-4 ratios in plasma and urine and the tizanidine/M-5, tizanidine/M-9 and tizanidine/M-10 ratios in urine (P < 0.05). In addition, it increased the plasma caffeine/paraxanthine ratio by 2.4-fold (95% CI 1.4, 3.4; P = 0.008) and this ratio correlated with the tizanidine/metabolite ratios. Finally, the AUC(0-25) of rofecoxib correlated with the placebo phase caffeine/paraxanthine ratio (r = 0.80, P = 0.01). CONCLUSIONS:Rofecoxib is a potent inhibitor of CYP1A2 and it greatly increases the plasma concentrations and adverse effects of tizanidine. The findings suggest that rofecoxib itself is also metabolized by CYP1A2, raising concerns about interactions between rofecoxib and other CYP1A2 substrate and inhibitor drugs.

背景与目标： 目的：病例报告表明罗非考昔与CYP1A2底物替扎尼定之间存在相互作用。我们的目标是探索这种可能的相互作用的程度和机制，并确定罗非昔布对CYP1A2的抑制作用。
方法：在一项随机，双盲，两阶段交叉研究中，九名健康受试者每天服用25毫克罗非考昔或安慰剂，持续4天，并在第4天，每人摄入4毫克替扎尼定。在长达24小时内测量替扎尼定，其代谢产物（M）和罗非考昔的血浆浓度和尿排泄，以及药效学变量。在第3天，进行了咖啡因测试以评估CYP1A2的活性。
结果：罗非昔布将替扎尼定的血浆浓度-时间曲线下面积（AUC（0-无穷大））增加了13.6倍[95％置信区间（CI）8.0、15.6； P <0.001），峰值血药浓度（C（max））从1.6到3.0 h的6.1倍（4.8，7.3; P <0.001）和消除半衰期（t（1/2））（P <0.001） 。因此，罗非昔布显着增强了替扎尼定的降压和镇静作用（P <0.05）。罗非昔布将血浆和尿液中替扎尼定/ M-3和替扎尼定/ M-4的比例提高了几倍，尿液中替扎尼定/ M-5，替扎尼定/ M-9和替扎尼定/ M-10的比例提高了几倍（P <0.05）。此外，它使血浆咖啡因/对黄嘌呤比率增加了2.4倍（95％CI 1.4、3.4； P = 0.008），并且该比率与替扎尼定/代谢产物比率相关。最后，罗非昔布的AUC（0-25）与安慰剂相咖啡因/对黄嘌呤的比​​例相关（r = 0.80，P = 0.01）。
结论：罗非昔布是一种有效的CYP1A2抑制剂，它大大提高了血浆浓度和替扎尼定的不良反应。研究结果表明罗非考昔本身也被CYP1A2代谢，引起对罗非考昔与其他CYP1A2底物和抑制剂药物之间相互作用的担忧。

BACKGROUND & AIMS: We studied changes in glutamate receptors, expression of immediate early genes, and AP-1 DNA binding activity in the brains of phenobarbital (PB)-dependent and -withdrawn rats to investigate the possible involvement of activation of glutamate receptors in PB withdrawal syndrome. PB-dependent rats were prepared by feeding drug-admixed food for 5 weeks. Autoradiographic analysis showed that binding of [3H(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imin e (MK-801), an antagonist of N-methyl-D-aspartic acid (NMDA) receptors, increased significantly in the cerebral cortices of PB-dependent and 24-h-withdrawn rats. However, [3H]MK-801 binding in the hippocampus and [3H]6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and [3H]kainic acid binding in the hippocampus and cerebral cortex were essentially unchanged in both groups. PB withdrawal seizures were followed by increased expression of c-fos mRNA in the hippocampus and cerebral cortex and of c-jun mRNA in the cerebral cortex. The induction of c-fos and c-jun mRNA was suppressed by administration of MK-801. Furthermore, PB withdrawal enhanced AP-1 DNA binding activity in the brain. The present findings suggest functional enhancement of glutamatergic neurotransmission during the development of PB withdrawal syndrome.

背景与目标： 我们研究了苯巴比妥（PB）依赖和戒断大鼠大脑中谷氨酸受体的变化，立即早期基因的表达以及AP-1 DNA结合活性，以研究谷氨酸受体激活在PB戒断综合征中的可能。通过喂食药物混合食物5周来制备PB依赖的大鼠。放射自显影分析表明，[3H（）-5-甲基-10,11-二氢-5H-二苯并[a，d]环庚烯-5,10-亚胺e（MK-801）与N-甲基- D-天冬氨酸（NMDA）受体，在PB依赖和24小时戒断大鼠的大脑皮层中显着增加。然而，在海马中的[3H] MK-801结合以及在海马和大脑皮层中的[3H] 6-氰基-7-硝基喹喔啉-2,3-二酮（CNQX）和[3H]海藻酸结合基本上没有变化。组。 PB抽搐发作后，海马和大脑皮层中c-fos mRNA的表达增加，大脑皮层中c-jun mRNA的表达增加。通过施用MK-801抑制了c-fos和c-jun mRNA的诱导。此外，PB撤离可增强大脑中AP-1 DNA的结合活性。目前的发现表明，在PB戒断综合征的发展过程中，谷氨酸能神经传递的功能增强。

BACKGROUND & AIMS: :The 6-h plasma profiles of adrenocorticotropic hormone (ACTH), cortisol, alpha-melanocyte-stimulating hormone (alpha-MSH), and GH were studied in 17 dogs with pituitary-dependent hyperadrenocorticism (PDH) before and after hypophysectomy. The aim of the study was to investigate the relation between the hormone profile characteristics and recurrence of PDH after surgery. The hormones were secreted in a pulsatile fashion. The basal plasma cortisol concentration and area under the curve (AUC) for cortisol were significantly higher in the PDH cases than in eight controls. The characteristics of the plasma profiles of ACTH and alpha-MSH were not significantly different between the PDH cases and the controls. In the PDH cases, less GH was secreted in pulses than in the controls, but the difference was not significant. The basal plasma cortisol concentration, the AUC for ACTH and cortisol, and the pulse frequency of ACTH and cortisol decreased significantly after hypophysectomy for the group of PDH cases. The basal plasma concentrations of ACTH and alpha-MSH, the AUC for alpha-MSH, and the characteristics of the plasma GH profiles of the PDH cases remained unchanged after hypophysectomy. No pulses of alpha-MSH were observed after hypophysectomy. The co-occurrence between the ACTH and cortisol pulses decreased significantly with hypophysectomy. The postoperative pulse frequency of ACTH was the only characteristic with predictive value for the recurrence of PDH after hypophysectomy. The results of this study demonstrate that ACTH, cortisol, alpha-MSH, and GH are secreted in a pulsatile fashion in dogs with PDH. Hypophysectomy effectively reduces the secretion of ACTH and cortisol. The presence of ACTH pulses after hypophysectomy is a risk factor for the recurrence of hyperadrenocorticism.

背景与目标： ：在垂体切除术前后垂体依赖的高肾上腺皮质激素（PDH）的17只狗中研究了促肾上腺皮质激素（ACTH），皮质醇，α-黑素细胞刺激激素（α-MSH）和GH的6小时血浆分布。该研究的目的是研究激素谱特征与PDH术后复发之间的关系。激素以搏动的方式分泌。 PDH患者的基础血浆皮质醇浓度和皮质醇曲线下面积（AUC）显着高于八个对照组。在PDH病例和对照之间，ACTH和α-MSH的血浆分布特征没有显着差异。在PDH病例中，与对照相比，脉冲中分泌的GH少，但差异不显着。对于PDH组，在进行了干性活检后，基础血浆皮质醇浓度，ACTH和皮质醇的AUC以及ACTH和皮质醇的脉冲频率均显着降低。垂体切除后，PDH病例的ACTH和α-MSH的基础血浆浓度，α-MSH的AUC以及血浆GH谱的特征保持不变。垂体切除术后未观察到α-MSH脉冲。垂体后叶切除术使ACTH和皮质醇脉冲之间的同时发生显着降低。 ACTH的术后脉冲频率是对垂体切除术后PDH复发的唯一具有预测价值的特征。这项研究的结果表明，PDH犬的搏动性分泌ACTH，皮质醇，α-MSH和GH。垂体切除术可有效减少ACTH和皮质醇的分泌。垂体切除术后ACTH脉冲的存在是肾上腺皮质功能亢进复发的危险因素。

BACKGROUND & AIMS: :This minireview considers the possibility that there is a correlation between the slow rate of morphological change and speciation events that has been occurred within the lungfish lineage since the Permian period, and the apparent slow rate of divergence in the amino acid sequences of lungfish opioid precursor sequences. The status of lungfish as "living fossils" is considered.

背景与目标： ：本篇小型综述认为，二叠纪以来在肺鱼谱系内发生的形态变化和物种形成的缓慢速率与形态上的缓慢变化与肺鱼阿片样物质前体的氨基酸序列的明显缓慢速率之间存在相关性的可能性序列。考虑到肺鱼作为“活化石”的地位。

BACKGROUND & AIMS: :Controlled activation of non-specific and specific immune defence mechanisms can beneficially manipulate the host's ability to attack malignant cells. In this context, migration and tissue distribution of immunocompetent cells may be prerequisites for an efficient immune surveillance. The effect of various non-cytotoxic concentrations of the Viscum album L. (mistletoe) preparation Iscadore QuFrF on the locomotory activity of immunomagnetically isolated human CD4+ and CD8+ T lymphocytes from healthy donors was investigated. Cellular migration was examined within a three-dimensional collagen matrix. Donor-dependent variations in baseline activities of spontaneously locomoting T cells were accompanied by individual response patterns of T cells from different donors in the presence of various concentrations of mistletoe preparation (0.25-2.5 micrograms/ml). Using the three-dimensional collagen matrix assay an induction of locomotory activity was detected in a highly reproducible fashion although the optimal concentration of mistletoe preparation and the time point of maximal response were individual for each donor. Our data suggest that the direct stimulation of T-cell migration by mistletoe components may modulate the system of immune surveillance and recognition in patients under mistletoe therapy.

背景与目标： ：非特异性和特异性免疫防御机制的受控激活可以有益地控制宿主攻击恶性细胞的能力。在这种情况下，免疫活性细胞的迁移和组织分布可能是有效免疫监视的先决条件。研究了Viscum album L.（槲寄生）制剂Iscadore QuFrF的各种非细胞毒性浓度对来自健康供体的免疫磁性分离的人CD4和CD8 T淋巴细胞运动功能的影响。在三维胶原蛋白基质中检查了细胞迁移。在各种浓度的槲寄生制剂（0.25-2.5微克/毫升）存在下，自发性自发性T细胞基线活动的供体依赖性变异伴随着来自不同供体的T细胞的个体反应模式。使用三维胶原蛋白基质测定法，以高度可重复的方式检测了运动活性的诱导，尽管对于每个供体而言，槲寄生制剂的最佳浓度和最大响应的时间点各不相同。我们的数据表明，槲寄生成分直接刺激T细胞迁移可能会调节槲寄生治疗下患者的免疫监视和识别系统。

BACKGROUND & AIMS: :Responses to [D-Ala2, MePhe4, Gly-ol5]enkephalin, a selective agonist for mu-receptors, were recorded intracellularly from 26 neurons in slices of guinea-pig hypothalamus. Of eight cells tested in the supraoptic nucleus, all of which had electrical properties characteristic of magnocellular neuroendocrine cells, four were sensitive to the agonist applied in the perfusion bath or with microdrops. The main effect was a decrease or suppression of spontaneous firing. In the paraventricular nucleus, seven of 18 cells tested also had electrophysiological characteristics similar to magnocellular neurons: two of them were sensitive to the mu-agonist and the effect was similar to that observed in the supraoptic nucleus. The remaining paraventricular neurons displayed low-threshold Ca2+ spikes, and thus had electrophysiological characteristics different from putative magnocellular neurons. Ten of 11 cells with low-threshold Ca2+ spikes were hyperpolarized by more than 10 mV by the mu-agonist, and showed a 33 +/- 1.9% (S.E.M.) decrease in input resistance. In both types of cells, when synaptic transmission was blocked with tetrodotoxin, the mu-agonist could still induce a hyperpolarization, suggesting that the effect was in part direct. Hyperpolarization was also obtained when the Cl- reversal potential was shifted to more positive values by using KCl electrodes, thus excluding a Cl- conductance mechanism. These results provide evidence that opioid peptides can directly inhibit hypothalamic neurons, that the mechanism is an increase in K+ conductance, and that two types of hypothalamic neurons appear to have different sensitivities to a mu-agonist.

背景与目标： ：对豚鼠下丘脑切片中26个神经元的细胞内记录了对[D-Ala2，MePhe4，Gly-ol5]脑啡肽（一种针对mu受体的选择性激动剂）的反应。在视上核中测试的8个细胞中，所有细胞均具有大细胞神经内分泌细胞的电特性，其中4个对灌注浴或微滴中使用的激动剂敏感。主要作用是减少或抑制自发放电。在脑室旁核中，测试的18个细胞中有7个也具有类似于大细胞神经元的电生理特性：其中两个对mu激动剂敏感，作用类似于在视上核中观察到的。其余的脑室旁神经元显示低阈值的Ca2尖峰，因此具有与假定的大细胞神经元不同的电生理特性。 mu激动剂将11个具有低阈值Ca2尖峰的细胞中的10个超极化了10 mV以上，显示输入电阻降低了33 /-1.9％（S.E.M.）。在两种类型的细胞中，当突触传递被河豚毒素阻断时，mu-激动剂仍可诱导超极化，这表明这种作用部分是直接的。当通过使用KCl电极将Cl-反转电位移动到更正值时，也获得了超极化，因此排除了Cl-电导机制。这些结果提供证据证明阿片样物质肽可以直接抑制下丘脑神经元，其机制是钾电导增加，并且两种类型的下丘脑神经元似乎对μ-激动剂具有不同的敏感性。

BACKGROUND & AIMS: UNLABELLED:The objective of the present study was to investigate whether the endogenous opioids are involved in the control of endothelin-1 release from the pituitary gland. To test this hypothesis we have measured the peripheral plasma concentration of ET-1 as well as the content of immunoreactive ET-1 (irET-1) in the pituitary in response to opioid receptors blockade in euhydrated and 24 h water-deprived Wistar-Kyoto rats. Placebo or naltrexone (50 micrograms/kg body wt.) were given i.v. in both groups. Trunk blood was collected to determine hematocrit, plasma sodium and ET-1 levels (RIA). Immunostaining of ET-1 in the whole pituitary glands was performed by colloidal gold labeling. The quantitative analysis of irET-1 was carried out under a light microscope using a computerized image analyzer (MultiScan). RESULTS:(1) Twenty-four-hour dehydration resulted in marked increase of peripheral concentration of ET-1. Naltrexone injection induced a significant elevation of ET-1 plasma concentration in both, dehydrated and control animals. (2) The content of irET-1 in anterior and intermediate lobes of the pituitary in dehydrated rats was markedly higher than in control group. (3) Naltrexone injection caused a rapid and significant reduction irET-1 within the anterior, intermediate and posterior lobes in dehydrated and control animals. CONCLUSIONS:(1) An elevation of irET-1 in the pituitary gland and peripheral circulation in dehydrated animals may play a role in maintaining of water-electrolyte balance. (2) The mu-opioid system appears to control the ET-1 release from the pituitary in normal and dehydrated animals.

背景与目标： 未标记：本研究的目的是调查内源性阿片类药物是否参与垂体中内皮素-1的释放。为了验证这一假设，我们测量了在无水和缺水24小时的Wistar-Kyoto中阿片受体阻滞后，垂体中ET-1的血浆浓度以及垂体中免疫反应性ET-1（irET-1）的含量。大鼠。静脉注射安慰剂或纳曲酮（50微克/千克体重）。在两组中。收集躯干血液以确定血细胞比容，血浆钠和ET-1水平（RIA）。 ET-1在整个垂体中的免疫染色是通过胶体金标记进行的。使用计算机图像分析仪（MultiScan）在光学显微镜下对irET-1进行定量分析。
结果：（1）脱水24小时导致ET-1的外周血浓度明显升高。纳曲酮注射液在脱水和对照动物中均引起ET-1血浆浓度的显着升高。 （2）脱水大鼠垂体前叶和中间叶中irET-1的含量明显高于对照组。 （3）纳曲酮注射液导致脱水和对照动物的前叶，中叶和后叶内的irET-1迅速大量降低。
结论：（1）脱水动物垂体中irET-1的升高和外周循环可能在维持水电解质平衡中发挥了作用。 （2）在正常和脱水动物中，μ阿片样物质系统似乎可以控制ET-1从垂体的释放。

BACKGROUND & AIMS: :The ovarian steroid hormone estrogen (E2) elicits a multiplicity of both systemic and uterotropic responses in vivo. For example, the administration of E2 to ovariectomized (Ovx) and sexually immature rodents leads to uterine-specific inflammatory infiltrates. In this study, we quantitated the number of eosinophils and BM8+, Ia+, and CD4+ cells in uteri obtained from adult Ovx control and E2-treated C57BL/6J, C3H/HeJ, and (C57BL/6J x C3H/HeJ) (B6C3) F1 hybrid mice. All three strains exhibited a significant increase in the number of uterine eosinophils and BM8+ macrophages after E2 treatment. However, C57BL/6J and B6C3 F1 hybrid mice responded with a greater number of infiltrating eosinophils and macrophages as compared with C3H/HeJ. A similar analysis of Ia+ and CD4+ cells showed that E2 treatment either down-regulates or does not affect the number of such cells in all three strains. Genome exclusion mapping using a (C57BL/6J x C3H/HeJ) x C3H/HeJ backcross population localized Est1, the major locus controlling the number of eosinophils infiltrating the uterus after E2 treatment, to chromosome 4. In addition, suggestive linkage to marker loci on chromosomes 10 and 16 was detected and evidence for locus interaction is presented. Our results conclusively demonstrate that E2-regulated/ dependent responses can be genetically controlled, indicating that the phenotypic variation observed in both the normal and pathological effects of E2 may, in part, be due to a genetic component.

背景与目标： ：卵巢类固醇激素雌激素（E2）在体内引起多种全身和子宫促反应。例如，将E2给予去卵巢（Ovx）和性不成熟的啮齿动物会导致子宫特异性炎症浸润。在这项研究中，我们量化了从成年Ovx对照和经E2处理的C57BL / 6J，C3H / HeJ和（C57BL / 6J x C3H / HeJ）（B6C3）获得的子宫中嗜酸性粒细胞和BM8，Ia和CD4细胞的数量F1杂种小鼠。在E2处理后，所有三个菌株均表现出子宫嗜酸性粒细胞和BM8巨噬细胞数量的显着增加。但是，与C3H / HeJ相比，C57BL / 6J和B6C3 F1杂种小鼠反应的浸润性嗜酸性粒细胞和巨噬细胞数量更多。对Ia和CD4细胞的类似分析显示，E2处理在所有三个菌株中均下调或不影响此类细胞的数量。使用（C57BL / 6J x C3H / HeJ）x C3H / HeJ回交群体定位的基因组排斥定位于Est1，Est1是控制E2处理后浸润子宫的嗜酸性粒细胞数量的主要基因座，并指向染色体4。检测到10号和16号染色体上的DNA，并提供了基因座相互作用的证据。我们的结果最终证明，E2调节/依赖性反应可以通过基因控制，这表明在E2的正常和病理效应中观察到的表型变异可能部分归因于遗传成分。

BACKGROUND & AIMS: :Rat basophilic leukemia (RBL 2H3) cells were passively sensitized by exposure to monoclonal anti-trinitrophenol mouse immunoglobulin E (anti-trinitrophenol IgE) (0.5 microgram/ml) and triggered by exposure to a sub-optimal concentration of trinitrophenol ovalbumin conjugate (5 ng/ml). At this concentration, trinitrophenol-ovalbumin increased histamine release from a basal rate of 4.8 +/- 0.5 to 28.5 +/- 4.6% and peptidoleukotrienes from less than 0.1 to 4.2 +/- 1.3 ng/10(6) cells in the activated cells. Ro 19-3704 and Ro 19-1400, platelet activating factor (PAF) antagonists which are structural analogs of PAF, potently inhibited both the IgE-dependent release of histamine (IC50 values of 3.0 and 3.6 microM, respectively) and LT release (IC50 values of 5.0 microM for both compounds) from the cells. These effects appeared to be independent to the ability of the compounds to act as PAF antagonists since PAF on its own had no effect on mediator release, and WEB 2086 and BN 52021, structurally distinct PAF antagonists, were relatively ineffective as inhibitors of mediator release. Ro 19-3704 and Ro 19-1400 were observed to be potent inhibitors of the soluble phospholipase A2 activity in synovial fluid from rheumatoid arthritic patients (IC50 values of 6.5 and 8.4 microM, respectively). In contrast, WEB 2086 and BN 52021 had no effect on this phospholipase A2. Ro 19-3704 significantly inhibited the IgE-dependent formation of inositol phosphates in RBL 2H3 cells (IC50 value of 7.0 microM). These data suggest that the mediator release inhibitory action of these compounds may be related to the ability of these compounds to inhibit phospholipase A2 and/or phospholipase C.

背景与目标： ：暴露于单克隆抗三硝基苯酚小鼠免疫球蛋白E（抗三硝基苯酚IgE）（0.5微克/毫升）可以被动致敏大鼠嗜碱性粒细胞白血病（RBL 2H3）细胞，并通过暴露于次适量浓度的三硝基苯酚卵白蛋白缀合物（5 ng / ml）。在此浓度下，三硝基苯酚-卵清蛋白将组胺释放从基础速率的4.8 /-0.5增加到28.5 /-4.6％，而肽白三烯从少于0.1到4.2 /-1.3 ng / 10（6）细胞增加。 Ro 19-3704和Ro 19-1400，血小板活化因子（PAF）拮抗剂，是PAF的结构类似物，可有效抑制IgE依赖的组胺释放（IC50分别为3.0和3.6 microM）和LT释放（IC50）。两种化合物的浓度值均为5.0 microM）。这些作用似乎与化合物充当PAF拮抗剂的能力无关，因为PAF本身对介质释放没有影响，并且结构不同的PAF拮抗剂WEB 2086和BN 52021作为介质释放抑制剂相对无效。观察到Ro 19-3704和Ro 19-1400是类风湿关节炎患者滑液中可溶性磷脂酶A2活性的有效抑制剂（IC50值分别为6.5和8.4 microM）。相反，WEB 2086和BN 52021对这种磷脂酶A2没有影响。 Ro 19-3704显着抑制RBL 2H3细胞中IgE依赖性肌醇磷酸的形成（IC50值为7.0 microM）。这些数据表明，这些化合物的介质释放抑制作用可能与这些化合物抑制磷脂酶A2和/或磷脂酶C的能力有关。

BACKGROUND & AIMS: Many genotoxic agents kill tumor cells by inducing apoptosis; hence, mutations that suppress apoptosis produce resistance to chemotherapy. Although directly activating the apoptotic machinery may bypass these mutations, how to achieve this activation in cancer cells selectively is not clear. In this study, we show that the drug-resistant 293 cell line is unable to activate components of the apoptotic machinery-the ICE-like proteases (caspases)-following treatment with an anticancer drug. Remarkably, extracts from untreated cells spontaneously activate caspases and induce apoptosis in a cell-free system, indicating that drug-resistant cells have not only the apoptotic machinery but also its activator. Comparing extracts from cells with defined genetic differences, we show that this activator is generated by the adenovirus E1A oncogene and is absent from normal cells. We provide preliminary characterization of this oncogene generated activity (OGA) and show that partially purified OGA activates caspases when added to extracts from untransformed cells. We suggest that agents that link OGA to caspases in cells would kill tumor cells otherwise resistant to conventional cancer therapy. As this killing relies on an activity generated by an oncogene, the effect of these agents should be selective for transformed cells.

背景与目标： 许多遗传毒性剂通过诱导细胞凋亡杀死肿瘤细胞。因此，抑制细胞凋亡的突变产生了对化学疗法的抗性。尽管直接激活凋亡机制可能绕过这些突变，但是如何在癌细胞中选择性地实现这种激活尚不清楚。在这项研究中，我们显示抗药性293细胞系无法激活抗凋亡药物ICE样蛋白酶（胱天蛋白酶）的凋亡机制的组成部分。值得注意的是，未经处理的细胞提取物可自发激活胱天蛋白酶并在无细胞系统中诱导凋亡，这表明耐药细胞不仅具有凋亡机制，还具有其激活剂。比较具有确定的遗传差异的细胞提取物，我们表明该激活剂是由腺病毒E1A癌基因产生的，而正常细胞中却不存在。我们提供了此致癌基因产生的活性（OGA）的初步表征，并表明当添加到未转化细胞的提取物中时，部分纯化的OGA会激活胱天蛋白酶。我们建议，将OGA与细胞中的半胱氨酸蛋白酶连接的药剂会杀死肿瘤细胞，否则它们会对常规的癌症治疗产生抵抗力。由于这种杀伤作用依赖于癌基因产生的活性，因此这些药剂对转化细胞的作用应该是选择性的。

BACKGROUND & AIMS: :Kennedy disease, a degenerative disorder characterized by androgen-dependent neuromuscular weakness, is caused by a CAG/glutamine tract expansion in the androgen receptor (Ar) gene. We developed a mouse model of Kennedy disease, using gene targeting to convert mouse androgen receptor (AR) to human sequence while introducing 113 glutamines. AR113Q mice developed hormone and glutamine length-dependent neuromuscular weakness characterized by the early occurrence of myopathic and neurogenic skeletal muscle pathology and by the late development of neuronal intranuclear inclusions in spinal neurons. AR113Q males unexpectedly died at 2-4 months. We show that this androgen-dependent death reflects decreased expression of skeletal muscle chloride channel 1 (CLCN1) and the skeletal muscle sodium channel alpha-subunit, resulting in myotonic discharges in skeletal muscle of the lower urinary tract. AR113Q limb muscles show similar myopathic features and express decreased levels of mRNAs encoding neurotrophin-4 and glial cell line-derived neurotrophic factor. These data define an important myopathic contribution to the Kennedy disease phenotype and suggest a role for muscle in non-cell autonomous toxicity of lower motor neurons.

背景与目标： ：肯尼迪病是一种以雄激素依赖性神经肌肉无力为特征的变性疾病，是由雄激素受体（Ar）基因中的CAG /谷氨酰胺束扩张引起的。我们开发了肯尼迪病的小鼠模型，使用基因靶向技术将小鼠雄激素受体（AR）转化为人类序列，同时引入113种谷氨酰胺。 AR113Q小鼠发展出激素和谷氨酰胺长度依赖性神经肌肉无力，其特征是肌病性和神经源性骨骼肌病理的早期发生以及脊髓神经元中神经元核内包涵体的发育较晚。 AR113Q男性意外死于2-4个月。我们表明，这种雄激素依赖性死亡反映了骨骼肌氯化物通道1（CLCN1）和骨骼肌钠通道α亚基的表达下降，导致下尿路骨骼肌的肌强直放电。 AR113Q肢体肌肉表现出相似的肌病特征，并表达编码神经营养蛋白4和神经胶质细胞源性神经营养因子的mRNA降低水平。这些数据定义了对肯尼迪病表型的重要肌病性贡献，并暗示了肌肉在下运动神经元的非细胞自主毒性中的作用。

BACKGROUND & AIMS: CONTEXT:Chronic pain in patients with advanced cancer poses a serious clinical challenge. The Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (U.S. Adopted Name, nabiximols; Sativex(®)) is a novel cannabinoid formulation currently undergoing investigation as an adjuvant therapy for this treatment group. OBJECTIVES:This follow-up study investigated the long-term safety and tolerability of THC/CBD spray and THC spray in relieving pain in patients with advanced cancer. METHODS:In total, 43 patients with cancer-related pain experiencing inadequate analgesia despite chronic opioid dosing, who had participated in a previous three-arm (THC/CBD spray, THC spray, or placebo), two-week parent randomized controlled trial, entered this open-label, multicenter, follow-up study. Patients self-titrated THC/CBD spray (n=39) or THC spray (n=4) to symptom relief or maximum dose and were regularly reviewed for safety, tolerability, and evidence of clinical benefit. RESULTS:The efficacy end point of change from baseline in mean Brief Pain Inventory-Short Form scores for "pain severity" and "worst pain" domains showed a decrease (i.e., improvement) at each visit in the THC/CBD spray patients. Similarly, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 scores showed a decrease (i.e., improvement) from baseline in the domains of insomnia, pain, and fatigue. No new safety concerns associated with the extended use of THC/CBD spray arose from this study. CONCLUSION:This study showed that the long-term use of THC/CBD spray was generally well tolerated, with no evidence of a loss of effect for the relief of cancer-related pain with long-term use. Furthermore, patients who kept using the study medication did not seek to increase their dose of this or other pain-relieving medication over time, suggesting that the adjuvant use of cannabinoids in cancer-related pain could provide useful benefit.

背景与目标： 背景：晚期癌症患者的慢性疼痛提出了严峻的临床挑战。 Δ9-四氢大麻酚（THC）/大麻二酚（CBD）口腔粘膜喷雾剂（美国采用名称，nabiximols;Sativex®）是一种新型大麻素制剂，目前正在接受治疗，作为该治疗组的辅助疗法。
目的：这项随访研究调查了THC / CBD喷雾剂和THC喷雾剂在缓解晚期癌症患者的疼痛方面的长期安全性和耐受性。
方法：共有43例癌症相关疼痛患者尽管使用了阿片类药物长期服用，但仍没有足够的镇痛作用，他们参加了先前的三组试验（THC / CBD喷雾剂，THC喷雾剂或安慰剂），为期两周的父母随机对照试验，参加了这项开放性，多中心的后续研究。患者自行滴定THC / CBD喷雾剂（n = 39）或THC喷雾剂（n = 4）以缓解症状或最大剂量，并定期检查其安全性，耐受性和临床获益证据。
结果：THC / CBD喷剂患者每次就诊时，“疼痛严重程度”和“最严重疼痛”域的平均简短疼痛清单-简表得分的基线变化的功效终点显示出降低（即改善）。同样，欧洲癌症生活质量研究和治疗组织问卷-C30的得分显示，失眠，疼痛和疲劳程度较基线水平有所降低（即有所改善）。这项研究没有引起与THC / CBD喷雾剂的广泛使用相关的新安全隐患。
结论：这项研究表明，长期使用THC / CBD喷雾剂通常具有良好的耐受性，没有证据表明长期使用THC / CBD喷雾剂可减轻癌症相关疼痛。此外，继续使用研究药物的患者并未寻求随时间增加这种药物或其他缓解疼痛药物的剂量，这表明在与癌症相关的疼痛中辅助使用大麻素可提供有益的益处。

BACKGROUND & AIMS: :Strigolactones control many aspects of plant growth and development, but the active form(s) of strigolactones and their mode of action at the molecular level are unknown. A new study provides evidence that an α/β-fold protein plays a central multifunctional role in strigolactone metabolism, perception and signalling.

背景与目标： ：Strigolactones控制植物生长和发育的许多方面，但是strigolactones的活性形式及其在分子水平上的作用方式尚不清楚。一项新的研究提供了证据，表明α/β折叠蛋白在松果内酯的代谢，感知和信号传导中起着重要的多功能作用。

BACKGROUND & AIMS: Importance:Opioid use disorder (OUD) frequently begins in adolescence and young adulthood. Intervening early with pharmacotherapy is recommended by major professional organizations. No prior national studies have examined the extent to which adolescents and young adults (collectively termed youth) with OUD receive pharmacotherapy. Objective:To identify time trends and disparities in receipt of buprenorphine and naltrexone among youth with OUD in the United States. Design, Setting, and Participants:A retrospective cohort study was conducted using deidentified data from a national commercial insurance database. Enrollment and complete health insurance claims of 9.7 million youth, aged 13 to 25 years were analyzed, identifying individuals who received a diagnosis of OUD between January 1, 2001, and June 30, 2014, with final follow-up date December 31, 2014. Analysis was conducted from April 25 to December 31, 2016. Time trends were identified and multivariable logistic regression was used to determine sociodemographic factors associated with medication receipt. Exposures:Sex, age, race/ethnicity, neighborhood education and poverty levels, geographic region, census region, and year of diagnosis. Main Outcomes and Measures:Dispensing of a medication (buprenorphine or naltrexone) within 6 months of first receiving an OUD diagnosis. Results:Among 20 822 youth diagnosed with OUD (0.2% of the 9.7 million sample), 13 698 (65.8%) were male and 17 119 (82.2%) were non-Hispanic white. Mean (SD) age was 21.0 (2.5) years at the first observed diagnosis. The diagnosis rate of OUD increased nearly 6-fold from 2001 to 2014 (from 0.26 per 100 000 person-years to 1.51 per 100 000 person-years). Overall, 5580 (26.8%) youth were dispensed a medication within 6 months of diagnosis, with 4976 (89.2%) of medication-treated youth receiving buprenorphine and 604 (10.8%) receiving naltrexone. Medication receipt increased more than 10-fold, from 3.0% in 2002 (when buprenorphine was introduced) to 31.8% in 2009, but declined in subsequent years (27.5% in 2014). In multivariable analyses, younger individuals were less likely to receive medications, with adjusted probability for age 13 to 15 years, 1.4% (95% CI, 0.4%-2.3%); 16 to 17 years, 9.7% (95% CI, 8.4%-11.1%); 18 to 20 years, 22.0% (95% CI, 21.0%-23.0%); and 21 to 25 years, 30.5% (95% CI, 30.0%-31.5%) (P < .001 for difference). Females (7124 [20.3%]) were less likely than males (13 698 [24.4%]) to receive medications (P < .001), as were non-Hispanic black (105 [14.8%]) and Hispanic (1165 [20.0%]) youth compared with non-Hispanic white (17 119 [23.1%]) youth (P < .001). Conclusions and Relevance:In this first national study of buprenorphine and naltrexone receipt among youth, dispensing increased over time. Nonetheless, only 1 in 4 commercially insured youth with OUD received pharmacotherapy, and disparities based on sex, age, and race/ethnicity were observed.

背景与目标： 重要性：阿片类药物使用障碍（OUD）经常在青春期和成年期开始。主要专业组织建议尽早进行药物治疗。以前的国家研究都没有研究OUD的青少年和年轻人（统称为青年）接受药物治疗的程度。
目的：确定美国OUD青年中丁丙诺啡和纳曲酮的接受时间趋势和差异。
设计，地点和参与者：使用来自国家商业保险数据库的身份不明数据进行回顾性队列研究。分析了970万年龄在13至25岁之间的970万青年的入学和完全健康保险理赔，确定了在2001年1月1日至2014年6月30日期间被诊断为OUD的个人，最终随访日期为2014年12月31日。分析于2016年4月25日至12月31日进行。确定了时间趋势，并使用多变量logistic回归确定与用药相关的社会人口统计学因素。
暴露：性别，年龄，种族/民族，邻里教育和贫困程度，地理区域，人口普查区域和诊断年份。
主要结果和措施：在首次接受OUD诊断后的6个月内分发药物（丁丙诺啡或纳曲酮）。
结果：在20822名被诊断为OUD的青年中（占970万样本的0.2％），男性中有13698名（65.8％），非西班牙裔白人中有17119名（82.2％）。在首次观察到的诊断中，平均（SD）年龄为21.0（2.5）岁。从2001年到2014年，OUD的诊断率增长了近6倍（从每100000人年0.26增至每100000人年1.51）。总体而言，在诊断后的6个月内分配了5580（26.8％）名年轻人用药，其中接受丁丙诺啡的4976（89.2％）名接受药物治疗的青年人和接受纳曲酮的604名（10.8％）。药物治疗的收入增加了十倍以上，从2002年的3.0％（引入丁丙诺啡时）到2009年的31.8％，但随后几年却下降了（2014年为27.5％）。在多变量分析中，年龄较小的个体接受药物治疗的可能性较小，年龄调整为13至15岁的概率为1.4％（95％CI，0.4％-2.3％）； 16至17年，9.7％（95％CI，8.4％-11.1％）； 18至20年，22.0％（95％CI，21.0％-23.0％）；和21至25年，分别为30.5％（95％CI，30.0％-31.5％）（差异P <<。001）。与非西班牙裔黑人（105名[14.8％]）和西班牙裔（1165名[20.0]）相比，女性（7124名[20.3％]）与男性（13698名[24.4％]）接受药物治疗的可能性较小（P <.001）。 ％]的年轻人与非西班牙裔白人（17119 [23.1％]）的年轻人相比（P <）。001）。
结论和相关性：在这项关于丁丙诺啡和纳曲酮的年轻人接受的首次国家研究中，随着时间的流逝，配药量增加了。尽管如此，只有四分之一的有OUD的商业保险青年接受了药物治疗，并且观察到了基于性别，年龄和种族/民族的差异。