5名电离辐射事故患者外周血T细胞T细胞抗原受体、T细胞分化抗原决定簇－3效应的研究

文中报道了５名事故性急性骨髓型放射病患者照后２．５和３．５年外周血Ｔ淋巴细胞Ｔ细胞受体（ＴＣＲ）基因，ＴＣＲ、Ｔ细胞分化抗原决定簇－３（ＣＤ_３）表达与ＴＣＲ／ＣＤ_３复合物功能的辐射效应．发现５名患者于照后２．５年，２名（５．２Ｇｙ和２．４Ｇｙ，５５岁）于照后３．５年外周血Ｔ细胞应答抗ＣＤ３单抗刺激而增殖的能力尚未完全恢复；经同时用ＩＬ－２和抗ＣＤ_３单抗刺激，增殖能力比单用抗ＣＤ_３单抗刺激有所增强；后２名的外周血ＴＣＲ、ＣＤ_３阳性细胞百分率一直低于正常对照和其他患者；并见一患者出现ＤＮＡ重排杂交带型．本文并从ＴＣＲ／ＣＤ_３在介导Ｔ细胞抗原刺激反应中的作用，电离辐射对ＴＣＲ／ＣＤ_３复合物的影响，后果和意义等方面进行了讨论．     

Inhibition of growth of PC-82 human prostate cancer line xenografts in nude mice by bombesin antagonist RC-3095 or combination of agonist [D-Trp6]-luteinizing hormone-releasing hormone and somatostatin analog RC-160.

The effects of treatment with a bombesin receptor antagonist [D-Tpi6, Leu13 psi (CH2NH) Leu14]BN(6-14)(RC-3095) and the combination of an agonist of luteinizing hormone-releasing hormone [D-Trp6]-LH-RH and somatostatin analog D-Phe-Cys-Tyr-D-Trp-Lys-Val- Cys-Trp-NH2 (RC-160) were studied in nude mice bearing xenografts of the hormone-dependent human prostate tumor PC-82. During the 5 weeks of treatment, tumor growth was decreased in all treated groups compared with controls. Bombesin antagonist RC-3095 and the combination of [D-Trp6]-LH-RH and RC-160 caused a greater inhibition of tumor growth than [D-Trp6]-LH-RH or RC-160 alone as based on measurement of tumor volume and percentage change in tumor volume. The largest decrease in tumor weight was also seen in the groups treated with the bombesin antagonist and with the combination of RC-160 and [D-Trp6]-LH-RH. Serum prostatic-specific antigen levels were greatly decreased, and insulin-like growth factor I (IGF-I) as well as growth hormone levels were reduced in all treated groups. Specific binding sites for [D-Trp6]-LH-RH, epidermal growth factor (EGF), IGF-I, and somatostatin (SS-14) were found in the tumor membranes. Receptors for EGF were significantly down-regulated by treatment with the bombesin antagonist or RC-160. Combination of LH-RH agonists with somatostatin analog RC-160 might be considered for improvement of hormonal therapy for prostate cancer. The finding that bombesin antagonist RC-3095 inhibits the growth of PC-82 prostate cancer suggests the merit of further studies to evaluate the possible usefulness of antagonists of bombesin in the management of prostatic carcinoma.     

Saturation analysis of specific 11C Ro 15-1788 binding to the human neocortex using positron emission tomography

The ¹¹C-labelled benzodiazepine antagonist Ro 15–1788 (flumazenil) and positron emission tomography (PET) were used to determine quantitative characteristics of benzodiazepine receptor binding in the neocortex of healthy young men. Saturating doses of unlabelled flumazenil administered i.v., before or together with the ligand-reduced ¹¹C-flumazenil accumulation in the neocortex by about 90 per cent. Saturating doses of unlabelled flumazenil had little effect on the accumulation of radioactivity in the benzodiazepine receptor-poor regions such as pons or white matter. By giving graded doses of unlabelled flumazenil together with the tracer, saturation isotherms were obtained allowing the calculation of receptor density (B_max) and equilibrium dissociation constant (K_d) values on the basis of certain assumptions B_max values were in the order of 90 pmol/g and K_d values in the order of 10 nM in the neocortex. Scatchard and Hill plots of the radioactivity data indicated that ¹¹C-flumazenil binds to saturable sites of a homogeneous population. The data indicate that intravenous doses of 1 or 2 mg flumazenil result in a benzodiazepine receptor occupancy of about 50 per cent. The method described should be useful for studying regional differences in benzodiazepine receptor characteristics in the living human brain in healthy subjects and neuropsychiatric disorders, and also in relation to treatment with drugs interacting with benzodiazepine receptors.     

TLR4 Asp299Gly、Thr399Ile基因多态性对变应性哮喘的发病及IgE水平的影响

目的　探讨TLR4 (toll likereceptor 4 )Asp2 99Gly、Thr399Ile基因多态性对变应性哮喘的发病和血浆IgE水平的影响。方法　利用聚合酶链反应 限制性片段长度多态性分析技术 (PCR RFLP) ,对 1 97例变应性哮喘患者和 1 5 6例健康人进行TLR4的Asp2 99Gly、Thr399Ile两位点的基因型检测。同时利用免疫发光法检测血浆IgE的水平。结果　 1 97例变应性哮喘患者TLR4基因Asp2 99Gly位点Asp Asp、Asp Gly和Gly Gly的基因型频率为 0 .81 7、0 .1 4 7和 0 .0 36 ,与正常对照组相比差异无统计学意义 (χ2 =0 .0 32 ,P =0 .984 ) ;但变应性哮喘患者Gly Gly、Asp Gly基因型血浆总IgE对数值 ( x±s:2 .6 1 5± 0 .6 0 0 1 ,n =36 )与Asp Asp基因型血浆总IgE对数值 ( x±s:2 .2 4 0± 0 .6 894 ,n =1 6 1 )相比较高 ,差异有统计学意义 (P =0 .0 0 2 )。TLR4基因Thr399Ile位点Thr Thr、Thr Ile和Ile Ile的基因型频率为 0 .970、0 .0 2 0和 0 .0 1 0 ,与正常对照组相比差异无统计学意义 (χ2 =0 .6 2 0 ,P =0 .733) ;变应性哮喘患者Ile Ile、Thr Ile基因型血浆总IgE对数值 ( x±s:2 .4 1 7± 0 .4 4 2 3,n =6 )与Thr Thr基因型血浆总IgE对数值 ( x±s:2 .30 5± 0 .6 94 9,n =1 91 )相比差异无统计学意义 (P =0 .5 71 )。     

Time-dependent changes in sensitivity to apomorphine and monoamine receptors following withdrawal from continuous cocaine administration in rats

The effects of withdrawal from continuous administration of cocaine on behavioral sensitivity to apomorphine and monoamine receptor density were examined in rats. Subdermal minipumps that delivered either saline or 20 mg/kg/day cocaine hydrochloride were implanted for 2 weeks. Apomorphine-induced stereotypy (0.5 mg/kg, SC) was examined in separate groups of rats either 4 hr or 7, 28, or 60 days after removal of the minipumps. Transient enhanced sensitivity to apomorphine-induced stereotypy occurred during the course of withdrawal. Animals withdrawn from cocaine for 4 hours did not differ from controls in their sensitivity to apomorphine, whereas animals withdrawn from cocaine for 7 days exhibited an increase in apomorphine-induced oral stereotypy relative to controls. However, the enhanced stereotypy response was no longer evident in animals withdrawn for 28–60 days. The animals were sacrificed after behavioral testing, and their brains were assayed for changes in monoamine receptor density in the frontal cortex, caudate-putamen, and nucleus accumbens. The density of ³H-SCH-23390-labeled D1 receptors was altered in all three regions examined in a time-dependent manner that paralleled the changes in behavioral sensitivity to apomorphine. There was a transient decrease in D1 receptor density that was evident by 7 days following withdrawal from continuous cocaine administration and was no longer evident 28 or 60 days posttreatment. There were no changes in ³H-spiroperidol-labeled D2 receptors, ¹²⁵-pindolol-labeled β-adrenergic receptors, or ³H-ketanserin-labeled 5-HT₂ receptors in any of the regions examined at both 4 hr and 7 days after termination of the cocaine infusion. These findings are discussed in terms of their relevance to developing pharmacologic treatments for withdrawal from cocaine. © 1994 Wiley-Liss, Inc.     

Combined treatment with a 5HT1A receptor agonist and a muscarinic acetylcholine receptor antagonist disrupts water maze navigation behavior

The present study was designed to investigate the effects of combined treatment with a serotonin (5-HT)_1A receptor agonist, 8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT), and a muscarinic acetylcholine receptor antagonist, scopolamine, on water maze (WM) navigation. Treatment with either 8-OH-DPAT or scopolamine before daily behavioral training disrupted spatial navigation at medium doses and cue navigation at high doses. Pretraining treatment with a combination of subthreshold doses of 8-OH-DPAT and scopolamine impaired WM spatial and cue navigation, but did not impair the WM performance if the drugs were injected post-training. In trained rats, combined injections of subthreshold doses of 8-OH-DPAT and scopolamine given pretraining did not impair the rats' ability to find the platform in a familiar or in a novel position. The combination of 8-OH-DPAT and scopolamine also disrupted WM navigation in rats with central 5-HT depletion. A combination of a peripheral muscarinic acetylcholine receptor antagonist and 8-OH-DPAT had no effect on WM navigation. These data suggest that combined treatment with drugs blocking muscarinic acetylcholine receptors and activating 5-HT_1A receptors greatly impairs WM learning/performance, but does not impair spatial memory per se.     

Analgesia produced by intrathecal administration of the kappa opioid agonist, U-50,488H, on formalin-evoked cutaneous pain in the rat

The antinociceptive activity of the selective k opioid agonist U-50,488H, given intrathecally (i.t.) against chemically induced cutaneous pain in rats, was assessed from cumulative dose-response experiments and the formalin test. Three successive i.t. doses of 5, 10 and 35 nmol of U-50,488H produced a gradual reduction of pain scores which was statistically significant at all observation periods. This effect was antagonized significantly by 3 mg/kg i.p. of the opiate antagonists, naloxone and WIN 44,441-3. The analgesia profile showed a clear dose-response relationship. A dose producing 50% ‘maximum posible analgesia’ of 6.20 nmol (95% confidence interval: 3.05–12.59 nmol) was calculated. The results indicated that cutaneous pain of a chemical/inflammatory nature is highly sensitive to activation of k receptors of the spinal cord dorsal horn.     

Synaptic potentials and effects of amino acid antagonists in the auditory cortex

Neurons of in vitro guinea pig and rat auditory cortex receive a complex synaptic pattern of afferent information. As many as four synaptic responses to a single-stimulus pulse to the gray or white matter can occur; an early-EPSP followed, sequentially, by an early-IPSP, late-EPSP, and late-IPSP. Paired pulse stimulation and pharmacological studies show that the early-IPSP can modify information transmission that occurs by way of the early-EPSP. Each of these four synaptic responses differed in estimated reversal potential, and each was differentially sensitive to antagonism by pharmacological agents. DNQX (6,7-dinitroquinoxaline-2,3-dione), a quisqualate/kainate receptor antagonist, blocked the early-EPSP, and the late-EPSP was blocked by the NMDA receptor antagonist APV (D-2-amino-5-phosphonovalerate). The early-IPSP was blocked by the GABA-a receptor antagonist bicuculline, and the late-IPSP by the GABA-b receptor antagonists 2-OH saclofen or phaclofen. Presentation of stimulus trains, even at relatively low intensities, could produce a long-lasting APV-sensitive membrane depolarization. Also discussed is the possible role of these synaptic potentials in auditory cortical function and plasticity.     

Development of computer-assisted simulation procedure to analyze receptor modulatory processes

Summary Experimentally induced changes in neurotransmitter receptors have been analyzed by means of a computer assisted simulation procedure over a wide range of free ligand concentrations. This approach allows to evaluate, for a given range of ligand concentrations, the relative influence of simultaneous variations in binding parameters (i.e. dissociation constant or K_d and in maximal number of binding sites or B_m) and to predict the net and final effect of the experimental condition on the receptor-mediated transmission line. The function representing the changes in bound values versus the respective free ligand concentrations, has been studied analytically on the basis of all the possible values that the percent changes in both K_d and B_m parameters induced by a given experimental condition can assume. A well characterized change in the pattern of bound radioligand could in this way be defined. This approach, developed to show in an immediate and clear way treatment-induce changes in receptor populations or to fit directly rough experimental data expressed as differences in bound values versus free ligand concentrations, seems to be an useful complement to the widely used saturation analysis of binding data.     

Synaptic and extrasynaptic NMDA receptors: Problems and prospects

This review is devoted to the problem of induction of differently directed NMDA-dependent longterm plasticity in the central nervous system and their transformation into pathological changes. Their hypothetical mechanisms and the corresponding experimental data are discussed. Special attention is paid to the functional characteristics of synaptic and extrasynaptic NR1/NR2A and NR1/NR2B receptors, their different involvement in the spatiotemporal organization of Ca²⁺ signaling, and peculiarities of biochemical reactions of the cell. The possible structural reorganization of NMDA receptors as one of the kinds of plasticity is also analyzed.