多种信号途径介导花生四烯酸与5-羟色胺在促人类血小板凝集中的协同作用

AIM: To examine the signalling mechanisms involved in the synergistic interaction of 5-hydroxytryptamine (5-HT) and arachidonic acid (AA) in human platelet aggregation. METHODS: Blood was obtained from healthy human subjects, mixed with 3.8 % sodium citrate (9:1), and centrifuged to prepare platelet rich plasma (PRP). Aggregation was monitored using a Dual-channel Lumi-aggregometer. The agonist-induced influx of Ca^2 was measured using Fura-2 AM. TXA2 formation was studied using radiochemical method. RESULTS: Subthreshold concentration of 5-HT (2μmol/L) potentiated the effect of low dose of AA (0.2 mmol/L) in human platelets. This synergistic effect was blocked by 5-HT2 receptor antagonist (methysergide IC50=5.2 nmol/L; cyproheptadine IC50=0.6 nmol/L), and thromboxane A2 receptor antagonist (SQ 29 548; IC5o=30 nmol/L), showing that the effect is receptor-mediated.To examine the down-stream signalling pathways, we found that such an interaction was inhibited by calcium channel blockers (diltiazem; IC50=3 μmol/L and verapamil; IC50=5 μmol/L), phospholipase C (PLC) inhibitor (U73122;IC50=4 μmol/L), cyclooxygenase inhibitor, (indomethacin; IC50=0.2 μmol/L) and mitogen-activated protein (MAP) kinase inhibitor (PD98059; IC5o=3 ktmol/L). The effect was also inhibited by a specific tyrosine light chain kinase(TLCK) inhibitor, herbimycin A with IC50 value of 5 μmol/L. Pretreatment of platelet with 5-HT and AA induced rise in intracellular calcium and this effect was blocked by verapamil. CONCLUSION: The synergism between 5-HT and AA in platelet aggregation involves activation of PLC/Ca^2 , COX, and MAP kinase pathways.     

Prefrontal,accumbal [shell] and ventral striatal mechanisms in jaw movements and non-cyclase-coupled dopamine D1-like receptors

The effect on jaw movements of intracerebral injections of the dopamine D1-like receptor agents SK&F 83959 (3-methyl-6-chloro-7,8-dihydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), SK&F 38393 ([R]-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and of injections of the dopamine D2-like receptor agonist quinpirole into the ventrolateral striatum, accumbens shell or prefrontal cortex were studied. SK&F 38393 and SK&F 83959 injected into the ventrolateral striatum synergised with i.v. quinpirole; in the shell of accumbens, SK&F 38393 evidenced weaker synergism with quinpirole, while SK&F 83959 did not synergise with it; neither agent synergised with quinpirole in the prefrontal cortex. Co-injection of SCH 23390 or SK&F 83959 into the prefrontal cortex antagonised jaw movements induced by injection of SK&F 83959 into the ventrolateral striatum in combination with i.v. quinpirole. Injection of SK&F 83959 + quinpirole into the ventrolateral striatum, but not into the accumbens shell, resulted in synergism. These findings indicate a primary, but not exclusive, role for ventral striatal, non-cyclase-coupled dopamine D1-like receptors in the induction of jaw movements. These processes appear to require tonic activity of prefrontal cyclase-linked dopamine D1A [and/or D1B] receptors.     

Rationale for intralesional valrubicin in chemoradiation of squamous cell carcinoma of the head and neck

OBJECTIVES/HYPOTHESIS: With some advanced squamous cell carcinomas (SCCs) of the head and neck, chemoradiation therapy may obviate the need for surgical intervention. However, both modalities are known to produce organ toxicities, and tumor insensitivity remains problematic. Thus there is a clear need for the development of new treatment strategies. Accordingly, preclinical studies to evaluate the use of valrubicin, a contact-safe, mechanistically novel antitumor agent, combined with low-dose radiation for the therapy of SCC have been conducted. METHODS: The comparative in vitro antitumor activities of valrubicin with or without irradiation versus cisplatin were evaluated using human-derived sensitive and cisplatin-resistant SCC cell lines. A hamster cheek pouch model of SCC was used to assess the efficacy of weekly intratumoral valrubicin injections with and without concurrent low-dose irradiation. RESULTS: Valrubicin cytotoxicity was found to be comparable in both sensitive and platinum-resistant cell lines and superior to cisplatin. The addition of minimally cytotoxic cell irradiation (300-450 cGy) resulted in prolonged G2/M cell cycle arrest and a supraadditive increase in apoptotic cell death. In hamsters, once a week x 3 intratumoral drug injections (3, 6, or 9 mg) were growth inhibitory; however, when valrubicin (6 mg) was combined with minimally cytotoxic irradiation (150, 250, or 350 cGy) significant tumor shrinkage was observed. CONCLUSIONS: Valrubicin produces supra-additive effects against SCC when combined with low-dose irradiation. This effect appears to correlate with the ability of valrubicin, a cytoplasmic-localizing drug, to inhibit protein kinase C. Therapeutic use of valrubicin against SCC could provide for reduced radiation doses with consequent improved efficacy and reduction in host toxicity.     

进口与国产培高利特治疗帕金森病的疗效比较

目的 :比较进口与国产培高利特治疗帕金森病的疗效。方法 :在并用 (进口组有 6例不并用 )左旋多巴 苄丝肼下 ,进口组帕金森病 68例 ,男性 35例 ,女性 33例 ,年龄 64a±s 12a ,给进口培高利特从 0 .0 2 5mg·d- 1开始 ;国产组 70例 ,男性 37例 ,女性 33例 ,年龄 64a± 9a ,给国产培高利特从 0 .0 5mg·d- 1开始 ,均逐渐增至 0 .5～ 0 .75mg·d- 1,于 3mo后评定疗效。结果 :进口组总有效率 91% ,运动波动总有效率 94 % ,平均每例左旋多巴 苄丝肼剂量减少 2 8% ,国产组分别为 4 6% ,35% ,8%。差异有非常显著意义 (P <0 .0 1)。进口组副作用略多于国产组。结论 :进口培高利特治疗帕金森病效果优于国产品 ,副作用较国产培高利特略明显。     

Interaction of neuropeptides and biogenic amines on cyclic adenosine monophosphate accumulation in hypothalamic nuclei

Neuropeptides and biogenic amines known to be present in neurons or afferent terminals in the paraventricular nucleus (PVH), supraoptic nucleus (SON) and/or lateral hypothalamus (LH) were added to small areas of these structures obtained by micropuncture and cyclic adenosine monophosphate (cAMP) levels were measured. cAMP accumulation occurred in PVH, SON and LH in response to neuropeptides of the secretin family, such as vasoactive intestinal peptide (VIP) and in response to catecholamines. Bradykinin, alpha-melanocyte-stimulating (alpha-MSH), luteinizing hormone-releasing hormone (LH-RH), oxytocin and carbamylcholine stimulated cAMP accumulation selectively in one or two of the above structures. Glucagon, cholecystokinin (CCK), somatostatin (SRIF), corticotropin-releasing factor (CRF), thyrotropin-releasing hormone (TRH), adrenocorticotropin (ACTH), melanocyte-stimulating hormone (MSH), methionine enkephalin (Met-Enk), beta-endorphin, neurotensin, bombesin and angiotensin II did not effect cAMP levels while leucine enkephalin (Leu-Enk), arginine vasopressin and gamma-aminobutyric acid (GABA) elicited regionally selective decreases in basal levels of cAMP. When interactions between some of these compounds were measured, VIP and norepinephrine exerted a more than additive effect on cAMP elevation in the PVH, while the effect on cAMP of the SON and LH was additive.     

长春瑞滨对人肺腺癌973细胞放射增敏作用的实验研究

目的：探讨长春瑞滨（NVB）对非小细胞肺癌细胞放射效应影响及其与放射的最佳结合序贯。方法：以指数生长期的人肺腺癌973细胞为研究对象，采用克隆形成分析法进行0．1nM及1nMNVB与放射不同结合序贯实验，研究NVB与放射结合效应，利用“多靶单击”数学模型（SF=1-（1-e^-D/D0）N）进行曲线拟合，获得细胞存活曲线及平均致死剂量、准阈剂量、D。比和增敏比等参数，进行效应评估。结果：0．1nM及1nMNVB照前、照后给药组的增敏比（SER）分别为0．957和0．989，1．295和1．042；0．1nM及1nMNVB照前、照后给药组的D0比分别为1．073和1．099，1．374和1．106。表明0．1nMNVB照前、照后给药时均无放射增敏作用；1nMNVB照前、照后给药时均与放射效应具有较明显协同作用，且照前给药组的协同作用明显强于照后给药组。结论：0．1nMNVB不具有增强放射效应的作用，1nMNVB具有较明显放射效应增强作用，且照前给药组的协同作用明显强于照后给药组。     

超声波与消毒剂协同杀菌作用的实验研究

试验表明超声波与洗必泰、新洁尔灭、过氧化氢、过氧乙酸及醛醇合剂对细菌芽胞具有协同杀灭作用。     

Bacteriolysis – a mere laboratory curiosity?

The role of bacteriolysis in the pathophysiology of microbial infections dates back to 1893 when Buchner and Pfeiffer reported for the first time the lysis of bacteria by immune serum and related this phenomenon to the immune response. Later on, basic anti-microbial peptides and certain beta-lactam antibiotics have been shown not only to kill microorganisms but also to induce bacteriolysis and the release of cell-wall components.

In 2009, a novel paradigm was offered suggesting that the main cause of death in sepsis is due to the exclusive release from activated human phagocytic neutrophils (PMNs) traps adhering upon endothelial cells of highly toxic nuclear histone. Since activated PMNs also release a plethora of pro-inflammatory agonists, it stands to reason that these may act in synergy with histone to damage cells. Since certain beta lactam antibiotics may induce bacteriolysis, it is questioned whether these may aggravate sepsis patient's condition. Enigmatically, since the term bacteriolysis and its possible involvement in sepsis is hardly ever mentioned in the extensive clinical articles and reviews dealing with critical care, we hereby aim to refresh the concept of bacteriolysis and its possible role in the pathogenesis of post infectious sequelae.