BACKGROUND & AIMS: BACKGROUND:A 79-year-old woman was referred for evaluation of her painful and swollen joints. She had a medical history of congestive heart failure, renal insufficiency and peptic ulcer disease. For the past 3 years she had experienced recurrent bouts of debilitating arthritis, lasting approximately 3-4 weeks at a time. The symptoms were most severe in the hands and knees, where the joints were warm, swollen and tender. During each flare-up, the patient was housebound and required therapeutic dosing of nonsteroidal anti-inflammatory drugs and codeine to control joint pain. INVESTIGATIONS:Physical examination, fine-detailed radiographs of the hands, standing radiographs of the knees, arthrocentesis including cell count and gram stain, compensated polarized light microscopy, alizarin-red staining, X-ray diffraction, scanning and transmission electron microscopy with energy dispersive spectrometry, electron microprobe analysis with energy dispersive spectrometry, Fourier transform infrared spectroscopy, and atomic force microscopy. DIAGNOSIS:Carbonated-substituted apatite arthropathy. MANAGEMENT:Both knees were aspirated and large volumes of a straw-colored synovial fluid was removed. The knees were injected with corticosteroid, resulting in excellent symptomatic response.

背景与目标：

BACKGROUND & AIMS: :The main purpose of the present study was to learn how mathematical abilities are located and develop in the brain with respect to language. Mathematical abilities were assessed in six right-handed patients affected by aphasia following a lesion to their non-dominant hemisphere (crossed aphasia) and in two left-handed aphasics with a right-sided lesion. Acalculia, although in different degrees, was found in all cases. The type of acalculia depended on the type of aphasia, following patterns that have been previously observed in the most common aphasias resulting from left hemisphere lesions. No sign of right hemisphere or spatial acalculia (acalculia in left lateralised right-handed subjects) was detected. These results suggest that, as a rule, language and calculation share the same hemisphere. A primitive computational mechanism capable of recursion may be the precursor of both functions.

背景与目标： : 本研究的主要目的是了解语言在大脑中如何定位和发展数学能力。在六名非优势半球病变 (交叉失语症) 后受失语症影响的右手患者和两名右侧病变的左手失语症患者中评估了数学能力。尽管在不同程度上，但在所有情况下都发现了Acalculia。Aalculia的类型取决于失语症的类型，遵循先前在左半球病变引起的最常见失语症中观察到的模式。未检测到右半球或空间无alculia (左侧右手受试者中的无alculia) 的迹象。这些结果表明，通常，语言和计算具有相同的半球。能够递归的原始计算机制可能是这两个功能的前身。

BACKGROUND & AIMS: :In 4 experiments, the authors investigated the reversal of spatial congruency effects when participants concurrently practiced incompatible mapping rules (J. G. Marble & R. W. Proctor, 2000). The authors observed an effect of an explicit spatially incompatible mapping rule on the way numerical information was associated with spatial responses. The authors also observed an effect of an incompatible numerical mapping rule (if smaller than 5, press right; if larger than 5, press left) on the Simon effect. This effect was observed only when both tasks used the same effectors. The results point to a shared spatial representation for explicit spatial information (locations) and implicit spatial information (numbers).

背景与目标： : 在4个实验中，作者研究了参与者同时实践不兼容映射规则时空间一致性效应的逆转 (J. G. Marble & R. W. Proctor，2000)。作者观察到明确的空间不兼容映射规则对数字信息与空间响应相关联的方式的影响。作者还观察到不兼容的数值映射规则 (如果小于5，则按右; 如果大于5，则按左) 对Simon效果的影响。仅当两个任务使用相同的效应器时才观察到这种效果。结果指向显式空间信息 (位置) 和隐式空间信息 (数字) 的共享空间表示。

BACKGROUND & AIMS: OBJECTIVE:The purpose of our study was to evaluate the effects of 0.3-second high-resolution CT (HRCT) of the lung using partial reconstruction on cardiac motion artifacts and image noise. SUBJECTS AND METHODS:Thirty-seven pairs of 0.3-second (partial reconstruction) and 0.75-second (full reconstruction) HRCT images were obtained for the lower lung zone during full-inspiration breath-holding. Imaging parameters other than temporal resolution were identical for each patient. Two radiologists visually graded motion artifacts of the cardiac border, bronchi, pulmonary vessels, and fissure in the left lung on a 4-point scale (with 4 indicating no artifacts). The maximum width of motion along the left cardiac border and the area percentage of motion artifacts in the left lung were calculated. Image noise in the air and lung was also determined. Cardiac motion artifacts and image noises were compared between the two sets of CT images. RESULTS:Visual grades for the cardiac border (4 +/- 0), bronchi (3.8 +/- 0.7), pulmonary vessels (3.6 +/- 0.8), and fissure (3.9 +/- 0.5) were higher for 0.3-second images than for 0.75-second images (1.7 +/- 0.7, 2.0 +/- 1.0, 1.6 +/- 0.7, and 2.4 +/- 0.9, respectively) (p < 0.001). The maximum width of motion along the left cardiac border (0.1 +/- 0.5 mm) and the area percentage of motion artifacts in the left lung (6.7% +/- 18.4%) were smaller for 0.3-second images than for 0.75-second images (4.5 +/- 1.7 mm and 36.2% +/- 20.9%, respectively) (p < 0.001). Image noises in the air (38.0 +/- 9.2) and the lung (86.0 +/- 23.1) were greater for 0.3-second images than for 0.75-second images (35.6 +/- 9.6 and 76.0 +/- 20.3, respectively) (p < 0.01). CONCLUSION:Compared with 0.75-second HRCT using full reconstruction, 0.3-second HRCT using partial reconstruction substantially reduces cardiac motion artifacts in the lung at the expense of increasing image noise.

背景与目标：

BACKGROUND & AIMS: :The signaling pathways mediating lysophosphatidic acid (LPA)-stimulated PKD(2) activation and the potential contribution of PKD(2) in regulating LPA-induced interleukin 8 (IL-8) secretion in nontransformed, human colonic epithelial NCM460 cells were examined. Treatment of serum-deprived NCM460 cells with LPA led to a rapid and striking activation of PKD(2), as measured by in vitro kinase assay and phosphorylation at the activation loop (Ser706/710) and autophosphorylation site (Ser876). PKD(2) activation induced by LPA was abrogated by preincubation with selective PKC inhibitors GF-I and Ro-31-8220 in a dose-dependent manner. These inhibitors did not have any direct inhibitory effect on PKD(2) activity. LPA induced a striking increase in IL-8 production and stimulated NF-kappaB activation, as measured by NF-kappaB-DNA binding, NF-kappaB-driven luciferase reporter activity, and IkappaBalpha phosphorylation. PKD(2) gene silencing utilizing small interfering RNAs targeting distinct PKD(2) sequences dramatically reduced LPA-stimulated NF-kappaB promoter activity and IL-8 production. PKD(2) activation is a novel early event in the biological action of LPA and mediates LPA-stimulated IL-8 secretion in NCM460 cells through a NF-kappaB-dependent pathway. Our results demonstrate, for the first time, the involvement of a member of the PKD family in the production of IL-8, a potent proinflammatory chemokine, by epithelial cells.

背景与目标： : 检测了介导溶血磷脂酸 (LPA) 刺激的PKD(2) 激活的信号通路，以及PKD(2) 在调节LPA诱导的白介素8 (IL-8) 分泌中的潜在作用。未转化的人结肠上皮NCM460细胞。用LPA处理血清剥夺的NCM460细胞导致PKD(2) 的快速和惊人的激活，如通过体外激酶测定和激活环 (Ser706/710) 和自磷酸化位点 (Ser876) 测量的。通过与选择性PKC抑制剂gf-i预孵育消除LPA诱导的PKD(2) 激活，并以剂量依赖性方式Ro-31-8220。这些抑制剂对PKD(2) 活性没有任何直接抑制作用。通过NF-κ b-DNA结合，NF-κ b驱动的荧光素酶报告活性和ikappaba磷酸化来测量，LPA诱导了IL-8产生的显着增加并刺激了NF-κ b活化。利用靶向不同PKD(2) 序列的小干扰rna沉默PKD(2) 基因显著降低LPA刺激的NF-κ b启动子活性和IL-8产生。PKD(2) 激活是LPA生物学作用中的一个新的早期事件，并通过NF-κ b依赖性途径介导NCM460细胞中LPA刺激的IL-8分泌。我们的结果首次证明了PKD家族成员参与了上皮细胞产生IL-8 (一种有效的促炎趋化因子)。

BACKGROUND & AIMS: :The gram-negative bacterium Bartonella henselae is capable of causing angiogenic lesions as a result of infection. Previously, it has been shown that B. henselae infection can result in production of the chemokine interleukin-8 (IL-8). In this study, we demonstrated that monocytes, endothelial cells, and hepatocytes produce IL-8 in response to B. henselae infection. We also investigated the role of IL-8 in B. henselae-induced endothelial cell proliferation and capillary tube formation. Both in vitro angiogenesis assays were IL-8 dependent. B. henselae-mediated inhibition of apoptosis, as indicated by gene expression of Bax and Bcl-2, was also shown to be IL-8 dependent in endothelial cells. Furthermore, infection of endothelial cells with B. henselae stimulated upregulation of the IL-8 chemokine receptor CXCR2. Infection of human endothelial cells by B. henselae resulting in IL-8 production likely plays a central role in the ability of this organism to cause angiogenesis during infection.

背景与目标： : 革兰氏阴性细菌Bartonella henselae能够由于感染而引起血管生成病变。以前，已经显示出B. henselae感染可导致趋化因子interleukin-8 (IL-8) 的产生。在这项研究中，我们证明了单核细胞，内皮细胞和肝细胞对B. henselae感染产生IL-8。我们还研究了IL-8在B. henselae诱导的内皮细胞增殖和毛细管形成中的作用。两种体外血管生成测定都是IL-8依赖性的。B. henselae介导的凋亡抑制，如Bax和Bcl-2的基因表达所表明的，也显示在内皮细胞中IL-8依赖性。此外，B. henselae感染内皮细胞会刺激IL-8趋化因子受体cxcr2的上调。B. henselae感染人内皮细胞导致IL-8产生可能在该生物体在感染期间引起血管生成的能力中起核心作用。

BACKGROUND & AIMS: :Sympathetically maintained pain could either be mediated by ephaptic interactions between sympathetic efferent and afferent nociceptive fibers or by catecholamine-induced activation of nociceptive nerve endings. We report here single fiber recordings from C nociceptors in a patient with sympathetically maintained pain, in whom sympathetic blockade had repeatedly eliminated the ongoing pain in both legs. We classified eight C-fibers as mechano-responsive and six as mechano-insensitive nociceptors according to their mechanical responsiveness and activity-dependent slowing of conduction velocity (latency increase of 0.5+/-1.1 vs. 7.1+/-2.0 ms for 20 pulses at 0.125 Hz). Two C-fibers were activated with a delay of several seconds following strong endogenous sympathetic bursts; they were also excited for about 3 min following the injection of norepinephrine (10 microl, 0.05%) into their innervation territory. In these two fibers, a prolonged activation by injection of low pH solution (phosphate buffer, pH 6.0, 10 microl) and sensitization of their heat response following prostaglandin E2 injection were recorded, evidencing their afferent nature. Moreover, their activity-dependent slowing was typical for mechano-insensitive nociceptors. We conclude that sensitized mechano-insensitive nociceptors can be activated by endogenously released catecholamines and thereby may contribute to sympathetically maintained pain. No evidence for ephaptic interaction between sympathetic efferent and nociceptive afferent fibers was found.

背景与目标： : 交感神经的维持性疼痛可以通过交感神经传出和传入伤害性纤维之间的触感相互作用来介导，也可以通过儿茶酚胺诱导的伤害性神经末梢的激活来介导。我们在此报告了一名患有交感持续疼痛的患者的C伤害感受器的单纤维记录，其中交感神经阻滞反复消除了双腿的持续疼痛。我们根据八种C纤维的机械响应性和与活动有关的传导速度减慢 (在0.125Hz下20个脉冲的0.5/-1.1与7.1/-2.0 ms的潜伏期增加)，将它们分类为机械敏感的伤害感受器。强烈的内源性交感神经爆发后，两根C纤维被激活，延迟数秒; 在将去甲肾上腺素 (10 microl，0.05%) 注射到其神经支配区域后，它们也被兴奋约3分钟。在这两种纤维中，记录了通过注射低pH溶液 (磷酸盐缓冲液，pH 6.0，10μl) 而延长的活化以及前列腺素E2注射后它们的热响应的敏化，证明了它们的传入性质。此外，对于机械不敏感的伤害感受器，它们的活性依赖性减慢是典型的。我们得出的结论是，内源性释放的儿茶酚胺可以激活敏感的机械不敏感伤害感受器，从而可能导致交感疼痛。没有发现交感传出和伤害性传入纤维之间的触觉相互作用的证据。

BACKGROUND & AIMS: :Rhodopseudomonas palustris is a purple, facultatively phototrophic bacterium that uses hydrogen gas as an electron donor for carbon dioxide fixation during photoautotrophic growth or for ammonia synthesis during nitrogen fixation. It also uses hydrogen as an electron supplement to enable the complete assimilation of oxidized carbon compounds, such as malate, into cell material during photoheterotrophic growth. The R. palustris genome predicts a membrane-bound nickel-iron uptake hydrogenase and several regulatory proteins to control hydrogenase synthesis. There is also a novel sensor kinase gene (RPA0981) directly adjacent to the hydrogenase gene cluster. Here we show that the R. palustris regulatory sensor hydrogenase HupUV acts in conjunction with the sensor kinase-response regulator protein pair HoxJ-HoxA to activate hydrogenase expression in response to hydrogen gas. Transcriptome analysis indicated that the HupUV-HoxJA regulatory system also controls the expression of genes encoding a predicted dicarboxylic acid transport system, a putative formate transporter, and a glutamine synthetase. RPA0981 had a small effect in repressing hydrogenase synthesis. We also determined that the two-component system RegS-RegR repressed expression of the uptake hydrogenase, probably in response to changes in intracellular redox status. Transcriptome analysis indicated that about 30 genes were differentially expressed in R. palustris cells that utilized hydrogen when growing photoheterotrophically on malate under nitrogen-fixing conditions compared to a mutant strain that lacked uptake hydrogenase. From this it appears that the recycling of reductant in the form of hydrogen does not have extensive nonspecific effects on gene expression in R. palustris.

背景与目标： : 红假单胞菌 (Rhodopseudomonas palustris) 是一种紫色的兼性光养细菌，在光自养生长过程中使用氢气作为电子供体进行二氧化碳固定或在固氮过程中进行氨合成。它还使用氢作为电子补充剂，以使氧化的碳化合物 (例如苹果酸盐) 在光异养生长过程中完全同化为细胞材料。R. palustris基因组预测了膜结合的镍铁吸收氢化酶和几种控制氢化酶合成的调节蛋白。还有一个新的传感器激酶基因 (RPA0981) 直接与氢化酶基因簇相邻。在这里，我们显示了R. palustris调节传感器氢化酶HupUV与传感器激酶响应调节蛋白对HoxJ-HoxA共同作用，以响应氢气激活氢化酶表达。转录组分析表明，HupUV-HoxJA调节系统还控制编码预测的二羧酸转运系统，推定的甲酸转运蛋白和谷氨酰胺合成酶的基因的表达。RPA0981在抑制氢化酶合成方面的作用很小。我们还确定，两组分系统RegS-RegR抑制了摄取氢化酶的表达，可能是对细胞内氧化还原状态变化的响应。转录组分析表明，与缺乏摄取氢化酶的突变菌株相比，在固氮条件下在苹果酸上光异养生长时利用氢的R. palustris细胞中约30个基因差异表达。由此看来，以氢形式回收还原剂对R. palustris的基因表达没有广泛的非特异性影响。

BACKGROUND & AIMS: :Statins are increasingly being used for the treatment of a variety of conditions beyond their original indication for cholesterol lowering. We previously reported that simvastatin increased dopamine receptors in the rat prefrontal cortex [Q. Wang, W.L. Ting, H. Yang, P.T. Wong, High doses of simvastatin upregulate dopamine D(1) and D(2) receptor expression in the rat prefrontal cortex: possible involvement of endothelial nitric oxide synthase, Br. J. Pharmacol. 144 (2005) 933-939] and restored its downregulation in a model of Parkinson's disease (PD) [Q. Wang, P.H. Wang, C. McLachlan, P.T. Wong, Simvastatin reverses the downregulation of dopamine D1 and D2 receptor expression in the prefrontal cortex of 6-hydroxydopamine-induced Parkinsonian rats, Brain Res. 1045 (2005) 229-233]. Here we explore the effects of simvastatin treatment on tissue dopamine content and reuptake. Sprague-Dawley rats were given simvastatin (1 and 10 mg kg(-1)day(-1), p.o.) for 4 weeks. Brain tissue from prefrontal cortex and striatum were taken out for dopamine content and its reuptake. Using high-performance liquid chromatographic-mass spectrometer (HPLC-MS), simvastatin (10 mg kg(-1)day(-1)) was found to increase dopamine content by 110% in the striatum but decreased by 76% in the prefrontal cortex compared with the saline treated group. Dopamine (DA) reuptake was unchanged in both brain regions. These results suggest that chronic treatment with high dose of simvastatin may affect DA tissue level in prefrontal cortex and striatum without changing on DA reuptake. This may have important clinical implications in psychiatric and striatal dopaminergic disorders.

背景与目标： : 他汀类药物越来越多地用于治疗各种疾病，超出了其降低胆固醇的原始适应症。我们先前报道辛伐他汀增加了大鼠前额叶皮层的多巴胺受体 [Q. Wang，W.L. Ting，H. Yang，P.T. Wong，高剂量辛伐他汀上调了大鼠前额叶皮层的多巴胺D(1) 和D(2) 受体表达: 可能参与内皮型一氧化氮合酶，br.J. Pharmacol. 144 (2005) 933-939] 并在帕金森氏病 (PD) 模型中恢复了其下调 [Q. Wang，P.H. Wang，C. McLachlan，P.T. Wong，辛伐他汀可逆转6-羟基多巴胺诱导的帕金森病大鼠前额叶皮层多巴胺D1和D2受体表达的下调，脑Res. 1045 (2005) 229-233]。在这里，我们探讨辛伐他汀治疗对组织多巴胺含量和再摄取的影响。Sprague-Dawley大鼠给予辛伐他汀 (1和10 mg kg(-1) 天 (-1)，p.o.) 4周。取出前额叶皮层和纹状体的脑组织以获取多巴胺含量及其再摄取。使用高效液相色谱-质谱仪 (hplc-ms)，发现辛伐他汀 (10 mg kg(-1) 天 (-1)) 在纹状体中110% 增加多巴胺含量，但在前额叶皮层中减少76% 与生理盐水治疗组相比。两个大脑区域的多巴胺 (DA) 再摄取均未改变。这些结果表明，高剂量辛伐他汀的慢性治疗可能会影响前额叶皮层和纹状体的DA组织水平，而不会改变DA的再摄取。这可能对精神病和纹状体多巴胺能疾病具有重要的临床意义。

BACKGROUND & AIMS: :Heat shock protein 90 (HSP90) is required for structural folding and maintenance of conformational integrity of various proteins, including several associated with cellular signaling. Recent studies utilizing 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, demonstrated an antitumor effect in solid tumors. To test whether HSP90 could be targeted in multiple myeloma (MM) patients, we first investigated expression of HSP90 by immunofluorescence and flow cytometric analysis in a myeloma cell line (U266) and primary myeloma cells. Following demonstration of HSP90 expression in myeloma cells, archival samples of 32 MM patients were analysed by immunoperoxidase staining. Myeloma cells in all patients showed strong cytoplasmic expression of HSP90 in all samples and 55% also demonstrated concurrent nuclear immunopositivity. Treatment of U266 and primary MM cells with 17AAG resulted in significantly increased apoptosis compared to untreated control cells. Analysis of anti-apoptotic BCL2 family proteins and akt in MM cells incubated with 17-AAG revealed down-regulation of BCL-2, BCL-XL, MCL-1 and akt. Furthermore, although a low concentration of bortezomib resulted in no cell death, a combination of 17AAG and bortezomib treatment revealed a synergistic apoptotic effect on the U266 cell line. These data suggest that targeted inhibition of HSP90 may prove to be a valid and innovative strategy for the development of future therapeutic options for MM patients.

背景与目标： : 热休克蛋白90 (HSP90) 是各种蛋白质的结构折叠和构象完整性维持所必需的，包括与细胞信号传导相关的几种。利用HSP90抑制剂17-allylamino-17-demethoxygeldanamycin (17-AAG) 的最新研究表明，在实体瘤中具有抗肿瘤作用。为了测试HSP90是否可以靶向多发性骨髓瘤 (MM) 患者，我们首先通过免疫荧光和流式细胞仪分析研究了HSP90在骨髓瘤细胞系 (U266) 和原发性骨髓瘤细胞中的表达。在证明骨髓瘤细胞中HSP90表达后，通过免疫过氧化物酶染色分析了32 MM患者的档案样本。所有患者的骨髓瘤细胞在所有样品中均显示出HSP90的强细胞质表达，并且55% 还显示出同时的核免疫阳性。与未处理的对照细胞相比，用17AAG处理U266和原代MM细胞可显着增加细胞凋亡。对与17-aag孵育的MM细胞中抗凋亡BCL2家族蛋白和akt的分析表明，BCL-2，BCL-XL，MCL-1和akt下调。此外，尽管低浓度的硼替佐米不会导致细胞死亡，但17AAG和硼替佐米的组合治疗显示出对U266细胞系的协同凋亡作用。这些数据表明，靶向抑制HSP90可能被证明是开发MM患者未来治疗选择的有效且创新的策略。

BACKGROUND & AIMS: :Fludarabine and alemtuzumab are routinely used for treatment of B-cell chronic lymphocytic leukemia (B-CLL). The present study aimed to compare the expression of signaling molecules and cytokine production by T cells of B-CLL patients in long-term unmaintained remission/plateau phase following fludarabine or alemtuzumab treatment with that of indolent/untreated B-CLL patients and healthy donors. The frequency and intensity of TCR-CD3zeta chain, p56lck, p59fyn, ZAP-70, PI3-kinase and interferon (IFN)-gamma/interleukin (IL)-4 production in CD4 and CD8 T cells was examined by flow cytometry. T-cell function was assessed by stimulation with purified protein derivative (PPD) and phytohemagglutinin (PHA). Despite a reduction in number, the expression of IFN-gamma/IL-4 in T-cells in patients was significantly higher than in healthy donors. The intensity of most signaling molecules in treated patients was relatively unaffected vs. healthy donors but lower than untreated-indolent patients. However, the total number of T cells which expressed each of the signaling molecules was decreased in patients, with no difference between fludarabine- and alemtuzumab-treated patients. The T-cell response to PHA but not PPD was reduced in treated patients. The results suggest that, despite some alterations in signaling molecules and a reduction in T-cell number, overall T-cell functions may be relatively well preserved long-term after treatment with fludarabine and alemtuzumab.

背景与目标： : 氟达拉滨和阿仑单抗通常用于治疗b细胞慢性淋巴细胞白血病 (b-cll)。本研究旨在比较在氟达拉滨或阿仑单抗治疗后长期未维持缓解/平台期的b-cll患者的T细胞与惰性/未治疗的b-cll患者的信号分子表达和细胞因子产生和健康供体。通过流式细胞术检查CD4和CD8 T细胞中TCR-CD3zeta链，p56lck，p59fyn，ZAP-70，PI3-kinase和干扰素 (IFN)-γ/白细胞介素 (IL)-4产生的频率和强度。通过纯化蛋白衍生物 (PPD) 和植物血凝素 (PHA) 刺激来评估T细胞功能。尽管数量减少，但患者T细胞中IFN-γ/IL-4的表达显着高于健康供体。与健康供体相比，接受治疗的患者中大多数信号分子的强度相对不受影响，但低于未经治疗的惰性患者。然而，在患者中表达每种信号分子的T细胞总数减少，而氟达拉滨和阿仑单抗治疗的患者之间没有差异。在治疗的患者中，T细胞对PHA的反应降低，但对PPD的反应降低。结果表明，尽管信号分子发生了一些变化，T细胞数量减少，但在用氟达拉滨和阿仑单抗治疗后，总体T细胞功能可能长期保持良好。

BACKGROUND & AIMS: :1. Tolerance to the hypotensive effect of nitroglycerin (NG) blocks preconditioning induced by rapid ventricular pacing (RVP) in rabbits. In the present work the effect of continuous versus intermittent treatment with transdermal nitroglycerin on the pacing-induced preconditioning phenomenon was studied in conscious rabbits. 2. RVP (500 beats min-1 over 5 min) increased left ventricular end-diastolic pressure (LVEDP) from baseline 4.1 +/- 0.9 to postpacing 13.8 +/- 2.9 mmHg (P < 0.001) with a right intraventricular ST-segment elevation of 1.25 +/- 0.13 mV, two indicators of myocardial ischaemia. These changes were significantly attenuated when the RVP period was preceded by a preconditioning pacing of the same rate and duration with an interpacing interval of 5 min. 3. Protection by preconditioning was abolished when the animals had been made tolerant to the vasodilator effect of 30 micrograms kg-1 NG by the application of transdermal NG (approx. 0.07 mg kg-1 h-1) over 7 days. Furthermore, transdermal NG per se attenuated both RVP-induced ST-segment elevation and LVEDP-increase over the 7 day period. 4. With intermittent transdermal NG treatment (12 h 'patch on' vs 'patch off'), neither development of vascular tolerance nor attenuation of the NG- or preconditioning-induced anti-ischaemic effects were observed. However, the severity of pacing-induced myocardial ischaemia was significantly increased during the 'patch off' periods. 5. In a second set of experiments, postpacing changes in cardiac cyclic GMP and cyclic AMP levels were determined by means of radioimmunoassay in chronically instrumented anaesthetized open-chest rabbits with the same NG-treatment protocols. Preconditioning reduced postpacing increase in cyclic AMP with an increase in cyclic GMP concentrations in hearts of the untreated animals and in those given patches intermittently during both 'patch on' and 'patch off' periods. However, the preconditioning effect on either cyclic nucleotide was blocked in the tolerant animals. 6. Transdermal NG increased resting levels of both cardiac cyclic nucleotides in the non-tolerant but not in the tolerant state. The postpacing increase in cyclic AMP content was inhibited by transdermal NG, independent of vascular tolerance development, whereas an cyclic GMP content was exclusively seen in the non-tolerant animals. 7. We conclude that the anti-ischaemic effect of NG is independent of the cyclic GMP mechanism in the tolerant state. While intermittent NG therapy prevents development of vascular tolerance and preserves preconditioning, the nitrate-free periods yield an increased susceptibility of the heart to ischaemic challenges.

背景与目标： : 1。对硝酸甘油 (NG) 的降压作用的耐受性阻断了兔快速心室起搏 (RVP) 引起的预处理。在本工作中，在清醒的兔子中研究了经皮硝酸甘油连续治疗与间歇治疗对起搏诱导的预处理现象的影响。2. RVP (500搏动min-1超过5分钟) 使左室舒张末期压 (LVEDP) 从基线4.1 +/- 0.9增加至起搏后13.8 +/- 2.9 mmHg (P <0.001)，右室ST段抬高1.25 +/- 0.13 mV，心肌缺血的两个指标。当在RVP期之前进行相同速率和持续时间的预处理起搏并间隔5分钟时，这些变化会显着减弱。3.当通过在7天内应用透皮NG (约0.07 mg kg-1 h-1) 使动物耐受30微克kg-1 NG的血管舒张作用时，取消了预处理的保护。此外，透皮NG本身在7天内减弱了RVP诱导的ST段抬高和LVEDP升高。4.间歇性经皮NG治疗 (12 h “贴剂” vs “贴剂”)，既没有观察到血管耐受性的发展，也没有观察到NG或预处理诱导的抗缺血作用的减弱。然而，起搏引起的心肌缺血的严重程度在 “修补” 期间显着增加。5.在第二组实验中，通过放射免疫分析法确定了具有相同NG治疗方案的慢性仪器麻醉开胸兔的心脏循环GMP和循环AMP水平的起搏后变化。预处理在未处理的动物心脏和给定的补片中，在 “补片” 和 “补片” 期间间歇性地减少了循环AMP的起搏后增加，循环GMP浓度增加。然而，在耐受性动物中，对任一环核苷酸的预处理作用均被阻断。6.透皮NG在非耐受状态下增加了两个心脏环核苷酸的静息水平，但在耐受状态下不增加。经皮NG抑制了循环AMP含量的起搏后增加，与血管耐受性的发展无关，而在非耐受性动物中仅观察到循环GMP含量。7.我们得出结论，在耐受状态下，NG的抗缺血作用与循环GMP机制无关。尽管间歇性NG疗法可防止血管耐受性的发展并保留预处理，但无硝酸盐期会增加心脏对缺血性挑战的敏感性。

BACKGROUND & AIMS: BACKGROUND:Despite the recent improvement in techniques and patient selection, post-ERCP pancreatitis remains the most frequent and dreaded complication of ERCP. Recent studies suggest that pretreatment with glyceryl trinitrate (GTN) may prevent post-ERCP pancreatitis and improve cannulation success. OBJECTIVE:To evaluate the effect of transdermal GTN on ERCP cannulation success and post-ERCP pancreatitis. DESIGN:Prospective, double-blind, placebo-controlled trial. SETTING:Tertiary referral university hospital. PATIENTS:A total of 318 patients (mean age 62 years, 61% women) were randomized to either active (n = 155) or placebo (n = 163) arms. INTERVENTIONS:Active patch (GTN) versus placebo patch. MAIN OUTCOME MEASUREMENTS:Cannulation time and success. Post-ERCP pancreatitis rates. RESULTS:There was no significant difference between the active or placebo arms for the following: successful initial cannulation (96.8% vs 98.8%), deep cannulation (96.1% vs 98.8%), time to successful cannulation, use of guidewire (27% vs 25%) or needle knife (13% vs 13%), and post-ERCP pancreatitis (7.4% of placebo patients and 7.7% active patients). Multivariate analysis identified women, younger patients, pancreatogram, number of attempts on papilla, and poor pancreatic-duct emptying after opacification as risk factors for post-ERCP pancreatitis. Transdermal GTN did not reduce post-ERCP pancreatitis in any of the identified high-risk groups. CONCLUSIONS:Transdermal GTN did not improve the rate of success in ERCP cannulation or prevent post-ERCP pancreatitis in either average or high-risk patient groups.

背景与目标：

BACKGROUND & AIMS: :Intrathecal injection of mice with substance P or its C-terminal fragments evokes a well documented behavioral syndrome characterized by caudally-directed biting and scratching. We have previously shown that repeated injections of substance P result in naloxone-sensitive desensitization to this substance P-induced behavior, possibly through interactions of N-terminal fragments of substance P with mu opiate binding sites. The present investigation tests the hypothesis that substance P metabolites play a role in the development of desensitization to substance P by using the biting and scratching behavioral paradigm. While substance P-induced behaviors are produced by as little as 1 pmol of substance P, repeated injections of 7.5 pmol at 60-s intervals was found to be the minimum dose capable of causing desensitization. The C-terminal peptides, substance P3-11 and substance P5-11, elicited substance P-like behaviors, but repeated injection of these compounds did not result in desensitization to this behavior. In contrast to C-terminal fragments, intrathecal injection of N-terminal fragments, (substance P1-4, substance P1-7 and substance P1-9), did not elicit any overt substance P-like behaviors when administered alone, but when co-administered with substance P, decreased the magnitude of substance P-induced behaviors in a dose-related fashion. Various peptidase inhibitors significantly inhibited the catabolism of co-administered substance P. Co-administration of substance P with peptidase inhibitors enhanced and prolonged the substance P-induced behavioral episode, but also prevented the development of substance P-induced desensitization. Together these results support the hypothesis that the accumulation of endogenously generated N-terminal metabolites of substance P mediate desensitization to substance P-induced behaviors in the spinal cord. Substance P metabolism may therefore decrease ongoing substance P activity both by the hydrolysis of the C-terminal portion of substance P as well as by the production of N-terminal metabolites that are capable of inhibiting the effects of substance P.

背景与目标： : 鞘内注射p物质或其C末端碎片的小鼠会引起一种有据可查的行为综合症，其特征是尾侧指向的咬伤和抓挠。我们先前已经表明，重复注射p物质会导致纳洛酮对该p物质诱导的行为敏感的脱敏，这可能是通过p物质的N末端片段与mu阿片结合位点的相互作用。本研究通过使用咬和刮擦行为范式来检验p物质代谢物在对p物质脱敏过程中起作用的假设。虽然只有1 pmol的p物质产生p物质诱导的行为，但发现以60s间隔重复注射7.5 pmol是能够引起脱敏的最小剂量。C端肽，物质P3-11和物质P5-11引起了物质P样行为，但是反复注射这些化合物并未导致对该行为的脱敏。与C末端片段相反，鞘内注射N末端片段 (物质P1-4，物质P1-7和物质P1-9) 在单独给药时不会引起任何明显的p物质样行为，但与p物质共同给药时，以剂量相关的方式降低p物质诱导的行为的程度。各种肽酶抑制剂可显着抑制共同施用的p物质的分解代谢。P物质与肽酶抑制剂的共同给药增强并延长了p物质诱导的行为发作，但也阻止了p物质诱导的脱敏反应的发展。这些结果共同支持以下假设: p物质的内源性N末端代谢物的积累介导了对p物质诱导的脊髓行为的脱敏。因此，p物质的代谢可能会通过水解p物质的C末端部分以及产生能够抑制p物质作用的N末端代谢物来降低正在进行的p物质活性。

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： : 从豚鼠下丘脑切片中的26个神经元在细胞内记录了对 [D-Ala2，MePhe4，Gly-ol5] 脑啡肽 (mu受体的选择性激动剂) 的反应。在视上核中测试的八个细胞中，所有这些细胞均具有大细胞神经内分泌细胞的电特性，其中四个对灌注浴或微滴中使用的激动剂敏感。主要效果是减少或抑制自发发射。在室旁核中，测试的18个细胞中有7个具有类似于大细胞神经元的电生理特征: 其中两个对mu激动剂敏感，其作用类似于在视上核中观察到的作用。其余的室旁神经元显示出低阈值的Ca2尖峰，因此具有与假定的大细胞神经元不同的电生理特征。具有低阈值Ca2尖峰的11个细胞中的10个被mu激动剂超极化超过10 mV，并显示输入阻力降低了33/- 1.9% (s.e.M.)。在两种类型的细胞中，当河豚毒素阻断突触传递时，mu激动剂仍可诱导超极化，这表明该作用部分是直接的。当使用KCl电极将Cl反转电位移至更多正值时，也获得了超极化，从而排除了Cl电导机制。这些结果提供了证据，表明阿片肽可以直接抑制下丘脑神经元，其机制是K电导的增加，并且两种类型的下丘脑神经元似乎对mu激动剂具有不同的敏感性。