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细胞慢性淋巴细胞性白血病（B-CLL）。本研究旨在比较氟达拉滨或alemtuzumab治疗后长期未维持的缓解/高原期的B-CLL患者的信号分子的表达和T细胞的细胞因子产生与惰性/未经治疗的B-CLL患者和健康供体的长期比较。通过流式细胞术检测TCR-CD3zeta链，p56lck，p59fyn，ZAP-70，PI3-激酶和干扰素（IFN）-γ/白介素（IL）-4在CD4和CD8 T细胞中的产生频率和强度。通过用纯化的蛋白质衍生物（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的表达明显高于健康供体。与健康供体相比，已治疗患者中大多数信号分子的强度相对未受影响，但低于未治疗的惰性患者。但是，表达每种信号分子的T细胞总数在患者中减少了，在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，对PHA而非TPD的T细胞反应降低。结果表明，尽管在用氟达拉滨和阿仑单抗治疗后，长期而言，尽管信号分子发生了某些变化并且T细胞数量有所减少，但总体T细胞功能仍可以得到较好的保留。

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： 背景：尽管最近在技术和患者选择方面已有改进，但ERCP后胰腺炎仍然是ERCP最常见和最可怕的并发症。最近的研究表明，用三硝酸甘油酯（GTN）进行预处理可以预防ERCP后胰腺炎并提高插管成功率。
目的：评价经皮GTN对ERCP插管成功和ERCP术后胰腺炎的影响。
设计：一项前瞻性，双盲，安慰剂对照试验。
单位：大专转诊大学医院。
患者：共有318例患者（平均年龄62岁，女性占61％）被随机分配到活动组（n = 155）或安慰剂组（n = 163）。
干预措施：主动贴片（GTN）与安慰剂贴片。
主要观察指标：排尿时间和成功率。 ERCP后胰腺炎发生率。
结果：主动或安慰剂组之间在以下方面没有显着差异：成功的初始插管（96.8％vs 98.8％），深层插管（96.1％vs 98.8％），成功插管的时间，使用导丝（27％vs 25％）或针刀（13％比13％）以及ERCP后胰腺炎（安慰剂患者为7.4％，活动患者为7.7％）。多变量分析确定女性，年轻患者，胰腺造影，乳头尝试次数以及混浊后胰管排空不良是ERCP后胰腺炎的危险因素。在任何已确定的高危人群中，经皮GTN均不能减轻ERCP后胰腺炎的发生。
结论：无论是普通患者还是高危患者，经皮GTN均不能提高ERCP插管成功率或预防ERCP术后胰腺炎。

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。这些结果提供证据表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: BACKGROUND:Pulmonary surfactant dysfunction may contribute to the development of ventilator induced lung injury (VILI). Tracheal gas insufflation (TGI) is a technique in which fresh gas is introduced into the trachea and augment ventilation by reducing the dead space of ventilatory system, reducing ventilatory pressures and tidal volume (V(T)) while maintaining constant partial arterial CO2 pressure (PaCO(2)). We hypothesised that TGI limited peak inspiratory pressure (PIP) and V(T) and would minimize conventional mechanical ventilation (CMV) induced pulmonary surfactant dysfunction and thereby attenuate VILI in rabbits with acute lung injury (ALI). METHODS:ALI was induced by intratracheal administration of lipopolysaccharide in anaesthetized, ventilated healthy adult rabbits randomly assigned to continuous TGI at 0.5 L/min (TGI group) or CMV group (n = 8 for each group), and subsequently ventilated with limited PIP and V(T) to maintain PaCO(2) within 35 to 45 mmHg for 4 hours. Physiological dead space to V(T) ratio (V(D)/V(T)), dynamic respiratory compliance (Cdyn) and partial arterial O(2) pressure (PaO(2)) were monitored. After ventilation, lungs were analysed for total phospholipids (TPL), total proteins (TP), pulmonary surfactant small to large aggregates ratio (SA/LA) in bronchoalveolar lavage fluid (BALF) and for determination of alveolar volume density (V(V)), myeloperoxidase and interleukin (IL)-8. RESULTS:TGI resulted in significant (P < 0.05 or P < 0.01) decrease in PIP [(22.4 +/- 1.8) cmH2O vs (29.5 +/- 1.1) cmH2O], V(T) [(6.9 +/- 1.3) ml/kg vs (9.8 +/- 1.11) ml/kg], V(D)/V(T) [(32 +/- 5)% vs (46 +/- 2)%], TP [(109 +/- 22) mg/kg vs (187 +/- 25) mg/kg], SA/LA (2.5 +/- 0.4 vs 5.4 +/- 0.7), myeloperoxidase [(6.2 +/- 0.5) U/g tissue vs (12.3 +/- 0.8) U/g tissue] and IL-8 [(987 +/- 106) ng/g tissue vs (24 +/- 3) mN/m] of BALF, and significant (P < 0.05) increase in Cdyn [(0.47 +/- 0.02) ml.cmH2O(-1).kg(-1) vs (0.31 +/- 0.02) ml.cmH2O(-1).kg(-1)], PaO(2) [(175 +/- 24) mmHg vs (135 +/- 26) mmHg], TPL/TP (52 +/- 8 vs 33 +/- 11) and Vv (0.65 +/- 0.05 vs 0.44 +/- 0.07) as compared with CMV. CONCLUSIONS:In this animal model of ALI, TGI decreased ventilatory requirements (PIP, V(T) and V(D)/V(T)), resulted in more favourable alveolar pulmonary surfactant composition and function and less severity of lung injury than CMV. TGI in combination with pressure limited ventilation may be a lung protective strategy for ALI.

背景与目标： 背景：肺表面活性物质功能障碍可能导致呼吸机诱发的肺损伤（VILI）的发展。气管内注气（TGI）是一种将新鲜气体引入气管并通过减少通气系统的死腔，降低通气压力和潮气量（V（T））并保持恒定的局部动脉CO2压力来增强通气的技术（ PaCO（2））。我们假设TGI限制了峰值吸气压力（PIP）和V（T），并且将传统机械通气（CMV）引起的肺表面活性剂功能异常减至最小，从而减轻了急性肺损伤（ALI）兔的VILI。
方法：通过气管内脂多糖经气管内施用麻醉的，通气的健康成年兔，以0.5 L / min（TGI组）或CMV组（每组n = 8）随机分配为连续TGI，然后在有限的PIP和通气条件下通气，从而诱发ALI。 V（T）将PaCO（2）维持在35至45 mmHg的范围内4个小时。监测生理死区与V（T）的比率（V（D）/ V（T）），动态呼吸顺应性（Cdyn）和部分动脉O（2）压力（PaO（2））。通气后，对肺中的总磷脂（TPL），总蛋白（TP），支气管肺泡灌洗液（BALF）中的肺表面活性剂小到大聚集比（SA / LA）进行分析，并测定肺泡体积密度（V（V）） ），髓过氧化物酶和白介素（IL）-8。
结果：TGI导致PIP显着降低（P <0.05或P <0.01）[（22.4 /-1.8）cmH2O与（29.5 /-1.1）cmH2O]，V（T）[（6.9 /-1.3）ml / kg vs（9.8 /-1.11）ml / kg]，V（D）/ V（T）[（32 /-5）％vs（46 /-2）％]，TP [（109 /-22）mg / kg vs（187 /-25）mg / kg]，SA / LA（2.5 /-0.4 vs 5.4 /-0.7），髓过氧化物酶[（6.2 /-0.5）U / g组织vs（12.3 /-0.8）U / g组织]和IL-8 [（987 /-106）ng / g组织vs（24 /-3）mN / m] BALF，Cdyn [（0.47 /-0.02）ml.cmH2O显着（P <0.05）增加（-1）.kg（-1）vs（0.31 /-0.02）ml.cmH2O（-1）.kg（-1）]，PaO（2）[（175 /-24）mmHg vs（135 /-26 ）mmHg]，TPL / TP（52 /-8 vs 33 /-11）和Vv（0.65 /-0.05 vs 0.44 /-0.07）。
结论：在这种ALI动物模型中，TGI降低了通气需求（PIP，V（T）和V（D）/ V（T）），与CMV相比，肺泡表面活性剂的肺泡表面活性剂组成和功能更佳，肺部损伤的严重程度更低。 TGI结合限压通气可能是ALI的肺保护策略。

BACKGROUND & AIMS: :A major problem in the search for new cancer drug targets is that the drugs are often toxic to normal tissues and require high doses to kill tumor cells. Therefore cellular targets which appear to involve low dose responses to cancer therapy are especially interesting since they could selectively target normal tissues which are not targeted by the treatment and thus may be responsible for unpleasant side effects or may be amenable to exploitation in order to improve the therapeutic ratio. One such target, which is the subject of this review, is radiation-induced bystander effects [RIBE], which result in the observation of radiation like responses in cells which have not been irradiated. RIBE is a novel phenomenon which indicates that at low doses, cell signaling is more important than direct DNA damage. Historically, DNA has always been considered to be the target for radiation therapy. The growing realization that signaling is important opens up several important therapeutic strategies which will be discussed in this review. RIBE appears to be the result of a generalized stress response in tissues or cells which is expressed at the level of the tissue, organ or organism rather than at the level of the individual cell. The signals may be produced by all exposed cells, but the response may require a quorum of cells in order to be expressed. The major response involving low LET (x- or gamma-ray) radiation exposure discussed in the existing literature is a death response. This has many characteristics of apoptosis but may be detected in cell lines without p53 expression, although the death response is suppressed in many tumor cell lines. While a death response in unirradiated normal cells around a tumor might appear to be adverse, it can in fact be protective and remove damaged cells from the population. If harnessed correctly, it could lead to the development of new drugs aimed not at tissue destruction but at enabling homeostatic mechanisms to control tumor expansion. In this scenario, the level of harmful or beneficial response will be related to the background damage, carried by the cell population, and the genetic programme determining response to damage. This focus may be important when attempting to predict the consequences of mixed therapies involving radiation and other cytotoxic agents. In this review, our current knowledge of the mechanisms underlying the induction of bystander effects by ionizing radiation is reviewed, and the question of how bystander effects may be harnessed to produce a new generation of anti-cancer drugs aimed at stabilization of tissue homeostasis rather than tissue destruction is considered.

背景与目标： ：寻找新的癌症药物靶标的主要问题是该药物通常对正常组织有毒性，需要高剂量才能杀死肿瘤细胞。因此，细胞靶标似乎涉及对癌症治疗的低剂量反应，因此特别令人感兴趣，因为它们可以选择性地靶向未被治疗靶标的正常组织，因此可能引起令人不快的副作用，或者可能适合于剥削以改善治疗效果。治疗比率。辐射诱导的旁观者效应[RIBE]是本综述的主题之一，该效应导致在未辐射的细胞中观察到辐射样反应。 RIBE是一种新现象，表明在低剂量时，细胞信号传导比直接DNA损伤更为重要。从历史上看，DNA一直被认为是放射治疗的目标。人们日益认识到信号转导很重要，这开启了几种重要的治疗策略，本文将对此进行讨论。 RIBE似乎是组织或细胞中普遍的应激反应的结果，这种应激反应是在组织，器官或生物体的水平而不是单个细胞的水平表达的。信号可能由所有暴露的细胞产生，但响应可能需要一定数量的细胞才能表达。现有文献中讨论的涉及低LET（X射线或γ射线）辐射暴露的主要反应是死亡反应。这具有许多细胞凋亡特征，但尽管在许多肿瘤细胞系中死亡反应受到抑制，但在没有p53表达的细胞系中可能检测到。虽然在肿瘤周围未照射的正常细胞中的死亡反应似乎是不利的，但实际上可以起到保护作用，并从群体中清除受损的细胞。如果利用得当，它可能会导致开发新药物，其目的不是破坏组织，而是使稳态机制能够控制肿瘤的扩展。在这种情况下，有害或有益反应的水平将与细胞群所携带的背景损伤以及决定对损伤的反应的遗传程序有关。当试图预测涉及放射线和其他细胞毒剂的混合疗法的后果时，这一重点可能很重要。在这篇综述中，我们对电离辐射诱发旁观者效应的潜在机制的现有知识进行了综述，并探讨了如何利用旁观者效应来生产旨在稳定组织稳态而不是稳定组织的新一代抗癌药物的问题。考虑组织破坏。

BACKGROUND & AIMS: :JMV 236, a new cholecystokinin-octapeptide-sulfate (CCK 8 S) derivative (Boc-Tyr (SO3)-Nle-Gly-Trp-Nle-Asp-Phe-NH2) has been synthesized in the Centre de Pharmacologie-Endocrinologie (Montpellier). This peptide has been shown to present the same activity as CCK 8 S on pancreatic amylase secretion and has the advantage of a better chemical stability. With a view to further characterization, the effect of JMV 236 on food intake and brain monoamine and metabolite variations was assayed in the rat after intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administrations. JMV 236 decreased food intake 2 and 3 hours after i.p. administration of 12.5 and 50 micrograms/kg but was inactive after i.c.v. injection. Its global action was similar to that of CCK 8 S, but was less marked with delayed onset of response. As in our previous work with CCK 8 S, JMV 236 was more potent in inducing monoaminergic variations after i.p. than after i.c.v. administration. The main effects were decreases in striatal dopamine metabolite levels and increases in hypothalamic and striatal serotonin metabolite (5-HIAA) levels. These effects are classically observed with CCK 8 S and are described in our previous reports. The interesting peptide will require further characterization and may serve as a possible reference compound for studies on CCK derivatives.

背景与目标： ：JMV 236是一种新的胆囊收缩素-八肽硫酸盐（CCK 8 S）衍生物（Boc-Tyr（SO3）-Nle-Gly-Trp-Nle-Asp-Phe-NH2），已在药理学-内分泌中心（蒙彼利埃）。已显示该肽在胰腺淀粉酶分泌方面具有与CCK 8 S相同的活性，并且具有更好的化学稳定性的优点。为了进一步表征，在腹膜内（i.p.）和脑室内（i.c.v.）给药后，在大鼠中测定了JMV 236对食物摄入以及脑单胺和代谢产物变化的影响。腹腔注射后2和3小时，JMV 236的食物摄入量减少了。静脉注射12.5和50微克/公斤，但在静脉内注射后无效。注射。它的整体作用与CCK 8 S相似，但反应迟发的症状较少。正如我们以前使用CCK 8 S所做的工作一样，JMV 236腹腔注射后在诱导单胺能变化方面更有效。比在i.c.v.之后行政。主要影响是纹状体多巴胺代谢物水平降低，下丘脑和纹状体5-羟色胺代谢物（5-HIAA）水平升高。这些效应在CCK 8 S上得到了经典观察，并在我们以前的报告中有所描述。令人感兴趣的肽将需要进一步表征，并可能用作研究CCK衍生物的可能参考化合物。

BACKGROUND & AIMS: :During maximal whole body exercise VO2 peak is limited by O2 delivery. In turn, it is though that blood flow at near-maximal exercise must be restrained by the sympathetic nervous system to maintain mean arterial pressure. To determine whether enhancing vasodilation across the leg results in higher O2 delivery and leg VO2 during near-maximal and maximal exercise in humans, seven men performed two maximal incremental exercise tests on the cycle ergometer. In random order, one test was performed with and one without (control exercise) infusion of ATP (8 mg in 1 ml of isotonic saline solution) into the right femoral artery at a rate of 80 microg.kg body mass-1.min-1. During near-maximal exercise (92% of VO2 peak), the infusion of ATP increased leg vascular conductance (+43%, P<0.05), leg blood flow (+20%, 1.7 l/min, P<0.05), and leg O2 delivery (+20%, 0.3 l/min, P<0.05). No effects were observed on leg or systemic VO2. Leg O2 fractional extraction was decreased from 85+/-3 (control) to 78+/-4% (ATP) in the infused leg (P<0.05), while it remained unchanged in the left leg (84+/-2 and 83+/-2%; control and ATP; n=3). ATP infusion at maximal exercise increased leg vascular conductance by 17% (P<0.05), while leg blood flow tended to be elevated by 0.8 l/min (P=0.08). However, neither systemic nor leg peak VO2 values where enhanced due to a reduction of O2 extraction from 84+/-4 to 76+/-4%, in the control and ATP conditions, respectively (P<0.05). In summary, the VO2 of the skeletal muscles of the lower extremities is not enhanced by limb vasodilation at near-maximal or maximal exercise in humans. The fact that ATP infusion resulted in a reduction of O2 extraction across the exercising leg suggests a vasodilating effect of ATP on less-active muscle fibers and other noncontracting tissues and that under normal conditions these regions are under high vasoconstrictor influence to ensure the most efficient flow distribution of the available cardiac output to the most active muscle fibers of the exercising limb.

背景与目标： ：在最大程度的全身运动过程中，VO2峰值受O2释放量的限制。反过来，虽然必须在交感神经系统的约束下进行接近最大运动量的血流以维持平均动脉压。为了确定在近乎最大和最大运动量的情况下，增强腿部血管舒张程度是否会导致较高的O2输送量和腿部VO2，七名男性在自行车测功计上进行了两次最大的增量运动测试。以随机顺序进行一项试验，一项试验不进行（对照运动）以80 microg.kg体重-1.min-的速率向右股动脉中输注ATP（1毫升等渗盐溶液中8毫克）。 1。在接近最大运动量（VO2峰值的92％）期间，输注ATP可增加腿部血管电导率（43％，P <0.05），腿部血流量（20％，1.7 l / min，P <0.05）和腿部O2递送（20％，0.3l / min，P ＜0.05）。没有观察到对腿或全身VO2的影响。输注腿中的腿部O2分数提取率从85 / -3（对照）降至78 / -4％（ATP）（P <0.05），而在左腿中则保持不变（84 / -2和83 /- 2％；对照和ATP； n = 3）。进行最大运动量的ATP输注可使腿部血管电导增加17％（P <0.05），而腿部血流则倾向于增加0.8 l / min（P = 0.08）。但是，在对照和ATP条件下，由于O2提取量分别从84 / -4降低到76 / -4％，全身和腿部VO2峰值均未升高（P <0.05）。总之，在人类进行近乎最大或最大运动时，下肢骨骼肌的VO2不会因肢体血管扩张而得到增强。 ATP输注导致运动腿上的O2提取减少的事实表明ATP对不太活跃的肌纤维和其他非收缩性组织的血管舒张作用，并且在正常情况下，这些区域处于高血管收缩作用下，以确保最有效的血流有效心输出量到运动肢体最活跃的肌肉纤维的分布。

BACKGROUND & AIMS: :Long-term cold exposure (5-7 days) is known to induce concomitant increases in the levels of adrenomedullary tyrosine hydroxylase (TH) RNA, protein, and enzyme activity. In this report, we compare the time courses of these changes and investigate the effects of cold exposure on the levels of biopterin, the cofactor required for tyrosine hydroxylation. After only 1 h of cold exposure, TH mRNA abundance increased 71% compared with nonstressed controls. Increases in total cellular TH RNA levels were maximal (threefold over control values) within 3-6 h of cold exposure and remained elevated throughout the duration of the experiment (72 h). TH protein levels increased rapidly after 24 h of cold exposure and reached a maximal value threefold above that of controls at 48-72 h. Despite the relatively rapid and large elevations in TH RNA and protein content, only modest increases in TH activity were detected during the initial 48 h of cold exposure. Adrenomedullary biopterin increased rapidly after the onset of cold exposure, rising to a level approximately twofold that of the nonstressed controls at 24 h, and remained at this level throughout the duration of the stress period. Taken together, the results of this time course study indicate that cold-induced alterations in adrenal TH activity are mediated by multiple cellular control mechanisms, which may include pre- and posttranslational regulation. Our findings also suggest that cold stress-induced increases in the levels of the TH cofactor may represent another key event in the sympathoadrenal system's response to cold stress.

背景与目标： ：已知长期冷暴露（5-7天）会引起肾上腺髓质酪氨酸羟化酶（TH）RNA，蛋白质和酶活性的同时升高。在本报告中，我们比较了这些变化的时程，并研究了冷暴露对生物蝶呤水平的影响，生物蝶呤是酪氨酸羟化所需的辅助因子。低温暴露仅1小时后，与未受压力的对照组相比，TH mRNA的丰度增加了71％。在冷暴露的3-6小时内，总细胞TH RNA水平的增加最大（比对照值高三倍），并且在整个实验过程中（72小时）保持升高。在冷暴露24小时后，TH蛋白水平迅速升高，在48-72 h时达到最大值，是对照的三倍。尽管TH RNA和蛋白质含量的升高相对较快且幅度较大，但在冷暴露的最初48小时内仅检测到TH活性的适度增加。冷暴露开始后，肾上腺髓质生物蝶呤迅速增加，在24 h时升高至非应激对照组的两倍，并在整个应激期一直保持在该水平。两者合计，此时间过程研究的结果表明，冷诱导的肾上腺TH活性的改变是由多种细胞控制机制介导的，其中可能包括翻译前和翻译后调控。我们的发现还表明，冷应激诱导的TH辅助因子水平升高可能代表交感肾上腺系统对冷应激反应的另一个关键事件。

BACKGROUND & AIMS: AIMS:We tested whether brain event-related potentials (ERPs) are normal in children with congenital hypothyroidism (CH) after early high-dose levothyroxine treatment. METHODS:Auditory ERPs were recorded in 33 normal controls and in 15 children with CH at 5 years 9/12. Based on bone maturation at diagnosis, the CH group was divided into severe (n = 8) and moderate (n = 7) subgroups. CH patients were treated at a median age of 14 days with a mean initial dose of levothyroxine of 11.6 microg/kgxday. Two ERP components (N100 and N200) were measured and clinical follow-up variables collected. RESULTS:The functional anatomical and cognitive organisation of the auditory system, as revealed by the analyses of ERP measures, did not differ between CH and controls, or between severe and moderate CH subjects. However, N200 latency was globally longer in the CH than in the control group (p = 0.01) and was positively correlated with the over-treatment index (r = 0.61; p < 0.05) and verbal IQ. N200 amplitude was negatively correlated with initial dose (r = -0.74; p < 0.005). CONCLUSION:These data suggest that sensitive tools such as ERPs can reveal differences between CH and controls and relate these differences to the adequacy of treatment of CH.

背景与目标： 目的：我们测试了大剂量左甲状腺素早期治疗后先天性甲状腺功能减退症（CH）儿童的脑事件相关电位（ERP）是否正常。
方法：在33名正常对照者和15名5岁9/12的CH儿童中记录了听诊ERP。根据诊断时的骨成熟度，将CH组分为严重（n = 8）和中度（n = 7）亚组。 CH患者的中位年龄为14天，左甲状腺素的平均初始剂量为11.6 microg / kgxday。测量了两个ERP组件（N100和N200），并收集了临床随访变量。
结果：ERP措施的分析显示，听觉系统的功能解剖和认知组织在CH和对照之间，或在重度和中度CH患者之间没有差异。但是，CH中的N200潜伏期总体上比对照组长（p = 0.01），并且与过度治疗指数（r = 0.61; p <0.05）和言语智商呈正相关。 N200振幅与初始剂量呈负相关（r = -0.74； p <0.005）。
结论：这些数据表明，诸如ERPs之类的敏感工具可以揭示CH与对照之间的差异，并将这些差异与CH的治疗充分性联系起来。

BACKGROUND & AIMS: :Peripheral neuropathic pain is a unique form of chronic pain that afflicts up to 50% of persons with AIDS. The purpose of this pilot study was to examine the effects of ice massage to reduce neuropathic pain and improve sleep quality and to determine the feasibility of a larger study. A repeated measures design was used. The three treatments consisted of ice massage, dry-towel massage, and presence. Consecutive sampling was used to select 33 persons with AIDS who had neuropathic pain. Although the results of the study were negative, there was a decrease in pain intensity over time with both the ice massage and towel massage, suggesting that the intervention has some clinical benefit.

背景与目标： ：周围神经性疼痛是慢性疼痛的一种独特形式，可折磨多达50％的艾滋病患者。这项初步研究的目的是检验冰按摩对减轻神经性疼痛和改善睡眠质量的作用，并确定一项更大研究的可行性。使用了重复测量设计。这三种治疗包括冰按摩，干毛巾按摩和临场感。连续抽样选择了33名患有神经性疼痛的艾滋病患者。尽管研究结果为阴性，但冰按摩和毛巾按摩的疼痛强度均随时间降低，表明该干预措施具有一定的临床益处。

BACKGROUND & AIMS: :Peroxisome proliferator-activated receptors (PPARs) are expressed on vascular tissue. To investigate the direct vasoprotective effects of PPARgamma and PPARalpha ligands, pioglitazone (3 mg/kg/day) and bezafibrate (10 mg/kg/day) were given by gavage to streptozotocin-induced diabetic rats for 4 weeks. Streptozotocin (65 mg/kg, i.p.) significantly increased NADPH oxidase, vascular call adhesion molecule-1 (VCAM-1), and osteopontin mRNA levels in the aorta, as determined by reverse transcription (RT)-polymerase chain reaction (PCR). Immunohistochemical analysis revealed that the expression of osteopontin protein was also enhanced in the streptozotocin-injected rat aorta. Pioglitazone or bezafibrate attenuated the streptozotocin-induced increase in the expression of NADPH oxidase and VCAM-1 mRNA. The enhanced expression of osteopontin gene and protein induced by streptozotocin was suppressed by pioglitazone, whereas treatment with bezafibrate had no effect on the expression of osteopontin. We also demonstrated that pioglitazone or bezafibrate prevented the streptozotocin-induced increase in angiotensin converting enzyme (ACE) gene and protein content, by the means of RT-PCR and Western blotting. On the other hand, the treatment of pioglitazone or bezafibrate in the present study did not affect glucose tolerance, serum insulin or lipid level in streptozotocin-induced diabetic rats. These results suggest that the direct anti-oxidant and anti-inflammatory effects of PPARs ligands in the aorta of streptozotocin-induced diabetic rats were not likely to have been mediated by the normalization of glucose or lipid metabolism, but instead these salutary effects appear to have been associated with the inhibition of the expression of ACE. In addition, pioglitazone appeared to be more effective on the suppression of osteopontin expression compared with bezafibrate.

背景与目标： ：过氧化物酶体增殖物激活受体（PPAR）在血管组织上表达。为了研究PPARγ和PPARα配体的直接血管保护作用，通过链饲法对链脲佐菌素诱导的糖尿病大鼠给予吡格列酮（3 mg / kg /天）和苯扎贝特（10 mg / kg /天）。通过逆转录（RT）-聚合酶链反应（PCR）确定，链脲佐菌素（65 mg / kg，腹膜内）显着增加主动脉中的NADPH氧化酶，血管调用粘附分子1（VCAM-1）和骨桥蛋白mRNA水平。免疫组织化学分析显示，在注射链脲佐菌素的大鼠主动脉中，骨桥蛋白的表达也得到了增强。吡格列酮或苯扎贝特减弱了链脲佐菌素诱导的NADPH氧化酶和VCAM-1 mRNA表达的增加。吡格列酮抑制了链脲佐菌素诱导的骨桥蛋白基因和蛋白质表达的增强，而苯扎贝特治疗对骨桥蛋白的表达没有影响。我们还证明了吡格列酮或苯扎贝特通过RT-PCR和Western印迹可以阻止链脲佐菌素诱导的血管紧张素转化酶（ACE）基因和蛋白质含量的增加。另一方面，本研究中吡格列酮或苯扎贝特的治疗并未影响链脲佐菌素诱发的糖尿病大鼠的葡萄糖耐量，血清胰岛素或血脂水平。这些结果表明，链脲佐菌素诱导的糖尿病大鼠主动脉中PPARs配体的直接抗氧化和抗炎作用不可能由葡萄糖或脂质代谢的正常化介导，但是这些有益的作用似乎具有与抑制ACE表达有关。此外，吡格列酮似乎比苯扎贝特对抑制骨桥蛋白的表达更有效。

BACKGROUND & AIMS: :Cyclic AMP levels in rabbit carotid bodies incubated under control conditions, 100% O2- or 95% O2/5% CO2- equilibrated medium, are close to 1 pmol/mg wet tissue (range 0.4-2.43 pmol/mg). Isobutylmethylxanthine (0.5 mM) increases cyclic AMP levels by a factor of 14 and 8 in HEPES- and CO2/CH3O(-)-buffered medium, respectively. Forskolin (0.5-10 microM) applied during 30 min increases cyclic AMP levels in a dose-dependent manner. Incubation of carotid bodies at low O2 tensions resulted in an elevation of cyclic AMP levels both in the absence and in the presence of isobutymethylxanthine. In the latter conditions cyclic AMP increase was maximum at an O2 tension of 46 mm Hg and tended to decrease at extremely low PO2. In isobutylmethylxanthine-containing Ca2(+)-free medium, cyclic AMP increased linearly with decreasing PO2 from 66 to 13 mm Hg; the absolute cyclic AMP levels attained in Ca2(+)-free medium were smaller than those observed in Ca2(+)-containing medium at any PO2. The differences between Ca2(+)-free and Ca2(+)-containing media appear to be due to the action of released neurotransmitters in the latter conditions, because dopamine and norepinephrine, which are known to be released by hypoxia in a Ca2(+)-dependent manner, increase cyclic AMP in the carotid body. Low pH/high PCO2 and high [K+]e increase cyclic AMP levels only in Ca2(+)-containing medium. Forskolin potentiates the release of catecholamines induced by low PO2. These results suggest that cyclic AMP plays an important role in the modulation of the chemoreception process.

背景与目标： ：在对照条件下，100％O2-或95％O2 / 5％CO2平衡的培养基中孵育的兔颈动脉体中的循环AMP水平接近1 pmol / mg湿组织（0.4-2.43 pmol / mg范围）。在HEPES-和CO2 / CH3O（-）缓冲的培养基中，异丁基甲基黄嘌呤（0.5 mM）将循环AMP的水平分别提高14和8倍。在30分钟内施用的Forskolin（0.5-10 microM）以剂量依赖性方式增加循环AMP的水平。在不存在和存在异丁甲基黄嘌呤的情况下，在低O2张力下孵育颈动脉都会导致环AMP含量升高。在后一种情况下，循环AMP的增加在O2张力为46 mm Hg时最大，而在极低的PO2下趋于减少。在不含异丁基甲基黄嘌呤的不含Ca2（）的介质中，环状AMP随着PO2从66 mmHg降低到13 mm Hg而线性增加。不含Ca2（）的培养基中获得的绝对循环AMP水平要小于任何PO2含Ca2（）的培养基中观察到的绝对值。不含Ca2（）和含Ca2（）的培养基之间的差异似乎是由于后者条件下释放的神经递质的作用所致，因为已知多巴胺和去甲肾上腺素在依赖Ca2（）的低氧状态下会释放方式，增加颈动脉体中的循环AMP。低pH /高PCO2和高[K] e仅在含Ca2（）的培养基中会增加循环AMP的水平。 Forskolin增强了低PO2诱导的儿茶酚胺释放。这些结果表明，环状AMP在化学感受过程的调节中起重要作用。

BACKGROUND & AIMS: BACKGROUND:Diabetes mellitus (DM) is associated with hyperglycemia, inflammatory disorders and abnormal lipid profiles, currently the extracts from leaves of cynara scolymus has been discovered to treat metabolic disorders and has been stated by multitudinous scientists according to a good source of polyphenols compounds. The present study aimed to evaluate the protective effect of the ethanol leaves extract of C. scolymus in alloxan induced stress oxidant, hepatic-kidney dysfunction and histological changes in liver, kidney and pancreas of different experimental groups of rats. METHODS:We determinate the antioxidant activity by ABTS .+ and antioxidant total capacity (TAC) of all extracts of C. scolymus leaves, the inhibition of α-amylase activity in vitro was also investigated. Forty male Wistar rats were induced to diabetes with a single dose intraperitoneal injection (i.p.) of alloxan (150 mg/kg body weight (b.w.)). Diabetic rats were orally and daily administrated of ethanol extract from C. scolymus at two doses (200-400 mg/kg, b.w) or (12 mg/kg, b.w) with anti-diabetic reference drug, Acarbose for one month. Ethanol extract of C. scolymus effect was confirmed by biochemical analysis, antioxidant activity and histological study. RESULTS:The results indicated that the ethanol extract from leaves of C. scolymus showed the highest antioxidant activity by ABTS .+ (499.43g± 39.72 Trolox/g dry extract) and (128.75 ± 8.45 mg VC /g dry extract) for TAC and endowed the powerful inhibition in vitro of α-amylase activity with IC50=72,22 ug/uL. In vivo, the results showed that ethanol extract from the leaves of C. scolymus (200-400 mg/kg) decreased significantly (p < 0.001) the α-amylase levels in serum of diabetic rats, respectively associated with significant reduction (p < 0.001) in blood glucose rate of 42,84% and 37,91% compared to diabetic groups after 28 days of treatment, a significant lowered of plasma total cholesterol (T-Ch) by 18,11% and triglyceride (TG) by 60,47%, significantly and low-density lipoproteins (LDL-C) by 37,77%, compared to diabetic rats, moreover, the administration of ethanol extract appears to exert anti-oxidative activity demonstrated by the increase of CAT, SOD and GSH activities in liver, kidney and pancreas of diabetic rats. This positive effect of the ethanol extract from C. scolymus was confirmed by histological study. CONCLUSION:These observed strongly suggest that ethanol extract from the leaves of C. scolymus has anti-hyperglycemic properties, at least partly mediated by antioxidant and hypolipidemic effects.

背景与目标： 背景：糖尿病（DM）与高血糖，炎性疾病和异常脂质状况相关，目前已发现粘虫c叶片的提取物可治疗代谢紊乱，许多科学家已经根据多酚化合物的良好来源进行了陈述。本研究旨在评价鳞球菌乙醇叶提取物对四氧嘧啶诱导的应激氧化剂，肝肾功能障碍以及不同实验组大鼠肝，肾和胰腺组织学变化的保护作用。
方法：我们通过ABTS测定抗氧化活性。鼠尾草叶片的所有提取物的抗氧化剂和总抗氧化剂（TAC），还研究了其对α-淀粉酶活性的体外抑制作用。通过单剂量腹膜内注射（i.p.）四氧嘧啶（150 mg / kg体重（b.w.））将40只雄性Wistar大鼠诱发为糖尿病。糖尿病大鼠口服和每天服用两种剂量（200-400 mg / kg，b.w）或（12 mg / kg，b.w）的鼠尾草乙醇提取物和抗糖尿病参考药物阿卡波糖（acarbose）。通过生化分析，抗氧化活性和组织学研究证实了粘液梭状芽胞杆菌的乙醇提取物作用。
结果：结果表明，ABTS从粘枝sco叶片中提取的乙醇具有最高的抗氧化活性。 （499.43g±39.72 Trolox / g干提取物）和（128.75±8.45 mg VC / g干提取物）用于TAC，并在体外有效抑制α-淀粉酶活性，IC50 = 72.22 ug / uL。在体内，结果显示，从粘液梭菌的叶子中提取乙醇（200-400 mg / kg）显着降低（p <0.001）糖尿病大鼠血清中的α-淀粉酶水平，分别与显着降低有关（p <0.001）。在治疗28天后，与糖尿病组相比，血糖比率分别为0.001、42.84％和37.91％，血浆总胆固醇（T-Ch）显着降低了18.11％，甘油三酸酯（TG）显着降低了60与糖尿病大鼠相比，低密度脂蛋白（LDL-C）降低了47.7％，低密度脂蛋白（LDL-C）降低了37.77％，此外，乙醇提取物的给药似乎表现出抗氧化活性，这是由于CAT，SOD和GSH的增加所证明的在糖尿病大鼠肝，肾和胰腺中的活性。组织学研究证实了粘液梭菌乙醇提取物的这种积极作用。
结论：这些观察结果强烈表明，从粘液梭菌的叶子中提取乙醇具有抗降血糖作用，至少部分是由抗氧化剂和降血脂作用介导的。

BACKGROUND & AIMS: :The unique role of the EEG alpha rhythm in different states of cortical activity is still debated. The main theories regarding alpha function posit either sensory processing or attention allocation as the main processes governing its modulation. Closing and opening eyes, a well-known manipulation of the alpha rhythm, could be regarded as attention allocation from inward to outward focus though during light is also accompanied by visual change. To disentangle the effects of attention allocation and sensory visual input on alpha modulation, 14 healthy subjects were asked to open and close their eyes during conditions of light and of complete darkness while simultaneous recordings of EEG and fMRI were acquired. Thus, during complete darkness the eyes-open condition is not related to visual input but only to attention allocation, allowing direct examination of its role in alpha modulation. A data-driven ridge regression classifier was applied to the EEG data in order to ascertain the contribution of the alpha rhythm to eyes-open/eyes-closed inference in both lighting conditions. Classifier results revealed significant alpha contribution during both light and dark conditions, suggesting that alpha rhythm modulation is closely linked to the change in the direction of attention regardless of the presence of visual sensory input. Furthermore, fMRI activation maps derived from an alpha modulation time-course during the complete darkness condition exhibited a right frontal cortical network associated with attention allocation. These findings support the importance of top-down processes such as attention allocation to alpha rhythm modulation, possibly as a prerequisite to its known bottom-up processing of sensory input.

背景与目标： ：大脑皮层活动的不同状态中的脑电图阿尔法节律的独特作用仍在争论中。有关阿尔法功能的主要理论将感觉处理或注意力分配作为控制其调制的主要过程。闭眼和睁眼是一种众所周知的阿尔法节奏控制方法，尽管在光照过程中还伴随着视觉变化，但可以将其视为从内到外的注意力分配。为了弄清注意力分配和感觉视觉输入对alpha调制的影响，要求14名健康受试者在明亮和完全黑暗的条件下睁开并闭上眼睛，同时获取EEG和fMRI的同步记录。因此，在完全黑暗的情况下，睁开眼睛的条件与视觉输入无关，而仅与注意力分配有关，从而可以直接检查其在alpha调制中的作用。将数据驱动的岭回归分类器应用于EEG数据，以确定在两种光照条件下阿尔法节律对睁眼/闭眼推断的贡献。分类器的结果表明，在明亮和黑暗条件下，阿尔法贡献都很大，这表明阿尔法节奏调节与注意力方向的变化紧密相关，而与视觉感官输入无关。此外，在完全黑暗的条件下，从α调制时程导出的fMRI激活图显示了与注意力分配相关的右额叶皮层网络。这些发现支持自上而下的过程的重要性，例如将注意力分配到阿尔法节奏调节上，这可能是其已知的自下而上的感觉输入处理的先决条件。

BACKGROUND & AIMS: :More than one-third of cellular proteomes traffic into and across membranes. Bacteria have invented several sophisticated secretion systems that guide various proteins to extracytoplasmic locations and in some cases inject them directly into hosts. Of these, the Sec system is ubiquitous, essential and by far the best understood. Secretory polypeptides are sorted from cytoplasmic ones initially due to characteristic signal peptides. Then they are targeted to the plasma membrane by chaperones/pilots. The translocase, a dynamic nanomachine, lies at the centre of this process and acts as a protein-conducting channel with a unique property; allowing both forward transfer of secretory proteins but also lateral release into the lipid bilayer with high fidelity and efficiency. This process, tightly orchestrated at the expense of energy, ensures fundamental cell processes such as membrane biogenesis, cell division, motility, nutrient uptake and environmental sensing. In the present review, we examine this fascinating process, summarizing current knowledge on the structure, function and mechanics of the Sec pathway.

背景与目标： ：三分之一以上的细胞蛋白质组进入和穿过膜。细菌已经发明了几种复杂的分泌系统，可以将各种蛋白质引导到胞外位置，在某些情况下可以将它们直接注射到宿主中。在这些系统中，Sec系统无处不在，必不可少，是迄今为止最广为人知的系统。最初，由于特征性信号肽，分泌多肽从细胞质中分离出来。然后它们被伴侣/飞行员靶向质膜。转运酶，一个动态的纳米机器，位于这一过程的中心，并作为具有独特性质的蛋白质传导通道。既可以使分泌蛋白向前转移，又可以高保真度和效率横向释放到脂质双层中。以能量为代价精心安排的这一过程可确保基本的细胞过程，例如膜生物发生，细胞分裂，运动，养分吸收和环境感知。在当前的审查中，我们检查了这个迷人的过程，总结了有关Sec途径的结构，功能和力学的当前知识。