• 【吸收氢化酶的调节和氢利用对沼泽红假单胞菌基因表达的影响。】 复制标题 收藏 收藏
    DOI:10.1128/JB.00381-06 复制DOI
    作者列表:Rey FE,Oda Y,Harwood CS
    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。
  • 【大剂量辛伐他汀对SD大鼠前额叶皮层和纹状体多巴胺水平及其再摄取的影响。】 复制标题 收藏 收藏
    DOI:10.1016/j.neulet.2006.09.009 复制DOI
    作者列表:Wang Q,Tang XN,Wang L,Yenari MA,Ying W,Goh BC,Lee HS,Wilder-Smith EP,Wong PT
    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。
  • 【热休克蛋白-90 (HSP90) 在多发性骨髓瘤中的表达及HSP90抑制剂 (17-AAG) 的作用分析。】 复制标题 收藏 收藏
    DOI:10.1080/10428190500472123 复制DOI
    作者列表:Duus J,Bahar HI,Venkataraman G,Ozpuyan F,Izban KF,Al-Masri H,Maududi T,Toor A,Alkan S
    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。
  • 【B细胞慢性淋巴细胞白血病患者T细胞中的信号分子和细胞因子产生: 氟达拉滨和阿仑单抗治疗的长期影响。】 复制标题 收藏 收藏
    DOI:10.1080/10428190600565503 复制DOI
    作者列表:Kiaii S,Choudhury A,Mozaffari F,Rezvany R,Lundin J,Mellstedt H,Osterborg A
    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患者和健康的T细胞的信号分子表达和细胞因子产生供体。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。
  • 【ERCP透皮三硝酸甘油的前瞻性,随机,安慰剂对照试验: 对技术成功和ERCP后胰腺炎的影响。】 复制标题 收藏 收藏
    DOI:10.1016/j.gie.2005.11.060 复制DOI
    作者列表:Kaffes AJ,Bourke MJ,Ding S,Alrubaie A,Kwan V,Williams SJ
    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:
  • 【阿片肽对 μ 受体选择性的直接作用: 豚鼠室旁和视上核的细胞内记录。】 复制标题 收藏 收藏
    DOI:10.1016/0306-4522(90)90426-5 复制DOI
    作者列表:Wuarin JP,Dudek FE
    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。
  • 【在台湾,替加环素与其他抗菌剂对肺炎链球菌,流感嗜血杆菌和卡他莫拉菌的体外活性比较。】 复制标题 收藏 收藏
    DOI:10.1089/mdr.2006.12.130 复制DOI
    作者列表:Lau YJ,Hsueh PR,Liu YC,Shyr JM,Huang WK,Teng LJ,Liu CY,Luh KT
    BACKGROUND & AIMS: :We compared the in vitro activities of tigecycline to those of other agents against 300 nonduplicate isolates of Streptococcus pneumoniae (194 isolates), Haemophilus influenzae (60 isolates), and Moraxella catarrhalis (46 isolates) recovered from patients treated in three major hospitals in Taiwan from August through December, 2003. All of these isolates were inhibited at 0.5 mg/L of tigecycline. For S. pneumoniae isolates, 72% were not susceptible to penicillin (69% intermediate and 3% resistant) and 96% were not susceptible to azithromycin. Among the 178 isolates resistant to azithromycin, 53 isolates (30%) had the M phenotype and 70% had the cMLSB phenotype. The rate of nonsusceptibility to ertapenem, telithromycin, moxifloxacin, and quinupristindalfopristin in S. pneumoniae was 3%, 2%, 1%, and 57%, respectively. For H. influenzae, 36 (60%) were not susceptible to ampicillin, among which 31 possessed beta-lactamase. A high rate (8.3%) of H. influenzae isolates with beta-lactamase-negative and ampicillin-resistant phenotype was found. All H. influenzae isolates were susceptible to azithromycin, but 40% of them were not susceptible to clarithromycin. Ninety-eight percent (44 isolates) of M. catarrhalis possessed beta-lactamase. All three fluoroquinolones tested were highly active (MIC90 < or =0.12 mg/L) against H. influenzae and M. catarrhalis.
    背景与目标: : 我们比较了替加环素与其他药物对300种非重复肺炎链球菌分离株 (194株),流感嗜血杆菌 (60株) 和卡他莫拉菌 (46株) 的体外活性,这些分离株是从8月到2003年12月在台湾的三家主要医院中康复的。在0.5 mg/L替加环素的浓度下,所有这些分离株均被抑制。对于肺炎链球菌分离株,72% 对青霉素不敏感 (69% 中间体和3% 耐药),96% 对阿奇霉素不敏感。在对阿奇霉素耐药的178株中,53株 (30% 株) 具有M表型,70% 株具有cMLSB表型。肺炎链球菌对厄他培南,泰利霉素,莫西沙星和奎奴普汀的不敏感性分别为3%,2%,1% 和57%。对于流感嗜血杆菌,36 (60%) 对氨苄青霉素不敏感,其中31具有 β-内酰胺酶。发现具有 β-内酰胺酶阴性和氨苄青霉素抗性表型的流感嗜血杆菌分离株率高 (8.3%)。所有流感嗜血杆菌分离株对阿奇霉素敏感,但其中40% 对克拉霉素不敏感。卡他氏杆菌的百分之九十八 (44个分离株) 具有 β-内酰胺酶。测试的所有三种氟喹诺酮类药物对流感嗜血杆菌和卡他氏杆菌具有高度活性 (MIC90 <或 = 0.12 mg/L)。
  • 【压力限制通气期间持续气管气吹入对急性肺损伤家兔肺表面活性物质的影响。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Zhu GF,Zhang W,Zong H,Liang Y
    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:
  • 【关系质量,激素避孕选择和青少年妇女不使用避孕套的发展关联。】 复制标题 收藏 收藏
    DOI:10.1016/j.jadohealth.2005.12.027 复制DOI
    作者列表:Sayegh MA,Fortenberry JD,Shew M,Orr DP
    BACKGROUND & AIMS: PURPOSE:Consistent condom use is critical to efforts to prevent sexually transmitted infections among adolescents, but condom use may decline as relationships and contraceptive needs change. The purpose of this research is to assess changes in condom non-use longitudinally in the context of changes in relationship quality, coital frequency and hormonal contraceptive choice. METHODS:Participants were women (aged 14-17 years at enrollment) recruited from three urban adolescent medicine clinics. Data were collected at three-month intervals using a face-to-face structured interview. Participants were able to contribute up to 10 interviews, but on average contributed 4.2 interviews over the 27-month period. Independent variables assessed partner-specific relationship quality (five items; scale range 5-25; alpha = .92, e.g., this partner is a very important person to me); and, number of coital events with a specific partner. Additional items assessed experience with oral contraceptive pills (OCP) use and injected depo medroxy-progesterone acetate (DMPA). The outcome variable was number of coital events without condom use during the past three months. Analyses were conducted as a three-level hierarchical linear growth curve model using HLM 6. The Level 1 predictor was time, to test the hypothesis that condom non-use increases over time. Level 2 predictors assessed relationship quality and coital frequency across all partners to assess hypotheses that participants' condom non-use increases over time as a function of relationship quality and coital frequency. Level 3 predictors assessed the participant-level influence of OCP or DMPA experience on time-related changes in condom non-use. RESULTS:A total of 176 women reported 279 sex partners and contributed 478 visits. Both average coital frequency and average condom non-use linearly increased during the 27-month follow-up. At any given follow-up, about 35% reported recent OCP use, and 65% reported DMPA use. HLM analyses showed that condom non-use increased as a function of time (beta = .12; p = .03, Level 1 analysis). Increased condom non-use over time was primarily a function of increased coital frequency (beta = .01; p = .00), although higher levels of relationship quality were associated with increased condom non-use at enrollment (beta = .44; p = .00, Level 2 analysis). The temporal rise in condom non-use significantly increased among DMPA users (beta = .06; p = .00) but not OCP users (Level 3 analysis) (beta = -.04; p = .06). CONCLUSIONS:Developmentally, relationship characteristics and coital frequency appear to have increasing weight in decisions about condom use. Hormonal contraceptive methods are not equivalently associated with the overall temporal decline in condom use. Future research associated with dual contraceptive/condom use should address differential factors associated condom use in combination with different hormonal methods.
    背景与目标:
  • 【氟化分子作为中枢神经系统中的药物和显像剂。】 复制标题 收藏 收藏
    DOI:10.2174/156802606777951046 复制DOI
    作者列表:Sun S,Adejare A
    BACKGROUND & AIMS: :The strategic use of fluorine substitution in drug discovery and drug development is well documented. The small size and high electronegativity of fluorine are among properties of this element that lend special advantages. Applications in drugs targeted to the central nervous system (CNS) have been particularly fruitful in addition to favorable properties seen in many peripherally acting drugs. Fluorine substitution can be used to solve problems unique to the CNS, such as blood brain barrier (BBB) penetration. Likewise, use of the positron emitting isotope, (18)F, provides a unique tool for non-invasive imaging and diagnoses in the CNS. In this review, fluorine in CNS drugs and drug discovery are discussed.
    背景与目标: : 氟替代在药物发现和药物开发中的战略用途已得到充分证明。氟的小尺寸和高电负性是该元素的特殊优点之一。除了在许多外周作用药物中看到的有利特性外,针对中枢神经系统 (CNS) 的药物中的应用特别富有成效。氟替代可用于解决CNS特有的问题,例如血脑屏障 (BBB) 渗透。同样,使用正电子发射同位素 (18)F为CNS中的非侵入性成像和诊断提供了独特的工具。本文对中枢神经系统药物中的氟和药物发现进行了讨论。
  • 【辐射诱导的旁观者和其他非靶向效应: 癌症治疗的新干预要点?】 复制标题 收藏 收藏
    DOI:10.2174/156800906777723976 复制DOI
    作者列表:Mothersill C,Seymour C
    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一个主要问题是,这些药物通常对正常组织有毒,需要高剂量才能杀死肿瘤细胞。因此,似乎涉及对癌症治疗的低剂量反应的细胞靶标是特别令人感兴趣的,因为它们可以选择性地靶向不被治疗靶向的正常组织,并且因此可能导致令人不快的副作用或可能易于利用以提高治疗比率。作为本综述主题的一个这样的目标是辐射诱导的旁观者效应 [RIBE],该效应导致在未辐照的细胞中观察到类似辐射的反应。RIBE是一种新现象,表明在低剂量下,细胞信号传导比直接DNA损伤更重要。从历史上看,DNA一直被认为是放射治疗的目标。越来越多的意识到信号很重要,这开辟了一些重要的治疗策略,这些策略将在本文中进行讨论。RIBE似乎是组织或细胞中普遍应激反应的结果,该应激反应在组织,器官或生物体的水平而不是单个细胞的水平上表达。信号可能由所有暴露的细胞产生,但是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射线或伽马射线) 辐射暴露的主要反应是死亡反应。这具有许多凋亡特征,但可以在没有p53表达的细胞系中检测到,尽管在许多肿瘤细胞系中死亡反应受到抑制。虽然肿瘤周围未照射的正常细胞的死亡反应似乎是不利的,但实际上它可以起到保护作用并从人群中清除受损的细胞。如果正确使用,它可能会导致新药的开发,其目的不是组织破坏,而是使稳态机制能够控制肿瘤的扩张。在这种情况下,有害或有益反应的水平将与细胞群体携带的背景损害以及确定对损害反应的遗传程序有关。在尝试预测涉及辐射和其他细胞毒性药物的混合疗法的后果时,此重点可能很重要。在这篇综述中,我们对电离辐射诱导旁观者效应的潜在机制的当前知识进行了综述,并讨论了如何利用旁观者效应来生产旨在稳定组织稳态而不是组织破坏的新一代抗癌药物的问题。
  • 【一种新的胆囊收缩素类似物 (JMV 236) 对大鼠食物摄入和脑单胺的影响。】 复制标题 收藏 收藏
    DOI:10.1016/0143-4179(90)90158-u 复制DOI
    作者列表:Gourch A,Orosco M,Rodriguez M,Martinez J,Cohen Y,Jacquot C
    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 236,一种新的胆囊收缩素-八肽-硫酸盐 (CCK 8 S) 衍生物 (Boc-Tyr (SO3)-Nle-Gly-Trp-Nle-Asp-Phe-NH2) 已在药物内分泌中心 (蒙彼利埃) 合成。已显示该肽在胰腺淀粉酶分泌上具有与CCK 8 s相同的活性,并且具有更好的化学稳定性的优势。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物变化的影响。静脉注射后2小时和3小时,JMV 236降低了食物摄入量。施用12.5和50微克/千克,但在静脉注射后无效。它的全局作用与CCK 8 s相似,但反应延迟发作的特征较小。与我们先前使用CCK 8 s的工作一样,JMV 236在i.p.之后更有效地诱导单胺能变化。比i.c.v.管理后还要多。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。这些影响在CCK 8 s中经典观察到,并在我们之前的报告中进行了描述。该有趣的肽将需要进一步的表征,并且可以作为CCK衍生物研究的可能参考化合物。
  • 【ATP诱导的腿部血管舒张对人体最大运动过程中VO2峰值和腿部O2提取的影响。】 复制标题 收藏 收藏
    DOI:10.1152/ajpregu.00746.2005 复制DOI
    作者列表:Calbet JA,Lundby C,Sander M,Robach P,Saltin B,Boushel R
    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: : 在最大的全身运动期间,VO2峰值受到O2输送的限制。反过来,尽管在接近最大运动时的血流必须受到交感神经系统的限制,以维持平均动脉压。为了确定在人类接近最大和最大运动期间,增强腿部的血管舒张是否会导致较高的O2递送和腿部VO2,七名男子在自行车测功机上进行了两次最大增量运动测试。以随机顺序,进行一次测试,其中一次 (对照运动) 以80微克kg身体mass-1.min-1的速率将ATP (8 mg在1毫升的等渗盐溶液中) 输注到右股动脉中。在接近最大运动 (VO2峰的92%) 期间,ATP的输注增加了腿部血管电导 (43%,P<0.05),腿部血流量 (20%,1.7 l/min,P<0.05) 和腿部O2的输送 (20%,0.3 l/min,P<0.05)。未观察到对腿部或全身vo2的影响。腿部O2分数提取在输注的腿部从85 +/-3 (对照) 降低到78 +/-4% (ATP) (P & lt; 0.05),而在左腿保持不变 (84 +/-2和83 +/-2%; 对照和ATP; n = 3)。最大运动时ATP输注可增加17% (P<0.05),而腿部血流量可增加0.8 l/min (P = 0.08)。然而,在对照和ATP条件下,由于O2提取从84 +/-4降低到76 +/-4% 而增强的体循环或腿部峰值VO2值都没有增强 (P<0.05)。总而言之,在人类几乎最大或最大的运动中,肢体血管舒张不会增强下肢骨骼肌的VO2。ATP输注导致运动腿部O2提取减少的事实表明,ATP对活动较少的肌纤维和其他非收缩组织具有血管舒张作用,并且在正常条件下,这些区域处于较高的血管收缩作用下,以确保最有效的血流分布。锻炼肢体的肌肉纤维。
  • 【冷暴露对大鼠肾上腺酪氨酸羟化酶的影响: RNA,蛋白质,酶活性和辅因子水平的分析。】 复制标题 收藏 收藏
    DOI:10.1111/j.1471-4159.1990.tb01232.x 复制DOI
    作者列表:Baruchin A,Weisberg EP,Miner LL,Ennis D,Nisenbaum LK,Naylor E,Stricker EM,Zigmond MJ,Kaplan BB
    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增加。在本报告中,我们比较了这些变化的时间过程,并研究了冷暴露对酪氨酸羟基化所需的辅因子生物蝶呤水平的影响。冷暴露仅1小时后,与无应激对照相比,TH mRNA丰度71% 增加。在冷暴露的3-6小时内,总细胞TH RNA水平的增加最大 (是对照值的三倍),并且在整个实验期间 (72小时) 保持升高。冷暴露24小时后,TH蛋白水平迅速增加,并在48-72小时达到对照组的三倍的最大值。尽管TH RNA和蛋白质含量的升高相对较快且较大,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小时时升至非应激对照的大约两倍,并在整个应激期内保持在该水平。总之,该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的调节。我们的发现还表明,冷应激引起的TH辅因子水平的增加可能是交感肾上腺系统对冷应激反应的另一个关键事件。
  • 【早期大剂量左甲状腺素治疗对先天性甲状腺功能减退儿童入学听觉脑事件相关电位的影响。】 复制标题 收藏 收藏
    DOI:10.1159/000095069 复制DOI
    作者列表:Marti S,Alvarez M,Simoneau-Roy J,Leroux S,Van Vliet G,Robaey P
    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:

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