• 【顺铂释放到可生物降解的聚-d-l-乳酸中。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Natsugoe S,Kumanohoso T,Tokuda K,Shimada M,Mueller J,Nakamura K,Yamada K,Fukuzaki H,Aikou T
    BACKGROUND & AIMS: Using a melt-pressing technique, we produced a small solid cylinder containing cisplatin (CDDP) embedded in poly-d, l-lactic acid (CDDP-PLA). The in vitro release of CDDP from the polymer was examined in an immersion system. CDDP was released continuously for more than four weeks with no initial burst. Drug distribution for CDDP-PLA was compared with CDDP solution (CDDP-SOL) by subcutaneous administration into the back of rats. In the CDDP-PLA group, a high concentration of CDDP was maintained in the subcutaneous tissues near the implants for 20 days. However, in the CDDP-SOL group, the concentration of CDDP was low by 10 days after drug administration. CDDP-PLA may become a useful tool in locoregional chemotherapy as a solid type of drug delivery system with longlasting release.

    背景与目标: 使用熔融压制技术,我们生产了一个小的固态圆柱体,其中含有嵌入聚-d-L-乳酸(CDDP-PLA)中的顺铂(CDDP)。在浸没系统中检查了CDDP从聚合物中的体外释放。 CDDP连续释放了四个多星期,没有最初的爆发。通过向大鼠背部皮下给药,将CDDP-PLA的药物分布与CDDP溶液(CDDP-SOL)进行比较。在CDDP-PLA组中,在植入物附近的皮下组织中维持高浓度的CDDP达20天。但是,在CDDP-SOL组中,给药后10天CDDP的浓度低。 CDDP-PLA作为局部释放持久释放的固体药物传递系统,可能成为局部化疗的有用工具。

  • 【头孢吡肟和头孢哌啶联合阿米卡星,庆大霉素或环丙沙星对肺炎克雷伯菌产生广谱β-内酰胺酶的体外时间杀伤曲线。】 复制标题 收藏 收藏
    DOI:10.1159/000239575 复制DOI
    作者列表:Elkhaïli H,Kamili N,Linger L,Levêque D,Pompei D,Monteil H,Jehl F
    BACKGROUND & AIMS: Extended-spectrum beta-lactamases (ESBLs) are found in numerous Enterobacteriaceae, mainly in Klebsiella pneumoniae. We investigated the pharmacodynamics of two new extended-spectrum cephalosporins, cefepime and cefpirome, alone and combined with either amikacin or gentamicin or ciprofloxacin by means of time-kill curves against ESBL-producing, aminoglycoside-resistant K. pneumoniae. When used alone, cefepime (8 and 16 mg/l) resulted in a 2 and 3 log decrease at 6 h, respectively, but at 24 h regrowth occurred. The combination of cefepime (8 mg/l) with amikacin (4 mg/l) resulted in a 4 log decrease at 6 h, but there were no surviving bacteria at 6 h when combined with amikacin (8 mg/l). The combination of cefepime (16 mg/l) with gentamicin (4 mg/l) resulted in a 4 log decrease in 24 h. The antimicrobial combination of cefepime (32 mg/l) with ciprofloxacin (2 mg/l) resulted in a 4 log decrease in 24 h. Cefpirome (8 mg/l) induced a 2 log decrease at 4 h; 32 mg/l cefpirome resulted in a 3 log decrease followed by regrowth at 24 h. The regrowth observed in the late phase with cefpirome alone disappeared when combined with aminoglycoside. When cefpirome (32 mg/l) was used in combination with ciprofloxacin (1 mg/l), it resulted in a 4 log decrease in 24 h.

    背景与目标: 在许多肠杆菌科中发现了广谱β-内酰胺酶(ESBLs),主要存在于肺炎克雷伯菌中。我们研究了两种新的广谱头孢菌素(头孢吡肟和头孢吡肟)的药效学,它们分别通过抗ESBL产生,对氨基糖苷类耐药的肺炎克雷伯菌的时间杀灭曲线与阿米卡星或庆大霉素或环丙沙星合用。单独使用时,头孢吡肟(8和16 mg / l)分别在6 h减少2和3 log,但在24 h发生再生长。头孢吡肟(8 mg / l)与丁胺卡那霉素(4 mg / l)的组合在6 h时降低了4 log,但与丁胺卡那霉素(8 mg / l)组合时在6 h没有存活细菌。头孢吡肟(16毫克/升)与庆大霉素(4毫克/升)的组合在24小时内降低了4 log。头孢吡肟(32 mg / l)与环丙沙星(2 mg / l)的抗菌组合导致24小时内下降4 log。头孢哌酮(8 mg / l)在4 h导致2 log下降; 32 mg / l头孢哌酮导致3 log下降,然后在24 h再生长。与氨基糖苷类药物合用时,仅在头孢哌酮的晚期观察到的再生长消失了。当头孢哌酮(32 mg / l)与环丙沙星(1 mg / l)组合使用时,导致24小时内减少4 log。

  • 【多巴胺D1和NMDA受体之间的突触后相互作用通过腺苷释放促进大鼠伏隔核中的突触前抑制。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Harvey J,Lacey MG
    BACKGROUND & AIMS: :The mechanism underlying dopamine D1 receptor-mediated attenuation of glutamatergic synaptic input to nucleus accumbens (NAcc) neurons was investigated in slices of rat forebrain, using whole-cell patch-clamp recording. The depression by dopamine of EPSCs evoked by single-shock cortical stimulation was stimulus-dependent. Synaptic activation of NMDA-type glutamate receptors was critical for this effect, because dopamine-induced EPSC depressions were blocked by the competitive NMDA receptor antagonist D/L-2-amino-5-phosphonopentanoate (AP5). Application of NMDA also depressed the EPSC, and both this effect and the dopamine depressions were blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), implicating adenosine release in the EPSC depression. A1 receptor agonists also depressed EPSCs by a presynaptic action, causing increased paired-pulse facilitation, but this was insensitive to AP5. Activation of D1 receptors enhanced both postsynaptic inward currents evoked by NMDA application and the isolated NMDA receptor-mediated component of synaptic transmission. The biochemical processes underlying the dopamine-induced EPSC depression did not involve either protein kinase A or the production of cAMP and its metabolites, because this effect was resistant to the protein kinase inhibitors H89 and H7 and the cAMP-specific phosphodiesterase inhibitor rolipram. We conclude that activation of postsynaptic D1 receptors enhances the synaptic activation of NMDA receptors in nucleus accumbens neurons, thereby promoting a transsynaptic feedback inhibition of glutamatergic synaptic transmission via release of adenosine. Unusually for D1 receptors, this phenomenon occurs independently of adenylyl cyclase stimulation. This process may contribute to the locomotor stimulant action of dopaminergic agents in the NAcc.
    背景与目标: :使用全细胞膜片钳记录技术,在大鼠前脑切片中研究了多巴胺D1受体介导的伏谷核(NAcc)神经元的谷氨酸能突触输入衰减的机制。单电刺激皮层刺激引起的EPSCs的多巴胺抑制与刺激有关。 NMDA型谷氨酸受体的突触激活对此效应至关重要,因为多巴胺诱导的EPSC抑制被竞争性NMDA受体拮抗剂D / L-2-氨基-5-膦基戊酸酯(AP5)阻止。 NMDA的应用也抑制了EPSC,这种作用和多巴胺抑制均被A1受体拮抗剂8-环戊基-1,3-二丙基黄嘌呤(DPCPX)阻断,这暗示了EPSC抑制中腺苷的释放。 A1受体激动剂也通过突触前作用抑制EPSC,导致成对脉冲促进作用增强,但这对AP5不敏感。 D1受体的激活增强了由NMDA引起的突触后内向电流和分离的NMDA受体介导的突触传递成分。多巴胺引起的EPSC抑郁症的生化过程既不涉及蛋白激酶A,也不涉及cAMP及其代谢产物的产生,因为这种作用对蛋白激酶抑制剂H89和H7以及cAMP特异性磷酸二酯酶抑制剂咯利普兰具有抵抗力。我们得出的结论是,突触后D1受体的激活增强伏隔核神经元中NMDA受体的突触激活,从而通过释放腺苷促进谷氨酸能突触传递的突触反馈抑制。对于D1受体,这种现象通常与腺苷酸环化酶的刺激无关地发生。该过程可能有助于NAcc中多巴胺能药物的运动刺激作用。
  • 【最少的体外循环会减弱冠状动脉搭桥术中的中性粒细胞活化和细胞因子释放。】 复制标题 收藏 收藏
    DOI:10.1007/s10047-007-0377-0 复制DOI
    作者列表:Ohata T,Mitsuno M,Yamamura M,Tanaka H,Kobayashi Y,Ryomoto M,Yoshioka Y,Miyamoto Y
    BACKGROUND & AIMS: :The minimal cardiopulmonary bypass (mini-CPB) circuit, a closed system with neither cardiotomy suction nor an open venous reservoir and thus no air-blood interface, reportedly reduces blood loss and inflammatory reactions associated with coronary bypass surgery. We evaluated the inflammatory reactions in patients in whom coronary bypass operations were performed with conventional CPB or mini-CPB (n=15 each). Interleukin (IL)-6, IL-8, and neutrophil elastase levels; the neutrophil count; and the C-reactive protein value were measured before and immediately after surgery and on postoperative days 1 and 2. In addition, intraoperative blood loss and the transfusion volume were evaluated in these groups. Neutrophil elastase levels were lower in the mini-CPB group than in the conventional group on postoperative days 1 (127 +/- 52 vs. 240 +/- 100 microg/l, P=0.013) and 2 (107 +/- 17 vs. 170 +/- 45 micro/l, P=0.0001), as was the IL-8 level on postoperative day 1 (8.3 +/- 6.4 vs. 19 +/- 11 pg/ml, P=0.016). The intraoperative blood loss and transfusion volumes were significantly lower in the mini-CPB group than in the conventional group (510 +/- 244 vs. 1046 +/- 966 ml, P=0.012, and 691 +/- 427 vs. 1416 +/- 918 ml, P=0.0033). Thus, mini-CPB appears to attenuate neutrophil activation and cytokine release after coronary bypass surgery and, in addition, has some beneficial effects on blood conservation.
    背景与目标: :据报道,最小的体外循环(mini-CPB)回路是一个既没有心脏切开术也没有开放的静脉储液器的封闭系统,因此没有气血界面,据报道可减少失血和与冠状动脉搭桥手术相关的炎症反应。我们评估了使用常规CPB或mini-CPB(每组n = 15)进行冠状动脉搭桥手术的患者的炎症反应。白介素(IL)-6,IL-8和中性粒细胞弹性蛋白酶水平;中性粒细胞计数;在术前和术后以及术后第1和2天测量C和C反应蛋白值。此外,评估这些组的术中失血量和输血量。术后1天(127 /-52 vs. 240 /-100 microg / l,P = 0.013)和2(107 /-17 vs. 170 / -45 micro / l,P = 0.0001),术后第1天的IL-8水平也是如此(8.3 /-6.4 vs. 19 /-11 pg / ml,P = 0.016)。 mini-CPB组的术中失血量和输血量显着低于常规组(510 /-244 vs. 1046 /-966 ml,P = 0.012和691 /-427 vs. 1416 /-918 ml ,P = 0.0033)。因此,mini-CPB似乎减弱了冠状动脉搭桥手术后中性粒细胞的活化和细胞因子的释放,此外,对血液保存也有一些有益的作用。
  • 【不同有机酸对头孢泊肟普罗西汀速释片溶解性增强的影响及其稳定性研究。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Jabeen S,Hassan F,Yousuf RI,Shoaib MH,Israr F,Hasan SMF,Saeed R,Farooqi S
    BACKGROUND & AIMS: :Cefpodoxime proxetil is a third generation cephalosporin antibiotic demonstrates pH dependent solubility and is highly soluble only in acidic pH. The purpose of this investigation was to design and develop immediate release tablets of cefpodoxime proxetil by direct compression method and determine the effect of different solid buffers (organic acids) such as fumaric acid (formulations F1-F4), maleic acid (formulations M1-M4) and citric acid (formulations C1-C4) by using cefpodoxime and acid in the ratios of 4:1, 2:1, 1:1 and 1:2 to achieve pH-independent release of the drug. Physical parameters and assay were found to be within the acceptable range as prescribed in USP 36 / NF 31. In vitro dissolution studies of each formulation were performed in distilled water, USP dissolution medium, HCl buffer solution of pH 1.2, phosphate buffer solutions of pH 4.5 and 6.8 to observe the drug release. The formulations F3, F4, M4 were selected for film coating on the basis of better drug release profile, to protect the drug from chemical degradation through hydrolysis. Film coated formulation F3, F4 and M4 showed a remarkable in vitro release of the drug (72.88±0.43 to 92.67±0.71%) within 30min of observation in all dissolution media and further evaluated by model independent and model dependent approaches. The drug release was found to be best fit to Weibull model as highest r2adjusted (0.924-0.998) and lowest AIC (18.416-54.710) values were obtained in all dissolution media. R Gui® applied for stability studies of F3 and F4 formulations, showing shelf lives of 28 & 27months at ambient and 33 months at accelerated temperatures. Formulation F4 was chosen as best formulation on the basis of physical properties, highest dissolution rate and stability studies.
    背景与目标: :头孢泊肟酯是第三代头孢菌素抗生素,显示出pH依赖性溶解度,仅在酸性pH值下高度可溶。这项研究的目的是通过直接压缩方法设计和开发头孢泊肟肟酯的速释片,并确定不同的固体缓冲剂(有机酸)如富马酸(配方F1-F4),马来酸(配方M1-M4)的作用。 )和柠檬酸(配方C1-C4),使用头孢泊肟和酸的比例为4:1、2:1、1:1和1:2,以实现不依赖pH值的药物释放。发现物理参数和测定均在USP 36 / NF 31规定的可接受范围内。每种制剂的体外溶出度研究是在蒸馏水,USP溶出介质,pH 1.2的HCl缓冲溶液,pH 1.2的磷酸盐缓冲溶液中进行的。 4.5和6.8观察药物释放情况。基于更好的药物释放曲线,选择制剂F3,F4,M4进行薄膜包衣,以保护药物免受水解的化学降解。薄膜包衣的制剂F3,F4和M4在观察到的30分钟内在所有溶出介质中均显示出显着的药物体外释放(72.88±0.43至92.67±0.71%),并通过模型独立和模型依赖的方法进行了进一步评估。发现在所有溶出介质中均获得了最高的r2调整值(0.924-0.998)和最低的AIC值(18.416-54.710),从而使药物释放最适合于Weibull模型。 RGui®应用于F3和F4配方的稳定性研究,在环境温度下的货架期为28和27个月,在加速温度下的货架期为33个月。根据物理性能,最高的溶出速率和稳定性研究,选择配方F4作为最佳配方。
  • 【铝和哇巴因对突触体胆碱摄取,乙酰胆碱释放和(Na / K)ATPase的比较作用。】 复制标题 收藏 收藏
    DOI:10.1016/j.tox.2007.04.017 复制DOI
    作者列表:Silva VS,Nunes MA,Cordeiro JM,Calejo AI,Santos S,Neves P,Sykes A,Morgado F,Dunant Y,Gonçalves PP
    BACKGROUND & AIMS: :Closing the gap between adverse health effects of aluminum and its mechanisms of action still represents a huge challenge. Cholinergic dysfunction has been implicated in neuronal injury induced by aluminum. Previously reported data also indicate that in vivo and in vitro exposure to aluminum inhibits the mammalian (Na(+)/K(+))ATPase, an ubiquitous plasma membrane pump. This study was undertaken with the specific aim of determining whether in vitro exposure to AlCl(3) and ouabain, the foremost utilized selective inhibitor of (Na(+)/K(+))ATPase, induce similar functional modifications of cholinergic presynaptic nerve terminals, by comparing their effects on choline uptake, acetylcholine release and (Na(+)/K(+))ATPase activity, on subcellular fractions enriched in synaptic nerve endings isolated from rat brain, cuttlefish optic lobe and torpedo electric organ. Results obtained show that choline uptake by rat synaptosomes was inhibited by submillimolar AlCl(3), whereas the amount of choline taken up by synaptosomes isolated from cuttlefish and torpedo remained unchanged. Conversely, choline uptake was reduced by ouabain to a large extent in all synaptosomal preparations analyzed. In contrast to ouabain, which modified the K(+) depolarization evoked release of acetylcholine by rat, cuttlefish and torpedo synaptosomal fractions, AlCl(3) induced reduction of stimulated acetylcholine release was only observed when rat synaptosomes were challenged. Finally, it was observed that the aluminum effect on cuttlefish and torpedo synaptosomal (Na(+)/K(+))ATPase activity was slight when compared to its inhibitory action on mammalian (Na(+)/K(+))ATPase. In conclusion, inhibition of (Na(+)/K(+))ATPase by AlCl(3) and ouabain jeopardized the high-affinity (Na(+)-dependent, hemicholinium-3 sensitive) uptake of choline and the Ca(2+)-dependent, K(+) depolarization evoked release of acetylcholine by rat, cuttlefish and torpedo synaptosomal fractions. The effects of submillimolar AlCl(3) on choline uptake and acetylcholine release only resembled those of ouabain when rat synaptosomes were assayed. Therefore, important differences were found between the species regarding the cholinotoxic action of aluminum. The variability of (Na(+)/K(+))ATPase sensitivity to aluminum of cholinergic neurons might contribute to their differential susceptibility to this neurotoxic agent.
    背景与目标: :缩小铝的不良健康影响与其作用机制之间的差距仍然是巨大的挑战。胆碱能功能障碍与铝诱导的神经元损伤有关。先前报道的数据还表明,体内和体外暴露于铝会抑制普遍存在的质膜泵哺乳动物(Na()/ K())ATPase。进行这项研究的特定目的是确定体外暴露于AlCl(3)和ouabain(最主要利用的(Na()/ K())ATPase的选择性抑制剂)是否诱导胆碱能突触前神经末梢的类似功能修饰。比较它们对胆碱摄取,乙酰胆碱释放和(Na()/ K())ATPase活性的影响,对富集自大鼠脑,墨鱼视神经叶和鱼雷电器官的突触神经末梢富集的亚细胞级分。获得的结果表明,大鼠毫微摩尔的AlCl(3)抑制了大鼠突触小体对胆碱的摄取,而从墨鱼和鱼雷分离的突触小体对胆碱的吸收量却保持不变。相反,在所有分析的突触体制剂中,哇巴因在很大程度上降低了胆碱的摄取。相比于哇巴因,它修饰了大鼠,乌贼和鱼雷突触小体部分的K()去极化引起乙酰胆碱的释放,仅当挑战大鼠突触体时才观察到AlCl(3)诱导的乙酰胆碱释放减少。最后,观察到铝对墨鱼和鱼雷突触体(Na()/ K())ATPase活性的抑制作用与其对哺乳动物(Na()/ K())ATPase的抑制作用相比是轻微的。总之,AlCl(3)和哇巴因对(Na()/ K())ATPase的抑制作用损害了胆碱和Ca(2)依赖的高亲和性(Na(依赖),hemicholinium-3敏感)的摄取。 ,K()去极化引起大鼠,墨鱼和鱼雷突触体级分释放乙酰胆碱。当测定大鼠突触小体时,亚毫摩尔AlCl(3)对胆碱摄取和乙酰胆碱释放的影响仅类似于哇巴因。因此,在物种之间发现了关于铝的胆碱毒性作用的重要差异。 (Na()/ K())ATPase对胆碱能神经元铝的敏感性的变异性可能有助于它们对这种神经毒性剂的敏感性不同。
  • 7 Results of endoscopic plantar fascia release. 复制标题 收藏 收藏

    【内镜下足底筋膜释放的结果。】 复制标题 收藏 收藏
    DOI:10.3113/FAI.2007.0549 复制DOI
    作者列表:Bazaz R,Ferkel RD
    BACKGROUND & AIMS: BACKGROUND:Conservative treatment for plantar fasciitis usually provides improvement, but some patients progress to surgery. Open release is most commonly performed but is associated with prolonged recovery and complications. Endoscopic plantar fascia release (EPFR) has become popular recently. We present our results. METHODS:Twenty patients (23 feet) had EPFR. Sixteen patients (19 feet) were available for followup after at least 1 year. Ten were women and 6 were men, with an average age of 44.7 (range 28 to 70) years. The average followup was 47 months. The American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale and Maryland Foot Score were used for evaluation. Gender, obesity, severity, length of preoperative symptoms, and workers compensation (WC) status were studied. RESULTS:The average AOFAS and Maryland scores improved postoperatively (66 to 88, p<0.05; 62 to 83, p<0.05, respectively). Women improved 25 (AOFAS) and 23 points (Maryland) points. Men improved 16 (AOFAS) and 17 points (Maryland) points. Obese patients improved 38 and 28 points, respectively. Normal weight patients improved 16 and 19 points, respectively. Postoperative scores for patients with high preoperative severity improved from 58 to 81 (AOFAS) and from 52 to 73 (Maryland). Patients with moderate preoperative severity achieved scores from 72 to 93 and from 70 to 91. Patients who had symptoms longer than 2 years before EPFR had lower postoperative scores. Non-WC patients improved 25 (AOFAS) and 24 (Maryland) points. WC patients improved 18 and 16 points, respectively. CONCLUSIONS:EPFR provides significantly improved patient outcomes. Patients with more severe symptoms before EPFR and those with symptoms for longer than 2 years had worse results. Obesity had no negative effect on outcome. WC patients had inferior results compared to non-WC patients. Women achieved better results than men. This finding may be biased because most WC patients were men.
    背景与目标: 背景:足底筋膜炎的保守治疗通常可以改善病情,但有些患者可以接受手术治疗。公开释放最常执行,但与恢复时间延长和并发症相关。内窥镜足底筋膜释放术(EPFR)最近变得很流行。我们介绍我们的结果。
    方法:20名患者(23英尺)患有EPFR。至少1年后可对16例患者(19英尺)进行随访。女性10名,男性6名,平均年龄为44.7岁(28至70岁)。平均随访47个月。使用美国骨科足踝协会(AOFAS)的踝部-足部评分表和马里兰州的足部评分进行评估。研究者对性别,肥胖,严重程度,术前症状持续时间和工人补偿(WC)状况进行了研究。
    结果:术后AOFAS和马里兰州的平均评分有所改善(分别为66至88,p <0.05; 62至83,p <0.05)。妇女提高了25分(AOFAS)和23分(马里兰)。男子提高16(AOFAS)和17点(马里兰)。肥胖患者分别改善了38点和28点。体重正常的患者分别改善了16点和19点。术前严重程度高的患者的术后评分从58分(81)(AOFAS)和52分(73)(马里兰州)提高。术前轻度中度的患者得分分别为72分至93分和70分至70分。症状出现时间超过EPFR前2年的患者术后得分较低。非WC患者提高了25(AOFAS)和24(Maryland)点。 WC患者分别改善了18点和16点。
    结论:EPFR可显着改善患者预后。 EPFR前症状较重的患者和症状超过2年的患者的病情较差。肥胖对结局没有负面影响。与非WC患者相比,WC患者的结果较差。妇女取得了比男子更好的结果。由于大多数WC患者是男性,因此该发现可能有偏见。
  • 【在日本三级儿科医院住院的患者中,直肠产生广谱β-内酰胺酶的肠杆菌科细菌的比例。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Minami K,Shoji Y,Kasai M,Ogiso Y,Nakamura T,Kawakami Y,Saito Y,Kuzumoto K,Kubota N,Yumoto K,Ishii K
    BACKGROUND & AIMS: :Extended-spectrum β-lactamase (ESBL)-producing-Enterobacteriaceae strains were detected in 12% (6 out of 50) of fecal samples collected from the inpatients of a Japanese pediatric hospital. All the ESBLs belonged to the CTX-M-1 group. The proportion of carriage of ESBL producers was higher among patients who had received antibiotics within the past 3 months and among those who had cardiologic diseases.
    背景与目标: :从日本儿科医院住院患者收集的粪便样本中,有12%(50个中有6个)检测到产生超广谱β-内酰胺酶(ESBL)的肠杆菌科菌株。所有ESBL都属于CTX-M-1组。在过去3个月内接受过抗生素治疗的患者和患有心脏病的患者中,携带ESBL生产者的比例更高。
  • 【含有表皮葡萄球菌的凋亡中性粒细胞刺激巨噬细胞释放促炎细胞因子肿瘤坏死因子-α和白介素-6。】 复制标题 收藏 收藏
    DOI:10.1111/j.1574-695X.2008.00412.x 复制DOI
    作者列表:Wilsson A,Lind S,Ohman L,Nilsdotter-Augustinsson A,Lundqvist-Setterud H
    BACKGROUND & AIMS: :Staphylococcus epidermidis infections are usually nosocomial and involve colonization of biomaterials. The immune defense system cannot efficiently control the bacteria during these infections, which often results in protracted chronic inflammation, in which a key event is disturbed removal of neutrophils by tissue macrophages. While ingesting uninfected apoptotic neutrophils, macrophages release anti-inflammatory cytokines that lead to resolution of inflammation. In clinical studies, we have previously found elevated levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 in synovial fluid from prostheses infected with coagulase negative staphylococci. We show that macrophages phagocytosing apoptotic neutrophils containing S. epidermidis released TNF-alpha and interleukin-6, whereas macrophages phagocytosing spontaneously apoptotic neutrophils did not. This difference was not due to dissimilar phagocytic capacities, because macrophages ingested both types of neutrophils to the same extent. The activation was induced mainly by the apoptotic neutrophils themselves, not by the few remaining extracellular bacteria. Macrophages were not activated by apoptotic neutrophils that contained paraformaldehyde-killed S. epidermidis. Proinflammatory reactions induced by clearance of apoptotic neutrophils containing S. epidermidis might represent an important mechanism to combat the infective agent. This activation of macrophages may contribute to the development of chronic inflammation instead of inflammation resolution.
    背景与目标: :表皮葡萄球菌感染通常在医院内发生,涉及生物材料的定殖。在这些感染过程中,免疫防御系统无法有效控制细菌,这通常会导致长期的慢性炎症,其中关键事件是组织巨噬细胞对嗜中性白细胞的去除受到干扰。在摄取未感染的凋亡中性粒细胞时,巨噬细胞释放抗炎细胞因子,导致炎症消退。在临床研究中,我们以前发现来自被凝固酶阴性葡萄球菌感染的假体的滑液中促炎细胞因子肿瘤坏死因子-α(TNF-alpha)和白介素6的水平升高。我们显示巨噬细胞吞噬含有表皮葡萄球菌的凋亡嗜中性粒细胞释放TNF-α和白介素6,而巨噬细胞吞噬自发性凋亡的嗜中性粒细胞则没有。这种差异不是由于吞噬能力不同而引起的,因为巨噬细胞以相同程度摄入了两种类型的嗜中性粒细胞。活化主要是由凋亡的中性粒细胞本身诱导的,而不是由少数剩余的细胞外细菌诱导的。巨噬细胞没有被凋亡的嗜中性粒细胞激活,所述嗜中性粒细胞含有多聚甲醛杀死的表皮葡萄球菌。由含有表皮葡萄球菌的凋亡中性粒细胞清除引起的促炎反应可能代表了与传染病作斗争的重要机制。巨噬细胞的这种活化可能有助于慢性炎症的发展,而不是炎症的消退。
  • 【模仿内皮的聚合物涂层:将一氧化氮释放与表面结合的活性血栓调节蛋白和肝素结合在一起。】 复制标题 收藏 收藏
    DOI:10.1016/j.biomaterials.2007.06.002 复制DOI
    作者列表:Wu B,Gerlitz B,Grinnell BW,Meyerhoff ME
    BACKGROUND & AIMS: :Multi-functional bilayer polymeric coatings are prepared with both controlled nitric oxide (NO) release and surface-bound active thrombomodulin (TM) alone or in combination with immobilized heparin. The outer-layer is made of CarboSil, a commercially available copolymer of silicone rubber (SR) and polyurethane (PU). The CarboSil is either carboxylated or aminated via an allophanate reaction with a diisocyanate compound followed by a urea-forming reaction between the generated isocyanate group of the polymer and the amine group of an amino acid (glycine), an oligopeptide (triglycine) or a diamine. The carboxylated CarboSil can then be used to immobilize TM through the formation of an amide bond between the surface carboxylic acid groups and the lysine residues of TM. Aminated CarboSil can also be employed to initially couple heparin to the surface, and then the carboxylic acid groups on heparin can be further used to anchor TM. Both surface-bound TM and heparin's activity are evaluated by chromogenic assays and found to be at clinically significant levels. The underlying NO release layer is made with another commercial SR-PU copolymer (PurSil) mixed with a lipophilic NO donor (N-diazeniumdiolated dibutylhexanediamine (DBHD/N(2)O(2))). The NO release rate can be tuned by changing the thickness of top coatings, and the duration of NO release at physiologically relevant levels can be as long as 2 weeks. The combination of controlled NO release as well as immobilized active TM and heparin from/on the same polymeric surface mimics the highly thromboresistant endothelium layer. Hence, such multifunctional polymer coatings should provide more blood-compatible surfaces for biomedical devices.
    背景与目标: :多功能双层聚合物涂料既可通过控制一氧化氮(NO)释放,也可通过表面结合的活性血栓调节蛋白(TM)或与固定化的肝素联合使用来制备。外层由CarboSil制成,CarboSil是硅橡胶(SR)和聚氨酯(PU)的市售共聚物。 CarboSil通过与二异氰酸酯化合物的脲基甲酸酯反应被羧化或胺化,然后在聚合物的生成的异氰酸酯基团与氨基酸(甘氨酸),寡肽(三甘氨酸)或二胺的胺基之间形成脲形成反应。然后,可以通过在表面羧酸基团与TM的赖氨酸残基之间形成酰胺键,将羧化的CarboSil固定在TM上。也可以使用胺化的CarboSil首先将肝素偶联至表面,然后可以进一步使用肝素上的羧酸基团来固定TM。表面结合的TM和肝素的活性均通过生色测定法进行评估,并发现在临床上具有显着水平。下层的NO释放层是由另一种商业SR-PU共聚物(PurSil)与亲油的NO供体(N-重氮二醇二丁基己二胺(DBHD / N(2)O(2)))混合制成的。可以通过改变表面涂层的厚度来调节NO的释放速率,并且在生理上相关的水平上,NO的释放持续时间可以长达2周。从同一聚合物表面上/上的受控NO释放以及固定化的活性TM和肝素的组合模拟了高度抗血栓形成的内皮层。因此,这种多功能聚合物涂层应为生物医学装置提供更多的血液相容性表面。
  • 【静态收缩在麻醉的猫中引起反射诱导的精氨酸加压素释放。】 复制标题 收藏 收藏
    DOI:10.1016/s0361-9230(00)00331-2 复制DOI
    作者列表:Liviakis LR,Stebbins CL
    BACKGROUND & AIMS: :We tested the hypothesis that brief static contraction of the triceps surae muscle causes reflex-induced increases in plasma arginine vasopressin (AVP) in anesthetized cats. Arterial blood samples, for measurement of plasma AVP, were taken before and after 30 s of electrically stimulated static contraction performed at a low intensity (<20% of maximal; n = 5), a high intensity (>70% of maximal; n = 7), and a high intensity after denervation of the triceps surae (n = 5). The low intensity contraction protocol was repeated during alpha-adrenergic blockade (n = 7) to minimize potential baroreflex-induced inhibition of AVP release. Passive stretch of the triceps surae was conducted (n = 5) to determine effects of muscle mechanoreceptor stimulation on the release of AVP. Low intensity contraction had no effect on plasma AVP. During alpha-adrenergic blockade, this same contraction intensity caused this peptide to increase from 12.8 +/- 2.1 to 17.7 +/- 2.6 pg/ml. High intensity contraction caused an increase in AVP (13.2 +/- 3.5 to 26.1 +/- 6.6 pg/ml) that was abolished by denervation (14.4 +/- 3. 7 vs. 17.1 +/- 6.6 pg/ml). Passive stretch had no effect on plasma AVP. These findings suggest that brief static contraction causes increases in plasma AVP that are reflex in nature, intensity dependent, opposed by the arterial baroreflex, and probably unrelated to muscle mechanoreceptor activation.
    背景与目标: :我们测试了以下假设:麻醉的猫,肱三头肌的短暂静态收缩会导致反射引起的血浆精氨酸加压素(AVP)升高。在以低强度(<最大值的20%; n = 5),以高强度(最大值的> 70%; n)进行电刺激的静态收缩30 s之前和之后,采集动脉血样本以测量血浆AVP。 = 7),并且在肱三头肌肱神经去神经后强度很高(n = 5)。在α-肾上腺素能阻滞(n = 7)期间重复低强度收缩方案,以使潜在的压力反射诱发的对AVP释放的抑制作用最小化。进行三头肌肱三头肌的被动拉伸(n = 5)以确定肌肉机械感受器刺激对AVP释放的影响。低强度收缩对血浆AVP没有影响。在α-肾上腺素阻断期间,相同的收缩强度导致该肽从12.8 /-2.1增加至17.7 /-2.6 pg / ml。高强度收缩导致AVP增加(13.2 /-3.5至26.1 /-6.6 pg / ml),而被去神经支配(14.4 /-3. 7 vs. 17.1 /-6.6 pg / ml)取消。被动拉伸对血浆AVP没有影响。这些发现表明,短暂的静态收缩会导致血浆AVP的增加,而血浆AVP的性质是反射性的,强度依赖性的,与动脉压力反射相反的,并且可能与肌肉机械感受器的激活无关。
  • 【耐力运动可调节左旋多巴诱发帕金森氏病患者的生长激素释放。】 复制标题 收藏 收藏
    DOI:10.1016/j.neulet.2007.06.008 复制DOI
    作者列表:Müller T,Welnic J,Woitalla D,Muhlack S
    BACKGROUND & AIMS: :Acute levodopa (LD) application and exercise release human growth hormone (GH). An earlier trial showed, that combined stimulus of exercise and LD administration is the best provocative test for GH response in healthy participants. Objective was to show this combined effect of LD application and exercise on GH response and to investigate the impact on LD metabolism in 20 previously treated patients with Parkinson's disease (PD). We measured GH- and LD plasma concentrations following soluble 200 mg LD/50 mg benserazide administration during endurance exercise and rest on two separate consecutive days. GH concentrations significantly increased on both days, but GH release was significantly delayed during rest. LD metabolism was not altered due to exercise in a clinical relevant manner. Exercise induced a significant faster LD stimulated GH release in comparison with the rest condition. We did not find the supposed increase of LD induced GH release by endurance exercise. We assume, that only a limited amount of GH is available for GH release in the anterior pituitary following an acute 200 mg LD administration. GH disposal also depends on growth hormone releasing hormone (GHRH), which is secreted into hypothalamic portal capillaries. During the exercise condition, the resulting higher blood pressure supports blood flow and thus GHRH transport towards the GH producing cells in the pituitary. This might additionally have caused the significant faster GH release during exercise.
    背景与目标: :急性左旋多巴(LD)的应用和锻炼会释放人的生长激素(GH)。一项较早的试验表明,在健康的参与者中,将运动刺激与LD给药相结合是对GH反应的最佳挑衅性测试。目的是显示LD的应用和运动对GH反应的综合影响,并调查对20名先前接受治疗的帕金森氏病(PD)患者的LD代谢的影响。我们在耐力运动中服用可溶性200 mg LD / 50 mg苄丝肼后,分别连续两天休息,测量GH和LD血浆浓度。两天的生长激素浓度均显着增加,但休息期间生长激素的释放显着延迟。 LD代谢不会因临床相关方式的运动而改变。与静息状态相比,运动能显着加快LD刺激的GH释放。我们没有发现通过耐力运动可以使LD诱导的GH释放增加。我们假设急性200 mg LD给药后垂体前叶中仅有限量的GH可用于GH释放。 GH的处置还取决于分泌到下丘脑门静脉毛细血管中的生长激素释放激素(GHRH)。在运动状态下,所产生的较高的血压可支持血液流动,因此可促进GHRH向垂体中GH产生细胞的转运。另外,这可能导致运动过程中GH明显更快地释放。
  • 【患有情绪障碍的患者的功效,耐受性,依从性和生活质量已从喹硫平立即释放转为延长释放。】 复制标题 收藏 收藏
    DOI:10.1097/YIC.0b013e328358f0c6 复制DOI
    作者列表:Dell'Osso B,Arici C,Dobrea C,Benatti B,Altamura AC
    BACKGROUND & AIMS: :The present study aimed to assess switch from immediate-release (IR) to extended-release (XR) quetiapine in terms of efficacy, tolerability, compliance, and quality of life in a sample of patients with mood disorders. Thirty patients, 10 with major depressive disorder and 20 with bipolar disorder, with residual depressive symptoms, who had switched from quetiapine IR (mean 365 mg/day) to XR (mean 373 mg/day), were recruited and evaluated using different psychometric scales, administered at T0 (switch), T1, and T2 (1 and 6 weeks after the switch, respectively). A significant reduction from T0 to T2 of the total scores on the Hamilton depression rating scale (t=2.15; P=0.04), Hamilton anxiety scale (t=3.04; P=0.006), and clinical global impression-severity item (t=2.8; P=0.01) was found. No differences were found in terms of compliance and quality of life. The switch was well tolerated by 2/3 of patients. Most reported side effects were early/central insomnia with day drowsiness (16.7%), increased appetite and weight (8.4%), mild asthenia (4.2%), and constipation (4.2%), which, in two cases, led to switch interruption. Strategies to relieve side effects, including gradual cross-switch, improved switch feasibility. Switch from quetiapine IR to XR seems to be associated with clinical improvement in major depressives with residual symptoms, although some patients may report side effects because of the different pharmacokinetics.
    背景与目标: :本研究旨在评估情绪障碍患者样本中喹硫平从速释(IR)到缓释(XR)的转变。从不同的心理测验量表中招募并评估了30例患者,其中10例重度抑郁症和20例双相情感障碍并伴有抑郁症残留症状,他们从喹硫平IR(平均365 mg /天)转为XR(平均373 mg /天),并进行了评估。 ,分别在T0(切换),T1和T2(分别在切换后1周和6周)进行管理。汉密尔顿抑郁量表(t = 2.15; P = 0.04),汉密尔顿焦虑量表(t = 3.04; P = 0.006)和临床总体印象严重度项目(t = 2.8; P = 0.01)。在依从性和生活质量方面没有发现差异。 2/3的患者对开关的耐受性良好。报告的副作用最多的是早期/中枢失眠,伴有嗜睡(16.7%),食欲和体重增加(8.4%),轻度乏力(4.2%)和便秘(4.2%),其中两例导致开关中断。缓解副作用的策略(包括逐步交叉切换)提高了切换的可行性。从喹硫平IR转为XR似乎与具有残留症状的主要抑郁症的临床改善有关,尽管一些患者可能因药代动力学不同而报告副作用。
  • 【细胞外腺苷刺激从灌注大鼠肝脏中释放前列腺素D2和血栓烷B2。】 复制标题 收藏 收藏
    DOI:10.1042/bj2700039 复制DOI
    作者列表:vom Dahl S,Wettstein M,Gerok W,Häussinger D
    BACKGROUND & AIMS: :In isolated perfused rat liver, adenosine infusion (50 microM) led to increases in glucose output and portal pressure and a net K+ release of 3.7 +/- 0.21 mumol/g, which was followed by an equivalent net K+ uptake after cessation of the nucleoside infusion. These effects were accompanied by a transient stimulation of hepatic prostaglandin D2 and thromboxane B2 release. The Ca2+ release observed upon adenosine infusion (50 microM) was 23.5 +/- 5.2 nmol/g, i.e. 10-20% of the Ca2+ release observed with extracellular ATP (50 microM). Indomethacin (10 microM) prevented the adenosine-induced stimulation of glucose output and the increase in portal pressure by 79 and 63% respectively, and completely abolished the stimulation of prostaglandin D2 release. The thromboxane A2 receptor antagonist BM 13.177 (20 microM), the phospholipase A2 inhibitor 4-bromophenacyl bromide (20 microM) and the cyclo-oxygenase inhibitor ibuprofen (50 microM) also decreased the glycogenolytic and vasoconstrictive responses of the perfused rat liver upon adenosine infusion by 50-80%. When the indomethacin inhibition of adenosine-induced prostaglandin D2 release was titrated, a close correlation between prostaglandin D2 release and the metabolic and vascular responses to adenosine was observed. These findings suggest an important role for eicosanoids in mediating the nucleoside responses in the perfused rat liver. Since eicosanoids are known to be formed by non-parenchymal cells in rat liver [Decker (1985) Semin. Liver Dis. 5, 175-190], the present study gives further evidence for an important role of eicosanoids as signal molecules between the different liver cell populations.
    背景与目标: :在离体灌流的大鼠肝脏中,腺苷输注(50 microM)导致葡萄糖输出和门脉压力增加,净K释放量为3.7 /-0.21 mumol / g,随后在终止核苷后有相等的净K吸收量输液。这些作用伴随着肝脏前列腺素D2和血栓烷B2释放的短暂刺激。腺苷输注(50 microM)时观察到的Ca2释放为23.5 /-5.2 nmol / g,即细胞外ATP(50 microM)观察到的Ca2释放的10-20%。消炎痛(10 microM)分别阻止了腺苷诱导的葡萄糖输出刺激和门脉压力增加79%和63%,并完全取消了对前列腺素D2释放的刺激。血栓烷A2受体拮抗剂BM 13.177(20 microM),磷脂酶A2抑制剂4-溴苯甲酰溴(20 microM)和环加氧酶抑制剂布洛芬(50 microM)也降低了腺苷输注后灌注肝脏的糖原分解和血管收缩反应。减少了50-80%滴定吲哚美辛对腺苷诱导的前列腺素D2释放的抑制作用时,观察到前列腺素D2释放与对腺苷的代谢和血管反应之间存在密切的相关性。这些发现表明类花生酸在介导灌注大鼠肝脏中的核苷反应中起着重要作用。由于已知类花生酸是由大鼠肝脏中的非实质细胞形成的[Decker(1985)Semin。肝病[5,175-190],本研究为类花生酸作为不同肝细胞群之间的信号分子的重要作用提供了进一步的证据。
  • 【从可控壳厚度的单分散生物可降解双壁微球中控制蛋白质释放。】 复制标题 收藏 收藏
    DOI:10.1016/j.jconrel.2013.08.009 复制DOI
    作者列表:Xia Y,Ribeiro PF,Pack DW
    BACKGROUND & AIMS: :Biodegradable polymer microparticles are promising delivery depots for protein therapeutics due to their relatively simple fabrication and facile administration. Double-wall microspheres (DWMS) comprising a core and shell made of two distinct polymers may provide enhanced control of the drug release profiles. Using precision particle fabrication (PPF) technology, monodisperse DWMS were fabricated with model protein bovine serum albumin (BSA)-loaded poly(lactide-co-glycolide) (PLG) core and drug-free poly(d,l-lactic acid) (PDLL) shell of uniform thickness. Monolithic single-wall microspheres were also fabricated to mimic the BSA-loaded PLG core. Using ethyl acetate and dichloromethane as shell- and core-phase solvents, respectively, BSA was encapsulated selectively in the core region within DWMS with higher loading and encapsulation efficiency compared to using dichloromethane as core and shell solvents. BSA in vitro release rates were retarded by the presence of the drug-free PDLL shell. Moreover, increasing PDLL shell thickness resulted in decreasing BSA release rate. With a 14-μm thick PDLL shell, an extended period of constant-rate release was achieved.
    背景与目标: :可生物降解的聚合物微粒由于其相对简单的制造和便捷的给药方法,是用于蛋白质治疗的有前途的储库。包含由两种截然不同的聚合物制成的核和壳的双壁微球(DWMS)可以增强对药物释放曲线的控制。使用精密颗粒制造(PPF)技术,以负载模型蛋白牛血清白蛋白(BSA)的聚(丙交酯-乙交酯)(PLG)核心和不含药物的聚(d,l-乳酸)制成单分散DWMS( PDLL)厚度均匀的外壳。还制造了整体式单壁微球,以模拟负载BSA的PLG核心。分别使用乙酸乙酯和二氯甲烷作为壳层和核心相溶剂,与使用二氯甲烷作为核心和壳层溶剂相比,BSA被选择性地封装在DWMS的核心区域中,具有更高的负载和封装效率。无药物的PDLL壳的存在阻碍了BSA的体外释放速率。此外,增加PDLL外壳厚度会导致BSA释放速率降低。使用14μm厚的PDLL外壳,可以实现延长的恒定速率释放。

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