BACKGROUND & AIMS: BACKGROUND:The combination of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) is recommended by treatment guidelines for the treatment of persistent asthma. Two such combination products, salmeterol/fluticasone propionate (SFC, Seretide GSK, UK) and formoterol/budesonide (FBC, Symbicort, AstraZeneca, UK) are commercially available. OBJECTIVES:The purpose of these studies was to evaluate and compare the duration of bronchodilation of both combination products up to 24 hours after a single dose. METHODS:Two randomised, double blind, placebo-controlled, crossover studies were performed. Study A was conducted in 33 asthmatic adults receiving 400-1200 mcg of budesonide or equivalent. Serial forced expiratory volume in one second (FEV1) was measured over 24 hours to determine the duration of effect of both SFC (50/100 mcg) and FBC (4.5/160 mcg). Study B was conducted in 75 asthmatic adults receiving 800-1200 mcg of budesonide or equivalent and comprised a 4 week run-in of 400 mcg bd Becotide followed by 4 weeks treatment with either SFC 50/100 mcg bd or FBC 4.5/160 mcg bd taken in a cross-over manner. Serial 24-hour FEV1 was measured after the first dose and the last dose after each 4-weeks treatment period to determine the offset of action of each treatment. RESULTS:In study A, a single inhalation of SFC and FBC produced a sustained bronchodilation at 16 hours with an adjusted mean increase in FEV1 from pre-dose of 0.22 L (95% CI 0.19, 0.35 L) for SFC and 0.25 L (95% CI 0.21, 0.37 L) for FBC, which was significantly greater than placebo for both treatments (-0.05 L; p < 0.001). In study B, the slope of decline in FEV1 from 2-24 hours post dose was -16.0 ml/hr for SFC and -14.2 ml/hr for FBC. The weighted mean AUC over 24 hours was 0.21 Lxmin and 0.22 Lxmin and mean change from pre-dose FEV1 at 12 hours was 0.21 L for SFC and 0.20 L for FBC respectively CONCLUSION:Both SFC and FBC produced a similar sustained bronchodilator effect which was prolonged beyond 12 hours post dose and was clearly measurable at 24 h.

背景与目标： 摘要背景：吸入性糖皮质激素（ICS）和长效β2-激动剂（LABA）的结合被治疗指南推荐用于持续性哮喘的治疗。两种这样的组合产品，沙美特罗/丙酸氟替卡松（SFC，英国Seretide GSK）和福莫特罗/布地奈德（FBC，Symbicort，阿斯利康，英国）可商购。
目的：这些研究的目的是评估和比较两种组合产品在单剂给药后直至24小时的支气管扩张持续时间。
方法：进行了两项随机，双盲，安慰剂对照，交叉研究。研究A在接受400-1200 mcg布地奈德或同等剂量的33位哮喘成人中进行。在24小时内测量一秒钟的连续呼气量（FEV1），以确定SFC（50/100 mcg）和FBC（4.5 / 160 mcg）的作用持续时间。研究B是在75名接受800-1200 mcg布地奈德或同等水平的哮喘成年人中进行的，包括4周400 mcg bd的Becotide磨合，然后用SFC 50/100 mcg bd或FBC 4.5 / 160 mcg bd进行4周治疗以交叉方式拍摄。在每4周治疗期后的第一剂和最后一剂之后，测量连续的24小时FEV1，以确定每种治疗的作用抵消。
结果：在研究A中，单次吸入SFC和FBC在16小时产生了持续的支气管扩张作用，与SFC和0.25 L（95 FBC的％CI 0.21、0.37 L），均显着高于两种治疗的安慰剂（-0.05 L； p <0.001）。在研究B中，从剂量后2-24小时开始，FEV1的下降斜率对于SFC为-16.0 ml / hr，对于FBC为-14.2 ml / hr。在24小时内，加权平均AUC为0.21 Lxmin和0.22 Lxmin，对于SFC，从剂量前FEV1到12小时的平均变化分别为0.21 Lx和FBC 0.20 L
结论：SFC和FBC均产生相似的持续支气管扩张药作用，给药后延长至12小时以上，并且在24 h时明显可测量。

BACKGROUND & AIMS: :Immunocompromise after a major injury is presumed to be a predisposing factor for sepsis. Mice subjected to sublethal cecal ligation and puncture (CLP) and challenged 5 days later with Pseudomonas aeruginosa had more bacterial growth in lung tissue, lower serum interferon gamma (IFN-gamma) and interleukin (IL) 12,and higher serum IL-10 when compared with sham CLP mice challenged with Pseudomonas. To test the functional significance of these alterations in cytokine production in the immune response to bacteria, we administered IFN-gamma and anti-IL-10 to post-CLP mice before the Pseudomonas challenge. Administration of IFN-gamma and anti-IL-10 did not improve bacterial clearance or mortality in post-CLP mice. In further studies, we administered IFN-gamma to IL-10 knockout mice before a challenge with P. aeruginosa. Our results showed no significant differences in bacterial clearance or mortality in IL-10 knockout mice with or without IFN-gamma treatment compared with wild-type controls. Finally, because most mortality occurred within 2 to 3 days of the Pseudomonas challenge in the aforementioned studies and was likely associated with a marked proinflammatory response, we investigated the effect of IFN-gamma and anti-IL-10 on clearance of Pseudomonas in C3H/HeJ mice, which do not mount an exaggerated proinflammatory response to endotoxin or Gram-negative bacteria. Neither clearance of the Pseudomonas bacteria nor mortality was improved in C3H/HeJ mice receiving anti-IL-10 and IFN-gamma. These results suggest that the suppressed IFN-gamma and IL-12 responses, in combination with an exaggerated IL-10 response to P. aeruginosa challenge after injury, do not correlate with bacterial clearance or survival.

背景与目标： ：大伤后的免疫功能低下被认为是败血症的诱因。进行半致死盲肠结扎和穿刺（CLP）并在5天后用铜绿假单胞菌攻击的小鼠的肺组织中细菌生长更多，血清干扰素-γ（IFN-γ）和白介素（IL）12更低，而血清IL-10更高。与假单胞菌攻击的假CLP小鼠相比。为了测试这些变化对细菌免疫反应中细胞因子产生的功能意义，我们在假单胞菌攻击之前向CLP后小鼠施用了IFN-γ和抗IL-10。在CLP后小鼠中，IFN-γ和抗IL-10的使用不能改善细菌清除率或死亡率。在进一步的研究中，我们在铜绿假单胞菌攻击之前向IL-10敲除小鼠施用了IFN-γ。我们的结果表明，与野生型对照相比，接受或未接受IFN-γ治疗的IL-10基因敲除小鼠的细菌清除率或死亡率无显着差异。最后，由于在上述研究中大多数死亡发生在假单胞菌攻击后的2到3天内，并且可能与明显的促炎反应有关，因此我们研究了IFN-γ和抗IL-10对C3H / 3中假单胞菌清除的影响HeJ小鼠，对内毒素或革兰氏阴性细菌没有过度的促炎反应。接受抗IL-10和IFN-γ的C3H / HeJ小鼠的假单胞菌细菌清除率和死亡率均未提高。这些结果表明，损伤后抑制的IFN-γ和IL-12反应，加上对损伤后铜绿假单胞菌攻击的过度IL-10反应，与细菌清除率或存活率无关。

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: Etoposide produces reversible inhibition of topoisomerase II, leading to cleavage of DNA, and thereby has an antitumor effect. This mechanism suggests that the longer treatment is continued, the greater the antitumor effect will be. In the present study, both therapeutic and adverse effects of long-term treatment with low-dose oral etoposide were studied in 29 patients aged > or = 65 years with non-Hodgkin's lymphoma (NHL) for whom standard chemotherapy was not effective or refractory. These patients received etoposide at a dose of 50 mg/d for as long as possible. Treatment was continued until white blood cell count decreased to < or = 2,000/microL or the platelet count decreased to < or = 5 x 10(4)/microL. According to the World Health Organization (WHO) criteria of therapeutic effects, 6 (20.7%) of the 29 patients achieved complete remission and 13 patients (44.8%) had partial remission, for a response rate of 65.5%. Adverse effects of > or = grade 3 included leukopenia in 24 patients (82.8%) and anemia in 7 (24.1%). Granulocyte colony-stimulating factor (G-CSF) was given in combination with etoposide to eight patients because of leukopenia (granulocyte count < or = 1,000/microL). In view of the excellent subjective tolerance, low incidence of serious adverse effects, and good activity, single agent oral etoposide given continuously over prolonged periods represents a useful treatment for elderly patients with NHL.

背景与目标： 依托泊苷产生对拓扑异构酶II的可逆抑制，导致DNA裂解，因此具有抗肿瘤作用。该机制表明持续的治疗时间越长，抗肿瘤作用越大。在本研究中，对29岁年龄≥65岁的非霍奇金淋巴瘤（NHL）患者进行了长期低剂量口服依托泊苷的治疗，并对其不良反应进行了研究，这些患者对于标准化疗均无效或难治。这些患者尽可能长时间接受依托泊苷50 mg / d的剂量。继续治疗直至白细胞计数降低至<或= 2,000 / microL或血小板计数降低至<或= 5 x 10（4）/ microL。根据世界卫生组织（WHO）的治疗效果标准，这29例患者中有6例（20.7％）完全缓解，13例（44.8％）部分缓解，缓解率为65.5％。 ≥3级的不良反应包括24例白血球减少症（82.8％）和7例贫血（24.1％）。由于白细胞减少症（粒细胞计数<或= 1,000 / microL），八名患者与依托泊苷合用了粒细胞集落刺激因子（G-CSF）。鉴于出色的主观耐受性，严重不良反应的发生率低以及良好的活动性，长时间连续给予单剂口服依托泊苷对老年NHL患者是一种有用的治疗方法。

BACKGROUND & AIMS: High-dose chemotherapy often requires hematopoietic progenitor cell reinfusion, but drugs with extramedullary dose-limiting toxicity may be administered in the high-dose range by simple growth factor support. In this study, we evaluated the feasibility and toxicity of a three-drug high-dose regimen supported by recombinant human granulocyte colony-stimulating factor (rhG-CSF). Ten patients with histologically proven malignancy were enrolled. Eight had breast cancer, one non-Hodgkin's lymphoma, and one a mediastinal tumor of unknown origin. The regimen included cyclophosphamide (C) 5 g/m2, etoposide (E) 1.5 g/m2, and cisplatin (P) 150 mg/m2 (CEP), administered in a 3-day schedule followed by rhG-CSF, 300 micrograms once a day, beginning from day +5 (36 h after the end of chemotherapy). The cycle was repeated as clinically needed up to three times. After the first course, hematologic recovery was rapid and complete without documented infections, and no relevant extramyeloid toxicities were observed. Eight of 10 patients received a second course with comparably low toxicity, and three of them received a third course. We concluded that CEP therapy can be administered safely and even repeatedly, by simple growth factor support, in good performance status cancer patients.

背景与目标： 大剂量化学疗法通常需要重新注入造血祖细胞，但是可以通过简单的生长因子支持在大剂量范围内使用具有髓外剂量限制性毒性的药物。在这项研究中，我们评估了重组人粒细胞集落刺激因子（rhG-CSF）支持的三药大剂量方案的可行性和毒性。十名经组织学证实为恶性肿瘤的患者入选。 8例患有乳腺癌，1例非霍奇金淋巴瘤，1例起源不明的纵隔肿瘤。该方案包括环磷酰胺（C）5 g / m2，依托泊苷（E）1.5 g / m2和顺铂（P）150 mg / m2（CEP），分3天给药，随后用rhG-CSF给药，每次300微克从第5天（化疗结束后36小时）开始的一天。根据临床需要重复该循环多达三次。第一次疗程结束后，血液学恢复迅速且完全，没有记录的感染，也未观察到相关的髓外毒性。 10名患者中有8名接受了第二疗程，毒性较低，其中三名接受了第三疗程。我们得出的结论是，通过简单的生长因子支持，可以对处于良好状态的癌症患者安全，甚至重复使用CEP治疗。

BACKGROUND & AIMS: BACKGROUND:The combinations of methotrexate, vinblastine, Adriamycin, cisplatin (Pharmanell, Athens, Greece) (MVAC) or gemcitabine, cisplatin (GC) represent the standard treatment of advanced urothelial cancer (UC). Dose-dense (DD)-MVAC has achieved longer progression-free survival (PFS) than the conventional MVAC. However, the role of GC intensification has not been studied. We conducted a randomized, phase III study comparing a DD-GC regimen with DD-MVAC in advanced UC. PATIENTS AND METHODS:One hundred and thirty patients were randomly assigned between DD-MVAC: 66 (M 30 mg/m(2), V 3 mg/m(2), A 30 mg/m(2), C 70 mg/m(2) q 2 weeks) and DD-GC 64 (G 2500 mg/m(2), C 70 mg/m(2) q 2 weeks). The median follow-up was 52.1 months (89 events). RESULTS:The median overall survival (OS) and PFS were 19 and 8.5 months for DD-MVAC and 18 and 7.8 months for DD-GC (P = 0.98 and 0.36, respectively). Neutropenic infections were less frequent for DD-GC than for DD-MVAC (0% versus 8%). More patients on DD-GC received at least six cycles of treatment (85% versus 63%, P = 0.011) and the discontinuation rate was lower for DD-GC (3% versus 13%). CONCLUSIONS:Although DD-GC was not superior to DD-MVAC, it was better tolerated. DD-GC could be considered as a reasonable therapeutic option for further study in this patient population. Clinical Trial Number ACTRN12610000845033, www.anzctr.org.au.

背景与目标： 背景：甲氨蝶呤，长春碱，阿霉素，顺铂（Pharmanell，雅典，希腊）（MVAC）或吉西他滨，顺铂（GC）的组合代表了晚期尿路上皮癌（UC）的标准治疗方法。与传统的MVAC相比，剂量密集（DD）-MVAC获得了更长的无进展生存期（PFS）。但是，尚未研究GC强化的作用。我们进行了一项随机III期研究，比较了DD-GC方案与DD-MVAC在晚期UC中的比较。
患者与方法：一百三十名患者被随机分配至DD-MVAC：66（M 30 mg / m（2），V 3 mg / m（2），A 30 mg / m（2），C 70 mg / m（2）q 2周）和DD-GC 64（G 2500 mg / m（2），C 70 mg / m（2）q 2周）。中位随访时间为52.1个月（89事件）。
结果：DD-MVAC的中位总体生存期（OS）和PFS为19和8.5个月，DD-GC的中位总体生存期（OS）和PFS为18和7.8个月（分别为P = 0.98和0.36）。与DD-MVAC相比，DD-GC的中性粒细胞减少感染频率较低（0％对8％）。使用DD-GC的患者更多，至少接受了六个周期的治疗（85％对63％，P = 0.011），DD-GC的停药率较低（3％对13％）。
结论：尽管DD-GC并不优于DD-MVAC，但其耐受性更好。 DD-GC被认为是对该患者人群进行进一步研究的合理治疗选择。临床试验编号ACTRN12610000845033，www.anzctr.org.au。

BACKGROUND & AIMS: :Isolated tomato fruit cuticles were subjected to low dose (80Gy) γ-irradiation, as a potential methodology to prevent harvested fruit and vegetables spoilage. Both irradiated and non-irradiated samples have been morphologically and chemically characterized by scanning electron (SEM), atomic force (AFM), attenuated total reflectance Fourier transform infrared (ATR-FTIR) and X-ray photoelectron (XPS) spectroscopies. Additionally, electrochemical measurements comprising membrane potential and diffusive permeability were carried out to detect modifications in transport properties of the cuticle as the fruit primary protective membrane. It has been found that low dose γ-irradiation causes some textural changes on the surface but no significant chemical modification. Texture modification is found to be due to a partial removal of outermost (epicuticular) waxes which is accompanied by mild changes of electrochemical parameters such as the membrane fixed charge, cation transport number and salt permeability. The modification of such parameters indicates a slight reduction of the barrier properties of the cuticle upon low dose γ-irradiation.

背景与目标： ：对分离的番茄果实表皮进行低剂量（80Gy）γ射线照射，作为防止收获的水果和蔬菜变质的潜在方法。通过扫描电子（SEM），原子力（AFM），衰减的全反射傅立叶变换红外光谱（ATR-FTIR）和X射线光电子（XPS）光谱学，对经过辐照和未经辐照的样品进行了形态和化学表征。另外，进行了包括膜电位和扩散渗透性的电化学测量，以检测作为水果主要保护膜的角质层的转运性质的改变。已经发现，低剂量的γ射线辐照会在表面上引起一些纹理变化，但是没有明显的化学修饰。发现结构改性是由于最外层（蜡状）蜡的部分除去，同时伴随着电化学参数的温和变化，例如膜固定电荷，阳离子迁移数和盐渗透性。对这些参数的修改表明在低剂量γ辐照下，表皮的阻隔性能略有降低。

BACKGROUND & AIMS: :Light focusing through a microbead leads to the formation of a photonic nanojet functional for enhancing the spatial resolution of traditional optical systems. Despite numerous works that prove this phenomenon, a method to appropriately translate the nanojet on top of a region of interest is still missing. Here, by using advanced 3D fabrication techniques we integrated a microbead on an AFM cantilever thus realizing a system to efficiently position nanojets. This fabrication approach is robust and can be exploited in a myriad of applications, ranging from microscopy to Raman spectroscopy. We demonstrate the potential of portable nanojets by imaging different sub-wavelength structures. Thanks to the achieved portability, we were able to perform a detailed optical characterization of the resolution enhancement induced by the microbead, which sheds light into the many contradictory resolution claims present in literature. Our conclusions are strongly supported by rigorous data analysis and by numerical simulations, all in perfect agreement with experimental results.

背景与目标： ：通过微珠的光聚焦导致形成用于增强传统光学系统的空间分辨率的光子纳米射流。尽管有大量的工作证明了这种现象，但是仍然缺少一种在目标区域顶部适当平移纳米射流的方法。在这里，通过使用先进的3D制造技术，我们将微珠集成在AFM悬臂上，从而实现了有效定位纳米喷嘴的系统。这种制造方法坚固耐用，可以在从显微镜到拉曼光谱的众多应用中加以利用。我们通过成像不同的亚波长结构展示了便携式纳米射流的潜力。由于实现了便携性，我们能够对微珠引起的分辨率增强进行详细的光学表征，这为文献中存在的许多相互矛盾的分辨率要求提供了线索。严格的数据分析和数值模拟为我们的结论提供了有力的支持，所有这些都与实验结果完全吻合。

BACKGROUND & AIMS: BACKGROUND:Injectable daxibotulinumtoxinA (RT002) is an investigational botulinum toxin Type A in clinical development. It is formulated with a proprietary peptide and offers the potential of a longer acting neurotoxin therapy. OBJECTIVE:To compare the safety, efficacy, and duration of response of daxibotulinumtoxinA with onabotulinumtoxinA and placebo [www.clinicaltrials.gov NCT02303002]. METHODS:In this Phase 2, randomized, dose-ranging, parallel-group, double-blind, multicenter study, subjects with moderate or severe glabellar lines at maximum frown were randomly assigned to 20U, 40U, or 60U daxibotulinumtoxinA, 20U onabotulinumtoxinA, or placebo. Glabellar line severity was evaluated by investigators and subjects at least every 4 weeks, for at least 24 weeks. RESULTS:Overall, 268 subjects enrolled. Statistical and clinical superiority were observed for 40U and 60U daxibotulinumtoxinA over 20U onabotulinumtoxinA for a range of efficacy outcomes despite the study not being powered to detect statistically significant differences between these active treatment groups. CONCLUSION:The 40U dose of daxibotulinumtoxinA was well tolerated (e.g., absence of ptosis) and had the most favorable risk: benefit profile. Compared with 20U onabotulinumtoxinA, it exhibited a significantly greater response rate and a significantly longer duration of response (median of 24 weeks vs 19 weeks; p = .030).

背景与目标： 背景：可注射的daxibotulinumtoxinA（RT002）是临床开发中的一种研究型A型肉毒毒素。它由专有肽配制而成，具有长效神经毒素治疗的潜力。
目的：比较daxibotulinumtoxinA，onabotulinumtoxinA和安慰剂的安全性，疗效和反应持续时间[www.clinicaltrials.gov NCT02303002]。
方法：在该阶段2中，随机，剂量范围，平行分组，双盲，多中心研究将具有最大皱眉的中度或重度纹眉系的受试者随机分配至20U，40U或60U daxibotulinumtoxinA，20U onabotulinumtoxinA或安慰剂。研究者和受试者至少每4周，至少24周评估眉毛线的严重程度。
结果：总体上，招募了268名受试者。尽管该研究未能检测出这些活跃治疗组之间的统计学显着差异，但观察到40U和60U daxibotulinumtoxinA优于20U onabotulinumtoxinA在一系列功效方面的统计学和临床​​优势。
结论：40U剂量的daxibotulinumtoxinA具有良好的耐受性（例如，没有上睑下垂），并且具有最有利的风险：获益特征。与20U的肉毒杆菌毒素A相比，它显示出显着更高的应答率和显着更长的应答持续时间（中位24周vs 19周； p = .030）。

BACKGROUND & AIMS: :Forty-eight patients with advanced gastric cancer and measurable areas of malignant disease were treated with etoposide (130 mg/m2/day X 3 days) plus cisplatin (45 mg/m2day on days 2 and 3). Both drugs were given by constant intravenous infusion and repeated every 4 weeks. Common toxic reactions included nausea, vomiting, diarrhea, alopecia, peripheral neuropathy, leukopenia, and thrombocytopenia. Most patients experienced severe but reversible toxic reactions. In 46 evaluable patients an overall objective regression rate of 28% was obtained with a median duration of regression of 4 months. Regression rates were only modestly reduced among patients with prior chemotherapy exposure (21%). Whereas this combination of etoposide and cisplatin does not appear to offer any major advantage over other single and combination regimens in the treatment of advanced gastric cancer, it shows definite activity and its lack of cross-resistance with other commonly used agents for this disease could indicate a possible role in new combination or sequential chemotherapy approaches. As an interesting sidelight, we found that 21% of our patients had elevated human chorionic gonadotropin (HCG) levels, and among this group regression rates were higher than in HCG-negative patients. It would be of interest to extend these observations in other gastric carcinoma studies involving cisplatin regimens.

背景与目标： ：对48例晚期胃癌和可测量的恶性肿瘤患者进行了依托泊苷（130 mg / m2 /天X 3天）加顺铂（45 mg / m2天在第2天和第3天）的治疗。两种药物均通过持续静脉输注给药，每4周重复一次。常见的毒性反应包括恶心，呕吐，腹泻，脱发，周围神经病，白细胞减少症和血小板减少症。大多数患者经历了严重但可逆的毒性反应。在46位可评估的患者中，总体客观回归率为28％，中位回归时间为4个月。在先前接受过化疗的患者中，回归率仅适度降低（21％）。尽管依托泊苷和顺铂的这种组合在晚期胃癌的治疗中似乎没有比其他单一和组合方案提供任何主要优势，但它显示出一定的活性，并且与该疾病的其他常用药物缺乏交叉耐药性可能表明在新的联合疗法或顺序化疗方法中可能发挥作用。有趣的是，我们发现21％的患者绒毛膜促性腺激素（HCG）水平升高，并且这一组的回归率高于HCG阴性患者。在涉及顺铂方案的其他胃癌研究中扩展这些观察结果将是令人感兴趣的。

BACKGROUND & AIMS: :The present study was designed to investigate whether taxol in combination with cyclooxygenase (COX) inhibitors could be superior on inhibitory effect of ovarian cancer growth than taxol alone as drug therapy of mice implanted with human ovarian carcinoma cell line SKOV-3. The animals were treated with 100 mg/ kg celecoxib (a COX-2 selective inhibitor) alone or in combination with 3 mg/kg SC-560 (a COX-1 selective inhibitor) by gavage twice a day, 20mg/kg taxol alone by intraperitoneal (IP) once a week or in combination with celecoxib, or SC-560/celecoxib/taxol for 3 weeks. To test the mechanism of the combination treatment, the index of cell proliferation, expression of cyclin D1, and microvessel density (MVD) in tumor tissues were determined by immunohistochemistry and the index of apoptotic cells by the terminal-deoxynucleotidyl-transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) method. Mean tumor volume in the SC-560/celecoxib/taxol group was first significantly lower than control at day 14 (p < 0.05). In the SC-560/celecoxib/taxol group, the index of cell proliferation and apoptosis and quantification of cyclin D1-postive cells were 6.93%, 69.62%, and 19.14%, respectively, which are statistically significant compared with those of the control group (29.85%, p < 0.001; 32.81% and 36.99%, both p < 0.05). Statistical significance on MVD was observed between the SC-560/celecoxib/taxol (39.57 +/- 4.98) and the control (73.2 +/- 1.96) group (p < 0.001). Our results suggest that the combined antitumor efficacy of taxol and COX inhibitors may be superior to taxol alone as drug therapy against ovarian cancer in mice, and that synergism of the combination treatment in part may be mediated through accelerated apoptosis and suppression of cell proliferation and angiogenesis.

背景与目标： ：本研究旨在研究紫杉醇与环加氧酶（COX）抑制剂联合使用对人卵巢癌细胞株SKOV-3植入小鼠的卵巢癌生长抑制作用是否比单独使用紫杉醇更好。每天两次分别用100 mg / kg celecoxib（一种COX-2选择性抑制剂）或与3 mg / kg SC-560（一种COX-1选择性抑制剂）联合饲喂动物，分别用20 mg / kg紫杉醇治疗。每周一次腹膜内（IP）或与celecoxib或SC-560 / celecoxib /紫杉醇联合使用3周。为了测试联合治疗的机制，通过免疫组织化学测定肿瘤组织中细胞增殖指数，细胞周期蛋白D1的表达和微血管密度（MVD），并用末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸来检测凋亡细胞的指数。缺口标记（TUNEL）方法。第14天时，SC-560 /塞来昔布/紫杉醇组的平均肿瘤体积首先显着低于对照组（p <0.05）。在SC-560 /塞来昔布/紫杉醇组中，细胞周期cyclin D1阳性细胞的增殖指数和凋亡指数分别为6.93％，69.62％和19.14％，与对照组相比有统计学意义。 （29.85％，p ＜0.001； 32.81％和36.99％，均p ＜0.05）。在SC-560 / celecoxib /紫杉醇（39.57 /-4.98）和对照组（73.2 /-1.96）组之间观察到MVD的统计显着性（p <0.001）。我们的研究结果表明，紫杉醇和COX抑制剂的联合抗肿瘤药效可能优于单独使用紫杉醇作为抗小鼠卵巢癌的药物疗法，并且联合治疗的协同作用可能部分通过加速凋亡，抑制细胞增殖和血管生成来介导。 。

BACKGROUND & AIMS: :Obesity, diabetes, hypertension, and hyperlipidemia constitute risk factors for morbidity and premature mortality. Based on animal and in vitro studies, resveratrol reverts these risk factors via stimulation of silent mating type information regulation 2 homolog 1 (SIRT1), but data in human subjects are scarce. The objective of this study was to examine the metabolic effects of high-dose resveratrol in obese human subjects. In a randomized, placebo-controlled, double-blinded, and parallel-group design, 24 obese but otherwise healthy men were randomly assigned to 4 weeks of resveratrol or placebo treatment. Extensive metabolic examinations including assessment of glucose turnover and insulin sensitivity (hyperinsulinemic euglycemic clamp) were performed before and after the treatment. Insulin sensitivity, the primary outcome measure, deteriorated insignificantly in both groups. Endogenous glucose production and the turnover and oxidation rates of glucose remained unchanged. Resveratrol supplementation also had no effect on blood pressure; resting energy expenditure; oxidation rates of lipid; ectopic or visceral fat content; or inflammatory and metabolic biomarkers. The lack of effect disagrees with persuasive data obtained from rodent models and raises doubt about the justification of resveratrol as a human nutritional supplement in metabolic disorders.

背景与目标： 肥胖，糖尿病，高血压和高脂血症是发病率和过早死亡的危险因素。根据动物和体外研究，白藜芦醇通过刺激无声交配类型信息调节2同源物1（SIRT1）来逆转这些危险因素，但人类受试者的数据却很少。这项研究的目的是检查高剂量白藜芦醇在肥胖人类受试者中的代谢作用。在随机，安慰剂对照，双盲和平行组设计中，将24名肥胖但其他方面健康的男性随机分配到白藜芦醇或安慰剂治疗4周。在治疗之前和之后进行了广泛的代谢检查，包括评估葡萄糖更新和胰岛素敏感性（高胰岛素正常血糖钳夹）。两组的主要结果指标胰岛素敏感性均无显着性恶化。内源性葡萄糖的产生以及葡萄糖的周转率和氧化率保持不变。补充白藜芦醇对血压也没有影响。静息能量消耗；脂质的氧化速率；异位或内脏脂肪含量；或炎症和代谢生物标志物。缺乏效果与从啮齿动物模型获得的有说服力的数据不同，并引起人们对白藜芦醇作为代谢障碍中人类营养补充剂的合理性的怀疑。

BACKGROUND & AIMS: :Although low-dose acetylsalicylic acid (ASA) is recommended for prevention of cardiovascular events in at-risk patients, its long-term use can be associated with the risk of peptic ulcer and upper gastrointestinal (GI) symptoms that may impact treatment compliance. This prespecified secondary analysis of the OBERON study (NCT00441727) determined the efficacy of esomeprazole for prevention/resolution of low-dose ASA-associated upper GI symptoms. A post hoc analysis of predictors of symptom prevention/resolution was also conducted. Helicobacter pylori-negative patients taking low-dose ASA (75-325 mg) for cardiovascular protection who had ≥1 upper GI risk factor were eligible. The patients were randomized to once-daily esomeprazole 40 mg, 20 mg, or placebo, for 26 weeks; 2303 patients (mean age 67.6 years; 36% aged >70 years) were evaluable for upper GI symptoms. The proportion of patients with dyspeptic or reflux symptoms (self-reported Reflux Disease Questionnaire) was significantly lower (P < 0.0001) in those treated with esomeprazole versus in those treated with placebo. Treatment with esomeprazole (P < 0.0001), age >70 years (P < 0.01), and the absence of upper GI symptoms at baseline (P < 0.0001) were all factors associated with prevention/resolution of upper GI symptoms. Together, these analyses demonstrate that esomeprazole is effective in preventing and resolving patient-reported upper GI symptoms in low-dose ASA users at increased GI risk.

背景与目标： ：虽然建议使用低剂量的乙酰水杨酸（ASA）预防高危患者的心血管事件，但长期使用它可能会引起消化性溃疡和上消化道（GI）症状，可能会影响治疗依从性。这项对OBERON研究（NCT00441727）的预先指定的二次分析确定了埃索美拉唑预防/缓解低剂量ASA相关的上消化道症状的功效。还对症状预防/缓解的预测因素进行事后分析。服用低剂量ASA（75-325 mg）进行心血管保护的幽门螺杆菌阴性患者且具有≥1的上消化道危险因素。将患者随机分为每天一次的埃索美拉唑40 mg，20 mg或安慰剂，共26周。 2303例患者（平均年龄67.6岁； 36％的年龄> 70岁）可评估上消化道症状。消化不良或反流症状（自我报告的反流病问卷）患者的比例与安慰剂相比明显降低（P <0.0001）。埃索美拉唑治疗（P <0.0001），年龄> 70岁（P <0.01）和基线时没有上消化道症状（P <0.0001）是与预防/缓解上消化道症状相关的所有因素。总之，这些分析表明，埃索美拉唑可有效预防和解决胃肠道风险增加的低剂量ASA用户中患者报告的上消化道症状。

BACKGROUND & AIMS: 1. Selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors (SSRIs) cause a greater increase in extracellular 5-HT in the forebrain when the somatodendritic 5-HT1A autoreceptor is blocked. Here, we investigated whether blockade of the terminal 5-HT1B autoreceptor influences a selective 5-HT reuptake inhibitor in the same way, and whether there is an additional effect of blocking both the 5-HT1A and 5-HT1B autoreceptors. 2. Extracellular 5-HT was measured in frontal cortex of the anaesthetized rat by use of brain microdialysis. In vivo extracellular recordings of 5-HT neuronal activity in the dorsal raphe nucleus (DRN) were also carried out. 3. The selective 5-HT reuptake inhibitor, paroxetine (0.8 mg kg-1, i.v.), increased extracellular 5-HT about 2 fold in rats pretreated with the 5-HT1A receptor antagonist, WAY100635. When administered alone neither paroxetine (0.8 mg kg-1, i.v.) nor WAY100635 (0.1 mg kg-1, i.v.) altered extracellular 5-HT levels. 4. Paroxetine (0.8 mg kg-1, i.v.) did not increase 5-HT in rats pretreated with the 5-HT1B/D receptor antagonist, GR127935 (1 mg kg-1, i.v.). GR127935 (1 and 5 mg kg-1, i.v.) had no effect on extracellular 5-HT when administered alone. 5. Interestingly, paroxetine (0.8 mg kg-1, i.v.) caused the greatest increase in 5-HT (up to 5 fold) when GR127935 (1 or 5 mg kg-1, i.v.) was administered in combination with WAY100635 (0.1 mg kg-1, i.v.). Administration of GR127935 (5 mg kg-1, i.v.) plus WAY100635 (0.1 mg kg-1, i.v.) without paroxetine, had no effect on extracellular 5-HT in the frontal cortex. 6. Despite the lack of effect of GR127935 on 5-HT under basal conditions, when 5-HT output was elevated about 3 fold (by adding 1 microM paroxetine to the perfusion medium), the drug caused a dose-related (1 and 5 mg kg-1, i.v.) increase in 5-HT. 7. By itself, GR127935 slightly but significantly decreased 5-HT cell firing in the DRN at higher doses (2.0-5.0 mg kg-1, i.v.), but did not prevent the inhibition of 5-HT cell firing induced by paroxetine. 8. In summary, our results suggest that selective 5-HT reuptake inhibitors may cause a large increase in 5-HT in the frontal cortex when 5-HT autoreceptors on both the somatodendrites (5-HT1A) and nerve terminals (5-HT1B) are blocked. This increase is greater than when either set of autoreceptors are blocked separately. The failure of a 5-HT1B receptor antagonist alone to enhance the effect of the selective 5-HT reuptake inhibitor in our experiments may be related to a lack of tone on the terminal 5-HT1B autoreceptor due to a continued inhibition of 5-HT cell firing. These results are discussed in relation to the use of 5-HT autoreceptor antagonists to augment the antidepressant effect of selective 5-HT reuptake inhibitors.

背景与目标： 1.当抑制体树突状5-HT1A自体受体时，选择性5-羟色胺（5-HT； 5-羟色胺）再摄取抑制剂（SSRIs）导致前脑细胞外5-HT的增加。在这里，我们调查了终端5-HT1B自身受体的阻断作用是否以相同的方式影响选择性5-HT再摄取抑制剂，以及是否存在阻断5-HT1A和5-HT1B自身受体的其他作用。 2.通过使用脑微透析在麻醉的大鼠的额皮质中测量细胞外5-HT。还进行了背缝核（DRN）中5-HT神经元活性的体内细胞外记录。 3.选择性5-HT再摄取抑制剂帕罗西汀（0.8mg kg-1，静脉内）在用5-HT1A受体拮抗剂WAY100635预处理的大鼠中使细胞外5-HT增加约2倍。当单独给药时，帕罗西汀（0.8 mg kg-1，i.v.）和WAY100635（0.1 mg kg-1，i.v.）均未改变细胞外5-HT水平。 4.在用5-HT1B / D受体拮抗剂GR127935（1 mg kg-1，i.v.）预处理的大鼠中，帕罗西汀（0.8 mg kg-1，i.v.）不会增加5-HT。单独给药时，GR127935（1和5 mg kg-1，静脉内）对细胞外5-HT无效。 5.有趣的是，当GR127935（1或5 mg kg-1，iv）与WAY100635（0.1 mg）联合使用时，帕罗西汀（0.8 mg kg-1，iv）引起5-HT的最大增加（最多5倍）。千克-1，iv）。不含帕罗西汀的GR127935（5 mg kg-1，i.v.）加上WAY100635（0.1 mg kg-1，i.v.）的给药对额皮质中的细胞外5-HT没有影响。 6.尽管在基本条件下GR127935对5-HT缺乏影响，但当5-HT产量提高了约3倍时（通过向灌注培养基中添加1 microM帕罗西汀），该药物引起了剂量相关（1和5 mg kg-1，iv）5-HT升高。 7.就其本身而言，GR127935在较高剂量（2.0-5.0 mg kg-1，i.v.）的DRN中略微但显着降低了5-HT细胞的发射，但并未阻止帕罗西汀诱导的5-HT细胞发射的抑制。 8.总而言之，我们的研究结果表明，当在肢体树突（5-HT1A）和神经末梢（5-HT1B）上都存在5-HT自身受体时，选择性5-HT再摄取抑制剂可能会导致额叶皮层5-HT大量增加。被阻止。该增加量大于分别封闭任一组自动受体时的增加量。在我们的实验中，单独使用5-HT1B受体拮抗剂未能增强选择性5-HT再摄取抑制剂的作用可能与由于持续抑制5-HT细胞而导致末端5-HT1B自体受体缺乏音调有关射击。这些结果与使用5-HT自身受体拮抗剂增强选择性5-HT再摄取抑制剂的抗抑郁作用有关。

BACKGROUND & AIMS: PURPOSE:Noncompliance is one of the limiting factors in the success of occlusion therapy for amblyopia. Electronic monitoring was used to investigate predictors of noncompliance, and, in a prospective randomized clinical trial, determined the effectiveness of an educational program. METHODS:Compliance was measured electronically during 1 week every 3 months in 310 newly diagnosed amblyopic children. The family's demographic parameters and the child's clinical parameters were assessed for their influence on the level of compliance. In addition to standard orthoptic care, children were randomized to receive an educational cartoon story, reward stickers, and an information sheet for the parents (intervention group), or a picture to color (reference group). These and the electronic device were distributed during home visits by researchers. The primary outcome measure was the percentage of compliance (actual/prescribed occlusion time) in the two groups. The secondary outcome measure was the influence of demographic and clinical factors on compliance. RESULTS:Compliance was associated with parental fluency in the national language, country of origin, level of education, and initial visual acuity of the child. During the first 1-week measurement period children in the intervention group had better compliance than the reference group had (78% +/- 32% vs. 57% +/- 40%; P < 0.0001), and fewer children were not occluded at all (3 vs. 23 in the reference group; P < 0.0001). This difference remained throughout the study period. CONCLUSIONS:Poor parental fluency in the national language, a low level of education, and poor acuity at the start of treatment were predictors of low compliance. An educational program primarily aimed at the child improved compliance and reduced the number of children who did not comply with occlusion at all.

背景与目标： 目的：不依从性是弱视闭塞治疗成功的限制因素之一。电子监控用于调查违规行为的预测因素，并在一项前瞻性随机临床试验中确定了教育计划的有效性。
方法：在310名新诊断的弱视儿童中，每3个月以电子方式测量其依从性，每3个月一次。评估了家庭的人口统计学参数和孩子的临床参数对依从性水平的影响。除了标准的矫正照护外，还对儿童进行随机分组，以接受教育性卡通故事，奖励贴纸和针对父母的信息表（干预组），或为图片着色（参考组）。这些和电子设备是在研究人员进行家庭访问时分发的。主要结局指标是两组的依从性百分比（实际/规定的咬合时间）。次要结果指标是人口统计学和临床​​因素对依从性的影响。
结果：依从性与父母的母语，母语，原籍国，受教育程度以及孩子的初始视敏度有关。在最初的1周测量期间，干预组的孩子比对照组的依从性更好（78％/-32％vs. 57％/-40％； P <0.0001），并且完全没有被闭塞的儿童更少（参考组中3 vs. 23； P <0.0001）。在整个研究期间，这种差异仍然存在。
结论：父母母语流利程度低，教育程度低以及治疗开始时的敏锐度低是依从性低的预示因素。一项主要针对儿童的教育计划提高了依从性，并减少了完全不遵守闭塞的儿童人数。