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【利妥昔单抗-CHOP-ESHAP与CHOP-ESHAP-高剂量治疗与常规CHOP化疗治疗高中度和高风险的侵袭性非霍奇金淋巴瘤。】
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DOI：10.1080/10428190500525656
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BACKGROUND & AIMS: :With currently available combination chemotherapy regimens, the outcome of the patients newly diagnosed with aggressive non-Hodgkin's lymphoma (NHL) identified as 'high' and 'high-intermediate' risk groups according to the international prognostic index (IPI) is still unsatisfactory and a more innovative therapy is urgently required to improve the survival of the patients. The purpose of this study was to compare the efficacy of rituximab given in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and ESHAP (etoposide, methylprednisolone, high-dose Ara-C, cisplatin) vs CHOP-ESHAP and upfront high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) vs standard CHOP in patients aged < or = 65 years old newly diagnosed with 'high' and 'high-intermediate' risk aggressive lymphoma enrolled onto two consecutive treatment trials at the institute. Between May 1995 - July 2002, 84 patients, aged 15 - 65 years old, with newly diagnosed aggressive NHL and an age-adjusted IPI of 2 or 3 were enrolled. The median age of the patients was 38 years (range 15 - 65). The baseline demographic features, in particular the major prognostic variables, were similar between the treatment groups. Patients treated with rituximab-CHOP-ESHAP received eight cycles of rituximab (375 mg m(-2) on day 1 of cycles 1 - 6 and days 21 and 28 of cycle 7) plus CHOP (day 3 of cycles 1, 3 and 5) and ESHAP (day 3 of cycles 2, 4 and 6 and day 1 of cycle 7) at 21-day intervals. Patients enrolled onto the CHOP-ESHAP-HDT arm (n = 23) were treated with three courses of CHOP and then switched to two or four cycles of ESHAP followed by HDT. Patients treated with CHOP alone (n = 25) were treated with the standard eight cycles of CHOP. The rate of complete remission was significantly improved with rituximab-CHOP-ESHAP compared with either CHOP-ESHAP-HDT or CHOP alone (67% compared with 44% and 36%, respectively; p = 0.043). With a median follow-up time of 53 months, the 5-year overall survival (OS) was improved by the addition of rituximab-61% with rituximab-CHOP-ESHAP, compared with 43% for CHOP-ESHAP-HDT and 24% for CHOP alone (p = 0.088). Significant increases in failure-free survival (FFS) and disease-free survival (DFS) (61% and 96%), compared with CHOP-ESHAP-HDT (34% and 90%) and CHOP (16% and 44%; p = 0.002 and p < 0.001, respectively) were observed. Compared to CHOP, rituximab-CHOP-ESHAP yielded significantly superior OS (p = 0.014), FFS (p < 0.001) and DFS (p < 0.001). The survivals, however, were not significantly different from patients treated with CHOP-ESHAP-HDT. It is concluded that rituximab-ESHAP-CHOP is superior over standard CHOP and fares comparably to upfront HDT/ASCT in previously untreated patients with aggressive lymphoma. A prospective randomized controlled trial is warranted to confirm these results.背景与目标： ：在目前可用的联合化疗方案下，根据国际预后指数（IPI）刚被诊断为侵袭性非霍奇金淋巴瘤（NHL）的患者的预后仍然不尽人意，并且迫切需要一种更具创新性的疗法来提高患者的生存率。这项研究的目的是比较利妥昔单抗与CHOP（环磷酰胺，阿霉素，长春新碱，泼尼松）和ESHAP（依托泊苷，甲基泼尼松龙，大剂量Ara-C，顺铂）联合使用时与CHOP-ESHAP和前期高剂量联合治疗的疗效在该研究所进行的两项连续治疗试验中，对新诊断为“高”和“高中度”风险性侵袭性淋巴瘤的年龄≤65岁的患者进行剂量治疗（HDT）和自体干细胞移植（ASCT）与标准CHOP对照。在1995年5月至2002年7月之间，纳入了84例年龄在15至65岁之间，新诊断为侵袭性NHL且年龄校正后的IPI为2或3的患者。患者的中位年龄为38岁（范围15-65）。治疗组之间的基线人口统计学特征，尤其是主要的预后变量相似。接受利妥昔单抗-CHOP-ESHAP治疗的患者接受了八个周期的利妥昔单抗（第1-6周期的第1天以及第7周期的第21和28天）（375 mg m（-2））加CHOP（第1、3和5周期的第3天） ）和ESHAP（周期2、4和6的第3天和周期7的第1天），间隔为21天。入组CHOP-ESHAP-HDT组（n = 23）的患者接受了三个疗程的CHOP治疗，然后切换到ESSHAP的两个或四个周期，然后进行HDT。单独接受CHOP治疗的患者（n = 25）接受了标准的八个CHOP周期治疗。与单独使用CHOP-ESHAP-HDT或CHOP相比，利妥昔单抗-CHOP-ESHAP的完全缓解率显着提高（分别为67％，44％和36％； p = 0.043）。中位随访时间为53个月，利妥昔单抗-CHOP-ESHAP加利妥昔单抗-61％改善了5年总生存（OS），相比之下，CHOP-ESHAP-HDT和43％改善了5年总生存率仅适用于CHOP（p = 0.088）。与CHOP-ESHAP-HDT（34％和90％）和CHOP（16％和44％）相比，无失败生存率（FFS）和无病生存率（DFS）显着增加（61％和96％）；分别观察到= 0.002和p <0.001）。与CHOP相比，利妥昔单抗-CHOP-ESHAP产生显着优越的OS（p = 0.014），FFS（p <0.001）和DFS（p <0.001）。但是，其存活率与用CHOP-ESHAP-HDT治疗的患者无明显差异。结论是，对于以前未经治疗的侵袭性淋巴瘤患者，利妥昔单抗-ESHAP-CHOP优于标准CHOP，且其费用可与前期HDT / ASCT相提并论。必须进行前瞻性随机对照试验来证实这些结果。 -
【白色念珠菌myristoylCoA的选择性肽和拟肽抑制剂：蛋白N-肉豆蔻酰基转移酶：一种抗真菌治疗的新方法。】
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DOI：10.1002/(SICI)1097-0282(1997)43:1<43::AID-BIP5>3.0
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BACKGROUND & AIMS: MyristoylCoA:protein N-myristoyltransferase (NMT) catalyzes the cotranslational covalent attachment of a rare cellular fatty acid, myristate, to the N-terminal Gly residue of a variety of eukaryotic proteins. The myristoyl moiety is often essential for expression of the biological functions for these proteins.
Attachment of C14:0 alone provides barely enough hydrophobicity to allow stable association with membranes. The partitioning of N-myrisotylproteins is therefore often modulated by "switches" that function through additional covalent or noncovalent modifications. Candida albicans, the principal cause of systemic fungal infection in immunocompromised humans, contains a single NMT gene that is essential for its viability. The functional properties of the acylCoA binding site of human and C. albicans NMT are very similar. However, there are distinct differences in their peptide binding sites. An ADP ribosylation factor (Arf) is included among the few cellular protein substrates of the fungal enzyme. Alanine scanning mutagenesis of an octapeptide derived from an N-terminal Arf sequence (GLYASKLS-NH2) disclosed that Gly1, Ser5, and Lys6 play predominant roles in binding. ALYASKLS-NH2 is an inhibitor competitive for peptide [Ki(app) = 15.3 +/- 6.4 microM] and noncompetitive for myristoylCoA. Remarkably, replacement of the N-terminal tetrapeptide with an 11-aminoundecanoyl group results in a competitive inhibitor (11-aminoundecanoyl-SKLS-NH2) that is approximately 40-fold more potent [Ki(app) = 0.40 +/- 0.03 microM] than the starting octapeptide. Removal of Leu-Ser from the C-terminus generates a competitive dipeptide inhibitor (11-aminoundecanoyl-SK-NH2) with a Ki(app) of 11.7 +/- 0.4 microM, equivalent to that of the starting octapeptide. A derivative dipeptide inhibitor containing a C-terminal N-cyclohexylethyl lysinamide moiety has the advantage of being more potent (IC50 = 0.11 +/- 0.03 microM) and resistant to digestion by cellular carboxypeptidases. Rigidifying the flexible aminoundecanoyl chain results in very potent general NMT inhibitors (IC50 = 40-50 nM). Substituting a 2-methylimidazole for the N-terminal amine and adding a benzylic alpha-methyl group with R stereochemistry to the rigidifying element produces even more potent inhibitors (IC50 = 20-50 nM) that are up to 500-fold selective for the fungal compared to human enzyme. A related less potent member of this series of compounds is fungistatic. Its growth inhibitory effects are associated with a reduction in cellular protein N-myristoylation, judged using cellular Arf as a reporter. These studies establish that NMT is a new antifungal target.
背景与目标： MyristoylCoA ：蛋白N-肉豆蔻酰基转移酶（NMT）催化稀有细胞脂肪酸肉豆蔻酸酯与多种真核蛋白N-末端Gly残基的共翻译共价连接。肉豆蔻酰基部分通常对于表达这些蛋白质的生物学功能是必不可少的。
仅C14 ：0的附件仅提供了不足以使与膜稳定结合的疏水性。因此，N-肉豆蔻酰蛋白的分区通常由通过附加的共价或非共价修饰起作用的“开关”调节。白色念珠菌是免疫力低下的人体内全身真菌感染的主要原因，它包含一个对其生存能力至关重要的单个NMT基因。人和白色念珠菌NMT的酰基辅酶A结合位点的功能特性非常相似。但是，它们的肽结合位点存在明显差异。 ADP核糖基化因子（Arf）包括在真菌酶的几种细胞蛋白底物中。来自N末端Arf序列（GLYASKLS-NH2）的八肽的丙氨酸扫描诱变显示，Gly1，Ser5和Lys6在结合中起主要作用。 ALYASKLS-NH2是一种对肽[Ki（app）= 15.3 /-6.4 microM]具有竞争性的抑制剂，对肉豆蔻酰辅酶A不具有竞争性。值得注意的是，用11-氨基十一烷酰基取代N末端四肽会产生竞争性抑制剂（11-氨基十一烷酰基-SKLS-NH2），其效力比[Ki（app）= 0.40 /-0.03 microM]高40倍左右。起始八肽。从C末端去除Leu-Ser会产生竞争性的二肽抑制剂（11-氨基十一烷酰基-SK-NH2），Ki（app）为11.7 /-0.4 microM，与起始八肽相当。含有C-末端N-环己基乙基赖氨酰胺部分的衍生物二肽抑制剂具有更有效的优势（IC 50 ＝ 0.11 /0.03μM），并且对细胞羧肽酶的消化具有抵抗力。刚性化柔性氨基十一烷酰基链会产生非常有效的常规NMT抑制剂（IC50 = 40-50 nM）。用2-甲基咪唑代替N端胺，并在刚性元素中添加具有R立体化学的苄基α-甲基，可产生更强效的抑制剂（IC50 = 20-50 nM），对真菌的选择性高达500倍与人类酶相比。该系列化合物的一个相关的效力较弱的成员是抑真菌的。使用细胞Arf作为报告基因判断，其生长抑制作用与细胞蛋白N-肉豆蔻酰化的减少有关。这些研究确定NMT是一种新的抗真菌靶标。
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【辐射诱发的旁观者和其他非靶向效应：癌症治疗中的新干预点？】
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DOI：10.2174/156800906777723976
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BACKGROUND & AIMS: :A major problem in the search for new cancer drug targets is that the drugs are often toxic to normal tissues and require high doses to kill tumor cells. Therefore cellular targets which appear to involve low dose responses to cancer therapy are especially interesting since they could selectively target normal tissues which are not targeted by the treatment and thus may be responsible for unpleasant side effects or may be amenable to exploitation in order to improve the therapeutic ratio. One such target, which is the subject of this review, is radiation-induced bystander effects [RIBE], which result in the observation of radiation like responses in cells which have not been irradiated. RIBE is a novel phenomenon which indicates that at low doses, cell signaling is more important than direct DNA damage. Historically, DNA has always been considered to be the target for radiation therapy. The growing realization that signaling is important opens up several important therapeutic strategies which will be discussed in this review. RIBE appears to be the result of a generalized stress response in tissues or cells which is expressed at the level of the tissue, organ or organism rather than at the level of the individual cell. The signals may be produced by all exposed cells, but the response may require a quorum of cells in order to be expressed. The major response involving low LET (x- or gamma-ray) radiation exposure discussed in the existing literature is a death response. This has many characteristics of apoptosis but may be detected in cell lines without p53 expression, although the death response is suppressed in many tumor cell lines. While a death response in unirradiated normal cells around a tumor might appear to be adverse, it can in fact be protective and remove damaged cells from the population. If harnessed correctly, it could lead to the development of new drugs aimed not at tissue destruction but at enabling homeostatic mechanisms to control tumor expansion. In this scenario, the level of harmful or beneficial response will be related to the background damage, carried by the cell population, and the genetic programme determining response to damage. This focus may be important when attempting to predict the consequences of mixed therapies involving radiation and other cytotoxic agents. In this review, our current knowledge of the mechanisms underlying the induction of bystander effects by ionizing radiation is reviewed, and the question of how bystander effects may be harnessed to produce a new generation of anti-cancer drugs aimed at stabilization of tissue homeostasis rather than tissue destruction is considered.背景与目标： ：寻找新的癌症药物靶标的主要问题是该药物通常对正常组织有毒性，需要高剂量才能杀死肿瘤细胞。因此，细胞靶标似乎涉及对癌症治疗的低剂量反应，因此特别令人感兴趣，因为它们可以选择性地靶向未被治疗靶标的正常组织，因此可能引起令人不快的副作用，或者可能适合于剥削以改善治疗效果。治疗比率。辐射诱导的旁观者效应[RIBE]是本综述的主题之一，该效应导致在未辐射的细胞中观察到辐射样反应。 RIBE是一种新现象，表明在低剂量时，细胞信号传导比直接DNA损伤更为重要。从历史上看，DNA一直被认为是放射治疗的目标。人们日益认识到信号转导很重要，这开启了几种重要的治疗策略，本文将对此进行讨论。 RIBE似乎是组织或细胞中普遍的应激反应的结果，这种应激反应是在组织，器官或生物体的水平而不是单个细胞的水平表达的。信号可能由所有暴露的细胞产生，但响应可能需要一定数量的细胞才能表达。现有文献中讨论的涉及低LET（X射线或γ射线）辐射暴露的主要反应是死亡反应。这具有许多细胞凋亡特征，但尽管在许多肿瘤细胞系中死亡反应受到抑制，但在没有p53表达的细胞系中可能检测到。虽然在肿瘤周围未辐射的正常细胞中的死亡反应似乎是不利的，但实际上可以起到保护作用，并从群体中清除受损的细胞。如果利用得当，它可能会导致开发新药物，其目的不是破坏组织，而是使稳态机制能够控制肿瘤的扩展。在这种情况下，有害或有益反应的水平将与细胞群体所携带的背景损伤以及决定对损伤的反应的遗传程序有关。当试图预测涉及放射线和其他细胞毒剂的混合疗法的后果时，这一重点可能很重要。在这篇综述中，我们对电离辐射诱发旁观者效应的潜在机制的现有知识进行了综述，并探讨了如何利用旁观者效应来生产旨在稳定组织稳态而不是稳定组织的新一代抗癌药物的问题。考虑组织破坏。
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【肌营养不良症的遗传修饰因子：对治疗的意义。】
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DOI：10.1016/j.bbadis.2006.06.013
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BACKGROUND & AIMS: :The genetic understanding of the muscular dystrophies has advanced considerably in the last two decades. Over 25 different individual genes are now known to produce muscular dystrophy, and many different "private" mutations have been described for each individual muscular dystrophy gene. For the more common forms of muscular dystrophy, phenotypic variability can be explained by precise mutations. However, for many genetic mutations, the presence of the identical mutation is associated with marked phenotypic range that affects muscle function as well as cardiac function. The explanation for phenotype variability in the muscular dystrophies is only now being explored. The availability of genetically engineered animal models has allowed the generation of single mutations on the background of highly inbred strain. Phenotypic variation that is altered by genetic background argues for the presence of genetic modifier loci that can ameliorate or enhance aspects of the dystrophic phenotype. A number of individual genes have been implicated as modifiers of muscular dystrophy by studies in genetically engineered mouse models of muscular dystrophy. The value of these genes and products is that the pathways identified through these experiments may be exploited for therapy.背景与目标： 在过去的二十年中，人们对肌肉营养不良的遗传学认识有了很大的提高。现在已知产生肌营养不良症的超过25个不同的个体基因，并且对于每个个体肌营养不良症基因已经描述了许多不同的“私人”突变。对于更常见的肌肉营养不良形式，表型变异性可以通过精确的突变来解释。然而，对于许多遗传突变，相同突变的存在与影响肌肉功能以及心脏功能的显着表型范围有关。肌肉营养不良症的表型变异性的解释目前才被探索。基因工程动物模型的可用性允许在高度近交系的背景下产生单个突变。由遗传背景改变的表型变异主张存在可以改善或增强营养不良表型方面的遗传修饰基因座。通过对肌营养不良症的基因工程小鼠模型的研究，许多个体基因被认为是肌营养不良症的修饰因子。这些基因和产物的价值在于通过这些实验确定的途径可用于治疗。
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5 Up to one third of individual cardiac patients have a decline in quality of life post-intervention.
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【多达三分之一的心脏病患者的干预后生活质量下降。】
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DOI：10.1080/14017430600784343
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BACKGROUND & AIMS: OBJECTIVE:To investigate clinically relevant intra-individual and mean changes in health-related quality of life (HRQoL) with the Short Form-36 Health Survey (SF-36) need to acknowledge that SF-36 is trademarked ie: SF-36(R) following cardiac intervention for Australian and Danish patients. DESIGN:Prospective observational study in tertiary cardiac centres in Townsville, Queensland, Australia and Copenhagen, Denmark. Two hundred coronary artery bypass graft surgery (CABG) patients of two Townsville hospitals, and 47 CABG or percutaneous coronary intervention (PCI) patients of a Copenhagen hospital. The main outcome measures are eight SF-36 health subscales at baseline and six months post-intervention. RESULTS:Australian and Danish patients experienced similar HRQoL pre-intervention. By six months post-intervention, patients experienced a significant mean improvement in all subscales of the SF-36 survey (p < or = 0.05), although up to 27% of patients had a clinically significant decline in HRQoL from baseline. CONCLUSIONS:These results demonstrate that it is necessary to investigate intra-individual changes in HRQoL as well as group mean changes as they produce different conclusions. In addition, establishing clinically significant intra-individual change standards may assist researchers and clinicians in determining whether an individual may benefit from therapy or intervention.背景与目标： 目的：要通过36型健康调查（SF-36）调查与健康相关的生活质量（HRQoL）的临床相关个人和平均变化，需要承认SF-36是商标，即：SF-36（ R）对澳大利亚和丹麦患者进行心脏干预后。
设计：在澳大利亚昆士兰州汤斯维尔和丹麦哥本哈根的三级心脏中心进行前瞻性观察研究。两家汤斯维尔医院的200例冠状动脉搭桥术（CABG）患者，以及哥本哈根医院的47例CABG或经皮冠状动脉介入治疗（PCI）患者。主要结果指标是基线时和干预后六个月的八个SF-36健康子量表。
结果：澳大利亚和丹麦患者经历了类似的HRQoL干预前。干预后六个月，患者在SF-36调查的所有子量表中均经历了显着的平均改善（p <或= 0.05），尽管高达27％的患者的HRQoL与基线相比有临床上的显着下降。
结论：这些结果表明，有必要研究HRQoL的个体内部变化以及群体均值变化，因为它们会产生不同的结论。此外，建立具有临床意义的个体内部变更标准可能有助于研究人员和临床医生确定个人是否可以从治疗或干预中受益。 -
【麻醉师术前评估心输出量储备和输血可能性的差异：一项前瞻性研究。】
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DOI：10.1177/0310057X0603400407
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BACKGROUND & AIMS: :The aim of this pilot study was to investigate anaesthetists' assessment of the ability of patients to increase cardiac output over a range of clinical scenarios and of their perceived 'likelihood of transfusion' in these scenarios. Specialist anaesthetists were given a questionnaire with clinical cues in the form of diagnoses about theoretical patients. They were asked to use 100 mm visual analogue scales (VAS) for their assessments of each patient's cardiac reserve and their 'likelihood of transfusion' of these patients; the endpoints of the VAS being 'Very low' (0 mm) to 'High' (100 mm), and 'Do not transfuse' (0 mm) to 'Transfuse' (100 mm) respectively. The assessment of patients' cardiac output reserve by anaesthetists (n = 54) showed great variation; for example, a patient with severe aortic stenosis was perceived overall to have a limited ability to increase cardiac output (mean VAS 16 mm) but there was considerable variation between anaesthetists (25-75 percentiles 10 mm to 21 mm). Assessment of 'likelihood of transfusion' (n = 42) also had great variation; as an example a patient with 'angina' with a haemoglobin of 95 g l(-1) was perceived overall to have an average likelihood of transfusion of 50 mm, but the 25-75 percentiles ranged from 33 mm to 71 mm. This study suggests that inter-anaesthetist variability in the assessment of a patient's 'cardiac output reserve' and his 'likelihood of transfusion' is large.背景与目标： ：这项初步研究的目的是调查麻醉师对患者在一系列临床情况下增加心输出量的能力以及他们在这些情况下感知的“输血可能性”的评估。专家麻醉师接受了有关临床线索的问卷调查，形式是对理论患者的诊断。他们被要求使用100 mm视觉模拟量表（VAS）评估每个患者的心脏储备和这些患者的“输血可能性”。 VAS的端点分别为“非常低”（0毫米）至“高”（100毫米）和“请勿输液”（0毫米）至“输液”（100毫米）。麻醉师对患者心输出量储备的评估（n = 54）显示出很大的差异。例如，总的来说，严重的主动脉瓣狭窄患者的心输出量增加能力有限（平均VAS 16毫米），但是麻醉师之间的差异很大（10毫米至21毫米为25-75％）。对“输血可能性”的评估（n = 42）也有很大差异。例如，患有“心绞痛”且血红蛋白为95 g l（-1）的患者总体上被认为平均输血的可能性为50 mm，但25-75％的范围为33 mm至71 mm。这项研究表明，麻醉师之间在评估患者的“心输出量储备”和“输血可能性”方面存在很大差异。
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【睡眠剥夺与连续的睡眠阶段相结合可作为抑郁症的速效疗法：在有药和无药患者中进行的开放式试验。】
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DOI：10.1176/ajp.154.6.870
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BACKGROUND & AIMS: OBJECTIVE:The authors' goal was to test the hypothesis that the antidepressant effect of total sleep deprivation can be maintained by initially avoiding sleep during a supposedly "critical" time period in the early morning.
METHOD:They studied 33 inpatients with major depression, melancholic type, all of whom responded positively to total sleep deprivation. Twelve of the patients were men and 21 were women; their mean age was 46.7 years (SD = 13.7). After total sleep deprivation, the patients started a sleep schedule from 5:00 p.m. to 12:00 midnight, which then was shifted back by 1 hour each day until a sleep time of 11:00 p.m. to 6:00 a.m. was reached.
RESULTS:Twenty (61%) of the 33 patients who responded to total sleep deprivation with an improved state of mood maintained this improvement during sleep phase advance therapy. Drug-free and medicated patients did not differ from each other.
CONCLUSIONS:The rapid amelioration of mood observed with total sleep deprivation can be preserved with a succeeding phase shift of the sleep period.
背景与目标： 目标：作者的目标是检验以下假设：通过在清晨所谓的“关键”时间段内最初避免入睡，可以维持完全睡眠剥夺的抗抑郁作用。
< br> METHOD ：他们研究了33例重度抑郁，忧郁型抑郁症住院患者，所有患者对总睡眠不足的反应都积极。病人中有十二名是男性，二十一名是女性；他们的平均年龄为46.7岁（SD = 13.7）。在完全睡眠剥夺之后，患者从下午5:00开始睡眠计划。到午夜12:00，然后每天回移1小时，直到晚上11:00的睡眠时间。
结果：在对总睡眠剥夺有改善的情绪状态的33例患者中，有20例（61％）在睡眠阶段保持了这种改善提前治疗。没有药物治疗和药物治疗的患者之间没有什么不同。
结论：随着睡眠时间的相移，可以保持完全睡眠剥夺所观察到的情绪快速改善。 。
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【CHADS2评分与阵发性房颤患者抗心律失常药物治疗疗效之间的关系。】
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DOI：10.1253/circj.cj-12-0854
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BACKGROUND & AIMS: BACKGROUND:The Cardiac failure, Hypertension, Age, Diabetes, Stroke [Doubled] (CHADS(2)) score is a useful scheme for risk stratification of thromboembolism patients, but there is little information about its usefulness for the evaluation of antiarrhythmic drug (AAD) therapy. METHODS AND RESULTS:This study included 459 paroxysmal atrial fibrillation (AF) patients (309 men, mean age 66 ± 12 years, mean follow-up 50 ± 35 months) and prophylactic efficacy was analyzed on the basis of CHADS(2) score. (1) Survival rates free from AF recurrence at 1, 6, 12 and 24 months were, respectively, 89%, 74%, 63% and 47% in score-0 group (n=152); 92%, 68%, 59% and 48% in score-1 group (n=158); 86%, 64%, 56% and 46% in score-2 group (n=84); 81%, 65%, 51% and 35% in score-3 group (n=43); and 68%, 50%, 36% and 18% in ≥ score-4 group (n=22) (P<0.05; score-0, score-1 or score-2 vs. ≥ score-4 group). (2) Survival rates free from progression to chronic AF at 12, 36, 60 and 90 months were, respectively, 95%, 93%, 91% and 89% in score-0 group; 97%, 91%, 89% and 88% in score-1 group; 96%, 93%, 88% and 83% in score-2 group; 91%, 74%, 67% and 60% in score-3 group; and 91%, 82%, 68% and 55% in ≥ score-4 group (P<0.01; score-0, score-1 or score-2 vs. ≥ score-4 group). (3) In multivariate logistic regression analysis adjusted for potentially confounding variables, CHADS(2) score was associated with AF recurrence (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.16-1.81, P<0.001), and progression to chronic AF during AAD therapy (OR 1.64, 95% CI 1.04-2.69, P<0.001). CONCLUSIONS:When using a rhythm control strategy, the CHADS(2) score is a useful scheme for predicting the outcome of AAD treatment of patients with paroxysmal AF.背景与目标： 背景：心脏衰竭，高血压，年龄，糖尿病，中风[加倍]（CHADS（2））评分是对血栓栓塞患者进行风险分层的有用方案，但有关其对抗心律不齐药物（AAD）评估的有用性的信息很少） 治疗。
方法与结果：这项研究纳入459例阵发性房颤（AF）患者（309名男性，平均年龄66±12岁，平均随访50±35个月），并根据CHADS（2）评分分析了其预防性疗效。 （1）得分为0的组在1、6、12和24个月无房颤复发的生存率分别为89％，74％，63％和47％（n = 152）；得分1组（n = 158）为92％，68％，59％和48％；得分2组分别为86％，64％，56％和46％（n = 84）；得分3组（n = 43）分别为81％，65％，51％和35％； ≥4分组（n = 22）分别为68％，50％，36％和18％（P <0.05； 0分，1分或2分与≥4分组比较）。 （2）在0级评分组中，在12、36、60和90个月无进展为慢性房颤的生存率分别为95％，93％，91％和89％；得分1组分别为97％，91％，89％和88％；得分2组分别为96％，93％，88％和83％；分数3组的比例分别为91％，74％，67％和60％； ≥4分组分别为91％，82％，68％和55％（P <0.01； 0分，1分或2分与≥4分组比较）。 （3）在针对潜在混杂变量进行调整的多因素logistic回归分析中，CHADS（2）评分与房颤复发相关（几率[OR] 1.45、95％置信区间[CI] 1.16-1.81，P <0.001）和进展到AAD治疗期间的慢性房颤（OR 1.64，95％CI 1.04-2.69，P <0.001）。
结论：使用节律控制策略时，CHADS（2）评分是预测阵发性房颤患者AAD治疗结果的有用方案。 -
【放射性碘125种子定位在新辅助化疗后在保乳治疗中的作用。】
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DOI：10.1093/annonc/mds475
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BACKGROUND & AIMS: BACKGROUND:Neoadjuvant chemotherapy (NAC) is increasingly used in the framework of breast-conserving therapy (BCT). Localization of the initial tumor is essential to guide surgical resection after NAC. This study describes the results obtained with I-125 seed localization in BCT including NAC. PATIENTS AND METHODS:Between January 2009 and December 2010, 85 patients treated with NAC and BCT after I-125 seed localization were included. Radiological and pathological response and resection margins were retrospectively evaluated. RESULTS:BCT was carried out in 85 patients without secondary local excisions. Nineteen patients with unifocal tumors and seven patients with multifocal tumors showed a complete pathological response (P = 0.18). Tumor-free resection margins were obtained in 78 patients (50 patients with unifocal and 28 patients with multifocal tumors, P = 0.27). Focally involved margins were found in four patients (two patients with a unifocal and two patients with a multifocal tumor, P = 0.27). A subsequent mastectomy was carried out in three patients (two patients with multifocal tumors, P = 0.29). CONCLUSIONS:BCT after NAC can be carried out successfully after initial localization with I-125 seeds in both unifocal and multifocal breast tumors with complete resection rates of >90%.背景与目标： 背景：新辅助化疗（NAC）越来越多地用于保乳治疗（BCT）的框架中。初始肿瘤的定位对于NAC术后的手术切除至关重要。这项研究描述了I-125种子在包括NAC的BCT中的定位所获得的结果。
患者和方法：2009年1月至2010年12月，纳入I-125种子定位后接受NAC和BCT治疗的85例患者。回顾性评估放射学和病理学反应以及切除范围。
结果：85例患者均进行了BCT检查，未进行次要局部切除。 19例单灶性肿瘤患者和7例多灶性肿瘤患者表现出完全的病理反应（P = 0.18）。 78例患者获得了无肿瘤切除切缘（50例单灶患者和28例多灶肿瘤患者，P = 0.27）。在四名患者中发现了局部受累的切缘（两名单灶患者和两名多灶性肿瘤患者，P = 0.27）。随后在三名患者中进行了乳房切除术（两名患有多灶性肿瘤的患者，P = 0.29）。
结论：NAC后的BCT可以在单灶和多灶乳腺肿瘤中首次定位I-125种子后成功进行，完全切除率> 90％。 -
【基因治疗可减少色素失禁模型中的癫痫发作。】
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DOI：10.1002/ana.24981
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BACKGROUND & AIMS: OBJECTIVE:Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. METHODS:In a mouse model of IP, we administered a single intravenous dose of the adeno-associated virus (AAV) vector, AAV-BR1-CAG-NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood-brain barrier (BBB) were monitored. RESULTS:The endothelium-targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. INTERPRETATION:The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. Ann Neurol 2017;82:93-104.背景与目标： 目的：色素失禁（IP）是一种遗传性疾病，可导致严重的神经系统症状，例如癫痫发作，但尚无特效治疗方法。 IP是由使Nemo基因失活的致病变体引起的。通过基因疗法替代Nemo可能会提供治疗益处。
方法：在IP小鼠模型中，我们施用了单次静脉内剂量的腺相关病毒（AAV）载体AAV-BR1-CAG-NEMO，将Nemo基因传递至脑内皮。监测自发性癫痫发作和血脑屏障（BBB）的完整性。
结果：内皮靶向基因治疗改善了血脑屏障的完整性。同时，它减少了癫痫发作的发生并延缓了发作的发生。静脉内注射AAV-BR1-CAG-NEMO载体的新生小鼠在载体注射后11个月未发生肝细胞癌或其他重大不良反应，表明该载体具有良好的安全性。
解释：数据表明，血脑屏障是抗癫痫治疗的目标，更具体地说，它为脑内皮靶向基因疗法在IP中的治疗益处提供了证据。 Ann Neurol 2017; 82：93-104。 -
【贝伐单抗和厄洛替尼的靶向治疗针对复发性胶质母细胞瘤患者的分子情况进行了定制。初步经验。】
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DOI：10.1007/s00701-012-1536-5
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BACKGROUND & AIMS: BACKGROUND:Advances in comprehension of molecular biology of glioblastoma (GBM) have led to the development of targeted therapies. The aim of the present study was to evaluate the efficacy and safety of a targeted therapeutic approach in which administration of bevacizumab and erlotinib was tailored on the molecular profile of recurrent GBM. METHODS:We prospectively enrolled ten adult patients suffering from recurrent GBM who had undergone surgical resection and standard chemo-radiotherapy. Tumor tissue was assessed for the expression of EGFRvIII and MGMT promoter methylation by RT-PCR, and for PTEN and VEGF expression by immunohistochemistry. Normal PTEN status was required for inclusion. Patients with VEGF overexpressing tumors (10/10) were treated with bevacizumab (10 mg/kg iv every 2 weeks in 6-week cycles); patients whose tumor expressed EGFRvIII (4/10) added erlotinib (150 mg/day orally; 300 mg/day if on enzyme-inducing antiepileptic drugs). Therapy was continued until disease progression or unacceptable toxicity. Primary endpoints of the study were response rate (RR), 6-month progression-free survival (PFS-6), and safety profile. RESULTS:The RR and PFS-6 were 100 % (4/4) and 50 % (3/6) in patients treated with bevacizumab+erlotinib (n = 4) and bevacizumab (n = 6), respectively. In the whole cohort (n = 10), RR and PFS-6 were both 70 % (7/10); median PFS and overall survival (OS) were 8.0 (3.0-31.0) and 9.5 (5.0-31.0) months, respectively. No grade 3/4 adverse events were observed; three patients treated with bevacizumab+erlotinib displayed grade 1/2 rash not requiring dose reduction; one patient treated with bevacizumab developed intratumoral hemorrhage requiring treatment discontinuation. CONCLUSION:To our knowledge, this is the first study on recurrent GBM in which administration of bevacizumab and erlotinib was tailored on the molecular profile of the patient's tumor. Although we treated a limited number of patients, we obtained significantly higher RR and PFS-6 than those reported in a previous trial lacking molecular tumor analysis.背景与目标： 背景：胶质母细胞瘤（GBM）分子生物学的研究进展已导致靶向治疗的发展。本研究的目的是评估靶向治疗方法的疗效和安全性，在该治疗方法中，贝伐单抗和厄洛替尼的给药根据复发性GBM的分子特征进行了调整。
方法：我们前瞻性招募了10例患有GBM复发的成人患者，这些患者均接受了手术切除和标准化学放疗。通过RT-PCR评估肿瘤组织中EGFRvIII和MGMT启动子甲基化的表达，并通过免疫组织化学评估PTEN和VEGF的表达。包括在内需要正常的PTEN状态。用贝伐单抗（10 mg / kg，每2周静脉注射，每6周一次）治疗VEGF过表达肿瘤（10/10）的患者；肿瘤表达EGFRvIII（4/10）的患者加用厄洛替尼（口服150毫克/天；如果使用酶诱导的抗癫痫药，则为300毫克/天）。继续治疗直至疾病进展或出现不可接受的毒性。该研究的主要终点是缓解率（RR），6个月无进展生存期（PFS-6）和安全性。
结果：接受贝伐单抗厄洛替尼（n = 4）和贝伐单抗（n = 6）治疗的患者的RR和PFS-6分别为100％（4/4）和50％（3/6）。在整个队列中（n = 10），RR和PFS-6均为70％（7/10）; PFS中位数和总生存期（OS）分别为8.0（3.0-31.0）和9.5（5.0-31.0）个月。没有观察到3/4级不良反应；三名接受贝伐单抗厄洛替尼治疗的患者出现1/2级皮疹，无需降低剂量；一名接受贝伐单抗治疗的患者发生了肿瘤内出血，需要中止治疗。
结论：据我们所知，这是关于复发性GBM的第一项研究，其中根据患者肿瘤的分子特征量身定制了贝伐单抗和厄洛替尼的给药。尽管我们治疗的患者数量有限，但与先前缺乏分子肿瘤分析的试验中报道的结果相比，我们获得了更高的RR和PFS-6。 -
【睡眠障碍和相关危险因素的负担：中国艾滋病毒感染者抗逆转录病毒疗法的横断面调查。】
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DOI：10.1038/s41598-017-03968-3
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BACKGROUND & AIMS: :This study evaluated the prevalence and factors associated with sleep disturbance in a large cohort of HIV-infected patients across China. A cross-sectional study was conducted among HIV-infected patients on antiretroviral therapy at 20 AIDS clinics. The Pittsburgh Sleep Quality Index was self-administered by subjects. Socio-demographic characteristics, medical history and HIV-related clinical data were collected. 4103 patients had complete data for analysis. Sleep disturbances were observed in 43.1% of patients. Associated factors in multivariable analysis included psychological factors: anxiety (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.44-4.00; P < 0.001), depression (OR, 2.09; 95% CI, 1.70-2.57; P < 0.001), and both anxiety and depression (OR, 5.90; 95% CI, 4.86-7.16; P < 0.001); sociodemographic factors: MSM (OR, 1.26; 95% CI, 1.04-1.52; P = 0.018), being single (OR, 1.45; 95%CI 1.21-1.74; P < 0.001), higher education (OR, 1.25; 95% CI, 1.03-1.53; P = 0.025); and clinical factors: suboptimal adherence (OR,1.51; 95% CI,1.23-1.85; P < 0.001), regimen-switching (OR, 1.94; 95% CI, 1.12-3.35; P = 0.018), and antidepressant use (OR, 1.98; 95% CI, 1.47-2.67; P = 0.044). Prevalence of sleep disturbance is high in this large Chinese cohort. Associated factors appear related to psychological and social-demographic factors. Health workers may consider routinely assessing sleep disturbances among HIV-infected patients, especially in the first three months after HIV diagnosis, and referring for mental health services, which may positively impact adherence to treatment.背景与目标： ：这项研究评估了中国一大批感染HIV的患者的患病率和与睡眠障碍相关的因素。在20个艾滋病诊所中，对接受HIV感染的患者进行了抗逆转录病毒治疗的横断面研究。匹兹堡睡眠质量指数由受试者自行管理。收集了社会人口统计学特征，病史和与艾滋病相关的临床数据。 4103例患者有完整的数据需要分析。在43.1％的患者中观察到睡眠障碍。多变量分析中的相关因素包括心理因素：焦虑（赔率[OR]，3.13； 95％置信区间[CI]，2.44-4.00； P <0.001），抑郁（OR，2.09； 95％CI，1.70-2.57；抑郁（OR）。 P <0.001），以及焦虑和抑郁（OR，5.90； 95％CI，4.86-7.16； P <0.001）；社会人口统计学因素：MSM（OR，1.26; 95％CI，1.04-1.52; P = 0.018），单身（OR，1.45; 95％CI 1.21-1.74; P <0.001），高等教育程度（OR，1.25; 95％CI，1.03-1.53; P = 0.025）;临床因素：次最佳依从性（OR，1.51; 95％CI，1.23-1.85; P <0.001），方案转换（OR，1.94; 95％CI，1.12-3.35; P =）0.018），以及抗抑郁药的使用（OR ，1.98； 95％CI，1.47-2.67； P ＝ 0.044）。在这个庞大的中国人群中，睡眠障碍的患病率很高。相关因素似乎与心理和社会人口统计学因素有关。卫生工作者可以考虑常规评估艾滋病毒感染患者的睡眠障碍，尤其是在艾滋病毒确诊后的前三个月，并寻求心理健康服务，这可能会对坚持治疗产生积极影响。
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【低水平激光治疗对链脲佐菌素诱发的糖尿病大鼠骨缺损愈合的影响：组织学和形态计量学评估。】
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DOI：10.1080/14764172.2017.1341048
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BACKGROUND & AIMS: BACKGROUND:The aim of the present study was to evaluate the effects of low-level laser therapy (LLLT) on the healing of bone defects in rats with streptozotocin (STZ)-induced DM. METHODS:28 male Sprague-Dawley rats were used in this study. 14 animals received a single dose of STZ intraperitoneally (65 mg/kg) to induce Type I DM, whereas others were injected only with sterile saline solution. Four weeks later, standard bone defects were created in the tibiae of rats. Surgical wounds in one group from each of the diabetic and non-diabetic animals were irradiated with diode laser for every other day for 4 weeks and they were described as DM + LLLT and CONT + LLLT groups, respectively. Remaining two groups received no laser treatment. New bone formation, osteoblast and blood vessel counts were calculated in histologic sections. RESULTS:DM group had significantly smaller bone area and lower blood vessel count when compared to DM + LLLT, CONT and CONT + LLLT groups (p < 0.05 for each). CONT and CONT + LLLT groups had significantly larger bone area than DM + LLLT group (p < 0.05 for both). CONCLUSIONS:LLLT application promoted vascularization and new bone formation in animals with DM to a limited extent, since it was unable to support the healing process up to the level of non-diabetic animals.背景与目标： 背景：本研究的目的是评估低剂量激光疗法（LLLT）对链脲佐菌素（STZ）诱导的DM大鼠骨缺损愈合的作用。
方法：采用28只雄性Sprague-Dawley大鼠。 14只动物腹膜内接受单剂STZ（65 mg / kg）诱导I型DM，而其他动物仅注射无菌盐溶液。四周后，在大鼠胫骨中形成了标准的骨缺损。每隔一天用二极管激光照射来自糖尿病和非糖尿病动物中每组的一组手术伤口，持续4周，分别称为DM LLLT组和CONT LLLT组。其余两组未接受激光治疗。在组织学切片中计算新的骨形成，成骨细胞和血管计数。
结果：与DM LLLT，CONT和CONT LLLT组相比，DM组的骨面积显着更小，血管计数更低（每组p <0.05）。 CONT和CONT LLLT组的骨面积明显大于DM LLLT组（两者均p <0.05）。
结论：LLLT的应用在一定程度上促进了DM动物的血管形成和新骨形成，因为它无法支持非糖尿病动物的愈合过程。 -
14 Regional venous oxygen saturation versus mixed venous saturation after paediatric cardiac surgery.
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【小儿心脏手术后局部静脉血氧饱和度与混合静脉血饱和度的关系。】
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DOI：10.1111/aas.12016
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BACKGROUND & AIMS: BACKGROUND:Central venous oxygen saturation (ScvO2) remains the gold standard surrogate for tissue oxygen extraction in paediatric cardiac surgery. Near-infrared spectroscopy (NIRS) has been developed as a non-invasive diagnostic tool for regional oxygen saturation. The aim was to compare regional oxygen saturation measured by NIRS with ScvO2 in postoperative paediatric cardiac patients. METHODS:In this prospective study, we included newborns and infants younger than 45 days undergoing heart surgery. We recorded continuous ScvO2 and NIRS regional saturation placed on the forehead (B) and right flank (S) for 48 h postoperatively. A Bland-Altman's analysis was used to assess the agreement between these measurements. RESULTS:A total of 23 patients were included with a median age of 12 days (2-46) and median weight of 3.1 kg (2.3-4.47). The mean difference (MD) ScvO2- B NIRS was 10.45% with limits of agreement (LOA) -17.23 to 38.13% and ScvO2- S NIRS MD 7.16% with LOA: -25.51 to 39.84%. The single ventricle ScvO2- S NIRS subgroup had MD within ± 5%; however, wide LOA was observed. The remaining subgroups showed MD nearly above ± 5%, with wide LOA. CONCLUSIONS:The regional oxygen saturation of brain and kidney did not match ScvO2 as estimation of global tissue perfusion. Nevertheless, NIRS may still provide information regarding regional circulation that may help in the management of neonatal cardiac surgery patients.背景与目标： 背景：中央静脉血氧饱和度（ScvO2）仍然是小儿心脏外科手术中组织氧提取的金标准。近红外光谱法（NIRS）已被开发为一种用于区域血氧饱和度的非侵入性诊断工具。目的是比较由NIRS和ScvO2测得的小儿心脏术后患者的局部血氧饱和度。
方法：在这项前瞻性研究中，我们纳入了接受心脏手术的45天以下的新生儿和婴儿。我们记录了连续的ScvO2和NIRS区域饱和度放置在术后48 h的前额（B）和右胁（S）上。用布兰德-奥特曼（Bland-Altman）分析来评估这些测量之间的一致性。
结果：总共纳入23名患者，中位年龄为12天（2-46），中位体重为3.1 kg（2.3-4.47）。 ScvO2-B NIRS的平均差异（MD）为10.45％，协议限制（LOA）为-17.23至38.13％，Slovo2- S NIRS MD的7.16％LOA为-25.51至39.84％。单心室ScvO2-S NIRS亚组的MD≤±5％。但是，观察到广泛的LOA。其余亚组的MD值接近±5％，LOA较宽。
结论：脑和肾脏的局部血氧饱和度与ScvO2不符，无法估计整体组织灌注。尽管如此，NIRS仍可能提供有关区域循环的信息，这可能有助于新生儿心脏外科手术患者的管理。 -
【手性识别多沙唑嗪对映体在3个靶标中的治疗作用以及在动物实验中的不良药物反应。】
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DOI：10.1139/y2012-129
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BACKGROUND & AIMS: :Doxazosin used in benign prostatic hyperplasia has the side effects of causing hypotension and the risk of heart failure. The 3 targets of α(1A)-adrenoceptors (in the prostate), α(1D)-adrenoceptors (in the aorta), and an unknown mechanism (in the heart) are involved, respectively. We hypothesized that there is a chiral recognition of doxazosin enantiomers in the 3 targets. Using isolated rat aorta (α(1D)-adrenoceptors) and rabbit prostate (α(1A)-adrenoceptors), we examined pA(2) and pK(B) values of doxazosin enantiomers. We observed chronotropic and inotropic effects of doxazosin enantiomers in isolated rat and rabbit heart tissues. (-)Doxazosin and (+)doxazosin produced a shift to the right of concentration-contraction curves for noradrenalin (aorta) and phenylephrine (prostate smooth muscle). The pA(2) value of (-)doxazosin (8.625 ± 0.053) was smaller than (+)doxazosin (9.503 ± 0.051) in rat aorta, but their pK(B) values in rabbit prostate were the same. In rat and rabbit heart tissues, (+)doxazosin (3-30 µmol·L(-1)) significantly decreased atrial rate, and produced negative inotropic effects; however, (-)doxazosin did not affect the atrial rate, and produced positive inotropic effects in the atria. Thus, the chiral carbon atom of doxazosin does not affect its activity at the therapeutic target of α(1A)-adrenoceptors in the prostate, but significantly changes its blocking activity against α(1D)-adrenoceptors in the aorta, and produces opposite inotropic effects in the atria via an α(1)-adrenoceptor-independent mechanism.背景与目标： ：多沙唑嗪用于前列腺增生症具有引起低血压和心力衰竭风险的副作用。 α（1A）-肾上腺素受体（在前列腺中），α（1D）-肾上腺素受体（在主动脉中）和未知机制（在心脏中）的3个靶点分别涉及。我们假设在3个靶标中有手性识别多沙唑嗪对映体。使用分离的大鼠主动脉（α（1D）-肾上腺素受体）和兔前列腺（α（1A）-肾上腺素受体），我们检查了多沙唑嗪对映体的pA（2）和pK（B）值。我们观察到了多沙唑嗪对映异构体在离体大鼠和兔心脏组织中的变时性和变力作用。 （-）多沙唑嗪和（）多沙唑嗪使去甲肾上腺素（主动脉）和去氧肾上腺素（前列腺平滑肌）的浓度-收缩曲线向右移动。大鼠主动脉中（-）恶唑烷的pA（2）值（8.625±0.053）小于（）恶唑烷（9.503±0.051），但它们在兔前列腺中的pK（B）值相同。在大鼠和兔子的心脏组织中，（）多沙唑嗪（3-30 µmol·L（-1））显着降低心房率，并产生负性变力作用；然而，（-）doxazosin不会影响心房率，并在心房产生正性肌力作用。因此，多沙唑嗪的手性碳原子不影响其对前列腺中α（1A）-肾上腺素受体治疗靶点的活性，但会显着改变其对主动脉中α（1D）-肾上腺素受体的阻断活性，并产生相反的正性肌力作用通过独立于α（1）-肾上腺素受体机制的心房。
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