BACKGROUND & AIMS: :Matrix metalloproteinases (MMPs) have been the subject of intense research because of their roles in tumor metastasis and in the rise and spread of degenerative diseases such as osteo- and rheumatoid arthritis. A preliminary class of 140 druglike, small-molecule matrix metalloproteinase-3 inhibitors, intended as starting scaffolds for optimization and synthesis, has been designed in silico using a series of highly predictive three-dimensional quantitative structure-activity relationship models, including comparative molecular field analysis and comparative molecular similarity indices analysis, with docking and scoring. Thalidomide was chosen as the skeleton on which to base the new lead series, as it moderately inhibits MMP-3, is antiangiogenic, and lends itself easily to structural modifications. Most of the new compounds demonstrate medium to high predicted biological activity and good bioavailability as estimated by the octanol-water partition coefficient ClogP. Compound 102 in particular exhibits extremely favorable predicted activity against MMP-3; is moderately bioavailable; satisfies Lipinski's Rule of Five; and shows promise for further optimization, synthesis, and experimental evaluation as a potential adjunct anticancer or antirheumatic therapeutic.

背景与目标： ：基质金属蛋白酶（MMP）由于其在肿瘤转移中以及在变性疾病（例如骨和类风湿性关节炎）的发生和扩散中的作用而受到了广泛的研究。使用一系列高度预测的三维定量结构-活性关系模型，包括比较分子场，在计算机上设计了初步的140种药物样小分子基质金属蛋白酶3抑制剂，旨在作为优化和合成的起始支架。分析和比较分子相似性指数分析，以及对接和评分。选择沙利度胺作为新铅系列的基础，因为它能适度抑制MMP-3，具有抗血管生成作用，并易于进行结构修饰。正如辛醇-水分配系数ClogP所估计的那样，大多数新化合物都具有中等至较高的预测生物活性和良好的生物利用度。特别地，化合物102对MMP-3表现出非常有利的预测活性。具有中等生物利用度；满足Lipinski的五法则；并有望进一步优化，合成和进行实验评估，作为潜在的辅助抗癌药或抗风湿药。

BACKGROUND & AIMS: :We have constructed a physical map of a > 2-Mb region on mouse chromosome 6 that contains the natural killer gene complex (NKC). The map comprises a contig of 14 overlapping yeast artificial chromosomes onto which we positioned 25 NKC markers. NKC genetically linked genes encode > 17 proteins that directly control innate NK cell-mediated tumor lysis and disease resistance. Herein we show that Nkrp1 genes are clustered in a region flanked by A2m and Cd69 genes and that most Ly49 genes are clustered in a distal region -1 Mb distant. Importantly, syntenic intervals of mouse chromosome 6 and human chromosome 12p that include the NKC are conserved. NKC species conservation suggests that the human NKC may contain orthologues for the mouse viral disease resistance genes, Cmv1 and Rmp1. The high-resolution NKC map will facilitate investigation of NKC gene regulation and identification of phenotypically defined gene products that confer NK cell defense against viral pathogens.

背景与目标： ：我们在小鼠染色体6上构建了一个大于2-Mb区域的物理图，其中包含自然杀伤基因复合体（NKC）。该图包括14个重叠的酵母人工染色体的重叠群，我们在其上定位了25个NKC标记。 NKC遗传连锁基因编码> 17种蛋白质，这些蛋白质直接控制先天NK细胞介导的肿瘤溶解和疾病抵抗力。在本文中，我们显示Nkrp1基因聚集在A2m和Cd69基因侧翼的区域中，而大多数Ly49基因聚集在距离-1 Mb远的区域中。重要的是，保留了包含NKC的小鼠6号染色体和人类12p号染色体的同音间隔。 NKC物种保守性表明，人NKC可能含有小鼠病毒疾病抗性基因Cmv1和Rmp1的直向同源物。高分辨率的NKC图谱将有助于NKC基因调控的研究和表型定义的基因产物的鉴定，这些产物赋予NK细胞防御病毒病原体的能力。

BACKGROUND & AIMS: Here we describe the cloning of the human Achaete Scute Homologue 2 (HASH2) gene, officially designated ASCL2 (Achaete Scute complex like 2), a homologue of the Drosophila Achaete and Scute genes. In mouse, this gene is imprinted and maps to chromosome 7. We mapped the human homologue close to IGF2 and H19 at 11p15.5, the human region syntenic with mouse chromosome 7, indicating that this imprinted region is highly conserved in mouse and man. HASH2 is expressed in the extravillus trophoblasts of the developing placenta only. The lack of HASH2 expression in non-malignant hydatidiform (androgenetic) moles indicates that HASH2 is also imprinted in man.

背景与目标： 在这里，我们描述了人类Achaete Scute同源物2（HASH2）基因的克隆，该基因正式命名为ASCL2（Achaete Scute复合物类似2），是果蝇Achaete和Scute基因的同源物。在小鼠中，该基因被印迹并定位于7号染色体。我们在11p15.5处绘制了与IGF2和H19接近的人类同源基因，该区域与小鼠7号染色体呈同义关系，表明该印迹区域在小鼠和人类中高度保守。 HASH2仅在发育中的胎盘的绒毛外滋养细胞中表达。非恶性葡萄胎（雄激素性）痣中缺乏HASH2表达，这表明HASH2也被印在人体内。

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。 24小时的加权平均AUC为0.21 Lxmin和0.22 Lxmin，与12小时前剂量前FEV1相比，SFC和FBC的平均变化分别为0.21 L和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: Poly(1-vinyl-2-pyrrolidinone) (PVP) and copolymers of 1-vinyl-2-pyrrolidinone are insoluble in water when crosslinked but they can absorb very large amounts of water to become syringe-injectable hydrogels. Such gels have been investigated recently as potential substitutes for the vitreous humour in the eye. In this study, during the cytotoxic evaluation by sulforhodamine B colorimetric assay of variously crosslinked PVP gels, it was found that many of them showed protective/growth promoting effects on 3T3 mouse fibroblasts in static cultures, a phenomenon encountered previously only with aqueous solutions of a limited number of natural or synthetic polymers. Particularly, the gels crosslinked with diethylene glycol dimethacrylate (DEGDMA) induced a significant enhancement of cell proliferation, especially in serum-free cultures. No correlation between this effect and the essential gel properties (chemical composition, viscoelasticity and equilibrium water content) could be established. The study demonstrated that crosslinked PVP hydrogels showed a serum-like growth promoting effect on an anchorage-dependent cell line, which may be due to physical protection, inability of the insoluble gels to penetrate cell membranes, and their ability to mimic the extracellular matrix.

背景与目标： 聚（1-乙烯基-2-吡咯烷酮）（PVP）和1-乙烯基-2-吡咯烷酮的共聚物在交联时不溶于水，但它们可以吸收大量的水，成为可注射注射器的水凝胶。最近已经研究了这种凝胶作为眼睛中玻璃体液的潜在替代物。在这项研究中，通过磺酰罗丹明B比色法对各种交联的PVP凝胶进行细胞毒性评估时，发现它们中的许多在静态培养物中对3T3小鼠成纤维细胞均显示出保护/促生长作用，这种现象以前仅在A的水溶液中会遇到。数量有限的天然或合成聚合物。特别地，用二甘醇二甲基丙烯酸甲酯（DEGDMA）交联的凝胶诱导细胞增殖的显着增强，尤其是在无血清培养物中。在这种作用与基本的凝胶性质（化学组成，粘弹性和平衡水含量）之间没有相关性。该研究表明，交联的PVP水凝胶对锚定依赖性细胞系显示出类似血清的生长促进作用，这可能是由于物理保护，不溶性凝胶无法穿透细胞膜以及它们模仿细胞外基质的能力所致。

BACKGROUND & AIMS: :A part of the new biosynthetic gene cluster for 2-deoxystreptamine-containing antibiotics was identified from Streptoalloteichus hindustanus. The alloH gene in the gene cluster was deduced to encode 2-deoxy-scyllo-inosose synthase and the expressed protein AlloH was confirmed to have this enzyme activity. Furthermore, biochemical properties of AlloH were studied.

背景与目标： ：从印度链球菌中鉴定出了一种新的生物合成基因簇，用于含有2-脱氧链胺的抗生素。推导了基因簇中的alloH基因编码2-脱氧-鞘氨醇合酶，并证实表达的蛋白AlloH具有这种酶活性。此外，研究了AlloH的生化特性。

BACKGROUND & AIMS: :Adenovirus infection results in the suppression of cellular protein synthesis, but the mechanism has not been established. In this report we demonstrate that the shut-off of cellular protein synthesis by adenovirus is prevented in cells by treatment with the drug 2-aminopurine. Treatment with 2-aminopurine is shown to prevent suppression of cellular translation without disrupting the normal viral block in the transport of cellular mRNAs from the nucleus to the cytoplasm. We show that viral suppression of cellular protein synthesis occurs concomitant with activation of the interferon-induced double-stranded RNA-activated inhibitor (DAI), a protein kinase, and phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha), but that prevention of host cell shut-off by 2-aminopurine occurs without a decrease in kinase activity or a dephosphorylation of eIF-2 alpha. Results are presented that indicate that activation of DAI kinase and phosphorylation of eIF-2 alpha may be required but are not sufficient to achieve inhibition of cellular protein synthesis during adenovirus infection. We suggest that other events, in particular the modification of additional initiation factors, are likely involved in viral inhibition of cellular translation.

背景与目标： ：腺病毒感染导致细胞蛋白质合成受到抑制，但该机制尚未建立。在本报告中，我们证明了通过用2-氨基嘌呤药物治疗可防止腺病毒关闭细胞蛋白质合成。已显示用2-氨基嘌呤处理可防止细胞翻译受到抑制，而不会破坏细胞mRNA从细胞核到细胞质的运输过程中的正常病毒阻滞。我们显示病毒抑制细胞蛋白质合成的发生与干扰素诱导的双链RNA激活的抑制剂（DAI），蛋白激酶和真核生物起始因子2（eIF-2 alpha）的α亚基的磷酸化的激活同时发生。 ，但可以防止2-氨基嘌呤阻止宿主细胞的关闭，而不会降低激酶活性或eIF-2α的去磷酸化。结果表明，可能需要DAI激酶的激活和eIF-2 alpha的磷酸化，但不足以抑制腺病毒感染期间细胞蛋白质合成。我们建议其他事件，特别是其他起始因子的修饰，可能与细胞翻译的病毒抑制有关。

BACKGROUND & AIMS: Tricyclic antidepressants have been shown to be useful for the treatment of pain of varying etiology. Monoaminergic systems seem to be implicated in this phenomenon. In this study, the influence of the selective beta 1- (CGP 20712A) and beta 2- (ICI 118551) adrenergic blockers on the antinociceptive effect of desipramine and nortriptyline was studied in mice using physical and chemical nociceptive tests that implicate different levels of sensory-motor integration in the central nervous system (CNS). An activity test was performed to detect "false positive" or "false negative" results. Results obtained show that both CGP 20712A and ICI 118551 are able to antagonize the antinociceptive effect of these antidepressants in physical tests (hot-plate and tail-flick). However, in chemical tests (acetic acid and formalin), the analgesic effect of the antidepressants used was only antagonized by CGP 20712A. These results suggest that the analgesic effect of desipramine and nortriptyline is mediated by beta-adrenoceptors. The beta-adrenoceptor involved depends on the type of nociceptive stimulusbeta 1 and beta 2 are both implicated when the stimulus is physical, but only beta 1 is involved when the stimulus is chemical.

背景与目标： 三环抗抑郁药已被证明可用于治疗各种病因性疼痛。单胺能系统似乎与这种现象有关。在这项研究中，使用物理和化学伤害试验在小鼠中研究了选择性β1-（CGP 20712A）和β2-（ICI 118551）肾上腺素能阻滞剂对地昔帕明和去甲替林的镇痛作用的影响，这些试验暗示了不同水平的感觉-运动在中枢神经系统（CNS）中的整合。进行活动测试以检测“假阳性”或“假阴性”结果。获得的结果表明，CGP 20712A和ICI 118551均能够在物理测试（热板和甩尾）中拮抗这些抗抑郁药的镇痛作用。但是，在化学测试（乙酸和福尔马林）中，所用抗抑郁药的镇痛作用仅被CGP 20712A拮抗。这些结果表明，地昔帕明和去甲替林的镇痛作用是由β-肾上腺素能受体介导的。涉及的β-肾上腺素受体取决于伤害性刺激的类型。当刺激是物理刺激时，beta 1和beta 2都牵涉其中，但是当刺激是化学刺激时，仅涉及beta1。

BACKGROUND & AIMS: :The vascular endothelial growth factor (VEGF) family of cytokines is involved in the maintenance of existing adult blood vessels as well as in angiogenesis, the sprouting of new vessels. To study the proangiogenic activation of VEGF receptors (VEGFRs) by VEGF family members in skeletal muscle, we develop a computational model of VEGF isoforms (VEGF(121), VEGF(165)), their cell surface receptors, and the extracellular matrix in in vivo tissue. We build upon our validated model of the biochemical interactions between VEGF isoforms and receptor tyrosine kinases (VEGFR-1 and VEGFR-2) and nonsignaling neuropilin-1 coreceptors in vitro. The model is general and could be applied to any tissue; here we apply the model to simulate the transport of VEGF isoforms in human vastus lateralis muscle, which is extensively studied in physiological experiments. The simulations predict the distribution of VEGF isoforms in resting (nonexercising) muscle and the activation of VEGFR signaling. Little of the VEGF protein in muscle is present as free, unbound extracellular cytokine; the majority is bound to the cell surface receptors or to the extracellular matrix. However, interstitial sequestration of VEGF(165) does not affect steady-state receptor binding. In the absence of neuropilin, VEGF(121) and VEGF(165) behave similarly, but neuropilin enhances the binding of VEGF(165) to VEGFR-2. This model is the first to study VEGF tissue distribution and receptor activation in human muscle, and it provides a platform for the design and evaluation of therapeutic approaches.

背景与目标： ：细胞因子的血管内皮生长因子（VEGF）家族与现有成人血管的维护以及血管生成，新血管的萌发有关。为了研究骨骼肌中VEGF家族成员对VEGF受体（VEGFRs）的促血管生成激活作用，我们建立了VEGF同种型（VEGF（121），VEGF（165）），它们的细胞表面受体和细胞外基质的计算模型。体内组织。我们建立在我们的体外VEGF同工型和受体酪氨酸激酶（VEGFR-1和VEGFR-2）和非信号神经pilin-1共受体之间的生化相互作用的验证模型的基础上。该模型是通用模型，可以应用于任何组织。在这里，我们应用该模型来模拟VEGF同工型在人股外侧肌中的运输，这在生理实验中已得到广泛研究。模拟预测了静息（非运动）肌肉中VEGF亚型的分布和VEGFR信号的激活。肌肉中很少有VEGF蛋白以游离的，未结合的细胞外细胞因子的形式存在。大多数与细胞表面受体或细胞外基质结合。但是，间质隔离VEGF（165）不会影响稳态受体结合。在没有神经纤毛蛋白的情况下，VEGF（121）和VEGF（165）的行为相似，但是神经纤毛蛋白会增强VEGF（165）与VEGFR-2的结合。该模型是第一个研究人肌肉中VEGF组织分布和受体激活的模型，它为设计和评估治疗方法提供了平台。

BACKGROUND & AIMS: BACKGROUND:A few prospective controlled trials comparing early functional rehabilitation after Achilles tendon repair and non-operative immobilization have been reported. HYPOTHESES:There is no difference in Achilles tendon elongation between early motion and immobilization after Achilles tendon repair. Tendon elongation does not correlate with the clinical outcome. STUDY DESIGN:Randomized clinical trial; Level of evidence, 2. METHODS:Fifty patients with acute Achilles tendon rupture were randomized postoperatively to receive either early movement of the ankle between neutral and plantar flexion in a brace for 6 weeks or immobilization in tension using a below-knee cast with the ankle in a neutral position for 6 weeks. Full weightbearing was allowed after 3 weeks in both groups. Standardized radiographs to measure previously placed radiographic markers were taken on the first day postoperatively and at 1, 3, 6, 12, 24 weeks postoperatively, with the final radiograph a mean of 60 (SD, 6.4) weeks postoperatively. The outcome was assessed at the 3-month and final checkups by the clinical scoring method described by Leppilahti et al and included subjective factors and objective factors. RESULTS:Tendon elongation occurred in both groups but was somewhat less in the early motion group (median 2 mm in the early motion group vs median 5 mm in the cast group a mean of 60 weeks postoperatively, P = .054). The elongation curves first rose and then slowly fell in both groups. The patients who had less elongation achieved a better clinical outcome (rho = -.42, P = .017). Tendon elongation did not correlate significantly with age, body mass index, or isokinetic peak torques. CONCLUSION:Achilles tendon elongation was somewhat less in the early motion group and correlated with the clinical outcome scores. We recommend early functional postoperative treatment after Achilles rupture repair.

背景与目标： 背景：一些前瞻性对照试验比较了跟腱修复和非手术固定后的早期功能康复。
假设：跟腱修复后的早期运动和固定之间的跟腱伸长没有差异。肌腱伸长与临床结果无关。
研究设计：随机临床试验；证据水平2。
方法：将50例急性跟腱断裂患者术后随机接受踝关节在中性和足底屈曲之间的早期运动，持续6周，或使用膝下石膏将踝关节置于中性位置，以固定不动的张力，持续6周。周。两组均在3周后允许完全负重。术后第一天和术后1、3、6、12、24周拍摄标准化的X线照片以测量先前放置的X线标记，最后的X射线照片平均在术后60（SD，6.4）周。结果通过Leppilahti等人描述的临床评分方法在3个月及最终体检时进行评估，其中包括主观因素和客观因素。
结果：两组的肌腱伸长均发生，但早期运动组则有所减少（早期运动组中位2 mm，而石膏组中位5 mm，平均术后60周，P = .054）。两组的伸长率曲线先上升，然后缓慢下降。伸长率较低的患者获得较好的临床预后（rho = -.42，P = .017）。肌腱伸长率与年龄，体重指数或等速运动峰值扭矩无显着相关性。
结论：早期运动组跟腱伸长率略低，且与临床结果评分相关。我们建议跟腱断裂修复后尽早进行术后功能治疗。

BACKGROUND & AIMS: AIM:To evaluate photodynamic therapy (PDT) combined with the preferential the cyclooxygenase-2 (COX-2) inhibitor, nabumetone in the treatment of the neovascular age-related macular degeneration (ARMD). METHODS:A prospective, double-blind, randomized study on 60 patients with subfoveal CNV secondary to ARMD without any previous treatment. Patients were divided into a nabumetone or placebo group. The main endpoints were the change of best-corrected visual acuity (BCVA), central macular thickness (CRT) and number of required PDT treatments. RESULTS:In the nabumetone group, 27 patients (90%) and 28 (93%) in the placebo group completed the follow-up of 12 months. In the nabumetone group, the mean CRT decreased from 332 μm (SD 68 μm) to 220 μm (SD 46 μm). In the placebo group, CRT decreased from 331 μm (SD 72 μm) to 254 μm (SD 61 μm). The mean BCVA was 0.68 log MAR (SD 0.22 log MAR) in the nabumetone group and 0.62 log MAR (SD 0.23 log MAR) in the placebo group at baseline. This stabilised in the placebo group to 0.66 log MAR (SD 0.33) but deteriorated in the nabumetone group to 0.86 log MAR (SD 0.41 log MAR). There was a significant reduction in the number of required PDTs in the nabumetone group, but significant progression of the RPE atrophy area. CONCLUSION:Combined PDT with oral intake of the COX-2 inhibitor, nabumetone reduced the number of required PDT retreatments, but worsening BCVA caused by macular atrophy progression. Therefore the combination of the PDT with the nabumetone is not recommended.

背景与目标： 目的：评估光动力疗法（PDT）与优先使用环氧合酶-2（COX-2）抑制剂萘丁美酮的组合，以治疗新生血管性年龄相关性黄斑变性（ARMD）。
方法：一项前瞻性，双盲，随机对照研究，对60例继发于ARMD继发于中央凹下的CNV患者而未进行任何治疗。将患者分为萘丁美酮或安慰剂组。主要终点是最佳矫正视力（BCVA），中央黄斑厚度（CRT）和所需PDT治疗次数的改变。
结果：萘丁美通组中，安慰剂组27例（90％）和28例（93％）完成了12个月的随访。在萘丁美酮组中，平均CRT从332μm（SD 68μm）降至220μm（SD 46μm）。在安慰剂组中，CRT从331μm（SD 72μm）降至254μm（SD 61μm）。萘丁美tone组的平均BCVA为0.68 log MAR（SD 0.22 log MAR），而安慰剂组的基线BCVA为0.62 log MAR（SD 0.23 log MAR）。这在安慰剂组中稳定至0.66 log MAR（SD 0.33），但在萘丁美通组中恶化至0.86 log MAR（SD 0.41 log MAR）。萘丁美通组中所需PDT的数量显着减少，但RPE萎缩区域进展明显。
结论：萘丁美酮与PDT结合口服摄入COX-2抑制剂相结合，减少了所需的PDT再治疗次数，但由于黄斑萎缩的进展而使BCVA恶化。因此，不建议将PDT与萘丁美酮组合使用。

BACKGROUND & AIMS: :We recently showed that non-small cell lung carcinomas (NSCLCs) are of dismal prognosis when encompassing accelerated autophagic activity. The regulation of this abnormally functioning degradation system and its association with hypoxia and apoptosis in lung carcinoma patients is unexplored. In this study we used 115 NSCLC tissues to examine the immunohistochemical expression of four distinct molecules - the major regulator of autophagy Beclin 1, the anti-apoptotic and anti-autophagic protein Bcl-2, the pro-apoptotic and pro-autophagic protein BNIP3, and a marker of hypoxia and glucolysis, the glucose transporter Glut 1. Most cases showed reduced reactivity for Beclin 1 (62%) and Bcl-2 (82%) proteins, almost half of our sample revealed strong BNIP3 expression (57%), whereas most of the carcinomas strongly expressed Glut 1 antigen (71%). Beclin 1 expression showed no association with survival. Bcl-2 positivity was a marker of good prognosis (p = 0.04), whereas BNIP3 (p = 0.0004) and Glut 1 (p = 0.03) expression correlated with poor outcome in Stage I disease. Autophagic status was negatively associated with Bcl-2 (p = 0.0006), but positively with Glut 1 expression (p = 0.001). In conclusion, the accelerated autophagic status in NSCLC is unrelated to Beclin 1 and BNIP3 expression, but does show significant association with Bcl-2 reactivity. Furthermore, we showed important correlations between glucolysis and autophagy, guiding new pathways in future lung carcinoma research.

背景与目标： ：我们最近发现，非小细胞肺癌（NSCLC）包含加速自噬活性时预后不良。肺癌患者中这种功能异常的降解系统的调节及其与缺氧和细胞凋亡的关系尚待探索。在这项研究中，我们使用了115个非小细胞肺癌组织来检查四种不同分子的免疫组织化学表达-自噬Beclin 1的主要调节剂，抗凋亡和抗自噬蛋白Bcl-2，促凋亡和自噬蛋白BNIP3，葡萄糖转运蛋白Glut 1是缺氧和糖酵解的标志。大多数病例显示Beclin 1（62％）和Bcl-2（82％）蛋白的反应性降低，几乎一半的样本显示BNIP3表达强（57％），而大多数癌症强烈表达Glut 1抗原（71％）。 Beclin 1的表达与存活率无关。 Bcl-2阳性是预后良好的标志（p = 0.04），而BNIP3（p = 0.0004）和Glut 1（p = 0.03）的表达与I期疾病的不良预后相关。自噬状态与Bcl-2呈负相关（p = 0.0006），但与Glut 1表达呈正相关（p = 0.001）。总之，NSCLC中自噬状态的加速与Beclin 1和BNIP3的表达无关，但确实与Bcl-2的反应性显着相关。此外，我们显示了糖酵解与自噬之间的重要关联，为未来肺癌研究的新途径提供了指导。

BACKGROUND & AIMS: :Diffusion magnetic resonance imaging (MRI) provides a sensitive indicator of cerebral hypoxia. We investigated if apparent diffusion coefficient (ADC) and transverse relaxation (T(2)) predict symptoms of acute mountain sickness (AMS), or merely indicate the AMS phenotype irrespective of symptoms. Fourteen normal subjects were studied in two groups; unambiguous AMS and no-AMS at 3,800 m altitude (intermediate AMS scores were excluded). T(2) relaxation was estimated from a T(2) index of T(2)-weighted signal normalized by cerebrospinal fluid signal. Measurements were made in normoxia and repeated after 2 days sustained hypoxia (AMS group symptomatic and no-AMS group asymptomatic) and after 7 days hypoxia (both groups asymptomatic). Decreased ADC directly predicted AMS symptoms (P<0.05). Apparent diffusion coefficient increased in asymptomatic subjects, or as symptoms abated with acclimatization. This pattern was similar in basal ganglia, white matter, and gray matter. Corpus callosum behaved differently; restricted diffusion was absent (or rapidly reversed) in the splenium, and was sustained in the genu. In symptomatic subjects, T(2,index) decreased after 2 days hypoxia and further decreased after 7 days. In asymptomatic subjects, T(2,index) initially increased after 2 days, but decreased after 7 days. T(2,index) changes were not predictive of AMS symptoms. These findings indicate that restricted diffusion, an indicator of diminished cerebral energy status, directly predicts symptoms of AMS in humans at altitude.

背景与目标： ：扩散磁共振成像（MRI）提供了脑缺氧的敏感指标。我们调查了表观扩散系数（ADC）和横向弛豫（T（2））是否预测了急性高山病（AMS）的症状，还是仅指示了AMS表型，而与症状无关。 14个正常受试者分为两组进行研究；在3,800 m的高度进行明确的AMS和无AMS（不包括中级AMS分数）。根据脑脊髓液信号归一化的T（2）加权信号的T（2）指数估算T（2）弛豫。在常氧状态下进行测量，并在持续缺氧2天（AMS组有症状和无AMS组无症状）和缺氧7天（两组无症状）后重复进行。 ADC降低直接预测AMS症状（P <0.05）。无症状受试者的表观弥散系数增加，或者随着适应环境的减轻症状逐渐减轻。这种模式在基底神经节，白质和灰质中相似。 call体表现不同。脾中不存在（或迅速逆转）受限制的扩散，并且在脾中持续存在。在有症状的受试者中，缺氧2天后T（2，index）下降，而在7天后T（2，index）进一步下降。在无症状受试者中，T（2，index）最初在2天后升高，但在7天后降低。 T（2，index）的变化不能预测AMS症状。这些发现表明，限制扩散是大脑能量状态减弱的指标，可直接预测高海拔地区人类的AMS症状。

BACKGROUND & AIMS: :A 57-year-old woman showed frequent premature ventricular complexes (PVCs) originating from the right ventricular outflow tract (RVOT), and some of the PVCs triggered polymorphic ventricular tachycardia (PVT). Structural heart diseases were ruled out by conventional cardiac examinations. Radiofrequency catheter ablation was successful in eliminating the PVCs and subsequent PVT. However, epinephrine infusion unmasked her prolonged QT interval, and a genetic analysis revealed a KCNH2 mutation (R694H) as the cause of latent type-2 long QT syndrome (LQTS). This case suggests that latent LQTS may work as an arrhythmogenic substrate of PVT triggered by a benign form of RVOT-PVCs in patients with a structurally normal heart.

背景与目标： ：一名57岁的妇女表现出频繁的早产于右室流出道（RVOT）的心室复合物（PVC），并且其中一些PVC触发了多形性室性心动过速（PVT）。通过常规心脏检查排除了结构性心脏病。射频导管消融成功地消除了PVC和随后的PVT。然而，肾上腺素的注入掩盖了她延长的QT间隔，遗传分析显示KCNH2突变（R694H）是潜在的2型长QT综合征（LQTS）的病因。这种情况表明，在心脏结构正常的患者中，潜在的LQTS可能是由良性形式的RVOT-PVC触发的PVT的一种致心律失常底物。

BACKGROUND & AIMS: :Utilizing X-ray crystal structure analysis, (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides were designed and identified as renin inhibitors. The most potent compound 15 demonstrated favorable pharmacokinetic and pharmacodynamic profiles in rat.

背景与目标： ：利用X射线晶体结构分析，设计了（3S，5R）-5- [4-（2-氯苯基）-2,2-二甲基-5-氧哌嗪-1-基]哌啶-3-甲酰胺，并确定为肾素抑制剂。最有效的化合物15在大鼠中显示出良好的药代动力学和药效学特征。