BACKGROUND & AIMS: :Enzyme replacement therapy (ERT) became a reality for patients with Pompe disease, a fatal cardiomyopathy and skeletal muscle myopathy caused by a deficiency of glycogen-degrading lysosomal enzyme acid alpha-glucosidase (GAA). The therapy, which relies on receptor-mediated endocytosis of recombinant human GAA (rhGAA), appears to be effective in cardiac muscle, but less so in skeletal muscle. We have previously shown a profound disturbance of the lysosomal degradative pathway (autophagy) in therapy-resistant muscle of GAA knockout mice (KO). Our findings here demonstrate a progressive age-dependent autophagic buildup in addition to enlargement of glycogen-filled lysosomes in multiple muscle groups in the KO. Trafficking and processing of the therapeutic enzyme along the endocytic pathway appear to be affected by the autophagy. Confocal microscopy of live single muscle fibers exposed to fluorescently labeled rhGAA indicates that a significant portion of the endocytosed enzyme in the KO was trapped as a partially processed form in the autophagic areas instead of reaching its target--the lysosomes. A fluid-phase endocytic marker was similarly mistargeted and accumulated in vesicular structures within the autophagic areas. These findings may explain why ERT often falls short of reversing the disease process and point toward new avenues for the development of pharmacological intervention.

背景与目标： ：对于因糖原降解溶酶体酶酸性α-葡萄糖苷酶（GAA）不足而导致的致命性心肌病和骨骼肌肌病的庞贝病患者，酶替代疗法（ERT）成为现实。该疗法依赖于重组人GAA（rhGAA）的​​受体介导的内吞作用，似乎对心肌有效，但对骨骼肌则无效。先前我们已经证明了GAA基因敲除小鼠（KO）的抗治疗性肌肉中的溶酶体降解途径（自噬）受到严重干扰。我们的发现在这里表明，随着KO中多个肌肉群中糖原填充的溶酶体的增加，渐进性的年龄依赖性自噬逐渐增强。沿内吞途径的治疗性酶运输和加工似乎受到自噬的影响。暴露于荧光标记的rhGAA的活单肌纤维的共聚焦显微镜检查表明，KO中内吞酶的很大一部分以部分加工的形式被捕获在自噬区，而不是到达其靶标-溶酶体。类似地，液相吞噬标记物被错误定位并积聚在自噬区域内的囊泡结构中。这些发现可以解释为什么ERT通常不能逆转疾病过程，并为药物治疗的发展指明了新的途径。

BACKGROUND & AIMS: :Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract that share clinical and pathological characteristics. The most accredited hypothesis is that both CD and UC result from a deregulated mucosal immune response to normal constituents of the gut microflora. Evidence, however, indicates that the main pathological processes in these two diseases are distinct. In CD, the tissue-damaging inflammatory reaction is driven by activated type 1 helper T-cell (Th1), whereas a humoral response predominates in UC. Consistently, a marked accumulation of macrophages making interleukin (IL)-12, the major Th1-inducing factor, is seen in CD but not in UC mucosa. Preliminary studies also indicate that administration of a monoclonal antibody blocking the IL-12/p40 subunit can be useful to induce and maintain clinical remission in CD patients. Notably, the recently described IL-23 shares the p40 subunit with IL-12, raising the possibility that the clinical benefit of the anti-IL-12/p40 antibody in CD may also be due to the neutralization of IL-23 activity. This review summarizes the current information on the expression and functional role of IL-12 and IL-12-associated signaling pathways both in patients with CD and experimental models of colitis, thus emphasizing major differences between IL-12 and IL-23 activity on the development of intestinal inflammation.

背景与目标： ：克罗恩病（CD）和溃疡性结肠炎（UC）是胃肠道的慢性炎性疾病，具有临床和病理学特征。最公认的假设是CD和UC均来自对肠道菌群正常成分的粘膜免疫反应失控。然而，证据表明这两种疾病的主要病理过程是不同的。在CD中，组织破坏性炎症反应是由激活的1型辅助性T细胞（Th1）驱动的，而体液反应在UC中占主导地位。一致地，在CD中可见大量的巨噬细胞积聚，使白介素（IL）-12（主要的Th1诱导因子）在CD中可见，而在UC粘膜中则未见。初步研究还表明，给予阻断IL-12 / p40亚基的单克隆抗体可用于诱导和维持CD患者的临床缓解。值得注意的是，最近描述的IL-23与IL-12共有p40亚基，从而增加了抗IL-12 / p40抗体在CD中的临床益处也可能是由于IL-23活性的中和所引起的可能性。这篇综述总结了关于CD患者和结肠炎实验模型中IL-12和IL-12相关信号通路的表达和功能作用的最新信息，从而强调了IL-12和IL-23活性在结肠炎患者中的主要差异。肠道炎症的发展。

BACKGROUND & AIMS: OBJECTIVE:The goal of this study was to develop an improved (62)Zn/(62)Cu generator based on cation exchange resin and remote preparation at high radioactivity scale for clinical use. METHODS:A natural Cu target was irradiated with proton beam in the energy range of 30-->19 MeV at a beam current of 10 muA for 1 h to obtain around 1.7 GBq of (62)Zn. The (62)Zn was isolated from the Cu target on an anion exchange column with more than 97% yield within 2.5 h from the EOB. The (62)Zn/(62)Cu generator was prepared by loading the (62)Zn(2+) on a Sep-Pak plus CM cartridge. RESULTS:The generator showed high elution efficiency ( approximately 96%) using a small volume (ca. 3 ml) of a 200-mM glycine solution with a very low breakthrough of (62)Zn (<0.1%). CONCLUSIONS:This (62)Zn/(62)Cu generator has been proven to be highly useful as a source of (62)Cu for the synthesis of (62)Cu-labeled compounds. The clinical application of [(62)Cu]Cu-ATSM produced with this generator has been already approved by the Institutional Review Board at the National Institute of Radiological Sciences.

背景与目标： 目的：本研究的目的是开发一种基于阳离子交换树脂并以高放射性规模远程制备的改进的（62）Zn /（62）Cu生成器，以用于临床。
方法：在能量范围为30-> 19 MeV的质子束中，以10μA的束流对天然Cu靶辐照1 h，以获得约1.7 GBq的（62）Zn。从EOB到2.5 h内，从阴离子交换柱上的Cu靶中分离出（62）Zn。通过将（62）Zn（2）加载到Sep-Pak plus CM滤芯上来制备（62）Zn /（62）Cu发生器。
结果：使用少量（约3 ml）的200 mM甘氨酸溶液，生成器显示出高洗脱效率（约96％），而（62）Zn的穿透率极低（<0.1％）。
结论：该（62）Zn /（62）Cu生成物已被证明可作为（62）Cu的来源，用于合成（62）Cu标记的化合物。用这种发生器产生的[（62）Cu] Cu-ATSM的临床应用已经由美国放射科学学会的机构审查委员会批准。

BACKGROUND & AIMS: :Over recent years, with many advances in understanding the pathological processes that underlie many inflammatory conditions, it has become clear that targeting cytokines has proven to be highly effective therapeutically. The second International Cytokine symposium, held recently in Manchester UK, has provided an important forum for bringing basic and clinical scientists together to discuss many aspects of cytokine medicine from the laboratory to the clinic. In this article, we provide an overview of the main issues raised from this important conference and set the scene for more detailed reports that follow in subsequent articles in this journal.

背景与目标： 近年来，随着了解许多炎症条件的病理过程取得了许多进展，很明显，靶向细胞因子已被证明在治疗上非常有效。最近在英国曼彻斯特举行的第二届国际细胞因子研讨会为将基础和临床科学家聚集在一起，讨论了从实验室到诊所的细胞因子药物的许多方面提供了重要的论坛。在本文中，我们概述了本次重要会议提出的主要问题，并为随后在本期刊的后续文章中提供更详细的报告奠定了基础。

BACKGROUND & AIMS: Levodopa-induced psychosis can complicate the treatment of Parkinson's disease (PD). In this retrospective, uncontrolled report, we describe our experience treating PD-related psychosis with clozapine, emphasizing those patients treated for longer than 1 year. Twenty-seven patients were treated, 14 for longer than 1 year. Most patients showed a rapid improvement from baseline within 1 month using the Clinical Global Impression and Global Psychosis Rating Scores. Five patients discontinued the drug due to side effects, but only two patients reported side effects after 6 months of treatment. Clozapine appears to be effective in treating PD related psychotic symptoms while not interfering with motor function.

背景与目标： 左旋多巴引起的精神病会使帕金森氏病（PD）的治疗复杂化。在这份回顾性的，不受控制的报告中，我们描述了用氯氮平治疗PD相关性精神病的经验，强调那些接受治疗超过1年的患者。治疗了27例患者，其中14例的病程超过1年。使用临床总体印象和总体精神病评分分数，大多数患者在1个月内显示出从基线开始的快速改善。有5名患者由于副作用而停药，但只有2名患者在治疗6个月后报告了副作用。氯氮平似乎可以有效治疗PD相关的精神病症状，同时又不影响运动功能。

BACKGROUND & AIMS: :Cerebral metastases remain a common complication among patients with cancer. Historically, whole-brain radiotherapy has remained the standard of care, with surgery being reserved for selected cases. Recent advances have changed our practice, however. In particular, stereotactic radiosurgery has emerged as a vital treatment modality for this disease. In addition, chemotherapy, including temozolomide, topoisomerase inhibitors and antimetabolites, and treatment sensitizers, such as efaproxiral and motexafin gadolinium, are actively being assessed in clinical trials, and are likely to play an increasing role in the management of cerebral metastases in the future. Nonetheless, many uncertainties remain, such as the optimal combination and timing of therapeutics. As the arsenal of therapeutics expands, it will be increasingly important to select appropriate patients for a particular treatment paradigm. Understanding the efficacy and toxicity of treatment is essential to this task.

背景与目标： ：脑转移仍然是癌症患者中的常见并发症。从历史上看，全脑放射疗法一直是护理的标准，只有部分病例可以接受手术治疗。但是，最近的进展改变了我们的做法。特别地，立体定向放射外科手术已成为该疾病的重要治疗方式。此外，包括替莫唑胺，拓扑异构酶抑制剂和抗代谢物在内的化学疗法，以及诸如依法洛昔洛和莫他沙芬g等治疗敏化剂，正在临床试验中得到积极评估，并且将来可能在治疗脑转移中发挥越来越重要的作用。尽管如此，仍然存在许多不确定因素，例如治疗方法的最佳组合和时机。随着治疗手段的扩展，选择适合特定治疗范例的合适患者将变得越来越重要。了解治疗的功效和毒性对该任务至关重要。

BACKGROUND & AIMS: :The nature of the temporal relationship between antibacterial consumption and Streptococcus pneumoniae penicillin resistance is investigated using population level data across time. IMS Health Global Services provided national outpatient antibiotic prescription data for the years 1996-2003 from France, Spain, Italy, Germany, the United Kingdom, and the United States. Surveillance data consist of S. pneumoniae isolates obtained from a surveillance database in the same geographic regions from 1996 to 2003. A linear mixed model for repeated measures was used to analyze the association between resistance and several antibacterial classes through time. Changes in penicillin resistance through time in any country are better explained by the weighted cumulative antibacterial consumption with a 2-year lag. Narrow-spectrum penicillins are associated with lower resistance rates. Large reductions in consumption at the population level are needed to affect resistance. There is a peak level of penicillin resistance associated with cumulative exposure to a combination of antibiotic classes that is unique for every country.

背景与目标： ：使用跨时间的人口水平数据调查了抗菌药物消费与肺炎链球菌青霉素耐药性之间时间关系的性质。 IMS Health Global Services提供了1996-2003年法国，西班牙，意大利，德国，英国和美国的国家门诊抗生素处方数据。监测数据由1996年至2003年从同一地理区域的监测数据库中获得的肺炎链球菌分离株组成。采用线性混合模型进行重复测量，以分析耐药性与一段时间内几种抗菌剂类别之间的关联。在任何国家，青霉素耐药性随时间的变化都可以通过加权累积抗菌药消费量（滞后2年）来更好地说明。窄谱青霉素与较低的耐药率有关。需要在人口一级大幅度减少消费量以影响抵抗力。青霉素耐药性的峰值与每个国家所独有的抗生素类药物的累积接触有关。

BACKGROUND & AIMS: :There has been considerable recent interest in the use of cortical auditory evoked potentials (CAEPs) as an electrophysiological measure of human speech encoding in individuals with normal as well as impaired auditory systems. The development of such electrophysiological measures such as CAEPs is important because they can be used to evaluate the benefits of hearing aids and cochlear implants in infants, young children, and adults that cannot cooperate for behavioral speech discrimination testing. The current study determined whether CAEPs produced by seven different speech sounds, which together cover a broad range of frequencies across the speech spectrum, could be differentiated from each other based on response latency and amplitude measures. CAEPs were recorded from ten adults with normal hearing in response to speech stimuli presented at a conversational level (65 dB SPL) via a loudspeaker. Cortical responses were reliably elicited by each of the speech sounds in all participants. CAEPs produced by speech sounds dominated by high-frequency energy were significantly different in amplitude from CAEPs produced by sounds dominated by lower-frequency energy. Significant effects of stimulus duration were also observed, with shorter duration stimuli producing larger amplitudes and earlier latencies than longer duration stimuli. This research demonstrates that CAEPs can be reliably evoked by sounds that encompass the entire speech frequency range. Further, CAEP latencies and amplitudes may provide an objective indication that spectrally different speech sounds are encoded differently at the cortical level.

背景与目标： ：最近，人们对使用皮质听觉诱发电位（CAEP）作为正常和听觉系统受损的人的语音编码的电生理学方法感兴趣。诸如CAEPs之类的电生理指标的发展非常重要，因为它们可用于评估助听器和人工耳蜗在无法配合行为语音辨别力测试的婴儿，幼儿和成人中的益处。当前的研究确定了是否可以根据响应潜伏期和幅度度量来区分由七种不同的语音产生的CAEP，这些CAEP涵盖整个语音频谱的广泛频率范围。记录了十名成年人的CAEPs，这些成年人是通过扬声器以对话级别（65 dB SPL）呈现的语音刺激而正常听力的。在所有参与者中，每种语音都可靠地引起了皮层反应。由高频能量支配的语音产生的CAEP与由低频能量支配的声音产生的CAEP在幅度上有显着差异。还观察到了刺激持续时间的显着效果，持续时间较短的刺激比持续时间较长的刺激产生更大的振幅和更短的等待时间。这项研究表明，包含整个语音频率范围的声音可以可靠地诱发CAEP。进一步地，CAEP等待时间和幅度可以提供客观的指示，即频谱不同的语音在皮质水平上被不同地编码。

BACKGROUND & AIMS: :In a patient with temporomandibular disorder who does not respond to conservative treatment, treatment with intra-articular injection of high molecular weight sodium hyaluronate can be suggested. In our study, 27 patients with nonreduced disc displacement were diagnosed clinically and confirmed by magnetic resonance imaging. The age range was from 21 to 63 years old, with a mean of 39.3 years. Two cycles of injection of high molecular weight sodium hyaluronate was performed on alternative weeks. Pain intensity was measured by the visual analog scale. Maximal mouth opening, clicking joint noise, and lateral movement were measured before and after injection for more than 6 months. Reduction of pain intensity and improvement in the maximum mouth opening parameter was statistically significant. In conclusion, this intra-articular injection using high molecular weight sodium hyaluronate looks very positive for patients affected by nonreduced disc displacement and is encouraged to be used as a primary treatment of temporomandibular joint dysfunction.

背景与目标： ：对于颞下颌关节疾病，对保守治疗无反应的患者，建议采用关节内注射高分子量透明质酸钠进行治疗。在我们的研究中，临床上诊断出27例椎间盘移位未减少的患者，并通过磁共振成像对其进行了确认。年龄范围是21至63岁，平均39.3岁。每隔几个星期进行两次高分子量透明质酸钠注射。通过视觉模拟量表测量疼痛强度。在注射前后超过6个月，测量了最大张口，咔嗒声和侧向运动。疼痛强度的降低和最大张口参数的改善在统计学上是显着的。总之，这种高分子量透明质酸钠的关节腔内注射对于未减少椎间盘移位的患者看起来非常积极，因此被鼓励用作颞下颌关节功能障碍的主要治疗方法。

BACKGROUND & AIMS: :Agricultural soils of two Italian maize farms were treated for five years with an industrially produced high-quality compost. Cattle manure and the usual mineral fertilizer were used for comparison purposes. The effects of the organic and mineral fertilizer treatments were studied by analyzing the compost and manure, cultured soils, and harvested material. The grain yield was also determined. Organic fertilization improved soil pH, CEC, content of organic matter and NPK. Soil respiration and N mineralization were found to be higher than in the purely mineral-treated soil. Plant K take-up was improved, whereas grain yield was not affected. It was confirmed that organic fertilization, particularly compost use, maintained and increased soil fertility. The study demonstrated the feasibility of using in loco analytical facilities to follow the entire recycling process-from waste to compost production-and the use of the final product in the field.

背景与目标： ：意大利的两个玉米农场的农业土壤用工业生产的高质量堆肥处理了五年。为了比较，使用了牛粪和通常的矿物肥料。通过分析堆肥和肥料，耕种的土壤和收获的物料，研究了有机肥料和矿物肥料的处理效果。还确定了谷物产量。有机肥改善了土壤的pH，CEC，有机质含量和NPK。发现土壤呼吸和氮矿化比纯矿物处理过的土壤要高。钾素吸收量得到改善，而谷物单产却没有受到影响。可以肯定的是，有机肥，特别是堆肥的使用，保持并增加了土壤肥力。该研究证明了在机车分析设施中使用该方法以跟踪整个回收过程的可行性（从废物到堆肥的生产）以及最终产品在野外的使用。

BACKGROUND & AIMS: :Attention-deficit hyperactivity disorder (ADHD) is a common childhood psychiatric disorder. Despite intensive research efforts, the aetiology of ADHD remains unknown. Current evidence suggests that the aetiology of ADHD is heterogeneous, comprising of multiple factors. Recently, it has been proposed that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, may be implicated in the pathogenesis of ADHD. This hypothesis is supported by recent genetic studies in ADHD. Drawing on findings from studies into the drugs for ADHD relating to central BDNF expression, hyperactivity in BDNF knockout mice, BDNF effects in midbrain dopaminergic function and the close association between BDNF and the dopamine transporter (an important molecule for ADHD pathogenesis), it is proposed here that decreased central BDNF, particularly in the midbrain region, may play an important role in the pathogenesis ADHD. This hypothesis may have some implications for clinical findings in ADHD (for example, the co-morbidity between ADHD and major depression), and provide a new direction for the development of medication for ADHD treatment.

背景与目标： 注意缺陷多动障碍（ADHD）是儿童期常见的精神病。尽管进行了深入的研究，但多动症的病因仍然未知。当前证据表明，ADHD的病因是异质的，由多种因素组成。最近，已经提出，脑源性神经营养因子（BDNF），神经营养因子家族的成员，可能与ADHD的发病有关。这一假说得到了多动症最近的遗传学研究的支持。根据对ADHD药物的研究发现，该药物与中枢BDNF表达，BDNF基因敲除小鼠的过度活跃，BDNF对中脑多巴胺能功能的影响以及BDNF与多巴胺转运蛋白（ADHD发病机理的重要分子）之间的紧密联系有关，因此提出了这一建议。在这里，中央BDNF的降低，特别是在中脑区域，可能在ADHD的发病中起重要作用。该假设可能对ADHD的临床发现有一定的影响（例如，ADHD与严重抑郁症的合并症），并为ADHD治疗药物的开发提供了新的方向。

BACKGROUND & AIMS: PURPOSE:Consistent condom use is critical to efforts to prevent sexually transmitted infections among adolescents, but condom use may decline as relationships and contraceptive needs change. The purpose of this research is to assess changes in condom non-use longitudinally in the context of changes in relationship quality, coital frequency and hormonal contraceptive choice. METHODS:Participants were women (aged 14-17 years at enrollment) recruited from three urban adolescent medicine clinics. Data were collected at three-month intervals using a face-to-face structured interview. Participants were able to contribute up to 10 interviews, but on average contributed 4.2 interviews over the 27-month period. Independent variables assessed partner-specific relationship quality (five items; scale range 5-25; alpha = .92, e.g., this partner is a very important person to me); and, number of coital events with a specific partner. Additional items assessed experience with oral contraceptive pills (OCP) use and injected depo medroxy-progesterone acetate (DMPA). The outcome variable was number of coital events without condom use during the past three months. Analyses were conducted as a three-level hierarchical linear growth curve model using HLM 6. The Level 1 predictor was time, to test the hypothesis that condom non-use increases over time. Level 2 predictors assessed relationship quality and coital frequency across all partners to assess hypotheses that participants' condom non-use increases over time as a function of relationship quality and coital frequency. Level 3 predictors assessed the participant-level influence of OCP or DMPA experience on time-related changes in condom non-use. RESULTS:A total of 176 women reported 279 sex partners and contributed 478 visits. Both average coital frequency and average condom non-use linearly increased during the 27-month follow-up. At any given follow-up, about 35% reported recent OCP use, and 65% reported DMPA use. HLM analyses showed that condom non-use increased as a function of time (beta = .12; p = .03, Level 1 analysis). Increased condom non-use over time was primarily a function of increased coital frequency (beta = .01; p = .00), although higher levels of relationship quality were associated with increased condom non-use at enrollment (beta = .44; p = .00, Level 2 analysis). The temporal rise in condom non-use significantly increased among DMPA users (beta = .06; p = .00) but not OCP users (Level 3 analysis) (beta = -.04; p = .06). CONCLUSIONS:Developmentally, relationship characteristics and coital frequency appear to have increasing weight in decisions about condom use. Hormonal contraceptive methods are not equivalently associated with the overall temporal decline in condom use. Future research associated with dual contraceptive/condom use should address differential factors associated condom use in combination with different hormonal methods.

背景与目标： 目的：持续使用避孕套对于预防青少年性传播感染至关重要，但是随着人际关系和避孕需求的变化，避孕套的使用可能会减少。这项研究的目的是在关系质量，性交频率和激素避孕选择的变化的背景下，纵向评估未使用安全套的变化。
方法：参与者是从三个城市青少年医学诊所招募的女性（入学年龄14-17岁）。使用面对面的结构化访谈，每三个月收集一次数据。参加者最多可以贡献10个访谈，但在27个月内平均贡献了4.2个访谈。自变量评估了特定于伴侣的关系质量（五个项目；等级范围5-25；α= 0.92，例如，这个伴侣对我来说是非常重要的人）；以及与特定伴侣发生性行为的次数。其他项目评估了口服避孕药（OCP）的使用经验和注射醋酸去甲羟孕酮（DMPA）的经验。结果变量是在过去三个月中未使用安全套的性交事件的数量。使用HLM 6作为三级分层线性增长曲线模型进行了分析。1级预测因子是时间，以检验安全套不使用随时间增加的假设。 2级预测变量评估了所有伴侣之间的关系质量和性交频率，以评估以下假设：参与者不使用安全套会随着时间的推移而增加，这是关系质量和性交频率的函数。 3级预测变量评估了OCP或DMPA经验对安全套不使用时间相关变化的参与者水平影响。
结果：总共176名妇女报告了279个性伴侣，并贡献了478次探视。在27个月的随访中，平均性交频率和平均不使用安全套均呈线性增加。在任何给定的随访中，约35％的患者报告了最近的OCP使用，而65％的患者报告了DMPA的使用。 HLM分析表明，不使用安全套随时间增加（β= .12； p = .03，1级分析）。随着时间的流逝，不使用安全套的增加主要是性交频率增加的函数（β= .01； p = .00），尽管较高的关系质量与入学时不使用安全套的增加相关（β= .44； p = .00，第2级分析）。在DMPA用户中，未使用安全套的时间增加显着增加（β= .06； p = .00），但在OCP用户中则没有（第三级分析）（β= -.04； p = .06）。
结论：在发展上，关系特征和性交频率似乎在有关使用安全套的决策中具有越来越大的重要性。激素避孕方法与使用避孕套的总体时间下降没有同等的联系。与双重避孕/避孕套使用相关的未来研究应解决与不同激素方法结合使用避孕套相关的差异因素。

BACKGROUND & AIMS: :Left ventricular (LV) dysfunction and/or heart failure (HF) are frequent complications of hypertension and myocardial infarction (MI), placing affected patients at increased risk of significant morbidity and premature death. Given that the renin-angiotensin-aldosterone system (RAAS) is activated and of pathophysiological importance in such patients, a strong therapeutic rationale exists to target the main effector mechanism (that is, angiotensin II [Ang II]) in order to lessen the associated morbidity and mortality burden. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce mortality and LV dysfunction and to slow disease progression in patients with HF, including high-risk, post-MI patients. However, ACE inhibitors (ACE-Is) may not provide optimal long-term RAAS blockade (a finding that is associated with a worse prognosis) and many patients are unable to tolerate such therapy (because of troublesome dry cough, for example). In contrast, Ang II receptor blockers (ARBs) may block the RAAS more completely than ACE-Is and appear to be better tolerated. Several large-scale trials gave evaluated the efficacy of ARBs in patients with LV dysfunction and/or HF (including high-risk, post-MI patients), and have confirmed their utility as an efficacious and well-tolerated alternative to ACE-Is in this setting.

背景与目标： ：左心室（LV）功能障碍和/或心力衰竭（HF）是高血压和心肌梗塞（MI）的常见并发症，使受影响的患者罹患显着发病率和过早死亡的风险增加。鉴于肾素-血管紧张素-醛固酮系统（RAAS）已被激活并且在此类患者中具有重要的病理生理意义，因此存在针对主要效应机制（即血管紧张素II [Ang II]）的强大治疗原理，以减轻相关的疾病。发病率和死亡率负担。血管紧张素转换酶（ACE）抑制剂已被证明可以降低HF患者（包括高危MI后患者）的死亡率和LV功能障碍，并减缓疾病进展。但是，ACEI（ACE-Is）可能无法提供最佳的长期RAAS阻断作用（这一发现与更坏的预后相关），并且许多患者无法忍受此类治疗（例如，由于干咳引起的麻烦）。相比之下，Ang II受体阻滞剂（ARBs）可能比ACE-Is更完全地阻断RAAS，并且似乎具有更好的耐受性。几项大规模试验评估了ARB在LV功能不全和/或HF患者（包括高风险，MI后患者）中的疗效，并证实了其作为ACE-Is的有效且耐受性良好的替代品的用途。此设置。

BACKGROUND & AIMS: The in vivo effectiveness of therapeutic RNAs, like antisense molecules and ribozymes, relies on several featuresRNA molecules need to be expressed at high levels in the correct cellular compartment as stable and active molecules. The exploitation of "natural" small RNA coding genes as expressing cassettes gives high chances to fulfill these requirements. We have investigated the utilization of the adenoviral VAI RNA as a cytoplasmatic carrier for expressing ribozymes against HIV-1. The conserved 5' leader sequence of HIV was chosen as a target, because it is present in all the viral transcripts and is highly conserved. Hammerhead ribozymes were substituted to different portions of the VAI RNA and the resulting chimera were tested in the in vivo system of Xenopus laevis oocytes for their level of accumulation, cellular compartmentalization, and assembly in specific ribonucleoparticles containing the La antigen. Interesting differences in the activity of the different chimera were found in both in vitro cleavage assays and S100 extracts of injected oocytes where the catalytic activity of the ribozymes in the RNP context can be analyzed.

背景与目标： 像反义分子和核酶一样，治疗性RNA的体内有效性取决于几个特征。RNA分子需要在正确的细胞室内高水平表达为稳定和活跃的分子。利用“天然”小RNA编码基因作为表达盒可以满足这些要求。我们已经研究了腺病毒VAI RNA作为表达HIV-1核酶的细胞质载体的利用。选择了保守的HIV 5'前导序列作为靶标，因为它存在于所有病毒转录物中并且是高度保守的。将锤头状核酶替换为VAI RNA的不同部分，并在非洲爪蟾卵母细胞的体内系统中测试了所得嵌合体的积累水平，细胞区室化和在包含La抗原的特定核糖核酸颗粒中的组装。在体外卵裂分析和注射卵母细胞的S100提取物中都发现了不同嵌合体活性的有趣差异，其中可以分析核酶在RNP环境中的催化活性。

BACKGROUND & AIMS: :The physiological responses of potato (Solanum tuberosum L. cv. Folva) to partial root-zone drying (PRD) were investigated in potted plants in a greenhouse (GH) and in plants grown in the field under an automatic rain-out-shelter. In the GH, irrigation was applied daily to the whole root system (FI), or to one-half of the root system while the other half was dried, for 9 d. In the field, the plants were drip irrigated either to the whole root system near field capacity (FI) or using 70% water of FI to one side of the roots, and shifted to the other side every 5-10 d (PRD). PRD plants had a similar midday leaf water potential to that of FI, whereas in the GH their root water potential (Psi(r)) was significantly lowered after 5 d. Stomatal conductance (g(s)) was more sensitive to PRD than photosynthesis (A) particularly in the field, leading to greater intrinsic water use efficiency (WUE) (i.e. A/g(s)) in PRD than in FI plants on several days. In PRD, the xylem sap abscisic acid concentration ([ABA](xylem)) increased exponentially with decreasing Psi(r); and the relative [ABA](xylem) (PRD/FI) increased exponentially as the fraction of transpirable soil water (FTSW) in the drying side decreased. In the field, the leaf area index was slightly less in PRD than in FI treatment, while tuber biomass was similar for the two treatments. Compared with FI, PRD treatment saved 30% water and increased crop water use efficiency (WUE) by 59%. Restrictions on leaf area expansion and g(s) by PRD-induced ABA signals might have contributed to reduced water use and increased WUE.

背景与目标： ：在温室（GH）的盆栽植物和自动防雨棚田间种植的植物中，研究了马铃薯（Solanum tuberosum L. cv。Folva）对部分根区干燥（PRD）的生理响应。在GH中，每天对整个根系（FI）或一半的根系进行灌溉，而另一半干燥9 d。在田间，将植物滴灌至接近田间持水量（FI）的整个根系，或使用70％的FI水将其滴到根的一侧，然后每5-10 d（PRD）移至另一侧。珠三角植物的中午叶片水势与FI相似，而在GH中，其根系水势（Psi（r））在5天后显着降低。尤其是在田间，气孔电导（g（s））比光合作用（A）对PRD更敏感，因此在几个地方，PRD中的固有水分利用效率（WUE）（即A / g（s））比FI植物更大。天。在珠三角地区，木质部汁液中脱落酸的浓度（[ABA]（木质部））随着Psi（r）的降低呈指数增长。相对[ABA]（木质部）（PRD / FI）随干旱侧可蒸发土壤水（FTSW）比例的减少呈指数增长。在田间，珠三角的叶面积指数略低于FI处理，而两种处理的块茎生物量相似。与FI相比，PRD处理节省了30％的水，并使作物水分利用效率（WUE）提高了59％。 PRD诱导的ABA信号对叶面积扩大和g（s）的限制可能有助于减少用水量和增加WUE。