BACKGROUND & AIMS: :Parkinson's disease (PD) afflicts millions of people worldwide. There are numerous drugs available for PD; however, levodopa remains the gold standard of pharmacotherapy to which all other therapies are compared. Levodopa is quite effective for many motor symptoms (bradykinesia, tremor, rigidity) of PD; however, non-levodopa-responsive motor symptoms (postural instability) and nonmotor symptoms are frequently the most troublesome in middle and later stages of disease. Although motor symptoms remain an important focus for emerging drugs, current research is largely geared to identify and develop disease-slowing therapies. Another important area of focus has become treatment of the nonmotor symptoms of PD (especially depression and dementia). This review discusses emerging drugs in the management of the motor and nonmotor symptoms of PD and drugs under study as disease-slowing/neuroprotective agents.

背景与目标： : 帕金森氏病 (PD) 困扰着全世界数百万人。有许多可用于PD的药物; 但是，左旋多巴仍然是药物治疗的金标准，所有其他疗法都可以与之进行比较。左旋多巴对PD的许多运动症状 (运动迟缓，震颤，僵硬) 非常有效; 但是，非左旋多巴反应的运动症状 (姿势不稳) 和非运动症状通常在疾病的中期和晚期最麻烦。尽管运动症状仍然是新兴药物的重要焦点，但目前的研究主要是为了识别和开发减缓疾病的疗法。另一个重要的重点领域是治疗PD的非运动症状 (尤其是抑郁症和痴呆症)。这篇综述讨论了治疗PD的运动和非运动症状的新兴药物以及正在研究的作为疾病减缓/神经保护剂的药物。

BACKGROUND & AIMS: :The prokaryotic and eukaryotic cells of the colon exist in a highly complex, but harmonious relationship. Disturbances in this remarkable symbiosis can result in the development of inflammatory bowel diseases (IBD). Although the etiology of IBD is not entirely understood, it is known that the chronic inflammation of Crohn's disease, ulcerative colitis and chronic pouchitis are a result of an overly aggressive immune response to the commensal intestinal flora in genetically susceptible hosts. Recent studies have enhanced our ability to understand the interaction between the host and its intestinal microflora and the role the microflora plays in maintaining intestinal homeostasis. As we begin to understand the benefits conferred to the intestine by the microflora, the notion of modifying the composition of the bacterial load to improve human health has arisen. A significant body of research now exists investigating the role of probiotics and prebiotics in ameliorating chronic intestinal inflammation. This article will begin with an overview of the role of the commensal microflora in maintaining mucosal immune homeostasis, and how a dysregulated immune response to the intestinal microflora results in IBD. This will be followed by a summary of the use of probiotics and prebiotics in experimental and human IBD.

背景与目标： : 结肠的原核和真核细胞以高度复杂但和谐的关系存在。这种显着共生的干扰可能导致炎症性肠病 (IBD) 的发展。尽管IBD的病因尚不完全清楚，但众所周知，克罗恩病，溃疡性结肠炎和慢性胆囊炎的慢性炎症是对遗传易感宿主的共生肠道菌群过度激进的免疫反应的结果。最近的研究增强了我们了解宿主与其肠道菌群之间的相互作用以及微生物群在维持肠道稳态中的作用的能力。当我们开始了解微生物区系赋予肠道的益处时，就出现了改变细菌负荷的组成以改善人类健康的想法。目前存在大量研究，研究益生菌和益生元在改善慢性肠道炎症中的作用。本文将首先概述共生菌群在维持粘膜免疫稳态中的作用，以及对肠道菌群的免疫反应失调如何导致IBD。随后将总结益生菌和益生元在实验和人类IBD中的使用。

BACKGROUND & AIMS: INTRODUCTION:Tissue factor (TF) has been implicated in coronary artery disease (CAD). High levels of circulating TF are found in patients with acute atherothrombotic events. Whether high serum TF levels predict risk of future CAD independent of known risk factors remains unknown. METHODS:We conducted a prospective case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk population study. Cases (n=1037) were apparently healthy men and women, aged 45-79 years, who developed fatal or non-fatal CAD during follow-up. Controls (n=2005) were matched by age, sex, and enrolment time. Serum TF levels were measured using high-affinity antibodies. RESULTS:In men, median TF levels were not significant higher in cases than in controls (59.0 pg mL-1, range: 16.7-370.4 vs. 54.9 pg mL-1, range: 16.2-452.4). In women, median TF levels were not significant higher in controls than in cases (73.4 pg mL-1, range: 16.7-492.3 vs. 50.5 pg mL-1, range: 16.5-376.7). The incidence of smoking was about double in the lowest compared with the highest TF quartile. Correcting for sex, age, body mass index, smoking, diabetes, systolic blood pressure, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and C-reactive protein levels, the risk of future CAD was 1.05 (95% CI: 0.81-1.36) for people in the highest TF quartile, compared with those in the lowest (P-value for linearity=0.8). CONCLUSION:High levels of serum TF were not independently associated with an increased risk of future CAD in apparently healthy individuals.

背景与目标：

BACKGROUND & AIMS: OBJECTIVE:Patients with severe traumatic or burn injury and a mouse model of burn injury were studied early after injury to determine the relation of plasma endotoxin (lipopolysaccharide [LPS]) to the production of proinflammatory cytokines and subsequent resistance to infection.

SUMMARY BACKGROUND DATA:Elevated levels of plasma LPS have been reported in patients after serious injury. It has been suggested that circulating LPS may be a trigger for increased proinflammatory cytokine production and may play a role in the septic syndromes seen in a substantial portion of such patients. Yet, despite multiple reports of leakage of LPS from the gut and bacterial translocation after injury in animal models, there is little direct evidence linking circulating LPS with production of inflammatory mediators.

METHODS:The authors studied serial samples of peripheral blood from 10 patients with 25% to 50% surface area burns and 8 trauma patients (injury Severity Score, 25-57). Patients were compared with 18 healthy volunteers. The study was focused on the first 10 days after injury before the onset of sepsis or the systemic inflammatory response syndrome. Plasma samples were assayed for LPS, and adherent cells from the blood were studied for basal and LPS-stimulated production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6). The correlation of increased plasma LPS with TNF-alpha production was studied as was the association of increased plasma LPS and increased TNF-alpha production with subsequent septic complications. We also studied a mouse model of 25% burn injury. Burn mice were compared with sham burn control subjects. Plasma samples were assayed at serial intervals for LPS, and adherent cells from the spleens were studied for basal- and LPS-stimulated production of TNF-alpha, IL-1 beta, and IL-6. Expression of the messenger RNAs for IL-1 beta and TNF-alpha also was measured. The relation of increased TNF-alpha production with mortality from a septic challenge, cecal ligation and puncture (CLP), was determined. Finally, the effect of administration of LPS to normal mice on subsequent mortality after CLP and on TNF-alpha production was studied.

RESULTS:Elevated plasma LPS (> 1 pg/mL) was seen in 11 of the 18 patients within 10 days of injury and in no normal control subjects. In this period, patients as compared with control subjects showed increased stimulated production of TNF-alpha, IL-1 beta, and IL-6. Increased TNF-alpha production was not correlated with elevated plasma LPS in the same patients. Neither increased plasma LPS nor increased TNF-alpha production early after injury was correlated with subsequent development of systemic inflammatory response syndrome or sepsis in the patients. Burn mice, as compared with sham burn control subjects, showed elevated plasma LPS levels chiefly in the first 3 days after injury. Increased stimulated production of proinflammatory cytokines by adherent splenocytes from the burn mice also was seen at multiple intervals after injury and did not correlate with mortality from CLP. Increased production of TNF-alpha and IL-1 beta was associated with increased expression of messenger RNAs for these cytokines. Finally, two doses of 1 ng LPS administered 24 hours apart to normal mice had no effect on mortality from CLP performed 7 days later nor on the production of TNF-alpha at the time of CLP.

CONCLUSIONS:These findings call into question the idea that circulating LPS is the trigger for increased proinflammatory cytokine production, systemic inflammatory response syndrome, and septic complications in injured patients.

背景与目标： 目标 : 严重创伤或烧伤患者和烧伤小鼠模型在损伤后早期进行了研究，以确定血浆内毒素 (脂多糖 [LPS]) 与促炎细胞因子的产生以及随后对感染的抵抗力之间的关系。
摘要背景数据 : 据报道，严重损伤后患者血浆LPS水平升高。已经提出，循环LPS可能是促炎性细胞因子产生增加的触发因素，并且可能在此类患者的大部分脓毒症综合征中起作用。然而，尽管有多份动物模型中LPS从肠道泄漏和细菌移位的报道，但几乎没有直接证据将循环LPS与炎症介质的产生联系起来。
方法 : 作者研究了10例25% 至50% 表面积烧伤患者和8例创伤患者的外周血系列样本 (损伤严重程度评分，25-57)。将患者与18名健康志愿者进行比较。该研究的重点是败血症或全身性炎症反应综合征发作前的受伤后10天。测定血浆样品中的LPS，并研究血液中的贴壁细胞的基础和LPS刺激的肿瘤坏死因子-α (TNF-α)，interleukin-1 β (IL-1 β) 和interleukin-6 (IL-6) 的产生。研究了血浆LPS增加与TNF-α 产生的相关性，以及血浆LPS增加和TNF-α 产生增加与随后的败血症并发症的关联。我们还研究了25% 烧伤的小鼠模型。将烧伤小鼠与假烧伤对照组进行比较。以连续间隔测定血浆样品中的LPS，并研究来自脾脏的贴壁细胞的基础和LPS刺激的TNF-α，IL-1 β 和IL-6的产生。还测量了IL-1 β 和TNF-α 的信使rna的表达。确定了TNF-α 产生增加与败血性攻击，盲肠结扎和穿刺 (CLP) 造成的死亡率之间的关系。最后，研究了向正常小鼠施用LPS对CLP后后续死亡率和TNF-α 产生的影响。
结果 : 18例患者中有11例在受伤后10天内发现血浆LPS升高 (> 1 pg/mL)，而没有正常对照。在此期间，与对照组相比，患者表现出TNF-α，IL-1 β 和IL-6的刺激产生增加。在同一患者中，TNF-α 产生的增加与血浆LPS升高无关。损伤后早期血浆LPS的增加和TNF-α 的产生均与患者全身炎症反应综合征或败血症的后续发展无关。与假烧伤对照组相比，烧伤小鼠的血浆LPS水平主要在受伤后的前3天升高。烧伤小鼠的粘附脾细胞刺激促炎细胞的产生也在受伤后的多个间隔内增加，并且与CLP的死亡率无关。TNF-α 和IL-1 β 的产生增加与这些细胞因子的信使rna的表达增加有关。最后，对正常小鼠相隔24小时施用两次1 ng LPS对7天后进行的CLP的死亡率没有影响，也没有对CLP时TNF-α 的产生影响。
结论 : 这些发现使人们质疑循环LPS是导致受伤患者促炎性细胞因子产生增加，全身性炎症反应综合征和败血症并发症的诱因。

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： : 酶替代疗法 (ERT) 已成为Pompe病患者的现实，Pompe病是一种致命的心肌病和骨骼肌肌病，该病是由糖原降解溶酶体酶酸 α-葡萄糖苷酶 (GAA) 缺乏引起的。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，但对骨骼肌无效。我们以前已经显示出GAA基因敲除小鼠 (KO) 的抗药性肌肉中溶酶体降解途径 (自噬) 的严重干扰。我们在这里的发现表明，除了在KO的多个肌肉群中增加糖原填充的溶酶体外，还存在逐渐的年龄依赖性自噬积累。治疗酶沿内吞途径的运输和加工似乎受到自噬的影响。暴露于荧光标记的rhGAA的活的单根肌肉纤维的共聚焦显微镜显示，KO中很大一部分内吞酶被捕获为自噬区域中的部分加工形式，而不是达到其目标-溶酶体。类似地，液相内吞标记物被错误地捕获并积累在自噬区域内的囊泡结构中。这些发现可以解释为什么ERT经常无法逆转疾病过程，并为药物干预的发展指明了新的途径。

BACKGROUND & AIMS: :Theories explaining the etiopathogenesis of inflammatory bowel disease (IBD) have been proposed ever since Crohn's disease (CD) and ulcerative colitis (UC) were recognized as the two major forms of the disease. Although the exact cause(s) and mechanisms of tissue damage in CD and UC have yet to be completely understood, enough progress has occurred to accept the following hypothesis as valid: IBD is an inappropriate immune response that occurs in genetically susceptible individuals as the result of a complex interaction among environmental factors, microbial factors, and the intestinal immune system. Among an almost endless list of environmental factors, smoking has been identified as a risk factor for CD and a protective factor for UC. Among microbial factors, no convincing evidence indicates that classical infectious agents cause IBD, while mounting evidence points to an abnormal immune response against the normal enteric flora as being of central importance. Gut inflammation is mediated by cells of the innate as well as adaptive immune systems, with the additional contribution of non-immune cells, such as epithelial, mesenchymal and endothelial cells, and platelets.

背景与目标： : 自从克罗恩病 (CD) 和溃疡性结肠炎 (UC) 被认为是炎症性肠病 (IBD) 的两种主要形式以来，就提出了解释炎症性肠病 (IBD) 病因的理论。尽管CD和UC组织损伤的确切原因和机制尚未完全了解，但已经取得了足够的进展，接受以下假设是有效的: IBD是一种不适当的免疫反应，由于遗传易感个体的结果环境因素之间的复杂相互作用，微生物因素和肠道免疫系统。在几乎无穷无尽的环境因素列表中，吸烟已被确定为CD的危险因素和UC的保护因素。在微生物因素中，没有令人信服的证据表明经典的感染因子引起IBD，而越来越多的证据表明针对正常肠道菌群的异常免疫反应至关重要。肠道炎症是由先天免疫系统和适应性免疫系统的细胞介导的，非免疫细胞 (例如上皮，间充质和内皮细胞以及血小板) 的额外贡献。

BACKGROUND & AIMS: :Etanercept is a recombinant human soluble tumor necrosis factor (TNF-alpha) receptor fusion protein that inhibits TNF-alpha, a major mediator in the pathogenesis of graft-versus-host disease (GVHD). The purpose of our study was to evaluate the safety and efficacy of etanercept therapy in 21 patients with steroid-refractory acute GVHD (aGVHD) (n = 13) and chronic GVHD (cGVHD) (n = 8). Etanercept 25 mg was given subcutaneously twice weekly for 4 weeks followed by 25 mg weekly for 4 weeks. At the time of initiation of etanercept, 14 patients had skin, 13 had gastro-intestinal, 5 had liver, 5 had pulmonary, and 4 had oral involvement. Twelve patients (57%) completed 12 doses of therapy. Overall, 11 of 21 patients (52%) responded to the treatment with etanercept, including 6 patients (46%) with aGVHD [n = 4 complete response (CR), n = 2 partial response (PR)] and 5 patients (62%) with cGVHD (n = 1 CR, n = 4 PR). Clinical responses were most commonly seen in patients with refractory gut aGVHD with 55% of the patients having a CR and 9% having a PR. CMV reactivation occurred in 48% of patients, bacterial infections in 14% of patients, and fungal infections in 19% of patients. Fourteen patients (67%) were alive after a median follow-up of 429 days (range 71-1007 days) since initiation of etanercept. Seven patients died, 3 of infections, 2 of refractory aGVHD, and 2 of disease progression. In conclusion, our preliminary data indicate that etanercept is well tolerated and can induce a high response rate in patients with steroid-refractory aGVHD and cGVHD, particularly in the setting of GI involvement.

背景与目标： : 依那西普是一种重组人可溶性肿瘤坏死因子 (TNF-α) 受体融合蛋白，可抑制TNF-α，TNF-α 是移植物抗宿主病 (GVHD) 发病机理中的主要介质。我们研究的目的是评估依那西普治疗21例类固醇难治性急性GVHD (aGVHD) (n = 13) 和慢性GVHD (cGVHD) (n = 8) 患者的安全性和有效性。依那西普25 mg，每周皮下注射两次，持续4周，然后每周注射25 mg，持续4周。在开始使用依那西普时，14例患者有皮肤，13例有胃肠道，5例有肝脏，5例有肺部，4例有口腔受累。12名患者 (57%) 完成12剂治疗。总体而言，21例患者中有11例 (52%) 对依那西普治疗有反应，其中6例 (46% 例) aGVHD [n = 4完全缓解 (CR)，n = 2部分缓解 (PR)] 和5例 (62%) cGVHD (n = 1 CR，n = 4 PR)。临床反应最常见于难治性肠道aGVHD患者，其中55% 患者具有CR，9% 患者具有PR。48% 患者发生CMV再激活，14% 患者发生细菌感染，19% 患者发生真菌感染。自依那西普开始以来，中位随访429天 (范围71-1007天) 后，有14名患者 (67%) 还活着。7例患者死亡，3例感染，2例难治性aGVHD，2例疾病进展。总之，我们的初步数据表明，依那西普具有良好的耐受性，并且可以在类固醇难治性aGVHD和cGVHD患者中诱导高反应率，尤其是在GI受累的情况下。

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) 是胃肠道的慢性炎症性疾病，具有共同的临床和病理特征。最受认可的假设是，CD和UC都是由于对肠道微生物群落正常成分的粘膜免疫反应失调所致。然而，有证据表明，这两种疾病的主要病理过程是不同的。在CD中，破坏组织的炎症反应是由激活的1型辅助T细胞 (Th1) 驱动的，而在UC中，体液反应占主导地位。一致地，在CD中观察到产生主要Th1-inducing因子白介素 (IL)-12的巨噬细胞的明显积累，但在UC粘膜中未见。初步研究还表明，施用阻断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共享p40亚基，这增加了CD中anti-IL-12/p40抗体的临床益处也可能归因于IL-23活性的中和的可能性。这篇综述总结了有关CD患者和结肠炎实验模型中IL-12和IL-12-associated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活性在肠道炎症发展中的主要差异。

BACKGROUND & AIMS: UNLABELLED:In this study, we assessed the accuracy and reliability of MRI-guided SPECT measurements of medial temporal lobe blood flow in Alzheimer's disease (AD).

METHODS:Interactively aligned three-dimensional MP-RAGE MRI and 99mTc-HMPAO SPECT images were used for MRI-guided measurement of medial temporal lobe CBF in eight control subjects and eight patients with probable AD. Intraoperator reliability was assessed by repeated alignment and measurement by one experienced operator. Accuracy was assessed by examining two subjects with fiducial markers.

RESULTS:The alignment error was less than 1 SPECT pixel size (3.5 mm) and the coefficient of variation in repeated measures of medial temporal-to-cerebellar CBF ratios was 3.2%. The difference in mean medial temporal-to-cerebellar CBF ratios between eight control subjects and eight AD patients was 12%. Also by using three-dimensional seed-grow defined healthy brain reference regions, there were significant differences between control subjects and AD patients in medial temporal blood flow. Furthermore, the volumes of the MRI-defined medial temporal ROIs were smaller in the AD patients. The best separation between AD patients and control subjects was achieved by combining MRI measurements of atrophy and SPECT measurements of CBF.

CONCLUSION:These data show that the accuracy and reliability of MRI-guided SPECT measurements of medial temporal CBF clearly allow the detection of changes in AD. Also, a direct comparison of structural and functional changes is possible by this methodology, which might improve the early diagnosis of AD.

背景与目标： 未标记 : 在这项研究中，我们评估了MRI引导的SPECT测量阿尔茨海默氏病 (AD) 内侧颞叶血流的准确性和可靠性。
方法 : 交互式对齐的三维MP-RAGE MRI和99mTc-HMPAO SPECT图像用于MRI引导的8名对照受试者和8名可能患有AD的患者的内侧颞叶CBF测量。一位经验丰富的操作员通过重复对准和测量来评估操作员内部的可靠性。通过检查两个具有基准标记的受试者来评估准确性。
结果 : 对齐误差小于1 SPECT像素大小 (3.5毫米)，并且重复测量的变异系数内侧颞-小脑CBF比3.2%。12% 了八名对照受试者和八名AD患者之间平均内侧颞与小脑CBF比率的差异。同样，通过使用三维种子生长定义的健康大脑参考区域，对照组和AD患者在内侧颞血流方面存在显着差异。此外，在AD患者中，MRI定义的内侧颞roi的体积较小。通过结合萎缩的MRI测量和CBF的SPECT测量，可以实现AD患者与对照组之间的最佳分离。
结论 : 这些数据表明，MRI引导的内侧颞CBF SPECT测量的准确性和可靠性显然可以检测AD的变化。此外，通过这种方法可以直接比较结构和功能变化，这可能会改善AD的早期诊断。

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，不受控制的报告中，我们描述了我们用氯氮平治疗PD相关精神病的经验，强调了那些治疗时间超过1年的患者。27例患者接受了治疗，其中14例超过1年。使用临床总体印象和总体精神病评分，大多数患者在1个月内从基线显示出快速改善。五名患者因副作用而停药，但只有两名患者在治疗6个月后报告副作用。氯氮平似乎可有效治疗PD相关的精神病性症状，同时不干扰运动功能。

BACKGROUND & AIMS: :The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)-induced gamma-activating factor-mediated immunity and interferon alpha (IFNA)-induced interferon-stimulated genes factor 3-mediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles. Their phenotypic effects are however mediated by different molecular mechanisms, L706S affecting STAT1 phosphorylation and Q463H and E320Q affecting STAT1 DNA-binding activity. Heterozygous patients display specifically impaired IFNG-induced gamma-activating factor-mediated immunity, resulting in susceptibility to mycobacteria. Indeed, IFNA-induced interferon-stimulated genes factor 3-mediated immunity is not affected, and these patients are not particularly susceptible to viral disease, unlike patients homozygous for other, equally deleterious STAT1 mutations recessive for both phenotypes. The three STAT1 alleles are therefore dominant for IFNG-mediated antimycobacterial immunity but recessive for IFNA-mediated antiviral immunity at the cellular and clinical levels. These STAT1 alleles define two forms of dominant STAT1 deficiency, depending on whether the mutations impair STAT1 phosphorylation or DNA binding.

背景与目标： 转录因子信号转导和转录激活因子-1 (STAT1) 在抵抗分枝杆菌和病毒感染的免疫中起关键作用。在这里，我们描述了来自其他健康的分枝杆菌疾病患者的三个人类STAT1种系等位基因。先前报道的L706S，如新型Q463H和E320Q等位基因，对干扰素 γ (IFNG) 诱导的 γ 激活因子介导的免疫和干扰素 α (IFNA) 诱导的干扰素刺激基因因子3介导的免疫具有内在的有害作用，如用相应等位基因转染的STAT1-deficient细胞所示。然而，它们的表型效应是由不同的分子机制介导的，L706S影响STAT1磷酸化，Q463H和E320Q影响STAT1 DNA结合活性。杂合子患者表现出特异性受损的IFNG诱导的 γ 激活因子介导的免疫力，导致对分枝杆菌的敏感性。实际上，IFNA诱导的干扰素刺激基因因子3介导的免疫不受影响，并且这些患者对病毒性疾病并不特别敏感，这与其他纯合的患者不同，同样有害的STAT1突变对两种表型均隐性。因此，三个STAT1等位基因在IFNG介导的抗分枝杆菌免疫中占主导地位，但在细胞和临床水平上对IFNA介导的抗病毒免疫具有隐性。这些STAT1等位基因定义了两种形式的显性STAT1缺陷，具体取决于突变是否损害STAT1磷酸化或DNA结合。

BACKGROUND & AIMS: There is evidence that neutrophil functions such as chemotaxis and oxygen radical formation are disturbed in rheumatoid arthritis (RA). Medication might also influence these functions. Cyclic formation and depolymerisation of actin microfilaments is crucial in cell motility, but this phenomenon has not been studied in RA. The aim of this study was to investigate basal and dynamic (formyl-methionyl-leucyl-phenylalanine (fMLP)-induced) neutrophil actin polymerisation in ten RA patients (a) during therapy with non-steroidal anti-inflammatory drugs (NSAIDS) and (b) after stopping NSAIDS> The results were compared with those of ten age-matched controls. Basal F-actin content in RA patients with NSAIDS was significantly lower than in RA patients without NSAIDS and controls35.5 (25.0-49.0), 50.5 (27.0-75.0) and 52.5 (32.0-85.0), respectively. Conversely, upon stimulation with fMLP, the actin polymerisation curve of RA patients with NSAIDS was higher than for RA patients without NSAIDS and controls. These results suggest that, in RA, the effects orf NSAIDS on neutrophil functions might be related to changes in the actin polymerisation-depolymerisation cycle.

背景与目标： 有证据表明，类风湿性关节炎 (RA) 的中性粒细胞功能 (例如趋化性和氧自由基形成) 受到干扰。药物也可能影响这些功能。肌动蛋白微丝的循环形成和解聚对细胞运动至关重要，但尚未在RA中研究这种现象。这项研究的目的是研究10名RA患者 (a) 在非甾体类抗炎药 (nsaid) 治疗期间的基础和动态 (甲酰基-甲硫氨酸-亮氨酸-苯丙氨酸 (fMLP) 诱导的) 中性粒细胞肌动蛋白聚合反应 (a) 和 (b) 停止nsaid后的结果进行比较有十个年龄匹配的对照。患有NSAIDS的RA患者的基础F-肌动蛋白含量显着低于没有NSAIDS和对照组的RA患者35.5 (25.0-49.0)，50.5 (27.0-75.0) 和52.5 (32.0-85.0)。相反，用fMLP刺激后，患有NSAIDS的RA患者的肌动蛋白聚合曲线高于没有NSAIDS的RA患者和对照组。这些结果表明，在RA中，orf nsaid对中性粒细胞功能的影响可能与肌动蛋白聚合-解聚周期的变化有关。

BACKGROUND & AIMS: :Hepatic steatosis is defined by an increased content of hepatocellular lipids (HCLs) and is frequently observed in insulin-resistant states including type 2 diabetes mellitus. A dietary excess of saturated fat contributes significantly to HCL accumulation. Elevated HCL levels mainly account for hepatic insulin resistance, which is probably mediated by partitioning of free fatty acids to the liver (fat overflow) and by an imbalance of adipocytokines (decreased adiponectin and/or increased proinflammatory cytokines). Both free fatty acids and adipocytokines activate inflammatory pathways that include protein kinase C, the transcription factor nuclear factor kappaB, and c-Jun N-terminal kinase 1 and can thereby accelerate the progression of hepatic steatosis to nonalcoholic steatohepatitis and cirrhosis. Proton magnetic resonance spectroscopy has made it possible to quantify HCL concentrations and to detect even small changes in these concentrations in clinical settings. Moderately hypocaloric, fat-reduced diets can decrease HCL levels by approximately 40-80% in parallel with loss of up to 8% of body weight. Treatment with thiazolidinediones (e.g. pioglitazone and rosiglitazone) reduces HCL levels by 30-50% by modulating insulin sensitivity and endocrine function of adipose tissue in type 2 diabetes. Metformin improves hepatic insulin action without affecting HCL levels, whereas insulin infusion for 67 h increases HCL levels by approximately 18%; furthermore, HCL levels positively correlate with the insulin dosage in insulin-treated type 2 diabetes. In conclusion, liver fat is a critical determinant of metabolic fluxes and inflammatory processes, thereby representing an important therapeutic target in insulin resistance and type 2 diabetes mellitus.

背景与目标： : 肝脂肪变性是由肝细胞脂质 (HCLs) 含量增加定义的，在胰岛素抵抗状态 (包括2型糖尿病) 中经常观察到。饮食中过量的饱和脂肪会显着促进HCL的积累。HCL水平升高主要是导致肝胰岛素抵抗的原因，这可能是由游离脂肪酸分配到肝脏 (脂肪溢出) 和脂肪细胞因子失衡 (脂联素减少和/或促炎细胞因子增加) 介导的。游离脂肪酸和脂肪细胞因子都激活炎症途径，包括蛋白激酶C，转录因子核因子kappaB和c 6月N端激酶1，从而可以加速肝脂肪变性向非酒精性脂肪性肝炎和肝硬化的进展。质子磁共振波谱已使量化HCL浓度并在临床环境中检测到这些浓度的微小变化成为可能。中度低热量，减脂饮食可使HCL水平降低约40-80%，同时减少多达8% 的体重。噻唑烷二酮类药物 (例如吡格列酮和罗格列酮) 的治疗通过调节2型糖尿病中脂肪组织的胰岛素敏感性和内分泌功能，将HCL水平降低30-50%。二甲双胍改善肝胰岛素作用而不影响HCL水平，而胰岛素输注67小时可使HCL水平增加约18%; 此外，在胰岛素治疗的2型糖尿病中，HCL水平与胰岛素剂量呈正相关。总之，肝脏脂肪是代谢通量和炎症过程的关键决定因素，因此是胰岛素抵抗和2型糖尿病的重要治疗目标。

BACKGROUND & AIMS: PURPOSE:The value of high resolution computed tomography (HR-CT) in the recognition of pathologic changes of the lung parenchyma, especially in the diagnosis of sarcoidosis, is well established. The importance of these findings in regard to the inflammatory activity is not sufficiently documented, also because a direct histologic correlation is seldom possible.

METHOD:In a prospective study twenty-one patients with suspected or known sarcoidosis were evaluated. The diagnostic work up comprised the clinical examination, lung function tests, the radiological evaluation, including GH-CT, and bronchoscopy for bronchoalveolar lavage (BAL) and transbronchial biopsy.

RESULTS:The comparison of the HR-CT findings, like pathologic appearance of the bronchovascular bundle and intraparenchymal nodules, with serologic and BAL-parameters yielded high correlation coefficients with the total cell count in BAL and sIL-2R, and moderate correlations with the lavage lymphocyte count and the activity markers, like T4/T8 ratio, IL-2R and HLA-DR expression.

CONCLUSION:As a non invasive method, HR-CT depicts pathologic findings of the lung parenchyma which are associated with the inflammatory activity of sarcoidosis.

背景与目标： 目的 : 高分辨率计算机断层扫描 (hr-ct) 在识别肺实质的病理变化，特别是在结节病的诊断中的价值已得到充分确立。这些发现在炎症活性方面的重要性尚未得到充分证明，这也是因为很少有直接的组织学相关性。
方法 : 在一项前瞻性研究中，对21例疑似或已知结节病患者进行了评估。诊断工作包括临床检查，肺功能检查，放射学评估 (包括gh-ct) 以及支气管镜检查 (用于支气管肺泡灌洗 (BAL) 和经支气管活检)。
结果 : hr-ct结果的比较，像支气管血管束和实质内结节的病理外观一样，血清学和BAL参数与BAL和sIL-2R的总细胞计数具有高相关系数，与灌洗淋巴细胞计数和活性标志物 (如T4/T8比率) 具有中等相关性，IL-2R和hla-dr表达。
结论 : 作为一种非侵入性方法，hr-ct描述了与结节病的炎症活性相关的肺实质的病理发现。

BACKGROUND & AIMS: Activated neutrophils take a long time to pass through a narrow lumen like a micropore, and are supposed to play a deteriorating effect on microcirculation. Although the activation of neutrophils has been demonstrated in Behçet's disease, nobody analyzes the clinical activity of the disease by means of the rheological measure of neutrophils activity. Using a micropore (pore diameter 5 microns) filtration technique, we measured the filtration time of peripheral blood neutrophils, as a rheological measure of their activity, in order to determine the clinical activity of Behçet's disease. Twenty-one patients with Behçet's disease and 14 healthy control individuals were enrolled in the study. Symptoms and signs exhibited in the patients led us to distinguish the Behçet's disease into inactive and active cases. The latter were further differentiated into cases with absent symptoms and with present symptoms. Neutrophil filtration times were 11.5 +/- 4.8 s in the active cases with present symptoms, which were significantly (P < 0.05) larger than those (7.4 +/- 1.9 s) in the active cases with absent symptoms. The latter filtration times were further significantly (P < 0.001) larger than values (3.7 +/- 1.3 s) in the inactive cases and also those (4.8 +/- 1.2 s) in control subjects. Furthermore, increases in the filtration time obtained immediately after the exposure of cells to the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (FMLP10 nM) were significantly (P < 0.01) larger in the active cases with present symptoms than those in the active cases with absent symptoms. The latter were also larger, but not significantly, than those in the inactive cases, and were significantly (P < 0.01) larger than those in control subjects. The present results demonstrate that the micropore filtration method reflects well the rheological activity of neutrophils as well as the clinical status of Behçet's disease. This method is much better than the measurement of O2 production to differentiate between active cases with absent symptoms and inactive patients or even control individuals. Furthermore, it is more sensitive and useful than laboratory data like the CRP value or the number of peripheral blood neutrophils.

背景与目标： 活化的中性粒细胞需要很长时间才能通过像微孔一样的狭窄管腔，并且应该对微循环起到恶化的作用。尽管在beh ç et病中已经证明了中性粒细胞的激活，但没有人通过中性粒细胞活性的流变学测量来分析该疾病的临床活性。使用微孔 (孔径5微米) 过滤技术，我们测量了外周血中性粒细胞的过滤时间，作为其活性的流变学指标，以确定白塞氏病的临床活性。21名beh ç et病患者和14名健康对照者参加了这项研究。患者表现出的症状和体征使我们将白塞氏病区分为不活跃和活跃的病例。后者进一步分为无症状和现有症状的病例。有症状的活动病例的中性粒细胞过滤时间为11.5 +/- 4.8 s，显著 (P < 0.05) 大于无症状的活动病例的中性粒细胞过滤时间 (7.4 +/- 1.9 s)。后者的过滤时间进一步显著 (P < 0.001) 大于非活性情况下的值 (3.7 +/- 1.3 s)，也大于对照受试者中的值 (4.8 +/- 1.2 s)。此外，在细胞暴露于趋化肽甲酰基-甲硫酰基-亮氨酸-苯丙氨酸 (fmlp10nm) 后立即获得的过滤时间的增加在存在症状的活动病例中比在不存在症状的活动病例中显着 (P < 0.01) 大。后者也比不活跃的情况更大，但不显著，并且显著 (P < 0.01) 大于对照组。目前的结果表明，微孔过滤方法很好地反映了嗜中性粒细胞的流变活性以及白塞病的临床状况。此方法比O2产生的测量要好得多，可以区分无症状的活跃病例和不活跃的患者甚至对照组。此外，它比CRP值或外周血中性粒细胞数量等实验室数据更敏感和有用。