• 1 Emerging drugs for Parkinson's disease. 复制标题 收藏 收藏

    【帕金森病的新兴药物。】 复制标题 收藏 收藏
    DOI:10.1517/14728214.11.3.403 复制DOI
    作者列表:Morgan JC,Sethi KD
    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。
  • 【小鼠短暂性大脑中动脉闭塞后新皮层血管周围aquaporin-4的暂时性丧失。】 复制标题 收藏 收藏
    DOI:10.1073/pnas.0605796103 复制DOI
    作者列表:Frydenlund DS,Bhardwaj A,Otsuka T,Mylonakou MN,Yasumura T,Davidson KG,Zeynalov E,Skare O,Laake P,Haug FM,Rash JE,Agre P,Ottersen OP,Amiry-Moghaddam M
    BACKGROUND & AIMS: :The aquaporin-4 (AQP4) pool in the perivascular astrocyte membranes has been shown to be critically involved in the formation and dissolution of brain edema. Cerebral edema is a major cause of morbidity and mortality in stroke. It is therefore essential to know whether the perivascular pool of AQP4 is up- or down-regulated after an ischemic insult, because such changes would determine the time course of edema formation. Here we demonstrate by quantitative immunogold cytochemistry that the ischemic striatum and neocortex show distinct patterns of AQP4 expression in the reperfusion phase after 90 min of middle cerebral artery occlusion. The striatal core displays a loss of perivascular AQP4 at 24 hr of reperfusion with no sign of subsequent recovery. The most affected part of the cortex also exhibits loss of perivascular AQP4. This loss is of magnitude similar to that of the striatal core, but it shows a partial recovery toward 72 hr of reperfusion. By freeze fracture we show that the loss of perivascular AQP4 is associated with the disappearance of the square lattices of particles that normally are distinct features of the perivascular astrocyte membrane. The cortical border zone differs from the central part of the ischemic lesion by showing no loss of perivascular AQP4 at 24 hr of reperfusion but rather a slight increase. These data indicate that the size of the AQP4 pool that controls the exchange of fluid between brain and blood during edema formation and dissolution is subject to large and region-specific changes in the reperfusion phase.
    背景与目标: : 血管周围星形胶质细胞膜中的aquaporin-4 (AQP4) 池已被证明与脑水肿的形成和溶解密切相关。脑水肿是中风发病和死亡的主要原因。因此,必须了解缺血性损伤后AQP4的血管周围池是上调还是下调,因为这种变化将决定水肿形成的时间过程。在这里,我们通过定量免疫金细胞化学证明,在大脑中动脉闭塞90分钟后,缺血纹状体和新皮层在再灌注阶段显示出不同的AQP4表达模式。再灌注24小时时,纹状体核心显示血管周围AQP4丢失,没有随后恢复的迹象。皮质中受影响最大的部分也表现出血管周围aqp4的损失。这种损失的幅度与纹状体核心的损失相似,但在再灌注72小时后显示部分恢复。通过冷冻断裂,我们表明血管周围AQP4的丢失与颗粒的正方形晶格的消失有关,这些正方形晶格通常是血管周围星形胶质细胞膜的独特特征。皮质边界区与缺血性病变的中央部分不同,在再灌注24小时时未显示血管周围AQP4的丢失,但略有增加。这些数据表明,在水肿形成和溶解过程中控制大脑和血液之间流体交换的AQP4池的大小在再灌注阶段会发生较大且区域特定的变化。
  • 【表面上健康的男性和女性的组织因子血清水平和未来冠状动脉疾病的风险: EPIC-Norfolk前瞻性人群研究。】 复制标题 收藏 收藏
    DOI:10.1111/j.1538-7836.2006.02190.x 复制DOI
    作者列表:Keller TT,Choi D,Nagel C,Te Velthuis H,Gerdes VE,Wareham NJ,Bingham SA,Luben R,Hack CE,Reitsma PH,Levi M,Khaw KT,Boekholdt SM
    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:
  • 【庞贝病骨骼肌自噬和治疗酶的误用。】 复制标题 收藏 收藏
    DOI:10.1016/j.ymthe.2006.08.009 复制DOI
    作者列表:Fukuda T,Ahearn M,Roberts A,Mattaliano RJ,Zaal K,Ralston E,Plotz PH,Raben N
    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。
  • 【重组人可溶性肿瘤坏死因子受体融合蛋白治疗异基因造血干细胞移植后类固醇难治性移植物抗宿主病.】 复制标题 收藏 收藏
    DOI:10.1002/ajh.20752 复制DOI
    作者列表:Busca A,Locatelli F,Marmont F,Ceretto C,Falda M
    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。
  • 【克罗恩病的Interleukin-12和Th1免疫反应: 发病相关性和治疗意义。】 复制标题 收藏 收藏
    DOI:10.3748/wjg.v12.i35.5606 复制DOI
    作者列表:Peluso I,Pallone F,Monteleone G
    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。
  • 【MRI引导的阿尔茨海默病内侧颞叶血流的SPECT测量。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Julin P,Lindqvist J,Svensson L,Slomka P,Wahlund LO
    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。
  • 【氯氮平治疗帕金森氏病左旋多巴诱发的精神病: 回顾性研究。】 复制标题 收藏 收藏
    DOI:10.1177/089198879701000205 复制DOI
    作者列表:Widman LP,Burke WJ,Pfeiffer RF,McArthur-Campbell D
    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。
  • 【在其他健康的分枝杆菌疾病患者中发现新的STAT1等位基因。】 复制标题 收藏 收藏
    DOI:10.1371/journal.pgen.0020131 复制DOI
    作者列表:
    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。
  • 【冠状动脉患者预后评估: 通用严重度指标的性能和定制。】 复制标题 收藏 收藏
    DOI:10.1378/chest.111.6.1666 复制DOI
    作者列表:Sarmiento X,Rué M,Guardiola JJ,Toboso JM,Soler M,Artigas A
    BACKGROUND & AIMS: STUDY OBJECTIVE:To assess the prognostic performance of general severity systems (APACHE II [acute physiology and chronic health evaluation], simplified acute physiology score [SAPS II], and mortality probability models [MPM II]) in coronary patients and to derive new customized indexes for coronary patients using a reduced number of variables.

    DESIGN:Inception cohort.

    SETTING:Adult medical and surgical ICUs in 17 hospitals in Catalonia and the Balearic Islands.

    PATIENTS:Four hundred fifty-six patients with acute myocardial infarction.

    MEASUREMENTS AND RESULTS:The APACHE II, SAPS II, and MPM II variables and survival status at hospital discharge have been collected. Performance of the severity systems was assessed by evaluating calibration and discrimination. Logistic regression was used to customize the MPM II(24) and SAPS II indexes. Discrimination was high enough for all of the models. However, calibration of the MPM II(24) was not as satisfactory as for the other models. The MPM II(24) and SAPS II were both reduced to five variables (MPM II(24 cor:) age, PaO2, continuous vasoactive drugs, urinary output, and mechanical ventilation; SAPS II(cor:) age, PaO2/FI(O2) ratio, systolic BP, Glasgow coma score, and urinary output). Both models showed better calibration and discrimination than the original ones.

    CONCLUSIONS:Prognostic indexes developed for multidisciplinary patients show good performance when applied to patients with acute myocardial infarction, but customization can reduce the number of variables necessary to compute them without a loss of, and a possible improvement in, prognostic accuracy.

    背景与目标: 研究目标 : 评估一般严重程度系统 (APACHE II [急性生理学和慢性健康评估],简化的急性生理学评分 [SAPS II],和冠心病患者的死亡率概率模型 [MPM II]),并使用减少的变量数量为冠心病患者推导新的定制指标。
    设计 : 初始队列。
    设置 : 加泰罗尼亚和巴利阿里群岛17家医院的成人医疗和外科重症监护医师。
    患者 : 456例急性心肌梗死患者。
    测量和结果 : 已收集APACHE II,SAPS II和MPM II变量以及出院时的生存状态。通过评估校准和判别来评估严重性系统的性能。Logistic回归用于定制MPM II(24) 和SAPS II指数。歧视对于所有模型来说都足够高。但是,MPM II(24) 的校准不如其他模型令人满意。MPM II(24) 和SAPS II均降低为五个变量 (MPM II(24 cor :) 年龄,PaO2,持续血管活性药物,尿量和机械通气; SAPS II(cor :) 年龄,PaO2/FI(O2) 比,收缩压,格拉斯哥昏迷评分,和尿量)。两种模型均显示出比原始模型更好的校准和区分度。
    结论 : 为多学科患者开发的预后指标在应用于急性心肌梗死患者时显示出良好的表现,但是,自定义可以减少计算它们所需的变量数量,而不会损失预后准确性,并可能提高预后准确性。
  • 【疾病机制: 2型糖尿病的肝脂肪变性-发病机制和临床意义。】 复制标题 收藏 收藏
    DOI:10.1038/ncpendmet0190 复制DOI
    作者列表:Roden M
    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。
  • 【通过微孔过滤测量的外周血中性粒细胞流变学很好地反映了白塞氏病的活动。】 复制标题 收藏 收藏
    DOI:10.1016/s0923-1811(97)00599-9 复制DOI
    作者列表:Iijima S,Otsuka F
    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。
  • 【雌二醇通过上调Fas和Fas配体的表达来增加人冠状动脉内皮细胞的凋亡。】 复制标题 收藏 收藏
    DOI:10.1210/jc.2006-1225 复制DOI
    作者列表:Seli E,Guzeloglu-Kayisli O,Cakmak H,Kayisli UA,Selam B,Arici A
    BACKGROUND & AIMS: CONTEXT:In animal models, estrogen inhibits atherogenesis by inhibiting many of the early steps of atherosclerotic plaque formation. However, the lack of cardioprotective effect by postmenopausal hormone replacement therapy and possible increase in cardiovascular events observed during the first year after the initiation of hormone replacement therapy may suggest that once the plaque is formed, estrogen may have additional effects that may counteract its beneficial outcomes. Indeed, the effect of estrogen on plaque stability has not been identified. OBJECTIVE:We hypothesized that 17beta-estradiol (E2) may cause increased apoptosis in human coronary artery endothelial cells (HCAECs). This effect would explain an adverse effect on plaque stability in vivo. INTERVENTION(S) AND MAIN OUTCOME MEASURE(S):The effect of E2 on apoptosis, cell proliferation, and expression of proapoptotic molecules Fas and Fas ligand (FasL) in cultured HCAECs was evaluated. RESULTS:HCAECs in culture treated with E2 showed an increase in DNA strand breaks and nuclear fragmentation indicative of apoptosis. E2 treatment also induced a significant concentration-dependent increase in Fas mRNA and protein expressions in HCAECs. Moreover, the expression of FasL mRNA and secretion of FasL protein by HCAECs were enhanced in response to E2 treatments. CONCLUSIONS:E2 increases the apoptosis in cultured HCAECs. Enhanced Fas and FasL expressions in response to E2 suggest that activation of the Fas/FasL pathway may be a mediator of the proapoptotic effects of E2 in these cells.
    背景与目标:
  • 【肾动脉狭窄和单侧局灶性和节段性肾小球硬化。】 复制标题 收藏 收藏
    DOI:10.1016/s0272-6386(97)90469-8 复制DOI
    作者列表:Alkhunaizi AM,Chapman A
    BACKGROUND & AIMS: Focal and segmental sclerosed lesions in the glomeruli are found in several pathological entities and more often are found in the corticomedullary junction where renal blood flow and filtration pressure is maximal. Experimental data suggest that hyperfiltration injury results in focal and segmental glomerulosclerosis (FSGS). In keeping with this concept, malignant hypertension is a known cause of nephrotic-range proteinuria and nephrotic syndrome pathalobically represented by FSGS. We report a case of unilateral renal artery stenosis associated with nephrotic syndrome and FSGS in the contralateral kidney only. The kidney with the stenosed renal artery showed normal glomeruli with juxtaglomerular hyperplasia, suggesting that protection from hyperfiltration injury was provided by the presence of high-grade stenosis. Serum creatinine concentration, blood pressure, and proteinuria normalized after aorto-renal bypass surgery. This case shows the importance of hemodynamic factors on the pathogenesis of secondary FSGS and the progression of renal disease.

    背景与目标: 肾小球的局灶性和节段性硬化性病变在几种病理实体中发现,而在肾血流量和过滤压力最大的皮质管交界处更常见。实验数据表明,超滤损伤会导致局灶性和节段性肾小球硬化 (FSGS)。与这个概念保持一致,恶性高血压是由FSGS病理代表的肾病范围蛋白尿和肾病综合征的已知原因。我们报告了仅在对侧肾脏中与肾病综合征和FSGS相关的单侧肾动脉狭窄病例。肾动脉狭窄的肾脏显示正常的肾小球并伴有近肾小球增生,这表明高级别狭窄的存在可保护高滤过损伤。主动脉-肾搭桥手术后血清肌酐浓度,血压和蛋白尿正常化。该病例显示了血流动力学因素对继发性FSGS发病机理和肾脏疾病进展的重要性。
  • 【过敏性眼病结膜上皮结构蛋白减少。】 复制标题 收藏 收藏
    DOI:10.1111/j.1398-9995.2006.01207.x 复制DOI
    作者列表:Hughes JL,Lackie PM,Wilson SJ,Church MK,McGill JI
    BACKGROUND & AIMS: AIMS:Allergic eye disease affects up to 20% of the population with varying severity. The conjunctival epithelium plays a key role in allergic eye disease. The purpose of this study was to determine whether the conjunctival epithelium is abnormal in allergic eye disease. METHODS:Conjunctival biopsy samples were taken from patients with seasonal allergic conjunctivitis (SAC) 'in' and 'out of season' and nonatopic control subjects. Specimens were fixed in glycol methacrylate, 2 microm serial sections cut and Image-J used to assess the sites and areas of immuno-staining. RESULTS:E-cadherin, CD44, keratins K5/6, K8, K13, K14, K18 and pan-keratin immuno-staining were all significantly lower in patients 'out of season' compared with normal controls. No structural differences in the epithelium were observed between the two groups. The epithelium of patients 'in season' was thicker and immuno-staining of the above markers similar to controls. CONCLUSIONS:The expression of a wide spectrum of epithelial cell adhesion proteins and cytoskeletal elements is downregulated in the conjunctiva of SAC patients 'out of season' compared with normal controls. We suggest that this could have an important impact on the ability of the epithelium to protect itself against allergen penetration, potentially influencing the development and course of allergic eye disease and offering a novel area for therapeutic control.
    背景与目标:

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