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

    【帕金森氏病的新兴药物。】 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)困扰着全球数百万人。 PD有多种药物可供使用;然而,左旋多巴仍然是药物疗法的黄金标准,可与所有其他疗法进行比较。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。然而,在疾病的中晚期,非左旋多巴反应性运动症状(姿势不稳)和非运动症状通常是最麻烦的。尽管运动症状仍然是新兴药物的重要关注点,但当前的研究在很大程度上旨在识别和发展减慢疾病的疗法。另一个重要的重点领域已成为治疗PD的非运动性症状(尤其是抑郁症和痴呆症)的方法。这篇综述讨论了PD的运动和非运动症状管理中的新兴药物,以及正在研究的疾病缓解/神经保护剂药物。
  • 【显然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: 简介:组织因子(TF)与冠心病(CAD)有关。在患有急性动脉粥样硬化血栓形成事件的患者中发现高水平的循环TF。血清TF高水平是否能独立于已知的危险因素来预测未来CAD的风险仍然未知。
    方法:我们进行了一项前瞻性病例对照研究,该研究嵌套在欧洲癌症与营养前瞻性调查(EPIC)-诺福克人群研究中。病例(n = 1037)显然是健康的男性和女性,年龄在45-79岁之间,在随访期间发生了致命或非致命的CAD。对照组(n = 2005)按年龄,性别和入组时间进行匹配。使用高亲和力抗体测量血清TF水平。
    结果:在男性中,病例中的TF中位数没有显着高于对照组(59.0 pg / mL-1,范围:16.7-370.4 vs. 54.9 pg / mL-1,范围:16.2-452.4)。在女性中,对照的中位TF水平没有比病例高(73.4 pg / mL-1,范围:16.7-492.3 vs. 50.5 pg / mL-1,范围:16.5-376.7)。与最高四分位数的吸烟者相比,最低吸烟率的吸烟者约为两倍。校正性别,年龄,体重指数,吸烟,糖尿病,收缩压,低密度脂蛋白胆固醇,高密度脂蛋白胆固醇和C反应蛋白水平后,未来CAD的风险为1.05(95%CI: TF最高四分位数的人与最低TF四分位数的人(线性P值= 0.8)相比。
    结论:血清TF水平升高与明显健康的个体未来冠心病风险增加并没有独立的关系。
  • 【庞贝病骨骼肌中治疗酶的自噬和靶向错误。】 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: :对于因糖原降解溶酶体酶酸性α-葡萄糖苷酶(GAA)缺乏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。
  • 【重组人可溶性肿瘤坏死因子受体融合蛋白作为同种异体造血干细胞移植后类固醇难治性移植物抗宿主病的治疗方法。】 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: :Etanercept是一种重组人类可溶性肿瘤坏死因子(TNF-alpha)受体融合蛋白,可抑制TNF-alpha(一种在移植物抗宿主病(GVHD)发病机理中的主要介体)。本研究的目的是评估依那西普治疗21例激素抵抗性急性GVHD(aGVHD)(n = 13)和慢性GVHD(cGVHD)(n = 8)患者的安全性和有效性。每周两次皮下给予Etanercept 25 mg,持续4周,然后每周25 mg,持续4周。依那西普开始治疗时,有14例皮肤,13例胃肠,5例肝,5例肺,4例经口受累。 12名患者(57%)完成了12剂治疗。总体上,在21名患者中有11名患者(52%)对依那西普治疗有反应,包括6名患者(46%)患有aGVHD [n = 4完全缓解(CR),n = 2部分缓解(PR)]和5例(62 %)和cGVHD(n = 1 CR,n = 4 PR)。临床反应最常见于顽固性肠aGVHD患者,其中55%的患者为CR,9%的患者为PR。 CMV重新激活发生在48%的患者中,细菌感染发生在14%的患者中,而真菌感染发生在19%的患者中。自依那西普开始接受中位随访429天(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死亡,2例疾病进展。总之,我们的初步数据表明,依那西普耐受性好,在类固醇难治性aGVHD和cGVHD患者中可引起较高的应答率,尤其是在胃肠道受累的情况下。
  • 【克罗恩病中的白细胞介素12和Th1免疫应答:病原学意义和治疗意义。】 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。这篇综述总结了有关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。
  • 【在阿尔茨海默氏病中,MRI指导的SPECT测量颞叶内侧血流。】 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: UNLABELLED :在这项研究中,我们评估了MRI指导的SPECT测量中度颞叶血流在阿尔茨海默病(AD)中的准确性和可靠性。

    方法 strong>:交互式对准的三维MP-RAGE MRI和99mTc-HMPAO SPECT图像用于MRI指导的八名对照受试者和八名可能患有AD的患者的内侧颞叶CBF的测量。一位经验丰富的操作员通过反复对准和测量来评估操作员的可靠性。通过检查两个带有基准标记的受试者来评估准确性。

    结果:对准误差小于1个SPECT像素大小(3.5毫米),并且重复内侧测量的变异系数颞小脑CBF率为3.2%。八名对照受试者和八名AD患者之间的平均内侧颞小脑CBF比率的差异为12%。同样,通过使用定义的三维种子生长的健康大脑参考区域,对照受试者和AD患者之间的颞内侧血流存在显着差异。此外,在AD患者中,MRI定义的内侧颞部ROI的体积较小。通过将萎缩的MRI测量值和CBF的SPECT测量值相结合,可以使AD患者与对照组之间达到最佳分离。

    结论:这些数据表明,MRI指导的准确性和可靠性内侧颞CBF的SPECT测量清楚地允许检测AD的变化。同样,通过这种方法可以直接比较结构和功能的变化,这可能会改善AD的早期诊断。

  • 【氯氮平在帕金森氏病中治疗左旋多巴引起的精神病的回顾性研究。】 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。五名患者由于副作用而停药,但只有两个患者在治疗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。

  • 【在其他健康的分枝杆菌病患者中发现了新的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: 转录因子信号转导子和转录激活因子1(STAT1)在抵抗分枝杆菌和病毒感染的免疫中起着关键作用。在这里,我们表征了来自其他健康的分枝杆菌病患者的三个人STAT1种系等位基因。像新的Q463H和E320Q等位基因一样,先前报道的L706S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)诱导的干扰素刺激的基因因子3介导的免疫都具有内在的危害,如用相应等位基因转染的STAT1缺陷细胞所示。然而,它们的表型作用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别受损的IFNG诱导的γ活化因子介导的免疫力,导致对分枝杆菌的易感性。确实,IFNA诱导的干扰素刺激基因因子3介导的免疫性没有受到影响,并且这些患者对病毒性疾病特别不敏感,这与两种表型均隐性的其他同样有害的STAT1突变的患者不同。因此,在细胞和临床水平上,这三个STAT1等位基因在IFNG介导的抗分枝杆菌免疫中占主导地位,而在IFNA介导的抗病毒免疫中却处于隐性地位。这些STAT1等位基因定义了两种主要形式的STAT1缺陷,具体取决于突变是否损害STAT1磷酸化或DNA结合。
  • 【疾病机制:2型糖尿病的肝脂肪变性-发病机理和临床意义。】 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(HCL)含量增加所定义的,并且经常在包括2型糖尿病在内的胰岛素抵抗状态中观察到。饮食中饱和脂肪过多会大大增加HCL的积累。 HCL水平升高主要是肝脏胰岛素抵抗的原因,这可能是由于游离脂肪酸在肝脏中的分配(脂肪溢出)和脂肪细胞因子的失衡(脂联素减少和/或促炎性细胞因子增加)引起的。游离脂肪酸和脂肪细胞因子均激活包括蛋白激酶C,转录因子核因子kappaB和c-Jun N端激酶1在内的炎症途径,从而可以加速肝脂肪变性发展为非酒精性脂肪性肝炎和肝硬化。质子磁共振波谱使量化HCL浓度和检测临床环境中这些浓度的微小变化成为可能。适度低热量,低脂肪饮食可将HCL水平降低约40-80%,同时最多可减少8%的体重。噻唑烷二酮类药物(例如吡格列酮和罗格列酮)治疗可通过调节2型糖尿病的胰岛素敏感性和脂肪组织的内分泌功能将HCL水平降低30-50%。二甲双胍在不影响HCL水平的情况下改善了肝胰岛素的作用,而胰岛素输注67 h使HCL水平增加了约18%。此外,在用胰岛素治疗的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,因此代表了胰岛素抵抗和2型糖尿病的重要治疗靶标。
  • 【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贝塞特的疾病活动。】 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: 活化的嗜中性粒细胞需要很长时间才能通过像微孔一样的狭窄内腔,因此应该对微循环起恶化作用。尽管在白塞氏病中已证明嗜中性粒细胞的活化,但没有人通过流变学方法测量嗜中性粒细胞的活性来分析该疾病的临床活性。我们使用微孔(孔径为5微米)过滤技术,测量外周血中性粒细胞的过滤时间,作为其活性的流变学指标,以确定贝塞特氏病的临床活性。本研究招募了21名Behçet病患者和14名健康对照者。患者表现出的症状和体征使我们将Behçet病区分为非活跃和活跃病例。后者被进一步区分为无症状和有当前症状的病例。在有症状的活跃病例中,中性粒细胞过滤时间为11.5 /-4.8 s,比没有症状的活跃病例中的中性粒细胞过滤时间显着(P <0.05)大(P <0.05)。后者的过滤时间比不活动时的值(3.7 /-1.3 s)大得多(P <0.001),也比对照组的人(4.8 /-1.2 s)大。此外,在有症状的活动病例中,将细胞暴露于趋化肽甲酰基-甲硫酰基-亮氨酰-苯丙氨酸(FMLP10 nM)后立即获得的过滤时间增加明显大于活动病例(P <0.01)。没有症状。后者也比不活动者大,但不显着,并且比对照组大(P <0.01)。目前的结果表明,微孔过滤方法很好地反映了中性粒细胞的流变活性以及白塞氏病的临床状况。这种方法比测量氧气的产生要好得多,以区分没有症状的活动患者和无活动的患者,甚至是对照个体。此外,它比实验室数据(如CRP值或外周血中性粒细胞的数量)更为敏感和有用。

  • 【过敏性眼病的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: 目的:过敏性眼病可影响多达20%的人口,其严重程度各不相同。结膜上皮在过敏性眼病中起关键作用。这项研究的目的是确定在过敏性眼病中结膜上皮是否异常。
    方法:结膜活检样本取自“季节内”和“季节外”以及非特应性对照受试者的季节性过敏性结膜炎(SAC)患者。将样品固定在甲基丙烯酸乙二醇酯中,切成2微米的连续切片,用Image-J评估免疫染色的部位和面积。
    结果:与正常对照组相比,“过时”患者的E-钙粘蛋白,CD44,角蛋白K5 / 6,K8,K13,K14,K18和泛角蛋白免疫染色均显着降低。两组之间未观察到上皮的结构差异。 “季节”患者的上皮较厚,上述标记物的免疫染色与对照相似。
    结论:与正常对照组相比,SAC患者结膜中的上皮细胞粘附蛋白和细胞骨架成分的广泛表达被下调。我们建议这可能对上皮保护自身免受过敏原渗透的能力产生重要影响,从而可能影响过敏性眼病的发展和进程,并为治疗控制提供一个新领域。
  • 【荷兰用英夫利昔单抗治疗克罗恩病的指南。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Vermeire S
    BACKGROUND & AIMS: -2
    背景与目标: -2
  • 【腹腔疾病患者的小麦淀粉不耐症。】 复制标题 收藏 收藏
    DOI:10.1016/S0002-8223(97)00156-9 复制DOI
    作者列表:Chartrand LJ,Russo PA,Duhaime AG,Seidman EG
    BACKGROUND & AIMS: OBJECTIVE:Evaluate in patients with celiac disease the tolerance of prolonged consumption of small amounts of gliadin contained in products containing wheat starch.

    DESIGN:Open 1-year trial of the addition of wheat starch to a gluten-free diet in a cohort of adult patients with biopsy-proven celiac disease who had never consumed wheat starch. The control group consisted of patients with celiac disease who tolerated wheat starch.

    SUBJECTS:Seventeen patients with celiac disease and 14 control patients, all diagnosed according to criteria of the European Society of Pediatric Gastroenterology and Nutrition, were recruited from the Canadian Celiac Association and the Quebec Celiac Foundation.

    SETTING:The study was conducted in the outpatient clinic of the Gastroenterology and Nutrition Service of Ste Justine Hospital, Montreal, Quebec, Canada.

    INTERVENTIONS:Patients were asked to consume four to six portions daily of a wheat starch-containing product, mainly bread, for up to 1 year.

    MAIN OUTCOME MEASURES:The gliadin content of the wheat starch product used in this trial was quantified by enzyme-linked immunosorbent assay. Patient outcome measures included symptoms, nutritional parameters (anthropometric data, complete blood count, serum folate and iron levels), and immunologic parameters (antigliadin antibody and antiendomysium antibody titers).

    RESULTS:A quantifiable amount of immunoreactive gliadin (0.75 mg/100 g) was found in the wheat starch. The majority of the patients with celiac disease (11 of 17) who had never consumed wheat starch previously developed symptoms, which resolved within weeks of discontinuing the product. Relapse of skin lesions was seen in two of three patients with coexisting dermatitis herpetiformis. No weight loss or biochemical changes were observed. Despite the presence of symptoms, antigliadin antibody and antiendomysium antibody determinations were not useful to detect the clinical intolerance.

    APPLICATIONS:The innocuousness of the long-term ingestion of "gluten-free" products containing wheat starch is still unproven, and prolonged use of such products by patients with celiac disease cannot be recommended.

    背景与目标: 目标:评估患有乳糜泻的患者长期食用含小麦淀粉的产品中所含少量麦醇溶蛋白的耐受性。

    设计:打开1-在一群经活检证实为乳糜泻但从未食用过小麦淀粉的成年患者中,在无麸质饮食中添加小麦淀粉的一项年度试验。对照组包括耐受小麦淀粉的腹腔疾病患者。

    受试者:17例腹腔疾病患者和14例对照患者,均根据欧洲儿科学会的标准诊断胃肠病学和营养学是从加拿大乳糜泻协会和魁北克乳糜泻基金会招募的。

    设置:这项研究是在Ste Justine医院胃肠病学和营养服务的门诊进行的。 ,加拿大魁北克省蒙特利尔。

    干预措施:患者被要求每天食用4至6份含小麦淀粉的产品(主要是面包),最多1年。 br>
    主要观察指标:该试验中使用的小麦淀粉产品的麦醇溶蛋白含量通过酶联免疫吸附法进行了定量。患者的预后指标包括症状,营养参数(人体测量数据,全血细胞计数,血清叶酸和铁水平)和免疫学参数(抗麦胶蛋白抗体和抗内胚层抗体滴度)。

    结果:在小麦淀粉中发现了定量的免疫反应性麦醇溶蛋白(0.75 mg / 100 g)。从未食用小麦淀粉的大多数乳糜泻患者(17例中的11例)以前都出现了症状,在停产该产品后数周内症状消失了。在三例并存的疱疹样皮炎患者中,有两例发现皮肤病变复发。没有观察到体重减轻或生化变化。尽管有症状,但抗麦醇溶蛋白抗体和抗肌内膜抗体的测定仍不能用于检测临床耐受性。

    应用:长期摄入“不含麸质”的食物是无害的含有小麦淀粉的产品尚未得到证实,因此不建议乳糜泻患者长时间使用此类产品。

  • 【美国,1993-1995年,围产期B组链球菌疾病的发病率下降。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Centers for Disease Control and Prevention (CDC).
    BACKGROUND & AIMS: :Group B streptococcal (GBS) infections are the leading cause of bacterial disease and death among newborns in the United States and an important cause of morbidity among peripartum women and nonpregnant adults with chronic medical conditions. Disease in infants usually presents as sepsis, pneumonia or meningitis but also may include cellulitis or osteomyelitis. In 1990, GBS infections caused an estimated 7600 serious illnesses and 310 deaths among U.S. infants aged < or = 90 days; infections among infants aged < 7 days (i.e., early-onset disease) accounted for approximately 80% of these illnesses. To determine the incidence of GBS disease during 1993-1995, CDC conducted surveillance for this disease in an aggregate population of 12.5 million persons with 190,000 annual live-born infants. This report summarizes the findings of surveillance in this population, which indicate that a statistically significant decline in the incidence of early-onset GBS disease occurred in some surveillance areas.
    背景与目标: B组链球菌(GBS)感染是美国新生儿细菌性疾病和死亡的主要原因,也是围产期妇女和患有慢性病的未怀孕成年人中发病的重要原因。婴儿的疾病通常表现为败血症,肺炎或脑膜炎,但也可能包括蜂窝织炎或骨髓炎。 1990年,GBS感染在年龄小于或等于90天的美国婴儿中估计造成7600例严重疾病,并有310例死亡。小于7天的婴儿感染(即早发疾病)约占这些疾病的80%。为了确定1993-1995年间GBS疾病的发病率,疾病预防控制中心对1250万总人口和19万例活产婴儿进行了这种疾病的监测。该报告总结了该人群的监测结果,这表明在某些监测区域发生的早发性GBS疾病的发生率在统计学上显着下降。
  • 【Darier病影响牙龈和口腔粘膜表面。】 复制标题 收藏 收藏
    DOI:10.1016/j.tripleo.2005.10.040 复制DOI
    作者列表:Frezzini C,Cedro M,Leao JC,Porter S
    BACKGROUND & AIMS: :Darier disease is an uncommon genodermatosis reflecting defective desmosomal structure and function. The present report details the oral features of a patient with well-characterized Darier disease and reviews current knowledge of the genetic basis of this genodermatosis that can often affect the craniofacial tissues.
    背景与目标: :Darier病是一种罕见的遗传性皮肤病,反映了桥粒结构和功能的缺陷。本报告详细介绍了特征明确的Darier病患者的口腔特征,并回顾了这种遗传皮肤病的遗传基础的当前知识,这种遗传皮肤病通常会影响颅面组织。

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