• 【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。
  • 【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。
  • 【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:
  • 【荷兰用英夫利昔单抗治疗克罗恩病指南。】 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
  • 【乳糜泻患者的小麦淀粉不耐受。】 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 : 评估乳糜泻患者对含有小麦淀粉的产品中含有的少量麦醇溶蛋白的长期食用的耐受性。
    设计 : 在从未食用过小麦淀粉的活检证实的乳糜泻成年患者队列中,将小麦淀粉添加到无麸质饮食中进行了为期1年的开放试验。对照组由耐受小麦淀粉的乳糜泻患者组成。
    受试者 : 17例乳糜泻患者和14例对照患者,均根据欧洲儿科胃肠病与营养学会的标准进行诊断,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 : 该研究是在魁北克蒙特利尔Ste Justine医院胃肠病学和营养服务门诊进行的,加拿大。
    干预措施 : 要求患者每天食用四到六份含小麦淀粉的产品,主要是面包,长达1年。
    主要结果指标 : 通过酶联免疫吸附测定法对该试验中使用的小麦淀粉产品的麦醇溶蛋白含量进行了定量。患者结局指标包括症状,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 (抗麦醇溶蛋白抗体和抗肌内膜抗体滴度)。
    结果 : 在小麦淀粉中发现可定量的免疫反应性麦醇溶蛋白 (0.75 mg/100g)。以前从未食用过小麦淀粉的大多数乳糜泻患者 (17人中有11人) 出现症状,这些症状在停用该产品后的几周内得到缓解。在三名并存的疱疹样皮炎患者中,有两名发现了皮肤病变的复发。未观察到体重减轻或生化变化。尽管存在症状,但抗麦醇溶蛋白抗体和抗肌内膜抗体的测定对检测临床不耐受没有用。
    应用 : 长期摄入含有小麦淀粉的 “无麸质” 产品的无伤害性仍未得到证实,并且不建议乳糜泻患者长期使用此类产品。
  • 【围产期B组链球菌病发病率的降低-美国,1993-1995。】 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疾病的未怀孕成年人发病的重要原因。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 <或 = 90天的美国婴儿中导致估计7600种严重疾病和310例死亡; <7天的婴儿 (即早发疾病) 感染约占这些疾病的80%。为了确定1993-1995年期间GBS疾病的发生率,CDC对1250万名每年有190,000名活产婴儿的人群进行了该疾病的监测。该报告总结了该人群的监测结果,这表明在某些监测地区,早发性GBS疾病的发病率在统计学上显着下降。
  • 【影响牙龈和口腔粘膜表面的Darier病。】 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皮肤病,反映了桥粒体结构和功能缺陷。本报告详细介绍了患有特征性Darier疾病的患者的口腔特征,并回顾了有关这种通常会影响颅面组织的遗传皮肤病的遗传基础的最新知识。
  • 【JTE-607是一种多种细胞因子产生抑制剂,可改善SCID小鼠异种移植急性髓细胞性白血病模型中的疾病。】 复制标题 收藏 收藏
    DOI:10.1016/j.exphem.2006.05.016 复制DOI
    作者列表:Uesato N,Fukui K,Maruhashi J,Tojo A,Tajima N
    BACKGROUND & AIMS: OBJECTIVE:Accumulating findings suggest that in acute myeloid leukemia (AML) patients, proinflammatory cytokines and growth factors play important roles in the proliferation and survival of AML cells in an autocrine and paracrine manner, leading to deterioration of AML. JTE-607 is a multiple cytokine inhibitor that potently suppresses production of proinflammatory cytokines. In the present study, we investigated the potency of JTE-607 as an antileukemic agent by exploiting a SCID mouse acute leukemia model. METHODS:SCID mice injected with anti-asialo-GM1 antibody were exposed to sublethal total-body irradiation at a dose of 3 Gy and then inoculated intravenously with AML cells. JTE-607 was administered using osmotic minipumps. The effects of JTE-607 on mouse survival time, human interleukin (IL)-8 levels in mouse plasma, and proportion of human CD45(+) cells in the bone marrow were studied. RESULTS:The survival time of the mice was strictly dependent on the number of U-937 cells proliferating in vivo. Administration of JTE-607 during the initial 7 days significantly prolonged survival of the mice, suggesting killing activity of JTE-607 against AML cells in vivo. Delayed administration of JTE-607 also prolonged the survival of mice bearing established leukemia with an effect comparable to the maximum tolerable dose of cytarabine. Flow cytometer analysis of bone marrow cells revealed decreased number of human CD45(+) cells. Human IL-8 level was also reduced by JTE-607. CONCLUSION:Our results indicate that JTE-607 has potential to be a new class of antileukemic drug that exerts inhibitory activities against both the proliferation and proinflammatory cytokine production of AML cells.
    背景与目标:
  • 【雄激素依赖性病理学在小鼠敲入模型中证明了肌病对肯尼迪病表型的贡献。】 复制标题 收藏 收藏
    DOI:10.1172/JCI28773 复制DOI
    作者列表:Yu Z,Dadgar N,Albertelli M,Gruis K,Jordan C,Robins DM,Lieberman AP
    BACKGROUND & AIMS: :Kennedy disease, a degenerative disorder characterized by androgen-dependent neuromuscular weakness, is caused by a CAG/glutamine tract expansion in the androgen receptor (Ar) gene. We developed a mouse model of Kennedy disease, using gene targeting to convert mouse androgen receptor (AR) to human sequence while introducing 113 glutamines. AR113Q mice developed hormone and glutamine length-dependent neuromuscular weakness characterized by the early occurrence of myopathic and neurogenic skeletal muscle pathology and by the late development of neuronal intranuclear inclusions in spinal neurons. AR113Q males unexpectedly died at 2-4 months. We show that this androgen-dependent death reflects decreased expression of skeletal muscle chloride channel 1 (CLCN1) and the skeletal muscle sodium channel alpha-subunit, resulting in myotonic discharges in skeletal muscle of the lower urinary tract. AR113Q limb muscles show similar myopathic features and express decreased levels of mRNAs encoding neurotrophin-4 and glial cell line-derived neurotrophic factor. These data define an important myopathic contribution to the Kennedy disease phenotype and suggest a role for muscle in non-cell autonomous toxicity of lower motor neurons.
    背景与目标: : 肯尼迪病是一种以雄激素依赖性神经肌肉无力为特征的退行性疾病,是由雄激素受体 (Ar) 基因中的CAG/谷氨酰胺道扩增引起的。我们开发了肯尼迪病的小鼠模型,使用基因靶向将小鼠雄激素受体 (AR) 转化为人类序列,同时引入113谷氨酸。AR113Q小鼠出现激素和谷氨酰胺长度依赖性神经肌肉无力,其特征是肌病和神经源性骨骼肌病理的早期发生以及脊髓神经元核内包涵体的晚期发展。AR113Q男性在2-4个月时意外死亡。我们显示这种雄激素依赖性死亡反映了骨骼肌氯化物通道1 (CLCN1) 和骨骼肌钠通道 α 亚基的表达降低,导致下尿路骨骼肌中的肌强肌放电。AR113Q肢体肌肉显示出相似的肌病特征,并表达编码neurotrophin-4和神经胶质细胞系衍生的神经营养因子的mrna水平降低。这些数据定义了对肯尼迪病表型的重要肌病贡献,并暗示了肌肉在较低运动神经元的非细胞自主毒性中的作用。
  • 【暴露于含汞的亮肤霜后的最小变化疾病。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Tang HL,Chu KH,Mak YF,Lee W,Cheuk A,Yim KF,Fung KS,Chan HW,Tong KL
    BACKGROUND & AIMS: :A 34-year-old woman developed nephrotic syndrome after using a skin lightening cream that contained an extremely high level of mercury. Blood and urine mercury levels were elevated and a renal biopsy revealed minimal change disease. Membranous nephropathy was excluded using immunofluorescence and electron microscopy. Her proteinuria remitted 9 months after she stopped using the cosmetic cream. This is the first reported case in the English literature of proven minimal change disease secondary to mercury exposure. It is important that mercury poisoning due to cosmetic cream is considered in the differential diagnoses for any woman who presents with nephrotic syndrome.
    背景与目标: : 一名34岁的妇女在使用含有极高汞含量的亮肤霜后患上了肾病综合征。血液和尿液中的汞含量升高,肾脏活检显示出微小变化的疾病。使用免疫荧光和电子显微镜排除膜性肾病。停止使用美容霜9个月后,她的蛋白尿缓解了。这是英国文献中首次报道的经证实的继发于汞暴露的微小变化疾病的病例。对于任何患有肾病综合征的女性,在鉴别诊断中考虑由化妆品霜引起的汞中毒非常重要。
  • 【成年先天性心脏病患者的亚临床甲状腺功能减退。】 复制标题 收藏 收藏
    DOI:10.1007/s00246-012-0571-6 复制DOI
    作者列表:Martínez-Quintana E,Rodríguez-González F,Nieto-Lago V
    BACKGROUND & AIMS: :Subclinical hypothyroidism usually is asymptomatic, but it can be associated with various adverse cardiologic outcomes. With the objective of gaining insight into the role of thyroid-stimulating hormone (TSH) in congenital heart abnormalities, this study measured serum TSH concentrations in different subtypes of grown-up congenital heart disease (GUCHD) patients. Serum TSH (reference range, 0.34-5.6 mIU/L), creatinine, cholesterol, C-reactive protein (CRP), N-terminal proB-type natriuretic peptide (NT-pro-BNP), and 24-h proteinuria were measured in 249 GUCHD patients. Of 24 GUCHD patients (9.6 %) with a TSH level higher than 5.6 mUI/L, nine were cyanotic (37.5 %) and seven (29.1 %) had Down syndrome. The GUCHD patients with serum TSH exceeding 5.6 mIU/L had a significantly higher level of serum NT-pro-BNP (195.1 [0.28; 5,280.3] vs 57.6 [0.00; 929.8]; p = 0.001) and CRP (0.30 [0.06; 1.87] vs 0.16 [0.00; 1.40]; p = 0.011] than those with a TSH level of 5.6 mIU/L or lower. No significant differences were found in serum creatinine, lipids, or 24-h proteinuria between the two groups. The T4 concentrations in the GUCHD patients with TSH exceeding 5.6 mIU/L were within the normal range (0.89 ± 0.23 ng/dL). In the multivariate analysis, cyanosis (odds ratio [OR], 6,399; 95 % confidence interval [CI] 2,296-17,830; p < 0.001), Down syndrome (OR, 6,208; 95 % CI, 1,963-19,636; p = 0.002), and NT-pro-BNP concentrations (OR, 1,001; 95 % CI, 1,000-1,002; p < 0.026) proved to be risk factors for TSH levels higher than 5.6 mIU/L. Because subclinical hypothyroidism entails a cardiovascular risk, the authors postulate that TSH screening should be included in the routine follow-up evaluation of GUCHD patients with cyanosis or Down syndrome.
    背景与目标: : 亚临床甲状腺功能减退通常是无症状的,但它可能与各种不良的心脏结局有关。为了深入了解促甲状腺激素 (TSH) 在先天性心脏异常中的作用,本研究测量了成年先天性心脏病 (GUCHD) 患者不同亚型的血清TSH浓度。在249例GUCHD患者中测量了血清TSH (参考范围,0.34-5.6 mIU/L),肌酐,胆固醇,C反应蛋白 (CRP),N末端proB型利钠肽 (NT-pro-BNP) 和24小时蛋白尿。在TSH水平高于5.6 mUI/L的24例GUCHD患者 (9.6% 例) 中,9例为紫绀 (37.5% 例),7例 (29.1% 例) 患有唐氏综合症。血清TSH超过5.6 mIU/L的GUCHD患者的血清NT-pro-BNP水平 (195.1 [0.28; 5,280.3] vs 57.6 [0.00; 929.8]; p = 0.001) 和CRP (0.30 [0.06; 1.87] vs 0.16 [0.00; 1.40]; p = 0.011] 与TSH水平为5.6 mIU/L或更低者比较,血清肌酐、血脂、或两组之间的24小时蛋白尿。TSH超过5.6 mIU/L的GUCHD患者的T4浓度在正常范围内 (0.89 ± 0.23 ng/dL)。在多变量分析中,发绀 (优势比 [or],6,399; 95% 置信区间 [CI] 2,296-17,830; p <0.001),唐氏综合征 (OR,6,208; 95% CI,1,963-19,636; p = 0.002) 和NT-pro-BNP浓度 (OR,1,001; 95% CI,1,000-1,002; p < 0.026) 被证明是TSH水平高于5.6 mIU/L的危险因素。由于亚临床甲状腺功能减退会带来心血管风险,因此作者假设TSH筛查应包括在患有发绀或唐氏综合症的GUCHD患者的常规随访评估中。
  • 【甲基-β-环糊精的分析表征,具有减少Niemann-Pick病C1型细胞中溶酶体胆固醇积累的药理活性。】 复制标题 收藏 收藏
    DOI:10.1089/adt.2017.774 复制DOI
    作者列表:Li R,Hao J,Fujiwara H,Xu M,Yang S,Dai S,Long Y,Swaroop M,Li C,Vu M,Marugan JJ,Ory DS,Zheng W
    BACKGROUND & AIMS: :Methyl-β-cyclodextrin (MβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease type C1 (NPC1) patient fibroblasts. However, the pharmacological activity of MβCD reported by different laboratories varies. To determine the potential causes of this variation, we analyzed the mass spectrum characteristics, pharmacological activity of three preparations of MβCDs, and the protein expression profiles of NPC1 patient fibroblasts after treatment with different sources of MβCDs. Our data revealed varied mass spectrum profiles and pharmacological activities on the reduction of lysosomal cholesterol accumulation in NPC1 fibroblasts for these three preparations of MβCDs obtained from different batches and different sources. Furthermore, a proteomic analysis showed the differences of these three MβCD preparations on amelioration of dysregulated protein expression levels in NPC1 cells. The results demonstrate the importance of prescreening of different cyclodextrin preparations before use as a therapeutic agent. A combination of mass spectrum analysis, measurement of pharmacological activity, and proteomic profiling provides an effective analytical procedure for characterization of cyclodextrins for therapeutic applications.
    背景与目标: : 甲基-β-环糊精 (m β cd) 减少Niemann-Pick病C1 (NPC1) 患者成纤维细胞中的溶酶体胆固醇积累。但是,不同实验室报道的m β cd的药理活性有所不同。为了确定这种变异的潜在原因,我们分析了三种m β cds制剂的质谱特征,药理活性以及用不同来源的m β cds处理后NPC1患者成纤维细胞的蛋白表达谱。我们的数据揭示了从不同批次和不同来源获得的这三种m β cds制剂在NPC1成纤维细胞中减少溶酶体胆固醇积累的不同质谱谱和药理活性。此外,蛋白质组学分析表明,这三种m β cd制剂在改善NPC1细胞中蛋白表达水平失调方面存在差异。结果表明,在用作治疗剂之前,对不同的环糊精制剂进行预检查的重要性。质谱分析,药理活性测量和蛋白质组学分析相结合,为表征用于治疗应用的环糊精提供了有效的分析程序。
  • 14 Genetics of Alzheimer's disease. 复制标题 收藏 收藏

    【阿尔茨海默氏病的遗传学。】 复制标题 收藏 收藏
    DOI:10.1016/j.arcmed.2012.10.017 复制DOI
    作者列表:Alonso Vilatela ME,López-López M,Yescas-Gómez P
    BACKGROUND & AIMS: :Alzheimer's disease (AD) is the most frequent cause of dementia in the elderly and represents an important and increasing clinical challenge in terms of diagnosis and treatment. This review highlights the role of genetics in understanding the pieces of the complex AD puzzle and summarizes the genes known to be involved in Alzheimer's disease. The amount of risk of Alzheimer's disease that is attributable to genetics is estimated to be ∼70%. Mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) are responsible for early-onset autosomal dominant AD. Although mutations in these genes account for ∼1% of AD cases, their identification has been crucial to understand the molecular mechanisms of AD. For the more common complex late-onset AD, the ɛ-4 allele of the gene encoding apolipoprotein E (APOE) has been recognized as a major genetic risk factor. More recently, several potential disease risk genes have been identified with the use of advanced genomic methods like genome-wide association studies (GWAS). In the end, the knowledge of the pathophysiological mechanisms leading to AD will enable the development of more accurate diagnostic tests and new disease-treating strategies.
    背景与目标: : 阿尔茨海默氏病 (AD) 是老年人痴呆症的最常见原因,在诊断和治疗方面代表着重要且日益增长的临床挑战。这篇综述强调了遗传学在理解复杂的AD难题中的作用,并总结了已知与阿尔茨海默氏病有关的基因。可归因于遗传学的阿尔茨海默氏病的风险估计为〜70%。编码淀粉样蛋白前体蛋白 (APP),早老素1 (PSEN1) 和早老素2 (PSEN2) 的基因的突变是早发常染色体显性遗传AD的原因。尽管这些基因的突变占AD病例的约1%,但它们的鉴定对于理解AD的分子机制至关重要。对于更常见的复杂迟发性AD,编码载脂蛋白E (APOE) 的基因的 ɛ-4等位基因已被认为是主要的遗传危险因素。最近,通过使用先进的基因组方法 (例如全基因组关联研究 (gwa)),已经确定了几种潜在的疾病风险基因。最后,对导致AD的病理生理机制的了解将有助于开发更准确的诊断测试和新的疾病治疗策略。
  • 【双膦酸盐诱导的颌骨骨坏死: 对比增强MR成像,[18F] 氟化物PET/CT和圆锥束CT成像的疾病程度比较。】 复制标题 收藏 收藏
    DOI:10.3174/ajnr.A3355 复制DOI
    作者列表:Guggenberger R,Fischer DR,Metzler P,Andreisek G,Nanz D,Jacobsen C,Schmid DT
    BACKGROUND & AIMS: BACKGROUND AND PURPOSE:Imaging of bisphosphonate-induced osteonecrosis of the jaw is essential for surgical planning. We compared the extent of BONJ on contrast-enhanced MR imaging, [(18)F] fluoride PET/CT, and panoramic views derived from standard conebeam CT with clinical pre- and intraoperative examinations. MATERIALS AND METHODS:Between February 2011 and January 2012, ten subjects with written informed consent (9 women; mean, 69.6 years; range, 53-88 years) were included in this prospective ethics-board-approved study. Patients underwent CEMR imaging, [(18)F] fluoride PET/CT, and CBCT and were clinically examined pre- and intraoperatively. Surgery was performed, and BONJ was histologically confirmed in 9 patients. Location and extent of BONJ on different modalities/examinations were graphically compared (0 = no pathologic finding, 1 = smallest, 5 = largest extent of BONJ). Rank tests were used to assess overall and paired differences of ratings in 9 patients. A P value <.05 was considered statistically significant. RESULTS:Significant differences in BONJ extent among different modalities and examinations were found (P < .001). The highest median rank was seen in PET/CT (4 ± 1.12) and CEMR imaging (4 ± 1.01), followed by intraoperative examinations (3 ± 0.71), CBCT (2 ± 0.33), and preoperative examinations (1 ± 0). No significant differences were found between PET/CT and CEMR imaging (P = .23), except when comparing PET/CT to either CBCT, pre- and intraoperative examinations (all P < .05). Preoperative examinations showed significantly less extensive disease than all other modalities/examinations (all P < .05). CONCLUSIONS:[(18)F] fluoride PET/CT and CEMR imaging revealed more extensive involvement of BONJ compared with panoramic views from CBCT and clinical examinations.
    背景与目标:

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