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

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

BACKGROUND & AIMS: :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存在的其他同样有害的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。

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/或促炎细胞因子增加）介导的。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。

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的情况下的值（3.7 /-1.3 s）大得多（P <0.001），也比对照对象的值（4.8 /-1.2 s）大得多（P <0.001）。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。

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：过敏性眼病影响多达20％的人口，严重程度不同。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患者结膜中的各种上皮细胞粘附蛋白和细胞骨架成分的表达被“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。

BACKGROUND & AIMS: -2

背景与目标： -2

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-在一群经活组织检查证实患有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中的麦醇溶蛋白含量通过酶联免疫吸附法定量。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即可缓解。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。尽管存在症状，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。