Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome

TNF, acting through p55 tumor necrosis factor receptor 1 (TNFR1), contributes to the pathogenesis of many inflammatory diseases. TNFR-associated periodic syndrome (TRAPS, OMIM 142680) is an autosomal dominant autoinflammatory disorder characterized by prolonged attacks of fevers, peritonitis, and soft tissue inflammation. TRAPS is caused by missense mutations in the extracellular domain of TNFR1 that affect receptor folding and trafficking. These mutations lead to loss of normal function rather than gain of function, and thus the pathogenesis of TRAPS is an enigma. Here we show that mutant TNFR1 accumulates intracellularly in peripheral blood mononuclear cells of TRAPS patients and in multiple cell types from two independent lines of knockin mice harboring TRAPS-associated TNFR1 mutations. Mutant TNFR1 did not function as a surface receptor for TNF but rather enhanced activation of MAPKs and secretion of proinflammatory cytokines upon stimulation with LPS. Enhanced inflammation depended on autocrine TNF secretion and WT TNFR1 in mouse and human myeloid cells but not in fibroblasts. Heterozygous TNFR1-mutant mice were hypersensitive to LPS-induced septic shock, whereas homozygous TNFR1-mutant mice resembled TNFR1-deficient mice and were resistant to septic shock. Thus WT and mutant TNFR1 act in concert from distinct cellular locations to potentiate inflammation in TRAPS. These findings establish a mechanism of pathogenesis in autosomal dominant diseases where full expression of the disease phenotype depends on functional cooperation between WT and mutant proteins and also may explain partial responses of TRAPS patients to TNF blockade.     

鞍钢职工心脑血管疾病现状与发病趋势

目的分析鞍钢职工大样本人群心脑血管疾病的发病率及易患因素分布情况。方法通过对鞍钢集团95 912例职工的心脑血管疾病既往史、吸烟、血压、糖尿病、血清总胆固醇、高密度脂蛋白、体重指数、总胆固醇与高密度脂蛋白胆固醇的比值等数据的分析,前瞻性分析受检人群心脑血管疾病发病的危险分层。结果冠心病1 910例(2.00%),脑血管病607例(0.63%),吸烟19 453例(20.28%),糖尿病788例(0.82%),高血压31 698例(33.05%),高脂血症8 347例(8.70%),体重超重55 462例(57.83%),总胆固醇(TC)/高密度脂蛋白胆固醇(HDL-C)≥3.5的10 487例(10.93%);缺血性心血管病发病概率多分布于极低危(68.14%)和低危(5.75%),中危(0.865%)占很小的比例,颈动脉粥样硬化斑块发生概率多分布于高危(44.23%)、中危(23.21%)和极高危(10.51%),无低危和极低危。结论目前鞍钢职工的健康状况不容乐观,应进一步加大健康知识宣教力度。     

Paediatric aspects of coeliac disease: old challenges and new ones…

The concept of coeliac disease has expanded from a gastrointestinal disease with malabsorption to a systemic immunological disease with a genetic basis. Epidemiological studies indicate that environmental factors, like the infant feeding pattern, affect the clinical presentation while population-screening studies indicate that the prevalence, at least in Caucasian populations, is similar. Secondary complications, like malignancies, osteopenia - osteoporosis, gynaecological and obstetrical problems and autoimmune diseases, are common. The risk is reduced or prevented by treatment with a gluten-free diet. The basis for such a secondary prevention is: 1. early case-finding by a) knowledge about different presentations of the disease and factors affecting that, b) generous serological testing in patients with vague symptoms, c) screening of risk groups, and, 2. support for children and adolescents with coeliac disease to comply with the gluten-free diet.     

Chronic liver inflammation: Clinical implications beyond alcoholic liver disease

Chronic alcohol exposure can lead to alcoholic liver disease, including hepatitis, cirrhosis and hepatocellular carcinoma, and chronic inflammation can simultaneously cause systemic medical illness. Recent evidence suggests that alcoholic liver disease is a predictor for liver-related diseases, cardiovascular disease, immunologic disease, and bone disease. Chronic inflammation in alcoholic liver disease is mediated by a direct inflammatory cascade from the alcohol detoxification process and an indirect inflammatory cascade in response to gut microflora-derived lipopolysaccharides (LPS). The pathophysiology of alcoholic liver disease and its related systemic illness is characterized by oxidative stress, activation of the immune cascade, and gut-liver interactions. Integrative therapeutic strategies for alcoholic liver disease include abstaining from alcohol consumption; general anti-inflammatories such as glucocorticoid, pentoxifylline, and tumour necrosis factor-α antagonist; antioxidants such as N- acetylcysteine; gut microflora and LPS modulators such as rifaximin and/or probiotics. This review focuses on the impact of chronic liver inflammation on systemic health problems and several potential therapeutic targets.     

Graves病患者血清中TSH抗体检测及其免疫学意义

利用~(125)I标记的人TSH(~(125)I-hTSH)作为放射性示踪配体,对29例正常人和58例Graves病患者血清中抗hTSH自身抗体(TSHab)进行了检测。正常人TSHab指数(TSHabJ)为0.85±0.22;而32例初发患者和26例接受抗甲状腺药物治疗患者的TSHabJ分别为1.47±0.35(P<0.001)和1.19±0.37(P>0.05)。SPA菌体结合沉淀试验表明:这种与hTSH结合的抗体属于IgG成分。TSHab的存在提示Graves病的免疫学发病已涉及到独特型-抗独特型反应机理。     

Canadian Digestive Health Foundation Public Impact Series 4: celiac disease in Canada. Incidence, prevalence, and direct and indirect economic impact

The Canadian Digestive Health Foundation initiated a scientific program to assess the incidence, prevalence, mortality and economic impact of digestive disorders across Canada in 2009. The current article presents the updated findings from the study concerning celiac disease.     

Celiac Disease: A Disorder Emerging from Antiquity,Its Evolving Classification and Risk,and Potential New Treatment Paradigms

Celiac disease is a chronic genetically based gluten-sensitive immune-mediated enteropathic process primarily affecting the small intestinal mucosa. The disorder classically presents with diarrhea and weight loss; however, more recently, it has been characterized by subclinical occult or latent disease associated with few or no intestinal symptoms. Diagnosis depends on the detection of typical histopathological biopsy changes followed by a gluten-free diet response. A broad range of clinical disorders may mimic celiac disease, along with a wide range of drugs and other therapeutic agents. Recent and intriguing archeological data, largely from the Gobleki Tepe region of the Fertile Crescent, indicate that celiac disease probably emerged as humans transitioned from hunter-gatherer groups to societies dependent on agriculture to secure a stable food supply. Longitudinal studies performed over several decades have suggested that changes in the prevalence of the disease, even apparent epidemic disease, may be due to superimposed or novel environmental factors that may precipitate its appearance. Recent therapeutic approaches are being explored that may supplement, rather than replace, gluten-free diet therapy and permit more nutritional options for future management.     

Simultaneous operation of concomitant diseases in the esophagus and lung

The aim of this study was to retrospectively review our experience of performing simultaneous operations on concomitant diseases in the esophagus and lungs. From January 1998 to July 2009, simultaneous operations were performed on 13 patients with concomitant esophageal and pulmonary diseases, using coordinated surgical approaches. Among the 13 patients, six had primary cancers in the esophagus and lungs, five had primary esophageal cancer accompanied by a benign pulmonary disease, one had benign diseases in both esophagus and lung, and one had primary esophageal cancer with metastasis to the left lower lung. All patients survived the operations. Two major complications occurred postoperatively. One complication was bronchopleural fistula and the other was intrathoracic gastric laceration. Both patients recovered after additional treatments. Simultaneous operation of concomitant diseases in the esophagus and lungs is feasible and safe in selected patients who have received careful preoperative assessment, well‐designed surgical approach, and proper perioperative management.     

Prevalence of Coronary Artery Disease in Patients with Valvular Heart Disease

ABSTRACT. To evaluate the usefulness of preoperative coronary angiography in patients undergoing preoperative investigation because of valvular heart disease, we performed coronary angiography in a consecutive series of 329 patients. The prevalence of significant coronary artery disease was 32%. Asymptomatic coronary artery disease was present in 13%. Angina pectoris proved to be a poor predictor of coronary artery disease in aortic valve disease. In mitral valve disease, however, the specificity was high. A cost-benefit calculation was carried out in order to assess what advantage routine coronary angiography might have. According to this, coronary angiography should be performed in all patients suffering from valvular heart disease with angina pectoris, whereas it can be omitted in younger patients without angina. A cut-off point of 60 years seems appropriate for aortic valve disease and 65 years for mitral valve disease.     

Tailor-made RNAi knockdown against triplet repeat disease-causing alleles

Nucleotide variations, including SNPs, in the coding regions of disease genes are important targets for RNAi treatment, which is a promising medical treatment for intractable diseases such as triplet repeat diseases. However, the identification of such nucleotide variations and the design of siRNAs conferring disease allele-specific RNAi are quite difficult. In this study we developed a pull-down method to rapidly identify coding SNP (cSNP) haplotypes of triple repeat, disease-causing alleles, and we demonstrated disease allele-specific RNAi that targeted cSNP sites in mutant Huntingtin alleles, each of which possessed a different cSNP haplotype. Therefore, the methods presented here allow for allele-specific RNAi knockdown against disease-causing alleles by using siRNAs specific to disease-linked cSNP haplotypes, and advanced progress toward tailor-made RNAi treatments for triplet repeat diseases.     

川崎病的心血管病变观察

目的　观察川崎病 ( KD)的心血管病变。方法　对 2 6例 KD的住院患儿 ,于急性期或亚急性期行心电图、超声心动图、血清肌钙蛋白 I( c Tn I)及肌酸磷酸激酶 ( CK)及其同工酶 ( CK-MB)检查 ,并于病程不同时期 ( 6个月～ 2年 )进行复查。结果　冠状动脉病变 10例 ,占 3 8.5 % ,其中冠状动脉扩大 7例 ,冠状动脉瘤 3例 ,发生于急性期或亚急性期 9例 ,发生于病程第 9个月 1例。心肌炎 2例 ,主动脉瓣、二尖瓣反流各 1例。心电图异常 8例 ,占 3 0 .8%。血清 c Tn I阳性 12例 ,占 46.2 % ,CK-MB升高 7例 ,占 2 6.9%。结论　KD的心血管并发症表现形式多样 ,主要为冠状动脉扩大和冠状动脉瘤 ,其次是心电图异常 ,c Tn I阳性 ,CK-MB升高 ,主动脉瓣及二尖瓣反流。     

结缔组织病与甲状腺疾病的相关性

目的探讨常见结缔组织病(connective tissue disease,CTD)与甲状腺疾病的相关性。方法以济宁医学院附属医院2009年1月至2013年4月住院并接受甲状腺功能筛查CTD患者为研究对象,以普通人群为对照,比较CTD患者与普通人群甲状腺疾病的患病率,同时比较不同甲状腺疾病在不同CTD中的患病率。结果 CTD患者780例,包括类风湿关节炎438例(56.2%)、系统性红斑狼疮195例(25.0%)、原发性干燥综合征85例(10.9%)、混合结缔组织病44例(5.6%)、系统性硬化症(SSc)18例(2.3%),其中合并甲状腺疾病286例(36.7%),与普通人群比较(8.7%)明显升高(P0.05)。合并甲状腺疾病的CTD患者,发生率依次为混合结缔组织病61.4%、原发性干燥综合征54.1%、系统性红斑狼疮51.3%、系统性硬化症27.8%、类风湿关节炎24.7%;混合结缔组织病、原发性干燥综合征、系统性红斑狼疮发生率与类风湿关节炎比较,差异有统计学意义(P0.05)。CTD患者合并甲状腺疾病构成比依次为甲状腺功能减退29.4%、甲状腺功能亢进6.3%、桥本甲状腺炎18.5%、低T3综合征26.6%、结节性甲状腺肿18.8%、甲状腺肿瘤0.4%。结论 CTD合并甲状腺疾病发生率较高,应重视两种疾病的相互筛查。     

Impacts of biodiversity and biodiversity loss on zoonotic diseases

Zoonotic diseases are infectious diseases of humans caused by pathogens that are shared between humans and other vertebrate animals. Previously, pristine natural areas with high biodiversity were seen as likely sources of new zoonotic pathogens, suggesting that biodiversity could have negative impacts on human health. At the same time, biodiversity has been recognized as potentially benefiting human health by reducing the transmission of some pathogens that have already established themselves in human populations. These apparently opposing effects of biodiversity in human health may now be reconcilable. Recent research demonstrates that some taxa are much more likely to be zoonotic hosts than others are, and that these animals often proliferate in human-dominated landscapes, increasing the likelihood of spillover. In less-disturbed areas, however, these zoonotic reservoir hosts are less abundant and nonreservoirs predominate. Thus, biodiversity loss appears to increase the risk of human exposure to both new and established zoonotic pathogens. This new synthesis of the effects of biodiversity on zoonotic diseases presents an opportunity to articulate the next generation of research questions that can inform management and policy. Future studies should focus on collecting and analyzing data on the diversity, abundance, and capacity to transmit of the taxa that actually share zoonotic pathogens with us. To predict and prevent future epidemics, researchers should also focus on how these metrics change in response to human impacts on the environment, and how human behaviors can mitigate these effects. Restoration of biodiversity is an important frontier in the management of zoonotic disease risk.     

Estimation of the symptoms for GERD by GerdQ in the patients with rheumatic diseases

Objective: Gastroesophageal reflux disease (GERD) is one of the most common comorbidity in many diseases, but the frequency in rheumatic disease has not been well understood.

Methods: We investigated the prevalence of GERD by GerdQ in 530 rheumatic patients [systematic lupus erythematosus (SLE; n?=?120), rheumatoid arthritis (RA; n?=?117), polymyalgia rheumatica (PMR; n?=?40), dermatomyositis and polymyositis (PM/DM; n?=?38), systemic scleroderma (SSc; n?=?37), mixed connective tissue disease (MCTD; n?=?18), Behçet disease (BD; n?=?17), adult onset still disease (AOSD; n?=?14), and other rheumatic diseases (n?=?129)].

Results: The mean GerdQ scores of patients was 6.2?±?1.8, respectively, and no significant differences were observed between all patients. However, the GERD prevalence in SSc and BD was increased compared to that in SLE, RA, PMR, PM/DM, MCTD, and AOSD. In no medication of proton pump inhibitors (PPIs), a significant increase in the risk of GERD symptoms was 2.5 times compared with that in the medication of PPIs in all patients by multivariable regression analysis. On the other hand, there were no increased risks of GERD symptoms with corticosteroids.

Conclusion: In rheumatic diseases, GerdQ would be the useful tool of diagnosis GERD, regardless whether the patients complain or not about gastrointestinal (GI) symptoms.     

Carotid stenting with a new system for distal embolic protection and stenting in high-risk patients: the carotid revascularization with ev3 arterial technology evolution (CREATE) feasibility trial.

The purpose of this study was to evaluate the feasibility of carotid artery revascularization using a new system for carotid stenting and distal embolic protection in 30 patients with severe carotid stenosis and high risk for carotid endarterectomy (Carotid Revascularization With ev3 Arterial Technology Evolution, or CREATE). Previous studies suggest that patients with carotid stenosis and serious comorbid cardiopulmonary and anatomic conditions are at high risk for carotid endarterectomy. All patients underwent percutaneous revascularization using the Protégé GPS self-expanding nitinol stent (ev3, Plymouth, MN) and the Spider distal embolic protection system (ev3). In-hospital and 30-day outcomes were analyzed. High-risk features included age > 75 years (63%), left ventricular ejection fraction < 35% (20%), and restenosis after prior carotid endarterectomy (53%). Procedural success was 100%. In-hospital complications included severe vasovagal reactions in six patients (20%) and a popliteal embolus in one patient (3.3%), treated by successful embolectomy. During 30 days of follow-up, two patients (6.6%) experienced minor neurological deficits, including transient expressive aphasia that resolved without therapy in one patient and homonymous hemianopsia due to contralateral posterior circulation stroke in one patient. This study supports the feasibility of percutaneous carotid artery revascularization with the Protégé GPS self-expanding stent and Spider distal embolic protection system, which will be evaluated in a large multicenter pivotal trial (CREATE Pivotal Trial).     

我国多省市心血管病趋势及决定因素的人群监测(中国MONICA方案)Ⅰ.发病率和死亡率监测结果

为了解我国人群心血管病趋势及发病因素，北京心肺血管研究中心于１９８４年倡议组织了一项多省市心血管病人群监测协作研究，采用ＷＨＯＭＯＮＩＣＡ方案的方法和标准，总监测人口约５００万。经１９８５年～１９８６年２年试点后从１９８７年１月起正式开始收集研究资料，于１９９３年１２月底结束。主要结果如下：（１）我国人群冠心病事件发病率和死亡率低于国际平均水平。男性３５～６４岁年发病率最高为１０８．７／１０００００（１９８７～１９８９年），最低为３．３／１０００００，相差相当３２倍；（２）脑卒中事件年发病率和死亡率高于国际平均水平。男性３５～６４岁发病率最高为５５３．３／１０００００（１９８７年～１９８９年），最低为３３．０／１０００００，相差相当１６倍；（３）疾病率存在较显著的地区差异，北方省市普遍高于南方省市；（４）１９８７～１９９３年期间部分人群心血管病发病率和死亡率呈上升趋势，但多数无统计学显著性。     

Special issues in pediatric inflammatory bowel disease

The incidence of pediatric inflammatory bowel disease （IBD） is rising and recent advances in diagnostics and therapeutics have improved the care provided to these children. There are distinguishing features worth noting between early onset and adult onset IBD. Physical and psychosocial development remains a critical target for the comprehensive management of pediatric IBD. Children are not just little adults and consideration must be given to the stages of development and how these stages impact disease presentation and management. The final stage will be the transition from pediatric care to that of adult oriented care and special consideration must be given to make this a successful process. This review highlights special considerations in the management of the child with IBD.     

肺心病伴发冠心病18例病理与临床对比分析

经尸检证实肺心病伴发冠心病１８例，与单纯肺心病３０例对照，结果两组在心脏重量、右室厚度及左室厚度上差异无显著性（Ｐ＞０．０５），表明肺心病晚期也可累及左室，不管是否合并左室疾患。本组临床诊断正确率为３３．３％，漏诊冠心病为３８．９％，漏诊肺心病为２７．８％。临床单因素分析以年龄、高血压史、心绞痛史、心肌梗塞史、Ａ＿２＞Ｐ＿２、束支传导阻滞、异常Ｑ波、心电轴左偏或正常、程显声诊断标准和Ｓｅｌｖｅｓｔｅｒ心梗筛选标准对诊断伴发冠心病有显著意义（Ｐ＜０．０５）。多元前进法逐步回归分析表明心绞痛史、Ｓｅｌｖｅｓｔｅｒ心梗筛选标准和程显声标准为独立预告因子（Ｐ＜０．０３和０．０００）。上述结果缺乏特异性诊断方法，及早做冠脉造影可能是最佳选择。