卒中的遗传学和炎性机制

在美国，卒中仍然是第三大常见死亡原因。估计每53s就有1个美国人发生卒中，其中20％～25％的患者在发病后1年内死亡。而且，卒中也是长期致残的主要原因。针对纠正传统卒中危险因素所作的努力并未能有效降低美国的卒中发病率。在经过了几十年的降低之后，卒中发病率重新有所上     

卒中遗传学研究进展

无论是在中国和全世界范围内，卒中都是一种重要的公共卫生问题。近年来，卒中遗传学研究取得了很大进展，特别是全基因组关联研究（genome-wide association study，GWAS）和表观遗传学的出现给该领域带来突破性进展。它们分别从基因水平和环境因素层面研究卒中的发病机制。虽然目前仍存在众多问题，但卒中遗传学前景光明。     

卒中遗传学研究进展

无论是在中国和全世界范围内,卒中都是一种重要的公共卫生问题。近年来,卒中遗传学研究取得了很大进展,特别是全基因组关联研究(genome-wide association study,GWAS)和表观遗传学的出现给该领域带来突破性进展。它们分别从基因水平和环境因素层面研究卒中的发病机制。虽然目前仍存在众多问题,但卒中遗传...     

卒中的遗传学研究进展

人类基因编码的破译为卒中的遗传学研究提供了科学依据,并成为当今医学科学研究的热点。文章简要阐述了全身疾病引起卒中的遗传学,包括凝血性疾病、结缔组织病、血管病、代谢性疾病和病因不明的疾病和全身疾病引起出血性卒中的发病机制、临床特点、基因定位等遗传学研究进展。     

卒中的遗传学研究进展

人类基因编码的破译为卒中的遗传学研究提供了科学依据，并成为当今医学科学研究的热点。文章简要阐述了全身疾病引起卒中的遗传学，包括凝血性疾病、结缔组织病、血管病、代谢性疾病和病因不明的疾病和全身疾病引起出血性卒中的发病机制、临床特点、基因定位等遗传学研究进展。     

卒中的遗传学研究

对孪生子女、家族及不同种族和地域的卒中流行病学的研究表明，遗传基因在卒中发病中起重要作用。目前，除了一些符合Ｍｅｎｄｅｌ遗传规律的以脑血管病为主要临床表现的综合征上，有少数研究已深入到卒中的基因标记或分子遗传学水平。     

卒中的遗传学研究

对孪生子女、家族及不同种族和地域的卒中流行病学的研究表明，遗传基因在卒中发病中起重要作用。目前，除了一些符合Ｍｅｎｄｅｌ遗传规律的以脑血管病为主要临床表现的综合征外，有少数研究已深入到卒中的基因标记或分子遗传学水平。     

遗传学新概念与卒中预防

作者试图以遗传学新概念指导卒中防治工作。15年来,已发现单基因遗传性神经系统疾病的致病染色体200多种,其中12个是有严重卒中倾向的Ｍｅｎｄｅｌ基因位点,即ＣＡＣＮＬ1Ａ4、ｌｑ、Ｎｏｔｃｈ3、ＭｉｔｏｔＲＮＡｌｅｕ、Ｅｎｄｏｇｌｉｎ、活化素受体样激酶1(ａｃｔｉｖｉｎｒｅｃｅｐｔｏｒｌｉｋｅｋｉｎａｓｅ1)、7ｑ22、淀粉样前体蛋白、胱蛋白Ｃ、胶原3Ａ1、ｐｏｌｙｃｙｓｔｉｎ和原纤蛋白(ｆｉｂｒｉｌｌｉｎ)。迄今已确认Ｎｏｔｃｈ3和ＭｉｔｏｔＲＮＡｌｅｕ分别与引起缺血性卒中的伴皮质下梗死和白质脑病的常染色体显性遗传性…     

不同亚型缺血性卒中的遗传学

卒中是一类复杂性疾病,是多种环境因素和遗传因素共同作用的结果.随着分子生物学技术的发展,已发现大量与卒中相关的候选基因和易感区域.文章对不同亚型缺血性卒中的遗传学研究进展进行了综述.     

炎性标志物与缺血性卒中的研究进展

<正>脑梗死是指各种原因导致的脑内血液供应障碍,引起脑组织缺血、缺氧性坏死。脑血流中断5 min,神经细胞将出现不可逆损害。脑梗死病灶由缺血中心区和周围的缺血半暗带组成。缺血半暗带恰好是局部缺血引起炎症,造成脑损伤的关键部位。半暗带虽然有损伤,但仍然有大量存活的神经元,及时给予正确的治疗,可以逆转脑组织损伤。因此探讨缺血性脑卒中的炎性发生机制,合理利用炎性标志物,对脑卒中的诊断和预后评价尤为重要。阻断炎性通路,减轻神经元损伤,将成为治疗缺血性卒中的重要治疗靶点之一。1脑梗死的炎性细胞反应     

卒中后的全身炎症反应

近几年的研究表明,炎症反应是卒中后继发性损害的机制之一。急性卒中后缺血灶内及其周围存在明显的炎症细胞浸润和细胞因子表达增加,同时外周血白细胞、C-反应蛋白和各种细胞因子,如肿瘤坏死因子-α、白细胞介素-1和白细胞介素-6等水平增高。卒中并发的全身炎症反应综合征是导致多器官功能障碍综合征的主要发病基础。细胞因子的失控性释放在卒中并发全身炎症反应综合征向多器官功能障碍综合征的转化过程中起关键作用。     

Differences of Inflammatory Mechanisms in Asthma and COPD

Bronchial asthma and chronic obstructive pulmonary disease (COPD) are increasing common diseases. The major pathogenesis of both illnesses is chronic inflammation. However, the inflammatory pattern is distinct in each disease. In asthmatic airways, activated mast cells/eosinophils and T helper 2 lymphocytes (Th2) are predominant. In contrast, macrophages and neutrophils are important in COPD airways/lung. Although nitric oxide (NO) hyperproduction due to inducible NO synthase (iNOS) is observed in asthma and COPD, nitrotyro- sine formation via the reaction between NO and O2^- in addition to the myeloperoxidase-mediated pathway. These distinct inflammatory patterns in both diseases seem to cause pathological differences in asthma and COPD.     

Mechanisms and Consequences of Inflammatory Signaling in the Myocardium

To further understand chronic heart disease, such as heart failure and cardiomyopathy, we must fully define signaling pathways within the myocardium. Recent studies suggest that some forms of heart disease are associated with a chronic low-grade inflammation that promotes adverse ventricular remodeling and correlates with disease progression. Several inflammatory mediators, including TNF-??, IL-1??, and IL-6, are involved in cardiac injury subsequent to myocardial ischemia and reperfusion, sepsis, viral myocarditis, and transplant rejection. Once activated, components of the inflammatory response can have both beneficial and deleterious effects on the heart. In this review, we discuss the complex inflammatory signaling pathways in the myocardium and potential therapeutic implications.     

Vascular Mechanisms in the Pathogenesis of Stroke

Stroke is one of the most devastating manifestations of two common diseases, atherosclerosis and hypertension. It represents the second leading cause of death and a major cause of disability worldwide. Besides age (a nonmodifiable risk factor), hypertension is the most important cardiovascular risk factor for developing both ischemic and hemorrhagic stroke, as well as small vessel disease predisposing to lacunar infarction, white matter lesions, and cerebral microbleeds. In addition, hypertension predisposes to atherosclerosis and cardiac diseases (notably atrial fibrillation), thereby promoting cerebral embolism. Inflammatory mechanisms play a central role in the pathogenesis and progression of atherosclerosis, plaque rupture, thrombosis, and stroke. Endothelial dysfunction, in part resulting from excessive production of reactive oxygen species, is an important mechanism of cerebrovascular damage. This article reviews recent data on vascular mechanisms that participate in the pathogenesis of stroke.     

Genetic Susceptibility in Inflammatory Bowel Disease

The genetic susceptibility is clearly important in the complex inheritance of inflammatory bowel disease (IBD). Furthermore, the etiologic basis of the relationship between Crohn’s disease (CD) and ulcerative colitis (UC) is as yet unexplained. The strongest evidence supporting the contribution of inherited factors in the pathogenesis of CD and UC comes from concordance rates in twin pairs. The development of a linkage map of the human genome with informative microsatellite markers has enabled hypothesis-free scanning of the human genome for loci associated with the susceptibility to simple monogenic and polygenic diseases. Many susceptibility loci have been implicated in IBD with varying degrees of replication and statistical support. Genetic research in IBD has advanced in understanding the clinical heterogeneity of the disease and has started to tackle the complex interactions between genetic and environmental risk factors in IBD. It is probably to be possible in the future that these genetic markers will find their place in an integrated molecular diagnostic and prognostic approach to patients with IBD.     

Mechanisms of Cardiac Fibrosis in Inflammatory Heart Disease

Heart injury from many causes can end up in a common final pathway of pathologic remodeling and fibrosis, promoting heart failure development. Dilated cardiomyopathy is an important cause of heart failure and often results from virus-triggered myocarditis. Monocytes and monocyte-like cells represent a major subset of heart-infiltrating cells at the injury site. These bone marrow-derived cells promote not only tissue injury in the short term but also angiogenesis and collagen deposition in the long term. Thus, they are critically involved in the typical tissue fibrosis, which evolves in the dilating ventricle during the process of pathologic remodeling. Recent findings suggest that heart-infiltrating monocyte-like cells indeed contain a pool of progenitors, which represent the cellular source both for accumulation of differentiated monocytes during the acute inflammatory phase and for transforming growth factor-β-mediated myocardial fibrosis during the later chronic stages of disease. Obviously, a delicate balance of proinflammatory and profibrotic cytokines dictates the fate of bone marrow-derived heart-infiltrating progenitors and directly influences the morphologic phenotype of the affected heart. In this minireview, we provide an update on these mechanisms and discuss their significance in pathologic remodeling and heart failure progression after myocarditis.     

Genetic Mechanisms in Interval Colon Cancers

Background and Aim

The factors underlying the development of interval colon cancers are not well defined and are likely heterogeneous. We sought to determine whether there are distinct molecular properties associated with interval colon cancers.

Methods

Colon cancers diagnosed within 5 years of a complete and well-prepped colonoscopic examination were identified over a 7-year period at a single institution. The clinical and pathological features of the tumors were defined. Analysis of DNA mismatch repair (MMR) and genotyping of a panel of oncogenes associated with colon cancer were performed.

Results

Forty-two interval colon cancers were diagnosed at an average age of 70 years. 69 % of tumors were located in the right colon. 41 % of tumors exhibited DNA microsatellite instability (MSI). Loss of staining of DNA MMR proteins by immunohistochemistry (IHC) was confirmed in 82 % of the MSI-positive tumors. Among tumors with abnormal MSI and IHC, 54 % exhibited somatic methylation of the MLH1 promoter, but the remaining 43 % exhibited molecular features indicative of underlying Lynch syndrome (LS). The frequency of somatic mutations in the KRAS, BRAF, NRAS, and PIK3CA oncogenes was similar between interval cancer cases and controls.

Conclusions

Interval colon cancers are not distinguished by the activation of the KRAS, NRAS, BRAF, or PIK3CA oncogenic pathways. However, MSI pathway defects are present in a significant proportion of interval colon cancers. Underlying LS may explain nearly half of these MSI-positive cases, and the remaining cases appear to represent sporadic serrated pathway tumors.     

Peripheral and Central Mechanisms of Fatigue in Inflammatory and Noninflammatory Rheumatic Diseases

Fatigue is a common symptom in a large number of medical and psychological disorders, including many rheumatologic illnesses. A frequent question for health care providers is related to whether reported fatigue is ??in the mind?? or ??in the body????that is, central or peripheral. If fatigue occurs at rest without any exertion, this suggests psychological or central origins. If patients relate their fatigue mostly to physical activities, including exercise, their symptoms can be considered peripheral. However, most syndromes of fatigue seem to depend on both peripheral and central mechanisms. Sometimes, muscle biopsy with histochemistry may be necessary for the appropriate tissue diagnosis, whereas serological tests generally provide little reliable information about the origin of muscle fatigue. Muscle function and peripheral fatigue can be quantified by contractile force and action potential measurements, whereas validated questionnaires are frequently used for assessment of mental fatigue. Fatigue is a hallmark of many rheumatologic conditions, including fibromyalgia, myalgic encephalitis/chronic fatigue syndrome, rheumatoid arthritis, systemic lupus, Sjogren??s syndrome, and ankylosing spondylitis. Whereas many studies have focused on disease activity as a correlate to these patients?? fatigue, it has become apparent that other factors, including negative affect and pain, are some of the most powerful predictors for fatigue. Conversely, sleep problems, including insomnia, seem to be less important for fatigue. There are several effective treatment strategies available for fatigued patients with rheumatologic disorders, including pharmacological and nonpharmacological therapies.     

Mechanisms of Action of Intravenous Immunoglobulin in Inflammatory Muscle Disease

Intravenous immunoglobulin (IVIG) is a unique immune-modulating therapy that has a wide range of effects on the immune system at multiple levels. This allows it to be used successfully in a variety of immune-mediated, systemic, and neurological disorders, including the inflammatory myopathies. It is likely that the specific action of IVIG varies depending on the underlying pathogenesis of a given disease. In dermatomyositis (DM), IVIG has been shown to diminish the activity of complement and deposition of membrane attack complex on capillaries and muscle fibers, the expression of adhesion molecules, and cytokine production. IVIG also appears to modify gene expression in the muscle of DM patients. The mechanism by which IVIG affects muscle in polymyositis and inclusion body myositis has not been well-studied. However, it may work via suppression of T-cell activation (including cytotoxic T cells) and migration into muscle tissue and alterations in cytokine production. IVIG generally yields the greatest therapeutic benefit in DM and is often of marginal utility in inclusion body myositis. It is generally considered as second-line or adjunctive therapy in the inflammatory myopathies.