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《中国科学:生命科学英文版》2017,(7)
Characterized by their low prevalence, rare diseases are often chronically debilitating or life threatening. Despite their low prevalence, the aggregate number of individuals suffering from a rare disease is estimated to be nearly 400 million worldwide.Over the past decades, efforts from researchers, clinicians, and pharmaceutical industries have been focused on both the diagnosis and therapy of rare diseases. However, because of the lack of data and medical records for individual rare diseases and the high cost of orphan drug development, only limited progress has been achieved. In recent years, the rapid development of next-generation sequencing(NGS)-based technologies, as well as the popularity of precision medicine has facilitated a better understanding of rare diseases and their molecular etiology. As a result, molecular subclassification can be identified within each disease more clearly, significantly improving diagnostic accuracy. However, providing appropriate care for patients with rare diseases is still an enormous challenge. In this review, we provide a brief introduction to the challenges of rare disease research and make suggestions on where and how our efforts should be focused. 相似文献
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Selenium intake and cardiovascular risk: what is new? 总被引:1,自引:0,他引:1
PURPOSE OF REVIEW: Selenium is an essential element with a narrow safety margin. Adequate selenium intake is needed to maximize the activity of glutathione peroxidases and other selenoproteins. This review discusses recent experimental and epidemiologic contributions on the role of selenium for the prevention of atherosclerotic cardiovascular disease. RECENT FINDINGS: Few randomized trials have evaluated the efficacy of selenium supplementation on cardiovascular endpoints. Most trials, conducted in selenium-replete populations, found no evidence of cardiovascular protection. A meta-analysis of 13 prospective cohort studies found a moderate inverse relationship between plasma/serum selenium and coronary heart disease. The interpretation of these data is complicated, however, by potential residual confounding and publication bias. In contrast, recent data from trials of selenium-containing supplements and from epidemiologic studies suggest that chronically increased selenium intake in selenium-replete populations can induce diabetes and maybe also hypercholesterolemia. SUMMARY: Current evidence is insufficient to support a protective role for selenium in cardiovascular prevention. Large high-quality randomized controlled trials and observational studies are needed across populations with different levels of selenium intake. Furthermore, subjects living in regions with high selenium intake should be aware that selenium supplements may increase their risk of diabetes and hypercholesterolemia. 相似文献
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Szmitko PE Teoh H Stewart DJ Verma S 《American journal of physiology. Heart and circulatory physiology》2007,292(4):H1655-H1663
The cardiometabolic syndrome, associated with increased cardiovascular disease risk in the industrialized world, is estimated to affect one in four adults. Although the mechanisms linking obesity and cardiovascular disease remain unclear, research continues to unravel the molecular pathways behind this pandemic. Adipose tissue has emerged as a metabolically active participant in mediating vascular complications, serving as an active endocrine and paracrine organ secreting adipokines, which participate in diverse metabolic processes. Among these adipokines is adiponectin, which seems to possess antiatherogenic and anti-inflammatory effects and may be protective against cardiovascular disease development. The current review describes the pathophysiology of adiponectin in atherosclerotic disease. 相似文献
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《Insect biochemistry and molecular biology》1999,29(5):397-403
Recent advances in the molecular genetics of insecticide resistance have identified the point mutations associated with target site insensitivity in the genes encoding the three major insecticide targets: the Rdl GABA receptor, the para voltage gated sodium channel and insect acetylcholinesterase. However central questions relating to the origin, selection and fitness of these mutations in natural populations remain. This review examines the extent to which we understand how a specific subset of potential resistance associated mutations are selected, how often they may arise and/or recombine, and whether we can explain any potential fitness disadvantages based on our knowledge of the molecular mechanisms of resistance involved. 相似文献
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A general problem in single-cell research (SCR) is whether a representative cell is picked for analysis. In many cases, it may determine feasibility of SCR. Here, using a probability approach, we analyze this problem for laser tweezers Raman spectroscopy (LTRS), a promising technique for SCR. The results suggest that two main parameters determine the success and feasibility of SCR: the probability of picking a representative cell and the number of representative cells to be picked and analyzed. Both parameters determine the number of experiments required to obtain meaningful results. The approach is verified on several particular examples of SCR. 相似文献
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Rheumatoid arthritis, currently regarded as a complex multifactorial disease, was initially characterized as such at the turn of the 19th century. Ever since, multiple lines of investigation have attempted to elucidate the etiological factor(s) involved in disease incidence. Genes – including those risk alleles within HLA-DR4 – have been implicated but are insufficient to explain the vast majority of cases. Several environmental factors, therefore, are being studied. Among them, the role of periodontal disease and Porphyromonas gingivalis in the pathogenesis of rheumatoid arthritis has attracted both clinical and bench interest given supportive epidemiologic and mechanistic data.The notion that rheumatoid arthritis (RA) is a polygenic autoimmune disorder that requires environmental factors in order to become clinically apparent is not novel. Since the very beginning, infectious agents have been implicated. This includes early theories such as the ‘oral sepsis’ hypothesis, which supported the notion that periodontal infections were the true etiologic factors behind many chronic diseases. Soon after, dental extraction became a central part of the RA therapeutic armamentarium.Over the last decade, an ever-increasing body of literature has been devoted to study the association between periodontal disease, Porphyromonas gingivalis, and RA. In this issue of Arthritis Research & Therapy, Arvikar and colleagues [1] demonstrate a positive correlation between P. ginigivalis antibody responses and presence/levels of anti-cyclic citrullinated peptide antibodies in a subset of patients with early RA. Moreover, subjects with serological reactivity toward P. ginvgivalis also tended to have higher RA disease activity as measured by Disease Activity Score in 28 Joints and Clinical Disease Activity Index. This occurred both at baseline – that is, in recently diagnosed patients who have not previously been treated with disease-modifying anti-rheumatic drugs (DMARDs) – and 12 months after initiation of therapy.The study had several strengths. First, the authors enrolled early RA patients who were DMARD-naïve at the time of antibody measurements and clinical assessments. Second, patients were followed for a period of 1 year to address biologic and phenotypic alterations after initiation of therapy. This is of utmost importance since very few studies have addressed clinical and immunologic changes at the very onset of disease [2,3]. Too often, however, the natural history of RA is studied without considering the confounding effects of long-standing systemic inflammation or immunosuppressive therapies or both. It is almost certain that the use of DMARDs and biologics alters the quantification and behavior of multiple immune cells and proteins (including auto- and alloantibody responses), thus distorting the true understanding of disease pathogenesis. Efforts to elucidate the earliest changes in pre-clinical and clinical RA are underway [2,4].An accumulating body of evidence suggests a role for clinical periodontal diseases in RA pathogenesis. Periodontitis was more common and severe in patients with RA compared with osteoarthritis [5], and subjects with RA had an increased likelihood of periodontitis compared with controls [6]. Multiple recent studies have specifically implicated P. gingivalis, a periodontopathic bacterium, as a possible triggering factor. This microorganism has gained scientific attention given its ability to citrullinate peptides via unique enzymatic properties conferred by peptydil arginine deiminase (PAD), which reportedly promotes the generation of neoantigens and the subsequent production of antibodies to citrullinated protein antigens (ACPAs). Experimentally, P. gingivalis-PAD is capable of citrullinating human peptides [7] and ACPAs have proven pathogenic in murine models of arthritis [8].A decade ago, it was postulated that a specific humoral immune response to P. gingivalis was the actual stimulus for the development of RA [9]. Since then, multiple reports used serological methods [10,11] to correlate the generation of antibodies to P. gingivalis with autoimmunity (that is, ACPA antibodies) and clinical RA. Several lessons can be learned from these types of approaches. First, as in the case of reports by Arvikar and colleagues [1] and others [2,10,11], the methodology and antigens used to quantify anti-P. gingivalis antibodies have been heterogeneous. Prior studies used antibodies against whole-cell, bacterial lipopolysaccharide, or P. gingivalis-specific chaperone protein. The sensitivity and specificity of each one of these antibodies (and their measurements through different phases of disease) add to the complexity of correlating P. gingivalis serologic responses to RA pathogenesis. A concerted effort toward standardization is warranted in the interest of scientific validation and replication. Second, very few studies have reported the direct presence of P. gingivalis (or other periodontopathic bacteria) in subgingival biofilms of patients with RA. This can now be achieved without the need for laborious, classic microbiologic culture techniques. The advent of high-throughput, bacterial DNA sequencing has allowed taxonomic classification of multiple bacterial species within hundreds of samples (that is, microbiome analysis) in a matter of days.Finally, and perhaps more importantly, virtually all studies consistently reported only a small fraction of RA patients as being exposed to P. gingivalis (serologically, microbiologically, or both). This can have several (and possibly complementary) explanations. It is conceivable that the overabundance of other, non-measured, periodontopathic bacteria (or the lack of protective flora or both) contributes to disease initiation. Moreover, exposure to bacterial antigenic burden at other body sites, such as the lung or the gut, may represent triggering factors for RA. The intestinal microbiome, for example, is vast and diverse. It contains 100 times more protein-coding genes than the human genome and harbors 100 trillion cells (10-fold the amount of total host human cells). Studies in animal models support the notion that the oral, lung, or intestinal microbiome (or a combination thereof) is required to develop inflammatory arthritis. This is based on the fact that rodents do not develop joint inflammation under germ-free conditions or when treated with antibiotics. It is plausible, therefore, that an alteration in the bacterial taxa of several mucosal sites (including oral, lung, and intestinal microbiomes) is required for the transition from a pre-clinical, autoimmune phase of RA into clinically classifiable disease.Novel and comprehensive approaches for the study of the microbiome and the initiation of RA are now possible. Immunologic and microbiome analyses in prospective cohorts of subjects with periodontal disease and other risk factors for the development of RA (for example, first-degree relatives, discordant twins, or asymptomatic individuals with circulating autoantibodies or a combination thereof) may help elucidate some of these questions and ultimately target these organisms (or their components) as a diagnostic or even preventive strategy for RA. 相似文献
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Jan Wondergem Marjan Boerma Kazunori Kodama Fiona A. Stewart Klaus R. Trott 《Radiation and environmental biophysics》2013,52(4):425-434
The authors of this report met at the Head Quarter of the International Atomic Energy Agency (IAEA) in Vienna, Austria, on 2–4 July 2012, for intensive discussions of an abundance of original publications on new epidemiological studies on cardiovascular effects after low-dose exposure and radiotherapy and radiobiological experiments as well as several comprehensive reviews that were published since the previous meeting by experts sponsored by the IAEA in June 2006. The data necessitated a re-evaluation of the situation with special emphasis on the consequences current experimental and clinical data may have for clinical oncology/radiotherapy and radiobiological research. The authors jointly arrived at the conclusions and recommendations presented here. 相似文献
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An understanding of metabolic pathways based solely on biochemistry textbooks would underestimate the pervasive role of metabolism in essentially every aspect of biology. It is evident from recent work that many human diseases involve abnormal metabolic states--often genetically programmed--that perturb normal physiology and lead to severe tissue dysfunction. Understanding these metabolic outliers is now a crucial frontier in disease-oriented research. This Review discusses the broad impact of metabolism in cellular function and how modern concepts of metabolism can inform our understanding of common diseases like cancer and also considers the prospects of developing new metabolic approaches to disease treatment. 相似文献
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The p53 pathway is composed of hundreds of genes and their products that respond to a wide variety of stress signals. These responses to stress include apoptosis, cellular senescence or cell cycle arrest. In addition the p53-regulated genes produce proteins that communicate these stress signals to adjacent cells, prevent and repair damaged DNA and create feedback loops that enhance or attenuate p53 activity and communicate with other signal transduction pathways. Many questions remain to be explored in our understanding of how this network of genes plays a role in protection from cancers, therapy and integrating the homeostatic mechanisms of stress management and fidelity in a cell and organism. The goal of this chapter is to elucidate some of those questions and suggest new directions for this area of research. 相似文献
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Zicha J Pechánová O Cacányiová S Cebová M Kristek F Török J Simko F Dobesová Z Kunes J 《Physiological research / Academia Scientiarum Bohemoslovaca》2006,55(Z1):S49-S63
Hypertriglyceridemia and hypertension seem to be very important cardiovascular risk factors. The Prague hereditary hypertriglyceridemic (hHTG) rat was developed as a model of human hypertriglyceridemia. It was demonstrated that these rats are not obese, they are hypertensive and insulin resistant and they have some disturbances in glucose metabolism. Several QTLs were identified for blood pressure, its particular components (dependent on major vasoactive systems) and plasma triglycerides throughout the genome of hHTG rats by using of F(2) hybrids strategy. It is evident that hHTG rats are a suitable model for the study of metabolic disturbances in relation to blood pressure as well as for the search of genetic determinants of these abnormalities. Numerous abnormalities of blood pressure regulation as well as alterations in the structure and function of cardiovascular apparatus (heart, conduit and resistance arteries) were found in hHTG rats. A special attention was paid to possible changes in the efficiency of various vasoactive systems such as nitric oxide, renin-angiotensin-aldosterone system and sympathetic nervous system, which seem to contribute substantially to cardiovascular and/or metabolic abnormalities observed in Prague hereditary hypertriglyceridemic rats. 相似文献
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Otocka-Kmiecik A Mikhailidis DP Nicholls SJ Davidson M Rysz J Banach M 《Progress in lipid research》2012,51(4):314-324
High density lipoprotein (HDL) has many properties, which contribute to its atheroprotective role. However, some recent clinical trials have identified subjects with the progression of atherosclerosis despite normal levels of HDL cholesterol. This raises the question if all subfractions of HDL have the same properties. Moreover, recent investigations have shown that both acute and chronic inflammation may lead to structural and functional changes of HDL, which render the particles proinflammatory. Although therapeutic agents that increase HDL levels are now quite well established it is not clear whether they influence HDL quality. We review the current state of knowledge on the properties of HDL and factors/therapeutic agents which may restrain the transformation of normal HDL into dysfunctional HDL. 相似文献