Articles: disease.
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BACKGROUND Subclinical hypothyroidism (SCH) has been associated with ischemic heart disease (IHD); however, it is unknown whether treatment of SCH with levothyroxine sodium will reduce the risk of IHD. The aim of this study was to investigate the association between levothyroxine treatment of SCH with IHD morbidity and mortality. METHODS We used the United Kingdom General Practitioner Research Database to identify individuals with new SCH (serum thyrotropin levels of 5.01-10.0 mIU/L and normal free thyroxine levels) recorded during 2001 with outcomes analyzed until March 2009. ⋯ In contrast, in the older group there were 104 events in 819 treated patients (12.7%) vs 88 events in 823 untreated individuals (10.7%) (HR, 0.99; 95% CI, 0.59-1.33). CONCLUSIONS Treatment of SCH with levothyroxine was associated with fewer IHD events in younger individuals, but this was not evident in older people. An appropriately powered randomized controlled trial of levothyroxine in SCH examining vascular outcomes is now warranted.
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The individual human genome and epigenome are being defined at unprecedented resolution by current advances in sequencing technologies with important implications for human disease. This review uses examples relevant to clinical practice to illustrate the functional consequences of genetic and epigenetic variation. The insights gained from genome-wide association studies are described together with current efforts to understand the role of rare variants in common disease, set in the context of recent successes in Mendelian traits through the application of whole exome sequencing. The application of functional genomics to interrogate the genome and epigenome, build up an integrated picture of the regulatory genomic landscape and inform disease association studies is discussed, together with the role of expression quantitative trait mapping and analysis of allele-specific gene expression.
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Can different pathophysiological mechanisms and risk factors leading to various diseases be linked with altered transmission of signals by one common pathway? The present article provides evidence for the hypothesis that adequate vagal nerve activity reduces the risk of major diseases, via common basic mechanisms and interim risk factors. These diseases include cardiovascular disease, cancer, Alzheimer's disease and the metabolic syndrome. Three basic mechanisms contribute to such illnesses: local oxidative stress and DNA damage, inflammatory reactions and excessive sympathetic responses, all of which are inhibited by vagal nerve activity. ⋯ By proposing an integrative neurobiological model of major diseases, identifying people at risk for, and treating patients with, such diseases may be done more efficiently. People with low HRV may be identified and subsequently treated by vagus nerve activation to possibly prevent or treat such illnesses. This proposed disease paradigm may have important preventative and therapeutic implications, whose clinical effects need to be investigated.
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Inflammasomes are a group of protein complexes built around several proteins, including NLRP3, NLRC4, AIM2 and NLRP6. Recognition of a diverse range of microbial, stress and damage signals by inflammasomes results in direct activation of caspase-1, which subsequently induces secretion of potent pro-inflammatory cytokines and a form of cell death called pyroptosis. Inflammasome-mediated processes are important during microbial infections and also in regulating both metabolic processes and mucosal immune responses. We review the functions of the different inflammasome complexes and discuss how aberrations in them are implicated in the pathogenesis of human diseases.