ObjectiveWe reviewed the sources of lead in the environments of U.S. children, contributions to children’s blood lead levels, source elimination and control efforts, and existing federal authorities. Our context is the U.S. public health goal to eliminate pediatric elevated blood lead levels (EBLs) by 2010.Data sourcesNational, state, and local exposure assessments over the past half century have identified risk factors for EBLs among U.S. children, including age, race, income, age and location of housing, parental occupation, and season.Data extraction and synthesisRecent national policies have greatly reduced lead exposure among U.S. children, but even very low exposure levels compromise children’s later intellectual development and lifetime achievement. No threshold for these effects has been demonstrated. Although lead paint and dust may still account for up to 70% of EBLs in U.S. children, the U.S. Centers for Disease Control and Prevention estimates that ≥30% of current EBLs do not have an immediate lead paint source, and numerous studies indicate that lead exposures result from multiple sources. EBLs and even deaths have been associated with inadequately controlled sources including ethnic remedies and goods, consumer products, and food-related items such as ceramics. Lead in public drinking water and in older urban centers remain exposure sources in many areas.ConclusionsAchieving the 2010 goal requires maintaining current efforts, especially programs addressing lead paint, while developing interventions that prevent exposure before children are poisoned. It also requires active collaboration across all levels of government to identify and control all potential sources of lead exposure, as well as primary prevention.
Toll-like receptors (TLRs) are key mediators of innate immunity, and their activation by microbial components leads to the production of cytokines and interferons. Recombinant alpha interferon has been used to treat several viral diseases and is the current standard of care for hepatitis C virus (HCV) infection. Recently, agonists of TLR7 and TLR9 have been shown to have clinical efficacy in HCV patients, and this is correlated with their ability to induce endogenous type I interferon production. We have carried out a comprehensive study of agonists of TLRs 1 to 9 to determine if any additional TLRs can induce antiviral molecules from human peripheral blood mononuclear cells (PBMCs). The agonists were incubated with PBMCs, and the supernatant was then removed and added to HCV replicon cells to assess antiviral activity. Agonists of TLRs 3, 4, 7, 8, and 9 were found to be potent inducers of antiviral activity in PBMC supernatants, and the activity correlated with the induction of alpha interferon and the interferon-induced antiviral biomarker 2,5-oligoadenylate synthase. Antiviral activity of TLR7 and TLR8 agonists was blocked by an antibody that binds to the type I interferon receptor, confirming that the antiviral activity results from type I interferon induction. TLR4 and TLR8 agonists were found to strongly induce the proinflammatory cytokines interleukin 1 and tumor necrosis factor alpha at concentrations similar to those inducing antiviral activity. This raises concerns about adverse side effects if these were to be used as antiviral agents. We therefore conclude that TLRs 3, 7, and 9 represent the most attractive targets for the development of new HCV therapies.The World Health Organization reports that ϳ170 million people worldwide are infected with hepatitis C virus (HCV) (29). The disease affects primarily the liver, with 10 to 20% of chronic infections leading to cirrhosis and 1 to 5% leading to liver cancer. The recommended standard therapy for HCV is a once-weekly injection of pegylated interferon alpha 2a (IFN␣2a) plus daily oral ribavirin. The sustained viral response is approximately 50% (23), and the therapy is associated with significant side effects including flu-like symptoms, depression, and injection site reactions (9). In addition, some patients develop neutralizing antibodies to recombinant IFN, which may contribute to treatment failures (2, 13). There is therefore a need to discover new drugs with improved efficacy and reduced side effects.Toll-like receptors (TLRs) are a family of receptors that play a key role in innate immunity. On binding microbial ligands, they induce a signaling cascade resulting in the induction of type I IFNs and other cytokines, which drive an inflammatory response and activate the adaptive immune system (for a review, see reference 27). Whereas current IFN therapy involves the administration of a single IFN-␣ subtype (2a or 2b), TLR activation induces a range of different IFN subtypes. For example, the TLR7 agonist imiquimod has been shown to induce IFN-␣1, -␣2...
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