Activation of Toll-Like Receptor 3 Impairs the Dengue Virus Serotype 2 Replication through Induction of IFN-β in Cultured Hepatoma Cells

Toll-like receptors (TLRs) play an important role in innate immunity against invading pathogens. Although TLR signaling has been indicated to protect cells from infection of several viruses, the role of TLRs in Dengue virus (DENV) replication is still unclear. In the present study, we examined the replication of DENV serotype 2 (DENV2) by challenging hepatoma cells HepG2 with different TLR ligands. Activation of TLR3 showed an antiviral effect, while pretreatment of other TLR ligands (including TLR1/2, TLR2/6, TLR4, TLR5 or TLR7/8) did not show a significant effect. TLR3 ligand poly(I∶C) treatment prior to viral infection or simultaneously, but not post-treatment, significantly down-regulated virus replication. Pretreatment with poly(I∶C) reduced viral mRNA expression and viral staining positive cells, accompanying an induction of the type I interferon (IFN-β) and type III IFN (IL-28A/B). Intriguingly, neutralization of IFN-β alone successfully restored the poly(I∶C)-inhibited replication of DENV2. The poly(I∶C)-mediated effects, including IFN induction and DENV2 suppression, were significantly reversed by IKK inhibitor, further suggesting that IFN-β is the dominant factor involved in the poly(I∶C) mediated antiviral effect. Our study presented the first evidence to show that activation of TLR3 is effective in blocking DENV2 replication via IFN-β, providing an experimental clue that poly(I∶C) may be a promising immunomodulatory agent against DENV infection and might be applicable for clinical prevention

Internal medicine-pediatrics residency training: current program trends and outcomes.

PURPOSE: Combined internal medicine-pediatrics (med-peds) residency programs have existed since 1967. Due to the rapid growth in the number and size of programs during the 1990s, most current med-peds physicians completed their residency in the last ten

From theory to actual practice: Creation and application of milestones in an internal medicine residency program, 2004-2010

BACKGROUND: In the USA, the Accreditation Council of Graduate Medical Education, Educational Innovations Project is a partner in reshaping residency training to meet increasingly complex systems of health care delivery. AIM: We describe the creation and implementation of milestones as a vehicle for translating educational theory into practice in preparing residents to provide safe, autonomous patient care. METHOD: Six program faculty leaders, all with advanced medical education training, met in an iterative process of developing, implementing, and modifying milestones until a final set were vetted. RESULTS: We first formed the profile of a Master Internist. We then translated it into milestone language and implemented its integration across the program. Thirty-seven milestones were applied in all settings and rotations to reach explicit educational outcomes. We created three types of milestones: Progressive, build one on top of the other to mastery; additive, adding multiple behaviors together to culminate in mastery; and descriptive, using a proscribe set of complex, predetermined steps toward mastery. CONCLUSIONS: Using milestones, our program has enhanced an educational model into explicit, end of training goals. Milestone implementation has yielded positive results toward competency-based training and others may adapt our strategies in a similar effort