IMIQUIMOD IS a topically applied imidazoquinoline immunomodulator that has been shown to have efficacy in a wide range of infectious and neoplastic dermatologic conditions. This has generated some skepticism about how any single drug can work for so many indications. In 1997, it was approved for treating external perianal and genital warts.1 In addition, there are open-label trials and case reports showing success in treating of other virus-related conditions including flat warts2 and molluscum contagiosum.3 There are similar reports demonstrating successful treatment of intraepithelial neoplasms including Bowen disease,4 lentigo maligna,5 and extramammary Paget disease.6 A recent case report showed efficacy in treating cutaneous T-cell lymphoma.7 Imiquimod has also been used to effectively treat other neoplastic conditions such as actinic keratosis8 and superficial basal cell carcinoma.9
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TLR7 and TLR8 signaling pathway. When a ligand, such as imiquimod, binds to TLR7, the intracellular adapter protein MyD88 is recruited to the ligand/receptor complex.21 (All abbreviations not otherwise explained are expanded in a box on the next page.) In turn, MyD88 recruits IRAK/TOLLIP to the receptor complex.24 It is suggested that TOLLIP binds IRAK in the cytoplasm, which keeps IRAK inactive.22 When IRAK/TOLLIP binds to MyD88, IRAK is activated via autophosphorylation, which in turn causes dissociation of TOLLIP.22 Subsequently, IRAK dissociates from the receptor complex and then binds to TRAF6. TRAF6 ultimately leads, via various intermediate molecules, to the activation of NFκB and cJUN/cFOS.21 The incompletely characterized NFκB pathway starts with concomitant activation of ECSIT and the TAK1-TAB1-TAB2 complex. ECSIT activates MEKK1, which in turn likely activates IKKα24; MEKK1, it should be noted, is also involved in the JNK1 pathway discussed below.25 Activated TAK1 phosphorylates NIK, which phosphorylates IKKγ/NEMO.23,26 Activated IKKα/IKKβ/IKKγ/NEMO, also known as the signalosome, is responsible for phosphorylating IκB.27,28 Unphosphorylated IκB keeps NFκB in its inactive form in the cytoplasm. However, when IκB is phosphorylated by the signalosome, IκB is ubiquitinated and degraded.27 As a result, NFκB is free to move into the nucleus, where it serves as a transcription factor for genes coding for proinflammatory and stress cytokines.27 The cFOS/cJUN pathway also begins with activation of the TAK1-TAB1-TAB2 complex, which in turn activates MKK4 and MKK3/MKK6.29,30 MKK4 phosphorylates and activates JNK1, while MKK3/MKK6 phosphorylates and activates p38 MAP kinase.31 Activated JNK1 and p38 MAP kinase move into the nucleus, where they work together with the transcription factors cFOS and cJUN to activate transcription of genes involved in maturation of DCs and induction of TH1 responses.32,33 Similar pathways may be involved in TLR8 signaling, but they have not been shown to date. R-848-TLR7 and -TLR8 ligation appears to induce certain responses that differ from those induced by imiquimod-TLR7 ligation (personal communication, R. B. Slade, MD, May 4, 2003). Recently, an alternative MyD88-independent pathway for TLR signaling has been demonstrated,34 involving TRIF as the intracellular TLR-binding molecule (as opposed to MyD88), leading to the downstream activation of IFN-β (as opposed to NF-κB). The MyD88-independent pathway has been shown to play an important role in TLR4 signaling but not in TLR7 or TLR8 signaling.35
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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