Although good evidence suggests that many agents are effective in preventing osteoporotic fractures, the data are insufficient to determine the relative efficacy or safety of these agents.

Tumor necrosis factor-alpha (TNFα) antagonists including antibodies and soluble receptors have shown remarkable efficacy in various immune-mediated inflammatory diseases (IMID). As experience with these agents has matured, there is an emerging need to integrate and critically assess

Tumor necrosis factor-alpha (TNFα) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFα antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFα antibodies are effective in other IMIDs. Early efforts at understanding how TNFα antagonists act in IMIDs centered on their ability to neutralize soluble TNFα or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFα blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFα antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFα antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFα antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

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The present study evaluated auditory-visual speech perception in cochlear-implant users as well as normal-hearing and simulated-implant controls to delineate relative contributions between sensory experience and cues. Auditory-only, visual-only, or auditory-visual speech perception was examined in the context of categorical perception, in which an animated face mouthing /ba/, /da/, or /ga/ was paired with synthesized phonemes from an 11-token auditory continuum. A 3-alternative, forcedchoice, method was used to yield percent identification scores. Normal-hearing listeners showed sharp phoneme boundaries and strong reliance on the auditory cue, whereas actual and simulated implant listeners showed much weaker categorical perception but stronger dependence on the visual cue. The implant users were able to integrate both congruent and incongruent acoustic and optical cues to derive relatively weak but significant auditory-visual integration. This auditory-visual integration was correlated with the duration of the implant experience but not the duration of deafness. Compared with the actual implant performance, acoustic simulations of the cochlear implant could predict the auditory-only performance but not the auditory-visual integration. These results suggest that both altered sensory experience and improvised acoustic cues contribute to the auditory-visual speech perception in cochlear-implant users.