Visual evoked potentials to an illusory change in brightness: the Craik-Cornsweet-O'Brien effect.

Can brain electrical activity associated with the Craik-Cornsweet-O'Brien effect (CCOB) be identified in humans? Opposing luminance gradients met in the middle of a square image to create a luminance contrast-defined vertical border. The resulting rectangles on each side of the border were otherwise equiluminant, but appeared to differ in brightness, the CCOB effect. When the contrast gradients were swapped, the participants perceived darker and lighter rectangles trading places. This dynamic CCOB stimulus was reversed 1/s to elicit visual evoked potentials. The CCOB effect was absent in two control conditions. In one, the immediate contrast border, where the gradients met, was replaced by a dark vertical stripe; in the other, the outer segments of both rectangles, where the illusion would otherwise occur, were replaced by dark rectangles, leaving only the contrast-reversing gradients. Visual evoked potential components P1 and N2 were present for the CCOB stimuli, but not the control stimuli. Results are consistent with functional MRI and single unit evidence, suggesting that the brightness of the CCOB effect becomes dissociated from the luminance falling on the eye early in visual processing. These results favor explanations of brightness induction invoking rapid, early amplification of very low spatial-frequency information in the image to approximate natural scenes as opposed to a sluggish brightness adjustment spreading from the contrast border.

A Comparative Oncology Study of Iniparib Defines Its Pharmacokinetic Profile and Biological Activity in a Naturally-Occurring Canine Cancer Model.

Development of iniparib as an anti-cancer agent was hindered in part by lingering questions regarding its mechanism of action, the activity of its metabolites, and their potential accumulation in tumors. Due to strong similarities in metabolism of iniparib between humans and dogs, a veterinary clinical trial in pet dogs with spontaneous cancers was designed to answer specific questions pertaining to pharmacokinetic exposures and tolerability of iniparib. Dogs were treated with iniparib alone and in combination with carboplatin chemotherapy. Iniparib doses ranged between 10-70 mg/kg intravenously (IV). Plasma, tumor and normal tissue samples were collected before and at various time points scheduled after exposure for pharmacokinetic and biologic analysis. The primary endpoints included characterization of dose-limiting toxicities (DLT) and determination of the drug exposures that could be achieved in both normal and tumor tissues. Nineteen dogs were treated. DLT included fever, anorexia, diarrhea, neutropenia, and thrombocytopenia; most effects were attributable to carboplatin based on the timing of adverse event onset. The maximum tolerated dose (MTD) of iniparib was not identified. Moderate to high variability in plasma exposure was noted for iniparib and all metabolites between animals. When quantifiable, iniparib and metabolite plasma:tumor ratios were < 0.088 and <1.7, respectively. In this study, iniparib was well tolerated as a single agent and in combination with carboplatin over a range of doses. However, clinically relevant concentrations of the parent drug and selected metabolites were not detectable in canine tumor tissues at any studied dose, thus eliminating expectations for clinical responses in dogs or humans. Negative clinical trials in humans, and the uncertainties of its mechanism of action, ultimately led to the decision to stop clinical development of the drug. Nevertheless, the questions that can be asked and answered within the comparative oncology approach are evident from this successfully executed comparative clinical trial and exemplify the value of such studies in drug development.