CC-10004 but not thalidomide or lenalidomide inhibits lamina propria mononuclear cell TNF-α and MMP-3 production in patients with inflammatory bowel disease.

BACKGROUND: Thalidomide, one of whose activities is to inhibit Tumour Necrosis Factor (TNF)-α production, has been reported to be an effective treatment for refractory inflammatory bowel disease (IBD). TNF-α driven production of matrix metalloproteinase (MMP)-3 by gut lamina propria mononuclear cells (LPMCs) is a major pathway of tissue injury in IBD; however the effect of thalidomide and newer more potent immunomodulatory derivatives on this pathway has not been studied. AIM: To investigate the effect of thalidomide, CC-4047 (pomalidomide), CC-5013 (lenalidomide), and CC-10004 (apremilast) on gut LPMC TNFα and MMP-3 production in patients with IBD. METHODS: Gut LPMCs and myofibroblasts were isolated from patients with IBD, and cultured with thalidomide, CC-4047, CC-5013, and CC-10004. MMP-3 and TIMP-1 levels were determined by western blotting and real-time PCR, and TNF-α levels by ELISA. RESULTS: CC-10004 significantly reduced both TNF-α production and MMP-3 production by cultured LPMCs. Thalidomide and CC-4047 and CC-5013 had no significant effect on the production of TNF-α or MMP-3 by LPMCs. CONCLUSION: These results provides a mechanistic rationale for both the failure of lenalidomide (CC-5013) in a recent randomised controlled trial in Crohn's disease, and for the evaluation of CC-10004 as a novel oral therapy in the treatment of CD and UC.

The use of an independent visual background to reduce simulator side-effects.

BACKGROUND: Simulator sickness (SS) is a major problem which potentially limits interface applications that feature simulated motion. While display imperfections play a role, a large part of SS is motion sickness (MS). Sensory rearrangement theory holds that MS is related to conflicting motion cues; in the case of simulators, mainly a conflict between inertial cues (usually indicating no self-motion) and visual stimuli from the display (indicating self-motion). It is suggested that MS does not arise from conflicting motion cues per se, but rather from conflicting rest frames selected from those motion cues. There is strong evidence that the visual rest frame is heavily influenced by the visual background. Providing an independent visual background (IVB) consistent with the inertial rest frame may reduce SS, even when the simulator's content-of-interest (CI) is not consistent with the inertial rest frame. METHODS: In two experiments, a circular vection stimulus was shown for 3-4.5 min in a head-mounted display, comparing see-through (i.e., IVB) to occluded (i.e., no IVB) modes. Measures included a standard SS questionnaire and a pre-exposure ataxia measure. Experiment 2 added a visual task which forced attention into the CI and a post-exposure ataxia measure. In both experiments, subjects rated the CI as significantly more visible than the IVB. RESULTS: A large effect was found for the reduction of SS and ataxia in the first experiment, and for pre-exposure ataxia in the second. CONCLUSIONS: Future research will further test the IVB idea and examine applications to high-end simulators.

TOPPER, a software package in FORTRAN for scaling studies.

Scaling studies are concerned with the differences in structure, function, behaviour and life-history associated with differences in size in broadly similar organisms. These studies make extensive use of bivariate regression analysis. Often it is of interest to carry out such analyses on many different subpopulations within a given sample population. The programs described here allow these analyses to be carried out efficiently. The output gives a summary of taxonomic parameters in addition to the usual statistical parameters, such as standard deviations and mean percent deviation. Some improvements in the software which are currently being implemented are discussed briefly.