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.

Small brain, large brain -- a quest for nature's scale-up rules.

A scaling model of the gyrencephalic mammalian brain, invoking identical repeating cortical units, whose number and size both increase with increasing brain size, was described previously (Prothero, 1997a,b). Each repeating unit, of microscopic dimensions, is viewed as extending from the pial membrane to the underlying white matter. The model predicts discrete scaling exponents, all integral multiples of 1/9, as a function of brain size, as follows: cortical thickness (1/9), outer cortical surface area (6/9), total (folded) cortical surface area (8/9), cortical volume (9/9), white matter volume (9/9), neuron line-count (0/9) and neuron volume density (-3/9). In the present paper extensions to the model give discrete exponents for the scaling of the cross-sectional area of the corpus callosum (6/9), for mean foliar and gyral width (each 1/9), for foliar number (2/9), for mean foliar length (3/9), for mean foliar and gyral perimeter (each 3/9) and for total foliar and total gyral length (each 5/9). The predicted scaling exponent for cross-sectional area of the corpus callosum is in reasonable agreement with the empirical observations. Needed are more precise and more extensive data on cortical folding to stringently test the model predictions relating to cortical folding. On the whole, the model is in good agreement with a diverse body of empirical data bearing on the scaling of the gyrencephalic mammalian brain.

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.

Cortical scaling in mammals: a repeating units model.

A simple scaling model germane to the gyrencephalic mammalian cortex is proposed. The model aims to account for the empirical scaling of morphometric variables such as cortical thickness, surface area and volume, as a function of brain size. Several assumptions are made. Gyrencephalic cortices are assumed to be modular in construction, comprised of identical repeating units. Both the number and size of cortical units are assumed to increase with increasing brain size. The shape of the brain and of the repeating units are assumed not to vary systematically with brain size. The surface-density of repeating units is taken to be invariant. The model exponents for cortical thickness, folded surface area and volume, each as a function of cerebral volume, are one-ninth, eight-ninths and one, respectively. These discrete model exponents, and others, are in reasonable agreement with a diverse body of scaling data, both phylogenetic and ontogenetic. One interpretation is that phylogenetic scaling simply reflects ontogenetic scaling, extended over a wide range of adult brain sizes. The model is confined to ontogenetic/phylogenetic scaling. It is suggested that the model exponents are not adaptive, in the usual sense of that term.

Scaling of cortical neuron density and white matter volume in mammals.

A prior scaling model, based on repeating cortical units, whose number and size increase with brain size, gave discrete exponents for cortical thickness (1/9), outer (visible) surface area (2/3), folded cortical surface area (8/9) and cortical volume (1), each as a function of brain volume. These exponents are in reasonable agreement with a diversity of empirical data (Prothero, 1997). Rockel et al. (1980) reported that neuron number, assayed in a narrow column across cortex (pia to white matter) is invariant over several differing brain regions and species. Since cortical thickness scales, empirically, as about the 1/9 power of brain volume, their data imply that neuron line density (across cortex) scales with an exponent of about -1/9. Rockel et al. (1980) also urged that cortical neuron surface density is invariant. This extrapolation implies that neuron volume density scales, like line density, as the -1/9 power of brain volume, in marked disparity with the data of Haug (1987) and Tower (1954). The present model assumes an invariant number of neurons per repeating unit. Thus neuron number, assayed across cortical thickness, is independent of brain size, in accord with Rockel et al. (1980). The model predicts that neuron line density (in any direction) scales as the -1/9 power of brain volume. Now neuron volume density scales as the -1/3 power of brain volume, in reasonable agreement with the results of Haug (1987) and Tower (1954). For white matter, I assume that mean axon length scales with brain diameter (exponent of 1/3). The number of white matter axons scales in proportion to the number of repeating units (exponent of 2/3). Given an invariant size distribution of white matter axons, white matter volume thus scales with an exponent of one, in reasonable accord with Haug (1970).

Visualization-based mapping of language function in the brain.

Cortical language maps, obtained through intraoperative electrical stimulation studies, provide a rich source of information for research on language organization. Previous studies have shown interesting correlations between the distribution of essential language sites and such behavioral indicators as verbal IQ and have provided suggestive evidence for regarding human language cortex as an organization of multiple distributed systems. Noninvasive studies using ECoG, PET, and functional MR lend support to this model; however, there as yet are no studies that integrate these two forms of information. In this paper we describe a method for mapping the stimulation data onto a 3-D MRI-based neuroanatomic model of the individual patient. The mapping is done by comparing an intraoperative photograph of the exposed cortical surface with a computer-based MR visualization of the surface, interactively indicating corresponding stimulation sites, and recording 3-D MR machine coordinates of the indicated sites. Repeatability studies were performed to validate the accuracy of the mapping technique. Six observers-a neurosurgeon, a radiologist, and four computer scientists, independently mapped 218 stimulation sites from 12 patients. The mean distance of a mapping from the mean location of each site was 2.07 mm, with a standard deviation of 1.5 mm, or within 5.07 mm with 95% confidence. Since the surgical sites are accurate within approximately 1 cm, these results show that the visualization-based approach is accurate within the limits of the stimulation maps. When incorporated within the kind of information system envisioned by the Human Brain Project, this anatomically based method will not only provide a key link between noninvasive and invasive approaches to understanding language organization, but will also provide the basis for studying the relationship between language function and anatomical variability.

Scaling of organ subunits in adult mammals and birds: a model.

Members of one class of organs--including kidney and lung--consist chiefly of repeating units, or subunits, similar in size and shape. Across species, both the number and size of repeating units may increase with increasing organ size. A simple model is proposed, relating the scaling of unit-size and unit-number to that of organ volume. The model makes three structural assumptions, the crucial one, biologically speaking, being that the numerical density of repeating units scales as does organ surface-to-volume ratio. Data were collected from the literature bearing on the number, diameter, total surface area and total volume of such repeating units (i.e., alveoli, air capillaries, renal tubules and glomeruli), for avian and mammalian lung and for mammalian kidney, each as a function of organ size. These data, after log-log transformation, were submitted to standard linear least squares regression analysis. The resultant slopes for nine different regression lines are in good agreement with the model predictions. This finding suggests, surprisingly, that organ scale-up, at least for selected organs, expressed in terms of repeating units, as a function of organ volume, in mammals and birds, and conceivably in other phyla, may be based on a small number of elementary structural principles.

Visualization and mapping of neurosurgical functional brain data onto a 3-D MR-based model of the brain surface.

The Human Brain Project was initiated with the goal of developing methods for managing and sharing information about the brain. As a prototype Human Brain Project application we are developing a system for organizing, visualizing, integrating and sharing information about human language function. The goal of the brain mapping component of our work, described in this article, is to generate the 3D location and extent of cortical language sites with respect to a uniform, 3D patient coordinate system. The language sites of individual patients can then be combined with or related to other patient data in terms of a Talairach, surface-based, or other deformable coordinate systems. Language site mapping is done by visually comparing an intraoperative photograph with the rendered image (from MRI data). The techniques outlined in this article have been utilized to map cortical language sites of six patients. Preliminary results point to the adequacy of our volume visualizations for language mapping. The strength of the visualization scheme lies in the combination of interactive segmentation with volume and surface visualization. We are now in the process of acquiring more patient data to further validate the usefulness of our method.

Bone and fat as a function of body weight in adult mammals.

Three independent data sets, for both bone and fat weight, in adult mammals, expressed as a function of body weight, were submitted to linear regression analysis of the log-log transformed data. For land mammals generally, weighing up to 6.6 metric tons, the slope of the best-fit regression line for skeletal weight is 1.073 +/- 0.021. This regression line underestimates skeletal weight in the elephant by about 40%. For cetaceans, varying in body weight from about 0.1 to over 100 metric tons, the slope of the best-fit regression line for skeletal weight is 1.133 +/- 0.044. Since the slopes for these two groups of mammals are not statistically different, and since cetaceans are normally shielded from gravity, due to buoyancy, it is suggested that the slope (1.073) in land mammals may not be an adaption to gravity. After pooling the data from the three data sets for fat, the resultant regression has a slope of 1.146 +/- 0.026. It is argued, on theoretical grounds, that slopes greater than 1.2-1.3 will not be found for the log-log regression of any major tissue on body weight, taken over the whole mammalian weight range.

A resource guide to VR in medicine.

This guide provides a bibliography of many of the most noteworthy contributions to the emerging literature about virtual reality in medicine, along with listings of the most relevant conferences and resources for researchers. This is an abridged version of a continuously updated comprehensive document which is available on-line to the research community.

Adult life span as a function of age at maturity.

A regression analysis was made of age at first reproduction in female mammals, as a function of body weight, using the data of Wootton. Data on maximal life span, also expressed as a function of body weight, were used to calculate "adult" life span, wherever possible, by subtracting the cognate value for age at first reproduction. Then a regression analysis of adult life span as a function of age at first reproduction was made. In both cases global regression lines (i.e., for whole data sets) were computed by standard least squares and by a robust method, as well as local regression lines for subgroups classified by taxonomic and ecological criteria. The slopes of the various regression lines were found to vary widely as a function of the method of classification. This result argues against the notion that the ratio of life history variables is a constant, or that one life history variable is likely to be a simple function of another. The results for bats are anomalous, in that age at first reproduction appears to be independent of body weight (over about two orders of magnitude). It is concluded that a full understanding of life history variables, such as maximal life span and age at maturity, is likely to depend on combined physiological, ecological, and evolutionary insights.

Determination of relative fiber orientation in heart muscle: methodological problems.

Knowledge of the muscle pattern in the heart is important to understanding cardiac contraction and propagation of the electrical stimulus. Most work on this pattern has been carried out by blunt gross dissection, whereby fiber bundles are easily visible on the peeled heart wall. However, it has never been shown, to our knowledge, that the orientation of macroscopic fiber bundles seen in a peeled heart corresponds to that of the constituent myofibers (muscle cells). For this purpose, one needs to carry out a three-dimensional microscopic reconstruction within a documented macroscopic reference frame. To draw valid conclusions in such a coordinated macroscopic and microscopic study, one must estimate the (slice) angle between the long axis of a muscle cell and the plane of section. Otherwise any alleged differences between the macroscopic and microscopic orientations may be just an artifact of sectioning. In this study we have shown that, provided the images of the myofibers meet simple criteria, one can be reasonably confident that the potential error incurred by sectioning is small. On this basis, we demonstrated that while there is a general correspondence between the macroscopic fiber and the microscopic myofiber orientations, there are significant differences in detail.

Scaling of bodily proportions in adult terrestrial mammals.

To model body shape, a data base was constructed for body, forelimb, and hindlimb length, surface area, and girth, each as a function of body weight, in a diversity of mammals. These data were submitted to linear least-squares regression analysis. In addition, data on the partitioning of weight and surface area among the body segments (head-trunk, forelimbs, and hindlimbs) were collected. These data imply a relatively constant partitioning of body weight and surface area among the body segments. The regression parameters and the body segment data were used to build and test a model of bodily proportions. The model consists of three classes of cylinders, each specified by a length and a diameter, representing the three classes of body segments. The parameters of the model were constrained to enforce geometric similarity (constant shape). The model was found to agree reasonably well with an independent subset of the data. It is concluded that adult land mammals do exhibit geometric similarity over a substantial weight range.

Myofiber orientation in the weanling mouse heart.

This study provides a quantitative description at the cellular level of myofiber orientation throughout the ventricles of the mouse heart. We employed computer-based methods of three-dimensional reconstruction from 3 microns plastic-embedded serial sections. Registration marks were introduced by drilling minute holes into each plastic block. Subfields of selected sections were photographed at 20 x magnification, using a computer-controlled microscope. The 35-mm film frames were projected onto a digitizer tablet and the epi- and endocardial boundaries were digitized manually. The "heads" and "tails" of linear segments of a representative myofiber sample present in each projected image were digitized in point mode. The many x-, y-, z-coordinate tables generated by digitization were reassembled automatically, giving a numerical description of the myofiber pattern. This pattern was studied interactively on a high-performance graphics workstation. We find that the heart wall is, to a first approximation, a "sandwich," in which the myofibers in the middle layer run mainly circumferentially, whereas those in the inner and outer layers run parallel or oblique to the apical-basal axis, a variant of the classical model of the myofiber pattern. We observed a "sleeve" in the interventricular septum, formed by longitudinal and oblique myofibers, a feature which apparently has not been described previously. Myofibers not running parallel to the transverse or longitudinal planes were not resolved in this study. We conclude that three-dimensional reconstruction of the cardiac myofiber pattern at the light-microscopic level, while laborious, is technically feasible and scientifically worthwhile.

Three-dimensional reconstruction from serial sections. V. Calibration of dimensional changes incurred during tissue preparation and data processing.

Three-dimensional (3-D) reconstructions from serial tissue sections produce a table of x, y, z coordinates (i.e., a numerical description of the object) that will support 3-D computer graphics displays and morphometric analyses. While measures such as volume or surface area can be generated interactively, almost instantaneously, they are usually of unknown accuracy due to artifacts that may be introduced at two different stages: (1) tissue shrinkage during dehydration and polymerization of a plastic and compression or expansion during sectioning and mounting and (2) geometric and intensity distortions during image capture and data processing. This paper describes simple methods for (1) introducing fiducials (reference marks) that allow measurement of the net distortion incurred during tissue preparation and (2) estimating the amount of geometric distortion arising during image capture and data processing. Application of these methods showed that the net areal change introduced in dog and sheep hearts during tissue processing amounted to +/- 5%. Apparently, the substantial shrinkage that occurs during tissue processing is largely compensated for by the expansion during tissue sectioning and mounting. The methods described may have application to other semisolid tissues.

Lifetime energy budgets in mammals and birds.

1. Two data sets for standard energy metabolism (351 and 320 species, respectively) and one for maximal lifespan (494 species) in mammals have been assembled from the literature. 2. In addition smaller data sets of active (field) energy metabolism in mammals (36 species) and in birds (25 species) have been drawn on. 3. The products of the respective regression parameters as well as the products of energy metabolism and maximal lifespan in individual species have been computed in order to estimate lifetime energy metabolism in mammals generally and in various mammalian orders. 4. It is found that lifetime energy budgets in mammals generally, whether standard or active, very systematically with body mass with slopes between 0.87 and 0.93, significantly different from unity (P less than 0.001 or P less than 0.01). 5. In birds, lifetime energy budgets, whether standard or active, vary with slopes of 0.94 +/- 0.05 and 0.88 +/- 0.09, which are not significantly different from unity (P greater than 0.1). 6. In carnivores, artiodactyls, primates and bats the slopes for lifetime standard as well as lifetime active energy budgets are not significantly different from one in any of the investigated data sets. 7. In rodents the lifetime standard energy budgets have slope significantly different from one; in marsupials one data set for lifetime standard and the one for lifetime active energy budget lead to slopes significantly different from one. 8. It is concluded from this analysis that current data do not support the hypothesis that lifetime energy budgets, whether standard or active, vary as the first power of body mass in mammals generally.(ABSTRACT TRUNCATED AT 250 WORDS)

Independent evidence for a commitment model of clonal attenuation.

We previously reported a model of clonal attenuation which assumes three classes of cells: small highly replicative cells; intermediate size cells of limited replicative potential and large non-diving cells. Computer simulations carried out with the model lead to predictions of how the relative proportion of each cell type varies throughout the in vitro replicative life span of a mass population. These predictions appear to be broadly confirmed by independent data recently reported by another laboratory.

Cell enlargement: one possible mechanism underlying cellular senescence.

We previously demonstrated an inverse relationship between the G1 volume of human diploid fibroblast-like (HDFL) cells obtained from foreskin tissue and clonal replicative potential. On the basis of these results, we suggested that one process underlying in vitro senescence is a progressive increase in the mean cell volume of successive progeny within clonal lineages. We now report that the size of HDFL cells, as well as of chick embryo fibroblasts, can be increased in the virtual absence of cell division by culturing at low density and at low serum concentration (0.1-1.0%). Consequent to an increase in cell size, the replicative potential of the cells is reduced to the level of later-passage cells of similar size. By clonal analysis, the populations of enlarged cells contain up to three times as many nondividing cells as do controls. In the enlarged populations, the proportion of cells producing attenuated clones (four or fewer progeny) increases by about 30%, whereas the proportion of cells yielding greater than 32 cells declines by a similar percentage. These observations lead us to propose that replicative potential may be limited by cell size, which in turn may be regulated by a kinetic relationship between cellular growth and cell division cycles.