Influence of Cow's Milk and Esomeprazole on the Absorption of Erlotinib: A Randomized, Crossover Pharmacokinetic Study in Lung Cancer Patients.

INTRODUCTION: Erlotinib's gastrointestinal solubility and absorption are decreased by proton pump inhibitors (PPIs). Since erlotinib is a lipophilic drug, we hypothesized that concomitant intake with the fatty beverage milk may be a feasible way to increase erlotinib uptake. We performed a two-period, randomized, crossover study to investigate the influence of cow's milk with 3.9% fat on the exposure of erlotinib with and without the PPI esomeprazole in patients with non-small cell lung cancer (NSCLC). The effect of esomeprazole was studied in an additional intrapatient comparison. METHOD: Pharmacokinetic sampling was performed on days 7 and 14 during 24 consecutive hours. During the 7 days prior to pharmacokinetic sampling, erlotinib was taken daily with 250 mL of either water or milk. In the PPI arm, esomeprazole (40 mg once daily 3 h prior to erlotinib) was taken for 3 days. RESULTS: Erlotinib area under the curve from time zero to 24 h (AUC24) did not significantly change when administered with milk, compared with water, in both non-PPI users (n = 14; - 3%; 95% confidence interval [CI] - 12 to 8%; p = 0.57) and patients who used esomeprazole (n = 15; 0%; 95% CI - 15 to 17%; p = 0.95). Esomeprazole decreased erlotinib AUC24 by 47% (n = 9; 95% CI - 57 to - 34%; p < 0.001) and Cmax by 56% (95% CI - 64 to - 46%; p < 0.001). No differences in toxicities were observed between milk and water. CONCLUSION: Milk with 3.9% fat has no effect on the exposure to erlotinib in NSCLC patients, independent of PPI use. The combination with milk is safe and well tolerated. Concomitant esomeprazole treatment strongly decreased both erlotinib AUC24 and Cmax and should be avoided if possible.

Alterations in choice behavior by manipulations of world model.

How to compute initially unknown reward values makes up one of the key problems in reinforcement learning theory, with two basic approaches being used. Model-free algorithms rely on the accumulation of substantial amounts of experience to compute the value of actions, whereas in model-based learning, the agent seeks to learn the generative process for outcomes from which the value of actions can be predicted. Here we show that (i) "probability matching"-a consistent example of suboptimal choice behavior seen in humans-occurs in an optimal Bayesian model-based learner using a max decision rule that is initialized with ecologically plausible, but incorrect beliefs about the generative process for outcomes and (ii) human behavior can be strongly and predictably altered by the presence of cues suggestive of various generative processes, despite statistically identical outcome generation. These results suggest human decision making is rational and model based and not consistent with model-free learning.

Use of interreflection and shadow for surface contact.

The interaction of light with surfaces results in a number of lighting effects that may serve as valuable visual cues. Previous research on shadows has shown them to be effective in determining the three-dimensional (3-D) layout of a scene, but interreflections have been ignored as cues for spatial layout. Interreflections as well as shadows may help to disambiguate the 3-D layout of objects by providing information about an object's contact with a surface. We generated computer images of a box on an extended textured ground plane that was either in contact with the ground or was slightly above the ground. Images were rendered for four conditions: (1) no shadow + no interreflection, (2) shadow only, (3) interreflection only, and (4) shadow + interreflection. A photometrically incorrect condition was also included. The participants rated the degree of contact for each image on a scale, which was used to generate receiver operating characteristic (ROC) curves and a measure of sensitivity. In the images with no shadows or interreflections, the participants performed at chance levels. Interreflections, shadows, and a combination of interreflections and shadows all resulted in high sensitivity for judging object contact. More important, information from shadows and interreflections can be combined, resulting in near-perfect judgment of surface contact. Interreflections and shadows can be effective cues for object contact.

Invariant recognition of natural objects in the presence of shadows.

Shadows are frequently present when we recognize natural objects, but it is unclear whether they help or hinder recognition. Shadows could improve recognition by providing information about illumination and 3-D surface shape, or impair recognition by introducing spurious contours that are confused with object boundaries. In three experiments, we explored the effect of shadows on recognition of natural objects. The stimuli were digitized photographs of fruits and vegetables displayed with or without shadows. In experiment 1, we evaluated the effects of shadows, color, and image resolution on naming latency and accuracy. Performance was not affected by the presence of shadows, even for gray-scale, blurry images, where shadows are difficult to identify. In experiment 2, we explored recognition of two-tone images of the same objects. In these images, shadow edges are difficult to distinguish from object and surface edges because all edges are defined by a luminance boundary. Shadows impaired performance, but only in the early trials. In experiment 3, we examined whether shadows have a stronger impact when exposure time is limited, allowing little time for processing shadows; no effect of shadows was found. These studies show that recognition of natural objects is highly invariant to the complex luminance patterns caused by shadows.

Murine leukemia virus pseudotypes of La Crosse and Hantaan Bunyaviruses: a system for analysis of cell tropism.

We have developed a system for the preparation of La Crosse virus (LAC) and Hantaan virus (HTN) pseudotypes using a murine leukemia virus vector. After concentration, the pseudotypes were present in quantities sufficient to analyze cell tropism and neutralization. Cells resistant to LAC could not be infected with the MLV (LAC) pseudotypes, and the pseudotypes were sensitive to neutralizing monoclonal antibodies prepared against LAC glycoproteins, as well as to inhibition by a soluble form of the virus cell-attachment protein, G1. Perhaps because of lower expression of the HTN glycoproteins at the cell surface, MLV (HTN) pseudotypes were present at lower titers. However, they were also sensitive to appropriate neutralizing antibodies. This pseudotype system will be useful for analysis of the entry process of the Bunyaviridae, and for neutralization studies with some Bunyaviruses whose high virulence normally requires specialized containment facilities.

Dissociating stimulus information from internal representation--a case study in object recognition.

Human object recognition is a function of both internal memory representation(s) and stimulus input information. The role of the latter has been so far largely overlooked, and the nature of the representation is often directly equated with recognition performance. We quantify stimulus information for three classes of objects in order of decreasing object complexity: unconnected balls, balls connected with lines, and balls connected with cylinders. In an object discrimination task, subjects' performance improved with the decreasing object complexity. We show that input information also increases with decreasing object complexity. Therefore, the results could potentially be accounted for either by differences in the object representations learned for each class of objects, or by the increased information about the three-dimensional (3D) structure inherent in images of the less complex objects, or by both. We demonstrate that, when image information is taken into account, by computing efficiencies relative to a set of ideal observers, subjects were more efficient in recognizing the less complex objects. This suggests that differences in subjects' performance for different object classes is at least partly a function of the internal representations learned for the different object classes. We stress that this conclusion cannot be achieved without the quantitative analysis of stimulus input information.

Perception of three-dimensional shape influences colour perception through mutual illumination.

Objects in the natural world possess different visual attributes, including shape, colour, surface texture and motion. Previous perceptual studies have assumed that the brain analyses the colour of a surface independently of its three-dimensional shape and viewing geometry, although there are neural connections between colour and two-dimensional form processing early in the visual pathway. Here we show that colour perception is strongly influenced by three-dimensional shape perception in a novel, chromatic version of the Mach Card--a concave folded card with one side made of magenta paper and the other of white paper. The light reflected from the magenta paper casts a pinkish glow on the white side. The perceived colour of the white side changes from pale pink to deep magenta when the perceived shape of the card flips from concave to convex. The effect demonstrates that the human visual system incorporates knowledge of mutual illumination-the physics of light reflection between surfaces--at an early stage in colour perception.

Viewpoint-dependent recognition of familiar faces.

The question whether object representations in the human brain are object-centered or viewer-centered has motivated a variety of experiments with divergent results. A key issue concerns the visual recognition of objects seen from novel views. If recognition performance depends on whether a particular view has been seen before, it can be interpreted as evidence for a viewer-centered representation. Earlier experiments used unfamiliar objects to provide the experimenter with complete control over the observer's previous experience with the object. In this study, we tested whether human recognition shows viewpoint dependence for the highly familiar faces of well-known colleagues and for the observer's own face. We found that observers are poorer at recognizing their own profile, whereas there is no difference in response time between frontal and profile views of other faces. This result shows that extensive experience and familiarity with one's own face is not sufficient to produce viewpoint invariance. Our result provides strong evidence for viewer-centered representations in human visual recognition even for highly familiar objects.

Why the visual recognition system might encode the effects of illumination.

A key problem in recognition is that the image of an object depends on the lighting conditions. We investigated whether recognition is sensitive to illumination using 3-D objects that were lit from either the left or right, varying both the shading and the cast shadows. In experiments 1 and 2 participants judged whether two sequentially presented objects were the same regardless of illumination. Experiment 1 used six objects that were easily discriminated and that were rendered with cast shadows. While no cost was found in sensitivity, there was a response time cost over a change in lighting direction. Experiment 2 included six additional objects that were similar to the original six objects making recognition more difficult. The objects were rendered with cast shadows, no shadows, and as a control, white shadows. With normal shadows a change in lighting direction produced costs in both sensitivity and response times. With white shadows there was a much larger cost in sensitivity and a comparable cost in response times. Without cast shadows there was no cost in either measure, but the overall performance was poorer. Experiment 3 used a naming task in which names were assigned to six objects rendered with cast shadows. Participants practised identifying the objects in two viewpoints lit from a single lighting direction. Viewpoint and illumination invariance were then tested over new viewpoints and illuminations. Costs in both sensitivity and response time were found for naming the familiar objects in unfamiliar lighting directions regardless of whether the viewpoint was familiar or unfamiliar. Together these results suggest that illumination effects such as shadow edges: (1) affect visual memory; (2) serve the function of making unambigous the three-dimensional shape; and (3) are modeled with respect to object shape, rather than simply encoded in terms of their effects in the image.

2D observers for human 3D object recognition?

In human object recognition, converging evidence has shown that subjects' performance depends on their familiarity with an object's appearance. The extent of such dependence is a function of the inter-object similarity. The more similar the objects are, the stronger this dependence will be and the more dominant the two-dimensional (2D) image-based information will be. However, the degree to which three-dimensional (3D) model-based information is used remains an area of strong debate. Previously the authors showed that all models with independent 2D templates that allowed 2D rotations in the image plane cannot account for human performance in discriminating novel object views. Here the authors derive an analytic formulation of a Bayesian model that gives rise to the best possible performance under 2D affine transformations and demonstrate that this model cannot account for human performance in 3D object discrimination. Relative to this model, human statistical efficiency is higher for novel views than for learned views, suggesting that human observers have used some 3D structural information.

The perception of cast shadows.

When an object casts its shadow on a background surface, the shadow can be informative about the shape of the object, the shape of the background surface and the spatial arrangement of the object relative to the background. Among all these roles, we found that cast shadows were perceptually most relevant for the recovery of spatial arrangement, especially when the shadow is in motion. This finding is intriguing when one considers the ambiguities in the possible ways that shadow motion can be interpreted. We reasoned that the visual system must use a priori constraints to disambiguate the cast shadow motion. One of these constraints is that the light source is stationary. Though simple, the stationary-light-source constraint supports rich, reliable inferences about the qualitative motions of objects in three dimensions.

Geometry of shadows.

Shadows provide a strong source of information about the shapes of surfaces. We analyze the local geometric structure of shadow contours on piecewise smooth surfaces. Particular attention is paid to intrinsic shadows on a surface: that is, shadows created on a surface by the surface's own shape and placement relative to a light source. Intrinsic shadow contours provide useful information about the direction of the light source and the qualitative shape of the underlying surface. We analyze the invariants relating surface shape and light-source direction to the shapes and singularities of intrinsic shadow contours. The results suggest that intrinsic shadows can be used to directly infer illuminant tilt, qualitative global surface structure, and, at intersections with surface creases, the concavity/convexity of a surface. We show that the results obtained for point sources of light generalize in a straightforward way to extended light sources, under the assumption that light sources are convex.

Perceptual categories for spatial layout.

The central problems of vision are often divided into object identification and localization. Object identification, at least at fine levels of discrimination, may require the application of top-down knowledge to resolve ambiguous image information. Utilizing top-down knowledge, however, may require the initial rapid access of abstract object categories based on low-level image cues. Does object localization require a different set of operating principles than object identification or is category determination also part of the perception of depth and spatial layout? Three-dimensional graphics movies of objects and their cast shadows are used to argue that identifying perceptual categories is important for determining the relative depths of objects. Processes that can identify the causal class (e.g. the kind of material) that generates the image data can provide information to determine the spatial relationships between surfaces. Changes in the blurriness of an edge may be characteristically associated with shadows caused by relative motion between two surfaces. The early identification of abstract events such as moving object/shadow pairs may also be important for depth from shadows. Knowledge of how correlated motion in the image relates to an object and its shadow may provide a reliable cue to access such event categories.

Local and intra-articular infiltration of bupivacaine before surgery: effect on postoperative pain after anterior cruciate ligament reconstruction.

In a double-blind, randomized trial, 40 patients undergoing open anterior cruciate ligament (ACL) reconstruction using a bone-patellar tendon-bone autograft were randomly allocated to two groups: group A (n = 20) received an intra-articular instillation of 20 mL bupivacaine (0.25%) and a local infiltration of 20 mL bupivacaine (0.5%) 15 minutes before surgery. Group B (n = 20) received an injection of saline solution in the same manner. Patient-controlled on-demand analgesia (PCA) with intravenous piritramid was used for postoperative pain control. A significant decrease in pain scores on a visual analog scale (VAS scale, 0 to 10) was found in the bupivacaine group (group A) at bedrest on the day of surgery only (pain score, 5.5 v 7.3 (scale, 0 to 10), P < .05). At all other times, no significant differences were found. The overall supplemental opioid requirements were not different between the study groups (63.9 v 62.6 mg piritramid/72 hours). A long-lasting, clinically relevant, pain-reducing effect with infiltration of bupivacaine before surgery could not be shown with this study.

Moving cast shadows induce apparent motion in depth.

Phenomenally strong visual illusions are described in which the motion of an object's cast shadow determines the perceived 3-D trajectory of the object. Simply adjusting the motion of a shadow is sufficient to induce dramatically different apparent trajectories of the object casting the shadow. Psychophysical results obtained with the use of 3-D graphics are reported which show that: (i) the information provided by the motion of an object's shadow overrides other strong sources of information and perceptual biases, such as the assumption of constant object size and a general viewpoint; (ii) the natural constraint of shadow darkness plays a role in the interpretation of a moving image patch as a shadow, but under some conditions even unnatural light shadows can induce apparent motion in depth of an object; (iii) when shadow motion is caused by a moving light source, the visual system incorrectly interprets the shadow motion as consistent with a moving object, rather than a moving light source. The results support the hypothesis that the human visual system incorporates a stationary light-source constraint in the perceptual processing of spatial layout of scenes.

Microbiologic, radiographic, and anatomic study of the nasolacrimal duct apparatus in the rabbit (Oryctolagus cuniculus).

This study was motivated by the sporadic observation of epiphora in two male rabbits. The epiphora was unilateral and not associated with conjunctivitis or Pasteurella infection. To characterize the cause of epiphora, we studied 15 specific-pathogen-free New Zealand White rabbits. This study group was composed of the two affected males, four unaffected males, and nine unaffected females. Clinical evaluation consisted of bacterial culture of conjunctival specimens, examination of conjunctival scrapings for chlamydial inclusions, culture and cytologic examination of specimens from the nasolacrimal duct, plain and contrast radiography, latex casting, histologic examination, and the Schirmer tear test. Important differences found in the rabbits with epiphora included an opalescent, gritty, nasolacrimal duct flush fluid and marked unilateral dilatation of the duct proximal to a dorsal flexure at the caudal limit of the incisor tooth root. The flush solution from one affected rabbit cleared with ether, suggesting the presence of triglycerides or cholesterol. The organisms most commonly isolated from the conjunctiva were Moraxella sp., Oligella urethralis, Staphylococcus aureus, coagulase-negative Staphylococcus sp., and Streptococcus viridans. The organisms most commonly isolated from the nasolacrimal duct flush fluid were Moraxella sp., S. viridans, and Neisseria sp. Culture of the nasolacrimal duct flush fluid yielded microorganisms more consistently than did culture of the conjunctival specimens. All microorganisms isolated from affected rabbits also were isolated from unaffected rabbits. There was no apparent contribution of microorganisms to the development of epiphora, and Schirmer tear test results for affected animals were within the range seen in unaffected animals. Occlusion of the nasolacrimal duct was presumed to be attributable to fat droplets. This study augments the existing literature and represents the first report of anomalous nasolacrimal duct anatomic features in the rabbit.

Evidence in human subjects for independent coding of azimuth and elevation for direction of heading from optic flow.

We studied the accuracy of human subjects in perceiving the direction of self-motion from optic flow, over a range of directions contained in a 45 deg cone whose vertex was at the viewpoint. Translational optic flow fields were generated by displaying brief sequences (< 1.0 sec) of randomly positioned dots expanding in a radial fashion. Subjects were asked to indicate the direction of perceived self-motion at the end the display. The data were analyzed by factoring out the constant component of the error by means of a linear regression analysis performed on the azimuthal and elevational components of the settings. The analysis of the variable error revealed that: a) the variance of the settings is 3-45% greater along elevation than azimuth for five observers; b) azimuth and elevation correspond, on average, to the principal components of the error in the settings; c) there are differences in the variances of azimuthal and elevational errors between upper and lower visual fields. Moreover, the distribution of the errors for azimuth and elevation in the upper and lower hemifields is not the same. All of the above evidence supports the hypothesis that heading information is represented centrally in terms of its azimuthal and elevational components.

Illumination, shading and the perception of local orientation.

We investigated the perception of local surface orientation on a simple smooth object, under several different illumination conditions. The perceived local orientation was determined for several points on the surface and quantified as slant and tilt of the local tangent plane. We found an underestimation of the perceived slant and a larger variance for the perceived tilt than for the perceived slant. We found also that subjects were less biased at estimating the surface orientation when the shape was locally egg-shaped rather than saddle-shaped or cylindrical. In order to investigate the relationship between perceived shape and light source direction, we developed a method to compute the light source direction most consistent with an observer's settings. Also we compared human errors with those of an "ideal observer" which makes explicit assumptions about the illuminations, shapes and materials in its world. From converging evidence based on (i) the light direction most consistent with the observer's settings; (ii) a supplementary experiment where the object is displayed as a silhouette, and (iii) the computer simulations of the ideal observer, we conclude that the observers used the occluding contour of the object rather than shading to estimate the local surface orientation.

Phenomenal competition for poses of the human head.

We show a cylindrical projection of the human head. This projection is ambiguous with respect to head pose. Viewing such a projection produces perceptual competition for a few discrete views.