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Simulation and animation of musculoskeletal joint system.

This paper describes the development of computer-based software for three-dimensional geometric data base of the human musculoskeletal system. Using a computer graphics workstation, a user of the software will interactively display detailed information about the muscles, tendons, ligaments, bone, and joint anatomy. This software will enable a wide range of health care workers to visualize complex physiological data. In addition to geometric and visual realism, this software will include kinematic relationships which allow the calculation and display of the motion and forces of the joints, muscles, and tendons. This will permit a user to interactively move joints or tendons and display the resulting motion of the surrounding tissues, as well as internal reactive forces and joint pressure distribution. A two-dimensional version of this software is currently being used for knee and hip osteotomy preoperative planning, total joint replacement prosthesis design and dimensional selection, and osteochondral allograft sizing and reconstruction using radiographic data.

Computer Simulation↗

Swimming in Aplysia brasiliana: analysis of behavior and neuronal pathways.

Swimming of Aplysia brasiliana was analyzed using time-lapse video and computer graphics techniques to quantify the cyclical movements of different regions of the parapodia. Both the speed of swimming and the period of oscillation are temperature dependent, whereas the metachronal offset is not. The parapodial arterial supply is described; ligation of parapodial arteries does not affect the parapodial motions. Peripheral and central lesions indicated that (1) the anterior parapodial nerve plays the major role in parapodial flapping, (2) a separate neuronal oscillator resides in each pedal ganglion, (3) bilateral coordination is mediated via the pedal commissure, and (4) the swimming "command" pathway is the cerebro-pedal connective. During regular parapodial flapping the speed of level midwater swimming is constant throughout the cycle, suggesting that swimming is not produced by jet propulsion. An alternative propulsion model is advanced.

Animals↗

The fan-in projection method for analyzing dendrite and axon systems.

The fan-in projection is a computer graphical method of projecting onto a half plane the branching patterns of dendrites and axons that have already been 3-dimensionally digitized. It is suited for neurons possessing an axis of orientation (or elongation), such as cortical neurons. This axis is taken as the polar axis of a spherical coordinate system whose center is the soma. For cortical neurons, the equatorial plane corresponds to the tangential plane. Co-latitude is measured with respect to the positive polar axis. Longitude is discarded. What results is a projection in which dendrites and axons appear to be growing in a half plane whose boundary is the polar axis. The projection eliminates many of the distorting effects of depth foreshortening seen in conventional projections. In so doing it helps one to visualize branching properties that would otherwise be obscure.

Animals↗

The mechanical basis of cell rearrangement. I. Epithelial morphogenesis during Fundulus epiboly.

Many morphogenetic processes are accomplished by coordinated cell rearrangements. These rearrangements are accompanied by substantial shifts in the neighbor relationships between cells. Here we propose a model for studying morphogenesis in epithelial sheets by directed cell neighbor change. Our model describes cell rearrangements by accounting for the balance of forces between neighboring cells within an epithelium. Cell rearrangement and cell shape changes occur when these forces are not in mechanical equilibrium. We will show that cell rearrangement within the epidermal enveloping layer (EVL) of the teleost fish Fundulus during epiboly can be explained solely in terms of the balance of forces generated among constituent epithelial cells. Within a cell, we account for circumferential elastic forces and the force generated by hydrostatic and osmotic pressure. The model treats epithelial cells as two-dimensional polygons where the mechanical forces are applied to the polygonal nodes. A cell node protrudes or contracts when the nodal forces are not in mechanical equilibrium. In an epithelial sheet, adjacent cells share common boundary nodes; in this way, mechanical force is transmitted from cell to cell, mimicking junctional coupling. These junctional nodes can slide, and nodes may appear or disappear, so that the number of polygonal sides is variable. Computer graphics allows us to compare numerical simulations of the model with time-lapse cinemicroscopy of cell rearrangements in the living embryo, and data obtained from fixed and silver stained embryos. By manipulating the mechanical properties of the model cells we can study the conditions necessary to reproduce normal cell behavior during Fundulus epiboly. We find that simple stress relaxation is sufficient to account for cell rearrangements among interior cells of the EVL when they are isotropically contractile. Experimental observations show that the number of EVL marginal cells continuously decreases throughout epiboly. In order for the simulation to reproduce this behavior, cells at the EVL boundary must generate protrusive forces rather than contractile tension forces. Therefore, the simulation results suggest that the mechanical properties of EVL marginal cells at their leading edge must be quite different from EVL interior cells.

Animals↗

A new computer technique for continuous measurement of the pre-ejection period in the human fetus: physiologic significance of pre-ejection period patterns.

A new interactive computer graphics system was developed for continuous online or offline measurement of the pre-ejection period (PEP) in the human fetus during both the antepartum and the intrapartum period. A significant feature is the system's ability to accurately measure PEP from the onset of QRS complex to the beginning of aortic opening with a resolution of less than 2 milliseconds. Normal patterns of PEP prolongation were observed with fetal movement and occlusion of the umbilical cord, whereas progressive shortening of PEP was noticed with late decelerations associated with acute hypoxia. A pathologic pattern of PEP prolongation associated with late decelarations and poor heart rate variability was observed with chronic hypoxia and acidosis. These patterns suggest that continuous monitoring of PEP may be a useful adjunct to current monitoring methods when attempting to assess fetal cardiac performance and well-being.

Computers↗

A task-specific evaluation of three-dimensional image interpolation techniques.

Image interpolation is an important operation that is widely used in medical imaging, image processing, and computer graphics. A variety of interpolation methods are available in the literature. However, their systematic evaluation is lacking. In a previous paper, we presented a framework for the task-independent comparison of interpolation methods based on certain image-derived figures of merit using a variety of medical image data pertaining to different parts of the human body taken from different modalities. In this work, we present an objective task-specific framework for evaluating interpolation techniques. The task considered is how the interpolation methods influence the accuracy of quantification of the total volume of lesions in the brain of multiple sclerosis (MS) patients. Sixty lesion-detection experiments coming from ten patient studies, two subsampling techniques and the original data, and three interpolation methods are carried out, along with a statistical analysis of the results.

Brain↗

Model of a ternary complex between activated factor VII, tissue factor and factor IX.

Upon binding to tissue factor, FVIIa triggers coagulation by activating vitamin K-dependent zymogens, factor IX (FIX) and factor X (FX). To understand recognition mechanisms in the initiation step of the coagulation cascade, we present a three-dimensional model of the ternary complex between FVIIa:TF:FIX. This model was built using a full-space search algorithm in combination with computational graphics. With the known crystallographic complex FVIIa:TF kept fixed, the FIX docking was performed first with FIX Gla-EGF1 domains, followed by the FIX protease/EGF2 domains. Because the FIXa crystal structure lacks electron density for the Gla domain, we constructed a chimeric FIX molecule that contains the Gla-EGF1 domains of FVIIa and the EGF2-protease domains of FIXa. The FVIIa:TF:FIX complex has been extensively challenged against experimental data including site-directed mutagenesis, inhibitory peptide data, haemophilia B database mutations, inhibitor antibodies and a novel exosite binding inhibitor peptide. This FVIIa:TF:FIX complex provides a powerful tool to study the regulation of FVIIa production and presents new avenues for developing therapeutic inhibitory compounds of FVIIa:TF:substrate complex.

Algorithms↗

Morphometric analysis of lymphatic and blood vessels in human chronic viral liver diseases.

The purpose of this study was to elucidate the morphometric changes occurring in hepatic lymphatics in human chronic viral liver diseases and to investigate the relationship between liver fibrosis, liver inflammation, and these changes. The lymphatic vessels were stained intensely by enzyme histochemistry for 5'-nucleotidase, whereas blood vessels stained well for alkaline phosphatase. We performed a morphometric analysis to estimate the number of lymphatic and blood vessels and their areas, using computer graphics software (NIH Image). Both the number of lymphatics in the specimens and their areas were increased according to the degree of liver fibrosis, but neither showed any relationship with the degree of activity of hepatitis. Neither the number nor the areas of the blood vessels showed any obvious relationship with the degree of fibrosis or the activity of chronic hepatitis. Correlation between clinical and laboratory data and the sizes and number of the lymphatics supported these morphological data. Our results clarified that the sizes and number of lymphatics are related to the stage of fibrosis in chronic viral liver diseases. This is thought to be due to increased lymph production, which is caused by the disturbance of the microcirculation associated with liver fibrosis.

5'-Nucleotidase↗

Local mechanical anisotropy in human cranial dura mater allografts.

Human cranial dura mater (CDM) allograft's success as a repair biomaterial is partly due to its high mechanical strength, which facilitates its ability to form water-tight barriers and resist high in-vivo mechanical loads. Previous studies on CDM allograft mechanical behavior used large test specimens and concluded that the allograft was mechanically isotropic. However, we have quantified CDM microstructure using small angle light scattering (SALS) and found regions of well-aligned fibers displaying structural symmetry between the right and left halves (Jimenez et al., 1998). The high degree of fiber alignment in these regions suggests that they are mechanically anisotropic. However, identification of these regions using SALS requires irreversible tissue dehydration, which may affect mechanical properties. Instead, we utilized CDM structural symmetry to estimate the fiber architecture of one half of the CDM using computer graphics to flip the SALS fiber architecture map of the corresponding half about the plane of symmetry. Test specimens (20 mm x 4 mm) were selected parallel and perpendicular to the preferred fiber directions and subjected to uniaxial mechanical failure testing. CDM allografts were found to be locally anisotropic, having an ultimate tensile strength (UTS) parallel to the fibers of 12.76 +/- 1.65 MPa, and perpendicular to the fibers of 5.21 +/- 1.01 MPa (mean +/- sem). These results indicate that uniaxial mechanical tests on large samples used in previous studies tended to mask the local anisotropic nature of the smaller constituent sections. The testing methods established in this study can be used in the evaluation of new CDM processing methods and post-implant allograft mechanical integrity.

Aged↗

CT interpretation of craniofacial anomalies: a comparative analysis by undergraduate dental students.

The aim of this study was to evaluate the accuracy and reproducibility of computed tomography (CT) image interpretation made in axial slices (2D-CT) and 3D reconstructed images (3D-CT) of patients with craniofacial anomalies. The analyses were made by undergraduate dental students, and compared with the diagnoses considered upon surgical intervention. Computed tomography of 43 patients were analyzed independently by three calibrated examiners (undergraduate students) with, respectively, one, two, and three semesters of experience in craniofacial CT training and interpretation. The analysis of 2D-CT and 3D-CT images were performed at distinct times using an independent workstation associated with a specific computer graphics software for volumetric images. The analysis of inter-examiner agreement and of the agreement between observers and the gold standard was performed using the Kappa test. The accuracy evaluation presented a progressively higher value for examiners with progressively broader experience in 2D-CT and 3D-CT image interpretation. 3D-CT analyses allowed a higher inter-examiner agreement (1 - 0.896) than 2D-CT analyses (1 - 0.614). 3D-CT was considered more precise and accurate than 2D-CT for all students' evaluations. The reproducibility and accuracy varied according to the experience in CT interpretation, and the most experienced student achieved results closer to the gold standard.

Craniofacial Abnormalities↗

Volume measurements of normal orbital structures by computed tomographic analysis.

Computed tomographic digital data and special off-line computer graphic analysis were used to measure volumes of normal orbital soft tissue, extraocular muscle, orbital fat, and total bony orbit in vivo in 29 patients (58 orbits). The upper limits of normal for adult bony orbit, soft tissue exclusive of the globe, orbital fat, and muscle are 30.1 cm3, 20.0 cm3, 14.4 cm3, and 6.5 cm3, respectively. There are small differences in men as a group compared with women but minimal difference between right and left orbits in the same person. The accuracy of the techniques was established at 7%-8% for these orbit structural volumes in physical phantoms and in simulated silicone orbit phantoms in dry skulls. Mean values and upper limits of normal for volumes were determined in adult orbital structures for future comparison with changes due to endocrine ophthalmopathy, trauma, and congenital deformity.

Adult↗

Anatomic evidence of a three-dimensional mosaic pattern of tonotopic organization in the ventral complex of the lateral lemniscus in cat.

The ventral complex of the lateral lemniscus (VCLL, i.e., the ventral and intermediate nuclei) is composed of cells embedded in the fibers of the lateral lemniscus. These cells are involved in the processing of monaural information and receive input from the collaterals of the fibers ascending to the inferior colliculus. Whereas tonotopic organization is a feature of all other nuclei of the auditory system, this functional principle is debated in the VCLL. We have made focal injections of the tracer biotinylated dextran amine into different frequency band representations of the inferior colliculus in cat. Retrogradely labeled cells and terminal fibers (collaterals of efferent local axons and other ascending lemniscal fibers) were found in the ipsilateral VCLL. The spatial distribution of the labeling was analyzed using three-dimensional (3-D) reconstruction and computer graphical visualization techniques. A complex topographic organization was found. In all cases, labeled fibers and cells were distributed in multiple clusters throughout the dorsoventral extent of the VCLL. The shape, size, and location of the labeled clusters suggest an interdigitation of clusters assigned to different frequency-band representations. But an overall mediolateral distribution gradient was observed, with high frequencies represented medially and lower frequencies progressively more laterally. We conclude that the clusters may represent discontinuous frequency-band compartments as a counterpart to the continuous laminar compartments in the remaining auditory nuclei. The 3-D orderly mosaic pattern indicates that the VCLL preserves the spectral decomposition originated in the cochlea in a way that facilitates across-frequency integration.

Animals↗

CTL escape viral variants. I. Generation and molecular characterization.

Cytotoxic T lymphocytes (CTL) play a pivotal role in preventing persistent viral infections and aborting acute infections. H-2Db-restricted CTL optimally recognize a specific peptide of 9 to 11 amino acids (aa) derived from a viral protein and held in place (restricted) by a MHC class I glycoprotein on the surfaces of infected cells. Only three peptide sequences with the appropriate Db motif from lymphocytic choriomeningitis virus Armstrong strain (LCMV) are known to be presented to CTL by H-2Db molecules; they are from the glycoproteins (GP), residues 33-41 KAVYNFATC (GP1) and 276-286 SGVENPGGYCL (GP2), and the nucleoprotein (NP), 396-404 FQPQNGQFI. Incubation of virally infected H-2b cells with CTL clones that recognize only GP1, GP2, or NP leads to the selection of viral variants which upon infecting cells bearing H-2b molecules, escape recognition by CTL of the appropriate specificity. Nucleic acid sequencing showed a single mutation in GP1 (aa 38 F-->L), GP2 (aa 282 G-->D), or NP (aa 403 F-->L) in the variant viruses. When wild-type (wt) LCMV peptides and the three variant peptides (GP1, GP2, NP) were synthesized and subjected to a competitive inhibition binding assay, no differences in binding affinity for H-2Db were found between the wt and variant peptides. Uninfected cells coated with the wt peptide were recognized and lysed by the appropriate CTL clone or by in vivo-primed bulk CTL, but similar targets coated with the GP1, GP2, or NP variant peptides were not. This result, coupled with computer graphic analysis of these variant peptides with the recently solved three-dimensional structure for the Db MHC class I molecule, placed the side chain of the mutated residues on the outer surface of the MHC-peptide complex and accessible to the T cell receptor. Ala substitution at GP residue 38 or 282 or at NP 403 also abrogated CTL recognition and lysis. Inoculation of any one of the mutated viral variants into mice produced an effective CTL response to the other two nonmutated GP or NP peptides, suggesting that production of biologically relevant CTL escape virus variants in vivo requires selection of mutations in more than one and likely all the CTL epitopes, a low probability event.

Amino Acid Sequence↗

The effect of visual and interaction fidelity on spatial cognition in immersive virtual environments.

Accuracy of memory performance per se is an imperfect reflection of the cognitive activity (awareness states) that underlies performance in memory tasks. The aim of this research is to investigate the effect of varied visual and interaction fidelity of immersive virtual environments on memory awareness states. A between groups experiment was carried out to explore the effect of rendering quality on location-based recognition memory for objects and associated states of awareness. The experimental space, consisting of two interconnected rooms, was rendered either flat-shaded or using radiosity rendering. The computer graphics simulations were displayed on a stereo head-tracked Head Mounted Display. Participants completed a recognition memory task after exposure to the experimental space and reported one of four states of awareness following object recognition. These reflected the level of visual mental imagery involved during retrieval, the familiarity of the recollection, and also included guesses. Experimental results revealed variations in the distribution of participants' awareness states across conditions while memory performance failed to reveal any. Interestingly, results revealed a higher proportion of recollections associated with mental imagery in the flat-shaded condition. These findings comply with similar effects revealed in two earlier studies summarized here, which demonstrated that the less "naturalistic" interaction interface or interface of low interaction fidelity provoked a higher proportion of recognitions based on visual mental images.

Adult↗

Stereochemical complementarity of progesterone and cavities between base pairs in partially unwound double stranded DNA using computer modeling and energy calculations to determine degree of fit.

Computer modeling was applied for the first time to investigate previously reported complementarity of progesterone and cavities formed between base pairs in partially unwound double stranded DNA. Computer graphics enabled a more objective assessment of complementarity; energy calculations provided a rigorous method to evaluate degree of fit. Graphics confirmed that the complementarity was virtually "lock and key", i.e. close contacts were formed between van der Waals surfaces in the progesterone/DNA complexes and hydrogen bonds were formed between the two carbonyl groups on opposite ends of the steroid and phosphate groups on adjacent strands of DNA. Molecular mechanics calculations revealed that insertion of the steroid resulted in a relatively stable complex i.e. both van der Waals and electrostatic energies were lowered due to favorable steric interactions and stereospecific hydrogen bonds, respectively. Three published X-ray crystal structures of progesterone exhibited similar complementarity. Ent-progesterone which does not occur naturally possessed very poor complementarity. These findings confirm that the structure of progesterone is directly reflected in the stereochemistry of DNA. While no mechanistic explanation for these results is proffered, we hypothesize that such complementarity must have played a decisive role in the evolution of steroid hormone structure and function.

Base Composition↗

Visualizing cells in three dimensions using confocal microscopy, image reconstruction and isosurface rendering: application to glial cells in mouse central nervous system.

This paper describes a general method for visualizing individual cells in intact tissue in three dimensions. The method involves immunostaining intact tissue to label specific cells, "optical sectioning" the stained tissue by laser scanning confocal microscopy, computationally reconstructing a three dimensional image data set from the digitized confocal optical sections, delineating isosurfaces of specific intensity within the reconstructed image by a "marching cubes" algorithm to generate polygon meshes defining boundaries of cells, and displaying individual cells, identified as three dimensional objects enclosed by contiguous polygon meshes, using computer graphics techniques. Each of the components of this method has been described previously in conjunction with other applications. However the combination of these techniques to visualize a variety of different individual cell types in three dimensions in intact tissue represents a new approach. To illustrate the application of this method, we have visualized three different glial cell types in mouse CNS tissue. Oligodendrocytes, specifically stained with antibody to myelin basic protein, were used as an example of cells labelled with an internal membrane antigen. Astrocytes, specifically stained with antibody to glial fibrillary acidic protein, were used as an example of cells labelled with a cytoplasmic antigen. Microglia, specifically stained with Mac.1 antibody, were used as an example of cells labelled with an external membrane antigen. The images that are generated contain remarkably detailed volumetric and textural information that is not obtainable by conventional imaging techniques.

Algorithms↗

Chromatin texture measurement by Markovian analysis. Use of nuclear models to define and select texture features.

The use of nuclear grade as a prognostic indicator in breast cancer has been limited by its poor interobserver reproducibility. Automated cell classification using digital image analysis is one approach to this problem. Nuclear chromatin distribution, an important feature used in nuclear grading, can be quantitated with texture analysis. Markovian analysis is one method of analyzing texture features that is available in a commercially available image analysis system, the CAS-100. In order to select optimal Markovian features for use in nuclear grading of breast cancer, 16 nuclear models were created with computer graphics that demonstrated specific components of nuclear chromatin pattern, such as granularity, contrast, symmetry, peripheral chromatin clumping, and number and shape of nucleoli. These models were analyzed on the CAS-100 image analysis system using software capable of measuring 22 Markovian texture features at 20 levels of pixel resolution (grain). We were able to show that Markovian analysis performed well in discriminating between degrees of chromatin granularity (finely vs. coarsely clumped), amount of contrast (vesicular change), thickness of peripheral chromatin and number of nucleoli. Of the 22 Markovian features, 10 were selected as optimal for discriminating between the above chromatin patterns. Similar optimal Markovian features were found when measurements were performed on captured images of breast cancer cells. The use of these selected Markovian texture features may allow a more rational approach to the use of image analysis for cell classification.

Breast Neoplasms↗

Tumor volume: a novel prognostic factor in patients who undergo curative resection for gastric cancer.

BACKGROUND AND AIMS: The present study evaluates the significance of tumor volume as a prognostic factor in gastric cancer. PATIENTS/METHODS: Tumor volume was measured from serial tissue sections of 101 patients who had undergone curative resection for solitary carcinoma of the stomach using a computer graphics analysis program. These patients were analyzed with respect to survival based on univariate and multivariate analyses of clinicopathological factors, including tumor volume, to determine an independent prognostic factor. RESULTS: Significant differences in survival were found with respect to depth of tumor invasion (P=0.001), status of lymph-node metastasis (P=0.018), tumor diameter (P=0.005), and tumor volume (P<0.0001) based on univariate analysis. However, multivariate analysis indicated only tumor volume as a valid factor in determining prognosis among the nine variables and was significantly associated with the prognosis (P=0.0005; relative risk 18.23; 95% confidence interval 3.52-94.37). CONCLUSION: The present findings indicate that tumor volume is an important prognostic factor in patients who undergo curative resection for gastric cancer and may be an alternative to conventional factors, thus providing a novel independent prognostic factor in gastric cancer.

Adult↗