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The visualization and evaluation of bone architecture in the rat using three-dimensional X-ray microcomputed tomography.

Microcomputed tomography allows the true three-dimensional structure of bone to be assessed by a nondestructive analysis. This article describes how this technique has for the first time been applied to rat bone to determine the effects of aging, ovariectomy, and antiresorptive drugs on bone structure and how these results compare with those determined by histological and histomorphometric techniques. During the procedure, a micro X-ray source is directed toward the bone sample. Modifications in the X-ray beam induced by bone crystals are determined for a range of acquisitions before three-dimensional reconstruction of bone architecture is performed. Morphometric parameters determined were trabecular bone volume/tissue volume, trabecular number, and trabecular thickness. The results show that ovariectomy has a dramatic effect on rat bone structure. Following treatment with the bone resorption inhibitor tiludronate, the morphometric parameters were significantly improved. The results obtained with three-dimensional microcomputed tomography were in agreement with observations made using classical techniques. Microcomputed tomography should prove useful for evaluating the antiresorptive effects of bisphosphonates on bone architecture and in allowing between-drug comparisons.

Animals↗

A HIPAA-compliant architecture for securing clinical images.

The Health Insurance Portability and Accountability Act (HIPAA, instituted April 2003) Security Standards mandate health institutions to protect health information against unauthorized use or disclosure. One approach to addressing this mandate is by utilizing user access control and generating audit trails of the various authorized as well as unauthorized user access of health data. Although most current clinical image systems [e.g., picture archiving and communication system (PACS)] have components that generate log files for application debugging purposes, there is a lack of methodology to obtain and synthesize the pertinent data from the large volumes of log data generated by these multiple components within a PACS. We have designed a HIPAA-compliant architecture specifically for tracking and auditing the image workflow of clinical imaging systems such as PACS. As an initial first step, we developed HIPAA-compliant auditing system (H-CAS) based on parts of this HIPAA-compliant architecture. H-CAS was implemented within a test-bed PACS simulator located in the Image Processing and Informatics lab at the University of Southern California. Evaluation scenarios were developed where different user types performed legal and illegal access of PACS image data within each of the different components in the PACS simulator. Results were based on whether the scenarios of unauthorized access were correctly identified and documented as well as on normal operational activity. Integration and implementation pitfalls were also noted and included.

California↗

Nanoscale intracellular organization and functional architecture mediating cellular behavior.

Cells function based on a complex set of interactions that control pathways resulting in ultimate cell fates including proliferation, differentiation, and apoptosis. The inter-workings of this immensely dense network of intracellular molecules are influenced by more than random protein and nucleic acid distribution where their interactions culminate in distinct cellular function. By probing the design of these biological systems from an engineering perspective, researchers can gain great insight that will aid in building and utilizing systems that are on this size scale where traditional large-scale rules may fail to apply. The organized interaction and gradient distribution in intracellular space imply a structural architecture that modulates cellular processes by influencing biochemical interactions including transport and binding-reactions. One significant structure that plays a role in this modulation is the cell cytoskeleton. Here, we discuss the cytoskeleton as a central and integrating functional structure in influencing cell processes and we describe technology useful for probing this structure. We explain the nanometer scale science of cytoskeletal structure with respect to intracellular organization, mechanotransduction, cytoskeletal-associated proteins, and motor molecules, as well as nano- and microtechnologies that are applicable for experimental studies of the cytoskeleton. This biological architecture of the cytoskeleton influences molecular, cellular, and physiological processes through structured multimodular and hierarchical principles centered on these functional filaments. Through investigating these organic systems that have evolved over billions of years, understanding in biology, engineering, and nanometer-scaled science will be advanced.

Animals↗

The VEGF receptor tyrosine kinase inhibitor, ZD6474, inhibits angiogenesis and affects microvascular architecture within an orthotopically implanted renal cell carcinoma.

The proangiogenic vascular endothelial growth factor-A (VEGF) is essential for the development of new tumor vessels. ZD6474 is a novel inhibitor of VEGF receptor-2 (VEGFR-2) tyrosine kinase activity, which also has additional activity against epidermal growth factor (EGF) receptor tyrosine kinase. The antitumor activity of different schedules of ZD6474 in a clinically relevant, metastasizing, murine renal cell carcinoma (RENCA) model was evaluated in this study. RENCA cells were inoculated into the left kidney of 24 mice (day 0). Daily ZD6474 (50 mg/kg p.o.) treatment was initiated 1 day or 10 days after tumor cell inoculation and continued until day 21. Following treatment, kidney weight and volume were assessed and blood vessel density determined by CD31 staining. Visible metastases in the lungs, spleen, and lymph nodes were quantified using a dissection microscope. In an additional study, animals were treated according to the same regimen and quantitative three-dimensional microvascular corrosion casting was performed to enable detailed assessment of the tumor vascular architecture. Therapy initiated on day 1 or day 10 resulted in a 79% and 59% reduction in primary tumor volume, a 79% and 60% reduction in the number of lung metastases, and a 58% and 59% reduction in vessel density of primary tumors compared with the control group, respectively. Corrosion casting proved a 5.4- and 3.2-fold lower vascular volume compared with untreated tumors, observations that paralleled with significant architectural alterations. In this RENCA model, ZD6474 was a highly active inhibitor of tumor angiogenesis, primary tumor growth and tumor metastasis.

Animals↗

Genetic architecture of two fitness-related traits in Drosophila melanogaster: ovariole number and thorax length.

In Drosophila melanogaster, ovariole number and thorax length are morphological characters thought to be associated with fitness. Maximum daily egg production in females is positively correlated with ovariole number, while thorax length is correlated with male reproductive success and female fecundity. Though both traits are related to fitness, ovariole number is likely to be under stabilizing selection, while thorax length appears to be under directional selection. Current research has focused on examining the sources of variation for ovariole number in relation to fitness, with a view towards elucidating how segregating variation is maintained in natural populations. Here, we utilize a diallel design to explore the genetic architecture of ovariole number and thorax length in nine isogenic lines derived from a natural population. The full diallel design allows the estimation of general combining ability (GCA), specific combining ability (SCA), and also describes variation due to reciprocal effects (RGCA and RSCA). Ovariole number and thorax length differed with respect to their genetic architecture, reflective of the independent selective forces acting on the traits. For ovariole number, GCA accounted for the majority (67.3%) of variation segregating between the lines, with no evidence of reciprocal effects or inbreeding depression; SCA accounted for a small percentage (3.9%) of the variance, suggesting dominance variation; no reciprocal effects were observed. In contrast, for thorax length, the majority of the non-error variance was accounted for by SCA (17.9%), with only one third as much variance (6.2%) due to GCA. Interestingly, RSCA (nuclear-extranuclear interactions) accounted for slightly more variation (7.5%) than GCA in these data. Thus, genetic variation for thorax length is largely in accord with predictions for a fitness trait under directional selection: little additive genetic variation and substantial dominance variation (including a suggestion of inbreeding depression); while the mechanisms underlying the maintenance of variation for ovariole number are more complex.

Animals↗

Biomimetic mineral-organic composite scaffolds with controlled internal architecture.

Bone and cartilage generation by three-dimensional scaffolds is one of the promising techniques in tissue engineering. One approach is to generate histologically and functionally normal tissue by delivering healthy cells in biocompatible scaffolds. These scaffolds provide the necessary support for cells to proliferate and maintain their differentiated function, and their architecture defines the ultimate shape. Rapid prototyping (RP) is a technology by which a complex 3-dimensional (3D) structure can be produced indirectly from computer aided design (CAD). The present study aims at developing a 3D organic-inorganic composite scaffold with defined internal architecture by a RP method utilizing a 3D printer to produce wax molds. The composite scaffolds consisting of chitosan and hydroxyapatite were prepared using soluble wax molds. The behaviour and response of MC3T3-E1 pre-osteoblast cells on the scaffolds was studied. During a culture period of two and three weeks, cell proliferation and in-growth were observed by phase contrast light microscopy, histological staining and electron microscopy. The Giemsa and Gömöri staining of the cells cultured on scaffolds showed that the cells proliferated not only on the surface, but also filled the micro pores of the scaffolds and produced extracellular matrix within the pores. The electron micrographs showed that the cells covering the surface of the struts were flattened and grew from the periphery into the middle region of the pores.

3T3 Cells↗

Effect of changes in action potential spike configuration, junctional sarcoplasmic reticulum micro-architecture and altered t-tubule structure in human heart failure.

Using a Monte-Carlo model of L-type Ca2+ channel (DHPR) gating, we have examined the effect of changes in the early time course of the action potential as seen in human heart failure on excitation contraction coupling. The time course of DHPR Ca2+ influx was coupled into a simple model of sarcoplasmic reticulum Ca2+ release. Our model shows that the loss of the initial spike in human heart failure should reduce the synchrony of Ca2+ spark production and lead to the appearance of late Ca2+ sparks and greater non-uniformity of intracellular Ca2+. Within the junctional space of the cardiac dyad, a small increase in the mean distance of a DHPR from a RyR results in a marked decrease in the ability of the DHPR-mediated increase in local [Ca2+] concentration to activate RyRs. This suggests that the efficiency of EC coupling may be reduced if changes in micro-architecture develop and such effects have been noted in experimental models of heart failure. High resolution imaging of t-tubules in tachycardia-induced heart failure show deranged t-tubule structure. While in normal human hearts t-tubules run mainly in a radial direction, t-tubules in the heart failure samples were oriented more toward the long axis of the cell. In addition, t-tubules may become dilated and bifurcated. Our data suggest that changes in the micro-architecture of the cell and membrane structures associated with excitation-contraction coupling, combined with changes in early action potential configuration can reduce the efficiency by which Ca2+ influx via DHPRs can activate SR calcium release and cardiac contraction. While the underlying cause of these effects is unclear, our data suggest that geometric factors can play an important role in the pathophysilogy of the human heart in failure.

Action Potentials↗

Sex-specific genetic architecture of asthma-associated quantitative trait loci in a founder population.

Identifying genes that influence susceptibility to asthma-related and atopy-related phenotypes has been challenging, owing to clinical heterogeneity and a complex underlying genetic architecture that includes both gene-gene and gene-environment interactions. In this article, we report the results of genome-wide linkage and association studies of eight asthma-associated quantitative traits in the Hutterites, a founder population of European descent. Our study revealed significant sex-specific genetic architecture for at least five of these traits, and identified 13 genome-wide significant quantitative trait loci (QTL) by linkage or association that are present in only one of the sexes (nine in males, four in females).

Asthma↗

Current diagnostic techniques in the evaluation of bone architecture.

Bone quality, which encompasses trabecular bone and cortical bone architecture, bone mineralization, turnover, and microdamage, is an essential component of bone strength. Therefore, bone quality, bone density, and total content are the most important parameters in the diagnosis of osteoporosis. Noninvasive assessment of bone quality has recently received considerable attention because bone density alone is not a surrogate for fracture prevalence and occurrence, and does not completely explain the therapeutic efficacy of emerging treatments. This paper will focus on the noninvasive assessment of trabecular bone architecture, one of the factors that governs bone strength and may be categorized as a contributor to bone quality. The methodologies described will include magnetic resonance imaging, clinical multislice spiral computed tomography, and micro-computed tomography, along with computerized analysis of radiographic patterns of trabecular bone.

Aged↗

Bone architecture and fracture.

Bones are designed to carry out their requirements effectively. One of these requirements is to resist fracture. Two other important requirements are to be stiff and to be light. Few theories of adaptive modeling distinguish modeling for adequate stiffness from modeling for adequate strength. Bones achieve their architecture partially through genetics, the rough form of the bone being laid down in the genes, and partially through response to normal loading. Normal loading rarely includes traumatic loading and bones are not usually well adapted to resist trauma, though they are probably well adapted to fatigue loading. Some aspects of architectural function, such as hollowness, are well understood. Some aspects, such as the need for uniform loading in impact, are less understood, and some, such as size effects, are only now beginning to be investigated.

Bone Density↗

Current technologies in the evaluation of bone architecture.

In the context of osteoporosis, bone quality (which encompasses trabecular bone and cortical bone architecture), bone mineralization, turnover, and microdamage are all important, as are bone density and total content. Noninvasive assessment of bone quality has recently received considerable attention because bone density alone is not a surrogate for fracture prevalence and occurrence, and does not completely explain the therapeutic efficacy of emerging treatments. This paper focuses on the assessment of trabecular bone architecture, one of the factors that governs bone strength and may be categorized as a contributor to bone quality. The methodologies described include micro-computed tomography, magnetic resonance imaging, and computerized analysis of radiographic patterns of trabecular bone.

Bone Density↗

In vivo assessment of architecture and micro-finite element analysis derived indices of mechanical properties of trabecular bone in the radius.

Measurement of microstructural parameters of trabecular bone noninvasively in vivo is possible with high-resolution magnetic resonance (MR) imaging. These measurements may prove useful in the determination of bone strength and fracture risk, but must be related to other measures of bone properties. In this study in vivo MR imaging was used to derive trabecular bone structure measures and combined with micro-finite element analysis (microFE) to determine the effects of trabecular bone microarchitecture on bone mechanical properties in the distal radius. The subjects were studied in two groups: (I) postmenopausal women with normal bone mineral density (BMD) (n = 22, mean age 58 +/- 7 years) and (II) postmenopausal women with spine or femur BMD -1 SD to -2.5 SD below young normal (n = 37, mean age 62 +/- 11 years). MR images of the distal radius were obtained at 1.5 T, and measures such as apparent trabecular bone volume fraction (App BV/TV), spacing, number and thickness (App TbSp, TbN, TbTh) were derived in regions of interest extending from the joint line to the radial shaft. The high-resolution images were also used in a micro-finite element model to derive the directional Young's moduli (E1, E2 and E3), shear moduli (G12, G23 and G13) and anisotropy ratios such as E1/E3. BMD at the distal radius, lumbar spine and hip were assessed using dual-energy X-ray absorptiometry (DXA). Bone formation was assessed by serum osteocalcin and bone resorption by serum type I collagen C-terminal telopeptide breakdown products (serum CTX) and urinary CTX biochemical markers. The trabecular architecture displayed considerable anisotropy. Measures of BMD such as the ultradistal radial BMD were lower in the osteopenic group (p<0.01). Biochemical markers between the two groups were comparable in value and showed no significant difference between the two groups. App BV/TV, TbTh and TbN were higher, and App TbSp lower, in the normal group than the osteopenic group. All three directional measures of elastic and shear moduli were lower in the osteopenic group compared with the normal group. Anisotropy of trabecular bone microarchitecture, as measured by the ratios of the mean intercept length (MIL) values (MIL1/MIL3, etc.), and the anisotropy in elastic modulus (E1/E3, etc.), were greater in the osteopenic group compared with the normal group. The correlations between the measures of architecture and moduli are higher than those between elastic moduli and BMD. Stepwise multiple regression analysis showed that while App BV/TV is highly correlated with the mechanical properties, additional structural measures do contribute to the improved prediction of the mechanical measures. This study demonstrates the feasibility and potential of using MR imaging with microFE modeling in vivo in the study of osteoporosis.

Aged↗

Neurons of origin of striatonigral axons in the cat: connectivity and Golgi markers of somatodendritic architecture.

We identified adult cat striatonigral neurons and characterized their somatodendritic architecture by single- and double-labeling with connectivity and Golgi markers. Light and electron microscopic observations demonstrated two important structural variations among striatofugal neurons. First, striatonigral axons originate from multiple types of neurons. The principal striatonigral neurons are frequent throughout the caudate nucleus and putamen, have medium spherical or ovoidal cell bodies and form spine-laden distal dendrites. The 'accessory' striatonigral neurons are sparse in limited regions of the caudate nucleus and putamen, have large fusiform cell bodies and lack spinous processes. Second, the medium spiny striatonigral neurons exhibit a range of anatomical specializations. In some cases, these cells have folded nuclear envelopes. Some of these neurons have somatic and/or proximal dendritic as well as distal dendritic spines. We conclude that adult cat striatofugal neurons are morphologically heterogeneous in terms of regional locations, somatodendritic architecture and ultrastructure. These anatomical specializations may affect the origin and processing of synaptic inputs to the neostriatum to provide functionally different routes of neurotransmission through the basal ganglia.

Animals↗

Neurofilaments assume a less random architecture at nodes and in other regions of axonal compression.

Neurofilament distributions were mathematically characterized in four chicken somatic motor axons at each of four histologically distinct regions: compact myelinated regions, compact myelinated regions associated with Schwann cell nuclei, Schmidt-Lanterman clefts, and nodes of Ranvier. Compact myelinated regions had the largest cross-sectional areas, the lowest neurofilament densities, and the most random neurofilament organizations--nodes of Ranvier had the smallest cross-sectional areas, the highest neurofilament densities, and the most ordered architectures. In these myelinated axons, the closest natural neurofilament spacing was 25 nm. Mathematical analyses of serial sections suggested that neurofilament interactions are sufficiently weak and transient to permit a full range of variation from random to ordered cytoskeletal architectures as the neurofilaments move longitudinally through the few micron span of the paranodal-nodal region of a single axon.

Animals↗

Architectures for numerical cognition.

Current theories of numerical cognition differ in assumptions about the componential architecture of number processing and about the extent of notation-specific processes. To investigate these issues, 64 adult subjects were tested on simple addition and multiplication problems presented in Arabic digit or English number-word format. Overall, response times and error rates were much higher with the word format, but more importantly, presentation format interacted with arithmetic operation and problem size. Operation errors (2 + 4 = 8), operand-naming errors (2 + 8 = 8), and operand-intrusion errors (9 x 6 = 36) were each characterized by a different format x operation interaction, and analysis of inter-trial error priming showed selective interference from preceding trials as a function of number format. These types of format-specific retrieval interference and operation-specific effects of format are problematic for models that hypothesize notation-independent memory processes for arithmetic. Furthermore, analyses of operand-naming errors, operand-intrusion errors, and other operand-priming effects, revealed strong interactions of number reading and number-fact retrieval processes; processes that are typically posited to be functionally independent. The results suggest a complex encoding architecture that incorporates notation-dependent activation of addition and multiplication facts, as well as interpenetration of number reading and number-fact retrieval processes.

Adult↗

A neural network architecture for understanding discrete three-dimensional scenes in medical imaging.

Magnetic resonance and computed tomography produce sets of tomograms which are termed discrete 3D scenes. Usually, discrete 3D scenes are analyzed in two dimensions by observing each tomogram on a screen so that the three-dimensional information contained in the scene can be recovered only partially and qualitatively. The three-dimensional reconstruction of the shape of biological structures from discrete 3D scenes would allow a complete and quantitative recovery of the available information, but this task has proved hard for conventional processing techniques. In this paper we present a system architecture based on neural networks for the fully automated segmentation and recognition of structures of interest in discrete 3D scenes. The system includes a retina and two main processing modules, an Attention-Focuser System and a Region-Finder System, which have been implemented by using feed-forward nets trained with the back-propagation algorithm. This architecture has been tested on computer-simulated structures and has been applied to the reconstruction of the spinal cord and the brain from sets of tomograms.

Humans↗

Regulation of cytoskeletal architecture by platelet-derived growth factor, insulin and epidermal growth factor.

Addition of ng/ml quantities of the platelet-derived growth factor (PDGF) component of serum to the culture medium of quiescent monolayers of BALB/c-3T3 cells rapidly altered the actomyosin cytoskeletal system. PDGF triggered dispersal of microfilament bundles and induced phosphorylation of the 20 kD myosin light chain within 5 min of addition. Additional cytoskeletal responses followed the addition of insulin and of epidermal growth factor (EGF). Insulin alone induces a transient breakdown of well defined microtubule filaments. EGF and insulin together induced moderate perturbation of the cytoplasmic network of intermediate filaments which then reformed within a 90-180 min time frame. This response, however, was greatly enhanced in cells which were pretreated with PDGF and it appears to be a secondary event occurring as a consequence of cell growth. The PDGF-induced disruption of microfilament bundles could be blocked by phalloidin with no apparent inhibition of the mitogenic response. Insulin alone is only weakly mitogenic for 3T3 cells. The data thus indicate that the architecture of two discrete cytoskeletal elements (microtubules and microfilaments) is regulated directly by separate serum growth factors (insulin and PDGF). However the disruption of microfilament architecture by PDGF does not seem necessary for induction of cell growth and the disruption of microtubule filaments by insulin is not sufficient.

Animals↗

An architecture for a health care provider's workstation.

This paper presents an architecture for a health care provider's workstation designed to assist health care providers in performing their daily activities. The design is based on the concept of a clinician's associate which acts as an intelligent intermediary between the provider and a diverse collection of clinical, administrative, and educational information sources. The architecture is designed to be hardware platform independent, to work across different I/O capabilities, and to be open, allowing specialized applications to be easily integrated with the system and their functionality delivered through a common user environment.

Computer Communication Networks↗