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In the vertebrate embryo, the eyes develop from optic vesicles that grow laterally outward from the brain tube and contact the overlying surface ectoderm. Within the region of contact, each optic vesicle and the surface ectoderm thicken to form placodes, which then invaginate to create the optic cup and lens pit, respectively. Eventually, the optic cup becomes the retina, while the lens pit closes to form the lens vesicle. Here, we review current hypotheses for the physical mechanisms that create these structures and present novel three-dimensional computer (finite-element) models to illustrate the plausibility and limitations of these hypotheses. Taken together, experimental and numerical results suggest that the driving forces for early eye morphogenesis are generated mainly by differential growth, actomyosin contraction, and regional apoptosis, with morphology mediated by physical constraints provided by adjacent tissues and extracellular matrix. While these studies offer new insight into the mechanics of eye development, future work is needed to better understand how these mechanisms are regulated to precisely control the shape of the eye. [ABSTRACT FROM AUTHOR]

After decades focusing on the molecular and genetic aspects of organogenesis, researchers are showing renewed interest in the physical mechanisms that create organs. This review deals with the mechanical processes involved in constructing the heart and brain, concentrating primarily on cardiac looping, shaping of the primitive brain tube, and folding of the cerebral cortex. Recent studies suggest that differential growth drives large-scale shape changes in all three problems, causing the heart and brain tubes to bend and the cerebral cortex to buckle. Relatively local changes in form involve other mechanisms such as differential contraction. Understanding the mechanics of organogenesis is central to determining the link between genetics and the biophysical creation of form and structure. [ABSTRACT FROM AUTHOR]

Abstract: Researchers in developmental biology are increasingly recognizing the value of theoretical models in studies of morphogenesis. However, creating and testing realistic quantitative models for morphogenetic processes can be an extremely challenging task. The focus of this paper is on models for the mechanics of morphogenesis. Models for these problems often must include large changes in geometry, leading to highly nonlinear problems with the possibility of multiple solutions that must be sorted out using experimental data. Here, we illustrate our approach to these problems using the specific example of head fold formation in the early chick embryo. The interplay between experimental and theoretical results is emphasized throughout, as the model is gradually refined. Some of the limitations inherent in theoretical/computational modeling of biological systems are also discussed. [Copyright &y& Elsevier]

The heart is the first functioning organ to form during development. During gastrulation, the cardiac progenitors reside in the lateral plate mesoderm but maintain close contact with the underlying endoderm. In amniotes, these bilateral heart fields are initially organized as a pair of flat epithelia that move towards the embryonic midline and fuse above the anterior intestinal portal (AIP) to form the heart tube. This medial motion is typically attributed to active mesodermal migration over the underlying endoderm. In this model, the role of the endoderm is twofold: to serve as a mechanically passive substrate for the crawling mesoderm and to secrete various growth factors necessary for cardiac specification and differentiation. Here, using computational modeling and experiments on chick embryos, we present evidence supporting an active mechanical role for the endoderm during heart tube assembly. Label-tracking experiments suggest that active endodermal shortening around the AIP accounts for most of the heart field motion towards the midline. Results indicate that this shortening is driven by cytoskeletal contraction, as exposure to the myosin-II inhibitor blebbistatin arrested any shortening and also decreased both tissue stiffness (measured by microindentation) and mechanical tension (measured by cutting experiments). In addition, blebbistatin treatment often resulted in cardia bifida and abnormal foregut morphogenesis. Moreover, finite element simulations of our cutting experiments suggest that the endoderm (not the mesoderm) is the primary contractile tissue layer during this process. Taken together, these results indicate that contraction of the endoderm actively pulls the heart fields towards the embryonic midline, where they fuse to form the heart tube. [ABSTRACT FROM AUTHOR]

During early development, the initially straight heart tube (HT) bends and twists (loops) into a curved tube to lay out the basic plan of the mature heart. The physical mechanisms that drive and regulate looping are not yet completely understood. This paper reviews our recent studies of the mechanics of cardiac torsion during the first phase of looping (c-looping). Experiments and computational modeling show that torsion is primarily caused by forces exerted on the HT by the primitive atria and the splanchnopleure, a membrane that presses against the ventral surface of the heart. Experimental and numerical results are described and integrated to propose a hypothesis for cardiac torsion, and key aspects of our hypothesis are tested using experiments that perturb normal looping. For each perturbation, the models predict the correct qualitative response. These studies provide new insight into the mechanisms that drive and regulate cardiac looping. [ABSTRACT FROM AUTHOR]

Opening angles (OAs) are associated with growth and remodelling in arteries. One curiosity has been the relatively large OAs found in the aortic arch of some animals. Here, we use computational models to explore the reasons behind this phenomenon. The artery is assumed to contain a smooth muscle/collagen phase and an elastin phase. In the models, growth and remodelling of smooth muscle/collagen depends on wall stress and fluid shear stress. Remodelling of elastin, which normally turns over very slowly, is neglected. The results indicate that OAs generally increase with longitudinal curvature (torus model), earlier elastin production during development, and decreased wall stiffness. Correlating these results with available experimental data suggests that all of these effects may contribute to the large OAs in the aortic arch. The models also suggest that the slow turnover rate of elastin limits longitudinal growth. These results should promote increased understanding of the causes of residual stress in arteries. [ABSTRACT FROM AUTHOR]

Early in development, the heart is a single muscle-wrapped tube without formed valves. Yet survival of the embryo depends on the ability of this tube to pump blood at steadily increasing rates and pressures. Developmental biologists historically have speculated that the heart tube pumps via a peristaltic mechanism, with a wave of contraction propagating from the inflow to the outflow end. Physiological measurements, however, have shown that the flow becomes pulsatile in character quite early in development, before the valves form. Here, we use a computational model for flow though the embryonic heart to explore the pumping mechanism. Results from the model show that endocardial cushions, which are valve primordia arising near the ends of the tube, induce a transition from peristaltic to pulsatile flow. Comparison of numerical results with published experimental data shows reasonably good agreement for various pressure and flow parameters. This study illustrates the interrelationship between form and function in the early embryonic heart. [ABSTRACT FROM AUTHOR]

During the morphogenetic process of cardiac looping, the initially straight cardiac tube bends and twists into a curved tube. The biophysical mechanisms that drive looping remain unknown, but the process clearly involves mechanical forces. Hence, it is important to determine mechanical properties of the early heart, which is a muscle-wrapped tube consisting primarily of a thin outer layer of myocardium surrounding a thick extra- cellular matrix compartment known as cardiac jelly. In this work, we used microindentation experiments and finite element modeling, combined with an inverse computational method, to determine constitutive relations for the myocardium and cardiac jelly at the outer curvature of stage 12 chick hearts. Material coefficients for exponential strain-energy density functions were found by fitting force-displacement and surface displacement data near the indenter Residual stress in the myocardium also was estimated, These results should be useful for computational models of the looping heart. [ABSTRACT FROM AUTHOR]

Microindentation methods are commonly used to determine material properties of soft tissues at the cell or even sub-cellular level. In determining properties from forcedisplacement (FD) data, it is often assumed that the tissue is initially a stress-free, homogeneous, linear elastic half-space. Residual stress, however, can strongly influence such results. In this paper, we present a new microindentation method for determining both elastic properties and residual stress in soft tissues that, to a first approximation, can be regarded as a pre-stressed layer embedded in or adhered to an underlying relatively soft, elastic foundation. The effects of residual stress are shown using two linear elastic models that approximate specific biological structures. The first model is an axially loaded beam on a relatively soft, elastic foundation (i.e., stress-fiber embedded in cytoplasm), while the second is a radially loaded plate on a foundation (e.g., cell membrane or epithelium). To illustrate our method, we use a nonlinear finite element (FE) model and experimental FD and surface contour data to find elastic properties and residual stress in the early embryonic chick heart, which, in the region near the indenter tip, is approximated as an isotropic circular plate under tension on a foundation. It is shown that the deformation of the surface in a microindentation test can be used along with FD data to estimate material properties, as well as residual stress, in soft tissue structures that can be regarded as a plate under tension on an elastic foundation. This method may not be as useful, however, for structures that behave as a beam on a foundation. [ABSTRACT FROM AUTHOR]

Epicardial strains were measured in Hamburger–Hamilton stage 11 and 12 embryonic chick hearts (1.6–2.0 days of incubation). These stages include part of the early phase of cardiac looping, as the initially straight heart tube bends and twists to form a curved c-shaped tube. By analyzing the motion of microbeads placed on the myocardial surface, we measured strains near the outer curvature, in the central region, and near the inner curvature of the primitive ventricle. No significant differences in strain were found between stages. Relative to end diastole, all three regions shortened by about 10% during systole in the circumferential direction, and the outer curvature shortened longitudinally by about 5%. In contrast, and unlike strains in older hearts, the inner curvature and central regions elongated by approximately 5–10% in the longitudinal direction during systole. These results are consistent with microstructural data and suggest that the material properties of the outer curvature are relatively isotropic, whereas the properties of the central and inner curvature regions are orthotropic, with contractile stress exerted primarily in the circumferential direction. [Copyright &y& Elsevier]

Presents information on a study which measured intramyocardial pressure in the ventricle of the beating, stage 18 embryonic chick heart. Methodology; Results and discussion.

Investigates the use of a simple phenomenological model to study interrelations between material properties, growth-induced residual stresses and opening angle in arteries. Description of the artery; Computation of residual stress for configurations; Dependence of the opening angles magnitude on the heterogeneity of the material property of the vessel wall.

It long has been known that mechanical forces play a role in the development of the cardiovascular system, but only recently have biomechanical engineers begun to explore this field. This paper reviews some of this work. First, an overview of the relevant biology is discussed. Next, a mechanical theory is presented that can be used to model developmental processes. The theory includes the effects of finite volumetric growth and active contractile forces. Finally, applications of this and other theories to problems of cardiovascular development are discussed, and some future directions are suggested. The intent is to stimulate further interest among engineers in this important area of research. [ABSTRACT FROM AUTHOR]

Abstract. In a double-blind study, bronchiolitis associated with respiratory syncytial virus infection in 12 randomly selected patients treated with ribavirin aerosol improved more rapidly than in 14 control patients given saline aerosol (P = .044, Wilcoxon rank sum test, two-tailed). An estimated 10 mg of ribavirin per kilogram of body weight was administered in daily 12-hour treatments over a five-day period. Respiratory syncytial virus disappeared from secretions at about the same rate in treated and control patients. There was no local or systemic intolerance, and there was no evidence of hematologic or other organ toxicity in the ribavirin-treated patients. [ABSTRACT FROM AUTHOR]

Abstract. Thirty-nine breast-fed and 42 bottle-fed infants were followed up from birth over a four-year period. Virus infection was documented by culture and serologic testing, and history and physical examination were recorded for all episodes of respiratory illness. There were no statistically significant differences in rates or distributions of infection with individual viruses or with all viruses over the first three or six months or during the second six months of life in the two groups, nor were there statistically significant differences in rates or distributions of disease of the upper and lower respiratory tract or total respiratory disease, except for decreased disease of the lower respiratory tract in bottle-fed infants in the second six months. There were trends to decreased morbidity in breast-fed infants in the first three and six months and more episodes of pneumonia and bronchiolitis in bottle-fed infants in the first six months (P < .05) but similar use of medical care by both groups. High cord blood titers to two viruses were not associated with evidence of breast-feeding protection from infection with those two agents. Breast-fed babies do not have fewer respiratory virus infections or illnesses but may experience less severe illness. INSET: DRIED SKIMMED MILK, BREAST-FEEDING, AND ILLNESS EPISODES. [ABSTRACT FROM AUTHOR]

Abstract. For more than 30 years, penicillin has been the agent of choice for pneumococcal infections. During this time the majority of strains of Streptococcus pneumoniae have been highly susceptible to penicillin. However, during the last ten years there have been sporadic reports of pneumococci with increased resistance to penicillin. The case report of an 18-month-old white boy with meningitis due to a strain of S. pneumoniae with increased resistance to penicillin is presented. The MIC of the organism to penicillin was 0.2 micro g/ml and the MBC 0.39 micro g/ml. The patient had normal immunity and no demonstrable sequestered focus of infection but failed to respond to appropriate doses of intravenous penicillin. Treatment with chloramphenicol caused a dramatic bacteriologic and clinical response. This experience reemphasizes the existence of pneumococcal strains of intermediate penicillin sensitivity and the importance of in vitro susceptibility tests. Pediatrics 58:378-381, 1976, MENINGITIS, PENICILLIN RESISTANCE, PNEUMOCOCCUS. [ABSTRACT FROM AUTHOR]

Abstract. The exact incidence and importance of side effects associated with methicillin therapy in children is unknown. During the ten-year period from 1964 to 1974 approximately 3,000 Houston children who received methicillin were observed for side effects. The great majority of these patients received the drug for less than ten days; however, side effects were more common in patients receiving long-term therapy. In order to assess these side effects, experiences with 124 children who received methicillin for ten days or longer were reviewed in depth. The average dose of methicillin was 200 mg/kg/day and the average duration was 22 days. In this highly selected group there were no adverse side effects in 54.8% and only eosinophilia in an additional 13%. Leukopenia occurred in 16%, microscopic hematuria in 8%, gross hematuria in 4%, skin rash in 6%, and "drug fever" in 6%. In many instances several of these side effects occurred within a single patient so that the total number of patients with definite side effects was 39 of 124 (31.5%). The true incidence figure of overall side effects is much lower than 31.5%. Corrected incidence rates based on a conservative figure of 3,000 methicillin-treated children are less than 1.5% for all side effects. In some patients the mechanism producing the adverse reactions seemed to be chemical irritation or toxicity and in others hypersensitivity. In nine of the 39 patients follow-up studies were not optimal. In the other 30 patients all side effects were reversible. Pediatrics, 58:329-334, 1976, METHICILLIN, PENICILLIN, HEMATURIA, LEUKOPENIA, NEPHROPATHY. [ABSTRACT FROM AUTHOR]

The author introduces Dr. Peter Hunter as the co-Editor-in-Chief of "Biomechanics and Modeling in Mechanobiology" (BMMB) as the author's replacement and relates the decision of the journal to make mechanobiology its primary focus.

The article discusses various reports published within the issue, including one on creating tissues in vitro using strategies derived from embryos, another on some embryos' active response to mechanical perturbations, and a report on artery development at later stages.

The inclusion in the first issue of 2013 of the introductory editorial to the "Special Issue on Mechanics of Development" that was omitted from the previously published Volume 11(8)_2012 is announced.

For decades, it was commonly thought that the bilateral heart fields in the early embryo fold directly towards the midline, where they meet and fuse to create the primitive heart tube. Recent studies have challenged this view, however, suggesting that the heart fields fold diagonally. As early foregut and heart tube morphogenesis are intimately related, this finding also raises questions concerning the traditional view of foregut formation. Here, we combine experiments on chick embryos with computational modeling to explore a new hypothesis for the physical mechanisms of heart tube and foregut formation. According to our hypothesis, differential anisotropic growth between mesoderm and endoderm drives diagonal folding. Then, active contraction along the anterior intestinal portal generates tension to elongate the foregut and heart tube. We test this hypothesis using biochemical perturbations of cell proliferation and contractility, as well as computational modeling based on nonlinear elasticity theory including growth and contraction. The present results generally support the view that differential growth and actomyosin contraction drive formation of the foregut and heart tube in the early chick embryo. [ABSTRACT FROM AUTHOR]

We have developed a mathematical model for growth and remodeling of arteries. The model is a thick-walled tube composed of a constrained mixture of smooth muscle cells, elastin and collagen. Material properties are prescribed according to previously published data. Radial and axial distributions of each constituent are determined via histological staining. The analysis includes stress-dependent growth and contractility of the muscle and turnover of collagen fibers. Simulations were conducted for homeostatic conditions and for the temporal response following sudden hypertension. Numerical pressure-radius relations and opening angles (residual stress) show reasonable agreement with published experimental results. In particular, for realistic material and structural properties, the model predicts measured variations in opening angles along the length of the aorta with reasonable accuracy. These results provide a better understanding of the determinants of residual stress in arteries and could lend insight into the importance of constituent distributions in both natural and tissue-engineered blood vessels. [ABSTRACT FROM AUTHOR]

The objective of this study is to determine the role that mechanics plays in cardiac c-looping, which is the process by which the initially straight heart tube bends ventrally and twists rightward into a c-shaped tube. In particular, we show how linking computational (finite-element) modeling to quantitative experimental measurements on chick embryos provides new insight into the forces that drive and regulate c-looping. A key element of this study is a correlation of numerical and experimental results for various perturbations of looping, including chemical perturbations (actin and myosin disruption) and mechanical perturbations (tissue dissection). The results suggest that bending is driven primarily by actin polymerization within the heart tube, while rotation is driven by external loads exerted by a membrane (splanchnopleure) on the ventral surface of the heart tube and by the omphalomesenteric veins at the caudal end of the tube. The results also show that mechanical feedback may be involved in regulating the intrinsically generated morphogenetic forces in the heart. From these results, we conclude that mechanical forces play a fundamental role in early cardiac morphogenesis. [ABSTRACT FROM AUTHOR]

Precise shaping of the eye is crucial for proper vision. Here, we use experiments on chick embryos along with computational models to examine the mechanical factors involved in the formation of the optic vesicles (OVs), which grow outward from the forebrain of the early embryo. First, mechanical dissections were used to remove the surface ectoderm (SE), a membrane that contacts the outer surfaces of the OVs. Principal components analysis of OV shapes suggests that the SE exerts asymmetric loads that cause the OVs to flatten and shear caudally during the earliest stages of eye development and later to bend in the caudal and dorsal directions. These deformations cause the initially spherical OVs to become pear-shaped. Exposure to the myosin II inhibitor blebbistatin reduced these effects, suggesting that cytoskeletal contraction controls OV shape by regulating tension in the SE. To test the physical plausibility of these interpretations, we developed 2-D finite-element models for frontal and transverse cross-sections of the forebrain, including frictionless contact between the SE and OVs. With geometric data used to specify differential growth in the OVs, these models were used to simulate each experiment (control, SE removed, no contraction). For each case, the predicted shape of the OV agrees reasonably well with experiments. The results of this study indicate that differential growth in the OV and external pressure exerted by the SE are sufficient to cause the global changes in OV shape observed during the earliest stages of eye development. [ABSTRACT FROM AUTHOR]

During the third trimester of human brain development, the cerebral cortex undergoes dramatic surface expansion and folding. Physical models suggest that relatively rapid growth of the cortical gray matter helps drive this folding, and structural data suggest that growth may vary in both space (by region on the cortical surface) and time. In this study, we propose a unique method to estimate local growth from sequential cortical reconstructions. Using anatomically constrained multimodal surface matching (aMSM), we obtain accurate, physically guided point correspondence between younger and older cortical reconstructions of the same individual. From each pair of surfaces, we calculate continuous, smooth maps of cortical expansion with unprecedented precision. By considering 30 preterm infants scanned two to four times during the period of rapid cortical expansion (28-38 wk postmenstrual age), we observe significant regional differences in growth across the cortical surface that are consistent with the emergence of new folds. Furthermore, these growth patterns shift over the course of development, with noninjured subjects following a highly consistent trajectory. This information provides a detailed picture of dynamic changes in cortical growth, connecting what is known about patterns of development at the microscopic (cellular) and macroscopic (folding) scales. Since our method provides specific growth maps for individual brains, we are also able to detect alterations due to injury. This fully automated surface analysis, based on tools freely available to the brain-mapping community, may also serve as a useful approach for future studies of abnormal growth due to genetic disorders, injury, or other environmental variables. [ABSTRACT FROM AUTHOR]

In the early embryo, the eyes form initially as relatively spherical optic vesicles (OVs) that protrude from both sides of the brain tube. Each OV grows until it contacts and adheres to the overlying surface ectoderm (SE) via an extracellular matrix (ECM) that is secreted by the SE and OV. The OV and SE then thicken and bend inward (invaginate) to create the optic cup (OC) and lens vesicle, respectively. While constriction of cell apices likely plays a role in SE invagination, the mechanisms that drive OV invagination are poorly understood. Here, we used experiments and computational modeling to explore the hypothesis that the ECM locally constrains the growing OV, forcing it to invaginate. In chick embryos, we examined the need for the ECM by (1) removing SE at different developmental stages and (2) exposing the embryo to collagenase. At relatively early stages of invagination (Hamburger-Hamilton stage HH14 $$-$$ ), removing the SE caused the curvature of the OV to reverse as it 'popped out' and became convex, but the OV remained concave at later stages (HH15) and invaginated further during subsequent culture. Disrupting the ECM had a similar effect, with the OV popping out at early to mid-stages of invagination (HH14 $$-$$ to HH14 $$+$$ ). These results suggest that the ECM is required for the early stages but not the late stages of OV invagination. Microindentation tests indicate that the matrix is considerably stiffer than the cellular OV, and a finite-element model consisting of a growing spherical OV attached to a relatively stiff layer of ECM reproduced the observed behavior, as well as measured temporal changes in OV curvature, wall thickness, and invagination depth reasonably well. Results from our study also suggest that the OV grows relatively uniformly, while the ECM is stiffer toward the center of the optic vesicle. These results are consistent with our matrix-constraint hypothesis, providing new insight into the mechanics of OC (early retina) morphogenesis. [ABSTRACT FROM AUTHOR]

In the early embryo, the primitive heart tube (HT) undergoes the morphogenetic process of c-looping as it bends and twists into a c-shaped tube. Despite intensive study for nearly a century, the physical forces that drive looping remain poorly understood. This is especially true for the bending component, which is the focus of this paper. For decades, experimental measurements of mitotic rates had seemingly eliminated differential growth as the cause of HT bending, as it has commonly been thought that the heart grows almost exclusively via hyperplasia before birth and hypertrophy after birth. Recently published data, however, suggests that hypertrophic growth may play a role in looping. To test this idea, we developed finite-element models that include regionally measured changes in myocardial volume over the HT. First, models based on idealized cylindrical geometry were used to simulate the bending process in isolated hearts, which bend without the complicating effects of external loads. With the number of free parameters in the model reduced to the extent possible, stress and strain distributions were compared to those measured in embryonic chick hearts that were isolated and cultured for 24 h. The results show that differential growth alone yields results that agree reasonably well with the trends in our data, but adding active changes in myocardial cell shape provides closer quantitative agreement with stress measurements. Next, the estimated parameters were extrapolated to a model based on realistic 3D geometry reconstructed from images of an actual chick heart. This model yields similar results and captures quite well the basic morphology of the looped heart. Overall, our study suggests that differential hypertrophic growth in the myocardium (MY) is the primary cause of the bending component of c-looping, with other mechanisms possibly playing lesser roles. [ABSTRACT FROM AUTHOR]

Differences in brain structure between species have long fascinated evolutionary biologists. Understanding how these differences arise requires knowing how they are generated in the embryo. Growing evidence in the field of evolutionary developmental biology (evo-devo) suggests that morphological differences between species result largely from changes in the spatiotemporal regulation of gene expression during development. Corresponding changes in functional cellular behaviors (morphogenetic mechanisms) are only beginning to be explored, however. Here we show that spatiotemporal patterns of tissue contractility are sufficient to explain differences in morphology of the early embryonic brain between disparate species. We found that enhancing cytoskeletal contraction in the embryonic chick brain with calyculin A alters the distribution of contractile proteins on the apical side of the neuroepithelium and changes relatively round cross-sections of the tubular brain into shapes resembling triangles, diamonds, and narrow slits. These perturbed shapes, as well as overall brain morphology, are remarkably similar to those of corresponding sections normally found in species such as zebrafish and Xenopus laevis (frog). Tissue staining revealed relatively strong concentration of F-actin at vertices of hyper-contracted cross-sections, and a finite element model shows that local contraction in these regions can convert circular sections into the observed shapes. Another model suggests that these variations in contractility depend on the initial geometry of the brain tube, as localized contraction may be needed to open the initially closed lumen in normal zebrafish and Xenopus brains, whereas this contractile machinery is not necessary in chick brains, which are already open when first created. We conclude that interspecies differences in cytoskeletal contraction may play a larger role in generating differences in morphology, and at much earlier developmental stages, in the brain than previously appreciated. This study is a step toward uncovering the underlying morphomechanical mechanisms that regulate how neural phenotypic differences arise between species. [ABSTRACT FROM AUTHOR]

An abstract of an article on the physical mechanisms that provide the tissue-level forces in the head fold (HF) formation in an avian embryo is presented.

Accurate material properties of developing embryonic tissues are a crucial factor in studies of the mechanics ofmorphogenesis. In the present work, we characterize the viscoelastic material properties of the looping heart tube in the chick embryo through nonlinear finite element modeling and microindentation experiments. Both hysteresis and ramp-hold experiments were performed on the intact heart and isolated cardiac jelly (extracellular matrix). An inverse computational method was used to determine the constitutive relations for the myocardium and cardiac jelly. With both layers assumed to be quasilinear viscoelastic, material coefficients for an Ogden type strain-energy density function combined with Prony series of two terms or less were determined by fitting numerical results from a simplified model of a heart segment to experimental data. The experimental and modeling techniques can be applied generally for determining viscoelastic material properties of embryonic tissues? [ABSTRACT FROM AUTHOR]

The analysis of the biomechanics of growth and remodeling in soft tissues requires the formulation of specialized pseudoelastic constitutive relations. The nonlinear finite element analysis package ABAQUS allows the user to implement such specialized material responses through the coding of a user material subroutine called UMAT. However, hand coding UMAT subroutines is a challenge even for simple pseudoelastic materials and requires substantial time to debug and test the code. To resolve this issue, we develop an automatic UMAT code generation procedure for pseudoelastic materials using the symbolic mathematics package MATHEMATICA and extend the UMAT generator to include continuum growth. The performance of the automatically coded UMAT is tested by simulating the stress-stretch response of a material defined by a Fungorthotropic strain energy function, subject to uniaxial stretching, equibiaxial stretching, and simple shear in ABAQUS. The MATHEMATICA UMAT generator is then extended to include continuum growth by adding a growth subroutine to the automatically generated UMAT. The MATHEMATICA UMAT generator correctly derives the variables required in the UMAT code, quickly providing a ready-to-use UMAT. In turn, the UMAT accurately simulates the pseudoelastic response. In order to test the growth UMAT, we simulate the growth-based bending of a bilayered bar with differing fiber directions in a nongrowing passive layer. The anisotropic passive layer, being topologically tied to the growing isotropic layer, causes the bending bar to twist laterally. The results of simulations demonstrate the validity of the automatically coded UMAT, used in both standardized tests of hyperelastic materials and for a biomechanical growth analysis. [ABSTRACT FROM AUTHOR]

Folding of the cerebral cortex is a critical phase of brain development in higher mammals but the biomechanics of folding remain incompletely understood. During folding, the growth of the cortical surface is heterogeneous and anisotropic. We developed and applied a new technique to measure spatial and directional variations in surface growth from longitudinal magnetic resonance imaging (MRI) studies of a single animal or human subject. MRI provides high resolution 3D image volumes of the brain at different stages of development. Surface representations of the cerebral cortex are obtained by segmentation of these volumes. Estimation of local surface growth between two times requires establishment of a point-to-point correspondence ("registration") between surfaces measured at those times. Here we present a novel approach for the registration of two surfaces in which an energy function is minimized by solving a partial differential equation on a spherical surface. The energy function includes a strain-energy term due to distortion and an "error energy" term due to mismatch between surface features. This algorithm, implemented with the finite element method, brings surface features into approximate alignment while minimizing deformation in regions without explicit matching criteria. The method was validated by application, to three simulated test cases and applied to characterize growth of the ferret cortex during folding. Cortical surfaces were created from MRI data acquired in vivo at 14 days, 21 days, and 28 days of life. Deformation gradient and Lagrangian strain tensors describe the kinematics of growth over this interval. These quantitative results illuminate the spatial, temporal, and directional patterns of growth during cortical folding. [ABSTRACT FROM AUTHOR]

During human brain development, the cerebral cortex undergoes substantial folding, leading to its characteristic highly convoluted form. Folding is necessary to accommodate the expansion of the cerebral cortex; abnormal cortical folding is linked to various neurological disorders, including schizophrenia, epilepsy, autism, and mental retardation. Although this process requires mechanical forces, the specific force-generating mechanisms that drive folding remain unclear~ The two most widely accepted hypotheses are as follows: (1) Folding is caused by differential growth of the cortex and (2) folding is caused by mechanical tension generated in axons. Direct evidence supporting either theory, however, is lacking. Here we show that axons are indeed under considerable tension in the developing ferret brain, but the patterns of tissue stress are not consistent with a causal role for axonal tension. In particular microdissection assays reveal that significant tension exists along axons aligned circumferentially in subcortical white matter tracts, as well as those aligned radially inside developing gyri (outward folds). Contrary to previous speculation, however axonal tension is not directed across developing gyri, suggesting that axon tension does not drive folding. On the other hand, using computational (finite element) models, we show that differential cortical growth acconipanied by remodeling of the subplate leads to outward folds and stress fields that are consistent with our microdissection experiments, supporting a mechanism involving differential growth. Local perturbations, such as temporal differences in the initiation of cortical growth, can ensure consistent folding patterns. This study shows that a combination of experimental and computational mechanics can be used to evaluate competing hypotheses of morphogenesis, and illuminate the biomechanics of cortical folding. [ABSTRACT FROM AUTHOR]

Mechanical forces play an important role during brain development. In the early embryo, the anterior end of the neural tube enlarges and differentiates into the major brain subdivisions, including three expanding vesicles (forebrain, midbrain, and hindbrain) separated by two constrictions. Once the anterior neuropore and the spinal neurocoel occlude, the brain tube undergoes further regional growth and expansion in response to increasing cerebrospinal fluid pressure. Although this is known to be a response to mechanical loads, the mechanical properties of the developing brain remain largely unknown. In this work, we measured regional opening angles (due to residual stress) and stiffness of the embryonic chick brain during Hamburger-Hamilton stages 11-13 (approximately 42-51 h incubation). Opening angles resulting from a radial cut on transverse brain slices were about 40-110 deg (depending on region and stage) and served as an indicator of circumferential residual stress. In addition, using a custom-made microindentation device and finite-element models, we determined regional indentation stiffness and material properties. The results indicate that the modulus is relatively independent of position and stage of development with the average shear modulus being about 220 Pa for stages 11-13 chick brains. Information on the regional material properties of the early embryonic brain will help illuminate the process of early brain morphogenesis. [ABSTRACT FROM AUTHOR]

During the initial phase of cardiac looping, known as c-looping, the heart bends and twists into a c-shaped tube with the convex outer curvature normally directed toward the right side of the embryo. Despite intensive study for more than 80 years, the biophysical mechanisms that drive and regulate looping remain poorly understood, although some investigators have speculated that differential cytoskeletal contraction supplies the driving force for c-looping. The purpose of this investigation was to test this hypothesis. To inhibit contraction, embryonic chick hearts at stages 10–12 (10–16 somites, 33–48 h) were exposed to the myosin inhibitors 2,3-butanedione monoxime (BDM), ML-7, Y-27632, and blebbistatin. Experiments were conducted in both whole embryo culture and, to focus on bending alone, isolated heart culture. Measurements of heart stiffness and phosphorylation of the myosin regulatory light chains showed that BDM, Y-27632, and blebbistatin significantly reduced myocardial contractility, while ML-7 had a lesser effect. None of these drugs significantly affected looping during the studied stages. These results suggest that active contraction is not required for normal c-looping of the embryonic chick heart between stages 10 and 12. [ABSTRACT FROM AUTHOR]

Cardiac looping is a vital morphogenetic process that transforms the initially straight heart tube into a curved tube normally directed toward the right side of the embryo. While recent work has brought major advances in our understanding of the genetic and molecular pathways involved in looping, the biophysical mechanisms that drive this process have remained poorly understood. This paper examines the role of biomechanical forces in cardiac rotation during the initial stages of looping, when the heart bends and rotates into a c-shaped tube (c-looping). Embryonic chick hearts were subjected to mechanical and chemical perturbations, and tissue stress and strain were studied using dissection and fluorescent labeling, respectively. The results suggest that (1) the heart contains little or no intrinsic ability to rotate, as external forces exerted by the splanchnopleure (SPL) and the omphalomesenteric veins (OVs) drive rotation; (2) unbalanced forces in the omphalomesenteric veins play a role in left–right looping directionality; and (3) in addition to ventral bending and rightward rotation, the heart tube also bends slightly toward the right. The results of this study may help investigators searching for the link between gene expression and the mechanical processes that drive looping. [Copyright &y& Elsevier]

Between 1979 and 1989, families enrolled in the Houston Family Study were prospectively monitored for influenza virus infections. Reinfection with the H3N2 subtype occurred in a num-ber of family members, and 6 pairs of isolates (interval between collection of first and second iso-late, 2--5 years) were available for molecular analysis. Changes in the hemagglutinin genes of pairs of viruses isolated from the same individuals were examined to determine the molecular basis for reinfection. The findings of this study indicate that reinfection of an individual by viruses of the same subtype may occur within a relatively short period of time when the paired strains have genetically distinct hemagglutinin genes in which amino acid changes are present in the defined antigenic sites. [ABSTRACT FROM AUTHOR]

Provides information on a study regarding the effects of respiratory viral infections on pulmonary function in infants with cystic fibrosis. Respiratory tract illness and viral infection; Baseline demographic measures and medical status; Immunization response to trivalent influenza vaccine.

Abstract. Group B streptococcal colonization of normal newborn infants increased from 22.5% within 20 hours of birth to 65.4% at the time of hospital discharge (P < .001). In contrast, colonization in mothers did not change significantly between the time of admission to labor and delivery, (27.7%) and the time of discharge (31.1%). Epidemiologic data suggested but did not prove that the mode of nosocomial transmission of group B streptococci among infants was cross colonization via personnel contact. [ABSTRACT FROM AUTHOR]

Looping is a crucial early phase during heart development, as the initially straight heart tube (HT) deforms into a curved tube to lay out the basic plan of the mature heart. This paper focuses on the first phase of looping, called c-looping, when the HT bends ventrally and twists dextrally (rightward) to create a c-shaped tube. Previous research has shown that bending is an intrinsic process, while dextral torsion is likely caused by external forces acting on the heart. However, the specific mechanisms that drive and regulate looping are not yet completely understood. Here, we present new experimental data and finite element models to help define these mechanisms for the torsional component of c-looping. First, with regions of growth and contraction specified according to experiments on chick embryos, a three-dimensional model exhibits morphogenetic deformation consistent with observations for normal looping. Next, the model is tested further using experiments in which looping is perturbed by removing structures that exert forces on the heart—a membrane (splanchnopleure (SPL)) that presses against the ventral surface of the heart and the left and right primitive atria. In all cases, the model predicts the correct qualitative behavior. Finally, a two-dimensional model of the HT cross section is used to study a feedback mechanism for stress-based regulation of looping. The model is tested using experiments in which the SPL is removed before, during, and after c-looping. In each simulation, the model predicts the correct response. Hence, these models provide new insight into the mechanical mechanisms that drive and regulate cardiac looping. [ABSTRACT FROM AUTHOR]

During morphogenesis, epithelia (cell sheets) undergo complex deformations as they stretch, bend, and twist to form the embryo. Often these changes in shape create multivalued surfaces that can be problematic for strain measurements. This paper presents a method for quantifying deformation of such surfaces. The method requires four-dimensional spatiotemporal coordinates of a finite number of surface markers, acquired using standard imaging techniques. From the coordinates of the markers, various deformation measures are computed as functions of time and space using straightforward matrix algebra. This method accommodates sparse randomly scattered marker arrays, with reasonable errors in marker locations. The accuracy of the method is examined for some sample problems with exact solutions. Then, the utility of the method is illustrated by using it to measure surface stretch ratios and shear in the looping heart and developing brain of the early chick embryo. In these examples, microspheres are tracked using optical coherence tomography. This technique provides a new tool that can be used in studies of the mechanics of morphogenesis. [ABSTRACT FROM AUTHOR]