Biomedical subjects

Benedikt Hallgrímsson

Publications and source records attributed to Benedikt Hallgrímsson.

17 recordsLinked to original sources

PubMed2007

Age-dependent change in the 3D structure of cortical porosity at the human femoral midshaft.

Microstructural change associated with cortical bone remodeling has been extensively explored with 2D techniques. However, relatively little is known regarding the 3D dynamic microstructure of cortical bone. Therefore, we employed micro-CT imaging to investigate 3D remodeling-related change in the structure of cortical bone porosity across the human lifespan. Anterior femoral midshaft specimens (n=51 male, 28 female) spanning 18 to 92 years of age were scanned with 7 mum nominal isotropic resolution. Canal volume fraction (Ca.V/TV), mean diameter (Ca.Dm), mean separation (Ca.Sp), degree of anisotropy (DA), connectivity density (Ca.ConnD), and number (Ca.N) were calculated for subperiosteal cylindrical regions of interest. Ca.N was calculated in 2D (Ca.N(2D)) and 3D (Ca.N(3D)). Regression was used to examine the relation between the structural parameters and age. Additionally, the impact of sex, height, and weight were investigated collectively (MANCOVA) and individually (ANCOVA). For all analyses, Ca.V/TV and Ca.Dm were inverted (Ca.V/TV(-1), Ca.Dm(-1)) to establish normality and linear relations with age. Ca.N values (2D and 3D) were non-linearly (quadratic) related to age, increasing until the 6th decade then decreasing. This relation was only significant for the pooled sexes Ca.N(3D) values (p=0.012). Ca.ConnD was positively related to age (p<0.05), while all remaining 3D parameters, except DA for males (p=0.070), were negatively related (p<0.05). In all cases, the relation with age was strongest for females. MANCOVA revealed that age was the only significant (p<0.001) covariate overall. Univariate ANCOVA indicated significant differences between the sexes for Ca.V/TV(-1) and Ca.Dm(-1) (p=0.018 and 0.010, respectively). Relative to males, females had lower values for these parameters, translating into larger mean canal diameter and overall porosity. Body weight had a significant (p=0.043) positive relation with Ca.Dm(-1), indicating lower weight was also associated with increased mean canal diameter. Therefore, while age was the most important factor, sex and body size were found to play a role in parameters related to canal size and the overall level of porosity. This study is unique in that changes in cortical bone microstructure were examined across the adult human lifespan in three rather than two dimensions.

Adolescent↗

PubMed2006

Three-dimensional microcomputed tomography imaging of basic multicellular unit-related resorption spaces in human cortical bone.

This study employed microcomputed tomography (micro-CT) as a novel means for visualizing the morphology and quantifying the range (length) of basic multicellular unit (BMU)-related resorption spaces in human cortical bone. We tested the hypotheses that the density and range of spaces vary with age and sex. The sample included 82 human (18-92 years) anterior femoral midshaft samples. The morphology of the spaces (n = 99) was varied, including unidirectional, bidirectional, branched, and even highly clustered forms. The density of resorption spaces was negatively correlated with age for the combined sexes and females, with Spearman's rho values of -0.355 (P < 0.001) and -0.522 (P = 0.002), respectively. The density of spaces did not differ significantly between the sexes (P = 0.735). Mean range +/- SD for the combined sexes, females, and males was 2,706 +/- 1,177, 2,681 +/- 1,247, and 2,718 +/- 1,150 microm, respectively. Numerical simulation of the effect of the 7,000 microm scan field of view suggested that the actual mean range of the spaces for the pooled sample was actually on the order of 3,770 microm. Range did not correlate significantly with age for the combined sexes (P = 0.587) or females (P = 0.345) and males (P = 0.896) considered separately and was not significantly different (P = 0.883) between the sexes. These results suggest that the range of BMUs is not affected by age. The age-dependent decrease in resorption space density for the females and pooled sexes was most likely a consequence of cortical rarefaction, leading to difficulty detecting resorption spaces with micro-CT, rather than a decrease in overall remodeling activity.

Adolescent↗

PubMed2006

Canalization and developmental stability in the Brachyrrhine mouse.

The semi-dominant Br mutation affects presphenoid growth, producing the facial retrognathism and globular neurocranial vault that characterize heterozygotes. We analysed the impact of this mutation on skull shape, comparing heterozygotes to wildtype mice, to determine if the effects are skull-wide or confined to the sphenoid region targeted by the mutation. In addition, we examined patterns of variability of shape for the skull as a whole and for three regions (basicranium, face and neurocranium). We found that the Br mice differed significantly from wildtype mice in skull shape in all three regions as well as in the shape of the skull as a whole. However, the significant increases in variance and fluctuating asymmetry were found only in the basicranium of mutant mice. These results suggest that the mutation has a significant effect on the underlying developmental architecture of the skull, which produces an increase in phenotypic variability that is localized to the anatomical region in which the mean phenotype is most dramatically affected. These results suggest that the same developmental mechanisms that produce the change in phenotypic mean also produce the change in variance.

Animals↗

PubMed2005

Myf5-/- :MyoD-/- amyogenic fetuses reveal the importance of early contraction and static loading by striated muscle in mouse skeletogenesis.

The mechanical loading of striated muscle is thought to play an important role in shaping bones and joints. Here, we examine skeletogenesis in late embryogenesis (embryonic day 18.5) in Myf5-/-:MyoD-/- fetuses completely lacking striated muscle. The phenotype includes enlarged and fused cervical vertebrae and postural anomalies, some viscerocranial anomalies, long bone truncation and fusion, absent deltoid tuberosity of the humerus, scapular and clavicular hypoplasia, cleft palate, and cleft sternum. In contrast, neurocranial bone development was essentially normal. While the magnitude of individual effects varied throughout the skeletal system, the results are consistent with skeletal development depending on functional muscles. Novel abnormalities in the amyogenic fetuses relative to less severely paralyzed phenotypes extend our understanding of skeletogenic dependence on embryonic muscle contraction and static loading.

Animals↗

PubMed2005

Why are rare traits unilaterally expressed?: trait frequency and unilateral expression for cranial nonmetric traits in humans.

Based on an analysis of nonmetric trait databases from several large skeletal series in Northern Europe and South America, representing 27 bilateral traits, we report a predictable relationship between the frequency of nonmetric traits and the probability that they are expressed bilaterally. In a wider sampling of traits and populations, this study thus confirms the findings of an earlier study by Ossenberg ([1981] Am. J. Phys. Anthropol. 54:471-479), which reported the same relationship for two mandibular traits. This trend was previously explained by extending the multifactorial threshold model for discontinuous traits to incorporate either separate thresholds for unilateral or bilateral expression, or by a fuzzy threshold in which the probability of bilateral expression increases away from the median threshold value. We show that the trend is produced under the standard multifactorial threshold model for discontinuous traits simply if the within-individual or developmental instability variance remains relatively constant across the range of liability. Under this assumption, the number of individuals in which one side but not the other is pushed over the threshold for trait formation will be a larger proportion of the number of individuals expressing the trait when the trait frequency is low. As trait frequency increases, the significance of within-individual variance as a determinant of trait formation decreases relative to the genetic and among-individual environmental variance. These results have implications for interpreting nonmetric trait data as well as for understanding the prevalence of unilateral vs. bilateral expression of a wide variety of discontinuous traits, including dysmorphologies in humans.

Anthropology, Physical↗

PubMed2005

Degenerative knee joint disease in mice lacking 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (Papss2) activity: a putative model of human PAPSS2 deficiency-associated arthrosis.

OBJECTIVE: Murine brachymorphism (bm) results from an autosomal recessive mutation of the Papss2 gene that encodes 3'-phosphoadenosine 5'-phosphosulfate synthetase 2, one of the principal enzymes required for the sulfation of extracellular matrix molecules in cartilage and other tissues. A spondyloepimetaphyseal dysplasia has been identified in Pakistani kindred having a mutation of PAPSS2. In addition to skeletal malformations that include short stature evident at birth due to limb shortening, brachydactyly, and kyphoscoliosis, affected individuals demonstrate premature onset degenerative joint disease. We investigated whether loss of Papss2 activity would similarly lead to degenerative joint disease in mice. METHODS: Mice carrying the bm mutation on a C57BL/6 background were obtained from the Jackson Laboratory. Limbs were analyzed by micro-computed tomography (microCT) and histology. RESULTS: At 12 months of age both male and female bm mice exhibited severe degenerative knee joint disease, with cartilage damage being primarily evident in the patello-femoral and medial compartments. Control 12-14-month-old C57BL/6 mice, in contrast, only occasionally demonstrated minimal cartilage damage. muCT imaging of bm limbs revealed shortened diaphyses associated with flared metaphyses in the proximal elements of both fore and hind limbs. Additionally, the bm hind limbs demonstrated extensive structural alterations, characterized by distortion of the patello-femoral groove, and prominent bowing of both tibia and fibula. CONCLUSIONS: The bm mutant, which develops severe articular cartilage lesions of the knee joint by approximately 12 months of age, represents a novel example of murine degenerative joint disease, possibly representing a model of human PAPSS2 deficiency-associated arthrosis.

Animals↗

PubMed2005

The relationship between fluctuating asymmetry and environmental variance in rhesus macaque skulls.

This study measures the correlation between within- and among-individual variance to gain a greater understanding of the relationship of the underlying mechanisms governing developmental stability and canalization. Twenty-six landmarks were digitized in three dimensions from the crania of 228 adult macaques from Cayo Santiago. The phenotypic variance between individuals was measured and divided into its genetic and environmental components using matriline information. Within-individual variance was measured as the fluctuating asymmetry between bilateral landmarks. We found positive and significant correlations between the phenotypic, environmental, and fluctuating asymmetry variances for interlandmark distances. We also found low but significant correspondences between the covariation structures of the three variability components using both Procrustes and interlandmark distance data. Therefore, we find that in macaque skulls traits that exhibit greater levels of asymmetry deviations also exhibit greater levels of environmental variance, and that the covariances of absolute symmetry deviations partly correspond to covariances of mean deviations at the individual level. These results suggest that the underlying processes that determine canalization and developmental stability are at least partly overlapping. However, the low correlations reported here are also evidence for a degree of independence between these variability components.

Analysis of Variance↗

PubMed2005

Serial homology and the evolution of mammalian limb covariation structure.

The tetrapod forelimb and hindlimb are serially homologous structures that share a broad range of developmental pathways responsible for their patterning and outgrowth. Covariation between limbs, which can introduce constraints on the production of variation, is related to the duplication of these developmental factors. Despite this constraint, there is remarkable diversity in limb morphology, with a variety of functional relationships between and within forelimb and hindlimb elements. Here we assess a hierarchical model of limb covariation structure based on shared developmental factors. We also test whether selection for morphologically divergent forelimbs or hindlimbs is associated with reduced covariation between limbs. Our sample includes primates, murines, a carnivoran, and a chiropteran that exhibit varying degrees of forelimb and hindlimb specialization, limb size divergence, and/or phylogenetic relatedness. We analyze the pattern and significance of between-limb morphological covariation with linear distance data collected using standard morphometric techniques and analyzed by matrix correlations, eigenanalysis, and partial correlations. Results support a common limb covariation structure across these taxa and reduced covariation between limbs in nonquadruped species. This result indicates that diversity in limb morphology has evolved without signficant modifications to a common covariation structure but that the higher degree of functional limb divergence in bats and, to some extent, gibbons is associated with weaker integration between limbs. This result supports the hypothesis that limb divergence, particularly selection for increased functional specialization, involves the reduction of developmental factors common to both limbs, thereby reducing covariation.

Animals↗

PubMed2004

Craniofacial variability and modularity in macaques and mice.

Evolutionary developmental biology of primates will be driven largely by the developmental biology of the house mouse. Inferences from how known developmental perturbations produce phenotypic effects in model organisms, such as mice, to how the same perturbations would affect craniofacial form in primates must be informed by comparisons of phenotypic variation and variability in mice and the primate species of interest. We use morphometric methods to compare patterns of cranial variability in homologous datasets obtained for two strains of laboratory mice and rhesus macaques. C57BL/6J represents a common genetic background for transgenic models. A/WySnJ mice exhibit altered facial morphology which results from reduction in the growth of the maxillary process during formation of the face. This is relevant to evolutionary changes in facial prognathism in nonhuman primate and human evolution. Rhesus macaques represent a nonhuman primate about which a great deal of phenotypic and genetic information is available. We find significant similarities in covariation patterns between the C57BL/6J mice and macaques. Among-trait variation in genetic and phenotypic variances are fairly concordant among the three groups, but among-trait variation in developmental stability is not. Finally, analysis of modularity based on phenotypic and genetic correlations did not reveal a consistent pattern in the three groups. We discuss the implications of these results for the study of evolutionary developmental biology of primates and outline a research strategy for integrating mouse genomics and developmental biology into this emerging field.

Animals↗

PubMed2004

Composition of the founding population of Iceland: biological distance and morphological variation in early historic Atlantic Europe.

We examined the composition of the founding population of Iceland through the study of morphological traits in skeletons from Iceland, Ireland, Norway, and Greenland. This is the first study to address this issue from the Settlement Period of Iceland and contemporary samples from Ireland. We pose the following questions: 1) Was the founding population of Iceland of mixed or homogeneous origin? 2) Is there evidence for a significant Irish cohort in the founding population, as suggested in medieval Icelandic literature? Analysis of biodistance revealed that both Settlement Age and later samples from Iceland showed a greater degree of phenetic similarity to contemporary Viking Age Norwegians than to samples obtained from early medieval Ireland. Analysis of among-individual morphological variation showed that the Settlement Age population of Iceland did not exhibit an increase in variation in comparison to other populations in the sample, suggesting a relatively homogenous origin. However, estimation of admixture between the Irish and Norwegian populations indicated that 66% of the Icelandic settlers were of Norwegian origin. Comparison of the Icelandic samples to hybrid samples produced by resampling the Viking Age Norwegian and early medieval Irish samples revealed that the Icelandic samples are much closer to the Norwegian samples than expected, based on a 66:34 mixture of Norwegian and Irish settlers. We conclude that the Settlement Age population of Iceland was predominantly (60-90%) of Norwegian origin. Although this population was relatively homogenous, our results do not preclude significant contributions from Ireland as well as other sources not represented in our analysis.

Bone and Bones↗

PubMed2004

Craniofacial variability and morphological integration in mice susceptible to cleft lip and palate.

A/WySnJ mice are an inbred strain that develops cleft lip with or without cleft palate (CL/P) with a frequency of 25-30% and a predominantly unilateral expression pattern. As in humans, the pattern of incomplete penetrance, and variable and frequent unilateral expression suggests a role for altered regulation of variability (developmental stability, canalization and developmental integration) during growth. We compared both mean and variability parameters for craniofacial shape and size among A/WySnJ mice, a strain that does not develop CL/P (C57BL/6J) and their F1 cross. We show that adult A/WySnJ mice that do not express cleft lip exhibit decreased morphological integration of the cranium and that the co-ordination of overall shape and size variation is disrupted compared with both C57BL/6J mice and the F1 cross. The decrease in integration is most pronounced in the palate and face. The absence of this pattern in the F1 cross suggests that it is determined by recessive genetic factors. By contrast, the shape differences between the strains, which are thought to predispose A/WySnJ mice to CL/P, show a range of dominance which suggests a polygenic basis. We suggest that decreased integration of craniofacial growth may be an aetiological factor for CL/P in A/WySnJ mice.

Animals↗

PubMed2004

Stabilization and mobility of the head and trunk in wild monkeys during terrestrial and flat-surface walks and gallops.

This study investigated the patterns of rotational mobility (> or =20 degrees ) and stability (< or =20 degrees ) of the head and trunk in wild Indian monkeys during natural locomotion on the ground and on the flat-topped surfaces of walls. Adult hanuman langurs (Semnopithecus entellus) and bonnet macaques (Macaca radiata) of either gender were cine filmed in lateral view. Whole-body horizontal linear displacement, head and trunk pitch displacement relative to space (earth horizontal), and vertical head displacement were measured from the cine films. Head-to-trunk pitch angle was calculated from the head-to-space and trunk-to-space measurements. Locomotor velocities, cycle durations, angular segmental velocities, mean segmental positions and mean peak frequencies of vertical and angular head displacements were then calculated from the displacement data. Yaw rotations were observed qualitatively. During quadrupedal walks by both species, the head was free to rotate in the pitch and yaw planes on a stabilized trunk. By contrast, during quadrupedal gallops by both species, the trunk pitched on a stabilized head. During both gaits in both species, head and trunk pitch rotations were symmetrical about comparable mean positions in both gaits, with mean head position aligning the horizontal semicircular canals near earth horizontal. Head pitch direction countered head vertical displacement direction to varying degrees during walks and only intermittently during gallops, providing evidence that correctional head pitch rotations are not essential for gaze stabilization. Head-to-space pitch velocities were below 350 deg. s(-1), the threshold above which, at least among humans, the vestibulo-ocular reflex (VOR) becomes saturated. Mean peak frequencies of vertical translations and pitch rotations of the head ranged from 1 Hz to 2 Hz, a lower frequency range than that in which inertia is predicted to be the major stabilizer of the head in these species. Some variables, which were common to both walks and gallops in both species, are likely to reflect constraints in sensorimotor control. Other variables, which differed between the two gaits in both species, are likely to reflect kinematic differences, whereas variables that differed between the two species are attributed primarily to morphological and behavioural differences. It is concluded that either the head or the trunk can provide the nervous system with a reference frame for spatial orientation and that the segment providing that reference can change, depending upon the kinematic characteristics of the chosen gait.

Animals↗

PubMed2003

Embryological origins of developmental stability: size, shape and fluctuating asymmetry in prenatal random bred mice.

Ontogenetic patterns of fluctuating asymmetry (FA) can be used to test models for the mechanisms underlying stability during embryonic development (developmental stability). In this study, we ask whether developmental processes initially show high levels of instability that are subsequently dampened through active compensatory mechanisms or passive properties of developmental systems or whether the effects of instability accumulate during embryonic development causing random drift away from an earlier stable state. Previous work on this question has dealt with postnatal skeletal growth and thus been unable to effectively distinguish developmental instability from the effects of mechanically mediated variation in bone modeling and remodeling. Here, we report that FA variances of limb skeletal elements in CD1 mice decrease with gestational age from day 14 to birth (day 20.5). Thus, in mouse limbs, skeletal development is characterized by a high level of developmental instability initially that is reduced during subsequent prenatal development. These results are consistent with the existence of active mechanisms that compensate for the effects of minor perturbations or deviations during development. However, they are also consistent with Soule's model of allomeric variation in which the variance of structures is reduced as the number of independent developmental events that produce them increases. This study illustrates that predictions based on morphometric analyses can yield insights into general properties of developmental systems in cases where specific developmental mechanisms are not yet known.

Animals↗

PubMed2003

Imaging skeletal pathology in mutant mice by microcomputed tomography.

OBJECTIVE: We describe the utility of microcomputed tomography ( micro CT) for imaging skeletal abnormalities in rodent model systems. For the purpose of illustration, the progressive ankylosis (ank) mutant was selected. ank mice develop prominent articular and periarticular calcifications at multiple anatomical sites, including paws, elbows, knees, and vertebrae. METHODS: Forelimbs, hindlimbs, and proximal tail vertebrae of 4-month-old female ank/ank mice were scanned at 15 micro m resolution using a SkyScan 1072 micro CT instrument and images were generated using Analyze 4.0 software. RESULTS: This technique was able to show, in 3-dimensional images, the abnormal calcification of ank/ank mice, which was readily observed within joint surfaces, on periosteal surfaces, sesamoid bones, menisci, and joint capsules, as well as other periarticular ligamentous structures. CONCLUSION: As illustrated by the example of the progressive ankylosis mutant, micro CT represents a powerful emerging tool for identifying and monitoring the progression of developmental or acquired skeletal abnormalities within rodent models.

Animals↗

PubMed2002

Canalization, developmental stability, and morphological integration in primate limbs.

Canalization and developmental stability refer to the tendency of developmental processes to follow particular trajectories, despite external or internal perturbation. Canalization is the tendency for development of a specific genotype to follow the same trajectory under different conditions (different environments or different genetic backgrounds), while developmental stability is the tendency for the development of a specific genotype to follow the same trajectory under the same conditions. Morphological integration refers to the tendency for structures to show correlated variation because they develop in response to shared developmental processes or function in concert with other structures. All three phenomena are emergent properties of developmental systems that can affect the interaction of development and evolution. In this paper, we review the topics of canalization, developmental stability, and morphological integration and their relevance to primate and human evolution. We then test three developmentally motivated hypotheses about the patterning of variability components in the mammalian limb. We find that environmental variances and fluctuating asymmetries (FA) increase distally along the limb in adult macaques but not in fetal mice. We infer that the greater variability of more distal segments in macaques is due to postnatal mechanical effects. We also find that heritability and FA are significantly correlated when different limb measurements are compared in fetal mice. This supports the idea that the mechanisms underlying canalization and developmental stability are related. Finally, we report that the covariation structure of fore- and hindlimb skeletal elements shows evidence for morphological integration between serially homologous structures between the limbs. This is evidence for the existence of developmental modules that link structures between the limbs. Such modules would produce covariation that would need to be overcome by selection for divergence in hind- and forelimb morphology.

Anatomy, Comparative↗

PubMedDate not supplied

Effects of developmental and functional interactions on mouse cranial variability through late ontogeny.

The mammalian skull performs a variety of functions and its growth and development mirrors this complexity. Cranial growth and development have been actively studied for many years. Despite this interest, the variation in the patterns and processes of skull growth has attracted little attention. An important and unanswered question is the extent to which patterns of cranial covariation and variation are dynamically reworked throughout postnatal growth. To address this question, we examine patterns of variability in random-bred mouse skulls aged 35, 90, and 150 days. Using a battery of both Procrustes coordinate and Euclidean distance-based methods, we measure mean shape, canalization, developmental stability, and morphological integration in these skulls. We predict that the patterns of variability are dynamic, particularly between the youngest and the two oldest age groups due to the influence of functional effects such as postweaning mastication. We also hypothesize that patterns of variability are structured by the same functional and developmental factors that have been shown to influence cranial growth in primates. Our results indicate that contrary to our predictions, patterns of canalization, developmental stability, and morphological integration are stabilized before 35 days. The mean shape, however, changed significantly with growth. We found that only the facial region showed significant integration as predicted by the functional matrix model used in other studies of integration. These results indicate that phenotypic integration in these mice does not closely match those found for primate species, suggesting that comparisons between species should be made with care.

Age Factors↗

PubMedDate not supplied

The brachymorph mouse and the developmental-genetic basis for canalization and morphological integration.

Although it is well known that many mutations influence phenotypic variability as well as the mean, the underlying mechanisms for variability effects are very poorly understood. The brachymorph (bm) phenotype results from an autosomal recessive mutation in the phosphoadenosine-phosphosulfate synthetase 2 gene (Papps2). A major cranial manifestation is a dramatic reduction in the growth of the chondrocranium which results from undersulfation of glycosaminoglycans (GAGs) in the cartilage matrix. We found that this reduction in the growth of the chondrocranium is associated with an altered pattern of craniofacial shape variation, a significant increase in phenotypic variance and a dramatic increase in morphological integration for craniofacial shape. Both effects are largest in the basicranium. The altered variation pattern indicates that the mutation produces developmental influences on shape that are not present in the wildtype. As the mutation dramatically reduces sulfation of GAGs, we infer that this influence is variation among individuals in the degree of sulfation, or variable expressivity of the mutation. This variation may be because of genetic variation at other loci that influence sulfation, environmental effects, or intrinsic effects. We infer that chondrocranial development exhibits greater sensitivity to variation in the sulfation of chondroitin sulfate when the degree of sulfation is low. At normal levels, sulfation probably contributes minimally to phenotypic variation. This case illustrates canalization in a particular developmental-genetic context.

Anatomy, Comparative↗