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Biomedical subjects

R B Martin

Publications and source records attributed to R B Martin.

At least 37 records · Page 2Linked to original sources
PubMed2000

Does osteocyte formation cause the nonlinear refilling of osteons?

Marotti (Ital J Anat Embryol 1 01:25-79, 1996) described a theory of osteocyte differentiation from osteoblasts during bone formation. This theory postulates that, when a previously formed osteocyte is sufficiently covered by new bone and osteoid, it sends an inhibitory signal through its dendritic processes to the neighboring osteoblasts that reduces their individual apposition rates. The osteoblast most affected by this inhibition becomes buried by its neighbors, and becomes one of the next layer of osteocytes. By pursuing this concept, the present study develops a mathematical theory that predicts another observation about bone remodeling: the diminishment of the apposition rate during the refilling of basic multicellular units (BMUs). This decrease in apposition rate is different in osteonal and surface (e.g., trabecular) BMUs, and the theory shows that this result is consistent with the accrual of osteocyte inhibition throughout the refilling period, with the different ratios of bone volume to surface area in these two types of BMUs.

Bone Remodeling↗
PubMed2000

The trimmed-haplotype test for linkage disequilibrium.

Single-marker linkage-disequilibrium (LD) methods cannot fully describe disequilibrium in an entire chromosomal region surrounding a disease allele. With the advent of myriad tightly linked microsatellite markers, we have an opportunity to extend LD analysis from single markers to multiple-marker haplotypes. Haplotype analysis has increased statistical power to disclose the presence of a disease locus in situations where it correctly reflects the historical process involved. For maximum efficiency, evidence of LD ought to come not just from a single haplotype, which may well be rare, but in addition from many similar haplotypes that could have descended from the same ancestral founder but have been trimmed in succeeding generations. We present such an analysis, called the "trimmed-haplotype method." We focus on chromosomal regions that are small enough that disequilibrium in significant portions of them may have been preserved in some pedigrees and yet that contain enough markers to minimize coincidental occurrence of the haplotype in the absence of a disease allele: perhaps regions 1-2 cM in length. In general, we could have no idea what haplotype an ancestral founder carried generations ago, nor do we usually have a precise chromosomal location for the disease-susceptibility locus. Therefore, we must search through all possible haplotypes surrounding multiple locations. Since such repeated testing obliterates the sampling distribution of the test, we employ bootstrap methods to calculate significance levels. Trimmed-haplotype analysis is performed on family data in which genotypes have been assembled into haplotypes. It can be applied either to conventional parent-affected-offspring triads or to multiplex pedigrees. We present a method for summarizing the LD evidence, in any pedigree, that can be employed in trimmed-haplotype analysis as well as in other methods.

Alleles↗
PubMed1999

Elastic anisotropy and collagen orientation of osteonal bone are dependent on the mechanical strain distribution.

There is evidence that the collagen microarchitecture of bone is influenced by mechanical stresses or strains. We hypothesized that peak functional strains correlate with the elastic anisotropy and collagen orientation of bone tissue and that the bone anisotropy might be changed by altering the strain patterns in canine radii for 12 months. We tested these hypotheses in studies using nine adult foxhounds. The baseline group (n = 3) had three rosette strain gauges placed around the midshaft of the radius, and strain distributions were measured during walking. The osteotomy group (n = 3) had 2 cm of the ulna surgically removed, and the sham group (n = 3) received a sham osteotomy. The osteotomy and sham groups were allowed free movement in cages with runs for 12 months, after which strain distributions were measured on the radii during walking. Bone-tissue anisotropy and collagen architecture were measured in radii from which the in vivo longitudinal strain patterns had been measured. The collagen birefringence patterns were measured with use of a circularly polarized light technique, and the elastic anisotropy of the bone, mineral, and collagen matrix was evaluated with a novel acoustic microscopy technique. Peak longitudinal strains in the radius correlated with the normalized longitudinal structure index (a polarized light measure of collagen birefringence) and the tissue anisotropy ratio. The average anisotropy ratio was 1.28+/-0.01 in the posterior (compressive) cortex and 1.43+/-0.01 in the anterior (tensile) cortex (these values are significantly different at p < 0.0001). The ulnar osteotomy changed the strain pattern on the radius, causing increased tensile strains in the medial cortex by more than 5-fold that were associated with a significant increase in the anisotropy ratio in the bone tissue. The longitudinal structure index was strongly correlated (r = 0.62, p < 0.005) with the anisotropy ratio of demineralized bone but was not correlated with that of deproteinized bone; this indicates that it reflects collagen fibril orientation in the bone matrix. These results indicate that mechanical strains affect both collagen and mineral microarchitecture in bone tissue, i.e., tensile strains are associated with increased tissue anisotropy and compressive strains, with decreased anisotropy.

Animals↗
PubMed1999

The effects of testing methods on the flexural fatigue life of human cortical bone.

A flexural model of four-point bending fatigue that has been experimentally validated for human cortical bone under load control was used to determine how load and displacement control testing affects the fatigue behavior of human cortical bone in three-point and symmetric four-point bending. Under load control, it was predicted that three-point bending produced no significant differences in fatigue life when compared to four-point bending. However, three-point bending produced less stiffness loss with increasing cycles than four-point bending. In four-point bending, displacement control was predicted to produce about one and a half orders of magnitude greater fatigue life when compared to load control. This prediction agrees with experimental observations of equine cannon bone tested in load and displacement control (Gibson et al., 1998). Displacement controlled three-point bending was found to produce approximately a 25% greater fatigue life when compared to load control. The prediction of longer fatigue life under displacement control may have clinical relevance for the repair of damaged bone. The model can also be adapted to other geometric configurations, including modeling of whole long bones, and with appropriate fatigue data, other cortical bone types.

Bone and Bones↗
PubMed1999

The relationship between basic multicellular unit activation and origination in cancellous bone.

Activation frequency is often used as a measure of basic multicellular unit (BMU) activity in cancellous bone. However, activation frequency expresses the rate of BMU appearance in a histologic slide and not the rate of origination, which is a more physiologic indicator of remodeling activity and is necessary for the development of BMU-level bone remodeling simulations. Using identical assumptions to those for calculating the activation frequency, it is shown that the origination frequency in cancellous bone is equal to the activation frequency divided by the total distance traveled by the BMU and its width.

Bone Development↗
PubMed1998

A schizophrenia locus may be located in region 10p15-p11.

In our genomic scan of 265 Irish families with schizophrenia, we have thus far generated modest evidence for the presence of vulnerability genes in three chromosomal regions, i.e., 5q21-q31, 6p24-p22, and 8p22-p21. Outside of those regions, of all markers tested to date, D10S674 produced one of the highest pairwise heterogeneity lod (H-LOD) scores, 3.2 (P = 0.0004), when initially tested on a subset of 88 families. We then tested a total of 12 markers across a region of 32 centimorgans in region 10p15-p11 of all 265 families. The strongest evidence for linkage occurred assuming an intermediate phenotypic definition, and a recessive genetic model. The largest pairwise H-LOD score was found with marker D10S2443 (maximum 1.95, P = 0.005). Using multipoint H-LODs, we found a broad peak (maximum 1.91, P = 0.006) extending over the 11 centimorgans from marker D10S674 to marker D10S1426. Multipoint nonparametric linkage analysis produced a much broader peak, but with the maximum in the same location near D10S2443 (maximum z = 1.88, P = 0.03). Based on estimates from the multipoint analysis, this putative vulnerability locus appears to be segregating in 5-15% of the families studied, but this estimate should be viewed with caution. When evaluated in the context of our genome scan results, the evidence suggests the possibility of a fourth vulnerability locus for schizophrenia in these Irish families, in region 10p15-p11.

Chromosome Mapping↗
PubMed1998

The effect of voluntary eye movements on associations and mood.

The effects of eye movements induced by lights were compared to a non eye movement condition where subjects waited for a similar period of time. Subjects were first shown an emotional film which was interrupted just before its climax, and then exposed to 15 trials of 28-cycle eye movements or were exposed to the control waiting condition. After each trial they reported what they had thought about during the trial. Analysis of the themes and the depth of processing of these reports indicated that there was greater depth in the control than in the eye movement condition. There was little evidence of any effect on mood or emotional response, except that eye movements elicited greater hostile mood than the control condition.

Adolescent↗
PubMed1998

Parental genotype reconstruction: applications of haplotype relative risk to incomplete parental data.

Intended to resolve the problem of constructing a matched population-based control sample, haplotype relative risk techniques frequently suffer from loss of power for late-onset diseases due to unavailability of parental genotypes that are required to form parent-offspring pairs. However, much of this missing information can be reconstructed using the genotypes of the affected individual's siblings. For some cases, an estimate of the marker-allele frequencies for controls is needed. We have developed a technique based upon this idea and call it PGR (Parental Genotype Reconstruction). PGR represents a combination of the internal controls used by haplotype relative risk and controls based upon estimated allele frequencies. Although the latter is just what haplotype relative risk was designed to avoid, PGR has the potential to substantially boost power to detect linkage disequilibrium, for a relatively small increase in type I error. This performance is reasonably robust with respect to errors in the estimated allele frequencies, as we demonstrate by numerical simulation. A PGR software package has been written in FORTRAN and is available from Dr. Martin's web site at http://electro.psi.vcu.edu/rmartin/.

Alleles↗
PubMed1997

Surface remodeling of trabecular bone using a tissue level model.

We propose a two-dimensional mathematical model of trabecular bone remodeling that simulates the surface-based addition and removal of material in the actual physiological process. The model is based on a finite element representation of individual trabecular struts in which the material properties of the subtrabecular elements are constant. The remodeling stimulus is strain energy density, sensed and communicated through the osteocytic network as proposed by Mullender et al. We propose a modified osteocyte communication scheme that incorporates bone-lining cells and examines the implications of set point locations in one or the other of these two cell types. This model produces trabecular struts that align with its general loading direction. Placing the set point in the bone-lining cells rather than in the osteocytes makes the model more sensitive to changes in the other biological parameters. Introduction of a dead zone causes the model to reach a less oscillatory equilibrium in fewer iterations and produces better in-filling of trabecular strut intersections. The model gravitates to equilibrium states in which the average strain energy density is inversely proportional to the bone volume fraction to the 3.2 power.

Bone Remodeling↗
PubMed1997

Model of flexural fatigue damage accumulation for cortical bone.

Analytical models that predict modulus degradation in cortical bone subjected to uniaxial fatigue loading in tension and compression are presented. On the basis of experimental observations, damage was modeled as self-limiting for tension but not for compression. These mechanistic uniaxial damage models were then developed into a model for flexural fatigue of cortical bone based on laminated beam theory. The unknown coefficients in the uniaxial damage models were obtained by successfully fitting the resulting equations to uniaxial fatigue data from the literature on human cortical bone in tension and compression. Then, the predictions of the flexural model for the behavior of human cortical bone were compared with experimental results from a small but independent set of specimens tested at three different ranges of load in our laboratory. The behavior of the modulus degradation curves and the flexural fatigue lives of the specimens were in excellent agreement with the predictions of the model.

Bone and Bones↗
PubMed1997

Residual strength of equine bone is not reduced by intense fatigue loading: implications for stress fracture.

Fatigue or stress fractures are an important clinical problem in humans as well as racehorses. An important question in this context is, when a bone experiences fatigue damage during extreme use, how much is it weakened compared to its original state? Since there are very limited data on this question and stress fractures are common in racehorses, we sought to determine the effect of fatigue loading on the monotonic strength of equine cortical bone. Beams were machined from the dorsal, medial and lateral cortices of the third metacarpal bones of six thoroughbred racehorses. Beams from left and right bones were assigned to control and fatigue groups, respectively (N = 18 each). The fatigue group was cyclically loaded in three-point bending at 2 Hz for 100,000 cycles at 0-5000 microstrain while submerged in saline at 37 degrees C. These beams, as well as those in the control group, were then monotonically loaded to failure in three-point bending. The monotonic load-deflection curves were analyzed for differences using three-factor (fatigue loading, anatomic region, and horse) analysis of variance. The mean failure load was 3% less in the fatigue group, but this reduction was only marginally significant. Neither elastic modulus nor yield strength was significantly affected by the fatigue loading. The principal effects of fatigue loading were on post-yield behavior (yield being based on a 0.02% offset criterion). The work done and the load increase between yield and failure were both significantly reduced. All the variables except post-yield deflection were significantly affected by anatomic region. In summary, loading equivalent to a lifetime of racing does not significantly weaken equine cortical bone ex vivo. The clinical implication of this may be that the biological repair of fatigue damage can actually contribute to stress fracture if pressed too far.

Analysis of Variance↗
PubMed1997

Artifactual nonlinearity due to wear grooves and friction in four-point bending experiments of cortical bone.

Experiments and analyses were performed to determine the cause of a nonlinear force-deflection response observed in four-point flexural fatigue of beams of cortical bone machined from the mid-diaphysis of the equine third metacarpus. Observable grooves which formed on the beam surface at supports and load noses were found to be the primary cause of the nonlinearity. An additional geometric nonlinearity at large deflections revealed by finite element modeling may be minimized by using the smallest diameter supports and load noses recommended in ASTM 790. However, frictional constraint of the beams at the load noses and supports can occur at low load levels and should be avoided by using roller-bearing supports and load noses, or some equivalent method.

Animals↗
PubMed1997

Clearance of young parasite forms following treatment of falciparum malaria in humans: comparison of three simple mathematical models.

To characterize post-treatment clearance of young forms of Plasmodium falciparum from the blood, three differential equation models, a linear decline, a linear then logarithmic decline, and the Michaelis-Menten (MM) kinetic equation, were fitted to log-transformed serial parasite counts from 30 semi-immune patients with synchronous parasitaemias allocated one of six antimalarial drug regimens. The first two equations were solved analytically. The MM equation was solved numerically using a fifth-order Runge-Kutta method. For each equation, parasite clearance was assumed stochastic and log-transformed parasite counts were assumed to be normally distributed at each time-point. Comparisons between models were by Minimum Akaike Information Criterion Estimate. A constrained MM equation fitted the data at least as well as the other two models in 5 of 6 drug groups and also when pooled data were analysed, providing a single index which could be used in drug efficacy studies in similar situations or as part of more complex models that encompass asynchronous, complicated infections.

Adolescent↗
PubMed1997

Bone microdamage and skeletal fragility in osteoporotic and stress fractures.

The accumulation of bone microdamage has been proposed as one factor that contributes to increased skeletal fragility with age and that may increase the risk for fracture in older women. This paper reviews the current status and understanding of microdamage physiology and its importance to skeletal fragility. Several questions are addressed: Does microdamage exist in vivo in bone? If it does, does it impair bone quality? Does microdamage accumulate with age, and is the accumulation of damage with age sufficient to cause a fracture? The nature of the damage repair mechanism is reviewed, and it is proposed that osteoporotic fracture may be a consequence of a positive feedback between damage accumulation and the increased remodeling space associated with repair.

Aged↗
PubMed1996

In vitro fatigue behavior of the equine third metacarpus: remodeling and microcrack damage analysis.

We studied remodeling and microcrack damage in specimens of Thoroughbred racehorse third metacarpal bone that had been subjected to monotonic or fatigue failure. We asked three questions. What effects does mechanical loading have on histologically observable microcrack damage? Are there regional variations in remodeling of the equine cannon bone, and do these variations correlate with mechanical properties? To what extent are remodeling and microcrack damage age-dependent? Machined beams from the medial, lateral, and dorsal cortices were loaded to fracture in four-point bending monotonically, or cyclically at a load initially producing 10,000 microstrain. Specimens were then bulk-stained in basic fuchsin, and cross sections were prepared from loaded and load-free regions of each beam. Current and past remodeling, porosity, and microcrack density and length were determined histomorphometrically. Strained and unstained microcracks were observed. Unstained cracks were associated with regions of woven bone and appeared to be damaged Sharpey's fibers. Their density (approximately 30/mm2) did not increase after failure, but their length (approximately 25 microns) did, especially near the surfaces of the beam. Stained cracks were wider and longer than unstained cracks and were located primarily near the fracture surface and on the compressed side of the beam. Stained cracks after failure were more numerous in those beams having a higher elastic modulus, a shorter fatigue life, or greater deformation at failure. The extent of past remodeling increased with age, especially in the medial region; the rate of current remodeling generally declined with age, but not in the dorsal region, which has the best fatigue resistance. In summary, while remodeling varied with age and region, its effects on bone structure did not appear to influence microdamage. Basic fuchsin staining of damage in fractured equine bone was independent of age and region and confined to near the fracture surfaces. Distributed microdamage consisted only of what appeared to be subtle disruptions of Sharpey's fibers.

Age Distribution↗
PubMed1996

Noninvasive determination of bone mechanical properties using vibration response: a refined model and validation in vivo.

Accurate non-invasive mechanical measurement of long bones is made difficult by the masking effect of surrounding soft tissues. Mechanical response tissue analysis (MRTA) offers a method for separating the effects of the soft tissue and bone; however, a direct validation has been lacking. A theoretical analysis of wave propagation through the compressed tissue revealed a strong mass effect dependent on the relative accelerations of the probe and bone. The previous mathematical model of the bone and overlying tissue system was reconfigured to incorporate the theoretical finding. This newer model (six-parameter) was used to interpret results using MRTA to determine bone cross-sectional bending stiffness, EIMRTA. The relationship between EIMRTA and theoretical EI values for padded aluminum rods was R2 = 0.999. A biological validation followed using monkey tibias. Each bone was tested in vivo with the MRTA instrument. Postmortem, the same tibias were excised and tested to failure in three-point bending to determine EI3-PT and maximum load. Diaphyseal bone mineral density (BMD) measurements were also made. The relationship between EI3-PT and in vivo EIMRTA using the six-parameter model is strong (R2 = 0.947) and better than that using the older model (R2 = 0.645). EIMRTA and BMD are also highly correlated (R2 = 0.853). MRTA measurements in vivo and BMD ex vivo are both good predictors of scaled maximum strength (R2 = 0.915 and R2 = 0.894, respectively). This is the first biological validation of a non-invasive mechanical measurement of bone by comparison to actual values. The MRTA technique has potential clinical value for assessing long-bone mechanical properties.

Acceleration↗
PubMed1996

Calcium buffering is required to maintain bone stiffness in saline solution.

This work determined whether mineral dissolution due to prolonged testing or storage of bone specimens in normal saline would alter their elastic modulus. In one experiment, small pieces of equine third metacarpal bone were soaked in normal saline supplemented with varying amounts of CaCl2. Changing Ca ion concentrations in the bath were monitored and the equilibrium concentration was determined. In a second experiment, the elastic moduli of twenty 4 x 10 x 100 mm equine third metacarpal beams were determined non-destructively in four-point bending. Half the beams were then soaked for 10 days in normal saline, and the other half in saline buffered to the bone mineral equilibrium point with Ca ions. Modulus measurements were repeated at 6 and 10 days. The equilibrium Ca ion concentration for bone specimens was found to be 57.5 mg l-1. The modulus of bone specimens soaked in normal saline significantly diminished 2.4%, whereas the modulus of those soaked in calcium-buffered saline did not change significantly.

Animals↗