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Biomedical subjects

S C Miller

Publications and source records attributed to S C Miller.

At least 19 recordsLinked to original sources
PubMed2006

Adaptations in cortical and trabecular bone in response to mechanical loading with and without weight bearing.

Exercise that imparts rapid, high-magnitude mechanical loading is considered to be advantageous to bone health. Previous rodent studies have suggested that swimming may also be beneficial to bone. We investigated the differential effects of exercise with and without weight bearing on cortical and trabecular bone. Forty female Sprague-Dawley rats (120 days) were weight-stratified and randomized into four groups: swim control (Cs, n = 10), swim (S, n = 10), treadmill control (Ct, n = 10), and treadmill (T, n = 10). Treadmill speed was adjusted to match the average limb loading frequency used for swimming, and all training progressed to 1 hour/day, 5 days/week, for 12 weeks. Femurs and humeri were assessed for cortical morphometry by peripheral quantitative computed tomography, areal bone mineral density (BMD) by peripheral dual-energy X-ray absorptiometry, mineral content by ashing, strength by three-point bending, and trabecular volume (BV/TV) by micro-computed tomography. Swimming was associated with increases in cortical thickness and BMD in the humerus midshaft and trabecular BV/TV in the distal femur and proximal humerus compared with age-matched controls. Compared to swimming, treadmill training was associated with increases in percent ash of the femur and humerus and Young's modulus of the femur. Swimming appears to engender novel bone strains and osteogenic adaptations in the humerus and femur, which are different from those induced by normal cage activity. In summary, our findings suggest that when limb loading frequency is matched, swimming may afford greater benefits to cortical and trabecular bone than uphill treadmill work in rats.

Absorptiometry, Photon↗
PubMed2006

Modifying effects of health status, physiological, and dosimetric factors on extrapulmonary organ distribution and excretion of inhaled plutonium in workers at the Mayak Production Association.

This paper summarizes the systemic organ distribution of plutonium in workers exposed by chronic inhalation at the Mayak Production Association (MPA). Using results of radiochemical measurements in soft tissue and bone samples collected at autopsy of 853 autopsy cases, this paper provides data on the effects of various chronic diseases and malignant tumors as well as exposure time, age, sex, and body burden on systemic retention of plutonium in 22 extrapulmonary organs and on the urinary excretion rate of the nuclide. Some aspects of this work have been reported already. The results of present autopsy studies showed that liver pathology accompanied by strong fatty dystrophy of hepatocytes results in a significant relative decrease in the fraction of systemic plutonium in the liver and contravariant increase in the skeletal fraction. The average fractions of systemic plutonium in the liver and the skeleton of those MPA workers were 15% and 75%, respectively, in comparison with 47% and 45% in healthy individuals. Some of the plutonium also redistributed from the liver via blood to other systemic soft tissues. Plutonium not redistributed was excreted with urine. The results of multivariate regression analysis indicated some time-related and sex-related changes not connected with pathology for the liver and the skeleton retention fractions and excretion rate of plutonium. The current ICRP biokinetic models do not account for the influence of different pathological processes in the body on plutonium distribution in systemic organs and urinary excretion. This could have significant consequences for dosimetry calculations and risk estimations.

Administration, Inhalation↗
PubMed2006

Americium in the beagle dog: biokinetic and dosimetric model.

A biokinetic model of the systemic distribution of americium in the beagle dog is presented. The model is based on a previous biokinetic model of plutonium. The data sets used for the development of the model were the measurements of excreted activity (urine and feces) and organ burdens (skeleton, liver, and other soft tissues) for different levels of initial injected activity. In developing the model, the compartmental structure of the skeleton of the plutonium model was adopted, and only the numerical values of parameters were adapted. The model well describes the fractions of americium in the skeleton, liver, and soft tissues and the total fraction excreted in urine and feces. The tuning of the liver clearance parameter provides a realistic description of the change in the partitioning between liver and skeleton for different injection levels. The most significant features of the biokinetics and dosimetry of americium and plutonium in beagles are compared. The total fractions of the clearance to the skeleton and the liver are roughly equal to the value for plutonium, but the partitioning of americium between these organs is reversed with respect to the partitioning of plutonium. 241Am doses to liver and skeleton are similar to 239Pu doses, owing to some counteracting factors. For the highest injection level, the liver mass is dependent on the time post injection. For the skeletal tissues, the dose to the cortical endosteum by far exceeds the dose to the trabecular endosteum and the red marrow. The model provides the basis for statistical survival analyses and risk estimates.

Americium↗
PubMed2006

Ancestry of beagles in lifespan studies of radionuclide toxicity at the University of Utah.

Analysis of the ancestry of the 1,262 lifespan beagles (LSB) entered into lifespan studies at the Radiobiology Division, University of Utah, beginning in 1952 and ending in 1980, indicated that about 97% of ancestor citations in the various pedigrees were of only 10 breeding animals (breeders) among breeders within the beagle colony. In turn, just 18 AKC-registered "champion" beagles from outside of this colony (founders) accounted for about 98% of all ancestor citations among founders for the LSB. We conclude from this study that the animals used in the lifespan radionuclide experiments can be considered to be somewhat genetically interrelated.

Animals↗
PubMed2005

Melatonin, immune function and aging.

Aging is associated with a decline in immune function (immunosenescence), a situation known to correlate with increased incidence of cancer, infectious and degenerative diseases. Innate, cellular and humoral immunity all exhibit increased deterioration with age. A decrease in functional competence of individual natural killer (NK) cells is found with advancing age. Macrophages and granulocytes show functional decline in aging as evidenced by their diminished phagocytic activity and impairment of superoxide generation. There is also marked shift in cytokine profile as age advances, e.g., CD3+ and CD4+ cells decline in number whereas CD8+ cells increase in elderly individuals. A decline in organ specific antibodies occurs causing reduced humoral responsiveness. Circulating melatonin decreases with age and in recent years much interest has been focused on its immunomodulatory effect. Melatonin stimulates the production of progenitor cells for granulocytes-macrophages. It also stimulates the production of NK cells and CD4+ cells and inhibits CD8+ cells. The production and release of various cytokines from NK cells and T-helper lymphocytes also are enhanced by melatonin. Melatonin presumably regulates immune function by acting on the immune-opioid network, by affecting G protein-cAMP signal pathway and by regulating intracellular glutathione levels. Melatonin has the potential therapeutic value to enhance immune function in aged individuals and in patients in an immunocompromised state.

Journal Article↗
PubMed2005

Dietary Echinacea purpurea during murine pregnancy: effect on maternal hemopoiesis and fetal growth.

BACKGROUND: The medicinal benefits of Echinacea sp. plants in several disease conditions, including insect bites, respiratory ailments, and even cancer and AIDS, have been touted for decades. Echinacea sp.-based phytoceuticals are among the top selling herbals in the Western marketplace today. However, evidence is very scant concerning the effects of using Echinacea species herbals during pregnancy. While available data indicates that fetal malformations do not occur during pregnancy in humans consuming this herb, there are no formal studies aimed at assessing the possibility that consuming Echinacea herbals may promote spontaneous abortions, thereby reducing the number of live births upon which to assess the presence or absence of malformations. OBJECTIVES: We undertook a study in which pregnant mice were fed daily Echinacea purpurea from pregnancy onset until gestational days 10, 11, 12, 13, and 14. METHODS: Maternal spleen and bone marrow were taken for enumeration of cells in each of five separate hemopoietic lineages/organ, and fetal status was recorded. RESULTS: The data indicate that the significant, pregnancy-induced elevation in splenic lymphocytes and nucleated erythroid cells was all but eliminated in those females which consumed E. purpurea daily throughout their pregnancy. Moreover, consuming E. purpurea during pregnancy reduced the number of viable fetuses. CONCLUSIONS: The data may be extrapolated to suggest that in humans, abstention from consuming Echinacea products during the early/mid stages of pregnancy, may be prudent.

Animals↗
PubMed2005

Variation of long-lived free radicals responsible for the EPR native signal in bone of aged or diseased human females and ovariectomized adult rats.

The purpose of this study was to gain insights into the variations seen in the electron paramagnetic resonance (EPR) spectroscopy of the native signals of teeth and bones used for retrospective dosimetry measurements. We determined that changes occur in the long-lived free radicals responsible for the native signal of cortical bone in aging or diseased human females and aged ovariectomized rats. This was done by measuring the magnitude of the broad (BC) and narrow (NC) components of the native EPR signal of bone following chemical extraction, aging, crushing and thermal annealing. Bone from the upper midshaft of femora of young (17-34 years old, n=5) and elderly (70-92 years old, n=18) females was examined. The results showed that the elderly women had significantly higher BC than the younger women (P<0.01). A similar interpretation was made of the data from an aging female rat osteoporosis model. The results for the NC signals were similar. Finally, dramatic decreases in both NC and BC signals were seen in HIV positive and uncontrolled diabetic (one each) patients indicating the need for studying this signal for a broad spectrum of metabolic disorders. Experiments were performed which strongly indicate that iron liganded with organic molecules is the source of the BC signal. Finally, the accuracy achieved in this study indicates that resolving the dosimetric signal (g=2.0018) should be improved by subtraction of the deconvoluted NC and BC signals from the original spectrum.

Adolescent↗
PubMed2005

Adaptation of the ICRP publication 66 respiratory tract model to data on plutonium biokinetics for Mayak workers.

The biokinetics of inhaled plutonium were analyzed using compartment models representing their behavior within the respiratory tract, the gastrointestinal tract, and in systemic tissues. The processes of aerosol deposition, particle transport, absorption, and formation of a fixed deposit in the respiratory tract were formulated in the framework of the Human Respiratory Tract Model described in ICRP Publication 66. The values of parameters governing absorption and formation of the fixed deposit were established by fitting the model to the observations in 530 autopsy cases. The influence of smoking on mechanical clearance of deposited plutonium activity was considered. The dependence of absorption on the aerosol transportability, as estimated by in vitro methods (dialysis), was demonstrated. The results of this study were compared to those obtained from an earlier model of plutonium behavior in the respiratory tract, which was based on the same set of autopsy data. That model did not address the early phases of respiratory clearance and hence underestimated the committed lung dose by about 25% for plutonium oxides. Little difference in lung dose was found for nitrate forms.

Absorption↗
PubMed2005

Uncertainties analysis of doses resulting from chronic inhalation of plutonium at the Mayak production association.

A method is presented to determine the uncertainties in the reported dose due to incorporated plutonium for the Mayak Worker Cohort. The methodology includes errors generated by both detection methods and modeling methods. To accomplish the task, the method includes classical statistics, Monte Carlo, perturbation, and reliability groupings. Uncertainties are reported in percent of reported dose as a function of total body burden. The cohort was initially sorted into six reliability groups, with "A" being the data set that the investigators are most confident is correct and "G" being the data set with the most ambiguous data. Categories were adjusted based on preliminary calculation of uncertainties using the sorting criteria. Specifically, the impact of transportability (the parameter used to describe the transport of plutonium from the lung to systemic organs) was underestimated, and the structure of the sort was reorganized to reflect the impact of transportability. The finalized categories are designated with Roman numerals I through V, with "I" being the most reliable. Excluding Category V (neither bioassay nor autopsy), the highest uncertainty in lung doses is for individuals from Category IV-which ranged from 90-375% for total body burdens greater than 10 Bq, along with work histories that indicated exposure to more than one transportability class. The smallest estimated uncertainties for lung doses were determined by autopsy. Category I has a 32-38% uncertainty in the lung dose for total body burdens greater than 1 Bq. First, these results provide a further definition and characterization of the cohort and, second, they provide uncertainty estimates for these plutonium exposure categories.

Administration, Inhalation↗
PubMed2005

Mayak worker study: an improved biokinetic model for reconstructing doses from internally deposited plutonium.

The plutonium production facility known as the Mayak Production Association was put into operation in June 1948. A high incidence of cancer in the Mayak workers has been related to the level of exposure to plutonium, but uncertainties in tissue doses have hampered development of dose-risk relationships. As part of an effort to improve dose estimates for these workers, the systemic biokinetic model for plutonium currently recommended by the International Commission on Radiological Protection (ICRP) has been modified to reflect recently developed data and facilitate interpretation of case-specific information. This paper describes the proposed model and discusses its implications for dose reconstruction for the Mayak workers.

Bone and Bones↗
PubMed2004

Biokinetic model of radium in humans and beagles.

A compartmental model of the distribution of radium in humans and young adult beagle dogs (approximately 500-550 d) is presented. The model consists of one soft tissue compartment and seven skeletal compartments for humans, and five skeletal compartments for beagles. The number of transfer parameters to be estimated was reduced by using remodeling rates of bone and imposing several constraints deduced from known features of bone physiology, radium metabolism, and autoradiographic analyses. The model predictions are in good agreement with measured retentions in plasma, whole body, skeleton, and soft tissues of both species. Moreover, for beagles even the retention in individual bones can be predicted quite well if the relevant morphometric parameters are known. While some of the estimated transfer parameters are similar in both species, others differ by an order of magnitude or more. Wherever possible, a comparison of model parameters with those of previous models is given. The new model not only is instrumental for calculating local doses in the skeleton but also can be used for characterizing the microdistribution of radium in this organ.

Animals↗
PubMed2004

Survival and bone tumor hazard from internal deposition of 226Ra in beagles.

The survival of 132 young adult control beagles and 117 beagles receiving graded injections of 226Ra ranging from 0.27 kBq kg-1 to 384.2 kBq kg-1 body mass was analyzed. The hazards of natural deaths, all deaths in injection groups, and deaths by bone tumors were assumed to follow a Weibull distribution with a common shape factor of 6.3. Only the scale factors of the Weibull distributions depend on the injection level. There were no significant sex differences. The relative risk with respect to controls for all causes of death increases up to 6,925 for 384.2 kBq kg-1. The dependence of the scale factors for all deaths and death by bone tumors on injected activity was fitted to an empirical regression model, which also contains a term representing radiation-caused deaths other than bone tumors. The risk of bone tumors increases nearly as the square of the injected activity, whereas the risk of the other radiation caused deaths increases approximately in proportion to the injected activity. By means of the regression model, it is possible to predict median survival times for all deaths, bone tumor and non-bone tumor deaths for an arbitrary intake level. Also, simple expressions for the fraction of animals with bone tumors and other radiation-caused deaths can be derived. The empirical model of bone tumor induction, which was based on results from a single injection design, can be generalized to an arbitrary systemic intake schema. This is achieved by using the average dose and dose rate to the skeleton as indices of detriment. Applying the generalized model, it was confirmed that no significant differences in survival can be expected for two groups of beagles receiving multiple injections, if compared to the corresponding single injection groups of about the same total activity. The general model also predicts that even extensive protraction of the intake would increase the survival times only to a very limited extent.

Animals↗
PubMed2003

Effect over time of in-vivo administration of the polysaccharide arabinogalactan on immune and hemopoietic cell lineages in murine spleen and bone marrow.

Current evidence indicates an immunostimulating role for complex carbohydrates, i.e., polysaccharides, from several plant sources. In the present work, we determined the specific in vivo effects, with time of administration, of one such compound, a neutral arabinogalactan from larch not only on immune (lymphoid) cells, but also on natural killer (NK) lymphoid cells, as well as a variety of other hemopoietic cells in both the bone marrow and spleen of healthy, young adult mice. The latter were injected daily (i.p.) with arabinogalactan (500 microg in 0.1 ml pH 7.2 phosphate buffered saline-PBS) for 7 or 14 days. Additional, aged (1 1/2-2 yr) mice were similarly injected for 14 days only. Control mice were given the PBS vehicle in all cases, following the above injection regimen. Animals from all groups were sampled 24 h after the final injection and the immune and hemopoietic cell populations in the bone marow and spleen were assessed quantitatively. The results indicated that immediately following either 7 or 14 days of arabinogalactan administration to young, adult mice, lymphoid cells in the bone marrow were significantly decreased (p < 0.004; p < 0.001, respectively) relative to controls but remained unchanged at both time intervals in the spleen. NK cells, after 7 days of arabinogalactan exposure, were also decreased significantly in the bone marrow (p < 0.02), but unchanged in the spleen. After 14 days' exposure to the polysaccharide, NK cells in the bone marrow had returned to normal (control) levels, but were increased in the spleen (p < 0.004) to levels greater than 2-fold that of control. Among other hemopoietic cell lineages, none was influenced in the bone marrow or spleen by one-week administration of arabinogalactan; however, after two-week exposure, precursor myeloid cells and their mature (functional) progeny (granulocytes), were significantly reduced in the spleen (p < 0.043; p < 0.006, respectively), as were splenic monocytes (p < 0.001). These lineages in the bone marrow, however, remained steadfastly unaltered even after 14 days of continuous exposure to the agent. Of the vast cascade of cytokines induced in the presence of this polysaccharide, it appears that immunopoiesis- and hemopoiesis-inhibiting ones are most prevalent during at least the first two weeks of daily exposure.

Animals↗
PubMed2003

The effect of state of health on organ distribution and excretion of systemic plutonium in the Mayak workers.

The extrapulmonary distribution of plutonium in 20 organs (excluding the respiratory tract) was studied in workers who chronically inhaled plutonium at the radiochemical plants of the Mayak Production Association (Ozyorsk, Russia). The data were obtained by radiochemical analysis of soft tissue and bones samples collected at autopsy of 591 workers. The systemic plutonium distribution was determined in healthy individuals as well as in those with health impairment, specifically for those with liver diseases. Twenty-five years after the beginning of inhalation, systemic fractions in the liver and skeleton of individuals who were healthy at the time of death approximate the ratio 45%:45% proposed in the International Commission on Radiological Protection (ICRP) Publication 30. Pathological processes in the liver, accompanied by fatty dystrophy of hepatocytes, increased plutonium clearance from the liver. There was a considerable shift of the plutonium from the liver to the skeleton in individuals who died from liver disease. The average fractions of systemic plutonium in the liver and skeleton of those individuals were 14% and 78% respectively, which did not correspond to ICRP models, indicating a significant effect of disease conditions. Plutonium that was not redistributed was excreted. The urinary excretion rate of plutonium also correlated with state of health. The observed excretion as a fraction of systemic content was 1.64 x 10(-5) d(-1) for individuals in good health and 2.34 x 10(-5) d(-1) for individuals with various chronic diseases. The current models do not account for the influence of different pathological processes in the body on plutonium distribution and retention in systemic organs. This could have significant consequences for dosimetry calculations and risk estimations.

Body Burden↗
PubMed2003

Alterations in skeletal and mineral metabolism following thermal injuries.

Severe burns and other chronic inflammatory diseases are associated with altered skeletal metabolism that result in an increased incidence of osteopenia. In thermally injured children and adults there is a dramatic decrease in bone formation accompanied with an increase or maintenance of bone resorption. Children also exhibit a growth delay and subsequently fail to reach a predicted stature. Animal models, including the thermal injury mouse model, are being used to understand the mechanisms behind the uncoupling of bone formation and resorption that occurs following a major burn. The model has numerous commonalities with the human condition such as reduced bone formation, increased bone resorption, and decreased endochondral growth. The mechanisms that modulate calcium and skeletal metabolism following a thermal injury are complex and likely involve a number of endocrine, cytokine, and immune factors. Specifically, the potential roles of glucocorticoids, growth hormone, insulin-like growth factor-1, parathyroid hormone, interleukin-1 and -6, and tumor necrosis factor alpha are addressed. Subsequent to the increased survival rate of burn victims, there has been a heightened focus on therapeutic interventions that prevent or decrease the impact of thermal injuries on the skeletal system. These include exercise programs, exogenous recombinant human growth hormone, insulin, and oxandrolone.

Journal Article↗
PubMed2002

Effects of thermal injury on skeletal metabolism in two strains of mice.

Long-term growth retardation occurs in children and osteopenias occur among children and adults who have been burned or suffer other injuries that result in a systemic inflammatory response. The purpose of this study was to define some of the growth, and to determine cancellous and cortical bone changes that occur following thermal injury in several contrasting strains of mice. Male C3H/HeN and Balb/c mice were given about a 20% total body thermal injury and 10 days later skeletal tissues were collected. The bone ash weights of the burned animals from both strains were less than their sham controls. In both strains, cancellous bone volumes were less in the burned animals than in their respective sham or baseline control groups. The loss of bone was particularly evident in the secondary spongiosa regions and also included a decrease in trabecular thickness and connectivity and an increase in trabecular separation. Longitudinal (endochondral) growth was suppressed in the burn animals. In the burned animals, indices of cancellous bone formation were substantially reduced whereas those in cortical bone were essentially nonexistent. The numbers of osteoclasts were increased in cancellous bone, and endocortical eroded surface was increased in the burn animals. These data show that there are rapid and profound changes in skeletal growth and metabolism in an experimental model of thermal injury. In general, a greater relative response was observed in the Balb/c vs. the C3H/HeN strain. Thermal injury resulted in a rapid and dramatic suppression of bone formation and endochondral growth with increased bone resorption in both cancellous and cortical bone.

Animals↗
PubMed2002

Effect of age on rat bone solubility and crystallinity.

It has been shown that biominerals such as dental enamel and bone demonstrate a non-thermodynamic equilibrium state following initial dissolution where no further mineral dissolution or precipitation occurs; this state is termed metastable equilibrium solubility (MES). Furthermore, these minerals are composed of a distribution of domains each with their own MES. Recent studies have also demonstrated a linear relationship between crystallinity and the mean MES of these minerals, with solubility decreasing with increasing crystallinity. This study investigates the effect of age on the MES and crystallinity of rat bone mineral. The bone mineral samples were prepared by protein extraction with a series of hydrazine and alcohol solutions. The MES distributions of the bone mineral were measured by exposure to 0.1 M acetate buffers containing a range of calculated amounts of calcium (Ca) and phosphate for 48 h. The amount of mineral dissolved in each solution was determined from Ca and phosphate analyses of the undissolved residue. The full width of the half maximum (FWHM) of the 002 reflection of the X-ray powder diffraction was used as an indicator of crystallinity. The MES of mineral from bone of rats of different ages (1-25 months) were compared. Results of this study indicate that (l) there is a difference in the mean MES of bone mineral from rats of different ages, with older bone mineral being less soluble and more crystalline than bone mineral from younger rats; (2) the nature of the solubility distribution changes from a narrow to a broader distribution with age; and (3) all of the bone samples demonstrated an inverse-linear correlation between crystallinity and mean MES value consistent with previous results obtained with synthetic apatites and dental enamel.

Aging↗