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Scott C Miller

Publications and source records attributed to Scott C Miller.

At least 19 recordsLinked to original sources
PubMed2006

Age-associated iron accumulation in bone: implications for postmenopausal osteoporosis and a new target for prevention and treatment by chelation.

Iron accumulation in tissues is believed to be a characteristic of aged humans and a risk factor for some chronic diseases. However, it is not known whether age-associated iron accumulation is part of the pathogenesis of postmenopausal osteoporosis that affects approximately one out three women worldwide. Here, we confirmed that this accumulation of iron was associated with osteopenia in ovariectomized (OVX) rats (a model of peri- and postmenopausal osteoporosis due to estrogen deficiency). To further investigate whether the increased iron level plays a causal role in the onset of bone loss, we treated OVX rats with an orally active and bone targeted chelator that prevented iron accumulation in their skeletal tissues. The results showed that this treatment mitigated the loss of bone mass and the deterioration of bone micro-architecture. We also found that one possible mechanism of the protective action of iron chelation was to significantly reduce bone resorption. Thus, these findings provide a novel target and a potentially useful therapeutic strategy for the prevention and treatment of postmenopausal osteoporosis and perhaps other age-related diseases.

Acetates↗
PubMed2005

Efficacy of orally administered amphipathic polyaminocarboxylic acid chelators for the removal of plutonium and americium: comparison with injected Zn-DTPA in the rat.

Chelators are used to promote excretion of actinides and some other metals, but few are orally effective. The relative efficacies of orally administered triethylenetetraminepentaacetic acids (TT) with varying lipophilic properties on the removal of 241Am and 239Pu and comparison with parenteral Zn-DTPA was determined. The actinides were administered to adult rats 2 weeks prior to initiation of 30 d of chelation treatment. The TT compounds were given orally while Zn-DTPA was given twice weekly by injection. Total body content of 241Am was measured before and during the treatment period and organ contents of 241Am and 239Pu were measured at the end of the study. Significant reductions in 241Am occurred within the first week, with Zn-DTPA being the most effective. By 3 weeks, the most lipophilic chelator, C22TT was as effective as Zn-DTPA. After 30 d, reductions in organ content of 239Pu and 241Am directly correlated with increasing lipophilicity of the TT chelators. Oral C22TT was as effective as injected Zn-DTPA in liver and bone, the major organs of actinide deposition. The removal of 239Pu from the liver and reduction of redeposition of 239Pu in newly formed bone by C22TT was confirmed by neutron-induced autoradiographs. The amphipathic TT chelators may be useful as orally administered alternatives to current parenteral DTPA for the removal of actinide elements from the body, particularly for longer-term therapeutic applications.

Acetates↗
PubMed2005

Bone-targeting macromolecular therapeutics.

Musculoskeletal diseases such as osteoporosis are recognized as major public health problems worldwide. Many novel therapeutic agents have been identified for the treatment of these diseases. However, the majority of them are not specific to hard tissue, resulting significant toxicity. Bone-targeting drug delivery systems based on water-soluble polymers can specifically direct candidate drugs to bone thereby reducing side effects due to non-specific tissue interactions. Incorporation of a targeting moiety, a drug release mechanism, drug selection and optimization of the polymer carrier are all essential elements in the development of bone-targeting macromolecular therapeutics. Successful clinical application of this approach can significantly contribute to the development of treatments for many musculoskeletal diseases.

Animals↗
PubMed2005

Skeletal function and structure: implications for tissue-targeted therapeutics.

Osteoporosis, arthritis, and periodontal disease are common diseases of the skeleton, all of which could benefit from new therapeutic strategies, including targeted drug delivery. While bone is a rigid structure, it is not inert, with the cells of the skeleton being able to repair damage and respond to alterations in mechanical stimuli and various endocrine agents. Several important factors related to bone physiology that could influence the success of a pharmacological treatment include heterogeneity in bone remodeling activities throughout the skeleton, differences in blood supply and local vascularization, and the "blood-bone" barrier. The structural qualities of bone, especially the presence of hydroxyapatite crystals in the bone mineral and the established binding of certain molecules to this mineral phase, including tetracyclines, bisphosphonates, and other chelators, provide unique opportunities to treat skeletal diseases using targeted drug delivery. Additional opportunities exist in targeting sites with contrasting bone surface activities, including surfaces that are inactive, forming new bone or being resorbed. The ultimate key to developing new bone-targeted therapies is to understand and exploit the physiological characteristics at the desired target sites.

Bone Diseases↗
PubMed2005

Weaning initiates a rapid and powerful anabolic phase in the rat maternal skeleton.

Maternal skeletal mineral lost during lactation is rapidly restored after weaning. The purposes of this study were to determine when increases of bone formation occur after weaning, whether the expanding osteoblast population is derived from proliferating progenitors, and to relate these skeletal changes to known endocrine events at weaning. Female rats were allowed to complete one reproductive cycle. Half of these rats were mated a second time and allowed to lactate for 20 days. The other half served as an age-matched, normal estrus cycling comparison group. One day after weaning, the dams and their comparison group were given four injections of bromodeoxyuridine (BrdU) at 8-h intervals. Indices of bone formation and the kinetics of BrdU-labeled cells were measured in lumbar vertebral cancellous bone. At 2 days after weaning, cancellous bone formation rates were substantially greater than those in the nonmated rats. Indices of bone formation more than doubled from the second to seventh day after weaning. At 25 h after the first BrdU injection in the postweaned rats, considerable numbers of labeled cells were observed on or near the bone surface, with about 17% of the osteoblast population labeled. Labeled osteoblasts peaked at 20%-24% compared with 4% in the normal estrus cycling group. Immediately following weaning, there is a profound increase in the osteoblast population in maternal cancellous bone. Many, if not most of these newly formed osteoblasts were derived from proliferating progenitors. It is possible that the endocrine milieu of lactation expands or primes the osteoprogenitor pool for this rapid anabolic phase.

Animals↗
PubMed2005

Biopolymer-based delivery systems for advanced imaging and skeletal tissue-specific therapeutics.

There is considerable advantage in developing tissue-specific delivery systems for therapeutic and diagnostic applications. Synthetic water-soluble polymeric delivery systems have been developed to allow selective delivery of therapeutic and imaging agents to musculoskeletal tissues. For mineralized tissues, bone-targeting agents such as aspartic acid octapeptide could concentrate the polymer conjugates to bone surfaces including resorption sites, which was demonstrated with routine bone histomorphometry. For bone-associated soft tissues, other targeting approaches based on pathophysiological properties unique to the local tissue environment, such as the leaky vasculature in arthritic joints, were utilized to achieve the selective deposition of the polymeric delivery systems to the desired sites. For this study, magnetic resonance imaging (MRI) was used to assess real-time pharmacokinetics and biodistribution of the MRI contrast agent conjugated polymer in major organs including skeletal tissues. The MRI data were then correlated with other standard imaging methods such as pQCT and DXA as well as routine histopathology and skeletal histomorphometry. Clearly, biopolymeric delivery systems may be used to improve the pharmacological and pharmacokinetic properties of different therapeutic agents for musculoskeletal diseases such as osteoporosis and arthritis. In addition, this or related technologies may also be useful to improve diagnosis and medical imaging with positron emission tomography, gamma scintigraphy, or other technologies.

Animals↗
PubMed2005

Does the severity of radionuclide-induced skeletal malignancy depend upon radiation dose?

The severity of effect as a function of skeletal radiation dose for induced skeletal malignancy was investigated among a relatively large group of beagle dogs singly injected as young adults with soluble radionuclide. Bone-seeking radionuclides considered were 239Pu, 226Ra, 228Ra, 224Ra, 228Th, and 90Sr. Variables included skeletal radiation dose, tumor growth rate, maximum tumor volume, sex of the animals, growth period of the tumor, degree of calcification of the tumor, skeletal location of the tumor, year of death, and occurrence of metastases. Except for a significant relationship between tumor volume and metastatic process and for growth rate and tumor volume, no significant dependence of any two of these factors could be established. It is concluded from available data on skeletal malignancies among beagles exposed to bone-seeking radionuclides that the severity of the disease is not dependent upon skeletal radiation dose.

Animals↗
PubMed2004

Rapid improvements in cortical bone dynamics and structure after lactation in established breeder rats.

The mineral requirements for milk production during lactation usually result in a decrease in maternal skeletal mass during this period. The purpose of this study was to characterize changes in cortical bone formation, resorption, and structure after lactation in established breeder rats. Rats were taken at the end of the second pregnancy, second lactation, and at two, four, and six weeks after the pups were weaned. Age-related, nulliparous groups were included for comparison. Cortical bone structure and bone formation and resorption were measured at the tibiofibular junction using histomorphometric methods. As expected, there were decreases in cortical bone area, width, and minimum cortical thickness with an increase in marrow cavity area during lactation. Bone formation rates were essentially zero on the periosteal and endocortical surfaces at the end of lactation, while eroded (resorption) endocortical surface was greatly increased compared with the end of pregnancy. At or immediately after weaning, there was a rapid reversal of resorption to formation surface on the endocortical envelope similar to the events of true bone remodeling. Likewise, there was a commencement of bone formation on the periosteal surface. The volume- and surface-referent bone rates measured on the endocortical surface were substantially elevated over those measured at the end of the second pregnancy or in the nulliparous animals. Peak bone formation rates were observed on both the endocortical and periosteal surfaces by four weeks after weaning. These results show that the postlactation period is profoundly anabolic for cortical bone in the established breeder rat. The rapid and dramatic increases in bone formation likely serve to restore bone lost during lactation and to prepare the maternal skeleton for the next reproductive cycle.

Age Factors↗
PubMed2004

Alterations in bone characteristics associated with glycemic control in adolescents with type 1 diabetes mellitus.

OBJECTIVE: To determine whether bone characteristics in adolescents with type 1 diabetes mellitus (DM) are influenced by blood glucose regulation and disease duration. The subjects were adolescents with type 1 DM (n=55) recruited from the University of Utah's Primary Children's Pediatric Diabetes Treatment Center. A reference database consisting of 95 healthy adolescents from the same geographic area was used for comparison.Study design Measurements of the tibia by peripheral quantitative computed tomography were made to assess cortical and trabecular bone characteristics. Hip, spine, and whole body characteristics were measured by dual-energy x-ray absorptiometry. Height, weight, health histories, Tanner stage, disease duration, insulin regimen, and glycosylated hemoglobin values were recorded. RESULTS: Age, maturation, and body size and composition values were similar between the subjects with type 1 DM and reference. Subjects with type 1 DM had lower tibia trabecular and femoral neck density and whole body mineral content and density. The mean glycosylated hemoglobin value was inversely related to tibia trabecular bone density (R(2)=-0.30) and whole body bone mineral content (R(2)=-0.25) and accounted for 3.0% to 8.9% of the variance. CONCLUSIONS: Altered bone mineral acquisition in adolescents with type 1 DM may limit peak bone mass acquisition and increase the risk of osteoporosis in later life.

Absorptiometry, Photon↗
PubMed2004

The arthrotropism of macromolecules in adjuvant-induced arthritis rat model: a preliminary study.

PURPOSE: To study the accumulation of macromolecules into the arthritic joints and the possible applications of such phenomenon. METHODS: The accumulation of plasma albumin in the joints of adjuvant-induced arthritis (AIA) rat model was first visualized with Evans blue injection. A N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer contrast agent was then synthesized and injected into the AIA rats to allow qualitative examination of biodistribution and pharmacokinetics of the injected macromolecule with magnetic resonance imaging (MRI). Vital organs and the diseased joints were isolated and examined histologically to correlate with the MRI findings. RESULTS: Deep blue color developed around the arthritic joints of the AIA rat a few hours after the injection of Evans blue. MR imaging of the AIA rats injected with polymer contrast agent demonstrated a gradual but very strong accumulation of the injected polymer in the arthritic joints, which lasted for 1-2 days. Observed differences in the concentration of the injected polymer in the joints correlated with disease severity as assessed histologically. CONCLUSIONS: Profound arthrotropism of macromolecules in the AIA rat model was demonstrated with various imaging tools. These observations should help in the conceptual and practical design of novel macromolecular delivery systems for the imaging and treatment of rheumatoid arthritis.

Animals↗
PubMed2004

Acyclonucleoside iron chelators of 1-(2-hydroxyethoxy)methyl-2-alkyl-3-hydroxy-4-pyridinones: potential oral iron chelation therapeutics.

The method of synthesizing acyclonucleoside iron chelators is both convenient and cost effective compared to that of synthesizing ribonucleoside iron chelators. The X-ray crystal structural analysis shows that the 2-hydroxyethoxymethyl group does not affect the geometry of the iron chelating sites. Therefore, the iron binding and removal properties of the acyclonucleoside iron chelators should remain similar to the ribonucleoside iron chelators, which is confirmed by the titration and competition reaction of the acyclonucleoside chelators with iron and ferritin, respectively. The acyclonucleoside iron chelators are more lipophilic with measured n-octanol and Tris buffer distribution coefficients than ribonucleoside iron chelators.

Chelation Therapy↗
PubMed2004

Does malignant hematopoietic disease result from internal exposure to 239Pu?

Neither Fisher's Exact Test nor linear regression analysis (dose-response relationship) using average skeletal dose from 239Pu as a surrogate for marrow dose could establish a statistically significant association between malignant hematopoietic disease (MHD including leukemia and aleukemia) and exposure to 239Pu among dogs in the Utah beagle colony. In addition, when dog-years at risk was the parameter used to estimate the rate of expected malignant hematopoietic tumors in dogs exposed to 239Pu, the estimate was within the range of the 95% confidence limits of the control dogs for six cases (and also within the 95% confidence limits for five cases when the single case of lymphoma was omitted). It was concluded that if there was an effect of 239Pu exposure on the occurrence of MHD in this beagle experiment, it was not very meaningful. These data could not establish a significant susceptibility to neoplasia of either myeloid or lymphoid tissue of 239Pu exposure.

Age Distribution↗
PubMed2004

Does low dose internal radiation increase lifespan?

No significant differences in lifespan could be established between control dogs and dogs given 241Am, 228Th, 90Sr, 228Ra, 226Ra or monomeric 239Pu at low dosage levels that induced less than 10% skeletal malignancies (low dose animals) in the Utah beagle colony when all dogs surviving at least 1 y were included in the analysis and dogs given individual radionuclides were considered separately or together. Censoring or exclusion of dogs from these groups that were diagnosed with skeletal malignancies or that died in a gran mal epileptic seizure made no important difference to these results. Therefore, an enhanced lifespan of low dose dogs as compared with controls could not be established. It is concluded that low doses from internal (mainly skeletal) deposits of these radionuclides probably do not benefit the survival of individuals so exposed.

Animals↗
PubMed2003

Familial resemblance of bone mineralization, calcium intake, and physical activity in early-adolescent daughters, their mothers, and maternal grandmothers.

OBJECTIVE: To describe familial relationships among bone mineral density (BMD), calcium intake, and physical activity in early-adolescent daughters, their premenopausal mothers, and postmenopausal maternal grandmothers. SUBJECTS: Healthy, early-adolescent daughter and premenopausal mother pairs (n=72) were enrolled in the study. In addition, a cohort of 22 postmenopausal maternal grandmothers were measured for comparison of related triads (n=22). DESIGN: Cross-sectional measurements of hip (three sites) and lumbar spine BMD by dual energy x-ray absorptiometry (DXA), body height and weight, menstrual function, current calcium intake, and current and past physical activity patterns were assessed using recalls and questionnaires. STATISTICAL ANALYSIS: Correlational analysis was used to establish relationships between bone characteristics and body size, menstrual function, calcium intake, and physical activity. Multiple regression analyses with backward elimination were used to examine heritability of bone characteristics in daughter-mother and mother-grandmother pairs and daughter-mother-grandmother triads. Quick cluster analysis and cross-tabulation with Pearson's chi(2) were used to evaluate familial patterns for bone characteristics and lifestyle practices. RESULTS: Height, weight, and lumbar spine BMD were significantly correlated within mother-daughter pairs. Current and past calcium intakes were not related within pairs or triads or to BMD in the daughters or the grandmothers. A weak inverse relationship between calcium intake and the hip trochanter and lumbar spine BMD was observed in the mothers (R(2)=-0.25; P=.05). Physical activity, independent of calcium intake, was strong predictor of BMD for daughters and mothers. Among the daughters, the hertiability estimates for trochanter and lumbar spine BMD were 0.56 and 0.70, respectively (P<.01). The heritability estimate for premenopausal mothers were significant for lumbar spine BMD (h(2)=0.66; P<.01). Daughter-mother-grandmother triads with low physical activity had low femoral neck BMD whereas those with high physical activity had high femoral neck BMD (P<.001). APPLICATIONS: Making physical activity a part of the daily routine, in addition to an adequate intake of calcium and bone-related nutrients, is an important goal for maintaining or improving bone health for women of all ages.

Absorptiometry, Photon↗
PubMed2003

Dietary soy protein maintains some indices of bone mineral density and bone formation in aged ovariectomized rats.

Hormone replacement therapy (HRT) has been used to prevent osteoporosis in postmenopausal women. However, HRT may increase the incidence of some cancers and has other side effects. There is considerable interest in dietary alternatives that include the consumption of soy and isoflavones derived from soy. The purpose of this study was to determine the effects of dietary soy protein on bone density, formation and resorption in cortical and cancellous bone in aged, ovariectomized rats. Specific emphasis was placed on indices of bone formation. Rats were assigned to the following groups: baseline; sham surgery + casein diet; sham + soy protein diet; ovariectomy (Ovx) + casein diet; Ovx + soy protein diet. The diets were fed for 3 mo. The Ovx Soy group had a greater bone mineral density (BMD) than the Ovx Casein group. There was a trend (P < 0.10) for greater periosteal bone formation rates in the Sham Soy compared with the Sham Casein group. In the Ovx Soy group, indices of endocortical bone formation were greater than those of the Ovx Casein group. There were no significant differences in resorption indices or endochondral growth (bone elongation) rates with soy in either the Sham or Ovx groups. In cancellous bone, the double-labeled surface and bone formation rates were greater in the Ovx Soy group than in the Ovx Casein group. These results show that dietary soy had a beneficial effect on the preservation of BMD associated with estrogen deficiency bone loss in aged rats. These data also show that at the tissue level, soy functions in a manner different from estrogen by increasing or sustaining elevated bone formation rates after ovariectomy.

Aging↗
PubMed2003

Does soft tissue cancer affect the development of radionuclide-induced skeletal malignancy?

Data in the archives of the beagle project at the University of Utah were used to determine whether there might have been an association between the occurrence of soft tissue cancer and bone tumor (skeletal malignancy) among the dogs injected with bone-seeking radionuclides. In addition to comparing the numbers of animals with and without bone tumors and with and without soft tissue cancers, data on bone sarcomas and soft tissue sarcomas were compared. Longevity (postinjection survival) of the dogs was investigated. It appeared that survival (time between radionuclide injection and death) was important in the eventual expression of malignancies. There could not be established a possible susceptibility to skeletal malignancy associated with the occurrence of soft tissue cancer (or soft tissue sarcoma). We concluded that, although the literature reports an increased susceptibility for subsequent malignancies for individuals with naturally-occurring or radiation-induced cancer, the data derived from this study do not confirm the concept that the appearance of soft tissue cancer is strongly associated with an increased risk of developing a radionuclide-induced skeletal malignancy.

Animals↗