Biomedical subjects

Scott C Miller

Publications and source records attributed to Scott C Miller.

25 records · Page 2Linked to original sources

PubMed2003

Cortical bone dynamics, strength, and densitometry after induction of emphysema in hamsters.

Recent evidence suggests that patients suffering from chronic obstructive pulmonary disease are also at an increased risk of developing osteoporosis. The pathophysiological mechanism(s) linking these progressive diseases is unknown. The goal of this investigation was to determine whether there were alterations in bone mineral density and content, cortical bone structure and strength, and indexes of bone formation and resorption in the elastase-induced emphysematous hamster. At 3 wk after induction of emphysema, the femoral bone mineral content was 8% less (P = 0.026) and the femoral fracture strength was 6% less (P = 0.032) in the emphysematous hamster than in controls. The cortical area was 8.4% less (P = 0.013) and the periosteal mineral appositional rate was 27% less (P = 0.05) than in controls. Additionally, the endocortical eroded surface in the emphysematous group was about twice that in the control group (P = 0.003). Differences in some indexes of bone formation and resorption, paralleled by differences in bone structure and strength, were observed 3 wk after induction of emphysema. These differences in skeletal metabolism and strength may help explain some of the skeletal changes associated with chronic obstructive pulmonary disease in humans.

Animals↗

PubMed2003

Prostaglandin E--a powerful anabolic agent for generalized or site-specific bone formation.

Prostaglandins are locally secreted, rapidly metabolized, biologically active fatty acids first identified in the prostate. The role of prostaglandins in the inflammatory response has been widely studied. However, some prostaglandins, particularly those of the E series (PGEs), can suppress inflammation, making it difficult to understand the local events and their sequence. This bimodal potential of the PGEs has been poorly understood in skeletal biology, causing the initial report of PGEs as mediators of bone resorption to persist for more than two decades, despite ample evidence to the contrary. This resulted in part from the power of any initial report to overrule subsequent conflicting views and in part on the exclusive reliance on in vitro data to explain in vivo phenomena. Over a decade ago, the potential of PGEs as authentic anabolic skeletal agents was demonstrated convincingly in vivo by both systemic and local delivery. The potential clinical applications of the PGEs in skeletal biology have not yet been developed. Our purpose is to review the reasons for the delayed discovery of the true skeletal effects of the PGEs and to describe applications for this technology. With the development of appropriate delivery systems, one can anticipate widespread clinical applications of the PGEs to accelerate skeletal repair, and to treat skeletal pathologies and trauma.

Anabolic Agents↗

PubMed2003

Comparisons of the skeletal locations of putative plutonium-induced osteosarcomas in humans with those in beagle dogs and with naturally occurring tumors in both species.

Osteosarcomas occur from exposures to bone-seeking, alpha-particle-emitting isotopes, particularly plutonium. The skeletal distribution of putative 239Pu-induced osteosarcomas reported in Mayak Metallurgical and Radiochemical Plutonium Plant workers is compared with those observed in canine studies, and these are compared with distributions of naturally occurring osteosarcomas in both species. In the Mayak workers, 29% and 71% of the osteosarcomas were in the peripheral and central skeleton, respectively, with the spine having the most tumors (36%). An almost identical distribution of plutonium-induced osteosarcomas was reported for dogs injected with 239Pu as young adults. This distribution of osteosarcomas is quite different from the distributions of naturally occurring osteosarcomas for both species. In the Cooperative Osteosarcoma Study Group in humans (1,736 osteosarcomas from all ages), over 91% of the tumors occurred in the peripheral skeleton. In the Mayo Clinic group of older individuals (>40 years old), over 60% of the osteosarcomas appeared in the peripheral skeleton. The distribution of naturally occurring osteosarcomas in the canine is similar to that in the adult human. The similarities of the distributions of plutonium-associated osteosarcomas in the Mayak workers with those found in experimental studies suggest that many of the reported osteosarcomas may have been associated with plutonium exposures. These results also support the experimental paradigm that plutonium osteosarcomas have a preference for well vascularized cancellous bone sites. These sites have a greater initial deposition of plutonium, but also greater turnover due to elevated bone remodeling rates.

Adolescent↗

PubMed2002

The development of the plutonium lung clearance model for exposure estimation of the Mayak production association, nuclear plant workers.

The purpose of this study was to develop a biokinetic model that uses urinary plutonium excretion rate data to estimate the plutonium accumulation in the human respiratory tract after occupational exposure. The model is based on autopsy and urinalysis data, specifically the plutonium distribution between the respiratory tract and the remainder of the body, taken from 543 former workers of a radiochemical facility at the Mayak Production Association (MPA) plant. The metabolism of plutonium was represented with a compartmental model, which considers individual exposure histories and the inherent solubility properties of industrial plutonium aerosols. The transport properties of plutonium-containing aerosols were estimated by experimentally defining their in vitro solubility. The in vitro solubilities were found by dialysis in a Ringer's solution. Analysis of the autopsy data indicated that a considerable fraction of the inhaled plutonium is systemically redistributed rapidly after inhalation. After the initial dynamic period, a three-compartment model describes the retention in the respiratory tract. One compartment describes the nuclide retained in the lungs, the second compartment describes a plutonium lung concentration that exponentially decreases with time, and the third compartment describes the concentration in the pulmonary lymph nodes. The model parameters were estimated by minimizing sum squared of the error between the tissue and bioassay data and the model results. The parameters reflect the inverse relationship between plutonium retention in lungs and the experimentally derived aerosol transportability. The model was validated by comparing the autopsy results with in vivo data for 347 cases. The validation indicates that the model parameters are unbiased. This model is being used to estimate individual levels of nuclide accumulation and to compute radiation doses based upon the urinary excretion rates.

Autopsy↗

PubMed2002

The historical and current application of the FIB-1 model to assess organ dose from plutonium intakes in Mayak workers.

One of the objectives of the Joint Coordinating Committee for Radiation Effects Research Project 2.4 is to document the methodology used to determine the radiation doses in workers from the Mayak Production Association who were exposed to plutonium. The doses have been employed in numerous dose response studies measuring both stochastic and deterministic effects. This article documents both the historical (pre-1999) and current ("Doses 1999") methods used by the FIB-1 scientists to determine the doses. Both methods are based on a three-chamber lung model developed by the FIB-1 scientists. This method was developed in partial isolation from the West and has unique characteristics from the more familiar ICRP biokinetic models. Some of these characteristics are the use of empirically based transportability classifications and the parameter modification for chelation-therapy-enhanced excretion data. An example dose calculation is provided and compared to the dose that would be obtained if the ICRP models were used. The comparison demonstrates that the models are not interchangeable and produce different results.

Humans↗

PubMed2000

Activation of the calcium receptor by a calcimimetic compound halts the progression of secondary hyperparathyroidism in uremic rats.

The secondary hyperparathyroidism that develops in rats with chronic renal insufficiency (CRI) can be totally prevented by activation of the parathyroid Ca(2+) receptor with a calcimimetic compound, when treatment is initiated before parathyroid cell hyperplasia and increased circulating parathyroid hormone levels develop. In clinical practice, however, secondary hyperparathyroidism is usually manifest by the time CRI is diagnosed. This study examined the effects of daily oral gavage or continuous subcutaneous infusion for 8 wk of the calcimimetic NPS R-568 on the progression of established mild or moderate-to-severe secondary hyperparathyroidism in rats with CRI induced by 5/6 nephrectomy. Both oral and infused NPS R-568 completely prevented further hyperplasia but did not reduce total parathyroid cell number below that present at the initiation of treatment. This prevention of cellular proliferation occurred despite increases in plasma phosphate and decreases in Ca(2+) and 1, 25-dihydroxyvitamin D levels, and supports the view that the Ca(2+) receptor is the dominant regulator of parathyroid cell hyperplasia in addition to parathyroid hormone secretion. The clinical implications of these findings suggest that controlling Ca(2+) receptor activity with calcimimetic compounds could be sufficient to manage secondary hyperparathyroidism in CRI.

Analysis of Variance↗

PubMedDate not supplied

Pharmacokinetic and biodistribution studies of a bone-targeting drug delivery system based on N-(2-hydroxypropyl)methacrylamide copolymers.

Osteotropicity of novel bone-targeted HPMA copolymer conjugates has been demonstrated previously with bone histomorphometric analysis. The pharmacokinetics and biodistribution of this delivery system were investigated in the current study with healthy young BALB/c mice. The 125I-labeled bone-targeted and control (nontargeted) HPMA copolymers were administered intravenously to mice, and their distribution to different organs and tissues was followed using gamma counter and single photon emission computed tomography (SPECT). Both the invasive and noninvasive data further confirmed that the incorporation of D-aspartic acid octapeptide (D-Asp8) as bone-targeting moiety could favorably deposit the HPMA copolymers to the entire skeleton, especially to the high bone turnover sites. To evaluate the influence of molecular weight, three fractions (Mw of 24, 46, and 96 kDa) of HPMA copolymer-D-Asp8 conjugate were prepared and evaluated. Higher molecular weight of the conjugate enhanced the deposition to bone due to the prolonged half-life in circulation, but it weakened the bone selectivity. A higher content of bone-targeting moiety (D-Asp8) in the conjugate is desirable to achieve superior hard tissue selectivity. Further validation of the bone-targeting efficacy of the conjugates in animal models of osteoporosis and other skeletal diseases is needed in the future.

Animals↗