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Biomedical subjects

S C Miller

Publications and source records attributed to S C Miller.

At least 145 records · Page 8Linked to original sources
PubMed1993

Duration and dose-related effects of an orally administered, partially lipophilic polyaminocarboxylic acid on the decorporation of plutonium and americium.

A recently developed, orally administered, partially lipophilic polyaminocarboxylic acid-based chelator, docosyl-triethylenetetraminepentaacetic acid (C22TT), was tested for its ability to promote decorporation of 239Pu and 241Am. The effects of dose and duration of treatment were determined in rats injected with 239Pu or 239Pu/241Am 2 weeks before the initiation of C22TT treatment and compared with untreated controls. In the dose-effects study, significant reductions in total body Am content were seen within 3 days after the initiation of C22TT treatment. After 30 days of treatment, there were dose-related reductions in the Pu and Am content of soft tissues and bones. All doses of C22TT resulted in substantial reductions in Pu and Am content of the liver. In the time-response study, there were rapid reductions in total body Am content in the C22TT-treated animals. The greatest reductions occurred within the first 30 days of treatment. Significant decreases in Pu content of soft and hard tissue were observed in the treated animals at 30, 60 or 90 days compared with untreated controls. The greatest reductions in organ Pu content occurred within the first 30 days of treatment, particularly in the liver, but it continued throughout the experiment. Neutron-induced autoradiography showed that C22TT greatly reduced the incorporation of Pu into new bone and substantially reduced the Pu content of the bone marrow. There was no evidence of overt toxicity in either experiment. This study demonstrates that orally administered C22TT is effective in reducing soft and hard tissue content of internally deposited Pu and Am.

Acetates↗
PubMed1992

Age-related differences in the effect of in vivo administration of indomethacin on hemopoietic cell lineages of the spleen and bone marrow of mice.

During 21 days of indomethacin treatment, erythroid cells in the spleens of both young adult and older mice, and in the bone marrow of young adult mice, were increased significantly early in treatment, relative to age-matched control organs, and remained high throughout treatment. During drug exposure, the numbers of myeloid cells in young adult bone marrow, but not spleen, were reduced, but in older mice these cells were elevated in both organs. Lymphoid cells in the young adult and older mouse spleens decreased and increased, respectively, during treatment, but were unchanged and decreased, respectively, in the bone marrow of young adult and older mice. Monocyte-macrophage cells in the spleen were elevated but unchanged in the bone marrow of both age groups. During 14 days of indomethacin treatment of young adult mice, the proportions of precursor cells in DNA synthesis of only the splenic erythroid lineage were increased. Thus, the major hemopoietic lineages in both the bone marrow and spleen are affected by exposure to indomethacin in a time-dependent and age-dependent manner. For all lineages studied, those of the bone marrow were least disturbed and/or were first to recover, even during continued drug exposure.

Age Factors↗
PubMed1992

The microcirculation of bone and marrow in the diaphysis of the rat hemopoietic long bones.

The nature of the microcirculation of the diaphyseal portion of long bones and the adjacent bone marrow is poorly understood. The purpose of this study was to describe the blood supply in the diaphyseal cortex and the relationship of the bone vascular circulation to that of the bone marrow in the growing rat. India ink-gelatin was infused in the arterial system of 3-month-old rats and the vascularization was determined from histological sections. In some studies the periosteal circulation was blocked but the nutrient and metaphyseal arteriole systems were left intact. In the growing rat, most of the vascular flow appears to be centripetally through the diaphyseal cortex and this appears to be the primary blood supply for the adjacent bone marrow. The India ink traversed the cortex and entered the marrow through osteal canals at the endocortical surface. At the marrow-endocortical bone surface interface, ink exiting from the osteal canals filled the adjacent marrow sinusoids in what appeared as "bush-like" structures. From the bone marrow the ink appeared to drain into the central vein. Some arterioles from the nutrient system were found to penetrate the inner two thirds of the cortical bone and then re-enter the bone marrow. The centripetal flow of blood and the importance of the cortical flow for perfusion of the hemopoietic tissue was further documented when periosteal flow was obstructed. In this situation, the cortical bone and adjacent bone marrow were not perfused while the nutrient system and central vein were filled with ink.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Dose-related effects of 1,25-dihydroxyvitamin D3 on growth, modeling, and morphology of fetal mouse metatarsals cultured in serum-free medium.

A serum-free, fetal bone organ culture model that permits the simultaneous determination of modeling and growth parameters was used to examine the effects of a near physiologic and a pharmacologic dose of 1,25-dihydroxycholecalciferol [1,25-(OH)2D3]. The fetuses of pregnant mice were removed on day 17 of gestation, and three medial metatarsal rudiments were cleaned and after preculturing were cultured as pair-matched groups for 4 days in MEM supplemented with 0.2% BSA. 1,25-(OH)2D3 was added to the cultures at concentrations of 10(-12) or 10(-6) M. Cultures treated with the carrier and devitalized bones served as controls. For resorption studies, pregnant mice were given 45Ca on day 17 of pregnancy and fetal metatarsals harvested 24 h later. Resorption was determined by the amount of 45Ca released into the media. DNA synthesis was estimated by determining the incorporation of [3H]thymidine, collagen synthesis by measuring the incorporation of [3H]proline, mineralization by the incorporation of 45Ca, and proteoglycan synthesis by the incorporation of 35S. The amount of radiolabel was detected in media, as well as in noncultured, dead, and cultured rudiments. The total length of the rudiments and length of the calcified diaphyses were measured daily. In addition, rudiments from all experimental groups were prepared for light and electron microscopy. The high dose (10(-6) M) of 1,25-(OH)2D3 suppressed total rudiment growth but not the growth of the calcified diaphysis, 1,25-(OH)2D3 also decreased DNA, collagen, and proteoglycan synthesis, reduced calcification, and increased bone resorption in a dose-related manner. There were morphologic and ultrastructural changes in the osseous tissues and cells, particularly with the high dose of vitamin D, that supported the biochemical findings of suppressed activity of the osteogenic and chondrogenic cells. However, the suppression of collagen production and bone cell proliferation observed with the pharmacologic dose of vitamin D may be partially attributable to the decrease in bone mass (from increased resorption), thus resulting in less osseous tissue surface for these events to occur as endochondral osteogenesis progressed. The lower dose of vitamin D, however, had effects on 35S and 45Ca incorporation that could not be attributed to a decreased osseous tissue mass. This study emphasizes the importance of measuring specialized activities of the various cell populations in bone rudiment culture models to more fully understand the changes in tissue metabolism that result in changes in rudiment growth and modeling.

Animals↗
PubMed1992

Differences in cortical bone in overloaded and underloaded femurs from ovariectomized rats: comparison of bone morphometry with torsional testing.

Osteopenia and mechanical incompetence are the defining features of osteoporosis, yet the effects of changes in bone structure on mechanical properties are not completely understood. The primary objective of this study was to determine if in a rodent model, changes in cortical bone structure, as measured by static morphometry, would correlate with functional properties, as measured by torsional testing. For this, cortical bone structure and stiffness were determined in overloaded and underloaded limbs in rats rendered ovarian hormone-deficient by ovariectomy (OVX). Rats were OVX and six weeks later a hind limb was immobilized by casting for an additional six weeks. In all cases the femur from the underloaded, casted limb was compared with that from the contralateral, overloaded limb. The success of this experimental protocol was confirmed by differences in femoral cancellous bone volume by microradiography and single photon absorptiometry, with the overloaded limb having a greater bone volume and bone mineral density than the contralateral, immobilized controls. Morphometric differences in the femoral diaphyseal cortical bone included greater endocortical perimeter and endocortical osteoclast surface, less cortical area, less minimum cortical width, and less minimum cortical width at fracture planes when the bones were tested for stiffness in the underloaded, compared with the contralateral, overloaded limbs. Using a torsional test, the ultimate torque to failure and stiffness were less in the underloaded femurs compared with the contralateral, overloaded femurs. These results emphasize the importance of mechanical loading on bones from a gonad-deficient animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Decorporation of aged americium deposits by oral administration of lipophilic polyamino carboxylic acids.

Several new powerful chelating agents, suitable for the removal of a variety of certain heavy-metal ions from the body by oral application, have been synthesized and tested. Structurally, these compounds are partially lipophilic polyamino carboxylic acids (PACA). They were synthesized in nonaqueous media from triethylenetetramine (TT) by monoalkylation of a primary amino group, followed by exhaustive carboxymethylation of the remaining amino groups using ethyl bromoacetate and subsequent alkaline hydrolysis of the ester. Compounds were characterized using IR, 1H NMR, 13C NMR, and mass spectrometry. Synthesis and testing of two of these compounds, C12- and C22-triethylenetetraminepentaacetic acid (CnTT), is described in detail. Gel permeation chromatography of a mixture of the PACA and actinide elements have shown these substances to be strong chelating agents similar to EDTA or DTPA. They were capable of removing plutonium from contaminated liver cytosol in vitro. In contrast to their nonlipophilic counterparts EDTA and DTPA, the model substances exhibited appreciable absorption from the intestine and, therefore, can be administered orally. With increasing length of the alkyl chain, the chelons can be directed primarily to the liver, one of the target organs for actinide contamination. In vivo, absorption from the ligated duodenum and jejunum of rats after 2 h was 27% of the amount introduced. Compared to untreated controls, daily feeding of 200 mumol of the chelons (C12TT or C22TT)/kg of body weight to rats for 10 days reduced the whole body Am by 29% and 44%, respectively. Am was eliminated most efficiently from the liver, with a reduction of 71% and 89% (p less than 0.001). However, the skeletal retention also was reduced by 17% and 32% from the femora (p less than 0.001) and 20% and 37% from the carcass for the C12TT and C22TT compounds, respectively. No weight loss or other obvious signs of blood, kidney, liver, or intestinal toxicity were observed after the 10-day treatment. These new chelators are promising as agents for oral chelation therapy to remove actinides and possibly other elements from body stores.

Administration, Oral↗
PubMed1992

Promotion of radiation-induced liver neoplasia by ethanol.

The risk of americium-induced liver cancer in beagle dogs that received long-term dietary ethanol was two to three times that of their nonalcoholic cohorts, even though the radionuclide retention time in hepatic tissue was shortened by the alcohol treatment. Liver malignancies did not occur in the ethanol-treated, nonirradiated controls. An ethanol-induced tumor-promoting effect was not observed in organs or tissues other than the liver.

Americium↗
PubMed1992

Decorporation of plutonium by oral administration of a partially lipophilic polyaminocarboxylic acid.

A new, orally administered, partially lipophilic polyaminocarboxylic acid chelator was tested for its ability to remove incorporated 239Pu deposits in rats. Animals were injected with 239Pu-citrate and 14 d later were treated for an additional 10 d with docosyl-triethylenetetraminepentaacetic acid (C22TT) added to the diet. There were significant reductions in the 239Pu content of selected organs in the chelated animals compared with controls. These results suggest that this class of chelators should be studied further for their ability to remove plutonium deposits from the body when given orally.

Acetates↗
PubMed1992

Alveolar bone remodeling after tooth extraction in normal and osteopetrotic (ia) rats.

One of the osteopetrotic mutations in the rat, incisors-absent (ia), exhibits generalized skeletal sclerosis and failure or delay of tooth eruption, characteristics of other osteopetrotic mutations. Osteopetrosis in ia rats is known to be due to a reduction in bone resorption, the result of the inability of ia osteoclasts to elaborate a ruffled border. During healing of extraction wounds, especially the initial period, osteoclastic resorption of alveolar bone is considered to be a significant feature, followed by new bone formation. We have studied extraction wound healing in osteopetrotic (ia) rats histologically in order to determine if their systemic reduction in bone resorption changes the sequence or rate of alveolar bone healing within and outside the socket after tooth extraction, In ia rats, the healing process was delayed in comparison to that of normal rats. Many osteoclasts were observed on the surface of alveolar bone, but there was little evidence of resorption. Bone formation in the socket following bone resorption was reduced and the newly formed trabeculae were irregular. In contrast, the quantity of resorption-independent (periosteal) new bone formation outside the socket was exaggerated compared to normal animals. These data indicate that the disturbance of new bone formation in the socket is probably related to the reduction in osteoclastic bone resorption.

Alveolar Bone Loss↗
PubMed1992

What is the proper integration of optometry and ophthalmology?

The delivery of health care services in America today utilizes a variety of approaches based on many economic, political and social factors. The current health care system is coming under significant review and criticism. Many options are being considered and recommended. This paper addresses possible changes in the delivery of eye care, specifically the relationship between the professions of optometry and ophthalmology, that may be needed in the future.

Delivery of Health Care↗
PubMed1991

Iron-independent induction of ferritin H chain by tumor necrosis factor.

Iron increases the synthesis of the iron-storage protein, ferritin, largely by promoting translation of preexisting mRNAs for both the H and L ferritin isoforms (H, heavy, heart, acidic; L, light, liver, basic). We have recently cloned and sequenced a full-length cDNA to murine ferritin H and identified ferritin H as a gene induced by tumor necrosis factor alpha (TNF-alpha, cachectin). Using primary human myoblasts, we have now examined the relationship between TNF-alpha and iron in regulating ferritin. Four lines of evidence suggest that TNF-alpha regulates ferritin independently of iron. First, evaluation of mRNA showed that TNF-alpha increased ferritin H chain specifically, provoking no change in steady-state levels of ferritin L mRNA; iron, in contrast, increased the mRNA of both isoforms. Second, the increase in ferritin H protein synthesis observed during TNF-alpha treatment was dependent on an increase in ferritin H mRNA: actinomycin D blocked the TNF-alpha-induced changes in ferritin H but did not inhibit the translational induction of ferritin seen with iron treatment. Third, equal ferritin mRNA induction was observed in iron-loaded cells and in cells depleted of iron by a permeant chelator, 2,2'-dipyridyl. Fourth, ferritin H induction by TNF-alpha and iron was additive over the entire range of iron concentrations, even at TNF-alpha doses known to maximally stimulate ferritin H mRNA levels. Nonetheless, the role of iron in translational regulation of ferritin was retained in TNF-alpha-treated cells; effective biosynthesis of TNF-alpha-induced, H-subunit-predominant ferritin protein required iron and could be enhanced by treatment of the cells with additional iron or blocked by 2,2'-dipyridyl. Finally, we observed that the TNF-alpha-mediated increase in ferritin synthesis peaked at 8 hr and was followed by a decrease in both H and L isoferritin synthesis; the addition of iron, however, reversed the late-occurring depression in ferritin synthesis. This suggests that TNF-alpha-induced synthesis of H-rich ferritin may reduce the regulatory pool of intracellular iron, secondarily inhibiting iron-mediated translation of ferritin mRNA. We conclude that TNF-alpha acts independently of iron in its induction of ferritin H mRNA but requires the presence of iron for this effect to be fully expressed at the protein level.

2,2'-Dipyridyl↗
PubMed1991

Tumor necrosis factor-alpha and interleukin 1-alpha regulate transferrin receptor in human diploid fibroblasts. Relationship to the induction of ferritin heavy chain.

We have studied transferrin receptor expression in MRC5 human fibroblasts in response to tumor necrosis factor-alpha (TNF, cachectin) or interleukin 1-alpha (IL-1). Treatment of exponentially growing MRC5 cells with these cytokines led to a 3-4-fold increase in transferrin receptor mRNA and a coordinate increase in transferrin receptor protein by 24 h. Under these conditions, stimulation of [3H]thymidine incorporation was minimal, suggesting that the induction of transferrin receptor by TNF and IL-1 is mediated by a growth-independent regulatory mechanism. A study of the time course of this response showed that cytokine-mediated increases in transferrin receptor mRNA and protein proceeded after a lag of 12-24 h. A simultaneous analysis of the effects of TNF and IL-1 on ferritin in MRC5 cells was also performed. Ferritin L mRNA levels were unchanged. However, induction of ferritin H mRNA was seen within 4 h, preceding the induction of the transferrin receptor. The synthesis of ferritin H (but not ferritin L) protein peaked at 8 h after TNF or IL-1 treatment, followed by a rapid decrease in both ferritin H and L protein synthesis. As ferritin H synthesis declined, levels of transferrin receptor protein increased, reaching a maximum by 24 h. These results suggest that the cytokine-dependent induction of ferritin H and subsequent increase in the transferrin receptor are related and possibly interdependent events. This study demonstrates that the complex role of TNF and IL-1 in iron homeostasis includes modulation of the transferrin receptor.

Cell Division↗
PubMed1991

Evaluation of mRNA levels by the polymerase chain reaction in small cardiac tissue samples.

Doxurubicin is an effective and widely used chemotherapeutic agent. However, use of this drug is often limited by its cardiotoxic side effects. We have observed that an early event accompanying doxorubicin cardiomyopathy is a selective decrease in levels of muscle gene transcripts in cardiac tissue (Ito et al., Proc. Natl. Acad. Sci. USA 87: 4275-4279). Since this decrease precedes ultrastructural evidence of cardiac damage, measurements of muscle transcripts might assist in the clinical evaluation of doxorubicin cardiotoxicity. We have therefore assessed the utility of the polymerase chain reaction in the measurement of mRNA in control and doxorubicin-treated animals. These measurements were performed on small tissue samples that simulate endomyocardial biopsies. We measured cardiac alpha-actin transcripts as a fraction of ferritin heavy chain transcripts using the method described by Chelly et al. (Nature 333: 858-860, 1988). 0.5 micrograms of total RNA, an amount equivalent to that obtainable from a typical endomyocardial biopsy, was efficiently co-amplified with cardiac alpha-actin and ferritin heavy chain specific primers. The cardiac alpha-actin/ferritin heavy chain ratio calculated from the PCR results correlated well (R = 0.981) with results obtained using Northern blot analysis of 10 micrograms RNA. The correlation was maintained over a wide range of cardiac alpha-actin transcript abundance. These results show that mRNA from cardiac tissue can be estimated by the polymerase chain reaction, even from a small, endomyocardial biopsy-sized sample.

Actins↗
PubMed1991

Calcium absorption and osseous organ-, tissue-, and envelope-specific changes following ovariectomy in rats.

Because cancellous bone loss occurs following ovariectomy (OVX) in rats, this has become a popular model to explore therapeutic modalities for postmenopausal bone loss in humans. The purpose of this study was to determine intestinal calcium absorption in situ and organ-, tissue-, envelope-, and site-specific changes in osseous tissues at six weeks after OVX in rats using chemical, biochemical, absorptiometric, microradiographic, and morphometric methods. There were no changes in intestinal absorption of calcium, but duodenal weight per length was significantly increased in the OVX animals compared with age-matched, sham-operated controls. There was an increase in wet bone weight, but decreases in ash/dry bone weight, total bone Ca, and Ca per ash weight in the OVX animals. There were significant decreases in the OVX animals in metaphyseal bone mineral content, as determined by photon absorptiometry and metaphyseal cancellous bone volume. The perimeter to area ratio of the metaphyseal cancellous bone in the OVX animals was increased compared with controls. Endochondral growth rates were increased in the OVX animals, attributable to an increased growth plate hypertrophic cell size and rate of chondrocyte proliferation. In the OVX animals there was an increase in modeling in the formation mode of the periosteal surface at the tibio-fibular junction. Increased periosteal modeling in the formation mode was also observed in the body of the mandible, suggesting that the changes in periosteal bone formation are not strictly coupled with changes in endochondral growth. There was an increase in modeling in the resorption mode of the endocortical surface at the tibio-fibular junction in the OVX animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1991

Population dynamics of natural killer cells in the spleen and bone marrow of normal and leukemic mice during in vivo exposure to interleukin-2.

By quantitative and functional methods, changes were assessed in NK(ASGM-1+) cell numbers and NK cell-mediated lytic function of the spleen and bone marrow of mice bearing a tumor of hemopoietic origin (FLV-induced erythroleukemia) for 9 days +/- simultaneous administration of indomethacin (10 micrograms/ml drinking water) +/- rIL-2 (3x/day, 12 x 10(3) Units/injection) during the last 4 days of tumor-bearing. Recombinant IL-2 alone during the last 4 days of tumor-bearing increased both the NK(ASGM-1+) cell numbers (p less than 0.001) and the functional activity (24-fold) of the spleen. In the bone marrow, however, no change in the numbers of NK(ASGM-1+) cells was observed relative to untreated tumor-bearing mice, but the NK cell-mediated lytic activity of that organ was augmented 30-fold. The continuous presence of indomethacin from the onset of tumor-bearing prior to rIL-2 treatment during the last 4 days of tumor-bearing, further boosted both the already high, rIL-2 driven numbers of NK(ASGM-1+) cells in the spleen (p less than 0.01), as well as splenic NK cell lytic function (2-fold). In the bone marrow, continuous presence of indomethacin prior to and during the terminal 4 days of co-administration with rIL-2 increased 3-fold the numbers of NK(ASGM-1+) cells relative to that of the bone marrow of tumor-bearing mice given rIL-2 alone, and resulted in lytic activity of that organ which was 140% of that of the rIL-2 treated, tumor-bearing mice. The results indicate that under the combined influence of indomethacin and rIL-2, the production of NK(ASGM-1+) cells was augmented in the bone marrow of tumor-bearing mice, export of immature NK(ASGM-1+) cells from the bone marrow was increased, and import of immature NK(ASGM-1+) cells by the spleen was increased. The increased NK(ASGM-1+) cell numbers in each organ was reflected in increased lytic function.

Animals↗