Biomedical subjects

S C Miller

Publications and source records attributed to S C Miller.

At least 163 records · Page 9Linked to original sources

PubMed1991

Plutonium- or americium-induced liver tumors and lesions in beagles.

Plutonium-239 or 241Am administered intravenously in the monomeric citrate form was initially deposited in beagle livers principally in the hepatocytes and to a much lesser extent in the sinusoidal macrophages and connective tissues. The initial distribution was quite uniform throughout the hepatic parenchyma; however, at later postinjection intervals, depending on the amount of injected activity, the liver burden became increasingly more focal due to: (1) a progressive shift of the radionuclide from the hepatic epithelium to the macrophages; (2) the movement of such macrophages toward the portal or central regions of the lobule; and (3) the displacement of the older more radioactive tissue by regenerating hepatocytes, which generally have a much lower radionuclide content. The hepatic lesions produced by Pu or Am included: (1) necrosis and degenerative changes that were clinically serious or fatal in some of the animals injected with approximately 107 kBq kg-1; (2) marked structural and circulatory changes resulting from necrosis and focal hepatocyte hyperplasia; (3) a significant incidence of both benign and malignant primary liver tumors. In both Pu- and Am-treated dogs, the most frequently appearing neoplasm was the bile duct adenoma, followed by the cholangiocarcinoma. The most obvious difference between Pu- and Am-induced liver neoplasia was the greater frequency of fibrosarcomas and mast cell sarcomas in the Am-treated groups. Hepatomas were of relatively low frequency in animals with Pu or Am burdens. Although the incidence of bone neoplasia was high among the dogs in these studies, the risk of liver tumors, especially in the Am-treated animals, exceeded that of the skeleton in some of the lower dosage levels where the survival times were long. A risk coefficient of approximately 1200 fatal liver malignancies (10(4) beagle Gy)-1, derived from the dosage groups with long survival times, was calculated for combined Pu and Am animals. The prominence of the liver syndromes in beagles with burdens of Pu or Am indicates that humans with body burdens of 239Pu, 241Am, or other actinide elements may be at risk from radiation effects in the liver, including neoplasia development.

Adenoma↗

PubMed1991

Relationship between large and small tumor-binding cells in the spleen and bone marrow.

By employing a distinctive feature of natural killer (NK) cells, i.e., spontaneous target cell binding, the present study aimed to follow a relatively large cohort of target-binding cells (TBC), subdivided according to size and the presence of the radioautographically labelled nucleotide, tritiated thymidine, incorporated during a 1- or 6-hour exposure period. Labelling among all TBC in the spleen was 5% by 1 h after a single injection of the isotope and this value did not change significantly after 6 h of isotope exposure. There was an insignificant increase in the labelling index of spleen-localized, labelled, large TBC throughout and beyond the isotope exposure period for at least 48 h, concomitant with a significant increase in the labelling index of spleen-localized, small TBC during the same period. In the bone marrow, small TBC showed only 2% labelling by 1 h after a single injection of isotope, while 21% of large TBC in that organ were synthesizing DNA during the same period. The results are consistent with a precursor-product relationship between large and small TBC within the bone marrow but not the spleen, and with a bone marrow-to-spleen migration of small (+/- large) TBC. Moreover, a minor population of large TBC was detected in the spleen with kinetic characteristics distinct from those of the bone marrow.

Animals↗

PubMed1991

Effects of a low-pathogen environment on natural killer cells of normal and B lymphocyte-deficient mice.

The effect of short-term exposure (1 month) to a low-pathogen environment (LPE) on NK cell levels in the bone marrow and spleen of immunologically normal CBA/CaJ and B-lymphocyte-deficient CBA/N mice was assessed using both functional (51Cr release) and histological methods. The total NK activity (TNKA), i.e. the percentage specific lysis corrected for changes in whole organ cellularity, of the spleens of LPE-exposed CBA/CaJ mice was not significantly different from that of conventionally reared control mice of that strain (112%), while TNKA of the bone marrow of LPE-exposed mice fell to 27% of that of the bone marrow of conventionally reared controls. TNKA of the spleen and bone marrow of LPE-exposed CBA/N mice was reduced (30%) and elevated (120%), respectively, relative to their conventionally reared counterparts. The numbers of asialo-GM-1-positive (ASGM-1+) lymphoid cells, putative NK cells, in CBA/CaJ spleens were more numerous in conventionally reared than in LPE-exposed mice (4.9 X 10(6) vs. 2.7 X 10(6), and were also more numerous in the bone marrow of conventionally reared mice than in LPE-exposed animals (8.0 X 10(4), vs. 3.0 X 10(4) cells). Similarly, in LPE-exposed CBA/N mice, the numbers of ASGM-1+ lymphoid cells in the spleens and bone marrow were lower (2.7 X 10(6) and 5.4 X 10(4), respectively) than those of the spleens and bone marrow of their conventionally reared counterparts (3.8 X 10(6) and 10.0 X 10(4), respectively). The results demonstrate that short-term maintenance in an LPE affected the NK cells of both the spleen and bone marrow of immunologically normal and B-lymphocyte-deficient mice in a strain-specific manner and suggest that the external environment may regulate NK cell production and turnover.

Animals↗

PubMed1991

Ultrastructure, tartrate-resistant acid phosphatase activity and calcitonin responsiveness of osteoclasts at sites of demineralized bone matrix implant-induced osteogenesis.

The morphology, ultrastructure, tartrate-resistance acid phosphatase reactivity, and calcitonin responsiveness of osteoclasts induced at sites of demineralized bone matrix (DBM) implant-induced osteogenesis in rats were determined. Osteoclasts at these ectopic sites had a morphologic and ultrastructural appearance similar to osteoclasts normally found in skeletal tissues. When observed by scanning electron microscopy, resorption surfaces on the implants had well-defined resorption pits (Howship's lacunae), indicative of active bone resorption. The osteoclasts stained intensely for tartrate-resistance acid phosphatase, an enzyme that is specific for osteoclasts. In response to human calcitonin, hypocalcemia occurred and osteoclasts lost their ruffled borders, indicating that these cells are responsive to exogenous hormonal stimulation. The osteoclasts induced by subcutaneous implantation of DBM had morphologic and functional characteristics similar to osteoclasts normally found in skeletal tissues.

Acid Phosphatase↗

PubMed1991

The influence of age at time of exposure to 226Ra or 239Pu on distribution, retention, postinjection survival, and tumor induction in beagle dogs.

The influence of age at injection of 226Ra or 239Pu on skeletal deposition and local distribution, the pattern of bone tumor formation, and postinjection survival was assessed in parallel short-term studies of mechanisms and lifetime toxicity. Beagles received a single intravenous injection of 226Ra or 239Pu at 3 months (juveniles), 17-19 months (young adults) or 60 months (mature). Data from short-term studies of mechanisms and dosimetry and from one dosage level (41 kBq 226Ra/kg or 11 kBq 239Pu/kg body mass) of each of the toxicity experiments were compared. Skeletal growth and turnover produced differential initial deposition and distribution patterns typical for each age group. At 1 week after injection, skeletal retention of 226Ra or 239Pu was 68 and 68%, respectively, in the juveniles, 32 and 46% in the young adults, and 31 and 43% in the mature dogs. Comparing individual bones in the juveniles, gradients in the concentration of 239Pu were small since all bones were actively growing, but substantial gradients, corresponding to centers of ossification, were present within individual bones. In other age groups, local concentration gradients were less pronounced, but much larger differences were present among the various bones. In the toxicity study all animals injected with either 41 kBq 226Ra/kg or 11 kBq 239Pu/kg have died. The cumulative average skeletal doses to the presumed time of start of tumor growth (1 year before death) were 25 and 4 Gy, respectively, for the juveniles, 22 and 5 Gy for the young adults, and 15 and 4 Gy for the mature dogs. The highest bone tumor incidence was seen in the young adult groups. Differences were observed in location of bone tumors between dogs in the same age group given radium or plutonium and among age groups injected with either radionuclide, some of which could be explained by differences in local dose distributions. Median postinjection survival assessed by the Kaplan-Meier nonparametric method ranged from 2513 and 2592 days for the juveniles to 2099 and 1617 for the young adults to 2086 and 1421 in the mature groups. Cox regression analysis indicated no significant differences in postinjection survivals (uncorrected for the different preinjection periods) of groups injected with radium, but there was a statistically significant difference among the groups injected with plutonium. It was demonstrated that differences in the effects of 239Pu in the three groups were due primarily to the age- and time-dependent local distribution of the radionuclide.

Aging↗

PubMed1991

A comparison of the natural survival of beagle dogs injected intravenously with low levels of 239Pu, 226Ra, 228Ra, 228Th, or 90Sr.

The natural survival, relative to properly chosen controls, of 26 beagle dogs injected once intravenously with an average of 0.58 +/- 0.04 kBq 239Pu/kg, 23 dogs injected with 2.31 +/- 0.43 kBq 226Ra/kg, 13 dogs injected with 1.84 +/- 0.26 kBq 228Ra/kg, 12 dogs injected with 0.56 +/- 0.030 kBq 228Th/kg, and 12 dogs injected with 21.13 +/- 1.74 kBq 90Sr/kg was evaluated statistically. The amounts of these radionuclides are related directly to the estimated maximum permissible body burdens for humans suggested in ICRP II (1959). They constitute a level of exposure that initially was assumed to cause no deleterious effects in dogs. This study had two objectives: (1) identification of homogeneous control groups against which to evaluate the survival of the irradiated groups and (2) comparison of the survival characteristics and estimation of mortality or hazard rate ratios for control dogs vs dogs injected with the baseline dosages given above. It was shown, by goodness-of-fit plots, that the Cox proportional hazards model was an appropriate method of analysis. Therefore, covariates that possibly could influence survival were tested for significance. Only the effects of grand mal seizure, which is caused in epileptic dogs by an external stimulus and can be fatal if untreated, were significant (P less than 0.0001). Consequently, in the final model, death from grand mal seizure was considered as accidental. After censoring the dogs dying from grand mal seizure, it was established that the data for the control groups from previous and contemporary experiments could be pooled. The change in hazard rates relative to controls resulting from exposure to the baseline radionuclide level was modest, 1.6 times for 239Pu (P = 0.033), 1.0(4) for 226Ra (P = 0.86), 1.9 for 228Ra (P = 0.035), 2.5 for 228Th (P less than 0.001), and 0.52 for 90Sr (P = 0.041). Bone tumor induction was clearly elevated in dogs injected with 239Pu and 228Th. When the effect of these bone tumors on survival was removed by censoring, the dogs injected with 239Pu were indistinguishable from the controls. In contrast, the effects of bone tumor on group survival of the 228Ra and 228Th dogs were not significant. Thus, no additional life-shortening effects beyond those attributable to bone tumor were suggested by these data for 239Pu, but other, as yet unspecified, confounders are suggested for 228Ra and 228Th.

Analysis of Variance↗

PubMed1990

Interleukin 1 induces ferritin heavy chain in human muscle cells.

Interleukin 1 alpha (IL-1) and tumor necrosis factor alpha (TNF) are two monokines which play a prominent role in the response to inflammation and injury. We recently observed that TNF leads to an increase in the synthesis of the heavy chain of ferritin, suggesting that TNF may be involved in iron homeostasis (Torti et al. (1988) J. Biol. Chem. 263, 12638-12644). The experiments reported here demonstrate that in cultured human muscle cells, IL-1 induces ferritin H mRNA and protein as effectively as TNF. TNF and IL-1 were additive in their effects on ferritin H expression, and IL-1 induction of ferritin H was not blocked by anti-TNF antibodies. Ferritin H induction was a specific response not observed with beta or gamma interferon, nor with transforming growth factor beta. Both differentiated myotubes as well as myoblasts responded to IL-1 with the induction of ferritin H. These results suggest that monokine-mediated alterations in the subunit composition of the ferritin molecule may be of biological relevance in the response to inflammation and injury.

Cells, Cultured↗

PubMed1990

Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro.

The anthracycline antibiotic doxorubicin produces a characteristic myopathy in cardiac muscle that limits its use in cancer therapy. We have shown in cultured neonatal rat cardiac muscle cells that doxorubicin treatment resulted in a rapid, selective decrease in the expression of muscle-specific genes, which preceded other changes characteristic of doxorubicin cardiomyopathy. Doxorubicin selectively and dramatically decreased the levels of mRNA for the sarcomeric genes, alpha-actin, troponin I, and myosin light chain 2, as well as the muscle-specific, but nonsarcomeric M isoform of creatine kinase. However, doxorubicin did not affect nonmuscle gene transcripts (pyruvate kinase, ferritin heavy chain, and beta-actin). Actinomycin D, an inhibitor of DNA-dependent RNA polymerase, did not show a similar selective decrease of muscle-specific mRNAs but, rather, produced a nonspecific, dose-dependent decrease of muscle and nonmuscle transcripts. The doxorubicin effect on muscle gene expression was limited to cardiac muscle; cultured skeletal myocytes were resistant to the effects of doxorubicin at 100-fold greater doses than those causing changes in mRNA levels in cardiac muscle cells. These effects of doxorubicin were reproduced in vivo; rats injected with doxorubicin showed a dose-dependent decrease in the levels of mRNAs for alpha-actin, troponin I, myosin light chain 2, and M isoform of creatine kinase in cardiac but not skeletal muscle. These selective changes in gene expression in cardiocyte cultures and cardiac muscle precede classical ultrastructural changes and may explain the myofibrillar loss that characterizes doxorubicin cardiac injury.

Actins↗

PubMed1990

Kidney disease in beagles injected with polonium-210.

An unusually high incidence of kidney disease (tubular degeneration and necrosis with fibrous replacement) was observed among 24 beagles injected at about 5 years of age with 116 or 329 kBq 226Ra kg-1 but not among an additional 10 beagles given about 39 kBq 226Ra kg-1. This 226Ra solution also contained 210Pb, 210Bi, and 210Po. To determine whether the kidney disease was related to the radiation from 226Ra and its short-lived progeny or to the alpha radiation from 210Po, 2 beagles about 7 years of age were injected with 451 kBq 226Ra kg-1 of 210Po citrate. Measurements of polonium retention in the kidneys of 4 additional beagles given 210Bi citrate enabled us to model the retention of these emitters in the dog kidney and to estimate the kidney dose from the alpha radiation of 210Po following injection of either 226Ra + 210Bi + 210Po or 210Po only. Autoradiography revealed that almost equal concentrations of 210Po were in the tubular epithelium and/or its basement membrane and in the glomeruli, but very little of the 210Bi deposited in kidney tissue was present in the glomeruli. Radiation damage to the kidneys similar to that observed previously in beagles given 226Ra solutions that also contained 210Bi and 210Po was seen among the beagles given 210Po but not in the dogs given purified 226Ra. The analysis of these data indicated that the relatively high incidence of kidney disease among the mature beagles injected with 226Ra and its accompanying 210Bi and 210Po resulted from alpha irradiation of the kidneys by the substantial amount of 210Po that was in the injection solution.

Animals↗

PubMed1989

Protirelin (thyrotropin-releasing hormone) in amyotrophic lateral sclerosis. The role of androgens.

Protirelin (thyrotropin-releasing hormone) appears to be a neuromodulator in the extrahypothalamic nervous system and has been suggested as an adjunct in the treatment of amyotrophic lateral sclerosis (ALS). Clinical studies have been divided on the efficacy of protirelin (TRH) despite strong experimental findings that are consistent with a role for the peptide in ALS. Recent findings provide evidence of a gender-related specificity in the ability of protirelin to potentiate the monosynaptic reflex. While castration in male neonatal rats lowered the sensitivity to protirelin, testosterone treatment restored that sensitivity. An examination of the clinical studies reveals a failure either to identify patients' sex or to separate the results on the basis of sex. These findings provide convincing evidence for the potential efficacy of protirelin in ALS if the patient's sex and underlying hormonal status are taken into account.

Amyotrophic Lateral Sclerosis↗

PubMed1989

Increased cancellous bone remodeling during lactation in beagles.

Changes in bone mass and cancellous bone remodeling parameters were determined during lactation in adult beagles. Bone mineral content was determined by photon absorptiometry, fraction of mineralized cancellous bone area and perimeter to area ratios by image analysis of microradiographs, and bone remodeling parameters by fluorochrome-based histomorphometry. Bone mineral content of the intact proximal humerus and fraction of mineralized tissue areas of lumbar vertebral cancellous bone were decreased during lactation when compared with controls. There were significant increases during lactation in osteoid volumes and osteoid surface, although osteoid seam thickness was not changed. There were significant increases in the fraction of fluorochrome-labeled cancellous bone surfaces in the lactating dogs when compared with controls. The mineralizing surface, bone formation rate and activation frequency were significantly increased in the lactating dogs when compared with controls. There were also significant increases in resorption parameters during lactation. These data indicate that during lactation, bone remodeling and bone turnover is increased. Increased bone remodeling during lactation in a longer-lived mammal may represent an example of a "reversible mineral deficit" which may be an important physiological mechanism in nursing mothers to ensure adequate calcium for milk production. Increased bone remodeling may also provide a physiological mechanism to enhance the capacity of the skeleton to better accommodate the greatly increased and episodic changes in mineral homeostasis during lactation.

Animals↗

PubMed1989

Influence of age at exposure on concentrations of 239Pu in beagle gonads.

The influence of age at injection of 239Pu on the gonadal concentrations with time after injection in beagle dogs was determined. In addition, the distribution patterns of Pu within the organs were examined using fission track autoradiography. Beagles of different ages (juveniles approximately 90 d; young adults approximately 17 mo; aged approximately 5 y) were given a single injection of 239Pu(IV)-citrate and most were allowed to live out their natural lifespan. At times greater than 1,000 d after exposure, the concentrations of 239Pu (expressed as percent injected per gram organ weight) were higher in the testes and ovaries from animals injected as young adults (median 9.8 X 10(-4) and 15.4 X 10(-4%) g-1, respectively) when compared with the juveniles (median 2.8 X 10(-4) and 7.7 X 10(-4%) g-1, respectively) or aged (median 6.3 X 10(-4) and 17.2 X 10(-4%) g-1, respectively) animals. The lower concentrations found in the animals injected as juveniles can be attributed to the increase in gonadal size that occurs during organ maturation and puberty. Fission track autoradiographs from gonadal tissues at least 5 y after exposure confirm the nonuniform distribution of the nuclide in these organs. In the testis, Pu was found mostly in the interstitial tissues and in the ovary, was found in the stroma, particularly the medullary stroma.

Aging↗

PubMed1989

Impact of health care trends on the practice of optometry.

Major trends occurring within the health care field will impact on the future practice of optometry. This report reviews several trends relating to cost containment, alternative delivery systems, population demographics, competition, corporate involvement in health care, and health promotion and wellness programs. Predictions are made regarding changes that may occur in optometric practice in the future in response to these emerging health care trends.

Delivery of Health Care↗

PubMed1989

Calciotrophic hormone levels and calcium absorption during pregnancy in rats.

The mammalian maternal skeleton stores Ca during pregnancy perhaps for fetal skeletal mineralization in late pregnancy and milk production during lactation. The interrelationships between intestinal Ca absorption and hypertrophy and plasma levels of total Ca, ionized Ca, 25-hydroxyvitamin D3 [25(OH)D], 1,25-dihydroxyvitamin D3 [1,25(OH)2D], and parathyroid hormone (PTH) were determined at different stages of pregnancy in rats. By midpregnancy and before fetal skeletal mineralization, plasma ionized Ca levels, Ca absorption by duodenal tissue in vitro, Ca absorption by the duodenum in situ, and duodenal wet weight were increased and 25(OH)D was decreased. Later in pregnancy, during fetal skeletal mineralization, 1,25(OH)2D and PTH levels were also substantially increased and total serum Ca levels decreased. These data demonstrate changes by midpregnancy, before fetal skeletal mineralization, in maternal mineral homeostasis concomitant with known changes in skeletal metabolism. Some of the early changes in mineral metabolism may occur independent of the vitamin D and PTH endocrine system.

Animals↗

PubMed1989

Altered production and renewal of natural killer cells in B-lymphocyte-deficient CBA/N mice.

The present study was designed to measure by quantitative and kinetic methods the production and renewal of natural killer (NK) cells in congenitally B-lymphocyte-deficient (CBA/N) mice. The total NK activity (percent specific lysis corrected for changes in whole organ cellularity) of the bone marrow and spleen of immunologically normal (CBA/CaJ) and CBA/N mice was assayed prior to and immediately after 48 h treatment (2 X/day, i.p.) with the cell cycle poison hydroxyurea (HU) and at various intervals throughout the subsequent post-HU recovery period. The total NK activity (TNKA) of untreated CBA/N bone marrow was 154% of that of CBA/CaJ bone marrow while the TNKA of CBA/N spleen was not significantly different (112%) from that of CBA/CaJ spleen. At the conclusion of 48 h HU, bone marrow TNKA of CBA/N and CBA/CaJ mice fell to 60 and 49%, respectively, of their saline-injected (2 X/day, i.p.) control levels, while spleen TNKA fell to 42 and 61%, respectively, of their saline-injected control levels. In the bone marrow, NK cell depletion in response to HU was more rapid in CBA/N mice (day 0.5 after HU) than in CBA/CaJ mice (day 2 after HU). TNKA of the spleen also decreased more rapidly in CBA/N mice (day 2 after HU) than in CBA/CaJ mice (day 3 after HU). The data indicate an enhanced production and turnover of NK cells in CBA/N mice relative to CBA/CaJ mice. Moreover, increased production and renewal of NK cells in CBA/N mice together with virtually unchanged levels of NK activity (112% of CBA/CaJ mice) in CBA/N mouse spleens indicate that mature lytic NK cells in CBA/N spleen but not bone marrow have a significantly shorter post-mitotic life span than do NK cells in the spleens of immunologically normal (CBA/CaJ) mice.

Animals↗

PubMed1989

Osteoclast features of cells that resorb demineralized and mineral-containing bone implants in rats.

The comparative temporal tissue response to demineralized bone matrix powder (DBP) and devitalized mineral containing bone powder (MCP) implanted subcutaneously in rats was studied. The tissue response to implanted DBP followed the well described endochondral osteogenic pathway and included the appearance of osteoblasts and osteoclasts. On the other hand, implanted MCP resulted in the appearance of a large population of giant cells that resorbed the implants. At later times (3-4 weeks), most of the cells in the MCP implants appeared as typical foreign body giant cells with extensive membrane foldings, usually away from bone surface. Some cells did, however, have the histological appearance of osteoclasts, although this could not be completely confirmed by transmission electron microscopy. Scanning electron microscopy of anorganic preparations of the MCP following implantation showed resorption pits covering most of the surface, providing additional evidence that the resorption of bone by osteoclasts and giant cells may involve similar mechanisms. The observations suggest that both osteoclasts and giant cells may be involved with the resorption of ectopic MCP.

Animals↗

PubMed1989

Ultrastructural features of osteoclasts in situ.

The morphology of in situ osteoclasts on endocortical surfaces of the femoral midshaft was examined by scanning electron microscopy. Mice were perfusion fixed and bone marrow plugs were flushed out of femoral diaphyseal cylinders. The bones were split longitudinally and the endocortical surfaces examined. This method left on the bone surface most of the endosteal cells in their natural, in situ shape and position. Most of the bone surface was lined by contiguous bone lining cells covering resting bone surfaces, making a clear physical barrier between the bone and marrow compartments. On resorption surfaces, which were characterized by excavation cavities, osteoclasts were very polymorphic and spread on the bone surface, extending large pseudopods. The in vivo morphology of individual osteoclasts appears somewhat similar to that described by other investigators on calvaria surfaces and for isolated osteoclasts adherent to artificial substrates. In the resorption domains, osteoclasts appeared to be connected with adjacent osteoclasts, suggesting that the cells form a functional syncytium in resorption areas.

Animals↗

PubMed1989

Bone lining cells: structure and function.

Bone lining cells (BLC's) cover inactive (nonremodeling) bone surfaces, particularly evident in the adult skeleton. BLC's are thinly extended over bone surfaces, have flat or slightly ovoid nuclei, connect to other BLC's via gap junctions, and send cell processes into surface canaliculi. BLC's can be induced to proliferate and differentiate into osteogenic cells and may represent a source of "determined" osteogenic precursors. BLC's and other cells of the endosteal tissues may be an integral part of the marrow stromal system and have important functions in hematopoiesis, perhaps by controlling the inductive microenvironment. Because activation of bone remodeling occurs on inactive bone surfaces, BLC's may be involved in the propagation of the activation signal that initiates bone resorption and bone remodeling. Evidence also suggests that BLC's are important in the maintenance of the bone fluids and the fluxes of ions between the bone fluid and interstitial fluid compartments for mineral homeostasis.

Animals↗