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S C Miller

Publications and source records attributed to S C Miller.

At least 127 records · Page 7Linked to original sources
PubMed1995

Pharmacological characterization of a new class of nonpeptide neurokinin A antagonists that demonstrate species selectivity.

We examined the pharmacology of ZM253,270 and two representative examples of the pyrrolopyrimidines, a new class of nonpeptide, NK-2 receptor (NK-2R) antagonists. ZM253,270 competitively inhibited [3H]NKA binding to native or cloned NK-2R from hamster urinary bladder (Ki = 2 nM), but was a weaker (48-fold) inhibitor of [3H]NKA binding to cloned human NK-2R. A similar species selectivity was observed with less potent analogs of ZM253,270. The pyrrolopyrimidines demonstrated only marginal inhibition of [3H]SP binding to NK-1R in guinea pig lung membranes (Ki > 2 microM). In hamster trachea, ZM253,270 competitively antagonized the contractile response evoked by neurokinin A (NKA, -logKB = 7.5). In human bronchus, ZM253,270 was about 90-fold less potent as a competitive antagonist of NKA. The data from ligand binding assays in cloned receptors combined with functional receptor assays in airway smooth muscles, demonstrate that the nonpeptide antagonist ZM253,270 is selective for the NK2 receptor species that are prevalent in hamster, compared with those found in human tissues.

Animals↗
PubMed1994

Comparison of osteopenic changes in cancellous bone induced by ovariectomy and/or immobilization in adult rats.

BACKGROUND: Ovariectomy (OVX) and immobilization (IMM) in rats are useful models of osteopenia, replicating some aspects of osteoporosis in humans. The purpose of this study was to compare changes in cancellous bone after OVX and/or IMM. METHODS: Differences in cancellous bone were determined at 6 and 12 weeks after OVX or IMM. Comparisons were also made when rats were ovariectomized or immobilized for 6 weeks and then immobilized (OVX/IMM) and ovariectomized (IMM/OVX), respectively, for 6 more weeks. The femurs were used to determine bone mineral content (BMC) using single photon absorptiometry (SPA) and for scanning electron microscopy (SEM). Tibias were collected for microradiography, image analysis, and histomorphometry of metaphyseal cancellous bone. RESULTS: Six and 12 weeks after OVX, there was less cancellous bone mass, compared with controls, as indicated by SPA, SEM, microradiography, image analyses, and histomorphometry. Bone was lost primarily from the central metaphyseal regions in the OVX animals, whereas the loss occurred throughout the metaphyses in the IMM animals. There were more rodlike bone spicules and fewer platelike trabeculae in the OVX and IMM groups compared with controls. Differences in the structural aspects of the cancellous bone, including differences in the types of bone struts and marrow star volumes, indicated less trabecular connectivity and greater trabecular separation in the OVX and IMM animals, compared with controls. Endochondral growth indices in the IMM groups tended to be less, whereas the OVX groups tended to be greater than controls. Cancellous bone formation rates were generally greater in the OVX groups but less in the IMM groups compared with controls. Osteoclastic resorption surfaces were substantially elevated in the IMM and OVX groups, particularly the IMM groups. Changes reflecting OVX and IMM, independently, were apparent in the OVX/IMM and IMM/OVX groups and indices of osteopenia were different from controls, including less bone mass, trabecular connectivity, and greater trabecular separation, bone turnover rates, and osteoclastic surface. CONCLUSIONS: These results demonstrate differences in the osteopenic changes that occur in cancellous bone following OVX or IMM. The changes were generally more dramatic in the IMM than in the OVX animals. When OVX and IMM were applied in combination, the osteopenic changes are particularly severe, emphasizing the importance of mechanical usage even with a deficiency of gonadal hormones.

Animals↗
PubMed1994

Decline in natural killer cell-mediated immunosurveillance in aging mice--a consequence of reduced cell production and tumor binding capacity.

The mechanism(s) responsible for the functional deficiencies in aging mice of natural killer (NK) cells, the lymphocytes active in early neoplasia development, are unknown. The aim of the present study was to examine the effect of indomethacin, a prostaglandin synthetase inhibitor, and recombinant interleukin-2 (rIL-2), an NK cell stimulant, on the NK cell numbers and function of aging mice. This combination is highly effective in inducing proliferation and activation of the NK cells in young adult mice. Ten- to 13-month-old DBA/2 mice received either indomethacin daily for 9 days in their drinking water, or rIL-2 twice a day for 4 days, or both agents combined. Untreated aging mice had 50% fewer splenic NK cells than did young adult (5-8 weeks) DBA/2 mice, although bone marrow contained NK cell numbers similar to that of young adult mice. Neither indomethacin alone, rIL-2 alone nor the combination of both could induce an increase in NK cell numbers or function in aging mice. Radioautography combined with immunoperoxidase labelling techniques revealed that the production of new NK cells from the bone marrow of aging mice was significantly reduced relative to that of young adult mice. This was reflected in low numbers of newly formed NK cells accumulating in the spleens of aging mice. The target binding capacity, a necessary precytolytic event, of aging mouse NK cells was also reduced compared to that of young adult mice. The results suggest that the functional deficiencies of aging mouse NK cells are a consequence of multiple factors including an absolute loss of NK cells resulting from a reduced production of such cells in the bone marrow and a decreased capacity of NK cells to bind their tumor targets.

Aging↗
PubMed1994

The development of natural killer (NK) cells from Thy-1loLin-Sca-1+ stem cells: acquisition by NK cells in vivo of the homing receptor MEL-14 and the integrin Mac-1.

The present study aimed to follow the development of natural killer (NK) cells in lethally irradiated BA mice reconstituted with 500 syngeneic Thy 1.1loLin-Sca-1+ stem cells. The proportions of NK 1.1+ lymphoid cells were assessed from smears of cell suspensions from the spleen and bone marrow by means of immunofluorescence microscopy, at 7, 9, 11, 14, 17, 21, 24 and 28 days after stem cell injection. At the same intervals, moreover, the proportions of NK 1.1+ lymphoid cells bearing either the homing receptor recognized by mAb MEL-14, or the integrin Mac-1 were recorded using double immunofluorescence microscopy, labelling variously with fluorescein isothiocynate and avidin-Texas Red. The results demonstrate that NK 1.1+ lymphoid cells re-appear by 11 (spleen) to 14 (bone marrow) days after injecting syngeneic Thy 1.1loLin-Sca-1+ stem cells. Moreover, in the absence of apparent stimulation, the newly developed NK 1.1+ lymphoid cells spontaneously express the homing receptor MEL-14 and the integrin Mac-1. The very similar patterns of acquisition of these latter 2 molecules on NK 1.1+ cells in the spleen during their recovery in the post-stem cell injection period suggests that MEL-14 and Mac-1 may co-express on the same NK 1.1+ cells. The absence, or low levels of both molecules on the newly developed NK 1.1+ cells while still in the bone marrow suggests that NK cells may progressively acquire these molecules outside that organ, en route to and/or within the vasculature of the spleen, their normal, primary destiny.

Animals↗
PubMed1994

Skeletal malignancies among beagles injected with 241Am.

Seventy skeletal malignancies in 44 dogs were identified among 117 beagles injected as young adults with graded dosages of approximately 0.07 to 104 kBq 241Am kg-1 and maintained for lifetime observation. All of these tumors were osteosarcomas except four fibrosarcomas of bone and four chondrosarcomas of bone. Of these 117 animals, 114 survived beyond the minimum age (of 2.79 y) for radiation-induced bone cancer, and all are now dead. An expression was derived that described the dependence of percent occurrence of bone sarcoma on skeletal radiation dose of A = 0.76 + 30D, where A = percent of dogs with skeletal malignancy within any dosage group, D = average skeletal dose (< 3 Gy) at 1 y before death (average skeletal dose was calculated to the presumed start of tumor growth, which we have taken to be 1 y before death), and 0.76 represents the lifetime percent malignant bone tumor response among 132 suitable control dogs in our colony not given any radioactivity. All dosage groups with skeletal doses of > 3 Gy at 1 y before death exhibited close to 100% occurrence and appeared to be beyond the region of linearity. Therefore, they were excluded from the derivation of this expression. Similar analysis of corresponding data for beagles given 226Ra as young adults, excluding the two highest dosage groups in which the bone tumor response was approximately 100%, yielded the expression, A = 0.76 + 4.7D, (D < 20 Gy). A ratio of the coefficients in these two expressions indicates the effectiveness at low radiation doses for bone-cancer induction of 241Am relative to 226Ra, or (30 +/- 2.6)(4.7 +/- 0.47)-1 = 6 +/- 0.8. This compares to the relative effectiveness at low radiation doses that was obtained earlier for a 239Pu:226Ra toxicity ratio of about 16 +/- 5.

Americium↗
PubMed1994

Soft-tissue tumors among beagles injected with 226Ra.

A total of 409 primary soft-tissue tumors (189 malignant) occurred among 87 of 120 young adult beagles (72.5%) injected with 226Ra in eight dose levels ranging from 0.2-440 kBq kg-1 body mass, while a total of 565 primary soft-tissue tumors (208 of them malignant) were seen among 117 of 133 control beagles not given radioactivity (88%). Because the p-value for the difference in these two percentages was > 0.05, further comparisons were not made of all tumor locations or types taken together but only of the individual tumor locations or types. There was a clear excess of malignant tumors and all tumors (benign plus malignant) in the eye among dogs injected with radium (p < 0.05, p < 0.01, respectively), but the occurrence of all the other types of soft-tissue tumors was not greater in irradiated vs. control dogs (p > 0.05). This was also true for hematopoietic tumor types (including just one leukemia in a control and none in irradiated dogs) in which there was no difference between controls and dogs given radium. The following total tumors (benign plus malignant) occurred in control dogs but not in radium dogs: brain = 3, peritoneum = 1, and pituitary = 4. Malignant tumors other than leukemia appearing in control animals and not among radium dogs were brain = 2, lymph nodes = 1, adrenal = 3, uterus = 1, and pancreas = 5. Tumors that occurred in dogs given radium and not in controls were 3 mast cell sarcomas and 2 tumors of the thymus (1 malignant). Age at first tumor diagnosis for corresponding tumor types did not seem to differ (p > 0.10 or p > 0.05) between radium dogs and controls except for the eye (p < 0.05), with radium dogs being somewhat younger than controls at first diagnosis, at death, or at loss from the colony. Cox regression indicated differences between radium dogs and controls in risk of dying with specific tumors. The following tumors had p values of < 0.05 and risk ratios of > 2.2:eye, mouth (mostly melanomas), and thyroid for malignant tumors and for malignant and benign tumors together. When all sarcomas were considered as a group, there was no difference between controls and radium dogs but there was a difference for all carcinomas taken together, even when mammary tumors and eye tumors were excluded and when eye tumors alone were excluded.

Animals↗
PubMed1994

Occurrence of metastases in beagles with skeletal malignancies induced by internal irradiation.

Metastases from malignant bone tumors often are responsible for the fatal effects of these cancers. Characteristics of primary skeletal malignancies in beagles injected with bone-seeking radionuclides were studied by Thurman (1971) and summarized by Thurman et al. (1971). There were 212 tumors in 186 of these dogs for which we subsequently received information on bone tumor metastases. Evaluation of bone and soft tissue slides from these animals allowed us to compare parameters reported previously with the occurrence of grossly apparent bone tumor metastases. Data included growth-rate of the primary tumor, volume of the primary tumor at death, sex of the animal, growth period of the primary tumor, degree of calcification of the primary tumor, skeletal location of the primary tumor, cumulative radiation dose to the skeleton, dose equivalent to the skeleton, and year of death. For most of the comparisons, no significant differences could be established between dogs with and without metastases. However, tumor volume at death appeared to be correlated with probability of metastasis (p < 0.05), with the larger tumors being associated with higher rates of metastasis. Comparisons of dogs with and without metastases as a function of tumor growth-rate did not, for the most part, yield significantly different results between groups. Exceptions were when only one tumor per dog was considered for animals with multiple primary tumors and when only the tumor with the longest doubling time was included for all dogs with multiple primary tumors (p < 0.02). This effect was a result of only two tumors with doubling times > 45 d. Both had been characterized by Thurman (1971) as among the tumors with the least uncertainty in calculated doubling times. Rates of metastasis in dogs with primary tumors in paired bones were significantly higher than corresponding values of dogs with primary tumors in unpaired bones. Metastases in dogs with primary tumors in the ribs appeared to be more pronounced and those in the thoracic vertebrae appeared to be less pronounced than for animals with primary tumors in other bones as compared with the average for the whole skeleton.

Animals↗
PubMed1994

Eye tumors and other lesions among beagles given 90Sr or 226Ra.

Analysis of eye tumors and other eye lesions among beagles given either 90Sr or 226Ra, and among control animals, indicated that intraocular tumors in excess of the rate for our control animals were not associated with radiation from incorporated 90Sr + 90Y. It is unequivocal that eye melanomas were produced by injected 226Ra. Intraocular neoplasia, hyperplasia, hyperpigmentation, and melanosis in the eye all occurred in our control beagles given no radioactivity; however, tumor experience as currently reported for different beagle colonies may not be directly comparable because of differing rates of discovery, nonuniform nomenclature, and varying criteria for classification of lesions with their discordant interpretation by different pathologists.

Animals↗
PubMed1994

Distribution of skeletal malignancies in beagles injected with 239Pu citrate.

The distribution of skeletal malignancies among our beagles injected with 239Pu as young adults roughly seems to follow the distribution of skeletal mass and skeletal 239Pu. These findings are similar to those we reported previously for a group of dogs given 26Ra. Although there were differences in tumor distribution between the animals given 226Ra and those given 239Pu, most of them were not statistically significant; however, the radium dogs seemed to show a greater sensitivity to bone tumor origin in the tibia, while there may have been a tendency among the plutonium dogs toward increased relative sensitivity in the scapula, lumbar vertebrae, sacrum, and ribs. In contrast, the most common site for the formation of naturally-occurring bone malignancy in the dog is the distal radius. Perhaps there were too few tumors and too few dogs to establish statistical significance. A correlation between tumor location and at least two anatomical-physiological factors in the skeleton indicated that these two factors (site-specific bone turnover rate and percent of red marrow at the site, which is correlated with vascularity) may influence the appearance of malignancies both individually and in combination. Except for the femur, there appeared to be no difference between the relative distribution of skeletal malignancies of low-level (30 Bq-2 Bq kg-1 injected) and high-level (3-122 kBq kg-1) dogs. Distribution of bone tumors between the axial and appendicular skeleton was 50% vs. 50% for 239Pu (42 and 42), but it was 39% axial vs. 61% appendicular (22 and 35, respectively) for dogs given 226Ra. This difference was not significant (p > 0.2).

Animals↗
PubMed1994

Relative effectiveness of 239Pu and some other internal emitters for bone cancer induction in beagles.

The toxicity ratio (relative effectiveness per gray of average skeletal dose) has been estimated for bone cancer induction in beagles injected as young adults for a number of bone-seeking internal emitters. These experiments yielded calculated toxicity ratios (+/- SD) relative to 226Ra = 1.0 of 239Pu = 16 +/- 5 (single exposure to monomeric Pu) and 32 +/- 10 (continuous exposure from an extraskeletal deposit in the body), 224Ra = 16 +/- 5 (chronic exposure) and approximately 6 +/- 2 (single exposure), 228Th = 8.5 +/- 2.3, 241Am = 6 +/- 0.8, 228Ra = 2.0 +/- 0.5, 249Cf = 6 +/- 3, 252Cf = 4 +/- 2, 90Sr = 1.0 +/- 0.5 (for high doses) and 0.05 +/- 0.03 (for low doses) and 0.01 +/- 0.01 (for extremely low doses). Because no skeletal malignancies were observed among beagles given only 253Es, the toxicity ratio is undefined.

Animals↗
PubMed1994

Local delivery of prostaglandin E1 induces periodontal regeneration in adult dogs.

Formation of cementum, alveolar bone and periodontal ligament was produced in 18 sites on buccal surfaces of mandibular premolars and molars of 11 adult dogs near to sites of local delivery of prostaglandin E1 (PGE) for three weeks. Mineralizing bone and cementum were labelled with fluorescent dyes and polarizing microscopy showed periodontal ligament fibers between these new mineralized tissues. These observations extend recent demonstrations that local application of PGE causes formation of new bone on the mandible and suggest the potential for predictable, site-directed periodontal regeneration.

Alprostadil↗
PubMed1994

Effects of prostaglandins on the skeleton.

Prostaglandins (PGs), particularly those of the E series, have potent effects on bone resorption in vitro and on bone formation, bone remodeling, and bone modeling in vivo. When given systemically, PGEs have powerful anabolic effects--increasing bone formation rates, bone modeling in the formation mode, and remodeling with a net increase in bone mass. When applied locally, PGE1 increases periosteal bone formation and alveolar bone mass, and appears to promote periodontal soft-tissue regeneration. PGs have potential clinical application in the local restoration or augmentation of bone mass, focal stimulation or bone formation, and the regeneration of soft tissues associated with osseous tissues, such as fibrous and ligamentous insertions into bone.

Animals↗
PubMed1994

Occurrence of mammary tumors in beagles given radium-226.

A total of 128 primary mammary tumors (66 of them malignant) occurred in 35 female beagles injected with 226Ra at eight dose levels ranging from 0.2 to 440 kBq/kg body mass as young adults, while a total of 156 mammary tumors (57 of them malignant) were seen in 46 female control beagles not given any radioactivity. Sixty-three of 65 control dogs and 59 of 61 dogs given 226Ra survived the minimum age for diagnosis of mammary tumors of 3.75 years. Based on the observed age-dependent tumor incidence rates in the controls and on the corresponding number of dog-years at risk, the total number of observed malignant tumors in the radium group was statistically greater than the number of expected malignant tumors (66 observed vs 34 expected, P < 0.005). There was no such difference for the benign tumors. Cox regression analysis indicated no increased risk for the first tumor occurrence in irradiated dogs. Cox regression analysis of the multivariate risk sets showed no significantly increased risk for the occurrence of benign tumors but a statistically higher risk of 1.66 with a confidence interval of 1.15-2.40 for the occurrence of malignant tumors. The increased risk was dependent on dose, but a dependence on the frequency of previous occurrence of mammary tumors could not be confirmed. Censoring ovariectomized dogs at time of surgery decreased the relative risks slightly but did not alter the significance. Exposure to diagnostic X rays with cumulative exposures below 0.2 Gy had no effect on tumor formation. It is unknown whether the increased risk for malignant mammary tumors was due to some initial deposition of radium in sensitive tissue, a possible irradiation of fatty mammary tissue from transient radon-->polonium deposition, or a general effect of the overall radium deposition on the immune system of the dogs that lowered their resistance to formation of mammary tumors. Results of this study are potentially useful in understanding risks of radium-induced breast cancers in humans.

Age Factors↗
PubMed1993

Long-term osteopenic changes in cancellous bone structure in ovariectomized rats.

Cancellous bone mass decreases following ovariectomy in rodents, providing a useful model for post-menopausal bone loss in humans. This study describes and quantifies the longer-term changes in cancellous bone structure in the ovariectomized (OVX) rat. Rats were OVX or sham-OVX at 100 days of age and bones were collected 540 days later. Lumbar vertebral bodies were prepared for microradiography and structural analyses (nodal analyses and star volume analyses) of cancellous bone. Proximal humerii were prepared for scanning electron microscopy (SEM). Microradiography confirmed the loss of cancellous bone from the central spongiosa regions of the vertebral bodies and the humerii in the OVX rats. Changes in trabecular structural elements included relative increases in the number of free to free, cortical to free, cortical to node struts and decreases in the node to node struts in the OVX animals compared with controls. There were increases in average lengths of the node to free, node to node, and free to free trabecular struts in the OVX animals. The marrow star volume was increased in the OVX animals indicating a greater trabecular separation in these animals compared with controls. Viewed by SEM, metaphyseal trabeculae in the controls consisted of rods and plates but in the OVX animals the remaining trabeculae were mostly longitudinal rods with smaller transverse connecting rods. The remaining bone in the OVX animals was found in the lateral metaphyseal areas and is consistent with maintenance of the structural capacity of the bone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Bone cancer occurrence among beagles given 239Pu as young adults.

The occurrence of skeletal malignancies has been documented among 234 young adult beagles given single intravenous injections of monomeric 239Pu citrate. Occurrence has also been documented among 132 comparable control group animals surviving the minimum latent time period of 2.79 y for radiation-induced bone cancer, who were maintained for lifespan observation. Injected amounts ranged from about 0.02-106 kBq kg-1 body mass with factors of 2 or 3 between dose levels. There were 84 radiographically apparent bone tumors in 76 plutonium-injected dogs and one tumor in a control group dog. Most of these were osteosarcomas except for seven chondrosarcomas, one liposarcoma, and one plasma cell myeloma of bone. The relationship between percent of dogs at any dose level with bone malignancy and average skeletal dose at the presumed time of tumor initiation of 1 y before death appeared to be linear below about 1.3 Gy average skeletal dose. The observed data can be approximated by the expression A = 0.76 + 75 D, where A = percent of dogs with bone cancer at any dose level, D = average skeletal dose in Gy (for doses up to 1.3 Gy) at tumor initiation, and 0.76 represents the percent tumor response in the control animals not given plutonium. Similar analysis of our corresponding data for beagles given 226Ra, excluding the two highest dose levels (approximately 100% occurrence), yielded the expression A = 0.76 + 4.7 D, where D = the average skeletal dose in Gy (for doses up to 20 Gy) at 1 y before death. The ratio of coefficients indicates the effectiveness for bone cancer induction of 239Pu relative to 226Ra, or [(75 +/- 22.5)(4.7 +/- 0.47)-1] = 16 +/- 5 for a single, brief intake of either nuclide into blood.

Animals↗
PubMed1993

241Am-induced thyroid lesions in the beagle.

One of the features of 241Am metabolism in the beagle dog is a relatively high selective deposition in the thyroid glands, equal to approximately 0.06% of the injected dosage per gram. Retention is prolonged and principally in the interstitial connective tissue. The resulting average dose to the thyroid glands is about 1.42 and 0.76 times that delivered to the skeleton and the liver, respectively. This thyroid dose is much higher than has been reported in people. Although significant morphological changes and reductions in serum thyroxine occurred in this experiment, a significant increase in thyroid neoplasia was not observed.

Americium↗
PubMed1993

VISION USA--optometry's national charity program.

BACKGROUND: There are an estimated 18 million uninsured working Americans and their families who are unable to afford the cost of eye care. These individuals often fall between the cracks of government and private health care assistance. Members of the American Optometric Association have developed the VISION USA program to provide free eye care to those who might otherwise not receive it. METHODS: Nearly 8,000 doctors of optometry nationwide have volunteered to provide free eye examinations in their offices for VISION USA patients. Patients are screened for eligibility and matched to the nearest available participating doctor using a computerized ZIP code matching system. Examinations are usually provided each year during March in observance of Save Your Vision Week. RESULTS: In the first three years of the program, services have been provided to over 115,000 individuals. For over 21 percent of the patients seen, this was their first eye examination ever. More than 86 percent of the patients had one or more vision problems. More than 70 percent were given new or updated prescriptions. CONCLUSION: The VISION USA program is helping to meet a significant unmet need for eye care which exists within a segment of the American population. The program is an outstanding example of the willingness of doctors of optometry to give back to their communities, and to those in need, some of what they have gained from the practice of their profession.

Adolescent↗