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Biomedical subjects

S C Miller

Publications and source records attributed to S C Miller.

At least 73 records · Page 4Linked to original sources
PubMed1999

Relative radiosensitivity of bone tumor induction among beagles as a function of age at injection of 239Pu or 226Ra.

A comparison was made of the response to induction of skeletal malignancy from exposure of beagles to monomeric 239Pu or to 226Ra as juveniles (3 mo of age), young adults (1.5 y of age), or mature adults (5 y of age). This indicated that of these age groups, animals injected as young adults are most sensitive per Gy of average skeletal dose evaluated at 1 y before death. Dogs exposed either as juveniles or as mature adults appeared to be less sensitive. Relative radiosensitivities (RRS) of juvenile and mature beagles ranged between about 0.3 and 0.7 that of dogs injected as young adults. Mean values of RRS for both radionuclides were about 0.5, but RRS values derived from dogs given monomeric 239Pu appeared to be most reliable and were 0.27+/-0.09 for dogs injected as juveniles and 0.41+/-0.13 for animals exposed as mature adults.

Age Factors↗
PubMed1999

Some problems in the skeletal dosimetry of bone-seeking radionuclides.

There are fundamental problems with the calculation of radiation doses to the skeleton from internal emitters deposited in bone. Some of these include dose inhomogeneities, identity of cells at risk and their dynamics, changing deposition patterns of bone-seeking radionuclides with time after exposure, seemingly unique responses of the skeleton to each deposited radionuclide, the role of radioactive progeny produced by deposited emitters and their individual dynamics and effects, different responses of mammals of different ages at exposure to identical dosages, different responses to different chemical forms of a given radionuclide, and different responses to an identical dose from a given radionuclide at different dose-rates. This situation makes it necessary to choose some common dose parameter that will allow the overall effects of different radionuclides to be compared directly so that projected effects of each of them in humans can be estimated. For radiation protection purposes, it appears premature to abandon the concept of average skeletal dose (which appears to be a practical compromise for use) until an undelusive, non-artificial and uncontrived method of calculating absorbed dose to the appropriate cells in bone is developed that fulfills the requirement of equal cancer response for equal skeletal dose for all circumstances.

Age Factors↗
PubMed1999

Is there a difference in radionuclide-induced bone tumor sensitivity between male and female beagles?

An analysis of bone tumor occurrences among male and female beagles given monomeric 239Pu or 226Ra was not able to establish a difference in sensitivity to induction of bone malignancy by radium or plutonium exposure. This is in contrast to the situation reported for mice. Female mice are substantially more sensitive to 239Pu irradiation than males, but this difference is obliterated by gonadectomy, females becoming less sensitive and males becoming more sensitive. Although there may be some nonuniformity between human males and females for radiation-induced bone sarcoma occurrence, analysis of data sets containing both men and women exposed to 224Ra, 226Ra, 228Ra, or 226+228Ra appears not to reveal substantial differences in sensitivity by gender, a situation similar to that reported herein for beagles.

Animals↗
PubMed1999

NF-kappaB or AP-1-dependent reporter gene expression is not altered in human U937 cells exposed to power-line frequency magnetic fields.

A number of studies have reported that human leukemia cells respond to exposure to power-line frequency electromagnetic fields (EMFs), providing evidence for an EMF-induced signaling pathway involving activation of protein tyrosine kinases (PTKs), phospholipase-Cy and protein kinase C (PKC). Because activation of PKC is also important in the signaling pathways that regulate the transcription factors NF-kappaB and AP-1, we evaluated the effect of exposure to a 60 Hz EMF on NF-kappaB or AP-1-dependent reporter gene expression in cells of the human promonocytic U937 leukemia cell line. Reporter genes were electroporated into U937 cells and activation of the NF-kappaB or AP-1 signaling pathway was evaluated by measuring chloramphenicol acetyltransferase (CAT) protein by CAT ELISA. In contrast to the effects of well-understood chemical or biological agents, the exposure to magnetic-field intensities of 0.08, 0.1, 1.0 or 1.3 mT had no effect on the NF-kappaB or AP-1 signaling pathways.

Chloramphenicol O-Acetyltransferase↗
PubMed1998

Bruton's tyrosine kinase activity and inositol 1,4,5-trisphosphate production are not altered in DT40 lymphoma B cells exposed to power line frequency magnetic fields.

Exposure of wild-type DT40 lymphoma B cells or Bruton's tyrosine kinase (BTK)-deficient DT40 cells reconstituted with the human btk gene to a 1-gauss 60-Hz electromagnetic field (EMF) has been reported to rapidly increase inositol 1,4,5-trisphosphate (Ins 1,4, 5-P3) production (1,2). Here we have used BTK-deficient DT40 B cells reconstituted with the human btk gene to evaluate the reproducibility of these findings. An experimental design with blinded exposures and anti-IgM treatment to induce Ins 1,4,5-P3 production as a positive control, showed no significant effect of a 1-gauss 60-Hz EMF on Ins 1,4,5-P3 production. Because recent work has shown that the activation of BTK was required for EMF-responsiveness (2), we also evaluated the reproducibility of this finding in wild-type DT40 cells. BTK was activated in a dose- and time-dependent manner by treatment with the tyrosine phosphatase inhibitor pervanadate. However, the ability to detect BTK activation, as measured by increased autophosphorylation by immune complex kinase assay, was dependent on the kinase buffer. Using cells from the original investigators, no evidence was obtained to support the hypothesis that exposure to a 1-gauss 60-Hz EMF had a causal effect on protein-tyrosine kinase activities affecting Ins 1,4,5-P3 production.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1998

Molecular structure and biological and pharmacological properties of 3-hydroxy-2-methyl-1-(beta-D-ribofuranosyl or pyranosyl)-4-pyridinone: potential iron overload drugs for oral administration.

Replacing alkyl groups by sugar moieties at N-1 position of 3-hydroxy-2-methyl-4-pyridinone did not affect the geometry of the iron chelating sites but increased the hydrophilic nature. The formation of a polymer cluster through the intermolecular hydrogen bonds was also revealed by X-ray crystal structure analysis for the first time in all known 3-hydroxy-4-pyridinone crystal structures. Iron removal from ferritin by the title compounds was more efficient than with DFO.

Administration, Oral↗
PubMed1998

Chromosomal locations of three human nuclear genes (RPSM12, TUFM, and AFG3L1) specifying putative components of the mitochondrial gene expression apparatus.

We have mapped the chromosomal locations of three human nuclear genes for putative components of the apparatus of mitochondrial gene expression, using a combination of in situ hybridization and interspecies hybrid mapping. The genes RPMS12 (mitoribosomal protein S12, a conserved protein component of the mitoribosomal accuracy center), TUFM (mitochondrial elongation factor EF-Tu), and AFG3L1 (similar to the yeast genes Afg3 and Rca1 involved in the turnover of mistranslated or misfolded mtDNA-encoded polypeptides) were initially characterized by a combination of database sequence analysis, PCR, cloning, and DNA sequencing. RPMS12 maps to chromosome 19q13.1, close to the previously mapped gene for autosomal dominant hearing loss DFNA4. The TUFM gene is located on chromosome 16p11.2, with a putative pseudogene or variant (TUFML) located very close to the centromere of chromosome 17. AFG3L1 is located on chromosome 16q24, very close to the telomere. By virtue of their inferred functions in mitochondria, these genes should be regarded as candidates of disorders sharing features with mitochondrial disease syndromes, such as sensorineural deafness, diabetes, and retinopathy.

ATPases Associated with Diverse Cellular Activitie↗
PubMed1998

Photoperiod regulation of mineralocorticoid receptor mRNA expression in hamster hippocampus.

Hippocampal mineralocorticoid receptor mRNA expression was increased in male hamsters exposed to 18 days of short photoperiod relative to animals maintained under long day illumination (p < 0.05). Short day hamsters were also characterized by increased weight gain, and heavier adrenal glands (p < 0.05). The larger adrenals showed selective increases in the widths of the zonae reticularis and glomerulosa (p < 0.001). Incidences of torpor and reduced body temperature were observed in the short day animals. No changes were found in reproductive organ weights, systolic blood pressure, open-field behavior, or stress levels of plasma corticosteroids. We conclude that the hamster brain-adrenal axis responds rapidly to changes in photoperiod, raising the possibility that this axis is a primary mediator of shortened photoperiod responses.

Adrenal Cortex Hormones↗
PubMed1998

Comparison of bone loss during normal lactation with estrogen deficiency osteopenia and immobilization osteopenia in the rat.

BACKGROUND: Substantial changes in mineral and skeletal metabolism occur during pregnancy and lactation. The purpose of this study was to compare three contrasting osteopenic states in the rat: (1) physiological (lactation), (2) endocrine-deficiency (ovariectomy), and (3) lack of mechanical usage (immobilization). METHODS: One group of female rats went through a pregnancy and 21 days of lactation (LAC). Another group was ovariectomized (OVX) for 6 weeks, and another group had one hind limb immobilized (IMM) for 6 weeks. Bone mineral density was determined by photon absorptiometry, and changes in cancellous and cortical bone were determined by backscattered electron imaging (BSE), scanning electron microscopy (SEM), structural morphometry, and fluorochrome-based histomorphometry. RESULTS: The LAC group gained the most weight but had the least bone mineral density and metaphyseal bone mass. The OVX and IMM groups also had less bone mass than controls (CONT). Changes in cancellous bone structure occurred in all groups, but the IMM group had a more uniform distribution of metaphyseal bone loss. Longitudinal bone growth was greater in the IMM and OVX groups but less in the LAC group. Cancellous bone formation rates were greater in the OVX and LAC group. Cortical bone width was less in the LAC, IMM, and OVX groups. Periosteal bone formation was greater in the OVX group but less in the LAC group. CONCLUSIONS: Considerable osteopenic changes occur in cancellous and cortical bone during the first reproductive cycle in the rat. The osteopenia of lactation is somewhat similar to that observed after ovariectomy, likely because both are hypoestrogenic conditions. Because this bone loss occurs during a normal physiological event, these data suggest that before the first reproductive cycle, the female rat has a skeletal mass in excess of that needed for normal mechanical usage.

Absorptiometry, Photon↗
PubMed1998

Strain differences in natural killer cell-mediated immunity among mice: a possible mechanism for the low natural killer cell activity of A/J mice.

Natural killer (NK) cells are well established as fundamental elements in the early eradication of aberrant cells potentially leading to neoplasia. Moreover, it has also long been known that inbred strains of laboratory mice, as well as human individuals, demonstrate a wide range of NK cell-mediated immune response even to the same tumor. In the present study, various parameters which could lead ultimately to high, or low, NK cell-mediated functional activity have been assessed. Mice of the A/J strain demonstrate very low NK cell tumor-lytic activity and correspondingly high incidence of lymphoma. By contrast, C57B1/6 mice demonstrate relatively high NK cell activity and virtually never develop lymphomas. The results of this study have revealed that the absolute numbers of splenic NK cells were significantly lower in A/J vs C57B16/mice. Furthermore, the blood of A/J mice contained significantly fewer (30%) NK cells than did that of C57B1/6 mice. However, no significant difference between the 2 strains was found in the numbers of lymphocytic cells from NK cell-enriched fractions from the spleens, which possessed either the homing receptor MEL-14, or the integrin Mac-I, both essential surface molecules for transendothelial migration of lymphocytic cells from the circulation into organ parenchyma. Moreover, NK cells from both strains responded similarly to the NK cell stimulants, ATRA, indomethacin and interleukin-2. Finally, there was no significant difference between the 2 strains, in the numbers of lymphocytic cells in the bone marrow (including NK cells), which were radiolabelled with the DNA synthetic precursor, 3H-thymidine, indicative, thus, of equivalent levels of lymphocyte production by the bone marrow in the 2 strains. The observations collectively suggest that the low peripheral (spleen, blood) levels of NK cell-mediated functional activity found in the A/J strain of mouse at least, reflects either post-production, large-scale NK cell abortion/death, or a bone marrow-based microenvironmental deficiency which inhibits NK cells' exit from the bone marrow birth site.

Animals↗
PubMed1998

Disparate effects of mild, moderate, and severe secondary hyperparathyroidism on cancellous and cortical bone in rats with chronic renal insufficiency.

The subtotally nephrectomized rat has often been used to investigate the etiology and treatment of secondary hyperparathyroidism (secondaryHPT), but it has been used less frequently to study the effects of secondaryHPT on bone. The recent development of a reliable and specific rat parathyroid hormone (PTH) immunoradiometric assay has provided an opportunity for a thorough investigation of the relationship between circulating, biologically active PTH, and the skeletal abnormalities that occur in chronic renal insufficiency (CRI). Rats were 5/6 nephrectomized (Nx) or sham operated and fed diets with varying levels of Ca and P for 12-14 weeks to induce differing magnitudes of secondaryHPT. Parathyroid gland volume increased by 80%-90% in 5/6 Nx rats in the mild and moderate secondaryHPT groups (2.3- and 7.7-fold higher PTH levels, respectively) and by 3.3-fold in the severe secondaryHPT group (12-fold increase in PTH). The increases in gland volume were caused primarily by cell hyperplasia. Mild secondaryHPT resulted in a 12% decrease in bone mineral density (BMD) across the entire femur, increased osteoclast numbers (N.Oc), unchanged osteoblast numbers (N.Ob), and decreased cancellous bone volume (Cn.BV) in the tibial metaphysis but, apart from increased marrow area, no major changes in cortical bone at the tibio-fibular junction. Moderate secondaryHPT was associated with no changes in femoral BMD, or in tibial Cn.BV, but N.Ob and bone formation rate (BFR) were markedly elevated. Increased periosteal, intracortical, and endocortical BFR and turnover were evident, and contributed to increased cortical porosity (Ct.Po). The changes were exaggerated in the severe secondaryHPT group; BMD was lower in the proximal, but higher in the distal femur, and Cn.BV, N.Ob, N.Oc, and BFR were increased by six-, seven-, three-, and 30-fold, respectively. Endocortical BFR was elevated 31-fold and the extensive Ct.Po (10%) decreased bone strength. However, Ct.Po was not apparent until PTH levels exceeded 500 pg/mL. Thus, in rats with CRI of similar magnitude, progressive secondaryHPT is associated with dramatically different effects on bone. Mild secondaryHPT caused loss of cancellous and endocortical bone, and moderate secondaryHPT tended to maintain both types of osseous tissue, whereas PTH levels >500 pg/mL resulted in substantial cortical bone loss, but cancellous bone gain.

Animals↗
PubMed1998

The Medicare hospice benefit's influence on dying in nursing homes.

For dying nursing home residents, the prevalence of symptoms and care utilization prior to death has yet to be empirically described for a population-based sample. Yet, related work has suggested that the quality of care for dying nursing home residents is less optimal. The provision of Medicare hospice care in nursing homes offers a means for improving terminal care in nursing homes. However, other than controversial findings emanating from the U.S. Office of Inspector General's (OIG's) hospice studies, there is a dearth of evaluative research on the comparative costs and the benefits of Medicare hospice care in nursing homes. In this article, we discuss current knowledge concerning the dying experience of nursing home residents and of the influence of the Medicare hospice benefit in nursing homes. In doing so, we critique the OIG's study of hospice care in nursing homes and we raise concerns regarding access to the Medicare hospice benefit in nursing homes. We conclude by delineating the research needed to more fully understand the dying experience of nursing home residents and the influence of Medicare hospice care provision on this experience.

Journal Article↗
PubMed1998

Time to nursing home admission for persons with Alzheimer's disease: the effect of health care system characteristics.

OBJECTIVE: To study the influence of state health care system characteristics on time to nursing home admission (NHA) for persons with Alzheimer's disease (AD). METHOD: Up to nine years of Consortium to Establish a Registry for Alzheimer's Disease (CERAD) data on 639 non-Latino White individuals were merged with longitudinal data from the 28 states in which the CERAD participants resided. The state variables reflected characteristics of each state's long-term care (LTC) system, including Medicaid LTC spending practices and the supply of LTC providers. Cox Proportional Hazards Models with time-varying covariates were used to evaluate the risk factors associated with time to NHA. RESULTS: There was differential influence of state variables by marital status. For unmarried non-Latino White persons with AD, a higher percentage of Medicaid LTC spending on home and community-based services (HCBS) was significantly associated with a longer time to NHA. For married persons, a greater number of home health agencies was associated with a longer time to NHA. Other associations also varied by marital status. CONCLUSION: Study findings support the utility of targeted continued expanded provision of HCBS by states and provide a basis for future research regarding the impact of changing state health care systems on LTC utilization for persons with AD.

Aged↗
PubMed1998

Microdistribution of 239Pu in the beagle skeleton.

The microdistribution of 239Pu was analyzed in the humerus, lumbar vertebra, and proximal ulna of young adult beagles using neutron induced autoradiography. The animals were sacrificed serially in groups of three at 4, 8, 16, 32, and 64 wk after a single injection of 3.5 kBq kg(-1) body weight. The kinetic behavior of surface concentrations was modeled using a simple concept of deposition and clearance in skeletal regions. Bones with high turnover showed a larger initial uptake and a faster clearance than bones with low turnover rates. Using a regression procedure, the surface deposition and clearance of plutonium was calculated as a function of the turnover rate. With time after injection the initial nonuniformity of trabecular surface labels tends to become more uniform. The trabecular:cortical affinity ratio is about 10. Trabecular activity is gradually translocated to cortical sites. The affinity ratio of forming to resting surfaces is about three. In some bones a continuous increase of marrow stars was observed, whereas in other bones no clear-cut tendency could be seen. The highest level of marrow labeling occurred in the lumbar vertebra and the humerus shaft.

Animals↗
PubMed1998

Does age of the host affect growth rates of skeletal malignancies?

Statistical analysis of bone tumor growth rates as a function of age at initiation of radiation-induced skeletal malignancies in our animal colony indicated that the p value for an association between these parameters was <0.05, suggesting a correlation in beagle dogs. The youngest animals appeared to exhibit the most slowly growing tumors, and the trend was toward more rapidly growing tumors with increasing age. Less effective immune systems in older animals were invoked as a possible explanation of this relationship.

Age Factors↗
PubMed1998

Lack of effect of spaceflight on bone mass and bone formation in group-housed rats.

As part of an experiment to study the role of corticosteroids in bone changes during spaceflight, male Sprague-Dawley rats (6 wk old, 165 g body weight) were placed in orbit for 17 days, in groups of six, in animal-enclosure modules (AEMs) aboard the space shuttle Columbia (STS-78). Control rats were group housed in a similar manner in ground-based AEMs or standard vivarium cages. Adrenal hypertrophy occurred in flight rats, but bone histomorphometric analyses revealed a lack of significant changes in bone mass and bone formation in these animals. Cancellous bone volume and osteoblast surface in the proximal tibial metaphysis were nearly the same in flight and ground-based rats. Normal levels of cancellous bone mass and bone formation were also detected in the lumbar vertebrae and femoral necks of flight rats. In the tibial diaphysis, periosteal bone formation rate was found to be identical in flight and ground-based rats. The results indicate that, under conditions of group housing in AEMs, spaceflight has minimal effects on bone mass and bone formation in rapidly growing rats. These findings emphasize the need to investigate the importance of rat age, strain, and especially housing conditions for studies of the skeletal effects of spaceflight.

Adrenal Cortex Hormones↗
PubMed1998

Influence of an interferon inducer on bone marrow transplant reconstitution in irradiated, leukemic mice: elevated natural killer cell numbers and improved life span.

Interferon-gamma and interferon inducers such as polyinosinic-polycytidylic acid (poly I:C) promote natural-killer (NK)-cell-mediated killing of a wide range of tumor cells both in vitro and in vivo. The aim of the present work was to administer poly I:C to irradiated, leukemic mice, both before and after syngeneic bone marrow transplant with the intent of boosting the host's natural immunity in the critical peritransplant period. Briefly, DBA/2 mice were injected with Friend-virus-induced erythroleukemia cells. After 5 days of tumor growth, some mice received daily injections of poly I:C for the next 4 days while control, leukemic mice received the saline vehicle only. All mice were then irradiated (450 R x 2 at 4-hour intervals) and transplanted 1 day following irradiation with bone marrow from age- and sex-matched, normal DBA/2 donor mice. After transplant, daily injections of poly I:C (or vehicle) continued for 8 more days. On day 9 after transplant, treated and control mice were killed, and the total cellularity, total numbers of lymphoid cells, the total numbers of NK cells (identified by the presence of an immuno-labelled, specific cell surface marker) were obtained from both the spleen and the bone marrow. Other identically treated mice subjected, however, to several additional rounds of poly I:C treatment were sampled 3 and 6 months after irradiation and bone marrow transplant. The results indicated that (a) poly I:C administered in the peritransplant period (before and after transplant) significantly increases the absolute numbers of NK cells in both the bone marrow and spleen of the transplanted host at all time intervals studied, (b) no erythroleukemic tumor cells were found, even as late as 6 months after transplant in the poly-I:C-treated hosts in spite of the fact that poly I:C treatment in this group had been terminated more than 2 months prior to tissue sampling, and (c) survival was significantly improved by pre- and posttransplant treatment with poly I:C.

Animals↗