Search PubMed⌕ Search

Biomedical subjects

R A Miller

Publications and source records attributed to R A Miller.

At least 91 records · Page 5Linked to original sources
PubMed1999

Multiple organ carcinogenicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344/N rats and B6C3F1 mice and comparison of dose-response with 1,3-butadiene in mice.

Chloroprene (2-chloro-1,3-butadiene) is a high production chemical used almost exclusively in the production of polychloroprene (neoprene) elastomer. Because of its structural similarity to 1,3-butadiene, a trans-species carcinogen, inhalation studies were performed with chloroprene to evaluate its carcinogenic potential in rats and mice. Groups of 50 male and female F344/N rats and 50 male and female B6C3F1 mice were exposed to 0, 12.8, 32 or 80 p.p.m. chloroprene (6 h/day, 5 days/week) for 2 years. Under these conditions, chloroprene was carcinogenic to the oral cavity, thyroid gland, lung, kidney and mammary gland of rats, and to the lung, circulatory system (hemangiomas and hemangiosarcomas), Harderian gland, kidney, forestomach, liver, mammary gland, skin, mesentery and Zymbal's gland of mice. Survival adjusted tumor rates in mice were fit to a Weibull model for estimation of the shape of the dose-response curves, estimation of ED10 values (the estimated exposure concentration associated with an increased cancer risk of 10%) and comparison of these parameters with those for 1,3-butadiene. Butadiene has been identified as a potent carcinogen in mice and has been associated with increased risk of lymphatic and hematopoietic cancer in exposed workers. Shape parameter values for most of the neoplastic effects of chloroprene and 1,3-butadiene were consistent with linear or supralinear responses in the area near the lowest tested exposures. The most potent carcinogenic effect of 1,3-butadiene was the induction of lung neoplasms in female mice, which had an ED10 value of 0.3 p.p.m. Since the ED10 value for that same response in chloroprene exposed mice was also 0.3 p.p.m., we conclude that the carcinogenic potency of chloroprene in mice is similar to that of 1,3-butadiene. Cancer potency of chloroprene is greater in the mouse lung than in the rat lung, but greater in the rat kidney than in the mouse kidney and nearly equivalent in the mammary gland of each species.

Administration, Inhalation↗
PubMed1999

Multiple-trait quantitative trait loci analysis using a large mouse sibship.

Quantitative trait loci influencing several phenotypes were assessed using a genetically heterogeneous mouse population. The 145 individuals were produced by a cross between (BALB/cJ x C57BL/6J)F1 females and (C3H/HeJ x DBA/2J)F1 males. The population is genetically equivalent to full siblings derived from heterozygous parents, with known linkage phase. Each individual in the population represents a unique combination of alleles from the inbred grandparents. Quantitative phenotypes for eight T cell measures were obtained at 8 and 18 mo of age. Single-marker locus, repeated measures analysis of variance identified nine marker-phenotype associations with an experimentwise significance level of P < 0.05. Six of the eight quantitative phenotypes could be associated with at least one locus having experiment-wide significance. Composite interval, repeated measures analysis of variance identified 13 chromosomal regions with comparisonwise (nominal) significance associations of P < 0.001. The heterozygous-parent cross provides a reproducible, general method for identification of loci associated with quantitative trait phenotypes or repeated phenotypic measures.

Animals↗
PubMed1999

Kleemeier award lecture: are there genes for aging?

The question of whether aging - the process that converts fit adults into frailer adults with a progressively increased risk of illness, injury, and death - is under genetic control is ambiguous, and its answer depends on what one means by aging. Natural selection can select for genes that retard aging, but only in species and niches where the value of prolonged survival outweighs its costs. Although the form aging takes can be affected by variations at many genetic loci the number of loci that moderate the pace of synchronized decay may be far smaller. Single gene mutants can extend mouse lifespan by over 50%, and genetic selection for small body size also leads to dramatic life span extension in dogs, suggesting strongly that aging can be affected by genetic variations within a species, but identification of genetic differences that discriminate long-lived from short-lived species will require a combination of genetic and physiological analyses.

Aging↗
PubMed1999

Lifelong treatment with oral DHEA sulfate does not preserve immune function, prevent disease, or improve survival in genetically heterogeneous mice.

OBJECTIVES: To determine whether lifelong exposure to dehydroepiandrosterone sulfate extends the lifespan or retards immune senescence in mice. DESIGN: Double-blind, placebo-controlled intervention trial. SETTING: A specific pathogen-free rodent vivarium. PARTICIPANTS: 120 mice bred as a cross between CB6F1 females and C3D2F1 males. INTERVENTION: DHEAS at 100 microg/mL in drinking water from weaning until death. MEASUREMENT: Age at death, cause of death, antibody production after erythrocyte immunization, and T cell subset profiles in peripheral blood at ages 8 and 18 months. RESULTS: DHEAS ingestion did not lead to a significant increase in mean or maximal longevity: the 95% confidence interval for DHEAS effect on mean lifespan ranged from +35 days to -80 days. There were no significant effects of DHEAS on incidence of lethal illnesses, except for a trend toward higher levels of mammary adenocarcinoma in DHEAS-treated females and mouse urinary syndrome in DHEAS-treated males. DHEAS treatment did not improve the ability of middle-aged mice to produce antibody to a foreign particulate antigen, and it did not alter the proportions of age-sensitive T cell subsets in middle-aged animals. CONCLUSION: Although differences among species in pharmacokinetics complicate interpretation of studies in which DHEA or DHEAS is administered to rodents, our data provide no support for the idea that chronic exposure to this steroid retards immune senescence or prevents late life illness.

Adenocarcinoma↗
PubMed1999

Sorbitol-mannitol solution for urological electrosurgical resection-- a safer fluid than glycine 1.5%.

OBJECTIVE: To evaluate the safety and suitability of sorbitol-mannitol solution (Purisole((R)), Fresenius, Germany) as a fluid for irrigation during electrosurgical resection of prostate (TURP). PATIENTS AND METHODS: 120 sequential patients undergoing TURP were studied. Serum electrolytes were measured before and the day after surgery. Time and weight of resection were recorded. Use of blood transfusion was recorded. RESULTS: There were no adverse effects attributable to the use of the irrigant. There were no technical, electrical or instrument problems. None of the surgeons had any difficulties with clarity of view during resection when bleeding was light. There was no significant change in any of the serum electrolytes between pre-operative and postoperative values. No patient developed significant postoperative hyponatraemia or the 'TUR syndrome'. CONCLUSIONS: Purisole (sorbitol-mannitol) solution is entirely satisfactory as an irrigant for electrosurgical resection and in the present study there were no measurable changes in patients' electrolytes around the time of surgery. What small changes occurred indicate there is an overall mild dehydration effect through the process of surgery, which may be in part attributable to irrigant, but this change was small and does not reach either clinical or statistical significance. Purisole offers theoretical advantages over glycine solution and there are no obvious disadvantages. The authors would thereby recommend it in preference to glycine.

Absorption↗
PubMed1999

Frostbite: an orthopedic perspective.

Frostbite injury to the extremities has the potential for disastrous effects. This review provides information valuable to the orthopedic surgeon to aid in the evaluation and treatment of frostbite. The pathophysiology and predisposing factors that provide a basic understanding of the nature of frostbite are discussed. Accepted and experimental imaging studies and treatment options are also reviewed. An effort is made to give the orthopedic perspective on each issue, providing a valuable resource for all orthopedic surgeons involved in the care of the patient with frostbite.

Combined Modality Therapy↗
PubMed1999

Distributing knowledge maintenance for clinical decision-support systems: the "knowledge library" model.

The maintenance of knowledge-rich clinical decision-support systems is challenging, in particular in the complex setting of a large academic medical center. Distributing the maintenance tasks to the source of expertise can address scalability, accuracy and currency issues. It also helps to foster a more global sense of ownership among the system users. The knowledge maintenance model must provide processes and tools to deal with a wide range of stakeholders (resident and attending physicians, consulting specialists, other care providers, case managers, ancillary departments), with knowledge embedded in legacy departmental systems, and with the continuous evolution of the content and form of the knowledge base. We describe and illustrate the "knowledge library" model in use at Vanderbilt University Medical Center for the distributed maintenance of the integrated knowledge base that drives the WizOrder clinical decision-support, physician order entry, and notes capture system.

Artificial Intelligence↗
PubMed1998

Increased Zap-70 association with CD3zeta in CD4 T cells from old mice.

Aging diminishes the amount of phosphotyrosine in the CD3zeta chains of resting and activated mouse CD4 T cells by about threefold and might therefore be expected to a corresponding decline in Zap-70 association with CD3zeta and in Zap-70 kinase function in CD3zeta complexes. We show here that aging leads, unexpectedly, to an approximately twofold increase in the amount of Zap-70 associated with CD3zeta in resting CD4 T cells. There is, however, no effect of age on total intracellular Zap-70 content. Cross-linking CD3 to CD4 leads to an increase of only 50% in the functional activity of Zap-70 in CD3zeta complexes from freshly isolated CD4 T cells of young donors. Compared to Jurkat and HT-2 cells, fresh T cells show both higher baseline levels and lower induced levels of Zap-70 function in CD3zeta complexes. CD4 T cells from old mice have baseline levels of Zap-70 activity similar to those seen in activated T cells from young mice, and these levels do not increase after CD3/CD4 cross-linking. Tyrosine-specific phosphorylation of Zap-70 is also higher at rest in old T cells than in young T cells and inducible only in cells from young donors. These data suggest that age-related defects in T cell activation are not likely to be attributable simply to a decline in Zap-70 association with CD3zeta or to diminished Zap-70 phosphorylation. The increase with age in CD3zeta-Zap association, despite the loss with age in CD3zeta tyrosine phosphorylation, suggests that the pattern of tyrosine phosphate groups among CD3zeta ITAM groups may be different in T cells from young and old donors or that access to ITAM regions within CD3zeta may be blocked by inter- or intramolecular steric hindrance in young CD4 T cells.

Aging↗
PubMed1998

Analysis of Raf-1 activation in response to TCR activation and costimulation in murine T-lymphocytes: effect of age.

Stimulation of the ERK (MAPK) pathway in T-lymphocytes contributes to cell activation and IL-2 production. The ERK pathway is initiated by the activation of the serine/threonine kinase Raf-1 in a Ras-dependent manner. Raf-1 activates the dual-specific kinase MEK, which in turn activates ERK. To see if aging leads to an alteration of Raf-1 kinase activity we performed in vitro kinase assays on Raf-1 isolated from CD4(+) T-cells from young and old mice. We found an age-related impairment in the kinase activity of Raf-1 in T-cells stimulated by a combination of antibodies to the CD3epsilon chain of the T-cell receptor and CD4. Aging led to a two- to fourfold decline in Raf-1 activity (depending on the stimulation time) without a change in the kinetics of enzyme activation. We also found that Raf-1 activation by CD3/CD4 costimulation is lower in memory cells than in naïve cells from mice of the same age. However, aging also leads to a decline in Raf-1 activity in the naïve subset of CD4(+) T-cells, suggesting that two mechanisms lead to the age related decline in Raf-1 function. Finally, we found that antibodies to the costimulatory molecule CD28 trigger Raf-1 activation and enhance anti-CD3-mediated Raf-1 activation but cannot restore Raf-1 activation levels from old T-cells to those seen in young mice. Our data suggest that age-dependent declines in T-cell ERK function are caused by alterations in the signals that activate Raf-1 and that age-dependent defects in T-cell cytokine production and proliferation may be caused at least in part by defects in signals that activate Raf-1.

Aging↗
PubMed1998

Idiosyncratic alterations of TCR size distributions affecting both CD4 and CD8 T cell subsets in aging mice.

We have used a spectratyping method, which displays the size distribution for the complementarity-determining region 3 (CDR3) for T cells utilizing a specific TCR-Vbeta gene, to examine the effects of aging on the TCR repertoire of (BALB/c x C57BL/6)F1 hybrid mice. Although the size distributions from T cells of 8-month-old mice were typically symmetrically shaped around one or two bands of intermediate size, spectratypes from mice 16 or 24 months of age were frequently distorted, with specific size classes either over- or underrepresented compared to normal young controls. Each of 12 mice tested at 16 or 24 months of age had a skewed spectratype for at least one of the 24 Vbeta families examined, and some mice had more than 50% of their spectratypes skewed significantly, as judged by a chi2 test. Comparable age-associated skewing of the T cell repertoire occurred in the CD4 and CD8 subsets, and every mouse over 16 months of age exhibited at least one skewed Vbeta family in both the CD4 and CD8 populations. Although the mice were genetically identical and raised in common facilities, their spectratype patterns were nonetheless idiosyncratic: i.e., the specific set of abnormalities was distinct for each individual old mouse. Whether these distortions of the TCR repertoire in middle-aged and older mice lead to alterations in immune function remains to be determined.

Aging↗
PubMed1998

Generation of antigen-specific Th2 cells from unprimed mice in vitro: effects of dexamethasone and anti-IL-10 antibody.

We describe a system for the in vitro production of Ag-specific mouse CD4 cell lines from unprimed mice. Purified CD4+ CD45RB(high) T cells were exposed to Ag-pulsed accessory cells in serum-free medium for 24 h; cultured in the absence of Ag and in the presence of serum, IL-2, dexamethasone, and Abs to IL-10 for an additional 4 days; and then re-exposed to the original sensitizing Ag. The presence of dexamethasone and Abs to IL-10 during the initial expansion stage appeared to be critical for the ability of the stimulated and expanded T cells to respond to restimulation with the same Ag. Repeated cycles of in vitro stimulation led to increased specificity for the sensitizing Ag (in the current case, pigeon cytochrome c), a decline in production of IL-2 and IFN-gamma, and increased production of IL-4, IL-5, and IL-10. This culture protocol provides a test system for exploration of factors that regulate the conversion of naive cells to memory cells and the development of specific immune responses to protein Ags. The data are consistent with models that implicate glucocorticoids as regulators of immune response specificity.

Animals↗
PubMed1998

Carcinogenesis studies of tetrahydrofuran vapors in rats and mice.

Tetrahydrofuran (THF) is a widely used industrial solvent and was selected for carcinogenesis studies by the National Toxicology Program (NTP) because of its potential for widespread occupational exposure in humans and a lack of information on animal toxicity and carcinogenicity. Groups of 50 male and 50 female F344/N rats and B6C3F1 mice were exposed to 0, 200, 600, or 1800 ppm THF by inhalation, 6 h per day, 5 days per week, for 105 weeks. Survival and mean body weights of male and female rats exposed to THF were comparable to that of the controls. No clinical findings or nonneoplastic lesions related to THF exposure were observed in male or female rats. The incidences of renal tubule epithelial adenoma or carcinoma (combined) in exposed male rats occurred with a positive trend, and in males exposed to 600 and 1800 ppm exceeded the historical range for controls in 2-year NTP inhalation studies. There were no other neoplastic lesions related to THF exposure observed in male or female rats. After week 36, the survival of male mice exposed to 1800 ppm was significantly lower than that of the controls. Mean body weights of male and female mice exposed to THF were similar to those of the controls throughout the study. Male mice exposed to 1800 ppm were observed in a state of narcosis during and up to 1 h after the exposure periods. Nonneoplastic lesions related to THF exposure were not observed in male or female mice. The neoplastic lesions related to THF exposure were seen in female mice only. In female mice exposed to 1800 ppm, the incidences of hepatocellular neoplasms were significantly greater than those in the controls. In conclusion, there was some evidence of carcinogenic activity of THF in male F344/N rats due to increased incidences of adenoma or carcinoma (combined) of the kidney at the 600 and 1800 ppm exposure levels. There was clear evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of hepatocellular neoplasms at the 1800 ppm exposure level. THF was not carcinogenic in female rats or male mice exposed at 200, 600, or 1800 ppm.

Animals↗
PubMed1998

Lung tumor induction by inhalation exposure to molybdenum trioxide in rats and mice.

Inhalation studies of molybdenum trioxide (MoO3) were conducted because of its wide use in industry, human exposure, and lack of data on carcinogenicity. Groups of 50 male and 50 female F344/N rats and B6C3F1 mice were exposed to MoO3 by inhalation at 0, 10, 30, or 100 mg/m3, 6 h/day, 5 days/week, for 2 years. In both rats and mice, survival and mean body weights of exposed groups of males and females were similar to those of their respective controls. There were significant exposure-dependent increases in blood molybdenum concentration in exposed rats and mice. There were no toxicological differences in bone density or curvature between exposed animals and their respective controls. In rats, dose-dependent increases in incidence of hyaline degeneration in the nasal olfactory epithelium and squamous metaplasia of the epithelium lining the base of the epiglottis were observed. The incidence of alveolar/bronchiolar adenoma or carcinoma (combined) was marginally increased in males but not in females compared with controls. In mice, the incidences of squamous metaplasia of the epithelium lining the base of the epiglottis, hyperplasia of the laryngeal epithelium, and metaplasia of the alveolar epithelium were significantly increased in all exposed males and females compared with controls. The incidence of alveolar/bronchiolar adenoma or carcinoma (combined) in exposed groups of males and females was significantly greater than that in the control groups.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1998

Multiple synchronization strategies in rhythmic sensorimotor tasks: phase vs period correction.

To characterize synchronisation strategies in the tracking of auditory rhythm with rhythmic finger tapping, the adaptation process after unexpected step changes of an interstimulus interval (ISI) of 500 ms was investigated. Step changes of 2% (10 ms), 4% (20 ms), and 10% (50 ms) of ISI were applied to the stimulus sequence. Synchronisation patterns of 5 subjects were analyzed based on synchronisation error (SE) and interresponse intervals (IRI). A strategy shift contigent upon the size of the introduced step change was detected. After small ISI changes, rapid IRI matching to the new ISI was accompanied by temporarily enlarged SE values, which slowly returned to preferred SE values before the step change. Large ISI changes showed quick SE adaptations accompanied by a temporary overcorrection of IRI. Response asymmetry between ISI decreases and increases emerged, showing a stronger adaptation during ISI increases. A two-dimensional difference equation was formulated to simulate the time series of intertap intervals and explain the control process during IRI and SE adjustments. The system constants were optimized to minimalize the deviations between the computed and the observed response trajectories, consisting of the time series of SE and IRI. It was shown that a successful model fit using a linear two-dimensional difference equation was based on the size and direction of the ISI changes. MANOVA procedures showed that differences in equation parameters during small and large step changes were statistically significant (P < 0.05). It is therefore suggested that a uniform model accounting for synchronization responses to all step changes would require the introduction of nonlinear system properties.

Acoustic Stimulation↗
PubMed1998

Dental anesthetic management of a patient with ventricular arrhythmias.

During routine deep sedation for endodontic therapy, a dentist-anesthesiologist observed premature ventricular contractions (PVCs) on a 62-yr-old woman's electrocardiogram (EKG) tracing. The dentist was able to complete the root canal procedure under intravenous (i.v.) sedation without any problems. The dentist-anesthesiologist referred the patient for medical evaluation. She was found to be free from ischemic cardiac disease with normal ventricular function. The patient was cleared to continue her dental treatment with deep sedation. She subsequently continued to undergo dental treatment with deep intravenous sedation without incident, although her EKG exhibited frequent PVCs, up to 20 per minute, including couplets and episodes of trigeminy. This article will review indications for medical intervention, antiarrhythmic medications, and anesthetic interventions for perioperative PVCs.

Anesthesia, Dental↗
PubMed1998

Country watch: Kenya.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗