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Biomedical subjects

R A Miller

Publications and source records attributed to R A Miller.

At least 109 records · Page 6Linked to original sources
PubMed1998

Thromboembolism after foot and ankle surgery. A multicenter study.

Thromboembolic disease presents a potentially fatal complication to patients undergoing orthopaedic surgery. Although the incidence after hip and knee surgery has been studied and documented, its incidence after surgery of the foot and ankle is unknown. For this reason, a prospective multicenter study was undertaken to identify patients with clinically evident thromboembolic disease to evaluate potential risk factors. Two thousand seven hundred thirty-three patients were evaluated for preoperative risk factors and postoperative thromboembolic events. There were six clinically significant thromboembolic events, including four nonfatal pulmonary emboli, after foot and ankle surgery. The incidence of deep vein thrombosis was six of 2733 (0.22%) and that of nonfatal pulmonary emboli was four of 2733 (0.15%). Factors found to correlate with an increased incidence of deep vein thrombosis were nonweightbearing status and immobilization after surgery. On the basis of these results, routine prophylaxis for thromboembolic disease after foot and ankle surgery probably is not warranted.

Adolescent↗
PubMed1998

Modeling concepts in medicine for medical language understanding.

Over the past two decades, the construction of models for medical concept representation and for understanding of the deep meaning of medical narrative texts have been challenging areas of medical informatics research. This review highlights how these two inter-related domains have evolved, emphasizing aspects of medical modeling as a tool for medical language understanding. A representation schema, which balances partially but accurately with complete but complex representations of domain-specific knowledge, must be developed to facilitate language understanding. Representative examples are drawn from two major independent efforts undertaken by the authors: the elaboration and the subsequent adjustment of the RECIT multilingual analyzer to include a robust medical concept model, and the recasting of a frame-based interlingua system, originally developed to map equivalent concepts between controlled clinical vocabularies, to invoke a similar concept model.

Artificial Intelligence↗
PubMed1998

Clinical application of the UMLS in a computerized order entry and decision-support system.

Vanderbilt University Medical Center uses the UMLS as a dictionary, an interlingua, and a knowledge source within the WizOrder system. WizOrder provides direct care-provider order entry and integrated clinical decision-support capabilities. Linking the two functions enables efficient decision-support during the "normal" workflow of care providers, at the point where decisions are made. WizOrder uses the UMLS as a dictionary to encode free-text entries into controlled vocabularies such as ICD9. As an interlingua, the UMLS provides mapping between vocabularies, allowing to translate patient-specific information to MeSH terms and perform automated literature retrieval. WizOrder uses the tables of co-occurring concepts and the Semantic Network to provide sensible lists of potential drug interactions and adverse drug reactions, and generate fully-formed MEDLINE queries for PubMed.

Decision Support Systems, Clinical↗
PubMed1997

CD30-regulated apoptosis in murine CD8 T cells after cessation of TCR signals.

A variety of culture systems have been developed to study mechanisms of activation-induced cell death in peripheral T lymphocytes either during the initial period after exposure to an activating stimulus or following repeated stimulation of activated T cells. In this study we describe a new culture model for the analysis of apoptosis after withdrawal of TCR signals from activated T cells. T cells activated by anti-CD3 antibodies for 48 h and then further cultured in the presence of IL-2 but absence of continued CD3/TCR stimulation underwent dramatic cell death approximately 4 days following removal of the TCR stimulus. Apoptotic cells generated in this protocol, unlike those produced by hyperstimulation, retained substantial levels of degraded DNA following fixation, consistent with death in the G0/G1 phase of the cell cycle. This "agonist withdrawal" cell death occurred largely within the CD8 T cell subset, with CD4 cells showing lower levels of apoptosis. This form of cell death did not appear to be the result of IL-2 exhaustion, since repeated addition of IL-2 during the culture period did not significantly alter the number of apoptotic cells. Apoptosis induced by agonist withdrawal was not blocked by Fas antigen fusion protein or by anti-TNF alpha-neutralizing antibodies, suggesting a mechanism independent of Fas/FasL and TNF alpha/TNF-R interactions. Cell death was, however, significantly inhibited by treatment with a CD30 fusion protein. CD30 was found to be transiently expressed on CD8 T cells immediately prior to death, with lower expression on CD4 cells, while CD30 ligand was found to be expressed most strongly by CD4 T cells. These results suggest a role for CD30 in regulating the onset of apoptosis in CD8 T cells after interruption of CD3/TCR.

Animals↗
PubMed1997

Summary recommendations for responsible monitoring and regulation of clinical software systems. American Medical Informatics Association, The Computer-based Patient Record Institute, The Medical Library Association, The Association of Academic Health Science Libraries, The American Health Information Management Association, and The American Nurses Association.

Clinical software systems are becoming ubiquitous. A growing literature documents how these systems can improve health care delivery, but concerns about patient safety must now be formally addressed. In 1996, the U.S. Food and Drug Administration (FDA) called for discussions on regulation of software programs as medical devices. In response, a consortium of organizations dedicated to improving health care through information technology developed recommendations for the responsible regulation and monitoring of clinical software systems by users, vendors, and regulatory agencies. These recommendations were revised and approved by the American Medical informatics Association Public Policy Committee and Board. Other organizations reviewed, modified, and approved the recommendations, and the Boards of Directors of most of the organizations in the consortium endorsed the guidelines. The consortium proposes four categories of clinical system risk and four classes of monitoring and regulatory action that can be applied on the basis of the risk level. The consortium recommends that most clinical software systems be supervised locally and that developers of health care information systems adopt a code of good business practices. Budgetary and other constraints limit the type and number of systems that the FDA can regulate effectively; therefore, the FDA should exempt most clinical software systems and focus on systems that pose high clinical risk and provide limited opportunity for competent human intervention.

Clinical Medicine↗
PubMed1997

In vitro production of antigen-specific T cells from unprimed mice: role of dexamethasone and anti-IL-10 antibodies.

We describe here a culture system for studying the development, in vitro, of antigen-specific CD4 T cells from unprimed mice. T cells from young mice are initially exposed to antigen, such as pigeon cytochrome C or keyhole limpet hemocyanin, in the presence of adherent accessory cells and then allowed to proliferate in the absence of antigen but in the presence of IL-2, 10(-8) M dexamethasone, and antibodies to IL-10. Proliferation and IL-2 production by T cells harvested from such expansion cultures are antigen-dependent but not antigen-specific and at different doses can be either stimulated or inhibited both by the priming antigen and by irrelevant proteins. Antigen-specific T cell reactions can be elicited by any of three modifications of the culture protocol: (a) absorption of nonspecific cells on accessory cell monolayers bearing irrelevant proteins; (b) increased doses of dexamethasone during the expansion phase; or (c) a second cycle of antigen activation and antigen-free expansion. These observations provide a foundation for further analysis of in vitro maturation of primary immune responses and suggest an important role for IL-10 and glucocorticoids in regulating the early stages of activation and proliferation by naive T cells.

Animals↗
PubMed1997

Differential tyrosine phosphorylation of zeta chain dimers in mouse CD4 T lymphocytes: effect of age.

Antibody to the zeta chain of the CD3/TCR signal transduction complex precipitates a series of tyrosine-phosphorylated proteins that can be discriminated by electrophoresis in nonreducing polyacrylamide gels. Stimulation of resting mouse splenic CD4 T cells by cross-linking CD3 to CD4 leads to increases in tyrosine phosphorylation of five such proteins, of which three are likely to be dimeric forms of zeta as judged by behavior on two-dimensional gels. Two other phosphoproteins, of MW 38 and 55 kDa, also coprecipitate with the CD3zeta complex. The level of induced phosphorylation of each of these five stimulus-responsive phosphoproteins declines with donor age, T cells from 18-month-old mice being almost wholly nonresponsive. Resting T cells have only a single major form of tyrosine-phosphorylated zetazeta. Phosphorylation of this rapidly migrating species is not influenced by activation, but is about threefold lower in resting T cells from 12- to 18-month-old mice than in cells from 6-month-old animals. Thus the phosphorylation of the CD3-zeta chain of CD4 T cells from aged mice exhibits abnormalities both in the resting state and within the first 5 min of the activation process.

Aging↗
PubMed1997

Diminished activation of the MAP kinase pathway in CD3-stimulated T lymphocytes from old mice.

Stimulation of the ERK family of protein kinases ('extracellular signal regulated kinases', also known as MAP kinases) plays an important role in the activation of many cell types, including T lymphocytes. ERKs are activated when they are phosphorylated by an upstream activator, the dual-specific protein kinase MEK. To see if aging leads to an impairment of MEK activation in mouse T cells, we used a mobility shift assay in which activation of MEK leads to phosphorylation and altered mobility of ERK-2 kinase. Similarly, we monitored mobility of pp90rsk, a known ERK substrate, as an indication of ERK function. We found an age-related decline in the ability of mouse T cells to activate both MEK and ERK function in response to stimulation by antibodies to the CD3 chain of the T cell receptor. Aging did not alter the kinetics of enzyme activation, but did diminish (by about 2-fold) the maximal level of substrate converted into the slower migrating form. Naive and memory CD4 T cells from young mice were equally able to convert ERK2 to its slower migrating form, suggesting that the decline in MEK function is not likely to be attributable to the shift, with age, from naive to memory T cell predominance. Our data suggest that age-dependent declines in gene activation, including genes for key cytokines like IL-2, may be due to declines in the upstream signals that lead to activation of the MEK/ERK protein kinase cascade.

Aging↗
PubMed1997

Age-related changes in T cell surface markers: a longitudinal analysis in genetically heterogeneous mice.

In a longitudinal design in which each animal was examined repeatedly throughout its life, we used flow cytometry to determine the numbers or proportions of a variety of T lymphocyte subsets in the peripheral blood of mice aged 8-20 months. Half of the 128 mice were given a low calorie diet which is known to extend lifespan and to reduce the rate of age-associated change in T cell immune function. In these genetically heterogeneous mice, bred as the progeny of CB6F1 females and C3D2F1 males, aging led to statistically significant increases in the number of CD3 cells and the proportions of CD4 memory and CD8 memory cells, and declines in the proportions of CD4 cells and CD4 virgin cells. Older mice also had increased proportions of CD4 and CD8 cells that were able to extrude the fluorochrome R123 through the action of P-glycoprotein. Caloric restriction delayed or prevented most of these age-dependent changes, but had little effect on expression of P-glycoprotein. Correlation analysis showed that those individual mice with high levels of CD4 memory or CD8 memory T cells tended also to have relatively low levels of CD4 virgin cells and low proportions of CD4 T cells, particularly at older ages. In addition, those mice which had the greatest rate of increase in CD4 memory and CD8 memory T cells also tended to show the greatest decline in CD4 virgin and in the proportion of CD4 cells. High numbers of CD4R (and high rates of change in the CD4R subset) were associated with high numbers (and change scores) for the CD8R subset, but there were no strong correlations between the R123-extruding subsets and other age-sensitive markers. Thus some, but not all, age-sensitive T cell subsets show correlated levels and correlated rates of change throughout the middle of the lifespan.

Aging↗
PubMed1997

Desiderata for product labeling of medical expert systems.

The proliferation and increasing complexity of medical expert systems raise ethical and legal concerns about the ability of practitioners to protect their patients from defective or misused software. Appropriate product labeling of expert systems can help clinical users to understand software indications and limitations. Mechanisms of action and knowledge representation schema should be explained in layperson's terminology. User qualifications and resources available for acquiring the skills necessary to understand and critique the system output should be listed. The processes used for building and maintaining the system's knowledge base are key determinants of the product's quality, and should be carefully documented. To meet these desiderata, a printed label is insufficient. The authors suggest a new, more active, model of product labeling for medical expert systems that involves embedding 'knowledge of the knowledge base', creating user-specific data, and sharing global information using the Internet.

Artificial Intelligence↗
PubMed1997

Candidate biomarkers of aging: age-sensitive indices of immune and muscle function covary in genetically heterogeneous mice.

A longitudinal experiment was designed to test the hypothesis that individual mice differ in their aging rate and to validate candidate biomarkers proposed to measure the rate of aging. Mice were bred as the genetically heterogeneous progeny of a cross between CB6F1 mothers and C3D2F1 fathers. Half of the mice were fed ad libitum (AL group), and the other half were subjected to 60% calorie restriction (CR group). Each mouse was tested at about 9 months of age using age-sensitive tests of immune status, and then again at about 12 months of age using age-sensitive tests of muscle function. The data were then analyzed using the method of partial least squares to determine the combinations of test weights that maximize the covariance of the weighted sum of immune measures with the weighted sum of muscle function measures. Both AL and CR mice exhibited a statistically significant relation between the immune status tests and the muscle function tests. Maximal covariance was obtained with a set of weighting coefficients consistent with our working hypothesis: mice with high levels of CD4 memory T cells (which increase with age) also had relatively low levels of muscle strength and endurance. Low strength was associated with low CD8 cells in the AL mice, with high numbers of CD8 memory cells in the CR mice and with low CD3 cells in both diet groups. The partial least squares method generates composite indices of immune status and muscle function that can be evaluated as biomarkers of aging rate in these mice. Further work will be needed to assess whether these tests predict either longevity or the trajectory of change in other age-sensitive molecular and physiological traits.

Aging↗
PubMed1997

Cytokine production by subsets of CD4 memory T cells differing in P-glycoprotein expression: effects of aging.

We have shown previously that the mouse CD4 memory cell subset can be divided into two subpopulations based on differential expression of P-glycoprotein. Cells with high levels of P-glycoprotein can be detected by extrusion of the fluorochrome Rhodamine 123; they are referred to as R123lo cells. These R123lo T cells increase with age and have been shown not to respond to anti-CD3 and IL-2 by proliferation or IL-4 production. We report here (a) that the failure of the R123lo CD4 memory population to respond to anti-CD3/IL-2 stimulation cannot be overcome by addition of anti-CD28, PMA, IL-4 or IL-12, alone or in various combinations, and (b) that this age-dependent subset exhibits impaired production of IL-5 and IL-10 as well as decreased proliferation. R123lo CD4 memory cells from young mice are also deficient in IFN gamma secretion by this subset. Although the R123lo cells respond poorly to receptor-dependent agonists, they can be triggered to proliferate and produce IFN gamma by the combination of PMA and ionomycin. In addition to increasing the proportion of R123lo cells in the memory CD4 pool, aging also leads to a decline in the ability of R123hi cells to produce IL-5 and IL-10. Thus, the accumulation of R123lo cells cannot by itself account for the poor proliferation and Th2 cytokine production of aged T cells in cytokine-supplemented culture conditions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗