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Biomedical subjects

R A Miller

Publications and source records attributed to R A Miller.

At least 307 records · Page 17Linked to original sources
PubMed1989

Pgp-1hi T lymphocytes accumulate with age in mice and respond poorly to concanavalin A.

Aging is associated with an accumulation of T cells functionally hyporesponsive to the effects of mitogens such as concanavalin A. Recent studies in mice and human have identified surface markers useful for distinguishing antigen-stimulated memory T cells from virgin T cells. In mice, memory T cells within the CD8+ cell population have been shown to express relatively high levels of the cell surface glycoprotein Pgp-1. On the theory that aging might diminish the supply of virgin thymic emigrants without compromising the production of memory T cells, we examined the proportion of Pgp-1hiCD4+ and CD8+ cells in the spleen, blood and lymph nodes of mice of varying age. We found a dramatic (2.5-fold) age-associated increase in the percentage of cells with the Pgp-1hi phenotype. By limiting dilution methods, the frequency of concanavalin A-responsive T cells was found to be significantly reduced in the Pgp-1hi cell pool, whether measured by interleukin 2-dependent proliferation, interleukin 2 production or generation of cytotoxic effectors. Pgp-1hi and Pgp-1lo T cells from young mice proliferate equally well when stimulated by optimal doses of phorbol myristate acetate and ionomycin suggesting that the poor responses to concanavalin A do not simply reflect low viability. Aging leads both to an increase in mitogen-hyporesponsive Pgp-1hi T cells, and also to lower responsiveness of cells in the Pgp-1hi subset.

Aging↗
PubMed1989

Defective control of cytoplasmic calcium concentration in T lymphocytes from old mice.

Cytoplasmic calcium concentration ([Ca]i) rises within minutes of exposure of T lymphocytes to a mitogen. T cells from old mice are defective in this reaction, a defect that could reflect either altered signal transduction or instead a more general age-associated change in intracellular calcium regulation. We therefore tested the ability of T cells from old mice to regulate their [Ca]i concentration after exposure to low concentrations of ionomycin, an agent that raises [Ca]i but bypasses receptor-mediated signal transduction mechanisms. Exposure of T cells to ionomycin leads to an abrupt increase in [Ca]i followed by stabilization at a dose-dependent plateau level that is affected by extracellular EGTA, by calmodulin inhibitors, and by modulators of protein kinase C. Plateau levels of [Ca]i after ionomycin challenge were consistently lower in T cells from old mice than in T cells from young mice. Flow cytometric experiments showed that while essentially all T cells from both old and young mice responded to ionomycin, they did so to an extent that depended on donor age. The age-dependent increase in resistance to ionomycin-induced changes in [Ca]i cannot be attributed to diminished membrane permeability to the ionomycin-calcium complex. The data suggest that aging may lead, in T lymphocytes, to a relative resistance to increases in [Ca]i, a resistance that in turn prevents cell activation.

Aging↗
PubMed1989

Legal issues related to medical decision support systems.

The use of computer-based decision support programs in medicine will result in litigation when adverse health care outcomes affect patients. This paper reviews how the United States legal system is likely to handle such cases. To date, there is minimal direct experience with such cases in the American legal system. Medical decision support systems are more likely to be viewed as tools used by physicians in providing a service to patients than as products owned by patients. Therefore, it is fairly certain that the negligence principles applied in medical malpractice cases will also be applied in cases involving computer-based medical decision support systems. Only under special circumstances will principles of strict product liability apply. As there are no existing standards, and medical decision support programs are hybrids having characteristics of both services and products, future litigation will be handled on a case by case basis.

Decision Making, Computer-Assisted↗
PubMed1989

Vascular endothelial cells enhance T cell responses by markedly augmenting IL-2 concentrations.

Cultured human endothelial cells (EC), dermal fibroblasts (DF), and blood monocytes were compared for their effects on IL-2 concentration measured in the medium of both unfractionated peripheral blood mononuclear cells (PBMC) and highly enriched CD4+ T cell populations maximally stimulated by the polyclonal mitogen phytohemagglutinin (PHA). EC, but not DF or blood monocytes, could markedly augment IL-2 concentrations, up to 30-fold or more. This action of EC could not be replaced by fixed EC, EC-conditioned medium, or recombinant IL-1. Antibody to CD2 but not to CD18 blocked the EC effect. The augmented IL-2 concentrations generated in the presence of EC appeared biologically active in that the addition of living EC conferred a proliferative advantage to PBMC at suboptimal PHA concentrations, an effect which could be mimicked by exogenous IL-2. We propose that EC augmentation of IL-2 synthesis may contribute to the relatively unique ability of EC to stimulate a primary allogeneic response in vitro and may function in vivo to boost T cell responses to limiting quantities of antigen.

Adult↗
PubMed1989

Acute microvascular effects of the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine: comparisons with leukotriene B4.

Acute effects of the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) on microvessels of the hamster cheek pouch were studied using intravital and electron microscopy. FMLP (1.0 microM) applied topically to the pouch microvasculature produced transient vasoconstriction of second- and third-order arterioles, which was accompanied by modest narrowing of pericytic venules, leukocyte adherence, diapedesis, and macromolecular extravasation. Contrary to observations of leukotriene B4 (LTB4)-exposed venules in the same animal model, electron micrographs of fMLP-treated venules supported junctional, vesicular, and potential transcellular modes of transendothelial protein transport. Endothelial junctions were not characterized by large gaps, but failure of endothelial processes to effectively bridge diapedesing cells and reestablish junctional contact resulted in substantial deposition of subendothelial reaction product. Venous microvessels 18-21 micron in diameter were particularly susceptible to the deleterious effects of fMLP and revealed the highest percentage of total junctions or endothelial cells labeled by reaction product. Implied barrier dysfunction was more prevalent in fMLP-treated vessels exhibiting adherence and/or diapedesis; however, the presence of barrier defects was not correlated with leukocyte margination and/or emigration (Marg/Emig). The absence of simple correlation, without persuasive evidence for direct vasopermeability effects, recognizes that some Marg/Emig events may not have been present at the time of fixation and suggests the potential for neutrophil-mediated endothelial dysfunction, governed by multiple determinants, is often unrealized.

Animals↗
PubMed1989

Integrated cystoscope: first rigid multipurpose operating cystoscope for local anesthetic endoscopy.

The Miller Integrated Cystoscope is the first small-diameter (17 Ch), rigid, multipurpose, operating cystoscope (biopsy, urethrotomy, ureteric catheterization, cutting, retrieval of stones and foreign bodies, and injection) designed with patient comfort in mind. Despite a small outside diameter, the 8.7-Ch instrument channel conducts a 7.5-Ch accessory including the unique rigid Endoknife, which converts it into an optical urethrotome and rigid Endoneedle which can deliver local anesthetic and other pharmacologic agents into the bladder, prostate, and urethra of both male and female patients. The simplicity of design has dispensed with the need for more costly and conventional instrumentation (e.g., optical urethrotome, Albarron lever) at a fraction of the cost. The urologist can not only inspect the lower urinary tract (Cf fiberscopes) but also perform endoscopic procedures short of a full transurethral prostatectomy with maximum patient comfort.

Ambulatory Surgical Procedures↗
PubMed1989

Plasma cell panniculitis: a unique clinical and pathologic presentation of linear scleroderma.

A 64-year-old woman had an 11-month history of a highly inflamed linear eruption that affected the left arm, including the dorsal aspect of the hand. It was characterized histologically by an intense plasma cell infiltrate extending throughout the dermis and subcutaneous fat. During the subsequent 2 years, the area evolved into a linear sclerotic plaque in keeping with the diagnosis of linear scleroderma. This case represents a clinical and pathologic presentation of linear scleroderma not previously emphasized in the literature.

Age Factors↗
PubMed1989

Neoplastic lesions induced by 1,3-butadiene in B6C3F1 mice.

1,3-butadiene (CAS No. 106-99-0) was evaluated for carcinogenicity and chronic toxicity by inhalation exposure in B6C3F1 mice because of its high production volume, widespread exposure of workers, and the lack of carcinogenicity and toxicity data (NTP Report #228, 1984). Butadiene (BD) had long been considered to have low toxicity. The long-term studies established that BD is a potent mouse carcinogen with multiple organ carcinogenicity (Huff et al. 1985; Melnick et al. 1988). This paper presents morphological descriptions and illustrations of the neoplastic lesions induced by 1,3-butadiene in B6C3F1 mice.

Adenocarcinoma↗
PubMed1989

Defective calcium signal generation in a T cell subset that accumulates in old mice.

Table 2 outlines our current understanding of the bases for activation defects in T cells from old mice, with speculative ideas indicated by a question mark. Many, though not all, T cells from old mice show defects in the generation of Ca2+ signals within the first few minutes of exposure to a mitogenic lectin or to antibody to components of the T cell receptor. These defects seem to involve an increased resistance to changes in cytoplasmic free calcium ion concentration, perhaps though changes in the calcium extrusion pump. Diminished rates of uptake of calcium from extracellular sources also contribute to defective calcium signal generation. Some aspects of the activation process, including production of inositol phosphates, seem in contrast not to be altered by aging in mice. T cells with defects in Ca2+ responses seem to be contained preferentially within the PGP-1hi subsets of both the helper and cytotoxic lineages, subsets that accumulate dramatically in old mice. Since the PGP-1hi phenotype is thought to distinguish memory T cells from virgin thymic emigrants, we propose a model in which aging leads to the progressive conversion of virgin to memory T cells, which in turn gradually lose the ability to respond to activating stimuli.

Aging↗
PubMed1989

Factors in snake venoms that increase capillary permeability.

Capillary permeability increasing (CPI) activity is a phenomenon of the microvasculature caused by many agents such as snake venoms, histamine, 5-hydroxytryptamine (5-HT), prostaglandins and leukotrienes. Since no systematic study has been done to determine what components of snake venom cause CPI activity, a CPI factor from Naja naja atra (Taiwan cobra) venom was isolated using intravenous injections of Evan's blue dye as the indicator of increased permeability and the factor's properties were extensively studied. Cardiotoxin from Naja naja kaouthia (Thailand cobra) and Mojave toxin from Crotalus scutulatus scutulatus (Mojave rattlesnake) venoms demonstrated CPI activity. Postsynaptic neurotoxins from an elapid and a hydrophid and myotoxin a from Crotalus viridis viridis (prairie rattlesnake) showed no CPI activity at the dose studied. The purified CPI active component from Naja naja atra venom was found to have cardiotoxic activity. Therefore, Elapidae cardiotoxins are CPI active factors. However, CPI activity is not due to cardiotoxins alone as the presynaptic neurotoxin, Mojave toxin, also showed CPI activity. Selective inhibitors were used to indicate possible mechanisms of action on the capillaries by Naja naja atra venom and Crotalus scutulatus scutulatus venom. The histamine H1-receptor blockers diphenhydramine, promethazine, and cyproheptadine were effective against both venoms in preventing increased capillary permeability. These results suggested that histamine release activity is the most likely mechanism resulting in CPI activity from these venoms.

Amino Acids↗
PubMed1989

Evaluation issues in the development of expert systems in medicine.

Evaluation of medical decision support software (MDSS)--computer programs to assist health professionals with diagnostic and/or therapeutic decisions--has not kept pace with the development of such programs. This article describes the following formative evaluation issues that must be addressed by developers of MDSS to evaluate these programs properly: (1) How can systematic feedback be obtained about an evolving program? (2) How can enough data to evaluate the program be obtained? (3) How much instruction is necessary? (4) What are the most important aspects for users to evaluate? and (5) How can the appropriate use of a developing MDSS be assured? Data from an ongoing evaluation of an existing MDSS, Quick Medical Reference, are used to illustrate the issues and to suggest recommendations for addressing them.

Data Collection↗
PubMed1989

TSH binding correlates with TSH-stimulated thyroid adenylate cyclase activity in human thyroid tissues.

Thyroid-stimulating hormone (TSH) stimulates adenylate cyclase (AC) activity and the growth and differentiation of thyroid cancers of follicular cell origin. Thyroid neoplasms generally have higher TSH-stimulated AC activity than normal thyroid tissue from the same patients. To determine whether differences in TSH receptors could account for the differences in AC activity, we studied the 8000 g membrane particulate fraction from 28 thyroid tissues (10 papillary carcinomas, 6 multinodular goiters, 4 follicular adenomas, 3 follicular carcinomas, 2 Graves, 1 normal, 1 Hürthle cell adenoma, and 1 thyroiditis). TSH receptors were measured by competitive inhibition using radioactive iodine-labeled bovine TSH (125I-bTSH). Maximal binding capacity (Bmax) and dissociation constant (Kd) were calculated by Scatchard analysis. AC activity was measured by the conversion of alpha-[32P]-ATP to [32P]-cAMP in the maximally (300 mU/ml) TSH-stimulated state. The basal and forskolin-stimulated (100 mmol/L) AC activity were also measured, and the ratios to TSH-stimulated AC activity were calculated (TSH/Basal ratio and TSH/Forskolin ratio). We found a strong correlation between the percent specific binding (%SB) of 125I-bTSH and TSH/Basal ratio (r = 0.70, p = 0.0001), between Bmax and the TSH/Basal ratio (r = 0.71, p = 0.001), between %SB and TSH/Forskolin ratio (r = 0.44, p = 0.02), and between Bmax and TSH/Forskolin ratio (r = 0.65, p = 0.0002). This strong correlation between TSH binding and the TSH-stimulated AC activity suggests that in some thyroid neoplasms the higher AC response to TSH may be due to an increased number of TSH receptors.

Adenylyl Cyclases↗