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Biomedical subjects

R A Miller

Publications and source records attributed to R A Miller.

At least 325 records · Page 18Linked to original sources
PubMed1989

Senescence of T cells: a potential consequence of the Maillard reaction?

The immune system of old mice is heterogeneous, containing a mixture of long and short-lived T cells, some of which respond to activating mitogens, amid others that do not. Studies of T cell activation have revealed defects in calcium signal generation and oncogene expression, among others, that are gradually revealing the molecular basis for immunosenescence. New evidence suggests that the proportion of longer lived cells, detectable with antibodies to the PGP-1 surface glycoprotein, increases with age in mice, and that it is the PGP-1hi T cell subpopulation that is least responsive to mitogens. It is now possible to test the idea that the longest-lived T cells may contain stable components whose nonenzymatic glycosylation contributes to their poor T cell function.

Aging↗
PubMed1989

Use of the Quick Medical Reference (QMR) program as a tool for medical education.

The original goal of the INTERNIST-1 project, as formulated in the early 1970s, was to develop an expert consultant program for diagnosis in general internal medicine. By the early 1980s, it was recognized that the most valuable product of the project was its medical knowledge base (KB). The INTERNIST-1/QMR KB comprehensively summarizes information contained in the medical literature regarding diagnosis of disorders seen in internal medicine. The QMR program was developed to enable its users to exploit the contents of the INTERNIST-1/QMR KB in educationally, clinically, and computationally useful ways. Utilizing commonly available microcomputers, the program operates at three levels--as an electronic textbook, as an intermediate level spreadsheet for the combination and exploration of simple diagnostic concepts, and as an expert consultant program. The electronic textbook contains an average of 85 findings and 8 associated disorders relevant to the diagnosis of approximately 600 disorders in internal medicine. Inverting the disease profiles creates extensive differential diagnosis lists for the over 4250 patient findings known to the system. Unlike a standard printed medical textbook, the QMR knowledge base can be manipulated "on the fly" to format displays that match the information needs of users. Preliminary use of the program for education of medical students and medical house officers at several sites has met with an enthusiastic response.

Computer-Assisted Instruction↗
PubMed1989

Creation of realistic appearing simulated patient cases using the INTERNIST-1/QMR knowledge base and interrelationship properties of manifestations.

The Internist-1/Quick Medical Reference (QMR) knowledge base (KB) describes the clinical manifestations of some 600 diseases in the domain of internal medicine. This KB, while not representing deep causal modelling of disease processes, is nonetheless effective in providing medical diagnostic assistance through the QMR medical decision support system. One potential application of this extensive KB is the generation of simulated patient cases for use in educating health professionals. However, the "flat" KB is not adequate for this because the clinical manifestations used in the disease descriptions are not mutually independent. While it is theoretically possible to construct disease descriptions which embody pathophysiologic mechanisms of disease causality, it is not practical from the standpoint of resource utilization. Short of constructing a causal knowledge base, the authors herein describe the generation of realistic appearing simulated patient case data using existing information in the knowledge base. This existing information in the KB is in the form of properties which represent a shallow form of interrelationships of the manifestations. The authors conclude that this ability to generate simulated cases represents another view in which to look at an extensive knowledge base, as well as having application to constructing intelligent tutoring systems for health professionals in training.

Artificial Intelligence↗
PubMed1989

Effect of a computer-assisted general medicine diagnostic consultation service on housestaff diagnostic strategy.

Quick Medical Reference (QMR) is a microcomputer-based decision support system designed to provide diagnostic assistance in the field of internal medicine. In addition to providing plausible diagnostic hypotheses based upon patient specific findings, the program highlights history, physical and laboratory items which are potentially useful in discriminating among the diagnoses under consideration. We have evaluated the impact of a computer-assisted diagnostic consultation service on the diagnostic and management strategy of a housestaff in a university internal medicine training program. Differential diagnoses were obtained before and after the use of the program, and a questionnaire was used to assess the educational value of the service and the effect of the service on the diagnosis and planned management. Over an eight week period, 31 cases were identified which met inclusion criteria. The QMR consultation added a diagnosis to the original list in 14 out of 31 cases. The consultation reordered the diagnosis in an additional 7 cases, and in 8 cases a diagnosis was ruled out by the use of the program. After the use of the program the housestaff reported they would obtain an additional lab test in 10 cases, change the order of planned tests in two cases and eliminate a lab test in one case. The use of the program was rated as helpful educationally in 81% of the cases, and helpful with respect to management in also 81% of the cases.

Diagnosis, Computer-Assisted↗
PubMed1988

Frequencies of IL-2- and IL-4-secreting T cells in naive and antigen-stimulated lymphocyte populations.

The relative frequencies of IL-2-and IL-4-secreting precursors in naive and Ag-primed populations were investigated by using limiting dilution analysis. Cells capable of IL-4 production in lymphoid populations freshly isolated from mice were rare in comparison with those producing IL-2 when the cells were stimulated by nominal Ag, by alloantigens, or by mitogens. One cycle of in vitro Ag restimulation and rest, however, enabled us to detect high proportions of IL-4-secreting cells among keyhole limpet hemocyanin-primed lymph node cells. With cultures set up at monoclonal cell doses, it was shown that IL-2 and IL-4 are secreted by separate precursor populations at this stage of their development. The IL-4-secreting cells were further shown to be dependent upon the presence of IL-2, either secreted by separate precursors or exogenously added, for the production of detectable amounts of IL-4. Analysis of the frequencies of helper cells producing both IL-2 and IL-4 at various stages of the in vivo immune response and the requirements for their growth and differentiation should give a better understanding of the relative contributions of each cell type.

Animals↗
PubMed1988

Outpatients: can we save time and reduce waiting lists?

The amount of time that one consultant urologist wasted on unnecessary administration while seeing outpatients was noted over six weeks. Searching for missing clinical data and the time spent on non-medical clerical tasks took up nearly half of the consultant's sessions. This seemed to be due to insufficient clerical and secretarial staff. Because low salaries are offered to such staff vast sums of money are being paid to agencies who are providing an appreciable number (40%) of the secretarial staff in our hospitals. Urgent action from the government is needed to remedy this and thus make substantial reductions in outpatient waiting lists nationally. It would greatly improve morale in this important sector of the health service without increasing total costs.

Appointments and Schedules↗
PubMed1988

Defective T lymphocytes in old mice. Diminished production of mature c-myc RNA after mitogen exposure not attributable to alterations in transcription or RNA stability.

To gain further insight into the mechanism of age-associated loss of T cell proliferative responses to mitogenic lectins, we measured c-myc specific mRNA accumulation in Con A-stimulated cultures of spleen cells from old and young mice using Northern blot and S1 nuclease protection analyses. Aging led to a consistent decline (an average of approximately 60%) in the level of c-myc mRNA in stimulated cells. The time course for c-myc RNA accumulation was similar for old and young mice. Nuclear runoff experiments showed that mitogen stimulation leads to an equivalent increase in transcription of the c-myc gene in T cells from old and young mice. Furthermore, in the presence of 5,6-dichlorobenzimidazole riboside, a selective inhibitor of RNA polymerase II, c-myc mRNA decayed with equal kinetics in cells from mice of different ages. These results show that lymphocytes from aged mice exhibit defects in gene expression very early in the activation process and suggest that these deficits may involve, at least for some genes, alterations in post-transcriptional processing.

Aging↗
PubMed1988

Cyclic AMP concentrations modulate both calcium flux and hydrolysis of phosphatidylinositol phosphates in mouse T lymphocytes.

Activation of T cells by lectins or mAb directed at components of the Ag-specific TCR results in hydrolysis of phosphorylated derivatives of phosphatidylinositol and an increase in intracellular free calcium concentration (Cai). We report that cholera toxin, which activates adenylate cyclase by ADP ribosylation of a G protein, also reduces both inositol phosphate (IP) production and the rise in Cai in Con A-stimulated murine T cells. We find that similar dose-dependent inhibitory effects can be induced by each of four other agents that raise cAMP levels in such cells: forskolin, PGE2, 2-chloroadenosine, and isoproterenol. The effects of these agents on IP production are reversible and therefore do not simply reflect cytotoxicity. Activation by PHA and by antibody to the T3-epsilon-chain of the TCR complex are also inhibited by agents that increase intracellular cAMP. Thus, changes in cAMP concentration seem to regulate both IP production and the Ca2+ response, two early components of the mitogen-induced activation process.

2-Chloroadenosine↗
PubMed1988

Neonatal tolerance induction to Mlsa. I. Tolerance to Mlsa is restricted by shared MHC determinants.

In this paper we have examined the influence of MHC (major histocompatibility complex) on neonatal tolerance to Mlsa (minor lymphocyte stimulating). By employing a novel approach we have shown that tolerance to Mlsa is restricted by shared MHC determinants. Thus, neonatal Mlsb mice, injected at birth with spleen cells from Mlsa mice, were tested as adults for Mlsa specific responses by interleukin-2 limiting dilution analysis, a technique which allows us to discriminate between responses to MHC + Mlsa and to MHC alone. Tolerance to Mlsa was in the context of any MHC type examined--donor, host, and third-party MHC products. These results show that tolerance to Mlsa is restricted by shared MHC determinants and extend previous studies indicating that activation of Mlsa responses is similarly restricted.

Animals↗
PubMed1988

Respiratory tract lesions in F344/N rats and B6C3F1 mice after inhalation exposure to 1,2-epoxybutane.

1,2-Epoxybutane, a short-chain epoxide used as a stabilizer in chlorinated hydrocarbon solvents, was administered by inhalation exposure as a vapor 6 h/day, 5 day/week, for 24 months at exposure concentrations of 0, 200 or 400 ppm to F344/N rats and 0, 50, or 100 ppm to B6C3F1 mice. Survival of all groups of rats was 50% or greater until week 98 but was reduced in exposed groups by the end of the study. Survival in male mice was comparable among groups. Survival in female mice was greater than 50% until week 86, but was then reduced in the high-exposure group of mice. Exposure-related inflammatory, degenerative, and proliferative lesions occurred in the nasal cavity of both rats and mice. Seven papillary adenomas occurred in the nasal passages of high-exposure male rats and 2 in the nasal passages of high-exposure female rats. Alveolar/bronchiolar adenoma or carcinoma (combined) occurred with increased incidence in exposed male rats relative to controls. No exposure-related neoplastic lesions were seen in mice. After inhalation exposure, 1,2-epoxybutane was carcinogenic in rodents as were other epoxides or related compounds including propylene oxide, 1,3-butadiene, and ethylene oxide. The site of carcinogenic activity was considered to be related to length of the carbon chain.

Administration, Inhalation↗
PubMed1988

Suprapubic endoscopy: a percutaneous approach.

We have assessed whether suprapubic endoscopic surgery can be helpful in situations where transurethral access is inadequate, difficult or likely to be associated with urethral damage and have applied a modified version of the well known techniques for creating and dilating a track for percutaneous renal access to the bladder. This method has been used in a series of clinical cases and in certain experimental studies. Assessment of the techniques has allowed their modification and the development of a specially designed access cannula--the St Peter's Hospital cannula.

Endoscopy↗
PubMed1988

Human T cell leukemia virus-I-associated T-suppressor cell inhibition of erythropoiesis in a patient with pure red cell aplasia and chronic T gamma-lymphoproliferative disease.

Human retroviruses have recently been linked with T cell lymphoproliferative disorders and with the acquired immune deficiency syndrome. We investigated the mechanisms for acquired pure red cell aplasia and cutaneous anergy in a patient with the chronic T gamma-lymphoproliferative disease (T gamma-LPD) syndrome. Patient marrow erythroid progenitors (BFU-E) were 17 +/- 9% of control and were selectively increased to 88-102% of control after marrow T cell depletion. Patient Leu 2+ suppressor T cells spontaneously produced high titers of human gamma-interferon and resulted in a concentration-dependent selective inhibition (74-91%) of BFU-E when co-cultured with autologous or allogeneic marrow. Conditioned media (CM) derived from patient Leu 2+ T cells similarly inhibited growth of autologous or allogeneic marrow BFU-E. The inhibitory factor derived from patient CM was acid-labile (pH 2) and sensitive to trypsin; prior treatment of patient T cells with anti-HLA-DR monoclonal antibody plus complement abrogated the suppressive effect of T cell-derived CM. Patient peripheral blood mononuclear cells (PBMC) were unable to support growth of cultured interleukin 2 (IL 2)-dependent T cells, but responded to exogenous IL 2 in vitro with a 16-21-fold augmentation, relative to control, in mitogen-induced proliferation. Antibodies to HTLV-I core proteins p19 and p24 but not to HTLV-III proteins were detected in patient serum by Western blotting; patient cultured PBMC stained (7-11%) with antibodies to p19 and p24. Patient cultured PBMC demonstrated integrated HTLV-I genomic sequences by the Southern technique and expressed both specific HTLV-I genomic sequences by RNA dot blot plus reverse transcriptase activity. Utilizing a cloned DNA probe for the beta chain of the T cell receptor gene, patient PMBC demonstrated gene rearrangements providing presumptive evidence for clonality. The presence in serum of HTLV-I p19 and p24 antibodies, the expression of p19 and p24 core antigens on patient mononuclear cells, the evidence of HTLV-I proviral integration sequences and the expression of HTLV-I genomic sequences in patient cells, indicates infection with HTLV-I and raises the possibility of an etiologic link between human retrovirus infection and some instances of large granular lymphocytic leukemia (T gamma-LPD).

Anemia, Aplastic↗
PubMed1988

Primary cardiac hemangiosarcomas induced by 1,3-butadiene in B6C3F1 hybrid mice.

Proliferative vascular lesions of the heart were found in mice exposed chronically to 1,3-butadiene by inhalation with an overall incidence of 30% in males and 43% in females. Based on histological criteria, the lesions were subclassified as endothelial hyperplasia with an incidence of 7% in males and 13% in females and hemangiosarcoma with an incidence of 23% and 30%, respectively. A dose-relationship for both lesions was observed in females, but not in males. The absence of a dose response in males was most likely due to the lower survival rate for high-dose animals (14%) when compared to the lower-dose animals (22%). Endothelial hyperplasia was characterized by widened vascular spaces lined by a single layer of plump endothelial cells. When cellular pleomorphism and piling up of endothelial nuclei were observed, the lesion was diagnosed as hemangiosarcoma. Ultrastructural examination of hemangiosarcomas revealed lumen formation, intercellular junctions and cytoplasmic filaments. Pinocytotic vesicles which are 1 of the characteristics of endothelial cells could not be identified with certainty. Weibel-Palade bodies were not detected in the neoplastic endothelium. Metastatic lesions were observed in liver, lung and kidney. To date, 1,3-butadiene is the only carcinogen reported that induces proliferative vascular lesions in the heart of mice.

Animals↗
PubMed1988

Stimulatory effect of vasoactive intestinal polypeptide on human normal and neoplastic thyroid tissue.

Recent investigations suggest that although thyroid-stimulating hormone (TSH) is the major regulator of thyroid gland function, it is not the only hormone that regulates the thyroid gland. Another factor regulating thyroid gland function is vasoactive intestinal polypeptide (VIP), which is present in nerves that innervate thyroid blood vessels and follicles. Previous studies have documented that VIP stimulates adenylate cyclase (AC) activity in cultured normal and hyperplastic (Graves) thyroid tissue, thus increasing intracellular cyclic AMP concentration. To our knowledge, however, there is no information concerning the effect of VIP on neoplastic thyroid tissue. Therefore we studied the effect of VIP on normal and neoplastic human thyroid tissue from 10 patients (follicular adenomas, 4; follicular carcinomas, 3; and papillary carcinomas, 3). Adenylate cyclase activity was measured in a 8000 g membrane preparation in the basal state and when incubated with VIP, TSH, and both. VIP increased AC activity in normal tissue and tumor in a dose-dependent manner, with maximal stimulation at 10(-6) mol/L (p less than 0.05). In normal tissue, 10(-6) mol/L VIP and a maximally stimulating concentration of TSH (300 mU/ml) stimulated AC to the same degree. In tumors, although both TSH and VIP increased AC activity, the response to TSH was greater (p less than 0.01). VIP and TSH had an additive effect in normal tissue (p less than 0.05), whereas in tumors the AC response to VIP and TSH was the same as with TSH alone (p = 0.66). This study documents that VIP is a potent stimulator of adenylate cyclase in both normal and neoplastic human thyroid tissues. The magnitude of this effect is similar to that produced by TSH, which implies that VIP plays a physiologically important role in the regulation of the secretion and growth of normal and neoplastic thyroid tissues.

Adenocarcinoma↗
PubMed1988

Large-scale production of murine monoclonal antibodies using hollow fiber bioreactors.

We have produced large quantities of murine monoclonal antibodies for in vivo human clinical trials using hollow fiber bioreactors (HFBRs). Thirty-three different hybridoma cell lines have been evaluated in various HFBR systems. Monoclonal antibody (Ab) productivity is highly dependent on the intrinsic secretory rate of each cell line. Other factors that affect Ab production include capillary membrane molecular weight cutoff, and HFBR design. Studies comparing HFBRs to static and suspension culture systems revealed similar Ab productivity. An advantage of the HFBR is that the Ab is concentrated in the extracapillary space, simplifying downstream processing.

Animals↗