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Biomedical subjects

R A Miller

Publications and source records attributed to R A Miller.

At least 19 recordsLinked to original sources
PubMed1992

Induction of immune responses in patients with B-cell lymphoma against the surface-immunoglobulin idiotype expressed by their tumors.

BACKGROUND: The idiotypic determinants of the surface immunoglobulin of a B-cell lymphoma can serve as a clonal tumor-specific marker, which may have implications for immunotherapy. We sought to determine whether idiotype-specific immune responses against this autologous antigen could be induced in patients with B-cell lymphoma. METHODS: Nine patients were selected who had minimal residual disease or a complete remission after chemotherapy. Each received a series of subcutaneous injections of the immunoglobulin derived from his or her tumor cells (immunoglobulin-idiotype protein), which had been conjugated to a protein carrier and mixed with an immunologic adjuvant. RESULTS: In seven of the nine patients the injections induced sustained idiotype-specific immunologic responses of the humoral type (two patients), the cell-mediated type (four patients), or both (one patient). The use of an adjuvant was essential for these immune responses. The induced antibodies bound specifically to autologous immunoglobulin idiotype, inhibited the binding of murine monoclonal antiidiotype antibodies, and bound autologous tumor cells. Cell-mediated responses were demonstrated by the specific proliferation of immune peripheral-blood mononuclear cells to the soluble immunoglobulin-idiotype protein in vitro. The tumors of both of the patients with measurable disease regressed completely. Toxicity associated with the vaccine was minimal and consisted only of mild reactions at the site of intramuscular injection. CONCLUSIONS: These results demonstrate that autologous immunoglobulin idiotype can be formulated into an immunogenic, tumor-specific antigen in humans with B-cell lymphoma, and they provide the background for large-scale trials of active specific immunotherapy of this disease.

Adjuvants, Immunologic↗
PubMed1992

Monoclonal anti-idiotype antibody therapy of B-cell lymphoma: the addition of a short course of chemotherapy does not interfere with the antitumor effect nor prevent the emergence of idiotype-negative variant cells.

The Ig idiotype of B-cell lymphoma can be used as a tumor-specific target. Prior trials with monoclonal anti-idiotype antibodies alone and combined with alpha-interferon have shown significant antitumor activity. In some patients, idiotype-negative tumors emerged after treatment. In this trial, patients with relapsed non-Hodgkin's lymphoma were treated with two identical courses of monoclonal anti-idiotype anti-body therapy. Concurrent with the second course, at a time when idiotype-negative cells were suspected to be proliferating, a pulse dose of chlorambucil was administered. Tumor biopsies obtained before the first and second courses of treatment and at relapse were analyzed for idiotype expression and proliferation. Thirteen patients received 24 courses of antibody with minimal toxicity. Eleven had tumor regression, with 1 complete remission, 8 partial remissions, and 2 minor remissions, with freedom from progression lasting a median of 7 months in responding patients. Idiotype-negative tumor cells appeared in some relapse specimens despite the use of chlorambucil. In retrospect, this was not surprising because there was no increase in the proliferative rate of these tumors at the time the drug was used. Anti-idiotype antibodies continue to demonstrate antitumor activity against B-cell lymphoma with minimal toxicity. The mechanism of the effect is presumed to involve both direct antiproliferative effects of the antibody on the tumor cells as well as indirect, more long-lasting effects on the host. The addition of a mild chemotherapeutic agent in the dose and schedule used here to the second cycle of antibody therapy did not interfere with the antitumor effect, nor did it decrease the emergence of idiotype-negative cells.

Adult↗
PubMed1992

Age-associated changes in mitogen-induced protein phosphorylation in murine T lymphocytes.

Since T lymphocyte proliferation declines with age, and since activation of a still only partially defined set of protein kinases is thought to play a critical role in T cell activation, we have carried out a systematic survey of age-related changes in protein phosphorylation in T lymphocytes. We used two-dimensional electrophoretic analysis to examine lysates prepared from T cells after 10 min of exposure to mitogens [anti-CD3, concanavalin A (Con A) and phorbol 12-myristate 13-acetate (PMA) plus ionomycin] and nonmitogenic activators (PMA or ionomycin used separately). Our results show a progressive, life-long decline in the levels of anti-CD3-induced phosphorylation of all 16 phosphoproteins that respond vigorously in T cells of young mice. Mice 10-18 months of age showed levels of response that were clearly below those induced in young mice, while responses of mice 22-24 months of age were even more severely diminished. Responses to Con A, PMA, ionomycin and a combination of PMA plus ionomycin were equally blunted in old mice, except for 2 (of 12) phosphoproteins that continued to respond to PMA even in the old animals. None of the phosphoproteins which were ionomycin responsive in young mice continued to respond in old mice, although 1 (of 3) ionomycin-inhibitable phosphoproteins remained inhibitable in old mice. We also found three phosphoproteins which became phosphorylated in response to anti-CD3, PMA and Con A (but not ionomycin) only in old mice, and a pair of phosphoproteins which were unresponsive to all mitogens but showed a higher "baseline" phosphorylation in T cells from old mice. Comparing phosphoprotein patterns between CD8- and CD8-CD45RB- T cells from young mice allowed us to identify nine phosphoproteins that were strongly responsive to anti-CD3 only when CD45RB+ (i.e. virgin) cells were present. Although the immune system of old mice consists largely of memory T cells, the change in phosphoprotein phosphorylation patterns cannot simply be explained by the accumulation of this cell type. We conclude that aging leads to a global impairment of several distinct protein kinase pathways in both virgin and memory T cell sets.

Adenosine Triphosphate↗
PubMed1992

Memory T lymphocyte hyporesponsiveness to non-cognate stimuli: a key factor in age-related immunodeficiency.

Previous studies from our laboratory have suggested that aging leads to an accumulation of cells expressing high levels of CD44, thought to be a marker for memory lymphocytes, and that positively selected CD44hi T cells, from mice of any age, respond poorly to concanavalin A (Con A) in limiting dilution estimates of interleukin (IL)-2-producing cells. We now report the results of a more comprehensive analysis of memory T cell function, in old and young mice, to non-cognate activators (Con A and the staphylococcal enterotoxin SEB). We report that memory T cells, isolated by removing cells bearing the CD45RB determinant, contain very few cells able to respond to either Con A or SEB under limiting dilution culture conditions, whether the responses are measured by IL-2 or by IL-3 accumulation. As a control, we show that memory T cells do respond strongly, at limiting dilution, to recently encountered priming antigens, i.e. Schistosoma mansoni egg antigen; the limiting dilution culture protocol thus does not preclude activation of memory T cells when cognate stimuli are presented to antigen-specific cells. These data suggest that virgin and memory T cells may differ fundamentally in their activation requirements, and suggest further that the accumulation, with age, of memory T cells accounts for the low responsiveness of old mice to non-cognate mitogens.

Aging↗
PubMed1992

Immunoglobulin idiotype expression in reactive lymphoid tissues and B-cell lymphomas.

In an investigation of the immunoglobulin idiotypic expression of non-tumour and neoplastic B lymphocytes in situ, fresh-frozen specimens of reactive tonsils, lymph nodes and B-cell malignant lymphomas (B-MLs) from Japanese patients were studied immunohistochemically with 39 different anti-idiotype antibodies. In reactive lymphoid tissues, while idiotype-bearing cells were largely distributed sparsely in follicles and perifollicular areas, some were heavily crowded in particular germinal centres (GCs), suggesting the presence of oligoclonal proliferations of B-cells in GCs. Forty-eight out of 100 B-MLs reacted with anti-idiotype antibodies. This proportion was significantly higher than those reported in Western cases (27-36%), indicating that Japanese B-MLs share public idiotypes much frequently than western cases. The idiotypes demonstrated in these lymphomas, in contrast to those not expressed in any B-ML, were found much commonly in non-tumour lymphocytes, suggesting that such public idiotypes as were common in B-MLs were frequently shared by normal B-lymphocytes.

Antibodies↗
PubMed1992

Expanding the concept of medical information: an observational study of physicians' information needs.

Obtaining and managing clinically relevant information constitutes a major problem for physicians, for which the development of automated tools is often proposed as a solution. However, designing and implementing appropriate automated solutions presumes knowledge of physicians' information needs. We describe an empirical study of information needs in four clinical settings in internal medicine in a university teaching hospital. In contrast to the retrospective data often used in previous studies, this research used ethnographic techniques to facilitate direct observation of communication about information needs. On the basis of this experience, we address two main issues: how to identify and interpret expressions of information needs in medicine and how to broaden our conception of "information needs" to account for the empirical data.

Computer Systems↗
PubMed1992

Cellular determinants of age-related decrements in the T-cell mitogen response of B6CBAF1 mice.

Age-related changes in the cellular composition of the immune system that are associated with an impaired proliferative response to T-cell mitogens were identified for B6CBAF1 mice. The frequencies of precursors of Con A-induced IL-2-secreting cells (pHTL) and of Con A-induced cytotoxic cells (pCTL), determined by limiting dilution analysis, were lower for splenocytes from old mice, as were the proliferative responses to Con A and PHA, determined in conventional high cell density cultures for the same mice. The pHTL frequency correlated with the proliferative response to Con A (r2 = .94) and to PHA (r2 = .83) among old mice, but not among young; there were no correlations of pCTL frequency with proliferative responses. The reduced pHTL frequency in old mice resulted from: (a) an age-related doubling of the number of splenic B cells that diluted T cells, and (b) a 67% decline in the absolute number of Con A-reactive pHTL cells in the spleen that appeared despite the maintenance of normal numbers of total splenic CD4+ and CD8+ cells. Thus, both a decline in absolute pHTL numbers and an increase in the number of non-T cells in the spleen result in a diminished pHTL frequency that is closely linked to the impaired mitogen response observed for old B6CBAF1 mice.

Aging↗
PubMed1992

Tyrosine-specific protein phosphorylation in response to anti-CD3 antibody is diminished in old mice.

Antiphosphotyrosine immunoblots were used to characterize phosphotyrosine-containing proteins (PY-PPNs) in anti-CD3 stimulated murine T lymphocytes. Activation led to increased phosphorylation of three PY-PPNs (MWs of 120, 80, and 40 kD) within 2 minutes, and maximal phosphoprotein levels were sustained for at least 30 min. There was a progressive decline with age in the responses of these three PY-PPNs to anti-CD3 stimulation, and some 20-23-month-old mice were virtually nonresponsive. A second group of PY-PPNs was present in unstimulated cells and not affected by anti-CD3 treatment or by age. Responses to Con A and to an antibody to the T-cell receptor were also found to be lower in old mice. Our data show that the pattern of tyrosine-specific phosphorylation in normal murine T cells is similar but not identical to patterns previously defined in murine tumor T-cell lines, and that T cells in old mice have defects in tyrosine-specific phosphorylation that could contribute to their diminished responsiveness to mitogenic stimuli.

Aging↗
PubMed1992

Memory and anergy: challenges to traditional models of T lymphocyte differentiation.

Traditional paradigms suggest that encounter with an antigen converts naive peripheral T cells into memory cells with less stringent requirements for activation and increased capacities for lymphokine production. Recent evidence argues that this view may be over-simplified in two ways. First, an encounter with antigen in the absence of certain costimulatory factors can render a T cell anergic--that is, unable to respond to antigen under normal conditions. Second, although cells of the memory T cell population are more responsive than naive cells to some stimuli, these cells are hyporesponsive in other situations. Intrinsic resistance of memory T cells to elevation of intracellular calcium ion concentrations may contribute to their poor responsiveness to agents that activate naive cells. Thus, aspects of the costimulatory environment can determine whether a resting T cell is activated or rendered anergic and may also influence the kinds of stimuli to which a memory T cell will respond.

Animals↗
PubMed1992

Dynamic clearance: mathematical assessment of flow mechanics in prostatic resection.

The understanding of flow mechanics in endoscopy is poor. In prostatic surgery, emphasis has been placed on limiting the rise of intravesical pressure with little regard to the effect on flow mechanics and visibility. A model has been developed using dynamic clearance to compare different methods of prostatic resection. The results show that in a 0.95-cm glass urethra, continuous flow irrigation has slower clearance at all flow rates when compared with intermittent irrigation and suprapubic suction. Although intravesical pressure is important, attention should also be paid to flow dynamics and more emphasis should be placed on this when new instruments and fluid delivery systems are developed.

Endoscopy↗
PubMed1992

Histologic methods and interspecies variations in the laryngeal histology of F344/N rats and B6C3F1 mice.

The relatively high incidence and variety of lesions induced in the upper respiratory tract of rodents by inhalation of xenobiotics has resulted in considerable attention given to the microscopic anatomy of this area. Specific areas of the rodent laryngeal mucosa appear to be more sensitive to inhaled materials and more likely to contain cellular changes in response to injury. These include the epithelium covering the base of the epiglottis, ventral pouch, and the medial surfaces of the vocal processes of the arytenoid cartilages. There are few good landmarks for trimming rodent larynges to get consistent and accurate sections through these target areas. We have obtained consistently reproducible results by cutting transversely through the easily palpable cricothyroid notch and embedding the entire larynx anterior to this in paraffin with the cut surface against the face of the block. Multiple sections are cut from the caudal larynx toward the epiglottis, unstained sections examined microscopically for orientation, and sections from target areas selected for staining and histopathologic examination. Routine use of these methods for preparation and microscopic examination of sections of the larynx has revealed some variations in normal laryngeal anatomy between Fischer 344 (F344/N) rats and B6C3F1 mice.

Aging↗
PubMed1992

Does too much urology damage your eyesight? Study of macular function.

A study comparing the macular function of both eyes of 130 urological surgeons was carried out to investigate whether the increased light exposure to the endoscoping eye caused any deterioration of macular function. The non-endoscoping eye was used as a control. A sophisticated computer test of colour contrast sensitivity was used. The computer assesses the degree of brightness at which the subject is just able to detect a coloured grating, and for each eye this is expressed as a threshold for the red/green axis and the blue/yellow (tritan) axis. The subjects also completed a questionnaire about their working patterns and their general and ophthalmic history and had a brief examination of the fundus. The results do not suggest that urologists are suffering any significant macular damage as a result of their work with endoscopes.

Color Perception↗
PubMed1992

Blue light emission from urological equipment. Can it damage the eyes?

Blue light present in the visible spectrum at the lower wavelengths can cause damage to the retinas of monkeys and rats. In the present study the light sources and instrumentation available to the urologist were evaluated to see whether they posed a hazard. The light emitting directly from the sources, cables and telescopes was tested and these levels were found to be dangerous to the eye when compared with the safety limit recommended by the American Conference of Governmental Industrial Hygienists (ACGIH). When the light at the eyepiece of the telescopes which had been reflected off a surface was measured, the blue light levels did not appear to be harmful when compared with the ACGIH safety limit. The use of filters is discussed and the transmission of 2 types of filters shown. While the level of blue light emission from the eyepiece remains within the ACGIH level, there are no data on long-term exposure. The addition of a blue light filter may be beneficial until such time as videoendoscopy becomes the norm. The light from light sources should be protected by a shutter and more care taken with the emission from cables and telescopes.

Equipment Safety↗
PubMed1992

CHARTLINE: providing bibliographic references relevant to patient charts using the UMLS Metathesaurus Knowledge Sources.

A successful medical informatics program helps its users to match their information needs as closely and efficiently as possible to the capabilities of the system. CHARTLINE is a computer program whose input is a free text, "natural language" patient chart in ASCII format. Using the UMLS Metathesaurus Knowledge Sources, CHARTLINE can suggest bibliographic references relevant to the patient case described in the chart. The program does not attempt to "understand" the natural language content of the chart. CHARTLINE only recognizes UMLS Metathesaurus Main Concept terms (or their synonyms) as they occur in the medical text, since those terms represent the tokens used to index the literature. The program depends on user feedback to determine which topics of a large number of potentially relevant subjects are of interest to the user.

Diagnosis, Computer-Assisted↗