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Biomedical subjects

R A Miller

Publications and source records attributed to R A Miller.

At least 361 records · Page 20Linked to original sources
PubMed1987

Antibodies to phenolic glycolipid-I during long-term therapy: serial measurements in individual patients.

Levels of IgM antibody to phenolic glycolipid-I (PGL-I) were measured in serum specimens collected over the initial 5 or more years of therapy from 11 leprosy patients. All three patients with paucibacillary disease had undetectable levels of antibody throughout their treatment. The eight patients with multibacillary disease had initially elevated levels which fell quite rapidly with treatment, reaching levels of 10% to 30% of their initial pre-treatment level after 5 years of therapy. The single patient with prolonged therapeutic noncompliance had an increase in antibody level, although clinical or bacteriologic relapse was not documented. These results in individual patients demonstrate that IgM antibody to PGL-I declines rapidly and consistently with treatment in multibacillary patients.

Antibodies, Bacterial↗
PubMed1987

Anti-idiotypes in B-cell tumor therapy.

Thirteen patients with B-cell lymphomas were treated with mouse monoclonal anti-idiotype antibodies. All but 1 of the patients in this study had received extensive prior treatment with conventional therapy for lymphoma. The treatment protocol initially included an escalating dose schedule which was intended to help us evaluate toxicity and pharmacokinetics and, eventually, to achieve appreciable levels of free mouse antibody in the circulation. The last 4 patients received substantial initial doses. Tumor sampling was performed before and during therapy for evaluation of tissue penetration by antibody. Patients received antibodies of gamma 1, 2a, or 2b isotype. None of the patients had serum paraproteins by routine clinical testing, but 6 had an idiotype protein detectable by a sensitive immunoassay at levels greater than 1 microgram/ml, two of which were greater than 200 micrograms/ml. These levels were temporarily reduced by plasma-pheresis. However, the presence of serum idiotype increased the requirement for mouse antibody to achieve tumor penetration. Another obstacle to treatment was immune response to mouse Ig that occurred in 5 of the 13 patients. Once an immune response had begun, further infusions of antibody failed to reach the tumor or induce tumor regression and were associated with toxicity. Our initial patient remains in an unmaintained complete remission 50 months after receiving antibody. Six of 12 additional patients have had objective remissions which also were clinically significant. However, these remissions were not complete. This therapy shows promise as an alternative modality for the treatment of B-cell lymphoma. We will need further studies to determine the mechanisms of the antitumor effect and to improve the clinical results.

Antibodies, Monoclonal↗
PubMed1987

The limited spectrum of antinuclear antibodies in leprosy.

Sera from 46 consecutive patients with leprosy were collected and tested against an extensive panel of defined nuclear antigens. Antinuclear antibodies (ANA) were present in 16% of patients, but the titer was uniformly low and there was no consistent fluorescence pattern. None of the ANA positive sera contained antibodies which reacted with native DNA, or which were directed against histones, centromeres, SSB, Sm, or ribonucleoprotein. These more specific autoantibody assays thus retained their clinical utility in the differential diagnosis of rheumatologic complaints in patients with leprosy.

Adolescent↗
PubMed1987

Adaptation and habituation of motion-induced vomiting in squirrel monkeys.

Nonrestrained adult squirrel monkeys were found to be prolific vomiters when rotated in the horizontal plane for at least 1 h with visual cues available. When multiple daily spins were given, monkeys who vomited early during the first session tended to habituate during subsequent rotations. Subjects who vomited late during the first spin tended to vomit increasingly earlier for several days before the trend reverted to habituation. When a single rotation was continued for up to 8 h, emetic waves occurred with a high probability density for about 2 h, then ceased for many hours with an occasional animal exhibiting isolated emetic episodes. Adaptation effects were transient; when retested beyond a week, most subjects vomited in less time than did inexperienced monkeys on their first exposure to rotation. Attempts to confirm the findings using sinusoidal vertical acceleration were unsuccessful because of failure to induce vomiting using this type of motion.

Adaptation, Physiological↗
PubMed1986

Stimulation of murine B cells by the combination of calcium ionophore plus phorbol ester.

The ability of calcium ionophore and phorbol ester to stimulate entry into S phase was assessed during short-term cultures of murine B cells extensively depleted of T cells. Neither ionomycin alone nor PMA alone stimulated DNA synthesis. However, the combination of ionomycin plus PMA acted in synergy to induce initiation of DNA synthesis in murine B cells. A role for protein kinase C was implied by the inability of 4 alpha-phorbol didecanoate to reproduce the effects of PMA. The combination of ionomycin plus PMA also stimulated DNA synthesis in xid-defective B cells.

Animals↗
PubMed1986

Immunodeficiency of aging: restorative effects of phorbol ester combined with calcium ionophore.

Current models for lectin-induced T cell proliferation suggest that activation of protein kinase C (PK-C) and elevation of cytoplasmic Ca2+ may both play important roles in the earliest phases of signal transduction. To learn more about the relative inability of T cells from old mice to proliferate in response to mitogenic stimuli, we attempted to stimulate T cells by the synergistic effects of a PK-C activator, phorbol myristate acetate (PMA), and the calcium ionophore ionomycin. T cells from young mice respond as well to optimal combinations of these agents as they do to the strong polyclonal activator Con A, but T cells from old mice respond much better to PMA plus ionomycin than they do to Con A. This result suggests that an inability to transduce the signal supplied by extracellular ligands into the intracellular signals represented by Ca2+ and PK-C activators may underlie the age-associated loss of T cell reactivity. We also found evidence for a second defect in old T cells related to their response to elevated intracellular Ca2+: old T cells, compared with young, required higher levels of ionomycin for maximal proliferation.

Aging↗
PubMed1986

Long-lasting deficit of functional T cell precursors in human bone marrow transplant recipients revealed by limiting dilution methods.

We have applied limiting dilution methods suitable for the estimation of mitogen-reactive helper (pHTL) and cytotoxic (pCTL) T cell frequencies to the analysis of immune function in patients 1 mo to 6 yr after allogeneic bone marrow transplantation (BMT). Although the majority of these patients have regained normal levels of Leu-3+ (helper) and Leu-2+ (killer/suppressor) cells by 6 to 12 mo after BMT as assessed by cytofluorimetry, the fraction of these cells that can function in limiting dilution cultures is substantially below normal levels in nearly all patients. Although some BMT patients eventually recover normal frequencies of pCTL and pHTL, values typically remain greatly depressed even in patients transplanted as many as 4 to 6 yr previously. In contrast, recovery of precursors able to proliferate (without expressing either helper or cytotoxic function) in response to phytohemagglutinin (PHA) and interleukin 2 occurs in many patients by 1 yr after transplant. In spite of the decreased frequency of functional precursor cells found after BMT, each precursor is capable of giving rise to the same amount of function at limiting dilutions as that produced by cells from normal controls. In many BMT patients, proliferation in conventional PHA-stimulated cultures returns to near-normal levels even though precursor frequencies remain low. The limiting dilution method is sensitive to residual immune dysfunction in BMT recipients not easily quantitated by other, more conventional techniques.

Adolescent↗
PubMed1986

Estimation by limiting dilution analysis of human IL 2-secreting T cells: detection of IL 2 produced by single lymphokine-secreting T cells.

We present here a culture method for the estimation, in human blood, of the number of lymphocytes that can respond to mitogen by producing interleukin 2 (IL 2). T cells are cultured at limiting dilutions with PHA or Con A in the presence of Epstein Barr virus-transformed human lymphoblastoid cells (EB-LCL), and supernatants are tested 3 days later for IL 2 content by a cell proliferation assay. The distribution of negative wells follows the expected Poisson "single-hit" relationship, suggesting that the assay is sensitive to single cells of a single limiting cell type. On average, 16.3% of peripheral blood mononuclear cells can produce IL 2 in such clonal cultures (mean of 12 determinations; SD = 5.6%). Surprisingly, irradiation (up to 2000 rad) of the titrated responder cell population diminishes the estimated frequencies by less than 50%. The ability to detect IL 2 levels in cultures containing only a single, nonproliferating T lymphocyte allows us to estimate the amount of IL 2 generated by an individual effector cell during a 3-day culture interval after mitogen stimulation. The average responding, irradiated T cell generates 0.92 pg of IL 2 (median) within 3 days. The method presented provides a straightforward way to provide independent estimates of responding cell number and of lymphokine production per cell in a variety of clinical situations.

Cells, Cultured↗
PubMed1986

Stages of T cell activation: continued antigen dependence of IL 2-producing cells after IL 2 receptor expression.

Alloantigen stimulation leads, within 48 to 72 hr, to the expression of IL 2 receptors (IL 2R) on the surface of most of the helper T cells with specificity for the stimulating antigens. The IL 2R-bearing cells, separated by flow cytometry from 3-day human or mouse mixed lymphocyte cultures, were found by limiting dilution methods to be enriched 10- to 20-fold (compared to IL 2R- cells) for antigen-specific helper T cells detected by IL 2 production. Although these cells have been activated to an IL 2R+ stage, most of them are unable to produce detectable IL 2 unless they are cultured together with the original, activating antigen. Even when IL 2 is supplied, and lymphokine production measured by assay of a second factor, IL 3, the large majority of individual activated helper T cells remain dependent on further antigenic exposure for their continued maturation into lymphokine-secreting effectors. Helper T cells at this early stage of activation can therefore proliferate when given IL 2 alone, but lymphokine secretion involves a second antigen-dependent step.

Animals↗
PubMed1986

Lung development and postnatal survival for rats exposed in utero to a high-boiling coal liquid.

Previous studies performed in this laboratory indicated that exposure of rat fetuses to high-boiling coal liquids from 12-14 days of gestation (dg) induced a number of major malformations, including cleft palate, diaphragmatic hernia and small lungs. The study reported here was designed to determine postnatal viability and development of survivors following in utero exposure to Harmarville process solvent (HPS), a wide-boiling-range (150 to greater than 455 degrees C) coal liquid. For this study, 0.74 g kg-1 of the coal liquid was administered (by intragastric intubation) to rats from 12 to 14 dg. Offspring were evaluated for postnatal survival, growth and lung and thymus weights. Randomly selected pups from control and treated litters were killed and necropsied at 1, 3, 7 and 21 days postpartum. In addition, data for control pups were obtained at 0.25 and 0.5 days postpartum for comparison with body, lung and thymus weights of pups that died during this interval. Fifty-four per cent of the exposed pups and 9% of the control pups died between birth and 3 days postpartum. Of the treated pups that died, 10% (6/5; pups/litters) had cleft palate, 27% (17/9) had small lungs and 33% (21/8) had both cleft palate and small lungs. No gross malformations were observed in the remaining 30% of the dead pups. Microscopic examination of lungs from HPS-treated pups revealed no evident histological abnormalities. Body, lung and thymus weights for treated animals that died were significantly less than those of controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Reproductive toxicology of inhaled styrene oxide in rats and rabbits.

Experiments were performed to evaluate reproductive and developmental toxicology in rats and rabbits exposed to styrene oxide by inhalation. Female rats were exposed to 100 or 300 ppm styrene oxide or to filtered air for 7 h/day, 5 days/week for 3 weeks. Extensive mortality occurred in rats that received prolonged exposure to 100 ppm styrene oxide while 300 ppm was rapidly lethal. As a result exposures were terminated in this latter group and the group was eliminated from further study. The rats of the 0 and 100 ppm groups were then mated and exposed to 0 or 100 ppm styrene oxide daily through 18 days of gestation (dg). Female rabbits were artificially inseminated and exposed for 7 h daily to 0, 15, or 50 ppm styrene oxide through 24 dg. Both of these lower concentrations used for exposure of the rabbits produced mortality of does. The rats were killed at 20 dg and the rabbits at 30 dg. Pregnant animals were examined for toxic changes including altered tissue weights and histopathologic effects. Litters were evaluated using several measures of embryotoxicity, and live fetuses were examined for external, visceral, and skeletal malformations. Exposure during gestation appeared to increase preimplantation loss in rats, and tended to increase the incidence of resorptions in rabbits. In both species, fetal weights and crown-rump lengths were reduced by gestational exposure. The incidences of ossification defects of the sternebrae aned occipital bones were increased by gestational exposure of rats to styrene oxide. These results indicate that inhalation exposures at these concentrations produce reproductive and development toxicity, as well as maternal toxicity.

Abnormalities, Drug-Induced↗
PubMed1986

Effects of inhalation exposure to a high-boiling (288 to 454 degrees C) coal liquid.

Coal liquids have been evaluated in a variety of short-term toxicological assays; however, few studies have been conducted to determine the systemic effects after inhalation exposure to these materials. To extend the data base on potential health effects from coal liquefaction materials, we performed a study with solvent refined coal (SRC)-II heavy distillate (HD). Fischer-344 rats were exposed for 6 hr/day, 5 days/week for 5 or 13 weeks to an aerosol of HD (boiling range, 288 to 454 degrees C) at concentrations of 0.69, 0.14, 0.03, or 0.0 mg/liter of air for the high, middle, low, and control groups, respectively. Survival through 13 weeks of exposure was greater than 90% for all groups; body weights for exposed animals were decreased in a dose-dependent manner. Significant increases in liver weights and decreases in thymus and ovary weights were observed for treated animals compared with controls. There were also significant treatment-related decreases in erythrocytes, hemoglobin, volume of packed red blood cells, lymphocytes, eosinophils, and total white blood cells. After 5 weeks of exposure serum cholesterol concentrations increased in a dose-dependent manner for both sexes and serum triglyceride amounts decreased for males but not for females. After 13 weeks of exposure, high-dose animals had significant increases in cholesterol (males only), triglycerides, blood urea nitrogen, and serum glutamic pyruvic transaminase (SGPT; males) and significant decreases in albumin, SGPT (females), and lactate dehydrogenase (LDH). Examination of bone-marrow preparations from exposed animals demonstrated consistent decreases in the degree of cellularity, suggesting that this organ is a target for HD. Microscopic evaluation of organ sections indicated exposure-related changes for nasal mucosa, pulmonary macrophages, thymus, liver, kidney, bone marrow, ovaries, and cecum. Results from this study indicated dose-dependent increases in the severity of the lesions observed, with few effects in the low-exposure group that were attributable to the exposure.

Animals↗
PubMed1986

Decline, with age, in the proportion of mouse T cells that express IL-2 receptors after mitogen stimulation.

Receptors for IL-2 can be demonstrated on the majority of mouse splenic T cells within 48 h after stimulation with Concanavalin A. We show here that aging leads to a decline in the frequency of cells able to generate detectable levels of IL-2 receptor, as measured by cytofluorimetry using antibodies to the receptor. The age-associated deficit cannot be overcome either by increasing the mitogen dose, or by supplementing the cultures with exogenous IL-2. At least a part of the decline, with age, in T cell-mediated immunity may represent an inability of individual T cells to produce sufficient IL-2 receptor to enable them to reach the IL-2 dependent phases of their first cell cycle.

Aging↗
PubMed1986

Toxicity of formaldehyde vapor in B6C3F1 mice exposed for 13 weeks.

Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 2, 4, 10, 20, or 40 ppm of formaldehyde vapor 6 h/day, 5 days/week for 13 weeks. Clinical abnormalities (dyspnea, listlessness, and hunched posture), significant mortality, and body weight loss were observed in the 40 ppm groups. Pathologic changes were observed in the nose, larynx, trachea, and bronchi of treated males and females and in the uterus and ovaries of treated females. Squamous metaplasia and inflammation were present in the nasal tissues of male and female mice in the 10, 20, and 40 ppm groups and in the larynx of males and females in the 20 and 40 ppm groups. The trachea had squamous metaplasia and hyperplasia of the epithelium in addition to submucosal fibrosis and inflammation in the 20 and 40 ppm groups. In some mice, epithelial-lined, irregular connective tissue bands spanned the tracheal lumen. Metaplasia of the bronchial epithelium was confined to the 40 ppm exposure groups. These effects on the respiratory system were more prevalent in male than in female mice. Hypoplasia of the uterus and ovaries, probably secondary to body weight loss, was confined to the 40 ppm exposure group. In conclusion, 13-week inhalation exposures of B6C3F1 mice to 10, 20, and 40 ppm of formaldehyde vapor induced histologic lesions in the upper respiratory system and concentrations of 40 ppm were lethal to those mice.

Animals↗
PubMed1986

Corynebacterium pseudodiphtheriticum pneumonia in an immunologically intact host.

Corynebacterium pseudodiphtheriticum, a gram-positive bacillus commonly found in the human oropharynx, has been reported as a rare cause of infection in compromised hosts. We report herein a case of lower respiratory tract infection with Corynebacterium pseudodiphtheriticum in a previously healthy 29-yr-old trauma victim. The organism was the predominant bacterial isolate from two endotracheal aspirates and a specific humoral response was demonstrated by enzyme-linked immunosorbent assay.

Adult↗