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Biomedical subjects

L C Miller

Publications and source records attributed to L C Miller.

At least 19 recordsLinked to original sources
PubMed1992

Coordinated antiinflammatory effects of interleukin 4: interleukin 4 suppresses interleukin 1 production but up-regulates gene expression and synthesis of interleukin 1 receptor antagonist.

Interleukin 1 receptor antagonist (IL-1ra), a naturally occurring polypeptide with amino acid sequence homology to interleukin 1 alpha (IL-1 alpha) and interleukin 1 beta (IL-1 beta), prevents Escherichia coli-induced shock and death. Both IL-1 and IL-1ra are produced by monocytes stimulated with lipopolysaccharide (LPS). Because interleukin 4 (IL-4) suppresses IL-1 production, we investigated whether IL-4 modulated IL-1ra synthesis in LPS-stimulated human peripheral blood mononuclear cells. IL-1 beta and IL-1ra were measured by specific RIAs. IL-4 alone (0.01-100 ng/ml) did not stimulate IL-1 beta synthesis but rather induced IL-1ra (4.82 +/- 0.94 ng/ml). LPS induced synthesis of both IL-1 beta (6.67 +/- 1.06 ng/ml) and IL-1ra (10.77 +/- 2.79 ng/ml). IL-4 suppressed LPS-induced IL-1 beta mRNA accumulation and synthesis. However, IL-4 acted synergistically with LPS in inducing IL-1ra. IL-4 enhanced LPS-induced IL-1ra mRNA accumulation 4-fold and IL-1ra protein synthesis nearly 2-fold. Moreover, IL-1ra mRNA levels were maximal after 6 hr of exposure to LPS but peaked within the first 3 hr in the presence of IL-4. IL-4 added as late as 12 hr after LPS stimulation still enhanced IL-1ra synthesis. In human peripheral blood mononuclear cells stimulated with IL-1 alpha, IL-4 markedly suppressed IL-1 beta production but enhanced IL-1ra synthesis greater than 2-fold. Because IL-4 favors synthesis of the natural antagonist IL-1ra over synthesis of the agonist IL-1, IL-4 may exert potent antiinflammatory effects on host responses to Gram-negative infections.

Gene Expression↗
PubMed1992

Methotrexate treatment of recalcitrant childhood dermatomyositis.

OBJECTIVE: To review the clinical course of 16 children with recalcitrant dermatomyositis (DM), who were treated with oral methotrexate (MTX) in addition to prednisone. METHODS: Sixteen patients with recalcitrant DM who were treated with MTX in addition to prednisone were followed between 1984 and 1990. The patients' clinical responses to treatment, including alterations in muscle strength and muscle enzyme levels, changes in prednisone dosage, and development of toxicity or complications were reviewed retrospectively. RESULTS: All 12 patients who received MTX for at least 8 months regained normal muscle strength. In 11 of the 12, the prednisone dosage could eventually be tapered to < or = 5 mg/day. Complications during MTX treatment required discontinuation of MTX in 5 patients, and were unrelated to the cumulative dose of the drug. Active disease recurred in 5 patients in whom MTX had been discontinued after apparent clinical remission had been achieved. CONCLUSION: MTX, in combination with prednisone, is a useful adjunct in the treatment of recalcitrant childhood DM. However, recurrence of disease after withdrawal of MTX suggests that the drug may have a suppressive, rather than a remittive, effect.

Adolescent↗
PubMed1992

Interleukin-1 (IL-1) receptor blockade reduces endotoxin and Borrelia burgdorferi-stimulated IL-8 synthesis in human mononuclear cells.

Interleukin-1 (IL-1) is a potent stimulator of IL-8 production by fibroblasts and monocytes. In the present study, we asked how much of endotoxin (LPS)-induced IL-8 production by human peripheral blood mononuclear cells was due to IL-1 induced by LPS. Cells were stimulated with either IL-1 beta, LPS, or Borrelia burgdorferi, and total IL-8 was determined by a specific radioimmunoassay. The addition of saturating concentrations of IL-1 receptor antagonist protein (IRAP) reduced the IL-1 beta-, LPS-, and B. burgdorferi-induced IL-8 synthesis by 85, 50, and 40%, respectively. Increasing the concentration of LPS did not affect the reduction in IL-8 synthesis observed in the presence of IRAP. Significant inhibition of the IL-1 beta-induced IL-8 synthesis was observed when IRAP was added 60 or 90 min after IL-1 beta; similarly, IL-8 synthesis after LPS was also reduced by delayed addition of IRAP. These data suggest that the ameliorative effects of IL-1 receptor blockade in models of inflammation and infection may be due, in part, to suppression of IL-1-induced IL-8.

Borrelia burgdorferi Group↗
PubMed1992

Live Borrelia burgdorferi preferentially activate interleukin-1 beta gene expression and protein synthesis over the interleukin-1 receptor antagonist.

Lyme arthritis is one of the few forms of chronic arthritis in which the cause is known with certainty. Because cytokines are thought to contribute to the pathogenesis of chronic arthritis, we investigated the effect of the Lyme disease spirochete, Borrelia burgdorferi, on the gene expression and synthesis of IL-1 beta and the IL-1 receptor antagonist (IL-1ra) in human peripheral blood mononuclear cells. Live B. burgdorferi induced fivefold more IL-1 beta than IL-1 alpha and sevenfold more IL-1 beta than IL-1ra; LPS or sonicated B. burgdorferi induced similar amounts of all three cytokines. This preferential induction of IL-1 beta was most dramatic in response to a low passage, virulent preparation of B. burgdorferi vs. three high passage avirulent strains. No difference in induction of IL-1ra was seen between these strains. The marked induction of IL-1 beta was partially diminished by heat-treatment and abrogated by sonication; IL-1ra was not affected. This suggested that a membrane component(s) accounted for the preferential induction of IL-1 beta. However, recombinant outer surface protein beta induced little IL-1 beta. By 4 h after stimulation, B. burgdorferi induced sixfold more IL-1 beta protein than LPS. In contrast to LPS-induced IL-1 beta mRNA which reached maximal accumulation after 3 h, B. burgdorferi-induced IL-1 beta mRNA showed biphasic elevations at 3 and 18 h. B. burgdorferi-induced IL-1ra mRNA peaked at 12 h, whereas LPS-induced IL-1ra mRNA peaked at 9 h. IL-1 beta synthesis increased in response to increasing numbers of spirochetes, whereas IL-1ra synthesis did not. The preferential induction by B. burgdorferi of IL-1 beta over IL-1ra is an example of excess agonist over antagonist synthesis induced by a microbial pathogen, and may contribute to the destructive lesion of Lyme arthritis.

Adult↗
PubMed1992

Musculoskeletal signs of metabolic and systemic diseases in childhood.

Many metabolic and systemic disorders affect the musculoskeletal system in growing children. This review surveys some of the recent literature in several diverse areas, including new radiologic methods to determine bone mineralization and their use in children with juvenile arthritis and other systemic diseases, bone disorders in childhood, and the association of endocrinopathies and musculoskeletal symptoms.

Child↗
PubMed1992

Serum interleukin-2 and tumor necrosis factor-alpha in primary biliary cirrhosis: decrease by colchicine and relationship to HLA-DR4.

Colchicine improves liver function tests and survival in primary biliary cirrhosis (PBC); however, its mechanism of action in PBC is unknown. Because elevated interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF) have been found in various inflammatory diseases, we measured serum levels of IL-2 and TNF in 28 PBC patients before and during treatment with either colchicine or placebo. Compared with normal controls, untreated PBC patients had increased serum IL-2 (39 +/- 13 U/ml vs. 0.8 +/- 0.5) and TNF (549 +/- 162 pg/ml vs. nondetectable). During colchicine treatment, both IL-2 and TNF levels decreased significantly (57 +/- 24 to 40 +/- 22, p less than 0.04; 586 +/- 295 to 445 +/- 295, p less than 0.02). No significant changes in IL-2 or TNF levels occurred in the placebo-treated patients. DR4-positive patients had elevated levels of IL-2 at entry, compared with DR4-negative patients (67 +/- 26 vs. 14 +/- 5, p less than 0.04). The effect of colchicine in PBC may be due, in part, to modulation of IL-2 and TNF levels. Alternatively, the changes in IL-2 and TNF may simply reflect the overall improvement in biochemical tests of liver function related to colchicine therapy. DR4 appears to relate to serum levels of these cytokines in PBC and, possibly, also to the response to colchicine.

Biological Assay↗
PubMed1991

Histamine suppresses gene expression and synthesis of tumor necrosis factor alpha via histamine H2 receptors.

Histamine and tumor necrosis factor alpha (TNF-alpha) can each contribute to the pathogenesis of allergic reactions and chronic inflammatory diseases. We now report the effect of histamine on gene expression and total cellular synthesis of TNF-alpha. Lipopolysaccharide (LPS)-induced synthesis of TNF-alpha in peripheral blood mononuclear cells (PBMC) from 18 healthy donors was suppressed by histamine concentrations from 10(-6) to 10(-4) M, levels comparable with those measured in tissues after mast cell degranulation. Histamine (10(-5) M) markedly suppressed LPS-induced synthesis of TNF-alpha in both unfractionated PBMC (83% inhibition, p less than 0.001) and monocytes purified by positive selection of LeuM3+ cells (62% inhibition, p less than 0.05). The suppressive effect of histamine on TNF-alpha synthesis did not require the presence of T cells. The histamine-mediated decrease in TNF-alpha synthesis was not affected by indomethacin, nor by diphenhydramine, an H1 receptor antagonist, but was reversed by cimetidine or ranitidine, H2 receptor antagonists, in a dose-dependent manner. Suppression of TNF-alpha synthesis by histamine is likely to be a transcriptional event, since histamine (10(-5) M) reduced TNF-alpha mRNA levels fourfold. These results suggest that histamine release from mast cells may paradoxically limit the extent of inflammatory and immune reactions by suppressing local cytokine synthesis in H2 receptor-bearing cells.

Cells, Cultured↗
PubMed1991

Rheumatic fever, reactive arthritis, and musculoskeletal infections in children.

Infections may cause musculoskeletal symptoms either by inducing reactive disease or by directly infecting bone, joints, or muscle. Differentiation of reactive disease from direct infections of the musculoskeletal system is an important clinical problem. Both reactive disease and direct infections result from interactions of the host, the environment, and the infecting agent. This review provides an update of the recent literature on rheumatic fever, the classic example in rheumatology of reactive disease, and direct musculoskeletal infections.

Arthritis, Infectious↗
PubMed1990

Neonatal interleukin-1 beta, interleukin-6, and tumor necrosis factor: cord blood levels and cellular production.

In a prospective study, levels of interleukin-1 beta (IL-1 beta), interleukin-6) (IL-6), and tumor necrosis factor (TNF) were measured in a blind fashion in cord blood plasma from 92 neonates by specific immunoassays, and were correlated with the clinical courses of the infants, including type of delivery and perinatal complications. Plasma IL-1 beta concentration was undetectable in infants born by normal vaginal delivery or elective cesarean section but was significantly increased in infants born after induced vaginal deliveries (142 +/- 68 pg/ml) or urgent cesarean section (290 +/- 21 pg/ml; both p less than 0.05 compared with normal deliveries). The IL-1 beta levels were elevated in infants with severe perinatal complications (282 +/- 116 pg/ml; p less than 0.001), whereas TNF and IL-6 levels were not related to these complications. Infants with isolated perinatal infectious complications had elevated levels of plasma IL-6 compared with those of sick neonates without infection (p less than 0.001). In contrast, TNF plasma levels and IL-1 beta production by cord blood leukocytes were decreased in infants with infectious complications alone (both p less than 0.05). These studies suggest that the levels of IL-1 beta, IL-6, and TNF in the cord plasma relate differentially to clinical complications in the perinatal period.

Delivery, Obstetric↗
PubMed1990

Intimacy and liking: mutual influence and the role of unique relationships.

Traditional assumptions (e.g., there are traitlike differences in disclosure) predict that people who are generally liked should generally disclose (e.g., individual-level effects). In contrast, dynamic interactional models predict that significant disclosure-liking effects are apt to be a function of mutual influences in particular dyads (e.g., dyadic-level effects). To directly explore these issues and separately examine individual and dyadic effects, 45 sorority women were asked to indicate how much they disclosed to, received disclosure from, and liked each other. Social relations analysis (Kenny & LaVoie, 1984) revealed significant disclosure-liking effects only at the dyadic level, casting doubts on traditional assumptions and supporting a dynamic interaction model of disclosure-liking effects. Implications for personality and interpersonal relationships are discussed.

Adult↗
PubMed1990

Behavioral responsiveness to strangers in young chimpanzees (Pan troglodytes).

Earlier studies of responses of primate infants to strangers were frequently confounded with separation from the attachment figure and/or removal to an unfamiliar setting. In the present study, young chimpanzees were tested in a familiar setting with a human female caretaker who served as an attachment figure. Two strangers were introduced: a human female, approximately the size of the caretaker, who refrained from initiating interactions and a larger human male, who repeatedly approached and initiated contact with the subjects. A somewhat more intense response was elicited by the larger, more assertive male stranger, but neither stranger elicited severe distress. The behavior of the chimpanzees is better described as wary, rather than fearful. These results may be attributable to the continued presence of the caretaker in contrast to previous studies reporting severe distress to strangers when chimpanzees are tested alone. A wariness of strangers in nursery-reared chimpanzees may develop by 6 months of age and may diminish somewhat by 2 years of age under the conditions of this study.

Animals↗
PubMed1989

The role of causal sequence in the meaning of actions.

Single actions, taken out of context, typically have numerous meanings. Yet, when we observe such actions as part of a sequence of behaviour, we are often unaware of this multiplicity of possible meanings. In this article, we argue that the specific meaning of an action is the result of a process in which people, by making appropriate inferences, relate the actions in a sequence to each other and construct a coherent scenario from them. One implication of this position is that the meaning of actions should be extremely sensitive to the order in which they occur, since order affects which knowledge structures are currently active and is an important clue to the causal and means-end relations among actions. In fact, meaning should be so sensitive to order that it should be possible to construct sets of actions, such that merely by changing the order, the same set of actions could have two radically different meanings. Five sets of such actions were designed. Subjects read one of the two orders for each set of actions and then answered a number of open-ended questions about them. Subjects receiving different orders identified different causes and reasons for the actions, made different predictions about what would happen next, and came to different conclusions about the identities of actors and and objects in the sequences, thus indicating that they had constructed very different meanings for the same actions.

Concept Formation↗
PubMed1989

Distribution of cells bearing "rheumatic" antigens in peripheral blood of patients with rheumatic fever/rheumatic heart disease.

Cell surfaces of some peripheral blood cells from individuals with a history of rheumatic fever/rheumatic heart disease (RHD) have been demonstrated by the use of monoclonal antibodies to be antigenically distinct from the majority of the population. Our study examines the distribution of cells bearing these "rheumatic" antigens in 23 subjects with rheumatic fever/RHD of Maori, Polynesian and Caucasian ancestry and 182 members of their families (rheumatic fever/RHD families) as well as in 46 members of families in which no member had been demonstrated to have had rheumatic fever/RHD (control families). Mononuclear cells from the blood of all cooperating family members were prepared and non-T cells isolated by sheep red blood cell rosette depletion. The binding of monoclonal antibodies 83S19.23 and D8103 to non-T cells was measured using an immunoperoxidase technique. Subjects with rheumatic fever/RHD had a significantly higher proportion of cells binding the antibodies than the unaffected members of all families. Unaffected members of rheumatic fever/RHD families had significantly higher levels of such rheumatic cells than control families. An increase in the proportion of rheumatic cells with age was noted in unaffected members of rheumatic fever/RHD families but not in rheumatic fever/RHD subjects of control families. A level of 13% 83S19.23 positive non-T cells optimally discriminated between rheumatic and nonrheumatic individuals. The relative risk for rheumatic fever/RHD with 13% or greater positive cells was 9.48. The negative predictive value of having less than 13% positive cells was 98.3%. In the population studied, 83S19.23 seems especially capable of identifying those with low risk for rheumatic fever/RHD.

Aging↗
PubMed1989

Cytokines and immunoglobulin in rheumatic heart disease: production by blood and tonsillar mononuclear cells.

Rheumatic fever and rheumatic heart disease are considered to result from abnormal immune responses after Group A streptococcal pharyngitis. Production of interleukin 1 (IL-1), tumor necrosis factor-alpha (TNF), interleukin 2 (IL-2) and immunoglobulin (Ig) by blood and tonsillar mononuclear cells from rheumatic or healthy children was measured after stimulation in vitro by pokeweed mitogen (PWM) or the streptococcal extracellular product, blastogen A (BLA). Tonsillar cells from patients with rheumatic heart disease produced significantly less IL-1, TNF, IL-2, and Ig than control tonsillar cells. In contrast, blood mononuclear cell cultures from rheumatic children produced more TNF and IL-2 than controls. Our findings suggest that abnormal regulation of cytokine and Ig production may contribute to the pathogenesis of acute rheumatic fever and rheumatic heart disease.

Cells, Cultured↗