David S. Matheson

Intravenous immunoglobulin induces interferon-gamma and interleukin-6 in vivo.

Immunoglobulin is known to be an immunomodulator. It can induce protein mediators from mononuclear cells, particularly monocytesin vitro. Intravenous immunoglobulin (IVIg) has been used as a therapy in several clinical situations. In this study, the influence of IVIg infusion on the plasma levels of two protein mediators, interferon-γ (IFN-γ) and interleukin-6 (IL-6), was assessed in patients with secondary generalized epilepsy. Compared to preinfusion levels, plasma interferon-γ was increased in 18 of 18 patients 20 min after the 6- to 8-hr infusion of IVIg. Plasma interferon-γ levels reached their peak at various times from 20 min to 3 days post IVIg infusion, dependent upon the individual patient. Plasma IL-6 levels also increased after IVIg infusion. Generally, IL-6 reached its peak level after IFN-γ. No activated T cells or B cells were observed as determined by the expression of surface CD25, CD23, and HLA-DR 20 min following the infusion when the IFN-γ and IL-6 levels were assessed. The expression of the high-affinity receptor for IgG, CD64, on monocytes was significantly enhanced after IVIg infusion, while the low-affinity receptor for IgG, CD32, was only slightly increased. Cytoplasmic staining of PBMC indicates that both CD16-positive and CD16-negative cells may contribute to the increase seen in plasma IFN-γ. These data raise the possibility that the therapeutic effects of intravenous immunoglobulin may be related, at least in part, to the immunomodulatory activity as demonstrated by the changes in plasma levels of IFN-γ and IL-6.

Aggregated immunoglobulin and Fc fragment of IgG induce IL-6 release from human monocytes

The Fc fragment of immunoglobulin (Ig) has been shown to play an important role in the regulation of humoral immunity, cellular immunity, lymphocyte and monocyte activation, and immune mediator secretion. We wished to determine if Ig or Fc fragments would induce IL-6 production from monocytes. Incubation of monocytes purified from human peripheral blood mononuclear cells with aggregated Ig or Fc fragments of Ig induced interleukin-6 (IL-6) activity in the supernatants. Monomeric Ig taken from an intravenous preparation of Ig, from which all aggregated Ig are removed, would not induce IL-6 production from monocytes whereas as a heat-treated aliquot, presumably containing aggregates, did induce IL-6. The supernatants were assayed according to their ability to induce growth in a murine hybridoma cell line B9, or enhance Ig secretion of B cells stimulated with Staphylococcus aureus Cowan 1 (SAC). The IL-6 activity in the supernatants could be neutralized by a polyclonal rabbit anti-human IL-6 antiserum in both assays of IL-6 activity. Exposure of T-enriched or B-enriched lymphocyte subpopulations to Fc fragments did not induce the release of any IL-6 after 12 hr of incubation, but small amounts of IL-6 were produced by B-enriched cells after 60 hr of exposure to Fc fragments. Hence Fc fragments and aggregated Ig induce peripheral blood monocytes to rapidly secrete large quantities of interleukin-6.

Bayesian optimization in a billion dimensions via random embeddings

Bayesian optimization techniques have been successfully applied to robotics, planning, sensor placement, recommendation, advertising, intelligent user interfaces and automatic algorithm configuration. Despite these successes, the approach is restricted to problems of moderate dimension, and several workshops on Bayesian optimization have identified its scaling to high-dimensions as one of the holy grails of the field. In this paper, we introduce a novel random embedding idea to attack this problem. The resulting Random EMbedding Bayesian Optimization (REMBO) algorithm is very simple, has important invariance properties, and applies to domains with both categorical and continuous variables. We present a thorough theoretical analysis of REMBO. Empirical results confirm that REMBO can effectively solve problems with billions of dimensions, provided the intrinsic dimensionality is low. They also show that REMBO achieves state-of-the-art performance in optimizing the 47 discrete parameters of a popular mixed integer linear programming solver.

A comparison of decision-making by physicians and administrators in healthcare settings.

Physicians and administrators are committed to the same goal of providing quality care at affordable costs. Their perceptions of each other and their resulting behaviors, however, may lead to conflict. We offer some insight into these perceptions and behaviors, and provide a framework to improve communication and to reduce misunderstanding.

Regulation of Fc-induced IL-6 from human peripheral blood mononuclear cells

Previous experiments demonstrated that aggregated immunoglobulin and the Fc fragment of human IgG can induce interleukin-6 (IL-6) secretion from peripheral blood monocytes. The data herein indicate that Fc-induced IL-6 is modulated by IL-1, IL-4 and interferon (IFN-gamma). When added with Fc fragments, IL-1 and IFN-gamma increased IL-6 production. IL-4 added with Fc fragment did not influence IL-6 production although IL-4 added with LPS was inhibitory to IL-6 production. However, when PBMC were pre-treated with IL-4, IL-4 downregulated Fc-induced IL-6 secretion. The inhibitory effect of IL-4 in the pre-treatment phase could be overcome with a high concentration of IFN-gamma added with the IL-4. Both IL-4 and IFN-gamma acted in a dose- and time-dependent manner. By dot blot analysis, IL-6 mRNA production appeared to be decreased in amount and duration by IL-4 whereas IFN-gamma increased the amount of IL-6 mRNA production. Hence, IL-4 and IFN-gamma appear to have opposing effects and may play a balancing role in the regulation of IL-6 production secondary to Fc exposure.

Particle concentration fluorescence immunoassay for measuring interleukin-6 receptor numbers

Analysis of the number of receptors per cell and the affinity of the ligand/receptor interaction has provided considerable insight into the functioning of numerous cytokines. Interleukin-6 (IL-6) is a multifunctional cytokine which may have considerable clinical relevance in inflammatory or immunodeficiency diseases. Using particle concentration fluorescence immunoassay (PCFIA) technology, an assay is described which calculates the receptor number and affinity on small numbers of human cells. Resting B cells are shown to lack IL-6 receptors but activation of B cells induces up to 1,300 receptors per cell, with Kd of 1 x 10(-11) to 2 x 10(-11) M. Other recombinant mediators do not alter the binding of labeled IL-6 to the cells. PCFIA avoids the use of radioactivity and requires very small numbers of cells (2 x 10(4) per well). Potential application to the study of regulatory mechanisms and to clinical situations where small samples of blood are available is feasible.