Quantum Non-Gaussianity of Multiphonon States of a Single Atom.

Quantum non-Gaussian mechanical states are already required in a range of applications. The discrete building blocks of such states are the energy eigenstates-Fock states. Despite progress in their preparation, the remaining imperfections can still invisibly cause loss of the aspects critical for their applications. We derive and apply the most challenging hierarchy of quantum non-Gaussian criteria on the characterization of single trapped-ion oscillator mechanical Fock states with up to 10 phonons. We analyze the depth of these quantum non-Gaussian features under intrinsic mechanical heating and predict their requirement for reaching quantum advantage in the sensing of a mechanical force.

Nonclassical Light from Large Ensembles of Trapped Ions.

The vast majority of physical objects we are dealing with are almost exclusively made of atoms. Because of their discrete level structure, single atoms have proved to be emitters of light, which is incompatible with the classical description of electromagnetic waves. We demonstrate this incompatibility for atomic fluorescence when scaling up the size of the source ensemble, which consists of trapped atomic ions, by several orders of magnitude. The presented measurements of nonclassical statistics on light unconditionally emitted from ensembles containing up to more than a thousand ions promise further scalability to much larger emitter numbers. The methodology can be applied to a broad range of experimental platforms focusing on the bare nonclassical character of single isolated emitters.

Interleukin 1 of the central nervous system is produced by ameboid microglia.

By screening specific populations of rat brain cells, we found that ameboid microglia secrete an 18 kD peptide with IL-1 biological activity. The IL-1 activity released by microglia was found to be identical to rat macrophage IL-1 on fractionation by gel filtration and high pressure liquid anion-exchange chromatography, and it was neutralized by an antiserum specific for murine IL-1. When added to astroglia grown in culture, microglial IL-1 increased the cell number of five- to sevenfold, and increased astroglial incorporation of [3H]thymidine by three- to fivefold. We propose that the proliferation of astroglia in specific brain regions may be regulated by the signaled release of IL-1 from activated microglial cells.

Role of interleukin 1 in anti-immunoglobulin-induced B cell proliferation.

In this report we describe conditions for polyclonal activation of small numbers of highly purified mouse B lymphocytes. Three signals are required for induction of DNA synthesis by the particular subset of small B lymphocytes investigated: a signal delivered by antibodies specific for the IgM receptor expressed on the B cell membrane; a signal delivered by a T cell-derived factor (B cell growth factor [BCGF]); and a signal delivered by the macrophage-derived factor interleukin 1 (IL-1). The conclusion that IL-1 has B cell co-stimulator activity is based on the findings that highly purified preparations of mouse and human IL-1 have the capacity to cause proliferation in B cells treated with anti-IgM and BCGF. Such cultures show an absolute dependence on exogenously added IL-1 when 2-mercaptoethanol is omitted from the medium. BCGF and IL-1 each act in a non-antigen-specific, non-H-2-restricted, synergistic manner. Their requirement is not observed when B cells are cultured at high density, presumably reflecting accessory cell contamination and endogenous factor production under these conditions. The B cell activation induced by these three signals is restricted to proliferation without the production of antibody-forming cells.

Streptococcal cell walls and synovial cell activation. Stimulation of synovial fibroblast plasminogen activator activity by monocytes treated with group A streptococcal cell wall sonicates and muramyl dipeptide.

Group A streptococcal peptidoglycan has previously been shown to be arthritogenic in rats and has been implicated as a structure present in a class of possible etiologic agents for rheumatoid arthritis. The present study reports that conditioned medium from human monocytes, after interaction with cell wall sonicates of four group A streptococcal strains, stimulates the plasminogen activator (PA) activity of nonrheumatoid synovial fibroblasts. Low concentrations of N-acetylmuramyl-L-alanyl-D isoglutamine (muramyl dipeptide) can also generate this synovial activator (SA) activity from human monocytes. Preliminary biochemical data suggest that the SA activity is distinct from interferon-gamma, interleukin 1, and interleukin 2. These results indicate that agents that are arthritogenic in rats can modulate human synovial fibroblast functions via monocytes. The findings are proposed to have possible significance for an understanding of the cellular interactions involved in the formation and function of the rheumatoid pannus, because PA has been invoked as possibly being generally important for the processes of cell migration, tissue remodeling, and inflammation.

The functional relationship of the interleukins.

The mechanism of the lymphoproliferative effect of the macrophage product lymphocyte-activating factor [LAF(IL1] appears to be mediated by the stimulation of the release of T cell growth factor [TCGF(IL2)] by T cells. The magnitude of the resultant T cell proliferative clonal expansion is thus dependent upon the quantity of both LAF(IL1) and TCGF(IL2) induced by antigen or lectin stimulation. These observations, coupled with the ability to measure the production and actions of these hormone-like lymphokines, should allow for increased insight into the mode of action of immunoenhancing and immunosuppressive agents, as well as for new therapeutic approaches to disease states involving T lymphocytes.

Effect of interleukin 1 on human thymocytes and purified human T cells.

Human Interleukin 1 (IL-1) purified by molecular weight fractionation, isoelectric focusing, and gel electrophoresis has been tested on human thymocytes and highly purified human T cells. IL-1 prepared in this manner could not support the long-term growth of T cells yet would augment lectin-stimulated mitogenesis. The IL-1 preparations were shown to possess the lectin-augmenting activity at dilutions containing less than 1 ng of the measurable protein. These data are in agreement with the model that IL-1 stimulates production of IL-2 from lectin-stimulated lymphocytes.

Interleukin 1 stimulation of collagenase production by cultured fibroblasts.

Interleukin 1 is a monokine that exerts biological effects on a variety of target cells in vitro. In this report, interleukin 1 has been found to be capable of stimulating collagenase production by cultured dermal fibroblasts. The concentrations of interleukin 1 that stimulate fibroblast collagenase production are similar to those that stimulate mouse thymocyte proliferation. Analyses by high performance liquid chromatography indicate that interleukin 1, rather than a contaminating monokine, is responsible for this effect on fibroblasts. Interleukin 1, released in vivo by macrophages infiltrating sites of tissue damage or inflammation, may function to stimulate the release of collagenase by connective tissue fibroblasts.

Lymphokine-activated killer cell phenomenon. III. Evidence that IL-2 is sufficient for direct activation of peripheral blood lymphocytes into lymphokine-activated killer cells.

Purified interleukin 2 (IL-2) was found to be sufficient for direct activation of peripheral blood lymphocytes into lymphokine-activated killer (LAK) cells. The LAK activation factor was directly and consistently associated with IL-2 activity using classic protein purification techniques, adsorption to IL-2-dependent cell lines, and inhibition with anti-Tac antibody. As yet, no other cytokines have been found that perform the same role.

2020 Heart Failure Society of South Africa perspective on the 2016 European Society of Cardiology Chronic Heart Failure Guidelines.

Heart failure with a reduced ejection fraction (HFrEF) is a condition frequently encountered by healthcare professionals and, in order to achieve the best outcomes for patients, needs to be managed optimally. This guideline document is based on the European Society of Cardiology Guidelines for the treatment of acute and chronic heart failure published in 2016, and summarises what is considered the best current management of patients with the condition. It provides information on the definition, diagnosis and epidemiology of HFrEF in the African context. The best evidence-based treatments for HFrEF are discussed, including established therapies (beta-blockers, ACE-i/ARBs, mineralocorticoid receptor antagonists (MRAs), diuretics) that form the cornerstone of heart failure management as well as therapies that have only recently entered clinical use (angiotensin receptor-neprilysin inhibitor (ARNI), sodium/glucose cotransporter-2 (SGLT2) inhibitors). Guidance is offered in terms of more invasive therapies (revascularisation, implantable cardioverter defibrillators (ICDs) and cardiac resynchronisation therapy (CRT) by implantation of a biventricular pacemaker with (CRT-D) or without (CRT-P) an ICD, left ventricular assist device (LVAD) use and heart transplantation) in order to ensure efficient use of these expensive treatment modalities in a resource-limited environment. Furthermore, additional therapies (digoxin, hydralazine and nitrates, ivabradine, iron supplementation) are discussed and advice is provided on general preventive strategies (vaccinations). Sections to discuss conditions that are particularly prevalent in sub-Saharan Africa (HIV-associated cardiomyopathy (CMO), peripartum CMO, rheumatic heart disease, atrial fibrillation) have been added to further improve clinical care for these commonly encountered disease processes. You are encouraged to read the complete 2016 ESC Heart Failure guideline: Ponikowski P, Voors AA, Anker SD, et al.; on behalf of the European Society of Cardiology. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016,37:2129-2200.

Monocyte-conditioned medium, interleukin-1, and tumor necrosis factor stimulate the acute phase response in human hepatoma cells in vitro.

Human hepatoma cells mimic the acute phase response after treatment with monocyte-conditioned medium. Levels of secreted fibrinogen, alpha-1 acid glycoprotein, C-reactive protein, haptoglobin, and the third component of complement were elevated compared with control levels after 48 h of incubation with conditioned supernatant medium from an enriched fraction of normal peripheral monocytes. Albumin levels declined and alpha-1 antitrypsin remained unchanged. Levels of specific mRNA were measured by hybridization to slot blots and Northern blots and changed in correspondence with protein alterations. Interleukin-1 and tumor necrosis factor stimulated the third component of complement, but did not elevate any other member of the acute phase group and were therefore only partially active in this system. The identification of an in vitro model of the human acute phase response will permit analysis of the molecular basis for coordinate regulation of this group of facultative genes.

Interleukin-1 stimulation of astroglial proliferation after brain injury.

The interleukins, which have a regulatory role in immune function, may also mediate inflammation associated with injury to the brain. In experiments to determine the effect of these peptide hormones on glial cell proliferation in culture, interleukin-1 was a potent mitogen for astroglia but had no effect on oligodendroglia. Interleukin-2 did not alter the growth of either type of glial cell. Activity similar to that of interleukin-1 was detected in brains of adult rats 10 days after the brains had been injured. These findings suggest that interleukin-1, released by inflammatory cells, may promote the formation of scars by astroglia in the damaged mammalian brain.

Stimulation of glycosaminoglycan synthesis in cultured human dermal fibroblasts by interleukin 1. Induction of hyaluronic acid synthesis by natural and recombinant interleukin 1s and synthetic interleukin 1 beta peptide 163-171.

Hyaluronic acid (HA) is believed to play a critical role in wound healing and in morphogenesis. Factors controlling the production of HA by fibroblasts in normal and pathological states are not completely understood. In this report we have observed that natural human interleukin (IL-1)1 beta and human recombinant (hrIL)-1 alpha and beta are potent stimulators of HA production by fibroblasts in vitro. Hyaluronic acid is the major species of glycosaminoglycan (GAG) stimulated by IL-1 in fibroblasts. PGE2 does not appear to be involved directly in this IL-1 effect on fibroblasts, but stimulation of HA production by IL-1 is dependent on protein synthesis. The synthetic human IL-1 beta peptide 163-171 (Val-Gln-Gly-Glu-Glu-Ser-Asn-Asp-Lys), which has been previously shown to stimulate thymocyte proliferation but not fibroblast PGE2 production, is also able to stimulate fibroblast HA production. The synthesis and secretion of IL-1 by mononuclear phagocytes at sites of inflammation and immune reactions in vivo could potentially serve as a signal for fibroblasts to synthesize HA, which in turn could serve to facilitate and modulate reparative and immune processes by virtue of its ability to alter cell-cell, cell matrix, and cell-membrane receptor interactions.

HLA-A2.1-restricted T cells react to SEREX-defined tumor antigen CML66L and are suppressed by CD4+CD25+ regulatory T cells.

The question of whether T cell responses to SEREX-defined tumor antigens are under regulation of naturally occurring CD4+CD25+ regulatory T cells (nTreg cells) has not been answered. To address this issue, we first identified an HLA-A2.1-restricted T cell antigen epitope of SEREX-identified tumor antigen CML66L, 66Pa. The HLA-A2.1/66Pa peptide complex in vitro stimulated the in vivo-primed T cells as shown by increased T cell proliferation, higher secretion of the T cell cytokine interferon-gamma (IFN-gamma), increased production of intracellular IFN-gamma in CD8+ T cells, and higher T cell-mediated cytotoxicities of CML66L+ human tumor cells. This suggests that CML66L elicits T cell immune responses. We also developed a novel internal reference epitope for identification of T cell epitopes by construction of chimeric CML66L containing myeloid antigen proteinase 3 epitope Pr1 as a control. Finally, we found that nTreg cells regulates T cell responses to 66Pa, and that depletion of nTreg cells via a pro-apoptotic protein Bax-dependent mechanism enhances polyclonal T cell responses to 66Pa. These findings provide new insights into the T cell participation in SEREX-defined anti-tumor immune responses and novel direction in enhancement of anti-leukemia immunotherapy by modulation of homeostasis of nTreg cells.

Inhibition of interleukin-1-alpha-induced nitric oxide synthase in vascular smooth muscle and full reversal of interleukin-1-alpha-induced hypotension by N omega-amino-L-arginine.

BACKGROUND: Interleukin-1-alpha (IL-1) is a cytokine with potentially therapeutic immunoproliferative and tumoricidal activities. Preliminary clinical studies suggest that use of IL-1 may be restricted by dose-limiting hypotension. PURPOSE: The purpose of this study was to investigate the role of nitric oxide (NO.) as a possible mediator of this hypotension. METHODS: Cytokine-treated rat aortic smooth muscle cells were assayed for nitrite production, a stable breakdown product of nitric oxide. Nitric oxide synthase from smooth muscle cells was partially characterized in cytosol preparations using a novel Fe(2+)-myoglobin method to test for nitric oxide production. To determine the role of NO. on the immunorestorative and antineoplastic activity of IL-1, N omega-amino-L-arginine (NAA) or N omega-monomethyl-L-arginine (NMA), inhibitors of nitric oxide synthase, were added to either cultures of IL-1-dependent T cells or A375 melanoma cells exposed to IL-1. To investigate the effects of NAA in vivo, pentobarbital anesthetized dogs, which were made hypotensive by administration of IL-1, received a single intravenous bolus dose of NAA. The effects of NAA were then reversed by the administration of L-arginine. RESULTS: Our results show that cultured IL-1-activated rat aortic smooth muscle cells synthesize nitric oxide, a potent vasodilator. Induction of nitric oxide synthase is augmented by interferon-gamma and blocked by IL-1 receptor antagonist and by inhibitors of RNA or protein synthesis. Nitric oxide synthesis by IL-1-activated smooth muscle cells is inhibited by NAA, NMA, and N omega-nitro-L-arginine (NNA) with ED50 (i.e., effective dose for 50% inhibition) values of 20, 60, and 1000 microM, respectively; this rank order of inhibition is characteristic of an agonist-unregulated, inducible isoform of nitric oxide synthase. In smooth muscle cells, inhibition of NO. synthesis by NAA is reversed by excess L-arginine. Consistent with the induction of unregulated NO. synthesis in vascular smooth muscle in vivo, administration of IL-1 (50 micrograms/kg) to dogs caused a 33.5% decrease in systemic vascular resistance and a 28% decrease in blood pressure within 3 hours. Subsequent administration of NAA (20 mg/kg) rapidly and completely reversed the hypotension and increased systemic vascular resistance; these effects of NAA were reversed by L-arginine. Neither the immunoproliferative nor the tumoricidal activity of IL-1 was diminished by NAA. CONCLUSIONS: Our results indicate that (a) vascular smooth muscle is a likely source as well as a target of IL-1-induced NO. synthesis, causing vasodilatation and hypotension, (b) nitric oxide synthase inhibitors can fully reverse this hypotension, and (c) the therapeutically useful properties of IL-1 are not diminished by nitric oxide synthase inhibitors. IMPLICATIONS: Administration of inhibitors of nitric oxide synthase can reverse the pathological cardiovascular effects of IL-1 at concentrations that do not interfere with the potentially useful immunoproliferative or tumoricidal effects of this cytokine. In the context of the current clinical trials of IL-1, this finding would represent a very significant advantage.

Effect of recombinant granulocyte/macrophage colony-stimulating factor on human monocyte activity in vitro and following intravenous administration.

The purpose of these studies was to examine the antitumor properties of blood monocytes from patients undergoing a phase I trial with recombinant granulocyte/macrophage colony-stimulating factor (rGM-CSF). Peripheral blood monocytes from 7 patients receiving various doses of rGM-CSF by continuous infusion were isolated prior to therapy and at various times during the 2-wk infusion. Monocytes/cubic centimeter of blood increased in a dose-dependent fashion in patients receiving rGM-CSF. However, activation of monocyte-mediated tumorilytic properties was seen in only 1 of 7 patients. rGM-CSF administration also did not stimulate interleukin-1 or tumor necrosis factor production by blood monocytes. The failure to detect monocyte-mediated tumoricidal activation was not secondary to an inherent "defect" in the patients' monocytes because in vitro incubation with lipopolysaccharide alone or human recombinant gamma-interferon plus muramyl dipeptide resulted in monocyte-mediated cytotoxicity and in the secretion of interleukin-1 and tumor necrosis factor. rGM-CSF in vitro also did not stimulate the tumoricidal function of normal monocytes or the secretion of interleukin-1 or tumor necrosis factor. We concluded that systemic administration of rGM-CSF did not result in routine activation of monocyte-mediated cytotoxicity but did result in a dose-dependent rise in the number of circulating monocytes. Because these monocytes could be activated in vitro, we propose that, in an adjuvant therapy setting, rGM-CSF be combined with other activating agents to increase the pool of potential killer cells.

Classification of human leukemia by membrane antigen analysis with xenoantisera.

Rabbit and monkey antisera after appropriate absorption were rendered specific for normal or leukemic lymphoid- and myeloid-associated antigens. Antisera defining a common peripheral blood T-cell antigen, a thymus leukemia antigen, HLA-DR or Ia-like antigen, common acute lymphoblastic leukemia antigen (CALLA), and a myeloid-monocyte (M) antigen were used in a microcytotoxicity assay to classify leukemic cells from 30 patients in a double blind study. The antisera to the M antigen reacted with adherent peripheral blood cells and polymorphonuclear leukocytes and failed to react with nonadherent mononuclear cells and enriched T-cells and chronic lymphocytic leukemia cells. The M antisera also reacted with U937, a monocytic-type cell line, and with HL60, a promyelocytic-type cell line, but failed to react with T and B lymphoblastoid cell lines. The specificities of the other antisera have been described in previous reports. Cells from three of the patients could not be phenotyped by microcytotoxicity testing. Cells from 25 patients had a consensus morphological or histochemical diagnosis of either acute lymphoblastic leukemia or acute nonlymphocytic leukemia. The serological classification of these patients using the five types of antisera listed above were consistent with the consensus diagnosis. In addition, the lymphoid cancers were further subclassified as to T-, B-, or thymus antigen types. There was no consensus lymphoid versus myeloid diagnosis on cells from two patient. The serological classification in both cases favored a diagnosis of myeloid rather than lymphoid leukemia.

DNA vaccination against neu reduces breast cancer incidence and metastasis in mice.

The gene for HER2/neu is overexpressed in 30-40% of breast and ovarian cancers, and this overexpression correlates with increased metastasis and poor prognosis. The HER2/neu gene product, a transmembrane protein kinase member of the EGF receptor family, has significant potential as a tumor antigen for vaccination. We inserted the sequence for neu into a novel plasmid called ELVIS containing a Sindbis virus replicon that reproduces multiple copies of mRNA. Mice vaccinated one time intramuscularly demonstrated a strong antibody response against A2L2, a murine breast cancer cell line transfected to express neu. Vaccinated mice challenged in the mammary fatpad with A2L2 had reduced tumor incidence and reduced tumor mass compared to mice challenged with tumor cells lacking the neu insert. Intradermal vaccination was also protective and required 80% less plasmid for a similar level of protection. Vaccination reduced the incidence of lung metastasis from mammary fatpad tumors and reduced the number of lung metastases resulting from intravenous injection of A2L2 cells. Cytotoxic T lymphocytes cultures of immune spleen cells with P815-neu cells produced high levels of interferon-gamma indicating an antigen-specific Th1-type immune response resulting from the vaccination. In a spontaneous breast tumor model using neu transgenic mice, vaccination with ELVIS-neu protected against development of spontaneous breast tumors. Our preclinical data indicate that therapeutic vaccination of patients with ELVIS-neu may reduce metastasis from HER2/neu-expressing breast and ovarian tumors.

Antitumor effects of liposomal IL1 alpha and TNF alpha against the pulmonary metastases of the B16F10 murine melanoma in syngeneic mice.

Interleukin 1 alpha (IL1 alpha) and tumor necrosis factor alpha (TNF alpha) have been successfully incorporated into specific phosphatidylcholine (PC) and phosphatidylserine (PS) multilamellar vesicle (MLV) liposomes by modifying the concentration of calcium ion and pH of the encapsulation buffer. Under these conditions, some of the cytokines may attach to the exterior surface of the MLV and therefore be readily accessible to target cells for receptor binding and signal transduction. These cytokine-associated liposomes are stable for up to 2 weeks in serum-free buffer, and leakage of cytokines into medium containing 10% fetal bovine serum was about 50% at the end of a 3-day incubation period at 37 degrees C. The biological activities mediated by liposomal IL1 alpha and TNF alpha were specific: the stimulation of thymidine uptake in T-helper D10 lymphocytes and the cytolysis of TNF alpha-sensitive L929 target cells could be blocked by specific neutralizing antibodies in a dose-dependent fashion. When administered intravenously into C57BL/6 mice bearing the syngeneic B16F10 murine melanoma cells, dual entrapment of liposomal IL1 alpha and TNF alpha significantly reduced the number of metastatic tumor nodules in the lungs and prolonged the life span of the animals. Thus, liposomal IL1 alpha and TNF alpha displayed significant in vivo antitumor activity against the IL1 alpha- and TNF alpha-resistant B16F10 metastatic murine melanoma.

Cellular interactions in marrow-grafted patients. III. Normal interleukin 1 and defective interleukin 2 production in short-term patients and in those with chronic graft-versus-host disease.

Peripheral blood mononuclear leukocytes (cells of marrow donor origin) from 89 patients were collected at various times after allogeneic marrow transplantation, stimulated in vitro by phytohemagglutinin, and assayed for the production of interleukin 2 (IL-2). This was done by testing culture supernatants for their ability to induce proliferation of human lymphoblasts and/or IL-2-dependent cultured murine cytotoxic cells. Supernatants from cultures of patient cells were compared with those of marrow donor cells. Supernatants produced by cells from most short-term marrow recipients (30-101 days postgrafting), regardless of the presence or absence of acute graft-versus-host disease (GVHD), and those from most long-term patients with chronic GVHD (103-1932 days postgrafting) had significantly lower-than-normal IL-2 activity, whereas cells from most long-term marrow recipients without GVHD (353-1934 days postgrafting) had essentially normal IL-2 activity. Additionally, we tested the ability of monocytes from 35 marrow recipients to produce interleukin 1 (IL-1) in response to lipopolysaccharide as compared with monocytes from marrow donors or normal unrelated individuals. IL-1 activity in culture supernatants of patient cells, regardless of the time of testing after marrow grafting and the status of GVHD, was found not to differ from that in supernatants of normal cells. These findings suggest that impaired T cell functions seen in some (but not all) marrow recipients are probably not due to IL-1 but to IL-2 deficiency or to the mechanism that causes IL-2 deficiency.