Identification of Racial Inequities in Access to Specialized Inpatient Heart Failure Care at an Academic Medical Center.

Background: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race.

Secretion of the Phosphorylated Form of S100A9 from Neutrophils Is Essential for the Proinflammatory Functions of Extracellular S100A8/A9.

S100A8 and S100A9 are members of the S100 family of cytoplasmic EF-hand Ca-binding proteins and are abundantly expressed in the cytosol of neutrophils. In addition to their intracellular roles, S100A8/A9 can be secreted in the extracellular environment and are considered as alarmins able to amplify the inflammatory response. The intracellular activity of S100A8/A9 was shown to be regulated by S100A9 phosphorylation, but the importance of this phosphorylation on the extracellular activity of S100A8/A9 has not yet been extensively studied.

Regulation of Neutrophil Degranulation and Cytokine Secretion: A Novel Model Approach Based on Linear Fitting.

Neutrophils participate in the maintenance of host integrity by releasing various cytotoxic proteins during degranulation. Due to recent advances, a major role has been attributed to neutrophil-derived cytokine secretion in the initiation, exacerbation, and resolution of inflammatory responses. Because the release of neutrophil-derived products orchestrates the action of other immune cells at the infection site and, thus, can contribute to the development of chronic inflammatory diseases, we aimed to investigate in more detail the spatiotemporal regulation of neutrophil-mediated release mechanisms of proinflammatory mediators.

An essential role of syntaxin 3 protein for granule exocytosis and secretion of IL-1α, IL-1β, IL-12b, and CCL4 from differentiated HL-60 cells.

Besides their roles in the killing of pathogens, neutrophils have the capacity to package a variety of cytokines into cytoplasmic granules for subsequent release upon inflammatory conditions. Because the rapid secretion of cytokines orchestrates the action of other immune cells at the infection site and thus, can contribute to the development and chronicity of inflammatory diseases, we aimed to determine the intracellular SNARE machinery responsible for the regulation of cytokine secretion and degranulation. From a constructed gene-expression network, we first selected relevant cytokines for functional validation by the CBA approach.

Factors influencing the use of intensive procedures at the end of life.

Objectives: To examine individual and regional factors associated with the use of intensive medical procedures in the last 6 months of life.

Design: Retrospective cohort study.

Setting: The Health and Retirement Study (HRS), a longitudinal nationally representative cohort of older adults.

The recruitment of p47(phox) and Rac2G12V at the phagosome is transient and phosphatidylserine dependent.

Background Information: During phagocytosis, neutrophils internalise pathogens in a phagosome and produce reactive oxygen species (ROS) by the NADPH oxidase to kill the pathogen. The cytosolic NADPH oxidase subunits p40(phox), p47(phox), p67(phox) and Rac2 translocate to the phagosomal membrane to participate in enzyme activation. The kinetics of this recruitment and the underlying signalling pathways are only partially understood.

Gravity changes during animal development affect IgM heavy-chain transcription and probably lymphopoiesis.

Our previous research demonstrated that spaceflight conditions affect antibody production in response to an antigenic stimulation in adult amphibians. Here, we investigated whether antibody synthesis is affected when animal development occurs onboard a space station. To answer this question, embryos of the Iberian ribbed newt, Pleurodeles waltl, were sent to the International Space Station (ISS) before the initiation of immunoglobulin heavy-chain expression.

New insights into the regulation of neutrophil NADPH oxidase activity in the phagosome: a focus on the role of lipid and Ca(2+) signaling.

Significance: Reactive oxygen species, produced by the phagosomal NADPH oxidase of neutrophils, play a significant physiological role during normal defense. Their role is not only to kill invading pathogens, but also to act as modulators of global physiological functions of phagosomes. Given the importance of NADPH oxidase in the immune system, its activity has to be decisively controlled by distinctive mechanisms to ensure appropriate regulation at the phagosome.

Stress response and humoral immune system alterations related to chronic hypergravity in mice.

Spaceflights are known to induce stress and immune dysregulation. Centrifugation, as hindlimb unloading, is a good ground based-model to simulate altered gravity which occurs during space missions. The aim of this study was to investigate the consequences of a long-term exposure to different levels of hypergravity on the stress response and the humoral immunity in a mouse model.

An essential role of STIM1, Orai1, and S100A8-A9 proteins for Ca2+ signaling and FcγR-mediated phagosomal oxidative activity.

Phagocytosis is a process of innate immunity that allows for the enclosure of pathogens within the phagosome and their subsequent destruction through the production of reactive oxygen species (ROS). Although these processes have been associated with increases of intracellular Ca(2+) concentrations, the mechanisms by which Ca(2+) could regulate the different phases of phagocytosis remain unknown. The aim of this study was to investigate the Ca(2+) signaling pathways involved in the regulation of FcγRs-induced phagocytosis.

Sphingosine kinases regulate NOX2 activity via p38 MAPK-dependent translocation of S100A8/A9.

Neutrophils play a fundamental role in host defense by neutralizing pathogens through the generation of ROS by NOX2. In nonexcitable cells, Ca(2+) influx is essentially mediated via SOCE, a complex mechanism in which depletion of intracellular Ca(2+) stores from the ER results in Ca(2+) entry through Ca(2+) SOCs at the plasma membrane. In this regard, it is well established that extracellular Ca(2+) entry participates to NOX2 activation.

iPLA2, a novel determinant in Ca2+- and phosphorylation-dependent S100A8/A9 regulated NOX2 activity.

The neutrophil NADPH oxidase (NOX2) is a key enzyme responsible for host defense against invading pathogens, via the production of reactive oxygen species. Dysfunction of NOX2 can contribute to inflammatory processes, which could lead to the development of diseases such as atherosclerosis. In this paper, we characterize a pathway leading to NOX2 activation in which iPLA(2)-regulated p38 MAPK activity is a key regulator of S100A8/A9 translocation via S100A9 phosphorylation.

Could spaceflight-associated immune system weakening preclude the expansion of human presence beyond Earth's orbit?

This year, we celebrate the 40th birthday of the first landing of humans on the moon. By 2020, astronauts should return to the lunar surface and establish an outpost there that will provide a technical basis for future manned missions to Mars. This paper summarizes major constraints associated with a trip to Mars, presents immunological hazards associated with this type of mission, and shows that our current understanding of the immunosuppressive effects of spaceflight is limited.

STIM1 but not STIM2 is an essential regulator of Ca2+ influx-mediated NADPH oxidase activity in neutrophil-like HL-60 cells.

Extracellular Ca2+ entry, primarily mediated through store-operated Ca2+ entry (SOCE), is known to be a critical event for NADPH oxidase (NOX2) regulation in neutrophils. While defective NOX2 activity has been linked to various inflammatory diseases, regulatory mechanisms that control Ca2+ influx-induced NOX2 activation are poorly understood in SOCE. The role of STIM1, a Ca2+ sensor that transduces the store depletion signal to the plasma membrane, seems well established and supported by numerous studies in non-phagocytic cells.

Spaceflight-associated changes in immunoglobulin VH gene expression in the amphibian Pleurodeles waltl.

Understanding why the immune system is depressed during spaceflight is of obvious importance for future human deep-space missions, such as the foreseen missions to Mars. However, little is known about the effects of these flights on humoral immunity. We previously immunized adult Pleurodeles waltl (urodele amphibian) onboard the Mir space station and showed that heavy-chain variable (VH) domains of specific IgM antibodies are encoded by genes belonging to the VHII and VHVI families.

OAG induces an additional PKC-, PI3K-, and Rac2-mediated signaling pathway up-regulating NOX2 activity, independently of Ca2+ entry.

The requirement of calcium ion (Ca(2)(+)) entry for neutrophil NADPH oxidase (NOX2) regulation is clearly established. However, its role in the signaling pathway leading to NOX2 activation is still elusive. 1-oleoyl-2-acetyl-sn-glycerol (OAG) causes an increase in NOX2 activity and has been shown to directly modulate Ca(2)(+) channels unrelated to the well-known store-operated Ca(2)(+) entry (SOCE) mechanism.

The Use of In Vitro Systems for Evaluating Immunotoxicity: The Report and Recommendations of an ECVAM Workshop.

This is the report of a workshop organised by the European Centre for the Validation of Alternative Methods (ECVAM). ECVAM's main goal, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods that are of importance to the biosciences and which replace, reduce or refine the use of laboratory animals. One of the first priorities set by ECVAM was the implementation of procedures that would enable it to become well informed about the state-of-the-art of non-animal test development and validation, and the potential for the possible incorporation of alternative tests into regulatory procedures.

Co-cultures of human coronary smooth muscle cells and dimethyl sulfoxide-differentiated HL60 cells upregulate ProMMP9 activity and promote mobility-modulation by reactive oxygen species.

Vascular cells and leukocytes, involved in the development of atherosclerosis, produce cytokines and/or reactive oxygen species (ROS) and matrix metalloproteinases (MMPs) implicated in cell mobility. We investigated by co-culture experiments the effects of human coronary smooth muscle cells (HCSMC) on MMPs characteristics and mobility of neutrophil-like dimethyl sulfoxide-differentiated HL60 cells (not equal HL60). The effects of superoxide dismutase (SOD) and catalase were also analyzed.

Regulation of superoxide production in neutrophils: role of calcium influx.

Upon stimulation, activation of NADPH oxidase complexes in neutrophils produces a burst of superoxide anions contributing to oxidative stress and the development of inflammatory process. Store-operated calcium entry (SOCE), whereby the depletion of intracellular stores induces extracellular calcium influx, is known to be a crucial element of NADPH oxidase regulation. However, the mechanistic basis mediating SOCE is still only partially understood, as is the signal-coupling pathway leading to modulation of store-operated channels.

Store-operated Ca2+ channels formed by TRPC1, TRPC6 and Orai1 and non-store-operated channels formed by TRPC3 are involved in the regulation of NADPH oxidase in HL-60 granulocytes.

Ca(2+) influx has been shown to be essential for NADPH oxidase activity which is involved in the inflammatory process. Ca(2+) conditions underlying the oxidative response are clearly delineated. Here, we show that store-operated Ca(2+) entry (SOCE) is required at the beginning of NADPH oxidase activation in response to fMLF (N-formyl-L-methionyl-L-leucyl-L-phenylalanine) in neutrophil-like HL-60 cells.

Rosuvastatin treatment protects against nitrate-induced oxidative stress in eNOS knockout mice: implication of the NAD(P)H oxidase pathway.

Nitrate tolerance is associated with an enhanced superoxide anion (O(2)(-)) production and may be attenuated by statins as they interact with the two main endothelial NO synthase (eNOS) and NAD(P)H oxidase pathways involved in this oxidative stress. Groups of wild-type (wt, C57Bl/6J) and eNOS knock-out mice (eNOS(-/-)) received rosuvastatin (20 mg kg(-1) day(-1) p.o.

Modulation by cADPr of Ca2+ mobilization and oxidative response in dimethylsulfoxide- or retinoic acid-differentiated HL-60 cells.

In human phagocytic cells, reactive oxygen species (ROS) generation in response to N-formyl-L-Methionyl-L-Leucyl-L-Phenylalanine (fMLF) is largely dependent on cytosolic free calcium concentration ([Ca2+]i). Cyclic ADP-ribose (cADPr) is able to regulate Ca2+ release from intracellular stores through the ryanodine receptor but its potential role in biological responses has so far not been determined. In this study, we examined whether extracellular and intracellular cADPr is required in fMLF-induced [Ca2+]i rise and consequently in the oxidative response in human neutrophil-like HL-60 cells differentiated with dimethylsulfoxide or all-trans-retinoic acid (ATRA).

Oxidative stress activates MMP-2 in cultured human coronary smooth muscle cells.

Oxidative stress is a cardinal feature of the inflammatory process and is involved in various pathologies including atherosclerosis. One of the important mechanisms in which oxidative stress may play a role is activation of matrix metalloproteinases such as MMP-2, which are involved in plaque destabilization. We investigated the mechanisms by which oxidative stress induces MMP-2 activation in cultured human coronary artery smooth muscle cells.

Interleukin-8 primes oxidative burst in neutrophil-like HL-60 through changes in cytosolic calcium.

In response to a variety of stimuli, neutrophils release large amount of reactive oxygen species (ROS) generated by NADPH oxidase. This process known as the respiratory burst is dependent on cytosolic free calcium concentration ([Ca(2+)](i)). Proinflammatory cytokines such as interleukin-8 (IL-8) may modulate ROS generation through a priming phenomenon.

Human umbilical cord blood monocyte-derived eosinophils produce superoxide but not nitric oxide.

Objective: To investigate whether in vitro derived eosinophils release nitric oxide (NO), whose role in the pathogenesis of asthma is under intense debate.

Materials And Methods: Human umbilical cord mononuclear cells were isolated from umbilical cord blood cells and cultured in vitro in presence of interleukin-3 and interleukin-5. Superoxide generation was monitored with dihydrorhodamine-123, NO release was estimated by measuring the accumulation of nitrite.