bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential production of MCP-1 and cytokine-induced neutrophil chemoattractant in the ischemic brain after transient focal ischemia in rats
Authors: Yamagami Shinsuke , Tamura Mizuho , Hayashi Minoru , Endo Noriaki , Tanabe Hirofumi , Katsuura Yasuhiro , Komoriya Keiji
Published: January 2018

Chemokines have been shown to play an important role in leukocyte infiltration into ischemic lesions. Recently, the increased expression of monocyte chemoattractant protein-1 (MCP-1) and cytokine-induced neutrophil chemoattractant (CINC) was observed in experimental stroke models where infiltrated leukocytes were supposed to induce tissue injury, however, the protein level and time course of these chemokines have not been fully elucidated. Therefore, we analyzed the time-dependent production of MCP-1 and CINC in the rat brain after transient middle cerebral artery occlusion (MCAO) by means of specific enzyme-linked immunosorbent assay systems. The MCP-1 levels in the ipsilateral hemispheres increased from 6 h, peaked at 2 days, and thereafter gradually decreased. The peak MCP-1 concentration was 89.2 ± 28.2 ng/g tissue wet weight (mean ± sem, n = 5, 49.3-fold greater than the contralateral value at the same time, P < 0.05), which is supposed to be high enough to exert its biological effects. In contrast, the maximum CINC concentration that corresponded to 2.9 ± 0.7 ng/g tissue wet weight (mean ± sem, n = 5, 55.0-fold greater than the contralateral value at the same time, P < 0.05), was observed at 6 h. In addition, we confirmed the temporal profile of leukocyte subtypes that infiltrated into the ischemic brain, thus, neutrophil infiltration occurred at early stages (1–3 days), followed by massive infiltration of macrophages at later stages (2–7 days). These studies suggest that MCP-1 in cerebral ischemia actually plays a significant role in the migration of macrophages into the lesion and that the differential temporal production of these chemokines contributes to the regulation of infiltrated leukocyte subtypes. J. Leukoc. Biol. 65: 744–749; 1999.
Blockade of nitric oxide formation down-regulates cyclooxygenase-2 and decreases PGE2 biosynthesis in macrophages
Authors: Perkins Douglas J , Kniss Douglas A
Published: January 2018

Elevated levels of nitric oxide (NO) produced by expression of inducible nitric oxide synthase (iNOS/NOS type 2) and high levels of prostaglandins (PGs) generated by expression of inducible cyclooxygenase (COX-2/PGH2 synthase-2) are important mediators of immune and inflammatory responses. Previous studies have shown that endogenous levels of NO˙ can influence the formation of PGs. We examined the mechanism by which NO˙ regulates PG biosynthesis in macrophages. Treatment of a murine macrophage cell line (ANA-1) with lipopolysaccharide (LPS, 10 ng/mL) and interferon-γ (IFN-γ, 10 U/mL) for 20 h elicited high levels of nitrite (NO2−) and prostaglandin E2 (PGE2) that were inhibited in a dose-dependent fashion by the NOS inhibitor, aminoguanidine (AG), with IC50 values of 15.06 and 0.38 μM for NO2− and PGE2, respectively. Stimulation of cultures with LPS and IFN-γ for 20 h induced de novo iNOS protein expression that was not altered by the addition of AG (0.1, 10, or 1000 γM). In contrast, treatment of cultures with LPS and IFN-γ for 20 h promoted COX-2 mRNA and protein expression that were decreased in a dose-dependent fashion by AG (P < 0.05 with 10 and 1000 μM). LPS and IFN-γ-induced COX-2 protein expression was not decreased in cultures treated with AG for 2 h, illustrating that AG does not inhibit the formation of COX-2 protein. Analysis of partially purified enzyme extracts demonstrated that AG did not directly inhibit the enzymatic activity of COX. Additional experiments revealed that NO^ donors (S-nitroso-N-aceytl-d-l-pencillamine, SNAP, at 0.1, 10, and 1000 μM) did not induce de novo COX-2 protein expression or potentiate COX-2 expression in cells treated with LPS and/or IFN-γ. Our results suggest that, while endogenous NO˙ is not required for de novo COX-2 mRNA and protein expression, NO˙ is necessary for maintaining prolonged COX-2 gene expression. J. Leukoc. Biol. 65: 792–799; 1999.
Inhibition of microglial cell RANTES production by IL-10 and TGF-β
Authors: Hu Shuxian , Chao Chun C , Ehrlich Laura C , Sheng Wen S , Sutton Richard L , Rockswold Gaylan L , Peterson Phillip K
Published: January 2018

Using human fetal microglial cell cultures, we found that the gram-negative bacterial cell wall component lipopolysaccharide (LPS) stimulated RANTES (regulated upon activation of normal T cell expressed and secreted) production through the protein kinase C signaling pathway and that activation of transcription nuclear factor (NF)-κB was required for this effect. Similarly, the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-α dose-dependently stimulated microglial cell RANTES production via NF-κB activation. Anti-inflammatory cytokines, IL-10, and transforming growth factor (TGF)-β sequentially inhibited LPS- and cytokine-induced microglial cell NF-κB activation, RANTES mRNA expression, and protein release. Proinflammatory cytokines but not LPS also stimulated RANTES production by human astrocytes. These findings demonstrate that human microglia synthesize RANTES in response to proinflammatory stimuli, and that the anti-inflammatory cytokines IL-10 and TGF-β down-regulate the production of this β-chemokine. These results may have important therapeutic implications for inflammatory diseases of the brain. J. Leukoc. Biol. 65: 815–821; 1999.
ICAM-3 (CD50) cross-linking augments signaling in CD3-activated peripheral human T lymphocytes
Authors: Berney Seth Mark , Schaan Tonya , Alexander J Steven , Peterman Gary , Hoffman Patricia A , Wolf Robert E , van der Heyde Henri , Atkinson T Prescott
Published: January 2018

ICAM-3 is a pan-hematopoietic, constitutive adhesion molecule. ICAM-3 binds to LFA-1 on antigen-presenting cells (APC) stabilizing the T cell-APC interaction, facilitating signaling through the CD3/TCR complex. However, recent evidence using cultured and transformed T cells suggests ICAM-3 may also function in signaling. Because ICAM-3 is constitutively expressed on resting T cells, we postulated that signaling through ICAM-3 in resting T cells represents an important costimulatory mechanism in these cells. In purified resting human T cells, cross-linking both ICAM-3 and CD3 with plate-bound antibodies resulted in a marked increase in cell size (consistent with blastogenesis), synergistically increased surface expression of CD25 and CD69, and increased T cell metabolism. Similarly, concomitant ICAM-3 and CD3 stimulation significantly (P < 0.001) increased resting human T cell phosphatidylinositol hydrolysis and phospholipase C-γ1 phosphorylation. These results indicate that ICAM-3 augments signaling through CD3, functioning as a costimulatory molecule for resting T cells in the initial activation step. J. Leukoc. Biol. 65: 867–874; 1999.
Corticosteroids inhibit the production of inflammatory mediators in immature monocyte-derived DC and induce the development of tolerogenic DC3
Authors: de Jong Esther C , Vieira Pedro L , Kalinski Pawel , Kapsenberg Martien L
Published: January 2018

Corticosteroids (CS) are potent immunosuppressive agents that are known to affect T cell-mediated inflammation by the inhibition of proliferation and cytokine production, as well as the immunostimulatory function of monocytes and macrophages. Not much is known of the effect of corticosteroids on dendritic cells (DC), the professional T cell stimulatory antigen-presenting cells. We report that the endogenous CS hydrocortisone and the synthetic CS clobetasol-17-propionate strongly inhibited the production of the inflammatory mediators interleukin (IL)-12 p70, tumor necrosis factor α (TNF-α), and IL-6 by lipopolysaccharide (LPS)-stimulated monocyte-derived immature DC (iDC) in vitro. In contrast, the stimulatory capacity, antigen uptake, and the expression of costimulatory molecules were not affected. In accordance with the decreased production of IL-12 p70, CS-treated iDC induced less production of the inflammatory Th1 cytokine interferon-γ and enhanced levels of the Th2 cytokines IL-10 and IL-5 in staphylococcal enterotoxin B-stimulated CD4+ Th cells. Furthermore, CS inhibited the maturation of iDC as assessed by the lack of expression of CD83 as well as by the prevention of the loss of antigen uptake capacities. These type 3 DC (DC3) matured in the presence of CS produce less IL-12 p70 and have a decreased T cell stimulatory capacity. Moreover, uncommitted T cells that encounter the CS-induced DC3 develop into Th2-biased cells, which may additionally decrease the Th1-mediated tissue damage but, on the other hand, Th2 cytokines may promote undesirable elevation of IgE and eosinophilia. These findings indicate that suppression of T cell-mediated inflammation by CS not only relies on direct effects on T cells, but also on various effects on DC, their professional antigen- presenting cells. J. Leukoc. Biol. 66: 201–204; 1999.
S100A8: emerging functions and regulation
Authors: Passey Robert J , Xu Ken , Hume David A , Geczy Carolyn L
Published: January 2018

The functional importance of members of the S100 Ca2+-binding protein family is becoming apparent. Murine (m)S100A8 (initially named CP-10) is a potent chemoattractant (10−13 to 10−11 M) for myeloid cells and the chemotactic activity of other S100s has since been reported, suggesting a new class of chemoattractants. Murine S100A8 has been associated with a number of acute and chronic inflammatory conditions including bacterial infection, atherogenesis, and cystic fibrosis. It is expressed constitutively with S100A9 in neutrophils and is regulated by inflammatory stimulants in macrophages and microvascular endothelial cells. The lack of co-expression of S100A9 with S100A8 in activated macrophages suggests distinct functions for the proteins expressed by different cell types. Glucocorticoids up-regulate induction of mS100A8 by inflammatory mediators, and its exquisite sensitivity to oxidation suggests that it may protect against oxidative tissue damage. Inactivation of the mS100A8 gene is embryonic lethal, providing the first evidence for non-redundant function of a member of the S100 gene family. S100A8 may have an immunoregulatory role by contributing to the regulation of fetal-maternal interactions. It may play a protective role and its absence may allow infiltration by maternal cells, a process eventually manifesting as resorption. This review focuses on the variety of emerging functions attributed to murine S100A8, a protein implicated in embryogenesis, growth, differentiation, and immune and inflammatory processes. J. Leukoc. Biol. 66: 549–556; 1999.
The amyloid precursor protein of Alzheimer disease in human brain and blood
Authors: Li Qiao-Xin , Fuller Stephanie J , Beyreuther Konrad , Masters Colin L
Published: January 2018

Studies of the metabolism and function of the amyloid precursor protein (APP) and its proteolytic fragment Aβ in cultured cells, transgenic mice, and post-mortem brain tissue have advanced our understanding of Alzheimer disease (AD). However, the molecular pathogenesis of the disease is still not clear, and we are a long way from finding a cure for the disease. Studies carried out on human platelets and leukocytes have also helped shed light on APP and Aβ metabolism and function. Platelet and leukocyte APP isoforms are processed using mechanisms similar to those in neuronal cells to generate Aβ and soluble forms of APP. The activation of platelets and leukocytes leads to the secretion of APP and Aβ, resulting in higher levels of these proteins in serum. APP and Aβ in the circulation may be involved in the regulation of platelet function and in the modulation of immune responses. Because human platelets and lymphocytes produce all forms of APP and secrete amyloidogenic Aβ peptides, these tissues may be useful in monitoring responses to therapeutic interventions directed at APP metabolism. Although not of neuronal origin, further studies on the more accessible ex vivo tissues, including platelets and leukocytes and other blood components, may reveal potential peripheral markers for AD and will further our understanding of the molecular pathogenesis of AD. J. Leukoc. Biol. 66: 567–574; 1999.
Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction
Authors: Alexander Warren S , Starr Robyn , Metcalf Donald , Nicholson Sandra E , Farley Alison , Elefanty Andrew G , Brysha Marta , Kile Benjamin T , Richardson Rachel , Baca Manuel , Zhang Jian-Guo , Willson Tracy A , Viney Elizabeth M , Sprigg Naomi S , Rakar Steven , Corbin Jason , Mifsud Sandra , DiRago Ladina , Cary Dale , Nicola Nicos A , Hilton Douglas J
Published: January 2018

SOCS-1 was originally identified as an inhibitor of interleukin-6 signal transduction and is a member of a family of proteins (SOCS-1 to SOCS-7 and CIS) that contain an SH2 domain and a conserved carboxyl-terminal SOCS box motif. Mutation studies have established that critical contributions from both the amino-terminal and SH2 domains are essential for SOCS-1 and SOCS-3 to inhibit cytokine signaling. Inhibition of cytokine-dependent activation of STAT3 occurred in cells expressing either SOCS-1 or SOCS-3, but unlike SOCS-1, SOCS-3 did not directly interact with or inhibit the activity of JAK kinases. Although the conserved SOCS box motif appeared to be dispensable for SOCS-1 and SOCS-3 action when over-expressed, this domain interacts with elongin proteins and may be important in regulating protein turnover. In gene knockout studies, SOCS-1−/− mice were born but failed to thrive and died within 3 weeks of age with fatty degeneration of the liver and hemopoietic infiltration of several organs. The thymus in SOCS-1−/− mice was small, the animals were lymphopenic, and deficiencies in B lymphocytes were evident within hemopoietic organs. We propose that the absence of SOCS-1 in these mice prevents lymphocytes and liver cells from appropriately controlling signals from cytokines with cytotoxic side effects. J. Leukoc. Biol. 66: 588–592; 1999.
α9β1 Integrin is expressed on human neutrophils and contributes to neutrophil migration through human lung and synovial fibroblast barriers
Authors: Shang Terry , Yednock Ted , Issekutz Andrew C
Published: January 2018

Accumulation of leukocytes in inflamed tissue involves their migration through vascular endothelium and then in the connective tissue. Recently we utilized a barrier of human synovial, dermal, and lung fibroblasts (HSF, HDF, and HLF) grown on polycarbonate filters as a model of human polymorphonuclear leukocyte (PMN) migration through connective tissue. The β2 integrins (CD11/CD18) and α4, α5, and α6β1 (VLA-4, -5, and -6) integrins each contributed to this PMN migration. Here we report that on human blood leukocytes, α9β1 (VLA-9) is expressed only on PMNs and that it is up-regulated after PMN activation. Based on monoclonal antibody (mAb) blocking studies, α9β1 integrin contributed to C5a-induced PMN migration through fibroblast (HLF and HSF) barriers. This role was apparent only when alternate mechanisms such as CD18, α4, α5, and α6β1 integrins were blocked and then mAb to α9β1 integrin inhibited the residual PMN migration (by 40–50%) through the HLF or HSF barrier, resulting in ≥75% inhibition overall. In contrast, PMN migration across interleukin-1-activated endothelium (HUVEC) in response to a C5a gradient, which is partly (30–40%) via CD11/CD18-independent mechanisms, was not inhibited by adhesion blocking by mAbs to α4, α5, α6, and α9β1 even in combination. These results indicate that α9β1 integrin on PMN may have a special role, in conjunction with other β1 integrins, in mediating PMN migration in the extravascular space, and may contribute to differential neutrophil function within tissues. J. Leukoc. Biol. 66: 809–816; 1999.
Transforming growth factor β from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes
Authors: Cook Gordon , Campbell John D M , Carr Christine E , Boyd Kelly S , Franklin Ian M
Published: January 2018

Multiple myeloma (MM) is a cancer of plasma cells, characterized by profound suppression of host immune responses. Here we show that MM cell lines significantly suppress the proliferation, blasting, response to interleukin-2 (IL-2), and expression of CD25 by concanavalin A (Con A)-activated or allostimulated peripheral blood T lymphocytes. T cells arrest in the G1 stage of the cell cycle, and do not enter the IL-2 autocrine growth pathway. T cell inhibition was mediated by a soluble factor. MM cell lines did not produce IL-10 but did produce large amounts of transforming growth factor β1 (TGF-β1). T cells were assessed for their ability to respond to IL-2 when co-cultured with MM cells in the presence or absence of the TGF-β inhibitor, TGF-β latency-associated peptide (LAP). MM cells suppressed IL-2 responses but this inhibition was completely reversed by TGF-β LAP. A CD25−, IL-2-dependent blast cell line was not inhibited by MM cells or rhTGF-β, confirming the specificity of the inhibition mechanism for the IL-2 autocrine growth pathway. We conclude that MM cells suppress T cells in their entry into the autocrine IL-2/CD25 pathway and in response to IL-2, and that TGF-β has a significant role to play. J. Leukoc. Biol. 66: 981–988; 1999.
c-Kit and c-kit mutations in mastocytosis and other hematological diseases
Authors: Boissan Mathieu , Feger Frédéric , Guillosson Jean-Jacques , Arock Michel
Published: January 2018

Mast cells (MC) are tissue elements derived from hematopoietic stem cells. Their differentiation and proliferation processes are under the influence of cytokines, including one of utmost importance known as stem cell factor (SCF). SCF receptor is encoded by the protooncogene c-kit, belongs to the type III receptor tyrosine kinase subfamily, and is also expressed on other hematopoietic or non-hematopoietic cells. Ligation of c-kit receptor by SCF induces its dimerization, followed by induction of multiple intracellular signaling pathways leading to cell proliferation and activation. Mastocytosis, a relatively rare group of diseases characterized by accumulation of MC in various tissues, are found isolated or sometimes associated with other hematological malignancies in humans. Although the initial events leading to mastocytosis are not yet unraveled, alterations of the c-kit gene have been described. Particularly interesting are acquired mutations resulting in a constitutively activated receptor, possibly involved in the increased numbers of MC in tissues. For this reason, future strategies might be envisaged to target specifically the mutated c-kit and/or its intracellular signaling. J. Leukoc. Biol. 67: 135–148; 2000.
Differential role of tyrosine phosphorylation in adhesion-induced transcription, mRNA stability, and cytoskeletal organization in human monocytes
Authors: Mondal Krishna , Sirenko Oksana I , Lofquist Alan K , Morris John S , Haskill J Stephen , Watson Joanna M
Published: January 2018

Monocyte adhesion resulted in rapid tyrosine phosphorylation and subsequent cytokine mRNA induction. The objective of this study was to determine the role of specific tyrosine phosphorylation events, particularly those involving members of the MAP kinase family, in regulating adhesion-induced cytokine expression. Using nuclear run-on analyses, we demonstrated that on adhesion, monocytes rapidly transcriptionally activated numerous cytokine mRNAs, coincident with the activation of the transcription factors NF-κB and AP-1. Both an inhibitor of tyrosine phosphorylation, genistein, and the cytoplasmic tyrosine phosphatase PTP1B, were unable to prevent adhesion-mediated transcriptional activation. However, both blocked adhesion-induced ERK and JNK but not p38 kinase activation and at the same time decreased the stability of interleukin-1β (IL-1β) and IL-8 transcripts. In addition, whereas adhesive events occurred in the presence of genistein and PTP1B, monocyte spreading was markedly inhibited. Our results suggest that the majority of protein phosphorylation events are associated with adhesion-induced cytokine expression through transcript stabilization and cytoskeletal organization. A minority of protein phosphorylation events, not sensitive to genistein or PTP1B exposure, may be instrumental in regulating transcription. Thus the spectrum of protein tyrosine kinases required for transcription appear distinct from those involved in maintaining the stability of some cytokine mRNAs and the integrity of the cytoskeleton to which mRNA destined for translation must be associated. J. Leukoc. Biol. 67: 216–225; 2000.
Regulatory roles for FcγRIII (CD16) and FcγRII (CD32) in the development of T- and B-lineage lymphoid cells
Authors: Lynch Richard G
Published: January 2018

IgG Fc receptors (FcγR) occur on all hematopoietic lineages and participate in a diversity of functions that reflect the combined effects of the molecular heterogeneity of FcγR and the inherent specialization of the FcγR  +  cells. An extensive literature describes the functions of FcγR on mature myeloid and lymphoid cells in humans and mice but little has been published about FcγR on lineage progenitor cells. Several studies suggest that FcγR can influence leukocyte development and that FcγRII (CD32) and FcγRIII (CD16) can regulate murine T- and B-lineage development at stages before the expression of clonal antigen receptors. The nominal ligand of FcγR is IgG and the physiologically relevant ligand is the IgG-antigen complex, but it is also known that alternative, non-Ig ligands exist for Fc receptors. A role for FcγR in the regulation of leukocyte development has potential relevance for clinical situations in which the levels of nominal and/or alternative ligands of FcγR are elevated, or the production of soluble forms of FcγR is increased. J. Leukoc. Biol. 67: 279–284; 2000.
Increased expression of the tetraspanins CD53 and CD63 on apoptotic human neutrophils
Authors: Beinert Thomas , Münzing Silvia , Possinger K , Krombach Fritz
Published: January 2018

The recently discovered tetraspanin superfamily comprises a group of cell-surface proteins that are suggested to be involved in cell activation and signal transduction as well as in cell adhesion, motility, and metastasis. In this study, we have assessed the expression of two tetraspanins, CD53 and CD63, and two principal leukocyte adhesion molecules, CD11b and CD62L, on human apoptotic neutrophils. After aging of human neutrophils for 20 and 40 h in vitro, apoptosis was analyzed by light microscopy and flow cytometry. The binding of monoclonal antibodies directed against CD11b, CD62L, CD53, and CD63 on apoptotic and nonapoptotic cells was determined by dual-color flow cytometry. Aging of neutrophils in vitro resulted in a significant (P < 0.05) down-regulation of expression of the selectin CD62L, and a significantly increased expression of the two tetraspanins CD53 and CD63. The selective analysis of apoptotic versus nonapoptotic cells proved that both the increased expression of the tetraspanins and the loss of CD62L were restricted to the apoptotic subpopulation. An identical pattern of surface molecule expression was detected at 12 h after induction of apoptosis by an agonistic anti-Fas IgM monoclonal antibody. Further studies are required to clarify whether tetraspanins participate in the recognition of apoptotic circulating or extrava-sated neutrophils by macrophages. J. Leukoc. Biol. 67: 369–373; 2000.
Receptor reserve analysis of the human CCR3 receptor in eosinophils and CCR3-transfected cells
Authors: Umland Shelby P , Wan Yuntao , Shortall Jennifer , Shah Himanshu , Jakway James , Garlisi Charles G , Tian Fang , Egan Robert W , Billah M Motasim
Published: January 2018

A novel pharmacological study of CCR3 receptor reserve in a CCR3-transfected cell (CREM3) and human eosinophils was done; functional responses measured were increases in intracellular calcium and chemotaxis. Eotaxin, eotaxin-2, monocyte chemoattractant protein-4 (MCP-4), RANTES, and MCP-3 induced similar maximal eosinophil chemotaxis, whereas MCP-3 and RANTES induced submaximal calcium responses in eosinophils compared to eotaxin, MCP-4, and eotaxin-2. This suggested a receptor reserve in the chemotaxis response. Receptor reserve was quantitated for eotaxin. Occupancy of all CCR3 receptors was required for a maximal calcium response in both CREM3 and eosinophils (reserve = 1.0 or 0.17, respectively); the stimulus-calcium response relationship was linear, indicating no receptor reserve. In contrast, in eosinophils a large receptor reserve (6.5) was found for chemotaxis, where occupancy of 15% receptors drove half-maximal responses. These studies indicate that CCR3 interacts with G-proteins that are poorly coupled to the calcium response, whereas coupling efficiency and/or amplification to the chemotaxis apparatus in human eosinophils is significantly greater. J. Leukoc. Biol. 67: 441–447; 2000.
Does innate immune privilege exist?
Authors: Streilein J Wayne , Stein-Streilein Joan
Published: January 2018

Immune privilege in the eye is believed to originate from the eye's need to avoid the sight-destroying consequences of inflammation. Over the past 25 years, many of the anatomical, cellular, and molecular mechanisms by which the eye avoids inflammation secondary to adaptive immune responses have been elucidated. In the recent past, it has become increasingly clear that innate immune responses play a critical role in activating the adaptive immune response. Moreover, innate immunity itself carries a heavy burden of inflammation, thereby posing a threat to vision if it should occur intraocularly. Ocular immunologists have now begun to inquire into the extent to which the eye regulates the expression of innate immunity in oculi. Evidence is presented which indicates that factors found in normal aqueous humor (1) prevent NK cells from lysing their targets, (2) inhibit neutrophil activation by CD95 ligand, (3) suppress nitric oxide production by activated macrophages, and (4) interfere with complement activation via the alternative pathway. These factors include transforming growth factor-β2, α-melanocyte-stimulating hormone, calcitonin gene-related peptide, and migration inhibitory factor. The ability of the eye to prevent intraocular activation of innate immune effectors spares the corneal endothelium (which expresses CD95 ligand constitutively, but low levels of MHC class I molecules) from destruction by NK cells and neutrophils, and protects the visual axis from distortion by macrophage and complement-mediated inflammation. Thus, privilege exists in the eye for both adaptive and innate immunity. J. Leukoc. Biol. 67: 479–487; 2000.
Neutrophil chemotaxis in moving gradients of fMLP
Authors: Ebrahimzadeh P R , Högfors C , Braide M
Published: January 2018

In this study the fluid gradient chamber, a modified version of the Boyden chamber that enables mobile gradients, was used to study the migration of human granulocytes in gradients of fMLP. Temporal chemotactic gradients were created by moving density-stabilized spatial gradients at different velocities in relation to migrating cells. Random and directed cell migration was quantified by applying a theoretical population distribution model to experimental cell distributions obtained from cell counts at different depths in the filters. Rates of random and directed migration generally increased with gradient velocity. At negative gradient velocities, i.e., when the gradients were moved in a direction opposite to that of cell migration to decrease fMLP concentration over time, random and directed migration was inhibited. At positive gradient velocities, migration rates were not significantly different from those seen in immobile gradients. The fact that the rate of directed migration was smaller at negative gradient velocities indicates that negative temporal gradients reduced the average speed and/or orientation of the chemotactically migrating cells. In immobile gradients, the cells generated a small concentration increase over time when they migrated in the up-gradient direction. Consequently, a positive temporal gradient as perceived by the cells may act as a positive feedback signal to maintain chemotactic migration. J. Leukoc. Biol. 67: 651–661; 2000.
Role of mast cell leukotrienes in neutrophil recruitment and bacterial clearance in infectious peritonitis
Authors: Malaviya Ravi , Abraham Soman N
Published: January 2018

Stimulated mast cells release a variety of chemotactic factors such as tumor necrosis factor α (TNF-α) and leukotriene B4. Recent studies have shown that mast cell-derived TNF-α plays a critical role in host defense against Gram negative bacterial infections by the recruitment of neutrophils to the sites of infection. In the present study, we sought to investigate if mast cells release leukotriene (LT) B4 in response to bacteria and, if so, to establish its in vivo relevance. We show that mast cells release significant amounts of LTB4 and LTC4 in response to exposure to FimH-expressing type 1 fimbriated Escherichia coli in vitro. To test the functional significance of mast cell-derived LTs during an E. coli infection in vivo, we examined the effect of a LT-synthesis inhibitor, A-63162, on bacterial clearance and neutrophil influx in an infectious peritonitis model in mast cell-deficient mice (WBB6F1-W/WV) and their normal congenic control (WBB6F1-+/+) mice. Our results show that a treatment with A-63162 reduced neutrophil influx and bacterial clearance in the peritoneal cavities of mast cell-sufficient but not -deficient mice. Thus, mast cell-derived LTs contribute to host defense by mediating early neutrophil influx and bacterial clearance at sites of infection. J. Leukoc. Biol. 67:841–846; 2000.
Aspirin-induced increases in soluble IL-1 receptor type II concentrations in vitro and in vivo
Authors: McHugh Shannon L , Yamamoto Yoshimasa , Klein Thomas W , Friedman Herman
Published: January 2018

Virulent Legionella pneumophila replicate readily in thioglycollate-elicited peritoneal macrophages from genetically permissive A/J mice, but avirulent L. pneumophila do not. The production of cytokines by macrophages infected with L. pneumophila has been studied, but the correlation of bacterial virulence with immune responses of macrophages, such as proinflammatory cytokine production, is not well understood. In this regard, production of the cytokines tumor necrosis factor α (TNF-α), interleukin (IL)-1α, IL-1β, and IL-6 were examined in macrophage cultures infected in vitro with virulent vs. avirulent L. pneumophila. Infection of macrophages from A/J mice with the virulent L. pneumophila up-regulated mRNA expression for these cytokines, whereas avirulent bacteria resulted in only a slight or no detectable increase in cytokine mRNA. Similarly, virulent L. pneumophila induced the macrophages to produce relatively high levels of TNF-α, IL-1α, IL-1β, and IL-6 proteins as measured by enzyme-linked immunosorbent assays, whereas avirulent bacteria induced only low or often undetectable amounts of these cytokines. Thus, these results show the murine macrophages from susceptible A/J mice are readily infected with virulent L. pneumophila in vitro and stimulated to produce the proinflammatory acute-phase cytokines TNF-α, IL-1α, IL-1β, and IL-6, but avirulent L. pneumophila did not. Such differences in induction of these proinflammatory cytokines by macrophages in response to virulent vs. avirulent L. pneumophila infections may be an important factor in the pathogenesis induced by these intracellular bacteria. J. Leukoc. Biol. 67: 863–868; 2000.
Vermicomposting: A sustainable tool for environmental equilibria
Authors: Singh Archana , Singh Gopal Shankar
Published: January 2018

Improperly managed organic waste constitutes a serious environment threat across the globe. This has led to a worldwide struggle to strike a balance between the rapid generation of such wastes and protection of the environment. With the unique advantages of lower operational and maintenance costs compared with other waste management technologies, the use of vermicomposting to manage organic wastes has been increasing rapidly in recent years. Still, some factors (e.g., characteristics of substrate composition before and after treatment) are in need of additional, specific studies so that researchers can better understand the metabolism involved in the process. Vermicomposting provides employment opportunities as it protects the environment, augmenting crop productivity when it is used as a fertilizer supplement and helping to maintain ecological balance. Thus, vermicompost plays an important role in the circular economy. This article provides an overview of the research activities that have been conducted on the use of vermicomposts to remove pollutants from the soil, in wastewater treatment, and in organic waste recycling throughout the world. Circular economic assessment has revealed that vermicomposting technology is usually feasible except in certain cases. Most other methods of waste disposal lead to soil deterioration, toxic effects, and increased pollution affecting land, air, water, and living beings, in addition to the sometimes considerable expense of their implementation. Thus, an eco‐friendly method that removes waste in one step is needed. Determining the long‐term performance and sustainable operation of vermicomposting systems still poses a challenge, however, as treatment performance is affected by design parameters, operational conditions, and environmental factors. This article summarizes the factors influencing pollutant removal through the vermicomposting process. Finally, this article highlights additional research that should be conducted on these issues to improve the performance of vermicomposting.
Changing Forms of Corruption in India
Authors: GUPTA AKHIL
Published: January 2018

This article has four important goals. First, I want to ask why liberalization and market-friendly reforms failed to curb corruption in India. Indeed, confounding the predictions of most proponents of reform, corruption seems to have increased after the neoliberal reforms of 1991. Second, I aim to develop a typology in which the importance of particular sectors to corrupt practices is highlighted and explained. Third, I point out that India has failed to make the ‘transition’ historically seen in low-income countries as they develop. Nation-states have in the past moved from a system of vertical corruption—marked by the extraction of small sums from a large number of transactions with citizens in everyday life—to a system of horizontal corruption, in which governmental elites extract large sums in a small number of transactions from corporate and commercial bodies. Finally, I argue that anti-corruption movements cannot be understood without paying attention to the affective and emotional ties that bind citizens to the state. We have to take account of contradictory feelings about the state: cynicism about the state and popular anger against corruption on one side, and an attachment to popular sovereignty and patronage on the other. These contradictory sentiments will better enable us to understand the conjunctures that lead to effective institutional change.
OP30 Health Technology Assessment And The Decision-Making Process Of New Drug Listing In Hong Kong
Authors: Wong Carlos , Wu Olivia , Cheung Bernard
Published: January 2018

INTRODUCTION:

In Hong Kong, the Drug Advisory Committee (DAC) has had the role of evaluating and advising new drugs to be included in the listing of the Hospital Authority Drug Formulary since July 2005. The drug review process was subject to challenge due to a lack of transparency to members of the public and documentation of the scientific basis for decision making. The purpose of this review was to describe the process, evaluation criteria and possible outcomes of decision making for new drugs listed in the Hong Kong Hospital Authority Drug Formulary in comparison to Health Technology Assessment (HTA) policies in overseas countries.

METHODS:

Details of the decision-making processes including new drug listing submissions, the DAC meeting, procedures before and after the meeting, were extracted from the official Hong Kong Hospital Authority drug formulary management website and manual. Publicly available information related to new drug decision making processes for four HTA agencies (National Institute for Health and Clinical Excellence (NICE), Scottish Medicines Consortium (SMC), Australian Pharmaceutical Benefits Advisory Committee (PBAC), and Canadian Agency for Drugs and Technologies in Health (CADTH)) were reviewed and retrieved from official documents on their public domains.

RESULTS:

The DAC is in charge of the systematical and critical appraisal of new drugs for listing on the formulary, reviewing submitted applications, and making decisions of drug listing based on scientific evidence in which safety, efficacy and cost-effectiveness are primary considerations. When compared to other HTA agencies, transparency of decision-making processes of the DAC, relevance of clinical and health economic evidence, and lack of health economic and methodological input to submissions were major challenges of the new drug listing policy in Hong Kong.

CONCLUSIONS:

Despite the challenges identifed, this review provided suggestions for establishing a more transparent, credible, evidence-based decision-making process for the Hong Kong Hospital Authority Drug Formulary. Proposals for improvement in the listing of new drugs in the formulary should be a priority in healthcare reform.
OP131 Cost-Effectiveness Of Dexamethasone And Adalimumab For Uveitis
Authors: Bermejo Inigo , Squires Hazel , Poku Edith , Cooper Katy , Stevens John , Hamilton Jean , Wong Ruth
Published: January 2018

INTRODUCTION:

Uveitis is inflammation inside the eye whose underlying cause may be infectious or non-infectious. The objective of our study was to assess the cost-effectiveness of the dexamethasone implant and adalimumab compared with current practice (immunosuppressants and systemic corticosteroids) in patients with non-infectious intermediate, posterior or pan-uveitis.

METHODS:

A Markov model was built to estimate costs and benefits of the interventions. Systematic reviews were performed to identify the relevant evidence. Quality of life data collected in three key randomized-controlled trials (1-3) was used to estimate the interventions effectiveness compared with the trials comparator arms, which consisted of placebo plus limited current practice (LCP). An indirect treatment comparison between adalimumab and dexamethasone was considered inappropriate due to lack of necessary evidence. For adalimumab, patients with active and inactive uveitis were considered separately. Due to the short duration of the trials, the rate of blindness, an important complication of uveitis, was highly uncertain. Substantial exploratory analyses were therefore undertaken. The analysis was performed from the perspective of the National Health Service (NHS) and Personal Social Services (PSS). Costs were calculated based on standard United Kingdom sources.

RESULTS:

The estimated incremental cost-effectiveness (ICER) of dexamethasone compared with LCP was GBP19,509 per quality-adjusted life year (QALY) gained. The estimated ICER of adalimumab compared with LCP was GBP94,523 and GBP317,547 per QALY in patients with active and inactive uveitis respectively. The factors with the largest impact upon the ICERs were the rate of blindness and the proportion of cases of blindness avoided by interventions.

CONCLUSIONS:

Dexamethasone and adalimumab resulted in health gains, but at significant extra costs, especially adalimumab which is unlikely to be considered a cost-effective use of NHS resources. The results of the analysis are highly uncertain due to the limited availability of evidence on: the comparative effectiveness of dexamethasone, adalimumab and current practice; the effectiveness of treatments in avoiding blindness; and, the effectiveness of interventions in different subgroups.
PP013 Pain Management And Substance Abuse In Sickle Cell Disease Patients
Authors: Santos Mariana , Travi Diego , Ribeiro Camila , Pianca Thiago , Saccilotto Indara , Silla Lúcia , Picon Paulo
Published: January 2018

INTRODUCTION:

Drug abuse is a social and public health problem because of its negative consequences of emotional and physical development in individuals. There are few studies evaluating substance abuse by individuals with sickle cell disease (SCD). These patients have severe and recurrent pain crises (1), frequently needing opioids to control it (2). The compromised quality of life can predispose this population to the occurrence of non-psychotic disorders such as depression, making them vulnerable to substance abuse (3).

METHODS:

We evaluated the consumption of alcohol and drugs in a cohort followed at the Sickle Cell Disease Reference Center (CRAF), at Hospital de Clínicas de Porto Alegre, estimating the percentage of patients in treatment of SCD who abuse alcohol and drugs, mainly opioids. A cross-sectional study was of a convenience sample of 139 patients with SCD treated at CRAF. The pattern of substance use was evaluated using the Brazilian version of Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). The exposure to opioids was measured by their use and prescription in the 24 months before the interview. The Self-Reporting Questionnaire (SRQ-20) was used to estimate the occurrence of non-psychotic disorders in this population. Descriptive analyses were performed using absolute and relative frequencies. The association between the variables was verified using the chi-square test or Fisher's exact test.

RESULTS:

The prevalence of abusive use was 1.5 percent for alcohol and 3.0 percent for tobacco, with no abusive use of any other substance including opioids was identified. Of note was the pattern for substance use that was not influenced by exposure to substances or the presence of non-psychotic disorders.

CONCLUSIONS:

Our data shows that use of opioid analgesics for the management of SCD painful crises is safe and does not induce substance abuse. Regular follow-up of these patients is recommended. The results of this study might be useful in other countries.
PP037 Quality Criteria And Good Practices In The Health Technology Assessment Spanish Network
Authors: Márquez-Peláez Sergio , Navarro-Palenzuela Carmen , Molina-Lopez Teresa , del Mar Castellano-Zurera María , Castro-Campos José Luis
Published: January 2018

INTRODUCTION:

The Spanish Network of Agencies for Health Technology Assessment (REDETS) is a group of eight agencies, units and services, depending on National and Regional Governments that coordinate their work within a common methodological framework, guided by the principles of mutual recognition and cooperation. In this work, guided by the necessity of implementing a Quality Management System, we present the process to achieve this objective.

METHODS:

As an initial step, a review was carried out based on a structured search strategy in the main electronic databases Medline and EMBASE, and a manual search in websites of national and international agencies (March 2016) in order to collate previous knowledge and experiences. Through the information included in this review, a proposal to create a quality, self-evaluating tool is necessary.

RESULTS:

In total, 800 references were found and finally 6 studies were included in the review (1-3). All had a similar structure. Some lists of good practices, classified in dimensions related to different quality aspects in Health Technology Assessment (HTA) organizations, were found. Also some information about questions for evaluating quality standards was indicated. Taking all this information, a proposal of sixty-six standard titles was put forward. These standards were then grouped into twelve quality criteria structured in four dimensions: I Responsibility, II Clients and Stakeholders, III Production Process and IV Resources.

CONCLUSIONS:

Based on the systematic review, we developed a proposal for a self-evaluating tool and this is the baseline for a common Quality Management System for the Spanish Network of HTA Agencies. The quality management process will require the development of a handbook by each member of REDETS that will be based on agreed quality standards.
PP040 Hospitalization Costs In Schizophrenia: Long-acting Injectable Antipsychotics Versus Oral Antipsychotic Use
Authors: Greene Mallik , Chang Eunice , Hartry Ann , Broder Michael
Published: January 2018

INTRODUCTION:

Existing findings on effectiveness of long-acting injectable antipsychotics (LAIs) versus oral antipsychotics in preventing hospitalizations are inconclusive. This study was conducted to compare hospitalization costs between Medicaid patients diagnosed with schizophrenia who initiated a LAI and those who changed from one oral antipsychotic to another.

METHODS:

This retrospective cohort analysis used the Truven Health Analytics MarketScan® Medicaid claims database to study patients ≥18 years with schizophrenia. The two cohorts were: “LAI”, defined as initiating LAI (no prior LAI therapy) between 1 January 2013 and 30 June 2014; and “oral”, defined as changing from one oral antipsychotic to another during the same period. The first day of LAI or the new oral antipsychotic was the index date. A linear regression model was conducted to estimate hospitalization costs.

RESULTS:

The final sample included 2,861 (36.7 percent) LAI and 4,926 (63.3 percent) oral users. Compared to oral users, LAI patients were younger (mean (Standard Deviation, SD): 39.9 (13.2) versus 42.7 (13.1); p<.001) and had a lower mean Charlson Comorbidity Index score (mean (SD): 1.1 (1.9) versus 1.7 (2.3); p<.001). Of the 877 LAI initiators and 1,688 oral users who were hospitalized during the 1-year post-index follow-up period, the unadjusted mean hospitalization costs for LAI and oral users were USD32,626 and USD36,048, respectively. After adjusting for patient demographic and clinical characteristics, baseline medication use, and baseline ED or hospitalizations, the adjusted average hospitalization costs were USD1,170 lower in LAI initiators than oral users. None of the unadjusted or adjusted differences were statistically significant.

CONCLUSIONS:

This real-world study suggests that among hospitalized patients, hospitalization costs are lower in LAI initiators than in oral antipsychotic users, although the difference is not statistically significant. Our study is limited as our results are reflective of a multi-state Medicaid population. Future studies are warranted to confirm the results in non-Medicaid patient populations.