bluuebunny/crossref_metadata_2025 huggingface dataset:
fMLP-induced in vitro nitric oxide production and its regulation in murine peritoneal macrophages
Authors: Sodhi Ajit , Biswas Subhra K
Published: September 2022

Bacterial N-formyl peptides such asN-formyl-methionyl-leucyl-phenylalanine (fMLP) are important mediators of monocyte/macrophage recruitment and activation at the sites of inflammation. In the current study, the role of nitric oxide (NO) in the activation of murine peritoneal macrophages to tumoricidal state in response to in vitro fMLP treatment has been investigated. Murine peritoneal macrophages on treatment with fMLP showed a dose- and time-dependent production of NO together with increased tumoricidal activity against P815 mastocytoma cells. L-NMMA, a specific inhibitor of L-arginine pathway, inhibited the fMLP-induced NO secretion and macrophage-mediated tumoricidal activity against P815 cells. These results indicate the L-arginine-dependent production of NO to be one of the effector mechanisms contributing to the tumoricidal activity of fMLP-treated macrophages. The expression of iNOS protein and iNOS mRNA is also observed. The pharmacological inhibitors genistein, wortmannin, H7, PD98059, TPCK, and pertussis toxin (PTX) blocked the fMLP-induced NO production, suggesting the involvement of tyrosine kinases, PI3K, PKC, p42/44 MAPkinase, NF-κB, and G-proteins. The expression of phospho-p42/44 MAPK and phospho-IκB was also observed. The role of protein phosphatases in the above pathway has been suggested using the specific inhibitors of these phosphatases, i.e., okadaic acid and sodium orthovanadate.
Cyclosporin A inhibition of macrophage colony-stimulating factor (M-CSF) production by activated human T lymphocytes
Authors: Frétier Stéphanie , Besse Arnaud , Delwail Adriana , Garcia Martine , Morel Franck , Leprivey-Lorgeot Valérie , Wijdenes John , Praloran Vincent , Lecron Jean-Claude
Published: September 2022

M-CSF is a pleiotropic cytokine involved in the survival, proliferation, and differentiation of cells of the monocyte/macrophagelineage. M-CSF is produced by numerous cells including CD3-activated Tcells. M-CSF serum levels are increased during acute graft rejection. We tested the in vitro production of M-CSF, GM-CSF, IL-2, and IL-4 byT-cell clones costimulated by CD3 and accessory activation pathways and the effects of cyclosporin A and methylprednisolone. The nine clonesstudied and CD4+ cells purified from peripheral bloodmononuclear cells (PBMC) spontaneously produced low levels of M-CSF, which PMA and CD3 mAb strongly enhanced. In contrast to IL-2, CD28 mAbdid not further enhance this production. CsA inhibited M-CSF productionby clones and purified CD4 T cells. Addition of IL-2, anti IL-2, oranti CD25 mAb to the cultures demonstrated that CsA down-regulatedM-CSF synthesis by activated T cells through its inhibition of IL-2synthesis. These results could help to better understand the complexmechanisms of acute graft rejection and immunosuppression.
Cytokine-mediated regulation of CXCR4 expression in human neutrophils
Authors: Nagase Hiroyuki , Miyamasu Misato , Yamaguchi Masao , Imanishi Masako , Tsuno Nelson H , Matsushima Kouji , Yamamoto Kazuhiko , Morita Yutaka , Hirai Koichi
Published: September 2022

Several lines of evidence have suggested that a CXC chemokine receptor 4 (CXCR4)/stromal cell-derived factor-1 [SDF-1; CXC chemokine ligand 12 (CXCL12)] pair is involved in baseline trafficking of leukocytes into extravascular tissues and that modulation of surface CXCR4 expression may represent an alternative mechanism for control of cell-specific biological responses to SDF-1/CXCL12. We explored the regulation of CXCR4 expression by cytokines in polymorphonuclear neutrophils (PMNs). No significant surface expression of CXCR4 in freshly isolated PMNs was detected, but expression became apparent gradually during incubation. SDF-1α/CXCL12 initiated Ca2+ mobilization and migratory responses in 20 h cultured PMNs. The surface CXCR4 expression was suppressed most potently by interferon-γ (IFN-γ). IFN-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF also inhibited spontaneous CXCR4 expression. Real-time, quantitative PCR experiments revealed that a spontaneous increase and an IFN-γ-mediated decrease in surface CXCR4 paralleled changes in the CXCR4 mRNA level. These results on PMNs support the argument that the SDF-1 (CXCL12)/CXCR4 system is regulated by cell type-specific mechanisms.
Fas activation opposes PMA-stimulated changes in the localization of PKCδ: a mechanism for reducing neutrophil adhesion to endothelial cells
Authors: Hendey Bill , Zhu Chun Liu , Greenstein Stephanie
Published: September 2022

We have shown previously that Fas activation results in a partial reduction of phorbol 12-myristate 13-acetate (PMA)-stimulated neutrophil adhesion to endothelial cells. The reduction in adhesion precedes early membrane markers of apoptosis and is not associated with any loss of membrane integrity. Rather, Fas activation reduces the PMA-stimulated expression and aggregation of β2 integrins responsible for endothelial adhesion. A possible signaling mechanism for Fas effects on adhesion is the localization of protein kinase C δ (PKCδ). Western blot and immunofluorescence studies indicated that 1 h of Fas activation is required to reduce PMA-stimulated translocation of PKCδ to the membrane and adhesion. Rottlerin, a PKCδ inhibitor, also reduced PMA-induced PKCδ translocation and adhesion. In contrast, Gö6976, an inhibitor of conventional PKC isotypes, did not affect PMA-stimulated PKCδ translocation or reduce adhesion. There was no additive effect of Fas activation and rottlerin on reducing adhesion, suggesting that both agents were using a common pathway.
Chemotactic activity of human blood leukocytes in plasma treated with EDTA: chemoattraction of neutrophils about monocytes is mediated by the generation of NAP-2
Authors: Malawista Stephen E , Van Damme Jo , Smallwood Joan I , de Boisfleury Chevance Anne
Published: September 2022

In slide preparations of human blood leukocytes in autologous plasma containing EDTA, many adherent monocytes are initially chemotactic for neutrophils (PMN). We have identified the chemotactic factor that they generate as neutrophil-activating peptide-2 (NAP-2), as evidenced by distraction of the gradient by authentic human NAP-2, the importance of platelets in the media, which elaborate the precursor of NAP-2, and suppression of the chemotactic response by serine protease inhibitors, which would block the monocyte-derived serine esterase that creates NAP-2 from its immediate precursor. Consistent with this conclusion is inhibition of the chemotactic response to monocytes by agents that block CXCR2, the receptor that NAP-2 uses. Later, when the monocyte moves from the center of chemoattraction, the activated PMN themselves, whose own chemotactic properties are enhanced in EDTA/plasma, appear to take over generation of the gradient, resulting in a prolonged ingress of PMN from outside the field (“second wave”). Chemoattraction by monocytes seems to be simply one way of stimulating the PMN, which, once activated, fail in EDTA/plasma to efficiently shut off their own chemoattraction for other PMN. We suggest that these exaggerated chemotactic effects are due to the loss of normal modulation by a regulatory factor(s) designed to keep the chemotactic response from getting out of hand—i.e., a tonic inhibitor of chemotaxis in plasma.
Modulation of monocyte signaling and pore formation in response to agonists of the nucleotide receptor P2X7
Authors: Aga Mini , Johnson Christopher J , Hart Arlene P , Guadarrama Arturo G , Suresh M , Svaren John , Bertics Paul J , Darien Benjamin J
Published: September 2022

Previous reports about the nucleotide receptor P2X7, which exhibits ion channel and pore-forming activity and is known to promote IL-1β processing, have centered largely on its role in macrophage function, whereas its participation in monocyte activity has been unclear. However, because extracellular ATP has been shown to affect monocytes with respect to IL-1β release, we hypothesized that the P2X7 receptor is also present and functional in a subpopulation of blood monocytes. Flow cytometric analysis revealed that about 70% of monocytes isolated from normal human donors expressed the P2X7 receptor. Activation of P2X7 receptor-associated pore formation by the agonist BzATP resulted in a 9- to 15-fold increase in the uptake of the membrane-impermeant fluorescent dye YO-PRO, and this dye uptake is markedly inhibited by the P2X7 receptor antagonists KN-62 and oATP. Evidence supporting the presence of the functional P2X7 receptor in monocytes also includes the observation that BzATP exposure results in a dose-dependent increase in the activation of mitogen-activated 2protein kinases and the nuclear translocation of the transcription factor NF-κB in human monocytes and in THP-1 human monocytic cells. Furthermore, treatment of monocytes with BzATP induced the expression of cyclooxygenase-2 (COX-2) and tissue factor, which are two important endpoints that have not been previously shown to be regulated by nucleotide receptor action in monocytes. Together, these data indicate that a subpopulation of human monocytes express P2X7 receptors that are functional with respect to pore formation, signal transduction, and mediator production, further supporting a key role for this nucleotide receptor in host immune responses.
Concanavalin-A-induced liver injury is severely impaired in mice deficient in P-selectin
Authors: Massaguer Anna , Perez-del-Pulgar Sofía , Engel Pablo , Serratosa Joan , Bosch Jaime , Pizcueta Pilar
Published: September 2022

P-selectin (CD62P) is an adhesion molecule that mediates the initial attachment of leukocytes to activated platelets and endothelial cells in damaged tissues. We evaluated the role of P-selectin in concanavalin A (Con A)-induced hepatitis, a model characterized by CD4+ T cell activation and infiltration of the liver. Con A injection induced transient P-selectin expression on hepatic venules and platelets. Mice lacking P-selectin showed impaired lymphocyte adhesion to liver venules and sinusoids, a striking reduction in intrasinusoidal occlusion, and decreased lymphocyte infiltration of liver parenchyma. The reduction in transaminase levels and the almost complete abolition of necrotic injury demonstrated that liver damage was lower in P-selectin-deficient mice. In wild-type mice, pretreatment with the P-selectin-blocking monoclonal antibody attenuated the sinusoidal occlusion and reduced the rise in transaminases after Con A treatment. These results implicate P-selectin in the development of Con A-induced liver injury and reveal the protective effect of blocking P-selectin in this hepatitis.
Proteoglycans guide SDF-1-induced migration of hematopoietic progenitor cells
Authors: Netelenbos Tanja , Zuijderduijn Suzanne , van den Born Jacob , Kessler Floortje L , Zweegman Sonja , Huijgens Peter C , Dräger Angelika M
Published: September 2022

Stromal cell-derived factor-1 (SDF-1) is a chemoattractant involved in hematopoietic progenitor cell (HPC) trafficking to the bone marrow. We studied the role of bone marrow endothelial proteoglycans (PGs) in SDF-1-mediated migration of HPC using a transwell assay. A subclone of progenitor cell line KG-1 (KG-1v) was used, displaying CXCR4-dependent transmigration. Cell surface PGs on bone marrow endothelial cell line 4LHBMEC did not mediate SDF-1-induced transendothelial migration. In contrast, transwell filters precoated with various glycosaminoglycans (GAGs) enhanced migration toward SDF-1. SDF-1-induced migration was reduced by degradation of heparan sulfate in subendothelial matrix produced by 4LHBMEC. The stimulating effect of GAGs was caused by the formation of a stable haptotactic SDF-1 gradient, as SDF-1 bound to immobilized GAGs and triggered migration. Soluble heparan sulfate enhanced SDF-1-induced migration dose-dependently, suggesting that SDF-1-heparan sulfate complexes optimized SDF-1 presentation. In conclusion, we provide evidence that PGs in the subendothelial matrix establish an SDF-1 gradient guiding migrating HPC into the bone marrow.
Population analysis of CD4+ T cell chemokine receptor transcript expression during in vivo type-1 (mycobacterial) and type-2 (schistosomal) immune responses
Authors: Chiu Bo-Chin , Shang Xiao-Zhou , Stolberg Valerie R , Komuniecki Eric , Chensue Stephen W
Published: September 2022

Chemokine receptor transcripts were defined among CD4+ T cells in lymph nodes of mice with type-1 and type-2 inflammation, respectively, elicited by mycobacterial and schistosomal Ag. CXCR3 and CCR6 transcripts were biased to type-1, and CCR4 transcripts increased in type-1 and type-2 populations. CCR3 and CCR5 signals were too weak to establish differences. CCR8 transcripts were not increased among unstimulated populations. Compared to naïve, type-1 and type-2 populations had reduced CCR7 and enhanced CXCR5 transcripts, consistent with a shift to memory cells. Subset depletion revealed that transcript expression was induced among CD44+ memory T cells. Surprisingly, CCR3 transcripts were enriched among CD44lo fractions. Ag stimulation augmented CXCR3, CCR4, and CCR8 but down-regulated CCR6 and CXCR5. CCR4 showed association with IFN-γ- and IL-4-producing cells, but other receptor transcripts were expressed among IFN-γ/IL-4 negative memory T cells. These studies provide several novel findings regarding Th cell chemokine receptor expression in vivo.
Identification of human cysteine-rich secretory protein 3 (CRISP-3) as a matrix protein in a subset of peroxidase-negative granules of neutrophils and in the granules of eosinophils
Authors: Udby Lene , Calafat Jero , Sørensen Ole E , Borregaard Niels , Kjeldsen Lars
Published: September 2022

Cysteine-rich secretory protein 3 (CRISP-3; also known as SGP28) was originally discovered in human neutrophilic granulocytes. We have recently developed a sensitive sandwich enzyme-linked immunosorbent assay for CRISP-3 and demonstrated the presence of CRISP-3 in exocrine secretions. To investigate the subcellular localization and mobilization of CRISP-3 in human neutrophils, we performed subcellular fractionation of resting and activated neutrophils on thee-layer Percoll density gradients, release-studies of granule proteins in response to different secretagogues, and double-labeling immunogold electron microscopy. CRISP-3 was found to be localized in a subset of granules with overlapping characteristics of specific and gelatinase granules and mobilized accordingly, thus confirming the hypothesis that peroxidase-negative granules exist as a continuum from specific to gelatinase granules regarding protein content and mobilization. CRISP-3 was found to be a matrix protein, which is stored in granules as glycosylated and as unglycosylated protein. The subcellular distribution of the two forms of CRISP-3 was identical. In addition, CRISP-3 was found as a granule protein in eosinophilic granulocytes. The presence of CRISP-3 in peroxidase-negative granules of neutrophils, in granules of eosinophils, and in exocrine secretions indicates a role in the innate host defense.
Human eosinophils express and release IL-13 following CD28-dependent activation
Authors: Woerly Gaetane , Lacy Paige , Ben Younes Amena , Roger Nadine , Loiseau Sylvie , Moqbel Redwan , Capron Monique
Published: September 2022

Human eosinophils produce a large number of cytokines, including immunoregulatory cytokines. Given that eosinophils store and release interleukin (IL)-4, a key cytokine in the pathogenesis of allergic inflammation, and that IL-4 and IL-13 share common biological functions, we investigated the possibility that IL-13 may be synthesized by these cells. Using flow cytometry and immunocytochemistry, we show that eosinophils synthesize and store IL-13. Granule localization was demonstrated after subcellular fractionation, and IL-13 immunoreactivity was localized to crystalloid, granule-enriched fractions. Furthermore, electron microscopic analyses specifically localized IL-13 to the dense cores of bicompartmental secondary granules. Upon CD28 ligation, IL-13 was released by eosinophils, whereas a combination of CD28 and immunoglobulin A complexes resulted in decreased IL-13 secretion. Furthermore, eosinophil-derived IL-13 exerts a biological effect, inducing CD23 expression on B cells. By having the capacity to synthesize and release IL-13, eosinophils may participate in the development and maintenance of the T helper cell type 2 response, a prominent feature of allergic diseases.
Dissociated ROS production and ceramide generation in sulfasalazine-induced cell death in Raw 264.7 cells
Authors: Salh B , Assi K , Huang S , O'Brien L , Steinbrecher U , Gómez-Muñoz A
Published: September 2022

Sulfasalazine (SSZ) is a drug used in inflammatory bowel disease, whose precise mechanism of action remains to be clarified. Here, we report that incubation of Raw 264.7 cells with SSZ but not salicylates [acetylsalicylic acid (ASA), 4-aminosalicylic acid (4-ASA), and 5-ASA] causes a mixed apoptotic and necrotic form of cell death. In contrast to its metabolites, sulfapyridine and 5-ASA, SSZ exposure in Raw 264.7 cells resulted in a threefold increase in ceramide generation, as well as a robust production of reactive oxygen species (ROS). However, inhibition of ceramide production by fumonisin B1 failed to attenuate cell death. Preincubation with catalase, cyclosporin A (CsA), and bongkrekic acid attenuated ROS production. When dead cells were quantified for apoptotic versus necrotic cell death, catalase and N-acetylcysteine reproducibly attenuated apoptosis, whereas CsA, in addition to reducing apoptosis, was observed to dramatically enhance necrosis. In conclusion, the cell-death response induced by SSZ in Raw 264.7 cells involves ROS in the apoptotic limb but is independent of ceramide formation.
Interleukin-2 family cytokines stimulate phosphorylation of the Pro-Ser-Pro motif of Stat5 transcription factors in human T cells: resistance to suppression of multiple serine kinase pathways
Authors: Nagy Zsuzsanna S , Wang Yuling , Erwin-Cohen Rebecca A , Aradi János , Monia Brett , Wang Li Hua , Stepkowski Stanislaw M , Rui Hallgeir , Kirken Robert A
Published: September 2022

Signal transducer and activator of transcription (Stat)5a and Stat5b are critical for normal immune function. Progression of T cells through G1-S phase of cell cycle requires T cell receptor (TCR)- and/or cytokine-inducible tyrosine phosphorylation of Stat5a/b. Stat5a/b may also, in a cell-dependent manner, be constitutively or cytokine-inducibly phosphorylated on a Pro-Ser-Pro (PSP) motif located within the transcriptional activation domain. Phosphorylation of the PSP motif is needed for maximal transcriptional activation by Stat5, at least in certain promoter contexts. The basal and cytokine-inducible serine phosphorylation state of Stat5a/b has not been determined in T cells. Using primary human T cells and T lymphocytic cell lines coupled with novel phospho-specific antibodies to this conserved phosphoserine motif in Stat5a or Stat5b, we report that: Stat5a and Stat5b were unphosphorylated on the PSP motif under basal conditions and became markedly phosphorylated in response to several T cell growth factor stimuli, including interleukin (IL)-2, -7, -9, and -15 and phorbol ester 12-myristate 13-acetate but not TCR engagement; inducible Stat5a/b serine phosphorylation differed quantitatively and temporally; and Stat5a/b serine phosphorylation was, in contrast to inducible Stat3 serine phosphorylation, insensitive to inhibitors of mitogen-activated protein kinase, phosphatidylinositol-3 kinase, and mammalian target of rapamycin or deletion of Raf-A, -B, or -C by antisense oligonucleotides. We conclude that IL-2 family cytokines tightly control Stat5 serine phosphorylation through a kinase distinct from the Stat3 serine kinase.
Inducible expression of an antimicrobial peptide of the innate immunity in polymorphonuclear leukocytes
Authors: Tomasinsig Linda , Scocchi Marco , Di Loreto Carla , Artico Daria , Zanetti Margherita
Published: September 2022

Epithelia- and leukocyte-associated antimicrobial peptides provide immediate protection against microbial infections by rapidly inactivating potential pathogens. Bac5 is a member of the cathelicidin family of antimicrobial peptides and is stored in the cytoplasmic granules of bovine neutrophils. We investigated the expression of this gene in airway and intestine, and although the gene was not found to be locally expressed in these tissues, a strong Bac5 induction signal was detected by in situ hybridization in neutrophils infiltrating infected lung, consistent with expression of this gene in activated neutrophils. The Bac5 gene was also induced in bovine peripheral neutrophils stimulated with Escherichia coli or purified lipopolysaccharide (LPS) but not in other blood cells and in resting neutrophils. The levels of Bac5 mRNA increased at 12–24 h post-stimulation, and a dose-dependent increase in Bac5 expression was determined in the presence of increasing amounts of LPS. A metabolically labeled product with a molecular weight compatible with that of proBac5 was immunoprecipitated from cell-free media of stimulated neutrophils, suggesting that the newly synthesized polypeptide is released extracellularly. Collectively, these results provide the first evidence that fully differentiated neutrophils are capable of de novo synthesis and secretion of a granule-associated antimicrobial peptide.
Granulocyte macrophage-colony stimulating factor delays neutrophil apoptosis and primes its function through Ia-type phosphoinositide 3-kinase
Authors: Yasui Kozo , Sekiguchi Yukio , Ichikawa Motoki , Nagumo Haruo , Yamazaki Takashi , Komiyama Atsushi , Suzuki Harumi
Published: September 2022

Phosphoinositide 3-kinases (PI3Ks) constitute a family of lipid kinases that regulate an array of fundamental cellular responses by neutrophils [polymorphonuclear leukocytes (PMN)]. p85α Gene-disrupted mice were used to help accurately identify the physiological role of the PI3K isoform in PMN activation in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF). PMN from the p85α−/− mice showed normal cellular motility, and the quantity of superoxide anion (O2−) produced by PMN upon stimulation with formyl-Met-Leu-Phe did not significantly differ between p85α−/− and wild-type mice under controlled conditions. In p85α−/− mice, the O2− production by PMN was enhanced (primed) by GM-CSF when stimulated with the chemotactic peptide but to a significantly lesser extent than in wild-type mice. In addition, no major GM-CSF-dependent delay in apoptosis or activation of Akt protein phosphorylation by GM-CSF was observed in the p85α−/− mice. In terms of targeting strategy, however, the mutation actually expressed a small amount of Ia-type (p85α-regulated) PI3K activity (partially abrogated) in the mice. These results demonstrate that Ia-type PI3K plays a critical role in the enhancement of the GM-CSF-modulated function of PMN and in the PI3K/Akt pathway-dependent delay of PMN apoptosis.
Molecular profiling of the role of the NF-κB family of transcription factors during alloimmunity
Authors: Finn Patricia W , He Hongzhen , Ma Chunyan , Mueller Thomas , Stone James R , Liou Hsiou-Chi , Boothby Mark R , Perkins David L
Published: September 2022

Allograft rejection involves a complex network of multiple immune regulators and effector mechanisms. In the current study, we focused on the role of nuclear factor (NF)-κB/Rel. Previous studies had established that deficiency of the p50 NF-κB family member prolonged allograft survival only modestly. However, because of its crucial role in signal transduction in inflammatory and immune responses, we hypothesized that other NF-κB/Rel family members may produce more profound effects on alloimmunity. Therefore, in addition to p50, we analyzed the role of c-Rel, which is expressed predominantly in lymphocytes. Also, to investigate NF-κB activation in T cells, we examined transgenic mice that express a transdominant inhibitor of NF-κB [IκB(ΔN)] regulated by a T cell-restricted promoter. Allograft survival was prolonged indefinitely in the c-Rel-deficient and IκB(ΔN)-transgenic recipients. To determine the molecular basis of NF-κB modulation of rejection, we analyzed a panel of 58 parameters including effector molecules, chemokines, cytokines, receptors, and cellular markers using hierarchical clustering algorithms and self-organizing maps in p50−/−, c-Rel−/−, and IκB(ΔN)-transgenic, experimental groups plus allogeneic-, syngeneic-, and lymphocyte-deficient (alymphoid) control groups. Surprisingly, profiles of gene expression in the c-Rel recipients (which have indefinite graft survival) were similar to the p50−/− and allogeneic recipients (which rapidly reject grafts). As expected, gene expression in the IκB(ΔN) recipients (which also have indefinite graft survival) was similar to profiles of nonrejecting syngeneic and alymphoid recipients. Importantly, self-organizing maps identified a small subset of genes including several chemokine receptors and cytokines with expression profiles that correlate with graft survival. Thus, our results demonstrate a crucial role for NF-κB in acute allograft rejection, identify different molecular mechanisms of rejection by distinct NF-κB family members, and identify a small subset of inducible genes whose inhibition is linked to graft acceptance.
Dendritic cell maturation and IL-12 synthesis induced by the synthetic immune-response modifier S-28463
Authors: Fogel Mirjana , Long Julie A , Thompson Philip J , Upham John W
Published: September 2022

Dendritic cells (DC) play a prominent role in the development of T cell-immune responses to antigens and have a key influence over the differentiation of naive T cells into T helper cell type 1 (Th1) or Th2 effector cells. Consequently, there is considerable interest in pharmacological agents that might alter DC function and thereby modulate allergic inflammation. We examined the effects of the imidazoquinoline S-28463 on human monocyte-derived DC (Mo-DC) cultured in granuloctye macrophage-colony stimulating factor and interleukin (IL)-4 to determine whether this agent might be useful in augmenting Th1 immunity. We determined that S-28463 acts directly on Mo-DC, inducing their maturation and enhancing their capacity to present antigen. Importantly, S-28463 strongly induces synthesis of bioactive IL-12 p70, a key Th1-polarizing cytokine. We also examined the ability of S-28463 to modulate DC function in the context of transforming growth factor-β (TGF-β), a negative, immunoregulatory cytokine released from the epithelium of nonlymphoid organs. S-28463 was able to induce IL-12 synthesis even in the presence of TGF-β, whereas lipopolysaccharide (LPS) + interferon-γ-stimulated DC did not produce IL-12 in the presence of TGF-β. Taken together, our findings suggest that S-28463 and LPS are exerting their effects via distinctly different pathways and indicate that S-28463 may be beneficial in polarizing immune responses toward a Th1 response.
Pertussis toxin and the adenylate cyclase toxin fromBordetella pertussisactivate human monocyte-derived dendritic cells and dominantly inhibit cytokine production through a cAMP-dependent pathway
Authors: Bagley Kenneth C , Abdelwahab Sayed F , Tuskan Robert G , Fouts Timothy R , Lewis George K
Published: September 2022

Pertussis toxin (PT) and adenylate cyclase toxin (AT) are AB enterotoxins produced by Bordetella pertussis. PT is a powerful mucosal adjuvant whose cellular target and mechanism of action are unknown; however, emerging evidence suggests that dendritic cells (DC) may be a principal adjuvant target of PT. Here, we investigate the mechanism underlying the effects of these toxins on human monocyte-derived DC (MDDC) in vitro. We found that the effects of PT and AT on MDDC, including maturation, are mediated by cyclic adenosine monophosphate (cAMP). In this regard, adenosine 5′-diphosphate-ribosylation-defective derivatives of PT failed to induce maturation of MDDC, whereas dibutyryl-cAMP (d-cAMP) and Forskolin mimic the maturation of MDDC and dominant inhibition of cytokine production induced by these toxins. Also, cAMP-dependent kinase inhibitors blocked the ability of PT, AT, d-cAMP, and Forskolin to activate MDDC. Taken together, these results show that the effects of PT and AT on MDDC are mediated strictly by cAMP.
HMGB1 as a DNA-binding cytokine
Authors: Andersson Ulf , Erlandsson-Harris Helena , Yang Huan , Tracey Kevin J
Published: September 2022

HMGB1 (high mobility group box chromosomal protein 1), historically known as an abundant, nonhistone architectural chromosomal protein, is extremely conserved across species. As a nuclear protein, HMGB1 stabilizes nucleosomes and allows bending of DNA that facilitates gene transcription. Unexpectedly, recent studies identified extracellular HMGB1 as a potent macrophage-activating factor, signaling via the receptor for advanced glycation end-products to induce inflammatory responses. It is released as a late mediator during inflammation and participates in the pathogenesis of systemic inflammation after the early mediator response has resolved. HMGB1 occupies a critical role as a proinflammatory mediator passively released by necrotic but not apoptotic cells. Necrotic Hmgb1−/− cells mediate minimal inflammatory responses. Stimulated macrophages actively secrete HMGB1 to promote inflammation and in turn, stimulate production of multiple, proinflammatory cytokines. HMGB1 mediates endotoxin lethality, acute lung injury, arthritis induction, activation of macrophages, smooth muscle cell chemotaxis, and epithelial cell barrier dysfunction. HMGB1 is structurally composed of three different domains: two homologous DNA-binding sequences entitled box A and box B and a highly, negatively charged C terminus. The B box domain contains the proinflammatory cytokine functionality of the molecule, whereas the A box region has an antagonistic, anti-inflammatory effect with therapeutic potential. Administration of highly purified, recombinant A box protein or neutralizing antibodies against HMGB1 rescued mice from lethal sepsis, even when initial treatment was delayed for 24 h after the onset of infection, establishing a clinically relevant therapeutic window that is significantly wider than for other known cytokines.
Immune complex stimulation of human neutrophils involves a novel Ca2+/H+ exchanger that participates in the regulation of cytoplasmic pH: flow cytometric analysis of Ca2+/pH responses by subpopulations
Authors: Bernardo John , Hartlaub Hilary , Yu Xin , Long Heidi , Simons Elizabeth R
Published: September 2022

The activation of human phagocytic leukocytes by immune complexes (IC) or opsonized microbes via their Fc and complement receptors has been well-described (for reviews, see refs. [1–3]). The mechanisms involved in this process are complex and depend on the receptors involved. The biochemical events that lead to the destruction of invading organisms in turn display varying degrees of interdependence, but the controlling elements that lead to the ultimate killing of ingested organisms within phagosomes by lysosomal enzymes and reactive oxygen intermediates are still not completely understood. We have addressed these mechanisms by following and correlating the kinetics of responses by individual cells, using multiparameter flow cytometry [3, 4]. Using nonopsonized IC as stimuli, we document here the presence of a novel Ca2+/H+ voltage-independent channel in human neutrophils, which helps to control their cytoplasmic pH.
Institution of Standardized Consultation Criteria to Increase Early Palliative Care Utilization in Older Patients With Acute Leukemia
Authors: Rosenblum Rachel E. , Ormond Ellen , Smith Crystal W. , Bilderback Andrew L. , Altieri Dunn Stefanie C. , Buchanan Dan , Geramita Emily M. , Rossetti James M. , Bhatnagar Mamta , Arnold Robert M.
Published: September 2022

PURPOSE:

Older patients with acute leukemia (AL) have a high symptom burden and poor prognosis. Although integration of palliative care (PC) with oncologic care has been shown to improve quality-of-life and end-of-life care in patients with AL, the malignant hematologists at our tertiary care hospital make limited use of PC services and do so late in the disease course. Using the Plan-Do-Study-Act (PDSA) methodology, we aimed to increase early PC utilization by older patients with newly diagnosed AL.

METHODS:

We instituted the following standardized criteria to trigger inpatient PC consultation: (1) age 70 years and older and (2) new AL diagnosis within 8 weeks. PC consultations were tracked during sequential PDSA cycles in 2021 and compared with baseline rates in 2019. We also assessed the frequency of subsequent PC encounters in patients who received a triggered inpatient PC consult.

RESULTS:

The baseline PC consultation rate before our intervention was 55%. This increased to 77% and 80% during PDSA cycles 1 and 2, respectively. The median time from diagnosis to first PC consult decreased from 49 days to 7 days. Among patients who received a triggered PC consult, 43% had no subsequent inpatient or outpatient PC encounter after discharge.

CONCLUSION:

Although standardized PC consultation criteria led to earlier PC consultation in older patients with AL, it did not result in sustained PC follow-up throughout the disease trajectory. Future PDSA cycles will focus on identifying strategies to maintain the integration of PC with oncologic care over time, particularly in the ambulatory setting.
Acid–Base Imbalance in Pseudohypoaldosteronism Type 1 in Comparison With Type IV Renal Tubular Acidosis
Authors: Adachi Masanori , Nagahara Keiko , Ochi Ayako , Toyoda Junya , Muroya Koji , Mizuno Katsumi
Published: September 2022

Context

Pseudohypoaldosteronism type 1 (PHA1) has been treated as a genetic variant of type IV renal tubular acidosis (RTA), leading to the conception that PHA1 develops hyperchloremic acidosis with a normal anion gap (AG).

Objective

To delineate the acid–base imbalance in PHA1A (dominant type) and PHA1B (recessive type).

Methods

We conducted the following: (1) a retrospective chart review of our patient with PHA1B, and (2) a literature search of PHA1 cases focusing on acid–base balance. The main outcome measures were the incidence and nature of acidosis, including chloride levels and AG.

Results

In our patient with PHA1B, 7 salt-wasting episodes were analyzed. Acidosis was ascertained each time, and it was accompanied by hypochloremia except in 1 episode. AG was elevated in 5 episodes, while hyperlacticaemia was present in 3. In the literature, 41 cases of PHA1A and 65 cases of PHA1B have been identified. During salt-wasting crises, acidosis developed in 85% of PHA1A cases and 87% of PHA1B cases. Hypochloremia was present in 69% of PHA1A cases with available data (n = 13) and 54% of eligible PHA1B cases (n = 13), with mean chloride levels of 96 mEq/L and 95 mEq/L, respectively. Increased AG was less frequently reported (14% in PHA1A and 44% in PHA1B).

Conclusions

Patients with PHA1 frequently presented with metabolic acidosis. However, hyperchloremia may not be a universal finding, whereas hypochloremia and increased AG may occur in a substantial proportion of the patients.
Insulin Resistance and Its Association With Osteoporosis in People Living With HIV
Authors: Caeran Gabriela , de Almeida Luciana L , Ilha Thales A S H , de Carvalho José A M , Stein Carolina , Moresco Rafael N , Haygert Carlos J P , Comim Fabio V , Premaor Melissa O
Published: September 2022

Background

Despite the gain in life expectancy that people living with HIV (PLHIV) have had in the past few years, the disease is accompanied by an increase in the prevalence of noninfectious chronic diseases. PLHIV have a higher prevalence of osteoporosis, fracture, diabetes mellitus, and insulin resistance than the general population. It is unknown if insulin resistance is associated with osteoporosis and fractures in PLHIV. Our study aimed to assess the association between insulin resistance and osteoporosis in PLHIV.

Methods

A cross-sectional study was carried out in southern Brazil. PLHIV ages 50 years or older on antiretroviral treatment were included. Insulin resistance was considered present when the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was higher than expected for the Brazilian population (>2.7). The triglyceride-glucose (TyG) index was also calculated.

Results

Of the 101 PLHIV who agreed to participate, 84 underwent insulin and bone mineral density measurements. The prevalence of osteoporosis was 19%. The frequency of insulin resistance calculated by HOMA-IR was 68.2%. Participants with osteoporosis had lower body mass index (BMI) and triglyceride values than those without it. HOMA-IR [4.8(6.6) vs 8.68(9.6), P = 0.013] and TyG [5.0(0.3) vs 5.2 (0.4), P = 0.029]. The association between the total femur t-score disappeared after correction for BMI in the linear regression model. There was no association between vertebral fractures and insulin resistance.

Conclusion

In our study, PLHIV with osteoporosis have lower insulin resistance than PLHIV without it. However, this finding appears to be related to lower BMI. The association between insulin resistance and bone in PLHIV appears to be somewhat similar to that of the general population.
Whaddayou Mean “ςπουδαιογɛλοιον”?: Nabi's Last Laugh
Authors: Marshall T. C.
Published: September 2022

In his late unpublished essay “Dionysus in 1992,” Norman O. Brown arrived at the ancient Greek term “spoudaiogeloion” to express his idea of a “serious laughter” that could respond to dialectical tensions without unbalancing them. Brown had, in 1959, converted Freud's Witz book into a serious theory of art. This turned the focus on humor into a focus on art, subtly repressing the place of laughter in art and thinking for Brown and those who took him seriously. His casual conversation was always full of fun, but his formal thought lacked that liberating concept until the last decade of his life. Not even the accusation by Marcuse of “mystification” could bring him out of his idealizations—until he saw the dialectical power of humor's ambivalence. “Spoudaiogeloion,” with room for Joyce's farcical wit and Blake's high visions, gave Brown a useful “way out” of tensions between “high” and “low” art or philosophy.
Nobby, or Metamorphosis
Authors: Schelling Andrew
Published: September 2022

Andrew Schelling recalls and discusses a college course, “World Poetry,” which Norman O. Brown taught at University of California, Santa Cruz, in 1974. The turbulent politics and weird, harrowing culture changes of North America set a context. Brown's class met weekly in a remote meadow ringed by second-growth redwoods. Brown developed his interest in the “law of metamorphosis,” which he thought poetry captures, and put his attention on how the human body changes, producing text as sound or performance. Using two anthologies compiled by Jerome Rothenberg, Brown drew students into a poetry that was physical, raw, multilingual, and perhaps a scriptural base for the era's counterculture. Schelling portrays Brown as a quixotic figure, Sir John Falstaff among scholars. A quick sketch of the “Santa Cruz ecosystem” brings into the mix Gregory Bateson, whose thoughts on evolution paralleled Brown's on poetry, and Jan Willis, veteran civil rights activist and scholar of Sanskrit.
Introduction to the Correspondence of Robert Duncan and Norman O. Brown
Authors: Davidson Michael
Published: September 2022

The following selections from letters exchanged between Robert Duncan and Norman O. Brown display the range and interest of their extensive correspondence. The correspondence was generative for both figures, and shows a degree of mutual affection and personal concern beyond their intellectual interests. The letters are retrieved from the special collections libraries at the University of California, Santa Cruz, and the University of Buffalo.
To Greet the Return of the Gods: A Guide for Teachers
Authors: Brown Norman O.
Published: September 2022

In this introduction to the Book of Ours student manual and its accompanying lectures and workshops, Norman O. Brown discusses processes for transforming the structure, dynamics, and spirit of conventional large-enrollment undergraduate courses. Brown maps the aims and intentions of the Book of Ours project as a recreation of “mythic consciousness by mythopoeic activity,” and in this way lays out a path to a more “poetical and sacred” style of academic engagement.
“A More Personal Look at Her Life”: Family Narrative, Gender, and Transnational Memories in The Girl and the Picture
Authors: Zhang Pingfan
Published: September 2022

Recent decades have witnessed a booming film industry portraying the Nanjing Massacre, both within and outside Mainland China, which is closely related to contemporary Chinese political, socioeconomic, and cultural transformations. This article examines the USC Shoah Foundation's 2018 documentary film The Girl and the Picture, featuring the well-known Nanjing Massacre female survivor Xia Shuqin. It argues that the cinematic rendition of Xia's family stories serves as a piercing incision into Nanjing Massacre historical memories and weaves together the personal with the national, and transgenerational with transnational memories. The Girl and the Picture radicalizes cinematic discourses on the Nanjing Massacre from multiple angles and not only sheds light on the emerging field of Nanjing Massacre studies but also contributes to our understanding of the ongoing memory boom of the Nanjing Massacre in the context of globalization. By delivering the stories of Xia along both family and transnational lines, The Girl and the Picture points out a new way to cope with the memory crisis of the Nanjing Massacre, and to take responsibility for transmitting the memories across generational, national, gender, and ethnic boundaries.
The Language(s) of Self-Representation
Authors: Allan Michael
Published: September 2022

This essay tracks Karl Marx's famous line “They cannot represent themselves; they must be represented” as it travels from a translated epigraph in Edward Said's Orientalism to Gayatri Chakravorty Spivak's “Can the Subaltern Speak?” What follows from this minor textual detail is a broader exploration of how “other” languages take place in postcolonial theory—not only Said and Spivak's German, but Abdelfattah Kilito's Italian and Frantz Fanon's Arabic. What is the place of translation in self-representation? How do instances of textual citation complicate the self of self-representation? In the ricochet between citation and translation, language matters not necessarily as a sign of fluency, but as part of a pragmatics of critique, positionality, and ultimately solidarity. Each instance of language-use (German, Italian, Arabic) highlights the potentials of re-use, citation, and re-imagination for consolidating the bonds of anticolonial struggle and a vision of a postcolonial future. Shifting from translation to resonance and from language to voice, the essay ultimately engages the poetic potentials of translation as part of a pragmatics of anticolonial solidarity, integral to and beyond the self at the heart of self-representation.
Using Individual-Level Randomized Treatment to Learn about Market Structure
Authors: Casaburi Lorenzo , Reed Tristan
Published: September 2022

Interference across competing firms in RCTs can be informative about market structure. An experiment that subsidizes a random subset of traders who buy cocoa from farmers in Sierra Leone illustrates this idea. Interpreting treatment-control differences in prices and quantities purchased from farmers through a model of Cournot competition reveals differentiation between traders is low. Combining this result with quasi-experimental variation in world prices shows that the number of traders competing is 50 percent higher than the number operating in a village. Own-price and cross-price supply elasticities are high. Farmers face a competitive market in this first stage of the value chain. (JEL L13, L14, O13, Q12, Q13)
Premature Ejaculatory Dysfunction in Rheumatoid Arthritis (PED-RA Study)
Authors: Wagan Abrar Ahmed , Chandio Sultan Ahmed , Surahyo Paras
Published: September 2022

Objective: To determine the frequency of premature ejaculatory dysfunction in rheumatoid arthritis patients.

Methods: After approval from IRB, cross sectional study was conducted from November 1st, 2020 to August 1st, 2021 at Department of Rheumatology, Indus Medical College, Pakistan. RA patients were included, written and informed consents were taken. Demographic data was noted and detailed history and examination was carried out. Each participant BMI and Blood pressure was measured. Afterward 5-ml of blood was drawn by a trained phlebotomist for CBC, ESR, fasting blood sugar levels, HBs Ag and anti HCV Antibody test. DAS-28 Calculator was used for RA clinical activity. Premature ejaculation diagnostic tool was used for the assessment of premature ejaculation.

Results: Total 168 patients with mean age 32.27 (SD=±9.49) and mean disease duration of 6.35 (SD=±3.95) years were included,. Prevalence of premature ejaculation dysfunction was (44.6%), with mean PED of score 9.17 (SD=±5.23). Hypertension, HCV, Hakeem medications, use of DMARDS had positive association while High BMI and higher DAS-28 has negative association with PED (p<0.05).

Conclusion: There is high prevalence of PED in RA, it needs proper evaluation, treatment and urgent research is needed to know more about it.

doi: https://doi.org/10.12669/pjms.38.8.5698

How to cite this:Wagan AA, Chandio SA, Surahyo P. Premature Ejaculatory Dysfunction in Rheumatoid Arthritis (PED-RA Study). Pak J Med Sci. 2022;38(8):---------. doi: https://doi.org/10.12669/pjms.38.8.5698

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ανοικτοί χώροι-ιστορικοί χώροι. Η φιλοσοφία ανάδειξης του ιστορικού τοπίου σε συνδυασμό με το σύγχρονο και τις περιβαλλοντικές αξίες
Authors: Αντωνάρα Ελένη
Published: September 2022

Στο νέο αφήγημα που αναζητά η Ευρώπη για το σχεδιασμό των μελλοντικών της πολιτικών, προτάσσει ως βασικό πυλώνα χάραξης πολιτικής, την αξιοποίηση του πολιτισμικού αποθέματος των χωρών – μελών της, ως θεματοφύλακα των κοινών αξιών που συγκροτούν την ευρωπαϊκή ταυτότητα και ταυτόχρονα, ως θεμελιακό παράγοντα της βιώσιμης ανάπτυξης. Το ιστορικό τοπίο, ως δημόσιο αγαθό και δυναμική οντότητα μέσα στο χρόνο αποτελεί φορέα πολιτισμού και αξιών, οπότε ως τέτοιο οφείλει να αντιμετωπίζεται σε κάθε απόπειρα ανάδειξης και διαχείρισης του. Στο πλαίσιο αυτό του σύγχρονου προβληματισμού, η διατριβή προσπαθεί να συμβάλλει στην κατάρτιση της στρατηγικής η οποία, μέσα από την πολιτισμική συμμετοχική διαδικασία, θα οδηγήσει στη δημιουργία νέας γενιάς πολιτιστικών διαχειριστών για την οικοδόμηση της αειφορίας.