bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inappropriately low reticulocytosis in severe malarial anemia correlates with suppression in the development of late erythroid precursors
Authors: Chang Kai-Hsin , Tam Mifong , Stevenson Mary M. 
Published: January 2004

AbstractInappropriately low reticulocytosis may exacerbate malarial anemia, but the under-lying mechanism is not clear. In this study, naive and infected mice were treated with recombinant murine erythropoietin (EPO), and the upstream events of erythropoiesis affected by blood-stage Plasmodium chabaudi AS were investigated. Malaria infection, with or without EPO treatment, led to a suboptimal increase in TER119+ erythroblasts compared with EPO-treated naive mice. Furthermore, a lower percentage of TER119+ erythroblasts in infected mice were undergoing terminal differentiation to become mature hemoglobin-producing erythroblasts. The impaired maturation of erythroblasts during infection was associated with a shift in the transferrin receptor (CD71) expression from the TER119+ population to B220+ population. Moreover, the suboptimal increase in TER119+ erythroblasts during infection coincided with a blunted proliferative response by splenocytes to EPO stimulation in vitro, although a high frequency of these splenocytes expressed EPO receptor (EPOR). Taken together, these data suggest that during malaria, EPO-induced proliferation of early EPOR-positive erythroid progenitors is suppressed, which may lead to a suboptimal generation of TER119+ erythroblasts. The shift in CD71 expression may result in impaired terminal maturation of these erythroblasts. Thus, inadequate reticulocytosis during malaria is associated with suppressed proliferation, differentiation, and maturation of erythroid precursors.
Human immunodeficiency virus facilitates infection/replication of hepatitis C virus in native human macrophages
Authors: Laskus Tomasz , Radkowski Marek , Jablonska Joanna , Kibler Karen , Wilkinson Jeffrey , Adair Debra , Rakela Jorge 
Published: January 2004

AbstractHepatitis C virus (HCV) was found to replicate in monocytes/macrophages particularly in patients with human immunodeficiency virus type 1 (HIV-1) infection. This study was undertaken to determine whether HIV facilitates HCV infection of native human macrophages in vitro. Monocytes/macrophages were collected from healthy donors, infected with HIV M-tropic molecular clone, and then exposed to HCV-positive sera. Presence of positive and negative HCV RNA strands was determined with a novel strand-specific quantitative real-time reverse transcription–polymerase chain reaction (RT-PCR). Preceding as well as near-simultaneous infection with HIV made the macrophages more susceptible to infection with HCV; in particular, an HCV RNA–negative strand was detectable almost exclusively in the setting of concomitant HIV infection. Furthermore, HCV RNAload correlated with HIV replication level in the early stage of infection. The ratio of positive to negative strand in macrophages was lower than in control liver samples. HIV infection was also found to facilitate HCV replication in a Daudi B-cell line with engineered CD4 expression. It seems that HIV infection can facilitate replication of HCV in monocytes/macrophages either by rendering cells more susceptible to HCV infection or by increasing HCV replication. This could explain the presence of extrahepatic HCV replication in HIV-coinfected individuals.
Thrombin-activatable fibrinolysis inhibitor and the risk for recurrent venous thromboembolism
Authors: Eichinger Sabine , Schönauer Verena , Weltermann Ansgar , Minar Erich , Bialonczyk Christine , Hirschl Mirko , Schneider Barbara , Quehenberger Peter , Kyrle Paul A. 
Published: January 2004

Abstract
The impact of fibrinolysis for predicting the risk for recurrent venous thromboembolism (VTE) is low. We prospectively followed up 600 patients with a first VTE and evaluated the thrombin-activatable fibrinolysis inhibitor (TAFI) as a risk factor for recurrence. A high TAFI level (75th or higher percentile in thrombosis patients) was associated with a 2-fold higher risk for recurrence compared with lower levels. The probability of recurrence 2 years after anticoagulation was 14.5% (95% confidence interval [CI], 8.6-20.4) among patients with high TAFI levels and 6.8% (95% CI, 4.3-9.3) among patients with lower levels (P = .006). Our data also support the concept of a linkage between fibrinolysis and the coagulation system. Patients with high TAFI levels had significantly higher levels of factors XI, VIII, and IX, and a high risk of recurrence was seen among patients with high TAFI levels and high levels of one of these factors. The relative risk (RR) for recurrence was highest among patients with high TAFI and high factor XI (RR, 2.9; 95% CI, 1.3-6.9), high factor VIII (RR, 6.5; 95% CI, 2.9-14.8), or high factor IX (RR, 2.0; 95% CI, 1.0-3.9) levels compared with patients with low levels of TAFI and one of these factors.
Atypical features of familial hemophagocytic lymphohistiocytosis
Authors: Busiello Rosanna , Adriani Marsilio , Locatelli Franco , Galgani Mario , Fimiani Giorgia , Clementi Rita , Ursini Matilde Valeria , Racioppi Luigi , Pignata Claudio 
Published: January 2004

Abstract
Familial hemophagocytic lymphohistiocytosis (FHLH) is a rare, rapidly progressive disorder of early childhood characterized by uncontrolled activation of T cells and macrophages. Although perforin gene mutations have been described in a proportion of patients with FHLH, the genotype/phenotype correlation is still limited. Only a few patients with late onset clinical manifestations have been reported. The biochemical and immunologic alterations in the asymptomatic phase are not well known. We report on a family in which 2 fraternal twins both homozygous for a perforin mutation previously described as causative of the disease, markedly differed in phenotypic expression of FHLH. The twins also had a second novel heterozygous mutation. Natural killer (NK) activity was severely impaired in the patient and was normal in the asymptomatic fraternal twin. Our report highlights that FHLH may present after a long disease-free interval during which biochemical or immunologic alterations may be not evident, thus implying a role for interfering factors. (Blood. 2004;103:4610-4612)
Induction of human T-cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism
Authors: Lan Ping , Wang Lan , Diouf Bintou , Eguchi Hiroshi , Su Hui , Bronson Roderick , Sachs David H. , Sykes Megan , Yang Yong-Guang 
Published: January 2004

AbstractXenotransplantation from pigs could provide a potential solution to the severe shortage of allogeneic donor organs. Because xenogeneic tissues are subject to vigorous immune rejection, tolerance induction is likely to be essential to the success of clinical xenotransplantation. Here we explore the possibility of inducing human T-cell tolerance to porcine xenografts through mixed chimerism. We previously showed that NOD/SCID-Tg mice expressing porcine cytokine transgenes permit the induction of durable porcine hematopoietic chimerism. In this study we achieved human T-cell development in these mice by engrafting human fetal thymus/liver tissues. In porcine hematopoietic chimeras, human thymus grafts were populated with porcine class IIhigh cells in addition to human cells, and human T cells were tolerant of the porcine hematopoietic donor as measured by mixed lymphocyte reaction assay and skin grafting. This study proves the principle that porcine chimerism induces tolerance of xenoreactive human T cells.
Genetic variation responsible for mouse strain differences in integrin α2 expression is associated with altered platelet responses to collagen
Authors: Li Tong-Tong , Larrucea Susana , Souza Shiloe , Leal Suzanne M. , López José A. , Rubin Edward M. , Nieswandt Bernhard , Bray Paul F. 
Published: January 2004

Abstract
As mouse models have become commonplace for studying hemostasis and thrombosis, we considered whether the mouse system had utility for assessing genetic alterations in platelet receptors. Platelets from 5 mouse strains (C57BL/6 [C57], FVB/N [FVB], BALB/c, C3H/He, and 129Sv) showed only minor differences in the expression of integrin αIIb, integrin β3, glycoprotein (GP) Ibα, or GPVI across strains. However, FVB platelets expressed approximately 50% the level of integrin α2 as platelets from other strains (P &lt; .0001). We bred FVB mice with C57 and assessed α2 expression in FVB/C57xFVB/C57 (F2) offspring. Linkage analysis demonstrated the gene responsible for α2 levels is tightly linked to the D13mit260 marker (log odds [lod] score 6.7) near the α2 gene. FVB platelets showed reduced aggregation and a longer lag phase to collagen. FVB and C57 platelets aggregated similarly to collagen-related peptide, but FVB platelets showed a reduction in rhodocytin-induced Syk and PLCγ2 tyrosine phosphorylation. Thus, FVB platelets express half the level of α2 as other mouse strains, a trait linked to the α2 gene and seemingly responsible for reduced platelet aggregation to collagen. These strain differences serve as a useful model for the 2-fold difference in human platelet α2β1 expression and demonstrate that α2β1 participates in signaling during platelet activation. (Blood. 2004;103:3396-3402)
Hepatic low-density lipoprotein receptor–related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol
Authors: Espirito Santo Sonia M. S. , Pires Nuno M. M. , Boesten Lianne S. M. , Gerritsen Gery , Bovenschen Niels , van Dijk Ko Willems , Jukema J. Wouter , Princen Hans M. G. , Bensadoun André , Li Wei-Ping , Herz Joachim , Havekes Louis M. , van Vlijmen Bart J. M. 
Published: January 2004

AbstractThe low-density lipoprotein (LDL) receptor–related protein (LRP) has a well-established role in the hepatic removal of atherogenic apolipoprotein E (APOE)–rich remnant lipoproteins from plasma. In addition, LRP recognizes multiple distinct pro- and antiatherogenic ligands in vitro. Here, we investigated the role of hepatic LRP in atherogenesis independent of its role in removal of APOE-rich remnant lipoproteins. Mice that allow inducible inactivation of hepatic LRP were combined with LDL receptor and APOE double-deficient mice (MX1Cre+LRPflox/floxLDLR–/–APOE–/–). On an LDLR–/–APOE–/– background, hepatic LRP deficiency resulted in decreased plasma cholesterol and triglycerides (cholesterol: 17.1 ± 5.2 vs 23.4 ± 6.3 mM, P = .025; triglycerides: 1.1 ± 0.5 vs 2.2 ± 0.8 mM, P = .002, for MX1Cre+LRPflox/flox-LDLR–/–APOE–/– and control LRPflox/flox-LDLR–/–APOE–/– mice, respectively). Lower plasma cholesterol in MX1Cre+LRPflox/flox-LDLR–/–APOE–/– mice coincided with increased plasma lipoprotein lipase (71.2 ± 7.5 vs 19.1 ± 2.4 ng/ml, P = .002), coagulation factor VIII (4.4 ± 1.1 vs 1.9 ± 0.5 U/mL, P = .001), von Willebrand factor (2.8 ± 0.6 vs 1.4 ± 0.3 U/mL, P = .001), and tissue-type plasminogen activator (1.7 ± 0.7 vs 0.9 ± 0.5 ng/ml, P = .008) compared with controls. Strikingly, MX1Cre+LRPflox/floxLDLR–/–APOE–/– mice showed a 2-fold higher atherosclerotic lesion area compared with controls (408.5 ± 115.1 vs 219.1 ± 86.0 103μm2, P = .003). Our data indicate that hepatic LRP plays a clear protective role in atherogenesis independent of plasma cholesterol, possibly due to maintaining low levels of its proatherogenic ligands.
Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study
Authors: Dispenzieri Angela , Kyle Robert A. , Lacy Martha Q. , Therneau Terry M. , Larson Dirk R. , Plevak Matthew F. , Rajkumar S. Vincent , Fonseca Rafael , Greipp Philip R. , Witzig Thomas E. , Lust John A. , Zeldenrust Steven R. , Snow Denise S. , Hayman Susan R. , Litzow Mark R. , Gastineau Dennis A. , Tefferi Ayalew , Inwards David J. , Micallef Ivana N. , Ansell Stephen M. , Porrata Luis F. , Elliott Michelle A. , Gertz Morie A. 
Published: January 2004

AbstractPrimary systemic amyloidosis (AL) is a plasma cell dyscrasia resulting in multisystem failure and death. High-dose chemotherapy with peripheral blood stem cell transplantation (PBSCT) has been associated with higher response rates and seemingly higher overall survival than standard chemotherapy. Selection bias, however, confounds interpretation of these results. We performed a case-match-control study comparing overall survival of 63 AL patients undergoing transplantation with 63 patients not undergoing transplantation. Matching criteria included age, sex, time to presentation, left ventricular ejection fraction, serum creatinine, septal thickness, nerve involvement, 24-hour urine protein, and serum alkaline phosphatase. According to design, there was no difference between the groups with respect to sex (57% males), age (median, 53 years), left ventricular ejection fraction (65%), number of patients with peripheral nerve involvement (17%), cardiac interventricular septal wall thickness (12 mm), serum creatinine (1.1 mg/dL [97.24 μmol/L]), and bone marrow plasmacytosis (8%). Sixty-six patients have died (16 cases and 50 controls). For PBSCT and control groups, respectively, the 1-, 2-, and 4-year overall survival rates are 89% and 71%; 81% and 55%; and 71% and 41%. Outside a randomized clinical trial, these results present the strongest data supporting the role of PBSCT in selected patients with AL.
Virally stimulated plasmacytoid dendritic cells produce chemokines and induce migration of T and NK cells
Authors: Megjugorac Nicholas J , Young Howard A , Amrute Sheela B , Olshalsky Stacey L , Fitzgerald-Bocarsly Patricia 
Published: January 2004

AbstractThe natural interferon (IFN)-producing cell is now known to be identical to the plasmacytoid dendritic cell (PDC). These are Lin−, CD123+, CD11c−, and human leukocyte antigen-DR+ cells that secrete large amounts of IFN-α (1–2 IU/cell) when stimulated by enveloped viruses such as herpes simplex virus. In the current study, we have evaluated chemokine expression by virally stimulated PDC. Up-regulation of mRNA for CCL4, CCL3, CCL5, CCL2, and CXC chemokine ligand (CXCL)10 in herpes simplex virus-stimulated PDC was detected by RNAse protection assays. In contrast, PDC-depleted peripheral blood mononuclear cells did not up-regulate these mRNA species upon viral stimulation. Enzyme-linked immunosorbent assay and/or intracellular flow cytometry confirmed production of these proteins, and studies indicated overlapping production of IFN-α and the other cytokines/chemokines by PDC. Endocytosis plays a critical role in chemokine induction, as disruption of the pathway inhibits the response. However, transcription of viral genes is not required for chemokine induction. Autocrine IFN-α signaling in the PDC could account for a portion of the CXCL10 and CCL2 production in virally stimulated PDC but was not responsible for the induction of the other chemokines. To evaluate the functional role of the chemokines, chemotaxis assays were performed using supernatants from virally stimulated PDC. Activated T cells and natural killer cells, but not naïve T cells, were preferentially recruited by these PDC supernatants. Migration was subsequently inhibited by addition of neutralizing antibody to CCL4 and CXCL10. We hypothesize that virally induced chemokine production plays a pivotal role in the homing of leukocytes to PDC.
Delay of neutrophil apoptosis in acute coronary syndromes
Authors: Garlichs C D , Eskafi S , Cicha I , Schmeisser A , Walzog B , Raaz D , Stumpf C , Yilmaz A , Bremer J , Ludwig J , Daniel W G 
Published: January 2004

AbstractApoptosis of polymorphonuclear neutrophils (PMN) is currently discussed as a key event in the control of inflammation. This study determined PMN apoptosis and its underlying mechanisms in controls (C), patients with stable (SAP) or unstable angina (UAP), and with acute myocardial infarction (AMI). Blood was drawn from 15 subjects of each C, SAP, UAP, and AMI. Apoptosis was measured by flow cytometry in isolated PMN (propidium iodide staining) and PMN from whole blood (CD16, FcγRIII). Serum cytokines were determined by enzyme-linked immunosorbent assay. Apoptosis of isolated PMN was delayed significantly in acute coronary syndromes (ACS) as compared with SAP or C (C, 51.2±12.6%; SAP, 44.9±13.6%; UAP, 28.4±10.1%; AMI, 20.3±8.5%; AMI or UAP vs. SAP or C, P&lt;0.001). These results were confirmed by measurement of PMN apoptosis in cultured whole blood from patients and controls. Moreover, serum of patients with ACS markedly reduced apoptosis of PMN from healthy donors. Analysis of patients’ sera revealed significantly elevated concentrations of tumor necrosis factor α, interferon-γ (IFN-γ), granulocyte macrophage-colony stimulating factor (GM-CSF), and interleukin (IL)-1β in ACS (vs. C and SAP). IFN-γ, GM-CSF, and IL-1β significantly delayed PMN apoptosis in vitro. Furthermore, coincubation of PMN with adenosine 5′-diphosphate-activated platelets significantly inhibited PMN apoptosis as compared with coculture with unstimulated platelets. This study demonstrates a pronounced delay of PMN apoptosis in UAP and AMI, which may result from increased serum levels of IFN-γ, GM-CSF, and IL-1β and from enhanced platelet activation. Therapeutical modulation of these determinants of PMN lifespan may provide a new concept for the control of inflammation in ACS.
Diversity in the Sir2 family of protein deacetylases
Authors: Buck Stephen W , Gallo Christopher M , Smith Jeffrey S 
Published: January 2004

AbstractThe silent information regulator (Sir2) family of protein deacetylases (Sirtuins) are nicotinamide adenine dinucleotide (NAD)+-dependent enzymes that hydrolyze one molecule of NAD+ for every lysine residue that is deacetylated. The Sirtuins are phylogenetically conserved in eukaryotes, prokaryotes, and Archeal species. Prokaryotic and Archeal species usually have one or two Sirtuin homologs, whereas eukaryotes typically have multiple versions. The founding member of this protein family is the Sir2 histone deacetylase of Saccharomyces cerevisiae, which is absolutely required for transcriptional silencing in this organism. Sirtuins in other organisms often have nonhistone substrates and in eukaryotes, are not always localized in the nucleus. The diversity of substrates is reflected in the various biological activities that Sirtuins function, including development, metabolism, apoptosis, and heterochromatin formation. This review emphasizes the great diversity in Sirtuin function and highlights its unusual catalytic properties.
Preassociation of nonactivated STAT3 molecules demonstrated in living cells using bioluminescence resonance energy transfer: a new model of STAT activation?
Authors: Schröder Martina , Kroeger Karen M , Volk Hans-Dieter , Eidne Karin A , Grütz Gerald 
Published: January 2004

AbstractSignal transducers and activators of transcription (STATs) are crucial molecules in cytokine signaling. In th conventional model of STAT activation, STAT molecules are recruited from a latent pool of cytoplasmic monomers to the activated cytokine receptor. After binding to the receptor, they get tyrosine-phosphorylated, dissociate from the receptor, and translocate to the nucleus as activation-induced dimers. Recently, several publications questioned this model of STAT activation and showed the existence of preassociated STAT molecules before activation. We were able to demonstrate the existence of these preassociated STAT3 molecules in living mammalian cells using bioluminescence resonance energy transfer. Our results support the new hypothesis that STAT molecules exist in the cytoplasm as dimers or multimers and point to an activation-induced change in STAT3 conformation. Therefore, we propose a new model of STAT activation and discuss a hypothetical structure of “cytoplasmic” STAT dimers as opposed to the known “activation-induced” dimer.
Induction of various immune modulatory molecules in CD34+ hematopoietic cells
Authors: Umland Oliver , Heine Holger , Miehe Michaela , Marienfeld Kathleen , Staubach Karl H , Ulmer Artur J 
Published: January 2004

AbstractLipopolysaccharide (LPS) has been shown to induce proliferation of human T-lymphocytes only in the presence of monocytes and CD34+ hematopoietic cells (HCs) from peripheral blood. This finding provided evidence of an active role of CD34+ HCs during inflammation and immunological events. To investigate mechanisms by which CD34+ HCs become activated and exert their immune-modulatory function, we used the human CD34+ acute myeloid leukemia cell line KG-1a and CD34+ bone marrow cells (BMCs). We showed that culture supernatants of LPS-stimulated mononuclear cells (SUPLPS) as well as tumor necrosis factor α (ΤNF-α), but not LPS alone, can activate nuclear factor-κB in KG-1a cells. By cDNA subtraction and multiplex polymerase chain reaction, we revealed differential expression of cellular inhibitor of apoptosis protein-1, inhibitor of κB (IκB)/IκBα (MAD-3), and intercellular adhesion molecule-1 (ICAM-1) in SUPLPS-stimulated KG-1a cells and up-regulation of interferon (IFN)-inducible T cell-chemoattractant, interleukin (IL)-8, macrophage-inflammatory protein-1α (MIP-1α), MIP-1β, RANTES, CD70, granulocyte macrophage-colony stimulating factor, and IL-1β in stimulated KG-1a cells and CD34+ BMCs. Although monokine induced by IFN-γ, IFN-inducible protein 10, and IFN-γ were exclusively up-regulated in KG-1a cells, differential expression of monocyte chemoattractant protein-1 (MCP-1), macrophage-derived chemokine, myeloid progenitor inhibitory factor-2, and IL-18 receptor was only detectable in CD34+ BMCs. More importantly, CD34+ BMCs stimulated by TNF-α also showed enhanced secretion of MCP-1, MIP-1α, MIP-1β, and IL-8, and increased ICAM-1 protein expression could be detected in stimulated KG-1a cells and CD34+ BMCs. Furthermore, we revealed that T cell proliferation can be induced by TNF-α-stimulated KG-1a cells, which is preventable by blocking anti-ICAM-1 monoclonal antibodies. Our results demonstrate that CD34+ HCs have the potential to express a variety of immune-regulatory mediators upon stimulation by inflammatory cytokines including TNF-α, which may contribute to innate- and adaptive-immune processes.
Stimulated human neutrophils form biologically active kinin peptides from high and low molecular weight kininogens
Authors: Stuardo Miguel , Gonzalez Carlos B , Nualart Francisco , Boric Mauricio , Corthorn Jenny , Bhoola Kanti D , Figueroa Carlos D 
Published: January 2004

AbstractHuman neutrophils play a pivotal role in acute inflammation. However, their capacity to generate bioactive kinin peptides has not been established as yet. We have examined the ability of neutrophil enzymes to release biologically active kinins in vitro from purified human H- and L-kininogens. Neutrophils isolated from human blood were stimulated with f-Met-Leu-Phe, thrombin, or human immunoglobulin G adsorbed to silica particles. Supernatants were incubated with iodinated kininogens, and polyacrylamide gel electrophoresis analyzed aliquots taken after a range of incubation times. A time-course analysis demonstrated that supernatants from stimulated neutrophils caused a rapid hydrolysis of both substrates, resulting in an accumulation of fragments ranging from 20 to less than 10 kDa. Radioimmunoassay (RIA) revealed that all supernatants were able to generate kinins in vitro. High-performance liquid chromatography of the generated peptides indicated that they had a retention time similar to that of bradykinin and Met-Lys-bradykinin, clearly recognized as kinin peptides when the corresponding fractions were tested by RIA. The kinin-immunoreactive fractions produced lowering of blood pressure and a dramatic increase in venular permeability. Biological activity of the neutrophil-generated kinins was completely abolished by the B2 receptor antagonist HOE140, indicating that over the time-course of the experiments, only kinin B2 agonists appeared to have been generated and that cellular actions of these were mediated by kinin B2 receptors. Together, our results demonstrate that human neutrophil proteases can release kinins from both plasma kininogens, suggesting that these peptides may participate actively during acute inflammation.