bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Prevalence of Serum Cryoglobulins in Multitransfused Hemophilic Patients With Chronic Hepatitis C
Authors: Santagostino E. , Colombo M. , Cultraro D. , Muça-Perja M. , Gringeri A. , Mannucci P.M. 
Published: October 2019

Abstract
The prevalence, clinical relevance, and risk factors of serum cryoglobulins in hemophilic patients with chronic hepatitis C virus (HCV) infection are unknown. We studied 135 consecutive hemophilic patients (median age, 31 years; range, 10 to 69 years) with chronic hepatitis C, exposed to the virus for 10 to 41 years. A total of 67 patients were coinfected with the human immunodeficiency virus (HIV), and 3 (2%) had signs of cirrhosis. Serum samples were tested for the presence of cryoglobulins, hepatitis B virus (HBV) markers, including HBV-DNA by hybridization assay, and antibody to HCV by enzyme immunoassay (EIA). Serum HCV-RNA was tested by polymerase chain reaction and typed with a hybridization technique. Samples were also tested for antitissue antibodies, immunoglobulins, rheumatoid factor, and C3 and C4 proteins of complement. Forty-two hemophiliacs (31%) circulated cryoglobulins (median levels, 166 mg/L; range, 66 to 480) predominantly type III (62%; and 29% type II). None of the patients had clinical signs or symptoms of systemic vasculitis. Cryoglobulinemic patients had more often serum HCV-RNA (95% v 80%, P &lt; .05), rheumatoid factor (20% v 6%, P &lt; .05), higher levels of IgG (2,354 ± 682 mg/dL v 1,928 ± 557 mg/dL,P &lt; .0005) and IgM (323 ± 226 mg/dL v 244 ± 243 mg/dL, P &lt; .05), and lower levels of serum C4 (19 ± 8 mg/dL v 24 ± 8 mg/dL, P &lt; .05) than patients without cryoglobulins. The risk of producing cryoglobulins was greater for 114 patients circulating HCV-RNA than for 21 nonviremic patients (odds ratio [OR] = 4.9, 95% confidence interval [CI] = 1.1 to 22.0) and for the 31 patients with longer exposure to HCV (more than 26 years) than for the 24 patients with shorter (17 years or less) exposure (OR = 4.4 95% CI = 1.1 to 18.0). In conclusion a large number of multitransfused hemophiliacs with chronic HCV infection circulated serum cryoglobulins but none had clinical signs or symptoms of vasculitis. The risk of developing cryoglobulins parallels the duration of exposure to HCV.
Detection of Microchimerism After Allogeneic Blood Transfusion Using Nested Polymerase Chain Reaction Amplification With Sequence-Specific Primers (PCR-SSP): A Cautionary Tale
Authors: Carter Anthony S. , Bunce Mike , Cerundolo Lucia , Welsh Ken I. , Morris Peter J. , Fuggle Susan V. 
Published: October 2019

Abstract
In bone marrow transplantation, the detection of chimerism is an important adjunct to the repertoire of tests available for determining acceptance of the graft. In solid organ transplantation, there is currently intense interest in the role that chimerism plays in both short- and long-term host reactivity to the graft. Allogeneic blood transfusion has been associated with a subtle immunosuppressive effect in renal transplantation and chimerism is implicated as a possible mechanism for this effect. To assess the survival of allogeneic cells after blood transfusion or transplantation, we have developed a technique based on molecular typing for HLA class II alleles, which enables the detection of donor-derived cells in patients receiving blood transfusions. While developing this technology, we investigated why we and others observe false amplification. Sequencing of false products has shown that they arise from amplification of both pseudogenes and non-pseudogenes present in the DNA under test. Elucidation of this phenomenon allows the amplification of these false products to be predicted in any given combination and hence avoided by the judicious selection of primers. Validation has been achieved by following donor alleles after transfusion of blood containing defined numbers of leukocytes expressing selected mismatched antigens.
Antigen Presenting Phenotype of Hodgkin Reed-Sternberg Cells: Analysis of the HLA Class I Processing Pathway and the Effects of Interleukin-10 on Epstein-Barr Virus-Specific Cytotoxic T-Cell Recognition
Authors: Lee Steven P. , Constandinou Christothea M. , Thomas Wendy A. , Croom-Carter Debbie , Blake Neil W. , Murray Paul G. , Crocker John , Rickinson Alan B. 
Published: October 2019

AbstractApproximately 40% of Hodgkin's disease (HD) cases in Western countries carry Epstein-Barr virus (EBV) in the malignant Hodgkin-Reed-Sternberg (H-RS) cells. HLA class I–restricted cytotoxic T lymphocytes (CTLs) with specificity for viral antigens expressed in H-RS cells therefore have therapeutic potential. However, a prerequisite for CTL therapy is that the tumor target be capable of processing and presenting endogenously expressed antigens via the transporter associated with antigen processing (TAP)-dependent HLA class I pathway. We have assessed the antigen-presenting phenotype of H-RS cells in two ways. First, immunohistochemical analysis of 38 HD biopsies showed that H-RS cells were uniformly TAP1/TAP2-positive and expressed HLA class I in the majority (18 of 24, 75%) of EBV-positive cases compared with only 4 of 14 (29%) of EBV-negative cases. Second, using a panel of 5 H-RS cell lines, we showed that 4 of 5 could process and present EBV proteins to HLA class I–restricted EBV-specific CTL clones. Others have reported that human interleukin-10 (IL-10), which is expressed by H-RS cells in the majority of EBV-positive HD cases, can abrogate CTL recognition in some circumstances. However, IL-10 pretreatment of the H-RS lines or of the EBV-specific CTLs had no such effect in this system. These results support the possibility that EBV-specific CTLs may be used to treat virus-positive HD.© 1998 by The American Society of Hematology.
Triggering of CD40 Antigen Inhibits Fludarabine-Induced Apoptosis in B Chronic Lymphocytic Leukemia Cells
Authors: Romano Maria Fiammetta , Lamberti Annalisa , Tassone Pierfrancesco , Alfinito Fiorella , Costantini Silvia , Chiurazzi Federico , Defrance Thierry , Bonelli Patrizio , Tuccillo Franca , Turco Maria Caterina , Venuta Salvatore 
Published: October 2019

AbstractWe analyzed the effect of CD40 triggering on the fludarabine-induced apoptosis of B chronic lymphocytic leukemia (B-CLL) cells. Peripheral blood samples obtained from 15 patients were incubated with fludarabine in the absence or the presence of the anti-CD40 monoclonal antibody (MoAb) G28-5. In 12 patients a significant proportion of apoptotic cells, ranging from 22% to 38% (mean ± SE: 28.5 ± 1.6), were detected after 3 days of culture. In 9 of these samples, the addition of G28-5 reduced apoptosis by at least 30.1% and by 57.1% ± 7.8% on average (P = .0077). Because the CD40 antigen activates NF-κB/Rel transcription factors in B cells, and NF-κB/Rel complexes can inhibit cell apoptosis, we investigated whether the antiapoptotic effect of G28-5, in our system, could be related to modulation of NF-κB/Rel activity. As expected, B-CLL cells displayed significant levels of nuclear NF-κB/Rel activity; p50, RelA, and c-Rel components of the NF-κB/Rel protein family were identified in these complexes. After exposure to fludarabine, NF-κB/Rel complexes were decreased in the nuclei. The addition of G28-5 upregulated the NF-κB/Rel levels. To determine the involvement of NF-κB/Rel activity in the G28-5–mediated inhibition of apoptosis, we blocked the transcription factor with a decoy oligonucleotide, corresponding to the NF-κB/Rel consensus sequence. Cells incubated with the anti-CD40 MoAb in the presence of the decoy oligonucleotide but not a control oligonucleotide displayed a complete impairment of the G28-5 antiapoptotic effect, indicating that NF-κB/Rel activity was required for the inhibition of apoptosis. These results suggest that CD40 triggering in vivo could counteract the apoptotic effect of fludarabine on B-CLL cells and that its neutralization, or the use of NF-κB/Rel inhibitors, could improve the therapeutic effect of fludarabine.© 1998 by The American Society of Hematology.
Compstatin Inhibits Complement and Cellular Activation in Whole Blood in Two Models of Extracorporeal Circulation
Authors: Nilsson Bo , Larsson Rolf , Hong Jaan , Elgue Graciela , Ekdahl Kristina Nilsson , Sahu Arvind , Lambris John D. 
Published: October 2019

AbstractRecently, a C3-binding cyclic synthetic peptide (Compstatin) has been identified that binds to complement component C3 and inhibits complement activation. Here we have examined the influence of Compstatin on complement activation and its indirect effects on cellular responses in whole blood in two models for extracorporeal circulation. Compstatin effectively inhibited the generation of C3a and sC5b-9 and the binding of C3/ C3 fragments to the polymer surface. As a result of the inhibition of complement activation, the activation of polymorphonuclear leukocytes (PMNs; as assessed by the expression of CD11b) and the binding of these cells (CD16+) to the polymer surface were almost completely lost. In contrast, blood cell counts were not affected. Using surface plasmon resonance technology, we have confirmed that Compstatin exerts its inhibitory effect on complement activation by binding to native C3. These data show that complement activation, leading to activation and binding of PMNs to the biomaterial surface, can be abolished by the addition of Compstatin. The properties of Compstatin make Compstatin a promising drug for use in extracorporeal circuits to avoid bioincompatibility reactions, eg, during cardiopulmonary bypass, but also a favorable precursor peptide for the development of an anticomplement drug for oral use.© 1998 by The American Society of Hematology.
Antisense to the Epstein-Barr Virus (EBV)-Encoded Latent Membrane Protein 1 (LMP-1) Suppresses LMP-1 and Bcl-2 Expression and Promotes Apoptosis in EBV-Immortalized B Cells
Authors: Kenney Jamie L. , Guinness Mary E. , Curiel Tyler , Lacy Jill 
Published: October 2019

AbstractThe Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP-1) is required for viral transformation and functions to protect cells from apoptotic cell death, in part, by induction of antiapoptotic genes, including Bcl-2 and A20. We have used antisense oligodeoxynucleotides targeted to LMP-1 as a strategy to suppress LMP-1 expression and thereby inhibit its functions. We have shown that levels of LMP-1 protein in EBV-positive lymphoblastoid cell lines can be reduced by in vitro treatment with unmodified oligodeoxynucleotides targeted to the first five codons of the LMP-1 open-reading frame. Furthermore, suppression of LMP-1 was associated with molecular and phenotypic effects that included downregulation of the LMP-1–inducible antiapoptotic genes, Bcl-2 and Mcl-1, inhibition of proliferation, stimulation of apoptosis, and enhancement of sensitivity to the chemotherapeutic agent, etoposide. These effects were largely sequence-specific and observed in EBV-positive, but not EBV-negative cell lines. These studies suggest that lowering expression of LMP-1 in EBV-associated malignancy might have therapeutic effects and might synergize with other antitumor agents.© 1998 by The American Society of Hematology.
Long-Term Follow-Up of Patients With Hairy Cell Leukemia After Cladribine Treatment
Authors: Saven Alan , Burian Carol , Koziol James A. , Piro Lawrence D. 
Published: October 2019

AbstractHairy cell leukemia is a chronic B-cell disorder that follows an indolent, but progressive course. Cladribine (2-chlorodeoxyadenosine) induces complete remissions in the majority of patients after a single course. We report the long-term outcomes, including response rates and their duration; time-to-treatment failure (TTF) rates; retreatment results; toxicities; and survival rates of patients treated at Scripps Clinic (La Jolla, CA). A total of 358 patients with hairy cell leukemia were treated with cladribine at 0.087 or 0.1 mg/kg body weight per day by continuous intravenous infusion for 7 days. The expected number of second neoplasms was based on the National Cancer Institute’s Surveillance Epidemiology and End Results data. Of 349 evaluable patients, 319 (91%) achieved an initial complete response and 22 (7%) a partial response with an overall median duration of response follow-up of 52 months. Ninety patients (26%) had relapsed at a median of 29 months. The TTF rate for all 341 responders was 19% at 48 months, 16% for complete responders, and 54% for partial responders. Of 53 evaluable patients treated with second courses of cladribine at first relapse, 33 (62%) achieved complete responses and 14 (26%) partial responses. Twenty-seven patients (8%) developed second neoplasms (only 1 hematopoietic) with an observed-to-expected ratio of 1.88 (95% confidence interval, 1.24 to 2.74). The overall survival rate was 96% at 48 months. Single courses of cladribine induced long-lasting complete responses in the vast majority of patients. Relapse rates for complete responders were low. Patients who relapse can be successfully retreated with cladribine. Cladribine has high efficacy and a favorable acute and long-term toxicity profile when administered to patients with hairy cell leukemia.© 1998 by The American Society of Hematology.
Activation of the Small GTPase Rap1 in Human Neutrophils
Authors: M’Rabet Laura , Coffer Paul , Zwartkruis Fried , Franke Barbara , Segal Anthony W. , Koenderman Leo , Bos Johannes L. 
Published: October 2019

AbstractThe small GTPase Rap1 is highly expressed in human neutrophils, but its function is largely unknown. Using the Rap1-binding domain of RalGDS (RalGDS-RBD) as an activation-specific probe for Rap1, we have investigated the regulation of Rap1 activity in primary human neutrophils. We found that a variety of stimuli involved in neutrophil activation, including fMet-Leu-Phe (fMLP), platelet-activating factor (PAF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IgG-coated particles, induce a rapid and transient Rap1 activation. In addition, we found that Rap1 is normally activated in neutrophils from chronic granulomatous disease patients that lack cytochrome b558 or p47phox and have a defective NADPH oxidase system. From these results we conclude that in neutrophils Rap1 is activated independently of respiratory burst induction. Finally, we found that Rap1 is activated by both the Ca2+ ionophore ionomycin and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), indicating that phospholipase C (PLC) activation leading to elevated levels of intracellular free Ca2+ and diacylglycerol (DAG) can mediate Rap1 activation. However, inhibition of PLC and Ca2+ depletion only marginally affected fMLP-induced Rap1 activation, suggesting that additional pathways may control Rap1 activation.© 1998 by The American Society of Hematology.
Overlapping Functions of E- and P-Selectin in Neutrophil Recruitment During Acute Inflammation
Authors: Homeister Jonathon W. , Zhang Mengkun , Frenette Paul S. , Hynes Richard O. , Wagner Denisa D. , Lowe John B. , Marks Rory M. 
Published: October 2019

AbstractSelectin adhesion molecules mediate leukocyte rolling on activated endothelium, a prerequisite to leukocyte accumulation at sites of inflammation. The precise role of each selectin (E-, P-, and L-) in this process is unclear and may vary depending on the particular inflammatory stimulus, vascular bed, leukocyte subset, and species; most data suggest discrete functional roles for each selectin. To define the relative roles of E- and P-selectin in mediating neutrophil accumulation in acute dermal inflammation, mice genetically deficient in E-selectin, P-selectin, or both E- and P-selectin were injected intradermally with zymosan. Luminal endothelial expression of E- and P-selectin in response to zymosan was documented in wild-type mice by intravenous administration of fluorochrome-labeled anti–E- and anti–P-selectin antibodies. In mice deficient in E- or P-selectin, neutrophil accumulation was unchanged or only subtly reduced relative to wild-type control mice. In mice deficient in both E- and P-selectin, neutrophil accumulation was significantly reduced (87% at 4 hours and 79% at 8 hours). These data demonstrate that, in this model of acute inflammation, there is considerable overlap in the functions of E- and P-selectin; loss of both selectins was required to impair neutrophil accumulation.
Interleukin-4 and -13 Induce Upregulation of the Murine Macrophage 12/15-Lipoxygenase Activity: Evidence for the Involvement of Transcription Factor STAT6
Authors: Heydeck Dagmar , Thomas Leo , Schnurr Kerstin , Trebus Frank , Thierfelder William E. , Ihle James N. , Kühn Hartmut 
Published: October 2019

AbstractWhen human monocytes or alveolar macrophages are cultured in the presence of interleukin (IL)-4 or IL-13, the expression of the reticulocyte-type 15-lipoxygenase is induced. In mice a 15-lipoxygenase is not expressed, but a leukocyte-type 12-lipoxygenase is present in peritoneal macrophages. To investigate whether both lipoxygenase isoforms exhibit a similar regulatory response toward cytokine stimulation, we studied the regulation of the leukocyte-type 12-lipoxygenase of murine peritoneal macrophages by interleukins and found that the activity of this enzyme is upregulated in a dose-dependent manner when the cells were cultured in the presence of the IL-4 or IL-13 but not by IL-10. When peripheral murine monocytes that do not express the lipoxygenase were treated with IL-4 expression of 12/15-lipoxygenase mRNA was induced, suggesting pretranslational control mechanisms. In contrast, no upregulation of the lipoxygenase activity was observed when the macrophages were prepared from homozygous STAT6-deficient mice. Peritoneal macrophages of transgenic mice that systemically overexpress IL-4 exhibited a threefold to fourfold higher 12-lipoxygenase activity than cells prepared from control animals. A similar upregulation of 12-lipoxygenase activity was detected in heart, spleen, and lung of the transgenic animals. Moreover, a strong induction of the enzyme was observed in red cells during experimental anemia in mice. The data presented here indicate that (1) the 12-lipoxygenase activity of murine macrophages is upregulated in vitro and in vivo by IL-4 and/or IL-13, (2) this upregulation requires expression of the transcription factor STAT6, and (3) the constitutive expression of the enzyme appears to be STAT6 independent. The cytokine-dependent upregulation of the murine macrophage 12-lipoxygenase and its induction during experimental anemia suggests its close relatedness with the human reticulocyte-type 15-lipoxygenase despite their differences in the positional specificity of arachidonic acid oxygenation.
Plasma Endothelin-1, Cytokine, and Prostaglandin E2Levels in Sickle Cell Disease and Acute Vaso-Occlusive Sickle Crisis
Authors: Graido-Gonzalez Evangeline , Doherty James C. , Bergreen Eric W. , Organ Gregory , Telfer Margaret , McMillen Marvin A. 
Published: October 2019

AbstractThe relative contributions of microvascular inflammation and vasomotor dysregulation to the development of acute vaso-occlusive crisis in sickle cell disease have been intensely studied. The present observational study was designed to examine the levels of circulating proinflammatory cytokines, anti-inflammatory cytokines, and vasoactive mediators during and after acute painful crisis. In symptomatic sickle cell patients, plasma levels of endothelin-1 and prostaglandin E2 were elevated during crises compared with healthy African-American controls. These levels had decreased, but not normalized, when patients were seen 1 to 3 weeks after discharge from hospital. Other mediators (tumor necrosis factor α [TNFα], interleukin-1β [IL-1β], IL-6, IL-8, and IL-10) were neither elevated in asymptomatic sickle cell disease nor in acute vaso-occlusive crisis. As a potent long-acting mediator of vasoconstriction and inflammation, endothelin-1 may play a key role in the cycle of ischemia and inflammation that initiates and sustains pain of crisis. The downregulatory effects of prostaglandin E2on immune cell function may contribute to the increased susceptibility to infection observed in patients with sickle cell disease.
A Regulatory Role for Fcγ Receptors CD16 and CD32 in the Development of Murine B Cells
Authors: de Andres Belen , Mueller Allan L. , Verbeek Sjef , Sandor Matyas , Lynch Richard G. 
Published: October 2019

AbstractEarly in development, murine B-lineage progenitor cells express two classes of IgG Fc receptors (FcγR) designated as FcγRII (CD32) and FcγRIII (CD16), but mature B lymphocytes only express FcγRII (CD32), which functions as an inhibitor of B-cell activation when it is induced to associate with mIgM. The functions of CD16 and CD32 on B-lineage precursor cells have not previously been investigated. To search for FcγR functions on developing B-lineage cells, normal murine bone marrow cells were cultured in the presence of 2.4G2, a rat monoclonal antibody that binds to CD16 and CD32, or in the presence of control normal rat IgG, and then the B-lineage compartment was analyzed for effects. Cultures that contained 2.4G2 showed enhanced growth and differentiation of B-lineage cells compared with control cultures. The enhancing effect of 2.4G2 also occurred when fluorescence-activated cell-sorted B-cell precursors (B220+, sIgM−, HSAhigh, FcγR+) from normal bone marrow were cocultured with BMS2, a bone marrow stromal cell line, but not when they were cultured in BMS2-conditioned media. The enhancement of B-lineage development induced by 2.4G2 was CD16-dependent and CD32-dependent, because 2.4G2 did not effect B-lineage growth or differentiation in cultures of bone marrow from mice in which either the gene encoding CD16 or CD32 had been disrupted. Analysis of fresh bone marrow from the CD16 gene-disrupted mice showed normal numbers and distribution of cells within the B-cell compartment, but in CD32 gene-disrupted mice, the B-cell compartment was significantly enlarged. These experiments provide several lines of evidence that the FcγR expressed on murine B-cell precursors can influence their growth and differentiation.© 1998 by The American Society of Hematology.