bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning
Authors: Bethge Wolfgang A. , Hegenbart Ute , Stuart Monic J. , Storer Barry E. , Maris Michael B. , Flowers Mary E. D. , Maloney David G. , Chauncey Thomas , Bruno Benedetto , Agura Ed , Forman Stephen J. , Blume Karl G. , Niederwieser Dietger , Storb Rainer , Sandmaier Brenda M. 
Published: October 2003

AbstractThis study retrospectively analyzed data from 446 patients given hematopoietic cell transplants from HLA-matched related or unrelated donors after conditioning with 2 Gy total body irradiation with or without fludarabine and postgrafting immunosuppression with mycophenolate mofetil and cyclosporine following grafting. Fifty-three of 446 patients received donor lymphocyte infusion (DLI) with a median CD3 dose of 1 × 107 cells/kg. Their diagnoses included myelodysplastic syndrome (n = 10), acute leukemia (n = 10), chronic leukemia (n = 11), multiple myeloma (n = 9), lymphoma (n = 9), and solid tumors (n = 4). Patients received DLI for persistent disease (n = 8), disease relapse (n = 17), progressive disease (n = 12), low donor chimerism with disease (n = 11), or low chimerism with disease remission (n = 5). Seventeen of the 53 patients (32%) are alive with a median follow-up of 30 months; 5 are in complete remission (CR), 2 are in partial remission (PR), and 10 have stable or progressive disease. Nine of 53 patients (17%) developed grades II to IV acute graft-versus-host disease. Of 48 patients receiving DLI for treatment of disease, 7 achieved CR and 5 PR, with an overall response rate of 25%. Six of 16 patients who received DLI for chimerism had increases in donor chimerism leading to sustained engraftment, whereas 10 eventually rejected their grafts. In conclusion, DLI is a potential treatment strategy, with acceptable toxicity, for patients with persistent, relapsed, or progressive disease after nonmyeloablative hematopoietic cell transplantation.
Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1α
Authors: Blouin Caroline C. , Pagé Elisabeth L. , Soucy Guylaine M. , Richard Darren E. 
Published: October 2003

AbstractHypoxia-inducible factor 1 (HIF-1) regulates many genes induced by low oxygen conditions. The expression of important hypoxic genes such as glucose transporter 1 and vascular endothelial growth factor are increased in macrophages during wound healing and in the presence of the endotoxin, lipopolysaccharide (LPS). Recent studies have demonstrated that nonhypoxic stimuli can also activate HIF-1 in a cell-specific manner. Here, we demonstrate that in macrophages, LPS can control the activation of hypoxia-regulated genes through the HIF-1 pathway. We show that in these cells, protein expression levels of HIF-1α are strongly increased to levels comparable to hypoxic induction. HIF-1α mRNA levels are markedly increased following LPS stimulation, suggesting a transcriptional induction. In functional studies, the LPS-induced HIF-1 complex could specifically bind to the HIF-1 DNA-binding motif. Additionally, when cells were transfected with an HIF-1-specific reporter construct, LPS could strongly activate the expression of the reporter to levels that surpassed those observed after hypoxic induction. This induction was blocked by the cotransfection of a dominant-negative form of HIF-1α. These results indicate that the HIF-1 complex is involved in macrophage gene activation following LPS exposure and identify a novel pathway that could play a determinant role during inflammation and wound healing. (Blood. 2004;103:1124-1130)
Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants
Authors: Marr Kieren A. , Crippa Fulvio , Leisenring Wendy , Hoyle Maggie , Boeckh Michael , Balajee S. Arunmozhi , Nichols W. Garrett , Musher Benjamin , Corey Lawrence 
Published: October 2003

Abstract
Prophylactic fluconazole prevents candidiasis; however, this drug has no activity against molds. We performed a randomized trial to determine whether prophylactic itraconazole prevents invasive mold infections (IMIs). A total of 304 patients receiving allogeneic stem cell transplants (SCT) were randomized to receive fluconazole (400 mg/d) or itraconazole (oral solution 2.5 mg/kg 3 times daily, or intravenous 200 mg daily) for 180 days after SC transplantation, or until 4 weeks after discontinuation of graft-versus-host disease (GVHD) therapy. Proven or probable invasive fungal infections (IFI) were evaluated by intent-to-treat and “on-treatment” analyses. More patients in the itraconazole arm developed hepatotoxicities, and more patients were discontinued from itraconazole because of toxicities or gastrointestinal (GI) intolerance (36% versus 16%, P &lt; .001). Intent-to-treat analysis demonstrated no difference in the incidence of IFI during the intended study period (fluconazole 16% versus itraconazole 13%, P = .46); however, fewer patients in the itraconazole arm developed IFI on treatment (fluconazole 15% versus itraconazole 7%, P = .03). Itraconazole provided better protection against IMI (fluconazole 12% versus itraconazole 5%, P = .03), but similar protection against candidiasis (3% versus 2%, P = .69). There was no difference in overall or fungal-free survival. Itraconazole appears to prevent IMI in the subset of patients who tolerate the drug; however, toxicities and poor tolerability limit its success as prophylactic therapy.
T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome
Authors: Piliero Lisa M. , Sanford Amy N. , McDonald-McGinn Donna M. , Zackai Elaine H. , Sullivan Kathleen E. 
Published: October 2003

AbstractPatients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) typically exhibit thymic hypoplasia, conotruncal cardiac defects, and hypoparathyroidism. The immunodeficiency that results from the thymic hypoplasia has been extensively described and consists primarily of T-cell lymphopenia. A curious feature of the T-cell lymphopenia is that the age-related rate of decline of T-cell numbers is slower in patients than controls. This leads to T-cell numbers in adulthood that are minimally decreased compared with controls. This suggests that homeostatic mechanisms might be acting to preserve the peripheral blood T-cell numbers in patients. We characterized changes in CD4/CD45RA and CD4/CD45RO T-cell populations in patients and controls of various ages and determined T-cell recombination excision circles and telomere length within the CD4/CD45RA population. Patients had evidence of accelerated conversion of naive to memory cells and had evidence of more extensive replicative history within the CD4/CD45RA compartment compared with controls. Oligoclonal T-cell receptor (TCR) Vβ families and missing Vβ families were seen more often in patients than controls. These data are consistent with homeostatic proliferation of T cells in patients with limited T-cell production due to thymic hypoplasia. (Blood. 2004;103:1020-1025)
Significance of lipopolysaccharide-binding protein (an acute phase protein) in monitoring critically ill patients
Authors: Prucha Miroslav , Herold Ivan , Zazula Roman , Dubska Ladislava , Dostal Miroslav , Hildebrand Thomas , Hyanek Josef 
Published: October 2003

Abstract
Introduction
The present study was conducted to assess the value of serum concentration of lipopolysaccharide-binding protein (LBP) in patients with systemic inflammatory response syndrome (SIRS), sepsis and septic shock with respect to its ability to differentiate between infectious and noninfectious etiologies in SIRS and to predict prognosis.

Methods
This prospective cohort study was conducted in a multidisciplinary intensive care unit. Sixty-eight patients, admitted consecutively to the intensive care unit and who met criteria for SIRS, sepsis or septic shock were included. Serum LBP was measured using an immunochemiluminiscence assay.

Results
Serum levels of LBP were significantly increased in patients with SIRS (n = 40; median 30.6 μg/ml, range 9.2–79.5 μg/ml), sepsis (n = 19; median 37.1 μg/ml, range 11.8–76.2 μg/ml) and septic shock (n = 9; median 59.7 μg/ml, range 31.1–105 μg/ml), as compared with levels in the healthy volunteers (5.1 ± 2.2 μg/ml; P < 0.0001). Serum LBP at study entry was statistically significantly lower in patients with SIRS than in those with septic shock (P < 0.014); no statistically significant difference existed between patients with SIRS and those with sepsis (P = 0.61). Specificity and sensitivity of an LBP concentration of 29.8 μg/ml to distinguish between infectious and noninfectious etiologies for SIRS were 50% and 74.2%, respectively. There was no statistically significant difference in LBP concentration between survivors and nonsurvivors in both groups of patients. Furthermore, in septic patients the LBP response appeared to exhibit a decreased magnitude.

Conclusion
LBP is a nonspecific marker of the acute phase response and cannot be used as a diagnostic tool for differentiating between infectious and noninfectious etiologies of SIRS.
Apoptosis-induced proteinase 3 membrane expression is independent from degranulation
Authors: Durant Stéphanie , Pederzoli Magali , Lepelletier Yves , Canteloup Sandrine , Nusbaum Patrick , Lesavre Philippe , Witko-Sarsat Véronique 
Published: October 2003

AbstractProteinase 3 (PR3) and human neutrophil elastase (HNE) are serine proteinases stored in the azurophilic granules of neutrophils. In contrast to HNE, PR3 is the target of antineutrophil cytoplasm antibodies (ANCA) in Wegener’s granulomatosis. The mechanisms leading to the membrane expression of PR3 and HNE are still unclear and appear to be critical to understand the pathophysiological role of ANCA. Stably transfected rat basophilic cell lines (RBL) with PR3 or HNE were used to analyze the PR3 and HNE secretion mechanisms and differentiate between them. RBL cells were lacking endogenous PR3 and HNE. They were stably transfected with HNE or PR3 or an inactive mutant of PR3 (PR3S203A). Using the calcium ionophore A23187 as a secretagogue, higher serine proteinase activity was secreted in the supernatant of RBL/HNE than in RBL/PR3. It is interesting that PR3 and PR3/S203A were also expressed at the plasma membrane, thus demonstrating that serine protease activity was not required for plasma membrane expression. In contrast, no expression of plasma membrane HNE could be detected in RBL/HNE. Apoptosis induced by etoposide was evaluated by DNA fragmentation, the presence of cytoplasmic histone-associated DNA fragments, and annexin V labeling. No membrane HNE was detected in RBL/HNE. In contrast, in RBL/PR3 and in RBL/PR3S203A, the membrane expression of PR3 and PR3S203A increased with etoposide concentrations and appeared closely related to annexin V labeling. Our data suggest that membrane PR3 originates from two distinct pools, the granular pool mobilized following degranulation or a plasma membrane pool mobilized upon apoptosis.
Notch signaling in the immune system
Authors: Hoyne Gerard F 
Published: October 2003

AbstractNotch signaling plays a preeminent role during development in not only regulating cell fate decisions, but it can also influence growth and survival of progenitor cells. In the immune system, Notch is required for the maintenance of hematopoietic stem cells and in directing T- versus B-lineage commitment. In this review, I will summarize some of the recent findings relating to the function of Notch in the immune system during lymphocyte development and in the generation and function of mature cells.
Monoclonal LYM-1 antibody-dependent cytolysis by human neutrophils exposed to GM-CSF: auto-regulation of target cell attack by cathepsin G
Authors: Ottonello Luciano , Epstein Alan L , Mancini Marina , Dapino Patrizia , Dallegri Franco 
Published: October 2003

AbstractMurine monoclonal antibody (mAb) Lym-1 is an immunoglobulin G2a specific for certain human leukocyte antigen-DR variants expressed on the surface of malignant B cells. It has been proposed for serotherapy in patients with B lymphomas. We have previously shown thatmAb Lym-1 synergizes with granulocyte macrophage-colony stimulating factor to promote Raji B-lymphoid cell lysis by human neutrophils via the intervention of neutrophil Fc receptors type II and D-mannose-inhibitable interactions between CD11b–CD18 integrins and CD66b glycoproteins. Here, we provide evidence that the process is oxygen-independent by inference related to the release of primary granules and is regulated by cathepsin G activity. The lysis was indeed reproduced by replacing normal neutrophils with cells from three patients suffering from chronic granulomatous disease, i.e., neutrophils genetically incapable of generating oxidants. Moreover, the lysis was inhibited by the serine protease inhibitor 3,4-dichloroisocoumarin and by Z-glycyl-leucyl-phenyl-chloromethyl ketone (Z-Gly-Leu-Phe-CMK), which blocks cathepsin G. Conversely, the lysis was unaffected by N-methoxysuccinyl-alanyl-alanyl-prolyl-alanyl-CMK (MeOSuc-Ala-Ala-Pro-Ala-CMK; elastase inhibitor) and MeOSuc-Ala-Ala-Pro-valine (Val)-CMK, which inhibits elastase and proteinase 3. The ability of neutrophils, engaged in cytolysis, to release cathepsin G was proved by detecting this enzymatic activity spectrophotometrically and immunocytochemically. Moreover, inhibition of cathepsin G activity by concentrations of Z-Gly-Leu-Phe-CMK, incapable of affecting elastase activity, was found to reduce the release of elastase and myeloperoxidase from neutrophils under conditions similar to those used for cytolytic assays. These findings suggest that neutrophils auto-regulate their lytic efficiency by controlling the exocytosis of primary granules via their cathepsin G activity.
Functional repertoire of dendritic cells generated in granulocyte macrophage-colony stimulating factor and interferon-α
Authors: Della Bella Silvia , Nicola Stefania , Riva Antonio , Biasin Mara , Clerici Mario , Villa Maria Luisa 
Published: October 2003

AbstractMonocyte-derived dendritic cells (DCs) generated in granulocyte macrophage-colony stimulating factor GM-CSF) and interleukin-4 (IL-4–DCs) are used to enhance antitumor immunity in cancer patients, although recent evidence suggests that their functional repertoire may be incomplete; in particular, IL-4–DCs appear unable to induce type 2 cytokine-producing T helper (Th) cells. To assess whether type 1 interferon (IFN) could replace IL-4 and generate DCs with a more complete repertoire, we characterized in detail DCs generated from human monocytes cultured with GM-CSF and IFN-α (IFN–DCs). We found that IFN-α induces DC differentiation more efficiently than IL-4, yielding similar numbers of DCs in a shorter time and that this differentiation persists upon removal of cytokines. Although IFN–DCs had a more mature immunophenotype than IL-4–DCs, showing higher expression of CD80, CD86, and CD83, they still preserved comparable endocytic and phagocytic capacities and responsiveness to maturation stimuli. IFN–DCs had strong antigen-presenting capacity, inducing intense proliferation of T cells to alloantigens or influenza virus. Moreover, IFN–DCs produced lower levels of IL-12p70 and higher levels of IFN-α, IL-4, and IL-10 than IL-4–DCs. As a consequence of this different pattern of cytokine secretion, IFN–DCs induced T cells to produce type 1 (IFN-γ) and type 2 (IL-4 and IL-10) cytokines, and as expected, IL-4–DCs induced only Th1 differentiation. As immune responses with extreme Th1 bias are considered inadequate for the induction of optimal, systemic antitumor immunity, the ability of IFN–DCs to promote more balanced cytokine responses may suggest the advisability to consider these cells in the development of future, DC-based immunotherapy trials.
The Src kinase Lyn is a negative regulator of mast cell proliferation
Authors: Hernandez-Hansen Valerie , Mackay Graham A , Lowell Clifford A , Wilson Bridget S , Oliver Janet M 
Published: October 2003

AbstractPrevious investigators have reported that deletion of the protein tyrosine kinase Lyn alters mast cell (MC) signaling responses but does not affect or reduces the cytokine-mediated proliferation of mouse bonemarrow-derived MC (BMMC) precursors and of mature MC. We observed that Lyn-deficient mice have more peritoneal MC than wild-type (WT) mice. Studies to explore this unexpected result showed that Lyn−/− BM cells expand faster than WT cells in response to interleukin (IL)-3 and stem-cell factor over the 4–5 weeks required to produce a &gt;95% pure population of granular, receptor with high affinity for immunoglobulin E-positive BMMC. Furthermore, differentiated Lyn−/− BMMC continue to proliferate more rapidly than WT BMMC and undergo less apoptosis in response to cytokine withdrawal. Additionally, Lyn−/− BMMC support greater IL-3-mediated phosphorylation of the prosurvival kinase, Akt, and the proliferative kinase, extracellular-regulated kinase 1/2. These results identify Lyn as a negative regulator of murine MC survival and proliferation.
Prevention of Descending Pneumonia in Rats with Perflubron‐delivered Tobramycin
Authors: Dickson Eric W. , Doern Gary V. , Trevino Leo , Mazzoni Michelle , Heard Stephen O. 
Published: October 2003

Abstract Objectives: Patients undergoing emergent endotracheal intubation are at increased risk for developing pneumonia. Although numerous strategies have been investigated to reduce ventilator‐associated pneumonia (VAP), the incidence of VAP and its associated mortality remains high. This investigation tested the hypothesis that LiquiVent (Alliance Pharmaceutical, San Diego, CA–LV) delivered antibiotics (via spray‐dried microspheres–SDM) would improve survival in a rat model of descending gram‐negative pneumonia. Methods: Wistar rats (n= 49) were randomized to receive prophylaxis with 1) nothing (controls); 2) intramuscular (IM) tobramycin, 3) intratracheal LV plus SDM shells (vehicle), 4) intratracheal LV plus SDM shells plus IM tobramycin, or 5) intratracheal LV plus SDM containing 1 mg/kg of tobramycin. All interventions were given 24 hours before a bacterial challenge with 108 colony‐forming units of intratracheal Klebsiella pneumoniae. Mortality at ten days was the sole outcome measure. Survival in individual groups was compared with controls by Fisher's exact test with Bonferroni correction for multiple comparisons. Results: All animals in the control group died of pneumonia within ten days of bacterial inoculation (0% survival). Prophylaxis with either IM tobramycin or SDM vehicle plus IM tobramycin provided no protection (0% survival). This is in sharp contrast to the cohort receiving pretreatment with tobramycin‐containing SDM delivered via LV, in which 60% of the animals survived to study completion (p < 0.05). Conclusions: Prophylaxis with SDM containing antibiotics delivered in low‐dose LV provided significant protection in a rat model of descending gram‐negative pneumonia. These data support the hypothesis that perfluorocarbon‐delivered intratracheal antimicrobials may be useful in the prevention of VAP.
Focused Training of Emergency Medicine Residents in Goal‐directed Echocardiography: A Prospective Study
Authors: Jones Alan E. , Tayal Vivek S. , Kline Jeffrey A. 
Published: October 2003

Abstract Objectives: To determine if a focused transthoracic echocardiography (TTE) training course would improve the accuracy of completion and interpretation of a goal‐directed TTE by emergency medicine residents. Methods: This was a prospective, observational, educational study of the impact of a focused training course on the change in physician performance on pre‐ and postcourse examinations testing competency in goal‐directed TTE defined by five criteria: 1) image orientation, 2) anatomy identification, 3) chamber size grading, 4) ventricular function estimation, and 5) pericardial effusion identification. Subjects included were emergency medicine residents with between ten and 20 hours of noncardiac ultrasound didactics and between 20 and >150 proctored noncardiac ultrasound examinations. All underwent five hours of focused echocardiography didactics and one hour of proctored practical echocardiography training designed and implemented by an emergency physician ultrasound director and a cardiologist. Before the start of the training course, participants completed two examinations: 1) written 23‐question test on the above concepts and 2) performance of a TTE on a healthy subject testing 16 elements that define a properly performed examination. After the training course, participants again completed both examinations. Results: A total of 21 emergency medicine residents qualified for and underwent standardized testing and training. The percentage correct on the precourse written examination was 54% (95% CI = 50% to 59%), and the postcourse examination score was 76% (95% CI = 71% to 80%) (p < 0.005, paired t‐test). The percentage correct on the precourse practical examination was 56% (95% CI = 51% to 60%), and the postcourse examination score was 94% (95% CI = 91% to 96%) (p < 0.005). Conclusions: A focused six‐hour echocardiography training course significantly improved emergency medicine residents' percentage scores on both written and practical examinations testing essential components required for correct goal‐directed TTE performance and interpretation.
The Emergency Severity Index Triage Algorithm Version 2 Is Reliable and Valid
Authors: Eitel David R. , Travers Debbie A. , Rosenau Alexander M. , Gilboy Nicki , Wuerz Richard C. 
Published: October 2003

AbstractObjectives:Initial studies have shown improved reliability and validity of a new triage tool, the Emergency Severity Index (ESI), over conventional three‐level scales at two university medical centers. After pilot implementation and validation, the ESI was revised to include pediatric and updated vital signs criteria. The goal of this study was to assess ESI version (v.) 2 reliability and validity at seven emergency departments (EDs) in three states.Methods:In part 1, interrater reliability was assessed using weighted kappa analysis of written training cases and postimplementation by a random sampling of actual patient triages. In part 2, validity was analyzed using a prospective cohort with stratified random sampling at each site. The ESI was compared with outcomes including resource consumption, inpatient admission, ED length of stay, and 60‐day all‐cause mortality.Results:Weighted kappa analysis of interrater reliability ranged from 0.70 to 0.80 for the written scenarios (n= 3,289) and 0.69 to 0.87 for patient triages (n= 386). Outcomes for the validity cohort (n= 1,042) included hospitalization rates by ESI triage level: level 1, 83%; 2, 67%; 3, 42%; 4, 8%; level 5, 4%. Sixty‐day all‐cause mortality by triage level was as follows: level 1, 25%; 2, 4%; 3, 2%; 4, 1%; and 5, 0%.Conclusions:ESI v. 2 triage produced reliable, valid stratification of patients across seven sites. ESI triage should be evaluated as an ED casemix identification system for uniform data collection in the United States and compared with other major ED triage methods.