bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Adjustment for People with Chronic Conditions in Private Sector Health Plans
Authors: Mark Tami L. , Ozminkowski Ronald J. , Kirk Adele , Ettner Susan L. , Drabek John
Published: October 2003

Background. Although the problem of adverse selection into more generous health insurance plans has been the focus of previous work, risk adjustment systems have only recently begun to be implemented to blunt its effect. Objectives. This study examines the ability of the leading risk adjustment systems to predict health care expenditures for people with chronic conditions, using claims and enrollment data from 2 large employers. Research design. Predictive errors and total financial losses/gains are compared for different risk adjustment approaches (primarily hierarchical condition categories [HCCs] and adjusted clinical groups) for several chronic conditions. Results. One of the best performing risk adjusteent systems was a regression-based HCC method, which had an average under-prediction error rate of 9% or 6%, depending on the employer. In comparison, more typical actuarial risk adjustments based on just age, gender, and prevailing area wages lead to a prediction error of at least 50%. We did not find evidence that payments for particular chronic conditions would be consistently and significantly under- or overestimated. Conclusion. The leading risk adjustment approaches substantially reduce the incentives for adverse se-lection but do not eliminate them.
A Priori Risk and Optimal Test Accuracy in Prenatal Diagnostics
Authors: Felder Stefan , Werblow Andreas , Robra Bernt-Peter
Published: October 2003

The prevalence of fetal chromosome anomalies rises exponentially with the age of the pregnant woman. The risk of fetal anomalies can be specified using biochemical screening tests such as the triple test. This test substantially reduces the number of amniocenteses and proportionally the number of procedure-related miscarriages. However, disadvantages of the triple test include the utility loss of pregnant women who, following a false-negative test result, do not undergo amniocentesis and bear a disabled child as well as the intangible cost of a false-positive triple test. This paper employs a decision-analytic model to reveal the evaluation of this tradeoff, which is implicitly fixed by policy recommendations for a direct amniocentesis at maternal age of 35. It then determines the optimal level of cutoff risk for the triple test, and derives comparative static results: the optimal test accuracy decreases with increasing a-priori risk and increases with a rise in the miscarriage risk and in the woman's preference for detecting an affected fetus as compared to avoiding a miscar-riage of an unaffected fetus. These results are in contrast to current clinical practice, where the cutoff of the triple test usually remains fixed.
Effect of Assessment Method on the Discrepancy between Judgments of Health Disorders People have and do not have: A Web Study
Authors: Baron Jonathan , Asch David A. , Fagerlin Angela , Jepson Christopher , Loewenstein George , Riis Jason , Stineman Margaret G. , Ubel Peter A.
Published: October 2003

Three experiments on the World Wide Web asked subjects to rate the severity of common health disorders such as acne or arthritis. People who had a disorder (“Haves”) tended to rate it as less severe than people who did not have it (“Not-haves”). Two explanations of this Have versus Not-have discrepancy were rejected. By one account, people change their reference point when they rate a disorder that they have. More precise reference points would, on this account, reduce the discrepancy, but, if anything, the discrepancy was larger. By another account, people who do not have the disorder focus on attributes that are most affected by it, and the discrepancy should decrease when people make ratings on several attributes. Again, if anything, the discrepancy increased when ratings were on separate attributes (combined by a weighted average). The discrepancy varied in size and direction across disorders. Subjects also thought that they would be less affected than others.
Epidemiology of human parvovirus B19 in children with sickle cell disease
Authors: Smith-Whitley Kim , Zhao Huaqing , Hodinka Richard L. , Kwiatkowski Janet , Cecil Renèe , Cecil Tamara , Cnaan Avital , Ohene-Frempong Kwaku
Published: October 2003

Human parvovirus (HPV) B19 causes significant morbidity and mortality in children with sickle cell disease (SCD), but little data are published about the epidemiology of HPV B19 infection and its associated complications in this patient population. In this study, prevalence and incidence rates of HPV B19 were determined in 633 patients with SCD followed at The Children's Hospital of Philadelphia between November 1996 and December 2001. Thirty percent (30%) were HPV B19 immunoglobulin G (IgG) positive at first testing, and the 70% without evidence of past HPV B19 infection were tested annually. One hundred ten patients developed evidence of HPV B19 infection for an incidence rate of 11.3 per 100 patientyears. Sixty-eight episodes of HPV B19–induced transient red cell aplasia occurred with the following clinical events: fever (89.7%), pain (61.8%), acute splenic sequestration (19.1%), and acute chest syndrome (11.8%). Pain, fever, and acute splenic sequestration were more frequent events with acute HPV B19 infections compared with acute events in uninfected patients. The results of this epidemiologic study, the largest and most comprehensive to date, justify the development of HPV B19 prevention strategies to diminish the frequent and often severe complications associated with HPV B19 infections in patients with SCD.
Elevated interleukin-7 levels not sufficient to maintain T-cell homeostasis during simian immunodeficiency virus–induced disease progression
Authors: Muthukumar Alagarraju , Wozniakowski Aneta , Gauduin Marie-Claire , Paiardini Mirko , McClure Harold M. , Johnson R. Paul , Silvestri Guido , Sodora Donald L.
Published: October 2003

Elevated levels of interleukin 7 (IL-7) have been correlated with various T-cell depletion conditions, including HIV infection, and suggested as an indicator of HIV disease progression (AIDS and death). Here, the assessment of pathogenic simian immunodeficiency virus (SIVmac239) infection in rhesus macaques demonstrated a clear association between a significant elevation in IL-7 levels and disease progression. In 5 macaques that progressed to simian AIDS and death, elevated IL-7 levels were unable to restore T-cell homeostasis. In contrast, increased IL-7 levels were followed by relatively high and stable T-cell numbers in the SIV-infected macaques with a slow-progressing phenotype. Further, studies in sooty mangabeys that do not progress to simian AIDS and that maintain stable T-cell numbers despite high levels of viral replication support the importance of IL-7 and T-cell homeostasis in disease progression. These data suggest that during pathogenic SIV infection with high viral replication, elevated IL-7 levels are unable to recover T-cell homeostasis, thereby leading to disease progression. The utility of IL-7 as a potential immunotherapeutic agent to improve HIV/SIV-related T-cell depletion may therefore depend on controlling the pathogenic effects of viral replication prior to the administration of IL-7. (Blood. 2004;103:973-979)
IFN-α promotes the rapid differentiation of monocytes from patients with chronic myeloid leukemia into activated dendritic cells tuned to undergo full maturation after LPS treatment
Authors: Gabriele Lucia , Borghi Paola , Rozera Carmela , Sestili Paola , Andreotti Mauro , Guarini Anna , Montefusco Enrico , Foà Robert , Belardelli Filippo
Published: October 2003

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease arising from the clonal expansion of a stem cell expressing the bcr/abl oncogene. CML patients frequently respond to treatment with interferon-α (IFN-α), even though the mechanisms of the response remain unclear. In the present study, we evaluated the role of IFN-α in differentiation and activity of monocyte-derived dendritic cells (DCs) from CML patients as well as in modulation of the cell response to lipopolysaccharide (LPS). Treatment of CML monocytes with IFN-α and granulocyte-macrophage colony-stimulating factor (GM-CSF) resulted in the rapid generation of activated DCs (CML-IFN-DCs) expressing interleukin-15 (IL-15) and the antiapoptotic bcl-2 gene. These cells were fully competent to induce IFN-γ production by cocultured autologous T lymphocytes and expansion of CD8+ T cells. LPS treatment of CML-IFN-DCs, but not of immature DCs generated in the presence of IL-4/GM-CSF, induced the generation of CD8+ T cells reactive against autologous leukemic CD34+ cells. Altogether, these results suggest that (1) the generation of highly active monocyte-derived DCs could be important for the induction of an antitumor response in IFN-treated CML patients and (2) IFN-α can represent a valuable cytokine for the rapid generation of active monocyte-derived DCs to be utilized for vaccination strategies of CML patients. (Blood. 2004;103:980-987)
The in vitro production and characterization of neutrophils from embryonic stem cells
Authors: Lieber Jonathan G. , Webb Saiphone , Suratt Benjamin T. , Young Scott K. , Johnson Gary L. , Keller Gordon M. , Worthen G. Scott
Published: October 2003

An embryonic stem (ES) cell/OP9 coculture system for the effective production of functional neutrophils is described. A 3-step differentiation strategy was developed that uses liquid culture, enabling reliable and abundant production of neutrophils at high purity without the need of sorting for isolation of mature neutrophils. Use of the OP9 stromal cell line significantly enhances the number, percentage, and duration of differentiated neutrophils produced from embryonic stem cells. Effective and sustained differentiation of ES cells into neutrophils provides a useful model system for studying neutrophil differentiation and function and the factors that regulate them. Morphologic and functional evaluation of these ES-derived neutrophils indicates that large numbers of mature neutrophils can be produced from pluripotent ES cells in vitro. Specifically, their morphology, ability to produce superoxides, flux calcium, undergo chemotaxis in response to macrophage inflammatory protein 2 (MIP-2), stain for the granulocyte-specific marker–specific chloroacetate esterase, and contain the neutrophil-specific markers Gr-1 and the mouse neutrophil-specific antigen indicates that they are comparable with purified mouse bone marrow neutrophils. They also express gelatinase and lactoferrin granule proteins. During the differentiation of these ES-derived neutrophils, regional areas of neutrophil production can be identified that have been designated as neutrophil generating regions (NGRs).
Development of both human connective tissue-type and mucosal-type mast cells in mice from hematopoietic stem cells with identical distribution pattern to human body
Authors: Kambe Naotomo , Hiramatsu Hidefumi , Shimonaka Mika , Fujino Hisanori , Nishikomori Ryuta , Heike Toshio , Ito Mamoru , Kobayashi Kimio , Ueyama Yoshito , Matsuyoshi Norihisa , Miyachi Yoshiki , Nakahata Tatsutoshi
Published: October 2003

The transplantation of primitive human cells into sublethally irradiated immune-deficient mice is the well-established in vivo system for the investigation of human hematopoietic stem cell function. Although mast cells are the progeny of hematopoietic stem cells, human mast cell development in mice that underwent human hematopoietic stem cell transplantation has not been reported. Here we report on human mast cell development after xenotransplantation of human hematopoietic stem cells into nonobese diabetic severe combined immunodeficient \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \((\mathrm{NOD{/}SCID}){/}{\gamma}_{\mathrm{c}}^{null}\) \end{document} (NOG) mice with severe combined immunodeficiency and interleukin 2 (IL-2) receptor γ-chain allelic mutation. Supported by the murine environment, human mast cell clusters developed in mouse dermis, but they required more time than other forms of human cell reconstitution. In lung and gastric tract, mucosal-type mast cells containing tryptase but lacking chymase located on gastric mucosa and in alveoli, whereas connective tissue-type mast cells containing both tryptase and chymase located on gastric submucosa and around major airways, as in the human body. Mast cell development was also observed in lymph nodes, spleen, and peritoneal cavity but not in the peripheral blood. Xenotransplantation of human hematopoietic stem cells into NOG mice can be expected to result in a highly effective model for the investigation of human mast cell development and function in vivo.
In vitro and in vivo evidence of PNH cell sensitivity to immune attack after nonmyeloablative allogeneic hematopoietic cell transplantation
Authors: Takahashi Yoshiyuki , McCoy J. Philip , Carvallo Cristian , Rivera Candido , Igarashi Takehito , Srinivasan Ramaprasad , Young Neal S. , Childs Richard W.
Published: October 2003

It has been proposed that paroxysmal nocturnal hemoglobinuria (PNH) cells may proliferate through their intrinsic resistance to immune attack. To evaluate this hypothesis, we examined the impact of alloimmune pressure on PNH and normal cells in the clinical setting of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Five patients with severe PNH underwent HCT from an HLA-matched family donor after conditioning with cyclophosphamide and fludarabine. PNH neutrophils (CD15+/CD66b–/CD16–) were detected in all patients at engraftment, but they subsequently declined to undetectable levels in all cases by 4 months after transplantation. To test for differences in susceptibility to immune pressure, minor histocompatibility antigen (mHa)–specific T-cell lines or clones were targeted against glycosylphosphatidylinositol (GPI)–negative and GPI-positive monocyte and B-cell fractions purified by flow cytometry sorting. Equivalent amounts of interferon-γ (IFN-γ) were secreted following coculture with GPI-negative and GPI-positive targets. Furthermore, mHa-specific T-cell lines and CD8+ T-cell clones showed similar cytotoxicity against both GPI-positive and GPI-negative B cells. Presently, all 5 patients survive without evidence of PNH 5 to 39 months after transplantation. These in vitro and in vivo studies show PNH cells can be immunologically eradicated following nonmyeloablative HCT. Relative to normal cells, no evidence for a decreased sensitivity of PNH cells to T-cell–mediated immunity was observed.
Erythropoietin regulates endothelial progenitor cells
Authors: Bahlmann Ferdinand H. , de Groot Kirsten , Spandau Jens-Michael , Landry Aimee L. , Hertel Barbara , Duckert Thorsten , Boehm Sascha M. , Menne Jan , Haller Hermann , Fliser Danilo
Published: October 2003

Circulating bone marrow–derived endothelial progenitor cells (EPCs) promote vascular reparative processes and neoangiogenesis, and their number in peripheral blood correlates with endothelial function and cardiovascular risk. We tested the hypothesis that the cytokine erythropoietin (EPO) stimulates EPCs in humans. We studied 11 patients with renal anemia and 4 healthy subjects who received standard doses of recombinant human EPO (rhEPO). Treatment with rhEPO caused a significant mobilization of CD34+/CD45+ circulating progenitor cells in peripheral blood (measured by flow cytometry), and increased the number of functionally active EPCs (measured by in vitro assay) in patients (week 2, 312% ± 31%; week 8, 308% ± 40%; both P < .01 versus baseline) as well as in healthy subjects (week 8, 194% ± 15%; P < .05 versus baseline). The effect on EPCs was already observed with an rhEPO dose of about 30 IU/kg per week. Administration of rhEPO increased the number of functionally active EPCs by differentiation in vitro in a dose-dependent manner, assessed in cell culture and by tube formation assay. Furthermore, rhEPO activates the Akt protein kinase pathway in EPCs. Erythropoietin increases the number of functionally active EPCs in humans. Administration of rhEPO or EPO analogs may open new therapeutic strategies in regenerative cardiovascular medicine.
Induction of caspase-dependent programmed cell death in B-cell chronic lymphocytic leukemia by anti-CD22 immunotoxins
Authors: Decker Thomas , Oelsner Madlene , Kreitman Robert J. , Salvatore Giuliana , Wang Qing-cheng , Pastan Ira , Peschel Christian , Licht Thomas
Published: October 2003

B cells of chronic lymphocytic leukemia (CLL) are long-lived in vivo, possibly because of defects in apoptosis. We investigated BL22, an immunotoxin composed of the Fv portion of an anti-CD22 antibody fused to a 38-kDa Pseudomonas exotoxin-A fragment. B cells from 22 patients with CLL were immunomagnetically enriched (96% purity) and were cultured with BL22 or an immunotoxin that does not recognize hematopoietic cells. The antileukemic activity of BL22 was correlated with CD22 expression, as determined by flow cytometry. BL22 induced caspase-9 and caspase-3 activation, poly(adenosine diphosphate [ADP]-ribose)polymerase (PARP) cleavage, DNA fragmentation, and membrane flipping. Cell death was associated with the loss of mitochondrial membrane potential and the down-regulation of Mcl-1 and X-chromosomal inhibitor of apoptosis protein (XIAP). Furthermore, BL22 induced a proapoptotic 18-kDa Bax protein and conformational changes of Bax. Z-VAD.fmk abrogated apoptosis, confirming that cell death was executed by caspases. Conversely, interleukin-4, a survival factor, inhibited spontaneous death in culture but failed to prevent immunotoxin-induced apoptosis. BL22 cytotoxicity was markedly enhanced when combined with anticancer drugs including vincristine. We also investigated HA22, a newly engineered immunotoxin, in which BL22 residues are mutated to improve target binding. HA22 was more active than BL22. In conclusion, these immunotoxins induce caspase-mediated apoptosis involving mitochondrial damage. Combination with chemotherapy is expected to improve the efficacy of immunotoxin treatment. (Blood. 2004;103:2718-2726)
Presence of functional dendritic cells in patients chronically infected with hepatitis C virus
Authors: Longman Randy S. , Talal Andrew H. , Jacobson Ira M. , Albert Matthew L. , Rice Charles M.
Published: October 2003

The absence of expanded numbers of hepatitis C virus (HCV)-reactive CD8+ T lymphocytes (CTLs) in patients chronically infected with HCV has led to the investigation of dendritic cell (DC) function in this population as a potential cause for this defect. Several studies have shown evidence for impaired monocyte-derived DCs in chronically infected patients. As it is difficult to reconcile these data with the fact that patients with chronic HCV are immune competent, we re-evaluated this finding, carefully assessing phenotypic markers and functional activity of patient DCs as compared with noninfected controls. In contrast to these prior studies, DCs from 13 of 13 chronic HCV patients expressed typical maturation markers. These mature DCs were capable of priming allogeneic T lymphocytes, as well as stimulating influenza-specific memory T cells. This finding is consistent with clinical and immunologic data that the deficit in the patient's immune repertoire is HCV-specific and suggests that refined models are required for understanding the role of DCs in HCV pathogenesis. (Blood. 2004;103:1026-1029)
Gene expression patterns associated with recurrent chromosomal translocations in acute lymphoblastic leukemia
Authors: Fine Bernard M. , Stanulla Martin , Schrappe Martin , Ho Minh , Viehmann Susanne , Harbott Jochen , Boxer Linda M.
Published: October 2003

We obtained a global view of gene expression in both cell lines and pediatric acute lymphoblastic leukemia (ALL) samples that harbor one of several selected chromosomal abnormalities. When the cell lines were studied alone, we found that these chromosomal abnormalities were associated with the predominant variation in transcriptional programs across the set of cell lines studied. When cell lines and clinical samples were studied together, we found that each chromosomal abnormality (TEL/AML1, BCR/ABL, or MLL abnormalities) was associated with a characteristic gene expression signature that was shared by both cell lines and clinical samples. However, BCR/ABL was associated with a much more heterogeneous pattern of expression than were TEL/AML1 and MLL abnormalities. This observation has important implications for the study of BCR/ABL ALL. In addition, we systematically identified genes whose expression was associated with TEL/AML1, BCR/ABL, or MLL abnormalities in both clinical samples and cell lines. Although some of these genes have previously been described, many have not previously been reported to be associated with one of these chromosomal abnormalities. Notably, we found that the erythropoietin receptor (EPOR) is consistently highly expressed in TEL/AML1 ALL compared with BCR/ABL or MLL. (Blood. 2004;103:1043-1049)
Haploinsufficiency of Runx1 results in the acceleration of mesodermal development and hemangioblast specification upon in vitro differentiation of ES cells
Authors: Lacaud Georges , Kouskoff Valerie , Trumble Anne , Schwantz Staci , Keller Gordon
Published: October 2003

The AML1 gene (recently renamed Runx1), which encodes the DNA-binding subunit of a transcription factor of the core binding factor (CBF) family, is required for the establishment of definitive hematopoiesis. We have previously demonstrated that Runx1 is expressed in yolk sac mesodermal cells prior to the establishment of the blood islands and in the embryoid body (EB)–derived blast-colony–forming cells (BL-CFCs), the in vitro equivalent of the hemangioblast. Analysis of Runx1-deficient embryonic stem (ES) cells demonstrated that this gene is essential for the generation of normal numbers of blast colonies, the progeny of the BL-CFCs. In the present study, we analyzed the potential of Runx1+/– ES cells to determine if heterozygosity at the Runx1 locus impacts early developmental events leading to the commitment of the BL-CFCs. Our results indicate that Runx1 heterozygosity leads to an acceleration of mesodermal commitment and specification to the BL-CFCs and to the hematopoietic lineages in EBs.
Vascular endothelial growth factor (VEGF) induces rapid prourokinase (pro-uPA) activation on the surface of endothelial cells
Authors: Prager Gerald W. , Breuss Johannes M. , Steurer Stefan , Mihaly Judit , Binder Bernd R.
Published: October 2003

Vascular endothelial growth factor (VEGF) is the pivotal angiogenic growth factor activating endothelial cells to migrate, proliferate, and form capillary tubes. For an ordered endothelial cell migration, tissue invasion, and degradation of the extracellular matrix, proteolytic machinery is indispensable. Such machinery, suitable for localized proteolysis, is provided by the prourokinase-urokinase-plasmin system. Prourokinase (pro-uPA), the initial component of this system, is, however, synthesized in its inactive precursor form and as such bound to its cellular receptor uPAR. Here we identify a mechanism via which VEGF165 interacting with its receptor VEGFR-2 rapidly induces prourokinase activation that is dependent on a change in integrin affinity, activation of matrix metalloproteinase 2 (MMP-2), and pro-uPA being bound to its surface receptor uPAR. This VEGF-induced pro-uPA activation on endothelial cells is responsible for VEGF-dependent local fibrinolytic activity and might be one of the initial steps in the angiogenic process. (Blood. 2004;103:955-962)
Association of CBFA2 mutation with decreased platelet PKC-θ and impaired receptor-mediated activation of GPIIb-IIIa and pleckstrin phosphorylation: proteins regulated by CBFA2 play a role in GPIIb-IIIa activation
Authors: Sun Liansheng , Mao Guangfen , Rao A. Koneti
Published: October 2003

The mechanisms by which agonists activate glycoprotein (GP) IIb-IIIa function remain unclear. We have reported data on a patient with thrombocytopenia and impaired receptor-mediated aggregation, phosphorylation of pleckstrin (a protein kinase C [PKC] substrate), and activation of the GPIIb-IIIa complex. Abnormalities in hematopoietic transcription factors have been associated with thrombocytopenia and platelet dysfunction. To define the molecular mechanisms, we amplified from patient platelet RNA exons 3 to 6 of core-binding factor A2 (CBFA2) cDNA, which encompasses the DNA-binding Runt domain; a 13-nucleotide (nt) deletion was found (796-808 nt). The gDNA revealed a heterozygous mutation (G>T) in intron 3 at the splice acceptor site for exon 4, leading to a frameshift with premature termination in the Runt domain. On immunoblotting, platelet CBFA2, PKC-θ, albumin, and IgG were decreased, but pleckstrin, PKC-α, -βI, -βII, -η, -ϵ, -δ, and -ζ, and fibrinogen were normal. Our conclusions are that (1) CBFA2 mutation is associated with not only thrombocytopenia, but also impaired platelet protein phosphorylation and GPIIb-IIIa activation; (2) proteins regulated by CBFA2 are required for inside-out signal transduction-dependent activation of GPIIb-IIIa; and (3) we have documented the first deficiency of a human PKC isozyme (PKC-θ), suggesting a major role of this isozyme in platelet production and function. (Blood. 2004;103:948-954)
Activated Fps/Fes partially rescues the in vivo developmental potential of Flk1-deficient vascular progenitor cells
Authors: Haigh Jody J. , Ema Masatsugu , Haigh Katharina , Gertsenstein Marina , Greer Peter , Rossant Janet , Nagy Andras , Wagner Erwin F.
Published: October 2003

Relatively little is known about the modulators of the vascular endothelial growth factor A (VEGF-A)/Flk1 signaling cascade. To functionally characterize this pathway, VEGF-A stimulation of endothelial cells was performed. VEGF-A–mediated Flk1 activation resulted in increased translocation of the endogenous Fps/Fes cytoplasmic tyrosine kinase to the plasma membrane and increased tyrosine phosphorylation, suggesting a role for Fps/Fes in VEGF-A/Flk1 signaling events. Addition of a myristoylation consensus sequence to Fps/Fes resulted in VEGF-A–independent membrane localization of Fps/Fes in endothelial cells. Expression of the activated Fps/Fes protein in Flk1-deficient embryonic stem (ES) cells rescued their contribution to the developing vascular endothelium in vivo by using ES cell–derived chimeras. Activated Fps/Fes contributed to this rescue event by restoring the migratory potential to Flk1 null progenitors, which is required for movement of hemangioblasts from the primitive streak region into the yolk sac proper. Activated Fps/Fes in the presence of Flk1 increased the number of hemangioblast colonies in vitro and increased the number of mesodermal progenitors in vivo. These results suggest that Fps/Fes may act synergistically with Flk1 to modulate hemangioblast differentiation into the endothelium. We have also demonstrated that activated Fps/Fes causes hemangioma formation in vivo, independently of Flk1, as a result of increasing vascular progenitor density.
Fiber-modified adenoviruses generate subgroup cross-reactive, adenovirus-specific cytotoxic T lymphocytes for therapeutic applications
Authors: Leen Ann M. , Sili Uluhan , Savoldo Barbara , Jewell Alan M. , Piedra Pedro A. , Brenner Malcolm K. , Rooney Cliona M.
Published: October 2003

Adenovirus (Ad) infections are responsible for considerable morbidity and mortality, particularly in pediatric hematopoietic stem cell transplant (HSCT) recipients. To date there is no therapy. The present study was motivated by the potential for using adoptive immunotherapy as either prophylaxis or treatment for Ad infections and associated diseases. The authors have developed a protocol to reactivate Ad-specific memory T cells from peripheral blood mononuclear cells (PBMCs) using a clinical-grade adenoviral vector. Such lines contain a specific CD4 and CD8 T-cell component and are capable of recognizing and lysing target cells infected with wild-type Ad serotypes from different Ad groups. Furthermore, the frequency of Ad-specific precursors can be determined in PBMCs ex vivo and used as a means to assess changes in Ad-specific T-cell memory responses after infusion. This is the first report of a simple and reproducible method to activate and expand Ad-specific cytotoxic T lymphocytes (CTLs), which should be protective against the range of different Ad subtypes that affect transplant recipients. (Blood. 2004;103:1011-1019)
The MHC class II transcriptional activator (CIITA) inhibits HTLV-2 viral replication by blocking the function of the viral transactivator Tax-2
Authors: Casoli Claudio , De Lerma Barbaro Andrea , Pilotti Elisabetta , Bertazzoni Umberto , Tosi Giovanna , Accolla Roberto S.
Published: October 2003

The human T-cell leukemia virus type 2 (HTLV-2), an oncogenic retrovirus closely related to HTLV-1, produces a lifelong infection whose possible association to certain human diseases is still debated. Although some viral products can influence the expression and action of cellular genes, very little is known about the molecular mechanisms involved. Here we show that the AIR-1-encoded human major histocompatibility complex (MHC) class II transactivator (CIITA) strongly inhibits viral replication, but not virus entry, in human B- and T-cell susceptible targets. This effect results from CIITA inhibiting the Tax-mediated transactivation of the HTLV-2 long-term repeat. Further molecular analysis shows that the N-terminal region of CIITA encompassing the first 321 amino acids is responsible for the inhibitory effect on viral replication. This region is crucial for the transactivation of human MHC class II genes and includes the activation domain as well as domains interacting with coactivators that also are used by the viral transactivator Tax to modulate cellular functions. These results represent the first evidence that a cellular transcriptional activator, controlling the coordinate expression of the entire family of MHC class II antigen-presenting molecules, inhibits HTLV-2 viral replication by a distinct mechanism. In this new role CIITA may represent a new tool for therapeutic strategies aimed at counteracting HTLV-2 replication and spreading. (Blood. 2004;103:995-1001)
Association of CD26 with CD45RA outside lipid rafts attenuates cord blood T-cell activation
Authors: Kobayashi Seiji , Ohnuma Kei , Uchiyama Masahiko , Iino Kouichi , Iwata Satoshi , Dang Nam H. , Morimoto Chikao
Published: October 2003

CD26 is a T-cell activation antigen that contains dipeptidyl peptidase IV activity and binds adenosine deaminase. Recent work showed that specialized membrane microdomains, also known as lipid rafts, play a key role in T-cell signaling. In this study, we investigate the role of CD26 in cord blood T-cell activation and signal transduction. We demonstrated that different expression levels of CD26 were observed between cord blood T cells (CBTCs) and peripheral blood T cells (PBTCs) and that CD26+CD45RA+ CBTCs were different compared with CD26+CD45RA+ PBTCs. Moreover, the comitogenic effect of CD26 was not as pronounced in CBTCs as in PBTCs. We also showed that CD26 cross-linking induced less phosphorylation of T-cell receptor-signaling molecules, lymphoid T-cell protein tyrosine kinase (Lck), zeta-associated protein 70 (ZAP-70), T-cell receptor ζ (TCRζ), and linker for activator of T cells (LAT) in CBTCs than in PBTCs. Furthermore, CD26 molecules associated with CD45RA molecules outside lipid rafts in CBTCs. Our results suggest that strong physical linkage of CD26 with CD45RA outside lipid rafts may be responsible for the attenuation of T-cell activation signaling through CD26, which may be responsible for immature immune response and the low incidence of severe graft-versus-host disease in cord blood transplantation. (Blood. 2004;103:1002-1010)
Incomplete restoration of colony-stimulating factor 1 (CSF-1) function in CSF-1–deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1
Authors: Dai Xu-Ming , Zong Xiao-Hua , Sylvestre Vonetta , Stanley E. Richard
Published: October 2003

The primary macrophage growth factor, colony-stimulating factor 1 (CSF-1), is expressed as a secreted glycoprotein or proteoglycan found in the circulation or as a biologically active cell surface glycoprotein (csCSF-1). To investigate the in vivo roles of csCSF-1, we created mice that exclusively express csCSF-1, in a normal tissue-specific and developmental manner, by transgenic expression of csCSF-1 in the CSF-1-deficient osteopetrotic (Csf1op/Csf1op) background. The gross defects of Csf1op/Csf1op mice, including growth retardation, failure of tooth eruption, and abnormal male and female reproductive functions were corrected. Macrophage densities in perinatal liver, bladder, sublinguinal salivary gland, kidney cortex, dermis, and synovial membrane were completely restored, whereas only partial or no restoration was achieved in adult liver, adrenal gland, kidney medulla, spleen, peritoneal cavity, and intestine. Residual osteopetrosis, significantly delayed trabecular bone resorption in the subepiphyseal region of the long bone, and incomplete correction of the hematologic abnormalities in the peripheral blood, bone marrow, and spleens of CSF-1-deficient mice were also found in mice exclusively expressing csCSF-1. These data suggest that although csCSF-1 alone is able to normalize several aspects of development in Csf1op/Csf1op mice, it cannot fully restore in vivo CSF-1 function, which requires the presence of the secreted glycoprotein and/or proteoglycan forms. (Blood. 2004;103:1114-1123)
Gene microarray analysis reveals interleukin-5–dependent transcriptional targets in mouse bone marrow
Authors: Byström Jonas , Wynn Thomas A. , Domachowske Joseph B. , Rosenberg Helene F.
Published: October 2003

Interleukin-5 (IL-5) is a hematopoietic differentiation factor that promotes the development of mature eosinophils from progenitors in bone marrow. We present a multifactorial microarray study documenting the transcriptional events in bone marrow of wild-type and IL-5–deficient mice at baseline and in response to infection with Schistosoma mansoni. The microarray data were analyzed by a 4-way subtractive algorithm that eliminated confounding non-IL-5–related sequelae of schistosome infection as well as alterations in gene expression among uninfected mice. Among the most prominent findings, we observed 7- to 40-fold increased expression of transcripts encoding the classic eosinophil granule proteins (eosinophil peroxidase, major basic protein, the ribonucleases) together with arachidonate-15-lipoxygenase and protease inhibitor plasminogen activator inhibitor 2 (PAI-2), in the IL-5–producing, infected wild-type mice only. This was accompanied by increased transcription of genes involved in secretory protein biosynthesis and granule-vesicle formation. Interestingly, we did not detect increased expression of genes encoding eosinophil-related chemokine receptors (CCR1, CCR3) or members of the GATA or CCAAT/enhancer binding protein (C/EBP) transcription factor families. These data suggest that the IL-5–responsive progenitors in the mouse bone marrow are already significantly committed to the eosinophil lineage and that IL-5 promotes differentiation of these committed progenitors into cells with recognizable and characteristic cytoplasmic granules and granule proteins.
Differential processing of stromal-derived factor-1α and stromal-derived factor-1β explains functional diversity
Authors: De La Luz Sierra Maria , Yang Fuquan , Narazaki Masashi , Salvucci Ombretta , Davis David , Yarchoan Robert , Zhang Hongwei H. , Fales Henry , Tosato Giovanna
Published: October 2003

The chemokine stromal-derived factor-1 (SDF-1), which is constitutively expressed in most tissues as SDF-1α and SDF-1β resulting from alternative gene splicing, regulates hematopoiesis, lymphocyte homing, B-lineage cell growth, and angiogenesis. Because SDF-1α and SDF-1β are constitutively and ubiquitously expressed, their degradation must serve an important regulatory role. Here we show that SDF-1α and SDF-1β are secreted as full-length molecules. When exposed to human serum, full-length SDF-1α (1-68) undergoes processing first at the COOH terminus to produce SDF-1α 1-67 and then at the NH2 terminus to produce SDF-1α 3-67. By contrast, full-length SDF-1β (1-72) is processed only at the NH2 terminus to produce SDF-1β 3-72. CD26/dipeptidyl peptidase is responsible for serum cleavage of SDF-1α and SDF-1β at the NH2 terminus. Serum processing of SDF-1α at the COOH terminus, which has not been previously reported, reduces the ability of the polypeptide to bind to heparin and to cells and to stimulate B-cell proliferation and chemotaxis. The additional processing at the NH2 terminus renders both forms of SDF-1 unable to bind to heparin and to activate cells. The differential processing of SDF-1α and SDF-1β provides biologic significance to the existence of 2 splice forms of the chemokine and adds a tool to precisely regulate SDF-1's biologic activity by changes in specific activity.
A comparison of respiratory function in Afro-Caribbean and Caucasian infants
Authors: Stocks J , Gappa M , Rabbette PS , Hoo AF , Mukhtar Z , Costeloe KL
Published: October 2003

Race is recognized as an important determinant of lung function in children and adults, but limited data exist for infants. Accurate interpretation of lung function tests during the neonatal period may depend on appropriate values for predicting normality. The aim of this study was to compare tidal breathing parameters, Hering-Breuer reflex (HBR) activity, and total respiratory compliance (Crs) in healthy newborn caucasian (white) and Afro-Caribbean (black) infants, to determine whether separate reference values were required for these two ethnic groups. Respiratory function was measured in 33 healthy black infants, 18 of whom were premature, and 33 healthy white infants matched for sex, gestational age, weight, postnatal age, and maternal smoking during pregnancy. There were no significant paired differences between black and white infants with respect to minute ventilation, respiratory frequency, the ratio of time to reach peak expiratory flow to total expiratory time, or HBR activity. Values of Crs were similar in black and white full-term infants (37.5 (SD 9.0) versus 35.0 (6.3) ml.kPa-1, respectively) suggesting that, in the immediate newborn period, separate reference values are not necessary for these parameters. However, Crs was somewhat lower in black than white preterm infants (26.0(5.2) versus 29.5(7.2) ml.kPa-1, this difference reaching statistical significance if results were expressed in relation to body weight (95% confidence interval of within-pair differences -4.0 to -0.02 ml.kPa-1 x kg-1; p < 0.05). We conclude that no separate reference values for tidal breathing, Hering-Breuer reflex activity or total respiratory compliance are required for white and black babies in the immediate newborn period.(ABSTRACT TRUNCATED AT 250 WORDS)
Respiratory muscle function and exercise capacity in multiple sclerosis
Authors: Foglio K , Clini E , Facchetti D , Vitacca M , Marangoni S , Bonomelli M , Ambrosino N
Published: October 2003

Patients with multiple sclerosis (MS) show a poor exercise tolerance. A reduction in respiratory muscle strength has also been reported. The purpose of this study was to evaluate whether reduction in exercise tolerance was related to respiratory muscle dysfunction. Twenty four multiple sclerosis patients (mean +/- SD age: 48 +/- 9 yrs, duration of illness 12.2 +/- 6 yrs, severity of illness as assessed by Expanded Disability Scale Score (EDSS) 5.3 +/- 2), underwent detailed evaluation of lung function tests, arterial blood gas analysis, respiratory muscle strength and endurance, and exercise test on an arm ergometer. Sixteen of the 24 patients were able to perform the exercise test (Group I), whilst the other eight were not (group II). Arterial blood gases and lung function tests were normal for both groups. Respiratory muscle strength as assessed both by maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) was significantly reduced (MIP 18-76 cmH2O; MEP 16-82 cmH2O) compared to predicted values. Inspiratory muscle endurance time was significantly reduced in Group II in comparison to Group I (247 +/- 148 vs 397 +/- 154 s, respectively). Both MIP and MEP were significantly related to inspiratory muscle endurance time. Endurance time, MIP and MEP were inversely significantly related to duration of illness, whilst only endurance time was significantly related to Expanded Disability Scale Score.(ABSTRACT TRUNCATED AT 250 WORDS)
Validity of ECSC prediction equations for spirometric indices in Dutch conscripts
Authors: Stevens WH , van Hartevelt JH , The PE , Smink HA , Quanjer PH
Published: October 2003

A study was performed to determine whether prediction equations issued by the European Community for Steel and Coal (ECSC) and the European Respiratory Society (ERS) fit spirometric data in young adult males. The study comprised 246 randomly selected Dutch conscripts, who participated in the study on the basis of informed consent. A questionnaire was used to assess respiratory symptoms and smoking habits. Maximal expiratory flow-volume curves were obtained with a rolling seal spirometer, and summary statistics selected according to ECSC/ERS recommendations. In addition, standing height and body weight were obtained. We analysed the data of 100 conscripts of European descent, with no history of respiratory symptoms. They were all life-long nonsmokers. Their mean (SD) age was 18 (0.12) yrs (range 17.9-19.0 yrs), with a mean (SD) standing height of 1.84 (0.06) m (range 1.68-2.00 m). The data for forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and maximal mid-expiratory flow (MMEF) agreed well with ECSC predictions; 95% confidence intervals (95% CI) of differences between measured and predicted values were -0.174 to 0.044 l, -0.012 to 0.174 l.s-1 and -0.114 to 0.302 l.s-1, respectively. Peak expiratory flow was systematically larger than predicted, as was FEV1 % FVC (95% CI 0.74 to 1.31 l.s-1 and 2.50 to 5.24%, respectively), due to the intercept being inappropriate. The residual standard deviation in the conscripts was somewhat less than in the ECSC/ERS predictions equations, except for peak expiratory flow (PEF).(ABSTRACT TRUNCATED AT 250 WORDS)
Respiratory health screening using pulmonary function tests and lung sound analysis
Authors: Gavriely N , Nissan M , Cugell DW , Rubin AH
Published: October 2003

Lung sounds (LS) analysis is a potential source of additional objective, noninvasive and quantitative information on the status of the pulmonary system. We have examined the hypothesis that the addition of lung sounds analysis to spirometry increases the sensitivity of objective population screening, as compared to the use of spirometry alone. Questionnaires, spirometry and lung sounds were obtained in 493 active workers. Lung sounds analysis consisted of the averaged power spectra of breath sounds, measured separately during inspiration and expiration at four standard locations over the trachea and the chest-wall. Of the 493 subjects, 91 had an obstructive lung disease, including 27 with chronic bronchitis identified by a history of prolonged cough and sputum production but with normal spirometry. Twelve additional workers had a restrictive lung disease. Abnormal spirometric results were found in 74 of the patients. Abnormal lung sounds analyses were found in 54 patients, including 14 of the chronic bronchitis cases, so that the overall sensitivity of objective screening tests increased from 71% to 87% by combining the two tests. Thirty three of the subjects considered normal by evaluation of their questionnaire and spirometry had abnormal lung sounds. Of the twenty four who were re-evaluated 12-18 months after the first tests, three had developed a lung or heart disease. We conclude that the combination of spirometry and lung sounds analysis significantly increased the sensitivity of detection of pulmonary diseases by objective tests, and provided an early sign of lung disease that was not detected by spirometry alone.
Refractoriness to inhaled sodium metabisulphite in subjects with mild asthma
Authors: Pavord ID , Wisniewski A , Tattersfield AE
Published: October 2003

Refractoriness occurs after challenges causing mediator release in asthma, by a mechanism which may involve inhibitory prostaglandins. Bronchoconstriction due to inhaled sodium metabisulphite is thought to involve neural pathways and to be independent of mediator release; whether it shows refractoriness is uncertain. We have sought evidence of refractoriness to the bronchoconstrictor response to inhaled sodium metabisulphite in subjects with mild asthma, and have tested the hypothesis that the development of refractoriness involves inhibitory prostaglandins. Twelve subjects were challenged twice with a dose of sodium metabisulphite, previously shown to cause a 20% fall in forced expiratory volume in one second (FEV1); the second challenge proceeded after recovery from the first. The response to sodium metabisulphite was expressed as the maximum % fall in FEV1 and area under the change in FEV1 curve over 20 min (AUC). Nine subjects were studied after double-blind treatment with oral indomethacin, 50 mg t.d.s., or placebo, for 3 days. The second sodium metabisulphite challenge caused significantly less bronchoconstriction than the first (mean maximum fall in FEV1 13.1 and 24.3%, respectively). Nine subjects showed a greater than 50% reduction in the response to the second challenge (mean reduction in AUC 73.7%). In these subjects, indomethacin did not alter the response to the first sodium metabisulphite challenge, or the mean maximum fall in FEV1 in response to the second challenge (placebo 9.7%, indomethacin 11.2%), but significantly increased the AUC of the second challenge (placebo 55, indomethacin 114). The mean reduction in AUC from first to second challenge was 78% with placebo and 48% with indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)
Quality of life, symptoms and pulmonary function in asthma: long-term treatment with nedocromil sodium examined in a controlled multicentre trial. Nedocromil Sodium Quality of Life Study Group
Authors: Jones PW
Published: October 2003

This study was designed to measure improvement in quality of life of patients with asthma, using a standardized disease-specific questionnaire, the St George's Respiratory Questionnaire, in a year long double-blind, placebo-controlled, group comparative study with nedocromil sodium. Two other questionnaires were used: the Sickness Impact Profile (a measure of general health) and the Hospital Anxiety and Depression Scale. Measurements were made at baseline and following 24 and 48 weeks of treatment. Response to therapy was also evaluated using daily diary card and peak flow measurements, clinic assessments and spirometry. Following a 4 week baseline, 719 adult asthmatics were randomized to treatment with 4 mg nedocromil sodium or placebo. Patients currently maintained on inhaled corticosteroids received treatments four times daily, those on bronchodilator alone received treatments twice daily. The Impacts component of the St George's Respiratory Questionnaire was significantly improved in patients receiving nedocromil sodium, as were night-time asthma, asthma severity at clinic, and daytime inhaled bronchodilator use. In patients receiving placebo, most of the traditional variables improved, and all three questionnaires recorded significant improvements in health. Patients and clinicians judged nedocromil sodium more effective than placebo. The improvement in St George's Questionnaire score in the nedocromil sodium treated patients was approximately double the change considered to be clinically significant. The study has shown that improvements in health with prophylactic therapy for asthma may be quantified by the use of a standardized disease-specific questionnaire.