bluuebunny/crossref_metadata_2025 huggingface dataset:
Personality, Family Satisfaction, and Demographic Factors That Help Mexican American Students Succeed Academically
Authors: Cornelius-White Jeffrey H. D. , Garza Aida C. , Hoey Ann T.
Published: June 2004

This study examined 122 high academic achieving Mexican American seniors from 7 schools in South Texas. The results found that fathers’ education, families’ equal use of English and Spanish, family support of students’ growth into areas of their own particular interests, and students’ openness to experience had the highest correlations with achievement. The authors provide policy recommendations to increase adolescent reasoning over memorization, exploration over conformity, and responsible expressiveness over repression in the classroom, the community, and the home.
The Accommodation of University Students with Disabilities Inventory (AUSDI): Assessing American and Mexican Faculty Attitudes toward Students with Disabilities
Authors: Wolman Clara , McCrink Carmen Suarez , Rodríguez Sebastián Figueroa , Harris-Looby Judy
Published: June 2004

An instrument was constructed to assess faculty attitudes toward university students with disabilities and accommodations in the United States and México. Faculty in the United States were more positive about their professional development and had more positive general assumptions about students with disabilities. Faculty in both countries were very similar in their willingness to accommodate most types of students with disabilities and to become friends with people with disabilities.
Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers α-defensin production
Authors: Chalifour Anick , Jeannin Pascale , Gauchat Jean-François , Blaecke Aline , Malissard Martine , N'Guyen Thien , Thieblemont Nathalie , Delneste Yves
Published: June 2004

Although human CD56+CD3- natural killer (NK) cells participate in immune responses against microorganisms, their capacity to directly recognize and be activated by pathogens remains unclear. These cells encode members of the Toll-like receptor (TLR) family, involved in innate cell activation on recognition of pathogen-associated molecular patterns (PAMPs). We therefore evaluated whether the 2 bacterial protein PAMPs, the outer membrane protein A from Klebsiella pneumoniae (KpOmpA) and flagellin, which signal through TLR2 and TLR5, respectively, may directly stimulate human NK cells. These proteins induce interferon-γ (IFN-γ) production by NK cells and synergize with interleukin-2 (IL-2) and proinflammatory cytokines in PAMP-induced activation. Similar results were obtained using CD56+CD3+ (NKR-expressing) T cells. NK cells from TLR2-/- mice fail to respond to KpOmpA, demonstrating TLR involvement in this effect. Defensins are antimicrobial peptides expressed mainly by epithelial cells and neutrophils that disrupt the bacterial membrane, leading to pathogen death. We show that NK cells and NKR-expressing T cells constitutively express α-defensins and that KpOmpA and flagellin rapidly induce their release. These data demonstrate for the first time that highly purified NK cells directly recognize and respond to pathogen components through TLRs and evidence defensins as a novel and direct cytotoxic pathway involved in NK cell-mediated protection against microorganisms. (Blood. 2004;104:1778-1783)
Targeted delivery of adenoviral vectors by cytotoxic T cells
Authors: Yotnda Patricia , Savoldo Barbara , Charlet-Berguerand Nicolas , Rooney Cliona , Brenner Malcolm
Published: June 2004

Effective targeting of vectors to tumor cells that have metastasized to multiple different tissue sites remains a major challenge for gene therapy. Tumor-specific cytotoxic T lymphocytes (CTLs) have been shown in animal models and in humans to be able to cross tissue barriers and traffic to tumor cells. However, their capacity to eliminate malignancy has been limited by tumor immune evasion strategies. We now use a model of Epstein-Barr virus–mediated malignancy to show that human CTLs themselves may be modified to release therapeutic vectors following engagement of their antigen-specific receptors and that these vectors will effectively transduce and destroy tumor targets. We generated EBV-specific CTLs that were transgenic for the adenoviral E1 gene under the control of the cell activation-dependent CD40 ligand (CD40L) promoter. Following transduction with E1-deficient adenoviral vectors, these CTLs produced infectious virus when exposed to HLA-matched EBV-expressing targets, but not on exposure to major histocompatibility complex (MHC)–mismatched or otherwise irrelevant cells. This approach provides a means of delivering oncolytic/therapeutic vectors not only to locally accessible macroscopic tumors as is presently the case, but also to disseminated metastatic disease, while avoiding the risks associated with systemic administration of large doses of adenoviral vectors.
Antioxidative stress–associated genes in circulating progenitor cells: evidence for enhanced resistance against oxidative stress
Authors: Dernbach Elisabeth , Urbich Carmen , Brandes Ralf P. , Hofmann Wolf K. , Zeiher Andreas M. , Dimmeler Stefanie
Published: June 2004

Adult and embryonic stem cells hold great promise for regenerative medicine. Expression profiling of stem cells revealed a characteristic imprint of genes, so-called “stemness” genes, providing resistance to stress. Circulating progenitor cells with an endothelial phenotype (EPCs) can be isolated from peripheral blood and contribute to neovascularization and endothelial regeneration. We investigated whether EPCs are equipped with an antioxidative defense to provide resistance against oxidative stress. EPCs exhibited a significantly lower basal reactive oxygen species (ROS) concentration as compared with mature umbilical vein endothelial cells (HUVECs). Incubation with H2O2 (500 μM) or the redox cycler LY-83583 (10 μM) profoundly increased the ROS concentration to 3- and 4-fold and induced apoptosis in HUVECs. In contrast, H2O2 and LY-83583 induced only a minor increase in intracellular ROS levels and apoptosis in EPCs. Consistently, the expression of the intracellular antioxidative enzymes catalase, glutathione peroxidase and manganese superoxide dismutase (MnSOD), was significantly higher in EPCs versus HUVECs and human microvascular endothelial cells. In accordance, combined inhibition of these antioxidative enzymes increased ROS levels in EPCs and impaired EPC survival and migration. Taken together, EPCs reveal a higher expression of antioxidative enzymes and, thus, are exquisitely equipped to be protected against oxidative stress consistent with their progenitor cell character.
Integrin α4β7 and its counterreceptor MAdCAM-1 contribute to hematopoietic progenitor recruitment into bone marrow following transplantation
Authors: Katayama Yoshio , Hidalgo Andrés , Peired Anna , Frenette Paul S.
Published: June 2004

Previous studies have shown that α4β1 (very late activation antigen-4 [VLA-4]) and vascular cell adhesion molecule-1 (VCAM-1) play a major role in hematopoietic progenitor cell (HPC) homing to bone marrow (BM). However, the antibody used to block VLA-4 function in the mouse (hybridoma clone PS/2) is not specific to VLA-4 but inhibits both α4β1 and α4β7 integrins. Here we have evaluated the contribution of α4β7 in HPC homing to BM. LineagenegSca-1posc-kitpos cells from adult mouse BM and the factor-dependent cell progenitor (FDCP)—mix progenitor cell line express similar levels of α4β7 by flow cytometry. The α4β7 complex was functional since the chemokine CXCL12 enhanced the adhesion of FDCP-mix to immobilized mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and this was completely abrogated by anti-α4β7 (hybridoma clone DATK32) or anti-α4 integrins (PS/2). BM intravital microscopy revealed that α4β7 plays a predominant role in initial tethering and rolling but not in firm adhesion of FDCP-mix cells. Using homing assays, we demonstrate that α4β7 on HPCs contributes to about half of all α4 integrin–mediated homing activity following BM transplantation. MAdCAM-1 is likely expressed since its inhibition significantly reduced HPC homing. Although there may be other α4β7 integrin ligands involved (eg, fibronectin and VCAM-1), these data thus suggest that α4β7 and its counterreceptor MAdCAM-1 represent a novel adhesion pathway mediating HPC homing to BM.
The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion–mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase
Authors: Schmidmaier Ralf , Baumann Philipp , Simsek Meral , Dayyani Farshid , Emmerich Bertold , Meinhardt Gerold
Published: June 2004

Primary drug resistance is a major problem in multiple myeloma, an incurable disease of the bone marrow. Cell adhesion-mediated drug resistance (CAM-DR) causes strong primary resistance. By coculturing multiple myeloma cells with bone marrow stromal cells (BMSCs), we observed a CAM-DR of about 50% to melphalan, treosulfan, doxorubicin, dexamethasone, and bortezomib, which was not reversed by secreted soluble factors. Targeting the adhesion molecules lymphocyte function–associated antigen 1 (LFA-1) and very late antigen 4 (VLA-4) by monoclonal antibodies or by the LFA-1 inhibitor LFA703 reduced CAM-DR significantly. Only statins such as simvastatin and lovastatin, however, were able to completely restore chemosensitivity. All these effects were not mediated by deadhesion or reduced secretion of interleukin 6. Targeting geranylgeranyl transferase (GGTase) and Rho kinase by specific inhibitors (GGTI-298 and Y-27632), but not inhibition of farnesyl transferase (FTase) by FTI-277, showed similar reduction of CAM-DR. Addition of geranylgeranyl pyrophosphate (GG-PP), but not of farnesyl pyrophosphate (F-PP), was able to inhibit simvastatin-induced CAM-DR reversal. Our data suggest that the 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA)/GG-PP/Rho/Rho-kinase pathway mediates CAM-DR and that targeting this pathway may improve the efficacy of antimyeloma therapies by reduction of CAM-DR.
Heat-shock protein 70 exerts opposing effects on Vpr-dependent and Vpr-independent HIV-1 replication in macrophages
Authors: Iordanskiy Sergey , Zhao Yuqi , DiMarzio Paola , Agostini Isabelle , Dubrovsky Larisa , Bukrinsky Michael
Published: June 2004

HIV-1 viral protein R (Vpr) shuttles between the nucleus and the cytoplasm and is believed to contribute to the process of nuclear translocation of the viral preintegration complex, thus facilitating HIV-1 replication in macrophages. In this report, we demonstrate that Hsp70, a heat-shock protein contributing to cellular stress responses, inhibits nuclear translocation of HIV-1 Vpr. In macrophages, Hsp70 is induced shortly after HIV-1 infection. Recombinant Hsp70 or a mild heat shock diminished replication of the wild-type HIV-1, suggesting that Hsp70 might function as an innate antiviral factor. Surprisingly, Hsp70 stimulated nuclear import and replication in macrophages of the Vpr-deficient HIV-1 construct. This finding suggests that Hsp70 and Vpr may function in a similar manner when expressed separately, but they neutralize each other's activity when present together. Consistent with this interpretation, Hsp70 coprecipitated with Vpr from HIV-1–infected cells.
Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders
Authors: Pardanani Animesh , Tefferi Ayalew
Published: June 2004

Imatinib mesylate is a small molecule drug that in vitro inhibits the Abelson (Abl), Arg (abl-related gene), stem cell factor receptor (Kit), and platelet-derived growth factor receptor A and B (PDGFRA and PDGFRB) tyrosine kinases. The drug has acquired therapeutic relevance because of similar inhibitory activity against certain activating mutations of these molecular targets. The archetypical disease in this regard is chronic myeloid leukemia, where abl is constitutively activated by fusion with the bcr gene (bcr/abl). Similarly, the drug has now been shown to display equally impressive therapeutic activity in eosinophilia-associated chronic myeloproliferative disorders that are characterized by activating mutations of either the PDGFRB or the PDGFRA gene. The former usually results from translocations involving chromosome 5q31-33, and the latter usually results from an interstitial deletion involving chromosome 4q12 (FIP1L1-PDGFRA). In contrast, imatinib is ineffective, in vitro and in vivo, against the mastocytosis-associated c-kit D816V mutation. However, wild-type and other c-kit mutations might be vulnerable to the drug, as has been the case in gastrointestinal stomal cell tumors. Imatinib is considered investigational for the treatment of hematologic malignancies without a defined molecular drug target, such as polycythemia vera, myelofibrosis with myeloid metaplasia, and acute myeloid leukemia.
A urokinase-activated recombinant diphtheria toxin targeting the granulocyte-macrophage colony-stimulating factor receptor is selectively cytotoxic to human acute myeloid leukemia blasts
Authors: Abi-Habib Ralph J. , Liu Shihui , Bugge Thomas H. , Leppla Stephen H. , Frankel Arthur E.
Published: June 2004

Novel agents to treat acute myeloid leukemia (AML) are needed with increased efficacy and specificity. We have synthesized a dual-specificity fusion toxin DTU2GMCSF composed of the catalytic and translocation domains of diphtheria toxin (DT) fused to the granulocyte-macrophage colony-stimulating factor (GM-CSF) in which the DT furin cleavage site 163RVRRSV170 is modified to a urokinase plasminogen activator (uPA) cleavage site 163GSGRSA170, termed U2. DTU2GMCSF was highly toxic to the TF1-vRaf AML cell line (proliferation inhibition assay; IC50 = 3.14 pM), and this toxicity was greatly inhibited following pretreatment with anti-uPA and anti-GM-CSF antibodies. The activity of this toxin was then tested on a larger group of 13 human AML cell lines; 5 of the 13 cell lines were sensitive to DTU2GMCSF. An additional 5 of the 13 cell lines became sensitive when exogenous pro-uPA was added. Sensitivity to DTU2GMCSF strongly correlated with the expression levels of uPA receptors (uPARs) and GM-CSF receptors (GM-CSFRs) as well as with total uPA levels. DTU2GMCSF was less toxic to normal cells expressing uPAR or GMCSFR alone, that is, human umbilical vein endothelial cells and peripheral macrophages, respectively. These results indicate that DTU2GMCSF may be a selective and potent agent for the treatment of patients with AML. (Blood. 2004;104:2143-2148)
Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database
Authors: Goldin Lynn R. , Pfeiffer Ruth M. , Li Xinjun , Hemminki Kari
Published: June 2004

The importance of genetic factors in etiology of chronic lymphocytic leukemia (CLL) is suggested by family and population studies. However, the spectrum of malignancies sharing common genetic factors with CLL and the effects of sex and age on familial risk are unknown. We used the Swedish Family-Cancer Database to test for increased familial risks of CLL and other lymphoproliferative tumors. Cancer diagnoses from 1958 to 1998 were assessed in 14 336 first-degree relatives of 5918 CLL cases and in 28 876 first-degree relatives of 11 778 controls. Cancer risks in relatives of cases were compared with those in relatives of controls using marginal survival models. Relatives of cases were at significantly increased risk for CLL (relative risk [RR] = 7.52; 95% confidence interval [CI], 3.63-15.56), for non-Hodgkin lymphoma (RR = 1.45; 95% CI, 0.98-2.16), and for Hodgkin lymphoma (RR = 2.35; 95% CI, 1.08-5.08). CLL risks were similar in parents, siblings, and offspring of cases, in male and female relatives, and were not affected by the case's age at diagnosis. Anticipation was not significant when analyzed using life table methods. We conclude that the familial component of CLL is shared with other lymphoproliferative malignances, suggesting common genetic pathways. However, because clinically diagnosed CLL is uncommon, absolute excess risk to relatives is small.
Adenovirus-mediated intralesional interferon-γ gene transfer induces tumor regressions in cutaneous lymphomas
Authors: Dummer Reinhard , Hassel Jessica C. , Fellenberg Friederike , Eichmüller Stefan , Maier Tanja , Slos Philippe , Acres Bruce , Bleuzen Pascal , Bataille Vincent , Squiban Patrick , Burg Günter , Urosevic Mirjana
Published: June 2004

Primary cutaneous lymphomas have been successfully treated with interferons (IFNs), counterbalancing the T-helper 2 (Th2)-skewing state. We undertook a phase 1, open-label, dose-escalating trial of repeated intratumoral administration of TG1042 in patients with advanced primary cutaneous T-cell lymphomas (CTCLs) and multilesional cutaneous B-cell lymphomas (CBCLs). TG1042 is a third-generation, nonreplicating human adenovirus vector containing a human IFN-γ cDNA insert. Nine patients (7 CTCL, 2 CBCL) were enrolled at the following TG1042 doses: 3 × 109, 3 × 1010, and 3 × 1011 total particles. Local clinical response was observed in 5 of 9 treated patients (3 patients with complete response [CR] and 2 patients with partial response [PR]). Out of these, 3 patients showed systemic CR with the clearance of other noninjected skin lesions. Clinical response lasted for a median of 3 months (range, 1-6 months). Adverse events were mostly of grades 1 and 2. Seven of 9 treated patients had a detectable TG1042-derived IFN-γ message in injected lesions after the first treatment cycle. A TG1042-IFN-γ message was also detectable after several treatment cycles. We demonstrate the induction of humoral immune response to lymphoma tumor-antigen se70-2 after treatment. Our study shows that intralesional injections of TG1042 are both safe and well tolerated. (Blood. 2004;104:1631-1638)
Cholesterol synthesis and import contribute to protective cholesterol increments in acute myeloid leukemia cells
Authors: Banker Deborah E. , Mayer Sasha J. , Li Henry Y. , Willman Cheryl L. , Appelbaum Frederick R. , Zager Richard A.
Published: June 2004

Cholesterol levels are abnormally increased in many acute myeloid leukemia (AML) samples exposed in vitro to chemotherapy. Blocking these acute cholesterol responses selectively sensitizes AML cells to therapeutics. Thus, defining the molecular mechanisms by which AML cells accomplish these protective cholesterol increments might elucidate novel therapeutic targets. We now report that the levels of mRNAs encoding the cholesterol synthesis-regulating enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and the cholesterol-importing low-density lipoprotein (LDL) receptor were both increased by daunorubicin (DNR) or cytarabine (ARA-C) treatments in almost three fourths of cultured AML samples. However, less than one third of AML samples significantly increased LDL accumulation during drug treatments, suggesting that de novo synthesis is the primary mechanism by which most AML cells increase cholesterol levels during drug exposures. LDL increments were not correlated with cholesterol increments in ARA-C–treated AML samples. However, LDL and cholesterol increments did correlate in DNR-treated AML samples where they were measured, suggesting that a subset of AMLs may rely on increased LDL accumulation during treatment with particular drugs. Our data suggest that cholesterol synthesis inhibitors may improve the efficacy of standard antileukemia regimens, but that for maximum benefit, therapy may need to be tailored for individual patients with leukemia.
Murine plasmacytoid dendritic cells induce effector/memory CD8+ T-cell responses in vivo after viral stimulation
Authors: Schlecht Géraldine , Garcia Sylvie , Escriou Nicolas , Freitas Antonio A. , Leclerc Claude , Dadaglio Gilles
Published: June 2004

Like their human counterparts, mouse plasmacytoid dendritic cells (pDCs) play a central role in innate immunity against viral infections, but their capacity to prime T cells in vivo remains unknown. We show here that virus-activated pDCs differentiate into antigen-presenting cells able to induce effector/memory CD8+ T-cell responses in vivo against both epitopic peptides and endogenous antigen, whereas pDCs activated by synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG) acquire only the ability to recall antigen-experienced T-cell responses. We also show that immature pDCs are unable to induce effector or regulatory CD8+ T-cell responses. Thus, murine pDCs take part in both innate and adaptive immune responses by directly priming naive CD8+ T cells during viral infection.
Do antiangiogenic protein fragments have amyloid properties?
Authors: Gebbink Martijn F. B. G. , Voest Emile E. , Reijerkerk Arie
Published: June 2004

Tumor growth requires proteolytic activity. As a consequence, protein breakdown products are present in the circulation of patients with cancer. Within the past decade a large number of proteolytic fragments have been identified that inhibit angiogenesis and tumor growth. The mechanism of action of these inhibitors is still poorly understood. We recently found that the effects of the angiogenesis inhibitor endostatin on endothelial cells is critically dependent on the presence of cross-β structure, a structure also present in amyloidogenic polypeptides in plaques of patients with amyloidosis, such as Alzheimer disease. We also showed that cross-β structure containing endostatin is a ligand for tissue-type plasminogen activator (tPA). We noted that many angiogenesis inhibitors stimulate tPA-mediated plasminogen activation. Because the presence of cross-β structure is the common denominator in tPA-binding ligands, we hypothesize that these endogenous antiangiogenic proteolytic fragments share features with amyloidogenic polypeptides. We postulate that the cross-β structural fold is present in these antiangiogenic polypeptide fragments and that this structure mediates the inhibitory effects. The hypothesis provides new insights in the potential mechanisms of these angiogenesis inhibitors and offers opportunities to improve their use. (Blood. 2004;104:1601-1605)
Inhibition of tumor angiogenesis in vivo by a monoclonal antibody targeted to domain 5 of high molecular weight kininogen
Authors: Song James S. , Sainz Irma M. , Cosenza Stephen C. , Isordia-Salas Irma , Bior Abdel , Bradford Harlan N. , Guo Yan-Lin , Pixley Robin A. , Reddy E. Premkumar , Colman Robert W.
Published: June 2004

We have shown that human high molecular weight kininogen is proangiogenic due to release of bradykinin. We now determined the ability of a murine monoclonal antibody to the light chain of high molecular weight kininogen, C11C1, to inhibit tumor growth compared to isotype-matched murine IgG. Monoclonal antibody C11C1 efficiently blocks binding of high molecular weight kininogen to endothelial cells in a concentration-dependent manner. The antibody significantly inhibited growth of human colon carcinoma cells in a nude mouse xenograft assay and was accompanied by a significant reduction in the mean microvascular density compared to the IgG control group. We also showed that a hybridoma producing monoclonal antibody C11C1 injected intramuscularly exhibited markedly smaller tumor mass in a syngeneic host compared to a hybridoma producing a monoclonal antibody to the high molecular weight kininogen heavy chain or to an unrelated plasma protein. In addition, tumor inhibition by purified monoclonal antibody C11C1 was not due to direct antitumor effect because there was no decrease of tumor cell growth in vitro in contrast to the in vivo inhibition. Our results indicate that monoclonal antibody C11C1 inhibits angiogenesis and human tumor cell growth in vivo and has therapeutic potential for treatment of human cancer. (Blood. 2004;104:2065-2072)
Pathogenic antiphospholipid antibody: an antigen-selected needle in a haystack
Authors: Lieby Patricia , Poindron Vincent , Roussi Stamatiki , Klein Cyril , Knapp Anne-Marie , Garaud Jean-Claude , Cerutti Martine , Martin Thierry , Pasquali Jean-Louis
Published: June 2004

Antiphospholipid antibodies represent a heterogeneous group of autoantibodies directed against anionic phospholipids (PLs) usually linked to protein cofactors. Their presence during the antiphospholipid syndrome is associated with risks of thrombosis and fetal losses. Among 5 randomly selected monoclonal antiphospholipid antibodies, all originating from a single patient suffering from this autoimmune disease, only 1 induced fetal losses when passively injected into pregnant mice. Its antiphospholipid activity was dependent on annexin A5, and its variable regions contained mainly 3 replacement mutations. To clarify the role of these mutations in the pathogenicity of the antibody, they were in vitro reverted to the germ line configuration. The resulting “germ line” antibody reacted with multiple self-antigens and only partially lost its reactivity against PLs, but it was no more dependent on annexin A5 and, more importantly, was no more pathogenic. This study illustrates that the in vivo antigen-driven maturation process of natural autoreactive B cells can be responsible for pathogenicity. (Blood. 2004;104:1711-1715)
Differential regulation of gene expression following CD40 activation of leukemic compared to healthy B cells
Authors: Gricks Clair S. , Zahrieh David , Zauls A. Jason , Gorgun Gullu , Drandi Daniela , Mauerer Katja , Neuberg Donna , Gribben John G.
Published: June 2004

It is possible to differentiate malignant from healthy cells and to classify diseases based on identification of specific gene expression profiles. We hypothesized that gene expression profiling could also be used to identify differential activation of healthy and malignant cells, and as a model for this, we examined the molecular sequelae of CD40 activation of healthy and B-cell chronic lymphocytic leukemia (CLL) cells. Hierarchical clustering analysis of gene expression signatures grouped samples by CD40 activation status and further subclassified CD40-activated CLL cells from healthy B cells. Supervised analyses in healthy B cells compared to CLL cells identified differential regulation of genes governing cell cycle progression and apoptosis. CD40 signaling of CLL cells increases their susceptibility to immune recognition, but promotes survival and cell cycle arrest, making these cells potentially more resistant to chemotherapy. These results illustrate the utility of gene expression profiling to elucidate the molecular sequelae of signaling in healthy cells and altered signaling pathways in malignant cells. This type of approach should be useful to identify targets of therapy of malignant diseases. (Blood. 2004;104:4002-4009)
Directed differentiation and mass cultivation of pure erythroid progenitors from mouse embryonic stem cells
Authors: Carotta Sebastian , Pilat Sandra , Mairhofer Andreas , Schmidt Uwe , Dolznig Helmut , Steinlein Peter , Beug Hartmut
Published: June 2004

Differentiating embryonic stem (ES) cells are an increasingly important source of hematopoietic progenitors, useful for both basic research and clinical applications. Besides their characterization in colony assays, protocols exist for the cultivation of lymphoid, myeloid, and erythroid cells. With the possible exception of mast cells, however, long-term expansion of pure hematopoietic progenitors from ES cells has not been possible without immortalization caused by overexpression of exogenous genes. Here, we describe for the first time an efficient yet easy strategy to generate mass cultures of pure, immature erythroid progenitors from mouse ES cells (ES-EPs), using serum-free medium plus recombinant cytokines and hormones. ES-EPs represent long-lived, adult, definitive erythroid progenitors that resemble immature erythroid cells expanding in vivo during stress erythropoiesis. When exposed to terminal differentiation conditions, ES-EPs differentiated into mature, enucleated erythrocytes. Importantly, ES-EPs injected into mice did not exhibit tumorigenic potential but differentiated into normal erythrocytes. Both the virtually unlimited supply of cells and the defined culture conditions render our system a valuable tool for the analysis of factors influencing proliferation and maturation of erythroid progenitors. In addition, the system allows detailed characterization of processes during erythroid proliferation and differentiation using wild-type (wt) and genetically modified ES cells.
Extracellular nucleotides are potent stimulators of human hematopoietic stem cells in vitro and in vivo
Authors: Lemoli Roberto M. , Ferrari Davide , Fogli Miriam , Rossi Lara , Pizzirani Cinzia , Forchap Sylvia , Chiozzi Paola , Vaselli Diletta , Bertolini Francesco , Foutz Thomas , Aluigi Michela , Baccarani Michele , Di Virgilio Francesco
Published: June 2004

Although extracellular nucleotides support a wide range of biologic responses of mature blood cells, little is known about their effect on blood cell progenitor cells. In this study, we assessed whether receptors for extracellular nucleotides (P2 receptors [P2Rs]) are expressed on human hematopoietic stem cells (HSCs), and whether activation by their natural ligands, adenosine triphosphate (ATP) and uridine triphosphate (UTP), induces HSC proliferation in vitro and in vivo. Our results demonstrated that CD34+ HSCs express functional P2XRs and P2YRs of several subtypes. Furthermore, stimulation of CD34+ cells with extracellular nucleotides caused a fast release of Ca2+ from intracellular stores and an increase in ion fluxes across the plasma membrane. Functionally, ATP and, to a higher extent, UTP acted as potent early acting growth factors for HSCs, in vitro, because they strongly enhanced the stimulatory activity of several cytokines on clonogenic CD34+ and lineage-negative CD34- progenitors and expanded more primitive CD34+-derived long-term culture-initiating cells. Furthermore, xenogenic transplantation studies showed that short-term preincubation with UTP significantly expanded the number of marrow-repopulating HSCs in nonobese diabetic/severe combined immunodeficiency mice. Our data suggest that extracellular nucleotides may provide a novel and powerful tool to modulate HSC functions. (Blood. 2004;104:1662-1670)
Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma
Authors: Kaufmann Hannes , Raderer Markus , Wöhrer Stefan , Püspök Andreas , Bankier Alexander , Zielinski Christoph , Chott Andreas , Drach Johannes
Published: June 2004

We evaluated a treatment strategy targeting both lymphoma cells (by rituximab) and the microenvironment (by thalidomide) in 16 patients with relapsed/refractory mantle cell lymphoma (MCL). Rituximab was administered at 375 mg/m2 for 4 weekly doses concomitantly with thalidomide (200 mg daily, with a dose increment to 400 mg on day 15), which was continued as maintenance therapy until progression/relapse. Thirteen patients (81%) experienced an objective response, with 5 complete responders (31%). Median progression-free survival (PFS) was 20.4 months (95% confidence interval [CI], 17.3-23.6 months), and estimated 3-year survival was 75%. In patients achieving a complete response, PFS after rituximab plus thalidomide was longer than PFS after the preceding chemotherapy. Severe adverse events included 2 thromboembolic events and 1 grade IV neutropenia associated with thalidomide. Our results suggest that rituximab plus thalidomide has marked antitumor activity in relapsed/refractory MCL and a low toxicity profile, which warrants further evaluation in MCL.
Bystander destruction of hematopoietic progenitor and stem cells in a mouse model of infusion-induced bone marrow failure
Authors: Chen Jichun , Lipovsky Karen , Ellison Felicia M. , Calado Rodrigo T. , Young Neal S.
Published: June 2004

Infusion of parental lymph node (LN) cells into sublethally irradiated hybrid F1 recipients created a murine model for bone marrow (BM) failure. Affected animals developed fatal pancytopenia within 2 to 3 weeks, accompanied by BM oligoclonal T-cell infiltration and severe marrow hypoplasia indicated by approximately 10-fold declines in total BM cellularity, 15-fold declines in BM Lin-Sca1+c-Kit+ cells, 100-fold declines in spleen colony-forming units, and 100-fold declines in hematopoietic progenitor and stem cells as estimated by irradiation protection in vivo. LN cells of both H2b/b and H2d/d haplotypes were effectors. Serum interferon-γ (IFN-γ) concentration increased 2- to 3-fold. Marrow cells were severely apoptotic, with high proportions of Fas+ and annexin V+ cells. Cotransplantation of 5 × 105 BM cells from clinically affected donors and 106 BM cells from H2 identical healthy mice could not rescue lethally irradiated recipients. Recipients had significantly lower cellularity in peripheral blood and BM, and cell mixtures failed to produce a stromal feeder layer to support marrow cell growth in vitro. Pathogenic T cells from donors after BM failure appeared capable of destroying hematopoietic progenitor, stem, and stromal cells from fully compatible healthy donors as “innocent bystanders.” This effect can be partially abrogated by anti-IFN-γ antibody. (Blood. 2004;104:1671-1678)
Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors
Authors: Zhang Jing , Lodish Harvey F.
Published: June 2004

Oncogenic mutations in ras genes frequently occur in patients with myeloid disorders, and in these patients erythropoiesis is often affected. Previously, we showed that expression of oncogenic H-ras in purified mouse primary fetal liver erythroid progenitors blocks terminal erythroid differentiation and supports erythropoietin (Epo)-independent proliferation. As a first step in understanding the underlying molecular mechanisms we examined the signaling pathways downstream of Ras in primary erythroid cells. We found that 3 major pathways are abnormally activated by oncogenic H-ras: Raf/ERK (extracellular signal-regulated kinase), phosphatidyl inositol 3 (PI3)-kinase/Akt, and RalGEF/RalA. However, only constitutive activation of the MEK (MAPK [mitogen-activated protein kinase]/ERK kinase)/ERK pathway alone could recapitulate all of the effects of oncogenic H-ras expression in blocking erythroid differentiation and inducing Epo-independent proliferation. Although expression of a constitutively active Akt kinase (ca.Akt) in erythroid progenitors does not significantly affect erythroid differentiation in the presence of Epo, coexpression of ca.Akt together with a constitutively active MEK causes prolonged Epo-independent proliferation of erythroid progenitors in addition to a block in differentiation. Moreover, the effects of oncogenic H-ras expression on primary erythroid cells are blocked by the addition of U0126, a specific inhibitor of MEK1 and MEK2, allowing normal terminal erythroid proliferation and differentiation. Our data suggest that the interruption of constitutive MEK/ERK signaling is a potential therapeutic strategy to correct impaired erythroid differentiation in patients with myeloid disorders. (Blood. 2004;104: 1679-1687)
Somatoform disorders: A help or hindrance to good patient care?
Authors: Sharpe Michael , Mayou Richard
Published: June 2004

The paper by de Waal and colleagues (2004, this issue) reports on the prevalence of somatoform disorders in Dutch primary care. They found that at least one out of six patients seen by general practitioners could be regarded as having a somatoform disorder, almost all in the non-specific category of undifferentiated somatoform disorder. The prevalence of the condition has major implications for medical services but what does this diagnosis mean? Is receiving a diagnosis of somatoform disorder of any benefit to the patient? Does it help the doctor to provide treatment?
Attention-deficit hyperactivity disorder and life-span development
Authors: McArdle Paul
Published: June 2004

Developmentally inappropriate degrees of hyperactivity, inattention and impulsivity are common symptoms in childhood. If of early onset (before 7 years), present in different settings and to a degree that causes functional impairment, a diagnosis of attention-deficit hyperactivity disorder (ADHD) or ‘hyperkinetic disorder’ should be considered. The age criterion is crucial to distinguish ADHD and hyperkinetic disorder from later-onset conditions such as agitated depression, adolescent-onset socialised conduct disorder (probably not linked to ADHD) or hypomania, that might appear superficially similar. Attention-deficit hyperactivity disorder and hyperkinetic disorder are commonly associated with language, learning and social impairments. Indeed, in severe cases hyperactivity could be a marker of a multifaceted developmental disorder. Hence, competent assessment usually requires a thorough history, often using a number of sources.
Somatoform disorders in general practice
Authors: De Waal Margot W M. , Arnold Ingrid A. , Eekhof Just A. H. , Van Hemert Albert M.
Published: June 2004

Background

General practitioners play a pivotal part in the recognition and treatment of psychiatric disorders. Identifying somatoform disorders is important for the choice of treatment.

Aims

To quantify the prevalence of, and functional impairment associated with, somatoform disorders, and their comorbidity with anxiety/depressive disorders.

Method

Two-stage prevalence study: a set of questionnaires was completed by 1046 consecutive patients of general practitioners (aged 25–80 years), followed by a standardised diagnostic interview (SCAN 2.1).

Results

The prevalence of somatoform disorders was 16.1% (95% CI 12.8-19.4). When disorders with only mild impairment were included, the prevalence increased to 21.9%. Comorbidity of somatoform disorders and anxiety/depressive disorders was 3.3 times more likely than expected by chance. In patients with comorbid disorders, physical symptoms, depressive symptoms and functional limitations were additive.

Conclusions

Our findings underline the importance of a comprehensive diagnostic approach to psychiatric disorders in general practice.
Prevalence of chronic disabling fatigue in children and adolescents
Authors: Farmer Anne , Fowler Tom , Scourfield Jane , Thapar Anita
Published: June 2004

Background

The epidemiology of chronic fatiguing illnesses in young people is poorly understood.

Aims

To estimate the lifetime prevalence of different definitions of chronic fatigue in 8-to 17-year-olds.

Method

Participants came from two population-based twin series. Parents completed self-report questionnaires that enquired whether either child had ever experienced more than a few days of disabling fatigue. Telephone interviews were undertaken for individuals who had experienced such an episode.

Results

Questionnaires were returned by 1468 families (65% response rate) and telephone interviews were undertaken regarding 99 of the 129 subjects (77%) who had experienced fatigue. The lifetime prevalence estimates ranged from 2.34% (95% CI 1.75–2.94) for disabling fatigue lasting 3 months to 1.29% (95% CI 0.87–1.71) for a disorder resembling adult operationally defined chronic fatigue syndrome.

Conclusions

From the age of 11 years, young people have similar rates and types of chronic fatiguing illnesses to adults.
Age of traumatisation as a predictor of post-traumatic stress disorder or major depression in young women
Authors: Maercker Andreas , Michael Tanja , Fehm Lydia , Becker Eni S. , Margraf Jürgen
Published: June 2004

Background

Findings in developmental psychopathology suggest that traumatisation in childhood may increase the risk of both post-traumatic stress disorder (PTSD) and major depressive disorder, whereas traumatisation in adolescence is more likely to lead to elevated PTSD risk.

Aims

To estimate the impact of traumatisation in childhood or adolescence in a community sample.

Method

A representative sample of 1966 young women from Dresden aged 18–45 years were interviewed for occurrence of traumatic events and the onset of PTSD and major depression. The sample was subdivided into a childhood trauma group (trauma up to age 12 years) and an adolescent trauma group (trauma from age 13 years).

Results

A quarter of all participants reported traumatic events meeting the DSM AI criterion. In the childhood group conditional risks for PTSD and major depressive disorder were 17.0% and 23.3%, respectively, compared with risks of 13.3% and 6.5%, respectively, in the adolescent group. In 29% of those with PTSD, major depression was also present.

Conclusions

The risk of developing major depressive disorder after traumatisation in childhood is approximately equal to the risk of developing PTSD. After age 13 years, the risk of PTSD is greater than the risk of major depression after traumatisation.
Hippocampal volume change in depression: Late- and early-onset illness compared
Authors: Lloyd Adrian J. , Ferrier I. Nicol , Barber Robert , Gholkar Anil , Young Allan H. , O'Brien John T.
Published: June 2004

Background

Evidence for structural hippocampal change in depression is limited despite reports of neuronal damage due to hypercortisolaemia and vascular pathology.

Aims

To compare hippocampal and white matter structural change in demographically matched controls and participants with early-onset and late-onset depression.

Method

High-resolution volumetric magnetic resonance imaging (MRI) and rating of MRI hyperintensities.

Results

A total of 51 people with depression and 39 control participants were included. Participants with late-onset depression had bilateral hippocampal atrophy compared with those with early-onset depression and controls. Hippocampal volumes did not differ between control participants and those with early-onset depression. Age of depression onset correlated (negatively) with hippocampal volume but lifetime duration of depression did not. Hyperintensity ratings did not differ between groups.

Conclusions

Results suggest that acquired biological factors are of greater importance in late-than in early-onset illness and that pathological processes other than exposure to hypercortisolaemia of depression underlie hippocampal atrophy in depression of late life.
Hypothalamic-pituitary-adrenal axis function in patients with bipolar disorder
Authors: Watson Stuart , Gallagher Peter , Ritchie James C. , Ferrier I. Nicol , Young Allan H.
Published: June 2004

Background

Hypothalamic-pituitary-adrenal (HPA) axis function, as variously measured by the responses to the combined dexamethasone/ corticotrophin-releasing hormone (dex/ CRH) test, the dexamethasone suppression test (DST) and basal cortisol levels, has been reported to be abnormal in bipolar disorder.

Aims

To test the hypothesis that HPA axis dysfunction persists in patients in remission from bipolar disorder.

Method

Salivary cortisol levels and the plasma cortisol response to the DST and dex/CRH test were examined in 53 patients with bipolar disorder, 27 of whom fulfilled stringent criteria for remission, and in 28 healthy controls. Serum dexamethasone levels were measured.

Results

Patients with bipolar disorder demonstrated an enhanced cortisol response to the dex/CRH test compared with controls (P=0.001). This response did not differ significantly between remitted and non-remitted patients. These findings were present after the potentially confounding effects of dexamethasone levels were accounted for.

Conclusions

The dex/CRH test is abnormal in both remitted and non-remitted patients with bipolar disorder. Thismeasure of HP Aaxis dysfunction is a potential trait marker in bipolar disorder and thus possibly indicative of the core pathophysiological process in this illness.
Effects of long-term prolactin-raising antipsychotic medication on bone mineral density in patients with schizophrenia
Authors: Meaney Anna Maria , Smith Shubulade , Howes O. D. , O'Brien Moira , Murray Robin M. , O'Keane Veronica
Published: June 2004

Background

High rates of osteoporosis in schizophrenia may result from the prolactin-raising effects of some antipsychotic medication.

Aims

To examine bone mineral density in relation to relevant endocrine variables in patients with schizophrenia taking prolactin-raising antipsychotics.

Method

Fifty-five patients who had been receiving prolactin-raising antipsychotic medication for > 10 years underwent dual-energy X-ray absorptiometry of their lumbar and hip bones. Among the endocrine variables assessed were plasma prolactin and sex hormones.

Results

Age-related reduced bone mineral density measures were found in 17 (57%) of the male and 8 (32%) of the female patients. Higher doses of medication were associated with increased rates of both hyperprolactinaemia and bone mineral density loss. Bone loss for the whole group was correlated with medication dose, and for men was inversely correlated with testosterone values.

Conclusions

These results suggestthat patients with schizophrenia on long-term prolactin-raising antipsychotic medication are at high risk of developing reduced bone mineral density as a consequence of hyperprolactinaemia-induced hypogonadism.
Non-adherence to antipsychotic medication regimens: Associations with resource use and costs
Authors: Knapp Martin , King Derek , Pugner Klaus , Lapuerta Pablo
Published: June 2004

Background

Several factors are thought to influence resource use and costs in treating schizophrenia.

Aims

To assess the relative impact of non-adherence and other factors associated with resource use and costs incurred by people with schizophrenia.

Method

Secondary analyses were made of data from a 1994 national survey of psychiatric morbidity among adults living in institutions in the UK. Factors potentially relating to resource use and costs were examined using two-part models.

Results

Patients who failed to adhere to their medication regimen were over one-and-a-halftimes as likely as patients who did adhere to it to report use of in-patient services. Non-adherence is one of the most significant factors in increasing external service costs, by a factor of almost 3. Non-adherence predicted an excess annual cost per patient of approximately $2500 for in-patient services and over $5000 for total service use.

Conclusions

Resource use and costs are influenced by various factors. Medication non-adherence consistently exhibits an association with higher costs. Further important factors are patient needs and the ability of the system to address them.
Premorbid, psychosocial and clinical predictors of the costs of schizophrenia and other psychoses
Authors: Carr Vaughan J. , Lewin Terry J. , Neil Amanda L. , Halpin Sean A. , Holmes Scott
Published: June 2004

Background

Predictors of the costs of psychosis have received insufficient research attention, particularly factors associated with indirect costs.

Aims

To identify the predictors of direct mental health care costs and indirect or time-loss costs in psychotic disorders and to discuss their implications for future interventions.

Method

Structured interview data from the Low Prevalence Disorders Study (n=980) were used to examine predictors of the costs of psychosis in Australia. Estimates of annual costs per patient were derived from the perspectives of government and society. Hierarchical regressions were used to assess the contributions to costs of premorbid, psychosocial and clinical factors.

Results

Schizophrenia involved greater costs than other psychotic disorders. Non-completion of high-school education and chronicity of illness course were predictive of higher costs across all categories, and some factors were linked primarily with mental health care costs (e.g. age at onset, current symptomatology) or indirect costs (e.g. male gender, overall disability).

Conclusions

Several concurrent strategies were recommended, including early intervention programmes and assertive evidence-based rehabilitation and supported employment programmes aimed at reducing disability The cost-effectiveness of these approaches needs to be evaluated from the perspectives of both government and society.