bluuebunny/crossref_metadata_2025_split huggingface dataset:
International Comparison of Stroke Cost Studies
Authors: Evers Silvia M.A.A. , Struijs Jeroen N. , Ament André J.H.A. , van Genugten Marianne L.L. , Jager J. (Hans) C. , van den Bos Geertrudis A.M. 
Published: April 2004

Purpose—With the rapid international spread of interventions, there is a need to understand the economic implications of these changes and to interpret these economic implications on the international level. The purpose of this study is to systematically compare total health care expenditures on stroke, the costs of stroke per capita, and the distribution of stroke costs within different countries, with special attention to the allocation of resources among different health care facilities.Methods—Studies for this literature review were selected by conducting a literature search from January 1966 to July 2003. Key methodological, country-related, and monetary issues of the selected stroke cost studies were evaluated using a checklist.Results—After selection, 25 stroke cost studies were reviewed. Although the selected cost of illness studies used different methodologies, the estimated expenditures for stroke are approximately similar. The proportion of national health care in the 8 countries studied is unequivocal for the more recent studies, ie, ≈3% of total health care expenditures. A shift is observed from the inpatient treatment costs (in the first year) toward outpatient treatment and long-term care costs (in the latter years). Furthermore, it is remarkable that in the studies, little attention is paid to costs borne by the patient and family or to the costs of comorbidity.Conclusions—This study highlights the importance of studying the economic consequences of stroke and of interpreting the results on the international level. The results of stroke cost studies provide insight into the distribution of the costs of stroke and the impact of stroke on the national expenditure on health care.
CorMet: A Computational, Corpus-Based Conventional Metaphor Extraction System
Authors: Mason Zachary J. 
Published: April 2004

CorMet is a corpus-based system for discovering metaphorical mappings between concepts. It does this by finding systematic variations in domain-specific selectional preferences, which are inferred from large, dynamically mined Internet corpora. Metaphors transfer structure from a source domain to a target domain, making some concepts in the target domain metaphorically equivalent to concepts in the source domain. The verbs that select for a concept in the source domain tend to select for its metaphorical equivalent in the target domain. This regularity, detectable with a shallow linguistic analysis, is used to find the metaphorical interconcept mappings, which can then be used to infer the existence of higher-level conventional metaphors. Most other computational metaphor systems use small, hand-coded semantic knowledge bases and work on a few examples. Although Cor Met's only knowledge base is Word Net (Fellbaum 1998) it can find the mappings constituting many conventional metaphors and in some cases recognize sentences instantiating those mappings. CorMet is tested on its ability to find a subset of the Master Metaphor List (Lakoff, Espenson, and Schwartz 1991).
HIV-1 Tat enhances Kaposi sarcoma–associated herpesvirus (KSHV) infectivity
Authors: Aoki Yoshiyasu , Tosato Giovanna 
Published: April 2004

Abstract
The high frequency of Kaposi sarcoma (KS) in immunodeficiency states, particularly in patients with AIDS, has been attributed to increased replication of KS-associated herpesvirus (KSHV), a necessary cofactor for KS development. However, experimental KSHV infection of endothelial lineage cells that compose KS lesions has been difficult even in the absence of immune cells. Here we show that HIV-1 Tat protein can directly promote KSHV transmission. Full-length HIV-1 Tat and a 13–amino-acid peptide corresponding to the basic region of Tat specifically enhances the entry of KSHV into endothelial and other cells, presenting evidence for an active role of HIV-1 in the development of KSHV-associated diseases. These results can explain why AIDS-KS is more frequent and clinically more aggressive than KS in other immunodeficiency states.
An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder
Authors: Jordan Michael B. , Hildeman David , Kappler John , Marrack Philippa 
Published: April 2004

AbstractHemophagocytic lymphohistiocytosis (HLH) is a rare disorder with familial and acquired forms. The familial form is associated with mutations in the perforin gene and both forms are associated with severe defects in lymphocyte cytotoxic function. We examined perforin-deficient mice as a model of HLH in order to gain insight into this poorly understood disorder. While these mice do not spontaneously develop HLH-like symptoms, we found that they manifest all of the features of HLH after infection with lymphocytic choriomeningitic virus (LCMV). Following LCMV infection, perforin-deficient mice develop fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevation of multiple serum cytokine levels, and hemophagocytosis is evident in many tissues. Investigation into how this phenotype develops has revealed that CD8+ T cells, but not natural killer (NK) cells, are necessary for the development of this disorder. Cytokine neutralization studies have revealed that interferon gamma (IFNγ) is uniquely essential as well. Finally, the excessive amount of IFNγ seen in affected mice appears to be driven by increased antigen presentation to CD8+ T cells. These studies provide insight into the pathophysiology of HLH, and provide new targets for specific therapeutic intervention in this fatal disorder.
Role of a NK receptor, KLRE-1, in bone marrow allograft rejection: analysis with KLRE-1–deficient mice
Authors: Shimizu Eiko , Koike Junzo , Wakao Hiroshi , Seino Ken-ichiro , Koseki Haruhiko , Kakiuchi Terutaka , Nakayama Toshinori , Taniguchi Masaru 
Published: April 2004

AbstractNatural killer (NK) cells play a pivotal role in the immune reaction during the bone marrow allograft rejection. Little is known, however, about the molecular mechanisms underlying the NK cell–mediated allograft recognition and rejection. In this report, we assessed the role of a recently identified NK receptor, killer cell lectinlike receptor 1 (KLRE-1), by generating knock-out mice. KLRE-1–deficient mice were born at an expected frequency and showed no aberrant phenotype on growth and lymphoid development. Nevertheless, KLRE-1–deficient cells showed a severely compromised allogeneic cytotoxic activity compared with the wild-type cells. Furthermore, allogeneic bone marrow transfer culminated in colony formation in the spleen of KLRE-1–deficient mice, whereas no colony formation was observed in wild-type recipient mice. These results demonstrate that KLRE-1 is a receptor mediating recognition and rejection of allogeneic target cells in the host immune system.
Donor-derived TNF-α regulates pulmonary chemokine expression and the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation
Authors: Hildebrandt Gerhard C. , Olkiewicz Krystyna M. , Corrion Leigh A. , Chang Yayi , Clouthier Shawn G. , Liu Chen , Cooke Kenneth R. 
Published: April 2004

AbstractIdiopathic pneumonia syndrome (IPS) is a significant cause of mortality after allogeneic bone marrow transplantation (allo-BMT), and tumor necrosis factor-α (TNF-α) is a significant effector molecule in this process. However, the relative contribution of donor-versus host-derived TNF-α to the development of IPS has not been elucidated. Using a lethally irradiated parent → F1 mouse IPS model, we showed that 5 weeks after transplantation allo-BMT recipients developed significant lung injury compared with syngeneic controls, which was associated with increased bronchoalveolar lavage (BAL) fluid levels of TNF-α, elevated numbers of donor-derived TNF-α-secreting T cells, and increased pulmonary macrophage production of TNF-α to lipopolysaccharide (LPS) stimulation. Allo-BMT with TNF-α-/- donor cells resulted in significantly reduced IPS severity, whereas utilization of TNF-α-deficient mice as BMT recipients had no effect on IPS. We next determined that TNF-α secretion from both donor accessory cells (monocytes/macrophages) and T cells significantly contributed to the development of IPS. Importantly, the absence of donor T-cell-derived TNF-α resulted in a significant decrease in inflammatory chemokine production in the lung and near complete abrogation of IPS. Collectively, these data demonstrate that donor TNF-α is critical to the development of IPS and reveal a heretofore unknown mechanism for T-cell-derived TNF-α in the evolution of this process. (Blood. 2004;104:586-593)
Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS
Authors: de Lima Marcos , Couriel Daniel , Thall Peter F. , Wang Xuemei , Madden Timothy , Jones Roy , Shpall Elizabeth J. , Shahjahan Munir , Pierre Betty , Giralt Sergio , Korbling Martin , Russell James A. , Champlin Richard E. , Andersson Borje S. 
Published: April 2004

AbstractPostulating favorable antileukemic effect with improved safety, we used intravenous busulfan and fludarabine as conditioning therapy for allogeneic hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Fludarabine 40 mg/m2 and intravenous busulfan 130 mg/m2 were given once daily for 4 days, with tacrolimus-methotrexate as graft-versus-host disease (GVHD) prophylaxis. We treated 74 patients with AML and 22 patients with MDS; patients had a median age of 45 years (range, 19-66 years). Only 20% of the patients were in first complete remission (CR) at transplantation. Donors were HLA-compatible related (n = 60) or matched unrelated (n = 36). The CR rate for 54 patients with active disease was 85%. At a median follow-up of 12 months, 1-year regimen-related and treatment-related mortalities were 1% and 3%, respectively. Two patients had reversible hepatic veno-occlusive disease. Actuarial 1-year overall survival (OS) and event-free survival (EFS) were 65% and 52% for all patients, and 81% and 75% for patients receiving transplants in CR. Recipient age and donor type did not influence OS or EFS. Median busulfan clearance was 109 mL/min/m2 and median daily area-under-the-plasma-concentration-versus-time-curve was 4871 μmol-min, with negligible interdose variability in pharmacokinetic parameters. The results suggest that intravenous busulfan-fludarabine is an efficacious, reduced-toxicity, myeloablative-conditioning regimen for patients with AML or MDS undergoing HSCT.
On the link between Bcl-2 family proteins and glucocorticoid-induced apoptosis
Authors: Almawi Wassim Y , Melemedjian Ohannes K , Jaoude Maroun M Abou 
Published: April 2004

AbstractAs immunosuppressive agents, glucocorticoids (GCs) act by inhibiting the expression of cytokines and adhesion molecules at the transcriptional and post-transcriptional levels. In addition, GCs exerted their effects by modulating apoptosis. In view of the central role of the Bcl-2 family protein in regulating apoptosis, it was tempting to speculate that GCs modulated apoptosis through modulation of the expression of proapoptotic (Bax, Bcl-XS, Bak) and prosurvival (Bcl-2, Bcl-XL, Bcl-w) Bcl-2 family members. Prosurvival Bcl-2 family members in various cell types antagonized GC-induced apoptosis, thereby suggesting a causal relationship between GC-induced apoptosis and Bcl-2 proteins. The antagonism of apoptosis afforded by prosurvival Bcl-2 proteins appeared to be specific for the GCs, as Bcl-2 and Bcl-xL blocked GC-induced apoptosis in T cell hybridomas but did not affect Fas or activation-induced apoptosis. Although it is speculated that GC-induced apoptosis may be mediated through the activation of proapoptotic Bcl-2 proteins, recent findings suggest that this may vary depending on the conditions and the cell types used. The mechanism by which Bcl-2 inhibited GC-induced apoptosis remains uncertain. It was suggested that Bcl-2 acted on outer mitochondrial membranes to preserve their function. Bcl-2 overexpression also inhibited GC-induced apoptotic events, including caspase activation and mitochondrial dysfunction. The cross-talk of the GC receptors with other secondary messengers could lead to modulation of the activity of Bcl-2 proteins through modification of their phosphorylation status, without ruling out the possibility of a physical interaction between activated GR with Bcl-2 proteins.
Synergy between proinflammatory ligands of G protein-coupled receptors in neutrophil activation and migration
Authors: Gouwy Mieke , Struyf Sofie , Catusse Julie , Proost Paul , Van Damme Jo 
Published: April 2004

AbstractThe chemokine dose and the time period during which the chemotactic gradient is established determine the number of leukocytes that infiltrate inflamed tissues. At suboptimal chemokine concentrations, neutrophils may require a priming agent or a second stimulus for full activation. An interesting mode of cooperative action to reach maximal migration is synergy between chemokines. This was first observed between the plasma CC chemokine regakine-1 and the tissue CXC chemokine ligand interleukin-8 (IL-8/CXCL8) in neutrophil chemotaxis. Addition of antibodies against IL-8 or regakine-1 in the Boyden microchamber assay abrogated this synergy. Other CC chemokines, such as CC chemokine ligand-2 monocyte chemotactic protein-1 (MCP-1/CCL2), MCP-2 (CCL8), and MCP-3 (CCL7) as well as the CXC chemokine receptor-4 (CXCR4) agonist stromal cell-derived factor-1α (SDF-1α/CXCL12), also dose-dependently enhanced neutrophil chemotaxis toward a suboptimal concentration of IL-8. These chemokines synergized equally well with the anaphylatoxin C5a in neutrophil chemotaxis. Alternatively, IL-8 and C5a did not synergize with an inactive precursor form of CXCL7, connective tissue-activating peptide-III/CXCL7, or the chemoattractant neutrophil-activating peptide-2/CXCL7. In the chemotaxis assay under agarose, MCP-3 dose-dependently increased the migration distance of neutrophils toward IL-8. In addition, the combination of IL-8 and MCP-3 resulted in enhanced neutrophil shape change. AMD3100, a specific CXCR4 inhibitor, reduced the synergistic effect between SDF-1α and IL-8 significantly. SDF-1α, but not MCP-1, synergized with IL-8 in chemotaxis with CXCR1-transfected, CXCR4-positive Jurkat cells. Thus, proinflammatory chemokines (IL-8, MCP-1), coinduced during infection in the tissue, synergize with each other or with constitutive chemokines (regakine-1, SDF-1α) to enhance the inflammatory response.
Genetic fusions with viral chemokines target delivery of nonimmunogenic antigen to trigger antitumor immunity independent of chemotaxis
Authors: Ruffini Pier Adelchi , Biragyn Arya , Coscia Marta , Harvey Linda K , Cha Soung-Chul , Bogen Bjarne , Kwak Larry W 
Published: April 2004

AbstractThe ideal vaccine carrier should be able to target antigen delivery and possibly recruit antigen-presenting cells (APC) and deliver an activation signal to promote adaptive immune responses. Ligands for chemokine receptors expressed on APC may be attractive candidates, as they can both target and attract APC. To investigate the requirement for APC recruitment, we used a pair of viral chemokines, agonist herpes simplex virus 8-derived macrophage inflammatory protein–I (vMIP-I) and antagonist MC148, which induce and suppress chemotaxis, respectively. Chemokine-antigen fusions efficiently delivered a model nonimmunogenic tumor antigen to APC for processing and presentation to antigen-specific T cells in vitro. Physical linkage of chemokine and antigen and specific binding of chemokine receptor by the fusion protein were required. Mice immunized with vMIP-I or MC148 fusion DNA vaccines elicited protection against tumor challenge. Therefore, vaccine efficacy depends primarily on the ability of the carrier to target antigen delivery to APC for subsequent processing and presentation, and chemotaxis directly induced by the chemokine moiety in the fusion may not be necessary.
The nucleotide receptor P2X7 mediates actin reorganization and membrane blebbing in RAW 264.7 macrophages via p38 MAP kinase and Rho
Authors: Pfeiffer Zachary A , Aga Mini , Prabhu Usha , Watters Jyoti J , Hall David J , Bertics Paul J 
Published: April 2004

AbstractExtracellular nucleotides regulate macrophage function via P2X nucleotide receptors that form ligand-gated ion channels. In particular, P2X7 activation is characterized by pore formation, membrane blebbing, and cytokine release. P2X7 is also linked to mitogen-activated protein kinases (MAPK) and Rho-dependent pathways, which are known to affect cytoskeletal structure in other systems. As cytoskeletal function is critical for macrophage behavior, we have tested the importance of these pathways in actin filament reorganization during P2X7 stimulation in RAW 264.7 macrophages. We observed that the P2X7 agonists adenosine 5′-triphosphate (ATP) and 3′-O-(4-benzoylbenzoyl) ATP (BzATP) stimulated actin reorganization and concomitant membrane blebbing within 5 min. Disruption of actin filaments with cytochalasin D attenuated membrane blebbing but not P2X7-dependent pore formation or extracellular-regulated kinase (ERK)1/ERK2 and p38 activation, suggesting that these latter processes do not require intact actin filaments. However, we provide evidence that p38 MAPK and Rho activation but not ERK1/ERK2 activation is important for P2X7-mediated actin reorganization and membrane blebbing. First, activation of p38 and Rho was detected within 5 min of BzATP treatment, which is coincident with membrane blebbing. Second, the p38 inhibitors SB202190 and SB203580 reduced nucleotide-induced blebbing and actin reorganization, whereas the MAPK kinase-1/2 inhibitor U0126, which blocks ERK1/ERK2 activation, had no discernable effect. Third, the Rho-selective inhibitor C3 exoenzyme and the Rho effector kinase, Rho-associated coiled-coil kinase, inhibitor Y-27632, markedly attenuated BzATP-stimulated actin reorganization and membrane blebbing. These data support a model wherein p38- and Rho-dependent pathways are critical for P2X7-dependent actin reorganization and membrane blebbing, thereby facilitating P2X7 involvement in macrophage inflammatory responses.
Antioxidant Effect of Adrenomedullin on Angiotensin II-Induced Reactive Oxygen Species Generation in Vascular Smooth Muscle Cells
Authors: Yoshimoto Takanobu , Fukai Nozomi , Sato Ryuji , Sugiyama Toru , Ozawa Naoko , Shichiri Masayoshi , Hirata Yukio 
Published: April 2004

AbstractRecent adrenomedullin (AM) gene-targeting studies have proposed a novel concept that AM plays a protective role against oxidative stress in vivo. The present study was undertaken to explore the underlying molecular mechanism of the putative antioxidant action of AM against angiotensin II (Ang II)induced reactive oxygen species (ROS) generation in rat vascular smooth muscle cells (VSMCs). Intracellular ROS levels were measured by dichlorofluoroscein fluorescence. Redox-sensitive c-Jun amino-terminal kinase (JNK) and ERK1/2 activation and gene expression induced by Ang II in VSMCs were also studied. AM dose-relatedly (10−8–10−7m) inhibited intracellular ROS generation stimulated by Ang II (10−7m), as mimicked by dibutyl-cAMP, the effect of which was inhibited by the pretreatment with N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide hydrochloride, a protein kinase A inhibitor, and calcitonin gene-related peptide(8–37), an AM/calcitonin gene-related peptide receptor antagonist. Ang II induced JNK and ERK1/2 activation via a redox-sensitive manner, whereas AM inhibited JNK, but not ERK1/2, activation by Ang II. Furthermore, AM inhibited Ang II-induced redox-sensitive gene expression (plasminogen activator inhibitor-1 and monocyte chemoattractant protein-1) in the same manner as N-acetyl-l-cysteine, a potent antioxidant. AM also inhibited Ang II-induced up-regulation of Nox1, a critical membrane-bound component of reduced nicotinamide adenine dinucleotide phosphate oxidase in VSMCs, in the same degree as N-acetyl-l-cysteine. Our study demonstrates for the first time that AM directly inhibits intracellular ROS generation via an AM receptor-mediated and c-AMP-protein kinase A-dependent mechanism in VSMCs and that AM with its potent antioxidant action inhibits redox-sensitive JNK activation and gene expression induced by Ang II. These data suggest that AM plays a protective role as an endogenous antioxidant in Ang II-induced vascular injury.
Pituitary Expression of Type I and Type II Glucocorticoid Receptors during Chicken Embryonic Development and Their Involvement in Growth Hormone Cell Differentiation
Authors: Bossis Ioannis , Nishimura Shotaro , Muchow Michael , Porter Tom E. 
Published: April 2004

AbstractGlucocorticoids can induce somatotroph differentiation in vitro and in vivo during chick embryonic and rat fetal development. In the present study, we identified the nuclear receptors involved in somatotroph differentiation and examined their ontogeny and cellular distribution during pituitary development in the chicken embryo. Several steroids were tested for their ability to induce GH cell differentiation. Only glucocorticoids and aldosterone were effective at low nanomolar concentrations, suggesting involvement of both type I (mineralocorticoid) and type II (glucocorticoid) receptors (MR and GR, respectively). ZK98299 and spironolactone (GR and MR antagonists, respectively) when used alone were unable to block corticosterone or aldosterone (2 nm)-induced somatotroph differentiation. However, ZK98299 and spironolactone in combination abolished corticosterone or aldosterone (2 nm)-induced somatotroph differentiation. When used separately, both antagonists attenuated induction of GH mRNA by corticosterone. Spironolactone alone blocked somatotroph differentiation induced by 0.2 nm corticosterone or aldosterone, indicating that corticosteroids at subnanomolar concentrations act only through the MR. GR protein was detected in pituitary extracts as early as embryonic d 8, whereas MR protein was readily detectable only around d 12. GR were expressed in greater than 95% of all pituitary cells, whereas MR were expressed in about 40% of all pituitary cells. Dual-label immunofluorescence revealed that the majority of somatotrophs on d 12 expressed MR. Given the high affinity of corticosteroids for MR and that corticosteroid concentrations during embryonic development are in the subnanomolar range, expression of MR may constitute a significant developmental event during somatotroph differentiation.