bluuebunny/crossref_metadata_2025 huggingface dataset:
Transfinite methods in metric fixed‐point theory
Authors: Kirk W. A.
Published: March 2003

This is a brief survey of the use of transfinite induction in metric fixed‐point theory. Among the results discussed in some detail is the author′s 1989 result on directionally nonexpansive mappings (which is somewhat sharpened), a result of Kulesza and Lim giving conditions when countable compactness implies compactness, a recent inwardness result for contractions due to Lim, and a recent extension of Caristi′s theorem due to Saliga and the author. In each instance, transfinite methods seem necessary.
Fixed points of holomorphic mappings for domains in Banach spaces
Authors: Harris Lawrence A.
Published: March 2003

We discuss the Earle‐Hamilton fixed‐point theorem and show how it can be applied when restrictions are known on the numerical range of a holomorphic function. In particular, we extend the Earle‐Hamilton theorem to holomorphic functions with numerical range having real part strictly less than 1. We also extend the Lumer‐Phillips theorem estimating resolvents to dissipative holomorphic functions.
Coincidence theorems for families of multimaps and their applications to equilibrium problems
Authors: Lin Lai-Jiu , Chen Hsin I
Published: March 2003

We apply some continuous selection theorems to establish
coincidence theorems for a family of multimaps under various conditions. Then we apply these coincidence theorems to study the equilibrium problem with m families of players and 2m families of constraints on strategy sets. We establish the existence theorems of equilibria of this problem and existence theorem of equilibria of abstract economics with two families of players.
Conditional value‐at‐risk bounds for compound Poisson risks and anormal approximation
Authors: Hürlimann Werner
Published: March 2003

A considerable number of equivalent formulas defining
conditional value‐at‐risk and expected shortfall are
gathered together. Then we present a simple method to bound the
conditional value‐at‐risk of compound Poisson loss distributions
under incomplete information about its severity distribution,
which is assumed to have a known finite range, mean, and variance.
This important class of nonnormal loss distributions finds
applications in actuarial science, where it is able to model the
aggregate claims of an insurance‐risk business.
Variational and numerical analysis of the Signorini′s contact problem in viscoplasticity with damage
Authors: Fernández J. R. , Sofonea M.
Published: March 2003

We consider the quasistatic Signorini′s contact problem with damage for elastic‐viscoplastic bodies. The mechanical damage of the material, caused by excessive stress or strain, is described by a damage function whose evolution is modeled by an inclusion of parabolic type. We provide a variational formulation for the mechanical problem and sketch a proof of the existence of a unique weak solution of the model. We then introduce and study a fully discrete scheme for the numerical solutions of the problem. An optimal order error
estimate is derived for the approximate solutions under suitable solution regularity. Numerical examples are presented to show the performance of the method.
A generalization of the Bernoulli polynomials
Authors: Natalini Pierpaolo , Bernardini Angela
Published: March 2003

A generalization of the Bernoulli polynomials and, consequently, of the Bernoulli numbers, is defined starting from suitable generating functions. Furthermore, the differential equations of these new classes of polynomials are derived by means of the factorization method introduced by Infeld and Hull (1951).
Finite difference solution of radiation effects on MHDunsteady free‐convection flow over vertical plate withvariable surface temperature
Authors: Abd El-Naby M. A. , Elbarbary Elsayed M. E. , Abdelazem Nader Y.
Published: March 2003

An analysis is performed to study radiation effects on
magnetohydrodynamic (MHD) unsteady free‐convection flow past a semi‐infinite vertical plate with variable surface temperature in the presence of transversal uniform magnetic field. The boundary layer equations are transformed into a linear algebraic system by an implicit finite‐difference method. A parametric study is performed to illustrate the influence of radiation parameter, magnetic parameter, and Prandtl number on the velocity and temperature profiles. The numerical results reveal that the radiation has significant influences on the velocity and temperature profiles, skin friction, and Nusselt number. The results indicate that the velocity, temperature, and local and average skin friction increase as the radiation parameter increases, while the local and average Nusselt numbers decrease as the radiation parameter increases.
Perturbed spectra of defective matrices
Authors: Konstantinov Mihail , Mehrmann Volker , Petkov Petko
Published: March 2003

This paper is devoted to the perturbation theory for defective
matrices. We consider the asymptotic expansions of the perturbed
spectrum when a matrix A is changed to A + tE, where E ≠ 0 and
t > 0 is a small parameter. In particular, we analyse the rational
exponents that may occur when the matrix E varies over the sphere
‖E‖  = ρ > 0. We partially characterize the leading exponents
noting that the description of the set of all leading exponents
remains an open problem.
Deficiency of the Cysteine Protease Cathepsin S Impairs Microvessel Growth
Authors: Shi G.-P. , Sukhova G.K. , Kuzuya M. , Ye Q. , Du J. , Zhang Y. , Pan J.-H. , Lu M.L. , Cheng X.W. , Iguchi A. , Perrey S. , Lee A.M.-E. , Chapman H.A. , Libby P.
Published: March 2003

During angiogenesis, microvascular endothelial cells (ECs) secrete proteinases that permit penetration of the vascular basement membrane as well as the interstitial extracellular matrix. This study tested the hypothesis that cathepsin S (Cat S) contributes to angiogenesis. Treatment of cultured ECs with inflammatory cytokines or angiogenic factors stimulated the expression of Cat S, whereas inhibition of Cat S activity reduced microtubule formation by impairing cell invasion. ECs from Cat S–deficient mice showed reduced collagenolytic activity and impaired invasion of collagens type I and IV. Cat S–deficient mice displayed defective microvessel development during wound repair. This abnormal angiogenesis occurred despite normal vascular endothelial growth factor and basic fibroblast growth factor levels, implying an essential role for extracellular matrix degradation by Cat S during microvessel formation. These results demonstrate a novel function of endothelium-derived Cat S in angiogenesis.
Sustained Reentry in the Left Ventricle of Fibrillating Pig Hearts
Authors: Rogers Jack M. , Huang Jian , Melnick Sharon B. , Ideker Raymond E.
Published: March 2003

It has been proposed that ventricular fibrillation (VF) is driven by sustained reentry. However, mapping studies have not detected such “mother rotors” in large mammalian hearts. We mapped VF from three 21×12 unipolar electrode arrays in 6 pigs. Two of the arrays were adjacent to each other on the left-ventricular epicardium. Electrode spacing was 2 mm. The third array consisted of 21 needles (0.5-mm diameter, 12 electrodes, 1-mm spacing) inserted in a row (2-mm spacing) between the epicardial arrays. A total of 88 5-second VF epochs were analyzed with automatic reentry detection algorithms. Although intramural reentry was sporadically present (29 total occurrences), it was always short-lived with a mean life span of 127±57 ms. However, in 3 of the 6 animals, sustained epicardial reentry (ie, reentry persisting for more than a few cycles) was consistently present, often lasting for several seconds. For each epoch, we computed indices characterizing (1) the relative duration of reentry on the two epicardial arrays (R), (2) the flow of wavefronts between epicardial arrays (W), and (3) the relative activation rates of the two epicardial arrays (F).Rdid not correlate with eitherWorFindicating that rotor-containing regions did not produce a net outflow of wavefronts and were not faster than neighboring regions. Thus, sustained epicardial, but not intramural, rotors were consistently present in some large animal hearts during VF. However, we found no evidence that these rotors were responsible for sustaining VF through the mechanisms outlined in the mother rotor hypothesis.
A Machine Learning Approach to Modeling Scope Preferences
Authors: Higgins Derrick , Sadock Jerrold M.
Published: March 2003

This article describes a corpus-based investigation of quantifier scope preferences. Following recent work on multimodular grammar frameworks in theoretical linguistics and a long history of combining multiple information sources in natural language processing, scope is treated as a distinct module of grammar from syntax. This module incorporates multiple sources of evidence regarding the most likely scope reading for a sentence and is entirely data-driven. The experiments discussed in this article evaluate the performance of our models in predicting the most likely scope reading for a particular sentence, using Penn Treebank data both with and without syntactic annotation. We wish to focus attention on the issue of determining scope preferences, which has largely been ignored in theoretical linguistics, and to explore different models of the interaction between syntax and quantifier scope.
The Prelude to Nationwide Surveillance in East Germany: Stasi Operations and Threat Perceptions, 1945–1953
Authors: Bruce Gary S.
Published: March 2003

Many observers have been puzzled by the extent of the uprising that swept through East Germany in June 1953, given the legendary efficiency of the East German state security (Stasi) forces and their vast network of informants. Some scholars have even attempted to explain the Stasi's inability to foresee and prevent the uprising by arguing that the Stasi conspired with the demonstrators. The opening of the archives of the former German Democratic Republic has shed valuable light on this issue. Based on extensive research in the archives of the Stasi and of the former Socialist Unity Party of East Germany, as well as materials from the West German archives, this article shows that the Stasi did not fail its party superiors in being unable to foresee the uprising of June 1953. There was, in fact, no way that the organization could have foreseen the rebellion. Prior to 1953 the Stasi was not outfitted with a massive surveillance apparatus, nor was it mandated for broad internal surveillance. Rather, it primarily targeted well-known opposition groups at home and anti-Communist organizations based in West Berlin. The criticism directed against the Stasi after the uprising was attributable mainly to Walter Ulbricht's embattled leadership position and his need for a scapegoat.
Peace Probes and the Bombing Pause: Hungarian and Polish Diplomacy During the Vietnam War, December 1965–January 1966
Authors: Hershberg James G.
Published: March 2003

Archival materials from Budapest and Warsaw have shed valuable light on the role that Hungary and Poland played as intermediaries between Washington and Hanoi during the 37-day pause in the U.S. bombing campaign against North Vietnam in December 1965–January 1966. It is now possible to trace contacts between the East European countries and Hanoi and to see how the Hungarian and Polish governments coordinated their diplomatic activities with the Soviet Union. Although the new evidence does not reveal any “missed opportunities” in early 1966 for the opening of direct peace negotiations between Washington and Hanoi, it does cast doubt on the way that former U.S. officials and most historians have interpreted these events. Up to now, almost all accounts have dismissed Hungary's and Poland's efforts as insincere and deceptive, and some observers have even questioned whether the two countries were genuinely in contact with North Vietnamese leaders. The documentary evidence leaves many questions unanswered, but it permits a far more nuanced assessment of East European diplomacy during the bombing pause.
Review Essay: Efforts to Make Sense of the Vietnam War
Authors: Neu Charles E.
Published: March 2003

The Vietnam War is notoriously difficult to explain. The war lasted so long, passed through so many phases, and involved such a wide range of people and groups in Vietnam, the United States, and other countries that the task of explaining it all in a single volume is nearly impossible. Several recent books have tried to make sense of the conflict, with varying degrees of success. The books under review are syntheses aimed at undergraduate students and general readers. Although both books have their strong points, neither of them provides a comprehensive or satisfactory account of the war.
Review Essay: Better Late Than Never? The Delayed Debate over the Costs of Vietnam
Authors: Moise Edwin
Published: March 2003

In 1965, President Lyndon Johnson sharply escalated the U.S. military effort in Vietnam and prepared for further escalation in 1966. He and his aides, notably Defense Secretary Robert McNamara, did their best to forestall a public debate about the potential costs of the war. They concealed their plans for increased military expenditures and expanded commitments of American troops. Not until the United States was deeply embroiled in Vietnam did a full-fledged public debate finally emerge, along with protests and demonstrations at American universities. If the administration had been more candid about its plans from the outset, U.S. policy might have gone in a different direction, and the domestic and international costs of the war might not have been as onerous.
World Summit on Sustainable Development: Toward a Post-Jo'burg Environmentalism
Authors: Wapner Paul
Published: March 2003

This article provides a first-hand account of the World Summit on Sustainable Development (WSSD) and an analysis of how to advance environmentalist concerns in the post-Jo'burg era. It reviews some of the achievements and disappointments of the Summit and describes significant changes in global environmental affairs that the WSSD was unable fully to appreciate and which, therefore, must be addressed in the post-Jo'burg world. One change is a switch in emphasis in the North and South in terms of sustainable development. For too long we've been told that the North is concerned with the environment while the South is focused on development. At the WSSD it became clear, however, that this is no longer the case. Many in the North now claim a development focus although, to be sure, through the more fundamental goal of economic globalization. Concomitantly, many in the South voice a commitment to environmental sustainability as a way to reduce poverty. A second change has to do with the power of environmentalism. After enjoying much strength, concern for the environment is flagging throughout much of the world as key states find themselves distracted by geo-political concerns in the aftermath of the September 11th attacks. Both changes indicate the need to rethink environmentalist strategies in a post-Jo'burg era. The article offers several suggestions including abandoning sustainable development as a policy objective (although keeping it as a conceptual framework) and resuscitating the older, more narrow and arguably less complicated goals of environmental protection.
Understanding Policy Change in Developing Countries: The Spheres of Influence Framework
Authors: Steinberg Paul F.
Published: March 2003

National policy reform is a prerequisite for improved stewardship of the global environment and figures prominently among the goals of international environmental diplomacy and transnational advocacy campaigns. Yet research on global environmental politics has proceeded absent models of policy change in developing countries, where most of the planet's people, land, and biological diversity are found. In this article I present a theoretical framework to explain the domestic responses of developing countries to global environmental concerns. Drawing on research in Costa Rica and Bolivia, I situate the impact of global environmentalism in the context of complex, decades-long domestic struggles to create effective institutions. When international outcomes depend on protracted reforms in nations that are sovereign yet poor, policy change is driven by actors who successfully pair international resources (technical, financial, and ideational) with the domestic political resources needed to see through major policy innovations.
Principles for Sustainability: From Cooperation and Efficiency to Sufficiency
Authors: Princen Thomas
Published: March 2003

If analysts of political and ecological economy take seriously critical trends in environmental degradation and accept social responsibility for contributing to the reversal of such trends, they must go beyond the descriptive and predictive to the prescriptive, beyond marginal environmental improvement to sustainability, beyond cooperation and efficiency to sufficiency.

Cooperation and efficiency principles are useful when biophysical underpinnings remain intact. Otherwise, sufficiency principles—restraint, precaution, polluter pays, zero, reverse onus—address the defining characteristics of current trends, namely environmental criticality, risk export, and responsibility evasion. They engage overconsumption. They compel decision-makers to ask when too much resource use or too little regeneration risks important values such as ecological integrity and social cohesion, when material gains now preclude material gains in the future, when consumer gratification or investor reward threatens economic security, when benefits internalized depend on costs externalized. Under sufficiency, one necessarily asks what are the risks, not just in the short term and for immediate beneficiaries, but in the longterm and for the under-represented.
Two Steps Forward, One Step Backward: Societal Capacity and Israel's Implementation of the Barcelona Convention and the Mediterranean Action Plan
Authors: Weinthal Erika , Parag Yael
Published: March 2003

A large literature exists regarding explanations for the emergence of cooperation in the Mediterranean basin, but there is less information regarding the effectiveness of Mediterranean cooperation and its programs. Through a case study of Israel's implementation and compliance with the Barcelona Convention and the Mediterranean Action Plan, we evaluate the effectiveness of these international institutions. We find that international institutions and their efforts to target state capacity as the mechanism to improve compliance and effectiveness are often misguided unless their efforts are also directed towards enhancing societal capacity. We then explicate the way in which societal actors such as environmental NGOs can improve domestic compliance and effectiveness. These findings are illuminated through an assessment of the activities of several environmental NGOs in Israel to target Mediterranean pollution and coastal management policies. Where NGOs have taken action, they have often proved successful in forcing the Israeli government and the business sector to honor its environmental commitments.
Implementing International Environmental Agreements in Russia: Lessons from Fisheries Management, Nuclear Safety and Air Pollution Control
Authors: Hønneland Geir , Jørgensen Anne-Kristin
Published: March 2003

The article discusses implementation of Russia's international obligations in fisheries management, nuclear safety and air pollution control. Empirical evidence is taken from the country's northwestern region. A main theoretical question is to what extent the observed level of compliance with international agreements can be explained by the nature of the problem and agreements at hand, and by the implementation activities of public authorities and target groups. The implementation performance in the case of fisheries management can be explained mainly by both positive and negative elements in public authorities' implementation efforts. In air pollution control, the nature of the commitments, i.e. the very limited need for behavioral changes, is the main explanation for implementation performance. The picture is a bit more complex in the case of nuclear safety where all the factors reviewed have had a moderate or considerable effect on implementation performance. Notably, institutional conflict at the federal level has hampered implementation, while regional authorities have since the mid-1990s indulged in constructive collaboration with various federal agencies.
Toward Renewed Legitimacy? Nuclear Power, Global Warming, and Security
Authors: Stoett Peter
Published: March 2003

With calls for the renewal of the nuclear energy industry in the United States and elsewhere, the international political economy of this troubled industry assumes increased importance. Though technical difficulties have plagued the industry for many decades, it is the equally problematic task of establishing public trust on which the article focuses. Arguably, with the advent of widespread concern over global warming, nuclear power offers a low-emission alternative. Yet safety, security, and political concerns color this highly centralized energy source, as well as its export-based political economy. The article traces the history of global nuclear commerce, as well as recent attempts to revive the industry. I suggest that efforts to re-legitimize the state-industry-power complex by way of nuclear commerce and associated discourse may have some success, but this will be tempered by sustained opposition to the centralizing tendencies of nuclear power and continued safety concerns.
CYP1A1*2B (Val) allele is overrepresented in a subgroup of acute myeloid leukemia patients with poor-risk karyotype associated with NRAS mutation, but not associated withFLT3 internal tandem duplication
Authors: Bowen David T. , Frew Marion E. , Rollinson Sara , Roddam Philippa L. , Dring Ann , Smith Martyn T. , Langabeer Stephen E. , Morgan Gareth J.
Published: March 2003

The etiology of acute myeloid leukemia (AML) is largely unknown. Biologic and epidemiologic data implicate exogenous toxicants, including cytotoxic drugs, benzene, radiation, and cigarette smoking. Allelic variation in genes encoding enzymes such as NADP(H) quinone oxidoreductase (NQO1) and glutathione S-transferase T1 (GSTT1) that metabolize environmental toxicants predispose to subtypes of AML, including therapy-related AML. We assayed NRAS oncogene mutation and FLT3 internal tandem duplication in 447 AML patients with an abnormal karyotype treated in Medical Research Council (MRC) AML clinical trials. Functional allelic variant frequencies in genes encoding carcinogen-metabolizing enzymesGSTT1, GSTM1, CYP1A1,CYP2D6, CYP2C19, SULT1A1, and NQO1 were previously determined for this cohort. FLT3 internal tandem duplication (ITD) frequency was 17%, and NRAS mutation 12% for the entire cohort. The 2 mutations were found together in only 4 patients. No association was found between enzyme allelic variant frequencies and the presence of FLT3 ITD for the entire cohort or within cytogenetic subgroups. CYP1A1*2B (Val) high-inducibility variant allele was overrepresented in patients with NRAS mutation compared with no mutation, for (1) the entire AML cohort (n = 8/53 vs 26/371; odds ratio [OR] = 2.36; 95% confidence interval [CI] 1.01-5.53) and (2) the poor-risk karyotype group (n = 6/14 vs 4/89; OR = 15.94; 95% CI 3.71-68.52) comprising patients with partial/complete deletion of chromosome 5 or 7, or abnormalities of chromosome 3. The CYP1A1*2B allele may predispose to the development of these subgroups of AML by augmented phase 1 metabolism to highly reactive intermediates of CYP1A1 substrates, including polycyclic aromatic hydrocarbons, or by generation of oxidative stress as a metabolic by-product.
Bcl-XL is required for heme synthesis during the chemical induction of erythroid differentiation of murine erythroleukemia cells independently of its antiapoptotic function
Authors: Hafid-Medheb Khalid , Augery-Bourget Yvette , Minatchy Marie-Nathalie , Hanania Nicole , Robert-Lézénès Jacqueline
Published: March 2003

Bcl-XL is essential for the survival and normal maturation of erythroid cells, especially at the late stage of erythroid differentiation. It remains unclear whether Bcl-XL serves only as a survival factor for erythroid cells or if it can induce a signal for differentiation. We have previously shown that dimethyl sulfoxide (DMSO) induction of erythroid differentiation in murine erythroleukemia (MEL) cells correlates with delay of apoptosis and specific induction of Bcl-XL. In this study, we investigate the contribution of Bcl-2 and Bcl-XL to survival and erythroid differentiation by generating stable MEL transfectants expressing these antiapoptotic regulators. Overexpression of Bcl-2 completely prevented apoptosis of MEL cells before and after DMSO induction, whereas overexpression of Bcl-XL only delayed it. Overexpression of Bcl-2 or Bcl-XL neither induced spontaneous erythroid differentiation nor accelerated DMSO-induced differentiation. Inhibition of Bcl-XL by antisense transcripts accelerated apoptosis in DMSO-treated MEL cells and blocked the synthesis of hemoglobin without altering the growth arrest associated with terminal erythroid differentiation. An antisense oligonucleotide to Bcl-XL did not induce apoptosis in MEL cells overexpressing Bcl-2 but greatly decreased their hemoglobin synthesis when treated with DMSO, suggesting that Bcl-XL is necessary for erythroid differentiation independently of its antiapoptotic function. Importantly, Bcl-XL antisense transcripts prevented heme synthesis but not globin mRNA induction in DMSO-treated MEL cells. Furthermore, inhibition of hemoglobin synthesis by Bcl-XLantisense was reversed by addition of exogenous hemin. Finally, Bcl-XL localized to mitochondria during MEL erythroid differentiation, suggesting that it may mediate a critical mitochondrial transport function related to heme biosynthesis.
Pathogenic molds (including Aspergillus species) in hospital water distribution systems: a 3-year prospective study and clinical implications for patients with hematologic malignancies
Authors: Anaissie Elias J. , Stratton Shawna L. , Dignani M. Cecilia , Lee Choon-kee , Summerbell Richard C. , Rex John H. , Monson Thomas P. , Walsh Thomas J.
Published: March 2003

The incidence of mold infections in patients with hematologic malignancies continues to increase despite the widespread use of air filtration systems, suggesting the presence of other hospital sources for these molds. Water sources are known to harbor pathogenic molds. We examined samples from water, water surfaces, air, and other environment sources from a bone marrow transplantation unit with optimal air precautions. Molds (Aspergillus species, others) were recovered in 70% of 398 water samples, in 22% of 1311 swabs from plumbing structures and environmental surfaces, and in 83% of 274 indoor air samples. Microscopic examination of the water plumbing lines revealed hyphal forms compatible with molds. Four findings suggest that indoor airborne molds were aerosolized from the water: (1) higher mean airborne concentrations of molds in bathrooms (16.1 colony-forming units [CFU]/m3) than in patient rooms (7 CFU/m3) and hallways (8.6 CFU/m3;P = .00005); (2) a strong type and rank correlation between molds isolated from hospital water and those recovered from indoor hospital; (3) lack of seasonal correlation between the airborne mold concentration in outdoor and indoor air; and (4) molecular relatedness between a clinical strain and a water-related strain (previously reported). Hospital water distribution systems may serve as a potential indoor reservoir of Aspergillus and other molds leading to aerosolization of fungal spores and potential exposure for patients.
Felic (CIP4b), a novel binding partner with the Src kinase Lyn and Cdc42, localizes to the phagocytic cup
Authors: Dombrosky-Ferlan Patrice , Grishin Anatoly , Botelho Roberto J. , Sampson Matthew , Wang Lin , Rudert William A. , Grinstein Sergio , Corey Seth J.
Published: March 2003

Through its Src homology 3 (SH3) and SH2 domains, the Src kinase Lyn interacts with a small number of phosphoproteins, such as Shc, Cbl, and Vav, which regulate cell cycle and the cytoskeleton. Using Lyn's Unique, SH3, and SH2 domains as bait in a yeast 2–hybrid screen, we isolated a novel gene product with features of a scaffolding protein. We named it Felic because it contains a domain homologous to the tyrosine kinase Fes and the cytoskeletal proteinezrin and forms a Lyn interaction with the GTPase Cdc42 (Felic). Felic was expressed in both hematopoietic and nonhematopoietic tissues. Because it represents an alternative splice product related to the Cdc42-interacting protein 4, CIP4, we also refer to Felic as CIP4b. Felic contains an SH3 recognition site RXPXXP and multiple tyrosine residues. In insulin or serum-stimulated HEK293 cells, Felic became tyrosine phosphorylated. Like CIP4, Felic associated with Cdc42 in its activated form only. Unlike CIP4, Felic does not possess a C-terminal SH3 domain. Coprecipitation studies show that Felic bound to Lyn or activated forms of Cdc42. Overexpression of Felic or CIP4 inhibited NIH 3T3 cell invasiveness in a Matrigel assay. Because Lyn and Cdc42 are involved in phagocytosis, we examined the distribution of Felic in RAW macrophages during particle ingestion. Felic was recruited more efficiently than CIP4 to the phagocytic cups. Altogether, these data suggest that CIP4/Felic constitute a novel family of cytoskeletal scaffolding proteins, integrating Src and Cdc42 pathways. The absence of an SH3 domain in Felic provides a structural basis for functional differences.
Antihirudin antibodies following low-dose subcutaneous treatment with desirudin for thrombosis prophylaxis after hip-replacement surgery: incidence and clinical relevance
Authors: Greinacher Andreas , Eichler Petra , Albrecht Dorothea , Strobel Ulrike , Pötzsch Bernd , Eriksson Bengt I.
Published: March 2003

Recombinant hirudin has been found to be immunogenic in patients treated with lepirudin following heparin-induced thrombocytopenia (HIT). We assessed the incidence of immunoglobulin G (IgG) antihirudin antibodies by enzyme-linked immunosorbent assay in 112 patients enrolled in a dose-finding study with desirudin. Patients received desirudin subcutaneously following orthopedic hip surgery at 10 mg twice a day (n = 17), 15 mg twice a day (n = 75), and 20 mg twice a day (n = 20). Of 112 patients, 11 (9.8%) developed antihirudin antibodies independently of the dose. The rate of immunization did not differ from that observed in HIT patients treated with lepirudin (P = .113). Plasma concentrations of desirudin did not differ between antihirudin antibody–positive and –negative patients. Antihirudin antibodies had no impact on incidences of deep vein thrombosis and/or pulmonary embolism, allergic reactions, and hemorrhage. However, the total number of immunized patients observed was low and so infrequent (but severe) effects of antihirudin antibodies cannot be excluded.
A1 is a growth-permissive antiapoptotic factor mediating postactivation survival in T cells
Authors: Gonzalez Juana , Orlofsky Amos , Prystowsky Michael B.
Published: March 2003

The regulation of cell death in activated naive T cells is not well understood. We examined the expression of A1, an antiapoptotic member of the Bcl-2 family, following activation of naive mouse splenocytes. A1 gene expression was strongly but transiently induced during the first day of activation, with a peak at 2 to 6 hours, whereas Bcl-2 mRNA was simultaneously transiently down-regulated. Transgenic (Tg) overexpression of A1-a in T cells via the lck distal promoter resulted in decreased apoptosis following activation either with concanavalin A or with antibodies to CD3 and CD28 and led to a doubling of T-cell yield by 5 days. Tg A1-a also partially protected thymocytes from several proapoptotic stimuli but did not protect T-cell blasts from cell death induced by reactivation via the T-cell receptor. Tg Bcl-2 and Tg A1-a showed a similar ability to reduce apoptosis in both resting and activated T cells. However, in activated splenocyte cultures, the increase in 5-day T-cell yield observed with Tg Bcl-2 was only half that produced by Tg A1-a. This difference could be attributed at least in part to the fact that A1, unlike Bcl-2, did not inhibit S-phase entry of activated cells. The A1 protein may represent an adaptation of the Bcl-2 gene family to the need for survival regulation in the context of a proliferative stimulus.
Antigen presentation by mouse CD4+ T cells involving acquired MHC class II:peptide complexes: another mechanism to limit clonal expansion?
Authors: Tsang Julia Y. S. , Chai Jian Guo , Lechler Robert
Published: March 2003

Antigen presentation by activated human and rat CD4+ T cells has long been known to induce hyporesponsiveness due to a combination of anergy and apoptosis. It has been assumed that no such phenomenon occurs in mice due to the inability of mouse T cells to synthesize major histocompatibility complex (MHC) class II molecules. There have been several recent descriptions of the transfer of molecules, including MHC molecules, from antigen-presenting cells (APCs) to T cells. Here, we describe the acquisition of MHC class II molecules by T-cell receptor (TCR)–transgenic T cells and T-hybridoma cells following culture with APCs. Acquisition was markedly enhanced by T-cell activation either due to cognate recognition of antigen or anti-CD3 activation. When activation was induced by antigen recognition, preferential acquisition of complexes of class II molecules displaying cognate peptide was observed; in contrast, following activation by anti-CD3 the acquisition of class II molecules was MHC unrestricted. T cells that had acquired MHC class II:peptide complexes were able to act as APCs and induced proliferation and interleukin-2 secretion by resting T cells. However, when activated T cells that had acquired MHC class II:peptide complexes engaged in T:T interactions, this led to an increase in apoptosis and the induction of hyporesponsiveness. These results raise the possibility that the acquisition of MHC class II:peptide complexes by T cells during an immune response may serve to limit clonal expansion, including that induced by alloantigen following tissue or stem cell transplantation.
Nongastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
Authors: Zucca Emanuele , Conconi Annarita , Pedrinis Ennio , Cortelazzo Sergio , Motta Teresio , Gospodarowicz Mary K. , Patterson Bruce J. , Ferreri Andrés J. M. , Ponzoni Maurilio , Devizzi Liliana , Giardini Roberto , Pinotti Graziella , Capella Carlo , Zinzani Pier Luigi , Pileri Stefano , López-Guillermo Armando , Campo Elias , Ambrosetti Achille , Baldini Luca , Cavalli Franco
Published: March 2003

A retrospective survey of patients with pathologically reviewed extragastric mucosa-associated lymphoma tissue (MALT) lymphomas from 20 institutions was performed. A total of 180 patients with histologically confirmed diagnosis of extragastric MALT lymphomas were studied. Their median age was 59 years (range, 21-92 years). Ann Arbor stage I disease was present in 115 patients (64%) and stage II disease in 16 (9%). Most cases were in the low or low-intermediate risk groups according to the International Prognostic Index (IPI). Forty-one (23%) patients had involvement of more than one extranodal site at diagnosis and in 24 cases (13%) the lymphoma presented at multiple mucosal sites (9 of them with only mucosal involvement, without bone marrow or nodal disease). Lymph node involvement was present in 21%. Patients were treated with a variety of therapeutic strategies, including chemotherapy in 78 cases. The median overall survival (OS) was not reached; the 5-year OS rate was 90% (95% CI, 82%-94%), the 5-year cause-specific survival (CSS) was 94% (95% CI, 87%-97%), and the 5-year progression-free survival (PFS) was 60% (95% CI, 50%-70%). Multivariate analysis showed that Ann Arbor stage was significantly associated with longer OS, nodal involvement with longer CSS, and favorable IPI score with better PFS. At a median follow-up of 3.4 years, 48 patients (27%; 95% CI, 20%-34%) had a relapse, 6 (3%; 95% CI, 1%-7%) showed histologic transformation, and 18 (10%; 95% CI, 6%-15%) experienced the development of a second tumor. Our data confirm the indolent nature of nongastric MALT lymphomas and the high rate of patients presenting with disseminated disease, which, when limited to mucosal sites, was not associated with a poorer outcome.
Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells
Authors: Fiuza Carmen , Bustin Michael , Talwar Shefali , Tropea Margaret , Gerstenberger Eric , Shelhamer James H. , Suffredini Anthony F.
Published: March 2003

Systemic inflammation because of sepsis results in endothelial cell activation and microvascular injury. High-mobility group protein-1 (HMGB1), a novel inflammatory molecule, is a late mediator of endotoxin shock and is present in the blood of septic patients. The receptor for advanced glycation end products (RAGE) is expressed on endothelium and is a receptor for HMGB1. Here we examine the effects of HMGB1 on human endothelial cell function. Recombinant human HMGB1 (rhHMGB1) was cloned and expressed in Escherichia coli and incubated with human microvascular endothelium. rhHMGB1 caused a dose- and time-dependent increase in the expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and RAGE. rhHMGB1 induced the secretion of tumor necrosis factor-α (TNFα), interleukin 8 (IL-8), monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), and tissue plasminogen activator (tPA) (P < .01). rhHMGB1 stimulation resulted in transient phosphorylation of mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), Jun N-terminal kinase (JNK), and p38, and in nuclear translocation of transcription factors NF-κB and Sp1. These effects are partially mediated by TNFα autocrine stimulation, as anti-TNFα antibodies significantly decrease chemokine and adhesion molecule responses (P ≤ .002). Thus, rhHMGB1 elicits proinflammatory responses on endothelial cells and may contribute to alterations in endothelial cell function in human inflammation.
The roles of αIIbβ3-mediated outside-in signal transduction, thromboxane A2, and adenosine diphosphate in collagen-induced platelet aggregation
Authors: Cho Moon J. , Liu Junling , Pestina Tamara I. , Steward Shirley A. , Thomas Dennis W. , Coffman Thomas M. , Wang Demin , Jackson Carl W. , Gartner T. Kent
Published: March 2003

Collagen-induced activation of platelets in suspension leads to αIIbβ3-mediated outside-in signaling, granule release, thromboxane A2 (TxA2) production, and aggregation. Although much is known about collagen-induced platelet signaling, the roles of TxA2 production, adenosine diphosphate (ADP) and dense-granule secretion, and αIIbβ3-mediated outside-in signaling in this process are unclear. Here, we demonstrate that TxA2 and ADP are required for collagen-induced platelet activation in response to a low, but not a high, level of collagen and that αIIbβ3-mediated outside-in signaling is required, at least in part, for this TxA2 production and ADP secretion. A high level of collagen can activate platelets deficient in PLCγ2, Gαq, or TxA2 receptors, as well as platelets treated with a protein kinase C inhibitor, Ro31-8220. Thus, activation of αIIbβ3 in response to a high level of collagen does not require these signaling proteins. Furthermore, a high level of collagen can cause weak TxA2 and ADP-independent aggregation, but maximal aggregation induced by a high level of collagen requires TxA2 or secretion.
HbF reactivation in sibling BFU-E colonies: synergistic interaction of kit ligand with low-dose dexamethasone
Authors: Gabbianelli Marco , Testa Ugo , Massa Adriana , Morsilli Ornella , Saulle Ernestina , Sposi Nadia Maria , Petrucci Eleonora , Mariani Gualtiero , Peschle Cesare
Published: March 2003

Mechanisms underlying fetal hemoglobin (HbF) reactivation in stress erythropoiesis have not been fully elucidated. We suggested that a key role is played by kit ligand (KL). Because glucocorticoids (GCs) mediate stress erythropoiesis, we explored their capacity to potentiate the stimulatory effect of KL on HbF reactivation, as evaluated in unilineage erythropoietic culture of purified adult progenitors (erythroid burst-forming units [BFU-Es]). The GC derivative dexamethasone (Dex) was tested in minibulk cultures at graded dosages within the therapeutical range (10−6 to 10−9M). Dex did not exert significant effects alone, but synergistically it potentiated the action of KL in a dose-dependent fashion. Specifically, Dex induced delayed erythroid maturation coupled with a 2-log increased number of generated erythroblasts and enhanced HbF synthesis up to 85% F cells and 55% γ-globin content at terminal maturation (ie, in more than 80%-90% mature erythroblasts). Equivalent results were obtained in unicellular erythroid cultures of sibling BFU-Es treated with KL alone or combined with graded amounts of Dex. These results indicate that the stimulatory effect of KL + Dex is related to the modulation of γ-globin expression rather than to recruitment of BFU-Es with elevated HbF synthetic potential. At the molecular level, Id2 expression is totally suppressed in control erythroid culture but is sustained in KL + Dex culture. Hypothetically, Id2 may mediate the expansion of early erythroid cells, which correlates with HbF reactivation. These studies indicate that GCs play an important role in HbF reactivation. Because Dex acts at dosages used in immunologic disease therapy, KL + Dex administration may be considered to develop preclinical models for β-hemoglobinopathy treatment.
A comparison of allogeneic and autologous bone marrow transplantation for lymphoblastic lymphoma
Authors: Levine John E. , Harris Richard E. , Loberiza Fausto R. , Armitage James O. , Vose Julie M. , Van Besien Koen , Lazarus Hillard M. , Horowitz Mary M.
Published: March 2003

Lymphoblastic lymphoma (LBL) is a rare, clinically aggressive neoplasm of the young that frequently involves the bone marrow (BM) and/or central nervous system. Because LBL is similar to acute lymphoblastic leukemia, some centers prefer allogeneic hematopoietic stem cell (SC) transplantation to autologous SC transplantation. We retrospectively analyzed outcomes for patients who underwent autologous (auto, n = 128) or HLA-identical sibling (allo, n = 76) SC transplantations from 1989 to 1998 and were reported to International Bone Marrow Transplant Registry (IBMTR) or Autologous Blood and Marrow Transplant Registry (ABMTR). Allo stem cell transplant (SCT) recipients had higher treatment-related mortality (TRM) at 6 months (18% versus 3%, P = .002), and this disadvantage persisted at 1 and 5 years. Early relapse rates after alloSC transplantation and autoSC transplantation were similar, but significantly lower relapse rates were observed in alloSCT recipients at 1 and 5 years (32% versus 46%, P = .05; and 34% versus 56%,P = .004, respectively). No differences were noted in lymphoma-free survival rates between alloSC transplantations and autoSC transplantations (5-year rates 36% versus 39%,P = .82). AutoSCT recipients had higher overall survival at 6 months (75% versus 59%, P = .01), but survival did not significantly differ between the 2 groups at 1 and 5 years (60% versus 49%, P = .09; 44% versus 39%,P = .47, respectively). Multivariate analyses to account for confounding factors confirmed these results. Independent of SCT type, BM involvement at the time of transplantation and disease status more advanced than first complete remission were associated with inferior outcomes. In summary, alloSC transplantation for LBL is associated with fewer relapses than with autoSC transplantation, but higher TRM offsets any potential survival benefit.
Type I interferon differential therapy for erythroleukemia: specificity of STAT activation
Authors: Cull Vanessa S. , Tilbrook Peta A. , Bartlett Emmalene J. , Brekalo Natalie L. , James Cassandra M.
Published: March 2003

Type I interferons (IFNs), pleiotropic cytokines with antiviral, antiproliferative, apoptotic, and immunoregulatory functions, are efficacious in the treatment of malignancies, viral infections, and autoimmune diseases. Binding of these cytokines to their cognate receptor leads to activation of the Jak-signal transducers and activators of transcription (STAT) signaling pathway and altered gene expression. This signal pathway has been intensely studied using human IFN-α2 and IFN-β. However, there are over 14 human IFN-α subtypes and over 10 murine IFN-α subtypes, with a single IFN-β subtype in both species. J2E cells are immortalized at the proerythroblast stage of development and produce a rapid and fatal erythroleukemia in vivo. These cells retain the ability to respond to erythropoietin in vitro by proliferating, differentiating, and remaining viable in the absence of serum. Here, we show that J2E cells are also functionally regulated differentially by IFN subtype treatment in vitro. A novel finding was the selective activation of STAT and mitogen-activated protein kinase (MAPK) molecules by different subtypes binding the IFN receptor. These findings indicate distinct effects for individual type I IFN subtypes, which are able to differentially activate members of the STAT and MAPK family. Finally, we investigated the efficacy of IFN naked DNA therapy in treating J2E-induced erythroleukemia in athymic nude mice. IFN subtypes differentially regulated the onset of erythroleukemia with delayed onset and increased survival, possibly via a reduction in cell viability, and enhanced antiproliferative and apoptotic effects observed for IFNA6 and IFNA9treatment, respectively. Moreover, these data highlight the necessity to choose the best IFN subtype in disease treatment.
Aspects of hydrodynamic shear regulating shear-induced platelet activation and self-association of von Willebrand factor in suspension
Authors: Shankaran Harish , Alexandridis Paschalis , Neelamegham Sriram
Published: March 2003

The binding of plasma von Willebrand factor (VWF) to platelet receptor GpIb under high hydrodynamic shear leads to platelet activation and subsequent shear-induced platelet aggregation (SIPA). We quantitatively examined the aspects of fluid flow that regulate platelet activation by subjecting human blood and isolated platelets to well-defined shear conditions in a cone-plate viscometer. We made the following observations. First, Annexin V binding to phosphatidyl serine expressed on activated cells was detectable within 10 seconds of shear application. Second, fluid shear stress rather than shear rate controls platelet activation, and a threshold shear stress of approximately 80 dyn/cm2 is necessary to induce significant activation. Under these conditions, individual domains of soluble VWF and platelet GpIb are subjected to similar magnitudes of fluid forces on the order of 0.1 pN, whereas GpIb with bound VWF is subjected to 1 pN. Third, cell-cell collisions and time-varying stresses are not essential for platelet activation. Fourth, the mechanism of platelet activation can be resolved in 2 steps based on the contribution of VWF and fluid forces. Fluid shear and VWF are required during the first step, when GpIb-VWF binding likely occurs. Subsequently, high shear forces alone in the absence of VWF in suspension can induce platelet activation. In other experiments, purified VWF was subjected to shear in the viscometer, and VWF morphology was assessed using light scattering. These studies demonstrate, for the first time, the ability of hydrodynamic forces to induce VWF aggregation in suspension. This VWF self-association may be an additional feature involved in controlling cell adhesion rates in circulation.