bluuebunny/crossref_metadata_2025 huggingface dataset:
Negotiating a Resolution to the Cyprus Problem: Is Potential European Union Membership a Blessing or a Curse?
Authors:   Sozen,   Yesilada
Published: October 2003

This article provides a game theoretic analysis of how the candidacy of Cyprus for European Union (EU) membership presents an important challenge for both the Union's eastern enlargement plans and current international efforts aimed at resolving the Cyprus problem. The conclusions indicate that the Cypriot conflict has entered a very delicate period in its protracted and troublesome history characterized by a deadlock game. Strong domestic and international factors have created the conditions for each side to follow a non-cooperative strategy aimed at unilateral victory rather than a compromise. In this regard, the EU's promise to the Greek Cypriots of membership in the Union, regardless of the settlement of the Cyprus problem, serves as a side payment that enforces non-cooperative strategy. Likewise, Turkey's overwhelming military superiority in the region and its unconditional support for the Turkish Cypriots strengthens the Turkish side's rigid position in the Cyprus negotiations. Under these circumstances, it is argued that an influential third party like the United States is needed to coordinate the efforts of the UN and EU to move the two parties away form a deadlock game. This effort requires a package approach to the issues surrounding the Cyprus problem, the island's membership in the EU, and EU-Turkey relations.
Coalition Diversity and Normative Legitimacy in Human Security Negotiations
Authors: Hampson Fen Osler , Reid Holly
Published: October 2003

This article explores coalition dynamics in the negotiations leading up to the international Anti-personnel Landmines Convention and the Rome Treaty for an International Criminal Court. It discusses how "core" coalitions in the two cases formed and how these coalitions acquired international support and legitimacy. It suggests that multilateral negotiation processes on human security issues reflect a new kind of dynamics in multilateral negotiation processes where successful international coalitions draw strength and legitimacy through numbers and the mobilization of "boundary role" players in civil society and non-governmental organizations. The article also suggests that didactic leadership has a critical role to play in assembling these coalitions and generating the requisite levels of international attention and support to carry human security initiatives forward.
Strategic Simplification: Toward a Theory of Modular Design in Negotiation
Authors: Watkins Michael
Published: October 2003

Using Richard Holbrooke's negotiations in Bosnia as an instructive example, this article examines structural complexity as a barrier to agreement and proposes approaches to "strategic simplification" that are inspired by research on modular design of new products. This article represents an initial step toward development of a broader theory of complexity management in negotiation.
History and Coalitions: The Vienna Congress (1814–1815)
Authors: Dupont Christophe
Published: October 2003

This note describes and analyzes the coalition patterns that developed during the 1814–1815 Congress of Vienna negotiations. Useful insights for theory and practice are derived from this historical case, including the dynamics of stability, complexity and ambiguity on the value and effectiveness of coalitions.
Mid-Life Parental Support for Adult Children in New Zealand
Authors: Hillcoat-Nallétamby Sarah , Dharmalingam A.
Published: October 2003

Research often focuses on exchanges of help between mature adult children and ageing parents, but not between young adults and parents. As transitions to adulthood become more complex, and mid-life is increasingly associated with competing roles, this article examines factors influencing the likelihood that a mid-life parent continues to support an adult child who has left home. Empirical analysis uses data from New Zealand's 1997 `Transactions in the Mid-life Family' survey. Parents continue to support their child, but the factors influencing the flow of help vary by type of help. A child's, but not a parent's age, and the gender of both, have a significant influence on the provision of help, and although infrequent contact and long distances make exchanges more difficult, they do not completely inhibit them.
Mediation in Peacekeeping Missions
Authors: Wall James A. , Druckman Daniel
Published: October 2003

Mediation in peacekeeping missions and the role of dispute severity, time pressure, and the peacekeeper's rank in that process are investigated. A set of hypotheses concerning the effects of these factors is developed. A test of the hypotheses reveals that dispute severity has a strong effect on the peacekeepers' choice of techniques. Time pressure does not influence technique selection or interact with dispute severity, and rank has a moderate effect on technique choice. Contributions to the peacekeeping literature are discussed, and implications are developed for an agenda of research on mediation processes.
Toward a Structural Understanding of Coup Risk
Authors: Belkin Aaron , Schofer Evan
Published: October 2003

Although coup risk plays an important role in theories of war, revolution, and democratization, scholars have not developed a rigorous conceptualization and valid measure of the concept. We develop a structural understanding of coup risk as distinct from proximate causes of coups as well as coup-proofing strategies that regimes implement to avert coups. Theoretical insights into factors that predispose regimes toward coup vulnerability provide the groundwork for an improved measure based on strength of civil society, legitimacy, and past coups. Cross-national statistical analyses are used to significantly improve on previous coupincidence models and highlight deficiencies of the common approach to measuring coup risk. The structural conceptualization of coup risk enhances understanding of broader civil-military dynamics, in particular the well-known distinction between motives and opportunities for launching coups. This distinction is shown to be insensitive to an important observational equivalence: that coups may be rare in both high-and low-risk cases.
The Use of Gene Tests to Detect Hereditary Predisposition to Chronic Disease: Is Cost-Effectiveness Analysis Relevant?
Authors: Col Nananda F.
Published: October 2003

Screening for genetic susceptibility provides new opportunities for preventing common diseases, but whether such screening will result in substantial costs or savings is unclear. Cost-effectiveness analyses (CEAs) provide a theoretical framework for guiding clinical decisions about genetic tests. However, CEAs have been largely irrelevant in informing policy, clinical decisions, or patient demand concerning these genetic tests. Genetic tests have often proceeded directly from development and preliminary validation into clinical practice, with little understanding of their clinical, economic, and psychosocial implications. Using screening for BRCA mutations as an example, the accuracy of the tests and the effectiveness of many interventions among those who screen positive remain in question. CEAs do not seem to have played an important role in identifying whom to offer genetic testing nor how to manage those found to carry the gene marker. Credible CEAs are needed to provide guidance about screening decisions.
Use of Regression Modeling to Simulate Patient-Specific Decision Analysis for Patients with Nonvalvular Atrial Fibrillation
Authors: Johnston Joseph A. , Eckman Mark H.
Published: October 2003

Purpose. To create a Web-based decision support tool that uses a simple regression equation to simulate performance of patient-specific decision analysis (PSDA) for patients with nonvalvular atrial fibrillation. Methods. Patient-level data were used, along with decision model estimates of the gain in quality-adjusted life expectancy associated with anticoagulant therapy to train regression models. Models involving successively higher order polynomial functions were evaluated. Results. Quadratic (R2 = 0.89) and cubic (R2 = 0.97) regression models provided incremental benefit over a simple linear model (R2 = 0.56). For the cubic model, 95% of estimates were within 0.26 QALYs of wdecision model estimates. The cubic model accurately predicted actual decision model recommendations (AUROC of 0.957). Conclusions. Regression modeling can be used to simulate the performance of PSDA for patients with atrial fibrillation. This approach can be used to create fast, reliable, and portable decision support tools to improve patient care.
The Impact of Ignoring Population Heterogeneity when Markov Models are Used in Cost-Effectiveness Analysis
Authors: Zaric Gregory S.
Published: October 2003

Many factors related to the spread and progression of diseases vary throughout a population. This heterogeneity is frequently ignored in cost-effectiveness analyses by using aver-age or representative values or by considering multiple risk groups. The author explores the impact that such simplifying assumptions may have on the results and interpretation of cost-effectiveness analyses when Markov models are used to calculate the costs and health impact of interventions. A discrete-time Markov model for a disease is defined, and 5 potential interventions are considered. Health benefits, costs, and incremental cost-effectiveness ratios are calculated for each intervention. It is assumed that the population is heterogeneous with respect to the probability of becoming sick. Ignoring this heterogeneity may lead to optimistic or pessimistic estimates of cost-effectiveness ratios, depending on the intervention and, in some cases, the parameter values. Implications are discussed of this finding on the use of league tables and on comparisons of cost-effectiveness ratios versus commonly accepted threshold values.
Utilities Derived from Visual Analog Scale Scores in Patients with HIV/AIDS
Authors: Mrus Joseph M. , Yi Michael S. , Freedberg Kenneth A. , Wu Albert W. , Zackin Robert , Gorski Heather , Tsevat Joel
Published: October 2003

Background. Visual analog scale (VAS) scores are used as global quality-of-life indicators and, unlike true utilities (which assess the desirability of health states v. an external metric), are often collected in HIV-related clinical trials. The purpose of this study was to derive and evaluate transformations relating aggregate VAS scores to utilities for current health in patients with HIV/AIDS. Methods. HIV-specific transformations were developed using linear and nonlinear regression to attain models that best fit mean VAS and standard gamble (SG) utility values directly derived from 299 patients with HIV/AIDS participating in a multicenter study of health values. The authors evaluated the transformations using VAS and SG utility values derived directly from patients in other HIV/AIDS studies. Derived transformations were also compared with published transformations. Results. A simple linear transformation was derived (u = 0.44v + 0.49), as was the exponent for a curvilinear model (u = 1-[1- v ]1.6 ), where u = the sample mean utility and v the sample mean VAS score. The curvilinear transformation predicted values within 0.10 of the actual SG utility in 5 of 8 estimates and within 0.05 in 3 of 8 estimates (absolute error ranged from -0.01 to +0.21). The linear transformation performed some-what better, predicting within 0.10 of the actual SG value in 6 of 8 cases and within 0.05 in 5 of 8 estimates (absolute error ranged from -0.05 to +0.13). An alternative linear model (u =v + 0.018) derived from the literature performed similarly to our linear model (7 of 8 predictions within 0.10, 1 of 8 estimates within 0.05, and absolute error ranging from -0.15 to +0.10), whereas an alternative published curvilinear model (u = 1 - [1 - v ]2.3 ) performed the least well (2 of 8 estimates within 0.10 of the actual values and no estimates within 0.05). Conclusions. Predicted utilities are a reasonable alter-native for use in HIV/AIDS decision analyses and costeffectiveness analyses. Linear transformations performed better than curvilinear transformations in this context and can be used to convert aggregate VAS scores to aggregate SG values in large HIV/AIDS studies that collect VAS data but not utilities.
Validity of Standard Gamble Utilities as Measured by Transplant Readiness in Lung Transplant Candidates
Authors: Singer Lianne G. , Theodore James , Gould Michael K.
Published: October 2003

Purpose. To evaluate the validity of standard gamble (SG)utilities, by comparing utilities with decision-making behavior in a group of lung transplant candidates facing a risky health decision. Methods. The authors elicited SG utilities for current health from 57 transplant candidates. They assessed the concordance between utility scores and patients' self-reported readiness to be placed on the transplant waiting list(“listed”). Because transplantation represents a real-life gamble with a short-term survival probability of 85%, the authors defined their minimum validity criterion as utility for current health 0.85 in transplant-ready patients. Results. Utilities were significantly higher in patients who were not ready for listing (n = 22, median utility = 0.79, range 0.06-1) than in those who were ready or listed (n = 35, median utility = 0.50, range 0-0.85, P < 0.00005). All transplant-ready patients had utilities 0.85 for current health. Conclusions. Low SG utilities were associated with transplant readiness in this population of lung transplant candidates. These results provide one line of evidence supporting the validity of SG utilities as a measure of health-related quality of life, using the criterion of decision-making behavior.
Cryptochrome, Compound Eyes, Hofbauer-Buchner Eyelets, and Ocelli Play Different Roles in the Entrainment and Masking Pathway of the Locomotor Activity Rhythm in the Fruit Fly Drosophila Melanogaster
Authors: Rieger Dirk , Stanewsky Ralf , Helfrich-Förster Charlotte
Published: October 2003

The fly Drosophila melanogaster possesses five photoreceptors and/or photopigments that appear to be involved in light reception and synchronization of the circadian clock: (1) the compound eyes, (2) the ocelli, (3) the Hofbauer-Buchner eyelets, (4) the blue-light photopigment cryptochrome, and (5) unknown photopigments in the clock-gene-expressing dorsal neurons. To understand the contributions of these photoreceptors and photopigments to synchronization, the authors monitored the flies' activity rhythms under artificial long and short days. They found that all the different photoreceptors and photo-pigments contribute significantly to entrainment under each photoperiod, but the compound eyes are especially important for entrainment to extreme photoperiods. The compound eyes are, furthermore, necessary for adjusting the phase of the activity rhythm, for distinguishing long days from constant light, and for the normal masking effects of light—namely, promotion of activity by lights-on and inhibition of activity by darkness. Cryptochrome is important for period lengthening under long days, although it is more important for entrainment to short days than to long days and is, furthermore, important for after effects of the photoperiod on the internal clock. The specific roles of the remaining photoreceptors are more difficult to assess.
Competencies and Rewards: Substance or Just Style?
Authors: Zingheim Patricia K. , Schuster Jay R.
Published: October 2003

Competency pay is at a critical stage in its development. The next few years will define its potentially important role in company human resource strategies and tactics. The future solution must be simpler, more business-focused and pragmatic and more readily implemented and justified in terms of a powerful business case for change. Attention should be given to competencies as a foundation for pay and rewards to make them more straightforward and understandable, less vague and ambiguous. Competency pay must also be more directly connected to the realities of the competitive labor market, less laborious and time-consuming when staffs are lean and better sponsored and championed by company leaders. The new agenda to allocate an important share of available dollars to the company's “superkeepers”—people the company must keep because they possess the company's critical core competencies—makes it imperative to make competency pay workable and more business-justified.
Refocusing Performance Management for High Performance
Authors: Risher Howard
Published: October 2003

Performance appraisal has transitioned in most organizations to performance management, but the basic model has not changed in any significant way in roughly 40 years. This article looks at the implications triggered by the new work paradigm and the new focus on high performance. It outlines several changes that would better support this new direction. The traditional appraisal model was developed for a different era. It focused on the individual employee with little regard for the work context or working relationships. Employees were effectively “cogs in the wheel” and expected only to meet performance expectations. Performance dimensions like “dependability” or “cooperation” were indicative of the management philosophy. The new interest in creating high-performance organizations suggests a need to reconsider how employee performance is viewed. The “meets expectations” now has to shift to stretch goals and competencies that contribute to success in this environment. The role of the manager in raising the bar and in creating a supportive culture also must be considered.
Treatment of Pain in Pediatric Patients
Authors: Walker Paul C. , Wagner Deborah S.
Published: October 2003

A growing body of evidence demonstrates that untreated pain is associated with adverse consequences that can compromise clinical and developmental outcomes in children but that these adverse consequences can be prevented or attenuated by appropriate analgesic therapy. Thus, effective treatment of acute pain must be a clinical priority for children of all ages. Over the past 20 years, extensive pediatric research exploring pain assessment, developmental pharmacology of analgesics, and the clinical use of analgesics has dispelled many myths and misconceptions about pain management in pediatric patients; proven that analgesics can be used safely in neonates, infants, and children; and provided a framework for the development of pediatric pain management guidelines. This article reviews guidelines recommended for managing acute pain in pediatric patients and the treatment options for children experiencing acute pain. Contemporary issues regarding acetaminophen, nonsteroidal anti-inflammatory agents, and opioids are discussed.
After Enron
Authors: Kienzler Donna , David Carol
Published: October 2003

Recent scandals in the business community have alerted professional writing teachers to the importance of highlighting ethics in the curriculum. From former experiences in teaching courses emphasizing ethics, the authors have adapted the curriculum to include a limited discussion of ethical approaches and terms and assigned group writing projects that consider the effects of business on the broader community. As a result of the integration of this ethical component into the entire course, students learn major ethical approaches; gain a vocabulary of ethical terms they can apply in the business world; interrogate the larger questions of business and its interactions with the local, national, and international community; and engage in the kind of dialectical discussions that require critical thinking.
Making Sense of Different Types of Crises
Authors: Nord Lars W. , Strömbäck Jesper
Published: October 2003

How did the Swedish media coverage of the terror attacks against the United States and the U.S. attacks in Afghanistan differ when it came to the use of sources, speculations, and anti-American and anti-Muslim reporting? That is the central question in this study. The results show that the Swedish media coverage of the terror attacks and the war in Afghanistan differed in many respects. There are many reasons for this, but one main explanation maybe found in the different categories of the two crises with regard to media preparations and media routines. Another important explanation might be the increasing commercialization and reliance on a particular kind of media logic within Swedish media.
Evaluation of an HIV and STD Prevention Program for Adolescents in Juvenile Rehabilitation Centers
Authors: Godin Gaston , Michaud Francine , Alary Michel , Otis Johanne , Mâsse Benoît , Fortin Christian , Gagnon Marie-Pierre , Gagnon Hélène
Published: October 2003

The aim of this study was to evaluate a sexual and STD/AIDS prevention program tailored for adolescents with social adaptation difficulties in juvenile rehabilitation facilities. The impact of the intervention on the psychosocial determinants of condom use were assessed, using a pretest post-test quasi-experimental design. A total of 296 adolescents participated in the program (experimental group) while 240 adolescents did not receive the intervention (control group). The program led to positive outcomes among participants with respect to several of the main psychosocial determinants of condom use for sexual intercourse with a new partner. The results suggest that interventions that draw upon a combination of theoretical knowledge and consideration of the specific characteristics of the milieu could be efficient in promoting safer sexual practices among adolescents in juvenile rehabilitation centers.
Effects of Morphine and Time of Day on Pain and Beta-Endorphin
Authors: Rasmussen Natalie Ann , Farr Lynne A.
Published: October 2003

Clients report more pain at some times of day than at others due, in part, to the temporal variation of the body's inhibitory pain response. The analgesic effectiveness of morphine varies with the time of day, perhaps due to the inhibiting or enhancing effects of the drug on plasma beta-endorphin (BE). This experiment was designed to examine the timed effects of morphine on the pain-induced BE response. Six groups of treatment mice (injected with morphine sulfate) and 6 groups of control mice (injected with saline) were exposed to an acute pain stimulus at 4-h intervals, and blood was collected. Plasma BE was analyzed using radioimmunoassay. Control mice showed a robust cir-cadian BE-response rhythm with a peak at 0000 and a nadir at 1200, whereas the BE response of mice that received morphine was arrhythmic. Animals that received morphine tolerated the noxious stimulus longer, but the analgesia varied with time of day. These results indicate that morphine abolishes the rhythmic BE response to pain and does not inhibit pain equally at all times of day. Morphine doses should be titrated to maximize the endogenous pain control system while achieving analgesia with decreased dosages.
Teachers' Roles: Literacy-Related Play of Kindergarten Spanish-Speaking Students
Authors: Saracho Olivia N.
Published: October 2003

The purpose of this study was to provide teachers with a literacy intervention method and to assess the roles teachers of Spanish-speaking kindergarten students assume in the context of literacy-related play and how these roles promote the students' literacy development. The data sources consisted of systematic videotaped observations of teacher interaction during student play. Data were analyzed through inductive content analysis, which ideneified roles teachers assumed during literacy-related play of kindergarten Spanish-speaking students.
Hispanic-Serving Institutions in the 21st Century: Overview, Challenges, and Opportunities
Authors: De Los Santos Alfredo G. , De Los Santos Gerardo E.
Published: October 2003

This research studyreports the responses of presidents, chancellors, and CEOs of Hispanic-serving institutions who responded to a survey on is-sues/challenges/problems facing their institutions. The responses are categorized into five general topics: funding, technology, faculty, growth and diversity, and student academic preparation, retention, and graduation. The respondents were equally divided on whether the issues/challenges/problems they identified are directly related to the fact that their institutions are Hispanic-serving institutions.
Gyriform Liver Foci in Chronic Hepatic Porphyria
Authors: Berkovic Dinko , Nolte Wilhelm
Published: October 2003

A patient with suspected liver metastases detected by routine sonography of the abdomen was admitted to our clinic for further testing. Liver sonography disclosed multiple irregular gyriform foci of a hyperechoic structure with a maximum diameter of 3.5 cm. In magnetic resonance imaging, these foci appeared as hyperintense in T1-weighted images and isointense in T2-weighted images. A biopsy showed a discrete portal and periportal fibrosis. UV light fluorescence of the specimen was negative. Analysis of urine revealed an almost fourfold el-evation of total porphyrin of 591 µg/24 h, proving the diagnosis of chronic hepatic porphyria. Characteristic liver foci in hepatic porphyria are detected by sonography in some affected patients. Usually, they can also be depicted by magnetic resonance imaging and computed tomography. These foci often appear before any other symptoms of the disease and are reversible when triggering factors, such as certain drugs or alcohol, are discontinued.
Lymphodepletion in the ApcMin/+ mouse model of intestinal tumorigenesis
Authors: Coletta P. Louise , Müller Albrecht M. , Jones Elena A. , Mühl Bettina , Holwell Sarah , Clarke Deborah , Meade Josephine L. , Cook Graham P. , Hawcroft Gillian , Ponchel Frederique , Lam Wai K. , MacLennan Ken A. , Hull Mark A. , Bonifer Constanze , Markham Alexander F.
Published: October 2003

Germ line mutations in the Adenomatous polyposis coli tumor suppressor gene cause a hereditary form of intestinal tumorigenesis in both mice and man. Here we show that in ApcMin/+ mice, which carry a heterozygous germ line mutation at codon 850 of Apc, there is progressive loss of immature and mature thymocytes from approximately 80 days of age with complete regression of the thymus by 120 days. In addition, ApcMin/+ mice show parallel depletion of splenic natural killer (NK) cells, immature B cells, and B progenitor cells in bone marrow due to complete loss of interleukin 7 (IL-7)-dependent B-cell progenitors. Using bone marrow transplantation experiments into wild-type recipients, we have shown that the capacity of transplanted ApcMin/+ bone marrow cells for T- and B-cell development appears normal. In contrast, although the ApcMin/+ bone marrow microenvironment supported short-term reconstitution with wild-type bone marrow, ApcMin/+ animals that received transplants subsequently underwent lymphodepletion. Fibroblast colony-forming unit (CFU-F) colony assays revealed a significant reduction in colony-forming mesenchymal progenitor cells in the bone marrow of ApcMin/+ mice compared with wild-type animals prior to the onset of lymphodepletion. This suggests that an altered bone marrow microenvironment may account for the selective lymphocyte depletion observed in this model of familial adenomatous polyposis. (Blood. 2004;103:1050-1058)
Assessment of removal of human cytomegalovirus from blood components by leukocyte depletion filters using real-time quantitative PCR
Authors: Visconti Micaela Rios , Pennington Joanne , Garner Stephen F. , Allain Jean-Pierre , Williamson Lorna M.
Published: October 2003

To assess removal of cytomegalovirus (CMV) by leukocyte depletion (LD) filters, we developed a spiking model of latent virus using peripheral blood mononuclear cells (PBMCs) infected by coculture with CMV-infected human fibroblasts. Infected PBMCs were purified by dual magnetic column selection and then spiked into whole blood units or buffy coat pools prior to LD by filtration. CMV load and fibroblast contamination were assessed using quantitative CMV DNA real-time PCR and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) of mRNA encoding the fibroblast-specific splice variant of prolyl-4-hydroxylase, respectively. After correcting for fibroblast-associated CMV, the mean CMV load was reduced in whole blood by LD from 7.42 × 102 to 1.13 copies per microliter (2.8110log reduction) and from 3.8 × 102 to 4.77 copies per microliter (1.910log reduction) in platelets. These results suggest that LD by filtration reduces viral burden but does not completely remove CMV from blood components. (Blood. 2004;103:1137-1139)
Ex vivo depletion of alloreactive cells based on CFSE dye dilution, activation antigen selection, and dendritic cell stimulation
Authors: Godfrey Wayne R. , Krampf Mark R. , Taylor Patricia A. , Blazar Bruce R.
Published: October 2003

Eliminating alloreactive cells from T-cell populations would enable the transfer of immune function to patients who receive stem cell transplants. However, high-efficiency depletion has proved difficult to achieve. We sought to develop ex vivo approaches for the maximal depletion of alloreactive CD4+ T cells. Using a flow cytometric cell sorting approach after mixed lymphocyte reaction (MLR) culture, we have found that sorted CFSEbright (5-(and-6)-carboxyfluorescein diacetate succinmidyl ester) (nondivided) and activation antigen-negative cells are markedly depleted of alloreactivity. With HLA-mismatched peripheral blood mononuclear cell (PBMC) stimulators we have consistently attained (90%-95%) depletion of alloreactivity. Importantly, when purified matured monocyte-derived dendritic cells (DCs) are used as stimulators, a 100-fold (99%) reduction in alloreactivity was attained, resulting in abrogation of the secondary MLR. Significantly, the CFSEbright CD25- cells recovered from these cultures retained general immunoreactivity, including responses to Candida and cytomegalovirus (CMV) antigens. In addition, a CFSE-based approach was tested and found to be sufficient for graft-versus-host disease (GVHD) prevention in vivo, in a major histocompatibility complex (MHC) class II disparate murine model. This efficient approach to selectively deplete mature alloantigen-specific T cells may permit enhanced immune reconstitution without GVHD. (Blood. 2004;103:1158-1165)
Donor immune reconstitution after liver–small bowel transplantation for multiple intestinal atresia with immunodeficiency
Authors: Gilroy Richard K. , Coccia Peter F. , Talmadge James E. , Hatcher Lori I. , Pirruccello Samuel J. , Shaw Byers W. , Rubocki Ronald J. , Sudan Debra L. , Langnas Alan N. , Horslen Simon P.
Published: October 2003

The syndrome of multiple intestinal atresia with immunodeficiency is a rare, invariably fatal congenital disorder. At 16 months of age, a child with this syndrome underwent liver-small bowel transplantation from a 1-of-6 HLA-matched donor. He acquired full enteral tolerance and normal liver function and has never shown evidence of allograft rejection. After mild graft-versus-host disease developed, studies revealed that more than 99% of his CD3+ lymphocytes and 50% of his CD19+ lymphocytes were of donor origin, whereas granulocytes and monocytes remained of recipient origin. He synthesizes polyclonal immunoglobulin G (IgG), IgA, and IgM and has developed antibodies to cytomegalovirus (CMV) and parainfluenza 3. His T lymphocytes are predominately CD3+CD4-CD8- with T-cell receptor γδ heterodimers and CD3+CD4-CD8+ with CD8αα homodimers, populations consistent with an intraepithelial lymphocyte phenotypic profile. We postulate that he has engrafted a donor intestine-derived immune system and is incapable of rejecting his engrafted organs. (Blood. 2004;103:1171-1174)
CD44: a new means to inhibit acute myeloid leukemia cell proliferation via p27Kip1
Authors: Gadhoum Zeineb , Leibovitch Marie-Pierre , Qi Junyuan , Dumenil Dominique , Durand Laetitia , Leibovitch Serge , Smadja-Joffe Florence
Published: October 2003

Acute myeloid leukemia (AML) is sustained by the extensive proliferation of leukemic stem and progenitor cells, which give rise to the population of leukemic blasts with defective differentiation and low proliferative capacity. We have recently shown that ligation of CD44, a cell surface molecule present on AML cells, with specific monoclonal antibodies (mAbs) inhibits their proliferation. However, its mechanism has not been investigated yet. Here, using the NB4 cell line as a model of proliferating human AML cells, and the A3D8 mAb to ligate CD44, we show for the first time that CD44 ligation stabilizes the cyclin-dependent kinase inhibitor p27Kip1 (p27) protein, resulting in increased association with cyclin E/Cdk2 complexes and inhibition of their kinase activity. Moreover, using a p27 antisense vector, we provide direct evidence that p27 is the main mediator of cell growth arrest by CD44. CD44 ligation also leads to p27 accumulation in THP-1, KG1a, and HL60 cell lines and in primary leukemic cells, suggesting that this process is general in AML. Taken together, our present results suggest that CD44 is a new and efficient means to increase the expression of p27 in AML cells. Considering that elevated expression of p27 is a factor of good prognosis in AML, these results provide a new basis for developing CD44-targeted therapy in AML. (Blood. 2004;103:1059-1068)
Single administration of stem cell factor, FLT-3 ligand, megakaryocyte growth and development factor, and interleukin-3 in combination soon after irradiation prevents nonhuman primates from myelosuppression: long-term follow-up of hematopoiesis
Authors: Drouet Michel , Mourcin Frédéric , Grenier Nancy , Leroux Valérie , Denis Josianne , Mayol Jean-François , Thullier Philippe , Lataillade Jean-Jacques , Herodin Francis
Published: October 2003

Preservation of hematopoietic stem and progenitor cell survival is required for recovery from radiation-induced myelosuppression. We recently showed that short-term injection of antiapoptotic cytokine combinations into mice soon after lethal gamma irradiation promoted survival. The present study investigated the hematopoietic response of cynomolgus monkeys to a single dose of stem cell factor, FLT-3 ligand, megakaryocyte growth and development factor, and interleukin-3 in combination (4F, each factor given intravenously at 50 μg/kg) administered 2 hours after 5-Gy gamma irradiation. Treated monkeys (n = 4) experienced no thrombocytopenia. Only 1 in 4 displayed a transient period of neutropenia (neutrophil [ANC] count < 0.5 × 109/L), whereas all irradiated controls (n = 4) experienced neutropenia (5-12 days) and thrombocytopenia (platelet [PLT] count < 20 × 109/L, 5-31 days). Treated animals exhibited an impressive 2-wave PLT response that peaked at days 8 and 22 after total body irradiation (TBI). Areas under the curve (AUC) of PLTs, ANCs, white blood cells (WBCs), and red blood cells (RBCs) between days 0 and 90 were significantly higher in treated animals than in controls. Humeral bone marrow–derived clonogenic activity was significantly spared at 24 hours and 4 days after TBI in treated monkeys. No apparent impairment of the hematopoietic status and stem cell pool, in terms of long-term culture–initiating cells (LTC-ICs) and side population (SP) cells, was observed after 15 months. These results strongly suggest that the 4F cytokine combination, as a single dose regimen, could act as an emergency treatment for nuclear accident or terrorism victims.
The natural history of respiratory syncytial virus infection in cancer and transplant patients: implications for management
Authors: Anaissie Elias J. , Mahfouz Tahsine H. , Aslan Turan , Pouli Anastasia , Desikan Rahman , Fassas Athanasios , Barlogie Bart
Published: October 2003

Respiratory syncytial virus (RSV) has been reported to cause severe morbidity and mortality among cancer patients receiving chemotherapy with or without autologous peripheral blood stem cell transplantation (APBSCT). However, little is known about the natural history of this infection in these patients, and current standard practice, aerosolized ribavirin plus intravenous immunoglobulin (IVIG), is extremely expensive, difficult to use, and not supported by controlled clinical trials. The purpose of this observational study was to determine the frequency, seasonality, morbidity, and mortality of RSV infection in a group of cancer patients receiving cytotoxic chemotherapy with neither ribavirin nor IVIG treatment. During the period of October 3, 1997, through October 14, 1998, 190 cancer patients (median age, 58 years; 71 women) underwent viral nasopharyngeal washing prior to chemotherapy. Multiple myeloma (MM) accounted for most patients (147, 77%). RSV was recovered from cultures taken from 71 patients (37%) throughout the year, although more frequently during fall and winter seasons (P < .001) than spring and summer. Serious respiratory complications developed in 19 (27%) of 71 RSV-positive patients versus 24 (20%) of 119 patients whose RSV cultures were negative (P = .384). The presence of renal failure or increased lactate dehydrogenase (LDH) prior to chemotherapy and the development of mucositis were the only predictive factors for severe respiratory complications. Recovery of RSV from nasopharyngeal washings among cancer patients is common, occurs throughout the year, and does not appear to increase serious morbidity or mortality. RSV infection may not necessarily be a contraindication for APBSCT or an indication for therapy with aerosolized ribavirin and IVIG.
An amino acid polymorphism in von Willebrand factor correlates with increased susceptibility to proteolysis by ADAMTS13
Authors: Bowen Derrick John , Collins Peter William
Published: October 2003

The hypothesis that increased ADAMTS13 (a disintegrin and metalloprotease with thrombospondin repeats) activity or increased susceptibility of von Willebrand factor (VWF) to proteolysis by ADAMTS13 may underlie type I von Willebrand disease (VWD) in some patients was investigated. Plasma from 4 patients with type I VWD was cryoprecipitated. ADAMTS13 activity in the VWF-poor cryodepleted fraction was assessed by incubation with purified VWF; susceptibility to proteolysis of the VWF in the VWF-rich cryoprecipitate was assessed by incubation with a normal, group O cryodepleted plasma. ADAMTS13 activity was similar in all 4 type I VWD cryodepleted plasmas and comparable to a normal control plasma. In contrast, the VWF of one patient showed increased susceptibility to proteolysis by ADAMTS13. Investigation of additional family members indicated that increased susceptibility was heritable, but it did not track uniquely with type I VWD. Sequence analysis of VWF exon 28 indicated that increased susceptibility to proteolysis tracked with the “G” allele of the A/G polymorphism at position 24/1282, encoding the amino acid polymorphism Tyr/Cys1584 (“G” = Cys1584). A prospective study of 200 individuals yielded 2 Tyr/Cys1584 heterozygotes; for both, plasma VWF showed increased susceptibility to proteolysis. The finding that an amino acid polymorphism in VWF may influence susceptibility to ADAMTS13 has potentially significant implications in diverse areas. (Blood. 2004;103:941-947)
The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice
Authors: Chand Hitendra Singh , Du Xin , Ma Duan , Inzunza Hector David , Kamei Shintaro , Foster Donald , Brodie Steven , Kisiel Walter
Published: October 2003

Human tissue factor pathway inhibitor-2 (TFPI-2) is a matrix-associated Kunitz inhibitor that inhibits the plasmin- and trypsin-mediated activation of zymogen matrix metalloproteinases involved in tumor progression, invasion, and metastasis. To directly assess its role in tumor growth and metastasis in vivo, we stably transfected HT-1080 fibrosarcoma cells expressing either fully active wild-type human TFPI-2 (WT) or inactive R24Q TFPI-2 (QT) and examined their ability to form tumors and metastasize in athymic mice in comparison to mock-transfected cells (MT). MT and QT fibrosarcoma tumors grew 2 to 3 times larger than WT tumors. Tumor metastasis was confined to the lung and was observed in 75% of mice treated with either MT or QT cells, whereas only 42% of mice treated with WT cells developed lung metastases. Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analyses of each tumor group revealed 3- to 6-fold lower levels of murine vascular endothelial growth factor gene expression in WT tumors in relation to either MT or QT tumors. Comparative tumor gene expression analysis revealed that several human genes implicated in oncogenesis, invasion, metastasis, apoptosis, and angiogenesis had significantly altered levels of expression in WT tumors. Our collective data demonstrate that secretion of inhibitory TFPI-2 by a highly metastatic tumor cell markedly inhibits its growth and metastasis in vivo by regulating pericellular extracellular matrix (ECM) remodeling and angiogenesis. (Blood. 2004;103:1069-1077)
Bifunctional role for VEGF-induced heme oxygenase-1 in vivo: induction of angiogenesis and inhibition of leukocytic infiltration
Authors: Bussolati Benedetta , Ahmed Asif , Pemberton Helen , Landis R. Clive , Di Carlo Francesco , Haskard Dorian O. , Mason Justin C.
Published: October 2003

Heme-oxygenases (HOs) catalyze the conversion of heme into carbon monoxide and biliverdin. HO-1 is induced during hypoxia, ischemia/reperfusion, and inflammation, providing cytoprotection and inhibiting leukocyte migration to inflammatory sites. Although in vitro studies have suggested an additional role for HO-1 in angiogenesis, the relevance of this in vivo remains unknown. We investigated the involvement of HO-1 in angiogenesis in vitro and in vivo. Vascular endothelial growth factor (VEGF) induced prolonged HO-1 expression and activity in human endothelial cells and HO-1 inhibition abrogated VEGF-driven angiogenesis. Two murine models of angiogenesis were used: (1) angiogenesis initiated by addition of VEGF to Matrigel and (2) a lipopolysaccharide (LPS)–induced model of inflammatory angiogenesis in which angiogenesis is secondary to leukocyte invasion. Pharmacologic inhibition of HO-1 induced marked leukocytic infiltration that enhanced VEGF-induced angiogenesis. However, in the presence of an anti-CD18 monoclonal antibody (mAb) to block leukocyte migration, VEGF-induced angiogenesis was significantly inhibited by HO-1 antagonists. Furthermore, in the LPS-induced model of inflammatory angiogenesis, induction of HO-1 with cobalt protoporphyrin significantly inhibited leukocyte invasion into LPS-conditioned Matrigel and thus prevented the subsequent angiogenesis. We therefore propose that during chronic inflammation HO-1 has 2 roles: first, an anti-inflammatory action inhibiting leukocyte infiltration; and second, promotion of VEGF-driven noninflammatory angiogenesis that facilitates tissue repair.
Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning
Authors: Bethge Wolfgang A. , Hegenbart Ute , Stuart Monic J. , Storer Barry E. , Maris Michael B. , Flowers Mary E. D. , Maloney David G. , Chauncey Thomas , Bruno Benedetto , Agura Ed , Forman Stephen J. , Blume Karl G. , Niederwieser Dietger , Storb Rainer , Sandmaier Brenda M.
Published: October 2003

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

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

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