bluuebunny/crossref_metadata_2025 huggingface dataset:
New developments on the Turkish school library scene
Authors: Önal H. Inci
Published: September 2005

The overall purpose of this article is to describe the history, growth and development of school libraries in Turkey from 1923 to 2004. For now and the foreseeable future, school librarians will be simultaneously working in the library of yesterday and deeply affected by the library of tomorrow. Changing information needs make it necessary to extend school library services to include new information resources. School librarians must help students understand their information needs and the resources and information technologies available. The research on which this article is based used the survey method. Data were collected through literature analysis, questionnaires, interviews and observation. Observations and interviews were conducted and 3000 questionnaires were distributed in 100 secondary education institutions in Ankara, Turkey during the academic year 2003-4. The research in this article explores the historical background and the current status, role and function of school libraries in providing information resources to help meet the information needs of students in Turkey. It is concluded that in order to optimally deliver information services in secondary education institutions, it is necessary to connect with and guide users by all means available, thereby providing endless possibilities for perpetual connectivity and human development.
Globalization
Authors: Ani Okon E. , Biao Esohe Patience
Published: September 2005

This article reports on a study which investigated the impact of globalization on scientific research in Nigeria. The research data were collected using a questionnaire survey which was administered to academics in science-based disciplines in four Nigerian universities: University of Calabar, University of Uyo, University of Lagos and University of Ibadan. The results of the study show that ease of scientific communication, an increased access to current scientific books/journals and improvements in the quality of research were considered the main effects of globalization on scientific research in Nigeria. The findings of the study also show that the major factors considered to impede globalization of science in the country were frequent power cuts, a poor maintenance culture of ICT infrastructures/facilities, and an inadequate knowledge/awareness of the potential and capabilities of ICT by Nigerian scientists. Relevant recommendations based on these findings are made.
Reactive Agents and Perceptual Ambiguity
Authors: van Dartel Michel , Sprinkhuizen-Kuyper Ida , Postma Eric , van den Herik Jaap
Published: September 2005

Reactive agents are generally believed to be incapable of coping with perceptual ambiguity (i.e., identical sensory states that require different responses). However, a recent finding suggests that reactive agents can cope with perceptual ambiguity in a simple model (Nolfi, 2002). This paper investigates to what extent reactive and nonreactive agents can cope with perceptual ambiguity, and which strategies are employed when doing so. A model of active categorical perception (called Acp) is introduced. In Acp, situated agents with different types of neurocontrollers are optimized to categorize objects by adaptively coordinating action and perception. Our experiments show that both nonreactive and reactive agents can cope with perceptual ambiguity. An analysis of the behavior reveals that nonreactive agents use their internal memory to cope with perceptual ambiguity, while reactive agents use the environment as an external memory to compensate for their lack of an internal memory. We conclude that reactive agents can cope with perceptual ambiguity in the context of active categorical perception, and that they can organize their behavior according to stimuli that are no longer present, especially when they incorporate a nonlinear sensorimotor mapping. Moreover, we may conclude that sensory state-transition diagrams provide insight into the strategies employed by reactive agents to deal with perceptual ambiguity, and their use of the environment as an external memory.
The culture of cancer and the therapeutic impact of qualitative research interviews
Authors: Colbourne Linda , Sque Magi
Published: September 2005

This paper is an account of the potential therapeutic impact of research interviews encountered while conducting a qualitative research study. Similarities between the therapeutic (or psychoanalytic) interview and the qualitative research interview are discussed and explored, with examples drawn from a current study. It is suggested that, as a listener, the nurse researcher may offer the participant a mechanism for reflection, greater self-awareness, finding a voice, obtaining information, and venting repressed emotions. Within the context of cancer the participant might have multiple care and information needs to which he/she may expect a therapeutic interaction from a nurse researcher. The potential therapeutic component of the nurse researcher role in the context of cancer care is described and considered. The paper suggests that there may be positive and negative aspects of a therapeutic component to the researcher role and that the researcher should think carefully concerning the stance that he/she will take in the field.
The strengths and weaknesses of research designs involving quantitative measures
Authors: Walker Wendy
Published: September 2005

This paper presents a critical review of the strengths and weaknesses of research designs involving quantitative measures and, in particular, experimental research. The review evolved during the planning stage of a PhD project that sought to determine the effects of witnessed resuscitation on bereaved relatives. The discussion is therefore supported throughout by reference to bereavement research. Three levels of quantitative research are presented: descriptive, correlational and experimental. The findings suggest that experimental research is subject to a number of methodological limitations that may jeopardise internal and external validity of the research results and, consequently, limit their applicability for practice. Nurses are therefore encouraged to carefully consider the virtues of experimental designs, in their quest for evidence-based practice and in the planning of future research.
Indoor Air Problems in a Healthcare Centre – A Case Report of a Follow-up
Authors: Aarnio P. , Mussalo-Rauhamaaa H. , Mäkinen-Kiljunen S. , Saarela K. , Loft S.
Published: September 2005

Indoor air problems present a considerable challenge for workplace personnel. Here, we report the follow-up results of employees in a healthcare centre in Southern Finland. In this building there was moisture damage, including moulds and other microbial growth, as well as associated indoor air problems, such as sporadic high ammonia concentrations, and there was suspicion of mites. The indoor air quality was determined through mould and volatile organic compound measurements. Symptoms were recorded on the MM-40-FIN questionnaire. Two employees were also examined at the Clinic for Indoor Air Health Problems, Helsinki University Central Hospital. Employees’ complaints about dustiness and stuffiness remained mostly unchanged during the 6 follow-up years. After several renovations of the building, the eye complaints diminished to about half. Two case reports showed disappearance of symptoms when their exposure ceased. However, the complexity of indoor air problems makes it difficult to improve the indoor climate and relieve symptoms with simple renovations. Sensitive or allergic individuals may more readily react than others to these moistureassociated problems.
Selected Ion Monitoring – Gas Chromatography/Mass Spectrometry Determination of Halothane Fumes in Operating Theatres
Authors: Nicoarã Simona , Culea Monica , Nicac Alina Nicoleta , Culea E. , Cozarb O.
Published: September 2005

Halothane vapour, used as an inhaled anaesthetic for narcosis, is released during surgical operations causing occupational exposure to medical staff and nurses. The current work continues the controversial issues related to the biological side effects of halothane, and gives a simple method for sampling and determining the air concentration of the anaesthetic in different rooms used for surgical operations. Air contaminants were collected on active charcoal, using a portable pump. Liquid extraction with toluene was followed by injection of the eluate onto a GC capillary column coupled to a quadrupole mass detector. The method was validated with respect to linearity, precision and accuracy. The concentration of halothane in the air was found to depend on room volume, air ventilation rate inside the theatres, and on the technical condition of the vaporiser and anaesthesia devices. Introduction
An Example of Solution Multiplicity in a Building with Bi-directional Flow Openings
Authors: Duan Shuangping , Lia Yuguo
Published: September 2005

We addressed the question of whether the assumption of unidirectional flow found in previous studies has led to the existence of two stable ventilation solutions in a two-opening building. The findings of multiple solutions in building ventilation raise the question of whether the macroscopic flow analysis and/or computational fluid dynamics simulations can provide sufficient accuracy to predict airflow patterns for guiding practical design of natural and hybrid ventilation. We extended previous analyses of a building with two unidirectional flow openings to one with two bi-directional flow openings. We considered natural ventilation driven by combined thermal buoyancy and opposing wind forces. A Newton–Rapson method was used to solve the non-linear governing equations for air-flows and a Runge–Kutta method was used for heat balance in the building. The airflow and heat balance calculations are fully coupled. We found that two stable solution sexisted under a certain combination of identical natural driving forces and a certain combination of large openings with bi-directional flows. The existence of the two stable solutions diminished when the vertical distance between the two openings was equal to or less than the opening height. This observation reveals that the assumption of unidirectional flow has indeed led to the existence of two stable solutions under these conditions for the simple building considered. These results provide more evidence of the existence of multiple solutions for building ventilation in general building configurations and also suggest the need for careful examination of the underlying physical assumptions in the solution multiplicity analyses.
Multiple Solutions in a Building with Four Openings Ventilated by Combined Forces
Authors: Li Yuguo , Duan Shuangping , Zhang Guoqiang
Published: September 2005

Ever since the existence of two stable ventilation solutions in a two-opening building was identified, questions have been asked whether multiple solutions of natural ventilation exist in complex buildings and what are the physical mechanisms that can lead to the existence of multiple solutions in complex buildings. We examined a simple one-zone building with four openings using the simple macroscopic method of thermo-fluid modelling by assuming that the air temperature in the building was uniform. A conventional network modelling computer program was used to simulate the four-opening building ventilated by combined buoyancy and wind forces. The ventilation flow rate in the simple four-opening building was found to be a linear superimposition of that in two corresponding twoopening buildings with opposing and assisting winds respectively. We have shown that when the ventilation flow in the two-opening building with opposing wind is sufficiently strong, two stable solutions and one unstable solution can exist in the corresponding fouropening building. There is a good agreement between the ventilation flow rates predicted by the network modelling method and our simple analytical solutions. The findings suggest the possible existence of multiple solutions in complex building configurations.
Numerical Simulation and Controller Development for Energy Transfer in Imperfectly Mixed Fluids
Authors: Desta T. Zerihun , Van Brecht A. , Meyers J. , Baelmans M. , Berckmans D.
Published: September 2005

This paper describes the possibility of using Computational Fluid Dynamics (CFD) models for developing Model Predictive Controller (MPC) algorithms. In this work a complex CFD model is combined with a reduced order Data-Based Mechanistic (DBM) formulation so that the low-order model can be used for control applications. To demonstrate the methodology, a Single Input-Single Output (SISO) ventilated installation is used. Initially, a CFD model is used for the installation. At the inlet a step rise in air temperature is applied and temperature responses at 36 monitoring positions are extracted. Then a reduced order model is formulated for the test case and model parameters are identified using the data generated by the CFD model. Finally the reduced order CFD model is used to develop an MPC algorithm. The developed algorithm is found to be robust for disturbance effects and capable of tracking the desired reference temperature trajectory very well.
Size Distribution of Atmospheric Aerosols in Kolkata, India and the Assessment of Pulmonary Deposition of Particle Mass
Authors: Nag Subhankar , Gupta A. K. , Mukhopadhyay U. K.
Published: September 2005

Aerosol size distributions were measured at three stations in Kolkata city, during December 2003 to February 2004 using an 8-stage cascade impactor with a back-up filter. Hi-volume samplers were used at the 3 sites for measuring PM2.5 and PM10 concentration. The results showed that the total average number distributed in the size range of 0 to 10 μ m for particulates of size Dp could be represented as a Junge distribution dN/d log(Dp) = 1282.6 (Dp) − 3.803. Aerosol mass distribution by size showed that of the collected fractions most of the PM10 were in the size range of 0 ≤ Dp ≤ 0.43 μ m (15.73%) followed by 0.65 ≤ Dp ≤ 1.1 μ m (15.72%) and then 0.43 ≤ Dp ≤ 0.65 μ m (14.73%). Particle size distributions were trimodal with fine mode Dp ≤ 1.1 μ m (MMAD = 0.51 μ m, GSD = 2.15), medium mode 1.1 ≤ Dp ≤ 4.7 μ m (MMAD = 2.53 μ m, GSD = 1.54) and coarse mode 4.7 ≤ Dp ≤ 10 μ m (MMAD = 8.16 μ m, GSD = 1.38). Average concentrations of PM2.5 and PM10 were in the range of 96.31–363.63 μ gám −3and 140.50–637.70 μ gám −3, respectively. Correlation analysis showed that the highest correlation (0.91) was observed between the particle ranges of 9.0–10.0 μ m and 3.3–4.7 μ m followed by 0.89 between 9.0–10.0 and 5.8–9.0 μ m. Regression analysis showed that PM2.5 was about 60% of PM10 concentration. A widely used ICRP model was used to estimate pulmonary deposition. The result showed that 36% of deposited PM10 was accumulated in the alveolar region and nearly 49% of deposited PM10 was accumulated in the tracheobronchial region.
Social Justice, Voluntarism, and Liberal Nationalism
Authors: Green Michael
Published: September 2005

The view that social justice takes priority over both global justice and the demands of sub-groups faces two critics. Particularist critics ask why societies should have fundamental significance compared with other groups as far as justice is concerned. Cosmopolitan critics ask why any social unit short of humanity as a whole should have fundamental significance as far as justice is concerned. One way of trying to answer these critics is to show that members of societies have special obligations to one another. This paper considers voluntarist and liberal nationalist accounts of such special obligations. It is especially concerned with developing a strong, sympathetic case for the less familiar nationalist position. Nonetheless, in each case the best arguments against the cosmopolitan critic require important concessions to the particularist critic. This suggests that there is a general problem with defending social justice against both critics at the same time.
The Difference Principle, Equality of Opportunity, and Cosmopolitan Justice
Authors: Brock Gillian
Published: September 2005

What kinds of principles of justice should a cosmopolitan support? In recent years some have argued that a cosmopolitan should endorse a Global Difference Principle. It has also been suggested that a cosmopolitan should support a Principle of Global Equality of Opportunity. In this paper I examine how compelling these two suggestions are. I argue against a Global Difference Principle, but for an alternative Needs-Based Minimum Floor Principle (where these are not co-extensive, as I explain). Though I support a negative version of the Global Equality of Opportunity Principle, I argue that a more positive version of the ideal remains elusive.
The Law of Peoples: The Old and the New
Authors: Naticchia Chris
Published: September 2005

John Rawls produced two versions of the law of peoples: an article, published in 1993, and a book, published in 1999. Both versions defend basic human rights as a minimum requirement of a just law of peoples. However, in an apparent effort to strengthen his defense of this requirement, the argument changed. This paper examines the apparent difficulties that forced the changes and maintains that they still do not succeed in justifying basic human rights. The source of the difficulty, I argue, is Rawls’s reluctance to impose liberal values on nonliberal societies, and the imposition of such values, I suggest, is unavoidable if basic human rights are to be justified. Hence, if our best attempts to justify basic human rights ultimately show that appeals to liberal values are unavoidable, then we should regard such appeals as no more of an imposition than the expectation that all societies must protect basic human rights. Even more significantly, if such appeals justify liberal freedoms that go beyond basic human rights, then arguments in support of basic human rights would also justify international efforts to advance further liberal reforms within nonliberal societies.
Scleromyxedema: role of high-dose melphalan with autologous stem cell transplantation
Authors: Donato Michele L. , Feasel Adrienne M. , Weber Donna M. , Prieto Victor G. , Giralt Sergio A. , Champlin Richard E. , Duvic Madeleine
Published: September 2005

Scleromyxedema, the most severe manifestation of the spectrum of lichen myxedematosus, is characterized by cutaneous mucinosis, extracutaneous manifestations, and a monoclonal gammopathy. Seven of 8 patients evaluated at our center were treated with high-dose melphalan (180 mg/m2 intravenously) and autologous peripheral blood stem cell transplantation, with marked improvement of gastrointestinal, central nervous system, pulmonary manifestations, and Karnofsky performance status. Five patients obtained a cutaneous complete remission and 2 patients had partial remissions. Three patients with slight progression in the skin at 12, 8, and 4 months after treatment received a second cycle of high-dose melphalan and had further symptomatic improvement. The lichen myxedematosus–scleromyxedema spectrum appears to be a continuum that requires the presence of a serum paraprotein and differs in severity of skin lesions, extracutaneous manifestations, and performance status. High-dose melphalan followed by autologous transplantation appears effective for improving the symptoms and systemic manifestations of scleromyxedema.
Seasonal variation of pretransfusion hemoglobin levels in patients with thalassemia major
Authors: Borgna-Pignatti Caterina , Ventola Mariela , Friedman David , Cohen Alan R. , Origa Raffaella , Galanello Renzo , Lindeman Robert , Francis Sally , Reverberi Roberto , Volpato Stefano
Published: September 2005

Patients with thalassemia major often report that they do not maintain their usual pretransfusion hemoglobin concentration during the summer season. We collected 3977 pretransfusion hemoglobin values, amount of blood transfused, and intertransfusion intervals for 94 patients with thalassemia major from 4 centers worldwide. We also assessed the hematocrits of blood donors, the hemoglobin content of units transfused in one center, and the local mean monthly temperatures during the periods of data collection. Pretransfusion hemoglobin levels were significantly lower during the summer in all centers except the one center where monthly temperatures have the least variation throughout the year. A similar relationship to temperature was observed for the hematocrits of blood donors and the hemoglobin content of donor units. This study confirms that pretransfusion hemoglobin levels in patients with thalassemia major are lower in the summertime. Possible mechanisms include expansion of plasma volume with resultant hemodilution in the patient and lower hemoglobin content in donor blood.
Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia
Authors: Mayr Christine , Speicher Michael R. , Kofler David M. , Buhmann Raymund , Strehl John , Busch Raymonde , Hallek Michael , Wendtner Clemens-Martin
Published: September 2005

In chronic lymphocytic leukemia (CLL), chromosomes usually evade detailed cytogenetic analyses because cells poorly respond to the traditionally used set of mitogens. We applied novel technologies, such as stimulation of CLL cells either with CD40 ligand or with a combination of CpG-oligodeoxynucleotides and IL-2, to increase the freequncy of metaphase spreads for detailed chromosome analysis in 96 patients with CLL. This approach revealed that translocations occurred in 33 of 96 (34%) of our patients with CLL. The presence of translocations defined a new prognostic subgroup because these patients have significantly shorter median treatment-free survival (24 months vs 106 months; P < .001) and significantly inferior overall survival (OS; median, 94 months) than patients without translocations (346 months; P < .001). In multivariate analysis—including Binet stage, complex karyotype, CD38 expression, and 17p deletions—translocation proved to be the prognostic marker with the highest impact for an unfavorable clinical outcome (P < .001). In summary, we identified a new subgroup of patients with CLL defined by chromosomal trans-locations and poor prognosis. Our data may facilitate the identification of molecular events crucial for transforming activity in this disease and should have implications for risk-adapted clinical management of patients with CLL. (Blood. 2006;107:742-751)
β-Glucan enhances complement-mediated hematopoietic recovery after bone marrow injury
Authors: Cramer Daniel E. , Allendorf Daniel J. , Baran Jarek T. , Hansen Richard , Marroquin Jose , Li Bing , Ratajczak Janina , Ratajczak Mariusz Z. , Yan Jun
Published: September 2005

Myelotoxic injury in the bone marrow (BM) as a consequence of total body irradiation (TBI) or granulocyte colony-stimulating factor (G-CSF) mobilization results in the deposition of iC3b on BM stroma (stroma-iC3b). In the present study, we have examined how stroma-iC3b interacts with hematopoietic progenitor cells (HPCs) and the role of complement (C) and complement receptor 3 (CR3) in BM injury/repair. We demonstrate here that stroma-iC3b tethers HPCs via the inserted (I) domain of HPC complement receptor 3 (CR3, CD11b/CD18, Mac-1). Following irradiation, stroma-iC3b was observed in the presence of purified IgM and normal mouse serum (NMS), but not serum from Rag-2-/- mice, implicating a role for antibody (Ab) and the classic pathway of C activation. Furthermore, a novel role for soluble yeast β-glucan, a ligand for the CR3 lectin-like domain (LLD), in the priming of CR3+ HPC is suggested. Soluble yeast β-glucan could enhance the proliferation of tethered HPCs, promote leukocyte recovery following sublethal irradiation, and increase the survival of lethally irradiated animals following allogeneic HPC transplantation in a CR3-dependent manner. Taken together, these observations suggest a novel role for C, CR3, and β-glucan in the restoration of hematopoiesis following injury. (Blood. 2006;107:835-840)
Key role of the p110δ isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110δ function in B cells
Authors: Bilancio Antonio , Okkenhaug Klaus , Camps Montserrat , Emery Juliet L. , Ruckle Thomas , Rommel Christian , Vanhaesebroeck Bart
Published: September 2005

Mouse gene–targeting studies have documented a central role of the p110δ isoform of phosphoinositide 3-kinase (PI3K) in B-cell development and function. A defect in B-cell antigen receptor (BCR) signaling is key to this B-cell phenotype. Here we further characterize this signaling defect and report that a p110δ-selective small molecule inhibitor mirrors the effect of genetic inactivation of p110δ in BCR signaling. p110δ activity is indispensable for BCR-induced DNA synthesis and phosphorylation of Akt/protein kinase B (PKB), forkhead transcription factor/forkhead box O3a (FOXO3a), and p70 S6 kinase (p70 S6K), with modest effects on the phosphorylation of glycogen synthase kinase 3 α/β (GSK3α/β) and extracellular signal-regulated kinase (Erk). The PI3K-dependent component of intracellular calcium mobilization also completely relies on p110δ catalytic activity. Resting B cells with inactive p110δ fail to enter the cell cycle, correlating with an incapacity to up-regulate the expression of cyclins D2, A, and E, and to phosphorylate the retinoblastoma protein (Rb). p110δ is also critical for interleukin 4 (IL-4)–induced phosphorylation of Akt/PKB and FOXO3a, and protection from apoptosis. Taken together, these data show that defects observed in p110δ mutant mice are not merely a consequence of altered B-cell differentiation, and emphasize the potential utility of p110δ as a drug target in autoimmune diseases in which B cells play a crucial role.
An easy approach to the Robins-Breslow-Greenland variance estimator
Authors: Silcocks Paul
Published: September 2005

The Mantel-Haenszel estimate for the odds ratio (and its logarithm) in stratified case control studies lacked a generally acceptable variance estimate for many years. The Robins-Breslow-Greenland estimate has met this need, but standard textbooks still do not provide an explanation of how it is derived. This article provides an accessible derivation which demonstrates the link between the Robins-Breslow-Greenland estimate and the familiar Woolf estimate for the variance of the log odds ratio, and which could easily be included in Masters level courses in epidemiology. The relationships to the unconditional and conditional maximum likelihood estimates are also reviewed.
Idiopathic chronic cough: a real disease or a failure of diagnosis?
Authors: McGarvey LPA
Published: September 2005

Despite extensive diagnostic evaluation and numerous treatment trials, a number of patients remain troubled by a chronic and uncontrollable cough. Eosinophilic bronchitis, atopic cough and non-acid reflux have been recently added to the diagnostic spectrum for chronic cough. In some cases, failure to consider these conditions may explain treatment failure. However, a subset of patients with persisting symptoms may be regarded as having an idiopathic cough. These individuals are most commonly female, of postmenopausal age and frequently report viral upper respiratory tract infections as an initiating event. This paper seeks to explore the validity of idiopathic cough as a distinct clinical entity.
Positive association between mammographic breast density and bone mineral density in the Postmenopausal Estrogen/Progestin Interventions Study
Authors: Crandall Carolyn , Palla Shana , Reboussin Beth A , Ursin Giske , Greendale Gail A
Published: September 2005

Introduction

Mammographic breast density is a strong independent risk factor for breast cancer. We hypothesized that demonstration of an association between mammographic breast density and bone mineral density (BMD) would suggest a unifying underlying mechanism influencing both breast density and BMD.

Methods

In a cross-sectional analysis of baseline data from the Postmenopausal Estrogen/Progestin Interventions Study (PEPI), participants were aged 45 to 64 years and were at least 1 year postmenopausal. Mammographic breast density (percentage of the breast composed of dense tissue), the outcome, was assessed with a computer-assisted percentage-density method. BMD, the primary predictor, was measured with dual-energy X-ray absorptiometry. Women quitting menopausal hormone therapy to join PEPI were designated recent hormone users.

Results

The mean age of the 594 women was 56 years. The average time since menopause was 5.6 years. After adjustment for age, body mass index, and cigarette smoking, in women who were not recent hormone users before trial enrollment (n = 415), mammographic density was positively associated with total hip (P = 0.04) and lumbar (P = 0.08) BMD. Mammographic density of recent hormone users (n = 171) was not significantly related to either total hip (P = 0.51) or lumbar (P = 0.44) BMD. In participants who were not recent hormone users, mammographic density was 4% greater in the highest quartile of total hip BMD than in the lowest. In participants who were not recent hormone users, mammographic density was 5% greater in the highest quartile of lumbar spine BMD than in the lowest.

Conclusion

Mammographic density and BMD are positively associated in women who have not recently used postmenopausal hormones. A unifying biological mechanism may link mammographic density and BMD. Recent exogenous postmenopausal hormone use may obscure the association between mammographic density and BMD by having a persistent effect on breast tissue.
Prognostic Analysis for Survival in Adult Solid Organ Transplant Recipients With Post-Transplantation Lymphoproliferative Disorders
Authors: Ghobrial Irene M. , Habermann Thomas M. , Maurer Matthew J. , Geyer Susan M. , Ristow Kay M. , Larson Timothy S. , Walker Randall C. , Ansell Stephen M. , Macon William R. , Gores Gregory G. , Stegall Mark D. , McGregor Christopher G.
Published: September 2005

Purpose

The objective of this study was to determine prognostic factors for overall survival in patients with post-transplantation lymphoproliferative disorders (PTLDs).

Patients and Methods

This study focused on the 107 adult solid organ transplantation patients who were diagnosed with PTLDs at Mayo Clinic (Rochester, MN) between December 1970 and May 2003.

Results

The median age at the time of diagnosis was 48 years (range, 15 to 75 years). Extranodal disease including grafted organ involvement was present in 85 patients (80%). The graft organ was involved in 30 patients (28%). At the time of these analyses, 62 patients (58%) had died. The median survival for the entire cohort was 31.5 months (95% CI, 10.7 to 72.5 months). The median follow-up of living patients was 51.8 months (range, 5.6 to 202.6 months). In univariate analyses for overall survival from the time of PTLD diagnosis, the following poor prognostic factors were identified: poor performance status with Eastern Cooperative Oncology Group levels 3 and 4 (P < .0001), grafted organ involvement (P = .0005), the presence of one or more extranodal sites (P = .005), both nodal and extranodal disease (P = .002), high International Prognostic Index (P = .006), advanced stage (P = .001), and elevated lactate dehydrogenase (P = .03). A final multivariable model for survival was constructed using three factors: poor performance status (3 to 4), monomorphic disease, and graft organ involvement.

Conclusion

A prognostic model has been developed for PTLD patients using one center's 30 years of experience. We propose additional confirmation and validation of these prognostic factors in larger prospective studies.
Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Advanced Chronic Lymphocytic Leukemia
Authors: O'Brien Susan M. , Cunningham Charles C. , Golenkov Anatoliy K. , Turkina Anna G. , Novick Steven C. , Rai Kanti R.
Published: September 2005

Purpose

To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL).

Patients and Methods

Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients.

Results

Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included ≥ 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), ≥ 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and ≥ 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance.

Conclusion

Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.
Epstein-Barr Virus As a Marker of Survival After Hodgkin's Lymphoma: A Population-Based Study
Authors: Keegan Theresa H.M. , Glaser Sally L. , Clarke Christina A. , Gulley Margaret L. , Craig Fiona E. , DiGiuseppe Joseph A. , Dorfman Ronald F. , Mann Risa B. , Ambinder Richard F.
Published: September 2005

Purpose

Epstein-Barr virus (EBV) in Hodgkin's lymphoma (HL) cells has been considered as a prognostic marker for this heterogeneous disease, but studies have yielded mixed findings, likely because of selected patient series and failure to acknowledge an effect of age on outcome. This study assessed survival after HL in a population-based cohort large enough to examine the joint effects of EBV with other factors including age, sex, and histologic subtype.

Patients and Methods

Included were 922 patients with classical HL diagnosed between mid-1988 and 1997 in the Greater San Francisco Bay Area, with archived biopsy specimens assayed for EBV with immunohistochemistry and in situ hybridization. Vital status was followed through December 30, 2003 (median follow-up time, 97 months). Overall and disease-specific survival were analyzed with the Kaplan-Meier method and Cox proportional hazards regression models.

Results

In children less than 15 years old, EBV presence was suggestively associated (P = .07) with favorable survival. In adults aged 15 to 44 years, EBV did not affect HL outcome, although a protective effect was suggested. In older adults (45 to 96 years), EBV presence nearly doubled the risk of overall and HL-specific mortality but only for patients with nodular sclerosis (NS) histologic subtype (hazard ratio for death = 2.5; 95% CI, 1.5 to 4.3).

Conclusion

In HL, EBV tumor cell presence is associated with better survival in young patients and poorer survival in older patients with NS, independent of other factors. Variation in outcome by age and histology could indicate biologically distinct disease entities. Evidence that EBV is a meaningful prognostic marker may have therapeutic relevance.
Bleomycin Pulmonary Toxicity Has a Negative Impact on the Outcome of Patients With Hodgkin's Lymphoma
Authors: Martin William G. , Ristow Kay M. , Habermann Thomas M. , Colgan Joseph P. , Witzig Thomas E. , Ansell Stephen M.
Published: September 2005

Purpose

Bleomycin pulmonary toxicity (BPT) has been well described in Hodgkin's lymphoma (HL) patients treated with bleomycin-containing chemotherapy regimens. The influence of this pulmonary complication, along with the omission of bleomycin from further chemotherapy, on overall survival (OS) and progression-free survival (PFS) in HL remains unclear. We reviewed our experience with BPT in HL to better delineate outcome and appropriate treatment in these patients.

Patients and Methods

One hundred forty-one patients who were treated with bleomycin-containing chemotherapy for newly diagnosed HL between January 1986 and February 2003 were eligible for this retrospective review. BPT was defined by the presence of pulmonary symptoms, bilateral interstitial infiltrates, and no evidence of an infectious etiology.

Results

BPT was observed in 18% of patients. Increasing age, doxorubicin, bleomycin, vinblastine, and dacarbazine as initial therapy, and granulocyte colony-stimulating factor use were associated with the development of BPT. Patients with BPT had a median 5-year OS rate of 63% v 90% (P = .001) in unaffected patients. The mortality rate from BPT was 4.2% in all patients and 24% in patients who developed the pulmonary syndrome. BPT incidence and mortality were highest in patients older than 40 years. The omission of bleomycin had no impact on obtaining a complete remission, PFS, or OS.

Conclusion

BPT results in a significant decrease in 5-year OS in patients who are treated for HL. Age ≥ 40 years seems to add substantially to the risk. In patients who do not die from acute pulmonary toxicity, both OS and PFS seem equal, despite the omission of bleomycin.
Betacellulin Overexpression in Transgenic Mice Causes Disproportionate Growth, Pulmonary Hemorrhage Syndrome, and Complex Eye Pathology
Authors: Schneider Marlon R. , Dahlhoff Maik , Herbach Nadja , Renner-Mueller Ingrid , Dalke Claudia , Puk Oliver , Graw Jochen , Wanke Rüdiger , Wolf Eckhard
Published: September 2005

The EGF family comprises a network of ligands and receptors that regulate proper development and elicit diverse functions in physiology and pathology. Betacellulin (BTC) is a rather poorly characterized member of the EGF family whose in vivo effects have been linked mainly to endocrine pancreas, intestine, and mammary gland function. In vitro studies revealed that this growth factor is a potent mitogen for diverse cell types and suggested unique receptor-binding properties. Genetic ablation of BTC in mice yielded a mild phenotype, probably because of opportunistic compensation by other EGF receptor ligands. To study the biological capabilities of BTC in vivo, we generated transgenic mice overexpressing BTC ubiquitously, with highest expression levels in heart, lung, brain, and pancreas. Mice overexpressing BTC exhibit high early postnatal mortality, reduced body weight gain, and impaired longitudinal growth. In addition, a variety of pathological alterations were observed. Cataract and abnormally shaped retinal layers as well as bone alterations leading to a dome-shaped, round head form were hallmarks of BTC transgenic mice. The most important finding and the cause of reduced life expectancy of BTC transgenic mice were severe alterations of the lung. Pulmonary pathology was primarily characterized by alveolar hemorrhage, thickening of the alveolar septa, intraalveolar accumulation of hemosiderin-containing macrophages, and nodular pulmonary remodeling. Thus, our model uncovers multiple consequences of BTC overexpression in vivo. These transgenic mice provide a useful model for examining the effects of BTC excess on different organs.
Impaired Regulation of Gonadotropins Leads to the Atrophy of the Female Reproductive System in klotho-Deficient Mice
Authors: Toyama Ryusuke , Fujimori Toshihiko , Nabeshima Yoko , Itoh Yoshiko , Tsuji Yoshihito , Osamura R. Yoshiyuki , Nabeshima Yo-Ichi
Published: September 2005

klotho-Deficient mice exhibit a syndrome resembling human premature ageing, with multiple pathological phenotypes in tissues including reproductive organs. It was proposed that Klotho might possess the hormonal effects on many organs. In this study, the female reproductive system of klotho mice was examined to reveal the mechanism that brought the female sterility by histological and molecular approaches. We observed cessation of ovarian follicular maturation at the preantral stage and the presence of numerous atretic ovarian follicles and atrophic uteri. In situ hybridization analysis revealed that LH receptor and aromatase P450 were not expressed in the ovaries. These results suggest the impairment of gonadal development during the antral transition process. We next addressed the responsible organs for the failure of antral transition. Transplantation of klotho ovaries to wild-type mice resulted in the ability to bear offspring. Administration of FSH or GnRH induced advanced maturation of ovaries and uteri in klotho mice. These results indicate that the female reproductive organs in klotho mice are potentially functional and that klotho gene deficiency leads to the atrophy of reproductive organs via impairment of the hypothalamic-pituitary axis. Absence of the estrus cycle and constant low trends of both FSH and LH levels were found in female klotho mice. Immunohistochemical analysis revealed that the production of both FSH and LH were decreased in pituitary gland. Taken together, our findings suggest the involvement of klotho in the regulatory control of pituitary hormones.
Two Promoters Mediate Transcription from the Human LHX3 Gene: Involvement of Nuclear Factor I and Specificity Protein 1
Authors: Yaden Benjamin C. , Garcia Marin , Smith Timothy P. L. , Rhodes Simon J.
Published: September 2005

The LHX3 transcription factor is required for pituitary and nervous system development in mammals. Mutations in the human gene are associated with hormone-deficiency diseases. The gene generates two mRNAs, hLHX3a and hLHX3b, which encode three proteins with different properties. Here, the cis elements and trans-acting factors that regulate the basal transcription of the two mRNAs are characterized. A comparative approach was taken featuring analysis of seven mammalian Lhx3 genes, with a focus on the human gene. Two conserved, TATA-less, GC-rich promoters that are used to transcribe the mRNAs precede exons 1a and 1b of hLHX3. Transcription start sites were mapped for both promoters. Deletion experiments showed most activity for reporter genes containing the basal promoters in the context of −2.0 kb of hLHX3a and 1.8 kb of intron 1a (hLHX3b). Transfection, site-directed mutation, electrophoretic mobility shift, Southwestern blot, and chromatin immunoprecipitation approaches were used to characterize the interaction of transcription factors with conserved elements in the promoters. Specificity protein 1 is a regulator of both promoters through interaction with GC boxes. In addition, a distal element within intron 1a that is recognized by nuclear factor I is critical for hLHX3b promoter function. We conclude that dual promoters allow regulated production of two hLHX3 mRNAs.
Differential Recruitment of p160 Coactivators by Glucocorticoid Receptor between Schwann Cells and Astrocytes
Authors: Grenier Julien , Trousson Amalia , Chauchereau Anne , Cartaud Jean , Schumacher Michael , Massaad Charbel
Published: September 2005

In the nervous system, glucocorticoids can exert beneficial or noxious effects, depending on their concentration and the duration of hormonal stimulation. They exert their effects on neuronal and glial cells by means of their cognate receptor, the glucocorticoid receptor (GR), which recruits the p160 coactivator family members SRC-1 (steroid receptor coactivator 1), SRC-2, and SRC-3 after hormone binding. In this study, we investigated the molecular pathways used by the GR in cultured glial cells of the central and the peripheral nervous systems, astrocytes and Schwann cells (MSC80 cells), respectively. We performed functional studies based on transient transfection of a minimal glucocorticoid-sensitive reporter gene into the glial cells to test the influence of overexpression or selective inhibition by short interfering RNA of the three p160 coactivator family members on GR transactivation. We demonstrate that, depending on the glial cell type, GR differentially recruits p160 family members: in Schwann cells, GR recruited SRC-1a, SRC-1e, or SRC-3, whereas in astrocytes, SRC-1e and SRC-2, and to a lesser extent SRC-3, were active toward GR signaling. The C-terminal nuclear receptor-interacting domain of SRC-1a participates in its exclusion from the GR transcriptional complex in astrocytes. Immunolocalization experiments revealed a cell-specific intracellular distribution of the p160s, which was dependent on the duration of the hormonal induction. For example, within astrocytes, SRC-1 and SRC-2 were mainly nuclear, whereas SRC-3 unexpectedly localized to the lumen of the Golgi apparatus. In contrast, in Schwann cells, SRC-1 showed a nucleocytoplasmic shuttling depending on hormonal stimulation, whereas SRC-2 remained strictly nuclear and SRC-3 remained predominantly cytoplasmic. Altogether, these results highlight the cell specificity and the time dependence of p160s recruitment by the activated GR in glial cells, revealing the complexity of GR-p160 assembly in the nervous system.
Motility and growth of human bone-marrow mesenchymal stem cells during ex vivo expansion in autologous serum
Authors: Kobayashi T. , Watanabe H. , Yanagawa T. , Tsutsumi S. , Kayakabe M. , Shinozaki T. , Higuchi H. , Takagishi K.
Published: September 2005

Human bone-marrow mesenchymal stem cells have an important role in the repair of musculoskeletal tissues by migrating from the bone marrow into the injured site and undergoing differentiation. We investigated the use of autologous human serum as a substitute for fetal bovine serum in the ex vivo expansion medium to avoid the transmission of dangerous transfectants during clinical reconstruction procedures.

Autologous human serum was as effective in stimulating growth of bone-marrow stem cells as fetal bovine serum. Furthermore, medium supplemented with autologous human serum was more effective in promoting motility than medium with fetal bovine serum in all cases. Addition of B-fibroblast growth factor to medium with human serum stimulated growth, but not motility. Our results suggest that autologous human serum may provide sufficient ex vivo expansion of human bone-marrow mesenchymal stem cells possessing multidifferentiation potential and may be better than fetal bovine serum in preserving high motility.
Results of open arthrolysis for the treatment of stiffness after total knee replacement
Authors: Hutchinson J. R. M. , Parish E. N. , Cross M. J.
Published: September 2005

Stiffness is an uncommon but potentially debilitating complication following total knee replacement (TKR). The treatment of this condition remains difficult and controversial. We present the results of 13 patients who underwent open arthrolysis for stiffness. The mean time between TKR and arthrolysis was 14 months. The mean follow-up was 7.2 years (2 to 10). The mean range of movement prior to arthrolysis was 55°. This increased to 91°, six months after arthrolysis (p < 0.005). The improved range of movement was maintained during the follow-up period. No patient has required revision of their components. We have found arthrolysis to be a useful and successful approach to post-TKR stiffness.