bluuebunny/crossref_metadata_2025 huggingface dataset:
Sclerostin in Mineralized Matrices and van Buchem Disease
Authors: van Bezooijen R.L. , Bronckers A.L. , Gortzak R.A. , Hogendoorn P.C.W. , van der Wee-Pals L. , Balemans W. , Oostenbroek H.J. , Van Hul W. , Hamersma H. , Dikkers F.G. , Hamdy N.A.T. , Papapoulos S.E. , Löwik C.W.G.M.
Published: July 2009

Sclerostin is an inhibitor of bone formation expressed by osteocytes. We hypothesized that sclerostin is expressed by cells of the same origin and also embedded within mineralized matrices. In this study, we analyzed (a) sclerostin expression using immunohistochemistry, (b) whether the genomic defect in individuals with van Buchem disease (VBD) was associated with the absence of sclerostin expression, and (c) whether this was associated with hypercementosis. Sclerostin was expressed by cementocytes in mouse and human teeth and by mineralized hypertrophic chondrocytes in the human growth plate. In individuals with VBD, sclerostin expression was absent or strongly decreased in osteocytes and cementocytes. This was associated with increased bone formation, but no overt changes in cementum thickness. In conclusion, sclerostin is expressed by all 3 terminally differentiated cell types embedded within mineralized matrices: osteocytes, cementocytes, and hypertrophic chondrocytes.
The Outreach of Dialogue
Authors: Friedman Maurice
Published: July 2009

This talk, which is a lightly edited transcription of an award address, summarizes the author’s latest thinking about the value and practical application of Buber’s dialogical approach to relationships, both for individuals and society at large.
Is Community-Based Participatory Research Postnormal Science?
Authors: Bidwell David
Published: July 2009

Conventional, positivist science is not well suited for addressing the contemporary risk landscape. To address high-uncertainty, high-stakes risks, Funtowicz and Ravetz have called for a postnormal science. Two key characteristics of postnormal science are the involvement of an extended peer community and the deliberation of extended facts. The health research community has responded to the shortcomings of normal science with approaches to field research, known collectively as community-based participatory research (CBPR). A review of case literature shows that although CBPR is not inherently postnormal, it can be friendly to a postnormal approach. A postnormal CBPR practice would rely more heavily on a deliberative process, which engages a broad range of expertise, including experts in normal science, in decisions about data collection, analysis, and actions.
National Biobanks: Clinical Labor, Risk Production, and the Creation of Biovalue
Authors: Mitchell Robert , Waldby Catherine
Published: July 2009

The development of genomics has dramatically expanded the scope of genetic research, and collections of genetic biosamples have proliferated in countries with active genomics research programs. In this essay, we consider a particular kind of collection, national biobanks. National biobanks are often presented by advocates as an economic ‘‘resource’’ that will be used by both basic researchers and academic biologists, as well as by pharmaceutical diagnostic and clinical genomics companies. Although national biobanks have been the subject of intense interest in recent social science literature, most prior work on this topic focuses either on bioethical issues related to biobanks, such as the question of informed consent, or on the possibilities for scientific citizenship that they make possible. We emphasize, by contrast, the economic aspect of biobanks, focusing specifically on the way in which national biobanks create biovalue. Our emphasis on the economic aspect of biobanks allows us to recognize the importance of what we call clinical labor—that is, the regularized, embodied work that members of the national population are expected to perform in their role as biobank participants—in the creation of biovalue through biobanks. Moreover, it allows us to understand how the technical way in which national biobanks link clinical labor to databases alters both medical and popular understandings of risk for common diseases and conditions.
Researching Strategy Practices: A Genealogical Social Theory Perspective
Authors: Rasche Andreas , Chia Robert
Published: July 2009

This paper explores the meaning and significance of the term `social practice' and its relation to strategy-as-practice research from the perspective of social theory. Although our remarks are also applicable to other practice-based discussions in management, we discuss strategy practices as a case in point and thus contribute to the strategy-as-practice literature in three ways. First, instead of simply accepting the existence of a unified `practice theory', we outline a genealogical analysis revealing the historical-contingent conditions of its creation. This analysis shows that social practices in general and strategy practices in particular can be approached from either a neo-structuralist and/or neo-interpretative perspective. Second, based on this theoretical argument, we discuss different characteristics of strategy practices and emphasize those aspects not yet fully considered by strategy-as-practice research (e.g. the physical nature of practices). Third, we show that, when studying strategy practices, given an understanding of the alternative theoretical approaches available, the practice of strategy research itself needs to be adjusted so as to accommodate a stronger emphasis on an ethnographic approach that is directed towards uncovering the contextual and hidden characteristics of strategy-making.
Representational Predicaments at Three Hong Kong Sites
Authors: Snell Robin Stanley , Wong May Mei-ling
Published: July 2009

Representational predicaments arise when a job incumbent believes that attributions and images assumed by dominant authorities unfavourably ignore, or disproportionately and unfavourably emphasize, aspects of the incumbent's own work and social identity. This is likely to happen when the incumbent does not have a close relationship with a dominant authority, and when power asymmetries give the former relatively little control over which aspects of their work and social identity are made visible or invisible to the latter. We draw on critical incident interviews from three organizations to illustrate a typology of six types of representational predicament: invasive spotlighting, idiosyncratic spotlighting, embedded background work, paradoxical social visibility, standardization of work processes, and standardization of work outputs. We analyse responses to representational predicaments according to whether they entailed exit, voice, loyalty, or neglect. Incumbents tended to respond with loyalty if they felt able and willing to accommodate their work behaviour and/or social identity to the dominant representations, and if there were sufficient compensatory factors, such as intrinsic rewards from the work or solidarity with colleagues. Exit or neglect appeared to reflect the belief that it was impossible to accommodate. Power asymmetries appeared to deter voice. Individual employees with a close and cordial working relationship with a member of a dominant authority group, or who were relationally networked to one, appeared not to experience representational predicaments.
Bridging the Gap?
Authors: Salter Colin
Published: July 2009

The political context of the conversion of the Historic Tramway Bridge, adjacent to Sandon Point in Bulli (NSW, Australia), and how this was exploited to serve predetermined ends, illustrates that technologies can be designed to have particular social (and political) effects. Through reflection on this relatively small engineering project, this paper provides a concrete example of what Langdon Winner (1986) attempted to expose in his (in)famous and contested analysis of “the low bridges of Robert Moses”. The means through which this project reflected specific political and economic interests, and how such interests were largely unmarked and unquestioned, locate issues of concerns for the broader public and the engineering profession as a whole. In reflecting on the Tramway Bridge conversion, consideration is given to how far the project of creating the new engineer has progressed in seeking to address the great social, economic, environmental and cultural challenges of our time (Johnson, 1996).
Goal Ambiguity, Work Complexity, and Work Routineness in Federal Agencies
Authors: Jung Wook Lee  , Rainey Hal G. , Young Han Chun
Published: July 2009

Prominent scholars have observed that public organizations and policies tend to have ambiguous goals, but research on these assertions is scarce. This analysis adds to a recent set of studies that developed measures of organizational goal ambiguity and found that federal agencies vary on these measures due to differences in funding patterns and other variables. This study adds variables representing the nature of the agencies’ work—the routineness and complexity of their technologies and tasks. As hypothesized, complexity relates positively to one dimension of goal ambiguity, “directive goal ambiguity.” Routineness of tasks relates negatively to “evaluative goal ambiguity,” whereas complexity relates positively to it. These results further evince the value of the measures of goal ambiguity and their potential contribution to analysis of variations among government agencies, and to such issues as the applicability of various managerial reforms to different agencies. The results also contribute indicators of organizational task complexity and routineness that researchers can use to take into account the type of work that an agency does, in analyzing government agencies and differences among them.
Microbial methane oxidation processes and technologies for mitigation of landfill gas emissions
Authors: Scheutz Charlotte , Kjeldsen Peter , Bogner Jean E. , De Visscher Alex , Gebert Julia , Hilger Helene A. , Huber-Humer Marion , Spokas Kurt
Published: July 2009

Landfill gas containing methane is produced by anaerobic degradation of organic waste. Methane is a strong greenhouse gas and landfills are one of the major anthropogenic sources of atmospheric methane. Landfill methane may be oxidized by methanotrophic microorganisms in soils or waste materials utilizing oxygen that diffuses into the cover layer from the atmosphere. The methane oxidation process, which is governed by several environmental factors, can be exploited in engineered systems developed for methane emission mitigation. Mathematical models that account for methane oxidation can be used to predict methane emissions from landfills. Additional research and technology development is needed before methane mitigation technologies utilizing microbial methane oxidation processes can become commercially viable and widely deployed.
Black—White Disparities in Disability Among Older Americans
Authors: Fuller-Thomson Esme , Nuru-Jeter A. , Minkler Meredith , Guralnik Jack M.
Published: July 2009

Objectives: To explore the impact of adjusting for income and education on disparities in functional limitations and limitations in activities of daily living (ADLs) between Black and White older Americans. Method: Data from the 2003 American Community Survey were used to examine the associations of education and income, stratified by race and gender, with functional limitations and ADLs, in a sample of 16,870 non-Hispanic Blacks and 186,086 non-Hispanic Whites aged 55 to 74. Sequential logistic regressions were used to examine the relative contribution of income and education to racial disparities. Results: Ninety percent of the Black—White difference in disability rates for men and 75% of the difference for women aged 55 to 64 were explained by income and education. Discussion: The greatly elevated risk of disability among Blacks aged 55 to 74 is largely explained by differences in socioeconomic status. Reductions in Black—White health disparities require a better understanding of the mechanisms whereby lower income and education are associated with functional outcomes in older persons.
The Vote of Acute Medical Inpatients
Authors: Bosquet Antoine , Medjkane Amar , Voitel-Warneke Dorit , Vinceneux Philippe , Mahé Isabelle
Published: July 2009

Objective: There may be ethical issues associated with allowing certain inpatients to vote as some may be cognitively impaired. During the 2007 elections in France, we conducted a prospective observational study on voting among hospitalized patients. Method: Patients hospitalized in an Internal Medicine and Geriatric Department on election day were included. The primary outcome was the turnout among registered inpatients, and secondary outcomes were Mini-Mental State Examination (MMSE) scores and reasons for abstention. Results: Of 142 inpatients (mean age 73 years), 84 were eligible to vote, and 22 actually voted (turnout 25.2%). Among the voters, 23% had an MMSE score of less than 12; 58% of abstentions were procedure-related. Discussion: In our study, some inpatients did not vote as a result of procedural issues. When patients with severe cognitive impairment vote, there is a potential risk of vote diversion. Voting procedures should be improved to give inpatients easier access to the ballot while protecting them from the risk of fraud.
Persuasion in Fundraising Letters: An Interdisciplinary Study
Authors: Goering Elizabeth , Connor Ulla M. , Nagelhout Ed , Steinberg Richard
Published: July 2009

In this article, we report experimental evidence on the effectiveness of several techniques of persuasion commonly utilized in direct-mail solicitation. The study is built on theory-based, descriptive models of fundraising discourse and on comparisons of recommended and actual practices related to three dimensions of persuasion: rhetorical, visual, and linguistic. The specific rhetorical variable included is persuasive appeal (rational, credibility, or affective). The visual variable selected for the study is the presence or absence of bulleted lists, and the linguistic variable included is readability or the complexity of exposition. Participants were presented with pairs of fictive direct-mail appeals from imaginary universities that differ in these dimensions and asked to allocate a hypothetical US$100 across each pair. Results suggest that letters utilizing credibility appeals and letters written at a high level of readability produce the highest donations.
The Whole Story of NGO Mandate Change: The Peacebuilding Work of World Vision, Catholic Relief Services, and Mennonite Central Committee
Authors: Gerstbauer Loramy Conradi
Published: July 2009

Relief and development NGOs have been recognized for their role in peacebuilding in conflicts. The literature tends to focus on external forces, such as the changing nature of conflict and state funding, as an impetus for these NGOs to adopt peacebuilding mandates. However, this is not the complete story of mandate change. Typical explanations and theories used to explain the adoption of peacebuilding underemphasize the autonomy of NGOs and internal factors leading to mandate change. The cases of World Vision, Catholic Relief Services, and Mennonite Central Committee are used to reveal the overlooked factors contributing to adoption of peacebuilding mandates, including agency leadership and the importance of the compatibility of peacebuilding with the NGOs’ primary missions as faith-based relief and development NGOs. Why NGOs engage in peacebuilding is an important question given the critiques they have received over their competency for the task.
Doing Therapy Out of My Purse
Authors: Webb-Henderson Scarlet
Published: July 2009

The practice of speech—language pathology in the home health care setting is challenging, requiring complex organization of information, deductive and diagnostic skill, and grasp of functional outcomes targeting the patient’s goals. Strong interpersonal communication ability is needed to communicate with the patient, family, and team members in the home care environment. This article discusses the need for on the spot training and adapting care to the home care setting. This author discusses how their orientation, education, and training formed the foundation for practice, but the reality provided the true experience for delivery of speech pathology services within the patient’s home.
Audio Watermarking Based on Advanced Wigner Distribution and Important Frequency Peaks
Authors: Do Van Tuan  , Chong Ui-Pil
Published: July 2009

An algorithm in which a multi-bit watermark is embedded into the important frequency peaks of an audio file is presented. In this algorithm, an advanced Wigner distribution method is used to estimate the most significant frequency band of the audio file. This method is based on the short-time Fourier transform (STFT) and the Wigner distribution methods, and has advantages over other methods. The important frequency peaks are selected from the most significant frequency band. Once broadcasted, an audio file is subject to many attacks such as compression and quantization. However, the main feature of the audio signal is its important frequency peaks, which are invariant. We exploit this invariance to embed the multi-bit watermark into the important frequency peaks. The simulation results show that the proposed algorithm is robust to the strong attacks such as noise addition, filtering, re-sampling and MP3 compression.
An Approach for the Evaluation of Effective Elastic Properties of Honeycomb Cores by Finite Element Analysis of Sandwich Panels
Authors: Aydincak İlke , Kayran Altan
Published: July 2009

Different detailed finite element model alternatives are developed to come up with the most reliable finite element model of the sandwich panel, with the actual honeycomb core geometry, to evaluate the existing equivalent continuum models of aluminum honeycomb cores. Finite element models of sandwich panels with effective elastic constants of the honeycomb core are generated based on the existing continuum models of the honeycomb core. The evaluation of the effective elastic constants of honeycomb cores is based on the comparison of the total reaction forces, calculated by both finite element models, on the supported faces of sandwich panels due to different in-plane and out-of-plane uniform input displacements applied to the faces of the panels. The results show that the reliability of the individual in-plane and out-of-plane effective elastic constants of the existing continuum models of the honeycomb cores can be successfully evaluated based on the comparative study.
Foetal personhood and representations of the absent child in pregnancy loss memorialization
Authors: Keane Helen
Published: July 2009

Because mourning and memorializing a miscarriage seems to imply acceptance of foetal personhood, feminists have been reluctant to address the often traumatic but common experience of pregnancy loss. Feminist anthropologists of reproduction have argued that adopting a view of personhood as constructed and negotiated, rather than inherent, solves this dilemma and enables the development of a feminist discourse of pregnancy loss. This article aims to make a critical contribution to such a discourse by analysing representations of lost babies and children in online pregnancy loss memorials. It focuses on two genres of representation, idealized angels and medical ultrasound images. It argues that the dominance of a biological model of personhood limits the ability of both forms of representation to secure the status of memorialized children as real. However, pregnancy loss memorials do communicate the anguish of grieving parents, in part through the very unrepresentability of their loss. They also provoke a questioning of the taken for granted subject of `the child', whether imagined or real, absent or present.
Seeing and knowing
Authors: Palmer Julie
Published: July 2009

Foetal images have been central to the medicalized abortion debate since the 1960s. Feminists have extensively analysed such pictures, arguing that the pregnant body is separated from the foetus and erased from view, and that the rights of women and foetuses are set in opposition. In this article I introduce the latest image in this debate, the 3D sonogram, which is widely reported as new evidence for a reduction in the gestational time limit. Through close analysis of two examples, I argue that the rhetorical use of these images can be characterized by a conflation of knowing with seeing. With the new clarity of sonograms to the untrained eye, image producers are legitimated by a discourse of public information and concerned citizens are called upon to exercise their rights to see/know. For feminist theory, this implies the need for continued analysis of the epistemology of foetal images and renewed focus on the subject position of the viewer.
Popular culture and reproductive politics
Authors: Latimer Heather
Published: July 2009

This article takes the recent rash of unwanted pregnancy films, such as 2007's Juno and Knocked Up, as an opportunity to revisit Margaret Atwood's influential 1985 novel, The Handmaid's Tale. It argues that the novel deals with the same themes the films evoke during a pivotal time for reproductive politics, generally, and abortion politics, specifically. It argues that the novel offers several lessons and warnings on the nature of reproductive politics that are still relevant today. These lessons are connected to how and why these films are able to `make sense' in naturalizing their heroines' choice to keep an unwanted pregnancy.
Refusing disembodiment
Authors: Hanafin Patrick
Published: July 2009

Employing insights from Italian sexual difference theory on law and rights, this article examines how both the text of the Italian Abortion Law of 1978 and its operation reveal the contradictions within liberal rights discourse on reproductive freedom. The Act itself contains traces of both Roman Catholic and liberal pluralist worldviews and has, since its introduction, been the site of conflict over competing notions of citizenship and legal identity. This article explores the impact of the Act's paradoxical nature on its operation against the background of the complex debates within the different strands of feminist theory in Italy over the question of reproductive freedom.
The OECD's Discourse on the Reconciliation of Work and Family Life
Authors: Mahon Rianne
Published: July 2009

The Organisation for Economic Co-operation and Development (OECD) can be considered a pioneer of soft forms of transnational governance. For some it has used its `soft powers' to contribute to the construction of a neoliberal world order, however Neoliberal solutions are not the only ones it has to offer, especially in the area of social policy. What accounts for the ability of one unit (the Directorate on Employment, Labour and Social Affairs, DELSA) of the Organization to fashion and enunciate such different prescriptions from that prescribed by the dominant Economic Department? In this article I suggest that development of the concept of `organizational discourse(s)' offers some insight. I develop the concept and use it to compare two moments in the formation of the OECD's discourses on the `reconciliation of work and family life', an area of social policy that has grown in importance as a result of women's rising labour force participation rates, the increase in the number of lone parent families, and the demographic challenges posed by falling fertility/ageing of OECD societies.
Global Social Policy and International Organizations
Authors: Seckinelgin Hakan
Published: July 2009

This article analyses the inequality of access of people to the international policy process. It is argued that this presents an important challenge for global social policy considerations. The work explores the question of how these inequalities are produced, maintained and reproduced by looking at the relationship between international organizations and non-governmental organizations. As an entry point discussions of social exclusion are introduced and then linked to the concept of durable inequality. This move provides a way of looking at how conditions of exclusion are maintained and reproduced over time. Two instances of IO/NGO relationship are looked at as illustrative examples. The first case looks at the processes whereby international gay and lesbian organizations are trying to obtain formal NGO consultative status with the United Nations by applying to the UN's Economic and Social Council (ECOSOC). The second case looks at the role of NGOs within the formal structure of the Joint United Nations Programme on HIV/AIDS (UNAIDS), which has created a new perspective for international organizations.
Social Security and the Global Socio-economic Floor
Authors: Van Ginneken Wouter
Published: July 2009

This article shows that the commitment towards economic and social human rights, including the right to social security, will provide a strong force towards realizing the global socio-economic floor. The right to social security has become realizable in a growing number of countries that have focused on the extension of social security coverage. This article shows that a global social security floor is affordable, including in low-income countries, with the initial support from the international community. The article then explores how a global socio-economic floor could be better implemented through a human rights-based approach, and it reviews some of the recent initiatives undertaken by the UN Human Rights Council. It suggests a number of steps to improve the effective implementation of the human rights-based approach. It concludes that such an approach can help achieve the Millennium Development Goals, and provide the framework for global policies for development and poverty eradication beyond 2015.
Identification of cancer stem cells in a Tax-transgenic (Tax-Tg) mouse model of adult T-cell leukemia/lymphoma
Authors: Yamazaki Jumpei , Mizukami Takuo , Takizawa Kazuya , Kuramitsu Madoka , Momose Haruka , Masumi Atsuko , Ami Yasushi , Hasegawa Hideki , Hall William W. , Tsujimoto Hajime , Hamaguchi Isao , Yamaguchi Kazunari
Published: July 2009

Adult T-cell leukemia/lymphoma (ATL) is a malignant lymphoproliferative disorder caused by HTLV-I infection. In ATL, chemotherapeutic responses are generally poor, which has suggested the existence of chemotherapy-resistant cancer stem cells (CSCs). To identify CSC candidates in ATL, we have focused on a Tax transgenic mouse (Tax-Tg) model, which reproduces ATL-like disease both in Tax-Tg animals and also after transfer of Tax-Tg splenic lymphomatous cells (SLCs) to nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. Using a limiting dilution transplantation, it was estimated that one CSC existed per 104 SLCs (0.01%). In agreement with this, we have successfully identified candidate CSCs in a side population (0.06%), which overlapped with a minor population of CD38−/CD71−/CD117+ cells (0.03%). Whereas lymphoma did not develop after transplantation of 102 SLCs, 102 CSCs could consistently regenerate the original lymphoma. In addition, lymphoma and CSCs could also be demonstrated in the bone marrow and CD117+ CSCs were observed in both osteoblastic and vascular niches. In the CSCs, Tax, Notch1, and Bmi1 expression was down-regulated, suggesting that the CSCs were derived from Pro-T cells or early hematopoietic progenitor cells. Taken together, our data demonstrate that CSCs certainly exist and have the potential to regenerate lymphoma in our mouse model.
A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425
Authors: Schwartz Cindy L. , Constine Louis S. , Villaluna Doojduen , London Wendy B. , Hutchison Robert E. , Sposto Richard , Lipshultz Steven E. , Turner Charles S. , deAlarcon Pedro A. , Chauvenet Allen
Published: July 2009

Current treatment strategies for Hodgkin lymphoma result in excellent survival but often confer significant long-term toxicity. We designed ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) to (1) enhance treatment efficacy by dose-dense drug delivery and (2) reduce risk of long-term sequelae by response-based reduction of cumulative chemotherapy. Efficient induction of early response by dose-dense drug delivery supported an early-response–adapted therapeutic paradigm. The 216 eligible patients were younger than 22 years with intermediate- or high-risk Hodgkin lymphoma. ABVE-PC was administered every 21 days. Rapid early responders (RERs) to 3 ABVE-PC cycles received 21 Gy radiation to involved regions; RER was documented in 63% of patients. Slow early responders received 2 additional ABVE-PC cycles before 21 Gy radiation. Five-year event-free-survival was 84%: 86% for the RER and 83% for the slow early responders (P = .85). Only 1% of patients had progressive disease. Five-year overall survival was 95%. With this regimen, cumulative doses of alkylators, anthracyclines, and epipodophyllotoxins are below thresholds usually associated with significant long-term toxicity. ABVE-PC is a dose-dense regimen that provides outstanding event-free survival/overall survival with short duration, early-response–adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00005578.
A nonfibrin macromolecular cofactor for tPA-mediated plasmin generation following cellular injury
Authors: Samson Andre L. , Borg Rachael J. , Niego Be'eri , Wong Connie H. Y. , Crack Peter J. , Yongqing Tang , Medcalf Robert L.
Published: July 2009

Tissue-type plasminogen activator (tPA) is an extracellular protease that converts plasminogen into plasmin. For tPA to generate plasmin under biologic conditions, a cofactor must first bring tPA and plasminogen into physical proximity. Fibrin provides this cofactor for tPA-mediated plasmin generation in blood. Despite being naturally devoid of fibrin(ogen), tPA-mediated plasmin formation also occurs in the brain. The fibrin-like cofactor(s) that facilitates plasmin formation in the injured brain has remained unknown. Here we show that protein aggregates formed during neuronal injury provide a macromolecular, nonfibrin cofactor that promotes tPA-mediated plasmin formation and subsequent cell breakdown. The binding of plasminogen and tPA to these protein aggregates occurs via distinct mechanisms. Importantly, nonneuronal cell types also exhibit this cofactor effect upon injury, indicating a general phenomenon. This novel cofactor identified in nonviable cells has ramifications for ischemic stroke where tPA is used clinically and where plasmin activity within the injured brain is unwanted. A means of selectively inhibiting the binding of tPA to nonviable cells while preserving its association with fibrin may be of benefit for the treatment of ischemic stroke.
miR-34a contributes to megakaryocytic differentiation of K562 cells independently of p53
Authors: Navarro Francisco , Gutman David , Meire Eti , Cáceres Mario , Rigoutsos Isidore , Bentwich Zvi , Lieberman Judy
Published: July 2009

The role of miRNAs in regulating megakaryocyte differentiation was examined using bipotent K562 human leukemia cells. miR-34a is strongly up-regulated during phorbol ester–induced megakaryocyte differentiation, but not during hemin-induced erythrocyte differentiation. Enforced expression of miR-34a in K562 cells inhibits cell proliferation, induces cell-cycle arrest in G1 phase, and promotes megakaryocyte differentiation as measured by CD41 induction. miR-34a expression is also up-regulated during thrombopoietin-induced differentiation of CD34+ hematopoietic precursors, and its enforced expression in these cells significantly increases the number of megakaryocyte colonies. miR-34a directly regulates expression of MYB, facilitating megakaryocyte differentiation, and of CDK4 and CDK6, to inhibit the G1/S transition. However, these miR-34a target genes are down-regulated rapidly after inducing megakaryocyte differentiation before miR-34a is induced. This suggests that miR-34a is not responsible for the initial down-regulation but may contribute to maintaining their suppression later on. Previous studies have implicated miR-34a as a tumor suppressor gene whose transcription is activated by p53. However, in p53-null K562 cells, phorbol esters induce miR-34a expression independently of p53 by activating an alternative phorbol ester-responsive promoter to produce a longer pri-miR-34a transcript.
Minimal residual disease levels assessed by NPM1 mutation–specific RQ-PCR provide important prognostic information in AML
Authors: Schnittger Susanne , Kern Wolfgang , Tschulik Claudia , Weiss Tamara , Dicker Frank , Falini Brunangelo , Haferlach Claudia , Haferlach Torsten
Published: July 2009

Nucleophosmin (NPM1)–mutated acute myeloid leukemia (AML), which is recognized as a provisional entity in the World Health Organization 2008 classification of myeloid neoplasms, accounts for 30% of AML. We analyzed 1227 diagnostic and follow-up samples in 252 NPM1-mutated AML patients with 17 different NPM1 mutation–specific real-time quantitative polymerase chain reaction (RQ-PCR) assays. Paired diagnostic/relapse samples of 84 patients revealed stable NPM1 mutations in all cases, suggesting that they are pathogenetically early events and thus applicable for minimal residual disease detection. A total of 47 relapses were predictable because of an NPM1 mutation level (%NPM1/ABL1) increase of at least 1 log or in 15 cases because of NPM1 mutation levels not decreasing less than 3 log ranges. A high prognostic value of NPM1 levels was shown for 4 different intervals after therapy was initiated. Furthermore, thresholds of 0.1 and 0.01%NPM1/ABL1 during/after treatment discriminated between prognostic subgroups. Univariate analyses, including age, white blood cell count, blast count, CD34 positivity, FLT3 mutations status, FAB type, karyotype, NPM1 mutation type, and pretreatment NPM1 mutational level, showed that, besides NPM1 mutation level, only age and FLT3-LM mutation status were prognostically significant for EFS. Multivariate analysis, including age, FLT3-LM status, and NPM1 mutation level at different time points, demonstrated that NPM1 level was the most relevant prognostic factor during first-line treatment. Similar results were obtained in patients undergoing second-line chemotherapy or allogeneic stem cell transplantation.
Tricyclic pyrone compounds prevent aggregation and reverse cellular phenotypes caused by expression of mutant huntingtin protein in striatal neurons
Authors: Trushina Eugenia , Rana Sandeep , McMurray Cynthia T , Hua Duy H
Published: July 2009

Background

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion mutation in the coding region of a novel gene. The mechanism of HD is unknown. Most data suggest that polyglutamine-mediated aggregation associated with expression of mutant huntingtin protein (mhtt) contributes to the pathology. However, recent studies have identified early cellular dysfunctions that preclude aggregate formation. Suppression of aggregation is accepted as one of the markers of successful therapeutic approaches. Previously, we demonstrated that tricyclic pyrone (TP) compounds efficiently inhibited formation of amyloid-β (Aβ) aggregates in cell and mouse models representing Alzheimer's Disease (AD). In the present study, we aimed to determine whether TP compounds could prevent aggregation and restore early cellular defects in primary embryonic striatal neurons from animal model representing HD.

Results

TP compounds effectively inhibit aggregation caused by mhtt in neurons and glial cells. Treatment with TP compounds also alleviated cholesterol accumulation and restored clathrin-independent endocytosis in HD neurons.

Conclusion

We have found that TP compounds not only blocked mhtt-induced aggregation, but also alleviated early cellular dysfunctions that preclude aggregate formation. Our data suggest TP molecules may be used as lead compounds for prevention or treatment of multiple neurodegenerative diseases including HD and AD.
Optimising corticosteroid injection for lateral epicondylalgia with the addition of physiotherapy: A protocol for a randomised control trial with placebo comparison
Authors: Coombes Brooke K , Bisset Leanne , Connelly Luke B , Brooks Peter , Vicenzino Bill
Published: July 2009

Background

Corticosteroid injection and physiotherapy are two commonly prescribed interventions for management of lateral epicondylalgia. Corticosteroid injections are the most clinically efficacious in the short term but are associated with high recurrence rates and delayed recovery, while physiotherapy is similar to injections at 6 weeks but with significantly lower recurrence rates. Whilst practitioners frequently recommend combining physiotherapy and injection to overcome harmful effects and improve outcomes, study of the benefits of this combination of treatments is lacking. Clinicians are also faced with the paradox that the powerful anti-inflammatory corticosteroid injections work well, albeit in the short term, for a non-inflammatory condition like lateral epicondylalgia. Surprisingly, these injections have not been rigorously tested against placebo injections. This study primarily addresses both of these issues.

Methods

A randomised placebo-controlled clinical trial with a 2 × 2 factorial design will evaluate the clinical efficacy, cost-effectiveness and recurrence rates of adding physiotherapy to an injection. In addition, the clinical efficacy and adverse effects of corticosteroid injection beyond that of a placebo saline injection will be studied. 132 participants with a diagnosis of lateral epicondylalgia will be randomly assigned by concealed allocation to one of four treatment groups – corticosteroid injection, saline injection, corticosteroid injection with physiotherapy or saline injection with physiotherapy. Physiotherapy will comprise 8 sessions of elbow manipulation and exercise over an 8 week period. Blinded follow-up assessments will be conducted at baseline, 4, 8, 12, 26 and 52 weeks after randomisation. The primary outcome will be a participant rating of global improvement, from which measures of success and recurrence will be derived. Analyses will be conducted on an intention-to-treat basis using linear mixed and logistic regression models. Healthcare costs will be collected from a societal perspective, and along with willingness-to-pay and quality of life data will facilitate cost-effectiveness and cost-benefit analyses.

Conclusion

This trial will utilise high quality trial methodologies in accordance with CONSORT guidelines. Findings from this study will assist in the development of evidence based practice recommendations and potentially the optimisation of resource allocation for rehabilitating lateral epicondylalgia.

Trial registration

Australian New Zealand Clinical Trials Register ACTRN12609000051246
Comparison of different methods to obtain and store liver biopsies for molecular and histological research
Authors: Hoffmann Gaby , Ijzer Jooske , Brinkhof Bas , Schotanus Baukje A , van den Ingh Ted SGAM , Penning Louis C , Rothuizen Jan
Published: July 2009

Background

To minimize the necessary number of biopsies for molecular and histological research we evaluated different sampling techniques, fixation methods, and storage procedures for canine liver tissue. For addressing the aim, three biopsy techniques (wedge biopsy, Menghini, True-cut), four storage methods for retrieval of RNA (snap freezing, RNAlater, Boonfix, RLT-buffer), two RNA isolation procedures (Trizol and RNAeasy), and three different fixation protocols for histological studies (10% buffered formalin, RNAlater, Boonfix) were compared. Histological evaluation was based on hematoxylin-eosin (HE) and reticulin (fibrogenesis) staining, and rubeanic acid and rhodanine stains for copper. Immunohistochemical evaluation was performed for cytokeratin-7 (K-7), multidrug resistance binding protein-2 (MRP-2) and Hepar-1.

Results

RNA quality was best guaranteed by the combination of a Menghini biopsy with NaCl, followed by RNAlater preservation and RNAeasy mini kit extraction. These results were confirmed by quantitative RT-PCR testing. Reliable histological assessment for copper proved only possible in formalin fixed liver tissue. Short formalin fixation (1–4 hrs) improved immunohistochemical reactivity and preservation of good morphology in small liver biopsies.

Conclusion

At least two biopsies (RNAlater and formalin) are needed. Since human and canine liver diseases are highly comparable, it is conceivable that the protocols described here can be easily translated into the human biomedical field.
Erythropoietin improves operant conditioning and stability of cognitive performance in mice
Authors: El-Kordi Ahmed , Radyushkin Konstantin , Ehrenreich Hannelore
Published: July 2009

Background

Executive functions, learning and attention are imperative facets of cognitive performance, affected in many neuropsychiatric disorders. Recently, we have shown that recombinant human erythropoietin improves cognitive functions in patients with chronic schizophrenia, and that it leads in healthy mice to enhanced hippocampal long-term potentiation, an electrophysiological correlate of learning and memory. To create an experimental basis for further mechanistic insight into erythropoietin-modulated cognitive processes, we employed the Five Choice Serial Reaction Time Task. This procedure allows the study of the effects of erythropoietin on discrete processes of learning and attention in a sequential fashion.

Results

Male mice were treated for 3 weeks with erythropoietin (5,000 IU/kg) versus placebo intraperitoneally every other day, beginning at postnatal day 28. After termination of treatment, mice were started on the Five Choice Serial Reaction Time Task, with daily training and testing extending to about 3 months.

Overall, a significantly higher proportion of erythropoietin-treated mice finished the task, that is, reached the criteria of adequately reacting to a 1.0 sec flash light out of five arbitrarily appearing choices. During acquisition of this capability, that is, over almost all sequential training phases, learning readouts (magazine training, operant and discriminant learning, stability of performance) were superior in erythropoietin-treated versus control mice.

Conclusion

Early erythropoietin treatment leads to lasting improvement of cognitive performance in healthy mice. This finding should be exploited in novel treatment strategies for brain diseases.
Improvement of a real-time RT-PCR assay for the detection of enterovirus RNA
Authors: Piqueur Marian AC , Verstrepen Walter A , Bruynseels Peggy , Mertens An H
Published: July 2009

We describe an improvement of an earlier reported real-time RT-PCR assay for the detection of enterovirus RNA, based on the 5' exonuclease digestion of a dual-labeled fluorogenic probe by Taq DNA polymerase. A different extraction method, real-time RT-PCR instrument and primer set were evaluated. Our data show that the optimized assay yields a higher sensitivity and reproducibility and resulted in a significant reduced hands-on time per sample.
Morphogen-defined patterning of Escherichia coli enabled by an externally tunable band-pass filter
Authors: Sohka Takayuki , Heins Richard A , Ostermeier Marc
Published: July 2009

Background

Gradients of morphogens pattern cell fate – a phenomenon that is especially important during development. A simple model system for studying how morphogens pattern cell behavior would overcome difficulties inherent in the study of natural morphogens in vivo. A synthetic biology approach to building such a system is attractive.

Results

Using an externally-tunable band-pass filter paradigm, we engineered Escherichia coli cells to function as a model system for the study of how multiple morphogens can pattern cell behavior. We demonstrate how our system exhibits behavior such as morphogen crosstalk and how the cells' growth and fluorescence can be patterned in a number of complex patterns. We extend our cell patterning from 2D cultures on the surface of plates to 3D cultures in soft agarose medium.

Conclusion

Our system offers a convenient, well-defined model system for fundamental studies on how multiple morphogen gradients can affect cell fate and lead to pattern formation. Our design principles could be applied to eukaryotic cells to develop other models systems for studying development or for enabling the patterning of cells for applications such as tissue engineering and biomaterials.
Negative association of the chemokine receptor CCR5 d32 polymorphism with systemic inflammatory response, extra-articular symptoms and joint erosion in rheumatoid arthritis
Authors: Rossol Manuela , Pierer Matthias , Arnold Sybille , Keyßer Gernot , Burkhardt Harald , Baerwald Christoph , Wagner Ulf
Published: July 2009

Introduction

Chemokines and their receptors control immune cell migration during infections as well as in autoimmune responses. A 32 bp deletion in the gene of the chemokine receptor CCR5 confers protection against HIV infection, but has also been reported to decrease susceptibility to rheumatoid arthritis (RA). The influence of this deletion variant on the clinical course of this autoimmune disease was investigated.

Methods

Genotyping for CCR5d32 was performed by PCR and subsequent electrophoretic fragment length determination. For the clinical analysis, the following extra-articular manifestations of RA were documented by the rheumatologist following the patient: presence of rheumatoid nodules, major organ vasculitis, pulmonary fibrosis, serositis or a Raynaud's syndrome. All documented CRP levels were analyzed retrospectively, and the last available hand and feet radiographs were analyzed with regards to the presence or absence of erosive disease.

Results

Analysis of the CCR5 polymorphism in 503 RA patients and in 459 age-matched healthy controls revealed a significantly decreased disease susceptibility for carriers of the CCR5d32 deletion (Odds ratio 0.67, P = 0.0437). Within the RA patient cohort, CCR5d32 was significantly less frequent in patients with extra-articular manifestations compared with those with limited, articular disease (13.2% versus 22.8%, P = 0.0374). In addition, the deletion was associated with significantly lower average CRP levels over time (median 8.85 vs. median 14.1, P = 0.0041) and had a protective effect against the development of erosive disease (OR = 0.40, P = 0.0047). Intriguingly, homozygosity for the RA associated DNASE2 -1066 G allele had an additive effect on the disease susceptibility conferred by the wt allele of CCR5 (OR = 2.24, P = 0.0051 for carrier of both RA associated alleles)

Conclusions

The presence of CCR5d32 significantly influenced disease susceptibility to and clinical course of RA in a German study population. The protective effect of this deletion, which has been described to lead to a decreased receptor expression in heterozygous patients, underlines the importance of chemokines in the pathogenesis of RA.