bluuebunny/crossref_metadata_2025 huggingface dataset:
Does the human leukaemia differentiation factor fragment HLDF6 improve memory via brain DNA and protein synthesis?
Authors: Sewell Robert D. E. , Gruden Marina A. , Pache David M. , Storogeva Zinaida I. , Kostanyan Irina A. , Proshin Andrei T. , Yurasov Vasily V. , Sherstnev Vladimir V.
Published: November 2005

The novel human differentiating factor peptide fragment HLDF6 (Thr-Gly-Glu-Asn-His-Arg) was synthesized and purified. HLDF6 (0.1mg/kg i.p. but not 1mg/kg i.p.) improved not only long-term (24h) memory in adult rats in the water maze behavioural paradigm but also performance in the delayed matching-to-position (DMTP) task (0.3 and 1.0 but not 0.1mg/kg i.p). Hence, HLDF6 not only enhanced allocentric spatial learning and reference memory (water maze) but also improved temporal, spatial and working memory processes in the DMTP behavioural paradigm. Immunoreactivity blotting analysis of HLDF (the protein precursor of HLDF6) was performed and the following rank order of visual intensities from brain structures was noted: hippocampus cerebral cortex cerebellum hypothalamus striatum. Subsequently, we found that the highest absolute levels of HLDF were expressed in the hippocampus and cerebral cortex as detected by ELISA. We also demonstrated that HLDF6 enhanced [3H]-thymidine and [14C]-leucine incorporation into whole brain and hippocampal homogenates (maxima occurring within the range 10 12-10 6 M) suggesting that this hexapeptide promoted de novo DNA and protein biosynthesis. We discuss this data in terms of their implications for links with other integrative metabolic pathways involving immediate early gene activation which may underpin a potential application for HLDF6 in limiting memory impairments associated with neurodegenerative diseases.
Fatal poisoning with antipsychotic drugs, England and Wales 1993-2002
Authors: Griffiths C. , Flanagan R. J.
Published: November 2005

Prescription of atypical antipsychotics has increased in recent years. There have also been changes in the guidance on using older drugs, particularly the restriction in the use of thioridazine. We analysed deaths due to poisoning involving antipsychotics in England and Wales, 1993-2002, by age, sex, intent, and agents involved. We also studied antipsychotic prescribing in the community and poisoning deaths in England. Deaths attributed to adverse reactions in the course of normal treatment were not studied because these deaths are not classified as ‘poisonings’. The number of deaths involving antipsychotics increased from around 55 per year 1993-1998 to 74 in 2000, and then fell to 53 in 2002. Around 25% of deaths had a verdict of accidental death and in about 60% of deaths a verdict of suicide or an open verdict was recorded. There were no deaths involving thioridazine in 2002, following its removal from use in 2001. However, the number of deaths associated with atypicals, most notably olanzapine and clozapine, has increased. Age-specific death rates were highest in those aged 30-39 and 40-49 years, and were very low in those aged under 20 and 70 or over. Death rates in males were greater than in females. For many drugs the proportion mentions either alone or with ethanol, was 25-45%, but for clozapine and olanzapine such mentions totalled 65-69%. Deaths per million prescriptions (clozapine excluded) were highest for quetiapine (31.3 per million), chlorpromazine (29.4 per million) and thioridazine (15.5 per million).
Transient memory impairment after acute dose of 75mg 3.4-Methylene-dioxymethamphetamine
Authors: Kuypers Kim P. C. , Ramaekers Jan G.
Published: November 2005

A range of studies has indicated that users of 3.4-Methylene-dioxymethamphetamine (MDMA, ‘Ecstasy’) display cognitive deficits, particularly memory impairment, as compared to non-drug using controls. Yet it is difficult to determine whether these deficits are caused by MDMA or some other confounding factor, such as polydrug use. The present study was designed to establish the direct relation between MDMA and memory impairment under placebo-controlled conditions. Eighteen recreational MDMA users participated in a double blind, placebo controlled, 3-way crossover design. They were treated with placebo, MDMA 75mg and methylphenidate 20mg. Memory tests were conducted between 1.5-2h (intoxication phase) and between 25.5-26h (withdrawal phase) post dosing. Results showed that a single dose of MDMA caused impairment of immediate and delayed recall on a verbal learning task during the intoxication phase. However, there was no residual memory impairment during the withdrawal phase. Subjects reported more fatigue and less vigour, but no symptoms of depression during the withdrawal phase of MDMA treatment.

Methylphenidate did not affect memory or mood at any time of testing. A single dose of MDMA produces transient memory impairment.
Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology
Authors: Baldwin David S. , Anderson Ian M. , Nutt David J. , Bandelow Borwin , Bond A. , Davidson Jonathan R. T. , den Boer J. A. , Fineberg Naomi A. , Knapp Martin , Scott J. , Wittchen H. -U.
Published: November 2005

These British Association for Psychopharmacology guidelines cover the range and aims of treatment for anxiety disorders. They are based explicitly on the available evidence and are presented as recommendations to aid clinical decision making in primary and secondary medical care. They may also serve as a source of information for patients and their carers. The recommendations are presented together with a more detailed review of the available evidence. A consensus meeting involving experts in anxiety disorders reviewed the main subject areas and considered the strength of evidence and its clinical implications. The guidelines were constructed after extensive feedback from participants and interested parties. The strength of supporting evidence for recommendations was rated. The guidelines cover the diagnosis of anxiety disorders and key steps in clinical management, including acute treatment, relapse prevention and approaches for patients who do not respond to first-line treatments.
The Rise and Stall of Prison Privatization: An Integration of Policy Analysis Perspectives
Authors: Culp Richard F.
Published: November 2005

This article examines prison privatization policy in the United States from 1984 to the turn of the century by integrating several policy analysis perspectives. Kingdon's theory of multiple streams provides an overarching context, and elements of the advocacy coalition framework, the subgovernment perspective, and disjointed incrementalism explain steps along the way. The private prison industry expanded in the midst of rapidly increasing inmate populations and widespread federal court oversight of public prisons. Serious incidents in private prisons prompted the development of an extensive regulatory framework that essentially molded private prisons into mirror images of their public sector counterparts. By the turn of the 21st century, the incentive for privatization began to fade as prison population growth leveled off and federal court oversight of prisons declined. Concurrently, antiprivatization advocacy efforts gained strength, particularly within the faith-based community, limiting the prospect of broader expansion of prison privatization policy.
Reducing False Security Alarm Calls for Police Service: A Policy Research Note
Authors: Gilbertson Troy A.
Published: November 2005

False alarm calls are a substantial resource allocation problem for police administrators even though the issue tends not to be high profile. A panel design is utilized to describe how one municipal fine schedule affects the generation of false security alarm calls for police service by residential, commercial, and nonprofit property types. It was found that property type accounts for12% of the variation in annual false alarm generation and that, on average, false alarm production decreased substantially over time.
Empires of Law: Discipline and Resistance within the Transnational System
Authors: Goodale Mark
Published: November 2005

This article explores the idea that law has become newly constitutive in a postmodern transnational system in which modernity's classic polarities have become obscured, the discipline of late capitalism has become widely if partially internalized outside of institutional domains, liberalism's foot soldiers (rights, citizenship, nation statism, 'free' markets) have gained new forward momentum despite a period of supposed ideological hybridity described by that overheated but ill-theorized concept 'globalization', and, finally, most arguments for socialist/egalitarian revolution or system transformation must now be seen as anachronisms. The article locates these processes as essential features of a particular disciplinary regime in which the grandeur of liberal legality is used to create loyalty to the wider project of liberalism within the consolidation of late capitalism. These regimes are called 'empires of law', and the theoretical framework within which empires of law are rendered intelligible as actual sociolegal phenomena draws from, but critically reframes, insights found in Hardt and Negri's book Empire (2000).
Being Hated: Stranger or Familiar?
Authors: Mason Gail
Published: November 2005

Like all emotions, hate is comprised of a number of interacting, sometimes contradictory, feelings. This article looks at hate as a form of affect that is tied to the collective sense of estrangement that exists between insider and outsider groups. This link between hatred and estrangement is closely connected to the assumption that the perpetrators of 'real' hate crime are predominantly strangers to the victim. By drawing upon the results of a study into racial and homophobic harassment recorded by the London Metropolitan Police Service, the article questions the stranger-danger image of hate crime and explores the significance of location to the ways in which victims and perpetrators of harassment know each other. It suggests that the spatial ambiguity embodied by estrangement - physical proximity coupled with emotional distance - injects an ambivalence into the victim-perpetrator relationship that has implications for the definition of all hate crime.
Tax Competition and Tax Co-Operation in the EU
Authors: Holzinger Katharina
Published: November 2005

It took the European Union (EU) 35 years to achieve a co-operative agreement on co-ordinated measures of savings taxation. Political science has offered two explanations for this. First, co-operation is difficult to achieve as a result of heterogeneity. Countries with a small domestic tax base favor tax competition, while countries with a large tax base prefer tax co-operation. Second, co-operation is difficult as a consequence of specific characteristics of the collective action problem involved. The actors face a prisoners’ dilemma. Both explanations have their limits. The first approach is not very good at predicting actual policy preferences of governments and the second approach dismisses the fact that the EU offers cooperative institutions that should be able to resolve a dilemma. The paper refines these explanations such that the theory fits better the empirical positions of EU governments and their problems of finding an agreement.
Getting Personal: Reflexivity and Autoethnographic Vignettes
Authors: Humphreys Michael
Published: November 2005

The original research contribution of this article is in its advocacy of autoethnographic vignettes as a means of enhancing the representational richness and reflexivity of qualitative research. A personal story of career change is used to illustrate how research accounts enriched by the addition of autoethnographic detail can provide glimpses into what Van Maanen called “the ethnographer’s own taken-for-granted understandings of the social world under scrutiny.” Although the overall aim is to respond to Dyer and Wilkins’s exhortation to scholars that they should “try to tell good stories,” the article also has general methodological implications for qualitative researchers seeking to enhance the reflexivity of their work, particularly those pursuing autoethnographic or autobiographical studies.
“Go Ugly Early”: Fragmented Narrative and Bricolage as Interpretive Method
Authors: Markham Annette N.
Published: November 2005

This article presents findings from an ethnographic research project as well as a study of method that explores the meaning of the popular phrase “Go Ugly Early” as it is claimed and lived out by a group of males in a popular bar. Acknowledging that similar methods can accomplish some of the same results and effects, this piece is an example of writing as inquiry, layered account, impressionist/mixed genre tale, or hypertext. Through form and content, the author illustrates the political value of fragmented narrative as it disrupts the linear flow of argument, reveals disparate and disjunctive influences on the researcher’s process of sense making through the course of a study, and opens more spaces for multiplicity. Through fragmented segments of scholarly, fictional, research journal, and participant narratives, the article explores how these sources of information play and interweave in the interpretive sense-making process and the construction of a research report.
Romantic Product Salesmen: A Bygone Occupation
Authors: Athens Lonnie
Published: November 2005

Romantic product salesmen sold what now are popularly known as “sex toys” but in their day were called “marital or sex aids.” They plied their trade in the Bible Belt and served a primarily male clientele. By playing on their clientele’s sexual ignorance and sexist attitudes, romantic product salesmen were able to sell merchandise that ironically, increased rather than decreased their customers’ sexual frustration at outrageously inflated prices. With the spread of X-rated bookstores to the Bible Belt in the mid-1960s, this little-known and secretive occupation vanished from the American cultural landscape.
The Amorous Salesman Pays A Call: (“Be Patient Please, Floyd Pumice Aims To Please”)
Authors: Athens Lonnie
Published: November 2005

While Pop works in the lot behind his café, Floyd Pumice, a romantic product salesman, drops in. Although Pop frowns on Pumice for selling his merchandise in the café, his counterman, “Pete the Greek,” welcomes the opportunity to watch Pumice ply his trade on the café’s patrons. Pumice, who adroitly tailors his sales pitch to his customers, closes sales with a long-married, middle-aged man with a wife of the same age, a young single man who is desperate for sexual relations with his steady girlfriend, and a young single man suffering from feelings of sexual inadequacy. When Pop unexpectedly enters the café, Pete the Greek and Pumice must find a quick and graceful way to get out of an awkward situation.
A/r/tography as Living Inquiry Through Art and Text
Authors: Springgay Stephanie , Irwin Rita L. , Kind Sylvia Wilson
Published: November 2005

There is a substantial body of literature on arts-based forms of research demonstrating scholars’ endeavors to theorize the production of the arts as a mode of scholarly inquiry and as a method of representation. However, if arts-based research is to be taken seriously as an emerging field of educational research, then perhaps it needs to be understood as a methodology in its own right. This entails moving beyond the use of existing criteria that exists for qualitative research and toward an understanding of interdisciplinarity not as a patchwork of different disciplines and methodologies but as a loss, a shift, or a rupture where in absence, new courses of action un/fold. This article proposes an understanding of arts-based research as enacted, living inquiry through six renderings of a/r/tography: contiguity, living inquiry, openings, metaphor/metonymy, reverberations, and excess.
Putting Out The Trash
Authors: Moore Adrian , Nolan James , Segal Geoffrey F.
Published: November 2005

There is a considerable literature describing the performance of municipal services that often uses imperfect or partial measures of efficiency. Data envelopment analysis (DEA) has emerged as an effective tool for measuring the relative efficiency of public service provision. This article uses DEA to measure the relative efficiency of 11 municipal services in 46 of the largest cities in the United States over a period of 6 years. In addition, this information is used to explore efficiency differences between cities and services and provide input into a statistical analysis to explore factors that may explain differences in efficiency between cities. Finally, the authors discuss municipal governments’ use of performance measures and problems with collecting municipal data for benchmarking.
A Parallel Distributed Solver for Large Dense Symmetric Systems: Applications to Geodesy and Electromagnetism Problems
Authors: Baboulin Marc , Giraud Luc , Gratton Serge
Published: November 2005

In this paper we describe the parallel distributed implementation of a linear solver for large-scale applications involving real symmetric positive definite or complex symmetric non-Hermitian dense systems. The advantage of this routine is that it performs a Cholesky factorization by requiring half the storage needed by the standard parallel libraries ScaLAPACK and PLAPACK. Our solver uses a Jvariant Cholesky algorithm and a one-dimensional blockcyclic column data distribution but gives similar Gigaflops performance when applied to problems that can be solved on moderately parallel computers with up to 32 processors. Experiments and performance comparisons with ScaLAPACK and PLAPACK on our target applications are presented. These applications arise from the Earth's gravity field recovery and computational electromagnetics.
Process Fault Tolerance: Semantics, Design and Applications for High Performance Computing
Authors: Fagg Graham E. , Gabriel Edgar , Chen Zizhong , Angskun Thara , Bosilca George , Pjesivac-Grbovic Jelena , Dongarra Jack J.
Published: November 2005

With increasing numbers of processors on current machines, the probability for node or link failures is also increasing. Therefore, application-level fault tolerance is becoming more of an important issue for both end-users and the institutions running the machines. In this paper we present the semantics of a fault-tolerant version of the message passing interface (MPI), the de-facto standard for communication in scientific applications, which gives applications the possibility to recover from a node or link error and continue execution in a well-defined way. We present the architecture of fault-tolerant MPI, an implementation of MPI using the semantics presented above as well as benchmark results with various applications. An example of a fault-tolerant parallel equation solver, performance results as well as the time for recovering from a process failure are furthermore detailed.
Parallel Computation of the Regional Ocean Modeling System
Authors: Wang Ping , Song Y. Tony , Chao Yi , Zhang Hongchun
Published: November 2005

The Regional Ocean Modeling System (ROMS) is a regional ocean general circulation modeling system solving the free surface, hydrostatic, primitive equations over varying topography. It is free software distributed worldwide for studying both complex coastal ocean problems and the basin-to-global scale ocean circulation. The original ROMS code could only be run on shared-memory systems. With the increasing need to simulate larger model domains with finer resolutions and on a variety of computer platforms, there is a need in the ocean-modeling community to have a ROMS code that can be run on any parallel computer ranging from 10 to hundreds of processors. Recently, we have explored parallelization for ROMS using the Message-Passing Interface (MPI) programming model. In this paper, we present an efficient parallelization strategy for such a large-scale scientific software package, based on an existing shared-memory computing model. In addition, we discuss scientific applications and data-performance issues on a couple of SGI systems, including Columbia, the world's third-fastest supercomputer.
Assessing African Party Systems after the Third Wave
Authors: Manning Carrie
Published: November 2005

In this article, I explore the nature of party systems that have emerged in Africa in the wake of the adoption of democratic political systems after 1990. Although political parties help shape core democratic processes and institutions, parties and party systems have received relatively scant attention in the scholarly literature on democratization in Africa. I argue that party systems in most African countries are built on quite a different foundation from the one that undergirds both advanced industrial democracies and the theories about party systems generated by their experiences. I assess the strengths and limitations of the comparative literature on party system development in the light of African experiences, and argue for a more critical examination of concepts from that literature that have been widely used to assess the prospects and progress of party system institutionalization, including pluralism, system fragmentation and volatility.
Designing the Smart House
Authors: Spigel Lynn
Published: November 2005

This article analyzes recent architectural and product designs for computerized smart homes. The smart home is a sentient space where human subjects and domestic objects speak to one another via intelligent agents and internet connections. This article explores the industrial logic behind this new vision of home (i.e. the links between the hi-tech industry and the building/home appliance industries) and examines the mode of subjectivity the smart home demands. It calls this mode of subjectivity 'posthuman domesticity' (a term to explore the way that everyday human experience is orchestrated by telerobotics and intelligent agents). Analyzing architectural designs, advertisements and magazines, the article focuses on how the smart home industry promotes an ideal of 'conspicuous production' in which the luxury home is no longer just a site of leisure and consumption, but also the ultimate workplace. It argues that smart homes reconfigure but also reinforce gendered patterns of domestic labor and leisure.
Not the Final Answer
Authors: Holmes Su
Published: November 2005

The article aims to address and explore the apparent neglect of the quiz show in television and cultural studies by focusing on the programme Who Wants To Be A Millionaire(1998–, UK). Existing work in the field emerged in the late 1970s/early 1980s, and this article argues that a key reason for critical neglect of the quiz show is the centrality of 'class' in the genre – a focus which has increasingly receded from view in television and cultural studies. The article operates under the assumption that as television studies develops a longer history of critical and theoretical approaches to the medium, it becomes crucial to respond to innovations by developing 'new' methodological approaches and to reconsider the relevance and dynamics of existing models. In this respect, an analysis of Millionairesuggests that the emphasis on 'class', work and production remains central to the quiz show, and its political and ideological significance.
Calculation, Community and Cues
Authors: Hooghe Liesbet , Marks Gary
Published: November 2005

This article summarizes and extends the main lines of theorizing on public opinion on European integration. We test theories of economic calculus and communal identity in a multi-level analysis of Eurobarometer data. Both economic calculus and communal identity are influential, but the latter is stronger than the former. We theorize how the political consequences of identity are contested and shaped - that is to say, politically cued - in national contexts. The more national elites are divided, the more citizens are cued to oppose European integration, and this effect is particularly pronounced among citizens who see themselves as exclusively national. A model that synthesizes economic, identity, and cue theory explains around one-quarter of variation at the individual level and the bulk of variation at the national and party levels.
Nationality and the Preferences of the European Public toward EU Policy-Making
Authors: Vössing Konstantin
Published: November 2005

Analyses of covariance for Eurobarometer data from 1990 to 1994 demonstrate a significant effect of individuals' nationalities on their preferences toward the scope and content of European Union policy-making, while controlling for sociodemographic characteristics. The observed national differences are more pronounced for the scope than for the content dimension. An investigation of the causal mechanisms underpinning these effects concludes that it can be either national identities or nation-specific constellations of political conflict that mediate the effect of nationality for a particular nation. These novel findings qualify the expectations of the European political space approach concerning the existence of an integrated and somewhat autonomous space of political contestation toward the EU, but the observed decline of cross-national differences over time indicates that at least a trend in this direction exists.
Persuasion in Social Work Interviewing
Authors: Suoninen Eero , Jokinen Arja
Published: November 2005

The article collects the variation of forms of subtle persuasion embedded in social work interviewing. It is based on the constructionist idea that institutional interviewing is not an innocent practice of information gathering, but a practice that also produces knowledge and creates identities. A detailed analysis of interview episodes from different social work settings is used to illustrate interview practices, which persuade a client to reconstruct his/her ‘story’. The analysis focuses on four basic devices of persuasion: ‘persuasive questions’, ‘persuasive responses’, ‘asking explanations’ and ‘encouraging questions’. The devices are not clear-cut entities, but they seem in an interesting way to be complementary, and also overlapping in the functions they fulfil. By explicating the interactional construction of the devices, the article aims at contributing to social workers’ understanding of the nature of the means through which practical activities are achieved.
Research nurse or nurse researcher: How much value is placed on research undertaken by nurses?
Authors: Deave Toity
Published: November 2005

The argument for evidence-based nursing practice informed by research has placed nursing research capacity-building firmly on the agenda. Despite the recognition of the need for sustainable sources of funding, the emphasis has remained on NHS R&D undertaken by doctor, supported by other professions such as nurses. Indeed, it is common for nurses to be employed in the role of research assistant or data collector, under the supervision of a doctor. The titles ‘Research Nurse’ and ‘Nurse Researcher’ are used interchangeably and this paper highlights the distinction between the two, the requirements of their posts, reasons why nurses may become involved in research and the difficulties that this may entail. We draw attention to the expectations of the research training that first-level nurses receive, the assumption that it results in them being research competent, and the implications for the status of nursing research. Investment in research capacity-building needs to be reflected in the organisation and infrastructure of academic departments and NHS trusts. Joint, long-term educator/practitioner/researcher appointees are required to facilitate the nurseorientated research necessary to inform the increasing demands on practice. If the practice of nursing, midwifery and health visiting is to be underpinned by a scientific evidence-base specific to its own needs, it is necessary to foster an environment conducive to reflection on practice and cultivation of ideas.
HLAMatchmaker-driven analysis of responses to HLA-typed platelet transfusions in alloimmunized thrombocytopenic patients
Authors: Nambiar Ashok , Duquesnoy Rene J. , Adams Sharon , Zhao Yingdong , Oblitas Jaime , Leitman Susan , Stroncek David , Marincola Francesco
Published: November 2005

This study describes a novel application of HLAMatchmaker to determine platelet compatibility in 16 alloimmunized patients with aplastic anemia refractory to random donor platelet transfusions. HLAMatchmaker is a software algorithm that predicts HLA compatibility by identifying immunogenic epitopes represented by amino acid triplets in antibody-accessible regions of human leukocyte antigen (HLA) molecules and determines the number of triplet mismatches (TMMs) and highly immunogenic triplet mismatches (HIMMs). Corrected count increments (CCIs) and molecular HLA typing were available for 523 transfusions. Conventional compatibility assessment based on cross-reactive group (CREG) determination was not predictive of transfusion outcome. Low HIMMs and TMMs numbers were associated with a higher likelihood of satisfactory (CCIs ≥ 8) compared with unsatisfactory (CCIs < 8) outcomes (median HIMMs = 4 vs 6, p2 value < .001; median TMMs = 11 vs 13, p2 value < .001). Although receiver operator characteristic curves revealed that HIMMs or TMMs number are not powerful predictors of individual transfusion outcome, a threshold of at least 3 HIMMs or at least 9 TMMs appeared to be associated with successful transfusions. Triplet-matched transfusions were successful, regardless of CREG matching. Our data validate HLAMatchmaker for platelet transfusions and demonstrate its potential to refine and expand donor selection for HLA-alloimmunized patients.
CD43 is a ligand for E-selectin on CLA+ human T cells
Authors: Fuhlbrigge Robert C. , King Sandra L. , Sackstein Robert , Kupper Thomas S.
Published: November 2005

The recruitment of memory T cells from blood into tissues is a central element of immune surveillance and adaptive immune responses and a key feature of chronic cutaneous inflammatory diseases such as psoriasis and atopic dermatitis. Human memory T cells that infiltrate skin express the carbohydrate epitope cutaneous lymphocyte-associated antigen (CLA). Expression of the CLA epitope on T cells has been described on P-selectin glycoprotein ligand-1 (PSGL-1) and associated with the acquisition of both E-selectin and P-selectin ligand functions. In this report, we show that CD43, a sialomucin expressed constitutively on T cells, can also be decorated with the CLA epitope and serve as an E-selectin ligand. CLA expressed on CD43 was found exclusively on the high-molecular-weight (125 kDa) glycoform bearing core-2-branched O-linked glycans. CLA+ CD43 purified from human T cells supported tethering and rolling in shear flow via E-selectin but did not support binding of P-selectin. The identification and characterization of CD43 as a T-cell E-selectin ligand distinct from PSGL-1 expands the role of CD43 in the regulation of T-cell trafficking and provides new targets for the modulation of immune functions in skin.
Survival of the fittest: in vivo selection and stem cell gene therapy
Authors: Neff Tobias , Beard Brian C. , Kiem Hans-Peter
Published: November 2005

Stem cell gene therapy has long been limited by low gene transfer efficiency to hematopoietic stem cells. Recent years have witnessed clinical success in select diseases such as X-linked severe combined immunodeficiency (SCID) and ADA deficiency. Arguably, the single most important factor responsible for the increased efficacy of these recent protocols is the fact that the genetic correction provided a selective in vivo survival advantage. Since, for most diseases, there will be no selective advantage of gene-corrected cells, there has been a significant effort to arm vectors with a survival advantage. Two-gene vectors can be used to introduce the therapeutic gene and a selectable marker gene. Efficient in vivo selection strategies have been demonstrated in clinically relevant large-animal models. Mutant forms of the DNA repair-enzyme methylguanine methyltransferase in particular have allowed for efficient in vivo selection and have achieved sustained marking with virtually 100% gene-modified cells in large animals, and with clinically acceptable toxicity. Translation of these strategies to the clinical setting is imminent. Here, we review how in vivo selection strategies can be used to make stem cell gene therapy applicable to the treatment of a wider scope of genetic diseases and patients.
Remodeling specific immunity by use of MHC tetramers: demonstration in a graft-versus-host disease model
Authors: Kappel Barry J. , Pinilla-Ibarz Javier , Kochman Adam A. , Eng Jeffrey M. , Hubbard Vanessa M. , Leiner Ingrid , Pamer Eric G. , Heller Glen , van den Brink Marcel R. M. , Scheinberg David A.
Published: November 2005

Major histocompatibility complex (MHC) molecules carrying selected peptides will bind specifically to their cognate T-cell receptor on individual clones of reactive T cells. Fluorescently labeled, tetrameric MHC-peptide complexes have been widely used to detect and quantitate antigen-specific T-cell populations via flow cytometry. We hypothesized that such MHC-peptide tetramers could also be used to selectively deplete unique reactive T-cell populations, while leaving the remaining T-cell repertoire and immune response intact. In this report, we successfully demonstrate that a tetramer-based depletion of T cells can be achieved in a murine model of allogeneic bone marrow transplantation. Depletion of a specific alloreactive population of donor splenocytes (< 0.5% of CD8+ T cells) prior to transplantation significantly decreased morbidity and mortality from graft-versus-host disease. There was no early regrowth of the antigen-specific T cells in the recipient and in vivo T-cell proliferation was greatly reduced as well. Survival was increased more than 3-fold over controls, yet the inherent antitumor activity of the transplant was retained. This method also provides the proof-of-concept for similar strategies to selectively remove other unwanted T-cell clones, which could result in novel therapies for certain autoimmune disorders, T-cell malignancies, and solid organ graft rejection.
A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation
Authors: Porter David L. , Levine Bruce L. , Bunin Nancy , Stadtmauer Edward A. , Luger Selina M. , Goldstein Steven , Loren Alison , Phillips Julie , Nasta Sunita , Perl Alexander , Schuster Steven , Tsai Donald , Sohal Ambika , Veloso Elizabeth , Emerson Stephen , June Carl H.
Published: November 2005

Donor lymphocyte infusions (DLIs) induce potent graft versus tumor (GVT) effects for relapsed chronic myelogenous leukemia (CML) after allogeneic stem cell transplantation (SCT) but are disappointing for other diseases. Disease resistance can occur if donor T cells are not appropriately activated in vivo. Ex vivo T-cell activation might overcome disease-induced anergy and augment GVT activity. We performed a phase 1 trial of ex vivo–activated DLI (aDLI) for 18 patients with relapse after SCT. Activated donor T cells are produced through costimulation with anti-CD3– and anti-CD28–coated beads. Patients with aggressive malignancies received induction chemotherapy, and all patients received conventional DLI (median, 1.5 × 108 mononuclear cells/kg) followed 12 days later by aDLI. Activated DLI was dose escalated from 1 × 106 to 1 × 108 CD3+ cells per kilogram in 5 levels. Seven patients developed acute graft versus host disease (GVHD) (5 grade I-II, 2 grade III), and 4 developed chronic GVHD. Eight patients achieved complete remission, including 4 of 7 with acute lymphocytic leukemia (ALL), 2 of 4 with acute myelogenous leukemia (AML), 1 with chronic lymphocytic leukemia (CLL), and 1 of 2 with non-Hodgkin lymphoma (NHL). Four complete responders relapsed while 4 remain alive in remission a median 23 months after aDLI. Overall, 10 of 18 remain alive 11 to 53 months after aDLI. Adoptive transfer of costimulated activated allogeneic T cells is feasible, does not result in excessive GVHD, and may contribute to durable remissions in diseases where conventional DLI has been disappointing.
Isolation of human β-defensin-4 in lung tissue and its increase in lower respiratory tract infection
Authors: Yanagi Shigehisa , Ashitani Jun-ichi , Ishimoto Hiroshi , Date Yukari , Mukae Hiroshi , Chino Naoyoshi , Nakazato Masamitsu
Published: November 2005

Background

Human β-defensin-4 (hBD-4), a new member of the β-defensin family, was discovered by an analysis of the genomic sequence. The objective of this study was to clarify hBD-4 expression in human lung tissue, along with the inducible expression in response to infectious stimuli, localization, and antimicrobial activities of hBD-4 peptides. We also investigated the participation of hBD-4 in chronic lower respiratory tract infections (LRTI) by measuring the concentrations of hBD-4 peptides in human bronchial epithelial lining fluid (ELF).

Methods

The antimicrobial activity of synthetic hBD-4 peptides against E. coli and P. aeruginosa was measured by radial diffusion and colony count assays. We identified hBD-4 in homogenated human lung tissue by reverse-phase high-performance liquid chromatography coupled with a radioimmunoassay (RIA). Localization of hBD-4 was studied through immunohistochemical analysis (IHC). We investigated the effects of lipopolysaccharide (LPS) on hBD-4 expression and its release from small airway epithelial cells (SAEC). We collected ELF from patients with chronic LRTI using bronchoscopic microsampling to measure hBD-4 concentrations by RIA.

Results

hBD-4 exhibited salt-sensitive antimicrobial activity against P. aeruginosa. We detected the presence of hBD-4 peptides in human lung tissue. IHC demonstrated the localization of hBD-4-producing cells in bronchial and bronchiolar epithelium. The levels of hBD-4 peptides released from LPS-treated SAECs were higher than those of untreated control cells. ELF hBD-4 was detectable in 4 of 6 patients with chronic LRTI, while the amounts in controls were all below the detectable level.

Conclusion

This study suggested that hBD-4 plays a significant role in the innate immunity of the lower respiratory tract.
Avoid, attack or do both? Behavioral and physiological adaptations in natural enemies faced with novel hosts
Authors: Vacher Corinne , Brown Sam P , Hochberg Michael E
Published: November 2005

Background

Confronted with well-defended, novel hosts, should an enemy invest in avoidance of these hosts (behavioral adaptation), neutralization of the defensive innovation (physiological adaptation) or both? Although simultaneous investment in both adaptations may first appear to be redundant, several empirical studies have suggested a reinforcement of physiological resistance to host defenses with additional avoidance behaviors. To explain this paradox, we develop a mathematical model describing the joint evolution of behavioral and physiological adaptations on the part of natural enemies to their host defenses. Our specific goals are (i) to derive the conditions that may favor the simultaneous investment in avoidance and physiological resistance and (ii) to study the factors that govern the relative investment in each adaptation mode.

Results

Our results show that (i) a simultaneous investment may be optimal if the fitness costs of the adaptive traits are accelerating and the probability of encountering defended hosts is low. When (i) holds, we find that (ii) the more that defended hosts are rare and/or spatially aggregated, the more behavioral adaptation is favored.

Conclusion

Despite their interference, physiological resistance to host defensive innovations and avoidance of these same defenses are two strategies in which it may be optimal for an enemy to invest in simultaneously. The relative allocation to each strategy greatly depends on host spatial structure. We discuss the implications of our findings for the management of invasive plant species and the management of pest resistance to new crop protectants or varieties.
RB1 gene mutation up-date, a meta-analysis based on 932 reported mutations available in a searchable database
Authors: Valverde José R , Alonso Javier , Palacios Itziar , Pestaña Ángel
Published: November 2005

Background

Retinoblastoma, a prototype of hereditary cancer, is the most common intraocular tumour in children and potential cause of blindness from therapeutic eye ablation, second tumours in germ line carrier's survivors, and even death when left untreated. The molecular scanning of RB1 in search of germ line mutations lead to the publication of more than 900 mutations whose knowledge is important for genetic counselling and the characterization of phenotypic-genotypic relationships.

Results

A searchable database (RBGMdb) has been constructed with 932 published RB1 mutations. The spectrum of these mutations has been analyzed with the following results: 1) the retinoblastoma protein is frequently inactivated by deletions and nonsense mutations while missense mutations are the main inactivating event in most genetic diseases. 2) Near 40% of RB1 gene mutations are recurrent and gather in sixteen hot points, including twelve nonsense, two missense and three splicing mutations. The remainder mutations are scattered along RB1, being most frequent in exons 9, 10, 14, 17, 18, 20, and 23. 3) The analysis of RB1 mutations by country of origin of the patients identifies two groups in which the incidence of nonsense and splicing mutations show differences extremely significant, and suggest the involvement of predisposing ethnic backgrounds. 4) A significant association between late age at diagnosis and splicing mutations in bilateral retinoblastoma patients suggests the occurrence of a delayed-onset genotype. 5) Most of the reported mutations in low-penetrance families fall in three groups: a) Mutations in regulatory sequences at the promoter resulting in low expression of a normal Rb; b) Missense and in-frame deletions affecting non-essential sequence motifs which result in a partial inactivation of Rb functions; c) Splicing mutations leading to the reduction of normal mRNA splicing or to alternative splicing involving either true oncogenic or defective (weak) alleles.

Conclusion

The analysis of RB1 gene mutations logged in the RBGMdb has shown relevant phenotype-genotype relationships and provided working hypothesis to ascertain mechanisms linking certain mutations to ethnicity, delayed onset of the disease and low-penetrance. Gene profiling of tumors will help to clarify the genetic background linked to ethnicity and variable expressivity or delayed onset phenotypes.
Fluid-structure interaction in abdominal aortic aneurysms: effects of asymmetry and wall thickness
Authors: Scotti Christine M , Shkolnik Alexander D , Muluk Satish C , Finol Ender A
Published: November 2005

Background

Abdominal aortic aneurysm (AAA) is a prevalent disease which is of significant concern because of the morbidity associated with the continuing expansion of the abdominal aorta and its ultimate rupture. The transient interaction between blood flow and the wall contributes to wall stress which, if it exceeds the failure strength of the dilated arterial wall, will lead to aneurysm rupture. Utilizing a computational approach, the biomechanical environment of virtual AAAs can be evaluated to study the affects of asymmetry and wall thickness on this stress, two parameters that contribute to increased risk of aneurysm rupture.

Methods

Ten virtual aneurysm models were created with five different asymmetry parameters ranging from β = 0.2 to 1.0 and either a uniform or variable wall thickness to study the flow and wall dynamics by means of fully coupled fluid-structure interaction (FSI) analyses. The AAA wall was designed to have a (i) uniform 1.5 mm thickness or (ii) variable thickness ranging from 0.5 – 1.5 mm extruded normally from the boundary surface of the lumen. These models were meshed with linear hexahedral elements, imported into a commercial finite element code and analyzed under transient flow conditions. The method proposed was then compared with traditional computational solid stress techniques on the basis of peak wall stress predictions and cost of computational effort.

Results

The results provide quantitative predictions of flow patterns and wall mechanics as well as the effects of aneurysm asymmetry and wall thickness heterogeneity on the estimation of peak wall stress. These parameters affect the magnitude and distribution of Von Mises stresses; varying wall thickness increases the maximum Von Mises stress by 4 times its uniform thickness counterpart. A pre-peak systole retrograde flow was observed in the AAA sac for all models, which is due to the elastic energy stored in the compliant arterial wall and the expansion force of the artery during systole.

Conclusion

Both wall thickness and geometry asymmetry affect the stress exhibited by a virtual AAA. Our results suggest that an asymmetric AAA with regional variations in wall thickness would be exposed to higher mechanical stresses and an increased risk of rupture than a more fusiform AAA with uniform wall thickness. Therefore, it is important to accurately reproduce vessel geometry and wall thickness in computational predictions of AAA biomechanics.
Osteoporosis, inflammation and ageing
Authors: Ginaldi Lia , Di Benedetto Maria Cristina , De Martinis Massimo
Published: November 2005

Osteoporosis is a condition characterized by low bone mass and increased bone fragility, putting patients at risk of fractures, which are major causes of morbidity substantially in older people. Osteoporosis is currently attributed to various endocrine, metabolic and mechanical factors. However, emerging clinical and molecular evidence suggests that inflammation also exerts significant influence on bone turnover, inducing osteoporosis. Numerous proinflammatory cytokines have been implicated in the regulation of osteoblasts and osteoclasts, and a shift towards an activated immune profile has been hypothesized as important risk factor. Chronic inflammation and the immune system remodelling characteristic of ageing, as well as of other pathological conditions commonly associated with osteoporosis, may be determinant pathogenetic factors. The present article will review the current perspectives on the interaction between bone and immune system in the elderly, providing an interpretation of osteoporosis in the light of inflamm-ageing.