bluuebunny/crossref_metadata_2025 huggingface dataset:
An Event-related fMRI Study of Exogenous Orienting: Supporting Evidence for the Cortical Basis of Inhibition of Return?
Authors: Mayer Andrew R. , Seidenberg Michael , Dorflinger Jill M. , Rao Stephen M.
Published: September 2004

This event-related fMRI experiment examined the neural substrates of exogenous visuospatial attention. Exogenous attention produces a biphasic response pattern denoted by facilitation at short cue–target intervals and inhibition of return (IOR) at longer intervals. Whereas the volitional orienting of attention has been well described in the literature, the neural systems that support exogenous facilitation and IOR in humans are relatively unknown. In direct comparisons to valid facilitation trials, valid IOR trials produced unique foci of activation in the right posterior parietal, superior temporal, middle temporal, middle occipital, anterior cingulate, and dorsal medial thalamic areas. Valid IOR trials also resulted in activation of motor exploratory and frontal areas previously associated with inhibition and oculomotor control. In contrast, invalid IOR compared to facilitation trials only activated anterior cortical structures. These results provide support for both attentional and oculomotor theories of IOR and suggest that IOR may be mediated by two networks. One network may mediate the inhibitory bias following an exogenous cue, whereas a separate network may be activated when a response must be made to stimuli that appear in inhibited locations of space.
Common and Contrasting Areas of Activation for Abstract and Concrete Concepts: An H2
15O PET Study
Authors: Whatmough Christine , Verret Louis , Fung Dion , Chertkow Howard
Published: September 2004

Lesion studies indicate that the lateral and inferior temporal cortex is a critical area of semantic memory storage, but little is known about the cortical organization of semantics within this area. One proposition has been that dominant physical characteristics of objects (structure, motility) are determining factors. A positron emission tomography experiment using the H2 15O bolus method was performed to test this hypothesis by contrasting activation for concrete and abstract concepts. Unlike previous studies that considered this question, the task required explicit word meaning judgments, and blocks of trials were designed to be of equal difficulty for the two word classes. The task required elderly participants to read aloud the pair of words that was closer in meaning (e.g., spade–shovel vs. spade–carpet). Subtraction analyses that compared the semantic judgment tasks with a baseline condition indicated that both abstract and concrete concepts activated the left lateral temporal cortex. A direct comparison of abstract versus concrete scans indicated differences in the lateralization of fusiform activation. We conclude that although concreteness might be a critical factor in the fusiform cortex, it is not dominant in the lateral temporal cortex. A multistudy overview suggests that tasks that focus on one concept per trial activate areas posterior to y = −40, whereas those that invoke several concepts, as in the present study, activate areas anterior to this. Increased processing complexity may proceed in a posterior– anterior direction in the lateral temporal cortex.
Dissociating Confidence and Accuracy: Functional Magnetic Resonance Imaging Shows Origins of the Subjective Memory Experience
Authors: Chua Elizabeth F. , Rand-Giovannetti Erin , Schacter Daniel L. , Albert Marilyn S. , Sperling Reisa A.
Published: September 2004

Successful memory typically implies both objective accuracy and subjective confidence, but there are instances when confidence and accuracy diverge. This dissociation suggests that there may be distinct neural patterns of activation related to confidence and accuracy. We used event-related functional magnetic resonance imaging to study the encoding of novel face–name associations, assessed with a postscan memory test that included objective measures of accuracy and subjective measures of confidence. We showed specific neural activity in the left inferior prefrontal cortex associated with trials when subjects expressed high confidence that they had chosen the correct name for the face and made a correct identification. Moreover, we found that this region was also associated with imparting high confidence when subjects chose the incorrect name. However, medial temporal lobe regions showed activity only for high-confidence correct trials. Many functional magnetic resonance imaging studies have shown that the medial temporal lobe and left prefrontal regions are particularly important for the successful formation of memories by using a combination of subjective and objective measures. Our findings suggest that these regions may be differentially involved in the objective and subjective components of memory and that the origins of confidence–accuracy dissociations may be related to incomplete activation of the neural pattern seen in successful encoding. These findings may also aid understanding of eyewitness misidentifications and memory distortions.
Suffering in Silence: Bodily Politics in Post-1995 French Film
Authors: O’Shaughnessy Martin
Published: September 2004

Developing earlier research by the author that had sought to trace the specificity of the current wave of socio-politically engaged films, this article focuses on the body, suggesting that it has become a core vector of ‘raw’ expressivity in recent French cinema due to the withdrawal of the discourse of the organised left as mediating instance. Brooks’s celebrated analysis of melodrama and the political philosophy of Rancière and Laclau and Mouffe are drawn on to examine the political content of Cabrera’s Retiens la nuit and Devers’ La Voleuse de St. Lubin. Engaging with theobjectified, embodied and isolated social suffering that runs through current cinema, the two films’ particular significance lies in their exploration of the possibilities of and obstacles to its articulation within an oppositional politics.
‘Elle est où, ta place?’ The Social-Realist Melodramas of Laurent Cantet:
Authors: Higbee Will
Published: September 2004

This article analyses the social-realist melodramas of director Laurent Cantet: Ressources humaines (2000) and Emploi du temps (2001). It considers the socio-political subject matter of the two films in relation to so-called New Realism and the ‘return of the political’ in French cinema since the mid-1990s. The article also examines Cantet’s use of melodrama – the function of mise-en-scène, emphasis on the family as the site of wider social crisis, and the director’s apparent pre-occupation with father–son relationships – as a means of articulating the affects/effects of broader social and political forces on the individual. Finally, the article considers how Cantet’s social melodramas are intricately bound to the theme of masculinity in crisis, through the relationship of the white, middle-class, male bodies of the central protagonists to the various spaces – physical, social, economic – that they occupy during the film.
The Amateur Actors of Cannes 1999: A Shock to the (Star) System
Authors: Austin Guy
Published: September 2004

At the Cannes film festival in 1999 the perennial tension within French film between popular cinema and auteur cinema came to a head with the award of the Palme d’Or to the Dardenne brothers’ Rosetta. Moreover, three amateurs were given Best Actor awards: Émilie Dequenne for Rosetta, plus Emmanuel Schotté and Séverine Caneele for L’Humanité. This article analyses the performances of the amateur actors in the above films, and evaluates to what extent they offer a challenge to conventional modes of representation, and in particular to the idealised embodiments of masculinity and femininity traditionally presented by film stars. The notion of the amateur as Bressonian model will also be addressed, as will the possibility of amateur actors challenging the supremacy of the auteur and moving into the realm of popular stardom.
Digitizing Frenchness in 2001: On a ‘Historic’ Moment in the French Cinema
Authors: Austin James F.
Published: September 2004

Inexorably intertwined with American cinema, the digital French cinema has defined itself with and against its ever-present rival across the Atlantic. This article attempts to complicate what would be a predictable narrative of Americanization of French cinema, or the Gallicization of an American cinema by suggesting that at stake in this process is the historically rooted identity of Frenchness itself. It recalls that as the cinema has been one of the preeminent cultural activities of the French in terms of time and money spent, it is logically a privileged space in which to study the evolution of French culture and identity.1
The Death of an Icon: Le Fabuleux Destin d’Amélie Poulain
Authors: Ezra Elizabeth
Published: September 2004

Amid the furore surrounding Amélie ’s digitally enhanced Paris, what has been overlooked is the fact that the film self-consciously thematises evolving technologies of vision and the modes of temporality they deploy, using the death of Princess Diana as the pretext for a meditation on the nature of iconicity. Amélie may be of the digital age, but it continually points nostalgically to the indexical, privileging the immediacy of human contact over mediatised, iconic identification. The film emphasises contingency as a form of resistance against hyper-rationalised, linear temporality, reflected in the tension between singularity and systematisation, or chance and fate ( le destin).
Evaluating Public-Participation Exercises: A Research Agenda
Authors: Rowe Gene , Frewer Lynn J.
Published: September 2004

The concept of public participation is one of growing interest in the UK and elsewhere, with a commensurate growth in mechanisms to enable this. The merits of participation, however, are difficult to ascertain, as there are relatively few cases in which the effectiveness of participation exercises have been studied in a structured (as opposed to highly subjective) manner. This seems to stem largely from uncertainty in the research community as to how to conduct evaluations. In this article, one agenda for conducting evaluation research that might lead to the systematic acquisition of knowledge is presented. This agenda identifies the importance of defining effectiveness and of operationalizing one’s definition (i.e., developing appropriate measurement instruments and processes). The article includes analysis of the nature of past evaluations, discussion of potential difficulties in the enactment of the proposed agenda, and discussion of some potential solutions.
Gender and Science in Development: Women Scientists in Ghana, Kenya, and India
Authors: Campion Patricia , Shrum Wesley
Published: September 2004

Why do women have more difficulty pursuing research careers than men? Although this topic has been extensively investigated in industrialized countries, prior studies provide little comparative evidence from less-developed areas. Based on a survey of 293 scientists in Ghana, Kenya, and the Indian state of Kerala, this article examines gender differences on a variety of individual, social, and organizational dimensions. The results show small or nonexistent differences between women and men in individual characteristics, professional resources, and the organizational conditions under which research is conducted. The article argues that a combination of educational and research localism increases the likelihood of restricted professional networks for women. Gender inequality in the research systems of the developing world may be based on systemic deficits in the acquisition of social rather than material resources. The most important implication is that educational policy for development should focus on international opportunities for women in the near future.
Cognitive Representations and Institutional Hybridity in Agrofood Innovation
Authors: Allaire Gilles , Wolf Steven A.
Published: September 2004

Product differentiation has emerged as a central dynamic in contemporary agrofood systems. Departure from the mode of standardization emblematic of agrofood modernization raises questions about future technical trajectories and the ways in which learning will be sustained. This article examines two innovation trajectories: (1) the rapid coupling of biotechnologies and information technologies to yield products differentiated by constituent components—a model based on a cognitive logic of decomposition/ recomposition—and (2) the proliferation of product networks that mobilize distinctive, localized resources to create complete identities—a model based on a cognitive logic of identity. The article analyzes the information structures—institutional mechanisms that support information exchange and learning—in each of these opposed development paradigms. We find that knowledge creation under each of the logics occurs through mechanisms not recognized within the respective paradigms. On this basis, we derive institutional hybridity as a fundamental resource in systems of innovation.
Grammar as a Feature of Text Construction
Authors: Liddicoat Anthony J.
Published: September 2004

This article investigates one aspect of scientific style in French: the use of tenses. It investigates the claims made in the literature that the verb system of scientific French is a temporal. The frequency of tensed finite forms in 10 French language journal articles on biological sciences is examined. The rhetorical function of past and future tenses is examined and six functions of tense choice are isolated. This analysis suggests that tense marking is actually more complex than previous claims have maintained and that tense choice serves to encode (a) temporal, (b) rhetorical, and (c) structural processes in the scientific text. Tense choice is therefore part of the communicative repertoire of the scientific writer, which writers use to create and communicate information, and which is responsive to the rhetorical demands of communicating about science.
Differential Error Types in Second-Language Students’ Written and Spoken Texts
Authors: Makalela Leketi
Published: September 2004

This article reports on an empirical study undertaken at the University of the North, South Africa, to test personal classroom observation and anecdotal evidence about the persistent gap between writing and spoken proficiencies among learners of English as a second language. A comparative and contrastive analysis of speech samples in the study showed a significant higher proportion of morpho-syntactic nonstandard forms in the learners’ written compositions and more nonstandard discourse forms in their oral presentations. As a result, it is argued that this gap may be minimized when learners’written interlanguage variety is used productively as a means toward normative writing proficiency. Recommendations for remedial instruction in second-language writing pedagogy, within the framework of Cummins’s conversational abilities and academic language proficiency, are offered for adaptation in comparable situations.
Clinical Neurophysiological Assessment of Residual Motor Control in Post-Spinal Cord Injury Paralysis
Authors: McKay W. B. , Lim H. K. , Priebe M. M. , Stokic D. S. , Sherwood A. M.
Published: September 2004

Objective. This study was designed to characterize the rudimentary residual lower-limb motor control that can exist in clinically paralyzed spinal-cord-injured individuals. Methods. Sixty-seven paralyzed spinal-cord-injured subjects were studied using surface electromyography recorded from muscles of the lower limbs and analyzed for responses to a rigidly administered protocol of reinforcement maneuvers, voluntary movement attempts, vibration, or the ability to volitionally suppress withdrawal evoked by plantar surface stimulation. Results. Markers for the subclinical discomplete motor syndrome were found in 64% of the subjects. The tonic vibration response was recorded in 37%, volitional plantar surface stimulation response suppression in 27%, and reinforcement maneuver responses in 6% of the subjects. Three subjects, 4%, produced reliable but very low amplitude surface electromyography during the voluntary movement segment of the protocol. Surface electromyography recorded during passive leg movement was related to Ashworth scores as was the tonic vibration response marker (P < 0.05). Conclusions. Multimuscle surface electromyography patterns recorded during a rigidly administered protocol of motor tasks can be used to differentiate between clinically paralyzed spinal-cord-injured individuals using subclinical motor output to identify the translesional neural connections that remain available for intervention testing and treatment planning after spinal cord injury.
Improved Hemiparetic Muscle Activation in Treadmill versus Overground Walking
Authors: Harris-Love Michelle L. , Macko Richard F. , Whitall Jill , Forrester Larry W.
Published: September 2004

Objective. Treadmill training is a promising tool for retraining gait after stroke. The treadmill induces an immediate shift toward symmetry and longer paretic stance times due to altered muscle activation (active) or the motorized belt (passive). The authors investigated vastus lateralis and medial hamstrings activation differences between treadmill and overground walking in participants with stroke. Methods. Vastus lateralis and medial hamstrings surface electromyography was recorded during velocity-matched overground and treadmill walking in 19 chronically hemiparetic subjects. Variables from ensemble averages of electromyography included burst onset and offset times (% cycle), duration (% cycle), integrated amplitude (mV· % cycle), and onset relative to foot strike (% cycle). Conditions were compared using paired t- tests (α = 0.05). Results. Paretic vastus lateralis onset occurred earlier in the treadmill condition (overground: 47.1%, treadmill: 41.9%, P = 0.01). For nonparetic vastus lateralis in the treadmill condition, onset occurred later (overground: 85.2%, treadmill: 87.6%, P = 0.09), offset occurred earlier (overground: 54.7%, treadmill: 47.8%, P = 0.03), duration was shorter (overground: 69.1%, treadmill: 61.2%, P = 0.01), and integrated amplitude was lower (overground: 14.1, treadmill: 10.6, P = 0.05). Within limbs, paretic vastus lateralis onset occurred earlier relative to paretic foot strike. Nonparetic vastus lateralis onset occurred later relative to nonparetic foot strike. Conclusions. Treadmill walking induces immediate changes in vastus lateralis, but not medial ham-strings, activation patterns. These alterations (earlier paretic vastus lateralis onset and later nonparetic vastus lateralis onset) during treadmill versus overground walking parallel the increased symmetry in gait patterning.
Risks of Diuretic Usage following Stroke
Authors: Churchill Matthew , Grimm Sean , Reding Michael
Published: September 2004

Objective. To assess the effects of diuretic use on hydration status following stroke. Methods. Admission serum hydration markers and neurologic assessments were prospectively recorded for 296 stroke rehabilitation inpatients with stable renal function. Dysphagia was defined by bedside dysphagia evaluation and subsequent modified barium swallow, if necessary. Serum hydration markers were checked at approximate 10-day intervals. Analysis of variance was used to test the effects of clinical variables on serum markers for hydration during the rehabilitation hospital stay. Odds ratios were used to quantify the risks of developing a blood urea nitrogen value≥ 45 mg/dl. Results. The mean peak blood urea nitrogen associated with each of the following were diuretic usage yes/no (33 mg/dl ± 18/26 ± 17, P < 0.01), dysphagia yes/no (32 ± 21/25 ± 14, P < 0.001), and need for thin-liquid restriction yes/no (34 ± 20/25 ± 15, P < 0.001). The odds ratio for developing a peak blood urea nitrogen≥ 45 for patients taking a diuretic with evidence of penetration or aspiration documented by modified barium swallow was (19.8, P < 0.001). The odds ratio for developing a peak blood urea nitrogen≥ 45 for those taking a diuretic who needed thin-liquid restriction was (4.8, P = 0.004). Conclusions. Diuretic usage was associated with a significant increase in peak blood urea nitrogen across the entire stroke study sample. The highest odds ratio for developing a peak blood urea nitrogen≥ 45 was 19.8 for patients taking a diuretic who had dysphagia plus modified barium swallow evidence of penetration-aspiration.
Effects of Transcutaneous Electrical Nerve Stimulation (TENS) on Self-Efficacy and Mood in Elderly with Mild Cognitive Impairment
Authors: Luijpen Marijn W. , Swaab Dick F. , Sergeant Joseph A. , Scherder Erik J. A.
Published: September 2004

In previous studies, transcutaneous electrical nerve stimulation (TENS) has been applied to patients with either Alzheimer’s disease (AD) or incipient dementia, resulting in an enhancement in memory and verbal fluency. Moreover, affective behavior was shown to improve. Based on the positive effects of TENS in AD, it was hypothesized that TENS would improve self-efficacy in nondemented elderly with mild cognitive impairment (MCI) who live in a residential home. Four outcome measures, that is, a Dutch translation of the General Self-Efficacy Scale (Algemene Competentie Schaal), the Groninger Activity Restriction Scale, the Philadelphia Geriatric Center Morale Scale, and the Geriatric Depression Scale, were administered. Overall, the results suggest that the experimental group showed a mild improvement in self-efficacy and mood. In contrast, the placebo group showed a considerable reduction in self-efficacy and an increase in depression. Limitations of the present study and suggestions for future research are discussed.
Cerebellar Stroke Impairs Temporal but not Spatial Accuracy during Implicit Motor Learning
Authors: Boyd Lara A. , Winstein Carolee J.
Published: September 2004

Objective. Numerous studies have demonstrated cerebellar activity during implicit motor learning, but few have addressed its specific role. The purpose of this study was to determine if specific components (spatial or temporal) of an implicit motor-tracking task were affected by cerebellar stroke. Methods. The authors studied the performance of individuals with unilateral cerebellar stroke (n =7)and a control group (n = 10) across 3 acquisition days and at a delayed retention test as they practiced a unimanual tracking task with the contralesional upper extremity. Results. After cerebellar stroke, participants demonstrated reduced tracking errors for repeating sequences compared to random sequences; however, decomposition of tracking performance into temporal and spatial components revealed persistent deficits in tracking time lag despite improved spatial accuracy. A lesion analysis showed that the dentate nucleus was the only common region affected by all cerebellar strokes. Conclusions. During implicit motor learning, the cerebellum appears to participate in the formation of predictive strategies for the timing of motor responses, rather than for the accuracy of motor execution. Because deficits were found in the contralesional upper extremity, the authors suggest that this function is not lateralized to 1 hemisphere; cerebellar output may affect the formation of an internal model for timing movements in both upper extremities.
Role of trans-cellular IL-15 presentation in the activation of NK cell–mediated killing, which leads to enhanced tumor immunosurveillance
Authors: Kobayashi Hisataka , Dubois Sigrid , Sato Noriko , Sabzevari Helen , Sakai Yoshio , Waldmann Thomas A. , Tagaya Yutaka
Published: September 2004

Interleukin 15 (IL-15) is a critical factor for the proliferation and activation of natural killer (NK) and CD8 T cells. Recently, we demonstrated that IL-15Rα expressed on monocytes/dendritic cells captures and presents IL-15 to neighboring cells in trans (trans-presentation of IL-15) through cell-cell contact. In the current study, we provide evidence that the IL-15 presented in trans, but not soluble IL-15 at physiologic concentrations, augments the killing activity mediated by NK cells in vitro. In addition, transfection of IL-15Rα into a colon carcinoma cell line (MC38) enabled these cells to present IL-15 in trans to NK cells and augmented their killing activity, resulting in the efficient lysis of MC38 cells by NK cells in vitro. Furthermore, these transfected MC38 cells no longer form fatal pulmonary metastases in mice. It was also shown that NK cells play an important role in the rejection of MC38 cells under these circumstances. These results collectively suggest that the IL-15 trans-presentation mechanism operates in vivo to augment the tumor immune surveillance mechanism. Furthermore, our observation provides the scientific basis for a novel strategy to prevent cancer development/metastasis.
Deficiency of somatic hypermutation of the antibody light chain is associated with increased frequency of severe respiratory tract infection in common variable immunodeficiency
Authors: Andersen Pernille , Permin Henrik , Andersen Vagn , Schejbel Lone , Garred Peter , Svejgaard Arne , Barington Torben
Published: September 2004

Reduced levels of somatic hypermutation (SHM) have recently been described in IgG-switched immunoglobulin genes in a minority of patients with common variable immunodeficiency (CVID), demonstrating a disruption of the normal linkage between isotype switch and SHM. To see if, irrespective of isotype, there is a tendency to use unmutated immunoglobulin genes in CVID, we studied SHM in κ light-chain transcripts using a VκA27-specific restriction enzyme-based hot-spot mutation assay (IgκREHMA). Hot-spot mutations were found in 48% (median; reference interval, 28%-62%) of transcripts from 53 healthy controls. Values were significantly lower in 31 patients (median, 7.5%; range, 0%-73%; P < .0000001) of whom 24 (77%) had levels below the reference interval. Low levels of SHM correlated with increased frequency of severe respiratory tract infection (SRTI; P < .005), but not with diarrhea (P = .8). Mannose-binding lectin (MBL) deficiency also correlated with SRTI score (P = .009). However, the correlation of SHM and SRTI was also seen when only patients with normal MBL genotypes were analyzed (n = 18, P = .006). A slight decline of mutated fractions over years was noted (P = .01). This suggests that most patients with CVID fail to recruit affinity-maturated B cells, adding a qualitative deficiency to the quantitative deficiency characterizing these patients.
Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen
Authors: Rao Kanchan , Amrolia Persis J. , Jones Alison , Cale Catherine M. , Naik Paru , King Doug , Davies Graham E. , Gaspar H. Bobby , Veys Paul A.
Published: September 2004

The optimal approach to stem cell transplantation in children with immunodeficiency who lack a matched family donor is controversial. Unrelated donor stem cell transplantation gives equivalent outcome to mismatched family donor stem cell transplantation in severe combined immunodeficiency, whereas unrelated donors may be preferable in non–severe combined immunodeficiency children. However, unrelated donor stem cell transplantation with conventional conditioning regimens has been associated with significant treatment-related toxicity, particularly in non–severe combined immunodeficiency patients with preexisting organ dysfunction. We report the outcome of a series of 33 consecutive unrelated donor transplantations performed at our center in children with primary immunodeficiency using a reduced-intensity conditioning regimen between 1998 and 2001. We have compared these outcomes with a retrospective control cohort of 19 patients who underwent transplantation with myeloablative conditioning between 1994 and 1998. All children in both groups had primary engraftment. There was no statistical difference in the speed of immune reconstitution or incidence of graft-versus-host disease between the 2 groups. Overall survival was significantly better in the reduced-intensity conditioning group: 31 (94%) of 33 patients survived, compared with 10 (53%) of 19 in the myeloablative conditioning group (P = .014). We conclude that the reduced-intensity conditioning regimen results in improved survival and reduced transplantation-related mortality compared with myeloablative conditioning in high-risk patients undergoing unrelated donor transplantation.
Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors
Authors: Remberger Mats , Beelen Dietrich W. , Fauser Axel , Basara Nadezda , Basu Oliver , Ringdén Olle
Published: September 2004

The long-term follow-up of a study including 214 patients receiving either peripheral blood stem cells (PBSCs) or bone marrow (BM) from an HLA-A, -B, and -DR–compatible unrelated donor is presented. Median follow-up was 4.4 (2.3-7.3) and 5.0 (0.7-8.4) years in the 2 groups, respectively. Cumulative incidence of overall chronic graft-versus-host disease (GVHD) was similar in the 2 groups (78% vs 71%), while extensive chronic GVHD was significantly more common in the PBSC group compared with the BM group (39% vs 24%, P = .03). The 5-year transplant-related mortality (TRM) was 37% in the PBSC group and 35% in the BM controls (P = .7), and overall survival was 42% in both groups. The relapse incidences were 26% and 27% in the 2 groups, respectively, resulting in a disease-free survival of 41% in both groups. In conclusion, PBSCs from HLA-compatible unrelated donors results in similar outcome compared to BM but implies an increased risk for extensive chronic GVHD.
Enforced fucosylation of neonatal CD34+ cells generates selectin ligands that enhance the initial interactions with microvessels but not homing to bone marrow
Authors: Hidalgo Andrés , Frenette Paul S.
Published: September 2004

Hematopoietic progenitor/stem cell homing to the bone marrow requires the concerted action of several adhesion molecules. Endothelial P- and E-selectins play an important role in this process, but their ligands on a large subset of neonate-derived human CD34+ cells are absent, leading to a reduced ability to interact with the bone marrow (BM) microvasculature. We report here that this deficiency results from reduced α1,3-fucosyltransferase (FucT) expression and activity in these CD34+ cells. Incubation of CD34+ cells with recombinant human FucTVI rapidly corrected the deficiency in nonbinding CD34+ cells and further increased the density of ligands for both P- and E-selectins on all cord blood–derived CD34+ cells. Intravital microscopy studies revealed that these FucTVI-treated CD34+ cells displayed a marked enhancement in their initial interactions with the BM microvasculature, but unexpectedly, homing into the BM was not improved by FucTVI treatment. These data indicate that, although exogenous FucT enzyme activity can rapidly modulate selectin binding avidity of cord blood CD34+ cells, further studies are needed to understand how to translate a positive effect on progenitor cell adhesion in bone marrow microvessels into one that significantly influences migration and lodgement into the parenchyma.
Role of the renin-angiotensin system in primitive erythropoiesis in the chick embryo
Authors: Savary Katia , Michaud Annie , Favier Judith , Larger Etienne , Corvol Pierre , Gasc Jean-Marie
Published: September 2004

Inactivation of the gene encoding mouse angiotensin I-converting enzyme (ACE), which converts angiotensin I into angiotensin II, results in anemia in adult animals. This anemia is corrected by angiotensin II, demonstrating the involvement of angiotensin II in adult (definitive) erythropoiesis. We investigated the possible role of the renin-angiotensin system (RAS) in primitive erythropoiesis in the yolk sac of the chicken embryo. Enzymatically active ACE was detected in the yolk sac endoderm, concomitantly with the differentiation of blood islands in the adjacent yolk sac mesoderm. The simultaneous presence of all the other components of the RAS (renin, angiotensinogen, angiotensin II receptor) in the vicinity of the blood islands suggests that this system is involved in erythropoiesis. This role was confirmed by in vivo blockade of the RAS with fosinoprilate, a specific inhibitor of chicken ACE, which decreased hematocrit by 15%. A similar decrease in hematocrit was observed following treatment with the angiotensin II receptor antagonist Sar1-Ile8-Angiotensin II, suggesting that this effect was mediated by angiotensin II. Both treatments affected hematocrit by decreasing erythroblast proliferation. Thus, the RAS, and its effector peptide angiotensin II in particular, modulates primitive erythropoiesis.
A sustained and pancellular reversal of gamma-globin gene silencing in adult human erythroid precursor cells
Authors: Bhanu Natarajan V. , Trice Tiffany A. , Lee Y. Terry , Gantt Nicole M. , Oneal Patricia , Schwartz Joseph D. , Noel Pierre , Miller Jeffery L.
Published: September 2004

We systematically compared cytokine-mediated increases or decreases in proliferation with globin gene and protein expression in adult human erythroblasts. Despite their opposite effects on growth, stem cell factor (SCF) and transforming growth factorbeta (TGF-B) had synergistic effects with respect to fetal hemoglobin (HbF): average HbF/HbF + adult hemoglobin (HbA) ratio in erythropoietin (EPO) = 1.4 ± 1.0%; EPO + TGF-B = 10.8 ± 1.9%; EPO + SCF = 19.1 ± 6.2%; and EPO + SCF + TGF-B (EST) = 39.3 ± 6.3%. Polymerase chain reaction (PCR) revealed significant increases in gamma-globin transcripts that were balanced by reduced beta-globin transcripts. Single-cell quantitative PCR demonstrated a complete reversal of gamma-globin gene silencing with detectable gamma-globin mRNA in more than 95% of the cells. Immunostaining with HbF antibodies also showed a pancellular distribution in EST (96.2 ± 0.01% HbF positive) compared with a heterocellular distribution in EPO (42.9 ± 0.01% HbF positive). As shown here for the first time, a robust and pancellular reversal of gamma-globin gene silencing among hemoglobinized erythroblasts from adult humans may be achieved in the absence of hereditary mutation or direct genomic manipulation. (Blood. 2005;105:387-393)
ICAM-1 recycling in endothelial cells: a novel pathway for sustained intracellular delivery and prolonged effects of drugs
Authors: Muro Silvia , Gajewski Christine , Koval Michael , Muzykantov Vladimir R.
Published: September 2004

Intercellular adhesion molecule-1 (ICAM-1) is a target for drug delivery to endothelial cells (ECs), which internalize multivalent anti-ICAM nanocarriers (anti-ICAM/NCs) within 15 to 30 minutes. The concomitant ICAM-1 disappearance from the EC surface transiently inhibited subsequent binding and uptake of anti-ICAM/NCs. Within 1 hour, internalized ICAM-1 diverged from anti-ICAM/NCs into prelysosomal vesicles, resurfaced, and enabled uptake of a subsequent anti-ICAM/NC dose. Thus, internalized ICAM-1 was able to recycle back to the plasma membrane. In vivo pulmonary targeting of a second anti-ICAM/NC dose injected 15 minutes after the first dose was decreased by 50% but recovered between 30 minutes and 2.5 hours, comparable to cultured ECs. Anti-ICAM/NCs affected neither EC viability nor fluid-phase endocytosis and traffic to lysosomes. However, lysosomal trafficking of the second dose of anti-ICAM/NCs was decelerated at least 2-fold versus the first dose; hence the major fraction of anti-ICAM/NCs resided in prelysosomal vesicles for at least 5 hours without degradation. Two successive doses of anti-ICAM/NC/catalase protected ECs against H2O2 for at least 8 hours versus 2 hours afforded by a single dose, suggesting that recurrent targeting to ICAM-1 affords longer effects. ICAM-1 recycling and inhibited lysosomal traffic/degradation of subsequent doses may help to prolong activity of therapeutic agents delivered into ECs by anti-ICAM/NCs.
The efficiency of transfusing high doses of platelets in hematologic patients with thrombocytopenia: results of a prospective, randomized, open, blinded end point (PROBE) study
Authors: Sensebé Luc , Giraudeau Bruno , Bardiaux Laurent , Deconinck Eric , Schmidt Aline , Bidet Marie-Laure , LeNiger Catherine , Hardy Elisabeth , Babault Catherine , Senecal Delphine
Published: September 2004

We performed a prospective, randomized, open, blinded end point (PROBE) study to assess the efficiency of transfusing high doses of platelets in patients with thrombocytopenia, either acute leukemia (AL) or those undergoing autologous hematopoietic stem cell transplantation (AT). Patients were randomly assigned to receive transfusions with a target dose of 0.5 × 1011/10 kg (arm A) or 1 × 1011/10 kg (arm B). A total of 101 patients were included, of whom 96 were given at least one transfusion. The median time between the first transfusion and when the platelet count reached at least 20 × 109/L increased from 63 hours to 95 hours in the arm B group (P = .001), and the median number of transfusions was lower in this group (2; P = .037). The total number of transfused platelets did not differ between groups (14.9 × 1011 for arm A versus 18.5 × 1011 for arm B; P = .156). In such patients, a prophylactic strategy of high doses of platelets could improve platelet transfusion efficiency.
Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin
Authors: Studt Jan-Dirk , Hovinga Johanna A. Kremer , Antoine Gerhard , Hermann Martin , Rieger Manfred , Scheiflinger Friedrich , Lämmle Bernhard
Published: September 2004

Severe ADAMTS13 deficiency in thrombotic thrombocytopenic purpura (TTP) is either constitutional and caused by ADAMTS13 mutations, or acquired and most often due to ADAMTS13 inhibitory autoantibodies. In strongly hemolytic serum of a pediatric patient, diagnosed with TTP postmortem, ADAMTS13 activity was less than 3%. Both parents had an ADAMTS13 activity of approximately 50%. Sequencing of the ADAMTS13 gene revealed an intronic 687-2A>G substitution affecting exon 7, homozygous in the propositus and heterozygous in both parents, confirming constitutional ADAMTS13 deficiency. ADAMTS13 activity of normal plasma was inhibited by incubation with the propositus' serum, suggesting alloantibody formation to ADAMTS13. However, immunoglobulin purified from serum had no ADAMTS13 inhibitory effect, whereas the immunoglobulin-depleted hemolytic serum inhibited ADAMTS13 activity of normal plasma, suggesting an inhibitory effect of hemolysis products. Incubation of hemoglobin, recombinant and from lysed erythrocytes, with normal plasma revealed an ADAMTS13 inhibitory effect at hemoglobin concentrations of 2 g/L or higher.
Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell–mediated elimination of tumor cells
Authors: Palumbo Joseph S. , Talmage Kathryn E. , Massari Jessica V. , La Jeunesse Christine M. , Flick Matthew J. , Kombrinck Keith W. , Jirousková Markéta , Degen Jay L.
Published: September 2004

To test the hypothesis that platelet activation contributes to tumor dissemination, we studied metastasis in mice lacking Gαq, a G protein critical for platelet activation. Loss of platelet activation resulted in a profound diminution in both experimental and spontaneous metastases. Analyses of the distribution of radiolabeled tumor cells demonstrated that platelet function, like fibrinogen, significantly improved the survival of circulating tumor cells in the pulmonary vasculature. More detailed studies showed that the increase in metastatic success conferred by either platelets or fibrinogen was linked to natural killer cell function. Specifically, the pronounced reduction in tumor cell survival observed in fibrinogen- and Gαq-deficient mice relative to control animals was eliminated by the immunologic or genetic depletion of natural killer cells. These studies establish an important link between hemostatic factors and innate immunity and indicate that one mechanism by which the platelet-fibrin(ogen) axis contributes to metastatic potential is by impeding natural killer cell elimination of tumor cells.
Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo
Authors: Lin Boris , Catley Laurence , LeBlanc Richard , Mitsiades Constantine , Burger Renate , Tai Yu-Tzu , Podar Klaus , Wartmann Markus , Chauhan Dharminder , Griffin James D. , Anderson Kenneth C.
Published: September 2004

In this study, we investigated the in vitro and in vivo efficacy of patupilone (epothilone B, EPO906), a novel nontaxane microtubule stabilizing agent, in treatment of multiple myeloma (MM). Patupilone directly inhibited growth and survival of MM cells, including those resistant to conventional chemotherapies, such as the taxane paclitaxel. Patupilone induced G2M arrest of MM cells, with subsequent apoptosis. Interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1), 2 known growth and survival factors for MM, did not protect MM.1S cells against patupilone-induced cell death. Proliferation of MM cells induced by adherence to bone marrow stromal cells (BMSCs) was also inhibited by patupilone and was paralleled by down-regulation of vascular endothelial growth factor (VEGF) secretion. Importantly, stimulation of cells from patients with MM, either with IL-6 or by adherence to BMSCs, enhanced the anti-proliferative and proapoptotic effects of patupilone. Moreover, patupilone was effective against MM cell lines that overexpress the MDR1/P-glycoprotein multidrug efflux pump. In addition, patupilone was effective in slowing tumor growth and prolonging median survival of mice that received orthotopical transplants with MM tumor cells. Taken together, these preclinical findings suggest that patupilone may be a safe and effective drug in the treatment of MM, providing the framework for clinical studies to improve patient outcome in MM. (Blood. 2005;105:350-357)
Immunogenicity of Bcl-2 in patients with cancer
Authors: Andersen Mads Hald , Svane Inge Marie , Kvistborg Pia , Nielsen Ove Juul , Balslev Eva , Reker Sine , Becker Jürgen C. , Straten Per thor
Published: September 2004

B-cell lymphoma 2 (Bcl-2) is a pivotal regulator of apoptotic cell death and it is overexpressed in many cancers. Consequently, the Bcl-2 protein is an attractive target for drug design, and Bcl-2–specific antisense oligonucleotides or small-molecule Bcl-2 inhibitors have shown broad anticancer activities in preclinical models and are currently in several clinical trials. The clinical application of immunotherapy against cancer is rapidly moving forward in multiple areas, including the adoptive transfer of anti–tumor-reactive T cells and the use of “therapeutic” vaccines. The overexpression of Bcl-2 in cancer and the fact that immune escape by down-regulation or loss of expression of this protein would impair sustained tumor growth makes Bcl-2 a very attractive target for anticancer immunotherapy. Herein, we describe spontaneous T-cell reactivity against Bcl-2 in peripheral blood from patients suffering from unrelated tumor types (ie, pancreatic cancer, breast cancer, acute myeloid leukemia [AML], and chronic lymphocytic leukemia [CLL]). Additionally, we show that these Bcl-2–reactive T cells are indeed peptide-specific, cytotoxic effector cells. Thus, Bcl-2 may serve as an important and widely applicable target for anticancer immunotherapeutic strategies (eg, in the combination with conventional radiotherapy and chemotherapy).
Determination of the differentially expressed genes in microarray experiments using local FDR
Authors: Aubert J , Bar-Hen A , Daudin J-J , Robin S
Published: September 2004

Background

Thousands of genes in a genomewide data set are tested against some null hypothesis, for detecting differentially expressed genes in microarray experiments. The expected proportion of false positive genes in a set of genes, called the False Discovery Rate (FDR), has been proposed to measure the statistical significance of this set. Various procedures exist for controlling the FDR. However the threshold (generally 5%) is arbitrary and a specific measure associated with each gene would be worthwhile.

Results

Using process intensity estimation methods, we define and give estimates of the local FDR, which may be considered as the probability for a gene to be a false positive. After a global assessment rule controlling the false positive error, the local FDR is a valuable guideline for deciding wether a gene is differentially expressed. The interest of the method is illustrated on three well known data sets. A R routine for computing local FDR estimates from p-values is available at http://www.inapg.fr/ens_rech/mathinfo/recherche/mathematique/outil.html.

Conclusions

The local FDR associated with each gene measures the probability that it is a false positive. It gives the opportunity to compute the FDR of any given group of clones (of the same gene) or genes pertaining to the same regulation network or the same chromosomic region.
DIALIGN P: Fast pair-wise and multiple sequence alignment using parallel processors
Authors: Schmollinger Martin , Nieselt Kay , Kaufmann Michael , Morgenstern Burkhard
Published: September 2004

Background

Parallel computing is frequently used to speed up computationally expensive tasks in Bioinformatics.

Results

Herein, a parallel version of the multi-alignment program DIALIGN is introduced. We propose two ways of dividing the program into independent sub-routines that can be run on different processors: (a) pair-wise sequence alignments that are used as a first step to multiple alignment account for most of the CPU time in DIALIGN. Since alignments of different sequence pairs are completely independent of each other, they can be distributed to multiple processors without any effect on the resulting output alignments. (b) For alignments of large genomic sequences, we use a heuristics by splitting up sequences into sub-sequences based on a previously introduced anchored alignment procedure. For our test sequences, this combined approach reduces the program running time of DIALIGN by up to 97%.

Conclusions

By distributing sub-routines to multiple processors, the running time of DIALIGN can be crucially improved. With these improvements, it is possible to apply the program in large-scale genomics and proteomics projects that were previously beyond its scope.