bluuebunny/crossref_metadata_2025 huggingface dataset:
Civic Service in Western Europe
Authors: Smith Justin Davis
Published: November 2004

This article reviews current research and debates on civic service in Western Europe. Drawing a distinction between civic service and traditional volunteering, it traces the history of the concept in the region and the resurgence of government interest in it over the past decade, fueled in particular by the decline in military service brought about by the end of the Cold War. The article explores both the strengths and weaknesses of government action in this field and looks at the challenges facing the voluntary sector in managing its development. It concludes with a review of the evidence of the effect of civic service on the key stakeholder groups and makes recommendations for policy makers, for practitioners, and for further research.
Civic Service in the Arab Region
Authors: Kandil Amani
Published: November 2004

This article summarizes historical and cultural influences on the development of voluntary action in the Arab region. The role of religion is highlighted. Also discussed are demo-graphic, economic, and political factors that have influenced the development of volunteer and civic service programs in the region. Although systematic information and research are limited, civic service program examples are detailed. These examples include religiously based service programs, service-learning programs at the university level, and local programs. Official civic service initiatives and national policies are not specified or widespread, but program developments may have the potential to develop into such policies. More research is recommended regarding the role of the state and civil society in the development of civic service programs and the role of civic service in social and economic development.
Developing a Research Agenda on Civic Service
Authors: Hodgkinson Virginia A.
Published: November 2004

This article evaluates the state of research on civic service as presented by the authors of this volume. The article reviews various issues related to the research, including definitions, the purposes of programs, the programs’ sponsors, and the forms and goals of civic service programs and recommends steps needed to develop a research agenda potentially leading to a new field of study.
Civic Service in East Asia and the Pacific
Authors: Co Edna Estifania A.
Published: November 2004

Civic service in the East Asia and Pacific region is historically complex and is currently not equivalent to the Western concept of civic service. Civic service in the region began as a concept and practice of moral suasion and responsibility to nation, obeisance to authority, and traditional belief of coresponsibility to serve and help others. In the beginning, acts of civic service were led and managed by the state. As colonialism waned and independence ensued, civic service assumed democratic features characterized by the emergence of voluntary groups that rendered service and less state centeredness, and the forms significantly changed from patriotic acts of national defense to localized community development. Several developments became obvious: international service rather than just locally based service, leadership by voluntary organizations, and expressions of service across age groups and service providers. Implications for research on the nature, forms, and effects of service are noted.
Dharma Dancing: Ballroom Dancing and the Relational Order
Authors: Picart Caroline Joan (Kay) S. , Gergen Kenneth
Published: November 2004

Extending Norman Denzin’s innovations in ethnography, and reflecting his concerns with cultural interpretation and visual media, this article offers a multimedia excursion into the conjunction of ballroom dancing and relational theory. By creating a relationship between multiple media (photography and videography) and modes of human communication (poetry, prose, dance, visual art), the article brings forth possibilities not contained in any one alone. Simultaneously, the authors attempt to expand on the implications of relational theory. Through visual art, poetry, and prose, the authors discover new facets of what it means to be related and variously bring into focus issues of aesthetics, gender, power, and the dynamics of daily life.
Positionality and the Pen: Reflections on the Process of Becoming a Feminist Researcher and Writer
Authors: Deutsch Nancy L.
Published: November 2004

During her years as a graduate student, the author was involved in not only the outward process of research but also the inward process of developing her own identity as a researcher. This article outlines her experiences as a woman and as a researcher engaging in the process of becoming a qualitative researcher and writer. It grapples with the issues she faced during her fieldwork, specifically, with concerns about her own positionality in relation to her research participants, and discusses how feminist methodology both challenged her and allowed her to see herself as part of a research community. By telling her story, she hopes both to create a more honest analytic process for her own research and to reassure other young feminist researchers that they are not alone.
Enabling Reflexivity in a Mentoring Relationship
Authors: Chawla Devika , Rawlins William K.
Published: November 2004

This essay enacts a performance space in which the authors explore (an) “enabling” reflexivity through reconstructed conversations and a dialogic metanarrative about their evolving relationship as doctoral student and advisor. They narrate turning points, setbacks, and triumphs that show their struggles to evolve as intellectuals deeply committed to embodying the beneficial interrelations among their public and private dialogues. Their goal is to summon the reader and listener to reflect on her or his own ideas about the inherent embeddedness of intellectual and personal life in mentoring relationships. Their hope is that through showing, telling, doing, and witnessing, this performance space enables moments of reflexivity among listeners and readers.
HOXB6 overexpression in murine bone marrow immortalizes a myelomonocytic precursor in vitro and causes hematopoietic stem cell expansion and acute myeloid leukemia in vivo
Authors: Fischbach Neal A. , Rozenfeld Sofia , Shen Weifang , Fong Stephen , Chrobak Daniel , Ginzinger David , Kogan Scott C. , Radhakrishnan Archana , Le Beau Michelle M. , Largman Corey , Lawrence H. Jeffrey
Published: November 2004

The HOX family of homeobox genes plays an important role in normal and malignant hematopoiesis. Dysregulated HOX gene expression profoundly effects the proliferation and differentiation of hematopoietic stem cells (HSCs) and committed progenitors, and aberrant activation of HOX genes is a common event in human myeloid leukemia. HOXB6 is frequently overexpressed in human acute myeloid leukemia (AML). To gain further insight into the role of HOXB6 in hematopoiesis, we overexpressed HOXB6 in murine bone marrow using retrovirus-mediated gene transfer. We also explored structure-function relationships using mutant HOXB6 proteins unable to bind to DNA or a key HOX-binding partner, pre–B-cell leukemia transcription factor-1 (PBX1). Additionally, we investigated the potential cooperative interaction with myeloid ecotropic viral integration site 1 homolog (MEIS1). In vivo, HOXB6 expanded HSCs and myeloid precursors while inhibiting erythropoiesis and lymphopoiesis. Overexpression of HOXB6 resulted in AML with a median latency of 223 days. Coexpression of MEIS1 dramatically shortened the onset of AML. Cytogenetic analysis of a subset of HOXB6-induced AMLs revealed recurrent deletions of chromosome bands 2D-E4, a region frequently deleted in HOXA9-induced AMLs. In vitro, HOXB6 immortalized a factor-dependent myelomonocytic precursor capable of granulocytic and monocytic differentiation. These biologic effects of HOXB6 were largely dependent on DNA binding but independent of direct interaction with PBX1.
An erythroid differentiation–specific splicing switch in protein 4.1R mediated by the interaction of SF2/ASF with an exonic splicing enhancer
Authors: Yang Guang , Huang Shu-Ching , Wu Jane Y. , Benz Edward J.
Published: November 2004

Protein 4.1R is a vital component of the red blood cell membrane cytoskeleton. Promotion of cytoskeletal junctional complex stability requires an erythroid differentiation stage–specific splicing switch promoting inclusion of exon 16 within the spectrin/actin binding domain. We showed earlier that an intricate combination of positive and negative RNA elements controls exon 16 splicing. In this report, we further identified 3 putative exonic splicing enhancers within exon 16 and investigated the function of the sequence CAGACAT in the regulation of exon 16 splicing. Mutation of these sequences leads to increased exclusion of exon 16 in both in vivo and in vitro splicing assays, indicating that CAGACAT is a functional exonic splicing enhancer. UV cross-linking further detects an approximately 33-kDa protein that specifically binds to the CAGACAT-containing transcript. An anti-SF2/ASF antibody specifically immunoprecipitates the approximately 33-kDa protein. Furthermore, SF2/ASF stimulates exon 16 inclusion in both in vitro complementation assays and minigene-transfected mouse erythroleukemia cells (MELCs). Finally, SF2/ASF expression is up-regulated and correlates with exon 16 inclusion in differentiated MELCs. These results suggest that increased splicing factor 2/alternative splicing factor (SF2/ASF) expression in differentiated mouse erythroleukemia mediates a differentiation stage–specific exon 16 splicing switch through its interaction with the exonic splicing enhancer.
Deregulated expression of the Myc cellular oncogene drives development of mouse “Burkitt-like” lymphomas from naive B cells
Authors: Zhu Delin , Qi Chen Feng , Morse Herbert C. , Janz Siegfried , Stevenson Freda K.
Published: November 2004

Chromosomal translocations juxtaposing immunoglobulin (Ig) and MYC genes are the hallmarks of human Burkitt lymphoma (BL), with deregulated MYC expression being a critical factor in pathogenesis. By inserting an intact mouse Myc gene into the mouse genome, proximal to the Ig enhancer Eμ, the effect of a precise mimic of the major t(8;14) translocation of human endemic BL (eBL) could be investigated. Knock-in mice developed IgM-positive B-cell tumors, with most being typical of eBL by histology and immunophenotype, including expression of the germinal center (GC)–associated protein, BCL6. Unlike eBL, however, analysis of Ig VH sequences revealed no significant level of somatic mutation. Thus, constitutive expression of Myc in the knock-in mice is apparently able to induce “Burkitt-like” lymphomas before antigen stimulation and formation of a GC. In contrast, human eBL development occurs in a GC or post-GC site with a likely contribution to pathogenesis from Epstein-Barr virus (EBV) and other epigenetic factors.
Neuropilin-1 regulates attachment in human endothelial cells independently of vascular endothelial growth factor receptor-2
Authors: Murga Matilde , Fernandez-Capetillo Oscar , Tosato Giovanna
Published: November 2004

Neuropilin-1 (NRP-1) is a type 1 membrane protein that binds the axon guidance factors belonging to the class-3 semaforin family. In endothelial cells, NRP-1 serves as a co-receptor for vascular endothelial growth factor (VEGF) and regulates VEGF receptor 2 (VEGFR-2)–dependent angiogenesis. Although gene-targeting studies documenting embryonic lethality in NRP-1 null mice have demonstrated a critical role for NRP-1 in vascular development, the activities of NRP-1 in mature endothelial cells have been incompletely defined. Using RNA interference-mediated silencing of NRP-1 or VEGFR-2 in primary human endothelial cells, we confirm that NRP-1 modulates VEGFR-2 signaling-dependent mitogenic functions of VEGF. Importantly, we now show that NRP-1 regulates endothelial cell adhesion to extracellular matrix proteins independently of VEGFR-2. Based on its dual role as an enhancer of VEGF activity and a mediator of endothelial cell adhesiveness described here, NRP-1 emerges as a promising molecular target for the development of antiangiogenic drugs.
Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis
Authors: Nie Guangjun , Sheftel Alex D. , Kim Sangwon F. , Ponka Prem
Published: November 2004

Cytosolic ferritin sequesters and stores iron and, consequently, protects cells against iron-mediated free radical damage. However, the function of the newly discovered mitochondrial ferritin (MtFt) is unknown. To examine the role of MtFt in cellular iron metabolism, we established a cell line that stably overexpresses mouse MtFt under the control of a tetracycline-responsive promoter. The overexpression of MtFt caused a dose-dependent iron deficiency in the cytosol that was revealed by increased RNA-binding activity of iron regulatory proteins (IRPs) along with an increase in transferrin receptor levels and decrease in cytosolic ferritin. Consequently, the induction of MtFt resulted in a dramatic increase in cellular iron uptake from transferrin, most of which was incorporated into MtFt. The induction of MtFt caused a shift of iron from cytosolic ferritin to MtFt. In addition, iron inserted into MtFt was less available for chelation than that in cytosolic ferritin and the expression of MtFt was associated with decreased mitochondrial and cytosolic aconitase activities, the latter being consistent with the increase in IRP-binding activity. In conclusion, our results indicate that overexpression of MtFt causes a dramatic change in intracellular iron homeostasis and that shunting iron to MtFt likely limits its availability for active iron proteins.
Hematopoietic stem cells from NOD mice exhibit autonomous behavior and a competitive advantage in allogeneic recipients
Authors: Chilton Paula M. , Rezzoug Francine , Ratajczak Mariusz Z. , Fugier-Vivier Isabelle , Ratajczak Janina , Kucia Magda , Huang Yiming , Tanner Michael K. , Ildstad Suzanne T.
Published: November 2004

Type 1 diabetes is a systemic autoimmune disease that can be cured by transplantation of hematopoietic stem cells (HSCs) from disease-resistant donors. Nonobese diabetic (NOD) mice have a number of features that distinguish them as bone marrow transplant recipients that must be understood prior to the clinical application of chimerism to induce tolerance. In the present studies, we characterized NOD HSCs, comparing their engraftment characteristics to HSCs from disease-resistant strains. Strikingly, NOD HSCs are significantly enhanced in engraftment potential compared with HSCs from disease-resistant donors. Unlike HSCs from disease-resistant strains, they do not require graft-facilitating cells to engraft in allogeneic recipients. Additionally, they exhibit a competitive advantage when coadministered with increasing numbers of syngeneic HSCs, produce significantly more spleen colony-forming units (CFU-Ss) in vivo in allogeneic recipients, and more granulocyte macrophage–colony-forming units (CFU-GMs) in vitro compared with HSCs from disease-resistant controls. NOD HSCs also exhibit significantly enhanced chemotaxis to a stromal cell–derived factor 1 (SDF-1) gradient and adhere significantly better on primary stroma. This enhanced engraftment potential maps to the insulin-dependent diabetes locus 9 (Idd9) locus, and as such the tumor necrosis factor (TNF) receptor family as well as ski/sno genes may be involved in the mechanism underlying the autonomy of NOD HSCs. These findings may have important implications to understand the evolution of autoimmune disease and impact on potential strategies for cure.
High throughput mRNA profiling highlights associations between myocardial infarction and aberrant expression of inflammatory molecules in blood cells
Authors: Bezzina Wettinger Stephanie , Doggen Carine J. M. , Spek C. Arnold , Rosendaal Frits R. , Reitsma Pieter H.
Published: November 2004

Studies on the role of inflammation in cardiovascular disease focus on surrogate markers like plasma levels of C-reactive protein or interleukins that are affected by several factors. In this study we employ an approach in which the inflammatory mRNA profile of leucocytes is measured directly in a multigene system. We investigated the mRNA profile for 35 inflammatory markers in blood samples in a case-control study including 524 men with a history of myocardial infarction and 628 control subjects. Compared with controls, patients showed mRNA profiles with increased levels of most inflammatory mRNAs. The 2 most prominent mRNA risk indicators encoded the secreted protein macrophage migration inhibitory factor (crude odds ratio [OR], 3.4 for the highest quartile versus the lowest quartile (95% confidence interval [CI95], 2.3-4.9), and the intracellular regulator proteinase inhibitor 9 (OR, 2.5 for the highest versus the lowest quartile (CI95, 1.8-3.5), both showing an increase in odds ratio with increasing quartiles. Leucocytes in the blood of patients with myocardial infarction are more active in transcription of inflammatory genes, as evidenced by mRNA profiling. These data support the hypothesis that an inflammatory response involving leucocytes plays a role in the pathogenesis of myocardial infarction.
Gapped alignment of protein sequence motifs through Monte Carlo optimization of a hidden Markov model
Authors: Neuwald Andrew F , Liu Jun S
Published: November 2004

Background

Certain protein families are highly conserved across distantly related organisms and belong to large and functionally diverse superfamilies. The patterns of conservation present in these protein sequences presumably are due to selective constraints maintaining important but unknown structural mechanisms with some constraints specific to each family and others shared by a larger subset or by the entire superfamily. To exploit these patterns as a source of functional information, we recently devised a statistically based approach called c ontrast h ierarchical a lignment and i nteraction n etwork (CHAIN) analysis, which infers the strengths of various categories of selective constraints from co-conserved patterns in a multiple alignment. The power of this approach strongly depends on the quality of the multiple alignments, which thus motivated development of theoretical concepts and strategies to improve alignment of conserved motifs within large sets of distantly related sequences.

Results

Here we describe a hidden Markov model (HMM), an algebraic system, and Markov chain Monte Carlo (MCMC) sampling strategies for alignment of multiple sequence motifs. The MCMC sampling strategies are useful both for alignment optimization and for adjusting position specific background amino acid frequencies for alignment uncertainties. Associated statistical formulations provide an objective measure of alignment quality as well as automatic gap penalty optimization. Improved alignments obtained in this way are compared with PSI-BLAST based alignments within the context of CHAIN analysis of three protein families: Giα
subunits, prolyl oligopeptidases, and transitional endoplasmic reticulum (p97) AAA+ ATPases.

Conclusion

While not entirely replacing PSI-BLAST based alignments, which likewise may be optimized for CHAIN analysis using this approach, these motif-based methods often more accurately align very distantly related sequences and thus can provide a better measure of selective constraints. In some instances, these new approaches also provide a better understanding of family-specific constraints, as we illustrate for p97 ATPases. Programs implementing these procedures and supplementary information are available from the authors.
Multivariate search for differentially expressed gene combinations
Authors: Xiao Yuanhui , Frisina Robert , Gordon Alexander , Klebanov Lev , Yakovlev Andrei
Published: November 2004

Background

To identify differentially expressed genes, it is standard practice to test a two-sample hypothesis for each gene with a proper adjustment for multiple testing. Such tests are essentially univariate and disregard the multidimensional structure of microarray data. A more general two-sample hypothesis is formulated in terms of the joint distribution of any sub-vector of expression signals.

Results

By building on an earlier proposed multivariate test statistic, we propose a new algorithm for identifying differentially expressed gene combinations. The algorithm includes an improved random search procedure designed to generate candidate gene combinations of a given size. Cross-validation is used to provide replication stability of the search procedure. A permutation two-sample test is used for significance testing. We design a multiple testing procedure to control the family-wise error rate (FWER) when selecting significant combinations of genes that result from a successive selection procedure. A target set of genes is composed of all significant combinations selected via random search.

Conclusions

A new algorithm has been developed to identify differentially expressed gene combinations. The performance of the proposed search-and-testing procedure has been evaluated by computer simulations and analysis of replicated Affymetrix gene array data on age-related changes in gene expression in the inner ear of CBA mice.
Gel shift analysis of the empA promoter region in Vibrio anguillarum
Authors: Denkin Steven M , Sekaric Pedja , Nelson David R
Published: November 2004

Background

The induction of metalloprotease encoded by empA in Vibrio anguillarum occurs at high cell density in salmon intestinal mucus. Previously we have shown that there are significant differences in empA expression in two strains of V. anguillarum, M93Sm and NB10. It is hypothesized that differences in empA regulation are due to differences in binding of regulatory elements.

Results

Two strains of V. anguillarum, M93Sm and NB10, were examined and compared for the presence of DNA regulatory proteins that bind to and control the empA promoter region. Gel mobility shift assays, using a digoxigenin (DIG)-labeled oligomer containing a lux box-like element and the promoter for empA, were done to demonstrate the presence of a DNA-binding protein. Protein extracts from NB10 cells incubated in Luria Bertani broth + 2% NaCl (LB20), nine salts solution + 200 μg/ml mucus (NSSM), 3M (marine minimal medium), or NSS resulted in a gel mobility shift. No gel mobility shift was seen when protein extracts from either LB20- or NSSM-grown M93Sm cells were mixed with the DIG-labeled empA oligomer. The azocasein assay detected protease activity in all incubation conditions for NB10 culture supernatants. In contrast, protease activity was detected in M93Sm culture supernatants only when incubated in NSSM. Since the luxR homologue in V. anguillarum, vanT, has been cloned, sequenced, and shown to be required for protease activity, we wanted to determine if vanT mutants of NB10 exhibit the same gel shift observed in the wild-type. Site-directed mutagenesis was used to create vanT mutants in V. anguillarum M93Sm and NB10 to test whether VanT is involved with the gel mobility shift. Both vanT mutants, M02 and NB02, did not produce protease activity in any conditions. However, protein extracts from NB02 incubated in each condition still exhibited a gel shift when mixed with the DIG-labeled empA oligomer.

Conclusions

The data demonstrate that protein extracts of V. anguillarum NB10 cells contain a protein that binds to a 50 bp oligomer containing the empA promoter-lux box-like region. NB10 cells express empA during stationary phase in all growth conditions. The DNA binding protein is not present in M93Sm extracts. M93Sm cells express protease activity only when incubated at high cell density in fish gastrointestinal mucus. The gel shift observed with NB10 cells is not due to VanT binding. The data also suggest that the DNA binding protein is responsible for the less restrictive expression of empA in NB10 compared to M93Sm.
Long-term age-dependent behavioral changes following a single episode of fetal N-methyl-D-Aspartate (NMDA) receptor blockade
Authors: Mickley G Andrew , Kenmuir Cynthia L , McMullen Colleen A , Snyder Alicia , Yocom Anna M , Likins-Fowler Deborah , Valentine Elizabeth L , Weber Bettina , Biada Jaclyn M
Published: November 2004

Background

Administration of the N-methyl-D-aspartate (NMDA) antagonist ketamine during the perinatal period can produce a variety of behavioral and neuroanatomical changes. Our laboratory has reported reliable changes in learning and memory following a single dose of ketamine administered late in gestation. However, the nature of the drug-induced changes depends on the point during embryonic development when ketamine is administered. Embryonic day 18 (E18) rat fetuses pre-treated with ketamine (100 mg/kg, i.p. through the maternal circulation) and taught a conditioned taste aversion (CTA) learn and remember the CTA, whereas E19 fetuses do not. The current study sought to determine if long-term behavioral effects could be detected in animals that received ketamine or a saline control injection on either E18 or E19. Rat behavior was evaluated on two different measures: spontaneous locomotion and water maze learning. Measurements were collected during 2 periods: Juvenile test period [pre-pubertal locomotor test: Postnatal Day 11 (P11); pre-pubertal water maze test: P18] or Young-adult test period [post-pubertal locomotor test: P60; post-pubertal water maze test: P81].

Results

Water maze performance of ketamine-treated rats was similar to that of controls when tested on P18. Likewise, the age of the animal at the time of ketamine/saline treatment did not influence learning of the maze. However, the young-adult water maze test (P81) revealed reliable benefits of prenatal ketamine exposure – especially during the initial re-training trial. On the first trial of the young adult test, rats treated with ketamine on E18 reached the hidden platform faster than any other group – including rats treated with ketamine on E19. Swim speeds of experimental and control rats were not significantly different. Spontaneous horizontal locomotion measured during juvenile testing indicated that ketamine-treated rats were less active than controls. However, later in development, rats treated with ketamine on E18 were more active than rats that received the drug on E19.

Conclusion

These data suggest that both the day in fetal development when ketamine is administered and the timing of post-natal behavioral testing interact to influence behavioral outcomes. The data also indicate that the paradoxical age-dependent effects of early ketamine treatment on learning, previously described in fetuses and neonates, may also be detected later in young adult rats.
Gastro-enteritis outbreak among Nordic patients with psoriasis in a health centre in Gran Canaria, Spain: a cohort study
Authors: Eriksen Hanne M , Guerin Philippe J , Nygård Karin , Hjertqvist Marika , de Jong Birgitta , Rose Angela MC , Kuusi Markku , Durr Ulrike , Rojas AG , Mør Cato , Aavitsland Preben
Published: November 2004

Background

Between November 2 and 10, 2002 several patients with psoriasis and personnel staying in the health centre in Gran Canaria, Spain fell ill with diarrhoea, vomiting or both. Patient original came from Norway, Sweden and Finland. The patient group was scheduled to stay until 8 November. A new group of patients were due to arrive from 7 November.

Methods

A retrospective cohort study was conducted to assess the extent of the outbreak, to identify the source and mode of transmission and to prevent similar problems in the following group.

Results

Altogether 41% (48/116) of persons staying at the centre fell ill. Norovirus infection was suspected based on clinical presentations and the fact that no bacteria were identified. Kaplan criteria were met. Five persons in this outbreak were hospitalised and the mean duration of diarrhoea was 3 days. The consequences of the illness were more severe compared to many other norovirus outbreaks, possibly because many of the cases suffered from chronic diseases and were treated with drugs reported to affect the immunity (methotrexate or steroids).

During the two first days of the outbreak, the attack rate was higher in residents who had consumed dried fruit (adjusted RR = 3.1; 95% CI: 1.4–7.1) and strawberry jam (adjusted RR = 1.9; 95% CI: 0.9–4.1) than those who did not. In the following days, no association was found. The investigation suggests two modes of transmission: a common source for those who fell ill during the two first days of the outbreak and thereafter mainly person to person transmission. This is supported by a lower risk associated with the two food items at the end of the outbreak.

Conclusions

We believe that the food items were contaminated by foodhandlers who reported sick before the outbreak started. Control measures were successfully implemented; food buffets were banned, strict hygiene measures were implemented and sick personnel stayed at home >48 hours after last symptoms.
Seroprevalence of simian immunodeficiency virus in wild and captive born Sykes' monkeys (Cercopithecus mitis) in Kenya
Authors: Ellis Brett R , Munene Elephas , Elliott Debra , Robinson James , Otsyula Moses G , Michael Scott F
Published: November 2004

Background

The Sykes' monkey and related forms (Cercopithecus mitis) make up an abundant, widespread and morphologically diverse species complex in eastern Africa that naturally harbors a distinct simian immunodeficiency virus (SIVsyk). We carried out a retrospective serological survey of SIV infection from both wild and captive Sykes' monkeys from Kenya. We compared two commercially available, cross-reactive ELISA tests using HIV antigens with a novel SIVsyk antigen-specific Western blot assay and analyzed the data by origin, subspecies, age and sex.

Results

The SIVsyk antigen-specific Western blot assay detected more serum samples as positive than either of the cross-reactive ELISA assays. Using this assay, we found that seroprevalence is higher than previously reported, but extremely variable in wild populations (from 0.0 to 90.9%). Females were infected more often than males in both wild and captive populations. Seropositive infants were common. However, no seropositive juveniles were identified.

Conclusion

We have developed a specific and sensitive Western blot assay for anti-SIVsyk antibody detection. Sykes' monkeys are commonly infected with SIVsyk, but with extremely variable prevalence in the wild. Higher infection prevalence in females suggests predominantly sexual transmission. High infection prevalence in infants, but none in juveniles, suggests maternal antibodies, but little or no vertical transmission.
Knowledge discovery in databases of biomechanical variables: application to the sit to stand motor task
Authors: Vannozzi Giuseppe , Della Croce Ugo , Starita Antonina , Benvenuti Francesco , Cappozzo Aurelio
Published: November 2004

Background

The interpretation of data obtained in a movement analysis laboratory is a crucial issue in clinical contexts. Collection of such data in large databases might encourage the use of modern techniques of data mining to discover additional knowledge with automated methods. In order to maximise the size of the database, simple and low-cost experimental set-ups are preferable. The aim of this study was to extract knowledge inherent in the sit-to-stand task as performed by healthy adults, by searching relationships among measured and estimated biomechanical quantities. An automated method was applied to a large amount of data stored in a database. The sit-to-stand motor task was already shown to be adequate for determining the level of individual motor ability.

Methods

The technique of search for association rules was chosen to discover patterns as part of a Knowledge Discovery in Databases (KDD) process applied to a sit-to-stand motor task observed with a simple experimental set-up and analysed by means of a minimum measured input model. Selected parameters and variables of a database containing data from 110 healthy adults, of both genders and of a large range of age, performing the task were considered in the analysis.

Results

A set of rules and definitions were found characterising the patterns shared by the investigated subjects. Time events of the task turned out to be highly interdependent at least in their average values, showing a high level of repeatability of the timing of the performance of the task.

Conclusions

The distinctive patterns of the sit-to-stand task found in this study, associated to those that could be found in similar studies focusing on subjects with pathologies, could be used as a reference for the functional evaluation of specific subjects performing the sit-to-stand motor task.
Lysophosphatidic acid triggers calcium entry through a non-store-operated pathway in human neutrophils
Authors: Itagaki Kiyoshi , Kannan Kolenkode B , Hauser Carl J
Published: November 2004

Lysophosphatidic acid (LPA) is a bioactive lipid, which is structurally similar to sphingosine 1-phosphate (S1P) and which can mobilize Ca2+ in multiple cell types. We recently showed that S1P induces Ca2+ entry directly through store-operated Ca2+ entry (SOCE) channels in human polymorphonuclear neutrophils (PMN) [1]. We therefore examined the mechanisms by which LPA induces intracellular Ca2+ mobilization in PMN. External application of low micromolar LPA caused dose-dependent Ca2+ influx without releasing Ca2+ stores, whereas G-protein-coupled (GPC) LPA receptors respond to nanomolar LPA. Additive Ca2+ influx by LPA compared with 100 nM ionomycin-induced Ca2+ influx suggests that LPA-induced Ca2+ influx does not pass through SOCE channels. Ca2+ influx was resistant to inhibition of Gi/o by pertussis toxin, of phospholipase C by U73122, and of G12/13/Rho by Y27632, all demonstrating GPC receptor independence. This Ca2+ influx was inhibited by Gd3+, La3+, Zn2+, or MRS1845 but not by Ni2+ or the sphingosine kinase inhibitor dimethylsphingosine. In addition, we found that LPA has no effect on neutrophil chemotaxis; however, it has stimulatory effects on neutrophil respiratory burst in a dose-response manner. These findings suggest that LPA-induced Ca2+ influx in PMN occurs through a mechanism other than SOCE channels, independent of Ca2+ store-depletion and S1P synthesis, and that the characteristics of LPA-induced Ca2+ influx are similar to those of S1P-induced influx in terms of sensitivity to inorganic inhibitors. Unlike S1P, LPA has stimulatory effects on neutrophil respiratory burst.
The CD4+ T cell immunodominant Anaplasma marginale major surface protein 2 stimulates γδ T cell clones that express unique T cell receptors
Authors: Lahmers Kevin K , Norimine Junzo , Abrahamsen Mitchell S , Palmer Guy H , Brown Wendy C
Published: November 2004

Major surface protein 2 (MSP2) of the bovine rickettsial pathogen Anaplasma marginale is an abundant, serologically immunodominant outer membrane protein. Immunodominance partially results from numerous CD4+ T cell epitopes in highly conserved amino and carboxy regions and the central hypervariable region of MSP2. However, in long-term cultures of lymphocytes stimulated with A. marginale, workshop cluster 1 (WC1)+ γδ T cells and CD4+ αβ T cells proliferated, leading to a predominance of γδ T cells. As γδ T cells proliferate in A. marginale-stimulated lymphocyte cultures, this study hypothesized that γδ T cells respond to the abundant, immunodominant MSP2. To test this hypothesis, γδ T cell clones were isolated from MSP2 vaccinates and assessed for antigen-specific proliferation and interferon-γ secretion. Seven WC1+ γδ T cell clones responded to A. marginale and MSP2, and three of these proliferated to overlapping peptides from the conserved carboxy region. The γδ T cell response was not major histocompatibility complex-restricted, although it required antigen-presenting cells and was blocked by addition of antibody specific for the T cell receptor (TCR). Sequence analysis of TCR-γ and -δ chains of peripheral blood lymphocytes identified two novel TCR-γ chain constant (Cγ) regions. It is important that all seven MSP2-specific γδ T cell clones used the same one of these novel Cγ regions. The TCR complementarity-determining region 3 was less conserved than those of MSP2-specific CD4+ αβ T cell clones. Together, these data indicate that WC1+ γδ T cells recognize A. marginale MSP2 through the TCR and contribute to the immunodominant response to this protein.
The Women's Health Initiative Study of Cognitive Aging (WHISCA): a randomized clinical trial of the effects of hormone therapy on age-associated cognitive decline
Authors: Resnick Susan M , Cokerb Laura H , Makia Pauline M , Rapp Stephen R , Espeland Mark A , Shumakerb Sally A
Published: November 2004

The Women's Health Initiative Study of Cognitive Aging (WHISCA) was a two armed, randomized, placebo controlled, clinical trial designed to assess the efficacy of postmenopausal hormone therapy on age related changes in specific cognitive functions. WHISCA was an ancillary study to the Women's Health Initiative (WHI) and the WHI Memory Study (WHIMS) and enrolled 2302 women aged 66 to 84 years (mean 73.9; standard deviation 3.8) who did not meet criteria for dementia. Women were randomly assigned by the WHI to hormone treatment (unopposed conjugated estrogens (CEE) 0.625 mg/day if they were without a uterus; CEE combined with medroxyprogesterone acetate (MPA) 2.5 mg/day otherwise) or placebo for an average of three years before the first WHISCA assessment. WHISCA investigated the effects of hormone therapy on rates of change over time in memory, other aspects of cognition (language, attention, spatial ability), motor function, and mood. In this paper, we present the study rationale and design, including specific cognitive measures, and the challenges of incorporating WHISCA into an ongoing randomized trial. WHISCA provided a unique opportunity to investigate the potential of hormone therapy to modify age related changes in specific cognitive functions. WHISCA also demonstrated the feasibility of adding a detailed cognitive assessment into an ongoing clinical trial to address an important issue in women's health, despite the challenges of maintaining the integrity of the parent studies, ensuring high retention, and achieving high quality assurance across sites.
Statistical issues in multisite effectiveness trials: the case of brief strategic family therapy for adolescent drug abuse treatment
Authors: Feaster Daniel J , Robbins Michael S , Horigian Viviana , Szapocznik José
Published: November 2004

The statistical development of the multisite Brief Strategic Family Therapy (BSFT) Trial of the National Institute on Drug Abuse's Clinical Trials Network provides a useful, real example of how an effectiveness trial can differ from an efficacy trial. In particular, two design elements distinguish this effectiveness trial from an efficacy trial. First, because the goal of the trial is to show that the use of BSFT would be an improvement on current practice, it was decided to compare BSFT to treatment as usual at each location. This decision ensures that the trial has the most ecological validity to the participating community treatment providers. Second, the desire to generalize the results to general clinical practice dictates that variability (in effect) across community treatment providers be estimated using a random effects model. These two decisions jointly influence the sample size calculations. Allowing variation in treatment as usual, will increase the variability in effect sizes across sites and estimation of this variability as a random effect necessitates a larger sample size (both number of community treatment providers and participants per community treatment provider), than is the case for a fixed site effect estimate. Details of these effects and their implications for the statistical design are presented.
Statistical evaluation of learning curve effects in surgical trials
Authors: Cook Jonathan A , Ramsaya Craig R , Fayers Peter
Published: November 2004

Randomized controlled trials (RCTs) in surgery have been impeded by concerns that improvements in the technical performance of a new technique over time (a “learning curve”) may distort comparisons. The statistical assessment of learning curves in trials has received little attention. In this paper, we discuss what a learning curve effect is, the factors which effect it, how to display it, and how to incorporate the learning effect into the trial analysis. Bayesian hierarchical models are proposed to adjust the trial results for the existence of a learning curve effect. The implications for trial evaluation and data collection are considered.
Regulatory reforms and GCP clinical trials with new drugs in India
Authors: Maggon Krishan
Published: November 2004

Current Indian drug regulations do not allow for toxicology testing and clinical trials in India with compounds or molecules discovered abroad, except for treatments of tropical, cancer and cardiovascular diseases as part of global studies. The number of GCP Phase II/III trials by foreign sponsors has increased dramatically since 1995, attesting to the potential of India for lower cost trials and reduction in drug development costs and time, due to rapid patient recruitment. However, there have been problems with regard to intellectual property protection and adherence to informed consent guidelines. Starting in 2005, a series of regulatory reforms and patent protection will be instituted that are designed to address many of these concerns; the nature of these reforms are presented and discussed. However, sponsors need to pay close attention to informed consent and other ethical issues in Indian trials, which enroll mainly poor and uneducated patients.
Temporal complexity within a translational control element in thenanosmRNA
Authors: Forrest Kevin M. , Clark Ira E. , Jain Roshan A. , Gavis Elizabeth R.
Published: November 2004

Translational control of gene expression plays a fundamental role in the early development of many organisms. In Drosophila, selective translation of nanos mRNA localized to the germ plasm at the posterior of the embryo, together with translational repression of nanos in the bulk cytoplasm, is essential for development of the anteroposterior body pattern. We show that both components to spatial control of nanos translation initiate during oogenesis and that translational repression is initially independent of Smaug, an embryonic repressor of nanos. Repression during oogenesis and embryogenesis are mediated by distinct stem loops within the nanos 3′ untranslated region;the Smaug-binding stem-loop acts strictly in the embryo, whereas a second stem-loop functions in the oocyte. Thus, independent regulatory modules with temporally distinct activities contribute to spatial regulation of nanos translation. We propose that nanos evolved to exploit two different stage-specific translational regulatory mechanisms.
Accumulation of type IV collagen in dilated ER leads to apoptosis inHsp47-knockout mouse embryos via induction of CHOP
Authors: Marutani Toshihiro , Yamamoto Akitsugu , Nagai Naoko , Kubota Hiroshi , Nagata Kazuhiro
Published: November 2004

Hsp47 is an endoplasmic reticulum (ER)-resident molecular chaperone that is specific for collagen. In Hsp47–/– mouse embryos at 9.5 days postcoitus (dpc), immunostaining indicated the absence of type IV collagen, but not of laminin and nidogen-1, in the basement membrane (BM). Electron immunomicroscopy revealed accumulation of type IV collagen in dilated ERs, but not in the BM of Hsp47–/– embryos, whereas it was only present in the BM in Hsp47+/+ embryos. The BM structures stained with anti-laminin and anti-nidogen-1 antibody became disrupted in Hsp47–/– embryos at 10.5 dpc. Thus, in the absence of type IV collagen in the BM owing to the lack of Hsp47, the structure of the BM cannot be maintained during the dramatic morphological changes that take place around 10.5 dpc. Type IV collagen is therefore indispensable for the maintenance of BM structures during the late-stage development of mouse embryos, although not essential for the initial formation of the BM. Just before the death of Hsp47–/– embryos, DNA fragmentation typical of apoptosis was observed at 10.5 dpc together with significantly upregulated CHOP mRNA expression. ER stress caused by the accumulation of misfolded collagen may have induced apoptosis in Hsp47-knockout embryos through the upregulation of CHOP.
A simple model to predict crack growth in bonded joints and laminates under variable-amplitude fatigue
Authors: Ashcroft I. A
Published: November 2004

It is now well established that adhesives and fibre-reinforced polymers (FRPs) can fail at far lower loads under fatigue loading than under quasi-static loading. Most of the work on the fatigue of these materials has been under constant amplitude (CA); however, recent work has shown that fatigue crack growth acceleration and unstable crack growth can be seen under conditions of variable-amplitude (VA) fatigue. In this paper, further evidence of this effect is given. This phenomenon is attributed to the influence of VA fatigue on the evolution of a damage zone ahead of the main crack front and results from the characterization of these damage zones are also presented. Finally, a simple fracture mechanics-based model for predicting crack growth under VA fatigue is proposed. This is shown to be entirely consistent with the experimental observations.
Numerical evaluation of residual stress relaxation by cyclic load
Authors: Dattoma V , De Giorgi M , Nobile R
Published: November 2004

The aim of this work is to evaluate by numerical simulation the real stress state of a welded component subjected to a sinusoidal external load. In particular, the relaxation process of the residual stress, due to the application of a cyclic external load, has been studied. Longitudinal welded joints, laser welded and 3 mm thick, are analysed in this work following the residual stress evolution during a fatigue test. A numerical procedure, implemented by the ABAQUS code, carries out the residual stress field originated by a welding process and it is taken as a pre-stress condition in the present ABAQUS simulations. In order to evaluate the influence of the amplitude level on the residual stress relaxation, eight different sinusoidal loads at the load ratio R = 0.1 are applied to the model.

The results show a significant reduction in the initial residual stress level, even after the first load cycle. They offer a very precise explanation of the fatigue behaviour of this kind of welded joints, confirming the behaviour experimentally observed.
Analytic approach to obtain shear traction in a cylindrical contact with reverse slip
Authors: Tur M , Sáez R. C , Fuenmayor F. J
Published: November 2004

This paper presents an analytic approach for obtaining the contact shear traction in cylindrical contact during a fretting fatigue test under conditions of partial reverse slip. The case of a cylinder on plane contact is considered. The stress distribution at the contact area is generated by a normal load and a tangential load in addition to the bulk stress of the specimen. The bodies are supposed to be elastically similar and behave as infinite half-planes. The paper presents the equations governing the problem of cylindrical contact with partial slip and a solution that fulfills these equations is proposed. The validity of the approach has been verified and compared to the numerical solutions available in the literature.