bluuebunny/crossref_metadata_2025 huggingface dataset:
Behavior, Knowledge, Attitude, and Other Characteristics of Men Who Had Sex With Female Commercial Sex Workers in Kenya
Authors: Hong Rathavuth
Published: October 2007

We examined sociodemographic characteristics, knowledge, behavior, and attitude of men who had sex with commercial sex workers (CSWs) in Kenya. About 15% of the men had sex with CSWs. Men who had two or more partners, were away from home five or more times in the past year, and used condoms consistently with their last three partners were likely to have had sex with CSWs (odds ratio [OR] = 2.70, p = .000; OR = 1.43, p = .044; OR = 2.50, p = .000, respectively). Men with better knowledge of HIV/AIDS prevention methods were likely to have had sex with CSWs (OR = 1.62, p = .004). As expected, having had sex with CSWs was associated with higher risk of sexually transmitted infection (OR = 3.62, p = .000). This unexpected association between knowledge and behavior could be bidirectional or reverse causality. Nonetheless, knowledge in prevention has not been translated to practice and change in behavior. These processes require continuous efforts, including assertive campaigns on sexual practices and behaviors.
Fibroblast growth factor controls the timing of Scl, Lmo2, and Runx1 expression during embryonic blood development
Authors: Walmsley Maggie , Cleaver David , Patient Roger
Published: October 2007

To program pluripotent cells into blood, a knowledge of the locations of precursors during their journey through the embryo and the signals they experience would be informative. The anterior (a) and posterior (p) ventral blood islands (VBIs) in Xenopus are derived from opposite sides of the pregastrula embryo. The aVBI goes through a “hemangioblast” state, characterized by coexpression of blood and endothelial genes at neurula stages, whereas the pVBI expresses these genes in a nonoverlapping fashion several hours later, after commitment to either a blood or an endothelial fate. We describe a novel role for fibroblast growth factor (FGF) in controlling the timing of Scl, Lmo2, and Runx1 expression in the 2 VBI compartments. Blocking FGF signaling during gastrulation expands expression at neurula stages into posterior regions. We show, by lineage labeling, explant analysis, and targeted blocking of FGF signaling, that this is due to the pVBI prematurely expressing these genes with the timing of the aVBI. In contrast, overexpression of FGF in aVBI precursors eliminates the anterior hemangioblast program. Using this information, we have recapitulated the anterior hemangioblast program in pluripotent cells in vitro by inhibiting FGF signaling in anterior mesoderm induced by activin and exposed to bone morphogenetic protein (BMP) signaling.
The dual effects of TNFα on neutrophil apoptosis are mediated via differential effects on expression of Mcl-1 and Bfl-1
Authors: Cross Andrew , Moots Robert J. , Edwards Steven W.
Published: October 2007

Neutrophils have a very short half-life in the circulation, undergoing rapid death by apoptosis, but a number of agents can either delay or accelerate the rate at which these cells undergo death. TNFα can exert opposing, concentration-dependent effects on neutrophils to either accelerate their apoptosis or enhance their survival. We show that TNFα greatly increases the rate of turnover of Mcl-1, an antiapoptotic protein that plays a key role in neutrophil survival. In contrast to Mcl-1 turnover in control- or granulocyte-macrophage colony-stimulating factor (GM-CSF)–treated neutrophils that occurs via the proteasome, TNFα-accelerated Mcl-1 turnover occurs via activation of caspases. Mcl-1–depleted cells thus have accelerated rates of apoptosis. While TNFα had no effect on MCL-1 transcription, it induced expression of another antiapoptotic molecule, BFL-1. Low concentrations of TNFα (≤ 1 ng/mL) stimulated BFL-1 expression, whereas higher concentrations (≥ 10 ng/mL) triggered caspase-dependent acceleration of Mcl-1 turnover. These opposing effects on 2 separate antiapoptotic systems of neutrophils explain the divergent effects of TNFα on neutrophil apoptosis and have important implications for understanding how TNFα may affect immune function in inflammatory diseases.
The multiple myeloma–associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity
Authors: Lauring Josh , Abukhdeir Abde M. , Konishi Hiroyuki , Garay Joseph P. , Gustin John P. , Wang Qiuju , Arceci Robert J. , Matsui William , Park Ben Ho
Published: October 2007

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by recurrent chromosomal translocations. Patients with t(4;14)(p16;q32) are the worst prognostic subgroup in MM, although the basis for this poor prognosis is unknown. The t(4;14) is unusual in that it involves 2 potential target genes: fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET). MMSET is universally overexpressed in t(4;14) MM, whereas FGFR3 expression is lost in one-third of cases. Nonetheless, the role of MMSET in t(4;14) MM has remained unclear. Here we demonstrate a role for MMSET in t(4;14) MM cells. Down-regulation of MMSET expression in MM cell lines by RNA interference and by selective disruption of the translocated MMSET allele using gene targeting dramatically reduced colony formation in methylcellulose but had only modest effects in liquid culture. In addition, MMSET knockdown led to cell-cycle arrest of adherent MM cells and reduced the ability of MM cells to adhere to extracellular matrix. Finally, MMSET knockdown and knockout reduced tumor formation by MM xenografts. These results provide the first direct evidence that MMSET plays a significant role in t(4;14) MM and suggest that therapies targeting this gene could impact this particular subset of poor-prognosis patients.
Repertoire and frequency of immune cells reactive to Epstein-Barr virus–derived autologous lymphoblastoid cell lines
Authors: Bhaduri-McIntosh Sumita , Rotenberg Marisa J. , Gardner Benjamin , Robert Marie , Miller George
Published: October 2007

Answers to questions about frequency and repertoire of immune cells, relative contributions made by different types of immune cells toward the total Epstein-Barr virus (EBV)–directed response and the variation of such responses in healthy persons have been elusive because of disparities in assays, antigen presenting cells, and antigenic sources used in previous experiments. In this study, we addressed these questions using an assay that allowed direct comparison of responses generated by different types of cells of the immune system. This short-term (20-hour) ex vivo assay measured interferon-γ production by blood cells in response to autologous EBV-transformed lymphoblastoid cell lines (LCLs). Our experiments defined the variation in responses among persons and clearly distinguished 10 healthy EBV-immune from 10 healthy EBV-naive persons. In EBV-immune persons, 33% of responding cells were CD4+, 43.3% were CD8+, and 12.9% were γ-δ T cells. LCL-reactive CD8+ T cells were only 1.7-fold more frequent than similarly reactive CD4+T cells. Responses by γ-δ T cells were 6-fold higher in seropositive than in seronegative persons. Our findings emphasize the importance of CD4+ and γ-δ T-cell responses and have implications for immunotherapy and for identifying defects in T-cell populations that might predispose to development of EBV-associated lymphomas.
Strainer: software for analysis of population variation in community genomic datasets
Authors: Eppley John M , Tyson Gene W , Getz Wayne M , Banfield Jillian F
Published: October 2007

Background

Metagenomic analyses of microbial communities that are comprehensive enough to provide multiple samples of most loci in the genomes of the dominant organism types will also reveal patterns of genetic variation within natural populations. New bioinformatic tools will enable visualization and comprehensive analysis of this sequence variation and inference of recent evolutionary and ecological processes.

Results

We have developed a software package for analysis and visualization of genetic variation in populations and reconstruction of strain variants from otherwise co-assembled sequences. Sequencing reads can be clustered by matching patterns of single nucleotide polymorphisms to generate predicted gene and protein variant sequences, identify conserved intergenic regulatory sequences, and determine the quantity and distribution of recombination events.

Conclusion

The Strainer software, a first generation metagenomic bioinformatics tool, facilitates comprehension and analysis of heterogeneity intrinsic in natural communities. The program reveals the degree of clustering among closely related sequence variants and provides a rapid means to generate gene and protein sequences for functional, ecological, and evolutionary analyses.
CATMA, a comprehensive genome-scale resource for silencing and transcript profiling of Arabidopsis genes
Authors: Sclep Gert , Allemeersch Joke , Liechti Robin , De Meyer Björn , Beynon Jim , Bhalerao Rishikesh , Moreau Yves , Nietfeld Wilfried , Renou Jean-Pierre , Reymond Philippe , Kuiper Martin TR , Hilson Pierre
Published: October 2007

Background

The Complete Arabidopsis Transcript MicroArray (CATMA) initiative combines the efforts of laboratories in eight European countries [1] to deliver gene-specific sequence tags (GSTs) for the Arabidopsis research community. The CATMA initiative offers the power and flexibility to regularly update the GST collection according to evolving knowledge about the gene repertoire. These GST amplicons can easily be reamplified and shared, subsets can be picked at will to print dedicated arrays, and the GSTs can be cloned and used for other functional studies. This ongoing initiative has already produced approximately 24,000 GSTs that have been made publicly available for spotted microarray printing and RNA interference.

Results

GSTs from the CATMA version 2 repertoire (CATMAv2, created in 2002) were mapped onto the gene models from two independent Arabidopsis nuclear genome annotation efforts, TIGR5 and PSB-EuGène, to consolidate a list of genes that were targeted by previously designed CATMA tags. A total of 9,027 gene models were not tagged by any amplified CATMAv2 GST, and 2,533 amplified GSTs were no longer predicted to tag an updated gene model. To validate the efficacy of GST mapping criteria and design rules, the predicted and experimentally observed hybridization characteristics associated to GST features were correlated in transcript profiling datasets obtained with the CATMAv2 microarray, confirming the reliability of this platform. To complete the CATMA repertoire, all 9,027 gene models for which no GST had yet been designed were processed with an adjusted version of the Specific Primer and Amplicon Design Software (SPADS). A total of 5,756 novel GSTs were designed and amplified by PCR from genomic DNA. Together with the pre-existing GST collection, this new addition constitutes the CATMAv3 repertoire. It comprises 30,343 unique amplified sequences that tag 24,202 and 23,009 protein-encoding nuclear gene models in the TAIR6 and EuGène genome annotations, respectively. To cover the remaining untagged genes, we identified 543 additional GSTs using less stringent design criteria and designed 990 sequence tags matching multiple members of gene families (Gene Family Tags or GFTs) to cover any remaining untagged genes. These latter 1,533 features constitute the CATMAv4 addition.

Conclusion

To update the CATMA GST repertoire, we designed 7,289 additional sequence tags, bringing the total number of tagged TAIR6-annotated Arabidopsis nuclear protein-coding genes to 26,173. This resource is used both for the production of spotted microarrays and the large-scale cloning of hairpin RNA silencing vectors. All information about the resulting updated CATMA repertoire is available through the CATMA database http://www.catma.org.
The Protein Identifier Cross-Referencing (PICR) service: reconciling protein identifiers across multiple source databases
Authors: Côté Richard G , Jones Philip , Martens Lennart , Kerrien Samuel , Reisinger Florian , Lin Quan , Leinonen Rasko , Apweiler Rolf , Hermjakob Henning
Published: October 2007

Background

Each major protein database uses its own conventions when assigning protein identifiers. Resolving the various, potentially unstable, identifiers that refer to identical proteins is a major challenge. This is a common problem when attempting to unify datasets that have been annotated with proteins from multiple data sources or querying data providers with one flavour of protein identifiers when the source database uses another. Partial solutions for protein identifier mapping exist but they are limited to specific species or techniques and to a very small number of databases. As a result, we have not found a solution that is generic enough and broad enough in mapping scope to suit our needs.

Results

We have created the Protein Identifier Cross-Reference (PICR) service, a web application that provides interactive and programmatic (SOAP and REST) access to a mapping algorithm that uses the UniProt Archive (UniParc) as a data warehouse to offer protein cross-references based on 100% sequence identity to proteins from over 70 distinct source databases loaded into UniParc. Mappings can be limited by source database, taxonomic ID and activity status in the source database. Users can copy/paste or upload files containing protein identifiers or sequences in FASTA format to obtain mappings using the interactive interface. Search results can be viewed in simple or detailed HTML tables or downloaded as comma-separated values (CSV) or Microsoft Excel (XLS) files suitable for use in a local database or a spreadsheet. Alternatively, a SOAP interface is available to integrate PICR functionality in other applications, as is a lightweight REST interface.

Conclusion

We offer a publicly available service that can interactively map protein identifiers and protein sequences to the majority of commonly used protein databases. Programmatic access is available through a standards-compliant SOAP interface or a lightweight REST interface. The PICR interface, documentation and code examples are available at http://www.ebi.ac.uk/Tools/picr.
Automated group assignment in large phylogenetic trees using GRUNT: GRouping, Ungrouping, Naming Tool
Authors: Dalevi Daniel , DeSantis Todd Z , Fredslund Jakob , Andersen Gary L , Markowitz Victor M , Hugenholtz Philip
Published: October 2007

Background

Accurate taxonomy is best maintained if species are arranged as hierarchical groups in phylogenetic trees. This is especially important as trees grow larger as a consequence of a rapidly expanding sequence database. Hierarchical group names are typically manually assigned in trees, an approach that becomes unfeasible for very large topologies.

Results

We have developed an automated iterative procedure for delineating stable (monophyletic) hierarchical groups to large (or small) trees and naming those groups according to a set of sequentially applied rules. In addition, we have created an associated ungrouping tool for removing existing groups that do not meet user-defined criteria (such as monophyly). The procedure is implemented in a program called GRUNT (GRouping, Ungrouping, Naming Tool) and has been applied to the current release of the Greengenes (Hugenholtz) 16S rRNA gene taxonomy comprising more than 130,000 taxa.

Conclusion

GRUNT will facilitate researchers requiring comprehensive hierarchical grouping of large tree topologies in, for example, database curation, microarray design and pangenome assignments. The application is available at the greengenes website [1].
Common cellular events occur during wound healing and organ regeneration in the sea cucumber Holothuria glaberrima
Authors: San Miguel-Ruiz José E , García-Arrarás José E
Published: October 2007

Background

All animals possess some type of tissue repair mechanism. In some species, the capacity to repair tissues is limited to the healing of wounds. Other species, such as echinoderms, posses a striking repair capability that can include the replacement of entire organs. It has been reported that some mechanisms, namely extracellular matrix remodeling, appear to occur in most repair processes. However, it remains unclear to what extent the process of organ regeneration, particularly in animals where loss and regeneration of complex structures is a programmed natural event, is similar to wound healing. We have now used the sea cucumber Holothuria glaberrima to address this question.

Results

Animals were lesioned by making a 3–5 mm transverse incision between one of the longitudinal muscle pairs along the bodywall. Lesioned tissues included muscle, nerve, water canal and dermis. Animals were allowed to heal for up to four weeks (2, 6, 12, 20, and 28 days post-injury) before sacrificed. Tissues were sectioned in a cryostat and changes in cellular and tissue elements during repair were evaluated using classical dyes, immmuohistochemistry and phalloidin labeling. In addition, the temporal and spatial distribution of cell proliferation in the animals was assayed using BrdU incorporation. We found that cellular events associated with wound healing in H. glaberrima correspond to those previously shown to occur during intestinal regeneration. These include: (1) an increase in the number of spherule-containing cells, (2) remodeling of the extracellular matrix, (3) formation of spindle-like structures that signal dedifferentiation of muscle cells in the area flanking the lesion site and (4) intense cellular division occurring mainly in the coelomic epithelium after the first week of regeneration.

Conclusion

Our data indicate that H. glaberrima employs analogous cellular mechanisms during wound healing and organ regeneration. Thus, it is possible that regenerative limitations in some organisms are due either to the absence of particular mechanisms associated with repair or the inability of activating the repair process in some tissues or stages.
Assisted Reproductive Technology affects developmental kinetics, H19 Imprinting Control Region methylation and H19gene expression in individual mouse embryos
Authors: Fauque Patricia , Jouannet Pierre , Lesaffre Corinne , Ripoche Marie-Anne , Dandolo Luisa , Vaiman Daniel , Jammes Hélène
Published: October 2007

Background

In the last few years, an increase in imprinting anomalies has been reported in children born from Assisted Reproductive Technology (ART). Various clinical and experimental studies also suggest alterations of embryo development after ART. Therefore, there is a need for studying early epigenetic anomalies which could result from ART manipulations, especially on single embryos. In this study, we evaluated the impact of superovulation, in vitro fertilization (IVF) and embryo culture conditions on proper genomic imprinting and blastocyst development in single mouse embryos.

In this study, different experimental groups were established to obtain embryos from superovulated and non-superovulated females, either from in vivo or in vitro fertilized oocytes, themselves grown in vitro or not. The embryos were cultured either in M16 medium or in G1.2/G2.2 sequential medium. The methylation status of H19 Imprinting Control Region (ICR) and H19 promoter was assessed, as well as the gene expression level of H19, in individual blastocysts. In parallel, we have evaluated embryo cleavage kinetics and recorded morphological data.

Results

We show that:

1. The culture medium influences early embryo development with faster cleavage kinetics for culture in G1.2/G2.2 medium compared to M16 medium.

2. Epigenetic alterations of the H19 ICR and H19 PP are influenced by the fertilization method since methylation anomalies were observed only in the in vitro fertilized subgroup, however to different degrees according to the culture medium.

3. Superovulation clearly disrupted H19 gene expression in individual blastocysts. Moreover, when embryos were cultured in vitro after either in vivo or in vitro fertilization, the percentage of blastocysts which expressed H19 was higher in G1.2/G2.2 medium compared to M16.

Conclusion

Compared to previous reports utilizing pools of embryos, our study enables us to emphasize a high individual variability of blastocysts in the H19 ICR and H19 promoter methylation and H19 gene expression, with a striking effect of each manipulation associated to ART practices. Our results suggest that H19 could be used as a sensor of the epigenetic disturbance of the utilized techniques.
Molecular evolution of the human SRPX2 gene that causes brain disorders of the Rolandic and Sylvian speech areas
Authors: Royer Barbara , Soares Dinesh C , Barlow Paul N , Bontrop Ronald E , Roll Patrice , Robaglia-Schlupp Andrée , Blancher Antoine , Levasseur Anthony , Cau Pierre , Pontarotti Pierre , Szepetowski Pierre
Published: October 2007

Background

The X-linked SRPX2 gene encodes a Sushi Repeat-containing Protein of unknown function and is mutated in two disorders of the Rolandic/Sylvian speech areas. Since it is linked to defects in the functioning and the development of brain areas for speech production, SRPX2 may thus have participated in the adaptive organization of such brain regions. To address this issue, we have examined the recent molecular evolution of the SRPX2 gene.

Results

The complete coding region was sequenced in 24 human X chromosomes from worldwide populations and in six representative nonhuman primate species. One single, fixed amino acid change (R75K) has been specifically incorporated in human SRPX2 since the human-chimpanzee split. The R75K substitution occurred in the first sushi domain of SRPX2, only three amino acid residues away from a previously reported disease-causing mutation (Y72S). Three-dimensional structural modeling of the first sushi domain revealed that Y72 and K75 are both situated in the hypervariable loop that is usually implicated in protein-protein interactions. The side-chain of residue 75 is exposed, and is located within an unusual and SRPX-specific protruding extension to the hypervariable loop. The analysis of non-synonymous/synonymous substitution rate (Ka/Ks) ratio in primates was performed in order to test for positive selection during recent evolution. Using the branch models, the Ka/Ks ratio for the human branch was significantly different (p = 0.027) from that of the other branches. In contrast, the branch-site tests did not reach significance. Genetic analysis was also performed by sequencing 9,908 kilobases (kb) of intronic SRPX2 sequences. Despite low nucleotide diversity, neither the HKA (Hudson-Kreitman-Aguadé) test nor the Tajima's D test reached significance.

Conclusion

The R75K human-specific variation occurred in an important functional loop of the first sushi domain of SRPX2, indicating that this evolutionary mutation may have functional importance; however, positive selection for R75K could not be demonstrated. Nevertheless, our data contribute to the first understanding of molecular evolution of the human SPRX2 gene. Further experiments are now required in order to evaluate the possible consequences of R75K on SRPX2 interactions and functioning.
Hfq stimulates the activity of the CCA-adding enzyme
Authors: Scheibe Marion , Bonin Sonja , Hajnsdorf Eliane , Betat Heike , Mörl Mario
Published: October 2007

Background

The bacterial Sm-like protein Hfq is known as an important regulator involved in many reactions of RNA metabolism. A prominent function of Hfq is the stimulation of RNA polyadenylation catalyzed by E. coli poly(A) polymerase I (PAP). As a member of the nucleotidyltransferase superfamily, this enzyme shares a high sequence similarity with an other representative of this family, the tRNA nucleotidyltransferase that synthesizes the 3'-terminal sequence C-C-A to all tRNAs (CCA-adding enzyme). Therefore, it was assumed that Hfq might not only influence the poly(A) polymerase in its specific activity, but also other, similar enzymes like the CCA-adding enzyme.

Results

Based on the close evolutionary relation of these two nucleotidyltransferases, it was tested whether Hfq is a specific modulator acting exclusively on PAP or whether it also influences the activity of the CCA-adding enzyme. The obtained data indicate that the reaction catalyzed by this enzyme is substantially accelerated in the presence of Hfq. Furthermore, Hfq binds specifically to tRNA transcripts, which seems to be the prerequisite for the observed effect on CCA-addition.

Conclusion

The increase of the CCA-addition in the presence of Hfq suggests that this protein acts as a stimulating factor not only for PAP, but also for the CCA-adding enzyme. In both cases, Hfq interacts with RNA substrates, while a direct binding to the corresponding enzymes was not demonstrated up to now (although experimental data indicate a possible interaction of PAP and Hfq). So far, the basic principle of these stimulatory effects is not clear yet. In case of the CCA-adding enzyme, however, the presented data indicate that the complex between Hfq and tRNA substrate might enhance the product release from the enzyme.
Systematic analysis of alternative first exons in plant genomes
Authors: Chen Wei-Hua , Lv Guanting , Lv Congying , Zeng Changqing , Hu Songnian
Published: October 2007

Background

Alternative splicing (AS) contributes significantly to protein diversity, by selectively using different combinations of exons of the same gene under certain circumstances. One particular type of AS is the use of alternative first exons (AFEs), which can have consequences far beyond the fine-tuning of protein functions. For example, AFEs may change the N-termini of proteins and thereby direct them to different cellular compartments. When alternative first exons are distant, they are usually associated with alternative promoters, thereby conferring an extra level of gene expression regulation. However, only few studies have examined the patterns of AFEs, and these analyses were mainly focused on mammalian genomes. Recent studies have shown that AFEs exist in the rice genome, and are regulated in a tissue-specific manner. Our current understanding of AFEs in plants is still limited, including important issues such as their regulation, contribution to protein diversity, and evolutionary conservation.

Results

We systematically identified 1,378 and 645 AFE-containing clusters in rice and Arabidopsis, respectively. From our data sets, we identified two types of AFEs according to their genomic organisation. In genes with type I AFEs, the first exons are mutually exclusive, while most of the downstream exons are shared among alternative transcripts. Conversely, in genes with type II AFEs, the first exon of one gene structure is an internal exon of an alternative gene structure. The functionality analysis indicated about half and ~19% of the AFEs in Arabidopsis and rice could alter N-terminal protein sequences, and ~5% of the functional alteration in type II AFEs involved protein domain addition/deletion in both genomes. Expression analysis indicated that 20~66% of rice AFE clusters were tissue- and/or development- specifically transcribed, which is consistent with previous observations; however, a much smaller percentage of Arabidopsis AFEs was regulated in this manner, which suggests different regulation mechanisms of AFEs between rice and Arabidopsis. Statistical analysis of some features of AFE clusters, such as splice-site strength and secondary structure formation further revealed differences between these two species. Orthologous search of AFE-containing gene pairs detected only 19 gene pairs conserved between rice and Arabidopsis, accounting only for a few percent of AFE-containing clusters.

Conclusion

Our analysis of AFE-containing genes in rice and Arabidopsis indicates that AFEs have multiple functions, from regulating gene expression to generating protein diversity. Comparisons of AFE clusters revealed different features in the two plant species, which indicates that AFEs may have evolved independently after the separation of rice (a model monocot) and Arabidopsis (a model dicot).
Clinical and neuroimaging correlates of antiphospholipid antibodies in multiple sclerosis: a preliminary study
Authors: Bidot Carlos J , Horstman Lawrence L , Jy Wenche , Jimenez Joaquin J , Bidot Carlos , Ahn Yeon S , Alexander J Steven , Gonzalez-Toledo Eduardo , Kelley Roger E , Minagar Alireza
Published: October 2007

Background

The presence of antiphospholipid antibodies (APLA) in multiple sclerosis (MS) patients has been reported frequently but no clear relationship between APLA and the clinical and neuroimaging features of MS have heretofore been shown. We assessed the clinical and neuroimaging features of MS patients with plasma APLA.

Methods

A consecutive cohort of 24 subjects with relapsing-remitting (RR) MS were studied of whom 7 were in remission (Rem) and 17 in exacerbation (Exc). All subjects were examined and underwent MRI of brain. Patients' plasma was tested by standard ELISA for the presence of both IgM and IgG antibodies using a panel of 6 targets: cardiolipin (CL), β2 glycoprotein I (β2GPI), Factor VII/VIIa (FVIIa), phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidylethanolamine (PE).

Results

In exacerbation up to 80% of MS subjects had elevated titers of IgM antibodies directed against the above antigens. However, in remission, less than half of MS patients had elevated titers of IgM antibodies against one or more of the above antigens. This difference was significant, p < 0.01, for all 6 target antigens. Interestingly, none of the MS patients had elevated plasma titers of IgG against any of the target antigens tested. Correlation analysis between MRI enhancing lesions and plasma levels of APLA revealed high correlation for aPC, aPS and aFVIIa (p ≤ 0.0065), a trend for aPE and aCL (p = 0.056), and no correlation for aβ2GP1. The strongest correlation was for aFVIIa, p = 0.0002.

Conclusion

The findings of this preliminary study show that increased APLA IgM is associated with exacerbations of MS. Currently, the significance of this association in pathogenesis of MS remains unknown. However, systematic longitudinal studies to measure APLA in larger cohorts of patients with relapsing-remitting MS, particularly before and after treatment with immunomodulatory agents, are needed to confirm these preliminary findings.
Validity and reliability of the multidimensional health locus of control scale for college students
Authors: Moshki Mahdi , Ghofranipour Fazlollah , Hajizadeh Ebrahim , Azadfallah Parviz
Published: October 2007

Background

The purpose of the present study was to assess the validity and reliability of Form A of Multidimensional Health Locus of Control scales in Iran. Health locus of control is one of the most widely measured parameters of health belief for the planning of health education programs.

Methods

496 university students participated in this study. The reliability coefficients were calculated in three different methods: test-retest, parallel forms and Cronbach alpha. In order to survey validity of the scale we used three methods including content validity, concurrent validity and construct validity.

Results

We established the content validity of the Persian translation by translating (and then back-translating) each item from the English version into the Persian version. The concurrent validity of the questionnaire, as measured by Levenson's IPC scale was .57 (P < .001), .49 (P < .01) and .53 (P < .001) for IPC, respectively. Exploratory principal components analysis supported a three-factor structure that items loading adequately on each factor. Moreover, the approximate orthogonal of the dimensions were obtained through correlation analyses. In addition, the reliability results were acceptable, too.

Conclusion

The results showed that the reliability and validity of Persian Form A of MHLC was acceptable and respectable and is suggested as an applicable criterion for similar studies in Iran.
Diffusion of good practices of care and decline of the association with case volume: the example of breast conserving surgery
Authors: Fedeli Ugo , Alba Natalia , Schievano Elena , Visentin Cristiana , Rosato Rosalba , Zorzi Manuel , Ruscitti Giancarlo , Spolaore Paolo
Published: October 2007

Background

Several previous studies conducted on cancer registry data and hospital discharge records (HDR) have found an association between hospital volume and the recourse to breast conserving surgery (BCS) for breast cancer. The aim of the current study is to depict concurrent time trends in the recourse to BCS and its association with hospital volume.

Methods

Admissions of breast cancer patients for BCS or mastectomy in the period 2000–2004 were identified from the discharge database of the Veneto Region (Italy). The role of procedural volume (low < 50, medium 50–100, high > 100 breast cancer surgeries/year), and of individual risk factors obtainable from HDR was assessed through a hierarchical log-binomial regression.

Results

Overall, the recourse to BCS was higher in medium (risk ratio = 1.12, 95% confidence interval 1.07–1.18) and high-volume (1.09, 1.03–1.14) compared to low-volume hospitals. The proportion of patients treated in low-volume hospitals dropped from 22% to 12%, with a concurrent increase in the activity of medium-volume providers. The increase over time in breast conservation (globally from 56% to 67%) was steeper in the categories of low- and medium-volume hospitals with respect to high caseload.

Conclusion

The growth in the recourse to BCS was accompanied by a decline of the association with hospital volume; larger centers probably acted as early adopters of breast conservation strategies that subsequently spread to smaller providers.
Microfinance investments in quality at private clinics in Uganda: a case-control study
Authors: Seiber Eric E , Robinson Amara L
Published: October 2007

Background

Small private-sector health care providers can play an important role in meeting the developing country health care needs, but a lack of credit can prove major constraint to small-provider expansion. This study examines the potential of small, microfinance loans to strengthen the private health sector and improve access to quality preventive and curative health services in Uganda.

Methods

This study estimates logistic regressions using 2,387 client exit interviews to assess the impact of microfinance loans on perceived quality and the viability and sustainability of small, private clinics.

Results

The study finds perceived quality improved with loan recipients' clients being more likely to choose clinics on the basis of drug availability, fair charges, cleanliness, and confidentiality. In addition, the assessment found evidence of increased client flows, but the changes produced mixed results for sustainability with respondents being only half as likely to "always" visit a particular clinic.

Conclusion

The results indicate that the microfinance program improved perceived quality at loan recipient clinics, especially as reliable drug outlets.
Implication of BRCA2 -26G>A 5' untranslated region polymorphism in susceptibility to sporadic breast cancer and its modulation by p53codon 72 Arg>Pro polymorphism
Authors: Gochhait Sailesh , Bukhari Syed Irfan Ahmad , Bairwa Narendra , Vadhera Shivani , Darvishi Katayoon , Raish Mohammad , Gupta Pawan , Husain Syed Akhtar , Bamezai Rameshwar NK
Published: October 2007

Introduction

The absence of mutation or promoter hypermethylation in the BRCA2 gene in the majority of breast cancer cases has indicated alternative ways of its involvement, deregulated expression being one possibility. We show how a polymorphism in the 5' untranslated region (UTR) of BRCA2 can serve as one such factor. Based on the hypothesis that variants of genes involved in the same pathway can influence the risk provided for breast cancer, the status of p53 codon 72 polymorphism was also investigated and a possible interaction between the polymorphisms was examined.

Methods

The luciferase reporter assay followed by RNA secondary structure analysis was used for the functional characterization of -26 5' UTR G>A polymorphism in BRCA2. The genotype and the allele frequency for the polymorphisms were determined and relative risk adjusted for age was calculated in a case-control study of 576 individuals (243 patients and 333 controls) from north India.

Results

-26 G>A polymorphism in the 5' UTR of BRCA2 was found to be functional whereby the A allele increased the reporter gene expression by twice that of the G allele in MCF-7 (P = 0.003) and HeLa (P = 0.013) cells. RNA secondary structure analysis by two different programs predicted the A allele to alter the stability of a loop in the vicinity of the translation start site. Its direct implication in breast cancer became evident by a case-control study in which the heterozygous genotype was found to be protective in nature (Pheterozygote advantage model = 0.0005, odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.4 to 0.8), which was further supported by trends observed in a genomic instability study. The p53 codon 72 Arg homozygous genotype was found to be over-represented in patients (P = 0.0005, OR = 2.3, 95% CI = 1.4 to 3.6). The interaction study indicated an increased protection under simultaneous presence of protector genotypes of both the polymorphic loci (P = 0.0001, OR = 0.2, 95% CI = 0.1 to 0.4).

Conclusion

Our study shows that -26 5' UTR polymorphism in BRCA2 can modulate the fine-tuned regulation of the multifunctional gene BRCA2 and renders risk or protection according to the genotype status in the sporadic form of breast cancer, which is further influenced by the germline genetic backgrounds of codon 72 polymorphism of p53.
Gene expression profiling of Hfe
-/-liver and duodenum in mouse strains with differing susceptibilities to iron loading: identification of transcriptional regulatory targets of Hfe and potential hemochromatosis modifiers
Authors: Coppin Hélène , Darnaud Valérie , Kautz Léon , Meynard Delphine , Aubry Marc , Mosser Jean , Martinez Maria , Roth Marie-Paule
Published: October 2007

Background

Hfe disruption in mouse leads to experimental hemochromatosis by a mechanism that remains elusive. Affymetrix GeneChip® Mouse Genome 430 2.0 microarrays and bioinformatics tools were used to characterize patterns of gene expression in the liver and the duodenum of wild-type and Hfe-deficient B6 and D2 mice (two inbred mouse strains with divergent iron loading severity in response to Hfe disruption), to clarify the mechanisms of Hfe action, and to identify potential modifier genes.

Results

We identified 1,343 transcripts that were upregulated or downregulated in liver and 370 in duodenum of Hfe-/- mice, as compared to wild-type mice of the same genetic background. In liver, Hfe disruption upregulated genes involved in antioxidant defense, reflecting mechanisms of hepatoprotection activated by iron overload. Hfe disruption also downregulated the expression of genes involved in fatty acid β-oxidation and cholesterol catabolism, and of genes participating in mitochondrial iron traffic, suggesting a link between Hfe and the mitochondrion in regulation of iron homeostasis. These latter alterations may contribute to the inappropriate iron deficiency signal sensed by the duodenal enterocytes of these mice, and the subsequent upregulation of the genes encoding the ferrireductase Dcytb and several iron transporters or facilitators of iron transport in the duodenum. In addition, for several genes differentially expressed between B6 and D2 mice, expression was regulated by loci overlapping with previously mapped Hfe-modifier loci.

Conclusion

The expression patterns identified in this study contribute novel insights into the mechanisms of Hfe action and potential candidate genes for iron loading severity.
Thymosin β‐4 and Venous Ulcers
Authors: GUARNERA GIORGIO , DE ROSA ALFONSO , CAMERINI ROBERTO
Published: October 2007

Abstract:  The objective of this double‐blind, placebo‐controlled, dose‐escalation study is to evaluate safety, tolerability, and enhancement on healing of thymosin β‐4 (Tβ‐4) administered topically in patients with venous ulcers. Three groups of patients, coming from 10 sites, 5 from Italy and 5 from Poland, will be enrolled sequentially. Twenty‐four patients within each group will be randomized to Tβ‐4  or placebo in a 3:1 ratio and will be treated with increasing doses of Tβ‐4. When review safety data show no‐dose‐limiting adverse events, a new group will be enrolled. So, the study design comprehends 72 patients treated for 84 days and followed for 14 days at the end of treatment. Blood samples will be taken on day 0 and at the end of treatment visit to measure plasma levels of Tβ‐4. Every week each patient is visited and blood samples are taken for clinical chemistry, hematology, coagulation, and urinalysis. Each ulcer is treated with debridement, if necessary, and compression therapy with standard compression stockings class 2. Efficacy parameters are incidence of healing defined as the percentage of patients who have complete closure of the index ulcer at day 84 and, mean time to complete healing. Ulcer area will be calculated by digital planimetry and photographic analysis. The study is ongoing and a total of 21 patients have been enrolled so far in the first treatment group at the lower dose. Patients' compliance and motivated and well‐trained teams seem to be the most suitable parameters of a successfully conducted study.
Thymosin β‐4 and the Eye
Authors: SOSNE GABRIEL , QIU PING , KURPAKUS‐WHEATER MICHELLE
Published: October 2007

Abstract:  The cornea epithelium responds to injury by synthesizing several cytokines, growth factors, and tissue remodeling molecules. Proinflammatory cytokines have been implicated in the inflammation that follows corneal epithelial injury and cytokine‐mediated processes play a significant role in corneal epithelial wound healing. Poorly regulated corneal inflammatory reactions that occur after injury can retard healing. In turn, persistent corneal epithelial defects and inflammation may lead to ocular morbidity and permanent visual loss. Therefore, treatments with agents that enhance corneal reepithelialization and regulate the inflammatory response without the deleterious side effects of currently used agents, such as corticosteroids, would result in improved clinical outcome and would represent a major advance in the field. Evidence is mounting to support the idea that thymosin β‐4 (Tβ‐4) has multiple, seemingly diverse, cellular functions. In the cornea, as in other tissues, Tβ‐4 promotes cell migration and wound healing, has anti‐inflammatory properties, and suppresses apoptosis. Prior studies from our laboratory have demonstrated the potent wound healing and anti‐inflammatory effects of Tβ‐4 in numerous models of corneal injury. Recently, we demonstrated that Tβ‐4 suppresses the activation of the transcription factor, nuclear factor‐kappa b (NF‐κB) in TNF‐α‐stimulated cells. TNF‐α initiates cell signaling pathways that converge on the activation of NF‐κB, thus both are known mediators of the inflammatory process. These results have important clinical implications for the potential role of Tβ‐4 as a corneal anti‐inflammatory and wound‐healing agent.
Issues in Pharmaceutical Development of Thymosin α1 from Preclinical Studies through Marketing
Authors: TUTHILL CYNTHIA
Published: October 2007

Abstract:  SciClone Pharmaceuticals licensed the commercial and patent rights to thymosin α1, for geographical regions of the world excluding the United States and Europe, in the early 1990s. With this license, SciClone embarked on global drug development, and the issues encountered for thymosin α1 are reflective of the roller coaster of modern approval of pharmaceuticals. Most of the required toxicology studies had been completed prior to licensure, but some newer studies had to be conducted to obtain approvals in certain countries. The recent development of the “International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use” (ICH) guidelines allows for a clearer definition of the required battery of toxicology studies, although some countries still have not adopted these guidelines, and the local regulations have had to be understood and followed. Other hurdles include the complications that manufacturing requirements can differ between countries, and certain countries require local clinical experience trials in addition to SciClone's cumulative clinical data. A further obstacle was the pleiotropic nature of the mechanism of action of thymosin α1, with the resulting difficulty in the unraveling of its pharmacologic effects. With close attention to these regulatory details, SciClone has obtained approvals in more than 30 countries and has successfully begun commercial sales.
The β‐Thymosin/WH2 Fold
Authors: DOMINGUEZ ROBERTO
Published: October 2007

Abstract:  Remodeling of the actin cytoskeleton in cells is tightly regulated by a vast number of actin‐binding proteins (ABPs). These proteins interact with actin via a limited set of conserved folding motifs. One of the most abundant actin‐binding motifs is the β‐thymosin fold, represented by the prototypical actin‐monomer sequestering protein thymosin‐β4. Among many cytoskeletal proteins, the β‐thymosin fold adopts a shorter form, known as the WASP homology domain 2. Some characteristic features of the β‐thymosin/WH2 fold include its small size (17–43 aa), significant sequence and length variability, frequent occurrence in the form of tandem repeats, and remarkable multifunctionality. This paper discusses the relationship between structure and function of the β‐thymosin/WH2 fold on the basis of four examples: (1) actin monomer sequestration (thymosin‐β4), (2) actin filament nucleation (WASP‐Arp2/3 complex, Lmod, and spire), (3) actin filament elongation (Ena/VASP), and (4) cytoskeleton scaffolding (IRSp53 and MIM). Although the core function of the β‐thymosin/WH2 domain in all these proteins is actin binding, specific changes in the sequence of the domain and modular organization of the proteins in which it is found give rise to diverse functions in the regulation of actin cytoskeleton dynamics.
One‐Trial In Vitro Conditioning of Hermissenda Regulates Phosphorylation of Ser‐122 of Csp24
Authors: CROW TERRY , XUE‐BIAN JUAN‐JUAN
Published: October 2007

Abstract:  The regulation of the intrinsic excitability of a neuron is an important aspect of cellular and synaptic plasticity underlying learning and memory. Various voltage‐dependent K+ channels have been shown to be critical for the modification of membrane excitability. Components of the cytoskeleton have been proposed to contribute to the location, distribution, and function of diverse K+ channels. However, the mechanisms underlying the regulation of the cytoskeleton by signaling pathways and the role of the cytoskeleton in the induction of intrinsic excitability is not understood. Hermissenda Csp24 is a beta‐thymosin‐like protein containing multiple actin‐binding domains that contributes to intrinsic enhanced excitability produced by Pavlovian conditioning. One‐trial in vitro conditioning produces a significant reduction in the A‐type transient K+ current (IA) and a depolarized shift in the steady‐state activation curve of IA. Intermediate and long‐term enhanced excitability produced by one‐trial conditioning is also dependent on the expression and phosphorylation of Csp24. Blocking the expression of Csp24 with an antisense oligonucleotide inhibits the development of intermediate‐term enhanced excitability and the concomitant reduction in IA normally produced by one‐trial in vitro conditioning. In this report using two‐dimensional gel PAGE and electrospray mass spectrometry, we have identified two phosphorylation sites on Csp24. Using phospho‐specific antibodies with Western blot analysis and immunoprecipitation procedures we show that one‐trial in vitro conditioning results in an increase in the phosphorylation of Ser‐122, but not Ser‐49 of Csp24.