bluuebunny/crossref_metadata_2025 huggingface dataset:
Wine Tourism in Champagne
Authors: Charters Steve , Menival David
Published: November 2010

The goal of this article is to expand the understanding of wine tourism in a European context (less closely researched than that of New World countries) by examining aspects of its operation in Champagne. Two separate studies contribute toward this goal. The first qualitative project examined the perceptions of small champagne producers on a range of tourism-related issues. The second quantitative project investigated the perspectives of visitors to the region. The article offers three conclusions. First, it suggests that producers show three varying approaches to wine tourism (related to structural factors in the businesses concerned) with most feeling it was not relevant to them even though they sell wine direct. Second, producers may have little idea of what tourists find acceptable. Finally, it demonstrates that tourism may be a way for smaller producers to add value to their product, as tourists display a propensity to pay more than local purchasers.
Development of a Measure of “Acculturation” for Ethnic Fijians: Methodologic and Conceptual Considerations for Application to Eating Disorders Research
Authors: Becker Anne E. , Fay Kristen , Agnew-Blais Jessica , Guarnaccia Peter M. , Striegel-Moore Ruth H. , Gilman Stephen E.
Published: November 2010

Acculturation has been examined as a risk factor for eating disorders, but interpretation of findings has been limited by inconsistent operationalization of this construct across studies. The study aim was to develop and evaluate a population-specific measure of acculturation for ethnic Fijian adolescent schoolgirls, to use in future analyses related to eating disorders. Our findings suggest that acculturation is a multidimensional construct characterized by distinct, though related, dimensions of orientation to ethnic Fijian and/or western/global culture with respect to a range of behaviors and attitudes. In contrast to theoretical models positing uni-dimensional, orthogonal, or oblique relations between cultural identities in individuals undergoing acculturation, our study findings support a heterogeneous pattern among correlations of dimensions across contrasting cultural identities. We suggest multidimensional measures of acculturation are optimal — and socio-demographic proxies inadequate — for characterization of this complex process for health research.
The Role of Acculturation in Suicidal Ideation among Second-Generation Immigrant Adolescents in France
Authors: van Leeuwen Nikki , Rodgers Rachel , Régner Isabelle , Chabrol Henri
Published: November 2010

This study explored the contributions of sociocultural and psychopathological factors to suicidal ideation among adolescents. A sample of 292 French high school students with an immigrant background completed a questionnaire assessing suicidal ideation, borderline personality traits, depressive symptoms, parental attachment, life events, acculturation orientations, ethnic identity, cannabis and alcohol consumption, socioeconomic status and academic failure. Although stressful life events, depressive symptoms, and individualism were risk factors, and attachment to parents a protective factor for both boys and girls, some gender differences emerged. Borderline traits (risk factor), assimilation and marginalization (both protective factors) were significant predictors only among girls.
Multicultural Evidence-Based Assessment of Child and Adolescent Psychopathology
Authors: Achenbach Thomas M.
Published: November 2010

This article presents multicultural ways to advance knowledge of children’s problems, to fashion conceptual and practical mental health tools, and to use these tools to help children. Diagnostically based scales and statistically derived syndromes are scored from parallel forms completed by population samples of parents, caregivers, teachers, and youths in many societies. The scores are incorporated into multicultural norms for evaluating individual children, as rated by different respondents in relation to relevant norms, such as norms for host societies where immigrant children reside and norms for their families’ home societies. Syndrome structures have been supported in 44 societies. Certain age, gender, and SES effects are consistent across many societies. As reported in over 7000 publications from 85 societies and cultural groups, evidence-based assessment provides a common data language for clinicians, trainees, and researchers around the world.
The Celebrity-Icon
Authors: Alexander Jeffrey C.
Published: November 2010

This article develops a non-reductive approach to celebrity, treating it as an iconic form of collective representation central to the meaningful construction of contemporary society. Like other compelling material symbols, the celebrity-icon is structured by the interplay of surface and depth. The surface is an aesthetic structure whose sensuous qualities command attention and compel attachment; the depth projects the sacred and profane binaries that structure meaning even in postmodern societies. While celebrity worship displays elements of totemism, it also reflects the eschatological hopes for salvation that mark post-Axial Age religion. The attacks on celebrity culture that inform critical public and intellectual thinking resemble iconoclastic criticisms of idol worship more than they do empirical social scientific study.
Telling Stories About Jesus: A Conversation with John Carroll
Authors: Tester Keith
Published: November 2010

Since the 1980s the Australian sociologist John Carroll has been engaged in a unique project. Over the course of a number of books he has sought to investigate the fate of authority, values and vocation in the tradition of Western culture. His books are characterised by a deep knowledge of the Western tradition of high culture, especially its art and texts; they are marked by historical sweep and seriousness of purpose. For Carroll, culture is the retelling of archetypal stories which take us beyond the ego and towards the work of soul-building. In 2007 he published the book The Existential Jesus which seeks to tell of the meaning of Jesus for contemporar y culture. This conversation uses the publication of the Jesus book as an opportunity to ask Carroll to reflect on his work. Consequently the article is also an invitation for the wider academic community to begin to engage with Carroll’s profound and challenging inquiry into the state of Western culture.
Lights … camera … infection prevention in action
Authors: Billings Angela
Published: November 2010

Infection prevention and control (IPC) education of independent contractors is a challenge for Infection Prevention and Control Practitioners (IPCP) working in community, due to the diversity of disciplines working across many services and their geographical locations. This article focuses on two differing and innovative teaching methods of play presentation and educational DVD used by the IPCP in a large city primary care trust—commissioning organisation aimed at general dental practice staff (GDPs). The experience suggests that innovative learning activities such as drama and scenario-based DVDs in teaching IPC principles may be applicable in other areas of primary care areas such as general practice, in the wider healthcare community within care homes and are transferable to acute care settings.
Performance Journalism: A Three-Template Model of Television News
Authors: Atkinson Joe
Published: November 2010

Journalists and their editorial managers are increasingly beholden to standards of performance built into industrial performance templates imported from outside what used to be regarded as the journalistic ‘field’. This paper distinguishes three sets of criteria for journalistic ‘performance’: ethical (P1), commercial (P2) and theatrical (P3). These are elaborated in turn with respect to their industrial origins, their underlying conceptions of the public interest, their political implications and their productive consequences. The three-template model extends Franklin’s (2003) critique of McJournalism by: a) providing a fuller account of the (P2) McDonaldization of television news, b) more precisely demarcating backstage (P2) and frontstage (P3) elements of journalistic performance, and c) elaborating a new P3 news template with reference to Bryman’s (2004) work on Disneyization. The paper concludes with a New Zealand case study highlighting tensions between P2 and P3 modes of performance and audience outcomes.
Osteoclast-gene expression profiling reveals osteoclast-derived CCR2 chemokines promoting myeloma cell migration
Authors: Moreaux Jerome , Hose Dirk , Kassambara Alboukadel , Reme Thierry , Moine Philippe , Requirand Guilhem , Goldschmidt Hartmut , Klein Bernard
Published: November 2010

Multiple myeloma is characterized by the clonal expansion of malignant plasma cells (multiple myeloma cells [MMCs]), in the bone marrow. Osteolytic bone lesions are detected in 80% of patients because of increased osteoclastic bone resorption and reduced osteoblastic bone formation. MMCs are found closely associated with sites of increased bone resorption. Osteoclasts strongly support MMC survival in vitro. To further elucidate the mechanisms involved in osteoclast/MMC interaction, we have identified 552 genes overexpressed in osteoclasts compared with other bone marrow cell subpopulations. Osteoclasts express specifically genes coding for 4 CCR2-targeting chemokines and genes coding for MMC growth factors. An anti-CCR2 monoclonal antibody blocked osteoclast chemoattractant activity for MMC, and CCR2 chemokines are also MMC growth factors, promoting mitogen-activated protein kinase activation in MMC. An anti-insulin growth factor-1 receptor monoclonal antibody completely blocked the osteoclast-induced survival of MMC suppressing both osteoclast and MMC survival. Specific a proliferation-inducing ligand or IL-6 inhibitors partially blocked osteoclast-induced MMC survival. These data may explain why newly diagnosed patients whose MMC express high levels of CCR2 present numerous bone lesions. This study displays additional mechanisms involved in osteoclast/MMC interaction and suggests using CCR2 and/or insulin growth factor-1 targeting strategies to block this interaction and prevent drug resistance.
Sbds is required for Rac2-mediated monocyte migration and signaling downstream of RANK during osteoclastogenesis
Authors: Leung Roland , Cuddy Karl , Wang Yongqiang , Rommens Johanna , Glogauer Michael
Published: November 2010

Shwachman-Diamond syndrome (SDS) results from mutations in the SBDS gene, characterized by exocrine pancreatic insufficiency and hematologic and skeletal abnormalities. Neutropenia and neutrophil dysfunction are hallmark features of SDS; however, causes for the bone defects are unknown. Dysfunction of bone-resorbing osteoclasts, formed by the fusion of monocytic progenitors derived from the same granulocytic precursors as neutrophils, could be responsible. We report that Sbds is required for in vitro and in vivo osteoclastogenesis (OCG). Sbds-null murine monocytes formed osteoclasts of reduced number and size because of impaired migration and fusion required for OCG. Phenotypically, Sbds-null mice exhibited low-turnover osteoporosis consistent with findings in SDS patients. Western blotting of Rho GTPases that control actin dynamics and migration showed a 5-fold decrease in Rac2, whereas Rac1, Cdc42, and RhoA were unchanged or only mildly reduced. Although migration was rescued on Rac2 supplementation, OCG was not. This was attributed to impaired signaling downstream of receptor activator of nuclear factor-κB (RANK) and reduced expression of the RANK-ligand-dependent fusion receptor DC-STAMP. We conclude that Sbds is required for OCG by regulating monocyte migration via Rac2 and osteoclast differentiation signaling downstream of RANK. Impaired osteoclast formation could disrupt bone homeostasis, resulting in skeletal abnormalities seen in SDS patients.
Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17–secreting T cells
Authors: Dusseaux Mathilde , Martin Emmanuel , Serriari Nacer , Péguillet Isabelle , Premel Virginie , Louis Delphine , Milder Maud , Le Bourhis Lionel , Soudais Claire , Treiner Emmanuel , Lantz Olivier
Published: November 2010

Mucosal-associated invariant T (MAIT) cells are very abundant in humans and have antimicrobial specificity, but their functions remain unclear. MAIT cells are CD161hiIL-18Rα+ and either CD4−CD8− (DN) or CD8αβint T cells. We now show that they display an effector-memory phenotype (CD45RA−CD45RO+CD95hiCD62Llo), and their chemokine receptor expression pattern (CCR9intCCR7−CCR5hiCXCR6hiCCR6hi) indicates preferential homing to tissues and particularly the intestine and the liver. MAIT cells can represent up to 45% of the liver lymphocytes. They produce interferon-γ and Granzyme-B as well as high levels of interleukin-17 after phorbol myristate acetate + ionomycin stimulation. Most MAIT cells are noncycling cells (< 1% are Ki-67+) and express the multidrug resistance transporter (ABCB1). As expected from this phenotype, MAIT cells are more resistant to chemotherapy than other T-cell populations. These features might also allow MAIT cells to resist the xenobiotics potentially secreted by the gut bacteria. We also show that this population does not appear to have antiviral specificity and that CD8 MAIT cells include almost all the ABCB1+CD161hi CD8 T cells. Together with their already known abundance and antimicrobial specificity, the gut-liver homing characteristics, high expression of ABCB1, and ability to secrete interleukin-17 probably participate in the antibacterial properties of MAIT cells.
mpeg1 promoter transgenes direct macrophage-lineage expression in zebrafish
Authors: Ellett Felix , Pase Luke , Hayman John W. , Andrianopoulos Alex , Lieschke Graham J.
Published: November 2010

Macrophages and neutrophils play important roles during the innate immune response, phagocytosing invading microbes and delivering antimicrobial compounds to the site of injury. Functional analyses of the cellular innate immune response in zebrafish infection/inflammation models have been aided by transgenic lines with fluorophore-marked neutrophils. However, it has not been possible to study macrophage behaviors and neutrophil/macrophage interactions in vivo directly because there has been no macrophage-only reporter line. To remove this roadblock, a macrophage-specific marker was identified (mpeg1) and its promoter used in mpeg1-driven transgenes. mpeg1-driven transgenes are expressed in macrophage-lineage cells that do not express neutrophil-marking transgenes. Using these lines, the different dynamic behaviors of neutrophils and macrophages after wounding were compared side-by-side in compound transgenics. Macrophage/neutrophil interactions, such as phagocytosis of senescent neutrophils, were readily observed in real time. These zebrafish transgenes provide a new resource that will contribute to the fields of inflammation, infection, and leukocyte biology.
Predicting genome-wide redundancy using machine learning
Authors: Chen Huang-Wen , Bandyopadhyay Sunayan , Shasha Dennis E , Birnbaum Kenneth D
Published: November 2010

Background

Gene duplication can lead to genetic redundancy, which masks the function of mutated genes in genetic analyses. Methods to increase sensitivity in identifying genetic redundancy can improve the efficiency of reverse genetics and lend insights into the evolutionary outcomes of gene duplication. Machine learning techniques are well suited to classifying gene family members into redundant and non-redundant gene pairs in model species where sufficient genetic and genomic data is available, such as Arabidopsis thaliana, the test case used here.

Results

Machine learning techniques that combine multiple attributes led to a dramatic improvement in predicting genetic redundancy over single trait classifiers alone, such as BLAST E-values or expression correlation. In withholding analysis, one of the methods used here, Support Vector Machines, was two-fold more precise than single attribute classifiers, reaching a level where the majority of redundant calls were correctly labeled. Using this higher confidence in identifying redundancy, machine learning predicts that about half of all genes in Arabidopsis showed the signature of predicted redundancy with at least one but typically less than three other family members. Interestingly, a large proportion of predicted redundant gene pairs were relatively old duplications (e.g., Ks > 1), suggesting that redundancy is stable over long evolutionary periods.

Conclusions

Machine learning predicts that most genes will have a functionally redundant paralog but will exhibit redundancy with relatively few genes within a family. The predictions and gene pair attributes for Arabidopsis provide a new resource for research in genetics and genome evolution. These techniques can now be applied to other organisms.
Difference in gene duplicability may explain the difference in overall structure of protein-protein interaction networks among eukaryotes
Authors: Hase Takeshi , Niimura Yoshihito , Tanaka Hiroshi
Published: November 2010

Background

A protein-protein interaction network (PIN) was suggested to be a disassortative network, in which interactions between high- and low-degree nodes are favored while hub-hub interactions are suppressed. It was postulated that a disassortative structure minimizes unfavorable cross-talks between different hub-centric functional modules and was positively selected in evolution. However, by re-examining yeast PIN data, several researchers reported that the disassortative structure observed in a PIN might be an experimental artifact. Therefore, the existence of a disassortative structure and its possible evolutionary mechanism remains unclear.

Results

In this study, we investigated PINs from the yeast, worm, fly, human, and malaria parasite including four different yeast PIN datasets. The analyses showed that the yeast, worm, fly, and human PINs are disassortative while the malaria parasite PIN is not. By conducting simulation studies on the basis of a duplication-divergence model, we demonstrated that a preferential duplication of low- and high-degree nodes can generate disassortative and non-disassortative networks, respectively. From this observation, we hypothesized that the difference in degree dependence on gene duplications accounts for the difference in assortativity of PINs among species. Comparison of 55 proteomes in eukaryotes revealed that genes with lower degrees showed higher gene duplicabilities in the yeast, worm, and fly, while high-degree genes tend to have high duplicabilities in the malaria parasite, supporting the above hypothesis.

Conclusions

These results suggest that disassortative structures observed in PINs are merely a byproduct of preferential duplications of low-degree genes, which might be caused by an organism's living environment.
Combining target enrichment with barcode multiplexing for high throughput SNP discovery
Authors: Cummings Nik , King Rob , Rickers Andre , Kaspi Antony , Lunke Sebastian , Haviv Izhak , Jowett Jeremy BM
Published: November 2010

Background

The primary goal of genetic linkage analysis is to identify genes affecting a phenotypic trait. After localisation of the linkage region, efficient genetic dissection of the disease linked loci requires that functional variants are identified across the loci. These functional variations are difficult to detect due to extent of genetic diversity and, to date, incomplete cataloguing of the large number of variants present both within and between populations. Massively parallel sequencing platforms offer unprecedented capacity for variant discovery, however the number of samples analysed are still limited by cost per sample. Some progress has been made in reducing the cost of resequencing using either multiplexing methodologies or through the utilisation of targeted enrichment technologies which provide the ability to resequence genomic areas of interest rather that full genome sequencing.

Results

We developed a method that combines current multiplexing methodologies with a solution-based target enrichment method to further reduce the cost of resequencing where region-specific sequencing is required. Our multiplex/enrichment strategy produced high quality data with nominal reduction of sequencing depth. We undertook a genotyping study and were successful in the discovery of novel SNP alleles in all samples at uniplex, duplex and pentaplex levels.

Conclusion

Our work describes the successful combination of a targeted enrichment method and index barcode multiplexing to reduce costs, time and labour associated with processing large sample sets. Furthermore, we have shown that the sequencing depth obtained is adequate for credible SNP genotyping analysis at uniplex, duplex and pentaplex levels.
Genome-wide promoter analysis of histone modifications in human monocyte-derived antigen presenting cells
Authors: Tserel Liina , Kolde Raivo , Rebane Ana , Kisand Kai , Org Tõnis , Peterson Hedi , Vilo Jaak , Peterson Pärt
Published: November 2010

Background

Monocyte-derived macrophages and dendritic cells (DCs) are important in inflammatory processes and are often used for immunotherapeutic approaches. Blood monocytes can be differentiated into macrophages and DCs, which is accompanied with transcriptional changes in many genes, including chemokines and cell surface markers.

Results

To study the chromatin modifications associated with this differentiation, we performed a genome wide analysis of histone H3 trimethylation on lysine 4 (H3K4me3) and 27 (H3K27me3) as well as acetylation of H3 lysines (AcH3) in promoter regions. We report that both H3K4me3 and AcH3 marks significantly correlate with transcriptionally active genes whereas H3K27me3 mark is associated with inactive gene promoters. During differentiation, the H3K4me3 levels decreased on monocyte-specific CD14, CCR2 and CX3CR1 but increased on DC-specific TM7SF4/DC-STAMP, TREM2 and CD209/DC-SIGN genes. Genes associated with phagocytosis and antigen presentation were marked by H3K4me3 modifications. We also report that H3K4me3 levels on clustered chemokine and surface marker genes often correlate with transcriptional activity.

Conclusion

Our results provide a basis for further functional correlations between gene expression and histone modifications in monocyte-derived macrophages and DCs.
Genomic evolution and complexity of the Anaphase-promoting Complex (APC) in land plants
Authors: Lima Marcelo deF , Eloy Núbia B , Pegoraro Camila , Sagit Rauan , Rojas Cristian , Bretz Thiago , Vargas Lívia , Elofsson Arne , de Oliveira Antonio Costa , Hemerly Adriana S , Ferreira Paulo CG
Published: November 2010

Background

The orderly progression through mitosis is regulated by the Anaphase-Promoting Complex (APC), a large multiprotein E3ubiquitin ligase that targets key cell-cycle regulators for destruction by the 26 S proteasome. The APC is composed of at least 11 subunits and associates with additional regulatory activators during mitosis and interphase cycles. Despite extensive research on APC and activator functions in the cell cycle, only a few components have been functionally characterized in plants.

Results

Here, we describe an in-depth search for APC subunits and activator genes in the Arabidopsis, rice and poplar genomes. Also, searches in other genomes that are not completely sequenced were performed. Phylogenetic analyses indicate that some APC subunits and activator genes have experienced gene duplication events in plants, in contrast to animals. Expression patterns of paralog subunits and activators in rice could indicate that this duplication, rather than complete redundancy, could reflect initial specialization steps. The absence of subunit APC7 from the genome of some green algae species and as well as from early metazoan lineages, could mean that APC7 is not required for APC function in unicellular organisms and it may be a result of duplication of another tetratricopeptide (TPR) subunit. Analyses of TPR evolution suggest that duplications of subunits started from the central domains.

Conclusions

The increased complexity of the APC gene structure, tied to the diversification of expression paths, suggests that land plants developed sophisticated mechanisms of APC regulation to cope with the sedentary life style and its associated environmental exposures.
Association of IL1B -511C/-31T haplotype and Helicobacter pylori vacA genotypes with gastric ulcer and chronic gastritis
Authors: Martínez-Carrillo Dinorah N , Garza-González Elvira , Betancourt-Linares Reyes , Mónico-Manzano Trinidad , Antúnez-Rivera Cuauhtémoc , Román-Román Adolfo , Flores-Alfaro Eugenia , Illades-Aguiar Berenice , Fernández-Tilapa Gloria
Published: November 2010

Background

The association between proinflammatory cytokine gene polymorphisms and gastric diseases related to Helicobacter pylori varies by population and geographic area.

Our objective was to determine if the IL-1B -511 T>C and -31 C>T polymorphisms and H. pylori vacA genotypes are associated with risk of chronic gastritis and gastric ulcer in a Mexican population.

Methods

We conducted endoscopic studies in 128 patients with symptoms of dyspepsia. We took two biopsies from the body, antrum, or ulcer edge from each patient, and classified our histopathological findings according to the Sydney System. H. pylori infection and vacA genotyping were accomplished via PCR from total DNA of the gastric biopsies. We confirmed the presence of anti-H. pylori serum IgG and IgM in 102 control subjects. In both case subjects and control subjects, the IL-1B -511 T>C polymorphism was genotyped by PCR-RFLPs and the IL-1B -31 C>T polymorphism was genotyped by pyrosequencing.

Results

Sixty-two point seven (62.7%) of the 102 control subjects were H. pylori-seropositive. Among the case subjects, 100 were diagnosed with chronic gastritis and 28 with gastric ulcer. We found that 77% of the patients with chronic gastritis and 85.7% of the patients with gastric ulcer were H. pylori-positive. The predominant H. pylori genotype was vacA s1m1 (58.4%) and the most frequent subtype was vacA s1. The -511 TC, (rs16944 -511 T>C) genotype and the -511C allele were associated with chronic gastritis (OR = 3.1, 95% CI = 1.4-6.8 and OR = 3.0, 95% CI = 1.4-6.0, respectively). The subjects carrying -31T (rs1143627 -31 C>T) were found to be at a higher risk of having chronic gastritis (OR = 2.8, 95% CI = 1.3-5.8). The IL-1B -511C/-31T haplotype was associated with chronic gastritis (OR = 2.1, 95% CI = 1.2-3.8) but not with gastric ulcer.

Conclusions

The H. pylori vacA genotypes identified herein were similar to those reported for other regions of Mexico. The vacA s1m1 genotype was not associated with gastric ulcer. In the southern Mexican population, the IL-1B -511C and -31T alleles and the -511C/-31T and -511T/-31T haplotypes are associated with increased risk of chronic gastritis and gastric ulcer.
Molecular measurement of BCR-ABL transcript variations in chronic myeloid leukemia patients in cytogenetic remission
Authors: Serpa Mariana , Sanabani Sabri S , Dorliac-Llacer Pedro Enrique , Conchon Monika , Pereira Thales Dalessandro Meneguin , Nardinelli Luciana , Costa Juliana Lima , Novaes Mafalda Megumi Yoshinaga , Ferreira Patricia de Barros , Bendit Israel
Published: November 2010

Background

The monitoring of BCR-ABL transcript levels by real-time quantitative polymerase chain reaction (RT-qPCR) has become important to assess minimal residual disease (MRD) and standard of care in the treatment of chronic myeloid leukemia (CML). In this study, we performed a prospective, sequential analysis using RT-qPCR monitoring of BCR-ABL gene rearrangements in blood samples from 91 CML patients in chronic phase (CP) who achieved complete cytogenetic remission (CCyR) and major molecular remission (MMR) throughout imatinib treatment.

Methods

The absolute level of BCR-ABL transcript from peripheral blood was serially measured every 4 to 12 weeks by RT-qPCR. Only level variations > 0.5%, according to the international scale, was considered positive. Sequential cytogenetic analysis was also performed in bone marrow samples from all patients using standard protocols.

Results

Based on sequential analysis of BCR-ABL transcripts, the 91 patients were divided into three categories: (A) 57 (62.6%) had no variation on sequential analysis; (B) 30 (32.9%) had a single positive variation result obtained in a single sample; and (C) 4 (4.39%) had variations of BCR-ABL transcripts in at least two consecutive samples. Of the 34 patients who had elevated levels of transcripts (group B and C), 19 (55.8%) had a < 1% of BCR-ABL/BCR ratio, 13 (38.2%) patients had a 1% to 10% increase and 2 patients had a >10% increase of RT-qPCR. The last two patients had lost a CCyR, and none of them showed mutations in the ABL gene. Transient cytogenetic alterations in Ph-negative cells were observed in five (5.5%) patients, and none of whom lost CCyR.

Conclusions

Despite an increase levels of BCR-ABL/BCR ratio variations by RT-qPCR, the majority of CML patients with MMR remained in CCyR. Thus, such single variations should neither be considered predictive of subsequent failure and nor an indication for altering imatinib dose or switching to second generation therapy. Changing of imatinib on the basis of BCR-ABL/BCR% sustained increase and mutational studies is a prudent approach for preserving other therapeutic options in imatinib-resistant patients.
Microbicide excipients can greatly increase susceptibility to genital herpes transmission in the mouse
Authors: Moench Thomas R , Mumper Russell J , Hoen Timothy E , Sun Mianmian , Cone Richard A
Published: November 2010

Background

Several active ingredients proposed as vaginal microbicides have been shown paradoxically to increase susceptibility to infection in mouse genital herpes (HSV-2) vaginal susceptibility models and in clinical trials. In addition, "inactive ingredients" (or excipients) used in topical products to formulate and deliver the active ingredient might also cause epithelial toxicities that increase viral susceptibility. However, excipients have not previously been tested in susceptibility models.

Methods

Excipients commonly used in topical products were formulated in a non-toxic vehicle (the "HEC universal placebo"), or other formulations as specified. Twelve hours after exposure to the excipient or a control treatment, mice were challenged with a vaginal dose of HSV-2, and three days later were assessed for infection by vaginal lavage culture to assess susceptibility.

Results

The following excipients markedly increased susceptibility to HSV-2 after a single exposure: 5% glycerol monolaurate (GML) formulated in K-Y® Warming Jelly, 5% GML as a colloidal suspension in phosphate buffered saline, K-Y Warming Jelly alone, and both of its humectant/solvent ingredients (neat propylene glycol and neat PEG-8). For excipients formulated in the HEC vehicle, 30% glycerin significantly increased susceptibility, and a trend toward increased HSV-2 susceptibility was observed after 10% glycerin, and 0.1% disodium EDTA, but not after 0.0186% disodium EDTA. The following excipients did not increase susceptibility: 10% propylene glycol, 0.18%, methylparaben plus 0.02% propylparaben, and 1% benzyl alcohol.

Conclusions

As reported with other surfactants, the surfactant/emulsifier GML markedly increased susceptibility to HSV-2. Glycerin at 30% significantly increased susceptibility, and, undiluted propylene glycol and PEG-8 greatly increased susceptibility.
Hypercholesterolemia and microvascular dysfunction: interventional strategies
Authors: Stapleton Phoebe A , Goodwill Adam G , James Milinda E , Brock Robert W , Frisbee Jefferson C
Published: November 2010

Hypercholesterolemia is defined as excessively high plasma cholesterol levels, and is a strong risk factor for many negative cardiovascular events. Total cholesterol levels above 200 mg/dl have repeatedly been correlated as an independent risk factor for development of peripheral vascular (PVD) and coronary artery disease (CAD), and considerable attention has been directed toward evaluating mechanisms by which hypercholesterolemia may impact vascular outcomes; these include both results of direct cholesterol lowering therapies and alternative interventions for improving vascular function. With specific relevance to the microcirculation, it has been clearly demonstrated that evolution of hypercholesterolemia is associated with endothelial cell dysfunction, a near-complete abrogation in vascular nitric oxide bioavailability, elevated oxidant stress, and the creation of a strongly pro-inflammatory condition; symptoms which can culminate in profound impairments/alterations to vascular reactivity. Effective interventional treatments can be challenging as certain genetic risk factors simply cannot be ignored. However, some hypercholesterolemia treatment options that have become widely used, including pharmaceutical therapies which can decrease circulating cholesterol by preventing either its formation in the liver or its absorption in the intestine, also have pleiotropic effects with can directly improve peripheral vascular outcomes. While physical activity is known to decrease PVD/CAD risk factors, including obesity, psychological stress, impaired glycemic control, and hypertension, this will also increase circulating levels of high density lipoprotein and improving both cardiac and vascular function. This review will provide an overview of the mechanistic consequences of the predominant pharmaceutical interventions and chronic exercise to treat hypercholesterolemia through their impacts on chronic sub-acute inflammation, oxidative stress, and microvascular structure/function relationships.
One life ends, another begins: Management of a brain-dead pregnant mother-A systematic review-
Authors: Esmaeilzadeh Majid , Dictus Christine , Kayvanpour Elham , Sedaghat-Hamedani Farbod , Eichbaum Michael , Hofer Stefan , Engelmann Guido , Fonouni Hamidreza , Golriz Mohammad , Schmidt Jan , Unterberg Andreas , Mehrabi Arianeb , Ahmadi Rezvan
Published: November 2010

Background

An accident or a catastrophic disease may occasionally lead to brain death (BD) during pregnancy. Management of brain-dead pregnant patients needs to follow special strategies to support the mother in a way that she can deliver a viable and healthy child and, whenever possible, also be an organ donor. This review discusses the management of brain-dead mothers and gives an overview of recommendations concerning the organ supporting therapy.

Methods

To obtain information on brain-dead pregnant women, we performed a systematic review of Medline, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). The collected data included the age of the mother, the cause of brain death, maternal medical complications, gestational age at BD, duration of extended life support, gestational age at delivery, indication of delivery, neonatal outcome, organ donation of the mothers and patient and graft outcome.

Results

In our search of the literature, we found 30 cases reported between1982 and 2010. A nontraumatic brain injury was the cause of BD in 26 of 30 mothers. The maternal mean age at the time of BD was 26.5 years. The mean gestational age at the time of BD and the mean gestational age at delivery were 22 and 29.5 weeks, respectively. Twelve viable infants were born and survived the neonatal period.

Conclusion

The management of a brain-dead pregnant woman requires a multidisciplinary team which should follow available standards, guidelines and recommendations both for a nontraumatic therapy of the fetus and for an organ-preserving treatment of the potential donor.
An experimental study of pathologist's navigation patterns in virtual microscopy
Authors: Roa-Peña Lucia , Gómez Francisco , Romero Eduardo
Published: November 2010

In virtual microscopy, a sequential process of captures of microscopical fields, allows to construct a virtual slide which is visualized using a specialized software, called the virtual microscopy viewer. This tool allows useful exploration of images, composed of thousands of microscopical fields of view at different levels of magnification, emulating an actual microscopical examination. The aim of this study was to establish the main pathologist's navigation patterns when exploring virtual microscopy slides, using a graphical user interface, adapted to the pathologist's workflow. Four pathologists with a similar level of experience, graduated from the same pathology program, navigated six virtual slides. Different issues were evaluated, namely, the percentage of common visited image regions, the time spent at each and its coincidence level, that is to say, the region of interest location. In addition, navigation patterns were also assessed, i.e., mouse movement velocities and linearity of the diagnostic paths. Results suggest that regions of interest are determined by a complex combination of the visited area, the time spent at each visit and the coincidence level among pathologists. Additionally, linear trajectories and particular velocity patterns were found for the registered diagnostic paths.
The Rx for Change database: a first-in-class tool for optimal prescribing and medicines use
Authors: Weir Michelle C , Ryan Rebecca , Mayhew Alain , Worswick Julia , Santesso Nancy , Lowe Dianne , Leslie Bill , Stevens Adrienne , Hill Sophie , Grimshaw Jeremy M
Published: November 2010

Background

Globally, suboptimal prescribing practices and medication errors are common. Guidance to health professionals and consumers alone is not sufficient to optimise behaviours, therefore strategies to promote evidence-based decision making and practice, such as decision support tools or reminders, are important. The literature in this area is growing, but is of variable quality and dispersed across sources, which makes it difficult to identify, access, and assess. To overcome these problems, by synthesizing and evaluating the data from systematic reviews, we have developed Rx for Change to provide a comprehensive, online database of the evidence for strategies to improve drug prescribing and use.

Methods

We use reliable and valid methods to search and screen the literature, and to appraise and analyse the evidence from relevant systematic reviews. We then present the findings in an online format which allows users to easily access pertinent information related to prescribing and medicines use. The database is a result of the collaboration between the Canadian Agency for Drugs and Technologies in Health (CADTH) and two Cochrane review groups.

Results

To capture the body of evidence on interventions to improve prescribing and medicines use, we conduct comprehensive and regular searches in multiple databases, and hand-searches of relevant journals. We screen articles to identify relevant systematic reviews, and include them if they are of moderate or high methodological quality. Two researchers screen, assess quality, and extract data on demographic details, intervention characteristics, and outcome data. We report the results of our analysis of each systematic review using a standardised quantitative and qualitative format. Rx for Change currently contains over 200 summarised reviews, structured in a multi-level format. The reviews included in the database are diverse, covering various settings, conditions, or diseases and targeting a range of professional and consumer behaviors.

Conclusions

Rx for Change is a novel database that synthesizes current research evidence about the effects of interventions to improve drug prescribing practices and medicines use.
Modeling cardiac β-adrenergic signaling with normalized-Hill differential equations: comparison with a biochemical model
Authors: Kraeutler Matthew J , Soltis Anthony R , Saucerman Jeffrey J
Published: November 2010

Background

New approaches are needed for large-scale predictive modeling of cellular signaling networks. While mass action and enzyme kinetic approaches require extensive biochemical data, current logic-based approaches are used primarily for qualitative predictions and have lacked direct quantitative comparison with biochemical models.

Results

We developed a logic-based differential equation modeling approach for cell signaling networks based on normalized Hill activation/inhibition functions controlled by logical AND and OR operators to characterize signaling crosstalk. Using this approach, we modeled the cardiac β1-adrenergic signaling network, including 36 reactions and 25 species. Direct comparison of this model to an extensively characterized and validated biochemical model of the same network revealed that the new model gave reasonably accurate predictions of key network properties, even with default parameters. Normalized Hill functions improved quantitative predictions of global functional relationships compared with prior logic-based approaches. Comprehensive sensitivity analysis revealed the significant role of PKA negative feedback on upstream signaling and the importance of phosphodiesterases as key negative regulators of the network. The model was then extended to incorporate recently identified protein interaction data involving integrin-mediated mechanotransduction.

Conclusions

The normalized-Hill differential equation modeling approach allows quantitative prediction of network functional relationships and dynamics, even in systems with limited biochemical data.
MATH5 controls the acquisition of multiple retinal cell fates
Authors: Feng Liang , Xie Zheng-hua , Ding Qian , Xie Xiaoling , Libby Richard T , Gan Lin
Published: November 2010

Math5-null mutation results in the loss of retinal ganglion cells (RGCs) and in a concurrent increase of amacrine and cone cells. However, it remains unclear whether there is a cell fate switch of Math5-lineage cells in the absence of Math5 and whether MATH5 cell-autonomously regulates the differentiation of the above retinal neurons. Here, we performed a lineage analysis of Math5-expressing cells in developing mouse retinas using a conditional GFP reporter (Z/EG) activated by a Math5-Cre knock-in allele. We show that during normal retinogenesis, Math5-lineage cells mostly develop into RGCs, horizontal cells, cone photoreceptors, rod photoreceptors, and amacrine cells. Interestingly, amacrine cells of Math5-lineage cells are predominately of GABAergic, cholinergic, and A2 subtypes, indicating that Math5 plays a role in amacrine subtype specification. In the absence of Math5, more Math5-lineage cells undergo cell fate conversion from RGCs to the above retinal cell subtypes, and occasionally to cone-bipolar cells and Müller cells. This change in cell fate choices is accompanied by an up-regulation of NEUROD1, RXRγ and BHLHB5, the transcription factors essential for the differentiation of retinal cells other than RGCs. Additionally, loss of Math5 causes the failure of early progenitors to exit cell cycle and leads to a significant increase of Math5-lineage cells remaining in cell cycle. Collectively, these data suggest that Math5 regulates the generation of multiple retinal cell types via different mechanisms during retinogenesis.
Microbiological contamination of cubicle curtains in an out‐patient podiatry clinic
Authors: Woodland Ria , Whitham Deborah , O'Neil Bill , Otter Simon
Published: November 2010

Background

Exposure to potential pathogens on contaminated healthcare garments and curtains can occur through direct or indirect contact. This study aimed to identify the microorganisms present on podiatry clinic curtains and measure the contamination pre and post a standard hospital laundry process.

Method

Baseline swabs were taken to determine colony counts present on cubical curtains before laundering. Curtains were swabbed again immediately after, one and three weeks post laundering. Total colony counts were calculated and compared to baseline, with identification of micro‐organisms.

Results

Total colony counts increased very slightly by 3% immediately after laundry, which was not statistically significant, and declined significantly (p = 0.0002) by 56% one‐week post laundry. Three weeks post laundry colony counts had increased by 16%; although clinically relevant, this was not statistically significant. The two most frequent microorganisms present throughout were Coagulase Negative Staphylococcus and Micrococcus species. Laundering was not completely effective, as both species demonstrated no significant change following laundry.

Conclusion

This work suggests current laundry procedures may not be 100% effective in killing all microorganisms found on curtains, although a delayed decrease in total colony counts was evident. Cubicle curtains may act as a reservoir for microorganisms creating potential for cross contamination. This highlights the need for additional cleaning methods to decrease the risk of cross infection and the importance of maintaining good hand hygiene.
Using mammographic density to predict breast cancer risk: dense area or percentage dense area
Authors: Stone Jennifer , Ding Jane , Warren Ruth ML , Duffy Stephen W , Hopper John L
Published: November 2010

Introduction

Mammographic density (MD) is one of the strongest risk factors for breast cancer. It is not clear whether this association is best expressed in terms of absolute dense area or percentage dense area (PDA).

Methods

We measured MD, including nondense area (here a surrogate for weight), in the mediolateral oblique (MLO) mammogram using a computer-assisted thresholding technique for 634 cases and 1,880 age-matched controls from the Cambridge and Norwich Breast Screening programs. Conditional logistic regression was used to estimate the risk of breast cancer, and fits of the models were compared using likelihood ratio tests and the Bayesian information criteria (BIC). All P values were two-sided.

Results

Square-root dense area was the best single predictor (for example, χ12 = 53.2 versus 44.4 for PDA). Addition of PDA and/or square-root nondense area did not improve the fit (both P > 0.3). Addition of nondense area improved the fit of the model with PDA (χ12 = 11.6; P < 0.001). According to the BIC, the PDA and nondense area model did not provide a better fit than the dense area alone model. The fitted values of the two models were highly correlated (r = 0.97). When a measure of body size is included with PDA, the predicted risk is almost identical to that from fitting dense area alone.

Conclusions

As a single parameter, dense area provides more information than PDA on breast cancer risk.
Macrophage motility requires distinct α5β1/FAK and α4β1/paxillin signaling events
Authors: Abshire Michelle Y , Thomas Keena S , Owen Katherine A , Bouton Amy H
Published: November 2010

Macrophages function as key inflammatory mediators at sites of infection and tissue damage. Integrin and growth factor receptors facilitate recruitment of monocytes/macrophages to sites of inflammation in response to numerous extracellular stimuli. We have shown recently that FAK plays a role in regulating macrophage chemotaxis and invasion. As FAK is an established downstream mediator of integrin signaling, we sought to define the molecular circuitry involving FAK and the predominant β1 integrin heterodimers expressed in these cells—α4β1 and α5β1. We show that α4β1 and α5β1 integrins are required for efficient haptotactic and chemotactic invasion and that stimulation of these integrin receptors leads to the adoption of distinct morphologies associated with motility. FAK is required downstream of α5β1 for haptotaxis toward FN and chemotaxis toward M-CSF-1 and downstream of α4β1 for the adoption of a polarized phenotype. The scaffolding molecule paxillin functions independently of FAK to promote chemotaxis downstream of α4β1. These studies expand our understanding of β1 integrin signaling networks that regulate motility and invasion in macrophages and thus, provide important new insights into mechanisms by which macrophages perform their diverse functions.