bluuebunny/crossref_metadata_2025 huggingface dataset:
A Phase I Dose‐Ranging Study of the Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of AVN944, an IMPDH Inhibitor, in Healthy Male Volunteers
Authors: Hamilton J. Michael , Harding Matthew W. , Genna Thomas , Bol David K.
Published: October 2008

A phase I study of AVN944, an inosine monophosphate dehydrogenase (IMPDH) inhibitor, was carried out to assess its safety, tolerability, pharmacokinetics, and pharmacodynamics. Healthy male volunteers (N = 25) participated in this double‐blind, randomized, placebo‐controlled trial. Sixteen received oral doses ranging from 25 to 250 mg on 3 separate occasions at intervals of 3 or 6 days after overnight fasting. Six participants received two 100‐mg doses, and 2 participants received 2 placebo doses, one with food and the other after fasting overnight. Clinical and laboratory parameters, including excretion of AVN944 and thiocyanate and IMPDH inhibition, were made at intervals for 48 hours postdosing. There were 13 mild and 2 moderate but no serious adverse events. One mild and 1 moderate event could be treatment related. AVN944 disappeared rapidly from plasma, but clearance decreased at doses >50 mg. Food reduced absorption, with a geometric mean Cmax ratio of 33% and a geometric mean AUC0‐∞ ratio of 44%. Urinary excretion was negligible. AVN944 doses >100 mg showed definite IMPDH inhibition lasting at least 4 to 6 hours. AVN944, when administered orally to healthy volunteers, is well tolerated, absorbs better with fasting, and exhibits a pharmacodynamic profile that suggests potential for significant anticancer activity.
The Prominent Role of the Liver in the Elimination of Asymmetric Dimethylarginine (ADMA) and the Consequences of Impaired Hepatic Function
Authors: Richir Milan C. , Bouwman Roderick H. , Teerlink Tom , Siroen Michiel P.C. , de Vries Theo P.G.M. , van Leeuwen Paul A.M.
Published: October 2008

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS), the enzyme which converts the amino acid arginine into nitric oxide (NO). ADMA has been identified as an important risk factor for cardiovascular diseases. Besides the role of ADMA in cardiovascular diseases, it also seems to be an important determinant in the development of critical illness, (multiple) organ failure, and the hepatorenal syndrome. ADMA is eliminated from the body by urinary excretion, but it is mainly metabolized by the dimethylarginine dimethylaminohydrolase (DDAH) enzymes that convert ADMA into citrulline and dimethylamine. DDAH is highly expressed in the liver, which makes the liver a key organ in the regulation of the plasma ADMA concentration. The prominent role of the liver in the elimination of ADMA and the consequences of impaired hepatic function on ADMA levels will be discussed in this article.
The Use of an Inflammation‐Modulating Diet in Patients With Acute Lung Injury or Acute Respiratory Distress Syndrome: A Meta‐Analysis of Outcome Data
Authors: Pontes‐Arruda Alessandro , DeMichele Stephen , Seth Anand , Singer Pierre
Published: October 2008

Background: This meta‐analysis of clinical trials compares an inflammation‐modulating diet enriched with eicosapentaenoic acid (EPA),γ ‐linolenic acid (GLA), and elevated antioxidants (EPA + GLA) vs a control diet to determine the effectiveness of this specialized diet on oxygenation and clinical outcomes in mechanically ventilated patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Methods: MEDLINE, EMBASE, Cochrane Clinical Trials Register, and the U.S. National Institute of Health Clinical Trials databases were searched. The outcome measures assessed were 28‐day in‐hospital mortality, 28‐day ventilator‐free and intensive care unit (ICU)‐free days, and the development of new organ failures. An evaluation of oxygenation and ventilatory variables was also performed. Outcomes were analyzed using both fixed‐effects and random‐effects models. Results: Three randomized controlled studies (n = 411 patients) were included in this meta‐analysis. Among the most important findings of this evaluation is a significant reduction in the risk of mortality (odds ratio [OR] = 0.40; 95% confidence interval [CI] = 0.24–0.68; P = .001), with significant reductions in the risk of developing new organ failures (OR = 0.17; 95% CI = 0.08–0.34; P < .0001), time on mechanical ventilation (standardized mean difference [SMD] = 0.56; 95% CI = 0.32–0.79; P < .0001), and ICU stay (SMD = 0.51; 95% CI = 0.27–0.74; P < .0001) in patients who received EPA + GLA. Conclusions: The meta‐analysis showed a significant reduction in the risk of mortality as well as relevant improvements in oxygenation and clinical outcomes of ventilated patients with ALI/ARDS given EPA + GLA.
Pediatric Obesity: An Inflammatory Condition?
Authors: Sacheck Jennifer
Published: October 2008

Childhood obesity has grown at an alarming rate, and concomitant with this rise there is an increasing prevalence of metabolic risk factors in young children and adolescents. These metabolic risk factors include elevated circulating triglycerides and low levels of high‐density lipoprotein, but also an increase in inflammatory biomarkers such as C‐reactive protein and interleukin‐6. Each of these factors has been associated with the development of chronic diseases such as type 2 diabetes and cardiovascular disease. Recent research has indicated that dietary modifications such as increased intakes of antioxidants or ω‐3 fatty acids or increased physical activity and physical fitness may independently modify the inflammation associated with excess adiposity. Additional research on the impact of diet and exercise on inflammation in children is warranted, especially studies that are prospective in nature. Finally, current biomarkers of inflammation may not be sensitive enough to detect metabolic risk in youth, and novel biomarkers may be needed to detect the subtle changes in inflammation due to diet and physical activity modifications.
Myeloid‐Derived Suppressor Cells in Cancer Cachexia Syndrome: A New Explanation for an Old Problem
Authors: Winfield Robert D. , Delano Matthew J. , Pande Kalyan , Scumpia Philip O. , LaFace Drake , Moldawer Lyle L.
Published: October 2008

Cachexia accompanies many chronic inflammatory diseases, including cancer. Lean tissue wasting is only one component of the cancer cachexia response, which also includes anemia, anorexia, a hepatic acute phase protein response, and increased susceptibility to secondary infections. The etiologies of cancer cachexia are multifactorial and include an overproduction of inflammatory mediators, including cytokines produced by inappropriate activation of innate immunity. However, anticytokine therapies have generally not been seriously considered for cancer cachexia, in large part because of the overlapping activities of several inflammatory cytokines and the inability to prospectively identify the contributions of individual mediators. In contrast, recent evidence has focused on an immature myeloid cell population that expands dramatically in the tumors and secondary lymphoid organs of animals with some actively growing tumors. These immature GR‐1+CD11b+ cells are metabolically active and secrete large quantities of inflammatory cytokines and chemokines with the potential to produce cachexia. Their expansion is temporally associated with the development of cachexia. Future studies are required to determine whether therapeutic efforts intended to block the expansion of these cells can prevent the lean tissue wasting that accompanies active tumor growth.
Inflammation and Intestinal Function: Where Does It Start and What Does It Mean?
Authors: Tappenden Kelly A.
Published: October 2008

Various key elements of intestinal function, such as digestion, absorption, and barrier function, are impaired during inflammation. Although intestinal damage associated with inflammation originating within the intestine is well‐known, inflammation in distant organs can impair intestinal function, despite normal histological appearance of the impacted intestinal mucosa. Widespread clinical dogma indicating that intestinal dysfunction drives inflammation should be reconsidered based on data indicating that, in many situations, inflammation precedes intestinal damage and appears to be the injurious factor. Finally, various nutrients have been shown to protect and/or repair the intestinal mucosa from the effects of inflammation; therefore, strategies for optimizing the nutrients provided during inflammatory states should be considered.
Adipose Inflammation, Insulin Resistance, and Cardiovascular Disease
Authors: Shah Arti , Mehta Nehal , Reilly Muredach P.
Published: October 2008

Adiposity‐associated inflammation and insulin resistance are strongly implicated in the development of type 2 diabetes and atherosclerotic cardiovascular disease. This article reviews the mechanisms of adipose inflammation, because these may represent therapeutic targets for insulin resistance and for prevention of metabolic and cardiovascular consequences of obesity. The initial insult in adipose inflammation and insulin resistance, mediated by macrophage recruitment and endogenous ligand activation of Toll‐like receptors, is perpetuated through chemokine secretion, adipose retention of macrophages, and elaboration of pro‐inflammatory adipocytokines. Activation of various kinases modulates adipocyte transcription factors, including peroxisome proliferator‐activated receptor‐γ and NFκB, attenuating insulin signaling and increasing adipocytokine and free fatty acid secretion. Inflammation retards adipocyte differentiation and further exacerbates adipose dysfunction and inflammation. Paracrine and endocrine adipose inflammatory events induce a local and systemic inflammatory, insulin‐resistant state promoting meta‐bolic dyslipidemia, type 2 diabetes, and cardiovascular disease. Developing therapeutic strategies that target both adipose inflammation and insulin resistance may help to prevent type 2 diabetes and cardiovascular disease in the emerging epidemic of obesity.
Obesity and Inflammation: Lessons From Bariatric Surgery
Authors: Compher Charlene , Badellino Karen O.
Published: October 2008

Background: Obesity is associated with a series of comorbid conditions that are characterized by an inflammatory state. The purpose of this review is to update knowledge about obesity, adipose tissue, and inflammation. Methods: Review of the published literature using search terms of adipose, inflammation, obesity, and insulin resistance in combinations. Results: Adipose tissue elaborates proinflammatory cytokines such as interleukin‐6 and tumor necrosis factor‐α, with greater secretion from the stromal vascular fraction than from adipocytes and with greater secretion from visceral than subcutaneous adipose tissue sites. This proinflammatory state is associated with insulin resistance and ameliorated by weight loss, with concurrent increase in production of the anti‐inflammatory adipokine adiponectin. Conclusion: Although these associations between obesity and inflammation are clearly important, many questions remain unresolved. It is unclear if benefits of weight loss pertain only to those with a proinflammatory profile, who receive a particular type of obesity surgical procedure, or whether these benefits are sustained over a lifetime. The outcomes associated with anti‐inflammatory nutrient supplementation, with or without weight loss, in the obese would also increase our understanding.
Characteristics Associated With Longer Breastfeeding Duration: An Analysis of a Peer Counseling Support Program
Authors: Bolton Tracie A. , Chow Tan , Benton Patricia A. , Olson Beth H.
Published: October 2008

Breastfeeding peer counseling support programs for low-income women have been implemented across the United States. Data from one such program were used to examine participant and program characteristics, of those enrolled prenatally (n = 2168) or postnatally (n = 2899), and to determine how these characteristics affected breastfeeding outcomes. Shorter breastfeeding duration was significantly predicted by introduction of formula on day 1 postpartum in participants enrolled prenatally (—37.9 days [95% CI: —57.9 to —17.9]) as well as postnatally (—49.1 days [95% CI: —63.4 to —34.8]). In both groups, increasing maternal age and previous breastfeeding experience were associated with significantly longer breastfeeding duration. Breastfeeding duration may be improved in programs by targeting younger mothers, those without breastfeeding experience, and focusing on delaying the introduction of formula. J Hum Lact. 25(1):18-27.
Exploring the Influence of Psychological Factors on Breastfeeding Duration, Phase 1: Perceptions of Mothers and Clinicians
Authors: O'Brien Maxine , Buikstra Elizabeth , Fallon Tony , Hegney Desley
Published: October 2008

Breastfeeding duration rates in Australia are low, prompting a search for modifiable factors capable of increasing the duration of breastfeeding. In this study, participants were asked which psychological factors they believed influence breastfeeding duration. Participants included 3 groups of mothers who had breastfed for varied lengths of time (n = 17), and 1 group of breastfeeding clinicians (n = 4). The nominal group technique was employed, involving a structured group meeting progressing through several steps. Analyses included collation of individual and group responses, group comparisons, and a thematic analysis of group discussions. Forty-five psychological factors thought to influence the duration of breastfeeding were identified. Factors considered most important included the mother's priorities and mothering self-efficacy, faith in breast milk, adaptability, stress, and breastfeeding self-efficacy. In addition to informing the design of phase 2 of this study, these results add to our knowledge of this emerging research area. J Hum Lact. 25(1):55-63.
“This isn't Paradise—I Work Here”
Authors: Vandegrift Darcie
Published: October 2008

Tourism has received relatively scant attention in feminist analysis of women's work under economic restructuring. The industry creates a sector without a shop floor based on the provision of authenticity, leisure, and price-sensitive services. Migrant women from the First World and the Third World labor with national workers in a highly informalized and stratified employment setting. This article examines how structural conditions shape tourism employment in Puerto Viejo, Costa Rica. Drawing from data including observation, interviews, and a longitudinal business survey, I offer several findings. The tourism industry segments possibilities for women who vary in their ability to produce and interpret/translate authentic cultural experiences. As a result, women working in tourism constitute a nationally and ethnically more diverse workforce compared with other global industry sectors. The particular demands of tourism create an important case to further understand how social location shapes women's working lives in the global economy.
“Rednecks,” “Rutters,” and `Rithmetic
Authors: Morris Edward W.
Published: October 2008

Research with predominately minority, urban students has documented an educational “gender gap,” where girls tend to be more likely to go to college, make higher grades, and aspire to higher status occupations than boys. We know less, however, about inequality, gender, and schooling in rural contexts. Does a similar gap emerge among the rural poor? How does gender shape the educational experiences of rural students? This article explores these questions by drawing on participant observation and student interviews at a predominately white and low-income rural high school. I find a substantial gap favoring girls in this context, and I analyze how understandings of masculinity shaped schooling using the theory of hegemonic masculinity. The findings suggest that boys' underachievement is actually rooted in masculine dominance and related to particular constructions of gender and social class.
Mothers in “Good” and “Bad” Part-time Jobs
Authors: Webber Gretchen , Williams Christine
Published: October 2008

Part-time work schedules are a popular option for many women struggling to reconcile the competing demands of employment and motherhood. They are controversial among feminists because they are associated with job penalties that promote gender inequality. Previous research on this topic has focused on issues confronting women workers in professional and managerial jobs. In this article, we compare and contrast the experiences of women in professional and secondary part-time jobs, drawing on 60 in-depth interviews with mothers working in such “good” and “bad” jobs. We find that mothers at the top and at the bottom of the employment hierarchy face unique disadvantages from their part-time employment to which they respond in different ways. Yet in both instances, mothers assume responsibility for their “choices,” which absolves organizations of blame for exploitation and discrimination against part-time workers. We suggest alternative possibilities for the organization of work in the conclusion.
Between Women's Rights and Men's Authority
Authors: Wyrod Robert
Published: October 2008

Across the African continent, women's rights have become integral to international declarations, regional treaties, national legislation, and grassroots activism. Yet there is little research on how African men have understood these shifts and how African masculinities are implicated in such changes. Drawing on a year of ethnographic research in the Ugandan capital Kampala, this article investigates how ordinary men and women in Uganda understand women's rights and how their attitudes are tied to local conceptions of masculinity. The author argues that a new configuration of gender relations is evident in urban Uganda—one that accommodates some aspects of women's rights while retaining previous notions of innate male authority. This article therefore illustrates the complex and often contradictory engagements with human rights that occur in local contexts and how such engagements are shaped by—and are shaping—gender relations, including conceptions of masculinity.
Risk-Taking Reproductive Competition Explains National Murder Rates Better Than Socioeconomic Inequality
Authors: Minkov Michael
Published: October 2008

This article presents evidence that national murder rates are not well explained as a function of socioeconomic inequality; risk-taking reproductive competition (RTRC) provides a better explanation. RTRC is a single nation-level dimension, measurable through national road death tolls, adolescent fertility rates, and Gini coefficients (thus, socioeconomic inequality is just one facet of it). RTRC explains 50% of the variance in national differences in murder rates— far more than Gini coefficients alone. RTRC correlates highly with national values that explicitly reflect full approval of interpersonal competition as well as perceptions of full life control (being free to act as one pleases). Respondents from societies that score higher on RTRC tend to perceive their fellow citizens as more emotional, impulsive, and lacking deliberation. The author discusses the origins of the national differences in RTRC and he proposes that high-scoring countries do not have a long history of intensive agriculture.
Europe and the Silence about Race
Authors: Lentin Alana
Published: October 2008

This article argues that, despite the efforts to expunge race from the European political sphere, racism continues to define the sociality of Europe. The post-war drive to replace race with other signifiers, such as culture or ethnicity, has done little to overcome the effects of the race idea, one less based on naturalist conceptions of hierarchical humanity, and more on fundamental conceptions of Europeanness and non-Europeanness. The silence about race in Europe allows European states to declare themselves non-racist, or even anti-racist, while at the same time continuing to imply an inherent European superiority, which determines both international relationships and relationships with those seen as `in but not of Europe' within its domestic spheres. The article concludes by asking what the repercussions of this are in the context of the contemporary discourse on cohesion and integration that replaces multiculturalism as a possible way of living together in a Europe always less homogeneous in reality than it is commonly imagined to be.
`Not just a colour': pink as a gender and sexuality marker in visual communication
Authors: Koller Veronika
Published: October 2008

This article investigates the functions of the colour pink as a marker of gender and sexuality in cultural models and the multimodal texts they inform. To this end, tendencies suggested by a pilot survey on colour associations are traced in a number of visual texts such as leaflets, advertisements, websites and magazines, where pink functions to gender textual referents, attract female readers' attention and index both sexuality and sexual identity. Both informants' associations and the multimodal text analysis show evidence of an emergent schema that relates pink to post-feminist femininity. This is seen as complementing and extending conventional and counter-cultural associations of pink with stereotypically feminine characteristics or gayness, respectively. Ultimately, the author argues for an approach to colour that combines social semiotics with cognitive semantics.
Water-proof Breathable Coatings Based on Poly(vinyl alcohol) for Cellulosic Fabric
Authors: Palanikkumaran M. , Agrawal Ashwini K. , Jassal Manjeet
Published: October 2008

Hydrophilic breathable coatings were developed by coating the cotton fabric with poly(vinyl alcohol) (PVA) solution (20 wt%) containing poly(acrylic acid) (PAAc) (10% neutralized using sodium hydroxide) as a cross-linker, followed by drying and curing. The effect of cross-linker concentration and add-on on the properties of coated textile was studied. The coated substrate with the combination of molar ratio of PVA to PAAc of 25 and coating add-on of 18 wt% was found to have high integrity with the optimum breathable properties. This sample showed high resistance to hydrostatic head at 1400mm and very high water vapor transmission rate (WVTR) at 2165g/m2 24 h, which was ~50% of the WVTR value shown by the uncoated substrate (cotton fabric). Physical investigation of the surface morphology showed that the coating was continuous without cracks or pin holes and appeared to be well adhered to the substrate even after a harsh wash.
Utilization of Carpet Waste in Reinforcement of Substandard Soils
Authors: Miraftab Mohsen , Lickfold Ann
Published: October 2008

In the UK, 400 million tonnes of waste are generated each year. A considerable amount of this waste is attributed to construction and demolition wastes that are destined for landfill sites. Textiles, including carpet waste, on the other hand, account for only 2% of all wastes by weight but because of their high volume-to-weight ratio, once dumped into landfills they occupy large spaces. Besides, given the high added values of carpets, carpet waste account for almost £70 million of lost revenue per year in the UK. Increasing public concern for the environment and higher taxations imposed on landfill dumping are forcing manufacturers of various disciplines to seriously reduce their waste and/or find new applications for their inevitable waste. This article reports on one such application where carpet fibrous waste is included in clayey or substandard soils with the intention of enhancing soil cohesion and reinforcement. The findings suggest that inclusion of as much as 10% fibers can be tolerated and would enhance internal cohesion, shear and comprehensive strength as well as load-bearing capacity of this kind of soils. Soil moisture content is also reported to play an important role in enhancing cohesion and compressive strength of such combinations.
`Yeah Looks Like It N'All . . .': The `Live Action' Universe and Abridged Figurative Design and Computer Animation within Modern Toss
Authors: Norris Van
Published: October 2008

This article will discuss formal aspects of the Channel Four TV show Modern Toss. Through a minimalism in image and dialogue it looks at how a range of characters negotiate miniature social rebellions. What is of interest here is the highly distinctive approach to animation form that utilizes deliberately abstracted figurative designs framed in collusion with previously filmed backgrounds and actors. This specific approach of placing Flash computer figures within an agreed universe accesses, firstly, a sense of `distance' that is pertinent to the show's humorous register. Secondly, this complements the fatalism inherent within the narratives themselves and then, lastly, this process allies the show to the original graphic/web cartoon sources in service of a signature aesthetic endemic to this concept.
Hematopoietic cell–derived interferon controls viral replication and virus-induced disease
Authors: Lang Philipp A. , Cervantes-Barragan Luisa , Verschoor Admar , Navarini Alexander A. , Recher Mike , Pellegrini Marc , Flatz Lukas , Bergthaler Andreas , Honda Kenya , Ludewig Burkhard , Ohashi Pamela S. , Lang Karl S.
Published: October 2008

Type I interferon (IFN-I) strongly inhibits viral replication and is a crucial factor in controlling virus infections and diseases. Cellular activation through pattern recognition receptors induces interferon production in a wide variety of hematopoietic and nonhematopoietic cell types, including dendritic cells, fibroblasts, hepatocytes, and cells of neuronal origin. The relative contribution of hematopoietic and nonhematopoietic cells to the overall interferon response is an important issue which has not been fully addressed. Using irf7−/− and wild-type bone marrow chimeras we analyzed the contribution of IFN-I from bone marrow–derived sources in the control of viral infections and immunopathology in mice. We found that during systemic cytopathic virus infection, hematopoietic cells were essential for production of IFN-I, inhibition of viral spread to peripheral organs, and limiting cell damage. In a model of autoimmune diabetes induced by noncytopathic virus infection, hematopoietic cell–derived IFN-I was essential for CD8+ T cell–dependent cytotoxicity in pancreatic β-islet cells and induction of diabetes. These data suggest that during systemic viral infection primarily hematopoietic cell–derived IFN-I controls viral replication and viral-induced disease.
A key role for Toll-like receptor-3 in disrupting the hemostasis balance on endothelial cells
Authors: Shibamiya Aya , Hersemeyer Karin , Schmidt Wöll Thomas , Sedding Daniel , Daniel Jan-Marcus , Bauer Stefan , Koyama Takatoshi , Preissner Klaus T. , Kanse Sandip M.
Published: October 2008

Various virus infections cause dysfunctional hemostasis and in some instances lead to the development of viral hemorrhagic fever syndrome. How do diverse viruses induce the expression of tissue factor on vascular cells? We hypothesize that a direct stimulation of pattern recognition receptors (PRR) by viral nucleic acids may be the key. Double-stranded RNA (dsRNA) is produced by many viruses and is recognized by various PRR, including Toll-like receptor-3 (TLR3). We have investigated whether poly I:C, a model for viral dsRNA, can influence cellular hemostasis. Poly I:C could up-regulate tissue factor and down-regulate thrombomodulin expression on endothelial cells but not on monocytes. The response to poly I:C was diminished upon small interfering RNA (siRNA)–mediated inhibition of TLR3, but not other PRR. In vivo, application of poly I:C induced similar changes in the aortic endothelium of mice as determined by enface microscopy. D-dimer, a circulating marker for enhanced coagulation and fibrinolysis, and tissue fibrin deposition was elevated. All the hemostasis-related responses to poly I:C, but not cytokine secretion, were blunted in TLR3−/− mice. Hence, the activation of TLR3 can induce the procoagulant state in the endothelium, and this could be relevant for understanding the mechanisms of viral stimulation of hemostasis.
Solid cancers after allogeneic hematopoietic cell transplantation
Authors: Rizzo J. Douglas , Curtis Rochelle E. , Socié Gérard , Sobocinski Kathleen A. , Gilbert Ethel , Landgren Ola , Travis Lois B. , Travis William D. , Flowers Mary E. D. , Friedman Debra L. , Horowitz Mary M. , Wingard John R. , Deeg H. Joachim
Published: October 2008

Transplant recipients have been reported to have an increased risk of solid cancers but most studies are small and have limited ability to evaluate the interaction of host, disease, and treatment-related factors. In the largest study to date to evaluate risk factors for solid cancers, we studied a multi-institutional cohort of 28 874 allogeneic transplant recipients with 189 solid malignancies. Overall, patients developed new solid cancers at twice the rate expected based on general population rates (observed-to-expected ratio 2.1; 95% confidence interval 1.8-2.5), with the risk increasing over time (P trend < .001); the risk reached 3-fold among patients followed for 15 years or more after transplantation. New findings showed that the risk of developing a non–squamous cell carcinoma (non-SCC) following conditioning radiation was highly dependent on age at exposure. Among patients irradiated at ages under 30 years, the relative risk of non-SCC was 9 times that of nonirradiated patients, while the comparable risk for older patients was 1.1 (P interaction < .01). Chronic graft-versus-host disease and male sex were the main determinants for risk of SCC. These data indicate that allogeneic transplant survivors, particularly those irradiated at young ages, face increased risks of solid cancers, supporting strategies to promote lifelong surveillance among these patients.
CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival
Authors: Landsman Limor , Bar-On Liat , Zernecke Alma , Kim Ki-Wook , Krauthgamer Rita , Shagdarsuren Erdenechimeg , Lira Sergio A. , Weissman Irving L. , Weber Christian , Jung Steffen
Published: October 2008

CX3CR1 is a chemokine receptor with a single ligand, the membrane-tethered chemokine CX3CL1 (fractalkine). All blood monocytes express CX3CR1, but its levels differ between the main 2 subsets, with human CD16+ and murine Gr1low monocytes being CX3CR1hi. Here, we report that absence of either CX3CR1 or CX3CL1 results in a significant reduction of Gr1low blood monocyte levels under both steady-state and inflammatory conditions. Introduction of a Bcl2 transgene restored the wild-type phenotype, suggesting that the CX3C axis provides an essential survival signal. Supporting this notion, we show that CX3CL1 specifically rescues cultured human monocytes from induced cell death. Human CX3CR1 gene polymorphisms are risk factors for atherosclerosis and mice deficient for the CX3C receptor or ligand are relatively protected from atherosclerosis development. However, the mechanistic role of CX3CR1 in atherogenesis remains unclear. Here, we show that enforced survival of monocytes and plaque-resident phagocytes, including foam cells, restored atherogenesis in CX3CR1-deficent mice. The fact that CX3CL1-CX3CR1 interactions confer an essential survival signal, whose absence leads to increased death of monocytes and/or foam cells, might provide a mechanistic explanation for the role of the CX3C chemokine family in atherogenesis.
Sequence space coverage, entropy of genomes and the potential to detect non-human DNA in human samples
Authors: Liu Zhandong , Venkatesh Santosh S , Maley Carlo C
Published: October 2008

Background

Genomes store information for building and maintaining organisms. Complete sequencing of many genomes provides the opportunity to study and compare global information properties of those genomes.

Results

We have analyzed aspects of the information content of Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana, Saccharomyces cerevisiae, and Escherichia coli (K-12) genomes. Virtually all possible (> 98%) 12 bp oligomers appear in vertebrate genomes while < 2% of 19 bp oligomers are present. Other species showed different ranges of > 98% to < 2% of possible oligomers in D. melanogaster (12–17 bp), C. elegans (11–17 bp), A. thaliana (11–17 bp), S. cerevisiae (10–16 bp) and E. coli (9–15 bp). Frequencies of unique oligomers in the genomes follow similar patterns. We identified a set of 2.6 M 15-mers that are more than 1 nucleotide different from all 15-mers in the human genome and so could be used as probes to detect microbes in human samples. In a human sample, these probes would detect 100% of the 433 currently fully sequenced prokaryotes and 75% of the 3065 fully sequenced viruses. The human genome is significantly more compact in sequence space than a random genome. We identified the most frequent 5- to 20-mers in the human genome, which may prove useful as PCR primers. We also identified a bacterium, Anaeromyxobacter dehalogenans, which has an exceptionally low diversity of oligomers given the size of its genome and its GC content. The entropy of coding regions in the human genome is significantly higher than non-coding regions and chromosomes. However chromosomes 1, 2, 9, 12 and 14 have a relatively high proportion of coding DNA without high entropy, and chromosome 20 is the opposite with a low frequency of coding regions but relatively high entropy.

Conclusion

Measures of the frequency of oligomers are useful for designing PCR assays and for identifying chromosomes and organisms with hidden structure that had not been previously recognized. This information may be used to detect novel microbes in human tissues.
An optimized procedure for the design and evaluation of Ecotilling assays
Authors: Coassin Stefan , Brandstätter Anita , Kronenberg Florian
Published: October 2008

Background

Single nucleotide polymorphisms (SNPs) are the most common form of genetic variability in the human genome and play a prominent role in the heritability of phenotypes. Especially rare alleles with frequencies less than 5% may exhibit a particularly strong influence on the development of complex diseases. The detection of rare alleles by standard DNA sequencing is time-consuming and cost-intensive. Here we discuss an alternative approach for a high throughput detection of rare mutations in large population samples using Ecotilling embedded in a collection of bioinformatic analysis tools. Ecotilling originally was introduced as TILLING for the screening for rare chemically induced mutations in plants and later adopted for human samples, showing an outstanding suitability for the detection of rare alleles in humans. An actual problem in the use of Ecotilling for large mutation screening projects in humans without bioinformatic support is represented by the lack of solutions to quickly yet comprehensively evaluate each newly found variation and place it into the correct genomic context.

Results

We present an optimized strategy for the design, evaluation and interpretation of Ecotilling results by integrating several mostly freely available bioinformatic tools. A major focus of our investigations was the evaluation and meaningful economical combination of these software tools for the inference of different possible regulatory functions for each newly detected mutation.

Conclusion

Our streamlined procedure significantly facilitates the experimental design and evaluation of Ecotilling assays and strongly improves the decision process on prioritizing the newly found SNPs for further downstream analysis.
Microarray analysis of Foxa2 mutant mouse embryos reveals novel gene expression and inductive roles for the gastrula organizer and its derivatives
Authors: Tamplin Owen J , Kinzel Doris , Cox Brian J , Bell Christine E , Rossant Janet , Lickert Heiko
Published: October 2008

Background

The Spemann/Mangold organizer is a transient tissue critical for patterning the gastrula stage vertebrate embryo and formation of the three germ layers. Despite its important role during development, there are still relatively few genes with specific expression in the organizer and its derivatives. Foxa2 is a forkhead transcription factor that is absolutely required for formation of the mammalian equivalent of the organizer, the node, the axial mesoderm and the definitive endoderm (DE). However, the targets of Foxa2 during embryogenesis, and the molecular impact of organizer loss on the gastrula embryo, have not been well defined.

Results

To identify genes specific to the Spemann/Mangold organizer, we performed a microarray-based screen that compared wild-type and Foxa2 mutant embryos at late gastrulation stage (E7.5). We could detect genes that were consistently down-regulated in replicate pools of mutant embryos versus wild-type, and these included a number of known node and DE markers. We selected 314 genes without previously published data at E7.5 and screened for expression by whole mount in situ hybridization. We identified 10 novel expression patterns in the node and 5 in the definitive endoderm. We also found significant reduction of markers expressed in secondary tissues that require interaction with the organizer and its derivatives, such as cardiac mesoderm, vasculature, primitive streak, and anterior neuroectoderm.

Conclusion

The genes identified in this screen represent novel Spemann/Mangold organizer genes as well as potential Foxa2 targets. Further investigation will be needed to define these genes as novel developmental regulatory factors involved in organizer formation and function. We have placed these genes in a Foxa2-dependent genetic regulatory network and we hypothesize how Foxa2 may regulate a molecular program of Spemann/Mangold organizer development. We have also shown how early loss of the organizer and its inductive properties in an otherwise normal embryo, impacts on the molecular profile of surrounding tissues.
Genomic plasticity of the immune-related Mhc class I B region in macaque species
Authors: Bonhomme Maxime , Doxiadis Gaby GM , Heijmans Corrine MC , Vervoort Virginie , Otting Nel , Bontrop Ronald E , Crouau-Roy Brigitte
Published: October 2008

Background

In sharp contrast to humans and great apes, the expandedMhc-Bregion of rhesus and cynomolgus macaques is characterized by the presence of differential numbers and unique combinations of polymorphic class IBgenes per haplotype. The MIB microsatellite is closely linked to the single class IBgene in human and in some great apes studied. The physical map of theMhcof a heterozygous rhesus monkey provides unique material to analyze MIB andMamu-Bcopy number variation and then allows one to decipher the compound evolutionary history of this region in primate species.

Results

In silicoresearch pinpointed 12 MIB copies (duplicons), most of which are associated with expressedB-genes that cluster in a separate clade in the phylogenetic tree. Generic primers tested on homozygous rhesus and pedigreed cynomolgus macaques allowed the identification of eight to eleven MIB copies per individual. The number of MIB copies present per haplotype varies from a minimum of three to six in cynomolgus macaques and from five to eight copies in rhesus macaques. Phylogenetic analyses highlight a strong transpecific sharing of MIB duplicons. Using the physical map, we observed that, similar to MIB duplicons, highly divergentMamu-Bgenes can be present on the same haplotype. Haplotype variation as reflected by the copy number variation of class IBloci is best explained by recombination events, which are found to occur between MIBs andMamu-B.

Conclusion

The data suggest the existence of highly divergent MIB andMamu-Blineages on a given haplotype, as well as variable MIB andBcopy numbers and configurations, at least in rhesus macaque. Recombination seems to occur between MIB andMamu-Bloci, and the resulting haplotypic plasticity at the individual level may be a strategy to better cope with pathogens. Therefore, evolutionary inferences based on the multiplicated MIB loci but also other markers close toB-genes appear to be promising for the study ofB-region organization and evolution in primates.
Serological survey on immunity status against polioviruses in children and adolescents living in a border region, Apulia (Southern Italy)
Authors: Tafuri Silvio , Prato Rosa , Martinelli Domenico , Calvario Agata , Bozzi Anna , Labianca Michele , Patti Annamaria , Lopalco Pietro Luigi , Germinario Cinzia
Published: October 2008

Background

In 1988 the World Health Assembly adopted the goal to eradicate poliomyelitis by routine immunization using Oral Polio Vaccine (OPV). On 21 June 2002 the WHO European Region was declared polio-free. In 2008 poliomyelitis is still endemic in 4 countries (Nigeria, India, Pakistan, and Afghanistan), where 1201 new cases were registered in 2007; 107 sporadic cases were also notified in countries where poliovirus is not endemic. The aim of this work was to verify the level of antipoliomyelitis immunity status in children and adolescents in the Apulia region (south of Italy), which may be considered a border region due to its position.

Methods

704 blood specimens from a convenience sample were collected in six laboratories. The age of subjects enrolled was 0–15 years. The immunity against poliomyelitis was evaluated by neutralizing antibody titration in tissue culture microplates.

Results

Seropositivity (neutralising antibodies titre ≥ 8) for polioviruses 1, 2 and 3 was detected in 100%, 99.8% and 99.4% of collected sera. Antibody titres were not lower in subjects who received either four doses of inactivated polio vaccine (IPV) or a sequential schedule consisting of two doses of IPV and two of oral polio vaccine than in subjects who received four doses of OPV.

Conclusion

These results confirmed current data of vaccine coverage for poliomyelitis: during the last ten years in Apulia, the coverage in 24 months old children was more than 90%. The high level of immunization found confirms the effectiveness both of the sequential schedule IPV-OPV and of the schedule all-IPV. Apulia region has to face daily arrivals of refugees and remains subject to the risk of the importation of poliovirus from endemic areas. Surveys aimed at determining anti-polio immunity in subpopulations as well as in the general population should be carried out.
Fetal age assessment based on 2nd trimester ultrasound in Africa and the effect of ethnicity
Authors: Salpou Daniel , Kiserud Torvid , Rasmussen Svein , Johnsen Synnøve Lian
Published: October 2008

Background

The African population is composed of a variety of ethnic groups, which differ considerably from each other. Some studies suggest that ethnic variation may influence dating. The aim of the present study was to establish reference values for fetal age assessment in Cameroon using two different ethnic groups (Fulani and Kirdi).

Methods

This was a prospective cross sectional study of 200 healthy pregnant women from Cameroon. The participants had regular menstrual periods and singleton uncomplicated pregnancies, and were recruited after informed consent. The head circumference (HC), outer-outer biparietal diameter (BPDoo), outer-inner biparietal diameter and femur length (FL), also called femur diaphysis length, were measured using ultrasound at 12–22 weeks of gestation. Differences in demographic factors and fetal biometry between ethnic groups were assessed by t- and Chi-square tests.

Results

Compared with Fulani women (N = 96), the Kirdi (N = 104) were 2 years older (p = 0.005), 3 cm taller (p = 0.001), 6 kg heavier (p < 0.0001), had a higher body mass index (BMI) (p = 0.001), but were not different with regard to parity. Ethnicity had no effect on BPDoo (p = 0.82), HC (p = 0.89) or FL (p = 00.24). Weight, height, maternal age and BMI had no effect on HC, BPDoo and FL (p = 0.2–0.58, 0.1–0.83, and 0.17–0.6, respectively).

When comparing with relevant European charts based on similar design and statistics, we found overlapping 95% CI for BPD (Norway & UK) and a 0–4 day difference for FL and HC.

Conclusion

Significant ethnic differences between mothers were not reflected in fetal biometry at second trimester. The results support the recommendation that ultrasound in practical health care can be used to assess gestational age in various populations with little risk of error due to ethnic variation.
Co-regulation analysis of closely linked genes identifies a highly recurrent gain on chromosome 17q25.3 in prostate cancer
Authors: Bermudo Raquel , Abia David , Ferrer Berta , Nayach Iracema , Benguria Alberto , Zaballos Ángel , del Rey Javier , Miró Rosa , Campo Elías , Martínez-A Carlos , Ortiz Ángel R , Fernández Pedro L , Thomson Timothy M
Published: October 2008

Background

Transcriptional profiling of prostate cancer (PC) has unveiled new markers of neoplasia and allowed insights into mechanisms underlying this disease. Genomewide analyses have also identified new chromosomal abnormalities associated with PC. The combination of both classes of data for the same sample cohort might provide better criteria for identifying relevant factors involved in neoplasia. Here we describe transcriptional signatures identifying distinct normal and tumoral prostate tissue compartments, and the inference and demonstration of a new, highly recurrent copy number gain on chromosome 17q25.3.

Methods

We have applied transcriptional profiling to tumoral and non-tumoral prostate samples with relatively homogeneous epithelial representations as well as pure stromal tissue from peripheral prostate and cultured cell lines, followed by quantitative RT-PCR validations and immunohistochemical analysis. In addition, we have performedin silicocolocalization analysis of co-regulated genes and validation by fluorescent in situ hybridization (FISH).

Results

The transcriptomic analysis has allowed us to identify signatures corresponding to non-tumoral luminal and tumoral epithelium, basal epithelial cells, and prostate stromal tissue. In addition,in silicoanalysis of co-regulated expression of physically linked genes has allowed us to predict the occurrence of a copy number gain at chromosomal region 17q25.3. This computational inference was validated by fluorescentin situhybridization, which showed gains in this region in over 65% of primary and metastatic tumoral samples.

Conclusion

Our approach permits to directly link gene copy number variations with transcript co-regulation in association with neoplastic states. Therefore, transcriptomic studies of carefully selected samples can unveil new diagnostic markers and transcriptional signatures highly specific of PC, and lead to the discovery of novel genomic abnormalities that may provide additional insights into the causes and mechanisms of prostate cancer.