Breast cancer risk factors in relation to breast density (United States)

OBJECTIVES: Evaluate known breast cancer risk factors in relation to breast density. METHODS: We examined factors in relation to breast density in 144,018 New Hampshire (NH) women with at least one mammogram recorded in a statewide mammography registry. Mammographic breast density was measured by radiologists using the BI-RADS classification; risk factors of interest were obtained from patient intake forms and questionnaires. RESULTS: Initial analyses showed a strong inverse influence of age and body mass index (BMI) on breast density. In addition, women with late age at menarche, late age at first birth, premenopausal women, and those currently using hormone therapy (HT) tended to have higher breast density, while those with greater parity tended to have less dense breasts. Analyses stratified on age and BMI suggested interactions, which were formally assessed in a multivariable model. The impact of current HT use, relative to nonuse, differed across age groups, with an inverse association in younger women, and a positive association in older women (p < 0.0001 for the interaction). The positive effects of age at menarche and age at first birth, and the inverse influence of parity were less apparent in women with low BMI than in those with high BMI (p = 0.04, p < 0.0001 and p = 0.01, respectively, for the interactions). We also noted stronger positive effects for age at first birth in postmenopausal women (p = 0.004 for the interaction). The multivariable model indicated a slight positive influence of family history of breast cancer. CONCLUSIONS: The influence of age at menarche and reproductive factors on breast density is less evident in women with high BMI. Density is reduced in young women using HT, but increased in HT users of age 50 or more

Developmentally Regulated Sphingolipid Degradation in Leishmania major

Leishmania parasites alternate between extracellular promastigotes in sandflies and intracellular amastigotes in mammals. These protozoans acquire sphingolipids (SLs) through de novo synthesis (to produce inositol phosphorylceramide) and salvage (to obtain sphingomyelin from the host). A single ISCL (Inositol phosphoSphingolipid phospholipase C-Like) enzyme is responsible for the degradation of both inositol phosphorylceramide (the IPC hydrolase or IPCase activity) and sphingomyelin (the SMase activity). Recent studies of a L. major ISCL-null mutant (iscl−) indicate that SL degradation is required for promastigote survival in stationary phase, especially under acidic pH. ISCL is also essential for L. major proliferation in mammals. To further understand the role of ISCL in Leishmania growth and virulence, we introduced a sole IPCase or a sole SMase into the iscl− mutant. Results showed that restoration of IPCase only complemented the acid resistance defect in iscl− promastigotes and improved their survival in macrophages, but failed to recover virulence in mice. In contrast, a sole SMase fully restored parasite infectivity in mice but was unable to reverse the promastigote defects in iscl−. These findings suggest that SL degradation in Leishmania possesses separate roles in different stages: while the IPCase activity is important for promastigote survival and acid tolerance, the SMase activity is required for amastigote proliferation in mammals. Consistent with these findings, ISCL was preferentially expressed in stationary phase promastigotes and amastigotes. Together, our results indicate that SL degradation by Leishmania is critical for parasites to establish and sustain infection in the mammalian host

Incorporation of a Horizontally Transferred Gene into an Operon during Cnidarian Evolution

Genome sequencing has revealed examples of horizontally transferred genes, but we still know little about how such genes are incorporated into their host genomes. We have previously reported the identification of a gene (flp) that appears to have entered the Hydra genome through horizontal transfer. Here we provide additional evidence in support of our original hypothesis that the transfer was from a unicellular organism, and we show that the transfer occurred in an ancestor of two medusozoan cnidarian species. In addition we show that the gene is part of a bicistronic operon in the Hydra genome. These findings identify a new animal phylum in which trans-spliced leader addition has led to the formation of operons, and define the requirements for evolution of an operon in Hydra. The identification of operons in Hydra also provides a tool that can be exploited in the construction of transgenic Hydra strains

BluePort: A Platform to Study the Eosinophilic Response of Mice to the Bite of a Vector of Leishmania Parasites, Lutzomyia longipalpis Sand Flies

transmission in residents of endemic areas has been attributed to the acquisition of immunity to sand fly salivary proteins. One theoretical way to accelerate the acquisition of this immunity is to increase the density of antigen-presenting cells at the sand fly bite site. Here we describe a novel tissue platform that can be used for this purpose. sand flies. Results presented indicate that a shift in the inflammatory response, from neutrophilic to eosinophilic, is the main histopathological feature associated with the immunity acquired through repeated exposure to the bite of sand flies, and that the BluePort tissue compartment could be used to accelerate this process. In addition, changes observed inside the BluePort parenchyma indicate that it could be used to study complex immunobiological processes, and to develop ectopic secondary lymphoid structures.Understanding the characteristics of the dermal response to the bite of sand flies is a critical element of strategies to control leishmaniasis using vaccines that target salivary proteins. Finding that dermal eosinophilia is such a prominent component of the anti-salivary immunity induced by repeated exposure to sand fly bites raises one important consideration: how to avoid the immunological conflict derived from a protective Th2-driven immunity directed to sand fly saliva with a protective Th1-driven immunity directed to the parasite. The BluePort platform is an ideal tool to address experimentally this conundrum

In vivo PET imaging of the neuroinflammatory response in rat spinal cord injury using the TSPO tracer [F-18]GE-180 and effect of docosahexaenoic acid

Centre for Trauma Sciences, funded by the Barts & The London Charity, GE Healthcare Ltd, the Experimental Medicine Awards from the Blizard Institute and the Imaging Centre at the Barts Cancer Institute

How does the tobacco industry attempt to influence marketing regulations? A systematic review

BACKGROUND: The Framework Convention on Tobacco Control makes a number of recommendations aimed at restricting the marketing of tobacco products. Tobacco industry political activity has been identified as an obstacle to Parties' development and implementation of these provisions. This study systematically reviews the existing literature on tobacco industry efforts to influence marketing regulations and develops taxonomies of 1) industry strategies and tactics and 2) industry frames and arguments. METHODS: Searches were conducted between April-July 2011, and updated in March 2013. Articles were included if they made reference to tobacco industry efforts to influence marketing regulations; supported claims with verifiable evidence; were written in English; and concerned the period 1990-2013. 48 articles met the review criteria. Narrative synthesis was used to combine the evidence. RESULTS: 56% of articles focused on activity in North America, Europe or Australasia, the rest focusing on Asia (17%), South America, Africa or transnational activity. Six main political strategies and four main frames were identified. The tobacco industry frequently claims that the proposed policy will have negative unintended consequences, that there are legal barriers to regulation, and that the regulation is unnecessary because, for example, industry does not market to youth or adheres to a voluntary code. The industry primarily conveys these arguments through direct and indirect lobbying, the promotion of voluntary codes and alternative policies, and the formation of alliances with other industrial sectors. The majority of tactics and arguments were used in multiple jurisdictions. CONCLUSIONS: Tobacco industry political activity is far more diverse than suggested by existing taxonomies of corporate political activity. Tactics and arguments are repeated across jurisdictions, suggesting that the taxonomies of industry tactics and arguments developed in this paper are generalisable to multiple jurisdictions and can be used to predict industry activity

Development and Validation of an Automated High-Throughput System for Zebrafish In Vivo Screenings

The zebrafish is a vertebrate model compatible with the paradigms of drug discovery. The small size and transparency of zebrafish embryos make them amenable for the automation necessary in high-throughput screenings. We have developed an automated high-throughput platform for in vivo chemical screenings on zebrafish embryos that includes automated methods for embryo dispensation, compound delivery, incubation, imaging and analysis of the results. At present, two different assays to detect cardiotoxic compounds and angiogenesis inhibitors can be automatically run in the platform, showing the versatility of the system. A validation of these two assays with known positive and negative compounds, as well as a screening for the detection of unknown anti-angiogenic compounds, have been successfully carried out in the system developed. We present a totally automated platform that allows for high-throughput screenings in a vertebrate organism

Projected Loss of a Salamander Diversity Hotspot as a Consequence of Projected Global Climate Change

Background: Significant shifts in climate are considered a threat to plants and animals with significant physiological limitations and limited dispersal abilities. The southern Appalachian Mountains are a global hotspot for plethodontid salamander diversity. Plethodontids are lungless ectotherms, so their ecology is strongly governed by temperature and precipitation. Many plethodontid species in southern Appalachia exist in high elevation habitats that may be at or near their thermal maxima, and may also have limited dispersal abilities across warmer valley bottoms. Methodology/Principal Findings: We used a maximum-entropy approach (program Maxent) to model the suitable climatic habitat of 41 plethodontid salamander species inhabiting the Appalachian Highlands region (33 individual species and eight species included within two species complexes). We evaluated the relative change in suitable climatic habitat for these species in the Appalachian Highlands from the current climate to the years 2020, 2050, and 2080, using both the HADCM3 and the CGCM3 models, each under low and high CO 2 scenarios, and using two-model thresholds levels (relative suitability thresholds for determining suitable/unsuitable range), for a total of 8 scenarios per species. Conclusion/Significance: While models differed slightly, every scenario projected significant declines in suitable habitat within the Appalachian Highlands as early as 2020. Species with more southern ranges and with smaller ranges had larger projected habitat loss. Despite significant differences in projected precipitation changes to the region, projections did no