Equivalent titanium dioxide nanoparticle deposition by intratracheal instillation and whole body inhalation: the effect of dose rate on acute respiratory tract inflammation

BACKGROUND: The increased production of nanomaterials has caused a corresponding increase in concern about human exposures in consumer and occupational settings. Studies in rodents have evaluated dose–response relationships following respiratory tract (RT) delivery of nanoparticles (NPs) in order to identify potential hazards. However, these studies often use bolus methods that deliver NPs at high dose rates that do not reflect real world exposures and do not measure the actual deposited dose of NPs. We hypothesize that the delivered dose rate is a key determinant of the inflammatory response in the RT when the deposited dose is constant. METHODS: F-344 rats were exposed to the same deposited doses of titanium dioxide (TiO(2)) NPs by single or repeated high dose rate intratracheal instillation or low dose rate whole body aerosol inhalation. Controls were exposed to saline or filtered air. Bronchoalveolar lavage fluid (BALF) neutrophils, biochemical parameters and inflammatory mediator release were quantified 4, 8, and 24 hr and 7 days after exposure. RESULTS: Although the initial lung burdens of TiO(2) were the same between the two methods, instillation resulted in greater short term retention than inhalation. There was a statistically significant increase in BALF neutrophils at 4, 8 and 24 hr after the single high dose TiO(2) instillation compared to saline controls and to TiO(2) inhalation, whereas TiO(2) inhalation resulted in a modest, yet significant, increase in BALF neutrophils 24 hr after exposure. The acute inflammatory response following instillation was driven primarily by monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, mainly within the lung. Increases in heme oxygenase-1 in the lung were also higher following instillation than inhalation. TiO(2) inhalation resulted in few time dependent changes in the inflammatory mediator release. The single low dose and repeated exposure scenarios had similar BALF cellular and mediator response trends, although the responses for single exposures were more robust. CONCLUSIONS: High dose rate NP delivery elicits significantly greater inflammation compared to low dose rate delivery. Although high dose rate methods can be used for quantitative ranking of NP hazards, these data caution against their use for quantitative risk assessment

Open Access

Equivalent titanium dioxide nanoparticle deposition by intratracheal instillation and whole body inhalation: the effect of dose rate on acute respiratory tract inflammatio

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

Embedding Patients, Providers, and Community Stakeholders in Research to Improve Transgender Health

Background/Aims: The Institute of Medicine in its 2011 report highlights unique health challenges facing the transgender community. Evaluations of outcomes for medical gender reassignment (more appropriately termed “gender confirmation”) are rare and of low quality. The literature on treatment-related quality of life is limited and little is known about the long-term effects of contra-sex hormones on the risk of age-related chronic conditions. The Study of Transition, Outcomes & Gender (STRONG) research program will provide critical information about morbidity and mortality following gender confirmation treatments. It will also assess the comparative effectiveness of gender confirmation therapies for improving quality of life and alleviating gender dysphoria. The multidisciplinary STRONG research team includes investigators from five institutions. Members of the transgender community and health professionals who care for transgender individuals are an integral part of the team and are directly involved in all aspects of this research program including refinement of research questions, development of methods and content for data collection, and evaluation and dissemination of results. Methods: We identified the population of transgender individuals enrolled in the Veterans Administration and Kaiser Permanente health plans in Georgia and Northern and Southern California with a combination of validated ICD codes and keyword string searches. To evaluate mortality and morbidity, we will conduct an electronic medical record-based retrospective cohort study. To assess quality of life and other patient reported outcomes, we will conduct an online cross-sectional survey. Online and in-person focus groups with transgender stakeholders will guide data collection and interpretation of results. Results: ICD codes and keywords identified nearly 15,000 individuals. These preliminary findings indicate the STRONG program will represent the largest cohort of transgender individuals to date and the first such research effort in the United States. Six in-person focus groups have been completed with six more in progress. The study survey has been developed, programmed and pretested via online focus groups. Discussion: The STRONG research program will help close the health disparities gap for the transgender community through increasing scientific knowledge. The research findings will provide guidance to clinicians and policy makers in the care they provide to this sizeable, but underserved, community

Embedding Patients, Providers, and Community Stakeholders in Research to Improve Transgender Health

Background/Aims: The Institute of Medicine in its 2011 report highlights unique health challenges facing the transgender community. Evaluations of outcomes for medical gender reassignment (more appropriately termed “gender confirmation”) are rare and of low quality. The literature on treatment-related quality of life is limited and little is known about the long-term effects of contra-sex hormones on the risk of age-related chronic conditions. The Study of Transition, Outcomes & Gender (STRONG) research program will provide critical information about morbidity and mortality following gender confirmation treatments. It will also assess the comparative effectiveness of gender confirmation therapies for improving quality of life and alleviating gender dysphoria. The multidisciplinary STRONG research team includes investigators from five institutions. Members of the transgender community and health professionals who care for transgender individuals are an integral part of the team and are directly involved in all aspects of this research program including refinement of research questions, development of methods and content for data collection, and evaluation and dissemination of results. Methods: We identified the population of transgender individuals enrolled in the Veterans Administration and Kaiser Permanente health plans in Georgia and Northern and Southern California with a combination of validated ICD codes and keyword string searches. To evaluate mortality and morbidity, we will conduct an electronic medical record-based retrospective cohort study. To assess quality of life and other patient reported outcomes, we will conduct an online cross-sectional survey. Online and in-person focus groups with transgender stakeholders will guide data collection and interpretation of results. Results: ICD codes and keywords identified nearly 15,000 individuals. These preliminary findings indicate the STRONG program will represent the largest cohort of transgender individuals to date and the first such research effort in the United States. Six in-person focus groups have been completed with six more in progress. The study survey has been developed, programmed and pretested via online focus groups. Discussion: The STRONG research program will help close the health disparities gap for the transgender community through increasing scientific knowledge. The research findings will provide guidance to clinicians and policy makers in the care they provide to this sizeable, but underserved, community

Surface characterization of nanomaterials and nanoparticles: Important needs and challenging opportunities

This review examines characterization challenges inherently associated with understanding nanomaterials and the roles surface and interface characterization methods can play in meeting some of the challenges. In parts of the research community, there is growing recognition that studies and published reports on the properties and behaviors of nanomaterials often have reported inadequate or incomplete characterization. As a consequence, the true value of the data in these reports is, at best, uncertain. With the increasing importance of nanomaterials in fundamental research and technological applications, it is desirable that researchers from the wide variety of disciplines involved recognize the nature of these often unexpected challenges associated with reproducible synthesis and characterization of nanomaterials, including the difficulties of maintaining desired materials properties during handling and processing due to their dynamic nature. It is equally valuable for researchers to understand how characterization approaches (surface and otherwise) can help to minimize synthesis surprises and to determine how (and how quickly) materials and properties change in different environments. Appropriate application of traditional surface sensitive analysis methods (including x-ray photoelectron and Auger electron spectroscopies, scanning probe microscopy, and secondary ion mass spectroscopy) can provide information that helps address several of the analysis needs. In many circumstances, extensions of traditional data analysis can provide considerably more information than normally obtained from the data collected. Less common or evolving methods with surface selectivity (e.g., some variations of nuclear magnetic resonance, sum frequency generation, and low and medium energy ion scattering) can provide information about surfaces or interfaces in working environments (operando or in situ) or information not provided by more traditional methods. Although these methods may require instrumentation or expertise not generally available, they can be particularly useful in addressing specific questions, and examples of their use in nanomaterial research are presented