Modulation of human macrophage responses to mycobacterium tuberculosis by silver nanoparticles of different size and surface modification

Exposure to silver nanoparticles (AgNP) used in consumer products carries potential health risks including increased susceptibility to infectious pathogens. Systematic assessments of antimicrobial macrophage immune responses in the context of AgNP exposure are important because uptake of AgNP by macrophages may lead to alterations of innate immune cell functions. In this study we examined the effects of exposure to AgNP with different particle sizes (20 and 110 nm diameters) and surface chemistry (citrate or polyvinlypyrrolidone capping) on cellular toxicity and innate immune responses against Mycobacterium tuberculosis (M.tb) by human monocyte-derived macrophages (MDM). Exposures of MDM to AgNP significantly reduced cellular viability, increased IL8 and decreased IL10 mRNA expression. Exposure of M.tb-infected MDM to AgNP suppressed M.tb-induced expression of IL1B, IL10, and TNFA mRNA. Furthermore, M.tb-induced IL-1β, a cytokine critical for host resistance to M.tb, was inhibited by AgNP but not by carbon black particles indicating that the observed immunosuppressive effects of AgNP are particle specific. Suppressive effects of AgNP on the M.tb-induced host immune responses were in part due to AgNP-mediated interferences with the TLR signaling pathways that culminate in the activation of the transcription factor NF-κB. AgNP exposure suppressed M.tb-induced expression of a subset of NF-κB mediated genes (CSF2, CSF3, IFNG, IL1A, IL1B, IL6, IL10, TNFA, NFKB1A). In addition, AgNP exposure increased the expression of HSPA1A mRNA and the corresponding stress-induced Hsp72 protein. Up-regulation of Hsp72 by AgNP can suppress M.tb-induced NF-κB activation and host immune responses. The observed ability of AgNP to modulate infectious pathogen-induced immune responses has important public health implications

Personalized Exposure Assessment: Promising Approaches for Human Environmental Health Research

New technologies and methods for assessing human exposure to chemicals, dietary and lifestyle factors, infectious agents, and other stressors provide an opportunity to extend the range of human health investigations and advance our understanding of the relationship between environmental exposure and disease. An ad hoc Committee on Environmental Exposure Technology Development was convened to identify new technologies and methods for deriving personalized exposure measurements for application to environmental health studies. The committee identified a “toolbox” of methods for measuring external (environmental) and internal (biologic) exposure and assessing human behaviors that influence the likelihood of exposure to environmental agents. The methods use environmental sensors, geographic information systems, biologic sensors, toxicogenomics, and body burden (biologic) measurements. We discuss each of the methods in relation to current use in human health research; specific gaps in the development, validation, and application of the methods are highlighted. We also present a conceptual framework for moving these technologies into use and acceptance by the scientific community. The framework focuses on understanding complex human diseases using an integrated approach to exposure assessment to define particular exposure–disease relationships and the interaction of genetic and environmental factors in disease occurrence. Improved methods for exposure assessment will result in better means of monitoring and targeting intervention and prevention programs

Quantifying children's aggregate (dietary and residential) exposure and dose to permethrin: application and evaluation of EPA's probabilistic SHEDS-Multimedia model

Reliable, evaluated human exposure and dose models are important for understanding the health risks from chemicals. A case study focusing on permethrin was conducted because of this insecticide's widespread use and potential health effects. SHEDS-Multimedia was applied to estimate US population permethrin exposures for 3- to 5-year-old children from residential, dietary, and combined exposure routes, using available dietary consumption data, food residue data, residential concentrations, and exposure factors. Sensitivity and uncertainty analyses were conducted to identify key factors, pathways, and research needs. Model evaluation was conducted using duplicate diet data and biomonitoring data from multiple field studies, and comparison to other models. Key exposure variables were consumption of spinach, lettuce, and cabbage; surface-to-skin transfer efficiency; hand mouthing frequency; fraction of hand mouthed; saliva removal efficiency; fraction of house treated; and usage frequency. For children in households using residential permethrin, the non-dietary exposure route was most important, and when all households were included, dietary exposure dominated. SHEDS-Multimedia model estimates compared well to real-world measurements data; this exposure assessment tool can enhance human health risk assessments and inform children's health research. The case study provides insights into children's aggregate exposures to permethrin and lays the foundation for a future cumulative pyrethroid pesticides risk assessment

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Random sampling-high dimensional model representation (RS-HDMR) and orthogonality of its different order component functions

High dimensional model representation is under active development as a set of quantitative model assessment and analysis tools for capturing high-dimensional input-output system behavior based on a hierarchy of functions of increasing dimensions. The HDMR component functions are optimally constructed from zeroth order to higher orders step-by-step. This paper extends the definitions of HDMR component functions to systems whose input variables may not be independent. The orthogonality of the higher order terms with respect to the lower order ones guarantees the best improvement in accuracy for the higher order approximations. Therefore, the HDMR component functions are constructed to be mutually orthogonal. The RS-HDMR component functions are efficiently constructed from randomly sampled input-output data. The previous introduction of polynomial approximations for the component functions violates the strictly desirable orthogonality properties. In this paper, new orthonormal polynomial approximation formulas for the RS-HDMR component functions are presented that preserve the orthogonality property. An integrated exposure and dose model as well as ionospheric electron density determined from measured ionosonde data are used as test cases, which show that the new method has better accuracy than the prior one

Modeling in vitro cellular responses to silver nanoparticles

© 2014 Dwaipayan Mukherjee et al.Engineered nanoparticles (NPs) have been widely demonstrated to induce toxic effects to various cell types. In vitro cell exposure systems have high potential for reliable, high throughput screening of nanoparticle toxicity, allowing focusing on particular pathways while excluding unwanted effects due to other cells or tissue dosimetry. The work presented here involves a detailed biologically based computational model of cellular interactions with NPs; it utilizes measurements performed in human cell culture systems in vitro, to develop a mechanistic mathematical model that can support analysis and prediction of in vivo effects of NPs. The model considers basic cellular mechanisms including proliferation, apoptosis, and production of cytokines in response to NPs. This new model is implemented for macrophages and parameterized using in vitro measurements of changes in cellular viability and mRNA levels of cytokines: TNF, IL-1b, IL-6, IL-8, and IL-10. The model includes in vitro cellular dosimetry due to nanoparticle transport and transformation. Furthermore, the model developed here optimizes the essential cellular parameters based on in vitro measurements, and provides a stepping stone for the development of more advanced in vivo models that will incorporate additional cellular and NP interactions

Visual field improvement after treatment of optic disk pit maculopathy with the macular buckling procedure

Purpose: To evaluate visual field changes in 18 of 21 patients with unilateral optic disk pit maculopathy who were successfully treated with the macular buckling procedure. Methods: In this prospective study, visual field examination with the Humphrey analyzer (programs 30-2 and 10-2) was recorded before treatment, repeated 1 month after the operation, and repeated every 6 months thereafter. All 18 patients were treated with the macular buckling procedure. The operation consisted of fixation of a silastic sponge explant at the posterior pole corresponding to the macula. Results: In 18 eyes included in the study and successfully treated, an improvement in visual field indices was recorded. The mean deviation improved from -7.75 +/- 3.15 (program 30-2) and -10.19 +/- 3.66 (program 10-2) decibels before surgery to -6.25 +/- 2.61 (P < 0.0001) and -8.56 +/- 3.13 (P < 0.0001) decibels at the last examination, respectively. No additional visual field defect was induced in any of the 18 eyes after treatment. Also, the majority of the eyes (16/18) gained from 1 to 7 Snellen lines of visual acuity (P < 0.0001). Conclusion: Improvement of central and peripheral visual field (within 30 degrees of fixation) was recorded after the treatment of optic disk pit maculopathy with the macular buckling procedure. This technique seems to be effective for treatment of the disease with good anatomic and functional results