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To make valid inferences from recurrence plots for time-delay embedded signals, two underlying key questions are: (1) to what extent does an unthresholded recurrence (URP) plot carry the same information as the signal that generated it, and (2) how does the information change when the URP gets distorted. We studied the first question in our earlier work [1], where it was shown that the URP admits the reconstruction of the underlying signal (up to its mean and a choice of sign) if and only if an associated graph is connected. Here we refine this result and we give an explicit condition in terms of the embedding parameters and the discrete Fourier spectrum of the URP. We also develop a method for the reconstruction of the underlying signal which overcomes several drawbacks that earlier approaches had. To address the second question we investigate robustness of the proposed reconstruction method under disturbances. We carry out two simulation experiments which are characterized by a broad band and a narrow band spectrum respectively. For each experiment we choose a noise level and two different pairs of embedding parameters. The conventional binary recurrence plot (RP) is obtained from the URP by thresholding and zero-one conversion, which can be viewed as severe distortion acting on the URP. Typically the reconstruction of the underlying signal from an RP is expected to be rather inaccurate. However, by introducing the concept of a multi-level recurrence plot (MRP) we propose to bridge the information gap between the URP and the RP, while still achieving a high data compression rate. We demonstrate the working of the proposed reconstruction procedure on MRPs, indicating that MRPs with just a few discretization levels can usually capture signal properties and morphologies more accurately than conventional RPs. (C) 2016 Elsevier B.V. All rights reserved.

Stakeholders in Zuid-Limburg hebben zich verenigd om te komen tot een Gezondheidsakkoord, met als doel de gezondheid en de participatiegraad te verhogen tot minimaal het landelijk gemiddelde. Aanleiding en verloop van het proces worden geschetst. Grote vraag blijft: komt de beweging op gang en is men in staat om voldoende gas te geven? Net als in het energieakkoord zijn de doelstellingen ambitieus en door geen enkele partij alleen te bereiken. De uitdaging is om te bewerkstelligen dat partijen sectoroverstijgend denken en samenwerken, en vasthouden aan gezamenlijk gemaakte afspraken.

The polyphenol quercetin (Q) that has a high antioxidant capacity is a lead compound in the design of antioxidants. We investigated the possibility of modifying quercetin while retaining its antioxidant capacity as much as possible. To this end, the antioxidant capacities of Q, rutin, monohydroxyethyl rutinoside (monoHER) and a series of synthesized methylated Q derivatives were determined. The results confirm that the electron donating effect of the hydroxyl groups is essential. It was also found that the relatively planar structure of Q needs to be conserved. This planar conformation enables the distribution of the electron donating effect through the large conjugated pi-system over the entire molecule. This is essential for the cooperation between the electron donating groups. Based on the activity of the compounds tested, it was concluded that structural modification at the 5 or 7 position is the most optimal to retain most of the antioxidant capacity of Q. This was confirmed by synthesizing and testing Q5OMe (Q6) and Q7OMe (Q7) that indeed displayed antioxidant capacities closest to Q.

We address the information content of unthresholded recurrence plots, generated by the time-delay embedding method from scalar signals admitting a Fourier series representation (including periodic and sampled signals). This is important for making valid inferences from unthresholded recurrence plots. A graph theoretic framework is developed to give a complete analysis of the impact of the choice of time-delay and embedding dimension on information content. A distance measure for unthresholded recurrence plots is introduced to approach signal reconstruction and approximation by minimization, robust to inaccuracies and noise. Examples and an application from EEG analysis clarify the theoretical results and demonstrate their practical potential.

Little is known about antioxidant status, selenium status in particular, and lung response to NO2, which acts as a proinflammatory air pollutant. The effects of a low selenium diet (1.3 mu g Se/d) with or without selenium supplementation were therefore studied in 128 Wistar rats, 2 mo old, male exposed to either acute (50 ppm, 30 min), intermittent subacute (5 ppm, 6 h/d, 5 d), intermittent long-term NO2 (1 ppm, 10 ppm, 6 h/d, 5 d/wk, 28 d), or normal atmospheric air (controls). Following sacrifice, measurements of lipid peroxidation ( thiobarbituric acid-reactive substances, chemiluminescence), antioxidative protective enzymes (glutathione peroxidase [GPx], superoxide dismutase [SOD], glutathione S-transferase [GST], ceruloplasmin), lung damage ( lactate dehydrogenase, alkaline and acid phosphatases), lung permeability ( total protein, albumin), and inflammation (cell populations), along with the determination of new biomarkers such as CC16 (Clara-cell protein), were performed in serum and bronchoalveolar lavage fluid (BALF). While selenium-supplemented animals had increased GPx activity in serum prior to inhalation experiments, they also had decreased BALF CC16, blood SOD, and GST levels. Nevertheless, the protective role of normal selenium status with respect to NO2 lung toxicity was evident both for long-term and acute exposures, as the increase in BALF total proteins and corresponding decrease in serum (indicating increased lung permeability) was significantly more pronounced in selenium-deficient animals. During the various inhalation experiments, serum CC16 demonstrated its key role as an early marker of increased lung permeability. These findings corroborate the important role of selenium status in NO2 oxidative damage modulation, but also indicate, in view of its negative impact on CC16, a natural anti-inflammatory and immunosuppressor, that caution should be used prior to advocating selenium supplementation.

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) convened a workshop in Barcelona, Spain, in November 2005 to develop testing strategies to establish the safety of nanomaterials. It brought together about 70 scientific and clinical experts from industry, academia, government agencies, research institutes, and nongovernmental organizations. The primary questions to be addressed were the following: What can we do today, and what do we need tomorrow? The three major themes of the workshop were: (1) the need for enhanced efforts in nanomaterial characterization; (2) methodologies for assessments of airborne and internal exposures to nanomaterials; and (3) evaluation of the hazard potential--primarily focusing on pulmonary or dermal routes of exposures. Some of the summary conclusions of the workshop included the following: For the development of nanoparticle characterization, the working definition of nanoparticles was defined as < 100 nm in one dimension or < 1000 nm to include aggregates and agglomerates. Moreover, it was concluded that although many physical factors can influence toxicity, including nanoparticle composition, it is dissolution, surface area and characteristics, size, size distribution, and shape that largely determine the functional, toxicological and environmental impact of nanomaterials. In addition, most of the information on potential systemic effects has thus far been derived from combustion-generated particles. With respect to the assessment of external exposures and metrics appropriate for nanoparticles, the general view of the meeting was that currently it is not possible or desirable to select one form of dose metric (i.e., mass, surface area, or particle number) as the most appropriate measure source. However, it was clear that the surface area metric was likely to be of interest and requires further development. In addition, there is a clear and immediate need to develop instruments which are smaller, more portable, and less expensive than the currently available state of the art instrumentation. With regard to a general testing approach for human health hazard evaluation of nanoparticles, a first step to determine potency may include a prioritization-related in vitro screening strategy to assess the possible reactivity, biomarkers of inflammation and cellular uptake of nanoparticles; however this process should be validated using in vivo techniques. A Tier 1 in vivo testing strategy could include a short-term inhalation or intratracheal instillation of nanoparticles as the route of exposure in the lungs of rats or mice. The endpoints that should be assessed include indices of lung inflammation, cytotoxicity, and cell proliferation, as well as histopathology of the respiratory tract and the major extrapulmonary organs. For Tier 2 in vivo testing for hazard identification, a longer term inhalation study is recommended, and this would include more substantive mechanistic endpoints such as determination of particle deposition, translocation, and disposition within the body. Additional studies could be designed with specific animal models to mimic sensitive populations. With regard to dermal exposures, currently there is little evidence that nanoparticles at a size exceeding 100 nm penetrate through the skin barrier into the living tissue (i.e., dermal compartment). The penetration of nanoparticles at a size less than 100 nm should be a topic of further investigation. Moreover, considering the impacts of dermal exposures and corresponding hazard potential of nanoparticles, it must be taken into consideration that the dermal uptake of nanoparticles will be an order of magnitude smaller than the uptake via the inhalation or oral routes of exposure. For the evaluation of the health risk of nanoparticles, it has to be determined whether they are harmful to living cells and whether, under real conditions, they penetrate through the skin barrier into the living tissue. For the evaluation of the penetration processes, in principle, three methods are available. Using the method of differential stripping, the penetration kinetics of nanoparticles in the stratum corneum and the hair follicles can be evaluated. This analysis can be carried out in vivo. Diffusion cell experiments are an efficient method for in vitro penetration studies. Also, laser scanning microscopy is well suited to test penetration kinetics, although requiring fluorescent-labeled nanoparticles. Emerging topics such as (1) environmental safety testing, (2) applications of nanoparticles for medical purposes, and (3) pathways of inhaled nanoparticles to the central nervous system were also briefly addressed during this workshop. However, it has become clear that these topics should be the subjects of separate workshops and they are not further addressed in this report.

A method for the synthesis of both spherically shaped micro/nano silica particles and silica hybrid particles using a novel inverse sol–gel suspension technique was developed. The technique enables the synthesis of beads within seconds and provides a simple basis for quantum dot and biosubstances encapsulation. The carriers can be used as DNA adsorbents, individually addressable optical codes for bioassays and biomolecule library screening as well as photonic crystals.

Ultrafine (Uf) particles are a component of particulate air pollution suggested to be responsible for the health effects associated with elevations of this pollutant. We have previously suggested that Uf particles, through the induction of oxidative stress, may induce inflammation in the lung, thus exacerbating preexisting illness in susceptible individuals. Alveolar macrophages are considered to play a key role in particlemediated inflammation and lung disease. The effect of Uf particles on rat alveolar macrophages and human blood monocytes was investigated with reference to the roles of calcium and reactive oxygen species (ROS). TNF-alpha protein release, intracellular calcium concentration, TNF-alpha mRNA expression, and transcription factor activation were studied as end points after treatment of rat alveolar macrophages or peripheral blood monocytes. The calcium channel blocker verapamil, the intracellular calcium chelator BAPTA-AM, the calmodulin inhibitor W-7, and the antioxidants Trolox and Nacystelin (NAL) were included in combination with Uf particles. Verapamil reduced intracellular calcium concentration in rat alveolar macrophages on stimulation with Uf particles. This effect was also apparent with transcription factor AP-1 activation. All antagonists and antioxidants reduced Uf-stimulated nuclear localization of the p50 and p65 subunits of NF-kappaB in human monocytes. Verapamil, BAPTA-AM, and NAL reduced Uf-stimulated TNF-alpha protein release, whereas only verapamil reduced Uf-stimulated mRNA expression in rat alveolar macrophages. In human monocytes, verapamil, Trolox, BAPTA-AM, and W-7 reduced Uf-stimulated TNF-alpha protein release. These findings suggest that Uf particles may exert proinflammatory effects by modulating intracellular calcium concentrations, activation of transcription factors, and cytokine production through a ROS-mediated mechanism.

Rationale Mineral particles in the lung cause inflammation and silicosis. In myeloid and bronchial epithelial cells the inflammasome plays a role in responses to crystalline silica. Thioredoxin (TRX) and its inhibitory protein TRX-interacting protein link oxidative stress with inflammasome activation. We investigated inflammasome activation by crystalline silica polymorphs and modulation by TRX in vitro, as well as its localization and the importance of silica surface reactivity in rats. Methods We exposed bronchial epithelial cells and differentiated macrophages to silica polymorphs quartz and cristobalite and measured caspase-1 activity as well as the release of IL-1β, bFGF and HMGB1; including after TRX overexpression or treatment with recombinant TRX. Rats were intratracheally instilled with vehicle control, Dörentruper quartz (DQ12) or DQ12 coated with polyvinylpyridine N-oxide. At days 3, 7, 28, 90, 180 and 360 five animals per treatment group were sacrificed. Hallmarks of silicosis were assessed with Haematoxylin-eosin and Sirius Red stainings. Caspase-1 activity in the bronchoalveolar lavage and caspase-1 and IL-1β localization in lung tissue were determined using Western blot and immunohistochemistry (IHC). Results Silica polymorphs triggered secretion of IL-1β, bFGF and HMGB1 in a surface reactivity dependent manner. Inflammasome readouts linked with caspase-1 enzymatic activity were attenuated by TRX overexpression or treatment. At day 3 and 7 increased caspase-1 activity was detected in BALF of the DQ12 group and increased levels of caspase-1 and IL-1β were observed with IHC in the DQ12 group compared to controls. DQ12 exposure revealed silicotic nodules at 180 and 360 days. Particle surface modification markedly attenuated the grade of inflammation and lymphocyte influx and attenuated the level of inflammasome activation, indicating that the development of silicosis and inflammasome activation is determined by crystalline silica surface reactivity. Conclusion Our novel data indicate the pivotal role of surface reactivity of crystalline silica to activate the inflammasome in cultures of both epithelial cells and macrophages. Inhibitory capacity of the antioxidant TRX to inflammasome activation was evidenced. DQ12 quartz exposure induced acute and chronic functional activation of the inflammasome in the heterogeneous cell populations of the lung in associated with its crystalline surface reactivity. Electronic supplementary material The online version of this article (doi:10.1186/s12989-014-0058-0) contains supplementary material, which is available to authorized users.

We address redundancy in the information content of unthresholded recurrence plots (URPs). The theory of framework rigidity is employed to explain and analyze this redundancy geometrically. First we show that the domain of a URP can be restricted to just a finite number of vertical or horizontal lines without loss of information. Then we construct a globally rigid framework to demonstrate a similar property for diagonal lines. This result gives theoretical support to recurrence quantification analysis (RQA), which analyzes and extracts features from an RP along such lines. Third, we construct a finite set of curves, one of which is a contour line, for which it again holds that the URP contains all information along them. This links the information content of lossy (thresholded) recurrence plots to that of URPs. This study is also a starting point in employing redundancy to improve existing recurrence plots based methods and algorithms, and to develop new ones. Several examples clarify the methods and an application from EEG artifact detection shows some of their practical potential.

We address the information content of unthresholded recurrence plots for complex-valued signals admitting a Fourier series representation (including periodic and sampled signals). Unthresholded recurrence plots of complex-valued signals contain the information of two real-valued signals simultaneously and can therefore be used to study the relationship between these signals. The graph theoretic procedure in our recent work [1], which was developed to characterize the uniqueness conditions for real-valued signals, is extended to the class of complex-valued signals. The special properties of complex signal representations provide alternative ways to employ unthresholded recurrence plots on narrow band signals. Examples and an application from EEG analysis clarify the results.

In 1997, an IARC Working Group classified quartz (crystalline silica) as a Group 1 lung carcinogen, but only in some industries, i.e., the quartz hazard is a variable entity. The reactivity of the quartz surface may underlie its ability to cause inflammation, and treatments that ameliorate this reactivity will reduce the quartz hazard. In this study we treated quartz (Q) with aluminium lactate (AL), a procedure that is reported to decrease the quartz hazard, and explored the effect this had on the highly reactive quartz surface and on proinflammatory events in rat lungs. Aluminium lactate-treated quartz showed a reduced surface reactivity as measured by electron spin resonance and the hemolysis assay. Eighteen hours after instillation of Q into the rat lung, there was massive inflammation as indicated by the number of neutrophils in the bronchoalveolar lavage (BAL). In addition, Q induced an increase in BAL macrophage inflammatory protein-2 (MIP-2) while ALQ had no significant effect compared to control. Epithelial damage, as indicated by BAL protein and gamma glutamyl transpeptidase, also increased with Q but not with ALQ. Furthermore, Q induced an increase in MIP-2 mRNA by BAL cells while ALQ had no effect compared to controls. There was an increase in nuclear binding of the transcription nuclear factor kappaB (NF-kappaB) in the Q-exposed BAL cells and again no effect on nuclear NF-kappaB binding in BAL cells from ALQ-exposed rats. In conclusion, treatment of the quartz surface with aluminium lactate reduced the reactivity of the particles both in terms of hydroxyl radical generation and in terms of the induction of molecular signaling events leading to inflammation.

Hum Exp Toxicol 2001 May;20(5):259-65 Related Articles, Books, LinkOut Ambient particulate matter induces relaxation of rat aortic rings in vitro.Knaapen AM, den Hartog GJ, Bast A, Borm PJ.Department of Fibre and Particle Toxicology, Medical Institute of Environmental Hygiene, Dusseldorf, Germany.Epidemiological studies have shown an association between ambient levels of particulate matter (PM) and increased mortality from cardiovascular diseases. However, the underlying mechanisms are still not clear. We hypothesised that PM, when translocated after inhalation, could affect vascular smooth muscle function. Therefore, total suspended particulate matter (TSP) was sampled and investigated for its ability to affect aortic muscle contraction. Both TSP and TSP supernatant (TSP-sup) induced a concentration-dependent relaxation of phenylephrine (PE)-precontracted aortic rings. Relaxation induced by 100 microg/ml TSP was 51.5 +/- 3.1% of total contraction. At 60 and 100 microg/ml, relaxation induced by TSP was significantly higher compared to TSP-sup. Ultrafine TiO2, used as a model to investigate the role of ultrafine particles, did not show an effect. Soluble iron, present in TSP suspensions, seems not to be involved, as chelating with deferoxamine did not affect TSP-induced relaxation. However, TSP effects were inhibited by Trolox, suggesting a role of oxidants. Nudation of aortic rings showed that effects of TSP were only partly endothelium-dependent, while preincubation with L-NAME increased TSP-induced relaxation. From these data, we conclude that both the particle core and soluble components of TSP can affect the smooth muscle function, leading to changes in the vascular contractile response.

The aim of this study was to evaluate the influence of bandwidth and echotime on the size of signal voids created by iron oxide nanoparticles on a guidewire.

Epidemiological studies have shown that respirable exposure to emitted cement particulate matter is associated with adverse health risk for human. The underlying mechanisms, however, are poorly understood. To examine the effect of cement, nine blinded cement-related particulates (

Mining, crushing, grinding, sandblasting and construction are high-risk activities with regard to crystalline silica exposure, especially in developing countries. Respirable crystalline silica (quartz and cristobalite) inhaled from occupational sources has been reclassified as a human carcinogen in 1997 by the International Agency for Research on Cancer. However, the biological activity of crystalline silica has been found to be variable among different industries, and this has formed the basis for further in vivo/in vitro mechanistic research and epidemiologic studies. This study was conducted for genotoxicity evaluation in a population of workers (e.g. glass industry workers, sandblasters, and stone grinders) mainly exposed to crystalline silica in four different workplaces in Turkey. The micronucleus (MN) assay was applied both in peripheral blood lymphocytes (PBL) as a surrogate tissue and in nasal epithelial cells (NEC) as a target tissue of the respiratory tract. Our study revealed significantly higher MN frequencies in the workers (n = 50) versus the control group (n = 29) (P < 0.001) and indicated a significant effect of occupational exposure on MN induction in both of the tissues. For the NEC target tissue, the difference in MN frequencies between the workers and control group was 3-fold, whereas in peripheral tissue, it was 2-fold. Respirable dust and crystalline silica levels exceeding limit values and mineralogical/elemental dust composition of the dust of at least 70% SiO2 were used as markers of crystalline silica exposure in each of the workplaces. Moreover, 24% of the current workers were found to have early radiographical changes (profusion category of 1). In conclusion, although the PBL are not primary target cells for respiratory particulate toxicants, an evident increase in MN frequencies in this surrogate tissue was observed, alongside with a significant increase in NEC and may be an indicator of the accumulated genetic damage associated with crystalline silica exposure.

Fine particulate matter (PM(2.5)) was sampled at an urban background site in Tartu, Estonia over one-year period during the ECRHS II study. The elemental composition of 71 PM(2.5) samples was analyzed for different chemical elements using energy-dispersive X-ray fluorescence spectrometry (ED-XRF). The oxidative activity of 36 samples was assessed by measuring their ability to generate hydroxyl radicals in the presence of hydrogen peroxide. The origin of air masses was determined by computing 96-hour back trajectories of air masses with the HYSPLIT Model. The trajectories of air masses were divided into four sectors according to geographical patterns: "Russia," "Eastern Europe," "Western Europe," and "Scandinavia." During the study period, approximately 30% of air masses originated from "Scandinavia." The other three sectors had slightly lower values (between 18 and 22%). In spring, summer, and winter, higher total PM levels originated from air masses from continental areas, namely "Russia" and "Eastern Europe" (18.51+/-7.33 and 19.96+/-9.23microg m(-3), respectively). In autumn, the PM levels were highest in "Western Europe". High levels of Fe, Ti, and AlCaSi (Al, Ca, and Si) were also detected in air masses from the Eurasian continent. The oxidative properties were correlated to the origin of air masses. The OH values were approximately 1.5 times higher when air masses originated from the direction of "Eastern Europe" or "Russia." The origin of measured particles was evaluated using principal component factor analysis. When comparing the PM(2.5) elemental composition with seasonal variation, factor scores, and other studies, the factors represent: (1) combustion of biomass; (2) crustal dust; (3) traffic; and (4) power plants and industrial processes associated with oil burning. The total PM(2.5) is driven mainly by biomass and industrial combustion (63%) and other unidentified sources (23%). Other sources of PM, such as crustal dust and traffic, contribute a total of 13%.

Background Ambient particulate matter and nanoparticles have been shown to translocate to the brain, and potentially influence the central nervous system. No data are available whether this may lead to functional changes in the brain. Methods We exposed 10 human volunteers to dilute diesel exhaust (DE, 300 μg/m3) as a model for ambient PM exposure and filtered air for one hour using a double blind randomized crossover design. Brain activity was monitored during and for one hour following each exposure using quantitative electroencephalography (QEEG) at 8 different sites on the scalp. The frequency spectrum of the EEG signals was used to calculate the median power frequency (MPF) and specific frequency bands of the QEEG. Results Our data demonstrate a significant increase in MPF in response to DE in the frontal cortex within 30 min into exposure. The increase in MPF is primarily caused by an increase in fast wave activity (β2) and continues to rise during the 1 hour post-exposure interval. Conclusion This study is the first to show a functional effect of DE exposure in the human brain, indicating a general cortical stress response. Further studies are required to determine whether this effect is mediated by the nanoparticles in DE and to define the precise pathways involved.

We previously demonstrated the importance of the surface area burden as the key dose metric in the elicitation of inflammation in rat lungs by low-solubility, low-toxicity particles (LSLTP). We have now explored the dosimetry of LSLTP in vitro using epithelial cell interleukin (IL)-8 gene expression as a surrogate for potential of particles to cause inflammation. The proximal alveolar region (PAR) of the lung has been identified as a key site for the retention of respirable particles, as it receives high deposition but has slow clearance compared to the larger airways. For these reasons, a few days after exposure to particles the residual dose is concentrated in the PAR region. Re-expressing our rat lung data as particle surface area burden per unit of PAR surface area we obtained a threshold value for onset of inflammation of 1 cm(2)/cm(2). We carried out dose responses in vitro for onset of IL-8 gene expression with the same particles as we had used in vivo. When we expressed the in vitro dose as surface area dose per unit A549cell culture surface area, we obtained a threshold of 1 cm(2)/cm(2). This concordance between proinflammatory effects in vivo (PMN in BAL) and in vitro (epithelial IL-8 gene expression) confirms and supports the utility of the particle surface area metric and the importance of the PAR. These studies also open the way for future in vitro approaches to studying proinflammatory effects of a range of toxic particles based on sound dosimetry that complements animal use in particle toxicology.

Engineered nanoparticles are an important tool for future nanomedicines to deliver and target drugs or bring imaging agents to the targets where they are required. Since the original application of liposomes in the 1970s, a wealth of carrier and imaging systems has been developed, including magnetoliposomes, dendrimers, fullerenes and polymer carriers. However, to make use of this potential, toxicological issues must be addressed, in particular because of findings on combustion-derived nanoparticles in environmentally exposed populations, which show effects in those with respiratory or cardiovascular diseases. These effects are mediated by oxidative stress, lung and systemic inflammation and different mechanisms of internalization and translocation. Many effects found with combustion-derived nanoparticles have now tested positive with engineered nanoparticles, such as single-wall nanotubes. This article aims to identify common concepts in the action of nanoparticles in order to enable future cross-talk and mutual use of concepts.

Background A symposium on the mechanisms of action of inhaled airborne particulate matter (PM), pathogenic particles and fibers such as silica and asbestos, and nanomaterials, defined as synthetic particles or fibers less than 100 nm in diameter, was held on October 27 and 28, 2005, at the Environmental Protection Agency (EPA) Conference Center in Research Triangle Park, North Carolina. The meeting was the eighth in a series of transatlantic conferences first held in Penarth, Wales, at the Medical Research Council Pneumoconiosis Unit (1979), that have fostered long-standing collaborations between researchers in the fields of mineralogy, cell and molecular biology, pathology, toxicology, and environmental/occupational health. Results The goal of this meeting, which was largely supported by a conference grant from the NHLBI, was to assemble a group of clinical and basic research scientists who presented and discussed new data on the mechanistic effects of inhaled particulates on the onset and development of morbidity and mortality in the lung and cardiovascular system. Another outcome of the meeting was the elucidation of a number of host susceptibility factors implicated in adverse health effects associated with inhaled pathogenic particulates. Conclusion New models and data presented supported the paradigm that both genetic and environmental (and occupational) factors affect disease outcomes from inhaled particulates as well as cardiopulmonary responses. These future studies are encouraged to allow the design of appropriate strategies for prevention and treatment of particulate-associated morbidity and mortality, especially in susceptible populations.

Dissolution, translocation, and disposition have been shown to play a key role in the fate and effects of inhaled particles and fibers. Concepts that have been applied in the micron size range may be usefully applied to the nanoscale range, but new challenges are presented based on the small size and possible change in the dissolution:translocation relationship. The size of the component molecule itself may be on the nanoscale. Solute concentration, surface area, surface morphology, surface energy, dissolution layer properties, adsorbing species, and aggregation are relevant parameters in considering dissolution at the nanoscale. With regard to the etiopathology caused by these types of particulates, the metrics of dose (particle number, surface area, mass or shape) is not yet well defined. Analytical procedures for assessing dissolution and translocation include chemical assay and particle characterization. Leaching of substituents from particle surfaces may also be important. Compartmentalization within the respiratory tract may add another dimension of complexity. Dissolution may be a critical step for some nanoscale materials in determining fate in the environment and within the body. This review, combining aspects of particle toxicology, material science, and analytical chemistry, is intended to provide a useful basis for developing relevant dissolution assay(s) for nanoscale particles.

The chemical composition and toxicity of wintertime urban-air particulate matter with an aerodynamic diameter of10 microm (PM10), derived mostly from long-range transport and local combustion sources, were compared with those of springtime PM10 derived mostly from the resuspension of road dust.Water-soluble ions and elements and polycyclic aromatic hydrocarbons (PAH) were analyzed from seasonally pooled PM10 samples collected at a busy traffic site in Helsinki in 1999. These PM10 samples were also tested for cytotoxicity [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide test] and the production of proinflammatory cytokines [tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6)] and nitric oxide (NO) in the mouse macrophage cell line RAW 264.7. Their oxidative capacity and the associated DNA (deoxyribonucleic acid) damage were investigated by electron paramagnetic resonance and the formation of 8-hydroxy-2'-deoxyguanosine (8-OH-DG) in isolated calf thymus DNA, respectively.The late wintertime and springtime PM10 had similar compositions of water-soluble ions and elements, but the winter PM10 had a higher content of PAH. The spring PM10 was a much more potent inducer of TNF-alpha and IL-6 production than the winter PM10 was, but there were no consistent differences in cytotoxic potency. In contrast, the winter PM10 was a significantly more potent inducer of NO production and 8-OH-DG formation. The large cytokine responses to the spring PM10 were caused by its insoluble fraction and largely inhibited by the endotoxin antagonist polymyxin B. The transition metal chelator deferoxamine did not modify the proinflammatory or cytotoxic responses to the PM10 samples.The toxicity profile of urban-air PM10 changed with season in a subarctic climate. Particulate-bound endotoxin from soil gram-negative bacteria is suggested as a highly proinflammatory constituent of springtime resuspended road dust.

Johan W Molling, Jacques W Seezink, Birgit EJ Teunissen, Inhua Muijrers-Chen, Paul JA Borm Zuyd University of Applied Sciences, Heerlen, the Netherlands Background: Bacterial resistance against the classic antibiotics is posing an increasing challenge for the prevention and treatment of infections in health care environments. The introduction of antimicrobial nanocoatings with active ingredients provides alternative measures for active killing of microorganisms, through a preventive hygiene approach. Purpose: The purpose of this study was to investigate the antimicrobial activity of a panel of antimicrobial coatings available on the European market. Methods: A comparative, biased selection of commercially available antimicrobial coatings was tested for antimicrobial efficiency. Suppliers were contacted to deliver their coatings on glass and/or stainless steel substrates. In total, 23 coatings from eleven suppliers were received, which were investigated for their effect on the growth of Escherichia coli, using the International Organization for Standardization (ISO) 22196 protocol. Results: The majority of nanomaterial-containing coatings (n=13) contained nanosilver (n=12), while only one had photocatalytic TiO2 as the active particle. The differences in antimicrobial activity among all of the coatings, expressed as log reduction values, varied between 1.3 and 6.6, while the variation within the nanomaterial-based group was between 2.0 and 6.2. Although nanosilver coatings were on average very effective in reducing the number of viable bacteria after challenge, the strongest log reduction (6.6) was seen with a coating that has immobilized, covalently bound quaternary ammonium salt in its matrix. Besides these two compounds, coatings containing TiO2, poly(dimethylsiloxane), triclosan, or zinc pyrithione evoked 100% killing of E. coli. Conclusion: Our findings indicate that nanosilver dominates the nanoparticle-based coatings and performs adequately. However, considering the unknowns in relation to ecotoxicological emission and effects, it needs further consideration before widespread application into different environments. Keywords: coatings, nanotechnology, nanosilver, biocides&nbsp

J Psychosom Res 2001 Jan;50(1):21-7 Related Articles, Books, LinkOut Psychological job demands as a risk factor for common cold in a Dutch working population.Mohren DC, Swaen GM, Borm PJ, Bast A, Galama JM.Department of Epidemiology, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands. dcl.mohren@epid.unimaas.nlOBJECTIVE: We investigated the effect of Psychological Job Demands (PJD) on the occurrence of the clinical symptoms of common cold. METHODS: Subjects, participating in a large prospective cohort study on psychological determinants of fatigue at work, were asked to fill in a questionnaire on the occurrence of common cold during the previous four months. High PJD were considered as a potential risk factor. Other factors such as age, gender, and having young children were considered as potential confounders. RESULTS: In logistic regression analysis, the adjusted odds ratio (OR) for having a recent cold in subjects reporting high PJD vs. those reporting low PJD was 1.20 (95% confidence interval (CI), 1.08-1.33). A higher risk emerged among those with young children (OR, 1.70; 95% CI, 1.47-1.96), those having a history of asthma (OR, 1.69; 95% CI, 1.28-2.22), or being under the age of 40 (OR, 1.28; 95% CI, 1.14-1.43) and among smokers (OR, 1.23; 95% CI, 1.09-1.38). CONCLUSION: The results support an association between PJD and common cold. In spite of the almost inevitable shortcoming of a large cohort study using questionnaires, this study gave us the opportunity to study the relationship between common cold and work-related factors in a nonexperimental setting with participants observed in a natural environment with all the normal everyday hassles.

Ultrafine particles have been shown to induce pro-inflammatory effects both in vivo and in vitro. Increased expression of pro-inflammatory genes probably requires the activation of specific transcription factors such as nuclear factor kappa B (NF-kappaB) via a number of possible pathways including Ca2+ and reactive oxygen species. The fluorescent dye fura 2, was used to measure cytosolic Ca2+ in the human monocytic cell line, Monomac 6 on exposure to 66 microg x mL(-1) of either ultrafine carbon black (ufCB; diameter 14 nm), carbon black (CB; diameter 260 nm), quartz (diameter 1.45 microm), or medium alone. UfCB but not fine CB induced a 1.6-fold increase (p

Department of Health Risk Analysis and Toxicology, Maastricht University, The Netherlands.The 32P-post-labelling assay for DNA adduct quantification gives the opportunity to examine endogenous exposure to DNA reactive compounds. Most human biomonitoring studies applied white blood cells (WBC) or cells obtained by broncho-alveolar lavages (BAL) as source of DNA, but still it is not clear what cell type represents the most reliable indicator for exposure to cigarette smoke-associated genotoxins. At first, we examined DNA adduct levels by means of nuclease P1 (NP1) enriched 32P-post-labelling in separated WBC subpopulations after in vitro incubations for 18 h with 10 microM benzo[a]pyrene (B[a]P). DNA adduct levels were highest in monocytes (10.7 +/- 2.9 adducts/10(8) nucleotides, n = 8), followed by lymphocytes (5.9 +/- 1.7, n = 8), and granulocytes (0.5 +/- 0.2, n = 8). Secondly, aromatic-DNA adduct levels were determined in BAL cells and WBC-subsets from (non-)smoking volunteers. In smoking individuals, adduct levels were in the ranking order: BAL cells (3.7 +/- 1.0, n = 5) > monocytes (2.0 +/- 0.5, n = 8) > or = lymphocytes (1.6 +/- 0.4, n = 8) > granulocytes (0.8 +/- 0.2, n = 8) by NP1-enrichment and monocytes (9.0 +/- 3.2, n = 5) > or = lymphocytes (8.0 +/- 2.1, n = 6) > granulocytes (2.1 +/- 0.3, n = 7) by butanol-enriched 32P-post-labelling. Aromatic-DNA adduct levels were significantly higher in WBC-subsets of smokers as compared with non-smokers, except for DNA adducts in granulocytes using butanol enrichment. Thirdly, dose-response relationships were investigated in mononuclear white blood cells (MNC, i.e. monocytes plus lymphocytes) and BAL-cells of a larger group of smoking individuals (n = 78). Adduct levels in MNC were related to daily exposure to cigarette-tar (r = 0.31, P < 0.01). Adduct levels in BAL cells seemed to be correlated with pack-years, but after correction for age this relationship was lost. Butanol extraction resulted in 5-6-fold higher DNA adduct levels in MNC, whereas butanol extraction of BAL-DNA of the same individuals yielded only 2-fold higher adduct levels. The two enrichment procedures of 32P-post-labelling were correlated in BAL cells (r = 0.86, P < 0.001, n = 12). We conclude that particularly MNC are good surrogates for the detection of smoking-related DNA adducts.

Exposure to quartz dusts has been associated with lung cancer and fibrosis. Although the responsible mechanisms are not completely understood, progressive inflammation with associated induction of persistent oxidative stress has been discussed as a key event for these diseases. Previously we have evaluated the kinetics of pulmonary inflammation in the rat model following a single intratracheal instillation of 2mg DQ12 quartz, either in its native form or upon its surface modification with polyvinylpyridine-N-oxide or aluminium lactate. This model has been applied now to evaluate the role of inflammation in the kinetics of induction of DNA damage and response at 3, 7, 28, and 90 days after treatment. Bronchoalveolar lavage (BAL) cell counts and differentials as well as BAL fluid myeloperoxidase activity were used as markers of inflammation. Whole lung homogenate was investigated to determine the induction of the oxidative and pre-mutagenic DNA lesion 8-hydroxy-2-deoxy-guanosine (8-OHdG) by HPLC/ECD, while mRNA and protein expression of oxidative stress and DNA damage response genes including hemeoxygenase-1 (HO-1) and apurinic/apyrimidinic endonuclease (APE/Ref-1) were evaluated using Western blotting and real time PCR. Isolated lung epithelial cells from the treated rats were used for DNA strand breakage analysis using the alkaline comet assay as well as for micronucleus scoring in May-Gruenwald-Giemsa stained cytospin preparations. In the rats that were treated with quartz, no increased 8-OHdG levels were observed, despite the presence of a marked and persistent inflammation. However, DNA strand breakage in the lung epithelial cells of the quartz treated rats was significantly enhanced at 3 days, but not at 28 days. Moreover, significantly enhanced micronucleus frequencies were observed for all four time points investigated. In the animals that were treated with the PVNO modified quartz, micronuclei scores did not differ from controls, while in those treated with the aluminium coated quartz intermediate effects were found. These findings were in line with the kinetics of inflammation and epithelial proliferation in the rat lungs for the different treatments. Notably, a highly significant correlation was observed between neutrophil numbers and micronucleus frequencies, indicative for a role of inflammation in eliciting genomic instability in target cells of quartz-induced carcinogenesis. Our ongoing investigations focus on the evaluation of the causality between both in relation to quartz exposure.

Particle research and particle toxicology have been historically closely connected to industrial activities or materials, such as coal, asbestos and manmade mineral fibers. Until the early nineties papers on these icons of exposure dominated the literature in classical journals with a strong occupational or hygiene approach. Along with the evolution in our understanding of general disease, particle toxicology has benefited from the developments in molecular medicine. Over time there has been a considerable change in the experimental approach taken by particle toxicologists. Nowadays inflammation as a key response to particle deposition in tissue and a process in particle effects has been inexorable and inflammation now lies at the very heart of our understanding of lung and systemic disease associated with particle exposure. As in all molecular medicine, there has been a huge concentration on the regulation of gene expression as a basis for disease, and this continues. Oxidative stress has emerged as the dominant paradigm for how particles initiate inflammation and genotoxicity, a stress further augmented by inflammatory cells releasing their arsenal of oxidants. Between 1995 and 2005, the health effects of ambient particulate matter and explanations for their effects have dominated research meetings and journals. Ambient particles suddenly were responsible for effects not only in the lung, but also in the heart, the vascular system and recently also the brain [1,2]. A new age of interaction with other disciplines and clinical specialties was started. With these changing targets and approaches also the array of journals available for publication expanded, and interestingly particle-induced effects have reached the forefront of the general medical journals, as well the specialty journals on lung, heart and other diseases. Particle research has reached a professional quality and impact it has never seen before. Particle and Fibre Toxicology was started in 2004 at the very summit of this interaction, and has published articles on a variety of toxicological endpoints and mechanisms associated to particles. A total of 45 was articles were published in four years, on a variety of particles. About half of the articles covered particles such as asbestos, quartz, diesel or ambient particle matter. Although the number of manuscripts was rather low over the total period, the citation data based on Scopus data [3] showed 250 cites on the first 40 articles. Based on this data, if the journal was to receive an impact factor for 2007 (based on 2007 citations to 2005 and 2006 articles) this would be in the region of 5.7. The high number of citations is in part driven by a number of review articles concerning the effects of nanomaterials and combustion nanoparticles [2,4-6]. In addition, the fact that Particle and Fibre Toxicology is the only journal on this topic which is free access and online, has contributed extensively on its use and citation in many other journals and reports. The journal wants to play a decisive role in a decade where particle research will be challenged and driven by the developments and applications of nanomaterials. Already more than 40% of articles in Particle and Fibre Toxicology since the start of the journal in late 2004 were on this topic, and we want to stimulate the interaction of producers, users and testers of nanomaterials in a variety of fields. They are used in new polymers, so-called nanocomposites and coatings, but also in drug delivery as well as medical imaging through MRI and fluorescence. Most of these applications and particles are new to the field, and we have only started to understand how surface and its chemical properties do determine their aptness for interaction with biological targets. However, studies have demonstrated that even inert materials like gold and TiO2 in nanosize can become chemically active. In other words, inert materials can become reactive just by making them smaller. Nowadays nanoparticles are generated from highly skilled research labs and produced for many applications and in many countries. In the near future upscaling of production is expected and worker exposure and consumer contact are expected to increase dramatically over the years to come. Nanomaterials have already proven to be slippery customers for regulators and regulations such as REACH, since one chemical identity can show different physical properties based in size and shape. Consequently the field of particle toxicology faces a number of challenges and opportunities in the near future. These challenges include: - to generate understanding of the biological action of nanomaterials - denominate the relevant material metrics - attract new young top researchers to the field - Use, communicate and adapt current particle paradigms - Bridge know-how between different application area's of nanomaterials - Communicate findings to the broad public in an increasing relevant society These challenges imposed by nanomaterials demand for new collaborations between toxicologist and chemists, material scientists, and engineers. Competence centers, or virtual networks, where nanomaterials can be made and tested, will be vital for further development of sustainable nanomaterials. Particle and Fibre Toxicology wants to play a role in this process, and has recently recruited three new Associate Editors from China, Japan and the USA and is still working on a complete Editorial Board setting. In addition, we now welcome manuscripts on areas such as biomaterials, drug delivery and imaging in an effort to bridge the available know-how in classic particle toxicology to these areas that have co-existed without much communication for so long. As the new Editor-in-Chief of this journal I firmly believe in open access publication. I also find it a privilege to contribute to the development of particle toxicology as an open access discipline for many other disciplines, in their effort to understand the toxicological action of (nano) materials, thereby creating a platform to help and create sustainable materials for the future.

The widely used plasticiser di(2-ethylhexyl)phthalate (DEHP) has been reported to have some toxicological effects on pulmonary tissue. Inhalation of DEHP may cause pulmonary edema and bronchial asthma. Moreover intravenous injection of DEHP induces pulmonary inflammation and hemorrhage of the lungs. We now report that DEHP might cause bronchial hyperresponsiveness. The metabolite of DEHP mono(2-ethylhexyl)phthalate (MEHP) induces in vitro a dose-dependent increase in -log EC50 for methacholine dose response curves in rat tracheal tissue. Moreover MEHP induces a decrease in maximal effect of the methacholine dose response curve. We concluded that DEHP due to the formation of MEHP in vivo, may cause bronchial hyperresponsiveness.

The anti-oxidant phenotype was determined in red blood cell haemolysates of 62 healthy elderly persons (Mean age: 56) and a number of male silicosis patients (Mean age: 65, n = 19). Moreover, analysis of water-soluble fluorescent substances in plasma, recently introduced as a new test for in vivo lipid-peroxidation, was included. Within the control group results were analyzed on the effect of smoking (no effect), use of medication (lowered GSH-content) or gender (no differences apart from haemoglobin content). No simple relationship between any pair of the measured parameters in erythrocytes was present. When comparing the male control persons with the silicosis group a significantly higher red blood cell GSH-level was observed in the latter. Moreover, some factors of the anti-oxidant system are strongly correlated in the diseased, but not in the healthy subjects.

Two cell isolation procedures, i.e. a scraping/collagenase-treatment and a new vibration procedure in EDTA containing medium, were used to isolate intestinal epithelial cells. In both cell populations the metabolism of 7-ethoxycoumarin and 7-hydroxycoumarin was studied. Moreover, the time course and extent of induction of both steps in the biotransformation were investigated after oral 3-methylcholanthrene pretreatment of the rats. Twenty four hours after 3-methylcholanthrene pretreatment (20 mg kg-1) monooxygenase activity was induced about 6-fold and 2.5-fold when studied with cells of the vibratory and enzymic procedures, respectively. Control 7-ethoxycoumarin deethylase activity and 7-hydroxycoumarin glucuronidation were about the same when comparing both methods for cell-isolation. The formation of glucuronides in cells (both methods) is significantly lowered by 3-MC pretreatment, while sulphation remains unaffected. Results indicate that using enzymic treatment of mucosal scrapings, cell-populations are obtained containing relatively more differentiated (tip) cells. A number of advantages of the new (vibration) method are: better recovery, viability and reproducibility.

A novel, sensitive (0.5 ng) assay for acetaminophen, using HPLC with selective electro-chemical detection, enabled us to study rat small intestinal O-deethylation of phenacetin and compare it with corresponding 7-ethoxycoumarin-O-deethylation. Two in vitro systems, i.e. isolated intestinal mucosal cells and microsomal fractions thereof, were used to study kinetics for the O-deethylation of both substrates. Kmapp- and Vmax-values are similar for 7-ethoxycoumarin- and phenacetin-O-deethylation. Apparent Km-values varied between 50 and 70 μM in control rats and decreased after 3-methylcholanthrene pretreatment to 20–45 μM. Vmax-values were increased by 3-methylcholanthrene pretreatment. O-Deethylation was inhibited equally in cells and microsomes by α-naphtoflavone, but is inhibited more markedly in intestinal preparations after pretreatment with 3-methylcholanthrene. It is suggested that 7-ethoxycoumarin and phenacetin are O-deethylated by different forms of cytochrome P-450 with almost identical Kmapp and that these enzymes have a different distribution along the villus.

Rat intestinal epithelial cells were isolated by EDTA-chelation, combined with gentle shaking (modified Weiser procedure) or with strong longitudinal vibration (Harrison/Webster procedure). Both methods yield large numbers of viable cells and are relatively easy to use. Electronmicroscopical and biochemical data indicate that cell fractions from different levels of the villous region can be obtained only by the modified Weiser procedure. When strong mechanical forces are involved (Harrison-Webster procedure) the villus epithelium is released according to an all-or-nothing process. The biotransformational capacity of cell fractions, obtained from different levels of the villi by the modified Weiser procedure, was investigated. It was shown that the rate of metabolism of 7-ethoxycoumarin and 1-naphthol was substantially higher in lower villous cells than in cells isolated from the upper villous region. O-Deethylation of 7-ethoxycoumarin decreases from 145 +/- 13 pmole/min mg cell protein (72 +/- 4% conjugated) in lower villous cells to 62 +/- 12 pmole/min mg cell protein (37 +/- 6% conjugated) in tip cells. Glucuronidation of 1-naphthol decreased from 495 +/- 23 pmole/min mg cell protein (lower villous cells) to 137 +/- 13 pmole/min mg cell protein (tip cells).