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Objective.The scientific community has considered internal dosimetry by the Monte Carlo method the gold standard. However, there is a trade-off between simulation processing time and the statistical quality of the results that makes it a challenge to obtain accurate absorbed dose values in some situations, such as dose estimation in organs affected by cross-irradiation or limited computing power. Variance reduction techniques are used to reduce computational processing time without impairing the statistical quality of the results, such as tracking energy cutoff, secondary particle production threshold, and parallelism of different types of emissions from radionuclides.Approach.In this work, GATE Monte Carlo code and its variance reduction techniques were evaluated to calculateSvalues of organs from the international commission on radiological protection (ICRP) report 110 male phantom for the lutetium-177, iodine-131, yttrium-90, and radium-223 radionuclides. The results are compared with the data from the OpenDose collaboration.Main results.A cutoff of 5 MeV for local electron deposition and 2.0 mm of secondary particle production range resulted in a computational efficiency increase of 7.9 and 1.05 times, respectively. Simulation of ICRP 107 spectra-based source proved to be about 5 times more efficient when compared to a decay simulation usingG4RadioactiveDecay(Geant4-based radioactive decay processes). Track length estimator (TLE) and split exponential track length estimator (seTLE) techniques were used to calculate the absorbed dose of photon emissions, resulting in computational efficiency up to 29.4 and 62.5 times higher when compared to traditional simulations, respectively. In particular, the seTLE technique accelerates the simulation time by up to 1426 times, achieving a statistical uncertainty of 10% in volumes affected by cross-irradiation.Significance.The variance reduction techniques used in this work drastically reduced the simulation time and maintained the statistical quality of the calculated absorbed dose values, proving the feasibility of the use of the Monte Carlo method in internal dosimetry under challenging situations and making it viable for clinical routine or web applications.

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Background: The pathogenesis of chronic obstructive pulmonary disease (COPD) is associated with oxidative stress. Both iron (Fe) and oxygen are involved in the chemical reactions that lead to increased formation of reactive oxygen species. Oxidative reactions are prevented by antioxidants such as carotenoids. Objective: To study the differences in Fe status, carotenoid levels, healthy eating habits, and markers of inflammation and oxidative damage on proteins in subjects with severe COPD ± long-term oxygen therapy (LTOT) and lung-healthy control subjects. Methods: Sixty-six Caucasians with advanced COPD (28 with LTOT) and 47 control subjects were included. Questionnaires about general health, lifestyle, and dietary habits were answered. Lung function tests and blood sampling were performed. Results: COPD subjects (±LTOT) did not demonstrate increased oxidative damage, assessed by protein carbonylation (PC), while levels of soluble transferrin receptors (sTfRs) were slightly elevated. Soluble TfRs, which is inversely related to Fe status, was negatively associated with PC. Levels of carotenoids, total and ß-cryptoxanthin, α- and ß-carotenes, were significantly lower in COPD subjects, and their diet contained significantly less fruits and vegetables. Lutein correlated inversely with IL-6, lycopene correlated inversely with SAT, while ß-carotene was positively associated with a Mediterranean-like diet. Conclusions: Fe could favor oxidative stress in COPD patients, suggesting a cautious use of Fe prescription to these patients. COPD subjects ate a less healthy diet than control subjects did and would, therefore, benefit by dietary counseling. COPD patients with hypoxemia are probably in particular need of a lycopene-enriched diet.

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BACKGROUND AND AIM: Carotenoids in plasma are inversely associated with cardiovascular risk. Low levels can be explained by low dietary intake but also by a number of other factors including inflammatory activity. Given that matrix metalloproteinase (MMP)-9 has an important role in inflammation and cardiovascular disease, we hypothesized that circulating MMP-9 levels would be inversely related to total or single carotenoids in a general population cohort. METHODS: A well-characterized population-based cohort of 285 Swedish men and women (45-69 years) was used for the present study. The intake of carotenoid-rich fruits and vegetables was estimated from a food frequency questionnaire. Levels of MMP-9, C-reactive protein (CRP), interleukin (IL)-6 and six major carotenoids [ß-cryptoxanthine, α-carotene, ß-carotene, lutein (+zeaxanthin) and lycopene] were determined in plasma. RESULTS: Lower plasma levels of total and single carotenoids were associated with lower dietary intake of carotenoids, older age, male sex, lower physical activity, higher alcohol consumption, higher body mass index (BMI), higher systolic and diastolic blood pressures, lower levels of total cholesterol and HDL cholesterol and higher levels of CRP, IL-6 and MMP-9. After multivariate adjustments, plasma levels of total carotenoids and provitamin A carotenoids (ß-cryptoxanthine, α-carotene and ß-carotene) remained independently associated with sex, dietary intake of carotenoids, BMI, HDL cholesterol and MMP-9, whilst associations with CRP and IL-6 were not maintained. Neither dietary intake of carotenoid-rich fruits and vegetables, nor vitamin supplement use was associated with MMP-9, CRP or IL-6 levels. CONCLUSION: Plasma carotenoids were associated with a variety of factors including age, sex, dietary intake and metabolic variables. A new finding was the independent relationship in plasma between low provitamin A carotenoids and high MMP-9, suggesting a link between these carotenoids, matrix turnover and arterial remodelling.

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BACKGROUND AND AIMS: Carotenoids are potent antioxidants mainly transported in the low density lipoprotein (LDL) fraction. They may also influence the immune response and inverse associations with inflammatory markers have been reported. We investigated whether simvastatin, by exerting both lipid-lowering and anti-inflammatory effects, altered the carotenoid status in plasma. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled study design was applied. Eighty volunteers with mild to moderate hypercholesterolemia received either simvastatin 40 mg or placebo for 6 weeks. Lipids, oxidized LDL (ox-LDL), C-reactive protein (CRP), interleukin (IL)-6, oxygenated carotenoids (lutein, zeaxanthin, ß-cryptoxanthin) and hydrocarbon carotenoids (α-carotene, ß-carotene, lycopene) were measured in plasma. Simvastatin use was associated with significant reductions in total cholesterol, LDL, ox-LDL and CRP. Simvastatin therapy also resulted in reduced plasma levels of both oxygenated and hydrocarbon carotenoids. However, when adjusted for lipids, all carotenoids except ß-cryptoxanthin showed significant increases after simvastatin therapy. Both crude and lipid-adjusted carotenoids were inversely correlated with CRP and IL-6 in plasma but the change in carotenoid status during simvastatin therapy was not specifically related to any changes in inflammatory markers. CONCLUSIONS: To summarize, the change in carotenoid status during simvastatin therapy was mainly attributed to the lowering of cholesterol and not to the suppression of inflammatory activity. After adjustment for lipids, the levels of lutein, lycopene, α-carotene and ß-carotene were significantly increased by simvastatin suggesting an increased ratio of carotenoids per particle.

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We recently showed that Chlamydia pneumoniae activates platelets in vitro, with an associated oxidation of low-density lipoproteins. The aim of this study was to investigate whether C. pneumoniae is released during percutaneous coronary intervention (PCI) and, thereby, causes platelet activation and lipid peroxidation. Seventy-three patients undergoing coronary angiography and following PCI or coronary artery bypass graft (CABG) and 57 controls were included in the study. C. pneumoniae antibodies, serotonin and lipid peroxidation were measured before and 24 h, 1 month and 6 months after angiography. The results show that serum C. pneumoniae IgA concentrations were significantly higher in patients than in the controls. Furthermore, in 38% of the C. pneumoniae IgG positive patients, the C. pneumoniae IgG concentration increased 1 month after PCI. The levels of C. pneumoniae IgG antibodies 1 month after PCI correlated with plasma-lipid peroxidation (r = 0.91, P < 0.0001) and platelet-derived serotonin (r = 0.62, P = 0.02). There was no elevation in the total serum IgG 1 month after PCI. In conclusion, the present results suggest that PCI treatment of coronary stenosis releases C. pneumoniae from the atherosclerotic lesions, which leads to platelet activation and lipid peroxidation.

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OBJECTIVE: Several studies support an association between periodontal disease and atherosclerosis with a crucial role for the pathogen Porphyromonas gingivalis. This study aims at investigating the proteolytic and oxidative activity of P. gingivalis on LDL in a whole blood system using a proteomic approach and analysing the effects of P. gingivalis-modified LDL on cell proliferation. METHODS: The cellular effects of P. gingivalis in human whole blood were assessed using lumi-aggregometry analysing reactive oxygen species production and aggregation. Blood was incubated for 30 min with P. gingivalis, whereafter LDL was isolated and a proteomic approach was applied to examine protein expression. LDL-oxidation was determined by analysing the formation of protein carbonyls. The effects of P. gingivalis-modified LDL on fibroblast proliferation were studied using the MTS assay. RESULTS: Incubation of whole blood with P. gingivalis caused an extensive aggregation and ROS production, indicating platelet and leucocyte activation. LDL prepared from bacteria-exposed blood showed an increased protein oxidation, elevated levels of apoM and formation of two apoB-100 N-terminal fragments. Porphyromonas gingivalis-modified LDL markedly increased the growth of fibroblasts. Inhibition of gingipain R suppressed the modification of LDL by P. gingivalis. CONCLUSIONS: The ability of P. gingivalis to change the protein expression and proliferative capacity of LDL may represent a crucial event in periodontitis-associated atherosclerosis.

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Psychosocial factors and interleukin-6 (IL-6) levels are both related to risk of morbidity and mortality. The aim of this study was to investigate how a broad range of psychosocial factors related to levels of IL-6 in different media. Fifty-nine men and women aged 30-65 were recruited from a larger study and selected to cover a broad range of psychosocial status. IL-6 levels were analyzed in serum, in saliva collected at home at three different time points during a day, and in the supernatant of cell cultures stimulated in vitro with lipopolysaccharide. After adjustments for age, gender, self-reported health problems, and lifestyle factors, IL-6-levels in serum were negatively correlated with coping and self-esteem, and positively correlated with cynicism, hostile affect, hopelessness, depression, and vital exhaustion. In saliva samples, at all time points, IL-6 levels were positively correlated to cynicism, and IL-6 levels 30 min after awakening were also positively correlated with hopelessness, depression, and vital exhaustion. After adjustment for age and gender, cynicism, depression, and vital exhaustion were negatively correlated to IL-6 levels in the supernatant of cell cultures stimulated in vitro with lipopolysaccharide, but this effect was lost after control for self-reported health problems and lifestyle factors. In conclusion, we found that IL-6 levels in serum and saliva were negatively related to psychosocial resources and positively related to psychosocial risk factors. These data strengthen the argument that IL-6 is involved in mediating the risk for disease development that has been associated with psychosocial factors.

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OBJECTIVES: Acrylate-styrene copolymer polish has been used to protect the surface of linoleum flooring since the 1960s. Problems with powdering of floor polish were observed at an early stage. In a secondary school in Linköping, Sweden, this phenomenon occurred in the winter of 1994-1995 and the pupils frequently reported irritative symptoms from the eyes and airways. This study was undertaken to assess the potential effect of powdering floor polish on the mucous membranes of the eyes and respiratory tract. METHODS: Repeated questionnaire-based surveys were conducted with identical questions in the spring of 1995 (during the powdering period) and in the autumn of 1995 (after the polish was removed). The questions dealt with irritative symptoms from the nose, eye, throat and lower respiratory tract. RESULTS: A preventive effect related to the removal of polish was found for irritative symptoms in all locations mentioned above, but was particularly clear for the lower respiratory tract (prevalence rate ratio = 0.37, 95% CI = 0.23-0.59). CONCLUSIONS: The results of this study indicate that the powdering of floor polish may cause irritative symptoms from the eyes and airways in school children.

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Exposure to zinc fume may cause metal fume fever, an acute reaction characterized by an invasion of neutrophils into the airways. This investigation was conducted to examine the possibility that Zn2+ and ZnO might stimulate the formation of oxygen radicals by human neutrophils. Luminol-amplified chemiluminescence (CL) was monitored during 2 h from human neutrophils exposed to Zn2+ or ZnO. The response was compared to that of other metal ions and to that of endotoxin and phorbol myristate acetate (PMA). Zn2+ (6-50 microM) gradually caused a 2-6-fold increase of CL that reached an optimum after 70- 80 min. By contrast, Cd2+, Cr2+, Cr3+, Fe2+, Fe3+, Ni2+ or Co2+ in corresponding concentrations did not increase the CL. Similar to Zn2+, endotoxin (40-640 micrograms/ml) caused a 2-5-fold increase of CL with an optimum after 70 min, and endotoxin (40 micrograms/ml) together with Zn2+ (50 microM) synergistically increased the CL. ZnO (12-100 micrograms/ml) also augmented CL, with a 1.5-5-fold increase at 25-100 micrograms/ml ZnO but with a time response similar to that found after PMA stimulation, in which CL peaked after 20-40 min incubation. Both Zn(2+)- and ZnO-induced CL was inhibited by manoalide, a phospholipase A2 inhibitor, with IC50 of 0.25 microM and 0.66 microM respectively. These results indicate that Zn2+ and ZnO both stimulates oxygen radical formation in human neutrophils and that this might contribute to the pathogenesis of zinc fume fever.

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Beta-glucans are known for their potent ability to induce nonspecific inflammatory reactions and are believed to play a role in bioaerosol-induced respiratory symptoms seen in both occupational and residential environments. Here, the ability of a (1→3)-ß-d-glucan (Curdlan) to stimulate nitric oxide generation and cytokine mRNA expression in rat alveolar macrophages (AMs) and the murine monocyte/macrophage cell line, RAW 264.7 was investigated. Exposure to (1→3)-ß-d-glucan (20, 100 and 500 µg/ml) induced a dose-dependent increase in the expression of inducible nitric oxide synthase mRNA and a release of nitric oxide into the culture medium in both rat AMs and RAW 264.7 cells. The mRNA expression of a number of other inflammatory mediators such as interleukin-1ß, interleukin-6, tumor necrosis factor-α and cyclooxygenase-2 was also increased by the exposure to ß-glucan. The capability of (1→3)-ß-d-glucan (500 µg/ml) to induce mRNA synthesis of these various mediators were comparable to that of endotoxin (1 µg/ml). These results imply that (1→3)-ß-d-glucan stimulates the generation of nitric oxide, cytokines and prostaglandins in macrophages and suggest the possibility that this may contribute to bioaerosol-induced respiratory symptoms seen in exposed individuals.

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Nitric oxide (NO) has a number of important functions in biological systems and may play a role in the toxicity of mineral fibers. We investigated whether NO might be present on the surface of mineral fibers and if crocidolite could adsorb NO from NO gas or cigarette smoke. NO was determined with a new gas chromatography-ultraviolet spectrophotometric technique after thermal desorption from the fiber surface and injection in a gas flow cell. NO was found in different amounts on chrysotile B, crocidolite, amosite, and silicon carbide whiskers. There was a strong correlation between the amount of NO and the specific surface area of these fibers (r = 0.98). NO could not be demonstrated on rockwool fibers [man-made vitreous fiber(s) (MMVF)21 and MMVF22] or silicon nitride whiskers. NO on crocidolite, amosite, and silicon carbide whiskers was readily desorbed from the fibers at increased temperature, while NO on chrysotile B seemed to be more firmly adsorbed to the fiber and required a longer period of time to be desorbed. The amount of NO bound to crocidolite increased from 34 micrograms/g fiber to 85 and 474 micrograms/g after exposing the fibers to cigarette smoke and NO gas, respectively. These findings indicate that a) NO adsorbs to fiber surfaces, b) some fibers adsorb more NO than others, c) some fibers adsorb NO more strongly than others, and d) the amounts of NO on fibers may be increased after exposure of the fiber to cigarette smoke or other sources of NO. The biological significance of NO on mineral fibers remains to be investigated.

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The objectives of this work were to investigate the toxicity of silicon carbide whiskers and powders and silicon nitride whiskers and powders and to compare their toxicity with the toxicity of crocidolite. The effects studied were inhibition of the cloning efficiency of V79 cells, formation of DNA strand breaks by means of a nick translation assay, formation of oxygen radicals in three different assays, and the ability to stimulate neutrophils to produce hydroxyl radicals. All materials showed concentration-dependent inhibition of the cloning efficiency of V79 cells. The inhibition by the most toxic whiskers was in the same order of magnitude as that of crocidolite. Milled whiskers and powders were less toxic than the whiskers. There was a high DNA breaking potential for crocidolite and four of the silicon carbide whiskers and a rather low one for the other materials. Formation of hydroxyl radicals was found for crocidolite and one of the silicon carbide whiskers. In the neutrophil activation test, there was a great variation in the different materials' abilities to activate neutrophils. There was also a good correlation between chemiluminescence and H2O2 formation. The highest activation was found in neutrophils exposed to two of the silicon carbide whiskers and one milled whisker. The conclusion of the investigation is that some of the ceramic materials studied had damaging biological effects comparable to or greater than those of crocidolite. The results from the investigation clearly imply that caution is needed in the introduction of new ceramic fiber materials, so that the correct precautions and protective devices are used in order to avoid harm to the personnel handling the material.

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The influence of green tea polyphenols (GTP) on the formation of DNA strand breaks (DNA-SB) and lipid peroxidation products (LPP) in cultured human lung cells (A 549) exposed to different oxidants was investigated. Cells were pretreated with GTP for 2 h and then exposed to cigarette smoke solution, H2O2 or FeCl3 for 30 min. After exposure, the cells were analyzed for DNA-SB, LPP, and viability. In addition, the effects of GTP added directly to the incubation mixtures during exposure were examined, using the same end points. It appeared that pretreatment with GTP inhibited both cigarette smoke- and H2O2-induced DNA breakage; i.e., following exposure to cigarette smoke or H2O2, the fraction of DNA passing through a microfilter increased significantly in cells not subjected to GTP, but this effect was prevented or inhibited in GTP-treated cells. Pretreatment with GTP also reduced the overall toxicity of H2O2 as determined by cell growth after exposure. Moreover, addition of GTP during exposure reduced both cigarette smoke- and H2O2-induced DNA breakage as well as formation of LPP after exposure to Fe3+. These results indicate that GTP inhibit the formation of DNA-SB in cells exposed to oxidants. It is possible that this ability to GTP to inhibit DNA-SB formation might contribute to the antitumorogenic properties of green tea.

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The formation of DNA-strand breaks was studied in cultured human lung cells (A 549) subjected to iron, either in the form of iron(III) citrate or in combination with the metal chelators ethylene diamine tetra-acetic acid (EDTA), nitrilo triacetic acid (NTA), or 8-hydroxyquinoline (8HQ). After 15 min exposure to 5 microM iron(III) citrate or iron chelate, the cellular levels of iron were found to be three times higher in cells subjected to iron-8HQ than in cells subjected to iron(III) citrate, iron-EDTA or iron-NTA. Exposure to iron-8HQ caused extensive DNA-strand breakage, whereas no such breakage was found in cells exposed to iron-EDTA or iron-NTA. The DNA damage caused by iron-8HQ increased with time and dose, and DNA-strand breakage was clearly demonstrable in cells after 15 min exposure to as little as 0.1 microM iron-8HQ. Moreover, iron-8HQ was strongly toxic to the cells and inhibited their growth after exposure. Along with the formation of DNA-strand breaks, the concentration of cellular malondialdehyde increased four-fold after exposure to iron-8HQ and two-fold after exposure to iron-EDTA or iron-NTA, suggesting that reactive oxygen metabolites might be involved in the toxic action. Moreover, both iron-EDTA and iron-NTA caused a considerable hydroxylation of deoxyguanosine (dG) residues in DNA in vitro, whereas iron(III) citrate and iron-8HQ only caused a minor hydroxylation of dG. This points to the possibility that iron-8HQ-mediated DNA-strand breakage in cells might be due to the action of a metal-bound oxyl radical formed from the iron-8HQ complex rather than to the formation of hydroxyl radicals. Altogether, these findings indicate that iron bound to the lipophilic chelator, 8HQ, has strong toxic properties and that it may cause substantial DNA-strand breakage and lipid peroxidation in living cells.

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Occupational exposure to hard metal dust may cause interstitial pulmonary fibrosis and asthma. The cause of asthma is well established, whereas the cause of lung fibrosis is still under debate. Recently, slightly reduced airborne tunsten oxide fibres, the role of which in hard metal pneumoconiosis has never been accounted for, were detected in an air sample from a hard metal production plant. In this study, the capacity to generate hydroxyl radicals, toxicity to cultured human lung cells and haemolytic activity of tungsten oxide fibres were compared with crocidolite asbestos fibres. The results show (a) that tungsten oxide fibres can generate hydroxyl radicals, and (b) that tunsten oxide fibres were more cytotoxic to human lung cells than was crocidolite, but (c) that the haemolytic activity of tungsten oxide fibres was lower than for crocidolite.

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The ability of the heterocyclic compound EDU (N-[2-(2-oxo-1-imidazolindinyl)-ethyl]-N'-phenylurea) to affect polymorphonuclear leukocyte (PMNL) activation was examined by measuring superoxide anion, hydrogen peroxide and hydroxyl radical release from human PMNLs stimulated by phorbol ester. Results demonstrated that EDU effectively interferes with PMNLs reactive oxygen intermediate production, making it a potentially useful compound to be used to modulate PMNL-associated oxidant damage of inflamed tissues.

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We have investigated the ability of aqueous cigarette tar extracts to promote human polymorphonuclear leukocyte (PMNL)- and hydrogen peroxide (H2O2)-induced DNA single-strand breaks (DNA-SSB) in cultured human lung cells. Tar extract itself did not cause any DNA-SSB formation, whereas PMNL (activated with phorbol myristate acetate (PMA)) and H2O2 both caused a small but significant DNA-SSB formation on their own. On the other hand, if cells were first treated with tar extract and then exposed to PMA-activated PMNL or H2O2, the DNA-SSB formation increased considerably. Pretreatment with iron-loaded tar extracts caused a greater increase after PMNL exposure than pretreatment with regular tar extracts. No DNA-SSB formation was found if catalase was present during the PMNL exposure, indicating that H2O2 was important for the PMNL-induced DNA damage. These findings suggest that cigarette tar promotes neutrophil-induced DNA damage in human lung cells and that this effect can be further potentiated by iron. This can be of importance in explaining the carcinogenic effects of cigarette smoking and the increased risk of lung cancer among asbestos workers and iron miners who smoke.

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A simple method for detection of DNA single-strand breaks (DNA-SSB) in cultured cells is described, based on filtration of alkaline-lysed cells through microfilters. After exposure to potentially DNA damaging agents, the cells are transferred to 0.8 micron cellulose acetate filters mounted in microfilter devices where they are washed, lysed and centrifuged to separate undamaged DNA from damaged DNA. When human bronchiolar cells (14Br) were exposed to different DNA damaging agents, hydrogen peroxide, N-methyl-N-nitro-N-nitrosoguanidine or 4-nitroquinoline-1-oxide, there was good correlation between the extent of DNA damage assessed by this filtration technique and by DNA precipitation assay. DNA-SSB were also detected by the filtration technique after exposure of bronchiolar cells to phorbol ester-stimulated human neutrophils. The filtration assay is easy to perform, the sample handling capacity is very high, and no expensive or complicated laboratory equipment is required. It may therefore be an alternative, or a complement, to other methods for detection of DNA-SSB.

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In relation to their potential genotoxic properties, the ability of inorganic particles to induce activated species of oxygen with strong oxidative properties can be studied by various methods. In this study the oxidative surface properties of 10 different natural and synthetic mineral fibres were investigated by: (1) an electron paramagnetic resonance technique in which formate was used to trap oxidative species; and (2) a high performance liquid chromatography (HPLC) based method in which deoxyguanosine was used as a trapping agent and the formation of 8-hydroxy-deoxyguanosine (8 OHdG) was analysed. Ground iron-containing fibres such as crocidolite and amosite were the most reactive, whereas fibres without iron--for example, ceramic fibres, xonotlite, and Tismo L--were completely inactive. A good correlation was found when the results from the two methods were compared (r = 0.86).

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