Apolar Extracts of St. John's Wort Alleviate the Effects of ß-Amyloid Toxicity in Early Alzheimer's Disease.

Hypericum perforatum (St. John's wort) has been described to be beneficial for the treatment of Alzheimer's disease (AD). Different extractions have demonstrated efficiency in mice and humans, esp. extracts with a low hypericin and hyperforin content to reduce side effects such as phototoxicity. In order to systematically elucidate the therapeutic effects of H. perforatum extracts with different polarities, APP-transgenic mice were treated with a total ethanol extract (TE), a polar extract obtained from TE, and an apolar supercritical CO2 (scCO2) extract. The scCO2 extract was formulated with silicon dioxide (SiO2) for better oral application. APP-transgenic mice were treated with several extracts (total, polar, apolar) at different concentrations. We established an early treatment paradigm from the age of 40 days until the age of 80 days, starting before the onset of cerebral ß-amyloid (Aß) deposition at 45 days of age. Their effects on intracerebral soluble and insoluble Aß were analyzed using biochemical analyses. Our study confirms that the scCO2H. perforatum formulation shows better biological activity against Aß-related pathological effects than the TE or polar extracts. Clinically, the treatment resulted in a dose-dependent improvement in food intake with augmentation of the body weight, and, biochemically, it resulted in a significant reduction in both soluble and insoluble Aß (-27% and -25%, respectively). We therefore recommend apolar H. perforatum extracts for the early oral treatment of patients with mild cognitive impairment or early AD.

Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.

PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.

Influence of quartz exposure on lung cancer types in cases of lymph node-only silicosis and lung silicosis in German uranium miners.

Inhaled crystalline quartz is a carcinogen. Analyses show differences in the distribution of lung cancer types depending on the status of silicosis. Using 2,524 lung tumor cases from the WISMUT autopsy repository database, silicosis was differentiated into cases without silicosis in lung parenchyma and its lymph nodes, with lymph node-only silicosis, or with lung silicosis including lymph node silicosis. The proportions of adenocarcinoma, squamous cell carcinoma, and small-cell lung carcinoma mortality for increasing quartz exposures were estimated in a multinomial logistic regression model. The relative proportions of the lung cancer subtypes in lymph node-only silicosis were more similar to lung silicosis than without any silicosis. The results support the hypothesis that quartz-related carcinogenesis in case of lymph node-only silicosis is more similar to that in lung silicosis than in without silicosis.

Association of exposure to manganese and iron with striatal and thalamic GABA and other neurometabolites - Neuroimaging results from the WELDOX II study.

OBJECTIVE: Magnetic resonance spectroscopy (MRS) is a non-invasive method to quantify neurometabolite concentrations in the brain. Within the framework of the WELDOX II study, we investigated the association of exposure to manganese (Mn) and iron (Fe) with γ-aminobutyric acid (GABA) and other neurometabolites in the striatum and thalamus of 154 men. MATERIAL AND METHODS: GABA-edited and short echo-time MRS at 3T was used to assess brain levels of GABA, glutamate, total creatine (tCr) and other neurometabolites. Volumes of interest (VOIs) were placed into the striatum and thalamus of both hemispheres of 47 active welders, 20 former welders, 36 men with Parkinson's disease (PD), 12 men with hemochromatosis (HC), and 39 male controls. Linear mixed models were used to estimate the influence of Mn and Fe exposure on neurometabolites while simultaneously adjusting for cerebrospinal fluid (CSF) content, age and other factors. Exposure to Mn and Fe was assessed by study group, blood concentrations, relaxation rates R1 and R2* in the globus pallidus (GP), and airborne exposure (active welders only). RESULTS: The median shift exposure to respirable Mn and Fe in active welders was 23µg/m3 and 110µg/m3, respectively. Airborne exposure was not associated with any other neurometabolite concentration. Mn in blood and serum ferritin were highest in active and former welders. GABA concentrations were not associated with any measure of exposure to Mn or Fe. In comparison to controls, tCr in these VOIs was lower in welders and patients with PD or HC. Serum concentrations of ferritin and Fe were associated with N-acetylaspartate, but in opposed directions. Higher R1 values in the GP correlated with lower neurometabolite concentrations, in particular tCr (exp(ß)=0.87, p<0.01) and choline (exp(ß)=0.84, p=0.04). R2* was positively associated with glutamate-glutamine and negatively with myo-inositol. CONCLUSIONS: Our results do not provide evidence that striatal and thalamic GABA differ between Mn-exposed workers, PD or HC patients, and controls. This may be due to the low exposure levels of the Mn-exposed workers and the challenges to detect small changes in GABA. Whereas Mn in blood was not associated with any neurometabolite content in these VOIs, a higher metal accumulation in the GP assessed with R1 correlated with generally lower neurometabolite concentrations.

Combusting vegetable oils in diesel engines: the impact of unsaturated fatty acids on particle emissions and mutagenic effects of the exhaust.

High particle emissions and strong mutagenic effects were observed after combustion of vegetable oil in diesel engines. This study tested the hypothesis that these results are affected by the amount of unsaturated or polyunsaturated fatty acids of vegetable oils. Four different vegetable oils (coconut oil, CO; linseed oil, LO; palm tree oil, PO; and rapeseed oil, RO) and common diesel fuel (DF) were combusted in a heavy-duty diesel engine. The exhausts were investigated for particle emissions and mutagenic effects in direct comparison with emissions of DF. The engine was operated using the European Stationary Cycle. Particle masses were measured gravimetrically while mutagenicity was determined using the bacterial reverse mutation assay with tester strains TA98 and TA100. Combustion of LO caused the largest amount of total particulate matter (TPM). In comparison with DF, it particularly raised the soluble organic fraction (SOF). RO presented second highest TPM and SOF, followed by CO and PO, which were scarcely above DF. RO revealed the highest number of mutations of the vegetable oils closely followed by LO. PO was less mutagenic, but still induced stronger effects than DF. While TPM and SOF were strongly correlated with the content of polyunsaturated fatty acids in the vegetable oils, mutagenicity had a significant correlation with the amount of total unsaturated fatty acids. This study supports the hypothesis that numbers of double bounds in unsaturated fatty acids of vegetable oils combusted in diesel engines influence the amount of emitted particles and the mutagenicity of the exhaust. Further investigations have to elucidate the causal relationship.

Component-resolved diagnosis of baker's allergy based on specific IgE to recombinant wheat flour proteins.

BACKGROUND: Sensitization to wheat flour plays an important role in the development and diagnosis of baker's asthma. OBJECTIVES: We evaluated wheat allergen components as sensitizers for bakers with work-related complaints, with consideration of cross-reactivity to grass pollen. METHODS: Nineteen recombinant wheat flour proteins and 2 cross-reactive carbohydrate determinants were tested by using CAP-FEIA in sera of 101 bakers with wheat flour allergy (40 German, 37 Dutch, and 24 Spanish) and 29 pollen-sensitized control subjects with wheat-specific IgE but without occupational exposure. IgE binding to the single components was inhibited with wheat flour, rye flour, and grass pollen. The diagnostic efficiencies of IgE tests with single allergens and combinations were evaluated by assessing their ability to discriminate between patients with baker's allergy and control subjects based on receiver operating characteristic analyses. RESULTS: Eighty percent of bakers had specific IgE levels of 0.35 kUA/L or greater and 91% had specific IgE levels of 0.1 kUA/L or greater to at least one of the 21 allergens. The highest frequencies of IgE binding were found for thiol reductase (Tri a 27) and the wheat dimeric α-amylase inhibitor 0.19 (Tri a 28). Cross-reactivity to grass pollen was proved for 9 components, and cross-reactivity to rye flour was proved for 18 components. A combination of IgE tests to 5 components, Tri a 27, Tri a 28, tetrameric α-amylase inhibitor CM2 (Tri a 29.02), serine protease inhibitor-like allergen (Tri a 39), and 1-cys-peroxiredoxin (Tri a 32), produced the maximal area under the curve (AUC = 0.84) in receiver operating characteristic analyses, but this was still lower than the AUC for wheat- or rye flour-specific IgE (AUC = 0.89 or 0.88, respectively). CONCLUSIONS: Component-resolved diagnostics help to distinguish between sensitization caused by occupational flour exposure and wheat seropositivity based on cross-reactivity to grass pollen. For routine diagnosis of baker's allergy, however, allergen-specific IgE tests with whole wheat and rye flour extracts remain mandatory because of superior diagnostic sensitivity.

Combustion of hydrotreated vegetable oil and jatropha methyl ester in a heavy duty engine: emissions and bacterial mutagenicity.

Research on renewable fuels has to assess possible adverse health and ecological risks as well as conflicts with global food supply. This investigation compares the two newly developed biogenic diesel fuels hydrotreated vegetable oil (HVO) and jatropha methyl ester (JME) with fossil diesel fuel (DF) and rapeseed methyl ester (RME) for their emissions and bacterial mutagenic effects. Samples of exhaust constituents were compared after combustion in a Euro III heavy duty diesel engine. Regulated emissions were analyzed as well as particle size and number distributions, carbonyls, polycyclic aromatic hydrocarbons (PAHs), and bacterial mutagenicity of the exhausts. Combustion of RME and JME resulted in lower particulate matter (PM) compared to DF and HVO. Particle numbers were about 1 order of magnitude lower for RME and JME. However, nitrogen oxides (NOX) of RME and JME exceeded the Euro III limit value of 5.0 g/kWh, while HVO combustion produced the smallest amount of NOX. RME produced the lowest emissions of hydrocarbons (HC) and carbon monoxide (CO) followed by JME. Formaldehyde, acetaldehyde, acrolein, and several other carbonyls were found in the emissions of all investigated fuels. PAH emissions and mutagenicity of the exhausts were generally low, with HVO revealing the smallest number of mutations and lowest PAH emissions. Each fuel showed certain advantages or disadvantages. As proven before, both biodiesel fuels produced increased NOX emissions compared to DF. HVO showed significant toxicological advantages over all other fuels. Since jatropha oil is nonedible and grows in arid regions, JME may help to avoid conflicts with the food supply worldwide. Hydrogenated jatropha oil should now be investigated if it combines the benefits of both new fuels.

NOTCH1, HIF1A and other cancer-related proteins in lung tissue from uranium miners--variation by occupational exposure and subtype of lung cancer.

BACKGROUND: Radon and arsenic are established pulmonary carcinogens. We investigated the association of cumulative exposure to these carcinogens with NOTCH1, HIF1A and other cancer-specific proteins in lung tissue from uranium miners. METHODOLOGY/PRINCIPAL FINDINGS: Paraffin-embedded tissue of 147 miners was randomly selected from an autopsy repository by type of lung tissue, comprising adenocarcinoma (AdCa), squamous cell carcinoma (SqCC), small cell lung cancer (SCLC), and cancer-free tissue. Within each stratum, we additionally stratified by low or high level of exposure to radon or arsenic. Lifetime exposure to radon and arsenic was estimated using a quantitative job-exposure matrix developed for uranium mining. For 22 cancer-related proteins, immunohistochemical scores were calculated from the intensity and percentage of stained cells. We explored the associations of these scores with cumulative exposure to radon and arsenic with Spearman rank correlation coefficients (r(s)). Occupational exposure was associated with an up-regulation of NOTCH1 (radon r(s) = 0.18, 95% CI 0.02-0.33; arsenic: r(s) = 0.23, 95% CI 0.07-0.38). Moreover, we investigated whether these cancer-related proteins can classify lung cancer using supervised and unsupervised classification. MUC1 classified lung cancer from cancer-free tissue with a failure rate of 2.1%. A two-protein signature discriminated SCLC (HIF1A low), AdCa (NKX2-1 high), and SqCC (NKX2-1 low) with a failure rate of 8.4%. CONCLUSIONS/SIGNIFICANCE: These results suggest that the radiation-sensitive protein NOTCH1 can be up-regulated in lung tissue from uranium miners by level of exposure to pulmonary carcinogens. We evaluated a three-protein signature consisting of a physiological protein (MUC1), a cancer-specific protein (HIF1A), and a lineage-specific protein (NKX2-1) that could discriminate lung cancer and its major subtypes with a low failure rate.

Association between lymph node silicosis and lung silicosis in 4,384 German uranium miners with lung cancer.

This study investigates the association between lymph node-only and lung silicosis in uranium miners with lung cancer and exposure to quartz dust. Tissue slides of 4,384 German uranium miners with lung cancer were retrieved from an autopsy archive and reviewed by 3 pathologists regarding silicosis in the lungs and lymph nodes. Cumulative exposure to quartz dust was assessed with a quantitative job-exposure matrix. The occurrence of silicosis by site was investigated with regression models for exposure to quartz dust. Miners with lung silicosis had highest cumulative quartz exposure, followed by lymph node-only silicosis and no silicosis. At a cumulative quartz exposure of 40 mg/m(3) × years, the probability of lung silicosis was above 90% and the likelihood of lymph node-only silicosis and no silicosis do not differ anymore. The results support that lymph node silicosis can precede lung silicosis, at least in a proportion of subjects developing silicosis, and that lung silicosis strongly depends on the cumulative quartz dose.

Major histopathological patterns of lung cancer related to arsenic exposure in German uranium miners.

OBJECTIVE: The mechanisms of action of arsenic in the development of lung cancer are still not yet elucidated. Considering the relationship between arsenic and squamous cell carcinomas of the skin, we hypothesized that arsenic exposure may be more closely associated with squamous cell carcinoma of the lung. METHODS: A comprehensive histopathological database and a detailed job-exposure matrix developed for former German uranium miners with exposure to arsenic, radon, and quartz were analyzed to quantitatively assess the effect of arsenic regarding cell type of lung cancer. The distributions of major lung cancer cell types in 1,786 German uranium miners were associated with levels of arsenic exposure under control for the other lung carcinogens. To evaluate the arsenic effects in association with a frequent occupational lung disease in miners stratification by silicosis was performed. RESULTS: There was an arsenic-related increase of the proportion of squamous cell carcinoma of the lung but restricted to miners without silicosis. The increase was found at all levels of co-exposure to radon and quartz dust. In miners with silicosis, the proportion of adenocarcinoma increased with rising arsenic exposure. Arsenic exposure was associated with non-small cell lung cancer. Silicosis turned out as major determinant of the cell type related with arsenic. CONCLUSION: These results indicate a cell type characteristic effect of arsenic in the development of lung cancer.

A study on lung cancer mortality related to radon, quartz, and arsenic exposures in German uranium miners.

Between 1946 and 1990 uranium mining was undertaken on a large scale in East Germany. This study evaluates the proportional lung cancer risk of German uranium miners from radon, quartz, and arsenic exposure during mining operations at the WISMUT Corporation. The database of the WISMUT tissue repository and a comprehensive job-exposure matrix were used to compare exposure levels of lung cancer cases with deaths from diseases of the circulatory system for risk analysis. In addition, the ratio of lung cancer cases was compared to cases from diseases of the circulatory system to the corresponding ratio in the general population. The proportional lung cancer mortality of German uranium miners was 2.9-fold higher than in the general population of East Germany. Cumulative radon, quartz, and arsenic exposure were determined as risk factors for lung cancer among German uranium miners, where silicosis modified the risk of cumulative radon and quartz exposure. Silicotics were exposed to higher levels of quartz, radon, and arsenic than nonsilicotics. Because selection of the study population was based on a tissue repository, the results need to be interpreted with caution.

Strong mutagenic effects of diesel engine emissions using vegetable oil as fuel.

Diesel engine emissions (DEE) are classified as probably carcinogenic to humans. In recent years every effort was made to reduce DEE and their content of carcinogenic and mutagenic polycyclic aromatic compounds. Since 1995 we observed an appreciable reduction of mutagenicity of DEE driven by reformulated or newly designed fuels in several studies. Recently, the use of rapeseed oil as fuel for diesel engines is rapidly growing among German transportation businesses and agriculture due to economic reasons. We compared the mutagenic effects of DEE from two different batches of rapeseed oil (RSO) with rapeseed methyl ester (RME, biodiesel), natural gas derived synthetic fuel (gas-to-liquid, GTL), and a reference diesel fuel (DF). The test engine was a heavy-duty truck diesel running the European Stationary Cycle. Particulate matter from the exhaust was sampled onto PTFE-coated glass fibre filters and extracted with dichloromethane in a soxhlet apparatus. The gas phase constituents were sampled as condensates. The mutagenicity of the particle extracts and the condensates was tested using the Salmonella typhimurium/mammalian microsome assay with tester strains TA98 and TA100. Compared to DF the two RSO qualities significantly increased the mutagenic effects of the particle extracts by factors of 9.7 up to 59 in tester strain TA98 and of 5.4 up to 22.3 in tester strain TA100, respectively. The condensates of the RSO fuels caused an up to factor 13.5 stronger mutagenicity than the reference fuel. RME extracts had a moderate but significant higher mutagenic response in assays of TA98 with metabolic activation and TA100 without metabolic activation. GTL samples did not differ significantly from DF. In conclusion, the strong increase of mutagenicity using RSO as diesel fuel compared to the reference DF and other fuels causes deep concern on future usage of this biologic resource as a replacement of established diesel fuels.

Influence of fuel properties, nitrogen oxides, and exhaust treatment by an oxidation catalytic converter on the mutagenicity of diesel engine emissions.

Particle emissions of diesel engines (DEP) content polycyclic aromatic hydrocarbons (PAH) these compounds cause a strong mutagenicity of solvent extracts of DEP. We investigated the influence of fuel properties, nitrogen oxides (NO( x )), and an oxidation catalytic converter (OCC) on the mutagenic effects of DEP. The engine was fuelled with common diesel fuel (DF), low-sulphur diesel fuel (LSDF), rapeseed oil methyl ester (RME), and soybean oil methyl ester (SME) and run at five different load modes in two series with and without installation of an OCC in the exhaust pipe. Particles from the cooled and diluted exhaust were sampled onto glass fibre filters and extracted with dichloromethane in a soxhlet apparatus. The mutagenicity of the extracts was tested using the Salmonella typhimurium/mammalian microsome assay with tester strains TA98 and TA100. Without OCC the number of revertant colonies was lower in extracts of LSDF than in extracts of DF. The lowest numbers of revertant colonies were induced by the plant oil derived fuels. In three load modes, operation with the OCC led to a reduction of the mutagenicity. However, direct mutagenic effects under heavy duty conditions (load mode A) were significantly increased for RME (TA98, TA100) and SME (TA98). A consistent but not significant increase in direct mutagenicity was observed for DF and LSDF at load mode A, and for DF at idling (load mode E) when emissions were treated with the OCC. These results raise concern over the use of oxidation catalytic converters with diesel engines. We hypothesise that the OCC increases formation of direct acting mutagens under certain conditions by the reaction of NO( x ) with PAH resulting in the formation of nitrated-PAH. Most of these compounds are powerful direct acting mutagens.

Role of exposure to radon and silicosis on the cell type of lung carcinoma in German uranium miners.

BACKGROUND: In East Germany, uranium mining was undertaken on a large scale from 1946 to 1990. Poor working conditions led to a high level of exposure to ionizing radiation and quartz dust. This analysis evaluates the histopathology of lung carcinoma in uranium miners in relation to radon exposure and silicosis. METHODS: A database developed for autopsy cases ascertained in a pathological tissue repository of German uranium miners was used to estimate odds ratios for developing lung carcinoma by major cell type with regard to radon exposure and silicosis. Silicosis information was extracted from autopsy protocols. Working level months (WLM) were calculated with a job-exposure matrix to assess lifetime radon exposure. Risk estimates were based on 3414 male miners who died from small cell lung carcinoma (SCLC, n = 1446), squamous cell carcinoma (SqCC, n = 1006), or adenocarcinoma (AC, n = 962) between 1957 and 1990. RESULTS: SCLC and SqCC seem more likely to be associated with high radon exposure than AC. Mean cumulative radon exposure was 868 (SD 631) WLM in SCLC, 871 (SD 652) WLM in SqCC, and 743 (SD 598) WLM in AC. Silicosis prevalence was 26% in SCLC, 38% in SqCC, and 30% in AC. In silicotics, AC and SqCC had a relatively higher frequency at the expense of SCLC. SCLC occurred earlier than AC and SqCC. CONCLUSION: High radon exposure was associated with a higher relative frequency of SCLC and SqCC than AC. Silicosis tended to increase the appearance of SqCC and AC.