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  • Klionsky, Daniel J, et al. (författare)
  • Guidelines for the use and interpretation of assays for monitoring autophagy
  • 2012
  • Ingår i: Autophagy. - Landes Bioscience. - 1554-8635. ; 8:4, s. 445-544
  • Forskningsöversikt (refereegranskat)abstract
    • In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
  • Fratiglioni, Laura, et al. (författare)
  • Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
  • 2017
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 49:9, s. 1373-
  • Tidskriftsartikel (refereegranskat)abstract
    • We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 x 10(-4)) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 x 10(-8)) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p. Pro522Arg, P = 5.38 x 10(-10), odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p. Ser209Phe, P = 4.56 x 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p. Arg62His, P = 1.55 x 10(-14), OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
  • Albin, Maria, et al. (författare)
  • Aktuella arbets- och miljömedicinska problem
  • 2010
  • Ingår i: Arbets- och miljömedicin - en lärobok om hälsa och miljö. - Studentlitteratur AB. - 978-91-44-05399-8 ; s. 165-176
  • Bokkapitel (refereegranskat)
  • Edling, Christer, et al. (författare)
  • Arbets- och miljömedicin- begrepp och trender
  • 2009
  • Ingår i: Arbets- och miljömedicin - en lärobok om hälsa och miljö. - Studentlitteratur AB. - 978-91-44-05399-8 ; s. 13-24
  • Bokkapitel (refereegranskat)
  • Albin, Maria, et al. (författare)
  • Risk Assessment for Carbon Nanotubes
  • 2011
  • Ingår i: Arbete och hälsa. - Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg. - 0346-7821. ; 45:5, s. 1-1
  • Konferensbidrag (refereegranskat)
  • Hedmer, Maria, et al. (författare)
  • Diesel Exhaust Exposure Assessment Among Tunnel Construction Workers—Correlations Between Nitrogen Dioxide, Respirable Elemental Carbon, and Particle Number
  • 2017
  • Ingår i: Annals of Work Exposures and Health. - Oxford University Press. - 2398-7308. ; 61:5, s. 539-553
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Occupational exposure to diesel exhaust is common due the widespread use of dieselpowered combustion engines. Diesel exhaust is chemically complex and consists of thousands of compounds present as gases and particulate matter. Both nitrogen dioxide (NO2) and elemental carbon (EC) have been used as markers for diesel exhaust exposure. Currently EC is regarded as the best surrogate of diesel exhaust. The objective was to quantify the occupational exposure to diesel exhaust in underground tunnel construction work using a multi-metric approach, and to investigate the correlations between NO2, respirable EC, respirable organic carbon (OC), respirable total carbon (TC), respirable dust (RD), and particle number. Also, the use of NO2 as a proxy for diesel exhaust was evaluated, how much of the variability in the diesel exhaust exposure was attributed to within and between individual factors and if there was a difference between expert and self-administered measurements of NO2. Methods: The personal exposure to diesel exhaust was assessed by expert supervised measurements of NO2, EC, OC, TC, RD and particle number in the breathing zones of underground tunnel workers. Stationary sampling of NO2, EC, OC, TC, RD, size-fractioned mass concentration, and particle number were conducted. The personal and stationary measurements were conducted on three occasions simultaneously. The workers measured their exposure by repeated self-administered measurements of NO2. The self-administered measurements were performed twice for each worker with at least one month lag between the samplings. Results: In the simultaneous sampling of diesel exhaust, the geometric mean (GM) concentration of NO2 and respirable EC were 72 μg m−3 (10th–90th percentile 34–140 μg m−3) and 2.6 μg m−3 (10th–90th percentile 1.6–7.3 μg m−3), respectively. The GM for OC and TC was 28 μg m−3 (10th–90th percentile 20–42 μg m−3) and 31 μg m−3 (10th–90th percentile 20–50 μg m−3), respectively. The GM for RD and particle number was 180 μg m−3 (10th–90th percentile 20–530 μg m−3) and 47 900 cm−3 (10th–90th percentile (27 500–94 100 cm−3), respectively. A significant correlation was found between NO2 and respirable EC [Spearman’s correlation r = 0.53 (P = 0.05)]. The within-worker variability of NO2 was 45.5% and the between-worker variability was 54.5%. The self-administered measured concentrations of NO2 (GM 70 μg m−3) did not statistically differ from the NO2 concentrations measured by an expert (P > 0.35). Conclusion: The diesel exhaust exposure in tunnel construction work was low. A significant correlation between NO2 and EC was observed. This indicates that NO2 could be used as a proxy for diesel exhaust in tunnel work if diesel exhaust is the only source of NO2 and if the ratio between EC and NO2 is known and constant. Passive sampling of NO2 is much easier and cheaper to perform compared with active sampling of EC. It is possible to utilize self-administered NO2 measurements in extreme and inaccessible work environments. This study adds support to continued use of NO2 as an exposure marker in combination with EC for diesel exhaust exposure. In tunnel construction work, the variability in the diesel exhaust exposure was high both between- and within-workers.
  • Hedmer, Maria, et al. (författare)
  • Validation of urinary excretion of cyclophosphamide as a biomarker of exposure by studying its renal clearance at high and low plasma concentrations in cancer patients
  • 2008
  • Ingår i: International Archives of Occupational and Environmental Health. - Springer. - 1432-1246. ; 81:3, s. 285-293
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Cyclophosphamide (CP) is an alkylating agent classified as a human carcinogen. Health care workers handling this drug may be exposed during, e.g., preparation or administration. Cyclophosphamide is readily absorbed by inhalation and by dermal uptake. A biomarker, CP in urine, has frequently been used to assess the occupational exposure to CP, but has not been fully validated. The aim of this study was to investigate if the proportion of the CP dose that is excreted in urine (renal clearance) is constant over different plasma drug concentrations and other pharmacokinetic parameters, e.g., urine flow. METHODS: Pharmacokinetics of CP were studied in 16 breast cancer patients that were treated with postoperative adjuvant chemotherapy including CP. Plasma and urine from the patients were collected at different occasions up to 12 days after the dose. Urine was collected during 4-h periods and blood was sampled at the end of each period. Analysis of CP was performed by liquid chromatography tandem mass spectrometry. The limit of detection for CP in urine and plasma was 0.01 and 0.02 ng/ml, respectively. The precisions of the developed methods were determined to </=8%. RESULTS: The administered doses of CP in absolute amounts ranged between 800 and 2,240 mg. Mean renal clearance of CP was 8.6 (confidence interval 6.5-10.7) ml/min and was not significantly dependent of the plasma drug concentration. However, a significant correlation between renal clearance and urine flow was observed. There was a large inter-individual variation in the plasma and urine concentrations even when the same doses were given. CONCLUSIONS: Cyclophosphamide in urine can be continued to be used as a biomarker to monitor occupational exposure to CP, however the inter-individual variability of excretion of CP in urine, and its dependency on urine flow must be taken into consideration in future applications.
  • Hossain, Bakhtiar, et al. (författare)
  • Exposure to welding fumes is associated with hypomethylation of the F2RL3 gene: a cardiovascular disease marker.
  • 2015
  • Ingår i: Occupational and Environmental Medicine. - BMJ Publishing Group. - 1470-7926. ; 72:12, s. 845-851
  • Tidskriftsartikel (refereegranskat)abstract
    • Welders are at risk for cardiovascular disease. Recent studies linked tobacco smoke exposure to hypomethylation of the F2RL3 (coagulation factor II (thrombin) receptor-like 3) gene, a marker for cardiovascular disease prognosis and mortality. However, whether welding fumes cause hypomethylation of F2RL3 remains unknown.
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