| 1. |
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| 2. |
- Falchi, M., et al.
(author)
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Low copy number of the salivary amylase gene predisposes to obesity
- 2014
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:5, s. 492-497
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Journal article (peer-reviewed)abstract
- Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10-14) and serum enzyme levels (P < 2.20 × 10-16), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy =-0.15 (0.02) kg/m 2; P = 6.93 × 10-10) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13-1.26; P = 1.46 × 10-10). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies. © 2014 Nature America, Inc. All rights reserved.
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| 3. |
- Moustafa, J. S. E., et al.
(author)
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Novel association approach for variable number tandem repeats (VNTRs) identifies DOCK5 as a susceptibility gene for severe obesity
- 2012
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:16, s. 3727-3738
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Journal article (peer-reviewed)abstract
- Variable number tandem repeats (VNTRs) constitute a relatively under-examined class of genomic variants in the context of complex disease because of their sequence complexity and the challenges in assaying them. Recent large-scale genome-wide copy number variant mapping and association efforts have highlighted the need for improved methodology for association studies using these complex polymorphisms. Here we describe the in-depth investigation of a complex region on chromosome 8p21.2 encompassing the dedicator of cytokinesis 5 (DOCK5) gene. The region includes two VNTRs of complex sequence composition which flank a common 3975 bp deletion, all three of which were genotyped by polymerase chain reaction and fragment analysis in a total of 2744 subjects. We have developed a novel VNTR association method named VNTRtest, suitable for association analysis of multi-allelic loci with binary and quantitative outcomes, and have used this approach to show significant association of the DOCK5 VNTRs with childhood and adult severe obesity (P-empirical 8.9 10(8) and P 3.1 10(3), respectively) which we estimate explains approximate to 0.8 of the phenotypic variance. We also identified an independent association between the 3975 base pair (bp) deletion and obesity, explaining a further 0.46 of the variance (P-combined 1.6 10(3)). Evidence for association between DOCK5 transcript levels and the 3975 bp deletion (P 0.027) and both VNTRs (P-empirical 0.015) was also identified in adipose tissue from a Swedish family sample, providing support for a functional effect of the DOCK5 deletion and VNTRs. These findings highlight the potential role of DOCK5 in human obesity and illustrate a novel approach for analysis of the contribution of VNTRs to disease susceptibility through association studies.
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| 5. |
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| 6. |
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| 7. |
- Ahlin, Sofie, 1985, et al.
(author)
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Macrophage Gene Expression in Adipose Tissue is Associated with Insulin Sensitivity and Serum Lipid Levels Independent of Obesity.
- 2013
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In: Obesity (Silver Spring, Md.). - : Wiley. - 1930-739X .- 1930-7381. ; 21:12
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Journal article (peer-reviewed)abstract
- Objective: Obesity is linked to both increased metabolic disturbances and increased adipose tissue macrophage infiltration. However, whether macrophage infiltration directly influences human metabolism is unclear. The aim of this study was to investigate if there are obesity-independent links between adipose tissue macrophages and metabolic disturbances. Design and Methods: Expression of macrophage markers in adipose tissue was analyzed by DNA microarrays in the SOS Sib Pair study and in patients with type 2 diabetes and a BMI-matched healthy control group. Results: The expression of macrophage markers in adipose tissue was increased in obesity and associated with several metabolic and anthropometric measurements. After adjustment for BMI, the expression remained associated with insulin sensitivity, serum levels of insulin, C-peptide, high density lipoprotein cholesterol (HDL-cholesterol) and triglycerides. In addition, the expression of most macrophage markers was significantly increased in patients with type 2 diabetes compared to the control group. Conclusion: Our study shows that infiltration of macrophages in human adipose tissue, estimated by the expression of macrophage markers, is increased in subjects with obesity and diabetes and associated with insulin sensitivity and serum lipid levels independent of BMI. This indicates that adipose tissue macrophages may contribute to the development of insulin resistance and dyslipidemia.
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| 8. |
- Assarsson, E, et al.
(author)
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2B4/CD48-mediated regulation of lymphocyte activation and function
- 2005
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In: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 175:4, s. 2045-2049
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Journal article (peer-reviewed)abstract
- 2B4 (CD244) is a member of the CD2 subset of the Ig superfamily. This molecule is expressed on innate immune cells, including NK cells, and on subsets of T cells. The 2B4 molecule interacts with CD48, which is widely expressed on hemopoietic cells. Although earlier reports demonstrated a role for 2B4 as an activating receptor in both mice and humans, recent studies of 2B4-deficient mice have suggested that 2B4 functions predominantly as an inhibitory receptor in mice. In addition, 2B4 may also act as a costimulatory ligand for cells expressing CD48. Thus, the 2B4 molecule is more multifunctional than previously understood. In this study, we delineate the current view of 2B4-CD48 interactions among lymphocytes and other cells.
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| 9. |
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| 10. |
- Assarsson, E, et al.
(author)
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CD8+ T cells rapidly acquire NK1.1 and NK cell-associated molecules upon stimulation in vitro and in vivo
- 2000
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In: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 165:7, s. 3673-3679
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Journal article (peer-reviewed)abstract
- NKT cells express both NK cell-associated markers and TCR. Classically, these NK1.1+TCRαβ+ cells have been described as being either CD4+CD8− or CD4−CD8−. Most NKT cells interact with the nonclassical MHC class I molecule CD1 through a largely invariant Vα14-Jα281 TCR chain in conjunction with either a Vβ2, -7, or -8 TCR chain. In the present study, we describe the presence of significant numbers of NK1.1+TCRαβ+ cells within lymphokine-activated killer cell cultures from wild-type C57BL/6, CD1d1−/−, and Jα281−/− mice that lack classical NKT cells. Unlike classical NKT cells, 50–60% of these NK1.1+TCRαβ+ cells express CD8 and have a diverse TCR Vβ repertoire. Purified NK1.1−CD8α+ T cells from the spleens of B6 mice, upon stimulation with IL-2, IL-4, or IL-15 in vitro, rapidly acquire surface expression of NK1.1. Many NK1.1+CD8+ T cells had also acquired expression of Ly-49 receptors and other NK cell-associated molecules. The acquisition of NK1.1 expression on CD8+ T cells was a particular property of the IL-2Rβ+ subpopulation of the CD8+ T cells. Efficient NK1.1 expression on CD8+ T cells required Lck but not Fyn. The induction of NK1.1 on CD8+ T cells was not just an in vitro phenomenon as we observed a 5-fold increase of NK1.1+CD8+ T cells in the lungs of influenza virus-infected mice. These data suggest that CD8+ T cells can acquire NK1.1 and other NK cell-associated molecules upon appropriate stimulation in vitro and in vivo.
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| 11. |
- Assarsson, E, et al.
(author)
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NK cells stimulate proliferation of T and NK cells through 2B4/CD48 interactions
- 2004
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In: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 173:1, s. 174-180
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Journal article (peer-reviewed)abstract
- Few studies have addressed the consequences of physical interactions between NK and T cells, as well as physical interactions among NK cells themselves. We show in this study that NK cells can enhance T cell activation and proliferation in response to CD3 cross-linking and specific Ag through interactions between 2B4 (CD244) on NK cells and CD48 on T cells. Furthermore, 2B4/CD48 interactions between NK cells also enhanced proliferation of NK cells in response to IL-2. Overall, these results suggest that NK cells augment the proliferation of neighboring T and NK cells through direct cell-cell contact. These results provide new insights into NK cell-mediated control of innate and adaptive immunity and demonstrate that receptor/ligand-specific cross talk between lymphocytes may occur in settings other than T-B cell or T-T cell interactions.
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| 12. |
- Assarsson, Maria, et al.
(author)
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Restoring proper radical generation by azide binding to the iron site of the E238A mutant R2 protein of ribonucleotide reductase from Escherichia coli.
- 2001
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 276:29, s. 26852-26859
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Journal article (peer-reviewed)abstract
- The enzyme activity of Escherichia coli ribonucleotide reductase requires the presence of a stable tyrosyl free radical and diiron center in its smaller R2 component. The iron/radical site is formed in a reconstitution reaction between ferrous iron and molecular oxygen in the protein. The reaction is known to proceed via a paramagnetic intermediate X, formally a Fe(III)-Fe(IV) state. We have used 9.6 GHz and 285 GHz EPR to investigate intermediates in the reconstitution reaction in the iron ligand mutant R2 E238A with or without azide, formate, or acetate present. Paramagnetic intermediates, i.e. a long-living X-like intermediate and a transient tyrosyl radical, were observed only with azide and under none of the other conditions. A crystal structure of the mutant protein R2 E238A/Y122F with a diferrous iron site complexed with azide was determined. Azide was found to be a bridging ligand and the absent Glu-238 ligand was compensated for by azide and an extra coordination from Glu-204. A general scheme for the reconstitution reaction is presented based on EPR and structure results. This indicates that tyrosyl radical generation requires a specific ligand coordination with 4-coordinate Fe1 and 6-coordinate Fe2 after oxygen binding to the diferrous site.
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| 13. |
- Eisemann, E., et al.
(author)
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Efficient real-time shadows
- 2012
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In: ACM Special Interest Group on Computer Graphics and Interactive Techniques Conference, SIGGRAPH'12, Los Angeles, 5-9 August 2012. - New York, NY, USA : ACM. - 9781450316781
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Conference paper (peer-reviewed)abstract
- This course is a resource for applying efficient, real-time shadow algorithms. It builds on a solid foundation (previous courses at SIGGRAPH Asia 2009 and Eurographics 2010, including comprehensive course notes) and the 2011 book Real-Time Shadows (AK Peters) written by four of the presenters. The book is a compendium of many topics in the realm of shadow computation. The course provides an overview of various techniques but moves beyond the basics to practical solutions and game-relevant techniques summarized by a presenter from the production industry. Topics include: the theory behind shadow computation, when physical accuracy can be replaced with plausible shadows, implementation details, and practical issues such as budget considerations and performance trade-offs. Case studies illustrate the techniques behind major game titles and upcoming engines.
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| 14. |
- Enroth, Stefan, 1976-, et al.
(author)
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A two-step strategy for identification of plasma protein biomarkers for endometrial and ovarian cancer
- 2018
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In: Clinical Proteomics. - : Springer Science and Business Media LLC. - 1542-6416 .- 1559-0275. ; 15
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Journal article (peer-reviewed)abstract
- BackgroundOver 500,000 women worldwide are diagnosed with ovarian or endometrial cancer each year. We have used a two-step strategy to identify plasma proteins that could be used to improve the diagnosis of women with an indication of gynecologic tumor and in population screening.MethodsIn the discovery step we screened 441 proteins in plasma using the proximity extension assay (PEA) and five Olink Multiplex assays (CVD II, CVD III, INF I, ONC II, NEU I) in women with ovarian cancer (n=106), endometrial cancer (n=74), benign ovarian tumors (n=150) and healthy population controls (n=399). Based on the discovery analyses a set of 27 proteins were selected and two focused multiplex PEA assays were developed. In a replication step the focused assays were used to study an independent set of cases with ovarian cancer (n=280), endometrial cancer (n=228), women with benign ovarian tumors (n=76) and healthy controls (n=57).ResultsIn the discovery step, 27 proteins that showed an association to cancer status were identified. In the replication analyses, the focused assays distinguished benign tumors from ovarian cancer stage III-IV with a sensitivity of 0.88 and specificity of 0.92 (AUC=0.92). The assays had a significantly higher AUC for distinguishing benign tumors from late stage ovarian cancer than using CA125 and HE4 (p=9.56e-22). Also, population controls could be distinguished from ovarian cancer stage III-IV with a sensitivity of 0.85 and a specificity of 0.92 (AUC=0.89).ConclusionThe PEA assays represent useful tools for identification of new biomarkers for gynecologic cancers. The selected protein assays could be used to distinguish benign tumors from ovarian and endometrial cancer in women diagnosed with an unknown suspicious pelvic mass. The panels could also be used in population screening, for identification of women in need of specialized gynecologic transvaginal ultrasound examination.FundingThe Swedish Cancer Foundation, Vinnova (SWELIFE), The Foundation for Strategic Research (SSF), Assar Gabrielsson Foundation.
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| 15. |
- Enroth, Stefan, 1976-, et al.
(author)
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High throughput proteomics identifies a high-accuracy 11 plasma protein biomarker signature for ovarian cancer
- 2019
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In: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 2
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Journal article (peer-reviewed)abstract
- Ovarian cancer is usually detected at a late stage and the overall 5-year survival is only 30-40%. Additional means for early detection and improved diagnosis are acutely needed. To search for novel biomarkers, we compared circulating plasma levels of 593 proteins in three cohorts of patients with ovarian cancer and benign tumors, using the proximity extension assay (PEA). A combinatorial strategy was developed for identification of different multivariate biomarker signatures. A final model consisting of 11 biomarkers plus age was developed into a multiplex PEA test reporting in absolute concentrations. The final model was evaluated in a fourth independent cohort and has an AUC = 0.94, PPV = 0.92, sensitivity = 0.85 and specificity = 0.93 for detection of ovarian cancer stages I-IV. The novel plasma protein signature could be used to improve the diagnosis of women with adnexal ovarian mass or in screening to identify women that should be referred to specialized examination.
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| 16. |
- Jiang, Zheshun, et al.
(author)
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Hexavalent chromium still a concern in Sweden : Evidence from a cross-sectional study within the SafeChrom project
- 2024
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In: International journal of hygiene and environmental health. - : Elsevier. - 1438-4639 .- 1618-131X. ; 256
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Journal article (peer-reviewed)abstract
- ObjectivesHexavalent chromium (Cr(VI)) is classified as a human carcinogen. Occupational Cr(VI) exposure can occur during different work processes, but the current exposure to Cr(VI) at Swedish workplaces is unknown.MethodsThis cross-sectional study (SafeChrom) recruited non-smoking men and women from 14 companies with potential Cr(VI) exposure (n = 113) and controls from 6 companies without Cr(VI) exposure (n = 72). Inhalable Cr(VI) was measured by personal air sampling (outside of respiratory protection) in exposed workers. Total Cr was measured in urine (pre- and post-shift, density-adjusted) and red blood cells (RBC) (reflecting Cr(VI)) in exposed workers and controls. The Bayesian tool Expostats was used to assess risk and evaluate occupational exposure limit (OEL) compliance.ResultsThe exposed workers performed processing of metal products, steel production, welding, plating, and various chemical processes. The geometric mean concentration of inhalable Cr(VI) in exposed workers was 0.15 μg/m3 (95% confidence interval: 0.11–0.21). Eight of the 113 exposed workers (7%) exceeded the Swedish OEL of 5 μg/m3, and the Bayesian analysis estimated the share of OEL exceedances up to 19.6% for stainless steel welders. Median post-shift urinary (0.60 μg/L, 5th-95th percentile 0.10–3.20) and RBC concentrations (0.73 μg/L, 0.51–2.33) of Cr were significantly higher in the exposed group compared with the controls (urinary 0.10 μg/L, 0.06–0.56 and RBC 0.53 μg/L, 0.42–0.72). Inhalable Cr(VI) correlated with urinary Cr (rS = 0.64) and RBC-Cr (rS = 0.53). Workers within steel production showed the highest concentrations of inhalable, urinary and RBC Cr. Workers with inferred non-acceptable local exhaustion ventilation showed significantly higher inhalable Cr(VI), urinary and RBC Cr concentrations compared with those with inferred acceptable ventilation. Furthermore, workers with inferred correct use of respiratory protection were exposed to significantly higher concentrations of Cr(VI) in air and had higher levels of Cr in urine and RBC than those assessed with incorrect or no use. Based on the Swedish job-exposure-matrix, approximately 17 900 workers were estimated to be occupationally exposed to Cr(VI) today.ConclusionsOur study demonstrates that some workers in Sweden are exposed to high levels of the non-threshold carcinogen Cr(VI). Employers and workers seem aware of Cr(VI) exposure, but more efficient exposure control strategies are required. National strategies aligned with the European strategies are needed in order to eliminate this cause of occupational cancer.
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| 17. |
- Jiang, Zheshun, et al.
(author)
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P-205 THE SAFECHROM PROJECT - EVIDENCE FROM A CROSS-SECTIONAL STUDY SHOWS THAT HEXAVALENT CHROMIUM IS STILL A CONCERN IN SWEDEN
- 2024
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In: Occupational Medicine. - 0962-7480. ; 74:Suppl 1, s. 291-292
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Conference paper (other academic/artistic)abstract
- Hexavalent chromium Cr(VI) is a human carcinogen, but the current exposure to Cr(VI) at Swedish workplaces is unknown.Recruitment of 113 workers with potential Cr(VI) exposure and 72 controls was combined with measurements of inhalable Cr(VI) (only exposed workers) and total Cr in urine and red blood cells (RBC), Bayesian analysis of occupational exposure limit (OEL) compliance was used, as well as the Swedish job-exposure-matrix.Exposed workers performed processing of metal products, steel production, welding, and plating. The geometric mean concentration of inhalable Cr(VI) in exposed workers was 0.15 μg/m3. Eight workers (7\ exceeded the Swedish OEL (5 μg/m3), and the share of OEL exceedances was estimated to be up to 19.6\ and RBC-Cr were significantly higher in exposed workers compared with controls. Workers with inferred non-acceptable local exhaustion ventilation showed significantly higher inhalable Cr(VI), urine- and RBC-Cr than those with acceptable ventilation. Workers with inferred correct use of respiratory protection had higher inhalable Cr(VI), and, paradoxically, higher urine- and RBC-Cr concentrations than workers with incorrect use. We estimate that ~17 900 Swedish workers are occupationally exposed to Cr(VI) today.Our study showed that although most air measurements were relatively low, 7\ and particularly stainless steel workers are at risk for exceeding the OEL. The existing protective measures implemented at workplaces are still inadequate and insufficient.Some workers in Sweden are exposed to high levels of the non-threshold carcinogen Cr(VI). National strategies aligned with European strategies are needed to eliminate occupational cancer.
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| 22. |
- Rukh, Gull, et al.
(author)
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Dietary starch intake modifies the relation between copy number variation in the salivary amylase gene and BMI
- 2017
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In: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165. ; 106:1, s. 256-262
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Journal article (peer-reviewed)abstract
- Background: Studies have shown conflicting associations between the salivary amylase gene (AMY1) copy number and obesity. Salivary amylase initiates starch digestion in the oral cavity; starch is a major source of energy in the diet. Objective: We investigated the association between AMY1 copy number and obesity traits, and the effect of the interaction between AMY1 copy number and starch intake on these obesity traits. Design: We first assessed the association between AMY1 copy number (genotyped by digital droplet polymerase chain reaction) and obesity traits in 4800 individuals without diabetes (mean age: 57 y; 60% female) from the Malmo "Diet and Cancer Cohort. Then we analyzed interactions between AMY1 copy number and energyadjusted starch intake (obtained by a modified diet history method) on body mass index (BMI) and body fat percentage. Results: AMY1 copy number was not associated with BMI (P = 0.80) or body fat percentage (P = 0.38). We observed a significant effect of the interaction between AMY1 copy number and starch intake on BMI (P-interaction = 0.007) and body fat percentage (P-interaction = 0.03). Upon stratification by dietary starch intake, BMI tended to decrease with increasing AMY1 copy numbers in the low-starch intake group (P = 0.07) and tended to increase with increasing AMY1 copy numbers in the high-starch intake group (P = 0.08). The lowest mean BMI was observed in the group of participants with a low AMY1 copy number and a high dietary intake of starch. Conclusions: Our findings suggest an effect of the interaction between starch intake and AMY1 copy number on obesity. Individuals with high starch intake but low genetic capacity to digest starch had the lowest BMI, potentially because larger amounts of undigested starch are transported through the gastrointestinal tract, contributing to fewer calories extracted from ingested starch.
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| 23. |
- Taj, Tahir, et al.
(author)
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Effect of welding fumes on the cardiovascular system: a six-year longitudinal study
- 2021
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In: Scandinavian Journal of Work Environment & Health. - : Scandinavian Journal of Work, Environment and Health. - 0355-3140 .- 1795-990X. ; 47:1, s. 52-61
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Journal article (peer-reviewed)abstract
- Objective This study investigated whether low-to-moderate exposure to welding fumes is associated with adverse effects on the cardiovascular system. Methods To test this, we performed a longitudinal analysis of 78 mild steel welders and 96 controls; these subjects were examined twice, six years apart (ie, timepoints 1 and 2). All subjects (male and non-smoking at recruitment) completed questionnaires describing their health, work history, and lifestyle. We measured their blood pressure, endothelial function (by EndoPAT), and risk markers for cardiovascular disease [low-density lio-protein (LDL), homocysteine, C-reactive protein]. Exposure to welding fumes was assessed from the responses to questionnaires and measurements of respirable dust in their breathing zones adjusted for use of respiratory protection equipment. Linear mixed-effect regression models were used for the longitudinal analysis. Results Median respirable dust concentrations, adjusted for respirable protection, of the welders were 0.7 (5-95 percentile range 0.2-4.2) and 0.5 (0.1-1.9) mg/m 3 at timepoints 1 and 2, respectively. Over the six-year period, welders showed a statistically significant increase in systolic [5.11 mm Hg, 95% confidence interval (CI) 1.92-8.31] and diastolic (3.12 mm Hg, 95% CI 0.74-5.5) blood pressure compared with controls (multi-variable adjusted mixed effect models). Diastolic blood pressure increased non-significantly by 0.22 mm Hg (95% CI-0.02-0.45) with every additional year of welding work. No consistent significant associations were found between exposure and endothelial function, LDL, homocysteine, or C-reactive protein. Conclusion Exposure to welding fumes at low-to-moderate levels is associated with increased blood pressure, suggesting that reducing the occupational exposure limit (2.5 mg/m(3) for inorganic respirable dust in Sweden) is needed to protect cardiovascular health of workers.
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