| 1. |
- Penell, Johanna, et al.
(author)
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Persistent organic pollutants are related to the change in circulating lipid levels during a 5 year follow-up
- 2014
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In: Environmental Research. - : Elsevier BV. - 0013-9351 .- 1096-0953. ; 134, s. 190-197
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Journal article (peer-reviewed)abstract
- When reporting circulating levels of persistent organic pollutants (POPs), usually lipid-normalized values are given. However, animal experiments and some human data indicate that exposure to POPs may change lipid values. The aim of the present study is to investigate if POP levels can predict future changes in levels of circulating lipids. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, lipids were measured at age 70 and at age 75 in 598 subjects without lipid-lowering medication. Twenty-three different POPs, including 16 polychlorinated biphenyls (PCBs), five organochlorine pesticides, one dioxin (OCDD) and one flame retardant brominated compound (BDE47) were analyzed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) at age 70. Strong relationships were seen among the baseline levels of the non-dioxin-like PCBs 194, 206 and 209 and the degree of increase in total serum cholesterol and LDL-cholesterol during the 5 year follow-up. These relationships were generally stronger when lipidnormalized levels were used compared to wet-weight based levels. On the contrary, for two of the pesticides, hexachlorobenzene and trans-nonachlordane, levels were inversely related to the change in LDL-cholesterol, with strongest associations found using wet-weight based levels. PCBs 194, 206 and 209 were inversely related to the change in HDL-cholesterol, in particular for wet-weight based levels. However, these relationships were only significant for wet-weight PCB 194 following adjustment for multiple testing. None of the POPs was related to the change in serum triglycerides. When investigating the association between the change in total serum cholesterol and LDL-cholesterol across different categories of change in BMI, we noted robust results especially in the group with stable BMI, suggesting that the observed relationships were not due to fluctuations in BMI over time. In conclusion, POPs are related to the change in lipids over time, especially LDL-cholesterol. This may explain why POP exposure previously has been linked to atherosclerosis and cardiovascular disease.
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| 2. |
- Joshi, Peter K, et al.
(author)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Journal article (peer-reviewed)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 3. |
- Lind, Lars, et al.
(author)
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Genetic variation in the CYP1A1 gene is related to circulating PCB118 levels in a population-based sample
- 2014
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In: Environmental Research. - : Elsevier BV. - 0013-9351 .- 1096-0953. ; 133, s. 135-140
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Journal article (peer-reviewed)abstract
- Several of the polychlorinated biphenyls (PCBs), i.e. the dioxin-like PCBs, are known to induce the P450 enzymes CYP1A1, CYP1A2 and CYP1B1 by activating the aryl hydrocarbon receptor (Ah)-receptor. We evaluated if circulating levels of PCBs in a population sample were related to genetic variation in the genes encoding these CYPs. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), 21 SNPs in the CYP1A1, CYP1A2 and CYP1B1 genes were genotyped. Sixteen PCB congeners were analysed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS). Of the investigated relationships between SNPs in the CYP1A1, CYP1A2 and CYP1B1 and six PCBs (congeners 118, 126, 156, 169, 170 and 206) that captures > 80% of the variation of all PCBs measured, only the relationship between CYP1A1 rs2470893 was significantly related to PCB118 levels following strict adjustment for multiple testing (p=0.00011). However, there were several additional SNPs in the CYP1A2 and CYP1B1 that showed nominally significant associations with PCB118 levels (p-values in the 0.003-0.05 range). Further, several SNPs in the CYP1B1 gene were related to both PCB156 and PCB206 with p-values in the 0.005-0.05 range. Very few associations with p < 0.05 were seen for PCB126, PCB169 or PCB170. Genetic variation in the CYP1A1 was related to circulating PCB118 levels in the general elderly population. Genetic variation in CYP1A2 and CYP1B1 might also be associated with other PCBs.
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| 4. |
- Lind, Lars, et al.
(author)
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Global DNA hypermethylation is associated with high serum levels of persistent organic pollutants in an elderly population
- 2013
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In: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 59, s. 456-461
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Journal article (peer-reviewed)abstract
- Dioxin exposure has experimentally been associated with changes in DNA methylation, an epigenetic change that is associated with disease. The present study aims to investigate if serum levels of dioxin and other persistent environmental pollutants are related to global DNA methylation in a human sample. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (all aged 70), global DNA methylation was measured by the Luminometric Methylation Assay in 524 subjects. Twenty-three different POPs, including 16 PCBs, five pesticides, one dioxin (OCDD) and one brominated flame retardant (BDE47) were analysed by HRGC/HRMS. Ten single nucleotide polymorphisms (SNPs) in the Aryl hydrocarbon (Ah)-receptor were analysed by mini-sequencing. High levels of toxic equivalency (TEQ) for PCBs and dioxin were associated with DNA hypermethylation (p = 0.030). This was mainly attributed to coplanar non-ortho PCBs. While no significant associations were found between DNA methylation and SNPs in the Ah-receptor, an interaction was found between the SNP rs2237297 and TEQ so that TEQ was associated with hypermethylation (p = 0.009) only in subjects with one G-allele (n = 103). Also high levels of the PCB126 congener, the OCDD, and the pesticide metabolite p,p'-DDE were related to DNA hypermethylation (p = 0.01, 0.03 and 0.003, respectively). In conclusion, in a sample of elderly subjects, high TEQ including PCBs and the dioxin OCDD and high serum levels of PCB126, OCDD, and p,p'-DDE were related to global DNA hypermethylation in a cross-sectional analysis. (C) 2013 Elsevier Ltd. All rights reserved.
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| 5. |
- Lind, Monica P., et al.
(author)
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Circulating levels of p,p '-DDE are related to prevalent hypertension in the elderly
- 2014
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In: Environmental Research. - San Diego : Academic Press. - 0013-9351 .- 1096-0953. ; 129, s. 27-31
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Journal article (peer-reviewed)abstract
- Background: Polychlorinated biphenyls (PCBs) and dioxin given to experimental animals increase the blood pressure. We therefore investigated if circulating levels of persistent organic pollutants (POPs) were related to hypertension in a population-based sample of men and women.Methods: One thousand and sixteen subjects aged 70 years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Twenty-three POPs were analyzed using high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS). Hypertension was defined as a systolic blood pressure >= 140 mmHg or a diastolic blood pressure >= 90 mmHg, and/or use of antihypertensive medication.Results: Seven hundred and thirty-two subjects (72%) showed hypertension. When the POPs were treated as continuous variables and adjusted for gender only, two PCBs with a low number of chlorine atoms (PCB 105 and 118) were related to prevalent hypertension. Also the OC pesticide p,p'-DDE was related to hypertension. The strongest of these associations was seen for p,p'-DDE (OR 135 for a 1 SD change, 95% CI 1.17-1.56, p < 0.0001). Following further adjustment also for BMI, smoking status, education level and exercise habits, only p,p'-DDE was still significantly related to hypertension (OR 1.23 for a 1 SD change, 95% CI 1.06-1.43, p=0.006).Conclusion: In this cross-sectional analysis of an elderly population, high levels of circulating levels of p,p'-DDE were associated with prevalent hypertension, further strengthening the experimental findings that POPs might influence blood pressure. (C) 2013 Elsevier Inc. All rights reserved.
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| 6. |
- Penell, Johanna Christina, et al.
(author)
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Concentrations of nine endogenous steroid hormones in 70-year-old men and women
- 2021
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In: Endocrine Connections. - : Bioscientifica. - 2049-3614. ; 10:5, s. 511-520
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Journal article (peer-reviewed)abstract
- ObjectivesCirculating concentrations of endogenous steroids have systemic implications on health in elderly. However, population-based age- and ethnicity-specific data are scarce. The aim was to report sex-specific plasma concentrations of endogenous sex and adrenal steroids in elderly Swedish Caucasians, to examine the impact of BMI and to present concentrations in apparently healthy subjects.MethodsA population-based observational study of 70-year olds, including 684 community-dwelling men and women enrolled in the PIVUS study, Sweden. Median plasma concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for pregnenolone, 17-hydroxypregnenolone, 17-hydroxy-progesterone, 11-deoxycortisol, DHEA, androstenedione, testosterone, estrone and estradiol.ResultsPlasma concentrations were significantly higher in men (n = 452) than in women (n = 232) for estradiol: median 61.3 pmol/L (95% CI, 11.4, 142.7) vs 18.4 (4.0, 127.3), for estrone: 92.8 (33.3, 206) vs 71.6 (17.8, 209) pmol/L, and for testosterone 13.8 (5.7, 28.0) vs 0.7 (0.2, 2.0) nmol/L. Higher concentrations of estrone and estradiol were observed in obese than non-obese women. Compared to non-obese men, obese men had lower concentrations of testosterone and its precursors: 17-hydroxypregnenolone, 17-hydroxyprogesterone, androstenedione and DHEA. The subgroup of apparently healthy individuals had median values > 20% lower for estrone and estradiol in women but slightly higher for testosterone in both sexes.ConclusionsConcentrations of estradiol, estrone and testosterone were higher in 70-year-old men than in women. BMI associated positively to estradiol and estrone in women and negatively to testosterone in men. Apparently healthy women had lower median concentrations of estradiol and estrone and men had higher median testosterone compared to all individuals.
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| 7. |
- Penell, Johanna, et al.
(author)
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Genetic variation in the CYP2B6 Gene is related to circulating 2,2 ',4,4 '-tetrabromodiphenyl ether (BDE-47) concentrations : an observational population-based study
- 2014
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In: Environmental Health. - London : BioMed Central (BMC). - 1476-069X. ; 13, s. 34-
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Journal article (peer-reviewed)abstract
- Background: Since human CYP2B6 has been identified as the major CYP enzyme involved in the metabolism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and that human 2B6 is a highly polymorphic CYP, with known functional variants, we evaluated if circulating concentrations of a major brominated flame retardant, BDE-47, were related to genetic variation in the CYP2B6 gene in a population sample.Methods: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (men and women all aged 70), 25 single nucleotide polymorphisms (SNPs) in the CYP2B6 gene were genotyped. Circulating concentrations of BDE-47 were analyzed by high-resolution gas chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS).Results: Several SNPs in the CYP2B6 gene were associated with circulating concentrations of BDE-47 (P = 10(- 4) to 10(-9)). The investigated SNPs came primarily from two haplotypes, although the correlation between the haplotypes was rather high. Conditional analyses adjusting for the SNP with the strongest association with the exposure (rs2014141) did not provide evidence for independent signals.Conclusion: Circulating concentrations of BDE-47 were related to genetic variation in the CYP2B6 gene in an elderly population.
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| 8. |
- Wuttke, Matthias, et al.
(author)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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In: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Journal article (peer-reviewed)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 9. |
- Berndt, Sonja I., et al.
(author)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Journal article (peer-reviewed)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 10. |
- Carlsson, Axel C, et al.
(author)
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Kidney injury molecule (KIM)-1 is associated with insulin resistance : results from two community-based studies of elderly individuals
- 2014
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In: Diabetes Research and Clinical Practice. - : Elsevier. - 0168-8227 .- 1872-8227. ; 103:3, s. 516-21
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Journal article (peer-reviewed)abstract
- BACKGROUND AND OBJECTIVES: Insulin resistance has been shown to be closely associated with glomerular filtration rate and urinary albumin/creatinine ratio, even prior to the development of diabetes. Urinary kidney injury molecule 1 (KIM-1) is a novel, highly specific marker of kidney tubular damage. The role of insulin resistance in the development of kidney tubular damage is not previously reported. Thus, we aimed to investigate the associations between insulin sensitivity (assessed by HOMA) and urinary KIM-1.DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Two community-based cohorts of elderly individuals were investigated: Prospective Investigation of the vasculature in Uppsala seniors (PIVUS, n=701; mean age 75 years, 52% women); and Uppsala Longitudinal Study of adult men (ULSAM, n=533; mean age 78 years).RESULTS: Lower insulin sensitivity was associated with higher urinary KIM-1 in both cohorts after adjustments for age, BMI, blood pressure, antihypertensive treatment, glomerular filtration rate, and urinary albumin-creatinine ratio (PIVUS: regression coefficient for 1-SD higher HOMA-IR 0.11, 95% CI 0.03-0.20, p=0.009, and ULSAM: 0.13, 95% CI 0.04-0.22, p=0.007). Results were similar in individuals without diabetes, with normal kidney function and normo-albuminuria.CONCLUSIONS: Our findings in elderly individuals support the notion that the interplay between an impaired glucose metabolism and renal tubular damage is evident even prior to the development of diabetes and overt kidney disease.
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| 11. |
- Carlsson, Axel C, et al.
(author)
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Soluble TNF receptors and kidney dysfunction in the elderly
- 2014
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In: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 25:6, s. 1313-1320
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Journal article (peer-reviewed)abstract
- The importance of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in the development of kidney disease is being unraveled. Yet, community-based data regarding the role of sTNFRs are lacking. We assessed serum sTNFRs and aspects of kidney damage cross-sectionally in two independent community-based cohorts of elderly participants: Prospective Investigation of the Vasculature in Uppsala Seniors (n=815; mean age, 75 years; 51% women) and Uppsala Longitudinal Study of Adult Men (n=778; mean age, 78 years). Serum sTNFR1 correlated substantially with different aspects of kidney pathology in the Uppsala Longitudinal Study of Adult Men cohort (R=-0.52 for estimated GFR, R=0.22 for urinary albumin-to-creatinine ratio, and R=0.17 for urinary kidney injury molecule-1; P<0.001 for all), with similar correlations in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. These associations remained significant after adjustment for age, sex, inflammatory markers, and cardiovascular risk factors and were also evident in participants without diabetes. Serum sTNFR2 was associated with all three markers in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort (P<0.001 for all). Our findings from two independent community-based cohorts confirm and extend results of previous studies supporting circulating sTNFRs as relevant biomarkers for kidney damage and dysfunction in elderly individuals, even in the absence of diabetes.
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| 12. |
- Carlsson, Axel C, et al.
(author)
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Urinary kidney injury molecule 1 and incidence of heart failure in elderly men
- 2013
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In: European Journal of Heart Failure. - : Oxford University Press. - 1388-9842 .- 1879-0844. ; 15:4, s. 447-446
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Journal article (peer-reviewed)abstract
- AIMS: There is growing recognition of the clinical importance of cardiorenal syndrome-the bidirectional interplay between kidney and cardiac dysfunction. Yet, the role of kidney tubular damage in the development of heart failure is less studied. The objective of this study was to investigate whether urinary kidney injury molecule (KIM)-1, a specific marker of tubular damage, predisposes to an increased heart failure risk.METHODS AND RESULTS: This was a community-based cohort study [Uppsala Longitudinal study of Adult Men (ULSAM)] of 565, 77-year-old men free from heart failure at baseline. Heart failure hospitalizations were used as outcome. During follow-up (median 8.0 years), 73 participants were hospitalized for heart failure. In models adjusted for cardiovascular risk factors (age, systolic blood pressure, diabetes, smoking, body mass index, LDL/HDL ratio, antihypertensive treatment, lipid-lowering treatment, aspirin treatment, LV hypertrophy, and prevalent cardiovascular disease) and markers of kidney dysfunction and damage [cystatin C-based glomerular filtration rate (GFR) and urinary albumin/creatinine ratio], a higher urinary KIM-1/creatinine ratio was associated with higher risk for heart failure (hazard ratio upper vs. lower tertile, 1.81; 95% confidence interval 1.01-3.29; P < 0.05). Participants with a combination of low GFR (<60 mL/min/1.72 m(2)) and high KIM-1/creatinine (>128 ng/mmol) had a 3-fold increase in heart failure risk compared with participants with normal GFR and KIM-1 (P < 0.001).CONCLUSION: Our findings suggest that kidney tubular damage predisposes to an increased risk for heart failure in the community. Further studies are needed to clarify the causal role of KIM-1 in the development of heart failure, and to evaluate the clinical utility of urinary KIM-1 measurements.
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| 13. |
- Carlsson, Axel C, et al.
(author)
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Urinary kidney injury molecule-1 and the risk of cardiovascular mortality in elderly men
- 2014
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In: American Society of Nephrology. Clinical Journal. - 1555-9041 .- 1555-905X. ; 9:8, s. 1393-1401
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Journal article (peer-reviewed)abstract
- BACKGROUND AND OBJECTIVES: Kidney injury molecule-1 (KIM-1) has been suggested as a clinically relevant highly specific biomarker of acute kidney tubular damage. However, community-based data on the association between urinary levels of KIM-1 and the risk for cardiovascular mortality are lacking. This study aimed to investigate the association between urinary KIM-1 and cardiovascular mortality.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a prospective study, using the community-based Uppsala Longitudinal Study of Adult Men (N=590; mean age 77 years; baseline period, 1997-2001; median follow-up 8.1 years; end of follow-up, 2008).RESULTS: During follow-up, 89 participants died of cardiovascular causes (incidence rate, 2.07 per 100 person-years at risk). Models were adjusted for cardiovascular risk factors (age, systolic BP, diabetes, smoking, body mass index, total cholesterol, HDL cholesterol, antihypertensive treatment, lipid-lowering treatment, aspirin treatment, and history of cardiovascular disease) and for markers of kidney dysfunction and damage (cystatin C-based eGFR and urinary albumin/creatinine ratio). Higher urinary KIM-1/creatinine (from 24-hour urine collections) was associated with a higher risk for cardiovascular mortality (hazard ratio per SD increase, 1.27; 95% confidence interval [95% CI], 1.05 to 1.54; P=0.01). Participants with a combination of high KIM-1/creatinine (upper quintile, ≥175 ng/mmol), low eGFR (≤60 ml/min per 1.73 m(2)), and microalbuminuria/macroalbuminuria (albumin/creatinine ratio≥3 g/mol) had a >8-fold increased risk compared with participants with low KIM-1/creatinine (<175 ng/mmol), normal eGFR (>60 ml/min per 1.73 m(2)), and normoalbuminuria (albumin/creatinine ratio<3 g/mol) (hazard ratio, 8.56; 95% CI, 4.17 to 17.56; P<0.001).CONCLUSIONS: These findings suggest that higher urinary KIM-1 may predispose to a higher risk of cardiovascular mortality independently of established cardiovascular risk factors, eGFR, and albuminuria. Additional studies are needed to further assess the utility of measuring KIM-1 in the clinical setting.
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| 14. |
- Caspers, Irene A., et al.
(author)
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The impact of sex on treatment and outcome in relation to histological subtype in patients with resectable gastric cancer : Results from the randomized CRITICS trial
- 2024
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In: Journal of Surgical Oncology. - : John Wiley & Sons. - 0022-4790 .- 1096-9098. ; 129:4, s. 734-744
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Journal article (peer-reviewed)abstract
- Background and ObjectiveThis study aims to investigate the impact of sex on outcome measures stratified by histological subtype in patients with resectable gastric cancer (GC).MethodsA post-hoc analysis of the CRITICS-trial, in which patients with resectable GC were treated with perioperative therapy, was performed. Histopathological characteristics and survival were evaluated for males and females stratified for histological subtype (intestinal/diffuse). Additionally, therapy-related toxicity and compliance were compared.ResultsData from 781 patients (523 males) were available for analyses. Female sex was associated with a distal tumor localization in intestinal (p = 0.014) and diffuse tumors (p < 0.001), and younger age in diffuse GC (p = 0.035). In diffuse GC, tumor-positive resection margins were also more common in females than males (21% vs. 10%; p = 0.020), specifically at the duodenal margin. During preoperative chemotherapy, severe toxicity occurred in 327 (63%) males and 184 (71%) females (p = 0.015). Notwithstanding this, relative dose intensities were not significantly different between sexes.ConclusionsPositive distal margin rates were higher in females with diffuse GC, predominantly at the duodenal site. Females also experience more toxicity, but this neither impacts dose intensities nor surgical resection rates. Clinicians should be aware of these different surgical outcomes when treating males and females with GC.
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| 15. |
- Chavez, Johanna, et al.
(author)
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Unexpectedly low UV-sensitivity in a bird, the budgerigar.
- 2014
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In: Biology letters. - : The Royal Society. - 1744-9561 .- 1744-957X. ; 10:11
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Journal article (peer-reviewed)abstract
- Photoreceptor adaptation ensures appropriate visual responses during changing light conditions and contributes to colour constancy. We used behavioural tests to compare UV-sensitivity of budgerigars after adaptation to UV-rich and UV-poor backgrounds. In the latter case, we found lower UV-sensitivity than expected, which could be the result of photon-shot noise corrupting cone signal robustness or nonlinear background adaptation. We suggest that nonlinear adaptation may be necessary for allowing cones to discriminate UV-rich signals, such as bird plumage colours, against UV-poor natural backgrounds.
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| 16. |
- Dimas, Antigone S, et al.
(author)
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Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.
- 2014
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 63:6, s. 2158-2171
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Journal article (peer-reviewed)abstract
- Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
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| 17. |
- Do, Ron, et al.
(author)
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Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
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Journal article (peer-reviewed)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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| 18. |
- Ejhed, Helene, et al.
(author)
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Belastning och påverkan från dagvatten : Källor till föroreningar i dagvatten, potentiell effekt, och jämförelser med belastning från andra källor
- 2018
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Reports (other academic/artistic)abstract
- SMED har på uppdrag av Naturvårdsverket tagit fram denna rapport om föroreningar och belastning från dagvatten. Studien är en del av ett Regeringsuppdrag ”Föreslå etappmål om dagvatten”. Syftet med projektet har varit att ta fram en sammanställning om belastning av föroreningar från dagvatten till vattenrecipienter. Primära källor, potentiella toxiska och hormonstörande effekter samt belastning på ytvatten har sammanställts och beräknats av ett urval av prioriterade ämnen och Särskilda Förorenande Ämnen (SFÄ) och omfattande sammanlagt 22 st näringsämnen, metaller och organiska miljöföroreningar. Dessa ämnen valdes ut eftersom de är kända ämnen i dagvatten, prioriterade ämnen av Vattenmyndigheterna på grund av att de orsakar att god kemisk eller ekologisk status inte uppnås i många vattenförekomster samt att det var möjligt att göra beräkningar av belastning av dessa tack vare att det fanns data tillgängligt. Dessa 22 ämnen har sådana ekologiska, toxiska och/eller hormonstörande effekter i akvatisk miljö att belastningen av samtliga av dessa ämnen bör begränsas eller helt förhindras. Dagvattnets påverkan och effekter på miljön har sammanställts utifrån tillgänglig litteratur. Studierna är dock få och av varierande karaktär, vilket gör det svårt att dra några generella slutsatser gällande dagvattnet påverkan.Antalet föroreningar i dagvatten kan dock vara många fler än de 22 utvalda ämnena. Uppmätta halter i dagvatten har sammanställts från Naturvårdsverkets Screeningdatabas i denna rapport och visar att 74 st ämnen förekommer i samtliga prover av dagvatten där de har analyserats, och ytterligare 117 st ämnen förekommer i en del av dagvattenproverna. Många är ämnen som ännu inte är prioriterade av vattenförvaltningen. Bland annat förekommer ofta metaller och grundämnen, vissa dioxiner och furaner, alkylfenoler, antioxidanter, bekämpningsmedel, kolväten, LAS (Linear alkyl benzene sulfonate) och olika flamskyddsmedel. Resultat av belastningsberäkningarna visar att dagvatten är en betydande spridningsväg till belastningen i recipienter för vissa ämnen trots att arealen tätort är mindre än 1% av Sveriges totala yta. För metallerna kadmium, zink, bly och koppar så har bidragen från dagvatten beräknats till mellan 15% och 17% av den totala belastningen till recipienter i Sverige och kan anses vara betydande belastning. I mellan 451 och 1090 st enskilda vattenförekomstområden är belastningen från dagvatten den dominerande spridningsvägen (>50% av total belastning) till de olika metallerna. Dagvatten utgör 100% av belastningen i 17 st vattenförekomster för koppar, zink och bly, i 12 st vattenförekomster för kadmium och nickel och i enbart 3 st vattenförekomster för kvicksilver. För de organiska ämnena är uppgifterna om utsläpp väldigt osäkra eller saknas helt för många källor till total belastning i Sverige, så som läckage från olika marktyper, jordbruksmark och skog, men de tillgängliga data och beräkningarna som gjorts indikerar att dagvatten utgör en viktig spridningsväg för PAH16, DEHP, Nonylfenol, HCH, TBT, PBDE, PFOS och PCB7 till vattenrecipienter.Betydande bidrag (>25%) till belastningen i dagvatten kommer ifrån mark inom tätorter som används till ”industri, handelsplats, grus- och sandtag, hamn och deponiverksamhet” för samtliga metaller, för nonylfenol (58%), PFOS (54%), PAH16 (40%), HCH (23%), PCB7 (23%), PBDE (22%) och oktylfenol (18%). Industri och handelsplats utgör den största arealen inom den markanvändningsklassen och bör prioriteras i det fortsatta arbetet. Industri och handelsplatser har höga typhalter och höga avrinningskoefficienter som orsakar den höga belastningen. Belastningen i dagvatten av ftalaten DEHP kommer däremot till största del ifrån ytor av ”enstaka hus, mycket grönyta” (35%), ”bostadsområde, mindre grönyta” (29%) samt ”urbant grönområde, idrottsanläggning, flygfält gräs” (25%). Markanvändningsklassen ”enstaka hus, mycket grönyta” utgör den största arealen totalt inom tätorter i Sverige (35% av arean), vilket innebär att den ytan bidrar med generellt stor belastning.Det finns stora osäkerheter i resultaten beroende bland annat på brist på mätningar av ämnen i dagvatten. Beräkningarna i denna rapport baseras på markanvändning som sammanställts av SMED till HELCOM Pollution Load Compilation (PLC7) rapporteringen, typhalter och avrinningskoefficienter inom tätorter från Stormtac databasen samt rapporterade utsläpp i miljörapporter från avloppsreningsverk och industrier i Svenska Miljörapporteringsportalen. Framförallt för organiska ämnen är dataunderlaget litet, vilket gör dessa uppskattningar mer osäkra. Utökad miljöövervakning av metaller och organiska ämnen behövs för att kunna följa trender och sätta in rätt åtgärder uppströms vid källorna och nedströms genom rening av dagvatten.Det stora antalet ämnen som har uppmätts i dagvatten och den betydande belastningen som dagvatten har beräknats bidra med, indikerar trots osäkerheterna på att miljöproblemen med dagvatten kan vara omfattande. Påverkan i form av eventuella överskridanden av miljökvalitetsnormer i recipienterna har inte kunnat beräknas inom ramen för detta projekt.
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| 19. |
- Ejhed, Helene, et al.
(author)
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Beräkning av utsläpp av läkemedelsrester från kommunala avloppsreningsverk och potentiell koncentration i recipientvatten
- 2018
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Reports (other academic/artistic)abstract
- SMED har på uppdrag av Naturvårdsverket beräknat potentiella utsläpp av diklofenak, 17-β-östradiol (östradiol) och 17-α-etinylöstradiol (etinylöstradiol) från kommunala avloppsreningsverk till Sveriges delavrinningsområden och uppskattat potentiell koncentration av de tre ämnena i berörda recipienter i delavrinningsområden (SMHIs delavrinningsområden version SVAR_2016) i inland. Resultaten i rapporten baseras helt på beräkningar, eftersom mätningar av koncentrationen av läkemedelsrester i utgående avloppsvatten och i mottagande recipienter enbart finns tillgängligt för ett fåtal avloppsreningsverk i dagsläget. Mätningar behövs för att ge ett säkrare underlag om behov av eventuella åtgärder. Denna rapport ger ett underlag för att prioritera vid vilka avloppsreningsverk som mätningar borde genomföras.Beräkningarna utgick ifrån tillgängliga försäljningssiffror av läkemedel per person (länsvisa för diklofenak, samt nationella för östradiol och etinylöstradiol), antal anslutna personekvivalenter (pe) till varje avloppsreningsverk, rapporterat vattenflöde från varje avloppsreningsverk, vattenföring i varje delavrinningsområde som är recipient till utgående avloppsvatten och litteraturdata på reningseffektivitet i avloppsreningsverk. I beräkningarna användes samma värde för reningseffektivitet för alla avloppsreningsverk på grund av brist på mätdata. Reningseffektiviteten motsvarade medianvärdet från mätvärden i litteraturstudien, som omfattande närmare 70 st referenser, där slutligen 17 st referenser kunde användas. I beräkningarna antogs vidare fullständig utsöndring från kroppen (100% av försåld mängd) för alla tre ämnen i hela Sverige. Det finns stora variationer i uppmätta halter i utgående vatten från enskilda avloppsreningsverk och resultaten i detta projekt bör undersökas vidare med faktiska mätningar.Resultaten i detta projekt visar att de avloppsreningsverk som hade flest antal anslutna pe och därmed störst belastning (kg/år) av läkemedelsrester i inkommande och utgående avloppsvatten var Ryaverket (Göteborg), Henriksdal, Käppalaverket (Stockholm) och Sjölunda avloppsreningsverk (Malmö). I framtiden bör man undersöka utsläppen och koncentrationen i recipienter från de största anläggningarna som utgör en stor källa av läkemedelsrester till recipienter i kusten.Resultaten visar också att av de anläggningar som hade högst beräknad koncentration i utgående avloppsvatten var nästan alla belägna i turistområden (Tandådalen, Ransby-Branäs, Björnrike, Kläppen, Sälfjället, Böda och Vimmerby). Skillnad i beräknad koncentration i utgående avloppsvatten mellan olika avloppsreningsverk beror till största del på antalet anslutna i förhållande till utgående flöde. Avloppsanläggningarna i turistområdena har därmed flest antal anslutna i förhållande till volym utgående flöde. Turistområdena har vidare stor variation i antalet personer som belastar avloppsreningsverken beroende på säsong, men flödet beror både på tillförsel av avloppsvatten från personer och på annat vatten som belastar avloppsreningsverken. Därför kan det även vara viktigt att genomföra mätningar av koncentrationen i utgående avloppsvatten och i recipienter under olika säsonger. Säsongsvariationer har inte kunnat beräknas inom ramen för detta projekt.56 st delavrinningsområden avseende diklofenak, 12 st avseende östradiol och 24 st avseende etinylöstradiol hade högre beräknad koncentration i delavrinningsområdet än gränsvärdet för årsmedelhalten av Särskilda Förorenande Ämnen (SFÄ) i ytvattenförekomster. För att bekräfta resultaten bör faktiska mätningar genomföras i dessa delavrinningsområden.
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| 20. |
- ElMeligy, Tarek Aly, et al.
(author)
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Synthesis, characterization, properties, first principles calculations, and X-ray photoelectron spectroscopy of bulk Mn5SiB2 and Fe5SiB2 ternary borides
- 2021
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In: Journal of Alloys and Compounds. - : ELSEVIER SCIENCE SA. - 0925-8388 .- 1873-4669. ; 888
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Journal article (peer-reviewed)abstract
- Herein, we synthesize fully dense, bulk, predominantly single-phase, polycrystalline samples of the layered ternary transition metal borides Mn5SiB2 and Fe5SiB2 by reactively hot-pressing Mn, Fe, FeB, Si, and B powders. The atomic structures were imaged using high-resolution scanning transmission electron mi-croscopy and revealed high-crystal quality. Elongated striped defects, confined below the nanometer in width, were observed. Selected area electron diffraction further accentuates the high-crystal quality by discrete spots of pattern, that is expected from a tetragonal crystal structure along the [001] zone axis. With Vickers hardness values of 12.1 +/- 0.4 GPa, and 12.7 +/- 0.1 GPa, for Mn5SiB2 and Fe5SiB2 respectively, these borides are relatively soft. The room temperature electrical resistivities were 1.5 +/- 0.1 and 1.2 +/- 0.1 mu Omega m, for Mn5SiB2 and Fe5SiB2, respectively. The binding energies of the Mn, Fe and Si measured by X-ray photoelectron spectroscopy bolster the idea that the bonds are quite metallic in character. Density functional theory (DFT) calculations confirm that the ground states of both compounds are ferromagnetic as observed experimentally. We also use DFT to predict the elastic and electronic properties. In both compounds, the density of states at the Fermi level are dominated by the d-orbitals of the transition metals. Neither material was readily machinable with conventional tooling, but is so with sharp cobalt steel bits or electro-discharge machining (EDM). (C) 2021 Elsevier B.V. All rights reserved.
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| 21. |
- Etman, Ahmed, et al.
(author)
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Computationally Driven Discovery of Quaternary Tantalum-Based MAB-Phases: Ta4M & DPRIME;SiB2 (M & DPRIME; = V, Cr, or Mo): Synthesis, Characterization, and Elastic Properties
- 2023
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In: Crystal Growth & Design. - : AMER CHEMICAL SOC. - 1528-7483 .- 1528-7505. ; 23:6, s. 4442-4447
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Journal article (peer-reviewed)abstract
- Out-of-plane chemically ordered transitionmetal boride(o-MAB) phases, Ta4M & DPRIME;SiB2 (M & DPRIME; = V, Cr), and a structurally equivalent disordered solidsolution MAB phase, Ta4MoSiB2, are synthesized.DFT calculations are used to examine the dynamic stability, elasticproperties, and electronic density states of the MAB phases. We report on the synthesis of computationally predictedout-of-planechemically ordered transition metal borides labeled o-MAB phases, Ta4M & DPRIME;SiB2 (M & DPRIME; =V, Cr), and a structurally equivalent disordered solid solution MABphase Ta4MoSiB2. The boride phases were preparedusing solid-state reaction sintering of the constituting elements.High-resolution scanning transmission electron microscopy along withRietveld refinement of the powder-X-ray diffraction patterns revealedthat the synthesized o-MAB phases Ta4CrSiB2 (98 wt % purity) and Ta4VSiB2 (81 wt% purity) possess chemical ordering with Ta preferentially residingin the 16l position and Cr and V in the 4c position, whereas Ta4MoSiB2 (46wt % purity) was concluded to form a disordered solid solution. Densityfunctional theory (DFT) calculations were used to investigate thedynamic stability, elastic properties, and electronic density statesfor the MAB phases, confirming the stability and suggesting the boridesbased on Cr and Mo to be stiffer than those based on V and Nb.
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| 22. |
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| 23. |
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| 24. |
- Feldreich, T., et al.
(author)
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Urinary osteopontin predicts incident chronic kidney disease, while plasma osteopontin predicts cardiovascular death in elderly men
- 2017
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In: CardioRenal Medicine. - : S. Karger AG. - 1664-3828 .- 1664-5502. ; 7:3, s. 245-254
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Journal article (peer-reviewed)abstract
- Background and Objectives: The matricellular protein osteopontin is involved in the pathogenesis of both kidney and cardiovascular disease. However, whether circulating and urinary osteopontin levels are associated with the risk of these diseases is less studied.Design, Setting, Participants, and Measurements: A community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men [ULSAM]; n = 741; mean age: 77 years) was used to study the associations between plasma and urinary osteopontin, incident chronic kidney disease, and the risk of cardiovascular death during a median of 8 years of follow-up.Results: There was no significant cross-sectional correlation between plasma and urinary osteopontin (Spearman Ï = 0.07, p = 0.13). Higher urinary osteopontin, but not plasma osteopontin, was associated with incident chronic kidney disease in multivariable models adjusted for age, cardiovascular risk factors, baseline glomerular filtration rate, urinary albumin/creatinine ratio, and the inflammatory markers interleukin 6 and high-sensitivity C-reactive protein (odds ratio for 1 standard deviation [SD] of urinary osteopontin, 1.42, 95% CI 1.00-2.02, p = 0.048). Conversely, plasma osteopontin, but not urinary osteopontin, was independently associated with cardiovascular death (multivariable hazard ratio per SD increase, 1.35, 95% CI 1.14-1.58, p < 0.001, and 1.00, 95% CI 0.79-1.26, p = 0.99, respectively). The addition of plasma osteopontin to a model with established cardiovascular risk factors significantly increased the C-statistics for the prediction of cardiovascular death (p < 0.002).Conclusions: Higher urinary osteopontin specifically predicts incident chronic kidney disease, while plasma osteopontin specifically predicts cardiovascular death. Our data put forward osteopontin as an important factor in the detrimental interplay between the kidney and the cardiovascular system. The clinical implications, and why plasma and urinary osteopontin mirror different pathologies, remain to be established.
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| 25. |
- Fellström, Bengt, 1947-, et al.
(author)
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Albumin Urinary Excretion Is Associated with Increased Levels of Urinary Chemokines, Cytokines, and Growth Factors Levels in Humans
- 2021
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In: Biomolecules. - : MDPI. - 2218-273X. ; 11:3
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Journal article (peer-reviewed)abstract
- The aim of the present study was to study the associations between urine albumin excretion, and a large number of urinary chemokines, cytokines, and growth factors in a normal population. We selected 90 urine samples from individuals without CVD, diabetes, stroke or kidney disease belonging to the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females, all aged 75 years). Urinary cytokine levels were analyzed with two multiplex assays (proximity extension assays) and the cytokine levels were correlated with urine albumin. After adjustment for sex, body mass index (BMI), estimated glomerular filtration rate (eGFR), smoking and multiplicity testing, 11 biomarkers remained significantly associated with urine albumin: thrombospondin 2, interleukin 6, interleukin 8, hepatocyte growth factor, matrix metalloproteinase-12 (MMP-12), C-X-C motif chemokine 9, tumor necrosis factor receptor superfamily member 11B, osteoprotegerin, growth-regulated alpha protein, C-X-C motif chemokine 6, oncostatin-M (OSM) and fatty acid-binding protein, intestinal, despite large differences in molecular weights. In this study, we found associations between urinary albumin and both small and large urine proteins. Additional studies are warranted to identify cytokine patterns and potential progression markers in various renal diseases.
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