| 1. |
- Lind, Lars, et al.
(författare)
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Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)
- 2021
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Ingår i: eLife. - : eLife Sciences Publications Ltd. - 2050-084X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions.
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| 2. |
- Bixby, H., et al.
(författare)
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Rising rural body-mass index is the main driver of the global obesity epidemic in adults
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 569:7755, s. 260-4
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Tidskriftsartikel (refereegranskat)abstract
- Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.
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| 3. |
- Mishra, A, et al.
(författare)
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Diminishing benefits of urban living for children and adolescents' growth and development
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 615:7954, s. 874-883
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Tidskriftsartikel (refereegranskat)abstract
- Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Vogel, Jacob W., et al.
(författare)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 8. |
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| 9. |
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| 10. |
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| 11. |
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| 12. |
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| 13. |
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 18. |
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| 19. |
- Bentham, James, et al.
(författare)
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A century of trends in adult human height
- 2016
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Ingår i: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3– 19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8– 144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 20. |
- Walters, R G, et al.
(författare)
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A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 463:7281, s. 671-5
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Tidskriftsartikel (refereegranskat)abstract
- Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.
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| 21. |
- Bentham, James, et al.
(författare)
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A century of trends in adult human height
- 2016
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Ingår i: eLIFE. - 2050-084X. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.522.7) and 16.5 cm (13.319.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 22. |
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| 23. |
- Dongiovanni, P, et al.
(författare)
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Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver.
- 2018
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Ingår i: Journal of internal medicine. - : Wiley. - 1365-2796 .- 1365-2796 .- 0954-6820. ; 283:4, s. 356-370
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance.We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS).Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases.These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease.
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| 24. |
- Medina-Gomez, C., et al.
(författare)
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Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects
- 2018
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 102:1, s. 88-102
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Tidskriftsartikel (refereegranskat)abstract
- Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course. © 2017 American Society of Human Genetics
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| 25. |
- Dongiovanni, P., et al.
(författare)
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Transmembrane 6 Superfamily Member 2 Gene Variant Disentangles Nonalcoholic Steatohepatitis From Cardiovascular Disease
- 2015
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Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 61:2, s. 506-514
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Tidskriftsartikel (refereegranskat)abstract
- Excess hepatic storage of triglycerides is considered a benign condition, but nonalcoholic steatohepatitis (NASH) may progress to fibrosis and promote atherosclerosis. Carriers of the TM6SF2 E167K variant have fatty liver as a result of reduced secretion of very-low-density lipoproteins (VLDLs). As a result, they have lower circulating lipids and reduced risk of myocardial infarction. In this study, we aimed to assess whether TM6SF2 E167K affects liver damage and cardiovascular outcomes in subjects at risk of NASH. Liver damage was evaluated in 1,201 patients who underwent liver biopsy for suspected NASH; 427 were evaluated for carotid atherosclerosis. Cardiovascular outcomes were assessed in 1,819 controls from the Swedish Obese Subjects (SOS) cohort. Presence of the inherited TM6SF2 E167K variant was determined by TaqMan assays. In the liver biopsy cohort, 188 subjects (13%) were carriers of the E167K variant. They had lower serum lipid levels than noncarriers (P<0.05), had more-severe steatosis, necroinflammation, ballooning, and fibrosis (P<0.05), and were more likely to have NASH (odds ratio [OR]: 1.84; 95% confidence interval [CI]: 1.23-2.79) and advanced fibrosis (OR, 2.08; 95% CI: 1.20-3.55), after adjustment for age, sex, body mass index, fasting hyperglycemia, and the I148M PNPLA3 risk variant. However, E167K carriers had lower risk of developing carotid plaques (OR, 0.49; 95% CI: 0.25-0.94). In the SOS cohort, E167K carriers had higher alanine aminotransferase ALT and lower lipid levels (P<0.05), as well as a lower incidence of cardiovascular events (hazard ratio: 0.61; 95% CI: 0.39-0.95). Conclusions: Carriers of the TM6SF2 E167K variant are more susceptible to progressive NASH, but are protected against cardiovascular disease. Our findings suggest that reduced ability to export VLDLs is deleterious for the liver. (Hepatology 2015;61:506-514)
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| 26. |
- Falchi, M., et al.
(författare)
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Low copy number of the salivary amylase gene predisposes to obesity
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:5, s. 492-497
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Tidskriftsartikel (refereegranskat)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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| 27. |
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| 28. |
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| 29. |
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| 30. |
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| 31. |
- Wilking, N., et al.
(författare)
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Long-term follow-up of the SBG 9401 study comparing tailored FEC-based therapy versus marrow-supported high-dose therapy
- 2007
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 18:4, s. 694-700
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Tidskriftsartikel (refereegranskat)abstract
- Background: The purpose was to investigate adjuvant marrow-supportive high-dose chemotherapy compared with an equitoxicity-tailored comparator arm. Patients and methods: Five hundred and twenty-five women below theage of 60 years with operated high-risk primary breast cancer were randomised to nine cycles of granulocyte colony-stimulating factor supported and individually tailored FEC (5-fluorouracil, epirubicin, cyclophosphamide), (n = 251) or standard FEC followed by marrow-supported high-dose therapy with CTCb (cyclophosphamide, thiotepa, carboplatin) therapy (n = 274), followed by locoregional radiotherapy and tamoxifen for 5 years. Results: There were 104 breast cancer relapses in the tailored FEC group versus 139 in the CTCb group (double triangular method by Whitehead, P = 0.046), with a median follow-up of all included patients of 60.8 months. The event-free survival demonstrated 121 and 150 events in the tailored FEC- and CTCb group, respectively [P = 0.074, hazard ratio (HR) 0.804, 95% confidence interval (CI) 0.633-1.022]. Ten patients in the tailored FEC regimen developed acute myeloid leukaemia (AML)/myelodysplasia (MDS). One hundred deaths occurred in the tailored FEC group and 121 in the CTCb group (P = 0.287, HR 0.866, 95% CI 0.665-1.129). Conclusion: The update of this study shows an improved outcome linked to the tailored FEC treatment in relation to breast cancer relapse, but also an increased incidence of AML/MDS. © 2007 Oxford University Press.
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| 32. |
- Brunkwall, J., et al.
(författare)
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Endovascular Repair of Acute Uncomplicated Aortic Type B Dissection Promotes Aortic Remodelling: 1 Year Results of the ADSORB Trial
- 2014
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Ingår i: European Journal of Vascular and Endovascular Surgery. - : Elsevier BV. - 1532-2165 .- 1078-5884. ; 48:3, s. 285-291
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Uncomplicated acute type B aortic dissection (AD) treated conservatively has a 10% 30-day mortality and up to 25% need intervention within 4 years. In complicated AD, stent grafts have been encouraging. The aim of the present prospective randomised trial was to compare best medical treatment (BMT) with BMT and Gore TAG stent graft in patients with uncomplicated AD. The primary endpoint was a combination of incomplete/no false lumen thrombosis, aortic dilatation, or aortic rupture at 1 year. Methods: The AD history had to be less than 14 days, and exclusion criteria were rupture, impending rupture, malperfusion. Of the 61 patients randomised, 80% were DeBakey type IIIB. Results: Thirty-one patients were randomised to the BMT group and 30 to the BMT+TAG group. Mean age was 63 years for both groups. The left subclavian artery was completely covered in 47% and in part in 17% of the cases. During the first 30 days, no deaths occurred in either group, but there were three crossovers from the BMT to the BMT TAG group, all due to progression of disease within 1 week. There were two withdrawals from the BMT+TAG group. At the 1-year follow up there had been another two failures in the BMT group: one malperfusion and one aneurysm formation (p = .056 for all). One death occurred in the BMT TAG group. For the overall endpoint BMT+TAG was significantly different from BMT only (p < .001). Incomplete false lumen thrombosis, was found in 13 (43%) of the TAG+BMT group and 30 (97%) of the BMT group (p < .001). The false lumen reduced in size in the BMT+TAG group (p < .001) whereas in the BMT group it increased. The true lumen increased in the BMT TAG (p < .001) whereas in the BMT group it remained unchanged. The overall transverse diameter was the same at the beginning and after 1 year in the BMT group (42.1 mm), but in the BMT+TAG it decreased (38.8 mm; p = .062). Conclusions: Uncomplicated AD can be safely treated with the Gore TAG device. Remodelling with thrombosis of the false lumen and reduction of its diameter is induced by the stent graft, but long term results are needed. (C) 2014 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.
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| 33. |
- Carlsson, Ella, et al.
(författare)
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Mass composition of the escaping plasma at Mars
- 2006
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Ingår i: Icarus. - : Elsevier BV. - 0019-1035 .- 1090-2643. ; 182:2, s. 320-328
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Tidskriftsartikel (refereegranskat)abstract
- Data from the Ion Mass Analyzer (IMA) sensor of the ASPERA-3 instrument suite on Mars Express have been analyzed to determine the mass composition of the escaping ion species at Mars. We have examined 77 different ion-beam events and we present the results in terms of flux ratios between the following ion species: CO2+/O+ and O-2(+)/O+. The following ratios averaged over all events and energies were identified: CO2+/O+ = 0.2 and O-2(+)/O+ = 0.9. The values measured are significantly higher, by a factor of 10 for O-2(+)/O+, than a contemporary modeled ratio for the maximum fluxes which the martian ionosphere can supply. The most abundant ion species was found to be O+, followed by O-2(+) and CO2+. We estimate the loss of CO2+ to be 4.0 x 10(24) s(-1) (0.29 kg s(-1)) by using the previous measurements of Phobos-2 in our calculations. The dependence of the ion ratios in relation to their energy ranges we studied, 0.3-3.0 keV, indicated that no clear correlation was found.
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| 34. |
- Chauvier, D, et al.
(författare)
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Targeting neonatal ischemic brain injury with a pentapeptide-based irreversible caspase inhibitor.
- 2011
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Ingår i: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Brain protection of the newborn remains a challenging priority and represents a totally unmet medical need. Pharmacological inhibition of caspases appears as a promising strategy for neuroprotection. In a translational perspective, we have developed a pentapeptide-based group II caspase inhibitor, TRP601/ORPHA133563, which reaches the brain, and inhibits caspases activation, mitochondrial release of cytochrome c, and apoptosis in vivo. Single administration of TRP601 protects newborn rodent brain against excitotoxicity, hypoxia-ischemia, and perinatal arterial stroke with a 6-h therapeutic time window, and has no adverse effects on physiological parameters. Safety pharmacology investigations, and toxicology studies in rodent and canine neonates, suggest that TRP601 is a lead compound for further drug development to treat ischemic brain damage in human newborns.
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| 35. |
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| 36. |
- Hoscheidt, S. M., et al.
(författare)
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Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults
- 2016
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Ingår i: Journal of Alzheimers Disease. - 1387-2877. ; 52:4, s. 1373-1383
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Tidskriftsartikel (refereegranskat)abstract
- Background: Type 2 diabetes is associated with an increased risk for Alzheimer's disease (AD). Regulation of normal insulin function may be important in reducing the prevalence of dementia due to AD, particularly in individuals who harbor genetic risk for or have a parental family history of AD. The relationship between insulin resistance (IR) and AD pathology remains poorly understood, particularly in midlife prior to the onset of clinical metabolic disease or cognitive decline. Objective: We examined associations between IR as indexed by HOMA-IR, cerebrospinal fluid (CSF) biomarkers of AD pathology, and memory in middle-aged adults enriched for AD. We postulated that higher HOMA-IR and APOE epsilon 4 carriage would be associated with greater CSF AD pathology and poor memory performance. Methods: Cognitively asymptomatic middle-aged adults (N = 70, mean age = 57.7 years) from the Wisconsin Alzheimer's Disease Research Center with a parental family history of dementia due to AD underwent lumbar puncture, blood draw, and neuropsychological testing. CSF AD biomarkers including soluble amyloid-beta protein precursor beta (sA beta PP beta), amyloid-beta 42 (A beta(42)), and phosphorylated tau (P-tau(181)) were examined with respect to HOMA-IR and APOE epsilon 4 status. Delayed memory performance was examined with respect to HOMA-IR, CSF AD biomarkers, and APOE epsilon 4 status. Results: Higher HOMA-IR was associated with higher sA beta PP beta and A beta(42). APOE epsilon 4 carriers had significantly higher levels of sA beta PP beta, sA beta PP beta, and P-tau(181)/A beta(42) compared to noncarriers. The concurrent presence of higher HOMA-IR and CSF AD pathology predicted worse delayed memory performance. Conclusion: Overall, the findings suggest that IR and APOE epsilon 4 are contributing factors to the development of AD pathology in midlife, and provide support for targeting insulin function as a potentially modifiable risk factor for AD.
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| 37. |
- Hultborn, Ragnar, 1946, et al.
(författare)
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Efficacy of pamidronate in breast cancer with bone metastases: a randomized, double-blind placebo-controlled multicenter study
- 1999
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Ingår i: Anticancer Res. - 0250-7005. ; 19:4C, s. 3383-92
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To evaluate the efficacy of pamidronate 60 mg i.v. q 4 weeks in women with advanced breast cancer with skeletal metastases. PATIENTS AND METHODS: 404 woman with skeletal metastases from breast cancer in Sweden and Norway were included in a randomized, placebo-controlled, multicenter study. Except for the study medication, other palliative treatment was chosen at the discretion of the physician. Skeletal related events, i.e. increased pain, treatment of hypercalcemia, pathologic fractures of long bones or pelvis, paralyses due to vertebral compression, palliative radiotherapy for skeletal metastases, surgery on bone and change of antitumor therapy were recorded every third month as well as a self-estimated pain-score using visual Analog Scales and analgesic consumption. RESULTS: There was a significantly increased time to progression of pain (p < 0.01), to hypercalcemic events (p < 0.05) as well as for the cumulative number of skeletal related events (p < 0.01) in favor for the pamidronate group. No statistically significant reduction of pathologic fractures of long bones or pelvis, or pareses due to vertebral compression occurred. No statistically significant differences were found for the need of radiotherapy and surgery on bone. The pamidronate group faired better regarding performance status (p < 0.05). There was a statistically not significant lower consumption of opioid analgesics in the pamidronate group (p = 0.14). CONCLUSION: Pamidronate 60 mg i.v. q 4 weeks reduces skeletal events and improves the quality of life in women with bone metastases from breast cancer.
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| 38. |
- Johnson, Magnus S.C. 1969, et al.
(författare)
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Interaction of scavenger receptor class B type I with peroxisomal targeting receptor Pex5p.
- 2003
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Ingår i: Biochemical and biophysical research communications. - 0006-291X. ; 312:4, s. 1325-34
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Tidskriftsartikel (refereegranskat)abstract
- Scavenger receptor class B type I (SR-BI) is an HDL receptor that mediates selective HDL lipid uptake. Peroxisomes play an important role in lipid metabolism and peroxisomal targeting signal type 1 (PTS1)-containing proteins are translocated to peroxisomes by the peroxisomal targeting import receptor, Pex5p. We have previously identified a PTS1 motif in the intracellular domain of rat SR-BI. Here, we examine the possible interaction between Pex5p and SR-BI. Expression of a Flag-tagged intracellular domain of SR-BI resulted in translocation to the peroxisome as demonstrated by double labeling with anti-Flag IgG and anti-catalase IgG analyzed by confocal microscopy. Immunoprecipitation experiments with anti-SR-BI antibody showed that Pex5p co-precipitated with SR-BI. However, when an antibody against Pex5p was used for immunoprecipitation, only the 57kDa, non-glycosylated form, of SR-BI co-precipitated. We conclude that the PTS1 domain of SR-BI is functional and can mediate peroxisomal interaction via Pex5p, in vitro.
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| 39. |
- Langefeld, Carl D., et al.
(författare)
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Transancestral mapping and genetic load in systemic lupus erythematosus
- 2017
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
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| 40. |
- Lehmann, O. J., et al.
(författare)
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Novel anterior segment phenotypes resulting from forkhead gene alterations: Evidence for cross-species conservation of function
- 2003
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404 .- 1552-5783. ; 44:6, s. 2627-2633
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. Mutations in murine and human Versions of an ancestrally related gene usually result in similar phenotypes. However, interspecics differences exist, and in the case of two forkhead transcription factor genes (FOXC1 and FOXC2), these differences include corneal or anterior segment phenotypes, respectively. This study was undertaken to determine whether such discrepancies provide an opportunity for identifying novel human-murine ocular phenotypes. METHODS. Four pedigrees with early-onset glaucoma phenotypes secondary to segmental chromosomal duplications or deletions encompassing FOXC1 and 18 individuals from 9 FOXC2 mutation pedigrees underwent detailed ocular phenotyping. Subsequently, mice with mutations in Foxc1 or a related forkhead gene, Foxe3, were assessed for features of the human phenotypes. RESULTS. A significant increase in central corneal thickness was present in affected individuals from the segmental duplication pedigrees compared with their unaffected relatives (mean increase 13%, maximum 35%, P < 0.05). Alterations in corneal thickness were present in mice heterozygous and homozygous for Foxe3 mutations but neither in Foxc1 heterozygotes nor the small human segmental deletion pedigree. Mutations in FOXC2 resulted in ocular anterior segment anomalies. These were more severe and prevalent with mutations involving the forkhead domain. CONCLUSIONS. Normal corneal development is dependent on the precise dose and levels of activity of certain forkhead transcription factors. The altered corneal thickness attributable to increased forkhead gene dosage is particularly important, because it may affect the clinical management of certain glaucoma subtypes and lead to excessive treatment. The FOXC1 and Foxe3 data, taken together with the novel ocular phenotypes of FOXC2 mutations, highlight the remarkable cross-species conservation of function among forkhead genes.
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| 41. |
- Mattsson, S., et al.
(författare)
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Radiation Dose to Patients from from Radiopharmaceuticals: a Compendium of Current Information Related to Frequently Used Substances.
- 2015
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This report provides a compendium of current information relating to radiation dose to patients, including biokinetic models, biokinetic data, dose coefficients for organ and tissue absorbed doses, and effective dose for major radiopharmaceuticals based on the radiation protection guidance given in Publication 60 (ICRP, 1991). These data were mainly compiled from Publications 53 , 80, and 106 (ICRP, 1987, 1998, 2008), and related amendments and corrections. This report also includes new information for 82 Rb-chloride, iodide (123 I, 124 I, 125 I, and 131 I) and 123 Ilabelled 2.-carbomethoxy 3.-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FPCIT). The coefficients tabulated in this publication will be superseded in due course by values calculated using new International Commission on Radiation Units and Measurements/International Commission on Radiological Protection adult and paediatric reference phantoms and Publication 103 methodology (ICRP, 2007). The data presented in this report are intended for diagnostic nuclear medicine and not for therapeutic applications.
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| 42. |
- Tsiligiannis, Epameinondas, et al.
(författare)
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A Four Carbon Organonitrate as a Significant Product of Secondary Isoprene Chemistry
- 2022
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Ingår i: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 49:11
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Tidskriftsartikel (refereegranskat)abstract
- Oxidation of isoprene by nitrate radicals (NO3) or by hydroxyl radicals (OH) under high NOx conditions forms a substantial amount of organonitrates (ONs). ONs impact NOx concentrations and consequently ozone formation while also contributing to secondary organic aerosol. Here we show that the ONs with the chemical formula C4H7NO5 are a significant fraction of isoprene-derived ONs, based on chamber experiments and ambient measurements from different sites around the globe. From chamber experiments we found that C4H7NO5 isomers contribute 5%-17% of all measured ONs formed during nighttime and constitute more than 40% of the measured ONs after further daytime oxidation. In ambient measurements C4H7NO5 isomers usually dominate both nighttime and daytime, implying a long residence time compared to C-5 ONs which are removed more rapidly. We propose potential nighttime sources and secondary formation pathways, and test them using a box model with an updated isoprene oxidation scheme.
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| 43. |
- Wharton, W., et al.
(författare)
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The Effects of Ramipril in Individuals at Risk for Alzheimer's Disease: Results of a Pilot Clinical Trial
- 2012
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 32:1, s. 147-156
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Tidskriftsartikel (refereegranskat)abstract
- Research shows that certain antihypertensives taken during midlife confer Alzheimer's disease (AD) related benefits in later life. We conducted a clinical trial to evaluate the extent to which the angiotensin converting enzyme inhibitor (ACE-I), ramipril, affects AD biomarkers including cerebrospinal fluid (CSF) amyloid-beta (A beta) levels and ACE activity, arterial function, and cognition in participants with a parental history of AD. This four month randomized, double-blind, placebo-controlled, pilot clinical trial evaluated the effects of ramipril, a blood-brain-barrier crossing ACE-I, in cognitively healthy individuals with mild, or Stage I hypertension. Fourteen participants were stratified by gender and apolipoprotein E epsilon 4 (APOE epsilon 4) status and randomized to receive 5mg of ramipril or matching placebo daily. Participants were assessed at baseline and month 4 on measures of CSF A beta(1-42) and ACE activity, arterial function, and cognition. Participants were middle-aged (mean 54 y) and highly educated (mean 15.4 y), and included 50% men and 50% APOE epsilon 4 carriers. While results did not show a treatment effect on CSF A beta(1-42) (p = 0.836), data revealed that ramipril can inhibit CSF ACE activity (p = 0.009) and improve blood pressure, however, there were no differences between groups in arterial function or cognition. In this study, ramipril therapy inhibited CSF ACE activity and improved blood pressure, but did not influence CSF A beta(1-42). While larger trials are needed to confirm our CSF A beta results, it is possible that prior research reporting benefits of ACE-I during midlife may be attributed to alternative mechanisms including improvements in cerebral blood flow or the prevention of angiotensin II-mediated inhibition of acetylcholine.
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| 44. |
- Wu, R. R., et al.
(författare)
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Molecular composition and volatility of multi-generation products formed from isoprene oxidation by nitrate radical
- 2021
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Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 21:13, s. 10799-10824
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Tidskriftsartikel (refereegranskat)abstract
- Isoprene oxidation by nitrate radical (NO3) is a potentially important source of secondary organic aerosol (SOA). It is suggested that the second or later-generation products are the more substantial contributors to SOA. However, there are few studies investigating the multi-generation chemistry of isoprene-NO3 reaction, and information about the volatility of different isoprene nitrates, which is essential to evaluate their potential to form SOA and determine their atmospheric fate, is rare. In this work, we studied the reaction between isoprene and NO3 in the SAPHIR chamber (Julich) under near-atmospheric conditions. Various oxidation products were measured by a high-resolution time-offlight chemical ionization mass spectrometer using Br as the reagent ion. Most of the products detected are organic nitrates, and they are grouped into monomers (C-4 and C-5 products) and dimers (C-10 products) with 1-3 nitrate groups according to their chemical composition. Most of the observed products match expected termination products observed in previous studies, but some compounds such as monomers and dimers with three nitrogen atoms were rarely reported in the literature as gas-phase products from isoprene oxidation by NO3. Possible formation mechanisms for these compounds are proposed. The multi-generation chemistry of isoprene and NO3 is characterized by taking advantage of the time behavior of different products. In addition, the vapor pressures of diverse isoprene nitrates are calculated by different parametrization methods. An estimation of the vapor pressure is also derived from their condensation behavior. According to our results, isoprene monomers belong to intermediate-volatility or semi-volatile organic compounds and thus have little effect on SOA formation. In contrast, the dimers are expected to have low or extremely low volatility, indicating that they are potentially substantial contributors to SOA. However, the monomers constitute 80% of the total explained signals on average, while the dimers contribute less than 2 %, suggesting that the contribution of isoprene NO3 oxidation to SOA by condensation should be low under atmospheric conditions. We expect a SOA mass yield of about 5% from the wall-loss- and dilution-corrected mass concentrations, assuming that all of the isoprene dimers in the low- or extremely low-volatility organic compound (LVOC or ELVOC) range will condense completely.
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| 45. |
- Zhou, Bin, et al.
(författare)
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Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants
- 2016
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Ingår i: The Lancet. - : Elsevier B.V.. - 0140-6736 .- 1474-547X. ; 387:10027, s. 1513-1530
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Tidskriftsartikel (refereegranskat)abstract
- Background: One of the global targets for non-communicable diseases is to halt, by 2025, the rise in the age standardised adult prevalence of diabetes at its 2010 levels. We aimed to estimate worldwide trends in diabetes, how likely it is for countries to achieve the global target, and how changes in prevalence, together with population growth and ageing, are aff ecting the number of adults with diabetes.Methods: We pooled data from population-based studies that had collected data on diabetes through measurement of its biomarkers. We used a Bayesian hierarchical model to estimate trends in diabetes prevalence-defined as fasting plasma glucose of 7.0 mmol/L or higher, or history of diagnosis with diabetes, or use of insulin or oral hypoglycaemic drugs-in 200 countries and territories in 21 regions, by sex and from 1980 to 2014. We also calculated the posterior probability of meeting the global diabetes target if post-2000 trends continue.Findings: We used data from 751 studies including 4372000 adults from 146 of the 200 countries we make estimates for. Global age-standardised diabetes prevalence increased from 4.3% (95% credible interval 2.4-17.0) in 1980 to 9.0% (7.2-11.1) in 2014 in men, and from 5.0% (2.9-7.9) to 7.9% (6.4-9.7) in women. The number of adults with diabetes in the world increased from 108 million in 1980 to 422 million in 2014 (28.5% due to the rise in prevalence, 39.7% due to population growth and ageing, and 31.8% due to interaction of these two factors). Age-standardised adult diabetes prevalence in 2014 was lowest in northwestern Europe, and highest in Polynesia and Micronesia, at nearly 25%, followed by Melanesia and the Middle East and north Africa. Between 1980 and 2014 there was little change in age-standardised diabetes prevalence in adult women in continental western Europe, although crude prevalence rose because of ageing of the population. By contrast, age-standardised adult prevalence rose by 15 percentage points in men and women in Polynesia and Micronesia. In 2014, American Samoa had the highest national prevalence of diabetes (>30% in both sexes), with age-standardised adult prevalence also higher than 25% in some other islands in Polynesia and Micronesia. If post-2000 trends continue, the probability of meeting the global target of halting the rise in the prevalence of diabetes by 2025 at the 2010 level worldwide is lower than 1% for men and is 1% for women. Only nine countries for men and 29 countries for women, mostly in western Europe, have a 50% or higher probability of meeting the global target.Interpretation: Since 1980, age-standardised diabetes prevalence in adults has increased, or at best remained unchanged, in every country. Together with population growth and ageing, this rise has led to a near quadrupling of the number of adults with diabetes worldwide. The burden of diabetes, both in terms of prevalence and number of adults aff ected, has increased faster in low-income and middle-income countries than in high-income countries.
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| 46. |
- Allison, S. L., et al.
(författare)
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Comparison of different MRI-based morphometric estimates for defining neurodegeneration across the Alzheimer's disease continuum
- 2019
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Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several neurodegeneration (N) metrics using structural MRI are used for the purpose of Alzheimer's disease (AD)-related staging, including hippocampal volume, global atrophy, and an “AD signature” composite consisting of thickness or volumetric estimates derived from regions impacted early in AD. This study sought to determine if less user-intensive estimates of global atrophy and hippocampal volume were equivalent to a thickness-based AD signature from FreeSurfer for defining N across the AD continuum (i.e., individuals who are amyloid-positive (A+)). Methods: Cognitively unimpaired (CU) late middle-aged and older adults, as well as A+ mild cognitive impairment (MCI) and A+ AD dementia individuals, with available CSF and structural MRI scan <1.5 years apart, were selected for the study (n = 325, mean age = 62). First, in a subsample of A+ AD dementia and matched biomarker-negative (i.e., A- and tau tangle pathology (T)-) CU controls (n = 40), we examined ROC characteristics and identified N cut-offs using Youden's J for neurofilament light chain protein (NfL) and each of three MRI-based measures: a thickness-based AD signature from FreeSurfer, hippocampal volume (using FIRST), and a simple estimate of global atrophy (the ratio of intracranial CSF segmented volume to brain tissue volume, using SPM12). Based on the results from the ROC analyses, we then examined the concordance between NfL N positivity and N positivity for each MRI-based metric using Cohen's Kappa in the remaining subsample of 285 individuals. Finally, in the full sample (n = 325), we examined the relationship between the four measures of N and group membership across the AD continuum using Kruskal-Wallis tests and Cliff's deltas. Results: The three MRI-based metrics and CSF NfL similarly discriminated between the A-T- CU (n = 20) and A+ AD (n = 20) groups (AUCs ≥0.885; ps < 0.001). Using the cut-off values derived from the ROCs to define N positivity, there was weak concordance between NfL and all three MRI-derived metrics of N in the subsample of 285 individuals (Cohen's Kappas ≤0.429). Finally, the three MRI-based measures of N and CSF NfL showed similar associations with AD continuum group (i.e., Kruskal-Wallis ps < 0.001), with relatively larger effect sizes noted when comparing the A-T- CU to the A+ MCI (Cliff's deltas ≥0.741) and A+ AD groups (Cliff's deltas ≥0.810) than to the A+T- CU (Cliff's deltas = 0.112–0.298) and A + T+ CU groups (Cliff's deltas = 0.212–0.731). Conclusions: These findings suggest that the three MRI-based morphometric estimates and CSF NfL similarly differentiate individuals across the AD continuum on N status. In many applications, a simple estimate of global atrophy may be preferred as an MRI marker of N across the AD continuum given its methodological robustness and ease of calculation when compared to hippocampal volume or a cortical thickness AD signature. © 2019
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| 47. |
- Bauer, K., et al.
(författare)
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Welcome message from the PADE chairs
- 2013
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Ingår i: Welcome message from the PADE chairs (Editorial). - : IEEE Computer Society. - 9781479905379 ; , s. lxi-lxii
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 48. |
- Bettcher, B. M., et al.
(författare)
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Cerebrospinal Fluid and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer's Disease Pathology and Neuronal Damage
- 2018
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 62:1, s. 385-397
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Tidskriftsartikel (refereegranskat)abstract
- Inflammatory markers have been shown to predict neurocognitive outcomes in aging adults; however, the degree to which peripheral markers mirror the central nervous system remains unknown. We investigated the association between plasma and cerebrospinal fluid (CSF) markers of inflammation, and explored whether these markers independently predict CSF indicators of Alzheimer's disease (AD) pathology or neuronal damage. Plasma and CSF samples were analyzed for inflammatory markers in a cohort of asymptomatic older adults (n = 173). CSF samples were analyzed for markers of AD pathology (A beta(42), phosphorylated tau [p-tau], sA beta PP beta) or neuronal damage (total tau; neurofilament light chain) (n = 147). Separate linear models for each analyte were conducted with CSF and plasma levels entered simultaneously as predictors and markers of AD pathology or neuronal damage as outcome measures. Strong associations were noted between CSF and plasma MIP-1 beta levels, and modest associations were observed for remaining analytes. With respect to AD pathology, higher levels of plasma and CSF IL-8, CSF MIP-1 beta, and CSF IP-10 were associated with higher levels of p-tau. Higher levels of CSF IL-8 were associated with higher levels of CSF A beta(42). Higher CSF sA beta PP beta levels were associated with higher plasma markers only (IL-8; MCP-1). In terms of neuronal injury, higher levels of plasma and CSF IL-8, CSF IP-10, and CSF MIP-1 beta were associated with higher levels of CSF total tau. Exploratory analyses indicated that CSF A beta(42) modifies the relationship between plasma inflammatory levels and CSF tau levels. Results suggest that both plasma and CSF inflammatory markers independently relay integral information about AD pathology and neuronal damage.
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| 49. |
- Brownwood, B., et al.
(författare)
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Gas-Particle Partitioning and SOA Yields of Organonitrate Products from NO3-Initiated Oxidation of Isoprene under Varied Chemical Regimes
- 2021
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Ingår i: Acs Earth and Space Chemistry. - : American Chemical Society (ACS). - 2472-3452. ; 5:4, s. 785-800
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Tidskriftsartikel (refereegranskat)abstract
- Alkyl nitrate (AN) and secondary organic aerosol (SOA) from the reaction of nitrate radicals (NO3) with isoprene were observed in the Simulation of Atmospheric PHotochemistry In a large Reaction (SAPHIR) chamber during the NO(3)Isop campaign in August 2018. Based on 15 day-long experiments under various reaction conditions, we conclude that the reaction has a nominally unity molar AN yield (observed range 90 +/- 40%) and an SOA mass yield of OA + organic nitrate aerosol of 13-15% (with similar to 50 mu g m(-3) inorganic seed aerosol and 2-5 mu g m-3 total organic aerosol). Isoprene (5-25 ppb) and oxidant (typically similar to 100 ppb O-3 and 5-25 ppb NO2) concentrations and aerosol composition (inorganic and organic coating) were varied while remaining close to ambient conditions, producing similar AN and SOA yields under all regimes. We observe the formation of dinitrates upon oxidation of the second double bond only once the isoprene precursor is fully consumed. We determine the bulk partitioning coefficient for ANs (K-p similar to 10(-3) m(3) mu g(-1)), indicating an average volatility corresponding to a C-5 hydroxy hydroperoxy nitrate.
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| 50. |
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