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  • Forsberg, Lars A., et al. (författare)
  • Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer
  • 2014
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 46:6, s. 624-628
  • Tidskriftsartikel (refereegranskat)abstract
    • Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained(1,2). Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells(3,4), but the phenotypic consequences of LOY have been elusive(5-10). From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91, 95% confidence interval (CI) = 1.17-3.13; 637 events) and non-hematological cancer mortality (HR = 3.62, 95% CI = 1.56-8.41; 132 events). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter. Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.
  • Fox, Glen A, et al. (författare)
  • Health of herring gulls (Larus argentatus) in relation to breeding location in the early 1990s III. Effects on the bone tissue
  • 2008
  • Ingår i: Journal of Toxicology and Environmental Health. - 1528-7394 .- 1087-2620. ; 71:21, s. 1448-1456
  • Tidskriftsartikel (refereegranskat)abstract
    • Health effects associated with the Great Lakes environment were assessed in adult herring gulls (Larus argentatus) in the early 1990s, including the size and quality of their bones. Femurs were excised from 140 individuals from 10 colonies distributed throughout the Great Lakes and 2 reference colonies in Lake Winnipeg (freshwater) and the Bay of Fundy (marine). Femurs of gulls from the Great Lakes differed from the freshwater or marine reference for 9 of 12 variables of size, composition, and strength assessed using peripheral quantitative computed tomography (pQCT) and biomechanical testing. Femurs of Great Lakes gulls were significantly smaller in length (-2.9%), periosteal circumference (-2.4%), and cross-sectional area (-5.4%) than freshwater reference birds. Femurs of the Great Lakes gulls had a lower significant cortical bone mineral content (-8.1%) and density (-2%) than the marine reference. A significant increase in the amount the bone could bend before it broke (+34%) and the energy required to break it (+44%) and a significant decrease (-16.3%) in stiffness during three-point biomechanical bending test were also detected in Great Lakes versus the freshwater gulls. These differences are indicative of impaired mineralization. When divided into high and low 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity equivalent (TCDD-TEQ) colonies, the amount the bone could bend before it broke and the energy required to break it were significantly higher in the high TEQ colonies, but not high polychlorinated biphenyl (PCB) colonies. Breeding location and dietary choices of Great Lakes herring gulls in the early 1990s resulted in modulations of physiological processes that affected the size, mineralization, and biomechanical properties of bone.
  • Jobs, Elisabeth, et al. (författare)
  • Serum cathepsin S is associated with decreased insulin sensitivity and the development of diabetes type 2 in a community-based cohort of elderly men
  • 2013
  • Ingår i: Diabetes Care. - 0149-5992 .- 1935-5548. ; 36:1, s. 163-165
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE:To investigate associations between serum cathepsin S, impaired insulin sensitivity, defective insulin secretion, and diabetes risk in a community-based sample of elderly men without diabetes.RESEARCH DESIGN AND METHODS:Serum cathepsin S, insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin secretion (early insulin response during an oral glucose tolerance test) were measured in 905 participants of the Uppsala Longitudinal Study of Adult Men (mean age, 71 years). Thirty participants developed diabetes during 6 years of follow-up.RESULTS:After adjustment for age, anthropometric variables, and inflammatory markers, higher cathepsin S was associated with decreased insulin sensitivity (regression coefficient per SD increase -0.09 [95% CI -0.14 to -0.04], P = 0.001), but no association with early insulin response was found. Moreover, higher cathepsin S was associated with a higher risk for developing diabetes (odds ratio per SD increase 1.48 [1.08-2.01], P = 0.01).CONCLUSIONS:Cathepsin S activity appears to be involved in the early dysregulation of glucose and insulin metabolism.
  • Jobs, Elisabeth, et al. (författare)
  • Serum cathepsin S is associated with serum C-reactive protein and interleukin-6 independently of obesity in elderly men
  • 2010
  • Ingår i: Journal of Clinical Endocrinology and Metabolism. - 0021-972X .- 1945-7197. ; 95:9, s. 4460-4464
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Cathepsin S has been suggested provide a mechanistic link between obesity and atherosclerosis, possibly mediated via adipose tissue-derived inflammation. Previous data have shown an association between circulating cathepsin S and inflammatory markers in the obese, but to date, community-based reports are lacking. Accordingly, we aimed to investigate the association between serum levels of cathepsin S and markers of cytokine-mediated inflammation in a community-based sample, with prespecified subgroup analyses in nonobese participants. METHODS: Serum cathepsin S, C-reactive protein (CRP), and IL-6 were measured in a community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men; mean age 71 years, n = 991). CRP and IL-6 were also measured at a reexamination after 7 yr. RESULTS: After adjustment for age, body mass index, fasting plasma glucose, diabetes treatment, systolic blood pressure, diastolic blood pressure, hypertension treatment, serum cholesterol, serum high-density lipoprotein cholesterol, prior cardiovascular disease, smoking, and leisure time physical activity, higher cathepsin S was associated with higher CRP (regression coefficient for 1 sd increase, 0.13; 95% confidence interval 0.07-0.19; P < 0.001) and higher serum IL-6 (regression coefficient for 1 sd increase, 0.08; 95% confidence interval 0.01-0.14; P = 0.02). These associations remained similar in normal-weight participants (body mass index <25 kg/m(2), n = 375). In longitudinal analyses, higher cathepsin S at baseline was associated with higher serum CRP and IL-6 after 7 yr. CONCLUSIONS: These results provide additional evidence for the interplay between cathepsin S and inflammatory activity and suggest that this association is present also in normal-weight individuals in the community.
  • Joshi, Peter K, et al. (författare)
  • Directional dominance on stature and cognition in diverse human populations
  • 2015
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
  • Tidskriftsartikel (refereegranskat)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.
  • Kullberg, Joel, et al. (författare)
  • Practical approach for estimation of subcutaneous and visceral adipose tissue
  • 2007
  • Ingår i: Clinical Physiology and Functional Imaging. - 1475-0961 .- 1475-097X. ; 27:3, s. 148-153
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: The first objective was to investigate the correlations between anthropometrical measurements and visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in two cohorts differing in age using magnetic resonance imaging (MRI) as reference. A second objective was to investigate the potential usage of abdominal diameters in practical estimation of adipose tissue compartments using these cohorts. Methods: Measurements of body mass index, waist circumference, sagittal abdominal diameter (sagittal AD) and transverse abdominal diameter (transverse AD) were obtained from 336 volunteers of age 14-70 years. Manual measurements of VAT and SAT from single slice MRI at the L4-L5 level were used as reference. The abdominal diameters were measured from the MR images. Linear correlations between the anthropometrical measurements and the reference were studied. Results: Sagittal AD showed the strongest correlation to VAT (r > 0·780, P<0·0001) and transverse AD was found to give information about the amount of SAT (r > 0·866, P<0·0001). The ellipse spanned by the sagittal AD and the transverse AD was strongly correlated to the total amount of adipose tissue (r ≥ 0·962 P<0·0001). Conclusion: Strong correlations were found between sagittal and transverse abdominal diameters, assessed using MRI, and VAT and SAT, respectively. These results suggest the use of abdominal diameters in practical estimations of VAT and SAT depots.
  • Kumar, Jitender, et al. (författare)
  • Influence of persistent organic pollutants on oxidative stress in population-based samples
  • 2014
  • Ingår i: Chemosphere. - 0045-6535 .- 1879-1298. ; 114, s. 303-309
  • Tidskriftsartikel (refereegranskat)abstract
    • Persistent organic pollutants (POPs) are a large group of chemicals widely used and produced in various industrial applications. Many cell culture/animal studies have shown that POPs can induce oxidative stress. Since such data is lacking in humans, we conducted a large population-based study to analyze associations between POPs and oxidative stress markers. We measured following POPs; 16 polychlorinated biphenyls (PCBs), 5 organochlorine (OC) pesticides, octachlorinated dibenzo-p-dioxin, and polybrominated diphenyl ether 47, and oxidative stress markers; homocysteine, reduced [GSH] and oxidized glutathione [GSSG], glutathione ratio [GSSG/GSH], total glutathione, oxidized low-density lipoprotein [ox-LDL], ox-LDL antibodies, conjugated dienes, baseline conjugated dienes of LDL, and total anti-oxidative capacity in plasma samples collected from 992 70-year old individuals (50% women) from the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Linear regression analyses were performed to study the associations between oxidative stress markers and summary measures of POPs including the total toxic equivalence (TEQ), sums of PCBs and BC pesticides (main exposures) while adjusting for potential confounders. In multivariable-adjusted analyses, sum of PCBs showed strong associations with ox-LDL (beta = 0.94; P = 2.9 * 10(-6)). Further, sum of PCBs showed association with glutathione-related markers (GSSG: beta = 0.01; P = 6.0 *10(-7); GSSG/GSH: beta = 0.002; P = 9.7 * 10(-10)), although in reverse direction. Other summary measures did not show any significant association with these markers. In our study of elderly individuals from the general population, we show that plasma levels of POPs are associated with markers of increased oxidative stress thereby suggesting that even low dose background exposure to POPs may be involved in oxidative stress.
  • Lee, Duk-Hee, et al. (författare)
  • Associations of persistent organic pollutants with abdominal obesity in the elderly : The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study
  • 2012
  • Ingår i: Environment International. - Elsevier. - 0160-4120. ; 40, s. 170-178
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: In animal experiments, persistent organic pollutants (POPs) have induced visceral obesity. To address this possibility in humans, we evaluated associations between POPs and abdominal obesity both cross-sectionally and prospectively.Methods: Twenty-one plasma POPs (16 polychlorinated biphenyl (PCB) congeners, 3 organochlorine (OC) pesticides, 1 brominated diphenyl ether (BDE), and 1 dioxin) were measured at baseline in 970 participants aged 70 years of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), with prospective analyses in 511 participants re-examined after 5 years. Abdominal obesity was defined by an increased waist circumference.Results: In the cross-sectional analyses, concentrations of the less chlorinated PCBs, OC pesticides such as p,p'-DDE and dioxin had adjusted odds ratios of 2 to 3 for abdominal obesity. Many relations had inverted U-shapes rather than being linear, particularly in women. In contrast, concentrations of highly chlorinated PCBs were strongly inversely associated with abdominal obesity. In a single model including summary measures of the less chlorinated PCBs, highly chlorinated PCBs, and OC pesticides, both the positive associations and inverse associations strengthened. Similar but somewhat weaker associations were seen between POPs and risk of development of abdominal obesity in the prospective analyses.Conclusion: Using both a cross-sectional and a prospective design, low-dose exposure to less chlorinated PCBs, p,p'-DDE, and dioxin, were associated with existence or development of abdominal obesity, while highly chlorinated PCBs had an opposite association in an elderly population, despite the previous observation of higher incident diabetes associated with these same PCBs.
  • Lee, Duk-Hee, et al. (författare)
  • Does Mortality Risk of Cigarette Smoking Depend on Serum Concentrations of Persistent Organic Pollutants? Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study
  • 2014
  • Ingår i: PLoS ONE. - 1932-6203 .- 1932-6203. ; 9:5, s. e95937
  • Tidskriftsartikel (refereegranskat)abstract
    • Cigarette smoking is an important cause of preventable death globally, but associations between smoking and mortality vary substantially across country and calendar time. Although methodological biases have been discussed, it is biologically plausible that persistent organic pollutants (POPs) like polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides can affect this association. This study was performed to evaluate if associations of cigarette smoking with mortality were modified by serum concentrations of PCBs and OC pesticides. We evaluated cigarette smoking in 111 total deaths among 986 men and women aged 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) with mean follow-up for 7.7 years. The association between cigarette smoking and total mortality depended on serum concentration of PCBs and OC pesticides (P value for interaction = 0.02). Among participants in the highest tertile of the serum POPs summary score, former and current smokers had 3.7 (95% CI, 1.5-9.3) and 6.4 (95% CI, 2.3-17.7) times higher mortality hazard, respectively, than never smokers. In contrast, the association between cigarette smoking and total mortality among participants in the lowest tertile of the serum POPs summary score was much weaker and statistically nonsignificant. The strong smoking-mortality association observed among elderly people with high POPs was mainly driven by low risk of mortality among never smokers with high POPs. As smoking is increasing in many low-income and middle-income countries and POPs contamination is a continuing problem in these areas, the interactions between these two important health-related issues should be considered in future research.
  • Lee, Duk-Hee, et al. (författare)
  • Polychlorinated biphenyls and organochlorine pesticides in plasma predict development of type 2 diabetes in the elderly : the prospective investigation of the vasculature in Uppsala Seniors (PIVUS) study
  • 2011
  • Ingår i: Diabetes Care. - 0149-5992 .- 1935-5548. ; 34:8, s. 1778-1784
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Persistent organic pollutants (POPs), lipophilic chemicals that accumulate mainly in adipose tissue, have recently been linked to type 2 diabetes. However, evidence from prospective studies is sparse. This study was performed to evaluate prospective associations of type 2 diabetes with selected POPs among the elderly.RESEARCH DESIGN AND METHODS: Nineteen POPs (14 polychlorinated biphenyl [PCB] congeners, 3 organochlorine pesticides, 1 brominated diphenyl ether, and 1 dioxin) were measured in plasma collected at baseline in 725 participants, aged 70 years, of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS).RESULTS: After adjusting for known type 2 diabetes risk factors, including obesity, odds ratios (ORs) (95% CIs) for type 2 diabetes at age 75 years (n = 36) according to the quintiles of a summary measure of concentrations of PCBs (vs. the lowest quintile) were 4.5, 5.1, 8.8 (1.8-42.7), and 7.5 (1.4-38.8) (P(trend) <0.01). Among organochlorine pesticides, adjusted ORs across concentrations of trans-nonachlor showed that P(trend) = 0.03. Adjusted ORs (95% CIs) across quintiles of the sum of three organochlorine pesticides were 1.1, 1.6, 1.5, and 3.4 (1.0-11.7) (P(trend) = 0.03). Neither brominated diphenyl ether 47 nor dioxin was significantly associated with incident diabetes. The sum of PCBs improved reclassification significantly when added to traditional risk factors for diabetes.CONCLUSIONS: Despite the small number of incident cases, this study found that environmental exposure to some POPs substantially increased risk of future type 2 diabetes in an elderly population.
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