75 results on '"Ulrika Andersson"'
Search Results
2. Body Composition During Pregnancy: Longitudinal Changes and Method Comparisons
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Louise Andersson, Therese Karlsson, Lars Ellegård, Marja Bosaeus, Ulrika Andersson-Hall, and Agneta Holmäng
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Adult ,Bioelectrical impedance analysis ,0301 basic medicine ,Longitudinal study ,medicine.medical_specialty ,Nutritional Status ,030209 endocrinology & metabolism ,Body composition ,Child health ,Body Mass Index ,Quantitative magnetic resonance ,Young Adult ,03 medical and health sciences ,Absorptiometry, Photon ,0302 clinical medicine ,Pregnancy ,Electric Impedance ,Humans ,Medicine ,Longitudinal Studies ,Obesity ,Whole-body air displacement plethysmography ,Sweden ,030109 nutrition & dietetics ,business.industry ,Obstetrics ,Limits of agreement ,Obstetrics and Gynecology ,Middle Aged ,medicine.disease ,Cross-Sectional Studies ,Adipose Tissue ,Method comparison ,Air displacement plethysmography ,Female ,Original Article ,business ,Follow-Up Studies - Abstract
The Pregnancy Obesity Nutrition and Child Health study is a longitudinal study of reproductive health. Here we analyzed body composition of normal-weight and obese Swedish women by three methods during each trimester of pregnancy. Cross-sectional and longitudinal fat mass estimates using quantitative magnetic resonance (QMR) and bioelectrical impedance analysis (BIA) (Tanita MC-180MA-III) were compared with fat mass determined by air displacement plethysmography (ADP) in pregnancy weeks 8–12, 24–26, and 35–37 in normal-weight women (n = 122, BMI = 22.1 ± 1.6 kg/m2) and obese women (n = 29, BMI = 34.6 ± 3.6 kg/m2). ADP results were calculated from pregnancy-adjusted fat-free mass densities. Mean fat mass by QMR and ADP were similar in obese women, although with wide limits of agreement. In normal-weight women, QMR overestimated mean fat mass in all trimesters, with systematic overestimation at low fat mass values in trimesters 1 and 3. In obese women, fat mass by BIA was grossly underestimated and imprecise in all trimesters, especially at higher values in trimester 2. In normal-weight women, fat mass by BIA was moderately lower than by ADP in trimester 1, similar in trimester 2, and moderately higher in trimester 3. QMR and ADP assessed fat mass changes similarly in obese women, whereas BIA overestimated fat mass changes in normal-weight women. Mean fat mass and fat mass changes by QMR and pregnancy-adjusted ADP were similar in pregnant obese women. Mean fat mass by QMR and fat mass changes by BIA were higher than corresponding values determined by pregnancy-adjusted ADP in normal-weight women.
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- 2020
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3. Longitudinal changes in adipokines and free leptin index during and after pregnancy in women with obesity
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Ulrika Andersson-Hall, Agneta Holmäng, Pernilla Svedin, Henrik Svensson, Malin Lönn, and Carina Mallard
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Adult ,Leptin ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Medicine (miscellaneous) ,Adipokine ,030209 endocrinology & metabolism ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Adipokines ,Pregnancy ,Internal medicine ,medicine ,Humans ,Obesity ,030212 general & internal medicine ,Nutrition and Dietetics ,Leptin receptor ,Adiponectin ,business.industry ,Body Weight ,medicine.disease ,Gestational Weight Gain ,Pregnancy Complications ,Endocrinology ,Body Composition ,Homeostatic model assessment ,Gestation ,Female ,Insulin Resistance ,business - Abstract
Detailed data on adipokines and body composition during and after pregnancy in women of different BMI categories are lacking. Furthermore, adipokine regulation during pregnancy and the factors contributing to gestational insulin resistance are not completely understood. The objective was to longitudinally determine adipokine levels, body composition, and insulin sensitivity during and after pregnancy in women of healthy weight (HW) and with obesity (OB), and identify factors associated with insulin resistance. Women (30 HW, 19 OB) underwent blood sampling and body composition examination, by air-displacement plethysmography, longitudinally during pregnancy (trimesters 1, 2, 3) and after pregnancy (6, 12, 18 months postpartum). Serum leptin, soluble leptin receptor (sOB-R), and adiponectin levels were measured and free leptin index (FLI) and homeostatic model assessment of insulin resistance (HOMA-IR) determined. Fat mass and leptin increased during pregnancy in the HW (p
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- 2019
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4. Environmental factors influence the epigenetic signature of newborns from mothers with gestational diabetes
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Ulrika Andersson-Hall, Emil Andersen, Agneta Holmäng, Romain Barrès, and Ali Altıntaş
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0301 basic medicine ,Cancer Research ,endocrine system diseases ,Mothers ,Physiology ,Environment ,Biology ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Genetics ,medicine ,Epigenetic Profile ,Humans ,Obesity ,Epigenetics ,Infant, Newborn ,nutritional and metabolic diseases ,DNA Methylation ,medicine.disease ,female genital diseases and pregnancy complications ,Gestational diabetes ,Diabetes, Gestational ,030104 developmental biology ,030220 oncology & carcinogenesis ,DNA methylation ,Female ,Analysis of variance - Abstract
AIM: To investigate the degree by which epigenetic signatures in children from mothers with gestational diabetes mellitus (GDM) are influenced by environmental factors.METHODS: We profiled the DNA methylation signature of blood from lean, obese and GDM mothers and their respective newborns.RESULTS: DNA methylation profiles of mothers showed high similarity across groups, while newborns from GDM mothers showed a marked distinct epigenetic profile compared with newborns of both lean and obese mothers. Analysis of variance in DNA methylation levels between newborns showed higher variance in the GDM group.CONCLUSION: Our results suggest that environmental factors, rather than direct transmission of epigenetic marks from the mother, are involved in establishing the epigenetic signature associated with GDM.CLINICAL TRIAL REGISTRATION NUMBER: Dnr 402-08.
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- 2019
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5. Physical activity during pregnancy and association with changes in fat mass and adipokines in women of normal-weight or with obesity
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Ulrika Andersson-Hall, Freja Askeli, Hanna K de Maré, Mats Börjesson, and Agneta Holmäng
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Adult ,medicine.medical_specialty ,Physiology ,Science ,Adipose tissue ,Adipokine ,Article ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Pregnancy ,Internal medicine ,medicine ,Aerobic exercise ,Humans ,Obesity ,Exercise ,030219 obstetrics & reproductive medicine ,Multidisciplinary ,Leptin receptor ,Adiponectin ,business.industry ,Leptin ,030229 sport sciences ,medicine.disease ,Gestational Weight Gain ,Pregnancy Complications ,Adipose Tissue ,Body Composition ,Medicine ,Female ,medicine.symptom ,business ,Weight gain - Abstract
Adipose tissue and adipokine concentrations change markedly during pregnancy, but the effects of physical activity on these changes are rarely studied. We aimed to assess physical activity levels in pregnant women of normal-weight (NW) or with obesity (OB), and to determine the relation with changes in fat mass and adipokines. In each trimester, pregnant women (136 NW, 51 OB) were interviewed about their physical activity and had their body composition, leptin, soluble leptin receptor (sOB-R) and adiponectin determined. NW reported higher activity and more aerobic exercise than OB during early pregnancy. Both groups maintained training frequency but reduced overall activity as pregnancy progressed. NW women reporting aerobic and/or resistance exercise and OB women reporting aerobic exercise had greater sOB-R increases (independent of BMI or gestational weight gain). In NW, exercise also associated with lower fat mass and leptin increases. Higher activity levels associated with lower gestational weight gain in both groups. The relationship between physical activity and adiponectin differed between NW and OB. Maternal exercise may partly mediate its beneficial effects through regulation of leptin bioavailability, by enhancing pregnancy-induced increases in sOB-R. This could be of particular importance in OB with pre-gestational hyperleptinemia and leptin resistance.
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- 2021
6. Growth-differentiation-factor 15 levels in obese and healthy pregnancies: Relation to insulin resistance and insulin secretory function
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Louise Joelsson, Agneta Holmäng, Carina Mallard, Pernilla Svedin, and Ulrika Andersson-Hall
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Blood Glucose ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,030209 endocrinology & metabolism ,Body Mass Index ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Insulin resistance ,Downregulation and upregulation ,Pregnancy ,Internal medicine ,medicine ,Humans ,Insulin ,Obesity ,business.industry ,Cell Differentiation ,medicine.disease ,030220 oncology & carcinogenesis ,Homeostatic model assessment ,Gestation ,Female ,GDF15 ,Beta cell ,Insulin Resistance ,business - Abstract
Objective/aim Growth-differentiation-factor 15 (GDF15) has been suggested to improve or protect beta cell function. During pregnancy, beta cell numbers and function increase to overcome the natural rise in insulin resistance during gestation. In this study, we longitudinally measured serum GDF15 levels during and after pregnancy in women of normal weight (NW) and in women with obesity (OB) and explored associations between GDF15 and changes in beta cell function by homeostatic model assessment (HOMA). Methods The cohort participants were 38 NW (BMI 22.3 ± 1.7) and 35 OB (BMI 35.8 ± 4.2). Blood was sampled and body composition measured at each trimester (T1, T2, and T3) and at 6, 12 and 18 months postpartum. Fasting glucose, insulin and GDF15 were measured, and HOMA for insulin resistance (HOMA-IR) and beta cell function (HOMA-B) determined. Results GDF15 levels increased significantly each trimester and were ~200-fold higher at T3 than in the nonpregnant postpartum state. GDF15 was higher in NW than OB during pregnancy, but was reversed after pregnancy with a significant interaction effect. GDF15 correlated inversely with BMI and fat-free mass at T3. Low GDF15 was associated with lower incidence of nausea and with carrying a male foetus. The pregnancy induced increase in GDF15 associated with increased HOMA-B in OB and with reduced fasting glucose in all women. Conclusion Large gestational upregulation of GDF15 levels may help increase insulin secretory function to overcome pregnancy-induced insulin resistance.
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- 2021
7. Growth differentiation factor 15 increases in both cerebrospinal fluid and serum during pregnancy
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Kaj Blennow, Carina Mallard, Agneta Holmäng, Ulrika Andersson-Hall, Pernilla Svedin, and Henrik Zetterberg
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0301 basic medicine ,Leptin ,Blood Glucose ,Physiology ,medicine.medical_treatment ,Maternal Health ,Peptide Hormones ,Placenta ,Nervous System ,Biochemistry ,0302 clinical medicine ,Cerebrospinal fluid ,Endocrinology ,Pregnancy ,Medicine and Health Sciences ,Medicine ,Insulin ,Receptor ,Cerebrospinal Fluid ,0303 health sciences ,Multidisciplinary ,Obstetrics and Gynecology ,Body Fluids ,Blood ,C-Reactive Protein ,Physiological Parameters ,Obstetric Procedures ,Homeostatic model assessment ,Female ,Adiponectin ,Anatomy ,Research Article ,Adult ,medicine.medical_specialty ,Growth Differentiation Factor 15 ,Science ,030209 endocrinology & metabolism ,Surgical and Invasive Medical Procedures ,Carbohydrate metabolism ,03 medical and health sciences ,Internal medicine ,Humans ,030304 developmental biology ,Nutrition ,Diabetic Endocrinology ,business.industry ,Cesarean Section ,Body Weight ,Biology and Life Sciences ,medicine.disease ,Hormones ,Diet ,030104 developmental biology ,Food ,Women's Health ,GDF15 ,business ,Follow-Up Studies - Abstract
Aim Growth differentiation factor 15 (GDF15) increases in serum during pregnancy to levels not seen in any other physiological state and is suggested to be involved in pregnancy-induced nausea, weight regulation and glucose metabolism. The main action of GDF15 is regulated through a receptor of the brainstem, i.e., through exposure of GDF15 in both blood and cerebrospinal fluid (CSF). The aim of the current study was to measure GDF15 in both CSF and serum during pregnancy, and to compare it longitudinally to non-pregnant levels. Methods Women were sampled at elective caesarean section (n = 45, BMI = 28.1±5.0) and were followed up 5 years after pregnancy (n = 25). GDF15, insulin and leptin were measured in CSF and serum. Additional measurements included plasma glucose, and serum adiponectin and Hs-CRP. Results GDF15 levels were higher during pregnancy compared with follow-up in both CSF (385±128 vs. 115±32 ng/l, PPPP = 0.98). Both CSF and serum GDF15 were highest in women carrying a female fetus (P Conclusion This, the first study to measure CSF GDF15 during pregnancy, demonstrated increased GDF15 levels in both serum and CSF during pregnancy. The results suggest that effects of GDF15 during pregnancy can be mediated by increases in both CSF and serum levels.
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- 2021
8. Pregnancy-induced changes in serum concentrations of perfluoroalkyl substances and the influence of kidney function
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Christian H. Lindh, Ying Li, Agneta Holmäng, Ulf Ekström, Kristina Jakobsson, Yiyi Xu, Christel Nielsen, and Ulrika Andersson Hall
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Glomerular filtration rate, glomerular pore size ,Adult ,Time Factors ,Health, Toxicology and Mutagenesis ,Renal function ,Physiology ,010501 environmental sciences ,Kidney ,Kidney Function Tests ,01 natural sciences ,Perfluorononanoic acid ,03 medical and health sciences ,chemistry.chemical_compound ,lcsh:RC963-969 ,Young Adult ,0302 clinical medicine ,Pregnancy ,Medicine ,Humans ,030212 general & internal medicine ,0105 earth and related environmental sciences ,Sweden ,Creatinine ,Fluorocarbons ,biology ,business.industry ,lcsh:Public aspects of medicine ,Research ,Public Health, Environmental and Occupational Health ,lcsh:RA1-1270 ,medicine.disease ,Gestational diabetes ,Perfluorooctane ,Perfluoroalkyl substances ,chemistry ,Cystatin C ,biology.protein ,lcsh:Industrial medicine. Industrial hygiene ,Perfluorooctanoic acid ,Environmental Pollutants ,Female ,sense organs ,business ,Glomerular Filtration Rate - Abstract
Background Epidemiological associations between maternal concentrations of perfluoroalkyl substances (PFAS) and birth weight are inconsistent. There is concern that studies based on samples collected in late pregnancy may be confounded by kidney function but studies of the relation between pregnancy-induced changes in PFAS and kidney function are lacking. Our aims were to investigate changes in serum concentrations of perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) from early to late pregnancy and to explore relations to changes in glomerular filtration rate (GFR) and glomerular pore size. Methods We conducted the study in a cohort of 73 pregnancies of normal-weight Swedish women without gestational diabetes and preeclampsia, enrolled 2009–2014. Blood was collected in median weeks 11 and 36, respectively, and analysed PFAS using liquid chromatography-tandem-mass-spectrometry. We estimated GFR based on creatinine and cystatin C and used the ratio eGFRcystatin C/eGFRcreatinine to indicate glomerular pore size. We used Wilcoxon signed-rank test to compare early and late measures and partial Spearman rank correlations to explore relations between changes in PFAS and kidney function. Results Median concentrations of PFNA, PFOA and PFOS decreased by 15–21% but changes were uncorrelated to changes in kidney function (partial R = − 0.06–0.11). The observed increase in median PFHxS concentration of 69% was likely an artefact of systematic measurement error caused by coeluting endogenous inferences. Conclusions Serum concentrations of PFNA, PFOA and PFOS decrease during pregnancy but the magnitudes of change are unrelated to parallel changes in eGFR and glomerular pore size, suggesting that changes in these indicators of kidney function are not important confounders in studies of PFAS and birth weight in pregnancies without gestational diabetes and preeclampsia.
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- 2020
9. Age‐specific genome‐wide association study in glioblastoma identifies increased proportion of ‘lower grade glioma’‐like features associated with younger age
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Meredith Yeager, Beatrice Melin, Helen M. Hansen, Ulrika Andersson, Martha S. Linet, Ryan Merrell, Preetha Rajaraman, Elizabeth B. Claus, Lucie McCoy, Ben Kinnersley, John K. Wiencke, Christoffer Johansen, Georgina Armstrong, Christopher I. Amos, Margaret Wrensch, Stephen J. Chanock, Rose Lai, Daniel H. Lachance, Zhaoming Wang, Quinn T. Ostrom, Terri Rice, Jeanette E. Eckel-Passow, Joellen M. Schildkraut, Richard S. Houlston, Jonine L. Bernstein, Siegal Sadetzki, Melissa L. Bondy, Dora Il'yasova, Sanjay Shete, Yanwen Chen, Sara H. Olson, Joshua B. Rubin, Robert B. Jenkins, and Jill S. Barnholtz-Sloan
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Adult ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Genome-wide association study ,urologic and male genital diseases ,Polymorphism, Single Nucleotide ,Article ,Young Adult ,03 medical and health sciences ,Glioma ,Internal medicine ,Humans ,Medicine ,Young adult ,Aged ,Neoplasm Grading ,Brain Neoplasms ,urogenital system ,business.industry ,Incidence (epidemiology) ,Age Factors ,Case-control study ,Middle Aged ,medicine.disease ,Age specific ,female genital diseases and pregnancy complications ,nervous system diseases ,030104 developmental biology ,Case-Control Studies ,Female ,Glioblastoma ,business ,Genome-Wide Association Study - Abstract
Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18–53, 54–64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p(54–63)=1.50×10(−9), OR(54–63)=1.28, 95%CI(54–63)=1.18–1.39; p(64+)=2.14×10(−11), OR(64+)=1.32, 95%CI(64+)=1.21–1.43] and rs11979158 [p(54–63)=6.13×10(−8), OR(54–63)=1.35, 95%CI(54–63)=1.21–1.50; p(64+)=2.18×10(−10), OR(64+)=1.42, 95%CI(64+)=1.27–1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18–53 (p(18–53)=9.30×10(−11), OR(18–53)=1.76, 95%CI(18–53)=1.49–2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of ‘LGG’-like tumor characteristics in GBM samples in those 18–53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54–63] and 0.8% [64+] (p=0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18–53 suggests that more younger individuals may present initially with ‘secondary glioblastoma.’
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- 2018
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10. Metabolism and Whole-Body Fat Oxidation Following Postexercise Carbohydrate or Protein Intake
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Klavs Madsen, Stefan Pettersson, Ulrika Andersson-Hall, Fredrik Edin, Anders Pedersen, and Daniel Malmodin
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Adult ,Blood Glucose ,medicine.medical_specialty ,Medicine (miscellaneous) ,030209 endocrinology & metabolism ,endurance exercise ,Placebo ,maximal fat oxidation ,Young Adult ,03 medical and health sciences ,Oxygen Consumption ,0302 clinical medicine ,Fat oxidation ,Endurance training ,Internal medicine ,Journal Article ,Dietary Carbohydrates ,medicine ,Humans ,Insulin ,Orthopedics and Sports Medicine ,Exercise ,Cross-Over Studies ,Nutrition and Dietetics ,Chemistry ,030229 sport sciences ,General Medicine ,Metabolism ,Carbohydrate ,Protein intake ,post-exercise drinks ,Endocrinology ,Dietary protein ,Adipose Tissue ,Exercise Test ,Metabolome ,Female ,Dietary Proteins ,Whole body ,Oxidation-Reduction - Abstract
Purpose: This study investigated how postexercise intake of placebo (PLA), protein (PRO), or carbohydrate (CHO) affected fat oxidation (FO) and metabolic parameters during recovery and subsequent exercise. Methods: In a cross-over design, 12 moderately trained women (VO2max 45 ± 6 ml·min−1·kg−1) performed three days of testing. A 23-min control (CON) incremental FO bike test (30–80% VO2max) was followed by 60 min exercise at 75% VO2max. Immediately postexercise, subjects ingested PLA, 20 g PRO, or 40 g CHO followed by a second FO bike test 2 h later. Results: Maximal fat oxidation (MFO) and the intensity at which MFO occurs (Fatmax) increased at the second FO test compared to the first following all three postexercise drinks (MFO for CON = 0.28 ± 0.08, PLA = 0.57 ± 0.13, PRO = 0.52 ± 0.08, CHO = 0.44 ± 0.12 g fat·min−1; Fatmax for CON = 41 ± 7, PLA = 54 ± 4, PRO = 55 ± 6, CHO = 50 ± 8 %VO2max, p max were not significantly different between PLA and PRO, but lower for CHO. PRO and CHO increased insulin levels at 1 h postexercise, though both glucose and insulin were equal with PLA at 2 h postexercise. Increased postexercise ketone levels only occurred with PLA. Conclusion: Protein supplementation immediately postexercise did not affect the doubling in whole body fat oxidation seen during a subsequent exercise trial 2 h later. Neither did it affect resting fat oxidation during the postexercise period despite increased insulin levels and attenuated ketosis. Carbohydrate intake dampened the increase in fat oxidation during the second test, though a significant increase was still observed compared to the first test.
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- 2018
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11. Growth-differentiation factor 15 and risk of major bleeding in atrial fibrillation: Insights from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial
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Salim Yusuf, Stuart J. Connolly, Agneta Siegbahn, Jonas Oldgren, Ziad Hijazi, John W. Eikelboom, Michael D. Ezekowitz, Ulrika Andersson, Paul A. Reilly, and Lars Wallentin
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Male ,Canada ,medicine.medical_specialty ,Growth Differentiation Factor 15 ,Time Factors ,Randomization ,medicine.drug_class ,Hemorrhage ,030204 cardiovascular system & hematology ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Atrial Fibrillation ,medicine ,Natriuretic peptide ,Humans ,030212 general & internal medicine ,Stroke ,Aged ,Retrospective Studies ,Sweden ,Dose-Response Relationship, Drug ,Troponin T ,business.industry ,Proportional hazards model ,Incidence ,Hazard ratio ,Anticoagulants ,Atrial fibrillation ,Middle Aged ,Prognosis ,medicine.disease ,United States ,Surgery ,Survival Rate ,embryonic structures ,Female ,GDF15 ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Follow-Up Studies - Abstract
To evaluate and validate the prognostic value of growth-differentiation factor 15 (GDF-15) beyond clinical characteristics and other biomarkers concerning bleeding and stroke outcomes in patients with atrial fibrillation in the RE-LY trial.GDF-15 was measured in samples collected at randomization in 8,474 patients with a median follow-up time of 1.9 years. Patients were stratified based on predefined GDF-15 cutoffs: group 1,1,200 ng/L (the 90th percentile in healthy individuals); group 2, 1,200-1,800; and group 3,1,800 ng/L (high-risk individuals). Efficacy and safety outcomes were compared across groups of GDF-15 in Cox models adjusted for baseline characteristics, cardiac (N-terminal pro-b-type natriuretic peptide, high-sensitive troponin T), inflammatory (interleukin 6, C-reactive protein) and coagulation (D-dimer) biomarkers, and randomized treatment.GDF-15 concentrations were1,200 ng/L in 2,647 (31.2%), between 1,200 and 1,800 ng/L in 2,704 (31.9%), and1,800 ng/L in 3,123 (36.9%) participants, respectively. Annual rates of stroke, major bleeding, and mortality increased with higher GDF-15 levels. The prognostic value of GDF-15 was independent of clinical characteristics for these outcomes. In models also adjusted for biomarkers, GDF-15 remained significantly associated with major bleeding (hazard ratio [95% CI] group 3 vs group 1 1.76 [1.28-2.42], P.0005) and all-cause mortality (hazard ratio 1.72 [1.30-2.29], P.0005). GDF-15 improved the c index of both the HAS-BLED (0.62-0.69) and ORBIT (0.68-0.71) bleeding risk scores.In patients with atrial fibrillation, GDF-15 is an independent risk indicator for major bleeding and all-cause mortality, but not for stroke. Therefore, GDF-15 seems useful as a specific marker of bleeding in patients with AF on oral anticoagulant treatment.
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- 2017
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12. Cardiac Biomarkers and Left Ventricular Hypertrophy in Relation to Outcomes in Patients With Atrial Fibrillation: Experiences From the RE‐LY Trial
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Paolo Verdecchia, Jonas Oldgren, Lars Wallentin, Giovanni Mazzotta, Fabio Angeli, Stuart J. Connolly, Ziad Hijazi, Michael D. Ezekowitz, Salim Yusuf, Giuseppe Di Pasquale, John W. Eikelboom, Gianpaolo Reboldi, and Ulrika Andersson
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Male ,Global Health ,Left ventricular hypertrophy ,Ventricular Function, Left ,risk prediction ,Electrocardiography ,Risk Factors ,Cause of Death ,Atrial Fibrillation ,atrial fibrillation ,Cardiac and Cardiovascular Systems ,Arrhythmia and Electrophysiology ,Stroke ,Original Research ,Kardiologi ,Incidence ,Atrial fibrillation ,Prognosis ,left ventricular hypertrophy ,Survival Rate ,Cardiology ,biomarker ,Biomarker (medicine) ,Female ,Hypertrophy, Left Ventricular ,Mortality/Survival ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,Cardiac biomarkers ,Risk Assessment ,Troponin T ,Internal medicine ,medicine ,Humans ,In patient ,cardiovascular diseases ,Ischemic Stroke ,Aged ,Retrospective Studies ,Biomarker ,Risk prediction ,business.industry ,Troponin I ,Anticoagulants ,Hypertrophy ,medicine.disease ,business ,Biomarkers ,Follow-Up Studies - Abstract
Background Cardiac biomarkers and left ventricular hypertrophy ( LVH ) are related to the risk of stroke and death in patients with atrial fibrillation. We investigated the interrelationship between LVH and cardiac biomarkers and their independent associations with outcomes. Methods and Results Plasma samples were obtained at baseline in 5275 patients with atrial fibrillation in the RE ‐ LY (Randomized Evaluation of Long‐Term Anticoagulation Therapy) trial. NT ‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), cardiac troponin I and T, and growth differentiation factor‐15 were determined using high‐sensitivity (hs) assays. LVH was defined by ECG . Cox models were adjusted for baseline characteristics, LVH , and biomarkers. LVH was present in 1257 patients. During a median follow‐up of 2.0 years, 165 patients developed a stroke and 370 died. LVH was significantly ( P NT ‐pro BNP , 1.32 (1.25–1.38); hs cardiac troponin I, 1.67 (1.57–1.78); hs troponin T, 1.38 (1.32–1.44); and growth differentiation factor‐15, 1.09 (1.05–1.12). For stroke, the hazard ratios (95% CIs) per 50% increase were as follows: NT ‐pro BNP, 1.09 (1.00–1.19); hs cardiac troponin I, 1.09 (1.03–1.15); hs troponin T, 1.14 (1.06–1.24); and growth differentiation factor‐15, 1.22 (1.08–1.38) (all P NT ‐pro BNP , 1.24 (1.17–1.31); hs cardiac troponin I, 1.13 (1.10–1.17); hs troponin T, 1.28 (1.23–1.34); and growth differentiation factor‐15, 1.31 (1.22–1.42) (all P LVH was not significantly associated with stroke or death after adjustment for biomarkers. Conclusions Cardiac biomarkers are significantly associated with LVH . The prognostic value of biomarkers for stroke and death is not affected by LVH . The prognostic information of LVH is attenuated in the presence of cardiac biomarkers. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00262600.
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- 2019
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13. The association between longer relative leukocyte telomere length and risk of glioma is independent of the potentially confounding factors allergy, BMI, and smoking
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Melissa L. Bondy, Carl Wibom, Ulrika Andersson, Sofie Degerman, Gunnar Johansson, Beatrice Melin, and Anna M. Dahlin
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Allergy ,EGFR ,Relative leukocyte telomere length (rLTL) ,Body Mass Index ,03 medical and health sciences ,BMI ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Glioma ,Epidemiology ,medicine ,Hypersensitivity ,Leukocytes ,1p/19q ,Humans ,030212 general & internal medicine ,Association (psychology) ,Aged ,Aged, 80 and over ,Sweden ,Cancer och onkologi ,Hematology ,business.industry ,Brain Neoplasms ,Confounding ,Smoking ,Confounding Factors, Epidemiologic ,Public Health, Global Health, Social Medicine and Epidemiology ,Middle Aged ,Telomere ,medicine.disease ,Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi ,Phenotype ,030220 oncology & carcinogenesis ,Case-Control Studies ,Cancer and Oncology ,Female ,IDH1 ,business - Abstract
Purpose: Previous studies have suggested an association between relative leukocyte telomere length (rLTL) and glioma risk. This association may be influenced by several factors, including allergies, BMI, and smoking. Previous studies have shown that individuals with asthma and allergy have shortened relative telomere length, and decreased risk of glioma. Though, the details and the interplay between rLTL, asthma and allergies, and glioma molecular phenotype is largely unknown. Methods: rLTL was measured by qPCR in a Swedish population-based glioma case–control cohort (421 cases and 671 controls). rLTL was related to glioma risk and health parameters associated with asthma and allergy, as well as molecular events in glioma including IDH1 mutation, 1p/19q co-deletion, and EGFR amplification. Results: Longer rLTL was associated with increased risk of glioma (OR = 1.16; 95% CI 1.02–1.31). Similar to previous reports, there was an inverse association between allergy and glioma risk. Specific, allergy symptoms including watery eyes was most strongly associated with glioma risk. High body mass index (BMI) a year prior diagnosis was significantly protective against glioma in our population. Adjusting for allergy, asthma, BMI, and smoking did not markedly change the association between longer rLTL and glioma risk. rLTL among cases was not associated with IDH1 mutation, 1p/19q co-deletion, or EGFR amplification, after adjusting for age at diagnosis and sex. Conclusions: In this Swedish glioma case–control cohort, we identified that long rLTL increases the risk of glioma, an association not confounded by allergy, BMI, or smoking. This highlights the complex interplay of the immune system, rLTL and cancer risk.
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- 2019
14. Metabolomic screening of pre-diagnostic serum samples identifies association between α- and γ-tocopherols and glioblastoma risk
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Ulrika Andersson, Pär Jonsson, Beatrice Melin, Benny Björkblom, Henrik Antti, Lina Mörén, Hilde Langseth, Tom Børge Johannesen, and Carl Wibom
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Metabolite ,medicine.medical_treatment ,alpha-Tocopherol ,gamma-Tocopherol ,vitamin E ,Biology ,Pharmacology ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,serum metabolite ,0302 clinical medicine ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Metabolomics ,Hypoxanthine ,Cancer och onkologi ,Brain Neoplasms ,Vitamin E ,Case-control study ,Odds ratio ,Middle Aged ,population-based ,030104 developmental biology ,antioxidants ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer and Oncology ,Case-Control Studies ,Female ,Sample collection ,Glioblastoma ,Oxidation-Reduction ,brain tumor ,Research Paper - Abstract
Glioblastoma is associated with poor prognosis with a median survival of one year. High doses of ionizing radiation is the only established exogenous risk factor. To explore new potential biological risk factors for glioblastoma, we investigated alterations in metabolite concentrations in pre-diagnosed serum samples from glioblastoma patients diagnosed up to 22 years after sample collection, and undiseased controls. The study points out a latent biomarker for future glioblastoma consisting of nine metabolites (gamma-tocopherol, alpha-tocopherol, erythritol, erythronic acid, myo-inositol, cystine, 2-keto-L-gluconic acid, hypoxanthine and xanthine) involved in antioxidant metabolism. We detected significantly higher serum concentrations of alpha-tocopherol (p=0.0018) and gamma-tocopherol (p=0.0009) in future glioblastoma cases. Compared to their matched controls, the cases showed a significant average fold increase of alpha- and gamma-tocopherol levels: 1.2 for alpha-T (p=0.018) and 1.6 for gamma-T (p=0.003). These tocopherol levels were associated with a glioblastoma odds ratio of 1.7 (alpha-T, 95% CI: 1.0-3.0) and 2.1 (gamma-T, 95% CI: 1.2-3.8). Our exploratory metabolomics study detected elevated serum levels of a panel of molecules with antioxidant properties as well as oxidative stress generated compounds. Additional studies are necessary to confirm the association between the observed serum metabolite pattern and future glioblastoma development.
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- 2016
15. Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma
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Carl Wibom, Irina Golovleva, Beatrice Melin, Anna M. Dahlin, Ulrika Andersson, Soma Ghasimi, and Thomas Brännström
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Male ,0301 basic medicine ,Cancer Research ,Neurologi ,Somatic cell ,Genome-wide association study ,medicine.disease_cause ,Germline ,Immunoenzyme Techniques ,0302 clinical medicine ,Risk Factors ,In Situ Hybridization, Fluorescence ,Aged, 80 and over ,Genetics ,Mutation ,Brain Neoplasms ,Glioma ,CDKN2A/B ,Middle Aged ,Prognosis ,ErbB Receptors ,Survival Rate ,Neurology ,Oncology ,030220 oncology & carcinogenesis ,Female ,Adult ,Adolescent ,EGFR ,Clinical Neurology ,SNP ,Biology ,Cdkn2a b ,Polymorphism, Single Nucleotide ,Young Adult ,03 medical and health sciences ,FISH ,Biomarkers, Tumor ,medicine ,Humans ,Genetic Predisposition to Disease ,Gene ,Cyclin-Dependent Kinase Inhibitor p16 ,Aged ,Cyclin-Dependent Kinase Inhibitor p15 ,Cancer och onkologi ,fungi ,DNA Helicases ,RTEL1 ,medicine.disease ,030104 developmental biology ,ASCAT ,Cancer and Oncology ,Laboratory Investigation ,Neurology (clinical) ,Neoplasm Grading ,Follow-Up Studies - Abstract
During the last years, genome wide association studies have discovered common germline genetic variants associated with specific glioma subtypes. We aimed to study the association between these germline risk variants and tumor phenotypes, including copy number aberrations and protein expression. A total of 91 glioma patients were included. Thirteen well known genetic risk variants in TERT, EGFR, CCDC26, CDKN2A, CDKN2B,PHLDB1, TP53, and RTEL1 were selected for investigation of possible correlations with the glioma somatic markers: EGFR amplification, 1p/19q codeletion and protein expression of p53, Ki-67, and mutated IDH1. The CDKN2A/B risk variant, rs4977756, and the CDKN2B risk variant, rs1412829 were inversely associated (p = 0.049 and p = 0.002, respectively) with absence of a mutated IDH1, i.e., the majority of patients homozygous for the risk allele showed no or low expression of mutated IDH1. The RTEL1 risk variant, rs6010620 was associated (p = 0.013) with not having 1p/19q codeletion, i.e., the majority of patients homozygous for the risk allele did not show 1p/19q codeletion. In addition, the EGFR risk variant rs17172430 and the CDKN2B risk variant rs1412829, both showed a trend for association (p = 0.055 and p = 0.051, respectively) with increased EGFR copy number, i.e., the majority of patients homozygote for the risk alleles showed chromosomal gain or amplification of EGFR. Our findings indicate that CDKN2A/B risk genotypes are associated with primary glioblastoma without IDH mutation, and that there is an inverse association between RTEL1 risk genotypes and 1p/19q codeletion, suggesting that these genetic variants have a molecular impact on the genesis of high graded brain tumors. Further experimental studies are needed to delineate the functional mechanism of the association between genotype and somatic genetic aberrations. Electronic supplementary material The online version of this article (doi:10.1007/s11060-016-2066-4) contains supplementary material, which is available to authorized users.
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- 2016
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16. Biomarkers of inflammation and risk of cardiovascular events in anticoagulated patients with atrial fibrillation
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Michael G. Hanna, Julia Aulin, John D. Horowitz, Ziad Hijazi, Renato D. Lopes, Ulrika Andersson, Elaine M. Hylek, John H. Alexander, Agneta Siegbahn, Lars Wallentin, Christopher B. Granger, and Bernard J. Gersh
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Male ,medicine.medical_specialty ,Pyridones ,Hemorrhage ,030204 cardiovascular system & hematology ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Thromboembolism ,Internal medicine ,Atrial Fibrillation ,medicine ,Humans ,030212 general & internal medicine ,Myocardial infarction ,Risk factor ,Stroke ,Aged ,Inflammation ,biology ,Interleukin-6 ,business.industry ,C-reactive protein ,Warfarin ,Anticoagulants ,Atrial fibrillation ,Middle Aged ,Prognosis ,medicine.disease ,C-Reactive Protein ,Cystatin C ,biology.protein ,Cardiology ,Pyrazoles ,Female ,Apixaban ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Follow-Up Studies ,medicine.drug - Abstract
Objective Atrial fibrillation (AF) is a risk factor for stroke and mortality and the prothrombotic state has been linked to inflammation. In this study we evaluated the relationship between inflammatory biomarkers at baseline and future risk of cardiovascular events in the Apixaban for Reduction In Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Methods The ARISTOTLE trial randomised 18 201 patients with AF to apixaban or warfarin. Interleukin 6 (IL-6) and C reactive protein (CRP) were analysed in plasma obtained at randomisation from 14 954 participants, and median follow-up was 1.9 years. Association between quartile groups of IL-6 and CRP and outcomes were analysed by Cox regression adjusted for clinical risk factors and other cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C). Results The IL-6 median level was 2.3 ng/L (IQR 1.5–3.9), median CRP level was 2.2 mg/L (1.0–4.8). IL-6 and CRP were significantly associated with all-cause mortality independent of clinical risk factors and other biomarkers (HR (95% CI) 1.93 (1.57 to 2.37) and 1.49 (1.24 to 1.79), respectively, Q4 vs Q1). IL-6 was associated with myocardial infarction, cardiovascular mortality, and major bleeding beyond clinical risk factors but not in the presence of cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C). Neither inflammatory biomarker was associated with stroke/systemic embolism. Risk prediction for stroke, death and major bleeding was not improved by IL-6 or CRP when added to clinical risk factors and the other cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C). Conclusions In patients with AF on anticoagulation, after accounting for clinical risk factors and other biomarkers, biomarkers of inflammation were significantly associated with an increased risk of mortality. However, there were no associations with the risk of stroke or major bleeding. Trial registration number ClinicalTrials.gov identifier: NCT00412984 post-results.
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- 2016
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17. Adipose tissue and body composition in women six years after gestational diabetes: factors associated with development of type 2 diabetes
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Malin Lönn, Eva Jennische, Ulrika Andersson-Hall, Agneta Holmäng, Henrik Svensson, Staffan Edén, and Louise Wetterling
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0301 basic medicine ,Adult ,Blood Glucose ,medicine.medical_specialty ,Histology ,endocrine system diseases ,type 2 diabetes mellitus ,Adipose tissue ,Adipokine ,030209 endocrinology & metabolism ,adipocyte size ,Type 2 diabetes ,prediabetes ,Weight Gain ,Body Mass Index ,03 medical and health sciences ,adipocyte fatty acid-binding protein ,BMI ,0302 clinical medicine ,Adipokines ,Pregnancy ,Internal medicine ,Glucose Intolerance ,medicine ,Adipocytes ,Humans ,Prediabetes ,body composition ,business.industry ,Type 2 Diabetes Mellitus ,nutritional and metabolic diseases ,Cell Biology ,medicine.disease ,gestational diabetes mellitus ,adipose tissue ,Gestational diabetes ,Diabetes, Gestational ,030104 developmental biology ,Endocrinology ,Adipocyte fatty acid binding protein ,Diabetes Mellitus, Type 2 ,Female ,medicine.symptom ,Insulin Resistance ,business ,Weight gain ,Follow-Up Studies ,Research Paper - Abstract
Factors differentiating women at highest risk of progression to type 2 diabetes mellitus (T2DM) after gestational diabetes mellitus (GDM) are incompletely known. Our aim was to characterize adipose tissue and body composition in relation to glucose metabolism in women with a history of GDM and to identify factors associated with development of T2DM. We examined glucose tolerance (OGTT), insulin sensitivity (HOMA-IR), body composition (anthropometry, air displacement plethysmography), and blood chemistry in 39 women 6 years after GDM. An adipose tissue biopsy was obtained to assess the size, number, and lipolytic activity of adipocytes, and adipokine release and density of immune cells and blood vessels in adipose tissue. Normal glucose tolerance (NGT) was identified in 31 women and impaired glucose metabolism (IGM) in 8. Women with IGM had higher BMI/fat mass, and related expected adipose tissue features, than women with NGT. Ethnicity was similar in the groups, but numerically there was a higher proportion of European women in the NGT group and a higher proportion of non-European women in the IGM group. BMI was the best discriminator of NGT versus IGM (multivariable logistic regression: OR = 1.34, P
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- 2018
18. Genetic Variants in the 9p21.3 Locus Associated with Glioma Risk in Children, Adolescents, and Young Adults: A Case-Control Study
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Christina M. Hultman, Carl Wibom, Jonas Bybjerg-Grauholm, Robert Karlsson, Isabelle Deltour, Ulf Hjalmars, Ulrika Andersson, Anna K. Kähler, Anna M. Dahlin, Beatrice Melin, and David M. Hougaard
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0301 basic medicine ,Adult ,Male ,Adolescent ,Epidemiology ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,Germline ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Risk Factors ,Glioma ,medicine ,Humans ,Genetic Predisposition to Disease ,Young adult ,Child ,Genetic association ,Genetics ,Case-control study ,Genetic variants ,Infant, Newborn ,Infant ,medicine.disease ,030104 developmental biology ,Oncology ,Genetic Loci ,030220 oncology & carcinogenesis ,Case-Control Studies ,Child, Preschool ,Early adolescents ,Female ,Genome-Wide Association Study - Abstract
Background: Genome-wide association studies have identified germline genetic variants in 25 genetic loci that increase the risk of developing glioma in adulthood. It is not known if these variants increase the risk of developing glioma in children and adolescents and young adults (AYA). To date, no studies have performed genome-wide analyses to find novel genetic variants associated with glioma risk in children and AYA. Methods: We investigated the association between 8,831,628 genetic variants and risk of glioma in 854 patients diagnosed up to the age of 29 years and 3,689 controls from Sweden and Denmark. Recruitment of patients and controls was population based. Genotyping was performed using Illumina BeadChips, and untyped variants were imputed with IMPUTE2. We selected 41 established adult glioma risk variants for detailed investigation. Results: Three adult glioma risk variants, rs634537, rs2157719, and rs145929329, all mapping to the 9p21.3 (CDKN2B-AS1) locus, were associated with glioma risk in children and AYA. The strongest association was seen for rs634537 (odds ratioG = 1.21; 95% confidence interval = 1.09–1.35; P = 5.8 × 10−4). In genome-wide analysis, an association with risk was suggested for 129 genetic variants (P Conclusions: Carriers of risk alleles in the 9p21.3 locus have an increased risk of glioma throughout life. The results from genome-wide association analyses require validation in independent cohorts. Impact: Our findings line up with existing evidence that some, although not all, established adult glioma risk variants are associated with risk of glioma in children and AYA. Validation of results from genome-wide analyses may reveal novel susceptibility loci for glioma in children and AYA.
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- 2018
19. Use of Biomarkers to Predict Specific Causes of Death in Patients With Atrial Fibrillation
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Abhinav, Sharma, Ziad, Hijazi, Ulrika, Andersson, Sana M, Al-Khatib, Renato D, Lopes, John H, Alexander, Claes, Held, Elaine M, Hylek, Sergio, Leonardi, Michael, Hanna, Justin A, Ezekowitz, Agneta, Siegbahn, Christopher B, Granger, and Lars, Wallentin
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Male ,Growth Differentiation Factor 15 ,Time Factors ,Pyridones ,Hemorrhage ,Risk Assessment ,Double-Blind Method ,Troponin T ,Predictive Value of Tests ,Risk Factors ,Cause of Death ,Atrial Fibrillation ,Natriuretic Peptide, Brain ,Humans ,Aged ,Aged, 80 and over ,Heart Failure ,Interleukin-6 ,Anticoagulants ,Middle Aged ,Peptide Fragments ,Stroke ,Death, Sudden, Cardiac ,Treatment Outcome ,Pyrazoles ,Female ,Warfarin ,Biomarkers ,Factor Xa Inhibitors - Abstract
Atrial fibrillation is associated with an increased risk of death. High-sensitivity troponin T, growth differentiation factor-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and interleukin-6 levels are predictive of cardiovascular events and total cardiovascular death in anticoagulated patients with atrial fibrillation. The prognostic utility of these biomarkers for cause-specific death is unknown.The ARISTOTLE trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients (1.9 years median follow-up). Cox models were used to identify clinical variables and biomarkers independently associated with each specific cause of death.In total, 1272 patients died: 652 (51%) cardiovascular, 32 (3%) bleeding, and 588 (46%) noncardiovascular/nonbleeding deaths. Among cardiovascular deaths, 255 (39%) were sudden cardiac deaths, 168 (26%) heart failure deaths, and 106 (16%) stroke/systemic embolism deaths. Biomarkers were the strongest predictors of cause-specific death: a doubling of troponin T was most strongly associated with sudden death (hazard ratio [HR], 1.48; P0.001), NT-proBNP with heart failure death (HR, 1.62; P0.001), and growth differentiation factor-15 with bleeding death (HR, 1.72; P=0.028). Prior stroke/systemic embolism (HR, 2.58; P0.001) followed by troponin T (HR, 1.45; P0.0029) were the most predictive for stroke/ systemic embolism death. Adding all biomarkers to clinical variables improved discrimination for each cause-specific death.Biomarkers were some of the strongest predictors of cause-specific death and may improve the ability to discriminate among patients' risks for different causes of death. These data suggest a potential role of biomarkers for the identification of patients at risk for different causes of death in patients anticoagulated for atrial fibrillation.URL: https://www.clinicaltrials.gov . Unique identifier: NCT00412984.
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- 2018
20. Comparison of bleeding risk scores in patients with atrial fibrillation: insights from the RE-LY trial
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John W. Eikelboom, Marco Proietti, Jonas Oldgren, Salim Yusuf, Lars Wallentin, Stuart J. Connolly, Vanessa Roldán, Michael D. Ezekowitz, Deirdre A. Lane, Ziad Hijazi, and Ulrika Andersson
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Male ,medicine.medical_specialty ,Time Factors ,Hemorrhage ,030204 cardiovascular system & hematology ,Global Health ,Risk Assessment ,Antithrombins ,Dabigatran ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Clinical information ,Atrial Fibrillation ,Internal Medicine ,medicine ,Humans ,In patient ,030212 general & internal medicine ,Oral anticoagulation ,Aged ,Aged, 80 and over ,Dose-Response Relationship, Drug ,business.industry ,anticoagulation treatment ,atrial fibrillation ,bleeding risk scores ,dabigatran ,major bleeding ,Incidence ,Warfarin ,Anticoagulants ,Atrial fibrillation ,medicine.disease ,Stroke ,Stroke prevention ,Cardiology ,Female ,business ,Major bleeding ,medicine.drug ,Follow-Up Studies - Abstract
Background Oral anticoagulation is the mainstay of stroke prevention in atrial fibrillation (AF), but must be balanced against the associated bleeding risk. Several risk scores have been proposed for prediction of bleeding events in patients with AF. Objectives To compare the performance of contemporary clinical bleeding risk scores in 18 113 patients with AF randomized to dabigatran 110 mg, 150 mg or warfarin in the RE-LY trial. Methods HAS-BLED, ORBIT, ATRIA and HEMORR2HAGES bleeding risk scores were calculated based on clinical information at baseline. All major bleeding events were centrally adjudicated. Results There were 1182 (6.5%) major bleeding events during a median follow-up of 2.0 years. For all the four schemes, high-risk subgroups had higher risk of major bleeding (all P
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- 2018
21. Investigation of Established Genetic Risk Variants for Glioma in Prediagnostic Samples from a Population-Based Nested Case–Control Study
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Carl Wibom, Eivind Hovig, Preetha Rajaraman, Hilde Langseth, Tom Børge Johannesen, Beatrice Melin, Ulrika Andersson, Florentin Späth, and Anna M. Dahlin
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Adult ,Male ,Epidemiology ,Nerve Tissue Proteins ,Genome-wide association study ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,law.invention ,Young Adult ,Risk Factors ,law ,Polymorphism (computer science) ,Glioma ,Humans ,Medicine ,Prospective Studies ,Registries ,Polymerase chain reaction ,Aged ,Genetic association ,Genetics ,Brain Neoplasms ,business.industry ,DNA Helicases ,Intracellular Signaling Peptides and Proteins ,Case-control study ,Genetic Variation ,Genes, erbB-1 ,Middle Aged ,medicine.disease ,Survival Rate ,Oncology ,Case-Control Studies ,Nested case-control study ,Etiology ,Female ,RNA, Long Noncoding ,Tumor Suppressor Protein p53 ,business - Abstract
Background: Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case–control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included. Methods: To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research. Results: We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study. Conclusions: Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis. Impact: Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology. Cancer Epidemiol Biomarkers Prev; 24(5); 810–6. ©2015 AACR.
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- 2015
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22. Comparison of Cardiac Troponins I and T Measured with High-Sensitivity Methods for Evaluation of Prognosis in Atrial Fibrillation: An ARISTOTLE Substudy
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Ziad Hijazi, Renato D. Lopes, Agneta Siegbahn, John D. Horowitz, Ulrika Andersson, Steen Husted, Lars Wallentin, John J.V. McMurray, John H. Alexander, Michael G. Hanna, Veli-Pekka Harjola, Elaine M. Hylek, Christopher B. Granger, Dan Atar, Bertil Lindahl, and Bernard J. Gersh
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Male ,medicine.medical_specialty ,Clinical Biochemistry ,macromolecular substances ,Troponin T ,Troponin complex ,Risk Factors ,Internal medicine ,Atrial Fibrillation ,Troponin I ,medicine ,Humans ,cardiovascular diseases ,Myocardial infarction ,Stroke ,Aged ,biology ,business.industry ,Biochemistry (medical) ,Hazard ratio ,Atrial fibrillation ,Middle Aged ,musculoskeletal system ,Prognosis ,medicine.disease ,Troponin ,Cardiovascular Diseases ,Heart failure ,cardiovascular system ,biology.protein ,Cardiology ,Female ,business - Abstract
BACKGROUND Although cardiac troponin is associated with outcomes in atrial fibrillation (AF), the complementary prognostic information provided by cardiac troponin I (cTnI) and cTnT is unknown. This study investigated the distribution, determinants, and prognostic value of cTnI and cTnT concentrations in patients with AF. METHODS Samples were collected. At the time of randomization, we analyzed cTnI and cTnT concentrations of 14806 AF patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial using high-sensitivity assays. Correlations (Spearman), determinants (multivariable linear regression), and outcomes (adjusted Cox models and c-statistics) were investigated. RESULTS Concentrations of cTnI and cTnT were correlated (r = 0.70) and measurable in most participants [cTnI 98.5% (median 5.4 ng/L, ≥99th percentile in 9.2%) and cTnT 93.5% (median 10.9 ng/L, ≥99th percentile in 34.4%)]. Renal impairment was the most important factor affecting the concentrations of both troponins. cTnI increase was more associated with heart failure, vascular disease, and persistent/permanent AF, and cTnT with age, male sex, and diabetes. Over a median 1.9 years of follow-up, patients with both troponins above the median had significantly higher risk for stroke/systemic embolism [hazard ratio (HR) 1.72 (95% CI 1.31–2.27)], cardiac death [3.14 (2.35–4.20)], and myocardial infarction [2.99 (1.78–5.03)] than those with both troponins below median (all P < 0.005). Intermediate risks were observed when only 1 troponin was above the median. When combined with clinical information, each marker provided similar prognostication and had comparable c-index. CONCLUSIONS cTnI and cTnT concentrations are moderately correlated and measurable in plasma of most AF patients. The risk of stroke and cardiovascular events is highest when both troponins are above median concentrations. Each troponin provides comparable prognostic information when combined with clinical risk factors. ClinicalTrials.gov/NCT00412984
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- 2015
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23. Sex-specific gene and pathway modeling of inherited glioma risk
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Ulrika Andersson, Sanjay Shete, Joellen M. Schildkraut, Sara H. Olson, Jeanette E. Eckel-Passow, Jonine L. Bernstein, Joshua B. Rubin, Georgina Armstrong, John K. Wiencke, Elizabeth B. Claus, Preetha Rajaraman, Dora Il'yasova, Beatrice Melin, Peter Liao, Daniel H. Lachance, Rose Lai, Christopher I. Amos, Melissa L. Bondy, Warren Coleman, Ryan Merrell, Gil Speyer, Zhaoming Wang, Christoffer Johansen, Michael E. Berens, William Huang, Martha S. Linet, Siegal Sadetzki, Stephen J. Chanock, Lucie McCoy, Terri Rice, Richard S. Houlston, Justin D. Lathia, Quinn T. Ostrom, Meredith Yeager, Robert B. Jenkins, Jill S. Barnholtz-Sloan, Margaret Wrensch, and Helen M. Hansen
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Genotype ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Glioma ,Biomarkers, Tumor ,medicine ,Humans ,Genetic Predisposition to Disease ,Telomerase ,Gene ,X chromosome ,030304 developmental biology ,Genetic association ,Genetics ,Sex Characteristics ,0303 health sciences ,Models, Genetic ,Case-control study ,Pascal (unit) ,Prognosis ,medicine.disease ,Telomere ,ErbB Receptors ,Survival Rate ,Case-Control Studies ,030220 oncology & carcinogenesis ,Basic and Translational Investigations ,Medical genetics ,Female ,Neurology (clinical) ,030217 neurology & neurosurgery ,Follow-Up Studies ,Genome-Wide Association Study ,Signal Transduction ,Sex characteristics - Abstract
BackgroundGenome-wide association studies (GWAS) have identified 25 risk variants for glioma, which explain ~30% of heritable risk. Most glioma histologies occur with significantly higher incidence in males. A sex-stratified analysis ide7ntified sex-specific glioma risk variants, and further analyses using gene- and pathway-based approaches may further elucidate risk variation by sex.MethodsResults from the Glioma International Case-Control Study were used as a testing set, and results from three GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for autosomal SNPs found to be nominally significant (p−6in ⅔ algorithms.Results25 genes within five regions and 19 genes within six regions reached the set significance threshold in at least 2/3 algorithms in males and females, respectively.EGFRandRTEL1-TNFRSF6Bwere significantly associated with all glioma and glioblastoma in males only, and a female-specific association inTERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the Telomeres, Telomerase, Cellular Aging, and Immortality pathway in both males and females.ConclusionsThese results suggest that there may be biologically relevant significant differences by sex in genetic risk for glioma. Additional gene- and pathway-based analyses may further elucidate the biological processes through which this risk is conferred.
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- 2017
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24. Central and peripheral leptin and agouti-related protein during and after pregnancy in relation to weight change
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Ulf Andreasson, Magnus Gren, Pernilla Svedin, Aurimantas Pelanis, Ameli Ingemansson, Kaj Blennow, Henrik Zetterberg, Agneta Holmäng, Ulrika Andersson-Hall, and Carina Mallard
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0301 basic medicine ,Adult ,Leptin ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Adipokine ,030209 endocrinology & metabolism ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Insulin resistance ,Pregnancy ,Internal medicine ,Medicine ,Humans ,Insulin ,Agouti-Related Protein ,Leptin receptor ,Adiponectin ,business.industry ,digestive, oral, and skin physiology ,Weight change ,Body Weight ,medicine.disease ,030104 developmental biology ,Receptors, Leptin ,Female ,medicine.symptom ,business ,Weight gain ,hormones, hormone substitutes, and hormone antagonists - Abstract
OBJECTIVE: To study changes of neuropeptides and adipokines in cerebrospinal fluid (CSF) and serum from pregnancy to postpregnancy in relation to weight changes, fat mass and glucose metabolism. CONTEXT: With high postpartum weight retention being a risk factor in future pregnancies and of lifelong obesity, we evaluated neuropeptide and adipokine changes in women who either gained weight or were weight stable. DESIGN: Women were followed for 5 ± 1 years after pregnancy and divided into two groups, weight stable and weight gain, by weight change from start of pregnancy. PATIENTS: Twenty‐five women (BMI 27 ± 5 kg/m2) recruited at admission for elective caesarean section. MEASUREMENTS: CSF and serum levels of agouti‐related protein (AgRP), leptin and insulin, and serum levels of adiponectin and soluble leptin receptor were measured during and after pregnancy. These measurements were further related to fat mass and insulin sensitivity (HOMA‐IR). RESULTS: S‐AgRP levels during pregnancy were lower in the weight stable group and a 1 unit increase in s‐AgRP was associated with 24% higher odds of pertaining to the weight gain group. After pregnancy, s‐AgRP increased in the weight stable group but decreased in the weight gain group. Decreased transport of leptin into CSF during pregnancy was reversed by an increased CSF:serum leptin ratio after pregnancy. In women who returned to their prepregnancy weight, serum adiponectin increased after pregnancy and correlated negatively with HOMA‐IR. CONCLUSION: S‐AgRP concentration in late pregnancy may be one factor predicting weight change after pregnancy, and circulating AgRP may be physiologically important in the long‐term regulation of body weight.
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- 2017
25. Efficacy and safety of dabigatran compared with warfarin in patients with atrial fibrillation in relation to renal function over time-A RE-LY trial analysis
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Paul A. Reilly, Stuart J. Connolly, John W. Eikelboom, Ziad Hijazi, Lars Wallentin, Salim Yusuf, Ulrika Andersson, Jonas Oldgren, Stefan H. Hohnloser, and Michael D. Ezekowitz
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Relative risk reduction ,Male ,medicine.medical_specialty ,Internationality ,Time Factors ,Renal function ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Kidney Function Tests ,Risk Assessment ,Dabigatran ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,Cause of Death ,Atrial Fibrillation ,medicine ,Humans ,030212 general & internal medicine ,Aged ,Proportional Hazards Models ,Creatinine ,Proportional hazards model ,business.industry ,Hazard ratio ,Warfarin ,Anticoagulants ,Atrial fibrillation ,Middle Aged ,medicine.disease ,Survival Analysis ,Stroke ,Treatment Outcome ,chemistry ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug ,Follow-Up Studies ,Glomerular Filtration Rate - Abstract
Background Renal function may decline over time, and the efficacy and safety of dabigatran in atrial fibrillation (AF) in relation to renal function changes are unknown. Methods The RE-LY trial randomized 18,113 patients with AF to 2 doses of dabigatran or warfarin for stroke prevention. Serial creatinine measurements were available in 16,988 patients. The relations between treatment, outcomes, and renal function (Cockcroft-Gault) were investigated using Cox-regression (1) with renal function as a time-dependent covariate and (2) according to worsening renal function (WRF) during follow-up, predefined as a decline in estimated glomerular filtration rate >20% from baseline. Results During a median follow-up of 1.8 years, 4,106 (24.2%) participants were observed to have WRF, and 12,882 (75.8%) had stable renal function. The risks of all-cause mortality and major bleeding were higher in patients with WRF versus those with stable renal function (hazard ratio [95% CI]: 2.17 [1.81-2.59] and 1.43 [1.19-1.71], respectively; both P 80 mL/min) during follow-up (interaction P = .026). Conclusions In AF, WRF was associated with a higher risk of death and major bleeding. The efficacy and safety profile of dabigatran compared with warfarin was similar irrespective of renal function changes over time. Dabigatran 110 mg showed a greater relative risk reduction of major bleeding in patients with normal renal function during follow-up.
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- 2017
26. Pregnancy to postpartum transition of serum metabolites in women with gestational diabetes
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Kerstin Berntorp, Carolina Gustavsson, Tommy Olsson, Jatta Puhkala, Agneta Holmäng, Riitta Luoto, Elin Chorell, and Ulrika Andersson Hall
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Adult ,Blood Glucose ,0301 basic medicine ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,030209 endocrinology & metabolism ,Context (language use) ,Type 2 diabetes ,Endocrinology and Diabetes ,Gestational diabetes mellitus ,Mass Spectrometry ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Insulin resistance ,Pregnancy ,Internal medicine ,Diabetes mellitus ,Type 2 diabetes mellitus ,medicine ,Humans ,Metabolomics ,business.industry ,Obstetrics ,Insulin ,Postpartum Period ,nutritional and metabolic diseases ,Type 2 Diabetes Mellitus ,medicine.disease ,Branched-chain amino acids ,Multivariate statistics ,Gestational diabetes ,Diabetes, Gestational ,030104 developmental biology ,Female ,sense organs ,business ,Amino Acids, Branched-Chain ,Biomarkers - Abstract
Context Gestational diabetes is commonly linked to development of type 2 diabetes mellitus (T2DM). There is a need to characterize metabolic changes associated with gestational diabetes in order to find novel biomarkers for T2DM. Objective To find potential pathophysiological mechanisms and markers for progression from gestational diabetes mellitus to T2DM by studying the metabolic transition from pregnancy to postpartum. Design The metabolic transition profile from pregnancy to postpartum was characterized in 56 women by mass spectrometry-based metabolomics; 11 women had gestational diabetes mellitus, 24 had normal glucose tolerance, and 21 were normoglycaemic but at increased risk for gestational diabetes mellitus. Fasting serum samples collected during trimester 3 (gestational week 32 ± 0.6) and postpartum (10.5 ± 0.4 months) were compared in diagnosis-specific multivariate models (orthogonal partial least squares analysis). Clinical measurements (e.g., insulin, glucose, lipid levels) were compared and models of insulin sensitivity and resistance were calculated for the same time period. Results Women with gestational diabetes had significantly increased postpartum levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine, and their circulating lipids did not return to normal levels after pregnancy. The increase in BCAAs occurred postpartum since the BCAAs did not differ during pregnancy, as compared to normoglycemic women. Conclusions Postpartum levels of specific BCAAs, notably valine, are related to gestational diabetes during pregnancy.
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- 2017
27. Repeated Measurements of Cardiac Biomarkers in Atrial Fibrillation and Validation of the ABC Stroke Score Over Time
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Bertil Lindahl, Lars Wallentin, Elaine M. Hylek, Agneta Siegbahn, John H. Alexander, Bernard J. Gersh, Ziad Hijazi, Veli-Pekka Harjola, Renato D. Lopes, Johan Lindbäck, Christopher B. Granger, Ulrika Andersson, Michael G. Hanna, Jonas Oldgren, HUS Emergency Medicine and Services, Clinicum, University of Helsinki, Department of Diagnostics and Therapeutics, and Anestesiologian yksikkö
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Male ,Time Factors ,TROPONIN-I ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,Arrhythmias ,0302 clinical medicine ,Risk Factors ,TERM INDIVIDUAL VARIATION ,cardiac biomarkers ,Troponin I ,Atrial Fibrillation ,Natriuretic Peptide, Brain ,Medicine ,ARTERY-DISEASE ,Arrhythmia and Electrophysiology ,030212 general & internal medicine ,Stroke ,Original Research ,Framingham Risk Score ,biology ,troponin ,THROMBOEMBOLIC EVENTS ,Atrial fibrillation ,Middle Aged ,Prognosis ,stroke ,3. Good health ,ARISTOTLE TRIAL ,Cardiology ,Biomarker (medicine) ,HEART-FAILURE ,Female ,RISK-ASSESSMENT ,Cardiology and Cardiovascular Medicine ,medicine.medical_specialty ,risk score ,Risk Assessment ,Decision Support Techniques ,03 medical and health sciences ,Double-Blind Method ,Troponin T ,Predictive Value of Tests ,Internal medicine ,T ASSAY ,Humans ,Aged ,Proportional Hazards Models ,natriuretic peptide ,business.industry ,Proportional hazards model ,ACUTE CORONARY SYNDROMES ,Reproducibility of Results ,medicine.disease ,Troponin ,Peptide Fragments ,Heart failure ,3121 General medicine, internal medicine and other clinical medicine ,biology.protein ,Linear Models ,Cerebrovascular Disease/Stroke ,business ,Biomarkers - Abstract
Background Cardiac biomarkers are independent risk markers in atrial fibrillation, and the novel biomarker–based ABC stroke score (age, biomarkers, and clinical history of prior stroke) was recently shown to improve the prediction of stroke risk in patients with atrial fibrillation. Our aim was to investigate the short‐term variability of the cardiac biomarkers and evaluate whether the ABC stroke risk score provides a stable short‐term risk estimate. Methods and Results According to the study protocol, samples were obtained at entry and also at 2 months in 4796 patients with atrial fibrillation followed for a median of 1.8 years in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Cardiac troponin I, cardiac troponin T, and N‐terminal pro‐B‐type natriuretic peptide were measured with high‐sensitivity immunoassays. Associations with outcomes were evaluated by Cox regression. C indices and calibration plots were used to evaluate the ABC stroke score at 2 months. The average changes in biomarker levels during 2 months were small (median change cardiac troponin T +2.8%, troponin I +2.0%, and N‐terminal pro‐B‐type natriuretic peptide +13.5%) and within‐subject correlation was high (all ≥0.82). Repeated measurement of cardiac biomarkers provided some incremental prognostic value for mortality but not for stroke when combined with clinical risk factors and baseline levels of the biomarkers. Based on 8702 person‐years of follow‐up and 96 stroke/systemic embolic events, the ABC stroke score at 2 months achieved a similar C index of 0.70 (95% CI, 0.65–0.76) as compared with 0.70 (95% CI, 0.65–0.75) at baseline. The ABC stroke score remained well calibrated using predefined risk classes. Conclusions In patients with stable atrial fibrillation, the variability of the cardiac biomarkers and the biomarker‐based ABC stroke score during 2 months are small. The prognostic information by the ABC stroke score remains consistent and well calibrated with similar good predictive performance if patients are retested after 2 months. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT 00412984.
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- 2017
28. D‐dimer and risk of thromboembolic and bleeding events in patients with atrial fibrillation – observations from the ARISTOTLE trial
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Jack Ansell, Christopher B. Granger, Bernard J. Gersh, Elaine M. Hylek, John H. Alexander, Lars Wallentin, Agneta Siegbahn, Steen Elkjær Husted, Christina Christersson, R. De Caterina, Kurt Huber, Renato D. Lopes, Ulrika Andersson, John D. Horowitz, and Michael G. Hanna
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Male ,medicine.medical_specialty ,Vitamin K ,Randomization ,Pyridones ,Embolism ,Administration, Oral ,Hemorrhage ,Risk Assessment ,Cohort Studies ,Fibrin Fibrinogen Degradation Products ,Fibrinolytic Agents ,Predictive Value of Tests ,Risk Factors ,Thromboembolism ,Internal medicine ,Atrial Fibrillation ,Humans ,Medicine ,Stroke ,Aged ,business.industry ,Incidence ,Hazard ratio ,Warfarin ,Anticoagulants ,Atrial fibrillation ,Hematology ,Middle Aged ,medicine.disease ,Confidence interval ,Treatment Outcome ,Cohort ,Cardiology ,Pyrazoles ,Female ,Apixaban ,business ,medicine.drug - Abstract
Background D-dimer is related to adverse outcomes in arterial and venous thromboembolic diseases. Objectives To evaluate the predictive value of D-dimer level for stroke, other cardiovascular events, and bleeds, in patients with atrial fibrillation (AF) treated with oral anticoagulation with apixaban or warfarin; and to evaluate the relationship between the D-dimer levels at baseline and the treatment effect of apixaban vs. warfarin. Methods In the ARISTOTLE trial, 18 201 patients with AF were randomized to apixaban or warfarin. D-dimer was analyzed in 14 878 patients at randomization. The cohort was separated into two groups; not receiving vitamin K antagonist (VKA) treatment and receiving VKA treatment at randomization. Results Higher D-dimer levels were associated with increased frequencies of stroke or systemic embolism (hazard ratio [HR] [Q4 vs. Q1] 1.72, 95% confidence interval [CI] 1.14–2.59, P = 0.003), death (HR [Q4 vs. Q1] 4.04, 95% CI 3.06–5.33) and major bleeding (HR [Q4 vs. Q1] 2.47, 95% CI 1.77–3.45, P
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- 2014
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29. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
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Hidemi Ito, Stephen K. Van Den Eeden, Abdisamad M. Ibrahim, Ching C. Lau, Preetha Rajaraman, Gloria M. Petersen, Judith Hoffman-Bolton, Colin P.N. Dinney, Chang Hyun Kang, Melinda C. Aldrich, Mark P. Purdue, Xiao-Ou Shu, William J. Blot, Sanjay Shete, Alpa V. Patel, Charles Kooperberg, Paolo Vineis, David Van Den Berg, Chao A. Hsiung, Anthony J. Swerdlow, Qing Lan, Wu Chou Su, Afshan Siddiq, Ulrike Peters, Katia Scotlandi, Sara H. Olson, Kendra Schwartz, Kelly L. Bolton, Chancellor Hohensee, Josep Lloreta, Kevin B. Jacobs, Debra T. Silverman, Rudolf Kaaks, Wei Zheng, Steven Gallinger, Junwen Wang, Angela Carta, Massimo Serra, Petra H.M. Peeters, Victoria L. Stevens, Yasushi Yatabe, Geraldine Cancel-Tassin, Joshua N. Sampson, Young Tae Kim, Graham A. Colditz, Pan-Chyr Yang, Baosen Zhou, Fredrick R. Schumacher, Nicolas Wentzensen, Evelyn Tay, Claudia Maria Hattinger, Chen Wu, Pilar Amiano, Mattias Johansson, Maxwell P. Lee, Christian P. Kratz, Michael B. Cook, Mingfeng Zhang, Kay-Tee Khaw, Jian-Min Yuan, Anne Zeleniuch-Jacquotte, Jinping Jia, Roberto Tirabosco, Jing Ma, Neil E. Caporaso, Christopher A. Haiman, Bu Tian Ji, Adrienne M. Flanagan, Neyssa Marina, Eric J. Jacobs, Sophia S. Wang, Chong-Jen Yu, Edward Giovannucci, Margaret Wrensch, Robert L. Grubb, Bin Zhu, Daniel O. Stram, Manolis Kogevinas, Margaret R. Karagas, Mazda Jenab, Alison M. Mondul, Jun Xu, Preethi S. Raj, Anders Ahlbom, Christine D. Berg, Shelley Niwa, Kala Visvanathan, Loic Le Marchand, Jorge R. Toro, Robert N. Hoover, Heather Spencer Feigelson, Michelle Brotzman, Laurence N. Kolonel, Krista A. Zanetti, Chengfeng Wang, Mary Ann Butler, Ann Truelove, Irene L. Andrulis, Hongbing Shen, H. Dean Hosgood, Ming Shyan Huang, Gee-Chen Chang, Jianjun Liu, John K. Wiencke, Stephanie J. Weinstein, Beatrice Melin, Kouya Shiraishi, Zhihua Yin, Lee E. Moore, Börje Ljungberg, Jolanta Lissowska, Elizabeth M. Gillanders, M. T. Landi, Cari M. Kitahara, Maria Feychting, Kuan-Yu Chen, Matthias Simon, Brian M. Wolpin, Hemang Parikh, Hannah P. Yang, Graham G. Giles, Alison Johnson, Demetrius Albanes, Carlos González, Brian E. Henderson, Xifeng Wu, Harvey A. Risch, Amy Hutchinson, Christopher Hautman, Constance Chen, Zhibin Hu, Donghui Li, Elio Riboli, Julie E. Buring, Curtis C. Harris, Xu Che, Núria Malats, Roger Henriksson, Rosario Tumino, Joanne S. Colt, Alfredo Carrato, Paolo Boffetta, Maria Pik Wong, Hideo Tanaka, Federico Canzian, Alan D. L. Sihoe, Chien-Jen Chen, Kenneth Muir, Chen Ying, Qincheng He, Melissa C. Southey, Marc Sanson, Victoria K. Cortessis, Sharon A. Savage, Wei Hu, Yao Tettey, Daniela S. Gerhard, Sofia Pavanello, Guangwen Cao, H. Barton Grossman, Michael Goggins, Hideo Kunitoh, Peter D. Inskip, Seth P. Lerner, Peter Kraft, David Thomas, Peng Guan, Chung Hsing Chen, I. Shou Chang, Christoffer Johansen, Roberta McKean-Cowdin, Lee J. Helman, Yuh Min Chen, Ana Patiño-García, Pär Stattin, Xiaoping Miao, Tangchun Wu, Jay S. Wunder, Ann W. Hsing, Yu-Tang Gao, Brooke L. Fridley, Tania Carreón, Charles C. Chung, Nan Hu, Yoo Jin Jung, Richard B. Biritwum, Eric J. Duell, Philip R. Taylor, Satu Männistö, Kai Yu, Meredith Yeager, Xia Pu, Vittorio Krogh, Anand P. Chokkalingam, Susan M. Gapstur, W. Ryan Diver, Yuanqing Ye, Keitaro Matsuo, Cecilia Arici, You-Lin Qiao, Alan R. Schned, Dominique S. Michaud, Joanne W. Elena, Christopher Kim, Dongxin Lin, Yun-Chul Hong, Daru Lu, Reina García-Closas, Jonine D. Figueroa, Linda M. Liao, Yi-Long Wu, Heiner Boeing, Mark Lathrop, Göran Hallmans, Elizabeth A. Holly, Carol Giffen, Andrew A. Adjei, Consol Serra, Anne Tjønneland, Joseph F. Fraumeni, Alisa M. Goldstein, Ruth C. Travis, Rebecca Troisi, Dalsu Baris, Nalan Gokgoz, Olivier Cussenot, Xiang Deng, Yeul Hong Kim, Malin Sund, Sonja I. Berndt, E. David Crawford, Edward D. Yeboah, Sook Whan Sung, Françoise Clavel-Chapelon, Woon-Puay Koh, Nilgun Kurucu, Richard B. Hayes, Ashish M. Kamat, Beata Peplonska, Laurie Burdette, Ze Zhang Tang, Alan A. Arslan, Malcolm C. Pike, Sabina Sierri, J. Michael Gaziano, Lorna H. McNeil, Katherine A. McGlynn, Ulla Vogel, Logan G. Spector, H. Bas Bueno-de-Mesquita, Stephen J. Chanock, Jae Yong Park, Jennifer Prescott, Fernando Lecanda, Margaret A. Tucker, Ti Ding, Christian C. Abnet, Jenny Chang-Claude, Dimitrios Trichopoulos, Wei-Yen Lim, Wen Tan, Nick Orr, Jin Hee Kim, Stefano Porru, Chand Khanna, Robert R. McWilliams, Zhaoming Wang, Jeong Seon Ryu, David V. Conti, Alison P. Klein, Adonina Tardón, Robert J. Klein, Rebecca J. Rodabough, Mark H. Greene, Aruna Kamineni, Jie Lin, Rachael Z. Stolzenberg-Solomon, Patricia Hartge, Susan E. Hankinson, Young-Chul Kim, In Sam Kim, Luis Sierrasesúmaga, Roel Vermeulen, Paige M. Bracci, Mariana C. Stern, Louise A. Brinton, Myron D. Gross, Yong-Bing Xiang, Chih Yi Chen, G. A. Gerald Andriole, Paul S. Meltzer, Ying-Huang Tsai, Faith G. Davis, Ulrika Andersson, Paul Brennan, Sara Lindström, Chaoyu Wang, Giuseppe Mastrangelo, Laufey T. Amundadottir, Immaculata De Vivo, Bryan A. Bassig, Elisabete Weiderpass, Takashi Kohno, Nilanjan Chatterjee, Margaret R. Spitz, Pier Alberto Bertazzi, William Wheeler, David J. Hunter, Wei Tang, Qiuyin Cai, Naomi E. Allen, Molly Schwenn, Emily White, Min Shen, Adeline Seow, Laura E. Beane Freeman, James E. Mensah, Howard D. Sesso, Anna Luisa Di Stefano, Amanda Black, Manuela Gago-Dominguez, Christine B. Ambrosone, Avima M. Ruder, Martha S. Linet, Meir J. Stampfer, Robert C. Kurtz, Donald A. Barkauskas, Lisa W. Chu, Montserrat Garcia-Closas, Jason W. Hoskins, Melissa A. Austin, Kyoung Mu Lee, Jianxin Shi, Charles S. Fuchs, Nathaniel Rothman, Richard Gorlick, Piero Picci, Gianluca Severi, Ann G. Schwartz, Jian Gu, Christopher I. Amos, Marie-Christine Boutron-Ruault, Salvatore Panico, Alicja Wolk, Sara S. Strom, Lisa Mirabello, Jin-Hu Fan, Chin-Fu Hsiao, Neal D. Freedman, Geoffrey S. Tobias, Julie M. Gastier-Foster, Wang, Z, Zhu, B, Zhang, M, Parikh, H, Jia, J, Chung, Cc, Sampson, Jn, Hoskins, Jw, Hutchinson, A, Burdette, L, Ibrahim, A, Hautman, C, Raj, P, Abnet, Cc, Adjei, Aa, Ahlbom, A, Albanes, D, Allen, Ne, Ambrosone, Cb, Aldrich, M, Amiano, P, Amos, C, Andersson, U, Andriole G., Jr, Andrulis, Il, Arici, C, Arslan, Aa, Austin, Ma, Baris, D, Barkauskas, Da, Bassig, Ba, Beane Freeman, Le, Berg, Cd, Berndt, Si, Bertazzi, Pa, Biritwum, Rb, Black, A, Blot, W, Boeing, H, Boffetta, P, Bolton, K, Boutron Ruault, Mc, Bracci, Pm, Brennan, P, Brinton, La, Brotzman, M, Bueno de Mesquita, Hb, Buring, Je, Butler, Ma, Cai, Q, Cancel Tassin, G, Canzian, F, Cao, G, Caporaso, Ne, Carrato, A, Carreon, T, Carta, A, Chang, Gc, Chang, I, Chang Claude, J, Che, X, Chen, Cj, Chen, Cy, Chen, Ch, Chen, C, Chen, Ky, Chen, Ym, Chokkalingam, Ap, Chu, Lw, Clavel Chapelon, F, Colditz, Ga, Colt, J, Conti, D, Cook, Mb, Cortessis, Vk, Crawford, Ed, Cussenot, O, Davis, Fg, De Vivo, I, Deng, X, Ding, T, Dinney, Cp, Di Stefano, Al, Diver, Wr, Duell, Ej, Elena, Jw, Fan, Jh, Feigelson, H, Feychting, M, Figueroa, Jd, Flanagan, Am, Fraumeni JF, Jr, Freedman, Nd, Fridley, Bl, Fuchs, C, Gago Dominguez, M, Gallinger, S, Gao, Yt, Gapstur, Sm, Garcia Closas, M, Garcia Closas, R, Gastier Foster, Jm, Gaziano, Jm, Gerhard, D, Giffen, Ca, Giles, Gg, Gillanders, Em, Giovannucci, El, Goggins, M, Gokgoz, N, Goldstein, Am, Gonzalez, C, Gorlick, R, Greene, Mh, Gross, M, Grossman, Hb, Grubb R., 3rd, Gu, J, Guan, P, Haiman, Ca, Hallmans, G, Hankinson, Se, Harris, Cc, Hartge, P, Hattinger, C, Hayes, Rb, He, Q, Helman, L, Henderson, Be, Henriksson, R, Hoffman Bolton, J, Hohensee, C, Holly, Ea, Hong, Yc, Hoover, Rn, Hosgood HD, 3rd, Hsiao, Cf, Hsing, Aw, Hsiung, Ca, Hu, N, Hu, W, Hu, Z, Huang, M, Hunter, Dj, Inskip, Pd, Ito, H, Jacobs, Ej, Jacobs, Kb, Jenab, M, Ji, Bt, Johansen, C, Johansson, M, Johnson, A, Kaaks, R, Kamat, Am, Kamineni, A, Karagas, M, Khanna, C, Khaw, Kt, Kim, C, Kim, I, Kim, Yh, Kim, Yc, Kim, Yt, Kang, Ch, Jung, Yj, Kitahara, Cm, Klein, Ap, Klein, R, Kogevinas, M, Koh, Wp, Kohno, T, Kolonel, Ln, Kooperberg, C, Kratz, Cp, Krogh, V, Kunitoh, H, Kurtz, Rc, Kurucu, N, Lan, Q, Lathrop, M, Lau, Cc, Lecanda, F, Lee, Km, Lee, Mp, Le Marchand, L, Lerner, Sp, Li, D, Liao, Lm, Lim, Wy, Lin, D, Lin, J, Lindstrom, S, Linet, M, Lissowska, J, Liu, J, Ljungberg, B, Lloreta, J, Lu, D, Ma, J, Malats, N, Mannisto, S, Marina, N, Mastrangelo, G, Matsuo, K, Mcglynn, Ka, McKean Cowdin, R, Mcneill, Lh, Mcwilliams, Rr, Melin, B, Meltzer, P, Mensah, Je, Miao, X, Michaud, D, Mondul, Am, Moore, Le, Muir, K, Niwa, S, Olson, Sh, Orr, N, Panico, Salvatore, Park, Jy, Patel, Av, Patino Garcia, A, Pavanello, S, Peeters, Ph, Peplonska, B, Peters, U, Petersen, Gm, Picci, P, Pike, Mc, Porru, S, Prescott, J, Pu, X, Purdue, Mp, Qiao, Yl, Rajaraman, P, Riboli, E, Risch, Ha, Rodabough, Rj, Rothman, N, Ruder, Am, Ryu, J, Sanson, M, Schned, A, Schumacher, Fr, Schwartz, Ag, Schwartz, Kl, Schwenn, M, Scotlandi, K, Seow, A, Serra, C, Serra, M, Sesso, Hd, Severi, G, Shen, H, Shen, M, Shete, S, Shiraishi, K, Shu, Xo, Siddiq, A, Sierrasesumaga, L, Sierri, S, Loon Sihoe, Ad, Silverman, Dt, Simon, M, Southey, Mc, Spector, L, Spitz, M, Stampfer, M, Stattin, P, Stern, Mc, Stevens, Vl, Stolzenberg Solomon, Rz, Stram, Do, Strom, S, Su, Wc, Sund, M, Sung, Sw, Swerdlow, A, Tan, W, Tanaka, H, Tang, W, Tang, Zz, Tardon, A, Tay, E, Taylor, Pr, Tettey, Y, Thomas, Dm, Tirabosco, R, Tjonneland, A, Tobias, G, Toro, Jr, Travis, Rc, Trichopoulos, D, Troisi, R, Truelove, A, Tsai, Yh, Tucker, Ma, Tumino, R, Van Den Berg, D, Van Den Eeden, Sk, Vermeulen, R, Vineis, P, Visvanathan, K, Vogel, U, Wang, C, Wang, J, Wang, S, Weiderpass, E, Weinstein, Sj, Wentzensen, N, Wheeler, W, White, E, Wiencke, Jk, Wolk, A, Wolpin, Bm, Wong, Mp, Wrensch, M, Wu, C, Wu, T, Wu, X, Wu, Yl, Wunder, J, Xiang, Yb, Xu, J, Yang, Hp, Yang, Pc, Yatabe, Y, Ye, Y, Yeboah, Ed, Yin, Z, Ying, C, Yu, Cj, Yu, K, Yuan, Jm, Zanetti, Ka, Zeleniuch Jacquotte, A, Zheng, W, Zhou, B, Mirabello, L, Savage, Sa, Kraft, P, Chanock, Sj, Yeager, M, Landi, Mt, Shi, J, Chatterjee, N, Amundadottir, Lt, Wang, Z., Zhu, B., Zhang, M., Parikh, H., Jia, J., Chung, C.C., Sampson, J.N., Hoskins, J.W., Hutchinson, A., Burdette, L., Ibrahim, A., Hautman, C., Raj, P.S., Abnet, C.C., Adjei, A.A., Ahlbom, A., Albanes, D., Allen, N.E., Ambrosone, C.B., Aldrich, M., Amiano, P., Amos, C., Andersson, U., Gerald Andriole, G.A., Jr., Andrulis, I.L., Arici, C., Arslan, A.A., Austin, M.A., Baris, D., Barkauskas, D.A., Bassig, B.A., Freeman, L.E.B., Berg, C.D., Berndt, S.I., Bertazzi, P.A., Biritwum, R.B., Black, A., Blot, W., Boeing, H., Boffetta, P., Bolton, K., Boutron-Ruault, M.-C., Bracci, P.M., Brennan, P., Brinton, L.A., Brotzman, M., Bueno-de-Mesquita, H.B., Buring, J.E., Butler, M.A., Cai, Q., Cancel-Tassin, G., Canzian, F., Cao, G., Caporaso, N.E., Carrato, A., Carreon, T., Carta, A., Chang, G.-C., Chang, I.-S., Chang-Claude, J., Che, X., Chen, C.-J., Chen, C.-Y., Chen, C.-H., Chen, C., Chen, K.-Y., Chen, Y.-M., Chokkalingam, A.P., Chu, L.W., Clavel-Chapelon, F., Colditz, G.A., Colt, J.S., Conti, D., Cook, M.B., Cortessis, V.K., Crawford, E.D., Cussenot, O., Davis, F.G., De Vivo, I., Deng, X., Ding, T., Dinney, C.P., Di Stefano, A.L., Diver, W.R., Duell, E.J., Elena, J.W., Fan, J.-H., Feigelson, H.S., Feychting, M., Figueroa, J.D., Flanagan, A.M., Fraumeni, J.F., Jr., Freedman, N.D., Fridley, B.L., Fuchs, C.S., Gago-Dominguez, M., Gallinger, S., Gao, Y.-T., Gapstur, S.M., Garcia-Closas, M., Garcia-Closas, R., Gastier-Foster, J.M., Gaziano, J.M., Gerhard, D.S., Giffen, C.A., Giles, G.G., Gillanders, E.M., Giovannucci, E.L., Goggins, M., Gokgoz, N., Goldstein, A.M., Gonzalez, C., Gorlick, R., Greene, M.H., Gross, M., Grossman, H.B., Grubb, R., III and Gu, J., Guan, P., Haiman, C.A., Hallmans, G., Hankinson, S.E., Harris, C.C., Hartge, P., Hattinger, C., Hayes, R.B., He, Q., Helman, L., Henderson, B.E., Henriksson, R., Hoffman-Bolton, J., Hohensee, C., Holly, E.A., Hong, Y.-C., Hoover, R.N., Dean Hosgood, H., Hsiao, C.-F., Hsing, A.W., Hsiung, C.A., Hu, N., Hu, W., Hu, Z., Huang, M.-S., Hunter, D.J., Inskip, P.D., Ito, H., Jacobs, E.J., Jacobs, K.B., Jenab, M., Ji, B.-T., Johansen, C., Johansson, M., Johnson, A., Kaaks, R., Kamat, A.M., Kamineni, A., Karagas, M., Khanna, C., Khaw, K.-T., Kim, C., Kim, I.-S., Kim, J.H., Kim, Y.H., Kim, Y.-C., Kim, Y.T., Kang, C.H., Jung, Y.J., Kitahara, C.M., Klein, A.P., Klein, R., Kogevinas, M., Koh, W.-P., Kohno, T., Kolonel, L.N., Kooperberg, C., Kratz, C.P., Krogh, V., Kunitoh, H., Kurtz, R.C., Kurucu, N., Lan, Q., Lathrop, M., Lau, C.C., Lecanda, F., Lee, K.-M., Lee, M.P., Marchand, L.L., Lerner, S.P., Li, D., Liao, L.M., Lim, W.-Y., Lin, D., Lin, J., Lindstrom, S., Linet, M.S., Lissowska, J., Liu, J., Ljungberg, B., Lloreta, J., Lu, D., Ma, J., Malats, N., Mannisto, S., Marina, N., Mastrangelo, G., Matsuo, K., McGlynn, K.A., McKean-Cowdin, R., McNeil, L.H., McWilliams, R.R., Melin, B.S., Meltzer, P.S., Mensah, J.E., Miao, X., Michaud, D.S., Mondul, A.M., Moore, L.E., Muir, K., Niwa, S., Olson, S.H., Orr, N., Panico, S., Park, J.Y., Patel, A.V., Patino-Garcia, A., Pavanello, S., Peeters, P.H.M., Peplonska, B., Peters, U., Petersen, G.M., Picci, P., Pike, M.C., Porru, S., Prescott, J., Pu, X., Purdue, M.P., Qiao, Y.-L., Rajaraman, P., Riboli, E., Risch, H.A., Rodabough, R.J., Rothman, N., Ruder, A.M., Ryu, J.-S., Sanson, M., Schned, A., Schumacher, F.R., Schwartz, A.G., Schwartz, K.L., Schwenn, M., Scotlandi, K., Seow, A., Serra, C., Serra, M., Sesso, H.D., Severi, G., Shen, H., Shen, M., Shete, S., Shiraishi, K., Shu, X.-O., Siddiq, A., Sierrasesumaga, L., Sierri, S., Sihoe, A.D.L., Silverman, D.T., Simon, M., Southey, M.C., Spector, L., Spitz, M., Stampfer, M., Stattin, P., Stern, M.C., Stevens, V.L., Stolzenberg-Solomon, R.Z., Stram, D.O., Strom, S.S., Su, W.-C., Sund, M., Sung, S.W., Swerdlow, A., Tan, W., Tanaka, H., Tang, W., Tang, Z.-Z., Tardon, A., Tay, E., Taylor, P.R., Tettey, Y., Thomas, D.M., Tirabosco, R., Tjonneland, A., Tobias, G.S., Toro, J.R., Travis, R.C., Trichopoulos, D., Troisi, R., Truelove, A., Tsai, Y.-H., Tucker, M.A., Tumino, R., Van Den Berg, D., Van Den Eeden, S.K., Vermeulen, R., Vineis, P., Visvanathan, K., Vogel, U., Wang, C., Wang, J., Wang, S.S., Weiderpass, E., Weinstein, S.J., Wentzensen, N., Wheeler, W., White, E., Wiencke, J.K., Wolk, A., Wolpin, B.M., Wong, M.P., Wrensch, M., Wu, C., Wu, T., Wu, X., Wu, Y.-L., Wunder, J.S., Xiang, Y.-B., Xu, J., Yang, H.P., Yang, P.-C., Yatabe, Y., Ye, Y., Yeboah, E.D., Yin, Z., Ying, C., Yu, C.-J., Yu, K., Yuan, J.-M., Zanetti, K.A., Zeleniuch-Jacquotte, A., Zheng, W., Zhou, B., Mirabello, L., Savage, S.A., Kraft, P., Chanock, S.J., Yeager, M., Landi, M.T., Shi, J., Chatterjee, N., and Amundadottir, L.T.
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Male ,SINGLE-NUCLEOTIDE POLYMORPHISM ,Genome-wide association study ,Epigenesis, Genetic ,Gene Frequency ,Molecular Biology ,Genetics ,Genetics (clinical) ,Neoplasms ,Odds Ratio ,Genome-wide association studies (GWAS) ,Telomerase ,DNA METHYLATION Author Information ,Association Studies Articles ,General Medicine ,PANCREATIC-CANCER ,PROSTATE-CANCER ,Neoplasm Proteins ,POSTMENOPAUSAL BREAST-CANCER ,TERT PROMOTER MUTATIONS ,Gene Expression Regulation, Neoplastic ,2 SUSCEPTIBILITY LOCI ,DNA methylation ,Chromosomes, Human, Pair 5 ,Female ,Risk ,Locus (genetics) ,Single-nucleotide polymorphism ,TERT and CLPTM1L gene ,Biology ,Polymorphism, Single Nucleotide ,LUNG-CANCER ,Humans ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,Allele ,Gene ,Allele frequency ,Alleles ,Genetic association ,chromosome 5p15.33 ,Computational Biology ,Membrane Proteins ,DNA Methylation ,Genetic Loci ,TELOMERE LENGTH ,Genome-Wide Association Study - Abstract
Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10(-39); Region 3: rs2853677, P = 3.30 x 10(-36) and PConditional = 2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and PConditional = 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10(-15) and PConditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10(-18) and PConditional = 7.06 x 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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- 2014
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30. High-Sensitivity Troponin I for Risk Assessment in Patients With Atrial Fibrillation
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Renato D. Lopes, Ziad Hijazi, Agneta Siegbahn, Ulrika Andersson, Bernard J. Gersh, Dan Atar, Steen Husted, Elaine M. Hylek, Puneet Mohan, Christopher B. Granger, John D. Horowitz, Lars Wallentin, Veli-Pekka Harjola, John J.V. McMurray, and John H. Alexander
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Male ,medicine.medical_specialty ,Pyridones ,Population ,Hemorrhage ,macromolecular substances ,Sensitivity and Specificity ,Double-Blind Method ,Fibrinolytic Agents ,Risk Factors ,Thromboembolism ,Physiology (medical) ,Internal medicine ,Troponin I ,medicine ,Humans ,atrial fibrillation ,education ,Stroke ,Aged ,education.field_of_study ,troponin ,business.industry ,Incidence ,Warfarin ,Anticoagulants ,risk assessment ,Atrial fibrillation ,Middle Aged ,musculoskeletal system ,medicine.disease ,cardiovascular diseases ,Death ,Treatment Outcome ,Quartile ,cardiovascular system ,Cardiology ,Pyrazoles ,Female ,Apixaban ,Cardiology and Cardiovascular Medicine ,business ,biological markers ,Fibrinolytic agent ,medicine.drug - Abstract
Background— High-sensitivity troponin-I (hs-TnI) measurement improves risk assessment for cardiovascular events in many clinical settings, but the added value in atrial fibrillation patients has not been described. Methods and Results— At randomization, hs-TnI was analyzed in 14 821 atrial fibrillation patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban with warfarin. The associations between hs-TnI concentrations and clinical outcomes were evaluated by using adjusted Cox analysis. The hs-TnI assay detected troponin (≥1.3 ng/L) in 98.5% patients, 50% had levels >5.4, 25% had levels >10.1, and 9.2% had levels ≥23 ng/L (the 99th percentile in healthy individuals). During a median of 1.9 years follow-up, annual rates of stroke or systemic embolism ranged from 0.76% in the lowest hs-TnI quartile to 2.26% in the highest quartile (>10.1 ng/L). In multivariable analysis, hs-TnI was significantly associated with stroke or systemic embolism, adjusted hazard ratio 1.98 (1.42–2.78), P =0.0007. hs-TnI was also significantly associated with cardiac death; annual rates ranged from 0.40% to 4.24%, hazard ratio 4.52 (3.05–6.70), P P =0.0250. Adding hs-TnI levels to the CHA 2 DS 2 VASc score improved c-statistics from 0.629 to 0.653 for stroke or systemic embolism, and from 0.591 to 0.731 for cardiac death. There were no significant interactions with study treatment. Conclusions— Troponin-I is detected in 98.5% and elevated in 9.2% of atrial fibrillation patients. The hs-TnI level is independently associated with a raised risk of stroke, cardiac death, and major bleeding and improves risk stratification beyond the CHA 2 DS 2 VASc score. The benefits of apixaban in comparison with warfarin are consistent regardless of hs-TnI levels. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00412984.
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- 2014
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31. High-performance liquid chromatography analysis of ganglioside carbohydrates at the picomole level after ceramide glycanase digestion and fluorescent labeling with 2-aminobenzamide
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T D Butters, Frances M. Platt, Gabriele Reinkensmeier, David Harvey, Ulrika Andersson, V Hunnam, David R. Wing, Brett Garner, and Raymond A. Dwek
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Ceramide ,Glycan ,Glycoside Hydrolases ,Resolution (mass spectrometry) ,Molecular Sequence Data ,Biophysics ,Aminopyridines ,Oligosaccharides ,CHO Cells ,Mass spectrometry ,Sensitivity and Specificity ,Biochemistry ,Glycosphingolipids ,Mice ,chemistry.chemical_compound ,Glycolipid ,Exoglycosidase ,Cricetinae ,Animals ,Humans ,ortho-Aminobenzoates ,Molecular Biology ,Chromatography, High Pressure Liquid ,Fluorescent Dyes ,Ganglioside ,Chromatography ,biology ,Chemistry ,Sarcoma ,Cell Biology ,Matrix-assisted laser desorption/ionization ,Carbohydrate Sequence ,Liver ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Uterine Neoplasms ,biology.protein ,Female ,Chromatography, Thin Layer ,Glycolipids - Abstract
The functional importance of glycolipids has emphasized the need for more sensitive methods of detection, characterization, and quantification than has often been possible using traditional thin-layer chromatographic techniques. We describe the use of ceramide glycanase and HPLC to identify and quantify gangliosides in which the carbohydrate is in Glcbeta1--> linkage with ceramide. Detection of released carbohydrate was by fluorescent labeling with 2-aminobenzamide at the reducing terminal prior to HPLC analysis. Under the conditions described, ceramide glycanase hydrolyzed all of the common gangliosides studied, offering a broad spectrum of specificity. Release and detection of carbohydrate were linear over a wide range (over two orders of magnitude) of micromolar glycolipid substrate concentrations. Use of an N-linked glycan as an internal standard allowed accurate quantification and a recovery of 93% was achieved. The method additionally maintained the sensitivity (chromatographic peaks containing 1 pmol were readily detected from tissue samples) and comparable resolution to related assays. This was shown by the separation, not only of isomeric carbohydrates from the "a" and "b" series, but also of ganglioside carbohydrate differing only by the presence of either N-acetyl- or N-glycolylneuraminic acid. Application of the method to neutral glycosphingolipids and to tissue samples, including 10-microl quantities of plasma, is illustrated. Glycan structures were confirmed by exoglycosidase digestion and/or matrix-assisted laser desorption/ionization mass spectrometry.
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- 2016
32. N-butyldeoxygalactonojirimycin: a more selective inhibitor of glycosphingolipid biosynthesis than N-butyldeoxynojirimycin, in vitro and in vivo
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Frances M. Platt, Ulrika Andersson, Raymond A. Dwek, and Terry D. Butters
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1-Deoxynojirimycin ,medicine.medical_treatment ,Pharmacology ,Biology ,Disaccharidases ,Biochemistry ,Glycosphingolipids ,Sucrase ,chemistry.chemical_compound ,Mice ,In vivo ,medicine ,Lysosomal storage disease ,Animals ,Humans ,Tissue Distribution ,Carbon Radioisotopes ,Lymphocytes ,Enzyme Inhibitors ,Lactase ,Glycosphingolipid ,medicine.disease ,Sphingolipid ,Mice, Inbred C57BL ,chemistry ,Liver ,Enzyme inhibitor ,biology.protein ,Female ,Maltase ,Cell Division ,Glycogen - Abstract
N-Butyldeoxynojirimycin (NB-DNJ) inhibits the ceramide glucosyltransferase which catalyses the first step in glycosphingolipid (GSL) biosynthesis. It has the potential to be used for the treatment of the GSL lysosomal storage diseases and is currently in clinical trials for the treatment of type 1 Gaucher's disease. However, NB-DNJ is also a potent inhibitor of other enzymes, including alpha-glucosidase I and II, which could potentially cause side effects in patients receiving life-long therapy. Wetherefore evaluated a potentially more selective GSL biosynthesis inhibitor, N-butyldeoxygalactonojirimycin (NB-DGJ), in vitro and in vivo. The distribution and degree of GSL depletion in the liver of mice treated with NB-DGJ or NB-DNJ were equivalent. Mice treated with NB-DGJ had normal body weights and lymphoid organ sizes, whereas NB-DNJ-treated mice showed weight loss and partial lymphoid organ shrinkage. NB-DNJ inhibited glycogen catabolism in the liver, whereas NB-DGJ did not. NB-DNJ was also a potent inhibitor of sucrase and maltase in vitro but not of lactase, while NB-DGJ inhibited lactase but not sucrase or maltase. NB-DGJ is therefore more selective than NB-DNJ, and deserves to be evaluated for human therapy.
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- 2016
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33. Inhibition of glycogen breakdown by imino sugars in vitro and in vivo
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Ulrika Andersson, Gabriele Reinkensmeier, Frances M. Platt, Raymond A. Dwek, and Terry D. Butters
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medicine.medical_specialty ,1-Deoxynojirimycin ,Biochemistry ,Glycogen debranching enzyme ,Glycogen phosphorylase ,chemistry.chemical_compound ,Mice ,In vivo ,Lysosome ,Internal medicine ,Glycogen branching enzyme ,medicine ,Animals ,Glycoside Hydrolase Inhibitors ,Glycogen synthase ,Pharmacology ,biology ,Glycogen ,Mice, Inbred C57BL ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Glycogenesis ,biology.protein ,Female - Abstract
The imino sugar N-butyldeoxynojirimycin (NB-DNJ) is a glucose analogue which inhibits the glycoprotein N-glycan processing enzymes alpha-glucosidases I and II and the ceramide glucosyltransferase that catalyses the first step of glycosphingolipid biosynthesis. This and other N-alkylated DNJ compounds have the potential to inhibit other glucosidase, including acid alpha-glucosidase and alpha-1,6-glucosidase, enzymes involved in glycogen breakdown. We have investigated the effect of NB-DNJ and N-nonyldeoxynojirimycin (NN-DNJ) on glycogen catabolism. Both NB-DNJ and NN-DNJ were potent inhibitors of acid alpha-glucosidase and alpha-1,6-glucosidase in vitro. NB-DNJ and NN-DNJ inhibited liver glycogen breakdown in vivo in fasting mice. Inhibition of glycogen catabolism occurred in the cytosol and lysosomes. The liver glycogen breakdown inhibition was only induced at high doses of NB-DNJ, whereas NN-DNJ caused glycogen accumulation at lower doses. The in vivo effect of NB-DNJ on liver glycogen was transient as there was no inhibition of breakdown after 90 days of treatment. The inhibition by NN-DNJ, was more pronounced, reached a plateau at 50 days and then remained unchanged. Increased glycogen was also observed in skeletal muscle in NB-DNJ- and NN-DNJ-treated mice. Since the effects on glycogen metabolism by NB-DNJ are transient and only occur at high concentrations, it is not predicted that glycogen breakdown will be impaired in patients receiving NB-DNJ therapy. NN-DNJ is the prototype of long alkyl chain derivatives of DNJ that are entering pre-clinical development as potential hepatitis B/hepatitis C (HBV/HCV) therapeutics. Depending on the dose of these compounds used, there is the potential for glycogen catabolism to be partially impaired in experimental animals and man.
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- 2016
34. Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation in Relation to Renal Function Over Time: Insights From the ARISTOTLE Randomized Clinical Trial
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Renato D. Lopes, Lars Wallentin, Ziad Hijazi, Agneta Siegbahn, Stefan H. Hohnloser, Jose Lopez-Sendon, Alexander Parkhomenko, Christopher B. Granger, John H. Alexander, Matyas Keltai, Michael G. Hanna, and Ulrika Andersson
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Male ,medicine.medical_specialty ,Pyridones ,Renal function ,030204 cardiovascular system & hematology ,Kidney ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,Atrial Fibrillation ,medicine ,Humans ,030212 general & internal medicine ,Prospective Studies ,Stroke ,Aged ,Creatinine ,business.industry ,Warfarin ,Anticoagulants ,Atrial fibrillation ,medicine.disease ,Treatment Outcome ,chemistry ,Embolism ,Cardiology ,Pyrazoles ,Apixaban ,Female ,Kidney Diseases ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug ,Kidney disease - Abstract
Importance Renal impairment confers an increased risk of stroke, bleeding, and death in patients with atrial fibrillation. Little is known about the efficacy and safety of apixaban in relation to renal function changes over time. Objectives To evaluate changes of renal function over time and their interactions with outcomes during a median of 1.8 years of follow-up in patients with atrial fibrillation randomized to apixaban vs warfarin treatment. Design, Setting, and Participants The prospective, randomized, double-blind Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) clinical trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Serial creatinine measurements were available in 16 869 patients. Worsening of renal function was defined as an annual decrease in estimated glomerular filtration more than 20%. The relations between treatment, outcomes, and renal function were investigated using Cox regression models, with renal function as a time-dependent covariate. Main Outcomes and Measures Stroke or systemic embolism (primary outcome), major bleeding (safety outcome), and mortality were examined in relation to renal function over time estimated with both the Cockcroft-Gault and Chronic Kidney Disease Epidemiology Collaboration equations. Results Among 16 869 patients, the median age was 70 years and 65.2% of patients were men. Worsening in estimated glomerular filtration more than 20% was observed in 2294 patients (13.6%) and was associated with older age and more cardiovascular comorbidities. The risks of stroke or systemic embolism, major bleeding, and mortality were higher in patients with worsening renal function (HR, 1.53; 95% CI, 1.17-2.01 for stroke or systemic embolism; HR, 1.56; 95% CI, 1.27-1.93 for major bleeding; and HR, 2.31; 95% CI, 1.98-2.68 for mortality). The beneficial effects of apixaban vs warfarin on rates of stroke or systemic embolism and major bleeding were consistent in patients with normal or poor renal function over time and also in those with worsening renal function. Conclusions and Relevance In patients with atrial fibrillation, declining renal function was more common in elderly patients and those with cardiovascular comorbidities. Worsening renal function was associated with a higher risk of subsequent cardiovascular events and bleeding. The superior efficacy and safety of apixaban as compared with warfarin were similar in patients with normal, poor, and worsening renal function. Trial Registration clinicaltrials.gov Identifier:NCT00412984.
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- 2016
35. Asymmetric and Symmetric Dimethylarginine Predict Outcomes in Patients With Atrial Fibrillation: An ARISTOTLE Substudy
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John D, Horowitz, Raffaele, De Caterina, Tamila, Heresztyn, John H, Alexander, Ulrika, Andersson, Renato D, Lopes, Philippe Gabriel, Steg, Elaine M, Hylek, Puneet, Mohan, Michael, Hanna, Petr, Jansky, Christopher B, Granger, and Lars, Wallentin
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Aged, 80 and over ,Male ,Pyridones ,Anticoagulants ,asymmetric dimethylarginine (ADMA) ,Middle Aged ,thromboembolism ,Arginine ,Treatment Outcome ,Editorial ,Double-Blind Method ,Predictive Value of Tests ,Atrial Fibrillation ,symmetric dimethylarginine (SDMA) ,Humans ,Pyrazoles ,Female ,Warfarin ,Biomarkers ,Aged ,Factor Xa Inhibitors - Abstract
There is little mechanistic information on factors predisposing atrial fibrillation (AF) patients to thromboembolism or bleeding, but generation of nitric oxide (NO) might theoretically contribute to both.The authors tested the hypothesis that plasma levels of the methylated arginine derivatives asymmetric and symmetric dimethylarginine (ADMA/SDMA), which inhibit NO generation, might be associated with outcomes in AF.Plasma samples were obtained from 5,004 patients with AF at randomization to warfarin or apixaban in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. ADMA and SDMA concentrations were measured by high-performance liquid chromatography. Relationships to clinical characteristics were evaluated by multivariable analyses. Associations with major outcomes, during a median of 1.9 years follow-up, were evaluated by adjusted Cox proportional hazards models.Both ADMA and SDMA plasma concentrations at study entry increased significantly with patients' age, female sex, renal impairment, permanent AF, or congestive heart failure. ADMA and SDMA increased (p 0.001) with both increased CHAIn anticoagulated patients with AF, elevated ADMA levels are weakly associated with thromboembolic events, elevated SDMA levels with bleeding events and both are strongly associated with increased mortality. These findings suggest that disturbances of NO function modulate both thrombotic and hemorrhagic risk in anticoagulated patients with AF. (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]; NCT00412984).
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- 2016
36. Whole-body fat oxidation increases more by prior exercise than overnight fasting in elite endurance athletes
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Klavs Madsen, Ulrika Andersson Hall, Fredrik Edin, and Anders Pedersen
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Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Magnetic Resonance Spectroscopy ,fasting ,Hydrocortisone ,Physiology ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Fatty Acids, Nonesterified ,03 medical and health sciences ,0302 clinical medicine ,Oxygen Consumption ,Fat oxidation ,Physiology (medical) ,Medicine ,Humans ,Insulin ,Metabolomics ,Exercise ,Breakfast ,Nutrition and Dietetics ,Cross-Over Studies ,biology ,business.industry ,Athletes ,maximal fat oxidation capacity ,endurance athletes ,Calorimetry, Indirect ,030229 sport sciences ,General Medicine ,Fasting ,biology.organism_classification ,Lipid Metabolism ,metabolomics ,Bicycling ,Adipose Tissue ,Multivariate Analysis ,Physical therapy ,Linear Models ,Physical Endurance ,Female ,prior exercise ,Whole body ,business - Abstract
The purpose of this study was to compare whole-body fat oxidation kinetics after prior exercise with overnight fasting in elite endurance athletes. Thirteen highly trained athletes (9 men and 4 women; maximal oxygen uptake: 66 ± 1 mL·min−1·kg−1) performed 3 identical submaximal incremental tests on a cycle ergometer using a cross-over design. A control test (CON) was performed 3 h after a standardized breakfast, a fasting test (FAST) 12 h after a standardized evening meal, and a postexercise test (EXER) after standardized breakfast, endurance exercise, and 2 h fasting recovery. The test consisted of 3 min each at 30%, 40%, 50%, 60%, 70%, and 80% of maximal oxygen uptake and fat oxidation rates were measured through indirect calorimetry. During CON, maximal fat oxidation rate was 0.51 ± 0.04 g·min−1 compared with 0.69 ± 0.04 g·min−1 in FAST (P < 0.01), and 0.89 ± 0.05 g·min−1 in EXER (P < 0.01). Across all intensities, EXER was significantly higher than FAST and FAST was higher than CON (P < 0.01). Blood insulin levels were lower and free fatty acid and cortisol levels were higher at the start of EXER compared with CON and FAST (P < 0.05). Plasma nuclear magnetic resonance-metabolomics showed similar changes in both EXER and FAST, including increased levels of fatty acids and succinate. In conclusion, prior exercise significantly increases whole-body fat oxidation during submaximal exercise compared with overnight fasting. Already high rates of maximal fat oxidation in elite endurance athletes were increased by approximately 75% after prior exercise and fasting recovery.
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- 2016
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37. History of bleeding and outcomes with apixaban versus warfarin in patients with atrial fibrillation in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial
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Sana M. Al-Khatib, Jose Lopez-Sendon, John H. Alexander, Ulrika Andersson, Renato D. Lopes, Lars Wallentin, Elaine M. Hylek, M. Cecilia Bahit, Christopher B. Granger, Shinya Goto, Stefan H. Hohnloser, Raffaele De Caterina, Fernando Lanas, Michael G. Hanna, John D. Horowitz, Giulia Renda, Claes Held, Bergman, Ebba, Cook, Elizabeth, and ARISTOTLE Investigators
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Male ,medicine.medical_specialty ,Pyridones ,Population ,Hemorrhage ,030204 cardiovascular system & hematology ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Thromboembolism ,Atrial Fibrillation ,Medicine ,Humans ,Cardiac and Cardiovascular Systems ,ddc:610 ,030212 general & internal medicine ,education ,Stroke ,Aged ,education.field_of_study ,Kardiologi ,business.industry ,Proportional hazards model ,Hazard ratio ,Warfarin ,Anticoagulants ,Atrial fibrillation ,Middle Aged ,medicine.disease ,Outcome and Process Assessment, Health Care ,Cardiology ,Pyrazoles ,Apixaban ,Female ,Drug Monitoring ,business ,Cardiology and Cardiovascular Medicine ,medicine.drug - Abstract
Aims History of bleeding strongly influences decisions for anticoagulation in atrial fibrillation (AF). We analyzed outcomes in relation to history of bleeding and randomization in ARISTOTLE trial patients. Methods and results The on-treatment safety population included 18,140 patients receiving at least 1 dose of study drug (apixaban) or warfarin. Centrally adjudicated outcomes in relation to bleeding history were analyzed using a Cox proportional hazards model adjusted for randomized treatment and established risk factors. Efficacy end points were analyzed on the randomized (intention to treat) population. A bleeding history was reported at baseline in 3,033 patients (16.7%), who more often were male, with a history of prior stroke/transient ischemic attack/systemic embolism and diabetes; higher CHADS 2 scores, age, and body weight; and lower creatinine clearance and mean systolic blood pressure. Major (but not intracranial) bleeding occurred more frequently in patients with versus without a history of bleeding (adjusted hazard ratio 1.35, 95% CI 1.14-1.61). There were no significant interactions between bleeding history and treatment for stroke/systemic embolism, hemorrhagic stroke, death, or major bleeding, with fewer outcomes with apixaban versus warfarin for all of these outcomes independent of the presence/absence of a bleeding history. Conclusion In patients with AF in a randomized clinical trial of oral anticoagulants, a history of bleeding is associated with several risk factors for stroke and portends a higher risk of major—but not intracranial—bleeding, during anticoagulation. However, the beneficial effects of apixaban over warfarin for stroke, hemorrhagic stroke, death, or major bleeding remains consistent regardless of history of bleeding.
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- 2016
38. Known glioma risk loci are associated with glioma with a family history of brain tumours-A case-control gene association study
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Göran Hallmans, Patricia Hartge, Melissa L. Bondy, Zhaoming Wang, Cari M. Kitahara, Anders Ahlbom, Mary Ann Butler, Anna M. Dahlin, Avima M. Ruder, Mark P. Purdue, Martha S. Linet, Peter D. Inskip, Elizabeth M. Gillanders, Preetha Rajaraman, Beatrice Melin, Ann W. Hsing, Christoffer Johansen, Tania Carreón, Maria Feychting, Leah E. Mechanic, Sophia S. Wang, Meredith Yeager, Ulrika Andersson, Stephen J. Chanock, and Roger Henriksson
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Genotype ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Article ,Internal medicine ,Glioma ,Odds Ratio ,medicine ,Humans ,SNP ,Genetic Predisposition to Disease ,Family history ,neoplasms ,Telomerase ,Cyclin-Dependent Kinase Inhibitor p16 ,Genetic Association Studies ,Aged ,Cyclin-Dependent Kinase Inhibitor p15 ,Genetic association ,Aged, 80 and over ,Sweden ,Genetics ,Brain Neoplasms ,DNA Helicases ,Case-control study ,food and beverages ,Odds ratio ,Middle Aged ,medicine.disease ,United States ,Case-Control Studies ,Female ,Glioblastoma - Abstract
Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first- or second-degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty-one glioma cases and 2,868 cancer-free controls were identified from four case-control studies and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case-control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.25-0.61; Bonferroni adjusted ptrend , 1.7 × 10(-4) ). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours.
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- 2012
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39. Genome-wide association study of glioma and meta-analysis
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Joseph L. Wiemels, Ching C. Lau, Sanjay Shete, Alicja Wolk, Tania Carreón, Patricia Hartge, Melissa L. Bondy, Ulrike Peters, Graham G. Giles, Mark P. Purdue, Victoria L. Stevens, Brooke L. Fridley, Wei Zheng, Matthew L. Kosel, Joseph F. Fraumeni, Avima M. Ruder, Anders Ahlbom, Meredith Yeager, Martha S. Linet, Meir J. Stampfer, Sarah Fleming, Richard S. Houlston, Gianluca Severi, Melissa Z. Braganza, Anthony J. Swerdlow, Zhaoming Wang, Yong-Bing Xiang, Stephen J. Chanock, Victor Enciso-Mora, Nilanjan Chatterjee, Maria Feychting, Howard D. Sesso, Kala Visvanathan, Loic Le Marchand, Laura E. Beane Freeman, Anne Zeleniuch-Jacquotte, Margaret Wrensch, Preetha Rajaraman, Judith Hoffman-Bolton, Julie E. Buring, Roger Henriksson, Xiao-Ou Shu, Terri Rice, Nathaniel Rothman, Dominique S. Michaud, J. Michael Gaziano, Ulrika Andersson, Robert N. Hoover, Mary Ann Butler, Paul A. Decker, Sophia S. Wang, Robert B. Jenkins, John K. Wiencke, Cari M. Kitahara, Matthias Simon, Yuanyuan Xiao, Daniel H. Lachance, Peter D. Inskip, Marc Sanson, Beatrice Melin, Susan M. Gapstur, Emily White, Stefan Lonn, Mark Lathrop, Chenwei Liu, Christoffer Johansen, Roberta McKean-Cowdin, Göran Hallmans, Yu-Tang Gao, and Demetrius Albanes
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Male ,Population ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Bioinformatics ,Polymorphism, Single Nucleotide ,Article ,Cohort Studies ,Paediatrics and Reproductive Medicine ,Rare Diseases ,Complementary and Alternative Medicine ,Clinical Research ,Glioma ,Genetics ,medicine ,Humans ,2.1 Biological and endogenous factors ,Polymorphism ,Aetiology ,education ,Telomerase ,Genetics (clinical) ,Aged ,Cyclin-Dependent Kinase Inhibitor p15 ,Cancer ,Genetic association ,Genetics & Heredity ,education.field_of_study ,Brain Neoplasms ,Prevention ,Human Genome ,DNA Helicases ,Neurosciences ,Case-control study ,Single Nucleotide ,Middle Aged ,medicine.disease ,Brain Disorders ,Brain Cancer ,Case-Control Studies ,Cohort ,Female ,Glioblastoma ,Genome-Wide Association Study ,Cohort study - Abstract
Gliomas account for approximately 80% of all primary malignant brain tumors and, despite improvements in clinical care over the last 20years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.
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- 2012
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40. Genome-Wide High-Density SNP Linkage Search for Glioma Susceptibility Loci: Results from the Gliogene Consortium
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Melissa L. Bondy, Christoffer Johansen, Chris Man, Beatrice Melin, Jonine L. Bernstein, Jill S. Barnholtz-Sloan, Michael Kosteljanetz, Lisa M. DeAngelis, Eastwood Leung, Christina Corpuz, Lindsay B. Robertson, Lucie McCoy, Yanhong Liu, Mark R. Gilbert, Amanda L. Rynearson, Georgina Armstrong, Roger Henriksson, Fay J. Hosking, Jeffrey S. Weinberg, Hanne Bødtcher, Lili Aslanov, Kenneth Aldape, Elli Papaemmanuil, Revital Bar Sade Bruchim, Robert Yu, Helle Broholm, Galit Hirsh Yechezkel, Dora Il'yasova, Bridget J. McCarthy, Erika Florendo, Michael E. Scheurer, Joellen M. Schildkraut, Gene Barnett, Margaret Wrensch, Karen Devine, Rose Lai, John K. Wiencke, Elizabeth B. Claus, Ulrika Andersson, Ching C. Lau, Sivashankarappa Gurusiddappa, Sanjay Shete, Ping Yang, Andrew E. Sloan, Sara H. Olson, Rita Cheng, Nicholas A. Vick, Rudy Guerra, Siegal Sadetzki, Faith G. Davis, Joseph L. Wiemels, Delcia Rivas, Thomas Brännström, Yingli Wolinsky, Caleb F. Davis, Christopher I. Amos, Erica Schubert, Robert B. Jenkins, and Richard S. Houlston
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Adult ,Male ,Cancer Research ,Linkage disequilibrium ,Adolescent ,Genotype ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Article ,Linkage Disequilibrium ,Genetic Heterogeneity ,Young Adult ,Glioma ,medicine ,Humans ,SNP ,Genetic Predisposition to Disease ,Child ,Aged ,Genetic association ,Family Health ,Genetics ,Brain Neoplasms ,Genome, Human ,Genetic heterogeneity ,Chromosome Mapping ,Middle Aged ,medicine.disease ,United States ,Pedigree ,Oncology ,Genetic epidemiology ,Female ,Lod Score ,Genome-Wide Association Study - Abstract
Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma. Cancer Res; 71(24); 7568–75. ©2011 AACR.
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- 2011
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41. Effects of rose hip intake on risk markers of type 2 diabetes and cardiovascular disease: a randomized, double-blind, cross-over investigation in obese persons
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Ulrika Andersson, A. Högberg, Mona Landin-Olsson, Karin Berger, and Cecilia Holm
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Adult ,Male ,medicine.medical_specialty ,glucose tolerance ,Medicine (miscellaneous) ,Blood lipids ,Inflammation ,Blood Pressure ,Type 2 diabetes ,Rosa ,Risk Assessment ,Impaired glucose tolerance ,chemistry.chemical_compound ,body weight ,Double-Blind Method ,Risk Factors ,Internal medicine ,Glucose Intolerance ,medicine ,Humans ,Obesity ,Aged ,Nutrition and Dietetics ,Cross-Over Studies ,business.industry ,Cholesterol ,Cholesterol, HDL ,cholesterol ,Cholesterol, LDL ,Middle Aged ,medicine.disease ,Blood pressure ,Endocrinology ,chemistry ,Diabetes Mellitus, Type 2 ,inflammation ,Cardiovascular Diseases ,Fruit ,Original Article ,Female ,Plant Preparations ,medicine.symptom ,business ,Biomarkers ,Lipoprotein ,Phytotherapy - Abstract
BACKGROUND/OBJECTIVES: In studies performed in mice, rose hip powder has been shown to both prevent and reverse high-fat diet-induced obesity and glucose intolerance as well as reduce plasma levels of cholesterol. The aim of this study was to investigate whether daily intake of rose hip powder over 6 weeks exerts beneficial metabolic effects in obese individuals. SUBJECTS/METHODS: A total of 31 obese individuals with normal or impaired glucose tolerance were enrolled in a randomized, double-blind, cross-over study in which metabolic effects of daily intake of a rose hip powder drink over 6 weeks was compared with a control drink. Body weight, glucose tolerance, blood pressure, blood lipids and markers of inflammation were assessed in the subjects. RESULTS: In comparison with the control drink, 6 weeks of daily consumption of the rose hip drink resulted in a significant reduction of systolic blood pressure (−3.4% P=0.021), total plasma cholesterol (−4.9% P=0.0018), low-density lipoprotein (LDL) cholesterol (−6.0% P=0.012) and LDL/HDL ratio (−6.5% P=0.041). The Reynolds risk assessment score for cardiovascular disease was decreased in the rose hip group compared with the control group (−17% P=0.007). Body weight, diastolic blood pressure, glucose tolerance, and plasma levels of high-density lipoprotein (HDL) cholesterol, triglycerides, incretins and markers of inflammation did not differ between the two groups. CONCLUSIONS: Daily consumption of 40 g of rose hip powder for 6 weeks can significantly reduce cardiovascular risk in obese people through lowering of systolic blood pressure and plasma cholesterol levels.
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- 2011
42. Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas
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Carl Wibom, Ulrika Andersson, Sarah Fleming, Christoffer Johansson, Anja Smits, Helle Broholm, Sara Sjöström, Shala Ghaderi Berntsson, Patricia A. McKinney, Roger Henriksson, Thomas Brännström, Lara Bethke, Beatrice Melin, and Richard S. Houlston
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,DNA Repair ,Genotype ,DNA repair ,NEIL1 ,Antineoplastic Agents ,Single-nucleotide polymorphism ,Kaplan-Meier Estimate ,Biology ,Polymorphism, Single Nucleotide ,Text mining ,Patient age ,Polymorphism (computer science) ,Internal medicine ,medicine ,Humans ,Poly-ADP-Ribose Binding Proteins ,Gene ,Proportional Hazards Models ,Brain Neoplasms ,business.industry ,DNA Helicases ,Glioma ,Middle Aged ,DNA Repair Enzymes ,Neurology ,Female ,Neurology (clinical) ,Neoplasm Grading ,business ,ERCC6 - Abstract
The purpose of this study was to explore the variation in DNA repair genes in adults with WHO grade II and III gliomas and their relationship to patient survival. We analysed a total of 1,458 tagging single-nucleotide polymorphisms (SNPs) that were selected to cover DNA repair genes, in 81 grade II and grade III gliomas samples, collected in Sweden and Denmark. The statistically significant genetic variants from the first dataset (P < 0.05) were taken forward for confirmation in a second dataset of 72 grade II and III gliomas from northern UK. In this dataset, eight gene variants mapping to five different DNA repair genes (ATM, NEIL1, NEIL2, ERCC6 and RPA4) which were associated with survival. Finally, these eight genetic variants were adjusted for treatment, malignancy grade, patient age and gender, leaving one variant, rs4253079, mapped to ERCC6, with a significant association to survival (OR 0.184, 95% CI 0.054-0.63, P = 0.007). We suggest a possible novel association between rs4253079 and survival in this group of patients with low-grade and anaplastic gliomas that needs confirmation in larger datasets.
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- 2011
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43. Rose hip exerts antidiabetic effects via a mechanism involving downregulation of the hepatic lipogenic program
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Kristoffer Ström, Olga Göransson, Ulrika Andersson, Cecilia Holm, Emma Henriksson, and Jan Alenfall
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medicine.medical_specialty ,Physiology ,Adipose Tissue, White ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Hypercholesterolemia ,Down-Regulation ,Adipose tissue ,Biology ,Rosa ,Mice ,Random Allocation ,chemistry.chemical_compound ,Physiology (medical) ,Internal medicine ,Glucose Intolerance ,medicine ,Animals ,Hypoglycemic Agents ,Obesity ,RNA, Messenger ,Beta oxidation ,Adiposity ,Cholesterol ,Lipogenesis ,Insulin ,Lipid metabolism ,Dietary Fats ,Fatty Liver ,Mice, Inbred C57BL ,Endocrinology ,Diabetes Mellitus, Type 2 ,Liver ,chemistry ,Gluconeogenesis ,Dietary Supplements ,Female ,Anti-Obesity Agents ,Phytotherapy ,Lipoprotein - Abstract
The aim of this study was to investigate the metabolic effects of a dietary supplement of powdered rose hip to C57BL/6J mice fed a high-fat diet (HFD). Two different study protocols were used; rose hip was fed together with HFD to lean mice for 20 wk (prevention study) and to obese mice for 10 wk (intervention study). Parameters related to obesity and glucose tolerance were monitored, and livers were examined for lipids and expression of genes and proteins related to lipid metabolism and gluconeogenesis. A supplement of rose hip was capable of both preventing and reversing the increase in body weight and body fat mass imposed by a HFD in the C57BL/6J mouse. Oral and intravenous glucose tolerance tests together with lower basal levels of insulin and glucose showed improved glucose tolerance in mice fed a supplement of rose hip compared with control mice. Hepatic lipid accumulation was reduced in mice fed rose hip compared with control, and the expression of lipogenic proteins was downregulated, whereas AMP-activated protein kinase and other proteins involved in fatty acid oxidation were unaltered. Rose hip intake lowered total plasma cholesterol as well as the low-density lipoprotein-to-high-density lipoprotein ratio via a mechanism not involving altered gene expression of sterol regulatory element-binding protein 2 or 3-hydroxymethylglutaryl-CoA reductase. Taken together, these data show that a dietary supplement of rose hip prevents the development of a diabetic state in the C57BL/6J mouse and that downregulation of the hepatic lipogenic program appears to be at least one mechanism underlying the antidiabetic effect of rose hip.
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- 2011
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44. Genetic variations in VEGF and VEGFR2 and glioblastoma outcome
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Sara Sjöström, Yufei Liu, Christoffer Johansen, Roger Henriksson, Helle Broholm, Thomas Brännström, Beatrice Melin, Carl Wibom, Helle Collatz-Laier, Ulrika Andersson, and Melissa L. Bondy
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Adult ,Male ,Vascular Endothelial Growth Factor A ,Oncology ,Cancer Research ,medicine.medical_specialty ,Survival ,Genotype ,Glioblastoma outcome ,Clinical Neurology ,Single-nucleotide polymorphism ,Biology ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,Young Adult ,chemistry.chemical_compound ,Internal medicine ,Genetic variation ,Biomarkers, Tumor ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic variability ,Receptor ,Aged ,Brain Neoplasms ,Vascular endothelial growth factor (VEGF) ,Kinase insert domain receptor ,Middle Aged ,Prognosis ,Vascular Endothelial Growth Factor Receptor-2 ,Association study ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,Clinical Study – Patient Study ,Neurology ,chemistry ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Immunology ,cardiovascular system ,Female ,Neurology (clinical) ,Glioblastoma ,Vascular endothelial growth factor receptor (VEGFR) - Abstract
Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) are central components in the development and progression of glioblastoma. To investigate if genetic variation in VEGF and VEGFR2 is associated with glioblastoma prognosis, we examined blood samples from 154 glioblastoma cases collected in Sweden and Denmark between 2000 and 2004. Seventeen tagging single nucleotide polymorphisms (SNPs) in VEGF and 27 in VEGFR2 were genotyped and analysed, covering 90% of the genetic variability within the genes. In VEGF, we found no SNPs associated with survival. In VEGFR2, we found two SNPs significantly associated to survival, namely rs2071559 and rs12502008. However, these results are likely to be false positives due to multiple testing and could not be confirmed in a separate dataset. Overall, this study provides little evidence that VEGF and VEGFR2 polymorphisms are important for glioblastoma survival.
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- 2010
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45. Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 Genes Involved in the Double-Strand Break Repair Pathway Predict Glioblastoma Survival
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Sanjay Shete, Richard S. Houlston, Terri S. Armstrong, Spyros Tsavachidis, Kenneth Aldape, Margaret Wrensch, Georgina Armstrong, Mark R. Gilbert, Beatrice Melin, George A. Alexiou, Michael E. Scheurer, Melissa L. Bondy, Yanhong Liu, Ulrika Andersson, John K. Wiencke, Fu Wen Liang, Yuanyuan Xiao, Fay J. Hosking, Carol J. Etzel, and Lindsay B. Robertson
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Male ,Cancer Research ,Time Factors ,DNA Ligases ,DNA Repair ,DNA repair ,Kaplan-Meier Estimate ,LIG4 ,Bioinformatics ,Polymorphism, Single Nucleotide ,Risk Assessment ,DNA Ligase ATP ,HMGA2 ,Risk Factors ,Glioma ,Original Reports ,Odds Ratio ,medicine ,Humans ,DNA Breaks, Double-Stranded ,Genetic Predisposition to Disease ,Survivors ,Gene ,Proportional Hazards Models ,Regulation of gene expression ,Chi-Square Distribution ,biology ,Brain Neoplasms ,Proportional hazards model ,Decision Trees ,HMGA2 Protein ,Age Factors ,DNA Helicases ,Middle Aged ,medicine.disease ,Double Strand Break Repair ,Gene Expression Regulation, Neoplastic ,Treatment Outcome ,Oncology ,biology.protein ,Cancer research ,Female ,Carrier Proteins ,Glioblastoma - Abstract
Purpose Glioblastoma (GBM) is the most common and aggressive type of glioma and has the poorest survival. However, a small percentage of patients with GBM survive well beyond the established median. Therefore, identifying the genetic variants that influence this small number of unusually long-term survivors may provide important insight into tumor biology and treatment. Patients and Methods Among 590 patients with primary GBM, we evaluated associations of survival with the 100 top-ranking glioma susceptibility single nucleotide polymorphisms from our previous genome-wide association study using Cox regression models. We also compared differences in genetic variation between short-term survivors (STS; ≤ 12 months) and long-term survivors (LTS; ≥ 36 months), and explored classification and regression tree analysis for survival data. We tested results using two independent series totaling 543 GBMs. Results We identified LIG4 rs7325927 and BTBD2 rs11670188 as predictors of STS in GBM and CCDC26 rs10464870 and rs891835, HMGA2 rs1563834, and RTEL1 rs2297440 as predictors of LTS. Further survival tree analysis revealed that patients ≥ 50 years old with LIG4 rs7325927 (V) had the worst survival (median survival time, 1.2 years) and exhibited the highest risk of death (hazard ratio, 17.53; 95% CI, 4.27 to 71.97) compared with younger patients with combined RTEL1 rs2297440 (V) and HMGA2 rs1563834 (V) genotypes (median survival time, 7.8 years). Conclusion Polymorphisms in the LIG4, BTBD2, HMGA2, and RTEL1 genes, which are involved in the double-strand break repair pathway, are associated with GBM survival.
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- 2010
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46. A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk
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Spyros Tsavachidis, Roger Henriksson, Ulrika Andersson, Judith A. Schwartzbaum, Melissa L. Bondy, Maria Feychting, Anne Kiuru, Christoffer Johansen, Fredrik Wiklund, Sara Sjöström, Anders Ahlbom, Anthony J. Swerdlow, Yanhong Liu, Beatrice Melin, Minouk J. Schoemaker, Helle Collatz-Laier, Stefan Lönn, and Anssi Auvinen
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Genotype ,endocrine system diseases ,Receptor, ErbB-2 ,Denmark ,Brain tumor ,Polymorphism, Single Nucleotide ,Risk Assessment ,Linkage Disequilibrium ,Receptor tyrosine kinase ,Risk Factors ,Internal medicine ,Glioma ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Epidermal growth factor receptor ,neoplasms ,Gene ,Finland ,Aged ,Sweden ,integumentary system ,biology ,Brain Neoplasms ,business.industry ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,nervous system diseases ,ErbB Receptors ,England ,Haplotypes ,Case-Control Studies ,biology.protein ,Female ,business ,Glioblastoma - Abstract
Glioma is the most common type of adult brain tumor and glioblastoma, its most aggressive form, has a dismal prognosis. Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR, ERBB2, ERBB3, ERBB4) family, and the vascular endothelial growth factor receptor (VEGFR), play a central role in tumor progression. We investigated the genetic variants of EGFR, ERBB2, VEGFR and their ligands, EGF and VEGF on glioma and glioblastoma risk. In addition, we evaluated the association of genetic variants of a newly discovered family of genes known to interact with EGFR: LRIG2 and LRIG3 with glioma and glioblastoma risk. Methods. We analyzed 191 tag single nucleotide polymorphisms (SNPs) capturing all common genetic variation of EGF, EGFR, ERBB2, LRIG2, LRIG3, VEGF and VEGFR2 genes. Material from four case-control studies with 725 glioma patients (329 of who were glioblastoma patients) and their 1 610 controls was used. Haplotype analyses were conducted using SAS/Genetics software. Results. Fourteen of the SNPs were significantly associated with glioma risk at p0.05, and 17 of the SNPs were significantly associated with glioblastoma risk at p0.05. In addition, we found that one EGFR haplotype was related to increased glioblastoma risk at p=0.009, Odds Ratio [OR] = 1.67 (95% confidence interval (CI): 1.14, 2.45). The Bonferroni correction made all p-values non-significant. One SNP, rs4947986 next to the intron/exon boundary of exon 7 in EGFR, was validated in an independent data set of 713 glioblastoma and 2 236 controls, [OR] = 1.42 (95% CI: 1.06,1.91). Discussion. Previous studies show that regulation of the EGFR pathway plays a role in glioma progression but the present study is the first to find that certain genotypes of the EGFR gene may be related to glioblastoma risk. Further studies are required to reinvestigate these findings and evaluate the functional significance.
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- 2010
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47. Genetic variations in EGF and EGFR and glioblastoma outcome
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Helle Broholm, Thomas Brännström, Ulrika Andersson, Melissa L. Bondy, Roger Henriksson, Christoffer Johansen, Yanhong Liu, Beatrice Melin, Helle Collatz-Laier, and Sara Sjöström
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Adult ,Male ,Cancer Research ,Genotype ,EGFR ,Single-nucleotide polymorphism ,Biology ,Bioinformatics ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,polymorphism ,Young Adult ,Risk Factors ,Epidermal growth factor ,Polymorphism (computer science) ,Genetic variation ,Humans ,Receptor ,Gene ,EGF ,Aged ,Epidermal Growth Factor ,integumentary system ,Brain Neoplasms ,Haplotype ,glioblastoma ,Middle Aged ,Prognosis ,ErbB Receptors ,Oncology ,Basic and Translational Investigations ,outcome ,Cancer research ,Female ,Neurology (clinical) ,hormones, hormone substitutes, and hormone antagonists - Abstract
Few prognostic factors have been associated with glioblastoma survival. We analyzed a complete tagging of the epidermal growth factor (EGF) and EGF receptor (EGFR) gene polymorphisms as potential prognostic factors. Thirty tagging single-nucleotide polymorphisms (SNPs) in EGF and 89 tagging SNPs in EGFR were analyzed for association with survival in 176 glioblastoma cases. Validation analyses were performed for 4 SNPs in a set of 638 glioblastoma patients recruited at The University of Texas M. D. Anderson Cancer Center (MDACC). Three hundred and seventy-four glioblastoma patients aged 50 years or older at diagnosis were subanalyzed to enrich for de novo arising glioblastoma. We found 7 SNPs in haplotype 4 in EGF that were associated with prognosis in glioblastoma patients. In EGFR, 4 of 89 SNPs were significantly associated with prognosis but judged as false positives. Four of the significantly associated EGF polymorphisms in haplotype block 4 were validated in a set from MDACC; however, none of the associations were clearly replicated. rs379644 had a hazard ratio (HR) of 1.19 (0.94-1.51) in the whole population with 18.6 months survival in the risk genotype compared with 24.5 in the reference category. As the median age differed slightly between the 2 study sets, the MDACC cases aged 50 or older at diagnosis were analyzed separately (rs379644, HR 1.32 [0.99-1.78]), which is marginally significant and partially validates our findings. This study is, to our knowledge, the first to perform a comprehensive tagging of the EGF and EGFR genes, and the data give some support that EGF polymorphisms might be associated with poor prognosis. Further confirmation in independent data sets of prospective studies is necessary to establish EGF as prognostic risk factor.
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- 2010
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48. Metabolic effects of whole grain wheat and whole grain rye in the C57BL/6J mouse
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Liza Rosén, Ulrika Andersson, Kristoffer Ström, Inger Björck, Elin Östman, Cecilia Holm, and Nils Wierup
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Leptin ,Secale ,medicine.medical_specialty ,Edible Grain ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Weight Gain ,Mice ,NEFA ,Animal science ,Insulin resistance ,Internal medicine ,Dietary Carbohydrates ,medicine ,Animals ,Obesity ,Triglycerides ,Triticum ,Adiposity ,Nutrition and Dietetics ,biology ,Insulin ,Body Weight ,digestive, oral, and skin physiology ,food and beverages ,medicine.disease ,biology.organism_classification ,Mice, Inbred C57BL ,Cholesterol ,Endocrinology ,Blood chemistry ,Dietary Supplements ,Female ,Insulin Resistance ,medicine.symptom ,Weight gain - Abstract
Objective A diet rich in whole grain cereals is suggested to protect against type 2 diabetes and facilitate body weight regulation. However, little is known about the impact of different cereals and the underlying mechanisms. The objective of this study was to compare the long-term metabolic effects of diets supplemented with whole grain wheat or whole grain rye in the C57BL/6J mouse. Methods Mice were fed the whole grain supplements in a low-fat background diet for 22 wk. Oral and intravenous glucose tolerance tests were performed during the study and in vitro insulin secretion assays were performed at the end of the study. Body weight, energy intake, body fat content, and plasma parameters were measured during the study. Results A dietary supplement of whole grain rye suppressed body weight gain and resulted in significantly decreased adiposity, plasma leptin, total plasma cholesterol, and triacylglycerols compared with a supplement of whole grain wheat. Also, a slight improvement in insulin sensitivity was observed in the rye group compared with the wheat group. The decreases in body weight and adiposity were observed in the absence of differences in energy intake. Conclusion Long-term administration of whole grain rye evokes a different metabolic profile compared with whole grain wheat in the C57BL/6J mouse, the primary difference being that whole grain rye reduces body weight and adiposity compared with whole grain wheat. In addition, whole grain rye slightly improves insulin sensitivity and lowers total plasma cholesterol.
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- 2010
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49. MNS16A minisatellite genotypes in relation to risk of glioma and meningioma and to glioblastoma outcome
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Maria Feychting, Helle Broholm, Christoffer Johansen, Anssi Auvinen, Pia Osterman, Roger Henriksson, Thomas Brännström, Beatrice Malmer, Göran Roos, Helle Collatz Christensen, Stefan Lönn, Sara Sjöström, Anne Kiuru, Ulrika Andersson, Anthony J. Swerdlow, Minouk J. Schoemaker, and Anders Ahlbom
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Adult ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Telomerase ,Genotype ,Minisatellite Repeats ,Biology ,Meningioma ,Young Adult ,Tandem repeat ,Glioma ,Meningeal Neoplasms ,Carcinoma ,medicine ,Humans ,Telomerase reverse transcriptase ,Aged ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,United Kingdom ,Treatment Outcome ,Minisatellite ,Oncology ,Case-Control Studies ,Cancer research ,Female ,Glioblastoma - Abstract
The human telomerase reverse transcriptase (hTERT) gene is upregulated in a majority of malignant tumours. A variable tandem repeat, MNS16A, has been reported to be of functional significance for hTERT expression. Published data on the clinical relevance of MNS16A variants in brain tumours have been contradictory. The present population-based study in the Nordic countries and the United Kingdom evaluated brain-tumour risk and survival in relation to MNS16A minisatellite variants in 648 glioma cases, 473 meningioma cases and 1,359 age, sex and geographically matched controls. By PCR-based genotyping all study subjects with fragments of 240 or 271 bp were judged as having short (S) alleles and subjects with 299 or 331 bp fragments as having long (L) alleles. Relative risk of glioma or meningioma was estimated with logistic regression adjusting for age, sex and country. Overall survival was analysed using Kaplan-Meier estimates and equality of survival distributions using the log-rank test and Cox proportional hazard ratios. The MNS16A genotype was not associated with risk of occurrence of glioma, glioblastoma (GBM) or meningioma. For GBM there were median survivals of 15.3, 11.0 and 10.7 months for the LL, LS and SS genotypes, respectively; the hazard ratio for having the LS genotype compared with the LL was significantly increased HR 2.44 (1.56-3.82) and having the SS genotype versus the LL was nonsignificantly increased HR 1.46 (0.81-2.61). When comparing the LL versus having one of the potentially functional variants LS and SS, the HR was 2.10 (1.41-3.1). However, functionality was not supported as there was no trend towards increasing HR with number of S alleles. Collected data from our and previous studies regarding both risk and survival for the MNS16A genotypes are contradictory and warrant further investigations.
- Published
- 2009
- Full Text
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50. Cerebrospinal fluid levels of insulin, leptin, and agouti-related protein in relation to BMI in pregnant women
- Author
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Carolina, Gustavsson, Ulrika, Andersson Hall, Aurimantas, Pelanis, Ove I, Karlsson, Louise, Andersson, Pernilla, Svedin, Carina, Mallard, Alexandra, Myntti, Ulf, Andreasson, Henrik, Zetterberg, Kaj, Blennow, and Agneta, Holmäng
- Subjects
Adult ,Leptin ,Placenta ,Overweight ,Weight Gain ,Body Mass Index ,Pregnancy ,Humans ,Insulin ,Agouti-Related Protein ,Female ,Obesity ,Prospective Studies ,Energy Intake - Abstract
During pregnancy, metabolic interactions must be adapted, though neuroendocrine mechanisms for increased food intake are poorly understood. The objective of this study was to characterize differences in insulin, leptin, and agouti-related protein (AgRP) levels in serum and cerebrospinal fluid (CSF) in pregnant women with normal weight (NW) and pregnant women with overweight (OW) or obesity (OB). Placenta as a source for increased peripheral AgRP levels during pregnancy was also investigated.Women were recruited at admission for elective cesarean section. Insulin, AgRP, and leptin were measured in serum and CSF from 30 NW, 25 OW, and 21 OB at term. Serum during pregnancy and placenta at term were collected for further AgRP analysis.Immunohistology showed placental production of AgRP and serum AgRP levels increased throughout pregnancy. CSF AgRP, leptin, and insulin levels were higher in OW and OB than NW. Serum leptin and insulin levels were higher and AgRP lower in OB than NW.High serum AgRP levels might protect from the suppressive effects of leptin during pregnancy. Pregnant women with OB and OW might further be protected from the suppressive effect of leptin by high CSF AgRP levels. Evidence was found, for the first time, of human placental AgRP production mirrored by levels in the circulation.
- Published
- 2015
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