| 11. |
- Engström, Gunnar, et al.
(author)
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The Swedish CArdioPulmonary BioImage Study : objectives and design
- 2015
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 278:6, s. 645-659
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Journal article (peer-reviewed)abstract
- Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.
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| 12. |
- Ferreira, Daniel, et al.
(author)
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Brain changes in Alzheimer's disease patients with implanted encapsulated cells releasing nerve growth factor
- 2015
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 43, s. 1059-1072
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Journal article (peer-reviewed)abstract
- © 2015-IOS Press and the authors. New therapies with disease-modifying effects are urgently needed for treating Alzheimer's disease (AD). Nerve growth factor (NGF) protein has demonstrated regenerative and neuroprotective effects on basal forebrain cholinergic neurons in animal studies. In addition, AD patients treated with NGF have previously shown improved cognition, EEG activity, nicotinic binding, and glucose metabolism. However, no study to date has analyzed brain atrophy in patients treated with NGF producing cells. In this study we present MRI results of the first clinical trial in patients with AD using encapsulated NGF biodelivery to the basal forebrain. Six AD patients received the treatment during twelve months. Patients were grouped as responders and non-responders according to their twelve-months change in MMSE. Normative values were created from 131 AD patients from ADNI, selecting 36 age-and MMSE-matched patients for interpreting the longitudinal changes in MMSE and brain atrophy. Results at baseline indicated that responders showed better clinical status and less pathological levels of cerebrospinal fluid (CSF) Aβ1-42. However, they showed more brain atrophy, and neuronal degeneration as evidenced by higher CSF levels of T-tau and neurofilaments. At follow-up, responders showed less brain shrinkage and better progression in the clinical variables and CSF biomarkers. Noteworthy, two responders showed less brain shrinkage than the normative ADNI group. These results together with previous evidence supports the idea that encapsulated biodelivery of NGF might have the potential to become a new treatment strategy for AD with both symptomatic and disease-modifying effects.
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| 13. |
- Karami, Azadeh, et al.
(author)
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Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease
- 2015
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In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:11, s. 1316-1328
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Journal article (peer-reviewed)abstract
- Introduction: The extensive loss of central cholinergic functions in Alzheimer's disease (AD) brain is linked to impaired nerve growth factor (NGF) signaling. The cardinal cholinergic biomarker is the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), which has recently been found in cerebrospinal fluid (CSF). The purpose of this study was to see if EC-NGF therapy will alter CSF levels of cholinergic biomarkers, ChAT, and acetylcholinesterase. Method: Encapsulated cell implants releasing NGF (EC-NGF) were surgically implanted bilaterally in the basal forebrain of six AD patients for 12 months and cholinergic markers in CSF were analyzed. Results: Activities of both enzymes were altered after 12 months. In particular, the activity of soluble ChAT showed high correlation with cognition, CSF tau and amyloid-beta, in vivo cerebral glucose utilization and nicotinic binding sites, and morphometric and volumetric magnetic resonance imaging measures. Discussion: A clear pattern of association is demonstrated showing a proof-of-principle effect on CSF cholinergic markers, suggestive of a beneficial EC-NGF implant therapy.
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| 14. |
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| 15. |
- Lind, Monica, et al.
(author)
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Circulating levels of perfluoroalkyl substances and biomarkers of liver function in a large population based sample of elderly men and women from Sweden
- 2015
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In: Toxicology Letters. - : Elsevier. - 0378-4274 .- 1879-3169. ; 238:2, s. S91-S91
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Journal article (other academic/artistic)abstract
- Objective: Since perfluoroalkyl substances (PFAS), also called perfluorinated compounds (PFCs), have been shown to accumulate in the liver in experimental studies, we investigated the relationships between PFAS and biomarkers of liver function in the general population.Methods: 1016 subjects aged 70 years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Eight PFAS were detected in almost all participants era by liquid chromatograph/tandem mass spectrometry. Several biomarkers of liver function were measured in parallel.Results: Bilirubin levels were significantly related to several of the PFAS, like perfluoroheptanoic acid (PFHpA), perfluorooctanoicacid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA). Of those, PFHpA, PFOA, PFDA, and PFNA were also related to Alanine Aminotransferase (ALT) levels. PFNA and PFUnDA were inversely related to alkaline phosphatases, while only PFHpA levels were significantly related to gamma-glutamyl transferase (GGT) levels. All associations were adjusted for life-style factors, like smoking, education, exercise habits, energy and alcohol intake.Conclusion: Circulating level of PFAS were related to biomarkers of liver function in this population-based sample, suggesting that PFAS could have a negative effect on liver function also in humans.
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| 16. |
- Lorenz, M. W., et al.
(author)
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Carotid Intima-Media Thickness Progression and Risk of Vascular Events in People With Diabetes: Results From the PROG-IMT Collaboration
- 2015
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In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 38:10, s. 1921-1929
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Journal article (peer-reviewed)abstract
- OBJECTIVECarotid intima-media thickness (CIMT) is a marker of subclinical organ damage and predicts cardiovascular disease (CVD) events in the general population. It has also been associated with vascular risk in people with diabetes. However, the association of CIMT change in repeated examinations with subsequent CVD events is uncertain, and its use as a surrogate end point in clinical trials is controversial. We aimed at determining the relation of CIMT change to CVD events in people with diabetes.RESEARCH DESIGN AND METHODSIn a comprehensive meta-analysis of individual participant data, we collated data from 3,902 adults (age 33-92 years) with type 2 diabetes from 21 population-based cohorts. We calculated the hazard ratio (HR) per standard deviation (SD) difference in mean common carotid artery intima-media thickness (CCA-IMT) or in CCA-IMT progression, both calculated from two examinations on average 3.6 years apart, for each cohort, and combined the estimates with random-effects meta-analysis.RESULTSAverage mean CCA-IMT ranged from 0.72 to 0.97 mm across cohorts in people with diabetes. The HR of CVD events was 1.22 (95% CI 1.12-1.33) per SD difference in mean CCA-IMT, after adjustment for age, sex, and cardiometabolic risk factors. Average mean CCA-IMT progression in people with diabetes ranged between -0.09 and 0.04 mm/year. The HR per SD difference in mean CCA-IMT progression was 0.99 (0.91-1.08).CONCLUSIONSDespite reproducing the association between CIMT level and vascular risk in subjects with diabetes, we did not find an association between CIMT change and vascular risk. These results do not support the use of CIMT progression as a surrogate end point in clinical trials in people with diabetes.
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| 17. |
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| 18. |
- Lundberg, Christina, 1972-
(author)
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Screening for Atherosclerosis with Magnetic Resonance Imaging and Ultrasound
- 2015
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Doctoral thesis (other academic/artistic)abstract
- Atherosclerosis is a major cause of death and disability worldwide. Although traditional risk factors can identify the healthy or severely affected individuals, sudden lethal outcome is still frequent in those suggested as intermediate in risk for cardiovascular events (CVE). Adding imaging to the traditional scoring systems might improve risk stratification.This thesis investigates whether the addition of magnetic resonance imaging (MRI) and ultrasound (US) to traditional risk factors might render atherosclerosis suitable for mass screening, selective screening or screening in research settings.In paper I the carotid arteries were assessed in six different manners (carotid intima media thickness (CIMT) in two different locations, presence of plaque, number of plaques, plaque size and plaque composition) using US. More than 800 Caucasian subjects were assessed at ages 70 and 75, and outcome examined at 80 years of age. Plaques with an area exceeding 10mm2 in the bulb were found to be most closely related to CVE.Paper II established that carotid plaque volume measured with MRI did not correlate with carotid plaque area assessed with US. MRI reached the highest levels of reproducibility of the two methods.Paper III used the previously created total atherosclerotic score (TAS), a scoring system based on whole body magnetic resonance angiography (WBMRA) that assesses global atherosclerosis. TAS was found to predict CVE in 305 PIVUS-subjects at age 70 years during 5 years of follow-up. The risk for CVE was found to be eightfold with TAS>0.In paper IV CIMT was assessed with US at ages 70 and 75 years. CIMT at baseline, but not the change in CIMT over five years, was significantly related to TAS, thus suggesting carotid changes to correlate with atherosclerosis throughout the body.In conclusion, in research settings WBMRA and MRI, as well as US, can be used for screening and following up of atherosclerotic changes, as their predictive values and reproducibility are good. US might be feasible in selective screening but none of these methods are as of now suitable for mass screening.
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| 19. |
- Mahajan, Anubha, et al.
(author)
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Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus.
- 2015
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 11:1
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Journal article (peer-reviewed)abstract
- Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
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| 20. |
- Ng, Esther, et al.
(author)
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Genome-wide association study of plasma levels of polychlorinated biphenyls disclose an association with the CYP2B6 gene in a population-based sample
- 2015
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In: Environmental Research. - : Elsevier BV. - 0013-9351 .- 1096-0953. ; 140, s. 95-101
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Journal article (peer-reviewed)abstract
- Background: Polychlorinated biphenyls (PCBs) are a group of man-made environmental pollutants which accumulate in humans with adverse health effects. To date, very little effort has been devoted to the study of the metabolism of PCBs on a genome-wide level.Objectives: Here, we conducted a genome-wide association study (GWAS) to identify genomic regions involved in the metabolism of PCBs.Methods: Plasma levels of 16 PCBs ascertained in a cohort of elderly individuals from Sweden (n=1016) were measured using gas chromatography-high resolution mass spectrophotometry (GC-HRMS). DNA samples were genotyped on the Infinium Omni Express bead microarray, and imputed up to reference panels from the 1000 Genomes Project. Association testing was performed in a linear regression framework under an additive model.Results: Plasma levels of PCB-99 demonstrated genome-wide significant association with single nucleotide polymorphisms (SNPs) mapping to chromosome 19q13.2. The SNP with the strongest association was rs8109848 (p=3.7 x 10(-13)), mapping to an intronic region of CYP2B6. Moreover, when all PCBs were conditioned on PCB-99, further signals were revealed for PCBs -74, -105 and -118, mapping to the same genomic region. The lead SNPs were rs8109848 (p=3.8 x 10(-12)) for PCB-118, rs4802104 (p= 1.4 x 10(-9)) for PCB-74 and rs4803413 (p=2.5 x 10(-9)) for PCB-105, all of which map to CYP2B6.Conclusions: In our study, we found plasma levels of four lower-chlorinated PCBs to be significantly associated with the genetic region mapping to the CYP2B6 locus. These findings show that CYP2B6 is of importance for the metabolism of PCBs in humans, and may help to identify individuals who may be susceptible to PCB toxicity. (C) 2015 The Authors. Published by Elsevier Inc.
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