| 1. |
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| 2. |
- Axelsson, Malin, 1964, et al.
(författare)
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Chronic bronchitis in West Sweden - a matter of smoking and social class
- 2016
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Ingår i: European Clinical Respiratory Journal. - : Informa UK Limited. - 2001-8525. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although chronic bronchitis is associated with impaired quality of life, hospitalisations and increased mortality, it has been less in focus after the introduction of the term chronic obstructive pulmonary disease (COPD). There are no recent published data on the prevalence of chronic bronchitis from the Scandinavian countries. Aim: The main aim of the present study was to estimate the prevalence of chronic bronchitis in West Sweden by using data from a large-scale epidemiological study of the general population. A further aim was to identify current risk factors for chronic bronchitis in a population with a major decrease in the proportion of smokers. Methods: From the 18,087 questionnaire responders out of 30,000 invited to participate at the West Sweden Asthma Study, 2,000 subjects were randomly selected and invited to detailed clinical examinations performed during 2009-2013. A total of 1,172 subjects aged 17-79 participated in the examinations which included, among others, spirometry and structured interviews. Chronic bronchitis was defined according to reported symptoms. Results: The overall prevalence of chronic bronchitis was 7.2% (men 7.6%; women 6.8% ns), and it was 8.7% in subjects older than age 60. Chronic bronchitis was strongly associated with smoking, defined both as current smoking status and pack-years. Other risk factors were increasing age, low socio-economic class and urban living. Of those with chronic bronchitis, 22% fulfilled the GOLD criteria of COPD. Conclusion: The prevalence of chronic bronchitis was somewhat lower than found by studies in Sweden in the 1980s and the prevalence was now similar in men and women. Although smoking was still the dominating risk factor for chronic bronchitis, the relative importance of smoking had decreased parallel with a decreasing smoking prevalence, while the relative importance of other factors than smoking had increased compared to previous studies.
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| 3. |
- Bjerg, Anders, 1982, et al.
(författare)
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Higher Risk of Wheeze in Female than Male Smokers. Results from the Swedish GA(2)LEN Study
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Women who smoke have higher risk of lung function impairment, COPD and lung cancer than smoking men. An influence of sex hormones has been demonstrated, but the mechanisms are unclear and the associations often subject to confounding. This was a study of wheeze in relation to smoking and sex with adjustment for important confounders. Methods In 2008 the Global Allergy and Asthma European Network (GA2LEN) questionnaire was mailed to 45.000 Swedes (age 16–75 years), and 26.851 (60%) participated. “Any wheeze”: any wheeze during the last 12 months. “Asthmatic wheeze”: wheeze with breathlessness apart from colds. Results Any wheeze and asthmatic wheeze was reported by 17.3% and 7.1% of women, vs. 15.8% and 6.1% of men (both p<0.001). Although smoking prevalence was similar in both sexes, men had greater cumulative exposure, 16.2 pack-years vs. 12.8 in women (p<0.001). Most other exposures and characteristics associated with wheeze were significantly overrepresented in men. Adjusted for these potential confounders and pack-years, current smoking was a stronger risk factor for any wheeze in women aged <53 years, adjusted odds ratio (aOR) 1.85 (1.56–2.19) vs. 1.60 (1.30–1.96) in men. Cumulative smoke exposure and current smoking each interacted significantly with female sex, aOR 1.02 per pack-year (p<0.01) and aOR 1.28 (p = 0.04) respectively. Female compared to male current smokers also had greater risk of asthmatic wheeze, aOR 1.53 vs. 1.03, interaction aOR 1.52 (p = 0.02). These interactions were not seen in age ≥53 years. Discussion In addition to the increased risk of COPD and lung cancer female, compared to male, smokers are at greater risk of significant wheezing symptoms in younger age. This became clearer after adjustment for important confounders including cumulative smoke exposure. Estrogen has previously been shown to increase the bioactivation of several compounds in tobacco smoke, which may enhance smoke-induced airway inflammation in fertile women.
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| 4. |
- Bjerg, Anders, 1982, et al.
(författare)
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The association between asthma and rhinitis is stable over time despite diverging trends in prevalence
- 2015
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 0954-6111 .- 1532-3064. ; 109:3, s. 312-319
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite the well-known association between asthma and rhinitis, in Swedish adults the prevalence of rhinitis rose from 22% to 31% between 1990 and 2008 while asthma prevalence was unchanged. We tested whether the association of rhinitis with asthma was stable over time using the same population-based databases. Methods: Two surveys of adults (20-44 years) living in three regions of Sweden, carried out in 1990 (n = 8982) and 2008 (n = 9156) were compared. Identical questions regarding respiratory symptoms, asthma and rhinitis were used. Asthmatic wheeze: Wheeze with breathlessness apart from colds. Current asthma: Asthma attacks and/or asthma medication use. Results: Subjects with rhinitis had level time trends in asthmatic wheeze, current asthma and most nocturnal respiratory symptoms between 1990 and 2008, adjusted for age, sex, area and smoking. Any wheeze however decreased slightly. In never-smokers asthma symptoms were similarly associated with rhinitis in 1990 and 2008: any wheeze OR 4.0 vs. 4.4 (p = 0.339); asthmatic wheeze OR 6.0 vs. 5.9 (p = 0.937); and current asthma OR 9.6 vs. 7.7 (p = 0.213). In the whole population there were decreases in the asthma symptoms most closely associated to smoking, which decreased by half 1990-2008. Conversely current asthma, which was strongly associated with rhinitis and not with smoking, increased (p < 0.001). Conclusions: The association of rhinitis with asthma was stable between 1990 and 2008. The pattern in the time trends of asthma outcomes strongly suggests that decreased smoking counterbalanced the driving effect of increased rhinitis on asthma prevalence. The findings illustrate the public health benefits of decreased smoking. (c) 2015 Elsevier Ltd. All rights reserved.
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| 5. |
- Edvardsson Rasmussen, Jesper, 1984-
(författare)
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Inner ear proteomics and barriers : Clinical and experimental findings
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hearing is important in many aspects of life, including communication, assessing one’s surroundings, entertainment and social interaction. Hearing loss is common and according to the Global Burden of Disease Study, 5% of the global population require hearing rehabilitation (1). Pharmacological treatment options are limited, so understanding cellular mechanisms in the damaged inner ear is crucial for developing novel therapies.In this thesis, the human inner ear proteome in patients with sporadic vestibular schwannoma (VS) and its association with hearing loss were investigated. Ototoxic effects induced by furosemide were also examined, focusing on inner ear barrier function, furosemide sensitive Na-K-Cl co-transporter 1 (NKCC1), Fetuin-A, linked to tumour-associated hearing loss, and Pigment epithelium-derived factor (PEDF), potentially important for blood-endolymph barrier integrity.Translabyrinthine surgery on 35 patients, 32 with VS and three with meningioma, provided samples from perilymph, endolymph, endolymphatic sac tissue, VS biopsies and cerebrospinal fluid (CSF) for proteome analysis. Effects of furosemide on the inner ear barriers were studied in mice using 9.4Tesla MRI, and in guinea pigs using immunohistochemistry and mRNA in situ hybridisation focusing on NKCC1, Fetuin-A, and PEDF.Proteomic analysis revealed consistent sets of proteins in perilymph (91/315) and endolymph (545/1211). The proteomes of perilymph and CSF exhibited specific differences, with proteins unique to each fluid, thereby emphasizing the distinct origin of perilymph separate from CSF. Fetuin-A was inversely related to tumour-associated hearing loss, while patients with severe to profound hearing loss exhibited upregulation of complement factor H-related protein 2 (CFHR2).Furosemide compromised the blood-endolymph barrier, allowing gadolinium contrast into scala media. It affected NKCC1 of type II fibrocytes coinciding with the onset of hearing loss following high-dose furosemide, suggesting early disruption in potassium ion recirculation. Fetuin-A and PEDF were identified in the cochlea at protein and mRNA level. Their staining intensity increased in various cochlear subsites 120 minutes after furosemide administration, indicating their involvement in the cochlear response to the effects of furosemide.In summary, this thesis uncovered significant inter-individual variability in both the perilymph and endolymph proteome, alongside a consistent subset of proteins. Further, associations between hearing loss and proteome changes suggest inflammation as a potential mechanism for hearing degradation caused by vestibular schwannomas. Experimentally, impact of furosemide on blood-inner ear barriers were visualised in vivo and type II fibrocytes were identified as potential initial targets for NKCC1 blockade. Fetuin-A and PEDF were confirmed in several cell types in the cochlea and may increase in response to very high furosemide doses.
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| 6. |
- Eriksson, Jonas, 1984, et al.
(författare)
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Cigarette smoking is associated with high prevalence of chronic rhinitis and low prevalence of allergic rhinitis in men
- 2013
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Ingår i: Allergy. - : Wiley. - 0105-4538 .- 1398-9995. ; 68:3, s. 347-354
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Tidskriftsartikel (refereegranskat)abstract
- Background The harmful effects of tobacco smoke on human health, including respiratory health, are extensive and well documented. Previous data on the effect of smoking on rhinitis and allergic sensitization are inconsistent. We sought to investigate how smoking correlates with prevalence of allergic and chronic rhinitis among adults in Sweden. Methods The study population comprised 27 879 subjects derived from three large randomly selected cross-sectional population surveys conducted in Sweden between 2006 and 2008. The same postal questionnaire on respiratory health was used in the three surveys, containing questions about obstructive respiratory diseases, rhinitis, respiratory symptoms and possible determinants of disease, including smoking habits. A random sample from one of the cohorts underwent a clinical examination including skin prick testing. Results Smoking was associated with a high prevalence of chronic rhinitis in both men and women and a low prevalence of allergic rhinitis in men. These associations were dose dependent and remained when adjusted for a number of possible confounders in multiple logistic regression analysis. Prevalence of chronic rhinitis was lowest in nonsmokers and highest in very heavy smokers (18.5% vs 34.5%, P < 0.001). Prevalence of sensitization to common airborne allergens was lower in current smokers (25.9%, P = 0.008) and ex-smokers (28.2%, P = 0.022) than in nonsmokers (38.5%). Conclusion We found that smoking was associated with a high prevalence of chronic rhinitis in both sexes and a low prevalence of allergic rhinitis in men. The associations were dose dependent and remained when adjusting for several possible confounders.
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| 7. |
- Eriksson, Jonas, 1984, et al.
(författare)
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Growing up on a farm leads to lifelong protection against allergic rhinitis.
- 2010
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 65:11, s. 1397-403
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Tidskriftsartikel (refereegranskat)abstract
- Various studies have reported a low prevalence of allergic rhinitis in farmers and farmers' children. We sought to investigate whether the protective effect of childhood farm environment is conserved throughout adulthood and how it corresponds to different degrees of urbanization.
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| 8. |
- Eriksson, Jonas, 1984, et al.
(författare)
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Update of prevalence of self-reported allergic rhinitis and chronic nasal symptoms among adults in Sweden
- 2012
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Ingår i: The Clinical Respiratory Journal. - 1752-699X .- 1752-6981. ; 6:3, s. 159-168
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Tidskriftsartikel (refereegranskat)abstract
- Background: Allergic rhinitis (AR) is the most common immunologic disease, and it renders a considerable burden on both sufferers and society. The prevalence of AR has been increasing worldwide over the past century. The aim of this study was to assess the present prevalence, risk factor patterns and comorbidity of self-reported AR and chronic nasal symptoms in different age groups in Stockholm, Sweden. Methods: A postal questionnaire was sent on two occasions, in 2006 to a population aged 30-80 years, randomly selected 10 years previously, and in 2007 to a randomly selected sample of subjects aged 20-69 years. The response rates were 83% and 68%, respectively, and in total, 9792 subjects participated. The questionnaire included questions on self-reported AR, asthma, respiratory and nasal symptoms and possible determinants. Results: The prevalence of self-reported AR was 28.0% (men 26.6%, women 29.1%, P<0.01) similar to 10 years previously and 33.6% in ages 30-40 years. Allergic heredity [odds ratio (OR) 4.76, confidence interval (CI) 95% 4.25-5.33], physician-diagnosed asthma (OR 5.29, CI 95% 4.49-6.24) and occupational exposure to dust, gases and fumes (OR 1.49, CI 95% 1.30-1.72) were determinants for AR. Prevalence of chronic nasal congestion was 16.1% and of chronic rhinorrhea 14.1%. Conclusions: As a basis for understanding the disease, as well as in planning and prioritising health-care resources, the study provides information about the current prevalence and determinants of self-reported AR and chronic nasal symptoms. Further, comparing with previous studies, the present study suggests that a plateau in the prevalence of AR may have been reached in Sweden. Please cite this paper as: Eriksson J, Ekerljung L, Rönmark E, Dahlén B, Ahlstedt S, Dahlén S-E and Lundbäck B. Update of prevalence of self-reported allergic rhinitis and chronic nasal symptoms among adults in Sweden
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| 9. |
- Fredriksson, Robert, et al.
(författare)
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The polyamine transporter Slc18b1(VPAT) is important for both short and long time memory and for regulation of polyamine content in the brain.
- 2019
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 15:12
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Tidskriftsartikel (refereegranskat)abstract
- SLC18B1 is a sister gene to the vesicular monoamine and acetylcholine transporters, and the only known polyamine transporter, with unknown physiological role. We reveal that Slc18b1 knock out mice has significantly reduced polyamine content in the brain providing the first evidence that Slc18b1 is functionally required for regulating polyamine levels. We found that this mouse has impaired short and long term memory in novel object recognition, radial arm maze and self-administration paradigms. We also show that Slc18b1 KO mice have altered expression of genes involved in Long Term Potentiation, plasticity, calcium signalling and synaptic functions and that expression of components of GABA and glutamate signalling are changed. We further observe a partial resistance to diazepam, manifested as significantly lowered reduction in locomotion after diazepam treatment. We suggest that removal of Slc18b1 leads to reduction of polyamine contents in neurons, resulting in reduced GABA signalling due to long-term reduction in glutamatergic signalling.
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| 10. |
- Huvila, Isto, et al.
(författare)
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Technological and informational frames : explaining age-related variation in the use of patient accessible electronic health records as technology and information
- 2022
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Ingår i: Information Technology and People. - : Emerald Group Publishing Limited. - 0959-3845 .- 1758-5813. ; 35:8, s. 1-22
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Tidskriftsartikel (refereegranskat)abstract
- Purpose – Data from a national patient survey (N51,155) of the Swedish PAEHR “Journalen” users were analysed, and an extended version of the theory of technological frames was developed to explain the variation in the technological and informational framing of information technologies found in the data. Design/methodology/approach – Patient Accessible Electronic Health Records (PAEHRs) are implemented globally to address challenges with an ageing population. However, firstly, little is known about age-related variation in PAEHR use, and secondly, user perceptions of the PAEHR technology and the health record information and how the technology and information–related perceptions are linked to each other. The purpose of this study is to investigate these two under-studied aspects of PAEHRs and propose a framework based on the theory of technological frames to support studying the second aspect, i.e. the interplay of information and technology–related perceptions. Findings – The results suggest that younger respondents were more likely to be interested in PAEHR contents for general interest. However, they did not value online access to the information as high as older ones. Older respondents were instead inclined to use medical records information to understand their health condition, prepare for visits, become involved in their own healthcare and think that technology has a much potential. Moreover, the oldest respondents were more likely to consider the information in PAEHRs useful and aimed for them but to experience the technology as inherently difficult to use. Research limitations/implications – The sample excludes non-users and is not a representative sample ofthe population of Sweden. However, although the data contain an unknown bias, there are no specific reasons tobelieve that it would differently affect the survey’s age groups. Practical implications – Age should be taken into account as a key factor that influences perceptions of the usefulness of PAEHRs. It is also crucial to consider separately patients’ views of PAEHRs as a technology and of the information contained in the EHR when developing and evaluating existing and future systems and information provision for patients. Social implications – This study contributes to bridging the gap between information behaviour and systems design research by showing how the theory of technological frames complemented with parallel informational frames to provide a potentially powerful framework for elucidating distinct conceptualisations of (information) technologies and the information they mediate. The empirical findings show how information and information technology needs relating to PAEHRs vary according to age. In contrast to the assumptions in much of the earlier work, they need to be addressed separately. Originality/value – Few earlier studies focus on (1) age-related variation in PAEHR use and (2) user perceptions of the PAEHR technology and the health record information and how the technology and information–related perceptions are linked to each other.
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| 11. |
- Meier, Silvio R., et al.
(författare)
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11C-PiB and 124I-antibody PET provide differing estimates of brain amyloid-β after therapeutic intervention
- 2022
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 63:2, s. 302-309
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Tidskriftsartikel (refereegranskat)abstract
- PET imaging of amyloid-β (Aβ) has become an important component of Alzheimer disease diagnosis. 11C-Pittsburgh compound B (11C-PiB) and analogs bind to fibrillar Aβ. However, levels of nonfibrillar, soluble, aggregates of Aβ appear more dynamic during disease progression and more affected by Aβ-reducing treatments. The aim of this study was to compare an antibody-based PET ligand targeting nonfibrillar Aβ with 11C-PiB after β-secretase (BACE-1) inhibition in 2 Alzheimer disease mouse models at an advanced stage of Aβ pathology.Methods: Transgenic ArcSwe mice (16 mo old) were treated with the BACE-1 inhibitor NB-360 for 2 mo, whereas another group was kept as controls. A third group was analyzed at the age of 16 mo as a baseline. Mice were PET-scanned with 11C-PiB to measure Aβ plaque load followed by a scan with the bispecific radioligand 124I-RmAb158-scFv8D3 to investigate nonfibrillar aggregates of Aβ. The same study design was then applied to another mouse model, AppNL-G-F. In this case, NB-360 treatment was initiated at the age of 8 mo and animals were scanned with 11C-PiB-PET and 125I-RmAb158-scFv8D3 SPECT. Brain tissue was isolated after scanning, and Aβ levels were assessed.Results: 124I-RmAb158-scFv8D3 concentrations measured with PET in hippocampus and thalamus of NB-360–treated ArcSwe mice were similar to those observed in baseline animals and significantly lower than concentrations observed in same-age untreated controls. Reduced 125I-RmAb158-scFv8D3 retention was also observed with SPECT in hippocampus, cortex, and cerebellum of NB-360–treated AppNL-G-F mice. Radioligand in vivo concentrations corresponded to postmortem brain tissue analysis of soluble Aβ aggregates. For both models, mice treated with NB-360 did not display a reduced 11C-PiB signal compared with untreated controls, and further, both NB-360 and control mice tended, although not reaching significance, to show higher 11C-PiB signal than the baseline groups.Conclusion: This study demonstrated the ability of an antibody-based radioligand to detect changes in brain Aβ levels after anti-Aβ therapy in ArcSwe and AppNL-G-F mice with pronounced Aβ pathology. In contrast, the decreased Aβ levels could not be quantified with 11C-PiB PET, suggesting that these ligands detect different pools of Aβ.
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| 12. |
- Roshanbin, Sahar, 1984-, et al.
(författare)
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Reduction of alpha SYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody
- 2022
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 14:7
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy targeting aggregated alpha-synuclein (alpha SYN) is a promising approach for the treatment of Parkinson's disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated alpha SYN and binds to the transferrin receptor for facilitated brain uptake, was investigated to treat alpha SYN pathology in transgenic mice. Ex vivo analyses of the blood and brain distribution of RmAbSynO2-scFv8D3 and the unmodified variant RmAbSynO2, as well as in vivo analyses with microdialysis and PET, confirmed fast and efficient brain uptake of the bispecific format. In addition, intravenous administration was shown to be superior to intraperitoneal injections in terms of brain uptake and distribution. Next, aged female alpha SYN transgenic mice (L61) were administered either RmAbSynO2-scFv8D3, RmAbSynO2, or PBS intravenously three times over five days. Levels of TBS-T soluble aggregated alpha SYN in the brain following treatment with RmAbSynO2-scFv8D3 were decreased in the cortex and midbrain compared to RmAbSynO2 or PBS controls. Taken together, our results indicate that facilitated brain uptake of alpha SYN antibodies can improve treatment of alpha SYN pathology.
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| 13. |
- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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| 14. |
- Stevens, Marc, 1984-, et al.
(författare)
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Synthesis of 11C-labelled Sulfonyl Carbamates via a Multicomponent Reaction Employing Sulfonyl Azides, Alcohols and [11C]CO
- 2016
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Ingår i: ChemistryOpen. - : John Wiley & Sons. - 2191-1363. ; 5:6, s. 566-573
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Tidskriftsartikel (refereegranskat)abstract
- Herein we describe the development of new methodologyfocusing on 11C-labelling of sulfonyl carbamates in a multicomponentreaction comprising a sulfonyl azide, an alkyl alcohol and [11C]CO. Anumber of 11C-labelled sulfonyl carbamates were synthesised andisolated, and the developed methodology was then applied in thepreparation of a biologically active molecule. The target compoundwas obtained in 18±8% isolated radiochemical yield and wasevaluated for binding properties in a tumor cell assay, as well asundergoing in vivo biodistribution and imaging studies. Thisrepresents the first successful radiolabelling of C21, a non-peptideangiotensin II receptor subtype 2 agonist currently in clinical trials.
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| 15. |
- Syvänen, Stina, et al.
(författare)
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PET Imaging in Preclinical Anti-Aβ Drug Development
- 2022
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Ingår i: Pharmaceutical research. - : Springer Nature. - 0724-8741 .- 1573-904X. ; 39:7, s. 1481-1496
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Forskningsöversikt (refereegranskat)abstract
- Positron emission tomography (PET), a medical imaging technique allowing for studies of the living human brain, has gained an important role in clinical trials of novel drugs against Alzheimer’s disease (AD). For example, PET data contributed to the conditional approval in 2021 of aducanumab, an antibody directed towards amyloid-beta (Aβ) aggregates, by showing a dose-dependent reduction in brain amyloid after treatment. In parallel to clinical studies, preclinical studies in animal models of Aβ pathology may also benefit from PET as a tool to detect target engagement and treatment effects of anti-Aβ drug candidates. PET is associated with a high level of translatability between species as similar, non-invasive protocols allow for longitudinal rather than cross-sectional studies and can be used both in a preclinical and clinical setting. This review focuses on the use of preclinical PET imaging in genetically modified animals that express human Aβ, and its present and potential future role in the development of drugs aimed at reducing brain Aβ levels as a therapeutic strategy to halt disease progression in AD.
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| 16. |
- Vogelezang, Suzanne, et al.
(författare)
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Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.
- 2020
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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| 17. |
- Wennergren, Göran, 1947, et al.
(författare)
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Asthma in late adolescence - farm childhood is protective and the prevalence increase has levelled off
- 2010
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Ingår i: Pediatric Allergy and Immunology. - 1399-3038. ; 21:5, s. 806-813
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Tidskriftsartikel (refereegranskat)abstract
- While the prevalence of and risk factors for asthma in childhood have been studied extensively, the data for late adolescence are more sparse. The aim of this study was to provide up-to-date information on the prevalence of and risk factors for asthma in the transitional period between childhood and adulthood. A secondary aim was to analyze whether the increase in asthma prevalence has levelled off. A large-scale, detailed postal questionnaire focusing on asthma and respiratory symptoms, as well as possible risk factors, was mailed to 30 000 randomly selected subjects aged 16-75 in Gothenburg and the surrounding western Sweden region. The present analyses are based on the responses from 1261 subjects aged 16-20 (560 men and 701 women). The prevalence of physician-diagnosed asthma was 9.5%, while 9.6% reported the use of asthma medicine. In the multivariate analysis, the strongest risk factors for physician-diagnosed asthma and other asthma variables were heredity for asthma and heredity for allergy, particularly if they occurred together. Growing up on a farm significantly reduced the prevalence of physician-diagnosed asthma and the likelihood of using asthma medication, OR 0.1 (95% CI 0.02-0.95). Smoking increased the risk of recurrent wheeze, long-standing cough, and sputum production. In conclusion, the prevalence of physician-diagnosed asthma and the use of asthma medication in the 16- to 20-yr age group support the notion that the increase in asthma prevalence seen between the 1950s and the 1990s has now levelled off. In line with the hygiene hypothesis, a farm childhood significantly reduced the likelihood of asthma. The adverse effects of smoking could already be seen at this young age.
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| 18. |
- Xiong, Mengfei, et al.
(författare)
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[11C]PiB binding after treatment with an amyloid-beta antibody
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In several studies of anti-Aβ antibodies, the successful elimination of amyloid-beta (Aβ) plaques after treatment was indicated by substantially decreased amyloid levels in positron emission tomography (PET) imaging in Alzheimer's disease (AD) patients. However, this decrease in brain amyloid, as measured by PET, has not been matched by a similar substantial effect on cognitive function. Thus, we used one of the amyloid PET ligands, [11C]PiB, to evaluate if the decrease of the PET signal is due to the removal of amyloid pathology or if repeated antibody administration instead blocks [11C]PiB binding sites on the Aβ deposits in brain tissue.First, the ability of mAb158 (the murine version of anti-Aβ antibody lecanemab) to block thioflavin-S (ThS, structure similar to PiB) binding to Aβ deposits was investigated in mouse brain sections from 19-21 months old transgenic mice with Aβ pathology (tg-ArcSwe). Next, tg-ArcSwe mice received weekly treatment with 50 mg/kg of mAb158 or PBS for 3 weeks before i.v. administration of [11C]PiB. At 40 min post-injection, brain sections were prepared from the mice, and ex vivo autoradiography was carried out. Concentrations of total Aβ1-40 and Aβ1-42 in the brain were further measured by enzyme-linked immunosorbent assay (ELISA) and staining.Group comparison showed that the integrated density of in vitro ThS staining was similar in brain sections pre-incubated with PBS and mAb158. Ex vivo autoradiography after mAb158 treatment and [11C]PiB injection indicated that [11C]PiB binding in general was similar in mAb158- and PBS-treated animals but a small tendency of reduced signals existed in the mAb158-treated animals. The brain Aβ1-40 and Aβ1-42 concentrations measured by ELISA were similar in both treatment groups.The study suggested that [11C]PiB binding to Aβ deposits reflected brain Aβ load and that plaque decoration by administering therapeutic antibodies only had a limited blocking effect on amyloid radioligand binding.
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| 19. |
- Xiong, Mengfei, et al.
(författare)
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In vivo imaging of synaptic density with [C-11]UCB-J PET in two mouse models of neurodegenerative disease
- 2021
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Ingår i: NeuroImage. - : Elsevier. - 1053-8119 .- 1095-9572. ; 239
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Tidskriftsartikel (refereegranskat)abstract
- The positron emission tomography (PET) radioligand [C-11]UCB-J binds to synaptic vesicle protein 2A (SV2A) and is used to investigate synaptic density in the living brain. Clinical studies have indicated reduced [C-11]UCB-J binding in Alzheimer's disease (AD) and Parkinson's disease (PD) brains compared to healthy controls. Still, it is unknown whether [C-11]UCB-J PET can visualise synaptic loss in mouse models of these disorders. Such models are essential for understanding disease pathology and for evaluating the effects of novel disease-modifying drug candidates. In the present study, synaptic density in transgenic models of AD (ArcSwe) and PD (L61) was stud-ied using [C-11]UCB-J PET. Data were acquired during 60 min after injection, and time-activity curves (TACs) in different brain regions and the left ventricle of the heart were generated based on the dynamic PET images. The [C-11]UCB-J brain concentrations were expressed as standardised uptake value (SUV) over time. The area under the SUV curve (AUC), the ratio of AUC in the brain to that in the heart (AUCbrain/blood), and the volume of distribution (VT) obtained by kinetic modelling using the heart TAC as input were compared between trans-genic and age-matched wild type (WT) mice. The L61 mice displayed 11-13% lower AUCbrain/blood ratio and brain VT generated by kinetic modeling compared to the control WT mice. In general, also transgenic ArcSwe mice tended to show lower [C-11]UCB-J brain exposure than age-matched WT controls, but variation within the different animal groups was high. Older WT mice (18-20 months) showed lower [C-11]UCB-J brain exposure than younger WT mice (8-9 months). Together, these data imply that [C-11]UCB-J PET reflects synaptic density in mouse models of neurodegeneration and that inter-subject variation is large. In addition, the study suggested that model-independent AUCbrain/blood ratio can be used to evaluate [C-11]UCB-J binding as an alternative to full pharmacokinetic modelling.
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| 20. |
- Xiong, Mengfei, et al.
(författare)
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Synaptic density in aging mice measured by [18F]SynVesT-1 PET
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Synaptic alterations in certain brain structures are related to cognitive decline in neurodegeneration and aging. Synaptic loss in many neurodegenerative diseases can be visualized by positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A). However, the use of SV2A PET for studying synaptic changes during aging is not particularly explored. Thus, in the present study, PET ligand [18F]SynVesT-1, which binds to SV2A, was used to investigate synaptic density at different ages in healthy mice.Wild type C57Bl/6 mice divided into three age groups (4-5 months (n = 7), 12-14 months (n = 11), 17-19 months (n = 8)) were PET scanned with [18F]SynVesT-1. Brain retention of [18F]SynVesT-1 expressed as the volume of distribution (VT) was calculated using an image-derived input function. Estimates of VT were derived using either a one-tissue compartment model (1TCM), a two-tissue compartment model (2TCM), or the Logan plot with blood input to find the best-fit model for [18F]SynVesT-1. After the PET scans, tissue sections were immunostained for the detection of SV2A and neuronal markers.We found that [18F]SynVesT-1 data acquired 60 min post intravenously injection and analyzed with 1TCM described the brain pharmacokinetics of the radioligand in mice well. [18F]SynVesT-1 brain retention was lower in the oldest group of mice, indicating a decrease in synaptic density in this age group. However, no gradual age-dependent decrease in synaptic density at a region-specific level was observed. Immunostaining indicated that SV2A expression and neuron numbers were similar across all three age groups. In general, these data obtained in healthy aging mice are consistent with previous findings in humans where synaptic density appeared stable during aging up to a certain age, after which a small decrease is observed.
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| 21. |
- Xiong, Mengfei, et al.
(författare)
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Synaptic density in aging mice measured by [18F]SynVesT-1 PET
- 2023
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 277
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Tidskriftsartikel (refereegranskat)abstract
- Synaptic alterations in certain brain structures are related to cognitive decline in neurodegeneration and in aging. Synaptic loss in many neurodegenerative diseases can be visualized by positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A). However, the use of SV2A PET for studying synaptic changes during aging is not particularly explored. Thus, in the present study, PET ligand [18F]SynVesT-1, which binds to SV2A, was used to investigate synaptic density at different ages in healthy mice. Wild type C57BL/6 mice divided into three age groups (4-5 months ( n = 7), 12-14 months ( n = 11), 17- 19 months ( n = 7)) were PET scanned with [18F]SynVesT-1. Brain retention of [18F]SynVesT-1 expressed as the volume of distribution (VIDIF) was calculated using an image-derived input function. Estimates of VIDIF were derived using either a one-tissue compartment model (1TCM), a two-tissue compartment model (2TCM), or the Logan plot with blood input to find the best-fit model for [18F]SynVesT-1. After the PET scans, tissue sections were immunostained for the detection of SV2A and neuronal markers. We found that [18F]SynVesT-1 data acquired 60 min post intravenously injection and analyzed with 1TCM described the brain pharmacokinetics of the radioligand in mice well. [18F]SynVesT-1 brain retention was lower in the oldest group of mice, indicating a decrease in synaptic density in this age group. However, no gradual age dependent decrease in synaptic density at a region-specific level was observed. Immunostaining indicated that SV2A expression and neuron numbers were similar across all three age groups. In general, these data obtained in healthy aging mice are consistent with previous findings in humans where synaptic density appeared stable during aging up to a certain age, after which a small decrease is observed.
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