| 1. |
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| 2. |
- Vikner, Tomas, et al.
(författare)
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5-year associations among cerebral arterial pulsatility, perivascular space dilation, and white matter lesions
- 2022
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Ingår i: Annals of Neurology. - : John Wiley & Sons. - 0364-5134 .- 1531-8249. ; 92:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Objective: High cerebral arterial pulsatility index (PI), white matter lesions (WMLs), enlarged perivascular spaces (PVSs), and lacunar infarcts are common findings in the elderly population, and considered indicators of small vessel disease (SVD). Here, we investigate the potential temporal ordering among these variables, with emphasis on determining whether high PI is an early or delayed manifestation of SVD.Methods: In a population-based cohort, 4D flow MRI data for cerebral arterial pulsatility was collected for 159 participants at baseline (age 64–68), and for 122 participants at follow-up 5 years later. Structural MRI was used for WML and PVS segmentation, and lacune identification. Linear mixed-effects (LME) models were used to model longitudinal changes testing for pairwise associations, and latent change score (LCS) models to model multiple relationships among variables simultaneously.Results: Longitudinal 5-year increases were found for WML, PVS, and PI. Cerebral arterial PI at baseline did not predict changes in WML or PVS volume. However, WML and PVS volume at baseline predicted 5-year increases in PI. This was shown for PI increases in relation to baseline WML and PVS volumes using LME models (R (Formula presented.) 0.24; p < 0.02 and R (Formula presented.) 0.23; p < 0.03, respectively) and LCS models ((Formula presented.) = 0.28; p = 0.015 and (Formula presented.) = 0.28; p = 0.009, respectively). Lacunes at baseline were unrelated to PI.Interpretation: In healthy older adults, indicators of SVD are related in a lead–lag fashion, in which the expression of WML and PVS precedes increases in cerebral arterial PI. Hence, we propose that elevated PI is a relatively late manifestation, rather than a risk factor, for cerebral SVD.
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| 3. |
- Vikner, Tomas, et al.
(författare)
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Blood-brain barrier integrity is linked to cognitive function, but not to cerebral arterial pulsatility, among elderly
- 2024
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Blood-brain barrier (BBB) disruption may contribute to cognitive decline, but questions remain whether this association is more pronounced for certain brain regions, such as the hippocampus, or represents a whole-brain mechanism. Further, whether human BBB leakage is triggered by excessive vascular pulsatility, as suggested by animal studies, remains unknown. In a prospective cohort (N = 50; 68-84 years), we used contrast-enhanced MRI to estimate the permeability-surface area product (PS) and fractional plasma volume ( formula presented ), and 4D flow MRI to assess cerebral arterial pulsatility. Cognition was assessed by the Montreal Cognitive Assessment (MoCA) score. We hypothesized that high PS would be associated with high arterial pulsatility, and that links to cognition would be specific to hippocampal PS. For 15 brain regions, PS ranged from 0.38 to 0.85 (·10-3 min-1) and formula presented from 0.79 to 1.78%. Cognition was related to PS (·10-3 min-1) in hippocampus (β = - 2.9; p = 0.006), basal ganglia (β = - 2.3; p = 0.04), white matter (β = - 2.6; p = 0.04), whole-brain (β = - 2.7; p = 0.04) and borderline-related for cortex (β = - 2.7; p = 0.076). Pulsatility was unrelated to PS for all regions (p > 0.19). Our findings suggest PS-cognition links mainly reflect a whole-brain phenomenon with only slightly more pronounced links for the hippocampus, and provide no evidence of excessive pulsatility as a trigger of BBB disruption.
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| 4. |
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| 5. |
- Wan, Y., et al.
(författare)
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First reported nonpeptide AT1 receptor agonist (L-162,313) acts as an AT2 receptor agonist in vivo
- 2004
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Ingår i: J Med Chem. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:6, s. 1536-1546
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Tidskriftsartikel (refereegranskat)abstract
- In this investigation, it is demonstrated that the first nonpeptide AT(1) receptor agonist L-162,313 (1), disclosed in 1994, also acts as an agonist at the AT(2) receptor. In anesthetized rats, administration of compound 1 intravenously or locally in the duodenum increased duodenal mucosal alkaline secretion, effects that were sensitive to the selective AT(2) receptor antagonist PD-123,319. The data strongly suggest that 1 is an AT(2) receptor agonist in vivo. To the best of our knowledge, this substance is the first nonpeptidic low-molecular weight compound with an agonistic effect mediated through the AT(2) receptor.
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| 6. |
- Bignert, Anders, et al.
(författare)
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Comments Concerning the National Swedish Contaminant Monitoring Programme in Marine Biota, 2006
- 2006
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This report gives a summary of the monitoring activities within the national Swedishcontaminant programme in marine biota. It is the result from the joint efforts of: theInstitute of Applied Environmental Research at Stockholm University (analyses oforganochlorines), the Centre for Environmental Monitoring at the University of Agriculture(analyses of heavy metals) and the Contaminant Research Group at the Swedish Museumof Natural History (co-ordination, sample collection administration, sample preparation,recording of biological variables, minor additional analyses of organochlorines, storage offrozen biological tissues in the Environmental Specimen Bank for retrospective studies,data preparation and statistical evaluation). The monitoring programme is financiated by theEnvironmental Protection Agency (EPA) in Sweden.The data of concern in this report represent the bioavailable part of the investigatedcontaminants i.e. the part that has virtually passed through the biological membranes andmay cause biological effects. The objectives of the monitoring program in marine biotacould be summarised as follows:• to estimate the levels and the normal variation of various contaminants in marine biotafrom several representative sites, uninfluenced by local sources, along the Swedish coasts.The goal is to describe the general contaminant status and to supply reference values forregional and local monitoring programmes• to monitor long term time trends and to estimate the rate of found changes.quantified objective: to detect an annual change of 10% within a time period of 10 years with a power of 80%at a significance level of 5%.• to estimate the response in marine biota of measures taken to reduce the discharges ofvarious contaminantsquantified objective: to detect a 50% decrease within a time period of 10 years with a power of 80% at asignificance level of 5%.• to detect incidents of regional influence or widespread incidents of ‘Chernobyl’-character and to act as watchdog monitoring to detect renewed usage of bannedcontaminants.quantified objective: to detect an increase of 200% a single year with a power of 80% at a significance level of5%.• to indicate large scale spatial differencesquantified objective: to detect differences of a factor 2 between sites with a power of 80% at a significancelevel of 5%.• to explore the development and regional differences of the composition and pattern ofe.g. PCB’s, HCH’s and DDT’s as well as the ratios between various contaminants.• the time series are also relevant for human consumption since important commercial fishspecies like herring and cod are sampled. A co-operation with the Swedish FoodAdministration is established. Sampling is also co-ordinated with SSI (Swedish RadiationProtection Authority) for analysing radionuclides in fish and blue mussels (HELCOM,1992).• all analysed, and a large number of additional specimens, of the annually systematicallycollected material are stored frozen in the Environmental Specimen Bank.. This invaluable5material enables future retrospective studies of contaminants impossible to analyse today aswell as control analyses of suspected analytical errors.• although the programme is focused on contaminant concentration in biota, also thedevelopment of biological variables like e.g. condition factor (CF), liver somatic index(LSI) and fat content are monitored at all sites. At a few sites, integrated monitoring withfish physiology and population are running in co-operation with the University ofGothenburg and the Swedish Fishery Board.• experiences from the national program with several time series of over 25 years can beused in the design of regional and local monitoring programmes.• the perfectly unique material of high qualityand long time series is further used to explorerelationships among biological variables and contaminants concentrations in varioustissues; the effects of changes in sampling strategy, the estimates of variance componentsand the influence on the concept of power etc.• the accessibility of high quality data collected and analysed in a consistent manner is anindispensable prerequisite to evaluate the validity of hypothesis and models concerning thefate and distribution of various contaminants. It could furthermore be used as input of ‘real’data in the ongoing model building activities concerning marine ecosystems in general andin the Baltic and North Sea environment in particular.• the contaminant programme in marine biota constitute an integrated part of the nationalmonitoring activities in the marine environment as well as of the international programmeswithin ICES, OSPARCOM and HELCOM.The present report displays the timeseries of analysed contaminants in biota andsummarises the results from the statistical treatment. It does not in general give thebackground or explanations to significant changes found in the timeseries. Increasingconcentrations thus, urge for intensified studies.Short comments are given for temporal trends as well as for spatial variation and, for somecontaminants, differences in geometric mean concentration between various species caughtat the same site. Sometimes notes of seasonal variation and differences in concentrationbetween tissues in the same species are given. This information could say something aboutthe relative appropriateness of the sampled matrix and be of help in designing monitoringprogrammes. In the temporal trend part, an extract of the relevant findings is summarised inthe 'conclusion'-paragraph. It should be stressed though, that geographical differences maynot reflect antropogenic influence but may be due to factors like productivity, temperature,salinity etc.The report is continuously updated. The date of the latest update is reported at the beginningof each chapter. The creation date of each figure is written in the lower left corner.
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| 7. |
- Bignert, Anders, et al.
(författare)
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Comments Concerning the National Swedish Contaminant Monitoring Programme in Marine Biota, 2008
- 2008
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This report gives a summary of the monitoring activities within the national Swedish contaminant programme in marine biota. It is the result from the joint efforts of: the Department of Applied Environmental Science at Stockholm University (analyses of organochlorines), the Department of Environmental Assessment at Swedish University of Agricultural Sciences (analyses of heavy metals), Department of Chemistry at Umeå University (analyses of PCDD/PCDF) and the Department of Contaminant Research at the Swedish Museum of Natural History (co-ordination, sample collection administration, sample preparation, recording of biological variables, storage of frozen biological tissues in the Environmental Specimen Bank for retrospective studies, data preparation and statistical evaluation). The monitoring programme is financiated by the Environmental Protection Agency (EPA) in Sweden.The data of concern in this report represent the bioavailable part of the investigated contaminants i.e. the part that has virtually passed through the biological membranes and may cause toxic effects. The objectives of the monitoring program in marine biota could be summarised as follows:• to estimate the levels and the normal variation of various contaminants in marine biota from several representative sites, uninfluenced by local sources, along the Swedish coasts. The goal is to describe the general contaminant load and to supply reference values for regional and local monitoring programmes• to monitor long term time trends and to estimate the rate of found changes.quantified objective: to detect an annual change of 10% within a time period of 10 years with a power of 80% at a significance level of 5%.• to estimate the response in marine biota of measures taken to reduce the discharges of various contaminantsquantified objective: to detect a 50% decrease within a time period of 10 years with a power of 80% at a significance level of 5%.• to detect incidents of regional influence or widespread incidents of ‘Chernobyl’- character and to act as watchdog monitoring to detect renewed usage of banned contaminants.quantified objective: to detect an increase of 200% a single year with a power of 80% at a significance level of 5%.• to indicate large scale spatial differencesquantified objective: to detect differences of a factor 2 between sites with a power of 80% at a significance level of 5%.• to explore the development and regional differences of the composition and pattern of e.g. PCB’s, HCH’s and DDT’s as well as the ratios between various contaminants.• the time series are also relevant for human consumption since important commercial fish species like herring and cod are sampled. A co-operation with the Swedish Food Administration is established. Sampling is also co-ordinated with SSI (Swedish Radiation Protection Authority) for analysing radionuclides in fish and blue mussels (HELCOM, 1992).• all analysed, and a large number of additional specimens, of the annually systematically collected material are stored frozen in the Environmental Specimen Bank.. This invaluable4material enables future retrospective studies of contaminants impossible to analyse today as well as control analyses of suspected analytical errors.• although the programme is focused on contaminant concentration in biota, also the development of biological variables like e.g. condition factor (CF), liver somatic index (LSI) and fat content are monitored at all sites. At a few sites, integrated monitoring with fish physiology and population are running in co-operation with the University of Gothenburg and the Swedish Board of Fisheries.• experiences from the national programme with several time series of over 25 years can be used in the design of regional and local monitoring programmes.• the perfectly unique material of high quality and long time series is further used to explore relationships among biological variables and contaminant concentrations in various tissues; the effects of changes in sampling strategy, the estimates of variance components and the influence on the concept of power etc.• the accessibility of high quality data collected and analysed in a consistent manner is an indispensable prerequisite to evaluate the validity of hypothesis and models concerning the fate and distribution of various contaminants. It could furthermore be used as input of ‘real’ data in the ongoing model building activities concerning marine ecosystems in general and in the Baltic and North Sea environment in particular.• the contaminant programme in marine biota constitute an integrated part of the national monitoring activities in the marine environment as well as of the international programmes within ICES, OSPARCOM and HELCOM.The present report displays the timeseries of analysed contaminants in biota and summarises the results from the statistical treatment. It does not in general give the background or explanations to significant changes found in the timeseries. Increasing concentrations thus, urge for intensified studies.Short comments are given for temporal trends as well as for spatial variation and, for some contaminants, differences in geometric mean concentration between various species caught at the same site. Sometimes notes of seasonal variation and differences in concentration between tissues in the same species are given. This information could say something about the relative appropriateness of the sampled matrix and be of help in designing monitoring programmes. In the temporal trend part, an extract of the relevant findings is summarised in the 'conclusion'-paragraph. It should be stressed though, that geographical differences may not reflect antropogenic influence but may be due to factors like productivity, temperature, salinity etc.The report is continuously updated. The date of the latest update is reported at the beginning of each chapter. The creation date of each figure is written in the lower left corner.
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| 8. |
- Bignert, Anders, et al.
(författare)
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Temporal trends of Swedish environmental and human milk concentrations of dioxins, furans and dioxin-like PCBs, with forecasts to 2040
- 2020
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The report deals with temporal trends of measured concentrations of representative congenersof dioxin-like PCBs, dioxins (PCDDs) and furans (PCDFs) (here together called dioxins) inbiological samples from the Swedish marine and freshwater environment together with humanmilk and food.Dioxins are well-known for causing cancer, severe reproductive and developmental problems,damage the immune system and for interfering with hormonal systems. Dioxin exposure hasfurther been suggested to induce birth defects, reduced sperm counts, diabetes, learningdisabilities, immune system suppression, lung problems, skin disorders, lowered testosteronelevels and more.The data originates from national monitoring programs on contaminants financed by theSwedish Environmental Protection Agency (EPA) and accomplished by the Swedish FoodAgency (SFA), the Swedish Museum of Natural History (SMNH) and Stockholm University(SU). Temporal trends of the abovementioned chemicals have been studied, also, the trendshave been extrapolated in an attempt to forecast the situation during the coming 20 years.The present report focus on temporal trends and longer time series (often more than 2decades). Compilations that covers also shorter time-series, relations between variousbiological samples and geographical distribution can be found elsewhere. A thorough studydescribing the dioxin situation in the Baltic was carried out by the Swedish EPA 2013(Wiberg et al., 2013).
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| 9. |
- Boutachkov, P., et al.
(författare)
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High-spin isomers in 96Ag : excitations across the Z=38 and Z=50, N=50 closed shells
- 2011
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 84:4
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Tidskriftsartikel (refereegranskat)abstract
- Excited states in (96)Ag were populated in fragmentation of an 850-MeV/u (124)Xe beam on a 4-g/cm(2) Be target. Three new high-spin isomers were identified and the structure of the populated states was investigated. The level scheme of (96)Ag was established, and a spin parity of (13(-)), (15(+)), and (19(+)) was assigned to the new isomeric states. Shell-model calculations were performed in various model spaces, including pi nu(p(1/2), g(9/2), f(5/2), p(3/2)) and the large-scale shell-model space pi nu(gds), to account for the observed parity changing M2 and E3 transitions from the (13(-)) isomer and the E2 and E4 transitions from the (19(+)) core-excited isomer, respectively. The calculated level schemes and reduced transition strengths are found to be in very good agreement with the experiment.
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| 10. |
- Ekström, Magnus, et al.
(författare)
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Exertional breathlessness related to medical conditions in middle-aged people: the population-based SCAPIS study of more than 25,000 men and women.
- 2024
-
Ingår i: Respiratory research. - : BioMed Central (BMC). - 1465-993X .- 1465-9921. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- Breathlessness is common in the population and can be related to a range of medical conditions. We aimed to evaluate the burden of breathlessness related to different medical conditions in a middle-aged population.Cross-sectional analysis of the population-based Swedish CArdioPulmonary bioImage Study of adults aged 50-64years. Breathlessness (modified Medical Research Council [mMRC]≥2) was evaluated in relation to self-reported symptoms, stress, depression; physician-diagnosed conditions; measured body mass index (BMI), spirometry, venous haemoglobin concentration, coronary artery calcification and stenosis [computer tomography (CT) angiography], and pulmonary emphysema (high-resolution CT). For each condition, the prevalence and breathlessness population attributable fraction (PAF) were calculated, overall and by sex, smoking history, and presence/absence of self-reported cardiorespiratory disease.We included 25,948 people aged 57.5±[SD] 4.4; 51% women; 37% former and 12% current smokers; 43% overweight (BMI 25.0-29.9), 21% obese (BMI≥30); 25% with respiratory disease, 14% depression, 9% cardiac disease, and 3% anemia. Breathlessness was present in 3.7%. Medical conditions most strongly related to the breathlessness prevalence were (PAF 95%CI): overweight and obesity (59.6-66.0%), stress (31.6-76.8%), respiratory disease (20.1-37.1%), depression (17.1-26.6%), cardiac disease (6.3-12.7%), anemia (0.8-3.3%), and peripheral arterial disease (0.3-0.8%). Stress was the main factor in women and current smokers.Breathlessness mainly relates to overweight/obesity and stress and to a lesser extent to comorbidities like respiratory, depressive, and cardiac disorders among middle-aged people in a high-income setting-supporting the importance of lifestyle interventions to reduce the burden of breathlessness in the population.
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| 11. |
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| 12. |
- Fellström, Bengt, et al.
(författare)
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Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT) trial
- 2004
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Ingår i: Kidney International. - : Elsevier BV. - 0085-2538 .- 1523-1755. ; 66:4, s. 1549-1555
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hyperlipidemia is a risk factor for long-term renal transplant dysfunction, but no prospective clinical trials have investigated the effects of statin treatment on graft function in renal transplant recipients. The aim of the present study was to evaluate the effect of fluvastatin on long-term renal transplant function and development of chronic allograft nephropathy in the ALERT (Assessment of Lescol in Renal Transplantation) study. METHODS: ALERT was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40 mg and 80 mg daily, in renal transplant recipients. Patients were randomized to receive either fluvastatin (N= 1050) or placebo (N= 1052) and followed for five to six years. Renal end points included graft loss or doubling of serum creatinine or death; glomerular filtration rate (GFR) was also measured during follow-up in a subset of patients (N= 439). RESULTS: There were 283 patients (13.5%) with graft loss, mainly due to chronic rejection (82%), yielding an annual rate of 2.4%. Fluvastatin treatment significantly lowered mean low-density lipoprotein (LDL)-cholesterol levels by 32% (95% CI -33 to -30) compared with placebo, but had no significant effect on the incidence of renal graft loss or doubling of serum creatinine, or decline in GFR throughout follow-up in the whole study population. Neither was any treatment effect by fluvastatin found in any of the subgroups analyzed. CONCLUSION: Fluvastatin treatment significantly improves lipid values in renal transplant recipients but has no effect on graft loss or doubling of serum creatinine.
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| 13. |
- Georgsson, Jennie, et al.
(författare)
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Angiotensin II Pseudopeptides Containing 1,3,5-Trisubstituted Benzene Scaffolds with High AT2 Receptor Affinity
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:21, s. 6620-6631
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Tidskriftsartikel (refereegranskat)abstract
- Two 1,3,5-trisubstituted aromatic scaffolds intended to serve as γ-turn mimetics have been synthesized and incorporated in five pseudopeptide analogues of angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), replacing Val-Tyr-Ile, Val-Tyr, or Tyr-Ile. All the tested compounds exhibited nanomolar affinity for the AT2 receptor with the best compound (3) having a Ki of 1.85 nM. Four pseudopeptides were AT2 selective, while one (5) also exhibited good affinity for the AT1 receptor (Ki = 30.3 nM). This pseudopeptide exerted full agonistic activity in an AT2 receptor induced neurite outgrowth assay but displayed no agonistic effect in an AT1 receptor functional assay. Molecular modeling, using the program DISCOtech, showed that the high-affinity ligands could interact similarly with the AT2 receptor as other ligands with high affinity for this receptor. A tentative agonist model is proposed for AT2 receptor activation by angiotensin II analogues. We conclude that the 1,3,5-trisubstituted benzene rings can be conveniently prepared and are suitable as γ-turn mimics.
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| 14. |
- Georgsson, Jennie, et al.
(författare)
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Short pseudopeptides containing turn scaffolds with high AT(2) receptor affinity
- 2006
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 14:17, s. 5963-5972
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Tidskriftsartikel (refereegranskat)abstract
- Two pentapeptides, Ac-Tyr-Ile-His-Pro-Phe/Ile, were synthesized and shown to have angiotensin II AT(2) receptor affinity and agonistic activity. Based on these peptides, a new series of 13 pseudopeptides was synthesized via introduction of five different turn scaffolds replacing the Tyr-Ile amino acid residues. Pharmacological evaluation disclosed subnanomolar affinities for some of these compounds at the AT(2) receptor. Substitution of Phe by Ile in this series of ligands enhanced the AT(2) receptor affinity of all compounds. These results suggest that the C-terminal amino acid residues can be elaborated on to enhance the AT(2) receptor affinity in truncated Ang II analogues.
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| 15. |
- Georgsson, Jennie, et al.
(författare)
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Synthesis of a new class of druglike angiotensin II C-terminal mimics with affinity for the AT2 receptor
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:7, s. 1711-1715
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Tidskriftsartikel (refereegranskat)abstract
- Four tripeptides corresponding to the C-terminal region of angiotensin II were synthesized. One of these peptides (Ac-His-Pro-Ile) showed moderate binding affinity for the AT2 receptor. Two aromatic histidine-related scaffolds were synthesized and introduced in the tripeptides to give eight new peptidomimetic structures. Three of the new peptide-derived druglike molecules exhibited selective, nanomolar affinity for the AT2 receptor. These ligands may become lead compounds in the future development of novel classes of selective AT2 receptor agonists.
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| 16. |
- Glynn, Anders, et al.
(författare)
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Jämförelser av tidstrender av miljöföroreningarna PCBer, HCB, dioxiner, bromerade flamskyddsmedel och perfluorerade alkylsyror i biota och människa – vilka faktorer bidrar till skillnader?
- 2020
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Naturvårdsverket har under flera decennier, inom den nationella miljöövervakningen, undersökt tidstrender av bioackumulerande/biomagnifierande organiska miljöföroreningar (persistent organic pollutants, POPs) i biota och människor, eftersom POPs kan utgöra hälsorisker för djur och människor. Ett viktigt syfte med detta monitoreringsprogram är att följa miljötillståndet i Sverige. Programmet används också för att följa upp resultat av de åtgärder som vidtagits nationellt och internationellt för att begränsa POP-förororeningen av miljön. I denna rapport undersöks tidstrender av POPs i människor från Sverige (modersmjölk och blodserum), sillgrisslor från Östersjön (ägg) och sill/strömming (muskel och lever) från svenska ost- och västkusten, och dessa trender kopplas samman med de viktigaste nationella/internationella åtgärderna (lagstiftning, råd/rekommendationer, frivilliga åtgärder, mm) som införts för att begränsa utsläppen i miljön. Syftet är att undersöka om det finns samband mellan åtgärder och förändringar av tidstrender i biota och människor. De studerade POPs omfattar industrikemikalierna polyklorerade bifenyler (PCB), de oavsiktligt bildade föroreningarna polyklorerade dibenso-para-dioxiner och dibensofuraner (PCDD/F), fungiciden hexaklorbensen (HCB), de bromerade flamskyddsmedlen (BFR) polybromerade difenyletrar (PBDE) och hexabromcyklododekan (HBCDD), och industrikemikalierna per- och polyfluorerade alkylsubstanser (PFAS).Resultaten visar att nationella/internationella förbud av produktion och användning av PCB och HCB relativt snabbt resulterade i minskande halter i alla studerade matriser. Liknande effekter observerades efter mer eller mindre frivilliga utfasningar av produktion och användning av vissa BFR och PFAS. Halterna av PCDD/F, som förekom som förorening i tekniska PCB-blandningar, minskade också efter att förbud mot PCB-produktion och användning infördes. Detta visar att eliminering av primära källor för utsläpp i miljön är en mycket effektiv åtgärd, som relativt snabbt leder till sjunkande halter i biota och människor även när det gäller så pass svårnedbrytbara substanser som de studerade POPs.När de flesta viktiga primära källorna har eliminerats finns det dock sekundära källor som kan vara mycket svårare, eller helt omöjliga, att eliminera. Detta illustreras av HCB, som för närvarande tycks öka i vissa delar av den svenska miljön. Det har föreslagits att detta fenomen till viss del beror på avdunstning av HCB från förorenad mark i områden som har haft en historiskt högre användning av fungiciden än i Sverige. När det avdunstade HCB med vindarna når Sverige sker en deposition på grund av ett kallare klimat. Diffusa primära källor för PCDD/F, som nu tycks dominera i Sverige, är också svåra att åtgärda, vilket kan förklara varför minskningen av halterna i flera av de studerade matriserna nu verkar gå långsammare än tidigare.Resultaten visar också att stegvis eliminering av produktion och användning av några få substanser i taget inom en grupp av POPs är ineffektivt ur miljömässig synvinkel. Detta exemplifieras av de studerade BFR och PFAS, som i motsats till PCB inte har reglerats gruppvis. Stegvisa åtgärder ger en mycket mer utdragen förbättringsprocess i miljön, där minskande halter av reglerade substanser motverkas av ökande halter av oreglerade substanser med liknande egenskaper. För att undvika denna, ur miljöns synvinkel, utdragna process bör ämnen med liknande egenskaper inom en POP-grupp regleras samtidigt.För vissa av de undersökta POPs har olika delar av den svenska miljön ”svarat” olika snabbt på vidtagna åtgärder. För tetra-pentaBDE vändes en ökning av halter till en minskning mer än 10 år tidigare i sillgrissla och strömming/sill än i modersmjölk. Även om det inte klart går att bevisa, så kan detta bero på att det vidtogs regionala åtgärder i ett tidigt skede som hade positiv effekt på utsläpp i Östersjön utan att nämnvärt påverka den svenska befolkningens exponering. Tidstrenderna i modersmjölk följde istället i hög grad förändringarna i världsproduktion av dessa PBDE.De retrospektiva studierna av BFR och PFAS trender visar att en oreglerad ökning av världsproduktion och -användning har resulterat i exponentiella ökningar av föroreningen av den svenska miljön. Det är därför av yttersta vikt att reglerande myndigheter/organisationer och industrin tillsammans anstränger sig att införa effektiva och snabba åtgärder på global nivå som minimerar risken för framtida miljöproblem orsakade av hittills ”okända” substansgrupper med POP-liknande egenskaper.
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| 17. |
- Harrison, Dick, et al.
(författare)
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Djingis khan
- 2013
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Ingår i: Legendariska fältherrar : från Hannibal till Rommel. - 9789155259013 ; , s. 49-60
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Bokkapitel (populärvet., debatt m.m.)
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| 18. |
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| 19. |
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| 20. |
- Johannesson, Petra, et al.
(författare)
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Angiotensin II analogues encompassing 5,9-and 5,10-fused thiabicycloalkane tripeptide mimetics
- 1999
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 42:22, s. 4524-4537
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Tidskriftsartikel (refereegranskat)abstract
- A simple experimental procedure on solid phase for the construction of new tripeptidic 5,9- and 5,10-fused thiazabicycloalkane scaffolds that adopt beta-turns has been developed. This N-terminal-directed bicyclization, relying on masked aldehyde precurso
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| 21. |
- Johannesson, Petra, et al.
(författare)
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Vinyl sulfide cyclized analogues of angiotensin II with high affinity and full agonist activity at the AT(1) receptor
- 2002
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 45:9, s. 1767-1777
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Tidskriftsartikel (refereegranskat)abstract
- Vinyl sulfide cyclized analogues of the octapeptide angiotensin II that are structurally related to the cyclic disulfide agonist c[Hcy(3,5)]Ang II have been prepared. The synthesis relies on the reaction of the mercapto group of a cysteine residue in position 3 with the formyl group of allysine incorporated in position 5 of angiotensin II. A mixture of the cis and the trans isomers was formed, and these were separated and isolated by RP-HPLC. Thus, the three-atom CH(2)[bond]S[bond]S element of the AT(1) receptor agonist c[Hcy(3,5)]Ang II has been displaced by a bioisosteric three-atom S[bond]CH[double bond]CH element. A comparative conformational analysis of the 13-membered ring systems of c[Hcy(3,5)]Ang II and the 13-membered cyclic vinyl sulfides with cis and trans configuration, respectively, suggested that all three systems adopted very similar low-energy conformations. This similarity was also reflected in the bioactivity. Both of the compounds that contained the ring systems encompassing the cis or trans vinyl sulfide elements between positions 3 and 5 exhibited K(i) values less than 2 nM and exerted full agonism at the AT(1) receptor. In contrast, vinyl sulfide cyclization involving the amino acid residues 5 and 7 rendered inactive compounds. The cyclic vinyl sulfides that have agonist activity were both shown to possess low-energy conformers compatible with the previously proposed 3D model for the bioactive conformation of Ang II.
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| 22. |
- Johansson, Jarkko, et al.
(författare)
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Longitudinal evidence that reduced hemispheric encoding/retrieval asymmetry predicts episodic-memory impairment in aging
- 2020
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Ingår i: Neuropsychologia. - : Elsevier BV. - 0028-3932 .- 1873-3514. ; 137
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Tidskriftsartikel (refereegranskat)abstract
- The HERA (Hemispheric Encoding/Retrieval Asymmetry) model captures hemispheric lateralization of prefrontal cortex (PFC) brain activity during memory encoding and retrieval. Reduced HERA has been observed in cross-sectional aging studies, but there is no longitudinal evidence, to our knowledge, on age-related changes in HERA and whether maintained or reduced HERA relates to well-preserved memory functioning. In the present study we set out to explore HERA in a longitudinal neuroimaging sample from the Betula study [3 Waves over 10 years; Wave-1: n = 363, W2: n = 227, W3: n = 101]. We used fMRI data from a face-name paired-associates task to derive a HERA index. In support of the HERA model, the mean HERA index was positive across the three imaging waves. The longitudinal age-HERA relationship was highly significant (p < 10(-11)), with a HERA decline occurring after age 60. The age-related HERA decline was associated with episodic memory decline (p < 0.05). Taken together, the findings provide large-scale support for the HERA model, and suggest that reduced HERA in the PFC reflects pathological memory aging possibly related to impaired ability to bias mnemonic processing according to the appropriate encoding or retrieval state.
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| 23. |
- Johansson, Jarkko, et al.
(författare)
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Model of brain maintenance reveals specific change-change association between medial-temporal lobe integrity and episodic memory
- 2022
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Ingår i: Aging Brain. - : Elsevier. - 2589-9589. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Brain maintenance has been identified as a major determinant of successful memory aging. However, the extent to which brain maintenance in support of successful memory aging is specific to memory-related brain regions or forms part of a brain-wide phenomenon is unresolved. Here, we used longitudinal brain-wide gray matter MRI volumes in 262 healthy participants aged 55 to 80 years at baseline to investigate separable dimensions of brain atrophy, and explored the links of these dimensions to different dimensions of cognitive change. We statistically adjusted for common causes of change in both brain and cognition to reveal a potentially unique signature of brain maintenance related to successful memory aging. Critically, medial temporal lobe (MTL)/hippocampal change and episodic memory change were characterized by unique, residual variance beyond general factors of change in brain and cognition, and a reliable association between these two residualized variables was established (r = 0.36, p < 0.01). The present study is the first to provide solid evidence for a specific association between changes in (MTL)/hippocampus and episodic memory in normal human aging. We conclude that hippocampus-specific brain maintenance relates to the specific preservation of episodic memory in old age, in line with the notion that brain maintenance operates at both general and domain-specific levels.
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| 24. |
- Lindman, Susanna, et al.
(författare)
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Synthesis, receptor binding affinities and conformational properties of cyclic methylenedithioether analogues of angiotensin II
- 2001
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 9:3, s. 763-772
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Tidskriftsartikel (refereegranskat)abstract
- Cyclic 12-, 13- and 14-membered ring angiotensin II analogues related to disulfides but encompassing methylenedithioether bridges have been prepared. The affinity data from these derivatives were compared to those from the disulfides. The methylenedithioether analogues displayed good binding affinities to rat liver AT1 receptors although in most cases somewhat lower than their disulfide counterparts. One of the methylenedithioethers with a 13-membered ring system demonstrated the highest binding affinity among the thioethers. Theoretical conformational analysis of model compounds of the two series were performed suggesting a similarity between the disulfide and the corresponding methylenedithioether analogues and also between the ring size homologues. This analysis also suggested that some of the model compounds were prone to adopt inverse γ-turn conformations, which was further supported by use of NMR spectroscopy of the 12-membered ring analogue in the series. The easily executed methylenedithioether cyclization should constitute a valuable complement to the common disulfide methodology for fine-tuning and for probing the bioactive conformation of peptides.
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| 25. |
- Micke, Patrick, et al.
(författare)
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Gene Copy Number Aberrations Are Associated with Survival in Histologic Subgroups of Non-small Cell Lung Cancer
- 2011
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Ingår i: Journal of Thoracic Oncology. - 1556-0864 .- 1556-1380. ; 6:11, s. 1833-1840
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Non-small cell lung cancer (NSCLC) is characterized by a multitude of genetic aberrations with unknown clinical impact. In this study, we aimed to identify gene copy number changes that correlate with clinical outcome in NSCLC. To maximize the chance to identify clinically relevant events, we applied a strategy involving two prognostically extreme patient groups. Methods: Short-term (<20 month; n = 53) and long-term survivors (>58 month; n = 47) were selected from a clinically well-characterized NSCLC patient cohort with available fresh frozen tumor specimens. The samples were analyzed using high-resolution single-nucleotide polymorphism array technology to assess gene copy number variations and array-based gene expression profiling. The molecular data were combined with information on clinical parameters. Results: Genetic aberrations were strongly associated with tumor histology. In adenocarcinoma (n = 50), gene copy number gains on chromosome 8q21-q24.3 (177 genes) were more frequent in long-term than in short-term survivors. In squamous cell carcinoma (n = 28), gains on chromosome 14q23.1-24.3 (133 genes) were associated with shorter survival, whereas losses in a neighboring region, 14q31.1-32.33 (110 genes), correlated with favorable outcome. In accordance with copy number gains and losses, messenger RNA expression levels of corresponding genes were increased or decreased, respectively. Conclusion: Comprehensive tumor profiling permits the integration of genomic, histologic, and clinical data. We identified gene copy number gains and losses, with corresponding changes in messenger RNA levels that were associated with prognosis in adenocarcinoma and squamous cell carcinoma of the lung.
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| 26. |
- Nyberg, Anders, et al.
(författare)
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Abdominal aortic aneurysm and cytomegalovirus infection
- 2008
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Ingår i: Journal of Medical Virology. - : Wiley. - 1096-9071 .- 0146-6615. ; 80:4, s. 667-669
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Tidskriftsartikel (refereegranskat)abstract
- Cytomegalovirus (CMV) has been implicated in the pathogenesis of atherosclerosis. Abdominal aortic aneurysm is regarded traditionally as a consequence of atherosclerosis. Several microorganisms have been suggested as possible contributing factors for the development of abdominal aortic aneurysm. The relevance of CMV in the processes underlying the development, expansion, and rupture of abdominal aortic aneurysm is unknown. The aim of the present study was to investigate whether CMV infection is related to abdominal aortic aneurysm rupture. One hundred nineteen patients with abdominal aortic aneurysm and 36 matched controls without abdominal aortic aneurysm were investigated prospectively by CMV serology. Patients with ruptured abdominal aortic aneurysm have similar levels of IgG antibodies against CMV as patients with nonruptured abdominal aortic aneurysm, small abdominal aortic aneurysm, and controls without abdominal aortic aneurysm. In conclusion, this study fails to demonstrate a connection between CMV infection and abdominal aortic aneurysm rupture.
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| 27. |
- Nyberg, Anders, et al.
(författare)
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Abdominal aortic aneurysm and infection with CagA positive strains of Helicobacter pylori
- 2008
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Ingår i: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 1651-1980 .- 0036-5548. ; 40:3, s. 204-207
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate whether virulent CagA positive Helicobacter pylori strains are those preferentially related to abdominal aortic aneurysm (AAA) rupture. Several microorganisms have been linked to aneurysm development. Chronic Chlamydophila pneumoniae infection has been suggested as a possible contributing factor for the development and expansion of AAA. Previous studies have shown increased risk of carotid atherosclerosis and coronary heart disease in subjects harbouring CagA positive strains of H. pylori. The relevance of CagA positive H. pylori involved in the processes underlying aneurysmal development, expansion, and rupture is unknown. In a case-control study, 119 patients with AAA and 36 matched controls were prospectively investigated with H. pylori serology. Patients with ruptured AAA have similar levels of IgG antibodies against H. pylori to patients with electively operated AAA, small AAA, and controls. In conclusion, this study fails to demonstrate a connection between H. pylori CagA seropositivity and abdominal aortic aneurysm rupture.
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| 28. |
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| 29. |
- Nyberg, Anders, et al.
(författare)
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Lack of association between Chlamydophila pneumoniae seropositivity and abdominal aortic aneurysm.
- 2007
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Ingår i: Vascular and Endovascular Surgery. - : SAGE Publications. - 1538-5744 .- 1938-9116. ; 41:3, s. 246-8
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Tidskriftsartikel (refereegranskat)abstract
- Chronic Chlamydophila pneumoniae infection has been suggested as a possible contributing factor for the development and expansion of abdominal aortic aneurysm (AAA). The relevance of C pneumoniae involved in the processes underlying aneurysmal rupture is unknown. The aim of this study was to examine the relationship between C pneumoniae seropositivity and AAA rupture. In a case-control study, 119 patients with AAA and 36 matched controls were prospectively investigated with C pneumoniae serology. Patients with ruptured AAA have similar levels of IgG antibodies against C pneumoniae as patients with an electively operated AAA, a small AAA, and controls. In conclusion, this study fails to demonstrate a connection between C pneumoniae seropositivity and AAA rupture.
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| 30. |
- Nyberg, Lars, et al.
(författare)
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Educational attainment does not influence brain aging
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 118:18
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Tidskriftsartikel (refereegranskat)abstract
- Education has been related to various advantageous lifetime outcomes. Here, using longitudinal structural MRI data (4,422 observations), we tested the influential hypothesis that higher education translates into slower rates of brain aging. Cross-sectionally, education was modestly associated with regional cortical volume. However, despite marked mean atrophy in the cortex and hippocampus, education did not influence rates of change. The results were replicated across two independent samples. Our findings challenge the view that higher education slows brain aging.
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| 31. |
- Nyberg, Lars, 1966-, et al.
(författare)
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Forecasting memory function in aging : pattern-completion ability and hippocampal activity relate to visuospatial functioning over 25 years
- 2020
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 94, s. 217-226
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Tidskriftsartikel (refereegranskat)abstract
- Heterogeneity in episodic memory functioning in aging was assessed with a pattern-completion functional magnetic resonance imaging task that required reactivation of well-consolidated face-name memory traces from fragmented (partial) or morphed (noisy) face cues. About half of the examined individuals (N = 101) showed impaired (chance) performance on fragmented faces despite intact performance on complete and morphed faces, and they did not show a pattern-completion response in hippocampus or the examined subfields (CA1, CA23, DGCA4). This apparent pattern-completion deficit could not be explained by differential hippocampal atrophy. Instead, the impaired group displayed lower cortical volumes, accelerated reduction in mini-mental state examination scores, and lower general cognitive function as defined by longitudinal measures of visuospatial functioning and speed-of-processing. In the full sample, inter-individual differences in visuospatial functioning predicted performance on fragmented faces and hippocampal CA23 subfield activity over 25 years. These findings suggest that visuospatial functioning in middle age can forecast pattern-completion deficits in aging.
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| 32. |
- Nyberg, Lars, 1966-, et al.
(författare)
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Frontal Contribution to Hippocampal Hyperactivity During Memory Encoding in Aging
- 2019
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Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media S.A.. - 1662-5099. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Hippocampal hypo- as well as hyper-activation have been reported during memory encoding in older individuals. Prefrontal cortex (PFC) provides top-down state signals to the hippocampus that bias its computation during memory encoding and retrieval, and disturbed top-down signals could contribute to hippocampal hyper-activation. Here, we used >500 cross-sectional and longitudinal observations from a face-name encoding-retrieval fMRI task to examine hippocampal hypo-and hyper-activation in aging. Age-related anterior hippocampal hypo-activation was observed during memory encoding. Next, older individuals who longitudinally dropped-out were compared with those who remained in the study. Older dropouts had lower memory performance and higher dementia risk, and hyper-activated right anterior and posterior hippocampus during memory encoding. During encoding, the dropouts also activated right prefrontal regions that instead were active during retrieval in younger and older remainers. Moreover, the dropouts showed altered frontal-hippocampal functional connectivity, notably elevated right PFC to anterior hippocampus (aHC) connectivity during encoding. In the context of a general pattern of age-related anterior hippocampal hypo-activation during encoding, these findings support a top-down contribution to paradoxically high anterior hippocampal activity in older dropouts who were at elevated risk of pathology.
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| 33. |
- Nyberg, Lars, 1966-, et al.
(författare)
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Individual differences in brain aging : heterogeneity in cortico-hippocampal but not caudate atrophy rates
- 2023
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Ingår i: Cerebral Cortex. - : Oxford University Press. - 1047-3211 .- 1460-2199. ; 33:9, s. 5075-5081
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Tidskriftsartikel (refereegranskat)abstract
- It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.
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| 34. |
- Nyberg, Martin, et al.
(författare)
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PCA3 as a diagnostic marker for prostate cancer: A validation study on a Swedish patient population.
- 2010
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Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 1651-2065 .- 0036-5599. ; 44, s. 378-383
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Objective. Prostate cancer antigen 3 in urine (uPCA3) has been shown to perform better than total prostate-specific antigen in serum (tPSA) to predict prostate cancer (PCa) detection. The aim of this study was to validate the diagnostic precision of uPCA3 in a mixed set of patients with no previous history of PCa, including patients with previous negative biopsies. Material and methods. The study included 62 men scheduled for prostate biopsy at Skåne University Hospital Malmö, Sweden. Urine samples were obtained according to the Progensa™ uPCA3 assay. Logistic regression and receiver operating characteristic curves were used to test associations between levels of biomarkers and prostate cancer. Results. According to pathological examination of core needle biopsies, PCa was found in 18 out of 62 patients. A one-step increase in uPCA3 was associated with an increase in the odds of cancer of 1.026 (p = 0.005). Differences in the odds ratio between uPCA3 and tPSA were not statistically significant. A model using both markers did not increase prediction of event. Areas under the curve for uPCA3, tPSA and a model combining uPCA3 and tPSA did not differ significantly. No significant correlation was found between uPCA3 and tPSA or prostate volume. Conclusion. In this small set of mixed patients uPCA3 alone and tPSA performed equally well as diagnostic markers for PCa. A combination of the two markers did not improve the diagnostic performance. This study does not support a role for the uPCA3 urine test to replace or be added to tPSA in PCa detection.
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| 35. |
- Rosenström, Ulrika, et al.
(författare)
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A Selective AT2 Receptor Ligand with a γ-Turn-Like Mimetic replacing the Amino Acid Residues 4-5 of Angiotensin II
- 2004
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:4, s. 859-870
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Tidskriftsartikel (refereegranskat)abstract
- Three angiotensin II (Ang II) analogues encompassing a benzodiazepine-based γ-turn-like scaffold have been synthesized. Evaluation of the compounds in a radioligand binding assay showed that they had no affinity to the rat liver AT1 receptor. However, one of the compounds displayed considerable affinity to the pig uterus AT2 receptor (Ki = 3.0 nM) while the other two lacked affinity to this receptor. It was hypothesized that the reason for the inactivity of one of these analogues to the AT2 receptor was that the guanidino group of the Arg2 residue and/or the N-terminal end of the pseudopeptide could not interact optimally with the receptor. To investigate this hypothesis, a conformational analysis was performed and a comparison was carried out with the monocyclic methylenedithioether analogue cyclo(S−CH2−S)[Cys3,5]Ang II which is known to bind with high affinity to the AT2 receptor (Ki = 0.62 nM). This comparison showed that, in the compounds with high AT2 receptor affinity, the guanidino group of the Arg2 residue and the N-terminal end could access common regions of space that were not accessible to the inactive compound. To examine the importance of the guanidino group for binding, the Arg side chain was removed by substituting Arg2 for Ala2 in the analogue having the high affinity. This analogue lacked affinity to AT2 receptors, which supports the role of the guanidino group in receptor binding.
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| 36. |
- Rosenström, Ulrika, et al.
(författare)
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Design, synthesis, and incorporation of a beta-turn mimetic in angiotensin II forming novel pseudopeptides with affinity for AT(1) and AT(2) receptors
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:20, s. 6133-6137
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Tidskriftsartikel (refereegranskat)abstract
- A benzodiazepine-based beta-turn mimetic has been designed, synthesized, and incorporated into angiotensin II. Comparison of the mimetic with beta-turns in crystallized proteins showed that it most closely resembles a type II beta-turn. The compounds exhibited high to moderate binding affinity for the AT(2) receptor, and one also displayed high affinity for the AT(1) receptor. Molecular modeling showed that the high-affinity compounds could be incorporated into a previously derived model of AT(2) receptor ligands.
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| 37. |
- Rosenström, Ulrika, et al.
(författare)
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New selective AT2 receptor ligands encompassing a γ-turn mimetic replacing the amino acid residues 4-5 of angiotensin II act as agonists
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:12, s. 4009-4024
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Tidskriftsartikel (refereegranskat)abstract
- New benzodiazepine-based γ-turn mimetics with one or two amino acid side chains were synthesized. The γ-turn mimetics were incorporated into angiotensin II (Ang II) replacing the Val3-Tyr4-Ile5 or Tyr4-Ile5 peptide segments. All of the resulting pseudopeptides displayed high AT2/AT1 receptor selectivity and exhibited AT2 receptor affinity in the low nanomolar range. Molecular modeling was used to investigate whether the compounds binding to the AT2 receptor could position important structural elements in common areas. A previously described benzodiazepine-based γ-turn mimetic with high affinity for the AT2 receptor was also included in the modeling. It was found that the molecules, although being structurally quite different, could adopt the same binding mode/interaction pattern in agreement with the model hypothesis. The pseudopeptides selected for agonist studies were shown to act as AT2 receptor agonists being able to induce outgrowth of neurite cells, stimulate p42/p44mapk, and suppress proliferation of PC12 cells.
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| 38. |
- Rosenström, Ulrika, et al.
(författare)
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Synthesis and AT2 receptor-binding properties of angiotensin II analogues
- 2004
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Ingår i: Journal of Peptide Research. - : Wiley. - 1397-002X .- 1399-3011. ; 64:5, s. 194-201
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Tidskriftsartikel (refereegranskat)abstract
- The present study investigates the importance of the amino acid side chains in the octapeptide angiotensin II (Ang II) for binding to the AT2 receptor. A Gly scan was performed where each amino acid in Ang II was substituted one-by-one with glycine. The resulting set of peptides was tested for affinity to the AT2 receptor (porcine myometrial membranes). For a comparison, the peptides were also tested for affinity to the AT1 receptor (rat liver membranes). Only the substitution of Arg2 reduced affinity to the AT2 receptor considerably (92-fold when compared with Ang II). For the other Gly-substituted analogues the affinity to the AT2 receptor was only moderately affected. To further investigate the role of the Arg2 side chain for receptor binding, we synthesized some N-terminally modified Ang II analogues. According to these studies a positive charge in the N-terminal end of angiotensin III [Ang II (2–8)] is not required for high AT2 receptor affinity but seems to be more important in Ang II. With respect to the AT1 receptor, [Gly2]Ang II and [Gly8]Ang II lacked binding affinity (Ki > 10 μm). Replacement of the Val3 or Ile5 residues with Gly produced only a slight decrease in affinity. Interestingly, substitution of Tyr4 or His6, which are known to be very important for AT1 receptor binding, resulted in only 48 and 14 times reduction in affinity, respectively.
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| 39. |
- Salami, Alireza, et al.
(författare)
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Longitudinal Evidence for Dissociation of Anterior and Posterior MTL Resting-State Connectivity in Aging : Links to Perfusion and Memory
- 2016
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Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 26:10, s. 3953-3963
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Tidskriftsartikel (refereegranskat)abstract
- Neuroimaging studies of spontaneous signal fluctuations as measured by resting-state functional magnetic resonance imaging have revealed age-related alterations in the functional architecture of brain networks. One such network is located in the medial temporal lobe (MTL), showing structural and functional variations along the anterior-posterior axis. Past cross-sectional studies of MTL functional connectivity (FC) have yielded discrepant findings, likely reflecting the fact that specific MTL subregions are differentially affected in aging. Here, using longitudinal resting-state data from 198 participants, we investigated 5-year changes in FC of the anterior and posterior MTL. We found an opposite pattern, such that the degree of FC within the anterior MTL declined after age 60, whereas elevated FC within the posterior MTL was observed along with attenuated posterior MTL-cortical connectivity. A significant negative change-change relation was observed between episodic-memory decline and elevated FC in the posterior MTL. Additional analyses revealed age-related cerebral blood flow (CBF) increases in posterior MTL at the follow-up session, along with a positive relation of elevated FC and CBF, suggesting that elevated FC is a metabolically demanding alteration. Collectively, our findings indicate that elevated FC in posterior MTL along with increased local perfusion is a sign of brain aging that underlie episodic-memory decline.
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| 40. |
- Schmidt, Boris, et al.
(författare)
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Design, synthesis, and biological activities of four angiotensin IIreceptor ligands with gamma-turn mimetics replacing amino acid residues 3-5
- 1997
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 40, s. 903-919
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Tidskriftsartikel (refereegranskat)abstract
- Disulfide cyclization is a powerful method for reducing the conformational space of a peptide. This in turn may enable the study of its bioactive conformation. Several analogues of angiotensin II (Ang II) containing a disulfide bridge between amino acids 3 and 5 have been reported. Among these the cyclic octapeptides c[Hcy3,5]-Ang II, c[Cys3,5]-Ang II, and c[Pen 3,5]-Ang II showed significant activity at Ang II receptors. We have performed conformational analysis studies using theoretical calculations and 1H-NMR spectroscopy on tripeptide model compounds of these cyclic octapeptides which show that the cyclic moieties of c[Cys3,5]-Ang II and c[Pen3,5]-Ang II preferentially assume an inverse gamma-turn conformation. On the basis of these results, we substituted amino acid residues 3-5 in Ang II with two different gamma-turn mimetics giving four diastereomeric Ang II analogues. Interestingly, two of these are equipotent to Ang II in binding to AT1 receptors. In the contractile test using rabbit aorta rings, one of the analogues is an agonist with full contractile activity approximately equipotent to c[Pen3,5]-Ang II but 300-fold less potent than Ang II. This low potency may suggest that Ang II does not adopt a gamma-turn in the 3-5 region when interacting with the receptor.
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| 41. |
- Semb, Gunvor, et al.
(författare)
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A Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 1. Planning and management.
- 2017
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Ingår i: Journal of Plastic Surgery and Hand Surgery. - : Taylor & Francis. - 2000-656X .- 2000-6764. ; 51:1, s. 2-13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Longstanding uncertainty surrounds the selection of surgical protocols for the closure of unilateral cleft lip and palate, and randomised trials have only rarely been performed. This paper is an introduction to three randomised trials of primary surgery for children born with complete unilateral cleft lip and palate (UCLP). It presents the protocol developed for the trials in CONSORT format, and describes the management structure that was developed to achieve the long-term engagement and commitment required to complete the project.METHOD: Ten established national or regional cleft centres participated. Lip and soft palate closure at 3-4 months, and hard palate closure at 12 months served as a common method in each trial. Trial 1 compared this with hard palate closure at 36 months. Trial 2 compared it with lip closure at 3-4 months and hard and soft palate closure at 12 months. Trial 3 compared it with lip and hard palate closure at 3-4 months and soft palate closure at 12 months. The primary outcomes were speech and dentofacial development, with a series of perioperative and longer-term secondary outcomes.RESULTS: Recruitment of 448 infants took place over a 9-year period, with 99.8% subsequent retention at 5 years.CONCLUSION: The series of reports that follow this introductory paper include comparisons at age 5 of surgical outcomes, speech outcomes, measures of dentofacial development and appearance, and parental satisfaction. The outcomes recorded and the numbers analysed for each outcome and time point are described in the series.TRIAL REGISTRATION: ISRCTN29932826.
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| 42. |
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| 43. |
- Vikner, Tomas, 1990-
(författare)
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Cerebral arterial pulsatility imaging using 4D flow MRI : methodological development and applications in brain aging
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 4D flow magnetic resonance imaging (MRI) is increasingly recognizedas a versatile tool to assess arterial and venous hemodynamics. Cerebral arterial pulsatility is typically assessed by analyzing flow waveforms over the cardiac cycle, where flow amplitude is a function of cardiac output, central arterial stiffness, and cerebrovascular resistance and compliance. Excessive pulsatility may propagate to the cerebral microcirculation, and constitute a harmful mechanism for the brain. Indeed, imaging studies have linked arterial pulsatility to hippocampus volume, cerebral small vessel disease (SVD), and Alzheimer’s disease (AD). In animal models, elevated pulsatility leads to blood-brain barrier (BBB) leakage, capillary loss, and cognitive decline. However, associations to cerebrovascular lesions and brain function in the spectrum of normal aging are less investigated. Further, previous 4D flow studies have mainly assessed pulsatility in relatively large cerebral arteries. When exploring links to microvascular damage and brain function, more distal measurements, closer to the microcirculation, are desired. This thesis aimed to develop 4D flow MRI post-processing methods to obtain pulsatile waveforms in small, distal cerebral arteries with noisy velocity data and a complex vascular anatomy, and to evaluate pulsatility (primarily assessed by the pulsatility index) in relation to aging, brain function, and other imaging biomarkers of cerebrovascular damage, with particular dedication towards the hippocampus and cerebral SVD. To assess pulsatility in distal cerebral arteries, a post-processing method that automatically samples waveforms from numerous small arteries, to obtain a whole-brain representation of the distal arterial waveform, was developed (Paper I). We demonstrated the importance of averaging flow waveforms along multiple vessel segments to avoid overestimations in the pulsatility index, showed agreement with reference methods, and linked distal arterial pulsatility to age. To explore links to hippocampal function, we evaluated pulsatility in relation to cognition, hemodynamic low-frequency oscillations (LFOs), perfusion, and hippocampus volume (Paper II). We found that higher pulsatility was linked to worse hippocampus-sensitive episodic memory, weaker hippocampal LFOs, and lower whole-brain perfusion. These findings aligned with models suggesting that hippocampal microvessels could be particularly susceptible to pulsatile stress.To inform on SVD pathophysiology, we evaluated 5-year associations among pulsatility, white matter lesions (WMLs) and perivascular space (PVS) dilation, using mixed models, factor analysis, and change score models (Paper III). Lead-lag analyses indicated that, while pulsatility at baseline could not predict WML nor PVS progression, WML and PVS volumes at baseline predicted 5-year pulsatility-increases. These findings indicate that individuals with a higher load of cerebrovascular damage are more prone to see increased pulsatility over time, and suggest that high pulsatility is a manifestation, rather a risk factor, for cerebral SVD. To shed light on the potential role of BBB leakage in aging and SVD, we used dynamic contrast enhanced (DCE) MRI and intravenous gadolinium injections to quantify BBB permeability (Paper IV). We found stepwise increases in permeability from healthy white matter to WMLs, supporting that BBB leakages are implicated in SVD. However, hippocampal BBB permeability was unrelated to age, indicating that this capillary property is maintained in aging. Finally, arterial pulsatility was unrelated to BBB permeability in WMLs and in the hippocampus, providing no evidence of excessive pulsatility as a trigger of BBB leakage. In conclusion, distal arterial pulsatility measurements are reliable when averaging 4D flow waveforms over a large number of vessels. Pulsatility increases with age, and individuals with more cerebrovascular lesions are prone to see larger increases over time. Pulsatility is negatively related to perfusion and hippocampal function. However, the temporal dynamics among the SVD biomarkers, and the absence of pulsatility–permeability associations, challenge the concept of excessive pulsatility as a trigger of microvascular damage. Future studies are needed to understand whether altered cerebral hemodynamics play a causal role in cognitive decline and dementia. Meanwhile, 4D flow hemodynamic parameters could be useful as biomarkers related to vessel properties and cerebrovascular health.
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| 44. |
- Vikner, Tomas, et al.
(författare)
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Cerebral arterial pulsatility is linked to hippocampal microvascular function and episodic memory in healthy older adults
- 2021
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016. ; 41:7, s. 1778-1790
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Tidskriftsartikel (refereegranskat)abstract
- Microvascular damage in the hippocampus is emerging as a central cause of cognitive decline and dementia in aging. This could be a consequence of age-related decreases in vascular elasticity, exposing hippocampal capillaries to excessive cardiac-related pulsatile flow that disrupts the blood-brain barrier and the neurovascular unit. Previous studies have found altered intracranial hemodynamics in cognitive impairment and dementia, as well as negative associations between pulsatility and hippocampal volume. However, evidence linking features of the cerebral arterial flow waveform to hippocampal function is lacking. We used a high-resolution 4D flow MRI approach to estimate global representations of the time-resolved flow waveform in distal cortical arteries and in proximal arteries feeding the brain in healthy older adults. Waveform-based clustering revealed a group of individuals featuring steep systolic onset and high amplitude that had poorer hippocampus-sensitive episodic memory (p = 0.003), lower whole-brain perfusion (p = 0.001), and weaker microvascular low-frequency oscillations in the hippocampus (p = 0.035) and parahippocampal gyrus (p = 0.005), potentially indicating compromised neurovascular unit integrity. Our findings suggest that aberrant hemodynamic forces contribute to cerebral microvascular and hippocampal dysfunction in aging.
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| 45. |
- Vikner, Tomas, et al.
(författare)
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Characterizing pulsatility in distal cerebral arteries using 4D flow MRI
- 2020
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016. ; 40:12, s. 2429-2440
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Tidskriftsartikel (refereegranskat)abstract
- Recent reports have suggested that age-related arterial stiffening and excessive cerebral arterial pulsatility cause blood-brain barrier breakdown, brain atrophy and cognitive decline. This has spurred interest in developing non-invasive methods to measure pulsatility in distal vessels, closer to the cerebral microcirculation. Here, we report a method based on four-dimensional (4D) flow MRI to estimate a global composite flow waveform of distal cerebral arteries. The method is based on finding and sampling arterial waveforms from thousands of cross sections in numerous small vessels of the brain, originating from cerebral cortical arteries. We demonstrate agreement with internal and external reference methods and show the ability to capture significant increases in distal cerebral arterial pulsatility as a function of age. The proposed approach can be used to advance our understanding regarding excessive arterial pulsatility as a potential trigger of cognitive decline and dementia.
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| 46. |
- Walhovd, Kristine B., et al.
(författare)
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Neurodevelopmental origins of lifespan changes in brain and cognition
- 2016
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 113:33, s. 9357-9362
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Tidskriftsartikel (refereegranskat)abstract
- Neurodevelopmental origins of functional variation in older age are increasingly being acknowledged, but identification of how early factors impact human brain and cognition throughout life has remained challenging. Much focus has been on age-specific mechanisms affecting neural foundations of cognition and their change. In contrast to this approach, we tested whether cerebral correlates of general cognitive ability (GCA) in development could be extended to the rest of the lifespan, and whether early factors traceable to prenatal stages, such as birth weight and parental education, may exert continuous influences. We measured the area of the cerebral cortex in a longitudinal sample of 974 individuals aged 4-88 y (1,633 observations). An extensive cortical region was identified wherein area related positively to GCA in development. By tracking area of the cortical region identified in the child sample throughout the lifespan, we showed that the cortical change trajectories of higher and lower GCA groups were parallel through life, suggesting continued influences of early life factors. Birth weight and parental education obtained from the Norwegian Mother-Child Cohort study were identified as such early factors of possible lifelong influence. Support for a genetic component was obtained in a separate twin sample (Vietnam Era Twin Study of Aging), but birth weight in the child sample had an effect on cortical area also when controlling for possible genetic differences in terms of parental height. Our results provide novel evidence for stability in brain-cognition relationships throughout life, and indicate that early life factors impact brain and cognition for the entire life course.
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| 47. |
- Zhou, Yihui, et al.
(författare)
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Chlorinated Paraffins in Human Milk from Urban Sites in China, Sweden, and Norway
- 2020
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 54:7, s. 4356-4366
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Tidskriftsartikel (refereegranskat)abstract
- Short-, medium-, and long-chain chlorinated paraffins (SCCPs, MCCPs, and LCCPs) were analyzed in human milk from the Yangtze River Delta (YRD) and Scandinavia. Individual samples were collected from Shanghai, Jiaxing, and Shaoxing (China), Stockholm (Sweden), and Bodø (Norway) between 2010 and 2016. Mean concentrations (range) of SCCPs, MCCPs, and LCCPs in samples from the YRD were 124 [-1 fat, respectively, all of which were significantly (p < 0.05) higher than 15.9 (-1 fat, respectively, in samples from Scandinavia. MCCPs predominate in most samples, and LCCP concentrations exceed reported for polybrominated diphenyl ethers in human milk from the same regions. This study is the first to confirm LCCP exposure via breastfeeding. Principal component analysis showed that the YRD samples were more influenced by SCCPs than the Scandinavian samples, which mirror different exposures to CPs between the regions. Because of a large variation in concentrations among individuals, SCCP intake via breastfeeding indicated a potential health concern in the 90th percentile among Chinese infants. Further, CP concentrations in the YRD samples from first-time mothers were on average three times higher than from second-time mothers. In order to limit the worldwide CP contamination, the inclusion of SCCPs as persistent organic pollutants in the Stockholm Convention needs to be followed up, with the inclusion of MCCPs and LCCPs as well.
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| 48. |
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| 49. |
- Akkoyun, S., et al.
(författare)
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AGATA - Advanced GAmma Tracking Array
- 2012
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Ingår i: Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. - : Elsevier BV. - 0168-9002 .- 0167-5087 .- 1872-9576. ; 668, s. 26-58
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Tidskriftsartikel (refereegranskat)abstract
- The Advanced GAmma Tracking Array (AGATA) is a European project to develop and operate the next generation γ-ray spectrometer. AGATA is based on the technique of γ-ray energy tracking in electrically segmented high-purity germanium crystals. This technique requires the accurate determination of the energy, time and position of every interaction as a γ ray deposits its energy within the detector volume. Reconstruction of the full interaction path results in a detector with very high efficiency and excellent spectral response. The realisation of γ-ray tracking and AGATA is a result of many technical advances. These include the development of encapsulated highly segmented germanium detectors assembled in a triple cluster detector cryostat, an electronics system with fast digital sampling and a data acquisition system to process the data at a high rate. The full characterisation of the crystals was measured and compared with detector- response simulations. This enabled pulse-shape analysis algorithms, to extract energy, time and position, to be employed. In addition, tracking algorithms for event reconstruction were developed. The first phase of AGATA is now complete and operational in its first physics campaign. In the future AGATA will be moved between laboratories in Europe and operated in a series of campaigns to take advantage of the different beams and facilities available to maximise its science output. The paper reviews all the achievements made in the AGATA project including all the necessary infrastructure to operate and support the spectrometer. © 2011 Elsevier B.V. All rights reserved.
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| 50. |
- Alfredsson, Ylvi, et al.
(författare)
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Electronic structure of a vapor-deposited metal-free phthalocyanine thin film
- 2005
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 122:21
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Tidskriftsartikel (refereegranskat)abstract
- The electronic structure of a vapor-sublimated thin film of metal-free phthalocyanine (H2Pc) is studied experimentally and theoretically. An atom-specific picture of the occupied and unoccupied electronic states is obtained using x-ray-absorption spectroscopy (XAS), core- and valence-level x-ray photoelectron spectroscopy (XPS), and density-functional theory (DFT) calculations. The DFT calculations allow for an identification of the contributions from individual nitrogen atoms to the experimental N1s XAS and valence XPS spectra. This comprehensive study of metal-free phthalocyanine is relevant for the application of such molecules in molecular electronics and provides a solid foundation for identifying modifications in the electronic structure induced by various substituent groups.
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