| 1. |
- Bäckman, Lars, et al.
(författare)
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Dopamine D(1) receptors and age differences in brain activation during working memory
- 2011
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Ingår i: Neurobiology of Aging. - Fayetteville, N.Y : Elsevier. - 0197-4580 .- 1558-1497. ; 32:10, s. 1849-1856
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Tidskriftsartikel (refereegranskat)abstract
- In an fMRI study, 20 younger and 20 healthy older adults were scanned while performing a spatial working-memory task under two levels of load. On a separate occasion, the same subjects underwent PET measurements using the radioligand [(11)C] SCH23390 to determine dopamine D(1) receptor binding potential (BP) in caudate nucleus and dorsolateral prefrontal cortex (DLPFC). The fMRI study revealed a significant load modulation of brain activity (higher load>lower load) in frontal and parietal regions for younger, but not older, adults. The PET measurements showed marked age-related reductions of D(1) BP in caudate and DLPFC. Statistical control of caudate and DLPFC D(1) binding eliminated the age-related reduction in load-dependent BOLD signal in left frontal cortex, and attenuated greatly the reduction in right frontal and left parietal cortex. These findings suggest that age-related alterations in dopaminergic neurotransmission may contribute to underrecruitment of task-relevant brain regions during working-memory performance in old age.
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| 2. |
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| 3. |
- Karlsson, Sari, et al.
(författare)
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Modulation of striatal dopamine D1 binding by cognitive processing
- 2009
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Ingår i: NeuroImage. - : Elsevier. - 1053-8119 .- 1095-9572. ; 48:2, s. 398-404
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Tidskriftsartikel (refereegranskat)abstract
- There is strong evidence that dopamine (DA) is implicated in higher-order cognitive functioning, but it remains controversial whether D1 receptor binding can be modified by cognitive activity. We examined striatal D1 binding potential (BP) in 20 younger (22-30 years) and 20 older (65-75 years) persons who underwent two [(11)C] SCH 23390 PET measurements, one while resting and one while performing a cognitive task taxing inhibitory functioning. The younger persons showed significant task-related BP reductions in sensorimotor, limbic, and associative striatum during cognitive activity compared to rest. Older persons showed no reliable BP reductions in any striatal subregion. These findings demonstrate that D1 receptor binding can be modified by cognitive activity in younger persons, but also provide novel evidence for the notion that human aging is associated not only with lower DA receptor density but also with altered modifiability of the DA system.
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| 4. |
- Karlsson, Sari, et al.
(författare)
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Relationship of dopamine D1 receptor binding in striatal and extrastriatal regions to cognitive functioning in healthy humans
- 2011
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Ingår i: NeuroImage. - : Elsevier. - 1053-8119 .- 1095-9572. ; 57:2, s. 346-351
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Tidskriftsartikel (refereegranskat)abstract
- Dopamine (DA) availability in both striatal and extrastriatal brain regions has been implicated in cognitive performance. Given that different brain regions are neuroanatomically and functionally different, DA receptor binding in different brain regions may be selectively important to specific cognitive functions. Using PET and the radioligand SCH23390, we measured D1 receptor binding potential (BP(ND)) in dorsolateral prefrontal cortex (DLPFC), hippocampus (HC), as well as in sensorimotor (SMST), associative (AST), and limbic (LST) striatum in 20 healthy younger persons. Subjects completed tasks assessing executive functioning, episodic memory, speed, and general knowledge. Unlike previous reports, we found no linear or curvilinear relationships between D1 receptor binding in DLPFC and performance in any cognitive task. However, BP(ND) in HC was positively linked to executive performance as well as to speed and knowledge. With regard to the striatal subregions, D1 BP(ND) in SMST was more strongly related to speed compared to the other striatal subregions, whereas D1 BP(ND) in AST was more strongly linked to general knowledge. These findings provide support for the notion that D1 receptors in separate brain regions are differentially related to performance in tasks tapping various cognitive domains.
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| 5. |
- Rieckmann, Anna, et al.
(författare)
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Dopamine D1 Receptor Associations within and between Dopaminergic Pathways in Younger and Elderly Adults : Links to Cognitive Performance
- 2011
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Ingår i: Cerebral Cortex. - Oxford : Oxford University Press. - 1047-3211 .- 1460-2199. ; 21:9, s. 2023-2032
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Tidskriftsartikel (refereegranskat)abstract
- Age-related dopamine (DA) losses have been extensively demonstrated for the D2 receptor subtype. Comparatively little is known about adult age changes regarding D1 receptors. In this study, we demonstrate marked age-related D1 receptor losses in striatal, limbic, and cortical areas using positron emission tomography and the radioligand [11C]SCH23390 in humans. Interregional correlations of binding potential (BP) values were high for areas within DA pathways in younger and elderly adults alike. Furthermore, interregional correlations in D1 BP between DA pathways were uniformly high in younger adults, indicating that D1 receptor densities in striatal, limbic, and cortical areas are not regulated independently, despite dopaminergic innervation from different midbrain areas. For elderly adults, between-pathway correlations of D1 receptor densities were preserved only between mesolimbic and mesocortical areas, whereas striatal BPs were weakly related to those in limbic and neocortical regions. Importantly, weak between-pathway correlations in elderly adults were found only for the slower half of the sample when BP was estimated during a cognitive interference task. These results suggest that D1 receptor densities in different pathways are not regulated independently in younger adults, but segregate in older age, and that this segregation of D1 receptor systems may be related to age-related cognitive slowing.
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| 6. |
- Ahmad, Amais, et al.
(författare)
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IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 4 : Prediction accuracy and software comparisons with improved data and modelling strategies
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 156, s. 50-63
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Tidskriftsartikel (refereegranskat)abstract
- Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlusTM (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project.Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters.On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.
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| 7. |
- Darwich, Adam S., et al.
(författare)
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IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 3 : Identifying gaps in system parameters by analysing In Silico performance across different compound classes
- 2017
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 96, s. 626-642
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Tidskriftsartikel (refereegranskat)abstract
- Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp (R) Simulator, and GastroPlus (TM)) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (F-oral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foralwas also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. F-oral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.
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| 8. |
- Ferencz, Beata, et al.
(författare)
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Promising Genetic Biomarkers of Preclinical Alzheimer's Disease : The Influence of APOE and TOMM40 on Brain Integrity
- 2012
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Ingår i: International Journal of Alzheimer's Disease. - : Hindawi Limited. - 2090-8024 .- 2090-0252. ; 2012
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Forskningsöversikt (refereegranskat)abstract
- Finding biomarkers constitutes a crucial step for early detection of Alzheimer's disease (AD). Brain imaging techniques have revealed structural alterations in the brain that may be phenotypic in preclinical AD. The most prominent polymorphism that has been associated with AD and related neural changes is the Apolipoprotein E (APOE) ε4. The translocase of outer mitochondrial membrane 40 (TOMM40), which is in linkage disequilibrium with APOE, has received increasing attention as a promising gene in AD. TOMM40 also impacts brain areas vulnerable in AD, by downstream apoptotic processes that forego extracellular amyloid beta aggregation. The present paper aims to extend on the mitochondrial influence in AD pathogenesis and we propose a TOMM40-induced disconnection of the medial temporal lobe. Finally, we discuss the possibility of mitochondrial dysfunction being the earliest pathophysiological event in AD, which indeed is supported by recent findings.
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| 9. |
- Laukka, Erika J., et al.
(författare)
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Genetic Effects on Old-Age Cognitive Functioning : A Population-Based Study
- 2013
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Ingår i: Psychology and Aging. - : American Psychological Association (APA). - 0882-7974 .- 1939-1498. ; 28:1, s. 262-274
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Tidskriftsartikel (refereegranskat)abstract
- Associations between genotypes and cognitive outcomes may provide clues as to which mechanisms cause individual differences in old-age cognitive performance. We investigated the effects of five polymorphisms on cognitive functioning in a population-based sample of 2,694 persons without dementia (60-102 years). A structural equation model (SEM) was fit to the cognitive data, yielding five specific latent factors (perceptual speed, episodic memory, semantic memory, category fluency, and letter fluency), as well as a global cognitive factor. These factors showed the expected associations with chronological age. Genotyping was performed for five single-nucleotide polymorphisms that have been associated with cognitive performance: APOE (rs429358), COMT (rs4680), BDNF (rs6265), KIBRA (rs17070145), and CLSTN2 (rs6439886). After controlling for age, gender, and education, as well as correcting for multiple comparisons, we observed negative effects of being an APOE ε4 carrier on episodic memory and perceptual speed. Furthermore, being a CLSTN2 TT carrier was associated with poorer semantic memory. For the global factor, the same pattern of results was observed. In addition, being a BDNF any A carrier was associated with better cognitive performance. Also, older age was associated with stronger genetic effects of APOE on global cognition. However, this interaction effect was partly driven by the presence of preclinical dementia cases in our sample. Similarly, excluding future dementia cases attenuated the effects of APOE on episodic memory and global cognition, suggesting that part of the effects of APOE on old-age cognitive performance may be driven by dementia-related processes.
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| 10. |
- Lundgren, Markus, et al.
(författare)
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Analgesic antipyretic use among young children in the TEDDY study : No association with islet autoimmunity
- 2017
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Ingår i: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. Methods: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. Results: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). Conclusions: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection.
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| 11. |
- MacDonald, Stuart WS, et al.
(författare)
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Aging-related increases in behavioral variability : relations to losses of dopamine D-1 receptors
- 2012
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 32:24, s. 8186-8191
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Tidskriftsartikel (refereegranskat)abstract
- Intraindividual variability (IIV) reflects within-person changes in performance, such as trial-by-trial fluctuations on a reaction-time (RT) task. The neural underpinnings of IIV remain largely unknown. The neurotransmitter dopamine (DA) is of particular interest here, as human populations that exhibit DA alterations, such as the elderly, attention deficit hyperactivity disorder children, persons with schizophrenia, and Parkinson patients, also show increased behavioral IIV. We examined links between DA D-1 binding potential (BP) in multiple brain regions and IIV for the control and interference conditions of the Multi-Source Interference Task (MSIT), tapping the cingulo-fronto-parietal attention network. Participants were 18 young and 20 healthy old adults. PET and the radioligand [C-11]SCH23390 were used to determine D-1 BP. The intraindividual standard deviation (ISD) was computed across successful latency trials of the MSIT conditions, independent of mean RT differences due to age, trial, and condition. Increasing ISDs were associated with increasing age and diminished D-1 binding in several brain regions (anterior cingulate gyrus, dorsolateral prefrontal cortex, and parietal cortex) for the interference, but not control, condition. Analyses of partial associations indicate that the association between age and IIV in the interference condition was linked to D-1 receptor losses in task-relevant brain regions. These findings suggest that dysfunctional DA modulation may contribute to increased variability in cognitive performance among older adults.
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| 12. |
- MacDonald, Stuart W S, et al.
(författare)
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Trajectories of cognitive decline following dementia onset : what accounts for variation in progression?
- 2011
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Ingår i: Dementia and Geriatric Cognitive Disorders. - Basel : Karger. - 1420-8008 .- 1421-9824. ; 31:3, s. 202-209
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Delineating the natural history of dementia progression has important clinical implications, including reducing caregiver burden and targeting effective drug trials. We examined whether trajectories of cognitive change differed reliably after diagnosis, and whether diverse predictors of such differences (demographic, psychological, biological, genetic, social) could be identified.METHODS: Cognitive change was examined for incident dementia cases (mild: n = 156; moderate: n = 77; severe: n = 73) and controls (n = 249) from the Kungsholmen Project, a community-based study of adults 75 years and older.RESULTS: For those with dementia, total variance attributed to between-person differences in cognitive decline was modest and linked to but a single predictor (history of cardiovascular disease). Although less variance in cognitive decline was observed for the similarly aged controls, numerous significant predictors of these differences were identified.CONCLUSION: The neurodegenerative process underlying dementia overshadows formerly significant predictors of cognitive change.
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| 13. |
- Margolskee, Alison, et al.
(författare)
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IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 2 : An introduction to the simulation exercise and overview of results
- 2017
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 96, s. 610-625
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Tidskriftsartikel (refereegranskat)abstract
- Orally administered drugs are subject to a number of barriers impacting bioavailability (F-oral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp (R), and GastroPlus (TM)) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters. Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exercise may not be representative of prospective modelling in industry, as API information was limited to sparse details. 43 active pharmaceutical ingredients (APIs) from the OrBiTo database were selected for the exercise. Over 4000 simulation output files were generated, representing over 2550 study arm-institution-software combinations and approximately 600 human clinical study arms simulated with overlap. 84% of the simulated study arms represented administration of immediate release formulations, 11% prolonged or delayed release, and 5% intravenous (i.v.). Higher percentages of i.v. predicted area under the curve (AUC) were within two-fold of observed (52.9%) compared to per oral (p.o.) (37.2%), however, F-oral and relative AUC (F-rel) between p.o. formulations and solutions were generally well predicted (64.7% and 75.0%). Predictive performance declined progressing from i.v. to solution and immediate release tablet, indicating the compounding error with each layer of complexity. Overall performance was comparable to previous large-scale evaluations. A general overprediction of AUC was observed with average fold error (AFE) of 1.56 over all simulations. AFE ranged from 0.0361 to 64.0 across the 43 APIs, with 25 showing overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms.
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| 14. |
- Nisula, Sara, et al.
(författare)
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Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units : the FINNAKI study
- 2013
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Ingår i: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 39:3, s. 420-428
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSEWe aimed to determine the incidence, risk factors and outcome of acute kidney injury (AKI) in Finnish ICUs.METHODSThis prospective, observational, multi-centre study comprised adult emergency admissions and elective patients whose stay exceeded 24 h during a 5-month period in 17 Finnish ICUs. We defined AKI first by the Acute Kidney Injury Network (AKIN) criteria supplemented with a baseline creatinine and second with the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We screened the patients' AKI status and risk factors for up to 5 days.RESULTSWe included 2,901 patients. The incidence (95 % confidence interval) of AKI was 39.3 % (37.5-41.1 %). The incidence was 17.2 % (15.8-18.6 %) for stage 1, 8.0 % (7.0-9.0 %) for stage 2 and 14.1 % (12.8-15.4 %) for stage 3 AKI. Of the 2,901 patients 296 [10.2 % (9.1-11.3 %)] received renal replacement therapy. We received an identical classification with the new KDIGO criteria. The population-based incidence (95 % CI) of ICU-treated AKI was 746 (717-774) per million population per year (reference population: 3,671,143, i.e. 85 % of the Finnish adult population). In logistic regression, pre-ICU hypovolaemia, diuretics, colloids and chronic kidney disease were independent risk factors for AKI. Hospital mortality (95 % CI) for AKI patients was 25.6 % (23.0-28.2 %) and the 90-day mortality for AKI patients was 33.7 % (30.9-36.5 %). All AKIN stages were independently associated with 90-day mortality.CONCLUSIONSThe incidence of AKI in the critically ill in Finland was comparable to previous large multi-centre ICU studies. Hospital mortality (26 %) in AKI patients appeared comparable to or lower than in other studies.
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| 15. |
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| 16. |
- Rasmussen, Pil U., et al.
(författare)
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Plant and insect genetic variation mediate the impact of arbuscular mycorrhizal fungi on a natural plant-herbivore interaction
- 2017
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Ingår i: Ecological Entomology. - : Wiley. - 0307-6946 .- 1365-2311. ; 42:6, s. 793-802
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Tidskriftsartikel (refereegranskat)abstract
- 1. While both arbuscular mycorrhizal (AM) fungi and plant and insect genotype are well known to influence plant and herbivore growth and performance, information is lacking on how these factors jointly influence the relationship between plants and their natural herbivores. 2. The aim of the present study was to investigate how a natural community of arbuscular mycorrhizal fungi affects the growth of the perennial herb Plantago lanceolata L. (Plantaginaceae), as well as its interaction with the Glanville fritillary butterfly [Melitaea cinxia L. (Nymphalidae)]. For this, a multifactorial experiment was conducted using plant lines originating from multiple plant populations in the angstrom land Islands, Finland, grown either with or without mycorrhizal fungi. For a subset of plant lines, the impact of mycorrhizal inoculation, plant line, and larval family on the performance of M. cinxia larvae were tested. 3. Arbuscular mycorrhizal inoculation did not have a consistently positive or negative impact on plant growth or herbivore performance. Instead, plant genetic variation mediated the impact of arbuscular mycorrhizal fungi on plant growth, and both plant genetic variation and herbivore genetic variation mediated the response of the herbivore. For both the plant and insect, the impact of the arbuscular mycorrhizal community ranged from mutualistic to antagonistic. Overall, the present findings illustrate that genetic variation in response to mycorrhizal fungi may play a key role in the ecology and evolution of plant-insect interactions.
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| 17. |
- Rieckmann, Anna, et al.
(författare)
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Caudate Dopamine D1 Receptor Density Is Associated with Individual Differences in Frontoparietal Connectivity during Working Memory
- 2011
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 31:40, s. 14284-14290
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Tidskriftsartikel (refereegranskat)abstract
- We assess the relationship of age-related losses in striatal D1 receptor densities to age-related reductions in functional connectivity between spatially distinct cortical regions in healthy human participants. Previous neuroimaging studies have reported age-related differences in functional connectivity of the frontoparietal working memory network and the default mode network during task performance. We used functional magnetic resonance imaging and seed-based connectivity (right dorsolateral and medial prefrontal cortex) to extend these findings: Anterior-posterior connectivity of both these functional networks was reduced in older (65-75 years, n = 18) compared with younger (20-30 years, n = 19) adults, whereas bilateral connectivity in prefrontal cortex was increased in older adults. Positron emission tomography with the D1 receptor ligand [(11)C]SCH23390 was used to assess caudate D1 receptor density in the same sample. Older adults showed significantly reduced caudate D1 receptor density compared to the younger adults. Of key interest, partial correlations showed that individual differences in caudate D1 receptor density were positively associated with individual differences in dorsolateral prefrontal connectivity to right parietal cortex (BA40) and negatively with medial prefrontal connectivity to right parietal cortex (BA40 and postcentral gyrus), after controlling for age. We found no correlation of caudate D1 receptor density with anterior-posterior coupling within the default mode network or with bilateral frontal connectivity. These results are consistent with animal work that has identified a role for caudate D1 receptors in mediating information transfer between prefrontal areas and parietal cortex.
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| 18. |
- Rieckmann, Anna, et al.
(författare)
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Increased Bilateral Frontal Connectivity during Working Memory in Young Adults under the Influence of a Dopamine D1 Receptor Antagonist
- 2012
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17067-17072
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Tidskriftsartikel (refereegranskat)abstract
- Increased frontal bilaterality in old compared with young adults during cognitive performance is a common finding in human functional neuroimaging studies. Age-related reductions in laterality are a widely debated topic and their origins and consequences may be manifold. The current study demonstrates that a dopamine (DA) D1 antagonist induces increased frontal bilateral connectivity in healthy young adults revealed by functional magnetic resonance imaging during a spatial working memory task. Moreover, increases in functional connectivity between right and left prefrontal cortex during the pharmacological challenge were associated with maintaining performance on drug. To our knowledge, this is the first study to pharmacologically induce increased frontal bilateral functional connectivity during a cognitive task in young adults and to show that increased bilaterality is associated with less severe cognitive impairment under the influence of a DA receptor antagonist.
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| 19. |
- Rosjo, Helge, et al.
(författare)
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Prognostic value of chromogranin A in severe sepsis : data from the FINNSEPSIS study
- 2012
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Ingår i: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 38:5, s. 820-829
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Tidskriftsartikel (refereegranskat)abstract
- To assess the prognostic information of chromogranin A (CgA), a marker associated with adrenergic tone and myocardial function, in patients with severe sepsis. CgA levels were measured at the time of study inclusion and 72 h later in 232 patients with severe sepsis recruited from 24 ICUs in Finland (FINNSEPSIS study). Sixty-five patients (28 %) died during the index hospitalization. CgA levels at inclusion and after 72 h correlated with several established indices of risk in sepsis. Patients who died during the hospitalization had higher baseline CgA levels than hospital survivors: 14.0 (Q1-3, 7.4-27.4) versus 9.1 (5.9-15.8) nmol/l, P = 0.002, and after 72 h: 16.2 (9.0-31.1) versus 9.8 (6.0-18.0) nmol/l, P = 0.001. Prior cardiovascular disease (P = 0.04) and cardiovascular SOFA levels on day 3 (P = 0.03) were associated with higher CgA levels after 72 h by linear regression. CgA levels on study inclusion and after 72 h were independently associated with hospital mortality by logistic regression: OR (logarithmically transformed CgA levels) 1.95 (95 % CI 1.01-3.77), P = 0.046 and OR 2.03 (95 % CI 1.18-3.49), P = 0.01, respectively. The prognostic accuracy was comparable for CgA measurements and SAPS II score, and the addition of CgA measurements to the SAPS II score improved risk stratification of the patients as assessed by the category-free net reclassification index. A CgA level > 6.6 nmol/l on study inclusion was associated with septic shock during the hospitalization. CgA levels measured during hospitalization for severe sepsis are associated with cardiovascular dysfunction and may provide additional prognostic information in patients with severe sepsis.
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| 20. |
- Ruilope, LM, et al.
(författare)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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| 21. |
- Røsjø, Helge, et al.
(författare)
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Prognostic Value of Secretoneurin in Critically III Patients With Infections
- 2016
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Ingår i: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 44:10, s. 1882-1890
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Tidskriftsartikel (refereegranskat)abstract
- Objectives : Secretoneurin is produced in neuroendocrine cells, and the myocardium and circulating secretoneurin levels provide incremental prognostic information to established risk indices in cardiovascular disease. As myocardial dysfunction contributes to poor outcome in critically ill patients, we wanted to assess the prognostic value of secretoneurin in two cohorts of critically ill patients with infections. Design: Two prospective, observational studies. Setting: Twenty-four and twenty-five ICUs in Finland. Patients: A total of 232 patients with severe sepsis (cohort #1) and 94 patients with infections and respiratory failure (cohort #2). Interventions: None. Measurements and Main Results: We measured secretoneurin levels by radioimmunoassay in samples obtained early after ICU admission and compared secretoneurin with other risk indices. In patients with severe sepsis, admission secretoneurin levels (logarithmically transformed) were associated with hospital mortality (odds ratio, 3.17 [95% CI, 1.12-9.00]; p = 0.030) and shock during the hospitalization (odds ratio, 2.17 [1.06-4.46]; p = 0.034) in analyses that adjusted for other risk factors available on ICU admission. Adding secretoneurin levels to age, which was also associated with hospital mortality in the multivariate model, improved the risk prediction as assessed by the category-free net reclassification index: 0.35 (95% CI, 0.06-0.64) (p = 0.02). In contrast, N-terminal pro B-type natriuretic peptide levels were not associated with mortality in the multivariate model that included secretoneurin measurements, and N-terminal pro B-type natriuretic peptide did not improve patient classification on top of age. Secretoneurin levels were also associated with hospital mortality after adjusting for other risk factors and improved patient classification in cohort #2. In both cohorts, the optimal cutoff for secretoneurin levels at ICU admission to predict hospital mortality was approximate to 175 pmol/L, and higher levels were associated with mortality also when adjusting for Simplified Acute Physiology Score II and Sequential Organ Failure Assessment scores. Conclusions: Secretoneurin levels provide incremental information to established risk indices for the prediction of mortality and shock in critically ill patients with severe infections.
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| 22. |
- Sawakuchi, Henrique Oliveira, et al.
(författare)
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Phosphorus Regulation of Methane Oxidation in Water From Ice-Covered Lakes
- 2021
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Ingår i: Journal of Geophysical Research - Biogeosciences. - : Wiley-Blackwell Publishing, Inc.. - 2169-8953 .- 2169-8961. ; 126:9
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Tidskriftsartikel (refereegranskat)abstract
- Winter methane (CH4) accumulation in seasonally ice-covered lakes can contribute to large episodic emissions to the atmosphere during spring ice melt. Biological methane oxidation can significantly mitigate such CH4 emissions, but despite favorable CH4 and O2 concentrations, CH4 oxidation appears constrained in some lakes for unknown reasons. Here we experimentally test the hypothesis that phosphorus (P) availability is limiting CH4 oxidation, resulting in differences in ice-out emissions among lakes. We observed a positive relationship between potential CH4 oxidation and P concentration across 12 studied lakes and found an increase in CH4 oxidation in response to P amendment, without any parallel change in the methanotrophic community composition. Hence, while an increase in sedimentary CH4 production and ebullitive emissions may happen with eutrophication, our study indicates that the increase in P associated with eutrophication may also enhance CH4 oxidation. The increase in CH4 oxidation may hence play an important role in nutrient-rich ice-covered lakes where bubbles trapped under the ice may to a greater extent be oxidized, reducing the ice-out emissions of CH4. This may be an important factor regulating CH4 emissions from high latitude lakes.
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| 23. |
- Vuorenpää, Sari, 1967-
(författare)
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Litteracitet genom interaktion
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The dissertation Litteracitet genom interaktion [‘Literacy through Interaction’] spotlights how literacy interaction can work in the primary school’s multilinguistic environments. It investigates conversations that occur in and around teaching about writing. The study material was collected from three different schools from year zero to year three, and special focus is given to what I call literacy chains. These chains are connected by the fact that they all concern a writing assignment that every pupil must complete, which in my material involves the text types narrative, factual text and poem. During the teaching sequences that unfold, there is an interplay of literary events in connection with speech, writing and various artefacts. My main object of inquiry is the interaction that occurs in these literacy chains.The dissertation demonstrates that the teachers’ lessons with the class as a whole lead to fixed conversational patterns, with pupils asked questions that require specific responses. The conversations tend to form either a so-called IRE pattern, where the reader’s initiative for a question demands a given answer in response which is then evaluated by the teacher, or a list pattern, with the pupils filling in answers.In situations involving the whole class, persistent, determined pupils are needed to break into the teacher’s monologue. When persistence wins out, from the pupil’s perspective, pupils can contribute new aspects to these conversations. In small groups and in one-on-one conversations, there are more pupil initiatives, since conversational patterns are not as fixed or predetermined.One key finding is that multilinguistic resources are sometimes made use of even though the schoolwork is usually based on a single-language conversational norm. Yet it is clear that multilingualism is a useful resource regardless of the teacher’s language background. On several occasions, we encounter participants who together construct a multilinguistic environment where languages are interwoven.All three literacy chains provide pupils with clear templates for writing, which determine what the pupils are supposed to do. The writing template in the poem chain serves as support for their writing but is not a straitjacket. This can be compared to the template for the factual text, which includes a copy of the model text.The written language norm of writing properly is communicated in great detail by the teachers to the pupils. Writing properly is not just having good, legible handwriting, but in school the writing norms to be applied in writing assignments are made relevant.On a more general level, the study illustrates that material resources vary in the schools, from green chalkboards to classroom resources that include laptops. However, schoolwork is predicated on paper-based writing. There is built-in stress, since schoolwork is governed by time, with a schedule that determines learning activities down to the minute, with them ending at a precise time. There is a race against time.
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| 24. |
- Watts, Nick, et al.
(författare)
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The Lancet Countdown : tracking progress on health and climate change
- 2017
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 389:10074, s. 1151-1164
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Forskningsöversikt (refereegranskat)abstract
- The Lancet Countdown: tracking progress on health and climate change is an international, multidisciplinary research collaboration between academic institutions and practitioners across the world. It follows on from the work of the 2015 Lancet Commission, which concluded that the response to climate change could be "the greatest global health opportunity of the 21st century". The Lancet Countdown aims to track the health impacts of climate hazards; health resilience and adaptation; health co-benefits of climate change mitigation; economics and finance; and political and broader engagement. These focus areas form the five thematic working groups of the Lancet Countdown and represent different aspects of the complex association between health and climate change. These thematic groups will provide indicators for a global overview of health and climate change; national case studies highlighting countries leading the way or going against the trend; and engagement with a range of stakeholders. The Lancet Countdown ultimately aims to report annually on a series of indicators across these five working groups. This paper outlines the potential indicators and indicator domains to be tracked by the collaboration, with suggestions on the methodologies and datasets available to achieve this end. The proposed indicator domains require further refinement, and mark the beginning of an ongoing consultation process-from November, 2016 to early 2017-to develop these domains, identify key areas not currently covered, and change indicators where necessary. This collaboration will actively seek to engage with existing monitoring processes, such as the UN Sustainable Development Goals and WHO's climate and health country profiles. The indicators will also evolve over time through ongoing collaboration with experts and a range of stakeholders, and be dependent on the emergence of new evidence and knowledge. During the course of its work, the Lancet Countdown will adopt a collaborative and iterative process, which aims to complement existing initiatives, welcome engagement with new partners, and be open to developing new research projects on health and climate change.
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