| 1. |
- Arvidsson, Ida, et al.
(författare)
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Early terminal complement blockade and C6 deficiency are protective in enterohemorrhagic Escherichia coli-infected mice
- 2016
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 197:4, s. 1276-1286
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Tidskriftsartikel (refereegranskat)abstract
- Complement activation occurs during enterohemorrhagic Escherichia coli (EHEC) infection and may exacerbate renal manifestations. In this study, we show glomerular C5b-9 deposits in the renal biopsy of a child with EHEC-associated hemolytic uremic syndrome. The role of the terminal complement complex, and its blockade as a therapeutic modality, was investigated in a mouse model of E. coli O157:H7 infection. BALB/c mice were treated with monoclonal anti-C5 i.p. on day 3 or 6 after intragastric inoculation and monitored for clinical signs of disease and weight loss for 14 d. All infected untreated mice (15 of 15) or those treated with an irrelevant Ab (8 of 8) developed severe illness. In contrast, only few infected mice treated with anti-C5 on day 3 developed symptoms (three of eight, p < 0.01 compared with mice treated with the irrelevant Ab on day 3) whereas most mice treated with anti-C5 on day 6 developed symptoms (six of eight). C6-deficient C57BL/6 mice were also inoculated with E. coli O157:H7 and only 1 of 14 developed disease, whereas 10 of 16 wild-type mice developed weight loss and severe disease (p < 0.01). Complement activation via the terminal pathway is thus involved in the development of disease in murine EHEC infection. Early blockade of the terminal complement pathway, before the development of symptoms, was largely protective, whereas late blockade was not. Likewise, lack of C6, and thereby deficient terminal complement complex, was protective in murine E. coli O157:H7 infection.
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| 2. |
- Englund Dimitrova, Birgitta, 1946-, et al.
(författare)
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Cognitive aspects of community interpreting : Toward a process model
- 2016
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Ingår i: Reembedding Translation Process Research. - Amsterdam : John Benjamins Publishing Company. - 9789027258748 - 9789027266347 ; , s. 195-214
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Bokkapitel (refereegranskat)abstract
- This article discusses cognitive aspects of professional community interpreting. We give an overview of earlier research into community interpreting, arguing that cognitive aspects have largely been neglected. We propose that in building a model of the mental processes of the community interpreter, different kinds of monitoring are a crucial and pervasive component. Monitoring contributes to and enables the double function of the interpreter: translating and managing the interaction of the interpreted encounter. We furthermore stress the importance of the notion of professional self-concept for explaining the interpreter’s decision-making and exemplify this by analyzing turn-taking in two Swedish-Spanish interpreted encounters.
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| 3. |
- Haglund, Mattias, et al.
(författare)
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A methodological study of locus coeruleus degeneration in dementing disorders
- 2016
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Ingår i: Clinical Neuropathology. - 0722-5091. ; 35:5, s. 287-294
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Tidskriftsartikel (refereegranskat)abstract
- Background: Degeneration of the locus coeruleus (LC) of the brain stem is a recognized phenomenon in Alzheimer's disease (AD), in dementia with Lewy bodies (DLB), and in Parkinson's disease with dementia (PDD). Prior studies have suggested that LC degeneration can be used to differentiate various dementing disorders histologically, but the paucity of methodological data may hamper systematic research on this nucleus. Purpose: The purpose of this study was to evaluate various approaches to quantifying LC degeneration in dementing disorders, and to inform future decisions regarding the most appropriate method for diagnostics and research. Methods: 105 LCs from brains of demented individuals with AD, DLB/PDD, vascular dementia (VaD), mixed dementia (AD+VaD), or frontotemporal lobar degeneration (FTLD) were examined, and the extent of LC degeneration was assessed using macroscopic evaluation, cell counting, and two degeneration scales. Scores were compared across diagnostic categories; diagnostic utility and intra- and interobserver reliability were assessed. Results: AD and DLB/PDD were associated with greater LC damage using either assessment method, significantly different from VaD and FTLD. Macroscopic appearance was informative, but cell counting was more sensitive and specific. The degeneration scales did not add significant diagnostic value over cell counting and were associated with greater observer variability. Conclusions: The LC degenerates in certain dementia subtypes, especially in AD and DLB/PDD. Macroscopic assessment of the LC postmortem can be used to differentiate between disorders associated with degeneration (AD, DLB/PDD) or sparing (VaD) of the LC, but counting LC cells in a representative pontine section is the most appropriate method by which to assess LC degeneration.
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| 4. |
- Jablonowski, Robert, et al.
(författare)
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The Authors Reply
- 2016
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Ingår i: JACC: Cardiovascular Imaging. - : Elsevier BV. - 1876-7591 .- 1936-878X. ; 9:8, s. 7-1016
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Tidskriftsartikel (refereegranskat)
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| 5. |
- LI, WEN, et al.
(författare)
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Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain.
- 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. - 1091-6490. ; 113:23, s. 6544-6549
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Tidskriftsartikel (refereegranskat)abstract
- Clinical trials using cells derived from embryonic ventral mesencephalon have shown that transplanted dopaminergic neurons can survive and function in the long term, as demonstrated by in vivo brain imaging using 18F-fluorodopa and 11C-raclopride positron emission tomography. Here we report the postmortem analysis of a patient with Parkinson’s disease who 24 y earlier underwent unilateral transplantation of embryonic dopaminergic neurons in the putamen and subsequently exhibited major motor improvement and recovery of striatal dopaminergic function. Histopathological analysis showed that a dense, near-normal graft-derived dopaminergic reinnervation of the putamen can be maintained for a quarter of a century despite severe host brain pathology and with no evidence of immune response. In addition, ubiquitin- and α-synuclein–positive inclusions were seen, some with the appearance of typical Lewy bodies, in 11–12% of the grafted dopaminergic neurons, reflecting the spread of pathology from the host brain to the transplants. Because the clinical benefits induced by transplantation in this patient were gradually lost after 14 y posttransplantation, our findings provide the first reported evidence, to our knowledge, that even a viable dopaminergic graft giving rise to extensive striatal reinnervation may lose its efficacy if widespread degenerative changes develop in the host brain.
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| 6. |
- Rodhe, Johanna, et al.
(författare)
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Spatio-temporal activation of caspase-8 in myeloid cells upon ischemic stroke
- 2016
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 4, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Ischemic stroke (caused by thrombosis, embolism or vasoconstriction) lead to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral macrophages, which contribute to an inflammatory response involved in regulation of the neuronal damage. We showed earlier that upon pro-inflammatory stimuli, the orderly activation of caspase-8 and caspase-3/7 regulates microglia activation through a protein kinase C-δ dependent pathway. Here, we present in vivo evidence for the activation of caspase-8 and caspase-3 in microglia/macrophages in post-mortem tissue from human ischemic stroke subjects. Indeed, CD68-positive microglia/macrophages in the ischemic peri-infarct area exhibited significant expression of the cleaved and active form of caspase-8 and caspase-3. The temporal and spatial activation of caspase-8 was further investigated in a permanent middle cerebral artery occlusion mouse model of ischemic stroke. Increasing levels of active caspase-8 was found in Iba1-positive cells over time in the peri-infarct area, at 6, 24 and 48 h after artery occlusion. Analysis of post-mortem brain tissue from human subject who suffered two stroke events, referred as recent and old stroke, revealed that expression of cleaved caspase-8 and -3 in CD68-positive cells could only be found in the recent stroke area. Analysis of cleaved caspase-8 and -3 expressions in a panel of human stroke cases arranged upon days-after stroke and age-matched controls suggested that the expression of these caspases correlated with the time of onset of stroke. Collectively, these data illustrate the temporal and spatial activation of caspase-8 and -3 in microglia/macrophages occurring upon ischemic stroke and suggest that the expression of these caspases could be used in neuropathological diagnostic work.
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| 7. |
- Smith, Ruben, et al.
(författare)
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18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers
- 2016
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 139:9, s. 2372-2379
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Tidskriftsartikel (refereegranskat)abstract
- Tau positron emission tomography ligands provide the novel possibility to image tau pathologyin vivo. However, little is known about howin vivo brain uptake of tau positron emission tomography ligands relates to tau aggregates observed post-mortem. We performed tau positron emission tomography imaging with F-18-AV-1451 in three patients harbouring a p.R406W mutation in theMAPT gene, encoding tau. This mutation results in 3- and 4-repeat tau aggregates similar to those in Alzheimer's disease, and many of the mutation carriers initially suffer from memory impairment and temporal lobe atrophy. Two patients with short disease duration and isolated memory impairment exhibited F-18-AV-1451 uptake mainly in the hippocampus and adjacent temporal lobe regions, correlating with glucose hypometabolism in corresponding regions. One patient died after 26 years of disease duration with dementia and behavioural deficits. Pre-mortem, there was F-18-AV-1451 uptake in the temporal and frontal lobes, as well as in the basal ganglia, which strongly correlated with the regional extent and amount of tau pathology in post-mortem brain sections. Amyloid-beta (F-18-flutemetamol) positron emission tomography scans were negative in all cases, as were stainings of brain sections for amyloid. This provides strong evidence that F-18-AV-1451 positron emission tomography can be used to accurately quantifyin vivo the regional distribution of hyperphosphorylated tau protein.
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| 8. |
- Smith, Ruben, et al.
(författare)
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18F-AV1451 pet detects tau pathology in mapt mutation carriers and correlates strongly with immunohistochemistry of tau aggregates
- 2016
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 12:7 Suppl, s. 723-724
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Konferensbidrag (refereegranskat)abstract
- Background: The Tau PET ligand 18F-AV1451 has been shown to reliably detect paired helical filaments of tau in Alzheimer's disease, but it is not yet known whether it binds to the tau aggregates present in patients with mutations in the gene (MAPT) coding for the tau protein. Further, no study has yet compared the cerebral retention of 18F -AV1451 with the tau aggregates revealed using neuropathology. Methods: Three patients from a Swedish family carrying the R406W mutation of MAPT were assessed with cognitive tests and subjects underwent 18F-AV1451 and 18F-Flutemetamol PET scans. Further one of younger subjects also underwent an 18F-FDG PET scan. The oldest subject died two weeks after the scan and the brain was processed for neuropathology. Tau immunohistochemistry was performed on brain sections from affected and unaffected brain regions. Results: Two mutation carriers, aged 56 and 60 years, had disease durations of 5-10 years and still only exhibited mild-moderate episodic memory impairment and no clear behavioural deficits. The MRI revealed only slight cortical atrophy and 18F-AV1451 PET imaging showed uptake in the hippocampus and the temporal lobes, especially in the inferior and anterior parts (Fig 1A, B). The uptake of 18F - AV1451 correlated well with hypometabolism revealed with FGD PET in one of the subjects. The third case, 76 years, had a disease duration of ≥20 years and exhibited clear cognitive impairment, behavioural disturbances, mutism and dysphagia. The CT scan showed generalised cortical atrophy with a pronounced temporal lobe atrophy and 18F -AV1451 PET imaging revealed uptake in the temporal and frontal lobes, as well as in the basal ganglia (Fig 1 C). The regional uptake of 18F -AV1451 correlated strongly with the tau aggregates revealed using immunohistochemistry (R2 = 0.80, P <0.01; Fig 2). All cases exhibited negative amyloid (18F -flutemetamol) PET scans. Conclusions: The in vivo uptake of 18F-AV1451 reflects the regional amount of tau aggregates revealed by neuropathological examination. Further, tau pathology in MAPT mutation carriers is accurately detected with 18F -AV1451 PET, which consequently can be used to track the effects of anti-tau therapies in this patient group. (Figure Presented) .
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| 9. |
- Szczepankiewicz, Filip, et al.
(författare)
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The link between diffusion MRI and tumor heterogeneity : Mapping cell eccentricity and density by diffusional variance decomposition (DIVIDE)
- 2016
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119. ; 142, s. 522-532
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Tidskriftsartikel (refereegranskat)abstract
- The structural heterogeneity of tumor tissue can be probed by diffusion MRI (dMRI) in terms of the variance of apparent diffusivities within a voxel. However, the link between the diffusional variance and the tissue heterogeneity is not well-established. To investigate this link we test the hypothesis that diffusional variance, caused by microscopic anisotropy and isotropic heterogeneity, is associated with variable cell eccentricity and cell density in brain tumors. We performed dMRI using a novel encoding scheme for diffusional variance decomposition (DIVIDE) in 7 meningiomas and 8 gliomas prior to surgery. The diffusional variance was quantified from dMRI in terms of the total mean kurtosis (MKT), and DIVIDE was used to decompose MKT into components caused by microscopic anisotropy (MKA) and isotropic heterogeneity (MKI). Diffusion anisotropy was evaluated in terms of the fractional anisotropy (FA) and microscopic fractional anisotropy (μFA). Quantitative microscopy was performed on the excised tumor tissue, where structural anisotropy and cell density were quantified by structure tensor analysis and cell nuclei segmentation, respectively. In order to validate the DIVIDE parameters they were correlated to the corresponding parameters derived from microscopy. We found an excellent agreement between the DIVIDE parameters and corresponding microscopy parameters; MKA correlated with cell eccentricity (r = 0.95, p < 10− 7) and MKI with the cell density variance (r = 0.83, p < 10− 3). The diffusion anisotropy correlated with structure tensor anisotropy on the voxel-scale (FA, r = 0.80, p < 10− 3) and microscopic scale (μFA, r = 0.93, p < 10− 6). A multiple regression analysis showed that the conventional MKT parameter reflects both variable cell eccentricity and cell density, and therefore lacks specificity in terms of microstructure characteristics. However, specificity was obtained by decomposing the two contributions; MKA was associated only to cell eccentricity, and MKI only to cell density variance. The variance in meningiomas was caused primarily by microscopic anisotropy (mean ± s.d.) MKA = 1.11 ± 0.33 vs MKI = 0.44 ± 0.20 (p < 10− 3), whereas in the gliomas, it was mostly caused by isotropic heterogeneity MKI = 0.57 ± 0.30 vs MKA = 0.26 ± 0.11 (p < 0.05). In conclusion, DIVIDE allows non-invasive mapping of parameters that reflect variable cell eccentricity and density. These results constitute convincing evidence that a link exists between specific aspects of tissue heterogeneity and parameters from dMRI. Decomposing effects of microscopic anisotropy and isotropic heterogeneity facilitates an improved interpretation of tumor heterogeneity as well as diffusion anisotropy on both the microscopic and macroscopic scale.
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