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  • Bonham, Luke W., et al. (författare)
  • Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia
  • 2019
  • Ingår i: Scientific reports. - 2045-2322. ; 9:1, s. 10854
  • Tidskriftsartikel (refereegranskat)abstract
    • The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration. © 2019, The Author(s).
  • Ferrari, Raffaele, et al. (författare)
  • Frontotemporal dementia and its subtypes: a genome-wide association study.
  • 2014
  • Ingår i: Lancet Neurology. - Lancet Ltd. - 1474-4465. ; 13:7, s. 686-699
  • Tidskriftsartikel (refereegranskat)abstract
    • Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
  • Santillo, Alexander Frizell, et al. (författare)
  • Diffusion Tensor Tractography versus Volumetric Imaging in the Diagnosis of Behavioral Variant Frontotemporal Dementia.
  • 2013
  • Ingår i: PLoS ONE. - Public Library of Science. - 1932-6203. ; 8:7
  • Tidskriftsartikel (refereegranskat)abstract
    • MRI diffusion tensor imaging (DTI) studies of white matter integrity in behavioral variant frontotemporal dementia have consistently shown involvement of frontal and temporal white matter, corresponding to regional loss of cortical volume. Volumetric imaging has a suboptimal sensitivity as a diagnostic tool and thus we wanted to explore if DTI is a better method to discriminate patients and controls than volumetric imaging. We examined the anterior cingulum bundle in 14 patients with behavioral variant frontotemporal dementia and 22 healthy controls using deterministic manual diffusion tensor tractography, and compared DTI parameters with two measures of cortical atrophy, VBM and cortical thickness, of the anterior cingulate cortex (ACC). Statistically significant changes between patients and controls were detected in all DTI parameters, with large effect sizes. ROC-AUC was for the best DTI parameters: 0.92 (fractional anisotropy) to 0.97 (radial diffusivity), 0.82 for the best cortical parameter, VBM of the ACC. Results from the AUC were confirmed with binary logistic regression analysis including demographic variables, but only for fractional anisotropy and mean diffusivity. Ability to classify patient/nonpatient status was significantly better for mean diffusivity vs. VBM (p=0.031), and borderline significant for fractional anisotropy vs. VBM (p=0.062). The results indicate that DTI could offer advantages in comparison with the assessment of cortical volume in differentiating patients with behavioral variant frontotemporal dementia and controls.
  • Santillo, Alexander Frizell, et al. (författare)
  • Grey and white matter clinico-anatomical correlates of disinhibition in neurodegenerative disease
  • 2016
  • Ingår i: PLoS ONE. - Public Library of Science. - 1932-6203. ; 11:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Disinhibition is an important symptom in neurodegenerative diseases. However, the clinico- anatomical underpinnings remain controversial. We explored the anatomical correlates of disinhibition in neurodegenerative disease using the perspective of grey and white matter imaging. Disinhibition was assessed with a neuropsychological test and a caregiver information- based clinical rating scale in 21 patients with prefrontal syndromes due to behavioural variant frontotemporal dementia (n = 12) or progressive supranuclear palsy (n = 9), and healthy controls (n = 25). Cortical thickness was assessed using the Freesurfer software on 3T MRI data. The integrity of selected white matter tracts was determined by the fractional anisotropy (FA) from Diffusion Tensor Imaging. Disinhibition correlated with the cortical thickness of the right parahippocampal gyrus, right orbitofrontal cortex and right insula and the FA of the right uncinate fasciculus and right anterior cingulum. Notably, no relationship was seen with the thickness of ventromedial prefrontal cortex. Our results support an associative model of inhibitory control, distributed in a medial temporal lobe-insularorbitofrontal network, connected by the intercommunicating white matter tracts. This reconciles some of the divergences among previous studies, but also questions the current conceptualisation of the prefrontal syndrome and the central role attributed to the ventromedial prefrontal cortex in inhibitory control.
  • Wallin, Anders, 1950-, et al. (författare)
  • Cognitive medicine - a new approach in health care science.
  • 2018
  • Ingår i: BMC psychiatry. - 1471-244X. ; 18:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The challenges of today's society call for more knowledge about how to maintain all aspects of cognitive health, such as speed/attention, memory/learning, visuospatial ability, language, executive capacity and social cognition during the life course. Main text: Medical advances have improved treatments of numerous diseases, but the cognitive implications have not been sufficiently addressed. Disability induced by cognitive dysfunction is also a major issue in groups of patients not suffering from Alzheimer's disease or related disorders. Recent studies indicate that several negative lifestyle factors can contribute to the development of cognitive impairment, but intervention and prevention strategies have not been implemented. Disability due to cognitive failure among the workforce has become a major challenge. Globally, the changing aging pyramid results in increased prevalence of cognitive disorders, and the diversity of cultures influences the expression, manifestation and consequences of cognitive dysfunction. Conclusions: Major tasks in the field of cognitive medicine are basic neuroscience research to uncover diverse disease mechanisms, determinations of the prevalence of cognitive dysfunction, health-economical evaluations, and intervention studies. Raising awareness for cognitive medicine as a clinical topic would also highlight the importance of specialized health care units for an integrative approach to the treatment of cognitive dysfunctions.
  • Eden, Arvid, et al. (författare)
  • Differential effects of efavirenz, lopinavir/r, and atazanavir/r on the initial viral decay rate in treatment naïve HIV-1-infected patients.
  • 2010
  • Ingår i: AIDS research and human retroviruses. - 1931-8405. ; 26:5, s. 533-40
  • Tidskriftsartikel (refereegranskat)abstract
    • Initial viral decay rate may be useful when comparing the relative potency of antiretroviral regimens. Two hundred twenty-seven ART-naive patients were randomized to receive efavirenz (EFV) (n=74), lopinavir/ritonavir (LPV/r) (n=77), or atazanavir/ritonavir (ATV/r) (n=79) in combination with two NRTIs. The most frequently used NRTI combinations in the EFV and ATV/r groups were the nonthymidine analogues tenofovir and emtricitabine or lamivudine (70% and 68%, respectively) and, in the LPV/r group, lamivudine and the thymidine analogue zidovudine (89%). HIV-1 RNA was monitored during the first 28 days after treatment initiation. Phase 1 and 2 decay rate was estimated in a subset of 157 patients by RNA decrease from days 0 to 7, and days 14 to 28. One-way ANOVA and subsequent Tukey's post hoc tests were used for groupwise comparisons. Mean (95% CI) HIV-1 RNA reductions from days 0 to 28 were 2.59 (2.45-2.73), 2.42 (2.27-2.57), and 2.13 (2.01-2.25) log(10) copies/ml for the EFV-, LPV/r-, and ATV/r-based treatment groups, respectively, with a significantly larger decrease in the EFV-based group at all time points compared with ATV/r (p<0.0001), and with LPV/r at days 7-21 (p<0.0001-0.03). LPV/r gave a greater RNA decrease compared with ATV/r from day 14 (p=0.02). Phase 1 decay rate was significantly higher in the EFV group compared with LPV/r (p=0.003) or ATV/r (p<0.0001). No difference was found in phase 2 decrease. EFV-based treatment gave a more rapid decline in HIV-1 RNA than did either of the boosted protease inhibitor-based regimens. The observed differences may reflect different inherent regimen potencies.
  • Eldh, Christer, et al. (författare)
  • Fika, hygge and hospitality : The cultural complexity of service organisation in the Öresund region
  • 2019
  • Ingår i: Fika, Hygge and Hospitality : The Cultural Complexity of Service Organisation in the Öresund Region - The Cultural Complexity of Service Organisation in the Öresund Region : The Cultural Complexity of Service Organisation in the Öresund Region. - Makadam förlag. - 2001-9874. - 978-91-7061-302-9 ; 39, s. 7-21
  • Bokkapitel (övrigt vetenskapligt)
  • Wahlin, Bjorn Engelbrekt, et al. (författare)
  • T Cells in Tumors and Blood Predict Outcome in Follicular Lymphoma Treated with Rituximab
  • 2011
  • Ingår i: Clinical Cancer Research. - American Association for Cancer Research. - 1078-0432. ; 17:12, s. 4136-4144
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: T cells influence outcome in follicular lymphoma, but their contributions seem to be modified by therapy. Their impact in patients receiving rituximab without chemotherapy is unknown. Experimental Design: Using flow cytometry, we evaluated the T cells in tumors and/or blood in a total of 250 follicular lymphoma patients included in two Nordic Lymphoma Group randomized trials that compared single rituximab with IFN-alpha 2a-rituximab combinations. Results: In univariate analysis, higher levels of CD3(+), CD4(+), and CD8(+) T cells in both tumors and blood correlated with superior treatment responses, and in multivariate analysis, tumor-CD3(+) (P = 0.011) and blood-CD4(+) (P = 0.029) cells were independent. CD4(+) cells were favorable regardless of treatment arm, but CD8(+) cells were favorable only in patients treated with single rituximab, because IFN-alpha 2a improved responses especially in patients with low CD8(+) cell levels. Higher levels of blood-CD3(+) (P = 0.003) and blood-CD4(+) (P = 0.046) cells predicted longer overall survival, and higher levels of blood-CD8(+) cells longer times to next treatment (P = 0.046). Conclusions: We conclude that therapeutic effects of rituximab are augmented by tumor-associated T cells for rapid responses and by systemic T cells for sustained responses. CD4(+) and CD8(+) cells are both favorable in patients treated with rituximab. IFN-alpha 2a abrogates the negative impact of few CD8(+) cells. Clin Cancer Res; 17(12); 4136-44. (C) 2011 AACR.
  • Ahlstrom, C, et al. (författare)
  • The impact of driver sleepiness on fixation-related brain potentials
  • 2019
  • Ingår i: Journal of Sleep Research. - 1365-2869 .- 0962-1105.
  • Tidskriftsartikel (refereegranskat)abstract
    • The effects of driver sleepiness are often quantified as deteriorated driving performance, increased blink durations and high levels of subjective sleepiness. Driver sleepiness has also been associated with increasing levels of electroencephalogram (EEG) power, especially in the alpha range. The present exploratory study investigated a new measure of driver sleepiness, the EEG fixation-related lambda response. Thirty young male drivers (23.6 +/- 1.7 years old) participated in a driving simulator experiment in which they drove on rural and suburban roads in simulated daylight versus darkness during both the daytime (full sleep) and night-time (sleep deprived). The results show lower lambda responses during night driving and with longer time on task, indicating that sleep deprivation and time on task cause a general decrement in cortical responsiveness to incoming visual stimuli. Levels of subjective sleepiness and line crossings were higher under the same conditions. Furthermore, results of a linear mixed-effects model showed that low lambda responses are associated with high subjective sleepiness and more line crossings. We suggest that the fixation-related lambda response can be used to investigate driving impairment induced by sleep deprivation while driving and that, after further refinement, it may be useful as an objective measure of driver sleepiness.
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