| 1. |
- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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| 6. |
- Kruse, N., et al.
(författare)
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Validation of a quantitative cerebrospinal fluid alpha-synuclein assay in a European-wide interlaboratory study
- 2015
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 36:9, s. 2587-2596
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Tidskriftsartikel (refereegranskat)abstract
- Decreased levels of alpha-synuclein (aSyn) in cerebrospinal fluid (CSF) in Parkinson's disease and related synucleinopathies have been reported, however, not consistently in all cross-sectional studies. To test the performance of one recently released human-specific enzyme-linked immunosorbent assay (ELISA) for the quantification of aSyn in CSF, we carried out a round robin trial with 18 participating laboratories trained in CSF ELISA analyses within the BIOMARKAPD project in the EU Joint Program -Neurodegenerative Disease Research. CSF samples (homogeneous aliquots from pools) and ELISA kits (one lot) were provided centrally and data reported back to one laboratory for data analysis. Our study showed that although factors such as preanalytical sample handling and lot-to-lot variability were minimized by our study design, we identified high variation in absolute values of CSF aSyn even when the same samples and same lots of assays were applied. We further demonstrate that although absolute concentrations differ between laboratories the quantitative results are comparable. With further standardization this assay may become an attractive tool for comparing aSyn measurements in diverse settings. Recommendations for further validation experiments and improvement of the interlaboratory results obtained are given. (C) 2015 Elsevier Inc. All rights reserved.
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| 7. |
- Thoma, B, et al.
(författare)
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An international, interprofessional investigation of the self-reported podcast listening habits of emergency clinicians: A METRIQ Study
- 2020
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Ingår i: CJEM. - : Springer Science and Business Media LLC. - 1481-8043 .- 1481-8035. ; 22:1, s. 112-117
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesPodcasts are increasingly being used for medical education. A deeper understanding of usage patterns would inform both producers and researchers of medical podcasts. We aimed to determine how and why podcasts are used by emergency medicine and critical care clinicians.MethodsAn international interprofessional sample (medical students, residents, physicians, nurses, physician assistants, and paramedics) was recruited through direct contact and a multimodal social media (Twitter and Facebook) campaign. Each participant completed a survey outlining how and why they utilize medical podcasts. Recruitment materials included an infographic and study website.Results390 participants from 33 countries and 4 professions (medicine, nursing, paramedicine, physician assistant) completed the survey. Participants most frequently listened to medical podcasts to review new literature (75.8%), learn core material (75.1%), and refresh memory (71.8%). The majority (62.6%) were aware of the ability to listen at increased speeds, but most (76.9%) listened at 1.0 x (normal) speed. All but 25 (6.4%) participants concurrently performed other tasks while listening. Driving (72.3%), exercising (39.7%), and completing chores (39.2%) were the most common. A minority of participants used active learning techniques such as pausing, rewinding, and replaying segments of the podcast. Very few listened to podcasts multiple times.ConclusionsAn international cohort of emergency clinicians use medical podcasts predominantly for learning. Their listening habits (rarely employing active learning strategies and frequently performing concurrent tasks) may not support this goal. Further exploration of the impact of these activities on learning from podcasts is warranted.
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| 13. |
- Mattsson, Niklas, 1979, et al.
(författare)
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CSF biomarker variability in the Alzheimer's Association quality control program
- 2013
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 9:3, s. 251-261
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Tidskriftsartikel (refereegranskat)abstract
- Background The cerebrospinal fluid (CSF) biomarkers amyloid beta 1–42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1–42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.
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| 14. |
- Tucker, S., et al.
(författare)
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Improving the mix of institutional and community care for older people with dementia : an application of the balance of care approach in eight European countries
- 2016
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Ingår i: Aging and Mental Health. - Abingdon : Informa UK Limited. - 1360-7863 .- 1364-6915. ; 20:12, s. 1327-1338
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To examine whether the mix of community and institutional long-term care (ILTC) for people with dementia (PwD) in Europe could be improved; assess the economic consequences of providing alternative services for particular groups of ILTC entrants and explore the transnational application of the ‘Balance of Care’ (BoC) approach. Method: A BoC study was undertaken in Estonia, Finland, France, Germany, the Netherlands, Spain, Sweden, and the UK as part of the RightTimePlaceCare project. Drawing on information about 2014 PwD on the margins of ILTC admission, this strategic planning framework identified people whose needs could be met in more than one setting, and compared the relative costs of the possible alternatives. Results: The findings suggest a noteworthy minority of ILTC entrants could be more appropriately supported in the community if enhanced services were available. This would not necessarily require innovative services, but more standard care (including personal and day care), assuming quality was ensured. Potential cost savings were identified in all countries, but community care was not always cheaper than ILTC and the ability to release resources varied between nations. Conclusions: This is believed to be the first transnational application of the BoC approach, and demonstrates its potential to provide a consistent approach to planning across different health and social care systems. Better comparative information is needed on the number of ILTC entrants with dementia, unit costs and outcomes. Nevertheless, the findings offer important evidence on the appropriateness of current provision, and the opportunity to learn from different countries' experience.
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| 15. |
- De Kort, A. M., et al.
(författare)
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Decreased Cerebrospinal Fluid Amyloid beta 38, 40, 42, and 43 Levels in Sporadic and Hereditary Cerebral Amyloid Angiopathy
- 2023
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Ingår i: Annals of neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 93:6, s. 1173-86
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Vascular amyloid beta (A beta) accumulation is the hallmark of cerebral amyloid angiopathy (CAA). The composition of cerebrospinal fluid (CSF) of CAA patients may serve as a diagnostic biomarker of CAA. We studied the diagnostic potential of the peptides A beta 38, A beta 40, A beta 42, and A beta 43 in patients with sporadic CAA (sCAA), hereditary Dutch-type CAA (D-CAA), and Alzheimer disease (AD).Methods: A beta peptides were quantified by immunoassays in a discovery group (26 patients with sCAA and 40 controls), a validation group (40 patients with sCAA, 40 patients with AD, and 37 controls), and a group of 22 patients with D-CAA and 54 controls. To determine the diagnostic accuracy, the area under the curve (AUC) was calculated using a receiver operating characteristic curve with 95% confidence interval (CI).Results: We found decreased levels of all A beta peptides in sCAA patients and D-CAA patients compared to controls. The difference was most prominent for A beta 42 (AUC of sCAA vs controls for discovery: 0.90, 95% CI = 0.82-0.99; for validation: 0.94, 95% CI = 0.89-0.99) and A beta 43 (AUC of sCAA vs controls for discovery: 0.95, 95% CI = 0.88-1.00; for validation: 0.91, 95% CI = 0.83-1.0). All A beta peptides except A beta 43 were also decreased in sCAA compared to AD (CSF A beta 38: AUC = 0.82, 95% CI = 0.71-0.93; CSF A beta 40: AUC = 0.88, 95% CI = 0.80-0.96; CSF A beta 42: AUC = 0.79, 95% CI = 0.66-0.92).Interpretation: A combined biomarker panel of CSF A beta 38, A beta 40, A beta 42, and A beta 43 has potential to differentiate sCAA from AD and controls, and D-CAA from controls. ANN NEUROL 2023
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| 16. |
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| 17. |
- Ramakers, I. H. G. B., et al.
(författare)
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Anxiety is related to Alzheimer cerebrospinal fluid markers in subjects with mild cognitive impairment
- 2013
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Ingår i: Psychological Medicine. - 0033-2917 .- 1469-8978. ; 43:5, s. 911-920
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Tidskriftsartikel (refereegranskat)abstract
- Background Anxiety, apathy and depression are common in subjects with mild cognitive impairment (MCI) and may herald Alzheimer's disease (AD). We investigated whether these symptoms correlated with cerebrospinal fluid (CSF) markers for AD in subjects with MCI. Method Subjects with MCI (n=268) were selected from the 'Development of screening guidelines and criteria for pre-dementia Alzheimer's disease' (DESCRIPA) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. We measured amyloid β(1-42) protein (Aβ42) and total tau (t-tau) in CSF. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory. Results Depressive symptoms were reported by 55 subjects (21%), anxiety by 35 subjects (13%) and apathy by 49 subjects (18%). The presence of anxiety was associated with abnormal CSF Aβ42 [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6-3.3] and t-tau (OR 2.6, 95% CI 1.9-3.6) concentrations and with the combination of abnormal concentrations of both Aβ42 and t-tau (OR 3.1, 95% CI 2.0-4.7). The presence of agitation and irritability was associated with abnormal concentrations of Aβ42 (agitation: OR 1.6, 95% CI 1.1-2.3; irritability: OR 2.2, 95% CI 1.5-3.3). Symptoms of depression and apathy were not related to any of the CSF markers. Conclusions In subjects with MCI, symptoms of anxiety, agitation and irritability may reflect underlying AD pathology, whereas symptoms of depression and apathy do not. © 2012 Cambridge University Press.
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| 18. |
- van Doorn, Ljcv, et al.
(författare)
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Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes
- 2017
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 56:2, s. 543-555
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., A beta(42), total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF A beta(42) levels inversely correlated to VV/TIV in the whole study population (A beta(42): r = -0.28; p < 0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r = -0.15; p-tau: r = -0.13; both p < 0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF A beta(42) alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF A beta(42) levels.
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| 19. |
- Van Wijk, Rob C., 1991-, et al.
(författare)
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Anti‐tuberculosis effect of isoniazid scales accurately from zebrafish to humans
- 2020
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 177:24, s. 5518-5533
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Tidskriftsartikel (refereegranskat)abstract
- Background and purposeThere is a strong need for innovation in anti-tuberculosis drug development. The zebrafish larva is an attractive disease model in tuberculosis research. To translate pharmacological findings to higher vertebrates, including humans, the internal exposure of drugs needs to be quantified and linked to observed response.Experimental approachIn zebrafish studies, drugs are commonly dissolved in the external water, posing a challenge to quantify internal exposure. We developed experimental methods to quantify internal exposure, including nano-scale blood sampling, and to quantify the bacterial burden, using automated fluorescence imaging analysis, with isoniazid as paradigm compound. We used pharmacokinetic-pharmacodynamic modelling to quantify the exposure-response relationship responsible for the antibiotic response. To translate isoniazid response to humans, the quantitative exposure-response relationship in zebrafish was linked to simulated concentration-time profiles in humans, and two quantitative translational factors on sensitivity to isoniazid and stage of infection were included.Key resultsBlood concentration was only 20% of the external drug concentration. The bacterial burden increased exponentially and an isoniazid dose corresponding to 15 mg·L-1internal concentration (minimum inhibitory concentration) lead to bacteriostasis of the mycobacterial infection in the zebrafish. The concentration-effect relationship was quantified, and based on that relationship and the translational factors, the isoniazid response was translated to humans, which correlated well with observed data.Conclusions and implicationsThis proof-of-concept confirms the potential of the zebrafish larvae as tuberculosis disease model in translational pharmacology, and contributes to innovative anti-tuberculosis drug development which is strongly needed.
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| 20. |
- Afram, Basema, et al.
(författare)
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Predicting institutional long-term care admission in dementia: a mixed-methods study of informal caregivers' reports
- 2015
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Ingår i: Journal of Advanced Nursing. - Chichester : Wiley. - 0309-2402 .- 1365-2648. ; 71:6, s. 1351-1362
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Tidskriftsartikel (refereegranskat)abstract
- AimTo investigate agreement between: (1) expected reasons and actual reasons for admission of people with dementia according to informal caregivers; (2) scores on measurement instruments prior to admission and the actual reasons for admission according to informal caregivers. BackgroundTimely admission of people with dementia is a crucial issue. Information is highly warranted on whether informal caregivers are capable of prior identification of causes of admission and, can thus be considered a reliable prospective source on causes of admission. DesignA cohort study among informal caregivers of people with dementia who made a transition to institutional long-term care. MethodsQualitative data on the expected and actual reasons for admission were collected via open-ended questions at baseline and follow-up. Furthermore, at baseline, data were collected using measurement instruments to measure pre-admission characteristics. Interviews took place between November 2010-April 2012. After categorizing the answers, the agreement between the expected and actual reasons was calculated. Furthermore, bivariate associations were calculated between the actual reasons for admission and scores on corresponding measurement instruments. Results/FindingsFor most informal caregivers, there was agreement between their statements on the expected reason and the actual reason for admission. A third of the caregivers showed no conformity. Bivariate associations showed that there is also agreement between the actual reasons for admission and scores on corresponding measurement instruments. ConclusionInformal caregivers can be considered reliable sources of information regarding what causes the admission of a person with dementia. Professional care should anticipate informal caregivers' statements and collaborate with them to strive for timely and appropriate admission.
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| 21. |
- Afram, Basema, et al.
(författare)
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Reasons for Institutionalization of People With Dementia: Informal Caregiver Reports From 8 European Countries
- 2014
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Ingår i: Journal of the American Medical Directors Association. - : Elsevier BV. - 1525-8610. ; 15:2, s. 108-116
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To explore reasons for institutionalization of people with dementia according to informal caregivers as well as variation in reasons between countries. Design: An explorative cross-sectional study was conducted in 8 European countries. Setting: Per country, a minimum of 3 long term care facilities, offering care and accommodation as a package, participated in this study. Participating countries were selected to represent different geographic areas in Europe. Participants: Of the 791 informal caregivers involved in the RightTimePlaceCare project of people with dementia who were recently admitted to a long term care facility, 786 were included for this study. Measurements: As part of a semistructured interview, informal caregivers were asked the main reason for institutionalization in an open-ended question. Answers were categorized according to a conventional coding approach. All reasons were then quantified and tested. Results: Mainly patient-related reasons were stated, such as neuropsychiatric symptoms (25%), care dependency (24%), and cognition (19%). Neuropsychiatric symptoms were among the most often mentioned reasons in most countries. Besides patient-related reasons, caregiver burden and the inability of the informal caregiver to care for the patient were stated as reasons (both 15%). Further analyses showed countries differ significantly in reasons according to informal caregivers. Additionally, reasons were analyzed for spouses and child-caregivers, showing that spouses more often stated reasons related to themselves compared with child-caregivers. Conclusion: Multiple reasons contribute to the institutionalization for people with dementia, with several factors that may influence why there were country differences. Variation in the organization of dementia care and cultural aspects, or the relationship between the informal caregiver and person with dementia may be factors influencing the reasons. Because of a wide variation in reasons between countries, no one-size-fits-all approach can be offered to guide informal caregivers when facing the possibility of institutionalization of the person with dementia. (C) 2014 - American Medical Directors Association, Inc. All rights reserved.
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| 24. |
- Fransen, M. F., et al.
(författare)
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A Restricted Role for FcgammaR in the Regulation of Adaptive Immunity
- 2018
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 200:8, s. 2615-2626
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Tidskriftsartikel (refereegranskat)abstract
- By their interaction with IgG immune complexes, FcgammaR and complement link innate and adaptive immunity, showing functional redundancy. In complement-deficient mice, IgG downstream effector functions are often impaired, as well as adaptive immunity. Based on a variety of model systems using FcgammaR-knockout mice, it has been concluded that FcgammaRs are also key regulators of innate and adaptive immunity; however, several of the model systems underpinning these conclusions suffer from flawed experimental design. To address this issue, we generated a novel mouse model deficient for all FcgammaRs (FcgammaRI/II/III/IV(-/-) mice). These mice displayed normal development and lymphoid and myeloid ontogeny. Although IgG effector pathways were impaired, adaptive immune responses to a variety of challenges, including bacterial infection and IgG immune complexes, were not. Like FcgammaRIIb-deficient mice, FcgammaRI/II/III/IV(-/-) mice developed higher Ab titers but no autoantibodies. These observations indicate a redundant role for activating FcgammaRs in the modulation of the adaptive immune response in vivo. We conclude that FcgammaRs are downstream IgG effector molecules with a restricted role in the ontogeny and maintenance of the immune system, as well as the regulation of adaptive immunity.
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| 25. |
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| 26. |
- Joshi, PK, et al.
(författare)
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Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity
- 2017
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1, s. 910-
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Tidskriftsartikel (refereegranskat)abstract
- Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents’ survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.
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| 27. |
- Le, Phu Tran Phong, et al.
(författare)
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Tailoring Vanadium Dioxide Film Orientation Using Nanosheets : a Combined Microscopy, Diffraction, Transport, and Soft X-Ray in Transmission Study
- 2020
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Ingår i: Advanced Functional Materials. - : WILEY-V C H VERLAG GMBH. - 1616-301X .- 1616-3028. ; 30:1
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Tidskriftsartikel (refereegranskat)abstract
- Vanadium dioxide (VO2) is a much-discussed material for oxide electronics and neuromorphic computing applications. Here, heteroepitaxy of VO2 is realized on top of oxide nanosheets that cover either the amorphous silicon dioxide surfaces of Si substrates or X-ray transparent silicon nitride membranes. The out-of-plane orientation of the VO2 thin films is controlled at will between (011)(M1)/(110)(R) and (-402)(M1)/(002)(R) by coating the bulk substrates with Ti0.87O2 and NbWO6 nanosheets, respectively, prior to VO2 growth. Temperature-dependent X-ray diffraction and automated crystal orientation mapping in microprobe transmission electron microscope mode (ACOM-TEM) characterize the high phase purity, the crystallographic and orientational properties of the VO2 films. Transport measurements and soft X-ray absorption in transmission are used to probe the VO2 metal-insulator transition, showing results of a quality equal to those from epitaxial films on bulk single-crystal substrates. Successful local manipulation of two different VO2 orientations on a single substrate is demonstrated using VO2 grown on lithographically patterned lines of Ti0.87O2 and NbWO6 nanosheets investigated by electron backscatter diffraction. Finally, the excellent suitability of these nanosheet-templated VO2 films for advanced lensless imaging of the metal-insulator transition using coherent soft X-rays is discussed.
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| 29. |
- Schulze, Steve, et al.
(författare)
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The Palomar Transient Factory Core-collapse Supernova Host-galaxy Sample. I. Host-galaxy Distribution Functions and Environment Dependence of Core-collapse Supernovae
- 2021
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Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 255:2
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Tidskriftsartikel (refereegranskat)abstract
- Several thousand core-collapse supernovae (CCSNe) of different flavors have been discovered so far. However, identifying their progenitors has remained an outstanding open question in astrophysics. Studies of SN host galaxies have proven to be powerful in providing constraints on the progenitor populations. In this paper, we present all CCSNe detected between 2009 and 2017 by the Palomar Transient Factory. This sample includes 888 SNe of 12 distinct classes out to redshift z approximate to 1. We present the photometric properties of their host galaxies from the far-ultraviolet to the mid-infrared and model the host-galaxy spectral energy distributions to derive physical properties. The galaxy mass function of Type Ic, Ib, IIb, II, and IIn SNe ranges from 10(5) to 10(11.5) M (circle dot), probing the entire mass range of star-forming galaxies down to the least-massive star-forming galaxies known. Moreover, the galaxy mass distributions are consistent with models of star-formation-weighted mass functions. Regular CCSNe are hence direct tracers of star formation. Small but notable differences exist between some of the SN classes. Type Ib/c SNe prefer galaxies with slightly higher masses (i.e., higher metallicities) and star formation rates than Type IIb and II SNe. These differences are less pronounced than previously thought. H-poor superluminous supernovae (SLSNe) and SNe Ic-BL are scarce in galaxies above 10(10) M (circle dot). Their progenitors require environments with metallicities of < 0.4 and < 1 solar, respectively. In addition, the hosts of H-poor SLSNe are dominated by a younger stellar population than all other classes of CCSNe. Our findings corroborate the notion that low metallicity and young age play an important role in the formation of SLSN progenitors.
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| 30. |
- Sharp, Phoebe E H, et al.
(författare)
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FcγRIIb on Myeloid Cells and Intrinsic Renal Cells Rather than B Cells Protects from Nephrotoxic Nephritis
- 2013
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 190:1, s. 340-348
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Tidskriftsartikel (refereegranskat)abstract
- FcγRIIb is the sole inhibitory FcR for IgG in humans and mice, where it is involved in the negative regulation of Ab production and cellular activation. FcγRIIb-deficient mice show exacerbated disease following the induction of nephrotoxic nephritis (NTN). In this study, we determined the cellular origin of the FcγRIIb-knockout phenotype by inducing NTN in mice with a deficiency of FcγRIIb on either B cells alone (FcγRIIBfl/fl/CD19Cre+) or myeloid cells (FcγRIIBfl/fl/CEBPαCre+). Deletion of FcγRIIb from B cells did not increase susceptibility to NTN, compared with wild-type (WT) mice, despite higher Ab titers in the FcγRIIBfl/fl/CD19Cre+ mice compared with the WT littermate controls. In contrast, mice lacking FcγRIIb on myeloid cells had exacerbated disease as measured by increased glomerular thrombosis, glomerular crescents, albuminuria, serum urea, and glomerular neutrophil infiltration when compared with WT littermate controls. The role for FcγRIIb expression on radioresistant intrinsic renal cells in the protection from NTN was then investigated using bone marrow chimeric mice. FcγRIIb−/− mice transplanted with FcγRIIb−/− bone marrow were more susceptible to NTN than WT mice transplanted with FcγRIIb−/− bone marrow, indicating that the presence of WT intrinsic renal cells protects from NTN. These results demonstrate that FcγRIIb on myeloid cells plays a major role in protection from NTN, and therefore, augmentation of FcγRIIb on these cells could be a therapeutic target in human Ab-mediated glomerulonephritis. Where there was a lack of FcγRIIb on circulating myeloid cells, expression of FcγRIIb on intrinsic renal cells provided an additional level of protection from Ab-mediated glomerulonephritis.
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| 31. |
- Sharp, Phoebe E H, et al.
(författare)
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Increased incidence of anti-GBM disease in Fcgamma receptor 2b deficient mice, but not mice with conditional deletion of Fcgr2b on either B cells or myeloid cells alone
- 2012
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Ingår i: Molecular Immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 50:1-2, s. 49-56
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Tidskriftsartikel (refereegranskat)abstract
- Fcgamma receptor 2b (Fcgr2b) is the only inhibitory Fcgamma receptor in both humans and mice, and is implicated in both antibody production and effector responses to antibody complexes. Reduced function of Fcgr2b has previously been associated with anti-glomerular basement membrane antibody (anti-GBM) disease in mice. However, the mice used had 129 genetic elements flanking the deleted Fcgr2b gene, which are known to increase susceptibility to autoimmunity. In order to confirm a role for Fcgr2b in protection from anti-GBM disease, wild type (WT) mice, mice lacking Fcgr2b on a pure C57BL/6 background, or mice lacking Fcgr2b on a C57BL/6 background with 129 flanking sequences, were immunized with the recombinant NC1 domain of alpha 3 Type IV collagen. Twenty two weeks after immunization, there was a higher incidence of crescentic glomerulonephritis, macrophage infiltration and renal dysfunction in both groups of Fcgr2b-/- mice, indicating an important role of Fcgr2b in regulating the development of anti-GBM disease, on both genetic backgrounds. In order to determine the cellular origin of the Fcgr2b-associated effect, disease was induced in mice with deficiency of Fcgr2b on either B cells alone (CD19Cre), or a subset of myeloid cells (LysozymeMCre). Neither B cell nor myeloid specific knockout mice developed crescentic glomeruonephritis with higher incidence than WT mice indicating that Fcgr2b deficiency on either B cells or a subset of myeloid cells alone is not sufficient to increase susceptibility to anti-GBM disease, but that a combination of cell types, or deficiency of Fcgr2b in a different cell type, is also required.
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| 32. |
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| 33. |
- van Waalwijk van Doorn, Linda J C, et al.
(författare)
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Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes
- 2017
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 56:2, s. 543-555
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r=-0.28; p<0.0001). For CSF t-tau and p-tau, this association only reached statistical significance in the combined MCI and AD group (t-tau: r=-0.15; p-tau: r=-0.13; both p<0.01). Correction for differences in VV/TIV improved the differentiation of AD versus controls based on CSF Aβ42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.
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| 34. |
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| 35. |
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| 36. |
- Andreasson, Ulf, 1968, et al.
(författare)
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A Practical Guide to Immunoassay Method Validation.
- 2015
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Ingår i: Frontiers in neurology. - : Frontiers Media SA. - 1664-2295. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Biochemical markers have a central position in the diagnosis and management of patients in clinical medicine, and also in clinical research and drug development, also for brain disorders, such as Alzheimer's disease. The enzyme-linked immunosorbent assay (ELISA) is frequently used for measurement of low-abundance biomarkers. However, the quality of ELISA methods varies, which may introduce both systematic and random errors. This urges the need for more rigorous control of assay performance, regardless of its use in a research setting, in clinical routine, or drug development. The aim of a method validation is to present objective evidence that a method fulfills the requirements for its intended use. Although much has been published on which parameters to investigate in a method validation, less is available on a detailed level on how to perform the corresponding experiments. To remedy this, standard operating procedures (SOPs) with step-by-step instructions for a number of different validation parameters is included in the present work together with a validation report template, which allow for a well-ordered presentation of the results. Even though the SOPs were developed with the intended use for immunochemical methods and to be used for multicenter evaluations, most of them are generic and can be used for other technologies as well.
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| 37. |
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| 38. |
- Bartels, Ronald H M A, et al.
(författare)
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External validation of a model to predict the survival of patients presenting with a spinal epidural metastasis.
- 2011
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Ingår i: Cancer metastasis reviews. - : Springer Science and Business Media LLC. - 1573-7233 .- 0167-7659. ; 30:2, s. 153-9
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Tidskriftsartikel (refereegranskat)abstract
- The surgical treatment of spinal metastases is evolving. The major problem is the selection of patients who may benefit from surgical treatment. One of the criteria is an expected survival of at least 3 months. A prediction model has been previously developed. The present study has been performed in order to validate externally the model and to demonstrate that this model can be generalized to other institutions and other countries than the Netherlands. Data of 356 patients from five centers in Germany, Spain, Sweden, and the Netherlands who were treated for metastatic epidural spinal cord compression were collected. Hazard ratios in the test population corresponded with those of the developmental population. However, the observed and the expected survival were different. Analysis revealed that the baseline hazard function was significantly different. This tempted us to combine the data and develop a new prediction model. Estimating iteratively, a baseline hazard was composed. An adapted prediction model is presented. External validation of a prediction model revealed a difference in expected survival, although the relative contribution of the specific hazard ratios was the same as in the developmental population. This study emphasized the need to check the baseline hazard function in external validation. A new model has been developed using an estimated baseline hazard.
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| 39. |
- Beerens, Hanneke C., et al.
(författare)
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Change in quality of life of people with dementia recently admitted to long-term care facilities
- 2015
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Ingår i: Journal of Advanced Nursing. - : Wiley. - 0309-2402. ; 71:6, s. 1435-1447
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Tidskriftsartikel (refereegranskat)abstract
- AimTo assess which factors are associated with change in quality of life of people with dementia who have recently been admitted to long-term care facilities. BackgroundMany people with dementia will be admitted to long-term care facilities at some point during their disease. It is currently unknown which factors are associated with improvement and/or deterioration of quality of life immediately following admission. DesignAn observational and longitudinal survey. MethodsData on 343 people with dementia who have been recently admitted to long-term care facilities across eight European countries were collected between November 2010-April 2012. Quality of life was assessed by people with dementia and their proxies using the Quality of Life-Alzheimer's Disease scale'. Explanatory variables included cognitive status, comorbidities, activities of daily living, depressive symptoms and neuropsychiatric symptoms. Descriptive and multilevel regression analyses were performed. ResultsBetter cognitive abilities at baseline were associated with a decrease in self-reported quality of life. Greater dependency and more depressive symptoms at baseline were associated with declined proxy-reported quality of life. Furthermore, an increased dependency and an increase of depressive symptoms between baseline and follow-up were associated with a decreased proxy-reported quality of life. On an individual level, three groups were identified, namely people whose quality of life: (1) decreased; (2) stayed the same; and (3) increased. ConclusionCognitive functioning, functional rehabilitation and treatment of depressive symptoms should receive special attention. However, quality of life of people with dementia does not necessarily decrease after institutionalization.
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| 40. |
- Bieber, A., et al.
(författare)
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Access to community care for people with dementia and their informal carers : Case vignettes for a European comparison of structures and common pathways to formalcare [Zugang zu professioneller Unterstützung für Menschen mit Demenz und ihre Angehörigen: Fallvignetten für den europäischen Vergleich von Strukturen und Zugangswegen zu professioneller Pflege]
- 2018
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Ingår i: Zeitschrift für Gerontologie und Geriatrie (Print). - : Springer Science and Business Media LLC. - 0948-6704 .- 1435-1269. ; 51:5, s. 530-536
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPeople with dementia and their informal carers often do not receive appropriate professional support or it is not received at the right time.ObjectivesDescription and comparison of common pathways to formal community dementia care in eight European countries as a part of the transnational Actifcare project.Materials and methodsThe German team was responsible for creating an individual case scenario as a starting point. The research teams in Ireland, Italy, the Netherlands, Norway, Portugal, Sweden, and the United Kingdom were then asked to describe a common pathway to formal dementia care by writing their own vignette using the provided individual case scenario.ResultsA transnational qualitative content analysis was used to identify the following categories as being the most important: involved professionals, dementia-specific and team-based approaches, proactive roles, and financial aspects. General practitioners (GPs) are described as being the most important profession supporting the access to formal care in all the involved countries. In some countries other professionals take over responsibility for the access procedure. Dementia-specific approaches are rarely part of standard care; team-based approaches have differing significances in each of the countries. Informal carers are mainly proactive in seeking formal care. The Nordic countries demonstrate how financial support enhances access to the professional system.ConclusionEnhanced cooperation between GPs and other professions might optimize access to formal dementia care. Team-based approaches focusing on dementia care should be developed further. Informal carers should be supported and relieved in their role. Financial barriers remain which should be further investigated and reduced.
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| 41. |
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| 42. |
- Bos, Isabelle, et al.
(författare)
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Cerebrovascular and amyloid pathology in predementia stages : the relationship with neurodegeneration and cognitive decline
- 2017
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Ingår i: Alzheimer's Research & Therapy. - : BioMed Central. - 1758-9193. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cerebrovascular disease (CVD) and amyloid-β (Aβ) often coexist, but their influence on neurodegeneration and cognition in predementia stages remains unclear. We investigated the association between CVD and Aβ on neurodegenerative markers and cognition in patients without dementia.METHODS: We included 271 memory clinic patients with subjective or objective cognitive deficits but without dementia from the BioBank Alzheimer Center Limburg cohort (n = 99) and the LeARN (n = 50) and DESCRIPA (n = 122) multicenter studies. CSF Aβ1-42 and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI) scans were used as measures of Aβ and CVD, respectively. Individuals were classified into four groups based on the presence (+) or absence (-) of Aβ and WMH. We investigated differences in phosphorylated tau, total tau (t-tau), and medial temporal lobe atrophy (MTA) between groups using general linear models. We examined cognitive decline and progression to dementia using linear mixed models and Cox proportional hazards models. All analyses were adjusted for study and demographics.RESULTS: MTA and t-tau were elevated in the Aβ - WMH+, Aβ + WMH-, and Aβ + WMH+ groups. MTA was most severe in the Aβ + WMH+ group compared with the groups with a single pathology. Both WMH and Aβ were associated with cognitive decline, but having both pathologies simultaneously was not associated with faster decline.CONCLUSIONS: In the present study, we found an additive association of Aβ and CVD pathology with baseline MTA but not with cognitive decline. Because our findings may have implications for diagnosis and prognosis of memory clinic patients and for future scientific research, they should be validated in a larger sample with longer follow-up.
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| 43. |
- Bos, Isabelle, et al.
(författare)
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Correction to : Cerebrovascular and amyloid pathology in predementia stages
- 2018
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Ingår i: Alzheimer's Research & Therapy. - : BioMed Central. - 1758-9193. ; 10:56
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Tidskriftsartikel (refereegranskat)abstract
- Upon publication of this article [1], it was noticed that there were some inconsistencies in Tables 1, 2 and 3. Some of the superscript letters were incorrectly assigned. Please see below the correct tables.
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| 44. |
- Bridel, Claire, et al.
(författare)
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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
- 2019
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
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Forskningsöversikt (refereegranskat)abstract
- Importance Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure The cNfL levels adjusted for age and sex across diagnoses.Results Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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| 45. |
- Galosi, Serena, et al.
(författare)
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De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus
- 2022
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 145:1, s. 208-223
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Tidskriftsartikel (refereegranskat)abstract
- Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy, and movement disorder. We evaluated a large cohort of patients (n=25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor, and ataxia. Later in the disease course they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration, and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibers and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders.
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| 46. |
- Gonzalez, Hugo, et al.
(författare)
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Cellular architecture of human brain metastases
- 2022
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Ingår i: Cell. - : Elsevier BV. - 0092-8674. ; 185:4, s. 20-745
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Tidskriftsartikel (refereegranskat)abstract
- Brain metastasis (BrM) is the most common form of brain cancer, characterized by neurologic disability and an abysmal prognosis. Unfortunately, our understanding of the biology underlying human BrMs remains rudimentary. Here, we present an integrative analysis of >100,000 malignant and non-malignant cells from 15 human parenchymal BrMs, generated by single-cell transcriptomics, mass cytometry, and complemented with mouse model- and in silico approaches. We interrogated the composition of BrM niches, molecularly defined the blood-tumor interface, and revealed stromal immunosuppressive states enriched with infiltrated T cells and macrophages. Specific single-cell interrogation of metastatic tumor cells provides a framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our resource provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental traits.
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| 47. |
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| 48. |
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| 49. |
- Herbert, MK, et al.
(författare)
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Disease specificity of autoantibodies to cytosolic 5'-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases
- 2016
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 75:4, s. 696-701
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Tidskriftsartikel (refereegranskat)abstract
- The diagnosis of inclusion body myositis (IBM) can be challenging as it can be difficult to clinically distinguish from other forms of myositis, particularly polymyositis (PM). Recent studies have shown frequent presence of autoantibodies directed against cytosolic 5′-nucleotidase 1A (cN-1A) in patients with IBM. We therefore, examined the autoantigenicity and disease specificity of major epitopes of cN-1A in patients with sporadic IBM compared with healthy and disease controls.MethodsSerum samples obtained from patients with IBM (n=238), PM and dermatomyositis (DM) (n=185), other autoimmune diseases (n=246), other neuromuscular diseases (n=93) and healthy controls (n=35) were analysed for the presence of autoantibodies using immunodominant cN-1A peptide ELISAs.ResultsAutoantibodies directed against major epitopes of cN-1A were frequent in patients with IBM (37%) but not in PM, DM or non-autoimmune neuromuscular diseases (<5%). Anti-cN-1A reactivity was also observed in some other autoimmune diseases, particularly Sjögren's syndrome (SjS; 36%) and systemic lupus erythematosus (SLE; 20%).ConclusionsIn summary, we found frequent anti-cN-1A autoantibodies in sera from patients with IBM. Heterogeneity in reactivity with the three immunodominant epitopes indicates that serological assays should not be limited to a distinct epitope region. The similar reactivities observed for SjS and SLE demonstrate the need to further investigate whether distinct IBM-specific epitopes exist.
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| 50. |
- Jansen, Willemijn J, et al.
(författare)
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Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.
- 2018
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Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 84-95
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P=.16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P<.001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P<.001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years.Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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