| 1. |
- Ahmad, Shahzad, et al.
(författare)
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CDH6 and HAGH protein levels in plasma associate with Alzheimer’s disease in APOE ε4 carriers
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Many Alzheimer’s disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (Aβ) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N = 441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (β = 0.638, P = 3.33 × 10−4) and HAGH (β = 0.481, P = 7.20 × 10−4), were significantly elevated in APOE ε4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (β = 1.365, P = 3.97 × 10−3) and HAGH proteins (β = 0.506, P = 9.31 × 10−7) when comparing cases and controls in APOE ε4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ε4 stratum (P < 1 × 10−3). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 × 10−9). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers.
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| 2. |
- Chu, Lianhe, et al.
(författare)
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In vivo drug discovery for increasing incretin-expressing cells identifies DYRK inhibitors that reinforce the enteroendocrine system
- 2022
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Ingår i: Cell Chemical Biology. - : Elsevier BV. - 2451-9456 .- 2451-9448. ; 29:9, s. 5-1380
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Tidskriftsartikel (refereegranskat)abstract
- Analogs of the incretin hormones Gip and Glp-1 are used to treat type 2 diabetes and obesity. Findings in experimental models suggest that manipulating several hormones simultaneously may be more effective. To identify small molecules that increase the number of incretin-expressing cells, we established a high-throughput in vivo chemical screen by using the gip promoter to drive the expression of luciferase in zebrafish. All hits increased the numbers of neurogenin 3-expressing enteroendocrine progenitors, Gip-expressing K-cells, and Glp-1-expressing L-cells. One of the hits, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor, additionally decreased glucose levels in both larval and juvenile fish. Knock-down experiments indicated that nfatc4, a downstream mediator of DYRKs, regulates incretin+ cell number in zebrafish, and that Dyrk1b regulates Glp-1 expression in an enteroendocrine cell line. DYRK inhibition also increased the number of incretin-expressing cells in diabetic mice, suggesting a conserved reinforcement of the enteroendocrine system, with possible implications for diabetes.
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| 3. |
- Foord, Emelie, et al.
(författare)
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Profound Functional Suppression of Tumor-Infiltrating T-Cells in Ovarian Cancer Patients Can Be Reversed Using PD-1-Blocking Antibodies or DARPin (R) Proteins
- 2020
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Ingår i: Journal of Immunology Research. - : Hindawi Limited. - 2314-8861 .- 2314-7156. ; 2020
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Tidskriftsartikel (refereegranskat)abstract
- PD-1/PD-L1 blockade has revolutionized the field of immunooncology. Despite the relative success, the response rate to anti-PD-1 therapy requires further improvements. Our aim was to explore the enhancement of T-cell function by using novel PD-1-blocking proteins and compare with clinically approved monoclonal antibodies (mAbs). We isolated T-cells from the ascites and tumor of 17 patients with advanced epithelial ovarian cancer (EOC) and analyzed the effects using the mAbs nivolumab and pembrolizumab and two novel engineered ankyrin repeat proteins (DARPin (R) proteins). PD-1 blockade with either mAb or DARPin (R) molecule significantly increased the release of IFN-gamma, granzyme B, IL-2, and TNF-alpha, demonstrating successful reinvigoration. The monovalent DARPin (R) protein was less effective compared to its bivalent equivalent, demonstrating that bivalency brings an additional benefit to PD-1 blockade. Overall, we found a higher fold increase of lymphokine secretion in response to the PD-1 blockade by tumor-derived T-cells; however, the absolute amounts were significantly lower compared to the release from ascites-derived T-cells. Our results demonstrate that PD-1 blockade can only partially reinvigorate functionally suppressed T-cells from EOC patients. This warrants further investigation preferably in combination with other therapeutics. The study provides an early pilot proof-of-concept for the potential use of DARPin (R) proteins as eligible alternative scaffold proteins to block PD-1.
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| 4. |
- Forsner, Maria, et al.
(författare)
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Mitt i informationsflödet om Covid 19 pandemin, en internationell webbenkätstudie till föräldrar och barn 7-12 år
- 2020
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Ingår i: State of Art- Covid 2019, Nationell digital konferens, Svenska läkarsällskpet.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Bakgrund: Tidigt under våren 2020 drabbades Sverige av Covid 19 pandemin. Med pandemin följe en infodemi. Barn skolåldern och deras förälder hamnade mitt i detta informationsflöde. Syfte: Att undersöka hur barn får och tolkar information om Covid 19 pandemin. Metod: Anonymiserad webbenkät. 2 enkäter til barn, respektive föräldrar. Översatt till respektive språk. Deltagare 390 barn, 7-12 är (Sv 50) och 1234 föräldrar ( Sv 235). Insamling april – 1 juni ( Sv 22 maj-1 juni). Initierat av Lucy Bray med team, Edge Hills universitet Storbritannien. Omvårdnad forskare från Sverige, Kanada , Australien, Brasilien och Spanien. Resultat: Majoriteten av barn från andra länderna fick information från föräldrarna. Svaren från de svenska barnen speglade myndighetens rekommendationer. Utomhus skildrades som en positiv plats för de svenska barnen. Teckningar från Sverige visade i stor utsträckning munskydd på både människor och djur. Slutsats: De sveks barnen var medvetna om att coronaviruset kunde vara farligt, vikten av att hålla avstånd och tvätta händerna och skydda de äldre. Svaren från Sverige skiljde sig från de andra länderna med att skolan var främsta och önskade informationskällan. Utomhusaktiviteter uppskattades som önskvärt.
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| 5. |
- Globisch, Maria A., et al.
(författare)
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Immunothrombosis and vascular heterogeneity in cerebral cavernous malformation
- 2022
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 140:20, s. 2154-2169
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral cavernous malformation (CCM) is a neurovascular disease that results in various neurological symptoms. Thrombi have been reported in surgically resected CCM patient biopsies, but the molecular signatures of these thrombi remain elusive. Here, we investigated the kinetics of thrombi formation in CCM and how thrombi affect the vasculature and contribute to cerebral hypoxia. We used RNA sequencing to investigate the transcriptome of mouse brain endothelial cells with an inducible endothelial-specific Ccm3 knock-out (Ccm3-iECKO). We found that Ccm3-deficient brain endothelial cells had a higher expression of genes related to the coagulation cascade and hypoxia when compared with wild-type brain endothelial cells. Immunofluorescent assays identified key molecular signatures of thrombi such as fibrin, von Willebrand factor, and activated platelets in Ccm3-iECKO mice and human CCM biopsies. Notably, we identified polyhedrocytes in Ccm3-iECKO mice and human CCM biopsies and report it for the first time. We also found that the parenchyma surrounding CCM lesions is hypoxic and that more thrombi correlate with higher levels of hypoxia. We created an in vitro model to study CCM pathology and found that human brain endothelial cells deficient for CCM3 expressed elevated levels of plasminogen activator inhibitor-1 and had a redistribution of von Willebrand factor. With transcriptomics, comprehensive imaging, and an in vitro CCM preclinical model, this study provides experimental evidence that genes and proteins related to the coagulation cascade affect the brain vasculature and promote neurological side effects such as hypoxia in CCMs. This study supports the concept that antithrombotic therapy may be beneficial for patients with CCM.
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| 6. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
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Tidskriftsartikel (refereegranskat)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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| 7. |
- Lingström, Peter, 1960, et al.
(författare)
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Chapter 2: Oral conditions
- 2020
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Ingår i: The Impact of Nutrition and Diet on Oral Health. Zohoori, F. Vida (red.). - : S. Karger AG. - 0077-0892. ; , s. 14-21
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- An improvement in oral health, not least dental caries and periodontal disease, has been seen during the last 50 years. Oral health is essential for both general health and quality of life. The mouth is a window into the health of the body and signs of nutritional deficiencies can be seen in the mouth at an early stage. Dental caries still constitutes the most common oral condition worldwide. It is the net result of an ecological imbalance in the oral biofilm where metabolism of fermentable carbohydrates may result in demineralisation. Early diagnosis of disease symptoms and preventive strategies are important for disease management. Dental erosion, where loss of tooth substance is a result of exposure to acidic substances, has become a common condition. Intrinsic factors, including diet/drinks and intake habits, are common etiological causes. Periodontal diseases constitute chronic, biofilm-initiated inflammatory conditions with multifactorial origin including inherited and acquired risk factors. Preventive strategies focus on mechanisms, which may influence the amount and composition of the subgingival biofilm. Oral cancer is one of the most commonly found forms of malignancies worldwide. It is a highly complex condition where lifestyle factors, particularly smoking cessation and moderate alcohol consumption, play a major role as deterrents. Hyposalivation is of multifactorial aetiology and may influence oral health as well as various aspects of quality of life. To control oral health, it is important to increase our knowledge of oral disease aetiology and focus on oral health promotion and preventive strategies including the control of diet and nutritional risk factors. © 2020 S. Karger AG, Basel.
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| 8. |
- Münger, Ann- Charlotte, 1962-, et al.
(författare)
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`The Needs of the Child Have Been Met´ : Preliminary Assessments regarding Domestic Violence in Swedish Child Protections Services
- 2020
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Ingår i: Nordic Journal of Social Research. - Elverum, Norway : Nordic Journal of Social Research. - 1892-2783 .- 2156-857X. ; 10:2, s. 100-113
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Tidskriftsartikel (refereegranskat)abstract
- The Swedish Child Protection Services (CPS) are responsible for providing support and protection to children experiencing domestic violence, but in a high proportion of cases where there is a suspicion that children are experiencing violence, no investigation is opened.The aim of this article is to explore on what grounds decisions were made not to open an investigation in cases initiated due to concerns that a child might have been experiencing domestic violence.The analysis is based on qualitative data consisting of 116 preliminary assessments that resulted in the cases being closed without further action. The analysis uses a theoretical model in which the CPS sorting process is understood as a way of describing a case in such a way that it fits into the organisation’s problem categories, rules and procedures.The analysis shows that a set of institutional assumptions and presuppositions affect the decision to screen out cases involving this form of child abuse. The legal requirement for voluntary parental cooperation has a profound impact on the outcome of a case. Cases are also screened out when the case workers find that parental cooperation is limited. Nor are there procedures for dealing with (psychological) violence that is not aimed directly at the child, but occurs between the parents. The outcome in these cases is that the parents’ interpretation is given precedence, while the needs of the child are seen as of less importance and become deprioritised.
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| 9. |
- Pereira, Joana B., et al.
(författare)
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Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer's disease
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:11, s. 3505-3516
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Tidskriftsartikel (refereegranskat)abstract
- Although recent clinical trials targeting amyloid-β in Alzheimer's disease have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with amyloid-β metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in Alzheimer's disease. However, so far, no studies have assessed whether astrocytosis is independently related to either amyloid-β or tau pathology in vivo. To address this question, we determined the levels of the astrocytic marker GFAP in plasma and CSF of 217 amyloid-β-negative cognitively unimpaired individuals, 71 amyloid-β-positive cognitively unimpaired individuals, 78 amyloid-β-positive cognitively impaired individuals, 63 amyloid-β-negative cognitively impaired individuals and 75 patients with a non-Alzheimer's disease neurodegenerative disorder from the Swedish BioFINDER-2 study. Participants underwent longitudinal amyloid-β (18F-flutemetamol) and tau (18F-RO948) PET as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all amyloid-β-positive groups compared with participants without amyloid-β pathology (P < 0.01). In addition, there were significant associations between plasma GFAP with higher amyloid-β-PET signal in all amyloid-β-positive groups, but also in cognitively normal individuals with normal amyloid-β values (P < 0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict amyloid-β-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, soluble TREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for amyloid-β-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-Alzheimer's disease patients compared to other groups (P < 0.05) and correlated with amyloid-β-PET only in amyloid-β-positive cognitively impaired individuals (P = 0.005). Finally, plasma GFAP was associated with both longitudinal amyloid-β-PET and cognitive decline, and mediated the effect of amyloid-β-PET on tau-PET burden, suggesting that astrocytosis secondary to amyloid-β aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain amyloid-β pathology but not tau aggregation, even in cognitively normal individuals with a normal amyloid-β status. This suggests that plasma GFAP should be incorporated in current hypothetical models of Alzheimer's disease pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to amyloid-β pathology.
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| 10. |
- Pettersson, Stefan, 1972, et al.
(författare)
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A Hydrogel Drink With High Fructose Content Generates Higher Exogenous Carbohydrate Oxidation and Lower Dental Biofilm pH Compared to Two Other, Commercially Available, Carbohydrate Sports Drinks
- 2020
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Ingår i: Frontiers in Nutrition. - : Frontiers Media SA. - 2296-861X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to evaluate the substrate oxidation of three commercially available, 14%-carbohydrate sports drinks with different compositions, osmolality, and pH for their impact on dental exposure to low pH. In a cross-over, randomized double-blinded design, 12 endurance athletes (age 31. 2 +/- 7.7 years, (V) over dotO(2max) 65.6 +/- 5.0 mL.kg(-1)) completed 180 min of cycling at 55% W-max. During the first 100 min of cycling, athletes consumed amylopectin starch (AP), maltodextrin+sucrose (MD+SUC), or maltodextrin+fructose hydrogel (MD+FRU) drinks providing 95 g carbohydrate.h(-1), followed by water intake only at 120 and 160 min. Fuel use was determined using indirect calorimetry and stable-isotope techniques. Additionally, dental biofilm pH was measured using the microtouch method in a subsample of participants (n= 6) during resting conditions before, and at different time intervals up to 45 min following a single bolus of drink. Exogenous carbohydrate oxidation (CHOEXO) during the 2nd hour of exercise was significantly (P< 0.05) different between all three drinks: MD+FRU (1.17 +/- 0.17 g.min(-1)), MD+SUC (1.01 +/- 0.13 g.min(-1)), and AP (0.84 +/- 0.11 g.min(-1)). At the end of exercise, CHO(EXO)and blood glucose concentrations (3.54 +/- 0.50, 4.07 +/- 0.67, and 4.28 +/- 0.47 mmol.L-1, respectively) were significantly lower post MD+FRU consumption than post MD+SUC and AP consumption (P< 0.05). Biofilm acidogenicity at rest demonstrated a less pronounced pH fall for MD+FRU compared to the acidulant-containing MD+SUC and AP (P< 0.05). In conclusion, while total intake of MD+FRU showed signs of completed uptake before end of monitoring, this was less so for MD+SUC, and not at all the case for AP. Thus, this study showed that despite carbohydrates being encapsulated in a hydrogel, a higher CHO(EXO)was observed following MD+FRU drink ingestion compared to AP and MD+SUC consumption upon exposure to the acidic environment of the stomach. This finding may be related to the higher fructose content of the MD+FRU drink compared with the MD+SUC and AP drinks. Furthermore, a carbohydrate solution without added acidulants, which are commonly included in commercial sport drinks, may have less deleterious effects on oral health.
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