| 1. |
- Cole, J. W., et al.
(författare)
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The copy number variation and stroke (CaNVAS) risk and outcome study
- 2021
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 16:4 April
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose The role of copy number variation (CNV) variation in stroke susceptibility and outcome has yet to be explored. The Copy Number Variation and Stroke (CaNVAS) Risk and Outcome study addresses this knowledge gap. Methods Over 24,500 well-phenotyped IS cases, including IS subtypes, and over 43,500 controls have been identified, all with readily available genotyping on GWAS and exome arrays, with case measures of stroke outcome. To evaluate CNV-associated stroke risk and stroke outcome it is planned to: 1) perform Risk Discovery using several analytic approaches to identify CNVs that are associated with the risk of IS and its subtypes, across the age-, sex- and ethnicity-spectrums; 2) perform Risk Replication and Extension to determine whether the identified stroke-associated CNVs replicate in other ethnically diverse datasets and use biomarker data (e.g. methylation, proteomic, RNA, miRNA, etc.) to evaluate how the identified CNVs exert their effects on stroke risk, and lastly; 3) perform outcome-based Replication and Extension analyses of recent findings demonstrating an inverse relationship between CNV burden and stroke outcome at 3 months (mRS), and then determine the key CNV drivers responsible for these associations using existing biomarker data. Results The results of an initial CNV evaluation of 50 samples from each participating dataset are presented demonstrating that the existing GWAS and exome chip data are excellent for the planned CNV analyses. Further, some samples will require additional considerations for analysis, however such samples can readily be identified, as demonstrated by a sample demonstrating clonal mosaicism. Conclusion The CaNVAS study will cost-effectively leverage the numerous advantages of using existing case-control data sets, exploring the relationships between CNV and IS and its subtypes, and outcome at 3 months, in both men and women, in those of African and European-Caucasian descent, this, across the entire adult-age spectrum. Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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| 2. |
- Alkaissi, Lina Y., et al.
(författare)
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Antagonism of Adherent Invasive E. coli LF82 With Human α-defensin 5 in the Follicle-associated Epithelium of Patients With Ileal Crohn’s Disease
- 2021
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Ingår i: Inflammatory Bowel Diseases. - : OXFORD UNIV PRESS INC. - 1078-0998 .- 1536-4844. ; 27:7, s. 1116-1127
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Tidskriftsartikel (refereegranskat)abstract
- Background: The first visible signs of Crohns disease (CD) are microscopic erosions over the follicle-associated epithelium (FAE). The aim of the study was to investigate the effects of human alpha-defensin 5 (HD5) on adherent-invasive Escherichia coli LF82 translocation and HD5 secretion after LF82 exposure in an in vitro model of human FAE and in human FAE ex vivo. Methods: An in vitro FAE-model was set up by the coculture of Raji B cells and Caco-2-cl1 cells. Ileal FAE from patients with CD and controls were mounted in Ussing chambers. The effect of HD5 on LF82 translocation was studied by LF82 exposure to the cells or tissues with or without incubation with HD5. The HD5 secretion was measured in human FAE exposed to LF82 or Salmonella typhimurium. The HD5 levels were evaluated by immunofluorescence, immunoblotting, and ELISA. Results: There was an increased LF82 translocation across the FAE-model compared with Caco-2-cl1 (P < 0.05). Incubation of cell/tissues with HD5 before LF82 exposure reduced bacterial passage in both models. Human FAE showed increased LF82 translocation in CD compared with controls and attenuated passage after incubation with sublethal HD5 in both CD and controls (P < 0.05). LF82 exposure resulted in a lower HD5 secretion in CD FAE compared with controls (P < 0.05), whereas Salmonella exposure caused equal secretion on CD and controls. There were significantly lower HD5 levels in CD tissues compared with controls. Conclusions: Sublethal HD5 reduces the ability of LF82 to translocate through FAE. The HD5 is secreted less in CD in response to LF82, despite a normal response to Salmonella. This further implicates the integrated role of antimicrobial factors and barrier function in CD pathogenesis.
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| 3. |
- Biskou, Olga, et al.
(författare)
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Increased Numbers of Enteric Glial Cells in the Peyers Patches and Enhanced Intestinal Permeability by Glial Cell Mediators in Patients with Ileal Crohns Disease
- 2022
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Ingår i: Cells. - Basel, Switzerland : MDPI. - 2073-4409. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- Enteric glial cells (EGC) are known to regulate gastrointestinal functions; however, their role in Crohns disease (CD) is elusive. Microscopic erosions over the ileal Peyers patches are early signs of CD. The aim of this work was to assess the localization of EGC in the follicle and interfollicular region of the Peyers patches and in the lamina propria and study the effects of EGC mediators on barrier function in CD patients and non-inflammatory bowel disease (non-IBD) controls. EGC markers, glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein β (S100β) were quantified by immunofluorescence and Western blotting. Both markers showed significantly more EGC in the Peyers patches and lamina propria of CD patients compared to the non-IBD controls. In CD patients there were significantly more EGC in Peyers patches compared to lamina propria, while the opposite pattern was seen in controls. Barrier function studies using Ussing chambers showed increased paracellular permeability by EGC mediators in CD patients, whereas permeability decreased by the mediators in controls. We show the accumulation of EGC in Peyers patches of CD patients. Moreover, EGC mediators induced barrier dysfunction in CD patients. Thus, EGC might have harmful impacts on ongoing inflammation and contribute to the pathophysiology of the disease.
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| 4. |
- Bonkhoff, A.K., et al.
(författare)
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Association of Stroke Lesion Pattern and White Matter Hyperintensity Burden With Stroke Severity and Outcome
- 2022
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Ingår i: Neurology. - 0028-3878. ; 99:13, s. 1364-1379
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectivesTo examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways.MethodsMR neuroimaging and NIH Stroke Scale data at index stroke and the modified Rankin Scale (mRS) score at 3-6 months after stroke were obtained from the MRI-Genetics Interface Exploration study of patients with acute ischemic stroke (AIS). Individual WMH volume was automatically derived from fluid-attenuated inversion recovery images. Stroke lesions were automatically segmented from diffusion-weighted imaging (DWI) images, parcellated into atlas-defined brain regions and further condensed to 10 lesion patterns via machine learning-based dimensionality reduction. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS score >2) were modeled within purpose-built Bayesian linear and logistic regression frameworks. Interaction effects between stroke lesions and a high vs low WMH burden were integrated via hierarchical model structures. Models were adjusted for age, age2, sex, total DWI lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts.ResultsA total of 928 patients with AIS contributed to acute stroke severity analyses (age: 64.8 [14.5] years, 40% women) and 698 patients to long-term functional outcome analyses (age: 65.9 [14.7] years, 41% women). Stroke severity was mainly explained by lesions focused on bilateral subcortical and left hemispherically pronounced cortical regions across patients with both a high and low WMH burden. Lesions centered on left-hemispheric insular, opercular, and inferior frontal regions and lesions affecting right-hemispheric temporoparietal regions had more pronounced effects on stroke severity in case of high compared with low WMH burden. Unfavorable outcomes were predominantly explained by lesions in bilateral subcortical regions. In difference to the lesion location-specific WMH effects on stroke severity, higher WMH burden increased the odds of unfavorable outcomes independent of lesion location.DiscussionHigher WMH burden may be associated with an increased stroke severity in case of stroke lesions involving left-hemispheric insular, opercular, and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporoparietal regions (potentially linked to attention). Our findings suggest that patients with specific constellations of WMH burden and lesion locations may have greater benefits from acute recanalization treatments. Future clinical studies are warranted to systematically assess this assumption and guide more tailored treatment decisions. © American Academy of Neurology.
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| 5. |
- Bonkhoff, A. K., et al.
(författare)
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Outcome after acute ischemic stroke is linked to sex-specific lesion patterns
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Acute ischemic stroke affects men and women differently. In particular, women are often reported to experience higher acute stroke severity than men. We derived a low-dimensional representation of anatomical stroke lesions and designed a Bayesian hierarchical modeling framework tailored to estimate possible sex differences in lesion patterns linked to acute stroke severity (National Institute of Health Stroke Scale). This framework was developed in 555 patients (38% female). Findings were validated in an independent cohort (n=503, 41% female). Here, we show brain lesions in regions subserving motor and language functions help explain stroke severity in both men and women, however more widespread lesion patterns are relevant in female patients. Higher stroke severity in women, but not men, is associated with left hemisphere lesions in the vicinity of the posterior circulation. Our results suggest there are sex-specific functional cerebral asymmetries that may be important for future investigations of sex-stratified approaches to management of acute ischemic stroke.
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| 6. |
- Bonkhoff, A. K., et al.
(författare)
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Sex-specific lesion pattern of functional outcomes after stroke
- 2022
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Relying on neuroimaging and clinical data of 822 acute stroke patients, Bonkhoff et al. report substantially more detrimental effects of lesions in left-hemispheric posterior circulation regions on functional outcomes in women compared to men. These findings may motivate a sex-specific clinical stroke management to improve outcomes in the longer term. Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men - women) = -0.295 (90% highest posterior density interval = -0.556 to -0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.
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| 7. |
- Dorvall, Malin, 1991, et al.
(författare)
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Mosaic Loss of Chromosome Y Is Associated With Functional Outcome After Ischemic Stroke.
- 2023
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Ingår i: Stroke. - : Wolters Kluwer. - 1524-4628 .- 0039-2499. ; 54:9, s. 2434-2437
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Tidskriftsartikel (refereegranskat)abstract
- Mosaic loss of chromosome Y (LOY) is associated with cardiovascular and neurodegenerative diseases in men, and genetic predisposition to LOY is associated with poor poststroke outcome. We, therefore, tested the hypothesis that LOY itself is associated with functional outcome after ischemic stroke.The study comprised male patients with ischemic stroke from the cohort studies SAHLSIS2 (Sahlgrenska Academy Study on Ischemic Stroke Phase 2; n=588) and LSR (Lund Stroke Register; n=735). We used binary logistic regression to analyze associations between LOY, determined by DNA microarray intensity data, and poor 3-month functional outcome (modified Rankin Scale score, >2) in each cohort separately and combined. Patients who received recanalization therapy were excluded from sensitivity analyses.LOY was associated with about 2.5-fold increased risk of poor outcome in univariable analyses (P<0.001). This association withstood separate adjustment for stroke severity and diabetes in both cohorts but not age. In sensitivity analyses restricted to the nonrecanalization group (n=987 in the combined cohort), the association was significant also after separate adjustment for age (odds ratio, 1.6 [95% CI, 1.1-2.4]) and when additionally adjusting for stroke severity and diabetes (odds ratio, 1.6 [95% CI, 1.1-2.5]).We observed an association between LOY and poor outcome after ischemic stroke in patients not receiving recanalization therapy. Future studies on LOY and other somatic genetic alterations in larger stroke cohorts are warranted.
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| 8. |
- Faisal, Mohammed, et al.
(författare)
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Effects of analgesic and surgical modality on immune response in colorectal cancer surgery
- 2021
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Ingår i: Surgial oncology. - : ELSEVIER SCI LTD. - 0960-7404 .- 1879-3320. ; 38
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Tidskriftsartikel (refereegranskat)abstract
- Background and objective: Different surgical methods, anesthesia, and analgesia are known to modify the surgical stress response, especially in patients with malignancy. We compared the impact of patient-controlled intravenous (PCA) versus epidural analgesia (EDA) on tumor-related mucosal immune response in patients undergoing open or laparoscopic surgery for colorectal cancer. Methods: In a University Hospital subgroup (n = 43) of a larger cohort (n = 235) of patients undergoing open or laparoscopic surgery for colorectal carcinoma randomized to PCA or EDA, colorectal tissues were stained for interleukin-10 (IL-10), tumor necrosis factor (TNF), and mast cell tryptase and then examined by immunofluorescence microscopy. Results: More IL-10+-cells were found in patients undergoing open compared to laparoscopic surgery in the PCA (P < 0.05) and EDA group (P < 0.0005), respectively, and numbers of TNF+-cells were higher in the open surgery group who received PCA (P < 0.05). No differences in IL-10 or TNF expressions were detected between EDA/PCA within the open or laparoscopic surgery groups, respectively. Fewer mast cells were observed in patients undergoing laparoscopic compared to open surgery combined with PCA (P < 0.05). Within the open surgery group, EDA resulted in fewer mucosal mast cells compared to the PCA group (P < 0.05). Conclusions: The surgical method, rather than type of analgesia, may have higher impact on peri-operative inflammation. Laparoscopic surgery when combined with EDA for colorectal cancer caused a decrease in the TNF and IL-10 expression and mast cells. EDA seems to have an anti-inflammatory effect on cancer-related inflammation during open surgery.
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| 9. |
- Fejrskov, Anja, et al.
(författare)
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Novel biomarker profiles to improve individual diagnosis and prognosis in patients with suspected inflammatory bowel disease : protocol for the Nordic inception cohort study (NORDTREAT)
- 2024
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Ingår i: BMJ Open. - : BioMed Central (BMC). - 2044-6055. ; 14:5
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, can be challenging to diagnose, and treatment outcomes are difficult to predict. In the NORDTREAT cohort study, a Nordic prospective multicentre study, we aim to identify novel molecular biomarkers of diagnostic value by assessing the diagnostic test accuracy (cross-sectionally), as well as the prognostic utility when used as prognostic markers in the long-term (cohort study). In the diagnostic test accuracy study, the primary outcome is a successful diagnosis using one or more novel index tests at baseline compared with the ECCO criteria as the reference standard. The composite outcome of the prognostic utility study is 'severe IBD' within 52 weeks from inclusion, defined as one or more of the following three events: IBD-related surgery, IBD-related hospitalisation or IBD-related death.METHODS AND ANALYSIS: We aim to recruit 800 patients referred on suspicion of IBD to this longitudinal observational study, a collaboration between 11 inclusion sites in Denmark, Iceland, Norway and Sweden. Inclusion will occur from February 2022 until December 2023 with screening and baseline visits for all participants and three outcome visits at weeks 12, 26 and 52 after baseline for IBD-diagnosed patients. Biological material (blood, faeces, biopsies, urine and hair), clinical data and lifestyle information will be collected during these scheduled visits.ETHICS AND DISSEMINATION: This study will explore novel biomarkers to improve diagnostic accuracy and prediction of disease progression, thereby improving medical therapy and the quality of life for patients with IBD.The study is approved by the Ethics Committee (DK: S-20200051, v1.4, 16.10.2021; IS: VSNb2021070006/03.01, NO: 193064; SE: DNR 2021-05090) and the Danish Data Protecting Agency (20/54594). Results will be disseminated through peer-reviewed journals, patient associations and presentations at international conferences.CLINICAL TRIAL REGISTRATION NUMBER: NCT05414578; Pre-results.
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| 10. |
- Johansson, Malin, et al.
(författare)
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Genetic Predisposition to Mosaic Chromosomal Loss Is Associated with Functional Outcome after Ischemic Stroke
- 2021
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Ingår i: Neurology: Genetics. - 2376-7839. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectivesTo test the hypothesis that a predisposition to acquired genetic alterations is associated with ischemic stroke outcome by investigating the association between a polygenic risk score (PRS) for mosaic loss of chromosome Y (mLOY) and outcome in a large international data set.MethodsWe used data from the genome-wide association study performed within the Genetics of Ischemic Stroke Functional Outcome network, which included 6,165 patients (3,497 men and 2,668 women) with acute ischemic stroke of mainly European ancestry. We assessed a weighted PRS for mLOY and examined possible associations with the modified Rankin Scale (mRS) score 3 months poststroke in logistic regression models. We investigated the whole study sample as well as men and women separately.ResultsIncreasing PRS for mLOY was associated with poor functional outcome (mRS score >2) with an odds ratio (OR) of 1.11 (95% confidence interval [CI] 1.03-1.19) per 1 SD increase in the PRS after adjustment for age, sex, ancestry, stroke severity (NIH Stroke Scale), smoking, and diabetes mellitus. In sex-stratified analyses, we found a statistically significant association in women (adjusted OR 1.20, 95% CI 1.08-1.33). In men, the association was in the same direction (adjusted OR 1.04, 95% CI 0.95-1.14), and we observed no significant genotype-sex interaction.DiscussionIn this exploratory study, we found associations between genetic variants predisposing to mLOY and stroke outcome. The significant association in women suggests underlying mechanisms related to genomic instability that operate in both sexes. These findings need replication and mechanistic exploration.
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| 11. |
- Kåberg, Martin, et al.
(författare)
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High risk of non-alcoholic liver disease mortality in patients with chronic hepatitis C with illicit substance use disorder
- 2020
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Ingår i: Scandinavian Journal of Gastroenterology. - : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 55:5, s. 574-580
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Hepatitis C virus (HCV) is a slowly progressive disease, often transmitted among people who inject drugs (PWID). Mortality in PWID is high, with an overrepresentation of drug-related causes. This study investigated the risk of death in patients with chronic hepatitis C virus (HCV) infection with or without illicit substance use disorder (ISUD).Methods: Patients with HCV were identified using the Swedish National Patient Registry according to the International Classification of Diseases-10 (ICD-10) code B18.2, with ≤5 matched comparators from the general population. Patients with ≥2 physician visits with ICD-10 codes F11, F12, F14, F15, F16, or F19 were considered to have ISUD. The underlying cause of death was analyzed for alcoholic liver disease, non-alcoholic liver disease, liver cancer, drug-related and external causes, non-liver cancers, or other causes. Mortality risks were assessed using the standardized mortality ratio (SMR) with 95% CIs and Cox regression analyses for cause-specific hazard ratios.Results: In total, 38,186 patients with HCV were included, with 31% meeting the ISUD definition. Non-alcoholic liver disease SMRs in patients with and without ISUD were 123.2 (95% CI, 103.7-145.2) and 69.4 (95% CI, 63.8-75.3), respectively. The significant independent factors associated with non-alcoholic liver disease mortality were older age, being unmarried, male sex, and having ISUD.Conclusions: The relative risks for non-alcoholic liver disease mortality were elevated for patients with ISUD. Having ISUD was a significant independent factor for non-alcoholic liver disease. Thus, patients with HCV with ISUD should be given HCV treatment to reduce the risk for liver disease.
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| 12. |
- Lindmark, Gudrun, et al.
(författare)
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qRT-PCR analysis of CEACAM5, KLK6, SLC35D3, MUC2 and POSTN in colon cancer lymph nodes : An improved method for assessment of tumor stage and prognosis
- 2024
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 154:3, s. 573-584
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Tidskriftsartikel (refereegranskat)abstract
- One fourth of colorectal cancer patients having curative surgery will relapse of which the majority will die. Lymph node (LN) metastasis is the single most important prognostic factor and a key factor when deciding on postoperative treatment. Presently, LN metastases are identified by histopathological examination, a subjective method analyzing only a small LN volume and giving no information on tumor aggressiveness. To better identify patients at risk of relapse we constructed a qRT-PCR test, ColoNode, that determines levels of CEACAM5, KLK6, SLC35D3, MUC2 and POSTN mRNAs. Combined these biomarkers estimate the tumor cell load and aggressiveness allocating patients to risk categories with low (0, −1), medium (1), high (2) and very high (3) risk of recurrence. Here we present result of a prospective, national multicenter study including 196 colon cancer patients from 8 hospitals. On average, 21 LNs/patient, totally 4698 LNs, were examined by both histopathology and ColoNode. At 3-year follow-up, 36 patients had died from colon cancer or lived with recurrence. ColoNode identified all patients that were identified by histopathology and in addition 9 patients who were undetected by histopathology. Thus, 25% of the patients who recurred were identified by ColoNode only. Multivariate Cox regression analysis proved ColoNode (1, 2, 3 vs 0, −1) as a highly significant risk factor with HR 4.24 [95% confidence interval, 1.42-12.69, P =.01], while pTN-stage (III vs I/II) lost its univariate significance. In conclusion, ColoNode surpassed histopathology by identifying a significantly larger number of patients with future relapse and will be a valuable tool for decisions on postoperative treatment.
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| 13. |
- Muhammad, Iram Faqir, et al.
(författare)
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Comparison of risk factors for ischemic stroke and coronary events in a population-based cohort
- 2021
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although coronary events (CE) and ischemic stroke share many risk factors, there are also some important differences. The aim of this paper was to assess the association of risk factors in relation to incident CE and ischemic stroke and to evaluate the heterogeneity in patterns of risk factors between the two outcomes.METHOD: Traditional risk factors and inflammatory markers associated with coronary events and ischemic stroke were measured in the Malmö Diet and Cancer Cohort (MDCS, n = 26 519), where a total of 2270 incident ischemic stroke and 3087 incident CE occurred during a mean follow up time 19 ± 6 years, and in relation to inflammatory markers in the cardiovascular sub-cohort (MDC-CV, n = 4795). Cox regression analysis was used to obtain hazard ratios. A modified Lunn-McNeil competing risk analysis was conducted to assess the significance of any differences in risk profiles of these outcomes.RESULTS: Most cardiovascular risk factors were associated both with incident CE and ischemic stroke. However, current smoking, ApoB, low ApoA1, male sex and education level of ≤ 9 years of schooling were preferentially associated with CE compared to ischemic stroke. Conversely, age showed a stronger association with ischemic stroke than with CE.CONCLUSION: CE and ischemic stroke have broadly similar risk factors profiles. However, there are some important differential associations, as well as substantial differences in the magnitude of the association. These could reflect the distinct biology of atherogenesis in different vascular beds. The difference in the determinants highlights the importance of looking at CE and ischemic stroke, two manifestations of cardiovascular disease, separately.
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| 14. |
- Song, Lu, et al.
(författare)
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Association of TIM-1 (T-Cell Immunoglobulin and Mucin Domain 1) With Incidence of Stroke
- 2020
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Ingår i: Arteriosclerosis, Thrombosis, and Vascular Biology. - 1524-4636. ; 40:7, s. 1777-1786
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of this study was to investigate if there is a causal relationship between circulating levels of TIM-1 (T-cell immunoglobulin and mucin domain 1) and incidence of stroke. Approach and Results: Plasma TIM-1 was analyzed in 4591 subjects (40% men; mean age, 57.5 years) attending the Malmö Diet and Cancer Study. Incidence of stroke was studied in relation to TIM-1 levels during a mean of 19.5 years follow-up. Genetic variants associated with TIM-1 (pQTLs [protein quantitative trait loci]) were examined, and a 2-sample Mendelian randomization analysis was performed to explore the role of TIM-1 in stroke using summary statistics from our pQTLs and the MEGASTROKE consortium. A total of 416 stroke events occurred during follow-up, of which 338 were ischemic strokes. After risk factor adjustment, TIM-1 was associated with increased incidence of all-cause stroke (hazards ratio for third versus first tertile, 1.44 [95% CI, 1.10-1.87]; P for trend, 0.004), and ischemic stroke (hazards ratio, 1.42 [95% CI, 1.06-1.90]; P for trend, 0.011). Nineteen independent lead SNPs, located in three genomic risk loci showed significant associations with TIM-1 (P<5×10-8). A 2-sample Mendelian Randomization analysis suggested a causal effect of TIM-1 on stroke (β=0.083, P=0.0004) and ischemic stroke (β=0.102, P=7.7×10-5). CONCLUSIONS: Plasma level of TIM-1 is associated with incidence of stroke. The genetic analyses suggest that this could be a causal relationship.
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| 15. |
- Song, Lu, et al.
(författare)
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Circulating Growth Differentiation Factor 15 Levels Are Associated With Risk of Both Intracerebral and Subarachnoid Hemorrhage
- 2021
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 12, s. 664010-664010
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Tidskriftsartikel (refereegranskat)abstract
- Background: Growth differentiation factor 15 (GDF-15) has been associated with the risk of developing major bleedings, including but not restricted to intracranial hemorrhages, in patients on oral anticoagulants or dual antiplatelet therapy. We hypothesized that there may be an association of GDF-15 with incidence of hemorrhagic strokes in the general population, which has not been investigated before. Methods: Two different case-control studies, one for intracerebral hemorrhage (ICH) and one for subarachnoid hemorrhage (SAH), nested within the population-based Malmö Diet and Cancer cohort, were defined using the incidence density sampling method. GDF-15 was analyzed in frozen blood samples taken at the baseline examination in 1991-1996. The associations between GDF-15 and incident ICH (220 cases, 244 controls) and incident SAH (79 cases, 261 controls), respectively, were explored using conditional logistic regression adjusting for risk factors. Results: GDF-15 levels at baseline were higher in both incident ICH and SAH cases, compared with their respective control subjects. After adjustment for risk factors, significant relationships with high GDF-15 concentrations were observed both for incident ICH (odds ratio (OR) per 1 log2 unit: 2.27, 95% confidence interval (CI): 1.52-3.41; P = 7.1 × 10-5) and incident SAH (OR: 2.16, 95% CI: 1.29-3.59; P = 0.0032). Conclusions: High circulating GDF-15 levels were associated with incident ICH and incident SAH, independently of the main risk factors.
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| 16. |
- Svensson, Edith H., et al.
(författare)
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Fibroblast growth factor 23 is associated with risk of intracerebral hemorrhage
- 2022
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 29:1, s. 114-120
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Fibroblast growth factor 23 (FGF23) is an osteogenic hormone associated with chronic kidney disease and is an emerging risk factor for several cardiovascular diseases. The association of FGF23 with stroke is unclear. The aim of this study was to investigate the association of FGF23 with incident intracerebral hemorrhage (ICH). Methods: This was a nested case–control study of 220 ICH cases and 244 age- and sex-matched controls from the population-based Malmö Diet and Cancer Study (n = 28,449). Incident ICH cases were ascertained using national registers and classified by bleeding location. Logistic regression was used to study the association of plasma levels of FGF23 with incident ICH, adjusting for potential ICH risk factors. Subgroup analyses were performed for lobar and non-lobar ICH, fatal ICH, ICH with large volume and ICH with poor functional outcome, respectively. Results: Higher FGF23 levels at baseline were significantly associated with incident ICH. After multivariable adjustment, the odds ratio for the association with all ICH was 1.84 (95% confidence interval [CI] 1.25–2.71, p = 0.002) per doubling of FGF23 concentration. For lobar and non-lobar ICH, odds ratios were 1.73 (95% CI 1.04–2.87, p = 0.035) and 2.13 (95% CI 1.32–3.45, p = 0.002), respectively. FGF23 was also significantly associated with fatal ICH, ICH with large volume and ICH with poor functional outcome. Conclusions: Higher FGF23 was associated with incident ICH in this nested case–control study. Further studies are required to explore whether the association is causal.
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| 17. |
- Svensson, Edith H., et al.
(författare)
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Risk factors for intracerebral haemorrhage – Results from a prospective population-based study
- 2020
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Ingår i: European Stroke Journal. - : SAGE Publications. - 2396-9873 .- 2396-9881. ; 5:3, s. 278-285
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: While the relationship between hypertension and incident intracerebral haemorrhage is well established, other risk factors are less clear. This study examined risk factors for primary intracerebral haemorrhage, separately for lobar and non-lobar intracerebral haemorrhage. Patients and methods: Incidence of intracerebral haemorrhage was studied among 28,416 individuals from the population-based Malmö Diet and Cancer cohort. Intracerebral haemorrhage cases were ascertained using the Swedish Hospital Discharge Register and the Stroke Register of Malmö, validated by review of hospital records and images, and classified by location by a neuroradiologist. Multivariable Cox regression was used. Results: Three hundred and thirty-three intracerebral haemorrhages occurred, mean follow-up time was 18.4 years. Systolic blood pressure (hazard ratio per 10 mmHg 1.19 [95% confidence interval 1.13–1.26], diastolic blood pressure (hazard ratio 1.42 [1.27–1.59]), oral anticoagulants (hazard ratio 4.26 [2.17–8.38]), smoking (hazard ratio 1.45 [1.14–1.87]), living alone (hazard ratio 1.32 [1.04–1.69]) and low apolipoprotein B (hazard ratio per 10 mg/dL: 0.94 [0.90–0.99]) were significantly associated with incident intracerebral haemorrhage after multivariable adjustment. Systolic blood pressure, smoking and oral anticoagulants were associated with lobar intracerebral haemorrhage. Systolic blood pressure, diastolic blood pressure, living alone and diabetes were associated with non-lobar intracerebral haemorrhage. Diabetes and diastolic blood pressure showed significantly different relationships with lobar and non-lobar intracerebral haemorrhage. Alcohol, apolipoprotein A1, body mass index, waist circumference, physical activity and education were not independently associated with intracerebral haemorrhage. Discussion and conclusions: Blood pressure, smoking, low apolipoprotein B, oral anticoagulants and living alone were associated with intracerebral haemorrhage. Diabetes was associated with non-lobar intracerebral haemorrhage only. Further research is required on differences between lobar and non-lobar intracerebral haemorrhage.
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| 18. |
- Söderholm, Martin, et al.
(författare)
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Blood cadmium concentration and risk of subarachnoid haemorrhage.
- 2020
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Ingår i: Environmental research. - : Elsevier BV. - 1096-0953 .- 0013-9351. ; 180
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Tidskriftsartikel (refereegranskat)abstract
- Cadmium is a toxic metal and exposure is mainly from diet and tobacco smoke. Cadmium is accumulated in blood vessels and may reduce synthesis of procollagen and inhibit proliferation of vascular smooth muscle cells. High blood cadmium has been associated with increased risk of myocardial infarction, stroke and unruptured intracranial aneurysms. We examined whether blood cadmium increase the risk of subarachnoid haemorrhage (SAH).The Malmö Diet and Cancer cohort (n=28,449) was examined in 1991-1996 and blood samples were taken. Incidence of SAH was followed up to 2014. Cadmium was measured in stored blood samples from incident SAH cases and matched controls (n=93 vs n=276) and odds ratio (OR) for SAH was assessed in a nested case control design.Subjects with cadmium concentration in the highest quartile had increased risk of SAH compared to those in the first quartile (OR: 3.22, 95%CI: 1.67-6.22). However, after adjusting for smoking, results were weakened and non-significant (OR: 1.57, 95%CI: 0.51-4.80).Cadmium concentration was associated with increased risk of SAH but this association was largely explained by smoking. Whether cadmium in tobacco may contribute to the vascular pathology and increased risk of SAH in smokers should be further studied.
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| 19. |
- Tschiderer, Lena, et al.
(författare)
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Age at menopause and the risk of stroke : observational and mendelian randomization analysis in 204 244 postmenopausal women
- 2023
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Ingår i: Journal of the American Heart Association. - : American Heart Association Inc.. - 2047-9980. ; 12:18
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear.METHODS AND RESULTS: We analyzed data of the UK Biobank and EPIC-CVD (European Prospective Investigation Into Cancer and Nutrition-Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC-CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow-up of 12.6 years (interquartile range, 11.8–13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07–1.12) for stroke, 1.09 (95% CI, 1.06–1.13) for ischemic stroke, 1.10 (95% CI, 1.04–1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08–1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84–1.20) for subarachnoid hemorrhage. When using 2-sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke.CONCLUSIONS: In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.
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| 20. |
- Zimmer, Christine L., et al.
(författare)
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A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells
- 2021
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Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 13:599
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Tidskriftsartikel (refereegranskat)abstract
- The human biliary system, a mucosal barrier tissue connecting the liver and intestine, is an organ often affected by serious inflammatory and malignant diseases. Although these diseases are linked to immunological processes, the biliary system represents an unexplored immunological niche. By combining endoscopy-guided sampling of the biliary tree with a high-dimensional analysis approach, comprehensive mapping of the human biliary immunological landscape in patients with primary sclerosing cholangitis (PSC), a severe biliary inflammatory disease, was conducted. Major differences in immune cell composition in bile ducts compared to blood were revealed. Furthermore, biliary inflammation in patients with PSC was characterized by high presence of neutrophils and T cells as compared to control individuals without PSC. The biliary T cells displayed a CD103(+)CD69(+) effector memory phenotype, a combined gut and liver homing profile, and produced interleukin-17 (IL-17) and IL-22. Biliary neutrophil infiltration in PSC associated with CXCL8, possibly produced by resident T cells, and CXCL16 was linked to the enrichment of T cells. This study uncovers the immunological niche of human bile ducts, defines a local immune network between neutrophils and biliary-resident T cells in PSC, and provides a resource for future studies of the immune responses in biliary disorders.
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