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1.
  • Zamora, Juan Carlos, et al. (författare)
  • Considerations and consequences of allowing DNA sequence data as types of fungal taxa
  • 2018
  • Ingår i: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
  • Tidskriftsartikel (refereegranskat)abstract
    • Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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2.
  • Ladds, Marcus J. G. W., et al. (författare)
  • A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
  • 2018
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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4.
  • Cagigi, Alberto, et al. (författare)
  • Airway antibodies emerge according to COVID-19 severity and wane rapidly but reappear after SARS-CoV-2 vaccination
  • 2021
  • Ingår i: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 6:22
  • Tidskriftsartikel (refereegranskat)abstract
    • Understanding the presence and durability of antibodies against SARS-CoV-2 in the airways is required to provide insights into the ability of individuals to neutralize the virus locally and prevent viral spread. Here, we longitudinally assessed both systemic and airway immune responses upon SARS-CoV-2 infection in a clinically well-characterized cohort of 147 infected individuals representing the full spectrum of COVID-19 severity, from asymptomatic infection to fatal disease. In addition, we evaluated how SARS-CoV-2 vaccination influenced the antibody responses in a subset of these individuals during convalescence as compared with naive individuals. Not only systemic but also airway antibody responses correlated with the degree of COVID-19 disease severity. However, although systemic IgG levels were durable for up to 8 months, airway IgG and IgA declined significantly within 3 months. After vaccination, there was an increase in both systemic and airway antibodies, in particular IgG, often exceeding the levels found during acute disease. In contrast, naive individuals showed low airway antibodies after vaccination. In the former COVID-19 patients, airway antibody levels were significantly elevated after the boost vaccination, highlighting the importance of prime and boost vaccinations for previously infected individuals to obtain optimal mucosal protection.
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6.
  • Wuttke, Matthias, et al. (författare)
  • A catalog of genetic loci associated with kidney function from analyses of a million individuals
  • 2019
  • Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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7.
  • Gafar, Fajri, et al. (författare)
  • Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents : a systematic review and individual patient data meta-analysis
  • 2023
  • Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 61:3
  • Forskningsöversikt (refereegranskat)abstract
    • Background Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.Methods We systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24 and Cmax were assessed with linear mixed-effects models.Results Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24 were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0–24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24 and slow acetylators had higher isoniazid AUC0–24 than intermediate acetylators. Determinants of Cmax were generally similar to those for AUC0–24.Conclusions This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.
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8.
  • Hober, Sophia, Professor, 1965-, et al. (författare)
  • Systematic evaluation of SARS-CoV-2 antigens enables a highly specific and sensitive multiplex serological COVID-19 assay
  • 2021
  • Ingår i: Clinical & Translational Immunology. - : Wiley. - 2050-0068. ; 10:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. The COVID-19 pandemic poses an immense need for accurate, sensitive and high-throughput clinical tests, and serological assays are needed for both overarching epidemiological studies and evaluating vaccines. Here, we present the development and validation of a high-throughput multiplex bead-based serological assay. Methods. More than 100 representations of SARS-CoV-2 proteins were included for initial evaluation, including antigens produced in bacterial and mammalian hosts as well as synthetic peptides. The five best-performing antigens, three representing the spike glycoprotein and two representing the nucleocapsid protein, were further evaluated for detection of IgG antibodies in samples from 331 COVID-19 patients and convalescents, and in 2090 negative controls sampled before 2020. Results. Three antigens were finally selected, represented by a soluble trimeric form and the S1-domain of the spike glycoprotein as well as by the C-terminal domain of the nucleocapsid. The sensitivity for these three antigens individually was found to be 99.7%, 99.1% and 99.7%, and the specificity was found to be 98.1%, 98.7% and 95.7%. The best assay performance was although achieved when utilising two antigens in combination, enabling a sensitivity of up to 99.7% combined with a specificity of 100%. Requiring any two of the three antigens resulted in a sensitivity of 99.7% and a specificity of 99.4%. Conclusion. These observations demonstrate that a serological test based on a combination of several SARS-CoV-2 antigens enables a highly specific and sensitive multiplex serological COVID-19 assay.
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9.
  • Laszlo, K. D., et al. (författare)
  • Loss of a close family member the year before or during pregnancy and the risk of placental abruption : a cohort study from Denmark and Sweden
  • 2014
  • Ingår i: Psychological Medicine. - 0033-2917 .- 1469-8978. ; 44:9, s. 1855-1866
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Maternal stress during pregnancy is associated with a modestly increased risk of fetal growth restriction and pre-eclampsia. Since placental abruption shares similar pathophysiological mechanisms and risk factors with fetal growth restriction and pre-eclampsia, we hypothesized that maternal stress may be implicated in abruption risk. We investigated the association between maternal bereavement during pregnancy and placental abruption. Method We studied singleton births in Denmark (1978-2008) and Sweden (1973-2006) (n=5103272). In nationwide registries, we obtained data on death of women's close family members (older children, siblings, parents, and partners), abruption and potential confounders. Results A total of 30312 (6/1000) pregnancies in the cohort were diagnosed with placental abruption. Among normotensive women, death of a child the year before or during pregnancy was associated with a 54% increased odds of abruption [95% confidence interval (CI) 1.30-1.82]; the increased odds were restricted to women who lost a child the year before or during the first trimester in pregnancy. In the group with chronic hypertension, death of a child the year before or in the first trimester of pregnancy was associated with eight-fold increased odds of abruption (odds ratio 8.17, 95% CI 3.17-21.10). Death of other relatives was not associated with abruption risk. Conclusions Loss of a child the year before or in the first trimester of pregnancy was associated with an increased risk of abruption, especially among women with chronic hypertension. Studies are needed to investigate the effect of less severe, but more frequent, sources of stress on placental abruption risk.
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10.
  • Linton, Steven J., 1952-, et al. (författare)
  • The effect of the work environment on future sleep disturbances : a systematic review
  • 2015
  • Ingår i: Sleep Medicine Reviews. - : W. B. Saunders. - 1087-0792 .- 1532-2955. ; 23:Oktober, s. 10-19
  • Forskningsöversikt (refereegranskat)abstract
    • Workers often attribute poor sleep to factors at work. Despite the large number of workers with sleep disturbances, there is a lack of consensus on the relationship between the work environment and sleep. The purpose of this systematic review therefore was to conduct a comprehensive evaluation. To this end, we employed standardized methods to systematically locate, review, and tabulate the results of prospective or randomized studies of the impact of work factors on sleep disturbances. From the 7981 articles located in five databases, 24 fulfilled our inclusion criteria and formed the base of the review including meta-analyses of the effect sizes. Results showed that the psychosocial work variables of social support at work, control, and organizational justice were related to fewer sleep disturbances, while high work demands, job strain, bullying, and effort-reward imbalance were related to more future sleep disturbances. Moreover, working a steady shift was associated with disturbances while exiting shift work was associated with less disturbed sleep. We conclude that psychosocial work factors and the scheduling of work have an impact on sleep disturbances and this might be utilized in the clinic as well as for planning work environments. Future research needs to employ better methodology and focus on underlying mechanisms.
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11.
  • Saxena, Richa, et al. (författare)
  • Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
  • 2007
  • Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 316:5829, s. 1331-1336
  • Tidskriftsartikel (refereegranskat)abstract
    • New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D - in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 - and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
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12.
  • Zhang, Yuan, et al. (författare)
  • Adiponectin Associates with Rheumatoid Arthritis Risk in Overweight and Obesity Independently of Other Adipokines
  • 2021
  • Ingår i: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 10:13
  • Tidskriftsartikel (refereegranskat)abstract
    • We recently reported that increased serum adiponectin was associated with rheumatoid arthritis (RA) risk in subjects with obesity. We hereby aim to determine if other adipokines associate with RA risk and if the association between adiponectin and RA is independent of other adipokines. Two nested-case control studies were performed in two different cohorts: 82 participants of the Swedish Obese Subjects (SOS) study who developed RA during follow-up matched with 410 controls, and 88 matched pairs from the Medical Biobank of Northern Sweden. Baseline levels of circulating adipokines were measured using ELISA. In a multivariable analysis in the SOS cohort, higher adiponectin was associated with an increased risk of RA independently of other adipokines (OR for RA risk: 1.06, 95% CI: 1.01-1.12, p = 0.02). No association between leptin, resistin, and visfatin levels and the risk of RA was detected. In the cohort from the Medical Biobank of Northern Sweden, higher adiponectin was associated with an increased risk of RA only in participants with overweight/obesity (OR: 1.17, 95% CI: 1.01-1.36, p = 0.03), independently of other adipokines. Our results show that in individuals with overweight/obesity, higher circulating levels of adiponectin, but not leptin, resistin, or visfatin, were associated with an increased RA risk.
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13.
  • Zhang, Y, et al. (författare)
  • Elevated adiponectin predicts the development of rheumatoid arthritis in subjects with obesity
  • 2020
  • Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 0300-9742 .- 1502-7732. ; 49:6, s. 452-460
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The aim of the current study is to determine whether baseline serum adiponectin levels predict the development of rheumatoid arthritis (RA). Method: The current report includes 3693 individuals from the Swedish Obese Subjects (SOS) study. The original SOS study is a longitudinal non-randomized controlled study aiming to assess the effect of bariatric surgery on obesity-related mortality and morbidity. Participants included in the present report had adiponectin measurement available at baseline and no prevalent RA. The diagnosis of RA was retrieved through the Swedish National Patient Register. Results: During a follow-up for up to 29years, 82 study participants developed RA. Elevated baseline adiponectin levels were associated with a higher risk of developing RA independently of other factors, including C-reactive protein (CRP) and smoking [hazard ratio (HR) 1.70, 95% confidence interval (CI) 1.12–2.60 for an increase in adiponectin of 10 mg/L, p =0.01]. After stratifying the population according to adiponectin and CRP median at baseline, study participants with both adiponectin and CRP above the median had a higher risk of developing RA compared to subjects with adiponectin and CRP below the median (HR 2.80, 95% CI 1.25–6.31, p =0.01). Conclusions: In this cohort of subjects with obesity followed up for up to 29years, high serum adiponectin levels at baseline were associated with an increased risk for RA. Moreover, subjects with both high adiponectin and CRP levels at baseline were at particular risk of developing RA. ClinicalTrials.gov Identifier: NCT01479452. © 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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14.
  • Berntsson, Jonna, et al. (författare)
  • The clinical impact of tumour-infiltrating lymphocytes in colorectal cancer differs by anatomical subsite : A cohort study
  • 2017
  • Ingår i: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 141:8, s. 1654-1666
  • Tidskriftsartikel (refereegranskat)abstract
    • Accumulating evidence demonstrates an association between dense infiltration of lymphocytes and prognosis in colorectal cancer (CRC), but whether this prognostic impact differs by tumour location remains unknown. This study investigated the prognostic impact of cytotoxic and regulatory T cells in CRC, with particular referennfiltrating T cce to the anatomical subsite of the primary tumour. The density of CD3(+), CD8(+) and FoxP3(+) tumour-iells was calculated in tissue microarrays with tumours from 557 incident CRC cases from a prospective population-based cohort. Kaplan-Meier and Cox regression analyses were applied to determine the impact of high and low lymphocyte density on 5-year overall survival, in subgroup analysis of right colon, left colon and rectum. High CD8(+) cell density was a favourable prognostic factor for patients with right-sided colon tumours (hazard ratio [HR]=0.53, 95% confidence interval [CI] 0.29-0.95), independent of age, sex, TNM stage, differentiation grade and vascular invasion, with a significant prognostic interaction between CD8(+) cells and right-sidedness (p=0.031). High FoxP3(+) cell density was an independent favourable prognostic factor only in patients with rectal tumours (HR=0.54, 95% CI 0.30-0.99), and CD3(+) cell density was an independent favourable prognostic factor for tumours in the right colon and rectum, but there was no significant prognostic interaction between CD3(+) or FoxP3(+) cells and sidedness. These results demonstrate that the prognostic impact of tumour-infiltrating lymphocytes in CRC differs by primary tumour site, further indicating that tumour location may be an important factor to take into consideration in therapeutic decisions, including eligibility for immunotherapy.
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15.
  • Boman, Andrea, et al. (författare)
  • Distinct lysosomal network protein profiles in parkinsonian syndrome cerebrospinal fluid
  • 2016
  • Ingår i: Journal of Parkinson's Disease. - : IOS Press. - 1877-7171 .- 1877-718X. ; 6:2, s. 307-315
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Clinical diagnosis of parkinsonian syndromes like Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy is hampered by overlapping symptomatology and lack of biomarkers for diagnosis, and definitive diagnosis is only possible post-mortem. Since impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that levels and profiles of lysosomal network proteins in cerebrospinal fluid could be changed in these parkinsonian syndromes.Methods: Cerebrospinal fluid samples were collected from Parkinson’s disease patients (n=18), clinically diagnosed 4-repeat tauopathy patients, corticobasal syndrome (n=6) and progressive supranuclear palsy (n=5), pathologically diagnosed progressive supranuclear palsy (n=8) and corticobasal degeneration patients (n=7). Each patient set was compared to its appropriate control group consisting of the same number of age and gender matched individuals. Lysosomal network protein levels were detected via Western blotting.Results: Lysosomal network proteins have markedly different cerebrospinal fluid protein levels and profiles in Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy. Lysosomal-associated membrane proteins 1 and 2 were significantly decreased in Parkinson´s disease; early endosomal antigen 1 was decreased and lysozyme increased in progressive supranuclear palsy; and lysosomal-associated membrane proteins 1 and 2, microtubule-associated protein 1 light chain 3 and lysozyme were increased in corticobasal degeneration.Conclusions: Lysosomal network proteins hold promise of being interesting novel candidates for biomarker studies and for elucidating disease mechanisms of Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy, but further validation studies will be needed to assess the specificity and the predictive value of these proteins in CSF.
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16.
  • Bracci, Alessandro, et al. (författare)
  • Research routes on awake bruxism metrics : implications of the updated bruxism definition and evaluation strategies.
  • 2024
  • Ingår i: Journal of Oral Rehabilitation. - : John Wiley & Sons. - 1365-2842. ; 51:1, s. 150-161
  • Forskningsöversikt (refereegranskat)abstract
    • OBJECTIVE: In line with a similar recent proposal for sleep bruxism (SB), defining clinically oriented research routes to implement knowledge on awake bruxism (AB) metrics is important for an enhanced comprehension of the full bruxism spectrum, i.e. better assessment and more efficient management.METHODS: We summarised current strategies for AB assessment and proposed a research route for improving its metrics.RESULTS: Most of the literature focuses on bruxism in general or SB in particular, whilst knowledge on AB is generally fragmental. Assessment can be based on non-instrumental or instrumental approaches. The former include self-report (questionnaires, oral history) and clinical examination, whilst the latter include electromyography (EMG) of jaw muscles during wakefulness as well as the technology-enhanced ecological momentary assesment (EMA). Phenotyping of different AB activities should be the target of a research task force. In the absence of available data on the frequency and intensity of wake-time bruxism-type masticatory muscle activity, any speculation about the identification of thresholds and criteria to identify bruxers is premature. Research routes in the field must focus on the improvement of data reliability and validity.CONCLUSIONS: Probing deeper into the study of AB metrics is a fundamental step to assist clinicians in preventing and managing the putative consequences at the individual level. The present manuscript proposes some possible research routes to advance current knowledge. At different levels, instrumentally-based and subject-based information must be gathered in a universally accepted standardized approach.
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17.
  • Covacu, Ruxandra, et al. (författare)
  • Nitric oxide exposure diverts neural stem cell fate from neurogenesis towards astrogliogenesis
  • 2006
  • Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 178, s. 268-268
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Regeneration of cells in the central nervous system is a process that might be affected during neurological disease and trauma. Because nitric oxide (NO) and its derivatives are powerful mediators in the inflammatory cascade, we have investigated the effects of pathophysiological concentrations of NO on neurogenesis, gliogenesis, and the expression of proneural genes in primary adult neural stem cell cultures. After exposure to NO, neurogenesis was downregulated, and this corresponded to decreased expression of the proneural gene neurogenin-2 and beta-III-tubulin. The decreased ability to generate neurons was also found to be transmitted to the progeny of the cells. NO exposure was instead beneficial for astroglial differentiation, which was confirmed by increased activation of the Janus tyrosine kinase/signal transducer and activator of transcription transduction pathway. Our findings reveal a new role for NO during neuroinflammatory conditions, whereby its proastroglial fate-determining effect on neural stem cells might directly influence the neuroregenerative process.
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18.
  • Forsberg-Nilsson, Karin, et al. (författare)
  • Oligodendrocyte precursor hypercellularity and abnormal retina development in mice overexpressing PDGF-B in myelinating tracts
  • 2003
  • Ingår i: Glia. - : Wiley. - 0894-1491 .- 1098-1136. ; 41:3, s. 276-89
  • Tidskriftsartikel (refereegranskat)abstract
    • Platelet-derived growth factor (PDGF) influences the generation of neurons and glia during embryogenesis and in early postnatal life. In an attempt to determine the consequences of an overexpression of PDGF-B during the first weeks of life, we targeted transgenic expression of a human PDGF-B cDNA to myelinating tracts using the promoter region of the myelin basic protein (MBP) gene. Transgenic mRNA and protein were expressed in the brain and the expression profile of the human PDGF-B during early postnatal development closely paralleled that of the endogenous mouse MBP gene. The gross morphological appearance of transgenic brains was normal but at the cellular level several phenotypic alterations could be identified. In white matter tracts such as the corpus callosum and cerebellar medulla, there was a marked hypercellularity. The number of oligodendrocyte precursors was increased and astrocytes were more abundant. In adult mice carrying the MBP-PDGF-B transgene, however, myelination appeared normal and the amount of oligodendrocytes was similar to that of control littermates. In addition to the phenotypic alterations in the brain, investigation of eye structure revealed a striking disorganization of retinal architecture. The retina was folded with cells collected in papillar or follicular-like structures. Retinal whole mount preparations after India ink perfusion revealed capillary disorganization with large-caliber vessels supporting only a few fine branches. Our observations strengthen the notion that PDGF is an important effector molecule in postnatal CNS development.
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19.
  • Forslund, Anna-Lena, 1964-, et al. (författare)
  • Direct repeat-mediated deletion of a type IV pilin gene results in major virulence attenuation of Francisella tularensis
  • 2006
  • Ingår i: Molecular Microbiology. - : Wiley-Blackwell. - 0950-382X .- 1365-2958. ; 59:6, s. 1818-1830
  • Tidskriftsartikel (refereegranskat)abstract
    • Francisella tularensis, the causative agent of tularaemia, is a highly infectious and virulent intracellular pathogen. There are two main human pathogenic subspecies, Francisella tularensis ssp. tularensis (type A), and Francisella tularensis ssp. holarctica (type B). So far, knowledge regarding key virulence determinants is limited but it is clear that intracellular survival and multiplication is one major virulence strategy of Francisella. In addition, genome sequencing has revealed the presence of genes encoding type IV pili (Tfp). One genomic region encoding three proteins with signatures typical for type IV pilins contained two 120 bp direct repeats. Here we establish that repeat-mediated loss of one of the putative pilin genes in a type B strain results in severe virulence attenuation in mice infected by subcutaneous route. Complementation of the mutant by introduction of the pilin gene in cis resulted in complete restoration of virulence. The level of attenuation was similar to that of the live vaccine strain and this strain was also found to lack the pilin gene as result of a similar deletion event mediated by the direct repeats. Presence of the pilin had no major effect on the ability to interact, survive and multiply inside macrophage-like cell lines. Importantly, the pilin-negative strain was impaired in its ability to spread from the initial site of infection to the spleen. Our findings indicate that this putative pilin is critical for Francisella infections that occur via peripheral routes.
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20.
  • Grankvist, Anna, et al. (författare)
  • Multilocus sequence analysis of clinical "candidatus neoehrlichia mikurensis" strains from Europe
  • 2015
  • Ingår i: Journal of Clinical Microbiology. - 0095-1137 .- 1098-660X. ; 53:10, s. 3126-3132
  • Tidskriftsartikel (refereegranskat)abstract
    • Copyright © 2015, American Society for Microbiology. All Rights Reserved. Candidatus Neoehrlichia mikurensis" is the tick-borne agent of neoehrlichiosis, an infectious disease that primarily affects immunocompromised patients. So far, the genetic variability of "Ca. Neoehrlichia" has been studied only by comparing 16S rRNA genes and groEL operon sequences. We describe the development and use of a multilocus sequence analysis (MLSA) protocol to characterize the genetic diversity of clinical "Ca. Neoehrlichia" strains in Europe and their relatedness to other species within the Anaplasmataceae family. Six genes were selected: ftsZ, clpB, gatB, lipA, groEL, and 16S rRNA. Each MLSA locus was amplified by real-time PCR, and the PCR products were sequenced. Phylogenetic trees of MLSA locus relatedness were constructed from aligned sequences. Blood samples from 12 patients with confirmed "Ca. Neoehrlichia" infection from Sweden (n9), the Czech Republic (n2), and Germany (n1) were analyzed with the MLSA protocol. Three of the Swedish strains exhibited identical lipA sequences, while the lipA sequences of the strains from the other nine patients were identical to each other. One of the Czech strains had one differing nucleotide in the clpB sequence from the sequences of the other 11 strains. All 12 strains had identical sequences for the genes 16S rRNA, ftsZ, gatB, and groEL. According to the MLSA, among the Anaplasmataceae, "Ca. Neoehrlichia" is most closely related to Ehrlichia ruminantium, less so to Anaplasma phagocytophilum, and least to Wolbachia endosymbionts. To conclude, three sequence types of infectious "Ca. Neoehrlichia" were identified: one in the west of Sweden, one in the Czech Republic, and one spread throughout Europe.
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21.
  • Gyllensten, Hanna, 1979, et al. (författare)
  • Comparing Methods for Estimating Direct Costs of Adverse Drug Events
  • 2017
  • Ingår i: Value in Health. - : Elsevier BV. - 1098-3015 .- 1524-4733. ; 20:10, s. 1299-1310
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: To estimate how direct health care costs resulting from adverse drug events (ADEs) and cost distribution are affected by methodological decisions regarding identification of ADEs, assigning relevant resource use to ADEs, and estimating costs for the assigned resources. Methods: ADEs were identified from medical records and diagnostic codes for a random sample of 4970 Swedish adults during a 3-month study period in 2008 and were assessed for causality. Results were compared for five cost evaluation methods, including different methods for identifying ADEs, assigning resource use to ADEs, and for estimating costs for the assigned resources (resource use method, proportion of registered cost method, unit cost method, diagnostic code method, and main diagnosis method). Different levels of causality for ADEs and ADEs contribution to health care resource use were considered. Results: Using the five methods, the maximum estimated overall direct health care costs resulting from ADEs ranged from Sk10,000 (Sk = Swedish krona; similar to(sic)1,500 in 2016 values) using the diagnostic code method to more than Sk3,000,000 (similar to(sic)414,000) using the unit cost method in our study population. The most conservative definitions for ADEs contribution to health care resource use and the causality of ADEs resulted in average costs per patient ranging from Sk0 using the diagnostic code method to Sk4066 (similar to(sic)500) using the unit cost method. Conclusions: The estimated costs resulting from ADEs varied considerably depending on the methodological choices. The results indicate that costs for ADEs need to be identified through medical record review and by using detailed unit cost data. Copyright (C) 2017, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc.
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22.
  • Johansson, Malin E V, 1971, et al. (författare)
  • Normalization of Host Intestinal Mucus Layers Requires Long-Term Microbial Colonization
  • 2015
  • Ingår i: Cell Host & Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 18:5, s. 582-592
  • Tidskriftsartikel (refereegranskat)abstract
    • The intestinal mucus layer provides a barrier limiting bacterial contact with the underlying epithelium. Mucus structure is shaped by intestinal location and the microbiota. To understand how commensals modulate gut mucus, we examined mucus properties under germ-free (GF) conditions and during microbial colonization. Although the colon mucus organization of GF mice was similar to that of conventionally raised (Convr) mice, the GF inner mucus layer was penetrable to bacteria-sized beads. During colonization, in which GF mice were gavaged with Convr microbiota, the small intestine mucus required 5 weeks to be normally detached and colonic inner mucus 6 weeks to become impenetrable. The composition of the small intestinal microbiota during colonization was similar to Convr donors until 3 weeks, when Bacteroides increased, Firmicutes decreased, and segmented filamentous bacteria became undetectable. These findings highlight the dynamics of mucus layer development and indicate that studies of mature microbe-mucus interactions should be conducted weeks after colonization.
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23.
  • Johnson, Charisse M., et al. (författare)
  • The role of social capital in explaining mental health inequalities between immigrants and Swedish-born : a population-based cross-sectional study
  • 2017
  • Ingår i: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 17
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Social capital may theoretically explain health inequalities between social groups, but empirical evidence is lacking. Some studies indicate that social capital may be particularly important for immigrant health. Nearly 16% of Sweden's population are foreign-born immigrants and research has shown them to be susceptible to psychological distress, though significant variation has been found between groups. In this study, we investigate the following hypotheses: 1) if non-refugees have better mental health than Swedish-born, and refugees experience worse mental health than Swedish-born; 2) if mental health status converges with that of Swedish-born with longer duration of residence; and 3) if social capital mediates the effect of immigrant status on psychological distress for different immigrant groups as compared to Swedish-born.Methods: This cross-sectional study uses baseline data from the Stockholm Public Health Cohort and includes 50,498 randomly-selected individuals from Stockholm County in 2002, 2006, and 2010. Mental health was measured as psychological distress, using the 12-item General Health Questionnaire. Social capital was measured using indicators of bonding, bridging, and linking social capital. Both cognitive and structural aspects were measured for the latter two indicators. Mediation was tested using logistic regression and the Sobel test.Results: The results show that refugees generally had greater odds of psychological distress than non-refugees compared to their respective Swedish-born counterparts. Among immigrant men, both refugees and non-refugees had significantly greater odds of psychological distress than Swedish-born men. Only refugee women in Sweden 10 years or more had significantly greater odds of psychological distress compared to Swedish-born women. The mediation analysis demonstrated that indicators of social capital mediated the association for all immigrant men (except non-refugees in Sweden 3-9 years) and for refugee women in Sweden 10 years or more. While bonding social capital showed the greatest mediatory role among the three social capital types, adding them together had the strongest explanatory effect.Conclusions: Social capital explains differences in mental health for some immigrant groups, highlighting its role as a potentially important post-migration factor. Increased investment from policy-makers regarding how social capital can be promoted among new arrivals may be important for preventing psychological distress.
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24.
  • Litjens, Carlijn H. C., et al. (författare)
  • Protein binding of rifampicin is not saturated when using high-dose rifampicin
  • 2019
  • Ingår i: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:4, s. 986-990
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. Objectives To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin. Methods Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10mg/kg daily) or high-dose (35mg/kg) rifampicin up to steady-state. The performance of total AUC(0-24) to predict unbound AUC(0-24) was evaluated. Results The in vitro free fraction of rifampicin remained unaltered (approximate to 9%) up to 21mg/L and increased up to 13% at 41mg/L and 17% at 64mg/L rifampicin. The highest (peak) concentration in vivo was 39.1mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC(0-24)in vivo was 13.3% (range=8.1%-24.9%) and 11.1% (range=8.6%-13.6%) for the standard group and the high-dose group, respectively (P=0.214). Prediction of unbound AUC(0-24) based on total AUC(0-24) resulted in a bias of -0.05% and an imprecision of 13.2%. Conclusions Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.
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25.
  • Maglio, Cristina, et al. (författare)
  • Bariatric surgery and the incidence of rheumatoid arthritis - a Swedish Obese Subjects study.
  • 2020
  • Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 59:2, s. 303-309
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to determine the effect of bariatric surgery on the incidence of RA in participants of the Swedish Obese Subjects (SOS) study.The SOS is a longitudinal study aiming to assess the effect of bariatric surgery on mortality and obesity-related diseases. This report includes 2002 subjects with obesity who underwent bariatric surgery and 2034 matched controls; none of them had RA at baseline. Cases of incident RA were identified through the Swedish National Patient Register by searching for International Classification of Diseases codes. Both intention-to-treat analyses and per-protocol analyses are reported. In the per-protocol analysis, participants from the control group who underwent bariatric surgery later on during follow-up were censored at the time of surgery.During follow-up, 92 study participants developed RA. The median follow-up was 21 years (range 0-29). Bariatric surgery was neither associated with the incidence of RA in the intention-to-treat analysis [hazard ratio (HR) 0.92 (95% CI 0.59, 1.46), P = 0.74], nor in the per-protocol analysis [HR 0.86 (95% CI 0.54, 1.38), P = 0.53]. Weight change at the 2 year follow-up, expressed as the change in BMI compared with baseline, did not associate with the development of RA. Higher serum CRP levels and smoking associated with the future development of RA independent of other factors.We did not detect any association between bariatric surgery and the incidence of RA in subjects affected by obesity followed up for up to 29 years.(http://clinicaltrials.gov): NCT01479452.
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26.
  • Martin, Oceane C. B., et al. (författare)
  • Infection with genotoxin-producing Salmonella enterica synergises with loss of the tumour suppressor APC in promoting genomic instability via the PI3K pathway in colonic epithelial cells
  • 2019
  • Ingår i: Cellular Microbiology. - : John Wiley & Sons. - 1462-5814 .- 1462-5822. ; 21:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Several commensal and pathogenic Gram-negative bacteria produce DNA-damaging toxins that are considered bona fide carcinogenic agents. The microbiota of colorectal cancer (CRC) patients is enriched in genotoxin-producing bacteria, but their role in the pathogenesis of CRC is poorly understood. The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis and in the majority of sporadic CRCs. We investigated whether the loss of APC alters the response of colonic epithelial cells to infection by Salmonella enterica, the only genotoxin-producing bacterium associated with cancer in humans. Using 2D and organotypic 3D cultures, we found that APC deficiency was associated with sustained activation of the DNA damage response, reduced capacity to repair different types of damage, including DNA breaks and oxidative damage, and failure to induce cell cycle arrest. The reduced DNA repair capacity and inability to activate adequate checkpoint responses was associated with increased genomic instability in APC-deficient cells exposed to the genotoxic bacterium. Inhibition of the checkpoint response was dependent on activation of the phosphatidylinositol 3-kinase pathway. These findings highlight the synergistic effect of the loss of APC and infection with genotoxin-producing bacteria in promoting a microenvironment conducive to malignant transformation.
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27.
  • Mochalina, Natalia, et al. (författare)
  • Antithrombotic therapy in patientswith non-valvular atrial fibrillation in Southern Sweden : A population-based cohort study
  • 2016
  • Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 140, s. 94-99
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Oral anticoagulants in patients with atrial fibrillation (AF) with moderate-to-high stroke risk are strongly recommended by the current guidelines.Materials and methods: Population-based register study of all 13,837 patients with incident non-valvular AF diagnosed during 2011-2014 in primary and secondary care (including all in-and outpatient visits) in Skane County, Sweden. The outcome was the prescription of direct-acting oral anticoagulants (DOAC), warfarin or acetylsalicylic acid (ASA).Results and conclusion: Guideline adherence increased from 47.6% in 2011 to 66.1% in 2014, mostly due to decrease in undertreatment. In patients with CHA(2)DS(2)-VASc score >= 2, ASA uptake decreased from 29.9% to 14.7% and DOAC uptake increased from 2.1% to 25.1%. The use of ASA was more common among elderly and with increasing stroke-and bleeding risk. Overall, 47.4% of patients with CHA(2)DS(2)-VASc score >= 2 did not receive oral anticoagulants. Undertreatment was particularly common in women < 65 years (55.8%) and in patients >84 years (65.3% in women and 62% in men). Overtreatment of patients at low stroke risk was 35.9% in men and 36.4% in women. Provider speciality affected the choice of treatment only to a minor degree. Despite increasing guideline adherence, there is a suboptimal use of antithrombotic therapy in a large proportion of AF patients diagnosed in different clinical settings. Efforts to further improve guideline adherence should particularly be targeted on women < 65 years, elderly > 84 years and patients at low stroke risk.
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28.
  • Möllsten, Anna, et al. (författare)
  • Glu298Asp and NOS4ab polymorphisms in diabetic nephropathy.
  • 2006
  • Ingår i: Annals of Medicine. - : Informa UK Limited. - 0785-3890 .- 1365-2060. ; 38:7, s. 522-528
  • Tidskriftsartikel (populärvet., debatt m.m.)abstract
    • BACKGROUND AND AIMS: The risk of diabetic nephropathy (DN) increases with increase in intraglomerular pressure, which may partly be regulated by nitric oxide (NO). NO-production can be affected by polymorphisms in the endothelial NO-synthase gene (NOS3), hyperglycaemia and smoking. We therefore studied association between DN and two polymorphisms in NOS3, Glu298Asp and NOS4ab, in Caucasian type 1 diabetes (T1D) patients. PATIENTS AND METHODS: A total of 1510 Finnish and Swedish T1D patients were included in a cross-sectional case-control study. Incipient DN was defined as an albumin excretion rate (AER) of 20-200 microg/min (n = 336). Overt DN = AER>200 microg/min or renal replacement therapy (n = 619). All patients with DN were considered as cases. The controls were T1D patients with diabetes duration 20 years, AER<20 microg/min and without antihypertensive treatment (n = 555). The genetic markers studied were a 27 bp repeat (NOS4ab) and Glu298Asp (rs1799983). RESULTS: Age at onset of diabetes, male sex, duration of diabetes, HbA1c, blood pressure and smoking were assessed as possible confounders in the logistic regression analysis, which showed that homozygosity for the Glu-allele of the Glu298Asp-polymorphism was independently associated with increased risk of DN (OR = 1.46; 95% CI = 1.12-1.91). The variables smoking (OR = 2.13; 95% CI = 1.63-2.78), male sex (OR = 1.61; 95% CI = 1.23-2.10), HbA1c (OR per % increase above upper limit of the normal reference range = 1.02; 95% CI = 1.02-1.03), systolic (OR = 1.05; 95% CI = 1.04-1.06) and diastolic blood pressure (OR = 1.04; 95% CI = 1.02-1.05) also significantly and independently increased the risk of DN when taking age at diabetes onset and diabetes duration into account. The NOS4 a-allele was not associated with DN. CONCLUSIONS: The Glu/Glu-genotype of the NOS3 Glu298Asp polymorphism may increase the risk of developing DN independently of other known risk factors.
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29.
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30.
  • Papadakos, Konstantinos S, et al. (författare)
  • The prognostic and potentially immunomodulatory role of cartilage oligomeric matrix protein in patients with gastric and esophageal adenocarcinoma
  • 2024
  • Ingår i: Cancer Immunology Immunotherapy. - 1432-0851. ; 73:5
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Cartilage oligomeric matrix protein (COMP) is a novel regulator of the tumor microenvironment. Studies in colon cancer and pancreatobiliary adenocarcinoma have revealed COMP expression to be associated with decreased infiltration of immune cells in the tumor microenvironment. Herein, the expression of COMP was investigated in gastric and esophageal adenocarcinoma with particular reference to its the relationship with the immune microenvironment.METHODS: COMP expression was evaluated in tissue microarrays representing primary tumors from 159 patients with chemo- and radiotherapy naïve esophageal and gastric adenocarcinoma and 67 matched samples of lymph node metastases using immunohistochemistry. Additionally, collagen fibers were stained with Sirius Red and evaluated with the FIJI macro TWOMBLI algorithm.RESULTS: The expression of COMP in cancer cells in the entire cohort was associated with shorter overall survival (OS) (p = 0.013) and recurrence-free survival (RFS) (p = 0.029), while COMP expression in the stroma was correlated with shorter RFS (p = 0.042). Similar correlations were found for patients with gastric adenocarcinoma, whereas COMP expression was not prognostic in esophageal adenocarcinoma. Further, in the entire cohort, the expression of COMP in the stroma was correlated with exclusion of different populations of immune cells (CD8+, CD3+, FoxP3+, CD20+) from the tumor microenvironment. Finally, higher density and alignment of collagen fibers were correlated with the expression of COMP in the stroma.CONCLUSIONS: Expression of COMP in gastric and esophageal adenocarcinoma was correlated with shorter OS and RFS. A reduced number of immune cells infiltrated the tumor microenvironment when COMP expression was detected. This phenomenon could be attributed to the denser collagen deposits, a hallmark of tumor fibrosis observed in COMP-expressing tumors.
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31.
  • Pelaseyed, Thaher, 1979, et al. (författare)
  • The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system
  • 2014
  • Ingår i: Immunological Reviews. - : Wiley. - 0105-2896 .- 1600-065X. ; 260:1, s. 8-20
  • Forskningsöversikt (refereegranskat)abstract
    • The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins MUC2 and MUC5AC are the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate-keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103+ type. In addition to the gel-forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy.
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32.
  • Schukfeh, Muhammed Ihab, et al. (författare)
  • Conductance Enhancement of InAs/InP Heterostructure Nanowires by Surface Functionalization with Oligo(phenylene vinylene)s
  • 2013
  • Ingår i: ACS Nano. - : American Chemical Society (ACS). - 1936-086X .- 1936-0851. ; 7:5, s. 4111-4118
  • Tidskriftsartikel (refereegranskat)abstract
    • We have investigated the electronic transport through 3 mu m long, 45 nm diameter InAs nanowires comprising a 5 nm long InP segment as electronic barrier. After assembly of 12 nm long oligo(phenylene vinylene) derivative molecules onto these InAs/InP nanowires, we observed a pronounced, nonlinear I-V characteristic with significantly increased currents of up to 1 mu A at 1 V bias, for a back-gate voltage of 3 V. As supported by our model calculations based on a nonequilibrium Green Function approach, we attribute this effect to charge transport through those surface-bound molecules, which electrically bridge both InAs regions across the embedded InP barrier.
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33.
  • Seblova, Dominika, et al. (författare)
  • Does Prolonged Education Causally Affect Dementia Risk When Adult Socioeconomic Status Is Not Altered? A Swedish Natural Experiment in 1.3 Million Individuals
  • 2021
  • Ingår i: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 190:5, s. 817-826
  • Tidskriftsartikel (refereegranskat)abstract
    • Intervening on modifiable risk factors to prevent dementia is of key importance, since progress-modifying treatments are not currently available. Education is inversely associated with dementia risk, but causality and mechanistic pathways remain unclear. We aimed to examine the causality of this relationship in Sweden using, as a natural experiment, data on a compulsory schooling reform that extended primary education by 1 year for 70% of the population between 1936 and 1949. The reform introduced substantial exogenous variation in education that was unrelated to pupils' characteristics. We followed 18 birth cohorts (n = 1,341,842) from 1985 to 2016 (up to ages 79-96 years) for a dementia diagnosis in the National Inpatient and Cause of Death registers and fitted Cox survival models with stratified baseline hazards at the school-district level, chronological age as the time scale, and cohort indicators. Analyses indicated very small or negligible causal effects of education on dementia risk (main hazard ratio = 1.01, 95% confidence interval: 0.98, 1.04). Multiple sensitivity checks considering only compliers, the pre-/post- design, differences in health-care-seeking behavior, and the impact of exposure misclassification left the results essentially unaltered. The reform had limited effects on further adult socioeconomic outcomes, such as income. Our findings suggest that without mediation through adult socioeconomic position, education cannot be uncritically considered a modifiable risk factor for dementia.
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34.
  • Svensson, Anna C., et al. (författare)
  • Cohort profile : the Stockholm public health cohort
  • 2013
  • Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 42:5, s. 1263-1272
  • Tidskriftsartikel (refereegranskat)abstract
    • The Stockholm Public Health Cohort was set up within the Stockholm County Council public health surveys to inform on determinants and consequences of significant contributors to the current burden of disease. Participants are 89 268 randomly selected individuals from the adult population of Stockholm County. Baseline surveys took place in 2002, 2006 and 2010 via self-administered questionnaires. So far, participants recruited in 2002 were re-surveyed twice, in 2007 and 2010, and those enrolled in 2006 were re-surveyed once, in 2010. Self-reported data are regularly supplemented by information from national and regional health data and administrative registers, for study participants and their relatives (including their offspring). Available data are extensive and include a wide array of health, lifestyle, perinatal, demographic, socio-economic and familial factors. The cohort is an international resource for epidemiological research, and the data available to the research community for specific studies obtained approval from the Stockholm Public Health Cohort Steering Committee and the Stockholm Regional Ethical Review Board.
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35.
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36.
  • Svensson, Anna C., et al. (författare)
  • Familial aggregation of schizophrenia : The moderating effect of age at onset, parental immigration, paternal age and season of birth
  • 2012
  • Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 40:1, s. 43-50
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: An abundance of evidence has firmly established the familial aggregation of schizophrenia. The aim of this study was to examine how age at onset, parental characteristics and season of birth modify the familiality in schizophrenia. Methods: A population-based cohort was created by linking the Swedish Multi-Generation and Hospital Discharge Registers. Among 5,075,998 full siblings born between 1932 through to 1990, 16,346 cases of schizophrenia were identified. Familial aggregation was measured by the sibling recurrence-risk ratio, defined as the risk of schizophrenia among full siblings of schizophrenia patients compared with the risk among siblings of unaffected people. Results: We found a statistically significantly lower recurrence-risk ratio in siblings of later onset cases (7.2; 95% confidence interval (95% CI) 6.7-7.9) than of early onset cases (10.8; 95% CI 9.4-12.2). A lower recurrence-risk ratio was observed among offspring to fathers above 40 years (6.3; 95% CI 5.3-7.3) as compared with offspring of younger fathers (8.6; 95% CI 8.0-9.3). Further, among offspring to parents born outside Sweden the recurrence-risk ratio was statistically significantly lower (maternal immigrants 4.8; 95% CI 4.0-5.7, paternal immigrants 5.7; 95% CI 4.6-6.9) than among offspring to parents born in Sweden. Conclusions: The familial aggregation of schizophrenia was reduced by higher age at onset, advancing paternal age and immigrant status of parents.
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37.
  • Svensson, Anna C., et al. (författare)
  • Fertility of first-degree relatives of patients with schizophrenia : A three generation perspective
  • 2007
  • Ingår i: Schizophrenia Research. - : Elsevier BV. - 0920-9964 .- 1573-2509. ; 91:1-3, s. 238-245
  • Tidskriftsartikel (refereegranskat)abstract
    • We explored the fertility in three generations; fertility of parents, siblings and offspring to patients with schizophrenia, to test the hypothesis that the decreased reproductive rate in the patients is compensated by an increased rate in their first-degree relatives. A population-based national database was created by linking the Swedish Multi-Generation and Hospital Discharge Registers. To maximize follow-up time for schizophrenia and reproductive history, three birth cohorts were selected: parental generation, born 1918–1927 (n=274464); affected generation, born 1932–1941 (n=108502) and offspring to affected generation, born 1951–1960 (n=103105). Ratios of estimated mean number of offspring were measured (fertility ratios), comparing the study subjects to the general population. The fertility among males with schizophrenia was decreased by over 70% (fertility ratiopatients/population=0.29, 95% CI 0.25–0.35), whereas female patients had less than half as many offspring as the general female population (fertility ratiopatients/population=0.48, 95% CI 0.42–0.55). When accounting for selection bias of larger families, no statistically significant difference was found among parents of patients with and without a diagnosis of schizophrenia. Further, the fertility among siblings of schizophrenic patients did not differ from the general population. A reduction in fertility was found among offspring to patients with schizophrenia, male offspring had 12% fewer offspring (fertility ratiooffspring/population=0.88, 95%CI 0.77–1.01), while female offspring had 6% fewer offspring (fertility ratiooffspring/population=0.94, 95% CI 0.84–1.05). In conclusion, we found reduced fertility in patients with schizophrenia and among their offspring that was not compensated by higher parental or sibling fertility.
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38.
  • Svensson, Anna C., et al. (författare)
  • Residential area and physical activity : A multi-level study of 68,000 adults in Stockholm County
  • 2017
  • Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1403-4948 .- 1651-1905. ; 45:1, s. 25-32
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: To determine whether there are systematic differences in physical activity between residential areas after extensive control for sociodemographic factors at the individual level. Methods: Multi-level regressions of walking/bicycling, sedentary activities, household work and exercise were carried out in a representative sample of 68,303 adults in 39 residential areas in Stockholm County, first adjusting at the individual level for country of birth, sex, age, education, occupational class and income. The type of housing was then considered at the individual level or, for walking/bicycling and exercise, at both the individual and area levels (as a measure of area density). Results: After adjustment for sociodemographic factors, differences between residential areas remained in walking/bicycling, corresponding to 0.27 SD, or 50 min/week between the most and least active areas. Forty per cent of this difference could be explained by the type of housing at the area level. For sedentary activities and household work, respectively, much of the variation that remained after adjustment for sociodemographic factors was, in turn, explained by the type of housing at the individual level, leaving a difference of 0.16 SD (80 min/week) and 0.13 SD (60 min/week), respectively. For exercise, the corresponding difference was 0.11 SD (11 min/week, not sensitive to housing). Conclusions: Area level factors may influence walking/bicycling. High area density was associated with more activity. However, high density also comes with a type of housing (apartments) that is associated with less household work and, surprisingly, more sedentary activities, introducing a challenging trade-off. The differences in exercise were smaller than for all other types of activities.
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39.
  • Svensson, Anna, et al. (författare)
  • Hydration of an amphiphilic excipient, Gelucire (R) 44/14
  • 2004
  • Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 1873-3476 .- 0378-5173. ; 281:1-2, s. 107-118
  • Tidskriftsartikel (refereegranskat)abstract
    • The incorporation of drugs into Gelucires has been reported to increase the dissolution rate of poorly soluble drugs, often leading to improved drug bioavailability. In pharmaceutical applications, it is important to know how the excipient interacts with the drug, and how the mixture behaves during manufacturing, storage as well as during administration. The uptake of water by an amphiphilic excipient, Gelucire(R) 44/14, has been investigated in two ways: storage in humid air and addition of liquid water. During exposure to humid air, the uptake goes in stages that correspond to the dissolution of the components of the excipient, starting with the most hydrophilic ones: glycerol, then polyethylene glycol (PEG), PEG esters (PEG monolaurate and PEG dilaurate), and finally glycerides (trilaurin). At each stage, the remaining: crystals are in equilibrium with an interstitial solution made of water and the dissolved components. In this range of hydrations, the total uptake is close to the sum of the equilibrium hydrations of the components. In the pharmaceutical formulation, the active ingredient could dissolve in the liquid phase. At larger hydrations obtained through addition of liquid water, the state of Gelucire(R) 44/14 differs from those of its components. Gelucire(R) 44/14 forms a lamellar phase and this phase melts at 30degreesC whereas the pure PEG esters form hexagonal and cubic mesophases. The cubic mesophases do not melt until the temperature exceeds 40degreesC. At body temperature, all crystals in Gelucire(R) 44/14 melt to an isotropic fluid as soon as the total water content exceeds 5%. Therefore the formulation of amphiphilic excipients can be optimized to avoid the formation of mesophases that impede dissolution of the excipient at body temperature. (C) 2004 Elsevier B.V. All rights reserved.
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40.
  • Svensson, Matilda1, et al. (författare)
  • Antibodies to Influenza Virus A/H1N1 Hemagglutinin in Type 1 Diabetes Children Diagnosed Before, During and After the SWEDISH A(H1N1)pdm09 Vaccination Campaign 2009-2010
  • 2014
  • Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 79:2, s. 137-148
  • Tidskriftsartikel (refereegranskat)abstract
    • We determined A/H1N1-hemagglutinin (HA) antibodies in relation to HLAD-Q genotypes and islet autoantibodies at clinical diagnosis in 1141 incident 0.7 to 18-year-old type 1 diabetes patients diagnosed April 2009-December 2010. Antibodies to S-35-methionine-labelled A/H1N1 hemagglutinin were determined in a radio-binding assay in patients diagnosed before (n = 325), during (n = 355) and after (n = 461) the October 2009-March 2010 Swedish A(H1N1) pdm09 vaccination campaign, along with HLA-DQ genotypes and autoantibodies against GAD, insulin, IA-2 and ZnT8 transporter. Before vaccination, 0.6% patients had A/H1N1-HA antibodies compared with 40% during and 27% after vaccination (P less than 0.0001). In children less than3 years of age, A/H1N1-HA antibodies were found only during vaccination. The frequency of A/H1N1-HA antibodies during vaccination decreased after vaccination among the 3 less than 6 (P = 0.006) and 13 less than 18 (P = 0.001), but not among the 6 less than 13-year-olds. HLA-DQ2/8 positive children less than3 years decreased from 54% (15/28) before and 68% (19/28) during, to 30% (9/30) after vaccination (P = 0.014). Regardless of age, DQ2/2; 2/X (n = 177) patients had lower frequency (P = 0.020) and levels (P = 0.042) of A/H1N1-HA antibodies compared with non-DQ2/2; 2/X (n = 964) patients. GADA frequency was 50% before, 60% during and 51% after vaccination (P = 0.009). ZnT8QA frequency increased from 30% before to 34% during and 41% after vaccination (P = 0.002). Our findings suggest that young (less than3 years) along with DQ2/2; 2/X patients were low responders to Pandemrix (R). As the proportion of DQ2/8 patients less than3 years of age decreased after vaccination and the frequencies of GADA and ZnT8QA were enhanced, it cannot be excluded that the vaccine affected clinical onset of type 1 diabetes.
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41.
  • Thomsson, Elisabeth, 1975, et al. (författare)
  • Recombinant glycoprotein E produced in mammalian cells in large-scale as an antigen for varicella-zoster-virus serology.
  • 2011
  • Ingår i: Journal of virological methods. - : Elsevier BV. - 1879-0984 .- 0166-0934. ; 175:1, s. 53-9
  • Tidskriftsartikel (refereegranskat)abstract
    • A recombinant glycoprotein E (gE) from varicella-zoster virus (VZV) was generated and produced in Chinese Hamster Ovary (CHO) cells, in the development of a specific antigen for analysis of IgG antibodies to VZV. Several stable gE-secreting clones were established and one clone was adapted to growth in serum-free suspension culture. When the cells were cultured in a perfusion bioreactor, gE was secreted into the medium, from where it could be easily purified. The recombinant gE was then evaluated as a serological antigen in ELISA. When compared to a conventional whole virus antigen, the VZV gE showed similar results in ELISA-based seroprevalence studies of 854 samples derived from blood donors, students, ischemic stroke patients and their controls, including samples with border-line results in previous analyses. Eight samples (0.9%) were discordant, all being IgG-negative by the VZV gE ELISA and positive by the whole virus ELISA. The sensitivity and specificity of the VZV gE ELISA were 99.9% and 100%, respectively, compared to 100% and 88.9% for the VZV whole virus ELISA. The elderly subjects showed similar reactivities to both antigens, while VZV gE gave lower signals in the younger cohorts, suggesting that antibodies to gE may increase with age. It was concluded that the recombinant VZV gE from CHO cells was suitable as a serological antigen for the detection of IgG antibodies specific for VZV.
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42.
  • Trkulja, C. L., et al. (författare)
  • Rational antibody design for undruggable targets using kinetically controlled biomolecular probes
  • 2021
  • Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:16
  • Tidskriftsartikel (refereegranskat)abstract
    • Several important drug targets, e.g., ion channels and G protein-coupled receptors, are extremely difficult to approach with current antibody technologies. To address these targets classes, we explored kinetically controlled proteases as structural dynamics-sensitive druggability probes in native-state and disease-relevant proteins. By using low-Reynolds number flows, such that a single or a few protease incisions are made, we could identify antibody binding sites (epitopes) that were translated into short-sequence antigens for antibody production. We obtained molecular-level information of the epitope-paratope region and could produce high-affinity antibodies with programmed pharmacological function against difficult-to-drug targets. We demonstrate the first stimulus-selective monoclonal antibodies targeting the transient receptor potential vanilloid 1 (TRPV1) channel, a clinically validated pain target widely considered undruggable with antibodies, and apoptosis-inducing antibodies selectively mediating cytotoxicity in KRAS-mutated cells. It is our hope that this platform will widen the scope of antibody therapeutics for the benefit of patients.
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43.
  • Vodnala, Suman K., et al. (författare)
  • Structure-Activity Relationships of Synthetic Cordycepin Analogues as Experimental Therapeutics for African Trypanosomiasis
  • 2013
  • Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:24, s. 9861-9873
  • Tidskriftsartikel (refereegranskat)abstract
    • Novel methods for treatment of African trypanosomiasis, caused by infection with Trypanosoma brucei are needed. Cordycepin (3'-deoxyadenosine, la) is a powerful trypanocidal compound in vitro but is ineffective in vivo because of rapid metabolic,degradation by adenosine deaminase (ADA). We elucidated the structural moieties of cordycepin required for trypanocidal activity and designed analogues that retained trypanotoxicity while gaining resistance to ADA-mediated metabolism. 2-Fluorocordycepin (2-fluoro3'-deoxyadenosine, 1b) was identified as a selective, potent, and ADA-resistant trypanocidal compound that cured T. brucei infection in mice. Compound 1b is transported through the high affinity TbAT1/P2 adenosine transporter and is a substrate of T. b. brucei adenosine kinase. 1b has good preclinical properties suitable for an, oral drug, albeit a relatively short plasma half-life. We present a rapid and efficient synthesis of 2-halogenated cordycepins, also useful synthons. for the development of additional novel C2-substituted 3'-deoxyadenosine analogues to be evaluated in development of experimental therapeutics.
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44.
  • Wennerholm, Ulla-Britt, 1948, et al. (författare)
  • Progesterone, cerclage, pessary, or acetylsalicylic acid for prevention of preterm birth in singleton and multifetal pregnancies : A systematic review and meta-analyses
  • 2023
  • Ingår i: Frontiers in Medicine. - : Frontiers Media S.A.. - 2296-858X. ; 10
  • Forskningsöversikt (refereegranskat)abstract
    • Background: Preterm birth is the leading cause of childhood mortality and morbidity. We aimed to provide a comprehensive systematic review on randomized controlled trials (RCTs) on progesterone, cerclage, pessary, and acetylsalicylic acid (ASA) to prevent preterm birth in asymptomatic women with singleton pregnancies defined as risk of preterm birth and multifetal pregnancies.Methods: Six databases (including PubMed, Embase, Medline, the Cochrane Library) were searched up to February 2022. RCTs published in English or Scandinavian languages were included through a consensus process. Abstracts and duplicates were excluded. The trials were critically appraised by pairs of reviewers. The Cochrane risk-of-bias tool was used for risk of bias assessment. Predefined outcomes including preterm birth, perinatal/neonatal/maternal mortality and morbidity, were pooled in meta-analyses using RevMan 5.4, stratified for high and low risk of bias trials. The certainty of evidence was assessed using the GRADE approach. The systematic review followed the PRISMA guideline.Results: The search identified 2,309 articles, of which 87 were included in the assessment: 71 original RCTs and 16 secondary publications with 23,886 women and 32,893 offspring. Conclusions were based solely on trials with low risk of bias (n = 50).Singleton pregnancies: Progesterone compared with placebo, reduced the risk of preterm birth < 37 gestational weeks: 26.8% vs. 30.2% (Risk Ratio [RR] 0.82 [95% Confidence Interval [CI] 0.71 to 0.95]) (high certainty of evidence, 14 trials) thereby reducing neonatal mortality and respiratory distress syndrome. Cerclage probably reduced the risk of preterm birth < 37 gestational weeks: 29.0% vs. 37.6% (RR 0.78 [95% CI 0.69 to 0.88]) (moderate certainty of evidence, four open trials). In addition, perinatal mortality may be reduced by cerclage. Pessary did not demonstrate any overall effect. ASA did not affect any outcome, but evidence was based on one underpowered study.Multifetal pregnancies: The effect of progesterone, cerclage, or pessary was minimal, if any. No study supported improved long-term outcome of the children.Conclusion: Progesterone and probably also cerclage have a protective effect against preterm birth in asymptomatic women with a singleton pregnancy at risk of preterm birth. Further trials of ASA are needed. Prevention of preterm birth requires screening programs to identify women at risk of preterm birth.
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45.
  • Wu, Haotian, et al. (författare)
  • Association of ambient PM2.5 exposure with maternal bone strength in pregnant women from Mexico City : a longitudinal cohort study
  • 2020
  • Ingår i: The Lancet Planetary Health. - 2542-5196. ; 4:11, s. E530-E537
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Pregnancy is associated with deteriorations in maternal bone strength and heightened susceptibility to bone fractures. We aimed to investigate whether ambient particulate matter (PM)(2.5) concentrations were associated with bone strength during pregnancy. Methods In this longitudinal cohort study, we analysed longitudinal data from women participating in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort in Mexico City, Mexico. Eligible women were aged 18 years or older, at less than 20 weeks' gestation at the time of recruitment, planning to stay in Mexico City for the next 3 years, without heart or kidney disease, did not use steroids or anti-epileptic drugs, were not daily consumers of alcohol, and had access to a telephone. Daily ambient PM2.5 concentrations were estimated from a spatio-temporal model that was based on the individual's address. Trabecular bone strength was measured using quantitative ultrasound from the radius of the middle finger and cortical bone strength from the proximal phalanx of the middle finger, during the second trimester, third trimester, and 1 and 6 months post partum. Bone strength T scores were modelled with PM2.5 concentrations using linear mixed models and distributed lag models. Findings Adjusting for multiple exposure windows, each 10 mu g/m(3) increase in PM2.5 exposure concentrations in the first trimester was associated with a 0.18 SD decrease (95% CI -0.35 to -0.01; p=0.033) in ultrasound speed-of-sound (SOS) T score of trabecular bone strength from the second trimester until 6 months post partum. Similarly, each 10 mu g/m(3) increase in third trimester PM2.5 exposure was associated with a 0.18 SD decrease (-0.36 to -0.01; p=0.044) in the SOS T score of trabecular bone strength from the third trimester until 6 months post partum. PM2.5 exposure in the first month post partum was associated with a 0.20 SD decline (-0.39 to -0.01; p=0.043) in cortical bone strength until 6 months post partum. Interpretation Ambient PM2.5 exposure during and after pregnancy was associated with diminished trabecular and cortical bone strength. Early pregnancy PM2.5 exposure was associated with a greater decline in bone strength later during pregnancy. Late pregnancy and early post-partum exposures adversely affected the post-partum bone strength recovery. Technological and policy solutions to reduce PM2.5 pollution could improve public health by reducing bone fracture risk.
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46.
  • Ziels, Ryan, et al. (författare)
  • Microbial community adaptation influences long-chain fatty acid conversion during anaerobic codigestion of fats, oils, and grease with municipal sludge
  • 2016
  • Ingår i: Water Research. - : Elsevier BV. - 0043-1354 .- 1879-2448. ; 103, s. 372-382
  • Tidskriftsartikel (refereegranskat)abstract
    • Codigesting fats, oils, and greases with municipal wastewater sludge can greatly improve biomethanerecovery at wastewater treatment facilities. Process loading rates of fats, oils, and greases have beenpreviously tested with little knowledge of the digester microbial community structure, and high transientfat loadings have led to long chain fatty acid (LCFA) accumulation and digester upsets. This studyutilized recently-developed quantitative PCR assays for syntrophic LCFA-degrading bacteria along with16S amplicon sequencing to relate changes in microbial community structure to LCFA accumulationduring transient loading increases to an anaerobic codigester receiving waste restaurant oil andmunicipal wastewater sludge. The 16S rRNA gene concentration of the syntrophic b-oxidizing genusSyntrophomonas increased to ~15% of the Bacteria community in the codigester, but stayed below 3% inthe control digester that was fed only wastewater sludge. Methanosaeta and Methanospirillum were thedominant methanogenic genera enriched in the codigester, and together comprised over 80% of theArchaea community by the end of the experimental period. Constrained ordination showed that changesin the codigester Bacteria and Archaea community structures were related to measures of digester performance.Notably, the effluent LCFA concentration in the codigester was positively correlated to thespecific loading rate of waste oil normalized to the Syntrophomonas 16S rRNA concentration. Specificloading rates of 0e1.5 1012 g VS oil/16S gene copies-day resulted in LCFA concentrations below 30 mg/g TS, whereas LCFA accumulated up to 104 mg/g TS at higher transient loading rates. Based on thecommunity-dependent loading limitations found, enhanced biomethane production from high loadingsof fats, oils and greases can be achieved by promoting a higher biomass of slow-growing syntrophicconsortia, such as with longer digester solids retention times. This work also demonstrates the potentialfor controlling the loading rate of fats, oils, and greases based on the analysis of the codigester communitystructure, such as with quantitative PCR measurements of syntrophic LCFA-degrading bacteriaabundance.
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