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1.	Hellberg, Victoria, et al. (författare) Cisplatin and oxaliplatin toxicity : importance of cochlear kinetics as a determinant for ototoxicity 2009 Ingår i: Journal of the National Cancer Institute. - Cary : Oxford University Press. - 0027-8874 .- 1460-2105. ; 101:1, s. 37-47 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Cisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained.METHODS: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration-time curve (AUC). Statistical tests were two-sided.RESULTS: In HCT-116 cells, cisplatin (20 microM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 microM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 microg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 microM x minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics.CONCLUSION: Cisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.
2.	Isaksson, Karin, 1984- (författare) Logistics Service Providers Going Green : A Framework for Developing Green Service Offerings 2014 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Environmental impact has increasingly become a “buzzword” and an important topic. This topic has been integrated into the agenda of many companies worldwide, and this dissertation focuses on the transportation and logistics industry. Environmental concerns have gained increased attention among many logistic service providers (LSPs) due to the environmental impact from their operations, and they have been identified of having a significant role in reducing the environmental burden in the supply chain. An environmental approach of the LSPs' business has also been identified as a way to achieve competitive advantage and provide market opportunities where the development and marketing of new products and services associated with green issues are suggested as important aspects for future growth. However, considering the scarcity of research regarding this topic, a study that reveals potential aspects in the development of green service offerings can bridge the knowledge gap and provide opportunities for further research within this field. The purpose of this dissertation is therefore to develop and explain a framework for LSPs’ development of green service offerings. The purpose is addressed by first investigating LSPs' service development from a general perspective in order to, in a second stage, reach a better understanding of the implications when integrating green aspects in LSPs' service development efforts.Theoretically, this dissertation departed from service marketing literature or more specifically new service development (NSD) research. This resulted in a conceptual framework including key dimensions and aspects regarding a company’s NSD efforts and activities. From this foundation, the theoretical framework was developed further based on research regarding LSPs' service development and innovation management. Finally the framework was extended with green logistics literature as well as research regarding LSPs' green development and influences on their service offerings.Empirically, this research is mainly based on qualitative data from an in-depth case study on a large LSP active on the Swedish market. In addition, empirical data from a multiple case study and a questionnaire survey conducted for the Licentiate thesis were used in order to enrich the analysis regarding the LSPs' development of green service offerings. The analysis followed a stepwise approach where literature and empirical data were analysed.One of the main results in this dissertation is the framework for LSPs' new service development, consisting of five dimensions: NSD culture, NSD strategy, NSD process focus, IT use and expertise and NSD knowledge and skills. The NSD framework presents a holistic view of the LSPs’ NSD efforts by revealing different dimensions, their roles and relations to each other as well as the pre-requisites to take into consideration in the development of new services. Thus, the different NSD dimensions should not solely be viewed as isolated dimensions; instead, there is a need for LSPs to have a holistic view and understanding of the NSD activities’ reciprocity.Another main result concerns the adaption of the NSD framework to green service development. The results reveal some pre-requisites relevant for LSPs to consider in their efforts to develop green service offerings and are summarised in the following main dimensions:Creating green awareness in the NSD culture – encourage participation regarding green initiatives within the organisation, defining a “common picture” in order to facilitate collaboration efforts and knowledge exchange concerning green expertise. The support from top management was also identified of having an influencing impact. Defining the strategic approach of green service offerings – integrate a green concern in the overall business strategy and to define the strategic role and incentives for developing green service offerings. The results also suggest LSPs to adapt green NSD efforts to different business contexts and market possibilities to match existing resources and skills with customers’ green requirements, and to perform a segmentation of customers’ environmental work and ambitions to increase the understanding of customers’ green attitudes and requirements.Create processes and routines to facilitate spreading of green knowledge – highlights the relevance of a process focus for spreading green knowledge both from an external and internal perspective. It involves e.g. adoption of certifications, procedures for environmental calculations and documentation as well as routines to spread and integrate green knowledge among employees as well as identification of customers’ green requirements.Improve green internal knowledge and build green collaborations – provide training and education to increase the level of green awareness and knowledge among employees as well as customers and strive for collaboration efforts both internally and externally to utilise each other’s knowledge and resources towards the development of green service offerings.Increase transparency of green information both internally and externally – improve green information transparency to build both internal and external trust and increase possibilities to effectively use other actors’ knowledge and resources to develop environmental improvements in the supply chain. Integration of IT expertise and synchronisations of IT systems to facilitate and support environmental work and development of green service offerings.
3.	Papapavlou Lingehed, Georgia, et al. (författare) Plasma protein profiling reveals dynamic immunomodulatory changes in multiple sclerosis patients during pregnancy 2022 Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13 Tidskriftsartikel (refereegranskat)abstract Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory and neurodegenerative disorder of the central nervous system. Pregnancy represents a natural modulation of the disease course, where the relapse rate decreases, especially in the 3(rd) trimester, followed by a transient exacerbation after delivery. Although the exact mechanisms behind the pregnancy-induced modulation are yet to be deciphered, it is likely that the immune tolerance established during pregnancy is involved. In this study, we used the highly sensitive and specific proximity extension assay technology to perform protein profiling analysis of 92 inflammation-related proteins in MS patients (n=15) and healthy controls (n=10), longitudinally sampled before, during, and after pregnancy. Differential expression analysis was performed using linear models and p-values were adjusted for false discovery rate due to multiple comparisons. Our findings reveal gradual dynamic changes in plasma proteins that are most prominent during the 3(rd) trimester while reverting post-partum. Thus, this pattern reflects the disease activity of MS during pregnancy. Among the differentially expressed proteins in pregnancy, several proteins with known immunoregulatory properties were upregulated, such as PD-L1, LIF-R, TGF-beta 1, and CCL28. On the other hand, inflammatory chemokines such as CCL8, CCL13, and CXCL5, as well as members of the tumor necrosis factor family, TRANCE and TWEAK, were downregulated. Further in-depth studies will reveal if these proteins can serve as biomarkers in MS and whether they are mechanistically involved in the disease amelioration and worsening. A deeper understanding of the mechanisms involved may identify new treatment strategies mimicking the pregnancy milieu.
4.	Svenvik, Maria, et al. (författare) Early prediction of spontaneous preterm birth before 34 gestational weeks based on a combination of inflammation-associated plasma proteins 2024 Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 15 Tidskriftsartikel (refereegranskat)abstract Background: In order to identify and possibly offer prophylactic treatment to women at risk for preterm birth (PTB), novel prediction models for PTB are needed. Our objective was to utilize high-sensitive plasma protein profiling to investigate whether early prediction of spontaneous PTB (sPTB) before 34 gestational weeks (gw) was possible in a low-risk population. Methods: A case-control study was conducted on 46 women with sPTB before 34 gw and 46 women with normal pregnancies and term deliveries. Prospectively collected plasma sampled at gw 11 (range 7-16) and gw 25 (range 23-30) was analyzed with a high-sensitivity Proximity Extension Assay for levels of 177 inflammation-associated proteins, and statistically processed with multivariate logistic regression analysis. Results: In the first trimester, higher levels of hepatocyte growth factor (HGF) were associated with sPTB <34 gw (OR 1.49 (1.03-2.15)). In the second trimester, higher levels of interleukin (IL)-10 (OR 2.15 (1.18-3.92)), IL-6 (OR 2.59 (1.34-4.99)), and the receptor activator of nuclear factor kappa B (RANK) (OR 2.18 (1.26-3.77)) were associated with sPTB <34 gw. The area under the curve for the prediction models including these proteins was 0.653 (0.534-0.759) in the first trimester and 0.854 (0.754-0.925) in the second trimester. Conclusion: A combination of inflammation-associated plasma proteins from the second trimester of pregnancy showed a good predictive ability regarding sPTB before 34 gw, suggesting it could be a valuable supplement for the assessment of the clinical risk of sPTB. However, although a high number (n=177) of plasma proteins were analyzed with a high-sensitivity method, the prediction of sPTB in the first trimester remains elusive.
5.	Tesi, Bianca, et al. (författare) Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study 2024 Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39 Tidskriftsartikel (refereegranskat)abstract BackgroundChildhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.MethodsgWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.FindingsThe prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).InterpretationOverall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.
6.	Zenere, Alberto, et al. (författare) Prominent epigenetic and transcriptomic changes in CD4(+) and CD8(+) T cells during and after pregnancy in women with multiple sclerosis and controls 2023 Ingår i: Journal of Neuroinflammation. - : BMC. - 1742-2094. ; 20:1 Tidskriftsartikel (refereegranskat)abstract BackgroundMultiple sclerosis (MS) is a neuroinflammatory disease in which pregnancy leads to a temporary amelioration in disease activity as indicated by the profound decrease in relapses rate during the 3rd trimester of pregnancy. CD4(+) and CD8(+) T cells are implicated in MS pathogenesis as being key regulators of inflammation and brain lesion formation. Although Tcells are prime candidates for the pregnancy-associated improvement of MS, the precise mechanisms are yet unclear, and in particular, a deep characterization of the epigenetic and transcriptomic events that occur in peripheral T cells during pregnancy in MS is lacking.MethodsWomen with MS and healthy controls were longitudinally sampled before, during (1st, 2nd and 3rd trimesters) and after pregnancy. DNA methylation array and RNA sequencing were performed on paired CD4(+) and CD8(+) T cells samples. Differential analysis and network-based approaches were used to analyze the global dynamics of epigenetic and transcriptomic changes.ResultsBoth DNA methylation and RNA sequencing revealed a prominent regulation, mostly peaking in the 3rd trimester and reversing post-partum, thus mirroring the clinical course with improvement followed by a worsening in disease activity. This rebound pattern was found to represent a general adaptation of the maternal immune system, with only minor differences between MS and controls. By using a network-based approach, we highlighted several genes at the core of this pregnancy-induced regulation, which were found to be enriched for genes and pathways previously reported to be involved in MS. Moreover, these pathways were enriched for in vitro stimulated genes and pregnancy hormones targets.ConclusionThis study represents, to our knowledge, the first in-depth investigation of the methylation and expression changes in peripheral CD4(+) and CD8(+) T cells during pregnancy in MS. Our findings indicate that pregnancy induces profound changes in peripheral T cells, in both MS and healthy controls, which are associated with the modulation of inflammation and MS activity.
7.	Aderne, Rian E., et al. (författare) On the energy gap determination of organic optoelectronic materials : the case of porphyrin derivatives 2022 Ingår i: Materials Advances. - : Royal Society of Chemistry. - 2633-5409. ; :3, s. 1791-1803 Tidskriftsartikel (refereegranskat)abstract The correct determination of the ionization potential (IP) and electron affinity (EA) as well as the energy gap is essential to properly characterize a series of key phenomena related to the applications of organic semiconductors. For example, energy offsets play an essential role in charge separation in organic photovoltaics. Yet there has been a lot of confusion involving the real physical meaning behind those quantities. Experimentally the energy gap can be measured by direct techniques such as UV-Vis absorption, or indirect techniques such as cyclic voltammetry (CV). Another spectroscopic method is the Reflection Electron Energy Loss Spectroscopy (REELS). Regarding data correlation, there is little consensus on how the REELS' energy gap can be interpreted in light of the energies obtained from other methodologies such as CV, UV-Vis, or photoemission. In addition, even data acquired using those traditional techniques has been misinterpreted or applied to derive conclusions beyond the limits imposed by the physics of the measurement. A similar situation also happens when different theoretical approaches are used to assess the energy gap or employed to explain outcomes from experiments. By using a set of porphyrin derivatives as model molecules, we discuss some key aspects of those important issues. The peculiar properties of these porphyrins demonstrate that even straightforward measurements or calculations performed in a group of very similar molecules need a careful interpretation of the outcomes. Differences up to 660 meV (similar to 190 meV) are found comparing REELS (electrochemical) measurements with UV-Vis energy gaps, for instance. From the theoretical point of view, a reasonable agreement with electrochemical measurements of the IP, EA, and the gap of the porphyrins is only obtained when the calculations involve the full thermodynamics of the redox processes. The purpose of this work is to shed light on the differences and similarities of those aforementioned characterization methods and provide some insight that might help one to develop a critical analysis of the different experimental and theoretical methodologies.
8.	Bachnick, Stefanie, et al. (författare) TAILR (Nursing-Sensitive Events and Their Association With Individual Nurse Staffing Levels) Project : Protocol for an International Longitudinal Multicenter Study 2024 Ingår i: JMIR Research Protocols. - 1929-0748. ; 13 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Nursing-sensitive events (NSEs) are common, accounting for up to 77% of adverse events in hospitalized patients (eg, fall-related harm, pressure ulcers, and health care-associated infections). NSEs lead to adverse patient outcomes and impose an economic burden on hospitals due to increased medical costs through a prolonged hospital stay and additional medical procedures. To reduce NSEs and ensure high-quality nursing care, appropriate nurse staffing levels are needed. Although the link between nurse staffing and NSEs has been described in many studies, appropriate nurse staffing levels are lacking. Existing studies describe constant staffing exposure at the unit or hospital level without assessing patient-level exposure to nurse staffing during the hospital stay. Few studies have assessed nurse staffing and patient outcomes using a single-center longitudinal design, with limited generalizability. There is a need for multicenter longitudinal studies with improved potential for generalizing the association between individual nurse staffing levels and NSEs.OBJECTIVE: This study aimed (1) to determine the prevalence, preventability, type, and severity of NSEs; (2) to describe individual patient-level nurse staffing exposure across hospitals; (3) to assess the effect of nurse staffing on NSEs in patients; and (4) to identify thresholds of safe nurse staffing levels and test them against NSEs in hospitalized patients.METHODS: This international multicenter study uses a longitudinal and observational research design; it involves 4 countries (Switzerland, Sweden, Germany, and Iran), with participation from 14 hospitals and 61 medical, surgery, and mixed units. The 16-week observation period will collect NSEs using systematic retrospective record reviews. A total of 3680 patient admissions will be reviewed, with 60 randomly selected admissions per unit. To be included, patients must have been hospitalized for at least 48 hours. Nurse staffing data (ie, the number of nurses and their education level) will be collected daily for each shift to assess the association between NSEs and individual nurse staffing levels. Additionally, hospital data (ie, type, teaching status, and ownership) and unit data (ie, service line and number of beds) will be collected.RESULTS: As of January 2024, the verification process for the plausibility and comprehensibility of patients' and nurse staffing data is underway across all 4 countries. Data analyses are planned to be completed by spring 2024, with the first results expected to be published in late 2024.CONCLUSIONS: This study will provide comprehensive information on NSEs, including their prevalence, preventability, type, and severity, across countries. Moreover, it seeks to enhance understanding of NSE mechanisms and the potential impact of nurse staffing on these events. We will evaluate within- and between-hospital variability to identify productive strategies to ensure safe nurse staffing levels, thereby reducing NSEs in hospitalized patients. The TAILR (Nursing-Sensitive Events and Their Association With Individual Nurse Staffing Levels) study will focus on the optimization of scarce staffing resources.INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/56262.
9.	Badam, Tejaswi, et al. (författare) CD4(+) T-cell DNA methylation changes during pregnancy significantly correlate with disease-associated methylation changes in autoimmune diseases 2022 Ingår i: Epigenetics. - : Taylor & Francis Group. - 1559-2294 .- 1559-2308. ; 17:9, s. 1040-1055 Tidskriftsartikel (refereegranskat)abstract Epigenetics may play a central, yet unexplored, role in the profound changes that the maternal immune system undergoes during pregnancy and could be involved in the pregnancy-induced modulation of several autoimmune diseases. We investigated changes in the methylome in isolated circulating CD4(+) T-cells in non-pregnant and pregnant women, during the 1(st) and 2(nd) trimester, using the Illumina Infinium Human Methylation 450K array, and explored how these changes were related to autoimmune diseases that are known to be affected during pregnancy. Pregnancy was associated with several hundreds of methylation differences, particularly during the 2(nd) trimester. A network-based modular approach identified several genes, e.g., CD28, FYN, VAV1 and pathways related to T-cell signalling and activation, highlighting T-cell regulation as a central component of the observed methylation alterations. The identified pregnancy module was significantly enriched for disease-associated methylation changes related to multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. A negative correlation between pregnancy-associated methylation changes and disease-associated changes was found for multiple sclerosis and rheumatoid arthritis, diseases that are known to improve during pregnancy whereas a positive correlation was found for systemic lupus erythematosus, a disease that instead worsens during pregnancy. Thus, the directionality of the observed changes is in line with the previously observed effect of pregnancy on disease activity. Our systems medicine approach supports the importance of the methylome in immune regulation of T-cells during pregnancy. Our findings highlight the relevance of using pregnancy as a model for understanding and identifying disease-related mechanisms involved in the modulation of autoimmune diseases.
10.	Blennborn, Maria, et al. (författare) The couple's decision-making in IVF : one or two embryos at transfer? 2005 Ingår i: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 20:5, s. 1292-1297 Tidskriftsartikel (refereegranskat)abstract The aim of this study was to evaluate the decision-making process and factors that contribute to the decision of IVF participants to choose one or two embryos at transfer.Methods: Two hundred and seventy-four IVF patients equally distributed in males and females were personally interviewed using a semi-structured questionnaire which included 82 items.Results: In the whole study population, previous childbirth [odds ratio (OR) 2.1; 95% confidence interval (CI) 1.9–3.6], and spare embryos to freeze (OR 23.6; 95% CI 11.2–54.5) emerged as the most important variables in patients who had one embryo transferred, while previous IVF treatments (OR 0.3; 95% CI 0.1–0.6) and the assumed increased pregnancy chance (OR 0.1; 95% CI 0.05–0.3) were the most important decision-making factors among those who had two embryos. The women were more satisfied with the information (83 versus 71%; P=0.02), and more aware of the risks with twin pregnancies (77 versus 66%; P=0.03) than the males. The women were also more concerned about their age. Knowledge about risks of multiple pregnancies was higher in females (77%) than in males (66%, P=0.03).Conclusion: The results of this study indicate that despite good information about the risks for complications with multiple pregnancies, many patients wish to have two embryos transferred. Spare embryos to freeze, improvement of pregnancy rate in single embryo transfer and young age of the woman are predictive of choosing single embryo transfer. However, the final decision must always be made in agreement with the physician.
11.	Bohm-Starke, Nina, et al. (författare) Development of a core outcome set for treatment studies for provoked vestibulodynia. 2024 Ingår i: Journal of Sexual Medicine. - : Oxford University Press. - 1743-6095 .- 1743-6109. ; 21:6, s. 556-565 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: There is an inconsistency in treatment outcomes used in clinical trials for provoked vestibulodynia (PVD), which makes it impossible to compare the effects of different interventions.AIM: In this study, we completed the first step in creating a core outcome set (COS), defining what outcomes should be measured in clinical trials for PVD.METHODS: Identification of outcomes used in studies was done by extracting data from clinical trials in a recently published systematic review and via review of clinical trials for PVD registered on ClinicalTrials.gov. The COS process consisted of 2 rounds of Delphi surveys and a consensus meeting, during which the final COS was decided through a modified nominal group technique.OUTCOMES: Consensus on what outcomes to include in a COS for PVD.RESULTS: Forty scientific articles and 92 study protocols were reviewed for outcomes. Of those, 36 articles and 25 protocols were eligible, resulting in 402 outcomes, which were then categorized into 63 unique outcomes. Participants consisted of patients, relatives/partners of patients, health care professionals, and researchers. Out of 463 who registered for participation, 319 and 213 responded to the first and second surveys, respectively. The consensus meeting consisted of 18 members and resulted in 6 outcomes for the COS to be measured in all treatment trials regardless of intervention: insertional pain (nonsexual), insertional pain (sexual), provoked vulvar pain by pressure/contact, pain-related interference on one's life, pain interference on sexual life, and sexual function.CLINICAL IMPLICATIONS: Critical outcomes to be measured in clinical trials will allow for accurate comparison of outcomes across treatment interventions and provide solid treatment recommendations.STRENGTHS AND LIMITATIONS: The major strengths of the study are the adherence to methodological recommendations and the intentional focus on aspects of diversity of participating stakeholders (eg, status such as patients with lived experience and researchers, inclusiveness with respect to sexual identity), the latter of which will allow for broader application and relevance of the COS. Among the limitations of the study are the low rate of participants outside North America and Europe and the lower response rate (about 50%) for the second Delphi survey.CONCLUSION: In this international project, patients, health care professionals, and researchers have decided what critical outcomes are to be used in future clinical trials for PVD. Before the COS can be fully implemented, there is also a need to decide on how and preferably when the outcomes should be measured.
12.	Borgquist, Ola, et al. (författare) Central venous stenosis after subclavian versus internal jugular dialysis catheter insertion (CITES) in adults in need of a temporary central dialysis catheter : study protocol for a two-arm, parallel-group, non-inferiority randomised controlled trial 2023 Ingår i: Trials. - 1745-6215. ; 24:1 Tidskriftsartikel (refereegranskat)abstract Background: The right internal jugular vein is currently recommended for temporary central dialysis catheters (tCDC) based on results from previous studies showing a lower incidence of central vein stenosis compared to the subclavian vein. Data is however conflicting, and there are several advantages when the subclavian route is used for tCDCs. This prospective, controlled, randomised, non-inferiority study aims to compare the incidence of post-catheterisation central vein stenosis between the right subclavian and the right internal jugular routes. Methods: Adult patients needing a tCDC will be included from several hospitals and randomised to either subclavian or internal jugular vein catheterisation with a silicone tCDC. Inclusion continues until 50 patients in each group have undergone a follow-up CT venography. The primary outcome is the incidence of post-catheterisation central vein stenosis detected by a CT venography performed 1.5 to 3 months after removal of the tCDC. Secondary outcomes include between-group comparisons of (I) the patients’ experience of discomfort and pain, (II) any dysfunction of the tCDC during use, (III) catheterisation success rate and (IV) the number of mechanical complications. Furthermore, the ability to detect central vein stenosis by a focused ultrasound examination will be evaluated using the CT venography as golden standard. Discussion: The use of the subclavian route for tCDC placement has largely been abandoned due to older studies with various methodological issues. However, the subclavian route offers several advantages for the patient. This trial is designed to provide robust data on the incidence of central vein stenosis after silicone tCDC insertion in the era of ultrasound-guided catheterisations. Trial registration: Clinicaltrials.gov; NCT04871568. Prospectively registered on May 4, 2021.
13.	Dammeyer, Pascal, et al. (författare) Cisplatin and oxaliplatin are toxic to cochlear outer hair cells and both target thioredoxin reductase in organ of Corti cultures 2014 Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 0001-6489 .- 1651-2251. ; 134:5, s. 448-454 Tidskriftsartikel (refereegranskat)abstract Conclusion: Inhibition of thioredoxin reductase (TrxR) may be a contributing factor in cisplatin- induced ototoxicity. Direct exposure of organ of Corti to cisplatin and oxaliplatin gives equal loss of hair cells. Objectives: Platinum- containing drugs are known to target the anti- oxidant selenoprotein TrxR in cancer cells. Two such anti- cancer, platinum- containing drugs, cisplatin and oxaliplatin, have different side effects. Only cisplatin induces hearing loss, i.e. has an ototoxic side effect that is not seen after treatment with oxaliplatin. The objective of this study was to evaluate if TrxR is a target in the cochlea. Loss of outer hair cells was also compared when cisplatin and oxaliplatin were administered directly to the organ of Corti. Methods: Organ of Corti cell culture was used for direct exposure to cisplatin and oxaliplatin. Hair cells were evaluated and the level of TrxR was assessed. Immunohistochemical staining for TrxR was performed. An animal model was used to evaluate the effect on TrxR after treatment with cisplatin and oxaliplatin in vivo. Results: Direct exposure of cochlear organotypic cultures to either cisplatin or oxaliplatin induced comparable levels of outer hair cell loss and inhibition of TrxR, demonstrating that both drugs are similarly ototoxic provided that the cochlea becomes directly exposed.
14.	Ewerman, Lea, et al. (författare) Immunomodulating Effects Depend on Prolactin Levels in Patients with Hyperprolactinemia 2020 Ingår i: Hormone and Metabolic Research. - Stuttgart : Thieme Medical Publishers. - 0018-5043 .- 1439-4286. ; 52:04, s. 228-235 Tidskriftsartikel (refereegranskat)abstract Prolactin is known to have immune modulatory effects acting through the prolactin receptor, which is present on a variety of immune cells. Certain chemokines contribute to form the type of T helper (Th) preponderance in the immune response. The objective of this work was to assess if hyperprolactinemia not related to pregnancy is associated with changes in circulating levels of chemokines and other immunological markers. In this cross sectional study, 35 patients with hyperprolactinemia (5 men), and 102 healthy blood donors (19 men) were included. Serum levels of Th1- Th2- and Th17-associated chemokines, C-reactive protein, immunoglobulins, and the B cell attracting chemokine CXCL13 were assessed. The hyperprolactinemic group had significantly higher levels of Th2 associated CCL22 (p=0.022), Th17 associated CXCL1 (p=0.001), B cell attracting CXCL13 (p=0.003), and C-reactive protein (p<0.001) compared to controls, and these proteins were also positively correlated with prolactin levels. While differences in CCL22, CXCL1, CXCL13, and C-reactive protein were present in patients with low or moderate hyperprolactinemia, no differences were observed at high (>3600 mU/l) prolactin levels. To evaluate a possible dose-associated response to prolactin, an in vitro model was used, showing prolactin-induced increase in T-helper cell activation at moderate levels, while activation decreased at higher levels. Hyperprolactinemia seems to have several immunomodulatory effects and was associated with increased levels of chemokines associated with Th2 and Th17 responses and B cell attraction. However, patients with greatly increased prolactin had normal levels of chemokines, and in vitro, high levels of prolactin decreased T-helper cell activation.
15.	Gliga, Anda R., et al. (författare) Maternal exposure to cadmium during pregnancy is associated with changes in DNA methylation that are persistent at 9 years of age 2022 Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 163 Tidskriftsartikel (refereegranskat)abstract Background: Cadmium (Cd) exposure during gestation has been associated with altered DNA methylation at birth, but it is not known if the changes in methylation persist into childhood. Objectives: To evaluate whether gestational Cd-related changes of DNA methylation persist from birth to 9 years of age. Methods: We studied mother–child dyads in a longitudinal cohort in rural Bangladesh. Cadmium concentrations in maternal blood (erythrocyte fraction; Ery-Cd) at gestational week 14 and in child urine (U-Cd, long-term exposure marker) at 9 years were measured using inductively coupled plasma mass spectrometry. The epigenome-wide DNA methylation was measured in mononuclear cells (PBMCs) prepared from cord blood and peripheral blood at 9 years in 71 children (hereafter referred to as the explorative group) by Infinium HumanMethylation450K BeadChip. Replication of one differentially methylated region (DMR; 9 CpG sites) was performed in PBMCs of 160 9-year-old children (validation group) by EpiTyper MALDI-TOF mass spectrometry. Results: The median maternal Ery-Cd concentration was 1.24 µg/kg (range 0.35, 4.55) in the explorative group and 0.83 µg/kg (0.08, 2.97) in the validation group. The median U-Cd concentration in the 9-year-old children was 0.26 µg/L (0.09, 1.06) in the explorative group and 0.32 µg/L (0.07, 1.33) in the validation group. In the explorative group, we identified ten DMRs, both in cord blood and in PBMCs at 9 years, that were associated with maternal Ery-Cd. Eight out of the ten DMRs were hypomethylated and three of the hypomethylated DMRs were located in the HLA region on chromosome 6. One of the DMRs (hypomethylated) in the HLA region (upstream of the zinc finger protein 57 homolog, ZFP57 gene) was replicated in the validation group, and we found that it was hypomethylated in relation to maternal Ery-Cd, but not child U-Cd. Conclusion: Gestational exposure to Cd appears to be associated with regional changes, especially hypomethylated, in DNA methylation that linger from birth up to prepubertal age.
16.	Hellberg, C, et al. (författare) Important research outcomes for treatment studies of perinatal depression: systematic overview and development of a core outcome set 2021 Ingår i: British Journal of Obstetrics and Gynecology. - : John Wiley & Sons. - 1470-0328 .- 1471-0528. ; 128:13, s. 2141-2149 Tidskriftsartikel (refereegranskat)abstract Objective To develop a Core Outcome Set (COS) for treatment of perinatal depression.Design Systematic overview of outcomes reported in the literature and consensus development study.SettingInternational.Population Two hundred and twenty-two participants, mainly patients, healthcare professionals and researchers, representing 13 countries.Methods A systematic overview of outcomes reported in recently published research, a two-round Delphi survey and a consensus meeting at which the final COS was decided using modified nominal group technique.Main results In the literature search, 1772 abstracts were identified and evaluated, and 165 studies were finally included in the review. In all, 106 outcomes were identified and included in the Delphi survey. In all, 222 participants registered for the first round of the Delphi survey and 151 (68%) responded. In the second round, 123 (55%) participants responded. Thirteen participants attended the consensus meeting, where the following nine outcomes were agreed upon for inclusion in the final COS: self-assessed symptoms of depression, diagnosis of depression by a clinician, parent to infant bonding, self-assessed symptoms of anxiety, quality of life, satisfaction with intervention, suicidal thoughts, attempted or committed suicide, thoughts of harming the baby, and adverse events.Conclusions The relevant stakeholders prioritised outcomes and reached consensus on a COS comprising nine outcomes. We expect that this COS will contribute to the consistency and uniformity of outcome selection and reporting in future clinical trials involving treatment of perinatal depression.
17.	Hellberg, Dan, et al. (författare) Defining women who are prone to have twins in in vitro fertilization--a necessary step towards single embryo transfer. 2005 Ingår i: J Assist Reprod Genet. - 1058-0468. ; 22:5, s. 199-206 Tidskriftsartikel (refereegranskat)
18.	Hellberg Lindqvist, Miriam, 1982-, et al. (författare) An Fnr-type transcriptional regulator is responsible for anoxic up-regulation of chlorite dismutase in Ideonella dechloratans Annan publikation (övrigt vetenskapligt/konstnärligt)
19.	Hellberg Lindqvist, Miriam, 1982-, et al. (författare) Anoxic induction of the chlorite dismutase gene of Ideonella dechloratans is dependent of the fumarate and nitrate reduction regulator Annan publikation (övrigt vetenskapligt/konstnärligt)
20.	Hellberg Lindqvist, Miriam, 1982-, et al. (författare) Chlorate reductase is cotranscribed with cytochrome c and other downstream genes in the gene cluster for chlorate respiration of Ideonella dechloratans 2015 Ingår i: FEMS Microbiology Letters. - : Oxford University Press (OUP). - 0378-1097 .- 1574-6968. ; 362:6 Tidskriftsartikel (refereegranskat)abstract The chlorate-respiring bacterium Ideonella dechloratans is a facultative anaerobe that can use both oxygen and chlorate as terminal electron acceptors. The genes for the enzymes chlorate reductase (clrABDC) and chlorite dismutase, necessary for chlorate metabolism and probably acquired by lateral gene transfer, are located in a gene cluster that also includes other genes potentially important for chlorate metabolism. Among those are a gene for cytochrome c (cyc) whose gene product may serve as an electron carrier during chlorate reduction, a cofactor biosynthesis gene (mobB) and a predicted transcriptional regulator (arsR). Only chlorate reductase and chlorite dismutase have been shown to be expressed in vivo. Here, we report the in vivo production of a single polycistronic transcript covering eight open reading frames including clrABDC, cyc, mobB and arsR. Transcription levels of the cyc and clrA genes were compared to each other by the use of qRT-PCR in RNA preparations from cells grown under aerobic or chlorate reducing anaerobic conditions. The two genes showed the same mRNA levels under both growth regimes, indicating that no transcription termination occurs between them. Higher transcription levels were observed at growth without external oxygen supply. Implications for electron pathway integration following lateral gene transfer are discussed.
21.	Hellberg Lindqvist, Miriam, 1982-, et al. (författare) Expression of chlorate reductase and chlorite dismutase in the chlorate-respiring bacterium Ideonella dechloratans 2012 Konferensbidrag (övrigt vetenskapligt/konstnärligt)
22.	Hellberg Lindqvist, Miriam, 1982-, et al. (författare) Expression of Chlorite Dismutase and Chlorate Reductase in the Prescence of Oxygen and/or Chlorate as the Terminal Electron Acceptor in Ideonella dechloratans 2012 Ingår i: Applied and Environmental Microbiology. - : American Society for Microbiology. - 0099-2240 .- 1098-5336. ; 78:12, s. 4380-4385 Tidskriftsartikel (refereegranskat)abstract The ability of microorganisms to perform dissimilatory (per)chlorate reduction is, for most species, known to be oxygen sensitive. Consequently, bioremediation processes for the removal of oxochlorates will be disturbed if oxygen is present. We measured the expression of chlorite dismutase and chlorate reductase in the presence of different terminal electron acceptors in the chlorate reducer Ideonella dechloratans. Enzyme activity assays and mRNA analyses by real-time quantitative reverse transcription (qRT)-PCR were performed on cell extracts from cells grown aerobically with and without chlorate and on cells grown anaerobically in the presence of chlorate. Our results showed that both chlorite dismutase and chlorate reductase are expressed during aerobic growth. However, transfer to anaerobic conditions with chlorate resulted in significantly enhanced enzyme activities and mRNA levels for both enzymes. Absence of oxygen was necessary for the induction to occur, since chlorate addition under aerobic conditions produced neither increased enzyme activities nor higher relative levels of mRNA. For chlorite dismutase, the observed increase in activity was on the same order of magnitude as the increase in the relative mRNA level, indicating gene regulation at the transcriptional level. However, chlorate reductase showed about 200 times higher enzyme activity in anaerobically induced cells, whereas the increase in mRNA was only about 10-fold, suggesting additional mechanisms influence the enzyme activity.
23.	Hellberg Lindqvist, Miriam, 1982-, et al. (författare) Expression of the gene cluster for chlorate metabolism in the chlorate-respiring bacterium Ideonella dechloratans 2012 Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - Frankfurt : Elsevier. - 0005-2728 .- 1879-2650. ; 1817, s. 157-158, s. S157-S158 Tidskriftsartikel (refereegranskat)abstract Ideonella dechloratans is a facultative anaerobe able to use chlorate as a terminal electron acceptor under anaerobic conditions. Two enzymes are necessary for the decomposition of chlorate to chloride and molecular oxygen; chlorate reductase (Clr) and chlorite dismutase (Cld). The genes for these two enzymes are close to each other in the genome and form, together with a cytochrome c and a mob B gene, a gene cluster for chlorate metabolism. The localization of the cyt c gene suggests a function in electron transport during chlorate reduction but the corresponding protein has not been found. We have addressed the questions of how the expression of Cld and Clr is regulated during the aerob/anaerob switch and if the cyt c gene is expressed in I. dechloratans. The enzyme activities of Cld and Clr were measured in extracts from cells grown at different conditions; aerobically or anaerobically [1]. Both enzymes were found to be active in all samples and the activity increased upon transfer of the cells from aerobic to anaerobic conditions, by five times for Cld and more than 200 times for Clr. Relative mRNA levels of Cld and Clr were determined by qRT-PCR in RNA preparations from cells grown under the same conditions as for the enzyme activity measurements. mRNA from both genes was detected in all preparations but with ten times higher levels in samples from anaerobic conditions. This increase in mRNA level is on the same scale as the increase in enzyme activity for Cld but accounts for less than a tenth of the activity enhancement seen for Clr. A possible effect of chlorate was tested by the addition of chlorate under aerobic conditions but this resulted in neither increased enzyme activities nor increased mRNA levels. qRT-PCR was performed with primers specific for the cyt c gene and this gene was also found to be expressed at both aerobic and anaerobic conditions. In summary, the results show that chlorate respiration is activated by anaerobiosis but not by chlorate in I. dechloratans and that this activation occurs at the transcriptional level. Due to the much larger increase in enzyme activity compared to the increase in mRNA level, the activity of Clr also seems to be effected by other mechanisms. Detection of cyt c mRNA suggests that its gene product can be found and the function investigated.
24.	Hellberg Lindqvist, Miriam, et al. (författare) Regulation of genes involved in microbial degradation of chlorate in the chlorate-respiring bacterium Ideonella dechloratans. 2013 Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract Regulation of genes involved in microbial degradation of chlorate in the chlorate-respiring bacterium Ideonella dechloratansIdeonella dechloratans is a facultative anaerobe and can use both oxygen and chlorate as terminal electron acceptors. Chlorate metabolism involves two enzymes; chlorate reductase (Clr) and chlorite dismutase (Cld). The genes are located in a cluster for chlorate metabolism that also includes the genes for a cytochrome c and a mob B gene. A possible function of the cyt c gene is electron transport during chlorate reduction but so far no corresponding protein has been found. Our aim is to study the expression and possible regulation of Cld and Clr during aerobic and anaerobic metabolism and to examine if the cytochrome c is expressed in I. dechloratans. We have previously reported expression of Clr and Cld, measured both at the mRNA level and as enzyme activities (1). In order to examine sequences important for gene regulation the upstream regions of Clr and Cld were cloned and inserted in a reporter vector and transformed into E. coli XL-1 Blue. The expression of the cyt c gene was analyzed with qRT-PCR in RNA preparations from cells grown under different growth conditions; aerobically or anaerobically. Our results show that the cloned upstream regions of Clr and Cld include functional promoter sequences and that cyt c is expressed in I. dechloratans with increased levels at growth without an external oxygen supply.1. Lindqvist, M. H., N. Johansson, T. Nilsson, and M. Rova. 2012. Expression of Chlorite Dismutase and Chlorate Reductase in the Presence of Oxygen and/or Chlorate as the Terminal Electron Acceptor in Ideonella dechloratans. Appl. Environ. Microbiol. 78:4380-4385.
25.	Hellberg, Maria, et al. (författare) Eradication of nasopharyngeal carriage of penicillin-non-susceptible Streptococcus pneumoniae-is it possible? 2012 Ingår i: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 1651-1980 .- 0036-5548. ; 44:12, s. 909-914 Tidskriftsartikel (refereegranskat)abstract Background: The South Swedish Pneumococcal Intervention Project (SSPIP) was started in 1995 with the aim of limiting the spread of penicillin-non-susceptible pneumococci (PNSP) in Skåne County, Sweden. As part of the SSPIP, eradication therapy with rifampicin in combination with 1 more antibiotic was considered on a social indication after prolonged carriage of 2-3 months. Methods: In this retrospective study, 125 medical records were analyzed. Children aged 0-10 y referred for eradication therapy in Malmö and Lund, due to a prolonged nasopharyngeal carriage of PNSP with a penicillin G minimum inhibitory concentration of ≥ 0.5 mg/l, between the y 1997 and 2011 were included. Two consecutive negative cultures, with the second one no shorter than 7 days after treatment completion, were required for the carriage to be considered eradicated. Results: Out of 125 children, 71 received treatment with rifampicin in combination with amoxicillin (n = 44), erythromycin (n = 22), or clindamycin (n = 5) for 7 days. Eradication treatment was successful in 91.5% of the children. Six children (8.5%) had treatment failure with amoxicillin and rifampicin; 3 were found by late follow-up. There was a trend towards a better outcome with erythromycin and clindamycin combinations in comparison to amoxicillin. Conclusions: Eradication therapy was successful, but a proper follow-up is essential.
26.	Hellberg, Miriam, et al. (författare) Regulation of the genes for chlorate reductase (Clr) and chlorite dismutase (Cld) in the chlorate-respiring bacterium Ideonella dechloratans 2010 Ingår i: FEBS Journal 277(2010) Supplement 1. Poster presentations. - : Wiley-Blackwell. ; , s. B4.62.- Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract Enzyme activities and mRNA levels of chlorate reductase and chlorite dismutase was investigated in whole cell extracts of Ideonella dechloratans grown under different growth conditions. This bacterium grows well both at aerobic and anaerobic conditions, using oxygen and chlorate, respectively, as a terminal electron acceptor. It was found that preparations from cells grown in the absence of chlorate under aerobic conditions showed activity of both chlorate reductase, measured as chlorate dependent reduction of methyl viologen, and chlorite dismutase, measured as chlorite dependent oxygen production. At aerobic growth conditions, the addition of chlorate resulted in an increased activity of chlorate reductase. The highest activity of chlorate reductase was found in preparations from cells grown anaerobically in the presence of chlorate. No increase in enzyme activity could be detected for chlorite dismutase during anaerobic or aerobic growth in the presence of chlorate, compared to aerobic growth in the absence of chlorate. The mRNA levels for Clr and Cld, measured by real-time quantitative PCR using 16SrRNA as an intern standard, was found to be equal in preparations from cells grown anaerobically in the presence of chlorate compared to cells grown under aerobic conditions in the absence of chlorate. The results suggest that, in I. dechloratans, the activity of chlorate reductase is up-regulated by at least two factors, anaerobiosis and the presence of chlorate. Interestingly, the results also indicate that the studied regulation occurs at post-transcriptional level, while most examples of oxygen regulation in bacteria are reported to occur at transcriptional level.
27.	Hellberg, Matthias, et al. (författare) Small Distal Muscles and Balance Predict Survival in End-Stage Renal Disease. 2014 Ingår i: Nephron Clinical Practice. - : S. Karger AG. - 1660-2110. ; 126:3, s. 116-123 Tidskriftsartikel (refereegranskat)abstract Background/Aims: Survival for patients on renal replacement therapy (RRT) has been shown to correlate to the level of physical activity and exercise capacity. We examined whether composite measures of functional status at the start of RRT predict survival. Methods: In this retrospective study, the same physiotherapist, using a standardized battery of tests for functional status, tested 134 patients at the start of RRT. Results: At the end of the observation period, 112 patients (84%) were still alive. Age (p < 0.0001), co-morbidity (p = 0.028), hand grip strength (right: p = 0.0065; left: p = 0.0039), standing heel rise (right: p = 0.011; left: p = 0.004) and functional reach (p = 0.015) were significant predictors of survival. After adjustment for sex, age and co-morbidity, hand grip strength left (p = 0.023) was a significant predictor of survival. Conclusion: Hand grip strength, standing heel rise and functional reach at the start of RRT seem to affect survival. A 50% reduction in hand grip strength left was associated with an almost 3-fold increase in mortality. Deterioration of function in small distal muscles and balance may be early signs of uraemic myopathy. A relatively simple and clinically feasible battery of tests can help detect patients at risk. © 2014 S. Karger AG, Basel.
28.	Hellberg, Sandra, et al. (författare) Dynamic Response Genes in CD4+ T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis 2016 Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 16:11, s. 2928-2939 Tidskriftsartikel (refereegranskat)abstract Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.
29.	Hellberg, Sandra, 1986- (författare) Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis 2019 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Multiple sclerosis (MS) is characterized by a dysregulated immune system leading to chronic inflammation in the central nervous system. Despite increasing number of treatments, many patients continue to deteriorate. A better understanding of the underlying disease mechanisms involved in driving disease is a pre-requisite for finding new biomarkers and new treatment targets. The improvement of MS during pregnancy, comparable to the beneficial effects of the most effective treatment, suggests that the transient and physiological immune tolerance established during pregnancy could serve as a model for successful immune regulation. Most likely the immune-endocrine alterations that take place during pregnancy to accommodate the presence of the semi-allogenic fetus contribute to the observed disease improvement.The aim of this thesis was to characterize the dysregulated immune system in MS and define potential factors and mechanisms established during pregnancy that could be involved in the pregnancy-induced effects in MS, focusing on CD4+ T cells as one of the main drivers in immunity and in the MS pathogenesis. Using a network-based modular approach based on gene expression profiling, we could show that CD4+ T cells from patients with MS displayed an altered dynamic gene response to activation, in line with a dysregulated immune system in MS. The resulting gene module disclosed cell activation and chemotaxis as central components in the deviating response, results that form a basis for further studies on its modulation during pregnancy. Moreover, a combination of secreted proteins (OPN+CXCL1-3+CXCL10-CCL2), identified from the module, could be used to separate patients and controls, predict disease activity after 2 years and discriminate between high and low responders to treatment, highlighting their potential use as biomarkers for predicting disease activity and response to treatment.The pregnancy hormone progesterone (P4), a potential factor involved in the pregnancy-induced amelioration of MS, was found to significantly dampen CD4+ T cell activation. Further detailed transcriptomic profiling revealed that P4 almost exclusively down-regulated immune-related pathways in activated T cells, several related to or downstream of T cell activation such as JAKSTAT signaling, T cell receptor signaling and cytokine-cytokine receptor interaction. In particular, P4 significantly affected genes of relevance to diseases known to be modulated during pregnancy, where genes associated to MS were most significantly affected, supporting a role for P4 in the pregnancy-induced immunomodulation. By using another approach, the role of thymus in T cell regulation during pregnancy was assessed. Two established measures of thymic output, CD31 expression and TREC content, were used and showed that thymic output of T cells is maintained during human pregnancy, or even possibly increased in terms of regulatory T cells.This thesis further supports a pivotal role for CD4+ T cells and T cell activation in the MS pathogenesis and adds to the knowledge of how they could be involved in driving disease. We identified a novel strategy for capturing central aspects of the deviating response to T cell activation that could be translated into potentially clinically relevant biomarkers. Further, P4 is emerging as a promising candidate for the pregnancy-induced immunomodulation that could be of importance as a future treatment option. Lastly, maintained thymic output of T cells during human pregnancy challenges the rodent-based dogma of an inactive thymus during pregnancy. Thymic dysfunction has been reported not only in MS but also in rheumatoid arthritis, another inflammatory disease that improves during pregnancy, which highlights a potential role for thymus in immune regulation that could be involved in the pregnancy-induced amelioration.
30.	Hellberg, Sandra, et al. (författare) Maintained thymic output of conventional and regulatory T cells during human pregnancy 2019 Ingår i: Journal of Allergy and Clinical Immunology. - Philadelphia, United States : American Academy of Allergy, Asthma and Immunology. - 0091-6749 .- 1097-6825. ; 143:2, s. 771-775.e7 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract During pregnancy, immunological tolerance toward the semiallogeneic fetus needs to be established while at the same time an effective immune defense must be maintained.1 The pregnancy-associated thymic involution reported in rodents2 has been suggested to support maternal immune regulation by reducing the output of potentially harmful TH cells. However, the functional importance of this thymic involution remains unclear and it is not known whether it even occurs in humans.3 In fact, the role of thymus during human pregnancy and in pregnancy-associated tolerance remains largely unknown,4 albeit a role for thymic-derived regulatory T (Treg) cells in pregnancy complications has been suggested,4 supporting a role for thymus in immune regulation during human pregnancy. The aim of this study was to assess the role of thymus in TH-cell regulation during human pregnancy by analyzing the output of different TH-cell populations.
31.	Hellberg, Sandra, et al. (författare) Progesterone Dampens Immune Responses in In Vitro Activated CD4(+) T Cells and Affects Genes Associated With Autoimmune Diseases That Improve During Pregnancy 2021 Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12 Tidskriftsartikel (refereegranskat)abstract The changes in progesterone (P4) levels during and after pregnancy coincide with the temporary improvement and worsening of several autoimmune diseases like multiple sclerosis (MS) and rheumatoid arthritis (RA). Most likely immune-endocrine interactions play a major role in these pregnancy-induced effects. In this study, we used next generation sequencing to investigate the direct effects of P4 on CD4(+) T cell activation, key event in pregnancy and disease. We report profound dampening effects of P4 on T cell activation, altering the gene and protein expression profile and reversing many of the changes induced during the activation. The transcriptomic changes induced by P4 were significantly enriched for genes associated with diseases known to be modulated during pregnancy such as MS, RA and psoriasis. STAT1 and STAT3 were significantly downregulated by P4 and their downstream targets were significantly enriched among the disease-associated genes. Several of these genes included well-known and disease-relevant cytokines, such as IL-12 beta, CXCL10 and OSM, which were further validated also at the protein level using proximity extension assay. Our results extend the previous knowledge of P4 as an immune regulatory hormone and support its importance during pregnancy for regulating potentially detrimental immune responses towards the semi-allogenic fetus. Further, our results also point toward a potential role for P4 in the pregnancy-induced disease immunomodulation and highlight the need for further studies evaluating P4 as a future treatment option.
32.	Hellberg, Åsa, et al. (författare) A novel single-nucleotide substitution in the proximal ABO promoter gives rise to the B3 phenotype 2019 Ingår i: Transfusion. - : Wiley. - 0041-1132 .- 1537-2995. ; 59:10, s. 1-3 Tidskriftsartikel (refereegranskat)
33.	Henningsson, Anna J., 1972-, et al. (författare) Genome-wide DNA Methylation Profiling in Lyme Neuroborreliosis Reveals Altered Methylation Patterns of HLA Genes 2024 Ingår i: Journal of Infectious Diseases. - : OXFORD UNIV PRESS INC. - 0022-1899 .- 1537-6613. ; 229:4, s. 1209-1214 Tidskriftsartikel (refereegranskat)abstract Lyme neuroborreliosis (LNB) is a complex neuroinflammatory disorder caused by Borrelia burgdorferi, which is transmitted through tick bites. Epigenetic alterations, specifically DNA methylation (DNAm), could play a role in the host immune response during infection. In this study, we present the first genome-wide analysis of DNAm in peripheral blood mononuclear cells from patients with LNB and those without LNB. Using a network-based approach, we highlighted HLA genes at the core of these DNAm changes, which were found to be enriched in immune-related pathways. These findings shed light on the role of epigenetic modifications in the LNB pathogenesis that should be confirmed and further expanded upon in future studies. We present the first genome-wide analysis of DNA methylation in peripheral blood mononuclear cells from patients with and those without the tick-borne infection Lyme neuroborreliosis (LNB). Our findings show that LNB is associated with immune-related DNA methylation changes.
34.	Henriksson, Emma, et al. (författare) Differential Expression of the P-k Histo-Blood Group Antigen in Individuals with the Common P-1 and P-2 Phenotypes Predicts Susceptibility to HIV-1 Infection In Vitro 2009 Ingår i: Transfusion. - 1537-2995. ; 49, s. 5-5 Konferensbidrag (refereegranskat)
35.	Hofmeyer, Syster, et al. (författare) Comparison of the subgross distribution of the lesions in invasive ductal and lobular carcinomas of the breast : a large-format histology study 2012 Ingår i: International journal of breast cancer. - : Hindawi Limited. - 2090-3189 .- 2090-3170. ; 2012, s. 436141- Tidskriftsartikel (refereegranskat)abstract To compare the lesion distribution and the extent of the disease in ductal and lobular carcinomas of the breast, we studied 586 ductal and 133 lobular consecutive cancers. All cases were documented on large-format histology slides. The invasive component of ductal carcinomas was unifocal in 63.3% (371/586), multifocal in 35.5% (208/586), and diffuse in 1.2% (7/586) of the cases. The corresponding figures in the lobular group were 27.8% (37/133), 45.9% (61/586), and 26.3% (35/133), respectively. When the distribution of the in situ and invasive component in the same tumors was combined to give an aggregate pattern, the ductal carcinomas were unifocal in 41.6% (244/586), multifocal in 31.6% (185/586), and diffuse in 26.8% (157/586) of the cases. The corresponding figures in the lobular category were 15.0% (20/133), 54.2% (72/133), and 30.8% (41/133), respectively. Ductal cancers were extensive in 45.7% (268/586), lobular in 65.4% (87/133) of the cases. All these differences were statistically highly significant (P < 0.0001). While the histological tumor type itself (ductal versus lobular) did not influence the lymph node status, multifocal and diffuse distribution of the lesions were associated with significantly increased risk of lymph node metastases in both ductal and lobular cancers.
36.	Larsson, Sam, et al. (författare) Missbruk och beroende av alkohol och narkotika: Kunskapsläget för utredningar och insatser inom socialtjänsten : En kartläggning av systematiska översikter 2019 Rapport (övrigt vetenskapligt/konstnärligt)
37.	Lilja, Mona, 1971, et al. (författare) Power, Resistance and Social Change 2023 Ingår i: Journal of Political Power. - 2158-379X .- 2158-3803. ; 16:2 Tidskriftsartikel (refereegranskat)
38.	Magnusson, Rasmus, et al. (författare) RNA-sequencing and mass-spectrometry proteomic time-series analysis of T-cell differentiation identified multiple splice variants models that predicted validated protein biomarkers in inflammatory diseases 2022 Ingår i: Frontiers in Molecular Biosciences. - : Frontiers Media SA. - 2296-889X. ; 9 Tidskriftsartikel (refereegranskat)abstract Profiling of mRNA expression is an important method to identify biomarkers but complicated by limited correlations between mRNA expression and protein abundance. We hypothesised that these correlations could be improved by mathematical models based on measuring splice variants and time delay in protein translation. We characterised time-series of primary human naive CD4(+) T cells during early T helper type 1 differentiation with RNA-sequencing and mass-spectrometry proteomics. We performed computational time-series analysis in this system and in two other key human and murine immune cell types. Linear mathematical mixed time delayed splice variant models were used to predict protein abundances, and the models were validated using out-of-sample predictions. Lastly, we re-analysed RNA-seq datasets to evaluate biomarker discovery in five T-cell associated diseases, further validating the findings for multiple sclerosis (MS) and asthma. The new models significantly out-performing models not including the usage of multiple splice variants and time delays, as shown in cross-validation tests. Our mathematical models provided more differentially expressed proteins between patients and controls in all five diseases. Moreover, analysis of these proteins in asthma and MS supported their relevance. One marker, sCD27, was validated in MS using two independent cohorts for evaluating response to treatment and disease prognosis. In summary, our splice variant and time delay models substantially improved the prediction of protein abundance from mRNA expression in three different immune cell types. The models provided valuable biomarker candidates, which were further validated in MS and asthma.
39.	Osterberg, Marie, et al. (författare) Core Outcome Sets (COS) related to pregnancy and childbirth : a systematic review 2021 Ingår i: BMC Pregnancy and Childbirth. - : BioMed Central (BMC). - 1471-2393 .- 1471-2393. ; 21:1 Forskningsöversikt (refereegranskat)abstract BackgroundSystematic reviews often conclude low confidence in the results due to heterogeneity in the reported outcomes. A Core Outcome Set (COS) is an agreed standardised collection of outcomes for a specific area of health. The outcomes included in a COS are to be measured and summarized in clinical trials as well as systematic reviews to counteract this heterogeneity.AimThe aim is to identify, compile and assess final and ongoing studies that are prioritizing outcomes in the area of pregnancy and childbirth.MethodsAll studies which prioritized outcomes related to pregnancy and childbirth using consensus method, including Delphi surveys or consensus meetings were included. Searches were conducted in Ovid MEDLINE, EMBASE, PsycINFO, Academic Search Elite, CINAHL, SocINDEX and COMET databases up to June 2021. For all studies fulfilling the inclusion criteria, information regarding outcomes as well as population, method, and setting was extracted. In addition, reporting in the finalized studies was assessed using a modified version of the Core Outcome Set-STAndards for Reporting.ResultsIn total, 27 finalized studies and 42 ongoing studies were assessed as relevant and were included. In the finalized studies, the number of outcomes included in the COS ranged from 6 to 51 with a median of 13 outcomes. The majority of the identified COS, both finalized as well as ongoing, were relating to physical complications during pregnancy.ConclusionThere is a growing number of Core Outcome Set studies related to pregnancy and childbirth. Although several of the finalized studies follow the proposed reporting, there are still some items that are not always clearly reported. Additionally, several of the identified COS contained a large number (n > 20) outcomes, something that possibly could hinder implementation. Therefore, there is a need to consider the number of outcomes which may be included in a COS to render it optimal for future research.
40.	Papapavlou, Georgia, et al. (författare) Differential effects of estradiol and progesterone on human T cell activation in vitro 2021 Ingår i: European Journal of Immunology. - : Wiley-VCH Verlagsgesellschaft. - 0014-2980 .- 1521-4141. ; 51:10, s. 2430-2440 Tidskriftsartikel (refereegranskat)abstract Estradiol (E2) and progesterone (P4) are steroid hormones important for the regulation of immune responses during pregnancy. Their increasing levels coincide with an improvement of T cell-mediated diseases such as multiple sclerosis (MS). Although immune-endocrine interactions are involved in this phenomenon, the relative contribution of hormones is not known. We here report a direct comparison of E2- and P4-mediated effects on human CD4+ T cells, key cells in immune regulation. T cells were stimulated to obtain different activation levels and exposed to a broad range of hormone concentrations. Activation level was assessed by CD69/CD25 expression by flow cytometry, and secreted proteins (n = 196) were measured in culture supernatants using proximity extension assay and electrochemiluminescence immunoassay. We found that in low activated cells, pregnancy-relevant E2 concentrations increased activation and the secretion of several immune- and inflammation-related proteins. P4, on the other hand, showed a biphasic pattern, where serum-related concentrations upregulated activation and protein secretion while placenta-relevant concentrations induced a prominent dampening irrespective of the initial activation level. Our results demonstrate the importance of P4 as a major hormone in the immune modulation of T cells during pregnancy and emphasize the need to further evaluate its potency in the treatment of diseases like MS.
41.	Pekar, Gyula, et al. (författare) Molecular Phenotype of the Foci in Multifocal Invasive Breast Carcinomas 2014 Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 120:1, s. 26-34 Tidskriftsartikel (refereegranskat)abstract BACKGROUND Multiple synchronous, ipsilateral, invasive foci of breast carcinomas are frequent and are associated with a poorer prognosis. Few studies have investigated the prognostic and therapeutic implications of heterogeneity of such foci.METHODS The authors reviewed the tumor type, grade, and size of all invasive foci in a series of 110 multifocal breast carcinomas documented on large-format slides. Molecular phenotype was determined by immunohistochemistry in tissue microarray blocks using 3 classification systems. The survival of patients who had tumors with microscopic (tumor type and/or grade) heterogeneity and of those who had tumors with phenotypic heterogeneity was compared with the survival of patients who had multifocal homogeneous tumors using Kaplan-Meier curves. The hazard ratio of dying from breast cancer was also calculated.RESULTS Intertumoral heterogeneity in tumor type and grade was detected in 16 of 110 tumors (14.6%) and in 6 of 110 tumors (5.5%), respectively. The molecular phenotype of invasive tumor foci within the same breast differed in 10% to 12.7% of patients (11-14 of 110 tumors), depending on the classification system used. Patients who had phenotypically heterogeneous, multifocal cancers had a greater risk of dying from disease (HR=2.879; 95%CI=1.084-7.649; P=.034) and had significantly shorter survival (P=.016). Phenotypic differences were most common in patients who had tumors that were homogeneous in terms of tumor type (11 of 18 tumors) and histology grade (14 of 18 tumors). Phenotyping additional tumor foci had the potential to influence the therapeutic decisions in up to 8 patients.CONCLUSIONS Phenotyping more than 1 invasive focus of multifocal breast carcinomas only if the individual foci deviate microscopically appears to be insufficient, because phenotypic intertumoral heterogeneity may be observed in microscopically identical foci and has potential prognostic and therapeutic consequences.
42.	Pekar, Gyula, et al. (författare) Multifocal breast cancer documented in large-format histology sections : long-term follow-up results by molecular phenotypes. 2013 Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 119:6 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The prognostic significance of molecular phenotype in breast cancer is well established in the literature. Recent studies have demonstrated that subgross lesion distribution (unifocal, multifocal, and diffuse) and disease extent also carry prognostic significance in this disease. However, the correlation of molecular phenotypes with subgross parameters has not yet been investigated in detail.METHODS: In total, 444 consecutive invasive breast cancers that were documented in large-format histology slides and worked up with detailed radiologic-pathologic correlation were sampled into tissue microarray blocks and stained immunohistochemically to delineate the molecular subtypes.RESULTS: Diffuse or multifocal distribution of the invasive component of breast carcinomas in this series was associated with a 4.14-fold respectively 2.75-fold risk of cancer-related death compared with unifocal tumors irrespective of molecular phenotype. Patients who had human epidermal growth factor receptor 2 (HER2)-positive cancers; estrogen receptor-negative, progesterone receptor-negative, and HER2-negative (triple-negative) cancers; or basal-like cancers had a 2.18-fold, 2.33-fold, and 4.07-fold risk of dying of disease, respectively, compared with patients who had luminal A carcinomas. Unifocal luminal A, HER2-positive, and basal-like cancers were associated with significantly better long-term survival outcomes than their multifocal or diffuse counterparts; luminal B and triple-negative tumors also had the same tendency. In multivariate analysis, patient age, tumor size category, lymph node status, lesion distribution, and molecular phenotypes remained significant.CONCLUSIONS: Multifocality and diffuse distribution of the invasive component were associated with significantly poorer survival in women with breast carcinomas compared with unifocal disease in patients with luminal A, HER2 type, and basal-like cancers. Molecular classification of breast cancer is a powerful tool but gains in power when combined with conventional and subgross morphologic parameters.
43.	Rigné, Eva Marie, et al. (författare) Utvärdering av projektet "Barns och ungdomars bästa" 2006 Ingår i: Utvärdering av projektet "Barns och ungdomars bästa". - Linköping : Linköping University Electronic Press. - 9185523887 ; , s. -218 Rapport (övrigt vetenskapligt/konstnärligt)abstract Inledningsvis vill utvärderarna framhålla att utvärderingen inte innebär kritik av enskilda personer eller projektdeltagares arbete, eller ambitioner. Många av de kritiska punkter som sammanfattas nedan är också återkommande iakttagelser gjorda i flera andra projekt i olika kommuner som engagerat CKS för utvärderingsinsatser av helt andra verksamheter. De återfinns också i flera utvärderingar gjorda av nationella utvecklingsprojekt. Utvärderingen av projektet ”Barns och ungdomars bästa” med fokus på de processer som utvecklats under projekttiden pekar på följande:Generellt finns det hos deltagarna i projektet en upplevelse av att det varit positivt och utvecklande att medverka, och inneburit ett stort utbyte i olika avseenden. Detta är inget oväntat, med tanke på att kriterierna för medverkan varit eget intresse och vilja att deltaga. Resultaten av projektarbetet kan således utifrån individernas upplevelser sammanfattas som givande. Å andra sidan finns också en osäkerhet om projektets räckvidd utanför dem som varit engagerade, vilket också flera deltagare själva utpekat som en svag punkt. Få projektdeltagare anser sig ha haft en upplevelse av att vara delar av en helhet, eller gemensamt ha arbetat mot övergripande mål. Den vanliga motsättningen mellan avgränsat projektarbete och kontinuerligt utvecklingsarbete förefaller alltså inte ha lösts, annat än inom ett fåtal delprojekt, och har också påverkats av omorganisationer under projektets avslutningsfas i de berörda verksamheterna.Projektorganisationen som byggts upp har haft svagheter. En sådan är att mycket arbete som borde föregått själva igångsättandet av projektet lagts inom detta, vilket framför allt påverkade initialfasen negativt. Ytterligare en består i att få medverkande förefaller haft kompetens eller fått stöd för att arbeta i projektform. En tredje är att är att den inte gett utrymme för jämställda positioner för olika medverkande i projektet. Projektorganisationen har genom sitt stora beroende av en enda persons arbete blivit onödigt sårbar, och har under projekttiden också i andra avseenden, framför allt administrativa, visat sig svårhanterlig. Mot bakgrund av detta, liksom av erfarenheterna från flera stora nationella projekt, kan det ifrågasättas om projektorganisationen är den lämpligaste arbetsformen för denna typ av utvecklingsarbete.Innehållet i projektet har fått en stark inriktning på intervention på individuell nivå, speciellt i form av olika typer av utbildningsinsatser. De projekt som förekommit inriktade på organisatorisk förändring gäller framför allt familjestödjande arbete i form av att försöka bygga upp familjecentraler, och i viss mån former för utåtriktat ungdomsarbete.Det har också blivit ett projekt som huvudsakligen kommit att präglas av de kommunala tjänstemän som arbetat inom dess ramar, och i liten utsträckning av kommuninvånare/medborgare.I projektet har också funnits olika uppfattningar om och definitioner av centrala inslag i projektarbetet, som exempelvis förebyggande arbete och samverkan, vilket i sin tur påverkat det konkreta arbetet. Utvärderarna menar att det hade varit till fördel för projektet om dessa hade bearbetats mer gemensamt av olika aktörer inom projektet i förarbete till projektet liksom i återkommande senare arbete under projekttiden, bl.a. för att på ett tydligare sätt kunna relatera dessa till mål både för de nationella uppdrag verksamheterna arbetar med och mål som formulerats för projektet.Delstudien av projektet ”Områdesanknutna socialarbetare” pekar på att socialsekreterarna kom in sent i projektet, och inte fick den formella position de med tanke på sitt uppdrag borde haft. De fick utöver sitt inledningsvis formulerade uppdrag också ett till, och har med skiftande framgång kunnat arbeta med två parallella uppdrag. Det visade sig under projekttiden också att det fanns mycket olika tolkningar av vad områdenas behov av socialsekreterare innebar, vilket ledde till svårigheter i arbetet. Utformningen av detta delprojekt styrdes heller inte av behovsanalys, utan hur stora resurser projektet ansåg sig kunna avsätta för arbetet. Med tanke på områdenas varierande karaktär hade en behovsanalys varit värdefull. Samtidigt kan vissa inslag i socialsekreterarnas arbete med fördel organiseras och genomföras centralt i stället för lokalt i områdena. För mer utförliga resonemang, hänvisas till delrapporten ”Områdesanknutna socialsekreterare” av Marie Gustavsson Holmström.Analysen av projektet i media pekar på hur projektet lyckats etablera en bild av sig som framgångsrikt, i stort sett helt baserad på utsagor från aktiva inom projektet. Huvudintrycket av innehållet i de artiklar som analyserats pekar på att detta innebär att en normativ och samtidigt starkt problemcentrerad framställning meddelas kring målgrupperna för projektet och de områden där verksamheten varit igång. Utifrånperspektivet som projektmedarbetare står för när de tillskriver områdena och invånarna en mängd brister och problem (ofta som individuella särdrag snarare än följden av strukturella omständigheter) balanseras inte av förmedling av inifrånperspektiv. Det finns en uppenbar risk att denna onyanserade bild får effekter i termer av en negativ stigmatisering. För mer utförliga resonemang hänvisas till delrapporten ”Projektet i pressen” av Maria-Monahov.Studien av det familjestödjande arbetet i form av uppbyggnadsarbete av familjecentraler, och föräldrautbildning enligt COPE-metoden, fokuserar innebörderna som givits detta arbete av olika aktörer engagerade i processen. Även här pekas på att olika aktörer definierar förebyggande arbete och samverkan på olika sätt och därmed också föreställer sig familjecentralerna som mötesplatser med olika utformning och inriktning på sin verksamhet. Avvägningen mellan det arbete som skall utföras inom familjecentralens ramar och annat arbete inom ens övriga verksamhet är inte klargjord. De tilltänkta brukarna av familjecentralerna har också olika förväntningar som inte på ett självklart sätt överensstämmer med personalens föreställningar om sin målgrupp. Bl.a. finns många negativa associationer hos föräldrarna kring begreppet ”familjecentral”. Vad föräldrarna ser, och värderar högt, är den öppna förskolans verksamhet. Föräldrautbildning enligt COPE-metoden problematiseras gällande dess tillämpbarhet på den målgrupp projektet har och aspekter av kontroll och styrning relaterade till målen för svensk förskola–skola; barn–föräldrarelationer, med mera. Den arena COPE-metoden erbjuder för föräldrautbildning är anpassad för, och når en typ av föräldrar som sannolikt inte är de som har störst behov av insatsen. För mer utförliga resonemang, se delrapporten ” Utvärdering av familjestödjande arbete” av Ingrid Hylander.Följande punkter föreslår utvärderarna kan vara särskilt viktiga att överväga inför framtida utvecklingsarbete:Är organisering av arbetet i projektform det lämpligaste i förhållande till de mål man vill uppnå?Om beslutet fattas att organisera utvecklingsarbete som projekt är det viktigt att utforma projektprocessen så att utrymme finns för en förberedelsefas. Innehållet i denna kan med fördel inriktas på ett systematiskt kunskapssökande i olika former, för att rikta in utvecklingsarbetet på adekvata områden och tillvarata tidigare kunskap och erfarenhet inom berörda utvecklingsområden. I föreliggande projekt har arbetets inriktning i hög grad blivit styrt av berörd personals uppfattningar och upplevelser av vad som är angeläget utvecklingsarbete.I projektprocessen bör på ett tidigt stadium konkretiseringar göras av vad samtliga inblandade aktörer lägger i begrepp som är styrande för projektets innehåll och kontinuerligt bearbetas i förhållande till andra relevanta målformuleringar.Personer som engageras i projektarbete bör ha eller ges tillfälle att inhämta, kunskap och kompetens i projektarbetets speciella karaktär. Det är vidare angeläget att bygga en projektorganisation med stabilitet både vad avser personers engagemang i tid, och deras inbördes ansvarsområden.Projekt som arbetar med mål inriktade på någon typ av mobilisering av medborgare/allmänhet kan på ett mer systematiskt sätt än vad som blivit fallet inom föreliggande projekt använda sig av självorganiserade grupper/ickeprofessionella aktörer för utvecklingsarbete.
44.	Rova, Maria, 1960-, et al. (författare) Heterologous expression of the gene for chlorite dismutase from Ideonella dechloratans is induced by an FNR-type transcription factor 2020 Ingår i: MicrobiologyOpen. - : WILEY. - 2045-8827. ; :7 Tidskriftsartikel (refereegranskat)abstract Regulation of the expression of the gene for chlorite dismutase (cld), located on the chlorate reduction composite transposon of the chlorate reducer Ideonella dechloratans, was studied. A 200 bp upstream sequence of the cld gene, and mutated and truncated versions thereof, was used in a reporter system in Escherichia coli. It was found that a sequence within this upstream region, which is nearly identical to the canonical FNR-binding sequence of E. coli, is necessary for anaerobic induction of the reporter gene. Anaerobic induction was regained in an FNR-deficient strain of E. coli when supplemented either with the fnr gene from E. coli or with a candidate fnr gene cloned from I. dechloratans. In vivo transcription of the suggested fnr gene of I. dechloratans was demonstrated by qRT-PCR. Based on these results, the cld promoter of I. dechloratans is suggested to be a class II-activated promoter regulated by an FNR-type protein of I. dechloratans. No fnr-type genes have been found on the chlorate reduction composite transposon of I. dechloratans, making anaerobic upregulation of the cld gene after a gene transfer event dependent on the presence of an fnr-type gene in the recipient.
45.	Rundquist, Olof, et al. (författare) Progesterone Inhibits the Establishment of Activation-Associated Chromatin During T(H)1 Differentiation 2022 Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13 Tidskriftsartikel (refereegranskat)abstract T(H)1-mediated diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) improve during pregnancy, coinciding with increasing levels of the pregnancy hormone progesterone (P4), highlighting P4 as a potential mediator of this immunomodulation. Here, we performed detailed characterization of how P4 affects the chromatin and transcriptomic landscape during early human T(H)1 differentiation, utilizing both ATAC-seq and RNA-seq. Time series analysis of the earlier events (0.5-24 hrs) during T(H)1 differentiation revealed that P4 counteracted many of the changes induced during normal differentiation, mainly by downregulating key regulatory genes and their upstream transcription factors (TFs) involved in the initial T-cell activation. Members of the AP-1 complex such as FOSL1, FOSL2, JUN and JUNB were particularly affected, in both in promoters and in distal regulatory elements. Moreover, the changes induced by P4 were significantly enriched for disease-associated changes related to both MS and RA, revealing several shared upstream TFs, where again JUN was highlighted to be of central importance. Our findings support an immune regulatory role for P4 during pregnancy by impeding T-cell activation, a crucial checkpoint during pregnancy and in T-cell mediated diseases, and a central event prior to T-cell lineage commitment. Indeed, P4 is emerging as a likely candidate involved in disease modulation during pregnancy and further studies evaluating P4 as a potential treatment option are needed.
46.	Simonsson, Maria, 1960-, et al. (författare) Samverkan mellan hem och fritidshem ska gynna skolresultaten 2015 Ingår i: Venue. - Linköpings : Linköpings Universitet. - 2001-788X. ; 01, s. 1-5- Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract I de nyligen publicerade Skolverkets allmänna råd om fritidshem betonas ett ökat samarbete mellan fritidshem och hemmet. Det innebär ökad delaktighet men också styrning och kontroll av såväl barn som kontakten med föräldrar/vårdnadshavare. På så sätt ska fritidshemmet komplettera skolans verksamhet och ge bättre skolresultat.
47.	Skogman, Barbro H, et al. (författare) Adaptive and Innate Immune Responsiveness to Borrelia burgdorferi sensu lato in Exposed Asymptomatic Children and Children with Previous Clinical Lyme Borreliosis 2012 Ingår i: Clinical & Developmental Immunology. - : Hindawi Publishing Corporation. - 1740-2522 .- 1740-2530. ; 2012:294587 Tidskriftsartikel (refereegranskat)abstract Why some individuals develop clinical manifestations in Lyme borreliosis (LB) while others remain asymptomatic is largely unknown. Therefore, we wanted to investigate adaptive and innate immune responsiveness to Borrelia burgdorferi sensu lato in exposed Borrelia-antibody-positive asymptomatic children (n = 20), children with previous clinical LB (n = 24), and controls (n = 20). Blood samples were analyzed for Borrelia-specific interferon (IFN)-gamma, interleukin (IL)-4, and IL-17 secretion by ELISPOT and Borrelia-induced IL-1 beta, IL-6, IL-10, IL-12(p70), and tumor necrosis factor (TNF) secretion by Luminex. We found no significant differences in cytokine secretion between groups, but a tendency towards an increased spontaneous secretion of IL-6 was found among children with previous clinical LB. In conclusion, the adaptive or innate immune responsiveness to Borrelia burgdorferi sensu lato was similar in Borrelia-exposed asymptomatic children and children with previous clinical LB. Thus, the immunological mechanisms of importance for eradicating the spirochete effectively without developing clinical manifestations of LB remain unknown.
48.	Studying the Agency of Being Governed 2014 Ingår i: Studying the Agency of Being Governed. - Abingdon; New York : Routledge. - 9780415623674 ; , s. 19- Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract This edited volume seeks to provide guidance on how we can approach questions of governing and agency—particularly those who endeavour to embark on grounded empirical research— by rendering explicit some key challenges, tensions, dilemmas, and confluences that such endeavours elicit. Indeed, the contributions in this volume reflect the growing tendency in governmentality studies to shift focus to empirically grounded studies. The volume thus explicitly aims to move from theory to practice, and to step back from the more top-down governmentality studies approach to one that examines how one can/does study how relations of power affect lives, experience and agency. This book offers insight into the intricate relations between the workings of governing and (the possibility for) people’s agency on the one hand, and about the possible effects of our attempts to engage in such studies on the other. In numerous ways, and from different starting points, the contributions to this volume provide thoughtful insights into, and creative suggestions for, how to work with the methodological challenges of studying the agency of being governed. This work will be of great interest to students and scholars of international relations, global governance and research methods.
49.	Tot, Tibor, et al. (författare) Breast cancer multifocality, disease extent, and survival 2011 Ingår i: Human Pathology. - Philadelphia, Pa. : Saunders. - 0046-8177 .- 1532-8392. ; 42:11, s. 1761-1769 Tidskriftsartikel (refereegranskat)abstract The prognostic information implied in subgross morphologic parameters such as lesion distribution (unifocal, multifocal, or diffuse) and disease extent in breast cancer has remained largely unexplored in the literature. We aimed to test whether these parameters influence survival in breast carcinoma. The parameters were assessed in a series of 574 cases, all documented in large-format histology sections. We used Cox proportional hazards regression accompanied by Kaplan-Meyer survival curves, with P < .05 regarded as significant. The invasive component was unifocal in 62% (311/499), multifocal in 24% (122/499), and diffuse in 5% (26/499) of the cases. Combining the in situ and invasive tumor components resulted in 48% (274/574) unifocal, 25% (141/574) multifocal, and 20% (117/574) diffuse tumors. Sixty percent (347/574) of the tumors were categorized as having limited extent (occupying an area <40 mm in largest dimension) and 29% (164/574) as extensive. Highly significant (P < .0001) differences were observed in 10-year disease-specific cumulative survival among the cases with unifocal, multifocal, and diffuse invasive (89.6%, 76.0%, and 63.6%, respectively) and combined (92.3%, 82.3%, and 75.7%, respectively) lesion distribution. Patients with extensive tumors exhibited a significantly lower cumulative survival (P < .0001) compared with those with limited extent (91.6% and 75.5%) and a statistically significantly 1.89-fold (95% confidence interval, 1.07-3.37; P = .03) risk for breast cancer death after controlling for tumor attributes, type of surgery, and adjuvant therapy. The hazard ratio for breast cancer death for mutifocal and/or diffuse tumors versus unifocal ones was 1.96 (95%; 1.11-3.48; P = .02) after controlling for the same factors. Lesion distribution and disease extent represent important independent survival-related prognostic parameters in breast carcinoma.
50.	Tot, Tibor, et al. (författare) Molecular phenotypes of unifocal, multifocal, and diffuse invasive breast carcinomas. 2011 Ingår i: Pathology research international. - : Sage-Hindawi. - 2042-003X. ; 2011, s. 480960- Tidskriftsartikel (refereegranskat)abstract We analyzed the subgross distribution of the invasive component in 875 consecutive cases of breast carcinomas using large-format histology sections and compared the immunophenotype (estrogen and progesterone receptor expression, HER2 overexpression and expression of basal-like markers, CK5/6, CK14, and epidermal growth factor receptor) in unifocal, multifocal, and diffuse tumors. Histology grade and lymph node status were also analyzed. Unifocal invasive carcinomas comprised 58.6% (513/875), multifocal invasive carcinomas 36.5% (319/875), and diffuse invasive carcinomas 4.9% (43/875) of the cases. The proportion of lymph node-positive cases was significantly higher in multifocal and diffuse carcinomas compared to unifocal cancers, but no other statistically significant differences could be verified between these tumor categories. Histological multifocality and diffuse distribution of the invasive tumor component seem to be negative morphologic prognostic parameters in breast carcinomas, independent of the molecular phenotype.

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