| 1. |
- Goncalves, Odete Sofia Lopes, et al.
(författare)
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The repeated 36 amino acid motif of Chlamydia trachomatis Hc2 protein binds to the major groove of DNA
- 2019
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Ingår i: Research in Microbiology. - : ELSEVIER. - 0923-2508 .- 1769-7123. ; 170:6-7, s. 256-262
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Tidskriftsartikel (refereegranskat)abstract
- The gram-negative, obligate intracellular human pathogen, Chlamydia trachomatis has a bi-phasic developmental cycle. The histone H1-like C. trachomatis DNA binding protein, Hc2, is produced late during the developmental cycle when the dividing reticulate body transforms into the smaller, metabolically inactive elementary body. Together with Hc1, the two proteins compact the chlamydial chromosome and arrest replication and transcription. Hc2 is heterogeneous in length due to variation in the number of lysine rich pentamers. Six pentamers and one hexamer constitute a 36 amino acid long repetitive unit that, in spite of variations, is unique for Chlamydiaceae. Using synthetic peptides, the DNA-binding capacity of the 36 amino acid peptide and that of a randomized peptide was analyzed. Both peptides bound and compacted plasmid DNA, however, electron microscopy of peptide/DNA complexes showed major differences in the resulting aggregated structures. Fluorescence spectroscopy was used to analyze the binding. After complexing plasmid DNA with each of three different intercalating dyes, increasing amounts of peptides were added and fluorescence spectroscopy performed. The major groove binder, methyl green, was displaced by both peptides at low concentrations, while the minor groove binder, Hoechts, and the intercalating dye, Ethidium Bromide, were displaced only at high concentrations of peptides. (C) 2019 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
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| 2. |
- Grünberg, John, 1985, et al.
(författare)
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Overexpressing the novel autocrine/endocrine adipokine WISP2 induces hyperplasia of the heart, white and brown adipose tissues and prevents insulin resistance.
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- WISP2 is a novel adipokine, most highly expressed in the adipose tissue and primarily in undifferentiated mesenchymal cells. As a secreted protein, it is an autocrine/paracrine activator of canonical WNT signaling and, as an intracellular protein, it helps to maintain precursor cells undifferentiated. To examine effects of increased WISP2 in vivo, we generated an aP2-WISP2 transgenic (Tg) mouse. These mice had increased serum levels of WISP2, increased lean body mass and whole body energy expenditure, hyperplastic brown/white adipose tissues and larger hyperplastic hearts. Obese Tg mice remained insulin sensitive, had increased glucose uptake by adipose cells and skeletal muscle in vivo and ex vivo, increased GLUT4, increased ChREBP and markers of adipose tissue lipogenesis. Serum levels of the novel fatty acid esters of hydroxy fatty acids (FAHFAs) were increased and transplantation of Tg adipose tissue improved glucose tolerance in recipient mice supporting a role of secreted FAHFAs. The growth-promoting effect of WISP2 was shown by increased BrdU incorporation in vivo and Tg serum increased mesenchymal precursor cell proliferation in vitro. In contrast to conventional canonical WNT ligands, WISP2 expression was inhibited by BMP4 thereby allowing normal induction of adipogenesis. WISP2 is a novel secreted regulator of mesenchymal tissue cellularity.
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| 3. |
- Holm, Anna, 1973-
(författare)
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Acute coronary syndrome : bleeding, platelets and gender
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUNDBleeding complications increase mortality in patients with acute coronary syndrome (ACS). Potential gender difference in bleeding regarding prevalence, location, severity and prognostic impact is still controversial and not well investigated. In regard to this aspect the relevance of triple antithrombotic therapy (TAT) is questioned. There is an ongoing debate on the clinical implications of TAT and furthermore assumed that bleeding complications, except impact on outcome, also are associated with great influence on health economy.The main focus of this thesis was to further investigate the incidence and impact of bleeding complications in patients treated for ACS, with special reference to gender disparities, TAT and health economics. The thesis will highlight the importance of improved bleeding prevention strategies for both men and women.METHODPaper I, II and IIIObservational studies from the SWEDEHEART register.In paper I we investigated patients hospitalised with myocardial infarction (MI) during 2006–2008. Outcomes were in-hospital bleedings, in-hospital mortality and one-year mortality in hospital survivors.In paper II, all patients with MI, in the County of Östergötland, Sweden during 2010 were included and followed for one year. The patients' medical records were evaluated, in relation to short and long-term bleeding complications, bleeding location, withdrawal of platelet inhibiting drugs and nonfatal MI and death.Paper III included all patients discharged with (TAT) in the County of Östergötland 2009-2015. Information about bleeds and ischemic complications during one-year follow-up were retrieved from the medical records. Estimation of the health care costs associated with bleeding episodes were added to the evaluation.Paper IVPatients with MI, scheduled for coronary angiography were recruited. All patients received clopidogrel and aspirin. A subgroup of patients received GP IIb/IIIa-inhibitor. Outcomes were platelet aggregation assessed at several time points, using a Multiplate impedance aggregometer, measurement of P-selectin in plasma, evaluation of high residual platelet reactivity (HRPR) and low residual platelet reactivity (LRPR) respectively and incidence of bleeding complications. A comparison between women and men was performed.RESULTSPaper IA total number of 50.399 patients were included, 36.6% women. In-hospital bleedings were more common in women (1.9% vs. 3.1%, p<0.001) even after multivariable adjustment (OR 1.17, 95%, CI 1.01–1.37). The increased risk for women was found in STEMI (OR 1.46, 95% CI 1.10–1.94) and in those who underwent PCI (OR 1.80, 95% CI 1.45–2.24).In contrast the risk was lower in medically treated women (OR 0.79, 95% CI 0.62–1.00). After adjustment, in-hospital bleeding was associated with higher risk of oneyear mortality in men (OR 1.35, 95% CI 1.04–1.74), whereas this was not the case in women (OR 0.97, 95% CI 0.72–1.31).Paper IIIn total 850 consecutive patients were included. The total incidence of bleeding events was 24.4% (81 women and 126 men, p=ns). The incidence of all in hospital bleeding events was 13.2%, with no gender difference. Women had significantly more minor nonsurgery related bleeding events than men (5% vs 2.2%, p=0.02). During follow-up, 13.5% had a bleeding, with more non-surgery related bleeding events among women, 14.7% vs 9.7% (p=0.03). The most common bleeding localisation was the gastrointestinal tract, more in women than men (12.1% vs 7.6%, p=0.03). Women also had more access site bleeding complications (4% vs 1.7%, p=0.04), while men had more surgery related bleeding complications (6.4% vs 0.9%, p≤0.001). Increased mortality was found only in men with non-surgery related bleeding events (p=0.008).Paper IIIAmong 272 identified patients, 156 bleeds occurred post-discharge, of which 28.8% were of gastrointestinal origin. In total 54.4% had at least one bleed during or after the index event and 40.1% bled post-discharge of whom 28.7% experienced a TIMI major or minor bleeding. Women discontinued TAT prematurely more often than men (52.9 vs 36.1%, p=0.01) and bled more (48.6 vs. 37.1%, p=0.09). One-year mean health care costs were EUR 575 and EUR 5787 in non-bleeding and bleeding patients, respectively.Paper IVWe recruited 125 patients (37 women and 88 men). We observed significantly more inhospital bleeding events in women as compared to men (18.9% vs 6.8%, p=0.04). There were no differences in platelet aggregation using three different agonists, reflecting treatment of GPIIb/IIIa inhibitors, clopidogrel and aspirin, at four different time-points nor were there any differences in p-selectin in plasma 3 days after admission.CONCLUSIONThere is a remarkably high bleeding incidence among patients treated with DAPT and even more so if treated with TAT. Female gender is an independent risk factor of inhospital bleeding after myocardial infarction, this higher bleeding risk in women appears to be restricted to invasively treated patients and STEMI patients. Even if women had higher short- and long-term mortality, there was no difference between the genders among those who bled. After multivariable adjustment the prognostic impact of bleeding complications was higher in menWomen seem to experience more minor/minimal bleeding complications than men, predominantly GI bleeding events and access site bleeding events, with no apparent impact on outcome.In contrast men with non-surgery related bleeding complications had higher mortality. There is a lack of differences between the genders concerning platelet aggregation. Our results do not support gender disparities in platelet reactivity and excess dosing as a major explanation for increased bleeding risk in women. Improved bleeding prevention strategies are warranted for both men and women.
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| 4. |
- Holm, Anna, et al.
(författare)
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Bleeding complications after myocardial infarction in a real world population - An observational retrospective study with a sex perspective
- 2018
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Ingår i: Thrombosis Research. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0049-3848 .- 1879-2472. ; 167, s. 156-163
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The aim of the current study was to assess bleeding events, including severity, localisation and prognostic impact, in a real world population of men and women with myocardial infarction (MI). Methods and results: In total 850 consecutive patients were included during 2010 and followed for one year. Bleeding complications were identified by searching of each patients medical records and characterised according to the TIMI criteria. For this analysis, only the first event was calculated. The total incidence of bleeding events was 24.4% (81 women and 126 men, p=ns). The incidence of all inhospital bleeding events was 13.2%, with no sex difference. Women had significantly more minor non-surgery related bleeding events than men (5% vs 2.2%, p=0.02). During follow-up, 13.5% had a bleeding, with more non-surgery related bleeding events among women, 14.7% vs 9.7% (p=0.03). The most common bleeding localisation was the gastrointestinal tract, more in women than men (12.1% vs 7.6%, p=0.03). Women had also more access site bleeding complications (4% vs 1.7%, p=0.04), while men had more surgery related bleeding complications (6.4% vs 0.9%, p=0.001). Increased mortality was found only in men with non-surgery related bleeding events (p=0.008). Conclusions: Almost one in four patients experienced a bleeding complication through 12 months follow-up after a myocardial infarction. Women experienced more non-surgery related minor/minimal bleeding complications than men, predominantly GI bleeding events and access site bleeding events, with no apparent impact on outcome. In contrast men with non-surgery related bleeding complications had higher mortality. Improved bleeding prevention strategies are warranted for both men and women.
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| 5. |
- Holm, Anna, et al.
(författare)
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Gender difference in prognostic impact of in-hospital bleeding after myocardial infarction - data from the SWEDEHEART registry.
- 2016
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Ingår i: European Heart Journal. - : Sage Publications. - 2048-8726 .- 2048-8734. ; 6, s. 463-472
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Bleeding complications increase mortality in myocardial infarction patients. Potential gender difference in bleeding regarding prevalence and prognostic impact is still controversial.OBJECTIVES: Gender comparison regarding incidence and prognostic impact of bleeding in patients hospitalised with myocardial infarction during 2006-2008.METHODS: Observational study from the SWEDEHEART register. Outcomes were in-hospital bleedings, in-hospital mortality and one-year mortality in hospital survivors.RESULTS: A total number of 50,399 myocardial infarction patients were included, 36.6% women. In-hospital bleedings were more common in women (1.9% vs. 3.1%, p<0.001) even after multivariable adjustment (odds ratio (OR) 1.17, 95% confidence interval (CI) 1.01-1.37). The increased risk for women was found in ST-elevation myocardial infarction (OR 1.46, 95% CI 1.10-1.94) and in those who underwent percutaneous coronary intervention (OR 1.80, 95% CI 1.45-2.24). In contrast the risk was lower in medically treated women (OR 0.79, 95% CI 0.62-1.00). After adjustment, in-hospital bleeding was associated with higher risk of one-year mortality in men (OR 1.35, 95% CI 1.04-1.74), whereas this was not the case in women (OR 0.97, 95% CI 0.72-1.31).CONCLUSIONS: Female gender is an independent risk factor of in-hospital bleeding after myocardial infarction. A higher bleeding risk in women appeared to be restricted to invasively treated patients and ST-elevation myocardial infarction patients. Even though women have higher short- and long-term mortality, there was no difference between the genders among bleeders. After multivariable adjustment the prognostic impact of bleeding complications was higher in men.
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| 6. |
- Holm, Anna, 1973-, et al.
(författare)
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Long term risk and costs of bleeding in men and women treated with triple antithrombotic therapy : An observational study
- 2021
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 16:3
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Bleeding is the most common non-ischemic complication in patients with coronary revascularisation procedures, associated with prolonged hospitalisation and increased mortality. Many factors predispose for bleeds in these patients, among those sex. Anyhow, few studies have characterised the population receiving triple antithrombotic therapy (TAT) as well as long term bleeds from a sex perspective. We investigated the one year rate of bleeds in patients receiving TAT, potential sex disparities and premature discontinuation of TAT. We also assessed health care costs in bleeders vs non-bleeders. Setting Three hospitals in the County of ostergotland, Sweden during 2009-2015. Participants All patients discharged with TAT registered in the SWEDEHEART registry. Primary and secondary outcome measures All bleeds receiving medical attention during one-year follow-up were collected by retrieving relevant information about each patient from medical records. Resource use associated with bleeds was assigned unit cost to estimate the health care costs associated with bleeding episodes. Results Among 272 patients, 156 bleeds occurred post-discharge, of which 28.8% were gastrointestinal. In total 54.4% had at least one bleed during or after the index event and 40.1% bled post discharge of whom 28.7% experienced a TIMI major or minor bleeding. Women discontinued TAT prematurely more often than men (52.9 vs 36.1%, p = 0.01) and bled more (48.6 vs. 37.1%, p = 0.09). One-year mean health care costs were EUR 575 and EUR 5787 in non-bleeding and bleeding patients, respectively. Conclusion The high bleeding incidence in patients with TAT, especially in women, is a cause of concern. There is a need for an adequately sized randomised, controlled trial to determine a safe but still effective treatment for these patients.
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| 7. |
- Holm, Anna, 1973-, et al.
(författare)
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Sex differences in platelet reactivity in patients with myocardial infarction treated with triple antiplatelet therapy-results from assessing platelet activity in coronary heart disease (APACHE)
- 2021
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Ingår i: Platelets. - : Taylor & Francis. - 0953-7104 .- 1369-1635. ; 32:1, s. 524-532
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Tidskriftsartikel (refereegranskat)abstract
- )Several earlier studies have reported increased risk of bleeding in women with myocardial infarction, (MI) compared to men. The reasons for the observed difference are incompletely understood, but one suggested explanation has been excess dosing of antithrombotic drugs in women. The aim of this prospective observational study was to assess sex differences in platelet activity in patients treated with three different platelet inhibitors. We recruited 125 patients (37 women and 88 men) with MI, scheduled for coronary angiography. All patients received clopidogrel and aspirin. A subgroup of patients received glycoprotein (GP) IIb/IIIa-inhibitor. Platelet aggregation in whole blood was assessed at several time points, using impedance aggregometry. SolubleP-selectin was measured 3 days after admission. There were no significant differences between women and men in baseline features or comorbidities except higher frequency of diabetes, lower hemoglobin value, and lower estimated glomerular filtration rate, in women on admission. We observed significantly more in-hospital bleeding events in women compared to men (18.9% vs. 6.8%,p= .04). There were no differences in platelet aggregation using three different agonists, reflecting treatment effect of GPIIb/IIIa-inhibitors, clopidogrel, and aspirin, 6-8 hours, 3 days, 7-9 days, or 6 months after loading dose. Moreover, there was no significant difference in solubleP-selectin. The main finding of this study was a consistent lack of difference between the sexes in platelet aggregation, using three different agonists at several time-points. Our results do not support excess dosing of anti-platelet drugs as a major explanation for increased bleeding risk in women.
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| 8. |
- Holm, Karolina, et al.
(författare)
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Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes
- 2012
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Ingår i: Molecular Oncology. - : Elsevier. - 1574-7891 .- 1878-0261. ; 6:5, s. 494-506
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Tidskriftsartikel (refereegranskat)abstract
- Polycomb repressive complex 2 (PRC2) and its core member enhancer of zeste homolog 2 (EZH2) mediate the epigenetic gene silencing mark: trimethylation of lysine 27 on histone 3 (H3K27me3). H3K27me3 is characteristic of the chromatin at genes involved in developmental regulation in undifferentiated cells. Overexpression of EZH2 has been found in several cancer types such as breast, prostate, melanoma and bladder cancer. Moreover, overexpression is associated with highly proliferative and aggressive types of breast and prostate tumors. We have analyzed the abundance of EZH2 and H3K27me3 using immunohistochemistry in two large and Well-characterized breast tumor data sets encompassing more than 400 tumors. The results have been analyzed in relation to the molecular subtypes of breast tumors (basal-like, luminal A, luminal B, HER2-enriched and normal-like), as well as in subtypes defined by clinical markers (triple negative, ER+/HER2-/Ki67low, ER+/HER2-/Ki67high and HER2+), and were validated in representative breast cancer cell lines by western blot. We found significantly different expression of both EZH2 and H3K27me3 across all subtypes with high abundance of EZH2 in basal-like, triple negative and HER2-enriched tumors, and high H3K27me3 in luminal A, HER2-enriched and normal-like tumors. Intriguingly, the two markers show an inverse correlation, particularly for the basal-like and triple negative tumors. Consequently, high expression of EZH2 was associated with poor distant disease-free survival whereas high expression of H3K27me3 was associated with better survival. Additionally, none of 182 breast tumors was found to carry a previously described EZH2 mutation affecting Tyr641. Our observation that increased expression of EZH2 does not necessarily correlate with increased abundance of H3K27me3 supports the idea that EZH2 can have effects beyond epigenetic silencing of target genes in breast cancer.
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| 9. |
- Holm, Sofia
(författare)
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Molecular genetic studies of psoriasis susceptibility in 6p21.3
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Psoriasis is a common and chronic skin disease with multifactorial background. It affects approximately 2% of the Swedish population and is characterized by inflammatory and scaly lesions. The aetiology of psoriasis is not yet known, however, the genetic contribution to the disease is strong. Several loci have been identified and among these, psoriasis susceptibility 1 (PSORS1) in chromosome region 6p21.3 is consistently described in populations of different ethnic background. A major factor involved in disease susceptibility is therefore believed to reside at this locus. Studies in this region are complicated by strong linkage disequilibrium and the previously identified associating allele of human leukocyte antigen C (HLA-C), HLACw*0602, was therefore believed to be a marker of a disease gene located nearby. The purpose of the studies that make up the main body of this thesis work is to characterize alternative candidate genes for association to psoriasis in the Swedish population. Each new candidate was compared to HLA-Cw*0602 and their relationship to this allele was also investigated. The HCR gene was characterized and found to be a very polymorphic gene and to be strongly associated to psoriasis. However, when compared to the level of association of HLACw*0602, variations in HCR appeared to be in linkage disequilibrium with this allele. Three new genes were identified upon further characterization of the region; psoriasis susceptibility 1 candidate 1-3 (PSORS1C1-C3). Several variants were identified and tested for association, but after comparison, the observed associations appeared to be dependent on the presence of HLA-Cw*0602. HLC-A therefore remains the strongest candidate in the region. The biological function of this molecule is to signal our immune system for self-recognition, and its main interacting partners are specific killer immunoglobulin like receptors (KIR) on natural killer (NK) cells. The presence and absence of these KIR genes and HLA-C alleles were investigated. KIR2DS1 showed association to psoriasis vulgaris. Furthermore, when combining HLA-C and KIR in potential NK cell responses, a clear difference was observed in guttate psoriasis. This group showed an increased potential for inhibition and had less individuals with an undetermined NK cell response. When adding HLA-Cw*0602 to these combinations the effect was even more pronounced. From this analysis HLA-Cw*0602 appears to play an important role in potential thresholds of NK cell responses associated to psoriasis. Continued functional studies on HLA-C and its interaction partners are needed in order to elucidate the involvement of this gene in psoriasis pathogenesis.
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| 10. |
- Hussamadin, Raafat, et al.
(författare)
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Process Platforms for Onsite Assemblies : A Case Study of Work Break Down Structures in SMEs
- 2020
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Ingår i: ICCREM 2020: Intelligent Construction and Sustainable Buildings. - Reston, VA : American Society of Civil Engineers (ASCE). ; , s. 190-197
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Konferensbidrag (refereegranskat)abstract
- Industrialized house-building companies predefine parameters in platforms. To identify processes platforms the use of work break down structures that support the assembly processes for small house building companies were studied. A case study of the onsite assembly activities were chosen at one small Swedish house builder that offer customization within their products. Based on the assembly processes, a work breakdown structure of the workflow predefinitions was identified for the process that didn’t compromise with product customization. Small companies can predefine elements within the product to simplify the work process on site. The work break down structure becomes a tool to find parts and process that predefine a house building platform. It can also be used for planning, delivery, cost, and resources in an overall view of the project. Because of the importance of planning during projects, together with the possible standardization of the company’s process, the use of a work break down could contribute to increase efficiency for onsite work.
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