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| 5. |
- Adolfsen Løhmann, DJ, et al.
(författare)
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Associations between Pre-therapeutic Body Mass Index, Outcome and Cytogenetic Abnormalities in Pediatric Acute Myeloid Leukemia
- 2019
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Ingår i: 38th NOPHO Annual meeting. Aalborg, Denmark 3-7 May.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Associations between body mass index (BMI), outcome and leukemia-related factors in children with acute myeloid leukemia (AML) are unclear. Aim: To investigate associations between pre-therapeutic BMI, cytogenetic abnormalities, and outcome in a large multinational cohort of children with AML. Methods: We included patients age 2–17 years, diagnosed with de novo AML from the five Nordic countries (2004–2016), Hong Kong (2007–2016), the Netherlands and Belgium (2010–2016), and Canada and USA (1995–2012). Cases with Down syndrome, acute promyelocytic leukemia, or isolated granulocytic sarcoma were excluded. Cases with missing data on pre-therapeutic BMI (n=7) were also excluded. BMI standard deviations score for age and sex was calculated and categorized according to the World Health Organization. Cumulative incidence functions, Cox regression and logistic regression were used to investigate associations. Results: In total, 867 patients were included. The median age was 10 years (range 2–17 years) and 53% were male. At diagnosis, 4% were underweight, 73% were healthy weight, 15% were overweight, and 9% were obese. Patients were treated on 17 different protocols with AAML0531, COG9421, NOPHO-AML 2004, DB AML-01 and NOPHO-DBH AML 2012 accounting for 79%. There was no difference in relapse risk, treatment-related mortality or overall mortality across BMI groups. The frequency of t(8;21) and inv(16) increased with increasing BMI. For obese patients, the sex, age and country adjusted odds ratio of having t(8;21) or inv(16) were 1.9 (95% confidence interval (CI) 1.1–3.4) and 2.8 (95% CI 1.3–5.8) respectively compared to healthy weight patients. Conclusion: This multi-institutional study of 867 pediatric patients with de novo AML did not confirm previous reports of associations between overweight and increased treatment-related or overall mortality in children. Obesity was associated with a higher frequency of t(8;21) and inv(16). AML cytogenetics appear to differ by BMI status.
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| 6. |
- Albertsen, B. K., et al.
(författare)
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Intermittent Versus Continuous PEG-Asparaginase to Reduce Asparaginase-Associated Toxicities: A NOPHO ALL2008 Randomized Study
- 2019
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Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 37:19, s. 1638-1646
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Asparaginase is an essential drug in childhood acute lymphoblastic leukemia (ALL) therapy and is frequently given for months to obtain continuous asparagine depletion. We randomly assigned patients to continuous versus intermittent pegylated-asparaginase (PEG-asp) treatment, hypothesizing there would be decreased toxicity with unchanged efficacy. METHODS Children (median age, 4.2 years) treated for non-high-risk ALL according to the Nordic Society for Pediatric Hematology and Oncology ALL2008 protocol received five intramuscular PEG-asp injections (1,000 IU/m(2)) every two weeks and were then randomly assigned to additional three doses (6-week intervals [experimental arm], n = 309) versus 10 doses (2-week intervals [standard arm], n = 316). The primary end point was noninferior (6% margin) disease-free survival. Toxicity reduction was a secondary end point. Occurrence of asparaginase-associated hypersensitivity, pancreatitis, osteonecrosis, and thromboembolism were prospectively registered. RESULTS After a median follow-up of 4.1 years, the 5-year disease-free survival was 92.2% (95% CI, 88.6 to 95.8) and 90.8% (95% CI, 87.0 to 94.6) in the experimental and standard arms, respectively. The 3-year cumulative incidence of any first asparaginase-associated toxicity (hypersensitivity [n = 13]; osteonecrosis [n = 29]; pancreatitis [n = 24]; thromboembolism [n = 17]) was 9.3% in the experimental arm and 18.1% in the standard arm (P = .001). Asparaginase-associated toxicity reduction was confirmed in sex- and risk-group-adjusted Cox regression analysis stratified by age (>= 10 and < 10 years; hazard ratio, 0.48; P = .001). The experimental arm had the lowest incidences of all four toxicities, reaching significance for pancreatitis (6-month risk, 5.8% v 1.3%; P = .002). CONCLUSION The excellent cure rates and reduced toxicity risk support the use of intermittent PEG-asp therapy after the first 10 weeks in future childhood ALL trials that apply prolonged PEG-asp therapy.
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| 7. |
- Juul-Dam, K. L., et al.
(författare)
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Measurable residual disease assessment by qPCR in peripheral blood is an informative tool for disease surveillance in childhood acute myeloid leukaemia
- 2020
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 190:2, s. 198-208
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Tidskriftsartikel (refereegranskat)abstract
- Serial assessments of measurable (or minimal) residual disease (MRD) by qPCR may identify nascent relapse in children with acute myeloid leukaemia (AML) and enable pre-emptive therapy. We investigated the kinetics and prognostic impact of recurrent fusion transcripts (RUNX1-RUNX1T1, CBFB-MYH11, KMT2A-MLLT3 or KMT2A-ELL) in 774 post-induction samples from bone marrow (BM, 347) and peripheral blood (PB, 427) from 75 children with AML. BM MRD persistence during consolidation did not increase the risk of relapse, and MRD at therapy completion did not correlate to outcome (HR=0·64/MRD log reduction (CI: 0·32–1·26), P=0·19). In contrast, 8/8 patients with detectable MRD in PB after first consolidation relapsed. Persistence (n=4) and shifting from negative to positive (n=10) in PB during follow-up predicted relapse in 14/14 patients. All 253PB samples collected during follow-up from 36 patients in continuous complete remission were MRD negative. In core-binding factor AML, persistent low-level MRD positivity in BM during follow-up was frequent but an increment to above 5×10−4 heralded subsequent haematological relapse in 12/12 patients. We demonstrate that MRD monitoring in PB after induction therapy is highly informative and propose an MRD increment above 5×10−4 in PB and BM as a definition of molecular relapse since it always leads to haematological relapse. © 2020 British Society for Haematology and John Wiley & Sons Ltd
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| 8. |
- Karlsson, Lene, et al.
(författare)
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Characteristics and outcome of primary resistant disease in paediatric acute myeloid leukaemia
- 2023
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 201:4, s. 757-765
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Tidskriftsartikel (refereegranskat)abstract
- A significant proportion of events in paediatric acute myeloid leukaemia (AML) are caused by resistant disease (RD). We investigated clinical and biological characteristics in 66 patients with RD from 1013 children with AML registered and treated according to the NOPHO-AML 93, NOPHO-AML 2004, DB AML-01 and NOPHO-DBH AML 2012 protocols. Risk factors for RD were age10 years or older and a white-blood-cell count (WBC) of 100 x 10(9)/L or more at diagnosis. The five-year overall survival (OS) was 38% (95% confidence interval [CI]: 28%-52%). Of the 63 children that received salvage therapy with chemotherapy, 59% (N = 37) achieved complete remission (CR) with OS 57% (95% CI: 42%-75%) compared to 12% (95% CI: 4%-35%) for children that did not achieve CR. Giving more than two salvage chemotherapy courses did not increase CR rates. OS for all 43 patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) was 49% (95% CI: 36%-66%). Those achieving CR and proceeding to HSCT had an OS of 56% (95% CI: 41%-77%, N = 30). This study showed that almost 40% of children with primary resistant AML can be cured with salvage therapy followed by HSCT. Children that did not achieve CR after two salvage courses with chemotherapy did not benefit from additional chemotherapy.
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| 9. |
- Le Roch, Sarah, et al.
(författare)
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European survey on criteria of aesthetics for periodontal evaluation: The ESCAPE study
- 2019
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Ingår i: Journal of Clinical Periodontology. - : Wiley. - 0303-6979 .- 1600-051X. ; 46:11, s. 1116-1123
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Tidskriftsartikel (refereegranskat)abstract
- © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: The ESCAPE multicentre survey was designed to (a) compare the agreement of three relevant aesthetic scoring systems among different centres, and (b) evaluate the reproducibility of each question of the questionnaires. Materials and Methods: EFP centres (n=14) were involved in an e-survey. Forty-two participants (28 teachers, 14 postgraduate students) were asked to score the one-year aesthetic outcomes of photographs using the Before–After Scoring System (BASS), the Pink Esthetic Score (PES) and the Root coverage Esthetic Score (RES). Mean values of kappa statistics performed on each question were provided to resume global agreement of each method. Results: Between teachers, a difference of kappa≥0.41 (p=.01) was found for BASS (75%) and PES (57%). Similarly, RES (84%) and PES (57%) were different (p<.001). No difference was found between BASS (75%) and RES (84%). No difference was found between students, whatever the scoring system. Questions of each scoring system showed differences in their reproducibility. Conclusions: The outcomes of this study indicate that BASS and RES scoring systems are reproducible tools to evaluate aesthetic after root coverage therapies between different centres. Among the various variables, lack of scar, degree of root coverage, colour match and gingival margin that follows the CEJ show the best reliability.
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| 12. |
- Abrahamsson, Jonas, 1954, et al.
(författare)
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Cholesteryl sulphate and phosphate in the solid state and in aqueous systems.
- 1977
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Ingår i: Chemistry and physics of lipids. - 0009-3084. ; 19:3, s. 213-22
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Tidskriftsartikel (refereegranskat)abstract
- Cholesteryl sodium sulphate (CS) crystallizes as the dihydrate, the crystal structure of which is known. On heating the dihydrate, solid state phase transitions are observed at 65 degrees C and 95 degrees C and melting occurs at 165 degrees C. The structure of the high temperature phase has not been determined. Cholesteryl dihydrogen phosphate (CP) is not isostructural with any phases of CS. It undergoes a phase transition at 50 degrees C and melts at 190 degrees C. In systems with water CS is unstable whereas it was possible to determine the phase diagram of CP. In most of the composition range a crystalline hydrate is in equilibrium with a gel-phase. The latter has remarkable properties in that lamellar order exists with the 46 A lipid bilayer interleaved with water layers up to 1000 A. The monofilm behaviour of CS and CP at different pH levels is also reported.
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| 14. |
- Benavent, N., et al.
(författare)
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Substantial contribution of iodine to Arctic ozone destruction
- 2022
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Ingår i: Nature Geoscience. - : Springer Science and Business Media LLC. - 1752-0894 .- 1752-0908. ; 15, s. 770-773
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Tidskriftsartikel (refereegranskat)abstract
- Unlike bromine, the effect of iodine chemistry on the Arctic surface ozone budget is poorly constrained. We present ship-based measurements of halogen oxides in the high Arctic boundary layer from the sunlit period of March to October 2020 and show that iodine enhances springtime tropospheric ozone depletion. We find that chemical reactions between iodine and ozone are the second highest contributor to ozone loss over the study period, after ozone photolysis-initiated loss and ahead of bromine.
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| 15. |
- Carvalho, E. de, et al.
(författare)
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EU FP7 INFSO-ICT-317669 METIS, D3.1 Positioning of multi-node/multi-antenna technologies
- 2013
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This document describes the research activity in multi-node/multi-antenna technologies within METIS and positions it with respect to the state-of-the-art in the academic literature and in the standardization bodies. Based on the state-of-the-art and as well as on the METIS objectives,we set the research objectives and we group the different activities (or technology components) into research clusters with similar research objectives. The technologycomponents and the research objectives have been set to achieve an ambidextrous purpose. On one side we aim at providing the METIS system with those technological components that are a natural but non-trivial evolution of 4G. On the other side, we aim at seeking for disruptivetechnologies that could radically change 5G with respect to 4G. Moreover, we mapped the different technology components to METIS’ other activities and to the overall goals of theproject.
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| 16. |
- Dellenmark-Blom, Michaela, 1983, et al.
(författare)
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Establishment of a condition-specific quality-of-life questionnaire for children born with esophageal atresia aged 2-7 across 14 countries
- 2023
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Ingår i: Frontiers in Pediatrics. - 2296-2360. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundEsophageal atresia (EA) is a rare congenital anomaly characterized by a discontinuity of the esophagus. Following surgical repair, survival rates have improved dramatically the past decenniums and today exceed 90%, but the children commonly present with esophageal and respiratory morbidity. In 2018, a condition-specific quality-of-life questionnaire for children with esophageal atresia (EA) aged 2-7 in Sweden-Germany was finalized (The EA-QOL questionnaire). The study aim was to describe the evaluation of the new translations across 12 new countries in Europe, Asia, Africa, Central-and North America.MethodsFollowing forward-backward translation into the new languages, the 17-item EA-QOL questionnaire was tested in cognitive debriefing interviews with parents of children with EA aged 2-7. Parents rated if each item was easy to understand (clarity) and sensitive to answer (interference with personal integrity). They could skip responding to a non-applicable/problematic item and give open comments. Predefined psychometric criteria were used; item clarity >= 80%/item sensitive to answer <= 20%/item feasibility <= 5% missing item responses. The decision to modify the translation was based on native expert, patient stakeholder, and instrument developer review, and the need for harmonization between translations.ResultsSimilar to findings in the Swedish-German cognitive debriefing, the cross-cultural analysis of input from 116 parents from 12 new countries (4-14 parents, median 9 parents/country) showed that all items in the EA-QOL questionnaire fulfilled the criteria for item clarity >= 80% and sensitive to answer (ranging from 1%-4.5%), although results varied between countries. Four items had missing responses between 5.2% and 13.4%, three within the same domain and were in line with parents' explanations. Poor translations and feasibility were improved.ConclusionsBased on parent input, the collaboration between native experts, patient stakeholders, and instrument developers, a linguistic version of the EA-QOL questionnaire for children aged 2-7 for use in and across 14 countries has been established. These efforts have set the conditions for a cross-cultural field test of the EA-QOL questionnaire and will open the doors for a new chapter in outcome research, registries, and clinical practice concerning children with EA. In the long-term, this will help increase knowledge of the disease's burden, promote patient-centeredness, exchange of information between nations, and strengthen evidence-based treatments for children born with EA.
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| 17. |
- Espersen, A. D. L., et al.
(författare)
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Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is associated with infancy and trisomy 19: Data from Nordic Society for Pediatric Hematology and Oncology (NOPHO-AML) and review of the literature
- 2018
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Ingår i: Genes Chromosomes & Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 57:7, s. 359-365
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Tidskriftsartikel (refereegranskat)abstract
- The t(7;12)(q36;p13) (MNX1/ETV6) is not included in the WHO classification but has been described in up to 30% of acute myeloid leukemia (AML) in children <2 years and associated with a poor prognosis. We present the clinical and cytogenetics characteristics of AML cases with t(7;12)(p36;p13). A literature review identified 35 patients with this translocation, published between 2000 and 2015. Outcome data were available in 22 cases. The NOPHO-AML (Nordic Society for Pediatric Hematology and Oncology) database contained 651 patients with AML from 1993 to 2014 and seven (1.1%) had the translocation. The t(7;12) was only present in patients <2 years of age (median age 6 months) but none was diagnosed as newborn. These patients constituted 4.3% of the patients <2 years of age. There was a strong association with trisomy 19 (literature: 86%, NOPHO: 100%) and +8 (literature: 19%, NOPHO: 14%). Seventeen of 22 patients from the literature with t(7;12) and four of seven patients from the NOPHO database suffered from relapse. The patients with t(7;12) had a 3-year event free survival of 24% (literature) vs. 43% (NOPHO) and a 3-year overall survival of 42% (literature) vs. 100% (NOPHO). None of the NOPHO patients was treated with hematopoietic stem cell transplantation (HSCT) in first complete remission. Relapse was frequent but the salvage rate using HSCT was high. We conclude that t(7;12)(q36;13) is a unique subgroup of childhood AML with presentation before 2 years of age with most cases being associated with +19.
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| 18. |
- Fantini, R, et al.
(författare)
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EU FP7 INFSO-ICT-317669 METIS, D3.2 First performance results for multi-node/multi-antenna transmission technologies
- 2014
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This deliverable describes the current results of the multi-node/multi-antenna technologies investigated within METIS and analyses the interactions within and outside Work Package 3. Furthermore, it identifies the most promising technologies based on the current state of obtained results. This document provides a brief overview of the results in its first part. The second part, namely the Appendix, further details the results, describes the simulation alignment efforts conducted in the Work Package and the interaction of the Test Cases. The results described here show that the investigations conducted in Work Package 3 are maturing resulting in valuable innovative solutions for future 5G systems.
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| 19. |
- Huang, Ping, et al.
(författare)
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Photo-induced oxidation of a dinuclear Mn-2(II,II) complex to the Mn-2(III,IV) state by inter- and intramolecular electron transfer to Ru-III tris-bipyridine
- 2002
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Ingår i: Journal of Inorganic Biochemistry. - 0162-0134 .- 1873-3344. ; 91:1, s. 159-172
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Tidskriftsartikel (refereegranskat)abstract
- To model the structural and functional parts of the water oxidizing complex in Photosystem 11, a dimeric manganese(II,11) complex (1) was linked to a ruthenium(II)tris-bipyridine (Ru-II(bpy)3) complex via a substituted L-tyrosine, to form the trinuclear complex 2 [J. Inorg. Biochem. 78 (2000) 15]. Flash photolysis of 1 and Ru-II(bpy), in aqueous solution, in the presence of an electron acceptor, resulted in the stepwise extraction of three electrons by Ru-III(bpy), from the Mn-2(II,II) dimer, which then attained the Mn-2(III,IV) oxidation state. In a similar experiment with compound 2, the dinuclear Mn complex reduced the photo-oxidized Ru moiety via intramolecular electron transfer on each photochemical event. From EPR it was seen that 2 also reached the Mn-2(III,IV) state. Our data indicate that oxidation from the Mn-2(II,II) state proceeds stepwise via intermediate formation of Mn-2(II,III) and Mn-2(III,III). In the presence of water, cyclic voltammetry showed an additional anodic peak beyond Mn-2(II,III/III,III) oxidation which was significantly lower than in neat acetonitrile. Assuming that this peak is due to oxidation to Mn-2(III,IV), this suggests that water is essential for the formation of the Mn-2(III,IV) oxidation state. Compound 2 is a structural mimic of the water oxidizing complex, in that it links a Mn complex via a tyrosine to a highly oxidizing photosensitizer. Complex 2 also mimics mechanistic aspects of Photosystem 11, in that the electron transfer to the photosensitizer is fast and results in several electron extractions from the Mn moiety.
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| 20. |
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| 21. |
- Krali, Olga, et al.
(författare)
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Dna methylation signatures predict cytogenetic subtype and outcome in pediatric acute myeloid leukemia (Aml)
- 2021
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Ingår i: Genes. - : MDPI AG. - 2073-4425. ; 12:6
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Tidskriftsartikel (refereegranskat)abstract
- Pediatric acute myeloid leukemia (AML) is a heterogeneous disease composed of clinically relevant subtypes defined by recurrent cytogenetic aberrations. The majority of the aberrations used in risk grouping for treatment decisions are extensively studied, but still a large proportion of pediatric AML patients remain cytogenetically undefined and would therefore benefit from additional molecular investigation. As aberrant epigenetic regulation has been widely observed during leukemogenesis, we hypothesized that DNA methylation signatures could be used to predict molecular subtypes and identify signatures with prognostic impact in AML. To study genome-wide DNA methylation, we analyzed 123 diagnostic and 19 relapse AML samples on Illumina 450k DNA methylation arrays. We designed and validated DNA methylation-based classifiers for AML cytogenetic subtype, resulting in an overall test accuracy of 91%. Furthermore, we identified methylation signatures associated with outcome in t(8;21)/RUNX1-RUNX1T1, normal karyotype, and MLL/KMT2A-rearranged subgroups (p < 0.01). Overall, these results further underscore the clinical value of DNA methylation analysis in AML. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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| 24. |
- Ringlander, Johan, et al.
(författare)
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Enrichment Reveals Extensive Integration of Hepatitis B Virus DNA in Hepatitis Delta Virus-Infected Patients
- 2024
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Ingår i: JOURNAL OF INFECTIOUS DISEASES. - 0022-1899 .- 1537-6613.
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Tidskriftsartikel (refereegranskat)abstract
- Background. Hepatitis B virus (HBV) DNA may become integrated into the human genome of infected human hepatocytes. Expression of integrations can produce the surface antigen (HBsAg) that is required for synthesis of hepatitis D virus (HDV) particles and the abundant subviral particles in the blood of HBV- and HDV-infected subjects. Knowledge about the extent and variation of HBV integrations and impact on chronic HDV is still limited. Methods. We investigated 50 pieces of liver explant tissue from 5 patients with hepatitis D-induced cirrhosis, using a deep-sequencing strategy targeting HBV RNA. Results. We found that integrations were abundant and highly expressed, with large variation in the number of integration-derived (HBV/human chimeric) reads, both between and within patients. The median number of unique integrations for each patient correlated with serum levels of HBsAg. However, most of the HBV reads represented a few predominant integrations. Conclusions. The results suggest that HBV DNA integrates in a large proportion of hepatocytes, and that the HBsAg output from these integrations vary >100-fold depending on clone size and expression rate. A small proportion of the integrations seems to determine the serum levels of HBsAg and HDV RNA in HBV/HDV coinfected patients with liver cirrhosis.
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| 25. |
- Schleiermacher, G., et al.
(författare)
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Emergence of New ALK Mutations at Relapse of Neuroblastoma
- 2014
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 32:25, s. 2727-2734
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Tidskriftsartikel (refereegranskat)abstract
- Purpose In neuroblastoma, the ALK receptor tyrosine kinase is activated by point mutations. We investigated the potential role of ALK mutations in neuroblastoma clonal evolution. We analyzed ALK mutations in 54 paired diagnosis-relapse neuroblastoma samples using Sanger sequencing. When an ALK mutation was observed in one paired sample, a minor mutated component in the other sample was searched for by more than 100,000 x deep sequencing of the relevant hotspot, with a sensitivity of 0.17%. All nine ALK-mutated cases at diagnosis demonstrated the same mutation at relapse, in one case in only one of several relapse nodules. In five additional cases, the mutation seemed to be relapse specific, four of which were investigated by deep sequencing. In two cases, no mutation evidence was observed at diagnosis. In one case, the mutation was present at a subclonal level (0.798%) at diagnosis, whereas in another case, two different mutations resulting in identical amino acid changes were detected, one only at diagnosis and the other only at relapse. Further evidence of clonal evolution of ALK-mutated cells was provided by establishment of a fully ALK-mutated cell line from a primary sample with an ALK-mutated cell population at subclonal level (6.6%). In neuroblastoma, subclonal ALK mutations can be present at diagnosis with subsequent clonal expansion at relapse. Given the potential of ALK-targeted therapy, the significant spatiotemporal variation of ALK mutations is of utmost importance, highlighting the potential of deep sequencing for detection of subclonal mutations with a sensitivity 100-fold that of Sanger sequencing and the importance of serial samplings for therapeutic decisions.
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| 26. |
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| 27. |
- Tulstrup, M., et al.
(författare)
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Effects of germ line DHFR and FPGS variants on methotrexate metabolism and relapse of leukemia
- 2020
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 136:10, s. 1161-1168
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Tidskriftsartikel (refereegranskat)abstract
- Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 x 10(-8)) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 x 10(-9)) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.
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| 28. |
- Tulstrup, M., et al.
(författare)
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NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia
- 2018
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 32:12, s. 2527-2535
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Tidskriftsartikel (refereegranskat)abstract
- The antileukaemic drug 6-mercaptopurine is converted into thioguanine nucleotides (TGN) and incorporated into DNA (DNA-TG), the active end metabolite. In a series of genome-wide association studies, we analysed time-weighted means ((wm)) of erythrocyte concentrations of TGN (Ery-TGN) and DNA-TG in 1009 patients undergoing maintenance therapy for acute lymphoblastic leukaemia (ALL). In discovery analyses (454 patients), the propensity for DNA-TG incorporation ((wm)DNA-TG/(wm)Ery-TGN ratio) was significantly associated with three intronic SNPs in NT5C2 (top hit: rs72846714; P - 2.09 x 10(-10), minor allele frequency 15%). In validation analyses (555 patients), this association remained significant during both early and late maintenance therapy (P - 8.4 x 10(-6) and 1.3 x 10(-3), respectively). The association was mostly driven by differences in (wm)Ery-TGN, but in regression analyses adjusted for wmEry-TGN (P < 0.0001), rs72846714-A genotype was also associated with a higher (wm)DNA-TG (P - 0.029). Targeted sequencing of NT5C2 did not identify any missense variants associated with rs72846714 or (wm)Ery-TGN/(wm)DNA-TG. rs72846714 was not associated with relapse risk, but in a separate cohort of 180 children with relapsed ALL, rs72846714-A genotype was associated with increased occurrence of relapse-specific NT5C2 gain-of-function mutations that reduce cytosol TGN levels (P = 0.03). These observations highlight the impact of both germline and acquired mutations in drug metabolism and disease trajectory.
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| 29. |
- White, T., et al.
(författare)
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Clinical outcomes of second relapsed and refractory first relapsed paediatric AML: A retrospective study within the NOPHO-DB SHIP consortium
- 2022
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 197:6, s. 755-765
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Tidskriftsartikel (refereegranskat)abstract
- As treatments for second relapsed and refractory first relapsed paediatric AML transition from purely palliative to more commonly curative in nature, comparative data is necessary for evaluating the effectiveness of emerging treatment options. Furthermore, little is known about predictors of prognosis following third-line therapy. From 2004 until 2019, 277 of the 869 patients enrolled in NOPHO-DB SHIP consortium trials experienced a first relapse and, of these patients, 98 experienced refractory first relapse and 59 a second relapse. Data on patient and disease characteristics within this cohort of 157 patients was analysed to determine probability of overall survival (pOS) and to identify factors influencing survival. Data on early treatment response and complete remission were not available. One and 5-year pOS were 22±3% and 14±3%, respectively. There was no statistically significant difference in survival between refractory first relapsed and second relapsed AML. Factors influencing prognosis included: late relapse, type of third-line treatment, FLT3 mutational status, and original treatment protocol. These data provide a baseline for evaluating the effectiveness of emerging therapies for the treatment of children with refractory first relapsed and second relapsed paediatric AML and evidence that select patients receiving third-line therapy can be cured. © 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
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| 30. |
- Aapro, M, et al.
(författare)
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Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel
- 2008
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Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 19:3, s. 420-432
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Tidskriftsartikel (refereegranskat)abstract
- Bisphosphonates (BP) prevent, reduce, and delay cancer-related skeletal complications in patients, and have substantially decreased the prevalence of such events since their introduction. Today, a broad range of BP with differences in potency, efficacy, dosing, and administration as well as approved indications is available. In addition, results of clinical trials investigating the efficacy of BP in cancer treatment-induced bone loss (CTIBL) have been recently published. The purpose of this paper is to review the current evidence on the use of BP in solid tumours and provide clinical recommendations. An interdisciplinary expert panel of clinical oncologists and of specialists in metabolic bone diseases assessed the widespread evidence and information on the efficacy of BP in the metastatic and nonmetastatic setting, as well as ongoing research on the adjuvant use of BP. Based on available evidence, the panel recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for patients with other solid tumours as primary disease. Dosing of BP should follow approved indications with adjustments if necessary. While i.v. administration is most often preferable, oral administration (clodronate, IBA) may be considered for breast cancer patients who cannot or do not need to attend regular hospital care. Early-stage cancer patients at risk of developing CTIBL should be considered for preventative BP treatment. The strongest evidence in this setting is now available for ZOL. Overall, BP are well-tolerated, and most common adverse events are influenza-like syndrome, arthralgia, and when used orally, gastrointestinal symptoms. The dose of BP may need to be adapted to renal function and initial creatinine clearance calculation is mandatory according to the panel for use of any BP. Subsequent monitoring is recommended for ZOL and PAM, as described by the regulatory authority guidelines. Patients scheduled to receive BP (mainly every 3-4 weeks i.v.) should have a dental examination and be advised on appropriate measures for reducing the risk of jaw osteonecrosis. BP are well established as supportive therapy to reduce the frequency and severity of skeletal complications in patients with bone metastases from different cancers.
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| 31. |
- Abbatt, J. P. D., et al.
(författare)
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Halogen activation via interactions with environmental ice and snow in the polar lower troposphere and other regions
- 2012
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Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 12:14, s. 6237-6271
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Tidskriftsartikel (refereegranskat)abstract
- The role of ice in the formation of chemically active halogens in the environment requires a full understanding because of its role in atmospheric chemistry, including controlling the regional atmospheric oxidizing capacity in specific situations. In particular, ice and snow are important for facilitating multiphase oxidative chemistry and as media upon which marine algae live. This paper reviews the nature of environmental ice substrates that participate in halogen chemistry, describes the reactions that occur on such substrates, presents the field evidence for ice-mediated halogen activation, summarizes our best understanding of ice-halogen activation mechanisms, and describes the current state of modeling these processes at different scales. Given the rapid pace of developments in the field, this paper largely addresses advances made in the past five years, with emphasis given to the polar boundary layer. The integrative nature of this field is highlighted in the presentation of work from the molecular to the regional scale, with a focus on understanding fundamental processes. This is essential for developing realistic parameterizations and descriptions of these processes for inclusion in larger scale models that are used to determine their regional and global impacts.
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| 32. |
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| 33. |
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- Abrahamsson, B., et al.
(författare)
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Six years of progress in the oral biopharmaceutics area - A summary from the IMI OrBiTo project
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : ELSEVIER. - 0939-6411 .- 1873-3441. ; 152, s. 236-247
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Tidskriftsartikel (refereegranskat)abstract
- OrBiTo was a precompetitive collaboration focused on the development of the next generation of Oral Biopharmaceutics Tools. The consortium included world leading scientists from nine universities, one regulatory agency, one non-profit research organisation, three small/medium sized specialist technology companies together with thirteen pharmaceutical companies. The goal of the OrBiTo project was to deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This goal was achieved through novel prospective investigations to define new methodologies or refinement of existing tools. Extensive validation has been performed of novel and existing biopharmaceutics tools using historical datasets supplied by industry partners as well as laboratory ring studies. A combination of high quality in vitro and in vivo characterizations of active drugs and formulations have been integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of gastrointestinal drug absorption and some of the best practices has been highlighted. This approach has given an unparalleled opportunity to deliver transformational change in European industrial research and development towards model based pharmaceutical product development in accordance with the vision of model-informed drug development.
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| 38. |
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| 39. |
- Abrahamsson, Christoffer, et al.
(författare)
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Scatter correction of transmission near-infrared spectra by photon migration data: Quantitative analysis of solids
- 2005
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Ingår i: Applied Spectroscopy. - 1943-3530. ; 59:11, s. 1381-1387
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Tidskriftsartikel (refereegranskat)abstract
- The scope of this work is a new methodology to correct conventional near-infrared (NIR) data for scattering effects. The technique aims at measuring the absorption coefficient of the samples rather than the total attenuation measured in conventional NIR spectroscopy. The main advantage of this is that the absorption coefficient is independent of the path length of the light inside the sample and therefore independent of the scattering effects. The method is based on time-resolved spectroscopy and modeling of light transport by diffusion theory. This provides an independent measure of the scattering properties of the samples and therefore of the path length of light. This yields a clear advantage over other preprocessing techniques, where scattering effects are estimated and corrected for by using the shape of the measured spectrum only. Partial least squares (PLS) calibration models show that, by using the proposed evaluation scheme, the predictive ability is improved by 50% as compared to a model based on conventional NIR data alone. The method also makes it possible to predict the concentration of active substance in samples with other physical properties than the samples included in the calibration model.
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| 40. |
- Abrahamsson, Hans, 1966, et al.
(författare)
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Pulsed Hot-Wire Measurements in Two- and Three-Dimensional Wall Jets
- 1999
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Ingår i: Experiments in Fluids. ; 27, s. 210-218
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Tidskriftsartikel (refereegranskat)abstract
- Pulsed Hot-Wire Anemometry (PHWA) measurements are performed in well defined two- and three-dimensional turbulent wall jets. For the two-dimensional wall jet the objective is to study reported differences between conventional Hot-Wire Anemometry (HWA) and Laser Doppler Anemometry (LDA) results. In the three-dimensional wall jet, new improved data are provided, employing a measuring technique suitable for highly turbulent flows. This, since only hot-wire results previously have been published for this flow. The pulsed wire results show good agreement with existing Laser Doppler anemometer data in the two-dimensional wall jet, both reporting significantly higher turbulence levels in the outer region of the flow than hot-wires do. The hot-wire anemometer errors generally increase with increasing local turbulence intensity and since the three-dimensional wall jet has a higher turbulence level than its two-dimensional equivalent, the new pulsed hot-wire results improve the information available for the turbulence field in this flow significantly.
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| 41. |
- Abrahamsson, Kate, 1959, et al.
(författare)
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Impaired ketogenesis in carnitine depletion caused by short-term administration of pivalic acid prodrug.
- 1994
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Ingår i: Biochemical medicine and metabolic biology. - : Elsevier BV. - 0885-4505. ; 52:1, s. 18-21
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Tidskriftsartikel (refereegranskat)abstract
- Long-term treatment with pivalic acid prodrug results in impaired ketone-body production. Therefore, it was of interest to investigate whether short-term treatment had any influence on the fatty acid oxidation. In this study six healthy males were given 1200 mg per day of pivmecillinam for 12 days to induce carnitine deficiency. The concentration of free carnitine in serum was reduced from a mean of 42.8 mumol/liter (range, 31-48) to 11.6 mumol/liter (range, 7.0-24), but the muscle carnitine concentration was not reduced. A 36-h fasting test was performed before and after drug administration to study the effect on ketone-body production. After treatment, the two subjects with the lowest level of serum free carnitine at the end of the fasting period had impaired ketogenesis. This indicates a carnitine deficiency in the liver which was reflected in the free carnitine concentration for by mobilization of muscle carnitine. We conclude that there is a substantial risk to develop carnitine deficiency and impaired fatty acid oxidation in the liver during short-term treatment with drugs conjugated with pivalic acid.
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| 42. |
- Abrahamsson, Kate, 1959, et al.
(författare)
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Pivalic acid-induced carnitine deficiency and physical exercise in humans.
- 1996
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Ingår i: Metabolism: clinical and experimental. - : Elsevier BV. - 0026-0495. ; 45:12, s. 1501-7
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Tidskriftsartikel (refereegranskat)abstract
- To study the effect of carnitine depletion on physical working capacity, healthy subjects were administered pivaloyl-conjugated antibiotics for 54 days. The mean carnitine concentration in serum decreased from 35.0 to 3.5 mmicromol/L, and in muscle from 10 to 4.3 micromol/g noncollagen protein (NCP). Exercise tests were performed before and after 54 days' administration of the drug. At submaximal exercise, there was a slight increase in the concentration of 3-hydroxybutyrate in serum, presumably caused by decreased fatty acid oxidation in the liver. There was also a decreased consumption of muscle glycogen, indicating decreased glycolysis in the skeletal muscle. The muscle presumably had enough energy available, since there was no significant decrease in the concentration of adenosine triphosphate (ATP) and creatine phosphate during exercise. The work at maximal oxygen uptake (VO2max) and the maximal heart rate were reduced. Since VO2max is considered dependent on heart function, carnitine depletion seemed to affect cardiac function.
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| 43. |
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| 44. |
- Abrahamsson, Kate, 1959, et al.
(författare)
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Transient reduction of human left ventricular mass in carnitine depletion induced by antibiotics containing pivalic acid.
- 1995
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Ingår i: British heart journal. - : BMJ. - 0007-0769. ; 74:6, s. 656-9
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Tidskriftsartikel (refereegranskat)abstract
- To study the effect of induced carnitine depletion on myocardial structure and function.7 healthy adult volunteers given 1200 mg pivmecillinam per day for 7-8 weeks were studied by echocardiography before and after 7-8 weeks of treatment and a 15 months follow up after the treatment period.Teaching hospital.Carnitine concentration in serum, urine, and muscle and echocardiographic measurements.After 7-8 weeks of treatment the median free serum carnitine concentration was reduced to 7% and the median total muscle carnitine concentration to 46% of the pretreatment levels. The median diastolic interventricular septum thickness decreased by 14% (mean 26%, P = 0.028) and the median left ventricular mass by 10% (mean 20%, P = 0.018). Fifteen months later these dimensions had increased but not completely returned to pretreatment values.Extended treatment with pivalic acid containing antibiotics causes carnitine depletion which may lead to changes in cardiac structure.
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| 45. |
- Abrahamsson, L., et al.
(författare)
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Behöver arbetslinjen inte forskning?
- 2007
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Ingår i: Svenska Dagbladet Brännpunkt (debattinlägg). ; :2007-11-28
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 46. |
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| 47. |
- Abrahamsson, M., et al.
(författare)
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Changes of visual function and visual ability in daily life following cataract surgery
- 2009
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Ingår i: Acta Ophthalmologica Scandinavica. - : Blackwell Publishing. - 1395-3907 .- 1600-0420. ; 74:1, s. 69-73
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a prospective study of 56 patients aged 70 to 79 years undergoing cataract surgery, in order to determine the impact of surgery on subjective and objective measurements of visual ability. In 46 cases we could obtain all necessary data. Binocular visual acuity, near vision and contrast sensitivity improved due to surgery. Self-assessed ability to perform visually related tasks was examined in form of a questionnaire. The results show that there was no simple relationship between objective measurements and perceived visual ability. An impairment in preoperative visual acuity cannot be related to a specific loss of visual ability. In order to increase the quality of cataract surgery more subtly, subjective aspects of vision must be taken into consideration when operation is decided upon and in the evaluation of the results.
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| 48. |
- Abrahamsson, Maria, 1975, et al.
(författare)
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High Extinction Coefficient Ru-Sensitizers that Promote Hole Transfer on Nanocrystalline TiO2
- 2014
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Ingår i: ChemPhysChem. - : Wiley. - 1439-7641 .- 1439-4235. ; 15:6, s. 1154-1163
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Tidskriftsartikel (refereegranskat)abstract
- Two series of Ru-II polypyridyl compounds with formulas [(bpy)(2)RuL](PF6)(2) and [(deeb)(2)RuL](PF6)(2), where bpy is 2,2-bipyridine, deeb is 4,4-diethylester-2,2-bpy, and L is one of several substituted 9-(1,3-dithiole-2-ylidene)-4,5-diazafluorene ligands, were studied as potential photosensitizers for TiO2. These compounds possess notably high extinction coefficients (40000M(-1)cm(-1) @470 nm) which are shown by time-dependent density functional theory (TD-DFT) calculations to result from overlapping metal-to-ligand charge transfer (MLCT) and ligand-localized transitions. Low-temperature absorption and photoluminescence measurements were suggestive of a short-lived MLCT excited state. When adsorbed onto TiO2 thin films, both the free ligands (L) and their corresponding [(deeb)(2)RuL](2+) complexes exhibited rapid excited-state electron injection into TiO2; in the case of the complexes, this was followed by rapid (k>10(8) s(-1)) hole transfer from Ru-III to the 1,3-dithiole ring of the L ligand. Observation of diffusion-limited reductive quenching of the [Ru(bpz)(3)](2+)* (bpz is 2,2-bipyrazine) excited state by the L ligands in solution supported the occurrence of intramolecular hole transfer following electron injection by the TiO2-anchored complexes.
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| 49. |
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| 50. |
- Abrahamsson, M. L. A., et al.
(författare)
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Ruthenium-manganese complexes for artificial photosynthesis : Factors controlling intramolecular electron transfer and excited-state quenching reactions
- 2002
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Ingår i: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 41:6, s. 1534-1544
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Tidskriftsartikel (refereegranskat)abstract
- Continuing our work toward a system mimicking the electron-transfer steps from manganese to P-680(+) in photosystem II (PS II), we report a series of ruthenium(II)-manganese(II) complexes that display intramolecular electron transfer from manganese(II) to photooxidized ruthenium(III). The electron-transfer rate constant (k(ET)) values span a large range, 1 X 10(5)-2 x 10(7) s(-1), and we have investigated different factors that are responsible for the variation. The reorganization energies determined experimentally (lambda = 1.5-2.0 eV) are larger than expected for solvent reorganization in complexes of similar size in polar solvents (typically lambda approximate to 1.0 eV). This result indicates that the inner reorganization energy is relatively large and, consequently, that at moderate driving force values manganese complexes are not fast donors. Both the type of manganese ligand and the link between the two metals are shown to be of great importance to the electron-transfer rate. In contrast, we show that the quenching of the excited state of the ruthenium(II) moiety by manganese(II) in this series of complexes mainly depends on the distance between the metals. However, by synthetically modifying the sensitizer so that the lowest metal-to-ligand charge transfer state was localized on the nonbridging ruthenium(II) ligands, we could reduce the quenching rate constant in one complex by a factor of 700 without changing the bridging ligand. Still, the manganese(II)-ruthenium (III) electrontransfer rate constant was not reduced. Consequently, the modification resulted in a complex with very favorable properties.
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