| 61. |
- Linder, Adam, et al.
(författare)
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Erysipelas Caused by Group A Streptococcus Activates the Contact System and Induces the Release of Heparin-Binding Protein.
- 2010
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 1523-1747 .- 0022-202X. ; 130, s. 1365-1372
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial skin infections, such as erysipelas or cellulitis, are characterized by fever and a painful erythematous rash. Despite the high prevalence of these infections, little is known about the underlying pathogenic mechanisms. This is partly due to the fact that a bacterial diagnosis is often difficult to attain. To gain insight into the pathogenesis of erysipelas, we investigated the samples obtained from infected and noninfected areas of skin from 12 patients with erysipelas. Bacterial cultures, detection of specific streptococcal antibodies in convalescent sera, and immunohistochemical analyses of biopsies indicated group A streptococcal etiology in 11 of the 12 patients. Also, electron micrographs of erythematous skin confirmed the presence of group A streptococcal cells and showed a limited solubilization of the surface-attached M protein. Degradation of high-molecular-weight kininogen and upregulation of the bradykinin-1 receptor in inflamed tissues indicated activation of the contact system in 11 patients. Analyses of release of the vasoactive heparin-binding protein (HBP) showed increased levels in the infected as compared with the noninfected areas. The results suggest that group A streptococci induce contact activation and HBP release during skin infection, which likely contribute to the symptoms seen in erysipelas: fever, pain, erythema, and edema.Journal of Investigative Dermatology advance online publication, 28 January 2010; doi:10.1038/jid.2009.437.
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| 62. |
- Lundin, Catarina, et al.
(författare)
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Clinical and genetic features of pediatric acute lymphoblastic leukemia in Down syndrome in the Nordic countries
- 2014
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Ingår i: Journal of Hematology & Oncology. - : Springer Science and Business Media LLC. - 1756-8722. ; 7, s. 32-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Children with Down syndrome (DS) have an increased risk for acute lymphoblastic leukemia (ALL). Although previous studies have shown that DS-ALL differs clinically and genetically from non-DS-ALL, much remains to be elucidated as regards genetic and prognostic factors in DS-ALL. Methods: To address clinical and genetic differences between DS-ALL and non-DS-ALL and to identify prognostic factors in DS-ALL, we ascertained and reviewed all 128 pediatric DS-ALL diagnosed in the Nordic countries between 1981 and 2010. Their clinical and genetic features were compared with those of the 4,647 B-cell precursor (BCP) ALL cases diagnosed during the same time period. Results: All 128 DS-ALL were BCP ALL, comprising 2.7% of all such cases. The 5-year event-free survival (EFS) and overall survival (OS) were significantly (P = 0.026 and P = 0.003, respectively) worse for DS-ALL patients with white blood cell counts >= 50 x 10(9)/l. The age distributions varied between the DS and non-DS cases, with age peaks at 2 and 3 years, respectively; none of the DS patients had infant ALL (P = 0.029). The platelet counts were lower in the DS-ALL group (P = 0.005). Abnormal karyotypes were more common in non-DS-ALL (P < 0.0001), and there was a significant difference in the modal number distribution, with only 2% high hyperdiploid DS-ALL cases (P < 0.0001). The 5-year EFS and 5-year OS were significantly worse for DS-ALL (0.574 and 0.691, respectively) compared with non-DS-ALL (0.783 and 0.894, respectively) in the NOPHO ALL-1992/2000 protocols (P < 0.001). Conclusions: The present study adds further support for genetic and clinical differences between DS-ALL and non-DS-ALL.
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| 63. |
- Lundin, Catarina, et al.
(författare)
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High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome
- 2012
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Ingår i: Genes, Chromosomes and Cancer. - Malden : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 51:2, s. 196-206
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Tidskriftsartikel (refereegranskat)abstract
- Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as less than10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrentdup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent.
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| 64. |
- Lundin, Catarina, et al.
(författare)
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Submicroscopic genomic imbalances in burkitt lymphomas/leukemias : Association with age and further evidence that 8q24/MYC translocations are not sufficient for leukemogenesis
- 2013
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 52:4, s. 370-377
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Tidskriftsartikel (refereegranskat)abstract
- Chromosome banding analyses reveal secondary chromosome abnormalities in addition to the MYC translocations t(8;14)(q24;q32), t(8;22)(q24;q11), and t(2;8)(p11;q24) in 60%80% of Burkitt lymphomas/leukemias (BL). The high incidence of such aberrations indicates that additional changes are important, perhaps necessary, for malignant transformation, i.e., the 8q24/MYC rearrangements may not be sufficient. To investigate this possibility, we performed single nucleotide polymorphism (SNP) array analysis on 20 cases of 8q24/MYC-positive BL. Nineteen (95%) harbored genomic imbalances; the only case without such aberrations displayed secondary changes by chromosome banding analysis. Thus, all BL cases had abnormalities in addition to the 8q24 translocation. The adult cases harbored more changes (median 3; range 121) than did the childhood cases (median 1.5; range 05) (P = 0.034). Several recurrent aberrations were detected by SNP array analysis, in particular losses of 6q14.1-q22.33, 9p21.3, and 13q14.2-q14.3, gains of 1q23.3-q31.3, chromosome 7, 13q31.3, and partial uniparental isodisomies for 6p12.2-pter, 9p23-pter, and 17p11.2-pter. The molecular genetic consequences of these changes include deletions of the CDKN2A and TP53 genes, and gains/losses of several genes, such as MIR17HG and E2F2K, involved in the MYC pathway. Thus, deregulation of the MYC pathway, both directly through the 8q24/MYC translocation and indirectly through secondary genomic imbalances, may be essential not only for the initiation but also for the progression of BL.
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| 65. |
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| 66. |
- Lundin, Kristina, et al.
(författare)
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Patterns and Frequencies of Acquired and Constitutional Uniparental Isodisomies in Pediatric and Adult B-Cell Precursor Acute Lymphoblastic Leukemia.
- 2016
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 55:5, s. 472-479
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Tidskriftsartikel (refereegranskat)abstract
- Single nucleotide polymorphism (SNP) arrays are increasingly being used in clinical routine for genetic analysis of pediatric B-cell precursor acute lymphoblastic leukemias (BCP ALL). Because constitutional DNA is not readily available as a control at the time of diagnosis, it is important to be able to distinguish between acquired and constitutional aberrations in a diagnostic setting. In the present study we focused on uniparental isodisomies (UPIDs). SNP array analyses of 143 pediatric and 38 adult B-cell precursor acute lymphoblastic leukemias and matched remission samples revealed acquired whole chromosome or segmental UPIDs (wUPIDs, sUPIDs) in 32 cases (18%), without any age- or gender-related frequency differences. Acquired sUPIDs were larger than the constitutional ones (mean 35.3 Mb vs. 10.7 Mb; P<0.0001) and were more often terminally located in the chromosomes (69% vs. 4.5%; P<0.0001). Chromosomes 3, 5, and 9 were most often involved in acquired wUPIDs, whilst recurrent acquired sUPIDs targeted 6p, 9p, 9q, and 14q. The majority (56%) of sUPID9p was associated with homozygous CDKN2A deletions. In pediatric ALL, all wUPIDs were found in high hyperdiploid (51-67 chromosomes) cases and an extended analysis, also including unmatched diagnostic samples, revealed a higher frequency of wUPID-positivity in higher modal number (56-67 chromosomes) than in lower modal number (51-55 chromosomes) high hyperdiploid cases (34% versus 11%; P=0.04), suggesting different underlying mechanisms of formation of these subtypes of high hyperdiploidy. This article is protected by copyright. All rights reserved.
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| 67. |
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| 68. |
- Lövenheim, Boel, et al.
(författare)
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Health risk assessment of reduced air pollution exposure when changing commuting by car to bike
- 2016
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Konferensbidrag (refereegranskat)abstract
- In this study we have assessed the reduction in traffic emissions and population exposure assuming all potential car commuters would switch to biking if they live within 30 minute travel by bike. The scenario would result in more than 100 000 new bikers and due to the reduced traffic emissions 42 premature deaths would be avoided per year. This is almost twice as large effect as the congestion tax in Stockholm. Introduction Regular physical activity has important and wide-ranging health benefits including reduced risk of chronic disease, and physical inactivity is mentioned as perhaps the most important public health problem of the 21st century. At the same time, the direct effects of traffic emissions is a major health problem. Transferring commuting by car to bike will increase physical activity and reduce emissions and reduce population exposure to traffic pollution. The exposure of commuters will also change; new bikers may get higher exposure whilst old bikers and car drivers may get lower exposures, depending on commuting route and distance. Methodology In this study we have calculated the potential number of car-to-bike switching commuters depending on distance, travel time, age of commuters, etc. We have made calculations for a 30-minute biking scenario, i.e. transferring all car commuters to bike if their travel time by bike is less than or equal to 30 minutes. The commuting distance depends on age and sex. For the travel and traffic modelling the LuTrans model was used. It includes all different modes of travel; walking, bicycling, public transport systems and car traffic. The model was developed based on travel survey data and is regularly calibrated using traffic counts. Emissions from road traffic were calculated based on HBEFA 3.2. A Gaussian dispersion model was used estimate exposures over the county of Stockholm. Results The 30 min scenario resulted in 106 881 more bikers, an increase of 2.6 times compared to base scenario. Of all bikers 50% were men and the mean age of all bikers was 42. The traffic emissions of NOx was reduced by up to 7%. Up to 20% reduction in traffic contribution to NOx concentrations was calculated as shown in Figure 1. The mean reduction in concentration for the whole area is 6% and the largest occur were most people live.The population weighted mean NOx concentration for 1.6 million people in Greater Stockholm is estimated to be reduced by 0.41 μg m-3. Assuming that the premature mortality is reduced by 8% per 10 μg m-3 (Nafstad et al., 2004), this corresponds to 42 avoided premature deaths every year or 514 gained life years gained. This is even somewhat more beneficial than the effects of the congestion charge in Stockholm (Johansson et al., 2009), which was estimated to save 27 premature deaths per year. The gain in reduced mortality is almost as large as the gain in health of the increased physical activity. Conclusions Transferring car commuters to bike is not only beneficial for the physical activity, but will also lead to reduced traffic emissions and reduced population exposure. Our estimates show that it may be even more beneficial for mortality due to air pollution exposure than the congestion charge in Stockholm. Acknowledgement This project was funded by the Swedish Research Council for Health, Working life and Welfare. References Johansson, C., Burman, L., Forsberg, B. 2009. The effects of congestions tax on air quality and health. Atmos. Environ. 43, 4843-4854.Nafstad, P., Lund Håheim, L., Wisloeff, T., Gram, G., Oftedal, B., Holme, I., Hjermann, I. and Leren, P. 2004. Urban Air Pollution and Mortality in a Cohort of Norwegian Men. Environ. Health Perspect. 112, 610-615.
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| 69. |
- Mandahl, Nils, et al.
(författare)
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Disease-associated patterns of disomic chromosomes in hyperhaploid neoplasms.
- 2012
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 51:6, s. 536-544
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Tidskriftsartikel (refereegranskat)abstract
- The chromosome number of human tumors varies widely, from near-haploidy to more than decaploidy. Overt hyperhaploid (24-34 chromosomes) tumors constitute a small minority (0.2-0.3% of cytogenetically investigated lesions), but occur in many different disease entities. In these karyotypes, most chromosomes are present in one copy; one or a few chromosomes are disomic. Published reports on 141 strictly hyperhaploid tumors, supplemented with nine previously unpublished cases, were used for evaluating the pattern of disomic chromosomes. Only one tumor type, acute lymphoblastic leukemia (ALL), was sufficiently common (n = 75) to allow proper evaluation; other neoplasms were lumped together in as reasonably logical groups as possible, including 10 myeloid leukemias (ML), nine plasma cell neoplasms (PCN), 13 chondrosarcomas (CS), 11 soft tissue tumors (STT), nine adeno- or squamous cell carcinomas (ASC), and eight tumors of the nervous system (TNS); the remaining 15 tumors could not be grouped. It was evident that the pattern of disomies is nonrandom. Moreover, unique signatures for each tumor group were detected. Among ALL, most disomies were independent of age and gender, except for disomy 10, which was overrepresented in females. Chromosome 21 was invariably disomic, whereas chromosome 17 was always monosomic. The most frequent disomies were two gonosomes in ML, chromosomes 7, 9, 11, 3, 18, and 19 in PCN, 7, 5, 20, 19, and 21 in CS, 20 in STT, 7 in ASC, and 1, 7, and 9 in TNS. Chromosome 1 was often partially disomic, due to unbalanced structural rearrangements, with segment 1q21-31 in common. Doubling of the hyperhaploid clone was found in at least one-third of the cases, apart from in ML where only one of 10 cases showed chromosome doubling. The present findings indicate that retention of disomy for some chromosomes is pathogenetically important and that the chromosome(s) maintained in two copies is related to cell type or histological context. © 2012 Wiley Periodicals, Inc.
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| 70. |
- Margolskee, Alison, et al.
(författare)
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IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 2 : An introduction to the simulation exercise and overview of results
- 2017
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 96, s. 610-625
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Tidskriftsartikel (refereegranskat)abstract
- Orally administered drugs are subject to a number of barriers impacting bioavailability (F-oral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp (R), and GastroPlus (TM)) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters. Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exercise may not be representative of prospective modelling in industry, as API information was limited to sparse details. 43 active pharmaceutical ingredients (APIs) from the OrBiTo database were selected for the exercise. Over 4000 simulation output files were generated, representing over 2550 study arm-institution-software combinations and approximately 600 human clinical study arms simulated with overlap. 84% of the simulated study arms represented administration of immediate release formulations, 11% prolonged or delayed release, and 5% intravenous (i.v.). Higher percentages of i.v. predicted area under the curve (AUC) were within two-fold of observed (52.9%) compared to per oral (p.o.) (37.2%), however, F-oral and relative AUC (F-rel) between p.o. formulations and solutions were generally well predicted (64.7% and 75.0%). Predictive performance declined progressing from i.v. to solution and immediate release tablet, indicating the compounding error with each layer of complexity. Overall performance was comparable to previous large-scale evaluations. A general overprediction of AUC was observed with average fold error (AFE) of 1.56 over all simulations. AFE ranged from 0.0361 to 64.0 across the 43 APIs, with 25 showing overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms.
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