| 1. |
- Book, Frida, 1989, et al.
(författare)
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Ecotoxicity screening of seven different types of commercial silica nanoparticles using cellular and organismic assays : Importance of surface and size
- 2019
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Ingår i: NanoImpact. - : Elsevier BV. - 2452-0748. ; 13, s. 100-111
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Tidskriftsartikel (refereegranskat)abstract
- We show that seven different types of commercial, biocide-free, colloidal silica products with mean particle sizes between 17 and 88 nm with 3 different surface chemistries (Na-stabilized, aluminized and silane-modified) are not toxic to the bacterium Pseudomonas putida, and the algae Raphidocelis subcapitata in the concentration range 5–500 mg/L. They are also not acutely toxic to Daphnia magna at concentrations up to 10,000 mg/L. Six silica particles are toxic to the gill cell line RTgill-W1 from Rainbow trout (Oncorhynchus mykiss), showing a clear concentration-response relationship with EC50 values between 13 and 92 mg/L. Toxicity in the fish cells decreases with increasing hydrodynamic size and is dependent on particle surface area. The average EC50 across the tested particles is 2.1 (±0.3) m2/L. Surface modifications clearly impact toxicity, with silane-modified particles showing no cytotoxicity. The reduced number of free silanol groups on the surface of the silane modified particle, in combination with an increased steric hindrance that prevents contact with the cells is a possible mechanism for the observed lack of toxicity. This is also in line with previous studies on silica nanoparticles in human toxicology. Overall, these findings show a generally low ecotoxicity of silica nanoparticles and indicate that silica particles of different sizes but identical surface chemistry could potentially be grouped into an assessment group under regulation such as REACH.
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| 2. |
- Ekvall-Hansson, Eva, et al.
(författare)
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Stroke and unsteadiness - A cross-sectional study from primary health care.
- 2014
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Ingår i: NeuroRehabilitation. - 1878-6448. ; 34:2, s. 221-226
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Tidskriftsartikel (refereegranskat)abstract
- Dizziness is seldom the only symptom among patients who develop stroke but patients, hospitalized for vertigo are at higher risk of stroke than the general population. The proportions of patients who have remaining dizziness after a stroke seem to be unclear.
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| 3. |
- Ekvall, Mikael, et al.
(författare)
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Three-dimensional tracking of small aquatic organisms using fluorescent nanoparticles.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Tracking techniques are vital for the understanding of the biology and ecology of organisms. While such techniques have provided important information on the movement and migration of large animals, such as mammals and birds, scientific advances in understanding the individual behaviour and interactions of small (mm-scale) organisms have been hampered by constraints, such as the sizes of existing tracking devices, in existing tracking methods. By combining biology, chemistry and physics we here present a method that allows three-dimensional (3D) tracking of individual mm-sized aquatic organisms. The method is based on in-vivo labelling of the organisms with fluorescent nanoparticles, so-called quantum dots, and tracking of the organisms in 3D via the quantum-dot fluorescence using a synchronized multiple camera system. It allows for the efficient and simultaneous study of the behaviour of one as well as multiple individuals in large volumes of observation, thus enabling the study of behavioural interactions at the community scale. The method is non-perturbing - we demonstrate that the labelling is not affecting the behavioural response of the organisms - and is applicable over a wide range of taxa, including cladocerans as well as insects, suggesting that our methodological concept opens up for new research fields on individual behaviour of small animals. Hence, this offers opportunities to focus on important biological, ecological and behavioural questions never before possible to address.
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| 4. |
- Ekvall, Sara, et al.
(författare)
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Co-Occurring SHOC2 and PTPN11 Mutations in a Patient With Severe/Complex Noonan Syndrome-Like Phenotype
- 2011
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Ingår i: American Journal of Medical Genetics Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 155:6, s. 1217-1224
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Tidskriftsartikel (refereegranskat)abstract
- Noonan syndrome (NS) is a heterogeneous disorder caused by activating mutations in the RAS-MAPK signaling pathway. It is associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity, and typical facial features and the inheritance is autosomal dominant. Here, we present a clinical and molecular characterization of a patient with Noonan-like syndrome with loose anagen hair phenotype and additional features including mild psychomotor developmental delay, osteoporosis, gingival hyperplasia, spinal neuroblastoma, intrathoracic extramedullary hematopoiesis, and liver hemangioma. Mutation analysis of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, NRAS, and SHOC2 was conducted, revealing a co-occurrence of two heterozygous previously identified mutations in the index patient. The mutation SHOC2 c.4A> G; p.Ser2Gly represents a de novo mutation, whereas, PTPN11 c. 1226G>C; p.Gly409Ala was inherited from the mother and also identified in the brother. The mother and the brother present with some NS manifestations, such as short stature, delayed puberty, keratosis pilaris, cafe-au-lait spots, refraction error (mother), and undescended testis (brother), but no NS facial features, supporting the notion that the PTPN11 p. Gly409Ala mutation leads to a relatively mild phenotype. We propose that, the atypical phenotype of the young woman with NS reported here is an additive effect, where the PTPN11 mutation acts as a modifier. Interestingly, co-occurrence of RAS-MAPK mutations has been previously identified in a few patients with variable NS or neurofibromatosis-NS phenotypes. Taken together, the results suggest that co-occurrence of mutations or modifying loci in the RAS-MAPK pathway may contribute to the clinical variability observed among NS patients.
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| 5. |
- Ekvall, Sara, 1982-
(författare)
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Genetic and Clinical Investigation of Noonan Spectrum Disorders
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Noonan spectrum disorders belong to the RASopathies, a group of clinically related developmental disorders caused by dysregulation of the RAS-MAPK pathway. This thesis describes genetic and clinical investigations of six families with Noonan spectrum disorders.In the first family, the index patient presented with severe Noonan syndrome (NS) and multiple café-au-lait (CAL) spots, while four additional family members displayed multiple CAL spots only. Genetic analysis of four RAS-MAPK genes revealed a de novo PTPN11 mutation and a paternally inherited NF1 mutation, which could explain the atypically severe NS, but not the CAL spots trait in the family. The co-occurrence of two mutations was also present in another patient with a severe/complex NS-like phenotype. Genetic analysis of nine RASopathy-associated genes identified a de novo SHOC2 mutation and a maternally inherited PTPN11 mutation. The latter was also identified in her brother. Both the mother and the brother displayed mild phenotypes of NS. The results from these studies suggest that an additive effect of co-occurring mutations contributes to severe/complex NS phenotypes.The inherent difficulty in diagnosing Noonan spectrum disorders is evident in families with neurofibromatosis-Noonan syndrome (NFNS). An analysis of nine RASopathy-associated genes in a five-generation family with NFNS revealed a novel NF1 mutation in all affected family members. Notably, this family was initially diagnosed with NS and CAL spots. The clinical overlap between NS and NFNS was further demonstrated in three additional NFNS families. An analysis of twelve RASopathy-associated genes revealed three different NF1 mutations, all segregating with the disorder in each family. These mutations have been reported in patients with NF1, but have, to our knowledge, not been associated with NFNS previously. Together, these findings support the notion that NFNS is a variant of NF1. Due to the clinical overlap between NS and NFNS, we propose screening for NF1 mutations in NS patients negative for mutations in NS-associated genes, preferentially when CAL spots are present.In conclusion, this thesis suggests that co-occurrence of mutations or modifying loci in the RAS-MAPK pathway contributes to the clinical variability observed within Noonan spectrum disorders and further demonstrates the importance of accurate genetic diagnosis.
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| 6. |
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| 7. |
- Ekvall, Sara, 1982-, et al.
(författare)
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Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome
- 2014
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Ingår i: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 164:3, s. 579-587
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Tidskriftsartikel (refereegranskat)abstract
- Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present.
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| 8. |
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| 9. |
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| 10. |
- Ekvall, Tomas, et al.
(författare)
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Towards Sustainable Waste Management - Popular Summary Report from a Swedish EPA Research Programme
- 2014
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The purpose of the research program Towards Sustainable Waste Management has been to assemble, develop and evaluate ideas for policy instruments for a more sustainable waste management. The waste management should contribute to reducing the environmental impact of the society, for example through reduced waste quantities and increased recycling. It should be cost-efficient and also be accepted among the public as well as other important stakeholders. Our aim was also to develop tools and methods to evaluate such instruments. For example we have developed a package of computer models to analyse the quantities of waste that can arise in the future (EMEC), how these different quantities might be treated (NatWaste), and how this can affect the environment (SWEA). The models also provide information about the cost of waste management and how the Swedish economy in general can be affected by the policy instruments. This package of models, together with our other models and methods, give us a unique capability for the assessment of new policy instruments and the analysis of complex questions on waste quantities and waste treatment. Our assessments and conclusions have a broad scientific basis. We combined the three models above with other calculations and with qualitative analysis and discussions, based on research in ethnology, psychology, economics, etc. This means that we are also able to analyze issues of acceptance and discuss how information should be designed to be effective. People often like to contribute to a good environment, through source separation, etc. However, each individual has a clear limit regarding how much effort to spend. A positive attitude towards source separation does not reach far, when the sorting of a waste fraction is considered difficult. Hence, it must be easy to do the right thing. We found that people who are not satisfied with the waste-management system are uncertain over it rather than unhappy with it. Clear information can be of great benefit, if adapted to the situation and audience, and especially when combined with other policy instruments. Besides information, we assessed fifteen other policy instruments that aim for waste prevention and increased recycling of materials:Raw materials taxTax on hazardous substancesRecycling certificatesProhibition of distribution of advertising to households that have not expressly agreed to thisReduced value added tax (VAT) on servicesNegative labeling of products with hazardous substancesRequirements for companies to work on waste minimizationImproved surveillance by authoritiesWeight-based waste-collection feeEnvironmentally differentiated waste-collection feeConsumer-friendly waste collection systemsClimate Tax on incineration of waste with fossil originWeight-based tax on incineration of wasteGreen electricity certificates for waste incinerationObligation to recycle recyclable materialsOf these, the obligation to recycle recyclables seems to provide the greatest environmental benefit. A weight-based waste fee also results in increased source separation and recycling. Raw material taxes and recycling certificates aim at stimulating or requiring a demand for recycled materials. The introduction of such instruments in a single country like Sweden has a small effect on the total recycling of the materials, partly because the supply of recycled material is insensitive to changes in the market. Reducing VAT on services helps to shift consumption away from goods to services. This reduces the quantity of waste per consumed Euro. The quantity of paper waste in the households is reduced if the distribution of advertising is prohibited to households that have not expressly agreed to this. The waste quantity can also be reduced through demanding waste-minimization plans or similar in companies and through improved surveillance of the companies by authorities. We expect each of these instruments to affect the waste quantity with a few percent or less, but together they can still have a significant effect. Some instruments are complementary and therefore good to combine. It is, for example, a good idea to combine the weight-based waste-collection fee with consumer-friendly collection and information, because this reduces the risk that households dispose of their waste illegally. Information can be a powerful tool if it is combined with other instruments, but isolated it is difficult to get it effective. In Towards Sustainable Waste Management we evaluated one or two versions of each instrument. Our studies in addition gave ideas for new versions of some of the investigated instruments and also ideas for completely new instruments. A substantial tax on the use of materials could, for example, lead to increased material efficiency in industry. Support to repairing services could extend the life of certain products and thus reduce the waste quantity. Allowing temporary landfill or storage of plastic waste that cannot be recycled could reduce greenhouse gas emissions. Well established tools like deposit systems and the landfill tax could be expanded to include more products and waste fractions. Further research or investigations are needed both on these new ideas about the instruments we have studied, to determine whether – and if so, how – they are inserted into practice. Among the instruments in place today, and also among the possible policy instruments that we have studied, there are a few that greatly affect the treatment of waste. Examples include landfill bans, the extended producer responsibility, and the obligation to recycle recyclables. However, it is more difficult to find instruments that drastically can reduce the waste quantity. This quantity seems to be decided mainly by the economic and technological development in the society, and by consumption patterns and the lifestyle of the citizens. To find policy instruments that can greatly reduce the quantity of waste we need further innovation in this area. The results from the research program have been published in more reports, scientific articles, etc., many of them in English. Visit our website www.sustainablewaste.info for a full list of publications.
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| 11. |
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| 12. |
- Gudmundsson, Sanna, et al.
(författare)
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Revertant mosaicism repairs skin lesions in a patient with keratitis-ichthyosis-deafness syndrome by second-site mutations in connexin 26
- 2017
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Ingår i: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 26:6, s. 1070-1077
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Tidskriftsartikel (refereegranskat)abstract
- Revertant mosaicism(RM) is a naturally occurring phenomenon where the pathogenic effect of a germline mutation is corrected by a second somatic event. Development of healthy-looking skin due to RM has been observed in patients with various inherited skin disorders, but not in connexin-related disease. We aimed to clarify the underlying molecular mechanisms of suspected RM in the skin of a patient with keratitis-ichthyosis-deafness (KID) syndrome. The patient was diagnosed with KID syndrome due to characteristic skin lesions, hearing deficiency and keratitis. Investigation of GJB2 encoding connexin (Cx) 26 revealed heterozygosity for the recurrent de novo germline mutation, c. 148G>A, p. Asp50Asn. At age 20, the patient developed spots of healthy-looking skin that grew in size and number within widespread erythrokeratodermic lesions. Ultradeep sequencing of two healthy-looking skin biopsies identified five somatic nonsynonymous mutations, independently present in cis with the p. Asp50Asn mutation. Functional studies of Cx26 in HeLa cells revealed co-expression of Cx26-Asp50Asn and wild-type Cx26 in gap junction channel plaques. However, Cx26-Asp50Asn with the second-site mutations identified in the patient displayed no formation of gap junction channel plaques. We argue that the second-site mutations independently inhibit Cx26-Asp50Asn expression in gap junction channels, reverting the dominant negative effect of the p. Asp50Asn mutation. To our knowledge, this is the first time RM has been reported to result in the development of healthy-looking skin in a patient with KID syndrome.
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| 13. |
- Gudmundsson, Sanna, 1989-, et al.
(författare)
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TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The TATA-box binding protein associated factor 1 (TAF1) protein is a key unit of the transcription factor II D complex that serves a vital function during transcription initiation. Variants of TAF1 have been associated with neurodevelopmental disorders, but TAF1's molecular functions remain elusive. In this study, we present a five-generation family affected with X-linked intellectual disability that co-segregated with a TAF1 c. 3568C>T, p.(Arg1190Cys) variant. All affected males presented with intellectual disability and dysmorphic features, while heterozygous females were asymptomatic and had completely skewed X-chromosome inactivation. We investigated the role of TAF1 and its association to neurodevelopment by creating the first complete knockout model of the TAF1 orthologue in zebrafish. A crucial function of human TAF1 during embryogenesis can be inferred from the model, demonstrating that intact taf1 is essential for embryonic development. Transcriptome analysis of taf1 zebrafish knockout revealed enrichment for genes associated with neurodevelopmental processes. In conclusion, we propose that functional TAF1 is essential for embryonic development and specifically neurodevelopmental processes.
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| 14. |
- Heimersson, Sara, 1984, et al.
(författare)
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Opportunities of consequential and attributional modelling in life cycle assessment of wastewater and sludge management
- 2019
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Ingår i: Journal of Cleaner Production. - : Elsevier BV. - 0959-6526. ; 222, s. 242-251
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Tidskriftsartikel (refereegranskat)abstract
- Despite general agreement on the importance of adjusting each life cycle assessment (LCA) to its goal, the methodological choices in previously published LCAs on wastewater and sludge management systems are surprisingly similar, even when the information sought in the studies most likely differ. We argue that the potential of LCA may not currently be fully utilised, partly due to particular methodological challenges arising in both attributional and consequential LCAs for this type of systems. By developing the theory for handling of allocation problems in attributional LCAs, and by elaborating on the different possible foreseeable consequences in consequential LCA, we aim to facilitate both attributional and consequential LCAs, and to show the importance of such choices for a specific wastewater and sludge management system. We introduce and apply a distinction between physically and legally joint processes as basis for the allocation of resource use and emissions in attributional LCA, and suggest that, when the joint process is not driven by commercial interests, allocation factors could be identified and quantified through stakeholder priorities. In consequential LCAs, the substitution depends on the subjective view on what consequences are foreseeable, for example based on short- or long-term considerations. All of these modelling aspects can, as our case study illustrates, affect the LCA results.
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| 15. |
- Johansson, Josefin, et al.
(författare)
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Gustavson syndrome is caused by an in-frame deletion in RBMX associated with potentially disturbed SH3 domain interactions
- 2024
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Ingår i: European Journal of Human Genetics. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 32:3, s. 333-341
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Tidskriftsartikel (refereegranskat)abstract
- RNA binding motif protein X-linked (RBMX) encodes the heterogeneous nuclear ribonucleoprotein G (hnRNP G) that regulates splicing, sister chromatid cohesion and genome stability. RBMX knock down experiments in various model organisms highlight the gene's importance for brain development. Deletion of the RGG/RG motif in hnRNP G has previously been associated with Shashi syndrome, however involvement of other hnRNP G domains in intellectual disability remain unknown. In the current study, we present the underlying genetic and molecular cause of Gustavson syndrome. Gustavson syndrome was first reported in 1993 in a large Swedish five-generation family presented with profound X-linked intellectual disability and an early death. Extensive genomic analyses of the family revealed hemizygosity for a novel in-frame deletion in RBMX in affected individuals (NM_002139.4; c.484_486del, p.(Pro162del)). Carrier females were asymptomatic and presented with skewed X-chromosome inactivation, indicating silencing of the pathogenic allele. Affected individuals presented minor phenotypic overlap with Shashi syndrome, indicating a different disease-causing mechanism. Investigation of the variant effect in a neuronal cell line (SH-SY5Y) revealed differentially expressed genes enriched for transcription factors involved in RNA polymerase II transcription. Prediction tools and a fluorescence polarization assay imply a novel SH3-binding motif of hnRNP G, and potentially a reduced affinity to SH3 domains caused by the deletion. In conclusion, we present a novel in-frame deletion in RBMX segregating with Gustavson syndrome, leading to disturbed RNA polymerase II transcription, and potentially reduced SH3 binding. The results indicate that disruption of different protein domains affects the severity of RBMX-associated intellectual disabilities.
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| 16. |
- Mattsson, Karin, et al.
(författare)
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Altered Behavior, Physiology, and Metabolism in Fish Exposed to Polystyrene Nanoparticles
- 2015
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Ingår i: Environmental Science & Technology. - : American Chemical Society (ACS). - 1520-5851 .- 0013-936X. ; 49:1, s. 553-561
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Tidskriftsartikel (refereegranskat)abstract
- The use of nanoparticles in consumer products, for example, cosmetics, sunscreens, and electrical devices, has increased tremendously over the past decade despite insufficient knowledge about their effects on human health and ecosystem function. Moreover, the amount of plastic waste products that enter natural ecosystems, such as oceans and lakes, is increasing, and degradation of the disposed plastics produces smaller particles toward the nano scale. Therefore, it is of utmost importance to gain knowledge about how plastic nanoparticles enter and affect living organisms. Here we have administered 24 and 27 nm polystyrene nanoparticles to fish through an aquatic food chain, from algae through Daphnia, and studied the effects on behavior and metabolism. We found severe effects on feeding and shoaling behavior as well as metabolism of the fish; hence, we conclude that polystyrene nanoparticles have severe effects on both behavior and metabolism in fish and that commonly used nanosized particles may have considerable effects on natural systems and ecosystem services derived from them.
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| 17. |
- Mattsson, Karin, et al.
(författare)
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Translocation of 40 nm diameter nanowires through the intestinal epithelium of Daphnia magna
- 2016
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Ingår i: Nanotoxicology. - : Informa UK Limited. - 1743-5390 .- 1743-5404. ; 10:8, s. 1160-1167
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Tidskriftsartikel (refereegranskat)abstract
- Nanowires (NWs) have unique electrical and optical properties of value for many applications including lighting, sensing, and energy harnessing. Consumer products containing NWs increase the risk of NWs being released in the environment, especially into aquatic ecosystems through sewage systems. Daphnia magna is a common, cosmopolitan freshwater organism sensitive to toxicity tests and represents a likely entry point for nanoparticles into food webs of aquatic ecosystems. Here we have evaluated the effect of NW diameter on the gut penetrance of NWs in Daphnia magna. The animals were exposed to NWs of two diameters (40 and 80 nm) and similar length (3.6 and 3.8 μm, respectively) suspended in water. In order to locate the NWs in Daphnia, the NWs were designed to comprise one inherently fluorescent segment of gallium indium phosphide (GaInP) flanked by a gallium phosphide (GaP) segment. Daphnia mortality was assessed directly after 24 h of exposure and 7 days after exposure. Translocation of NWs across the intestinal epithelium was investigated using confocal fluorescence microscopy directly after 24 h of exposure and was observed in 89% of Daphnia exposed to 40 nm NWs and in 11% of Daphnia exposed to 80 nm NWs. A high degree of fragmentation was observed for NWs of both diameters after ingestion by the Daphnia, although 40 nm NWs were fragmented to a greater extent, which could possibly facilitate translocation across the intestinal epithelium. Our results show that the feeding behavior of animals may enhance the ability of NWs to penetrate biological barriers and that penetrance is governed by the NW diameter.
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| 18. |
- Nordin, Gunnar, et al.
(författare)
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Accuracy of determination of the glomerular filtration marker iohexol by European laboratories as monitored by external quality assessment
- 2019
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Ingår i: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter. - 1434-6621 .- 1437-4331. ; 57:7, s. 1006-1011
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Tidskriftsartikel (refereegranskat)abstract
- Background Glomerular filtration is the most important kidney function. The most accurate glomerular filtration rate (GFR) estimates are based on the clearance of exogenous filtration markers. Of these, iohexol is the only exogenous marker that is included in an external quality assessment (EQA) scheme. The aim of the present study was to evaluate the performance of the European laboratories participating in Equalis' EQA scheme for iohexol. Methods Weighed amounts of iohexol (Omnipaque) were added to plasma samples and distributed to laboratories participating in the EQA scheme for iohexol. All laboratories performed the assays in a blinded fashion. Results The number of participating laboratories varied between 27 and 34 during the study period. Iohexol was determined by HPLC in 77% of the laboratories and by UPLC/MS/MS methods in 15% of the laboratories. The mean interlaboratory coefficient of variation was 4.7% for the HPLC methods and 6.4% for the UPLC/MS/MS methods. The mean bias between calculated and measured iohexol values was -1.3 mg/L (95% confidence interval ±0.3) during the first part of the study period and 0.1 mg/L (±0.3) during the later part. Conclusions The low interlaboratory variation demonstrates that iohexol can be measured reliably by many laboratories and supports the use of iohexol as a GFR marker when there is a need for high quality GFR measurements.
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| 19. |
- Nyström, Anna-Maja, et al.
(författare)
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A severe form of Noonan syndrome and autosomal dominant café-au-lait spots : evidence for different genetic origins
- 2009
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 98:4, s. 693-698
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The clinical overlap among Noonan syndrome (NS), cardio-facio-cutaneous (CFC), LEOPARD and Costello syndromes as well as Neurofibromatosis type 1 is extensive, which complicates the process of diagnosis. Further genotype–phenotype correlations are required to facilitate future diagnosis of these patients. Therefore, investigations of the genetic cause of a severe phenotype in a patient with NS and the presence of multiple café-au-lait spots (CAL) spots in the patient and four members of the family were performed. Methods: Mutation analyses of candidate genes, PTPN11, NF1, SPRED1 and SPRED2, associated with these syndromes, were conducted using DNA sequencing. Results: A previously identified de novo mutation, PTPN11 F285L and an inherited NF1 R1809C substitution in the index patient were found. However, neither PTPN11 F285L, NF1 R1809C, SPRED1 nor SPRED2 segregated with CAL spots in the family. The results indicate that the familial CAL spots trait in this family is caused by a mutation in another gene, distinct from previous genes associated with CAL spots in these syndromes. Conclusion: We suggest that the atypical severe symptoms in the index patient may be caused by an additive effect on the F285L mutation in PTPN11 by another mutation, for example the NF1 R1809C or alternatively, the not yet identified gene mutation associated with CAL spots in this family.
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| 20. |
- Nyström, Anna-Maja, et al.
(författare)
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Investigation of gene dosage imbalances in patients with Noonan syndrome using multiplex ligation-dependent probe amplification analysis
- 2010
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Ingår i: European Journal of Medical Genetics. - : Elsevier BV. - 1769-7212 .- 1878-0849. ; 53:3, s. 117-121
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Tidskriftsartikel (refereegranskat)abstract
- The RAS-MAPK syndromes are a group of clinically and genetically related disorders caused by dysregulation of the RAS-MAPK pathway. A member of this group of disorders, Noonan syndrome (NS), is associated with several different genes within the RAS-MAPK pathway. To date, mutations in PTPN11, SOS1, KRAS, RAF1 and SHOC2 are known to cause NS and a small group of patients harbour mutations in BRAF, MEK1 or NRAS. The majority of the mutations are predicted to cause an up-regulation of the pathway; hence they are gain-of-function mutations. Despite recent advances in gene identification in NS, the genetic aetiology is still unknown in about of patients.To investigate the contribution of gene dosage imbalances of RAS-MAPK-related genes to the pathogenesis of NS, a multiplex ligation-dependent probe amplification (MLPA) assaywas developed. Two probe sets were designed for seven RAS-MAPK-syndrome-related candidate genes: PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1 and MEK2. The probe sets were validated in 15 healthy control individuals and in glioma tumour cell lines. Subsequently, 44 NS patients negative for mutations in known NS-associated genes were screened using the two probe sets. The MLPA results for the patients revealed no gene dosage imbalances. In conclusion, the present results exclude copy number variation of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1 and MEK2 as a common pathogenic mechanism of NS. The validated and optimised RAS-MAPK probe sets presented here enable rapid high throughput screening of further patients with RAS-MAPK syndromes.
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| 21. |
- Nyström, Anna-Maja, et al.
(författare)
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Noonan and cardio-facio-cutanenous syndromes : two clinically and genetically overlapping disorders
- 2008
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 45:8, s. 500-506
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Tidskriftsartikel (refereegranskat)abstract
- Background: Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFC) are related disorders associated with disrupted RAS/RAF/MEK/ERK signalling. NS, characterised by facial dysmorphism, congenital heart defects and short stature, is caused by mutations in the genes PTPN11, SOS1, KRAS and RAF1. CFC is distinguished from NS by the presence of ectodermal abnormalities and more severe mental retardation in addition to the NS phenotype. The genetic aetiology of CFC was recently assigned to four genes: BRAF, KRAS, MEK1 and MEK2. Methods: A comprehensive mutation analysis of BRAF, KRAS, MEK1, MEK2 and SOS1 in 31 unrelated patients without mutations in PTPN11 is presented. Results: Mutations were identified in seven patients with CFC (two in BRAF, one in KRAS, one in MEK1, two in MEK2 and one in SOS1). Two mutations were novel: MEK1 E203Q and MEK2 F57L. The SOS1 E433K mutation, identified in a patient diagnosed with CFC, has previously been reported in patients with NS. In one patient with NS, we also identified a mutation, BRAF K499E, that has previously been reported in patients with CFC. We thus suggest involvement of BRAF in the pathogenesis of NS also. Conclusions: Taken together, our results indicate that the molecular and clinical overlap between CFC and NS is more complex than previously suggested and that the syndromes might even represent allelic disorders. Furthermore, we suggest that the diagnosis should be refined to, for example, NS–PTPN11-associated or CFC–BRAF-associated syndromes after the genetic defect has been established, as this may affect the prognosis and treatment of the patients.
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| 22. |
- Nyström, Anna-Maja, et al.
(författare)
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Noonan syndrome and Neurofibromatosis type I in a family with a novel mutation in NF1
- 2009
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 76:6, s. 524-534
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Tidskriftsartikel (refereegranskat)abstract
- Noonan Syndrome (NS) and Neurofibromatosis type I (NF1) belong to a group of clinically related disorders that share a common pathogenesis, dysregulation of the RAS-MAPK pathway. NS is characterized by short stature, heart defect, pectus deformity and facial dysmorphism, while skin manifestations, skeletal defects, Lisch nodules and neurofibromas are characteristic of NF1. Both disorders display considerable clinical variability. Features of NS have been observed in individuals with NF1 - a condition known as Neurofibromatosis-Noonan Syndrome (NFNS). The major gene causing NFNS is NF1. Rarely, a mutation in PTPN11 in addition to an NF1 mutation is present. We present the clinical and molecular characterization of a family displaying features of both NS and NF1, with complete absence of neurofibromas. To investigate the etiology of the phenotype, mutational analysis of NF1 was conducted, revealing a novel missense mutation in exon 24, p.L1390F, affecting the GAP-domain. Additional RAS-MAPK pathway genes were examined, but no additional mutations were identified. We confirm that NF1 mutations are involved in the etiology of NFNS. Furthermore, based on our results and previous studies we suggest that evaluation of the GAP-domain of NF1 should be prioritized in NFNS.
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| 23. |
- Svanström, Magdalena, 1969, et al.
(författare)
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Generating LCA partitioning factors for sewage sludge management using a Delphi procedure
- 2017
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- In attributional life cycle assessment (ALCA), the goal is to map the environmental impact from the system under study in such a way that it reveals what share of the total global environmental impact that belongs to the product or service investigated. Any process performing multiple functions then gives rise to an allocation problem. It has been recommended that the partitioning in ALCA studies should be based on the drivers of the system. Wastewater collection and treatment facilities are increasingly exploited in different resource recovery attempts and therefore increasingly result in allocation problems. The drivers of present wastewater and sludge management systems is a mix of various ideas and concerns relating to environmental protection, resource recovery, economy, and other interests, that seem to vary among stakeholders, over time and across regions. We developed a two-stage Delphi procedure for finding partitioning factors for use in ALCA studies where multiple drivers and stakeholders are present in relation to multifunctional systems and tested it for a wastewater and sludge management system. The paper reports on the method, on the experiences from applying the method and implications for ALCA studies.
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| 24. |
- Wilbe, Maria, et al.
(författare)
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MuSK : a new target for lethal fetal akinesia deformation sequence (FADS).
- 2015
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 52:3, s. 195-202
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Fetal akinesia deformation sequence syndrome (FADS, OMIM 208150) is characterised by decreased fetal movement (fetal akinesia) as well as intrauterine growth restriction, arthrogryposis, and developmental anomalies (eg, cystic hygroma, pulmonary hypoplasia, cleft palate, and cryptorchidism). Mutations in components of the acetylcholine receptor (AChR) pathway have previously been associated with FADS.METHODS AND RESULTS: We report on a family with recurrent fetal loss, where the parents had five affected fetuses/children with FADS and one healthy child. The fetuses displayed no fetal movements from the gestational age of 17 weeks, extended knee joints, flexed hips and elbows, and clenched hands. Whole exome sequencing of one affected fetus and the parents was performed. A novel homozygous frameshift mutation was identified in muscle, skeletal receptor tyrosine kinase (MuSK), c.40dupA, which segregated with FADS in the family. Haplotype analysis revealed a conserved haplotype block suggesting a founder mutation. MuSK (muscle-specific tyrosine kinase receptor), a component of the AChR pathway, is a main regulator of neuromuscular junction formation and maintenance. Missense mutations in MuSK have previously been reported to cause congenital myasthenic syndrome (CMS) associated with AChR deficiency.CONCLUSIONS: To our knowledge, this is the first report showing that a mutation in MuSK is associated with FADS. The results support previous findings that CMS and/or FADS are caused by complete or severe functional disruption of components located in the AChR pathway. We propose that whereas milder mutations of MuSK will cause a CMS phenotype, a complete loss is lethal and will cause FADS.
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| 25. |
- Wittström, Elisabeth, et al.
(författare)
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Morphological and functional changes in multifocal vitelliform retinopathy and biallelic mutations in BEST1
- 2011
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Ingår i: Ophthalmic Genetics. - : Informa UK Limited. - 1381-6810 .- 1744-5094. ; 32:2, s. 83-96
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To describe morphological and functional changes in a single patient with multifocal Best vitelliform macular dystrophy (BVMD) and to perform a genotype/phenotype correlation. Methods: The proband with multifocal BVMD and three of her family members were examined with electrooculography (EOG), full-field electroretinography (full-field ERG), multifocal electroretinography (mfERG) and optical coherence tomography (OCT). Genomic DNA was screened for mutation in the BEST1 gene by DNA sequencing analysis. Results: The proband was observed regularly during a follow-up period of 4 years. Full-field ERG demonstrated reduced and delayed responses of both rods and cones. OCT demonstrated intra- and subretinal fluid which seemed to fluctuate with periods of stress, similar to that seen in chronic central serous chorioretinopathy. Two distinct heterozygous BEST1 mutations were identified in the proband, the recurrent p.R141H mutation and the p.P233A mutation. Heterozygous p.R141H mutations were also identified in two family members, while p.P233A was a de novo mutation. Abnormal EOG findings were observed in both the proband and in the carriers of p.R141H. Heterozygous carriers showed delayed implicit times in a- and b-waves of combined total rod and cone full-field ERG responses. Conclusions: The p.R141H mutation is frequently seen together with multifocal vitelliform retinopathy and biallelic mutations in BEST1. Our results show that carriers of the p.R141H mutation are clinically unaffected but present with abnormal EOG and full-field ERG findings. A patient with biallelic mutations of the BEST1 gene, causing multifocal BVMD with progressive, widespread functional disturbance of the retina, confirmed by full-field and mfERG is described.
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